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

Federal RegisterJul 26, 2017

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 50

[EPA-HQ-OAR-2013-0146; FRL-9965-28-OAR]

RIN 2060-AR57

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

AGENCY:

Environmental Protection Agency (EPA).

ACTION:

Proposed rule.

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 nitrogen dioxide (NO

), the EPA is proposing to retain the current standards, without revision.

DATES:

Comments must be received on or before September 25, 2017.

Public Hearings:

If, by August 2, 2017, the EPA receives a request from a member of the public to speak at a public hearing concerning the proposed decision, we will hold a public hearing, with information about the hearing provided in a subsequent notice in the

Federal Register

To request a hearing, to register to speak at a hearing or to inquire if a hearing will be held, please contact Ms. Regina Chappell at (919) 541-3650 or by email at

chappell.regina@epa.gov.

The EPA will post all information regarding any public hearing on this proposed action, including whether a hearing will be held, its location, date, and time if applicable and any updates online at

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

ADDRESSES:

Submit your comments, identified by Docket ID No. EPA-HQ-OAR-2013-0146 to the

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

. Follow the online instructions for submitting comments. Once submitted, comments cannot be edited or withdrawn. The EPA may publish any comment received to its public docket. Do not submit electronically any information you consider to be Confidential Business Information (CBI) or other information whose disclosure is restricted by statute. Multimedia submissions (audio, video, etc.) must be accompanied by a written comment. The written comment is considered the official comment and should include discussion of all points you wish to make. The EPA will generally not consider comments or comment contents located outside of the primary submission (

i.e.,

on the Web, Cloud, or other file sharing system). For additional submission methods, the full EPA public comment policy, information about CBI or multimedia submissions, and general guidance on making effective comments, please visit

http://www2.epa.gov/dockets/commenting-epa-dockets

Docket:

All documents in the docket are listed on the

www.regulations.gov

Web site. This includes documents in the docket for the proposed decision (Docket ID No. EPA-HQ-OAR-2013-0146) and a separate docket, established for the Integrated Science Assessment (ISA) for this review (Docket ID No. EPA-HQ-ORD-2013-0232) that has been incorporated by reference into the docket for this proposed decision. All documents in these dockets are listed on the

www.regulations.gov

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

e.g.,

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

www.regulations.gov

or in hard copy at the Air and Radiation Docket 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

SUPPLEMENTARY INFORMATION:

General Information

Preparing Comments for the EPA

1. Submitting CBI.

Do not submit this information to the EPA through

www.regulations.gov

or email. Clearly mark the part or all of the information that you claim to be CBI. For CBI information in a disk or CD-ROM that you mail to the EPA, mark the outside of the disk or CD-ROM as CBI and then identify electronically within the disk or CD-ROM the specific information that is claimed as CBI. In addition to one complete version of the comment that includes information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public docket. Information so marked will not be disclosed except in accordance with procedures set forth in 40 Code of Federal Regulations (CFR) part 2.

2. Tips for Preparing Your Comments.

When submitting comments, remember to:

• Identify the action by docket number and other identifying information (subject heading,

Federal Register

date and page number).

• Follow directions—the agency may ask you to respond to specific questions or organize comments by referencing a CFR part or section number.

• Explain why you agree or disagree, suggest alternatives, and substitute language for your requested changes.

• Describe any assumptions and provide any technical information and/or data that you used.

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

• Explain your views as clearly as possible, avoiding the use of profanity or personal threats.

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

Availability of Information Related to This Action

A number of the documents that are relevant to this proposed decision are available through the EPA's Web site 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.

Table of Contents

The following topics are discussed in this preamble:

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

II. Rationale for Proposed Decisions on the Primary NO

Standards

A. General Approach

1. Approach in the Last Review

2. Approach for the Current Review

B. Characterization of NO

Air Quality

1. Atmospheric Chemistry

2. National Trends in NO

Emissions and Ambient NO

Concentrations

3. Near-Road NO

Air Quality

4. Relationships Between Hourly and Annual NO

Concentrations

C. Health Effects Information

1. Health Effects With Short-Term Exposure to NO

2. Health Effects With Long-Term Exposure to NO

3. Potential Public Health Implications

D. Human Exposure and Health Risk Characterization

1. Overview of Approach To Estimating Potential NO

Exposures

2. Results of Updated Analyses

3. Uncertainties

4. Conclusions

E. Summary of CASAC Advice

F. Proposed Conclusions on the Adequacy of the Current Primary NO

Standards

1. Evidence-Based Considerations

2. Exposure and Risk-Based Considerations

3. CASAC Advice

4. Administrator's Proposed Conclusions Regarding the Adequacy of the Current Primary NO

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. Paperwork Reduction Act (PRA)

C. Regulatory Flexibility Act (RFA)

D. Unfunded Mandates Reform Act (UMRA)

E. Executive Order 13132: Federalism

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

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

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

I. National Technology Transfer and Advancement Act (NTTAA)

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

K. Determination Under Section 307(d)

References

Executive Summary

This section summarizes background information about this proposed action and the Administrator's proposed decision to retain the current primary NO

standards.

Summary of Background Information

There are currently two primary standards for oxides of nitrogen. NO

is the component of oxides of nitrogen of greatest concern for health and is the indicator for the primary NAAQS. The two primary NO

standards are: A 1-hour standard established in 2010 at a level of 100 parts per billion (ppb) and 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 and based on annual average NO

concentrations.

Sections 108 and 109 of the Clean Air Act (CAA) govern the establishment, review, and revision, as appropriate, of the NAAQS to protect public health and welfare. The CAA requires the EPA to periodically review the air quality criteria—the science upon which the standards are based—and the standards themselves. This 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 proposed determination by July 14, 2017, and a final determination 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 ecological welfare effects associated with oxides of nitrogen, oxides of sulfur, and PM, and the protection provided by the secondary NO

, SO

and PM standards. (U.S. EPA, 2017b).

Summary of Proposed Decision

In this notice, the EPA is proposing to retain the current primary NO

standards, without revision. This proposed 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 ISA; analyses and considerations in the Policy Assessment (PA); and the advice and recommendations of the Clean Air Scientific Advisory Committee (CASAC).

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

exposures (

e.g.,

typically minutes to hours). In particular, the 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, pp. 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. Most of these studies were available in the last review and, consistent with the evidence in that review, an updated meta-analysis indicates increased AR in some people with asthma following resting exposures to NO

concentrations from 100 to 530 ppb. However, there is not an apparent dose-response relationship between NO

exposure and increased AR and there is uncertainty regarding the potential adversity of reported responses. In addition, these studies are largely focused on adults with mild asthma, rather than adults or children with more severe cases of the disease.

Evidence supporting the ISA conclusion also comes from epidemiologic studies reporting associations between short-term NO

exposures and an array of respiratory outcomes related to asthma exacerbation. Such studies consistently

report associations with several asthma-related outcomes, including asthma-related hospital admissions and emergency department visits in children and adults. The epidemiologic evidence that is newly available in the current review is consistent with evidence from the last review and does not fundamentally alter our understanding of respiratory effects related to short-term NO

exposures. While our fundamental understanding of such effects has not changed, recent epidemiologic studies do reduce some uncertainty from the last review by reporting health effect associations with short-term NO

exposures in copollutant models and by their use of improved exposure metrics.

In addition to the effects of short-term exposures, the 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. While these studies strengthen the evidence for effects of long-term exposures, compared to the last review, they are subject to uncertainties resulting from the methods used to assign NO

exposures, the high correlations between NO

and other traffic-related pollutants, and the lack of information regarding the extent to which reported effects are independently associated with NO

rather than the overall mixture of traffic-related pollutants. Additional support comes from experimental studies supporting the biological plausibility of a potential mode of action by which NO

exposures could cause asthma development. These include studies that support a potential role for repeated short-term NO

exposures in the development of asthma.

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, available studies do 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. In addition, while epidemiologic studies report relatively precise associations with serious NO

-related health outcomes (

i.e.,

emergency department 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.

Beyond the scientific evidence, the EPA also considers the extent to which quantitative analyses can inform conclusions on the adequacy of the public health protection provided by the current primary NO

standards. In particular, the EPA considers analyses estimating the potential for NO

exposures of public health concern that could be allowed by the current standards. Overall, these analyses indicate that the current 1-hour standard provides substantial protection against exposures to ambient NO

concentrations that have consistently been shown to increase AR in people with asthma, even under worst-case conditions across a variety of study areas in the U.S. Such NO

concentrations were not estimated to occur, even at monitoring sites adjacent to some of the most heavily trafficked roads. In addition, the analyses indicate that meeting the current 1-hour standard limits the potential for exposure to 1-hour NO

concentrations that have the potential to exacerbate symptoms in some people with asthma, but for which uncertainties in the evidence become increasingly important.

When taken together, the Administrator reaches the proposed conclusion that the current body of scientific evidence and the results of quantitative analyses support the degree of public health protection provided by the current 1-hour and annual primary NO

standards and do not call into question any of the elements of those standards. He additionally reaches the proposed conclusion that the current 1-hour and annual NO

primary standards, together, are requisite to protect public health with an adequate margin of safety.

These proposed conclusions are consistent with CASAC recommendations. In its advice to the Administrator, “the CASAC recommends 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 Administrator proposes to retain the current primary NO

standards, without revision. The Administrator solicits comment on his proposed conclusions regarding the public health protection provided by the current primary NO

standards and on his proposal to retain those standards in this review. He invites comment on all aspects of these proposed conclusions and their underlying rationales, as discussed in detail in section II below.

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, are requisite to protect the public health.”

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

The legislative history of section 109 indicates that a primary standard is to be set at “the maximum permissible ambient air level . . . which will protect the health of any [sensitive] group of the population,” and that for this purpose “reference should be made to a representative sample of persons comprising the sensitive group rather than to a single person in such a group.” 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 (DC Cir 1980),

cert. denied,

449 U.S. 1042 (1980);

American Petroleum Institute

Costle,

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

cert. denied,

455 U.S. 1034 (1982);

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

EPA,

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

In addressing the requirement for an adequate margin of safety, 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 notice, 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 life stage. As discussed more fully in section II.C.3 below, the identification of sensitive groups (called at-risk groups or at-risk populations) involves consideration of susceptibility and vulnerability.

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 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 EPA has established them. Under section 110 of the Act, 42 U.S.C. 7410, and related provisions, states are to submit, for EPA approval, state implementation plans (SIPs) that provide for the attainment and maintenance of such standards through control programs directed to sources of the pollutants involved. The states, in conjunction with EPA, also administer the prevention of significant deterioration program that covers these pollutants. See 42 U.S.C. 7470-7479. In addition, federal programs provide for nationwide reductions in emissions of these and other air pollutants under Title II of the Act, 42 U.S.C. 7521-7574, which involves controls for automobile, truck, bus, motorcycle, nonroad engine and equipment, and aircraft emissions; the new source performance standards (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 of 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, 2017 Figure 2-5), with the maximum DVs in 2015 being 30 ppb (annual) and 72 ppb (hourly) (U.S. EPA, 2017 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. These DVs are considered to be valid if the monitoring data used to calculate them meet completeness criteria described in 40 CFR 50.11 and Appendix S to Part 50.

For more information on estimated DVs, see Section 2.3 of the NO

PA.

While NO

(the sum of NO and 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 as a result of the ongoing implementation of mobile source emissions standards.

In particular, 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 nonroad 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.

Highway vehicles include all on-road vehicles, including light duty as well as heavy duty vehicles, both gasoline- and diesel-powered. Off-highway vehicles and engines include aircraft, commercial marine vessels, locomotives and non-road equipment. 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.

emissions from stationary fuel combustion sources are primarily from electric utility sources, both coal and gas-fired. NO

emissions from these sources, as well as for some large industrial combustion sources, are also expected to continue to decrease over the next decade as newer replacement units come on-line which will have to meet NSPS and SIP compliance limits, and as additional existing sources opt-in to NO

trading programs to maintain state emissions budget programs.

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 the 1971 proposal, the EPA used the term nitrogen oxides.

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 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 ISA and 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 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 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's recommendations on the second draft ISA and the draft REA Plan 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 CASAC's 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's 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

In addition, in July 2016, a lawsuit was filed against the EPA and 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 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.

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 ecological welfare effects associated with oxides of nitrogen, oxides of sulfur, and PM, and the protection provided by the secondary NO

, SO

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

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

II. Rationale for Proposed Decisions on the Primary NO2 Standards

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

primary standards. This rationale is based on a thorough review of the latest scientific information generally published through August 2014,

as presented in the ISA, on human health effects associated with NO

and pertaining to the presence of NO

in the ambient air. The Administrator's rationale also takes into account: (1) The EPA staff's consideration of the scientific evidence and technical information and staff's conclusions based on that evidence and information, presented in the PA; (2) the CASAC's advice and recommendations, as reflected in discussions at public meetings of drafts of the various documents that were prepared for this review, including the ISA and PA, and in the CASAC's letters to the Administrator; and (3) public input received during the development of these documents, either in connection with CASAC meetings or separately.

In addition to the review's opening “call for information” (77 FR 7149, February 10, 2012), “the U.S. EPA routinely conducted literature searches to identify relevant peer-reviewed studies published since the previous ISA (

i.e.,

from January 2008 through August 2014)” (U.S. EPA, 2016a p. 1-3). References that are cited in the ISA, the references that were considered for inclusion but not cited, and electronic links to bibliographic information and abstracts can be found at:

http://hero.epa.gov/oxides-of-nitrogen.

Public input during the review process, including on drafts of the ISA and PA, and CASAC's advice in light of that public input, were considered by the EPA staff in developing final documents.

In presenting the rationale for the Administrator's proposed decision and its foundations, Section II.A provides background on the general approach for review of the primary NO

NAAQS, including a summary of the approach used in the last review (Section II.A.1) and the general approach taken in the PA for the current review (Section II.A.2). Section II.B characterizes ambient NO

concentrations throughout the United States. Section II.C summarizes the body of available scientific evidence, focusing on consideration of key policy-relevant questions, and Section II.D summarizes the available information from quantitative analyses evaluating the potential for NO

exposures that could be of public health concern. Section II.E summarizes CASAC advice. Section II.F presents the Administrator's proposed conclusions on adequacy of the current standard, drawing on both evidence-based and exposure-/risk-based considerations (Sections II.F.1 and II.F.2, respectively), and advice from CASAC (Section II.F.3).

A. General Approach

The past and current approaches described below are both based, most fundamentally, on using the EPA's assessment of the current scientific evidence and associated quantitative analyses to inform the Administrator's judgment regarding primary NO

standards that protect public health with an adequate margin of safety. As noted in the PA (U.S. EPA, 2017a, section 1.4), 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 decisions draw 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 PA's approach to informing these judgments, discussed more fully below, is based on the recognition that the available health effects evidence generally reflects a continuum, consisting of higher concentrations at which scientists generally agree that health effects are likely to occur, through lower concentrations at which the likelihood and magnitude of the response become increasingly uncertain. This approach is consistent with the requirements of sections 108 and 109 of the Act and with how the EPA and the courts have historically interpreted the Act. These provisions require the establishment of primary standards that, in the judgment of the Administrator, are requisite to protect public health with an adequate margin of safety. In fulfilling this responsibility, 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.

1. Approach in the Last Review

The last review of the primary NO

NAAQS was completed in 2010 (75 FR 6474, February 9, 2010). In that review, the EPA established a new 1-hour standard to provide increased public health protection, including for people with asthma and other at-risk populations,

against an array of adverse respiratory health effects that had been linked to short-term NO

exposures (75 FR 6498 to 6502; U.S. EPA, 2008a, Sections 3.1.7 and 5.3.2.1; Table 5.3-1). Specifically, the EPA established a short-term standard defined by the 3-year average of the 98th percentile of the annual distribution of daily maximum 1-hour NO

concentrations, with a level of 100 ppb. In addition to setting the new 1-hour standard, the EPA retained the existing annual standard with its level of 53 ppb (75 FR 6502, February 9, 2010). The Administrator in that review concluded that, together, the two standards provide protection against adverse respiratory health effects associated with short-term exposures to NO

and effects potentially associated with long-term exposures. In conjunction with the revised primary NO

NAAQS, the EPA also established a multi-tiered monitoring network composed of (1) near-road monitors which would be placed near heavily trafficked roads in urban areas; (2) monitors located to characterize areas with the highest expected NO

concentrations at the neighborhood and

larger spatial scales (also referred to as “area-wide” monitors); and (3) forty NO

monitors to characterize air quality for susceptible and vulnerable communities, nationwide (75 FR 6505 to 6511). Subsequent to the 2010 rulemaking, the Agency adopted a phased implementation schedule for the near-road monitoring network and removed the requirement for near-road NO

monitoring in CBSAs with population of less than 1 million (78 FR 16184, March 14, 2013; 81 FR 96381, December 30, 2016). Key aspects of the Administrator's approach in the last review to reaching these decisions are described below.

a. Approach to Considering the Need for Revision in the Last Review

The 2010 decision to revise the existing primary NO

standard was based largely on the body of scientific evidence published through early 2008 and assessed in the 2008 ISA (U.S. EPA, 2008a); the quantitative exposure and risk analyses and the assessment of the policy-relevant aspects of the evidence presented in the REA (U.S. EPA, 2008b);

the advice and recommendations of the CASAC (Samet, 2008); and public comments on the proposal.

As discussed in the IRP for this review (U.S. EPA, 2014, Section 1.3), due to changes in the NAAQS process, the last review of the NO

NAAQS did not include a separate PA document. Rather, the REA for that review included a policy assessment chapter.

As an initial consideration in reaching that decision, the Administrator noted that the evidence relating short-term (minutes to weeks) NO

exposures to respiratory morbidity was judged in the ISA to be “sufficient to infer a likely causal relationship” (75 FR 6489, February 9, 2010; U.S. EPA, 2008a, Sections 3.1.7 and 5.3.2.1).

The scientific evidence included controlled human exposure studies providing evidence of increases in airway responsiveness in people with asthma following short-term exposures to NO

concentrations as low as 100 ppb

and epidemiologic studies reporting associations between short-term NO

exposures and respiratory effects in locations that would have met the annual standard.

In contrast, the evidence relating long-term (weeks to years) NO

exposures to health effects was judged to be either “suggestive of but not sufficient to infer a causal relationship” (respiratory morbidity) or “inadequate to infer the presence or absence of a causal relationship” (mortality, cancer, cardiovascular effects, reproductive/developmental effects) (75 FR 6478, February 9, 2010). The causal framework used in the ISA for the current review is discussed in Chapter 3 of the PA (U.S. EPA, 2017a).

Transient increases in airway responsiveness have the potential to increase asthma symptoms and worsen asthma control (74 FR 34415, July 15, 2009; U.S. EPA, 2008a, sections 5.3.2.1 and 5.4).

The quantitative analyses presented in the 2008 REA included exposure and risk estimates for air-quality adjusted to just meet the annual standard. The Administrator took note of the REA conclusion that risks estimated for air quality adjusted upward to simulate just meeting the current standard could reasonably be concluded to be important from a public health perspective, while additionally recognizing the uncertainties associated with adjusting air quality in such analyses (75 FR 6489, February 9, 2010). For air quality adjusted to just meet the existing annual standard, the REA findings given particular attention by the Administrator included the following: “a large percentage (8 to 9%) of respiratory-related [emergency department] visits in Atlanta could be associated with short-term NO

exposures; most people with asthma in Atlanta could be exposed on multiple days per year to NO

concentrations at or above 300 ppb; and most locations evaluated could experience on-/near-road NO

concentrations above 100 ppb on more than half of the days in a given year” (75 FR 6489, February 9, 2010; U.S. EPA, 2008b, Section 10.3.2).

In reaching the conclusion on adequacy of the annual standard alone, the Administrator also considered advice received from the CASAC. In its advice, the CASAC agreed that the primary concern in the review was to protect against health effects that have been associated with short-term NO

exposures. The CASAC also agreed that the annual standard alone was not sufficient to protect public health against the types of exposures that could lead to these health effects. As noted in its letter to the EPA Administrator, “[The] CASAC concurs with EPA's judgment that the current NAAQS does not protect the public's health and that it should be revised” (Samet, 2008, p. 2).

Based on the considerations summarized above, the Administrator concluded that the annual NO

NAAQS alone was not requisite to protect public health with an adequate margin of safety and that the standard should be revised in order to provide increased public health protection against respiratory effects associated with short-term exposures, particularly for at-risk populations and lifestages such as people with asthma, children, and older adults (75 FR 6490, February 9, 2010). Upon consideration of approaches to revising the standard, the Administrator concluded that it was appropriate to set a new short-term standard, in addition to the existing annual standard with its level of 53 ppb, as described below.

b. Approach to Considering the Elements of a Revised Standard in the Last Review

In considering appropriate revisions in the last review, each of the four basic elements of the NAAQS (indicator, averaging time, level, and form) were evaluated. The sections below summarize the approaches used by the Administrator, and her final decisions, on each of those elements.

i. Indicator

In the review completed in 2010, as well as in previous reviews, the EPA focused on NO

as the most appropriate indicator for oxides of nitrogen because the available scientific information regarding health effects was largely indexed by NO

. Controlled human exposure studies and animal toxicological studies provided specific evidence for health effects following exposures to NO

. In addition, epidemiologic studies typically reported effects associated with NO

concentrations

(75 FR 6490, February 9, 2010; U.S. EPA 2008a, Section 2.2.3). Based on the information available in the last review, and consistent with the views of the CASAC (Samet, 2008, p. 2; Samet, 2009, p. 2), the EPA concluded it was appropriate to continue to use NO

as the indicator for a standard that was intended to address effects associated with exposure to NO

, alone or in combination with other gaseous oxides of nitrogen. In so doing, the EPA recognized that measures leading to reductions in population exposures to NO

will also reduce exposures to other oxides of nitrogen (75 FR 6490, February 9, 2010).

The degree to which monitored NO

reflected actual NO

concentrations, as opposed to NO

plus other gaseous oxides of nitrogen, was recognized as an uncertainty (75 FR 6490, February, 9, 2010; U.S. EPA 2008b, section 2.2.3).

ii. Averaging Time

In considering the most appropriate averaging time(s) for the primary NO

NAAQS, the Administrator noted the available scientific evidence as assessed in the ISA, the air quality analyses presented in the REA, the conclusions of the policy assessment chapter of the REA, and recommendations from the CASAC.

Her key considerations are summarized below.

She also considered public comments received on the proposal (75 FR 6490, February, 9, 2010).

When considering averaging time, the Administrator first noted that the evidence relating short-term (minutes to weeks) NO

exposures to respiratory

morbidity was judged in the ISA to be “sufficient to infer a likely causal relationship” (U.S. EPA, 2008a, section 5.3.2.1). The Administrator concluded that this strength of evidence most directly supported consideration of an averaging time that focused protection on effects associated with short-term exposures to NO

. In considering the level of support available for specific short-term averaging times, the Administrator noted that the policy assessment chapter of the REA considered evidence from both experimental and epidemiologic studies. Controlled human exposure studies and animal toxicological studies provided evidence that NO

exposures from less than 1 hour up to 3 hours can result in respiratory effects such as increased AR and inflammation (U.S. EPA, 2008a, Section 5.3.2.7). The Administrator specifically noted the ISA conclusion that exposures of adults with asthma to 100 ppb NO

for 1-hour (or 200 to 300 ppb for 30 minutes) can result in small but statistically significant increases in nonspecific AR (U.S. EPA, 2008a, Section 5.3.2.1). In addition, the epidemiologic evidence provided support for short-term averaging times ranging from approximately 1 hour up to 24 hours (U.S. EPA, 2008a, Section 5.3.2.7). Based on this, the Administrator concluded that a primary concern with regard to averaging time is the degree of protection provided against effects associated with 1-hour NO

concentrations. Based on REA analyses of ratios between 1-hour and 24-hour NO

concentrations (U.S. EPA, 2008b, Section 10.4.2), she further concluded that a standard based on 1-hour daily maximum NO

concentrations could also be effective at protecting against effects associated with 24-hour NO

exposures (75 FR 6490).

Based on the above, the Administrator judged that it was appropriate to set a new NO

standard with a 1-hour averaging time. She concluded that such a standard would be expected to effectively limit short-term (

e.g.,

1- to 24-hours) exposures that have been linked to adverse respiratory effects. She also retained the existing annual standard to continue to provide protection against effects potentially associated with long-term exposures to oxides of nitrogen (75 FR 6502, February 9, 2010). These decisions were consistent with CASAC advice to establish a short-term primary standard for oxides of nitrogen based on using 1-hour maximum NO

concentrations and to retain the current annual standard (Samet, 2008, p. 2; Samet, 2009, p. 2).

iii. Level

With consideration of the available health effects evidence, exposure and risk analyses, and air quality information, the Administrator set the level of the new 1-hour NO

standard at 100 ppb. This standard was focused on limiting the

maximum

1-hour NO

concentrations in ambient air (75 FR 6474, February 9, 2010).

In establishing this new standard, the Administrator emphasized the importance of protecting against short-term exposures to peak concentrations of NO

such as those that can occur around major roadways. Available evidence and information suggested that roadways account for the majority of exposures to peak NO

concentrations and, therefore, are important contributors to NO

-associated public health risks (U.S. EPA, 2008b, Figures 8-17 and 8-18).

In conjunction with this new standard, the Administrator established a multi-tiered monitoring network that included monitors sited to measure the maximum NO

concentrations near major roadways, as well as monitors sited to measure maximum area-wide NO

concentrations and for the characterization of NO

exposure for susceptible and vulnerable populations.

In setting the level of the new 1-hour standard at 100 ppb, the Administrator noted that there is no bright line clearly directing the choice of level. Rather, the choice of what is appropriate is largely a public health policy judgment entrusted to the Administrator. This judgment must include consideration of the strengths and limitations of the evidence and the appropriate inferences to be drawn from the evidence and the exposure and risk assessments.

The Administrator judged that the existing evidence from controlled human exposure studies supported the conclusion that the NO

-induced increase in AR at or above 100 ppb presented a potential risk of adverse effects for some people with asthma, especially those with more serious (

i.e.,

more than mild) asthma. The Administrator noted that the risks associated with increased AR could not be fully characterized based on available controlled human exposure studies. However, the Administrator concluded that people with asthma, particularly those suffering from more severe asthma, warrant protection from the risk of adverse effects associated with the NO

-induced increase in AR. Therefore, the Administrator concluded that the controlled human exposure evidence supported setting a standard level no higher than 100 ppb to reflect a cautious approach to the uncertainty regarding the adversity of the effect. However, those uncertainties led her to also conclude that this evidence did not support setting a standard level lower than 100 ppb (75 FR 6500-6501, February 9, 2010).

The Administrator also considered the more serious health effects reported in NO

epidemiologic studies. She noted that a new standard focused on protecting against maximum 1-hour NO

concentrations in ambient air anywhere in an area, with a level of 100 ppb and an appropriate form (as discussed below), would be expected to limit area-wide

concentrations to below 85 ppb, which was the lowest 98th percentile 1-hour daily maximum NO

concentration in the cluster of five key epidemiologic studies which reported associations with respiratory-related hospital admissions or emergency department visits and which the Administrator gave substantial weight. The Administrator also concluded that such a 1-hour standard would be consistent with the REA conclusions based on the NO

exposure and risk information (75 FR 6501, February 9, 2010).

Area-wide concentrations refer to those measured by monitors that have been sited to characterize ambient concentrations at the neighborhood and larger spatial scales.

Given the above considerations and the comments received on the proposal, and considering the entire body of evidence and information before her, as well as the related uncertainties, the Administrator judged it appropriate to set a 1-hour standard with a level of 100 ppb. Specifically, she concluded that such a standard, with an appropriate form as discussed below, would provide a substantial increase in public health protection compared to that provided by the annual standard alone and would be expected to protect against the respiratory effects that have been linked with NO

exposures in both controlled human exposure and epidemiologic studies. This includes limiting exposures at and above 100 ppb for the vast majority of people, including those in at-risk groups, and maintaining maximum area-wide NO

concentrations below those in locations where key U.S. epidemiologic studies had reported that ambient NO

was associated with clearly adverse respiratory health effects, as indicated by increased hospital admissions and emergency department visits. The Administrator also noted that a standard level of 100 ppb was consistent with the consensus recommendation of the CASAC. (75 FR 6501, February 9, 2010).

In setting the standard level at 100 ppb rather than at a lower level, the Administrator also acknowledged the

uncertainties associated with the scientific evidence. She noted that a 1-hour standard with a level lower than 100 ppb would only result in significant further public health protection if, in fact, there is a continuum of serious, adverse health risks caused by exposure to NO

concentrations below 100 ppb and/or associated with area-wide NO

concentrations well below those in locations where key U.S. epidemiologic studies had reported associations with respiratory-related emergency department visits and hospital admissions. Based on the available evidence, the Administrator did not believe that such assumptions were warranted. Taking into account the uncertainties that remained in interpreting the evidence from available controlled human exposure and epidemiologic studies, the Administrator observed that the likelihood of obtaining benefits to public health with a standard set below 100 ppb decreased, while the likelihood of requiring reductions in ambient concentrations that go beyond those that are needed to protect public health increased. (75 FR 6501-02, February 9, 2010).

iv. Form

The “form” of a standard defines the air quality statistic that is to be compared to the level of the standard in determining whether an area attains the standard. The Administrator recognized that for short-term standards, concentration-based forms that reflect consideration of a statistical characterization of an entire distribution of air quality data, with a focus on a single statistical metric such as the 98th or 99th percentile, can better reflect pollutant-associated health risks than forms based on expected exceedances. This is the case because concentration-based forms give proportionally greater weight to days when pollutant concentrations are well above the level of the standard than to days when the concentrations are just above the level of the standard.

In addition, she recognized that it is desirable from a public health perspective to have a form that is reasonably stable and insulated from the impacts of extreme meteorological events, and concluded that when averaged over three years, these concentration-based forms provide an appropriate balance between limiting peak pollutant concentrations and providing a stable regulatory target (75 FR 6492, February 9, 2010).

Compared to an exceedance-based form, a concentration-based form reflects the magnitude of the exceedance of a standard level not just the fact that such an exceedance occurred.

In the last review, the EPA considered two specific concentration-based forms (

i.e.,

the 98th and 99th percentile concentrations), averaged over 3 years, for the new 1-hour NO

standard. The focus on the upper percentiles of the distribution was based, in part, on evidence of health effects associated with short-term NO

exposures from experimental studies which provided information on specific exposure concentrations that were linked to respiratory effects. In a letter to the Administrator following issuance of the Agency's proposed rule, the CASAC recommended a form based on the 3-year average of the 98th percentile of the distribution of 1-hour daily maximum NO

concentrations (Samet, 2009, p. 2). In making this recommendation, the CASAC noted the potential for instability in the higher percentile concentrations and the absence of data from the near-road monitoring network, which at that time had been proposed but was not yet established.

Given the limited available information on the variability in peak NO

concentrations near important sources of NO

, primarily near major roadways, and given the recommendation from the CASAC regarding the potential for instability in the 99th percentile concentrations, the Administrator judged it appropriate to set the form based on the 3-year average of the 98th percentile of the annual distribution of daily maximum 1-hour NO

concentrations. In addition, consistent with the CASAC's advice (Samet, 2008, p. 2; Samet, 2009, p. 2), the EPA retained the form of the annual standard (75 FR 6502, February 9, 2010).

c. Areas of Uncertainty in Last Review

While the available scientific information informing the last review was stronger and more consistent than in previous reviews and provided a strong basis for decision making in that review, the Agency recognized that areas of uncertainty remained. These were generally related to the following: (1) Understanding the role of NO

in the complex ambient mixture which includes a range of co-occurring pollutants (

e.g.,

fine particulate matter (PM

2.5

carbon monoxide (CO), and other traffic-related pollutants; ozone (O

); and sulfur dioxide (SO

)) (

e.g.,

75 FR 6485 February 9, 2010); (2) understanding the extent to which monitored ambient NO

concentrations used in epidemiologic studies reflect exposures in study populations and the range of ambient concentrations over which the evidence indicates confidence in the health effects observed in the epidemiologic studies (

e.g.,

75 FR 6501, February 9, 2010); (3) understanding the magnitude and potential adversity of NO

-induced respiratory effects reported in controlled human exposure studies (

e.g.,

75 FR 6500, February 9, 2010); and (4) understanding the NO

concentration gradients around important sources, such as major roads, and relating those gradients to broader ambient monitoring concentrations (

e.g.,

75 FR 6479, February 9, 2010).

In general terms, particulate matter with a nominal mean aerodynamic diameter less than or equal to 2.5 μm; a measurement of fine particles. In regulatory terms, particles with an upper 50% cut -point of 2.5 μm aerodynamic diameter (the 50% cut point diameter is the diameter at which the sampler collects 50% of the particles and rejects 50% of the particles) and a penetration curve as measured by a reference method based on Appendix L of 40 CFR part 50 and designated in accordance with 40 CFR part 53, by an equivalent method designated in accordance with 40 CFR part 53, or by an approved regional method designated in accordance with Appendix C of 40 CFR part 58.

2. Approach for the Current Review

The approach in this review of the primary NO

NAAQS takes into consideration the approach used in the last review, and addresses key policy-relevant questions in light of the currently available scientific and technical information. 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 that builds upon the general approach used in the last review and reflects the body of evidence and information now available. As summarized above, the decisions in the last review were based on the integration of NO

health effects information with judgments on the adversity and public health significance of key health effects, policy judgments as to when the standard is requisite to protect public health with an adequate margin of safety, consideration of CASAC advice, and consideration of public comments.

In the current review, the EPA's approach recognizes that the available health effects evidence reflects a continuum from relatively higher NO

concentrations, at which scientists generally agree that health effects are likely to occur, through lower concentrations, at which the likelihood and magnitude of a response become increasingly uncertain. In reaching a final decision on the current primary NO

standards, the Administrator will draw upon the available scientific

evidence for NO

-attributable health effects and upon information from available quantitative analyses, including judgments about the appropriate weight to assign the range of uncertainties inherent in the evidence and analyses. The Administrator will also consider advice from CASAC and public comments received in response to this proposed decision.

The final decision on the primary NO

standards is largely a public health policy judgment to be made by the EPA Administrator. The weight to be given to various elements of the evidence and the available quantitative analyses is part of the public health policy judgments that the Administrator will make in reaching decisions on the standards.

To inform the Administrator's judgments and decisions, the PA presents evidence-based and exposure/risk-based considerations. Evidence-based considerations focus on the findings of epidemiologic studies, controlled human exposure studies, and experimental animal studies evaluating health effects related to NO

exposures. The PA's consideration of such studies draws from the assessment of the evidence presented in the ISA (U.S. EPA, 2016a). Exposure/risk-based considerations draw upon the results of the PA's quantitative analyses of potential NO

exposures. The PA's consideration of the evidence and quantitative information is framed by a series of key policy-relevant questions (U.S. EPA, 2017a, Figure 1-1). These questions focus on the strength of the evidence for various NO

-related health effects and for potential at-risk populations, the NO

exposure concentrations at which adverse effects occur, the potential for NO

exposures and health effects of public health concern with NO

concentrations that meet the current standards, and uncertainties in the available evidence and information. The PA's consideration of these issues is intended to inform the Administrator's decisions as to whether, and if so how, to revise the current NO

standards. These considerations are discussed below (II.C to II.F).

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

It presents a summary of NO

atmospheric chemistry (II.B.1), trends in ambient NO

concentrations (II.B.2), ambient NO

concentrations measured at monitors near roads (II.B.3), the relationships between hourly and annual ambient NO

concentrations (II.B.4), and background concentrations of NO

(II.B.5).

The focus is on NO

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

1. Atmospheric Chemistry

Ambient concentrations of NO

are influenced by both direct NO

emissions and by emissions of nitric oxide (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.

27 28

This follows usages in the Clean Air Act Section 108(c): “Such criteria [for oxides of nitrogen] shall include a discussion of nitric and nitrous acids, nitrites, nitrates, nitrosamines, and other carcinogenic and potentially carcinogenic derivatives of oxides of nitrogen.” By contrast, within 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.

2. 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, 2017, 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, 2017, 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 ISA (U.S. EPA, 2016a, Section 2.5.6) and the PA (U.S. EPA, 2017, 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 whether specific sources may be responsible for these upward trends in ambient NO

concentrations. As discussed in the PA (U.S. EPA, 2017a, Section 2.1.2), since 1980 increases in NO

emissions have been observed for several types of sources, including oil and gas production, agricultural field burning, prescribed fires and mining. Though relatively small contributors nationally, emissions from these sources can be substantial in some areas (

e.g.,

see U.S. EPA, 2016a, Section 2.3.5).

3. 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 further 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 2010 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.

4. 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). When considering the change in NO

DVs since the 1980s, the median annual 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 and data from the new near-road monitoring network were not included in the analysis 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 indicate that 1-hour DVs at or below 100 ppb generally correspond to annual DVs below 35 ppb (U.S. EPA, 2017a p.2-21). Based on this, 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 reevaluate this relationship as more data become available from recently deployed near-road monitors.

As noted above (II.A.1), area-wide sites are intended to characterize ambient NO

concentrations at the neighborhood and larger spatial scales.

C. Health Effects Information

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 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 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, 2015, 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.

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.

With regard to characterization of the health effects evidence, the ISA uses a five-level hierarchy to classify the overall weight of evidence into one of the following categories: causal relationship; likely to be a causal relationship; suggestive of, 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, 2015, Preamble Table II). The PA considers the full body of health evidence addressed in the ISA, placing the greatest emphasis on the effects for which the evidence has been judged in the ISA to demonstrate a “causal” or a “likely to be a causal” relationship with NO

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

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 a 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.

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

Section II.C.1 summarizes the evidence for effects related to short-term NO

exposures (

e.g.,

minutes to weeks). Section II.C.2 summarizes the evidence for effects related to long-term NO

exposures (

e.g.,

months to years). Section II.C.3 discusses the potential public health implications of NO

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

-related effects.

1. Health Effects With Short-Term Exposure to NO

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

exposures. Section II.C.1.a 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 ISA. Section II.C.1.b discusses the NO

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

When considering the NO

concentrations at which health effects have been demonstrated to occur, the EPA places the greatest emphasis on evidence supporting health endpoints that the ISA has determined to have a “causal” or “likely to be a causal” relationship with NO

exposure.

a. 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 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 emergency department (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 ISA noted an overarching uncertainty in determining the extent to which NO

is independently associated with effects or if 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 critically evaluated in the 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).

In considering the available evidence and the causal determinations presented in the ISA, consistent with the PA (U.S. EPA, 2017a), this proposal focuses on respiratory effects (II.C.1.a.i), cardiovascular effects (II.C.1.a.ii), and mortality (II.C.1.a.iii).

A list of the causal determinations from the 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).

i. Respiratory Effects

The 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 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 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 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 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 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 current reviews of the primary NO

NAAQS, and the 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 ISA states that airway responsiveness is “inherent responsiveness of the airways to challenge by bronchoconstricting agents” (U.S. EPA, 2016a, p. 5-9). More specifically, 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-analyses 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. (Brown, 2015).

More information on the distribution of study subjects across NO

concentrations can be found below (II.C.1.b.i). Information on the fraction of individuals who experienced an increase versus a decrease stratified by concentration can also be found in this 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 cases of the disease. These controlled human exposure studies, the meta-analysis, and uncertainties in this body of evidence are discussed in greater detail below (II.C.1.b.i).

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

47 48

With regard to this approach, the 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 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 airway responsiveness 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 ISA to represent an increase in AR that indicates a clinically relevant response.

Based on a subset of the controlled human exposure studies considered in the ISA, Brown (2015) shows 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) for 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 this analysis is limited to a small subset of the studies included in the broader Brown et al. (2015) meta-analysis and given the lack of an apparent dose-response relationship.

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 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 ISA also describes consistent 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 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 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 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 poorly studied, but NO

associations

with asthma exacerbation tend to persist in the few available copollutant models. The ISA recognizes, however, that copollutant models have inherent limitations and cannot conclusively rule out confounding (U.S. EPA, 2015, Preamble, Section 4.b).

The 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 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 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 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 understanding of 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).

ii. Cardiovascular Effects

The evidence for cardiovascular health effects and short-term NO

exposures in the 2016 ISA was judged “suggestive of, but not sufficient to infer, a causal relationship” (U.S. EPA, 2016a, Section 5.3.11), which is stronger than the conclusion in the last review that the evidence was “inadequate to infer the presence or absence of a causal relationship.” The more recent causal determination was primarily supported by consistent epidemiologic evidence from multiple new studies indicating associations for triggering of a myocardial infarction. However, further evaluation and integration of evidence points to uncertainty related to exposure measurement error and potential confounding by traffic-related pollutants. There is consistent evidence demonstrating NO

-associated hospital admissions and ED visits for ischemic heart disease, myocardial infarction, and angina as well as all cardiovascular diseases combined, which is coherent with evidence from other studies indicating NO

-associated repolarization abnormalities and cardiovascular mortality. There are experimental studies that provide some evidence for effects on key events in the proposed mode of action (

e.g.,

systemic inflammation), but these studies do not provide evidence that is sufficiently coherent with the epidemiologic studies to help rule out chance, confounding, and other biases. In particular, the ISA concludes that “[t]here continues to be a lack of experimental evidence that is coherent with the epidemiologic studies to strengthen the inference of causality for NO

-related cardiovascular effects, including [myocardial infarction]” (U.S. EPA, 2016a, p. 5-335). Beyond evidence for myocardial infarction, there were studies examining other cardiovascular health effects, but results across these outcomes are inconsistent. Thus, while the evidence is stronger in the current review than in the last review, important uncertainties remain regarding the independent effects of NO

iii. Mortality

The ISA concludes that the evidence for 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). Several recent multicity studies add to the evidence base for the current review and demonstrate associations that are robust in copollutant models with PM

, O

, or SO

. However, confounding by traffic-related copollutants, which is of greatest concern, is not examined in the available copollutant models for NO

-associated mortality. Overall, the recent evidence assessed in the ISA builds upon and supports conclusions in the last review, but key limitations across the evidence include a lack of biological plausibility as experimental studies and epidemiologic studies on cardiovascular morbidity, a major cause of mortality, do not clearly provide a mechanism by which NO

-related effects could lead to mortality. In addition, important uncertainties remain regarding the independent effect of NO

(

i.e.,

independent of other traffic-related pollutants).

b. 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 strongest evidence supporting a causal relationship, as discussed 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 adverse 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 meeting existing standards. These considerations are discussed below for controlled human exposure studies (II.C.1.b.i) and epidemiologic studies (II.C.1.b.ii).

i. 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, 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 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 make it difficult to interpret the likelihood that these effects could potentially occur following NO

exposures at or below the level of the current standard.

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

-induced increases 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, and have the advantage of being based on the same exposure conditions. The meta-analysis by Brown (2015) aids in identifying trends in individual-level responses across studies and has the advantage of increased power to detect effects, even in the absence of statistically significant effects in individual studies.

Tables 3-2 and 3-3 in the NO

PA (adapted from the 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 provocative dose (PD; 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

In first considering controlled human exposure studies conducted at rest, 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. 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 results were not statistically significant (n=4; Orehek et al., 1976). Thus, 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 next considering studies in individuals with asthma conducted with exercise, 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 significant results. Only one of four studies with exercising exposures of 400 or 600 ppb reported statistically significant increases in airway responsiveness.

Consideration of Results From the Meta-Analysis

As discussed above, the 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 air exposure.

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 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)), contributing to the ISA's emphasis on studies of resting exposures and non-specific challenge agents. Overall, the 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).

The meta-analysis combined information from the studies presented in Tables 3-2 and 3-3 of the PA.

Brown et al. (2015) 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, first the PA considers results across all exposure conditions (

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 different than 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 (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 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 fractions 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 exposures concentrations evaluated (

<0.05).

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%, 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 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.

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

exposures.

Forty-eight percent 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 cases 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, 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 500 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; however, the lack of a dose-response relationship does not necessarily indicate that there is no relationship between the exposure and effect, particularly in these analyses based on between-subject comparisons (

i.e.,

as opposed to comparisons within the same subject exposed to multiple concentrations). As discussed in the ISA, there are a number of methodological differences across studies that could contribute to between-subject differences and that could obscure a dose-response relationship between NO

and AR. 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, it does not necessarily indicate the lack of an NO

effect.

An additional uncertainty in interpreting these studies within the context of considering the adequacy of the protection provided by the 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 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.D below.

Five studies provided data for each individual's provocative dose. 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 provocative dose (indicating increased AR) while 8% showed a doubling of the provocative dose (indicating decreased AR). The relative distributions of the provocative doses 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 small subset of studies and given the lack of an apparent dose-response relationship. 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 a 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.

ii. 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 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 standard, 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 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 over which the evidence indicates the most confidence in 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 is 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 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 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 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.

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), 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 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 I.B.2., 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 design value 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 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.B.3).

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 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 multi-city studies tend to have greater power to detect associations. The one multi-city 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% confidence intervals), 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

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 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 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).

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, 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 not statistically significant and imprecise, 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.

2. Health Effects With Long-Term Exposure to NO

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

exposures. Section II.C.2.a 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 ISA. Section II.C.2.b discusses the NO

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

a. 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, 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 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 (II.C.2.a.i), cardiovascular effects and diabetes (II.C.2.a.ii), reproductive and developmental effects (II.C.2.a. iii), premature mortality (II.C.2.a.iv), and cancer (II.C.2.a.v).

i. Respiratory Effects

The 2016 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 notice 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 a causal relationship” in the current review represents a change from 2008 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, 2016 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 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 (LUR) models with good NO

prediction in some studies.

While the causal determination has been strengthened in this review,

important uncertainties remain. For example, the 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 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 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 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 (FEV1) -0.98 (-1.70, -0.26), (FVC) -2.14 (-4.20, -0.04), (PEF) -1.04 (-1.94, -0.13).

While this uncertainty continues to apply to the epidemiologic evidence for asthma incidence in children, the ISA describes 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 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 provide 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.

Overall, the 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 and mode of action, 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.

ii. Cardiovascular Effects and Diabetes

In the previous review, the 2008 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 ISA judged the evidence to be

“suggestive, but not sufficient to infer” a causal relationship (U.S. EPA, 2016a, Section 6.3). The strongest evidence comes from recent epidemiologic studies reporting positive associations of NO

with heart disease and diabetes with improved exposure assessment (

i.e.,

residential estimates from models that well predict NO

concentrations in the study areas), but the evidence across experimental studies remains limited and inconsistent and does not provide sufficient biological plausibility for effects observed in epidemiologic studies. Specifically, the ISA concludes that “[e]pidemiologic studies have not adequately accounted for confounding by PM

2.5

, noise, or traffic-related copollutants, and there is limited coherence and biological plausibility for NO

-related development of heart disease” (U.S. EPA, 2016a, p. 6-98) or “for NO

-related development of diabetes” (U.S. EPA, 2016a, p. 6-99). Thus, substantial uncertainty exists regarding the independent effect of NO

and the total evidence is “suggestive of, but not sufficient to infer, a causal relationship” between long-term NO

exposure and cardiovascular effects and diabetes (U.S. EPA, 2016a, Section 6.3.9).

iii. 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 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 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 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. Evidence for effects on fertility, reproduction, and pregnancy and for effects on postnatal development is inconsistent across both epidemiologic and toxicological studies. Additionally, there are few toxicological studies available. The ISA concludes the change in the causal determination for birth outcomes reflects the large number of studies that generally observed associations with fetal growth restriction and the improved outcome assessment

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