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Citation: 75 Fed. Reg. 2938 2010

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### Federal Register/Vol. 75, No. 11/Tuesday, January 19, 2010/Proposed Rules

ENVIRONMENTAL PROTECTION
AGENCY

40 CFR Parts 50 and 58 [EPA-HQ-OAR-2005-0172; FRL-9102-1]
RIN2060-AP98

National Ambient AirQuality Standards for Ozone

AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.

SUMMARY: Based on itsreconsideration ofthe primary and secondary national ambient air quality standards (NAAQS) for ozone (03)set in March 2008, EPA proposes to set different primary and secondary standards than those set in 2008 toprovide requisite protection of public health and welfare, respectively. With regard to the primary standard for 03, EPAproposes thatthe level ofthe 8-hour primary standard, which was set at 0.075 ppm in the 2008final rule, should instead be set at alower level within the range of0.060 to 0.070parts per million (ppm),to provide increased protection for children and other "at risk" populations against an array of03- related adverse health effects thatrange from decreased lung function and increased respiratory symptoms to serious indicators ofrespiratory morbidity including emergency department visits and hospital admissions for respiratory causes, and possibly cardiovascular-related morbidity as well as total nonaccidental and cardiopulmonary mortality. With regard to the secondary standard for 03, EPA proposes that the secondary 03 standard, which was set identical to therevised primary standard in the 2008final rule, should instead be a new cumulative, seasonal standard expressed as an annual index ofthe sum of weighted hourly concentrations, cumulated over 12 hours per day (8 am to 8 pm) during the consecutive 3-month period withinthe 03 season with the maximum index value, set at a level within the range of 7to 15 ppm-hours, to provide increased protection against O3-related adverse impacts on vegetation and forested ecosystems. DATES: Written comments on this proposed rule must be received by March 22, 2010.

PublicHearings: Three public hearings are scheduled forthis proposed rule. Two ofthe public hearings will be held on February 2, 2010 in Arlington, Virginia, and Houston, Texas. The third public hearing willbe held on February 4, 2010 in Sacramento, California. ADDRESSES: Submit your comments, identified by Docket ID No.EPA-HQOAR-2005-0172, by one ofthe following methods:

* http://www.regulations.gov: Follow the on-line instructions for submitting
comments.

* E-mail:a-and-r-Docket@epa.gov. * Fax:202-566-9744. * Mail:Docket No. EPA-HQ-OAR2005-0172, Environmental Protection Agency, Mail code 6102T, 1200 Pennsylvania Ave., NW., Washington, DC 20460. Please include atotal oftwo copies.

e HandDelivery:Docket No. EPAHQ-OAR-2005-0172, Environmental Protection Agency, EPA West, Room 3334, 1301 Constitution Ave., NW., Washington, DC. Such deliveries are only accepted during the Docket's normal hours ofoperation, and special arrangements should be made for deliveries ofboxed information.

PublicHearings: Three public hearings are scheduled for this proposed rule. Two ofthe publichearings will be held on February 2, 2010 in Arlington, Virginia and Houston, Texas. The third public hearing willbe held onFebruary 4, 2010 in Sacramento, California. The hearings willbe held at the following locations: Arlington, Virginia-February 2, 2010 Hyatt Regency Crystal City @Reagan

National Airport, Washington Room (located on the Ballroom Level), 2799 Jefferson Davis Highway, Arlington, Virginia 22202, Telephone: 703-418-
1234.
Houston, Texas-February2,2010
Hilton Houston Hobby Airport, Moody

Ballroom (located on the ground floor), 8181 Airport Boulevard, Houston, Texas 77061, Telephone:
713-645-3000. Sacramento,California-February 4, 2010
Four Points by Sheraton Sacramento

International Airport, Natomas Ballroom, 4900 Duckhorn Drive, Sacramento, California 95834, Telephone: 916-263-9000. See the SUPPLEMENTARY INFORMATION under "Public Hearings" for further information.

Instructions: Direct your comments to Docket ID No. EPA-HQ-OAR-2005- 0172. The EPA's policyis that all
comments received willbe 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 thatyou consider to be CBIor otherwise protected through www.regulations.gov

ore-mail. The www.regulations.govWeb site is an "anonymous access" system, which means EPA will not know your identity or contact information unless
you provide itin the body ofyour comment. Ifyou send an e-mail
comment directly to EPA withoutgoing through www.regulations.gov,your email address will be automatically captured and included as part ofthe
comment that isplaced in the public docket and made available on the Internet. Ifyou submit an electronic comment, EPA recommends thatyou include your name and other contact information in the body ofyour comment and with any disk or CD-ROM
you submit. IfEPA cannot read your comment due to technical difficulties and cannot contact you for clarification, EPA may notbe able to consider your comment. Electronic files should avoid the use of special characters, any form ofencryption, andbe free ofany defects

orviruses.

Docket:All documents in the docket

are listed in the www.regulations.gov index. Although listed inthe index,

some information is not publicly available, e.g., CBI or other information whose disclosure is restricted by statute. Certain other material, such as copyrighted material, will be publicly available only in hard copy. Publicly available docket materials are available either electronically in www.regulations.govorin hard copy at the Air and Radiation Docket and Information Center, EPA/DC, EPAWest, 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 andInformation Center is (202) 566-1742.
FOR FURTHER INFORMATION CONTACT: Ms. Susan Lyon Stone, Health and Environmental Impacts Division, Office ofAir 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; e-mail: stone.susan@epa.gov.

SUPPLEMENTARY INFORMATION: 

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GeneralInformation

WhatShouldI ConsiderasIPrepare My Comments forEPA?
1. SubmittingCBI.Do not submit this information to EPA throughhttp:// www.regulations.govor e-mail. Clearly mark thepart or all ofthe information thatyou claim tobe CBI. ForCBI information in a disk orCD-ROM that
you mail to EPA, markthe outside ofthe disk orCD-ROM as CBIand then identify electronically within the disk or CD-ROM the specific information that is claimed as CBI. In addition to one complete version ofthe comment that includes information claimed as CBI, a copy ofthe comment that does not contain the information claimed as CBI
must be submitted for inclusion in the public docket. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2.

2. Tips forPreparingYour Comments. When submitting comments, remember
to:* Identify the rulemaking by docket number and other identifying information (subjectheading, Federal Register date and page number).

* Follow directions-The Agency
may askyou to respondto specific questions or organize comments by referencing a Code ofFederal Regulations (CFR)part or section number.

* Explain why you agree ordisagree, suggest alternatives, and substitute language for your requested changes.

* Describe any assumptions and provide any technical information and/

or data thatyou used.

* Provide specific examples to illustrate your concerns, and suggest alternatives.

* Explain yourviews as clearly as possible, avoiding the use ofprofanity

or personal threats.

* Make sure to submit your comments by the comment period deadline identified. AvailabilityofRelatedInformation

A number ofdocuments relevant to this rulemaking are available on EPA web sites. The Air Quality Criteria for Ozone and Related Photochemical Oxidants (2006 Criteria Document) (two volumes, EPA/and EPA/, date) is available on EPA's NationalCenter for Environmental Assessment Web site. To obtain this document, go tohttp:// www.epa.gov/ncea,and click on Ozone in the Quick Finder section. This will open a page with a link to the March 2006 Air Quality Criteria Document. The 2007 StaffPaper,human exposure and health risk assessments, vegetation exposure andimpact assessment, and other related technical documents are available on EPA's Office ofAir Quality Planning and Standards (OAQPS) Technology Transfer Network (TTN) web site. The updated final 2007 Staff Paper is available at: http://epa.gov/ttnl naaqs/standards/ozone/so3 cr sp.html and the exposure and risk assessments and other related technical documents

are available athttp://www.epa.gov/ttnl naaqs/standards/ozone!

s o3 cr td.html. The Response to Significant Comments Document is available at: http://www.epa.gov/ttnl naaqs/standards/ozone!

s o3 cr rc.html. These and otherrelated documents are also available for inspection and copying in the EPA docket identified above.

PublicHearings

The public hearings on February 2, 2010 and February 4, 2010 will provide interested parties the opportunity to present data, views, or arguments concerning the proposed rule. The EPA may ask clarifying questions during the oral presentations, but will not respond
to the presentations at that time. Written
statements and supporting information submitted during the comment period will be considered with the same weight

as any oral comments and supporting information presented at the public hearing. Written comments must be received by the last day ofthe comment period, as specified in this proposed rulemaking.

The public hearings will begin at 9:30

a.m. and continue until 7:30 p.m. (local time) or later, ifnecessary, depending

on the number of speakers wishing to participate. The EPA will make every effort to accommodate all speakers that arrive and registerbefore 7:30 p.m.A lunch break is scheduled from 12:30 p.m. until 2p.m.

Ifyou would like topresent oral testimony at the hearings, please notify Ms. Tricia Crabtree (C504-02), U.S. EPA, Research Triangle Park,NC 27711. The preferred method for registering is by e-mail (crabtree.tricia@epa.gov). Ms. Crabtree may be reached by telephone at (919) 541-5688. She will arrange a general time slot for you to speak. The EPA will make every effort tofollow the schedule as closely as possible on the day ofthe hearing. Oral testimony will be limited to five (5)minutes for each commenter to address the proposal. We will notbe providing equipment for commenters to show overhead slides ormake computerized slide presentations unless

we receive special requests in advance. Commenters should notify Ms. Crabtree ifthey will need specific audiovisual (AV)equipment. Commenters should also notify Ms. Crabtree ifthey need specific translation services for nonEnglish speaking commenters. The EPA
encourages commenters toprovide written versions oftheir oral testimonies either electronically on computer disk, CD-ROM, orin paper copy.

The hearing schedules, including lists ofspeakers, will be posted on EPA's Web site for the proposal at http:// www.epa.gov/ttn/naaqs/standards/ ozone/s o3 cr_fr.htmlprior to the hearing. Verbatim transcripts ofthe hearings and written statements willbe included in the rulemaking docket.

Children's EnvironmentalHealth
Consideration ofchildren's environmental health plays a central role in the reconsideration ofthe 2008 final decision on the 0 3NAAQS and EPA's decision to propose to set the 8-hourprimary 0 3 standard at a level within the range of0.060 to 0.070ppm. Technical information that pertains to children, including the evaluation of scientific evidence, policy considerations, and exposure andrisk assessments, is discussed in all ofthe documents listed above in the section

onthe availability ofrelated information. These documents include: the Air Quality Criteria for Ozone and OtherRelated Photochemical Oxidants; the 2007 StaffPaper; exposure and risk
assessments and other related documents; and the Response to Significant Comments. All of these documents are available on the Web, as described above, and are in the public docketfor this rulemaking. The public is invited to submit comments or identify peer-reviewed studies and data that assess effects ofearly life exposure

to 0 3. Table ofContents

The following topics are discussed in this preamble:
I.Background

A. Legislative Requirements B.Related ControlRequirements C.Review ofAirQuality Criteriaand

Standards for 03 D.Reconsideration ofthe 2008 03 NAAQS

Final Rule 1.Decisionto Initiate aRulemaking to

Reconsider 2.Ongoing Litigation II.Rationale forProposed Decision onthe Level ofthe Primary Standard A. HealthEffects Information 1.Overview ofMechanisms 2.Nature ofEffects 3. Interpretation and Integration ofHealth

Evidence 4. 03-Related Impacts onPublic Health B. Human Exposure and Health Risk

Assessments 

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1.Exposure Analyses 2. Quantitative Health Risk Assessment C. Reconsideration ofthe Level ofthe

Primary Standard 1.Evidence and Exposure/Risk-Based

Considerations 2. CASAC Views Prior to 2008 Decision 3. Basis for 2008 Decision on thePrimary

Standard 4. CASAC Advice Following 2008 Decision 5. Administrator's Proposed Conclusions D. Proposed Decision on the Level ofthe

Primary Standard III. Communication ofPublic Health Information IV. Rationale forProposed Decision on the Secondary Standard A. Vegetation Effects Information 1.Mechanisms 2. Nature ofEffects 3. Adversity ofEffects B. Biologically Relevant Exposure Indices C. Vegetation Exposure and Impact

Assessment 1.Exposure Characterization 2. Assessment ofRisksto Vegetation D. Reconsideration ofSecondary Standard 1.Considerations Regarding 2007 Proposed

Cumulative Seasonal Standard 2. Considerations Regarding 2007 Proposed

8-Hour Standard 3. Basis for 2008 Decision on the

Secondary Standard 4. CASAC Views Following 2008 Decision 5. Administrator's Proposed Conclusions E. Proposed Decision on the Secondary 03

Standard V. Revision ofAppendix P-Interpretation of the NAAQS for 03 and Proposed Revisions tothe Exceptional EventsRule A. Background B. Interpretation ofthe Secondary 03

Standard C. Clarifications Related to the Primary

Standard D. Revisions to Exceptions From Standard

Data Completeness Requirements forthe Primary Standard E. Elimination of theRequirement for 90

Percent Completeness of DailyData Across Three Years F. Administrator Discretion To Use

Incomplete Data G. Truncation Versus Rounding H. Data Selection I.Exceptional Events Information

Submission Schedule VI. Ambient Monitoring Related to Proposed
03 Standards A. Background B. Urban Monitoring Requirements C. Non-Urban Monitoring Requirements D. Revisions to the Length ofthe Required

03 Monitoring Season VII. Implementation ofProposed 03 Standards A. Designations B. State Implementation Plans C. Trans-boundary Emissions VIII. Statutory and Executive Order Reviews

A. Executive Order 12866: Regulatory

Planning and 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 WithIndian Tribal Governments G. Executive Order 13045: Protection of

Children FromEnvironmental Health and 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

The proposed decisions presented in this notice are based on a reconsideration ofthe 2008 03 NAAQS final rule (73 FR 16436, March 27, 2008), which revised the level ofthe 8- hour primary 03 standard to 0.075 ppm and revised the secondary 03 standard by making itidentical to the revised primary standard. This reconsideration isbased on the scientific andtechnical information and analyses on which the March 2008 03 NAAQS rulemaking was based. Therefore, much ofthe information included in this notice is drawn directly from information included in the 2007 proposed rule (72
FR 37818, July 11, 2007) and the 2008 final rule (73 FR 16436).

A. LegislativeRequirements

Two sections of the Clean Air Act (CAA) govern the establishment and revision oftheNAAQS. Section 108 (42 U.S.C. 7408) directs the Administrator
to identify and list "air pollutants" that in her "judgment, cause orcontribute to air pollution which may reasonably be anticipated to endanger public health or welfare" and satisfy two other criteria, including "whose presence * * * in the ambient air results from numerous or diverse mobile or stationary sources" and to issue air quality criteria for those that are listed. Air quality criteria are intended to "accurately reflect the latest scientific knowledge useful in indicating thekind and extent ofall identifiable effects on public health or welfare which maybe expected from the
presence of [a] pollutant in the ambient air. * * *"
Section 109 (42 U.S.C. 7409) directs the Administrator topropose and promulgate "primary" and "secondary" NAAQS for pollutants forwhich air quality criteria are issued. Section 109(b)(1) defines a primary standard as

one "the attainment and maintenance of which in thejudgment ofthe Administrator, based on such criteria and allowing an adequate margin of safety, are requisite toprotect the public health." IA secondary standard, as defined in section 109(b)(2), must "specify a level ofair quality the attainment and maintenance ofwhich, in the judgment ofthe Administrator, based onsuch criteria, isrequisite to protect the public welfare from any known oranticipated adverse effects associated with thepresence of such air pollutant in the ambient air." 2

The requirement thatprimary standards include an adequate margin of safety was intended to address uncertainties associated with inconclusive scientific and technical information available at the time of standard setting. It was also intended to provide a reasonable degree of protection against hazards thatresearch has not yet identified. LeadIndustries Associationv. EPA,647F.2d 1130, 1154 (DCCir 1980), cert.denied,449 U.S. 1042 (1980);AmericanPetroleum Institutev.Costle,665 F.2d 1176, 1186 (DC Cir. 1981), cert.denied,455 U.S. 1034 (1982). Both kinds ofuncertainties

are components ofthe risk associated with pollution at levels below those at which human health effects canbe said
to occur with reasonable scientific certainty. Thus, in selecting primary standards thatinclude an adequate margin ofsafety, the Administratoris seeking not only to prevent pollution levels thathave been demonstrated tobe harmful but also to prevent lower pollutant levels that maypose an unacceptable risk ofharm, even ifthe risk is not precisely identified asto nature or degree. The CAA does not require the Administrator to establish a primary NAAQS at a zero-risk level or atbackground concentration levels, see Lead IndustriesAssociation v. EPA, 647 F.2d at 1156 n. 51, butrather at a level that reduces risk sufficiently so as to protect public health with an adequate margin ofsafety.

In addressing the requirement for an adequate margin of safety, EPA considers such factors as the nature and severity ofthe health effects involved, the size ofthepopulation(s) at risk, and the kind and degree ofthe uncertainties

'The legislativehistory ofsection 109indicates that aprimary standard istobesetat "the maximum permissibleambient airlevel * * * which will protect thehealth ofany [sensitive] group ofthepopulation," and thatfor this purpose "reference shouldbe madeto arepresentative sample ofpersons comprising the sensitive group ratherthan to asingle person insuch a group" [S. Rep. No. 91-1196, 91st Cong., 2d Sess. 10 (1970)].

2Welfare effects as defined insection 302(h) (42 U.S.C. 7602(h)) include, but are notlimited to, "effects on soils, water, crops, vegetation,man-made materials, animals, wildlife, weather, visibility,and climate, damage to and deterioration ofproperty, and hazards to transportation, as well as effects on economic values and onpersonal comfort and wellbeing." 2940

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that mustbe addressed. The selection of
any particular approach to providing an adequate margin of safety is apolicy choice left specifically to the Administrator's judgment.Lead IndustriesAssociationv. EPA,647F.2d
at 1161-62; Whitman v.American TruckingAssociations,531 U.S. 457, 495 (2001).

In setting standards that are "requisite" to protect public health and welfare, as provided in section 109(b), EPA's task is to establish standards that

are neither more norless stringent than
necessary for these purposes. Whitman

v.America Trucking Associations,531 U.S. 457, 473. In establishing "requisite" primary and secondary standards, EPA
may not consider the costs of implementing the standards. Id.at 471.

Section 109(d)(1) ofthe CAA requires that "notlater than December 31, 1980, and at 5-year intervals thereafter, the Administrator shall complete a thorough review ofthe 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 ofthe 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 maybe appropriate. * * This independent review function is performed bythe Clean Air Scientific Advisory Committee (CASAC) ofEPA's Science Advisory Board.

B. RelatedControlRequirements

States have primary responsibility for ensuring attainment and maintenance of ambient air quality standards once EPA has established them. Under section 110 ofthe Act (42 U.S.C. 7410) andrelated provisions, States are to submit, forEPA approval, State implementation plans (SIPs) thatprovide forthe attainment andmaintenance ofsuch standards through control programs directed to emission sources.

The majority ofman-made nitrogen oxides (NOx) and volatile organic compounds (VOC)emissions that contribute to 03 formationin the United States come from three types ofsources: Mobile sources, industrial processes (whichinclude consumer and commercial products), and the electric power industry.3Mobile sources and the electric power industry were responsible for 78 percent of annual NOx emissions in 2004. That same year, 99 percent ofman-made VOC emissions

came from industrial processes (including solvents) and mobile sources. Emissions from natural sources, such as trees, may also comprise a significant portion oftotal VOC emissions in certain regions ofthe country, especially during the 03 season, which are considered natural background emissions.

The EPAhas developed new emissions standards for many types of stationary sources and for nearly every class ofmobile sources inthe last decade toreduce 03by decreasing emissions ofNOx and VOC. These
programs complement State and local efforts to improve 03 air quality and
meet the 0.084 ppm 8-hournational standards. Under title II ofthe CAA, 42 U.S.C. 7521-7574), EPAhas established

new emissions standards for nearly every type ofautomobile, truck,bus, motorcycle, earth mover, and aircraft engine, and for the fuels used to power these engines. EPA also established new standards for the smaller engines used in small watercraft, lawn and garden equipment. In March 2008, EPA promulgated new standards for locomotive and marine diesel engines and in August 2009, proposed to control emissions from ocean-going vessels.

Benefits from engine standards increase modestly each year as older, more-polluting vehicles and engines are replaced with newer, cleaner models.In time, these programs willyield substantial emission reductions. Benefits from fuel programs generally begin as soon as a new fuel is available.

The reduction ofVOC emissions from industrial processes has been achieved either directly or indirectly through implementation ofcontrol technology standards, including maximum achievable control technology, reasonably available control technology, and best available controltechnology standards; or are anticipated due to proposed orupcoming proposals based

on generally available control technology or best available controls under provisions related to consumer and commercial products. These standards have resulted in VOC emission reductions ofalmost amillion
tons per year accumulated starting in 1997 from avariety ofsources including combustion sources, coating categories, and chemical manufacturing. EPAhas

3SeeEPA report, EvaluatingOzone Control Programs in theEastern UnitedStates:Focuson the NO Budget TradingProgram, 2004. also finalized emission standards and fuel requirements for new stationary engines. In the area ofconsumer and commercial products, EPA has finalized

new national VOC emission standards for aerosol coatings and is working toward amending existing rules to establish new nationwide VOC content limits for household and institutional

consumer products and architectural andindustrial maintenance coatings. The aerosol coatings rule took effect in July 2009; the compliance date for both the amended consumer product rule and architectural coatings rule is anticipated tobe January 2011. These actions are expected toyield significant

new VOC reductions-about 200,000
tons per year. Additionally, in ozone nonattainment areas, we anticipate reductions ofan additional 25,000 tons per year as States adopt rules this year implementing control techniques recommendations issued in 2008 for 4 additional categories ofconsumer and commercial products, typically surface coatings and adhesives used in industrial manufacturing operations. These emission reductions primarily result from solvent controls and typically occur where and when the solvent isused, such as during manufacturing processes.

The power industry is one ofthe largest emitters ofNOx in the United States. Power industry emission sources include large electric generating units (EGU) and some large industrial boilers andturbines. The EPA's landmark Clean Air Interstate Rule (CAIR), issued on March 10, 2005, was designed to permanently cap power industry emissions ofNOx in the eastern United States. The first phase ofthe cap was to begin in 2009, and a lower second phase
cap was tobegin in 2015. The EPA had projected thatby 2015, the CAIR and other programs would reduce NOx emissions during the 03 season by about 50 percent and annual NOx emissions by about 60 percent from 2003 levels in the Eastern U.S. However, onJuly 11, 2008 and December 23, 2008, the U.S. Court ofAppeals for the DC Circuit issued decisions on petitions forreview ofthe CAIR. In itsJuly 11 opinion, the
court found CAIR unlawful and decided
tovacate CAIR andits associated Federal implementation plans (FIPs)in their entirety. On December 23, the
court granted EPA's petition for rehearing tothe extent thatit remanded without vacatur for EPA to conduct further proceedings consistent with the Court's prior opinion. Under this decision, CAIR will remain in place only until replacedby EPA with a rule that isconsistent with the Court'sJuly 

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11 opinion. The EPArecognizes the need in our CAIR replacement effort to address the reconsidered ozone standard, and we are currently assessing

our options for the best way to accomplish this. It should also be noted that new electric generating units (EGUs) are also subject to NOx limits under New Source Performance Standards (NSPS)under CAA section 111, as well as either nonattainment

new source review or prevention of significant deterioration requirements.

With respect to agricultural sources, the U.S. Department ofAgriculture (USDA) has approved conservation systems and activities thatreduce agricultural emissions ofNOx and VOC. Current practices thatmay reduce emissions ofNOx and VOC include engine replacement programs, diesel retrofit programs, manipulation of pesticide applications including timing ofapplications, and animal feeding operations waste management techniques. The EPA recognizes that USDA hasbeen working with the agricultural community to develop conservation systems and activities to control emissions of03 precursors.

These conservation activities are voluntarily adopted through the use of incentives provided to the agricultural producer. In cases where the States need these measures to attain the standard, the measures couldbe adopted. The EPA will continue to work with USDA

on these activities with efforts to identify and/or improve the control efficiencies, prioritize the adoption of these conservation systems and activities, and ensure that appropriate criteria are used for identifying the most effective application of conservation systems and activities.

The EPA will work together with USDA and with States to identify appropriate measures tomeet the primary and secondary standards, including site-specific conservation systems and activities. Based onprior experience identifying conservation

measures and practices tomeetthe PM NAAQS requirements, the EPA will use

a similar process to identify measures that could meet the 03 requirements. The EPA anticipates that certain USDAapproved conservation systems and activities that reduce agricultural emissions ofNOx and VOC maybe able
to satisfy the requirements for applicable sources to implement reasonably available control measures for purposes ofattaining the primary and secondary 03 NAAQS. C.Review of Air QualityCriteria and Standards for 03
In 1971, EPA first established primary and secondary NAAQS for photochemical oxidants (36 FR 8186). Both primary and secondary standards

were set at a level of0.08 partsper million (ppm), 1-hr average, total photochemical oxidants, not to be exceeded more than one hrper year. In 1977, EPA announced the first periodic review ofthe air quality criteria in accordance with section 109(d)(1) ofthe Act. The EPA published afinal decision in 1979 (44FR 8202). Both primary and secondary standard levels were revised from 0.08to 0.12 ppm.The indicator

was revised from photochemical oxidants to 03, and the form ofthe standards was revised from a deterministic to a statistical form, which defined attainment ofthe standards as occurring when the expected number of days per calendar year with maximum hourly average concentration greater than 0.12 ppm is equal to or lessthan

one. In 1983, EPA announced that the second periodic review ofthe primary and secondary standards for 03 had been initiated. Following review and publication ofair quality criteria and a supplement, EPA published a proposed decision (57 FR 35542) inAugust 1992 that announced EPA's intention to proceed as rapidly as possible with the
next review ofthe air quality criteria and standards for 03 in light of emerging evidence ofhealth effects related to 6- to 8-hr 03 exposures. In March 1993, EPA concluded the review by deciding that revisionsto the standards were not warranted at that time (58 FR 13008).

In August 1992 (57 FR 35542), EPA announced plans to initiate the third periodic review ofthe air quality criteria and 03 NAAQS. Onthe basis ofthe scientific evidence contained in the 1996 CD (U.S. EPA 1996a) and the 1996 StaffPaper (U.S. EPA, 1996b), and related technical support documents, linking exposures to ambient 03 to adverse health and welfare effects at levels allowed by the then existing standards, EPA proposed torevise the primary and secondary 03 standards in December 1996 (61 FR 65716). The EPA proposed to replace the then existing 1-hourprimary and secondary standards with 8-hour average 03 standards set at

a level of0.08 ppm (equivalent to 0.084 ppm using standard rounding conventions). The EPA also proposed, in the alternative, to establish a new distinct secondary standard using a biologically based cumulative seasonal form. The EPA completed the review in July 1997 (62 FR 38856)by setting the primary standard at a level of0.08 ppm, based onthe annual fourth-highest daily maximum 8-hr average concentration, averaged over three years, and setting the secondary standard identical to the revised primary standard.

The EPA initiated the most recent periodic review ofthe airquality criteria and standards for 03in September 2000 with a call for information (65 FR 57810; September 26, 2000) for the development ofa revised Air Quality Criteria Document for 03 and Other Photochemical Oxidants (henceforth the "2006 Criteria Document"). Aproject work plan (EPA, 2002) for the preparation ofthe Criteria Document

was released in November 2002 for CASAC and public review. The EPA held a series ofworkshops in mid-2003

on several draft chapters ofthe Criteria Document to obtain broad input from the relevant scientific communities. These workshops helped to inform the preparation ofthe first draft Criteria Document (EPA, 2005a), which was released for CASAC and public review

onJanuary 31, 2005; a CASAC meeting

was held on May 4-5, 2005 to review the first draft CriteriaDocument. A second draft Criteria Document (EPA, 2005b) was released forCASAC and public review on August 31, 2005, and

was discussed along with a first draft StaffPaper (EPA, 2005c) at a CASAC meeting held on December 6-8, 2005. In

aFebruary 16, 2006 letter to the Administrator, CASAC provided
comments on the second draft Criteria Document (Henderson, 2006a), and the final 2006 Criteria Document (EPA, 2006a) was released on March 21, 2006. In a June 8, 2006 letterto the Administrator (Henderson, 2006b), CASAC provided additional advice to the Agency concerning chapter 8 ofthe final 2006 Criteria Document (Integrative Synthesis) to help inform the second draft StaffPaper.

A second draft StaffPaper (EPA, 2006b) was released onJuly 17, 2006 andreviewed by CASAC on August 24- 25, 2006. In an October 24, 2006 letter
to the Administrator, CASACprovided advice and recommendations to the Agency concerning the second draft StaffPaper (Henderson, 2006c). Afinal 2007 StaffPaper (EPA, 2007a) was released onJanuary 31, 2007. In aMarch 26, 2007 letter (Henderson, 2007), CASAC offered additional advice to the Administrator with regard to recommendations and revisions tothe primary and secondary 03 NAAQS.

The schedule for completion ofthe 2008 rulemaking was governed by a consent decree resolving alawsuit filed in March 2003by a group ofplaintiffs representing national environmental 

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andpublic health organizations, alleging that EPAhad failed to complete the review within the period provided by statute.4The modified consent decree that governed the 2008 rulemaking, entered by the court on December 16, 2004, provided thatEPA sign for publication notices ofproposed and final rulemaking concerning its review ofthe 03NAAQS no later than March 28, 2007 and December 19, 2007, respectively. That consent decree was further modified in October 2006 to change these proposed and final rulemaking dates tono later than May 30, 2007 and February 20, 2008, respectively. These dates for signing the publication notices ofproposed and final rulemaking were further extended
to no later thanJune 20, 2007 and March 12, 2008, respectively. The proposed decision was signed onJune 20, 2007 and publishedin the Federal Register onJuly 11, 2007 (72 FR 37818).

Public hearings on the proposed decision were held on Thursday, August 30, 2007 in Philadelphia, PA and Los Angeles, CA. OnWednesday, September 5, 2007, hearings were held in Atlanta, GA, Chicago, IL, and Houston, TX. A large number ofcomments were received fromvarious commenters on the 2007 proposed revisions to the 03 NAAQS. Acomprehensive summary of all significant comments, along with EPA's responses (henceforth "Response
to Comments"), canbe found in the docketfor the 2008 rulemaking, which is also the docket for this reconsideration rulemaking.

The EPA's final decision on the 03 NAAAQS was published in theFederal Register on March 27, 2008 (73 FR 16436). In the 2008 rulemaking, EPA revised the level ofthe 8-hour primary standard for 03 to 0.075 parts per million (ppm),expressed to three decimal places. With regard to the secondary standard for 03, EPArevised the 8-hour standard by makingit identical to therevised primary standard. The EPA also made conforming changes tothe Air Quality Index (AQI) for 03, setting an AQI value of100 equal to 0.075 ppm, 8-hour average, and making proportional changes tothe AQIvalues of50, 150 and 200.

D.Reconsiderationofthe2008 03 NAAQS Final Rule
Consistent with a directive ofthe new Administration regarding the review of

new andpending regulations (Emanuel memorandum, 74 FR 4435;January 26, 2009), the Administrator reviewed a

4American LungAssociationv. Whitman (No. 1:03CV00778, D.DC 2003). number ofactions that were taken in the last year by the previous Administration. The 2008 final rule was included in this review in recognition of the central role that theNAAQS play in enabling EPA tofulfill its mission to protect the nation's public health and welfare. In her review, the Administrator was mindful ofthe need forjudgments concerning the NAAQS to be based on a strong scientific foundation which isdeveloped through

a transparent and credible NAAQS review process, consistent with the core values highlighted in President Obama's memorandum on scientific integrity (March9, 2009).

1.Decision To Initiate a Rulemaking To Reconsider

In her review ofthe 2008 final rule, several aspects ofthe final rule related
to the primary and secondary standards stood out to the Administrator. As an initial matter, the Administrator noted that the 2008 finalrule concluded that the 1997 primary and secondary 03 standards were not adequate to protect public health and public welfare, and that revisions were necessary to provide increased protection. With respectto revision oftheprimary standard, the Administrator noted that the revised level established in the 2008final rule

was above the range thathad been unanimously recommended by CASAC. 5 She also notedthat EPA received comments from a large number ofcommenters from the medical and public health communities, including EPA's Children's HealthProtection Advisory Committee, all ofwhich endorsed levels within CASAC's recommended range.

With respect to revision ofthe secondary 03 standard, the Administrator noted that the 2008 final rule differed substantially from CASAC's recommendations that EPA adopt a new secondary 03 standard based on a cumulative, seasonal

measure ofexposure. The 2008 final rule revised the secondary standard to be identical to the revised primary standard, which isbased on an 8-hour daily maximum measure ofexposure. She also noted that EPAreceived
comments from a number of
commenters representing environmental interests, all ofwhich endorsed CASAC;s recommendation for a new cumulative, seasonal secondary standard.6

5The levelofthe 8-hour primaryozone standard

was setat 0.075 ppm,while CASAC unanimously recommended arange between 0.060 and 0.070
ppm.

6The Administrator also noted the exchange that
had occurred between EPA and the Office of Subsequent toissuance ofthe 2008 final rule, in April 2008, CASACtook the unusual step of sending EPA a letter expressing strong, unanimous disagreement with EPA's decisions on both the primary and secondary standards (Henderson, 2008). The CASAC explained thatit did not endorse the revised primary 03 standard

as being sufficiently protective ofpublic healthbecause itfailed to satisfy the explicit stipulation ofthe Actto provide

an adequate margin ofsafety. The CASAC also expressed the view that failing to revise the secondary standard
to a cumulative, seasonal form was not supported bythe available science. In addition to CASAC's letter,the Administrator noted a recent adverse ruling issuedby the U.S. Court of Appeals for the District ofColumbia Circuit on another NAAQS decision. In February 2009, the DC Circuit remanded the Agency's decisions on the primary annual and secondary standards for fine particles (PM2. 5). In so doing, the Court found that EPAhad not adequately explained the basis for its decisions, including why CASAC's recommendations for a more healthprotective primary annual standard and for secondary standards different from the primary standards were not accepted. AmericanFarmBureauv. EPA,559 F.3d. 512 (DCCir. 2009).

Based on her review ofthe information described above, the Administrator is initiating a rulemaking
to reconsider parts ofthe 2008 final rule. Specifically, the Administrator is reconsidering the level ofthe primary standard to ensure that itis sufficiently protective ofpublic health, as discussed in section IIbelow, andis reconsidering all aspects ofthe secondary standard to

ensure that itappropriately reflects the available science and is sufficiently protective ofpublic welfare, as discussed in section IVbelow. Based on her review, the Administrator has serious cause for concern regarding whether therevisions to the primary and secondary 03 standards adopted in the 2008 final rule satisfy the requirements ofthe CAA, in light ofthe body of scientific evidence before the Agency. In addition, the importance of the 03 NAAQS to public health and welfare weigh heavily in favor of reconsidering parts ofthe 2008final rule as soon as possible, based on the scientific and technical information
upon which the 2008 finalrule was based.

Management and Budget (OMB) with regard to the final decision onthe secondary standard, as discussed inthe 2008 finalrule (73 FR 16497). 

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Also, EPA conducted a provisional
assessment of"new" scientific papers (EPA, 2009) ofscientific literature evaluating health and ecological effects of03 exposure published since the close ofthe 2006 CriteriaDocument upon which the 2008 03 NAAQS were based. The Administrator notes that the provisional assessment of "new"science found that such studies did not materially change the conclusions inthe 2006 CriteriaDocument. This provisional assessment is supportive of the Administrator's decision to reconsider parts of the 2008final rule at this time, based on the scientific and technical information available for the 2008 finalrule, as compared to foregoing such reconsideration and taking appropriate action inthe future

as part ofthe nextperiodic review ofthe air quality criteria and NAAQS, which will include such scientific and technical information.

The reconsideration ofparts ofthe 2008 finalrule discussed in this notice isbased on the scientific and technical record from the 2008 rulemaking, including public comments and CASAC advice and recommendations. The information thatwas assessed during the 2008 rulemaking includes information in the 2006 Criteria Document (EPA, 2006a), the 2007Policy Assessment of Scientific and Technical Information, referred to as the 2007 Staff Paper (EPA, 2007b), and related technical support documents including the 2007 REAs (U.S.EPA, 2007c; Abt Associates, 2007a,b). Scientific and technical information developed since the 2006 Criteria Document willbe considered in the nextperiodic review, instead ofthis reconsideration rulemaking, allowing the new information to receive careful and comprehensive reviewby CASAC and the public before itis used as abasis in

a rulemaking that determines whether to revise the NAAQS.

2.Ongoing Litigation

In May 2008, following publication of the 2008 final rule, numerous groups, including state, public health, environmental, and industry petitioners, challenged EPA's decisions in federal
court. The challenges were consolidated

as Stateof Mississippi,eta].v. EPA (No. 08-1200, DC Cir. 2008). On March 10, 2009, EPA filed an unopposed motion requesting thatthe Courtvacate the briefing schedule and hold the consolidated cases in abeyance. The Agency stated its desire to allow time for appropriate officials from the new Administration to review the 03 standards to determine whether they shouldbe maintained, modified or otherwise reconsidered. The EPA further requested thatitbe directed to notify the Court and all the parties of any actions ithas taken orintends to take, ifany, within 180 days ofthe Court vacating the briefing schedule. On March 19, 2009, the Court granted EPA's motion. Pursuant to the Court's order,

on September 16, 2009 EPA notifiedthe Court and the parties ofits decision to initiate a rulemaking toreconsider the primary and secondary 03 standards set in March 2008 to ensure they satisfy the requirements ofthe CAA. 7In itsnotice
to the Court, EPA stated thatthis notice ofproposed rulemaking would be signed byDecember 21, 2009, and that the finalrule will be signed by August 31, 2010.

II. Rationale forProposed Decision on the Level ofthePrimary Standard

As an initial matter, the Administrator
notes thatthe 2008 final rule concluded that the 1997 primary 03 standard was "not sufficient and thus not requisite to protect public health with an adequate margin ofsafety, and that revision is needed toprovide increased public health protection" (73 FR 16472). The Administrator is not reconsidering this aspect ofthe 2008 decision, which is based on the reasons discussed in section II.B ofthe 2008final rule (73 FR 16443-16472). The Administrator also
notes thatthe 2008 final rule concluded that itwas appropriate to retain the 03 indicator, the 8-hour averaging time, and form ofthe primary 03 standard (specifiedas the annual fourth-highest daily maximum 8-hour concentration, averaged over 3years), while concluding that revision ofthe standard level was appropriate. 8The Administrator is not reconsidering these aspects ofthe 2008 decision, which are based on the reasons discussed in sections II.C.1-3 ofthe 2008 finalrule, which address the indicator, averaging time, and form, respectively, ofthe primary 03 standard (73 FR 16472- 16475). For these reasons, the Administrator is not reopening the 2008

7 TheEPA also separately announced thatit will

move quickly to implement anynew standards that might result from this reconsideration. Toreduce the workload forstates during the interimperiod of reconsideration, the Agency intends to propose to defer compliance withthe CAA requirement to designate areas as attainment ornonattainment. EPA will work with states, local governments and tribes to ensure that airquality is protected during that time.

8The use of03 as the indicator for photochemical
oxidants was adopted in the 1979 final rule and retained insubsequent rulemaking. An8-hour averaging time and a formbased on the annual fourth-highest daily maximum 8-hour concentration, averaged over 3years, were adopted in the 1997 final rule and retained in the 2008 rulemaking. decision withregard to the need to revise the 1997 primary 03 standard nor with regard to the indicator, averaging time, and form ofthe 2008 primary 03 standard. Thus, the information that follows in this section specifically focuses on a reconsideration oflevel of the primary 03 standard.

This section presents the rationale for the Administrator's proposed decision that the 03 primary standard, which was set ata level of0.075 ppm inthe 2008 final rule, should instead be set at a lower level within the range from 0.060
to 0.070 ppm. As discussed more fully below, the rationale for theproposed range of standard levels isbased on a thorough review ofthe latest scientific information on human health effects associated with thepresence of03in the ambient air presented in the 2006 Criteria Document. This rationale also takes into account: (1)Staffassessments ofthe most policy-relevant information in the 2006 Criteria Document and staff analyses ofair quality, human exposure, and health risks, presented in the 2007 StaffPaper, upon which staff recommendations for revisions to the primary 03 standard in the 2008 rulemaking were based; (2)CASAC advice and recommendations, as reflected in discussions ofdrafts ofthe 2006 CriteriaDocument and 2007 Staff Paper atpublic meetings, in separate written comments, and in CASAC's letters to the Administrator both before and after the 2008 rulemaking; and (3) public comments received during the development ofthese documents, either in connection with CASAC meetings or separately, and on the 2007 proposed rule.

In developing this rationale, the Administrator recognizes that the CAA requires her to reach apublic health policy judgment as to what standard would be requisite toprotect public health with an adequate margin of safety, based on scientific evidence and technical assessments thathave inherent uncertainties and limitations. Thisjudgment requires making reasoned decisions as to whatweight to place onvarious types of evidence and assessments, and on the related uncertainties and limitations. Thus, in selecting standard levels to propose, and subsequently in selecting a final level, the Administrator is seeking not onlyto prevent 03 levels thathave been demonstrated tobe harmful but also to prevent lower 03 levels that may pose

an unacceptable risk ofharm, even ifthe risk is not precisely identified asto nature or degree.

In this proposed rule, EPA has drawn upon an integrative synthesis ofthe entire body ofevidence, published 

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through early 2006, on human health effects associated with the presence of 03in the ambient air. As discussed below in section ILA, this body of evidence addresses a broad range of health endpoints associated with
exposure to ambient levels of 03 (EPA, 2006a, chapter 8), and includes over one hundred epidemiologic studies conducted in the U.S., Canada, and
many countries around the world.9In reconsidering this evidence, EPA focuses on those health endpoints that have been demonstrated tobe caused by
exposure to 03, or for which the 2006 Criteria Document judges associations with 03 to be causal, likely causal, or for which the evidence ishighly suggestive that 03 contributes tothe reported effects. This rationale also draws upon the results ofquantitative exposure and risk assessments, discussed below in section II.B. Section II.C focuses on the considerations upon which the Administrator's proposed conclusions

on the level ofthe primary standard are based. Policy-relevant evidence-based and exposure/risk-based considerations

are discussed, and the rationale for the 2008 finalrulemaking on the primary standard and CASAC advice, givenboth prior to the development ofthe 2007 proposed rule and following the 2008 final rule, are summarized. Finally, the Administrator's proposed conclusions

on the level ofthe primary standard are presented. Section II.D summarizes the proposed decision on the level ofthe primary 03 standard and the solicitation ofpublic comments.

Judgments made in the 2006 Criteria Document and 2007 StaffPaper about the extent towhich relationships between various health endpoints and short-term exposures to ambient 03 are likely causal havebeen informed by several factors. As discussed below in section ILA, these factorsinclude the
nature ofthe evidence (i.e.,controlled human exposure, epidemiological, and/

ortoxicological studies) and the weight ofevidence, which takes into account such considerations as biological plausibility, coherence ofevidence, strength ofassociation, and consistency ofevidence.

In assessing thehealth effects data base for 03, it is clear thathuman studies provide the most directly applicable information for determining causalitybecause they are not limited

9In its assessment ofthe epidemiological evidence judged to bemostrelevant to making decisions on the level ofthe 03 primary standard, EPA has placed greater weight on U.S. and Canadian epidemiologic studies, since studies conducted in othercountries may wellreflect different demographic and airpollution characteristics. by the uncertainties ofdosimetry differences and species sensitivity differences, which would need to be addressed in extrapolating animal toxicology data to human health effects. Controlled human exposure studies provide data with the highest level of confidence since they provide human health effects data under closely monitored conditions and can provide
exposure-response relationships. Epidemiological data provide evidence ofassociations between ambient 03 levels and more serious acute and chronic health effects (e.g., hospital admissions and mortality) that cannot be assessed in controlled human
exposure studies. Forthese studies the degree ofuncertainty introduced by potentially confounding variables (e.g., other pollutants, temperature) and other factors affects the level ofconfidence that the health effects being investigated

are attributable to 03 exposures, alone and in combination with other copollutants.

In using a weight ofevidence approach to informjudgments about the degree ofconfidence thatvarious health effects are likely tobe caused by exposure to 03, confidence increases as the number of studies consistently reporting a particular health endpoint grows and as other factors, such as biological plausibility and strength, consistency, and coherence ofevidence, increase. Conclusions regarding biological plausibility, consistency, and coherence ofevidence of0 3-related health effects are drawn from the integration ofepidemiological studies with mechanistic information from controlled human exposure studies and animal toxicological studies. As discussed below, this type of mechanistic linkage has been firmly established for several respiratory endpoints (e.g., lung function decrements, lung inflammation) but remains far more equivocal for cardiovascular endpoints (e.g., cardiovascular-related hospital admissions). Forepidemiological studies, strength ofassociation refers to the magnitude ofthe association and its statistical strength, which includes
assessment ofboth effects estimate size and precision. In general, when associations yield large relative risk estimates, itis lesslikely thatthe association couldbe completely accounted for by apotential confounder

or some otherbias. Consistency refers to the persistent finding ofan association between exposure and outcome in multiple studies ofadequate power in different persons, places, circumstances and times. Forexample, the magnitude ofeffect estimates isrelatively consistent across recent studies showing associationbetween short-term, but not long-term, 03 exposure and mortality.

Based on the information discussed below in sections II.A.1-II.A.3, judgments concerning the extent to which relationships between various health endpoints and ambient 03
exposures are likely causal are summarized below in section II.A.3.c. These judgments reflect the nature of the evidence and the overall weight of the evidence, and are taken into consideration in the quantitative
exposure and risk assessments, discussed below in section II.B.

To putjudgments about health effects that havebeen demonstrated tobe caused by exposure to 03, or for which the 2006 Criteria Documentjudges associations with 03 tobe causal, likely causal, or for which the evidence is highly suggestive that 03 contributes to the reported effects into a broader public health context, EPA has drawn upon the results ofthe quantitative
exposure and risk assessments. These
assessments provide estimates ofthe likelihood that individuals inparticular population groups that are at risk for various 0 3-related physiological health effects would experience "exposures of concern" and specific health endpoints under varying air quality scenarios (i.e., just meeting various standards 10), as well as characterizations ofthe kind and degree ofuncertainties inherent in such estimates.

In the 2008 final rulemaking and in this reconsideration, the term "exposures ofconcern" is defined as personal exposures while at moderate or greater exertion to 8-hour average ambient 03 levels at and above specific benchmark levels which represent exposure levels at which 0 3-related health effects are known or can reasonably be inferred to occur in some individuals, as discussed below in section II.B.1.11 The EPA emphasizes

10

The exposure assessment done as part ofthe
2008 finalrulemaking considered several airquality scenarios, includingjust meeting what was then the
current standard set at a level of0.084 ppm, as well

as justmeeting alternative standards at levels of 0.080, 0.074, 0.070, and 0.064 ppm.

"Exposures ofconcern were alsoconsidered in the 1997 reviewof the 03 NAAQS, and werejudged by EPA to be an important indicator ofthe public health impacts ofthose 03-related effects for which information was too limited to develop quantitative estimates ofriskbut which had been observed in humans at and abovethe benchmark level of 0.08
ppm for 6- to 8-hour exposures * * * including increased nonspecific bronchial responsiveness (for example, aggravation ofasthma), decreased pulmonary defense mechanisms (suggestive of increased susceptibility to respiratory infection), and indicators of pulmonary inflammation (related
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that although the analysis of"exposures ofconcern" was conducted using three discrete benchmark levels (i.e.,0.080, 0.070, and 0.060 ppm), the concept is

more appropriately viewed as a continuum with greater confidence and less uncertainty about the existence of health effects at theupper end and less confidence and greater uncertainty as
one considers increasingly lower 03 exposure levels. The EPA recognizes that there is no sharp breakpoint within the continuum ranging from at and above 0.080 ppm down to 0.060 ppm. In considering the concept ofexposures of
concern, it is important to balance

concerns about the potential for health effects and their severity with the increasing uncertainty associated with

our understanding ofthe likelihood of such effects at lower 03 levels.

Within the context ofthis continuum, estimates ofexposures ofconcern at discrete benchmark levels provide some perspective onthe public health impacts of0 3-related health effects that have been demonstrated in controlled human exposure and toxicological studies but cannot be evaluated in quantitative risk assessments, such as lung inflammation, increased airway responsiveness, and changes in host defenses. They also help in understanding the extent to which such impacts have the potential tobe reduced by meeting various standards. These 03- related physiological effects are plausibly linked to the increased morbidity seen in epidemiological studies (e.g., as indicated by increased medication use in asthmatics, school absences in all children, and emergency department visits and hospital admissions in people with lung disease). Estimates ofthe number of people likely to experience exposures of

concern cannot be directly translated into quantitative estimates of the number ofpeople likely to experience specific health effects, since sufficient information to draw such comparisons is not available-if such information

were available, these health outcomes would have been included inthe quantitative risk assessment. Due to individual variability in responsiveness, only a subset ofindividuals who have
exposures atand above a specific benchmark level can be expected to experience such adverse health effects, and susceptible subpopulations such as those with asthma are expected to be affected more by such exposures than healthy individuals. The amount of weight toplace on the estimates of
exposures ofconcern at any ofthese

to potential aggravation ofchronic bronchitis or long-term damage to the lungs). (62 FR 38868) benchmark levels depends in part on the weight ofthe scientific evidence concerning health effects associated with 03 exposures at and above that benchmark level. Italso depends on judgments about the importance from a public health perspective ofthe health effects that are known or canreasonably be inferred to occur as a result of exposures at and above the benchmark level. Such public healthpolicy judgments are embodied in the NAAQS standard setting criteria (i.e., standards that, in the judgment ofthe Administrator, are requisite to protect public health with an adequate margin of safety).

As discussed below in section II.B.2, the quantitative health risk assessment conducted as part ofthe 2008 final rulemaking includes estimates ofrisks oflung function decrements in asthmatic and all school age children, respiratory symptoms in asthmatic children, respiratory-related hospital admissions, and non-accidental and cardiorespiratory-related mortality associated with recent ambient 03 levels, as well as riskreductions and remaining risks associated withjust meeting the then current 0.084 ppm standard andvarious alternative 03 standards in a number ofexample urban

areas. There are two partsto this risk
assessment: one part isbased on combining information from controlled human exposure studies with modeled population exposure, and the other part isbased on combining information from community epidemiological studies with either monitored or adjusted ambient concentrations levels. This
assessment provides estimates ofthe potential magnitude ofO3-related health effects, as well as a characterization of the uncertainties and variability inherent in such estimates. This
assessment also provides insights into the distribution ofrisks and patterns of riskreductions associated with meeting alternative 03 standards.

As discussed below, a substantial
amount ofnew research conducted since the 1997 review ofthe 03 NAAQS

was available to inform the 2008 final rulemaking, with important new information coming from epidemiologic studies as well as from controlled human exposure, toxicological, and dosimetric studies. The research studies newly available in the 2008 final rulemaking thatwere evaluated in the 2006 Criteria Document and the
exposure andrisk assessments presented in the 2007 Staff Paperhave undergone intensive scrutiny through multiple layers ofpeer review andmany opportunities for public review and
comment. While important uncertainties remain in the qualitative and quantitative characterizations of health effects attributable to exposure to ambient 03, and while different interpretations ofthese uncertainties

can result in different public health policy judgments, the review ofthis information hasbeen extensive and deliberate. In the judgment ofthe Administrator, this intensive evaluation ofthe scientific evidence provides an adequate basis for thisreconsideration ofthe 2008 finalrulemaking.

A. HealthEffectsInformation

This section outlines key information contained in the 2006 Criteria Document (chapters 4-8)and in the 2007 StaffPaper (chapter 3)on known

or potential effects on public health which maybe expected from the
presence of 03 in ambient air.The information highlighted here summarizes: (1)New information available on potential mechanisms for health effects associated with exposure to 03; (2)the nature of effects that have been associated directly with exposure to 03 and indirectly with the presence of 03 in ambient air; (3)an integrative interpretation ofthe evidence, focusing

on the biological plausibility and coherence ofthe evidence; and (4) considerations in characterizing the public health impact of03, including the identification of "atrisk" populations.

The decision in the 1997 review focused primarily on evidence from short-term (e.g., 1to 3hours) and prolonged (6 to 8 hours) controlledexposure studies reporting lung function decrements, respiratory symptoms, and respiratory inflammation in humans, aswell as epidemiology studies reporting excess hospital admissions and emergency department (ED)visits for respiratory

causes. The 2006 Criteria Document prepared for the 2008 rulemaking emphasized the large number of epidemiological studies published since the last review with these and additional health endpoints, including the effects ofacute (short-term and prolonged) and chronic exposures to 03

on lung function decrements and enhanced respiratory symptoms in asthmatic individuals, school absences, and premature mortality. It also emphasized important new information from toxicology, dosimetry, and controlled human exposure studies. Highlights ofthe evidence include: (1)Two new controlled humanexposure studies are now available that examine respiratory effects associated with prolonged 03 exposures at levels below 0.080 ppm, which was the lowest 

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exposure level thathad been examined in the 1997 review. (2)Numerous controlled humanexposure studies have examined indicators of0 3-induced inflammatory response in both the upper respiratory
tract (URT) and lower respiratory tract (LRT), and increased airway responsiveness to allergens in subjects with allergic asthma and allergic rhinitis exposed to03, while other studieshave examined changes in host defense capability following 03 exposure of healthy young adults. (3)Animal toxicology studies provide

new information regarding mechanisms ofaction, increased susceptibility to respiratory infection, and the biological plausibility ofacute effects and chronic, irreversible respiratory damage. (4) Numerous acute exposure epidemiological studies published during the past decade offer added evidence ofambient 0 3-related lung function decrements andrespiratory symptoms in physically active healthy subjects and greater responses in asthmatic subjects, as well as evidence

onnew health endpoints, such as the relationships between ambient 03 concentrations and asthma medication

use and school absenteeism, and between ambient 03 and cardiac-related physiological endpoints. (5)Several additional studies have been published over the last decade examining the temporal associations between 03 exposures and emergency department visits for asthma and other respiratory diseases and respiratoryrelated hospital admissions. (6) Alarge number ofnewly available epidemiological studies have examined the effects ofacute exposure to PM and
03 onmortality, notably including large multicity studies thatprovide much

more robust and credible information than was available in the 1997 review,

as well as recentmeta-analyses that have evaluated potential sources of heterogeneity in 0 3-mortality associations.

1.Overview ofMechanisms

Evidence on possible mechanisms by which exposure to 03 may result in
acute and chronic health effects is discussed in chapters 5and 6 ofthe 2006 CriteriaDocument. 12Evidence from dosimetry, toxicological, and

12While mostofthe available evidence addresses
mechanisms for 03, 03 clearly serves as an indicator for the total photochemical oxidant mixture found in the ambient air. Some effects maybe causedby

one ormore components inthe overall pollutant mix, either separately orin combination with 03. However, 03 clearly dominates these otheroxidants with their concentrations onlybeing a few percent ofthe 03 concentration. human exposure studies has contributed
to an understanding ofthe mechanisms that help to explain thebiological plausibility and coherence ofevidence for 0 3-inducedrespiratory health effects reported in epidemiological studies. More detailed information about the physiological mechanisms related to the respiratory effects ofshort- and longterm exposure to 03 can be found in section II.A.3.b.i and II.A.3.b.iii, respectively. In the past,however, little information was available to help explain potential biological mechanisms which linked 03 exposure to premature mortality or cardiovascular effects. As discussed more fully in section II.A.3.b.ii below, since the 1997review

an emerging body ofanimal toxicology and controlled human exposure evidence isbeginning to suggest mechanisms that may mediate acute 03 cardiovascular effects. While much is known about mechanisms thatplay a role in 0 3-related respiratory effects, additional research is needed to more clearly understand the role that 03 may have in contributing to cardiovascular effects.

With regard to the mechanisms related to short-term respiratory effects, scientific evidence discussed in the 2006 Criteria Document (section 5.2) indicates that reactions of03 with lipids and antioxidants in the epithelial lining fluid and the epithelial cell membranes ofthe lung can be the initial step in mediating deleterious health effects of 03. This initial step activates a cascade ofevents thatlead to oxidative stress, injury, inflammation, airway epithelial damage and increased alveolar permeability to vascular fluids. Inflammation canbe accompanied by increased airway responsiveness, which is an increased bronchoconstrictive
response to airway irritants and allergens. Continued respiratory inflammation also can alterthe ability of the body torespond to infectious agents, allergens and toxins. Acute inflammatory responses to 03 in some healthy people are well documented, and precursors to lung injury are observed within 3hours after exposure in humans. Repeated respiratory inflammation can lead to a chronic inflammatory state with altered lung
structure and lungfunction and may lead to chronic respiratory diseases such

as fibrosis and emphysema (EPA, 2006a, section 8.6.2). The severity ofsymptoms and magnitude ofresponse to acute exposures depend on inhaled dose, as well as on individual susceptibility to 03, as discussed below. Atthe same 03 dose, individuals who are more susceptible to 03 willhave alarger response than those who are less susceptible; among individuals with similar susceptibility, those who receive

a larger dose will have a larger response

to 03.

The inhaled dose is theproduct of 03 concentration (C), minuteventilation or ventilation rate, and duration of
exposure (T), or (C xventilation rate x T). A large body ofdataregarding the interdependent effect ofthese components ofinhaled dose on pulmonary responses was assessed in the 1986 and 1996 03 Criteria Documents. In an attempt to describe 03 dose-response characteristics, acute responses were modeled as a function of total inhaled 03 dose, which was generally found tobe a better predictor ofresponse than 03 concentration, ventilation rate, or duration ofexposure, alone, or as a combination ofany two ofthese factors (EPA 2006a, section 6.2). Predicted 0 3-induced decrements in lung function havebeen shown to be a function ofexposure concentration, duration and exercise level for healthy, young adults (McDonnell eta]., 1997). A meta-analysis of21 studies (Mudway and Kelly, 2004) showed thatmarkers of inflammation and increased cellular permeability in healthy subjects are associated with total 03 dose.

The 2006 Criteria Document summarizes information on potentially susceptible and vulnerable groups in section 8.7. As described there, the term susceptibilityrefers to innate (e.g., genetic ordevelopmental) or acquired (e.g.,personal risk factors, age)factors that make individuals more likelyto experience effects with exposure to pollutants. A number ofpopulation groups and lifestages have been identified as potentially susceptible to health effects as aresult of03 exposure, including people with existing lung diseases, including asthma, children and older adults, and people who have larger than normal lung function
responses that maybe dueto genetic susceptibility. In addition, some population groups and lifestages have been identified as having increased vulnerability to 0 3-related effects dueto increased likelihood of exposure while
at elevated ventilation rates, including healthy children and adults who are active outdoors, for example, outdoor workers, andjoggers. Takentogether, the susceptible andvulnerable groups

are more commonly referred to as "atrisk" groups, 1 3 as discussed more fully below in section II.A.4.b.

13Inprevious StaffPapers and Federal Register notices announcing proposed and final decisions on the 03 and other NAAQS, EPA has used the phrase
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Based on a substantial body ofnew evidence from animal, controlled human exposure and epidemiological studies, the 2006 Criteria Document concludes thatpeople with asthma and otherpreexisting pulmonary diseases

are likely to be amongthose at increased risk from 03 exposure. Altered physiological, morphological and biochemical states typical ofrespiratory diseases like asthma, COPD and chronic bronchitis may render people sensitive
to additional oxidative burden induced by 03 exposure (EPA 2006a, section 8.7). Children and adults with asthma

are the group thathas been studied most extensively. Evidence from controlled human exposure studies indicates that asthmatics may exhibit larger lung function decrements in response to 03 exposure than healthy controls. As discussed more fully in section II.A.4.b.ii below, asthmatics present a differential response profile for cellular, molecular, andbiochemical parameters (EPA, 2006a, section 8.7.1) that are altered in response to acute 03 exposure. They can have larger inflammatory responses, as manifested by larger increases in markers of inflammation such as whitebloods cells (e.g.,PMNs) or inflammatory cytokines. Asthmatics, and people with allergic rhinitis, are more likely to mount an allergic-type response upon exposure to 03, as manifested by increases inwhite blood cells associated with allergy (i.e., eosinophils) and related molecules, which increase inflammation in the airways. The increased inflammatory and allergic responses also may be associated with the larger late-phase
responses that asthmatics can experience, which can include increased bronchoconstrictor responses to irritant substances or allergens and additional inflammation. In addition to the experimental evidence of lung function decrements, respiratory symptoms, and other respiratory effects in asthmatic populations, two large U.S. epidemiological studies as well as several smaller U.S. and international studies, have reported fairly robust associations between ambient 03 concentrations and measures oflung function and daily symptoms (e.g., chest tightness, wheeze, shortness ofbreath) in children with moderate to severe asthma andbetween 03 and increased asthma medication use (EPA, 2007a, chapter 6). These responses in

"sensitivepopulation groups" to include both population groups that are at increasedriskbecause they are more intrinsically susceptible and population groups that are more vulnerable due to

an increased potential for exposure. In this notice,

weuse the phrase, "atrisk"populations to include bothtypes ofpopulation groups. asthmatics and others with lung disease provide biological plausibility for the

more serious respiratory morbidity effects observed in epidemiological studies, such as emergency department visits and hospital admissions.

Children with and without asthma

were found to be particularly susceptible to 03 effects onlung function and generally have greater lung function responses than older people. The American Academy ofPediatrics (2004) notes that children and infants

are among the population groups most susceptible to many air pollutants, including 03. This is in partbecause their lungs are still developing. For example, eightypercent ofalveoli are formed after birth, and changes in lung development continue through adolescence (Dieterteta]., 2000). Moreover, children have high minute ventilation rates and relatively high levels ofphysical activity which also increases their 03 dose (Plunketteta]., 1992). Thus, children are at-risk due to both their susceptibility and vulnerability.

Looking more broadly at age-related differences in susceptibility, several mortality studies have investigated agerelated differences in 03 effects (EPA, 2006a, section 7.6.7.2), primarily in the older adult population. Among the studies that observed positive associations between 03 andmortality,

a comparison ofall age oryounger age (65years ofage) 0 3-mortalityeffect estimates to that ofthe elderly population (>65 years) indicates that, in general, the elderly population is more susceptible to 03 mortality effects. There is supporting evidence ofagerelated differences in susceptibility to 03 lung function effects. The 2006 Criteria Document (section 7.6.7.2) concludes thatthe elderly population (>65 years ofage) appear tobe atgreater risk of0 3-related mortality and hospitalizations compared to all ages or younger populations, and children (<18
years ofage) experience other potentially adverse respiratory health
outcomes with increased 03 exposure.

Controlled human exposure studies have also indicated a high degree of interindividual variability in some of the pulmonary physiological parameters, such as lung function decrements. The variable effects in individuals have been found tobe reproducible, in other words, a person who has a large lung function response after exposure to 03will likely have about the same response ifexposed again to the same dose of03 (EPA 2006a, section 6.1). In controlled human exposure studies, group mean responses

are not representative ofthis segment of the population thathas muchlarger than average responses to03. Recent studies, discussed in section II.A.4.b.iv below, reported a role for genetic polymorphism (i.e.,the occurrence together in the same population ofmore than one allele or genetic marker at the

same locus with the leastfrequent allele

ormarker occurring more frequently than can be accounted for by mutation alone) in observed differences in antioxidant enzymes and genes involved in inflammation to modulate pulmonary function and inflammatory
responses to 03 exposure. These observations suggest a potential role for these markers in the innate susceptibility to 03, however, the validity ofthese markers and their relevance in the context ofprediction to population studies needs additional experimentation.

Controlled human exposure studies that provide information about mechanisms ofthe initial response to 03 (e.g., lung function decrements, inflammation, and injury to the lung) also inform the selection ofappropriate lag times to analyze in epidemiological studies through elucidation ofthe time

course ofthese responses (EPA 2006a, section 8.4.3). Based on the results of these studies, itwould be reasonable to expect thatlung function decrements could be detected epidemiologically within lags of0 (same day) or 

### 1to 2 days following 03 exposure, given the rapid onset oflung function changes andtheir persistence for 24 to 48hours among more responsive human subjects in controlled human exposure studies. Otherresponses take longer to develop and can persist for longer periods of time. Forexample, although asthmatic individuals may begin to experience symptoms soon after 03 exposure, it may take anywhere from 

### 1to 3days after exposure for these subjects to seek medical attention as a result of increased airway responsiveness or inflammation thatmay persist for 2to 3days. This maybe reflected by epidemiologic observations of significantly increased risk for asthmarelated emergency department visits or hospital admissions with 

### 1-to 3-day lags, or, perhaps, enhanced distributed lag risks (combined across 3 days) for such morbidity indicators. Analogously,

one mightproject increased mortality within 0- to 3-day lags as a possible
consequence of0 3-inducedincreases in clotting agents arising from the cascade ofevents, starting with cell injury described above, occurring within 12 to 24 hours of03 exposure. The time

course for many of these initial
responses to 03 ishighly variable. 

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Moreover these observations pertain onlyto the initial response to 03. Consequent responses can follow. For example, J6rres etal., (1996) found that in subjects with asthma and allergic rhinitis, a maximum percent fallin FEV1 of27.9% and 7.8%, respectively, occurred 3days after 03 exposure when they were challenged with ofthe highest

common dose ofallergen.

2.Nature ofEffects

The 2006 Criteria Document provides

new evidence thatnotably enhances our understanding ofshort-term and prolonged exposure effects, including effects on lung function, symptoms, and inflammatory effects reported in controlled exposure studies. These studies support and extend the findings ofthe previous Criteria Document. There is also a significant body ofnew epidemiological evidence of associations between short-term and prolonged exposure to03 and effects such as premature mortality, hospital admissions and emergency department visits for respiratory (e.g., asthma)

causes. Key epidemiological and controlled human exposure studies are summarized below and discussed in chapter 3ofthe 2007 StaffPaper, which isbased on scientific evidence critically reviewed in chapters 5,6, and 7ofthe 2006 CriteriaDocument, as well as the Criteria Document's integration of scientific evidence contained in chapter

8.14 Conclusions drawn about 0 3-related health effects are based upon the full body ofevidence from controlled human exposure, epidemiological and toxicological data contained in the 2006 Criteria Document.

a. Morbidity

This section summarizes scientific information on the effects ofinhalation of03, including public health effects of short-term, prolonged, and long-term
exposures onrespiratory morbidity and cardiovascular system effects, as discussed in chapters 6, 7and 8 ofthe 2006 CriteriaDocument and chapter 3of the 2007 StaffPaper. This section also summarizes the uncertainty about the potential indirect effects on public health associated with changes dueto increases in UV-B radiation exposure, such as UV-B radiation-related skin
cancers, that maybe associated with reductions in ambient levels ofgroundlevel 03, as discussed in chapter 10 of the 2006 Criteria Document and chapter 3ofthe 2007 StaffPaper.

14Health effects discussions are also drawn from the more detailedinformation andtables presented in theCriteria Document's annexes. i. Effects on the Respiratory System From Short-term and Prolonged 03 Exposures

Controlled human exposure studies have shown that 03 induces avariety of health effects, including: Lung function decrements, respiratory symptoms, increased airway responsiveness, respiratory inflammation and permeability, increased susceptibility to respiratory infection, and acute morphological effects. Epidemiology studies have reported associations between 03 exposures (i.e., 1-hour, 8- hour and 24-hour) and a wide range of respiratory-related health effects including: pulmonary function decrements; respiratory symptoms; increased asthma medication use; increased school absences; increased emergency department visits and hospital admissions. (a)Pulmonary Function Decrements, Respiratory Symptoms, and Asthma Medication Use (i) Results From Controlled Human Exposure Studies

A large number ofstudies published prior to 1996 that investigated shortterm 03 exposure health effects on the respiratory system from short-term 03 exposures were reviewed in the 1986 and 1996 CriteriaDocuments (EPA, 1986, 1996a). In the 1997 review, 0.50
ppm was the lowest 03 concentration at which statistically significant reductions in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1)were reported in sedentary subjects. During exercise, spirometric (lungfunction) and symptomatic responses were observed
at much lower 03 exposures. When minute ventilation was considerably increased by continuous exercise (CE) during 03 exposures lasting 2hour or less at> 0.12 ppm, healthy subjects generally experienced decreases in FEVI, FVC, and othermeasures oflung function; increases in specific airway resistance (sRaw), breathing frequency, and airway responsiveness; and symptoms such as cough, pain on deep inspiration, shortness ofbreath, throat irritation, and wheezing. When
exposures were increased to 4- to 8- hours in duration, statistically significant lung function and symptom responses were reported at 03 concentrations as low as 0.08 ppm and
at lower minute ventilation (i.e., moderate rather than high level exercise) than the shorter duration studies.

The mostimportant observations drawn from studies reviewed inthe 1996 Criteria Document were that: (1) Young healthy adults exposed to 03 concentrations >0.080 ppm develop significant, reversible, transient decrements in pulmonary function if minute ventilation or duration of
exposure is increased sufficiently; (2) children experience similar lung function responses but report lesser symptoms from 03 exposure relative to young adults; (3)0 3-inducedlung function responses are decreased in the elderly relative to young adults; (4) there isa large degree ofintersubject variability in physiological and symptomatic responses to 03but responses tend to be reproducible within a given individual over aperiod of several months; (5) subjects exposed repeatedly to 03 for several days show

an attenuation ofresponse upon successive exposures, but this attenuation is lost after about a week without exposure; and (6) acute 03 exposure initiates an inflammatory
response which may persistfor atleast 18 to 24 hours post exposure.

The development ofthese respiratory effects is time-dependent during both
exposure and recovery periods, with great overlap for development and disappearance ofthe effects. Inhealthy human subjects exposed totypical ambient 03 levels near 0.120 ppm, lung function responses largely resolve within 4 to 6 hourspostexposure, but cellular effects persist for about 24 hours. In these healthy subjects, small residual lung function effects are almost completely gone within 24 hours, while in hyperresponsive subjects, recovery

can take as much as 48hour toreturn tobaseline. The majority ofthese
responses are attenuated after repeated consecutive exposures, but such attenuation to 03 is lostone week postexposure.

Since 1996, there have been a number ofstudies published investigating lung function and symptomatic responses that generally support the observations previously drawn. Recent studies for
acute exposures of1 to 2hours and 6 to 8 hours in duration are compiled in the 2007 StaffPaper (Appendix 3C). As summarized in more detail in the 2007 StaffPaper (section 3.3.1.1), among the

more important ofthe recent studies that examined changes in FEV inlarge numbers ofsubjects over a range of 1-2 hours at exposure levels of0.080 to 0.40 ppm were studies by McDonnell et a]. (1997) andUltman eta]. (2004). These studies observed considerable intersubject variability in FEV decrements, which was consistent with findings in the 1996 Criteria Document.

For prolonged exposures (4 to 8 hours) in the range of0.080 to 0.160
ppm 03 using moderate intermittent 

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exercise and typically using squarewave exposure patterns (i.e.,a constant exposure level during time ofexposure), several pre- and post-1996 studies (Folinsbee etaL., 1988,1994; Horstman
eta]., 1990; Adams, 2002, 2003a, 2006) have reported statistically significant lung function responses and increased symptoms in healthy adults with increasing duration ofexposure, 03 concentration, andminute ventilation. Studies that employed triangular exposure patterns (i.e.,integrated
exposures that begin at a low level,rise
to a peak, and return to alow level during the exposure) (Hazucha etaL., 1992; Adams 2003a, 2006) suggest that the triangular exposure pattern can potentially lead to greater FEVI decrements andrespiratory symptoms than square-wave exposures (whenthe overall 03 doses are equal). These results suggest thatpeak exposures, reflective ofthe pattern ofambient 03 concentrations in some locations, are important in terms of 03 health effects.

McDonnell (1996) used data from a series ofstudies toinvestigate the frequency distributions ofFEVI decrements following 6.6 hour
exposures andfound statistically significant, but relatively small, group
mean decreases in average FEVI responses (between 5and 10 percent) at 0.080 ppm 03.15 Notably, about 26 percent ofthe 60 exposed subjects had lung function decrements > 10 percent, including about 8 percent ofthe subjects that experienced large decrements (>20 percent) (EPA, 2007b, Figure 3-1A). These results (whichwere not corrected for exercise in filtered airresponses) demonstrate thatwhile average responses may be relatively small at the 0.080 ppm exposure level, some individuals experience more severe effects that maybe clinically significant. Similarresults at the 0.080 ppm exposure level (for 6.6 hours during intermittent exercise) were seen in more recent studies of30 healthy young adultsby Adams (2002, 2006).16 In Adams (2006), relatively small but statistically significant lung function decrements andrespiratory symptom responses were found (forboth squarewave and triangular exposure patterns), with 17 percent ofthe subjects (5 of30) experiencing> 10 percent FEV1

15This study andother studies (Folinsbee etal., 1988; Horstman et al., 1990; and McDonnell et al., 1991), conducted inEPA's human studiesresearch facility inChapel Hill, NC, measured ozone concentrations to within +/ 5 percent or+/ 0.004 ppmat the 0.080 ppm exposure level.

16

Thesestudies, conducted at a facility atthe University ofCalifornia, inDavis, CA, reported 03 concentrations tobe accurate within +/ 0.003 ppm over the range ofconcentrations included in these studies. decrements (comparing pre- and postexposures) when the results were not corrected for the effects ofexercise alone in filtered air (EPA,2007b, Figure 3-iB) and with 23 percent of subjects (7 of30) experiencing such effects when the results were corrected (EPA, 2007b,
p. 3-6). 17

These studies by Adams (2002, 2006)

were notable in thatthey were the only controlled exposure human studies available at the time ofthe 2008 rulemaking that examined respiratory effects associated with prolonged 03 exposures at levels below 0.080 ppm, which was the lowest exposure level that hadbeen examined in the 1997 review. The Adams (2006) study investigated a range ofexposure levels (0.000, 0.040, 0.060, and 0.080 ppm 03) using square-wave and triangular
exposure patterns. The study was designed to examine hour-by-hour changes in pulmonary function (FEVI) and respiratory symptom responses (totalsubjective symptoms (TSS)and pain on deep inspiration (PDI)) between these various exposure protocols at six different time points within the exposure periods to investigate the effects ofdifferent patterns ofexposure. At the 0.060 ppm exposure level, the author reported no statistically significant differences for FEVI decrements nor for mostrespiratory symptoms responses. Statistically significant responses were reported only for TSS for thetriangular exposure pattern toward the end ofthe exposure period, with the PDI responses being noted as following a closely similar pattern (Adams, 2006, p. 131-132). EPA's reanalysis ofthe data from the Adams (2006) study addressed the more fundamental question ofwhether there

were statistically significant differences in responses before and after the 6.6 hour exposure period (Brown, 2007), and used a standard statistical method appropriate for a simple before-and-after comparison. The statistical method used by EPAhad been used previously by other researchers to address this same question. EPA's reanalysis ofthe data from the Adams (2006) study, comparing FEVI responses pre- and post-exposure at the 0.060 ppm exposure level, found small group mean differences from responses to filtered air that were statistically significant (Brown, 2007).18

17These distributionalresults presented inthe Criteria Document and StaffPaper for theAdams (2006) study are based on data for squate-wave exposures to 0.080 ppm thatwere notincluded in thepublication but wereobtained fromthe author.

1 8Dr. Adams submitted comments onEPA's reanalysis in which he concluded thatthe FEV1 responsein healthy young adults atthe 0.060 ppm Further examination ofthe postexposure FEV data and mean data at other time points and concentrations also suggest a pattern ofresponse at 0.06 ppm thatis consistent with a doseresponse relationship rather than random variability. For example, the
response at 5.6hours was similar to that ofthe post-exposure 6.6 hourresponse and appeared to also differ from the FA
response. Atthe 0.08 ppm level, the subjects in this study did not appear to be more responsive to 03 than subjects in previous studies, as the observed response was similar to that ofprevious studies (Adams, 2003a,b; Horstman et aL., 1990; McDonnell etaL., 1991). Although ofmuch smaller magnitude, the temporal pattern ofthe 0.06 ppm response was generally consistent with the temporal patterns ofresponse to higher concentrations of03 in this and other studies. These findings are not unexpected because thepreviously observed group mean FEVI responses to 0.08 ppm were in the range of6-9% suggesting that exposure to lower concentrations of03 would result in smaller, but real group mean FEVI decrements, i.e.,the responses to 0.060 ppm 03 are consistent with the presence ofa smooth exposure-response curve with responses that do not end abruptly below 0.080 ppm.

Moreover, the Adams studies (2002, 2006) also report a small percentage of subjects experiencing moderate lung function decrements (> 10 percent)at the 0.060 ppm exposure level. Based on study data (Adams, 2006) provided by the author, 7percent ofthe subjects (2 of30 subjects) experienced notable FEVI decrements (> 10 percent) withthe
square wave exposure pattern atthe 0.060 ppm exposure level (comparing
pre- and post-exposures) when the results were corrected for the effects of exercise alone in filtered air (EPA, 2007b, p. 3-6). Furthermore, in a prior publication (Adams, 2002), the author stated that, "some sensitive subjects experience notable effects at 0.06 ppm," based onthe observation that 20% of subjects exposed to 0.06 ppm 03 (in a face mask exposure study)had greater than a 10% decrement inFEVI even though the group mean response was not statistically different from the filtered air response. The effects described by Adams (2002), alongwith

exposure level inhis study (Adams, 2006a) does not demonstrate asignificant meaneffect by ordinarily acceptable statistical analysis,but israther in somewhat ofagray area, bothin terms ofa biologically meaningful response and astatistically significant response (Adams,2007). TheEPA responded to these comments inthe 2008 finalrule (73 FR 16455) and inthe Response to Comments (EPA, 2008, pp. 26-28). 2950

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the reanalysis ofthe Adams (2006) data

as described above, demonstrate considerable inter-individual variability in responses ofhealthy adults at the 0.060 ppm level with some individuals experiencing greater than 10% decrements in FEV1 .The observation of statistically significant small group

mean lung function decrements in healthy adults at 0.060 ppm 03 lowers the lowest-observed-effects level found in controlled human exposure studies for lung function decrements and respiratory symptoms.

Ofpotentially greater concern is the magnitude ofthe lungfunction decrements in the small group of healthy subjects who had the largest
responses (i.e.,FEV1 decrements > 10%). This is a concern because for active healthy people, moderate levels offunctional responses (e.g., FEV1 decrements of> 10%but < 20%) and/

or moderate symptomatic responses would likely interfere withnormal activity for relatively fewresponsive individuals. However, for people with lung disease, even moderate functional

or symptomatic responses would likely interfere with normal activity for many individuals, and wouldlikely result in

more frequent use ofmedication (see section II.A.4 below). (ii)Results ofEpidemiological and Field Studies

A relatively large number offield studies investigating the effects of ambient 03 concentrations, in combination with other air pollutants,

on lung function decrements and respiratory symptoms has been published over the last decade that support the major findings ofthe 1996 Criteria Document thatlung function changes, as measured by decrements in FEV1 or peak expiratory flow (PEF), and respiratory symptoms in healthy adults and asthmatic children are closely correlated to ambient 03 concentrations. Pre-1996 field studies focused primarily

on children attending summer camps and found 0 3-related impacts on

measures oflung function,but not respiratory symptoms, in healthy children. The newer studieshave expanded to evaluate 0 3-related effects

on outdoor workers, athletes, the elderly, hikers, school children, and asthmatics. Collectively, these studies confirm and extend clinical observations thatprolonged (i.e., 6-8 hour) exposure periods, combined with elevated levels ofexertion or exercise, increase the dose of03 to the lungs at

agiven ambient exposure level and result in larger lung function effects. The results ofone large study ofhikers (Korricketal., 1998), whichreported outcome measures stratified by several factors (e.g., gender, age, smoking status, presence ofasthma) within apopulation capable ofmore than normal exertion, provide useful insight.In this study, lung function was measured before and after hiking, and individual 03
exposures were estimated by averaging hourly 03 concentrations from ambient monitors located at thebase and summit. The mean 8-hour average 03 concentration was 0.040 ppm (8-hour
average concentration range of0.021 ppm to0.074 ppm 03). Decreased lung function was associated with 03
exposure, with the greatest effect estimates reported for the subgroup that reported having asthma or wheezing, and for those who hiked for longer periods oftime.

Asthma panel studies conducted both in the U.S. and in other countries have reported that decrements in PEF are associated with routine 03 exposures among asthmatic and healthy people. One large U.S. multicity study, the National Cooperative Inner CityAsthma Study or NCICAS, (Mortimer etal., 2002) examined 0 3-related changes in PEF in 846 asthmatic children from 8 urban areas and reported thatthe incidence of> 10 percent decrements in morning PEF are associated with increases in 8-hour average 03 for a 5- day cumulative lag, suggesting that 03 exposure may be associated with clinically significant changes in PEF in asthmatic children; however, no associations were reported with evening PEF. The mean 8-hour average 03 was 0.048 ppm across the 8 cities. Excluding days when 8-hour average 03 was greater than 0.080 ppm (lessthan 5 percent ofdays), the associations with morning PEF remained statistically significant. Mortimer eta]. (2002) discussed potential biological mechanisms for delayed effects on pulmonary function in asthma, which included increased nonspecific airway responsiveness secondary to airway inflammation due to03 exposure. Two other panel studies (Romieu etal., 1996, 1997) carried out simultaneously in northern and southwestern Mexico City with mildly asthmatic school children reported statistically significant 03- related reductions in PEF, with variations in effect depending on lag time and time ofday.Mean 1-hour maximum 03 concentrations in these locations ranged from 0.190 ppm in northern Mexico Cityto 0.196 ppm in southwestern Mexico City. While several studies report statistically significant associations between 03 exposure andreduced PEF in asthmatics, other studies did not, possibly due to low levels of 03 exposure. EPA concludes thatthese studies collectively indicate that 03 may be associated with short-term declines in lung function in asthmatic individuals andthat theMortimer eta]. (2002) study showed statistically significant effects at concentrations in the rangebelow 0.080 ppm 03.

Most ofthepanel studies which have investigated associations between 03 exposure and respiratory symptoms or increased use ofasthma medication are focused on asthmatic children. Two large U.S. studies (Mortimer etal., 2002; Gent etal., 2003) have reported associations between ambient 03 concentrations and daily symptoms/ asthma medication use, even after adjustment for copollutants. Results

were more mixed, meaning that a greater proportion ofstudies were not both positive and statistically significant, across smaller U.S. and international studies that focused on these health endpoints.

The NCICAS reported morning symptoms in 846 asthmatic children from 8 U.S. urban areas to be most strongly associated with a cumulative 1- to 4-day lag of 03 concentrations (Mortimer etal., 2002). The NCICAS used standard protocols thatincluded instructing caretakers ofthe subjects to record symptoms (includingcough, chest tightness, and wheeze) inthe daily diary by observing or asking the child. While these associations were not statistically significant in several cities, when the individual data are pooled from all eight cities, statistically significant effects were observed for the incidence of symptoms. The authors also reported thatthe odds ratios remained essentially the same and statistically significant for the incidence ofmorning symptoms when days with 8-hour 03 concentrations above 0.080
ppm were excluded. These days represented less than 5percent ofdays in the study.

Gent and colleagues (2003) followed 271 asthmatic children under age 12 andliving in southern New England for 6 months (Aprilthrough September) using a daily symptom diary. They found that mean 1-hour max 03 and 8- hour max 03 concentrations were 0.0586 ppm and 0.0513 ppm, respectively. The data were analyzed for
two separate groups of subjects, those who used maintenance asthma medications during the follow-up period and those who did not. The need for regular medication was considered
to be a proxy for more severe asthma. Not taking any medication on a regular basis and not needing touse a bronchodilator would suggest the 

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presence ofvery mild asthma. Statistically significant effects of1-day lag 03 were observed on avariety of respiratory symptoms only in the medication user group. Both daily 1-hour max and 8-hour max 03 concentrations were similarly related to symptoms such as chest tightness and shortness ofbreath. Effects of 03, but
not PM2

. 5,remained significant and

evenincreased in magnitude in twopollutant models. Some ofthe associations were noted at 1-hour max 03levels below 0.060 ppm. In contrast,

no effects were observed among asthmatics not usingmaintenance medication. In terms ofperson-days of follow-up, this is one ofthe larger studies currently available that address symptom outcomes in relation to03 and provides supportive evidence for effects of03 independent ofPM2. 5. Study limitations include the post-hoc nature ofthe population stratification by medication use. Also, the study did not account for all ofthe important meteorological factors thatmight influence these results, such as relative humidity or dew point.

The multicity study by Mortimer eta]. (2002), which examined an asthmatic population representative ofthe United States, and several single-city studies indicate a robust association of 03 concentrations with respiratory symptoms and increased medication use in asthmatics. While there are a number ofwell-conducted, albeit relatively smaller, U.S. studieswhich showed only limited or a lackofevidence for symptom increases associated with 03 exposure, these studies had less statistical power and/or were conducted in areas with relatively low 1-hour maximum average 03 levels, in the range of0.03 to0.09 ppm. The 2006 Criteria Document concludes thatthe asthma panel studies, as a group, and the NCICAS in particular, indicate a positive association between ambient concentrations and respiratory symptoms and increased medication use in asthmatics. The evidence has continued to expand since 1996 and

now is considered to be much stronger than in the 1997 review ofthe 03 primary standard.

School absenteeism is another potential surrogate for the health implications of03 exposure in children. The association between school absenteeism and ambient 03 concentrations was assessed intwo relatively large field studies. The first study, Chen eta]. (2000), examined total daily school absenteeism in about 28,000 elementary school students in Nevada over a 2-year period (after adjusting for PMo and CO concentrations) and found that ambient 03 concentrations with a distributed lag of 14 days were statistically significantly associated with an increased rate of school absences. The second study, Gilliland eta]. (2001), studied 0 3-related absences among about 2,000 4th grade students in 12 southern California communities and found statistically significant associations between 8-hour average 03 concentrations (witha distributed lag
out to 30 days) and all absence categories, and particularly for respiratory causes. Neither PM10 nor NO2were associated with any respiratory or nonrespiratory illnessrelated absences in single pollutant models. The 2006 Criteria Document concludes thatthese studies of school absences suggest that ambient 03 concentrations, accumulated over two to four weeks, may be associated with school absenteeism, and particularly illness-related absences, but further replication is needed before firm conclusions can be reached regarding the effect of03 on school absences. In addition, more research isneeded to help shed light on the implications of variation in the duration ofthe lag
structures (i.e., 1day, 5days, 14 days, and 30 days) found both across studies and within data sets byhealth endpoint and exposure metric. (b)Increased Airway Responsiveness

As discussed in more detail in the 2006 Criteria Document (section6.8) and the 2007 Staff Paper (section 3.3.1.1.2), increased airway responsiveness, also known as airway hyperresponsiveness (AHR) orbronchial hyperreactivity, refers to a condition in which the propensity for the airways to bronchoconstrict due to a variety of stimuli (e.g., exposure to cold air, allergens, or exercise) becomes augmented. This condition is typically quantified by measuring the decrement in pulmonary function after inhalation
exposure to specific (e.g., antigen, allergen) or nonspecific (e.g., methacholine, histamine) bronchoconstrictor stimuli. Exposure to 03 causes an increase in airway responsiveness as indicated by a reduction in the concentration of stimuli required toproduce a given reduction in FEV1 or increase in airway obstruction. Increased airway responsiveness is an important
consequence ofexposure to 03because its presence means thatthe airways are predisposed to narrowing on exposure to various stimuli, such as specific allergens, cold air or SO 2 .Statistically significant and clinically relevant decreases in pulmonary function have been observed in early phase allergen
response in subjects with allergic rhinitis after consecutive (4-day) 3-hour exposures to 0.125 ppm 03 (Holzetal., 2002). Similar increased airway responsiveness in asthmatics tohouse dust mite antigen 16 to 18 hours after
exposure to a single dose of 03 (0.160
ppm for 7.6 hours) was observed. These observations, based on 03 exposures to levels much higher than the 0.084 ppm standard level suggest that 03 exposure may be aclinically important factor that

can exacerbate the response to ambient bronchoconstrictor substances in individuals with preexisting allergic asthma orrhinitis. Further, 03 mayhave

an immediate impact on the lung function ofasthmatics as well as contribute to effects thatpersist for longer periods.

Kreit eta]. (1989) found that 03 can induce increased airway responsiveness in asthmatic subjects to 03,who typically have increased airway responsiveness at baseline. A subsequent study (J6rres eta]., 1996) suggested an increase in specific (i.e., allergen-induced) airway reactivity in subjects with allergic asthma, andto a lesser extent in subjects with allergic rhinitis after short-term exposure to higher 03 levels; other studies reported similar results. According to one study (Folinsbee and Hazucha, 2000), changes in airway responsiveness after 03 exposure resolve more slowly than changes in FEV or respiratory symptoms. Other studies ofrepeated
exposure to 03 suggest that changes in airway responsiveness tend tobe somewhat less affected by attenuation with consecutive exposures than changes in FEV (EPA, 2006a, section 6.8).

The 2006 Criteria Document (section 6.8) concludes that 03 exposure is linked with increased airway responsiveness. Both human and animal studies indicate that increased airway responsiveness is not mechanistically associated with inflammation, and does
not appear to be strongly associated with initial decrements in lung function

or increases in symptoms. As aresult of increased airway responsiveness induced by 0 3 exposure, human airways
may be more susceptible to a variety of stimuli, including antigens, chemicals, and particles. Because asthmatic subjects typically have increased airway responsiveness at baseline, enhanced bronchial response to antigens in asthmatics raises potential public health

concerns as they could lead to increased morbidity (e.g., medication usage, school absences, emergency room visits, hospital admissions) or to more persistent alterations in airway 

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responsiveness (EPA 2006a, p. 8-21). As such, increased airway responsiveness after 03 exposure represents a plausible link between 03 exposure and increased hospital admissions.
(c) Respiratory Inflammation and Increased Permeability

Based on evidence from the 1997 review, acute inflammatory responses in the lung havebeen observed subsequent
to 6.6 hour 03 exposures tothe lowest tested level-0.080 ppm-in healthy adults engaged in moderately high exercise (section6.9 ofthe 2006 Criteria
Document and section 3.3.1.3 ofthe 2007 StaffPaper). Some ofthese prior studies suggest thatinflammatory
responses may be detected in some individuals following 03 exposures in the absence of0 3-inducedpulmonary decrements in those subjects. These studies also demonstrate that short-term
exposures to 03 also can cause increased permeability in the lungs of humans and experimental animals. Inflammatory responses and epithelial permeability have been seen to be independent of spirometric responses. Not only are the newer lung inflammation and increased cellular permeability findings discussed in the 2006 CriteriaDocument (section8.4.2) consistent with the 1997 review, but they provide better characterization of the physiological mechanisms by which 03 causes these effects.

Lung inflammation and increased permeability, which are distinct events controlled by different mechanisms, are two commonly observed effects of03 exposure observed in all ofthe species studied.Increased cellular permeability is a disruption ofthe lung barrier that leads to leakage ofserum proteins, influx ofpolymorphonuclear leukocytes (neutrophils or PMNs), release of bioactive mediators, and movement of compounds from the airspaces into the blood.

A number ofcontrolled human
exposure studies have analyzed bronchoalveolar lavage (BAL) and nasal lavage (NL) 19 fluids and cells for markers ofinflammation and lung damage (EPA, 2006a, Annex AX6). Increased lung inflammation is demonstrated by the presence of neutrophils found in BAL fluid in the lungs, which has longbeen accepted as

a hallmark ofinflammation. It is apparent, however, that inflammation

19Graham and Koren (1990) compared inflammatory mediators present in NLand BAL fluids ofhumans exposed to 0.4 ppm 03 for 2hours and found similar increases in PMNs inboth fluids, suggesting a qualitative correlation between inflammatory changes in the lower airways (BAL) and upper respiratory tract (NL). within airway tissues may persist beyond the point that inflammatory cells are found in the BAL fluid. Soluble mediators ofinflammation, such as cytokines and arachidonic acid metabolites have been measured in the BAL fluid ofhumans exposed to 03. In addition totheir role in inflammation, many ofthese compounds have bronchoconstrictive properties and may be involved in increased airway responsiveness following 03 exposure. An in vitro study ofepithelial cells from nonatopic and atopic asthmatics exposed to 0.010 to 0.100 ppm 03 showed significantly increased permeability compared to cells from normal persons. This indicates a potentially inherent susceptibility of cells from asthmatic individuals for 03- induced permeability.

In the 1996 Criteria Document,
assessment ofcontrolled human exposure studies indicated that a single,
acute (1to 4hours) 03 exposure (>0.080
to 0.100 ppm) of subjects engaged in moderate to heavy exercise could induce a number ofcellular and biochemical changes suggestive of pulmonary inflammation and lung permeability (EPA, 2006a, p. 8-22). These changes persisted for atleast 18 hours. Markers from BAL fluid following both 2-hour and 4-hour 03
exposures repeated up to 5days indicate that there is ongoing cellular damage irrespective ofattenuation of

some cellular inflammatory responses of the airways, pulmonary function, and symptom scores (EPA, 2006a, p. 8-22). Acute airway inflammation was shown in Devlin eta]. (1990) to occur among adults exposed to0.080 ppm 03for 6.6 hours with exercise. McBride eta]. (1994) reported that asthmatic subjects

were more sensitive than nonasthmatics to upper airway inflammation for 03 exposures that did
not affect pulmonary function (EPA, 2006a, p. 6-33). However, the public health significance ofthese changes is
not entirely clear.

The studies reporting inflammatory
responses and markers oflung injury have clearly demonstrated thatthere is significant variation inresponse of subjects exposed, especially to 6.6 hours 03 exposures at 0.080 and 0.100 ppm. To provide some perspective on the public health impact forthese effects, the 2007 StaffPaper (section 3.3.1.1.3)
notes that one study (Devlinetal., 1991) showed thatroughly 10 to 50 percent of the 18 young healthy adult subjects experienced notable increases (i.e., > 2 fold increase) in mostofthe inflammatory and cellular injury indicators analyzed, associated with 6.6- hour exposures at 0.080 ppm. Similar, although in some cases higher, fractions ofthe population of 10 healthy adults tested saw > 2fold increases associated with 6.6-hour exposures to 0.100 ppm. The authors ofthis study expressed the view that "susceptible subpopulations such as the very young, elderly, and people withpulmonary impairment or disease maybe even more affected" (DevlinetaL., 1991).

Since 1996, a substantial number of human exposure studies havebeen published which have provided important new information on lung inflammation and epithelial permeability. Mudway and Kelly (2004) examined 0 3-induced inflammatory
responses and epithelial permeability with a meta-analysis of21 controlled human exposure studies and showed that an influx inneutrophils and protein in healthy subjects is associated with total 03 dose (product of03 concentration, exposure duration, and minute ventilation) (EPA, 2006a, p. 6- 34). Results ofthe analysis suggest that the time course for inflammatory
responses (includingrecruitment of neutrophils and other soluble mediators) isnot clearly established, but there isevidence that attenuation profiles for many ofthese parameters

are different (EPA, 2006a, p. 8-22).

The 2006 Criteria Document (chapter 8) concludes that interaction of03 with lipid constituents ofepithelial lining fluid (ELF) and cell membranes and the induction ofoxidative stress is implicated in injury and inflammation. Alterations in the expression of cytokines, chemokines, and adhesion molecules, indicative ofan ongoing oxidative stress response, as well as injury repair and regeneration
processes, havebeen reported in animal toxicology and human in vitro studies evaluating biochemical mediators implicated in injury and inflammation. While antioxidants in ELF confer some protection, 03 reactivity is not eliminated at environmentally relevant
exposures (2006 Criteria Document, p. 8-24). Further, antioxidant reactivity with 03 isboth species-specific and dose-dependent.
(d)Increased Susceptibility to Respiratory Infection

As discussed in more detail in the 2006 CriteriaDocument (sections 5.2.2, 6.9.6, and 8.4.2), short-term exposures to 03 havebeen shown to impair physiological defense capabilities in experimental animals by depressing alveolar macrophage (AM)functions and by altering the mucociliary clearance ofinhaled particles and microbes resulting in increased susceptibility to respiratory infection. 

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Short-term 03 exposures also interfere with the clearance process by accelerating clearance for low doses and slowing clearance for high doses. Animal toxicological studies have reported that acute 03 exposures suppress alveolar phagocytosis and immune system functions. Impairment ofhost defenses and subsequent increased susceptibility to bacterial lung infection in laboratory animals hasbeen induced by short-term exposures to 03 levels as low as 0.080 ppm.

A single controlled human exposure study reviewed in the 1996 Criteria Document (p. 8-26) reported that
exposure to 0.080 to 0.100 ppm 03 for 6.6 hours (withmoderate exercise) induced decrements in the ability of AMs to phagocytose microorganisms. Integrating the recent animal study results with human exposure evidence available in the 1996 Criteria Document, the 2006 Criteria Document concludes that available evidence indicates that short-term 03 exposures have the potential to impair host defenses in humans, primarily by interfering with AM function. Any impairment in AM function may lead to decreased clearance ofmicroorganisms or nonviable particles. Compromised AM functions in asthmatics may increase their susceptibility to other 03 effects, the effects ofparticles, andrespiratory infections (EPA, 2006a, p. 8-26). (e) Morphological Effects

The 1996 Criteria Document found that short-term 03 exposures cause similar alterations in lung morphology in all laboratory animal species studied, including primates. As discussed in the 2007 StaffPaper (section3.3.1.1.5), cells in the centriacinar region (CAR) ofthe lung (the segment between the last conducting airway and the gas exchange region) havebeen recognized as a primary target of0 3-induced damage (epithelialcell necrosis and remodeling ofrespiratory bronchioles), possibly because epithelium in this region receives the greatest dose of03 delivered tothe lowerrespiratory tract. Following chronic 03 exposure, structural changes have been observed in the CAR, theregion typically affected in most chronic airway diseases ofthe human lung (EPA, 2006a, p. 8-24).

Ciliated cells in the nasal cavity and airways, as well as Type I cells in the gas-exchange region, are also identified

as targets. While short-term 03
exposures can cause epithelial cell profileration and fibrolitic changes in the CAR, these changes appear to be transient with recovery occurring after exposure, depending on species and 03 dose. The potential impacts ofrepeated short-term and chronic morphological effects of03 exposure are discussed below in the section on effects from long-term exposures. Long-term or prolonged exposure has been found to

cause chronic lesions similar to early lesions found in individuals with respiratory bronchiolitis, which have the potential to progress to fibrotic lung disease (2006 Criteria Document, p. 8-25).

Recent studies continue to show that short-term and sub-chronic exposures to 03 cause similar alterations in lung
structure in avariety ofexperimental animal species. For example, a series of

new studies that used infant rhesus monkeys and simulated seasonal ambient exposure (0.5 ppm 8 hours/day for 5days, every 14 days for 11 episodes) reported remodeling inthe distal airways; abnormalities intracheal basement membrane; eosinophil accumulation in conducting airways; and decrements in airway innervation (2006 CriteriaDocument, p. 8-25). Based on evidence from animal toxicological studies, short-term and sub-chronic exposures to 03 can cause morphological changes in the respiratory systems, particularly in the CAR, ofa number oflaboratory animal species (EPA, 2006a, section 5.2.4). (f)Emergency Department Visits/ Hospital Admissions for Respiratory Causes

Increased summertime emergency department visits and hospital admissions for respiratory causes have been associated with ambient exposures
to 03. As discussed in section 3.3.1.1.6 ofthe 2007 StaffPaper, numerous studies conducted in various locations in the U.S. and Canada consistently have shown a relationship between ambient 03 levels and increased incidence ofemergency department visits and hospital admissions for respiratory causes, even after controlling for modifying factors, such as weather and copollutants. Such associations between elevated ambient 03 during

summer months and increased hospital admissions have a plausible biological basis in the human and animal evidence offunctional, symptomatic, and physiologic effects discussed above and in the increased susceptibility to respiratory infections observed in laboratory animals.

In the 1997 review ofthe 03NAAQS, the CriteriaDocument evaluated
emergency department visits and hospital admissions as possible
outcomes following exposure to 03 (EPA, 2006a, section 7.3). The evidence

was limited for emergency department visits, butresults of several studies generally indicated that short-term
exposures to 03 were associated with respiratory emergency department visits. The strongest and most consistent evidence, at both lower levels (i.e., below 0.120 ppm 1-hour max 03) and at higher levels (above 0.120 ppm 1-hour

max 03), was foundin the group of studies which investigated summertime 20 daily hospital admissions for respiratory causes in different eastern North American cities. These studies consistently demonstrated that ambient 03 levels were associated with increased hospital admissions and accounted for about one to three excess respiratory hospital admissions per million persons with each 0.100 ppm increase in 1-hour max 03, after adjustment for possible confounding effects oftemperature and copollutants. Overall, the 1996 CriteriaDocument concluded that there was strong evidence that ambient 03 exposures can

cause significant exacerbations of preexisting respiratory disease in the general public. Excess respiratoryrelated hospital admissions associated with 03 exposures for theNewYork City area (basedon Thurston etal., 1992) were included in the quantitative risk assessment in the 1997 review and

are included in the current assessment along with estimates for respiratoryrelated hospital admissions in Cleveland, Detroit, and Los Angeles based onmore recent studies (2007 Staff Paper, chapter 5). Significant uncertainties and the difficulty of obtaining reliable baseline incidence numbers resulted in emergency department visits notbeing usedin the quantitative risk assessment in either the 1997 orthe 2008 0 3 NAAQS review.

In the past decade, a number of studies have examined the temporal pattern associations between 03 exposures and emergency department visits for respiratory causes (EPA, 2006a, section 7.3.2). These studies are summarized in the 2006 Criteria Document (chapter 7Annex) and some

are shown in Figure 1 (in sectionII.A.3). Respiratory causes for emergency department visits include asthma, bronchitis, emphysema, pneumonia, and other upper and lower respiratory infections, such as influenza, but asthma visits typically dominate the daily incidence counts. Most studies report positive associations with 03. Among studies with adequate controls for seasonal patterns, many reported at least one significant positive association involving 03.

20Discussion ofthe reasons forfocusing on warm

season studies is found inthe section 2.A.3.a below. 

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In reviewing evidence for associations between emergency department visits for asthma and short-term 03 exposures, the 2006 Criteria Document (Figure 7- 8, p. 7-68) notes thatin general, 03 effect estimates from summer only analyses tended to be positive andlarger compared to results from cool season or allyear analyses. Several ofthe studies reported significant associations between 03 concentrations and emergency department visits for respiratory causes, in particular asthma. However, inconsistencies were observed which were at leastpartially attributable
to differences inmodel specifications and analysis approach among various studies. Forexample, ambient 03 concentrations, length ofthe study period, and statistical methods used to control confounding by seasonal patterns and copollutants appear to affect the observed 03 effect on emergency department visits.

Hospital admissions studies focus specifically onunscheduled admissions because unscheduled hospital admissions occur in response to unanticipated disease exacerbations and

are more likely than scheduled admissions tobe affected by variations in environmental factors, such as daily 03 levels. Results ofa fairly large number ofthese studies published during the past decade are summarized in 2006 Criteria Document (chapter 7 Annex), and results ofU.S. and Canadian studies are shown in Figure 1 below (in section II.A.3). As a group, these hospital admissions studies tend
to be larger geographically and temporally than the emergency department visit studies and provide results that are generally more consistent. The strongest associations of respiratory hospital admissions with 03 concentrations were observed using short lagperiods, in particular for a 0- day lag (same day exposure) and a 1-day lag (previous day exposure). Most studies in the United States and Canada indicated positive, statistically significant associations between ambient 03 concentrations and respiratory hospital admissions in the

warm season. However, not all studies found a statistically significant relationship with 03, possiblybecause ofvery low ambient 03 levels. Analyses for confounding using multipollutant regression models suggest that copollutants generally do not confound the association between 03 and respiratory hospitalizations. Ozone effect estimates were robust to PM adjustment in all-year and warm-season onlydata.

Overall, the 2006 Criteria Document concludes thatpositive and robust associations were found between ambient 03 concentrations andvarious respiratory disease hospitalization outcomes, when focusing particularly

on results ofwarm-season analyses. Recent studies also generally indicate a positive association between 03 concentrations and emergency department visits for asthma duringthe

warm season (EPA, 2006a, p. 7-175). These positive and robust associations

are supported bythe controlled human exposure, animal toxicological, and epidemiological evidence for lung function decrements, increased respiratory symptoms, airway inflammation, and increased airway responsiveness. Taken together, the overall evidence supports a causal relationship between acute ambient 03 exposures and increased respiratory morbidity outcomes resulting in increased emergency department visits and hospitalizations during the warm

season (EPA, 2006a, p. 8-77).

ii. Effects on the Respiratory System of Long-Term 03 Exposures

The 1996 Criteria Document concluded that there was insufficient evidence from the limited number of studies to determine whether long-term 03 exposures resulted in chronic health effects atambient levels observed in the U.S. However, the aggregate evidence suggested that 03 exposure, along with other environmental factors, couldbe responsible for health effects in exposed populations. Animal toxicological studies carried out inthe 1980's and 1990's demonstrated that long-term
exposures can result in a variety of morphological effects, including permanent changes in the small airways ofthe lungs, including remodeling of the distal airways and CAR and deposition ofcollagen, possibly representing fibrotic changes. These changes result from the damage and repair processes that occur with repeated exposure. Fibrotic changes

were also found to persist after months ofexposure providing a potential pathophysiologic basis for changes in airway function observed in children in

some recent epidemiological studies. It appears thatvariable seasonal ambient patterns ofexposure maybe ofgreater

concern than continuous daily
exposures. Several studies published since 1996 have investigated lung function changes

over seasonal time periods (EPA, 2006a, section 7.5.3). The 2006 Criteria Document (p. 7-114) summarizes these studies which collectively indicate that seasonal 03 exposure is associated with smaller growth-related increases in lung function in children than they would have experienced living in areas with lower 03levels. There is some limited evidence that seasonal 03 also may affect lung function growth in young adults, although the uncertainty about the role ofcopollutants makes it difficult to attribute the effects to 03 alone.

Lung capacity grows during childhood and adolescence asbody size increases, reaches a maximum during the twenties, and thenbegins to decline steadily and progressively with age. Long-term exposure to air pollution has long been thought to contribute to slower growth in lung capacity, diminished maximally attained capacity, and/or more rapid decline in lung capacity with age (EPA, 2006a, section 7.5.4). Toxicological findings evaluated in the 1996 Criteria Document demonstrated that repeated daily exposure ofrats to an episodic profile of 03 caused small, but significant, decrements in growth-related lung function thatwere consistent with early indicators offocal fibrogenesis in the proximal alveolar region, without overt fibrosis. Because 03 at sufficient concentrations is a strong respiratory irritant and hasbeen shown to cause inflammation and restructuring ofthe respiratory airways, itis plausible that long-term 03 exposures might have a negative impact on baseline lung function, particularly during childhood when these exposures mightbe associated with long-term risks.

Several epidemiological studies published since 1996 have examined the relationship between lung function development and long-term 03 exposure. The most extensive and robust study ofrespiratory effects in relation tolong-term air pollution
exposures among children in theU.S. is the Children's Health Study carried out in 12 communities of southern California starting in 1993. One analysis (Peters eta., 1999a) examined the relationship between long-term 03 exposures and self-reports ofrespiratory symptoms and asthma in a cross sectional analysis andfound a limited relationship between outcomes of
current asthma, bronchitis, cough and wheeze and a 0.040 ppm increase in 1- hour max 03 (EPA,2006a, p. 7-115). Another analysis (Peters eta]., 1999b) examined the relationship between lung function atbaseline and levels ofair pollution in the community. They reported evidence that annual mean 03 levels were associated with decreases in FVC, FEV1,PEF and forced expiratory flow (FEF25 -7) (the latter twobeing statistically significant) among females but not males. In a separate analysis (Gauderman eta]., 2000) of4th, 7th, and 

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10th grade students, a longitudinal analysis oflung function development

over four years found no association with 03 exposure. The Children's Health Study enrolled a second cohort ofmore than 1500 fourthgraders in 1996 (Gauderman eta]., 2002). While the strongest associations with negative lung function growth were observed with acidvapors in this cohort, children from communities with higher 4-year
average 03 levels also experienced smaller increases invarious lung function parameters. The strongest relationship with 03 was with PEF. Specifically, children from the leastpolluted community had a smallbut statistically significant increase inPEF

as compared tothose fromthe mostpolluted communities. In two-pollutant models, only 8-hour average 03 and NO2
were significant jointpredictors ofFEV1 andmaximal midexpiratory flow (MMEF). Although results from the second cohort ofchildren are supportive ofa weak association, the definitive 8-
year follow-up analysis ofthe first cohort (Gauderman eta]., 2004a) provides little evidence thatlong-term
exposure to ambient 03 at current levels is associated with significant deficits in the growth rate oflung function in children. Avol eta]. (2001) examined children who had moved away from participating communities in southern California to other states with improved air quality. They found that anegative, but not statistically significant, association was observed between 03 andlung function parameters. Collectively, theresults of these reports from the children's health cohorts provide little evidence to support an impact oflong-term 03 exposures on lung function development.

Evidence for a significant relationship between long-term 03 exposures and decrements in maximally attained lung function was reported in anationwide study offirst year Yale students (Kinney eta]., 1998; Galizia and Kinney, 1999) (EPA, 2006a, p. 7-120). Males had much larger effect estimates than females, which mightreflect higher outdoor activity levels and correspondingly higher 03 exposures during childhood. A similar study ofcollege freshmen at University ofCalifornia at Berkeley also reported significant effects oflong-term

03 exposures on lung function (Kiinzli
eta]., 1997; Tager eta]., 1998). In a comparison of students whose city of originwas either Los Angeles or San Francisco, long-term 03 exposures were associated with significant changes in mid- and end-expiratory flow measures, which couldbe considered early indicators for pathologic changes that might progress to COPD.

There havebeen a few studies that investigated associations between longterm 03 exposures andthe onset ofnew

cases ofasthma (EPA, 2006a, section 7.5.6). The Adventist Health and Smog (AHSMOG) study cohort ofabout 4,000

was drawn from nonsmoking, nonHispanic white adult Seventh Day Adventists living inCalifornia (Greer et a]., 1993; McDonnell eta]., 1999). During the ten-year follow-up in 1987,

a statistically significant increased relative risk ofasthma development was observed in males, compared to a nonsignificant relative risk in females (Greer eta]., 1993). In the 15-year follow-up in 1992, it was reported that for males, there was a statistically significant increased relative risk of developing asthma associated with8- hour average 03 exposures, but there

was no evidence ofan association in females. Consistency ofresults inthe
two studies with different follow-up times provides supportive evidence of the potential for an association between long-term 03 exposure and asthma incidence in adult males; however, representativeness ofthis cohort to the general U.S. population maybe limited (EPA, 2006a, p. 7-125).

In a similar study (McConnell etaL., 2002) ofincident asthma among children (ages 9 to 16 at enrollment), annual surveys of3,535 children initially without asthmawere used to identify new-onset asthma cases as part ofthe Children's Health Study. Six high-U3 and sixlow-U 3communities

were identified where the children resided. There were 265 children who reported new-onset asthma duringthe follow-up period. Although asthma risk

was no higher for all residents ofthe six high-U3communities versus the six low-U3communities, asthma risk was 3.3 times greater for children who played three or more sports as compared with children who played no sports within the high-U3communities. This association was absent in the communities with lower 03 concentrations. No other pollutants

were found to be associated with newonset asthma (EPA, 2006a, p. 7-125). Playing sports may result in extended outdoor activity and exposure occurring during periods when 03 levels are higher. Itshould be noted, however, that the results ofthe Children's Health Study were based on a small number of
new-onset asthma cases among children who played three or more sports. Future replication ofthese findings in other cohorts would help determine whether

a causal interpretation is appropriate. In animal toxicology studies, the progression ofmorphological effects reported during and after a chronic
exposure in the range of0.50 to 1.00
ppm 03 (wellabove current ambient levels) iscomplex, with inflammation peaking over the first few days of
exposure, then dropping, then plateauing, and finally, largely disappearing (EPA, 2006a, section 5.2.4.4). Bycontrast, fibrotic changes in the tissue increase very slowly over months ofexposure, and, after exposure ceases, the changes sometimes persist or increase. Epithelial hyperplasia peaks

soon after the inflammatory response but is usually maintained in both the

nose and lungs with continuous
exposure; italso does not returnto preexposure levels after the end of
exposure. Patterns ofexposure in this

same concentration range determine effects, with 18 months ofdaily exposure, causing less morphologic damage than exposures on alternating months. This is important as environmental 03 exposure is typically seasonal. Long-term studies byPlopper and colleagues (Evans eta]., 2003; Schelegle eta]., 2003; Chen eta]., 2003; Plopper and Fanucchi, 2000) investigated infant rhesus monkeys exposed to simulated, seasonal 03 and demonstrated: (1)Remodeling in the distal airways, (2)abnormalities in tracheal basement membrane; (3) eosinophil accumulation in conducting airways; and (4) decrements in airway innervation (EPA, 2006a, p. 5-45). These findings provide additional information regarding possible injuryrepair processes occurring with longterm 03 exposures suggesting thatthese
processes are only partially reversible and may progress following cessation of 03 exposure. Further, these processes may lead to nonreversible structural damage to lung tissue;however, there is still toomuch uncertainty to characterize the significance ofthese findings tohuman exposure profiles and effect levels (EPA, 2006a, p. 8-25).

In summary, in thepast decade, important new longitudinal studies have examined the effect ofchronic 03
exposure on respiratory health
outcomes. Limited evidence from recent long-term morbidity studies have suggested in some cases that chronic
exposure to 03 maybe associated with seasonal declines in lungfunction or reduced lung function development, increases in inflammation, and development ofasthma in children and adults. Seasonal decrements or smaller increases in lung function measures have been reported in several studies; however, the extent to which these 

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changes are transient remains uncertain. While there is supportive evidence from animal studies involving effects from chronic exposures, large uncertainties still remain as to whether current ambient levels and exposure patterns might cause these same effects in human populations. The 2006 Criteria Document concludes that epidemiological studies ofnew asthma development and longer-term lung function declines remain inconclusive
atpresent (EPA,2006a, p. 7-134).

iii. Effects on the Cardiovascular System of03 Exposure

At the time of the 1997review, the possibility of0 3-induced cardiovascular effects was largely unrecognized. Since then, avery limited body ofevidence from animal, controlled human
exposure, and epidemiologic studies has emerged thatprovides evidence for

some potential plausible mechanisms for how 03 exposures mightexert cardiovascular system effects, however further research is needed to substantiate these potential mechanisms. Possible mechanisms may involve 0 3-induced secretions of vasoconstrictive substances and/or effects on neuronal reflexes that may result in increased arterial blood
pressure and/or altered electrophysiologic control ofheart rate

or rhythm. Some animal toxicology studies have shown 03-induced decreases in heart rate, mean arterial
pressure, and core temperature. One controlled human exposure study that evaluated effects of03 exposure on cardiovascular health outcomes found

no significant 03-induceddifferences in ECG orblood pressure in healthy or hypertensive subjectsbut did observe a significant 03-inducedincrease the alveolar-to-arterial P0 2gradient and heart rate inboth groups resulting in an overall increase in myocardial work and impairment in pulmonary gas exchange (Gongeta]., 1998). In another controlled human exposure study, inhalation ofa mixture ofPM2.5 and 03 byhealthy subjects increasedbrachial artery vasoconstriction and reactivity (Brooket 

### a]., 2002).

The evidence from a few animal studies also includes potential direct effects such as 0 3-inducedrelease from lung epithelial cells ofplatelet activating factor (PAF)thatmay contribute to blood clotformation that would have the potential to increase the risk of serious cardiovascular outcomes (e.g.,heart attack, stroke, mortality). Also, interactions of03 with surfactant components in epithelial lining fluid of the lung may result inproduction of oxysterols and reactive oxygen species that may exhibit PAF-like activity contributing to clotting and also may exert cytotoxic effects on lung andheart muscle cells.

Epidemiological panel and field studies that examined associations between 03 and various cardiac physiologic endpoints haveyielded limited evidence suggestive ofa potential association between acute 03 exposure and altered heart rate variability (HRV), ventricular arrhythmias, and incidence ofheart attacks (myocardialinfarction or MI). A number ofepidemiological studies have also reported associations between short-term exposures and hospitalization for cardiovascular diseases. As shown in Figure 7-13 of the 2006 Criteria Document, many ofthe studies reported negative or inconsistent associations. Some other studies, especially those that examined the relationship when 03 exposures were higher, have found robustpositive associations between 03 and cardiovascular hospital admissions (EPA, 2006a, p. 7-82). For example, one study reported a positive association between 03 and cardiovascular hospital admissions in Toronto, Canada in a summer-only analysis (Burnett eta]., 1997b). The results were robustto adjustment forvarious PM indices, whereas the PM effects diminished when adjusted for gaseous pollutants. Other studies stratified their analysis by temperature (i.e.,bywarms days versus cool days). Several analyses using warm

season days consistently produced positive associations.

The epidemiologic evidence for cardiovascular morbidity ismuch weaker than for respiratory morbidity, with only one of several U.S. and Canadian studies showing statistically significant positive associations of cardiovascular hospitalizations with

warm-season 03 concentrations. Most of the available European and Australian studies, all ofwhich conducted all-year

03 analyses, did not find an association between short-term 03 concentrations and cardiovascular hospitalizations. Overall, the currently available evidence is inconclusive regarding an association between cardiovascular hospital admissions and ambient 03 exposure (EPA, 2006a, p. 7-83).

In summary, based onthe evidence from animal toxicology, controlled human exposure, and epidemiological studies, from the 2006 Criteria Document (p. 8-77) concludes thatthis generally limited body ofevidence is suggestive that 03 can directly and/or indirectly contribute to cardiovascularrelated morbidity, but that much needs
to be done tomore fully integrate links between ambient 03 exposures and adverse cardiovascular outcomes.
b. Mortality
i. Mortality and Short-term 03 Exposure

The 1996 Criteria Document concluded that an association between daily mortality and 03 concentration for

areas with high 03 levels (e.g., Los Angeles) was suggested. However, due
to avery limited number of studies available at thattime, there was insufficient evidence to conclude that the observed association was likely causal.

The 2006 Criteria Document included results from numerous epidemiological analyses ofthe relationship between 03 and mortality. Additional single city analyses have alsobeen conducted since 1996, however, the most pivotal studies in EPA's (andCASAC's) finding of increased support for the relationship between premature mortality and 03is in part related to differences in study design-limiting analyses to warm seasons, better control for copollutants, particularly PM, and use ofmulticity designs (bothtime series and metaanalytic designs). Key findings are available from multicity time-series studies that report associations between 03 andmortality. These studies include analyses using data from 90 U.S. cities in the National Mortality, Morbidity and Air Pollution (NMMAPS) study (Dominici etal., 2003) and from 95 U.S. communities in an extension tothe NMMAPS analyses (Belletal., 2004).

The original 90-city NMMAPS analysis, with data from 1987to 1994,

was primarily focused on investigating effects ofPM10 on mortality. A significant association was reported between mortality and 24-hour average 03 concentrations in analyses using all available data as well as in the warm

season only analyses (Dominici etal., 2003). The estimate using all available datawas about halfthatfor the summeronlydata at a lag of1-day. The extended NMMAPS analysis included data from 95 U.S. cities and included an additional 6 years ofdata, from 1987- 2000 (Bell etal., 2004). Significant associations were reported between 03 andmortality in analyses using all available data. The effect estimate for increased mortality was approximately 0.5 percent per 0.020 ppm change in 24- hour average 03 measured on the same day, and approximately 1.04 percent per 0.020 ppm change in 24-hour average 03 in a 7-day distributed lag model (EPA, 2006a, p. 7-88). In analyses using only data from the warm season, the results

were not significantly different from the full-year results. The authors also report 

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that 0 3-mortality associations were robust to adjustment for PM (EPA, 2006a, p. 7-100). Using a subset ofthe NMMAPS data set, Huang eta]. (2005) focused on associations between cardiopulmonary mortality and 03 exposure (24-hour average) during the

summer season only. The authors report

an approximate 1.47percent increase per 0.020 ppm change in 03 concentration measured on the same day and an approximate 2.52 percent increase per 0.020 ppm change in 03 concentration using a 7-day distributed lag model. These findings suggest that the effect of03 on mortality is immediate but also persists for several days.

As discussed below in section II.A.3.a, confounding by weather, especially temperature, is complicated by the fact thathigher temperatures are associated with the increased photochemical activities that are important for 03 formation. Using a

case-crossover study design, Schwartz (2005) assessed associations between daily maximum concentrations and mortality, matching case and control periods by temperature, and using data onlyfrom the warm season. The reported effect estimate of approximately 0.92 percent change in mortality per 0.040 ppm 03 (1-hour maximum) was similar totime-series analysis results with adjustment for temperature (approximately 0.76 percent per 0.040 ppm 03), suggesting that associations between 03 and mortality were robust tothe different adjustment methods for temperature.

An initial publication fromAPHEA, a European multicity study, reported statistically significant associations between daily maximum 03 concentrations and mortality in four cities in a fullyear analysis (Toulomi et a]., 1997). An extended analysis was done using data from 23 cities throughout Europe (Gryparis eta]., 2004). In this report, a positive but not statistically significant association was found between mortality and 1-hour daily maximum 03 in a full year analysis. Gryparis eta]. (2004) noted that there was a considerable seasonal difference in the 0 3 effect on mortality; thus, the small effectfor the all-year datamightbe attributable to inadequate adjustment for confounding by seasonality. Focusing on analyses using

summer measurements, the authors report statistically significant associations with total mortality, cardiovascular mortality and respiratory mortality (EPA, 2006a, p. 7-93, 7-99).

Numerous single-city analyses have alsoreported associations between mortality and short-term 03 exposure, especially for those analyses using

warm season data. As shown in Figure 7-21 ofthe 2006 Criteria Document, the results ofrecent publications show a pattern ofpositive, often statistically significant associations between shortterm 03 exposure and mortality during the warm season. In considering results from year-round analyses, there remains

a pattern ofpositive results but the findings are less consistent. Inmost single-city analyses, effect estimates

were not substantially changed with adjustment for PM (EPA, 2006a, Figure 7-22).

In addition, several meta-analyses have been conducted on the relationship between 03 andmortality. As described in section 7.4.4 ofthe 2006 Criteria Document, these analyses reported fairly consistent and positive combined effect estimates ranging from approximately 1.5 to 2.5 percent increase in mortality for a standardized change in 03 (EPA, 2006a, Figure 7-20). Three recent meta-analyses evaluated potential sources ofheterogeneity in 03- mortality associations (Belleta]., 2005; Ito eta]., 2005; Levy eta]., 2005). The 2006 Criteria Document (p. 7-96) observes common findings across all three analyses, in that all reported that effect estimates were largerin warm

season analyses, reanalysis ofresults using default convergence criteria in generalized additive models (GAM) did
not change the effect estimates, and there was no strong evidence of confounding by PM. Bell eta]. (2005) and Ito eta]. (2005) both provided suggestive evidence ofpublication bias, but 0 3-mortality associations remained after accounting for that potential bias. The 2006 Criteria Document concludes that the "positive 03 effects estimates, along with the sensitivity analyses in these three meta-analyses, provide evidence ofa robust association between ambient 03 and mortality" (EPA, 2006a, p. 7-97).

Most ofthe single-pollutant model estimates from single-city studies range from 0.5 to 5percent excess deaths per standardized increments. Corresponding summary estimates in large U.S. multicity studies ranged between 0.5 to 1percent with some studies noting heterogeneity across cities and studies (EPA, 2006a, p. 7-110).

Finally, from those studies that included assessment ofassociations with specific causes ofdeath, it appears that effect estimates for associations with cardiovascular mortality are larger than those for total mortality. The metaanalysis by Bell eta]. (2005) observed a slightly larger effect estimate for cardiovascular mortality compared to mortality from all causes. The effect estimate for respiratory mortality was approximately one-halfthat of cardiovascular mortality in the metaanalysis. However, other studieshave observed larger effect estimates for respiratory mortality compared to cardiovascular mortality. The apparent inconsistency regarding the effect size of 03-related respiratory mortality maybe due to reduced statistical power in this subcategory ofmortality (EPA, 2006a, p. 7-108).

In summary, many single- and multicity studies observed positive associations ofambient 03 concentrations with total nonaccidental and cardiopulmonary mortality. The 2006 CriteriaDocument finds thatthe results from U.S. multicity time-series studies provide the strongest evidence
to date for 03 effects on acute mortality. Recent meta-analyses also indicate positive risk estimates that are unlikely
tobe confounded by PM; however, future workis needed tobetter understand the influence ofmodel specifications on therisk coefficient (EPA, 2006a, p. 7-175). A meta-analysis that examined specific causes of mortality found thatthe cardiovascular mortality risk estimates were higher than those for total mortality.For cardiovascular mortality, the 2006 Criteria Document (Figure 7-25, p. 7- 106) suggests that effect estimates are consistently positive and more likely to be larger and statistically significant in

warm season analyses. The findings regarding the effect size for respiratory mortality have been less consistent, possibly because oflower statistical power in this subcategory ofmortality. The 2006 Criteria Document (p. 8-78) concludes thatthese findings are highly suggestive that short-term 03 exposure directly or indirectly contribute to nonaccidental and cardiopulmonary-related mortality, but additional research is needed to more fully establish underlying mechanisms by which such effects occur. 2'

21In commenting on the Criteria Document, the
CASAC Ozone Panel raised questions about the implications ofthesetime-series results in a policy context, emphasizing that * *while the timeseries studydesign is a powerful tool to detect very small effects that could notbe detected using other designs, it is also ablunt tool" (Henderson, 2006b). They notethat * *not only is the interpretation ofthese associations complicated by the fact that the day-to-dayvariation in concentrations ofthese pollutants is, to a varying degree, determined by meteorology, the pollutants are often part ofa large and highly correlated mix ofpollutants, only a very few ofwhich are measured" (Henderson, 2006b). Even with theseuncertainties, the CASAC Ozone Panel, in itsreview ofthe Staff Paper, found "* * * premature total non-accidental and cardiorespiratory mortality for inclusion in the quantitative risk assessment to be appropriate." (Henderson, 2006b) 

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ii. Mortality and Long-Term 03 Exposure

Little evidence was available in the 1997 review on the potential for associations between mortality and long-term exposure to 03. In the Harvard Six City prospective cohort analysis, the authors report that mortality was not associated with longterm exposure to 03 (Dockery eta., 1993). The authors note thatthe range of03 concentrations across the six cities

was small, which mayhave limited the
power ofthe study to detect associations between mortality and 03 levels (EPA, 2006a, p. 7-127).

As discussed in section 7.5.8 ofthe 2006 CriteriaDocument, in this review there are results available from three prospective cohort studies: the American Cancer Society (ACS)study (Pope eta]., 2002), the Adventist Health and Smog (AHSMOG) study (Beesonet a]., 1998; Abbey eta]., 1999), and the U.S. Veterans Cohort study (Lipfert et a]., 2000, 2003). In addition, amajor reanalysis report includes evaluation of datafrom the Harvard Six Citycohort study (Krewski eta]., 2000).22 This reanalysis also includes additional evaluation ofdata from the initial ACS cohort study report that had only reported results ofassociations between mortality and long-term exposure to fine particles and sulfates (Popeeta]., 1995). This reanalysis was discussed inthe 2007 StaffPaper (section3.3.2.2) but not in the 2006 Criteria Document.

In this reanalysis of datafrom the previous Harvard Six Cityprospective cohort study, the investigators replicated andvalidated the findings of the original studies, and the report included additional quantitative results beyond those available in the original report (Krewski eta]., 2000). In the reanalysis ofdata from the Harvard Six Cities study,the effect estimate for the association between long-term 03 concentrations and mortality was negative and nearly statistically significant (relative risk = 0.87, 95 percent CI: 0.76, 1.00).

The ACS study isbased on health data from a large prospective cohort of approximately 500,000 adults and air quality data from about 150 U.S. cities. The initial report (Pope eta]., 1995) focused on associations with fine particles and sulfates, forwhich significant associations hadbeen reported in the earlier Harvard Six Cities study (Dockery eta]., 1993). As part ofthe major reanalysis ofthese

22This reanalysis report and the original prospective cohort study findings are discussed in

more detail in section 8.2.3 oftheAirQuality Criteria forParticulate Matter(EPA, 2004). data, results for associations with other air pollutants were also reported, and the authors report thatno significant associations were found between 03 and all-cause mortality. However, a significant association was reported for cardiopulmonary mortality in the warm

season (Krewski eta]., 2000). The ACS II study (Pope eta]., 2002) reported results ofassociations with an extended data base; the mortality records for the cohort had been updated to include 16
years offollow-up (compared with 8
years in the first report)and more recent air quality data were included in the analyses. Similar to the earlier reanalysis, a marginally significant association was observed between longterm exposure to 03 and cardiopulmonary mortality in the warm

season. No other associations with mortality were observed inboth the fullyear and warm season analyses.

The Adventist Health and Smog (AHSMOG)cohort includes about 6,000 adults living in California. Intwo studies from this cohort, a significant association hasbeen reported between long-term 03 exposure and increased risk oflung cancer mortality among males only (Beeson eta]., 1998; Abbey

eta]., 1999). No significant associations

were reported between long-term 03
exposure andmortality from all causes

or cardiopulmonary causes. Due to the small numbers oflung cancer deaths (12 for males, 18 for females) and the precision ofthe effect estimate (i.e.,the wide confidence intervals), the 2006 Criteria Document (p. 7-130) discussed

concerns about the plausibility ofthe reported association with lung cancer.

The U.S. Veterans Cohort study (Lipferteta]., 2000, 2003) of approximately 50,000 middle-aged males diagnosed with hypertension, reported some positive associations between mortality and peak 03 exposures (95thpercentile level for several years ofdata). The study included numerous analyses using subsets ofexposure and mortality follow-up periods which spanned the
years 1960 to 1996. In the results of analyses using deaths and 03 exposure estimates concurrently across the study period, there were positive, statistically significant associations between peak 03 and mortality (EPA, 2006a, p. 7-129).

Overall, the 2006 CriteriaDocument (p. 7-130) concludes that consistent associations have notbeen reported between long-term 03 exposure and allcause, cardiopulmonary or lung cancer mortality. c. Role ofGround-Level 03 in Solar Radiation-Related Human Health Effects

Beyond the direct health effects attributable to inhalation exposure to 03 in the ambient air discussed above, the 2006 CriteriaDocument also assesses potential indirect effects related tothe
presence of03 in the ambient airby considering the role ofground-level 03 in mediating human health effects that may be directly attributable to exposure to solar ultraviolet radiation (UV-B). The 2006 Criteria Document (chapter 10) focuses this assessment on three key factors, including those factors that govern (1)UV-B radiation flux at the earth's surface, (2)human exposure to UV-B radiation, and (3)human health effects due to UV-B radiation. In so doing, the 2006 CriteriaDocument provides a thorough analysis ofthe
current understanding ofthe relationship between reducing groundlevel 03 concentrations and the potential impact these reductions might have on increasing UV-B surface fluxes and indirectly contributing to UV-B related health effects.

There are many factors thatinfluence UV-B radiation penetration to the earth's surface, including latitude, altitude, cloud cover, surface albedo, PM concentration and composition, and
gas phase pollution. Ofthese, only latitude and altitude can be defined with small uncertainty in any effort to

assess the changes in UV-B fluxthat may be attributable to any changes in tropospheric 03 as a result ofany revision to the 03 NAAQS. Such an assessment ofUV-B related health effects would also need to take into
account human habits, such as outdoor activities (including age- and occupation-related exposure patterns), dress and skin care to adequately estimate UV-B exposure levels. However, little is known about the impact ofthese factors on individual
exposure to UV-B.

Moreover, detailed information does
not exist regarding other factors that are relevant to assessing changes in disease incidence, including: Type (e.g.,peak or cumulative) and time period (e.g., childhood, lifetime, current) of
exposures related to various adverse health outcomes (e.g., damage to the skin, including skin cancer; damage to the eye, such as cataracts; andimmune system suppression); wavelength dependency ofbiological responses; and interindividual variability in UV-B resistance to such health outcomes. Beyond these well recognized adverse health effects associated with various wavelengths ofUV radiation, the 2006 Criteria Document (section 10.2.3.6) also 

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discusses protective effects ofUV-B radiation. Recent reports indicate the necessity ofUV-B in producing vitamin D. Vitamin D deficiency can cause metabolic bone disease among children and adults, and may alsoincrease the risk ofmany common chronic diseases (e.g., type Idiabetes and rheumatoid arthritis) as well as the risk ofvarious types ofcancers. Thus, the 2006 Criteria Document concludes that any assessment that attempts to quantify the
consequences ofincreased UV-B
exposure on humans due to reduced ground-level 03 must include consideration ofboth negative and positive effects. However, as with other impacts ofUV-B on human health, this beneficial effect ofUV-B radiation has
not been studied in sufficient detail to allow for a credible health benefits or risk assessment. In conclusion, the effect ofchanges in surface-level 03 concentrations on UV-B-induced health
outcomes cannot yetbe critically assessed within reasonable uncertainty (2006 Criteria Document, p. 10-36).

The Agency last considered indirect effects of03 inthe ambient air inits 2003 finalresponse to aremand ofthe Agency's 1997 decision to revise the 03 NAAQS. In so doing, based on the available information in the 1997 review, EPA determined thatthe information linking (a) changes in patterns ofground-level 03 concentrations likely to occur as aresult ofprograms implemented to attain the 1997 03 NAAQS to (b)changes in relevant exposures to UV-B radiation of

concern topublic health was too uncertain at that time to warrant any relaxation in the level ofpublichealth protection previously determined to be requisite to protect against the demonstrated direct adverse respiratory effects ofexposure to03 in the ambient air (68 FR 614). At thattime, the more recent information on protective effects ofUV-B radiation was not available, suchthat only adverse UV-B-related effects could be considered. Taking into consideration the more recent information available for the 2008 review, the 2006 Criteria Document and 2007 StaffPaper conclude thatthe effect ofchanges in ground-level 03 concentrations, likely to occur as a result ofrevising the 03NAAQS, on UV-B-induced health outcomes, including whether these changes would ultimately result in increased or decreased incidence ofUV-B-related diseases, cannot yet be critically assessed. 3.Interpretation and Integration of Health Evidence

As discussed below, in assessing the health evidence, the 2006Criteria Document integrates findings from experimental (e.g., toxicological, dosimetric and controlled human exposure) and epidemiological studies,
to makejudgments about the extent to which causal inferences can be made about observed associations between health endpoints and exposure to 03. In evaluating the evidence from epidemiological studies, the EPA focuses on well-recognized criteria, including: The strength ofreported associations, including the magnitude and precision ofreported effect estimates andtheir statistical significance; the robustness ofreported associations, or stability in the effect estimates after considering factors such

as alternative models and model specification, potential confounding by co-pollutants, and issues related to the
consequences ofexposure measurement
error; potential aggregation bias in pooling data; and the consistency ofthe effects associations as observed by looking across results ofmultiple- and single-city studies conducted by different investigators in different places and times. Consideration is also given to evaluating concentration-response relationships observed in epidemiological studies to inform judgments about the potential for threshold levels for 0 3-related effects. Integrating more broadly across epidemiological and experimental evidence, the 2006 Criteria Document also focuses on the coherence and plausibility ofobserved 0 3-related health effects toreachjudgments about the extent to which causal inferences

can be made about observed associations between health endpoints and exposure to 03 in the ambient air.

a. Assessment ofEvidence From Epidemiological Studies

Key elements ofthe evaluation of epidemiological studies are briefly summarized below.

(1)The strength ofassociations most directly refers to the magnitude ofthe reported relative risk estimates. Taking

a broader view, the 2006 Criteria Document draws upon the criteria summarized in a recent report from the U.S. Surgeon General, which define strength ofan association as "the magnitude ofthe association and its statistical strength" which includes
assessment ofboth effect estimate size and precision, which is related to the statistical power ofthe study (CDC, 2004). In general, when associations are strong in terms ofyielding large relative risk estimates, itis less likelythat the association could be completely accounted for by a potential confounder

or some other source ofbias, whereas with associations thatyield small relative risk estimates itis especially important to consider potential confounding and other factors in assessing causality. Effect estimates between 03 and some ofthe health
outcomes are generally small in size and could thus be characterized as weak.For example, effect estimates for associations with mortality generally range from 0.5 to 5percent increases per 0.040 ppm increase in 1-hour maximum 03 orequivalent, whereas associations for hospitalization range up to 50 percent increases per standardized 03 increment. However, the 2006 Criteria Document notes thatthere are large multicity studies thatfind small associations between short-term 03 exposure and mortality or morbidity andhave done so with great precision due to the statistical power ofthe studies (p. 8-40). Thatis, the power of the studies allows the authors toreliably distinguish even weak relationships from the nullhypothesis with statistical confidence.

(2)In evaluating the robustness of associations, the 2006 Criteria Document (sections 7.1.3 and 8.4.4.3) and 2007 StaffPaper (section 3.4.2) have primarily considered the impact of
exposure error, potential confounding by copollutants, and alternative models andmodel specifications.

In time-series and panel studies, the temporal (e.g., daily or hourly) changes in ambient 03 concentrations measured
at centrally-located ambient monitoring stations are generally used to represent

a community's exposure to ambient 03. In prospective cohort or cross-sectional studies, air quality data averaged over a period ofmonths toyears are used as indicators ofa community's long-term exposure to ambient 03 and other pollutants. In both types ofanalyses, exposure error is an important consideration, as actual exposures to individuals in the population will vary
across the community.

Ozone concentrations measured at central ambient monitoring sitesmay explain, at least partially, the variance in individual exposures to ambient 03; however, this relationship is influenced byvarious factors related to building ventilation practices and personal behaviors. Further, the pattern of
exposure misclassification error and the influence ofconfounders may differ

across the outcomes ofinterest as well

as in susceptible populations. As discussed in the 2006 Criteria Document 

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(section 3.9), only a limited number of studies have examined the relationship between ambient 03 concentrations and personal exposures to ambient 03. One ofthe strongest predictors ofthe relationship between ambient concentrations and personal exposures appears tobe time spent outdoors. The strongest relationships were observed in outdoor workers (Brauer and Brook, 1995, 1997; O'Neill et

### a.,2004). Statistically significant correlations between ambient concentrations and personal exposures were also observed for children, who likely spend more time outdoors in the warm season (Linn
eta]., 1996; Xu eta]., 2005). There is

some concern about the extent towhich ambient concentrations are representative ofpersonal 03 exposures ofanother particularly susceptible group ofindividuals, the debilitated elderly, since those who suffer from chronic cardiovascular or respiratory conditions may tend to protect themselves more than healthy individuals from environmental threats by reducing their exposure to both 03 andits confounders, such as high temperature and PM. Studies by Sarnat
eta]. (2001, 2005) that included this susceptible group reported mixed results for associations between ambient 03 concentrations and personal
exposures to 03.Collectively, these studies observed thatthe daily averaged personal 03exposures tend tobe well correlated with ambient 03 concentrations despite the substantial variability that existed among the personal measurements. These studies provide supportive evidence that ambient 03 concentrations from central monitors may serve asvalid surrogate

measures for mean personal exposures experienced by the population, which is ofmostrelevance for time-series studies. Abetter understanding ofthe relationship between ambient concentrations and personal exposures,

as well as ofthe other factors that affect relationship will improve the interpretation ofconcentrationpopulation health response associations observed.

The 2006 Criteria Document (section 7.1.3.1) also discusses the potential influence ofexposure error on epidemiologic study results. Zeger eta]. (2000) outlined the components to exposure measurement error, finding that ambient exposure canbe assumed
tobe the product ofthe ambient concentration and an attenuation factor (i.e.,building filter) andthat panel studies andtime-series studies that use ambient concentrations instead of personal exposure measurements will estimate a health risk that is attenuated by thatfactor. Navidi eta]. (1999) used data from a children's cohort study to compare effect estimates from a simulated "true"exposure level to results ofanalyses from 03 exposures determined by several methods, finding that 03 exposures based onthe use of ambient monitoring data overestimate the individual's 03 exposure and thus generally result in 03 effect estimates that are biased downward (EPA, 2006a,
p. 7-8). Similarly, in a reanalysis ofa study by Burnett eta]. (1994) on the
acute respiratory effects ofambient air pollution, Zidek eta]. (1998) reported that accounting for measurement error,

as well as making a few additional changes to the analysis, resulted in qualitatively similar conclusions, but the effects estimates were considerably larger in magnitude (EPA, 2006a, p. 7- 8). A simulation study by Sheppard et a]. (2005) also considered attenuation of the riskbased onpersonal behavior, their microenvironment, and the qualities ofthe pollutant intime-series studies. Ofparticular interest is their finding thatrisk estimates were not further attenuated in time-series studies

even when the correlations between personal exposures and ambient concentrations were weak. In addition
to overestimation ofexposure and the resulting underestimation ofeffects, the

use ofambient 03 concentrations may obscure the presence ofthresholds in epidemiologic studies (EPA, 2006a, p. 7-9).

As discussed in the 2006Criteria Document (section 3.9), using ambient concentrations to determine exposure generally overestimates true personal 03 exposures by approximately 2-to 4-fold in available studies, resulting in attenuated risk estimates. The implication isthatthe effects being estimated occur at fairly low exposures and the potency of03 is greater than these effects estimates indicate. As very few studies evaluating 03 health effects with personal 03 exposure measurements exist in the literature, effect estimates determined from ambient 03 concentrations mustbe evaluated and used with caution to

assess thehealth risks of03. Inthe absence ofavailable data on personal 03
exposure, the use ofroutinely monitored ambient 03 concentrations as

a surrogate for personal exposures isnot generally expected to change the principal conclusions from 03 epidemiologic studies. Therefore, population health risk estimates derived using ambient 03 levels from currently available observational studies, with appropriate caveats about personal exposure considerations, remain useful. The 2006 Criteria Document recommends caution in the quantitative

use ofeffect estimates calculated using ambient 03 concentrations asthey may lead to underestimation ofthe potency of 03. However, the 2007 Staff Paper observes that the use ofthese risk estimates for comparing relative risk reductions between alternative ambient

03 standards considered in the risk
assessment (discussedbelow in section II.B.2) is less likely to sufferfrom this

concern.

Confounding occurs when a health effect that iscaused by one risk factor is attributed to another variable thatis correlated with the causal risk factor; epidemiological analyses attempt to adjust or control for potential confounders. Copollutants (e.g., PM, CO, SO 2 and NO2) canmeet the criteria for potential confounding in 0 3-health associations ifthey are potential risk factors for the health effect under study and are correlated with 03. Effect modifiers include variables thatmay influence thehealth response to the pollutant exposure (e.g., co-pollutants, individual susceptibility, smoking or age). Both are important considerations for evaluating effects in amixture of pollutants, but for confounding, the emphasis ison controlling or adjusting for potential confounders in estimating the effects ofone pollutant, whilethe emphasis for effect modification is on identifying and assessing the effects for different modifiers.

The 2006 Criteria Document (p. 7-148) observes that 03 is generally not highly correlated with other criteria pollutants (e.g., PM1o,CO, SO2 and NO2), but maybe more highly correlated with secondary fine particles, especially during the summer months, andthat the degree ofcorrelation between 03 and other pollutants mayvary across

seasons. Forexample, positive associations are observed between 03 andpollutants such as fine particles during the warmer months,but negative correlations maybe observed during the coolermonths (EPA, 2006a, p. 7-17). Thus, the 2006 Criteria Document (section 7.6.4) paysparticular attention
to the results of season-specific analyses and studies that assess effects ofPM in potential confounding of0 3-health relationships. The 2006 Criteria Document also discussed the limitations ofcommonly used multipollutant models thatinclude the difficulty in interpreting results where the copollutants are highly colinear, or where correlations between pollutants change by season (EPA,2006a, p. 7-150). This is particularly the situation where 03 and a copollutant, such as 

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sulfates, are formed under the same atmospheric condition; in such cases multipollutant models would produce unstable and possibly misleading results (EPA, 2006a, p. 7-152).

For mortality, the results from

numerous multicity and single-city studies indicate that 03-mortality associations do not appear tobe substantially changed in multipollutant models including PM1

### oor PM2.5 (EPA, 2006a, p. 7-101; Figure 7-22). Focusing

on results ofwarm season analyses, effect estimates for 0 3-mortality associations are fairlyrobust to adjustment for PM in multipollutant models (EPA, 2006a, p. 7-102; Figure 7-23). The 2006 Criteria Document concludes thatin the few multipollutant analyses conducted for these endpoints, copollutants generally do not confound the relationship between 03 and respiratory hospitalization (EPA, 2006a, p. 7-79 to 7-80; Figure 7-12). Multipollutant models were not used as commonly in studies ofrelationships between respiratory symptoms or lung function with 03, but the 2006 Criteria Document reports thatresults of available analyses indicate that such associations generally were robustto adjustment for PM2.5 (p. 7-154). For example, in a large multicity study of asthmatic children (Mortimer etal., 2002), the 03 effectwas attenuated, but there was still a positive association; in Gent eta]. (2003), effects of03,but not PM2.5,remained statistically significant and even increased in magnitude in two-pollutant models (EPA, 2006a, p. 7-53). Considering thisbody ofstudies, the 2006 Criteria Document (p. 7-154) concludes: "Multipollultant regression analyses indicatedthat 03 risk estimates, in general, were not sensitive
to the inclusion ofcopollutants, including PM2.5 and sulfate. These results suggest thatthe effects of03 on respiratory health outcomes appear to be robust and independent ofthe effects ofother copollutants."

The 2006 Criteria Document (p. 7-14) observes that another challenge oftimeseries epidemiological analysis is assessing the relationship between 03 andhealth outcomes while avoiding bias due to confounding by other timevarying factors, particularly seasonal trends and weather variables. These variables are ofparticular interest because 03 concentrations have a wellcharacterized seasonal pattern and are also highly correlated with changes in temperature, such that itcan be difficult
to distinguish whether effects are associated with 03 or with seasonal or weather variables in statistical analyses.

The 2006 Criteria Document (section 7.1.3.4) discusses statistical modeling approaches thathave been used to adjust for time-varying factors, highlighting aseries ofanalyses that

were done in a Health EffectsInstitutefunded reanalysis ofnumerous timeseries studies. While the focus ofthese reanalyses was on associations with PM,

a number ofinvestigators also examined the sensitivity of03 coefficients to the
extent ofadjustment for temporal trends and weather factors. In addition, several
recent studies, including U.S. multicity studies (Belletal., 2005; Huang etal., 2005; Schwartz etal., 2005) and a metaanalysis study (Ito etal., 2005), evaluated the effect ofmodel specification on 0 3-mortality associations. As discussed in the 2006 Criteria Document (section 7.6.3.1), these studies generally report that associations reported with 03 are not substantially changed with alternative modeling strategies for adjusting for temporal trends and meteorologic effects. In the meta-analysis by Ito eta]. (2005), a separate multicity analysis was presented that found that alternative adjustments for weather resulted in up to 2-fold difference in the 03 effect estimate. Significant confounding can

occur when strong seasonal cycles are present, suggesting that season-specific results are more generally robust than year-round results in such cases. A number ofepidemiological studies have conducted season-specific analyses, and have generally reported stronger and

more precise effect estimates for 03 associations in the warm season than in analyses conducted in the cool seasons

or over the full year. (3)Consistency refers tothe persistent finding ofan association between
exposure and outcome in multiple studies ofadequate power in different
persons, places, circumstances and times (CDC, 2004). In considering results from multicity studies and single-city studies in different areas, the 2006 Criteria Document (p. 8-41) observes general consistency in effects of short-term 03 exposure on mortality, respiratory hospitalization and other respiratory health outcomes. The variations in effects that are observed
may be attributable to differences in relative personal exposure to03, as well

as varying concentrations and composition ofcopollutants presentin different regions. Thus, the 2006 Criteria Document (p. 8-41) concludes that "consideration ofconsistency or heterogeneity ofeffects is appropriately understood as an evaluation ofthe similarity or general concordance of results, rather than an expectation of finding quantitative results with a very

narrow range." (4) The 2007 StaffPaper recognizes that itis likely thatthere are biological thresholds for different health effects in individuals orgroups ofindividuals with similar innate characteristics and health status. For 03 exposure, individual thresholds would presumably vary substantially from
person toperson due to individual differences in genetic susceptibility, pre-existing disease conditions and possibly individual risk factors such as diet or exercise levels (andcould even vary from one time to anotherfor a given person). Thus, it wouldbe difficult to detect a distinct threshold at the population level below which no individual would experience agiven effect, especially ifsome members of a population are unusually sensitive even down to very low concentrations (EPA, 2004, p. 9-43, 9-44).

Some studies have tested associations between 03 andhealth outcomes after removal ofdays with higher 03levels from the data set; such analyses do not necessarily indicate thepresence or absence ofa threshold, butprovide

some information on whether the relationship is found using only lowerconcentration data. For example, using datafrom 95 U.S. cities, Bell eta]. (2004) found thatthe effect estimate for

an association between short-term 03
exposure and mortality was little changed when days exceeding 0.060 ppm (24-hour average) were excluded in the analysis. Using datafrom 8 U.S. cities, Mortimer and colleagues (2002) alsoreported that associations between 03 andboth lung function and respiratory symptoms remained statistically significant and ofthe same
or greater magnitude in effect size when concentrations greater than 0.080 ppm (8-houraverage) were excluded (EPA, 2006a, p. 7-46). Several single-city studies alsoreport similar findings of associations thatremain or are increased in magnitude and statistical significance when data at theupper end ofthe concentration range are removed (EPA, 2006a, section 7.6.5).

Other time-series epidemiological studies have used statistical modeling approaches to evaluate whether thresholds exist in associations between short-term 03 exposure and mortality. As discussed in section 7.6.5 ofthe 2006 Criteria Document, one European multicity study included evaluation of the shape ofthe concentration-response
curve, and observed no deviation from

a linear function across the range of03
measurements from the study (Gryparis

eta]., 2004; EPA, 2006ap. 7-154). Several single-city studies also observed

a monotonic increase in associations between 03 andmorbidity that suggest 

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that no population threshold exists (EPA, 2006a, p. 7-159).

On the other hand, a study in Korea used several different modeling approaches and reported that a threshold model provided thebest fitfor the data. The results suggested a potential threshold level ofabout 0.045 ppm (1-hour maximum concentration;

<0.035 ppm, 8-hour average) for an associationbetween mortality and shortterm 03 exposure during the summer months (Kim etal., 2004; EPA, 2006a, p. 8-43). The authors reported larger effect estimates for the association for data above the potential threshold level, suggesting that an 0 3-mortality association mightbe underestimated in the non-threshold model. Athreshold analysis recently reported by Bell eta]. (2006) for 98 U.S. communities, including the same 95 communities in Bell eta]. (2004), indicated that ifa population threshold existed for mortality, it would likelyfall below a 24-hour average 03 concentration of 0.015 ppm (< 0.025 ppm, 8-hour average). In addition, Burnett and colleagues (1997a,b) plotted the relationships between air pollutant concentrations andboth respiratory and cardiovascular hospitalization, and it appears in these results that the associations with 03 are found in the concentration range above about 0.030 ppm (1-hour maximum; < 0.025 ppm, 8- hour average). Vedal and colleagues (2003) reported a significant association between 03 andmortality in British Columbia where 03 concentrations were quite low (mean 1-hour maximum concentration of0.0273 ppm). The authors did not specifically test for threshold levels, but the factthatthe association was found in an area with such low 03 concentrations suggests that any potential threshold level would be quite low in this data set.

In summary, the 2006 Criteria Document finds that, taken together, the available evidence from controlled human exposure and epidemiological studies suggests thatno clear conclusion

cannowbe reached withregard to possible threshold levels for 0 3-related effects (EPA, 2006a, p. 8-44). Thus, the available epidemiological evidence neither supports norrefutes the existence ofthresholds at the population level for effects such as increased hospital admissions and premature mortality. There are limitations in epidemiological studies that make discerning thresholds in populations difficult, including low data density in the lower concentration ranges, the possible influence of exposure measurement error, and interindividual differences in susceptibility to0 3-related effects in populations. There is the possibility that thresholds for individuals may exist in reported associations at fairly low levels within the range ofair quality observed in the studies but notbe detectable as population thresholds in epidemiological analyses.

b. Biological Plausibility and Coherence ofEvidence

The body ofepidemiological studies discussed in the 2007 Staff Paper emphasizes therole of03 in association with avariety ofadverse respiratory and cardiovascular effects. While recognizing avariety ofplausible mechanisms, there exists a general

consensus suggesting that 03, could either directly or through initiation, interfere withbasic cellular oxidation
processes responsible for inflammation, reduced antioxidant capacity, atherosclerosis and other effects. Reasoning that 03 influences cellular chemistry throughbasic oxidative properties (as opposed to a unique chemical interaction), other reactive oxidizing species (ROS)in the atmosphere acting either independently

or in combination with 03 may also contribute to a number ofadverse respiratory and cardiovascular health effects. Consequently, the role of03 should be considered more broadly as 03 behaves as agenerator ofnumerous oxidative species in the atmosphere.

In considering thebiological plausibility ofreported 0 3-related effects, the 2007 StaffPaper (section 3.4.6) considers thisbroader question of health effects ofpollutant mixtures containing 03. The potential for 03- related enhancements ofPM formation, particle uptake, and exacerbation ofPMinduced cardiovascular effects underscores the importance of considering contributions of03 interactions with other often cooccurring air pollutants to health effects due to 0 3-containing pollutant mixes. The 2007 StaffPaper summarizes some examples ofimportant pollutant mixture effects from studies that evaluate interactions of03 with other co-occurring pollutants, as discussed in chapters 4, 5,and 6 ofthe 2006 Criteria Document.

All ofthe types ofinteractive effects of03 with other co-occurring gaseous and nongaseous viable and nonviable PM components ofambient air mixes noted above argue that03 acts not only alone but that 03 alsois a surrogate indicator for air pollution mixes which may enhance the risk ofadverse effects due to 03 acting in combination with other pollutants. Viewed from this perspective, those epidemiologic findings ofmorbidity and mortality associations, with ambient 03 concentrations extending to quite low levels in many cases, become more understandable and plausible.

The 2006 Criteria Document integrates epidemiological studies with mechanistic information from controlled human exposure studies and animal toxicological studies to draw conclusions regarding the coherence of evidence andbiological plausibility of 03-related health effects to reach judgments about the causal nature of observed associations. As summarized below, coherence andbiological plausibility is discussed for each ofthe following types of0 3-related effects: Short-term effects on the respiratory system, effects on the cardiovascular system, effects relatedto long-term 03 exposure, and short-term mortalityrelated health endpoints.

i. Coherence and Plausibility of ShortTerm Effects on the Respiratory System

Acute respiratory morbidity effects that havebeen associated with shortterm exposure to03 include such health endpoints as decrements in lung function, increased respiratory symptoms, increased airway responsiveness, airway inflammation, increased permeability related to epithelial injury, immune system effects, emergency department visits for respiratory diseases, and hospitalization due to respiratory illness.

Recent epidemiological studies have supported evidence available in the previous 03 NAAQS review on associations between ambient 03
exposure and decline in lung function for children. The 2006 Criteria Document (p. 8-34) concludes that
exposure to ambient 03has a significant effect on lung function and is associated with increased respiratory symptoms and medication use, particularly in asthmatics. Short-term exposure to 03 has alsobeen associated with more

severe morbidity endpoints, such as emergency department visits and hospital admissions for respiratory
cases, including specific respiratory illness (e.g., asthma) (EPA, 2006a, sections 7.3.2 and 7.3.3). In addition, a few epidemiological studies have reported positive associations between short-term 03 exposure and respiratory mortality, though the associations are not generally statistically significant (EPA, 2006a, p. 7-108).

Considering the evidence from epidemiological studies, theresults described above provide evidence for coherence in 0 3-related effects on the respiratory system. Effect estimates from U.S. and Canadian studies are shown in 

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Figure 1,where it canbe seenthat mostly positive associations havebeen reported with respiratory effects ranging from respiratory symptoms, such as cough or wheeze, tohospitalization for various respiratory diseases, and there is suggestive evidence for associations with respiratory mortality. Many ofthe reported associations are statistically significant, particularly in the warm

season. In Figure 1, the central effect estimate is indicated by a square for each result,with the vertical bar representing the 95 percent confidence interval around the estimate. In the discussions thatfollow, an individual study result isconsidered tobe statistically significant ifthe 95 percent confidence interval does not include

zero.23Positive effect estimates indicate

23Results for studies ofrespiratory symptoms are presented as odds ratios; an odds ratio of 1.0 is equivalent to no effect, and thus is presented as equivalent to the zero effect estimate line. increases in the health outcome with 03
exposure. In considering these results as

a whole, itis important to consider not only whether statistical significance at the 95 percent confidence level is reported in individual studies but also the general pattern ofresults, focusing in particular on studies with greater statistical power thatreport relatively

more precise results.

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HeinOnline -- 75 Fed. Reg. 2964 2010