Plan for Review of the National 

Ambient Air Quality Standards for 

Carbon Monoxide

August 2008
 EPA-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 2771
 ii 

DISCLAIMER

This integrated review plan serves as a public 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 the court-ordered schedule or information developed 

during this review, including advice 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. 
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TABLE OF CONTENTS

1. INTRODUCTION .............................................................................................................. 1-1 

1.1 OVERVIEW OF THE REVIEW PROCESS ......................................................... 1-1 

1.2 LEGISLATIVE REQUIREMENTS....................................................................... 1-3 

1.3 HISTORY OF REVIEWS 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 ................................................................................................................... 7-1 
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1. INTRODUCTION 

The U.S. Environmental Protection Agency (EPA) is conducting a review of the air 

quality criteria for carbon monoxide (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 assessment of relevant scientific information for 

CO and will focus on the basic elements of the standards: the indicator, averaging time, form,

and level. These elements, which serve to define 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 standard set at 35 parts per million (ppm), and an 

8-hour standard set at 9 ppm, neither to be exceeded more than once per year. There is currently 

no secondary standard for CO. 

This review plan is organized into six chapters. Chapter 1 presents background 

information on the review process, the legislative requirements for the review of the NAAQS, 

and past reviews of the NAAQS forCO. Chapter 2 presents the current review schedule. 

Chapter 3 presents a set of policy-relevant questions that will serve to focus this review on the 

critical scientific and policy issues. Chapters 4 through 6 discuss the planned scope and 

organization of the key assessment documents, the planned approaches for preparing the 

documents, and plans for scientific and 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 current review of the NAAQS forCO, contains four major components: an 

integrated review plan, a science assessment, a risk/exposure assessment, and a policy 

assessment/rulemaking. Each of these components is described in this section. 

 1

 This plan will generally refer to the review of the 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. 
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The review process starts with the development 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 Air and Radiation (OAR). This document represents the current 

plan and specifies the schedule for the entire review, the process for conducting the review, and 

the key policy-relevant science issues that will guide the review. 

The second component of the review process is the development of the science 

assessment, which consists of an Integrated Science Assessment (ISA) and supporting annexes. 

NCEA collaborates with contracted expert support to prepare these documents. The annexes will 

contain a comprehensive description of the full breadth of the current scientific literature 

pertaining to known and anticipated effects on public health and welfare 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 interpretation of health and welfare effects. NCEA will critically 

evaluate, integrate, and synthesize the most policy-relevant science into an ISA. The ISA is 

intended to provide information useful in forming 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 Criteria Document (AQCD) did 

in previous reviews. The schedule includes production of a first 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 planned 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 qualitative estimates of the exposures and risks of 

adverse health effects associated with current ambient levels of CO, with levels that just meet the 

current standards, and with levels that just meet possible alternative standards. 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 ISA 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 the 
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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 assessment reports that will focus on key results, 

observations, and uncertainties. 

The fourth component of the revised process will be a policy assessment/rulemaking. 

Under the new process, a staff paper, such as that prepared in previous NAAQS reviews, will not 

be prepared. Rather, Agency views on policy options 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) govern the establishment and revision of the 

NAAQS. Section 108 (42 U.S.C. 7408) directs the Administrator to identify and list air 

pollutants that “in his judgment, cause or contribute to air pollution which may reasonably be 

anticipated to endanger public health and welfare” and whose “presence . . . in the ambient air 

results from numerous or diverse mobile or stationary sources” and to issue air quality criteria 

for those that are listed. Air quality criteria are intended to “accurately reflect the latest scientific 

knowledge useful in indicating the kind and extent of identifiable effects on public health or 

welfare which may be expected from the presence 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 listed under section 108. Section 109(b)(1) 

defines a primary standard as one “the attainment and maintenance of which in the judgment of 

the Administrator, based on such criteria and allowing an adequate margin of safety, are requisite 

to protect the public health.”3

 A secondary standard, as defined in section 109(b)(2), must 

“specify a level of air quality the attainment and maintenance of which, in the judgment of the 

 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 that 
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Administrator, based on such criteria, is requisite to protect the public welfare from any known 

or anticipated adverse effects associated with the presence of [the] pollutant in the ambient air.”4

The requirement that primary standards include an adequate margin of safety was 

intended to address uncertainties associated with inconclusive scientific and technical 

information available at the time of standard setting. It was also intended to provide a reasonable 

degree of protection against hazards that research has not yet identified. 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 selecting primary standards that include an adequate 

margin of safety, the Administrator is seeking not only to prevent pollution levels that have been 

demonstrated to be harmful but also to prevent lower pollutant levels that may pose an 

unacceptable risk of harm, even if the risk is not precisely identified as to nature or degree. 

In selecting a margin of safety, the EPA considers such factors as the nature and severity 

of the health effects involved, the size of sensitive population(s) at risk, and the kind and degree 

of the uncertainties that must be addressed. The selection of any particular approach to 

providing an adequate margin of safety is a policy choice left specifically to the Administrator’s 

judgment. See Lead Industries Association v. EPA, 647 F.2d at 1161-62. 

In setting standards that are “requisite” to protect public health and welfare, as provided in 

section 109(b), EPA’s task is to establish standards that are neither more nor less stringent than 

necessary for these purposes. In so doing, EPA may not consider the costs of implementing the 

standards. 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 December 31, 1980, and at 5-year 

intervals thereafter, the Administrator shall complete a thorough review of the criteria 

 for this purpose “reference should be made to a representative sample of persons comprising the sensitive group 

rather than to a single person in such a group” S. Rep. No. 91-1196, 91st Cong., 2d Sess. 10 (1970).

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, animals, wildlife, weather, visibility and climate, damage to 

and deterioration of property, and hazards to transportation, as well as effects on economic values and on personal 

comfort and well-being.” 
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published under section 108 and the national ambient air quality standards . . . and shall make 

such revisions in such criteria and standards and promulgate such new standards as may be 

appropriate . . . .” Section 109(d)(2) requires that an independent scientific review committee 

“shall complete a review of the criteria . . . and the national primary and secondary ambient air 

quality standards . . . and shall recommend to the Administrator any new . . . standards and 

revisions of existing criteria and standards as may be appropriate . . . .” Since the early 1980's, 

this independent review function has been performed 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 identical 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 initialCO 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 for the final decision resulted in EPA’s announcing a second public 

comment period (47 FR 26407). Following 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 announced its final decision (50 FR 37484) not to 

revise the existing primary standard and to revoke the secondary standard for CO on September 

13, 1985, due to a lack of evidence of direct effects on public welfare at ambient concentrations. 

In 1987, EPA initiated action to revise the criteria for CO and released a revised AQCD 

for CASAC and public review. In a “closure letter” (McClellan, 1991) sent to the Administrator, 

the CASAC concluded that the AQCD (US EPA, 1991) “. . . provides a scientifically balanced 

and defensible summary of current knowledge of the effects of this pollutant 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 reviewed by CASAC and the public, and in a “closure 

 

5 See http://yosemite.epa.gov/sab/sabproduct.nsf/WebCASAC/CommitteesandMembership?OpenDocument for a 

list of members of CASAC and of the CASAC CO Review Panel. 
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letter” (McClellan, 1992) sent to the Administrator, it was stated “. . . that a standard of the 

present form and with a numerical value similar to that of the present standard would be 

supported by the present scientific data on health effects of exposure to carbon monoxide.” 

Based on the revised AQCD (US EPA, 1991) and staff conclusions and recommendations 

contained in the revised Staff Paper (US EPA. 1992), the Administrator announced the final 

decision (59 FR 38906) on August 1, 1994, that revision of the primary NAAQS for CO was not 

appropriate. 

 In 1997, revisions to the AQCD were initiated. 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 considered 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 released in August 2000. EPA put the review on 

hold when Congress called on the National Research Council (NRC) to conduct a review of the 

impact of meteorology and topography on ambient CO concentrations in high altitude and 

extreme cold regions of the U.S. In response, the NRC convened the committee on Carbon 

Monoxide Episodes in Meteorological and Topographical 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 offered a wide range of recommendations on 

management of CO air pollution, cold start emissions 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 standard, relevant scientific information on 

human exposures and health effects associated with exposure to ambient CO will be assessed. 

The possible influence of other atmospheric pollutants on the interpretation of the role ofCO in 

health effects studies will be considered. This will include other pollutants with the potential to 

co-occur in the environment (e.g., NO2, SO2, O3, and PM). The review will also assess any 

 
 1-7 

relevant scientific information associated with known or anticipated public welfare effects that 

may be identified. 
 2-1 

2. REVIEW SCHEDULE 

In September 2007, EPA’s National Center for Environmental Assessment in Research 

Triangle Park, NC (NCEA-RTP) announced the initiation of the current periodic review of the 

air quality criteria forCO 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 

FinalCO NAAQS IRP August 2008 

Science Assessment Prepare first 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 

Policy Assessment/ Proposed rulemaking October 28, 2010 

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. 
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3. KEY POLICY-RELEVANT ISSUES 

The key policy-relevant issues to be addressed in this review are presented below as a 

series of policy-relevant questions that will frame our approach to determining whether the 

current primary NAAQS for CO should be retained or revised and whether to set separate 

secondary standards. The ISA, health risk/exposure assessment, and any welfare-related 

assessment(s) to be conducted in this review will provide the basis 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 toCO is associated with a variety of acute health effects, 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. There was insufficient evidence of welfare effects 

occurring at or near ambient levels to justify 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 associated with 1-hour and 8-hour exposures to ambient CO. A 

separate long-term standard was not recommended. 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 forCO 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 health effects related to 
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exposure toCO in the ambient air. The ISA will consider a series of questions including the 

following: 

 Has new information altered the scientific support 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 outcomes. Is there new or emerging evidence on 

health effects beyond cardiovascular and respiratory 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 about high-exposure human subpopulations and the health 

effects ofCO? What information is available on elevated exposures due to other 

transportation sources, such as shipping, port operations, and recreational 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 evidence becoming available to improve our 

understanding of the health effects associated with various time periods of CO 

exposures, including not only daily, but also chronic (months to years) exposures? To 

what extent is critical research becoming available that could improve our 

understanding of the relationship between various health endpoints 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 the last review been reduced 

and/or have new uncertainties emerged? 
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 If the evidence suggests that revision of the current standards might be appropriate, we 

will consider whether the available body of evidence 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 adverse health effects at levels of CO lower 

than those observed previously, and conversely, is there evidence that suggests that 

effects occur only at higher levels than previously reported? If so, at what levels and 

what are the important uncertainties associated with that evidence?

 Do exposure estimates suggest that exposures of concern forCO-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 uncertainties associated with these exposure 

estimates? 

 Do health 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 health effects evidence and air 

quality/exposure assessments, and what are 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 should be considered. The answers to these 

questions, and the resulting conclusions regarding the corresponding policy issues, will inform 

the decision of whether to set secondary NAAQS for CO. 

The first step in reviewing the possible need for secondary NAAQS is to consider 

whether the available body of scientific literature, assessed in the ISA, provides evidence of 

welfare effects related to exposure toCO in the ambient air. The 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) welfare 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 evidence becoming available to improve our 

understanding of the welfare effects associated with various time periods of CO 

exposures, including not only daily, but also chronic (months to years) exposures? 

 Has new information, analytical tools/methods, or scientific insight altered conclusions 

from previous reviews regarding the plausibility of adverse welfare effects caused by 

CO exposure? 

 To what extent have important uncertainties identified in the last review been reduced 

or new uncertainties emerged? 

 If the evidence suggests that setting a secondary standard or standards might be 

appropriate, we will consider whether the available body of evidence supports consideration of 

various options. The following questions will inform this determination: 

 Is there evidence for the occurrence of adverse welfare effects at levels of CO lower 

than those observed previously? If so, at what levels and what are the important 

uncertainties associated with that evidence?

 Do exposure estimates suggest that exposures of concern forCO-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 uncertainties 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 are 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 are the uncertainties and limitations in the 

welfare effects evidence and air quality/exposure assessments? 
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4. SCIENCE ASSESSMENT 

4.1 SCOPE AND ORGANIZATION 

The science assessment forCO will consist of the ISA and its supporting annexes. The 

ISA will critically evaluate and integrate the scientific information on exposure, health effects, 

and welfare effects associated withCO 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 studies), and dosimetry, as well as human exposure and atmospheric 

science relevant to the review of the CO NAAQS. The ISA will draw from this evidence and 

synthesize the current state of knowledge on the most relevant issues pertinent to the review of 

the NAAQS forCO. A formal framework for the integration of health effects evidence, based on 

approaches formulated by other regulatory and science agencies, has been developed for the final 

ISA for NOx (U.S. EPA, 2008) and will be applied in the current CO review. Information from 

the scientific disciplines listed above will be integrated into the health effects evidence in order 

to contribute to a better understanding of population exposure and/or risk, or to a better 

understanding of the nature, sources, distribution, measurement, and/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 identified since the previous review of the air 

quality criteria forCO and on key science and policy issues raised during the last review, 

including issues addressed in the NRC committee report on CO (NRC, 2003). Findings and 

conclusions from the 2000 Air Quality Criteria Document (US EPA, 2000) for CO will be briefly 

summarized at the beginning of the ISA. The results of new studies will be integrated with 

previous findings. Important older studies will be more specifically discussed if they remain 

definitive or are open to reinterpretation in light of newer data. Information that has undergone 

scientific peer review and that has been published (or accepted for publication) in the open 

literature will be considered. Additionally, official studies and reports from governmental 

agencies may be included, as appropriate. Emphasis will be placed on studies conducted at or 
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nearCO concentrations found in ambient air. In recognition of the fact that toxicologic and 

human clinical studies do not necessarily reflect effects in the most sensitive population, studies 

at higher exposure levels will be included when they provide information relevant to previously 

unreported effects, evidence of the potential mechanism for an observed effect, or information on 

exposure-response relationships. 

4.2 ASSESSMENT APPROACH 

Introduction 

The EPA’s National Center for Environmental Assessment in Research Triangle Park 

(NCEA-RTP) is responsible for preparing the ISA and the related annexes forCO. Expert 

authors include EPA staff with extensive knowledge in their respective fields and extramural 

scientists contracted to the EPA. A diagram showing the standard protocol for development of 

an ISA, including both health and ecosystem effects, is presented in Figure 4.1. While no 

secondary standard currently exists for CO, any evidence of welfare effects of ambient CO (such 

as effects on domestic and wild animals, crops and forest vegetation, and microorganisms) 

identified during ISA development will also be included. The ISA for CO will focus primarily 

on scientific evidence relating to health effects. A complete description of the new NAAQS 

review process is presented in Section 1.1. 
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Figure 4.1. Protocol for ISA development, showing the steps involved in production of 

Integrated Science Assessments. 
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Literature Search 

NCEA-RTP will use a systematic approach to identify relevant studies for consideration. 

A Federal Register Notice (72 FR 52369, September 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, CH4, CO2, hydroxyl radical, carboxyhemoglobin, COHb, hypoxia, 

traffic, and combustion. Targeted searches will also be conducted to identify articles relevant to 

specific health, ecological, and physical science disciplines. As appropriate, the search strategies 

will be periodically reexamined and modified to enhance identification of pertinent published 

papers. Additional papers will be identified for inclusion 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, publications 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 determined to be as inclusive as possible given 

the relevant target dates in the NAAQS review schedule. Some additional 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 these approaches should produce the comprehensive 

collection of potentially pertinent studies needed to form the basis of the ISA. The following 

sections briefly summarize criteria for selection of studies for this draft ISA. 

General Criteria for Study Selection 

In assessing the scientific quality and relevance of epidemiological and human or animal 

toxicological studies, the following considerations will be taken into account. 

 To what extent are the aerometric data, exposure, or dose metrics of adequate quality 

and sufficiently representative of population exposure to serve as indicators of 

exposure to ambient CO? 

 Were the study populations adequately selected and are they sufficiently well defined 

to allow for meaningful, reliable comparisons between study groups? 

 Are the health endpoint measurements meaningful, reliable, and clinically 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-response relationships? 

 Are the statistical analyses appropriate, properly performed, and properly interpreted 

with sufficient statistical power? 

 Are likely covariates (i.e., potential confounders or effect modifiers) adequately 

controlled or taken into account in the study design and statistical analysis? 

 Are the reported findings internally consistent, biologically plausible, and coherent in 

terms of consistency with other known facts? 

Consideration of these issues, more fully discussed 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 ofCO; (2) health 

effects of CO or indicators related toCO 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 effects; and/or (5) important methodological issues (e.g., lag of 

effects, model specifications, thresholds, mortality displacement) related toCO exposure effects. 

All selected studies will be considered in the evaluation of the health evidence, including studies 

conducted in countries outside the United States and Canada. In drawing conclusions or 

recommendations pertinent for quantitative risk or exposure analyses, particular emphasis will be 

placed on those relevant to standard setting in the United States. Specifically, certain findings of 

studies conducted in the U.S. or Canada may be discussed in more detail than those from other 

geographic regions, as the potential impacts of housing characteristics, activity patterns, differing 

health care systems and the underlying health status of the populations 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 evaluating CO effects and that 
 4-6 

provide overall estimates for effects based on combined analyses of information pooled across 

multiple cities; (2) new studies that provide quantitative effect estimates for populations of 

interest; and (3) studies that considerCO as a component of a complex mixture of air pollutants. 

Criteria for Selecting Human Laboratory, Clinical, and Animal Toxicological Studies 

The review of research evaluating animal toxicological or controlled exposure studies will 

focus primarily on those studies conducted at physiologically relevant CO concentrations and 

those studies that approximate expected human exposure conditions in terms of concentration 

and duration. Studies that elucidate modes of action or mechanisms underlying biological effects 

and/or examine susceptibility will be considered. 

The selection of research evaluating controlled human exposures to CO will focus on 

studies in which subjects were exposed at conditions relevant either to ambient exposures or to 

determination of mechanism. For these controlled human exposures, emphasis will be placed on 

studies that: (1) investigate potentially susceptible populations such as individuals with 

cardiovascular disease, particularly studies that compare responses in susceptible individuals 

with those in age-matched healthy controls; (2) address issues such as dose-response or timecourse of responses; (3) investigate exposure to CO separately and in combination with other 

pollutants such as PM, O3, NO2 and SO2; (4) are appropriately blinded 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 evidence will focus on studies that approximate 

expected human dose conditions, which will vary depending on the toxicokinetics and biological 

sensitivity of the particular laboratory animals examined. In addition, resource constraints 

prevent animal researchers from testing hypotheses that require large numbers of animals 

exposed to ambient levels of CO over a prolonged period. Consequently, animal studies are 

typically used to acquire data relating to mechanisms, 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 understanding of interspecies differences and potential 

sensitivity differences between healthy 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 assurance plan for searching scientific literature 

which details an approach to gathering the scientific information found in peer-reviewed journal 

articles and government reports. Additionally, NCEA has data quality objectives which identify 

inputs to the science assessment and provide quality assurance (QA) instruction for researchers 

citing secondary information. 

Content and Organization of the ISA 

The organization of the ISA forCO 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 considering whether it is appropriate to retain 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 will 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 EPA campus in Research Triangle Park, NC. 

These policy-relevant questions are related to two overarching issues. 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 uncertainties from the last review have been 

addressed and/or whether new uncertainties 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 formation, degradation, and lifetime of CO in the 

atmosphere. 

 What are the strengths and weaknesses 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 ofCO 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 variability in concentrations? To what extent are 

ambient CO concentrations correlated with other air pollutants (e.g., NOx, O3, PM, 

SOx), 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) identified the spatial variability 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 are the implications of the current network configuration 

for the interpretation of CO-related health effects? 

 Using air quality and emissions data on CO and atmospheric chemistry models, what 

are likely policy relevant background concentrations ofCO? 

 Are there other techniques that can be used to better define the range of concentrations 

and the spatial and temporal variability ofCO 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 ofCO emissions? 

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

Human Exposure: The ISA will evaluate the factors that influence exposure toCO and the 

uncertainties associated with extrapolation from ambient concentrations to personal exposures to

CO of ambient origin, particularly in the context of interpreting results from epidemiologic 

studies. The issues of uncertainty differ by the exposure period of interest. Short-term exposure 

studies (e.g., population-level studies using time-series analyses, field/panel studies) primarily 

rely on temporal variation in exposure, while long-term exposure studies (e.g., longitudinal 

cohort studies) rely on spatial 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., NOx, O3, PM, SOx)? What factors affect 

these relationships (season, housing characteristics, activity patterns, etc.)? 

 What are the uncertainties when extrapolating 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 concentrations, and their use as a surrogate for 

personal exposure to CO of ambient origin. 

 What information is available on exposures to short-term (< 1 hr) peak CO 

concentrations? 

 To what extent do measurements from ambient CO monitors provide an estimate of 

ambient exposures for health studies, serve as an indicator of personal exposure toCO, 

and/or serve as an indicator of personal exposure to other gaseous pollutants 

(including O3 and NO2) and particulate pollutants generated by traffic? 

 What influence do the temporal and spatial patterns ofCO exposure, for both indoor 

and outdoor sources, have on evaluation of health effects? What is the exposure 

pattern for indoor sources, such as gas stoves and space heaters (i.e., peak, repeated 

peak, and averageCO) and how does it relate to ambient CO patterns? 

 What evidence is available on subpopulations likely to have high ambient CO 

exposures including those living, working and/or attending school near roadways and 

those in the vicinity of shipping or port operations? 

 What data are available to interpret 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 periods 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 toCO (particularly at low ambient levels). 

 How do modeled predictions ofCO 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 formation of COHb. Recent information relating to 

either the well-established Coburn-Forster-Kane model or alternative 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 evidence on uncertainties in modeling COHb as a 

function of inhaled CO. The contribution of endogenously produced CO to COHb is included in 

the Coburn-Forster-Kane model and will be considered in the integrative health effects section of 

the ISA. 

 What new information is available on the validity and applicability of the CoburnForster-Kane model? Are alternative approaches 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 formation in fetuses and infants? 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 literature related to health effects identified in the 2000 AQCD, 

as well as any additional health outcomes identified during the review. Previously identified 

health effects include cardiovascular effects (e.g., myocardial ischemia, angina, arrhythmia), 

central nervous system effects (e.g., loss of dexterity, visual impairment), respiratory effects, and 

birth outcomes (e.g., low birth weight, 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. Health effects that are associated with both shortand long-term exposures will be evaluated in epidemiologic, human clinical, and toxicologic 

studies. Recent studies regarding the formation of endogenous CO by cells and tissues and the 

resulting localized biological response will be evaluated in order to determine the relevance to 
 4-11 

biological responses following ambient CO exposure. Causality, uncertainty, biological 

mechanism of action, susceptible and vulnerable populations, and public health impact will all be 

considered. The data will be reviewed with the understanding that effects from ambient CO must 

be considered in conjunction with co-occurring pollutants (e.g., NOx, O3, PM, SOx). 

For a given type of health outcome, the ISA will evaluate the strength, robustness and 

consistency of the findings from the different disciplines. 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 attribution of health effects to CO as a component of multipollutant 

exposures. Efforts will be directed at identifying the lower levels at which effects are observed 

and at determining concentration-response relationships for CO. Concentration-response 

relationships among these studies will be evaluated 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 the public health implications related to ambient CO exposure. 

The evaluation will also focus on which exposure durations and developmental time periods of 

exposure are most strongly associated with effects, for both short-term and long-term exposures. 

Short-Term Exposure: 

 What do controlled human exposure, animal toxicologic, and epidemiologic studies 

indicate regarding the relationship between short-term exposures toCO and health 

effects of concern in both healthy individuals and in those 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 ofCO exposure on breathing rate and respiratory gas exchange in 

healthy and susceptible individuals (e.g., oxygen diffusion capacity and ventilationperfusion mismatches) and what is the potential clinical relevance of these effects? 

Does recent evidence indicate other respiratory effects from ambient CO exposure? 
 4-12 

 Is exposure toCO associated with mortality (total, respiratory or cardiovascular), 

hospital admissions, or emergency department visits as assessed using populationlevel datasets? What are the lowest ambientCO 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 confound or modify the effect observed due to exposure to 

CO? The utility of the statistical methods applied will be evaluated (i.e., time-series 

studies). As discussed above, the potential effects of exposure error on epidemiologic 

outcomes will be evaluated. 

 To what extent does exposure toCO contribute to health effects 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 particularly vulnerable periods for developmental effects of 

CO exposure? 

 What is the nature of health effects in persons exposed to multipollutant mixtures that 

containCO in comparison to exposure to CO alone? 

 Does exposure to ambient CO perturb the biologic 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 used in the assessments? What detectable 

biological changes will be considered adverse health effects? 

Long-Term Exposure: 

 Does the scientific evidence support the occurrence of health effects from long-term 

exposure (e.g., months to years) at ambient levels that are lower than previously 
 4-13 

observed? If so, what uncertainties are related to these associations, and are the health 

effects in question important from a public health perspective? 

 Can long-term exposures to CO result in chronic effects such as developmental effects 

or birth outcome effects? 

 What are relevant exposure periods for effects associated with birth outcomes? What 

metrics are appropriate for assessing developmental 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-termCO exposure and 

shortening of human life span via 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 relating to the existence or lack of a causal 

relationship between observed health outcomes andCO exposure using a framework developed 

by NCEA for the recent NOX ISA (U.S. EPA, 2008). This framework is designed to improve 

consistency and transparency by establishing uniform language to describe causal relationships 

and explicitly outlining the guidelines that are used to evaluate causality. These guidelines are 

based on those proposed by Sir Austin Bradford Hill in 1965 (Hill, 1965), including: 

consistency, strength, specificity, and temporality of the observed association; evidence of an 

exposure-response relationship; biological plausibility and coherence; experimental evidence 

from human populations; and analogy (e.g. mode of action for structural analogs). Individual 

studies may not provide information on all of these factors, yet remain informative for inferring 

causality. This approach draws from and is consistent with similar approaches formulated by 

government agencies and the wider scientific community, including the Institute of Medicine 

(IOM, 2007), the International Agency for Research 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 plausibility and coherence of the evidence will be key 

considerations in drawing conclusions about causality. The ISA will place emphasis on studies 
 4-14 

conducted at or near typical ambient levels, except regarding evidence of biological plausibility 

and mechanisms, as these may only be observable in animal or human exposure study 

populations at higher levels than they might be observed in susceptible human populations. The 

ISA will also assess any information available from “intervention” studies regarding the health 

impacts of decreases in ambient levels of CO that is relevant to the evaluation of causality in 

CO-health outcome relationships or benefits accruing from such interventions. 

 Does the evidence base contain new information to evaluate the case for or against a 

causal relationship between health effects andCO exposure? 

 What information is available regarding the health impacts of a decrease in ambient 

levels ofCO? 

 What insights can be gained regarding causality by comparing health effects observed 

in older multipollutant studies (with comparatively higher ambient CO levels) with 

more recent multipollutant studies? 

Uncertainties: The ISA will evaluate uncertainty in the scientific data, particularly in relation to 

observed epidemiologic findings and their consistency 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., O3, PM, SO2, and NO2) 

and meteorological factors influence the associations observed with CO for both shortand long-term exposures? The manner in which ambient CO concentration may serve 

as a surrogate for exposure to vehicle exhaust 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, genetic susceptibility factors, occupational 

exposure, and medical care)? 

 What is the shape of the concentration-response function (e.g., linear vs. threshold 

models)? 

 What are the uncertainties associated with comparing the results of birth outcome 

studies utilizing different study designs, metrics, and endpoints? 
 4-15 

 What uncertainties surround the evidence for long-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 toCO. 

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

 What are the potential mechanisms of response toCO, with a focus on 

physical-chemical characteristics, response pathway(s), and exposure-dose-response 

relationships? 

 What indicators other than carboxyhemoglobin (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 ofCO-induced injury? 

 What physiological characteristics of neonates may lead to differential responses and 

effects compared to adults? 

 WhichCO-induced health effects are sufficiently characterized to be quantitatively 

compared across species? 

 What are the interspecies differences in sensitivity to CO and in basic mechanisms of 

injury and repair? What are the implications 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 extrapolations possible for short- and for 

long-term exposures? 

Susceptible Populations: The ISA will examine health outcome data to identify specific groups 

that are more susceptible to the adverse effects ofCO exposure than normal healthy adults (e.g., 

persons with cardiovascular disease, COPD, or reduced or abnormal 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, COPD)? 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 healthy 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 conjunction with advanced age 

an important factor in susceptibility to mortality associated with exposure toCO? 

 Regarding morbidity health endpoints, to what 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 exposure-response characteristics, considering that these 

results may be driven by the more sensitive subpopulations? 

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

susceptibility? 

 What host and environmental factors (e.g., demographic, socioeconomic, and genetic) 

are associated with susceptibility to short- and long-term exposure toCO? 

Public Health Impact: The ISA will present concepts related to the potential for defining adverse 

health effects. To accomplish this, the implications for public health of different health effects 

will be discussed. This will include, as appropriate, an estimation of the potential number of 

persons at risk in specific susceptible and vulnerable at-risk population groups. The concept of 

attributable risk, which considers the exposure of a subpopulation along with relative risk, will 
 4-17 

be evaluated in consideration of the public health impact. Low-level effects will be interpreted 

in light of the policy-relevant background concentration of CO. Furthermore, the analysis will 

identify and address, as appropriate, disproportionately 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 coverage 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 considered during the review. Annexes also provide 

in-depth discussion of scientific topics supporting interpretation of exposure, health, and welfare 

effects. The annexes will provide information on: (1) the chemistry, physics, sources, and 

emissions of CO, as well as sampling and analytic methods for measurement ofCO; 2) 

environmental concentrations and human exposure toCO; (3) dosimetry; (4) toxicologic studies 

ofCO health effects in laboratory 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 toCO. 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 include information about: (1) concentrations ofCO 

levels and averaging times; (2) description of study methods employed; (3) results and 

comments; and (4) quantitative outcomes for CO measures. Additionally, annexes will contain 

background material on legislative requirements, the NAAQS review process, and the history of 

earlier CO reviews. 

4.3 SCIENTIFIC AND PUBLIC REVIEW 

Drafts of the ISA will be reviewed by the 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 review; however, CASAC 

members will not be specifically charged with reviewing the annexes. The CASAC CO Review 
 4-18 

Panel will review the first draft ISA and discuss 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 recommendations for revision of the document in a 

letter to the EPA Administrator. In revising the first draft ISA forCO, EPA will take into 

account any such recommendations, as well as comments received from CASAC or from the 

public at the meeting itself and any written comments received. EPA will prepare a second draft 

ISA for CASAC review and public comment. The CASAC CO Review Panel will review the 

second draft ISA and discuss their comments in a public meeting announced in the Federal 

Register. Again, based on CASAC’s past practice, EPA anticipates the CASAC chair will 

summarize key advice and recommendations for revision of the second draft ISA in a letter to the 

EPA Administrator. In finalizing the ISA, EPA will take into account any such 

recommendations. EPA will also consider comments received from CASAC or from the public 

at the meeting itself and any written public comments. 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 will 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 exposures and to characterize the potential health risks that are 

associated with current ambient levels, with ambient levels that just meet the existing standard, 

and with ambient levels that just meet alternative 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 atmospheric chemistry, air quality, human exposure, 

formation of COHb levels, and health effects of concern. In particular, the availability of 

concentration-response and dose-response data from the health effects literature will influence 

the type of exposure assessment and risk characterization that would be performed. 

The assessments will focus on exposures and dose 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 concern, 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 Assessment Plan: Scope and Methods for Exposure and 

Risk Assessment (hereafter, “Health Assessment Plan”). The Health Assessment Plan will be 

the subject of a consultation with the CASACCO 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 consideration. The REA document 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 forCO, a quantitative analysis of CO exposures in 

Denver, CO, was conducted to provide estimates 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 current CO standards and preliminary insight into 

the relative impact of certain indoor sources to total CO exposure. 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) current 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 the controlling standard for attainment (US EPA, 

1979b). Indoor sources that were considered included residential gas stoves and passive 

smoking. Other indoor sources, such as running automobiles in private or public garages and 

CO intrusion into a motor vehicle from the vehicle itself, were not included 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 Model (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 cardiovascular disease in Denver. In addition, 

estimates also were made of the percentage of the cardiovascular heart 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 derived by applying a modified version of the CoburnForster-Kane (CFK) differential equation that estimates COHb levels from CO exposure as a 

function of time and physiological and environmental factors (e.g., blood volume, altitude, 
 5-3 

endogenous CO production rate). It was estimated 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 disease experiencing exposures at or above 9 

ppm for 8 hours decreased by an order of magnitude or more, down to less than 1 percent of the 

total person-days in that population. Likewise, meeting the current 8-hour standard reduced the 

proportion of the nonsmoking cardiovascular-disease 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 percent of the nonsmoking cardiovascular-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 assessment, and considering the 1985 review of similar 

CO effects and effects levels, the Administrator concluded that the evaluation of adequacy of the 

existing CO standards should focus on reducing the number of individuals with cardiovascular 

disease from being exposed to CO levels in the ambient air that would result in COHb levels of 

2.1 percent or greater. The Administrator concluded that standards that limit the occurrence of 

COHb levels above 2.1 percent would provide an adequate margin of safety against effects of 

uncertain occurrence in the range of 2.1 to 2.9 percent, as well as those of clear concern that have 

been associated with COHb levels in the range 2.9 to 5.9 percent. The Administrator also 

concluded that relatively few people of the cardiovascular 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 standards are attained. The analysis also indicated, 

however, that certain indoor sources (e.g., passive smoking, gas stove usage) contributed to total 

CO exposure but could not be effectively mitigated 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 are often exposed in a particular location or 

activity (e.g., sleeping, working) and provided a good indicator for tracking continuous 

exposures that occurred during any 24-hour period. 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 exposures in the urban environment. Review of scientific information in the 
 5-4 

1991 Criteria Document indicated that these reasons for choosing averaging times for the CO 

standards remained valid and there 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 standards. For the above reasons, the Administrator determined 

under section 109(d)(1) that revisions 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 planned 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 analysis conducted in the previous review. In 

addition, Denver was one of a few areas where a personal CO exposure study had been 

conducted. After an initial review of the methodology, EPA planned to also conduct the 

analyses for LA for several reasons: (1) it presented the largest potential 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 model 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 and preliminary insight into the relative impact 

indoor sources may have on total exposure. The 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 planned for evaluation because previous analyses 

indicated that it was the controlling 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 and 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 NAAQS 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 current review will be informed by the 

previous reviews of the AQCDs for CO (US EPA, 1991, 2000) and information contained within 

the draft ISA and relevant Annexes. The goals of the CO exposure assessment are: (1) to 

identify locations where current ambient concentrations 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 ambient CO concentrations for use in assessing 

populations at risk; (4) to develop estimates of COHb levels in sensitive populations resulting 

from different CO exposure scenarios; and (5) to identify key assumptions 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 provided in the ISA and relevant 

Annexes. This analysis will include information on CO properties, current CO air quality 

patterns, historic trends, and policy-relevant background levels7

. This analysis will provide a 

frame of reference for subsequent discussions of current and possible alternative 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 anthropogenic (man-made) emissions ofCO in the U.S., Canada, and Mexico. 
 5-6 

 Obtain ambient monitoring data collected 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 short-term peak air quality indicators given 

attainment of the current CO standards and potential alternative standards. 

 Develop methods to adjust recent CO air quality data to simulate just meeting the 

current standards and any alternative CO standards. EPA will consider alternative air 

quality simulation procedures, including a proportional rollback procedure, for use in 

this current review. EPA will also evaluate candidate procedures for simulating 

changes in CO air quality likely to result from just meeting the current or alternative 

standards based on analyzing changes in CO levels that have been observed 

historically and/or analyzing changes in CO levels predicted by air quality models. 

EPA will consider factors which may influence the concentration distributions such as 

potential source contributions, as well as the influence of local and regional pollution. 

 Evaluate the relationship between 1-hour and 8-hour peak concentrations across 

multiple years for different geographic areas. 

Exposure Assessment 

The general approach would be to estimate population exposures to ambient CO in one or 

more urban areas across the United States. Areas included in the analysis would 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 account several important factors including the 

magnitude and duration of exposures, frequency of repeated high exposures, and breathing rate 

of individuals at the time of exposure. Estimates would be developed for multiple indicators of 

exposure including (1) counts of people exposed one or more times to a given CO concentration 

while at a specified breathing rate and (2) counts of person-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 estimates 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 the APEX model in detail (U.S. EPA 2006 a,b). 

The choice of areas to model and the exposure assessment methodology will be described in 

detail in the draft Health Assessment Plan. 

5.4 RISK CHARACTERIZATION APPROACH 

A two-tiered approach to characterizing health 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 characterize population health risks. In a second tier 

risk analysis, which would be conducted only if judged appropriate and if relevant data are 

available, an assessment using concentration-response or exposure/dose-response data would be 

conducted by combining this data with either ambient distributions or estimated exposure or dose 

distributions, respectively. 

The goals of a CO risk characterization would 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 simulated 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 conducted; and (3) to identify key assumptions and uncertainties in 

the risk estimates. 

Health Effect Benchmarks 

This type of risk characterization would use exposure and/or dose (e.g., COHb) estimates, 

along with potential health effect benchmarks that may be identified based on information in the 

draft ISA and relevant Annexes, to estimate (1) the number of individuals with exposures above 
 5-8 

levels expected to cause adverse health effects, 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 quality, with current air 

quality levels enhanced by including local source contributions, and/or with levels of CO 

associated with simulating just meeting the current 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., cardiopulmonary disease populations). 

The health risk characterization would require that averaging times be comparable for any 

estimated exposure or dose concentrations and health metrics. 

Dose-Response and Concentration-Response Functions 

Incorporating dose-response or concentration-response data into the risk characterization 

will depend on the availability of data from controlled human exposure studies and 

epidemiologic studies, respectively. If quantitative relationships provided by studies or derived 

from the data presented in studies are available that 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 potentially be applied to estimate health risk. 

Controlled human exposure studies involve volunteer subjects who are exposed to 

specified levels of CO under controlled conditions for specified lengths of time. The endpoints 

of interest in previous reviews were related to the cardiovascular and central nervous systems, 

including decrement in time to onset of chest pain and ST-segment suppression in patients with 

angina pectoris, reduced maximal exercise duration in healthy adults due to decreased oxygen 

uptake, increased number and complexity of arrhythmia in individuals with chronic arrhythmia, 

and short-term effects on hand-eye coordination and vigilance in healthy individuals. In the 

prior reviews, these responses formed the basis for the development of health benchmarks related 

to specified COHb levels. 

In contrast, epidemiological studies typically provide estimated concentration-response 

relationships based on data collected in environmentally-relevant settings. Ambient CO 

concentration is typically included in health effects models as the average of monitor-specific 

measurements. Common health responses that have been evaluated for CO include 

developmental effects, as well as cardiac and respiratory morbidity and mortality. In the 
 5-9 

previous review the epidemiologic evidence was judged to be too limited to form the basis for 

developing either potential health benchmarks or quantitative risk estimates. Again, depending 

on the type of health response function(s) available, ambient CO concentration data might be 

used for characterizing risks, and are most appropriately applied in the geographic area where the 

epidemiological study was performed. It should be noted that a risk characterization based on 

epidemiological studies also requires baseline incidence rates and population data for the risk 

assessment locations. 

Based on our current understanding of the available evidence, we do not anticipate that 

there will be sufficient exposure- or dose-response 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 from recently conducted epidemiologic studies. 

Following review of the draft ISA and considering comments and recommendations from 

CASAC and the public, the draft Health Assessment Plan will be designed to include such a 

proposed approach to characterizing 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 specific 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 considered 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-term repeated peak exposures and health 

outcomes; 
 5-10 

 New information regarding susceptible populations 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 microenvironmental concentrations (e.g., while 

traveling inside motor vehicles); 

 Analysis of exposure studies using non-routine monitoring, other local sources (e.g., 

rail-yards, airports), and/or modeled CO concentrations; 

 Existence of the data required to perform the analyses in each stage 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 representativeness 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 begin with a qualitative analysis and progress 

to a quantitative analysis if data are available to support such an analysis. The first step in the 

uncertainty analysis will be to identify the components of the assessment, determine whether 

uncertainty can be evaluated for each of those components, and provide a rationale for why this 

is the case. The second step will 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 over-estimate) on risk/exposure estimates. If sufficient data are 

available, and if the magnitude of uncertainty is judged significant, 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 with the model inputs (e.g., use of air quality data, 

time-location-activity diaries, microenvironmental factor distributions). The second is 

uncertainty associated with model formulation (e.g., algorithms included in the model). 
 5-11 

5.7 PUBLIC AND SCIENTIFIC REVIEW 

The CASAC CO Review Panel will be consulted 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 and discuss their comments in a 

public meeting announced in the Federal Register. Based on CASAC=s past practice, EPA 

expects that key advice and recommendations for revision of the document will be summarized 

by the CASAC Chair in a letter to the EPA Administrator. In revising the draft REA document 

for CO, EPA will take into account any such recommendations, 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 information and analyses related to health effects, 

population exposure and risks, and judgments about the appropriate 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 recognition that the available health effects evidence 

generally reflects a continuum consisting of ambient 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 provide an opportunity for CASAC and the public to 

evaluate the policy options under consideration and to offer comments 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 

Centers for Disease Control and Prevention (CDC) (2004). The Health Consequences of 

Smoking: A Report of The Surgeon General. Atlanta, GA: U.S. Department of Health 

and Human Services, National Center for Chronic Disease Prevention and Health 

Promotion, Office on Smoking and Health. Available at: 

http://www.cdc.gov/tobacco/data_statistics/sgr/sgr_2004/chapters.htm (13 May, 2008) 

Cullen AC and Frey HC (1999). Probabilistic Techniques in Exposure Assessment. A handbook 

for dealing with variability and uncertainty in models and inputs. New York, NY. 

Plenum Press. 

Hill, AB (1965). The environment and disease: association or causation? Proc. R. Soc. Med. 58: 

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Institute of Medicine (IOM) (2007). Improving the Presumptive Disability Decision-Making 

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International Agency for Research on Cancer (IARC) (2006). IARC Monographs on the 

Evaluation of Carcinogenic Risks to Humans: Preamble. Lyon, France: International 

Agency for Research on Cancer (IARC Monographs on the Evaluation of Carcinogenic 

Risks to Humans). Available at: 

http://monographs.iarc.fr/ENG/Preamble/CurrentPreamble.pdf (13 May, 2008). 

Johnson, T, Mihlan, G, LaPointe, J, Fletcher, K, Capel, J (1999) Estimation of Carbon Monoxide 

Exposures and Associated Carboxyhemoglobin levels in Denver Residents Using 

pNEM/CO (Version 2.0) prepared by ICF Kaiser Consulting Group for U.S. EPA, Office 

of Air Quality Planning and Standards, under Contract No. 68-D6-0064, WA Nos. 1-19 

and 2-24. 

McClellan, RO., Chairman, Clean Air Scientific Advisory Committee (1991). Letter to William 

K. Reilly, EPA Administrator, July 17, 1991. 

McClellan, RO, Chairman, Clean Air Scientific Advisory Committee (1992). Letter to William 

K. Reilly. EPA Administrator, August 1, 1992. 

National Research Council (2003) Managing Carbon Monoxide Pollution in Meteorological and 

Topographical Problem Areas. Washington, D.C. The National Academies Press. 

National Toxicology Program (NTP) (2005). Report on Carcinogens. 11th ed. Washington, DC: 

National Toxicology Program. 

US EPA (1979a) Air Quality Criteria for Carbon Monoxide. Research Triangle Park, NC: Office 

of Health and Environmental Assessment, Environmental Criteria and Assessment 

Office; report no. EPA-600/8-79-022. 

US EPA (1979b) Assessment of Adverse Health Effects from Carbon Monoxide and 

Implications for Possible Modifications of the Standard. Office of Air Quality Planning 

and Standards. Research Triangle Park, NC.

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Exposure: An Addendum to the 1979 EPA Air Quality Criteria Document for Carbon 

Monoxide. Office of Health and Environmental Assessment, Environmental Criteria and 

Assessment Office; US EPA No. EPA-600/8-83-033F. Research Triangle Park, NC 
 

US EPA (1984b) Review of the NAAQS for Carbon Monoxide: Reassessment of Scientific and 

Technical Information. Office of Air Quality Planning and Standards, U.S. EPA No. 

EPA-450/584-904. Research Triangle Park. NC. 

US EPA. (1991) Air Quality Criteria for Carbon Monoxide. Research Triangle Park, NC: Office 

of Health and Environmental Assessment, Environmental Criteria and Assessment 

Office; report no. EPA/600/8-90/045F. 

US EPA (1992). Review of the National Ambient Air Quality Standards for Carbon Monoxide: 

Assessment of Scientific and Technical Information. Office of Air Quality Planning and 

Standards Staff Paper. EPA-452/R-92-004. 

US EPA (2000). Air Quality Criteria for Carbon Monoxide. National Center for Environmental 

Assessment, Office of Research and Development, U.S. Environmental Protection 

Agency, Research Triangle Park, NC 27711; report no. EPA/600/P-99/001F. June 2000. 

Available: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=18163

US EPA (2005). Guidelines for Carcinogen Risk Assessment. Washington, DC: Risk 

Assessment Forum; report no. EPA/630/P-03/001F. Available at: 

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=116283 [13 May, 2008]. 

US EPA (2006a). Total Risk Integrated Methodology (TRIM) - Air Pollutants Exposure Model 

Documentation (TRIM.Expo / APEX, Version 4) Volume I: User’s Guide. Office of Air 

Quality Planning and Standards, Research Triangle Park, NC. June 2006. Available at: 

http://www.epa.gov/ttn/fera/human_apex.html. 

US EPA (2006b). Total Risk Integrated Methodology (TRIM) - Air Pollutants Exposure Model 

Documentation (TRIM.Expo / APEX, Version 4) Volume II: Technical Support 

Document. Office of Air Quality Planning and Standards, Research 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. Environmental 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 for 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/standards/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.