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

External Review DraftEPA-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 CarolinaDISCLAIMER

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 OAQ PS 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recommendation for use.March, 2010 Draft – Do Not Quote or Cite i TABLE OF CONTENTS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 ORGANI ZATION OF THE DOCUMENT.1-11 REFERENCES ..........................................................................................................1-12
2 REVIEW OF THE PRIMARY STANDA RDS 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 ALTER NATIVE 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 AREA S FOR FUTURE RESEARCH AND DATA COLLECTION...........................................................................2-57 REFERENCES ..........................................................................................................2-59
3 CONSIDERATION OF A SECO NDARY STANDARD FOR CO...................3-1
3.1 CONSIDERATION IN PR EVIOUS REVIEWS.............................................3-1March, 2010 Draft – Do Not Quote or Cite ii 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 emi ssions 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 (sec ond maximum 8-hour average) in the U.S., 1990-2008. ...............................................................................................1-10 Figure 1-3 Trends in CO concentration (sec ond 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-out come conceptual model measured in controlled human exposure and epidemio logical studies discussed in this document..................................................................................................2-15

LIST OF TABLES

Table 2-1 Information from U.S. epidemio logical studies of hospital admissions for ischemic heart disease (ISA, Figure 5-2), cardiovascular disease (ISA, Figure 5-5) and congestive he art failure (ISA, Figure 5-4) and on air quality during the study periods

. ....................................................2-13 Table 2-2 Carboxyhemoglobin levels and report ed 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 99 th percentile daily maximum form ..................................................................................................................2-52March, 2010 Draft – Do Not Quote or Cite iii 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 99 th percentile daily maximum form..........................................................................................................2-55

### 1 INTRODUCTION 1

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The U.S. Environm ental Protection Agency (EPA) is presently conducting a review of the carbon monoxide (CO) national ambient air qua lity 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 ques tions that frame our consideration of whether the current NAAQS for CO should be retained or revised. This Policy Assessment (PA), prepared by sta ff in EPA’s Office of Air Quality Planning and Standards (OAQPS), is intended to help “bri dge the gap” between the relevant scientific information and assessments and the judgmen ts 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 pr imary (health-based) standards and consideration of a secondary (w elfare-based) standard. It fo cuses on both evidence- and riskbased information in evaluating the adequacy of the current CO NAAQ S 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 Monoxid e 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 ba sic elements of NAAQS: indicator, 2 averaging time, form, 3 and level. These elements, which together serv e to define each standard, must be considered collectively in evaluating the health and welfar e 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 ha s some familiarity with the technical discussions contained in the ISA (USEPA, 2010a) and the second draft REA (USEPA, 2010b).

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

2 The “indicator” of a standard defines the chemical species or mixture that is to be measured in determining whether an area attains the standard.

3 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.

March 2010 Draft – Do Not Quote or Cite 1-11.2 BACKGROUND 1

1.2.1 Legislative requirements 2
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28 Two sections of the Clean Air Act (A ct) govern the establishment and revision of the NAAQS. Section 108 (42 U.S.C. 74 08) directs the Administrator to identify certain pollutants that meet specified criteria, including emissi ons which “may reasonably be anticipated to endanger public health and we lfare” 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 late st scientific knowledge useful in indicating the kind and extent of identifiable effects on public h ealth 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 li sted under section 10 8. Section 109(b)(1) defines a primary standard as one “the attainment and maintenance of which in the judgment of the Administrator, based on such criteria and allowi ng an adequate margin of safety, are requisite to protect the public health.” 4 A secondary standard, as defi ned 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 crit eria, is requisite to protect the public welfare from any known or anticipated adverse effects asso ciated with the presence of [the ] pollutant in the ambient air.” 5 The requirement that primary standards incl ude an adequate margin of safety was
intended to address uncertainties associated with inconclusive scientific and technical
information available at the time of standard set ting. It was also intended to provide a reasonable degree of protection against ha zards that research has not yet identified. Lead Industries Association v. EPA, 647 F.2d 1130, 1154 (D.C. Ci r 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 ar e 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. T hus, in selecting primary standa rds that include an adequate margin of safety, the Administrator is seeking no t only to prevent pollution levels that have been

4 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, 91 st Cong., Sess. 10 (1970)

5 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.”

March 2010 Draft – Do Not Quote or Cite 1-2demonstrated to be harmful but also to prev ent lower pollutant levels that may pose an unacceptable risk of harm, even if the risk is not precisely identified as to nature or degree. 1
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35 In selecting a margin of safety, the EPA consid ers such factors as the nature and severity of the health effects involved, the size of th e sensitive population(s) at risk, and the kind and degree of the uncertainties that must be addresse d. 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 Associati on v. EPA, supra, 647 F.2d at 1161-62. In setting standards that are “requisite” to protect public health a nd 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, EP A may not consider the costs of implementing the standards. See generally Whitman v. Amer ican 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 st andards . . . and shall make
such revisions in such criteri a and standards and promulgate such new standards as may be appropriate . . . .” Section 109(d)(2) requires th at an independent scie ntific review committee “shall complete a review of th e criteria . . . and the national primary and secondary ambient air quality standards . . . and sha ll recommend to the Administrato r any new . . . standards and revisions of existing criteria and standards as ma y be appropriate . . . .” Since the early 1980's, this independent review function has been pe rformed by the Clean Air Scientific Advisory Committee (CASAC) of EPA’s Science Advisory Board.

1.2.2 Previous Reviews

EPA initially estab lished NAAQS for CO, under section 109 of the Act, on April 30, 1971. The primary standards were establishe d to protect agains t 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 on ce per year (36 FR 8186). In the 1971 decision, the Administrator judged that attain ment 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 accordi ngly 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 sc ientific criteria upon which the initial CO standards were based through the publication of the 1979 Air Quality Criteria Document for

March 2010 Draft – Do Not Quote or Cite 1-3Carbon Monoxide (AQCD; USEPA, 1979a) and prepared a Staff Paper (USEPA, 1979b), which, along with the 1979 AQCD, served as the basis fo r the development of the notice of proposed rulemaking which was published on August 18, 1980 (45 FR 55066). Delays due to uncertainties regarding the scien tific basis for the final decision resulted in EPA’s announcing a second public comment period (47 FR 26407). Fo llowing 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 l ack of evidence of direct effects on public
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33 6 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 we re not warranted at that time (59 FR 38906). This decision reflected EPA's review of relevant sc ientific information assembled since the last review, as cont ained in the 1991 AQCD (U SEPA, 1991) and the 1992 Staff Paper (USEPA, 1992). Thus, the primary st andards 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 c ontained in the AQCD. On June 9, 1999, CASAC held a public meeting to review the first draf t AQCD and to provide a consultation on a draft exposure analysis methodology document. Co mments 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 revi sion of the second draft AQCD, the final 2000 AQCD (U.S. EPA, 2000) was released in Augus t 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.

6 EPA concluded in 1985 that “no standards appear to be requisite to protect the public welfare from any known or anticipated adverse effects from ambient CO exposures” (50 FR 37494).

March 2010 Draft – Do Not Quote or Cite 1-41.2.3 The Current Review 1
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31 On Septem ber 13, 2007, EPA issued a call for information from the public (72 FR 52369) requesting the submission of recent scientific in formation on specified topics. A workshop was held on January 28–29, 2008 (73 FR 2490) to discu ss policy-relevant scie ntific and technical information to inform EPA’s planning for the CO NAAQS review. Following the workshop, a draft IRP (USEPA, 2008a) was made availabl e in March 2008 for public comment and was discussed by the CASAC via a publicly accessi ble 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 au thors’ teleconference in November 2008 with invited scientific experts to di scuss preliminary draft materials prepared as part of the ongoing development of the CO ISA and its supplementa ry 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 Ma y 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 me eting 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 consultati on with CASAC and public review at the CASAC meeting held on May 12-13, 2009. Taking into consideration CA SAC and public comments on the draft Plan, OAQPS staff conducted a risk/exposur e assessment, and released for CASAC review and public comment a first draft REA (USEPA, 2009c), whic h was reviewed at the CASAC meeting held on November 16-17, 2009. A second draft REA wa s 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 rele ased 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 sc hedule 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

7 The lawsuit alleged that EPA had failed to perform its mandatory duty, under section 109(d)(1), of completing the current review within the period provided by statute. American Lung Association v. Whitman (No. 1:03CV00778, D.D.C. 2003).

March 2010 Draft – Do Not Quote or Cite 1-51.3 CURRENT AIR QUALITY 1 This section provides a genera l overview of the current air quality conditions to provide
context for this considera tion of the current standard s for carbon m onoxide. A more comprehensive discussion of air quality inform ation 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 sec ond draft REA (REA, chapter 3). 2
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Carbon m onoxide 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 fo ssil-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 mo re 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 sect ors 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 tem poral 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 thei r relatively greater motor vehicle density, the
contribution from mobile sources has been estima ted to be as high as 75% of all ambient CO
emissions in the 2002 National Emissions Inventor y (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, secti on 3.2), compared with 20% for rural Garfield County, Colorado 9 (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

8 EPA compiles CO emissions estimates for the U.S. in the National Emissions Inventory (NEI). The 2002 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 us e 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 approa ches, uncertainties are inhere nt 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).

9 The 2002 National Emissions Inventory estimate for on-road emissions in Garfield is 20,000 tons, and the 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 emissi ons (ISA, section 3, figure 3-6).

March 2010 Draft – Do Not Quote or Cite 1-6nationally is over 80%. Again using Denver County as an exam ple, all mobile sources are estimated to contribute about 98% of total CO emissions. 1
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7 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 vehi cles (ISA, Figure 3.-2).

Figure 1-1. Trends in anthropogenic CO emissions in the U.S. by source category for 6 1990 and 1996-2002. Source: U.S. EPA (2008c)

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18 19 1.3.2 Ambient Monitoring Network
Am bient 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 comp arison to the NAAQS is the State and Local Air Monitoring Stations (SLAMS) network. CO monito rs are typically sited to reflect one of the following spatial scales:

 Microscale: Data represent c oncentrations 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-roa d or street canyon environment.

 Middle scale: Data represent concentrati ons averaged over areas defined by 100 – 500 m radii. Measurements are intended to represent several city blocks.

March 2010 Draft – Do Not Quote or Cite 1-7 Neighborhood scale: Data repr esent concentrations averag ed over areas defined by 0.5 – 4.0 km radii. Measurements are intended to represent extended portions of a city. 1 2
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30 In addition to monitoring required for de termining compliance with the NAAQS, the EPA is currently in the process of implementing plans for a new network of multi-pollutant 4
stations called NCore that is intended to meet multiple monitoring objectives (ISA, p. 3-21). The 5 complete NCore network, required to be fully implemented by January 1, 2011, will consist of 6 approximately 63 urban and 20 rural stations a nd will include some existing SLAMS sites that 7
have been modified to include additional measurem ents. The majority of NCore stations will be 8 sited, however, to represent nei ghborhood, urban, and regional scal es, consistent with the NCore 9 network design objective of representing exposur e expected across urban and rural areas in 10
locations that are not do minated by local sources. 11 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, FE Ms). Given the levels of the CO NAAQS (35 ppm, 1-hour; 9 ppm, 8-hour), a lowe r 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 us e during 2005-2007 have LDL of 0.5 ppm (ISA, Appendix A, Table A-8). With ambient CO leve ls now routinely near or below 1 ppm, however, a large percentage of the measurements ar e below the LDL of conventional monitors, contributing greater uncertainty in a larger portion of the distri bution 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 re ported LDL of 0.5 ppm (ISA, p. 3-56). To reduce the uncertainty at these lower concentrat ions, a new generation of ambient CO monitors has been designed that provides improved sensitiv ity for measurements at or below the typical
ambient CO levels measured in most urban a nd 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 stati ons, 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 ne twork for which data were reported to EPA’s Air Quality System (AQS) between 2005 an d 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).

March 2010 Draft – Do Not Quote or Cite 1-8monitoring requirements for CO might either encourage or require such technological improvements. 1
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concentrations across the U.S. None of monitoring sites with extensive records 12 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 qua lity 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, Alab ama) 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 qua lity 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 signific antly declined since the last revi ew (Figures 1-2 and 1-3). At
the set of sites across the U.S. that have b een continuously monitored since 1990 the average 2 nd highest 8-hour and 1-hour concentrati ons have declined by nearly 70%.

12 During the period 2005-2007, 291 out of 376 monito rs sited in 243 differ ent counties, cities or municipalities, met the following dataset completeness criter ia: 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 comple te 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 Draft – Do Not Quote or Cite 1-9Figure 1-2. Trends in CO concentration (second maximum 8-hour average) in the U.S., 1 1990-2008. The white line indicates average acro ss the sites; ninety percent of sites have concentrations below the top line, while ten percent of sites have concentrations below the bottom line. 2 3 4

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2 1990-2008. The white line indicates average acro ss the sites; ninety percent of sites have concentrations below the top line, while ten percent of sites have concentrations below the bottom line

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1.4 GENERAL APPROACH AND ORGANI ZATION OF THE DOCUMENT 8
This draf t 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 st aff conclusions and the identification of a range of policy options for consideration in addressi ng public health and welf are effects associated
with ambient CO. Following this introductory chapter, chapter 2 focuses on review of the primary standards for CO, presenting background information on th e rationale for previous reviews and the approach followed in the current review. Ch apter 2 discusses the adequacy of the current standards, taking into account ev idence- and risk-based considera tions, and includes initial staff conclusions on adequacy. Chapter 2 also di scusses potential alternative standards for consideration, focusing on indicato r, averaging time, form, and le vel, and includes initial staff
conclusions on alternative standards for consider ation. Finally, chapter 3 discusses information
relevant to staff’s consideration of a secondary standard for CO.

March 2010 Draft – Do Not Quote or Cite 1-11REFERENCES 1
2 3

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10 11

12 13 14 15

16 17 18

19 20

21 22 23

24 25 26 27

28 29 30

31 32 33

34 35

36 37 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 C arbon 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 Effect s Asso ciated 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 M onoxide: Reassessment of Scientific and Technical Information. Office of Air Quality Planning and Stand ards, report no. EPA-450/584-904. Research Triangle Park. NC.

U.S. EPA. (1991). Air Quality Criteri a for C arbon Monoxide. Research Triangle Park, NC: Office of Health and Environmental Assessment, Environmental Criteria an d Assessment Office; report no. EPA/600/8-90/045F.

U.S. EPA (1992). Review of the National Ambient Air Quality Stan dards 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 Monoxi de. Nation al Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Age ncy, 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 th e 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 Ambi en t Air Quality Standards for Carbon Monoxide. U.S. Environmental Protection Agency, Research Triangle Park, NC, report no. EPA/452R-08-005. Also known

as Integr ated 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 Envi r onment (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 Pa rk, 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 Draft – Do Not Quote or Cite 1-12March 2010 Draft – Do Not Quote or Cite 1-13 1 2 U .S. EPA (2009b) Integrated Science Assessment for Carbon Monoxide, Second Ex ternal Review Draft, U.S Environmental Protection Agency, Research Triangle Park, NC, report no. EPA/600/R-09/019B. Available at: http://www.epa.gov/ttn/naaqs/s tanda rds/co/s_co_cr_isa.html 3

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 Re v iew Draft, U.S Environm ental Protection Agency, Research Triangle Park, NC, report no. EPA/600/R-09/019B. Available at: http://www.epa.gov/ttn/naaqs/sta n dards/co/s_co_cr_isa.html 7

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: http://www.epa.gov/ttn/naaqs/sta n dards/co/s_co_cr_isa.html 10

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 Re v iew Draft, U.S Environmental Protection Agency, Research Triangle Park, NC, report no. EPA/600/R-09/019B. Available at: http://www.epa.gov/ttn/naaqs/st an dards/co/s_co_cr_rea.html 14March 2010 Draft – Do Not Quote or Cite 2-1 

### 2 REVIEW OF THE PRIMARY STANDARDS FOR CARBON 1 

### MONOXIDE 2

This chapter presents initial staff conclusions for consideration in deciding whether the 3 existing primary standards for carbon monoxide (CO) should be revised and, if so, what 4 revisions are appropriate. The current primar y CO standards include a 1-hour and an 8-hour 5 standard to protect public health from exposure to CO. In initia lly evaluating the current primary 6 NAAQS we have reviewed, and as appropriate, updated, a series of key policy-relevant issues 7 initially presented in the Plan for Review of the National Ambient Air Quality Standards for 8
Carbon Monoxide (USEPA, 2008a, section 3.1). The answer s to these policy-re levant questions 9 will inform decisions on whether, and if so, how to revise the primary standards for CO. 10 Following a background section regarding consid erations in the previous review, the 11 discussion in this chapter focuses on two central issues related to: (1) the adequacy of the current 12 CO standards and (2) what potentia l alternative standards, if any, should be considered in this 13 review. Within each of these broad areas, a series of questions are addressed. The four basic 14 elements of the NAAQS (e.g., indicator, averaging time, level, and form) will be considered 15 collectively in evaluating the health protecti on afforded by the current or any alternative 16 standards considered. 17

2.1 APPROACH 18 For the purposes of this draft Policy Asse ssment (PA), staff has drawn from EPA’s 19 assessment and integrated synthesis of the scientific evidence presented in the Integrated Science 20 Assessment for Carbon Monoxide (USEPA, 2010a; henceforth referred to as the ISA) and 2000 21 Air Quality Criteria Document for Carbon Monoxide (USEPA, 2000; henceforth referred to as 22 the 2000 AQCD) and on the analyses presente d in the second draft Risk and Exposure 23 Assessment (USEPA, 2010b; henceforth referred to as the draft REA). The evidence-based 24 discussions presented in this chapter draw upon evidence from ep idemiologic studies, controlled 25 human exposure studies, and toxi cological studies evaluating shor t- or long-term exposures to 26 CO, as discussed in chapter 5 of the ISA, with supporting inform ation related to dosimetry and 27 potential mode of action evidence as presented in chapters 4 and 5 of the ISA, respectively, as 28 well as the integration of evidence across discipli nes presented in chapter 2 of the ISA. The 29 exposure/risk-based discussions have drawn fr om the quantitative hea lth analyses for CO 30 presented in the draft REA. Together the evid ence-based and risk-based considerations have 31 informed our conclusions related to the adequacy of the current CO st andards and alternative 32 standards that are support ed by the currently availa ble scientific evidence. 33March 2010 Draft – Do Not Quote or Cite 2-2 In presenting a range of primar y standard options for consider ation, we note that the final 1 decision is largely a public hea lth policy judgment. A final d ecision must draw upon scientific 2 information and analyses about health effects and risks, as well as judgments about how to deal 3 with the range of uncertainties that are inherent in the scientific evidence and analyses. Our 4 approach to informing these judgments, discusse d more fully below, is based on the recognition 5 that the available health eff ects evidence generally reflects a continuum, consisting of ambient 6 levels at which scientists generally agree that health effects are likely to occur, through lower 7 levels at which the likelihood and magnitude of the response become increasingly uncertain. 8 This approach is consistent with the requireme nts of the NAAQS provisions of the Act and with 9 how EPA and the courts have hist orically interpreted the Act. These provisions require the 10 Administrator to establish primar y standards that, in the Administ rator’s judgment, are requisite 11 to protect public health with an adequate margin of safely. In so doing, the Administrator seeks 12 to establish standards that are neither more nor less stringent th an necessary for this purpose. 13 The Act does not require that primary standards be set at a zero-risk level, but rather at a level 14 that avoids unacceptable risks to public health. 15 This section includes background information on the approach used in the previous 16 review of the CO standards (sec tion 2.1.1) and also a discussion of the approach for the current 17 review (section 2.1.2). 18

2.1.1 Approach Used in the Previous Review 19 The current primary standards for CO are se t at 9 parts per million (ppm) as an 8-hour 20 average and 35 ppm as a 1-hour aver age, neither to be exceeded more than once per year. These 21 standards were initially set in 1971to protect against th e occurrence of carboxyhemoglobin 22 (COHb) levels that may be associated with eff ects of concern (36 FR 8186). Reviews of these 23 standards in the 1980s and early 1990s, respectively, identified additional evidence regarding 24 ambient CO, COHb levels and health eff ects (USEPA, 1984a, 1984b; USEPA, 1991; USEPA, 25 1992; McClellan, 1991,1992). Assessment of the ev idence in those reviews led the EPA to 26 retain the existing standards without revision (59 FR 38906). 27 The 1994 decision to retain the primary st andards without revision was based on the 28 evidence published through 1990 and review ed in the 1991 AQCD (USEPA, 1991), the 1992 29 Staff Paper assessment of the policy-relevant information containe d in the AQCD and the 30 quantitative exposure assessment (USEPA, 1992) , and the advice and recommendations of 31 CASAC (McClellan 1991, 1992). At that time, as at the time of the prior NAAQS review (50 32 FR 37484), COHb levels in blood were recognized as the most useful estimates of exogenous 33 CO exposures and to serve as the best biomarker of CO toxicity for ambient-level exposures to 34March 2010 Draft – Do Not Quote or Cite 2-3 CO. Consequently, COHb levels were used as the indicator of health effects in the identification 1 of health effect levels of concern for CO (59 FR 38909). 2 In reviewing the standards in 1994 the Admi nistrator first rec ognized the need to 3 determine the COHb levels of concern “taking into account a large and diverse health effects 4 database”. The more uncertain and less quantifia ble evidence was taken into account to identify 5 the lower end of this range to prov ide an adequate margin of safety for effects of clear concern. 6 To consider ambient CO concentrations likely to result in COHb levels of concern, a model 7 solution to the Coburn-Forster-Kan e (CFK) differential equations was employed in the analysis 8 of CO exposures expected to occur under air qual ity scenarios related to just meeting the current 9 8-hour CO NAAQS, the controll ing standard (USEPA, 1992). 1 Key considerations in this 10 approach are described below 11
Carboxyhemoglobin Levels of Concern and Margin of Safety 12 The assessment of the science that wa s presented in the 1991 AQCD (USEPA, 1991) 13 indicated that CO is associated with effects in the cardiovascular system , central nervous system 14 (CNS), and the developing fetus. Additionally, f actors recognized as having potential interaction 15 with CO that may alter health effects included exposures to other pollutants, some drugs and 16 some environmental factors, such as altitude. Cardiovascular effects of CO, as measured by 17 decreased time to onset of angina and to ons et of significant electr ocardiogram (ECG) ST18 segment depression 2 were judged by the Administrator to be “the health effects of greater 19 concern, which clearly had been a ssociated with CO exposures at levels observed in ambient air” 20 (59 FR 38913). 21 Based on the consistent findings of response in patients with coronary artery disease 3 22 across the controlled human e xposure evidence (Adams et al., 1988; Allred et al., 1989a, 1989b, 23 1991; Anderson et al., 1973; Kleinman et al., 198 9, 1998; Sheps et al., 1987) and discussions of 24 adverse health consequences in the 1991 AQCD and the 1992 Staff Paper, at the CASAC 25

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 ex ercise. The duration of exercise require d to demonstrate chest pain and/or a 1- mm change in the ST segment of the ECG were key measurem ents 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 asso ciated 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 de pression, is asymptomatic (i.e., silent). Patients who experience angina typically have additional ischemic epis odes 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 meetings and in the July 1991 CA SAC letter, the Administrator concluded that “CO exposures 1 resulting in COHb levels of 2.9- 3.0 percent (CO-Ox) or higher in persons with heart disease have 2 the potential to increase the risk of decreased time to onset of angina pain and ST-segment 3 depression” (59 FR 38913). 4 Two of the five key studies were given particular emphasis in the 4 1991 AQCD to indicate the basis fo r conclusions regarding lowest observed-effect levels of 5 COHb in patients with exercise-induced isch emia, in terms of measured COHb and its 6 representation in terms of increase from baseline COHb on the order of 1.5 to 2.2% (USEPA, 7 1991, pp. 1-11 to 1-12; Allred et al., 1989a, 1989b, 1991; Anderson et al., 1973). 8 While EPA and CASAC recognized the existe nce of a range of views among health 9 professionals on the clinical signi ficance of the responses observ ed in the clinical studies, 10 CASAC noted that the dominant vi ew was that they should be c onsidered “adverse or harbinger 11 of adverse effect” (McClellan, 1991) and EPA rec ognized that it was “impor tant that standards 12 be set to appropriately reduce the risk of ambient exposures which produce COHb levels that 13 could induce such potentially adve rse effects” (59 FR 38913) as those occurring at COHb levels 14 of 2.9-3.0% (CO-oximeter) (59 FR 38913; USEP A, 1991, p. 1-12; USEPA, 1992, pp. 20-22). In 15 further considering additional re sults from the controlled human exposure evidence as well as 16 other aspects of the available evidence and uncer tainties regarding modeling estimates of COHb 17 formation and human exposure to COHb levels in the population associated with attainment of a 18 given CO NAAQS, the Administra tor recognized the need to extend the range of COHb levels 19 for consideration in evaluating wh ether the current CO standards pr ovide an adequate margin of 20 safety to those falling between 2.0 to 2.9 (59 FR 38913). Factors considered in recognizing this 21 margin of safety included the following (59 FR 38913). 22

 Uncertainty associated with the clinical im portance of cardiovascular effects associated 23 with exposures to CO that resulted in COHb levels of 2 to 3 percent. Although 24 recognizing the possibility that there is no threshold for these effects even at lower 25 COHb levels, the health si gnificance of the small changes in ST-segment depression 26 observed was considered somewhat minor. 27

 Findings of short-term reduction in maxi mal work capacity measured in trained 28 athletes exposed to CO at levels resulti ng in COHb levels of 2.3 to 7 percent. 29

 The potential that the most sensitive indi viduals have not been studied, the limited 30 information regarding the effects of ambien t CO in the developing fetus, and concern 31 about visitors to high altitudes, individuals w ith anemia or respiratory disease, or the 32 elderly. 33

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  Potential for short term peak CO exposur es to be responsible for impairments 1 (impairment of visual perception, sensorimot or performance, vigilance or other CNS 2 effects) which could be a matter of concern fo r complex activities such as driving a car, 3 although these effects had not been demonstrated to be caused by CO concentrations in 4 ambient air. 5

 Concern based on limited evidence for individua ls exposed to CO concurrently with 6 drugs (e.g., alcohol), during heat stress, or co-exposure to other pollutants. 7

 Large uncertainties remaining regarding modeling COHb formation and estimating 8 human exposure to CO which could lead to overestimation of COHb levels in the 9 population associated with attain ment of a given CO NAAQS. 10

 Uncertainty associated with COHb measur ements made using CO-Ox which may not 11 reflect COHb levels in angina patients studied, thereby creating uncertainty in 12 establishing a lowest effects level for CO. 13 Based on these considerations of the evidence, the Administrator id entified a range of 14 COHb levels of concern extending from 2.9% at the upper end down to 2% at the lower end and 15 concluded that “evaluation of the adequacy of the current standard s hould focus on reducing the 16
number of individuals with car diovascular disease from being exposed to CO levels in the 17
ambient air that would result in COHb levels of 2.1 percent.” She additionally concluded that 18 standards that “protect against COHb levels at the lower end of the range should provide an 19 adequate margin of safety against effects of un certain occurrence, as well as those of clear 20
concern that have been associated with COHb levels in the upper-e nd of the range” (59 FR 21 48914). 22
Estimation of Population Exposures 23 To estimate CO exposures and resulting COHb levels that might be expected under air 24 quality conditions that just met the current standards, an analys is of exposure and associated 25 internal dose in terms of COHb levels in the population of interest in the city of Denver, 26 Colorado was performed (59 FR 38906; USEPA, 1992). That analysis indicated that if the 9 27 ppm 8-hour standard were just met, the proportion of the nonsmoking population with 28 cardiovascular disease experiencing a daily maxi mum 8-hour exposure at or above 9 ppm for 8 29 hours decreased by an order of magnitude or more as compared to the proportion under then30 existing CO levels, down to less than 0.1 percent of the total person-days in that population. 31 More specifically, upon meeting the 8-hour standa rd, EPA estimated that less than 0.1% of the 32 nonsmoking cardiovascular-disease population would experience a COHb level greater than or 33 equal to 2.1%. A smaller percentage of the at-risk population was estimated to exceed higher 34March 2010 Draft – Do Not Quote or Cite 2-6 COHb levels. 5 Based on these estimates, the Administrator concluded that “relatively few 1 people of the cardiovascular sensitive population group analyzed will experience COHb levels ≥ 2 2.1 percent when exposed to CO levels in absenc e of indoor sources”. The analysis also took 3 into account that certain indoor sources (e.g., pa ssive smoking, gas stove usage) contributed to 4 total CO exposure and EPA recognized that such sources may be of concern for such high risk 5 groups as individuals with car diovascular disease, pregnant women, and their unborn children 6 but concluded that “the contribution of indoor sources cannot be effectively mitigated by 7 ambient air quality standards” (59 FR38914). 8
Decision Regarding Adequacy of the Standards 9 Based on consideration of the evidence and the quantitative results of the exposure 10 assessment, the Administrator conc luded that revisions of the cu rrent primary standards for CO 11 were not appropriate at that time (59 FR 38914). The Administrator additionally concluded that 12 both averaging times for the primary standards, 1-hour and 8-hour, be retained. The 1-hour and 13 8-hour averaging times were first chosen when EPA promulgated the primary NAAQS for CO in 14 1971. The selection of the 8-hour averaging time was based on the following: (a) most 15 individuals’ COHb levels appeared to approach equilibrium after 8 hours of exposure, (b) the 8- 16 hour time period corresponded to the blocks of time when people were often exposed in a 17 particular location or activity (e.g., working or sleeping), and (c) judgment that this provided a 18 good indicator for tracking continuous expos ures during any 24-hour period. The 1-hour 19 averaging time was selected as better represen ting a time period of intere st to short-term CO 20 exposure and providing protection from effects which might be en countered from very short 21 duration peak exposures in the urban environment (59 FR 38914). 22

2.1.2 Approach for the Current Review 23
To evaluate whether it is appropriate to consider reta ining the current primary CO 24 standards, or whether considerati on of revisions is appropriate, we adopted an approach in this 25 review that builds upon the general approach used in the last re view and reflects the broader 26 body of evidence and information now available. As summarized above, the Administrator’s 27 decisions in the previous review were based on an integration of information on health effects 28 associated with exposure to ambient CO; expert judgment on the adversity of such effects on 29 individuals; and policy j udgments as to when the standard is requisite to protect public health 30 with an adequate margin of safety, which were informed by air quality and related analyses, 31

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 sta ndard, 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 quantitative exposure and risk as sessments when possible, and qua litative assessment of impacts 1 that could not be quantified. 2 In conducting this assessment, we draw on the current evid ence and quantitative 3 assessments of exposure pertaining to the public h ealth risk of ambient CO . In considering the 4 scientific and technical informati on, we consider both the informati on available at the time of the 5 last review and information newly available sinc e the last review, including the current ISA and 6 the 2000 AQCD (USEPA, 2010; USEPA, 2000), as we ll as current and preceding quantitative 7 exposure/risk assessments (USEPA 2010b). As was the case at the time of the last review, the 8 best characterized health effect associated with CO levels of concern is hypoxia (reduced oxygen 9 availability) induced by increased COHb levels in blood (ISA, section 5.1.2). Accordingly, CO 10 is of particular concern for those with impaired cardiovascular systems, and the most compelling 11 evidence of cardiovascular effects is that from a series of controlled human exposure studies 12 among exercising individuals with coronary heart disease (CHD) also referred to as coronary 13 artery disease (CAD) (ISA, sec tions 5.2.4 and 5.2.6). Additionally av ailable in this review are a 14 number of epidemiological studies that investigated the associ ation of cardiovascular disease15 related health outcomes with concentrations of CO at ambient monitors. To inform our review 16 of the ambient standards, we performed a quant itative exposure and dose modeling analysis that 17 estimated COHb levels associated with differe nt air quality conditions in simulated at-risk 18 populations in two U.S. cities. Thus, in developing conclusions in this review as discussed in 19 sections 2.2 and 2.3 below, we have taken into account both evidence-based and exposure/risk20 based considerations framed by a series of key policy-relevant questions. 21

2.2 ADEQUACY OF THE CURRENT STANDARD 22 In considering the adequacy of the current CO standards, the overarching question we 23 consider is: 24

 Does the currently available scientific evidence- and exposure/risk-based 25 information, as reflected in the ISA and draft REA, support or call into question 26 the adequacy of the protection affo rded by the current CO standards? 27 To assist us in interpreting the currently av ailable scientific evidence and the results of 28 recent quantitative exposure/risk analyses to addr ess this question, we have focused on a series 29 of more specific questions, pos ed within sections 2.2.1 and 2.2.2 below. In considering the 30 scientific and technical informati on, we consider both the informati on available at the time of the 31 last review and information newly available sinc e the last review which has been critically 32 analyzed and characterized in the 2000 AQCD and more recently in the ISA. 33March 2010 Draft – Do Not Quote or Cite 2-8 2.2.1 Evidence-based Considerations 1 In considering the evidence with regard to th e issue of adequacy of the current standard, 2 we address a series of questions beginning with th e health effects associat ed with CO exposure, 3 followed by the use of COHb levels as the i ndicator of CO exposures and biomarker for 4 characterizing the potential for health effects asso ciated with exposures to ambient CO, and then 5 the identification of the populations most susceptible to the eff ects of CO. We next consider the 6 evidence regarding the levels of CO in ambient air associated with health effects and the 7 important uncertainties associated with the evidence. 8

 Does the current evidence alter our conc lusions from the previous review 9 regarding the health effects associated with exposure to CO? 10
The current evidence continue s to support our conclusions from the previous review 11 regarding key health eff ects associated with CO exposure. Th e best characterized effect of CO 12 continues to be related to the bi nding of CO to blood Hb to form increased levels of COHb (ISA, 13 sections 4.1 and 5.1.2) and the primary focus is on associated cardiov ascular effects (ISA, 14 section 5.2). In the scientific assessment for the current review, a likely causal relationship is 15 judged to exist between relevant CO exposures 6 and cardiovascular eff ects (ISA, section 2.5.1) 16 which is similar to conclusions in the last review. The evidence for effects on the central 17 nervous system, birth outcomes and developmental e ffects, and respiratory effects, while in some 18 cases expanded from that which was available at the time of the last review, is judged to be 19 suggestive of a causal relationship with relevant CO exposures (ISA, section 2.5). These overall 20 findings, additional details of which are described below, are consistent with and extend in some 21 ways conclusions drawn from the health effects evidence in the last review. 22 The long-standing body of evidence that has es tablished many aspects of the biological 23 effects of CO continues to cont ribute to our understanding of the health effects of ambient CO. 24 Upon inhalation, CO diffuses throug h the respiratory zone (alveoli ) to the blood where it binds to 25 Hb, forming COHb. This binding to reduced iron in heme protei ns and the alteration of their 26 function is the common mechanism underlying bi ological responses to CO. Accordingly, 27 inhaled CO elicits various heal th effects through binding to, a nd associated alteration of the 28 function of, a number of heme-containing molecules, mainly Hb (see e.g., ISA, section 4.1). The 29 best characterized health effect associated w ith CO levels of concer n is hypoxia (reduced O 2 30 availability) induced by increased COHb levels in blood and decreased o xygen availability to 31 critical tissues and organs, specifically the heart (ISA, section 5.1.2). Thus, people with a 32 cardiovascular disease that aff ects their ability to compensate for this effect (e.g., through 33

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 The 1 dose metric most commonly used as a bioindicator of exposure and health risk from CO is the 2 level of COHb in the blood (USEPA, 1991; 2002; 2010a). 3 The body of health effects evidence for CO ha s grown considerably since the previous 4 review with the addition of numerous epidemiological and toxicological studies (ISA; 2000 5 AQCD). This evidence provides additional detail and support to our prior understanding of CO 6 effects and population susceptibility. For exampl e, the currently availa ble evidence expands on 7 potential nonhypoxic mechanisms for CO effects, although the importance of such mechanisms 8 at environmentally-relevant CO exposures is unclear. Most notably, the current evidence 9 includes much expanded epidemiological ev idence that provides support for previous 10 conclusions regarding cardiovascul ar disease-related susceptibility and indications of air quality 11 conditions that may be associated with ambient CO-related risk. 12 In the most recent analysis of the health evidence EPA has developed a framework to 13 characterize the evidence as to likelihood of causal relationshi ps between exposure to ambient 14 CO and specific health effects (ISA, chapter 1). The clearest evidence is available for 15 cardiovascular effects, such that the major conc lusion drawn in the ISA regarding the critical 16 analysis of all available data on health effects of CO including the clinical and epidemiological 17 evidence is that "Given the consistent and c oherent evidence from ep idemiologic and human 18 clinical studies, along with biological plau sibility provided by CO’s role in limiting O 2 19 availability, it is concluded that a causal rela tionship is likely to exist between relevant [8] short20 term CO exposures and cardiovascular morbidity " (ISA, p. 2-6, section 2. 5.1). The evidence is 21 judged suggestive of causa l relationships between relevant sh ort- and long-term CO exposures 22 and CNS effects, birth outcomes and devel opmental effects following long-term exposure, 23 respiratory morbidity following short-term e xposure, and mortality following short-term 24 exposure (ISA, section 2.5, Table 2-1). It was co ncluded that there is not likely to be a causal 25 relationship between relevant long-term CO exposures and mortality (ISA, Table 2-1). 26 Similar to the previous re view, results from controlled human exposure studies of 27 individuals with coronary arte ry disease (Adams et al., 1988 ; Allred et al., 1989a, 1989b, 1991; 28 Anderson et al., 1973; Kleinman et al., 1989, 1998; Sheps et al., 1987;) are the “most compelling 29 evidence of CO-induced effects on the cardiovascul ar system” (ISA, Section 5.2). Additionally, 30

7 As described in discussing susceptibility below, card iovascular 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 ci rculatory 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 the use of an internal dose metr ic, COHb, adds to the strength of the findings in these controlled 1 exposure studies. As a group, th ese studies demonstrate the ro le of CO in increasing the 2 susceptibility of people with CAD to incidents of exercise-associated myocardial ischemia. 3 Among these controlled human exposure studie s, the ISA places principal emphasis on 4 the study of coronary artery di sease patients by Allred et al . (1989a, 1989b, 1991) which was key 5 to considerations from the previous review for the following reasons : 1) dose-response 6 relationships was observed; 2) e ffects were observed at the lowest COHb levels tested (mean of 7 2-2.4% COHb following experimental CO exposure ), providing no evidence of a threshold; 3) 8 objective measures of myocardial ischemia (ST- segment depression) were assessed, as well as 9 the subjective measure of decreased time to induc tion of angina; 4) measurements were taken 10 both by gas chromatography (GC), which provides a more accurate measurement of COHb blood 11 levels 9 , and by CO-Ox; 5) a large number of subjects were used; 6) a stri ct subject selection 12 protocol was employed to include only CAD patients with reproducible exercise-induced 13 angina.; and 7) the study was conducted at multiple laboratories around the U.S. This study 14 evaluated changes in time to exercise-induced onse t of markers of myocardial ischemia resulting 15 from two short CO exposures targeted to result in mean study subject C OHb levels of 2% and 16 4%, respectively (ISA, section 5.2.4). In this st udy, subjects (n=63) on th ree separate occasions 17 underwent an initial graded exercise treadmill test, followed by 50 to 70-minute exposures under 18 resting conditions to room air CO concentrations or CO concentr ations targeted for each subject 19 to achieve blood COHb levels of 2% and 4%. Th e exposures were to average CO concentrations 20 of 0.7 ppm (room air concentration range 0-2 ppm), 117 ppm (range 42-202 ppm) and 253 ppm 21 (range 143-357 ppm). After the 50- to 70-min exposures, subjects underw ent a second graded 22 exercise treadmill test, and the percent change in time to onset of angina and time to ST endpoint 23 between the first and second exercise tests wa s determined. For the two CO exposures, the 24 average post-exposure COHb concentrations were reported as 2.4% and 4.7%, and the 25 subsequent post-exercise aver age COHb concentrations were reported as 2.0% and 3.9%. 10 26

9 As stated in the ISA, the gas chromatographic t echnique for measuring COHb levels “is known to be more accurate than spectrophotometric measurements, particularly for sample s 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 ar e reported to overestimate CO Hb 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 ofCO-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 leve ls resulting from the lower experimental CO exposure.March 2010 Draft – Do Not Quote or Cite 2-11 Relative to clean-air exposure that resulte d in a mean COHb level of 0.6% (post1 exercise), exposure to CO resulting in post-exer cise mean COHb concentrations of 2.0% and 2 3.9% were observed to decrease the exercise time required to induce ST-segment depression by 3 5.1 (p=0.01) and 12.1% (p<0.001), respectively. Th ese changes were well correlated with the 4 onset of exercise-induced angi na, the time to which was shortened by 4.2% (p=0.027) and 7.1% 5 (p=0.002), respectively, for the two experiment al CO exposures (Allred et al., 1989a, 1989b, 6 1991). 11 As at the time of the last review, while ST-segment depression is recognized as an 7 indicator of myocardial ischemia , the exact physiological signifi cance of the observed changes is 8 unclear (ISA, p. 5-48). 9 No human clinical studies have been specifi cally designed to eval uate the effect of 10 controlled short-term exposures to CO resulting in COHb levels lower than a study mean of 2% 11 (ISA, section 5.2.6). However, an important fi nding of the multi-laboratory study was the dose12 response relationship (discussed further in addr essing a subsequent question below) observed 13 between COHb and the markers of myocardial is chemia, with effects observed at the lowest 14 increases in COHb tested, without evidence of a measurable thresh old effect. As reported by the 15 authors, the results comparing “the effects of increasing COHb from baseline levels (0.6%) to 2 16 and 3.9% COHb showed that each produced fu rther changes in objec tive ECG measures of 17 ischemia” implying that “small increments in CO Hb could adversely affect myocardial function 18 and produce ischemia” (Allred et al ., 1989b; Allred et al., 1991). 19 The epidemiological evidence has expanded cons iderably since the la st review including 20 numerous additional studies that are coherent with the evidence on markers of myocardial 21 ischemia from controlled human studies of CAD patients (ISA, section 2.7). The most recent 22 series of epidemiological studies have evaluated the associations between ambient concentrations 23 of multiple pollutants (i.e. PM 2.5 , NO 2 , SO 2 , O 3 and CO) at fixed-site m onitors and increases in 24 emergency department visits and hospital admissions for specific cardiovascular health outcomes 25 including ischemic heart disease (IHD), myocardi al infarction (MI), congestive heart failure 26 (CHF), and cardiovascular diseases (CVD) as a whole (Bell et al., 2009; Koken et al., 2003; Linn 27 et al., 2000; Mann et al., 2002; Metz ger et al., 2004; Peel et al ., 2007; Symons et al., 2006; 28 Tolbert et al., 2007; Wellenius et al., 2005). As noted by the ISA, “[s]tudies of hospital 29 admissions and ED visits for IHD provide the strongest [epidemiological] evidence of ambient 30 CO being associated with adverse CVD outcomes” (ISA, p. 5-40, section 5.2.3; Linn et al., 2000; 31

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 (A llred 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 Mann et al., 2002;Metzger et al., 2004; Peel et al., 2007). W ith regard to studies for other 1 measures of cardiovascular morb idity, the ISA notes that “[t]hough not as consistent as the IHD 2 effects, the effects for all CVD hospital admi ssions (which include IHD admissions) and CHF 3 hospital admissions also provide evidence for an association of cardi ovascular outcomes and 4 ambient CO concentrations” (ISA, section 5.2.3; Bell et al ., 2009; Tolbert et al., 2007). 12 5 The geographic areas in the studies for IHD a nd all CVD outcomes (whi ch is inclusive of 6 IHD) include Atlanta, urban ar eas of California and a group of 126 urban counties (Table 2-1 7 below; ISA, Figure 2-1). In these studies, di fferent multiple-year periods were assessed and the 8 air quality statistics an alyzed varied from 1 hour to 24 hour s. Together the individual study 9 periods spanned the period from 1988 through 2005. Further, the studies encompass a range of 10 air quality conditions, such that during the time periods of st udy for these outcomes, only the 11 three Atlanta studies (Metzger et al., 2004; Peel et al., 2007; Tolbert et al ., 2007) (and the studies 12 of CHF in Pittsburgh and Baltimore) 13 did not include years in whic h ambient CO concentrations 13 exceeded the 8-hour standard (Table 2-1). 14
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 compar ed to CO as a marker for the effects of another traffic-related pollutant or mix of pollutants, although the ISA concludes that the evid ence provides support for a di rect 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 Cite2-13Table 2-1.Information from U.S. epidemiologicalstudies of hospital admissions for ischemic heart disease (ISA, Figure 5-2),1cardiovascular disease (ISA, Figure 5-5) and congestive heart failure (ISA, Figure 5-4)and on air quality during2the study periods.3CO concentration instudy areas, in termsof air quality metricanalyzed (ppm)Range of design values(ppm) for study areasduring study periodStudy Reference Study AreaStudy TimePeriodHealthOutcomeRisk Estimate(confidence interval)Estimates arestandardized withinaveraging times.1Air QualityMetricAnalyzedwith HealthOutcomeMean ormedian(study)99thpercentile(AQS)1-hour 8-hourU.S. studies of hospital admissions for coronary heart disease (drawn from ISA, Figure 5-2).Metzger et al., 2004Atlanta 1993-2000 IHD 1-hr daily max 1.525.5 - 5.9 4.3 -16.3 3.2 - 5.3Peel et al., 2007Atlanta 1993-2000 IHD1.016 (0.999-1.034)1-hr daily max 1.8 5.5 - 5.9 4.3 -16.3 3.2 - 5.3Mann et al., 2002CA 1988-1995 IHD 1.0136 (1.0053-1.0220) 8-hr daily max 2.07 1.3 - 15.9 16.5 - 32 11.6 - 23.4Linn et al., 2000CA 1992-1995 MI 1.02 (1.01-1.03) 24-hr average 1.5 1.1 - 8.3 16.5 - 25 11.6 -16.4U.S. studies of hospital admissions for cardiovascular disease (drawn from ISA, Figure 5-5)Bell et al., 2009126 urban counties 1999-2005 CVD 65+ 1.0096 (1.0079-1.0112) 1-hr daily max 1.321.2 - 22.1 17.5-33.5 8.8-24.3Tolbert et al., 2007Atlanta 1993-2004 CVD 1.017 (1.008-1.027) 1-hr daily max 1.6 5.3 - 5.4 3.5 -16.3 2.5 - 5.3Linn et al., 2000CA 1992-1995 CVD 1.012 (1.005-1.020) 24-hr average 1.5 1.1 - 8.3 16.5 - 25 11.6 -16.4U.S. studies of hospital admissions for congestive heart failure (drawn from ISA, Figure 5-4)Linn et al., 2000CA 1992-1995 CHF 1.012 (1.005-1.020) 24-hr average 1.5 1.1 - 8.3 16.5 – 25 11.6 -16.4Mann et al., 2002CA 1988-1995 IHD+CHF 1.0304 (1.0135-1.0475) 8-hr daily max 2.07 1.3 - 15.9 16.5-32 11.6-23.4Symons et al., 2006Baltimore 2002 CHF 1.08 (0.40-2.99) 8-hr daily max 0.4 2.3 4.4-9.6 2.6-3.0Wellenius et al., 2005Pittsburgh 1987-1999 CHF 1.0843 (1.0614-1.1078)24-hr average 1.03 1.6-3.9 3.1-5.9 1.3-8.8Metzger et al., 2004Atlanta 1993-2000 CHF 1.01(0.99-1.03) 1-hr daily max 1.525.5 - 5.9 4.3-16.3 3.2-5.3Peel et al., 2007Atlanta 1993-2000 CHF 1.019 (0.997-1.041) 1-hr daily max 1.8 5.5 - 5.9 4.3-16.3 3.2-5.3Koken et al., 2003Denver 1993-1997 CHF 1.181 (1.002-1.393) 24-hr average 0.9 1.3-2.0 8.2-18.234.7-10.43Table legend.Information is from (a) studies that provide the strongest and most consistent weight of evidence from the epidemiological literature, and (b) additional supportive epidemiological studies.Presented are riskestimates (unadjusted for other pollutants) for hospital admissionsfor ischemic heart disease (IHD), myocardial infarction (MI), cardiovascular disease (CVD; Bell 2009included only subjects65 years old and above)outcomes, and congestive heart failure (CHF), with the study reported mean/median for the ambient CO concentration metric analyzed by the study authors. The 99thpercentile CO concentrations for the three studiedmetrics (1-, 8-hr daily max, or24-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 of the standard; presented is therange of 2ndmaximum 1-hour and 8-hour averageconcentrations at highest monitor in each studyarea across years (from AQS for the areas and time periods of the studies).1Estimates standardized for 1 ppm increase inCO concentration for 1-hour metric, 0.75 ppm for 8-hour metric and0.5 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 Bell et al., 2009 are the median.3These design values reflect full year of data, inclusive of study months (July-Aug).March 2010 Draft – Do Not Quote or Cite 2-14 Additional epidemiological studies have been conducted on associati ons of ambient CO 1 with other cardiovascular effects. For exampl e, preliminary evidence of a link between exposure 2 to CO and alteration of blood markers of coagul ation and inflammation in individuals with CAD 3 or CVD has been provided by a few well conducte d and informative studies (ISA, Table 5-6; 4 Delfino et al., 2008; Liao et al., 2005). As noted by the ISA, however, further studies are 5 warranted to investigate the role of these mark ers in prothrombotic ev ents and their possible 6 contribution to the pathophysiology of CO-induced aggravation of ischemic heart disease (ISA, 7 section 5.2.1.8). Other epidemiological studies (including field and or panel studies) also 8 provide some evidence of a link between CO expos ure and heart rate and heart rate variability 9 (ISA, section 5.2.1.1). With regard to the two of three studies reporting a positive association 10 with heart rate, the ISA concluded that “further research is warra nted” to corroborate the results, 11 while the larger number of studies for heart rate variability parameters is characterized as mixed 12 (ISA, p. 5-15). Additionally, of the two studi es of electrocardiogram changes indicative of 13 ischemic events (ISA, section 5.2.1.2), one found no association and, in the other study, unlike 14 the association with black carbon in that st udy, the associatio n with CO did not remain 15 significant in multipollutant models (ISA, p. 5-16). A limited numb er of epidemiological studies 16 (Bell et al., 2009; Linn et al., 2000 ) have investigated hospital ad missions for stroke (including 17 both hemorrhagic and ischemic forms) and gene rally report small or no associations with 18 ambient CO concentrations (ISA, sec tion 5.2.1.9, Table 5-8 and Figure 5-3). 19 Our consideration of these epidemiological st udies here reflects our understanding of CO 20 mechanisms and effects which is informed by the long-standing body of evidence for CO 21 summarized above. Figure 2-1 below presents a conceptual model of the pathway from CO 22 exposures to these effects. Fi gure 2-2 separately shows elemen ts of this conceptual model 23 investigated in clinical studies in contrast to those in the epidemiological studies discussed 24 above. More specifically, the clinical studie s provide linkages between directly measured 25 controlled short-term CO exposur es and COHb levels in CAD pa tients and between those COHb 26 levels and effects in that study group, specifically, markers of myo cardial ischemia. In contrast, 27 the epidemiological studies report associations be tween ambient CO concentrations at fixed-site 28 monitors and cardiovascu lar-related health outcomes (i.e ., hospital admissions and emergency 29 room visits). However, our ability to integrat e the evidence from these epidemiological studies 30 with our knowledge of CO-relate d effects based on the clinical evidence is limited in a few 31 aspects. Most particularly, we lack information on the actual CO exposures and associated 32 internal COHb levels that may have e licited the population res ponse observed in the 33 epidemiological studies, includi ng the extent to which the re sponse may be driven by CO 34 exposures other than the ambient CO concentrat ions. Moreover, it is also unknown how those 35 unmeasured exposures relate to th e exposure concentrations of the clinical studies (e.g., 1 hour at 36March 2010 Draft – Do Not Quote or Cite 2-15 approximately 50-200 ppm). We are also li mited in our understanding of the specific 1 relationship between the changes in indicators of myocardial isch emia observed in the controlled 2 human exposure studies and the hos pital admissions assessed in th e epidemiological studies. In 3 consideration of the epidemiological studies for cardiovascular outcomes in light of the larger 4 body of evidence, the ISA notes that the “known role of CO in limiting O 2 availability lends 5 biological plausibility to ischemia related he alth outcomes following CO exposure”, providing 6 coherence between the two sets of findings. The IS A additionally recognizes a lack of clarity as 7 to whether “the small changes in COHb associ ated with ambient CO exposures results in 8 substantially reduced O 2 delivery to tissues” (ISA, p. 5-48). 9

Exposure Internal Dose (e.g., COHb) Nonambient CO Ambient CO Health Outcomes (e.g., hospital admissions) Effects (e.g., markers of myocardial Ischemia) E ndogenous CO 10

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

Controlled CO Exposure Internal Dose (COHb) Effects (markers of myocardial Ischemia)

Ambient CO Health Outcomes (e.g., IHD hospital admissions) Epidemiological Studies Clinical Studies (CAD Patients) Baseline CO (endogenous + background)

12

Figure 2-2. Components of CO source-to-outcome conceptual model measured in 13 controlled human exposure and epidemio logical studies discussed in this 14 document. 15March 2010 Draft – Do Not Quote or Cite 2-16 Toxicological evidence presented in the curren t review provides further evidence of the 1 effects of CO in the cardiovascular system (e.g., aortic injury, micr ovascular permeability, 2 vascular remodeling, ventricular hy pertrophy) occurring at laborator y animal CO exposure levels 3 ranging from 35 to 200 ppm (ISA, section 5.2.5). 4 At the time of the last revi ew, there was evidence for eff ects other than cardiovascular 5 morbidity, including neurological, respiratory and developmental effects. With regard to 6 neurological effects, acute exposures to CO ha ve long been known to induce CNS effects such as 7 those observed with CO poisoning, although limited equivocal evidence available at the time of 8 the last review included indications of some neur obehavioral effects to re sult from CO exposures 9 resulting in a range of 5-20% COHb (2000 AQCD, section 6.3.2). No additional clinical or 10 epidemiological studies are now avai lable that investigated such e ffects of CO at ambient levels 11 (ISA, section 5.3). With regard to potential effects of CO on birth outcomes and developmental 12 effects, the currently availabl e evidence includes limited but s uggestive epidemiologic evidence 13 for a CO-induced effect on preterm- birth, birth defects, decrease in birth weight, other measures 14 of fetal growth, and infant mortality (ISA, s ection 5.4.3). The available animal toxicological 15 studies provide some support and coherence fo r these birth and developmental outcomes, 16 although a clear understanding of the mechanisms underlying potential reproductive and 17 developmental effects is still lacking (ISA, section 2.5.3). Ther e is limited evidence of an 18 association between short-term exposure to CO and respiratory-related outcomes, although only 19 preliminary evidence is available regarding a mechanism that coul d provide plausibility for CO20 induced effects. Thus, while there is some a dditional evidence on neurol ogical, respiratory and 21 developmental effects, it remains limited. 22 In summary, rather than altering our conclu sions from the previous review, the current 23 evidence provides continued support and some additional strength to our previous conclusions 24 regarding the health effects associated with exposure to CO and continues to indicate 25 cardiovascular effects, particularly effects re lated to the role of CO in limiting oxygen 26 availability, as those of greates t concern at low exposures. 27

 Does the current evidence continue to support a focus on COHb levels as the most 28 useful indicator of CO exposures and the best biomarker to characterize potential 29 for health effects associated with exposu res to ambient CO? Or does the current 30 evidence provide support for a focus on alt ernate dose indicators to characterize 31 potential for health effects? 32 As discussed in both the 2000 AQCD (USEPA, 2000) and the ISA, the best characterized 33 mechanism of action of CO is tissue hypoxia cau sed by binding of CO to hemoglobin to form 34 COHb. Increasing levels of COHb with subsequent decrease in oxygen availability for organs 35 and tissues are of concern in people with pr e-existing heart disease who have compromised 36March 2010 Draft – Do Not Quote or Cite 2-17 compensatory mechanisms (e.g., arteries unable to vasodilate, reduced capacity to increase 1 cardiac output) such as those affected with corona ry heart disease. The integrative review of 2 health effects of CO indicates th at “the clearest evidence indicate s that individuals with coronary 3 artery disease are most suscepti ble to an increase in CO-induced health e ffects” (ISA, section 4 5.7.8) and the evidence, including that from clinical studies described in addressing the previous 5 question (regarding health effects as sociated with exposure to CO), continues to support levels of 6 COHb as the most useful indicator of CO exposure that is related to the h ealth effects of CO of 7 major concern. 8 Alternative mechanisms of CO-i nduced effects primarily associated with CO’s ability to 9 bind heme-containing proteins other than he moglobin and myoglobin, and involving a wide 10 range of cellular tissues and CO concentrations, have been described in the 2000 AQCD 11 (USEPA, 2000, section 5.8) and in the ISA (ISA, section 5.1.3). Th e ISA notes that collectively 12 the older toxicological studies de monstrated that exposure to high concentrations of CO resulted 13 in altered functions of heme proteins other than myoglobin and hemoglobin which have the 14 potential to interfere with basic cell and mol ecular processes that could lead to dysfunction 15 and/or disease. More recent toxicological studies described in the ISA, conducted at CO 16 exposure levels ranging from 35 to 100 ppm have provided evidence of non-hypoxic 17 mechanisms involving binding of CO to reduced iron in heme proteins by which CO may be 18 causing cellular injury or toxic ity (ISA, section 2.5). The ISA notes that these mechanisms may 19 or may not be interrelated and include altera tion of nitric oxide si gnaling, inhibition of 20 cytochrome C oxidase, heme loss from protein, di sruption of iron homeostasis and alteration of 21 cellular redox status. Less understo od mechanisms noted in the IS A are alteration in ion channel 22 activity and modulation of protei n kinases signaling pathways. The ISA notes that “CO may be 23 responsible for a continuum of effects from cell si gnaling to adaptive responses to cellular injury, 24 depending on intracellular concentrations of CO , heme proteins and molecules which modulate 25 CO binding to heme proteins” (ISA, section 5.1.3.3). 26 Although there is evidence of additional biomarke rs potentially associated with effects of 27 CO, new research is needed to further understa nd these biomarkers a nd their linkage to CO28 induced effects in at-risk populati ons. Therefore, the evidence i ndicates that COHb continues to 29 be the most useful and well supported indicato r of CO exposures and the best biomarker to 30 characterize the potential for h ealth effects associated with exposures to ambient CO. 31March 2010 Draft – Do Not Quote or Cite 2-18  Does the current evidence alter our und erstanding of populations that are 1 particularly susceptible to CO exposu res? Is there new evidence that suggest 2 additional susceptible populations that sh ould be given increased focus in this 3 review? 4 The term susceptibility has been used to recognize populations that have a greater 5 likelihood of experiencing effects related to ambient CO exposure (ISA, section 5.7). Thus, 6 susceptible populations are at greater risk of CO effects and are referred to as at-risk in the 7 discussion here. This increased likelihood of response to CO ca n potentially result from many 8 factors, including pre-existing medi cal disorders or disease state, lifestage, gender, lifestyle or 9 increased exposures (ISA, section 5.7). 10 The current evidence, while much expanded in a number of ways, continues to support 11 our conclusions from the previous review rega rding the key and best-characterized at-risk 12 population for exposure to ambient CO. Based on the evidence from clinical studies also 13 considered in the last review, with which the now much-expanded epidemiological evidence 14 base is coherent, the populati on with pre-existing cardiovascu lar disease associated with 15 limitation in oxygen availability con tinues to be the best characte rized population at risk of 16 adverse CO-induced effects, with coronary ar tery disease (CAD) rec ognized as “the most 17 important susceptibility characteristic for in creased risk due to CO exposure” (ISA, section 18 2.6.1). An important factor determining the increa sed susceptibility of this population is their 19 inability to compensate for the reduction in oxygen levels due to an already compromised 20 cardiovascular system. Individuals with a heal thy cardiovascular system (i.e., with healthy 21 coronary arteries) have oper ative physiologic compensatory mechanisms (e.g., increased blood 22 flow and oxygen extraction) for CO-induced hypoxia a nd are unlikely to be at increased risk of 23 CO-induced effects (ISA, p. 2-10). 14 In addition, the high oxygen consumption of the heart, 24 together with the inability to compensate for the hypoxic effects of CO ma ke the cardiac muscle 25 of a person suffering with coronary artery disease a cri tical target for the hypoxic effects of CO. 26 In the current review, recognition of suscep tibility of the popula tion with pre-existing 27 cardiovascular disease, such as CAD, is s upported by the expanded epidemiological database, 28 which includes a number of studies reporting si gnificant increases in hospital admissions for 29 IHD, angina and MI in relation to CO exposures (ISA, section 2.7). Further support is provided 30 by epidemiologic studies (Mann et al., 2002; a nd Peel et al., 2007) of increased hospital 31 admissions and emergency department visits for IHD among individu als with secondary 32

14 The other well-studied individuals at the time of the last review were healthy male adults that experienced decreased exercise duratio n at similar COHb levels during s hort term maximal exercise. This population was of lesser concern since it represented a sma ller 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 diagnoses for other cardiovascular outcomes incl uding arrhythmia and congestive heart failure 1 (ISA, section 5.7), and toxicological studies repo rting altered cardiac outco mes in animal models 2 of cardiovascular disease (ISA, section 5.2.1.9). 3 Cardiovascular disease comprises many type s of medical disorder s, including heart 4 disease, cerebrovascular disease (e.g., stroke), hypertension (hi gh blood pressure), and peripheral 5 vascular diseases. Heart disease, in turn, comprises several types of disorders, including 6 ischemic heart disease (CHD or CAD, myocardial infarction, angina), congestive heart failure, 7 and disturbances in cardiac rhythm (2000 AQC D, section 7.7.2.1). Types of cardiovascular 8 disease other than those discusse d above may also contribute to increased susceptibility to the 9 adverse effects of low levels of CO (ISA, section 5.7.1.1). For example, some evidence with 10 regard to other types of cardiova scular disease such as congestiv e heart failure, arrhythmia, and 11 non-specific cardiovascular dis ease, although more limited fo r peripheral vascular and 12 cerebrovascular disease, indicates that “the continuous nature of the progression of CAD and its 13 close relationship with other forms of cardiovasc ular disease suggest th at a larger population 14 than just those individuals with a prior diagnosis of CAD may be suscepti ble to health effects 15 from CO exposure” (ISA, p. 5-117). 16 Although there was little experimental data ava ilable at the time of the last review to 17 adequately characterize specific health effects of CO at ambient levels for other potentially at18 risk populations, several other popula tions were identified as being potentially more at risk of 19 CO-induced effects due to a number of factors. These factors include pre-existing diseases that 20 could inherently decrease oxygen ava ilability to tissues, lifestage vul nerabilities (e.g., fetuses, the 21 elderly), gender, lifestyle, medica tions or alterations in the envir onment (e.g., increased altitude). 22 This is consistent with the ISA conclusions in the current review which recognize other 23 populations that may be potentially susceptible to the effects of CO as continuing to include: 24 those with other pre-ex isting diseases that may have already limited O 2 availability or increased 25 COHb production or levels, such as people with obstructive lung diseases, diabetes and anemia; 26 older adults and fetuses during critical phases of development; commuters and those living near 27 heavily traveled roadways; visito rs to high-altitude locations; and people ingesting medications 28 and other substances that enhance en dogenous or metabolic CO production. 29 Preliminary evidence from epidemiol ogical, controlled human exposure, and 30 toxicological studies indicate that people with obstructive lung di sease (e.g., COPD patients with 31 underlying hypoxia, asthmatics) may be a poten tially susceptible population (ISA, section 32 5.7.1.2). Overall, the few available epidemiol ogical studies have re ported weak, positive 33 associations between ambient CO and CVD hosp ital admissions for individuals with underlying 34 COPD. Additionally, a controlled human exposur e study of individuals with COPD reported 35 that two patients experienced COPD exacerbation and a slight an ti-inflammatory effect during 36March 2010 Draft – Do Not Quote or Cite 2-20 CO exposures of 100-125 ppm for 2 hours (ISA, s ection 5.5.1.2). Other epidemiological studies 1 (ISA, section 5.5.2.2) have reported weak associations in asthmatic s, which constitute another 2 population that can experience exercise-induced airflow limitation. Preliminary evidence was 3 also shown in one animal toxicological study (Ghio et al., 2008), indi cating mild pulmonary 4 inflammation upon exposure to 50 ppm CO. 5 With regard to other potentially at-risk populat ions, there is also limited epidemiological 6 data showing associations between CO exposures and di abetes (ISA, section 5.7.1.3). 7 Epidemiologic studies (Pereira Filho et al ., 2008; Zanobetti and Schwartz, 2001) provide 8 suggestive evidence that CVD patie nts with diabetes may be at greater risk of emergency 9 department visits and hospital admissions than those without diabetes (ISA, section 5.7.1.3). 10 Inferences may also be drawn from results from panel studies for individuals with metabolic 11 syndrome 15 that observed associations between short-term exposures to CO and changes in heart 12 rate variability parameters (ISA, section 5.2.1.1) and from a toxico logical study providing 13 evidence of vascular dysfunction associated w ith increases in endogenous CO in an animal 14 model of metabolic syndrome (ISA, section 5.7.1.3). People w ith anemia who have reduced 15 oxygen-carrying capacity and/or higher baselin e COHb levels are an additional population 16 considered to be potentially susceptible to th e hypoxic effects of CO. However, there are no 17 controlled human studies or epidemiological stud ies that have specifically examined the CO18 related health effects in individuals with anemia (ISA, section 2.6.1, p. 2-11). 19 Older adults (65+) have been considered as a potentially suscep tible population to the 20 effects of CO, primarily due to the increased prevalence of ca rdiovascular disease among this 21 population when compared to all age groups or lifestages. There is limited epidemiologic 22 evidence showing associations between short-te rm exposure to CO and increases in IHD or 23 myocardial infarction (MI) hospita l admissions among older adults as compared to all age groups 24 or younger adults. The combination of this limited epidemiological data and the fact that older 25 adults have a higher prevalence of CAD than the general population, indicat es that older adults 26 are a potentially susceptible population for increa sed health effects due to CO exposure (ISA, 27 section 5.7.2.1). 28 The developing fetus has been a population cons idered to be at potential risk of CO29 induced effects due to the higher affinity of their hemoglobin for CO when compared to that of 30 adults. Limited evidence indicates an associa tion of CO exposure duri ng early pregnancy with 31 pre-term births and birth def ects (ISA, p. 2-8). Toxicological studies reporting effects in 32 laboratory animals including decrements in birth weight, reduced prenatal growth, and effects on 33 the heart provide support to the epidemiological evidence. 34

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 Gender has also been considered as a possi ble source for susceptib ility. However, the 1 evidence is inconclusive based on the limited epidemiological data, and the gender-specific 2 variability in CO endogenous pr oduction (ISA, section 5.7.3). In creased altitude and physical 3 activity through their effect on CO uptake and elimination has also been considered to potentially 4 influence susceptibility. For example, resi dents of low altitudes visiting high altitudes, 5 especially the elderly and those with CAD (L eaf and Kleinman, 1996; Kleinman et al., 1998), 6 may be at greater risk from added effects of ambient CO than adapted residents (ISA, p. 2-12). 7 Other less certain susceptibility factors have been considered, such as those pertaining to the 8 taking of medications that may alter CO produc tion (ISA, p. 2-12). Lastly, people experiencing 9 increased CO exposures, such as those spe nding relatively greater amounts of time in 10 microenvironments with relativel y higher levels of ambient CO have been considered to be 11 potentially at risk to CO-indu ced effects (ISA, section 5.7.6). 12 As we recognize the potential susceptibility of the populations identified above, we also 13 note the lack of information on specific COHb levels that may be associated with health effects 14 in these other groups as well as a way to relate the specific evidence available for the CAD 15 population to these other populations. 16 In summary, the current evidence continues to support the identific ation of people with 17 cardiovascular disease as having susceptibility to CO-induced hea lth effects (ISA, 2-12), with 18 those having CAD as the best characterized population with increased susceptibility to CO19 induced health effects (ISA, sections 5.7.1.1 and 5.7.8). An important susceptibility 20 consideration for this populati on is the inability to compensate for CO-induced hypoxia since 21 individuals with CAD have an already compromised cardiovascular system. Included in this 22 susceptible population are those w ith angina pectoris (cardiac chest pain), those who have 23 experienced a heart attack, and those with silent ischemia or undiagnosed IHD (AHA, 2003). 24 People with other cardiovascular diseases, particularly heart diseases, are also at risk of CO25 induced health effects. We also recognize ot her populations potentially susceptible to CO26 induced effects, most particularly those with ot her pre-existing diseases that may have already 27 limited oxygen availability, increased COHb levels, or increased endogenous CO production, 28 such as people with obstruc tive lung diseases, diabetes a nd anemia; however, information 29 characterizing susceptibility is limited. 30March 2010 Draft – Do Not Quote or Cite 2-22  Does the current evidence alter our conc lusions from the previous review 1 regarding the levels of CO in ambient air associated with health effects? 2 At the time of the last review, EPA’s conc lusions regarding concentrations of CO in 3 ambient air that might be associated with risk of health effects were drawn from the combined 4 consideration of the evidence of COHb levels for which cardiova scular effects of concern had 5 been reported and the results of an exposure and dose modeling assessment (59 FR 38906). As 6 described in more detail in section 2.1.1 above, th e key effects judged to be associated with CO 7 exposures resulting from concentrations observed in ambient air were cardiovascular effects, as 8 measured by decreased time to onset of exerci se-induced angina and to onset of ECG ST9 segment depression (59 FR 38913). 10 Levels of COHb that have been associated with different types of effects in clinical 11 studies are summarized in Table 2- 2 below. At the time of the last review, decreases in time to 12 onset of exercise-induced angina (a symptom of myo cardial ischemia) had been documented in 13 multiple studies at post-exposure COHb leve ls ranging from 2.9 to 5.9% (CO-Ox), which 14 represented incremental increases of 1.5-4.4% COHb from baseline (Adams et al., 1988; Allred 15 et al., 1989a, 1989b, 1991; Anderson et al., 1973; Kleinman et al., 1989, 1998; Sheps et al., 16 1987). The matched measurements available fr om Allred et al. ( 1989a, 1989b, 1991) of CO-Ox 17 and gas chromatography, the method generally re cognized to be the more accurate for COHb 18 levels below 5% (ISA, section 5.2.4), indicate that CO-Ox measurements of 2.9 to 3.0% COHb 19 generally correspond to GC measur ements on the order of 2-2.4%. 16 Other groups for which 20 clinical studies have reported CO-related effects at slightly higher COHb le vels include effects in 21 subjects with cardiac arrhythmias and effects on exercise duration and maximal aerobic capacity 22 in healthy adults. Among the stud ies of myocardial ischemia indicators in patients with CAD, 23 the two studies involving the lo west experimental CO exposures (which resulted in average 24 increases in COHb of about 1.5% over pre-exposure baseline) were Anderson et al. (1973) 17 and 25 the more recent Allred et al. (1989a, 1989b, 1991) to which we give primary attention in this 26 review (discussed in more detail above). Ne ither study provided eviden ce of a measurable 27 threshold at the lowest experime ntal CO exposures and associat ed COHb levels assessed (mean 28 of 2.0-2.4% COHb, GC). Allred et al. (1989a , 1989b, 1991) further repo rted a dose-response 29 relationship between the increased COHb levels and the response of the assessed indicators of 30 myocardial ischemia (Allred et al., 1989a, 1989b, 1991). While this evidence informed our 31

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 conclusions regarding COHb le vels associated with health effects, the CO exposure 1 concentrations employed in the studies to achieve these COHb levels were substantially above 2 ambient concentrations. Thus, an exposure and do se assessment was performed to consider the 3 COHb levels that might be attained as a resu lt of exposures to ambien t CO allowed under the 4 current NAAQS, as described in section 2.1.1 above. 5 Since the time of the last review, there have been no new controlled human exposure 6 studies specifically designed to evaluate the eff ects of CO exposure in su sceptible populations at 7 COHb levels below 2%. Thus, similar to the la st review, the multilaboratory study by Allred et 8 al.(1989a, 1989b, 1991) continues to be the study that has evaluated cardi ovascular effects of 9 greatest concern (i.e., reduced time to exercise -induced myocardial ischemia as indicated by 10 ECG ST-segment changes and angina) at the lowest tested COHb levels (ISA, section 2.7). This 11 is currently considered the most rigorous and we ll designed study, presenting the most sensitive 12 analysis methods (GC used in addition to CO-Ox) to quantify COHb blood levels. Key findings 13 from that study with regard to levels of CO associated with h ealth effects include the following: 14

 Increases in COHb to mean levels of 2.0% and 3.9% from baselin e (0.6%) significantly 15 reduced exercise time required to induce ma rkers of myocardial ischemia in CAD 16 patients. 18 17

 The associated dose-response relationship between incremental changes in COHb and 18 change in time to myocardial ischemia in CAD patients indicates a 1.9% and 3.9% 19 reduction in time to onset of exercise-i nduced angina and ST-segment change, 20 respectively, per 1% increase in COHb con centration without evidence of a measurable 21 threshold. 22 Since the last review, there have been nu merous improvements to the exposure and 23 COHb models that we employ to estimate exposur e and dose for the current review. The results 24 of modeling using these improved tools in the current review and our conclusions based on it 25 with regard to the expectation for COHb levels of concern to occur in the at-risk population 26 under differing air quality conditions ar e described in section 2.2.2 below. 27

18 Relative to baseline (0.6% mean CO Hb), 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 Table 2-2. Carboxyhemoglobin levels and reported effects in CAD patients and healthy 1 adults. 2

%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 Since the time of the last review, a number of additional epidemiological studies have 4 been conducted of health outcome associations with different ambient CO metrics (e.g., ISA, 5 section 5.2). The majority of these epidemiologi cal studies, conducted in se lected urban areas of 6 the U.S. or Canada, were designed to evaluate the effects of multiple pollutants (i.e. PM 2.5 , NO 2 , 7
SO 2 , O 3 and CO). As discussed above, a number of these studies have reported associations 8 between concentrations of CO measured at fixed-site ambien t monitors and cardiovascular 9 endpoints other than stroke, particularly hospita lizations and emergency department visits for 10 specific cardiovascular health outcomes including ischemic heart disease (IHD), congestive heart 11 failure (CHF) and cardiovascular diseases (CVD) as a whole (Be ll et al., 2009; Koken et al., 12 2003; Linn et al., 2000; Mann et al., 2002; Metzger et al., 2004; Peel et al., 2007; Symons et al., 13March 2010 Draft – Do Not Quote or Cite 2-25 2006; Tolbert et al., 2007; Wellenius et al., 2005). In general, these studies report positive 1 associations and a number of th ese associations are statistical ly significant (ISA, sections 5.2.3 2 and 5.2.1.9; Table 2-1 above). 3 In considering these epidemiological studies in the case of CO, we r ecognize that there is 4 coherence between the available c linical and epidemiological eviden ce with regard to the health 5 effects of CO in the cardiovascul ar system (primarily for ischemic related events). As noted 6 above, however, we also recognize several gaps between the two lines of evidence which 7 complicate their integration, particularly with regard to ambient exposures and ambient 8 concentrations associated with health effect s of concern. As discussed in the ISA, the 9 epidemiological studies reported a ssociations with emergency depa rtment visits and/or hospital 10 admissions for IHD and other cardiovascular dis ease-related outcomes that are plausibly related 11 to the effects on physiological indicators of my ocardial ischemia (e.g., ST-segment changes) 12 demonstrated in the controlled human exposur e studies, providing coherence between the two 13 sets of findings. However, there is appreciab le uncertainty with regard to the specific 14 relationship between these two types of measures of cardiovascular morbidity. Furthermore, the 15 clinical studies document relations hips between controlled elevated exposures to CO and specific 16 levels of an internal dose metric, COHb, which e licited specific responses in CAD patients. This 17 informs our interpretation of th e associations we observe in th e epidemiological studies, although 18 COHb has not been monitored in the epidemio logical studies and th e personal CO exposure 19 concentrations eliciting the outcomes observed, including the contributions from ambient and 20 nonambient CO, are unknown (as illu strated in Figure 2-2 above). 19 Further, to achieve their 21 experimental target levels of COHb, the clinical studies used short (approximately 1-hour) 22 exposures to concentrations of CO that we re substantially higher than current commonly 23 occurring ambient concentrations (ISA, section 2.7). The relati onship of the clinical exposure 24 concentrations to exposure concentrations oc curring in the populations studied in the 25 epidemiological studies is unknown, but the clini cal exposures may be higher. For example, 26 individual exposure concentratio ns for the lower clinical expo sure ranged from 42 to 202 ppm 27 (Allred et al., 1989b). Experiment al studies have not been conducte d at COHb levels that might 28 be elicited in response to exposures to lower CO concentrations such as those within the ranges 29 of current maximum ambient con centrations (ISA, section 2.7) or closer to personal exposure 30 concentrations more commonly expected curre ntly (e.g., ISA, Figure 3-45). Gaps in our 31 understanding of the role of nonambient CO expo sures and their contribution to COHb levels 32

19 As recognized in the ISA in consideration of the epidemiological studies, the known role of CO in limiting O 2 availability lends biological plausibility to ischem ia-related health outcomes following CO exposures, although “it is not clear whether the small changes in COHb associated w ith ambient CO exposures results in substantially reduced O 2 delivery to tissues” (ISA, p. 5-48).March 2010 Draft – Do Not Quote or Cite 2-26 also complicates our ability to disentangle ambien t concentrations that may be related to health 1 effects. 2 In considering these epidemiological studies in the case of CO, we recognize several 3 uncertainties that complicate the quantitative interpretation with regard to ambient concentrations 4 that might be eliciting the repor ted health outcomes. These uncer tainties relate to conclusions 5 regarding CO as the pollutant eliciting the effect reported in these studies and to our 6 understanding of the ambient CO concentrations (and total c oncentrations) to which study 7 subjects demonstrati ng effects are exposed. 8

 With regard to the first, a major uncertainty relates to the difficulty in determining the 9 extent to which ambient CO is independently associated with cardiovascular effects or 10 if CO at ambient levels is acting as a surroga te for the effects of another traffic-related 11 pollutant or mixture of pollutants (ISA, s ection 5.2.3). As noted in the ISA, in 12 interpreting the epidemiologica l evidence for cardiovascular morbidity “[i]t is difficult 13 to determine from this group of studies th e extent to which CO is independently 14 associated with CVD outcomes or if CO is a marker for the effects of another traffic15 related pollutant or mix of pollutants. On-road vehicle e xhaust emissions are a nearly 16 ubiquitous source of combustion pollutant mi xtures that include CO and can be an 17 important contributor to CO in near-road locations” (ISA, p. 5-40 – 5-41). We also 18 note CASAC’s recognition of the potential fo r co-pollutants to pose confounding to be 19 “particularly problematic for CO” and the need to give considerati on to the possibility 20 of CO serving as a surrogate for a mixture of fossil- fuel-combus tion-related pollutants 21 (Brain and Samet, 2010). 22

 To identify the CO-specific effect, and a ssess and control for potential confounding of 23 CO-associated health effects by other pollutants for which measurements are available, 24 two-pollutant regression models are a comm only used statistical method (ISA, section 25 1.6.3). Although CO associations may, in so me studies, be slightly attenuated in 26 models adjusting for one other combustion- related pollutant, they generally remain 27 robust (Figures 5-6 and 5-7). However, ther e are several statistical issues influencing 28 results generated using multi-pollutant models , such as models that force all pollutants 29 to follow the same lag structure, the incl usion of correlated but noncausal variables, 30 and the potential omission of etiologically re levant co-pollutants. Although data for 31 co-pollutant modeling are avai lable for some of the other criteria pollutants, data are 32 not available for additional combustion-related pollutants, which may or may not 33 include all pollutants that elicit the health effects (ISA, section 2.5.1) . In light of the 34 uncertainty (referenced in di scussion of the question belo w) regarding the biological 35 plausibility of CO-related eff ects at low ambient concentrat ions, it is possible that the 36 CO risk estimates ascribed to measured am bient CO levels in ep idemiological studies 37 is instead another pollutant that is highly correlated with CO, but was not measured. 38

 With regard to the second, the presence of exposure erro r and/or measurement error 39 from reliance on fixed-site ambient CO monitors, a large portion of which are 40 measuring CO concentrations at or below detection limits can result in the over or 41 underestimation of the effects of the poorly measured pollutant. This limitation can 42 add uncertainty to the association between ambient concentrations of CO and health 43March 2010 Draft – Do Not Quote or Cite 2-27 effects estimates (ISA, p. 3-91) and constrai n their interpretation with regard to CO 1 exposure levels (Brain and Samet, 2010). 2 We have considered here the epidemiological studies in the U.S. for ischemia-related 3 outcomes. In Table 2-2, we focused on the U. S. studies of CHD hospital admissions for CHD 4 (i.e., IHD and MI), that provided the strongest and most consiste nt weight of evidence (ISA, 5 Figure 5-2, pp. 5-24 to 5-26). In Ta ble 2-3, we present the U.S. st udies for the broader category 6 of all CVD hospital admissions that also contributed to the ISA’ s causality determination (ISA, 7 Figure 5-5, pp. 5-33 to 5-36). In focusing on th ese studies, we did not include studies of 8 associations with CHF, a chronic condition for wh ich there are multiple causes and for which the 9 evidence is less clear. 20 We have focused here on studies for IHD, MI and all CVD outcomes 10 (which are inclusive of IHD), which we consider to be key due to the more direct conceptual 11 linkages that can be drawn between the these outcomes and the myocardial ischemia effects of 12 the CAD clinical studies. 13 Of particular interest in a ddressing the question posed here is information pertaining to 14 CO concentrations in ambient ai r that meet the current standar d. While, the full set of these 15 epidemiological studies, includi ng those reporting associations with ambient CO concentrations 16 under conditions when the current standards were not met, provide support to the previous 17 evidence regarding cardiovascular effects of CO, it is the studies involvin g air quality conditions 18 in which the current standards were met that are most informative wi thin the context of 19 considering the adequacy of the current standards. 21 Accordingly, in considering these 20 epidemiological studies, we have considered the air quality conditions during the periods of 21 study. 22 The areas of focus across these studies of IHD and CVD outcomes (inclusive of IHD) 23 include Atlanta, urban areas of Calif ornia and a group of 126 urban counties 22 and the multi-year 24 time periods for these studies together span the period from 1988 through 2005 (Tables 2-3 and 25 2-4 below). During the time periods of study, onl y the three Atlanta stud ies (Metzger et al., 26 2004; Peel et al., 2007; Tolbert et al., 2007) did not include years in which ambient CO 27 concentrations exceeded the 8-hour standard (Tab les 2-3 and 2-4). Based on data reported to 28 AQS for the general areas studied, ambient CO concentrations during a portion of the time 29 periods studied in the other three of these an alyses exceeded the leve l of the current 8-hour 30 NAAQS (Bell et al., 2007; Linn et al., 2000; Mann et al., 2002). Among these three studies, all 31

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 signific ant results focused on an area in which the current 8-hour standard was just met (K oken 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 of which reported statistically significant risk es timates, the highest 8- hour design values ranged 1 from 11.6-23.4 ppm, as compared to the 8-hour standard of 9 ppm. 23 In the Atlanta area, which 2 was the focus for the other three studies (Peel et al., 2007; Metzger et al., 2004; Tolbert et al., 3 2007), the second highest non-overla pping 8-hour average CO concen tration in a year (i.e., the 4 design value for the 8-hour standard) ranged fr om 3.2 up to 5.3 ppm over the combined 12 years 5 of study. One of these three studies (Tolbert et al., 2007) reported a statistically significant risk 6 estimate for cardiovascular hospital visits associat ed with CO concentratio ns, while the other two 7 did not. In the Atlanta area during the period studied, the 99 th percentile daily maximum 8-hour 8 CO concentration in a year ranged up to 4.9 ppm, while the yearly 99 th percentile daily 9 maximum 1-hour CO concentration ranged up 7.9 ppm. The studies in which CO concentrations 10 exceeded the current NAAQS during some porti on of the study period accordingly are less 11 informative to our overarching question regarding the adequacy of the protection afforded by the 12 current standard. We note that studies report ing associations with IHD or total CVD outcomes 13 for which air quality data reported to AQS do not indicate that the curre nt 8-hour standard was 14 exceeded during the study period are limited to those for Atlanta. 15

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 a ll cardiovascular outcomes, adjusted for NO 2 , 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 2 nd maximum in a year. This subset analysis fo und 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 NO 2 ), although confidence intervals increased at the lower cutoff values and th e proportion of values near and below the limit of detection grew larger.March 2010 Draft – Do Not Quote or Cite2-29Table 2-3.Air quality information for key U.S. epidemiological studiesof hospital admissionsfor coronary heart disease1(ISA, Figure 5-2).21-hour Daily Maximum(ppm)8-hour Daily Maximum(ppm)24-hour Average(ppm)Design Values (ppm)for Study AreasDuring Study PeriodStudy AreaStudyPeriodHealthOutcomeMean99thpercentile Mean99thpercentile Mean99thpercentile 1-hour 8-hourMetzger et al., 2004Atlanta 1993-2000 IHD 1.5*15.5-5.9 4.6-16.3 3.2-5.3Peel et al., 2007Atlanta 1993-2000 IHD 1.8* 5.5-5.9 4.6-16.3 3.2-5.31993 6.1 4.4 2.4 6.5 4.91994 6.3-6.6 4.3-4.9 2.7-3.3 7.1 5.31995 5.8-7.9 4.3-4.9 2.4-3.2 16.3 5.21996 5.3-6.1 3.5-3.6 2.0-2.7 6.6 3.81997 5-5.4 3.1-4.2 2.3-2.4 5.8 4.31998 4.8-4.9 2.8-3.9 2.1-2.4 5 4.11999 4.9-5.4 3-3.8 2.0-2.3 6.3 4.1AtlantaAirQualityData(from 3monitorsin 20counties)2000 4.9-5.4 3.0-3.8 1.5-1.8 4.6 3.2Mann et al., 2002CA 1988-1995 IHD 2 - 22 2.07* 1.3-15.9 16.5-32 11.6-23.41988 4.0-31.0 1.4-14.6 1.2-10.9 32 23.41989 2.0-22.0 2.0-10.1 1.7-6.9 28 18.31990 4.0-22.0 1.6-11.7 1.3-7.8 23 15.91991 2.0-21 2-10.7 2.0-8.7 29 15.71992 2.0-21.0 1.0-8.1 1.0-9.6 25 16.41993 2.0-19.0 1.1-7.6 1.1-8.0 20 13.81994 2.1-14.5 1.1-10.2 1.1-8.9 20.8 16CaliforniaAirQualityData(from 31monitorsin 4counties)1995 1.5-11.6 1-6.7 1.0-7.6 16.5 11.6Linn et al., 2000CA 1992-1995 MI 1.5* 1.1-8.3 16.5-25 11.6-16.4Table legend.This table presents information from key studies finding associations with coronary heart disease (ISA, section 5.2.3, Figure5-2). The health outcomes evaluated include hospitaladmissions for ischemic heart disease (IHD) and myocardial infarction (MI). The 99thpercentile (in ppm) of the CO concentration for the specific study metrics (i.e.,1-, 8-hour daily maximum, or24-hour average) were derived from AQS data for monitors in the study areas during the study period. Design values are valuesof CO concentration in the statistical form of the standard;presented here is the range of 2ndhighest 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 and timeperiods 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 Cite2-30Table 2-4.Air quality information for key U.S. epidemiological studiesof hospital admissions for CVD (ISA, Figure 5-5).11-hour DailyMaximum(ppm)8-hour DailyMaximum (ppm)24-hour Average(ppm)Design Values (ppm)for Study AreasDuring Study PeriodStudy Area Study PeriodHealthOutcomemean99thpercentilemean99thpercentilemean99thpercentile1-hour 8-hourBell et al., 2009126 urbancounties1999-2005 CVD 65+ 1.3* 1.2-22.1 17.5-33.5 8.8-24.3Tolbert et al., 2007 Atlanta 1993-2004 CVD 1.6* 5.3-5.4 3.5-16.3 2.5-5.3For 1993-2000, see Table 2-2 above2001 3.8-4.1 2.4-3.0 1.8-1.9 5.3 4.12002 4.2-4.3 2.2-2.5 1.5-1.6 4.6 3.62003 2.6-3.3 2-2.1 1.2-1.7 3.5 2.5Atlanta Air QualityData (3 monitorsin 20 counties)2004 2.9 2 1.5 4.6 2.5Linn et al., 2000 CA 1992-1995 CVD 1.5* 1.1-8.3 16.5-25 11.6-16.4Table legend. This table presents information from key studies finding associations with CVD (ISA , section 5.2.3, Figure 5-5). The healthoutcomes evaluated in these studiesinclude hospital admissions for cardiovascular disease (CVD; Bell et al (2009) only included subjects 65 years old and above),with the associated risk estimates, unadjusted forother pollutants. The 99thpercentile (in ppm) of the CO concentration for the specificstudy metrics (i.e.,1-, 8-hour daily maximum, or 24-hour average)were derived from AQS datafor monitors in the study areas during the study period. Designvalues are values of CO concentration in the statistical formof the standard; presented here is the range of 2ndhighest 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 and time periods of thestudies).* CO concentrations for the study metricas reported by the study authors.2March 2010 Draft – Do Not Quote or Cite 2-31 In summary, although there is no new evidence regarding lower COHb levels associated 1 with effects, the evidence is much e xpanded with regard to epidemiological 24 analyses of 2 ambient monitor concentrations, which observed associations between specific and overall 3 cardiovascular-related outcomes and ambient CO measurements. With regard to extending our 4 understanding of effects occurring below levels of CO observed in the clinical studies, however, 5 the epidemiological evidence for CO is somewhat limited. The epidemiological evidence lacks 6 measurements of COHb or pers onal exposure concentra tions that would faci litate integration 7 with the clinical data. Furthermore, as discus sed above, the full epidemiological evidence base 8 for IHD outcomes or CVD outcomes as a whole includes a number of studies involving 9 conditions in which the current standard was not met. Though these studies are informative to 10 consideration of the relationship of health effects to the full range of ambient CO concentrations, 11 they are less useful to informing our conclusions regarding adequacy of th e current standards. 12 Consideration of the sma ller set of studies under conditions wh ere the current standards were met 13 is considered to better inform our consideration of the adequacy of the standards or conditions of 14 lower ambient concentrations. Among the few studies for IHD or CVD outcomes under 15 conditions where the current stan dards were met, one study repor ted statistical significance for 16 IHD or CVD outcomes, and all of these studies ar e limited to a single stu dy area (i.e. Atlanta). 17 These limitations lessen the weight we give th ese studies for our purposes here in making 18 interpretations with regard to ambient concen trations of CO that may be eliciting health 19 outcomes, particularly in light of the availabi lity of strong evidence from controlled human 20 exposure studies. Therefore, with regard to this question of CO concentrations we have 21 primarily focused our consideration of the epidem iological studies on the extent to which this 22 evidence is consistent with and generally suppor tive of conclusions drawn from the combined 23 consideration of the c ontrolled human exposure evidence with estimates from the exposure and 24 dose assessment (section 2.2.2 below). As in the pr evious review, we belie ve the integration of 25 the controlled human exposure evidence with the exposure and dose estimates will be most 26 important to informing conclusions regarding ambient CO concentratio ns of public health 27

concern. 28

 To what extent have important uncertaint ies identified in the last review been 29 reduced and/or have new uncertainties emerged? 30
Since the time of the last re view, some important uncertainti es have been reduced, some 31 still remain and others associated with newly av ailable evidence have been identified. A range 32

24 Few epidemiological studies that had investigated the relationship between CO exposure and ischemic heart disease were available at the time of th e last review (USEPA, 1991, section 10.3.3).March 2010 Draft – Do Not Quote or Cite 2-32 of important uncertainties were identified in a nu mber of areas at the time of the last review (59 1 FR 38913, USEPA, 1992), including: 2

 The adverse nature and significance of the small changes in ST-segment depression 3 identified at the lowest COHb levels inve stigated in the controlled human exposure 4 studies, and the magnitude of risk associated with such changes for specific health 5 outcomes, such as myocardial infarction, or of slight but cumu lative myocardial 6 damage, among other possibilities. 7

 The extent to which COHb measurements made using CO-Ox do not reflect COHb 8 levels in angina patients studi ed and the potential for as ye t unidentified health effects 9 at COHb levels below 2%. 10

 The potential for short-term peak CO expos ures to contribute to CNS effects which 11 might affect individual’s perf ormance of complex activities su ch as driving a car or to 12 contribute to other effects of concern. 13

 Effects of ambient CO on potentially sus ceptible populations other than those with 14 cardiovascular disease, incl uding the developing fetus. 15

 Modeling of COHb formation associated with exposures to ambien t CO under different 16 air quality conditions, includi ng those associated with at tainment of different NAAQS. 17 As discussed below, some of these uncertainties have been reduced, while some still remain. 18 The CO-induced effects considered of concern at the time of the last review were reduced 19 time to exercise-induced angina and ST-segment depression in patients suffering from coronary 20 artery disease as a result of increases in COHb associated w ith short CO exposures. These 21 effects had been well documented in multiple studies, and it was r ecognized that the majority of 22 cardiologists at the time believed that recurrent exercise-induced angina was associated with 23 substantial risk of precipitating myocardial infa rction, fatal arrhythmia, or slight but cumulative 24 myocardial damage (USEPA, 1992, p. 22; 59 FR 38911; Basan, 1990; 1991 AQCD). As at the 25 time of the last review, although ST-segment depr ession is a recognized in dicator of myocardial 26 ischemia, the exact physiological significance of the observed changes among individuals with 27 CAD is unclear (ISA, p. 48). 28 In interpreting the study results at the time of the last review, EPA recognized uncertainty 29 in the COHb measurements made using CO-Ox and associated uncertainty in establishing a 30 lowest effects level for CO (USEPA, 1992, p. 31). A multicenter then-recent study (Allred et al., 31 1989a, 1989b, 1991) was of great importance at that ti me for several reasons including the large 32 number of subjects used, the rigor ous protocol used for subject selection, the us e of the most 33 accurate method to measure blood COHb levels and the finding of a dose-response relationship 34 between COHb levels and the is chemic events evaluated in the study. This study reported 35 changes in post-exercise ST-segment depression and reduced time to onset of exercise-induced 36 angina as a result of increases in COHb from a mean baseline of 0.6% to mean levels of 2% and 37March 2010 Draft – Do Not Quote or Cite 2-33 3.9% (ISA, section 5.2.4; (Allred et al., 1989a,19 89b, 1991). In the current review of the 1 evidence related to cardiovascular effects associ ated with CO exposure, the we place primary 2 emphasis on the findings of Allred et al. (1989a , 1989b, 1991) recognizing the superior quality of 3 the study, both in terms of the rigorous study design as well as the sensitivity of the analytical 4 methods used in determining COHb concentratio ns (ISA, Section 2.7). No additional clinical 5 studies are available that evalua te responses to lower COHb leve ls in the cardiovascular-disease 6 population, and uncertainties still re main in determining specific and quantitative relationships 7 between the CO-induced effects in these studie s and the increased risk of specific health 8 outcomes. Further, with regard to then uniden tified effects at lower COHb levels, no studies 9 have identified other effects on the CAD population or on other populations at lower exposures 10 (ISA, sections 5.2.2). 11 The last review recognized a variety of neurobehavioral e ffects associated with CO 12 exposure, including changes in visual perception, hearing, mo tor performance and vigilance 13 among other measures of neurobehavioral perfor mance based on a series of studies conducted 14 from the mid 1960’s through the early 1990’s (1991 AQC D). Since these effects were observed 15 at exposures to CO resulting in COHb levels ranging from 5-20%, and were poorly understood at 16 the time (1991 AQCD), the review focused on card iovascular effects, which had been observed 17 at COHb levels below 5% and consequently fo r which a focus would also provide adequate 18 protection against potential adve rse neurobehavioral effects. No new human clinical studies 19 have evaluated CNS or behavioral effects of exposure to CO (ISA, section 5.3.1). However, 20 given the drastic reduction in CO ambient concentrations, the o ccurrence of these effects in 21 response to ambient CO would be expected to be rare within the curren t population. Thus, our 22 uncertainty with regard to the pot ential for such effects to be a ssociated with current ambient CO 23 exposures is reduced. 24 At the time of the last revi ew, the developing fetus was reco gnized as having the potential 25 to be particularly vulnerable to the effects of CO exposures because human fetal development 26 often occurs at or near cr itical tissue oxygenation levels (Longo, 1977; 59 FR 38911; USEPA, 27 1992, p. 25). The human data at the time of the last review consisted of a limited set of studies 28 primarily considering the effects of maternal ci garette smoke in the developing fetus, many of 29 them conducted at very high exposure levels (500-1000 ppm). The effects observed included 30 spontaneous abortion and death due to decreased birth weight. Additional animal toxicological 31 studies, also conducted at CO con centrations higher than the am bient CO levels at the time, 32 provided suggestive evidence of fetal mort ality, teratogenicit y, reduced body weight, 33 morphological changes, altered ca rdiovascular development and neurochemical changes. Since 34 the last review, the epidemiologic and toxico logical evidence of effects on birth and 35 developmental outcomes has somewhat expa nded, although the availabl e evidence is still 36March 2010 Draft – Do Not Quote or Cite 2-34 considered limited with regard to effects on pr eterm birth, birth defects, decreases in birth 1 weight, measures of fetal growth, and infant mo rtality. Although there ar e animal toxicological 2 studies providing support and cohe rence for those effects, the unde rstanding of the mechanisms 3 underlying reproductive and developmental effects is still la cking (ISA, section 5.4.1). Thus, 4 although the evidence continues to “suggest[s] th at critical developmental phases may be 5 characterized by enhanced sensi tivity to CO exposure” (ISA, p. 2- 11), evidence is still lacking on 6 the potential for adverse effect s on birth and developmental outcomes at CO exposures near 7 those associated with current leve ls of ambient CO. As a result unc ertainty still remains in this 8

area. 9 Numerous improvements have been made over the last decade that have reduced the 10 uncertainties associated with the models used to estimate COHb levels resulting from ambient 11 CO exposures under different air qu ality conditions, including those associated with just meeting 12 the current CO NAAQS (draft REA, secti on 4.3). This progression in exposure model 13 development has led to the Agency’s currently used model (APEX4.3) that has an enhanced 14 capacity to estimate population CO exposures and more accurately predicts COHb levels in 15 persons exposed to CO. Our application of AP EX4.3 to the current situ ation, using updated data 16 and new algorithms to estimate exposures a nd doses experienced by individuals, better 17 represents the variability in population exposure and COHb dose levels. However, while APEX 18 4.3 is greatly improved when compared with previ ously used exposure mode ls, its application is 19 still limited with regard to data to inform our understanding of spatial relationships in ambient 20 CO concentrations and within microenvironments of particular interest . Further information 21 regarding model improvements and remaining expos ure modeling uncertainties are described in 22 section 2.2.2 below. 23 In the current review, we continue to rec ognize coronary artery disease as the most 24 important susceptibility characteristic for incr eased risk due to CO exposure (ISA, p. 2-10). 25 While a much expanded epidemiologic database inclusive of studies showing associations 26 between ambient CO monitor c oncentrations and increases in emergency room visits and 27 hospitalizations for ischemic hear t disease events suppor t this conclusion, a va riety of associated 28 uncertainties complicate the inte rpretation of these studies. A lthough CO associations generally 29 remain robust in copollutant models (ISA, Figures 5-6 and 5-7, section 2.7), disentangling a CO30 specific effect at low ambient concentrations from other pollutants remains of concern, 31 particularly for the quantitative interpretation of th ese studies. The potential for CO to act as a 32 surrogate for another combustion related pollutant included in a copollutant statistical model 33 “complicates quantitative interpretation of the effect estimates reported in epidemiologic studies” 34March 2010 Draft – Do Not Quote or Cite 2-35 (Tolbert 2007; ISA, p. 2-16). 25 Moreover, as recognized by CASAC, “the problem of co1 pollutants serving as potential confounders is particularly problematic for CO” and “a better 2 understanding of the possible role of co-polluta nts is relevant to regulation ... on the health 3 effects of CO” (Brain and Samet, 2010). Erro r in the assessment of personal CO exposure 4 through the use of fixed site-monitors measuring CO levels at or below the limit of detection of 5 the monitor is a new source of uncertainty since th e prior review due to an overall decrease in 6 ambient CO concentrations. This error may lead to an over or underestima tion of CO health risk 7 estimates. Thus, some uncertainties associated with the epidemiological evidence “complicate 8 the quantitative interpretation of the epidemiologi c findings, particularly re garding the biological 9 plausibility of health effects oc curring at COHb levels resulti ng from exposures to the ambient 10 CO concentrations” assessed in these studies (ISA, p. 2-17). 11
In summary, some important uncertainties fr om the last review have been reduced, 12 including those associated with concerns for ambien t levels of CO to pose neurobehavioral risks. 13 A variety of uncertainties still remain including the adverse nature and significance of the small 14 changes in ST-segment depression identified at the lowest COHb levels investigated, and the 15 magnitude of associated risk of specific health outcomes, as well as the potential for as yet 16 unidentified health effects at COHb levels be low 2%. Additionally, a lthough the evidence base 17 is somewhat expanded with regard to the pot ential for CO effects on the developing fetus, 18 uncertainties remain with regard to this poten tial susceptibility. Our exposure and dose models 19 have improved giving us increased confidence in th eir estimates. We additionally recognize that 20 the expanded body of epidemiological evidence in cludes its own set of uncertainties which 21 complicates its interpretation. 22

2.2.2 Exposure/Risk-based Considerations 23 Our consideration of the scientific evidence in the current review, as at the time of the 24 last review (summarized in section 2.1.1 above), is informed by results from a quantitative 25 analysis of estimated population exposure and resulta nt COHb levels. As in our consideration of 26 the evidence in section 2.2.1 above, we have or ganized the discussion that follows here around a 27 set of key questions to assist us in drawi ng from the draft assessment of CO exposure and 28 resultant COHb levels for at-risk populations living in two cities under current air quality 29

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 conditions and conditions simulated to just meet the current CO standards. These questions are 1 intended to inform consideration of the following overarching question. 2 Prior to addressing the series of questions below, we pr ovide a description of the 3 modeling tools used in and the design of the a ssessment, the magnitude of COHb levels. We 4 then consider the question rega rding the size of the simulated at-risk population estimated to 5 experience COHb levels of interest, followed by th e identification of key uncertainties associated 6 with our assessment of exposure and dose with rega rd to drawing conclusions as to the adequacy 7 of the protection afforded by the current CO stan dards. We then consider the exposure and dose 8 estimates from the quantitative assessment with rega rd to implications as to the extent of the 9 population provided protection from COHb levels of concern under the current standards to help 10 inform judgments about the extent to which such estimates may be judged to be important from a 11 public health perspective. 12 In the draft assessment conducted for this revi ew, described in detail in the draft REA and 13 summarized here, we have estimated CO exposur e and associated COHb levels in simulated 14 populations in two urban study areas in Denver and Los Angeles, in which current CO 15 concentrations are below the current standards. We selected these areas because: (1) both cities 16 have been included in prior CO NAAQS exposure assessments and thus serve as an important 17 connection with past assessments ; (2) historically, they have generally had the highest CO 18 ambient concentrations among urban areas in the U.S.; and (3) Denver is at high altitude and 19 represents an important risk scen ario due to the potent ial increased susceptibility to CO exposure 20 associated with high altitudes. In addition, of 10 urban areas across the U.S. selected for detailed 21 analysis in the ISA and having monitors meetin g a 75% completeness criteria, the two locations 22 were ranked first (Los Angeles) and second (D enver) regarding the percentage of elderly 23 population within 5, 10, and 15 km of monitor locations, and ranked first (Los Angeles) and fifth 24 (Denver) regarding number of 1- and 8-hour daily maximum CO concentration measurements 25 (ISA, section 3.5.1.1). 26 Estimates were developed for exposures associ ated with current “as is” conditions (2006 27 air quality) and also for higher ambient CO concen trations associated with air quality conditions 28 simulated to just meet th e current 8-hour standard. 26 In considering the adequacy of the current 29 standard, it is important to note th at over the last few years, th e standard has been met throughout 30 the country with few exceptions. 27 Although we consider it unlikel y that air concentrations in 31 many urban areas across the U.S. that are curre ntly well below the current standard would 32

26 As discussed elsewhere, the 8-hour stan dard 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 increase to just meet the standa rd, we also recognize the potential for CO concentrations in some 1 areas currently below the standard to increase to just meet the standar d. Accordingly, we have 2 simulated conditions of increased CO concentrations that just m eet the current standard in the 3 two study areas. In this scenari o, we note there is uncertainty a ssociated with simulating this 4 hypothetical profile of higher CO concentratio ns that just meet the current standard. 5 The exposure and dose modeling, presented in detail in the draft REA, relied on EPA’s 6 Air Pollutant Exposure model (APEX4.3), which estimates human exposure using a stochastic, 7 event-based microenvironmental approach. This model has a history of application, evaluation, 8 and progressive model development in estima ting human exposure and dose for several NAAQS 9 reviews, including CO, O 3 , NO 2 , and SO 2 . As mentioned above, we have made major changes to 10 the exposure modeling approach used in the la st CO review. The pr ior review relied on 11 estimated population exposure and dose generated from pNEM, a model that 1) employed a 12 cohort-based approach, 28 2) relied on a limited set of activ ity pattern data (approximately 3,600 13 person-days) 3) used four broadly defined categ ories to estimate breathi ng rates (i.e., slow14 sleeping, slow-awake, medium, and fast), and implemented a geodesic distance range 15 methodology to approximate workplace commutes (Johnson et al., 1992; USEPA, 1992). Each 16 of these approaches used by pNEM, while appropri ate given the data availa ble at the time would 17 tend to limit the ability to accura tely model the lower and upper tails of the population exposure 18 distribution. In contrast, APEX 4.3 includes new algorithms to 1) simulate activity sequences and 19 exposure profiles for individuals, 2) estim ate activity-specific minute-by-minute oxygen 20 consumption and breathing rates, 3) address spatial va riability in home and work-tract ambient 21 concentrations for commuters, and 4) estimate ev ent-based microenvironmental concentrations. 22 APEX also uses additional data available fr om recent activity pattern surveys (CHAD now has 23 about 34,000 person-days of data) and uses th e most recent US censu s data to represent 24 population demographics and home-to-workplace commutes. Modeling the prevalence of 25 exposures or dose in a population of interest (suc h as individuals with coronary heart disease) 26 has also been enhanced in APEX with the addi tion of output tables pr esenting statistics for 27 identified subpopulations and age groups (or life stages), using the updated census population 28 demographic data, and including options for appr oaches used to estimate microenvironmental 29 concentration. 30

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 neces sarily reflecting diffe rences 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 APEX probabilistically generates a sample of hypothetical indivi duals from an actual 1 population database and simulate s each individual’s movements through time and space (e.g., 2 indoors at home, inside vehicles ) to estimate his or her exposur e to a pollutant. Population 3 characteristics are taken into ac count to represent the demographi cs of each study area. With 4 regard to age and gender demographics for the simulated at-risk population (adults with 5 diagnosed and undiagnosed CAD), we augmented es timates of the prevalence of CAD provided 6 by the National Health Interview Su rvey with estimates of undiagnos ed ischemia that were based 7 on two assumptions: (1) there are 3.5 million pe rsons in U.S. with undiagnosed IHD (drawn 8 from an estimate by the American Heart Associ ation) and (2) persons with undiagnosed IHD are 9 distributed within the p opulation in the same manner as persons with diagnosed IHD (draft REA, 10 section 5.5.2). Based on expos ure concentrations, minute-by- minute activity levels, and 11 physiological characteristics of th e simulated person (see draft REA, chapters 4 and 5), APEX 12 estimates the level of COHb in the blood at the end of each hour based on solution to the 13 nonlinear Coburn-Forster-Kane equa tion (draft REA, section 4.4.7). 14 APEX simulations performed for this review have focused on exposures to ambient CO 15 occurring in eight microenvironments, with no ad ditional contribution from indoor CO sources. 16 We note that, where present, indoo r sources, including gas stoves and tobacco smoke can also be 17 important contributors to total CO exposure and may be of concern for at-risk populations. 18 Some assessments performed previously have included modeling simu lations both with and 19 without certain indoor sources a nd these assessments provide c ontext for the assessment of 20 ambient CO exposure and dose. For example, a 2000 exposure/dose assessment indicated that 21 the impact of such sources can be substant ial on the portion of the population experiencing 22 higher exposures and COHb levels (Johnson et al., 2000). In the last review it was noted that 23 while these indoor sources were shown to contri bute to total CO exposur e they would not be 24 effectively mitigated by setting more stringent ambient air quality standards (59 FR 38914). In 25 the current review, model simulations have not included indoor sources. 26 As discussed in the previous section (Section 2.2.1), people with cardiovascular disease 27 are the population of primary focus in this review . Further, based on the available evidence in 28 the current review, coronary artery disease, al so known as coronary hear t disease is the “most 29 important susceptibility characteristic for incr eased risk due to CO e xposure” (ISA, p. 2-11). 30 Controlled human exposure studies have provi ded specific quantitative COHb dose-response 31 information for this specific population with regard to effects on ma rkers of myocardial 32 ischemia. In identifying COHb levels associated with specific effects for CAD patients, we have 33 given primary focus to the multi-laboratory st udy in which COHb was analyzed by the more 34 accurate GC method (Allred et al., 1989a, 1989b, 1991) . Specifically, this study has documented 35 reductions in times to exercise-induced change in the ST-segment of an electrocardiogram and to 36March 2010 Draft – Do Not Quote or Cite 2-39 exercise-induced onset of angina, observed in response to CO exposures involving subjects with 1 pre-existing CAD, as descri bed in section 2.2.1 above. 2 Studies have not been designed to evaluate similar effects at CO exposure eliciting COHb 3 levels below this range. In addition, these st udies do not address the fraction of the population 4 experiencing a specified health effect at vari ous dose levels. These aspects of the evidence 5 contributed to EPA’s conclusion that there are currently insuffi cient controlled human exposure 6 data to support the developmen t of quantitative dose-response relationships which would be 7 required in order to conduct a qua ntitative risk assessmen t for this health e ndpoint, rather than a 8 benchmark level approach. Further, based on th e current evidence with regard to quantitative 9 information of COHb levels and association with specific health effects, the primary target 10 population for purposes of the quantitative asse ssment is adults with CHD (also known as 11 ischemic heart disease IHD or CAD), both diagnosed and undiagnosed. 29 Evidence 12 characterizing the nature of speci fic health effects of CO in ot her populations is limited and does 13 not include specific COHb levels related to hea lth effects in those groups. As a result, the 14 quantitative assessment does not develop separate quantitative dose estimates for populations 15 other than those with CAD. 16 We have reviewed COHb estimates developed in the draft REA for the simulated at-risk 17 population with attention to both COHb in absolute terms and based on consideration of the 18 contribution associated with ambient CO exposur es. For purposes of the review of COHb in 19 absolute terms, we identified benchmark leve ls of 1.5%, 2.0%, 2.5% and 3% COHb. Selection 20 of this range of benchmark levels is based on consideration of the ev idence from controlled 21 human clinical studies of CAD patients (discusse d in section 2.2.1 above). This range includes 22 the range of COHb levels identified as levels of concern in the review completed in 1994 (2.0 to 23 2.9%) and the level given particular focus (2.1% ), as described in section 2.1.1 above (USEPA, 24 1992; 59 FR 48914). The range of benchmark levels identified here exte nds below the lowest 25 mean COHb level (e.g., 2.0% post-ex ercise in Allred et al., 1989b) resulting from controlled 26 increased exposure to CO in the clinical evidence . The extension of this range reflects a number 27 of considerations, including: (1) comments from the CASAC CO panel on the draft Analysis 28 Plan (Brain, 2009); (2) c onsideration of the un certainties regarding th e actual COHb levels 29 experienced in the controlled human exposure stud ies; (3) that these st udies did not include 30 individuals with most seve re cardiovascular disease 30 ; (4) the lack of studies that have evaluated 31

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 mo st 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 effects of experimentally contro lled short-term CO exposures re sulting in mean COHb levels 1 below 2.0-2.4%; and (5) the lack of evidence of a threshold at the increased COHb levels 2 evaluated. We note that CASA C comments on the first draft RE A recommended the addition of 3 a benchmark at 1% COHb and we have presented results for this COHb le vel in the second draft 4 REA. Given that this level overlaps with the upper part of the range of endogenous levels in 5 healthy individuals as characteri zed in the ISA (ISA, p. 2-6) and is within the upper part of the 6 range of baseline COHb levels in the study by Allred et al (1989b, A ppendix B), however, we 7 considered that it may not be appropriate to place weight on it as a pot ential health effects 8 benchmark level and accordingly has not focu sed on dose estimates for it in the discussion 9 below. Additionally, in considering contribu tions to COHb associated with ambient CO 10 exposures, we recognize the findings of Allredet al (1989a, 1989b, 1991) with regard to a dose11 response relationship for decreases in time to ex ercise-induced angina and ST-segment change 12 per 1% increase in COHb concentration in pe rsons with pre-existing CAD (ISA, section 5.2.4; 13 Allred et al., 1989a, 1989b, 1991). In consider ing COHb estimates from the quantitative 14 assessment below, we take note of estimates of endogenous COHb levels from the quantitative 15 exposure and dose analysis which indicated that in the absence of ex ternal CO sources, 16 approximately 1.5% of the simulated at-risk population in one of th e two populations was 17 estimated to experience maximum end-of-hour e ndogenous COHb levels at or above 1% (draft 18 REA, section 6). 19 The benchmark levels identified are used to in terpret COHb levels estimated to occur in 20 the modeled population in response to exposures to ambient CO in different air quality scenarios 21 in light of the evidence for cardiovascular effect s in individuals with CHD when exposed to CO. 22 Specifically, in considering the exposure and dose es timates with regard to consideration of the 23 adequacy of the current standards here, we fo cus on estimates of the portion of this at-risk 24 population estimated to experience maximum end-of-hour COHb levels above these 25 benchmarks, and on information concerning th e COHb increment above endogenous levels 26 associated with ambient CO exposures. 27

 What is the magnitude of at-risk populat ion COHb levels estimated to occur in 28 areas simulated to just meet the current CO standards? What portion of the at29 risk population is estimated to experien ce maximum COHb levels above levels of 30 potential health concern? 31 In addressing this question, we consider the population COHb estimates provided by the 32 draft REA (draft REA, section 6.2) and summarized in Tables 2-5 and 2-6 below. These tables 33 include estimates associated with current “as is” conditions and c onditions simulated to just meet 34 the current standard. In considering these estimat es, we particularly focus on the extent to which 35 the current standards provide protection to the s imulated at-risk population from COHb levels of 36March 2010 Draft – Do Not Quote or Cite 2-41 potential concern, by comparing th e estimated levels in the popul ation to the potential health 1 effect benchmarks described above. As desc ribed above, the draft REA estimates of COHb 2 reflect the impact of exposures to ambient CO in addition to indi vidual endogenous levels (draft 3 REA, section 6.4). 4 Under “as is” conditions in the two study areas, fewer than 0.1 % and 2% of the 5 simulated at-risk population are estimated to expe rience an end-of-hour C OHb concentration at 6 or above 2% and 1.5%, respectively, with the re sults for the Los Angeles study area including 7 slightly larger portions of the population above these benchmarks than that estimated for the 8 Denver study area. Under conditions with higher am bient CO concentrations that just meet the 9 current 8-hour standard, the porti on of the simulated at-risk population estimated to experience 10 these levels of COHb is greater. But for th ese simulations, the relationship between the two 11 study areas is reversed with the Denver study area having higher COHb levels. In the Denver 12 study area 3.4% of the simulated at-risk populati on is estimated to experience a maximum end13 of-hour COHb level at or above 2%, while 19% of the population is estimated to experience a 14 maximum COHb level at or above 1.5%. For th e Los Angeles study area, less than 1% and 5% 15 of the population was estimated to experience maximum end-of-hour COHb levels at or above 16 2% and 1.5%, respectively (Table 2-5). 17

Table 2-5. Portion of simulated at-risk populat ion with maximum end-of-hour COHb 18 levels at or above the indicated leve l under air quality conditions simulated to 19 just meet the current standards and under “as is” (2006) conditions. COHb 20 levels reflect endogenous levels and ambient CO exposures. 21

Percentage (%) of Simulated At-risk Population
Just meeting current stan dards “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%
22March 2010 Draft – Do Not Quote or Cite 2-42  What are the key uncertainties associated with our exposure and dose estimates, 1 including those of particular significance with regard to drawing conclusions as to 2 the adequacy of the protection afforded by the current CO standards? 3 In considering the uncertaintie s associated with the quantitative estimates of exposure 4 and dose from the draft REA, we relied on an ap proach intended to identify and compare the 5 relative impact that important sources of uncerta inty may have on the estimated potential health 6 effect endpoints (i.e., estimates of the maximum end-of-hour COHb levels in the simulated at7 risk population). The approach used (as descri bed in section 7.2 of the second draft REA) was 8 developed using guidelines outlining how to c onduct a qualitative uncerta inty characterization 9 (WHO, 2008) and applied in the most recent NO 2 (US EPA, 2008b) and SO 2 NAAQS reviews 10 (US EPA, 2009). We employed the mainly qualita tive approach given the extremely limited data 11 available to inform probabilistic analyses. The qualitative approach used varies from that of 12 WHO (2008) in that a greater focus of the ch aracterization performed was placed on evaluating 13 the direction and the magnitude of the uncertainty; that is, qualit atively rating how the source of 14 uncertainty, in the presence of alternative information, may aff ect the estimated exposures and 15 health risk results. In addition and consistent with the WHO (2008) guidance, we discuss the 16 uncertainty in the knowledge-base (e.g., the accuracy of the data used, acknowledgement of data 17 gaps) and decisions made where possible (e.g., selection of particular model forms), though 18 qualitative ratings were assigned only to uncertainty regarding the knowledge-base. 19 In the characterization of uncertainty for the current analysis, we identified and evaluated 20 fourteen separate sources of uncertainty a ssociated with four ma in components of the 21

assessment: 22

 Ambient monitor CO concentrations 23

- database quality, spatial and tempor al representation, and missing data 24 substitution; 25

 Adjustment of air quality to simulate just meeting the current and potential alternative 26 standards 27

- historical data used, pro portional approach used; 28

 APEX inputs and algorithms 29

- population database, activity pattern data base, longitudinal profile algorithm, 30 meteorological data, micrenvironmenta l algorithm and input data, commuting 31 algorithm, CHD prevalence, physiological factors; and, 32

 Potential health effects benchmark leve ls for the simulated at-risk population. 33
34March 2010 Draft – Do Not Quote or Cite 2-43 By comparing judgments made regarding the magnitude and direction of influence the 1 identified sources have on estimated exposure concentrations and dose levels and the existing 2 uncertainties in the knowledge-base, we identifie d six sources (i.e., the spatial and temporal 3 representation, historical data used, activity pattern database, longitudinal profile algorithm, 4 microenvironmental algorithm and input data, and phys iological factors) that remain as the most 5 important uncertainties in this assessment. Ta king into consideration improvements in the model 6 algorithms and data since the last review, and having identified and characterized these 7 uncertainties here, we conclude that the estima tes associated with the current analysis, at a 8 minimum, better reflect the full distribution of ex posures and dose as compared to results from 9 the 1992 analysis. When considering the overa ll quality of the curr ent exposure modeling 10 approach, the algorithms, and input data us ed, alongside the iden tified limitations and 11 uncertainties, we conclude that the quantitative assessment provides reasonable estimates of CO 12 exposure and COHb dose for the simulated popula tion the assessment is intended to represent 13 (i.e., the population residing within the urban co re of each study area). We note somewhat 14 greater uncertainty in characterizing of the ends of the distribution of population exposures. 15

 To what extent are the estimates of at-risk population COHb levels under 16 conditions just meeting the current CO standards important from a public health 17 perspective? 18 In considering the public health implications of the quantitative dose estimates, we first 19 note the size of the at-risk population simulated in the draft REA, people with CAD, both 20 diagnosed and undiagnosed. This po pulation is recognized as that most susceptible to increased 21 risk of CO-induced health effects (ISA, s ections 5.7.1.1 and 5.7.8). The 2007 estimate from the 22 National Health Interview Survey (NHIS) perfor med by the U.S. Centers for Disease Control of 23 the size of the U.S. population with coronary hear t disease, angina pector is (cardiac chest pain) 24 or who have experienced a heart attack (ISA, Table 5-26) is 13.7 million people (ISA, pp.5-117). 25 Further, there are estimated to be three to four million additional people with silent ischemia or 26 undiagnosed IHD (AHA, 2003). In combination this represents a large population represented 27 by the draft REA analyses and for which the COHb benchmarks described above (based on 28 studies of CAD patients) are rele vant, that is more susceptible to ambient CO exposure when 29 compared to the general population (ISA, section 5.7). 30 As discussed above, the draft REA estimates that 0.5 percent of the Los Angeles and 31 3.4% of the Denver study CHD populations may e xperience maximum end-of-hour COHb levels 32 of the same magnitude as the average COHb leve l resulting for the lower experimental exposure 33 group in the study by Allred et al. (1989a, 1989b, 1991) which resulted in a statistically 34 significant reduction in the time to exercise-induced markers of myocardial ischemia (angina and 35 ECG ST-segment change) of 4-5% on average. While recognizing that the exposure resulting in 36March 2010 Draft – Do Not Quote or Cite 2-44 the 2% average COHb level asso ciated with this result was significantly over background (e.g., 1 approximately 1 hour at 50-200 ppm CO as compared to 0-2 ppm c linic air concentrations), we 2 also note the dose-response relationship was summ arized by the authors as indicating decreases 3 of roughly 1.9% in time to exercise-induced a ngina and 3.9% in time to exercise-induced ST4 segment change per 1% increase in COHb concen tration in persons with pre-existing CAD, as 5 discussed in section 2.2.1 above (ISA, section 5.2.4; Allred et al., 1989a,1989b, 1991). 31 As 6 noted in the ISA, the physiological significan ce of the observed ST-segment changes among 7 individuals with CAD is unclear and variability in severity of disease among individuals with 8 CAD is likely to influence the critical level of COHb which leads to adverse cardiovascular 9 effects (ISA, p. 2-6). 10 In addition to the population with diagnosed and undiagnosed CAD, we note implications 11 with regard to risk to people with other fo rms of CVD, which we recognize as potentially 12 susceptible (ISA, section 2.6.1). For example, NHIS estimates for 2007 indicate there are 13 approximately 12 million additional people with othe r types of heart disease (ISA, Table 5-26). 14 Within this broad group, implications are more significant for those includ ed in this population 15 for which their disease state aff ects their ability to compensate for the hypoxia-related effects of 16 CO (ISA, section 4.4.4). 17 Other potentially susceptible popu lations to the effects of CO include people with chronic 18 obstructive pulmonary disease, diabetes and anem ia, as well as older adults and fetuses during 19 critical phases of development (as discussed in section 2.2.1 above). In considering potential 20 impacts on such populations, however, we recognize limitations in the evidence in informing us 21 with regard to the specific effects of CO on these populations and, importantly, the exposures 22 and associated COHb levels associated with such effects. 23 In summary, we recognize that conclusions regarding the exte nt to which the estimates of 24 exposure and COHb associated with just meetin g the current standard are important from a 25 public health perspective depend in part on public health policy judgments about the significance 26 of effects at the COHb benchmark levels cons idered and judgments about the level of public 27 health protection with an adequate margin of safe ty. For example, we note that these estimates 28 indicate that the current 8-hour standard limits substantially the percent of the population 29 expected to experience maximum COHb levels at or above the higher benchmarks, while 30 limiting much less so the percen tage of the population with ma ximum COHb levels above the 31

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 monitore d 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 lowest benchmarks. Thus, we initially conclude that these estimates provide support for a range 1 of views regarding the importance of these es timates form a public health perspective. 2

2.2.3 Initial Staff Conclusions on Adequacy of the Current Standards 3 In considering the adequacy of the current st andard, staff gives great weight to the long4 standing body of evidence for CO, augmented in so me aspects since the last review, that has 5 established: the common mechan ism of CO health effects as involving binding to reduced iron 6 in heme proteins and the alteration of their functioning; the important role of hypoxia (reduced 7 oxygen availability) induced by increased COHb blood le vels in eliciting hea lth effects; the use 8 of COHb as the bioindicator and dose metric for evaluating CO exposure and potential for health 9 effects; and, people with cardi ovascular disease as a key popu lation at risk from low CO 10 exposures (ISA; 2000 AQCD; 1991 AQCD). We a dditionally recognize the expansion of the 11 epidemiological evidence that provides coherenc e with our conclusions regarding cardiovascular 12 disease-related susceptibility and may (recogniz ing various uncertainties associated with the 13 evidence in the particular case of CO) provide indications of ai r quality conditions associated 14 with ambient CO-related risk, most particular ly in areas during periods which included 15 exceedance of the current 8-hour standard (ISA, section 5.2.1). 16 As at the time of the last review, we give weight to COHb estimates developed from 17 modeling exposures to ambient CO under conditi ons simulated to just meet the current, 18 controlling, 8-hour standard. These COHb esti mates and the incremental contribution from 19 ambient CO exposures are considered in light of the clinical studies. These estimates indicate 20 that some 1-3 percent of the simulated at-ris k population are expected to experience maximum 21 COHb levels of a magnitude for which associa tion has been demonstrated with markers of 22 myocardial ischemia and larger portions of the population may experience maximum COHb 23 levels at or above the lowest benchmark consid ered. Further, in considering public health 24 significance of such estimates, while recognizing uncertainty in the clinical significance 25 associated with the smaller effects observed at the lower COHb levels, we note the substantial 26 size of the at-risk population in the U.S. and the existence of other potentially susceptible 27 populations for which evidence is more limited. 28 In summary, we draw initial conclusions w ith regard to the adequacy of the current 29 standard from both the evidence and from the expos ure and dose assessment, in light of related 30 limitations and uncertainties. We initially conclu de that the combined consideration of the body 31 of evidence and the quantitative exposure and dose estimates provi de support for a standard at 32 least as protective as the current standard. Furt her, we recognize that conclusions regarding the 33 adequacy of the current standard depend in pa rt on public health policy judgments about the 34 significance of effects at the C OHb benchmark levels considered and judgments about the level 35March 2010 Draft – Do Not Quote or Cite 2-46 of public health protection with an adequate margin of safety. Thus, we initially conclude that 1 the combined consideration of the evidence and quantitative estimates described above may be 2 viewed as providing support fo r either retaining or revising the curr ent 8-hour standard. 3 The extent to which the current standard is judged to be adequate or not depends on a 4 variety of factors, inclusive of technical considerations, sc ience policy judgments and public 5 health policy judgments. These include public h ealth policy judgments on the appropriate COHb 6 benchmark levels on which to place weight; judgme nts on the clinical significance of the effects 7 that have been observed at t hose levels; uncertainty associated with interpretation of the 8 epidemiological evidence as providing informati on on ambient CO as distinct from information 9 on the mixture of pollutants associated with traffic, and the weight to place on the 10 epidemiological studies for purposes of considering adequacy of the current standards, given that 11 few are available (in one city) during periods under air quality conditions that did not exceed the 12 current standard; and the weight to place on the re sults of the draft exposure assessment relative 13 to those from past assessments, recognizing th e implementation of a new modeling approach and 14 input data. 15 Staff’s initial conclusions with regard to el ements of revised primary standards for CO 16 that may be appropriate to cons ider are discussed in the followi ng sections. These conclusions 17 are drawn from consideration focused on the 8-h our standard in recogn ition of its role in 18 controlling ambient air quality conditions for CO. We give more specific consideration to each 19 of the two CO primary standards in the discussion of alternative standards in section 2.3 below. 20

2.3 CONSIDERATION OF ALTERNATIVE STANDARDS 21
To the extent that the information available in this review suggests that revision of the 22 current standards is appropriate to consider, staff has consider ed whether the available body of 23 evidence supports consideration of options that are different from the current standard, as 24 articulated by the following overarching question: 25

 To what extent does the currently availabl e scientific evidence- and exposure/risk26 based information, as reflected in the ISA and draft REA, support consideration 27 of alternatives to the current CO standa rds to provide increased protection from 28 ambient CO exposures? 29 To assist us in interpreting the currently av ailable scientific evidence and the results of 30 recent quantitative exposure/risk analyses to addr ess this question, we have focused on a series 31 of more specific questions in sections 2.3.1 and 2.3.2 below. In considering the scientific and 32 technical information, we consider both the inform ation available at the time of the last review 33 and information newly available since the last re view which has been critically analyzed and 34 characterized in the 2000 AQCD and more recently in the ISA. Specifically, we consider how 35March 2010 Draft – Do Not Quote or Cite 2-47 the currently available scientific evidence inform s decisions regarding the basic elements of the 1 NAAQS: indicator, averaging time, level and form. Considerations with re gard to indicator and 2 averaging time are presented in sections 2.3.1 a nd 2.3.2. Form and level are discussed in section 3
2.3.3. 4

2.3.1 Indicator 5
The indicator for carbon monoxi de is carbon monoxide as measured by the federal 6 reference methods and equivalent methods. Unlike several other criteria po llutants, there are not 7 multiple compounds or size fractions of carbon monoxide. Federal reference methods are 8 available that can effectively measure carbon m onoxide, and thus we have not identified any 9 basis for considering an indicator other than carbon monoxide for the standard. 10

2.3.2 Averaging Time 11 In considering potential alternative averagi ng times other than the current 1- and 8-hour 12 averaging times, we consid er the following question: 13

 Do health effects evidence and air qualit y/exposure assessments provide support 14 for considering different exposure indices or averaging times? 15 The averaging times for the current standard s are 1-hour (35 ppm) and 8-hours (9 ppm). 16 These averaging times were first chosen when EPA promulgated the primary NAAQS for CO in 17 1971 (36 FR 8186), and were retained in s ubsequent reviews (1980, 45 FR 55066; 1985, 50 FR 18 37485; and 1994, 59 FR 38906). 19 The 8-hour averaging time was selected pr imarily based on the rationale that most 20 individuals achieve steady-state blood levels of COHb after approximately 8 hours of continuous 21 CO exposure (USEPA, 1979; AQCD 2000, secti on 7.4; ISA, section 4.3.2.2). Another 22 consideration was that the 8-hour time-frame represented a go od basis for tracking continuous 23 exposures during any 24-hour peri od, recognizing that people may be exposed in approximately 24 8-hour blocks of time (e.g., working or sleeping). 25 The 1-hour averaging time primarily reflected consideration of th e potential impact of 26 exposures of 1 hour or shorter, such as very s hort duration peak exposures in urban environments 27 (59 FR 38914). Much of the health evidence, ho wever, is linked to exposures of 1 hour or 28 longer, such as the controlled human studies dem onstrating aggravation of myocardial ischemia 29 after exposure of individuals with coronary artery disease to CO for approximately 1-2 hours. 30 Further, based on consideration of air quality data patterns it wa s recognized that attainment of 31 the 8-hour standard would tend to also limit short- term peaks to levels below those of concern 32 (45 FR 55077). 33March 2010 Draft – Do Not Quote or Cite 2-48 In considering whether the information availabl e in this review supports consideration for 1 different averaging times for the CO standards, we note that the available information is 2 generally consistent with and s upportive of the conclusions reached in the previous reviews to 3 retain the 1- and 8-hour averaging times. 4

 Controlled human exposure studies, with wh ich epidemiological evidence is coherent, 5 provide the clearest evidence of short-term CO-induced eff ects and reflect exposures of 6 1-2 hours (ISA, sections 5.2, 5.2.6.1). 7

 Epidemiological studies provide evidence based on analyses of 1-, 8-, and 24-hour 8 averaging times (ISA, section 5.2.6). 9

 Most individuals would be expected to achie ve steady-state levels of blood COHb after 10 6-8 hours of continuous exposure to a fixed CO concentration. Therefore, 8 hours may 11 reasonably be considered closely represen tative of longer continuous exposures (2000 12 AQCD, section 7.4). 13

 The 1-hour averaging time is considered to provide protection from the occurrence of 14 shorter term peak exposure c oncentrations of ambient CO that may be encountered in 15 some environments, and from COHb levels that may result from such exposures (2000 16 AQCD, section 7.4; ISA, section 2.4.1). 17 Taken together, we initially conclude that th e information available in the current review 18 continues to support the 1- and 8-hour averaging times and does not provide information that 19 would lead to consideration of standa rds with alternative averaging times. 20

2.3.3 Form and Level 21 In considering potential alternative forms and levels for the standards, we focused 22 primarily on form and level for the 8-hour standar d, while also considering form and level for the 23 1-hour standard. In so doing, we addr essed the following overarching question: 24

 What is the range of alternative levels and forms for the standard that are 25 supported by the health effects evid ence and air quality/exposure assessments, 26 and what are the uncertainties and limitatio ns in that health effects evidence and 27 air quality/exposure assessments? 28 In this section, we focus on ge neral considerations with rega rd to form in section 2.3.2.1. 29 We then address specific considerations for both level and form in section 2.3.2.2, first with 30 regard to the 8-hour standard and then with regard to the 1-hour standard. 31

2.3.3.1 Potential Alternative Forms 32 When evaluating alternative forms in conjunction with specific levels, staff considers the 33 adequacy of the public health protection provided by the combination of level and form to be the 34 foremost consideration. In additi on, we recognize that it is prefer able to have a form that is 35 reasonably stable and relatively in sulated from the impacts of ex treme meteorological events or 36March 2010 Draft – Do Not Quote or Cite 2-49 other rare, transitory impacts on air quality. A sta ndard set with a high degree of instability could 1 have the effect of reducing public health protection because shifts in and out of attainment could 2 disrupt an area’s ongoing implementation pl ans and associated control programs. 3 Therefore, consistent with recent reviews of the O 3 , PM and NO 2 NAAQS, we have 4 focused here on a concentration-based form (a s compared with an expected or allowable 5 exceedance-based form) and are considering this with regard to an average over 3 years. As 6 noted in the review of the O 3 NAAQS (USEPA, 2007), conc entration-based forms 32 may better 7 reflect pollutant-associated health risks than forms based on expected exceedances because 8 concentration-based forms give proportionally great er weight to periods of time when pollutant 9 concentrations are well above the level of the sta ndard than to times when the concentrations are 10 just above the standard, while an expected ex ceedance form would give the same weight to 11 periods of time with concentrations that just exce ed the standard as to times when concentrations 12 greatly exceed the standard. Concentration-based forms also provide greater regulatory stability 13 than a form based on allowing only a single expected exceedance. 14 In considering specific concentration-based forms on which to focus the current review, 15 we have initially considered such forms as ha ve been considered in other NAAQS reviews, 16 including the 98 th and 99 th percentile forms averaged over thr ee years, which were considered in 17 the most recent PM and NO 2 NAAQS reviews (USEPA , 2005; USEPA, 2008b). 33 We note that 18
a 99 th percentile form for an 8-hour daily maximu m standard would correspond to the fourth 19 highest daily maximum 8-hour aver age concentration in a year. We have initially considered 20 that a 98 th percentile form or forms of 99 th percentile or fourth highest daily maximum would 21 provide appropriate balances be tween limiting peak CO concentra tions and providing a stable 22 regulatory target. 23 When considering results of the second draft REA as they relate to standard form, we 24 note that a decision on form must be made in conjunction with sel ection of a particular standard 25 level. The primary emphasis in such a decision will be on the level of public health protection 26 provided by the combination of form and level. The current form of both the 8-hour and 1-hour 27 standards is a maximum, not to be exceeded more than once per year. In the section below we 28 consider the results of the sec ond draft REA for different combinations of level with both a 99 th 29 percentile concentration-based form and the current “exceeded only once per year” form. 30

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 di stinguished 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, on ly 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 2.3.3.2 Potential Alternative Levels 1 In considering potential alternative standard levels with regard to their potential to 2 provide greater protection than that afforded by the current standard against CO-related adverse 3 health effects, we have taken into account scientific evidence from both experimental and 4 epidemiologic studies, as well as the uncertain ties and limitations in that evidence, and the 5 quantitative estimates of exposure and dose provide d by the second draft REA. We note that the 6 scientific evidence and quantitative assessment can provide insights into alternative standard 7 levels only within the context of specific averaging times and forms. Therefore, this section 8 considers the evidence and quantitative analysis as they relate to alternative levels particular to 9 different forms and averaging times. The primary focus of staff’s initial considerations in this 10 draft Policy Assessment is on the 8-hour standa rd because it has long been the controlling 11 standard for air quality. 12 As an initial matter, we recognize that indoor sources of CO can be important 13 determinants of population exposures to CO and to population distributions of COHb including 14 maximum COHb levels. For some portions of the population these sources may be the primary 15 influences on external exposure-related COHb leve ls. However, we take note of the conclusions 16 drawn in the previous review th at the contribution of indoor sour ces to individual exposures and 17 associated COHb levels cannot be effectively mitigated by ambient air quality standards (e.g., 59 18 FR 38914) and so focus here on COHb levels re sulting from ambient CO exposures. At the 19 same time, we additionally recognize people w hose exposures to nonambient CO result in 20 elevated COHb levels, and particularly those wh ose COHb levels may be appreciably influenced 21 by additional ambient CO exposures. Findings of previous quantitative assessments in which 22 some indoor sources were represented (e.g., gas stoves and tobacco smok e), however, indicated 23 that indoor source contributions to population maximum COHb levels were substantial in 24 comparison to ambient contributions. While we ar e limited with regard to information regarding 25 CO emissions from indoor sources today and how they may differ from the time of the 2000 26 assessment, we note that ambient contributions have notably declined and indoor source 27 contributions from some sources may also have declined. Thus, we have no firm basis to 28 conclude a different role for i ndoor sources today with regard to contribution to population CO 29 exposure and COHb levels. 30 We believe that the integration of the health effects evidence with the exposure and dose 31 estimates will be particularly important to info rming conclusions regardin g standard levels and 32 forms considered to provide protection of public hea lth with an adequate margin of safety. With 33 regard to the scientific eviden ce, as discussed in section 2.2.1 above, we have given principal 34 emphasis to findings of the multilaboratory cont rolled human exposure study of individuals with 35 pre-existing CAD (Allred et al., 1989a, 1989b, 1991) . In this study, controlled experimental 36March 2010 Draft – Do Not Quote or Cite 2-51 exposures to CO that resulted in a post-exercise study mean COHb level as low as 2.0% relative 1 to clean-air exposures that re sulted in a mean COHb level of 0.6% (post-exercise) were 2 associated with myocardial ischemia-related e ffects (including, specifically, reduced time to 3 exercise-induced angina and ST-segment change). A dose-response analysis of the study subject 4 specific data, in which individual regressions of study subject respons es at baseline COHb and at 5 the two increased COHb levels were averaged, indicated decreases of roughly 1.9% in time to 6 exercise-induced angina and 3.9% in time to exercise-induced ST-segment change per 1% 7 increase in COHb concentration, with no evidence of a measurable thres hold at the controlled 8 exposures evaluated (ISA, section 5.2.4; Allr ed et al., 1989a, 1989b, 1991). For our purposes 9 here, we additionally have considered the epidemio logical studies with regard to the extent to 10 which this evidence is consistent with and ge nerally supportive of conc lusions drawn from the 11 combined consideration of the controlled hum an exposure evidence with estimates from the 12 exposure and dose assessment. We take note of the epidemiological studies showing positive 13 associations with IHD and CHD health outcome s described in section 2.2.1 above, three of 14 which were based in a study area in which the curre nt standard was met, the association for one 15 of which was statistically significant. In our consideration of the evidence, we recognize 16 CASAC advice with regard to aspects of the ep idemiological evidence that are particularly 17 problematic for CO and the weight to be given to the well-conducted clini cal studies (Brain and 18 Samet, 2010). 19 In considering health risk implications fo r the simulated at-risk population associated 20 with dose estimates from the qua ntitative exposure/dose assessment we compared the estimates 21 to potential health effects benc hmark levels of 1.5%, 2.0%, 2.5% and 3% COHb (as described in 22 section 2.2.2 above). In considering the populat ion estimates of maximum end-of-hour COHb 23 levels from the draft REA for the purposes of co nsidering the level for th e 8-hour standard that 24 provides appropriate public hea lth protection, we have focused on the results in terms of 25 percentage of simulated at-risk population in each study area estimated to experience maximum 26 end-of-hour COHb levels below each of the two lower potential health effects benchmarks and 27 an intermediate COHb level. Ba sed on analysis of the air quality data used in the draft REA to 28 identify the equivalent levels for alternative forms, the five different air quality conditions 29 simulated for each of the two study areas provide in formation on an array of alternative levels for 30 the current and an alternative form (Table 2-6). 31 In considering the estimates provided by the draft REA (summarized in Table 2-6 below), 32 we note that differences between the two study areas with regard to the simulated at-risk 33 population distributions of maximu m end-of-hour COHb levels (noted in the section 6.2 of the 34 draft REA) lead to differences in the proportion of the populati on protected from maximum end35 of-hour COHb levels at or above the potential health effect benc hmarks being considered here. 36March 2010 Draft – Do Not Quote or Cite 2-52 For example, the percentage of the simula ted at-risk population es timated to experience 1 maximum COHb levels below 2% is 99.5% or gr eater in the Los Angeles study area for all 2 simulated levels for either form, while the pe rcentage of the simulated population in Denver 3 estimated to experience maximum end-of-hour COHb levels below 2% is less than 99% 4 (approximately 96.6%) for the highest alternative standa rd level simulated for either form. 5 Alternatively, the percentage of the simula ted population estimated to experience maximum 6 COHb levels below 1.5% is more than 95% in th e Los Angeles study area and more than 80% in 7 the Denver study area for all simulated levels for either form. Further, the percentage of the 8 simulated at-risk population estimated to e xperience maximum COHb levels below an 9 intermediate COHb level of 1.8%, is more than 99% in the Los Angeles study area and more 10 than 98% in the Denver study area for all simulated levels for either form. 11

Table 2-6. Portion of simulated at-risk populat ion with maximum end-of-hour COHb 12 levels below the indicated COHb level under alternative levels for the 8-hour 13 standard for the current form and a 99 th percentile daily maximum form. 14

< 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 96.2Second 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 Taking into account the differences between th e simulated at-risk popu lations in the two 16 study areas, recognizing considerat ions regarding maximum COHb benchmarks of 1.5 to 2% and 17 above, and being mindful of the support provided by the epidemiological studies, we consider 18 the draft REA estimates of maximum end-of-hour COHb levels with regard to level of protection 19March 2010 Draft – Do Not Quote or Cite 2-53 estimated to be provided by the di fferent alternative levels for the 8-hour standard (Table 2-6 1 below). In further considering th e weight to place on this inform ation, we are mindful of several 2 key aspects of the evidence (described in more detail in section 2.2.1 above): 3

 Uncertainty in the clinical significance of the effects observed in the controlled human 4 exposure studies of CAD patients. 5

 The lack of evidence for a measurable thresh old effect for the effects observed in the 6 human clinical studies and the lack of studies that have evaluated effects of 7 experimentally controlled short-term CO exposures of individuals with CAD that 8 resulted in study mean COHb levels below 2%. 9

 Uncertainty associated with interpretation of COHb levels estimated in the quantitative 10 assessment to result from simulated CO exposure concentrations much lower than the 11 experimental CO exposure concentrations used in the controlled human studies to 12 increase subject COHb leve ls to COHb study targets. 13

 The lack of studies of COHb levels associat ed with health effects in other potentially 14 susceptible populations. 15

 Limitations associated with the epidemiological studies for CO which complicate our 16 use for quantitative purposes. 17
18 Staff find that identification of the range of alternative sta ndards that may be appropriate 19 to consider differs based on th e weight placed on different aspects of the evidence and on 20 different aspects of the quantitative dose estima tes, as well as on public health policy decisions 21 regarding the significance of th e effects considered, the appropr iate COHb benchmark on which 22 to focus in considering maximum end-of-hour C OHb levels, and the targeted proportion of the 23 at-risk population. For example, focusing on the 2.0% COHb benchmark and considering a 24 target for the at-risk population of 95 or 96% across the two study areas would indicate support 25 for retaining the current level of the 8-hour standa rd. That is, the draft REA results in Table 2-6 26 indicate that under the current st andard, the maximum end-of-hour COHb levels for at least 96% 27 of the at-risk populations in the two study area s would be expected to fall below the 2% 28 benchmark. 34 Alternatively, consideration of a high er population target of 99% while focusing 29 on the 2% COHb benchmark, would lead to consid eration of a level of approximately 5 to 6 30 ppm, as would a population target of 98% belo w the 1.8% COHb benchmark, while a focus on a 31 COHb benchmark of 1.5% with a target of 95% for the at-risk population would indicate support 32 for consideration of a level somewhat below 5 ppm. On the other hand, cons ideration of a target 33 level of 99% in combination with a focus on the 1.5% COHb benchmark would indicate support 34 for a somewhat lower level, of about 3 ppm. 35

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 Thus, we note that placing weight on the exposure assessment results for the population 1 target of 95% or 96% for a benchmark level of 2% COHb, in combination with a recognition of 2 limitations in the epidemiological evidence for CO with regard to its use in drawing quantitative 3 conclusions regarding a level fo r the standard, would provide a basis for considering retaining 4 the current 8-hour standard. Alternatively, placi ng weight on the three epidemiological studies 5 for the location in which the current standard was met, the association in one of which 6 statistically significant, and c onsideration of the ambient CO concentrations in that study 7 (Atlanta, 99 th percentile 8-hour daily maximum ranging up to 4.9 ppm during the study period) 8 would lead to consideration of the lowe r part of the range identified above. 9 While the focus in this draft Policy Assessmen t is on consideration of the controlling 8- 10 hour standard, we have also considered the rationa le for the existing 1-hour standard as generally 11 providing protection from effects that might result from short p eak exposures ove r this shorter 12 exposure duration (as described in section 2.3.1 above). We find valu e in retaining this standard 13 for that purpose, recognizing that it may provide such protection independent from the type of 14 protection provided by the 8-hour standard. 15 We note that the results of the quantitative e xposure/dose analysis also provides estimates 16 for the ten model simulations (described in the dr aft REA) in terms of potential alternative levels 17 for a 1-hour standard either of current form or a revised 99 th percentile daily maximum form 18 (Table 2-7 below). These estimates indicate the extent to which levels for the 1-hour standard 19 that are appreciably lower than the current level might infl uence population maximum end-of20 hour COHb levels in the situati on where the 8-hour st andard was of a magn itude such that it no 21 longer was the controlling force for ambient CO c oncentrations. From these estimates it can be 22 seen that an appreciable reduc tion in the level for the 1-hour standard would be required to 23 achieve an impact on population COHb levels co mparable to those achieved by the current 8- 24 hour standard or levels only somewhat lower. For example, to achieve a similar distribution of 25 expected COHb levels as the current 8-hour standa rd, the results from the draft REA indicate that 26 a level of approximately 15 ppm would be required for the 1-hour standards, either in terms of 27 the current form or of a 99 th percentile daily maximum form (Table 2-7 below). 28March 2010 Draft – Do Not Quote or Cite 2-55 Table 2-7. Portion of simulated at-risk populat ion with maximum end-of-hour COHb 1 levels below the indicated COHb level under alternative levels for the 1-hour 2 standard for the current form and a 99 th percentile daily maximum form. 3

< 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 6.8 99.9 99.8 99.4 Second Highest 1- 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 With regard to the current 1-hour standard, staff has identified several policy options in 5 this draft Policy Assessment that may be appropriat e to consider. First, we note that the current 6 1-hour standard may be considered to provi de protection from effects which might be 7 encountered from infrequent, very short duration peak ambient con centrations. With regard to 8 such a purpose for the 1-hour standard independent of a focus on COHb leve ls as illustrated in 9 Table 2-7 above, we have not identified informati on that might provide for an alternative level 10 and form. Alternatively, while recognizing that the 8-hour standard has traditionally been the 11 controlling standard, we have also considered alternative levels for the 1-hour standard drawing 12 from the results of the draft REA in similar manner to the discussion above for the 8-hour 13 standard. In considering the alternatives for publ ic health policy judgments identified above for 14 the 8-hour standard, we note the resu lts of the draft REA with regard to alternative levels for the 15March 2010 Draft – Do Not Quote or Cite 2-56 1-hour standard might be concluded to indicate support for a range from approximately 15 ppm 1 at the upper end to approximately 5 pp m at the lower end, combined with a 99 th percentile form. 2 Further, in light of the role of the 8-h our standard as the controlling standard, and 3 depending on judgments made regarding additiona l protection that may be provided by the 1- 4 hour standard from infrequent, ve ry short duration peak ambient c oncentrations, we note that it 5 may also be appropriate to cons ider revoking the 1-hour standard in conjunction with revision of 6 the 8-hour standard to provide in creased protection from maximum COHb levels that may result 7 from ambient CO concentrations. 8

2.3.4 Initial Staff Conclusions on Alternative Standards 9
Initial staff conclusions for consideration in making decisions on the primary standards 10 for CO, together with supporting conclusions from sections 2.2.3 and 2.3.2 above, are briefly 11 summarized below. In drawing these initial c onclusions, we are mindful that the Act requires 12 standards to be set that, in th e Administrator’s judgment, are re quisite to protect public health 13 with an adequate margin of safety, such that the standards are to be neither more nor less 14 stringent than necessary. Thus, the Act does not require that NAAQS be set at zero-risk levels, 15 but rather at levels that avoid unacceptable risks to public health. 16
(1) Staff initially concludes that the combined consideration of the body of evidence and 17 the quantitative exposure and dose estimates provide support for sta ndards at least as 18 protective as the current su ite of standards to provid e appropriate public health 19 protection for susceptible populations, includ ing most particularly individuals with 20 cardiovascular disease, against effects of CO in exacerbating conditions of reduced 21 oxygen availability to the heart. 22 (2) Staff also initially concludes that, dependi ng on public health po licy judgments about 23 protecting public health with an adequate margin of safety, the information available 24 in this review supports consideration of eith er retaining or revising the current suite of 25 standards, with any such revisions focu sed on providing increased public health 26 protection. 27 (3) With regard to the indicator for the CO st andards, staff initially concludes that it is 28 appropriate to continue to use measurem ents of CO in accordance with federal 29 reference methods as the indicator to addre ss effects associated with exposure to CO. 30 (4) With regard to the current 8-hour standa rd, staff initially concludes that it is 31 appropriate to consider the fo llowing range of policy options: 32

a. Retaining the 8-hour averaging time. 33 b. Retaining or revising the level of the standard, with consideration given to 34 levels within the range from the current level of 9 ppm at the upper end to 35March 2010 Draft – Do Not Quote or Cite 2-57 approximately 3 ppm at the lower en d to provide prot ection from maximum 1 COHb levels that may result from ambient CO exposures. 2

c. In conjunction with considera tion of revising the level, it is also appropriate to 3 consider revising the form of the standard to a 99 th percentile or fourth-highest 4 daily maximum form, including considera tion of such a form that is the 5 average of this concentration across three years. 6
(5) With regard to the current 1-hour standa rd, staff initially concludes that it is 7 appropriate to consider the fo llowing range of policy options: 8

a. Retaining the current 1-hour standard to provide prot ection from effects which 9 might be encountered from infrequent, very short duration peak ambient 10 concentrations. 11

b. Revising the standard, with considerati on given to levels within the range 12 from approximately 15 ppm at the uppe r end to approximately 5 ppm at the 13 lower end, combined with a 99 th percentile or fourth-highest daily maximum 14 form, to provide protection from maximu m COHb levels that may result from 15 ambient CO exposures. Consideratio n of a revised level for the 1-hour 16 standard within this range would be in tended to provide the same protection as 17 revision of the 8-hour standard within th e range identified in item (4)b above. 18

c. In conjunction with consider ation of revising the leve l of the 8-hour standard 19 to a lower level, it is also appropriate to consider revoking the 1-hour standard 20 in recognition of the increased pr otection provided by a revised 8-hour 21 standard from maximum COHb levels that may result from ambient CO 22
exposures. 23

2.4 KEY UNCERTAINTIES AND AREA S FOR FUTURE RESEARCH AND 24 DATA COLLECTION 25 Staff believes it is important to highlight key uncertainties associated with establishing 26 ambient standards for CO. Such key uncerta inties and recommendations for health-related 27 research, model development, and data gathering ar e outlined below. In some cases, research in 28 these areas can go beyond aiding stan dard setting to aiding in the development of more efficient 29 and effective control strategies. We note, however, that a full set of research recommendations 30 to meet standards implementation and strategy development needs is beyond the scope of this 31 discussion. We have initially identified the fo llowing key uncertainties, research questions and 32 data gaps that have been high lighted in this review of the health-based primary standards. 33

 A critical aspect of our consideration of the eviden ce and the quantitative dose 34 estimates is our interpretation of the contro lled human clinical studies. Expansion of 35March 2010 Draft – Do Not Quote or Cite 2-58 this evidence base in several areas would reduce uncertainty in our interpretation for 1 purposes of risk characterization. 2

o Additional information relevant to health effects of short-term increases in CO 3 exposure resulting in COHb levels be low 2% in individuals with CAD. 4

o Additional research to clarify the clinical significance of the sensitive markers 5 of myocardial ischemia observed in controlled human exposure studies of 6 CAD patients. 7

o Research to reduce uncertainty associated with interpretation of COHb levels 8 estimated in the quantitative assessment to result from simulated CO exposure 9 concentrations much lower than the e xperimental CO exposure concentrations 10 used in the controlled human studies to increase subject COHb levels to 11 COHb study targets. 12

 Existing clinical data correlates CO-induced effects (i.e., cardiovascular ischemia 13 observed at specific COHb leve ls) to COHb levels resulti ng from short-term, high CO 14 exposure concentrations. However, there is l ack of studies evaluati ng effects of CO, in 15 terms of COHb levels, at lower ambient c oncentrations and/or longer term exposures 16 periods. 17

 Further research to characterize CO e ffects for other potentially susceptibility 18 populations, including populations with preexisting di seases other than CAD that limit 19 O 2 availability, such as anemia and obstruc tive respiratory diseases; populations at 20 certain lifestages (i.e., older adults and fe tuses at critical stages of development); 21 populations with elevated ba seline COHb due to increased CO production, such as 22 individuals with diabetes;, a nd visitors to high altitude. 23

 Our interpretation of the epidemiological ev idence for CO would benefit from a better 24 understanding of the possible role of co-pollutants. 25

 Our future assessments would benefit from research on studies evaluating effects of 26 CO linked to biomarkers other than C OHb and research on mechanisms of CO27 induced effects other that t hose associated with limiting O 2 availability at ambient CO 28 levels. 29March 2010 Draft – Do Not Quote or Cite 2-59 REFERENCES 1

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### 3 CONSIDERATION OF A SECO NDARY STANDARD FOR CO 1

This chapter focuses on the key policy-relevant issues related to th e review of welfare2 related effects of CO. Under Section 109(b) of th e Clean Air Act, a secondary standard is to be 3 established at a level “requisite to protect the public welfare from any known or anticipated 4
adverse effects associated with the presence of the pollutant in ambient air.” Section 302(h) of 5 the Act defines effects on welfare in part as “e ffects on soils, water, cr ops, vegetation, man-made 6 materials, animals, weather, visibility, and climate.” 7 Specifically, this chapter first summarizes the history of EPA’s consideration of 8 secondary standards for CO. Considerations is th en given to the evidence currently available for 9
welfare effects to inform decisions in this review as to whether, and if so how, to establish 10 secondary standards for CO based on public welfare considerations. Initia l staff conclusions are 11 based on the assessment and integrative synthesis of the scientific evidence presented in the ISA 12 (USEPA, 2010), building on the evidence de scribed in the 2000 AQCD (USEPA, 2000). 13

3.1 CONSIDERATION IN PREVIOUS REVIEWS 14 With the establishment of the first NAAQS for CO in 1971, secondary standards were set 15 identical to the primary standards. CO was not shown to produce detrimental effects on certain 16 higher plants at levels below 100 ppm. The onl y significant welfare eff ect identified for CO 17 levels possibly approaching those in ambient air was inhibition of nitrogen fixation by 18 microorganisms in the root nodules of legumes a ssociated with CO levels of 100 ppm for one 19 month (National Air Pollution Control Administra tion, 1970). In the firs t review of the CO 20 NAAQS, the threshold level for plant effects wa s recognized to occur well above ambient CO 21 levels, such that vegetation damage as a result of CO in ambient air was concluded to be very 22 unlikely (50 FR 37494). As a result, EPA c oncluded that the evidence did not support 23 maintaining a secondary standard for CO, as welf are-related effects had not been documented to 24
occur at ambient concentrati ons (50 FR 37494). Bsed on that conclusion, EPA rescinded the 25 secondary standard. In the most recent review of CO, which was completed in 1994, EPA again 26
concluded there was insufficient evidence of welfar e effects occurring at or near ambient levels 27 to support setting a secondary NAAQ S (59 FR 38906). That review did not consider climate28
related effects. 29

3.2 CONSIDERATION OF EVIDENCE AVAILABLE IN THE CURRENT 30 REVIEW 31
To evaluate whether consideration of estab lishment of a secondary standard for CO is 32 appropriate, we adopted an appro ach in this review that builds upon the general approach used in 33March 2010 Draft-Do Not Quote or Cite 3-2 the last review and reflects the broader body of evidence and information now available. In 1 developing conclusions in this review below, staff has taken into account the following 2 overarching question: 3

 Does the currently available scientif ic information provide support for 4 considering the establishment of a secondary standard for CO? 5 In considering this overarching question, we firs t note that the extensiv e literature search 6 performed for the current review did not identify any evidence of ecological effects of CO 7
unrelated to climate-related effect s, at or near ambient levels (I SA, section 1.3 p. 1-3). However, 8
ambient CO has been associated with welfare e ffects related to climat e (ISA, section 3.3). 9
Climate-related effects of CO we re considered for the first time in the 2000 AQCD. The greater 10
focus on climate in the current ISA relative to the 2000 AQCD reflects comments from CASAC 11
and increased attention to the ro le of CO in climate forcing (Brain and Samet, 2009). Based on 12 the current evidence, the ISA has concluded that “a causal relationship exists between current 13 atmospheric concentrations of CO and effects on climate” (ISA, section 2.2). Accordingly, the 14 following discussion focuses on climate-related eff ects of CO in addressing the question posed 15
above. 16 Recently available information does not alter the current well-established understanding 17 of the role of urban and regional CO in continen tal and global-scale chem istry, as outlined in the 18 2000 AQCD. CO is a weak direct contributo r to greenhouse warming. The most significant 19 effects on climate result indirectly from CO chemistry, related to the role of CO as a major 20 atmospheric sink for hydroxyl groups (OH). Incr eased concentrations of CO can lead to 21 increased concentrations of other gases whose lo ss processes also involve OH chemistry. Some 22 of these gases, such as methane (CH 4 ) and ozone (O 3 ), contribute to the greenhouse effect 23 directly while others deplete stratospheric O 3 (ISA, section 3.3 p. 3-11). 24 Advances in modeling and measurement have improved our understanding of the relative 25 contribution of CO to climate forcing. This link between ambient CO and climate is based on 26 both direct radiative forcing (R F) of CO estimated at 0.024 W/m 2 by Sinha and Toumi (1996) 27 and indirect effects of CO on climate through CH 4 , O 3 and carbon dioxide (CO 2 ) (Forster et al. 28 2007). The combined RF for these indire ct effects of CO was estimated by the 29 Intergovernmental Panel on Climate Change (IPCC) to be ~0.2 W/m 2 over the period 1750-2005 30 (Forster et al., 2007) with more than on e-half of the forcing attributed to O 3 formation. 31 Ambient CO, by itself, does not significantly absorb the Earth’s l ongwave radiation and 32 warm the atmosphere and surface (ISA, section 2. 2). Rather, the effects of CO emissions on 33 climate are felt indirectly because emissions of CO lead to increased ambient concentrations of 34 two important greenhouse gases, CH 4 and O 3 . This increase results in contributions to RF that 35 are significant (Forster et al. 2007 ). However, it is highly proble matic to evaluate the indirect 36March 2010 Draft-Do Not Quote or Cite 3-3 effects of CO on climate due to the spatial heterogeneity in its emissions and concentrations and 1
due to the localized chemical interdependencies involving CO, CH 4 , and O 3 , which also depend 2 on levels of NOx. (ISA section 3.3). 3
Most climate model simulations are based on global scale scenarios and have a high 4 degree of uncertainty associated with short-lived clim ate forcers such as CO (ISA, section 3.3. p. 5 3-16). These models may fail to consider the loca l variations in climate forcing due to emissions 6 sources and local meteorological pa tterns (ISA, section 3.3 p. 3-16). 7 With regard to time period, ambient CO emissions vary on an hourly basis and exhibit 8 seasonal and weekday/weekend fluctuations (ISA, section 3.5). This ep isodic emission pattern, 9 coupled with the relatively short atmospheri c lifetime of CO, has limited the ability to 10 characterize welfare-related exposures to this polluta nt. CO is classified as a short-lived climate 11 forcing agent, prompting CO emission reductions to be considered as a possible strategy to 12 mitigate effects of global warming. It is possibl e to compute individual contributions to RF of 13 CO from separate emissions sectors, although uncertainty in these estimates has not been 14 quantified (ISA, section 3.3 p. 3-13). 15 Additional sources of uncertainty in the current assessment include the chemical 16 interdependencies of CO and other climate fo rcing pollutants and the complexity of CO 17 atmospheric chemistry (ISA, section 3.2.2). Me asurement of and techniques for assessing 18 climate forcing are improving, but estimates of RF still have ~50% uncer tainty (ISA, section 3.3, 19 p. 3-13). Large regional variations in CO concentrations also c ontribute to the uncertainties in 20 the RF from CO and other trace ga ses (ISA, section 2.2 p. 3-12). 21

3.3 STAFF CONCLUSIONS FOR THE CURRENT REVIEW 22 In considering whether the currently availabl e scientific information indicates the need 23 for a secondary standard for CO, we have reached the following initial conclusions: 24
25 (1) With respect to non-climate we lfare effects, including eco logical effects and impacts 26 to vegetation, there is no currently availabl e scientific informati on that supports a CO 27 secondary standard. 28
29 (2) With respect to climate-related effects, we note that there is evidence of climate 30 forcing effects associated with CO (ISA, s ections 2.2 and 3.3). There are weak direct, 31 and stronger, but primarily highly variable, indirect continental and regional climate 32 forcing effects from CO. However, the av ailable information provides no basis for 33 estimating how localized changes in the te mporal, spatial and composition patterns of 34 ambient CO likely to occur across the US with (or without) a secondary standard 35March 2010 Draft-Do Not Quote or Cite 3-4 would affect local, regional, or nationwide changes in climate. For these reasons, it is 1 currently not feasible to conduct an anal ysis for the purpose of considering a CO 2 secondary standard based on climate considera tions. Moreover, more than half of the 3 indirect forcing effects of CO have been estimated to occur through O 3 formation, and 4
effects of O 3 are more appropriately c onsidered in the context of the review of the O 3 5 NAAQS, rather than in this CO NAAQS revi ew. Based on these considerations, staff 6 initially concludes there is insufficient information at this time to support the 7 consideration of a secondary NAAQS base d on CO effects on climate processes. 8
9March 2010 Draft-Do Not Quote or Cite 3-5 REFERENCES 1 2 Brain J. and Samet J. (2009) Clean Air Scientific Advisory Committee (CASAC) Carbon Monoxide Review Panel's 3 Review on EPA's Integrated Science Assessment for Carbon Monoxide (First External Review Draft) 4 Memorandum to Lisa Jackson, EPA Administrator, from Drs. Joseph Brain and Jonathan Samet. June. 5 Available at: 6 http://yosemite.epa.gov/sab/sabproduct.nsf/264cb1227d55e02c85257402007446a4/90e1eb5977789a4f8525 7 746e006275a8!OpenDocument&TableRow=2.3#2

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National Air Pollution Control Administration. (1970) Air Quality Criteria for Carbon Monoxide. Washington, DC: 15 U.S. Department of Health, Education and Welfare, Public Health Service; report no. NAPCA-PUB-AP16 62. Available from: NTIS, Springfield VA; PB-190261 17

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37United StatesEnvironmental ProtectionAgencyOffice of Air Quality Planning and StandardsHealth and Environmental Impacts DivisionResearch Triangle Park, NCPublication No. EPA-452/P-10-005March 2010