## Responses to Significant Comments on the 2011 Proposed Rule on the National Ambient Air Quality Standards

for Carbon Monoxide
(February 11, 2011; 76 FR 8158)

Docket Number EPA-HQ-OAR-2008-0015

U.S. Environmental Protection Agency August 2011

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### Table of Contents

Frequently Cited Documents .................................................................................................... ...... ii

I. INTRODUCTION ............................................................................................................... .........1

II. RESPONSES TO SIGNIFICANT COMMENTS ON PROPOSED RULEMAKING FOR CARBON MONOXIDE NAAQS ..................................................................................................2 A. Comments on Primary Standards ....................................................................................2 1. Support for Proposed Decision to Retain the Current Standards ...............................2 2. Comments Recommending Revi sion of the Current Standards ..............................3

3. Comments on Evidence-based Considerations .........................................................4 4. Comments on Exposure and Risk Considerations ..................................................15

5. Additional Comments on the Inte rpretation of Scientific Evidence ......................24 6. Additional Comments on the Exposure and Risk Assessment ...............................37

B. Comment on Consideration of a Secondary Standard .................................................40

C. Comments Related to Monitoring .................................................................................41 1. Sampling and Analysis Methods ...........................................................................41 2. Near-Roadway Monitors .........................................................................................44

3. Other Locations .......................................................................................................48 4. Other Monitoring Comments ..................................................................................50

III. RESPONSES TO SIGNIFICANT COMME NTS RELATED TO IMPLEMENTATION

OF STANDARDS .................................................................................................................. .......52

A. DESIGNATIONS ........................................................................................................52

B. OTHER..................................................................................................................... ....52

IV. RESPONSES TO SIGNIFICANT CO MMENTS RELATED TO EXCEPTIONAL

EVENTS ...................................................................................................................... ....55

V. RESPONSES TO LEGAL, ADMINIST RATIVE, AND PROCEDURAL ISSUES AND

MISPLACED COMMENTS .........................................................................................................55

VI. REFERENCES ............................................................................................................... ........59

APPENDIX A ................................................................................................................... .......63ii 

### Frequently Cited Documents

The following documents are frequently c ited throughout this response to comments document, often by means of the short names listed below:

Preamble to the final rule: Preamble to the Final Rule on the Review of the National Ambient Air Quality Standards for Carbon Monoxide: Final Rule. To be published in the Federal Register in August or September, 2011.

Proposal: National Ambient Air Quality Standards for Ozone: Proposed Rule. 76 FR 8158, February 11, 2011.

2010 Integrated Science Assessment (ISA): U.S. Environmental Protection Agency ( 2010a) Integrated Science Assessment for Carbon Monoxide (Final). Washington, DC, EPA/600/R-09/019F. Available online at: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=218686

Risk and Exposure Assessment (REA): U.S. Environmental Protection Agency (2010b) Quantitative Risk and Exposure Assessment for Carbon Monoxide - Amended. July 2010. Office of Air Quality Planning and Standards, Research Triangle Park, NC. EPA Report no. EPA-452/R-10/009.

Available online at: http://www.epa.gov/ttn/naaqs/sta ndards/co/data/CO-REA-AmendedJuly2010.pdf

Policy Assessment (PA): U.S. Environmental Protection Agency (2010c ) Policy Assessment for the Review of the Carbon Monoxide National Ambient Air Quality Standards. October 2007. Office of Air Quality Planning and Standards, Resear ch Triangle Park, NC. EPA report no. EPA452/R-10-007. Available online at: http://www.epa.gov/ttn/naaqs/st andards/co/data/20101022copafinal.pdf1 

## Responses to Significant Comment s on the 2011 Proposed Rule on the National Ambient Air Quality Standards

for Carbon Monoxide

I. INTRODUCTION

This document, together with the preamble to the final rule on the review of the national ambient air quality standards (NAAQS ) for carbon monoxide (CO), presents the responses of the Environmental Protection Agency (EPA) to some of the public comments received on the 2011 CO NAAQS proposal notice (76 FR 8158). All significant issues raised in timely public comments have been addressed. Where

comments were submitted after the close of the public comment period, EPA responded to the extent practicable.

Comments were received from two organi zations of state and local air agencies (National Association of Clean Air Agenci es [NACAA], and Northeast States for Coordinated Air Use Management [NESC AUM]), approximately 12 State and local government agencies, and a council of local governments (Southeas t Michigan Council of Governments [SEMCOG]); the American Thoracic Society and approximately 10 environmental or public health organizations or coalitions; three industry organizations (Alliance of Automobile Manufacturers [AAM], American Petroleum Institute [API], and American Electric Power Service Corporat ion [AEPSC]); an organization of state highway officials (American A ssociation of State Highway and Transportation Officials [AASHTO]); several individuals and a group of approximately 100 individuals.

This response-to-comments document does not generally cross-reference each response to the commenter(s) who raised the particular i ssue involved, although

commenters are identified in some cases wh ere they provided particularly detailed comments that were used to frame the overall response on an issue.

The responses presented in this docume nt are intended to augment the responses to comments that appear in the preamble to the final rule or to address comments not discussed in the preamble to the final rule. Although portions of the preamble to the final rule are paraphrased in this document where useful to add clarity to responses, the preamble itself remains the definitive statemen t of the rationale for the revisions to the standards adopted in the final rule.

In many instances, particular responses pr esented in this document include cross references to responses on related issues that are located either in th e preamble to the CO NAAQS final rule, or in this 2011 Response to Comments document. All issues on which the Administrator is taking final action in the CO NAAQS final rule are addressed in the CO NAAQS rulemaking record.2 Accordingly, this Response to Comments document, together with the preamble to the CO NAAQS final rule and the informa tion contained in the Integrated Science Assessment (EPA, 2010a), the Risk and Exposure Assessment (EPA, 2010b) and the Policy Assessment (EPA, 2010c), and the No tice of Proposed Rulemaking should be considered collectively as EPA’s response to all of the significant comments submitted on EPA’s 2011 CO NAAQS proposed rule. This document incorporates directly or by reference the significant public comment s addressed in the preamble to the CO NAAQS final rule as well as other significant public comments that were submitted on the 2011 proposed rule.

Consistent with the final decisions pr esented in the notice of final rulemaking,

comments on the CO standards are addressed in sections II.A and II.B. Comments on monitoring are addressed below in section II.C. Comments on implementation are addressed in III. Comments on exceptional events are addressed in section IV. Section V includes responses to legal, administrativ e, procedural, or misplaced comments.



### II. RESPONSES TO SIGNIFICANT COMMENTS ON PROPOSED

RULEMAKING FOR CARBON MONOXIDE NAAQS

A. Comments on Primary Standards

General comments based on relevant factors that eith er support or oppose retention of the current CO primary standards are addressed in section II.B of the preamble to the final

rule and/or in sections II.A.1 and II.A.2 of this document below. Additional comments

about the health effects evidence and the REA are addressed in sections II.A.3-5 below.

1. Support for the Proposed Decision to Retain the Current Standards

All of the state and local envi ronmental agencies or governments that provided comments on the Administrator’s proposed conclusion th at the current CO st andards provide the requisite protection of public hea lth with an adequate margin of safety concurred with the proposed decision. Additionally three industr y commenters also expressed agreement with EPA’s proposal to retain the current sta ndards, which they also viewed as providing the requisite level of public he alth protection. In support of this view, these commenters variously stated that:

 the current evidence indicates current st andards are protective for the sensitive group of people with heart disease;

 the proposed conclusions give appropriat e weight to epidemiological studies;

 the REA estimates of occurrences of carboxyhemoglobin (COHb) levels above 2% COHb in the at-risk populations are materially unchanged since last review, and;

 some aspects of the exposure and dose asse ssment lead the REA results to provide an overstatement of risk (furth er discussed in II.A.4.below) .3 These comments received in support of reta ining the current standards are generally addressed in Section II.B.3 of the preamble to the final rule. We additionally note here that EPA does not agree with commenters’ characterization of the REA results as an

overstatement of health risk as di scussed in section II.A.4 below.

2. Comments Recommending Revision of the Current Standards

Comments received on the proposal from severa l organizations and individuals asserted

that the evidence indicated the occurrence of health effects occurri ng at conditions below

the current CO standards and that revisions should be made to the standards. Among those recommending revisions to the current standards were joint comments submitted from the American Lung Association, the Amer ican Thoracic Societ y, the Environmental Defense Fund (ALA et al); joint comments submitted from Physicians for Social Responsibility and Albert Donnay (PSR et al), signed by 27 other organizations and several hundred individuals; joint comment s submitted from Center for Biological Diversity, Communities for a Better Environmen t, WildEarth Guardians, Coalition for a Safe Environment, and Alaska Center for the Environment (CBD et al); individual comments from Albert Donnay (Donnay) and a petition signed by 130 individuals. These various commenters recommended a range of lo wer levels for revised 1-hour and 8-hour

standards with considerati on of a revised form of 99 th percentile. The recommended levels were at or below the lowest part of th e range identified in the Policy Assessment. In supporting adoption of more stringent NAAQS for CO, these commenters generally stated that they supported comments provide d by CASAC on the draft Policy Assessment which indicated a preference for a lower st andard and recommended greater emphasis be given to epidemiological studies. The co mmenters also variously stated that:

 the available epidemiological studies provi de evidence of effects at levels below the current NAAQS;

 epidemiological studies indicate that the current standards do not provide protection for all sensitive populations, including speci fically fetuses, neonates and children; and;

 epidemiological studies provide evidence indicating that current standards do not provide protection agains t chronic CO exposures.

The NESCAUM also offered the view that a lo wer standard may be appropriate, “perhaps based on an alternate indicator”, noting CASAC’ s preference, but recognized that “at this time the available epidemiological studies do not clearly indicate a specific level for the one or eight-hour standard”.

Comments received that recommended revisi ng the current standards are addressed in section II.B.3 of the preamble to the final rule. Specific aspects to some of these comments are additionally discussed below.4 3. Comments on Evidence

­ based Considerations

(1) Comment: In support of their view that the current standards fa il to protect public health with an adequate margin of safety, one commenter (ALA et al) summarized findings for a number of studi es of associations of respiratory endpoints with ambient CO concentra tions, describing them as providing evidence of harm from CO exposure below the current standards. Two commenters (ALA et al and CBD et al ) indicated that the Clean Air Act compelled EPA to revise standards in light of the epidemiological evidence, regardless of uncertainties.

Response: In addressing this comment EPA not es that it is important to consider

both the extent to which the evidence supports a causal relationship between ambient CO exposures and respiratory effect s, as well as the extent to which there is evidence pertinent to su ch effects under air qualit y conditions in which the current standards are met. With regard to the latter point and focusing on the epidemiological evidence, it is the studi es involving air quality conditions in which the current standards were met that are most informative in evaluating the adequacy of the standards (PA, p. 2-30). Yet the commenter provides no evidence that the studies they cite, some of which are conducted outside the U.S.,

focused on conditions that meet the curre nt U.S. CO standards. And, when considering the publicly available inform ation on attainment and non-attainment of the current standards in the study locatio ns for the time periods relevant to the U.S. studies cited by the commenters, it can be documented that the current standards were met throughout the peri od of study in only two study areas (http://www.epa.gov/airtrends/reports.html).

Further, as described in the ISA, EPA has determined the body of evidence for short-term exposure and respiratory morb idity to be only suggestive of a causal relationship (ISA, section 5.5.5.1). This c onclusion was reached due to a lack of

evidence on mechanism or mode of action that might lend biological plausibility to such a relationship for the low ambi ent concentrations of CO observed in epidemiological studies. A dditionally, the inability to sufficiently rule out the role of chance, bias and confounding in th e epidemiological associations observed contributed to the “suggestive” causal de termination. EPA further determined that the evidence is inadequate to infe r a causal relationship between long-term exposure to ambient CO and respiratory morbidity (ISA, section 5.5.5.2). Both of

these determinations were reviewed and endorsed by CASAC in their January 2010 letter to the Administrator (Bra in and Samet, 2010a), with CASAC additionally stating that the evidence of a potential causal relationship between short-term CO exposure and adverse re spiratory outcomes “borders between suggestive and inadequate” (B rain and Samet, 2010a).

As noted in the ISA, PA, the proposal notice and advice received from CASAC, there are several aspects to the epidemio logical evidence for CO that complicate5 its interpretation with regard to ambien t concentrations of CO that might be eliciting the reported health outcomes. In particular, a major challenge relates to the difficulty in determining the extent to which ambient CO is independently

associated with health effects or if CO at ambient levels is acting as a surrogate

for the effects of another traffic-relate d pollutant or mixture of pollutants (e.g., PA, pp. 2-36 to 2-39). As noted in the ISA in interpreting the epidemiological evidence, “the limited amount of evidence fr om studies that examined the effect of gaseous pollutants on CO-respiratory morb idity risk estimates in two-pollutant models, specifically NO 2 , has contributed to the inabi lity to disentangle the effects attributed to CO from the larger comp lex air pollution mix (particularly motor vehicle emissions), and this limits interp retation of the results observed in the epidemiologic studies evaluated” (ISA, p. 5-100). The ISA further noted that a “key uncertainty in interpreting the ep idemiologic studies evaluated is the biological mechanism(s) that could explain the effect of CO on respiratory health” (ISA, p. 5-100). CASAC also acknowledge d the potential for co-pollutants to serve as confounders to be “particularly pr oblematic for CO” and the need to give consideration to the possibility of CO serving as a surrogate for a mixture of pollutants associated to fossil fuel co mbustion (Brain and Samet, 2010a).

After considering the evidence, together with these areas of uncertainty, the

Administrator concluded in the final rule that the epidemiological evidence does not lead her to identify a need for any gr eater protection than that provided by the

current standards.

EPA also disagrees with commenters (inc luding ALA et al and CBD et al) who

state that even if the evidence of adverse effects at and below the current standard is uncertain, there is sufficient evidence to warrant revision of the standards to provide an adequate margin of safety agai nst adverse health effects. EPA agrees that section 109 is precautionary in nature , and, as discussed in the preamble (e.g., section I), the standard is intended to protect against risk associated with pollution

at levels below those at which human hea lth effects can be said to occur with reasonable scientific certainty. Thus, in selecting primary standards that provide an adequate margin of safety, the Admi nistrator is seeking not only to prevent pollution levels that have been demonstrat ed to be harmful but also to prevent lower pollutant levels that may pose an un acceptable risk of harm, even if the risk is not precisely identified as to nature or degree. At the same time, the Clean Air Act (CAA) does not require the Administra tor to establish a primary NAAQS at a zero-risk level. Rather, EPA’s task is to establish standards that are neither more nor less stringent than necessary.

Accordingly, EPA disagrees with the view expressed in one comment that “the CAA requires that the EPA act to protect pub lic health as soon as there is any data suggesting health effects from a pollutant” ( CBD et al at p. 5) as well as the view

that the information available in this review necessitates stronger standards to provide a margin of safety. An approach that based the standard on the existence of “any data suggesting health effects,” absent a careful weig hing of the evidence6 and risks, may well result in standards mo re stringent than necessary to protect public health with an adequate margin of safety. In evaluating the air quality criteria and public comments, the Administ rator has not required certainty as to

the occurrence of adverse health effects but rather has made judgments about how to consider the range and magnitude of uncertainties that are inherent in the information and analyses. For the reasons explained above and in the preamble,

the Administrator has conclude d that the current standard s are requisite to protect public health with an adequate margin of safety.

(2) Comment: In support of their view that EP A’s proposed retention of the current standards would not be protective of sens itive populations, tw o commenters (PSR et al, Donnay) argued that the CO-associa ted risks identified in epidemiological studies of birth defects, lower birth weight, asthma and neonatal respiratory mortality indicate that the health risks for fetuses, infants and children are much higher than risks reported in adults. The commenters characterized the risk for birth defects and neonatal resp iratory mortality to be as high as one or two orders of magnitude greater than those faced by adults. Add itionally, one commenter, in citing three studies of CO poisoning and cardiovascular damage in children (Donnay at p. 16) suggested that, based on such studies, EPA should incorporate a larger margin of safety in the final rule. Another commenter (CBD et al) indicated that the EPA did not appropriately consider epidemiological evidence on negative birth and developmental outcomes, and also stated that the Clean Air Act compelled EPA to revise standards in light of this evidence.

Response: As an initial matter EPA notes that , in considering the adequacy of the current standards, it is impor tant to consider both the extent to which the evidence supports a causal relationship between am bient CO exposures and adverse health effects, as well as the extent to which th ere is evidence pertinent to such effects under air quality conditions in which the cu rrent standards are met. With regard to the latter point, and focusing on the ep idemiological evidence, it is the studies involving air quality conditions in which th e current standards were met that are most informative in evaluating the ade quacy of the standards (PA, p. 2-30). Yet, of the six epidemiological studies ci ted by the commenters (e.g., PSR et al at pp. 8-9), all three of the U.S. studies (Ritz et al., 2002, 2006; Maisonet et al., 2001), as well as a fourth study that was performed in Brazil, included conditions when the current CO 8-hour standard was exceeded in those study areas (http://www.epa.gov/airtrends/reports.htm l; Conceicao et al., 2001). Sufficient information to assess the air quality cond itions in relation to the U.S. NAAQS for

CO is not available for the other two st udies cited (performed in Taiwan and Seoul, Korea). We additionally note that one of these latter two studies focuses on assessing associations between respiratory effects and long-term concentrations of ambient CO; EPA has c oncluded that the available evidence is inadequate to infer a causa l relationship for long-term exposure and respiratory morbidity (ISA, p. 5-101). In light of th is information, EPA disagrees with the7 commenters suggestion that these studies pr ovide evidence of a lack of protection afforded by the current standards. 1

The commenters further emphasize their view that the magnitude of the risks of birth defects and neonatal mortality associ ated with ambient CO suggested by the cited studies are greater than the risk faced by adults in response to similar increases in ambient CO, and that EPA s hould consequently give greater weight to evidence regarding birt h defects and neonatal mortality. The commenters’ view appears to be based on their compar ison of effect estimates from studies finding associations for these different t ypes of health outc omes with various measures of ambient CO. EPA notes, howev er, that such a comparison of effect estimates for health outcomes reported in st udies of adults, such as cardiovascular outcomes, to those from the studies of de velopmental and neonatal outcomes cited by the commenters is inappropriate and mi sleading with regard to the difference in magnitude of risks potentially posed to exposed populations by ambient CO. Such an isolated comparison fails to cons ider critical differe nces between the two types of analyses and observed risks. Su ch differences include differences in the

ambient air metric associated with the eff ect estimate, differences in the form of the effect estimates across some studies, and the fact that effect estimates are

estimates of an increase in prevalence of specific out comes, relative to the underlying prevalence of the health outcomes being examined. 2

Contrary to the commenters’ assertion as to a lack of appropriate consideration of birth and developmental outcomes, EPA ha s fully assessed the evidence regarding relationships between birth and developm ental outcomes and exposure to ambient CO, including the studies cited by the commen ters (ISA, section 5.4). Further, in reaching a decision regarding the adequacy of the current CO standards, the

Administrator considered this assessment , as well as uncertainties and limitations of the evidence (preamble to final rule, section II.B.3). EPA’s assessment of the body of evidence for the health outc omes emphasized by the commenter, including that for birth outcomes and de velopmental effects, concluded that the evidence indicates a potential for suscep tibility during pren atal and neonatal periods, but that the eviden ce is only “suggestive” of a causal relationship with ambient CO (ISA, sections 2.5.3 and 2.6.1). Specifically, th e ISA notes that evidence is lacking on mechanism or mode of action that might lend biological plausibility to a causal relationship be tween birth outcomes and developmental

effects and the low ambient concentrati ons of CO observed in epidemiological studies (ISA, p. 5-80). Additi onally, the inability to sufficiently rule out the role of chance, bias and confounding in the epidemiological associations observed contributed to the “suggestive” causal determination (ISA, section 5.4.3, Table 1- 2). Thus, we recognize much greater un certainty associated with a relationship

1 See comment response 4, below, for further discu ssion of the evidence for adverse health effects from chronic low level exposure to ambient CO.

2 With regard to the consideratio n of prevalence, for example, a 10 % increase for a more prevalent outcome, such as cardiovascular dis ease events, would translate to a mu ch higher impact (in terms of size of the population affected) than for more ra re outcomes, such as birth outcomes.8 between ambient CO concentrations and th ese health outcomes as compared to a relationship with cardiovascula r effects. As discussed in the previous response, EPA recognizes that the NAA QS are intended to provide protection against risk associated with pollution at levels belo w those at which human health effects can

be said to occur with reasonable scientif ic certainty, but does not believe that the NAAQS should be set based on “any data suggesting health effects,” absent a careful weighing of th e evidence and risks.

With regard to the three studies of CO poisoning and cardiovascular damage cited by one commenter (Donnay at p. 16), EPA not es that these studies involve COHb levels many times higher than the lowest COHb levels assessed in the study of coronary artery disease (CAD) patients by Allred et al (1989), which EPA has weighed heavily in this review of the CO NAAQS. Consequently, EPA disagrees that these studies – or the larger eviden ce base as a whole- provides a basis for a larger margin of safety than that re presented by the decision described in the preamble to the final rule. Further, cont rary to the assertion by commenter that

EPA considers adults to be more se nsitive than children, EPA has concluded, based primarily on the controlled human exposure studies of CAD patients that people with heart disease, such as CAD, regardless of age, are particularly susceptible to ambient CO exposures.

For the reasons described above and in the preamble, based on consideration of all of the currently available evidence, EPA considers the current standards to provide the requisite protection, includi ng an adequate margin of safety, to potentially susceptible populations or lif estages, including pregnant women and infants, as well as to the widely recogni zed at-risk population of people with heart

disease.

(3) Comment: One commenter (Donnay) stated th at EPA should conclude that there is biological plausibility for causal re lationships between ambient CO exposure and a range of noncardiovascular health out comes. In support of this view, the commenter stated that evidence of (a) organ and pathway e ffects at acute CO poisoning levels, as well as, (b) the role of CO in important physiologic pathways, also provides support for concluding th at CO affects the same organs and pathways at much lower ambient CO expos ure levels (i.e., those which exist in recent epidemiological studies). As a result the commenter states that EPA should conclude causal relationships ex ist between ambient CO exposure and infant mortality, adverse birth outcomes , childhood respiratory or immune system morbidity, adult mortality, and adult mo rbidity for a range of organ systems beyond the cardiovascular system and that there is evidence of such effects based on which EPA should revise the current NAAQS.

Response: As an initial matter, EPA notes our use of a consistent and transparent

basis for the framework we use to eval uate the causal nature of air pollutioninduced health effects (ISA, section 1.6) . This framework establishes uniform9 language concerning causality and brings specificity to the findings. The standardized language employed in the framework was drawn from across the federal government and wider scientific community, especially from the recent National Academy of Sciences, In stitute of Medicine document, Improving the Presumptive Disability Decisi on-Making Process for Veterans (NAS, 2008) the most recent comprehensive work on evalua ting causality. Under this framework, EPA has determined the separate bodie s of evidence for birth outcomes and developmental effects, short-term expos ure and respiratory morbidity, and shortterm exposure and mortality to each be only suggestive of a causal relationship with ambient CO exposures (ISA, sections 5.4.3, 5.5.5.1, and 5.6.5.1). These

determinations were reviewed and endorsed by CASAC in their January 2010 letter to the Administrator (Brain an d Samet, 2010a), although we additionally

note CASAC’s comments that the associ ation for short-term CO exposure and adverse respiratory outcomes “borders be tween suggestive and inadequate” (Brain and Samet, 2010a, p. 12). Based on EPA’ s provisional consideration of the additional epidemiological studies cited by the commenter, in the context of the findings of the ISA, EPA concludes that the new information and findings do not materially change any of the broad scie ntific conclusions made in the 2010 CO ISA and thus do not warrant reopening the air quality cr iteria review.

In considering the body of evidence for each of these outcomes, EPA disagrees

with the commenter’s view that CO poisoning studies (e .g., studies involving accidental exposures to very high concentr ations of nonambient CO resulting in very high COHb levels) address uncertain ties with regard to the biological plausibility for CO effects at lower ex posures. Rather, EPA deliberately excluded studies involving CO poisoni ng (including the more than 100 publications cited by the commenter) from this review, judging th em to be “not directly relevant to ambient exposures” (ISA, pp. 1-6 and 1- 7). Such high-level CO exposures described in clinical reports are extr emely unlikely to be experienced under ambient exposure conditions, as demonstrated in the REA. In addition, the types of adverse effects (including severe neurological impair ment and death) observed at very high COHb levels have not been demonstrated following CO or COHb

concentrations associated with ambient exposure (ISA, section 5.3).

The commenter also states that CO effect s at the other end of the spectrum from CO poisoning – i.e., effects of endogenous CO – inform our consideration of the biological plausibility of a causal role for carbon monoxide in the identified health outcomes. The available literature on the topic of endogenous CO is vast. In fact,

the commenter cites 144 reviews of endogenous CO and heme oxygenase. The

EPA is aware of the literature on whic h these many reviews are based, and has included two timely review articles in on this topic in the ISA. 3 The important role played by endogenous CO in physiologic pathways and the potential for exogenous CO to influence these func tions is described in the ISA:

3 Review articles are generally not included in the ISA. Rather than bring forward new information in the form of original research or new analyses, these artic les typically present summaries or interpretations of existing studies.10  “CO is a ubiquitous cell signaling mol ecule with numerous physiological functions.” [ISA, p. 5-12]

 “A key issue in understanding the biol ogical effects of environmentallyrelevant exposures to CO is whether the resulting partial pressures of CO (pCO) in cells and tissue can initia te cell signaling which is normally mediated by endogenously generated CO or perturb signaling which is normally mediated by other signaling molecules such as NO.” [ISA, p. 5- 9]

Some recent animal in vivo and in vitro studies demonstrate exogenous CO effects on signaling pathways and tissue and ce llular levels of CO under certain conditions (ISA, tables 5-1 and 5-2). Little is known however regarding kinetics or compartmentalization of CO pools. Further, there is uncertainty in extrapolating cell signaling re sults to adverse health outcomes as recognized in

the ISA: “Whether or not environmentall y-relevant exposures to CO lead to adverse health effects through altered ce ll signaling is an open question for which

there are no definitive answers at this tim e” (ISA, p. 5-12). As a result of these considerations, the biological plausib ility for causal relationships between ambient CO exposure and a range of non cardiovascular health outcomes is not firmly established. More evidence is required to definitively link altered cell signaling with adverse health outcomes following environmentally-relevant CO

exposures.

In summary, EPA does not find the issues raised by the commenter to support a

conclusion that relevant ambient concentr ations of CO are causally related to a broad range of health effects, and furthe r disagrees with the commenter that there

is cause for concern for such health effects under conditions when the current

standards are met. For the reasons descri bed in response to comments (1) and (2) above, and in the preamble, based on consideration of all of the currently available evidence, EPA considers the curr ent standards to provide the requisite protection, including an adequate margin of safety, to potentially susceptible populations or lifestages, incl uding pregnant women and infants, as well as to the widely recognized at-risk population of people with heart disease.

(4) Comment: Two commenters (PSR et al; D onnay) stated that EPA should be concerned regarding chronic exposures to CO and that the evid ence indicates that the current standards do not afford prot ection against chronic exposures. In arguing that a range of health effect s (to neurological, respiratory and cardiopulmonary systems) reported to be associated with CO poisoning

conditions are relevant to much lower ambient CO concentrations, the second commenter (Donnay) additionally stated that “EPA should err on the side of caution in establishing the CO NAAQS by making the reas onable assumption that chronic or repeated low level CO expos ures may increase the risk of these outcomes.” Talking points provided by this commenter in written testimony accompanying their oral testimony stated th at “...chronic low-level CO exposures11 result in more severe and persistent CO illnesses than single high level acute exposures.” (Donnay written te stimony February 28, 2011, p. 5).

Response: EPA disagrees with the commenter that it is a “reasonable assumption that chronic or repeated low level CO e xposures may increase the risk” of a range of outcomes associated with CO pois oning conditions. Additional statements made by this commenter implied to be rele vant to chronic CO exposures are that low CO exposures result in a slower, mo re gradual uptake into the blood stream than higher CO exposures, providing a longer period during which CO “free in plasma” (i.e., not bound to hemoglobin) is av ailable for distribution into tissues. As an initial matter, EPA notes that, due to the strong affinity of hemoglobin (Hb) for CO, there is very little free CO occurri ng in plasma, with less than 1% of total body CO appearing as dissolved CO in body fluids (ISA, p. 4-12). In support of

the commenter’s view that chronic low CO exposures result in greater uptake into tissues, the commenter cites a small st udy involving 7 individuals where control subjects appeared to have higher CO upt ake into muscle tissue compared to COexposed subjects (ISA, p. 4-16). However, this study, in which direct measures of tissue CO were not reported, is in cont rast with evidence from a study which directly measured CO liberated from ti ssues and demonstrated that tissue CO increased with increasing COHb level (ISA, Table 4-2, p. 4-16), which is consistent with the prevailing theory on CO pharmacokinetics. Thus, while EPA agrees with the commenter that the e quilibrium between inhaled CO and blood COHb is approached more slowly at lower COHb levels compared to elevated COHb, a slower rate of uptake does not i ndicate greater total CO uptake. Rather, the rate and amount of upta ke into tissue compartments is controlled by the blood to tissue CO pressure differential, which is greater at higher COHb levels. Thus,

consistent with the lack of chronic effects observed in the CO evidence base (discussed below), the body of evid ence does not support the commenter’s contention of increased uptake over time at low CO concentrations.

EPA considered the evidence currently available on cardiovascular and respiratory morbidity and long-term (chroni c) CO exposures and determined that the evidence was inadequate to determin e that a causal relationship exists at relevant ambient CO exposures (ISA, pp. 2-6 and 2-9). EPA further considered the currently available evidence with re gard to neurological morbidity and longterm (chronic) CO exposures, concluding that the evidence was only suggestive of a causal relationship with relevant ambien t exposures. This conclusion is based on a lack of evidence, such as that wh ich might come from mechanistic studies, that might lend biological plausibility to epidemiological study results and the inability to sufficiently rule out the ro le of chance, bias and confounding in the epidemiological associations observe d (ISA, pp. 2-7, 1-14). Further, our conclusion regarding the evidence on chr onic exposures to CO in relation to mortality indicates “...that there is not likely to be a causal relationship between relevant long-term exposures to CO and mortality” (ISA, p. 2-10). During this review, CASAC endorsed EPA’s conclusi ons regarding chro nic exposures to ambient CO (Brain and Samet, 2010a, pp. 12, 16). Thus, EPA’s judgment is that12 the current body of evidence does not s upport the commenter’s view that the current standards fail to pr ovide adequate public health protection against chronic exposures to ambient CO.

(5) Comment: One commenter (Donnay) stated that the ISA and other documents developed in this review do not reflect the latest scien tific knowledge useful in identifying ambient CO effects as required by the Clean Air Act. This commenter

identified a number of st udies not discussed in the ISA which he describes as relevant. Another commenter (ALA et al) also identified two studies not

discussed in the ISA as relevant. Donna y further questioned EPA’s procedure for reviewing the relevant CO literature in preparation of the ISA, questioning “whether EPA conducted a sufficiently comprehensive literature review”, providing a list of articles, some of which were published prior to the cut-off date for the ISA and some published subsequently (Donnay, p. 8).

Response: EPA disagrees with the comment that the ISA does not reflect the latest scientific knowledge on effects of ambient CO. Rather, EPA considers the ISA to represent a thorough review of the latest scientific kn owledge pertaining to the effects of ambient CO, consistent w ith the requirements of CAA section 108. In their review of the second draft ISA, CASAC agreed, stating that the “CO ISA will be adequate for rulemaking with the incorporation of changes in response to the Panel’s major comment s and recommendations” (Brain and Samet, 2010a).

As to the comprehensiveness of the literature review conducted by EPA, as described in section 1.3 of the ISA, EPA scientists and collaborators conducted comprehensive literature searches in multiple health and atmospheric science disciplines to identify original peer-rev iewed research publishe d since the last CO NAAQS review. These searches focuse d on articles published between 1999 and May 2009, the cutoff date for articles to be included in the ISA. Researchers screened the large body of search results to identify potentially relevant articles to be considered in preparing the ISA. In addition to these broad searches, targeted searches were conducted using search strate gies such as review of pre-publication tables of contents of relevant journals , searches on specific topics, and citation mapping to find papers citing known articles . Additional articles were identified by the public and CASAC during external re view of two drafts of the ISA and

other review documents.

EPA notes that, in contrast to Air Qual ity Criteria Documents prepared during previous reviews, which were more en cyclopedic reviews of the scientific literature, ISAs developed under the current NAAQS process are intended to present a “concise evaluation and synthesi s of the most policy relevant science (ISA, p. 1-1). CASAC has endorsed this approach during the CO NAAQS review (Brain and Samet, 2009; Brain and Samet, 2010a). Policy-relevant questions critical to the review were identified prio r to preparation of th e first draft CO ISA through a kickoff workshop held Januar y 28-29, 2008 (73 FR 2490) and described in the Integrated Review Plan (USEPA, 2008), a draft of which was the subject of13 a consultation with CASAC (73 FR12998; Henderson, 2008). These policyrelevant questions, presented on page 1-1 of the CO ISA, formed the basis for

EPA’s consideration of the scientific evid ence. In considering the available CO literature, topics such as those raised by commenters (e.g., very high concentration exposures in humans and anim als) were not found to be informative

to assessment of the health effects of ambient CO or to the policy-relevant questions for this review (ISA, pp. 1-6. 1-7). Thus, these topics were not extensively discussed in the ISA.

EPA has considered the articles identif ied by commenters and determined that many of them were not included in the IS A as they fall outside the scope of the ISA document as they were not found to be informative to assessment of the

health effects of ambient CO or to the policy-relevant questio ns for this review (ISA, pp. 1-6, 1-7). Studies listed by comme nters that fall within the scope of the ISA (listed in Appendix A), including recent studies published after the cutoff date for inclusion, have been provisionally considered in topic-specific comments

elsewhere in this document. Based on th is provisional consid eration, we conclude that the information provided by these st udies does not materially change the

conclusions reached in the ISA. Accord ingly, as discussed in section I.C of the preamble, EPA is not re-opening the air quali ty criteria for this review to further

consider these studies.

(6) Comment: One commenter (Donnay) questions how EPA can rely on

consideration of the lowest tested COHb level in Allred et al (1989) study in judging the standards to provi de adequate public health protection when EPA has stated that this study provided no evidence of threshold. This commenter claims EPA has no scientific or legal basis for their consideration of the Allred results for this purpose, which the commenter clai ms to suggest a “reckless and wanton disregard for public health” (Donnay, p. 2). The commenter additionally

describes statements or actions of the World Health Organization (WHO), U.S. Agency for Toxic Substances and Disease Registry (ATSDR), and U.S. National Academies of Science, National Resear ch Council (NRC) as indicating that evidence is lacking to inform EPA’s decision regarding a CO NAAQS that protects public health with an adequate margin of safety.

Response: EPA first notes that, as discussed in section I.A of both the proposal and final notice, the Clean Air Act do es not require that the NAAQS be established at a zero-risk level, but rather at a level that reduces risk sufficiently so as to protect public health with an adequate margin of safety. In setting primary standards that are “requisite” to provide this degree of public health protection, the Supreme Court has affirmed that EPA’s task is to establish

standards that are neither more nor less st ringent than necessary for this purpose. Accordingly, a lack of evidence for a thre shold effect level for exercise-induced myocardial ischemia resulting from CO exposure does not mean that there is no14 standard level that would be protective of public health with an adequate margin of safety.

As noted in section I.A. of the final rule, in addressing the Clean Air Act requirement for an adequate margin of sa fety, the EPA considers such factors as the nature and severity of the health effects involved, the size of the sensitive population(s) at risk, and the kind and de gree of the uncertainties that must be addressed. The selection of any particul ar approach to providing an adequate margin of safety is a policy choice left specifically to the Administrator’s judgment. For example, in considering the controlled human exposure studies

that describe the effect of short- term CO exposure on exercise-induced myocardial ischemia in coronary artery disease patients, as described in section II.B.3 of the final rule, the Administrator c onsidered the nature and severity of the health effects involved, as we ll as the kind and degree of the uncertainties in those studies as well as in the exposure and dose assessment. Based on such considerations, as well as those concerning the rest of the evidence, as discussed in section II.B.3 of the final rule, the Administrator judged th e current standards to provide the requisite public health protection against effects of concern.

With regard to the commenter’s reference to a WHO publication, we note the citation is to an article by D. Schw ela (2000) in which WHO publications are reviewed. As the commenter notes, the summary for CO in this article, states that “[a]mbient CO may have even more serious health consequences than does COHb

formation and at lower levels than that mediated through elevated COHb levels”. Although somewhat unclear, this statemen t may be intended to reference the potential for effects of CO unrelat ed to COHb-mediated decreased oxygen delivery to tissues. EPA has considered the evidence that exogenous CO may initiate or alter cell signaling, as descri bed in section 5.1.3 of the ISA. These mechanisms are likely to involve the binding of CO to reduced iron in heme proteins other than Hb with subsequent alteration of heme protein function. COHb may play a role in these processe s by delivering CO to cells and tissues (ISA, p. 5-9), however, the role of these effects in producing health outcomes, as

well as whether these effects occur in response to CO e xposures relevant to those

associated with ambient air is still un certain (ISA, p. 5-12). The ATSDR report cited by the commenter points to a sim ilar mechanistic pathway: “ given the physiological role of endogenous CO...., any exogenous source of CO exposure” has “the potential for produc ing potentially adverse effects.” The ISA states that ambient CO has the potential to alter ce ll signaling processes which may result in

downstream health effects but notes that this is an area of uncertainty, stating that “[w]hether or not environm entally-relevant exposures to CO lead to adverse health effects through altered cell signa ling is an open question for which there are not definitive answers at this time” (ISA, p. 5-12). Thus, EPA assessed the evidence for these pathways in the ISA, and Administrator took into consideration the possibility of adverse health effect s together with the uncertainties, and concluded that the current standards pr ovide the requisite protection, with an adequate margin of safety.15 The commenter also points to the NRC’ s decision to not establish an acute exposure guideline level (AEGL) 4 for “non-disabling” effects (an AEGL-1) for CO, implying that this is related to co nsideration of uncer tainty regarding a threshold for effects. EPA notes, however, that that is not the basis for the NRC’s decision. Rather, as the NRC report de scribes, an AEGL-1 value was not recommended because susceptible persons may experience more serious effects (usually the basis for AEGL-2) at con centrations that do not yet cause nondisabling effects (usually the basis fo r the AEGL-1) in the general population (NRC, 2010). Thus consistent with th e NRC methodology for cases such as this (NRC, 2001, p. 41 5 ), the NRC did not set an AEGL-1. EPA additionally notes

that the data on which the NRC relied for their decisions was that which focused on effects observed in response to elevations in COHb (e.g., Allred et al., 1989). Thus, particularly given the widely differing purposes for AEGLs and NAAQS and the statutory framework for NAAQS, EPA does not believe that the NRC’s conclusions regarding AEGLs for CO are inconsistent with the Administrator’s judgment as to the degree of protection afforded by the current standards.

4. Comments on Exposure and Risk Considerations

Included in this section are comments con cerning consideration of the quantitative exposure and health risk assessments in the decision on the adequacy of the standards, which are generally not discussed in the preamble to the final rule.

(1) Comment: One industry commenter (AAM), in concurring with EPA that the current standards provide a high degree of protection for the COHb levels and associated health effects of concern, also identified aspects of the REA that in

their view result in the risk being overstated in the upper tail of the COHb

distribution.

 The reduced number of monitori ng sites from which ambient CO

measurements were drawn for the De nver study area inappropriately biases the exposure concentration distribu tion upward through giving relatively

4 Acute exposure guideline levels are established by the AEGL committee of the NRC for use in emergency planning. As defined by the NRC, an AEGL-1 is the airborne concentration of a substance “above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.” An AEGL-2 is defined as the airborne concentration of a substance “above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects, or an impaired ability to escape.” [NRC, 2001]

5 In cases in which the biologic criteria for the AEG L-1 value would be close to, or exceed, the AEGL-2 value, the conclusion is reached that it is “not recommended” (NR) to develop AEGL-1 values. In these cases, “detectability” by itself would indicate that a serious situation exists. In instances in which the AEGL-1 value approaches or exceeds the AEGL-2 valu e, it may erroneously be believed that people experiencing mild irritation are not at risk when in fact they have already been exposed to extremely hazardous or possibly lethal concentrations. [NRC, 2001, p. 41]16 greater weight to a site (in traffic isla nd) not representative of locations where people in the population spend their time.

 In-vehicle and near-roadway CO concen trations are overestimated; there is no evidence of 1-hour exposure concentrations as high as 60 parts per million (ppm) in vehicles in areas that meet th e current CO standards, indicating that the ratio method used for this microenvironment in the REA produces overestimates of exposure concentration.

 The cities on which the REA focused are worst case situations with regard to ambient CO concentrations nationally.

Response: With regard to the first REA aspect cited, AAM contend that the four

Denver monitors used in the current RE A overestimate risk relative to that estimated in the 2000 probabilistic NAAQS Exposure Model (pNEM) analysis (Johnson et al., 2000) which used ambient CO concentrations from six monitors. Specifically AAM charges that the approach used in the REA “biases the distribution upward by overs tating the number of peopl e exposed to high CO

concentrations.” EPA first notes that all four Denver monitors used in the current assessment were also used in the previous CO exposure and dose assessment conducted by Johnson et al. (2000) (see REA, Table 5-1). The two monitors that

were not used in the current assessment but used in the prior assessment were

located outside of the urban core of Denver. 6 Neither of these additional monitors reported CO measurements for 2006, the year selected to represent as is air quality in the REA. In developing the exposure modeling domain (described in REA sections 5.3 and 5.4), EPA staff elec ted to maintain consistency in the

ambient monitors chosen for the curren t assessment and considering the multiple air quality scenarios evaluated rather th an attempt to be consistent with the

ambient monitors used in the prior 2000 assessment.

While use of the four Denver urban core monitors may result in a greater percent of the population at or above selected benc hmarks when compared with that of a simulation conducted using the six monitors from the 2000 assessment (and assuming the added two monitors in the modeling domain have lower

concentrations relative to the four monitors used and all other modeling parameters are identical), EPA staff no te that the actual number of persons (and person-days) at or above a benchmark within the air districts de fined by these four monitors (all other modeling parameters held constant) would likely not be

different than if the simulation had cove red a larger study area inclusive of the areas surrounding the other two monitors that are outside of the Denver urban core. This is because the simulated popul ation residing within the census tracts and encompassed by the same air qua lity districts is identical.

The commenter additionally states that incl usion of the microscale site at the main

intersection in Denver overstates the number of people exposed to high CO

6 The first monitor was ID 080050002 sited in Littleton, Colorado (Arapahoe County). The second monitor was actually an aggregation of CO concentrations from two closely sited Boulder, Colorado monitors: ID 080130010 and 080131001 (Johnson et al., 2000).17 concentrations and the fraction of time exposed. EPA notes, however, that the

evidence indicates and CASAC also concl udes that there is a segment of the population that spend some of their time in proximity to locations such as the microscale, near-road site where short-term CO exposures may be elevated (REA, section 3.1.3). The importance of cap turing near-road microenvironments in considering ambient CO exposures was emphasized multiple times over the

course of this review in comments r eceived from CASAC who raised concerns with regard to the ability of the exis ting CO monitoring netw ork to provide for this aspect of CO population exposures. 7 Further, a simulation from which this monitor was omitted would lack representa tion of the large spatial variation in

short-term concentrations that the evid ence indicates generally occurs across an urban area as a result of the steep concen tration gradients near roadway locations

where it is formed. 8 Thus, EPA finds the use of the full set of monitors, including the microscale site to be appropriate. 9

As an initial point of clarification with regard to the statement made in the 2 nd
comment by AAM, the modeling for conditi ons just meeting the current 8-hour

standard did not use 1-hour in-vehicle concentrations approaching 60 ppm. As clearly stated in footnote d for the table referenced by AAM in making this statement (REA, table 6-9, p. 6-14), the microenvironmental CO concentrations presented are for exposure events that ranged in duration from 1 minute to 1

hour. 10,11 In fact, the highest concentration not ed in this table (for the simulation of conditions just meeting the current standard in Denver), which is 63.4 ppm,

7 See, for example, CASAC letter of June 24, 2009, in which they stated that “[r]elying only on EPA’s fixed monitoring network CO measurements may underestimate CO exposures for specific vulnerable populations such as individuals residing near heavily trafficked roads and who commute to work on a daily basis” and “[r]elevant microenvironments that are influenced by local fact ors, such as in-vehicles {sic} and in high proximity to roadways, are not well represented.”

8 The other three monitors in the study area are more similar to each other with regard to concentrations in the upper end of the distribution of 1-hour concentra tions than they are to the micro-scale site monitor identified by commenters (REA, Table 5-18).

9 EPA also notes that if the micro-scale site was omitted for the simulation of conditions just meeting the current 8-hour standard, another of the three monitors would be identified as the design monitor and all monitor concentrations would be adjusted to the point where that design monitor just met the current 8- hour standard. As these remaining three monitors are more similar to each other with regard to concentrations in the upper end of the distribution of 1- hour concentrations than th ey are to the micro-scale site monitor identified by AAM (REA, Table 5-18), the adjusted ambient CO concentrations would be generally higher across the full study area if only those th ree monitors were included in a simulation. This would be expected to contribute to a larger number of occurrences of generally higher CO exposures and might also include a greater percent of the CHD population with COHb levels over 2% or higher

benchmarks.

10 REA Table 6-9, footnote d states “The mean, standard deviation, and percentiles (p) were calculated using all events regardless of event duration. Note that based on the activity pattern diaries used, the length of an event can range from 1 minute to 1 hour.”

11 These event-level microenvironmental concentratio ns were generated from a model simulation designed to output minute-by-minute microenvironmental concentrations. As described in sections 5.10 and 6.1 of the REA, these microenvironmental concentration and ratio analyses were generated using a reduced model run of 5,000 persons per air quality scenario and with in each study area due to the magnitude of the files generated and the time required to process each persons’ event-level data. The full exposure model runs used 50,000 simulated individuals and generated summary output data files only.18 was estimated to occur for a single 2-mi nute exposure event and that event was in

an outdoor microenvironment and not inside a vehicle (see REA, figure 6-3). We note though that most (about 95%) of the highest microenvironmental concentrations ( ≥ 20 ppm) simulated in Denver were a ssociated with the in-vehicle microenvironment (REA, Figure 6-3). The highest estimated in-vehicle concentration, 56.9 ppm (REA, Table 6-9) , however, was associated with a 1- minute exposure event, not 1 hour. 12 In the simulation for the Los Angeles study area under conditions just meeting the cu rrent standard, maximum event-level microenvironmental concentrations (r anging from 1-minute to 1- hour in duration) were much lower than Denver and estimated to be at or above 30 ppm (REA, Table 6-12 and Figure 6-4), with most occurring inside vehicles. The maximum exposure concentration was 39.8 ppm (REA, Table 6-12) occurring for two exposure events with duration of 5 and 10 minutes, well short of the 1 hour duration stated by the commenter.

Further, EPA disagrees with the comment er’s contention that there are no data supporting the magnitude of the in-vehicle exposure concentrations in the REA. As noted in the REA (p. 6-17), “estima ted upper level concentrations [for both study areas] for the in-vehicle micr oenvironment are within the maximum measured peak level (one minute average) concentration report ed by Rodes et al. (1998) of 67 ppm during rush hour comm utes in Los Angeles (ISA, section 3.6.6.2).” The REA exposure concentrations are also consistent with the AAM statement that “both the Shikiya et al. and Rodes et al. studi es report peak CO concentrations of the order of 50 ppm” (AAM comments at p. 5).

EPA notes that under conditions just mee ting the current standard in the Denver and Los Angeles study areas, the ma ximum 1-hour microenvironmental

concentrations were estimated from th e 5,000-person simulations (see footnote 11 above) to be 37.1 ppm and 34.8 ppm, respec tively, both of which occurred inside

vehicles. 13 These event-level result s developed from the 5,000-person simulations are consistent with the results reported for the full model simulations (REA, Tables 6-7 and 6-10) and what is sp ecifically stated in the REA regarding maximum 1-hour exposure concentrations 14 in the Denver study area where the “highest 1-hour daily maximum exposure wa s estimated to be at or above 40 ppm (but below 60 ppm)” (REA, section 6.1.2, p. 6-11). Regarding the Los Angeles study area, the REA similarly states that “the range of the 1-hour daily maximum exposure distribution extends upward to 30 ppm, but less than 40 ppm.”

12 The duration of the exposure event in these microenvironments was obtained from analyzing the APEX events file for this simulation; it is not specifically reported in the REA.

13 These maximum 1-hour microenvironmental concentrations were not directly reported in the REA and are from the 5,000 person simulations, though they are consistent with the distribution of maximum 1-hour exposure concentrations that were reported in the REA for the full model runs.

14 In the full model runs, the 1-hour exposure concentrations are summarized by time-averaging across all microenvironments persons inhabited within the clock hour. As such, the 1-hour exposure concentration could be comprised of a single microenvironmental c oncentration (duration of 60 minutes) or multiple microenvironments (durations of less than 60 minutes). Specific microenvironment information is not included in these hourly summary output files.19 Therefore, assuming that most of th e highest CO exposure concentrations occurred inside vehicles, estimated 1-hour maximum concentrations were reported in the REA as mostly less than 40 ppm for the in-vehicle microenvironment and not “approaching 60 ppm” as charged by AAM.

In their rationale for concluding the REA overestimated in-vehicle concentrations, AAM also stated that Rodes et al. (1998) “reported in-vehicle CO concentrations between 3 and 5.4 ppm for 2-hour measuremen ts.” This refers to the range of

mean values calculated in the Rodes et al. (1998) study, which, as they are mean concentrations over periods well longer th an a few seconds, are more relevant to

the mean of the simulated in-vehicle concentration reported in REA Table 6-9

rather than to maximum microenvironmental concentrations. In fact the mean invehicle concentration in REA Table 6-9 is 3.5 ppm, falling toward the lower end of the range quoted by AAM. Even consid ering this excellent agreement between the Rodes et al (1998) mean measured in-v ehicle CO concentra tions and the mean modeled concentrations reported in the RE A, we note that the Rodes et al. (1998) study only included measurements for a few hours of the day, all occurring within a 9-day period in late September and early October 1997 in Los Angeles. In the REA, exposure concentrations are estim ated for, at a minimum, 8,260 exposure

events 15 of each simulated individual’s full year exposure profile. Throughout a year there are a variety of emission, mete orological, physical, a nd personal factors that influence ambient and exposure con centration variability captured by the model and likely not at all represen ted by the data typically reported in

measurement studies. The ISA indicates th at when considering four basic seasons of the year, the mean and maximum ambi ent CO concentrations are highest in winter for Los Angeles (ISA, Figure 3-22) , a time period represented by the REA exposure simulations but not by the Rodes et al., (1998) study. Given that, it is very likely that the Rodes et al. (1998) study does not represent the upper percentiles of the in-vehicle concentrati on distribution occurring for that year of the study (1997), thus limiting its compar ability with the REA in-vehicle

estimates.

AAM further compares REA estimated upper percentile in-vehicle concentrations from simulations for air quality that just meets the current standard to measurements reported by Westerdahl et al. (2005), a comparison which EPA notes is inappropriate. This comparison is inappropriate because the Westerdahl et al. (2005) study was conducted in 2003, a year having ambient CO

concentrations well below the curren t NAAQS. Median ambient 1-hour monitoring concentrations from th at 2003 study ranged from 0.6 to 1.0 ppm (Westerdahl et al., 2005, Table 2) and are more comparable with the REA as is air quality scenario that employed 2006 Lo s Angeles ambient monitoring data in

which median 1-hour concentrations ra nged from 0.3 to 0.7 ppm (REA, Table 5- 16).

15 As described in REA section 4.4.3.2, a person could be exposed for periods as short as 1 minute with a maximum duration of 1-hour, depending on the duration of the person’s activity performed or their time spent in a particular microenvironment.20 AAM also argue that the ratio method used by EPA to estimate in-vehicle

concentrations would tend to bias CO concentrations high, particularly in an urban area if ratios are generated from other less urbani zed areas having low background concentrations. In such inst ances, AAM allege that the distribution of derived ratios would be higher than sim ilar ratios generated in locations, such as urban areas, where background concen trations are typically higher. EPA responds, however, that the method used to estimate all microenvironmental concentrations (including in-vehicle) in the REA (which was derived from

measurement studies conducted in Denver and Los Angeles, as described in the REA section 4.4.4.3.1) would tend to guard agai nst the mismatching of high ratios with high ambient concentrations. The microenvironmental algorithm employs an exponential transformation of the ambi ent concentration (REA, sections 4.4.4.3 [pp. 4-19 to 4-20], 4.4.4.4 and 5.9.1 [pp. 5-27 to 5-29]) that effec tively produces a “compression” effect in which the ratio of outdoor CO to ambient monitor CO tends to become smaller (on average) as the ambient monitor concentration increases (REA, p. 5-28). Section 5.10.2 of the REA discusses the relationship

between estimated microenvironmental c oncentrations and their associated ambient monitor concentrations, and de monstrates that the phenomenon about

which the commenter is concerned does not occur. For example, ratios derived in

the REA of the estimated microenvironmen tal concentrations to the associated ambient concentrations (for the in-residence and in-vehicle microenvironments) illustrate an inverse relationship (REA, Figure 5-3), rather than the direct relationship that the commenter presum es. As stated in the REA, this demonstrates that the high ratios “tha t might have occurred when randomly sampling from the distributions used in Table 5-22 were effectively modified by the ambient concentration exponentia l adjustment (equation 4-11), thus controlling for extreme ratio and high c oncentration combinations in estimating

the microenvironmental concentr ations (REA, p. 5-35).”

As basis for the commenter’s statemen t that the study areas selected for

assessment in the REA would be considered a “worst case” situation, they cite the discussion of ambient monitoring in these cities reported by the National Research Council (NRC, 2003). EPA notes, that the NRC report mentions these two cities among a list of elev en locations across the U.S. 16 that were identified as locations where NAAQS attainment “has b een a particular ch allenge” because of a combination of conditions that may favor accumulation of CO emitted into the ambient air, and associated increas es in CO concentrations, including meteorological, topographical, vehicle emi ssion, and CO transport issues (NRC, 2003). The NRC report does not, however, identify Denver and Los Angeles as cities representing the worst cases among th e eleven identified, nor does it refer to the individual “CAMP” and “Lynwood” monitors mentioned by AAM as reporting “worst case” CO concentrations. In fact, when considering the current

16 The nine other locations identified in Table 1-1 of NRC (2003) include: Birmingham, AL; Calexico, CA; Fairbanks, AK; Phoenix, AZ; Spokane, WA; Las Vegas, NV; Anchorage, AK; El Paso, TX; and Kalispell,

MT.21 8-hour CO NAAQS, the NRC report identif ies a monitor in Birmingham Alabama (01-073-6004) as having the greatest number of exceedances during 1995-2001 (the period examined) of the 11 locations discussed (Table 1-1, NRC, 2003).

EPA does not consider the two study areas to represent “worst case” situations. As explained in the REA (section 5.3), st udy area selection criteria included “the prior analysis of these locations in CO NAAQS reviews, the areas having historically elevated CO concentrations , and the areas currently having some of the most complete ambient monitoring da ta available” (REA, p. 5-2). There are two benefits in using these two pa rticular study areas for our exposure assessment. Minimal adjustment was needed to simulate the air quality scenario of just meeting the current standard, as CO monitoring concentrations had in the past been at levels just a bove and below the current CO standards in both of these locations, thus providing a more realis tic simulation of such an air quality scenario, and previous CO exposure assessmen ts had also focused on these areas. Further, the relationship between 1-h our and 8-hour average ambient CO concentrations, a characteristic EPA noted as influential in differences in the population occurrences of elevated end-of -hour COHb estimates for the datasets for these two locations for the just mee ting the current standard simulations was described in the Policy Assessment (PA, p. 2-41). The ratios of 1-hour to 8-hour design values for the two study areas were not extreme among all U.S. counties in the most recent year for which data were available (2009). The ratio for the Los Angeles dataset corresponded to approximately the 25 th percentile of U.S.

counties in 2009 while the Denve r dataset corresponds to the 75 th percentile.

(2) Comment: Comments from one individual (Donnay) stated that the CoburnFoster-Kane (CFK) model used by the Agency is in error and should not be used to estimate COHb. Specifically, in usi ng selected results of a comparison of CFK model estimates to experimental COHb measurements published by Benignus et al. (1994), Mr. Donnay suggests the range of predicted error in the CFK model is “almost the 2% threshold upon which EPA’ s entire risk and exposure assessment modeling is based” (Donnay, p. 4).

Response: In considering this comment, EPA fi rst notes that there are occasions where the CFK model may either over or underestimate % COHb in an individual’s blood (thi s is referred to here as mode l or prediction error). In general, the frequency and magnitude of prediction errors in any model are commonly linked to the model’s ability to re present the most, if not all, influential variables that affect variability in the estimated values. Such occasions of CFK model prediction error, whic h are described in the 2000 Air Quality Criteria for

Carbon Monoxide (AQCD) (USEPA, 2000, pp. 5-14 to 5-15), can include specific minutes within a CO exposure time series, particularly those associated with substantial CO exposures, and su ch occasions are the focus of the commenter’s statements on this issue. However, EPA disagrees with the commenter’s limited interpretation of th e published findings by Benignus et al.22 (1994), which evaluated CFK model pr edictions against experimental measurements. The commenter did not fully consider the inte nt of the Benignus et al. (1994) research and study design, its many findings and conclusions, conclusions drawn from other publications that evaluated the CFK model, and thus, the relevance of Benignus et al. (1994) to the CFK modeling done in the

REA.

As an initial matter, by claiming that CF K predictions are in error by “almost the 2% threshold in % COHb” which is a benchmark used in the REA, the commenter is inappropriatel y citing a Benignus et al (1994) result for a single maximum underestimation by the CFK mode l of 3.8% in one participant at one time point, and implying that this study i ndicates that an underestimation of the same absolute value of the percentage COHb is likely in the REA. Notwithstanding the likely lower prediction error for the much lower exposures which are the focus of the REA, discusse d in more detail below, EPA notes that model prediction error from the Benignus et al (1994) paper is more appropriately considered in terms of the percentage of the total measured (or predicted) value that is represented by the absolute differe nce in values between the measured and predicted values. For example, in th e study by Benignus et al. (1994), for which

the total % COHb levels of the participants ranged from about 12 to 18% COHb, the underestimation of 3.8% cited by the commenter represented a maximum prediction error for that specific time point for that individual of about 20-30% of

the individual’s absolute COHb level. 17 Thus, if it were the case that the individual time point errors for the highe r CO exposures of Benignus et al. (1994) were predictive for the substantially lo wer exposures of the REA, this finding might indicate that the maximum predic tion error for an REA prediction of 2%

COHb could be as much as an incremen t of 0.6% COHb (i.e., 30% of 2% COHb).

Importantly, however, the CO exposures that are the focus of Benignus et al. (1994), and which are substantially higher th an those in the REA, are associated with higher prediction errors on individua l time points than occur for lower CO exposure scenarios. For example, as described in the 2000 AQCD, Hauck and Neuberger (1984) compared the 5-minute tim e series of COHb observations with CFK model predictions in four indivi duals, each exposed to varying CO concentrations, while at rest and perf orming moderate exercise (2000 AQCD, p. 5-14). While CO exposure concentrations in this study were still somewhat higher than those simulated in the REA (i.e., generally study participant were exposed to one hundred to hundreds of ppm) , the resulting COHb time-series for a few subjects fell within the range of about 1% to 4% COHb (see Figures 2 and 4 of Hauck and Neuberger, 1984), consistent with the range of % COHb estimates reported in the REA (REA, Tables 6-18 and 6-19). As noted in the 2000 AQCD, “[t]he agreement between measured a nd predicted COHb under these varied

17 This can be calculated as the difference of the measured from predicted [3.8%] divided by the absolute measured value [which, while not explicitly reported is described by Figure 1 of Benignus et. al. (1994) to range from 12-18%]).23 conditions was very good”, with a mean difference of only 7.4% of the nominal (maximal predicted) value (2000 AQCD, p. 5-14). 18

EPA further notes that, contrary to th e commenter’s assertion, the study by Benignus et al. (1994) in f act finds the CFK model estimates of COHb to be generally consistent with actual measurements of vC OHb, providing support for

our use of the CFK model. As shown in Table 2 of Benignus et al (1994), the averages of model predictions at all te sted time periods were not statistically significantly different from the corre sponding averages of venous COHb measurements (p>0.80, see Table 2 of Beni gnus et al. 1994). This finding is particularly significant gi ven the fact that the CO exposure concentrations investigated in Benignus et al. (1994) are much higher th an those assessed in the REA. In Benignus et al. (1994), CO expos ure concentrations were specifically selected to be so high and occur over such a short period of time that they would intentionally disrupt the concentration equilibrium that would normally exist

between the venous and arterial blood fl ows within study subjects if exposed to

lower CO concentrations. The administ ered CO exposure concentration to study subjects was 6,683 ppm occurri ng over period of about 5 minutes (Benignus et al., 1994). This is over one hundred time s the maximum single CO exposure

concentration estimated in the REA (i.e., 63.4 ppm for 2 minutes). 19

Further, although not mentioned in Mr. D onnay’s characterization of Benignus et al. (1994), EPA notes the discussion by Be nignus et al. (1994) that supports the CFK model assumption of a single well- mixed vascular compartment and the model’s accurate prediction of venous COHb at low CO exposure concentrations and for longer durations. For example, the paper states that when inspired CO “is low and exposure are long, as was the cas e during initial expe riments (Coburn et al., 1965), these assumptions [of a single well mixed compartment] are valid and the CFKE accurately predicts mean pe ripheral venous HbCO” (Benignus et al., 1994, p. 1743). As discussed more fully in the response to comment II.A.5(1) below, in considering the lag betwee n arterial and venous COHb, the paper

further states that “arterial blood mean Δ HbCO began to decline within 1 min of exposure cessation and progressively a pproach the mean venous value” and indicates that the equilibrium between ve nous and arterial COHb is reestablished within 3 minutes or less time (Benignus et al., 1994, p. 1743 and Figure 2). The

18 The absolute value of the mean percent deviation of % COHb (not total deviation in % COHb) in two persons experiencing this relevant range of %COHb across four experiments ranged from 5.4% to 14.1% (Table 3 of Hauck and Neuberger, 1984). Using this prediction error and the range of estimated % COHb experienced by the two study subjects, CFK model pred ictions could vary by an increment as little as ± 0.05-0.14% COHb at 1%COHb or at most, an increment of ± 0.22-0.56% COHb while at 4% COHb.

19 For added context, EPA notes that over 99% of all exposure events simulated by APEX in the REA for the highest CO exposure simulations in the Denver and Los Angeles study areas (Tables 6-9 and 6-12) had CO concentrations below 13 ppm and well below 9 ppm, respectively. While the duration of exposure events simulated by APEX can be as short as 1 to 5 minutes, it is certainly not the case that short-term CO concentrations would reach thousands of ppm during any time or would vary by such extremes over such a short time period as that assessed in Benignus et al. (1994) (i.e. start at 0 ppm, increase to 6,700 ppm for 5 minutes, then decrease to 0 ppm for about 5 minutes).24 CFK model assumption of equilibrium is also supported by several studies cited by Benignus et al. (1994) which involved C OHb levels more similar in magnitude

to those estimated in the REA and for which CFK model estimates are comparable to COHb measurements obtained from venous blood of study subjects. CFK model evaluation studies are discussed in depth in the 2000 AQCD. For example, based on experi ments performed for 10 different CO exposure profiles at several exercise le vels, the 2000 AQCD c oncluded that “the agreement between measured and predicted COHb under these varied conditions was very good” (2000 AQCD, p. 5-14).

5. Additional Comments on Interpretation of Scientific Evidence

Specific comments on the EPA’s interpretation of the scientific evidence not discussed in the preamble to the final rule are de scribed and addressed in this section.

(1) Comment: One commenter (Donnay) argued that the reliance on COHb for judging the effects of CO is inappropriat e, stating that venous COHb is “not a consistent or meaningful biomarker of eith er CO dose or effect”. In support of this view, the commenter first states that “vCOHb is a unreliable measure of any recent CO exposure”, which ”does not corr elate consistently with the symptoms, severity or outcomes of CO poisoni ng” because, in the commenter’s view, “[venous COHb] always rises more slowly than [arterial COHb] in response to any level of exposure ... taking anywhere from 6 to more than 20 hours to reach equilibrium with arteri al COHb” (Donnay, p. 4).

Response: The EPA disagrees with the commenter’s view that COHb should not be relied upon as a biomarker of CO exposure, dose, and effect. The EPA accepts that using the measurement and estimati on of COHb has limita tions in terms of interpretation of the immediate dose following CO inhalation (discussed in Section 4.2 of the ISA). However, COHb measured in venous blood remains the most extensively validated biomarker of CO exposure and effects, and is the metric used in published health outcome studies (ISA p. 4-1; ISA, section 5.2.4).

EPA agrees with the commenter that in response to changes in CO exposure

conditions the evidence indicates there is a period where the arterial and venous COHb levels are not equivalent. EPA notes, however, such periods are quite short and, based on the relationship betw een magnitude of exposure and size of the disparity, any such disparity is exp ected to be small under exposure conditions

associated with ambient CO. As discu ssed in the ISA (ISA, section 4.2.1), this disparity between venous COHb (vCOHb) and arterial COHb (aCOHb) was examined by Benignus et al. (1994). This study, also quoted by the commenter, concludes that “after rapid high concen tration CO uptake (6,683 ppm CO) in resting adults, the CFKE-predicted group mean change in COHb became indistinguishable from the group mean obs erved change in COHb in peripheral

venous blood within 2-5 min after the e nd of exposure”. Benignus et al. (1994) found that vCOHb and aCOHb equilibrate d in less than 10 minutes in most25 subjects exposed to high concentrations of CO, highlighting the short-lived nature of this inequality. Importantly, the a- vCOHb disparity was proportional to the COHb equilibrium level. Thus, although comparisons of arterial and venous

COHb concentrations have not been invest igated after ambient exposure to CO in a similar experimental manner as has been done for high concentration CO exposures, exposure to the much lower ambi ent levels of CO would be expected

to result in a much smaller difference between venous and arterial COHb making

the venous COHb an informative measure of arterial COHb and the distribution of CO among critical organs, such as the heart and brain.

(2) Comment: Some commenters (Donnay, PSR et al) questioned EPA’s reliance on the Allred et al. controlled human exposur e study in evaluating the health effects of CO, with one commenter stating that the age of the study (conducted more than 20 years ago) precludes it from meeting the CAA requirements for EPA to rely on the latest scientific knowledge. The commenters also argue that the study population was small and only incl uded non-smoking men, making the study “inappropriate for use as the primary basis for a national population standard” (PSR, p. 5) The commenters state that the study used exposure conditions significantly different from the low-leve l exposures experienced currently, and that the study results show high inte r-individual variability, limiting their biological significance.

Response: EPA strongly disagrees with the as sertion that older studies should, as a matter of course, be given less weight in evaluating the health effects of exposures to the criteria air pollutants, particularly in cases where these studies remain the definitive works available in the scientific literature. The study to which the commenter is referring (All red et al., 1989) is a well conducted, extensively reviewed, multi center investigation funde d by the Health Effects Institute evaluating the effect of carbon monoxide on the induction of myocardial ischemia among a relatively large number of human subjects with coronary artery

disease. The commenters are correct that the results of this study demonstrate considerable interindividual variability; how ever, it is important to note that even with this variability, the study was suffici ently powered to detect statistically significant CO-induced decreases in time to indicators of myocardial ischemia during exercise at both COHb concentrations (i.e., targeted COHb concentrations of 2% and 4%). As pointed out by the commenter, in order to achieve these COHb concentrations during a relative ly short exposure period (~60 minutes), average exposure concentrations that were higher than typical 1-hour ambient CO exposure concentrations were used by nece ssity. Nonetheless, as is illustrated by the REA, the resulting COHb concentra tions for the lower exposure conditions (which averaged 2-2.4% COHb 20 ) fall within those that might occur in response to ambient CO exposures under conditions when the current 8-hour standard (the

20 The average COHb level immediately upon cessatio n of CO exposure conditions was 2.4% and the average across the subjects after exer cise and at the time of response m easurement was 2.0% (Allred et al., 1989).26 controlling standard) is just met (e.g., PA, Table 2-4). Further, we note that the study was designed by an advisory co mmittee appointed by HEI’s Research Committee; three of the six advisory committee members were experts not affiliated with HEI. The overriding obj ective was to produce an independent, robust and high quality study that would be informative to the consideration of the

occurrence of exercise-induced myocardial ischemia that might be associated with exposures that may occur under the cu rrent NAAQS (Allred et al. 1989, p. 81).

With respect to the commenters’ view th at EPA has placed undue emphasis on the findings of Allred et al. ( 1989), it is important to note the results of this study are supported by other similar controlled hu man exposure studies (see ISA, section 5.2.4). As described in the ISA and allude d to by the commenters, differences in experimental protocols and analytical me thods across studies (Adams et al, 1988; Allred et al., 1989; Anderson et al. 1973; Kleinman et al., 1989; Kleinman et al., 1998) do not allow for an informative quantitative pooled or meta-analysis. Nonetheless, similar to Allred et al. ( 1989), these studies dem onstrate decreases in the time to onset of angina among indi viduals with corona ry artery disease following exposure to CO resulting in C OHb concentrations between 3% and 6%. Further, a much larger body of epidemio logic studies of cardiovascular outcomes (described in section 5.2.1 of the ISA) is coherent with this line of evidence (ISA, section 5.2.6.1). In evaluating the health e ffects evidence for relevant exposures to CO, EPA has integrated evidence from acr oss scientific disciplines, recognizing the strengths, limitations, and uncertainties associated with each study type, as

well as each of the individual studies reviewed. EPA requested that CASAC comment on the interpretation of the evidence and the causal determination reached for short-term exposure to CO a nd cardiovascular morbidity as a part of

the review of the second draft CO ISA. In their consen sus response to the Agency’s charge (Brain and Samet, 2010a), CASAC stated, “The most compelling CO-related CVD results remain those from the 20+-year-old controlled human exposure studies ... More recent human epidemiology studies of morbidity at ambient CO levels, incl uding data on hospital admissions, are consistent with and reinforce the observa tions from earlier controlled human

studies.” These statements provide strong s upport to the Agency’s consideration of the study by Allred et al (1989) in the scientific evaluations and conclusions

described in the ISA.

Thus, EPA concludes it is appropriate to place weight on the results of the study by Allred et al (1989) to in form our interpretation of dose estimates from the REA under conditions associated with just meeting the current standard. Such consideration of this study is consistent with the critical role of the study in providing quantitative evidence regarding health effects associated with shortterm exposures to ambient CO in the ISA, and with the complexity of drawing quantitative conclusions from the epidem iological studies of cardiovascular outcomes recognized in the ISA and by CASAC (ISA, p. 2-14; PA, pp. 2-34 to 2- 39; Brain and Samet, 2010a).27 (3) Comment: One commenter (PSR et al.) cont ends that the weight EPA gives to angina-related effects in patients with coronary artery disease (CAD) in considering the adequacy of the NAAQS is inappropriate. In support of this view, the commenter cites a CASAC comment regarding consideration of the epidemiological studies for various ca rdiovascular outcomes and potential uncertainty associated with identificati on of the population most susceptible to CO-induced effects, as well as the co mmenter’s own comparison of effect estimates reported from epidemiological st udies for various h ealth outcomes.

Response: As an initial matter, EPA notes th at we have not limited our focus in this review to angina (a symptom of myocardial ischemia, which does not occur in all individuals with myocardial isch emia). Rather, EPA has appropriately

focused on ischemia-related effects in patients with CAD as the population group

most sensitive to effects of ambient CO exposures (ISA, p. 2-10; 2000 AQCD, p. 4-3). The focus on ischemia-related eff ects is well-supported by the integrated

evaluation of the evidence from controll ed human exposure, toxicological and epidemiological evidence, rather than reliance on a singular outcome in the epidemiological evidence, as is implied by the commenter’s statements. In fact, the CO ISA concludes that “The most compelling evidence of a CO-induced effect on the cardiovascular system at COHb levels relevant to the current NAAQS comes from a series of cont rolled human exposure studies among individuals with CAD” (pg 5-47), whic h found decreased time to onset of exercise-induced angina a nd electrocardiogram changes indicative of myocardial ischemia. The findings from the epidemio logical studies are c oherent with this evidence, and the known role of CO in limiting O 2 availability lends biological plausibility to ischemia-related h ealth outcomes following CO exposures. Because the most compelling evidence is from controlled human exposure studies among individuals with CAD, a view endorsed by CASAC (Brain and Samet 2010a, p. 12), the focus on ischemia-rela ted effects in susceptible groups, including people with CAD and other t ypes of heart disease is appropriate.

In comparing effect estimates, the comm ent cites a single effect estimate from a single study of hospital visits for angina and some higher effect estimates for

individual studies of other cardiovascular endpoints (e.g., st roke and heart attack). In focusing on effect estimates from indivi dual studies, they ov erlook the need for an integrated assessment of the evidence which is provided by the ISA. In this assessment, EPA concludes that the ep idemiological studies of CAD outcomes

are coherent with the results of the c ontrolled human exposure studies and that, given this consistent and coherent ev idence from epidemiological and human clinical studies, along with biological plausibility provided by CO’s role in limiting oxygen availability, a causal relationship is likely to exist between relevant short-term exposures to CO a nd cardiovascular morbidity (ISA, p. 5-48). The commenter ignores the full range of epidemiological study results for ischemia-related outcomes. For example, Figure 5-2 of the ISA demonstrates that studies evaluating the asso ciation of CO concentra tions and ischemia-related28 outcomes (including ischemic heart diseas e, angina, and myocardial infarction) generally report increases in the numb er of hospital admissions for these outcomes, ranging in magnitude from appr oximately 1% to 20% (ISA, p. 5-27).

(4) Comment: One commenter (Donnay) stated that studies of the associations of effects with exhaled CO (eCO) were ignor ed in the CO ISA, and that eCO is a more consistent biomarker than COHb of both exogenous CO exposure and elevated endogenous CO production. This commenter further stated that EPA should rely more on exhaled CO (instead of COHb) as key metric for assessing CO effects and exposure.

Response: The commenter provides a bibl iography of additional references pertaining to eCO, some published after May 2009, the CO ISA reference date cut-off. The majority of the provided publications focus on the association of

eCO with various diseases not resulti ng from CO exposure. EPA agrees that endogenous CO is increased by a number of diseases and health conditions (ISA, section 4.5) and that these diseases result in increase d eCO (ISA, Figure 4-12). This is a result of up-regulation of he me oxygenase expression and activity and heme protein catabolism. However, thes e publications do not provide evidence of eCO as an indicator of CO exposure but in stead as an indicator of inflammatory

and oxidative health conditions that in crease endogenous CO production and thus elimination. Based on EPA’s provisional c onsideration of these studies, in the context of the findings of the ISA, EPA concludes that the new information and findings do not materially change any of the broad scien tific conclusions regarding effects as to the relevance of eCO as a biomarker of CO exposure made

in the 2010 CO ISA and thus do not warra nt reopening the ai r quality criteria

review.

The use of eCO as an indicator of clinical severity of diseas e is well documented (e.g., ISA, Figure 4-12, p. 4-25). However eCO has not been established as a biomarker of ambient air CO exposure. One study provided by the commenter elegantly describes the necessity of biomarker validation (Scherer, 2005) including understanding of specificity, sensitivity, population background levels, dose-response relationship, inter- and in tra-individual variability, kinetics, confounding, and modifying factor s. However, the use of eCO as a biomarker of ambient CO exposure has not been characteri zed with regard to these criteria. To date, evidence is lacking to fully charact erize the response of eCO concentrations

to inhaled CO concentrations and acco rdingly no quantitative models that describe this relationship are available, thus limiting the utility of eCO as a biomarker of exposure to ambient CO. As COHb has been used as the biomarker of CO exposure for decades the necessary validation of COHb as a biomarker has been conducted, including the developm ent of multiple quantitative models describing its generation in response to CO exposure (see ISA, section 4.2).29 Finally, as eCO has been the focus of recent research, whereas COHb has been used as a marker of CO dose for many year s, health effects studies have not used eCO as the primary dose metric when investigating the relationship between exogenous CO exposure and biological responses including ischemia-related cardiovascular outcomes, birth outcomes, or other health effects. Therefore, EPA does not find adequate support in the scie ntific evidence for the use of eCO in assessing CO effects and exposure.

(5) Comment: One commenter (Donnay) stated th at EPA did not give adequate

consideration to studies of effects other than C OHb-mediated hypoxia, and the commenter provided a list of publications he states provide evidence of other

measures of CO effects which should have been considered in this review, and which he considers to support his view that EPA should have focused less on

COHb in this review.

Response: The 14 publications cited by the commenter on other measures of CO effects include 10 studies of CO poisoni ng or intoxication. As discussed above (response to comment II.B.3(3) above), these studies are outside the scope of the ISA (ISA, section 1.5) because EPA judged them to be “not directly relevant to ambient exposures” (ISA, pp. 1-6 and 1-7). The other four st udies include one which describes a new method for measuring COHb, an animal study demonstrating the role of free radicals in ototoxicity resulting from noise plus CO exposure, a case report describing central nervous system effects thought to be associated with chronic CO exposure a nd an epidemiologic study describing an association of CO exposure w ith indices of atherosclero sis in barbecue workers. One of these latter two studies was publis hed after the cutoff date for the ISA.

Based on EPA’s provisional consideration of these studies, in the context of the findings of the ISA, EPA concludes that the new information and findings do not materially change any of the broad sc ientific conclusions regarding effects associated with CO exposure made in the 2010 CO ISA and thus do not warrant reopening the air quality criteria review . Furthermore, as described in the response to comment (II.B.5(1) above), EPA believes that the ISA’s focus on COHb is appropriate, given that COHb ha s been extensively validated over many years, is well-correlated with other bi omarkers, and is the basis for controlled human exposure studies investig ating health e ffects of CO.

(6) Comment: One commenter (Donnay) pointed EPA to consideration of a list of studies describing genetics and gene expression of heme oxygenase, by which endogenous CO is derived, including studi es of associations between heme oxygenase genetic polymorphisms and susceptib ility to coronary artery disease. In so doing, he stated that, as EPA ca nnot regulate endogenous CO, they should more tightly regulate exogenous CO expos ures in order to reduce total risk.30 Response: The EPA recognizes that there are numerous conditions and disease states where heme oxygenase (HO-1) is induced. As discussed in the ISA, the resulting excess endogenous CO may react intracellularly with heme proteins or diffuse into the blood according to the grad ient of pCO in the cell/tissue and blood compartments (ISA, section 5.1.3.3). S hort-term increases in HO-1 often represent adaptive responses to stress . Longer-term increases in HO-1 are sometimes associated with protective responses and sometimes with pathophysiologic responses. While it is possible that prol onged increases in endogenous CO production may result in le ss of a reserve capacity to handle

additional intracellular CO resulting from exogenous exposures, there is no experimental evidence to s upport this mechanism.

Similarly, polymorphisms of the heme oxygenase gene promoter may result in

inter-individual variation in endogenous CO levels. Since CO is a product of reactions catalyzed by heme oxygenase, altered expression of heme oxygenase

could lead to more or le ss intracellular CO. Some st udies, including some cited by the commenter, have linked lower HO-1 expression, which would lead to

lower endogenous CO, to increased susceptibi lity to coronary artery disease (or adverse cardiovascular outcomes) in humans . These results are consistent with cytoprotective effects of CO demonstrat ed experimentally (see ISA, sSection 5.3.1.2). Based on EPA’s provisional consid eration of these studies, in the context of the findings of the ISA, EPA concludes that the new information and findings do not materially change any of the broad scien tific conclusions regarding effects associated with CO e xposure made in the 2010 CO ISA and thus do not warrant reopening the air quality crite ria review. While these findings are intriguing and suggest that endogenous CO ma y play a role in susceptibility, other plausible mechanisms have not been ruled out. For example, iron and biliverdin, which are also products of heme oxygena se-catalyzed breakdown of heme and also bioactive, could medi ate the cytoprotec tive effects. Conversely, iron and biliverdin could mediate pathophysiologic effects associated with increased HO1.

Thus, while it is possible that prolonged increases in endogenous CO resulting from chronic diseases or deficits in endogenous CO resulting from genetic polymorphisms may provide a basis for the enhanced sensitivity of susceptible populations to CO-mediated health effect s, additional studies are required to investigate the relationship between inte rnal CO burden and associated health risk. As noted in the ISA, “CO may be responsible for a continuum of effects from cell signaling to adaptive response s to cellular injury...” (ISA, p. 5-11).

It should be noted that the commenter cited numerous studies of “genetics and gene expression of CO and its primar y endogenous source” (Donnay, p. 8). Only a minority of these studies address gene tic polymorphisms of heme oxygenase in humans. As described above, our provi sional consideration of these studies concludes that the study findings do not mate rially change any of the conclusions made in the ISA regarding effects associ ated with CO exposure and thus do not31 warrant reopening the air qua lity criteria review. The majority of the studies which were cited addressed other topics including the therapeutic effects of heme oxygenase achieved by transfection or ge ne therapy in animal models, the regulation of HO gene expression by cellula r signaling pathways and the role of CO in regulating the expre ssion of genes. These topi cs, while scientifically interesting, do not address th e issue of susceptibility in human populations or the health effects of ambient CO exposure, a nd as such are outside the scope of the

ISA.

(7) Comment: One commenter (AAM) stated that the evidence on potentially beneficial effects of exposure to CO s hould be considered by the Administrator, additionally claiming the information in this area is relevant to the interpretation of the epidemiological results.

Response: As the commenter recognizes, studi es on therapeutic or potentially beneficial aspects of CO applicati on (e.g., anti-inflammatory response) are discussed in the ISA (ISA, section 5.1.3.2). Accordingly, such effects are part of the body of evidence considered by the Ad ministrator during this review. The ISA notes, however, that dose-response re lationships between CO and these types of effects remain unexplored and that it is “unclear how these effects may be related to environmentally-relevant e xposures” (ISA, p. 5-7). For example, results of controlled human exposure stud ies, which evaluated the potential antiinflammatory effects of exposure to 100-500 ppm CO, were mixed. One of the two studies reported no effect, and a sec ond reported that tw o of the nineteen subjects experienced exacerbations of COPD. Thus, while some studies

demonstrate the involvement of CO in potentially beneficial physiological processes, uncertainties regarding dose -response relationships, the link between these effects and environmentally rele vant exposures, and the potential for concomitant adverse effects complicate the interpretation of this evidence with respect to health effects of CO in ambient air. While the commenter states that evidence on potentially beneficial effects of exposure to CO is relevant to the interpretation of epidemiological studie s, we note that to the extent some beneficial effect is exerted by ambient CO , it would inherently be reflected in the

studies.

CASAC agreed with EPA’s characterization of this evidence (Brain and Samet, 2010a, p. 13), saying that: There is a growing literature regarding possible therapeutic applications of CO at levels of ~250 ppm. These studies have beencarried out in some animal models and in cell culture. CO is a prooxidant and has profound extended pro-inflammatory effects. However, in specific scenarios w ith distinct organ systems or specific cell types, CO may have short-term anti-inflammatory effects. Clinical trials thus far have not supported health benefits of CO administration. Further, there is no evidence that the hypothetical therapeutic results pr ovide any insight into health32 effects of acute or chronic am bient exposures in the general population, and especially in subpop ulations susceptible to CO effects.

Thus, EPA does not believe the current evidence regarding possible therapeutic aspects of CO is informative to judgme nts regarding the adequacy of the CO NAAQS.

(8) Comment: One commenter (CBD et al) assert s that EPA, in judging the adequacy of the current standards, was not jus tified in giving less weight to the epidemiological evidence, claiming that this type of evidence is the only type available for noncardiovascular effects, and consequently, should be given weight. The commenter argue s that EPA has given weight to the epidemiological studies for other criteria pollutants, such as PM, after consid ering and rejecting concerns about confounding from other pol lutants, unlike its approach for CO,

and that two CO measurement issues not ed by EPA in the proposal would tend to only underestimate any existing effect of CO.

Response: As an initial matter, EPA notes that, contrary to the commenter’s assertion, epidemiological studies are not the only type of study available on

noncardiovascular effects of CO. For exam ple, as noted in the ISA’s summary of the long-standing database of CO toxi cological studies on birth outcomes and developmental effects, “in utero or peri natal CO exposure in pregnant dams or pups affects outcomes in the offspring, in cluding postnatal mortality, skeletal development, the ability of the developi ng fetus to tolerate maternal dietary manipulation, behavioral outcomes, neurot ransmitters, brain development, the auditory system, myocardial developmen t, and immune system development” (ISA, p. 5-63). 21 In considering whether exposures associated with CO in ambient air might be expected to elicit such effects, the 2000 AQCD went on to conclude that “it is unlikely that ambien t levels of CO typically encountered by pregnant women would cause increased fetal risk” (2000 AQCD, p. 6-44). In considering the full evidence base in th is review regarding the potential for

ambient concentrations of CO to elic it birth and developmental effects, we concluded it was only sugges tive of a causal relationship. In so concluding, we noted uncertainty regarding th e biological plausibility of ambient CO eliciting the

effects that were associated with ambien t CO in epidemiological studies and the inability to sufficiently rule out the role of chance, bias and confounding in those studies, in addition to the limited extent of the evidence and the mixed findings for some outcomes (ISA, pp. 1-14, 5-79, 5-80) , as described in the response to comment II.A.3(2).

21 The 2000 AQCD states that “[f]rom a ll of the laboratory animal studies, it is clear that severe, acute CO poisoning can be fetotoxic, although specification of maternal and fetal COHb levels is difficult” and that data reviewed in the 1991 AQCD “provide strong evidence that maternal CO exposures of 150 to 200 ppm, leading to approximately 15 to 25% COHb” produce a range of developmental effects with some isolated experiments suggesting that “some of these effects may be present at concentrations as low as 60 to 65 ppm (approximately 6 to 11% COHb) maintained throughout gestation” (2000 AQCD, p. 6-44).33 Thus, in considering the epidemiological studies for noncardiovascular effects, such as developmental effects, we ha ve recognized uncertainties of the CO evidence base related to biological plausibi lity of such effects being elicited by ambient concentrations of CO, and we have also taken note of the advice offered by CASAC regarding potentia l confounding (e.g., Brain and Samet, 2010a). In so doing, contrary to the commenter’s asse rtion, EPA has considered issues of potential confounding in epidemiological st udies using the same approach for CO

as we have for other criteria pollutants. That approach includes the consideration

of the full evidence base available for each pollutant for the array of health effects assessed. Accordingly, the Administrator’s j udgment as to the weight to give to epidemiological studies in judging the ade quacy of the current CO standards takes into consideration the full evidence base for CO, which includes epidemiological studies but is comprised largely of non-epidemiological studies and which provides the basis for our understanding of CO mechanisms of action, toxicity, and health effects, as well as the spat ial and temporal vari ability of ambient concentrations and exposures.

As noted above and elsewhere in th is document, the evidence for the noncardiovascular effects cited by the commenter is “suggestive” of a causal relationship with ambient CO, yet eviden ce is generally lacking on mechanism or mode of action that might lend biological plausibility to associations of effects

with low ambient concentrati ons observed in epidemiologi cal studies. In light of this uncertainty, particularly careful atte ntion must be paid to the possibility of confounding, and indeed CASAC commented that “the problem of co-pollutants serving as potential confounders is particularly problematic for CO” (Brain and Samet, 2010a). CASAC further stated that “consideration needs to be given to the possibility that in some situations CO ma y be a surrogate for exposure to a mix of pollutants generated by fossil fuel combus tion” and “a better understanding of the possible role of co-pollutants is releva nt to ... interpretation of epidemiologic

studies on the health eff ects of CO” (Brain and Samet, 2010a). We recognize that, as the commenter notes, some study au thors use statistical methods to adjust for multiple pollutant effects, typically through the use of two pollutant regression models (ISA, p. 1-11), and, in assessing th e evidence in the ISA, we considered

the results of such models. We also r ecognize, however, that, as also noted by CASAC, associations reported for CO may be related to the presence of other, etiologically-relevant pollutan ts that are correlated with CO yet absent from the analysis (PA, p. 2-37). We particularly recognize this potentia l in light of the understanding we draw from the larger CO evidence base and its various aspects, many of which differ from the evidence base s for other criteria pollutants, such as

PM and NO 2 (e.g., PA, pp. 2-36 to 2-39; 76 FR 8177-8178).

Moreover, a central question for this revi ew is what patterns of ambient CO concentrations might be expected to cause adverse health effects and whether the current standards provide requisite prot ection against such occurrences. Apart from uncertainty as to whether ambien t CO exposure is cau sally related to34 noncardiovascular health effects, the two ambient CO measurement issues described in section II.D.2(a) of the proposed rule complicate and contribute uncertainty to our interpretation of the ep idemiological studies with regard to the specific ambient CO concentrations that may have elicited the reported health

outcomes. 22 Thus, while we agree with the commenter’s statement that uncertainty associated with the two CO measurement issues they cite could

contribute to an underestimation of CO e ffect in the epidemiological studies, uncertainty in the size of effect estimates (e.g., change in health risk per unit of exposure metric) is not the uncertainty of primary concern for the central question posed above. Rather, the uncertainty of con cern to this question is related to what might be concluded from the studies with regard to what, if any, specific ambient concentrations of CO may have elicited the observed health outcomes. The two measurement issues as well as the pote ntial for confounding a nd the larger issue of biological plausibility at ambient CO concentrations, contribute to this uncertainty (PA, pp. 2-37 to 2-39; 76 FR 8177-8178).

In summary, we considered the epidemiologi cal evidence in this review in light of the full evidence base for CO, just as we do for other criteria pollutants. In considering the extent to which associati ons of health outcomes with ambient CO concentrations in epidemiological studies inform judgments in this review as to the adequacy of the current NAAQS, we firs t consider the extent to which the full evidence base supports a conclusion that the relationship of th e health outcomes with ambient concentrations may be causa l. Factors contributing uncertainty to

this conclusion for noncardiovascular health outcomes are discussed previously in this response and in responses to comment s (1) and (2) of section II.A.3 above. Secondly, we consider whether the curre nt standards were met during the study periods, and what might be concluded from the studies with regard to specific ambient concentrations eliciting the observed health outcomes. 23 In so doing, we have identified aspects of the CO eviden ce base which contribute uncertainty to and complicate our use of the epidemiological studies in this re gard. In light of these uncertainties and complications, these studies have been less informative to the Administrator in drawing conclusions regarding the adequacy of the current

22 As described in the proposal (76 FR 8177-8178), th e first of the two issues, the prevalence of ambient monitor measurements at or below detection limits, is a particular concern for the more recently available epidemiological studies in which ambient CO concentrations are much reduced from the past. The second issue relates to the use in the epidemiological studies of CO measurements from area-wide or central-site monitors which can obscure the significant spatial gradient that exists for CO with distance from source locations such as highly-trafficked roadways.

23 As we note in the PA and proposal, it is the studies conducted under conditions when the current standards were met that are particularly informative to the consideration of the adequacy of the current standards, and the identification of such studies requ ires consideration of all elements of the standard beyond just the level. For example, even when concen tration statistics reported in epidemiological studies (e.g., daily maximums at central site monitors, ofte n averaged over multiple days) are below the levels of the current standards, CO le vels stated in the form of the standard s (e.g., second highest daily maximum 1-

hour and 8-hour concen tration at a specific location) may, and in many studies do, exceed one of the standards (e.g., PA, p. 2-32). The form is an inte gral part of a NAAQS and its stringency. Thus, it is important to consider not simply the value of the ai r quality statistic reported compared to NAAQS level, but whether the air quality met the NAAQS.35 standards, than have other elements of the CO evidence base. Thus, the Administrator has fully considered and car efully weighed the available evidence, giving greater weight to those aspect s more fully supported in making her judgment on the adequacy of the curren t standards to provide the requisite protection.

(9) Comment: Comments from AAM state their view that little weight should be given to the epidemiological studies of CO based on several observations that they have previously brought to EPA’s at tention over the course of the review. Commenters additionally describe a recent study as suggesting that the epidemiological evidence relied on by EPA in the ISA is unsound.

Response: EPA carefully considered the epid emiological studies, in light of the

full evidence base for CO. While EPA has recognized a vari ety of uncertainties related to interpretation of CO epidemiologi cal studies, particular ly with regard to ambient concentrations that may elicit e ffects (preamble to final rule, section II.B.2), we also recognize the coherence of the study results for ischemia-related

outcomes with the results of controlled human exposure studies and the biological plausibility provided to these studies by the known role of CO in limiting oxygen availability (ISA, p. 5-48). These aspects of the full evidence base contribute to

our conclusion that a causal re lationship is likely to ex ist between relevant shortterm exposures to CO and cardiovascula r morbidity, a conclusion that has been favorably reviewed by the CASAC Pane l, with the Panel concluding the 2010 ISA to be “adequate for rulemaking with the incorporation of changes in response to the Panel’s major comments and r ecommendations” (Brain and Samet, 2010a).

In evaluating the epidemiological evidence in the ISA, EPA has considered comments provided by the commenter on th e ISA, some of which are also reflected in this comment submitted on the proposal. Across the documents prepared for this review, EPA has carefully considered the evidence, including the epidemiological evidence, taking particular note of potential areas of uncertainty. For example, in drawing conclusions on the effects of ambient CO, EPA has not relied on any one individual study or small cl uster of studies. Rather we consider the group of studies available for biologica lly plausible health outcomes, such as those related to ischemia following CO e xposure (ISA, p. 5-48). In so doing, we find the full body of epidemiological studi es of emergency room visits and hospital admissions for ischemic heart dis ease to be generally consistent with controlled human exposure and toxicol ogical evidence of cardiovascular morbidity effects, as noted above. Furt her, EPA agrees with commenters that issues related to model specification for epidemiologic studies, such as selection of models and approaches to adjust for meteorological and temporal variables are important considerations. The CO ISA de scribes how these issues were carefully considered in selecting studies for inclusion in the ISA and in interpreting the results of the body of epidemiologi c evidence (CO ISA, Figure 1-1 and accompanying text on p. 1-5). Furtherm ore, we recognize the phenomenon of publication bias as a potentia l source of uncertainty re garding the nature of the36 association and the magnitude of health risk estimates. Specifically, it is well understood that studies reporti ng non-null findings are more likely to be published than reports of null findings, and, thus, pub lication bias can resu lt in reporting of spurious associations and overestimati ng effects (Ioannidis, 2008). We do not agree, however, that publication bias limits the interpretation of published

associations between CO and health effects.

Finally, EPA disagrees with the commenter s’ assertion that the recent study cited by the commenter (Koop et al., 2010) calls into question the epidemiological

evidence for CO assessed in the ISA. EP A notes several aspects of the study by Koop et al. (2010) that limit its interpretation in light of the evid ence base for CO. For example, the authors use monthly pollu tant averages and monthly counts of hospital admissions, rather than daily data in their time-series analyses, which may overlook relationships in the shorter time-step data, which may have relevance to ambient CO. Among the h ealth outcome categor ies assessed, the authors have omitted chronic obstructive pulmonary disease, a respiratory

outcome that has been demonstrated to be associated with am bient concentrations of various air pollutants, while including tracheostomy malfunctions, an outcome unlikely to be associated with air pol lution. Further, by focusing on hospital admissions, rather than physician visits or emergency department visits, it is likely that the authors missed all but the most severe cases of some diseases. While this study (Koop et al., 2010) wa s published after the ISA, EPA has provisionally considered it and concludes th at it does not materia lly change any of the broad scientific conclusions regardi ng effects associated with CO exposure made in the 2010 CO ISA and thus does not warrant reopening the air quality

criteria review.

(10) Comment: Comments from NESCAUM stated that EPA should work toward a better understanding of the broad range of CO exposures, including those in vehicles, and the role of the CO NAAQS in addressing these exposures. They additionally state that curr ent research suggests that in-cabin CO may be higher than ambient levels and may be a main route of CO exposure.

Response: EPA agrees that in-vehicle exposur es are an important component of personal exposure to ambient CO, as indi cated by evidence described in the ISA (ISA, section 3.6.6) as well as the REA re sults. The ISA summarizes the current evidence with regard to roadway-relate d results (ISA, sections 3.6.6 and 3.5.1.3). Further, the REA which also informs our understanding, found that time spent on or near motor vehicle activity (e.g., in vehicles, in garages) was a major contributor to higher CO e xposures (e.g., REA, section 6.4 ). Lastly, we note the revisions to the CO monitoring network to include near-road monitors made in the final rule (preamble to final rule, section IV) is expected to help to improve our understanding of the gradients in ambien t CO concentrations in the near-road

environment which will in turn contri bute to an improved understanding of roadway-related exposures.37 6. Additional Comments on the Exposure and Health Risk Assessment

Comments related to the REA for CO that ar e not discussed in the preamble to the final rule (e.g., in sections II.B) are descri bed and addressed in this section.

(1) Comment: One public commenter (Thomas McCurdy) expressed concern with how alveolar ventilation rate (V A ) 24 is estimated by APEX and the resulting impact on estimating population COHb levels. In general, this commenter noted

that the V A to oxygen consumption rate (VO 2 ) relationship is va riable, both within and between individuals, and not consta nt as was assumed in the REA (i.e., a value of 19.63), particularly noting the ex istence of a non-linear relationship at high ventilation rates. The commenter furthe r indicated their view that accurately estimating VA is important because it plays a large role in estimating COHb

levels.

Response: EPA does not disagree with much of what the commenter states regarding the overall variability in the relationship between alveolar ventilation (V A ) and oxygen consumption (VO 2 ) rates. When modeling risk and exposure to any pollutant, there are always limits in re presenting the true va riability of model input variables. This is a common occurre nce due to the limited availability of input data that fully capture the influe ntial characteristics (e.g., age, gender, activity level, health status/condition) driving the variability of many physiological variables used in the model, including the V A /VO 2 relationship.

Given the time and resources available fo r this review, EPA did not perform a literature review to evaluate or improve the point estimate of 19.63 used in the

current REA. We add that this value has been used to estimate V A in prior CO exposure assessments (e.g., Johnson et al., 2000). Further, as described below, we have concluded that, given the relatively low influence of V A on REA results, the current approach was adequate to our n eeds in estimating exposure and dose in

this review.

In response to this comment, we first not e that the limitations of the currently used relationship, particularly rega rding the non-linear relationship of V A to VO 2 , was mentioned in the REA by EPA (and noted by the commenter), specifically “the point estimate of 19.63 used may not adequately represent the V A to VO 2 relationship at higher ventil ation rates” (REA, p. 7-21) . More specifically, we agree with the commenter’s statement that the V A /VO 2 relationship (if plotted as an x-y graph) can be “concave upward” (McCurdy, p. 2) at upper ventilation rates, hence this non- linearity in the V A /VO 2 relationship observed at upper

ventilation rates would lead to underestimations in V A if using a value of 19.63, and assuming this value is consistent w ith a ratio calculated while performing low exertion activities. In considering the V A /VO 2 ratios provided by the commenter

24 Alveolar ventilation rate is typically expressed as “ ܸ ஺ ሶ ”, though the volume associated with alveolar ventilation is commonly expressed as V A . For simplicity in the formatting in this document, the rate is expressed as V A and represents the rate, not the volume. This was also conferred to how oxygen consumption rate is expressed here (VO 2 is used); the accent over the “V” is not included.38 (McCurdy, Table 1, p. 5), we note that th e point estimate of 19.63 used in the REA falls within the range of these ratios, bounded by values of 17.33 and 26.69, representing resting and m oderate activity levels, respectively. Based on this information alone, V A for persons simulated in the REA while at rest or performing low exertion level activities ma y be slightly overestimated in using the value of 19.63, while for simulated pers ons performing at or above moderate exercise, V A may be underestimated. Regarding one variable potentially affecting inter-personal variability, V A /VO 2 is stated by McCurdy to decrease “moderately or greater with age” based on limited V A and VO 2max 25 data reported for females by Astrand (1960). This reported finding, if consistent in both genders and taken with the above remarks regarding th e non-linear relations hip observed while performing moderate to greater physical activities, suggests that there would likely be a lesser propensity to underestimate V A in older persons than in younger

persons. 26

We disagree, however, with the commente r’s statement regarding the magnitude of importance of V A in estimating COHb levels. Specifically Mr. McCurdy states

that because V A is used to estimate COHb levels , it “play[s] a large role in all conclusions regarding subsequent COHB distributions modeled”. Nowhere in Mr. McCurdy’s comments is provided evid ence to indicate the magnitude of the

role V A plays in the calculation of COHb levels. In reviewing a published sensitivity analysis of variables inpu t to the CFK model by McCartney (1990), it appears that V A does not have a large influential role in the estimation of COHb level. In McCartney (1990), the sensitivity of COHb to changes in V A (among other CFK equation variables) is evalua ted across five work/activity levels, ranging from at rest ventilation to pe rforming moderate exercise. McCartney (1990) reports “the effect of V A on the equilibrium value of [COHb](t) is small (Figure 3 [of publication]) and would be zero in the absence of endogenously produced CO.” In our review of Figure 3 in McCartney (1990), we note also that

there is a consistent trend of decreas ing sensitivity of COHb level to V A with increasing work level, with maximum sensitivity of equilibrium values of COHb

to V A observed while at rest (McCartney, 1990, Table V). This research suggests that when performing moderate or greate r exercise, any inaccuracies in estimates

of V A would have even less of an influen ce on estimated COHb levels using the CFK model than when at lower activity levels.

In the REA, EPA staff indicated that th e CO exposure concentration was one of the most important variables in estimati ng COHb levels. As noted in the REA, “most of the upper level exposure concentratio ns in this assessment are associated with time spent inside vehicles, where it is expected that the exertion level and breathing rate would be at a relatively lo w level” (REA, p. 7-21). The REA then concluded that “it may be that the point estimate [used to estimate V A from VO 2 ]

25 Maximal oxygen consumption rate (VO 2max ) or aerobic capacity is wh ere oxygen consumption plateaus or increases only slightly with increasing exercise intensity (McArdle, 2001).

26 Ischemia-related effects are more prevalent in older persons, and accordingly they are of greater importance for this assessment.39 is appropriately used for these activities [i.e., driving a vehicle] and the estimated

maximum end-of-hour COHb associated with the in-vehicle microenvironment may not be adversely affected” (REA, p. 7-21). As noted above regarding the range of V A /VO 2 ratios for low to moderate activity offered by McCurdy, driving

a motor vehicle would be characterized as a relatively low exertion activity, generally supporting the value of 19.63 used to estimate V A for simulated persons inhabiting this particul ar microenvironment.

There was limited time available to perform sensitivity analyses of the APEX modeling used in the REA given the revi ew schedule, however EPA was able to perform three separate evaluations of i nput data used and their affect on COHb estimates (REA, section7.2.2). The input va riables for which sensitivity analyses were performed were chosen based on careful considerati on of advice from CASAC (Brain, 2009; Brain and Samet, 2010b; Brain and Samet, 2010c), the situations being simulated and the model sp ecifications and performance. These model sensitivity analyses included: the spatial representati on of ambient CO concentrations (all ambient monitors ve rsus design monitor CO concentrations only), at-risk prevalence rates used (base prevalence versus increased undiagnosed CHD prevalence such that wo men equaled that of males), and the hemoglobin content of blood (a base leve l versus anemic population). Of these three APEX model input vari ables, variability in the spatial representation of

ambient CO concentrations contributed to the greatest amount of variability in percentage of persons at or above se lected COHb levels (REA, Tables 7-5 through 7-8). This relative importance of ambient CO concentration and its

influence on COHb levels was also indi cated by McCartney (1990), with inspired CO concentration among one of the few input variables conferring nearly an equivalent factor of influence on equilibrium COHb values. 27

Subsequent to completion of the REA, EPA performed additional analyses on the REA-generated APEX outputs to dete rmine the magnitude of influence V A and exposure concentrations have on estimated COHb levels using the event-level output data generated for the REA. 28 The results of an analysis of variance and multiple linear regression modeling indicat e that the combination of endogenous COHb, real-time CO exposure concentr ations, and CO exposure concentration

27 McCartney (1990) used fractional sensitivities to evaluate the influence of input variables in the CFK model, such that a value of unity (or 1) “means that an error in the selected variable propagates unattenuated to an error in calculated [COHb]( ∞ ).” Table V of McCartney (1990) indicates maximum sensitivity values for the nonlinear CFK equation, with inspired CO concentration ranked 4 th highest and having a maximum fractional sensitivity of 0.92, while the V A was ranked 11 th having a maximum fractional sensitivity of 0.53.

28 The additional analyses were performed using the 5,000 person APEX simulation event-level files generated in the REA for air quality just meeting the cu rrent standard and for both study areas. These files are described in Docket item EPA-HQ-OAR-2008-0015-0123. Data output to the APEX file and included in the analysis were end-of-event COHb, calculated endogenous end-of-event COHb from endogenous
simulations, event CO exposure concentration, event V A , event duration, hourly averaged CO exposure concentrations from hours 1, 2, and 3 prior to the event, and hourly average V A from hours 1, 2, and 3 prior

to the event.40 lags from prior hours were the most im portant input variables in explaining variability in COHb levels. While V A was a statistically significant explanatory variable in the statistical models, the overall contribution of variation in V A to variability in COHb level was neglig ible in comparison with the exposure

concentration variables and COHb resulting from endogenous CO production.

Therefore, the results of sensitivity an alyses by McCartney ( 1990), as well as our own APEX model sensitivity analyses a nd output data evaluations, indicate that CO exposure concentration is a much more in fluential variable re lative to that of

V A in estimating a person’s COHb level. Thus, although the V A approach used in the REA has recognized limitations (e.g., RE A, p. 7-21), the potential magnitude of influence of this APEX input variable is smaller than other variables, such as the time series of CO exposure concentrations.



### B. Comment on Consideration of a Secondary Standard

General comments based on relevant factors th at either support or oppose EPA’s decision that a secondary standard for CO is not re quisite to protect th e public welfare from

adverse effects associated with CO in ambi ent air are addressed in section II.C of the preamble to the final rule and/or in th is section of this document below.

(1) Comment: In testimony at the public heari ng, one commenter (Gossage) stated that EPA's consideration of a secondary standard lacked review of CO-related "hazards to transportation" which is included in CAA definition of welfare effects. In response to a query regarding the types of such hazards related to CO,

another commenter stated that there were studies of CO expo sure effects on the ability of drivers to manage the hazard s of driving at exposure ranges below the current one-hour standard, although references for such studies were not provided.

Response: EPA notes that it is not clear wh ether the neurological effects on drivers cited by the commenters fall within the meaning of “hazards to transportation” as that phrase is used in defining “welfare” for purposes of the NAAQS. Even assuming that these effect s would constitute adverse effects on public welfare, as well as adverse eff ects on public health, EPA does not believe there is evidence in the air quality criteria of such effects associated with ambient

concentrations of CO that would warran t establishment of a secondary standard (or revision of the primary standard), nor was such evidence provided by the commenter. EPA notes that the ISA characterized the evidence as only suggestive of a causal relationship between relevant short-term CO exposures and central nervous system (CNS) effects. The ISA further concluded that, while acute CO poisoning events (involving expos ure to levels much higher than the NAAQS) have been known to adversely affect CNS function, controlled human exposures have provided limited and e quivocal evidence fo r neurobehavioral effects resulting from somewhat lower leve ls of CO exposure. The lowest level evaluated in these studies, however, was associated with quite elevated COHb41 levels, in the range from 5 to 20% (PA, p. 2-16). As indicated by the REA results, little if any occurrence of COHb levels over 4% are expected under conditions associated with just meeting the current 8-hour standard (PA, Table 2-4).

(2) Comment: One commenter (CBD et al) stated that EPA should consider the role of CO in contributing to climate-related effects of ozone, objecting to EPA’s

conclusion that indirect effects of CO on climate that are attributable to ozone

formation should be addresse d through the ozone NAAQS.

Response: To the extent that indirect effect s of CO on climate are attributable to ozone it would be more appropriate to a ddress them in the review of the ozone NAAQS. The NAAQS for a criteria pollutant must be requisite to protect public

health and welfare in accordance with the Clean Air Act, and EPA does not believe it necessary or appropriate to a dditionally consider the adverse effects

attributable to one criteria pollutant in setting the standa rd for a different criteria pollutant which may also be a precursor to the first pollutant. For example, the NAAQS for oxides of nitroge n (long-recognized ozone precu rsors) are not set to establish requisite protection from the adverse effects of ozone.



### C. Comments Related to Monitoring

1. Sampling and Analysis Methods

Comments received (API) on the proposed re vision to part 50 and part 53 generally indicated support for the general proposed ch anges to update and clarify the CO Federal reference method (FRM). The commenter also welcomed the general upgrading of the analyzer performance requirements and that new candidate CO Federal equivalent methods (FEM) analyzers will be required to meet them. Comments on specific aspects of the proposed changes are addressed below.

(1) Comment: Part 50, appendix C – In section 4.2.1 (in the calibration procedure), EPA proposes to change the requirement fo r flow rate control and regulation to ±2% from the existing ±1% requirement. The commenter questioned whether this relaxation was intended or an oversight.

Response: This change is intended. In response to this comment, EPA has reconsidered this proposed change. Howe ver, it was again determined that the 1% requirement for flow rate control a nd regulation was unn ecessarily stringent in comparison with the level of overall uncertainty tolerable in the calibration system and in the monitoring instrument. This change is commensurate with the flow rate measurement accuracy requirement of 2% (which is unchanged from the existing requirement) in the succeeding section 4.2.2.42 (2) Comment: Part 50, appendix C- The commenter suggested that the numerator in Formula 1 (of the calibration procedure) s hould contain either parentheses or a multiplication symbol to indicate that the two terms are to be multiplied.

Response: EPA has made a change in res ponse to this comment. Although not mathematically necessary, the additi on of a multiplication symbol in the numerator of the formula will help to clarify that the two terms are to be multiplied.

(3) Comment: Part 50, appendix C – The commente r points out that in sections 4.4.5 and 4.4.6 (of the calibration procedure), no provision is made for connecting a data read-out device to the CO analyzer under calibration to f acilitate monitoring of the analyzer readings. Use of the anal yzer’s visual displa y may not accurately represent the way readings are routinely recorded.

Response: EPA has made a change in res ponse to this comment. Typically, FRMs do not contain such a provision, si nce it seems quite obvious that such a device is necessary. However, the sugge stion to include such an appropriate provision has merit and may help to improve the overall accuracy of the

calibration. Section 4.4.3 has been revise d to include a statement that the readout device used should represent the way that the routine analyzer readings are

recorded.

(4) Comment: Part 53, subpart B – The commenter stated they could not review the complete set of analyzer performance da ta that EPA cited as a basis for the proposed new FRM and FEM analyzer pe rformance requirements because the cited reference (a spreadsheet of analy zer manufacturers’ published performance data for various analyzers) did not in clude the performance data from FRM applications received by EPA that were also used by EPA for this purpose.

Response: In addition to the performance data included in the referenced spreadsheet, EPA also used data from recent CO FRM applications that EPA has received and processed under part 53. Th ese latter data could not be included in the referenced spreadsheet because the appl ications and all data they contain are identified by their respective applicants as confidential business information (CBI). EPA must treat data identified as CBI in accordance with 40 CFR part 2, which restricts its public release pending a fi nal determination of its status as CBI. Any person seeking to review data for wh ich a claim of CBI has been made may file a request under the Freedom of Information Act and 40 CFR part 2.

(5) Comment: Part 53, subpart B – The commenter stated that EPA did not provide or cite data to support its conclusi on that the existing performance limit requirement for the “total of all interf erents” is redundant with the individual

interferent limits for mode rn CO analyzers and the pr oposed withdrawal of this total interference limit requirement.43 Response: In response to this comment, EPA has re-examined the efficacy of the existing total interference limit require ment for CO analyzers and has again determined that it is not necessary. A ll CO analyzers in monitoring use today are FRMs, which use an infrared absorption measurement principle. For these analyzers, only 2 interferents are liste d in Table B-3 of 40 CFR part 53, and the analyzers’ responses to those interferences are typically well controlled. Even for other potential measurement principles lis ted in Table B-3 – none of which are represented in currently available CO analyzers – only a fe w interferences are listed, and they are quite unlikely to be a ll simultaneously elevated at typical CO monitoring sites. Thus, the limit for total interferences is of minimal efficacy, and

therefore EPA believes it can be eliminat ed. For analyzers opting to meet the proposed new lower measurement range, the individual inte rference limit is

reduced to 1⁄2 of the limit for the standard measurement range, again rendering the need for a total interference limit unnecessary.

(6) Comment: Part 53, subpart B – Similarly, the commenter states that EPA did not cite or provide data to support the pr oposed withdrawal of the existing limit requirement for span drift determined at a concentration of 20 % of the upper range limit (URL). The commenter conte nds that this requirement is important because 20 % of the standard range of 50 ppm is 10 ppm, wh ich is close to existing (and proposed) 8-hour NAAQS for CO and is closer to the 1-hour NAAQS than the 80% URL drift limit. Accordingly, the commenter suggests withdrawing the 80% URL drift limit instead of the 20 % URL limit.

Response: EPA does not agree that the 80% URL drift limit should be withdrawn in place of the 20% URL limit. The pur pose of the span drift limit is not to directly assess measurement error at a par ticular, mid-scale concentration level. That is the purpose of the 1-point qualit y control check for CO monitors described in Section 3.2.1 of appendix A of 40 CF R part 58. FRM and FEM CO analyzers have a measurement response function that is well defined and typically very nearly linear with respect to the input CO concentration. For the purpose of analyzer performance testing, this linear input/output functiona l characteristic is best described by its zero point and its slope, because these parameters are generally subject to change (drift) independently. Thus , zero drift (change in the zero point) and span drift (change in the slope ) are tested separately. Zero drift is, of course, measured at zero concentra tion, and span drift is most accurately

measured at a concentration near the URL. The span drift test at 80% URL (when the zero drift is within the specified requirement) adequately determines any change in the slope parameter. The curre ntly specified test at 20% URL serves little, if any, purpose in regard to dete rmining change in the slope and can

therefore be withdrawn.

(7) Comment: Part 53, subpart B - The comment er notes that new FRM and FEM analyzers would be subject to the new, more stringent requirements, but existing FRM analyzers, which have been appr oved based on the existing, less stringent requirements, would continue to be appr oved. EPA noted that most commercially44 available CO analyzers already meet th e proposed new performance requirements so it is unlikely that new analyzer th at are approved under the proposed new requirements would cost more, and thus there would be no economic impact on monitoring agencies. The commenter interp reted that statement to mean that EPA

is more concerned about cost than data quality. The commenter further suggested that existing FRM analyzers appr oved under the existing performance requirements may provide data quality infe rior to that of analyzers approved under the proposed new requirements and that older analyzers may be unacceptable for some applications that demand higher performance or higher data quality. A “tiered” approach was suggested to handle this situation.

Response: In proposing more stringent perfor mance requirements for approval of new FRM and FEM analyzers, EPA noted that the performance of analyzers approved under the existing performance requirements was fully adequate for most routine compliance monitoring app lications, and that the proposed new requirements were largely to bring the base FRM and FEM performance requirements up to date and more commens urate with the performance of modern commercially available CO analyzers. The commenter indicated that these changes were “long overdue and welcome. ” Since all currently designated FEM analyzers already meet the proposed new requirements, there would likely be no increase in cost for new analyzers that would be approved under the new requirements. Thus, EPA was merely pointing out that the new requirements were unlikely to impose a resultant ec onomic impact on monitoring agencies. EPA considers such impacts when proposi ng rule changes. More importantly, this means that routine CO monitoring da ta quality currently being obtained is already of the higher level portende d by the proposed new performance requirements. However, EPA did rec ognize that some special CO monitoring applications do require a higher level of performance than that required for routine applications. Therefore, EPA is, in fact, proposing a “tiered” approach by proposing optional, more stringent pe rformance requirements for analyzers having a more sensitive, “lower rang e” available for such applications. Applicants would be able to elect to ha ve such lower ranges approved as part of their FRM or FEM designation.

2. Near

­ Roadway Monitors

(1) Comment: Two commenters objected to the use of a near-road network for judging compliance with the NAAQS (Indiana Department of Environmental Management [IN DEM], South Caroli na Department of Health and Environmental Control [SC DHEC]). On e commenter (IN DEM) indicated their

view that roadside monitors did not provide a measurement that was “representative of ambient air quality ev erywhere in a city or county”. The second commenter, in addition to stating that data from this monitoring network were not appropriate for use in judging an area’s status in comparison to a NAAQS, further stated that such mon itoring “does not provide a mechanism to add further protection to th e general population or sus ceptible individuals” (SC DHEC).45 Response: The EPA notes that monito ring near roads for peak CO concentrations for compliance with the NAAQS is not a new concept, and has been in practice sin ce the 1970s. The Agency believe s that this final rule is updating the same intent that was original ly presented in monitoring regulations introduced in the May 1979 (44 FR 27571). Similarly, the data produced at nearroad monitoring stations would likely be treated as data from existing CO monitors near-roads, in downtown areas, or urban street canyons have been. EPA disagrees with commenters regarding th e protection provided by this monitoring. As discussed in the final rule, people who spend time on or around major roads (e.g., because they live there, go to school there, or commute in vehicles on major roads) can be exposed to elevated con centrations of ambient CO. Accordingly, monitoring in these locations does provi de further protection to the general population and susceptible individuals who are exposed in these areas, and is appropriate for judging compliance with the NAAQS regardless of whether such monitoring is indicative of concentr ations found throughout an urban area.

(2) Comment : The NYS DEC commented that CO monitors, due to collocation with

near-road NO 2 monitors, will be located in a range up to 50 meters from target road segments. The commenter stated that “data from these sites cannot adequately characterize near-road emissi ons nor would the data be comparable from one site or city to another.” The commenter goes on to state that the “final

NO 2 and proposed CO regulations have pr eceded an understanding of how these data will be used for anything other than for research.”

Response : The EPA understands the potential influence that monitor placement relatively nearer or further from a targ et road can have on resultant measured pollutant concentrations. However, the Ag ency believes that on the whole, nearroad monitors will be representative of exposures that can occur in the near-road environment. Further, the EPA recognizes the existence of a gradient in the nearroad environment within which, based on a number of physical factors, pollutant concentrations decrease with increasing di stance away from the source road. That was the rationale behind requiring near-road NO 2 sites within which CO monitors are required to be collocate d, to have monitor probes “ ...be as near as practicable to the outside nearest edge of the traffic lanes of the target road segment; but shall

not be located at a distance greater than 50 meters, in th e horizontal, from outside nearest edge of the traffic lanes of th e target road segment” (40 CFR part 58, appendix E, section 6.4(a)). The intent is to measure th e peak concentrations that are occurring in the near-road environm ent for a given urban area by being as close as practicable to target roads. EPA agrees that this data may be helpful to support research on near-road air quality a nd public health, which is one of the primary objectives for ambient monitoring ne tworks. However, EPA believes this data is also useful and necessary for en suring that near-road ambient air quality meets the NAAQS.46 (3) Comment : The TCEQ commented that in Texa s, frontage roads are included with the central line traffic counts. They stated that “the EPA’s interpretation that the access road through lanes in Texas are not tr affic lanes is incorrect...” and that the EPA needs to modify the interpreta tion to match conformity, National Environmental Policy Act (NEPA), and storm water reviews.

Response : In this rulemaking, the EPA has not taken a stance on the interpretation of how frontage roads are included in centr al line traffic counts. The regulation requiring near-road monitoring only references a ‘target’ road segment. In Texas’ case where frontage roads are included as part of a road segment, regardless of the physical configuration of that road, the out side edge of that road, whether it be frontage road or not, is the location from where measurements can appropriately be made to determine if a monitoring site is meeting siting criteria. Further, the EPA notes that siting criteria do not preclude the placement of a monitoring station in open space (not traffic lane s) within a road segment (e.g., between frontage lanes and so-called ‘through lanes’ if such a site is safely accessible and can meet siting criteria for probe placement in the vertical plane, and with respect

to obstructions.

(4) Comment: Some commenters (e .g., New York Department of Environmental Conservation [NYS DEC], NESCAUM, Texas Commission on Environmental Quality [TCEQ], AAM) expressed concern that near-road sites may not provide information representative of general population exposure, which one commenter claims is a primary monitoring objective. The AAM recommended that population exposure be included in siti ng and network design requirements, stating that at any new sites, there shou ld be “human exposure to the ambient air for time periods corresponding to th e 1-hour or 8-hour CO NAAQS.”

Response : As an initial matter, EPA notes th at as summarized in section IV.B.1 of the final rule, 40 CFR part 58, appendix D specifies three basic objectives for the design of ambient air monitoring networks : a) provide air pollution data to the general public in a timely manner; b) s upport compliance with ambient air quality standards and emissions strategy development; and, c) provide support for air pollution research studies. As described in the preamble to the final rule, the near-road monitoring requirement will assi st particularly with regard to the second objective. The EPA notes that, as de scribed in the ISA and consistent with findings of the REA, elevated short-term exposures to ambient CO are associated with near-roadway locations and other lo cations of motor ve hicle activity. The REA results indicated that key contri butors to highest ambient CO human exposures are in-vehicle and near-vehic le microenvironments (e.g., REA, Figure 6-4). While many vehicle-associated expos ures may be shorter than 8 hours, the 8-hour standard, as the controlling standa rd, provides contro l of shorter-term

elevations in concentration which also influence people’s CO exposures and associated COHb levels. Thus, siting monitors in near-roadway locations will47 help ensure compliance with the NAAQS and protection of the public from elevations in roadway-associated ambi ent CO concentrations of concern.

(5) Comment : Several commenters (e.g., AASHTO and New York State Department of Transportation [NYSDOT]) recommended that state and local air monitoring agencies be required to cooperate with state and local transportation agencies on the placement of near-road monitors

Response : The EPA is not in a position to requ ire state and local air agencies to cooperate or collaborate with their state or local transportation agencies in the implementation of required near-road m onitoring sites by rule. However, the EPA strongly encourages air monitoring agencies to work with their respective transportation counterparts, and believes th at air monitoring agencies are already inclined to do so. Further, the EP A believes that many candidate near-road monitoring stations will be in right-of-way locations, within which air agencies will have to work with transportation ag encies to negotiate access and ensure safety for the travelling public, air monito ring staff, and the associated monitoring

infrastructure.

(6) Comment: Several commenters (e.g., AAM, NACAA) suggested that required near-road monitors should be phased in over a period of time. For example,

NACAA cited a CASAC statement that th ere are benefits from implementing near-road monitors in stages, e .g., over a three year period.

Response : EPA agrees with these commenters that phasing in the implementation

of near-road CO monitors is warranted. Accordingly, in the final rule, EPA has required near-road CO monitors within CBSAs having populations of 2.5 million or more persons to be implemented by January 1, 2015, while those CBSAs having 1 million or more persons, but less than 2.5 million, are required to be operational by January 1, 2017. EPA intends to review the expe rience of states with the first round of near-road CO monitors and the data produced by such monitors and consider whether adjust ments to the network requirements are

warranted.

(7) Comment : A number of commenters (e.g., AASHTO, IN DEM, NYSDOT) expressed concern regarding safety for the public and air agency workers at monitoring stations in th e near-road environment.

Response : The EPA recognizes safety as a top priority in the implementation of any near-road monitoring sites. This is evident in the preamble to the final rule promulgating the requirements for near-road NO 2 monitors. By requiring CO

monitors to be collocated with near-road NO 2 monitors, network implementation issues such as safety will effec tively be handled as the near-road NO 2 network is48 installed. In an effort to support state and local air ag encies in the implementation

of near-road NO 2 sites, the EPA is collaborating with U.S. Department of Transportation, Federal Highw ay Administration and seve ral state Departments of Transportation (DOTs) (e.g., Florida & Texa s), along with partner state and local air agencies, to provide technical assistance on near-road site implementation to the air monitoring community. Safety is a key subject in that assistance, with topics covering issues of right-of-way access, the use of safety features such as guardrails or recognition of ‘clear zone s’, and how to engage DOTs or other transportation agencies to ensure safety of the travelling public, air monitoring staff, and air monitoring infrastructure at near-road monitoring sites. Further, monitoring by roads for CO is not a new con cept to states and local air agencies. They have been monitoring near roads, mainly in downtown areas and in urban street canyons, since the late 1970s. Th e EPA believes that state and local air agencies are very aware of safety issues , in part based on existing experience, and the Agency is confident that state and lo cal air agencies will be able to safely implement near-road monitoring sites thr ough the use of the technical assistance to be provided and by working with th eir respective partner transportation agencies as necessary.



### 3. Other Locations

(1) Comment: One commenter (Safe Air for Everyone) noted that agricultural burning can have a significant impact on populations in and around agricultural areas. Particularly, the commenter state stated that “EPA should be monitoring the impacts of CO on agri culturally burned lands to protect citizens since crop residue burning occurs in all 50 states.”

Response : In the preamble to the final rule, the EPA notes that a nationally applicable network design may not always account for all locations in every area where monitors may be warranted. The Agency believes that a minimum monitoring requirement to assess agricu ltural burning is not practical in a nationally applied network design. However, in this final rule, the Agency has given EPA Regional Administrators the discretion to requir e monitoring above the minimum requirements as necessary to address situations where minimum monitoring requirements are not sufficient to meet monitoring objectives. The EPA believes that the assessment of agri cultural burning may be another example of a situation where the EPA Regional Ad ministrators may work with state and local air monitoring agencies to consider deploying monitoring resources to assess air pollution. In addition to the Regional Administrator authority, state and local agencies can also deploy pollutant anal yzers on a temporary basis, as special purpose monitors, to explore potential pol lution issues in areas where problems are suspected due to agricultural burning. The Agency believes these two flexible approaches (with respect to location a nd duration) are appropriate to assess impacts of agricultural burning in lieu of nationally applie d minimum monitoring requirements near these sources.49 (2) Comment: NACAA stated that “EPA should al so take this opportunity to reevaluate the existing CO monitoring network and eliminate sites that are redundant or no longer necessary so that resource can be transferred to higher priority areas.” The commenter goes on to state that “providing clear guidance and support for the divestment of unnecessary monitors is essen tial to allow state and local agencies to best focus limited re sources, and is a necessary prerequisite to the relocation of existing CO monito rs for inclusion in the near roadway

network.”

Response : The Agency agrees with the commen ter that the removal or relocation

of redundant sites or those that are likel y no longer necessary is desirable. The

EPA will continue to work with state and local agencies to shut-down or relocate

these monitors that meet the criteria of 40 CFR 58.14 as they are identified and proposed for modification. EPA will also consider revisions to maintenance plans where monitors are currently required but otherwise meet the criteria of 40 CFR

58.14.

(3) Comment : API suggested that EPA require any CO monitors recording peak values that are greater than or e qual to 80% of NAAQS be retained.

Response : Existing monitoring sites are not allowed to be shut-down unless they meet certain criterion with respect to th eir data. These rules by which a monitor

can be considered for shut-down ar e maintained in 40 CFR Part 58, 58.14 System Modification . Among the criteria under which m onitors are eligible to be shut down is if there is less than a 10% proba bility that the monitor will record an

ambient concentration in excess of 80% of the NAAQS over the succeeding three years, and the monitor is not n eeded under the maintenance plan. 29 Further, as is noted in the preamble to the final rule, before any monitor can be shut-down, the state or local air agency must also recei ve EPA Regional Administrator approval. Accordingly EPA does not believe an a dditional requirement to retain CO monitors recording peak values abov e 80% of the NAAQS is necessary or appropriate.

(4) Comment : AASHTO asked for clarification on wh ether, or where, NCore sites in

areas where near-road monitor would also be required; and for clarification on

29 Other criteria include: (1) wher e a monitor has consistently measured lower concentrations than another monitor for the same pollutant in the same county (or portion of a county within a distinct attainment area, nonattainment area, or maintenance area, as applicab le) during the previous five years under certain circumstances; and (2) where a monitor has not measur ed violations of the applicable NAAQS in the previous five years, and the approved SIP provides for a specific, reproducible approach to representing the air quality of the affected county in the absence of actual monitoring data. See 40 CFR 58.14(c).50 whether NCore sites would provide bac kground data for conformity and NEPA

related issues.

Response : NCore site information is maintained by the EPA and available to the public through several different mediums. One resource is EPA’s AirExplorer,

which is an on-line tool that can be used to generate maps, data graphs, and data tables. AirExplorer is located at: http://www.epa.gov/airexplorer . Another resource is EPA’s Air Quality System (AQS) database.

NCore sites, which represent area-wide pollutant concentrat ions by nature, are already operational throughout the country. As noted in section IV.B.2.e of the preamble to the final rule, upon analysis of existing NCore stations and all other area-wide CO monitors opera ting nationwide, the EPA belie ves that there are only

four CBSAs that do not alre ady have an area-wide monitor where near-road CO monitors are required by the final rule. Th e EPA’s view is th at generally areawide monitors (e.g. those at sites with a spatial scale of neighborhood, urban, or regional) are likely appropriate to consid er as being representative of broader urban or background concentrations, de pending on their individual location. However, specific guidance on modeling for conformity and NEPA analyses is beyond the scope of this rulemaking.

4



### . Other Monitoring Comments

(1) Comment : Multiple commenters (e.g., NACAA, IN DEM, North Carolina Division of Air Quality [NCDAQ], SC DH EC, Wisconsin Department of Natural Resources [WIDNR]), stated that the EP A needs to provide full funding for any new monitoring requirements.

Response : The EPA notes that it has historica lly provided full or partial funding for the cost of installing and operatin g monitors used to satisfy minimum monitoring requirements, and the agency expects to follow this precedent for required monitoring associated with this rulemaking. EPA understands the financial hardship many state and local agencies are currently enduring, and will continue to identify sources of funding a nd work with air monitoring agencies to move funds to states and support the im plementation of all required monitoring. The Agency also notes that it expects st ates will be in a position to relocate existing CO monitors to satisfy the new minimum monitoring requirements. The Agency believes that in some cases, st ates may lower operating costs by shutting down some existing individual CO sites, wh ile moving those monitors to the nearroad sites required and imple mented as part of the NO 2 rulemaking.

(2) Comment : Several commenters (e.g., NAC AA and NESCAUM) suggested that EPA should support and/or facilitate th e introduction of trace level instruments into the state and local air monitoring networks while phasing out older monitors.51 Response : The EPA agrees that when possible the introduction of more sensitive

“trace-level” instrumentation into the SL AMS network is desirable. The EPA did not require the use of such instruments in this rulemaking because the required monitors are expected to be in locations of highest ambient CO concentrations. However, as state and local air agencies replace their inventor y of gas analyzers, the Agency strongly encourages the a doption of trace-level instrumentation instead of standard sensitivity or traditional analyzers.

(3) Comment : NACAA suggested that there is a n eed to provide traffic cameras at

near-road CO sites.

Response : The EPA did not propose or promulga te any requirement for state and local air agencies to install traffic came ras at near-road monitoring sites. The Agency agrees that traffic information w ould be very valuable in characterizing CO data (and other pollutant data) collected at the near -road site. In the site selection process for near-road monito ring sites the EPA is encouraging air monitoring agencies to place some additi onal consideration on near-road locations where utilities or other transportation ag ency infrastructure, such as traffic counters and/or cameras, are located. If an air agency does not place a near-road

site at a location with or near a tra ffic counter and/or camera, the Agency encourages those state and local air agencies to consider if a tr affic counter and/or camera is financially feasible and imple mentable at their site, which may be identified during the near-road site sel ection process, and/or by engaging their respective transportation agency.

(4) Comment : EPA received comments suggesting that near-road monitoring sites should be multipolluant monitoring sites, monitoring for pollutants such as air toxics, elemental carbon, or ganic carbon, and black carbon.

Response : The EPA has envisioned that near-road monitoring stations would be multipollutant monitoring sites. This concept fits with the Agency paradigm to promote multipollutant monitoring wherever possible. Multipollutant monitoring is viewed by the EPA as a means to br oaden the understand ing of air quality conditions and pollutant inte ractions, furthering the cap ability to evaluate air quality models, develop emission contro l strategies, and support research, including health studies. With that, the EPA agrees that the monitoring of other pollutants such as air toxics or black car bon, for example, is encouraged whenever feasible for state and local air agencies. The requirement of such monitoring in the near-road environment, other than for CO, is outside the scope of this rulemaking.

(5) Comment : It was suggested that the EPA should not claim that there are not significant costs associated with the proposed monitoring network requirements.52 Response : With the expectation that only approximately 52 (based on recent 2010 Census counts) CO monitors are being required with this rulemaking, the EPA believes that in almost all cases, st ate and local air monitoring agencies will be in a position to move existing monitors or put monitors back into service at required near-road sites. The costs of installing the near-road monitoring site infrastructure are to be borne by the implementation of near-road NO 2 sites. EPA recognizes that moving a CO monitor does have some associated costs but does not believe the costs associated with the monitoring requirements will be significant.



### III. RESPONSES TO SIGNIFICANT COMMENTS RELATED TO

IMPLEMENTATION OF STANDARDS

A. Designations

(1) Comment: Several commenters (including st ate transportation agencies, AAM, AASHTO, AEPSC and SEMCOG) commented on, and sought clarification of, issues related to designati on of nonattainment areas that could occur in the future following changes in the monitoring netw ork. For example, several commenters raised questions about whether such nonatta inment areas would be large, or very

localized.

Response : EPA is not revising the CO NAAQ S. Accordingly, EPA will not be undertaking the designation process set fo rth in CAA section 107(d)(1). EPA has no knowledge as to whether the new mon itoring network will produce air quality

data such that the Administrator will deem it appropriate to initiate the redesignation process. EPA also notes th at the CAA and judicial decisions make

clear that the economic and technical feasib ility of attaining am bient standards are not to be considered in setting or revising NAAQS (although su ch factors may be considered in the development of Stat e plans to implement the standards). Accordingly, EPA believes it is unnecessary and would be premature to address in this action issues as to the scope of potential nonattainment areas or the process

or factors to be considered if the Admi nistrator finds it appropriate to initiate redisignations.



### B. Other

(1) Comment: Several commenters, including NE SCAUM, state that there are many CO monitoring sites currently required by maintenance plans that are no longer needed. These sites have consistently measured levels of CO well below the current NAAQS, and they represent a res ource drain in light of state budget

constraints. States associated with NESCAUM urge EPA to develop a procedure

that would allow states to shut down thos e sites earlier than the dates of existing agreements, as appropriate. This coul d be achieved using a simple approach,53 possibly based on existing design value da ta being below a chosen threshold. Given that the nature of the agreements varies widely from state to state and across EPA regions, it is desira ble to have a consistent national approach to the expeditious closing of these sites.

Response: The EPA currently provides a process for the shutting down of monitors which is provided at 40 CFR 58.14, titled “system modification.” In order for a monitor to be shut down, a stat e, or where appropriate a local, agency must develop and implement a plan a nd schedule to modify the monitoring network that complies with the finding s of the network assessments required every 5 years by section 58.10(e). The state, or local agency, is then required to consult with the appropriate EPA Regiona l Administrator during the development of the schedule to modify the monitori ng program, and is required to make the plan and schedule available to the public for 30 days prior to submission to the EPA Regional Administrator.

Plans containing modifications to NCore St ations or PAMS Stations are required

to be submitted to the EPA Administra tor. The Regional Administrator is required to provide an opportunity for pub lic comment and is required to approve or disapprove submitted plans and schedules within 120 days. 40 CFR 58.14(c) provides that a State, or where appropriate a local, agency’s requests for a SLAMS monitor station disc ontinuation, subject to review of the Regional Administrator, will be approved if any of the following criteria are met and if the requirements of appendix D of 40 CFR 58 continue to be met. Other requests for discontinuation may also be approved on a cases-by-case basis if

discontinuance of the affected monito r does not compromise data collection needed for implementation of a NAAQS and if the requirements of appendix D of

40 CFR 58 continue to be met.

More specifically, as it relates to the shutting down of monitors in maintenance areas, 40 CFR 58.14(c)(1) stat es the following: “Any PM 2.5 , O 3 , CO, PM 10 , SO 2 , Pb, or NO 2 , SLAMS monitor which has shown attainment during the previous five years, that has a probability of le ss than 10 percent of exceeding 80 percent of the applicable NAAQS during th e next three years based on the levels, trends, and variability observed in the past, and which is not specifically required by an attainment plan or maintenance plan. In a nonattainment or maintenance area, if

the most recent attainment or maintena nce plan adopted by the state and approved by the EPA contains a contingency measur e to be triggered by an air quality

concentration and the monitor to be di scontinued is the only SLAMS monitor operating in the nonattainment or mainte nance area, the monitor may not be

discontinued.”

EPA is willing to work with States to identify reasonable approaches to demonstrating that a monitor meets the criteria of 40 CFR 58.14(c)(1), and to consider revisions to maintenance plans that currently require monitors that

otherwise meet those criteria.54 (2) Comment: Two state agencies (IN DEM and SC DHEC) submitted comments stating that if violations are measured by a roadside monitor, states do not possess the necessary authority to implement the required controls to establish attainment or meet their obligations for state im plementation plan development. The commenters stated that a significant percenta ge of vehicles that travel major urban roadways are registered outside of the state and are regula ted at the federal level. Transportation control measures could be implemented to reduce congestion and vehicle miles traveled, but only at th e local level and would not achieve substantial reductions in CO. Commenters further state that, until U.S. EPA petitions Congress for the necessary revi sions t the Clean Air Act, granting authority to states to have control over mobile source s, a means to develop an attainment strategy for roadside CO and NO2 must be established.

Response: As noted above, EPA is not revi sing the CO NAAQS. Accordingly, EPA will not be undertaking the designati on process set forth in CAA section 107(d)(1), or requiring SIP submissions pursuant to CAA section 110. EPA has no knowledge as to whether the new mon itoring network will produce air quality

data such that the Administrator will deem it appropriate to initiate the redesignation process.

EPA agrees that it is a federal responsibi lity to implement regulations that reduce emissions from new light- and heavy-duty motor vehicles. However, if it becomes necessary to achieve additional re ductions in ambient CO, states have authority that can be used to reduce emissions from in-use light- and heavy-duty vehicles. For example, CAA section 177 allows states to adopt California’s standards that apply to new motor vehicles or new motor vehicle engines. States can also implement programs to retrofit ol der heavy-duty diesel vehicles to reduce their CO emissions. States can also imple ment regulations to reduce or eliminate long-duration idling of hea vy-duty diesel vehicles. They can implement an inspection and maintenance pr ogram for light-duty vehicl es. Additionally, states can implement a wide range of programs to improve transportation efficiency (e.g., working with freight shippers).

It is EPA’s belief that a nu mber of states have already achieved reductions in CO

emissions from on-road sources. EPA antic ipates that if an area were to be designated nonattainment for the CO NAAQS , the state would evaluate a variety

of control measures to reduce emissions from mobile sources (which include nonroad engines), as well as other so urces that are contributing to the nonattainment problem.

If any areas are designated nonattainmen t at some point in the future, EPA expects that each state w ith a designated CO nonattain ment area would develop a SIP that brings the area into attainment by the applicable deadline and that each state would evaluate the potential for c ontrolling emissions from all sources that are contributing to the no nattainment problem.55 

### IV. RESPONSES TO SIGNIFICANT COMMENTS RELATED TO

EXCEPTIONAL EVENTS

(1) Comment: Several state departments of transportation (including those from New York, Texas, Virginia, and Washington) and the American Association of State Highway and Transportation Officials co mmented that the proposed monitoring requirements for near-road CO monitors would result in “hotspot” monitoring rather than monitoring of background concentration levels and that the Exceptional Events Rule should, therefore, be revised to recognize temporary traffic-related activities, such as cons truction and traffic congestion caused by accidents, as potential exceptional events.

Response: The Exceptional Events Rule (EER) and the accompanying preamble (72 FR 13560, March 22, 2007) created a regulatory process containing definitions, procedural requirements, requirements for state demonstrations, and criteria for EPA approval for the exclusi on of air quality data from regulatory

decisions under the EER. EPA believes that these criteria and procedures sufficiently address any exceptional even ts claim that may arise for the CO NAAQS, and that additions or modificati ons to the EER, specific to CO, are not needed. EPA further recognizes that te mporary traffic-related activities or conditions could be potential exceptional ev ents, and, therefore, created a data flag (i.e., Qualifier Code and Qualifier Description) in the Air Quality System (AQS) for “unique traffic disruption.” EPA believes that the general rule criteria and specific AQS flagging mechanisms provi de sufficient flexibility to identify and address near-road exceptional events.

In addition, EPA has developed draf t implementation guidance products, available by request at EEGuidanceComme nts@epa.gov, that cl arify the criteria

on which exclusion of event-affected da ta depend, describe the administrative process and associated timing for submitta l and review of demonstrations, and provide answers to frequently asked questions, including questions regarding temporary activities and “hot-spot” (i.e., microscale) monitors.



### V. RESPONSES TO LEGAL, ADMINISTRATIVE, AND PROCEDURAL

ISSUES AND MISPLACED COMMENTS

(1) Comment: Two commenters (PSR et al and Donnay) suggest that the rule be found subject to Executive Order 13045 (62 FR 19885, April 23, 1997), concerning the protection of children from e nvironmental health and safety risks.

Response: EPA found that the proposed rule was not subject to E.O. 13045 because it was not “economically signif icant” as defined in E.O. 12866, and because the Agency does not believe the environmental health or safety risks addressed by this action present a dispr oportionate risk to children. Likewise,56 EPA finds that the final rule is not s ubject to EO 13045 for the same reasons.

EPA notes that a rule must be “economica lly significant” to be subject to EO 13045. Accordingly, the fact that the rule is not economically significant is a sufficient reason why it is not subject to EO 13045. However, EPA has carefully

considered the risks from ambient CO for children. For the reasons discussed in the preamble (section II.B) and elsewhere in this document (e.g., see responses to comments at II.A.3(1), II.A.3(2) and II.A.5(8)), EPA disagrees with the

commenters’ view that there is eviden ce establishing that a range of health effects, including developmental and respirat ory effects, are occurring as a result of exposures to CO in ambient air at or below the current st andards, or that children are at a disproportionate risk fr om adverse health effects from ambient CO. EPA believes the current CO NAAQS provide the requisite protection for children, with an adequate margin of safety.

(2) Comment: Some comments stated that EP A failed to properly characterize CASAC's advice and to comply with it s obligation under the CAA to respond to

comments from CASAC.

Response : EPA believes the preamble to the proposed and final rules and this Response to Comments document fairly and adequately characterize CASAC's advice and that it has fully complied w ith its obligations under CAA section 307(d)(3) to "summarize and provide a reference to any pertinent findings, recommendations, and comments by [CASAC ] and, if the proposal differs in any important respect from any of these r ecommendations, an explanation of the

reasons for such differences."

EPA has explained in the preamble to the proposed and final rules that CASAC expressed a "preference" for a lowe r standard, stating that “[i]f the epidemiological evidence is given add itional weight, the conclusion could be drawn that health effects are occurring at levels below the current standard, which would support the tightening of the current standard” and further advised that "revisions that result in lowering the sta ndard should be considered" (see e.g., 76 FR 8183). However, EPA disagrees with th e comment that "[i]t is evident ... that

the CASAC believes the current standards are likely to be inadequate" (CBD et al, p. 7). The CASAC Panel explained its view s at greater length in its response to charge questions on the draft Policy A ssessment (Brain and Samet, 2010d, p. 12):

While there have been no new controlled human exposures designed to examine effects of CO at COHb levels below 2%, there have been numerous improvements to the exposure and COHb dosimetry models employed to provide exposure and risk estimates. The Staff analysis indicates that some of the uncertainties identified in previous reviews of the standard have been reduced. Based on their overall analysis, they conclude that the body of evidence and the quantitative exposure and dose estimates provide support for a standard at least as57 protective as the current standards. I.e. the data provide support for retaining or revising the current 8-hr standard.

Overall the Panel agrees with this conclusion. If the epidemiological evidence is given additional weight, the conclusion could be drawn that health effects are occurring at levels below the current standard, which would support the tightening of the current standard. The PA should include an analysis the number of exceedances that would have occurred if the standard had been based on the epidemiological

data. "

Based on this statement, and others, from CASAC, EPA explained in the proposed

notice that "the Administrator considers th e advice of CASAC, including both their overall agreement with the Policy Assessment conclusion that the current evidence and quantitative exposure a nd dose estimates provide support for retaining the current standard, as well as their view that in light of the epidemiological studies, revisions to lo wer the standards should be considered and their preference for a lower standard " (76 FR 8183). EPA believes this, and other statements in the proposed and final notices, and this Response to Comments document, fairly and adeq uately summarize CASAC's advice. Moreover, EPA believes it has acted c onsistent with CASAC's advice in considering a lower standard. Ultimatel y, after giving a balanced assessment of the various lines of evidence, including further consideration of the epidemiological evidence, and its asso ciated uncertainties (also noted by CASAC), the Administrator concluded that the current standards are requisite to protect public health with adequate margin of safety. Even if, for the sake of argument (despite CASAC's explicit recogn ition that the evidence supports either retaining or revising the standa rd), this conclusion were considered to differ in an important respect with the advice of CA SAC, EPA has fully explained the basis

for the Administrator's conclusion.

(3) Comment: Two commenters stated that th e Office of Management and Budget “classifies the CO NAAQS as a ‘majo r’ and ‘economically significant’ rule” (PSR at 10; Donnay at 60), and that therefore EPA is required to publish a Regulatory Impact Analysis (RIA), as EP A did during the last review. Another commenter (NYSDOT at 4) suggested that “if there are changes to CO attainment and nonattainment designations as a resu lt of near-road monitors, those impacts and added costs should be fully evaluate d and accounted for in this rule-making

effort in accordance with Executive Order 13563.”

Response: As noted in Section V of th e preamble, under Executive Order 12866 (58 FR 51735, October 4, 1993), this action is a "significant regulatory action” because it was deemed to “raise novel legal or policy issues.” Accordingly, EPA

submitted this action to the Office of Ma nagement and Budget (OMB) for review

under Executive Orders 12866 and 13563 (76 FR 3821, January 21, 2011). However, this action is not an “economically significant action” within the58 meaning of section 3(f)(1) of EO 12866, and therefore sectio n 6(a)(3)(C) of EO 12866 does not apply to this rulemaking and EPA was not required to prepare an RIA, which includes, to the extent feas ible, a quantification of the costs and benefits of the rulemaking. Likewise, this rule is not a “major rule” for purposes of the Congressional Review Act.

As noted above, EPA has no knowledge as to whether the new monitoring network will produce air quality data such that the Administrator will deem it appropriate to initiate th e redesignation process. Ho wever, EPA notes that the CAA and judicial decisions make clear th at the economic and t echnical feasibility of attaining ambient standa rds are not to be considered in setting or revising NAAQS (although such factors may be cons idered in the development of State plans to implement the standards). EPA acknowledges that we could have prepared an RIA, even though an RI A was not required under EO 12866 and EO 13563. However, in light of the facts that EPA was not proposing to change the standard, that evidence is limited on current ambient concentra tions near roads, and that any RIA would be irrelevant to a decision whether to change the standard, as well as EPA’s limited resour ces for preparing RIAs, EPA chose not to prepare an RIA for this action.59 

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### Appendix A. Studies cited by public commenters that were not included in the 2010 CO ISA (e.g., published after doc ument closure). These studies were provisionally considered by EPA, as disc ussed in section I.C of the preamble to

the final rule and in this document.

Andersen, Z. J.; Olsen, T. S.; Andersen, K. K.; Loft, S.; Ketzel, M.; Raaschou-Nielsen, O. (2010) Association between short-term exposure to ultrafine particles and hospital admissions for stroke in Cope nhagen, Denmark. European Heart Journal 31: 2034-2040. http://dx.doi .org/10.1093/eurheartj/ehq188.

Andersson, J. A.; Uddman, R.; Cardell, L. O. (2002) Increased carbon monoxide levels in the nasal airways of subjects with a hist ory of seasonal allerg ic rhinitis and in patients with upper respiratory tract infec tion. Clinical and Experimental Allergy

32: 224-227.

Andersson, M. F. and Møller, A. M. (2010) Assessment of carbon monoxide values in smokers: a comparison of carbon monoxide in expired air and carboxyhaemoglobin in arterial blood. Eur opean Journal of Anaesthesiology 27: 812-818. http://dx.doi.org/10.1097/EJA.0b013e32833a55ea.

Antczak, A.; Kharitonov, S. A.; Montuschi, P.; Gorski, P.; Barnes, P. J. (2005) Inflammatory response to sputum induction measured by exhaled markers. Respiration 72: 594-599. http://dx.doi.org/10.1159/000086721.

Antuni, J. D.; Kharitonov, S. A.; Hughes, D.; Hodson, M. E.; Barnes, P. J. (2000)

Increase in exhaled carbon monoxide duri ng exacerbations of cystic fibrosis.

Thorax 55: 138-142.

Antus, B. and Horváth, I. (2007) Exhaled nitr ic oxide and carbon monoxide in respiratory

diseases. Journal of Breath Rese arch 1: 024002. http://dx.doi.org/10.1088/1752-

7155/1/2/024002.

Arbex, M.; de Souza Conceicao, G.; Cendon, S.; Arbex, F.; Lopes, A.; Moyses, E., . . . Braga, A. (2009) Urban air pollution a nd chronic obstructive pulmonary diseaserelated emergency department visits. Journal of Epidemiology and Community Health 63: 777. http: //dx.doi.org/10.1136/jech.2008.078360.

Babusikova, E.; Jesenak, M.; Durdik, P.; Dobrota, D.; Banovcin, P. (2008) Exhaled carbon monoxide as a new marker of respir atory diseases in children. Journal of Physiology and Pharmacology 59: 9-17.

Bahcebasi, T.; Kandis, H.; Baltaci, D.; Kara , I. H. (2011) Factor s affecting exhaled

carbon monoxide levels in coffeehouses in the Western Black Sea region of Turkey. Toxicology and Indus trial Health 27: 195-204. http://dx.doi.org/10.1177/0748233710383888.64 Baja, E. S.; Schwartz, J. D.; Wellenius, G. A.; Coull, B. A.; Zanobetti, A.; Vokonas, P. S.; Suh, H. H. (2010) Traffic-related air pollution and QT interval: Modification by diabetes, obesity, and oxidative stre ss gene polymorphisms in the Normative Aging Study. Environmental Hea lth Perspectives 118: 840-846. http://dx.doi .org/10.1289/ehp.0901396.

Barak, M.; Oron, T.; Mimouni, F. B.; Dollb erg, S.; Littner, Y. (2005) Effect of

hematocrit on exhaled carbon monoxide in healthy newborn infants. Journal of Perinatology 25: 784-787. http ://dx.doi.org/10.10 38/sj.jp.7211388.

Baum, M.; Schiff, E.; Kreiser, D.; Dennery, P. A.; Stevenson, D. K.; Rosenthal, T.; Seidman, D. S. (2000) End-tidal carbon monoxide measurements in women with pregnancy-induced hypertension and pr eeclampsia. American Journal of Obstetrics and Gynecology 183: 900-903.

Beck-Ripp, J.; Latzin, P.; Gr iese, M. (2004) Exhaled ca rbon monoxide is not flow dependent in children with cystic fibr osis and asthma. European Journal of

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Biernacki, W. A.; Kharitonov, S. A.; Barnes, P. J. (2001) Exhaled carbon monoxide in patients with lower respiratory tract infection. Respiratory Medicine 95: 1003- 1005. http://dx.doi.org/10.1053/rmed.2001.1196.

Bruske, I.; Hampel, R.; Socher, M. M.; Ruck erl, R.; Schneider, A.; Heinrich, J., . . . Peters, A. (2010) Impact of ambient ai r pollution on the differential white blood cell count in patients with chronic pulm onary disease. Inhalation Toxicology 22: 245-252. http://dx.doi.org/10.3109/08958370903207274.

Cakmak, S.; Dales, R. E.; Judek, S. (2006) Do gender, education, and income modify the effect of air pollution gases on cardiac disease? Journal of Occupational and

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Cakmak, S.; Dales, R. E.; Vidal, C. B. (2010) Air pollution and hospitalization for epilepsy in Chile. Environment International 36: 501-505. http://dx.doi.org/ 10.1016/j.envint.2010.03.008.

Canova, C.; Torresan, S.; Simonato, L.; Scapella to, M. L.; Tessari, R.; Visentin, A., . . . Maestrelli, P. (2010) Carbon monoxide po llution is associated with decreased lung function in asthmatic adults. Eur opean Respiratory Journal 35: 266-272. http://dx.doi.org/10.1183/09031936.00043709.65 Cavaliere, F.; Volpe, C.; Gargaruti, R.; Posc ia, A.; Di Donato, M.; Grieco, G.; Moscato, U. (2009) Effects of acute hypoventila tion and hyperventilation on exhaled carbon monoxide measurement in healthy volunteers. BMC Pulmonary Medicine 9: 51. http://dx.doi.org/10.1186/1471-2466-9-51.

Chatkin, G.; Chatkin, J. M.; Aued, G.; Peterse n, G. O.; Jeremias, E. T.; Thiesen, F. V. (2010) Evaluation of the exhaled carbon m onoxide levels in smokers with COPD.

36: 332-338.

Chen, Y. H.; Lin, S. J.; Lin, M. W.; Tsai, H. L.; Kuo, S. S.; Chen, J. W., . . . Chau, L. Y. (2002) Microsatellite polymo rphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients. Human Genetics 111: 1-8. http://dx.doi.org/ 10.1007/s00439-002-0769-4.

Chen, Y. H.; Chau, L. Y.; Lin, M. W.; Chen, L. C.; Yo, M. H.; Chen, J. W.; Lin, S. J. (2004) Heme oxygenase-1 gene promotor microsatellite polymorphism is associated with angiographic restenosis after coronary sten ting. European Heart Journal 25: 39-47. http ://dx.doi.org/10.1016/j.ehj.2003.10.009.

Chen, Y. H.; Chau, L. Y.; Chen, J. W.; Li n, S. J. (2008) Serum bilirubin and ferritin levels link heme oxygenase-1 gene promot er polymorphism and susceptibility to coronary artery disease in diabetic patients. Diabetes Care 31: 1615-1620. http://dx.doi.or g/10.2337/dc07-2126.

Chen, R.; Pan, G.; Kan, H.; Tan, J.; Song, W.; Wu, Z., . . . Chen, B. (2010) Ambient air pollution and daily mortality in Anshan, China: A time-stratified case-crossover analysis. Science of the Total Environment 408: 6086-6091. http://dx.doi.org/ 10.1016/j.scitotenv.2010.09.018.

Cheng, M. F.; Tsai, S. S.; Yang, C. Y. ( 2009) Air pollution and hos pital admissions for myocardial infarction in a tropical city: Kaohsiung, Taiwan. Journal of Toxicology and Environmental Health, Part A: Current Issues 72: 1135-1140. http://dx.doi.org/10.1080/15287390903091756.

Cheng, S.; Lyass, A.; Massaro, J. M.; O'Connor, G. T.; Keaney, J. F.; Vasan, R. S. (2010)

Exhaled carbon monoxide and risk of metabolic syndrome and cardiovascular

disease in the communit y. Circulation 122: 1470-1477. http://dx.doi.org/10.1161/CIRCULATIONAHA.110.941013.

Chow, S.; Campbell, C.; Sandrini, A.; Thomas, P. S.; Johnson, A. R.; Yates, D. H. (2009)

Exhaled breath condensate biomarkers in asbestos-related lung disorders. 103: 1091-1097. http://dx.doi.org/10.1016/j.rmed.2009.04.009.

Ciarleglio, G.; Refini, R. M.; Pieroni, M. G.; Martino, V. A.; Bargagli, E.; Rottoli, P.; Sestini, P. (2008) Exhaled carbon monoxide in sarcoidosis. Sarc oidosis Vasculitis and Diffuse Lung Diseases 25: 46-50.66 Clark, N. A.; Demers, P. A.; Karr, C. J.; Ko ehoorn, M.; Lencar, C.; Tamburic, L.; Brauer, M. (2010) Effect of early life exposur e to air pollution on development of

childhood asthma. Environmental H ealth Perspectives 118: 284-290. http://dx.doi .org/10.1289/ehp.0900916.

Conceicao, G. M. S.; Miraglia, S.; Kishi, H. S.; Saldiva, P. H. N.; Singer, J. M. (2001) Air pollution and child mortality: a tim e-series study in Sao Paulo, Brazil. Environmental Health Perspectives 1093: 347-350.

Cope, K. A.; Solga, S. F.; Hummers, L. K.; Wigley, F. M.; Diehl, A. M.; Risby, T. H. (2006) Abnormal exhaled ethane concentra tions in scleroderma. Biomarkers 11: 70-84. http://dx.doi.org/10.1080/13547500500515046.

Cui, Y.; Zhang, Z. F.; Froines, J.; Zhao, J. ; Wang, H.; Yu, S. Z.; Detels, R. (2003) Air pollution and case fatality of SARS in the People's Republic of China: an ecologic study. Environmental Health 2: 15-19.

Cunnington, A. J. and Hormbrey, P. (2002) Brea th analysis to detect recent exposure to carbon monoxide. Postgraduate Medical Journal 78: 233-237.

Currie, J.; Neidell, M.; Schmieder, J. F. (2009) Air pollution and in fant health: Lessons from New Jersey. Journal of Health Economics 28: 688-703. http://dx.doi.org/ 10.1016/j.jhealeco.2009.02.001.

Czoga ł a, J.; Nowak, J.; Wardas, W. (2001) Dete rmination of carbon monoxide in blood by means of microdiffusion. Roczniki Pa ń stwowego Zak ł adu Higieny 52: 347-

351.

Dales, R. E.; Cakmak, S.; Doiron, M. S. ( 2006) Gaseous air pollutants and hospitalization for respiratory disease in the neonatal pe riod. Environmental Health Perspectives 114: 1751-1754. http://d x.doi.org/10.1289/ehp.9044.

Dales, R. E.; Cakmak, S.; Vidal, C. B. (2009) Air pollution and hospitalization for

headache in Chile. American Jour nal of Epidemiology 170: 1057-1066. http://dx.doi.or g/10.1093/aje/kwp217.

Davutoglu, V.; Zengin, S.; Sari, I.; Yildirim, C.; Al, B.; Yuce, M.; Ercan, S. (2009) Chronic carbon monoxide exposure is associ ated with the increases in carotid

intima-media thickness and C-reactiv e protein level. Tohoku Journal of Experimental Medicine 219: 201-206.

Dennekamp, M.; Akram, M.; Abramson, M. J.; Tonkin, A.; Sim, M. R.; Fridman, M.; Erbas, B. (2010) Outdoor air pollution as a trigger for out-of-hospital cardiac arrests. Epidemiology 21: 494-500. http://dx.doi.org/10.1097/EDE.0b013e3181e093db.67 Devine, S. A.; Kirkley, S. M.; Palumbo, C. L.; White, R. F. (2002) MRI and neuropsychological correlates of car bon monoxide exposure: a case report. Environmental Health Perspectives 110: 1051-1055.

Dunning, M. B. and Woehlck, H. J. (2005) Exha led CO after surgery: a consequence of postoperative narcotics. Anesthesia a nd Analgesia 100: 896; author reply 896. http://dx.doi.org/10.1213/01.ANE.0000146646.02457.55.

Economopoulou, A. A. and Economopoulos, A. P. (2002) Air pollution in Athens basin and health risk assessment. Environmental Monitoring and Assessment 80: 277-

299.

Fabricius, P.; Scharling, H.; Løkke, A.; Vestbo, J.; Lange, P. (2007) Exhaled CO, a predictor of lung function. Resp iratory Medici ne 101: 581-586. http://dx.doi.org/10.1016/j.rmed.2006.06.013.

Fritsch, T.; van Herpen, M.; von Basum, G.; Hering, P.; Mürtz, M. (2008) Is exhaled

carbon monoxide level associated with bl ood glucose level? A comparison of two breath analyzing methods. Journal of Biomedical Optics 13: 034012. http://dx.doi.org/10.1117/1.2937215.

Fung, K. Y.; Luginaah, I.; Gorey, K. M.; We bster, G. (2005) Air pollution and daily hospitalization rates for car diovascular and respiratory diseases in London,

Ontario. International Journal of Environmen tal Studies 62: 677-685.

Furne, J. (2003) Simplification of the e nd-alveolar carbon monoxide technique to assess erythrocyte survival. Journal of Labora tory and Clinical Medicine 142: 52-57. http://dx.doi.org/10.1016 /s0022-2143(03)00086-6.

Gajdócsy, R. and Horváth, I. (2010) Exhale d carbon monoxide in ai rway diseases: from research findings to clin ical relevance. Journal of Breath Research 4: 047102. http://dx.doi.org/ 10.1088/1752-7155/4/4/047102.

Giovannini, M.; Sala, M.; Riva, E.; Radael li, G. (2010) Hospital admissions for respiratory conditions in children and outdoor air pollution in Southwest Milan, Italy. Acta Paediatrica 99: 1180- 1185. http://dx.doi.org/10.1111/j.1651-

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Gomez, C.; Berlin, I.; Marquis, P.; Delc roix, M. (2005) Expired air carbon monoxide concentration in mothers and their spous es above 5 ppm is associated with decreased fetal growth. Prev entive Medicine 40: 10-15. http://dx.doi.org/10.1016/j.ypmed.2004.04.049.

Grover, R. S. and Kumar, R. (2008) Exhale d carbon monoxide levels : as a marker of clinical severity and control of asthma. Journal of Asthma 45: 677-680. http://dx.doi.org/10.1080/02770900802168687.68 Hanta, I.; Kocabas, A.; Olgunus, O.; Satar, S. ; Seydaoglu, G. (2007) Does the expired-air

carbon monoxide level reflect the se verity of inflammation in COPD? Bratislavske Lekarske Listy 108: 255-258.

Harrison, C. M. and Andersen, C. C. (2005) Exhaled breath measures of inflammation: are they useful in neonatal chronic lu ng disease. Archives of Disease in

Childhood: Fetal and Neona tal Edition 90: F6-10. http://dx.doi.or g/10.1136/adc.2003.040709.

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