# Plan for Review of the National Ambient Air Quality Standards for Carbon Monoxide

August 2008EPA-452/R-08-005 August 2008



# Plan for Review of the National Ambient Air Quality Standards for Carbon Monoxide

U. S. Environmental Protection Agency
National Center for Environmental Assessment Office of Research and Development and Office of Air Quality Planning and Standards Office of Air and Radiation
Research Triangle Park, North Carolina 2771ii 

### DISCLAIMER

This integrated review plan serves as a pub lic information document and as a management
tool for the U.S. Environmental Protection Agency's National Center for Environmental Assessment and the Office of Air Quality Planning and Standards in conducting the review of the national ambient air quality standards for carbon monoxide. The approach described in this plan may be modified to reflect changes in th e court-ordered schedule or information developed during this review, including a dvice and comments received from the Clean Air Scientific Advisory Committee and the public. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.iii 

### TABLE OF CONTENTS

1. INTRODUCTION .............................................................................................................. 1- 1 1.1 OVERVIEW OF THE RE VIEW PROCESS ......................................................... 1-1 1.2 LEGISLATIVE REQUIREMENTS....................................................................... 1-3 1.3 HISTORY OF REVIEW S OF THE NAAQS FOR CO.......................................... 1-5 1.4 SCOPE OF THE REVIEW................................................................1-6

2. REVIEW SCHEDULE ....................................................................................................... 2-1

3. KEY POLICY-RELEVANT ISSUES ................................................................................ 3-1 3.1 ISSUES TO BE CONSIDERED IN THE CURRENT REVIEW OF THE PRIMARY NAAQS............................................................................................... 3-1 3.2 ISSUES TO BE CONSIDERED IN THE CURRENT REVIEW OF A POSSIBLE SECONDARY NAAQS ........................................................................................ 3-3

4. SCIENCE ASSESSMENT ................................................................................................. 4-1 4.1 SCOPE AND ORGANIZATION........................................................................... 4-1 4.2 ASSESSMENT APPROACH................................................................................. 4-2 4.3 SCIENTIFIC AND PUBLIC REVIEW................................................................. 4-17

5. RISK/EXPOSURE ASSESSMENT ................................................................................... 5-1 5.1 SCOPE AND ORGANIZATION........................................................................... 5-1 5.2 HISTORICAL PERSPECTIVE.............................................................................. 5-1 5.3 EXPOSURE ASSESSMENT APPROACH........................................................... 5-5 5.4 RISK ASSESSMENT APPROACH ...................................................................... 5-7 5.5 ASSESSMENT CRITERIA.................................................................................... 5-9 5.6 UNCERTAINTY AND VARIABILITY................................................................5-10 5.7 PUBLIC AND SCIENTIFIC REVIEW .................................................................5-11

6. POLICY ASSESSMENT/RULEMAKING........................................................................ 6-1

7. REFERENCES .................................................................................................................. . 7-11-1 

## 1. INTRODUCTION

The U.S. Environmental Protection Agency (EPA) is conducting a review of the air quality criteria for carbon m onoxide (CO) and the national ambient air quality standards (NAAQS) for carbon monoxide (CO). The purpose of this document is to communicate the plan
for this review. 1 This review will provide an integrative assessm ent of relevant scientific information for
CO and will focus on the basic elements of the st andards: the indicator, averaging time, form, and level. These elements, which serve to defi ne each ambient air quality standard, must be considered collectively in evaluating the degree of protection afforded by the standard. The existing primary CO standards include a 1-hour sta ndard set at 35 parts per million (ppm), and an 8-hour standard set at 9 ppm, neither to be exceed ed more than once per year. There is currently no secondary standard for CO. This review plan is organized into si x chapters. Chapter 1 presents background information on the review process, the legisla tive requirements for the review of the NAAQS, and past reviews of the NAAQS for CO. Chapter 2 presents the current review schedule. Chapter 3 presents a set of policy-relevant questi ons that will serve to focus this review on the
critical scientific a nd policy issues. Chapters 4 thr ough 6 discuss the planned scope and organization of the key assessment documents, the planned approaches for preparing the documents, and plans for scientific a nd public review of the documents.

1.1 OVERVIEW OF THE REVIEW PROCESS The Agency has recently decided to make a number of changes to the process for reviewing the NAAQS (described at http://www.epa.gov/ttn/naaqs/ ) . This new process, which is being applied to the curren t review of the NAAQS for CO, contains four ma jor components: an integrated review plan, a sc ience assessment, a risk/expos ure assessment, and a policy assessment/rulemaking. Each of these co mponents is described in this section.

1 This plan will generally refer to the review of th e primary standards for CO because there is currently no secondary NAAQS for CO to review. However, the scope of EPA's review will include consideration of whether, based on the revised air quality criteria for CO, it is appropriate to propose a new secondary standard.1-2 The review process starts with the developmen t of an integrated review plan prepared jointly by EPA’s National Center for Environmental Assessment (NCEA), within the Office of Research and Development (ORD), and EPA’s Office of Air Quality Planning and Standards (OAQPS), within the Office of Ai r and Radiation (OAR). This document represents the current plan and specifies the schedule fo r the entire review, the proce ss for conducting the review, and the key policy-relevant science issu es that will guide the review. The second component of the review pro cess is the developm ent of the science assessment, which consists of an Integrated Sc ience Assessment (ISA) and supporting annexes.
NCEA collaborates with contracted expert support to prepare thes e documents. The annexes will contain a comprehensive descrip tion of the full breadth of the current scientific literature pertaining to known and anticipated effects on public health and we lfare associated with CO in the ambient air, emphasizing the information that has become available since the last review in order to reflect the current state of knowledge. The annexes also provide in-depth treatment of specific topics supporting interpre tation of health and welfare effects. NCEA will critically evaluate, integrate, and synthesi ze the most policy-relevant science into an ISA. The ISA is intended to provide information useful in form ing judgments about air quality indicator(s), form(s), averaging time(s) and level(s) for the CO NAAQS. Hence, the ISA and its associated annexes function in the new NAAQS review as the Air Quality Cr iteria Document (AQCD) did in previous reviews. The sche dule includes production of a firs t and second draft ISA, both of which will undergo CASAC and public review prior to completion of the final ISA. Section 4 provides a more detailed description of the pl anned scope, organization and assessment approach
for the annexes and ISA. In the third component of the revised review process, the risk/exposure assessment, EPA’s Office of Air Quality Planning and Standards (OAQPS) plans to draw upon the information presented in the ISA to develop quantitative or qu alitative estimates of th e exposures and risks of
adverse health effects associated with current ambien t levels of CO, with levels that just meet the current standards, and with levels that just meet possible alternative standa rds. Section 5 of this integrated plan contains more detail about possible approaches EPA could take in conducting the
human health assessments. Once the first draft IS A is complete, EPA will release a draft Scope
and Methods Plan for human health assessments that CASAC and the public will review. The Scope and Methods Plan will describe the planned scope of the analyses to be performed and the1-3 tools/methods that may be employed. Comments on the draft Scope and Methods Plan will be considered as EPA performs the actual analyses . The schedule includes production of first and second draft risk/exposure assessments, all of which will undergo CASAC and public review prior to completion of the final risk/exposure as sessment reports that will focus on key results, observations, and uncertainties. The fourth component of the revised pro cess will be a policy assessment/rulemaking. Under the new process, a staff paper, such as th at prepared in previous NAAQS reviews, will not be prepared. Rather, Agency views on policy opti ons will be published in the Federal Register as part of a notice of proposed action, to be followed by a public comment period. 2 Considering comments received on the proposed action, the Agency will issue a final decision to complete the
review.

1.2 LEGISLATIVE REQUIREMENTS Two sections of the Clean Air Act (CAA) gove rn the establishment and revision of the NAAQS. Section 108 (42 U.S.C. 7408) directs the Administrato r to identify and list air pollutants that “in his judgment, cause or contribute to air poll ution which may reasonably be anticipated to endanger public he alth and welfare” and whose “pre sence . . . in the ambient air
results from numerous or diverse mobile or statio nary sources” and to i ssue air quality criteria for those that are listed. Air quality criteria are in tended to “accurately reflect the latest scientific knowledge useful in indicating the kind and extent of identifiable effects on public health or welfare which may be expected from the presen ce of [a] pollutant in ambient air . . . .” Section 109 (42 U.S.C. 7409) directs the Administrator to propose and promulgate “primary” and “secondary” NAAQS for pollutants li sted under section 10 8. 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 allowi ng an adequate margin of safety, are requisite to protect the public health.” 3 A secondary standard, as define d in section 109(b)(2), must “specify a level of air quality the attainment and maintenance of which, in the judgment of the

2 In addition, EPA is considering whether, and at what point in the process, to issue an Advance Notice of Proposed Rulemaking prior to the proposal notice.

3 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 that1-4 Administrator, based on such crit eria, is requisite to protect the public welfare from any known or anticipated adverse effects asso ciated with the presence of [the ] pollutant in the ambient air.” 4 The requirement that primary standards incl ude an adequate margin of safety was
intended to address uncertainties associated with inconclusive scientific and technical
information available at the time of standard set ting. It was also intende d to provide a reasonable degree of protection against hazards that research has not yet identified. See Lead Industries
Association v. EPA , 647 F.2d 1130, 1154 (D.C. Cir 1980), cert. denied , 449 U.S. 1042 (1980);
American Petroleum Institute v. Costle , 665 F.2d 1176, 1186 (D.C. Cir. 1981), cert. denied , 455 U.S. 1034 (1982). Both kinds of uncertainties are components of the risk associated with pollution at levels below those at which human health effects can be said to occur with reasonable scientific certainty. Thus, in select ing primary standards that include an adequate margin of safety, the Administrator is seeking no t only to prevent pollution levels that have been demonstrated to be harmful but also to prev ent lower pollutant levels that may pose an unacceptable risk of harm, even if the risk is not precisely identified as to nature or degree. In selecting a margin of safety, the EPA consid ers such factors as th e nature and severity of the health effects involved, th e size of sensitive population(s) at risk, and the kind and degree
of the uncertainties that must be addressed. The selection of any pa rticular approach to providing an adequate margin of safety is a policy choice left specifically to the Administrator’s judgment. See Lead Industries Association v. EPA , 647 F.2d at 1161-62. In setting standards that are “requisite” to pr otect public health and we lfare, as provided in section 109(b), EPA’s task is to establish standard s that are neither more nor less stringent than necessary for these purposes. In so doing, EPA may not consider the costs of implementing the standards. See generally, Whitman v. American Trucking Associations , 531 U.S. 457, 465-472, 475-76 (2001). Section 109(d)(1) requires that “not later than Decemb er 31, 1980, and at 5-year intervals thereafter, the Admini strator shall complete a thor ough review of the criteria

for this purpose “reference should be made to a repres entative sample of persons comprising the sensitive group rather than to a single person in such a group” S. Rep. No. 91-1196, 91 st Cong., 2d Sess. 10 (1970).

4 Welfare effects as defined in section 302(h) (42 U.S.C. § 7602(h)) include, but are not limited to, “effects on soils, water, crops, vegetation, man-made materials, anim als, wildlife, weather, visibility and climate, damage to and deterioration of property, and hazards to transportation, as well as ef fects on economic values and on personal comfort and well-being.”1-5 published under section 108 and th e national ambient air quality st andards . . . and shall make
such revisions in such criteri a and standards and promulgate such new standards as may be appropriate . . . .” Section 109(d)(2) requires th at an independent scie ntific review committee “shall complete a review of th e criteria . . . and the national primary and secondary ambient air quality standards . . . and sha ll recommend to the Administrato r any new . . . standards and revisions of existing criteria and standards as ma y be appropriate . . . .” Since the early 1980's, this independent review function has been pe rformed by the Clean Air Scientific Advisory Committee (CASAC) of EPA’s Science Advisory Board. 5



### 1.3 HISTORY OF REVIEWS OF THE NAAQS FOR CO On April 30, 1971, EPA promulgated identi cal primary and secondary NAAQS for CO, under section 109 of the Act, set at 9 parts per million (ppm), 8-hour average and 35 ppm, 1-hour average, neither to be exceeded more than once per year (36 FR 8186). In 1979, EPA published Air Quality Criteria Document for Carbon Monoxide (AQCD) (US EPA, 1979a), which updated the scientific criteria upon which the initial CO standards were based. A Staff Paper (US EPA, 1979b) was prepared and, along with the AQCD, served as the basis for development of proposed rulemaking (45 FR 55066) published on August 18, 1980. Delays due to uncertainties regarding the scientific basis fo r the final decision resulted in EPA’s announcing a second public comment period (47 FR 26407). Foll owing substantial reexamination of the scientific data, EPA prepared an Addendum to the 1979 AQCD (EPA, 1984a) and an updated Staff Paper (US EPA, 1984b). Following review by CASAC, EPA announ ced its final decision (50 FR 37484) not to revise the existing primary standard and to re voke the secondary standa rd for CO on September 13, 1985, due to a lack of evidence of direct effect s on public welfare at ambi ent concentrations. In 1987, EPA initiated action to revise the crit eria for CO and released a revised AQCD for CASAC and public review. In a “closure letter” (M cClellan, 1991) sent to the Administrator, the CASAC concluded that the AQCD (US EPA, 1991) “. . . provides a scie ntifically balanced and defensible summary of current knowledge of the e ffects of this polluta nt and provides an adequate basis for the EPA to make a decision as to the appropriate primary NAAQS for CO.” A revised Staff Paper subsequently was review ed by CASAC and the public, and in a “closure

5 See http://yosemite.epa.gov/sab/sabproduct.nsf/Web CASAC/CommitteesandMembership?OpenDocument for a list of members of CASAC and of the CASAC CO Review Panel.1-6 letter” (McClellan, 1992) sent to the Administrator, it was stated “. . . that a standard of the present form and with a numerical value simila r to that of the pres ent standard would be supported by the present scientific data on he alth effects of exposure to carbon monoxide.” Based on the revised AQCD (US EPA, 1991) a nd staff conclusions and recommendations
contained in the revised Sta ff Paper (US EPA. 1992), the Ad ministrator announced the final decision (59 FR 38906) on August 1, 1994, that revi sion of the primary NAAQS for CO was not appropriate. In 1997, revisions to the AQCD were initia ted. A workshop was held in September 1998
to review and discuss material contained in the revised AQCD. On June 9, 1999, CASAC held a public meeting to review the draft AQCD and a draft exposure analysis methodology document. Comments from CASAC and the public were co nsidered in a second draft AQCD, which was reviewed at a CASAC meeting held on November 18, 1999. After revision of the second draft AQCD, the final AQCD (US EPA, 2000) was rel eased in August 2000. EPA put the review on hold when Congress called on the National Resear ch Council (NRC) to conduct a review of the impact of meteorology and topography on ambien t CO concentrations in high altitude and extreme cold regions of the U.S. In res ponse, the NRC convened the committee on Carbon Monoxide Episodes in Meteorological and Top ographical Problem Areas, which focused on Fairbanks, Alaska as a case study in an interim report, which was completed in 2002. A final report, “Managing Carbon Monoxide Pollution in Meteorological and Topographical Problem Areas,” was published in 2003 (NRC, 2003) and o ffered a wide range of recommendations on management of CO air pollution, cold start em issions standards, oxygenated fuels, and CO monitoring. EPA did not complete the review which started in 1997.



### 1.4 SCOPE OF THE REVIEW For the current review of the primary CO st andard, relevant scientific information on human exposures and health effects associated with exposure to ambient CO will be assessed. The possible influence of other atmospheric po llutants on the interpretation of the role of CO in
health effects studies will be c onsidered. This will include othe r pollutants with the potential to co-occur in the environment (e.g., NO 2 , SO 2 , O 3 , and PM). The review will also assess any1-7 relevant scientific information associated with known or anticipated publi c welfare effects that may be identified.2-1 

## 2. REVIEW SCHEDULE

In September 2007, EPA’s National Center fo r Environmental Assessment in Research Triangle Park, NC (NCEA-RTP) announced the initia tion of the current periodic review of the air quality criteria for CO and the CO NAAQS and issued a call for information in the Federal Register (72 FR 52369). Table 2-1 outlines the schedule under which the Agency is currently conducting this review. 6

Table 2-1. Proposed Schedule for Development of Revised CO Integrated Science Assessment (ISA) and CO Primary Standard Stage of Review Major Milestone Draft Target Dates Integrated Plan Literature Search Ongoing Federal Register Call for Information September 2007 Workshop on science/policy issues January 2008 Draft CO NAAQS Integrated Review Plan (IRP) March 2008 CASAC consultation on IRP April 2008 Final CO NAAQS IRP August 2008 Science Assessment Prepare firs t draft of ISA February 2009 CASAC/public review first draft ISA April 2009 Prepare second draft of ISA August 2009 CASAC/public review second draft ISA October 2009 Prepare final ISA January 29, 2010 Prepare assessment methodology March 2009 CASAC/public consultation on methodology April 2009 Prepare first draft risk and/or exposure assessments September 2009

CASAC/public review of the first draft October 2009 Prepare second draft of risk and/or exposure assessments February 2010

CASAC/public review of second draft risk and/or exposure assessments March 2010 Risk/Exposure Assessment

Prepare final risk and/or exposure assessments May 28, 2010 Proposed rulemaking October 28, 2010 Policy Assessment/ Rulemaking Final rulemaking May 13, 2011

6 This schedule is based on a court-ordered schedule that governs the completion of the review, See Communities for a Better Environment v, EPA , No. 07-3678 (N.D. Cal., May 5, 2008). Further orders of the court may require revisions to this schedule.3-1 

## 3. KEY POLICY-RELEVANT ISSUES

The key policy-relevant issues to be addresse d in this review are presented below as a series of policy-relevant questi ons that will frame our appro ach to determining whether the current primary NAAQS for CO should be retain ed or revised and whether to set separate secondary standards. The ISA, health risk /exposure assessment, a nd any welfare-related assessment(s) to be conducted in this review will provide the basi s for addressing these questions. The answers to these questions, and the resulting conclusions regarding the corresponding policy-relevant issues, will inform the policy assessment/rulemaking that will lead
to the decision of whether to retain or revise the current 1-hour and 8- hour primary standards and whether separate secondary standards for CO are needed. The most recent review of the NAAQS for CO, completed in 1994, concluded that exposure to CO is associated with a va riety of acute health effect s, but there was very limited evidence of chronic effects. The secondary NAAQS for CO were revoked in 1985, and there currently are no secondary standards for CO. Ther e was insufficient eviden ce of welfare effects occurring at or near ambient levels to justif y setting secondary NAAQS in 1994. That review resulted in EPA’s conclusion that the then existing primary CO NAAQS provided adequate protection from health effects asso ciated with 1-hour and 8-hour exposures to ambient CO. A separate long-term standard was not recommende d. The current levels for the 1-hour and 8-hour primary NAAQS for CO are 35 ppm and 9 ppm, respectively.



### 3.1 ISSUES TO BE CONSIDERED IN THE CURRENT REVIEW OF THE PRIMARY NAAQS In this review, a series of policy-relevant questions will frame our approach to determining whether the current primary NAAQS for CO should be retained or revised. The answers to these questions, and the resulting conclusions regarding the corresponding policy issues, will inform the decision of whether to retain or revise the current short-term (1- and 8- hour) primary NAAQS for CO. The first step in reviewing the adequacy of the current primary NAAQS is to consider whether the available body of scientific evidence, assessed in the ISA, supports or calls into question the scientific conclusions reached in the last review regarding he alth effects related to3-2 exposure to CO in the ambient air. The ISA will cons ider a series of questions including the following:

 Has new information altered the scientific s upport for the occurrence of health effects following short- and/or long-term exposure to levels of CO found in the ambient air?

 To what extent is key evidence becoming available that could inform our understanding of human subpopulations that are particularly sensitive to CO exposures? The NRC committee report (NRC, 2003) recommended additional
research on effects of CO on birth outcom es. Is there new or emerging evidence on health effects beyond cardiovasc ular and respirat ory endpoints (e.g., systemic effects, developmental effects, birth outcomes ) that suggest additional sensitive subpopulations should be given increased focus in this review (e.g., neonates)?

 What do recent studies focused on the near -roadway environment, including bus stops and intersections, tell us a bout high-exposure human subpop ulations and the health
effects of CO? What information is available on elevated exposures due to other transportation sources, such as shipping, por t operations, and recr eational vehicles?
What is the effect of altitude on CO sources and health effects?

 At what levels of CO exposure do health effects of concern occur?

 To what extent is key scientific ev idence becoming available to improve our understanding of the health effects associ ated with various time periods of CO exposures, including not only dail y, but also chronic (months to years) exposures? To
what extent is critical research be coming available that could improve our understanding of the relationship between va rious health endpoint s and different lag periods (e.g., single day, multi-day distributed lags)?

 To what extent does the evidence suggest that alternate dose indicators other than carboxyhemoglobin (COHb) levels (e.g.,tissue oxygenation) should be evaluated to characterize the biological effect?

 Has new information altered conclusions from previous reviews regarding the plausibility of adverse health effects caused by CO exposure?

 To what extent have important uncertainties identified in th e last review been reduced and/or have new uncertainties emerged?3-3 If the evidence suggests that revision of the current standa rds might be appropriate, we will consider whether the available body of evid ence supports consideration of options that are different from the current standard. The following questions will inform this determination:

 Is there evidence for the occurrence of advers e health effects at levels of CO lower than those observed previously, and convers ely, is there evidence that suggests that effects occur only at higher leve ls than previously reported? If so, at what levels and what are the important uncertainties associated with that evidence?

 Do exposure estimates suggest th at exposures of concern for CO-induced health effects will occur? If so, are these exposures of sufficient magnitude such that the health effects might reasonably be judged to be important from a public health perspective? What are the important uncer tainties associated with these exposure
estimates?

 Do health effects evidence and air qualit y/exposure assessments provide support for considering different exposure indices or averaging times?

 What range of levels is supported by the health effects evidence and air quality/exposure assessments, and what ar e the uncertainties and limitations in the
health effects evidence and air quality/exposure assessments?

 What is the range of forms supported by the health effects evidence and air quality/exposure assessments, and what are the uncertainties and limitations in that
health effects evidence and air quality/exposure assessments?



### 3.2 ISSUES TO BE CONSIDERED IN THE CURRENT REVIEW OF A POSSIBLE SECONDARY NAAQS In this review, a series of policy-relevant questions will frame our approach to determining whether secondary NAAQS for CO s hould be considered. The answers to these questions, and the resulting c onclusions regarding the corres ponding policy issues, will inform the decision of whether to set secondary NAAQS for CO. The first step in reviewing the possible n eed for secondary NAAQS is to consider whether the available body of sc ientific literature, assessed in the ISA, provides evidence of
welfare effects rela ted to exposure to CO in the ambient air. Th e ISA will evaluate the newly
available scientific evidence and will address a series of questions including the following:3-4  Have new information or scientific insights altered the scientific conclusions regarding the occurrence of direct (or indirect) welfar e effects associated with levels of CO
found in the ambient air?

 At what levels of ambient CO do welfare effects of concern occur?

 To what extent is key scientific ev idence becoming available to improve our understanding of the welfare effects associated with va rious time periods of CO exposures, including not only da ily, but also chronic (months to years) exposures?

 Has new information, analytical tools/methods, or scientific insight altered conclusions from previous reviews regarding the plausi bility of adverse we lfare effects caused by CO exposure?

 To what extent have important uncertainties identified in th e last review been reduced or new uncertainties emerged? If the evidence suggests th at setting a secondary standard or standards might be appropriate, we will consider whether the availa ble body of evidence supports consideration of various options. The following questions will inform this determination:

 Is there evidence for the occurrence of advers e welfare effects at levels of CO lower than those observed previously? If so, atwhat levels and what are the important
uncertainties associated with that evidence?

 Do exposure estimates suggest th at exposures of concern for CO-induced welfare effects will occur? If so, are these exposures of sufficient magnitude such that the welfare effects might reasonably be judged to be important from a public welfare perspective? What are the important uncer tainties associated with these exposure
estimates?

 Do welfare effects evidence and air quality /exposure assessments provide support for considering different exposure indices or averaging times?

 What range of levels is supported by the welfare effects evidence and air quality/exposure assessments, and what ar e the uncertainties and limitations in the
welfare effects evidence and air quality/exposure assessments?

 What is the range of forms supported by the welfare effects evidence and air quality/exposure assessments, and what ar e the uncertainties and limitations in the
welfare effects evidence and air quality/exposure assessments?4-1 

## 4. SCIENCE ASSESSMENT

4.1 SCOPE AND ORGANIZATION
The science assessment for CO will consist of the ISA a nd its supporting annexes. The ISA will critically evaluate and integrate the scie ntific information on exposure, health effects,
and welfare effects associated with CO in ambient air. The annexes, which will evaluate and summarize relevant studies, will provide more detailed information from the most pertinent
scientific literature in support of the ISA. The annexes will include scientific evidence organized by health outcome in the discipline areas of epidemiology, toxicology, controlled human exposures (human clinical stud ies), and dosimetry, as well as human exposure and atmospheric
science relevant to the review of the CO NA AQS. The ISA will draw from this evidence and synthesize the current state of know ledge on the most relevant issues pertinent to the review of the NAAQS for CO. A formal framework for the integrat ion of health effects evidence, based on approaches formulated by other regulatory and scie nce agencies, has been developed for the final
ISA for NO x (U.S. EPA, 2008) and will be applied in th e current CO review. Information from the scientific disciplines listed a bove will be integrated into the health effects evidence in order
to contribute to a better unde rstanding of population exposure and/or risk, or to a better understanding of the nature, source s, distribution, measurement, a nd/or concentrations of CO in
ambient air. The ISA discussions will be designed to focus on the key policy questions
described in Section 3 of this document.
The focus of the ISA will be on literature iden tified since the previ ous review of the air quality criteria for CO and on key science and policy issu es raised during the last review, including issues addressed in the NRC comm ittee report on CO (NRC, 2003). Findings and conclusions from the 2000 Air Quality Cr iteria Document (US EPA, 2000) for CO will be briefly summarized at the beginning of the ISA. The re sults of new studies will be integrated with previous findings. Important ol der studies will be more specifi cally discussed if they remain definitive or are open to reinterpretation in light of newer data. Information that has undergone scientific peer review and th at has been published (or accepte d for publication) in the open literature will be considered. Additionally, o fficial studies and repor ts from governmental agencies may be included, as appropriate. Emph asis will be placed on st udies conducted at or4-2 near CO concentrations found in ambient air. In recognition of the fact that toxicologic and human clinical studies do not necessarily reflec t effects in the most sensitive population, studies at higher exposure levels will be included when th ey provide information relevant to previously unreported effects, evidence of the potential mech anism for an observed effect, or information on exposure-response relationships.



### 4.2 ASSESSMENT APPROACH

Introduction
The EPA’s National Center for Environmenta l Assessment in Research Triangle Park (NCEA-RTP) is responsible for prepari ng the ISA and the related annexes for CO. Expert authors include EPA staff with extensive knowledge in their respective fi elds and extramural scientists contracted to the EPA. A diagram s howing the standard protoc ol for development of an ISA, including both health and ecosystem ef fects, is presented in Figure 4.1. While no secondary standard currently exis ts for CO, any evidence of welfar e effects of ambient CO (such as effects on domestic and wild animals, cr ops and forest vegetati on, and microorganisms) identified during ISA development will also be included. The ISA for CO will focus primarily on scientific evidence relating to health effect s. A complete descri ption of the new NAAQS review process is presented in Section 1.1.4-3 Figure 4.1. Protocol for ISA de velopment, showing the steps involved in production of Integrated Science Assessments.4-4 Literature Search NCEA-RTP will use a systematic approach to identify relevant studies for consideration. A Federal Register Notice (72 FR 52369, Sept ember 13, 2007) was published to announce the initiation of this review and request information from the public. An initial publication database will be established by searching the online databases MEDLINE, ISI Web of Knowledge, Toxfile, Pascal, Biosis, and Embase using as key words terms including carbon monoxide, methane, carbon dioxide, CO, CH 4 , CO 2 , hydroxyl radical, carboxyhe moglobin, COHb, hypoxia, traffic, and combustion. Ta rgeted searches will also be conducted to identify articles relevant to specific health, ecological, and physic al science disciplines. As a ppropriate, the search strategies will be periodically reexamined and modified to enhance identification of pertinent published papers. Additional papers will be identified for in clusion in the publication base in several ways. These include the review of pre-publication tables of contents for journals in which relevant papers may be published, as well as independent identification of relevant literature by expert authors. In addition, publicati ons that may be pertinent are identified by both the public and CASAC during the external review process. The studies identified will include research published or accepted for publication by a date determ ined to be as inclusive as possible given the relevant target dates in the NAAQS review schedule. Some additi onal studies, published after that date, may also be included if they provide new information that impacts one or more key scientific issues. The combination of th ese approaches should pr oduce the comprehensive collection of potentially pertinent studies needed to form the basis of the ISA. The following sections briefly summarize criteria for sele ction of studies for this draft ISA.

General Criteria for Study Selection In assessing the scientific quality and releva nce of epidemiological and human or animal toxicological studies, the following considerations will be taken into account.

 To what extent are the aerometric data, e xposure, or dose metrics of adequate quality and sufficiently representative of populati on exposure to serve as indicators of exposure to ambient CO?

 Were the study populations adequately select ed and are they sufficiently well defined to allow for meaningful, reliable comparisons between study groups?

 Are the health endpoint measurements meaningf ul, reliable, and clinic ally significant?4-5  Does the study contain unique data, such as the documentation of a previously unreported effect, documentation of the mechanism for an observed effect, or information on exposure-re sponse relationships?

 Are the statistical analyses appropriate, properly performed, and properly interpreted with sufficient statistical power?

 Are likely covariates (i.e., potential confounders or eff ect modifiers) adequately
controlled or taken into account in the study design and statistical analysis?

 Are the reported findings intern ally consistent, biologically plausible, and coherent in terms of consistency with other known facts? Consideration of these issues, more fully disc ussed in Annexes, informs our judgments on the relative quality of individual studies and allows us to focus the assessment on the most pertinent
studies.

Criteria for Selecting Epidemiological and Field Studies In selecting epidemiological studies for the present assessment, EPA will consider whether a given study contains information on: (1) associations with measured CO concentrations using short- or long-term exposures at or near ambient levels of CO; (2) health
effects of CO or indicators related to CO sources (e.g., motor vehicle emissions, fossil fuel combustion); (3) health endpoints and populations not previously extensively researched; (4) multiple pollutant analyses and other approaches to address issues related to potential confounding and modification of eff ects; and/or (5) important met hodological issues (e.g., lag of effects, model specifications, thresholds, mortality displacement) related to CO exposure effects.
All selected studies will be considered in the ev aluation of the health evidence, including studies
conducted in countries outside the United States and Canada. In drawing conclusions or recommendations pertinent for quant itative risk or exposure analyses, particular emphasis will be placed on those relevant to standard setting in th e United States. Specific ally, certain findings of
studies conducted in the U.S. or Canada may be discussed in mo re detail than those from other geographic regions, as the potenti al impacts of housing characterist ics, activity patterns, differing health care systems and the underlyi ng health status of the populati ons need to be accounted for in the assessment. Emphasis in the text will be placed on discussion of (1) new, multi-city studies that employ standardized methodological analyses for ev aluating CO effects and that4-6 provide overall estimates for effects based on co mbined analyses of information pooled across multiple cities; (2) new studies that provide quantitative effect estimates for populations of interest; and (3) studies that consider CO as a component of a comple x mixture of air pollutants.

Criteria for Selecting Human Laboratory, C linical, and Animal Toxicological Studies The review of research evaluating animal toxi cological or controlled exposure studies will focus primarily on those studies conducted at phy siologically relevant CO concentrations and those studies that approximate expected human exposure conditions in terms of concentration
and duration. Studies that eluc idate modes of action or mechanis ms underlying biol ogical effects and/or examine susceptibili ty will be considered. The selection of research evaluating contro lled human exposures to CO will focus on studies in which subjects were expo sed at conditions relevant eith er to ambient exposures or to
determination of mechanism

. For these controlled human expos ures, emphasis will be placed on studies that: (1) inve stigate potentially sus ceptible populations such as individuals with cardiovascular disease, particularly studies that compare responses in susceptible individuals with those in age-matched healt hy controls; (2) addre ss issues such as dose-response or timecourse of responses; (3 ) investigate exposure to CO separately and in combination with other pollutants such as PM, O 3, NO 2 and SO 2 ; (4) are appropriately b linded and include control exposures to filtered air with subjects serving as their own controls; and (5) have sufficient statistical power to assess findings. Review of the animal toxicological eviden ce will focus on studies that approximate expected human dose conditions, which will vary depending on the toxicoki netics and biological sensitivity of the particular la boratory animals examined. In addition, resource constraints prevent animal researchers from testing hypothe ses that require larg e numbers of animals exposed to ambient levels of CO over a prolong ed period. Consequently, animal studies are typically used to acquire data relating to mech anisms, and the exposures are purposefully high to assure a measurable response. Studies at high concentrations will be considered when they provide useful information to inform our understa nding of interspecies di fferences and potential sensitivity differences between heal thy and susceptible human populations.4-7 Quality Assurance Important quality assurance measures will be incorporated from the start of the current CO review. EPA uses an NCEA-RTP quality assura nce plan for searching scientific literature which details an approach to gathering the scie ntific information found in peer-reviewed journal articles and government reports. Additionally, NC EA has data quality objectives which identify inputs to the science assessment and provide qual ity assurance (QA) inst ruction for researchers citing secondary information.

Content and Organization of the ISA The organization of the ISA for CO will be consistent with that used in the recent draft ISAs for Oxides of Nitrogen and Oxides of Sulfur (US EPA, 2008, 2007). The ISA will contain
information relevant to consideri ng whether it is appropriate to re tain or revise the current 1-hour
and 8-hour standards and whether it is appropriate to consider setting a separate long-term exposure standard. The content of the ISA w ill be guided by a series of policy-relevant questions derived from the previous review of the CO NAAQS and from the Workshop to Discuss Policy-Relevant Science to Inform EPA’s Integrated Plan for the Review of the Primary CO NAAQS, held on January 28-29, 2008 at the EP A campus in Research Triangle Park, NC. These policy-relevant questions ar e related to two overarching issu es. The first issue is whether new evidence reinforces or calls into question the evidence presented and evaluated in the last NAAQS review. The second issue is whether un certainties from the last review have been
addressed and/or whether new unc ertainties have emerged. The specific questions that stem from these issues are listed below by topic area.

Source to Dose Air Quality and Atmospheric Chemistry : The ISA will present and evaluate data related to
ambient concentrations of CO; sources leading to the presence of CO in the atmosphere; and
chemical reactions that determine the forma tion, degradation, and lif etime of CO in the atmosphere.

 What are the strengths and weaknesse s of various methods for measuring CO? To what extent are these methods subject to positive or negative sampling artifacts or
to interference from other substances?4-8  Using recent air quality and emissions data, what are the current emission levels and
ambient concentrations of CO in the US? What spatial and temporal patterns can be seen in these CO air quality data, and how do these relate to patterns of human exposure? What are the effects of sample and measurement averaging time and range on the level of spatial and temporal variabil ity in concentrations? To what extent are
ambient CO concentratio ns correlated with othe r air pollutants (e.g., NO x , O 3 , PM,
SO x ), and do these possible correlations change spatially and temporally in significant ways? On what spatio-temporal scales does CO affect the production of ozone and other related pollutants?

 The NRC committee report (NRC, 2003) iden tified the spatial va riability of CO concentrations and the likely existence of high-concentration hot spots, potentially near susceptible subpopulations, as important issues in assessing the CO regulatory monitoring network. What ar e the implications of the cu rrent network configuration for the interpretation of CO-related health effects?

 Using air quality and emissi ons data on CO and atmospheric chemistry models, what are likely policy relevant background concentrations of CO?

 Are there other techniques that can be used to better define the ra nge of concentrations and the spatial and temporal variability of CO over the U.S.? Are satellite retrievals or three dimensional chemical transport models useful? Can satellite data be used on a regular basis to improve the characterization of CO emissions?

 What information is available on short-term ambient CO concentrations (< 1 hr)?

Human Exposure : The ISA will evaluate the f actors that influence exposure to CO and the
uncertainties associated with ex trapolation from ambient concentrations to personal exposures to CO of ambient origin, particularly in the c ontext of interpreting re sults from epidemiologic studies. The issues of uncertainty differ by the exposure period of interest. Short-term exposure studies (e.g., population-level studi es using time-series analyses, field/panel studies) primarily rely on temporal variation in exposure, while long-term e xposure studies (e.g., longitudinal cohort studies) rely on spatia l variability of exposure.4-9  What data exist on relationships between exposure to CO and corresponding exposure to gaseous and particulate co-pollutants (e.g., NO x , O 3 , PM, SO x )? What factors affect these relationships (season, housing characteristics, activity patterns, etc.)?

 What are the uncertainties when extrapol ating between stationary CO monitoring instruments and personal exposure to CO of ambient origin, especially for susceptible groups? Issues include measurement error in outdoor ambient monitors, the use of monitors for estimating community concentr ations, and their use as a surrogate for personal exposure to CO of ambient origin.

 What information is available on exposur es to short-term (< 1 hr) peak CO
concentrations?

 To what extent do measurements from ambi ent CO monitors provide an estimate of ambient exposures for health studies, serv e as an indicator of personal exposure to CO, and/or serve as an indicator of person al exposure to other gaseous pollutants (including O 3 and NO 2 ) and particulate pollutants generated by traffic?

 What influence do the tempor al and spatial patterns of CO exposure, for both indoor and outdoor sources, have on evaluation of h ealth effects? What is the exposure pattern for indoor sources, such as gas st oves and space heaters (i.e., peak, repeated peak, and average CO) and how does it relate to ambient CO patterns?

 What evidence is available on subpopulati ons likely to have high ambient CO exposures including those livi ng, working and/or attending school near roadways and those in the vicinity of sh ipping or port operations?

 What data are available to inte rpret both short- and long-term CO exposures (e.g., <1 hour, 1 hour, 8 hours, 24 hours, 2 weeks, or longer)? What data and models are available to support exposure estimates over pe riods that may be relevant to additional health endpoints, such as birth outcomes? This includes such information as air exchange rates, indoor sources, distance to highways, and performance indicators for methods of measuring personal exposures to CO (particularly at low ambient levels).

 How do modeled predictions of CO concentrations and exposures compare with monitoring results?4-10 Dosimetry of Inhaled CO : The ISA will evaluate the literature relating to pharmacokinetic modeling of CO uptake and the associated forma tion of COHb. Recent information relating to
either the well-established Cobur n-Forster-Kane model or alternativ e models will be integrated with literature summarized in the previous AQCD to assess the current state of knowledge on
COHb formation. The ISA will assess eviden ce on uncertainties in modeling COHb as a
function of inhaled CO. The contribution of en dogenously produced CO to COHb is included in
the Coburn-Forster-Kane model and will be considered in the integrative hea lth effects section of
the ISA.

 What new information is available on the validity and applicab ility of the CoburnForster-Kane model? Are alternative a pproaches available and preferable for modeling COHb formation from ambient CO?

 What factors contribute to uncertainty and variability in estimating COHb formation
from ambient CO?

 What information is available on COHb formati on in fetuses and infant s? Issues to be considered include COHb pharmacokinetics in neonates and the relationship between maternal CO exposure and fetal COHb concentration.

Health Effects

The ISA will evaluate the litera ture related to health eff ects identified in the 2000 AQCD, as well as any additional health outcomes iden tified during the review. Previously identified
health effects include cardiovasc ular effects (e.g., myocardial ischemia, angina, arrhythmia), central nervous system effects (e.g., loss of dexter ity, visual impairment), re spiratory effects, and birth outcomes (e.g., low birth we ight, preterm birth) associated with short and/or long term exposure to CO. This will include evaluation of emergency department visits, hospitalizations, and mortality associated with these effects. Heal th effects that are associ ated with both shortand long-term exposures will be evaluated in ep idemiologic, human clinical, and toxicologic studies. Recent studies regard ing the formation of endogenous CO by cells and tissues and the resulting localized biological response will be ev aluated in order to determine the relevance to4-11 biological responses following ambient CO e xposure. Causality, uncertainty, biological mechanism of action, susceptible and vulnerable popul ations, and public health impact will all be
considered. The data will be reviewed with the understanding that effect s from ambient CO must be considered in conjunction with co-occurring pollutants (e.g., NO x , O 3 , PM, SO x ).
For a given type of health outcome, the IS A will evaluate the strength, robustness and consistency of the findings from the different di sciplines. The health findings will be further integrated, using the toxicologic and human clinical studies to assess biologic plausibility and mechanistic evidence for the epidemiology findings. A key focus of the integration of health
evidence will be on the attributi on of health effects to CO as a component of multipollutant exposures. Efforts will be directed at identifyi ng the lower levels at which effects are observed and at determining concentration-response re lationships for CO. Concentration-response relationships among these studies will be evalua ted for coherence. The ISA will evaluate the
scientific evidence on the occurrence of health effects from long-term or short-term exposure to
CO at ambient levels. The ISA will also assess the evidence for uncertainties related to these
associations and information on th e public health implications re lated to ambient CO exposure. The evaluation will also focus on which exposure durations and developmental time periods of exposure are most strongly associ ated with effects, for both shor t-term and long-term exposures.

Short-Term Exposure :

 What do controlled human exposure, animal toxicologic, and epidemiologic studies indicate regarding the relationshi p between short-term exposures to CO and health
effects of concern in both healthy individuals and in t hose with preexisting disease states (e.g., individuals with cardiovascular or ischemic heart disease)? What new evidence is available on effects occurring from exposures at sub-daily averaging
times?

 What are the effects of CO exposure on breathing rate a nd respiratory gas exchange in healthy and susceptible individuals (e .g., oxygen diffusion capacity and ventilationperfusion mismatches) and what is the potenti al clinical relevance of these effects? Does recent evidence indicate other respirat ory effects from ambient CO exposure?4-12  Is exposure to CO associated with mortality (total, respiratory or cardiovascular), hospital admissions, or emergency departme nt visits as assessed using populationlevel datasets? What are the lowest ambient CO concentrations at which these
associations are observed? What evidence is available to inform selection of the appropriate lag structure for specific health outcomes? Do other gaseous pollutants and/or particulate matter c onfound or modify the effect observed due to exposure to CO? The utility of the sta tistical methods applied will be evaluated (i.e., time-series studies). As discussed above , the potential effects of e xposure error on epidemiologic
outcomes will be evaluated.

 To what extent does exposure to CO contribute to health eff ects in the cardiovascular or other systems? What information can be obtained from electrocardiogram changes that may indicate an adverse response to CO? How does CO affect vascular and endothelial function and through which pathways?

 What is the impact of short-term exposures (days or less) on birth outcomes? Which gestational ages represent pa rticularly vulnerable periods for developmental effects of CO exposure?

 What is the nature of health effects in persons exposed to multipollutant mixtures that
contain CO in comparison to exposure to CO alone?

 Does exposure to ambient CO perturb the biologi c function of endogenous CO (e.g., by generating unwanted or excessive CO)? What are the effects of ambient and endogenous CO on oxidative stress and acute inflammation and other biological responses involved in pathophysiology?

 What biomarkers of early effect may be us ed in the assessments? What detectable biological changes will be consid ered adverse health effects?

Long-Term Exposure :

 Does the scientific evidence support the occu rrence of health effects from long-term exposure (e.g., months to year s) at ambient levels that are lower than previously4-13 observed? If so, what uncertainties are relate d to these associations, and are the health effects in question important from a public health perspective?

 Can long-term exposures to CO result in ch ronic effects such as developmental effects
or birth outcome effects?

 What are relevant exposure periods for effect s associated with birth outcomes? What metrics are appropriate for assessing deve lopmental effects (e.g., low birth weight, preterm birth)? Are certain effects linked to specific exposure windows?

 To what extent does long-term CO exposure promote development of chronic
cardiovascular disease? What is the relationship between long-term CO exposure and shortening of human life span vi a promotion of such diseases?

 Are there annual and seasonal patterns of CO exposure that are associated with potentially harmful health effects?

Causality : The ISA will evaluate the evidence rela ting to the existence or lack of a causal relationship between obser ved health outcomes and CO exposure using a framework developed by NCEA for the recent NO X ISA (U.S. EPA, 2008). This fra mework is designed to improve consistency and transparency by establishing unif orm language to describe causal relationships and explicitly outlining the guidelines that are us ed to evaluate causality. These guidelines are based on those proposed by Sir Austin Brad ford Hill in 1965 (Hill, 1965), including: consistency, strength, specificit y, and temporality of the observe d association; evidence of an exposure-response relationship; bi ological plausibility and cohere nce; experimental evidence from human populations; and analogy (e.g. mode of action for structural analogs). Individual studies may not provide information on all of thes e factors, yet remain informative for inferring causality. This approach draws from and is c onsistent with similar a pproaches formulated by government agencies and the wider scientific community, including the Institute of Medicine (IOM, 2007), the International Agency for Re search on Cancer (IARC, 2006), the National Toxicology Program (NTP, 2005), EPA (U.S. EPA, 2005), and the Centers for Disease Control and Prevention (CDC, 2004). Biological plausibili ty and coherence of the evidence will be key considerations in drawing conclusions about cau sality. The ISA will place emphasis on studies4-14 conducted at or near typical ambient levels, exce pt regarding evidence of biological plausibility and mechanisms, as these may only be obser vable in animal or human exposure study populations at higher levels than they might be observed in su sceptible human populations. The ISA will also assess any information available from “intervention” studies regarding the health impacts of decreases in ambient le vels of CO that is relevant to the evaluation of causality in CO-health outcome relationships or benef its accruing from such interventions.

 Does the evidence base contain new informati on to evaluate the case for or against a causal relationship between health effects and CO exposure?

 What information is available regarding th e health impacts of a decrease in ambient
levels of CO?

 What insights can be gained regarding causa lity by comparing health effects observed in older multipollutant studies (with comp aratively higher ambient CO levels) with more recent multipollutant studies?

Uncertainties : The ISA will evaluate uncertainty in the sc ientific data, particularly in relation to observed epidemiologic findings and their cons istency with human laboratory, clinical, and animal toxicologic studies in terms of observed effects and biological pathways.

 How does confounding by coexposure to other pollutants (e.g., O 3 , PM, SO 2 , and NO 2 ) and meteorological factors influence the asso ciations observed with CO for both shortand long-term exposures? The manner in wh ich ambient CO concentration may serve as a surrogate for exposure to vehicle exhaus t pollutants, including gases and particles,
will be discussed.

 What are the uncertainties due to other factors in epidemiologic studies (e.g., demographic and lifestyle attributes, gene tic susceptibility factors, occupational exposure, and medical care)?

 What is the shape of the concentration-response functi on (e.g., linear vs. threshold models)?

 What are the uncertainties associated with comparing the results of birth outcome studies utilizing different study de signs, metrics, and endpoints?4-15  What uncertainties surround the evidence for lo ng-term effects such as life shortening and development/progression of disease?

Biological Mechanisms of Action : The ISA will evaluate the data examining mechanisms for the health outcomes associated with exposure to CO.

 Is there new information related to the path ways and biological mechanism of action?

 What are the potential mechanisms of response to CO, with a focus on physical-chemical characteristics, respons e pathway(s), and exposure-dose-response relationships?

 What indicators other than carboxyhem oglobin (COHb) may be relevant for characterizing physiological effects of CO exposure (e.g., tissue oxygenation)?

 What are the effects of age, gender, and pre-existing disease on cellular and tissue responses and the pathophysiology of CO-induced injury?

 What physiological characteristics of neonate s may lead to differential responses and effects compared to adults?

 Which CO-induced health effects are sufficiently characterized to be quantitatively compared across species?

 What are the interspecies differences in sens itivity to CO and in basic mechanisms of injury and repair? What are the impli cations of interspecies differences for extrapolation of results to humans?

 What is the state of knowledge of laboratory animal-to-man extrapolation of effects? Are credible qualitative and/ or quantitative extra polations possible for short- and for long-term exposures?

Susceptible Populations : The ISA will examine health outcom e data to identify specific groups that are more susceptible to the adverse effects of CO exposure than normal healthy adults (e.g., persons with cardiovascular dis ease, COPD, or reduced or ab normal hemoglobin, older adults,4-16 neonates). The host and environmental factors that are responsible for differential susceptibility to CO will be investigated.

 What do controlled human exposure, animal toxicologic, and epidemiologic studies indicate regarding the relationship between acute exposures to CO and health effects of concern in individuals who are healthy and in those individuals with preexisting diseases (e.g., cardiovascular diseases, CO PD)? What other medical conditions or
medications are identified as increasing susceptibility to CO effects? What are the pathways and mechanisms through which CO may be acting for these groups? Do pathophysiologic changes in these populations alter the normal compensatory responses to CO exposure observed in hea lthy individuals? What is the nature and time-course of the development of effects in healthy persons and in persons with preexisting disease?

 Is preexisting respiratory or cardiovascular disease in c onjunction with advanced age an important factor in susceptibility to mortality associated with exposure to CO?

 Regarding morbidity health endpoints, to wh at extent are older adults and neonates more sensitive than the general population to CO exposure?

 How should sensitive subpopulations be considered in interpretation of epidemiological results and e xposure-response charac teristics, considering that these results may be driven by the more sensitive subpopulations?

 Is susceptibility to the effects of short-term CO exposure associated with long-term CO susceptibility?

 What host and environmental factors (e.g., de mographic, socioeconomic, and genetic) are associated with susceptibility to short- and long-term exposure to CO?

Public Health Impact: The ISA will present concepts relate d to the potential for defining adverse health effects. To accomplish this, the implicatio ns for public health of different health effects will be discussed. This will include, as appropria te, an estimation of the potential number of persons at risk in specific susceptible and vul nerable at-risk population groups. The concept of attributable risk, which considers the exposure of a subpopulation along with relative risk, will4-17 be evaluated in consideration of the public health impact. Low-level effects will be interpreted in light of the policy-re levant background concentration of CO . Furthermore, the analysis will identify and address, as appropriate, dispr oportionately high and adverse human health or environmental effects of CO on minority populations and low-income populations, as recommended in the NRC committee report (NRC 2003).

Annexes to the ISA
The ISA will be supplemented by a series of annexes, which will provide detailed supporting information and more comprehensive cove rage of research areas summarized in the ISA. While studies with the most policy-relevant information are summarized in the ISA, the annexes present information on all studies consid ered during the review. Annexes also provide in-depth discussion of scientific topics supporting interpretation of exposur e, health, and welfare effects. The annexes will provide information on: (1) the chemistry, physics, sources, and emissions of CO, as well as sampling a nd analytic methods for measurement of CO; 2) environmental concentrations and human exposure to CO; (3) dosimetry; (4) toxicologic studies
of CO health effects in laborator y animals and in vitro systems; (5) human clinical studies examining health effects following controlled exposure to CO; and (6) epidemiologic studies of health effects from short- and long-term exposure to CO. More detailed information on various
methods and results for the health studies will be summarized in tabular form in the annexes. These tables will generally be organized to in clude information about: (1) concentrations of CO levels and averaging times; (2) description of study methods empl oyed; (3) results and comments; and (4) quantitative ou tcomes for CO measures. A dditionally, annexes will contain background material on legislative requirements, the NAAQS review process, and the history of
earlier CO reviews.



### 4.3 SCIENTIFIC A ND PUBLIC REVIEW Drafts of the ISA will be reviewed by th e CASAC CO Review Panel of EPA’s Science Advisory Board (SAB) and made available for public comment. The annexes to the ISA will
also be made available to CASAC in order to assist with their re view; however, CASAC members will not be specifically charged with reviewing the annexes. The CASAC CO Review4-18 Panel will review the first draft ISA and disc uss their comments in a public meeting announced in the Federal Register. Based on CASAC’s past practice, EPA expects that the CASAC chair will summarize key CASAC advice and recomme ndations for revision of the document in a
letter to the EPA Administrator. In revising the first draft ISA for CO, EPA will take into account any such recommendations, as well as co mments received from CASAC or from the public at the meeting itself and any written co mments received. EPA will prepare a second draft ISA for CASAC review and public comment. The CASAC CO Review Pane l will review the
second draft ISA and discuss their comments in a public meeting announced in the Federal Register. Again, based on CASA C’s past practice, EPA antici pates the CASAC chair will summarize key advice and recommenda tions for revision of the second draft ISA in a letter to the EPA Administrator. In finalizing the IS A, EPA will take into account any such
recommendations. EPA will also consider comme nts received from CASAC or from the public at the meeting itself and any written public co mments. After appropriate revision, the final document will be made publicly available on an EPA website and in hard copy. A notice announcing the availability of the final ISA w ill be published in the Federal Register. In addition, the final ISA will be placed in the rulemaking docket.5-1 

## 5. RISK/EXPOSURE ASSESSMENT

5.1 SCOPE AND ORGANIZATION The risk/exposure assessments for the current review of the primary CO NAAQS will be designed to estimate human exposur es and to characteri ze the potential hea lth risks that are associated with current ambient levels, with ambi ent levels that just meet the existing standard, and with ambient levels that just meet alternat ive standards that may be under consideration. The risk/exposure assessments will draw upon the information presented in the draft ISA and its
Annexes. This includes information on atmos pheric chemistry, air quality, human exposure, formation of COHb levels, and health effects of concern. In particular, the availability of concentration-response and dose-re sponse data from the health eff ects literature will influence the type of exposure assessment and risk ch aracterization that w ould be performed. The assessments will focus on exposures and dos e metrics that are consistent with health effects of concern and will be enhanced with available measurement and modeled data, where appropriate, to generate estimates of exposure. These estimates will then serve as a measure of comparison to identified health benchmarks to (1) estimate the number of individuals at risk of experiencing exposures of concer n, and (2) estimate the magnitude of exposures above levels of concern. The components of the exposure/risk assessments are outlined below and will be
described in detail in the draft Health Asse ssment Plan: Scope and Methods for Exposure and Risk Assessment (hereafter, “Health Assessment Plan”). The Health Assessment Plan will be the subject of a consu ltation with the CASAC CO Panel and will be made available to the public
for review and comment. The first draft risk and exposure assessment (REA) document will be prepared based on the draft Health Assessment Plan and will assess exposure and characterize health risks associated with recent air quality and air quality just meeting the current CO NAAQS. The second draft REA document will reflect comments from the CASAC CO Panel and the public and will also analyze exposure and characterize health risks associated with any potential alternative CO standards under consid eration. The REA documen t will be made final upon completion of the final ISA for CO and following review of the second draft REA document by the CASAC CO Panel and the public.5-2 

### 5.2 OVERVIEW OF PREVIOUS EXPOSURE ASSESSMENTS

1992 Exposure Analysis for Denver, Colorado In the previous review of the NAAQS for CO, a quantitative analysis of CO exposures in Denver, CO, was conducted to provide estimate s of CO exposure and their resultant COHb levels for people living in one city for different exposure scenarios. The analysis provided a basis for assessing protection afforded by the curre nt CO standards and preliminary insight into the relative impact of certain i ndoor sources to total CO exposur e. Denver was chosen because (1) in 1988 it violated both the current 1-hour and 8-hour CO NAAQS (one of only two areas that exceeded both standards at the time); (2) it had a relatively high 8-hour design value, 16.2 ppm -- the second-highest design value in the U.S. at the time; and (3) CO personal monitoring data were available for a rough validity check of the modeling effort. Four scenarios were modeled that provided insight into exposures related to (1) curren t air quality versus future air quality associated with just meeting the 8-hour CO NAAQS and (2) common indoor sources present versus ambient air without these indoor sources. Only the 8-hour NAAQS was evaluated since previous analyses indicated that it was th e controlling standard for attainment (US EPA, 1979b). Indoor sources that were considered included residential ga s stoves and passive smoking. Other indoor sources, such as running au tomobiles in private or public garages and
CO intrusion into a motor vehicle from the vehi cle itself, were not in cluded in any of the
scenarios. The model used for exposure analysis was pNEM/CO (probabilistic NEM applied to
CO ) , a version of the CO NAAQS Exposure Mode l (NEM) that incorporated Monte Carlo sampling and multiple runs, or realizations, of the model

. The major model outputs of interest were estimates of the number of person-days of exposure to various CO levels for the four
scenarios mentioned above for adults with car diovascular disease in Denver. In addition, estimates also were made of the percentage of the cardiovascular he art disease population in
Denver that would exceed selected COHb levels one or more times per year under the four
scenarios. The estimates of COHb were deri ved by applying a modifiedversion of the CoburnForster-Kane (CFK) differential equation that estimates COHb levels from CO exposure as a function of time and physiological and envir onmental factors (e.g., blood volume, altitude,5-3 endogenous CO production rate). It was estimat ed at the time that there were about 36,800 nonsmoking adults in Denver with diagnosed or undiagnosed (silent) ischemia. The analysis indicated that if the current 8-hour standard were just met, the proportion of the nonsmoking population with cardiovascular di sease experiencing exposures at or above 9 ppm for 8 hours decreased by an or der of magnitude or more, down to less than 1 percent of the total person-days in that populat ion. Likewise, meeting the curre nt 8-hour standard reduced the proportion of the nonsmoking cardiovascular-diseas e population person days at or above COHb levels of concern by an order of magnitude or more. Upon meeting the 8-hour standard, EPA estimated that less than 0.1 pe rcent of the nonsmoking cardiovasc ular-disease population would experience a COHb level of about 2.1 percent. A smaller population was estimated to exceed higher COHb percentages. Based on this assessm ent, and considering the 1985 review of similar CO effects and effects levels, th e Administrator concluded that th e evaluation of adequacy of the existing CO standards should focus on reducing th e number of individuals with cardiovascular disease from being exposed to CO levels in the am bient air that would result in COHb levels of 2.1 percent or greater. The Admi nistrator concluded that standard s that limit the occurrence of COHb levels above 2.1 percent would provide an ad equate margin of safety against effects of uncertain occurrence in the range of 2.1 to 2.9 percent, as well as t hose of clear concern that have been associated with COHb levels in the rang e 2.9 to 5.9 percent. The Administrator also concluded that relatively few people of the car diovascular sensitive population group analyzed would experience COHb levels ≥ 2.1 percent when exposed to CO levels in the absence of
indoor sources when the current ambient standard s are attained. The an alysis also indicated, however, that certain indoor sour ces (e.g., passive smoking, gas stove usage) contributed to total CO exposure but could not be effectively m itigated by ambient air quality standards.
The 8-hour standard was chosen because most individuals, even at rest, appeared to approach equilibrium levels of COHb after 8 hours of exposure. In addition the 8-hour period approximated blocks of time for which people ar e often exposed in a particular location or activity (e.g., sleeping, worki ng) and provided a good indica tor for tracking continuous exposures that occurred during any 24-hour perio d. The 1-hour standard was chosen because a 1-hour averaging period provided a better indicator of short-term health effects of CO and a lhour standard provided reasonable protection from effects that might be encountered from very short duration peak exposu res in the urban environment. Review of scientific information in the5-4 1991 Criteria Document indicated that these reasons for choosi ng averaging times for the CO
standards remained valid and th ere were no compelling arguments for selecting new or different averaging times. The Administrator also considered and concurred with the staff
recommendations contained in the 1992 Staff Paper that both averaging times should be retained for the primary CO sta ndards. For the above reasons, the Administrator determined under section 109(d)(1) that revi sions of the 1-hour (35 ppm) and 8-hour (9 ppm) primary
standards for CO were not appropriate at that time.

1999 Exposure Analysis for Denver Additional exposure analyses were planne d in 1999 using the Denver and Los Angeles (LA) areas to provide estimates of CO exposures and resultant COHb levels for adults in two
urban areas. Denver was included in the planned analyses for comparison purposes because it was the only city included in the exposure anal ysis conducted in the previous review. In addition, Denver was one of a few areas wh ere a personal CO exposure study had been
conducted. After an initial review of th e methodology, EPA planned to also conduct the analyses for LA for several reasons: (1) it pres ented the largest potentia l public health burden due to its ambient CO levels and potential population exposure; (2) an extensive monitoring network was available; and (3) an existing study of personal and indoor CO concentrations that potentially could be used to evaluate the m odel had been conducted in Los Angeles. The primary target population was adults with cardiovascular disease, as it was in the 1992 analysis. The 1999 analysis initially focused on several scenarios: (1) current air quality (1995 for Denver); and (2) the presence of indoor sources (gas stoves/ovens and passive smoking) versus
ambient air without indoor sources. The analyses were intended to provide a basis for assessing protection afforded by the current CO standards a nd preliminary insight into the relative impact indoor sources may have on total exposure. Th e model selected to estimate population exposure was an updated version of pNEM/CO that was used in the 1992 Denver analysis, with the major outputs of interest being estimates of the number and percentage of person-days of exposure to various CO levels and the number and percentage of person-hours and people exceeding various COHb levels. Only the 8-hour NAAQS was planne d for evaluation because previous analyses
indicated that it was the contro lling standard for attainment.5-5 A draft exposure analysis report (Johnson et al, 1999) applying the updated exposure model only to the Denver area was provided to the CASAC CO Panel and made available for public review in March 1999 for the purpose of obtaining scientific a nd public input on the proposed methodology. The CASAC CO Panel conducted a consultation on the methodology for the analysis on June 9-10, 1999. The CO NA AQS review was put on hold, however, and the exposure analysis was not completed. For this current review, EPA staff will build upon the 1999 work and subsequent improvements to the exposure model in developing its plan for CO exposure assessment.



### 5.3 EXPOSURE ASSESSMENT APPROACH The exposure assessment approach for the cu rrent review will be informed by the previous reviews of the AQCDs for CO (US EPA, 1991, 2000) and info rmation contained within the draft ISA and relevant Annexes. The goals of the CO exposure assessment are: (1) to identify locations where current ambient concen trations exceed health benchmarks of concern, (2) to estimate the number of people exposed to CO concentrations of concern considering current air quality and just meeting alternative CO standards; (3) to provide distributions of exposure estimates over the entire range of am bient CO concentrations for use in assessing populations at risk; (4) to devel op estimates of COHb levels in sensitive populations resulting from different CO exposure scenar ios; and (5) to identify key a ssumptions and uncertainties in the exposure estimates.

Air Quality Characterization The first step in the exposure/risk assessment will be to conduct an air quality analysis relying on ambient air quality data and the information provi ded in the ISA and relevant Annexes. This analysis will include informa tion on CO properties, current CO air quality patterns, historic trends, and policy-relevant background levels 7 . This analysis will provide a frame of reference for subsequent discussions of current and possible al ternative standards. General steps in the process include the following.

7 Policy-relevant background is defined as the distribution of CO concentrations that would be observed in the U.S. in the absence of anthropogen ic (man-made) emissions of CO in the U.S., Canada, and Mexico.5-6  Obtain ambient monitoring data collect ed since the prior NAAQS review (e.g., 1995- 2007)

 Estimate number of exceedances (if any) of the current CO standards using recent monitoring data

 Estimate number of exceedances of several s hort-term peak air quality indicators given
attainment of the current CO standard s and potential alternative standards.

 Develop methods to adjust recent CO air qua lity data to simulate just meeting the current standards and any alternative CO sta ndards. EPA will consider alternative air quality simulation procedures, including a pr oportional rollback pro cedure, for use in this current review. EPA will also evaluate candidate procedures for simulating changes in CO air quality likely to result fr om just meeting the current or alternative standards based on analyzing changes in CO levels that have been observed historically and/or analyzi ng changes in CO levels pred icted by air quality models. EPA will consider factors which may influence the concentration distributions such as potential source contributions, as well as th e influence of local and regional pollution.

 Evaluate the relationship be tween 1-hour and 8-hour p eak concentrations across multiple years for different geographic areas.

Exposure Assessment The general approach would be to estimate popul ation exposures to ambient CO in one or
more urban areas across the United States. Areas in cluded in the analysis w ould be selected with the goal of achieving variation in population, geography, demographics, climate, and CO air quality. Exposure estimates would be generated for current CO levels, for levels adjusted to just meet the current NAAQS, and for levels adjusted to simulate just meeting potential alternative
standards. The exposure assessment would take into acc ount several important factors including the magnitude and duration of exposur es, frequency of repeated high exposures, and breathing rate of individuals at the time of exposure. Estimat es would be developed for multiple indicators of exposure including (1) counts of pe ople exposed one or more times to a given CO concentration while at a specified breathing rate and (2) counts of pe rson-occurrences of particular exposures, which accumulate across all people in the population of interest.5-7 EPA’s Air Pollutants Exposure (APEX) model (also referred to as the Total Risk Integrated Methodology/Exposure (TRIM.Expo) model) would be used in this analysis. APEX
is a Monte Carlo simulation model that can be used to simulate a large number of randomly sampled individuals within each area thus generating area-wide es timates of population exposure. APEX simulates exposures in indoor , outdoor, and in-vehicle microenvironments while taking into consideration the movement of individuals through time and space. A user’s guide and technical support document describe th e APEX model in detail (U.S. EPA 2006 a,b). The choice of areas to model and the exposur e assessment methodology will be described in
detail in the draft Health Assessment Plan.



### 5.4 RISK CHARACTER IZATION APPROACH A two-tiered approach to characterizing hea lth risks will be employed. In a first tier analysis, potential health effect benchmarks will be identified based on information in the draft
ISA. These health benchmark levels would be combined with exposure or dose estimates from the exposure/dose assessment in order to charac terize population health ri sks. In a second tier risk analysis, which would be conducted only if judged appropriat e and if relevant data are available, an assessment using concentration-re sponse or exposure/dose- response data would be conducted by combining this data with either am bient distributions or es timated exposure or dose distributions, respectively. The goals of a CO risk characterization woul d be: (1) to estimate the number of people exposed to CO concentrations or COHb levels above health effects benchmarks considering current air quality and air quality levels simu lated to just meet the current and potential alternative CO standards; (2) to provide distributions of health risk estimates associated with recent air quality and air quality just meeting the current and potential alternative standards if a second tier risk analysis is c onducted; and (3) to identify key a ssumptions and uncertainties in
the risk estimates.

Health Effect Benchmarks This type of risk characterization would us e exposure and/or dose (e.g., COHb) estimates, along with potential health effect benchmarks th at may be identified based on information in the draft ISA and relevant Annexes, to estimate (1) the number of individuals with exposures above5-8 levels expected to cause adverse health effect s, and (2) the percent of at risk populations experiencing exposures and/or dose levels of concern. Multiple exposure scenarios will be considered, including exposure associated with current ambient air qual ity, with current air quality levels enhanced by including local sour ce contributions, and/or with levels of CO associated with simulating just meeting the cu rrent and potential alternative standards. The potential health effect benchmarks will account for those individuals who are particularly susceptible and/or vulnerable to the effects of CO (e.g., cardiopul monary disease populations).
The health risk characterizati on would require that averaging times be comparable for any estimated exposure or dose concen trations and health metrics.

Dose-Response and Concentration-Response Functions Incorporating dose-response or concentration- response data into the risk characterization will depend on the availa bility of data from controlled human exposure studies and epidemiologic studies, respectivel y. If quantitative relationships provided by studies or derived from the data presented in studies are available th at describe the change in concentration (either ambient or exposure) or dose ( e.g. COHb level) associated with a change in health response, then these relationships could potential ly be applied to estimate health risk. Controlled human exposure studies involve volunteer subjects who are exposed to specified levels of CO under c ontrolled conditions for specified lengths of time. The endpoints of interest in previous reviews were related to the cardiovascular and cen tral nervous systems, including decrement in time to onset of chest pa in and ST-segment suppre ssion in patients with angina pectoris, reduced maxima l exercise duration in healthy adults due to decreased oxygen uptake, increased number and comple xity of arrhythmia in indivi duals with chronic arrhythmia,
and short-term effects on hand- eye coordination and vigilance in healthy individuals. In the prior reviews, these responses fo rmed the basis for the development of health benchmarks related to specified COHb levels. In contrast, epidemiological studies typical ly provide estimated concentration-response relationships based on data collected in envi ronmentally-relevant settings. Ambient CO concentration is typically included in health e ffects models as the average of monitor-specific measurements. Common health responses th at have been evaluated for CO include developmental effects, as well as cardiac and respiratory morbidity and mortality. In the5-9 previous review the epidemiologic evidence was j udged to be too limited to form the basis for developing either potential hea lth benchmarks or quantitative risk estimates. Again, depending on the type of health response f unction(s) available, ambient CO concentration data might be used for characterizing risks, a nd are most appropriatel y applied in the geographic area where the epidemiological study was performed. It should be noted that a risk characterization based on epidemiological studies also requ ires baseline incidence rates and population data for the risk
assessment locations.
Based on our current understand ing of the available evidence , we do not anticipate that there will be sufficient exposure- or dose-respon se data from controlled human exposure studies
to characterize health risks in this manner. However, there may be limited data available to develop concentration-response relationships fr om recently conducted epidemiologic studies. Following review of the draft ISA and cons idering comments and recommendations from CASAC and the public, the draft Health Assessmen t Plan will be designed to include such a proposed approach to characteri zing health risk if warranted.



### 5.5 ASSESSMENT CRITERIA
Criteria will be established and described in the draft Health Assessment Plan to determine the level of detail warranted and the sp ecific design of the assessments. The criteria will be designed to determine the value added to the assessment as measured by the reduction of uncertainties in the exposure and risk estimates. In order to determine which level of detail is warranted, the following factors will be c onsidered by the workgroup and EPA management:

 Results of the ambient air quality indicator analysis;

 Weight-of-evidence, as provided in the ISA, from new controlled human exposure studies with relevant exposure-response data , particularly those conducted at or near current ambient concentrations;

 Weight-of-evidence, as provided in the ISA, from new epidemiological studies that evaluate the relationship between short-te rm repeated peak exposures and health
outcomes;5-10  New information regarding susceptible popula tions identified in previous reviews (e.g., those with pre-existing cardiovascular disease) or information regarding newly identified susceptible populations;

 Information and data defining the potential impact of roadway CO concentrations on nearby residents and on specific microenvi ronmental concentrations (e.g., while traveling inside motor vehicles);

 Analysis of exposure studies using non-r outine monitoring, other local sources (e.g., rail-yards, airports), and/or modeled CO concentrations;

 Existence of the data required to perform th e analyses in each st age of the assessment.



### 5.6 UNCERTAINTY AND VARIABILITY The uncertainty and variability inherent in estimates of exposure and risk will be characterized regardless of the type of exposure assessment and risk characterization conducted. Uncertainty reflects the degree of confidence in the representa tiveness of models or model components. Variability can be described in terms of empirical quantities that are inherently variable across time and space or between individuals (Cullen and Frey, 1999). Assessing uncertainty and variability will begi n with a qualitative analysis and progress to a quantitative analys is if data are available to support such an analysis . The first step in the uncertainty analysis will be to identify the co mponents of the assessment, determine whether uncertainty can be evaluated for each of those co mponents, and provide a rationale for why this is the case. The second step wi ll be to perform a qualitative uncertainty analysis for the appropriate components of the assessment. This qualitative analysis will result in a matrix describing, for each area of uncertainty, both the magnitude (minimal, moderate, major) and the direction of influence (under- or ov er-estimate) on risk/exposure esti mates. If sufficient data are available, and if the magnitude of uncertainty is judged significan t, a quantitative assessment of uncertainty will then be performed for selected components of the assessment. There are two primary sources of uncertainty that would be addressed in a quantitative analysis. The first is uncertainty associated w ith the model inputs (e.g., use of air quality data, time-location-activity diaries, microenvironmen tal factor distributions). The second is uncertainty associated with model formula tion (e.g., algorithms included in the model).5-11 

### 5.7 PUBLIC AND SCIENTIFIC REVIEW
The CASAC CO Review Panel will be consul ted on the assessment approach at a public meeting. Drafts of the REA document will also be reviewed by the CASAC CO Review Panel.
The CASAC CO Review Panel will review the draft document a nd discuss their comments in a public meeting announced in the Federal Register. Based on CASAC = s past practice, EPA expects that key advice and r ecommendations for revision of the document will be summarized by the CASAC Chair in a letter to the EPA Admi nistrator. In revising the draft REA document for CO, EPA will take into account any such reco mmendations, and will also consider comments received, from CASAC or from the public, at the meeting itself and any written comments received. EPA anticipates preparing a second draft of the REA document for CASAC review and public comment. After appropriate revision, the final document will be made available on an EPA website, with its public availability being announced in the Federal Register.6-1 

## 6. POLICY ASSESSMENT/RULEMAKING

The final decision to retain or revise the NAAQS is a public health policy judgment. A final decision should draw upon scientific informa tion and analyses relate d to health effects, population exposure and risks, and judgments about the appropriat e response to the range of
uncertainties that are inherent in the scientific evidence and analyses. The Agency’s approach to informing these judgments is based on a recogniti on that the available health effects evidence generally reflects a continuum consisting of ambien t levels at which scientists generally agree that health effects are likely to occur through lower levels at which the likelihood and magnitude of the response become increasingly uncertain. Based on the information in the ISA and the exposure assessment report, EPA will publish a notice of proposed rulemaking to provid e an opportunity for CASAC and the public to evaluate the policy options under consideration and to offer comm ents and recommendations to
inform the Administrator’s decision whether to retain or revise the primary CO NAAQS, and whether to promulgate a secondary NAAQS for CO. 8 Issuance of a final decision will complete the rulemaking process.

8 As noted above in Chapter 1, EPA is also considering whether, and at what point in the process, to issue an ANPR.

## 7. REFERENCES

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. US EPA (2006b). Total Risk Integrated Met hodology (TRIM) - Air Pollutants Exposure Model Documentation (TRIM.Expo / APEX, Vers ion 4) Volume II: Technical Support Document. Office of Air Qual ity Planning and Standards, Re search Triangle Park, NC. June 2006. Available at: http://www.epa.gov/ttn/fera/human_apex.html

. US EPA (2007). Integrated Science Assessment (ISA) for Sulfur Oxides – Health Criteria (First External Review Draft). U.S. Environmenta l Protection Agency, Research Triangle Park, NC, EPA/600/R-07/108. Available at: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=182057 US EPA (2008). Integrated Science Assessment fo r Oxides of Nitrogen – Health Criteria (Final Report). U.S. Environmental Protection Agency, Research Triangle Park, NC, EPA/600/R-08/071. Available at: http://www.epa.gov/ttn/naaqs/st andards/nox/s_nox_cr_isi.html World Health Organization. (2006) . WHO Air Quality Guidelines for Particulate Matter, Ozone, Nitrogen Dioxide, and Sulfur Dioxide. Global Update 2005. Summary of Risk Assessment. World Health Organization.United States Environmental Protection Agency Office of Air Quality Planning and Standards Health and Environmental Impacts Division Research Triangle Park, NC Publication No. EPA 452/R-08-005 August 2008

Postal information in this section where appropriate.