Review of the Primary National Ambient Air Quality Standards for Oxides of Nitrogen

Federal RegisterApr 18, 2018

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 50

[EPA-HQ-OAR-2013-0146; FRL-9976-78-OAR]

RIN 2060-AR57

Review of the Primary National Ambient Air Quality Standards for Oxides of Nitrogen

AGENCY:

Environmental Protection Agency (EPA).

ACTION:

Final action.

SUMMARY:

Based on the Environmental Protection Agency's (EPA's) review of the air quality criteria addressing human health effects of oxides of nitrogen and the primary national ambient air quality standards (NAAQS) for oxides of nitrogen, as measured by nitrogen dioxide (NO

), the EPA is retaining the current standards, without revision.

DATES:

This final action is effective on May 18, 2018.

ADDRESSES:

The EPA has established a docket for this action under Docket ID No. EPA-HQ-OAR-2013-0146. Incorporated into this docket is a separate docket established for the Integrated Science Assessment for this review (Docket ID No. EPA-HQ-ORD-2013-0232). All documents in these dockets are listed on the

www.regulations.gov

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

e.g.,

CBI or other information whose disclosure is restricted by statute. Certain other material, such as copyrighted material, is not placed on the internet and will be publicly available only in hard copy form. It may be viewed, with prior arrangement, at the EPA Docket Center. Publicly available docket materials are available either electronically in

www.regulations.gov

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

FOR FURTHER INFORMATION CONTACT:

Ms. Breanna Alman, 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) 541-2351; fax: (919) 541-0237; email:

alman.breanna@epa.gov.

Availability of Information Related to This Action

A number of the documents that are relevant to this decision are available through the EPA's website at

https://www.epa.gov/naaqs/nitrogen-dioxide-no2-primary-air-quality-standards.

These documents include the

Integrated Review Plan for the Primary National Ambient Air Quality Standards for Nitrogen Dioxide

(U.S. EPA, 2011a), available at

https://www3.epa.gov/ttn/naaqs/standards/nox/data/201406finalirpprimaryno2.pdf,

the

Integrated Science Assessment for Oxides of Nitrogen—Health Criteria

(U.S. EPA, 2016a), available at

https://cfpub.epa.gov/ncea/isa/recordisplay.cfm?deid=310879,

and the

Policy Assessment for the Review of the Primary National Ambient Air Quality Standards for Oxides of Nitrogen

(U.S. EPA, 2017a), available at

https://www.epa.gov/naaqs/policy-assessment-review-primary-national-ambient-air-quality-standards-oxides-nitrogen.

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

SUPPLEMENTARY INFORMATION:

Table of Contents

Executive Summary

I. Background

A. Legislative Requirements

B. Related NO

Control Programs

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

D. Summary of Proposed Decisions

E. Organization and Approach to Final Decisions

II. Rationale for Decision on the Primary Standards

A. Introduction

1. Characterization of NO

Air Quality

2. Overview of the Health Effects Evidence

3. Overview of Risk and Exposure Assessment Information

B. Conclusions on the Primary Standards

1. Basis for the Proposed Decision

2. The CASAC Advice in This Review

3. Comments on the Proposed Decision

4. Administrator's Conclusions

C. Decision on the Primary Standards

III. Statutory and Executive Order Reviews

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

B. Executive Order 13771: Reducing Regulation and Controlling Regulatory Costs

C. Paperwork Reduction Act (PRA)

D. Regulatory Flexibility Act (RFA)

E. Unfunded Mandates Reform Act (UMRA)

F. Executive Order 13132: Federalism

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

H. Executive Order 13045: Protection of Children From Environmental Health and Safety Risks

I. Executive Order 13211: Actions Concerning Regulations That Significantly Affect Energy Supply, Distribution or Use

J. National Technology Transfer and Advancement Act (NTTAA)

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

L. Determination Under Section 307(d)

M. Congressional Review Act (CRA)

References

Executive Summary

This document describes the completion of the EPA's current review of the primary NAAQS for oxides of nitrogen, of which nitrogen dioxide (NO

) is the component of greatest concern for health and is the indicator for the primary NAAQS. This review of the standards and the air quality criteria (the scientific information upon which the standards are based) is required by the Clean Air Act (CAA) on a periodic basis. In conducting this review, the EPA has carefully evaluated the currently available scientific literature on the health effects of NO

, focusing particularly on the information newly available since the conclusion of the last review. This section briefly summarizes background information about this action and the Administrator's decision to retain the current primary NO

standards. A full discussion of these topics is provided later in this document.

Summary of Background Information

There are currently two primary standards for oxides of nitrogen: A 1-hour standard established in 2010 at a level of 100 parts per billion (ppb) based on the 98th percentile of the annual distribution of daily maximum 1-hour NO

concentrations, averaged over 3 years, and an annual standard, originally set in 1971, at a level of 53 ppb based on annual average NO

concentrations.

Sections 108 and 109 of the CAA govern the establishment, review, and revision, as appropriate, of the NAAQS to protect public health and welfare. The CAA requires the EPA to periodically review the air quality criteria—the science upon which the standards are based—and the standards themselves. This review of the primary (health-based) NO

NAAQS is being conducted pursuant to these statutory requirements. The schedule for

completing this review is established by a federal court order, which requires signature of a notice setting forth the EPA's final decision by April 6, 2018.

The last review of the primary NO

NAAQS was completed in 2010. In that review, the EPA supplemented the existing primary annual NO

standard by establishing a new short-term standard with a level of 100 ppb, based on the 3-year average of the 98th percentile of the annual distribution of daily maximum 1-hour concentrations (75 FR 6474, February 9, 2010). Revisions to the NAAQS were accompanied by revisions to the data handling procedures and the ambient air monitoring and reporting requirements, including the establishment of requirements for states to locate monitors near heavily trafficked roadways in large urban areas and in other locations where maximum NO

concentrations can occur.

Consistent with the review completed in 2010, this review is focused on the health effects associated with gaseous oxides of nitrogen and on the protection afforded by the primary NO

standards. The gaseous oxides of nitrogen include NO

and nitric oxide (NO), as well as their gaseous reaction products. Total oxides of nitrogen include these gaseous species as well as particulate species (

e.g.,

nitrates). The EPA is separately considering the health and non-ecological welfare effects of particulate species in the review of the NAAQS for particulate matter (PM) (U.S. EPA, 2016b). In addition, the EPA is separately reviewing the welfare effects associated with NO

and SO

and the ecological welfare effects associated with PM. (U.S. EPA, 2017b).

Summary of Decision

In this action, the EPA is retaining the current primary NO

standards, without revision. This decision has been informed by a careful consideration of the full body of scientific evidence and information available in this review, giving particular weight to the assessment of the evidence in the 2016 NO

Integrated Science Assessment (ISA); analyses and considerations in the Policy Assessment (PA); the advice and recommendations of the Clean Air Scientific Advisory Committee (CASAC); and public comments.

Based on these considerations, the Administrator reaches the conclusion that the current body of scientific evidence and the results of quantitative analyses supports his judgment that the current 1-hour and annual primary NO

standards, together, are requisite to protect public health with an adequate margin of safety, and do not call into question any of the elements of those standards. These conclusions are consistent with the CASAC recommendations. In its advice to the Administrator, the CASAC “recommend[ed] retaining, and not changing the existing suite of standards” (Diez Roux and Sheppard, 2017). The CASAC further stated that “it is the suite of the current 1-hour and annual standards, together, that provide protection against adverse effects” (Diez Roux and Sheppard, 2017, p. 9). Therefore, in this review, the EPA is retaining the current 1-hour and annual NO

primary standards, without revision.

As in the last review, the strongest evidence continues to come from studies examining respiratory effects following short-term NO

exposures.

In particular, the 2016 NO

ISA concludes that “[a] causal relationship exists between short-term NO

exposure and respiratory effects based on evidence for asthma exacerbation” (U.S. EPA, 2016a, p. 1-17). The strongest support for this conclusion comes from controlled human exposure studies examining the potential for NO

-induced increases in airway responsiveness (AR) (which is a hallmark of asthma) in individuals with asthma. Additional supporting evidence comes from epidemiologic studies reporting associations between short-term NO

exposures and an array of respiratory outcomes related to asthma exacerbation (

e.g.,

asthma-related hospital admissions and emergency department (ED) visits in children and adults).

The 2016 NO

ISA defines short-term exposures as those with durations of minutes up to 1 month, with most studies examining effects related to exposures in the range of 1 hour to 1 week (U.S. EPA, 2016a, p. 1-15).

In addition to the effects of short-term exposures, the 2016 NO

ISA concludes that there is “likely to be a causal relationship” between long-term NO

exposures and respiratory effects, based on the evidence for asthma development in children. The strongest evidence supporting this conclusion comes from recent epidemiologic studies demonstrating associations between long-term NO

exposures and asthma incidence. Additional support comes from experimental studies supporting the biological plausibility of a potential mode of action by which NO

exposures could cause asthma development.

While the evidence supports the occurrence of adverse NO

-related respiratory effects at ambient NO

concentrations likely to have been above those allowed by the current primary NO

NAAQS, that evidence, together with analyses of the potential for NO

exposures, does not call into question the adequacy of the public health protection provided by the current standards. In particular, compared to the last review when the 1-hour standard was set, evidence from controlled human exposure studies has not altered our understanding of the NO

exposure concentrations that cause increased AR. Analyses based on information from these studies indicate that the current standards provide protection against the potential for NO

exposures that could increase AR in people with asthma. In addition, while epidemiologic studies report relatively precise associations with serious NO

-related health outcomes (

i.e.,

ED visits, hospital admissions, asthma incidence) in locations likely to have violated the current 1-hour and/or annual standards during portions of study periods, studies do not indicate such associations in locations with NO

concentrations that would have clearly met those standards.

After considering the current body of scientific evidence, the results of quantitative analyses, the CASAC advice, and public comments, the Administrator concludes that the current 1-hour and annual NO

primary standards, together, are requisite to protect public health with an adequate margin of safety. Therefore, in this review, the EPA is retaining the current 1-hour and annual NO

primary standards, without revision.

I. Background

A. Legislative Requirements

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

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

A secondary standard, as defined in section 109(b)(2), must “specify a level of air quality the attainment and maintenance of which, in the judgment of the Administrator, based on such criteria, is requisite to protect the public welfare from any known or anticipated adverse effects associated with the presence of [the] pollutant in the ambient air.”

The legislative history of section 109 indicates that a primary standard is to be set at “the maximum permissible ambient air level . . . which will protect the health of any [sensitive] group of the population,” and that for this purpose “reference should be made to a representative sample of persons comprising the sensitive group rather than to a single person in such a group.” See S. Rep. No. 91-1196, 91st Cong., 2d Sess. 10 (1970).

As specified in section 302(h) (42 U.S.C. 7602(h)) effects on welfare include, but are not limited to, “effects on soils, water, crops, vegetation, man-made materials, animals, wildlife, weather, visibility and climate, damage to and deterioration of property, and hazards to transportation, as well as effects on economic values and on personal comfort and well-being.”

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

See Lead Industries Association

EPA,

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

American Petroleum Institute

Costle,

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

American Farm Bureau Federation

EPA,

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

Association of Battery Recyclers

EPA,

604 F.3d 613, 617-18 (D.C. Cir. 2010). Both kinds of uncertainties are components of the risk associated with pollution at levels below those at which human health effects can be said to occur with reasonable scientific certainty. Thus, in selecting primary standards that provide an adequate margin of safety, the Administrator is seeking not only to prevent pollution levels that have been demonstrated to be harmful but also to prevent lower pollutant levels that may pose an unacceptable risk of harm, even if the risk is not precisely identified as to nature or degree. The CAA does not require the Administrator to establish a primary NAAQS at a zero-risk level,

see Lead Industries Association,

647 F.2d at 1156 n.51, but rather at a level that reduces risk sufficiently so as to protect public health with an adequate margin of safety.

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

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

See Lead Industries Association

EPA,

647 F.2d at 1161-62.

As used here and similarly throughout this document, the term population (or group) refers to persons having a quality or characteristic in common, such as a specific pre-existing illness or a specific age or lifestage.

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

See generally, Whitman

American Trucking Associations,

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

American Petroleum Institute

Costle,

665 F.2d at 1185.

Section 109(d)(1) requires that “not later than December 31, 1980, and at 5-year intervals thereafter, the Administrator shall complete a thorough review of the criteria published under section 108 and the national ambient air quality standards . . . and shall make such revisions in such criteria and standards and promulgate such new standards as may be appropriate . . . .” Section 109(d)(2) requires that an independent scientific review committee “shall complete a review of the criteria . . . and the national primary and secondary ambient air quality standards . . . and shall recommend to the Administrator any new . . . standards and revisions of existing criteria and standards as may be appropriate . . . .” Since the early 1980s, this independent review function has been performed by the Clean Air Scientific Advisory Committee (CASAC).

Lists of the CASAC members and members of the NO

Review Panel are available at:

http://yosemite.epa.gov/sab/sabproduct.nsf/WebCASAC/CommitteesandMembership?OpenDocument.

B. Related NO

Control Programs

States are primarily responsible for ensuring attainment and maintenance of ambient air quality standards once the EPA has established them. Under section 110 of the Act, 42 U.S.C. 7410, and related provisions, states are to submit, for the EPA's approval, state implementation plans (SIPs) that provide for the attainment and maintenance of such standards through control programs directed to sources of the pollutants involved. The states, in conjunction with the EPA, also administer the Prevention of Significant Deterioration permitting 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 (NSPS) 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 for the NO

NAAQS (see 77 FR 9532 (February 17, 2012)). In addition, there are currently no monitors where there are design values (DVs)

above either the 1-hour or annual standard (U.S. EPA, 2017a, Figure 2-5), with the maximum DVs in 2015 being 30 ppb (annual) and 72 ppb (hourly) (U.S. EPA, 2017a Section, 2.3.1).

The metric used to determine whether areas meet or exceed the NAAQS is called a design value (DV). In the case of the primary NO

NAAQS, there are 2 types of DVs: The annual DV and the hourly DV. The annual DV for a particular year is the average of all hourly values within that calendar year. The hourly DV is the three-year average of the 98th percentiles of the annual distributions of daily maximum 1-hour NO

concentrations. The requirements for calculating DVs for the primary NO

NAAQS from valid monitoring data are further specified in Appendix S to Part 50.

While NO

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

emissions are highway vehicles, off-highway vehicles, and stationary fuel combustion sources.

The EPA anticipates that NO

emissions will continue to decrease over the next 20 years. For example, Tier 2 and Tier 3 emission standards for new light-duty vehicles, combined with the reduction of gasoline sulfur content, will significantly reduce motor vehicle emissions of NO

, with Tier 3 standards phasing in from model year 2017 to model year 2025. For heavy-duty engines, new NO

standards were phased in between the 2007 and 2010 model years, following the introduction of ultra-low sulfur diesel fuel. More stringent NO

standards for non-road diesel engines, locomotives, and certain marine engines are becoming effective throughout the next decade. In future decades, these vehicles and engines meeting more stringent NO

standards will become an increasingly large fraction of in-use mobile sources, leading to large NO

emission reductions.

In this context, NO

refers to the sum of NO and NO

, as is common within air pollution research and control communities. However, in the larger context of this NAAQS review, the terms “oxides of nitrogen” and “nitrogen oxides” generally refer more broadly to gaseous oxides of nitrogen, which include NO

and NO, as well as their gaseous reaction products.

Highway vehicles include all on-road vehicles, including light duty as well as heavy duty vehicles,

both gasoline- and diesel-powered, and on-highway motorcycles. Off-highway engines, vehicles and equipment include aircraft, marine vessels, locomotives, off-highway motorcycles, recreational vehicles and other non-road products (

e.g.,

lawnmowers, portable generators, chainsaws, forklifts). Fuel combustion sources includes electric power generating units (EGUs), which derive their power generation from all types of fuels.

Reductions in ambient NO

concentrations could also result from the implementation of NAAQS for other pollutants (

e.g.,

ozone, PM), to the extent NO

emissions are reduced as part of the implementation of those standards.

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

In 1971, the EPA added oxides of nitrogen to the list of criteria pollutants under section 108(a)(1) of the CAA and issued the initial air quality criteria (36 FR 1515, January 30, 1971; U.S. EPA, 1971). Based on these air quality criteria, the EPA promulgated the NO

NAAQS (36 FR 8186, April 30, 1971). Both primary and secondary standards were set at 53 ppb,

annual average. Since then, the Agency has completed multiple reviews of the air quality criteria and primary NO

standards. In the last review, the EPA made revisions to the primary NO

NAAQS in order to provide requisite protection of public health. Specifically, the EPA supplemented the existing primary annual NO

standard by establishing a new short-term standard with a level of 100 ppb, based on the 3-year average of the 98th percentile of the annual distribution of daily maximum 1-hour concentrations (75 FR 6474, February 9, 2010). In addition, revisions to the NAAQS were accompanied by revisions to the data handling procedures and the ambient air monitoring and reporting requirements, including requirements for states to locate monitors near heavily trafficked roadways in large urban areas and in other locations where maximum NO

concentrations can occur.

In 1971, primary and secondary NO

NAAQS were set at levels of 100 micrograms per cubic meter (μg/m

), which equals 0.053 parts per million (ppm) or 53 ppb.

Industry groups filed petitions for judicial review of the 2010 rule in the U.S. Court of Appeals for the District of Columbia Circuit.

API

EPA,

684 F.3d 1342 (D.C. Cir. 2012). The court upheld the 2010 rule, denying the petitions' challenges to the adoption of the 1-hour NO

NAAQS and dismissing, for lack of jurisdiction, the challenges to statements regarding permitting in the preamble of the 2010 rule.

Id.

at 1354.

Subsequent to the 2010 rulemaking, the Agency revised the deadlines by which the near-road monitors were to be operational in order to implement a phased deployment approach (78 FR 16184, March 14, 2013), with a majority of the network becoming operational by 2015. In 2016, after analyzing available monitoring data, the Agency revised the size requirements of the near-road network, reducing the network to only operate in Core Based Statistical Areas (CBSAs) with populations of 1 million or more (81 FR 96381, December 30, 2016).

In February 2012, the EPA announced the initiation of the current periodic review of the air quality criteria for oxides of nitrogen and of the primary NO

NAAQS and issued a call for information in the

Federal Register

(77 FR 7149, February 10, 2012). A wide range of external experts as well as the EPA staff representing a variety of areas of expertise (

e.g.,

epidemiology, human and animal toxicology, statistics, risk/exposure analysis, atmospheric science, and biology) participated in a workshop held by the EPA on February 29 to March 1, 2012, in Research Triangle Park, NC. The workshop provided an opportunity for a public discussion of the key policy-relevant issues around which the Agency would structure this primary NO

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

Based in part on the workshop discussions, the EPA developed a draft plan for the NO

ISA and subsequently a draft Integrated Review Plan (IRP) outlining the schedule, process, and key policy-relevant questions that would guide the evaluation of the health-related air quality criteria for NO

and the review of the primary NO

NAAQS. The draft plan for the NO

ISA was released in May 2013 (78 FR 26026) and was the subject of a consultation with the CASAC on June 5, 2013 (78 FR 27234). Comments from the CASAC and the public were considered in the preparation of the first draft ISA and the draft IRP. In addition, preliminary draft materials for the NO

ISA were reviewed by subject matter experts at a public workshop hosted by the EPA's National Center for Environmental Assessment (NCEA) in May 2013 (78 FR 27374). The first draft ISA was released in November 2013 (78 FR 70040). During this time, the draft IRP was also in preparation and was released in February 2014 (79 FR 7184). Both the draft IRP and first draft ISA were reviewed by the CASAC at a public meeting held in March 2014 (79 FR 8701), and the first draft ISA was further discussed at an additional teleconference held in May 2014 (79 FR 17538). The CASAC finalized its recommendations on the first draft ISA and the draft IRP in letters dated June 10, 2014 (Frey, 2014a; Frey, 2014b), and the final IRP was released in June 2014 (79 FR 36801).

The EPA released the second draft ISA in January 2015 (80 FR 5110) and the Risk and Exposure Assessment (REA) Planning document in May 2015 (80 FR 27304). These documents were reviewed by the CASAC at a public meeting held in June 2015 (80 FR 22993). A follow-up teleconference with the CASAC was held in August 2015 (80 FR 43085) to finalize recommendations on the second draft ISA. The final ISA was released in January 2016 (81 FR 4910). The CASAC recommendations on the second draft ISA and the draft REA planning document were provided to the EPA in letters dated September 9, 2015 (Diez Roux and Frey, 2015a; Diez Roux and Frey, 2015b), and the final ISA was released in January 2016 (81 FR 4910).

After considering the CASAC advice and public comments, the EPA prepared a draft Policy Assessment (PA), which was released on September 23, 2016 (81 FR 65353). The draft PA was reviewed by the CASAC on November 9-10, 2016 (81 FR 68414), and a follow-up teleconference was held on January 24, 2017 (81 FR 95137). The CASAC recommendations, based on its review of the draft PA, were provided in a letter to the EPA Administrator dated March 7, 2017 (Diez Roux and Sheppard, 2017). The EPA staff took into account these recommendations, as well as public comments provided on the draft PA, when developing the final PA, which was released in April 2017.

This document may be found at:

https://www.epa.gov/naaqs/policy-assessment-review-primary-national-ambient-air-quality-standards-oxides-nitrogen.

On July 14, 2017, the proposed decision to retain the NO

NAAQS was signed, and it was published in the

Federal Register

on July 26 (82 FR 34792). The 60-day comment period ended on September 25, 2017, and comments were received from various government, industry, and environmental groups, as well as members of the general public.

In addition, in July 2016, a lawsuit was filed against the EPA that included a claim that EPA had failed to complete its review of the primary NO

NAAQS within five years, as required by the CAA.

Center for Biological Diversity et al.

McCarthy,

(No. 4:16-cv-03796-VC, N.D. Cal., July 7, 2016). Consistent with CAA section 113(g), a notice of a proposed consent decree to resolve this litigation was published in the

Federal Register

on January 17, 2017 (82 FR 4866). The EPA received two public comments on the proposed consent decree, neither of which disclosed facts or considerations indicating that the Department of Justice or the EPA should withhold consent.

The parties to the litigation filed a joint motion asking the court to enter the consent decree, and the court entered the consent decree as a consent judgment on April 28, 2017. The consent judgment established July 14, 2017 as the deadline for signature of a notice setting forth the proposed decision in this review and April 6, 2018 as the deadline for signature of a notice setting forth the final decision.

One comment was received from the American Petroleum Institute (API) and one was received from an anonymous commenter. These comments are available in the docket for the proposed consent decree (EPA-HQ-OGC-2016-0719).

Consistent with the review completed in 2010, this review is focused on health effects associated with gaseous oxides of nitrogen

and the protection afforded by the primary NO

standards. The gaseous oxides of nitrogen include NO

and NO, as well as their gaseous reaction products. Total oxides of nitrogen include these gaseous species as well as particulate species (

e.g.,

nitrates). Health effects and non-ecological welfare effects associated with the particulate species are addressed in the review of the NAAQS for PM (U.S. EPA, 2016b).

The EPA is separately reviewing the welfare effects associated with NO

and SO

and the ecological welfare effects associated with PM. (U.S. EPA, 2017a).

These gaseous oxides of nitrogen can also be referred to as “nitrogen oxides” and include a broad category of gaseous oxides of nitrogen (

i.e.,

oxidized nitrogen compounds), including NO

, NO, and their various reaction products.

Additional information on the PM NAAQS is available at:

https://www.epa.gov/naaqs/particulate-matter-pm-air-quality-standards.

Additional information on the ongoing and previous review of the secondary NO

and SO

NAAQS is available at:

https://www.epa.gov/naaqs/nitrogen-dioxide-no2-and-sulfur-dioxide-so2-secondary-air-quality-standards.

D. Summary of Proposed Decisions

For reasons discussed in the proposal and summarized in section II.B.1 below, the Administrator proposed to retain the current primary standards for NO

, without revision.

E. Organization and Approach to Final Decisions

This action presents the Administrator's final decision in the current review of the primary NO

standards. The final decision addressing the primary NO

standards is based on a thorough review in the 2016 NO

ISA of scientific information on known and potential human health effects associated with exposure to NO

associated with levels typically found in the ambient air. This final decision also takes into account the following: (1) Staff assessments in the PA of the most policy-relevant information in the ISA, as well as quantitative exposure and risk information; (2) the CASAC advice and recommendations, as reflected in its letters to the Administrator and its discussions of drafts of the ISA and PA at public meetings; (3) public comments received during the development of these documents, both in connection with the CASAC meetings and separately; and (4) public comments received on the proposal. The primary NO

standards are addressed in section II below. Section III addresses statutory and executive order reviews.

II. Rationale for Decision on the Primary Standards

This section presents the rationale for the Administrator's decision to retain the existing primary NO

standards. This rationale is based on a thorough review in the 2016 NO

ISA of the latest scientific information, generally published through August 2014, on human health effects associated with NO

and pertaining to the presence of NO

in the ambient air. This decision also takes into account: (1) The PA's staff assessments of the most policy-relevant information in the ISA and staff analyses of air quality, human exposure and health risks, upon which staff conclusions regarding appropriate considerations in this review are based; (2) the CASAC advice and recommendations, as reflected in discussions of drafts of the ISA and PA at public meetings, in separate written comments, and in the CASAC letters to the Administrator; (3) public comments received during the development of these documents, either in connection with the CASAC meetings or separately; and (4) public comments received on the proposal. Section II.A provides background on the general approach for review of the primary NO

standards and brief summaries of key aspects of the currently available air quality information, as well as health effects and exposure/risk information. Section II.B presents the Administrator's conclusions on the adequacy of the current primary NO

standards, drawing on consideration of this information, advice from the CASAC, and comments from the public. Section II.C summarizes the Administrator's decision on the primary NO

standards.

A. Introduction

The Administrator's approach to reviewing the current primary NO

standards is based, most fundamentally, on using the EPA's assessment of the current scientific evidence and associated quantitative analyses to inform his judgment regarding primary NO

standards that protect public health with an adequate margin of safety. In drawing conclusions with regard to the primary standards, the final decision on the adequacy of the current standards is largely a public health policy judgment to be made by the Administrator. The Administrator's final decision draws upon scientific information and analyses about health effects, population exposure and risks, as well as judgments about how to consider the range and magnitude of uncertainties that are inherent in the scientific evidence and analyses.

The approach to informing these judgments is based on the recognition that the available health effects evidence generally reflects a continuum, consisting of levels 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. This approach is consistent with the requirements of the NAAQS provisions of the Act and with how the EPA and the courts have historically interpreted the Act. These provisions require the Administrator to establish primary standards that, in the judgment of the Administrator, are requisite to protect public health with an adequate margin of safety. In so doing, the Administrator seeks to establish standards that are neither more nor less stringent than necessary for this purpose. The Act does not require that primary standards be set at a zero-risk

level, but rather at a level that avoids unacceptable risks to public health including the health of sensitive groups. The four basic elements of the NAAQS (indicator, averaging time, level, and form) are considered collectively in evaluating the health protection afforded by the current standards.

To evaluate whether it is appropriate to consider retaining the current primary NO

standards, or whether consideration of revision is appropriate, the EPA has adopted an approach in this review that builds upon the general approach used in the last review and reflects the broader body of evidence and information now available. The Administrator's decisions in the prior review were based on an integration of information on health effects associated with exposure to NO

with information on the public health significance of key health effects, as well as on policy judgments as to when the standard is requisite to protect public health with an adequate margin of safety and advice from the CASAC and public comments. These considerations were informed by air quality and related analyses and quantitative exposure and risk information. Similarly, in this review, as described in the PA, the proposal, and elsewhere in this document, we draw on the current evidence and quantitative assessments of exposure pertaining to the public health risk of NO

in ambient air. In considering the scientific and technical information here, as in the PA, we consider both the information available at the time of the last review and information newly available since the last review, including most particularly that which has been critically analyzed and characterized in the current ISA. In considering the entire body of evidence presented in the current ISA, as in the PA and as in the last review, we focus particularly on those health endpoints for which the ISA finds associations with NO

to be causal or likely causal. The evidence-based discussions presented below draw upon evidence from both controlled human exposure studies and epidemiologic studies. Sections II.A.1 through II.A.3 below provide an overview of the current NO

air quality, health effects, and quantitative exposure and risk information with a focus on the specific policy-relevant questions identified for these categories of information in the PA (U.S. EPA, 2017a, Chapter 3).

1. Characterization of NO

Air Quality

This section presents information on NO

atmospheric chemistry and ambient concentrations, with a focus on information that is most relevant for the review of the primary NO

standards. This section is drawn from the more detailed discussion of NO

air quality in the PA (U.S. EPA, 2017a, Chapter 2) and the 2016 NO

ISA (U.S. EPA, 2016a, Chapter 2).

It presents a summary of NO

atmospheric chemistry (section II.A.1.a), trends in ambient NO

concentrations (section II.A.1.b), ambient NO

concentrations measured at monitors near roads (section II.A.1.c), the relationships between hourly and annual ambient NO

concentrations (section II.A.1.d), and background concentrations of NO

(section II.A.1.e).

The focus is on NO

in this document, as this is the indicator for the current standards and is most relevant to the evaluation of health evidence. Characterization of air quality for the broader category of oxides of nitrogen is provided in the 2016 NO

ISA (U.S. EPA, 2016a, Chapter 2).

a. Atmospheric Chemistry

Ambient concentrations of NO

are influenced by both direct NO

emissions and by emissions of NO, with the subsequent conversion of NO to NO

primarily though reaction with ozone (O

). The initial reaction between NO and O

to form NO

occurs fairly quickly during the daytime, with reaction times on the order of minutes. However, NO

can also be photolyzed to regenerate NO, creating new O

in the process (U.S. EPA, 2016a, Section 2.2). A large number of oxidized nitrogen species in the atmosphere are formed from the oxidation of NO and NO

. These include nitrate radicals (NO

), nitrous acid (HONO), nitric acid (HNO

), dinitrogen pentoxide (N

), nitryl chloride (ClNO

), peroxynitric acid (HNO

), peroxyacetyl nitrate and its homologues (PANs), other organic nitrates, such as alkyl nitrates (including isoprene nitrates), and pNO

. The sum of these reactive oxidation products and NO plus NO

comprise the oxides of nitrogen.

17 18

This follows usages in 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 air pollution research and control communities, the terms “nitrogen oxides” and NO

are often restricted to refer only to the sum of NO and NO

See Figure 2-1 of the NO

PA for additional information (U.S. EPA, 2017a).

Due to the close relationship between NO and NO

, and their ready interconversion, these species are often grouped together and referred to as NO

. The majority of NO

emissions are in the form of NO. For example, 90% or more of tail-pipe NO

emissions are in the form of NO, with only about 2% to 10% emitted as NO

(Itano et al., 2014; Kota et al., 2013; Jimenez et al., 2000; Richmond-Bryant et al., 2016). NO

emissions require time and sufficient O

concentrations for the conversion of NO to NO

. Higher temperatures and concentrations of reactants result in shorter conversion times (

e.g.,

less than one minute under some conditions), while dispersion and depletion of reactants result in longer conversion times. The time required to transport emissions away from a roadway can vary from less than one minute (

e.g.,

under open conditions) to about one hour (

e.g.,

for certain urban street canyons) (Düring et al., 2011; Richmond-Bryant and Reff, 2012). These factors can affect the locations where the highest NO

concentrations occur. In particular, while ambient NO

concentrations are often elevated near important sources of NO

emissions, such as major roadways, the highest measured ambient concentrations in a given urban area may not always occur immediately adjacent to those sources.

Ambient NO

concentrations around stationary sources of NO

emissions are similarly impacted by the availability of O

and by meteorological conditions, although surface-level NO

concentrations can be less impacted in cases where stationary source NO

emissions are emitted from locations elevated substantially above ground level.

b. National Trends in NO

Emissions and Ambient NO

Concentrations

Ambient concentrations of NO

in the U.S. are due largely to NO

emissions from anthropogenic sources. Background NO

is estimated to make up only a small fraction of current ambient concentrations (U.S. EPA, 2016a, Section 2.5.6; U.S. EPA, 2017a, Section 2.3.4).

Nationwide estimates indicate that there has been a 61% reduction in total NO

emissions from 1980 to 2016 (U.S. EPA, 2017a, Section 2.1.2, Figure 2-2). These reductions have been driven primarily by decreases in emissions from mobile sources and fuel combustion (U.S. EPA, 2017a, Section 2.1.2, Figure 2-3).

Background concentrations of a pollutant can be defined in various ways, depending on context and circumstances. Background concentrations of NO

are discussed in the 2016 NO

ISA (U.S. EPA, 2016a, Section 2.5.6) and the PA (U.S. EPA, 2017a, Section 2.3.4).

Long-term trends in NO

DVs across the U.S. show that ambient concentrations of NO

have been declining, on average, since 1980 (U.S. EPA, 2017a, Figure 2-4). Data have been collected for at least some part of the period since 1980 at 2099 sites in the U.S., with individual sites having a wide range in duration and continuity of operations across multiple decades. Overall, the majority of sampling sites have observed statistically significant downward trends in ambient NO

concentrations (U.S. EPA, 2017a, Figure 2-5).

The annual and hourly DVs trended upward in less than 4% of the sites.

Even considering the fact that there are a handful of sites where upward trends in NO

concentrations have occurred, the maximum DVs in 2015 across the whole monitoring network were well below the NAAQS, with the highest values being 30 ppb (annual) and 72 ppb (hourly) (U.S. EPA, 2017a, Section 2.3.1).

Based on an analysis of data from sampling sites with sufficient data to produce at least five valid DVs.

It is not clear what specific sources may be responsible for the upward trends in ambient NO

concentrations at these sites. (

See

U.S. EPA, 2017a, Section 2.1.2).

c. Near-Road NO

Air Quality

The largest single source of NO

emissions is on-road vehicles, and emissions are primarily in the form of NO, with NO

formation requiring both time and sufficient O

concentrations. Depending on local meteorological conditions and O

concentrations, ambient NO

concentrations can be higher near roadways than at sites in the same area but farther removed from the road (and from other sources of NO

emissions).

When considering the historical relationships between NO

concentrations at monitors near roadways and monitors farther away from roads, NO

DVs are generally highest at sampling sites nearest to the road (less than 50 meters) and decrease as distance from the road increases (U.S. EPA, 2017a, Section 2.3.2, Figure 2-6). This relationship is more pronounced for annual DVs than for hourly DVs. The general pattern of decreasing DVs with increasing distance from the road has persisted over time, though the absolute difference (in terms of ppb) between NO

concentrations close to roads and those farther from roads has generally decreased over time (U.S. EPA, 2017a, Section 2.3.2, Figure 2-6).

In addition, data from the recently deployed network

of dedicated near-road NO

monitors indicate that daily maximum 1-hour NO

concentrations are generally higher at near-road monitors than at non-near-road monitors in the same CBSA (U.S. EPA, 2017a, Figures 2-7 to 2-10). The 98th percentiles of 1-hour daily maximum concentrations (the statistic most relevant to the 1-hour standard) were highest at near-road monitors (

i.e.,

higher than all non-near-road monitors in the same CBSA) in 58% to 77% of the CBSAs evaluated, depending on the year (U.S. EPA, 2017a, Section 2.3.2, Figures 2-7 to 2-10).

Prior to the 2010 rulemaking, monitors were “not sited to measure peak roadway-associated NO

concentrations . . . .” (75 FR 6479).

The upper end of this range (

i.e.,

77%) reflects more recent years during which most near-road monitors were in operation. The lower end of this range (

i.e.,

58%) reflects the smaller number of near-road monitors in operation during the early years of the deployment of the near-road network.

d. Relationships between Hourly and Annual NO

Concentrations

Control programs have resulted in substantial reductions in NO

emissions since the 1980s. These reductions in NO

emissions have decreased both short-term peak NO

concentrations and annual average concentrations (U.S. EPA, 2017a, Section 2.3.1). Since the 1980s, the median annual NO

DV has decreased by about 65% and the median 1-hour DV has decreased by about 50% (U.S. EPA, 2017a, Section 2.3.3, Figure 2-10). These DVs were measured predominantly by NO

monitors located at area-wide monitoring sites; data from the new near-road monitoring network were not included the analysis of the relationship between hourly and annual NO

concentrations due to the limited amount of data available.

At various times in the past, a number of these area-wide sites would have violated the 1-hour standard without violating the annual standard. However, no sites would have violated the annual standard without also violating the 1-hour standard (U.S. EPA, 2017a, p. 2-21). Furthermore, examination of historical data indicates that 1-hour DVs at or below 100 ppb generally correspond to annual DVs below 35 ppb, with many monitors recording annual concentrations around 30 ppb. (U.S. EPA, 2017a, p. 2-21, Figure 2-11). Based on this, an area meeting the 1-hour standard with its level of 100 ppb would be expected to maintain annual average NO

concentrations well below the 53 ppb level of the annual standard (U.S. EPA, 2017a, Figure 2-11). It will be important to re-evaluate the relationship between 1-hour and annual standards as more data become available from recently deployed near-road monitors.

Area-wide sites are intended to characterize ambient NO

concentrations at the neighborhood and larger spatial scales.

2. Overview of the Health Effects Evidence

This section summarizes the available scientific evidence on the health effects of NO

exposures. These summaries are based primarily on the assessment of the evidence in the 2016 NO

ISA (U.S. EPA, 2016a) and on the PA's consideration of that evidence in evaluating the public health protection provided by the current primary NO

standards (U.S. EPA, 2017a).

In the current review of the primary NO

NAAQS, the 2016 NO

ISA uses frameworks to characterize the strength of the available scientific evidence for health effects attributable to NO

exposures and to classify the evidence for factors that may increase risk in some populations

or lifestages (U.S. EPA, 2016a, Preamble, Section 6). These frameworks provide the basis for robust, consistent, and transparent evaluation of the scientific evidence, including uncertainties in the evidence, and for drawing conclusions on air pollution-related health effects and at-risk populations. With regard to characterization of the health effects evidence, the 2016 NO

ISA uses a five-level hierarchy to classify the overall weight of evidence into one of the following categories: Causal relationship; likely to be a causal relationship; suggestive of, but not sufficient to infer, a causal relationship; inadequate to infer a causal relationship; and not likely to be a causal relationship (U.S. EPA, 2016a, Preamble, Table II).

As discussed further below, in evaluating the public health protection provided by the current standards, the EPA's focus is on health effects determined to have a “causal” or a “likely to be causal” relationship with NO

exposures. In the ISA, a “causal” relationship is supported when, “the consistency and coherence of evidence integrated across scientific disciplines and related health outcomes are sufficient to rule out chance, confounding, and other biases with reasonable confidence” (U.S. EPA, 2016a, p. 1-5). A “likely to be causal” relationship is supported when “there are studies where results are not explained by chance, confounding, or other biases, but uncertainties remain in the evidence overall. For example, the influence of other pollutants is difficult to address, or evidence among scientific disciplines may be limited or inconsistent” (U.S. EPA, 2016a, p. 1-5). Many of the health effects evaluated in the ISA, have complex etiologies. For instance, diseases such as asthma are typically initiated by multiple agents. For example, outcomes depend on a

variety of factors such as age, genetic background, nutritional status, immune competence, and social factors (U.S. EPA, 2017a, Preamble, Section 5.b). Thus, exposure to NO

is likely one of several contributors to the health effects evaluated in the ISA.

The term “population” refers to people having a quality or characteristic in common, including a specific pre-existing illness or a specific age or lifestage.

In this review, as in past reviews, there were causal determination changes for different endpoint categories. For more information on changes in causal determinations from the previous review, see below and Table 1-1 of the 2016 NO

ISA (U.S. EPA, 2016a).

With regard to identifying specific populations or lifestages that may be at increased risk of health effects related to NO

exposures, the 2016 NO

ISA characterizes the evidence for a number of “factors”, including both intrinsic (

i.e.,

biologic, such as pre-existing disease or lifestage) and extrinsic (

i.e.,

non-biologic, such as diet or socioeconomic status) factors. The categories considered in classifying the evidence for these potential at-risk factors are “adequate evidence,” “suggestive evidence,” “inadequate evidence,” and “evidence of no effect” (U.S. EPA, 2016a, Section 5.c, Table II). Within the PA, the focus is on the consideration of potential at-risk populations and lifestages for which the 2016 NO

ISA judges there is “adequate” evidence (U.S. EPA, 2016a, Table 7-27).

The sections below summarize the evidence for effects related to short-term NO

exposures (

e.g.,

minutes up to 1 month) and the evidence for effects related to long-term NO

exposures (

e.g.,

months to years).

The final section discusses the potential public health implications of NO

exposures, based on the evidence for populations and lifestages at increased risk of NO

-related effects. The focus of these sections is on health effects that the 2016 NO

ISA has determined to have a “causal” or “likely to be causal” relationship with NO

. Health effects whose causal determinations have changed since the last review are also briefly addressed. More information on health effects for which causal determinations are suggestive of, but not sufficient to infer a causal relationship or inadequate to infer a causal relationship (

i.e.,

health effects for which the evidence is weaker) may be found in section II.C of the proposal (87 FR 34792, July 26, 2017).

Short-term exposures are defined as those with durations of minutes up to 1 month, with most studies examining effects related to exposures in the range of 1 hour to 1 week (2016 NO

ISA, p. 1-15).

a. Health Effects With Short-Term Exposure to NO

This section discusses the evidence for health effects following short-term NO

exposures. Section II.B.2.a.i discusses the nature of the health effects that have been shown to occur following short-term NO

exposures and the strength of the evidence supporting various effects, based on the assessment of that evidence in the 2016 NO

ISA. Section II.B.2.a.ii discusses the NO

concentrations at which health effects have been demonstrated to occur, based on the considerations and analyses included in the PA. Section II.B.2.a.iii discusses NO

concentrations in controlled human exposure studies, while section II.B.2.a.iv. discusses NO

concentrations in locations of epidemiologic studies.

i. Nature of Effects

Across previous reviews of the primary NO

NAAQS (U.S. EPA, 1993; U.S. EPA, 2008a), evidence has consistently demonstrated respiratory effects attributable to short-term NO

exposures. In the last review, the 2008 NO

ISA concluded that evidence was “sufficient to infer a likely causal relationship between short-term NO

exposure and adverse effects on the respiratory system” based on the large body of epidemiologic evidence demonstrating positive associations with respiratory symptoms and hospitalization or ED visits as well as supporting evidence from controlled human exposure and animal studies (U.S. EPA, 2008a, p. 5-6). Evidence for cardiovascular effects and mortality attributable to short-term NO

exposures was weaker and was judged “inadequate to infer the presence or absence of a causal relationship” and “suggestive of, but not sufficient to infer, a causal relationship,” respectively. The 2008 NO

ISA noted an overarching uncertainty in determining the extent to which NO

is independently associated with effects or whether NO

is a marker for the effects of another traffic-related pollutant or mix of pollutants (U.S. EPA, 2008a, Section 5.3.2.2 to 5.3.2.6).

For the current review, there is newly available evidence for both respiratory effects and other health effects that was critically evaluated in the 2016 NO

ISA as part of the full body of evidence informing the nature of the relationship between health effects and short-term exposures to NO

(U.S. EPA, 2016a).

Chapter 5 of the 2016 NO

ISA presents a detailed assessment of the evidence for health effects associated with short-term NO

exposures (U.S. EPA, 2016a). In considering the available evidence and the causal determinations presented in the 2016 NO

ISA, consistent with the PA (U.S. EPA, 2017a), this action focuses on respiratory effects described below. Cardiovascular effects and mortality are also briefly addressed.

A list of causal determinations from the 2016 NO

ISA for the current review, and those from the previous review, for respiratory effects, cardiovascular effects, and mortality is presented in Table 3-1 of the NO

PA (U.S. EPA, 2017a).

Respiratory Effects

The 2016 NO

ISA concludes that evidence supports a causal relationship between respiratory effects and short-term NO

exposures, primarily based on evidence for asthma exacerbation. In reaching this conclusion, the 2016 NO

ISA notes that “epidemiologic, controlled human exposure, and animal toxicological evidence together can be linked in a coherent and biologically plausible pathway to explain how NO

exposure can trigger an asthma exacerbation” (U.S. EPA, 2016a, p. 1-17). In the last review, the 2008 NO

ISA described much of the same evidence and determined it was “sufficient to infer a likely causal relationship” with respiratory effects, citing uncertainty as to whether the epidemiologic results for NO

could be disentangled from effects related to other traffic-related pollutants. In contrast to the current review, the 2008 NO

ISA evaluated evidence for the broad category of respiratory effects and did not explicitly evaluate the extent to which various lines of evidence supported effects on more specific endpoints such as asthma exacerbation (

i.e.,

asthma attacks). In the current review, the 2016 NO

ISA states that “the determination of a causal relationship is not based on new evidence as much as it is on the integrated findings for asthma attacks with due weight given to experimental studies” (U.S. EPA, 2016a, p. 1xxxiii).

Experimental studies, such as controlled human exposure studies, provide support for effects of exposures to NO

itself, and generally do not reflect the complex atmospheres to which people are exposed. Thus, unlike epidemiologic studies, experimental studies that evaluate exposures to NO

itself are not subject to uncertainties related to the potential for copollutant confounding.

Strong evidence supporting this causal determination in the 2016 NO

ISA comes from a meta-analysis of controlled human exposure studies that evaluate the potential for increased AR

following 20-minute to 1-hour NO

exposures (Brown, 2015).

While

individual controlled human exposure studies can lack statistical power to identify effects, the meta-analysis of individual-level data combined from multiple studies has greater statistical power due to increased sample size.

AR has been the key respiratory outcome from controlled human exposures in the previous and the current review of the primary NO

NAAQS. The 2016 NO

ISA specifically notes that “airway hyperresponsiveness can lead to poorer control of symptoms and is a hallmark of asthma” (U.S. EPA, 2016a, p. 1-18). Brown (2015) examined the relationship between AR and NO

exposures in subjects with asthma across the large body of controlled human exposure studies,

most of which were available in the last review (U.S. EPA, 2017a, Tables 3-2 and 3-3). More specifically, the meta-analysis identified the fraction of individuals having an increase in AR following NO

exposure, compared to the fraction having a decrease, across studies.

The meta-analysis also stratified the data to consider the influence of factors that may affect results including exercise versus rest and non-specific versus specific challenge agents.

The 2016 NO

ISA states that AR is “inherent responsiveness of the airways to challenge by bronchoconstricting agents” (U.S. EPA, 2016a, p. 5-9). Airway hyperresponsiveness refers to increased sensitivity of the airways to an inhaled bronchoconstricting agent. This is often quantified as the dose of challenge agent that results in a 20% reduction in forced expiratory volume for 1 second (FEV

), but some studies report the change in FEV

for a specified dose of challenge agent. The change in specific airways resistance (sRaw) is also used to quantify AR.

These studies evaluate the effect of inhaled NO

on the inherent responsiveness of the airways to challenge by bronchoconstricting agents.

A meta-analysis synthesizes data from multiple studies using statistical analyses.

These controlled human exposure studies were conducted in people with asthma, a group at increased risk for NO

-related effects. The severity of asthma varied across studies, ranging from inactive asthma up to severe asthma, with the majority of study participants having a mild form of asthma. (Brown, 2015).

More information on the distribution of study subjects across NO

concentrations can be found below (section II.A.2.ii). Information on the fraction of individuals who experienced an increase versus a decrease stratified by concentration can also be found in that section.

“Bronchial challenge agents can be classified as nonspecific (

e.g.,

histamine; SO

; cold air) or specific (

i.e.,

an allergen). Nonspecific agents can be differentiated between `direct' stimuli (

e.g.,

histamine, carbachol, and methacholine) which act on airway smooth muscle receptors and `indirect' stimuli (

e.g.,

exercise, cold air) which act on smooth muscle through intermediate pathways, especially via inflammatory mediators. Specific allergen challenges (

e.g.,

house dust mite, cat allergen) also act `indirectly' via inflammatory mediators to initiate smooth muscle contraction and bronchoconstriction.” (U.S. EPA, 2016a, p. 5-8).

The results from the meta-analysis demonstrate that the majority of study volunteers with asthma experienced increased AR following resting exposure to NO

concentrations ranging from 100 to 530 ppb, relative to filtered air. Limitations in this evidence result from the lack of an apparent dose-response relationship, uncertainty in the potential adversity of responses, and the general focus of available studies on people with mild asthma, rather than more severe asthma. These controlled human exposure studies, the meta-analysis, and uncertainties in this body of evidence are discussed in greater detail below.

The 2016 NO

ISA further characterizes the clinical relevance of these increases in AR, using an approach that is based on guidelines from the American Thoracic Society (ATS) and the European Respiratory Society (ERS) for the assessment of therapeutic agents (Reddel et al., 2009). Specifically, based on individual-level responses reported in a subset of studies, the 2016 NO

ISA considered a halving of the provocative dose (PD) to indicate responses that may be clinically relevant.

37 38

With regard to this approach, the 2016 NO

ISA notes that “in a joint statement of the [ATS] and [ERS], one doubling dose change in PD is recognized as a potential indicator, although not a validated estimate, of clinically relevant changes in AR (Reddel et al., 2009)” (U.S. EPA, 2016a, p. 5-12).

PD is the dose of challenge agent required to elicit a specified change in a measure of lung function, typically a 20% decrease in FEV

or a 100% increase in specific airway resistance (sRaw).

The 2016 NO

ISA's characterization of a clinically relevant response is based on evidence from controlled human exposure studies evaluating the efficacy of inhaled corticosteroids that are used to prevent bronchoconstriction and AR as described by Reddel et al. (2009). Generally, a change of at least one doubling dose is considered to be an indication of clinical relevance. Based on this, a halving of the PD is taken in the 2016 NO

ISA to represent an increase in AR that indicates a clinically relevant response.

Studies considered for inclusion into the meta-analyses by Brown (2015) were identified from the meta-analysis by Goodman et al. (2009), the 2016 NO

ISA, and a literature search for controlled human exposure studies of individuals with asthma exposed to NO

that were published since the 2008 NO

ISA. In one analysis, Brown (2015) showed that NO

exposures from 100 to 530 ppb resulted in a halving of the dose of a challenge agent required to increase AR (

i.e.,

a halving of the PD) in about a quarter of study volunteers. While these results support the potential for clinically relevant increases in AR in some individuals with asthma following NO

exposures within the range of 100 to 530 ppb, uncertainty remains given that the analysis of PD is limited to a subset of the studies in which non-specific AR was assessed in individuals following resting exposures to NO

and air.

In addition, compared to conclusions based on the entire range of NO

exposure concentrations evaluated (

i.e.,

100 to 530 ppb), there is greater uncertainty in reaching conclusions about the potential for clinically relevant effects at any particular NO

exposure concentration within this range.

Section 3.2.2.1 of the PA (U.S. EPA, 2017a) includes additional discussion of these uncertainties.

Controlled human exposure studies discussed in the 2016 NO

ISA also evaluated a range of other respiratory effects, including lung function decrements, respiratory symptoms, and pulmonary inflammation. The evidence does not consistently demonstrate these effects following exposures to NO

concentrations at or near those found in the ambient air in the U.S. However, a subset of studies using NO

exposures to 260 ppb for 15-30 min or 400 ppb for up to 6 hours provide evidence that study volunteers with asthma and allergy can experience increased inflammatory responses following allergen challenge. Evidence for pulmonary inflammation was more mixed across studies that did not use an allergen challenge following NO

exposures ranging from 300-1,000 ppb (U.S. EPA, 2016a, Section 5.2.2.5).

In addition to this evidence for NO

-induced increases in AR and allergic inflammation in controlled human exposure studies, the 2016 NO

ISA also describes evidence from epidemiologic studies for positive associations between short-term NO

exposures and an array of respiratory outcomes related to asthma. Thus, coherence and biological plausibility is demonstrated in the evidence integrated between controlled human exposure studies and the various asthma-related outcomes examined in epidemiologic studies. The 2016 NO

ISA indicates that epidemiologic studies consistently demonstrate NO

-health effect associations with asthma hospital admissions and ED visits among subjects of all ages and children, and with asthma symptoms in children (U.S. EPA, 2016a, Sections 5.2.2.4 and 5.2.2.3). The robustness of the evidence is demonstrated by associations found in studies conducted in diverse locations in the U.S., Canada, and Asia, including several multicity studies. The evidence for asthma exacerbation is substantiated by several recent studies with strong exposure assessment characterized by measuring NO

concentrations in subjects' location(s). Epidemiologic studies also demonstrated associations between short-term NO

exposures and respiratory symptoms, lung function decrements, and pulmonary inflammation, particularly for measures of personal total and ambient NO

exposures and NO

measured outside schools. This is important because there is considerable spatial variability in NO

concentrations, and measurements in subjects' locations may better represent variability in ambient NO

exposures compared to measurements at central site monitors (U.S. EPA, 2016a, Sections 2.5.3 and 3.4.4). Epidemiologic studies also consistently indicate ambient or personal NO

-associated increases in exhaled nitric oxide (eNO, a marker of airway inflammation), which is coherent with experimental findings for allergic inflammation (U.S. EPA, 2016a, Section 5.2.2.6).

In assessing the evidence from epidemiologic studies, the 2016 NO

ISA not only considers the consistency of effects across studies, but also evaluates other study attributes that affect study quality, including potential confounding and exposure assignment. Regarding potential confounding, the 2016 NO

ISA notes that NO

associations with asthma-related effects persist with adjustment for temperature; humidity; season; long-term time trends; and PM

, SO

, or O

. Recent studies also add findings for NO

associations that generally persist with adjustment for a key copollutant, including PM

2.5

and traffic-related copollutants such as elemental carbon (EC) or black carbon (BC), ultra-fine particles (UFPs), or carbon monoxide (CO) (U.S. EPA, 2016a, Figures 5-16 and 5-17, Table 5-38). Confounding by organic carbon (OC), PM metal species, or volatile organic compounds (VOCs) is rarely studied, but NO

associations with asthma exacerbation tend to persist in the few available copollutant models. The 2016 NO

ISA recognizes, however, that copollutant models have inherent limitations and cannot conclusively rule out confounding (U.S. EPA, 2015a, Preamble, Section 4.b).

The 2016 NO

ISA also notes that results based on personal exposures or pollutants measured at people's locations provide support for NO

associations that are independent of PM

2.5

, EC/BC, organic carbon (OC), or UFPs. Compared to ambient NO

concentrations measured at central-site monitors, personal NO

exposure concentrations and indoor NO

concentrations exhibit lower correlations with many traffic-related copollutants (

e.g.,

r = −0.37 to 0.31). Thus, these health effect associations with personal and indoor NO

may be less prone to confounding by these traffic-related copollutants (U.S. EPA, 2016a, Section 1.4.3).

Overall, the strongest evidence supporting the conclusion of the causal relationship determined in the 2016 NO

ISA comes from controlled human exposure studies demonstrating NO

-induced increases in AR in individuals with asthma, with supporting evidence for a range of respiratory effects from epidemiologic studies. The conclusion of a causal relationship in the 2016 NO

ISA is based on this evidence and its explicit integration within the context of effects related to asthma exacerbation. Most of the controlled human exposure studies assessed in the 2016 NO

ISA were available in the last review, particularly studies of non-specific AR, and thus do not themselves provide substantively new information. However, by pooling data from a subset of studies, the newly available meta-analysis (Brown, 2015) has partially addressed an uncertainty from the last review by demonstrating the potential for clinically relevant increases in AR following exposures to NO

concentrations in the range of 100 to 530 ppb.

Similarly, the epidemiologic evidence that is newly available in the current review is consistent with evidence from the last review and does not alter the fundamental understanding of the respiratory effects related to ambient NO

exposures. New epidemiologic evidence does, however, reduce some uncertainty from the last review regarding the extent to which effects may be independently related to NO

, as there is more evidence from studies using measures that may better capture personal exposure, as well as a more robust evidence base examining copollutant confounding. Some uncertainty remains in the epidemiologic evidence regarding confounding by the most relevant copollutants, as it can be difficult to disentangle the independent effects of highly correlated pollutants (

i.e.,

and traffic-related pollutants).

Cardiovascular Effects

The evidence for a causal relationship between cardiovascular health effects and short-term NO

exposures in the 2016 NO

ISA was judged “suggestive of, but not sufficient to infer, a causal relationship” (U.S. EPA, 2016a, Section 5.3.11), which reflects a conclusion that the evidence for a causal relationship is stronger in the last review, when the conclusion was that the evidence was “inadequate to infer the presence or absence of a causal relationship.” The 2016 determination was primarily supported by consistent epidemiologic evidence from multiple new studies indicating associations between NO

concentrations and myocardial infarction. More information on these health effects may be found in section II.C.1.a.ii of the proposal (87 FR 34792, July 26, 2017).

Mortality

The 2016 NO

ISA concludes that the evidence for a causal relationship between short-term NO

exposures and total mortality is “suggestive of, but not sufficient to infer, a causal relationship” (U.S. EPA, 2016a, Section 5.4.8), which is the same conclusion reached in the last review (U.S. EPA, 2008a). More information on these health effects may be found in section II.C.1.a.iii of the proposal (87 FR 34792, July 26, 2017).

ii. Short-Term NO

Concentrations in Health Studies

In evaluating what the available health evidence indicates with regard to the degree of public health protection provided by the current standards, it is appropriate to consider the short-term NO

concentrations that have been associated with various effects. The PA explicitly considers these NO

concentrations within the context of evaluating the public health protection provided by the current standards (U.S. EPA, 2017a, Section 3.2). This section summarizes those considerations from the PA.

In evaluating the NO

exposure concentrations associated with health effects within the context of considering the adequacy of the current standards, the PA focuses on the evidence for asthma-related effects (

i.e.,

the type of effect for which there is the strongest evidence supporting a causal relationship, as discussed in the section above). The PA specifically considers to what extent the evidence indicates adverse asthma-related effects attributable to short-term exposures to NO

concentrations lower than previously identified or below the existing standards (U.S. EPA, 2017a, p. 3-11). In addressing this issue, the PA considers the extent to which NO

-induced effects have been reported over the ranges of NO

exposure concentrations evaluated in controlled human exposure studies and the extent to which NO

-associated effects have been reported for distributions of ambient NO

concentrations in epidemiologic study locations that meet existing standards. These considerations are discussed below for controlled human exposure studies and epidemiologic studies.

iii. NO

Concentrations in Controlled Human Exposure Studies

Controlled human exposure studies, most of which were available and considered in the last review, have evaluated various respiratory effects following short-term NO

exposures. These include AR, inflammation and

oxidative stress, respiratory symptoms, and lung function decrements. Generally, when considering respiratory effects from controlled human exposure studies in healthy adults without asthma, the evidence does not indicate respiratory symptoms or lung function decrements following NO

exposures below 4,000 ppb, and limited evidence indicates airway inflammation following exposures below 1,500 ppb (U.S. EPA, 2016a, Section 5.2.7).

There is a substantial body of evidence demonstrating increased AR in healthy adults with exposures in the range of 1,500-3,000 ppb.

Exposure durations were from one to three hours in studies evaluating AR and respiratory symptoms, and up to five hours in studies evaluating lung function decrements.

Evidence for respiratory effects following exposures to NO

concentrations at or near those found in the ambient air is strongest for AR in individuals with asthma (U.S. EPA, 2016a, Section 5.2.2 p. 5-7). As discussed above, increased AR has been reported in people with asthma following exposures to NO

concentrations as low as 100 ppb. In contrast, controlled human exposure studies evaluated in the 2016 NO

ISA do not provide consistent evidence for respiratory symptoms, lung function decrements, or pulmonary inflammation in adults with asthma following exposures to NO

concentrations at or near those in ambient air (

i.e.,

<1,000 ppb; U.S. EPA, 2016a, Section 5.2.2). There is some indication of allergic inflammation in adults with allergy and asthma following exposures to 260-1,000 ppb. However, the generally high exposure concentrations in these studies make it difficult to interpret the likelihood that these effects could potentially occur following NO

exposures at or below the level of the current standards.

Despite the difficulty in interpreting the likelihood that these effects would occur at concentrations closer to the current standards, as described later (section II.A.3) the current standards are expected to protect against exposures at the exposure concentrations used in these studies.

Thus, in considering the exposure concentrations evaluated in controlled human exposure studies, the PA focuses on the body of evidence for NO

-induced increases in AR in adults with asthma. In evaluating the NO

exposure concentrations at which increased AR is observed, the PA considers both the group mean results reported in individual studies and the results evaluated across studies in the meta-analysis by Brown (2015; U.S. EPA, 2016a, Section 5.2.2.1). Group mean responses in individual studies, and the variability in those responses, can provide insight into the extent to which observed changes in AR are due to NO

exposures, rather than to chance alone, having the advantage of being based on the same exposure conditions. The meta-analysis by Brown (2015) can also provide insight into the extent to which observed changes are due to NO

exposures, with the additional benefit of aiding in the identification of trends in individual-level responses across studies and the advantage of increased power to detect effects, even in the absence of statistically significant effects in individual studies, although each study in the meta-analysis may not be based on the exact same exposure conditions.

Tables 3-2 and 3-3 in the NO

PA (adapted from the 2016 NO

ISA; U.S. EPA, 2016a, Tables 5-1 and 5-2) provide details for the studies examining AR in individuals with asthma at rest and with exercise, respectively. These tables note various study details including the exposure concentration, duration of exposure, type of challenge (nonspecific or specific), number of study subjects, number of subjects having an increase or decrease in AR following NO

exposure, average PD: The dose of challenge agent required to elicit a particular magnitude of change in FEV

or other measure of lung function) across subjects, and the statistical significance of the change in AR following NO

exposures.

Consideration of Group Mean Results From Individual Studies

Individual controlled human exposure studies have generally not reported statistically significant increases in AR following resting exposures to NO

concentrations from 100 to 200 ppb. In considering such studies, the PA notes that the lowest NO

concentration to which individuals with asthma have been exposed is 100 ppb, with an exposure duration of 60 minutes in all studies at this concentration. Of the five studies conducted at 100 ppb, a statistically significant increase in AR following exposure to NO

was only observed in the study by Orehek et al. (1976) (n = 20). Of the four studies that did not report statistically significant increases in AR following exposures to 100 ppb NO

, three reported weak trends towards decreased AR (n = 20, Ahmed et al., 1983b; n = 15, Hazucha et al., 1983; n = 8, Tunnicliffe et al., 1994), and one reported a trend towards increased AR (n = 20, Ahmed et al., 1983a). Resting exposures to 140 ppb NO

resulted in increases in AR that reached marginal statistical significance (n = 20, Bylin et al., 1988). In addition, the one study conducted at 200 ppb demonstrated a trend towards increased AR, but this study was small and its results were not statistically significant (n = 4, Orehek et al., 1976). Thus, as noted above, individual controlled human exposure studies have generally not reported statistically significant increases in AR following resting exposures to NO

concentrations from 100 to 200 ppb. Group mean responses in these studies suggest a trend towards increased AR following exposures to 140 and 200 ppb NO

, while trends in the direction of group mean responses were inconsistent following exposures to 100 ppb NO

In considering studies in individuals with asthma conducted with exercise and at lower concentrations, the PA notes that three studies evaluated NO

exposure concentrations between 150 and 200 ppb (n = 19, Roger et al., 1990; n = 31, Kleinman et al., 1983; n = 11, Jenkins et al., 1999). Of these studies, only Kleinman et al. (1983) reported a statistically significant increase in AR following NO

exposure (

i.e.,

at 200 ppb). Roger et al. (1990) and Jenkins et al. (1999) did not report statistically significant increases, but showed weak trends for increases in AR following exposures to 150 ppb and 200 ppb NO

, respectively. Thus, as with studies of resting exposures, studies that evaluated exposures to 150 to 200 ppb NO

with exercise report trends toward increased AR, though results are generally not statistically significant.

Several studies evaluated exposures of individuals with asthma to NO

concentrations above 200 ppb. Of the five studies that evaluated 30-minute resting exposures to NO

concentrations from 250 to 270 ppb, NO

-induced increases in AR were statistically significant in three (n = 14, Jörres et al., 1990; n = 18, Strand et al., 1988; n = 20, Bylin et al., 1988). Statistically significant increases in AR are also more consistently reported across studies that evaluated resting exposures to 400-530 ppb NO

, with three of four studies reporting a statistically significant increase in AR following such exposures. However, studies conducted with exercise do not indicate consistent increases in AR following exposures to NO

concentrations from 300 to 600 ppb (U.S. EPA, 2017a, Table 3-3).

There are eight additional studies with exercising exposures to 300-350 ppb NO

as presented in Table 3-3 of the NO

PA, with exposure durations ranging from 30-240 minutes. Results across these studies are inconsistent, with only two of eight reporting statistically significant results. Only one of four studies with exercising exposures of 400 or 600 ppb reported statistically significant increases in AR.

Consideration of Results From the Brown (2015) Meta-Analysis

As discussed above, the 2016 NO

ISA assessment of the evidence for AR

in individuals with asthma also focuses on a recently published meta-analysis (Brown, 2015) investigating individual-level data from controlled human exposure studies. While individual controlled human exposure studies can lack statistical power to identify effects, the meta-analysis of individual-level data combined from multiple studies (Brown, 2015) has greater statistical power due to increased sample size. The meta-analysis considered individual-level responses, specifically whether individual study subjects experienced an increase or decrease in AR following NO

exposure compared to exposure to filtered air.

Evidence was evaluated together across all studies and also stratified for exposures conducted with exercise and at rest, and for measures of specific and non-specific AR. The 2016 NO

ISA notes that these methodological differences may have important implications with regard to results (U.S. EPA, 2016a (discussing Brown, 2015; Goodman et al., 2009)), which informed the 2016 NO

ISA's emphasis on studies of resting exposures and non-specific challenge agents. Overall, the Brown meta-analysis presents the fraction of individuals having an increase in AR following exposure to various NO

concentrations (

i.e.,

100 ppb, 100 ppb to < 200 ppb, 200 ppb up to and including 300 ppb, and above 300 ppb) (U.S. EPA, 2016a, Section 5.2.2.1).

More specifically, the Brown (2015) meta-analysis combined information from the studies presented in Tables 3-2 and 3-3 of the PA. It compared the number of study participants who experienced an increase in AR following NO

exposures to the number who experienced a decrease in AR. Study participants who experienced no change in AR were not included in comparisons.

-value refers to the significance level of a two-tailed sign test.

The number of participants in each study and the number having an increase or decrease in AR is indicated in Tables 3-2 and 3-3 of the NO

PA.

When evaluating results from the meta-analysis, the PA first considers results across all exposure conditions combined (

i.e.,

resting, exercising, non-specific challenge, and specific challenge). For 100 ppb NO

exposures, Brown (2015) reported that, of the study participants who experienced either an increase or decrease in AR following NO

exposures, 61% experienced an increase (

= 0.08). For 100 to < 200 ppb NO

exposures, 62% of study subjects experienced an increase in AR following NO

exposures (

= 0.014). For 200 to 300 ppb NO

exposures, 58% of study subjects experienced an increase in AR following NO

exposures (

= 0.008). For exposures above 300 ppb NO

57% of study subjects experienced an increase in AR following NO

exposures, though this fraction was not statistically significantly different from the fraction experiencing a decrease.

The PA also considers the results of Brown (2015) for various subsets of the available studies, based on the exposure conditions evaluated (

i.e.,

resting, exercising) and the type of challenge agent used (

i.e.,

specific, non-specific). For exposures conducted at rest, across all exposure concentrations (

i.e.,

100-530 ppb NO

, n = 139; U.S. EPA, 2017a, Table 3-2), Brown (2015) reported that a statistically significant fraction of study participants (71%,

<0.001) experienced an increase in non-specific AR following NO

exposures, compared to the fraction that experienced a decrease in AR. The meta-analysis also presented results for various concentrations or ranges of concentrations. Following resting exposure to 100 ppb NO

66% of study participants experienced increased non-specific AR. For exposures to concentrations of 100 ppb to < 200 ppb, 200 ppb up to and including 300 ppb, and above 300 ppb, increased non-specific AR was reported in 67%, 78%, and 73% of study participants, respectively.

For non-specific challenge agents, the differences between the fraction of individuals who experienced increased AR following resting NO

exposures and the fraction who experienced decreased AR reached statistical significance for all of the ranges of exposure concentrations evaluated (

< 0.001).

For the exposure category of “above 300 ppb”, exposures included 400, 480, 500, and 530 ppb. No studies conducted at rest used concentrations between 300 and 400 ppb.

In contrast to the results from studies conducted at rest, the fraction of individuals having an increase in AR following NO

exposures with exercise was not consistently greater than 50%, particularly when looking at the allergen challenge group, and none of the results were statistically significant (Brown, 2015). Across all NO

exposures with exercise, measures of non-specific AR were available for 241 individuals, 54% of whom experienced an increase in AR following NO

exposures relative to air controls. There were no studies in this group conducted at 100 ppb, and for exercising exposures to 150-200 ppb, 250-300 ppb, and 350-600 ppb, the fraction of individuals with increased non-specific AR was 59%, 55%, and 49%, respectively.

In addition to examining results from studies of non-specific AR, the meta-analysis also considered results from studies that evaluated changes in specific AR (

i.e.,

AR following an allergen challenge; n = 130, U.S. EPA, 2017a, Table 3-3) following NO

exposures. The results do not indicate statistically significant fractions of individuals having an increase in specific AR following exposure to NO

at concentrations below 400 ppb, even when considering resting and exercising exposures separately (Brown, 2015). Of the three studies that evaluated specific AR at concentrations of 400 ppb, one was conducted at rest (Tunnicliffe et al., 1994). This study reported that all individuals experienced increased AR following 400 ppb NO

exposures (Brown, 2015, Table 4). In contrast, for exposures during exercise, most study subjects did not experience NO

-induced increases in specific AR. In contrast, for exposures during exercise, most study subjects did not experience NO

-induced increases in specific AR.

Overall, results across studies are less consistent for increases in specific AR following NO

exposures.

48% experienced increased AR and 52% experienced decreased AR, based on individual-level data for study participants exposed to 350 ppb (Riedl et al., 2012) or 400 ppb (Jenkins et al., 1999; Witten et al., 2005) NO

Uncertainties in Evidence for AR

When considering the evidence for NO

-induced increases in AR in individuals with asthma, there are important uncertainties that should be considered. One uncertainty is that available studies of NO

and AR have generally evaluated adults with mild asthma, while people with more severe asthma could experience more serious effects and/or effects following exposures to lower NO

concentrations.

Additional uncertainties include the lack of an apparent dose-response relationship and uncertainty in the potential adversity of the reported effects; each of these is discussed below.

Brown (2015) notes, however, that disease status varied in the studies included in the meta-analysis, ranging from “inactive asthma up to severe asthma in a few studies.”

Both the meta-analysis by Brown (2015) and an additional meta-analysis and meta-regression by Goodman et al. (2009) conclude that there is no indication of a dose-response relationship for exposures between 100 and 600 ppb NO

and increased AR in individuals with asthma. A dose-response relationship generally increases confidence that observed effects are due to pollutant exposures rather than to chance, and can be used to inform the characterization of the magnitude of the effects; however, the lack of an apparent dose-response relationship does not necessarily

indicate that there is no relationship between the exposure and effect, particularly in these analyses based largely on between-subject comparisons (

i.e.,

as opposed to comparisons within the same subject exposed to multiple concentrations). As discussed in the 2016 NO

ISA, there are a number of methodological differences across studies that could contribute to between-subject differences and that could obscure or complicate a dose-response relationship between NO

and AR (U.S. EPA, 2016a, section 5.2.2.1).

These include subject activity level (rest versus exercise) during NO

exposure, asthma medication usage, choice of airway challenge agent, method of administering the bronchoconstricting agents, and physiological endpoint used to assess AR. Such methodological differences across studies likely contribute to the variability and uncertainty in results across studies and complicate interpretation of the overall body of evidence for NO

-induced AR. Thus, while the lack of an apparent dose-response relationship adds uncertainty to the interpretation of controlled human exposure studies of AR and reduces the ability to fully characterize the health risks associated with these exposures, it does not indicate the lack of an NO

effect.

For instance, Brown (2015) notes that the few studies evaluating effects at multiple NO

concentrations and at resting exposures may indicate some support for a dose-response relationship, as they show increasing AR with increasing exposure concentrations.

An additional uncertainty in interpreting these studies within the context of considering the adequacy of the protection provided by the current primary NO

NAAQS is the potential adversity of the reported NO

-induced increases in AR. As discussed above, the meta-analysis by Brown (2015) used an approach that is consistent with guidelines from the ATS and the ERS for the assessment of therapeutic agents (Reddel et al., 2009) to assess the potential for clinical relevance of these responses. Specifically, based on individual-level responses reported in a subset of studies, Brown (2015) considered a halving of the PD to indicate responses that may be clinically relevant. With regard to this approach, the 2016 NO

ISA notes that “one doubling dose change in PD is recognized as a potential indicator, although not a validated estimate, of clinically relevant changes in AR (Reddel et al., 2009)” (U.S. EPA, 2016a, p. 5-12). While there is uncertainty in using this approach to characterize whether a particular response in an individual is “adverse,” it can provide insight into the potential for adversity, particularly when applied to a population of exposed individuals.

As noted above, the degree to which populations in U.S. urban areas have the potential for such NO

exposures is evaluated in Chapter 4 of the PA and described in Section II.A.3 below.

Five studies provided data for each individual's PD. These five studies provided individual-level data for a total of 72 study participants (116 AR measurements) and eight NO

exposure concentrations, for resting exposures and non-specific bronchial challenge agents. Across exposures to 100, 140, 200, 250, 270, 480, 500, and 530 ppb NO

, 24% of study participants experienced a halving of the PD (indicating increased AR) while 8% showed a doubling of the PD (indicating decreased AR). The relative distributions of the PDs at different concentrations were similar, with no dose-response relationship indicated (Brown, 2015). While these results support the potential for clinically relevant increases in AR in some individuals with asthma following NO

exposures within the range of 100 to 530 ppb, uncertainty remains given that this analysis is limited to a subset of studies. In addition, compared to conclusions based on the entire range of NO

exposure concentrations evaluated (

i.e.,

100 to 530 ppb), there is greater uncertainty in reaching conclusions about the potential for clinically relevant effects at any particular NO

exposure concentration within this range.

PA Conclusions on Short-Term NO

Concentrations in Controlled Human Exposure Studies

As in the last review, a meta-analysis of individual-level data supports the potential for increased AR in individuals with generally mild asthma following 30 minute to 1 hour exposures to NO

concentrations from 100 to 530 ppb, particularly for resting exposures and measures of non-specific AR (n = 33 to 70 for various ranges of NO

exposure concentrations). In about a quarter of these individuals, increases were large enough to be of potential clinical relevance. Individual studies most consistently report statistically significant NO

-induced increases in AR following exposures to NO

concentrations at or above 250 ppb. Individual studies (n = 4 to 20) generally do not report statistically significant increases in AR following exposures to NO

concentrations at or below 200 ppb, though the evidence suggests a trend toward increased AR following NO

exposures from 140 to 200 ppb. In contrast, individual studies do not indicate a consistent trend towards increased AR following 1-hour exposures to 100 ppb NO

. Important limitations in this evidence include the lack of an apparent dose-response relationship between NO

and AR and uncertainty in the adversity of the reported increases in AR. These limitations become increasingly important at the lower NO

exposure concentrations (

i.e.,

at or near 100 ppb), where the evidence for NO

-induced increases in AR is not consistent across studies. The PA placed weight on that lack of consistency, when considered in light of the lack of an apparent dose-response relationship between NO

and increased AR, as well as the uncertainty in the adversity of the reported effect.

iv. Consideration of NO

Concentrations in Locations of Epidemiologic Studies

In addition to considering the exposure concentrations evaluated in the controlled human exposure studies, the PA also considers distributions of ambient NO

concentrations in locations where epidemiologic studies have examined NO

associations with asthma-related hospital admissions or ED visits. These outcomes are clearly adverse and study results comprise a key line of epidemiologic evidence in the determination of a causal relationship in the 2016 NO

ISA (U.S. EPA, 2016a, Section 5.2.9). As in other NAAQS reviews (U.S. EPA, 2014; U.S. EPA, 2011), when considering epidemiologic studies within the context of evaluating the adequacy of the current standards, the PA emphasizes those studies conducted in the U.S. and Canada.

For short-term exposures to NO

, the PA emphasizes studies reporting associations with effects judged in the 2016 NO

ISA to be robust to confounding by other factors, including exposure to co-occurring air pollutants. In addition, the PA considers the statistical precision of study results and the inclusion of at-risk populations for which the NO

-health effect associations may be larger. These considerations help inform the range of ambient NO

concentrations where there is the most confidence for NO

-associated health effects and the range of concentrations over which confidence in such effects is appreciably

lower. In consideration of these issues, the PA specifically focuses on the following question: To what extent have U.S. and Canadian epidemiologic studies reported associations between asthma-related hospital admissions or ED visits and short-term NO

concentrations in study areas that would have met the current 1-hour NO

standard during the study period?

Such studies are likely to reflect air quality and exposure patterns that are generally applicable to the U.S. In addition, air quality data corresponding to study locations and study time periods are often readily available for studies conducted in the U.S. and Canada. Nonetheless, the PA recognizes the importance of all studies, including other international studies, in the 2016 NO

ISA's assessment of the weight of the evidence that informs the causal determinations.

Addressing this question can provide important insights into the extent to which NO

-associated health effects are present for distributions of ambient NO

concentrations that would be allowed by the current primary standards. The presence of such associations would support the potential for the current standards to allow the NO

-associated effects indicated by epidemiologic studies. To the degree studies have not reported associations in locations meeting the current NO

standards, there is greater uncertainty regarding the potential for the reported effects to occur following the NO

exposures associated with air quality meeting those standards.

The emphasis that the proposal and this final action place on studies to inform the question above is discussed in more detail in the proposal for this action (82 FR 34792, July 26, 2017, section II.F.4). Briefly, in addressing the question above, the PA places the greatest emphasis on studies reporting positive and relatively precise (

i.e.,

relatively narrow 95% confidence intervals (CI)) health effect associations. In evaluating whether such associations are likely to reflect NO

concentrations meeting the existing 1-hour standard, the PA considers the 1-hour ambient NO

concentrations measured at monitors in study locations during study periods. The PA also considers what additional information is available regarding the ambient NO

concentrations that could have been present in the study locations during the study periods (

e.g.,

around major roads). When considered together, this information can provide important insights into the extent to which NO

health effect associations have been reported for NO

air quality concentrations that likely would have met the current 1-hour NO

standard.

The PA evaluates U.S. and Canadian studies of respiratory-related hospital admissions and ED visits, with a focus on studies of asthma-related effects (studies identified from Table 5-10 in U.S. EPA, 2016a).

For each NO

monitor in the locations included in these studies, and for the ranges of years encompassed by studies, the PA identifies the 3-year averages of the 98th percentiles of the annual distributions of daily maximum 1-hour NO

concentrations.

These concentrations approximate the DVs that are used when determining whether an area meets the 1-hour primary NO

NAAQS.

Thus, these estimated DVs can provide perspective on whether study areas would likely have met or exceeded the primary 1-hour NO

NAAQS during the study periods. Based on this approach, study locations would likely have met the current 1-hour standard over the entire study period if all of the hourly DV estimates were at or below 100 ppb.

Strong support was also provided by epidemiologic studies for respiratory symptoms, but the majority of studies on respiratory symptoms were only conducted over part of a year, complicating the evaluation of a DV based on data from 3 years of monitoring data relative to the respective health effect estimates. For more information on these studies and the estimated DVs in the study locations, see Appendix A of the PA (U.S. EPA, 2017a).

All study locations had maximum annual DVs below 53 ppb (U.S. EPA, 2017a, Appendix A).

As described in section I.B., a DV is a statistic that describes the air quality status of a given area relative to the NAAQS and that is typically used to classify nonattainment areas, assess progress towards meeting the NAAQS, and develop control strategies. For the 1-hour NO

standard, the DV is calculated at individual monitors and based on 3 consecutive years of data collected from that site. In the case of the 1-hour NO

standard, the DV for a monitor is based on the 3-year average of the 98th percentile of the annual distribution of daily maximum 1-hour NO

concentrations. For more information on these studies and the calculation of the study area DVs estimates, see Appendix A of the NO

PA (U.S. EPA, 2017a).

A key limitation in these analyses of NO

DV estimates is that currently required near-road NO

monitors were not in place during study periods. The studies evaluated were based on air quality from 1980-2006, with most studies spanning the 1990s to early 2000s. There were no specific near-road monitoring network requirements during these years, and most areas did not have monitors sited to measure NO

concentrations near the most heavily trafficked roadways. In addition, mobile source NO

emissions were considerably higher during the time periods of the available epidemiologic studies than in more recent years (U.S. EPA, 2017a, section 2.1.2), suggesting that the NO

concentration gradients around major roads could have been more pronounced than indicated by data from recently deployed near-road monitors.

This information suggests that if the current near-road monitoring network had been in operation during study periods, NO

concentrations measured at near-road monitors would likely have been higher than those identified in the PA (U.S. EPA, 2017a, Figure 3-1). This uncertainty particularly limits the degree to which strong conclusions about whether an area would have met the current 1-hour standard during the study period can be reached based on study areas with DV estimates that are at or just below 100 ppb.

Recent data indicate that, for most near-road monitors, measured 1-hour NO

concentrations are higher than those measured at all of the non-near-road monitors in the same CBSA (Section II.A.1.d).

Epidemiologic studies that evaluate potential NO

health effect associations during time periods when near-road monitors are operational could reduce this uncertainty in future reviews.

With this key limitation in mind, the PA considers what the available epidemiologic evidence indicates with regard to the adequacy of the public health protection provided by the current 1-hour standard against short-term NO

exposures. To this end, the PA highlights the epidemiologic studies examining associations between asthma hospitalizations or ED visits and short-term exposures to ambient NO

that were conducted in the U.S. and Canada (U.S. EPA, 2017a, Figure 3-1). These studies were identified and evaluated in the 2016 NO

ISA and include both the few recently published studies and the studies that were available in the previous review.

In considering the epidemiologic information presented in the U.S. and Canadian studies, the PA notes that multicity studies tend to have greater power to detect associations. The one multicity study that has become available since the last review (Stieb et al., 2009) reported a null association with asthma ED visits, based on study locations with maximum estimated DVs ranging from 67-242 ppb (six of seven study cities had maximum estimated DVs at or above 85 ppb). Of the single-city studies identified, those reporting positive and relatively precise associations were conducted in locations with maximum, and often mean, estimated DVs at or above 100 ppb (

i.e.,

Linn et al., 2000; Peel et al., 2005; Ito et al., 2007; Villeneuve et al., 2007; Burnett et al., 1999; Strickland et al., 2010). Maximum estimated DVs from these study locations ranged from 100 to 242 ppb (U.S. EPA, Figure 3-1). For the other single-city studies, two reported more mixed results in locations with maximum estimated DVs around 90 ppb (Jaffe et al., 2003; ATSDR, 2006).

Associations in these studies

were generally not statistically significant, were less precise (

i.e.,

wider 95% CI), and included a negative association (Manhattan, NY). One single-city study was conducted in a location with 1-hour estimated DVs well below 100 ppb (Li et al., 2011), though the reported associations were not statistically significant and were relatively imprecise. Thus, of the U.S. and Canadian studies that can most clearly inform consideration of the adequacy of the current NO

primary standards, the lone multicity study did not report a positive health effect association, and the single-city studies reporting positive and relatively precise associations were generally conducted in locations with maximum 1-hour estimated DVs at or above 100 ppb (

i.e.,

up to 242 ppb). The evidence for associations in locations with maximum estimated DVs below 100 ppb is more mixed and reported associations are generally less precise.

The study by the U.S. Agency for Toxic Substances and Disease Registry (ATSDR) was not published in a peer-review journal. Rather, it was a report prepared by the New York State Department of Health's Center for Environmental Health, the New York State Department of Environmental Conservation and Columbia University in the course of performing work

contracted for and sponsored by the New York State Energy Research and Development Authority and the ATSDR.

An uncertainty in this body of evidence is the potential for copollutant confounding. Copollutant (two-pollutant) models can be used in epidemiologic studies in an effort to disentangle the independent pollutant effects, though there can be limitations in these models due to differential exposure measurement error and high correlations with traffic-related copollutants. For NO

, the copollutants that are most relevant to consider are those from traffic sources such as CO, EC/BC, UFP, and VOCs such as benzene, as well as PM

2.5

and PM

(U.S. EPA, 2016a, Section 3.5).

Of the studies examining asthma-related hospital admissions and ED visits in the U.S. and Canada, three examined copollutant models (Ito et al., 2007; Villeneuve et al., 2007; Strickland et al., 2010). Ito et al. (2007) found that in copollutant models with PM

2.5

, SO

, CO, or O

, NO

consistently had the strongest effect estimates that were robust to the inclusion of other pollutants. Villeneuve et al. (2007) utilized a model including NO

and CO (r = 0.74) for ED visits in the warm season and reported that associations for NO

were robust to CO. Strickland et al. (2010) found that the relationship between ambient NO

and asthma ED visits in Atlanta, GA, was robust in models including O

, but copollutant models were not analyzed for other pollutants, and the correlations between NO

and other pollutants were not reported. Taken together, these studies provide some evidence for independent effects of NO

for asthma-related hospital admissions and ED visits, but some important traffic-related copollutants (

e.g.,

EC/BC, VOCs) have not been examined in this body of evidence and the limitations of copollutant models in demonstrating an independent association are noted (U.S. EPA, 2016a, section 3.5).

In this case, differential exposure measurement error occurs when exposure measurement error varies by pollutant (

e.g.,

within a model exposure to PM

2.5

may be estimated with higher accuracy than exposure to SO

Considering this evidence together, the PA notes the following observations. First, the only recent multicity study evaluated, which had maximum estimated DVs ranging from 67 to 242 ppb, did not report a positive association between NO

and ED visits (Stieb et al., 2009). In addition, of the single-city studies reporting positive and relatively precise associations between NO

and asthma hospital admissions and ED visits, most locations likely had NO

concentrations above the current 1-hour NO

standard over at least part of the study period. Although maximum estimated DVs for the studies conducted in Atlanta were 100 ppb (Peel et al., 2005; Strickland et al., 2010), it is likely that those DVs would have been higher than 100 ppb if currently required near-road monitors had been in place. For the study locations with maximum estimated DVs below 100 ppb, mixed results are reported with associations that are generally lack precision and are not statistically significant, indicating that associations between NO

concentrations and asthma-related ED visits are more uncertain in locations that could have met the current standards. Given that near-road monitors were not in operation during study periods, it is not clear that these DVs below 100 ppb indicate study areas that would have met the current 1-hour standard.

Thus, while epidemiologic studies provide support for NO

-associated hospital admissions and ED visits at ambient NO

concentrations likely to have been above those allowed by the current 1-hour standard, the PA reaches the conclusion that available U.S. and Canadian epidemiologic studies do not provide support for such NO

-associated outcomes in locations with NO

concentrations that would have clearly met that standard.

b. Health Effects With Long-Term Exposure to NO

This section discusses the evidence for health effects associated with long-term NO

exposures. Section II.A.2.b.i discusses the nature of the health effects that have been shown to be associated with long-term NO

exposures and the strength of the evidence supporting various effects, based on the assessment of that evidence in the 2016 NO

ISA. Sections II.A.2.b.ii and II.A.2.b.iii discuss the NO

concentrations at which health effects have been demonstrated to occur based on the considerations and analyses included in the PA.

i. Nature of Effects

In the last review of the primary NO

NAAQS, evidence for health effects related to long-term ambient NO

exposure was judged “suggestive of, but not sufficient to infer a causal relationship” for respiratory effects and “inadequate to infer the presence or absence of a causal relationship” for several other health effect categories. These included cardiovascular effects and reproductive and developmental effects, as well as cancer and total mortality. In the current review, new epidemiologic evidence, in conjunction with explicit integration of evidence across related outcomes, has resulted in strengthening of some of the causal determinations. Though the evidence of health effects associated with long-term exposure to NO

is more robust than in previous reviews, there are still a number of uncertainties limiting understanding of the role of long-term NO

exposures in causing health effects.

Chapter 6 of the 2016 NO

ISA presents a detailed assessment of the evidence for health effects associated with long-term NO

exposures (U.S. EPA, 2016a). This evidence is summarized briefly below for respiratory effects. Cardiovascular effects and diabetes, reproductive and developmental effects, premature mortality, and cancer are also briefly addressed.

Respiratory Effects

The 2016 NO

ISA concluded that there is “likely to be a causal relationship” between long-term NO

exposure and respiratory effects, based primarily on evidence integrated across disciplines for a relationship with asthma development in children.

Evidence for other respiratory outcomes integrated across epidemiologic and experimental studies, including decrements in lung function and partially irreversible decrements in lung development, respiratory disease severity, chronic bronchitis/asthma incidence in adults, chronic obstructive

pulmonary disease (COPD) hospital admissions, and respiratory infections, is less consistent and has larger uncertainty as to whether there is an independent effect of long-term NO

exposure (U.S. EPA, 2016a, Section 6.2.9). As noted above, NO

is only one of many etiologic agents that may contribute to respiratory health effects such as the development of asthma in children.

Asthma development is also referred to as “asthma incidence” in this document and elsewhere. Both asthma development and asthma incidence refer to the onset of the disease rather than the exacerbation of existing disease.

The conclusion of a “likely to be causal relationship” in the current review represents a change from 2008 NO

ISA conclusion that the evidence was “suggestive of, but not sufficient to infer, a causal relationship” (U.S. EPA, 2008a, Section 5.3.2.4). This strengthening of the causal determination is due to the epidemiologic evidence base, which has expanded since the last review, and biological plausibility from some experimental studies (U.S. EPA, 2016a, Table 1-1). This expanded evidence includes several recently published longitudinal studies that indicate positive associations between asthma incidence in children and long-term NO

exposures, with improved exposure assessment in some studies based on NO

modeled estimates for children's homes or NO

measured near children's homes or schools. Associations were observed across various periods of exposure, including first year of life, year prior to asthma diagnosis, and cumulative exposure. In addition, the 2016 NO

ISA notes several other strengths of the evidence base including the general timing of asthma diagnosis and relative confidence that the NO

exposure preceded asthma development in longitudinal studies, more reliable estimates of asthma incidence based on physician-diagnosis in children older than 5 years of age from parental report or clinical assessment, as well as residential NO

concentrations estimated from land use regression models with good NO

prediction in some studies.

While the causal determination has been strengthened in this review, important uncertainties remain. For example, the 2016 NO

ISA notes that, as in the last review, a “key uncertainty that remains when examining the epidemiologic evidence alone is the inability to determine whether NO

exposure has an independent effect from that of other pollutants in the ambient mixture” (U.S. EPA, 2016a, Section 6.2.2.1, p. 6-21). While a few studies have included copollutant models for respiratory effects other than asthma development, the 2016 NO

ISA states that “[e]pidemiologic studies of asthma development in children have not clearly characterized potential confounding by PM

2.5

or traffic-related pollutants [

e.g.,

CO, BC/EC, volatile organic compounds (VOCs)]” (U.S. EPA, 2016a, p. 6-64). The 2016 NO

ISA further notes that “[i]n the longitudinal studies, correlations with PM

2.5

and BC were often high (

e.g., r

= 0.7-0.96), and no studies of asthma incidence evaluated models to address copollutant confounding, making it difficult to evaluate the independent effect of NO

” (U.S. EPA, 2016a, p. 6-64). High correlations between NO

and other traffic-related pollutants were based on modeling, and studies of asthma incidence that used monitored NO

concentrations as an exposure surrogate did not report such correlations (U.S. EPA, 2016a, Table 6-1). This uncertainty is important to consider when interpreting the epidemiologic evidence regarding the extent to which NO

is independently related to asthma development.

The 2016 NO

ISA also evaluated copollutant confounding in long-term exposure studies beyond asthma incidence to examine whether studies of other respiratory effects could provide information on the potential for confounding by traffic-related copollutants. Several studies examined correlations between NO

and traffic-related copollutants and found them to be relatively high in many cases, ranging from 0.54-0.95 for PM

2.5

, 0.54-0.93 for BC/EC, 0.2-0.95 for PM

, and 0.64-0.86 for OC (U.S. EPA, 2016a, Tables 6-1 and 6-3). While these correlations are often based on model estimates, some are based on monitored pollutant concentrations (

i.e.,

McConnell et al. (2003) reported correlations of 0.54 with PM

2.5

and EC) (U.S. EPA, 2016a, Table 6-3). Additionally, three studies (McConnell et al., 2003; MacIntyre et al., 2014; Gehring et al., 2013)

evaluated copollutant models with NO

and PM

2.5

, and some findings suggest that associations for NO

with bronchitic symptoms, lung function, and respiratory infection are not robust because effect estimates decreased in magnitude and became imprecise when a copollutant was added in the model. Overall, examination of evidence from studies of other respiratory effects indicates moderate to high correlations between long-term NO

concentrations and traffic-related copollutants, with very limited evaluation of the potential for confounding. Thus, when considering the collective evidence, it is difficult to disentangle the independent effect of NO

from other traffic-related pollutants or mixtures in epidemiologic studies (U.S. EPA, 2016a, Sections 3.4.4 and 6.2.9.5).

In single-pollutant models for various health endpoints, the studies reported the following effect estimates (95% CI): McConnell et al., 2003 (Bronchitic symptoms) 1.97 (1.22, 3.18); MacIntyre et al., 2014 (Pneumonia) 1.30 (1.02, 1.65), (Otitis Media) 1.09 (1.02, 1.16), (Croup) 0.96 (0.83, 1.12); Gehring et al., 2013 (forced expiratory volume in 1 second) −0.98 (−1.70, −0.26), (FVC) −2.14 (−4.20, −0.04), (peak expiratory flowF) −1.04 (−1.94, −0.13).

While this uncertainty continues to apply to the epidemiologic evidence for asthma incidence in children, the 2016 NO

ISA explains that the uncertainty is partly reduced by the coherence of findings from experimental studies and epidemiologic studies. Experimental studies demonstrate effects on key events in the mode of action proposed for the development of asthma and provide biological plausibility for the epidemiologic evidence. For example, one study demonstrated that airway hyperresponsiveness was induced in guinea pigs after long-term exposure to NO

(1,000-4,000 ppb; Kobayashi and Miura, 1995). Other experimental studies examining oxidative stress report mixed results, but some evidence from short-term studies supports a relationship between NO

exposure and increased pulmonary inflammation in healthy humans. The 2016 NO

ISA also points to supporting evidence from studies demonstrating that short-term exposure repeated over several days (260-1,000 ppb) and long-term NO

exposure (2,000-4,000 ppb) can induce T helper (Th)2 skewing/allergic sensitization in healthy humans and animal models by showing increased Th2 cytokines, airway eosinophils, and immunoglobulin E (IgE)-mediated responses (U.S. EPA, 2016a, Sections 4.3.5 and 6.2.2.3). Epidemiologic studies also provide some supporting evidence for these key events in the mode of action. Some evidence from epidemiologic studies demonstrates associations between short-term ambient NO

concentrations and increases in pulmonary inflammation in healthy children and adults, giving a possible mechanistic understanding of this effect (U.S. EPA, 2016a, Section 5.2.2.5). Overall, evidence from experimental and epidemiologic studies provides support for a role of NO

in asthma development by describing a potential role for repeated exposures to lead to recurrent inflammation and allergic responses.

To summarize, the 2016 NO

ISA notes that there is new evidence available that strengthens conclusions from the last review regarding respiratory health effects attributable to long-term ambient NO

-exposure. The

majority of new evidence is from epidemiologic studies of asthma incidence in children with improved exposure assessment (

i.e.,

measured or modeled at or near children's homes or schools), which builds upon previous evidence for associations of long-term NO

and asthma incidence and also partly reduces uncertainties related to measurement error. Explicit integration of evidence for individual outcome categories (

e.g.,

asthma incidence, respiratory infection) provides improved characterization of biological plausibility, including some new evidence from studies of short-term exposure supporting an effect on asthma development. Although this partly reduces the uncertainty regarding independent effects of NO

, the potential for confounding remains a concern when interpreting these epidemiologic studies as a result of the high correlation with other traffic-related copollutants and the general lack of copollutant models including these pollutants. In particular, it remains unclear the degree to which NO

itself may be causing the development of asthma versus serving as a surrogate for the broader traffic-pollutant mix.

Cardiovascular Effects and Diabetes

In the previous review, the 2008 NO

ISA stated that the evidence for cardiovascular effects attributable to long-term ambient NO

exposure was “inadequate to infer the presence or absence of a causal relationship.” The epidemiologic and experimental evidence was limited, with uncertainties related to traffic-related copollutant confounding (U.S. EPA, 2008a). For the current review, the body of epidemiologic evidence available is substantially larger than that in the last review and includes evidence for diabetes. The conclusion on causality is stronger in the current review with regard to the relationship between long-term exposure to NO

and cardiovascular effects and diabetes, as the 2016 NO

ISA judged the evidence to be “suggestive, but not sufficient to infer” a causal relationship (U.S. EPA, 2016a, Section 6.3). More information on these health effects may be found in section II.C.2.a.ii of the proposal (87 FR 34792, July 26, 2017).

Reproductive and Developmental Effects

In the previous review, a limited number of epidemiologic and toxicological studies had assessed the relationship between long-term NO

exposure and reproductive and developmental effects. The 2008 NO

ISA concluded that there was not consistent evidence for an association between NO

and birth outcomes and that evidence was “inadequate to infer the presence or absence of a causal relationship” with reproductive and developmental effects overall (U.S. EPA, 2008a). In the 2016 NO

ISA for the current review, a number of recent studies added to the evidence base, and reproductive effects were considered as three separate categories: birth outcomes; fertility, reproduction, and pregnancy; and postnatal development (U.S. EPA, 2016a, Section 6.4). Overall, the 2016 NO

ISA found the evidence to be “suggestive of, but not sufficient to infer, a causal relationship” between long-term exposure to NO

and birth outcomes and “inadequate to infer the presence or absence of a causal relationship” between long-term exposure to NO

and fertility, reproduction and pregnancy as well as postnatal development. More information on these health effects may be found in section II.C.2.a.iii of the proposal (87 FR 34792, July 26, 2017).

Total Mortality

In the 2008 NO

ISA, a limited number of epidemiologic studies assessed the relationship between long-term exposure to NO

and mortality in adults. The 2008 NO

ISA concluded that the scarce amount of evidence was “inadequate to infer the presence or absence of a causal relationship” (U.S. EPA, 2008a). The 2016 NO

ISA for the current review concludes that evidence is “suggestive of, but not sufficient to infer, a causal relationship” between long-term exposure to NO

and mortality among adults (U.S. EPA, 2016a, Section 6.5.3). More information on these health effects may be found in section II.C.2.a.iv of the proposal (87 FR 34792, July 26, 2017).

Cancer

The evidence evaluated in the 2008 NO

ISA was judged “inadequate to infer the presence or absence of a causal relationship” (U.S. EPA, 2008a) based on a few epidemiologic studies indicating associations between long-term NO

exposure and lung cancer incidence but lack of toxicological evidence demonstrating that NO

induces tumors. In the current review, the conclusion drawn from the integration of evidence is “suggestive of, but not sufficient to infer, a causal relationship” (U.S. EPA, 2016a, Section 6.6.9). More information on cancer outcomes may be found in section II.C.2.a.v of the proposal (87 FR 34792, July 26, 2017).

ii. Long-Term NO

Concentrations in Health Studies

In evaluating what the available health evidence indicates with regard to the degree of public health protection provided by the current standards, the EPA considers the long-term NO

concentrations that have been associated with various effects. The PA explicitly considers these NO

In evaluating the long-term NO

concentrations associated with health effects within the context of considering the adequacy of the current standards, the PA focuses on the evidence for asthma incidence (

i.e.,

the type of effect for which there is the strongest evidence supporting a “likely to be causal” relationship, as discussed above). The PA specifically considers: (1) The extent to which epidemiologic studies indicate associations between long-term NO

exposures and asthma development for distributions of ambient NO

concentrations that would likely have met the existing standards; and (2) the extent to which effects related to asthma development have been reported following the range of NO

exposure concentrations examined in experimental studies. These considerations are discussed below for epidemiologic studies and experimental studies.

Ambient NO

Concentrations in Locations of Epidemiologic Studies

As discussed above for short-term exposures (Section II.A.2.a), when considering epidemiologic studies of long term NO

exposures within the context of evaluating the adequacy of the current NO

standards, the PA emphasizes studies conducted in the U.S. and Canada. The PA considers the extent to which these studies report positive and relatively precise associations with long-term NO

exposures and the extent to which important uncertainties could impact the emphasis placed on particular studies. For the studies with potential to inform conclusions on adequacy, the PA also evaluates available air quality information in study locations, focusing on estimated DVs over the study periods.

The epidemiologic studies available in the current review that evaluate associations between long-term NO

exposures and asthma incidence are summarized in Table 6-1 of the 2016

ISA (U.S. EPA, 2016a, p. 6-7). In evaluating the adequacy of the current NO

standards, the PA places the greatest emphasis on the three U.S. and Canadian studies identified in the 2016 NO

ISA as providing key supporting evidence for the causal determination.

However, the PA also considers what the additional three U.S. and Canadian studies not identified as key studies in the 2016 NO

ISA can indicate about the adequacy of the current standards, while noting the increased uncertainty in these studies related to exposure measurement and copollutant confounding (Table 6-5 of the 2016 NO

ISA).

There are six longitudinal epidemiologic studies conducted in the U.S. or Canada that vary in terms of the populations examined and methods used. Of the six studies, the 2016 NO

ISA identifies three as key studies supporting the causal determination (Carlsten et al., 2011; Clougherty et al., 2007; Jerrett et al., 2008).

While it is appropriate to consider what these studies can tell us with regard to the adequacy of the existing primary NO

standards (see below), the emphasis that is placed on these considerations reflects important uncertainties related to the potential for confounding by traffic-related copollutants and for exposure measurement error.

While keeping in mind these uncertainties, the PA next considers the ambient NO

concentrations present at monitoring sites in locations and time periods of U.S. and Canadian epidemiologic studies. Specifically, the PA considers the following question: To what extent do U.S. and Canadian epidemiologic studies report associations with long-term NO

in locations likely to have met the current primary NO

standards?

As discussed above for short-term exposures (Section II.A.2.a), addressing this question can provide important insights into the extent to which NO

-health effect associations are present for distributions of ambient NO

concentrations that would be allowed by the current primary standards. The presence of such associations would support the potential for the current standards to allow the NO

-associated asthma development indicated by epidemiologic studies. To the degree studies have not reported associations in locations meeting the current primary NO

standards, there is greater uncertainty regarding the potential for the development of asthma to result from the NO

exposures associated with air quality meeting those standards.

To evaluate this issue, the PA compares NO

estimated DVs in study areas to the levels of the current primary NO

standards. In addition to comparing annual DVs to the level of the annual standard, support for consideration of 1-hour DVs comes from the 2016 NO

ISA's integrated mode of action information describing the biological plausibility for development of asthma (section II.B.1, below). In particular, studies demonstrate the potential for repeated short-term NO

exposures to induce pulmonary inflammation and development of allergic responses. The 2016 NO

ISA states that “findings for short-term NO

exposure support an effect on asthma development by describing a potential role for repeated exposures to lead to recurrent inflammation and allergic responses,” which are “identified as key early events in the proposed mode of action for asthma development” (U.S. EPA, 2016a, p. 6-66 and p. 6-64). More specifically, the 2016 NO

ISA states the following (U.S. EPA, 2016a, p. 4-64):

The initiating events in the development of respiratory effects due to long-term NO

exposure are recurrent and/or chronic respiratory tract inflammation and oxidative stress. These are the driving factors for potential downstream key events, allergic sensitization, airway inflammation, and airway remodeling, that may lead to the endpoint [airway hyperresponsiveness]. The resulting outcome may be new asthma onset, which presents as an asthma exacerbation that leads to physician-diagnosed asthma.

Thus, when considering the protection provided by the current standards against NO

-associated asthma development, the PA considers the combined protection afforded by the 1-hour and annual standards.

It is also the case that broad changes in NO

concentrations will affect both hourly and annual metrics. This is discussed in more detail in Section II.A.1 above, and in the CASAC letter to the Administrator on the draft PA (Diez Roux and Sheppard, 2017). Thus, as in the recent review of the O

NAAQS (80 FR 65292, October 26, 2015), it is appropriate here to consider the extent to which a short-term standard could provide protection against longer-term pollutant exposures.

To inform consideration of whether a study area's air quality could have met the current primary NO

standards during study periods, the PA presents DV estimates based on the NO

concentrations measured at existing monitors during the years over which the epidemiologic studies of long-term NO

exposures were conducted.

As discussed above for short-term exposures, the DVs estimates reported here are meant to approximate the values that are used when determining whether an area meets the primary NO

NAAQS (U.S. EPA, 2017a, Appendix A).

The DV estimates for the epidemiologic studies of asthma incidence conducted in the U.S. and Canada are presented in Figure 3-2 of the NO

PA (U.S. EPA, 2017a).

In interpreting these comparisons of DV estimates with the NO

standards, the PA also considers uncertainty in the extent to which identified DV estimates represent the higher NO

concentrations likely to have been present near major roads during study periods (section II.A.1, above). In particular, as discussed above for short-term exposures, study area DV estimates are based on NO

concentrations from the generally area-wide NO

monitors that were present during study periods. Calculated DV estimates could have been higher if the near-road monitors that are now required in major U.S. urban areas had been in place. On this issue, the PA notes that the published scientific literature supports the occurrence of higher NO

concentrations near roadways and that recent air quality information from the new near-road NO

monitoring network generally indicates higher NO

concentrations at near-road monitoring sites than at non near-road monitors in the same CBSA (section II.A.c, above). In addition, mobile source NO

emissions were substantially higher during the majority of study periods (1986-2006) than they are today (section II.A.b, above), and NO

concentration gradients around roadways were generally more pronounced during study periods than indicated by recent air quality information. Thus, even in cases where DV estimates during study periods are at or somewhat below the levels of current primary standards, it is not clear that study areas would have met the standards if the currently required near-road monitors had been in place.

As noted above for studies of short-term NO

exposures (II.A.2.a), epidemiologic studies that evaluate potential NO

health effect associations during time periods when near-road monitors are operational could reduce this uncertainty in future reviews.

In considering the epidemiologic studies looking at long-term NO

exposure and asthma development (U.S. EPA, 2017a, Figure 3-2), the PA first notes the information from the key studies as identified in the 2016 NO

ISA (Jerrett et al., 2008; Carlsten et al., 2011, Clougherty et al., 2007). Jerrett et al. (2008) reported positive and relatively precise associations with asthma incidence, based on analyses across several communities in Southern California. Of the 11 study communities evaluated by Jerrett et al. (2008), most (

i.e.,

seven) had maximum annual estimated DVs that were near (

i.e.,

46 ppb for the four communities represented by the Riverside estimated DVs) or above (

i.e.,

60 ppb for the three communities represented by the Los

Angeles estimated DVs) 53 ppb.

These seven communities also had 1-hour estimated DVs (maximum and mean) that were well above 100 ppb. The other key studies (

i.e.,

Carlsten et al., 2011; Clougherty et al., 2007), conducted in single cities, reported positive but statistically imprecise associations. The annual estimated DVs in locations of these studies during study years were below 53 ppb, but maximum 1-hour estimated DVs were near (Clougherty et al., 2007)

or above (Carlsten et al., 2011) 100 ppb.

For the studies by Jerrett et al. (2008) and McConnell et al. (2010), the majority of communities were located within the Los Angeles and Riverside CBSAs. Because of this, DV estimates for the Los Angeles and Riverside CBSAs were used to represent multiple study communities.

As noted above, even in cases where DV estimates during study periods are at or somewhat below the levels of current standards, it is not clear that study areas would have met the standards if the currently required near-road monitors had been in place during the study period.

The PA also considers the information from the other U.S. and Canadian studies available that, due to additional uncertainties, were not identified as key studies in the 2016 NO

ISA (Clark et al., 2010; McConnell et al., 2010; Nishimura et al., 2013). The multicity study by Nishimura et al. (2013) reports a positive and relatively precise association with asthma incidence, based on five U.S. cities and Puerto Rico (see “combined” estimate in Figure 3-2 of the NO

PA). Annual estimated DVs in all study cities were below 53 ppb, while maximum 1-hour estimated DVs were above 100 ppb in four of the five study cities (mean 1-hour estimated DVs were also near or above 100 ppb in most study cities). Nishimura et al. (2013) also reported mixed results in city-specific effects estimates. McConnell et al. (2010) also conducted a multi-community study in Southern California and reported a positive and relatively precise association between asthma incidence and long-term NO

exposures based on central-site measurements. This study encompasses some of the same communities as Jerrett et al. (2008), and while the annual DV estimates for these study years are more mixed, the 1-hour DV estimates representing 10 of 13 communities are near or above 100 ppb. Finally, Clark et al. (2010) reported a relatively precise and statistically significant association in a study conducted over a two-year period in British Columbia, with annual and hourly DV estimates of 32 ppb and 67 ppb, respectively. However, this result was based on central-site NO

measurements that have well-recognized limitations in reflecting variability in ambient NO

concentrations in a community and variability in NO

exposure among subjects.

PA Conclusions on Ambient NO

Concentrations in Locations of Epidemiologic Studies

Based on the information discussed above, while epidemiologic studies provide support for NO

-associated asthma development at ambient NO

concentrations likely to have been above those allowed by the current standards, these studies do not report such associations at ambient NO

concentrations that would have clearly met both of the current standards. Thus, in evaluating the adequacy of the public health protection provided by the current 1-hour and annual NO

standards, the PA concludes that epidemiologic studies do not provide a clear basis for concluding that ambient NO

concentrations allowed by the current standards are independently (

i.e.,

independent of co-occurring roadway pollutants) associated with the development of asthma (U.S. EPA, 2017a, section 3.3.2). This conclusion stems from consideration of the available evidence from U.S. and Canadian studies for NO

-associated asthma incidence, the ambient NO

concentrations present in study locations during study periods, and the uncertainties and limitations inherent in the evidence and in the analysis of study area DV estimates.

With regard to uncertainties in the evidence, the PA particularly notes the potential for confounding by co-occurring pollutants, as described above, given the following: (1) The relatively high correlations observed between long-term concentrations of NO

and long-term concentrations of other roadway-associated pollutants; and (2) the general lack of information from copollutant models on the potential for NO

associations that are independent of another traffic-related pollutant or mix of pollutants. This uncertainty is an important consideration in evaluating the potential support for adverse effects occurring below the levels of the current primary NO

standards.

Furthermore, the analysis of study area estimated DVs does not provide support for the occurrence of NO

-associated asthma incidence in locations with ambient NO

concentrations clearly meeting the current NAAQS. In particular, for most of the study locations evaluated in the lone key U.S. multi-community study (Jerrett et al., 2008), 1-hour estimated DVs were above 100 ppb, and annual DVs were near or above 53 ppb. In addition, the two key single-city studies evaluated reported positive, but relatively imprecise, associations in locations with 1-hour estimated DVs near (Clougherty et al., 2007 in Boston) or above (Carlsten et al., 2011 in Vancouver) 100 ppb. Had currently required near-road monitors been in operation during study periods, estimated DVs in U.S. study locations would likely have been higher. Other U.S. and Canadian studies evaluated were subject to greater uncertainties in the characterization of NO

exposures. Given this information and consideration of these uncertainties, the degree to which these epidemiologic studies can inform whether adverse NO

-associated effects (

i.e.,

asthma development) are occurring below the levels of the current primary NO

standards is limited.

iii. NO

Concentrations in Experimental Studies of Long-Term Exposure

In addition to the evidence from epidemiologic studies, the PA also considers evidence from experimental studies in animals and humans.

Experimental studies examining asthma-related effects attributable to long-term NO

exposures are largely limited to animals exposed to NO

concentrations well above those found in the ambient air (

i.e.,

≥1,000 ppb). As discussed above, the 2016 NO

ISA indicates that evidence from these animal studies supports the causal determination by characterizing “a potential mode of action linking NO

exposure with asthma development” (U.S. EPA, 2016a, p. 1-20). In particular, there is limited evidence for increased airway responsiveness in guinea pigs with exposures to 1,000-4,000 ppb for 6-12 weeks. There is inconsistent evidence for pulmonary inflammation across all studies, though effects were reported following NO

exposures of 500-2,000 ppb for 12 weeks. Despite providing support for the “likely to be a causal” relationship, these experimental studies, by themselves, do not provide insight into the occurrence of adverse health effects following exposures below the levels of the existing primary NO

standards.

While there are not controlled human exposure studies for long-term exposures, the 2016 NO

ISA and the PA consider the extent to which evidence from short-term studies can provide support for effects observed in long-term exposure studies (U.S. EPA 2016a, chapter 6; U.S. EPA, 2017a, section 3).

In addition, the 2016 NO

ISA draws from experimental evidence for short-term exposures to support the biological plausibility of asthma development. Consideration of the NO

exposure concentrations evaluated in these studies is discussed in Section II.A.2 above.

Overall Conclusions for Long Term Exposures

Taking all of the evidence and information together, including important uncertainties, the PA revisits the extent to which the evidence supports the occurrence of NO

-attributable asthma development in children at NO

concentrations below the existing standards. Based on the considerations discussed above, the PA concludes that the available evidence does not provide support for asthma development attributable to long-term exposures to NO

concentrations that would clearly meet the existing annual and 1-hour primary NO

standards. This conclusion recognizes the NO

air quality relationships, which indicate that meeting the 1-hour NO

standard would be expected to limit annual NO

concentrations to well below the level of the current annual standard (Section II.A.2.d, above). This conclusion also recognizes the uncertainties in interpreting the epidemiologic evidence within the context of evaluating the existing standards due to the lack of near-road monitors during study periods and due to the potential for confounding by co-occurring pollutants. Thus, the PA concludes that epidemiologic studies of long-term NO

exposures and asthma development do not provide a clear basis for concluding that ambient NO

concentrations allowed by the current primary NO

standards are independently (

i.e.,

independent of co-occurring roadway pollutants) associated with the development of asthma. In addition, while experimental studies provide support for NO

-attributable effects that are plausibly related to asthma development, the relatively high NO

exposure concentrations used in these studies do not provide insight into whether such effects would occur at NO

exposure concentrations that would be allowed by the current standards.

c. Potential Public Health Implications

Evaluation of the public health protection provided against ambient NO

exposures requires consideration of populations and lifestages that may be at greater risk of experiencing NO

-attributable health effects. In the last review, the 2008 NO

ISA noted that a considerable fraction of the U.S. population lives, works, or attends school near major roadways, where ambient NO

concentrations are often elevated (U.S. EPA, 2008a, Section 4.3). Of this population, the 2008 NO

ISA concluded that “those with physiological susceptibility will have even greater risks of health effects related to NO

” (U.S. EPA, 2008a, p. 4-12). With regard to susceptibility, the 2008 NO

ISA concluded that “[p]ersons with preexisting respiratory disease, children, and older adults may be more susceptible to the effects of NO

exposure” (U.S. EPA, 2008a, p. 4-12).

In the current review, the 2016 NO

ISA again notes that because of the large populations attending school, living, working, and commuting on or near roads, where ambient NO

concentrations can be higher than in many other locations (U.S. EPA, 2016a, Section 7.5.6),

there is widespread potential for elevated ambient NO

exposures. For example, Rowangould (2013) found that over 19% of the U.S. population lives within 100 m of roads with an annual average daily traffic (AADT) of 25,000 vehicles, and 1.3% lives near roads with AADT greater than 200,000. The proportion is much larger in certain parts of the country, mostly coinciding with urban areas. Among California residents, 40% live within 100 m of roads with AADT of 25,000 (Rowangould, 2013). In addition, 7% of U.S. schools serving a total of 3,152,000 school children are located within 100 m of a major roadway, and 15% of U.S. schools serving a total of 6,357,000 school children are located within 250 m of a major roadway (Kingsley et al., 2014). Thus, as in the last review, the available information indicates that large proportions of the U.S. population potentially have elevated NO

exposures as a result of living, working, attending school, or commuting on or near roadways.

The 2016 NO

ISA specifically notes that a zone of elevated NO

concentrations typically extends 200 to 500 m from roads with heavy traffic (U.S. EPA, 2016a, Section 2.5.3).

The impacts of exposures to elevated NO

concentrations, such as those that can occur around roadways, are of particular concern for populations at increased risk of experiencing adverse effects. In the current review, the PA's consideration of potential at-risk populations (U.S. EPA, 2017a, Section 3.4) draws from the 2016 NO

ISA's assessment of the evidence (U.S. EPA, 2016a, Chapter 7). The 2016 NO

ISA uses a systematic approach to evaluate factors that may increase risks in a particular population or during a particular lifestage, noting that increased risk could be due to “intrinsic or extrinsic factors, differences in internal dose, or differences in exposure” (U.S. EPA, 2016a, p. 7-1).

The 2016 NO

ISA evaluates the evidence for a number of potential at-risk factors, including pre-existing diseases like asthma (U.S. EPA, 2016a, Section 7.3), genetic factors (U.S. EPA, 2016a, Section 7.4), sociodemographic factors (U.S. EPA, 2016a, Section 7.5), and behavioral and other factors (U.S. EPA, 2016a, Section 7.6). The 2016 NO

ISA then uses a systematic approach for classifying the evidence for each potential at-risk factor (U.S. EPA, 2015a, Preamble, Section 6.a, Table III). The categories considered are “adequate evidence,” “suggestive evidence,” “inadequate evidence,” and “evidence of no effect” (U.S. EPA, 2016a, Table 7-1). Consistent with other recent NAAQS reviews (

e.g.,

the recently completed review for ozone, 80 FR 65292, October 26, 2015), the PA focuses the consideration of potential at-risk populations on those factors for which the 2016 NO

ISA determines there is “adequate” evidence (U.S. EPA, 2016a, Table 7-27). For NO

, the at-risk populations identified include people with asthma, children and older adults (U.S. EPA, 2016a, Table 7-27), and this information is based primarily on evidence for asthma exacerbation or asthma development as evidence for an independent relationship of NO

exposure with other health effects is more uncertain.

The PA's consideration of the evidence supporting conclusions regarding the populations at increased risk of NO

-related effects specifically focuses on the following question: To what extent does the currently available scientific evidence expand the understanding of populations and/or lifestages that may be at greater risk for NO

-related health effects? (U.S. EPA, 2017a, p. 3-40).

In addressing this question, the PA considers the evidence in the 2016 NO

ISA for effects in people with asthma, children, and older adults (U.S. EPA, 2016a, Chapter 7, Table 7-27), respectively, as described below.

People With Asthma

Approximately 8.0% of adults and 9.3% of children (age <18 years) in the U.S. currently have asthma (Blackwell et al., 2014; Bloom et al., 2013), and it is the leading chronic illness affecting children (U.S. EPA, 2016a, Section 7.3.1). Individuals with pre-existing diseases like asthma may be at greater risk for some air pollution-related health effects if they are in a compromised biological state.

As in the last review, controlled human exposure studies demonstrating NO

-induced increases in AR provide key evidence that people with asthma are more sensitive than people without asthma to the effects of short-term NO

exposures. In particular, a meta-analysis conducted by Folinsbee et al. (1992)

demonstrated that NO

exposures from 100 to 300 ppb increased AR in the majority of adults with asthma, while AR in adults without asthma was increased only for NO

exposure concentrations greater than 1,000 ppb (U.S. EPA, 2016a, Section 7.3.1). The Brown (2015) meta-analysis showed that following resting exposures to NO

concentrations in the range of 100 to 530 ppb, about a quarter of individuals with asthma experience clinically relevant increases in AR to non-specific bronchial challenge. Results of epidemiologic studies are less clear regarding potential differences between populations with and without asthma (U.S. EPA, 2016a, Section 7.3.1). Additionally, studies of activity patterns do not clearly indicate differences in time spent outdoors to suggest differences in NO

exposure. However, the Folinsbee et al. (1992) meta-analysis of information from controlled human exposure studies, which supported the 2016 NO

ISA's determination of a causal relationship between short-term exposures and respiratory effects, clearly demonstrates that adults with asthma are at increased risk for NO

-related respiratory health effects compared to healthy adults. Thus, consistent with observations made in the 2008 NO

ISA (U.S. EPA, 2008a), in the current review the 2016 NO

ISA determines that the “evidence is adequate to conclude that people with asthma are at increased risk for NO

-related health effects” (U.S. EPA, 2016a, p. 7-7).

Children

According to the 2010 census, 24% of the U.S. population is less than 18 years of age, with 6.5% less than 6 years of age (Howden and Meyer, 2011). The National Human Activity Pattern Survey shows that children spend more time than adults outdoors (Klepeis et al., 1996), and a longitudinal study in California showed a larger proportion of children reported spending time engaged in moderate or vigorous outdoor physical activity (Wu et al., 2011b). In addition, children have a higher propensity than adults for oronasal breathing (U.S. EPA, 2016a, Section 4.2.2.3) and the human respiratory system is not fully developed until 18−20 years of age (U.S. EPA, 2016

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