Policy Assessment for the Review of the 

Carbon Monoxide National Ambient Air 

Quality Standards 

External Review Draft 
EPA-452/P-10-005 

March 2010 

Policy Assessment for the Review of the Carbon Monoxide 

National Ambient Air Quality Standards 

External Review Draft

U.S. Environmental Protection Agency 

Office of Air Quality Planning and Standards 

Health and Environmental Impacts Division 

Research Triangle Park, North Carolina 
DISCLAIMER

This document has been reviewed by the Office of Air Quality Planning and Standards (OAQPS), U.S. 

Environmental Protection Agency (EPA), and approved for publication. This OAQPS Staff Paper contains the 

conclusions and recommendations of the staff of the OAQPS and does not necessarily reflect the views of the 

Agency. Mention of trade names or commercial products is not intended to constitute endorsement or 

recommendation for use. 
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TABLE OF CONTENTS 

 LIST OF FIGURES .................................................................................................. ii 

LIST OF TABLES .................................................................................................... ii

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

1.1 PURPOSE........................................................................................................1-1 

1.2 BACKGROUND .............................................................................................1-2 

1.2.1 Legislative requirements..........................................................................1-2 

1.2.2 Previous Reviews.....................................................................................1-3 

1.2.3 The Current Review.................................................................................1-5 

1.3 CURRENT AIR QUALITY ............................................................................1-6 

1.3.1 Sources to ambient air..............................................................................1-6 

1.3.2 Ambient Monitoring Network .................................................................1-7 

1.3.3 Ambient Monitoring Concentrations .......................................................1-9 

1.4 GENERAL APPROACH AND ORGANIZATION OF THE DOCUMENT.1-11 

REFERENCES ..........................................................................................................1-12 

2 REVIEW OF THE PRIMARY STANDARDS FOR CARBON MONOXIDE2-1

2.1 APPROACH ....................................................................................................2-1 

2.1.1 Approach Used in the Previous Review ..................................................2-2 

2.1.2 Approach for the Current Review............................................................2-6 

2.2 ADEQUACY OF THE CURRENT STANDARD..........................................2-7 

2.2.1 Evidence-based Considerations ...............................................................2-8 

2.2.2 Exposure/Risk-based Considerations.......................................................2-35 

2.2.3 Initial Staff Conclusions on Adequacy of the Current Standards............2-45 

2.3 CONSIDERATION OF ALTERNATIVE STANDARDS .............................2-46 

2.3.1 Indicator ...................................................................................................2-46 

2.3.2 Averaging Time .......................................................................................2-47 

2.3.3 Form and Level........................................................................................2-48 

2.3.3.1 Potential Alternative Forms ............................................................2-50 

2.3.3.2 Potential Alternative Levels............................................................2-50 

2.3.4 Initial Staff Conclusions on Alternative Standards..................................2-56 

2.4 KEY UNCERTAINTIES AND AREAS FOR FUTURE RESEARCH 

 AND DATA COLLECTION...........................................................................2-57 

REFERENCES ..........................................................................................................2-59 

3 CONSIDERATION OF A SECONDARY STANDARD FOR CO...................3-1

3.1 CONSIDERATION IN PREVIOUS REVIEWS.............................................3-1 
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3.2 CONSIDERATION OF EVIDENCE AVAILABLE IN THE CURRENT 

 REVIEW..........................................................................................................3-1 

3.3 STAFF CONCLUSIONS FOR THE CURRENT REVIEW...........................3-3 

REFERENCES ..........................................................................................................3-5 

LIST OF FIGURES 

Figure 1-1 Trends in anthropogenic CO emissions in the U.S. by source category for 

1990 and 1996-2002. Source: U.S. EPA (2008c) ....................................1-7 

Figure 1-2 Trends in CO concentration (second maximum 8-hour average) in the U.S., 

1990-2008. ...............................................................................................1-10 

Figure 1-3 Trends in CO concentration (second maximum 1-hour average) in the U.S., 

1990-2008 ................................................................................................1-11 

Figure 2-1 A conceptual model of CO source-to-health outcome pathway ..............2-15

Figure 2-2 Components of CO source-to-outcome conceptual model measured in 

controlled human exposure and epidemiological studies discussed in this 

document..................................................................................................2-15

LIST OF TABLES 

Table 2-1 Information from U.S. epidemiological studies of hospital admissions for 

ischemic heart disease (ISA, Figure 5-2), cardiovascular disease 

 (ISA, Figure 5-5) and congestive heart failure (ISA, Figure 5-4) and 

 on air quality during the study periods.....................................................2-13 

Table 2-2 Carboxyhemoglobin levels and reported effects in CAD patients and healthy 

adults........................................................................................................2-24 

Tabble 2-3 Air quality information for key U.S. epidemiological studies of hospital 

admissions for coronary heart disease (ISA, Figure 5-2) ........................2-29 

Table 2-4 Air quality information for key U.S. epidemiological studies of hospital 

admissions for CVD (ISA, Figure 5-5)....................................................2-30 

Table 2-5 Portion of simulated at-risk population with maximum end-of-hour COHb 

levels at or above the indicated level under air quality conditions simulated to 

just meet the current standards and under “as is” (2006) conditions. COHb 

levels reflect endogenous levels and ambient CO exposures ..................2-41 

Table 2-6 Portion of simulated at-risk population with maximum end-of-hour COHb 

levels below the indicated COHb level under alternative levels for the 8-hour 

standard for the current form and a 99th percentile daily maximum form 

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Table 2-7 Portion of simulated at-risk population with maximum end-of-hour COHb 

levels below the indicated COHb level under alternative levels for the 1-hour 

standard for the current form and a 99th percentile daily maximum 

 form..........................................................................................................2-55 
1 1 INTRODUCTION 

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2 1.1 PURPOSE 

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

the carbon monoxide (CO) national ambient air quality standards (NAAQS). The overall plan 

and schedule for this review were presented in the Plan for Review of the National Ambient Air 

Quality Standards for Carbon Monoxide (IRP; USEPA, 2008b).1 The IRP identified key policyrelevant issues to be addressed in this review as a series of questions that frame our consideration 

of whether the current NAAQS for CO should be retained or revised. 

This Policy Assessment (PA), prepared by staff in EPA’s Office of Air Quality Planning 

and Standards (OAQPS), is intended to help “bridge the gap” between the relevant scientific 

information and assessments and the judgments required of the EPA Administrator in 

determining whether, and if so, how it is appropriate to revise the NAAQS for CO. This draft 

PA presents factors relevant to EPA’s review of the current primary (health-based) standards and 

consideration of a secondary (welfare-based) standard. It focuses on both evidence- and riskbased information in evaluating the adequacy of the current CO NAAQS and in identifying 

potential alternative standards for consideration. In this draft PA, we consider the scientific and 

technical information available in this review as assessed in the Integrated Science Assessment 

for Carbon Monoxide (henceforth referred to as the ISA, USEPA, 2010a), prepared by EPA’s 

National Center for Environmental Assessment (NCEA), and the Risk and Exposure Assessment 

to Support the Review of the Carbon Monoxide Primary National Ambient Air Quality 

Standards: Second External Review Draft (henceforth referred to as the draft Risk and Exposure 

Assessment document or draft REA, USEPA, 2010b). In so doing, we focus on information that 

is most pertinent to evaluating the basic elements of NAAQS: indicator,2

 averaging time, form,3

and level. These elements, which together serve to define each standard, must be considered 

collectively in evaluating the health and welfare protection afforded by the PM standards. 

While this draft PA should be of use to all parties interested in the CO NAAQS review, it 

is written with an expectation that the reader has some familiarity with the technical discussions 

contained in the ISA (USEPA, 2010a) and the second draft REA (USEPA, 2010b). 

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 As described below in section 1.2.3, the schedule for this review is governed by a court order. 

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 The “indicator” of a standard defines the chemical species or mixture that is to be measured in 

determining whether an area attains the standard. 

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 The “form” of a standard defines the air quality statistic that is to be compared to the level of the standard 

in determining whether an area attains the standard. 

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1 1.2 BACKGROUND 

2 1.2.1 Legislative requirements 

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Two sections of the Clean Air Act (Act) govern the establishment and revision of the 

NAAQS. Section 108 (42 U.S.C. 7408) directs the Administrator to identify certain pollutants 

that meet specified criteria, including emissions 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 them. Air 

quality criteria are 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.”4

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

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

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

or anticipated adverse effects associated with the presence of [the] pollutant in the ambient air.”5

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. 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 

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 The legislative history of section 109 indicates that a primary standard is to be set at the “maximum 

permissible ambient air level...which will protect the health of any [sensitive] group of the population,” and that for 

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

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

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 Welfare effects as defined in section 302(h) (42U.S.C. 7602(h)) include, but are not limited to, “effects in 

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 effect on economic values on personal comfort 

and well-being.” 

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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. 

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

of the health effects involved, the size of the 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. Lead Industries Association v. EPA, supra, 647 F.2d at 1161-62. 

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

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

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

the standards. See generally Whitman v. American Trucking Associations, 531 U.S. 457, 465-

472, 475-76 (2001). 

Section 109(b)(1) of the Act requires that “not later than December 31, 1980, and at 5-

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

published under section 108 and the national ambient air quality standards . . . and shall make 

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

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

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

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

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

this independent review function has been performed by the Clean Air Scientific Advisory 

Committee (CASAC) of EPA’s Science Advisory Board. 

1.2.2 Previous Reviews 

EPA initially established NAAQS for CO, under section 109 of the Act, on April 30, 

1971. The primary standards were established to protect against the occurrence of 

carboxyhemoglobin levels in human blood associated with health effects of concern. The 

standards were set at 9 parts per million (ppm), as an 8-hour average and 35 ppm, as a 1-hour 

average, neither to be exceeded more than once per year (36 FR 8186). In the 1971 decision, the 

Administrator judged that attainment of these standards would provide protection of public 

health with an adequate margin of safety and would also protect against known and anticipated 

adverse effects on public welfare, and accordingly setting the secondary (welfare-based) 

standards identical to the primary (health-based) standards. 

In 1985, EPA concluded its first periodic review of the criteria and standards for CO (50 

FR 37484). In that review, EPA updated the scientific criteria upon which the initial CO 

standards were based through the publication of the 1979 Air Quality Criteria Document for 

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Carbon Monoxide (AQCD; USEPA, 1979a) and prepared a Staff Paper (USEPA, 1979b), which, 

along with the 1979 AQCD, served as the basis for the development of the notice of proposed 

rulemaking which was published on August 18, 1980 (45 FR 55066). 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 (USEPA, 1984a) and an updated 

Staff Paper (USEPA, 1984b). Following review by CASAC (McClellan, 1991, 1992), EPA 

announced its decision 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 (50 FR 37484).

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On August 1, 1994, EPA concluded its second periodic review of the criteria and 

standards for CO by deciding that revisions to the CO NAAQS were not warranted at that time 

(59 FR 38906). This decision reflected EPA's review of relevant scientific information 

assembled since the last review, as contained in the 1991 AQCD (USEPA, 1991) and the 1992 

Staff Paper (USEPA, 1992). Thus, the primary standards were retained at 9 parts per million 

(ppm), 8-hr average and 35 ppm, 1-hr average, neither to be exceeded more than once per year 

(59 FR 38906). 

The next periodic review was initiated in 1997, and a workshop was held in September 

1998 to review and discuss material to be contained in the AQCD. On June 9, 1999, CASAC 

held a public meeting to review the first draft AQCD and to provide a consultation on a draft 

exposure analysis methodology document. Comments from CASAC Panel members and the 

public on the AQCD 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 2000 

AQCD (U.S. EPA, 2000) was released in August 2000. EPA put this review on hold when 

Congress requested that the National Research Council (NRC) review 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. 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 regarding management of CO air pollution, cold start emissions standards, 

oxygenated fuels, and CO monitoring. Following completion of this NRC report, EPA did not 

conduct rulemaking to complete the review. 

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known or anticipated adverse effects from ambient CO exposures” (50 FR 37494). 

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1 1.2.3 The Current Review 

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On September 13, 2007, EPA issued a call for information from the public (72 FR 52369) 

requesting the submission of recent scientific information on specified topics. A workshop was 

held on January 28–29, 2008 (73 FR 2490) to discuss policy-relevant scientific and technical 

information to inform EPA’s planning for the CO NAAQS review. Following the workshop, a 

draft IRP (USEPA, 2008a) was made available in March 2008 for public comment and was 

discussed by the CASAC via a publicly accessible teleconference consultation on April 8, 2008 

(73 FR 12998). EPA made the final IRP available in August 2008 (USEPA, 2008b). 

In preparing the CO ISA, NCEA held an authors’ teleconference in November 2008 with 

invited scientific experts to discuss preliminary draft materials prepared as part of the ongoing 

development of the CO ISA and its supplementary Annexes. The first draft ISA (USEPA, 

2009a) for CO was made available for public review on March 12, 2009 (74 FR 10734) and 

reviewed by CASAC at a meeting held on May 12-13, 2009 (74 FR 15265). A second draft ISA 

(USEPA, 2009b) was released for CASAC and public review on September 23, 2009 (74 FR 

48536), and it was reviewed by CASAC at a meeting held on November 16-17, 2009 (74 FR 

54042). The final ISA was released in January 2010 (USEPA, 2010a). 

In preparing the REA, OAQPS first released a draft planning document, the draft Scope 

and Methods Plan, for consultation with CASAC and public review at the CASAC meeting held 

on May 12-13, 2009. Taking into consideration CASAC and public comments on the draft Plan, 

OAQPS staff conducted a risk/exposure assessment, and released for CASAC review and public 

comment a first draft REA (USEPA, 2009c), which was reviewed at the CASAC meeting held 

on November 16-17, 2009. A second draft REA was released for CASAC review and public 

comment in February 2010, and will be reviewed at an upcoming CASAC meeting scheduled for 

March 22-23, 2010. Drawing from information in the final CO ISA and the second draft REA, 

this draft PA is now being released for CASAC review and public comment at the same meeting. 

The schedule for completion of this review is governed by a court order resolving a 

lawsuit filed in March 2003 by a group of plaintiffs representing two regional environmental 

organizations.7

 The court order that governs this review, entered by the court on November 14, 

2008, provides that EPA will meet the following schedule in completing this review: a final 

risk/exposure assessment is to be completed by May 28, 2010 and notices of proposed and final 

rulemaking are to be signed by October 28, 2010 and May 13, 2011, respectively 

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completing the current review within the period provided by statute. American Lung Association v. Whitman (No. 

1:03CV00778, D.D.C. 2003). 

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1 1.3 CURRENT AIR QUALITY 

This section provides a general overview of the current air quality conditions to provide 

context for this consideration of the current standards for carbon monoxide. A more 

comprehensive discussion of air quality information is provided in the ISA (ISA, sections 3.2 

and 3.4), and a more detailed discussion of aspects particularly relevant to the exposure 

assessment is provided in the second draft REA (REA, chapter 3). 

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1.3.1 Sources to ambient air 

Carbon monoxide in ambient air is formed primarily by the incomplete combustion of 

carbon-containing fuels and by photochemical reactions in the atmosphere. As a result of the 

combustion conditions, CO emissions from large fossil-fueled power plants are typically very 

low because optimized fuel consumption conditions make boiler combustion highly efficient. In 

contrast, internal combustion engines used in many mobile sources have widely varying 

operating conditions. Therefore, higher and more varying CO formation results from the 

operation of these mobile sources (ISA, section 3.2). In the National Emissions Inventory for 

2002, CO emissions from on-road vehicles accounted for approximately half of the total CO 

emissions by individual source sectors in the U.S. (ISA, Figure 3-1.8

 As with previous reviews 

of the CO NAAQS, mobile sources continue to be a significant source sector for CO in ambient 

air. 

As discussed in the ISA, the spatial and temporal patterns of ambient CO concentrations 

are heavily influenced by the patterns associated with mobile source emissions (ISA, chapter 3). 

In metropolitan areas of the U.S., due to their relatively greater motor vehicle density, the 

contribution from mobile sources has been estimated to be as high as 75% of all ambient CO 

emissions in the 2002 National Emissions Inventory (ISA, p. 3-2). For example, emissions in 

urban Denver County, Colorado originating from on-road mobile sources are estimated to be 

about 71% of total CO emissions (ISA, section 3.2), compared with 20% for rural Garfield 

County, Colorado9

 (ISA, section 3, Figure 3-6). When considering all mobile sources 

nationwide (non-road and on-road combined), the contribution to total ambient CO emissions 

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NEI provides the most recent publicly available CO emissions estimates for the U.S. that meet EPA’s data quality 

assurance objectives. Estimates come from various sources and different data sources use different data collection 

methods, most of which are based on engineering calculations and estimates rather than measurements. Although 

these estimates are generated using well-established approaches, uncertainties are inherent in the emission factors 

and models used to represent sources for which emissions have not been directly measured. Uncertainties vary by 

source category, season and region (ISA, section 3.2.1). 

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total emissions from all sources is estimated to be 98,831 (99K) tons. Thus, in this example the on-road vehicles 

accounts for 20.2% of the total emissions (ISA, section 3, figure 3-6). 

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nationally is over 80%. Again using Denver County as an example, all mobile sources are 

estimated to contribute about 98% of total CO emissions. 

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National-scale anthropogenic CO emissions have decreased 35% between 1990 and 2002 

(Figure 1-1). Nearly all the national-level CO reductions since 1990 are the result of emission 

reductions in on-road vehicles (ISA, Figure 3.-2). 

6 Figure 1-1. Trends in anthropogenic CO emissions in the U.S. by source category for 

1990 and 1996-2002. Source: U.S. EPA (2008c) 

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1.3.2 Ambient Monitoring Network 

Ambient CO concentrations are measured by monitoring networks that are operated by 

state and local monitoring agencies in the U.S., and are funded in part by the EPA. The main 

network providing ambient data for use in comparison to the NAAQS is the State and Local Air 

Monitoring Stations (SLAMS) network. CO monitors are typically sited to reflect one of the 

following spatial scales: 

 Microscale: Data represent concentrations within a 100 m radius of the monitor. For 

CO, microscale monitors are sited 2 – 10 m from a roadway. Measurements are 

intended to represent the near-road or street canyon environment. 

 Middle scale: Data represent concentrations averaged over areas defined by 100 – 500 

m radii. Measurements are intended to represent several city blocks. 

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 Neighborhood scale: Data represent concentrations averaged over areas defined by 0.5 

– 4.0 km radii. Measurements are intended to represent extended portions of a city. 

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In addition to monitoring required for determining compliance with the NAAQS, the 

4 EPA is currently in the process of implementing plans for a new network of multi-pollutant 

5 stations called NCore that is intended to meet multiple monitoring objectives (ISA, p. 3-21). The 

6 complete NCore network, required to be fully implemented by January 1, 2011, will consist of 

7 approximately 63 urban and 20 rural stations and will include some existing SLAMS sites that 

8 have been modified to include additional measurements. The majority of NCore stations will be 

9 sited, however, to represent neighborhood, urban, and regional scales, consistent with the NCore 

10 network design objective of representing exposure expected across urban and rural areas in 

11 locations that are not dominated by local sources. 

To promote uniform enforcement of the air quality standards set forth under the CAA, 

EPA has established federal reference methods (FRMs) for ambient air sample collection and 

analysis. Measurements for determinations of NAAQS compliance must be made with FRMs or 

methods designated as equivalent (federal equivalent methods, FEMs). Given the levels of the 

CO NAAQS (35 ppm, 1-hour; 9 ppm, 8-hour), a lower detectable limit (LDL) on the order of 1.0 

ppm is well below the NAAQS levels and is therefore sufficient for demonstration of 

compliance.10 More than 95% of monitors in use during 2005-2007 have LDL of 0.5 ppm (ISA, 

Appendix A, Table A-8). With ambient CO levels now routinely near or below 1 ppm, however, 

a large percentage of the measurements are below the LDL of conventional monitors, 

contributing greater uncertainty in a larger portion of the distribution of monitoring data (ISA, 

section 3.4.1). For example, more than half of the dataset of nationally reported hourly data for 

2005-2007 analyzed in the ISA fell below the reported LDL of 0.5 ppm (ISA, p. 3-56). To 

reduce the uncertainty at these lower concentrations, a new generation of ambient CO monitors 

has been designed that provides improved sensitivity for measurements at or below the typical 

ambient CO levels measured in most urban and all rural locations. The number of active 

monitors employing such sensitive methods is increasing, primarily in association with the 

implementation of the NCore network.11 The extent to which these more sensitive monitors 

become integrated into non-NCore SLAMS stations, however, will depend on the availability of 

funding for states to replace existing legacy CO monitors as well as the possibility that 

10 Among the 13 approved FRMs in use in the SLAMS network for which data were reported to EPA’s Air 

Quality System (AQS) between 2005 and 2009, nine are “legacy” methods with a federal method detection limit 

(MDL) listed as 0.5 ppm. 

11 For example, four approved FRMs are newer, more sensitive methods with a federal MDL of 0.02 ppm 

and a growing body of ambient data from more sensitive CO instruments is becoming available. Testing performed 

by EPA on several such CO monitors in 2005 and 2006 demonstrated MDLs of approximately 0.017 – 0.018 ppm 

(17 – 18 ppb), slightly below the stated LDL of 0.02 – 0.04 ppm (ISA, section 3.4.1). 

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monitoring requirements for CO might either encourage or require such technological 

improvements. 

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1.3.3 Ambient Monitoring Concentrations 

Nearly 400 ambient monitoring stations report continuous hourly averages of CO 

concentrations across the U.S. None of monitoring sites with extensive records12 for 2007 in 243 

counties reported a second-highest 1-hour CO concentration above 35 ppm, the level of the 

current 1-hour NAAQS, while sites in two counties reported second-highest 1-hour CO 

concentrations between 15.1 and 35.0 ppm. Sites in five counties reported second-highest 8-hour 

CO concentration of 5.0 ppm or higher (ISA, section 3.5.1.1). 

For the most recent period for which air quality status relative to the CO NAAQS has 

been analyzed (2007-2008), all areas of the U.S. meet both CO NAAQS.13 In the previous two 

periods (2005-2006 and 2006-2007), one area, (Jefferson County, Alabama) has failed to meet 

the 8-hour standard. Further, one area of the country is designated in non-attainment with the 

CO NAAQS, however, air quality in that area currently meets the standards. 

The current levels of ambient CO across the U.S. reflect the steady declines in ambient 

concentrations that have occurred over the past several years. Both the 2nd highest 1-hour and 

8-hour concentrations have significantly declined since the last review (Figures 1-2 and 1-3). At 

the set of sites across the U.S. that have been continuously monitored since 1990 the average 2nd

highest 8-hour and 1-hour concentrations have declined by nearly 70%. 

12 During the period 2005-2007, 291 out of 376 monitors sited in 243 different counties, cities or 

municipalities, met the following dataset completeness criteria: 75% of the hours in a day, 75% of days in a 

calendar quarter and 3 complete quarters for 3 years (ISA, section 3.4.2.2). An exception was made for monitors in 

U.S. EPA Region 10 for which two rather than three complete quarters were considered to meet the criteria (ISA, p. 

3-20). 

13 The air quality status in areas monitored relative to the CO NAAQS is provided at 

http://www.epa.gov/air/airtrends/values.html. 

March 2010 1-9 Draft – Do Not Quote or Cite 
1 Figure 1-2. Trends in CO concentration (second maximum 8-hour average) in the U.S., 

1990-2008. The white line indicates average across the sites; ninety percent of 

sites have concentrations below the top line, while ten percent of sites have 

concentrations below the bottom line. 

2 

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March 2010 1-10 Draft – Do Not Quote or Cite 
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2 Figure 1-3. Trends in CO concentration (second maximum 1-hour average) in the U.S., 

1990-2008. The white line indicates average across the sites; ninety percent of 

sites have concentrations below the top line, while ten percent of sites have 

concentrations below the bottom line. 

8 1.4 GENERAL APPROACH AND ORGANIZATION OF THE DOCUMENT 

This draft PA includes staff’s evaluation of the policy implications of the scientific 

evidence reviewed in the ISA and the results of quantitative analyses based on that evidence. 

Taken together, this information informs initial staff conclusions and the identification of a range 

of policy options for consideration in addressing public health and welfare effects associated 

with ambient CO. 

Following this introductory chapter, chapter 2 focuses on review of the primary standards 

for CO, presenting background information on the rationale for previous reviews and the 

approach followed in the current review. Chapter 2 discusses the adequacy of the current 

standards, taking into account evidence- and risk-based considerations, and includes initial staff 

conclusions on adequacy. Chapter 2 also discusses potential alternative standards for 

consideration, focusing on indicator, averaging time, form, and level, and includes initial staff 

conclusions on alternative standards for consideration. Finally, chapter 3 discusses information 

relevant to staff’s consideration of a secondary standard for CO. 

March 2010 1-11 Draft – Do Not Quote or Cite 
1 REFERENCES 

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36 

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38 

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 

U.S. 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. 

U.S. 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. 

U.S. EPA (1984a). Revised Evaluation of Health Effects Associated with Carbon Monoxide 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; report ro. EPA-600/8-83-033F. 

Research Triangle Park, NC 

U.S. EPA (1984b). Review of the NAAQS for Carbon Monoxide: Reassessment of Scientific and Technical 

Information. Office of Air Quality Planning and Standards, report no. EPA-450/584-904. Research 

Triangle Park. NC. 

 U.S. 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. 

U.S. 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. report 

no.EPA/452/R-92-004.. 

U.S. 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 at: 

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

U.S. EPA (2008a). Draft Integrated Review Plan for the National Ambient Air Quality Standards for Carbon 

Monoxide. U.S. Environmental Protection Agency, Research Triangle Park, NC, report no. EPA/452D-08-

001. Availiable at: http://www.epa.gov/ttn/naaqs/standards/co/s_co_cr_pd.html. 

U.S. EPA (2008b). Plan for Review of the National Ambient Air Quality Standards for Carbon Monoxide. U.S. 

Environmental Protection Agency, Research Triangle Park, NC, report no. EPA/452R-08-005. Also known 

as Integrated Review Plan. Availiable at: http://www.epa.gov/ttn/naaqs/standards/co/s_co_cr_pd.html. 

U.S. EPA (2008c). U.S. EPA's 2008 Report on the Environment (Final Report). U.S. Environmental Protection 

Agency. DC. 

U.S. EPA (2009a) Integrated Science Assessment for Carbon Monoxide, First External Review Draft. U.S. 

Environmental Protection Agency, Research Triangle Park, NC, report no. EPA/600/R-08/071. Available 

at: http://www.epa.gov/ttn/naaqs/standards/co/s_co_cr_isa.html 

March 2010 1-12 Draft – Do Not Quote or Cite 
March 2010 1-13 Draft – Do Not Quote or Cite 

1 

2 

U.S. EPA (2009b) Integrated Science Assessment for Carbon Monoxide, Second External Review Draft, U.S 

Environmental Protection Agency, Research Triangle Park, NC, report no. EPA/600/R-09/019B. 

3 Available at: http://www.epa.gov/ttn/naaqs/standards/co/s_co_cr_isa.html

4 

5 

6 

U.S. EPA (2009c) Risk and Exposure Assessment to Support the Review of the Carbon Monoxide Primary National 

Ambient Air Quality Standards, First External Review Draft, U.S Environmental Protection Agency, 

Research Triangle Park, NC, report no. EPA/600/R-09/019B. Available at: 

7 http://www.epa.gov/ttn/naaqs/standards/co/s_co_cr_isa.html

8 

9 

U.S. EPA (2010a) Integrated Science Assessment for Carbon Monoxide, National Center for Environmental 

Assessment, Research Triangle Park, NC. EPA/600/R-09/019F. Available at: 

10 http://www.epa.gov/ttn/naaqs/standards/co/s_co_cr_isa.html

11 

12 

13 

U.S. EPA (2010b) Risk and Exposure Assessment to Support the Review of the Carbon Monoxide Primary National 

Ambient Air Quality Standards, Second External Review Draft, U.S Environmental Protection Agency, 

Research Triangle Park, NC, report no. EPA/600/R-09/019B. Available at: 

14 http://www.epa.gov/ttn/naaqs/standards/co/s_co_cr_rea.html
March 2010 Draft – Do Not Quote or Cite 2-1

1 2 REVIEW OF THE PRIMARY STANDARDS FOR CARBON 

2 MONOXIDE 

3 This chapter presents initial staff conclusions for consideration in deciding whether the 

4 existing primary standards for carbon monoxide (CO) should be revised and, if so, what 

5 revisions are appropriate. The current primary CO standards include a 1-hour and an 8-hour 

6 standard to protect public health from exposure to CO. In initially evaluating the current primary 

7 NAAQS we have reviewed, and as appropriate, updated, a series of key policy-relevant issues 

8 initially presented in the Plan for Review of the National Ambient Air Quality Standards for 

9 Carbon Monoxide (USEPA, 2008a, section 3.1). The answers to these policy-relevant questions 

10 will inform decisions on whether, and if so, how to revise the primary standards for CO. 

11 Following a background section regarding considerations in the previous review, the 

12 discussion in this chapter focuses on two central issues related to: (1) the adequacy of the current 

13 CO standards and (2) what potential alternative standards, if any, should be considered in this 

14 review. Within each of these broad areas, a series of questions are addressed. The four basic 

15 elements of the NAAQS (e.g., indicator, averaging time, level, and form) will be considered 

16 collectively in evaluating the health protection afforded by the current or any alternative 

17 standards considered. 

18 2.1 APPROACH 

19 For the purposes of this draft Policy Assessment (PA), staff has drawn from EPA’s 

20 assessment and integrated synthesis of the scientific evidence presented in the Integrated Science 

21 Assessment for Carbon Monoxide (USEPA, 2010a; henceforth referred to as the ISA) and 2000 

22 Air Quality Criteria Document for Carbon Monoxide (USEPA, 2000; henceforth referred to as 

23 the 2000 AQCD) and on the analyses presented in the second draft Risk and Exposure 

24 Assessment (USEPA, 2010b; henceforth referred to as the draft REA). The evidence-based 

25 discussions presented in this chapter draw upon evidence from epidemiologic studies, controlled 

26 human exposure studies, and toxicological studies evaluating short- or long-term exposures to 

27 CO, as discussed in chapter 5 of the ISA, with supporting information related to dosimetry and 

28 potential mode of action evidence as presented in chapters 4 and 5 of the ISA, respectively, as 

29 well as the integration of evidence across disciplines presented in chapter 2 of the ISA. The 

30 exposure/risk-based discussions have drawn from the quantitative health analyses for CO 

31 presented in the draft REA. Together the evidence-based and risk-based considerations have 

32 informed our conclusions related to the adequacy of the current CO standards and alternative 

33 standards that are supported by the currently available scientific evidence. 
March 2010 Draft – Do Not Quote or Cite 2-2

1 In presenting a range of primary standard options for consideration, we note that the final 

2 decision is largely a public health policy judgment. A final decision must draw upon scientific 

3 information and analyses about health effects and risks, as well as judgments about how to deal 

4 with the range of uncertainties that are inherent in the scientific evidence and analyses. Our 

5 approach to informing these judgments, discussed more fully below, is based on the recognition 

6 that the available health effects evidence generally reflects a continuum, consisting of ambient 

7 levels at which scientists generally agree that health effects are likely to occur, through lower 

8 levels at which the likelihood and magnitude of the response become increasingly uncertain. 

9 This approach is consistent with the requirements of the NAAQS provisions of the Act and with 

10 how EPA and the courts have historically interpreted the Act. These provisions require the 

11 Administrator to establish primary standards that, in the Administrator’s judgment, are requisite 

12 to protect public health with an adequate margin of safely. In so doing, the Administrator seeks 

13 to establish standards that are neither more nor less stringent than necessary for this purpose. 

14 The Act does not require that primary standards be set at a zero-risk level, but rather at a level 

15 that avoids unacceptable risks to public health. 

16 This section includes background information on the approach used in the previous 

17 review of the CO standards (section 2.1.1) and also a discussion of the approach for the current 

18 review (section 2.1.2). 

19 2.1.1 Approach Used in the Previous Review 

20 The current primary standards for CO are set at 9 parts per million (ppm) as an 8-hour 

21 average and 35 ppm as a 1-hour average, neither to be exceeded more than once per year. These 

22 standards were initially set in 1971to protect against the occurrence of carboxyhemoglobin 

23 (COHb) levels that may be associated with effects of concern (36 FR 8186). Reviews of these 

24 standards in the 1980s and early 1990s, respectively, identified additional evidence regarding 

25 ambient CO, COHb levels and health effects (USEPA, 1984a, 1984b; USEPA, 1991; USEPA, 

26 1992; McClellan, 1991,1992). Assessment of the evidence in those reviews led the EPA to 

27 retain the existing standards without revision (59 FR 38906). 

28 The 1994 decision to retain the primary standards without revision was based on the 

29 evidence published through 1990 and reviewed in the 1991 AQCD (USEPA, 1991), the 1992 

30 Staff Paper assessment of the policy-relevant information contained in the AQCD and the 

31 quantitative exposure assessment (USEPA, 1992), and the advice and recommendations of 

32 CASAC (McClellan 1991, 1992). At that time, as at the time of the prior NAAQS review (50 

33 FR 37484), COHb levels in blood were recognized as the most useful estimates of exogenous 

34 CO exposures and to serve as the best biomarker of CO toxicity for ambient-level exposures to 
March 2010 Draft – Do Not Quote or Cite 2-3

1 CO. Consequently, COHb levels were used as the indicator of health effects in the identification 

2 of health effect levels of concern for CO (59 FR 38909). 

3 In reviewing the standards in 1994 the Administrator first recognized the need to 

4 determine the COHb levels of concern “taking into account a large and diverse health effects 

5 database”. The more uncertain and less quantifiable evidence was taken into account to identify 

6 the lower end of this range to provide an adequate margin of safety for effects of clear concern. 

7 To consider ambient CO concentrations likely to result in COHb levels of concern, a model 

8 solution to the Coburn-Forster-Kane (CFK) differential equations was employed in the analysis 

9 of CO exposures expected to occur under air quality scenarios related to just meeting the current 

8-hour CO NAAQS, the controlling standard (USEPA, 1992).1 10 Key considerations in this 

11 approach are described below 

12 Carboxyhemoglobin Levels of Concern and Margin of Safety 

13 The assessment of the science that was presented in the 1991 AQCD (USEPA, 1991) 

14 indicated that CO is associated with effects in the cardiovascular system, central nervous system 

15 (CNS), and the developing fetus. Additionally, factors recognized as having potential interaction 

16 with CO that may alter health effects included exposures to other pollutants, some drugs and 

17 some environmental factors, such as altitude. Cardiovascular effects of CO, as measured by 

18 decreased time to onset of angina and to onset of significant electrocardiogram (ECG) STsegment depression2 19 were judged by the Administrator to be “the health effects of greater 

20 concern, which clearly had been associated with CO exposures at levels observed in ambient air” 

21 (59 FR 38913). 

Based on the consistent findings of response in patients with coronary artery disease3 22 

23 across the controlled human exposure evidence (Adams et al., 1988; Allred et al., 1989a, 1989b, 

24 1991; Anderson et al., 1973; Kleinman et al., 1989, 1998; Sheps et al., 1987) and discussions of 

25 adverse health consequences in the 1991 AQCD and the 1992 Staff Paper, at the CASAC 

 

1

 Air quality analyses of CO levels in the U.S. consistently demonstrate that attainment of the 8-hour 

standard results in 1-hour maximum concentrations well below the corresponding 1-hour standard. 2

 The ST-segment is a portion of the electrocardiogram, depression of which is an indication of insufficient 

oxygen supply to the heart muscle tissue (myocardial ischemia). Myocardial ischemia can result in chest pain 

(angina pectoris) or such characteristic changes in ECGs or both. In individuals with coronary artery disease, it 

tends to occur at specific levels of exercise. The duration of exercise required to demonstrate chest pain and/or a 1-

mm change in the ST segment of the ECG were key measurements in the multicenter study by Allred et al (1989a, 

1989b, 1991). 3

 Coronary artery disease (CAD), often also called coronary heart disease or ischemic heart disease is a 

category of cardiovascular disease associated with narrowed heart arteries. Individuals with this disease have 

myocardial ischemia, which occurs when the heart muscle receives insufficient oxygen delivered by the blood. 

Exercise-induced angina pectoris (chest pain) occurs in many of them. Among all patients with diagnosed CAD, the 

predominant type of ischemia, as identified by ST segment depression, is asymptomatic (i.e., silent). Patients who 

experience angina typically have additional ischemic episodes that are asymptomatic (2000 AQCD, section 7.7.2.1). 

In addition to such chronic conditions, CAD can include myocardial infarction (ISA, p. 5-24). 
March 2010 Draft – Do Not Quote or Cite 2-4

1 meetings and in the July 1991 CASAC letter, the Administrator concluded that “CO exposures 

2 resulting in COHb levels of 2.9-3.0 percent (CO-Ox) or higher in persons with heart disease have 

3 the potential to increase the risk of decreased time to onset of angina pain and ST-segment 

depression” (59 FR 38913).4 4 Two of the five key studies were given particular emphasis in the 

5 1991 AQCD to indicate the basis for conclusions regarding lowest observed-effect levels of 

6 COHb in patients with exercise-induced ischemia, in terms of measured COHb and its 

7 representation in terms of increase from baseline COHb on the order of 1.5 to 2.2% (USEPA, 

8 1991, pp. 1-11 to 1-12; Allred et al., 1989a, 1989b, 1991; Anderson et al., 1973). 

9 While EPA and CASAC recognized the existence of a range of views among health 

10 professionals on the clinical significance of the responses observed in the clinical studies, 

11 CASAC noted that the dominant view was that they should be considered “adverse or harbinger 

12 of adverse effect” (McClellan, 1991) and EPA recognized that it was “important that standards 

13 be set to appropriately reduce the risk of ambient exposures which produce COHb levels that 

14 could induce such potentially adverse effects” (59 FR 38913) as those occurring at COHb levels 

15 of 2.9-3.0% (CO-oximeter) (59 FR 38913; USEPA, 1991, p. 1-12; USEPA, 1992, pp. 20-22). In 

16 further considering additional results from the controlled human exposure evidence as well as 

17 other aspects of the available evidence and uncertainties regarding modeling estimates of COHb 

18 formation and human exposure to COHb levels in the population associated with attainment of a 

19 given CO NAAQS, the Administrator recognized the need to extend the range of COHb levels 

20 for consideration in evaluating whether the current CO standards provide an adequate margin of 

21 safety to those falling between 2.0 to 2.9 (59 FR 38913). Factors considered in recognizing this 

22 margin of safety included the following (59 FR 38913). 

23  Uncertainty associated with the clinical importance of cardiovascular effects associated 

24 with exposures to CO that resulted in COHb levels of 2 to 3 percent. Although 

25 recognizing the possibility that there is no threshold for these effects even at lower 

26 COHb levels, the health significance of the small changes in ST-segment depression 

27 observed was considered somewhat minor. 

28  Findings of short-term reduction in maximal work capacity measured in trained 

29 athletes exposed to CO at levels resulting in COHb levels of 2.3 to 7 percent. 

30  The potential that the most sensitive individuals have not been studied, the limited 

31 information regarding the effects of ambient CO in the developing fetus, and concern 

32 about visitors to high altitudes, individuals with anemia or respiratory disease, or the 

33 elderly. 

 

4

 Based on matched measurements available for CO-Ox and gas chromatography in this range, staff note 

that CO-oximetry measurements of 2.9 to 3.0 percent COHb appear to correspond to GC measurements on the order 

of 2% (Allred et al., 1991). 
March 2010 Draft – Do Not Quote or Cite 2-5

1  Potential for short term peak CO exposures to be responsible for impairments 

2 (impairment of visual perception, sensorimotor performance, vigilance or other CNS 

3 effects) which could be a matter of concern for complex activities such as driving a car, 

4 although these effects had not been demonstrated to be caused by CO concentrations in 

5 ambient air. 

6  Concern based on limited evidence for individuals exposed to CO concurrently with 

7 drugs (e.g., alcohol), during heat stress, or co-exposure to other pollutants. 

8  Large uncertainties remaining regarding modeling COHb formation and estimating 

9 human exposure to CO which could lead to overestimation of COHb levels in the 

10 population associated with attainment of a given CO NAAQS. 

11  Uncertainty associated with COHb measurements made using CO-Ox which may not 

12 reflect COHb levels in angina patients studied, thereby creating uncertainty in 

13 establishing a lowest effects level for CO. 

14 Based on these considerations of the evidence, the Administrator identified a range of 

15 COHb levels of concern extending from 2.9% at the upper end down to 2% at the lower end and 

16 concluded that “evaluation of the adequacy of the current standard should focus on reducing the 

17 number of individuals with cardiovascular disease from being exposed to CO levels in the 

18 ambient air that would result in COHb levels of 2.1 percent.” She additionally concluded that 

19 standards that “protect against COHb levels at the lower end of the range should provide an 

20 adequate margin of safety against effects of uncertain occurrence, as well as those of clear 

21 concern that have been associated with COHb levels in the upper-end of the range” (59 FR 

22 48914). 

23 Estimation of Population Exposures 

24 To estimate CO exposures and resulting COHb levels that might be expected under air 

25 quality conditions that just met the current standards, an analysis of exposure and associated 

26 internal dose in terms of COHb levels in the population of interest in the city of Denver, 

27 Colorado was performed (59 FR 38906; USEPA, 1992). That analysis indicated that if the 9 

28 ppm 8-hour standard were just met, the proportion of the nonsmoking population with 

29 cardiovascular disease experiencing a daily maximum 8-hour exposure at or above 9 ppm for 8 

30 hours decreased by an order of magnitude or more as compared to the proportion under then31 existing CO levels, down to less than 0.1 percent of the total person-days in that population. 

32 More specifically, upon meeting the 8-hour standard, EPA estimated that less than 0.1% of the 

33 nonsmoking cardiovascular-disease population would experience a COHb level greater than or 

34 equal to 2.1%. A smaller percentage of the at-risk population was estimated to exceed higher 
March 2010 Draft – Do Not Quote or Cite 2-6

COHb levels.5 1 Based on these estimates, the Administrator concluded that “relatively few 

2 people of the cardiovascular sensitive population group analyzed will experience COHb levels ≥

3 2.1 percent when exposed to CO levels in absence of indoor sources”. The analysis also took 

4 into account that certain indoor sources (e.g., passive smoking, gas stove usage) contributed to 

5 total CO exposure and EPA recognized that such sources may be of concern for such high risk 

6 groups as individuals with cardiovascular disease, pregnant women, and their unborn children 

7 but concluded that “the contribution of indoor sources cannot be effectively mitigated by 

8 ambient air quality standards” (59 FR38914). 

9 Decision Regarding Adequacy of the Standards 

10 Based on consideration of the evidence and the quantitative results of the exposure 

11 assessment, the Administrator concluded that revisions of the current primary standards for CO 

12 were not appropriate at that time (59 FR 38914). The Administrator additionally concluded that 

13 both averaging times for the primary standards, 1-hour and 8-hour, be retained. The 1-hour and 

14 8-hour averaging times were first chosen when EPA promulgated the primary NAAQS for CO in 

15 1971. The selection of the 8-hour averaging time was based on the following: (a) most 

16 individuals’ COHb levels appeared to approach equilibrium after 8 hours of exposure, (b) the 8-

17 hour time period corresponded to the blocks of time when people were often exposed in a 

18 particular location or activity (e.g., working or sleeping), and (c) judgment that this provided a 

19 good indicator for tracking continuous exposures during any 24-hour period. The 1-hour 

20 averaging time was selected as better representing a time period of interest to short-term CO 

21 exposure and providing protection from effects which might be encountered from very short 

22 duration peak exposures in the urban environment (59 FR 38914). 

23 2.1.2 Approach for the Current Review 

24 To evaluate whether it is appropriate to consider retaining the current primary CO 

25 standards, or whether consideration of revisions is appropriate, we adopted an approach in this 

26 review that builds upon the general approach used in the last review and reflects the broader 

27 body of evidence and information now available. As summarized above, the Administrator’s 

28 decisions in the previous review were based on an integration of information on health effects 

29 associated with exposure to ambient CO; expert judgment on the adversity of such effects on 

30 individuals; and policy judgments as to when the standard is requisite to protect public health 

31 with an adequate margin of safety, which were informed by air quality and related analyses, 

 

5

 In the 1992 assessment, the person-days (number of persons multiplied by the number of days per year 

exposed) and person-hours (number of persons multiplied by the number of hours per year exposed) were the 

reported exposure metrics. Upon meeting the 8-hour standard, it was estimated that less than 0.1% of the total 

person-days simulated for the nonsmoking cardiovascular-disease population were associated with a maximum 

COHb level greater than or equal to 2.1% (USEPA, 1992; Johnson et al., 1992). 
March 2010 Draft – Do Not Quote or Cite 2-7

1 quantitative exposure and risk assessments when possible, and qualitative assessment of impacts 

2 that could not be quantified. 

3 In conducting this assessment, we draw on the current evidence and quantitative 

4 assessments of exposure pertaining to the public health risk of ambient CO. In considering the 

5 scientific and technical information, we consider both the information available at the time of the 

6 last review and information newly available since the last review, including the current ISA and 

7 the 2000 AQCD (USEPA, 2010; USEPA, 2000), as well as current and preceding quantitative 

8 exposure/risk assessments (USEPA 2010b). As was the case at the time of the last review, the 

9 best characterized health effect associated with CO levels of concern is hypoxia (reduced oxygen 

10 availability) induced by increased COHb levels in blood (ISA, section 5.1.2). Accordingly, CO 

11 is of particular concern for those with impaired cardiovascular systems, and the most compelling 

12 evidence of cardiovascular effects is that from a series of controlled human exposure studies 

13 among exercising individuals with coronary heart disease (CHD) also referred to as coronary 

14 artery disease (CAD) (ISA, sections 5.2.4 and 5.2.6). Additionally available in this review are a 

15 number of epidemiological studies that investigated the association of cardiovascular disease16 related health outcomes with concentrations of CO at ambient monitors. To inform our review 

17 of the ambient standards, we performed a quantitative exposure and dose modeling analysis that 

18 estimated COHb levels associated with different air quality conditions in simulated at-risk 

19 populations in two U.S. cities. Thus, in developing conclusions in this review as discussed in 

20 sections 2.2 and 2.3 below, we have taken into account both evidence-based and exposure/risk21 based considerations framed by a series of key policy-relevant questions. 

22 2.2 ADEQUACY OF THE CURRENT STANDARD 

23 In considering the adequacy of the current CO standards, the overarching question we 

24 consider is: 

25  Does the currently available scientific evidence- and exposure/risk-based 

26 information, as reflected in the ISA and draft REA, support or call into question 

27 the adequacy of the protection afforded by the current CO standards? 

28 To assist us in interpreting the currently available scientific evidence and the results of 

29 recent quantitative exposure/risk analyses to address this question, we have focused on a series 

30 of more specific questions, posed within sections 2.2.1 and 2.2.2 below. In considering the 

31 scientific and technical information, we consider both the information available at the time of the 

32 last review and information newly available since the last review which has been critically 

33 analyzed and characterized in the 2000 AQCD and more recently in the ISA. 
March 2010 Draft – Do Not Quote or Cite 2-8

1 2.2.1 Evidence-based Considerations 

2 In considering the evidence with regard to the issue of adequacy of the current standard, 

3 we address a series of questions beginning with the health effects associated with CO exposure, 

4 followed by the use of COHb levels as the indicator of CO exposures and biomarker for 

5 characterizing the potential for health effects associated with exposures to ambient CO, and then 

6 the identification of the populations most susceptible to the effects of CO. We next consider the 

7 evidence regarding the levels of CO in ambient air associated with health effects and the 

8 important uncertainties associated with the evidence. 

9  Does the current evidence alter our conclusions from the previous review 

10 regarding the health effects associated with exposure to CO? 

11 The current evidence continues to support our conclusions from the previous review 

12 regarding key health effects associated with CO exposure. The best characterized effect of CO 

13 continues to be related to the binding of CO to blood Hb to form increased levels of COHb (ISA, 

14 sections 4.1 and 5.1.2) and the primary focus is on associated cardiovascular effects (ISA, 

15 section 5.2). In the scientific assessment for the current review, a likely causal relationship is 

judged to exist between relevant CO exposures6 16 and cardiovascular effects (ISA, section 2.5.1) 

17 which is similar to conclusions in the last review. The evidence for effects on the central 

18 nervous system, birth outcomes and developmental effects, and respiratory effects, while in some 

19 cases expanded from that which was available at the time of the last review, is judged to be 

20 suggestive of a causal relationship with relevant CO exposures (ISA, section 2.5). These overall 

21 findings, additional details of which are described below, are consistent with and extend in some 

22 ways conclusions drawn from the health effects evidence in the last review. 

23 The long-standing body of evidence that has established many aspects of the biological 

24 effects of CO continues to contribute to our understanding of the health effects of ambient CO. 

25 Upon inhalation, CO diffuses through the respiratory zone (alveoli) to the blood where it binds to 

26 Hb, forming COHb. This binding to reduced iron in heme proteins and the alteration of their 

27 function is the common mechanism underlying biological responses to CO. Accordingly, 

28 inhaled CO elicits various health effects through binding to, and associated alteration of the 

29 function of, a number of heme-containing molecules, mainly Hb (see e.g., ISA, section 4.1). The 

30 best characterized health effect associated with CO levels of concern is hypoxia (reduced O2

31 availability) induced by increased COHb levels in blood and decreased oxygen availability to 

32 critical tissues and organs, specifically the heart (ISA, section 5.1.2). Thus, people with a 

33 cardiovascular disease that affects their ability to compensate for this effect (e.g., through 

 

6

 Relevant CO exposures are defined in the ISA as "generally within one or two orders of magnitude of 

ambient CO concentrations" (ISA, section 2.5). 
March 2010 Draft – Do Not Quote or Cite 2-9

vasodilation or increased cardiac output) are a key population at risk from CO exposures.7 1 The 

2 dose metric most commonly used as a bioindicator of exposure and health risk from CO is the 

3 level of COHb in the blood (USEPA, 1991; 2002; 2010a). 

4 The body of health effects evidence for CO has grown considerably since the previous 

5 review with the addition of numerous epidemiological and toxicological studies (ISA; 2000 

6 AQCD). This evidence provides additional detail and support to our prior understanding of CO 

7 effects and population susceptibility. For example, the currently available evidence expands on 

8 potential nonhypoxic mechanisms for CO effects, although the importance of such mechanisms 

9 at environmentally-relevant CO exposures is unclear. Most notably, the current evidence 

10 includes much expanded epidemiological evidence that provides support for previous 

11 conclusions regarding cardiovascular disease-related susceptibility and indications of air quality 

12 conditions that may be associated with ambient CO-related risk. 

13 In the most recent analysis of the health evidence EPA has developed a framework to 

14 characterize the evidence as to likelihood of causal relationships between exposure to ambient 

15 CO and specific health effects (ISA, chapter 1). The clearest evidence is available for 

16 cardiovascular effects, such that the major conclusion drawn in the ISA regarding the critical 

17 analysis of all available data on health effects of CO including the clinical and epidemiological 

18 evidence is that "Given the consistent and coherent evidence from epidemiologic and human 

19 clinical studies, along with biological plausibility provided by CO’s role in limiting O2

availability, it is concluded that a causal relationship is likely to exist between relevant[8] 20 short21 term CO exposures and cardiovascular morbidity" (ISA, p. 2-6, section 2.5.1). The evidence is 

22 judged suggestive of causal relationships between relevant short- and long-term CO exposures 

23 and CNS effects, birth outcomes and developmental effects following long-term exposure, 

24 respiratory morbidity following short-term exposure, and mortality following short-term 

25 exposure (ISA, section 2.5, Table 2-1). It was concluded that there is not likely to be a causal 

26 relationship between relevant long-term CO exposures and mortality (ISA, Table 2-1). 

27 Similar to the previous review, results from controlled human exposure studies of 

28 individuals with coronary artery disease (Adams et al., 1988; Allred et al., 1989a, 1989b, 1991; 

29 Anderson et al., 1973; Kleinman et al., 1989, 1998; Sheps et al., 1987;) are the “most compelling 

30 evidence of CO-induced effects on the cardiovascular system” (ISA, Section 5.2). Additionally, 

 

7

 As described in discussing susceptibility below, cardiovascular disease comprises many types of medical 

disorders, including heart disease (e.g., CHD), cerebrovascular disease (e.g., stroke), hypertension (high blood 

pressure), and peripheral vascular diseases and heart disease patients often have markedly reduced circulatory 

capacity and reduced ability to compensate for increased circulatory demands during exercise and other stress (2000 

AQCD, p. 7-7). 8

 Relevant CO exposures are defined in the ISA as "generally within one or two orders of magnitude of 

ambient CO concentrations" (ISA, section 2.5). 
March 2010 Draft – Do Not Quote or Cite 2-10

1 the use of an internal dose metric, COHb, adds to the strength of the findings in these controlled 

2 exposure studies. As a group, these studies demonstrate the role of CO in increasing the 

3 susceptibility of people with CAD to incidents of exercise-associated myocardial ischemia. 

4 Among these controlled human exposure studies, the ISA places principal emphasis on 

5 the study of coronary artery disease patients by Allred et al. (1989a, 1989b, 1991) which was key 

6 to considerations from the previous review for the following reasons: 1) dose-response 

7 relationships was observed; 2) effects were observed at the lowest COHb levels tested (mean of 

8 2-2.4% COHb following experimental CO exposure), providing no evidence of a threshold; 3) 

9 objective measures of myocardial ischemia (ST-segment depression) were assessed, as well as 

10 the subjective measure of decreased time to induction of angina; 4) measurements were taken 

11 both by gas chromatography (GC), which provides a more accurate measurement of COHb blood 

levels9 12 , and by CO-Ox; 5) a large number of subjects were used; 6) a strict subject selection 

13 protocol was employed to include only CAD patients with reproducible exercise-induced 

14 angina.; and 7) the study was conducted at multiple laboratories around the U.S. This study 

15 evaluated changes in time to exercise-induced onset of markers of myocardial ischemia resulting 

16 from two short CO exposures targeted to result in mean study subject COHb levels of 2% and 

17 4%, respectively (ISA, section 5.2.4). In this study, subjects (n=63) on three separate occasions 

18 underwent an initial graded exercise treadmill test, followed by 50 to 70-minute exposures under 

19 resting conditions to room air CO concentrations or CO concentrations targeted for each subject 

20 to achieve blood COHb levels of 2% and 4%. The exposures were to average CO concentrations 

21 of 0.7 ppm (room air concentration range 0-2 ppm), 117 ppm (range 42-202 ppm) and 253 ppm 

22 (range 143-357 ppm). After the 50- to 70-min exposures, subjects underwent a second graded 

23 exercise treadmill test, and the percent change in time to onset of angina and time to ST endpoint 

24 between the first and second exercise tests was determined. For the two CO exposures, the 

25 average post-exposure COHb concentrations were reported as 2.4% and 4.7%, and the 

subsequent post-exercise average COHb concentrations were reported as 2.0% and 3.9%.10 26 

 

9

 As stated in the ISA, the gas chromatographic technique for measuring COHb levels “is known to be 

more accurate than spectrophotometric measurements, particularly for samples containing COHb concentrations < 

5%” (ISA, p. 5-41). CO-oximetry is a spectrophotometric method commonly used to rapidly provide approximate 

concentrations of COHb during controlled exposures (ISA, p. 5-41). At the low concentrations of COHb (<5%) 

more relevant to exposures to ambient CO, co-oximeters are reported to overestimate COHb levels compared to GC 

measurements, while at higher concentrations, this method is reported to produce underestimates (ISA, p.4-18). 10 While the COHb blood level for each subject during the exercise tests was intermediate between the 

post-exposure and subsequent post-exercise measurements (e.g., mean 2.0-2.4% and 3.9-4.7%), the study authors 

noted that the measurements at the end of the exercise test represented the COHb concentrations at the approximate 

time of onset of myocardial ischemia as indicated by angina and ST segment changes. The corresponding ranges of 

CO-Ox measurements for the two exposures were 2.7-3.2% and 4.7-5.6%. In this document, we refer to the GCmeasured mean of 2.0% or 2.0-2.4% for the COHb levels resulting from the lower experimental CO exposure. 
March 2010 Draft – Do Not Quote or Cite 2-11

1 Relative to clean-air exposure that resulted in a mean COHb level of 0.6% (post2 exercise), exposure to CO resulting in post-exercise mean COHb concentrations of 2.0% and 

3 3.9% were observed to decrease the exercise time required to induce ST-segment depression by 

4 5.1 (p=0.01) and 12.1% (p<0.001), respectively. These changes were well correlated with the 

5 onset of exercise-induced angina, the time to which was shortened by 4.2% (p=0.027) and 7.1% 

6 (p=0.002), respectively, for the two experimental CO exposures (Allred et al., 1989a, 1989b, 

1991).11 7 As at the time of the last review, while ST-segment depression is recognized as an 

8 indicator of myocardial ischemia, the exact physiological significance of the observed changes is 

9 unclear (ISA, p. 5-48). 

10 No human clinical studies have been specifically designed to evaluate the effect of 

11 controlled short-term exposures to CO resulting in COHb levels lower than a study mean of 2% 

12 (ISA, section 5.2.6). However, an important finding of the multi-laboratory study was the dose13 response relationship (discussed further in addressing a subsequent question below) observed 

14 between COHb and the markers of myocardial ischemia, with effects observed at the lowest 

15 increases in COHb tested, without evidence of a measurable threshold effect. As reported by the 

16 authors, the results comparing “the effects of increasing COHb from baseline levels (0.6%) to 2 

17 and 3.9% COHb showed that each produced further changes in objective ECG measures of 

18 ischemia” implying that “small increments in COHb could adversely affect myocardial function 

19 and produce ischemia” (Allred et al., 1989b; Allred et al., 1991). 

20 The epidemiological evidence has expanded considerably since the last review including 

21 numerous additional studies that are coherent with the evidence on markers of myocardial 

22 ischemia from controlled human studies of CAD patients (ISA, section 2.7). The most recent 

23 series of epidemiological studies have evaluated the associations between ambient concentrations 

24 of multiple pollutants (i.e. PM2.5, NO2, SO2, O3 and CO) at fixed-site monitors and increases in 

25 emergency department visits and hospital admissions for specific cardiovascular health outcomes 

26 including ischemic heart disease (IHD), myocardial infarction (MI), congestive heart failure 

27 (CHF), and cardiovascular diseases (CVD) as a whole (Bell et al., 2009; Koken et al., 2003; Linn 

28 et al., 2000; Mann et al., 2002; Metzger et al., 2004; Peel et al., 2007; Symons et al., 2006; 

29 Tolbert et al., 2007; Wellenius et al., 2005). As noted by the ISA, “[s]tudies of hospital 

30 admissions and ED visits for IHD provide the strongest [epidemiological] evidence of ambient 

31 CO being associated with adverse CVD outcomes” (ISA, p. 5-40, section 5.2.3; Linn et al., 2000; 

 

11 Another indicator measured in the study was the combination of heart rate and systolic blood pressure 

which provides a clinical index of the work of the heart and myocardial oxygen consumption, since heart rate and 

blood pressure are major determinants of myocardial oxygen consumption (Allred et al., 1991). A decrease in 

oxygen to the myocardium would be expected to be paralleled by ischemia at lower heart rate and systolic blood 

pressure. This heart rate-systolic blood pressure indicator at the time to ST-endpoint was decreased by 4.4% at the 

3.9% COHb dose level and by a nonstatistically-significant, smaller amount at the 2.0% COHb dose level. 
March 2010 Draft – Do Not Quote or Cite 2-12

1 Mann et al., 2002;Metzger et al., 2004; Peel et al., 2007). With regard to studies for other 

2 measures of cardiovascular morbidity, the ISA notes that “[t]hough not as consistent as the IHD 

3 effects, the effects for all CVD hospital admissions (which include IHD admissions) and CHF 

4 hospital admissions also provide evidence for an association of cardiovascular outcomes and 

ambient CO concentrations” (ISA, section 5.2.3; Bell et al., 2009; Tolbert et al., 2007).12 5 

6 The geographic areas in the studies for IHD and all CVD outcomes (which is inclusive of 

7 IHD) include Atlanta, urban areas of California and a group of 126 urban counties (Table 2-1 

8 below; ISA, Figure 2-1). In these studies, different multiple-year periods were assessed and the 

9 air quality statistics analyzed varied from 1 hour to 24 hours. Together the individual study 

10 periods spanned the period from 1988 through 2005. Further, the studies encompass a range of 

11 air quality conditions, such that during the time periods of study for these outcomes, only the 

12 three Atlanta studies (Metzger et al., 2004; Peel et al., 2007; Tolbert et al., 2007) (and the studies 

of CHF in Pittsburgh and Baltimore)13 13 did not include years in which ambient CO concentrations 

14 exceeded the 8-hour standard (Table 2-1). 

15 

16 

17 

 

12 As summarized further in response to a subsequent question below, the ISA notes the difficulty in 

determining from this group of studies on cardiovascular disease outcomes the extent to which CO is independently 

associated with CVD outcomes as compared to CO as a marker for the effects of another traffic-related pollutant or 

mix of pollutants, although the ISA concludes that the evidence provides support for a direct effect of short-term 

ambient CO exposure on CVD morbidity (ISA, pp. 5-40 to 5-41). 13 The study by Symons et al (2006) in Baltimore focused on an 8-month period from April to December, 

2002 (ISA, pp. 5-31, 5-32, C-21). 
March 2010 Draft – Do Not Quote or Cite 2-13

1 Table 2-1. Information from U.S. epidemiological studies of hospital admissions for ischemic heart diseas2 cardiovascular disease (ISA, Figure 5-5) and congestive heart failure (ISA, Figure 5-4) and on 3 the study periods. 

CO concentration in 

study areas, in terms 

of air quality metric 

analyzed (ppm) 

Study Reference Study Area Study Time Period Health Outcome 

Risk Estimate 

(confidence interval) 

Estimates are 

standardized within 

averaging times.1

Air Quality 

Metric 

Analyzed 

with Health 

Outcome 

Mean or median 

(study)

99th

percentile 

(AQS) 

 U.S. studies of hospital admissions for coronary heart disease (drawn from ISA, Figure 5-2). Metzger et al., 2004 Atlanta 1993-2000 IHD 1-hr daily max 1.52 5.5 - 5.9 Peel et al., 2007 Atlanta 1993-2000 IHD 

1.016 (0.999-1.034) 

1-hr daily max 1.8 5.5 - 5.9 

Mann et al., 2002 CA 1988-1995 IHD 1.0136 (1.0053-1.0220) 8-hr daily max 2.07 1.3 - 15.9 Linn et al., 2000 CA 1992-1995 MI 1.02 (1.01-1.03) 24-hr average 1.5 1.1 - 8.3  U.S. studies of hospital admissions for cardiovascular disease (drawn from ISA, Figure 5-5) Bell et al., 2009 126 urban counties 1999-2005 CVD 65+ 1.0096 (1.0079-1.0112) 1-hr daily max 1.32 1.2 - 22.1 Tolbert et al., 2007 Atlanta 1993-2004 CVD 1.017 (1.008-1.027) 1-hr daily max 1.6 5.3 - 5.4 Linn et al., 2000 CA 1992-1995 CVD 1.012 (1.005-1.020) 24-hr average 1.5 1.1 - 8.3 U.S. studies of hospital admissions for congestive heart failure (drawn from ISA, Figure 5-4)Linn et al., 2000 CA 1992-1995 CHF 1.012 (1.005-1.020) 24-hr average 1.5 1.1 - 8.3 Mann et al., 2002 CA 1988-1995 IHD+CHF 1.0304 (1.0135-1.0475) 8-hr daily max 2.07 1.3 - 15.9 Symons et al., 2006 Baltimore 2002 CHF 1.08 (0.40-2.99) 8-hr daily max 0.4 2.3 Wellenius et al., 2005 Pittsburgh 1987-1999 CHF 1.0843 (1.0614-1.1078) 24-hr average 1.03 1.6-3.9 Metzger et al., 2004 Atlanta 1993-2000 CHF 1.01(0.99-1.03) 1-hr daily max 1.52 5.5 - 5.9 Peel et al., 2007 Atlanta 1993-2000 CHF 1.019 (0.997-1.041) 1-hr daily max 1.8 5.5 - 5.9 Koken et al., 2003 Denver 1993-1997 CHF 1.181 (1.002-1.393) 24-hr average 0.9 1.3-2.0 Table legend. Information is from (a) studies that provide the strongest and most consistent weight of evidence from the epidemiological literature, and (b) additional supportive epidemiolo

estimates (unadjusted for other pollutants) for hospital admissions for ischemic heart disease (IHD), myocardial infarction (MI), cardiovascular disease (CVD; Bell 2009 included only subje

outcomes, and congestive heart failure (CHF), with the study reported mean/median for the ambient CO concentration metric analyzed by the study authors. The 99th percentile CO conce

metrics (1-, 8-hr daily max, or 24-hr average) were derived from AQS data for monitors in study areas during study time periods. Design values are CO concentrations in the statistical form 

range of 2nd maximum 1-hour and 8-hour average concentrations at highest monitor in each study area across years (from AQS for the areas and time periods of the studies). 1Estimates 

CO concentration for 1-hour metric, 0.75 ppm for 8-hour metric and 0.5 ppm for 24-hour metric. Lag period (e.g., 0, 1, 0-1, 0-2) varies by study. 2These values for Metzger et al., 2004 and 

3These design values reflect full year of data, inclusive of study months (July-Aug). 
March 2010 Draft – Do Not Quote or Cite 2-14

1 Additional epidemiological studies have been conducted on associations of ambient CO 

2 with other cardiovascular effects. For example, preliminary evidence of a link between exposure 

3 to CO and alteration of blood markers of coagulation and inflammation in individuals with CAD 

4 or CVD has been provided by a few well conducted and informative studies (ISA, Table 5-6; 

5 Delfino et al., 2008; Liao et al., 2005). As noted by the ISA, however, further studies are 

6 warranted to investigate the role of these markers in prothrombotic events and their possible 

7 contribution to the pathophysiology of CO-induced aggravation of ischemic heart disease (ISA, 

8 section 5.2.1.8). Other epidemiological studies (including field and or panel studies) also 

9 provide some evidence of a link between CO exposure and heart rate and heart rate variability 

10 (ISA, section 5.2.1.1). With regard to the two of three studies reporting a positive association 

11 with heart rate, the ISA concluded that “further research is warranted” to corroborate the results, 

12 while the larger number of studies for heart rate variability parameters is characterized as mixed 

13 (ISA, p. 5-15). Additionally, of the two studies of electrocardiogram changes indicative of 

14 ischemic events (ISA, section 5.2.1.2), one found no association and, in the other study, unlike 

15 the association with black carbon in that study, the association with CO did not remain 

16 significant in multipollutant models (ISA, p. 5-16). A limited number of epidemiological studies 

17 (Bell et al., 2009; Linn et al., 2000) have investigated hospital admissions for stroke (including 

18 both hemorrhagic and ischemic forms) and generally report small or no associations with 

19 ambient CO concentrations (ISA, section 5.2.1.9, Table 5-8 and Figure 5-3). 

20 Our consideration of these epidemiological studies here reflects our understanding of CO 

21 mechanisms and effects which is informed by the long-standing body of evidence for CO 

22 summarized above. Figure 2-1 below presents a conceptual model of the pathway from CO 

23 exposures to these effects. Figure 2-2 separately shows elements of this conceptual model 

24 investigated in clinical studies in contrast to those in the epidemiological studies discussed 

25 above. More specifically, the clinical studies provide linkages between directly measured 

26 controlled short-term CO exposures and COHb levels in CAD patients and between those COHb 

27 levels and effects in that study group, specifically, markers of myocardial ischemia. In contrast, 

28 the epidemiological studies report associations between ambient CO concentrations at fixed-site 

29 monitors and cardiovascular-related health outcomes (i.e., hospital admissions and emergency 

30 room visits). However, our ability to integrate the evidence from these epidemiological studies 

31 with our knowledge of CO-related effects based on the clinical evidence is limited in a few 

32 aspects. Most particularly, we lack information on the actual CO exposures and associated 

33 internal COHb levels that may have elicited the population response observed in the 

34 epidemiological studies, including the extent to which the response may be driven by CO 

35 exposures other than the ambient CO concentrations. Moreover, it is also unknown how those 

36 unmeasured exposures relate to the exposure concentrations of the clinical studies (e.g., 1 hour at 
March 2010 Draft – Do Not Quote or Cite 2-15

1 approximately 50-200 ppm). We are also limited in our understanding of the specific 

2 relationship between the changes in indicators of myocardial ischemia observed in the controlled 

3 human exposure studies and the hospital admissions assessed in the epidemiological studies. In 

4 consideration of the epidemiological studies for cardiovascular outcomes in light of the larger 

5 body of evidence, the ISA notes that the “known role of CO in limiting O2 availability lends 

6 biological plausibility to ischemia related health outcomes following CO exposure”, providing 

7 coherence between the two sets of findings. The ISA additionally recognizes a lack of clarity as 

8 to whether “the small changes in COHb associated with ambient CO exposures results in 

9 substantially reduced O2 delivery to tissues” (ISA, p. 5-48). 

Exposure Internal 

Dose

Nonambient (e.g., COHb)

CO

Ambient CO Health 

Outcomes

(e.g., hospital 

admissions)

Effects 

(e.g., markers 

of myocardial 

Endogenous Ischemia)

CO

10 

11 Figure 2-1. A conceptual model of CO source-to-health outcome pathway. 

Controlled CO Exposure Internal 

Dose 

(COHb) 

Effects 

(markers 

of myocardial 

Ischemia)

Ambient CO

Health 

Outcomes

(e.g., IHD 

hospital 

Epidemiological Studies admissions)

Clinical Studies (CAD Patients)

Baseline CO

(endogenous 

+ background)

12 

13 Figure 2-2. Components of CO source-to-outcome conceptual model measured in 

14 controlled human exposure and epidemiological studies discussed in this 

15 document. 
March 2010 Draft – Do Not Quote or Cite 2-16

1 Toxicological evidence presented in the current review provides further evidence of the 

2 effects of CO in the cardiovascular system (e.g., aortic injury, microvascular permeability, 

3 vascular remodeling, ventricular hypertrophy) occurring at laboratory animal CO exposure levels 

4 ranging from 35 to 200 ppm (ISA, section 5.2.5). 

5 At the time of the last review, there was evidence for effects other than cardiovascular 

6 morbidity, including neurological, respiratory and developmental effects. With regard to 

7 neurological effects, acute exposures to CO have long been known to induce CNS effects such as 

8 those observed with CO poisoning, although limited equivocal evidence available at the time of 

9 the last review included indications of some neurobehavioral effects to result from CO exposures 

10 resulting in a range of 5-20% COHb (2000 AQCD, section 6.3.2). No additional clinical or 

11 epidemiological studies are now available that investigated such effects of CO at ambient levels 

12 (ISA, section 5.3). With regard to potential effects of CO on birth outcomes and developmental 

13 effects, the currently available evidence includes limited but suggestive epidemiologic evidence 

14 for a CO-induced effect on preterm-birth, birth defects, decrease in birth weight, other measures 

15 of fetal growth, and infant mortality (ISA, section 5.4.3). The available animal toxicological 

16 studies provide some support and coherence for these birth and developmental outcomes, 

17 although a clear understanding of the mechanisms underlying potential reproductive and 

18 developmental effects is still lacking (ISA, section 2.5.3). There is limited evidence of an 

19 association between short-term exposure to CO and respiratory-related outcomes, although only 

20 preliminary evidence is available regarding a mechanism that could provide plausibility for CO21 induced effects. Thus, while there is some additional evidence on neurological, respiratory and 

22 developmental effects, it remains limited. 

23 In summary, rather than altering our conclusions from the previous review, the current 

24 evidence provides continued support and some additional strength to our previous conclusions 

25 regarding the health effects associated with exposure to CO and continues to indicate 

26 cardiovascular effects, particularly effects related to the role of CO in limiting oxygen 

27 availability, as those of greatest concern at low exposures. 

28  Does the current evidence continue to support a focus on COHb levels as the most 

29 useful indicator of CO exposures and the best biomarker to characterize potential 

30 for health effects associated with exposures to ambient CO? Or does the current 

31 evidence provide support for a focus on alternate dose indicators to characterize 

32 potential for health effects? 

33 As discussed in both the 2000 AQCD (USEPA, 2000) and the ISA, the best characterized 

34 mechanism of action of CO is tissue hypoxia caused by binding of CO to hemoglobin to form 

35 COHb. Increasing levels of COHb with subsequent decrease in oxygen availability for organs 

36 and tissues are of concern in people with pre-existing heart disease who have compromised 
March 2010 Draft – Do Not Quote or Cite 2-17

1 compensatory mechanisms (e.g., arteries unable to vasodilate, reduced capacity to increase 

2 cardiac output) such as those affected with coronary heart disease. The integrative review of 

3 health effects of CO indicates that “the clearest evidence indicates that individuals with coronary 

4 artery disease are most susceptible to an increase in CO-induced health effects” (ISA, section 

5 5.7.8) and the evidence, including that from clinical studies described in addressing the previous 

6 question (regarding health effects associated with exposure to CO), continues to support levels of 

7 COHb as the most useful indicator of CO exposure that is related to the health effects of CO of 

8 major concern. 

9 Alternative mechanisms of CO-induced effects primarily associated with CO’s ability to 

10 bind heme-containing proteins other than hemoglobin and myoglobin, and involving a wide 

11 range of cellular tissues and CO concentrations, have been described in the 2000 AQCD 

12 (USEPA, 2000, section 5.8) and in the ISA (ISA, section 5.1.3). The ISA notes that collectively 

13 the older toxicological studies demonstrated that exposure to high concentrations of CO resulted 

14 in altered functions of heme proteins other than myoglobin and hemoglobin which have the 

15 potential to interfere with basic cell and molecular processes that could lead to dysfunction 

16 and/or disease. More recent toxicological studies described in the ISA, conducted at CO 

17 exposure levels ranging from 35 to 100 ppm have provided evidence of non-hypoxic 

18 mechanisms involving binding of CO to reduced iron in heme proteins by which CO may be 

19 causing cellular injury or toxicity (ISA, section 2.5). The ISA notes that these mechanisms may 

20 or may not be interrelated and include alteration of nitric oxide signaling, inhibition of 

21 cytochrome C oxidase, heme loss from protein, disruption of iron homeostasis and alteration of 

22 cellular redox status. Less understood mechanisms noted in the ISA are alteration in ion channel 

23 activity and modulation of protein kinases signaling pathways. The ISA notes that “CO may be 

24 responsible for a continuum of effects from cell signaling to adaptive responses to cellular injury, 

25 depending on intracellular concentrations of CO, heme proteins and molecules which modulate 

26 CO binding to heme proteins” (ISA, section 5.1.3.3). 

27 Although there is evidence of additional biomarkers potentially associated with effects of 

28 CO, new research is needed to further understand these biomarkers and their linkage to CO29 induced effects in at-risk populations. Therefore, the evidence indicates that COHb continues to 

30 be the most useful and well supported indicator of CO exposures and the best biomarker to 

31 characterize the potential for health effects associated with exposures to ambient CO. 
March 2010 Draft – Do Not Quote or Cite 2-18

1  Does the current evidence alter our understanding of populations that are 

2 particularly susceptible to CO exposures? Is there new evidence that suggest 

3 additional susceptible populations that should be given increased focus in this 

4 review? 

5 The term susceptibility has been used to recognize populations that have a greater 

6 likelihood of experiencing effects related to ambient CO exposure (ISA, section 5.7). Thus, 

7 susceptible populations are at greater risk of CO effects and are referred to as at-risk in the 

8 discussion here. This increased likelihood of response to CO can potentially result from many 

9 factors, including pre-existing medical disorders or disease state, lifestage, gender, lifestyle or 

10 increased exposures (ISA, section 5.7). 

11 The current evidence, while much expanded in a number of ways, continues to support 

12 our conclusions from the previous review regarding the key and best-characterized at-risk 

13 population for exposure to ambient CO. Based on the evidence from clinical studies also 

14 considered in the last review, with which the now much-expanded epidemiological evidence 

15 base is coherent, the population with pre-existing cardiovascular disease associated with 

16 limitation in oxygen availability continues to be the best characterized population at risk of 

17 adverse CO-induced effects, with coronary artery disease (CAD) recognized as “the most 

18 important susceptibility characteristic for increased risk due to CO exposure” (ISA, section 

19 2.6.1). An important factor determining the increased susceptibility of this population is their 

20 inability to compensate for the reduction in oxygen levels due to an already compromised 

21 cardiovascular system. Individuals with a healthy cardiovascular system (i.e., with healthy 

22 coronary arteries) have operative physiologic compensatory mechanisms (e.g., increased blood 

23 flow and oxygen extraction) for CO-induced hypoxia and are unlikely to be at increased risk of 

CO-induced effects (ISA, p. 2-10).14 24 In addition, the high oxygen consumption of the heart, 

25 together with the inability to compensate for the hypoxic effects of CO make the cardiac muscle 

26 of a person suffering with coronary artery disease a critical target for the hypoxic effects of CO. 

27 In the current review, recognition of susceptibility of the population with pre-existing 

28 cardiovascular disease, such as CAD, is supported by the expanded epidemiological database, 

29 which includes a number of studies reporting significant increases in hospital admissions for 

30 IHD, angina and MI in relation to CO exposures (ISA, section 2.7). Further support is provided 

31 by epidemiologic studies (Mann et al., 2002; and Peel et al., 2007) of increased hospital 

32 admissions and emergency department visits for IHD among individuals with secondary 

 

14 The other well-studied individuals at the time of the last review were healthy male adults that 

experienced decreased exercise duration at similar COHb levels during short term maximal exercise. This 

population was of lesser concern since it represented a smaller sensitive group, and potentially limited to individuals 

that would engage in vigorous exercise such as competing athletes (1991 AQCD, section 10.3.2). 
March 2010 Draft – Do Not Quote or Cite 2-19

1 diagnoses for other cardiovascular outcomes including arrhythmia and congestive heart failure 

2 (ISA, section 5.7), and toxicological studies reporting altered cardiac outcomes in animal models 

3 of cardiovascular disease (ISA, section 5.2.1.9). 

4 Cardiovascular disease comprises many types of medical disorders, including heart 

5 disease, cerebrovascular disease (e.g., stroke), hypertension (high blood pressure), and peripheral 

6 vascular diseases. Heart disease, in turn, comprises several types of disorders, including 

7 ischemic heart disease (CHD or CAD, myocardial infarction, angina), congestive heart failure, 

8 and disturbances in cardiac rhythm (2000 AQCD, section 7.7.2.1). Types of cardiovascular 

9 disease other than those discussed above may also contribute to increased susceptibility to the 

10 adverse effects of low levels of CO (ISA, section 5.7.1.1). For example, some evidence with 

11 regard to other types of cardiovascular disease such as congestive heart failure, arrhythmia, and 

12 non-specific cardiovascular disease, although more limited for peripheral vascular and 

13 cerebrovascular disease, indicates that “the continuous nature of the progression of CAD and its 

14 close relationship with other forms of cardiovascular disease suggest that a larger population 

15 than just those individuals with a prior diagnosis of CAD may be susceptible to health effects 

16 from CO exposure” (ISA, p. 5-117). 

17 Although there was little experimental data available at the time of the last review to 

18 adequately characterize specific health effects of CO at ambient levels for other potentially at19 risk populations, several other populations were identified as being potentially more at risk of 

20 CO-induced effects due to a number of factors. These factors include pre-existing diseases that 

21 could inherently decrease oxygen availability to tissues, lifestage vulnerabilities (e.g., fetuses, the 

22 elderly), gender, lifestyle, medications or alterations in the environment (e.g., increased altitude). 

23 This is consistent with the ISA conclusions in the current review which recognize other 

24 populations that may be potentially susceptible to the effects of CO as continuing to include: 

25 those with other pre-existing diseases that may have already limited O2 availability or increased 

26 COHb production or levels, such as people with obstructive lung diseases, diabetes and anemia; 

27 older adults and fetuses during critical phases of development; commuters and those living near 

28 heavily traveled roadways; visitors to high-altitude locations; and people ingesting medications 

29 and other substances that enhance endogenous or metabolic CO production. 

30 Preliminary evidence from epidemiological, controlled human exposure, and 

31 toxicological studies indicate that people with obstructive lung disease (e.g., COPD patients with 

32 underlying hypoxia, asthmatics) may be a potentially susceptible population (ISA, section 

33 5.7.1.2). Overall, the few available epidemiological studies have reported weak, positive 

34 associations between ambient CO and CVD hospital admissions for individuals with underlying 

35 COPD. Additionally, a controlled human exposure study of individuals with COPD reported 

36 that two patients experienced COPD exacerbation and a slight anti-inflammatory effect during 
March 2010 Draft – Do Not Quote or Cite 2-20

1 CO exposures of 100-125 ppm for 2 hours (ISA, section 5.5.1.2). Other epidemiological studies 

2 (ISA, section 5.5.2.2) have reported weak associations in asthmatics, which constitute another 

3 population that can experience exercise-induced airflow limitation. Preliminary evidence was 

4 also shown in one animal toxicological study (Ghio et al., 2008), indicating mild pulmonary 

5 inflammation upon exposure to 50 ppm CO. 

6 With regard to other potentially at-risk populations, there is also limited epidemiological 

7 data showing associations between CO exposures and diabetes (ISA, section 5.7.1.3). 

8 Epidemiologic studies (Pereira Filho et al., 2008; Zanobetti and Schwartz, 2001) provide 

9 suggestive evidence that CVD patients with diabetes may be at greater risk of emergency 

10 department visits and hospital admissions than those without diabetes (ISA, section 5.7.1.3). 

11 Inferences may also be drawn from results from panel studies for individuals with metabolic 

syndrome15 12 that observed associations between short-term exposures to CO and changes in heart 

13 rate variability parameters (ISA, section 5.2.1.1) and from a toxicological study providing 

14 evidence of vascular dysfunction associated with increases in endogenous CO in an animal 

15 model of metabolic syndrome (ISA, section 5.7.1.3). People with anemia who have reduced 

16 oxygen-carrying capacity and/or higher baseline COHb levels are an additional population 

17 considered to be potentially susceptible to the hypoxic effects of CO. However, there are no 

18 controlled human studies or epidemiological studies that have specifically examined the CO19 related health effects in individuals with anemia (ISA, section 2.6.1, p. 2-11). 

20 Older adults (65+) have been considered as a potentially susceptible population to the 

21 effects of CO, primarily due to the increased prevalence of cardiovascular disease among this 

22 population when compared to all age groups or lifestages. There is limited epidemiologic 

23 evidence showing associations between short-term exposure to CO and increases in IHD or 

24 myocardial infarction (MI) hospital admissions among older adults as compared to all age groups 

25 or younger adults. The combination of this limited epidemiological data and the fact that older 

26 adults have a higher prevalence of CAD than the general population, indicates that older adults 

27 are a potentially susceptible population for increased health effects due to CO exposure (ISA, 

28 section 5.7.2.1). 

29 The developing fetus has been a population considered to be at potential risk of CO30 induced effects due to the higher affinity of their hemoglobin for CO when compared to that of 

31 adults. Limited evidence indicates an association of CO exposure during early pregnancy with 

32 pre-term births and birth defects (ISA, p. 2-8). Toxicological studies reporting effects in 

33 laboratory animals including decrements in birth weight, reduced prenatal growth, and effects on 

34 the heart provide support to the epidemiological evidence. 

 

15 These patients share risk factors with diabetics; see ISA section 5.7.1.3. 
March 2010 Draft – Do Not Quote or Cite 2-21

1 Gender has also been considered as a possible source for susceptibility. However, the 

2 evidence is inconclusive based on the limited epidemiological data, and the gender-specific 

3 variability in CO endogenous production (ISA, section 5.7.3). Increased altitude and physical 

4 activity through their effect on CO uptake and elimination has also been considered to potentially 

5 influence susceptibility. For example, residents of low altitudes visiting high altitudes, 

6 especially the elderly and those with CAD (Leaf and Kleinman, 1996; Kleinman et al., 1998), 

7 may be at greater risk from added effects of ambient CO than adapted residents (ISA, p. 2-12). 

8 Other less certain susceptibility factors have been considered, such as those pertaining to the 

9 taking of medications that may alter CO production (ISA, p. 2-12). Lastly, people experiencing 

10 increased CO exposures, such as those spending relatively greater amounts of time in 

11 microenvironments with relatively higher levels of ambient CO have been considered to be 

12 potentially at risk to CO-induced effects (ISA, section 5.7.6). 

13 As we recognize the potential susceptibility of the populations identified above, we also 

14 note the lack of information on specific COHb levels that may be associated with health effects 

15 in these other groups as well as a way to relate the specific evidence available for the CAD 

16 population to these other populations. 

17 In summary, the current evidence continues to support the identification of people with 

18 cardiovascular disease as having susceptibility to CO-induced health effects (ISA, 2-12), with 

19 those having CAD as the best characterized population with increased susceptibility to CO20 induced health effects (ISA, sections 5.7.1.1 and 5.7.8). An important susceptibility 

21 consideration for this population is the inability to compensate for CO-induced hypoxia since 

22 individuals with CAD have an already compromised cardiovascular system. Included in this 

23 susceptible population are those with angina pectoris (cardiac chest pain), those who have 

24 experienced a heart attack, and those with silent ischemia or undiagnosed IHD (AHA, 2003). 

25 People with other cardiovascular diseases, particularly heart diseases, are also at risk of CO26 induced health effects. We also recognize other populations potentially susceptible to CO27 induced effects, most particularly those with other pre-existing diseases that may have already 

28 limited oxygen availability, increased COHb levels, or increased endogenous CO production, 

29 such as people with obstructive lung diseases, diabetes and anemia; however, information 

30 characterizing susceptibility is limited.
March 2010 Draft – Do Not Quote or Cite 2-22

1  Does the current evidence alter our conclusions from the previous review 

2 regarding the levels of CO in ambient air associated with health effects? 

3 At the time of the last review, EPA’s conclusions regarding concentrations of CO in 

4 ambient air that might be associated with risk of health effects were drawn from the combined 

5 consideration of the evidence of COHb levels for which cardiovascular effects of concern had 

6 been reported and the results of an exposure and dose modeling assessment (59 FR 38906). As 

7 described in more detail in section 2.1.1 above, the key effects judged to be associated with CO 

8 exposures resulting from concentrations observed in ambient air were cardiovascular effects, as 

9 measured by decreased time to onset of exercise-induced angina and to onset of ECG ST10 segment depression (59 FR 38913). 

11 Levels of COHb that have been associated with different types of effects in clinical 

12 studies are summarized in Table 2-2 below. At the time of the last review, decreases in time to 

13 onset of exercise-induced angina (a symptom of myocardial ischemia) had been documented in 

14 multiple studies at post-exposure COHb levels ranging from 2.9 to 5.9% (CO-Ox), which 

15 represented incremental increases of 1.5-4.4% COHb from baseline (Adams et al., 1988; Allred 

16 et al., 1989a, 1989b, 1991; Anderson et al., 1973; Kleinman et al., 1989, 1998; Sheps et al., 

17 1987). The matched measurements available from Allred et al. (1989a, 1989b, 1991) of CO-Ox 

18 and gas chromatography, the method generally recognized to be the more accurate for COHb 

19 levels below 5% (ISA, section 5.2.4), indicate that CO-Ox measurements of 2.9 to 3.0% COHb 

generally correspond to GC measurements on the order of 2-2.4%.16 20 Other groups for which 

21 clinical studies have reported CO-related effects at slightly higher COHb levels include effects in 

22 subjects with cardiac arrhythmias and effects on exercise duration and maximal aerobic capacity 

23 in healthy adults. Among the studies of myocardial ischemia indicators in patients with CAD, 

24 the two studies involving the lowest experimental CO exposures (which resulted in average 

increases in COHb of about 1.5% over pre-exposure baseline) were Anderson et al. (1973)17 25 and 

26 the more recent Allred et al. (1989a, 1989b, 1991) to which we give primary attention in this 

27 review (discussed in more detail above). Neither study provided evidence of a measurable 

28 threshold at the lowest experimental CO exposures and associated COHb levels assessed (mean 

29 of 2.0-2.4% COHb, GC). Allred et al. (1989a, 1989b, 1991) further reported a dose-response 

30 relationship between the increased COHb levels and the response of the assessed indicators of 

31 myocardial ischemia (Allred et al., 1989a, 1989b, 1991). While this evidence informed our 

 

16 In the lower CO exposure group, the post-exposure mean COHb was 3.21% by CO-Ox and 2.38% by 

GC, while the post-exercise mean COHb was 2.65% by CO-Ox and 2.00% by GC (Allred et al., 1989a, 1989b, 

1991). 17 The study by Anderson et al. (1973) did not use GC to measure COHb levels, and reported reduced 

exercise duration due to increased chest pain at CO exposures resulting in 2.9% COHb (CO-Ox), representing a 

1.6% increase in average COHb levels over baseline. 
March 2010 Draft – Do Not Quote or Cite 2-23

1 conclusions regarding COHb levels associated with health effects, the CO exposure 

2 concentrations employed in the studies to achieve these COHb levels were substantially above 

3 ambient concentrations. Thus, an exposure and dose assessment was performed to consider the 

4 COHb levels that might be attained as a result of exposures to ambient CO allowed under the 

5 current NAAQS, as described in section 2.1.1 above. 

6 Since the time of the last review, there have been no new controlled human exposure 

7 studies specifically designed to evaluate the effects of CO exposure in susceptible populations at 

8 COHb levels below 2%. Thus, similar to the last review, the multilaboratory study by Allred et 

9 al.(1989a, 1989b, 1991) continues to be the study that has evaluated cardiovascular effects of 

10 greatest concern (i.e., reduced time to exercise-induced myocardial ischemia as indicated by 

11 ECG ST-segment changes and angina) at the lowest tested COHb levels (ISA, section 2.7). This 

12 is currently considered the most rigorous and well designed study, presenting the most sensitive 

13 analysis methods (GC used in addition to CO-Ox) to quantify COHb blood levels. Key findings 

14 from that study with regard to levels of CO associated with health effects include the following: 

15  Increases in COHb to mean levels of 2.0% and 3.9% from baseline (0.6%) significantly 

16 reduced exercise time required to induce markers of myocardial ischemia in CAD 

patients.18 17 

18  The associated dose-response relationship between incremental changes in COHb and 

19 change in time to myocardial ischemia in CAD patients indicates a 1.9% and 3.9% 

20 reduction in time to onset of exercise-induced angina and ST-segment change, 

21 respectively, per 1% increase in COHb concentration without evidence of a measurable 

22 threshold. 

23 Since the last review, there have been numerous improvements to the exposure and 

24 COHb models that we employ to estimate exposure and dose for the current review. The results 

25 of modeling using these improved tools in the current review and our conclusions based on it 

26 with regard to the expectation for COHb levels of concern to occur in the at-risk population 

27 under differing air quality conditions are described in section 2.2.2 below. 

 

18 Relative to baseline (0.6% mean COHb), mean COHb levels of 2.0-2.4% and 3.9-4.7% were associated 

with decreases in time to onset of exercise-induced ST-segment changes of 5.1% (p=0.01) and 12.1%(p<0.001), 

respectively. Similarly, the time to onset of exercise-induced angina was shortened by 4.2% (p=0.027) and 7.1% 

(p=0.002) for these two mean levels of COHb (Allred et al., 1989a, 1989b.1991). 
March 2010 Draft – Do Not Quote or Cite 2-24

1 Table 2-2. Carboxyhemoglobin levels and reported effects in CAD patients and healthy 

2 adults. 

%COHb 

(mean) Study 

Population Effect 

GC CO-Ox 

%COHb, 

increase 

over 

baseline 

Study 

Reduction in time to exercise-induced onset of 

myocardial ischemia 

- 5.1% decrease in time to ST- segment 

change, 4.2% decrease in time to angina 

- 12.1% decrease in time to ST- segment 

change, 7.1% decrease in time to angina 

2.0-2.4 

3.9-4.7 

2.7-3.2 

4.7-5.6 

1.4-1.7 

3.3-4.0 

Allred et al., 1989a, 

1989b, 1991 

Reduction in exercise duration prior to angina 

and/or ST segment changes NA** 2.8-5.2 1.5-4.2 

Adams et al., 1988; 

Anderson et al., 

1973; Kleinman et 

al., 1989; Kleinman 

et al., 1998; Sheps 

et al., 1987 

Patients with 

coronary 

artery 

disease* 

Exercise-induced arrhythmia NA 6 Sheps et. al., 1990, 

1991 

Reduction in exercise duration and maximal 

aerobic capacity NA 3-20 

Drinkwater et al., 

1974; Ekblom and 

Huot, 1972; 

Horvath, 1975; 

Raven et al., 

1974a, 1974b Healthy 

adults 

Equivocal behavioral effects (hand eye 

coordination, vigilance, continuous performance 

of critical tasks) 

NA 5 

Benignus et. al., 

1987, 1990a, 

1990b; Putz et. al., 

1976, 1979 

* All studies involved subjects with reproducible exercise-induced angina. 

** NA = not available. 

3 

4 Since the time of the last review, a number of additional epidemiological studies have 

5 been conducted of health outcome associations with different ambient CO metrics (e.g., ISA, 

6 section 5.2). The majority of these epidemiological studies, conducted in selected urban areas of 

7 the U.S. or Canada, were designed to evaluate the effects of multiple pollutants (i.e. PM2.5, NO2, 

8 SO2, O3 and CO). As discussed above, a number of these studies have reported associations 

9 between concentrations of CO measured at fixed-site ambient monitors and cardiovascular 

10 endpoints other than stroke, particularly hospitalizations and emergency department visits for 

11 specific cardiovascular health outcomes including ischemic heart disease (IHD), congestive heart 

12 failure (CHF) and cardiovascular diseases (CVD) as a whole (Bell et al., 2009; Koken et al., 

13 2003; Linn et al., 2000; Mann et al., 2002; Metzger et al., 2004; Peel et al., 2007; Symons et al., 
March 2010 Draft – Do Not Quote or Cite 2-25

1 2006; Tolbert et al., 2007; Wellenius et al., 2005). In general, these studies report positive 

2 associations and a number of these associations are statistically significant (ISA, sections 5.2.3 

3 and 5.2.1.9; Table 2-1 above). 

4 In considering these epidemiological studies in the case of CO, we recognize that there is 

5 coherence between the available clinical and epidemiological evidence with regard to the health 

6 effects of CO in the cardiovascular system (primarily for ischemic related events). As noted 

7 above, however, we also recognize several gaps between the two lines of evidence which 

8 complicate their integration, particularly with regard to ambient exposures and ambient 

9 concentrations associated with health effects of concern. As discussed in the ISA, the 

10 epidemiological studies reported associations with emergency department visits and/or hospital 

11 admissions for IHD and other cardiovascular disease-related outcomes that are plausibly related 

12 to the effects on physiological indicators of myocardial ischemia (e.g., ST-segment changes) 

13 demonstrated in the controlled human exposure studies, providing coherence between the two 

14 sets of findings. However, there is appreciable uncertainty with regard to the specific 

15 relationship between these two types of measures of cardiovascular morbidity. Furthermore, the 

16 clinical studies document relationships between controlled elevated exposures to CO and specific 

17 levels of an internal dose metric, COHb, which elicited specific responses in CAD patients. This 

18 informs our interpretation of the associations we observe in the epidemiological studies, although 

19 COHb has not been monitored in the epidemiological studies and the personal CO exposure 

20 concentrations eliciting the outcomes observed, including the contributions from ambient and 

nonambient CO, are unknown (as illustrated in Figure 2-2 above).19 21 Further, to achieve their 

22 experimental target levels of COHb, the clinical studies used short (approximately 1-hour) 

23 exposures to concentrations of CO that were substantially higher than current commonly 

24 occurring ambient concentrations (ISA, section 2.7). The relationship of the clinical exposure 

25 concentrations to exposure concentrations occurring in the populations studied in the 

26 epidemiological studies is unknown, but the clinical exposures may be higher. For example, 

27 individual exposure concentrations for the lower clinical exposure ranged from 42 to 202 ppm 

28 (Allred et al., 1989b). Experimental studies have not been conducted at COHb levels that might 

29 be elicited in response to exposures to lower CO concentrations such as those within the ranges 

30 of current maximum ambient concentrations (ISA, section 2.7) or closer to personal exposure 

31 concentrations more commonly expected currently (e.g., ISA, Figure 3-45). Gaps in our 

32 understanding of the role of nonambient CO exposures and their contribution to COHb levels 

 

19 As recognized in the ISA in consideration of the epidemiological studies, the known role of CO in 

limiting O2 availability lends biological plausibility to ischemia-related health outcomes following CO exposures, 

although “it is not clear whether the small changes in COHb associated with ambient CO exposures results in 

substantially reduced O2 delivery to tissues” (ISA, p. 5-48). 
March 2010 Draft – Do Not Quote or Cite 2-26

1 also complicates our ability to disentangle ambient concentrations that may be related to health 

2 effects. 

3 In considering these epidemiological studies in the case of CO, we recognize several 

4 uncertainties that complicate the quantitative interpretation with regard to ambient concentrations 

5 that might be eliciting the reported health outcomes. These uncertainties relate to conclusions 

6 regarding CO as the pollutant eliciting the effect reported in these studies and to our 

7 understanding of the ambient CO concentrations (and total concentrations) to which study 

8 subjects demonstrating effects are exposed. 

9  With regard to the first, a major uncertainty relates to the difficulty in determining the 

10 extent to which ambient CO is independently associated with cardiovascular effects or 

11 if CO at ambient levels is acting as a surrogate for the effects of another traffic-related 

12 pollutant or mixture of pollutants (ISA, section 5.2.3). As noted in the ISA, in 

13 interpreting the epidemiological evidence for cardiovascular morbidity “[i]t is difficult 

14 to determine from this group of studies the extent to which CO is independently 

15 associated with CVD outcomes or if CO is a marker for the effects of another traffic16 related pollutant or mix of pollutants. On-road vehicle exhaust emissions are a nearly 

17 ubiquitous source of combustion pollutant mixtures that include CO and can be an 

18 important contributor to CO in near-road locations” (ISA, p. 5-40 – 5-41). We also 

19 note CASAC’s recognition of the potential for co-pollutants to pose confounding to be 

20 “particularly problematic for CO” and the need to give consideration to the possibility 

21 of CO serving as a surrogate for a mixture of fossil- fuel-combustion-related pollutants 

22 (Brain and Samet, 2010). 

23  To identify the CO-specific effect, and assess and control for potential confounding of 

24 CO-associated health effects by other pollutants for which measurements are available, 

25 two-pollutant regression models are a commonly used statistical method (ISA, section 

26 1.6.3). Although CO associations may, in some studies, be slightly attenuated in 

27 models adjusting for one other combustion-related pollutant, they generally remain 

28 robust (Figures 5-6 and 5-7). However, there are several statistical issues influencing 

29 results generated using multi-pollutant models, such as models that force all pollutants 

30 to follow the same lag structure, the inclusion of correlated but noncausal variables, 

31 and the potential omission of etiologically relevant co-pollutants. Although data for 

32 co-pollutant modeling are available for some of the other criteria pollutants, data are 

33 not available for additional combustion-related pollutants, which may or may not 

34 include all pollutants that elicit the health effects (ISA, section 2.5.1). In light of the 

35 uncertainty (referenced in discussion of the question below) regarding the biological 

36 plausibility of CO-related effects at low ambient concentrations, it is possible that the 

37 CO risk estimates ascribed to measured ambient CO levels in epidemiological studies 

38 is instead another pollutant that is highly correlated with CO, but was not measured. 

39  With regard to the second, the presence of exposure error and/or measurement error 

40 from reliance on fixed-site ambient CO monitors, a large portion of which are 

41 measuring CO concentrations at or below detection limits can result in the over or 

42 underestimation of the effects of the poorly measured pollutant. This limitation can 

43 add uncertainty to the association between ambient concentrations of CO and health 
March 2010 Draft – Do Not Quote or Cite 2-27

1 effects estimates (ISA, p. 3-91) and constrain their interpretation with regard to CO 

2 exposure levels (Brain and Samet, 2010). 

3 We have considered here the epidemiological studies in the U.S. for ischemia-related 

4 outcomes. In Table 2-2, we focused on the U.S. studies of CHD hospital admissions for CHD 

5 (i.e., IHD and MI), that provided the strongest and most consistent weight of evidence (ISA, 

6 Figure 5-2, pp. 5-24 to 5-26). In Table 2-3, we present the U.S. studies for the broader category 

7 of all CVD hospital admissions that also contributed to the ISA’s causality determination (ISA, 

8 Figure 5-5, pp. 5-33 to 5-36). In focusing on these studies, we did not include studies of 

9 associations with CHF, a chronic condition for which there are multiple causes and for which the 

evidence is less clear.20 10 We have focused here on studies for IHD, MI and all CVD outcomes 

11 (which are inclusive of IHD), which we consider to be key due to the more direct conceptual 

12 linkages that can be drawn between the these outcomes and the myocardial ischemia effects of 

13 the CAD clinical studies. 

14 Of particular interest in addressing the question posed here is information pertaining to 

15 CO concentrations in ambient air that meet the current standard. While, the full set of these 

16 epidemiological studies, including those reporting associations with ambient CO concentrations 

17 under conditions when the current standards were not met, provide support to the previous 

18 evidence regarding cardiovascular effects of CO, it is the studies involving air quality conditions 

19 in which the current standards were met that are most informative within the context of 

considering the adequacy of the current standards.21 20 Accordingly, in considering these 

21 epidemiological studies, we have considered the air quality conditions during the periods of 

22 study. 

23 The areas of focus across these studies of IHD and CVD outcomes (inclusive of IHD) 

include Atlanta, urban areas of California and a group of 126 urban counties22 24 and the multi-year 

25 time periods for these studies together span the period from 1988 through 2005 (Tables 2-3 and 

26 2-4 below). During the time periods of study, only the three Atlanta studies (Metzger et al., 

27 2004; Peel et al., 2007; Tolbert et al., 2007) did not include years in which ambient CO 

28 concentrations exceeded the 8-hour standard (Tables 2-3 and 2-4). Based on data reported to 

29 AQS for the general areas studied, ambient CO concentrations during a portion of the time 

30 periods studied in the other three of these analyses exceeded the level of the current 8-hour 

31 NAAQS (Bell et al., 2007; Linn et al., 2000; Mann et al., 2002). Among these three studies, all 

 

20 We note that two of the studies listed in Tables 2-3 and 2-4 also reported positive associations with CHF 

(ISA, pp. 5-31 to 5-33). Additionally, there are three other studies of CHF associations shown in Table 2-1 above, 

two of which were statistically significant, with one of those with significant results focused on an area in which the 

current 8-hour standard was just met (Koken et al., 2003; Symons et al., 2006; Wellenius et al., 2005). 21 As at the time of the last review, the 8-hour standard continues to be the controlling standard. 

22 The 126 counties span some 40 states, including the District of Columbia. 
March 2010 Draft – Do Not Quote or Cite 2-28

1 of which reported statistically significant risk estimates, the highest 8-hour design values ranged 

from 11.6-23.4 ppm, as compared to the 8-hour standard of 9 ppm.23 2 In the Atlanta area, which 

3 was the focus for the other three studies (Peel et al., 2007; Metzger et al., 2004; Tolbert et al., 

4 2007), the second highest non-overlapping 8-hour average CO concentration in a year (i.e., the 

5 design value for the 8-hour standard) ranged from 3.2 up to 5.3 ppm over the combined 12 years 

6 of study. One of these three studies (Tolbert et al., 2007) reported a statistically significant risk 

7 estimate for cardiovascular hospital visits associated with CO concentrations, while the other two 

did not. In the Atlanta area during the period studied, the 99th 8 percentile daily maximum 8-hour 

CO concentration in a year ranged up to 4.9 ppm, while the yearly 99th 9 percentile daily 

10 maximum 1-hour CO concentration ranged up 7.9 ppm. The studies in which CO concentrations 

11 exceeded the current NAAQS during some portion of the study period accordingly are less 

12 informative to our overarching question regarding the adequacy of the protection afforded by the 

13 current standard. We note that studies reporting associations with IHD or total CVD outcomes 

14 for which air quality data reported to AQS do not indicate that the current 8-hour standard was 

15 exceeded during the study period are limited to those for Atlanta.

 

23 Staff also note that the national-scale study of 126 urban counties by Bell et al. (2009) included a subset 

analysis that evaluated associations for all cardiovascular outcomes, adjusted for NO2, after restricting the dataset to 

days with a 1-hour daily maximum CO concentration less than 35 ppm, which is the level of the 1-h standard 

although its form is the 2nd maximum in a year. This subset analysis found a statistically significant effect estimate 

identical to the estimated risk with the full data set. Further subset analyses by Bell et al. in this study using data 

below cutoff values of 1-10 ppm all found positive, statistically significant associations (with adjustment for NO2), 

although confidence intervals increased at the lower cutoff values and the proportion of values near and below the 

limit of detection grew larger. 
March 2010 Draft – Do Not Quote or Cite 2-29

1 Table 2-3. Air quality information for key U.S. epidemiological studies of hospital admissions for coronar2 (ISA, Figure 5-2). 

1-hour Daily Maximum (ppm) 

8-hour Daily Maximum (ppm) 

24-hour Average (ppm) 

Study Area 

Study Period 

Health Outcome Mean 

99th

percentile Mean 

99th

percentile Mean 

99th

percentile 

Metzger et al., 2004 Atlanta 1993-2000 IHD 1.5*1 5.5-5.9 Peel et al., 2007 Atlanta 1993-2000 IHD 1.8* 5.5-5.9 

1993 6.1 4.4 2.4 1994 6.3-6.6 4.3-4.9 2.7-3.3 1995 5.8-7.9 4.3-4.9 2.4-3.2 1996 5.3-6.1 3.5-3.6 2.0-2.7 1997 5-5.4 3.1-4.2 2.3-2.4 1998 4.8-4.9 2.8-3.9 2.1-2.4 1999 4.9-5.4 3-3.8 2.0-2.3 

Atlanta Air Quality Data (from 3 monitors in 20 counties) 2000 4.9-5.4 3.0-3.8 1.5-1.8 

Mann et al., 2002 CA 1988-1995 IHD 2 - 22 2.07* 1.3-15.9 

1988 4.0-31.0 1.4-14.6 1.2-10.9 1989 2.0-22.0 2.0-10.1 1.7-6.9 1990 4.0-22.0 1.6-11.7 1.3-7.8 1991 2.0-21 2-10.7 2.0-8.7 1992 2.0-21.0 1.0-8.1 1.0-9.6 1993 2.0-19.0 1.1-7.6 1.1-8.0 1994 2.1-14.5 1.1-10.2 1.1-8.9 

California Air Quality Data (from 31 monitors in 4 counties) 1995 1.5-11.6 1-6.7 1.0-7.6 

Linn et al., 2000 CA 1992-1995 MI 1.5* 1.1-8.3 Table legend. This table presents information from key studies finding associations with coronary heart disease (ISA, section 5.2.3, Figure 5-2). The health outcomeadmissions for ischemic heart disease (IHD) and myocardial infarction (MI). The 99th percentile (in ppm) of the CO concentration for the specific study metrics (i.e.,1

24-hour average) were derived from AQS data for monitors in the study areas during the study period. Design values are values of CO concentration in the statisticapresented here is the range of 2nd highest 1-hour and 8-hour average concentrations per year at the highest monitor in each study area (obtained from the AQS data

periods of the studies).  * Risk estimates and CO concentrations for the study metric as reported by the study authors. 

1This value for Metzger et al. (2004) is the median. 
March 2010 Draft – Do Not Quote or Cite 2-30

1 Table 2-4. Air quality information for key U.S. epidemiological studies of hospital admissions for CVD (I

1-hour Daily 

Maximum 

(ppm) 

8-hour Daily 

Maximum (ppm) 

24-hour Averag

(ppm) 

Study Area Study Period 

Health 

Outcome 

mean 

99th

percentile mean 

99th

percentile mean 

99th

percen

Bell et al., 2009 

126 urban counties 1999-2005 CVD 65+ 1.3* 1.2-22.1 

Tolbert et al., 2007 Atlanta 1993-2004 CVD 1.6* 5.3-5.4 

For 1993-2000, see Table 2-2 above 2001 3.8-4.1 2.4-3.0 1.8-1.9 2002 4.2-4.3 2.2-2.5 1.5-1.6 2003 2.6-3.3 2-2.1 1.2-1.7 

Atlanta Air Quality Data (3 monitors in 20 counties) 2004 2.9 2 1.5 

Linn et al., 2000 CA 1992-1995 CVD 1.5* 1.1-8.3 Table legend. This table presents information from key studies finding associations with CVD (ISA , section 5.2.3, Figure 5-5). The health outcomes include hospital admissions for cardiovascular disease (CVD; Bell et al (2009) only included subjects 65 years old and above), with the associated ri

other pollutants. The 99th percentile (in ppm) of the CO concentration for the specific study metrics (i.e.,1-, 8-hour daily maximum, or 24-hour averag

for monitors in the study areas during the study period. Design values are values of CO concentration in the statistical form of the standard; present

highest 1-hour and 8-hour average concentrations per year at the highest monitor in each study area (obtained from the AQS database for the areas studies). * CO concentrations for the study metric as reported by the study authors. 

2 
March 2010 Draft – Do Not Quote or Cite 2-31

1 In summary, although there is no new evidence regarding lower COHb levels associated 

with effects, the evidence is much expanded with regard to epidemiological24 2 analyses of 

3 ambient monitor concentrations, which observed associations between specific and overall 

4 cardiovascular-related outcomes and ambient CO measurements. With regard to extending our 

5 understanding of effects occurring below levels of CO observed in the clinical studies, however, 

6 the epidemiological evidence for CO is somewhat limited. The epidemiological evidence lacks 

7 measurements of COHb or personal exposure concentrations that would facilitate integration 

8 with the clinical data. Furthermore, as discussed above, the full epidemiological evidence base 

9 for IHD outcomes or CVD outcomes as a whole includes a number of studies involving 

10 conditions in which the current standard was not met. Though these studies are informative to 

11 consideration of the relationship of health effects to the full range of ambient CO concentrations, 

12 they are less useful to informing our conclusions regarding adequacy of the current standards. 

13 Consideration of the smaller set of studies under conditions where the current standards were met 

14 is considered to better inform our consideration of the adequacy of the standards or conditions of 

15 lower ambient concentrations. Among the few studies for IHD or CVD outcomes under 

16 conditions where the current standards were met, one study reported statistical significance for 

17 IHD or CVD outcomes, and all of these studies are limited to a single study area (i.e. Atlanta). 

18 These limitations lessen the weight we give these studies for our purposes here in making 

19 interpretations with regard to ambient concentrations of CO that may be eliciting health 

20 outcomes, particularly in light of the availability of strong evidence from controlled human 

21 exposure studies. Therefore, with regard to this question of CO concentrations we have 

22 primarily focused our consideration of the epidemiological studies on the extent to which this 

23 evidence is consistent with and generally supportive of conclusions drawn from the combined 

24 consideration of the controlled human exposure evidence with estimates from the exposure and 

25 dose assessment (section 2.2.2 below). As in the previous review, we believe the integration of 

26 the controlled human exposure evidence with the exposure and dose estimates will be most 

27 important to informing conclusions regarding ambient CO concentrations of public health 

28 concern. 

29  To what extent have important uncertainties identified in the last review been 

30 reduced and/or have new uncertainties emerged? 

31 Since the time of the last review, some important uncertainties have been reduced, some 

32 still remain and others associated with newly available evidence have been identified. A range 

 

24 Few epidemiological studies that had investigated the relationship between CO exposure and ischemic 

heart disease were available at the time of the last review (USEPA, 1991, section 10.3.3). 
March 2010 Draft – Do Not Quote or Cite 2-32

1 of important uncertainties were identified in a number of areas at the time of the last review (59 

2 FR 38913, USEPA, 1992), including: 

3  The adverse nature and significance of the small changes in ST-segment depression 

4 identified at the lowest COHb levels investigated in the controlled human exposure 

5 studies, and the magnitude of risk associated with such changes for specific health 

6 outcomes, such as myocardial infarction, or of slight but cumulative myocardial 

7 damage, among other possibilities. 

8  The extent to which COHb measurements made using CO-Ox do not reflect COHb 

9 levels in angina patients studied and the potential for as yet unidentified health effects 

10 at COHb levels below 2%. 

11  The potential for short-term peak CO exposures to contribute to CNS effects which 

12 might affect individual’s performance of complex activities such as driving a car or to 

13 contribute to other effects of concern. 

14  Effects of ambient CO on potentially susceptible populations other than those with 

15 cardiovascular disease, including the developing fetus. 

16  Modeling of COHb formation associated with exposures to ambient CO under different 

17 air quality conditions, including those associated with attainment of different NAAQS. 

18 As discussed below, some of these uncertainties have been reduced, while some still remain. 

19 The CO-induced effects considered of concern at the time of the last review were reduced 

20 time to exercise-induced angina and ST-segment depression in patients suffering from coronary 

21 artery disease as a result of increases in COHb associated with short CO exposures. These 

22 effects had been well documented in multiple studies, and it was recognized that the majority of 

23 cardiologists at the time believed that recurrent exercise-induced angina was associated with 

24 substantial risk of precipitating myocardial infarction, fatal arrhythmia, or slight but cumulative 

25 myocardial damage (USEPA, 1992, p. 22; 59 FR 38911; Basan, 1990; 1991 AQCD). As at the 

26 time of the last review, although ST-segment depression is a recognized indicator of myocardial 

27 ischemia, the exact physiological significance of the observed changes among individuals with 

28 CAD is unclear (ISA, p. 48). 

29 In interpreting the study results at the time of the last review, EPA recognized uncertainty 

30 in the COHb measurements made using CO-Ox and associated uncertainty in establishing a 

31 lowest effects level for CO (USEPA, 1992, p. 31). A multicenter then-recent study (Allred et al., 

32 1989a, 1989b, 1991) was of great importance at that time for several reasons including the large 

33 number of subjects used, the rigorous protocol used for subject selection, the use of the most 

34 accurate method to measure blood COHb levels and the finding of a dose-response relationship 

35 between COHb levels and the ischemic events evaluated in the study. This study reported 

36 changes in post-exercise ST-segment depression and reduced time to onset of exercise-induced 

37 angina as a result of increases in COHb from a mean baseline of 0.6% to mean levels of 2% and 
March 2010 Draft – Do Not Quote or Cite 2-33

1 3.9% (ISA, section 5.2.4; (Allred et al., 1989a,1989b, 1991). In the current review of the 

2 evidence related to cardiovascular effects associated with CO exposure, the we place primary 

3 emphasis on the findings of Allred et al. (1989a, 1989b, 1991) recognizing the superior quality of 

4 the study, both in terms of the rigorous study design as well as the sensitivity of the analytical 

5 methods used in determining COHb concentrations (ISA, Section 2.7). No additional clinical 

6 studies are available that evaluate responses to lower COHb levels in the cardiovascular-disease 

7 population, and uncertainties still remain in determining specific and quantitative relationships 

8 between the CO-induced effects in these studies and the increased risk of specific health 

9 outcomes. Further, with regard to then unidentified effects at lower COHb levels, no studies 

10 have identified other effects on the CAD population or on other populations at lower exposures 

11 (ISA, sections 5.2.2). 

12 The last review recognized a variety of neurobehavioral effects associated with CO 

13 exposure, including changes in visual perception, hearing, motor performance and vigilance 

14 among other measures of neurobehavioral performance based on a series of studies conducted 

15 from the mid 1960’s through the early 1990’s (1991 AQCD). Since these effects were observed 

16 at exposures to CO resulting in COHb levels ranging from 5-20%, and were poorly understood at 

17 the time (1991 AQCD), the review focused on cardiovascular effects, which had been observed 

18 at COHb levels below 5% and consequently for which a focus would also provide adequate 

19 protection against potential adverse neurobehavioral effects. No new human clinical studies 

20 have evaluated CNS or behavioral effects of exposure to CO (ISA, section 5.3.1). However, 

21 given the drastic reduction in CO ambient concentrations, the occurrence of these effects in 

22 response to ambient CO would be expected to be rare within the current population. Thus, our 

23 uncertainty with regard to the potential for such effects to be associated with current ambient CO 

24 exposures is reduced. 

25 At the time of the last review, the developing fetus was recognized as having the potential 

26 to be particularly vulnerable to the effects of CO exposures because human fetal development 

27 often occurs at or near critical tissue oxygenation levels (Longo, 1977; 59 FR 38911; USEPA, 

28 1992, p. 25). The human data at the time of the last review consisted of a limited set of studies 

29 primarily considering the effects of maternal cigarette smoke in the developing fetus, many of 

30 them conducted at very high exposure levels (500-1000 ppm). The effects observed included 

31 spontaneous abortion and death due to decreased birth weight. Additional animal toxicological 

32 studies, also conducted at CO concentrations higher than the ambient CO levels at the time, 

33 provided suggestive evidence of fetal mortality, teratogenicity, reduced body weight, 

34 morphological changes, altered cardiovascular development and neurochemical changes. Since 

35 the last review, the epidemiologic and toxicological evidence of effects on birth and 

36 developmental outcomes has somewhat expanded, although the available evidence is still 
March 2010 Draft – Do Not Quote or Cite 2-34

1 considered limited with regard to effects on preterm birth, birth defects, decreases in birth 

2 weight, measures of fetal growth, and infant mortality. Although there are animal toxicological 

3 studies providing support and coherence for those effects, the understanding of the mechanisms 

4 underlying reproductive and developmental effects is still lacking (ISA, section 5.4.1). Thus, 

5 although the evidence continues to “suggest[s] that critical developmental phases may be 

6 characterized by enhanced sensitivity to CO exposure” (ISA, p. 2-11), evidence is still lacking on 

7 the potential for adverse effects on birth and developmental outcomes at CO exposures near 

8 those associated with current levels of ambient CO. As a result uncertainty still remains in this 

9 area. 

10 Numerous improvements have been made over the last decade that have reduced the 

11 uncertainties associated with the models used to estimate COHb levels resulting from ambient 

12 CO exposures under different air quality conditions, including those associated with just meeting 

13 the current CO NAAQS (draft REA, section 4.3). This progression in exposure model 

14 development has led to the Agency’s currently used model (APEX4.3) that has an enhanced 

15 capacity to estimate population CO exposures and more accurately predicts COHb levels in 

16 persons exposed to CO. Our application of APEX4.3 to the current situation, using updated data 

17 and new algorithms to estimate exposures and doses experienced by individuals, better 

18 represents the variability in population exposure and COHb dose levels. However, while APEX 

19 4.3 is greatly improved when compared with previously used exposure models, its application is 

20 still limited with regard to data to inform our understanding of spatial relationships in ambient 

21 CO concentrations and within microenvironments of particular interest. Further information 

22 regarding model improvements and remaining exposure modeling uncertainties are described in 

23 section 2.2.2 below. 

24 In the current review, we continue to recognize coronary artery disease as the most 

25 important susceptibility characteristic for increased risk due to CO exposure (ISA, p. 2-10). 

26 While a much expanded epidemiologic database inclusive of studies showing associations 

27 between ambient CO monitor concentrations and increases in emergency room visits and 

28 hospitalizations for ischemic heart disease events support this conclusion, a variety of associated 

29 uncertainties complicate the interpretation of these studies. Although CO associations generally 

30 remain robust in copollutant models (ISA, Figures 5-6 and 5-7, section 2.7), disentangling a CO31 specific effect at low ambient concentrations from other pollutants remains of concern, 

32 particularly for the quantitative interpretation of these studies. The potential for CO to act as a 

33 surrogate for another combustion related pollutant included in a copollutant statistical model 

34 “complicates quantitative interpretation of the effect estimates reported in epidemiologic studies” 
March 2010 Draft – Do Not Quote or Cite 2-35

(Tolbert 2007; ISA, p. 2-16).25 1 Moreover, as recognized by CASAC, “the problem of co2 pollutants serving as potential confounders is particularly problematic for CO” and “a better 

3 understanding of the possible role of co-pollutants is relevant to regulation ... on the health 

4 effects of CO” (Brain and Samet, 2010). Error in the assessment of personal CO exposure 

5 through the use of fixed site-monitors measuring CO levels at or below the limit of detection of 

6 the monitor is a new source of uncertainty since the prior review due to an overall decrease in 

7 ambient CO concentrations. This error may lead to an over or underestimation of CO health risk 

8 estimates. Thus, some uncertainties associated with the epidemiological evidence “complicate 

9 the quantitative interpretation of the epidemiologic findings, particularly regarding the biological 

10 plausibility of health effects occurring at COHb levels resulting from exposures to the ambient 

11 CO concentrations” assessed in these studies (ISA, p. 2-17). 

12 In summary, some important uncertainties from the last review have been reduced, 

13 including those associated with concerns for ambient levels of CO to pose neurobehavioral risks. 

14 A variety of uncertainties still remain including the adverse nature and significance of the small 

15 changes in ST-segment depression identified at the lowest COHb levels investigated, and the 

16 magnitude of associated risk of specific health outcomes, as well as the potential for as yet 

17 unidentified health effects at COHb levels below 2%. Additionally, although the evidence base 

18 is somewhat expanded with regard to the potential for CO effects on the developing fetus, 

19 uncertainties remain with regard to this potential susceptibility. Our exposure and dose models 

20 have improved giving us increased confidence in their estimates. We additionally recognize that 

21 the expanded body of epidemiological evidence includes its own set of uncertainties which 

22 complicates its interpretation. 

23 2.2.2 Exposure/Risk-based Considerations 

24 Our consideration of the scientific evidence in the current review, as at the time of the 

25 last review (summarized in section 2.1.1 above), is informed by results from a quantitative 

26 analysis of estimated population exposure and resultant COHb levels. As in our consideration of 

27 the evidence in section 2.2.1 above, we have organized the discussion that follows here around a 

28 set of key questions to assist us in drawing from the draft assessment of CO exposure and 

29 resultant COHb levels for at-risk populations living in two cities under current air quality 

 

25 In interpreting the epidemiological evidence for cardiovascular morbidity the ISA notes that it “is 

difficult to determine from this group of studies the extent to which CO is independently associated with CVD 

outcomes or if CO is a marker for the effects of another traffic-related pollutant or mix of pollutants. On-road 

vehicle exhaust emissions are a nearly ubiquitous source of combustion pollutant mixtures that include CO and can 

be an important contributor to CO in near-road locations. Although this complicates the efforts to disentangle 

specific CO-related health effects, the evidence indicates that CO associations generally remain robust in copollutant 

models and supports a direct effect of short-term ambient CO exposure on CVD morbidity.” (ISA, pp. 5-40 to 5-41). 
March 2010 Draft – Do Not Quote or Cite 2-36

1 conditions and conditions simulated to just meet the current CO standards. These questions are 

2 intended to inform consideration of the following overarching question. 

3 Prior to addressing the series of questions below, we provide a description of the 

4 modeling tools used in and the design of the assessment, the magnitude of COHb levels. We 

5 then consider the question regarding the size of the simulated at-risk population estimated to 

6 experience COHb levels of interest, followed by the identification of key uncertainties associated 

7 with our assessment of exposure and dose with regard to drawing conclusions as to the adequacy 

8 of the protection afforded by the current CO standards. We then consider the exposure and dose 

9 estimates from the quantitative assessment with regard to implications as to the extent of the 

10 population provided protection from COHb levels of concern under the current standards to help 

11 inform judgments about the extent to which such estimates may be judged to be important from a 

12 public health perspective. 

13 In the draft assessment conducted for this review, described in detail in the draft REA and 

14 summarized here, we have estimated CO exposure and associated COHb levels in simulated 

15 populations in two urban study areas in Denver and Los Angeles, in which current CO 

16 concentrations are below the current standards. We selected these areas because: (1) both cities 

17 have been included in prior CO NAAQS exposure assessments and thus serve as an important 

18 connection with past assessments; (2) historically, they have generally had the highest CO 

19 ambient concentrations among urban areas in the U.S.; and (3) Denver is at high altitude and 

20 represents an important risk scenario due to the potential increased susceptibility to CO exposure 

21 associated with high altitudes. In addition, of 10 urban areas across the U.S. selected for detailed 

22 analysis in the ISA and having monitors meeting a 75% completeness criteria, the two locations 

23 were ranked first (Los Angeles) and second (Denver) regarding the percentage of elderly 

24 population within 5, 10, and 15 km of monitor locations, and ranked first (Los Angeles) and fifth 

25 (Denver) regarding number of 1- and 8-hour daily maximum CO concentration measurements 

26 (ISA, section 3.5.1.1). 

27 Estimates were developed for exposures associated with current “as is” conditions (2006 

28 air quality) and also for higher ambient CO concentrations associated with air quality conditions 

simulated to just meet the current 8-hour standard.26 29 In considering the adequacy of the current 

30 standard, it is important to note that over the last few years, the standard has been met throughout 

the country with few exceptions.27 31 Although we consider it unlikely that air concentrations in 

32 many urban areas across the U.S. that are currently well below the current standard would 

 

26 As discussed elsewhere, the 8-hour standard is the controlling standard for CO. 27 As described in section 1.3.3 above, in the most recent period analyzed (2007-2008), all areas of the U.S. 

met both CO NAAQS. In both of the previous periods (2005-2006 and 2006-2007), one area did not meet the 8-

hour standard. Further, one area of the country is designated in non-attainment with the CO NAAQS although air 

quality in that area has met the standards in the past three periods. 
March 2010 Draft – Do Not Quote or Cite 2-37

1 increase to just meet the standard, we also recognize the potential for CO concentrations in some 

2 areas currently below the standard to increase to just meet the standard. Accordingly, we have 

3 simulated conditions of increased CO concentrations that just meet the current standard in the 

4 two study areas. In this scenario, we note there is uncertainty associated with simulating this 

5 hypothetical profile of higher CO concentrations that just meet the current standard. 

6 The exposure and dose modeling, presented in detail in the draft REA, relied on EPA’s 

7 Air Pollutant Exposure model (APEX4.3), which estimates human exposure using a stochastic, 

8 event-based microenvironmental approach. This model has a history of application, evaluation, 

9 and progressive model development in estimating human exposure and dose for several NAAQS 

10 reviews, including CO, O3, NO2, and SO2. As mentioned above, we have made major changes to 

11 the exposure modeling approach used in the last CO review. The prior review relied on 

12 estimated population exposure and dose generated from pNEM, a model that 1) employed a 

cohort-based approach,28 13 2) relied on a limited set of activity pattern data (approximately 3,600 

14 person-days) 3) used four broadly defined categories to estimate breathing rates (i.e., slow15 sleeping, slow-awake, medium, and fast), and implemented a geodesic distance range 

16 methodology to approximate workplace commutes (Johnson et al., 1992; USEPA, 1992). Each 

17 of these approaches used by pNEM, while appropriate given the data available at the time would 

18 tend to limit the ability to accurately model the lower and upper tails of the population exposure 

19 distribution. In contrast, APEX4.3 includes new algorithms to 1) simulate activity sequences and 

20 exposure profiles for individuals, 2) estimate activity-specific minute-by-minute oxygen 

21 consumption and breathing rates, 3) address spatial variability in home and work-tract ambient 

22 concentrations for commuters, and 4) estimate event-based microenvironmental concentrations. 

23 APEX also uses additional data available from recent activity pattern surveys (CHAD now has 

24 about 34,000 person-days of data) and uses the most recent US census data to represent 

25 population demographics and home-to-workplace commutes. Modeling the prevalence of 

26 exposures or dose in a population of interest (such as individuals with coronary heart disease) 

27 has also been enhanced in APEX with the addition of output tables presenting statistics for 

28 identified subpopulations and age groups (or life stages), using the updated census population 

29 demographic data, and including options for approaches used to estimate microenvironmental 

30 concentration. 

 

28 When using the cohort approach, each cohort is assumed to contain persons with identical exposures 

during the specified exposure period. Thus, variability in exposure will be attributed to differences in how the 

cohorts are defined, not necessarily reflecting differences in how individuals might be exposed in a population. A 

total of 420 cohorts were used to estimate population exposure based on selected demographic information (11 

groups using age, gender, work status), residential location, work location, and presence of indoor gas stoves 

(Johnson, et al., 1992; USEPA, 1992). 
March 2010 Draft – Do Not Quote or Cite 2-38

1 APEX probabilistically generates a sample of hypothetical individuals from an actual 

2 population database and simulates each individual’s movements through time and space (e.g., 

3 indoors at home, inside vehicles) to estimate his or her exposure to a pollutant. Population 

4 characteristics are taken into account to represent the demographics of each study area. With 

5 regard to age and gender demographics for the simulated at-risk population (adults with 

6 diagnosed and undiagnosed CAD), we augmented estimates of the prevalence of CAD provided 

7 by the National Health Interview Survey with estimates of undiagnosed ischemia that were based 

8 on two assumptions: (1) there are 3.5 million persons in U.S. with undiagnosed IHD (drawn 

9 from an estimate by the American Heart Association) and (2) persons with undiagnosed IHD are 

10 distributed within the population in the same manner as persons with diagnosed IHD (draft REA, 

11 section 5.5.2). Based on exposure concentrations, minute-by-minute activity levels, and 

12 physiological characteristics of the simulated person (see draft REA, chapters 4 and 5), APEX 

13 estimates the level of COHb in the blood at the end of each hour based on solution to the 

14 nonlinear Coburn-Forster-Kane equation (draft REA, section 4.4.7). 

15 APEX simulations performed for this review have focused on exposures to ambient CO 

16 occurring in eight microenvironments, with no additional contribution from indoor CO sources. 

17 We note that, where present, indoor sources, including gas stoves and tobacco smoke can also be 

18 important contributors to total CO exposure and may be of concern for at-risk populations. 

19 Some assessments performed previously have included modeling simulations both with and 

20 without certain indoor sources and these assessments provide context for the assessment of 

21 ambient CO exposure and dose. For example, a 2000 exposure/dose assessment indicated that 

22 the impact of such sources can be substantial on the portion of the population experiencing 

23 higher exposures and COHb levels (Johnson et al., 2000). In the last review it was noted that 

24 while these indoor sources were shown to contribute to total CO exposure they would not be 

25 effectively mitigated by setting more stringent ambient air quality standards (59 FR 38914). In 

26 the current review, model simulations have not included indoor sources. 

27 As discussed in the previous section (Section 2.2.1), people with cardiovascular disease 

28 are the population of primary focus in this review. Further, based on the available evidence in 

29 the current review, coronary artery disease, also known as coronary heart disease is the “most 

30 important susceptibility characteristic for increased risk due to CO exposure” (ISA, p. 2-11). 

31 Controlled human exposure studies have provided specific quantitative COHb dose-response 

32 information for this specific population with regard to effects on markers of myocardial 

33 ischemia. In identifying COHb levels associated with specific effects for CAD patients, we have 

34 given primary focus to the multi-laboratory study in which COHb was analyzed by the more 

35 accurate GC method (Allred et al., 1989a, 1989b, 1991). Specifically, this study has documented 

36 reductions in times to exercise-induced change in the ST-segment of an electrocardiogram and to 
March 2010 Draft – Do Not Quote or Cite 2-39

1 exercise-induced onset of angina, observed in response to CO exposures involving subjects with 

2 pre-existing CAD, as described in section 2.2.1 above. 

3 Studies have not been designed to evaluate similar effects at CO exposure eliciting COHb 

4 levels below this range. In addition, these studies do not address the fraction of the population 

5 experiencing a specified health effect at various dose levels. These aspects of the evidence 

6 contributed to EPA’s conclusion that there are currently insufficient controlled human exposure 

7 data to support the development of quantitative dose-response relationships which would be 

8 required in order to conduct a quantitative risk assessment for this health endpoint, rather than a 

9 benchmark level approach. Further, based on the current evidence with regard to quantitative 

10 information of COHb levels and association with specific health effects, the primary target 

11 population for purposes of the quantitative assessment is adults with CHD (also known as 

ischemic heart disease IHD or CAD), both diagnosed and undiagnosed.29 12 Evidence 

13 characterizing the nature of specific health effects of CO in other populations is limited and does 

14 not include specific COHb levels related to health effects in those groups. As a result, the 

15 quantitative assessment does not develop separate quantitative dose estimates for populations 

16 other than those with CAD. 

17 We have reviewed COHb estimates developed in the draft REA for the simulated at-risk 

18 population with attention to both COHb in absolute terms and based on consideration of the 

19 contribution associated with ambient CO exposures. For purposes of the review of COHb in 

20 absolute terms, we identified benchmark levels of 1.5%, 2.0%, 2.5% and 3% COHb. Selection 

21 of this range of benchmark levels is based on consideration of the evidence from controlled 

22 human clinical studies of CAD patients (discussed in section 2.2.1 above). This range includes 

23 the range of COHb levels identified as levels of concern in the review completed in 1994 (2.0 to 

24 2.9%) and the level given particular focus (2.1%), as described in section 2.1.1 above (USEPA, 

25 1992; 59 FR 48914). The range of benchmark levels identified here extends below the lowest 

26 mean COHb level (e.g., 2.0% post-exercise in Allred et al., 1989b) resulting from controlled 

27 increased exposure to CO in the clinical evidence. The extension of this range reflects a number 

28 of considerations, including: (1) comments from the CASAC CO panel on the draft Analysis 

29 Plan (Brain, 2009); (2) consideration of the uncertainties regarding the actual COHb levels 

30 experienced in the controlled human exposure studies; (3) that these studies did not include 

individuals with most severe cardiovascular disease30 31 ; (4) the lack of studies that have evaluated 

 

29 As described in section1.2 above, this is the same population group that was the focus of the CO NAAQS 

exposure/dose assessments conducted previously (e.g., US EPA, 1992; Johnson et al., 2000). 30 Although the CAD patients evaluated in the controlled human exposure study by Allred et al. (1989a, 

1989b, 1991) are not necessarily representative of the most sensitive population, the level of disease in these 

individuals ranged from moderate to severe, with the majority either having a history of myocardial infarction or 

having ≥ 70% occlusion of one or more of the coronary arteries (ISA, p. 5-43). 
March 2010 Draft – Do Not Quote or Cite 2-40

1 effects of experimentally controlled short-term CO exposures resulting in mean COHb levels 

2 below 2.0-2.4%; and (5) the lack of evidence of a threshold at the increased COHb levels 

3 evaluated. We note that CASAC comments on the first draft REA recommended the addition of 

4 a benchmark at 1% COHb and we have presented results for this COHb level in the second draft 

5 REA. Given that this level overlaps with the upper part of the range of endogenous levels in 

6 healthy individuals as characterized in the ISA (ISA, p. 2-6) and is within the upper part of the 

7 range of baseline COHb levels in the study by Allred et al (1989b, Appendix B), however, we 

8 considered that it may not be appropriate to place weight on it as a potential health effects 

9 benchmark level and accordingly has not focused on dose estimates for it in the discussion 

10 below. Additionally, in considering contributions to COHb associated with ambient CO 

11 exposures, we recognize the findings of Allred et al (1989a, 1989b, 1991) with regard to a dose12 response relationship for decreases in time to exercise-induced angina and ST-segment change 

13 per 1% increase in COHb concentration in persons with pre-existing CAD (ISA, section 5.2.4; 

14 Allred et al., 1989a, 1989b, 1991). In considering COHb estimates from the quantitative 

15 assessment below, we take note of estimates of endogenous COHb levels from the quantitative 

16 exposure and dose analysis which indicated that in the absence of external CO sources, 

17 approximately 1.5% of the simulated at-risk population in one of the two populations was 

18 estimated to experience maximum end-of-hour endogenous COHb levels at or above 1% (draft 

19 REA, section 6). 

20 The benchmark levels identified are used to interpret COHb levels estimated to occur in 

21 the modeled population in response to exposures to ambient CO in different air quality scenarios 

22 in light of the evidence for cardiovascular effects in individuals with CHD when exposed to CO. 

23 Specifically, in considering the exposure and dose estimates with regard to consideration of the 

24 adequacy of the current standards here, we focus on estimates of the portion of this at-risk 

25 population estimated to experience maximum end-of-hour COHb levels above these 

26 benchmarks, and on information concerning the COHb increment above endogenous levels 

27 associated with ambient CO exposures. 

28  What is the magnitude of at-risk population COHb levels estimated to occur in 

29 areas simulated to just meet the current CO standards? What portion of the at30 risk population is estimated to experience maximum COHb levels above levels of 

31 potential health concern? 

32 In addressing this question, we consider the population COHb estimates provided by the 

33 draft REA (draft REA, section 6.2) and summarized in Tables 2-5 and 2-6 below. These tables 

34 include estimates associated with current “as is” conditions and conditions simulated to just meet 

35 the current standard. In considering these estimates, we particularly focus on the extent to which 

36 the current standards provide protection to the simulated at-risk population from COHb levels of 
March 2010 Draft – Do Not Quote or Cite 2-41

1 potential concern, by comparing the estimated levels in the population to the potential health 

2 effect benchmarks described above. As described above, the draft REA estimates of COHb 

3 reflect the impact of exposures to ambient CO in addition to individual endogenous levels (draft 

4 REA, section 6.4). 

5 Under “as is” conditions in the two study areas, fewer than 0.1 % and 2% of the 

6 simulated at-risk population are estimated to experience an end-of-hour COHb concentration at 

7 or above 2% and 1.5%, respectively, with the results for the Los Angeles study area including 

8 slightly larger portions of the population above these benchmarks than that estimated for the 

9 Denver study area. Under conditions with higher ambient CO concentrations that just meet the 

10 current 8-hour standard, the portion of the simulated at-risk population estimated to experience 

11 these levels of COHb is greater. But for these simulations, the relationship between the two 

12 study areas is reversed with the Denver study area having higher COHb levels. In the Denver 

13 study area 3.4% of the simulated at-risk population is estimated to experience a maximum end14 of-hour COHb level at or above 2%, while 19% of the population is estimated to experience a 

15 maximum COHb level at or above 1.5%. For the Los Angeles study area, less than 1% and 5% 

16 of the population was estimated to experience maximum end-of-hour COHb levels at or above 

17 2% and 1.5%, respectively (Table 2-5). 

18 Table 2-5. Portion of simulated at-risk population with maximum end-of-hour COHb 

19 levels at or above the indicated level under air quality conditions simulated to 

20 just meet the current standards and under “as is” (2006) conditions. COHb 

21 levels reflect endogenous levels and ambient CO exposures. 

Percentage (%) of Simulated At-risk Population 

Just meeting current standards “as is” conditions 

Maximum 

end-ofhour 

COHb 

Level Los Angeles Denver Los Angeles Denver 

> 3% <0.1 0.2 

> 2.5% <0.1 0.6 

0.0 

> 2% 0.5 3.4 <0.1 

0.0 

> 1.5% 4.6 19.1 1.5 0.6 

 * <0.1 is used to represent nonzero estimates below 0.1% 

22 
March 2010 Draft – Do Not Quote or Cite 2-42

1  What are the key uncertainties associated with our exposure and dose estimates, 

2 including those of particular significance with regard to drawing conclusions as to 

3 the adequacy of the protection afforded by the current CO standards? 

4 In considering the uncertainties associated with the quantitative estimates of exposure 

5 and dose from the draft REA, we relied on an approach intended to identify and compare the 

6 relative impact that important sources of uncertainty may have on the estimated potential health 

7 effect endpoints (i.e., estimates of the maximum end-of-hour COHb levels in the simulated at8 risk population). The approach used (as described in section 7.2 of the second draft REA) was 

9 developed using guidelines outlining how to conduct a qualitative uncertainty characterization 

10 (WHO, 2008) and applied in the most recent NO2 (US EPA, 2008b) and SO2 NAAQS reviews 

11 (US EPA, 2009). We employed the mainly qualitative approach given the extremely limited data 

12 available to inform probabilistic analyses. The qualitative approach used varies from that of 

13 WHO (2008) in that a greater focus of the characterization performed was placed on evaluating 

14 the direction and the magnitude of the uncertainty; that is, qualitatively rating how the source of 

15 uncertainty, in the presence of alternative information, may affect the estimated exposures and 

16 health risk results. In addition and consistent with the WHO (2008) guidance, we discuss the 

17 uncertainty in the knowledge-base (e.g., the accuracy of the data used, acknowledgement of data 

18 gaps) and decisions made where possible (e.g., selection of particular model forms), though 

19 qualitative ratings were assigned only to uncertainty regarding the knowledge-base. 

20 In the characterization of uncertainty for the current analysis, we identified and evaluated 

21 fourteen separate sources of uncertainty associated with four main components of the 

22 assessment: 

23  Ambient monitor CO concentrations 

24 - database quality, spatial and temporal representation, and missing data 

25 substitution; 

26  Adjustment of air quality to simulate just meeting the current and potential alternative 

27 standards 

28 - historical data used, proportional approach used; 

29  APEX inputs and algorithms 

30 - population database, activity pattern database, longitudinal profile algorithm, 

31 meteorological data, micrenvironmental algorithm and input data, commuting 

32 algorithm, CHD prevalence, physiological factors; and, 

33  Potential health effects benchmark levels for the simulated at-risk population. 

34 
March 2010 Draft – Do Not Quote or Cite 2-43

1 By comparing judgments made regarding the magnitude and direction of influence the 

2 identified sources have on estimated exposure concentrations and dose levels and the existing 

3 uncertainties in the knowledge-base, we identified six sources (i.e., the spatial and temporal 

4 representation, historical data used, activity pattern database, longitudinal profile algorithm, 

5 microenvironmental algorithm and input data, and physiological factors) that remain as the most 

6 important uncertainties in this assessment. Taking into consideration improvements in the model 

7 algorithms and data since the last review, and having identified and characterized these 

8 uncertainties here, we conclude that the estimates associated with the current analysis, at a 

9 minimum, better reflect the full distribution of exposures and dose as compared to results from 

10 the 1992 analysis. When considering the overall quality of the current exposure modeling 

11 approach, the algorithms, and input data used, alongside the identified limitations and 

12 uncertainties, we conclude that the quantitative assessment provides reasonable estimates of CO 

13 exposure and COHb dose for the simulated population the assessment is intended to represent 

14 (i.e., the population residing within the urban core of each study area). We note somewhat 

15 greater uncertainty in characterizing of the ends of the distribution of population exposures. 

16  To what extent are the estimates of at-risk population COHb levels under 

17 conditions just meeting the current CO standards important from a public health 

18 perspective? 

19 In considering the public health implications of the quantitative dose estimates, we first 

20 note the size of the at-risk population simulated in the draft REA, people with CAD, both 

21 diagnosed and undiagnosed. This population is recognized as that most susceptible to increased 

22 risk of CO-induced health effects (ISA, sections 5.7.1.1 and 5.7.8). The 2007 estimate from the 

23 National Health Interview Survey (NHIS) performed by the U.S. Centers for Disease Control of 

24 the size of the U.S. population with coronary heart disease, angina pectoris (cardiac chest pain) 

25 or who have experienced a heart attack (ISA, Table 5-26) is 13.7 million people (ISA, pp.5-117). 

26 Further, there are estimated to be three to four million additional people with silent ischemia or 

27 undiagnosed IHD (AHA, 2003). In combination this represents a large population represented 

28 by the draft REA analyses and for which the COHb benchmarks described above (based on 

29 studies of CAD patients) are relevant, that is more susceptible to ambient CO exposure when 

30 compared to the general population (ISA, section 5.7). 

31 As discussed above, the draft REA estimates that 0.5 percent of the Los Angeles and 

32 3.4% of the Denver study CHD populations may experience maximum end-of-hour COHb levels 

33 of the same magnitude as the average COHb level resulting for the lower experimental exposure 

34 group in the study by Allred et al. (1989a, 1989b, 1991) which resulted in a statistically 

35 significant reduction in the time to exercise-induced markers of myocardial ischemia (angina and 

36 ECG ST-segment change) of 4-5% on average. While recognizing that the exposure resulting in 
March 2010 Draft – Do Not Quote or Cite 2-44

1 the 2% average COHb level associated with this result was significantly over background (e.g., 

2 approximately 1 hour at 50-200 ppm CO as compared to 0-2 ppm clinic air concentrations), we 

3 also note the dose-response relationship was summarized by the authors as indicating decreases 

4 of roughly 1.9% in time to exercise-induced angina and 3.9% in time to exercise-induced ST5 segment change per 1% increase in COHb concentration in persons with pre-existing CAD, as 

discussed in section 2.2.1 above (ISA, section 5.2.4; Allred et al., 1989a,1989b, 1991).31 6 As 

7 noted in the ISA, the physiological significance of the observed ST-segment changes among 

8 individuals with CAD is unclear and variability in severity of disease among individuals with 

9 CAD is likely to influence the critical level of COHb which leads to adverse cardiovascular 

10 effects (ISA, p. 2-6). 

11 In addition to the population with diagnosed and undiagnosed CAD, we note implications 

12 with regard to risk to people with other forms of CVD, which we recognize as potentially 

13 susceptible (ISA, section 2.6.1). For example, NHIS estimates for 2007 indicate there are 

14 approximately 12 million additional people with other types of heart disease (ISA, Table 5-26). 

15 Within this broad group, implications are more significant for those included in this population 

16 for which their disease state affects their ability to compensate for the hypoxia-related effects of 

17 CO (ISA, section 4.4.4). 

18 Other potentially susceptible populations to the effects of CO include people with chronic 

19 obstructive pulmonary disease, diabetes and anemia, as well as older adults and fetuses during 

20 critical phases of development (as discussed in section 2.2.1 above). In considering potential 

21 impacts on such populations, however, we recognize limitations in the evidence in informing us 

22 with regard to the specific effects of CO on these populations and, importantly, the exposures 

23 and associated COHb levels associated with such effects. 

24 In summary, we recognize that conclusions regarding the extent to which the estimates of 

25 exposure and COHb associated with just meeting the current standard are important from a 

26 public health perspective depend in part on public health policy judgments about the significance 

27 of effects at the COHb benchmark levels considered and judgments about the level of public 

28 health protection with an adequate margin of safety. For example, we note that these estimates 

29 indicate that the current 8-hour standard limits substantially the percent of the population 

30 expected to experience maximum COHb levels at or above the higher benchmarks, while 

31 limiting much less so the percentage of the population with maximum COHb levels above the 

 

31 The dose-response relationship was derived as the average of the regressions of the individual study 

subject data for changes in time to onset of the monitored measures of ischemia across their range of COHb levels 

(from their baseline COHb to their two higher COHb levels resulting from the two experimental CO exposures). 

The clean-air exposure, post-exercise (baseline) COHb levels in the individual study subjects ranged from 0.2% to 

1.1%, their post-exercise COHb levels for the lower experimental CO exposure ranged from 1.0 to 3.0% and their 

post-exercise COHb levels for the higher experimental CO exposure ranged from 2.3 to 5.1% (Allred et al., 1989b). 
March 2010 Draft – Do Not Quote or Cite 2-45

1 lowest benchmarks. Thus, we initially conclude that these estimates provide support for a range 

2 of views regarding the importance of these estimates form a public health perspective. 

3 2.2.3 Initial Staff Conclusions on Adequacy of the Current Standards 

4 In considering the adequacy of the current standard, staff gives great weight to the long5 standing body of evidence for CO, augmented in some aspects since the last review, that has 

6 established: the common mechanism of CO health effects as involving binding to reduced iron 

7 in heme proteins and the alteration of their functioning; the important role of hypoxia (reduced 

8 oxygen availability) induced by increased COHb blood levels in eliciting health effects; the use 

9 of COHb as the bioindicator and dose metric for evaluating CO exposure and potential for health 

10 effects; and, people with cardiovascular disease as a key population at risk from low CO 

11 exposures (ISA; 2000 AQCD; 1991 AQCD). We additionally recognize the expansion of the 

12 epidemiological evidence that provides coherence with our conclusions regarding cardiovascular 

13 disease-related susceptibility and may (recognizing various uncertainties associated with the 

14 evidence in the particular case of CO) provide indications of air quality conditions associated 

15 with ambient CO-related risk, most particularly in areas during periods which included 

16 exceedance of the current 8-hour standard (ISA, section 5.2.1). 

17 As at the time of the last review, we give weight to COHb estimates developed from 

18 modeling exposures to ambient CO under conditions simulated to just meet the current, 

19 controlling, 8-hour standard. These COHb estimates and the incremental contribution from 

20 ambient CO exposures are considered in light of the clinical studies. These estimates indicate 

21 that some 1-3 percent of the simulated at-risk population are expected to experience maximum 

22 COHb levels of a magnitude for which association has been demonstrated with markers of 

23 myocardial ischemia and larger portions of the population may experience maximum COHb 

24 levels at or above the lowest benchmark considered. Further, in considering public health 

25 significance of such estimates, while recognizing uncertainty in the clinical significance 

26 associated with the smaller effects observed at the lower COHb levels, we note the substantial 

27 size of the at-risk population in the U.S. and the existence of other potentially susceptible 

28 populations for which evidence is more limited. 

29 In summary, we draw initial conclusions with regard to the adequacy of the current 

30 standard from both the evidence and from the exposure and dose assessment, in light of related 

31 limitations and uncertainties. We initially conclude that the combined consideration of the body 

32 of evidence and the quantitative exposure and dose estimates provide support for a standard at 

33 least as protective as the current standard. Further, we recognize that conclusions regarding the 

34 adequacy of the current standard depend in part on public health policy judgments about the 

35 significance of effects at the COHb benchmark levels considered and judgments about the level 
March 2010 Draft – Do Not Quote or Cite 2-46

1 of public health protection with an adequate margin of safety. Thus, we initially conclude that 

2 the combined consideration of the evidence and quantitative estimates described above may be 

3 viewed as providing support for either retaining or revising the current 8-hour standard. 

4 The extent to which the current standard is judged to be adequate or not depends on a 

5 variety of factors, inclusive of technical considerations, science policy judgments and public 

6 health policy judgments. These include public health policy judgments on the appropriate COHb 

7 benchmark levels on which to place weight; judgments on the clinical significance of the effects 

8 that have been observed at those levels; uncertainty associated with interpretation of the 

9 epidemiological evidence as providing information on ambient CO as distinct from information 

10 on the mixture of pollutants associated with traffic, and the weight to place on the 

11 epidemiological studies for purposes of considering adequacy of the current standards, given that 

12 few are available (in one city) during periods under air quality conditions that did not exceed the 

13 current standard; and the weight to place on the results of the draft exposure assessment relative 

14 to those from past assessments, recognizing the implementation of a new modeling approach and 

15 input data. 

16 Staff’s initial conclusions with regard to elements of revised primary standards for CO 

17 that may be appropriate to consider are discussed in the following sections. These conclusions 

18 are drawn from consideration focused on the 8-hour standard in recognition of its role in 

19 controlling ambient air quality conditions for CO. We give more specific consideration to each 

20 of the two CO primary standards in the discussion of alternative standards in section 2.3 below. 

21 2.3 CONSIDERATION OF ALTERNATIVE STANDARDS 

22 To the extent that the information available in this review suggests that revision of the 

23 current standards is appropriate to consider, staff has considered whether the available body of 

24 evidence supports consideration of options that are different from the current standard, as 

25 articulated by the following overarching question: 

26  To what extent does the currently available scientific evidence- and exposure/risk27 based information, as reflected in the ISA and draft REA, support consideration 

28 of alternatives to the current CO standards to provide increased protection from 

29 ambient CO exposures? 

30 To assist us in interpreting the currently available scientific evidence and the results of 

31 recent quantitative exposure/risk analyses to address this question, we have focused on a series 

32 of more specific questions in sections 2.3.1 and 2.3.2 below. In considering the scientific and 

33 technical information, we consider both the information available at the time of the last review 

34 and information newly available since the last review which has been critically analyzed and 

35 characterized in the 2000 AQCD and more recently in the ISA. Specifically, we consider how 
March 2010 Draft – Do Not Quote or Cite 2-47

1 the currently available scientific evidence informs decisions regarding the basic elements of the 

2 NAAQS: indicator, averaging time, level and form. Considerations with regard to indicator and 

3 averaging time are presented in sections 2.3.1 and 2.3.2. Form and level are discussed in section 

4 2.3.3. 

5 2.3.1 Indicator 

6 The indicator for carbon monoxide is carbon monoxide as measured by the federal 

7 reference methods and equivalent methods. Unlike several other criteria pollutants, there are not 

8 multiple compounds or size fractions of carbon monoxide. Federal reference methods are 

9 available that can effectively measure carbon monoxide, and thus we have not identified any 

10 basis for considering an indicator other than carbon monoxide for the standard. 

11 2.3.2 Averaging Time 

12 In considering potential alternative averaging times other than the current 1- and 8-hour 

13 averaging times, we consider the following question: 

14  Do health effects evidence and air quality/exposure assessments provide support 

15 for considering different exposure indices or averaging times? 

16 The averaging times for the current standards are 1-hour (35 ppm) and 8-hours (9 ppm). 

17 These averaging times were first chosen when EPA promulgated the primary NAAQS for CO in 

18 1971 (36 FR 8186), and were retained in subsequent reviews (1980, 45 FR 55066; 1985, 50 FR 

19 37485; and 1994, 59 FR 38906). 

20 The 8-hour averaging time was selected primarily based on the rationale that most 

21 individuals achieve steady-state blood levels of COHb after approximately 8 hours of continuous 

22 CO exposure (USEPA, 1979; AQCD 2000, section 7.4; ISA, section 4.3.2.2). Another 

23 consideration was that the 8-hour time-frame represented a good basis for tracking continuous 

24 exposures during any 24-hour period, recognizing that people may be exposed in approximately 

25 8-hour blocks of time (e.g., working or sleeping). 

26 The 1-hour averaging time primarily reflected consideration of the potential impact of 

27 exposures of 1 hour or shorter, such as very short duration peak exposures in urban environments 

28 (59 FR 38914). Much of the health evidence, however, is linked to exposures of 1 hour or 

29 longer, such as the controlled human studies demonstrating aggravation of myocardial ischemia 

30 after exposure of individuals with coronary artery disease to CO for approximately 1-2 hours. 

31 Further, based on consideration of air quality data patterns it was recognized that attainment of 

32 the 8-hour standard would tend to also limit short-term peaks to levels below those of concern 

33 (45 FR 55077). 
March 2010 Draft – Do Not Quote or Cite 2-48

1 In considering whether the information available in this review supports consideration for 

2 different averaging times for the CO standards, we note that the available information is 

3 generally consistent with and supportive of the conclusions reached in the previous reviews to 

4 retain the 1- and 8-hour averaging times. 

5  Controlled human exposure studies, with which epidemiological evidence is coherent, 

6 provide the clearest evidence of short-term CO-induced effects and reflect exposures of 

7 1-2 hours (ISA, sections 5.2, 5.2.6.1). 

8  Epidemiological studies provide evidence based on analyses of 1-, 8-, and 24-hour 

9 averaging times (ISA, section 5.2.6). 

10  Most individuals would be expected to achieve steady-state levels of blood COHb after 

11 6-8 hours of continuous exposure to a fixed CO concentration. Therefore, 8 hours may 

12 reasonably be considered closely representative of longer continuous exposures (2000 

13 AQCD, section 7.4). 

14  The 1-hour averaging time is considered to provide protection from the occurrence of 

15 shorter term peak exposure concentrations of ambient CO that may be encountered in 

16 some environments, and from COHb levels that may result from such exposures (2000 

17 AQCD, section 7.4; ISA, section 2.4.1). 

18 Taken together, we initially conclude that the information available in the current review 

19 continues to support the 1- and 8-hour averaging times and does not provide information that 

20 would lead to consideration of standards with alternative averaging times. 

21 2.3.3 Form and Level 

22 In considering potential alternative forms and levels for the standards, we focused 

23 primarily on form and level for the 8-hour standard, while also considering form and level for the 

24 1-hour standard. In so doing, we addressed the following overarching question: 

25  What is the range of alternative levels and forms for the standard that are 

26 supported by the health effects evidence and air quality/exposure assessments, 

27 and what are the uncertainties and limitations in that health effects evidence and 

28 air quality/exposure assessments? 

29 In this section, we focus on general considerations with regard to form in section 2.3.2.1. 

30 We then address specific considerations for both level and form in section 2.3.2.2, first with 

31 regard to the 8-hour standard and then with regard to the 1-hour standard. 

32 2.3.3.1 Potential Alternative Forms 

33 When evaluating alternative forms in conjunction with specific levels, staff considers the 

34 adequacy of the public health protection provided by the combination of level and form to be the 

35 foremost consideration. In addition, we recognize that it is preferable to have a form that is 

36 reasonably stable and relatively insulated from the impacts of extreme meteorological events or 
March 2010 Draft – Do Not Quote or Cite 2-49

1 other rare, transitory impacts on air quality. A standard set with a high degree of instability could 

2 have the effect of reducing public health protection because shifts in and out of attainment could 

3 disrupt an area’s ongoing implementation plans and associated control programs. 

4 Therefore, consistent with recent reviews of the O3, PM and NO2 NAAQS, we have 

5 focused here on a concentration-based form (as compared with an expected or allowable 

6 exceedance-based form) and are considering this with regard to an average over 3 years. As 

noted in the review of the O3 NAAQS (USEPA, 2007), concentration-based forms32 7 may better 

8 reflect pollutant-associated health risks than forms based on expected exceedances because 

9 concentration-based forms give proportionally greater weight to periods of time when pollutant 

10 concentrations are well above the level of the standard than to times when the concentrations are 

11 just above the standard, while an expected exceedance form would give the same weight to 

12 periods of time with concentrations that just exceed the standard as to times when concentrations 

13 greatly exceed the standard. Concentration-based forms also provide greater regulatory stability 

14 than a form based on allowing only a single expected exceedance. 

15 In considering specific concentration-based forms on which to focus the current review, 

16 we have initially considered such forms as have been considered in other NAAQS reviews, 

including the 98th and 99th 17 percentile forms averaged over three years, which were considered in 

the most recent PM and NO2 NAAQS reviews (USEPA, 2005; USEPA, 2008b).33 18 We note that 

a 99th 19 percentile form for an 8-hour daily maximum standard would correspond to the fourth 

20 highest daily maximum 8-hour average concentration in a year. We have initially considered 

that a 98th percentile form or forms of 99th 21 percentile or fourth highest daily maximum would 

22 provide appropriate balances between limiting peak CO concentrations and providing a stable 

23 regulatory target. 

24 When considering results of the second draft REA as they relate to standard form, we 

25 note that a decision on form must be made in conjunction with selection of a particular standard 

26 level. The primary emphasis in such a decision will be on the level of public health protection 

27 provided by the combination of form and level. The current form of both the 8-hour and 1-hour 

28 standards is a maximum, not to be exceeded more than once per year. In the section below we 

consider the results of the second draft REA for different combinations of level with both a 99th 29 

30 percentile concentration-based form and the current “exceeded only once per year” form. 

 

32 The term “concentration-based” forms is used here to refer to forms based on a concentration associated 

with a targeted point on the distribution of pollutant concentrations, as distinguished from a “not to be exceeded” or 

“to be exceeded no more than x times in a year’ form. 33 Given the limited time frame for this review, only one alternative form (for the 8-hour and 1-hour 

standards) has been evaluated in the REA, such that we do not have the results of the quantitative assessment in 

terms of a 98th percentile form available to us at this time. 
March 2010 Draft – Do Not Quote or Cite 2-50

1 2.3.3.2 Potential Alternative Levels 

2 In considering potential alternative standard levels with regard to their potential to 

3 provide greater protection than that afforded by the current standard against CO-related adverse 

4 health effects, we have taken into account scientific evidence from both experimental and 

5 epidemiologic studies, as well as the uncertainties and limitations in that evidence, and the 

6 quantitative estimates of exposure and dose provided by the second draft REA. We note that the 

7 scientific evidence and quantitative assessment can provide insights into alternative standard 

8 levels only within the context of specific averaging times and forms. Therefore, this section 

9 considers the evidence and quantitative analysis as they relate to alternative levels particular to 

10 different forms and averaging times. The primary focus of staff’s initial considerations in this 

11 draft Policy Assessment is on the 8-hour standard because it has long been the controlling 

12 standard for air quality. 

13 As an initial matter, we recognize that indoor sources of CO can be important 

14 determinants of population exposures to CO and to population distributions of COHb including 

15 maximum COHb levels. For some portions of the population these sources may be the primary 

16 influences on external exposure-related COHb levels. However, we take note of the conclusions 

17 drawn in the previous review that the contribution of indoor sources to individual exposures and 

18 associated COHb levels cannot be effectively mitigated by ambient air quality standards (e.g., 59 

19 FR 38914) and so focus here on COHb levels resulting from ambient CO exposures. At the 

20 same time, we additionally recognize people whose exposures to nonambient CO result in 

21 elevated COHb levels, and particularly those whose COHb levels may be appreciably influenced 

22 by additional ambient CO exposures. Findings of previous quantitative assessments in which 

23 some indoor sources were represented (e.g., gas stoves and tobacco smoke), however, indicated 

24 that indoor source contributions to population maximum COHb levels were substantial in 

25 comparison to ambient contributions. While we are limited with regard to information regarding 

26 CO emissions from indoor sources today and how they may differ from the time of the 2000 

27 assessment, we note that ambient contributions have notably declined and indoor source 

28 contributions from some sources may also have declined. Thus, we have no firm basis to 

29 conclude a different role for indoor sources today with regard to contribution to population CO 

30 exposure and COHb levels. 

31 We believe that the integration of the health effects evidence with the exposure and dose 

32 estimates will be particularly important to informing conclusions regarding standard levels and 

33 forms considered to provide protection of public health with an adequate margin of safety. With 

34 regard to the scientific evidence, as discussed in section 2.2.1 above, we have given principal 

35 emphasis to findings of the multilaboratory controlled human exposure study of individuals with 

36 pre-existing CAD (Allred et al., 1989a, 1989b, 1991). In this study, controlled experimental 
March 2010 Draft – Do Not Quote or Cite 2-51

1 exposures to CO that resulted in a post-exercise study mean COHb level as low as 2.0% relative 

2 to clean-air exposures that resulted in a mean COHb level of 0.6% (post-exercise) were 

3 associated with myocardial ischemia-related effects (including, specifically, reduced time to 

4 exercise-induced angina and ST-segment change). A dose-response analysis of the study subject 

5 specific data, in which individual regressions of study subject responses at baseline COHb and at 

6 the two increased COHb levels were averaged, indicated decreases of roughly 1.9% in time to 

7 exercise-induced angina and 3.9% in time to exercise-induced ST-segment change per 1% 

8 increase in COHb concentration, with no evidence of a measurable threshold at the controlled 

9 exposures evaluated (ISA, section 5.2.4; Allred et al., 1989a, 1989b, 1991). For our purposes 

10 here, we additionally have considered the epidemiological studies with regard to the extent to 

11 which this evidence is consistent with and generally supportive of conclusions drawn from the 

12 combined consideration of the controlled human exposure evidence with estimates from the 

13 exposure and dose assessment. We take note of the epidemiological studies showing positive 

14 associations with IHD and CHD health outcomes described in section 2.2.1 above, three of 

15 which were based in a study area in which the current standard was met, the association for one 

16 of which was statistically significant. In our consideration of the evidence, we recognize 

17 CASAC advice with regard to aspects of the epidemiological evidence that are particularly 

18 problematic for CO and the weight to be given to the well-conducted clinical studies (Brain and 

19 Samet, 2010). 

20 In considering health risk implications for the simulated at-risk population associated 

21 with dose estimates from the quantitative exposure/dose assessment we compared the estimates 

22 to potential health effects benchmark levels of 1.5%, 2.0%, 2.5% and 3% COHb (as described in 

23 section 2.2.2 above). In considering the population estimates of maximum end-of-hour COHb 

24 levels from the draft REA for the purposes of considering the level for the 8-hour standard that 

25 provides appropriate public health protection, we have focused on the results in terms of 

26 percentage of simulated at-risk population in each study area estimated to experience maximum 

27 end-of-hour COHb levels below each of the two lower potential health effects benchmarks and 

28 an intermediate COHb level. Based on analysis of the air quality data used in the draft REA to 

29 identify the equivalent levels for alternative forms, the five different air quality conditions 

30 simulated for each of the two study areas provide information on an array of alternative levels for 

31 the current and an alternative form (Table 2-6). 

32 In considering the estimates provided by the draft REA (summarized in Table 2-6 below), 

33 we note that differences between the two study areas with regard to the simulated at-risk 

34 population distributions of maximum end-of-hour COHb levels (noted in the section 6.2 of the 

35 draft REA) lead to differences in the proportion of the population protected from maximum end36 of-hour COHb levels at or above the potential health effect benchmarks being considered here. 
March 2010 Draft – Do Not Quote or Cite 2-52

1 For example, the percentage of the simulated at-risk population estimated to experience 

2 maximum COHb levels below 2% is 99.5% or greater in the Los Angeles study area for all 

3 simulated levels for either form, while the percentage of the simulated population in Denver 

4 estimated to experience maximum end-of-hour COHb levels below 2% is less than 99% 

5 (approximately 96.6%) for the highest alternative standard level simulated for either form. 

6 Alternatively, the percentage of the simulated population estimated to experience maximum 

7 COHb levels below 1.5% is more than 95% in the Los Angeles study area and more than 80% in 

8 the Denver study area for all simulated levels for either form. Further, the percentage of the 

9 simulated at-risk population estimated to experience maximum COHb levels below an 

10 intermediate COHb level of 1.8%, is more than 99% in the Los Angeles study area and more 

11 than 98% in the Denver study area for all simulated levels for either form. 

12 Table 2-6. Portion of simulated at-risk population with maximum end-of-hour COHb 

13 levels below the indicated COHb level under alternative levels for the 8-hour 

standard for the current form and a 99th 14 percentile daily maximum form. 

 

< 2 percent 

COHb 

< 1.8 percent 

COHb 

< 1.5 percent 

COHb 

Form Level 

Los 

Angeles Denver

Los 

Angeles Denver

Los 

Angeles Denver 

9.4 99.5 96.6 95.4 80.9 

6.5 99.9 99.2 99.7 98.1 98.6 92.9 

5.7 99.9 99.8 99.1 

5.6 99.9* 99.6 99.6* 98.9 98.5* 95.8 

5.4 99.9 99.6 99.8 99.2 99.4 96.2 

Second Highest Nonoverlapping 8-hour 

Concentration 3.1 100.0* 100.0* 99.4* 

8.2 99.5 95.4 

7.2 96.6 80.9 

5.7 99.9 99.7 98.6 

5.1 99.9* 99.6* 98.5* 

5.0 99.9 99.2 99.8 98.1 99.1 92.9 

4.7 99.9 99.8 99.4 

4.3 99.6 98.9 95.8 

4.1 99.6 99.2 96.2 

99th Percentile of 8-

hour Daily Maximum 

Concentration 2.8 100.0* 100.0* 99.4* 

* Asterisks indicate simulations based on “as is” (2006) air quality conditions. 

15 

16 Taking into account the differences between the simulated at-risk populations in the two 

17 study areas, recognizing considerations regarding maximum COHb benchmarks of 1.5 to 2% and 

18 above, and being mindful of the support provided by the epidemiological studies, we consider 

19 the draft REA estimates of maximum end-of-hour COHb levels with regard to level of protection 
March 2010 Draft – Do Not Quote or Cite 2-53

1 estimated to be provided by the different alternative levels for the 8-hour standard (Table 2-6 

2 below). In further considering the weight to place on this information, we are mindful of several 

3 key aspects of the evidence (described in more detail in section 2.2.1 above): 

4  Uncertainty in the clinical significance of the effects observed in the controlled human 

5 exposure studies of CAD patients. 

6  The lack of evidence for a measurable threshold effect for the effects observed in the 

7 human clinical studies and the lack of studies that have evaluated effects of 

8 experimentally controlled short-term CO exposures of individuals with CAD that 

9 resulted in study mean COHb levels below 2%. 

10  Uncertainty associated with interpretation of COHb levels estimated in the quantitative 

11 assessment to result from simulated CO exposure concentrations much lower than the 

12 experimental CO exposure concentrations used in the controlled human studies to 

13 increase subject COHb levels to COHb study targets. 

14  The lack of studies of COHb levels associated with health effects in other potentially 

15 susceptible populations. 

16  Limitations associated with the epidemiological studies for CO which complicate our 

17 use for quantitative purposes. 

18 

19 Staff find that identification of the range of alternative standards that may be appropriate 

20 to consider differs based on the weight placed on different aspects of the evidence and on 

21 different aspects of the quantitative dose estimates, as well as on public health policy decisions 

22 regarding the significance of the effects considered, the appropriate COHb benchmark on which 

23 to focus in considering maximum end-of-hour COHb levels, and the targeted proportion of the 

24 at-risk population. For example, focusing on the 2.0% COHb benchmark and considering a 

25 target for the at-risk population of 95 or 96% across the two study areas would indicate support 

26 for retaining the current level of the 8-hour standard. That is, the draft REA results in Table 2-6 

27 indicate that under the current standard, the maximum end-of-hour COHb levels for at least 96% 

28 of the at-risk populations in the two study areas would be expected to fall below the 2% 

benchmark.34 29 Alternatively, consideration of a higher population target of 99% while focusing 

30 on the 2% COHb benchmark, would lead to consideration of a level of approximately 5 to 6 

31 ppm, as would a population target of 98% below the 1.8% COHb benchmark, while a focus on a 

32 COHb benchmark of 1.5% with a target of 95% for the at-risk population would indicate support 

33 for consideration of a level somewhat below 5 ppm. On the other hand, consideration of a target 

34 level of 99% in combination with a focus on the 1.5% COHb benchmark would indicate support 

35 for a somewhat lower level, of about 3 ppm. 

 

34 Results are not currently available from the second draft REA for the percentage of the simulated at-risk 

population with end-of-hour COHb levels below 1.8%. 
March 2010 Draft – Do Not Quote or Cite 2-54

1 Thus, we note that placing weight on the exposure assessment results for the population 

2 target of 95% or 96% for a benchmark level of 2% COHb, in combination with a recognition of 

3 limitations in the epidemiological evidence for CO with regard to its use in drawing quantitative 

4 conclusions regarding a level for the standard, would provide a basis for considering retaining 

5 the current 8-hour standard. Alternatively, placing weight on the three epidemiological studies 

6 for the location in which the current standard was met, the association in one of which 

7 statistically significant, and consideration of the ambient CO concentrations in that study 

(Atlanta, 99th 8 percentile 8-hour daily maximum ranging up to 4.9 ppm during the study period) 

9 would lead to consideration of the lower part of the range identified above. 

10 While the focus in this draft Policy Assessment is on consideration of the controlling 8-

11 hour standard, we have also considered the rationale for the existing 1-hour standard as generally 

12 providing protection from effects that might result from short peak exposures over this shorter 

13 exposure duration (as described in section 2.3.1 above). We find value in retaining this standard 

14 for that purpose, recognizing that it may provide such protection independent from the type of 

15 protection provided by the 8-hour standard. 

16 We note that the results of the quantitative exposure/dose analysis also provides estimates 

17 for the ten model simulations (described in the draft REA) in terms of potential alternative levels 

for a 1-hour standard either of current form or a revised 99th 18 percentile daily maximum form 

19 (Table 2-7 below). These estimates indicate the extent to which levels for the 1-hour standard 

20 that are appreciably lower than the current level might influence population maximum end-of21 hour COHb levels in the situation where the 8-hour standard was of a magnitude such that it no 

22 longer was the controlling force for ambient CO concentrations. From these estimates it can be 

23 seen that an appreciable reduction in the level for the 1-hour standard would be required to 

24 achieve an impact on population COHb levels comparable to those achieved by the current 8-

25 hour standard or levels only somewhat lower. For example, to achieve a similar distribution of 

26 expected COHb levels as the current 8-hour standard, the results from the draft REA indicate that 

27 a level of approximately 15 ppm would be required for the 1-hour standards, either in terms of 

the current form or of a 99th 28 percentile daily maximum form (Table 2-7 below). 
March 2010 Draft – Do Not Quote or Cite 2-55

1 Table 2-7. Portion of simulated at-risk population with maximum end-of-hour COHb 

2 levels below the indicated COHb level under alternative levels for the 1-hour 

standard for the current form and a 99th 3 percentile daily maximum form. 

 

< 2 percent 

COHb 

< 1.8 percent 

COHb 

< 1.5 percent 

COHb 

Form Level 

Los 

Angeles Denver

Los 

Angeles Denver

Los 

Angeles Denver

16.2 96.6 100.0 80.9 

11.8 99.5 95.4 

11.2 99.2 98.1 92.9 

9.7 99.6 98.9 95.8 

9.3 99.6 99.2 96.2 

8.2 99.9* 99.6* 98.5* 

8.1 99.9 99.7 98.6 

7.2 99.9 99.8 99.1 

Second Highest 1- 6.8 99.9 99.8 99.4 

hour concentration 4.6 100.0* 100.0* 99.4* 

13.3 96.6 80.9 

11.6 99.5 95.4 

9.2 99.2 98.1 92.9 

8.0 99.9 99.6 99.7 98.9 98.6 95.8 

7.7 99.6 99.2 96.2 

7.4 99.9* 99.6* 98.5* 

7.1 99.9 99.8 99.1 

6.7 99.9 99.8 99.4 

99th percentile of 

1-hour Daily 

Maximum 

Concentration 4.5 100.0* 100.0* 99.4* 

* Asterisks indicate simulations based on “as is” (2006) air quality conditions. 

4 

5 With regard to the current 1-hour standard, staff has identified several policy options in 

6 this draft Policy Assessment that may be appropriate to consider. First, we note that the current 

7 1-hour standard may be considered to provide protection from effects which might be 

8 encountered from infrequent, very short duration peak ambient concentrations. With regard to 

9 such a purpose for the 1-hour standard independent of a focus on COHb levels as illustrated in 

10 Table 2-7 above, we have not identified information that might provide for an alternative level 

11 and form. Alternatively, while recognizing that the 8-hour standard has traditionally been the 

12 controlling standard, we have also considered alternative levels for the 1-hour standard drawing 

13 from the results of the draft REA in similar manner to the discussion above for the 8-hour 

14 standard. In considering the alternatives for public health policy judgments identified above for 

15 the 8-hour standard, we note the results of the draft REA with regard to alternative levels for the 
March 2010 Draft – Do Not Quote or Cite 2-56

1 1-hour standard might be concluded to indicate support for a range from approximately 15 ppm 

at the upper end to approximately 5 ppm at the lower end, combined with a 99th 2 percentile form. 

3 Further, in light of the role of the 8-hour standard as the controlling standard, and 

4 depending on judgments made regarding additional protection that may be provided by the 1-

5 hour standard from infrequent, very short duration peak ambient concentrations, we note that it 

6 may also be appropriate to consider revoking the 1-hour standard in conjunction with revision of 

7 the 8-hour standard to provide increased protection from maximum COHb levels that may result 

8 from ambient CO concentrations. 

9 2.3.4 Initial Staff Conclusions on Alternative Standards 

10 Initial staff conclusions for consideration in making decisions on the primary standards 

11 for CO, together with supporting conclusions from sections 2.2.3 and 2.3.2 above, are briefly 

12 summarized below. In drawing these initial conclusions, we are mindful that the Act requires 

13 standards to be set that, in the Administrator’s judgment, are requisite to protect public health 

14 with an adequate margin of safety, such that the standards are to be neither more nor less 

15 stringent than necessary. Thus, the Act does not require that NAAQS be set at zero-risk levels, 

16 but rather at levels that avoid unacceptable risks to public health. 

17 (1) Staff initially concludes that the combined consideration of the body of evidence and 

18 the quantitative exposure and dose estimates provide support for standards at least as 

19 protective as the current suite of standards to provide appropriate public health 

20 protection for susceptible populations, including most particularly individuals with 

21 cardiovascular disease, against effects of CO in exacerbating conditions of reduced 

22 oxygen availability to the heart. 

23 (2) Staff also initially concludes that, depending on public health policy judgments about 

24 protecting public health with an adequate margin of safety, the information available 

25 in this review supports consideration of either retaining or revising the current suite of 

26 standards, with any such revisions focused on providing increased public health 

27 protection. 

28 (3) With regard to the indicator for the CO standards, staff initially concludes that it is 

29 appropriate to continue to use measurements of CO in accordance with federal 

30 reference methods as the indicator to address effects associated with exposure to CO. 

31 (4) With regard to the current 8-hour standard, staff initially concludes that it is 

32 appropriate to consider the following range of policy options: 

33 a. Retaining the 8-hour averaging time. 

34 b. Retaining or revising the level of the standard, with consideration given to 

35 levels within the range from the current level of 9 ppm at the upper end to 
March 2010 Draft – Do Not Quote or Cite 2-57

1 approximately 3 ppm at the lower end to provide protection from maximum 

2 COHb levels that may result from ambient CO exposures. 

3 c. In conjunction with consideration of revising the level, it is also appropriate to 

consider revising the form of the standard to a 99th 4 percentile or fourth-highest 

5 daily maximum form, including consideration of such a form that is the 

6 average of this concentration across three years. 

7 (5) With regard to the current 1-hour standard, staff initially concludes that it is 

8 appropriate to consider the following range of policy options: 

9 a. Retaining the current 1-hour standard to provide protection from effects which 

10 might be encountered from infrequent, very short duration peak ambient 

11 concentrations. 

12 b. Revising the standard, with consideration given to levels within the range 

13 from approximately 15 ppm at the upper end to approximately 5 ppm at the 

lower end, combined with a 99th 14 percentile or fourth-highest daily maximum 

15 form, to provide protection from maximum COHb levels that may result from 

16 ambient CO exposures. Consideration of a revised level for the 1-hour 

17 standard within this range would be intended to provide the same protection as 

18 revision of the 8-hour standard within the range identified in item (4)b above. 

19 c. In conjunction with consideration of revising the level of the 8-hour standard 

20 to a lower level, it is also appropriate to consider revoking the 1-hour standard 

21 in recognition of the increased protection provided by a revised 8-hour 

22 standard from maximum COHb levels that may result from ambient CO 

23 exposures. 

24 2.4 KEY UNCERTAINTIES AND AREAS FOR FUTURE RESEARCH AND 

25 DATA COLLECTION 

26 Staff believes it is important to highlight key uncertainties associated with establishing 

27 ambient standards for CO. Such key uncertainties and recommendations for health-related 

28 research, model development, and data gathering are outlined below. In some cases, research in 

29 these areas can go beyond aiding standard setting to aiding in the development of more efficient 

30 and effective control strategies. We note, however, that a full set of research recommendations 

31 to meet standards implementation and strategy development needs is beyond the scope of this 

32 discussion. We have initially identified the following key uncertainties, research questions and 

33 data gaps that have been highlighted in this review of the health-based primary standards. 

34  A critical aspect of our consideration of the evidence and the quantitative dose 

35 estimates is our interpretation of the controlled human clinical studies. Expansion of 
March 2010 Draft – Do Not Quote or Cite 2-58

1 this evidence base in several areas would reduce uncertainty in our interpretation for 

2 purposes of risk characterization. 

3 o Additional information relevant to health effects of short-term increases in CO 

4 exposure resulting in COHb levels below 2% in individuals with CAD. 

5 o Additional research to clarify the clinical significance of the sensitive markers 

6 of myocardial ischemia observed in controlled human exposure studies of 

7 CAD patients. 

8 o Research to reduce uncertainty associated with interpretation of COHb levels 

9 estimated in the quantitative assessment to result from simulated CO exposure 

10 concentrations much lower than the experimental CO exposure concentrations 

11 used in the controlled human studies to increase subject COHb levels to 

12 COHb study targets. 

13  Existing clinical data correlates CO-induced effects (i.e., cardiovascular ischemia 

14 observed at specific COHb levels) to COHb levels resulting from short-term, high CO 

15 exposure concentrations. However, there is lack of studies evaluating effects of CO, in 

16 terms of COHb levels, at lower ambient concentrations and/or longer term exposures 

17 periods. 

18  Further research to characterize CO effects for other potentially susceptibility 

19 populations, including populations with preexisting diseases other than CAD that limit 

20 O2 availability, such as anemia and obstructive respiratory diseases; populations at 

21 certain lifestages (i.e., older adults and fetuses at critical stages of development); 

22 populations with elevated baseline COHb due to increased CO production, such as 

23 individuals with diabetes;, and visitors to high altitude. 

24  Our interpretation of the epidemiological evidence for CO would benefit from a better 

25 understanding of the possible role of co-pollutants. 

26  Our future assessments would benefit from research on studies evaluating effects of 

27 CO linked to biomarkers other than COHb and research on mechanisms of CO28 induced effects other that those associated with limiting O2 availability at ambient CO 

29 levels. 
March 2010 Draft – Do Not Quote or Cite 2-59

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15 at: http://www.epa.gov/ttn/fera/human_related.html. June 2000. 

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17 exposure to carbon monoxide in subjects with coronary artery disease. Arch. Environ. Health 44: 361-369. 

18 Kleinman MT, Leaf DA, Kelly E, Caiozzo V, Osann K, O'Niell T. (1998). Urban angina in the mountains: effects of 

19 carbon monoxide and mild hypoxemia on subjects with chronic stable angina. Arch. Environ.Health 53: 

20 388-397. 

21 Koken PJM; Piver WT; Ye F; Elixhauser A; Olsen LM; Portier CJ. (2003). Temperature, air pollution, and 

22 hospitalization for cardiovascular diseases among elderly people in Denver. Environ Health Perspect, 111: 

23 1312-1317. 

24 Leaf, D. A.; Kleinman, M. T. (1996a) Urban ectopy in the mountains: carbon monoxide exposure at high altitude. 

25 Arch. Environ. Health 51: 283-290. 

26 Linn WS; Szlachcic Y; Gong H Jr; Kinney PL; Berhane KT. (2000). Air pollution and daily hospital admissions in 

27 metropolitan Los Angeles. Environ Health Perspect, 108: 427-434. 

28 Longo, L. D. (1977) The biological effects of carbon monoxide on the pregnant woman, fetus, and newborn infant. 

29 Am. J. Obstet. Gunacol. 129: 69-103. 

30 Mann JK; Tager IB; Lurmann F; Segal M; Quesenberry CP Jr; Lugg MM; Shan J; Van den Eeden SK. (2002). Air 

31 pollution and hospital admissions for ischemic heart disease in persons with congestive heart failure or 

32 arrhythmia. Environ Health Perspect, 110: 1247-1252. 

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

34 Administrator, July 17, 1991. 

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

36 Administrator, August 1, 1992. 

37 Metzger KB; Tolbert PE; Klein M; Peel JL; Flanders WD; Todd KH; Mulholland JA; Ryan PB; Frumkin H. (2004). 

38 Ambient air pollution and cardiovascular emergency department visits. Epidemiology, 15: 46-56. 

39 Peel JL; Metzger KB; Klein M; Flanders WD; Mulholland JA; Tolbert PE. (2007). Ambient air pollution and 

40 cardiovascular emergency department visits in potentially sensitive groups. Am J Epidemiol, 165: 625-633. 
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1 Putz, V. R.; Johnson, B. L.; Setzer, J. V. (1976) Effects of CO on vigilance performance effects of low level carbon 

2 monoxide on divided attention, pitch discrimination, and the auditory eve pot tial. Cincinnati, OH: U. S. 

3 Department of Health, Education, and Welfare National Institute for Occupational Safety and Health; 

4 report no. NIOSH-77-124. Available from: NTIS, Springfield, VA; PB-274219. 

5 Putz, V. R.; Johnson, B. L; Setzer, J. V. (1979) A comparative study of the effects of carbon monoxide and 

6 methylene chloride on human performance. J. Environ. Pathol. Toxicol. 2: 97-112. 

7 Raven, P. B. Drinkwater, B. L.; Horvath, S. M.; Ruhling, R. O.; Gliner, J. A.; Sutton, J. C.; Bolduan, N. W. (1974a) 

8 Age, smoking habits, heat stress, and their interactive effects with carbon monoxide and 

9 peroxyacetylnitrate on man’s aerobic power. Int. J. Biometeorol. 18: 222-232. 

10 Raven, P. B.; Drinkwater, B. L.; Ruhling, R. O.; Taguchi, S.; Gliner, J.; Horvath, S. M. (1974b) Effect of carbon 

11 monoxide and peroxyacetyl itrate on man’s maximal aerobic capacity. J. Appl. Physiol. 36: 288-293. 

12 Sheps, D. S.; Adams, K. F., Jr.; Bromberg, P. A.; Goldstein, G. M.; O'Neil, J. J.; Horstman, D.; Koch, G. (1987) 

13 Lack of effect of low levels of carboxyhemoglobin on cardiovascular function in patients with ischemic 

14 heart disease. Arch. Environ. Health 42: 108-116. 

15 Sheps, D.S.; Herbst, M.C.; Hinderliter, A.L.; Adams, K.F.; Ekelund, L.G.; O'Neil, J.J.; Goldstein, G.M.; Bromberg, 

16 P.A.; Dalton, J.L.; Ballenger, M.N.; Davis, S.M.; Koch, G.G. (1990) Production of arrythmias by elevated 

17 carboxyhemoglobin in patients with coronary artery disease. Ann. Intern. Med. 113: 343-351. 

18 Symons JM; Wang L; Guallar E; Howell E; Dominici F; Schwab M; Ange BA; Samet J; Ondov J; Harrison D; Geyh 

19 A. (2006). A case-crossover study of fine particulate matter air pollution and onset of congestive heart 

20 failure symptom exacerbation leading to hospitalization. Am J Epidemiol, 164: 421-433. 

21 Tolbert PE; Klein M; Peel JL; Sarnat SE; Sarnat JA. (2007). Multipollutant modeling issues in a study of ambient air 

22 quality and emergency department visits in Atlanta. J Expo Sci Environ Epidemiol, 17: S29-S35. 

23 U.S. EPA (1979). Air Quality Criteria for Carbon Monoxide. Research Triangle Park, NC: Office of Health and 

24 Environmental Assessment, Environmental Criteria and Assessment Office, report no. EPA/600/8-79-022. 

25 U.S. EPA (1984a). Revised Evaluation of Health Effects Associated with Carbon Monoxide Exposure: An 

26 Addendum to the 1979 EPA Air Quality Criteria Document for Carbon Monoxide. Office of Health and 

27 Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. 

28 Report no. EPA-600/8-83-033F. 

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30 Information. Office of Air Quality Planning and Standards, Research Triangle Park. NC. Report no. EPA31 450/584-904. 

32 U.S. EPA. (1991). Air Quality Criteria for Carbon Monoxide. Office of Health and Environmental Assessment, 

33 Research Triangle Park, NC. EPA/600/8-90/045F.;.Available at: 

34 http://www.epa.gov/ttn/naaqs/standards/co/s_co_pr.html 

35 U.S. EPA (1992). Review of the National Ambient Air Quality Standards for Carbon Monoxide: Assessment of 

36 Scientific and Technical Information. OAQPS Staff Paper. Office of Air Quality Planning and Standards, 

37 Research Triangle Park, NC. EPA/452/R-92-004. 

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39 Office of Research and Development, Research Triangle Park, NC. EPA/600/P-99/001F. Available at: 

40 http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=18163. 
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3 Paper. Office of Air Quality Planning and Standards, Research Triangle Park, NC. EPA-452/R-05-005a. 

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5 and Technical Information OAQPS Staff Paper. Office of Air Quality Planning and Standards, Research 

6 Triangle Park, NC. EPA-452/R-07-007. 

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8 Environmental Protection Agency, Research Triangle Park, NC, report no. EPA/452R-08-005. Also known 

9 as Integrated Review Plan. Available at: http://www.epa.gov/ttn/naaqs/standards/co/s_co_cr_pd.html. 

10 U.S. EPA (2008b) Risk and Exposure Assessment to Support the Review of the NO2 Primary National Ambient Air 

11 Quality Standard. Office of Air Quality Planning and Standards, Research Triangle Park, NC. EPA-452/R12 08-008a. 

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17 Assessment, Research Triangle Park, NC. EPA/600/R-09/019F. Available at: 

18 http://www.epa.gov/ttn/naaqs/standards/co/s_co_cr_isa.html

19 U.S. EPA (2010b) Risk and Exposure Assessment to Support the Review of the Carbon Monoxide Primary National 

20 Ambient Air Quality Standards, Second External Review Draft, U.S Environmental Protection Agency, 

21 Research Triangle Park, NC, report no. EPA/600/R-09/019B. Available at: 

22 http://www.epa.gov/ttn/naaqs/standards/co/s_co_cr_rea.html

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24 hospitalization for congestive heart failure among medicare beneficiaries in Pittsburgh, Pennsylvania. Am J 

25 Epidemiol, 161: 1030-1036. 

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30 Respir Crit Care Med, 164: 831-833. 
March 2010 Draft-Do Not Quote or Cite 3-1

1 3 CONSIDERATION OF A SECONDARY STANDARD FOR CO 

2 This chapter focuses on the key policy-relevant issues related to the review of welfare3 related effects of CO. Under Section 109(b) of the Clean Air Act, a secondary standard is to be 

4 established at a level “requisite to protect the public welfare from any known or anticipated 

5 adverse effects associated with the presence of the pollutant in ambient air.” Section 302(h) of 

6 the Act defines effects on welfare in part as “effects on soils, water, crops, vegetation, man-made 

7 materials, animals, weather, visibility, and climate.” 

8 Specifically, this chapter first summarizes the history of EPA’s consideration of 

9 secondary standards for CO. Considerations is then given to the evidence currently available for 

10 welfare effects to inform decisions in this review as to whether, and if so how, to establish 

11 secondary standards for CO based on public welfare considerations. Initial staff conclusions are 

12 based on the assessment and integrative synthesis of the scientific evidence presented in the ISA 

13 (USEPA, 2010), building on the evidence described in the 2000 AQCD (USEPA, 2000). 

14 3.1 CONSIDERATION IN PREVIOUS REVIEWS 

15 With the establishment of the first NAAQS for CO in 1971, secondary standards were set 

16 identical to the primary standards. CO was not shown to produce detrimental effects on certain 

17 higher plants at levels below 100 ppm. The only significant welfare effect identified for CO 

18 levels possibly approaching those in ambient air was inhibition of nitrogen fixation by 

19 microorganisms in the root nodules of legumes associated with CO levels of 100 ppm for one 

20 month (National Air Pollution Control Administration, 1970). In the first review of the CO 

21 NAAQS, the threshold level for plant effects was recognized to occur well above ambient CO 

22 levels, such that vegetation damage as a result of CO in ambient air was concluded to be very 

23 unlikely (50 FR 37494). As a result, EPA concluded that the evidence did not support 

24 maintaining a secondary standard for CO, as welfare-related effects had not been documented to 

25 occur at ambient concentrations (50 FR 37494). Bsed on that conclusion, EPA rescinded the 

26 secondary standard. In the most recent review of CO, which was completed in 1994, EPA again 

27 concluded there was insufficient evidence of welfare effects occurring at or near ambient levels 

28 to support setting a secondary NAAQS (59 FR 38906). That review did not consider climate29 related effects. 

30 3.2 CONSIDERATION OF EVIDENCE AVAILABLE IN THE CURRENT 

31 REVIEW 

32 To evaluate whether consideration of establishment of a secondary standard for CO is 

33 appropriate, we adopted an approach in this review that builds upon the general approach used in 
March 2010 Draft-Do Not Quote or Cite 3-2

1 the last review and reflects the broader body of evidence and information now available. In 

2 developing conclusions in this review below, staff has taken into account the following 

3 overarching question: 

4  Does the currently available scientific information provide support for 

5 considering the establishment of a secondary standard for CO? 

6 In considering this overarching question, we first note that the extensive literature search 

7 performed for the current review did not identify any evidence of ecological effects of CO 

8 unrelated to climate-related effects, at or near ambient levels (ISA, section 1.3 p. 1-3). However, 

9 ambient CO has been associated with welfare effects related to climate (ISA, section 3.3). 

10 Climate-related effects of CO were considered for the first time in the 2000 AQCD. The greater 

11 focus on climate in the current ISA relative to the 2000 AQCD reflects comments from CASAC 

12 and increased attention to the role of CO in climate forcing (Brain and Samet, 2009). Based on 

13 the current evidence, the ISA has concluded that “a causal relationship exists between current 

14 atmospheric concentrations of CO and effects on climate” (ISA, section 2.2). Accordingly, the 

15 following discussion focuses on climate-related effects of CO in addressing the question posed 

16 above. 

17 Recently available information does not alter the current well-established understanding 

18 of the role of urban and regional CO in continental and global-scale chemistry, as outlined in the 

19 2000 AQCD. CO is a weak direct contributor to greenhouse warming. The most significant 

20 effects on climate result indirectly from CO chemistry, related to the role of CO as a major 

21 atmospheric sink for hydroxyl groups (OH). Increased concentrations of CO can lead to 

22 increased concentrations of other gases whose loss processes also involve OH chemistry. Some 

23 of these gases, such as methane (CH4) and ozone (O3), contribute to the greenhouse effect 

24 directly while others deplete stratospheric O3 (ISA, section 3.3 p. 3-11). 

25 Advances in modeling and measurement have improved our understanding of the relative 

26 contribution of CO to climate forcing. This link between ambient CO and climate is based on 

both direct radiative forcing (RF) of CO estimated at 0.024 W/m2 27 by Sinha and Toumi (1996) 

28 and indirect effects of CO on climate through CH4, O3 and carbon dioxide (CO2) (Forster et al. 

29 2007). The combined RF for these indirect effects of CO was estimated by the 

Intergovernmental Panel on Climate Change (IPCC) to be ~0.2 W/m2 30 over the period 1750-2005 

31 (Forster et al., 2007) with more than one-half of the forcing attributed to O3 formation. 

32 Ambient CO, by itself, does not significantly absorb the Earth’s longwave radiation and 

33 warm the atmosphere and surface (ISA, section 2.2). Rather, the effects of CO emissions on 

34 climate are felt indirectly because emissions of CO lead to increased ambient concentrations of 

35 two important greenhouse gases, CH4 and O3. This increase results in contributions to RF that 

36 are significant (Forster et al. 2007). However, it is highly problematic to evaluate the indirect 
March 2010 Draft-Do Not Quote or Cite 3-3

1 effects of CO on climate due to the spatial heterogeneity in its emissions and concentrations and 

2 due to the localized chemical interdependencies involving CO, CH4, and O3, which also depend 

3 on levels of NOx. (ISA section 3.3). 

4 Most climate model simulations are based on global scale scenarios and have a high 

5 degree of uncertainty associated with short-lived climate forcers such as CO (ISA, section 3.3. p. 

6 3-16). These models may fail to consider the local variations in climate forcing due to emissions 

7 sources and local meteorological patterns (ISA, section 3.3 p. 3-16). 

8 With regard to time period, ambient CO emissions vary on an hourly basis and exhibit 

9 seasonal and weekday/weekend fluctuations (ISA, section 3.5). This episodic emission pattern, 

10 coupled with the relatively short atmospheric lifetime of CO, has limited the ability to 

11 characterize welfare-related exposures to this pollutant. CO is classified as a short-lived climate 

12 forcing agent, prompting CO emission reductions to be considered as a possible strategy to 

13 mitigate effects of global warming. It is possible to compute individual contributions to RF of 

14 CO from separate emissions sectors, although uncertainty in these estimates has not been 

15 quantified (ISA, section 3.3 p. 3-13). 

16 Additional sources of uncertainty in the current assessment include the chemical 

17 interdependencies of CO and other climate forcing pollutants and the complexity of CO 

18 atmospheric chemistry (ISA, section 3.2.2). Measurement of and techniques for assessing 

19 climate forcing are improving, but estimates of RF still have ~50% uncertainty (ISA, section 3.3, 

20 p. 3-13). Large regional variations in CO concentrations also contribute to the uncertainties in 

21 the RF from CO and other trace gases (ISA, section 2.2 p. 3-12). 

22 3.3 STAFF CONCLUSIONS FOR THE CURRENT REVIEW 

23 In considering whether the currently available scientific information indicates the need 

24 for a secondary standard for CO, we have reached the following initial conclusions: 

25 

26 (1) With respect to non-climate welfare effects, including ecological effects and impacts 

27 to vegetation, there is no currently available scientific information that supports a CO 

28 secondary standard. 

29 

30 (2) With respect to climate-related effects, we note that there is evidence of climate 

31 forcing effects associated with CO (ISA, sections 2.2 and 3.3). There are weak direct, 

32 and stronger, but primarily highly variable, indirect continental and regional climate 

33 forcing effects from CO. However, the available information provides no basis for 

34 estimating how localized changes in the temporal, spatial and composition patterns of 

35 ambient CO likely to occur across the US with (or without) a secondary standard 
March 2010 Draft-Do Not Quote or Cite 3-4

1 would affect local, regional, or nationwide changes in climate. For these reasons, it is 

2 currently not feasible to conduct an analysis for the purpose of considering a CO 

3 secondary standard based on climate considerations. Moreover, more than half of the 

4 indirect forcing effects of CO have been estimated to occur through O3 formation, and 

5 effects of O3 are more appropriately considered in the context of the review of the O3

6 NAAQS, rather than in this CO NAAQS review. Based on these considerations, staff 

7 initially concludes there is insufficient information at this time to support the 

8 consideration of a secondary NAAQS based on CO effects on climate processes. 

9 
March 2010 Draft-Do Not Quote or Cite 3-5

1 REFERENCES 

2 

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28 at: http://www.epa.gov/ttn/naaqs/standards/co/s_co_cr_isa.html. 

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United States 

Environmental Protection Agency 

Office of Air Quality Planning and Standards 

Health and Environmental Impacts Division 

Research Triangle Park, NC 

Publication N