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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]

RIN 2060-AP98

National Ambient Air Quality

Standards for Ozone

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Proposed rule.

SUMMARY: Based on its reconsideration

of the 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 to provide requisite protection of

public health and welfare, respectively.

With regard to the primary standard for

03, EPA proposes that the level of the

8-hour primary standard, which was set

at 0.075 ppm in the 2008 final rule,

should instead be set at a lower level

within the range of 0.060 to 0.070 parts

per million (ppm), to provide increased

protection for children and other "at

risk" populations against an array of 03-

related adverse health effects that range

from decreased lung function and

increased respiratory symptoms to

serious indicators of respiratory

morbidity including emergency

department visits and hospital

admissions for respiratory causes, and

possibly cardiovascular-related

morbidity as well as total nonaccidental and cardiopulmonary

mortality. With regard to the secondary

standard for 03, EPA proposes that the

secondary 03 standard, which was set

identical to the revised primary

standard in the 2008 final rule, should

instead be a new cumulative, seasonal

standard expressed as an annual index

of the sum of weighted hourly

concentrations, cumulated over 12

hours per day (8 am to 8 pm) during the

consecutive 3-month period within the

03 season with the maximum index

value, set at a level within the range of

7 to 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.

Public Hearings: Three public

hearings are scheduled for this proposed

rule. Two of the public hearings will be

held on February 2, 2010 in Arlington,

Virginia, and Houston, Texas. The third

public hearing will be held on February

4, 2010 in Sacramento, California.

ADDRESSES: Submit your comments,

identified by Docket ID No. EPA-HQOAR-2005-0172, by one of the

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 a total of two

copies.

e Hand Delivery: 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 of operation, and special

arrangements should be made for

deliveries of boxed information.

Public Hearings: Three public

hearings are scheduled for this proposed

rule. Two of the public hearings will be

held on February 2, 2010 in Arlington,

Virginia and Houston, Texas. The third

public hearing will be held on February

4, 2010 in Sacramento, California. The

hearings will be 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-February 2, 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 policy is that all

comments received will be included in

the public docket without change and

may be made available online at

www.regulations.gov, including any

personal information provided, unless

the comment includes information

claimed to be Confidential Business

Information (CBI) or other information

whose disclosure is restricted by statute.

Do not submit information that you

consider to be CBI or otherwise

protected through www.regulations.gov

or e-mail. The www.regulations.gov Web

site is an "anonymous access" system,

which means EPA will not know your

identity or contact information unless

you provide it in the body of your

comment. If you send an e-mail

comment directly to EPA without going

through www.regulations.gov, your email address will be automatically

captured and included as part of the

comment that is placed in the public

docket and made available on the

Internet. If you submit an electronic

comment, EPA recommends that you

include your name and other contact

information in the body of your

comment and with any disk or CD-ROM

you submit. If EPA cannot read your

comment due to technical difficulties

and cannot contact you for clarification,

EPA may not be able to consider your

comment. Electronic files should avoid

the use of special characters, any form

of encryption, and be free of any defects

or viruses.

Docket: All documents in the docket

are listed in the www.regulations.gov

index. Although listed in the index,

some information is not publicly

available, e.g., CBI or other information

whose disclosure is restricted by statute.

Certain other material, such as

copyrighted material, will be publicly

available only in hard copy. Publicly

available docket materials are available

either electronically in

www.regulations.gov or in hard copy at

the Air and Radiation Docket and

Information Center, EPA/DC, EPA West,

Room 3334, 1301 Constitution Ave.,

NW., Washington, DC. The Public

Reading Room is open from 8:30 a.m. to

4:30 p.m., Monday through Friday,

excluding legal holidays. The telephone

number for the Public Reading Room is

(202) 566-1744 and the telephone

number for the Air and Radiation

Docket and Information Center is (202)

566-1742.

FOR FURTHER INFORMATION CONTACT: Ms.

Susan Lyon Stone, Health and

Environmental Impacts Division, Office

of Air Quality Planning and Standards,

U.S. Environmental Protection Agency,

Mail Code C504-06, Research Triangle

Park, NC 27711; telephone: 919-541-

1146; fax: 919-541-0237; e-mail:

stone.susan@epa.gov.

SUPPLEMENTARY INFORMATION:

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General Information

What Should I Consider as I Prepare My

Comments for EPA?

1. Submitting CBI. Do not submit this

information to EPA through http://

www.regulations.gov or e-mail. Clearly

mark the part or all of the information

that you claim to be CBI. For CBI

information in a disk or CD-ROM that

you mail to EPA, mark the outside of the

disk or CD-ROM as CBI and then

identify electronically within the disk or

CD-ROM the specific information that

is claimed as CBI. In addition to one

complete version of the comment that

includes information claimed as CBI, a

copy of the comment that does not

contain the information claimed as CBI

must be submitted for inclusion in the

public docket. Information so marked

will not be disclosed except in

accordance with procedures set forth in

40 CFR part 2.

2. Tips for Preparing Your Comments.

When submitting comments, remember

to:

* Identify the rulemaking by docket

number and other identifying

information (subject heading, Federal

Register date and page number).

* Follow directions-The Agency

may ask you to respond to specific

questions or organize comments by

referencing a Code of Federal

Regulations (CFR) part or section

number.

* Explain why you agree or disagree,

suggest alternatives, and substitute

language for your requested changes.

* Describe any assumptions and

provide any technical information and/

or data that you used.

* Provide specific examples to

illustrate your concerns, and suggest

alternatives.

* Explain your views as clearly as

possible, avoiding the use of profanity

or personal threats.

* Make sure to submit your

comments by the comment period

deadline identified.

Availability of Related Information

A number of documents relevant to

this rulemaking are available on EPA

web sites. The Air Quality Criteria for

Ozone and Related Photochemical

Oxidants (2006 Criteria Document) (two

volumes, EPA/and EPA/, date) is

available on EPA's National Center for

Environmental Assessment Web site. To

obtain this document, go to http://

www.epa.gov/ncea, and click on Ozone

in the Quick Finder section. This will

open a page with a link to the March

2006 Air Quality Criteria Document.

The 2007 Staff Paper, human exposure

and health risk assessments, vegetation

exposure and impact assessment, and

other related technical documents are

available on EPA's Office of Air Quality

Planning and Standards (OAQPS)

Technology Transfer Network (TTN)

web site. The updated final 2007 Staff

Paper is available at: http://epa.gov/ttnl

naaqs/standards/ozone/s o3 cr sp.html

and the exposure and risk assessments

and other related technical documents

are available at http://www.epa.gov/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 other related

documents are also available for

inspection and copying in the EPA

docket identified above.

Public Hearings

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 of the 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, if necessary, depending

on the number of speakers wishing to

participate. The EPA will make every

effort to accommodate all speakers that

arrive and register before 7:30 p.m. A

lunch break is scheduled from 12:30

p.m. until 2 p.m.

If you would like to present 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 to follow the

schedule as closely as possible on the

day of the hearing.

Oral testimony will be limited to five

(5) minutes for each commenter to

address the proposal. We will not be

providing equipment for commenters to

show overhead slides or make

computerized slide presentations unless

we receive special requests in advance.

Commenters should notify Ms. Crabtree

if they will need specific audiovisual

(AV) equipment. Commenters should

also notify Ms. Crabtree if they need

specific translation services for nonEnglish speaking commenters. The EPA

encourages commenters to provide

written versions of their oral testimonies

either electronically on computer disk,

CD-ROM, or in paper copy.

The hearing schedules, including lists

of speakers, will be posted on EPA's

Web site for the proposal at http://

www.epa.gov/ttn/naaqs/standards/

ozone/s o3 cr_fr.html prior to the

hearing. Verbatim transcripts of the

hearings and written statements will be

included in the rulemaking docket.

Children's Environmental Health

Consideration of children's

environmental health plays a central

role in the reconsideration of the 2008

final decision on the 0 3 NAAQS and

EPA's decision to propose to set the

8-hour primary 0 3 standard at a level

within the range of 0.060 to 0.070 ppm.

Technical information that pertains to

children, including the evaluation of

scientific evidence, policy

considerations, and exposure and risk

assessments, is discussed in all of the

documents listed above in the section

on the availability of related

information. These documents include:

the Air Quality Criteria for Ozone and

Other Related Photochemical Oxidants;

the 2007 Staff Paper; 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

docket for this rulemaking. The public

is invited to submit comments or

identify peer-reviewed studies and data

that assess effects of early life exposure

to 0 3 .

Table of Contents

The following topics are discussed in

this preamble:

I. Background

A. Legislative Requirements

B. Related Control Requirements

C. Review of Air Quality Criteria and

Standards for 03

D. Reconsideration of the 2008 03 NAAQS

Final Rule

1. Decision to Initiate a Rulemaking to

Reconsider

2. Ongoing Litigation

II. Rationale for Proposed Decision on the

Level of the Primary Standard

A. Health Effects Information

1. Overview of Mechanisms

2. Nature of Effects

3. Interpretation and Integration of Health

Evidence

4. 03-Related Impacts on Public Health

B. Human Exposure and Health Risk

Assessments

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1. Exposure Analyses

2. Quantitative Health Risk Assessment

C. Reconsideration of the Level of the

Primary Standard

1. Evidence and Exposure/Risk-Based

Considerations

2. CASAC Views Prior to 2008 Decision

3. Basis for 2008 Decision on the Primary

Standard

4. CASAC Advice Following 2008 Decision

5. Administrator's Proposed Conclusions

D. Proposed Decision on the Level of the

Primary Standard

III. Communication of Public Health

Information

IV. Rationale for Proposed Decision on the

Secondary Standard

A. Vegetation Effects Information

1. Mechanisms

2. Nature of Effects

3. Adversity of Effects

B. Biologically Relevant Exposure Indices

C. Vegetation Exposure and Impact

Assessment

1. Exposure Characterization

2. Assessment of Risks to Vegetation

D. Reconsideration of Secondary 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 of Appendix P-Interpretation of

the NAAQS for 03 and Proposed

Revisions to the Exceptional Events Rule

A. Background

B. Interpretation of the Secondary 03

Standard

C. Clarifications Related to the Primary

Standard

D. Revisions to Exceptions From Standard

Data Completeness Requirements for the

Primary Standard

E. Elimination of the Requirement for 90

Percent Completeness of Daily Data

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 of the Required

03 Monitoring Season

VII. Implementation of Proposed 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 With Indian Tribal

Governments

G. Executive Order 13045: Protection of

Children From Environmental 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 of the 2008 03 NAAQS

final rule (73 FR 16436, March 27,

2008), which revised the level of the 8-

hour primary 03 standard to 0.075 ppm

and revised the secondary 03 standard

by making it identical to the revised

primary standard. This reconsideration

is based on the scientific and technical

information and analyses on which the

March 2008 03 NAAQS rulemaking was

based. Therefore, much of the

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. Legislative Requirements

Two sections of the Clean Air Act

(CAA) govern the establishment and

revision of the NAAQS. Section 108 (42

U.S.C. 7408) directs the Administrator

to identify and list "air pollutants" that

in her "judgment, cause or contribute 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 the kind and extent of all

identifiable effects on public health or

welfare which may be expected from the

presence of [a] pollutant in the ambient

air. * * *"

Section 109 (42 U.S.C. 7409) directs

the Administrator to propose and

promulgate "primary" and "secondary"

NAAQS for pollutants for which air

quality criteria are issued. Section

109(b)(1) defines a primary standard as

one "the attainment and maintenance of

which in the judgment of the

Administrator, based on such criteria

and allowing an adequate margin of

safety, are requisite to protect the public

health." I A secondary standard, as

defined in section 109(b)(2), must

"specify a level of air quality the

attainment and maintenance of which,

in the judgment of the Administrator,

based on such criteria, is requisite to

protect the public welfare from any

known or anticipated adverse effects

associated with the presence of such air

pollutant in the ambient air." 2

The requirement that primary

standards include an adequate margin of

safety was intended to address

uncertainties associated with

inconclusive scientific and technical

information available at the time of

standard setting. It was also intended to

provide a reasonable degree of

protection against hazards that research

has not yet identified. Lead Industries

Association v. EPA, 647 F.2d 1130, 1154

(DC Cir 1980), cert. denied, 449 U.S.

1042 (1980); American Petroleum

Institutev. Costle, 665 F.2d 1176, 1186

(DC Cir. 1981), cert. denied, 455 U.S.

1034 (1982). Both kinds of uncertainties

are components of the risk associated

with pollution at levels below those at

which human health effects can be said

to occur with reasonable scientific

certainty. Thus, in selecting primary

standards that include an adequate

margin of safety, the Administrator is

seeking not only to prevent pollution

levels that have been demonstrated to be

harmful but also to prevent lower

pollutant levels that may pose an

unacceptable risk of harm, even if the

risk is not precisely identified as to

nature or degree. The CAA does not

require the Administrator to establish a

primary NAAQS at a zero-risk level or

at background concentration levels, see

Lead Industries Association v. EPA, 647

F.2d at 1156 n. 51, but rather at a level

that reduces risk sufficiently so as to

protect public health with an adequate

margin of safety.

In addressing the requirement for an

adequate margin of safety, EPA

considers such factors as the nature and

severity of the health effects involved,

the size of the population(s) at risk, and

the kind and degree of the uncertainties

'The legislative history of section 109 indicates

that a primary standard is to be set at "the

maximum permissible ambient air level * * *

which will protect the health of any [sensitive]

group of the population," and that for this purpose

"reference should be made to a representative

sample of persons comprising the sensitive group

rather than to a single person in such a group" [S.

Rep. No. 91-1196, 91st Cong., 2d Sess. 10 (1970)].

2 Welfare effects as defined in section 3 02(h) (42

U.S.C. 7602(h)) include, but are not limited to,

"effects on soils, water, crops, vegetation, man-made

materials, animals, wildlife, weather, visibility, and

climate, damage to and deterioration of property,

and hazards to transportation, as well as effects on

economic values and on personal comfort and wellbeing."

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that must be addressed. The selection of

any particular approach to providing an

adequate margin of safety is a policy

choice left specifically to the

Administrator's judgment. Lead

Industries Association v. EPA, 647 F.2d

at 1161-62; Whitman v. American

Trucking Associations, 531 U.S. 457,

495 (2001).

In setting standards that are "requisite" to protect public health and

welfare, as provided in section 109(b),

EPA's task is to establish standards that

are neither more nor less stringent than

necessary for these purposes. Whitman

v. 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) of the CAA requires

that "not later than December 31, 1980,

and at 5-year intervals thereafter, the

Administrator shall complete a

thorough review of the criteria

published under section 108 and the

national ambient air quality standards

* * * and shall make such revisions in

such criteria and standards and

promulgate such new standards as may

be appropriate. * * " Section 109(d)(2)

requires that an independent scientific

review committee "shall complete a

review of the criteria * * * and the

national primary and secondary ambient

air quality standards * * * and shall

recommend to the Administrator any

new * * * standards and revisions of

existing criteria and standards as may be

appropriate. * * This independent

review function is performed by the

Clean Air Scientific Advisory

Committee (CASAC) of EPA's Science

Advisory Board.

B. Related Control Requirements

States have primary responsibility for

ensuring attainment and maintenance of

ambient air quality standards once EPA

has established them. Under section 110

of the Act (42 U.S.C. 7410) and related

provisions, States are to submit, for EPA

approval, State implementation plans

(SIPs) that provide for the attainment

and maintenance of such standards

through control programs directed to

emission sources.

The majority of man-made nitrogen

oxides (NOx) and volatile organic

compounds (VOC) emissions that

contribute to 03 formation in the United

States come from three types of sources:

Mobile sources, industrial processes

(which include consumer and

commercial products), and the electric

power industry.3 Mobile sources and

the electric power industry were

responsible for 78 percent of annual

NOx emissions in 2004. That same year,

99 percent of man-made VOC emissions

came from industrial processes

(including solvents) and mobile sources.

Emissions from natural sources, such as

trees, may also comprise a significant

portion of total VOC emissions in

certain regions of the country, especially

during the 03 season, which are

considered natural background

emissions.

The EPA has developed new

emissions standards for many types of

stationary sources and for nearly every

class of mobile sources in the last

decade to reduce 03 by decreasing

emissions of NOx and VOC. These

programs complement State and local

efforts to improve 03 air quality and

meet the 0.084 ppm 8-hour national

standards. Under title II of the CAA, 42

U.S.C. 7521-7574), EPA has established

new emissions standards for nearly

every type of automobile, truck, bus,

motorcycle, earth mover, and aircraft

engine, and for the fuels used to power

these engines. EPA also established new

standards for the smaller engines used

in small watercraft, lawn and garden

equipment. 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 will yield

substantial emission reductions.

Benefits from fuel programs generally

begin as soon as a new fuel is available.

The reduction of VOC emissions from

industrial processes has been achieved

either directly or indirectly through

implementation of control technology

standards, including maximum

achievable control technology,

reasonably available control technology,

and best available control technology

standards; or are anticipated due to

proposed or upcoming proposals based

on generally available control

technology or best available controls

under provisions related to consumer

and commercial products. These

standards have resulted in VOC

emission reductions of almost a million

tons per year accumulated starting in

1997 from a variety of sources including

combustion sources, coating categories,

and chemical manufacturing. EPA has

3 See EPA report, Evaluating Ozone Control

Programs in the Eastern United States: Focus on the

NO Budget Trading Program, 2004.

also finalized emission standards and

fuel requirements for new stationary

engines. In the area of consumer 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

and industrial 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 to be January 2011. These

actions are expected to yield significant

new VOC reductions-about 200,000

tons per year. Additionally, in ozone

nonattainment areas, we anticipate

reductions of an additional 25,000 tons

per year as States adopt rules this year

implementing control techniques

recommendations issued in 2008 for 4

additional categories of consumer 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 is used, such as during

manufacturing processes.

The power industry is one of the

largest emitters of NOx in the United

States. Power industry emission sources

include large electric generating units

(EGU) and some large industrial boilers

and turbines. The EPA's landmark Clean

Air Interstate Rule (CAIR), issued on

March 10, 2005, was designed to

permanently cap power industry

emissions of NOx in the eastern United

States. The first phase of the cap was to

begin in 2009, and a lower second phase

cap was to begin in 2015. The EPA had

projected that by 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, on July 11,

2008 and December 23, 2008, the U.S.

Court of Appeals for the DC Circuit

issued decisions on petitions for review

of the CAIR. In its July 11 opinion, the

court found CAIR unlawful and decided

to vacate CAIR and its associated

Federal implementation plans (FIPs) in

their entirety. On December 23, the

court granted EPA's petition for

rehearing to the extent that it 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 replaced by EPA with a rule

that is consistent with the Court's July

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11 opinion. The EPA recognizes 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 of Agriculture

(USDA) has approved conservation

systems and activities that reduce

agricultural emissions of NOx and VOC.

Current practices that may reduce

emissions of NOx and VOC include

engine replacement programs, diesel

retrofit programs, manipulation of

pesticide applications including timing

of applications, and animal feeding

operations waste management

techniques. The EPA recognizes that

USDA has been working with the

agricultural community to develop

conservation systems and activities to

control emissions of 03 precursors.

These conservation activities are

voluntarily adopted through the use of

incentives provided to the agricultural

producer. In cases where the States need

these measures to attain the standard,

the measures could be adopted. The

EPA will continue to work with USDA

on these activities with efforts to

identify and/or improve the control

efficiencies, prioritize the adoption of

these conservation systems and

activities, and ensure that appropriate

criteria are used for identifying the most

effective application of conservation

systems and activities.

The EPA will work together with

USDA and with States to identify

appropriate measures to meet the

primary and secondary standards,

including site-specific conservation

systems and activities. Based on prior

experience identifying conservation

measures and practices to meet the PM

NAAQS requirements, the EPA will use

a similar process to identify measures

that could meet the 03 requirements.

The EPA anticipates that certain USDAapproved conservation systems and

activities that reduce agricultural

emissions of NOx and VOC may be able

to satisfy the requirements for

applicable sources to implement

reasonably available control measures

for purposes of attaining the primary

and secondary 03 NAAQS.

C. Review of Air Quality Criteria 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 of 0.08 parts per

million (ppm), 1-hr average, total

photochemical oxidants, not to be

exceeded more than one hr per year. In

1977, EPA announced the first periodic

review of the air quality criteria in

accordance with section 109(d)(1) of the

Act. The EPA published a final decision

in 1979 (44 FR 8202). Both primary and

secondary standard levels were revised

from 0.08 to 0.12 ppm. The indicator

was revised from photochemical

oxidants to 03, and the form of the

standards was revised from a

deterministic to a statistical form, which

defined attainment of the standards as

occurring when the expected number of

days per calendar year with maximum

hourly average concentration greater

than 0.12 ppm is equal to or less than

one. In 1983, EPA announced that the

second periodic review of the primary

and secondary standards for 03 had

been initiated. Following review and

publication of air quality criteria and a

supplement, EPA published a proposed

decision (57 FR 35542) in August 1992

that announced EPA's intention to

proceed as rapidly as possible with the

next review of the air quality criteria

and standards for 03 in light of

emerging evidence of health effects

related to 6- to 8-hr 03 exposures. In

March 1993, EPA concluded the review

by deciding that revisions to 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 of the air quality criteria

and 03 NAAQS. On the basis of the

scientific evidence contained in the

1996 CD (U.S. EPA 1996a) and the 1996

Staff Paper (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 to revise the

primary and secondary 03 standards in

December 1996 (61 FR 65716). The EPA

proposed to replace the then existing

1-hour primary and secondary standards

with 8-hour average 03 standards set at

a level of 0.08 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 of 0.08 ppm,

based on the annual fourth-highest daily

maximum 8-hr average concentration,

averaged over three years, and setting

the secondary standard identical to the

revised primary standard.

The EPA initiated the most recent

periodic review of the air quality criteria

and standards for 03 in September 2000

with a call for information (65 FR

57810; September 26, 2000) for the

development of a revised Air Quality

Criteria Document for 03 and Other

Photochemical Oxidants (henceforth the

"2006 Criteria Document"). A project

work plan (EPA, 2002) for the

preparation of the Criteria Document

was released in November 2002 for

CASAC and public review. The EPA

held a series of workshops in mid-2003

on several draft chapters of the Criteria

Document to obtain broad input from

the relevant scientific communities.

These workshops helped to inform the

preparation of the first draft Criteria

Document (EPA, 2005a), which was

released for CASAC and public review

on January 31, 2005; a CASAC meeting

was held on May 4-5, 2005 to review

the first draft Criteria Document. A

second draft Criteria Document (EPA,

2005b) was released for CASAC and

public review on August 31, 2005, and

was discussed along with a first draft

Staff Paper (EPA, 2005c) at a CASAC

meeting held on December 6-8, 2005. In

a February 16, 2006 letter to the

Administrator, 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 letter to the

Administrator (Henderson, 2006b),

CASAC provided additional advice to

the Agency concerning chapter 8 of the

final 2006 Criteria Document

(Integrative Synthesis) to help inform

the second draft Staff Paper.

A second draft Staff Paper (EPA,

2006b) was released on July 17, 2006

and reviewed by CASAC on August 24-

25, 2006. In an October 24, 2006 letter

to the Administrator, CASAC provided

advice and recommendations to the

Agency concerning the second draft

Staff Paper (Henderson, 2006c). A final

2007 Staff Paper (EPA, 2007a) was

released on January 31, 2007. In a March

26, 2007 letter (Henderson, 2007),

CASAC offered additional advice to the

Administrator with regard to

recommendations and revisions to the

primary and secondary 03 NAAQS.

The schedule for completion of the

2008 rulemaking was governed by a

consent decree resolving a lawsuit filed

in March 2003 by a group of plaintiffs

representing national environmental

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and public health organizations,

alleging that EPA had failed to complete

the review within the period provided

by statute. 4 The modified consent

decree that governed the 2008

rulemaking, entered by the court on

December 16, 2004, provided that EPA

sign for publication notices of proposed

and final rulemaking concerning its

review of the 03 NAAQS 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 to no later than May

30, 2007 and February 20, 2008,

respectively. These dates for signing the

publication notices of proposed and

final rulemaking were further extended

to no later than June 20, 2007 and

March 12, 2008, respectively. The

proposed decision was signed on June

20, 2007 and published in the Federal

Register on July 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. On Wednesday, September

5, 2007, hearings were held in Atlanta,

GA, Chicago, IL, and Houston, TX. A

large number of comments were

received from various commenters on

the 2007 proposed revisions to the 03

NAAQS. A comprehensive summary of

all significant comments, along with

EPA's responses (henceforth "Response

to Comments"), can be found in the

docket for the 2008 rulemaking, which

is also the docket for this

reconsideration rulemaking.

The EPA's final decision on the 03

NAAAQS was published in the Federal

Register on March 27, 2008 (73 FR

16436). In the 2008 rulemaking, EPA

revised the level of the 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, EPA revised

the 8-hour standard by making it

identical to the revised primary

standard. The EPA also made

conforming changes to the Air Quality

Index (AQI) for 03, setting an AQI value

of 100 equal to 0.075 ppm, 8-hour

average, and making proportional

changes to the AQI values of 50, 150

and 200.

D. Reconsideration of the 2008 03

NAAQS Final Rule

Consistent with a directive of the new

Administration regarding the review of

new and pending regulations (Emanuel

memorandum, 74 FR 4435; January 26,

2009), the Administrator reviewed a

4 American Lung Association v. Whitman (No.

1:03CV00778, D.DC 2003).

number of actions 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 the NAAQS play in

enabling EPA to fulfill its mission to

protect the nation's public health and

welfare. In her review, the

Administrator was mindful of the need

for judgments concerning the NAAQS to

be based on a strong scientific

foundation which is developed through

a transparent and credible NAAQS

review process, consistent with the core

values highlighted in President Obama's

memorandum on scientific integrity

(March 9, 2009).

1. Decision To Initiate a Rulemaking To

Reconsider

In her review of the 2008 final rule,

several aspects of the final rule related

to the primary and secondary standards

stood out to the Administrator. As an

initial matter, the Administrator noted

that the 2008 final rule 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 respect to

revision of the primary standard, the

Administrator noted that the revised

level established in the 2008 final rule

was above the range that had been

unanimously recommended by

CASAC. 5 She also noted that EPA

received comments from a large number

of commenters from the medical and

public health communities, including

EPA's Children's Health Protection

Advisory Committee, all of which

endorsed levels within CASAC's

recommended range.

With respect to revision of the

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 of exposure. The 2008 final

rule revised the secondary standard to

be identical to the revised primary

standard, which is based on an 8-hour

daily maximum measure of exposure.

She also noted that EPA received

comments from a number of

commenters representing environmental

interests, all of which endorsed

CASAC;s recommendation for a new

cumulative, seasonal secondary

standard.6

5 The level of the 8-hour primary ozone standard

was set at 0.075 ppm, while CASAC unanimously

recommended a range between 0.060 and 0.070

ppm.

6 The Administrator also noted the exchange that

had occurred between EPA and the Office of

Subsequent to issuance of the 2008

final rule, in April 2008, CASAC took

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 that it did not

endorse the revised primary 03 standard

as being sufficiently protective of public

health because it failed to satisfy the

explicit stipulation of the Act to provide

an adequate margin of safety. The

CASAC also expressed the view that

failing to revise the secondary standard

to a cumulative, seasonal form was not

supported by the available science. In

addition to CASAC's letter, the

Administrator noted a recent adverse

ruling issued by the U.S. Court of

Appeals for the District of Columbia

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 EPA had 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. American Farm Bureau v.

EPA, 559 F.3d. 512 (DC Cir. 2009).

Based on her review of the

information described above, the

Administrator is initiating a rulemaking

to reconsider parts of the 2008 final

rule. Specifically, the Administrator is

reconsidering the level of the primary

standard to ensure that it is sufficiently

protective of public health, as discussed

in section II below, and is reconsidering

all aspects of the secondary standard to

ensure that it appropriately reflects the

available science and is sufficiently

protective of public welfare, as

discussed in section IV below. Based on

her review, the Administrator has

serious cause for concern regarding

whether the revisions to the primary

and secondary 03 standards adopted in

the 2008 final rule satisfy the

requirements of the CAA, in light of the

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 of the 2008 final

rule as soon as possible, based on the

scientific and technical information

upon which the 2008 final rule was

based.

Management and Budget (OMB) with regard to the

final decision on the secondary standard, as

discussed in the 2008 final rule (73 FR 16497).

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Also, EPA conducted a provisional

assessment of "new" scientific papers

(EPA, 2009) of scientific literature

evaluating health and ecological effects

of 03 exposure published since the close

of the 2006 Criteria Document 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 in the

2006 Criteria Document. This

provisional assessment is supportive of

the Administrator's decision to

reconsider parts of the 2008 final rule at

this time, based on the scientific and

technical information available for the

2008 final rule, as compared to

foregoing such reconsideration and

taking appropriate action in the future

as part of the next periodic review of the

air quality criteria and NAAQS, which

will include such scientific and

technical information.

The reconsideration of parts of the

2008 final rule discussed in this notice

is based on the scientific and technical

record from the 2008 rulemaking,

including public comments and CASAC

advice and recommendations. The

information that was assessed during

the 2008 rulemaking includes

information in the 2006 Criteria

Document (EPA, 2006a), the 2007 Policy

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 will be

considered in the next periodic review,

instead of this reconsideration

rulemaking, allowing the new

information to receive careful and

comprehensive review by CASAC and

the public before it is used as a basis 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 State of Mississippi, et a]. v. EPA (No.

08-1200, DC Cir. 2008). On March 10,

2009, EPA filed an unopposed motion

requesting that the Court vacate 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

should be maintained, modified or

otherwise reconsidered. The EPA

further requested that it be directed to

notify the Court and all the parties of

any actions it has taken or intends to

take, if any, within 180 days of the

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 notified the

Court and the parties of its decision to

initiate a rulemaking to reconsider the

primary and secondary 03 standards set

in March 2008 to ensure they satisfy the

requirements of the CAA. 7 In its notice

to the Court, EPA stated that this notice

of proposed rulemaking would be

signed by December 21, 2009, and that

the final rule will be signed by August

31, 2010.

II. Rationale for Proposed Decision on

the Level of the Primary Standard

As an initial matter, the Administrator

notes that the 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 of safety, and that revision is

needed to provide increased public

health protection" (73 FR 16472). The

Administrator is not reconsidering this

aspect of the 2008 decision, which is

based on the reasons discussed in

section II.B of the 2008 final rule (73 FR

16443-16472). The Administrator also

notes that the 2008 final rule concluded

that it was appropriate to retain the 03

indicator, the 8-hour averaging time,

and form of the primary 03 standard

(specified as the annual fourth-highest

daily maximum 8-hour concentration,

averaged over 3 years), while

concluding that revision of the standard

level was appropriate. 8 The

Administrator is not reconsidering these

aspects of the 2008 decision, which are

based on the reasons discussed in

sections II.C.1-3 of the 2008 final rule,

which address the indicator, averaging

time, and form, respectively, of the

primary 03 standard (73 FR 16472-

16475). For these reasons, the

Administrator is not reopening the 2008

7 The EPA also separately announced that it will

move quickly to implement any new standards that

might result from this reconsideration. To reduce

the workload for states during the interim period of

reconsideration, the Agency intends to propose to

defer compliance with the CAA requirement to

designate areas as attainment or nonattainment.

EPA will work with states, local governments and

tribes to ensure that air quality is protected during

that time.

8 The use of 03 as the indicator for photochemical

oxidants was adopted in the 1979 final rule and

retained in subsequent rulemaking. An 8-hour

averaging time and a form based on the annual

fourth-highest daily maximum 8-hour

concentration, averaged over 3 years, were adopted

in the 1997 final rule and retained in the 2008

rulemaking.

decision with regard to the need to

revise the 1997 primary 03 standard nor

with regard to the indicator, averaging

time, and form of the 2008 primary 03

standard. Thus, the information that

follows in this section specifically

focuses on a reconsideration of level of

the primary 03 standard.

This section presents the rationale for

the Administrator's proposed decision

that the 03 primary standard, which was

set at a level of 0.075 ppm in the 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 the proposed

range of standard levels is based on a

thorough review of the latest scientific

information on human health effects

associated with the presence of 03 in

the ambient air presented in the 2006

Criteria Document. This rationale also

takes into account: (1) Staff assessments

of the most policy-relevant information

in the 2006 Criteria Document and staff

analyses of air quality, human exposure,

and health risks, presented in the 2007

Staff Paper, 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 of drafts of the

2006 Criteria Document and 2007 Staff

Paper at public 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 of these 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 a public health

policy judgment as to what standard

would be requisite to protect public

health with an adequate margin of

safety, based on scientific evidence and

technical assessments that have

inherent uncertainties and limitations.

This judgment requires making

reasoned decisions as to what weight to

place on various 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 only to

prevent 03 levels that have been

demonstrated to be harmful but also to

prevent lower 03 levels that may pose

an unacceptable risk of harm, even if the

risk is not precisely identified as to

nature or degree.

In this proposed rule, EPA has drawn

upon an integrative synthesis of the

entire body of evidence, published

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through early 2006, on human health

effects associated with the presence of

03 in 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. 9 In

reconsidering this evidence, EPA

focuses on those health endpoints that

have been demonstrated to be 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 is highly suggestive

that 03 contributes to the reported

effects. This rationale also draws upon

the results of quantitative 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 of the primary standard are

based. Policy-relevant evidence-based

and exposure/risk-based considerations

are discussed, and the rationale for the

2008 final rulemaking on the primary

standard and CASAC advice, given both

prior to the development of the 2007

proposed rule and following the 2008

final rule, are summarized. Finally, the

Administrator's proposed conclusions

on the level of the primary standard are

presented. Section II.D summarizes the

proposed decision on the level of the

primary 03 standard and the solicitation

of public comments.

Judgments made in the 2006 Criteria

Document and 2007 Staff Paper about

the extent to which relationships

between various health endpoints and

short-term exposures to ambient 03 are

likely causal have been informed by

several factors. As discussed below in

section ILA, these factors include the

nature of the evidence (i.e., controlled

human exposure, epidemiological, and/

or toxicological studies) and the weight

of evidence, which takes into account

such considerations as biological

plausibility, coherence of evidence,

strength of association, and consistency

of evidence.

In assessing the health effects data

base for 03, it is clear that human

studies provide the most directly

applicable information for determining

causality because they are not limited

9 In its assessment of the epidemiological

evidence judged to be most relevant to making

decisions on the level of the 03 primary standard,

EPA has placed greater weight on U.S. and

Canadian epidemiologic studies, since studies

conducted in other countries may well reflect

different demographic and air pollution

characteristics.

by the uncertainties of dosimetry

differences and species sensitivity

differences, which would need to be

addressed in extrapolating animal

toxicology data to human health effects.

Controlled human exposure studies

provide data with the highest level of

confidence since they provide human

health effects data under closely

monitored conditions and can provide

exposure-response relationships.

Epidemiological data provide evidence

of associations 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. For these studies the

degree of uncertainty introduced by

potentially confounding variables (e.g.,

other pollutants, temperature) and other

factors affects the level of confidence

that the health effects being investigated

are attributable to 03 exposures, alone

and in combination with other

copollutants.

In using a weight of evidence

approach to inform judgments about the

degree of confidence that various health

effects are likely to be caused by

exposure to 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 of evidence,

increase. Conclusions regarding

biological plausibility, consistency, and

coherence of evidence of 0 3-related

health effects are drawn from the

integration of epidemiological studies

with mechanistic information from

controlled human exposure studies and

animal toxicological studies. As

discussed below, this type of

mechanistic linkage has been firmly

established for several respiratory

endpoints (e.g., lung function

decrements, lung inflammation) but

remains far more equivocal for

cardiovascular endpoints (e.g.,

cardiovascular-related hospital

admissions). For epidemiological

studies, strength of association refers to

the magnitude of the association and its

statistical strength, which includes

assessment of both effects estimate size

and precision. In general, when

associations yield large relative risk

estimates, it is less likely that the

association could be completely

accounted for by a potential confounder

or some other bias. Consistency refers to

the persistent finding of an association

between exposure and outcome in

multiple studies of adequate power in

different persons, places, circumstances

and times. For example, the magnitude

of effect estimates is relatively

consistent across recent studies showing

association between short-term, but not

long-term, 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 put judgments about health effects

that have been demonstrated to be

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 is

highly suggestive that 03 contributes to

the reported effects into a broader

public health context, EPA has drawn

upon the results of the quantitative

exposure and risk assessments. These

assessments provide estimates of the

likelihood that individuals in particular

population groups that are at risk for

various 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 of the kind and

degree of uncertainties inherent in such

estimates.

In the 2008 final rulemaking and in

this reconsideration, the term

"exposures of concern" 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 of the

2008 final rulemaking considered several air quality

scenarios, including just meeting what was then the

current standard set at a level of 0.084 ppm, as well

as just meeting alternative standards at levels of

0.080, 0.074, 0.070, and 0.064 ppm.

"Exposures of concern were also considered in

the 1997 review of the 03 NAAQS, and were judged

by EPA to be an important indicator of the public

health impacts of those 03-related effects for which

information was too limited to develop quantitative

estimates of risk but which had been observed in

humans at and above the benchmark level of 0.08

ppm for 6- to 8-hour exposures * * * including

increased nonspecific bronchial responsiveness (for

example, aggravation of asthma), decreased

pulmonary defense mechanisms (suggestive of

increased susceptibility to respiratory infection),

and indicators of pulmonary inflammation (related

Continued

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that although the analysis of "exposures

of concern" was conducted using three

discrete benchmark levels (i.e., 0.080,

0.070, and 0.060 ppm), the concept is

more appropriately viewed as a

continuum with greater confidence and

less uncertainty about the existence of

health effects at the upper end and less

confidence and greater uncertainty as

one considers increasingly lower 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 of exposures of

concern, it is important to balance

concerns about the potential for health

effects and their severity with the

increasing uncertainty associated with

our understanding of the likelihood of

such effects at lower 03 levels.

Within the context of this continuum,

estimates of exposures of concern at

discrete benchmark levels provide some

perspective on the public health

impacts of 0 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 to be 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 of the number of

people likely to experience exposures of

concern cannot be directly translated

into quantitative estimates of the

number of people likely to experience

specific health effects, since sufficient

information to draw such comparisons

is not available-if such information

were available, these health outcomes

would have been included in the

quantitative risk assessment. Due to

individual variability in responsiveness,

only a subset of individuals who have

exposures at and above a specific

benchmark level can be expected to

experience such adverse health effects,

and susceptible subpopulations such as

those with asthma are expected to be

affected more by such exposures than

healthy individuals. The amount of

weight to place on the estimates of

exposures of concern at any of these

to potential aggravation of chronic bronchitis or

long-term damage to the lungs). (62 FR 38868)

benchmark levels depends in part on

the weight of the scientific evidence

concerning health effects associated

with 03 exposures at and above that

benchmark level. It also depends on

judgments about the importance from a

public health perspective of the health

effects that are known or can reasonably

be inferred to occur as a result of

exposures at and above the benchmark

level. Such public health policy

judgments are embodied in the NAAQS

standard setting criteria (i.e., standards

that, in the judgment of the

Administrator, are requisite to protect

public health with an adequate margin

of safety).

As discussed below in section II.B.2,

the quantitative health risk assessment

conducted as part of the 2008 final

rulemaking includes estimates of risks

of lung function decrements in

asthmatic and all school age children,

respiratory symptoms in asthmatic

children, respiratory-related hospital

admissions, and non-accidental and

cardiorespiratory-related mortality

associated with recent ambient 03

levels, as well as risk reductions and

remaining risks associated with just

meeting the then current 0.084 ppm

standard and various alternative 03

standards in a number of example urban

areas. There are two parts to this risk

assessment: one part is based on

combining information from controlled

human exposure studies with modeled

population exposure, and the other part

is based on combining information from

community epidemiological studies

with either monitored or adjusted

ambient concentrations levels. This

assessment provides estimates of the

potential magnitude of O3-related health

effects, as well as a characterization of

the uncertainties and variability

inherent in such estimates. This

assessment also provides insights into

the distribution of risks and patterns of

risk reductions associated with meeting

alternative 03 standards.

As discussed below, a substantial

amount of new research conducted

since the 1997 review of the 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 that were evaluated in the

2006 Criteria Document and the

exposure and risk assessments

presented in the 2007 Staff Paper have

undergone intensive scrutiny through

multiple layers of peer review and many

opportunities for public review and

comment. While important

uncertainties remain in the qualitative

and quantitative characterizations of

health effects attributable to exposure to

ambient 03, and while different

interpretations of these uncertainties

can result in different public health

policy judgments, the review of this

information has been extensive and

deliberate. In the judgment of the

Administrator, this intensive evaluation

of the scientific evidence provides an

adequate basis for this reconsideration

of the 2008 final rulemaking.

A. Health Effects Information

This section outlines key information

contained in the 2006 Criteria

Document (chapters 4-8) and in the

2007 Staff Paper (chapter 3) on known

or potential effects on public health

which may be 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 of the evidence, focusing

on the biological plausibility and

coherence of the evidence; and (4)

considerations in characterizing the

public health impact of 03, including

the identification of "at risk"

populations.

The decision in the 1997 review

focused primarily on evidence from

short-term (e.g., 1 to 3 hours) and

prolonged (6 to 8 hours) controlledexposure studies reporting lung

function decrements, respiratory

symptoms, and respiratory

inflammation in humans, as well as

epidemiology studies reporting excess

hospital admissions and emergency

department (ED) visits for respiratory

causes. The 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 of acute (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 of the 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 that had been examined

in the 1997 review.

(2) Numerous controlled humanexposure studies have examined

indicators of 0 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 to 03, while other studies have

examined changes in host defense

capability following 03 exposure of

healthy young adults.

(3) Animal toxicology studies provide

new information regarding mechanisms

of action, increased susceptibility to

respiratory infection, and the biological

plausibility of acute effects and chronic,

irreversible respiratory damage.

(4) Numerous acute exposure

epidemiological studies published

during the past decade offer added

evidence of ambient 0 3-related lung

function decrements and respiratory

symptoms in physically active healthy

subjects and greater responses in

asthmatic subjects, as well as evidence

on new 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) A large number of newly available

epidemiological studies have examined

the effects of acute exposure to PM and

03 on mortality, notably including large

multicity studies that provide much

more robust and credible information

than was available in the 1997 review,

as well as recent meta-analyses that

have evaluated potential sources of

heterogeneity in 0 3-mortality

associations.

1. Overview of Mechanisms

Evidence on possible mechanisms by

which exposure to 03 may result in

acute and chronic health effects is

discussed in chapters 5 and 6 of the

2006 Criteria Document. 12 Evidence

from dosimetry, toxicological, and

12 While most of the 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 may be caused by

one or more components in the overall pollutant

mix, either separately or in combination with 03.

However, 03 clearly dominates these other oxidants

with their concentrations only being a few percent

of the 03 concentration.

human exposure studies has contributed

to an understanding of the mechanisms

that help to explain the biological

plausibility and coherence of evidence

for 0 3-induced respiratory health effects

reported in epidemiological studies.

More detailed information about the

physiological mechanisms related to the

respiratory effects of short- 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 1997 review

an emerging body of animal toxicology

and controlled human exposure

evidence is beginning to suggest

mechanisms that may mediate acute 03

cardiovascular effects. While much is

known about mechanisms that play 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 of 03 with lipids

and antioxidants in the epithelial lining

fluid and the epithelial cell membranes

of the lung can be the initial step in

mediating deleterious health effects of

03. This initial step activates a cascade

of events that lead to oxidative stress,

injury, inflammation, airway epithelial

damage and increased alveolar

permeability to vascular fluids.

Inflammation can be accompanied by

increased airway responsiveness, which

is an increased bronchoconstrictive

response to airway irritants and

allergens. Continued respiratory

inflammation also can alter the ability of

the body to respond 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 3 hours after exposure

in humans. Repeated respiratory

inflammation can lead to a chronic

inflammatory state with altered lung

structure and lung function and may

lead to chronic respiratory diseases such

as fibrosis and emphysema (EPA, 2006a,

section 8.6.2). The severity of symptoms

and magnitude of response to acute

exposures depend on inhaled dose, as

well as on individual susceptibility to

03, as discussed below. At the same 03

dose, individuals who are more

susceptible to 03 will have a larger

response than those who are less

susceptible; among individuals with

similar susceptibility, those who receive

a larger dose will have a larger response

to 03.

The inhaled dose is the product of 03

concentration (C), minute ventilation or

ventilation rate, and duration of

exposure (T), or (C x ventilation rate x

T). A large body of data regarding the

interdependent effect of these

components of inhaled dose on

pulmonary responses was assessed in

the 1986 and 1996 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 to be a better predictor

of response than 03 concentration,

ventilation rate, or duration of exposure,

alone, or as a combination of any two

of these factors (EPA 2006a, section 6.2).

Predicted 0 3-induced decrements in

lung function have been shown to be a

function of exposure concentration,

duration and exercise level for healthy,

young adults (McDonnell et a]., 1997). A

meta-analysis of 21 studies (Mudway

and Kelly, 2004) showed that markers of

inflammation and increased cellular

permeability in healthy subjects are

associated with total 03 dose.

The 2006 Criteria Document

summarizes information on potentially

susceptible and vulnerable groups in

section 8.7. As described there, the term

susceptibility refers to innate (e.g.,

genetic or developmental) or acquired

(e.g., personal risk factors, age) factors

that make individuals more likely to

experience effects with exposure to

pollutants. A number of population

groups and lifestages have been

identified as potentially susceptible to

health effects as a result of 03 exposure,

including people with existing lung

diseases, including asthma, children

and older adults, and people who have

larger than normal lung function

responses that may be due to genetic

susceptibility. In addition, some

population groups and lifestages have

been identified as having increased

vulnerability to 0 3-related effects due to

increased likelihood of exposure while

at elevated ventilation rates, including

healthy children and adults who are

active outdoors, for example, outdoor

workers, and joggers. Taken together,

the susceptible and vulnerable groups

are more commonly referred to as "atrisk" groups, 1 3 as discussed more fully

below in section II.A.4.b.

13 In previous Staff Papers and Federal Register

notices announcing proposed and final decisions on

the 03 and other NAAQS, EPA has used the phrase

Continued

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Based on a substantial body of new

evidence from animal, controlled

human exposure and epidemiological

studies, the 2006 Criteria Document

concludes that people with asthma and

other preexisting pulmonary diseases

are likely to be among those at increased

risk from 03 exposure. Altered

physiological, morphological and

biochemical states typical of respiratory

diseases like asthma, COPD and chronic

bronchitis may render people sensitive

to additional oxidative burden induced

by 03 exposure (EPA 2006a, section

8.7). Children and adults with asthma

are the group that has been studied most

extensively. Evidence from controlled

human exposure studies indicates that

asthmatics may exhibit larger lung

function decrements in response to 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, and biochemical 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 white bloods cells

(e.g., PMNs) or inflammatory cytokines.

Asthmatics, and people with allergic

rhinitis, are more likely to mount an

allergic-type response upon exposure to

03, as manifested by increases in white

blood cells associated with allergy (i.e.,

eosinophils) and related molecules,

which increase inflammation in the

airways. The increased inflammatory

and allergic responses also may be

associated with the larger late-phase

responses that asthmatics can

experience, which can include

increased bronchoconstrictor responses

to irritant substances or allergens and

additional inflammation. 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 of lung

function and daily symptoms (e.g., chest

tightness, wheeze, shortness of breath)

in children with moderate to severe

asthma and between 03 and increased

asthma medication use (EPA, 2007a,

chapter 6). These responses in

"sensitive population groups" to include both

population groups that are at increased risk because

they are more intrinsically susceptible and

population groups that are more vulnerable due to

an increased potential for exposure. In this notice,

we use the phrase, "at risk" populations to include

both types of population 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 on lung

function and generally have greater lung

function responses than older people.

The American Academy of Pediatrics

(2004) notes that children and infants

are among the population groups most

susceptible to many air pollutants,

including 03. This is in part because

their lungs are still developing. For

example, eighty percent of alveoli are

formed after birth, and changes in lung

development continue through

adolescence (Dietert et a]., 2000).

Moreover, children have high minute

ventilation rates and relatively high

levels of physical activity which also

increases their 03 dose (Plunkett et a].,

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 and mortality,

a comparison of all age or younger age

(65 years of age) 0 3-mortality effect

estimates to that of the elderly

population (>65 years) indicates that, in

general, the elderly population is more

susceptible to 03 mortality effects.

There is supporting evidence of agerelated differences in susceptibility to

03 lung function effects. The 2006

Criteria Document (section 7.6.7.2)

concludes that the elderly population

(>65 years of age) appear to be at greater

risk of 0 3-related mortality and

hospitalizations compared to all ages or

younger populations, and children (<18

years of age) experience other

potentially adverse respiratory health

outcomes with increased 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 to be

reproducible, in other words, a person

who has a large lung function response

after exposure to 03 will likely have

about the same response if exposed

again to the same dose of 03 (EPA

2006a, section 6.1). In controlled human

exposure studies, group mean responses

are not representative of this segment of

the population that has much larger

than average responses to 03. 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 of more

than one allele or genetic marker at the

same locus with the least frequent allele

or marker occurring more frequently

than can be accounted for by mutation

alone) in observed differences in

antioxidant enzymes and genes

involved in inflammation to modulate

pulmonary function and inflammatory

responses to 03 exposure. These

observations suggest a potential role for

these markers in the innate

susceptibility to 03, however, the

validity of these markers and their

relevance in the context of prediction to

population studies needs additional

experimentation.

Controlled human exposure studies

that provide information about

mechanisms of the initial response to 03

(e.g., lung function decrements,

inflammation, and injury to the lung)

also inform the selection of appropriate

lag times to analyze in epidemiological

studies through elucidation of the time

course of these responses (EPA 2006a,

section 8.4.3). Based on the results of

these studies, it would be reasonable to

expect that lung function decrements

could be detected epidemiologically

within lags of 0 (same day) or 1 to 2

days following 03 exposure, given the

rapid onset of lung function changes

and their persistence for 24 to 48 hours

among more responsive human subjects

in controlled human exposure studies.

Other responses take longer to develop

and can persist for longer periods of

time. For example, although asthmatic

individuals may begin to experience

symptoms soon after 03 exposure, it

may take anywhere from 1 to 3 days

after exposure for these subjects to seek

medical attention as a result of

increased airway responsiveness or

inflammation that may persist for 2 to

3 days. This may be reflected by

epidemiologic observations of

significantly increased risk for 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 might project increased mortality

within 0- to 3-day lags as a possible

consequence of 0 3-induced increases in

clotting agents arising from the cascade

of events, starting with cell injury

described above, occurring within 12 to

24 hours of 03 exposure. The time

course for many of these initial

responses to 03 is highly variable.

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Moreover these observations pertain

only to the initial response to 03.

Consequent responses can follow. For

example, J6rres et al., (1996) found that

in subjects with asthma and allergic

rhinitis, a maximum percent fall in

FEV1 of 27.9% and 7.8%, respectively,

occurred 3 days after 03 exposure when

they were challenged with of the highest

common dose of allergen.

2. Nature of Effects

The 2006 Criteria Document provides

new evidence that notably enhances our

understanding of short-term and

prolonged exposure effects, including

effects on lung function, symptoms, and

inflammatory effects reported in

controlled exposure studies. These

studies support and extend the findings

of the previous Criteria Document.

There is also a significant body of new

epidemiological evidence of

associations between short-term and

prolonged exposure to 03 and effects

such as premature mortality, hospital

admissions and emergency department

visits for respiratory (e.g., asthma)

causes. Key epidemiological and

controlled human exposure studies are

summarized below and discussed in

chapter 3 of the 2007 Staff Paper, which

is based on scientific evidence critically

reviewed in chapters 5, 6, and 7 of the

2006 Criteria Document, 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 of evidence from controlled

human exposure, epidemiological and

toxicological data contained in the 2006

Criteria Document.

a. Morbidity

This section summarizes scientific

information on the effects of inhalation

of 03, including public health effects of

short-term, prolonged, and long-term

exposures on respiratory morbidity and

cardiovascular system effects, as

discussed in chapters 6, 7 and 8 of the

2006 Criteria Document and chapter 3 of

the 2007 Staff Paper. This section also

summarizes the uncertainty about the

potential indirect effects on public

health associated with changes due to

increases in UV-B radiation exposure,

such as UV-B radiation-related skin

cancers, that may be associated with

reductions in ambient levels of groundlevel 03, as discussed in chapter 10 of

the 2006 Criteria Document and chapter

3 of the 2007 Staff Paper.

14 Health effects discussions are also drawn from

the more detailed information and tables presented

in the Criteria 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 a variety of

health effects, including: Lung function

decrements, respiratory symptoms,

increased airway responsiveness,

respiratory inflammation and

permeability, increased susceptibility to

respiratory infection, and acute

morphological effects. Epidemiology

studies have reported associations

between 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 of studies 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 Criteria Documents (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 (lung function) and

symptomatic responses were observed

at much lower 03 exposures. When

minute ventilation was considerably

increased by continuous exercise (CE)

during 03 exposures lasting 2 hour or

less at > 0.12 ppm, healthy subjects

generally experienced decreases in

FEVI, FVC, and other measures of lung

function; increases in specific airway

resistance (sRaw), breathing frequency,

and airway responsiveness; and

symptoms such as cough, pain on deep

inspiration, shortness of breath, throat

irritation, and wheezing. When

exposures were increased to 4- to 8-

hours in duration, statistically

significant lung function and symptom

responses were reported at 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 most important observations

drawn from studies reviewed in the

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-induced lung

function responses are decreased in the

elderly relative to young adults; (4)

there is a large degree of intersubject

variability in physiological and

symptomatic responses to 03 but

responses tend to be reproducible

within a given individual over a period

of several months; (5) subjects exposed

repeatedly to 03 for several days show

an attenuation of response upon

successive exposures, but this

attenuation is lost after about a week

without exposure; and (6) acute 03

exposure initiates an inflammatory

response which may persist for at least

18 to 24 hours post exposure.

The development of these respiratory

effects is time-dependent during both

exposure and recovery periods, with

great overlap for development and

disappearance of the effects. In healthy

human subjects exposed to typical

ambient 03 levels near 0.120 ppm, lung

function responses largely resolve

within 4 to 6 hours postexposure, but

cellular effects persist for about 24

hours. In these healthy subjects, small

residual lung function effects are almost

completely gone within 24 hours, while

in hyperresponsive subjects, recovery

can take as much as 48 hour to return

to baseline. The majority of these

responses are attenuated after repeated

consecutive exposures, but such

attenuation to 03 is lost one week

postexposure.

Since 1996, there have been a number

of studies published investigating lung

function and symptomatic responses

that generally support the observations

previously drawn. Recent studies for

acute exposures of 1 to 2 hours and 6

to 8 hours in duration are compiled in

the 2007 Staff Paper (Appendix 3C). As

summarized in more detail in the 2007

Staff Paper (section 3.3.1.1), among the

more important of the recent studies

that examined changes in FEV in large

numbers of subjects over a range of

1-2 hours at exposure levels of 0.080 to

0.40 ppm were studies by McDonnell et

a]. (1997) and Ultman et a]. (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 of 0.080 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 of exposure),

several pre- and post-1996 studies

(Folinsbee et aL., 1988,1994; Horstman

et a]., 1990; Adams, 2002, 2003a, 2006)

have reported statistically significant

lung function responses and increased

symptoms in healthy adults with

increasing duration of exposure, 03

concentration, and minute ventilation.

Studies that employed triangular

exposure patterns (i.e., integrated

exposures that begin at a low level, rise

to a peak, and return to a low level

during the exposure) (Hazucha et aL.,

1992; Adams 2003a, 2006) suggest that

the triangular exposure pattern can

potentially lead to greater FEVI

decrements and respiratory symptoms

than square-wave exposures (when the

overall 03 doses are equal). These

results suggest that peak exposures,

reflective of the pattern of ambient 03

concentrations in some locations, are

important in terms of 03 health effects.

McDonnell (1996) used data from a

series of studies to investigate the

frequency distributions of FEVI

decrements following 6.6 hour

exposures and found statistically

significant, but relatively small, group

mean decreases in average FEVI

responses (between 5 and 10 percent) at

0.080 ppm 03.15 Notably, about 26

percent of the 60 exposed subjects had

lung function decrements > 10 percent,

including about 8 percent of the subjects

that experienced large decrements (> 20

percent) (EPA, 2007b, Figure 3-1A).

These results (which were not corrected

for exercise in filtered air responses)

demonstrate that while average

responses may be relatively small at the

0.080 ppm exposure level, some

individuals experience more severe

effects that may be clinically significant.

Similar results at the 0.080 ppm

exposure level (for 6.6 hours during

intermittent exercise) were seen in more

recent studies of 30 healthy young

adults by Adams (2002, 2006).16 In

Adams (2006), relatively small but

statistically significant lung function

decrements and respiratory symptom

responses were found (for both squarewave and triangular exposure patterns),

with 17 percent of the subjects (5 of 30)

experiencing > 10 percent FEV1

15 This study and other studies (Folinsbee et al.,

1988; Horstman et al., 1990; and McDonnell et al.,

1991), conducted in EPA's human studies research

facility in Chapel Hill, NC, measured ozone

concentrations to within +/ 5 percent or +/

0.004 ppm at the 0.080 ppm exposure level.

16 These studies, conducted at a facility at the

University of California, in Davis, CA, reported 03

concentrations to be accurate within +/ 0.003

ppm over the range of concentrations included in

these studies.

decrements (comparing pre- and postexposures) when the results were not

corrected for the effects of exercise

alone in filtered air (EPA, 2007b, Figure

3-iB) and with 23 percent of subjects (7

of 30) experiencing such effects when

the results were corrected (EPA, 2007b,

p. 3-6). 1 7

These studies by Adams (2002, 2006)

were notable in that they were the only

controlled exposure human studies

available at the time of the 2008

rulemaking that examined respiratory

effects associated with prolonged 03

exposures at levels below 0.080 ppm,

which was the lowest exposure level

that had been examined in the 1997

review. The Adams (2006) study

investigated a range of exposure 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

(total subjective 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 of different patterns of exposure.

At the 0.060 ppm exposure level, the

author reported no statistically

significant differences for FEVI

decrements nor for most respiratory

symptoms responses. Statistically

significant responses were reported only

for TSS for the triangular exposure

pattern toward the end of the exposure

period, with the PDI responses being

noted as following a closely similar

pattern (Adams, 2006, p. 131-132).

EPA's reanalysis of the data from the

Adams (2006) study addressed the more

fundamental question of whether 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 EPA had been used previously by

other researchers to address this same

question. EPA's reanalysis of the 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

17 These distributional results presented in the

Criteria Document and Staff Paper for the Adams

(2006) study are based on data for squate-wave

exposures to 0.080 ppm that were not included in

the publication but were obtained from the author.

1

8 Dr. Adams submitted comments on EPA's

reanalysis in which he concluded that the FEV1

response in healthy young adults at the 0.060 ppm

Further examination of the postexposure FEV data and mean data at

other time points and concentrations

also suggest a pattern of response at 0.06

ppm that is consistent with a doseresponse relationship rather than

random variability. For example, the

response at 5.6 hours was similar to that

of the post-exposure 6.6 hour response

and appeared to also differ from the FA

response. At the 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 of previous

studies (Adams, 2003a,b; Horstman et

aL., 1990; McDonnell et aL., 1991).

Although of much smaller magnitude,

the temporal pattern of the 0.06 ppm

response was generally consistent with

the temporal patterns of response to

higher concentrations of 03 in this and

other studies. These findings are not

unexpected because the previously

observed group mean FEVI responses to

0.08 ppm were in the range of 6-9%

suggesting that exposure to lower

concentrations of 03 would result in

smaller, but real group mean FEVI

decrements, i.e., the responses to 0.060

ppm 03 are consistent with the presence

of a 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, 7 percent of the subjects (2

of 30 subjects) experienced notable

FEVI decrements (> 10 percent) with the

square wave exposure pattern at the

0.060 ppm exposure level (comparing

pre- and post-exposures) when the

results were corrected for the effects of

exercise alone in filtered air (EPA,

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 on the observation that 20% of

subjects exposed to 0.06 ppm 03 (in a

face mask exposure study) had greater

than a 10% decrement in FEVI even

though the group mean response was

not statistically different from the

filtered air response. The effects

described by Adams (2002), along with

exposure level in his study (Adams, 2006a) does not

demonstrate a significant mean effect by ordinarily

acceptable statistical analysis, but is rather in

somewhat of a gray area, both in terms of a biologically meaningful response and a statistically

significant response (Adams, 2007). The EPA

responded to these comments in the 2008 final rule

(73 FR 16455) and in the Response to Comments

(EPA, 2008, pp. 26-28).

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the reanalysis of the Adams (2006) data

as described above, demonstrate

considerable inter-individual variability

in responses of healthy 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.

Of potentially greater concern is the

magnitude of the lung function

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

of functional responses (e.g., FEV1

decrements of > 10% but < 20%) and/

or moderate symptomatic responses

would likely interfere with normal

activity for relatively few responsive

individuals. However, for people with

lung disease, even moderate functional

or symptomatic responses would likely

interfere with normal activity for many

individuals, and would likely result in

more frequent use of medication (see

section II.A.4 below).

(ii) Results of Epidemiological and Field

Studies

A relatively large number of field

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 of the 1996

Criteria Document that lung function

changes, as measured by decrements in

FEV1 or peak expiratory flow (PEF), and

respiratory symptoms in healthy adults

and asthmatic children are closely

correlated to ambient 03 concentrations.

Pre-1996 field studies focused primarily

on children attending summer camps

and found 0 3-related impacts on

measures of lung function, but not

respiratory symptoms, in healthy

children. The newer studies have

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 that prolonged (i.e., 6-8

hour) exposure periods, combined with

elevated levels of exertion or exercise,

increase the dose of 03 to the lungs at

a given ambient exposure level and

result in larger lung function effects.

The results of one large study of hikers

(Korrick et al., 1998), which reported

outcome measures stratified by several

factors (e.g., gender, age, smoking status,

presence of asthma) within a population

capable of more than normal exertion,

provide useful insight. In this study,

lung function was measured before and

after hiking, and individual 03

exposures were estimated by averaging

hourly 03 concentrations from ambient

monitors located at the base and

summit. The mean 8-hour average 03

concentration was 0.040 ppm (8-hour

average concentration range of 0.021

ppm to 0.074 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 of time.

Asthma panel studies conducted both

in the U.S. and in other countries have

reported that decrements in PEF are

associated with routine 03 exposures

among asthmatic and healthy people.

One large U.S. multicity study, the

National Cooperative Inner City Asthma

Study or NCICAS, (Mortimer et al.,

2002) examined 0 3-related changes in

PEF in 846 asthmatic children from 8

urban areas and reported that the

incidence of > 10 percent decrements in

morning PEF are associated with

increases in 8-hour average 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 (less than 5

percent of days), the associations with

morning PEF remained statistically

significant. Mortimer et a]. (2002)

discussed potential biological

mechanisms for delayed effects on

pulmonary function in asthma, which

included increased nonspecific airway

responsiveness secondary to airway

inflammation due to 03 exposure. Two

other panel studies (Romieu et al., 1996,

1997) carried out simultaneously in

northern and southwestern Mexico City

with mildly asthmatic school children

reported statistically significant 03-

related reductions in PEF, with

variations in effect depending on lag

time and time of day. Mean 1-hour

maximum 03 concentrations in these

locations ranged from 0.190 ppm in

northern Mexico City to 0.196 ppm in

southwestern Mexico City. While

several studies report statistically

significant associations between 03

exposure and reduced PEF in

asthmatics, other studies did not,

possibly due to low levels of 03

exposure. EPA concludes that these

studies collectively indicate that 03 may

be associated with short-term declines

in lung function in asthmatic

individuals and that the Mortimer et a].

(2002) study showed statistically

significant effects at concentrations in

the range below 0.080 ppm 03.

Most of the panel studies which have

investigated associations between 03

exposure and respiratory symptoms or

increased use of asthma medication are

focused on asthmatic children. Two

large U.S. studies (Mortimer et al., 2002;

Gent et al., 2003) have reported

associations between ambient 03

concentrations and daily symptoms/

asthma medication use, even after

adjustment for copollutants. Results

were more mixed, meaning that a

greater proportion of studies were not

both positive and statistically

significant, across smaller U.S. and

international studies that focused on

these health endpoints.

The NCICAS reported morning

symptoms in 846 asthmatic children

from 8 U.S. urban areas to be most

strongly associated with a cumulative

1- to 4-day lag of 03 concentrations

(Mortimer et al., 2002). The NCICAS

used standard protocols that included

instructing caretakers of the subjects to

record symptoms (including cough,

chest tightness, and wheeze) in the daily

diary by observing or asking the child.

While these associations were not

statistically significant in several cities,

when the individual data are pooled

from all eight cities, statistically

significant effects were observed for the

incidence of symptoms. The authors

also reported that the odds ratios

remained essentially the same and

statistically significant for the incidence

of morning symptoms when days with

8-hour 03 concentrations above 0.080

ppm were excluded. These days

represented less than 5 percent of days

in the study.

Gent and colleagues (2003) followed

271 asthmatic children under age 12

and living in southern New England for

6 months (April through September)

using a daily symptom diary. They

found that mean 1-hour max 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 to use a

bronchodilator would suggest the

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presence of very mild asthma.

Statistically significant effects of 1-day

lag 03 were observed on a variety 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 of breath. Effects of 03, but

not PM 2.

5, remained significant and

even increased in magnitude in twopollutant models. Some of the

associations were noted at 1-hour max

03 levels below 0.060 ppm. In contrast,

no effects were observed among

asthmatics not using maintenance

medication. In terms of person-days of

follow-up, this is one of the larger

studies currently available that address

symptom outcomes in relation to 03 and

provides supportive evidence for effects

of 03 independent of PM 2.

5. Study

limitations include the post-hoc nature

of the population stratification by

medication use. Also, the study did not

account for all of the important

meteorological factors that might

influence these results, such as relative

humidity or dew point.

The multicity study by Mortimer et a].

(2002), which examined an asthmatic

population representative of the 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

of well-conducted, albeit relatively

smaller, U.S. studies which showed

only limited or a lack of evidence 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 of 0.03 to 0.09 ppm. The 2006

Criteria Document concludes that the

asthma panel studies, as a group, and

the NCICAS in particular, indicate a

positive association between ambient

concentrations and respiratory

symptoms and increased medication use

in asthmatics. The evidence has

continued to expand since 1996 and

now is considered to be much stronger

than in the 1997 review of the 03

primary standard.

School absenteeism is another

potential surrogate for the health

implications of 03 exposure in children.

The association between school

absenteeism and ambient 03

concentrations was assessed in two

relatively large field studies. The first

study, Chen et a]. (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 et a]. (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 (with a distributed lag

out to 30 days) and all absence

categories, and particularly for

respiratory causes. Neither PM10 nor

NO 2 were associated with any

respiratory or nonrespiratory illnessrelated absences in single pollutant

models. The 2006 Criteria Document

concludes that these 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 of 03 on school absences. In

addition, more research is needed to

help shed light on the implications of

variation in the duration of the lag

structures (i.e., 1 day, 5 days, 14 days,

and 30 days) found both across studies

and within data sets by health endpoint

and exposure metric.

(b) Increased Airway Responsiveness

As discussed in more detail in the

2006 Criteria Document (section 6.8)

and the 2007 Staff Paper (section

3.3.1.1.2), increased airway

responsiveness, also known as airway

hyperresponsiveness (AHR) or bronchial

hyperreactivity, refers to a condition in

which the propensity for the airways to

bronchoconstrict due to a variety of

stimuli (e.g., exposure to cold air,

allergens, or exercise) becomes

augmented. This condition is typically

quantified by measuring the decrement

in pulmonary function after inhalation

exposure to specific (e.g., antigen,

allergen) or nonspecific (e.g.,

methacholine, histamine)

bronchoconstrictor stimuli. Exposure to

03 causes an increase in airway

responsiveness as indicated by a

reduction in the concentration of

stimuli required to produce a given

reduction in FEV1 or increase in airway

obstruction. Increased airway

responsiveness is an important

consequence of exposure to 03 because

its presence means that the 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 (Holz et al.,

2002). Similar increased airway

responsiveness in asthmatics to house

dust mite antigen 16 to 18 hours after

exposure to a single dose of 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 a clinically important factor that

can exacerbate the response to ambient

bronchoconstrictor substances in

individuals with preexisting allergic

asthma or rhinitis. Further, 03 may have

an immediate impact on the lung

function of asthmatics as well as

contribute to effects that persist for

longer periods.

Kreit et a]. (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 et a]., 1996)

suggested an increase in specific (i.e.,

allergen-induced) airway reactivity in

subjects with allergic asthma, and to a

lesser extent in subjects with allergic

rhinitis after short-term exposure to

higher 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 of repeated

exposure to 03 suggest that changes in

airway responsiveness tend to be

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 a result 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 have been observed subsequent

to 6.6 hour 03 exposures to the lowest

tested level-0.080 ppm-in healthy

adults engaged in moderately high

exercise (section 6.9 of the 2006 Criteria

Document and section 3.3.1.3 of the

2007 Staff Paper). Some of these prior

studies suggest that inflammatory

responses may be detected in some

individuals following 03 exposures in

the absence of 0 3-induced pulmonary

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 Criteria Document (section 8.4.2)

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 of 03

exposure observed in all of the species

studied. Increased cellular permeability

is a disruption of the lung barrier that

leads to leakage of serum proteins,

influx of polymorphonuclear leukocytes

(neutrophils or PMNs), release of

bioactive mediators, and movement of

compounds from the airspaces into the

blood.

A number of controlled human

exposure studies have analyzed

bronchoalveolar lavage (BAL) and nasal

lavage (NL) 19 fluids and cells for

markers of inflammation and lung

damage (EPA, 2006a, Annex AX6).

Increased lung inflammation is

demonstrated by the presence of

neutrophils found in BAL fluid in the

lungs, which has long been accepted as

a hallmark of inflammation. It is

apparent, however, that inflammation

19 Graham and Koren (1990) compared

inflammatory mediators present in NL and BAL

fluids of humans exposed to 0.4 ppm 03 for 2 hours

and found similar increases in PMNs in both fluids,

suggesting a qualitative correlation between

inflammatory changes in the lower airways (BAL)

and upper respiratory tract (NL).

within airway tissues may persist

beyond the point that inflammatory

cells are found in the BAL fluid. Soluble

mediators of inflammation, such as

cytokines and arachidonic acid

metabolites have been measured in the

BAL fluid of humans exposed to 03. In

addition to their role in inflammation,

many of these compounds have

bronchoconstrictive properties and may

be involved in increased airway

responsiveness following 03 exposure.

An in vitro study of epithelial 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 of controlled human

exposure studies indicated that a single,

acute (1 to 4 hours) 03 exposure (> 0.080

to 0.100 ppm) of subjects engaged in

moderate to heavy exercise could

induce a number of cellular and

biochemical changes suggestive of

pulmonary inflammation and lung

permeability (EPA, 2006a, p. 8-22).

These changes persisted for at least 18

hours. Markers from BAL fluid

following both 2-hour and 4-hour 03

exposures repeated up to 5 days

indicate that there is ongoing cellular

damage irrespective of attenuation of

some cellular inflammatory responses of

the airways, pulmonary function, and

symptom scores (EPA, 2006a, p. 8-22).

Acute airway inflammation was shown

in Devlin et a]. (1990) to occur among

adults exposed to 0.080 ppm 03 for 6.6

hours with exercise. McBride et a].

(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 of these changes is

not entirely clear.

The studies reporting inflammatory

responses and markers of lung injury

have clearly demonstrated that there is

significant variation in response of

subjects exposed, especially to 6.6 hours

03 exposures at 0.080 and 0.100 ppm.

To provide some perspective on the

public health impact for these effects,

the 2007 Staff Paper (section 3.3.1.1.3)

notes that one study (Devlin et al., 1991)

showed that roughly 10 to 50 percent of

the 18 young healthy adult subjects

experienced notable increases (i.e., > 2

fold increase) in most of the

inflammatory and cellular injury

indicators analyzed, associated with 6.6-

hour exposures at 0.080 ppm. Similar,

although in some cases higher, fractions

of the population of 10 healthy adults

tested saw > 2 fold increases associated

with 6.6-hour exposures to 0.100 ppm.

The authors of this study expressed the

view that "susceptible subpopulations

such as the very young, elderly, and

people with pulmonary impairment or

disease may be even more affected"

(Devlin etaL., 1991).

Since 1996, a substantial number of

human exposure studies have been

published which have provided

important new information on lung

inflammation and epithelial

permeability. Mudway and Kelly (2004)

examined 0 3-induced inflammatory

responses and epithelial permeability

with a meta-analysis of 21 controlled

human exposure studies and showed

that an influx in neutrophils and protein

in healthy subjects is associated with

total 03 dose (product of 03

concentration, exposure duration, and

minute ventilation) (EPA, 2006a, p. 6-

34). Results of the analysis suggest that

the time course for inflammatory

responses (including recruitment of

neutrophils and other soluble

mediators) is not clearly established, but

there is evidence that attenuation

profiles for many of these parameters

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

The 2006 Criteria Document (chapter

8) concludes that interaction of 03 with

lipid constituents of epithelial lining

fluid (ELF) and cell membranes and the

induction of oxidative stress is

implicated in injury and inflammation.

Alterations in the expression of

cytokines, chemokines, and adhesion

molecules, indicative of an ongoing

oxidative stress response, as well as

injury repair and regeneration

processes, have been reported in animal

toxicology and human in vitro studies

evaluating biochemical mediators

implicated in injury and inflammation.

While antioxidants in ELF confer some

protection, 03 reactivity is not

eliminated at environmentally relevant

exposures (2006 Criteria Document, p.

8-24). Further, antioxidant reactivity

with 03 is both species-specific and

dose-dependent.

(d) Increased Susceptibility to

Respiratory Infection

As discussed in more detail in the

2006 Criteria Document (sections 5.2.2,

6.9.6, and 8.4.2), short-term exposures

to 03 have been shown to impair

physiological defense capabilities in

experimental animals by depressing

alveolar macrophage (AM) functions

and by altering the mucociliary

clearance of inhaled particles and

microbes resulting in increased

susceptibility to respiratory infection.

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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

of host defenses and subsequent

increased susceptibility to bacterial lung

infection in laboratory animals has been

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 (with moderate 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 of microorganisms or

nonviable particles. Compromised AM

functions in asthmatics may increase

their susceptibility to other 03 effects,

the effects of particles, and respiratory

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 Staff Paper (section 3.3.1.1.5), cells

in the centriacinar region (CAR) of the

lung (the segment between the last

conducting airway and the gas exchange

region) have been recognized as a

primary target of 0 3-induced damage

(epithelial cell necrosis and remodeling

of respiratory bronchioles), possibly

because epithelium in this region

receives the greatest dose of 03

delivered to the lower respiratory tract.

Following chronic 03 exposure,

structural changes have been observed

in the CAR, the region typically affected

in most chronic airway diseases of the

human lung (EPA, 2006a, p. 8-24).

Ciliated cells in the nasal cavity and

airways, as well as Type I cells in the

gas-exchange region, are also identified

as targets. While short-term 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 of repeated

short-term and chronic morphological

effects of 03 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 a variety of experimental

animal species. For example, a series of

new studies that used infant rhesus

monkeys and simulated seasonal

ambient exposure (0.5 ppm 8 hours/day

for 5 days, every 14 days for 11

episodes) reported remodeling in the

distal airways; abnormalities in tracheal

basement membrane; eosinophil

accumulation in conducting airways;

and decrements in airway innervation

(2006 Criteria Document, 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, of a number of laboratory animal

species (EPA, 2006a, section 5.2.4).

(f) Emergency Department Visits/

Hospital Admissions for Respiratory

Causes

Increased summertime emergency

department visits and hospital

admissions for respiratory causes have

been associated with ambient exposures

to 03. As discussed in section 3.3.1.1.6

of the 2007 Staff Paper, numerous

studies conducted in various locations

in the U.S. and Canada consistently

have shown a relationship between

ambient 03 levels and increased

incidence of emergency department

visits and hospital admissions for

respiratory causes, even after controlling

for modifying factors, such as weather

and copollutants. Such associations

between elevated ambient 03 during

summer months and increased hospital

admissions have a plausible biological

basis in the human and animal evidence

of functional, symptomatic, and

physiologic effects discussed above and

in the increased susceptibility to

respiratory infections observed in

laboratory animals.

In the 1997 review of the 03 NAAQS,

the Criteria Document 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, but results 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 found in 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 of temperature and copollutants.

Overall, the 1996 Criteria Document

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 the New York

City area (based on Thurston et al.,

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 on more recent studies (2007 Staff

Paper, chapter 5). Significant

uncertainties and the difficulty of

obtaining reliable baseline incidence

numbers resulted in emergency

department visits not being used in the

quantitative risk assessment in either

the 1997 or the 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 7 Annex) and some

are shown in Figure 1 (in section II.A.3).

Respiratory causes for emergency

department visits include asthma,

bronchitis, emphysema, pneumonia,

and other upper and lower respiratory

infections, such as influenza, but

asthma visits typically dominate the

daily incidence counts. Most studies

report positive associations with 03.

Among studies with adequate controls

for seasonal patterns, many reported at

least one significant positive association

involving 03.

20 Discussion of the reasons for focusing on warm

season studies is found in the 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 that in general, 03

effect estimates from summer only

analyses tended to be positive and larger

compared to results from cool season or

all year analyses. Several of the studies

reported significant associations

between 03 concentrations and

emergency department visits for

respiratory causes, in particular asthma.

However, inconsistencies were observed

which were at least partially attributable

to differences in model specifications

and analysis approach among various

studies. For example, ambient 03

concentrations, length of the 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 on unscheduled admissions

because unscheduled hospital

admissions occur in response to

unanticipated disease exacerbations and

are more likely than scheduled

admissions to be affected by variations

in environmental factors, such as daily

03 levels. Results of a fairly large

number of these studies published

during the past decade are summarized

in 2006 Criteria Document (chapter 7

Annex), and results of U.S. and

Canadian studies are shown in Figure 1

below (in section II.A.3). As a group,

these hospital admissions studies tend

to be larger geographically and

temporally than the emergency

department visit studies and provide

results that are generally more

consistent. The strongest associations of

respiratory hospital admissions with 03

concentrations were observed using

short lag periods, in particular for a 0-

day lag (same day exposure) and a 1-day

lag (previous day exposure). Most

studies in the United States and Canada

indicated positive, statistically

significant associations between

ambient 03 concentrations and

respiratory hospital admissions in the

warm season. However, not all studies

found a statistically significant

relationship with 03, possibly because

of very 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

only data.

Overall, the 2006 Criteria Document

concludes that positive and robust

associations were found between

ambient 03 concentrations and various

respiratory disease hospitalization

outcomes, when focusing particularly

on results of warm-season analyses.

Recent studies also generally indicate a

positive association between 03

concentrations and emergency

department visits for asthma during the

warm season (EPA, 2006a, p. 7-175).

These positive and robust associations

are supported by the 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 at ambient levels observed in the

U.S. However, the aggregate evidence

suggested that 03 exposure, along with

other environmental factors, could be

responsible for health effects in exposed

populations. Animal toxicological

studies carried out in the 1980's and

1990's demonstrated that long-term

exposures can result in a variety of

morphological effects, including

permanent changes in the small airways

of the lungs, including remodeling of

the distal airways and CAR and

deposition of collagen, possibly

representing fibrotic changes. These

changes result from the damage and

repair processes that occur with

repeated exposure. Fibrotic changes

were also found to persist after months

of exposure providing a potential

pathophysiologic basis for changes in

airway function observed in children in

some recent epidemiological studies. It

appears that variable seasonal ambient

patterns of exposure may be of greater

concern than continuous daily

exposures.

Several studies published since 1996

have investigated lung function changes

over seasonal time periods (EPA, 2006a,

section 7.5.3). The 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 03 levels. There is some limited

evidence that seasonal 03 also may

affect lung function growth in young

adults, although the uncertainty about

the role of copollutants makes it

difficult to attribute the effects to 03

alone.

Lung capacity grows during

childhood and adolescence as body size

increases, reaches a maximum during

the twenties, and then begins to decline

steadily and progressively with age.

Long-term exposure to air pollution has

long been thought to contribute to

slower growth in lung capacity,

diminished maximally attained

capacity, and/or more rapid decline in

lung capacity with age (EPA, 2006a,

section 7.5.4). Toxicological findings

evaluated in the 1996 Criteria Document

demonstrated that repeated daily

exposure of rats to an episodic profile of

03 caused small, but significant,

decrements in growth-related lung

function that were consistent with early

indicators of focal fibrogenesis in the

proximal alveolar region, without overt

fibrosis. Because 03 at sufficient

concentrations is a strong respiratory

irritant and has been shown to cause

inflammation and restructuring of the

respiratory airways, it is plausible that

long-term 03 exposures might have a

negative impact on baseline lung

function, particularly during childhood

when these exposures might be

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 of respiratory effects in

relation to long-term air pollution

exposures among children in the U.S. is

the Children's Health Study carried out

in 12 communities of southern

California starting in 1993. One analysis

(Peters et a., 1999a) examined the

relationship between long-term 03

exposures and self-reports of respiratory

symptoms and asthma in a cross

sectional analysis and found a limited

relationship between outcomes of

current asthma, bronchitis, cough and

wheeze and a 0.040 ppm increase in 1-

hour max 03 (EPA, 2006a, p. 7-115).

Another analysis (Peters et a]., 1999b)

examined the relationship between lung

function at baseline and levels of air

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 two being

statistically significant) among females

but not males. In a separate analysis

(Gauderman et a]., 2000) of 4th, 7th, and

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10th grade students, a longitudinal

analysis of lung function development

over four years found no association

with 03 exposure. The Children's

Health Study enrolled a second cohort

of more than 1500 fourth graders in

1996 (Gauderman et a]., 2002). While

the strongest associations with negative

lung function growth were observed

with acid vapors in this cohort, children

from communities with higher 4-year

average 03 levels also experienced

smaller increases in various lung

function parameters. The strongest

relationship with 03 was with PEF.

Specifically, children from the leastpolluted community had a small but

statistically significant increase in PEF

as compared to those from the mostpolluted communities. In two-pollutant

models, only 8-hour average 03 and NO 2

were significant joint predictors of FEV1

and maximal midexpiratory flow

(MMEF). Although results from the

second cohort of children are supportive

of a weak association, the definitive 8-

year follow-up analysis of the first

cohort (Gauderman et a]., 2004a)

provides little evidence that long-term

exposure to ambient 03 at current levels

is associated with significant deficits in

the growth rate of lung function in

children. Avol et a]. (2001) examined

children who had moved away from

participating communities in southern

California to other states with improved

air quality. They found that a negative,

but not statistically significant,

association was observed between 03

and lung function parameters.

Collectively, the results of these reports

from the children's health cohorts

provide little evidence to support an

impact of long-term 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 a nationwide

study of first year Yale students (Kinney

et a]., 1998; Galizia and Kinney, 1999)

(EPA, 2006a, p. 7-120). Males had much

larger effect estimates than females,

which might reflect higher outdoor

activity levels and correspondingly

higher 03 exposures during childhood.

A similar study of college freshmen at

University of California at Berkeley also

reported significant effects of long-term

03 exposures on lung function (Kiinzli

et a]., 1997; Tager eta]., 1998). In a

comparison of students whose city of

origin was either Los Angeles or San

Francisco, long-term 03 exposures were

associated with significant changes in

mid- and end-expiratory flow measures,

which could be considered early

indicators for pathologic changes that

might progress to COPD.

There have been a few studies that

investigated associations between longterm 03 exposures and the onset of new

cases of asthma (EPA, 2006a, section

7.5.6). The Adventist Health and Smog

(AHSMOG) study cohort of about 4,000

was drawn from nonsmoking, nonHispanic white adult Seventh Day

Adventists living in California (Greer et

a]., 1993; McDonnell et a]., 1999).

During the ten-year follow-up in 1987,

a statistically significant increased

relative risk of asthma development was

observed in males, compared to a

nonsignificant relative risk in females

(Greer et a]., 1993). In the 15-year

follow-up in 1992, it was reported that

for males, there was a statistically

significant increased relative risk of

developing asthma associated with 8-

hour average 03 exposures, but there

was no evidence of an association in

females. Consistency of results in the

two studies with different follow-up

times provides supportive evidence of

the potential for an association between

long-term 03 exposure and asthma

incidence in adult males; however,

representativeness of this cohort to the

general U.S. population may be limited

(EPA, 2006a, p. 7-125).

In a similar study (McConnell et aL.,

2002) of incident asthma among

children (ages 9 to 16 at enrollment),

annual surveys of 3,535 children

initially without asthma were used to

identify new-onset asthma cases as part

of the Children's Health Study. Six

high-U3 and six low-U 3 communities

were identified where the children

resided. There were 265 children who

reported new-onset asthma during the

follow-up period. Although asthma risk

was no higher for all residents of the six

high-U3 communities versus the six

low-U3 communities, asthma risk was

3.3 times greater for children who

played three or more sports as compared

with children who played no sports

within the high-U3 communities. 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. It should be noted, however, that

the results of the Children's Health

Study were based on a small number of

new-onset asthma cases among children

who played three or more sports. Future

replication of these findings in other

cohorts would help determine whether

a causal interpretation is appropriate.

In animal toxicology studies, the

progression of morphological effects

reported during and after a chronic

exposure in the range of 0.50 to 1.00

ppm 03 (well above current ambient

levels) is complex, 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). By contrast, fibrotic changes in

the tissue increase very slowly over

months of exposure, and, after exposure

ceases, the changes sometimes persist or

increase. Epithelial hyperplasia peaks

soon after the inflammatory response

but is usually maintained in both the

nose and lungs with continuous

exposure; it also does not return to preexposure levels after the end of

exposure. Patterns of exposure in this

same concentration range determine

effects, with 18 months of daily

exposure, causing less morphologic

damage than exposures on alternating

months. This is important as

environmental 03 exposure is typically

seasonal. Long-term studies by Plopper

and colleagues (Evans et a]., 2003;

Schelegle et a]., 2003; Chen et a]., 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 that these

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 too much uncertainty to

characterize the significance of these

findings to human exposure profiles and

effect levels (EPA, 2006a, p. 8-25).

In summary, in the past decade,

important new longitudinal studies

have examined the effect of chronic 03

exposure on respiratory health

outcomes. Limited evidence from recent

long-term morbidity studies have

suggested in some cases that chronic

exposure to 03 may be associated with

seasonal declines in lung function or

reduced lung function development,

increases in inflammation, and

development of asthma 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 of new asthma

development and longer-term lung

function declines remain inconclusive

at present (EPA, 2006a, p. 7-134).

iii. Effects on the Cardiovascular System

of 03 Exposure

At the time of the 1997 review, the

possibility of 0 3-induced cardiovascular

effects was largely unrecognized. Since

then, a very limited body of evidence

from animal, controlled human

exposure, and epidemiologic studies has

emerged that provides evidence for

some potential plausible mechanisms

for how 03 exposures might exert

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 of heart rate

or rhythm. Some animal toxicology

studies have shown 0 3-induced

decreases in heart rate, mean arterial

pressure, and core temperature. One

controlled human exposure study that

evaluated effects of 03 exposure on

cardiovascular health outcomes found

no significant 0 3-induced differences in

ECG or blood pressure in healthy or

hypertensive subjects but did observe a

significant 0 3-induced increase the

alveolar-to-arterial P0 2 gradient and

heart rate in both groups resulting in an

overall increase in myocardial work and

impairment in pulmonary gas exchange

(Gong et a]., 1998). In another controlled

human exposure study, inhalation of a

mixture of PM 2.5 and 03 by healthy

subjects increased brachial artery

vasoconstriction and reactivity (Brook et

a]., 2002).

The evidence from a few animal

studies also includes potential direct

effects such as 0 3-induced release from

lung epithelial cells of platelet

activating factor (PAF) that may

contribute to blood clot formation that

would have the potential to increase the

risk of serious cardiovascular outcomes

(e.g., heart attack, stroke, mortality).

Also, interactions of 03 with surfactant

components in epithelial lining fluid of

the lung may result in production of

oxysterols and reactive oxygen species

that may exhibit PAF-like activity

contributing to clotting and also may

exert cytotoxic effects on lung and heart

muscle cells.

Epidemiological panel and field

studies that examined associations

between 03 and various cardiac

physiologic endpoints have yielded

limited evidence suggestive of a

potential association between acute 03

exposure and altered heart rate

variability (HRV), ventricular

arrhythmias, and incidence of heart

attacks (myocardial infarction or MI). A

number of epidemiological 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 of the

studies reported negative or inconsistent

associations. Some other studies,

especially those that examined the

relationship when 03 exposures were

higher, have found robust positive

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 et a].,

1997b). The results were robust to

adjustment for various PM indices,

whereas the PM effects diminished

when adjusted for gaseous pollutants.

Other studies stratified their analysis by

temperature (i.e., by warms days versus

cool days). Several analyses using warm

season days consistently produced

positive associations.

The epidemiologic evidence for

cardiovascular morbidity is much

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 of which 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 on the evidence

from animal toxicology, controlled

human exposure, and epidemiological

studies, from the 2006 Criteria

Document (p. 8-77) concludes that this

generally limited body of evidence is

suggestive that 03 can directly and/or

indirectly contribute to cardiovascularrelated morbidity, but that much needs

to be done to more 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 a very limited number of studies

available at that time, there was

insufficient evidence to conclude that

the observed association was likely

causal.

The 2006 Criteria Document included

results from numerous epidemiological

analyses of the relationship between 03

and mortality. Additional single city

analyses have also been conducted since

1996, however, the most pivotal studies

in EPA's (and CASAC's) finding of

increased support for the relationship

between premature mortality and 03 is

in part related to differences in study

design-limiting analyses to warm

seasons, better control for copollutants,

particularly PM, and use of multicity

designs (both time series and metaanalytic designs). Key findings are

available from multicity time-series

studies that report associations between

03 and mortality. These studies include

analyses using data from 90 U.S. cities

in the National Mortality, Morbidity and

Air Pollution (NMMAPS) study

(Dominici et al., 2003) and from 95 U.S.

communities in an extension to the

NMMAPS analyses (Bell et al., 2004).

The original 90-city NMMAPS

analysis, with data from 1987 to 1994,

was primarily focused on investigating

effects of PM10 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 et al.,

2003). The estimate using all available

data was about half that for the summeronly data at a lag of 1-day. The extended

NMMAPS analysis included data from

95 U.S. cities and included an

additional 6 years of data, from 1987-

2000 (Bell et al., 2004). Significant

associations were reported between 03

and mortality 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 of the

NMMAPS data set, Huang et a]. (2005)

focused on associations between

cardiopulmonary mortality and 03

exposure (24-hour average) during the

summer season only. The authors report

an approximate 1.47 percent 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 of 03 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 that higher 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

only from 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 to time-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 to the different

adjustment methods for temperature.

An initial publication from APHEA, a

European multicity study, reported

statistically significant associations

between daily maximum 03

concentrations and mortality in four

cities in a full year analysis (Toulomi et

a]., 1997). An extended analysis was

done using data from 23 cities

throughout Europe (Gryparis et a].,

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 et a]. (2004) noted

that there was a considerable seasonal

difference in the 0 3 effect on mortality;

thus, the small effect for the all-year

data might be 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

also reported associations between

mortality and short-term 03 exposure,

especially for those analyses using

warm season data. As shown in Figure

7-21 of the 2006 Criteria Document, the

results of recent publications show a

pattern of positive, 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 of positive results but the

findings are less consistent. In most

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 and mortality.

As described in section 7.4.4 of the 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 of heterogeneity in 03-

mortality associations (Bell et a]., 2005;

Ito et a]., 2005; Levy et a]., 2005). The

2006 Criteria Document (p. 7-96)

observes common findings across all

three analyses, in that all reported that

effect estimates were larger in warm

season analyses, reanalysis of results

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 et a]. (2005)

and Ito et a]. (2005) both provided

suggestive evidence of publication 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 of a robust association

between ambient 03 and mortality"

(EPA, 2006a, p. 7-97).

Most of the single-pollutant model

estimates from single-city studies range

from 0.5 to 5 percent excess deaths per

standardized increments. Corresponding

summary estimates in large U.S.

multicity studies ranged between 0.5 to

1 percent with some studies noting

heterogeneity across cities and studies

(EPA, 2006a, p. 7-110).

Finally, from those studies that

included assessment of associations

with specific causes of death, it appears

that effect estimates for associations

with cardiovascular mortality are larger

than those for total mortality. The metaanalysis by Bell et a]. (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-half that of

cardiovascular mortality in the metaanalysis. However, other studies have

observed larger effect estimates for

respiratory mortality compared to

cardiovascular mortality. The apparent

inconsistency regarding the effect size of

0 3-related respiratory mortality may be

due to reduced statistical power in this

subcategory of mortality (EPA, 2006a, p.

7-108).

In summary, many single- and multicity studies observed positive

associations of ambient 03

concentrations with total nonaccidental

and cardiopulmonary mortality. The

2006 Criteria Document finds that the

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

to be confounded by PM; however,

future work is needed to better

understand the influence of model

specifications on the risk coefficient

(EPA, 2006a, p. 7-175). A meta-analysis

that examined specific causes of

mortality found that the 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 of lower statistical

power in this subcategory of mortality.

The 2006 Criteria Document (p. 8-78)

concludes that these 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'

21 In commenting on the Criteria Document, the

CASAC Ozone Panel raised questions about the

implications of these time-series results in a policy

context, emphasizing that * * while the timeseries study design is a powerful tool to detect very

small effects that could not be detected using other

designs, it is also a blunt tool" (Henderson, 2006b).

They note that * * not only is the interpretation

of these associations complicated by the fact that

the day-to-day variation in concentrations of these

pollutants is, to a varying degree, determined by

meteorology, the pollutants are often part of a large

and highly correlated mix of pollutants, only a very

few of which are measured" (Henderson, 2006b).

Even with these uncertainties, the CASAC Ozone

Panel, in its review of the 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 et a.,

1993). The authors note that the range

of 03 concentrations across the six cities

was small, which may have limited the

power of the study to detect associations

between mortality and 03 levels (EPA,

2006a, p. 7-127).

As discussed in section 7.5.8 of the

2006 Criteria Document, in this review

there are results available from three

prospective cohort studies: the

American Cancer Society (ACS) study

(Pope et a]., 2002), the Adventist Health

and Smog (AHSMOG) study (Beeson et

a]., 1998; Abbey et a]., 1999), and the

U.S. Veterans Cohort study (Lipfert et

a]., 2000, 2003). In addition, a major

reanalysis report includes evaluation of

data from the Harvard Six City cohort

study (Krewski et a]., 2000).22 This

reanalysis also includes additional

evaluation of data from the initial ACS

cohort study report that had only

reported results of associations between

mortality and long-term exposure to fine

particles and sulfates (Pope et a]., 1995).

This reanalysis was discussed in the

2007 Staff Paper (section 3.3.2.2) but not

in the 2006 Criteria Document.

In this reanalysis of data from the

previous Harvard Six City prospective

cohort study, the investigators

replicated and validated the findings of

the original studies, and the report

included additional quantitative results

beyond those available in the original

report (Krewski et a]., 2000). In the

reanalysis of data 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 is based 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 et a]., 1995)

focused on associations with fine

particles and sulfates, for which

significant associations had been

reported in the earlier Harvard Six

Cities study (Dockery et a]., 1993). As

part of the major reanalysis of these

22 This reanalysis report and the original

prospective cohort study findings are discussed in

more detail in section 8.2.3 of the Air Quality

Criteria for Particulate Matter (EPA, 2004).

data, results for associations with other

air pollutants were also reported, and

the authors report that no significant

associations were found between 03 and

all-cause mortality. However, a

significant association was reported for

cardiopulmonary mortality in the warm

season (Krewski et a]., 2000). The ACS

II study (Pope et a]., 2002) reported

results of associations with an extended

data base; the mortality records for the

cohort had been updated to include 16

years of follow-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 in both the fullyear and warm season analyses.

The Adventist Health and Smog

(AHSMOG) cohort includes about 6,000

adults living in California. In two

studies from this cohort, a significant

association has been reported between

long-term 03 exposure and increased

risk of lung cancer mortality among

males only (Beeson et a]., 1998; Abbey

et a]., 1999). No significant associations

were reported between long-term 03

exposure and mortality from all causes

or cardiopulmonary causes. Due to the

small numbers of lung cancer deaths (12

for males, 18 for females) and the

precision of the effect estimate (i.e., the

wide confidence intervals), the 2006

Criteria Document (p. 7-130) discussed

concerns about the plausibility of the

reported association with lung cancer.

The U.S. Veterans Cohort study

(Lipfert et a]., 2000, 2003) of

approximately 50,000 middle-aged

males diagnosed with hypertension,

reported some positive associations

between mortality and peak 03

exposures (95th percentile level for

several years of data). The study

included numerous analyses using

subsets of exposure 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 Criteria Document

(p. 7-130) concludes that consistent

associations have not been reported

between long-term 03 exposure and allcause, cardiopulmonary or lung cancer

mortality.

c. Role of Ground-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 Criteria Document also assesses

potential indirect effects related to the

presence of 03 in the ambient air by

considering the role of ground-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 Criteria Document

provides a thorough analysis of the

current understanding of the

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 that influence

UV-B radiation penetration to the

earth's surface, including latitude,

altitude, cloud cover, surface albedo,

PM concentration and composition, and

gas phase pollution. Of these, only

latitude and altitude can be defined

with small uncertainty in any effort to

assess the changes in UV-B flux that

may be attributable to any changes in

tropospheric 03 as a result of any

revision to the 03 NAAQS. Such an

assessment of UV-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 of these 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; and immune

system suppression); wavelength

dependency of biological responses; and

interindividual variability in UV-B

resistance to such health outcomes.

Beyond these well recognized adverse

health effects associated with various

wavelengths of UV radiation, the 2006

Criteria Document (section 10.2.3.6) also

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discusses protective effects of UV-B

radiation. Recent reports indicate the

necessity of UV-B in producing vitamin

D. Vitamin D deficiency can cause

metabolic bone disease among children

and adults, and may also increase the

risk of many common chronic diseases

(e.g., type I diabetes and rheumatoid

arthritis) as well as the risk of various

types of cancers. Thus, the 2006 Criteria

Document concludes that any

assessment that attempts to quantify the

consequences of increased UV-B

exposure on humans due to reduced

ground-level 03 must include

consideration of both negative and

positive effects. However, as with other

impacts of UV-B on human health, this

beneficial effect of UV-B radiation has

not been studied in sufficient detail to

allow for a credible health benefits or

risk assessment. In conclusion, the

effect of changes in surface-level 03

concentrations on UV-B-induced health

outcomes cannot yet be critically

assessed within reasonable uncertainty

(2006 Criteria Document, p. 10-36).

The Agency last considered indirect

effects of 03 in the ambient air in its

2003 final response to a remand of the

Agency's 1997 decision to revise the 03

NAAQS. In so doing, based on the

available information in the 1997

review, EPA determined that the

information linking (a) changes in

patterns of ground-level 03

concentrations likely to occur as a result

of programs implemented to attain the

1997 03 NAAQS to (b) changes in

relevant exposures to UV-B radiation of

concern to public health was too

uncertain at that time to warrant any

relaxation in the level of public health

protection previously determined to be

requisite to protect against the

demonstrated direct adverse respiratory

effects of exposure to 03 in the ambient

air (68 FR 614). At that time, the more

recent information on protective effects

of UV-B radiation was not available,

such that 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 Staff Paper conclude that the effect

of changes in ground-level 03

concentrations, likely to occur as a

result of revising the 03 NAAQS, on

UV-B-induced health outcomes,

including whether these changes would

ultimately result in increased or

decreased incidence of UV-B-related

diseases, cannot yet be critically

assessed.

3. Interpretation and Integration of

Health Evidence

As discussed below, in assessing the

health evidence, the 2006 Criteria

Document integrates findings from

experimental (e.g., toxicological,

dosimetric and controlled human

exposure) and epidemiological studies,

to make judgments 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 of reported

associations, including the magnitude

and precision of reported effect

estimates and their statistical

significance; the robustness of reported

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 of exposure measurement

error; potential aggregation bias in

pooling data; and the consistency of the

effects associations as observed by

looking across results of multiple- 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 of observed 0 3-related

health effects to reach judgments 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 of Evidence From

Epidemiological Studies

Key elements of the evaluation of

epidemiological studies are briefly

summarized below.

(1) The strength of associations most

directly refers to the magnitude of the

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 of an association as "the

magnitude of the association and its

statistical strength" which includes

assessment of both effect estimate size

and precision, which is related to the

statistical power of the study (CDC,

2004). In general, when associations are

strong in terms of yielding large relative

risk estimates, it is less likely that the

association could be completely

accounted for by a potential confounder

or some other source of bias, whereas

with associations that yield small

relative risk estimates it is especially

important to consider potential

confounding and other factors in

assessing causality. Effect estimates

between 03 and some of the 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 5 percent increases per

0.040 ppm increase in 1-hour maximum

03 or equivalent, whereas associations

for hospitalization range up to 50

percent increases per standardized 03

increment. However, the 2006 Criteria

Document notes that there are large

multicity studies that find small

associations between short-term 03

exposure and mortality or morbidity

and have done so with great precision

due to the statistical power of the

studies (p. 8-40). That is, the power of

the studies allows the authors to reliably

distinguish even weak relationships

from the null hypothesis 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 Staff Paper (section 3.4.2) have

primarily considered the impact of

exposure error, potential confounding

by copollutants, and alternative models

and model 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 of months to years are used as

indicators of a community's long-term

exposure to ambient 03 and other

pollutants. In both types of analyses,

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 sites may

explain, at least partially, the variance

in individual exposures to ambient 03;

however, this relationship is influenced

by various factors related to building

ventilation practices and personal

behaviors. Further, the pattern of

exposure misclassification error and the

influence of confounders may differ

across the outcomes of interest 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

of the strongest predictors of the

relationship between ambient

concentrations and personal exposures

appears to be 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

et a]., 1996; Xu et a]., 2005). There is

some concern about the extent to which

ambient concentrations are

representative of personal 03 exposures

of another particularly susceptible

group of individuals, 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

and its confounders, such as high

temperature and PM. Studies by Sarnat

et a]. (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 that the daily averaged

personal 03 exposures tend to be 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 as valid surrogate

measures for mean personal exposures

experienced by the population, which is

of most relevance for time-series

studies. A better understanding of the

relationship between ambient

concentrations and personal exposures,

as well as of the other factors that affect

relationship will improve the

interpretation of concentrationpopulation health response associations

observed.

The 2006 Criteria Document (section

7.1.3.1) also discusses the potential

influence of exposure error on

epidemiologic study results. Zeger et a].

(2000) outlined the components to

exposure measurement error, finding

that ambient exposure can be assumed

to be the product of the ambient

concentration and an attenuation factor

(i.e., building filter) and that panel

studies and time-series studies that use

ambient concentrations instead of

personal exposure measurements will

estimate a health risk that is attenuated

by that factor. Navidi et a]. (1999) used

data from a children's cohort study to

compare effect estimates from a

simulated "true" exposure level to

results of analyses from 03 exposures

determined by several methods, finding

that 03 exposures based on the 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 of a

study by Burnett et a]. (1994) on the

acute respiratory effects of ambient air

pollution, Zidek et a]. (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 risk based on personal behavior,

their microenvironment, and the

qualities of the pollutant in time-series

studies. Of particular interest is their

finding that risk 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 of exposure and the

resulting underestimation of effects, the

use of ambient 03 concentrations may

obscure the presence of thresholds in

epidemiologic studies (EPA, 2006a, p.

7-9).

As discussed in the 2006 Criteria

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 is that the effects being

estimated occur at fairly low exposures

and the potency of 03 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 must be

evaluated and used with caution to

assess the health risks of 03. In the

absence of available data on personal 03

exposure, the use of routinely

monitored ambient 03 concentrations as

a surrogate for personal exposures is not

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 of effect estimates calculated using

ambient 03 concentrations as they may

lead to underestimation of the potency

of 03. However, the 2007 Staff Paper

observes that the use of these risk

estimates for comparing relative risk

reductions between alternative ambient

03 standards considered in the risk

assessment (discussed below in section

II.B.2) is less likely to suffer from this

concern.

Confounding occurs when a health

effect that is caused by one risk factor

is attributed to another variable that is

correlated with the causal risk factor;

epidemiological analyses attempt to

adjust or control for potential

confounders. Copollutants (e.g., PM,

CO, SO 2 and NO 2) can meet the criteria

for potential confounding in 0 3-health

associations if they are potential risk

factors for the health effect under study

and are correlated with 03. Effect

modifiers include variables that may

influence the health response to the

pollutant exposure (e.g., co-pollutants,

individual susceptibility, smoking or

age). Both are important considerations

for evaluating effects in a mixture of

pollutants, but for confounding, the

emphasis is on controlling or adjusting

for potential confounders in estimating

the effects of one pollutant, while the

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, SO 2 and

NO2), but may be more highly correlated

with secondary fine particles, especially

during the summer months, and that the

degree of correlation between 03 and

other pollutants may vary across

seasons. For example, positive

associations are observed between 03

and pollutants such as fine particles

during the warmer months, but negative

correlations may be observed during the

cooler months (EPA, 2006a, p. 7-17).

Thus, the 2006 Criteria Document

(section 7.6.4) pays particular attention

to the results of season-specific analyses

and studies that assess effects of PM in

potential confounding of 0 3-health

relationships. The 2006 Criteria

Document also discussed the limitations

of commonly used multipollutant

models that include 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 0 3-mortality

associations do not appear to be

substantially changed in multipollutant

models including PM1 o or PM2.

5 (EPA,

2006a, p. 7-101; Figure 7-22). Focusing

on results of warm season analyses,

effect estimates for 0 3-mortality

associations are fairly robust to

adjustment for PM in multipollutant

models (EPA, 2006a, p. 7-102; Figure

7-23). The 2006 Criteria Document

concludes that in 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 of relationships

between respiratory symptoms or lung

function with 03, but the 2006 Criteria

Document reports that results of

available analyses indicate that such

associations generally were robust to

adjustment for PM 2.

5 (p. 7-154). For

example, in a large multicity study of

asthmatic children (Mortimer et al.,

2002), the 03 effect was attenuated, but

there was still a positive association; in

Gent et a]. (2003), effects of 03, but not

PM 2.5, remained statistically significant

and even increased in magnitude in

two-pollutant models (EPA, 2006a, p.

7-53). Considering this body of studies,

the 2006 Criteria Document (p. 7-154)

concludes: "Multipollultant regression

analyses indicated that 03 risk

estimates, in general, were not sensitive

to the inclusion of copollutants,

including PM 2.5 and sulfate. These

results suggest that the effects of 03 on

respiratory health outcomes appear to

be robust and independent of the effects

of other copollutants."

The 2006 Criteria Document (p. 7-14)

observes that another challenge of timeseries epidemiological analysis is

assessing the relationship between 03

and health outcomes while avoiding

bias due to confounding by other timevarying factors, particularly seasonal

trends and weather variables. These

variables are of particular interest

because 03 concentrations have a wellcharacterized seasonal pattern and are

also highly correlated with changes in

temperature, such that it can 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 that have been used to

adjust for time-varying factors,

highlighting a series of analyses that

were done in a Health Effects Institutefunded reanalysis of numerous timeseries studies. While the focus of these

reanalyses was on associations with PM,

a number of investigators also examined

the sensitivity of 03 coefficients to the

extent of adjustment for temporal trends

and weather factors. In addition, several

recent studies, including U.S. multicity

studies (Bell et al., 2005; Huang et al.,

2005; Schwartz et al., 2005) and a metaanalysis study (Ito et al., 2005),

evaluated the effect of model

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 et a].

(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 of epidemiological 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 to the persistent

finding of an association between

exposure and outcome in multiple

studies of adequate 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 to 03, as well

as varying concentrations and

composition of copollutants present in

different regions. Thus, the 2006 Criteria

Document (p. 8-41) concludes that

"consideration of consistency or

heterogeneity of effects is appropriately

understood as an evaluation of the

similarity or general concordance of

results, rather than an expectation of

finding quantitative results with a very

narrow range."

(4) The 2007 Staff Paper recognizes

that it is likely that there are biological

thresholds for different health effects in

individuals or groups of individuals

with similar innate characteristics and

health status. For 03 exposure,

individual thresholds would

presumably vary substantially from

person to person due to individual

differences in genetic susceptibility,

pre-existing disease conditions and

possibly individual risk factors such as

diet or exercise levels (and could even

vary from one time to another for a

given person). Thus, it would be

difficult to detect a distinct threshold at

the population level below which no

individual would experience a given

effect, especially if some 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 and health outcomes after

removal of days with higher 03 levels

from the data set; such analyses do not

necessarily indicate the presence or

absence of a threshold, but provide

some information on whether the

relationship is found using only lowerconcentration data. For example, using

data from 95 U.S. cities, Bell et a].

(2004) found that the 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 data from 8 U.S.

cities, Mortimer and colleagues (2002)

also reported that associations between

03 and both lung function and

respiratory symptoms remained

statistically significant and of the same

or greater magnitude in effect size when

concentrations greater than 0.080 ppm

(8-hour average) were excluded (EPA,

2006a, p. 7-46). Several single-city

studies also report similar findings of

associations that remain or are increased

in magnitude and statistical significance

when data at the upper end of the

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 of the 2006

Criteria Document, one European

multicity study included evaluation of

the shape of the concentration-response

curve, and observed no deviation from

a linear function across the range of 03

measurements from the study (Gryparis

et a]., 2004; EPA, 2006a p. 7-154).

Several single-city studies also observed

a monotonic increase in associations

between 03 and morbidity 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 the best fit for

the data. The results suggested a

potential threshold level of about 0.045

ppm (1-hour maximum concentration;

< 0.035 ppm, 8-hour average) for an

association between mortality and shortterm 03 exposure during the summer

months (Kim et al., 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 might be underestimated in

the non-threshold model. A threshold

analysis recently reported by Bell et a].

(2006) for 98 U.S. communities,

including the same 95 communities in

Bell et a]. (2004), indicated that if a

population threshold existed for

mortality, it would likely fall 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 and both 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 and mortality in British

Columbia where 03 concentrations were

quite low (mean 1-hour maximum

concentration of 0.0273 ppm). The

authors did not specifically test for

threshold levels, but the fact that the

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 that no clear conclusion

can now be reached with regard to

possible threshold levels for 0 3-related

effects (EPA, 2006a, p. 8-44). Thus, the

available epidemiological evidence

neither supports nor refutes the

existence of thresholds 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 to 0 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 of air quality observed

in the studies but not be detectable as

population thresholds in

epidemiological analyses.

b. Biological Plausibility and Coherence

of Evidence

The body of epidemiological studies

discussed in the 2007 Staff Paper

emphasizes the role of 03 in association

with a variety of adverse respiratory and

cardiovascular effects. While

recognizing a variety of plausible

mechanisms, there exists a general

consensus suggesting that 03, could

either directly or through initiation,

interfere with basic cellular oxidation

processes responsible for inflammation,

reduced antioxidant capacity,

atherosclerosis and other effects.

Reasoning that 03 influences cellular

chemistry through basic 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 of adverse

respiratory and cardiovascular health

effects. Consequently, the role of 03

should be considered more broadly as

03 behaves as a generator of numerous

oxidative species in the atmosphere.

In considering the biological

plausibility of reported 0 3-related

effects, the 2007 Staff Paper (section

3.4.6) considers this broader question of

health effects of pollutant mixtures

containing 03. The potential for 03-

related enhancements of PM formation,

particle uptake, and exacerbation of PMinduced cardiovascular effects

underscores the importance of

considering contributions of 03

interactions with other often cooccurring air pollutants to health effects

due to 0 3-containing pollutant mixes.

The 2007 Staff Paper summarizes some

examples of important pollutant

mixture effects from studies that

evaluate interactions of 03 with other

co-occurring pollutants, as discussed in

chapters 4, 5, and 6 of the 2006 Criteria

Document.

All of the types of interactive effects

of 03 with other co-occurring gaseous

and nongaseous viable and nonviable

PM components of ambient air mixes

noted above argue that 03 acts not only

alone but that 03 also is a surrogate

indicator for air pollution mixes which

may enhance the risk of adverse effects

due to 03 acting in combination with

other pollutants. Viewed from this

perspective, those epidemiologic

findings of morbidity 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 and biological plausibility of

0 3-related health effects to reach

judgments about the causal nature of

observed associations. As summarized

below, coherence and biological

plausibility is discussed for each of the

following types of 0 3-related effects:

Short-term effects on the respiratory

system, effects on the cardiovascular

system, effects related to 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 have been associated with shortterm exposure to 03 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 03 has 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 also been 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, the results

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 can be seen that

mostly positive associations have been

reported with respiratory effects ranging

from respiratory symptoms, such as

cough or wheeze, to hospitalization for

various respiratory diseases, and there is

suggestive evidence for associations

with respiratory mortality. Many of the

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 that follow, an individual

study result is considered to be

statistically significant if the 95 percent

confidence interval does not include

zero. 23 Positive effect estimates indicate

23 Results for studies of respiratory 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, it is important to consider not

only whether statistical significance at

the 95 percent confidence level is

reported in individual studies but also

the general pattern of results, focusing

in particular on studies with greater

statistical power that report relatively

more precise results.

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