EPA
             United States
             Environmental
             Protection Agency
Plan for Review of the
National Ambient Air
Quality Standards for
Carbon Monoxide
    U. S. Environmental Protection Agency

    National Center for Environmental Assessment
       Office of Research and Development
               and
     Office of Air Quality Planning and Standards
         Office of Air and Radiation

    Research Triangle Park, North Carolina 27711
             August 2008

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                                   DISCLAIMER

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

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                       TABLE OF CONTENTS
1.   INTRODUCTION	1-1
    1.1    OVERVIEW OF THE REVIEW PROCESS	1-1
    1.2    LEGISLATIVE REQUIREMENTS	1-3
    1.3    HISTORY OF REVIEWS OF THE NAAQS FOR CO	1-5
    1.4    SCOPE OF THE REVIEW	 1-
6

2.   REVIEW SCHEDULE	2-1

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

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

5.   RISK/EXPOSURE ASSESSMENT	5-1
    5.1    SCOPE AND ORGANIZATION	5-1
    5.2    HISTORICAL PERSPECTIVE	5-1
    5.3    EXPOSURE ASSESSMENT APPROACH	5-5
    5.4    RISK ASSESSMENT APPROACH	5-7
    5.5    ASSESSMENT CRITERIA	5-9
    5.6    UNCERTAINTY AND VARIABILITY	5-10
    5.7    PUBLIC AND SCIENTIFIC REVIEW	5-11
6.   POLICY ASSESSMENT/RULEMAKING	6-1

7.   REFERENCES	7-1
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                            1.    INTRODUCTION

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

1.1    OVERVIEW OF THE  REVIEW PROCESS
       The Agency has recently decided to make a number of changes to the process for
reviewing the NAAQS (described at http://www.epa.gov/ttn/naaqs/).  This new process, which is
being applied to the current review of the NAAQS for CO, contains four major components: an
integrated review plan, a science assessment, a risk/exposure assessment, and a policy
assessment/rulemaking. Each of these components is described in this section.
       1  This plan will generally refer to the review of the primary standards for CO because there is currently no
secondary NAAQS for CO to review.  However, the scope of EPA's review will include consideration of whether,
based on the revised air quality criteria for CO, it is appropriate to propose a new secondary standard.
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      The review process starts with the development of an integrated review plan prepared
jointly by EPA's National Center for Environmental Assessment (NCEA), within the Office of
Research and Development (ORD), and EPA's Office of Air Quality Planning and Standards
(OAQPS), within the Office of Air and Radiation (OAR). This document represents the current
plan and specifies the schedule for the entire review, the process for conducting the review, and
the key policy-relevant science issues that will guide the review.
      The second component of the review process is the development of the science
assessment, which consists of an Integrated Science Assessment (ISA) and supporting annexes.
NCEA collaborates with contracted expert support to prepare these documents. The annexes will
contain a comprehensive description of the full breadth of the current scientific literature
pertaining to known and anticipated effects on public health and welfare associated with CO in
the ambient air, emphasizing the information that has become available since the last review in
order to reflect the current state of knowledge. The annexes also provide in-depth treatment of
specific topics supporting interpretation of health and welfare effects. NCEA will critically
evaluate, integrate, and synthesize the most policy-relevant science into an ISA. The ISA is
intended to provide information  useful in forming judgments about air quality indicator(s),
form(s), averaging time(s) and level(s) for the CO NAAQS. Hence, the ISA and its associated
annexes function in the new NAAQS review as the Air Quality Criteria Document (AQCD) did
in previous reviews.  The schedule includes production of a first and second draft ISA, both of
which will undergo CAS AC and public review prior to completion of the final ISA.  Section 4
provides a more detailed description of the planned scope, organization and assessment approach
for the annexes and ISA.
      In the third component of the revised review process, the risk/exposure assessment,  EPA's
Office of Air Quality Planning and Standards (OAQPS) plans to draw upon the information
presented in the ISA to develop quantitative or qualitative estimates of the exposures and risks of
adverse health effects associated with current ambient levels of CO, with levels that just meet the
current standards, and with levels that just meet possible alternative standards. Section 5 of this
integrated plan contains more detail about possible approaches EPA could take in conducting the
human health assessments. Once the first draft ISA is complete, EPA will release a draft Scope
and Methods Plan for human health assessments that CASAC and the public will  review. The
Scope and Methods Plan will describe the planned scope of the analyses to be performed and the
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tools/methods that may be employed.  Comments on the draft Scope and Methods Plan will be
considered as EPA performs the actual analyses.  The schedule includes production of first and
second draft risk/exposure assessments, all of which will undergo CAS AC and public review
prior to completion of the final risk/exposure assessment reports that will focus on key results,
observations, and uncertainties.
      The fourth component of the revised process will be a policy assessment/rulemaking.
Under the new process, a staff paper, such as that prepared in previous NAAQS reviews, will not
be prepared. Rather, Agency views on policy options will be published in the Federal Register
as part of a notice of proposed action, to be followed by a public comment period.2 Considering
comments received on the proposed action, the Agency will issue a final decision to complete the
review.

1.2    LEGISLATIVE REQUIREMENTS
      Two sections of the Clean Air Act (CAA) govern the establishment and revision of the
NAAQS.  Section 108 (42 U.S.C. 7408) directs the Administrator to identify and list air
pollutants that "in his judgment, cause or contribute to air pollution which may reasonably be
anticipated to endanger public health and welfare" and whose "presence ... in the ambient air
results from numerous or diverse mobile or stationary sources" and to issue air quality criteria
for those that are listed.  Air quality criteria are intended to "accurately reflect the latest scientific
knowledge useful in indicating the kind and extent of identifiable effects on public health or
welfare which may be expected from the presence of [a] pollutant in ambient air ... ."
      Section 109 (42 U.S.C. 7409) directs the Administrator to propose and promulgate
"primary" and "secondary" NAAQS for pollutants listed under section 108.  Section 109(b)(l)
defines a primary standard as one "the attainment and maintenance of which in the judgment of
the Administrator, based on such criteria and allowing an adequate margin of safety, are requisite
to protect the public health."3 A secondary standard, as defined  in section 109(b)(2), must
"specify a level of air quality the attainment and maintenance of which, in the judgment of the
       2 In addition, EPA is considering whether, and at what point in the process, to issue an Advance Notice of
Proposed Rulemaking prior to the proposal notice.
        The legislative history of section 109 indicates that a primary standard is to be set at "the maximum
permissible ambient air level. . . which will protect the health of any [sensitive] group of the population," and that
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Administrator, based on such criteria, is requisite to protect the public welfare from any known
or anticipated adverse effects associated with the presence of [the] pollutant in the ambient air."4
       The requirement that primary standards include an adequate margin of safety was
intended to address uncertainties associated with inconclusive scientific and technical
information available at the time of standard setting. It was also intended to provide a reasonable
degree of protection against hazards that research has not yet identified. See Lead Industries
Association v. EPA, 647 F.2d 1130, 1154 (D.C. Cir 1980), cert,  denied, 449 U.S. 1042  (1980);
American Petroleum Institute v. Costle, 665 F.2d 1176, 1186 (D.C. Cir. 1981), cert, denied, 455
U.S. 1034 (1982). Both kinds of uncertainties are components of the risk associated with
pollution at levels below those at which human health effects can be said to occur with
reasonable scientific certainty. Thus, in selecting primary standards that include an adequate
margin of safety, the Administrator is seeking not only to prevent pollution levels that have been
demonstrated to be harmful but also to prevent lower pollutant levels that may pose an
unacceptable risk of harm, even if the risk is not precisely identified as to nature or degree.
       In selecting a margin of safety, the EPA considers such factors as the nature and severity
of the  health effects involved, the size of sensitive population(s) at risk, and the kind and degree
of the  uncertainties that must be addressed.  The selection of any particular approach to
providing an adequate margin of safety is a policy choice left specifically to the Administrator's
judgment.  See Lead Industries Association v. EPA, 647 F.2d at 1161-62.
       In setting standards that are  "requisite" to protect public health and  welfare, as provided in
section 109(b), EPA's task is to establish  standards that are neither more nor less stringent than
necessary for these purposes. In so doing, EPA may not consider the costs of implementing the
standards.  See generally, Whitman v. American Trucking Associations, 531 U.S. 457, 465-472,
475-76 (2001).
       Section 109(d)(l) requires that "not later than December 31, 1980, and at 5-year
intervals thereafter, the Administrator shall complete a thorough review of the criteria

for this  purpose "reference should be made to a representative sample of persons comprising the sensitive group
rather than to a single person in such a group" S. Rep. No. 91-1196, 91st Cong., 2d Sess. 10 (1970).
       4 Welfare effects as defined in section 302(h) (42 U.S.C.  7602(h)) include, but are not limited to, "effects
on soils, water, crops, vegetation, man-made materials, animals, wildlife, weather, visibility and climate, damage to
and deterioration of property, and hazards to transportation, as well as effects on economic values and on personal
comfort and well-being."
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published under section 108 and the national ambient air quality standards . . . and shall make
such revisions in such criteria and standards and promulgate such new standards as may be
appropriate . . . ."  Section 109(d)(2) requires that an independent scientific review committee
"shall complete a review of the criteria . . . and the national primary and secondary ambient air
quality standards . . . and shall recommend to the Administrator any new .  . . standards and
revisions of existing criteria and standards as may be appropriate . . . ."  Since the early 1980's,
this independent review function has been performed by the Clean Air Scientific Advisory
Committee (CASAC) of EPA's Science Advisory Board.5

1.3    HISTORY OF REVIEWS OF THE NAAQS FOR CO
      On April 30, 1971, EPA promulgated identical primary and secondary NAAQS for CO,
under section 109 of the Act, set at 9 parts per million (ppm), 8-hour average and 35 ppm, 1-hour
average, neither to be exceeded more than once per year (36 FR 8186). In 1979, EPA published
Air Quality Criteria Document for Carbon Monoxide (AQCD) (US EPA, 1979a), which updated
the scientific criteria upon which the initial CO standards were based. A Staff Paper (US  EPA,
1979b) was prepared and, along with the AQCD, served as the basis for development of
proposed rulemaking (45 FR 55066) published on August  18,  1980.  Delays due to uncertainties
regarding the scientific basis for the final decision resulted in EPA's announcing a second public
comment period (47 FR 26407). Following substantial reexamination of the scientific data, EPA
prepared an Addendum to the 1979 AQCD (EPA, 1984a) and an updated Staff Paper (US EPA,
1984b). Following review by CASAC, EPA announced its final decision (50 FR 37484) not to
revise the existing primary standard and to revoke the secondary standard for CO on September
13, 1985, due to a lack of evidence of direct effects on public welfare at ambient concentrations.
      In 1987, EPA initiated action to revise the criteria for CO and released a revised AQCD
for CASAC and public review. In a "closure letter" (McClellan, 1991) sent to the Administrator,
the CASAC concluded that the AQCD (US EPA, 1991) "... provides a scientifically balanced
and defensible summary of current knowledge of the effects of this pollutant and provides an
adequate basis for the EPA to make a  decision as to the appropriate primary NAAQS for CO."
A revised Staff Paper subsequently was reviewed by CASAC and the public, and in a  "closure
5 See http://vosemite.epa.gov/sab/sabproduct.nsfAVebCASAC/CommitteesandMembership7OpenDocument for a
list of members of CASAC and of the CASAC CO Review Panel.
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letter" (McClellan, 1992) sent to the Administrator, it was stated ". . . that a standard of the
present form and with a numerical value similar to that of the present standard would be
supported by the present scientific data on health effects of exposure to carbon monoxide."
Based on the revised AQCD (US EPA, 1991) and staff conclusions and recommendations
contained in the revised Staff Paper (US EPA. 1992), the Administrator announced the final
decision (59 FR 38906) on August 1, 1994, that revision of the primary NAAQS for CO was not
appropriate.
      In 1997, revisions to the AQCD were initiated.  A workshop was held in September 1998
to review and discuss material contained in the revised AQCD. On June 9,  1999, CASAC held a
public meeting to review the draft AQCD and a draft exposure analysis methodology document.
Comments from CASAC and the public were considered in a second draft AQCD, which was
reviewed at a CASAC meeting held on November 18, 1999. After revision of the second draft
AQCD, the final AQCD (US EPA, 2000) was released in August 2000. EPA put the review on
hold when Congress called on the National Research Council (NRC) to conduct a review of the
impact of meteorology and topography on ambient CO concentrations in high altitude and
extreme cold regions of the U.S.  In response, the NRC convened the committee on  Carbon
Monoxide Episodes in Meteorological and Topographical Problem Areas, which focused on
Fairbanks, Alaska as a case study in an interim report, which was completed in 2002.  A final
report, "Managing Carbon Monoxide Pollution in Meteorological and Topographical Problem
Areas," was published in 2003  (NRC, 2003) and offered a wide range of recommendations on
management of CO air pollution, cold start emissions standards, oxygenated fuels, and CO
monitoring. EPA did not complete the review which started in 1997.

1.4   SCOPE OF THE REVIEW
      For the current review of the primary CO standard, relevant scientific information on
human exposures and health effects associated with exposure to ambient CO will be assessed.
The possible influence of other atmospheric pollutants on the interpretation of the role of CO in
health effects studies will be considered.  This will include other pollutants with the potential to
co-occur in the environment (e.g., NO2, SO2, Os, and PM).  The review will also assess any
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relevant scientific information associated with known or anticipated public welfare effects that
may be identified.
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                          2.     REVIEW  SCHEDULE

       In September 2007, EPA's National Center for Environmental Assessment in Research
Triangle Park, NC (NCEA-RTP) announced the initiation of the current periodic review of the
air quality criteria for CO and the CO NAAQS and issued a call for information in the Federal
Register (72 FR 52369). Table 2-1 outlines the schedule under which the Agency is currently
conducting this review.6
 Table 2-1. Proposed Schedule for Development of Revised CO Integrated Science Assessment (ISA) and CO
           Primarv Standard
 Stage of Review
Major Milestone
Draft Target Dates
 Integrated Plan
Literature Search
Federal Register Call for Information
Workshop on science/policy issues
Draft CO NAAQS Integrated Review Plan (IRP)
CASAC consultation on IRP
Final CO NAAQS IRP
Ongoing
September 2007
January 2008
March 2008
April 2008
August 2008
 Science Assessment
Prepare first draft of ISA
CASAC/public review first draft ISA
Prepare second draft of ISA
CASAC/public review second draft ISA
Prepare final ISA
February 2009
April 2009
August 2009
October 2009
January 29, 2010
 Risk/Exposure
 Assessment
Prepare assessment methodology
CASAC/public consultation on methodology
Prepare first draft risk and/or exposure
assessments
CASAC/public review of the first draft
Prepare second draft of risk and/or exposure
assessments
CASAC/public review of second draft risk
and/or exposure assessments
Prepare final risk and/or exposure assessments
March 2009
April 2009
September 2009

October 2009
February 2010

March 2010

May 28, 2010
 Policy Assessment/
 Rulemaking
Proposed rulemaking
Final rulemaking
October 28, 2010
May 13,2011
         This schedule is based on a court-ordered schedule that governs the completion of the review, See
Communities for a Better Environment v, EPA, No. 07-3678 (N.D. Cal., May 5, 2008). Further orders of the court
may require revisions to this schedule.
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              3.    KEY POLICY-RELEVANT ISSUES

       The key policy-relevant issues to be addressed in this review are presented below as a
series of policy-relevant questions that will frame our approach to determining whether the
current primary NAAQS for CO should be retained or revised and whether to set separate
secondary standards.  The ISA, health risk/exposure assessment, and any welfare-related
assessment(s) to be conducted in this review will provide the basis for addressing these
questions. The answers to these questions, and the resulting conclusions regarding the
corresponding policy-relevant issues, will inform the policy assessment/rulemaking that will lead
to the decision of whether to retain or revise the current 1-hour and 8-hour primary standards and
whether separate secondary standards for CO are needed.
       The most recent review of the NAAQS for CO, completed in 1994, concluded that
exposure to CO is associated with a variety of acute health effects, but there was very limited
evidence of chronic effects.  The secondary NAAQS for CO were revoked in 1985, and there
currently are no secondary standards for CO. There was insufficient evidence of welfare effects
occurring at or near ambient levels to justify setting secondary NAAQS in 1994. That review
resulted in EPA's conclusion that the then existing primary CO NAAQS provided adequate
protection from health effects associated with 1-hour and 8-hour exposures to ambient CO. A
separate long-term standard was not recommended. The current levels for the 1-hour and 8-hour
primary NAAQS for CO are 35 ppm and 9 ppm, respectively.

3.1    ISSUES TO BE CONSIDERED  IN THE CURRENT REVIEW OF
       THE PRIMARY NAAQS
       In this review, a series of policy-relevant questions will frame our approach to
determining whether the current primary NAAQS for CO should be retained or revised. The
answers to these questions, and the resulting conclusions regarding the corresponding policy
issues, will inform the decision of whether to retain or revise the current short-term (1- and 8-
hour) primary NAAQS for CO.
       The first step in reviewing the adequacy of the current primary NAAQS is to consider
whether the available body of scientific evidence, assessed in the ISA, supports or calls into
question the scientific conclusions reached in the last review regarding health effects related to
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exposure to CO in the ambient air. The ISA will consider a series of questions including the
following:
        Has new information altered the scientific support for the occurrence of health effects
         following short- and/or long-term exposure to levels of CO found in the ambient air?
        To what extent is key evidence becoming available that could inform our
         understanding of human subpopulations that are particularly sensitive to CO
         exposures? The NRC committee report (NRC, 2003) recommended additional
         research on effects of CO on birth outcomes.  Is there new or emerging evidence on
         health effects beyond cardiovascular and respiratory endpoints (e.g., systemic effects,
         developmental effects, birth outcomes) that suggest additional sensitive
         subpopulations should be given increased focus in this review (e.g., neonates)?
        What do recent studies focused  on the near-roadway environment, including bus stops
         and intersections, tell us about high-exposure human subpopulations and the health
         effects of CO? What information is available on elevated exposures due to other
         transportation sources,  such as shipping, port operations, and recreational vehicles?
         What is the effect of altitude on CO sources and health effects?
        At what levels of CO exposure do health effects of concern occur?
        To what extent is key scientific  evidence becoming available to improve our
         understanding of the health effects associated  with various time periods of CO
         exposures, including not only daily, but also chronic (months to years) exposures? To
         what extent is critical research becoming available that could improve our
         understanding of the relationship between various health endpoints and different lag
         periods (e.g., single day, multi-day distributed lags)?
        To what extent does the evidence  suggest that alternate dose indicators other than
         carboxyhemoglobin (COHb) levels (e.g.,tissue oxygenation) should be evaluated to
         characterize the biological effect?
        Has new information altered conclusions from previous reviews regarding the
         plausibility of adverse health effects caused by CO exposure?
        To what extent have important uncertainties identified in the last review been reduced
         and/or have new uncertainties emerged?
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      If the evidence suggests that revision of the current standards might be appropriate, we
will consider whether the available body of evidence supports consideration of options that are
different from the current standard. The following questions will inform this determination:
         Is there evidence for the occurrence of adverse health effects at levels of CO lower
         than those observed previously, and conversely, is there evidence that suggests that
         effects occur only at higher levels than previously reported?  If so, at what levels and
         what are the important uncertainties associated with that evidence?
        Do exposure estimates suggest that exposures of concern for CO-induced health
         effects will occur? If so, are these exposures of sufficient magnitude such that the
         health effects might reasonably be judged to be important from a public health
         perspective? What are the important uncertainties associated with these exposure
         estimates?
        Do health effects evidence and air quality/exposure assessments provide support for
         considering different exposure indices or averaging times?
        What range of levels is supported by the health effects evidence and air
         quality/exposure assessments, and what are the uncertainties and limitations in the
         health effects evidence and air quality/exposure assessments?
        What is the range of forms supported by the health effects evidence and air
         quality/exposure assessments, and what are the uncertainties and limitations in that
         health effects evidence and air quality/exposure assessments?

3.2    ISSUES  TO BE CONSIDERED IN THE CURRENT REVIEW OF A
       POSSIBLE SECONDARY NAAQS
       In this review, a series of policy-relevant questions will frame our approach to
determining whether secondary NAAQS for CO should be considered. The answers to these
questions, and the resulting conclusions regarding the corresponding policy issues, will inform
the decision of whether to set secondary NAAQS for CO.
       The first step in reviewing the possible need for secondary NAAQS is to consider
whether the available body of scientific literature, assessed in the ISA, provides evidence of
welfare effects related to exposure to CO in the ambient air. The ISA will evaluate the newly
available scientific evidence and will address  a series of questions including the following:
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        Have new information or scientific insights altered the scientific conclusions regarding
         the occurrence of direct (or indirect) welfare effects associated with levels of CO
         found in the ambient air?
        At what levels of ambient CO do welfare effects of concern occur?
        To what extent is key scientific evidence becoming available to improve our
         understanding of the welfare effects associated with various time periods of CO
         exposures, including not only daily, but also chronic (months to years) exposures?
        Has new information, analytical tools/methods, or scientific insight altered conclusions
         from previous reviews regarding the plausibility of adverse welfare effects caused by
         CO exposure?
        To what extent have important uncertainties identified in the last review been reduced
         or new uncertainties emerged?
      If the evidence suggests that setting a secondary standard or standards might be
appropriate, we will consider whether the available body of evidence supports consideration of
various  options. The following questions will inform this determination:
         Is there evidence for the occurrence of adverse welfare effects at levels of CO lower
         than those observed previously? If so, at what levels  and what are the important
         uncertainties associated with that evidence?
        Do exposure estimates suggest that exposures of concern for CO-induced welfare
         effects will occur? If so, are these exposures of sufficient magnitude such that the
         welfare effects might reasonably be judged to be important from a public welfare
         perspective?  What are the important uncertainties associated with these exposure
         estimates?
        Do welfare effects evidence and air quality/exposure  assessments provide support for
         considering different exposure indices or averaging times?
        What range of levels is supported by the welfare effects evidence and air
         quality/exposure assessments, and what are the uncertainties and limitations in the
         welfare effects evidence and air quality/exposure assessments?
        What is the range of forms supported by the welfare effects evidence and air
         quality/exposure assessments, and what are the uncertainties and limitations in the
         welfare effects evidence and air quality/exposure assessments?
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                     4.     SCIENCE ASSESSMENT
4.1    SCOPE AND ORGANIZATION
      The science assessment for CO will consist of the ISA and its supporting annexes. The
ISA will critically evaluate and integrate the scientific information on exposure, health effects,
and welfare effects associated with CO in ambient air. The annexes, which will evaluate and
summarize relevant studies, will provide more detailed information from the most pertinent
scientific literature in support of the ISA. The annexes will include scientific evidence organized
by health outcome in the discipline areas of epidemiology, toxicology, controlled human
exposures (human clinical studies), and dosimetry, as well as human exposure and atmospheric
science relevant to the review of the CO NAAQS.  The ISA will draw from this evidence and
synthesize the current state of knowledge on the most relevant issues pertinent to the review of
the NAAQS for CO. A formal framework for the integration of health effects evidence,  based on
approaches formulated by other regulatory and science agencies, has been developed for the final
ISA for NOX (U.S. EPA, 2008) and will be applied in the current CO review. Information from
the scientific disciplines listed above will be integrated into the health effects evidence in order
to contribute to a better understanding of population exposure and/or risk, or to a better
understanding of the nature, sources, distribution, measurement, and/or concentrations of CO in
ambient air.  The ISA discussions will be designed to focus on the key policy questions
described in Section 3 of this document.
      The focus of the ISA will be on literature identified since the previous review of the air
quality criteria for CO and on key science and policy issues raised during the last review,
including issues addressed in the NRC committee report on CO (NRC, 2003).  Findings and
conclusions from the 2000 Air Quality Criteria Document (US EPA, 2000) for CO will be briefly
summarized at the beginning of the ISA.  The results of new studies will be integrated with
previous findings. Important older studies will be more specifically discussed if they remain
definitive or are open to reinterpretation in light of newer data.  Information that has undergone
scientific peer review and that has been published (or accepted for publication) in the open
literature will be considered.  Additionally, official studies and reports from governmental
agencies may be included, as appropriate. Emphasis will be placed on studies conducted at or
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near CO concentrations found in ambient air. In recognition of the fact that toxicologic and
human clinical studies do not necessarily reflect effects in the most sensitive population, studies
at higher exposure levels will be included when they provide information relevant to previously
unreported effects, evidence of the potential mechanism for an observed effect, or information on
exposure-response relationships.

4.2    ASSESSMENT APPROACH

Introduction
      The EPA's National Center for Environmental Assessment in Research Triangle Park
(NCEA-RTP) is responsible for preparing the ISA and the related annexes for CO.  Expert
authors include EPA staff with extensive knowledge in their respective fields and extramural
scientists contracted to the EPA. A diagram showing the standard protocol for development of
an ISA, including both health and ecosystem effects, is presented in Figure 4.1. While no
secondary standard currently exists for CO, any evidence of welfare effects of ambient CO (such
as effects on domestic and wild animals, crops and forest vegetation, and microorganisms)
identified during ISA development will also be included. The ISA for CO will focus primarily
on scientific evidence relating to health effects. A complete description of the new NAAQS
review process is presented in Section 1.1.
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                       Standard Protocol for ISA Development
                  Database
    Outside experts:
         Atmospheric science
         Exposure
         Dosimetry
         Animal Toxicology
         Clinical Studies
         Epidemiology
         Ecology
         Environmental Effects
      Peer Review
      Draft/Author Workshop
                                      NCEA staff review
                                     of literature (ongoing)
Draft  Integrated
  Review Plan
CAS AC consultation
 and public review
                                       Final Integrated
                                         Review Plan
                                        First External
                                      Review Draft ISA
                                    CASAC and public review
                                       Second External
                                       Review Draft ISA
                          Federal Register
                          Call for Information
Workshop on
science/policy issues

Science and policy
issues from previous
NAAQSreview
fi


                                    CASAC and public review
                                         Final ISA

Figure 4.1.  Protocol for ISA development, showing the steps involved in production of
Integrated Science Assessments.
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Literature Search
      NCEA-RTP will use a systematic approach to identify relevant studies for consideration.
A Federal Register Notice (72 FR 52369, September 13, 2007) was published to announce the
initiation of this review and request information from the public. An initial publication database
will be established by searching the online databases MEDLINE, ISI Web of Knowledge,
Toxfile, Pascal, Biosis, and Embase using as key words terms including carbon monoxide,
methane, carbon dioxide, CO, CH4, CC>2, hydroxyl radical, carboxyhemoglobin, COHb, hypoxia,
traffic, and combustion.  Targeted searches will also be conducted to identify articles relevant to
specific health, ecological, and physical science disciplines.  As appropriate, the search strategies
will be periodically reexamined and modified to enhance identification of pertinent published
papers.  Additional papers will be identified for inclusion in the publication base in several ways.
These include the review of pre-publication tables of contents for journals in which relevant
papers may be published, as well as independent identification of relevant literature by expert
authors. In addition, publications that may be pertinent are identified by both the public and
CASAC during the external review process. The studies identified will include research
published or accepted for publication by a date determined to be as inclusive as possible given
the relevant target dates in the NAAQS review schedule. Some additional studies, published
after that date, may also be included if they provide new information that impacts one or more
key scientific issues. The combination of these approaches should produce the comprehensive
collection of potentially pertinent studies needed to form the basis of the ISA.  The following
sections briefly summarize criteria for selection of studies for this draft ISA.

General Criteria for Study Selection
      In assessing the scientific quality and relevance of epidemiological and human or animal
toxicological  studies, the following considerations will be taken into account.
         To what extent are the aerometric data, exposure, or dose metrics of adequate quality
          and sufficiently representative of population exposure to serve as indicators of
          exposure to ambient CO?
         Were the study populations adequately selected and are they sufficiently well defined
          to allow for meaningful, reliable comparisons between study groups?
         Are the health endpoint measurements meaningful, reliable, and clinically significant?
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        Does the study contain unique data, such as the documentation of a previously
         unreported effect, documentation of the mechanism for an observed effect, or
         information on exposure-response relationships?
        Are the statistical analyses appropriate, properly performed, and properly interpreted
         with sufficient statistical power?
        Are likely covariates (i.e., potential confounders or effect modifiers) adequately
         controlled or taken into account in the study design and statistical analysis?
        Are the reported findings internally consistent, biologically plausible, and coherent in
         terms of consistency with other known facts?
Consideration of these issues, more fully discussed in Annexes, informs our judgments on the
relative quality of individual studies and allows us to focus the assessment on the most pertinent
studies.

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

Criteria for Selecting Human Laboratory, Clinical, and Animal Toxicological Studies
      The review of research evaluating animal toxicological or controlled exposure studies will
focus primarily on those studies conducted at physiologically relevant CO concentrations and
those studies that approximate expected human exposure conditions in terms of concentration
and duration.  Studies that elucidate modes of action or mechanisms underlying biological effects
and/or examine susceptibility will be considered.
      The selection of research evaluating controlled human exposures to CO will focus on
studies in which subjects were exposed at conditions relevant either to ambient exposures or to
determination  of mechanism.  For these controlled human exposures, emphasis will be placed on
studies that:  (1) investigate potentially susceptible populations such as  individuals with
cardiovascular disease, particularly studies that compare responses in susceptible individuals
with those in age-matched healthy controls; (2) address issues such as dose-response or time-
course of responses; (3) investigate exposure to CO separately and in combination with other
pollutants such as PM, Os, NO2 and SO2; (4) are appropriately blinded and include control
exposures to filtered air with subjects serving as their own controls; and (5) have sufficient
statistical power to assess findings.
      Review of the animal toxicological evidence will focus on studies that approximate
expected human dose conditions, which will vary depending on the toxicokinetics and biological
sensitivity of the particular laboratory animals examined. In addition, resource constraints
prevent animal researchers from testing hypotheses that require large numbers of animals
exposed to ambient levels of CO over a prolonged period. Consequently, animal studies are
typically used  to acquire data relating to mechanisms,  and the exposures are purposefully high to
assure a measurable response.  Studies at high concentrations will be  considered when they
provide useful information to inform our understanding of interspecies differences and potential
sensitivity differences between healthy and susceptible human populations.
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Quality Assurance
       Important quality assurance measures will be incorporated from the start of the current
CO review.  EPA uses an NCEA-RTP quality assurance plan for searching scientific literature
which details an approach to gathering the scientific information found in peer-reviewed journal
articles and government reports. Additionally, NCEA has data quality objectives which identify
inputs to the science assessment and provide quality assurance (QA) instruction for researchers
citing secondary information.

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

Source to Dose
Air Quality and Atmospheric Chemistry:  The ISA will present and evaluate data related to
ambient concentrations of CO; sources leading to the presence of CO in the atmosphere; and
chemical reactions that determine the formation, degradation, and lifetime of CO in the
atmosphere.
        What are the strengths and weaknesses of various methods for measuring CO?
         To what extent are these methods subject to positive or negative sampling artifacts or
         to interference from other substances?
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        Using recent air quality and emissions data, what are the current emission levels and
         ambient concentrations of CO in the US? What spatial and temporal patterns can be
         seen in these CO air quality data, and how do these relate to patterns of human
         exposure? What are the effects of sample and measurement averaging time and range
         on the level of spatial and temporal variability in concentrations? To what extent are
         ambient CO concentrations correlated with other air pollutants (e.g., NOX, Os, PM,
         SOX), and do these possible correlations change spatially and temporally in significant
         ways?  On what spatio-temporal scales does CO affect the production of ozone and
         other related pollutants?
        The NRC committee report (NRC, 2003) identified the spatial variability of CO
         concentrations and the likely existence of high-concentration hot spots, potentially
         near susceptible subpopulations, as important issues in assessing the CO regulatory
         monitoring network. What are the implications of the current network configuration
         for the interpretation of CO-related health effects?
        Using air quality and emissions data on CO and atmospheric chemistry models, what
         are likely policy relevant background concentrations of CO?
        Are there other techniques that can be used to better define the range of concentrations
         and the spatial and temporal variability of CO over the U.S.? Are satellite retrievals or
         three dimensional chemical transport models useful? Can satellite data be used on a
         regular basis to improve the characterization of CO emissions?
        What information is available on short-term  ambient CO concentrations (< 1 hr)?


Human Exposure: The ISA will  evaluate the factors that influence exposure to CO and the
uncertainties associated with extrapolation from ambient concentrations to personal exposures to
CO of ambient origin, particularly in the context of interpreting results from epidemiologic
studies.  The issues of uncertainty differ by the exposure period of interest. Short-term exposure
studies (e.g., population-level studies using time-series analyses, field/panel studies) primarily
rely on temporal variation in exposure, while long-term exposure studies (e.g., longitudinal
cohort studies) rely on spatial variability of exposure.
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What data exist on relationships between exposure to CO and corresponding exposure
to gaseous and paniculate co-pollutants (e.g., NOX, 63, PM, SOX)? What factors affect
these relationships (season, housing characteristics, activity patterns, etc.)?
What are the uncertainties when extrapolating between stationary CO monitoring
instruments and personal exposure to CO of ambient origin, especially for susceptible
groups? Issues include measurement error in outdoor  ambient monitors, the use of
monitors for estimating community concentrations, and their use as a surrogate for
personal exposure to CO of ambient origin.
What information is available on exposures to short-term (< 1 hr) peak CO
concentrations?
To what extent do measurements from ambient CO monitors provide an estimate of
ambient exposures for health studies, serve as an indicator of personal exposure to CO,
and/or serve as an indicator of personal exposure to other gaseous pollutants
(including Os and NO2) and particulate pollutants generated by traffic?
What influence do the temporal and spatial patterns of CO exposure, for both indoor
and outdoor sources, have on evaluation of health effects? What is the exposure
pattern for indoor sources,  such as gas  stoves and space heaters (i.e., peak, repeated
peak, and average CO) and how does it relate to ambient CO patterns?
What evidence is available on subpopulations likely to have high ambient CO
exposures including those living, working and/or attending school near roadways and
those in the vicinity of shipping or port operations?
What data are available to interpret both short- and long-term CO exposures (e.g., <1
hour, 1 hour, 8 hours, 24 hours, 2 weeks, or longer)? What data and models are
available to support exposure estimates over periods that may be relevant to additional
health endpoints, such as birth outcomes? This includes such information as air
exchange rates, indoor sources, distance to highways,  and performance indicators for
methods of measuring personal exposures to CO (particularly at low ambient levels).
How do modeled predictions of CO concentrations and exposures compare with
monitoring results?
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Dosimetry of Inhaled CO: The ISA will evaluate the literature relating to pharmacokinetic
modeling of CO uptake and the associated formation of COHb. Recent information relating to
either the well-established Coburn-Forster-Kane model or alternative models will be integrated
with literature summarized in the previous AQCD to assess the current state of knowledge on
COHb formation. The ISA will assess evidence on uncertainties in modeling COHb as a
function of inhaled CO.  The contribution of endogenously produced CO to COHb is included in
the Coburn-Forster-Kane model and will be considered in the integrative health effects section of
the ISA.
        What new information is available on the validity and applicability of the Coburn-
         Forster-Kane model?  Are alternative approaches available and preferable for
         modeling COHb formation from ambient CO?
        What factors contribute to uncertainty and variability in estimating COHb formation
         from ambient CO?
        What information is available on COHb formation in fetuses and infants? Issues to be
         considered include COHb pharmacokinetics in neonates and the relationship between
         maternal CO exposure and fetal COHb concentration.


Health Effects
       The ISA will evaluate the literature related to health effects identified in the 2000 AQCD,
as well as any additional health outcomes identified during the review. Previously identified
health effects include cardiovascular effects (e.g., myocardial ischemia, angina, arrhythmia),
central nervous system effects (e.g., loss of dexterity, visual impairment), respiratory effects, and
birth outcomes (e.g., low birth weight, preterm birth) associated with short and/or long term
exposure to CO. This will include evaluation of emergency department visits, hospitalizations,
and mortality associated with these effects.  Health effects that are associated with both short-
and long-term exposures will be evaluated in epidemiologic, human clinical, and toxicologic
studies. Recent studies regarding the formation of endogenous CO by  cells and tissues and the
resulting localized biological response will be evaluated in order to determine the relevance to
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biological responses following ambient CO exposure.  Causality, uncertainty, biological
mechanism of action, susceptible and vulnerable populations, and public health impact will all be
considered. The data will be reviewed with the understanding that effects from ambient CO must
be considered in conjunction with co-occurring pollutants (e.g., NOX, Os, PM, SOX).
       For a given type of health outcome, the ISA will evaluate the strength, robustness and
consistency of the findings from the different disciplines.  The health findings will be further
integrated, using the toxicologic and human clinical studies to assess biologic plausibility and
mechanistic evidence for the epidemiology findings. A key focus of the integration of health
evidence will be on the attribution of health effects to CO as a component of multipollutant
exposures. Efforts will be directed at identifying the lower levels at which effects are observed
and at determining concentration-response relationships for CO. Concentration-response
relationships among these studies will be evaluated for coherence. The ISA will evaluate the
scientific evidence on the occurrence of health effects from long-term or short-term exposure to
CO at ambient levels.  The ISA will also assess the evidence for uncertainties related to these
associations and information on the public health implications related to ambient CO exposure.
The evaluation will also focus on which exposure durations and developmental time periods of
exposure are most strongly associated with effects, for both short-term and long-term exposures.

Short-Term Exposure:
         What do controlled human exposure, animal toxicologic, and epidemiologic studies
          indicate regarding the relationship between short-term exposures to CO and health
          effects of concern in both healthy individuals and in those with preexisting disease
          states (e.g., individuals with cardiovascular or ischemic heart disease)?  What new
          evidence is available  on effects occurring from exposures at sub-daily averaging
          times?
         What are the effects of CO exposure on breathing rate and respiratory gas exchange in
          healthy and susceptible individuals (e.g., oxygen diffusion capacity and ventilation-
          perfusion mismatches) and what is the potential clinical relevance of these effects?
          Does recent evidence indicate other respiratory effects from ambient CO exposure?
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        Is exposure to CO associated with mortality (total, respiratory or cardiovascular),
         hospital admissions, or emergency department visits as assessed using population-
         level datasets? What are the lowest ambient CO concentrations at which these
         associations are observed?  What evidence is available to inform selection of the
         appropriate lag structure for specific health outcomes? Do other gaseous pollutants
         and/or particulate matter confound or modify the effect observed due to exposure to
         CO? The utility of the statistical methods applied will be evaluated (i.e., time-series
         studies). As discussed above, the potential effects of exposure error on epidemiologic
         outcomes will be evaluated.
        To what extent does exposure to CO contribute to health effects in the cardiovascular
         or other systems? What information can be obtained from electrocardiogram changes
         that may indicate an adverse response to CO? How does CO affect vascular and
         endothelial function and through which pathways?
        What is the impact of short-term exposures (days or less) on birth outcomes? Which
         gestational ages represent particularly vulnerable periods for developmental effects of
         CO exposure?
        What is the nature of health effects in persons exposed to multipollutant mixtures that
         contain CO in comparison to exposure to CO alone?
        Does exposure to ambient CO perturb the biologic function of endogenous CO (e.g.,
         by generating unwanted or  excessive CO)?  What are the effects of ambient and
         endogenous CO on oxidative stress and acute inflammation and other biological
         responses involved in pathophysiology?
        What biomarkers of early effect may be used in the assessments? What detectable
         biological changes will be considered adverse health effects?

Long-Term Exposure:
        Does the scientific evidence support the occurrence of health effects from long-term
         exposure (e.g., months to years) at ambient levels that are lower than previously
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         observed?  If so, what uncertainties are related to these associations, and are the health
         effects in question important from a public health perspective?
        Can long-term exposures to CO result in chronic effects such as developmental effects
         or birth outcome effects?
        What are relevant exposure periods for effects associated with birth outcomes? What
         metrics are appropriate for assessing developmental effects (e.g., low birth weight,
         preterm birth)? Are certain effects linked to specific exposure windows?
        To what extent does long-term CO exposure promote development of chronic
         cardiovascular disease? What is the relationship between long-term CO exposure and
         shortening of human life span via promotion of such diseases?
        Are  there annual and seasonal patterns of CO exposure that are associated with
         potentially harmful health effects?


Causality: The ISA will evaluate the evidence relating to the existence or lack of a causal
relationship between observed health outcomes  and CO exposure using a framework developed
by NCEA for the recent NOx ISA (U.S. EPA, 2008). This framework is designed to improve
consistency and transparency by establishing uniform language to describe causal relationships
and explicitly outlining the guidelines that are used to evaluate causality. These guidelines are
based on those proposed by Sir Austin Bradford Hill in 1965 (Hill,  1965), including:
consistency, strength, specificity, and temporality of the observed association; evidence of an
exposure-response relationship; biological plausibility and coherence; experimental evidence
from human populations; and analogy (e.g. mode of action for structural analogs).  Individual
studies may not provide information on all of these factors, yet remain informative for inferring
causality. This approach draws from and is consistent with similar  approaches formulated by
government agencies and the wider scientific community, including the Institute of Medicine
(IOM, 2007), the International Agency for Research on Cancer (IARC, 2006), the National
Toxicology Program (NTP, 2005), EPA (U.S. EPA, 2005), and the  Centers for Disease Control
and Prevention (CDC, 2004). Biological plausibility and coherence of the evidence will be key
considerations in drawing conclusions about causality.  The ISA will place emphasis on studies
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conducted at or near typical ambient levels, except regarding evidence of biological plausibility
and mechanisms, as these may only be observable in animal or human exposure study
populations at higher levels than they might be observed in susceptible human populations. The
ISA will also assess any information available from "intervention" studies regarding the health
impacts of decreases in ambient levels of CO that is relevant to the evaluation of causality in
CO-health outcome relationships or benefits accruing from such interventions.
        Does the evidence base contain new information to evaluate the case for or against a
         causal relationship between health effects and CO exposure?
        What information is available regarding the health impacts of a decrease in ambient
         levels of CO?
        What insights can be gained regarding causality by comparing health effects observed
         in older multipollutant studies (with comparatively higher ambient CO levels) with
         more recent multipollutant studies?


Uncertainties: The ISA will evaluate uncertainty in the scientific data, particularly in relation to
observed epidemiologic findings and their consistency  with human laboratory, clinical, and
animal toxicologic studies in terms of observed effects  and biological pathways.
        How does confounding by coexposure to other pollutants (e.g., Os, PM, SO2, and NO2)
         and meteorological factors influence the associations observed with CO for both short-
         and long-term exposures? The manner in which ambient CO concentration may serve
         as a surrogate for exposure to vehicle exhaust pollutants, including gases and particles,
         will be discussed.
        What are the uncertainties due to other factors in epidemiologic studies (e.g.,
         demographic and lifestyle attributes, genetic  susceptibility factors, occupational
         exposure, and medical care)?
        What is the shape of the concentration-response function (e.g., linear vs. threshold
         models)?
        What are the uncertainties associated with comparing the results of birth outcome
         studies utilizing different study designs, metrics, and endpoints?
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        What uncertainties surround the evidence for long-term effects such as life shortening
         and development/progression of disease?


Biological Mechanisms of Action:  The ISA will evaluate the data examining mechanisms for
the health outcomes associated with exposure to CO.
        Is there new information related to the pathways and biological mechanism of action?
        What are the potential mechanisms of response to CO, with a focus on
         physical-chemical characteristics, response pathway(s), and exposure-dose-response
         relationships?
        What indicators other than carboxyhemoglobin (COHb) may be relevant for
         characterizing physiological effects of CO exposure (e.g., tissue oxygenation)?
        What are the effects of age, gender, and pre-existing disease on cellular and tissue
         responses and the pathophysiology of CO-induced injury?
        What physiological characteristics of neonates may lead to differential responses and
         effects compared to adults?
        Which CO-induced health effects are sufficiently characterized to be quantitatively
         compared across species?
        What are the interspecies differences in sensitivity to CO and in basic mechanisms of
         injury and repair? What are the implications of interspecies differences for
         extrapolation of results to humans?
        What is the state of knowledge of laboratory animal-to-man extrapolation of effects?
         Are credible qualitative and/or quantitative extrapolations possible for short- and for
         long-term exposures?

Susceptible Populations: The ISA will examine health outcome data to identify specific groups
that are more susceptible to the adverse effects of CO exposure than normal healthy adults (e.g.,
persons with cardiovascular disease, COPD, or reduced or abnormal hemoglobin, older adults,
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neonates).  The host and environmental factors that are responsible for differential susceptibility
to CO will be investigated.
        What do controlled human exposure, animal toxicologic, and epidemiologic studies
         indicate regarding the relationship between acute exposures to CO and health effects
         of concern in individuals who are healthy and in those individuals with preexisting
         diseases (e.g., cardiovascular diseases, COPD)?  What other medical conditions or
         medications are identified as increasing susceptibility to CO effects? What are the
         pathways and mechanisms through which CO may be acting for these groups?  Do
         pathophysiologic changes in these populations alter the normal compensatory
         responses to CO exposure observed in healthy individuals? What is the nature and
         time-course of the development of effects in healthy persons and in persons with
         preexisting disease?
        Is preexisting respiratory or cardiovascular disease in conjunction with  advanced age
         an important factor in susceptibility to mortality  associated with exposure to CO?
        Regarding morbidity health endpoints, to what extent are older adults and neonates
       more sensitive than the general population to CO exposure?
        How should sensitive subpopulations be considered in interpretation of
         epidemiological results and exposure-response characteristics, considering that these
         results may be driven by the more sensitive subpopulations?
        Is susceptibility to the effects of short-term CO exposure associated with long-term CO
         susceptibility?
        What host and environmental factors (e.g., demographic, socioeconomic, and genetic)
         are associated with susceptibility to short- and long-term exposure to CO?


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

Annexes to the ISA
      The ISA will be supplemented by a series of annexes, which will provide detailed
supporting information and more comprehensive coverage of research areas summarized in the
ISA. While studies with the most policy-relevant information are summarized in the ISA, the
annexes present information on all studies considered during the review. Annexes  also provide
in-depth discussion of scientific topics supporting interpretation of exposure, health, and welfare
effects. The annexes will provide information on:  (1) the chemistry, physics, sources,  and
emissions of CO, as well as sampling and analytic methods for measurement of CO; 2)
environmental concentrations and human exposure to CO; (3) dosimetry; (4) toxicologic studies
of CO health effects in laboratory animals and in vitro systems; (5) human clinical studies
examining health effects following controlled exposure to CO; and (6) epidemiologic studies of
health effects from short- and long-term exposure to CO. More detailed information on various
methods and results for the health studies will be summarized in tabular form in the annexes.
These tables will generally be organized to include information about: (1) concentrations of CO
levels and averaging times; (2) description of study methods employed; (3) results and
comments; and (4) quantitative outcomes for CO measures.  Additionally, annexes will contain
background material on legislative requirements, the NAAQS review process, and the  history of
earlier CO reviews.
4.3    SCIENTIFIC AND PUBLIC REVIEW
       Drafts of the ISA will be reviewed by the CAS AC CO Review Panel of EPA's Science
Advisory Board (SAB) and made available for public comment.  The annexes to the ISA will
also be made available to CASAC in order to assist with their review; however, CASAC
members will not be specifically charged with reviewing the annexes.  The CASAC CO Review
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Panel will review the first draft ISA and discuss their comments in a public meeting announced
in the Federal Register. Based on CAS AC's past practice, EPA expects that the CAS AC chair
will summarize key CAS AC advice and recommendations for revision of the document in a
letter to the EPA Administrator. In revising the first draft ISA for CO, EPA will take into
account any such recommendations, as well as comments received from CASAC or from the
public at the meeting itself and any written comments received. EPA will prepare a second draft
ISA for CASAC review and public comment. The CASAC CO Review Panel will review the
second draft ISA and discuss their comments in a public meeting announced in the Federal
Register.  Again, based on CAS AC's past practice, EPA anticipates the CASAC chair will
summarize key advice and recommendations for revision of the second draft ISA in a letter to the
EPA Administrator. In finalizing the ISA, EPA will take into account any such
recommendations. EPA will also consider comments received from CASAC or from the public
at the meeting itself and any written public comments. After appropriate revision, the final
document will be made publicly available on an EPA website and in hard copy. A notice
announcing the availability  of the final ISA will be published in the Federal Register. In
addition, the final ISA will be placed in the rulemaking docket.
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               5.    RISK/EXPOSURE ASSESSMENT
5.1    SCOPE AND ORGANIZATION
      The risk/exposure assessments for the current review of the primary CO NAAQS will be
designed to estimate human exposures and to characterize the potential health risks that are
associated with current ambient levels, with ambient levels that just meet the existing standard,
and with ambient levels that just meet alternative standards that may be under consideration.
The risk/exposure assessments will draw upon the information presented in the draft ISA and its
Annexes. This includes information on atmospheric chemistry, air quality, human exposure,
formation of COHb levels, and health effects of concern. In particular, the availability of
concentration-response and dose-response data from the health effects literature will influence
the type of exposure assessment and risk characterization that would be performed.
       The assessments will focus on exposures and dose metrics that are consistent with health
effects of concern and will be enhanced with available measurement and modeled data, where
appropriate, to generate estimates of exposure.  These estimates will then serve as a measure of
comparison to identified health benchmarks to (1) estimate the number of individuals at risk of
experiencing exposures of concern, and (2) estimate the magnitude of exposures above levels of
concern. The components of the exposure/risk assessments are outlined below and will be
described in detail in the draft Health Assessment Plan: Scope and Methods for Exposure and
Risk Assessment (hereafter, "Health Assessment Plan"). The Health Assessment Plan will be
the subject of a consultation with the CAS AC CO Panel and will be made available to the public
for review and comment. The first draft risk and exposure assessment (REA) document will be
prepared based on the draft Health Assessment Plan and will assess exposure and characterize
health risks associated with recent air quality and air quality just meeting the current CO
NAAQS. The second draft REA document will reflect comments from the CASAC CO Panel
and the public and will also analyze exposure and characterize health risks  associated with any
potential alternative CO standards under consideration. The REA document will be made final
upon completion of the final ISA for CO and following review of the second draft REA
document by the CASAC CO Panel and the public.
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5.2    OVERVIEW OF PREVIOUS EXPOSURE ASSESSMENTS

1992 Exposure Analysis for Denver, Colorado
       In the previous review of the NAAQS for CO, a quantitative analysis of CO exposures in
Denver, CO, was conducted to provide estimates of CO exposure and their resultant COHb
levels for people living in one city for different exposure scenarios.  The analysis provided a
basis for assessing protection afforded by the current CO standards and preliminary insight into
the relative impact of certain indoor sources to total CO exposure. Denver was chosen because
(1) in 1988 it violated both the current 1-hour and 8-hour CO NAAQS (one of only two areas
that exceeded both standards at the time); (2) it had a relatively high 8-hour design value, 16.2
ppm  the second-highest design value in the U.S. at the time; and (3) CO personal monitoring
data were available for a rough validity check of the modeling effort. Four scenarios were
modeled that provided insight into exposures related to (1) current air quality versus future air
quality associated with just meeting the 8-hour CO NAAQS and (2) common indoor sources
present versus ambient air without these indoor sources.  Only the 8-hour NAAQS was evaluated
since previous analyses indicated that it was the controlling standard for attainment (US EPA,
1979b). Indoor sources that were considered included residential gas stoves and passive
smoking. Other indoor sources, such as running automobiles in private or public garages and
CO intrusion into a motor vehicle from the vehicle itself, were not included in any of the
scenarios.
       The model used for exposure analysis was pNEM/CO (probabilistic NEM applied to
CO), a version of the CO NAAQS Exposure Model (NEM) that incorporated Monte Carlo
sampling and multiple runs, or realizations, of the model.  The major model outputs of interest
were estimates of the number of person-days of exposure to various CO levels for the four
scenarios mentioned above for adults with cardiovascular disease in Denver. In addition,
estimates also were made of the percentage of the cardiovascular heart disease population in
Denver that would exceed selected COHb levels one or more times per year under the four
scenarios.  The estimates of COHb were derived by applying a modified version of the Coburn-
Forster-Kane (CFK) differential equation that estimates COHb levels from CO exposure as a
function of time and physiological and environmental factors (e.g., blood volume, altitude,
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endogenous CO production rate). It was estimated at the time that there were about 36,800 non-
smoking adults in Denver with diagnosed or undiagnosed (silent) ischemia.
       The analysis indicated that if the current 8-hour standard were just met, the proportion of
the nonsmoking population with cardiovascular disease experiencing exposures at or above 9
ppm for 8 hours decreased by an order of magnitude or more, down to less than 1 percent of the
total person-days in that population. Likewise, meeting the current 8-hour standard reduced the
proportion of the nonsmoking cardiovascular-disease population person days at or above COHb
levels of concern by an order of magnitude or more. Upon meeting the 8-hour standard, EPA
estimated that less than 0.1 percent of the nonsmoking cardiovascular-disease population would
experience a COHb level of about 2.1  percent. A smaller population was estimated to exceed
higher COHb percentages. Based on this assessment, and considering the 1985 review of similar
CO effects and effects levels, the Administrator concluded that the evaluation of adequacy of the
existing CO standards should focus on reducing the number of individuals with cardiovascular
disease from being exposed to CO levels in the ambient air that would result in COHb levels of
2.1 percent or greater. The Administrator concluded that standards that limit the occurrence of
COHb levels above 2.1 percent would provide an adequate margin of safety against effects of
uncertain occurrence in the range of 2.1 to 2.9 percent, as well as those of clear concern that have
been associated with COHb levels in the range 2.9 to 5.9 percent. The Administrator also
concluded that relatively few people of the cardiovascular sensitive population group  analyzed
would experience COHb levels > 2.1 percent when exposed to CO levels in the absence of
indoor sources when the current ambient standards are attained. The analysis also indicated,
however, that certain indoor sources (e.g., passive smoking, gas stove usage) contributed to total
CO exposure but could not be effectively mitigated by ambient air quality standards.
       The 8-hour standard was chosen because most individuals, even at rest, appeared to
approach equilibrium levels of COHb  after 8 hours of exposure. In addition the 8-hour period
approximated blocks of time for which people are often exposed in a particular location or
activity (e.g., sleeping, working) and provided a good indicator for tracking continuous
exposures that occurred during any 24-hour period. The  1-hour standard was chosen because a
1-hour averaging period provided a better indicator of short-term health effects of CO and a 1-
hour standard provided reasonable protection  from effects that might be encountered from very
short duration peak exposures in the urban environment.  Review of scientific information in the
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1991 Criteria Document indicated that these reasons for choosing averaging times for the CO
standards remained valid and there were no compelling arguments for selecting new or different
averaging times.  The Administrator also considered and concurred with the staff
recommendations contained in the  1992 Staff Paper that both averaging times should be
retained for the primary CO standards. For the above reasons, the Administrator determined
under section 109(d)(l) that revisions of the 1-hour (35 ppm) and 8-hour (9 ppm) primary
standards for CO were not appropriate at that time.

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

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

Air Quality Characterization
       The first step in the exposure/risk assessment will be to conduct an air quality analysis
relying on ambient air quality data and the information provided in the ISA and relevant
Annexes.  This analysis will include information  on CO properties, current CO air quality
patterns, historic trends, and policy-relevant background levels7.  This analysis will provide a
frame of reference for subsequent discussions of current and possible alternative standards.
General steps in the process  include the following.
7 Policy-relevant background is defined as the distribution of CO concentrations that would be observed in the U.S.
in the absence of anthropogenic (man-made) emissions of CO in the U.S., Canada, and Mexico.
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        Obtain ambient monitoring data collected since the prior NAAQS review (e.g., 1995-
         2007)
        Estimate number of exceedances (if any) of the current CO standards using recent
         monitoring data
        Estimate number of exceedances of several short-term peak air quality indicators given
         attainment of the current CO standards and potential alternative standards.
        Develop methods to adjust recent CO air quality data to simulate just meeting the
         current standards and any alternative CO standards.  EPA will consider alternative air
         quality simulation procedures, including a proportional rollback procedure, for use in
         this current review. EPA will also evaluate candidate procedures for simulating
         changes in CO air quality likely to result from just meeting the current or alternative
         standards based on analyzing changes in CO levels that have been observed
         historically and/or analyzing changes in CO levels predicted by air quality models.
         EPA will consider factors which may influence the concentration distributions such as
         potential source contributions, as well as the  influence of local and regional pollution.
        Evaluate the relationship between 1-hour and 8-hour peak concentrations across
         multiple years for different geographic areas.

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

5.4    RISK CHARACTERIZATION APPROACH
       A two-tiered approach to characterizing health risks will be employed. In a first tier
analysis, potential health effect benchmarks will be identified based on information in the draft
ISA.  These health benchmark levels would be combined with exposure or dose estimates from
the exposure/dose assessment in order to characterize population health risks. In a second tier
risk analysis, which would be conducted only if judged appropriate and if relevant data are
available,  an assessment using concentration-response or exposure/dose-response data would be
conducted by combining this data with either ambient distributions or estimated exposure or dose
distributions, respectively.
       The goals of a CO risk characterization would be: (1) to estimate the number of people
exposed to CO concentrations  or COHb levels above health effects benchmarks considering
current air quality and air quality levels simulated to just meet the current and potential
alternative CO standards; (2) to provide distributions of health risk estimates associated with
recent air quality and  air quality just meeting the current and potential alternative standards if a
second tier risk analysis is conducted; and (3) to identify key assumptions and uncertainties in
the risk estimates.

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

Dose-Response and Concentration-Response Functions
       Incorporating dose-response or concentration-response data into the risk characterization
will depend on the availability of data from controlled human exposure studies and
epidemiologic studies, respectively. If quantitative relationships provided by studies or derived
from the data presented in studies  are available that describe the change in concentration (either
ambient or exposure) or dose ( e.g. COHb level) associated with a change in health response,
then these relationships could potentially be applied to estimate health risk.
       Controlled human exposure studies involve volunteer subjects who are exposed to
specified levels of CO under controlled conditions for specified lengths of time. The endpoints
of interest in previous reviews were related to the cardiovascular and central  nervous systems,
including decrement in time to onset of chest pain and ST-segment suppression in patients with
angina pectoris, reduced maximal  exercise duration in healthy  adults due to decreased oxygen
uptake, increased number and complexity of arrhythmia in individuals with chronic arrhythmia,
and short-term effects on hand-eye coordination and vigilance  in healthy individuals. In the
prior reviews,  these responses formed the basis for the development of health benchmarks related
to specified COHb levels.
       In contrast, epidemiological studies typically provide estimated concentration-response
relationships based on data collected in environmentally-relevant settings.  Ambient CO
concentration is typically included in health effects models as the average of monitor-specific
measurements. Common health responses that have been evaluated for CO include
developmental effects, as well as cardiac and respiratory morbidity and mortality. In the
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previous review the epidemiologic evidence was judged to be too limited to form the basis for
developing either potential health benchmarks or quantitative risk estimates.  Again, depending
on the type of health response function(s) available, ambient CO concentration data might be
used for characterizing risks, and are most appropriately applied in the geographic area where the
epidemiological study was performed.  It should be noted that a risk characterization based on
epidemiological studies also requires baseline incidence rates and population data for the risk
assessment locations.
       Based on our current understanding of the available evidence, we do not anticipate that
there will be sufficient exposure- or dose-response  data from controlled human exposure studies
to characterize health risks in this manner.  However, there may be limited data available to
develop concentration-response relationships from  recently conducted epidemiologic studies.
Following review of the draft ISA and considering  comments and recommendations from
CASAC and the public, the draft Health Assessment Plan will be designed to include such a
proposed approach to characterizing health risk if warranted.


5.5    ASSESSMENT CRITERIA
       Criteria will be established and described in the draft Health Assessment Plan to
determine the level of detail warranted and the specific design of the assessments. The criteria
will be designed to determine the value added to the assessment as measured by the reduction of
uncertainties in the exposure and risk estimates. In order to determine which level of detail is
warranted, the following factors will be considered by the workgroup and EPA management:
        Results of the ambient air quality indicator analysis;
        Weight-of-evidence, as provided in the ISA, from new controlled human exposure
         studies with relevant exposure-response data, particularly those conducted at or near
         current ambient concentrations;
        Weight-of-evidence, as provided in the ISA, from new epidemiological studies that
         evaluate the relationship between short-term repeated peak exposures and health
         outcomes;
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        New information regarding susceptible populations identified in previous reviews
         (e.g., those with pre-existing cardiovascular disease) or information regarding newly
         identified susceptible populations;
        Information and data defining the potential impact of roadway CO concentrations on
         nearby residents and on specific microenvironmental concentrations (e.g., while
         traveling inside motor vehicles);
        Analysis of exposure studies using non-routine monitoring, other local sources (e.g.,
         rail-yards, airports), and/or modeled CO concentrations;
        Existence of the data required to perform the analyses in each stage of the assessment.

5.6    UNCERTAINTY AND VARIABILITY
       The uncertainty and variability inherent in estimates of exposure and risk will be
characterized regardless of the type of exposure assessment and risk characterization conducted.
Uncertainty reflects the degree of confidence in the representativeness of models or model
components.  Variability can be described in terms of empirical quantities that are inherently
variable across time and space or between individuals (Cullen and Frey, 1999).
       Assessing uncertainty and variability will begin with a qualitative analysis and progress
to a quantitative  analysis if data are available to support such an analysis. The first step in the
uncertainty analysis will be to identify the components of the assessment, determine whether
uncertainty can be  evaluated for each of those components, and provide a rationale for why this
is the case.  The  second step will be to perform a qualitative uncertainty analysis for the
appropriate components of the assessment.  This qualitative analysis will result in a matrix
describing, for each area of uncertainty, both the magnitude (minimal, moderate, major)  and the
direction of influence (under- or over-estimate) on risk/exposure estimates.  If sufficient data are
available, and if the magnitude of uncertainty is judged significant, a quantitative assessment of
uncertainty will then be performed for selected components of the assessment.
       There are two primary sources of uncertainty that would be addressed in a quantitative
analysis. The first is uncertainty associated with the model inputs (e.g., use of air quality data,
time-location-activity diaries, microenvironmental factor distributions). The second is
uncertainty associated with model formulation (e.g., algorithms included in the model).
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5.7   PUBLIC AND SCIENTIFIC REVIEW
      The CASAC CO Review Panel will be consulted on the assessment approach at a public
meeting. Drafts of the REA document will also be reviewed by the CASAC CO Review Panel.
The CASAC CO Review Panel will review the draft document and discuss their comments in a
public meeting announced in the Federal Register.  Based on CASAC's past practice, EPA
expects that key advice and recommendations for revision of the document will be summarized
by the CASAC Chair in a letter to the EPA Administrator. In revising the draft REA document
for CO, EPA will take into account any such recommendations, and will also consider comments
received, from CASAC or from  the public, at the meeting itself and any written comments
received.  EPA anticipates preparing a second draft of the REA document for CASAC review
and public comment. After appropriate revision, the final document will be made available on
an EPA website, with its public  availability being announced in the Federal Register.
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          6.    POLICY ASSESSMENT/RULEMAKING

      The final decision to retain or revise the NAAQS is a public health policy judgment. A
final decision should draw upon scientific information and analyses related to health effects,
population exposure and risks, and judgments about the appropriate response to the range of
uncertainties that are inherent in the scientific evidence and analyses. The Agency's approach to
informing these judgments is based on a recognition that the available health effects evidence
generally reflects a continuum consisting of ambient levels at which scientists generally agree
that health effects are likely to occur through lower levels at which the likelihood and magnitude
of the response become increasingly uncertain.
      Based on the information in the ISA and the exposure assessment report, EPA will
publish a notice of proposed rulemaking to provide an opportunity for CAS AC and the public to
evaluate the policy options under consideration and to offer comments and  recommendations to
inform the Administrator's decision whether to retain or revise the primary CO NAAQS, and
whether to promulgate a secondary NAAQS for CO.8 Issuance of a final decision will complete
the rulemaking process.
       8 As noted above in Chapter 1, EPA is also considering whether, and at what point in the process, to issue
an ANPR.
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                            7.    REFERENCES
Centers for Disease Control and Prevention (CDC) (2004). The Health Consequences of
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       http://www.cdc.gov/tobacco/data statistics/sgr/sgr 2004/chapters.htm (13 May, 2008)
Cullen AC and Frey HC (1999). Probabilistic Techniques in Exposure Assessment.  A handbook
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Hill, AB (1965). The environment and disease: association or causation? Proc. R. Soc. Med. 58:
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Institute of Medicine (IOM) (2007). Improving the Presumptive Disability Decision-Making
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International Agency for Research on Cancer (IARC) (2006). IARC Monographs on the
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       http://monographs.iarc.fr/ENG/Preamble/CurrentPreamble.pdf (13 May, 2008).
Johnson, T, Mihlan, G, LaPointe, J, Fletcher, K, Capel, J (1999) Estimation of Carbon Monoxide
       Exposures and Associated Carboxyhemoglobin levels in Denver Residents Using
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McClellan, RO., Chairman, Clean Air Scientific Advisory Committee (1991). Letter to William
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McClellan, RO, Chairman, Clean Air Scientific Advisory Committee (1992). Letter to William
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National Research Council (2003) Managing Carbon Monoxide Pollution in Meteorological and
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National Toxicology Program (NTP) (2005). Report on Carcinogens. 11th ed. Washington, DC:
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       Assessment Office; US EPA No. EPA-600/8-83-033F. Research Triangle Park, NC
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US EPA (1984b) Review of the NAAQS for Carbon Monoxide: Reassessment of Scientific and
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US EPA. (1991) Air Quality Criteria for Carbon Monoxide. Research Triangle Park, NC: Office
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US EPA (1992).  Review of the National Ambient Air Quality Standards for Carbon Monoxide:
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US EPA (2000). Air Quality Criteria for Carbon Monoxide. National Center for Environmental
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US EPA (2005). Guidelines for Carcinogen Risk Assessment. Washington, DC: Risk
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US EPA (2006a). Total Risk Integrated Methodology (TRIM) - Air Pollutants Exposure Model
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       http://www.epa.gov/ttn/fera/human apex.html.
US EPA (2006b). Total Risk Integrated Methodology (TRIM) - Air Pollutants Exposure Model
       Documentation (TRIM.Expo / APEX, Version 4) Volume II: Technical Support
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       June 2006.  Available at: http://www.epa.gov/ttn/fera/human apex.html.
US EPA (2007). Integrated Science Assessment (ISA) for Sulfur Oxides - Health Criteria (First
       External Review Draft). U.S. Environmental Protection Agency, Research Triangle Park,
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       http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=l 82057
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       Report). U.S. Environmental Protection Agency, Research Triangle Park, NC,
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       http://www.epa.gOv/ttn/naaqs/standards/nox/s noxcrisi.html
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       Assessment. World Health Organization.
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