Primary National Ambient Air Quality Standard for Nitrogen Dioxide

Federal RegisterJul 15, 2009

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Parts 50 and 58

[EPA-HQ-OAR-2006-0922; FRL-8926-3]

RIN 2060-AO19

Primary National Ambient Air Quality Standard for Nitrogen Dioxide

AGENCY:

Environmental Protection Agency (EPA).

ACTION:

Proposed rule.

SUMMARY:

Based on its review of the air quality criteria for oxides of nitrogen and the primary national ambient air quality standard (NAAQS) for oxides of nitrogen as measured by nitrogen dioxide (NO

), EPA proposes to make revisions to the primary NO

NAAQS in order to provide requisite protection of public health. Specifically, EPA proposes to supplement the current annual standard by establishing a new short-term NO

standard based on the 3-year average of the 99th percentile (or 4th highest) of 1-hour daily maximum concentrations. EPA proposes to set the level of this new standard within the range of 80 to 100 ppb and solicits comment on standard levels as low as 65 ppb and as high as 150 ppb. EPA also proposes to establish requirements for an NO

monitoring network that will include monitors within 50 meters of major roadways. In addition, EPA is soliciting comment on an alternative approach to setting the standard and revising the monitoring network. Consistent with the terms of a consent decree, the Administrator will sign a notice of final rulemaking by January 22, 2010.

DATES:

Comments must be received on or before September 14, 2009. Under the Paperwork Reduction Act, comments on the information collection provisions must be received by OMB on or before August 14, 2009.

Public Hearings:

EPA intends to hold public hearings on this proposed rule in August 2009 in Los Angeles, California and Arlington, VA. These will be announced in a separate

Federal Register

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

ADDRESSES:

Submit your comments, identified by Docket ID No. EPA-HQ-OAR-2006-0922 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-OAR-2006-0922, Environmental Protection Agency, Mail code 6102T, 1200 Pennsylvania Ave., NW., Washington, DC 20460. Please include a total of two copies.

•

Hand Delivery

: Docket No. EPA-HQ-OAR-2006-0922, Environmental Protection Agency, EPA West, Room 3334, 1301 Constitution Ave., NW., Washington, DC. Such deliveries are only accepted during the Docket's normal hours of operation, and special arrangements should be made for deliveries of boxed information.

Instructions

: Direct your comments to Docket ID No. EPA-HQ-OAR-2006-0922. EPA's policy is that all comments received will be included in the public docket without change and may be made available online at

http://www.regulations.gov

, including any personal information provided, unless the comment includes information claimed to be Confidential Business Information (CBI) or other information whose disclosure is restricted by statute. Do not submit information that you consider to be CBI or otherwise protected through

http://www.regulations.gov

or e-mail. The

http://www.regulations.gov

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

http://www.regulations.gov

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

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

Docket:

All documents in the docket are listed in the

http://www.regulations.gov

index. Although listed in the index, some information is not publicly available,

e.g.

, CBI or other information whose disclosure is restricted by statute. Certain other material, such as copyrighted material, will be publicly available only in hard copy. Publicly available docket materials are available either electronically in

http://www.regulations.gov

or in hard copy at the Air and Radiation Docket and Information Center, EPA/DC, EPA West, Room 3334, 1301 Constitution Ave., NW., Washington, DC. The Public Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal holidays. The telephone number for the Public Reading Room is (202) 566-1744 and the telephone number for the Air and Radiation Docket and Information Center is (202) 566-1742.

FOR FURTHER INFORMATION CONTACT:

Dr. Scott Jenkins, 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: 919-541-1167; fax: 919-541-0237; e-mail:

jenkins.scott@epa.gov

SUPPLEMENTARY INFORMATION:

General Information

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

Submitting CBI

. Do not submit this information to 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.

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 the documents that are relevant to this rulemaking are available through EPA's Office of Air Quality Planning and Standards (OAQPS) Technology Transfer Network (TTN) Web site at

http://www.epa.gov/ttn/naaqs/standards/nox/s_nox_index.html

. These documents include the Integrated Review Plan and the Health Assessment Plan, available at

http://www.epa.gov/ttn/naaqs/standards/nox/s_nox_cr_pd.html

, the Integrated Science Assessment (ISA), available at

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=194645

, and the Risk and Exposure Assessment (REA), available at

http://www.epa.gov/ttn/naaqs/standards/nox/s_nox_cr_rea.html

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

Table of Contents

The following topics are discussed in this preamble:

I. Background

A. Legislative Requirements

B. Related NO

Control Programs

C. Review of the Air Quality Criteria and Standards for Oxides of Nitrogen

II. Rationale for Proposed Decisions on the Primary Standard

A. Characterization of NO

Air Quality

1. Current Patterns of NO

Air Quality

2. NO

Air Quality and Gradients Around Roadways

B. Health Effects Information

1. Adverse Respiratory Effects and Short-Term Exposure to NO

a. Emergency Department Visits and Hospital Admissions

b. Respiratory Symptoms

c. Impaired Host Defense

d. Airway Response

e. Airway Inflammation

f. Lung Function

g. Conclusions From the ISA

2. Other Effects With Short-Term Exposure to NO

a. Mortality

b. Cardiovascular Effects

3. Health Effects With Long-Term Exposure to NO

a. Respiratory Morbidity

b. Mortality

c. Carcinogenic, Cardiovascular, and Reproductive/Developmental Effects

4. NO

-Related Impacts on Public Health

a. Pre-Existing Disease

b. Age

c. Genetics

d. Gender

e. Proximity to Roadways

f. Socioeconomic Status

g. Size of the At-Risk Population

C. Human Exposure and Health Risk Characterization

1. Evidence Base for the Risk Characterization

2. Overview of Approaches

3. Key Limitations and Uncertainties

D. Considerations in Review of the Standard

1. Background on the Current Standard

2. Approach for Reviewing the Need to Retain or Revise the Current Standard

E. Adequacy of the Current Standard

1. Evidence-Based Considerations

2. Exposure- and Risk-Based Considerations

3. Summary of Considerations From the REA

4. CASAC Views

5. Administrator's Conclusions Regarding Adequacy of the Current Standard

F. Conclusions on the Elements of a New Short-Term Standard and an Annual Standard

1. Indicator

2. Averaging Time

a. Short-Term Averaging Time

b. Long-Term Averaging Time

c. CASAC Views

d. Administrator's Conclusions on Averaging Time

3. Form

4. Level

a. Evidence-Based Considerations

b. Exposure- and Risk-Based Considerations

c. Summary of Consideration From the REA

d. CASAC Views

e. Administrator's Conclusions on Level for a 1-Hour Standard

f. Alternative Approach to Setting the 1-Hour Standard Level

g. Level of the Annual Standard

G. Summary of Proposed Decisions on the Primary Standard

III. Proposed Amendments to Ambient Monitoring and Reporting Requirements

A. Monitoring Methods

B. Network Design

1. Background

2. Proposed Changes

a. Monitoring in Areas of Expected Maximum Concentrations Near Major Roads

b. Area-Wide Monitoring at Neighborhood and Larger Spatial Scales

3. Solicitation for Comment on an Alternative Network Design

C. Data Reporting

IV. Proposed Appendix S—Interpretation of the Primary NAAQS for Oxides of Nitrogen and Proposed Revisions to the Exceptional Events Rule

A. Background

B. Interpretation of the Primary NAAQS for Oxides of Nitrogen

1. Annual Primary Standard

2. 1-Hour Primary Standard Based on the Annual 4th Highest Daily Value Form

3. 1-Hour Primary Standard Based on the Annual 99th Percentile Value Form

C. Exceptional Events Information Submission Schedule

V. Clean Air Act Implementation Requirements

A. Designations

B. Classifications

C. Attainment Dates

1. Attaining the NAAQS

2. Consequences of Failing to Attain by the Statutory Attainment Date

D. Section 110(a)(2) NAAQS Infrastructure Requirements

E. Attainment Planning Requirements

1. Nonattainment Area SIPs

2. New Source Review and Prevention of Significant Deterioration Requirements

3. General Conformity

4. Transportation Conformity

VI. Communication of Public Health Information

VII. Statutory and Executive Order Reviews

References

I. Background

A. Legislative Requirements

Two sections of the Clean Air Act (Act or CAA) govern the establishment and revision of the NAAQS. Section 108 of the Act directs the Administrator to identify and list air pollutants that meet certain criteria, including that the air pollutant “in his judgment, cause[s] or contribute[s] to air pollution which may reasonably be anticipated to endanger public health and welfare” and “the presence of which in the ambient air results from numerous or diverse mobile or stationary sources.” 42 U.S.C. 21 7408(a)(1)(A) & (B). For those air pollutants listed, section 108 requires the Administrator to issue air quality criteria that “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 ambient air * * *” 42 U.S.C. 7408(2).

Section 109(a) of the Act directs the Administrator to promulgate “primary” and “secondary” NAAQS for pollutants for which air quality criteria have been issued. 42 U.S.C. 7409(1). Section 109(b)(1) defines a primary standard as one “the attainment and maintenance of which in the judgment of the Administrator, based on [the air quality] criteria and allowing an adequate margin of safety, are requisite to protect the public health.”

42 U.S.C. 7409(b)(1). A secondary standard, in turn, must “specify a level of air quality the attainment and maintenance of which, in the judgment of the Administrator, based on [the air quality] criteria, is requisite to protect the public

welfare from any known or anticipated adverse effects associated with the presence of such pollutant in the ambient air.”

42 U.S.C. 7409(b)(2).

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).

EPA is currently conducting a separate review of the secondary NO

NAAQS jointly with a review of the secondary SO

NAAQS.

The requirement that primary standards include an adequate margin of safety is intended to address uncertainties associated with inconclusive scientific and technical information available at the time of standard setting. It is also intended to provide a reasonable degree of protection against hazards that research has not yet identified.

Lead Industries Association

EPA,

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

cert. denied,

449 U.S. 1042 (1980);

American Petroleum Institute

Costle,

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

cert. denied

, 455 U.S. 1034 (1982). Both kinds of uncertainties are components of the risk associated with pollution at levels below those at which human health effects can be said to occur with reasonable scientific certainty. Thus, in selecting primary standards that include an adequate margin of safety, the Administrator is seeking not only to prevent pollution levels that have been demonstrated to be harmful but also to prevent lower pollutant levels that may pose an unacceptable risk of harm, even if the risk is not precisely identified as to nature or degree.

In addressing the requirement for a margin of safety, EPA considers such factors as the nature and severity of the health effects involved, the size of the at-risk population(s), and the kind and degree of the uncertainties that must be addressed. The selection of any particular approach to providing an adequate margin of safety is a policy choice left specifically to the Administrator's judgment.

Lead Industries Association

EPA, supra,

647 F.2d at 1161-62.

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. In so doing, EPA may not consider the costs of implementing the standards.

Whitman

American Trucking Associations,

531 U.S. 457, 471, 475-76 (2001).

Section 109(d)(1) of the Act requires the Administrator to periodically undertake a thorough review of the air quality criteria published under section 108 and the NAAQS and to revise the criteria and standards as may be appropriate. 42 U.S.C. 7409(d)(1). The Act also requires the Administrator to appoint an independent scientific review committee composed of seven members, including at least one member of the National Academy of Sciences, one physician, and one person representing State air pollution control agencies, to review the air quality criteria and NAAQS and to “recommend to the Administrator any new standards and revisions of existing criteria and standards as may be appropriate under section 108 and subsection (b) of this section.” 42 U.S.C. 7409(d)(2). This independent review function is performed by the Clean Air Scientific Advisory Committee (CASAC) of EPA's Science Advisory Board.

B. Related NO

Control Programs

States are primarily responsible 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 sources of the pollutants involved. The States, in conjunction with EPA, also administer the prevention of significant deterioration program that covers these pollutants.

See

42 U.S.C. 7470-7479. In addition, Federal programs provide for nationwide reductions in emissions of these and other air pollutants under Title II of the Act, 42 U.S.C. 7521—7574, which involves controls for automobile, truck, bus, motorcycle, nonroad engine and equipment, and aircraft emissions; the new source performance standards under section 111 of the Act, 42 U.S.C. 7411; and the national emission standards for hazardous air pollutants under section 112 of the Act, 42 U.S.C. 7412.

Currently there are no areas in the United States that are designated as nonattainment of the NO

NAAQS. If the NO

NAAQS is revised as a result of this review, however, some areas could be classified as non-attainment. Certain States would then be required to develop SIPs that identify and implement specific air pollution control measures to reduce ambient NO

concentrations to attain and maintain the revised NO

NAAQS, most likely by requiring air pollution controls on sources that emit oxides of nitrogen (NO

In this document, the terms “oxides of nitrogen” and “nitrogen oxides” (NO

) refer to all forms of oxidized nitrogen (N) compounds, including NO, NO

, and all other oxidized N-containing compounds formed from NO and NO

. This follows usage in the Clean Air Act Section 108(c): “Such criteria [for oxides of nitrogen] shall include a discussion of nitric and nitrous acids, nitrites, nitrates, nitrosamines, and other carcinogenic and potentially carcinogenic derivatives of oxides of nitrogen.” By contrast, within the air pollution research and control communities, the terms “oxides of nitrogen” and “nitrogen oxides” are restricted to refer only to the sum of NO and NO

, and this sum is commonly abbreviated as NO

. The category label used by this community for the sum of all forms of oxidized nitrogen compounds including those listed in Section 108(c) is NO

While NO

is emitted from a wide variety of source types, the top three categories of sources of NO

emissions are on-road mobile sources, electricity generating units, and non-road mobile sources. EPA anticipates that NO

emissions will decrease substantially over about the next 20 years as a result of the ongoing implementation of mobile source emissions standards. In particular, Tier 2 NO

emission standards for light-duty vehicle emissions began phasing into the fleet beginning with model year 2004, in combination with low-sulfur gasoline fuel standards. For heavy-duty engines, new NO

standards are phasing in between the 2007 and 2010 model years, following the introduction of ultra-low sulfur diesel fuel. Lower NO

standards for nonroad diesel engines, locomotives, and certain marine engines are becoming effective throughout the next decade. In future decades, these lower-NO

vehicles and engines will become an increasingly large fraction of in-use mobile sources, effecting large NO

emission reductions.

C. Review of the Air Quality Criteria and Standards for Oxides of Nitrogen

On April 30, 1971, EPA promulgated identical primary and secondary NAAQS for NO

under section 109 of the Act. The standards were set at 0.053 parts per million (ppm) (53 ppb), annual average (36 FR 8186). EPA completed reviews of the air quality criteria and NO

standards in 1985 and 1996 with decisions to retain the standard (50 FR 25532, June 19, 1985; 61 FR 52852, October 8, 1996).

EPA initiated the current review of the air quality criteria for oxides of nitrogen and the NO

primary NAAQS on December 9, 2005 (70 FR 73236) with a general call for information. EPA's draft Integrated Review Plan for the Primary National Ambient Air Quality Standard for Nitrogen Dioxide (EPA, 2007a) was made available in February 2007 for public comment and was discussed by the CASAC via a publicly accessible teleconference on May 11, 2007. As noted in that plan, NO

includes multiple gaseous (

e.g.

, NO

, NO) and particulate (

e.g.

, nitrate) species. Because the health effects

associated with particulate species of NO

have been considered within the context of the health effects of ambient particles in the Agency's review of the NAAQS for particulate matter (PM), the current review of the primary NO

NAAQS is focused on the gaseous species of NO

and does not consider health effects directly associated with particulate species.

The first draft of the Integrated Science Assessment for Oxides of Nitrogen-Health Criteria (ISA) and the Nitrogen Dioxide Health Assessment Plan: Scope and Methods for Exposure and Risk Assessment (EPA, 2007b) were reviewed by CASAC at a public meeting held on October 24-25, 2007. Based on comments received from CASAC and the public, EPA developed the second draft of the ISA and the first draft of the Risk and Exposure Assessment to Support the Review of the NO

Primary National Ambient Air Quality Standard (Risk and Exposure Assessment (REA)). These documents were reviewed by CASAC at a public meeting held on May 1-2, 2008. Based on comments received from CASAC and the public at this meeting, EPA released the final ISA in July of 2008 (EPA, 2008a). In addition, comments received were considered in developing the second draft of the REA, which was released for public review and comment in two parts. The first part of this document, containing chapters 1-7, 9 and appendices A and C as well as part of appendix B, was released in August, 2008. The second part of this document, containing chapter 8 (describing the Atlanta exposure assessment) and a completed appendix B, was released in October of 2008. This document was the subject of CASAC reviews at public meetings on September 9 and 10, 2008 (for the first part) and on October 22, 2008 (for the second part). In preparing the final REA (EPA, 2008b), EPA considered comments received from the CASAC and the public at those meetings.

In the course of reviewing the second draft REA, CASAC expressed the view that the document would be incomplete without the addition of a policy assessment chapter presenting an integration of evidence-based considerations and risk and exposure assessment results. CASAC stated that such a chapter would be “critical for considering options for the NAAQS for NO

” (Samet, 2008a). In addition, within the period of CASAC's review of the second draft REA, EPA's Deputy Administrator indicated in a letter to the chair of CASAC, addressing earlier CASAC comments on the NAAQS review process (Henderson, 2008), that the risk and exposure assessment will include “a broader discussion of the science and how uncertainties may effect decisions on the standard” and “all analyses and approaches for considering the level of the standard under review, including risk assessment and weight of evidence methodologies” (Peacock, 2008, p.3; September 8, 2008).

Accordingly, the final REA included a new policy assessment chapter. This policy assessment chapter considered the scientific evidence in the ISA and the exposure and risk characterization results presented in other chapters of the REA as they relate to the adequacy of the current NO

primary NAAQS and potential alternative primary NO

standards. In considering the current and potential alternative standards, the final REA document focused on the information that is most pertinent to evaluating the basic elements of national ambient air quality standards: indicator, averaging time, form

, and level. These elements, which together serve to define each standard, must be considered collectively in evaluating the health protection afforded. CASAC discussed the final version of the REA, with an emphasis on the policy assessment chapter, during a public teleconference held on December 5, 2008. Following that teleconference, CASAC offered comments and advice on the NO

primary NAAQS in a letter to the Administrator (Samet, 2008b).

The “form” of a standard defines the air quality statistic that is to be compared to the level of the standard in determining whether an area attains the standard.

The schedule for completion of this review is governed by a judicial order resolving a lawsuit filed in September 2005, concerning the timing of the current review. The order that now governs this review, entered by the court in August 2007 and amended in December 2008, provides that the Administrator will sign, for publication, notices of proposed and final rulemaking concerning the review of the primary NO

NAAQS no later than June 26, 2009 and January 22, 2010, respectively.

This action presents the Administrator's proposed decisions on the current primary NO

standard. Throughout this preamble a number of conclusions, findings, and determinations proposed by the Administrator are noted. While they identify the reasoning that supports this proposal, they are not intended to be final or conclusive in nature. The EPA invites general, specific, and/or technical comments on all issues involved with this proposal, including all such proposed judgments, conclusions, findings, and determinations. Further, EPA invites specific comments from CASAC on the proposed approach of establishing a new 1-hour NO

standard in conjunction with a revised monitoring network that includes a substantial number of monitors placed near major roads. In addition to requesting comment on the overall approach, EPA invites specific comment on the level, or range of levels, appropriate for such a standard, as well as on the rationale that would support that level or range of levels.

II. Rationale for Proposed Decisions on the Primary Standard

This section presents the rationale for the Administrator's proposed decision to revise the existing NO

primary standard by supplementing the current annual standard with a 1-hour standard and to specify the standards to the nearest parts per billion (ppb). As discussed more fully below, this rationale takes into account: (1) Judgments and conclusions presented in the ISA and the REA; (2) CASAC advice and recommendations, as reflected in discussions of drafts of the ISA and REA at public meetings, in separate written comments, and in CASAC's letter to the Administrator (Samet, 2008b); and (3) public comments received at CASAC meetings during the development of the ISA and the REA.

In developing this rationale, EPA has drawn upon an integrative synthesis of the entire body of evidence on human health effects associated with the presence of NO

in the air. As discussed below, this body of evidence addresses a broad range of health endpoints associated with exposure to NO

. In considering this entire body of evidence, EPA focuses in particular on those health endpoints for which the ISA finds associations with NO

to be causal or likely causal (

see

section II.B below). This rationale also draws upon the results of quantitative exposure and risk assessments.

As discussed below, a substantial amount of new research has been conducted since the last review of the NO

NAAQS, with important new information coming from epidemiologic studies in particular. The newly available research studies evaluated in the ISA have undergone intensive scrutiny through multiple layers of peer review and opportunities for public review and comment. While important uncertainties remain in the qualitative and quantitative characterizations of health effects attributable to exposure to ambient NO

, the review of this

information has been extensive and deliberate.

The remainder of this section discusses the rationale for the Administrator's proposed decisions on the primary standard. Section II.A presents a discussion of NO

air quality, including discussion of the NO

concentration gradients that can exist around roadways, and the current NO

monitoring network. Section II.B includes an overview of the scientific evidence related to health effects associated with NO

exposure. This overview includes discussion of the health endpoints and at-risk populations considered in the ISA. Section II.C discusses the approaches taken by EPA to assess exposures and health risks associated with NO

, including a discussion of key uncertainties associated with the analyses. Section II.D presents the approach that is being used in the current review of the NO

NAAQS with regard to consideration of the scientific evidence and exposure-/risk-based results related to the adequacy of the current standard and potential alternative standards. Sections II.E and II.F discuss the scientific evidence and the exposure-/risk-based results specifically as they relate to the current and potential alternative standards, including discussion of the Administrator's proposed decisions on the standard. Section II.G summarizes the Administrator's proposed decisions with regard to the NO

primary NAAQS.

A. Characterization of NO

Air Quality

1. Current patterns of NO

Air Quality

The size of the State and local NO

monitoring network has remained relatively stable since the early 1980s, and currently has approximately 400 monitors reporting data to EPA's Air Quality System (AQS) database.

At present, there are no minimum monitoring requirements for NO

in 40 CFR part 58 Appendix D, other than a requirement for EPA Regional Administrator approval before removing any existing monitors, and that any ongoing NO

monitoring must have at least one monitor sited to measure the maximum concentration of NO

in that area (though, as discussed below monitors in the current network do not measure peak concentrations associated with on-road mobile sources that can occur near major roadways because the network was not designed for this purpose). EPA removed the specific minimum monitoring requirements for NO

of two monitoring sites per area with a population of 1,000,000 or more in the 2006 monitoring rule revisions (71 FR 61236), based on the fact that there were no NO

nonattainment areas at that time, coupled with trends evidence showing an increasing gap between national average NO

concentrations and the current annual standard. Additionally, the minimum requirements were removed to provide State, local, and Tribal air monitoring agencies flexibility in meeting higher priority monitoring needs for pollutants such as ozone and PM

2.5

, or implementing the new multi-pollutant sites (NCore network) required by the 2006 rule revisions, by allowing them to discontinue lower priority monitoring. There are requirements in 40 CFR part 58 Appendix D for NO

monitoring as part of the Photochemical Assessment Monitoring Stations (PAMS) network. However, of the approximately 400 NO

monitors currently in operation, only about 10 percent may be due to the PAMS requirements.

It should be noted that the ISA Section 2.4.1 references a different number of active monitors in the NO

network. The discrepancy between the ISA numbers and the number presented here is due to differing metrics used in pulling data from AQS. The ISA only references SLAMS, NAMS, and PAMS sites with defined monitoring objectives, while the Watkins and Thompson, 2008 value represents all NO

sites reporting data at any point during the year. These differences in numbers of active monitors per year also explain why the Watkins and Thompson 2008 document characterized the NO

network size as relatively stable since the early 1980s.

An analysis of the approximately 400 monitors comprising the current NO

monitoring network (Watkins and Thompson, 2008) indicates that the current NO

network has largely remained unchanged in terms of size and target monitor objective categories since it was introduced in the May 10, 1979 monitoring rule (44 FR 27571). The review of the current network found that the assessment of concentrations for general population exposure and maximum concentrations at neighborhood and larger scales were the top objectives. A review of the distribution of listed spatial scales of representation shows that only approximately 3 monitors are described as microscale, representing an area on the order of several meters to 100 meters, and approximately 23 monitors are described as middle scale, which represents an area on the order of 100 to 500 meters. This low percentage of smaller spatially representative scale sites within the network of approximately 400 monitoring sites indicates that the majority of monitors have, in fact, been sited to assess area-wide exposures on the neighborhood, urban, and regional scales, as would be expected for a network sited to support the current annual NO

standard and PAMS objectives. The current network does not include monitors placed near major roadways and, therefore, monitors in the current network do not necessarily measure the maximum concentrations that can occur on a localized scale near these roadways (as discussed in the next section). It should be noted that the network not only accommodates NAAQS related monitoring, but also serves other monitoring objectives such as support for photochemistry analysis, ozone modeling and forecasting, and particulate matter precursor tracking.

2. NO

Air Quality and Gradients Around Roadways

On-road and non-road mobile sources account for approximately 60% of NO

emissions (ISA, table 2.2-1) and traffic-related exposures can dominate personal exposures to NO

(ISA section 2.5.4). While driving, personal exposure concentrations in the cabin of a vehicle could be substantially higher than ambient concentrations measured nearby (ISA, section 2.5.4). For example, mean in-vehicle NO

concentrations have been reported to be 2 to 3 times higher than non-traffic ambient concentrations (ISA, sections 2.5.4 and 4.3.6). In addition, estimates presented in the REA suggest that on/near roadway NO

concentrations could be approximately 40% (REA, compare Tables 7-11 and 7-13) or 80% (REA, section 7.3.2) higher on average than concentrations away from roadways and that roadway-associated environments could be responsible for the large majority of 1-hour peak NO

exposures (REA, Figures 8-17 and 8-18). Because monitors in the current network are not sited to measure peak roadway-associated NO

concentrations, individuals who spend time on and/or near major roadways could experience NO

concentrations that are considerably higher than indicated by monitors in the current area-wide NO

monitoring network.

Research suggests that the concentrations of on-road mobile source pollutants such as NO

, carbon monoxide (CO), directly emitted air toxics, and certain size distributions of particulate matter (PM), such as ultrafine PM, typically display peak concentrations on or immediately adjacent to roads (ISA, section 2.5). This situation typically produces a gradient in pollutant concentrations, with concentrations decreasing with increasing distance from the road, and concentrations generally decreasing back to near area-wide ambient levels, or typical upwind urban background

levels, within several hundred meters downwind. While this general concept is applicable to almost all roads, the actual characteristics of the gradient and the distance that the mobile source pollutant signature from an individual road can be differentiated from background or upwind concentrations are heavily dependent on factors including traffic volumes, local topography, roadside features, meteorology, and photochemical reactivity conditions (Baldauf,

et al.

, 2009; Beckerman

et al.

, 2008; Clements

et al.

, 2008; Hagler

et al.

, 2009; Janssen

et al.

, 2001; Rodes and Holland, 1980; Roorda-Knape

et al.

, 1998; Singer

et al.

, 2004; Zhou and Levy, 2007).

Because NO

in the ambient air is due largely to the atmospheric oxidation of NO emitted from combustion sources (ISA, section 2.2.1), elevated NO

concentrations can extend farther away from roadways than the primary pollutants also emitted by on-road mobile sources. More specifically, review of the technical literature suggests that NO

concentrations may return to area-wide or typical urban background concentrations within distances up to 500 meters of roads, though the actual distance will vary with topography, roadside features, meteorology, and photochemical reactivity conditions (Baldauf

et al.

, 2009; Beckerman

et al.

, 2008; Clements

et al.

, 2008; Gilbert

et al.

2003; Rodes and Holland, 1980; Singer

et al.

, 2004; Zhou and Levy, 2007). Efforts to quantify the extent and slope of the concentration gradient that may exist from peak near-road concentrations to the typical urban background concentrations must consider the variability that exists across locations and for a given location over time. As a result, we have identified a range of concentration gradients in the technical literature which indicate that, on average, peak NO

concentrations on or immediately adjacent to roads may typically be between 30 and 100 percent greater than concentrations monitored in the same area but farther away from the road (ISA, Section 2.5.4; Beckerman

et al.

, 2008; Gilbert

et al.

, 2003; Rodes and Holland, 1980; Roorda-Knape

et al.

, 1998; Singer

et al.

, 2004). This range of concentration gradients has implications for revising the NO

primary standard and for the NO

monitoring network (

see

sections II.F.4 and III).

B. Health Effects Information

In the last review of the NO

NAAQS, the 1993 NO

Air Quality Criteria Document (1993 AQCD) (EPA, 1993) concluded that there were two key health effects of greatest concern at ambient or near-ambient concentrations of NO

(ISA, section 5.3.1). The first was increased airway responsiveness in asthmatic individuals after short-term exposures. The second was increased respiratory illness among children associated with longer-term exposures to NO

. Evidence also was found for increased risk of emphysema, but this appeared to be of major concern only with exposures to NO

at levels much higher than then current ambient levels (ISA, section 5.3.1). Controlled human exposure and animal toxicological studies provided qualitative evidence for airway hyperresponsiveness and lung function changes while epidemiologic studies provided evidence for increased respiratory symptoms with increased indoor NO

exposures. Animal toxicological findings of lung host defense system changes with NO

exposure provided a biologically-plausible basis for the epidemiologic results. Subpopulations considered potentially more susceptible to the effects of NO

exposure included persons with preexisting respiratory disease, children, and the elderly. The epidemiologic evidence for respiratory health effects was limited, and no studies had considered endpoints such as hospital admissions, emergency department visits, or mortality (ISA, section 5.3.1).

As discussed below, evidence published since the last review generally has confirmed and extended the conclusions articulated in the 1993 AQCD (ISA, section 5.3.2). The epidemiologic evidence has grown substantially with the addition of field and panel studies, intervention studies, time-series studies of endpoints such as hospital admissions, and a substantial number of studies evaluating mortality risk associated with short-term NO

exposures. While not as marked as the growth in the epidemiologic literature, a number of recent toxicological and controlled human exposure studies also provide insights into relationships between NO

exposure and health effects. The body of evidence that has become available since the last review focuses the current review on NO

-related respiratory effects at lower ambient and exposure concentrations.

The ISA, along with its associated annexes, provides a comprehensive review and assessment of the scientific evidence related to the health effects associated with NO

exposures. For these health effects, the ISA characterized judgments about causality with a hierarchy that contains five levels (ISA, section 1.3): sufficient to infer a causal relationship, sufficient to infer a likely causal relationship (

i.e.

, more likely than not), suggestive but not sufficient to infer a causal relationship, inadequate to infer the presence or absence of a causal relationship, and suggestive of no causal relationship. Judgments about causality were informed by a series of aspects that are based on those set forth by Sir Austin Bradford Hill in 1965 (ISA, Table 1.3-1). These aspects include strength of the observed association, availability of experimental evidence, consistency of the observed association, biological plausibility, coherence of the evidence, temporal relationship of the observed association, and the presence of an exposure-response relationship. A summary of each of the five levels of the hierarchy is provided in Table 1.3-2 of the ISA.

Judgments made in the ISA about the extent to which relationships between various health endpoints and exposure to NO

are likely causal have been informed by several factors. As discussed in the ISA in section 1.3, these factors include the nature of the evidence (

i.e.

, controlled human exposure, epidemiological, and/or toxicological studies) and the weight of evidence. The weight of evidence takes into account such considerations as biological plausibility, coherence of the evidence, strength of associations, and consistency of the evidence. Controlled human exposure studies provide directly applicable information for determining causality because these studies are not limited by differences in dosimetry and species sensitivity, which would need to be addressed in extrapolating animal toxicology data to human health effects, and because they provide data relating health effects specifically to NO

exposures, in the absence of the co-occurring pollutants present in ambient air. Epidemiologic studies provide evidence of associations between NO

concentrations and more serious health endpoints (

e.g.

, hospital admissions and emergency department visits) that cannot be assessed in controlled human exposure studies. For these studies the degree of uncertainty introduced by confounding variables (

e.g.

, other pollutants) affects the level of confidence that the health effects being investigated are attributable to NO

exposures alone and/or in combination with co-occurring pollutants.

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 NO

, confidence increases with the number of studies consistently reporting a particular health endpoint,

with increasing support for the biological plausibility of the health effects, and with the strength and coherence of the evidence. Conclusions regarding biological plausibility, consistency, and coherence of evidence of NO

-related health effects are drawn from the integration of epidemiologic studies with controlled human exposure studies and with mechanistic information from animal toxicological studies. As discussed below, the weight of evidence is strongest for respiratory morbidity endpoints (

e.g.

, respiratory symptoms, hospital admissions, and emergency department visits) associated with short-term (

e.g.

, 1 to 24 hours) NO

exposures.

For epidemiologic studies, strength of association refers to the magnitude of the association and its statistical strength, which includes assessment of both effect 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. Based on the information presented in the ISA and summarized below in sections II.B.1-II.B.3, this section discusses judgments concerning the extent to which relationships between various health endpoints and ambient NO

exposures have been judged in the ISA to be likely causal.

As noted above, this section is devoted to discussion of health effects associated with NO

exposure, as assessed in the ISA. Section II.B.1 below discusses respiratory morbidity associated with short-term exposure to NO

. The specific endpoints considered in this section are respiratory-related emergency department visits and hospital admissions, respiratory symptoms, lung host defense and immunity, airway responsiveness, airway inflammation, and lung function. Section II.B.2 discusses mortality and cardiovascular effects associated with short-term exposures. Section II.B.3 discusses effects that have been associated with long-term NO

exposures including respiratory morbidity, mortality, cancer, cardiovascular effects, and reproductive/developmental effects. Section II.B.4 discusses the potential NO

-related impacts on public health.

1. Adverse Respiratory Effects and Short-Term Exposure to NO

The ISA concluded that, taken together, recent studies provide scientific evidence that is sufficient to infer a likely causal relationship between short-term NO

exposure and adverse effects on the respiratory system (ISA, section 5.3.2.1). This determination was based on consideration of the broad array of relevant scientific evidence, as well as the uncertainties associated with that evidence. Specifically, this determination is supported by the large body of recent epidemiologic evidence as well as findings from human and animal experimental studies.

In considering the uncertainties associated with the epidemiologic evidence, the ISA (section 5.4) noted that it is difficult to determine “the extent to which NO

is independently associated with respiratory effects or if NO

is a marker for the effects of another traffic-related pollutant or mix of pollutants.” On-road vehicle exhaust emissions are a nearly ubiquitous source of combustion pollutant mixtures that include NO

and can be an important contributor to NO

levels in near-road locations. Although this complicates efforts to quantify specific NO

-related health effects, a number of epidemiologic studies have evaluated associations with NO

in models that also include co-occurring pollutants such as PM, O

, CO, and/or SO

. The evidence summarized in the ISA indicates that NO

associations generally remain robust in these multi-pollutant models and supports a direct effect of short-term NO

exposure on respiratory morbidity (

see

ISA Figures 3.1-7, 3.1-10, 3.1-11 and Figures 1 through 3 below). The plausibility and coherence of these effects are also supported by epidemiologic studies of indoor NO

as well as experimental (

i.e.

, toxicologic and controlled human exposure) studies that have evaluated host defense and immune system changes, airway inflammation, and airway responsiveness (

see

subsequent sections of this proposal and the ISA, section 5.3.2.1). The ISA (section 5.4) concluded that the robustness of epidemiologic findings to adjustment for co-pollutants, coupled with data from animal and human experimental studies, support a determination that the relationship between NO

and respiratory morbidity is likely causal, while still recognizing the relationship between NO

and other traffic related pollutants.

BILLING CODE 6560-50-P

EP15JY09.000

EP15JY09.001

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BILLING CODE 6560-50-C

The epidemiologic and experimental studies encompass a number of endpoints, including emergency department visits and hospitalizations, respiratory symptoms, airway hyperresponsiveness, airway inflammation, and lung function. Effect estimates from epidemiologic studies conducted in the United States and Canada generally indicate a 2-20%

increase in risks for emergency department visits and hospital admissions and higher risks for respiratory symptoms (ISA, section 5.4). The findings relevant to these endpoints, which provide the rationale to support the judgment of a likely causal relationship, are described in more detail below.

Effect estimates in the ISA were standardized to a 30 ppb increase in NO

concentrations and to a 20 ppb increase for studies that evaluated 24-hour average concentrations.

a. Emergency Department Visits and Hospital Admissions

Epidemiologic evidence exists for positive associations of short-term ambient NO

concentrations below the current NAAQS with increased numbers of emergency department visits and hospital admissions for respiratory causes, especially asthma (ISA, section 5.3.2.1). Total respiratory causes for emergency department visits and hospitalizations typically include asthma, bronchitis and emphysema (collectively referred to as COPD), pneumonia, upper and lower respiratory infections, and other minor categories. Temporal associations between respiratory emergency department visits or hospital admissions and ambient levels of NO

have been the subject of over 50 peer-reviewed research publications since the review of the NO

NAAQS that was completed in 1996. These studies have examined morbidity in different age groups and have often utilized multi-pollutant models to evaluate potential confounding effects of co-pollutants. Associations are particularly consistent among children (< 14 years) and older adults (> 65 years) when all respiratory outcomes are analyzed together (ISA, Figures 3.1-8 and 3.1-9) and among children and subjects of all ages for asthma admissions (ISA, Figures 3.1-12 and 3.1-13). When examined with co-pollutant models, associations of NO

with respiratory emergency department visits and hospital admissions were generally robust and independent of the effects of co-pollutants (

i.e.

, magnitude of effect estimates remained relatively unchanged) (ISA, Figures 3.1-10 and 3.1-11). The plausibility and coherence of these effects are supported by experimental (

i.e.

, toxicologic and controlled human exposure) studies that evaluate host defense and immune system changes, airway inflammation, and airway responsiveness (see subsequent sections of this document and ISA, section 5.3.2.1).

Of the respiratory emergency department visit and hospital admission studies reviewed in the ISA, 6 key studies were conducted in the United States (ISA, Table 5.4-1). Of these 6 studies, 4 evaluated associations with NO

using multi-pollutant models (Peel

et al.

, 2005 and updated in Tolbert

et al.

, 2007 in Atlanta; New York Department of Health (NYDOH), 2006 and Ito

et al.

, 2007 in New York City), while 2 studies evaluated only single pollutant models (Linn

et al.

, 2000 in Los Angeles; Jaffe

et al.

, 2003 in Cleveland/Cincinnati, OH). In the study by Peel and colleagues, investigators evaluated respiratory emergency department visits among all ages in Atlanta, GA during the period from 1993 to 2000. Using single pollutant models, a 2.4% (95% CI: 0.9%, 4.1%) increase in respiratory emergency department visits was associated with a 30-ppb increase in 1-hour maximum NO

concentrations. For asthma visits, a 4.1% (95% CI: 0.8%, 7.6%) increase was estimated in individuals 2 to 18 years of age. Tolbert and colleagues reanalyzed these data with 4 additional years of information and found essentially similar results in single pollutant models (2.0% increase, 95% CI: 0.5%, 3.3%). This same study found that the associations were positive, but not statistically significant, in multi-pollutant models that included PM

or O

(Figure 2 in published manuscript). In the study conducted by the NYDOH, investigators evaluated asthma

emergency department visits in Bronx and Manhattan, New York over the period of January 1999 to November 2000. In Bronx, a 6% (95% CI: 1%, 10%) increase in visits was estimated per 20 ppb increase in 24-hour average concentrations of NO

and a 7% (95% CI: 2%, 12%) increase in visits was estimated per 30 ppb increase in daily 1-hour maximum concentrations. These effects were not statistically significant in 2-pollutant models that included PM

2.5

or SO

(Tables 4a and 9 in manuscript). In Manhattan, the authors found non-significant decreases (3% for 24-hour and a 2% for daily 1-hour maximum) in asthma-related emergency department visits associated with increasing NO

. In the study by Ito and colleagues (2007), investigators evaluated respiratory emergency department visits for asthma in New York City during the years 1999 to 2002. A 12% (95% CI: 7%, 15%) increase in risk was estimated per 20 ppb increase in 24-hour ambient NO

. Risk estimates were robust and remained statistically significant in multi-pollutant models that included PM

2.5

, O

, CO, and SO

(figure 8 in manuscript). With regard to the studies that evaluated only single pollutant models, Linn

et al.

(2000) detected a statistically significant increase in respiratory hospital admissions and Jaffe

et al.

(2003) detected a positive, but not statistically significant, increase in respiratory emergency department visits associated with 24-hour NO

concentrations.

b. Respiratory Symptoms

Evidence for associations between NO

and respiratory symptoms is derived primarily from the epidemiologic literature, although the experimental evidence for airway inflammation and immune system effects (described in the ISA, section 3.1) does provide support for the plausibility and coherence for the epidemiologic results (ISA, section 5.3.2.1). Consistent evidence has been observed for an association of respiratory effects with indoor and personal NO

exposures in children (ISA, sections 3.1.5.1 and 5.3.2.1) and with ambient levels of NO

, as measured by area-wide monitors (ISA, sections 3.1.4.2 and 5.3.2.1,

see

Figure 3.1-6). In the results of multi-pollutant models, NO

associations in multicity studies are generally robust to adjustment for co-pollutants including O

, CO, and PM

(ISA, sections 3.1.4.3, 5.3.2.1 and Figure 3.1-7). Specific studies of respiratory symptoms are discussed in more detail below.

Epidemiologic studies using community ambient monitors have found associations between ambient NO

concentrations and respiratory symptoms (ISA, sections 3.1.4.2 and 5.3.2.1, Figure 3.1-6) in cities where the entire range of 24-hour average NO

concentrations were well below the level of the current NAAQS (0.053 ppm annual average). Several studies have been published since the last review including single-city studies (

e.g.

, Ostro

et al.

, 2001; Delfino

et al.

, 2002) and multicity studies in urban areas covering the continental United States and southern Ontario (Schwartz

et al.

, 1994; Mortimer

et al.

, 2002; Schildcrout

et al.

, 2006).

Schwartz

et al.

(1994) studied 1,844 schoolchildren, followed for 1 year, as part of the Six Cities Study that included the cities of Watertown, MA, St. Louis, MO, Kingston-Harriman, TN, Steubenville, OH, Topeka, KS, and Portage, WI. Respiratory symptoms were recorded daily. The authors reported a significant association between 4-day mean NO

levels and incidence of cough among all children in single-pollutant models, with an odds ratio (OR) of 1.61 (95% CI: 1.08, 2.43) standardized to a 20-ppb increase in NO

. The incidence of cough increased up to approximately mean NO

levels (13 ppb) (p = 0.01), after which no further increase was observed. The significant association between cough and 4-day mean NO

level remained unchanged in models that included O

but lost statistical significance in two-pollutant models that included PM

(OR = 1.37 [95% CI: 0.88, 2.13]) or SO

(OR = 1.42 [95% CI: 0.90, 2.28]).

Mortimer

et al.

(2002) studied the risk of asthma symptoms among 864 asthmatic children in New York City, NY, Washington, DC, Cleveland, OH, Detroit, MI, St Louis, MO, and Chicago, IL. Subjects were followed daily for four 2-week periods over the course of nine months with morning and evening asthma symptoms and peak flow recorded. The greatest effect was observed for morning symptoms using a 6-day moving average, with a reported OR of 1.48 (95% CI: 1.02, 2.16) per 20 ppb increase in NO

. Although the magnitudes of effect estimates were generally robust in multi-pollutant models that included O

(OR for 20-ppb increase in NO

= 1.40 [95% CI: 0.93, 2.09]), O

and SO

(OR for NO

= 1.31 [95% CI: 0.87, 2.09]), or O

, SO

, and PM

(OR for NO

= 1.45 [95% CI: 0.63, 3.34]), they were not statistically significant.

Schildcrout

et al.

(2006) investigated the association between ambient NO

and respiratory symptoms and rescue inhaler use as part of the Childhood Asthma Management Program (CAMP) study. The study reported on 990 asthmatic children living within 50 miles of an NO

monitor in Boston, MA, Baltimore, MD, Toronto, ON, St. Louis, MO, Denver, CO, Albuquerque, NM, or San Diego, CA. Symptoms and use of rescue medication were recorded daily, resulting in each subject having an average of approximately two months of data. The authors reported the strongest association between NO

and increased risk of cough for a 2-day lag, with an OR of 1.09 (95% CI: 1.03, 1.15) for each 20-ppb increase in NO

occurring 2 days before measurement. Multi-pollutant models that included CO, PM

, or SO

produced similar results (ISA, Figure 3.1-5, panel A). Additionally, increased NO

exposure was associated with increased use of rescue medication, with the strongest association for a 2-day lag. In the single-pollutant model, the relative risk (RR) for increased inhaler usage was 1.05 (95% CI: 1.01, 1.09).

Evidence supporting increased respiratory symptoms following NO

exposures is found in studies focused on indoor sources of NO

(ISA, section 3.1.4.1). These studies are not confounded by the same mix of co-pollutants present in the ambient air or by the contribution of NO

to the formation of secondary particles or O

(ISA, section 3.1.4.1). Specifically, in a randomized intervention study in Australia (Pilotto

et al.

, 2004), asthmatic students attending schools that switched out unvented gas heaters, a major source of indoor NO

, experienced a decrease in both levels of NO

and in respiratory symptoms (

e.g.

, difficulty breathing, chest tightness, and asthma attacks) compared to students in schools that did not switch out unvented gas heaters (ISA, section 3.1.4.1). An earlier indoor study by Pilotto and colleagues (1997) also found that students in classrooms with higher levels of NO

due primarily to indoor sources had higher rates of respiratory symptoms (

e.g.

, sore throat, cold) and absenteeism than students in classrooms with lower levels of NO

. This study detected a significant concentration-response relationship, strengthening the argument that NO

is causally related to respiratory morbidity. A number of other indoor studies conducted in homes with gas appliances have also detected significant associations between indoor NO

and respiratory symptoms (ISA, section 3.1.4.1).

c. Impaired Host Defense

Impaired host-defense systems and increased risk of susceptibility to both viral and bacterial infections after NO

exposures have been observed in

epidemiologic, controlled human exposure, and animal toxicological studies (ISA, section 3.1.1 and 5.3.2.1). A recent epidemiologic study (Chauhan

et al.

, 2003) provides evidence that increased personal exposure to NO

worsened virus-associated symptoms and decreased lung function in children with asthma. The limited evidence from controlled human exposure studies indicates that NO

may increase susceptibility to lung injury by subsequent viral challenge at exposures of as low as 600 ppb for 3 hours in healthy adults (Frampton

et al.

, 2002). Toxicological studies have shown that lung host defenses, including mucociliary clearance and immune cell function, are sensitive to NO

exposure, with effects observed at concentrations of less than 1000 ppb (ISA, section 3.1.7). When taken together, epidemiologic and experimental studies linking NO

exposure with viral illnesses provide coherent and consistent evidence that NO

exposure can result in lung host defense or immune system effects (ISA, sections 3.1.7 and 5.3.2.1). This group of outcomes also provides some plausibility for other respiratory system effects. For example, effects on ciliary action (clearance) or immune cell function (

i.e.

macrophage phagocytosis) could be the basis for the effects observed in epidemiologic studies, including increased respiratory illness or respiratory symptoms (ISA, section 5.3.2.1). Proposed mechanisms by which NO

, in conjunction with viral infections, may exacerbate airway symptoms are summarized in the ISA (Table 3.1-1).

d. Airway Response

In acute exacerbations of asthma, bronchial smooth muscle contraction occurs quickly to narrow the airway in response to exposure to various stimuli including allergens or irritants. Bronchoconstriction is the dominant physiological event leading to clinical symptoms and interference with airflow (National Heart, Lung, and Blood Institute, 2007). Inhaled pollutants such as NO

may enhance the inherent responsiveness of the airway to a challenge by allergens and nonspecific agents (ISA, section 3.1.3). In the laboratory, airway responses can be measured by assessing changes in pulmonary function (

e.g.

, decline in FEV1) or changes in the inflammatory response (

e.g.

, using markers in bronchoalveolar lavage (BAL) fluid or induced sputum) (ISA, section 3.1.3).

The ISA (section 5.3.2.1) drew two broad conclusions regarding airway responsiveness in asthmatics following NO

exposure. First, the ISA concluded that NO

exposure may enhance the sensitivity to allergen-induced decrements in lung function and increase the allergen-induced airway inflammatory response at exposures as low as 260 ppb NO

for 30 minutes (ISA, section 5.3.2.1 and Figure 3.1-2). Second, exposure to NO

has been found to enhance the inherent responsiveness of the airway to subsequent nonspecific challenges in controlled human exposure studies (section 3.1.3.2). In general, small but significant increases in nonspecific airway responsiveness were observed in the range of 200 to 300 ppb NO

for 30-minute exposures and at 100 ppb NO

for 60-minute exposures in asthmatics. These conclusions are consistent with results from animal toxicological studies which have detected 1) increased immune-mediated pulmonary inflammation in rats exposed to house dust mite allergen following exposure to 5000 ppb NO

for 3-h and 2) increased responsiveness to non-specific challenges following sub-chronic (6-12 weeks) exposure to 1000 to 4000 ppb NO

(ISA, section 5.3.2.1).

Enhanced airway responsiveness could have important clinical implications for asthmatics since transient increases in airway responsiveness following NO

exposure have the potential to increase symptoms and worsen asthma control (ISA, section 5.4). In addition, the ISA cited the controlled human exposure literature on the NO

airway response as being supportive of the epidemiologic evidence on respiratory morbidity (ISA, section 5.4). Because studies on airway responsiveness have been used to identify potential health effect benchmark values and to inform the identification of potential alternative standards for evaluation (

see

REA, sections 4.5 and 5), more detail is provided below on the specific studies that form the basis for the conclusions in the ISA regarding this endpoint.

Folinsbee (1992) conducted a meta-analysis using individual level data from 19 NO

controlled human exposure studies measuring airway responsiveness in asthmatics (ISA, section 3.1.3.2). These studies included NO

exposure levels between 100 and 1000 ppb and most of them used nonspecific bronchoconstricting agents such as methacholine, carbachol, histamine, or cold air. The largest effects were observed for asthmatics at rest. Among asthmatics exposed at rest, 76% experienced increased airway responsiveness following exposure to NO

levels between 200 and 300 ppb. Results from an update of this meta-analysis, which focused only on data for nonspecific responsiveness, are presented in the ISA (Table 3.1-3).

When exposed at rest, 66% of asthmatics experienced an increase in airway responsiveness following exposure to 100 ppb NO

, 67% of asthmatics experienced an increase in airway responsiveness following exposure to NO

concentrations between 100 and 150 ppb (inclusively), 75% of subjects experienced an increase in airway responsiveness following exposure to NO

concentrations between 200 and 300 ppb (inclusively), and 73% of subjects experienced an increase in airway responsiveness following exposure to NO

concentrations above 300 ppb. Effects of NO

exposure on the direction of airway responsiveness were statistically significant at all of these levels. Because this meta-analysis evaluated only the direction of the change in airway responsiveness, it is not possible to discern the magnitude of the change from these data. However, the results do suggest that short-term (

i.e.

, 30-min to 3-h) exposures to NO

at near-ambient levels (<300 ppb) can alter airway responsiveness in people with mild asthma (ISA, section 3.1.3.2).

The updated meta-analysis added a study that evaluated non-specific airway responsiveness following exposure to 260 ppb NO

and removed a study that evaluated allergen-induced airway responsiveness following exposure to 100 ppb NO

Several studies published since the 1996 review evaluate the potential for low-level exposures to NO

to enhance the response to specific allergen challenge in mild asthmatics (ISA, section 3.1.3.1). These studies suggest that NO

may enhance the sensitivity to allergen-induced decrements in lung function and increase the allergen-induced airway inflammatory response. Strand

et al.

(1997) demonstrated that single 30-minute exposures to 260 ppb NO

increased the late phase response to allergen challenge 4 hours after exposure, as measured by changes in lung function. In a separate study (Strand

et al.

, 1998), 4 daily repeated exposures to 260 ppb NO

for 30 minutes increased both the early and late-phase responses to allergen, as measured by changes in lung function. Barck

et al.

(2002) used the same exposure and challenge protocol in the earlier Strand study (260 ppb for 30 min, with allergen challenge 4 hours after exposure), and performed BAL 19 hours after the allergen challenge to determine NO

effects on the allergen-induced inflammatory response. Compared with air followed by allergen, NO

followed by allergen caused an

increase in the BAL recovery of polymorphonuclear (PMN) cells and eosinophil cationic protein (ECP) as well as a reduction in total BAL fluid volume and cell viability. ECP is released by degranulating eosinophils, is toxic to respiratory epithelial cells, and is thought to play a role in the pathogenesis of airway injury in asthma. Subsequently, Barck

et al.

(2005) exposed 18 mild asthmatics to air or 260 ppb NO

for 15 minutes on day 1, followed by two 15 minute exposures separated by 1 hour on day 2, with allergen challenge after exposures on both days 1 and 2. Sputum was induced before exposure on day 1 and after exposures (morning of day 3). Compared to air plus allergen, NO

plus allergen resulted in increased levels of ECP in both sputum and blood and increased myeloperoxidase levels in blood.

All exposures in these studies (Barck

et al.

, 2002, 2005; Strand

et al.

, 1997, 1998) used subjects at rest. They used an adequate number of subjects, included air control exposures, randomized exposure order, and separated exposures by at least 2 weeks. Together, they indicate the possibility for effects on allergen responsiveness in some asthmatics following brief exposures to 260 ppb NO

. Other recent studies have failed to find effects using similar, but not identical, approaches (ISA, section 3.1.3.1). The differing findings may relate in part to differences in timing of the allergen challenge, the use of multiple versus single-dose allergen challenge, the use of BAL versus sputum induction, exercise versus rest during exposure, and differences in subject susceptibility (ISA, section 3.1.3.1).

e. Airway Inflammation

Effects of NO

on airway inflammation have been observed in controlled human exposure and animal toxicological studies at higher than ambient levels (400-5000 ppb). Controlled human exposure studies provide evidence for increased airway inflammation at NO

concentrations of <2000 ppb. The onset of inflammatory responses in healthy subjects appears to be between 100 and 200 ppm-minutes,

i.e.

, 1000 ppb for 2 to 3 hours (ISA, Figure 3.1-1). Increases in biological markers of inflammation were not observed consistently in healthy animals at levels of less than 5000 ppb; however, increased susceptibility (as indicated by biochemical markers of inflammation) to NO

concentrations of as low as 400 ppb was observed when lung vitamin C was reduced (by diet) to levels that were <50% of normal. The few available epidemiologic studies were suggestive of an association between ambient NO

concentrations and inflammatory response in the airway in children, though the associations were inconsistent in the adult populations examined (ISA, section 3.1.2 and 5.3.2.1). These data provide some evidence for biological plausibility and one potential mechanism for other respiratory effects, such as exacerbation of asthma symptoms and increased emergency department visits for asthma (ISA, section 5.3.2.1).

f. Lung Function

Recent epidemiologic studies that examined the association between ambient NO

concentrations and lung function in children and adults have produced inconsistent results (ISA, sections 3.1.5.1 and 5.3.2.1). Controlled human exposure studies generally did not find direct effects of NO

on lung function in healthy adults at levels as high as 4000 ppb (ISA, section 5.3.2.1). For asthmatics, the direct effects of NO

on lung function also have been inconsistent at exposure concentrations of less than 1000 ppb NO

g. Conclusions From the ISA

As noted previously, the ISA concluded that the findings of epidemiologic, controlled human exposure, and animal toxicological studies provide evidence that is sufficient to infer a likely causal relationship for respiratory effects following short-term NO

exposure (ISA, sections 3.1.7 and 5.3.2.1). The ISA (section 5.4) concluded that the strongest evidence for an association between NO

exposure and adverse human health effects comes from epidemiologic studies of respiratory symptoms, emergency department visits, and hospital admissions. These studies include panel and field studies, studies that control for the effects of co-occurring pollutants, and studies conducted in areas where the whole distribution of ambient 24-hour average NO

concentrations was below the current NAAQS level of 53 ppb (annual average). With regard to this evidence, the ISA concluded that NO

epidemiologic studies provide “little evidence of any effect threshold” (ISA, section 5.3.2.9, p. 5-15). In studies that have evaluated concentration-response relationships, they appear linear within the observed range of data (ISA, section 5.3.2.9).

Overall, the epidemiologic evidence for respiratory effects has been characterized in the ISA as consistent, in that associations are reported in studies conducted in numerous locations with a variety of methodological approaches. Considering this large body of epidemiologic studies alone, the findings have also been characterized as coherent in that the studies report associations with respiratory health outcomes that are logically linked together. In addition, a number of these associations are statistically significant, particularly the more precise effect estimates (ISA, section 5.3.2.1). These epidemiologic studies are supported by evidence from toxicological and controlled human exposure studies, particularly those that evaluated airway hyperresponsiveness in asthmatic individuals (ISA, section 5.4). The ISA concluded that together, the epidemiologic and experimental data sets form a plausible, consistent, and coherent description of a relationship between NO

exposures and an array of adverse respiratory health effects that range from the onset of respiratory symptoms to hospital admissions.

2. Other Effects With Short-Term Exposure to NO

a. Mortality

The ISA concluded that the epidemiologic evidence is suggestive, but not sufficient, to infer a causal relationship between short-term exposure to NO

and all-cause and cardiopulmonary-related mortality (ISA, section 5.3.2.3). Results from several large U.S. and European multicity studies and a meta-analysis study indicate positive associations between ambient NO

concentrations and the risk of all-cause (nonaccidental) mortality, with effect estimates ranging from 0.5 to 3.6% excess risk in mortality per standardized increment (20 ppb for 24-hour averaging time, 30 ppb for 1-hour averaging time) (ISA, section 3.3.1, Figure 3.3-2, section 5.3.2.3). In general, the NO

effect estimates were robust to adjustment for co-pollutants. Both cardiovascular and respiratory mortality have been associated with increased NO

concentrations in epidemiologic studies (ISA, Figure 3.3-3); however, similar associations were observed for other pollutants, including PM and SO

. The range of risk estimates for excess mortality is generally smaller than that for other pollutants such as PM. In addition, while NO

exposure, alone or in conjunction with other pollutants, may contribute to increased mortality, evaluation of the specificity of this effect is difficult. Clinical studies showing hematologic effects and animal toxicological studies showing biochemical, lung host defense, permeability, and inflammation changes

with short-term exposures to NO

provide limited evidence of plausible pathways by which risks of mortality may be increased, but no coherent picture is evident at this time (ISA, section 5.3.2.3).

b. Cardiovascular Effects

The ISA concluded that the available evidence on cardiovascular health effects following short-term exposure to NO

is inadequate to infer the presence or absence of a causal relationship at this time (ISA, section 5.3.2.2). Evidence from epidemiologic studies of heart rate variability, repolarization changes, and cardiac rhythm disorders among heart patients with ischemic cardiac disease are inconsistent (ISA, section 5.3.2.2). In most studies, associations with PM were found to be similar or stronger than associations with NO

. Generally positive associations between ambient NO

concentrations and hospital admissions or emergency department visits for cardiovascular disease have been reported in single-pollutant models (ISA, section 5.3.2.2); however, most of these effect estimate values were diminished in multi-pollutant models that also contained CO and PM indices (ISA, section 5.3.2.2). Mechanistic evidence of a role for NO

in the development of cardiovascular diseases from studies of biomarkers of inflammation, cell adhesion, coagulation, and thrombosis is lacking (ISA, section 5.3.2.2). Furthermore, the effects of NO

on various hematological parameters in animals are inconsistent and, thus, provide little biological plausibility for effects of NO

on the cardiovascular system (ISA, section 5.3.2.2).

3. Health Effects With Long-Term Exposure to NO

a. Respiratory Morbidity

The ISA concluded that overall, the epidemiologic and experimental evidence is suggestive, but not sufficient, to infer a causal relationship between long-term NO

exposure and respiratory morbidity (ISA, section 5.3.2.4). The available database evaluating the relationship between respiratory illness in children and long-term exposures to NO

has increased since the 1996 review of the NO

NAAQS. A number of epidemiologic studies have examined the effects of long-term exposure to NO

and reported positive associations with decrements in lung function and partially irreversible decrements in lung function growth (ISA, section 3.4.1, Figures 3.4-1 and 3.4-2). Specifically, results from the California-based Children's Health Study, which evaluated NO

exposures in children over an 8-year period, demonstrated deficits in lung function growth (Gauderman

et al.

, 2004). This effect has also been observed in Mexico City, Mexico (Rojas-Martinez

et al.

, 2007a,b) and in Oslo, Norway (Oftedal

et al.

, 2008), with decrements ranging from 1 to 17.5 ml per 20-ppb increase in annual NO

concentration. Similar associations have been found for PM, O

, and proximity to traffic (<500 m), though these studies did not report the results of co-pollutant models. The high correlation among traffic-related pollutants makes it difficult to accurately estimate independent effects in these long-term exposure studies (ISA, section 5.3.2.4). With regard to asthma incidence and long-term NO

, two major cohort studies, the Children's Health Study (Gauderman

et al.

, 2005) and a birth cohort study in the Netherlands (Brauer

et al.

, 2007), observed significant associations. However, several other studies failed to find consistent associations between long-term NO

exposure and asthma outcomes (ISA, section 5.3.2.4). Similarly, epidemiologic studies conducted in the United States and Europe reported inconsistent results regarding an association between long-term exposure to NO

and respiratory symptoms (ISA, sections 3.4.3 and 5.3.2.4). While some positive associations were noted, a large number of symptom outcomes were examined and the results across specific outcomes were inconsistent (ISA, section 5.3.2.4).

Animal toxicological studies may provide biological plausibility for the chronic effects of NO

that have been observed in epidemiologic studies (ISA, sections 3.4.5 and 5.3.2.4). The main biochemical targets of NO

exposure appear to be antioxidants, membrane polyunsaturated fatty acids, and thiol groups. NO

effects include changes in oxidant/antioxidant homeostasis and chemical alterations of lipids and proteins. Lipid peroxidation has been observed at NO

exposures as low as 40 ppb for 9 months and at exposures of 1200 ppb for 1 week, suggesting lower effect thresholds with longer durations of exposure. Other studies showed decreases in formation of key arachidonic acid metabolites in alveolar macrophages following NO

exposures of 500 ppb. NO

has been shown to increase collagen synthesis rates at concentrations as low as 500 ppb. This could indicate increased total lung collagen, which is associated with pulmonary fibrosis, or increased collagen turnover, which is associated with remodeling of lung connective tissue. Morphological effects following chronic NO

exposures have been identified in animal studies that link to these increases in collagen synthesis and may provide plausibility for the deficits in lung function growth described in epidemiologic studies of long-term exposure to NO

(ISA, section 3.4.5).

b. Mortality

The ISA concluded that the epidemiologic evidence is inadequate to infer the presence or absence of a causal relationship between long-term exposure to NO

and mortality (ISA, section 5.3.2.6). In the United States and European cohort studies examining the relationship between long-term exposure to NO

and mortality, results have been inconsistent (ISA, section 5.3.2.6). Further, when associations were suggested, they were not specific to NO

but also implicated PM and other traffic indicators. The relatively high correlations reported between NO

and PM indices make it difficult to interpret these observed associations at this time (ISA, section 5.3.2.6).

c. Carcinogenic, Cardiovascular, and Reproductive/Developmental Effects

The ISA concluded that the available epidemiologic and toxicological evidence is inadequate to infer the presence or absence of a causal relationship for carcinogenic, cardiovascular, and reproductive and developmental effects related to long-term NO

exposure (ISA, section 5.3.2.5). Epidemiologic studies conducted in Europe have shown an association between long-term NO

exposure and increased incidence of cancer (ISA, section 5.3.2.5). However, the animal toxicological studies have provided no clear evidence that NO

acts as a carcinogen (ISA, section 5.3.2.5). The very limited epidemiologic and toxicological evidence do not suggest that long-term exposure to NO

has cardiovascular effects (ISA, section 5.3.2.5). The epidemiologic evidence is not consistent for associations between NO

exposure and fetal growth retardation; however, some evidence is accumulating for effects on preterm delivery (ISA, section 5.3.2.5). Scant animal evidence supports a weak association between NO

exposure and adverse birth outcomes and provides little mechanistic information or biological plausibility for the epidemiologic findings.

4. NO

-Related Impacts on Public Health

Specific groups within the general population are likely at increased risk

for suffering adverse effects from NO

exposure. This could occur because they are affected by lower levels of NO

than the general population (susceptibility), because they experience a larger health impact than the general population to a given level of exposure (susceptibility), and/or because they are exposed to higher levels of NO

than the general population (vulnerability). The term susceptibility generally encompasses innate (

e.g.

, genetic or developmental) and/or acquired (

e.g.

, age or disease) factors that make individuals more likely to experience effects with exposure to pollutants. The severity of health effects experienced by a susceptible subgroup may be much greater than that experienced by the population at large. Factors that may influence susceptibility to the effects of air pollution include age (

e.g.

, infants, children, elderly); gender; race/ethnicity; genetic factors; and pre-existing disease/condition (

e.g.

, obesity, diabetes, respiratory disease, asthma, chronic obstructive pulmonary disease (COPD), cardiovascular disease, airway hyperresponsiveness, respiratory infection, adverse birth outcome) (ISA, sections 4.3.1, 4.3.5, and 5.3.2.8). In addition, certain groups may experience relatively high exposure to NO

, thus forming a potentially vulnerable population (ISA, section 4.3.6). Factors that may influence exposures and/or susceptibility to air pollution include socioeconomic status (SES), education level, air conditioning use, proximity to roadways, geographic location, level of physical activity, and work environment (

e.g.

, indoor versus outdoor) (ISA, section 4.3.5). The ISA discussed factors that can confer susceptibility and/or vulnerability to air pollution with most of the discussion devoted to factors for which NO

-specific evidence exists (ISA, section 4.3). These factors are discussed below.

a. Pre-Existing Disease

A number of health conditions have been found to put individuals at greater risk for adverse events following exposure to air pollution. In general, these include asthma, COPD, respiratory infection, cardiac conduction disorders, congestive heart failure (CHF), diabetes, past myocardial infarction (MI), obesity, coronary artery disease, low birth weight/prematurity, and hypertension (ISA, sections 4.3.1, 4.3.5, and 5.3.2.9). In addition to these conditions, epidemiologic evidence indicates that individuals with bronchial or airway hyperresponsiveness, as determined by methacholine provocation, may be at increased risk for experiencing respiratory symptoms (ISA, section 4.3.1). In considering NO

specifically, the ISA evaluated studies on asthmatics, individuals with cardiopulmonary disease, and diabetics (ISA, sections 4.3.1.1 and 4.3.1.2). These groups are discussed in more detail below.

Epidemiologic and controlled human exposure studies, supported by animal toxicology studies, have provided evidence for associations between NO

exposure and respiratory effects in asthmatics (ISA, section 4.3.1.1). The ISA found evidence from epidemiologic studies for an association between ambient NO

and children's hospital admissions, emergency department visits, and calls to doctors for asthma. Long-term NO

exposure was associated with aggravation of asthma effects that include symptoms, medication use, and lung function. Time-series studies demonstrated a relationship in children between hospital admissions or emergency department visits for asthma and ambient NO

levels, even after adjusting for co-pollutants such as PM and CO (ISA, section 4.3.1.1). Important evidence was available from epidemiologic studies of indoor NO

exposures. Recent studies have shown associations with asthma attacks and severity of virus-induced asthma (ISA, section 4.3.1.1). In addition, in controlled human exposure studies, airway hyperresponsiveness in asthmatics occurred following exposure to ambient or near-ambient NO

concentrations (ISA, sections 5.3.2.1-5.3.2.6). Compared to asthma, less evidence is available to support cardiovascular disease as a mediator of susceptibility to NO

. However, recent epidemiologic studies report that individuals with preexisting conditions (

e.g.

, including diabetes, CHF, prior MI) may be at increased risk for adverse cardiac health events associated with ambient NO

concentrations (ISA, section 4.3.1.2). The small number of controlled human exposure and animal toxicological studies that have evaluated cardiovascular endpoints provide only limited supporting evidence for susceptibility to NO

in persons with cardiovascular disease (ISA, section 4.3.1.2).

b. Age

The ISA identified infants, children (

i.e.

, <18 years of age), and older adults (

i.e.

, >65 years of age) as groups that are potentially more susceptible than the general population to the health effects associated with ambient NO

concentrations (ISA, section 4.3.2). The ISA found evidence that associations of NO

with respiratory emergency department visits and hospitalizations were stronger among children and older adults, though not all studies had comparable findings on this issue (ISA, section 4.3.2). In addition, long-term exposure studies suggest effects in children that include impaired lung function growth, increased respiratory symptoms and infections, and onset of asthma (ISA, section 3.4 and 4.3.2). In some studies, associations between NO

and hospitalizations or emergency department visits for CVD have been observed in elderly populations. Among studies that observed positive associations between NO

and mortality, a comparison indicated that, in general, the elderly population was more susceptible than the non-elderly population to NO

effects (ISA, section 4.3.2).

c. Genetics

As noted in the ISA (section 4.3.4), genetic factors related to health outcomes and ambient pollutant exposures merit consideration. Several criteria should be satisfied in selecting and establishing useful links between polymorphisms in candidate genes and adverse respiratory effects. First, the candidate gene must be significantly involved in the pathogenesis of the adverse effect of interest. Second, polymorphisms in the gene must produce a functional change in either the protein product or in the level of expression of the protein. Third, in epidemiologic studies, the issue of confounding by other environmental exposures must be carefully considered (ISA, section 4.3.4). Investigation of genetic susceptibility to NO

effects has focused on the glutathione S-tranferase (GST) gene. Several GST genes have common, functionally-important alleles that affect host defense in the lung (ISA, section 4.3.4). GST genes are inducible by electrophilic species (

e.g.

, reactive oxygen species) and individuals with genotypes that result in enzymes with reduced or absent peroxidase activity are likely to have reduced defenses against oxidative insult. This could potentially result in increased susceptibility to inhaled oxidants and radicals. However, data on genetic susceptibility to NO

are only beginning to emerge and, while it remains plausible that there are genetic factors that can influence health responses to NO

, the few available studies do not provide specific support for genetic susceptibility to NO

exposure (ISA, section 4.3.4).

d. Gender

As reported in the ISA, a limited number of NO

studies have stratified results by gender. The results of these studies were mixed, and the ISA did not

draw conclusions regarding the potential for gender to confer susceptibility to the effects of NO

(ISA, section 4.3.3).

e. Proximity to Roadways

Certain groups may experience relatively high exposure to NO

, thus forming a potentially vulnerable population. The ISA included discussion of populations reported to experience increased NO

exposures on or near roadways (ISA, section 4.3.6). Large gradients in NO

concentrations near roadways may lead to increased exposures for individuals residing, working, traveling, or attending school in the vicinity of roadways. Many studies find that indoor, personal, and outdoor NO

levels are strongly associated with proximity to traffic or to traffic density (ISA, section 4.3.6).

That adverse respiratory effects can be associated with proximity to roadways has been demonstrated in a number of studies. For example, Gauderman and colleagues (2007) reported reduced lung function growth in children who lived within 500 m of a freeway compared to children who lived at least 1500 m from a freeway. In a separate study, Gauderman and colleagues (2005) reported that the incidence of physician-diagnosed asthma increased with both increasing NO

concentrations outside the child's residence and decreasing distance between the child's residence and a major freeway.

In addition to those who live near major roadways, individuals who spend time commuting on major roadways can also be exposed to relatively higher concentrations of NO

than the ones reported at monitors away from the roads. Due to high air exchange rates, NO

concentrations inside a vehicle can rapidly approach ambient concentrations on the roadway during commuting (ISA, section 4.3.6). Mean in-vehicle NO

concentrations are often between 2 and 3 times higher than ambient levels measured at monitors located away from the road (ISA, section 4.3.6). Due to the potential for high peak exposures while driving, total personal exposure could be underestimated if exposures while commuting are not considered. Therefore, individuals with occupations that require them to be in traffic or close to traffic (

e.g.

, bus and taxi drivers, highway patrol officers, toll collectors) and individuals with long commutes could be exposed to relatively high levels of NO

compared to the ambient levels measured at fixed-site monitors located away from the roadway.

f. Socioeconomic Status

The ISA discussed evidence that SES modifies the effects of air pollution (section 4.3.6). Many recent studies examined modification by SES indicators on the association between mortality and PM or other indices such as traffic density, distance to roadway, or a general air pollution index (ISA, section 4.3.6). SES modification of NO

associations has been examined in fewer studies. However, in a study conducted in Seoul, South Korea, community-level SES indicators modified the association of air pollution with emergency department visits for asthma. Of the five criteria air pollutants evaluated, NO

showed the strongest association in lower SES districts compared to high SES districts (Kim

et al.

, 2007). In addition, Clougherty

et al.

(2007) evaluated exposure to violence (a potential surrogate for SES) as a modifier of the effect of traffic-related air pollutants, including NO

, on childhood asthma. The authors reported an elevated risk of asthma with an increase in NO

exposure solely among children with above-median exposure to violence in their neighborhoods (ISA, section 4.3.6). Although these recent studies have evaluated the impact of SES on vulnerability to NO

, they are too few in number to draw definitive conclusions (ISA, section 5.3.2.8).

g. Size of the At-Risk Population

The population potentially affected by NO

is large. A considerable fraction of the population resides, works, or attends school near major roadways, and these individuals are likely to have increased exposure to NO

(ISA, section 4.4). Based on data from the 2003 American Housing Survey, approximately 36 million individuals live within 300 feet (~90 meters) of a four-lane highway, railroad, or airport (ISA, section 4.4).

Furthermore, in California, 2.3% of schools with a total enrollment of more than 150,000 students were located within approximately 500 feet of high-traffic roads, with a higher proportion of non-white and economically disadvantaged students attending those schools (ISA, section 4.4). Of this population, asthmatics and members of other susceptible groups discussed above will have even greater risks of experiencing health effects related to NO

exposure. In the United States, approximately 10% of adults and 13% of children have been diagnosed with asthma, and 6% of adults have been diagnosed with COPD (ISA, section 4.4). The prevalence and severity of asthma is higher among certain ethnic or racial groups such as Puerto Ricans, American Indians, Alaskan Natives, and African Americans (ISA, section 4.4). A higher prevalence of asthma among persons of lower SES and an excess burden of asthma hospitalizations and mortality in minority and inner-city communities have been observed (ISA, section 4.4). In addition, based on U.S. census data from 2000, about 72.3 million (26%) of the U.S. population are under 18 years of age, 18.3 million (7.4%) are under 5 years of age, and 35 million (12%) are 65 years of age or older. Therefore, large portions of the U.S. population are in age groups that are likely at-risk for health effects associated with exposure to ambient NO

. The size of the potentially at-risk population suggests that exposure to ambient NO

could have a significant impact on public health in the United States.

The most current American Housing Survey (

http://www.census.gov/hhes/www/housing/ahs/ahs.html

) is from 2007 and lists a higher fraction of housing units within the 300 foot boundary than do prior surveys. According to Table IA-6 from that report (

http://www.census.gov/hhes/www/housing/ahs/ahs07/tab1a-6.pdf

), out of 128,303,000 total housing units in the United States, 20,016,000 were reported by the surveyed occupant or landlord as being within 300 feet of a 4-or-more lane highway, railroad, or airport. That constitutes 15.613% of the total housing units in the U.S. Assuming equal distributions, with a current population of 306,330,199, that means that there would be 47.8 million people meeting the 300 foot criteria.

C. Human Exposure and Health Risk Characterization

To put judgments about NO

-associated health effects into a broader public health context, EPA has drawn upon the results of the quantitative exposure and risk assessments. Judgments reflecting the nature of the evidence and the overall weight of the evidence are taken into consideration in these quantitative exposure and risk assessments, discussed below. These assessments provide estimates of the likelihood that asthmatic individuals would experience exposures of potential concern and estimates of the incidence of NO

-associated respiratory emergency department visits under varying air quality scenarios (

e.g.

, just meeting the current or alternative standards), as well as characterizations of the kind and degree of uncertainties inherent in such estimates.

This section describes the approach taken in the REA to characterize NO

-related exposures and health risks. Goals of the REA included estimating short-term exposures and potential human health risks associated with (1) recent levels of ambient NO

; (2) NO

levels adjusted to simulate just meeting the current standard; and (3) NO

levels adjusted to simulate just meeting

potential alternative standards. This section discusses the scientific evidence from the ISA that was used as the basis for the risk characterization (II.C.1), the approaches used in characterizing exposures and risks (II.C.2), and important uncertainties associated with these analyses (II.C.3). The results of the exposure and risk analyses, as they relate to the current and potential alternative standards, are discussed in subsequent sections of this proposal (sections II.E and II.F, respectively).

1. Evidence Base for the Risk Characterization

For purposes of the quantitative characterization of NO

health risks, the REA determined that it was appropriate to focus on endpoints for which the ISA concluded that the available evidence is sufficient to infer either a causal or a likely causal relationship. This was generally consistent with judgments made in other recent NAAQS reviews (

e.g.

, see EPA, 2005).

As noted above in section II.A, the only health effect category for which the evidence was judged in the ISA to be sufficient to infer either a causal or a likely causal relationship is respiratory morbidity following short-term NO

exposure. Therefore, for purposes of characterizing health risks associated with NO

, the REA focused on respiratory morbidity endpoints that have been associated with short-term NO

exposures. Other health effects (

e.g.

, those associated with long-term exposures) are considered as part of the evidence-based evaluation of potential alternative standards (see section II.F.2). In evaluating the appropriateness of specific endpoints for use in the NO

risk characterization, the REA considered both epidemiologic and controlled human exposure studies.

When evaluating epidemiologic studies as to their appropriateness for use as the basis for a quantitative risk assessment, the REA considered several factors. First, the REA concluded that studies conducted in the United States are preferable to those conducted outside the United States given the potential for effect estimates to be impacted by factors such as the ambient pollutant mix, the placement of monitors, activity patterns of the population, and characteristics of the healthcare system. Second, the REA concluded that studies of ambient NO

are preferable to those of indoor NO

, which focus on individuals exposed to NO

from indoor sources. These indoor sources can result in exposure patterns, NO

levels, and co-pollutants that are different from those typically associated with ambient NO

. Therefore, although indoor studies made important contributions to the evidence base for causality judgments in the ISA, the preferred approach for conducting a quantitative risk assessment based on the epidemiologic literature to inform decisions regarding an ambient NO

standard is to consider studies of ambient NO

. Third, the REA concluded that it was appropriate to focus on studies of emergency department visits and hospital admissions given the clear public health significance of these endpoints and the availability of baseline incidence data. Finally, the REA concluded that it was appropriate to focus on studies that evaluated NO

health effect associations using both single- and multi-pollutant models. Taking these factors into consideration, the epidemiology-based risk assessment in the REA focused on the study conducted in Atlanta, Georgia by Tolbert

et al.

(2007). This assessment is described in more detail in the REA (chapter 9).

In identifying health endpoints from controlled human exposure studies on which to focus the characterization of NO

health risks, the REA concluded that it was appropriate to focus on endpoints that occur at or near ambient levels of NO

and endpoints that may be important from a public health perspective. Controlled human exposure studies have addressed the consequences of short-term (

e.g.

, 30-minutes to several hours) NO

exposures for a number of health endpoints including airway responsiveness, host defense and immunity, inflammation, and lung function (ISA, section 3.1). With regard to the NO

levels at which different effects have been documented, the ISA concluded: (1) In asthmatics NO

may increase the allergen-induced airway inflammatory response at exposures as low as 260 ppb for 30 min (ISA, Figure 3.1-2), and NO

exposures between 200 and 300 ppb for 30 minutes or 100 ppb for 60-minutes can result in small, but significant, increases in nonspecific airway responsiveness (ISA, section 5.3.2.1); (2) limited evidence indicates that NO

may increase susceptibility to injury by subsequent viral challenge following exposures of 600-1500 ppb for 3 hours; (3) evidence exists for increased airway inflammation at NO

concentrations less than 2000 ppb; and (4) the direct effects of NO

on lung function in asthmatics have been inconsistent at exposure concentrations below 1000 ppb (ISA, section 5.3.2.1). Therefore, of the health effects caused by NO

in controlled human exposure studies, the only effect identified by the ISA to occur at or near ambient levels is increased airway responsiveness in asthmatics.

The REA concluded that airway responsiveness in the asthmatic population is an appropriate focus for the risk characterization for several reasons. First, the ISA concluded that “persons with preexisting pulmonary conditions are likely at greater risk from ambient NO

exposures than the general public, with the most extensive evidence available for asthmatics as a potentially susceptible group” (ISA, section 5.3.2.8). Second, when discussing the clinical significance of NO

-related airway hyperresponsiveness in asthmatics, the ISA concluded that “transient increases in airway responsiveness following NO

exposure have the potential to increase symptoms and worsen asthma control” (ISA, sections 3.1.3 and 5.4). That this effect could have public health implications is suggested by the large size of the asthmatic population in the United States (ISA, Table 4.4-1). Third, NO

effects on airway responsiveness in asthmatics are part of the body of experimental evidence that provides plausibility and coherence for the effects observed on hospital admissions and emergency department visits in epidemiologic studies (ISA, section 5.3.2.1). As a result of these considerations, of the endpoints from controlled human exposure studies, the REA focused on airway responsiveness in asthmatics for purposes of quantifying risks associated with ambient NO

(

see

below).

Because many of the studies of airway responsiveness evaluated only a single level of NO

and because of methodological differences between the studies, the data are not sufficient to derive an exposure-response relationship in the range of interest. Therefore, the REA concluded that the most appropriate approach to characterizing risks based on the controlled human exposure evidence for airway responsiveness was to compare estimated NO

air quality and exposure levels with potential health effect benchmark levels. In this review, the term “exposures of potential concern” is defined as personal exposures to 1-hour ambient NO

concentrations at and above specific benchmark levels. Benchmark levels represent NO

exposure concentrations reported to increase airway responsiveness in most asthmatics, as discussed above in section II.B.1.d. Although the analysis of exposures of potential concern was conducted using discrete benchmark levels (

i.e.

, 100, 150, 200, 250, 300 ppb), EPA recognizes that there is no sharp

breakpoint within the continuum ranging from at and above 300 ppb down to 100 ppb. In considering the concept of exposures of potential 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 NO

levels. Within the context of this continuum, estimates of exposures of potential concern at discrete benchmark levels provide some perspective on the potential public health impacts of NO

-related health effects that have been demonstrated in controlled human exposure studies but cannot be evaluated in quantitative risk assessments (

i.e.

, increased airway responsiveness). They also help in understanding the extent to which such impacts could change by just meeting the current and potential alternative standards.

The NO

-related increase in airway responsiveness is plausibly linked to the NO

-associated morbidity reported in epidemiologic studies (

e.g.

, increased respiratory symptoms, emergency department visits and hospital admissions). However, estimates of the number of asthmatics likely to experience exposures of potential concern cannot be translated directly into quantitative estimates of the number of people likely to experience specific health effects, since sufficient information to draw such comparisons is not available. Due to individual variability in responsiveness, only a subset of asthmatics exposed at and above a specific benchmark level can be expected to experience health effects. The amount of weight to place on the estimates of exposures of potential concern at any of these benchmark levels depends in part on the weight of the scientific evidence concerning health effects associated with NO

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).

2. Overview of Approaches

As noted above, the purpose of the assessments described in the REA was to characterize air quality, exposures, and health risks associated with recent ambient levels of NO

, with NO

levels that could be associated with just meeting the current NO

NAAQS, and with NO

levels that could be associated with just meeting potential alternative standards. To characterize health risks, we employed three approaches in the REA. In the first approach, for each air quality scenario, NO

concentrations at fixed-site monitors and simulated concentrations on/near roadways were compared to potential health effect benchmark values derived from the controlled human exposure literature. In the second approach, modeled estimates of actual exposures in asthmatics were compared to potential health effect benchmarks. In the third approach, concentration-response relationships from an epidemiologic study were used in conjunction with baseline incidence data and recent or simulated ambient concentrations to estimate health impacts. An overview of the approaches to characterizing health risks is provided below and each approach has been described in more detail in the REA (chapters 6 through 9).

In the first approach, we compared ambient NO

concentrations with potential health effect benchmark levels for NO

. The ambient NO

concentrations used in these analyses were based on those measured at monitors in the current NO

monitoring network. These monitored concentrations were compared to benchmark levels directly and were also used, in conjunction with literature-derived characterizations of the NO

concentration gradient around roadways, as the basis for estimating NO

concentrations on/near roadways. Scenario-driven air quality analyses were performed using ambient NO

concentrations for the years 1995 though 2006. With this approach, NO

air quality serves as a surrogate for exposure. All U.S. monitoring sites where NO

data have been collected, and that met completeness criteria (REA, chapter 7), were represented by this analysis. As such, the results generated were considered a broad characterization of national air quality and human exposures that might be associated with these concentrations. An advantage of this approach is its relative simplicity; however, there is uncertainty associated with the assumption that NO

air quality can serve as an adequate surrogate for total exposure to ambient NO

. Actual exposures might be influenced by factors not considered by this approach, including small scale spatial variability in ambient NO

concentrations (which might not be captured by the network of fixed-site ambient monitors) and spatial/temporal variability in human activity patterns.

In the second approach, we used an inhalation exposure model to generate more realistic estimates of personal exposures in asthmatics (REA, chapter 8 for more detail on this assessment). This analysis estimated temporally and spatially variable ambient NO

concentrations and simulated human contact with these pollutant concentrations. The approach was designed to incorporate exposures that are not necessarily captured by the existing ambient monitoring data, including those that occur on or near roadways. AERMOD, an EPA dispersion model, was used to estimate 1-hour ambient NO

concentrations using emissions estimates from stationary and on-road mobile sources.

The Air Pollutants Exposure (APEX) model, an EPA human exposure model, was then used to estimate population exposures using the hourly census block level NO

concentrations estimated by AERMOD. A probabilistic approach was used to model individual exposures considering the time people spend in different microenvironments and the variable NO

concentrations that occur within these microenvironments across time, space, and microenvironment type. Estimates of personal exposure were compared to potential NO

health benchmark levels. This approach to assessing exposures was more resource intensive than using ambient levels as a surrogate for exposure; therefore, the final REA included the analysis of only one specific location in the U.S. (Atlanta MSA). Although the geographic scope of this analysis was restricted, the approach provided estimates of NO

exposures in asthmatics in Atlanta, particularly those exposures associated with important emission sources of NO

, and the analysis served to complement the broad air quality characterization.

Estimated emissions from Hartsfield International Airport in Atlanta, a non-road mobile source, were also included in this analysis.

For the characterization of risks in both the air quality analysis and the exposure modeling analysis described above, the REA used a range of short-term potential health effect benchmarks. As noted above, the levels of potential benchmarks are based on NO

exposure levels that have been associated with increased airway responsiveness in asthmatics in controlled human exposure studies (ISA, section 5.3.2.1). Benchmark values of 100, 150, 200, 250, and 300 ppb were compared to both NO

air quality levels and to estimates of NO

exposure in asthmatics. When

air quality was used as a surrogate for exposure, the output of the analysis was an estimate of the number of times per year specific locations experience 1-hour levels of NO

that exceed a particular benchmark. When personal exposures were simulated, the output of the analysis was an estimate of the number of asthmatics at risk for experiencing daily maximum 1-hour levels of NO

of ambient origin that exceed a particular benchmark. An advantage of using the benchmark approach to characterize health risks is that the effects observed in controlled human exposure studies clearly result from NO

exposure. A disadvantage of this approach is that the magnitude of the NO

effect on airway responsiveness can vary considerably from individual to individual and not all asthmatics would be expected to respond to the same levels of NO

exposure. Therefore, the public health impacts of NO

-induced airway hyperresponsiveness are difficult to quantify.

In the third approach, we estimated respiratory emergency department visits as a function of ambient levels of NO

measured at a fixed-site monitor representing ambient air quality for an urban area. In this approach, concentration-response functions from an epidemiologic study (Tolbert

et al.

, 2007) were used, in combination with baseline incidence data for respiratory emergency department visits in the Atlanta area and ambient NO

monitoring data, to estimate the impact on emergency department visits of ambient levels of NO

. Compared to the risk characterization based on the air quality and exposure analyses described above, this approach to characterizing health risks has several advantages. For example, the public health significance of respiratory emergency department visits is less ambiguous, in terms of its impact on individuals, than is an increase of unknown magnitude in the airway response. In addition, the concentration-response relationship reflects real-world levels of NO

and co-pollutants present in ambient air. However, as noted previously, a disadvantage of this approach is the ambiguity and complexity associated with quantifying the contribution of NO

to emergency department visits relative to the contributions of co-occurring pollutants.

3. Key Limitations and Uncertainties

A number of key uncertainties should be considered when interpreting the results of these analyses. While the air quality, exposure, and quantitative risk analyses are each associated with unique uncertainties, they also share some uncertainties in common. Important uncertainties shared by these analyses, as well as uncertainties specifically associated with the air quality, exposure, and risk analyses, are discussed below.

In order to simulate just meeting the current annual standard and many of the alternative 1-hour standards analyzed, an adjustment (either upward or downward) of recent ambient NO

concentrations was required. As noted in the REA, an upward adjustment does not reflect a judgment that levels of NO

are likely to increase across the country or in any specific location under the current standard or any of the potential alternative standards. However, it does acknowledge that, under the current standard and some of the alternative standards evaluated, an increase in NO

concentrations would be permitted. The benefit of these air quality adjustments is that they can inform consideration of the current and alternative standards by providing estimates of health risks that could be associated with ambient air quality levels that just meet these standards. In adjusting air quality to simulate just meeting these standards, the analyses in the REA assumed that the overall shape of the distribution of NO

concentrations in an area would not change. While the REA concluded that this is a reasonable assumption in the absence of evidence supporting a different distribution, and while available analyses support this approach (Rizzo, 2008), the REA recognized this as an important uncertainty. It may be an especially important uncertainty for those scenarios where considerable adjustment is required to simulate just meeting one or more of the standards (REA, section 8.12).

In addition, simulation of just meeting different alternative standards was achieved by adjusting NO

concentrations at monitors in the current area-wide network. Therefore, resulting estimates of the potential public health implications of different decisions are most directly relevant to a standard focused specifically on the area-wide NO

concentrations that are the primary target of the current monitoring network. However, as discussed below (sections II.F.4.e and III), with this notice the Administrator is proposing to establish a standard focused specifically on the peak concentrations to which individuals can be exposed from on-road mobile source emissions on or near major roadways and to support such a standard with a monitoring network that includes monitors placed near major roadways. This proposed shift in the monitoring network introduces uncertainty in the extent to which the exposure and risk analyses presented in the REA can directly inform decisions on the proposed standard.

In addition to the general uncertainties discussed above, some uncertainties are specific to the air quality analyses. In order to estimate ambient NO

concentrations on or near roadways in the air quality analyses, the REA used empirically-derived relationships between ambient concentrations measured at fixed-site monitors in the current NO

monitoring network and on/near-road concentrations. The data used to develop the relationships were likely collected under different conditions (

e.g.

, different meteorological conditions which can affect important parameters in this relationship, such as the production of NO

from NO). The REA noted that the extent to which these conditions are representative of the times and places included in our analyses is unknown. Therefore, there is uncertainty in the degree to which the relationships used to estimate on/near-road NO

concentrations reflect the actual relationship in the locations and over the time periods of interest.

Potential health benchmark levels used in the air quality analyses were based largely on a meta-analysis (ISA, Table 3.1-3) of controlled human exposure studies of airway hyperresponsiveness. One important source of uncertainty with regard to this approach is that controlled human exposure studies have typically involved volunteers with mild asthma. Data are lacking for more severely affected asthmatics, who may be more susceptible (ISA, section 3.1.3.2). As a result, the potential health effect benchmarks could underestimate risks in populations with greater susceptibility. While approaches to classifying asthma severity differ, some estimates indicate that over half of asthmatics could be classified as moderate or severe (Fuhlbrigge

et al.

, 2002; Stout

et al.

, 2006). A second important source of uncertainty with regard to this approach is that the meta-analysis showed increased airway responsiveness in asthmatics at the lowest NO

level for which data were available (

i.e.

100 ppb). Controlled human exposure studies have not evaluated the possibility of NO

effects on airway responsiveness in asthmatics at exposure concentrations below 100 ppb. A third important source of uncertainty associated with this approach is that the meta-analysis provided information on the direction of the NO

-induced airway response, but not on the magnitude of the response.

Therefore, although the ISA did conclude that increased airway responsiveness associated with NO

exposure could increase symptoms and worsen asthma control (ISA, section 5.4), the full public health implications of benchmark exceedances are uncertain.

The Atlanta exposure assessment was also associated with a number of key uncertainties that should be considered when interpreting the results with regard to decisions on the standard. Some of these uncertainties, including those associated with benchmark levels, were shared with the air quality analyses. Additional uncertainties associated specifically with the Atlanta exposure assessment are discussed briefly below.

When compared to ambient measurement data, predicted upper percentile NO

concentrations may be 10-50% higher. Because these predicted concentrations are used as inputs for the exposure modeling, this suggests the possibility that the exposure assessment is over-predicting upper percentile NO

exposures. Other approaches used to evaluate exposure results (

i.e.

, comparison to personal exposure monitoring results and comparison of exposure-to-ambient concentration ratios with those identified in the ISA) have suggested that exposure estimates are reasonable. However, the possibility cannot be ruled out that benchmark exceedances are over-predicted in the Atlanta exposure analysis.

The exposure assessment was limited to Atlanta and the extent to which these results are representative of other locations in the U.S. is uncertain. The REA (section 8.11) concluded that the Atlanta exposure estimates are likely representative of other moderate to large urban areas. However, the REA also recognized that, given the greater proximity of the population to mobile sources in large urban areas such as Los Angeles, New York, and Chicago (

see

REA, Tables 8-14 and 8-15), the estimates of benchmark exceedances in Atlanta may be smaller than in these larger cities.

A number of key uncertainties should also be considered when interpreting the results of the Atlanta risk assessment with regard to decisions on the standard. Some of these, including the appropriateness of generalizing results from Atlanta, are shared with the Atlanta exposure assessment. Additional uncertainties associated specifically with the Atlanta risk assessment are discussed briefly below.

There is uncertainty about whether the association between NO

and emergency department visits actually reflects a causal relationship across the range of daily and hourly concentration levels in the epidemiologic studies. The ISA (section 5.4, p. 5-15) noted that when interpreting the NO

epidemiologic results, “It is difficult to determine * * * the extent to which NO

is independently associated with respiratory effects or if NO

is a marker for the effects of another traffic-related pollutant or mix of pollutants (

see

section 5.2.2 for more details on exposure issues). A factor contributing to uncertainty in estimating the NO

-related effect from epidemiologic studies is that NO

is a component of a complex air pollution mixture from traffic related sources that include CO and various forms of PM.” This uncertainty should be considered when interpreting the quantitative NO

risk estimates based on the Atlanta epidemiologic study. However, in discussing these uncertainties, the ISA (section 5.4, p. 5-16) concluded that, “Although this complicates the efforts to disentangle specific NO

-related health effects, the evidence summarized in this assessment indicates that NO

associations generally remain robust in multi-pollutant models and supports a direct effect of short-term NO

exposure on respiratory morbidity at ambient concentrations below the current NAAQS. The robustness of epidemiologic findings to adjustment for co-pollutants, coupled with data from animal and human experimental studies, support a determination that the relationship between NO

and respiratory morbidity is likely causal, while still recognizing the relationship between NO

and other traffic-related pollutants.”

A related uncertainty is that associated with the estimated NO

coefficient in the concentration-response function. This coefficient has been characterized by confidence intervals reflecting sample size. However, these confidence intervals do not reflect all of the uncertainties related to the concentration-response functions, such as whether or not the model used in the epidemiologic study is the correct model form. Concerning the possible role of co-pollutants in the Tolbert

et al.

(2007) study, single-pollutant models may produce overestimates of the NO

effects if some of those effects are really due in whole or part to one or more of the other pollutants. On the other hand, effect estimates based on multi-pollutant models can be uncertain, and can result in statistically non-significant estimates where a true relationship exists, if the co-pollutants included in the model are highly correlated with NO

. As a result of these considerations, we report risk estimates based on both the single- and multi-pollutant models from Tolbert

et al.

(2007).

D. Considerations in Review of the Standard

This section presents the integrative synthesis of the evidence and information contained in the ISA and the REA with regard to the current and potential alternative standards. EPA notes that the final decision on retaining or revising the current primary NO

standard is a public health policy judgment to be made by the Administrator. This judgment will be informed by a recognition that the available health effects evidence reflects a continuum consisting of ambient levels of NO

at which scientists generally agree that health effects are likely to occur, through lower levels at which the likelihood and magnitude of the response become increasingly uncertain. The Administrator's final decision will draw upon scientific information and analyses related to health effects, population exposures, and risks; judgments about the appropriate response to the range of uncertainties that are inherent in the scientific evidence and analyses; and comments received in response to this proposal.

1. Background on the Current Standard

The current standard, which is an annual average of 0.053 ppm (53 ppb), was retained by the Administrator in the most recent review in 1996 (61 FR 52854 (October 8, 1996)). The decision in that review to retain the annual standard was based on consideration of available scientific evidence for health effects associated with NO

and on air quality information. With regard to these considerations, the Administrator noted that “a 0.053 ppm annual standard would keep annual NO

concentrations considerably below the long-term levels for which serious chronic effects have been observed in animals” and that “[r]etaining the existing standard would also provide protection against short-term peak NO

concentrations at the levels associated with mild changes in pulmonary function and airway responsiveness observed in controlled human studies” (60 FR 52874, 52880 (Oct. 11, 1995)). As a result, the Administrator concluded that “the existing annual primary standard appears to be both adequate and necessary to protect human health against both long- and short-term NO

exposures” and that “retaining the existing annual standard is consistent

with the scientific data assessed in the Criteria Document (EPA, 1993) and the Staff Paper (EPA, 1995) and with the advice and recommendations of CASAC” (61 FR 52852 at 52854).

As noted previously, the 1993 AQCD concluded that there were two key health effects of greatest concern at ambient or near-ambient levels of NO

: increased airway responsiveness in asthmatic individuals after short-term exposures and increased occurrence of respiratory illness in children with longer-term exposures. Evidence also was found for increased risk of emphysema, but this was of major concern only with exposures to levels of NO

much higher than then-current ambient concentrations. The evidence regarding airway responsiveness was drawn largely from controlled human exposure studies. The evidence for respiratory illness was drawn from epidemiologic studies that reported associations between respiratory symptoms and indoor exposures to NO

in people living in homes with gas stoves. The biological plausibility of the epidemiologic results was supported by toxicological studies that detected changes in lung host defenses following NO

exposure. Subpopulations considered potentially more susceptible to the effects of NO

included individuals with preexisting respiratory disease, children, and the elderly.

In that review, health risks were characterized by comparing ambient monitoring data, which were used as a surrogate for exposure, with potential health benchmark levels identified from controlled human exposure studies. At the time of the review, a meta-analysis of controlled human exposure studies indicated the possibility for adverse health effects due to short-term (

e.g.

, 1-hour) exposures between 200 ppb and 300 ppb NO

. Therefore, the focus of the assessment was on the potential for short-term (

i.e.

, 1-hour) exposures to NO

levels above potential health benchmarks in this range. The assessment used monitoring data from the years 1988-1992 and screened for sites with one or more hourly exceedances of potential short-term health effect benchmarks. Predictive models were then constructed to relate the frequency of hourly concentrations above short-term health effect benchmarks to a range of annual average concentrations, including the current standard. Based on the results of this analysis, both CASAC (Wolff, 1995) and the Administrator (60 FR 52874) concluded that the minimal occurrence of short-term peak concentrations at or above a potential health effect benchmark of 200 ppb (1-hour average) indicated that the existing annual standard would provide adequate health protection against short-term exposures. This conclusion, combined with the conclusion that the current annual standard would maintain annual average levels well-below those associated with serious effects in animal toxicological studies, formed a large part of the basis for the decision in the 1996 review to retain the existing annual standard.

2. Approach for Reviewing the Need To Retain or Revise the Current Standard

The decision in the present review on whether the current annual standard is requisite to protect public health with an adequate margin of safety will be informed by a number of scientific studies and analyses that were not available in the 1996 review. Specifically, as discussed above (section II), a large number of epidemiologic studies have been published since the 1996 review. Many of these studies evaluate associations between NO

and adverse respiratory endpoints (

e.g.

, respiratory symptoms, emergency department visits, hospital admissions) in locations where annual average NO

concentrations are well-below the level allowed by the current standard (53 ppb). In addition, the meta-analysis of controlled human exposure studies has been updated for this review to include information on additional exposure concentrations. Finally, the REA described estimates of NO

-associated health risks that could be present in locations that just meet the current annual standard. These types of risk estimates were not available in the last review. The approach for considering this scientific evidence and exposure/risk information is discussed below.

To evaluate whether the current primary NO

standard is adequate or whether consideration of revisions is appropriate, EPA is using an approach in this review that has been described in chapter 10 of the REA. The approach outlined in the REA builds upon the approaches used in reviews of other criteria pollutants, including the most recent reviews of the Pb, O

, and PM NAAQS (EPA, 2007d; EPA, 2007e; EPA, 2005), and reflects the body of evidence and information that is currently available. As in other recent reviews, EPA's considerations will include the implications of placing more or less weight or emphasis on different aspects of the scientific evidence and the exposure/risk-based information, recognizing that the weight to be given to various elements of the evidence and exposure/risk information is part of the public health policy judgments that the Administrator will make in reaching decisions on the standard.

A series of general questions frames this approach to considering the scientific evidence and exposure-/risk-based information. First, EPA's consideration of the scientific evidence and exposure/risk information with regard to the adequacy of the current standard is framed by the following questions:

• To what extent does evidence that has become available since the last review reinforce or call into question evidence for NO

-associated effects that were identified in the last review?

• To what extent has evidence for different health effects and/or sensitive populations become available since the last review?

• To what extent have uncertainties identified in the last review been reduced and/or have new uncertainties emerged?

• To what extent does evidence and exposure-/risk-based information that has become available since the last review reinforce or call into question any of the basic elements of the current standard?

To the extent that the available evidence and exposure-/risk-based information suggests it may be appropriate to consider revision of the current standard, EPA considers that evidence and information with regard to its support for consideration of a standard that is either more or less protective than the current standard. This evaluation is framed by the following questions:

• Is there evidence that associations, especially causal or likely causal associations, extend to ambient NO

concentrations as low as, or lower than, the concentrations that have previously been associated with health effects? If so, what are the important uncertainties associated with that evidence?

• Are exposures above benchmark levels and/or health risks estimated to occur in areas that meet the current standard? If so, are the estimated exposures and health risks important from a public health perspective? What are the important uncertainties associated with the estimated risks?

To the extent that there is support for consideration of a revised standard, EPA then considers the specific elements of the standard (indicator, averaging time, form, and level) within the context of the currently available information. In so doing, the Agency addresses the following questions:

• Does the evidence provide support for considering a different indicator for gaseous NO

• Does the evidence provide support for considering different averaging times?

• What ranges of levels and forms of alternative standards are supported by the evidence, and what are the associated uncertainties and limitations?

• To what extent do specific averaging times, levels, and forms of alternative standards reduce the estimated exposures above benchmark levels and risks attributable to NO

, and what are the uncertainties associated with the estimated exposure and risk reductions?

The questions outlined above have been addressed in the REA. The following sections present considerations regarding the adequacy of the current standard and potential alternative standards, as discussed in chapter 10 of the REA, in terms of indicator, averaging time, form, and level.

E. Adequacy of the Current Standard

In considering the adequacy of the current standard, the policy assessment chapter of the REA considered the scientific evidence assessed in the ISA and the quantitative exposure- and risk-based information presented in the REA. A summary of this evidence and information as well as CASAC recommendations and the Administrator's conclusions regarding the adequacy of the current standard are presented below.

1. Evidence-Based Considerations

As discussed in chapter 10 of the REA, evidence published since the last review generally has confirmed and extended the conclusions articulated in the 1993 AQCD (ISA, section 5.3.2). The epidemiologic evidence has grown substantially with the addition of field and panel studies, intervention studies, time-series studies of effects such as emergency department visits and hospital admissions, and a substantial number of studies evaluating mortality risk associated with short-term NO

exposures. As noted above, no epidemiologic studies were available in 1993 that assessed relationships between NO

and outcomes such as hospital admissions, emergency department visits, or mortality. In contrast, dozens of epidemiologic studies on such outcomes, conducted at recent and current ambient NO

concentrations, are now included in this evaluation (ISA, chapter 3). While not as marked as the growth in the epidemiologic literature, a number of recent toxicological and human clinical studies also provide insights into relationships between NO

exposure and health effects.

As an initial consideration with regard to the adequacy of the current standard, the REA noted that the evidence relating long-term (weeks to years) NO

exposures at current ambient concentrations to adverse health effects was judged in the ISA to be either “suggestive but not sufficient to infer a causal relationship” (respiratory morbidity) or “inadequate to infer the presence or absence of a causal relationship” (mortality, cancer, cardiovascular effects, reproductive/developmental effects) (ISA, sections 5.3.2.4-5.3.2.6). In contrast, the evidence relating short-term (minutes to hours) NO

exposures to respiratory morbidity was judged to be “sufficient to infer a likely causal relationship” (ISA, section 5.3.2.1). This judgment was supported primarily by a large body of recent epidemiologic evidence that evaluated associations of short-term NO

concentrations with respiratory symptoms, emergency department visits, and hospital admissions. These conclusions from the ISA suggest that, at a minimum, consideration of the adequacy of the current annual standard should take into account the extent to which that standard provides protection against respiratory effects associated with short-term NO

exposures. As noted in the REA, such an emphasis on health endpoints for which evidence has been judged to be sufficient to infer a likely causal relationship would be consistent with other recent NAAQS reviews (

e.g.

, EPA, 2005; EPA, 2007d; EPA, 2007e).

In considering the NO

epidemiologic studies as they relate to the adequacy of the current standard, the REA noted that annual average NO

concentrations were below the level of the current annual NO

NAAQS in many of the locations where positive, and often statistically significant, associations with respiratory morbidity endpoints have been reported (ISA, section 5.4). As discussed previously, the ISA characterized that evidence for respiratory effects as consistent and coherent. The evidence is consistent in that associations are reported in studies conducted in numerous locations and with a variety of methodological approaches (ISA, section 5.3.2.1). It is coherent in the sense that the studies report associations with respiratory health outcomes that are logically linked together (ISA, section 5.3.2.1). The ISA noted that when the epidemiologic literature is considered as a whole, there are generally positive associations between NO

and respiratory symptoms, hospital admissions, and emergency department visits. A number of these associations are statistically significant, particularly the more precise effect estimates (ISA, section 5.3.2.1).

As discussed previously, the interpretation of these NO

epidemiologic studies is complicated by the fact that on-road vehicle exhaust emissions are a nearly ubiquitous source of combustion pollutant mixtures that include NO

. In order to provide some perspective on the uncertainty related to the presence of co-pollutants, the ISA evaluated epidemiologic studies that employed multi-pollutant models, epidemiologic studies of indoor and personal NO

exposure, and experimental studies. Specifically, the ISA noted that a number of NO

epidemiologic studies have attempted to disentangle the effects of NO

from those of co-occurring pollutants by employing multi-pollutant models. When evaluated as a whole, NO

effect estimates in these models generally remained robust when co-pollutants were included. Therefore, despite uncertainties associated with separating the effects of NO

from those of co-occurring pollutants, the ISA (section 5.4, p. 5-16) concluded that “the evidence summarized in this assessment indicates that NO

associations generally remain robust in multi-pollutant models and supports a direct effect of short-term NO

exposure on respiratory morbidity at ambient concentrations below the current NAAQS.” With regard to indoor studies, the ISA noted that these studies can test hypotheses related to NO

specifically (ISA, section 3.1.4.1). Although confounding by indoor combustion sources is a concern, indoor studies are not confounded by the same mix of co-pollutants present in the ambient air or by the contribution of NO

to the formation of secondary particles or O

(ISA, section 3.1.4.1). The ISA noted that the findings of indoor NO

studies are consistent with those of studies using ambient concentrations from central site monitors and concluded that indoor studies provide evidence of coherence for respiratory effects (ISA, section 3.1.4.1). With regard to experimental studies, the REA noted that they have the advantage of providing information on health effects that are specifically associated with exposure to NO

in the absence of co-pollutants. The ISA concluded that the NO

epidemiologic literature is supported by (1) evidence from controlled human exposure studies of airway hyperresponsiveness in asthmatics, (2) controlled human exposure and animal toxicological studies of impaired host-defense systems and increased risk of susceptibility to viral and bacterial infection, and (3) controlled human exposure and animal toxicological studies of airway inflammation (ISA, section 5.3.2.1 and 5.4).

In drawing broad conclusions regarding the evidence, the ISA

considered the epidemiologic and experimental evidence as well as the uncertainties associated with that evidence. When this evidence and its associated uncertainties are taken together, the ISA concluded that the results of epidemiologic and experimental studies form a plausible and coherent data set that supports a relationship between NO

exposures and respiratory endpoints, including respiratory symptoms and emergency department visits, at ambient concentrations that are present in areas that meet the current NO

NAAQS. Thus, taking into consideration the evidence discussed above, particularly the epidemiologic studies reporting NO

-associated health effects in locations that meet the current standard, the REA concluded that the scientific evidence calls into question the adequacy of the current standard to protect public health.

2. Exposure- and Risk-Based Considerations

In addition to the evidence-based considerations described above, the REA considered the extent to which exposure- and risk-based information can inform decisions regarding the adequacy of the current annual NO

standard, taking into account key uncertainties associated with the estimated exposures and risks. As noted above, NO

-associated health risks were characterized with three approaches. In the first, NO

air quality from locations across the country was used as a surrogate for exposure. In the second, exposures were estimated for all asthmatics and for asthmatic children considering time spent in different microenvironments in one urban area, Atlanta, GA. For both of these analyses, health risks were characterized by comparing estimates of air quality or exposure to potential health benchmark levels. Benchmark levels spanned the range of NO

concentrations that have been reported to increase airway responsiveness in asthmatics (

i.e.

, 100-300 ppb). In the third approach to characterizing NO

-related health risks, occurrences of NO

-related respiratory emergency department visits were estimated for Atlanta. This quantitative risk assessment was based on NO

concentration-response relationships identified in an epidemiologic study of air pollution-related emergency department visits in Atlanta. The results of each of these analyses are discussed in this section, specifically as they relate to the current standard.

When considering the Atlanta risk assessment results as they relate to the adequacy of the current standard, the REA noted that central estimates of incidence of NO

-related respiratory emergency department visits in Atlanta ranged from approximately 8 to 9% of total respiratory-related emergency department visits per year (or 9,800-10,900 NO

-related incidences) based on single pollutant models when air quality is adjusted upward to simulate a situation where Atlanta just meets the current standard. Central estimates of incidence of NO

-related respiratory emergency department visits ranged from 2.9-7.7% of total respiratory-related emergency department visits per year (or 3,600-9,400 NO

-related incidences) based on two-pollutant models. Inclusion of O

and/or PM

in multi-pollutant models resulted in the inclusion of an estimate of zero NO

-related respiratory emergency department visits within the 95% confidence intervals.

When considering the Atlanta exposure results as they relate to the adequacy of the current standard, the REA noted the number of days per year asthmatics could experience exposure to NO

concentrations greater than or equal to potential health benchmark levels, given air quality that is adjusted upward to simulate just meeting the current standard. If NO

concentrations were such that the Atlanta area just meets the current standard, nearly all asthmatics in Atlanta (>97%) would be estimated to experience six or more days per year with 1-hour NO

exposure concentrations greater than or equal to our highest benchmark level (300 ppb) (REA, Figure 8-22). Six days per year was the largest number of days specifically considered in the REA, but these results suggest that some asthmatics could experience 1-hour NO

exposure concentrations greater than or equal to 300 ppb on more than six days per year. In addition, more frequent exceedances would be expected for the lower benchmark levels.

When considering the air quality-based results as they relate to the adequacy of the current standard, the REA noted the number of benchmark exceedances estimated to occur in different locations given air quality that just meets that standard. In situations where annual NO

concentrations were adjusted upward to simulate just meeting the current standard, 1-hour NO

concentrations measured at fixed-site monitors in locations across the U.S. could exceed benchmark levels. Most locations were estimated to experience at least 50 days per year with 1-hour ambient NO

concentrations at fixed-site monitors in the current network greater than or equal to 100 ppb (Figures 7-2 and 7-3 in the REA) under this hypothetical scenario. Far fewer ambient exceedances were predicted for the higher benchmark levels. For example, only 5 areas were estimated to experience any days with 1-hour ambient NO

concentrations at fixed-site monitors greater than or equal to 300 ppb, and none of those locations were estimated to experience more than 2 such days per year, on average (REA, Appendix A).

However, on-road NO

concentrations were estimated in this analysis to be an average of 80% higher than concentrations at fixed-site monitors (though this relationship will vary across locations and with time). In the majority of locations evaluated, roadway exceedances of the 100 ppb benchmark level could occur on most days of the year when air quality is adjusted upward to simulate just meeting the current standard (Figure 7-6 in the REA). Even for higher benchmark levels, most locations were estimated to have exceedances on roadways. All locations evaluated except one (Boston) were estimated to experience on-road NO

concentrations greater than or equal to 300 ppb (REA, Appendix A). Four of these locations were estimated to experience an average of greater than 20 days per year with on-road NO

concentrations greater than or equal to 300 ppb (REA, Appendix A).

3. Summary of Considerations From the REA

As noted above, the policy assessment chapter of the REA considered the scientific evidence with regard to the current standard. This included consideration of causality judgments made in the ISA regarding the level of support for effects associated with short-term and long-term exposures, the epidemiologic evidence described in the ISA including associated uncertainties, the conclusions in the ISA regarding the robustness of this evidence, and the support provided for epidemiologic findings by experimental studies. The REA concluded that, given these considerations, particularly the evidence for NO

-associated effects in locations that meet the current standard, the adequacy of the current standard to protect the public health is clearly called into question. This evidence provides support for consideration of an NO

standard that would provide increased health protection for at-risk groups, including asthmatics and individuals who spend time on or near major roadways, against health effects associated with short-term exposures ranging from increased asthma symptoms to respiratory-related emergency department visits and

hospital admissions, in addition to potential effects associated with long-term exposures.

In examining the exposure- and risk-based information with regard to the adequacy of the current annual NO

standard to protect the public health, the REA noted that estimated risks associated with air quality adjusted upward to simulate just meeting the current standard can reasonably be concluded to be important from a public health perspective. In particular, a large percentage (8-9%) of respiratory-related ED visits in Atlanta could be associated with short-term NO

exposures, most asthmatics in Atlanta could be exposed on multiple days per year to NO

concentrations at or above the highest benchmark evaluated, and most locations evaluated could experience on-/near-road NO

concentrations above benchmark levels on more than half of the days in a given year. Therefore, the REA noted that exposure- and risk-based results reinforce the scientific evidence in supporting the conclusion that consideration should be given to revising the current standard so as to provide increased public health protection, especially for at-risk groups, from NO

-related adverse health effects associated with short-term, and potential long-term, exposures.

4. CASAC Views

With regard to the adequacy of the current standard, CASAC conclusions were consistent with the views expressed in the policy assessment chapter of the REA. CASAC agreed that the primary concern in this review is to protect against health effects that have been associated with short-term NO

exposures. CASAC also agreed that the current annual standard is not sufficient to protect public health against the types of exposures that could lead to these health effects. Given these considerations, and as noted in their letter to the EPA Administrator, “CASAC concurs with EPA's judgment that the current NAAQS does not protect the public's health and that it should be revised” (Samet, 2008b). CASAC's views on how the standard should be revised are provided below within the context of discussions on the elements (

i.e.

, indicator, averaging time, form, level) of a new short-term standard.

5. Administrator's Conclusions Regarding Adequacy of the Current Standard

In considering the adequacy of the current NO

NAAQS, the Administrator has considered the conclusions of the ISA, the conclusions of the policy assessment chapter of the REA, and the views expressed by CASAC. In particular, the ISA concluded that the results of epidemiologic and experimental studies form a plausible and coherent data set that supports a likely causal relationship between short-term NO

exposures and adverse respiratory effects at ambient NO

concentrations that are present in locations meeting the current NO

NAAQS. With regard to the exposure and risk results, the REA concludes that central risk estimates suggest that the current standard could allow important adverse public health impacts.

Based on her consideration of these conclusions, as well as consideration of CASAC's conclusion that the current NO

NAAQS does not protect the public's health, the Administrator concludes that the current NO

standard does not provide the requisite degree of protection for public health against adverse effects associated with short-term exposures. In considering approaches to revising the current standard, the Administrator concludes that it is appropriate to consider setting a new short-term standard to supplement the current annual standard. The Administrator notes that such a short-term standard could provide increased public health protection, especially for members of at-risk groups, from effects described in both epidemiologic and controlled human exposure studies to be associated with short-term exposures to NO

F. Conclusions on the Elements of a New Short-Term Standard and an Annual Standard

In considering alternative NO

primary NAAQS, the Administrator notes the need to protect at-risk individuals from short-term exposures to NO

air quality that could cause the types of respiratory morbidity effects reported in epidemiologic studies and the need to protect at-risk individuals from short-term exposure to NO

concentrations reported in controlled human exposure studies to increase airway responsiveness in asthmatics. Considerations with regard to potential alternative standards and the specific options being proposed are discussed in the following sections in terms of indicator, averaging time, form, and level (sections II.F.1-II.F.4).

1. Indicator

In past reviews, EPA has focused on NO

as the most appropriate indicator for ambient NO

. In making a decision in the current review on the most appropriate indicator, the Administrator has considered the conclusions of the ISA and REA as well as the view expressed by CASAC. The REA noted that, while the presence of NO

species other than NO

has been recognized, no alternative to NO

has been advanced as being a more appropriate surrogate. Controlled human exposure studies and animal toxicology studies provide specific evidence for health effects following exposure to NO

. Epidemiologic studies also typically report levels of NO

though the degree to which monitored NO

reflects actual NO

levels, as opposed to NO

plus other gaseous NO

, can vary (REA, section 2.2.3). In addition, because emissions that lead to the formation of NO

generally also lead to the formation of other NO

oxidation products, measures leading to reductions in population exposures to NO

can generally be expected to lead to reductions in population exposures to other gaseous NO

. Therefore, an NO

standard can also be expected to provide some degree of protection against potential health effects that may be independently associated with other gaseous NO

even though such effects are not discernable from currently available studies indexed by NO

alone. Given these key points, the REA concluded that the evidence supports retaining NO

as the indicator. Consistent with this conclusion, the CASAC Panel recommended in its letter to the EPA Administrator that it “concurs with retention of NO

as the indicator” (Samet, 2008b). In light of the above considerations, the Administrator proposes to retain NO

as the indicator in the current review.

2. Averaging Time

The current annual averaging time for the NO

NAAQS was originally set in 1971, based on epidemiologic studies that supported a link between adverse respiratory effects and long-term exposure to low levels of NO

. As noted above, that annual standard was retained in subsequent reviews in part because an air quality assessment conducted by EPA concluded that areas that meet the annual standard would be unlikely to experience short-term ambient p

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