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> **UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON D.C. 20460**

> **OFFICE OF THE ADMINISTRATOR**
>
> **SCIENCE ADVISORY BOARD**

June 12, 2008

EPA-CASAC-08-013

The Honorable Stephen L. Johnson

Administrator

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, N.W.

Washington, D.C. 20460

> Subject: Consultation on EPA's *Draft Plan for Review of the Primary
> NAAQS for Carbon Monoxide* (March 2008)

Dear Administrator Johnson:

The Clean Air Scientific Advisory Committee (CASAC) Carbon Monoxide (CO)
Primary NAAQS Review Panel met on April 8, 2008, and has completed its
consultation on EPA's *Draft Plan for Review of the Primary NAAQS for
Carbon Monoxide* (March 2008). The CASAC uses a consultation as a
mechanism for individual technical experts to provide comments on the
Agency's draft plan for developing technical assessments as the basis of
the review of the primary NAAQS for CO. Written comments provided by the
individual Panelists are enclosed. Areas of concern emphasized by
panelists included (but were not limited to): 1) the need for a
multi-pollutant approach in considering CO standards; 2) the need to
consider both a secondary and a primary standard; 3) the inadequacy of
current monitoring data; and 4) the requirements related to the new
NAAQS review process.

As this is a consultation, we do not expect a formal response from the
Agency. We thank the Agency for the opportunity to provide advice early
in the NAAQS review process, and look forward to the review of the draft
Integrated Science Assessment in April 2009.

> Sincerely,
>
> ***/Signed/***
>
> Dr. Rogene Henderson, Chair
>
> Clean Air Scientific Advisory Committee

Enclosures

**U.S. Environmental Protection Agency**

**Clean Air Scientific Advisory Committee**

**CO Primary NAAQS Review Panel Roster**

**CASAC MEMBERS**

**Dr. Rogene Henderson (***Chair***)**, Scientist Emeritus, Lovelace
Respiratory Research Institute, Albuquerque, NM

**Dr. Ellis B. Cowling**, University Distinguished Professor At-Large
Emeritus, Colleges of Natural Resources and Agriculture and Life
Sciences, North Carolina State University, Raleigh, NC

**Dr. James D. Crapo**, Professor, Department of Medicine, National
Jewish Medical and

Research Center, Denver, CO

**Dr. Douglas Crawford-Brown**, Professor Emeritus and Director
Emeritus, Department of Environmental Sciences and Engineering and UNC
Institute for the Environment, University of North Carolina at Chapel
Hill, Chapel Hill, NC

**Dr. Donna Kenski,** Data Analysis Director, Lake Michigan Air
Directors Consortium, Rosemont, IL

**Dr. Armistead (Ted) Russell**, Professor, Department of Civil and
Environmental Engineering, Georgia Institute of Technology, Atlanta, GA

**Dr. Jonathan Samet**, Professor and Chairman, Department of
Epidemiology,

Bloomberg School of Public Health, Johns Hopkins University, Baltimore,
MD

**PANEL MEMBERS**

**Dr. Thomas Dahms**, Professor and Director, Anesthesiology Research,
Department of Anesthesiology and Critical Care, Saint Louis University
School of Medicine, St. Louis, MO

**Dr. Russell R. Dickerson,** Professor and Chair, Department of
Atmospheric and Oceanic Science, University of Maryland, College Park,
MD

**Laurence Fechter, Ph. D.,** Research Scientist and Professor, Loma
Linda VA Medical Center and Loma Linda University School of Medicine,
Loma Linda, CA

**Dr. Milan Hazucha,** Professor, University of North Carolina at Chapel
Hill, Chapel Hill, NC

**Dr. Michael T. Kleinman**, Professor, University of California --
Irvine, Irvine, CA

**Dr. Arthur Penn,** Professor, Louisiana State University, Baton Rouge,
LA

**Dr. Beate Ritz,** Professor, University of California -- Los Angeles,
Los Angeles, CA

**Dr. Paul T. Roberts**, Executive Vice President and Chief Scientific
Officer, Sonoma Technologies, Inc., Petaluma, CA

**Dr. Stephen R. Thom**, Professor and Chief of Service, Institute for
Environmental Medicine, University of Pennsylvania, Philadelphia, PA

**SCIENCE ADVISORY BOARD STAFF**

**Ms. Kyndall Barry**, Designated Federal Officer, 1200 Pennsylvania
Avenue, NW

1400F, Washington, DC, Phone: 202-343-9868, Fax: 202-233-0643,
(barry.kyndall@epa.gov)

**Compilation of Individual Panel Member Comments on EPA's *Draft Plan
for Review of the Primary NAAQS for Carbon Monoxide* (March 2008)**

**[Comments received:]{.underline}**

**Dr. Ellis B. Cowling [5](#dr.-ellis-b.-cowling)**

**Dr. James Crapo [12](#dr.-james-crapo)**

**Dr. Douglas Crawford-Brown [13](#dr.-douglas-crawford-brown)**

**Dr. Thomas Dahms [16](#dr.-thomas-dahms)**

**Dr. Russell R. Dickerson [19](#dr.-russell-r.-dickerson)**

**Dr. Milan Hazucha [21](#dr.-milan-hazucha)**

**Dr. Rogene Henderson [24](#dr.-rogene-henderson)**

**Dr. Donna Kenski [25](#dr.-donna-kenski)**

**Dr. Michael T. Kleinman [26](#dr.-michael-t.-kleinman)**

**Dr. Arthur Penn [28](#dr.-arthur-penn)**

**Dr. Beate Ritz [30](#dr.-beate-ritz)**

**Dr. Paul T. Roberts [31](#dr.-paul-t.-roberts)**

**Dr. Armistead Russell [33](#dr.-armistead-russell)**

**Dr. Jonathan M. Samet [35](#dr.-jonathan-m.-samet)**

**Dr. Stephen R. Thom [36](#dr.-stephen-r.-thom)**

# Dr. Ellis B. Cowling

**[Individual Comments on the March 2008 Draft Plan for Review of
the]{.underline}**

**[Primary National Ambient Air Quality Standard for Carbon
Monoxide]{.underline}**

**Very General Comments on these NAAQS Review Processes**

Before dealing with the details of my specific assignment during the
April 8, 2008 CASAC Consultation on the Primary (public-welfare based)
NAAQS for Carbon Monoxide (CO), I would like to offer a few general
comments about these periodic NAQQS Review processes and the changes
that are being made in both the organization and focus of these reviews.

As described on pages 1-2 of the "Draft Plan" for review of the primary
NAAQS for CO, the Clean Air Act of 1970 established two general goals
for management of air quality in the United States \-- protection of
human health and protection of public welfare. Section 108 of the CAA
directs the Administrator of EPA to identify and list "air pollutants"
that "in his judgment may reasonably be anticipated to endanger public
health and welfare" and to issue air quality criteria for those that are
listed -- hence the term "Criteria Pollutants."

Section 109 of the CAA further directs the Administrator of EPA to
propose and promulgate "Primary" National Ambient Air Quality Standards
to protect public health and "Secondary" National Ambient Air Quality
Standards to protect public welfare.

A secondary standard, as defined in Section 109, must "specify a level
of air quality the attainment and maintenance of which, in the judgment
of the Administrator, based on such criteria, is required to protect the
public welfare from any known or anticipated adverse effects associated
with the presence of \[the\] pollutant in the ambient air ..." The
welfare effects of concern 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."

So far, the several Administrators of EPA since 1970 have:

1)  Identified six specific "Criteria Pollutants" -- carbon monoxide,
    ozone and other photochemical oxidants, sulfur dioxide, oxides of
    nitrogen, particulate matter, and lead -- which have thus been
    designated officially as requiring development and implementation of
    National Ambient Air Quality Standards;

2)  Emphasized protection of public health as the principal (and
    overwhelmingly important) *de facto* focus of concern within the
    Agency, and public welfare as a (rarely openly acknowledged) but
    distinctly less important *de facto* focus of concern;

3)  Established Secondary (public-welfare-based) NAAQS standards for all
    six criteria pollutants that almost always were identical in form
    (including level, indicator, statistical form, and averaging time)
    to the Primary (public- health based) NAAQS standards for each of
    these six criteria pollutants;

4)  Developed a long-standing tradition of dealing with these six
    specific air pollutants mainly on a "one-at-a-time" basis rather
    than collectively -- i.e., without strong attention to the frequent
    interactions and simultaneous occurrence of some of these pollutants
    as mixtures within the air in various parts of our country;

5)  Maintained a reluctant attitude about the concepts of ecologically
    based "Critical Loads and Critical Levels" developed in Europe as
    possible alternative or additional approaches to air-quality
    management in the US; and

6)  Maintained a long-standing general focus on the related concepts of:

> a\) "attainment counties and non-attainment counties,"
>
> b\) "attainment demonstrations" based on mathematical modeling of a
> limited number of exceedance events under extreme weather conditions,
> and
>
> c\) "local anthropogenic sources" as opposed to "both local and
> regional biogenic and anthropogenic sources of emissions."

In recent years, in contrast to several of the six ideas listed above,
EPA has shown increased willingness to think more holistically -- and in
more fully integrated ways -- about both the policy-relevant science and
the practical arts of air quality management aimed at protection of both
public welfare and public health. These shifts in both emphasis and
approach have included:

1.  Participation with other federal agencies and international bodies
    in discussions about the "One Atmosphere," "Critical Loads--Critical
    Levels," and "Multiple-Pollutant--Multiple Effects" concepts;

> 2\) Adoption of the "NOx SIP Call" in 1999 and both the "Clean Air
> Interstate Rule" (CAIR) and the "Clean Air Mercury Rule" (CAMR) in
> 2005 with their more balanced perspectives about both regional
> (interstate) and local sources of emissions and interactions among
> NOx, SOx, VOCs, "air toxics," and mercury in the formation,
> accumulation, and biological effects of "ozone and other photochemical
> oxidants," and fine, coarse, thoracic, and secondary aerosol
> particles;
>
> 3\) Recognition of both fine and coarse PM as complex and
> geographically variable mixtures of sulfate-, nitrate-, and
> ammonium-dominated aerosols; natural biogenic and anthropogenic
> organic substances; heavy metals including cadmium, copper, zinc,
> lead, and mercury; and some other miscellaneous substances;
>
> 4\) More frequent discussion about of the occurrence and both
> ecologically-important and public-health impacts of mixtures of air
> pollutants; and, most recently
>
> 5\) Making the unprecedented decisions (at least in the case of the
> NAAQS reviews for oxides of nitrogen and sulfur) to:
>
> A\) Separate the preparation and review of documentation, the required
> CASAC and public reviews, and the final decision-making processes for
> the Secondary (public-welfare-based) National Ambient Air Quality
> Standards from the (previously always dominating) Primary
> (public-health-based) NAAQS review processes, and
>
> B\) Prepare and publish a single draft plan for integrated
> \[simultaneous\] of two different criteria pollutants (NOx and SOx),
> and
>
> 6\) Identify in advance a set of Key Policy-Relevant Questions that
> will be the primary focus of attention in the design and completion of
> all four major components of the new NAAQS review processes:
>
> A\) An Integrated Review Plan (IRP),
>
> B\) An Integrated Science Assessment (ISA),
>
> B\) A Risk/Exposure Assessment (REA), and
>
> C\) A Policy Assessment/Rulemaking document developed in the form of
> an Advanced Notice of Proposed Rule Making (ANPR).

All six of these adjustments in focus of attention, documentation
requirements, and sequential procedures are being undertaken with the
intention to:"

> "... improve the efficiency of the process while ensuring that the
> Agency's decisions are informed by the best available science and
> timely advice from CASA and the public" ... and
>
> "... help the agency meet the goal of reviewing each NAAQS on a 5-year
> cycles as required by the Clean Air Act without compromising the
> scientific integrity of the process."

**[Need for Policy Relevancy as the Dominant Concern in NAAQS Review
Processes]{.underline}**

In a May 12 2006 summary letter to Administrator Johnson, CASAC Chair,
Dr. Rogene Henderson, provided the following statement of purpose for
these periodic NAAQS review processes.

> "CASAC understands the goal of the NAAQS review process is to answer a
> critical scientific question: *"What evidence has been developed since
> the last review to indicate if the current primary and/or secondary
> NAAQS need to be revised or if an alternative level or form of these
> standards is needed to protect public health and/or public welfare?"*

During the past 18 months, CASAC has participated in reviews of three of
the existing six criteria pollutants -- particulate matter, ozone, and
lead. CASAC has also joined with senior EPA administrators in a
"top-to-bottom review" and the resulting recently-completed revision of
the NAAQS review processes. These two experiences have led to a
seemingly slight but important need for rephrasing and refocusing of
this very important "critical scientific question:"

> ***"What scientific evidence and/or scientific insights have been
> developed since the last review that either support or call into
> question the current public-health based and/or the current
> public-welfare based NAAQS, or if alternative levels, indicators,
> statistical forms, or averaging times of these standards are needed to
> protect public health with an adequate margin of safety and to protect
> public welfare?"***

With regard to the important distinction in purpose of the primary
(public health) and secondary (public welfare) NAAQS standards, it is
noteworthy that in all five cases in which a secondary NAAQS standard
has been established, the secondary standard has been set "Same as
Primary."

Thus, a second very critical scientific question that needs to be
answered for CO as well as the other criteria air pollutants is:

> ***"What scientific evidence and/or scientific insights have been
> developed since the last review to indicate whether, and if so, what
> particular ecosystem components or other air-quality-related public
> welfare values, are more or less sensitive than the populations of
> humans for which primary standards are established and for this reason
> may require a different level, indicator, statistical form, or
> averaging time of a secondary standard in order to protect public
> welfare."***

I hope these two "critical scientific questions" will be borne in mind
carefully as CASAC joins with the various relevant parts of the
Environmental Protection Agency in completing the upcoming reviews of
both the primary and secondary National Ambient Air Quality Standards
for CO, NOx, SOx, PM, ozone, and lead.

We now have the considerable advantage that a much more complete focus
can be achieved in the Integrated Science Assessment than has
historically been achieved in the encyclopedic Criteria Documents that
have been prepared during the years since 1970.

**Thus, I recommend that every chapter of the soon to be completed
Integrated Science Assessment, the Risk/Exposure Assessment, and the
Policy Assessment/Rule Making documents** for CO **contain a summary
section composed almost entirely of a series of very carefully crafted
statements of Conclusions and Scientific Findings that:**

1)  **Contain the distilled essence of the most important topics covered
    in each chapter, and**

2)  **Are as directly relevant as possible to the two Critically
    Important Scientific Questions written in bold italic type above**.

**In this connection, I call attention once again to the attached
"*Guideline for Formulation of Statements of Scientific Findings to be
Used for Policy Purposes.*"** These guidelines were developed and
published in 1991 by the Oversight Review Board for the National Acid
Precipitation Assessment Program. They are the best guides that I know
of for formulation of scientific findings to be used for policy
purposes.

**GUIDELINES FOR FORMULATION OF SCIENTIFIC FINDINGS**

###### TO BE USED FOR POLICY PURPOSES

The following guidelines in the form of checklist questions were
developed by the NAPAP Oversight Review Board to assist scientists in
formulating presentations of research results to be used in policy
decision processes.

1\) **IS THE STATEMENT SOUND?** Have the central issues been clearly
identified? [Does each statement contain the distilled essence of
present scientific and technical understanding of the phenomenon or
process to which it applies]{.underline}? Is the statement consistent
with all relevant evidence -- evidence developed either through NAPAP
research or through analysis of research conducted outside of NAPAP? Is
the statement contradicted by any important evidence developed through
research inside or outside of NAPAP? Have apparent contradictions or
interpretations of available evidence been considered in formulating the
statement of principal findings?

2\) **IS THE STATEMENT DIRECTIONAL AND, WHERE APPROPRIATE,
QUANTITATIVE?** Does the statement correctly quantify both the direction
and magnitude of trends and relationships in the phenomenon or process
to which the statement is relevant? When possible, [is a range of
uncertainty given for each quantitative result]{.underline}? Have
various sources of uncertainty been identified and quantified, for
example, does the statement include or acknowledge errors in actual
measurements, standard errors of estimate, possible biases in the
availability of data, extrapolation of results beyond the mathematical,
geographical, or temporal relevancy of available information, etc. In
short, [are there numbers in the statement? Are the numbers correct? Are
the numbers relevant to the general meaning of the
statement]{.underline}?

3\) **IS THE DEGREE OF CERTAINTY OR UNCERTAINTY OF THE STATEMENT
INDICATED CLEARLY?** [Have appropriate statistical tests been applied to
the data used in drawing the conclusion]{.underline} set forth in the
statement? If the statement is based on a mathematical or novel
conceptual model, has the model or concept been validated? Does the
statement describe the model or concept on which it is based and the
degree of validity of that model or concept?

4\) **IS THE STATEMENT CORRECT WITHOUT QUALIFICATION?** [Are there
limitations of time, space, or other special circumstances in which the
statement is true]{.underline}? If the statement is true only in some
circumstances, are these limitations described adequately and briefly?

5\) **IS THE STATEMENT CLEAR AND UNAMBIGUOUS?** [Are the words and
phrases used in the statement understandable by the decision makers of
our society]{.underline}? Is the statement free of specialized jargon?
Will too many people misunderstand its meaning?

6\) **IS THE STATEMENT AS CONCISE AS IT CAN BE MADE WITHOUT RISK OF
MISUNDERSTANDING?** Are there any excess words, phrases, or ideas in the
statement which are not necessary to communicate the meaning of the
statement? Are there so many caveats in the statement that the statement
itself is trivial, confusing, or ambiguous?

7\) **IS THE STATEMENT FREE OF SCIENTIFIC OR OTHER BIASES OR
IMPLICATIONS OF SOCIETAL VALUE JUDGMENTS?** Is the statement free of
influence by specific schools of scientific thought? Is the statement
also free of words, phrases, or concepts that have political, economic,
ideological, religious, moral, or other personal-, agency-, or
organization-specific values, overtones, or implications? [Does the
choice of how the statement is expressed rather than its specific words
suggest underlying biases or value judgments]{.underline}? Is the tone
impartial and free of special pleading? If societal value judgments have
been discussed, have these judgments been identified as such and
described both clearly and objectively?

8\) **HAVE SOCIETAL IMPLICATIONS BEEN DESCRIBED OBJECTIVELY?**
Consideration of alternative courses of action and their consequences
inherently involves judgments of their feasibility and the importance of
effects. For this reason, it is important to ask if a reasonable range
of alternative policies or courses of action have been evaluated? Have
societal implications of alternative courses of action been stated in
the following general form?:

\"[If this]{.underline} \[particular option\] were adopted [then
that]{.underline} \[particular outcome\] would be expected.\"

9\) **HAVE THE PROFESSIONAL BIASES OF AUTHORS AND REVIEWERS BEEN
DESCRIBED OPENLY?** Acknowledgment of potential sources of bias is
important so that readers can judge for themselves the credibility of
reports and assessments.

**My Assignment in this CASAC Consultation on the Draft Plan for**

**Review of the NAAQS Primary Standard for Carbon Monoxide**

My specific assignment in preparation for the April 8, 2008 CASAC
Consultation on the Draft Plan for review of the NAAQS for CO, as
outlined in Chairman Rogene Henderson's memo of 7 March 2008, is \--
*Key Policy-Relevant Issues*. Rogene also asked Jim Crapo to deal with
these same issues. Thus, I am very much looking forward to comparing
notes with Jim during our Consultation on April 8 -- especially since he
knows so much more than I do about public health effects of CO and other
Criteria Pollutants.

These Key Policy-Relevant Questions are summarized on pages 3-1 through
3-3 in Section 3.2 and are presented as a series of thirteen major
policy-focused "Issues to be considered in the current review". In
addition, several other detailed questions are presented in the several
Sub-sections of Chapter 4. In most cases, however, these more detailed
questions are focused mainly on scientific issues rather than policy
issues and, I presume, will be dealt with adequately by other members of
our CASAC Carbon Monoxides Panel.

I see the decision to develop "Key Policy-Relevant Policy Questions" as
a part of these Draft Plans for NAAQS reviews as a major step forward. I
am also very satisfied with the particular set of 13 such questions
listed in Chapter 3 of this Draft Plan. Of course they all relate to the
effects of CO on public health -- which is the principal focus of this
NAAQS review.

In addition, however, I also note that Section 1.3 -- History of Reviews
of the NAAQS for CO \-- indicates that identical primary and secondary
NAAQS standards for CO were promulgated in 1971 and that the decision
was made in 1985 to revoke the secondary standard. The rationale for
this decision was not included in this "History" section,

But Section 1.4 -- Scope of the Review -- also indicates that

> " ... relevant scientific information on human exposures and health
> effects associated with exposures to ambient concentrations of CO will
> be assessed. The possible influence of other atmospheric pollutants on
> the interpretation of the role of CO in health effects studies will e
> considered. This will include other pollutants with the potential to
> co-occur in the environment (e.g., NO~2~, SO~2~, O~3~, and PM). The
> review will also assess any relevant scientific information associated
> with known or anticipated public welfare effects that may be
> identified."

Thus, because of my keen scientific interest in the welfare effects of
criteria pollutants, I believe it is essential that both current and
past scientific literature be examined closely to determine if:

A)  **The 1985 decision to revoke the secondary NAAQS standard for CO is
    valid in the context of current scientific knowledge \--especially
    about the effects of CO on the health of both domestic and wild
    animals, and perhaps also on crop, forest, and ornamental plants,
    insects, and microorganisms as well.**

B)  **There are significant interactions of ambient concentrations of CO
    with other co-occurring Criteria Pollutants in terms of their
    potential to cause either additive, competitive, or no significant
    interactions with regard to the effects of CO on both public health
    and public welfare, and**

C)  **There are significant times and places in the US where ambient
    concentrations of CO are adding to the total oxidative capacity of
    the atmosphere and thus increase the rate of accumulation of ozone
    near the ground in urban, suburban, rural, and even remote parts of
    the United States. Although CO is not a very reactive volatile
    organic compound, when present in high concentrations, as often
    occurs in the vicinity of municipal waste incinerators and in the
    plumes of wild fires in grasslands and forests, CO can be a very
    significant precursor of tropospheric ozone.**

I suggest this last issue for inclusion in the First Draft Integrated
Science Assessment for CO as a result of the discovery by Wotawa and
Trainer during the 1994 and 1995 Nashville-Middle Tennessee Ozone Study
by the Southern Oxidants Study \-- where a coherent plume containing
extraordinarily high concentrations of CO were observed for several days
about 50 miles east of Nashville and could be traced to wild fires in
the Northwest Territories of Canada that persisted over a six-week
period.

Wotawa, G. and M. Trainer. 2000. The influence of Canadian forest fires
on pollutant

concentrations in the United States. Science 288:324-328.

Other important sources of insight about the influence of CO emissions
from wild fires include the following important references:

Forster, C., U. Wandingrer, G. Wotawa, P. James, I. Mattis, D.
Althausen, P. Simmonds, S.

O'Doherty, S. G. Jennings, C. Kleefeld, J. Schneider, T. Trickly, S.
Kreipl, H. Jäger and

A.  Srohl. 2001. Transport of boreal forest fire emissions from Canada
    to Europe. J.

> Geophys. Res. 106(D19)12,887-22,906.

McKeen, S. A., G. Wotawa, D. D. Parrish, J. S. Holloway, M., G. Hübler,
F. C. Fehsenfeld, and

> J. F. Meagher. 2002. Ozone production from Canadian wildfires during
> June and July of 1995. J. Geophys. Res. Vol. 107, NO. D14,4192,
> 10.1029/2001JD000697. ACH 7-1 to ACH 7-25.

Westerling, A. L., H. G. Hidalgo, D. R. Cayan, and T. W. Sweetman. 2006.
Warming and

Earlier Spring Increase Western U. S. Forest Wildfire Activity. Science
313:940-943.

Wotawa, G., P. C. Novelli, M. Trainer, and C. Granier. 2001.
Inter-annual variability of

> summertime CO concentrations in the Northern Hemisphere explained by
> boreal forest fires in North American and Russia. Geophys. Res. Lett.
> 28:4575-4578.

# Dr. James Crapo

The basic plan laid out by EPA staff for review of the primary National
Ambient Air Quality Standard (NAAQS) for carbon monoxide is appropriate.
The work in implementing this plan should focus primarily on new data
(studies carried out and published since the last CO review) and both on
low level effects of CO that are relevant to the NAAQS and on sensitive
populations who may be at risk.

For this review process to be effective, it is important that the EPA
staff and administration provide a clear policy assessment document that
gives the range of opinions the agency will consider as well as the
scientific basis for those decisions. Advance notice of proposed
rule-making documents needs to include the material that would have been
included in staff papers for prior NAAQS reviews and needs to include an
assessment of realistic options that could be considered for the CO
NAAQS as well as the rigorous scientific justification for those
options. CASAC can be of greatest assistance to the EPA administration
if open dialogue on these topics is engaged in as early as possible in
the review process.

It will also be important to carry out a rigorous review of the value of
an independent secondary standard for CO.

A primary limitation of review of single pollutants is the absence of
detailed consideration of the effects of complex pollutant interactions.
The proposed review process is appropriate for consideration of the
NAAQS for CO; however, the EPA should consider moving in the future to
an analysis of multiple pollutants and their interactions, with the
consideration of setting NAAQS based not only on individual pollutant
levels but also on multiple pollutant interactions.

# Dr. Douglas Crawford-Brown

**Review of EPA's Draft Plan for Review of the Primary NAAQS for Carbon
Monoxide**

The document is intended solely to provide the general structure of a
review, rather than details as to how this will be carried out. As a
result, the following comments are general in nature and may change as
the actual plan is formalized.

My most general comment is that the draft plan contains all of the
relevant sections that must be completed to produce a full review. The
authors have therefore not left out any major considerations. However,
throughout the document, the authors raise a series of questions that
will be addressed in each section without providing a succinct statement
as to the role the answers to these questions will play in specific
policy considerations. As a result, the reader is left unclear as to how
any specific answer to any specific question might push the discussion
of a NAAQS decision in any particular direction. Perhaps this was
intentional on the part of the authors: trying not to judge how a
particular answer might inform a final decision. But it leaves the
reader unclear as to the intent behind specific questions, other than
providing a scientific base on which any manner of decision might be
based.

The authors raise the issue of co-pollutants, which will be important in
using epidemiological studies. It is not clear, however, how these
co-pollutants will be analyzed. Is the plan to treat them as confounders
and then work to extract this confounding from any slope factors
developed? Is the intent to examine the effect of CO exposures on the
sensitivity of individuals to the co-pollutants, and the effect of the
co-pollutants on the sensitivity of individuals to CO? The document
doesn't give much of a hint as to how this issue will be treated. There
is a sense at several points in the document that clinical, controlled
studies might form the basis for any effects measures, which could avoid
this issue, but this sense is never made fully concrete. There also is a
hint that the assessment might stop at exposure or at blood levels,
which again would avoid this issue (much as in the case of the early Pb
standards). It would be good if some clarity on this issue could be
provided.

On Page 3-2, the authors ask whether new data might indicate that
effects occur at exposures lower than those previously found to induce
effects. This question is too one-sided. It presumes that the only thing
new data can do is push the assumed threshold for effects to lower
values. New data might suggest that previous data suggesting a lower
threshold were incorrect, and that the threshold is in fact higher than
thought.

On Page 4-1, the authors mention a formal framework for integrating
health effects, found in the second draft of the NOx document. The
reader should not need to go to that document to at least find a summary
of this framework, and in any event that document provides no such
summary framework and so readers will come away from it with different
conceptions of what the framework might be when applied to CO. More
clarity is needed on precisely what this framework consists of.

On Page 4-2, the authors state that welfare effects will be noted if any
are found during the search. However, the literature that is mentioned
as forming the basis for the search, rooted only in human health
sciences, is not the appropriate set of disciplines to locate papers on
welfare effects. So I cannot see how the literature review will
constitute a "hard look" at the relevant science on welfare effects.

Around Pages 4-7 and 4-8, the authors discuss the need to perform
analyses of spatial and temporal variability. There is no description,
however, of the role of these analyses in any specific decision on
exposure, exposure-response, risk, etc. I certainly agree that analysis
of variability is needed, but without a clear statement as to the
purpose of the analyses, and the questions they are intended to support,
it will not be possible to determine whether appropriate statistical
methods and databases are being used.

The same problem arises on Page 4-8 when the authors discuss uncertainty
analyses. They mention, for example, uncertainty in extrapolating
between area monitors and personal exposures. However, no insight is
provided as to why this uncertainty would be important for specific
questions to be addressed (I agree it IS important, but the document
doesn't give a hint as to why).

On Page 4-9, at the bottom, the authors list a series of effects that
will be considered. While I agree with this list, no hint is given as to
how it was compiled based on past studies. Clarity is needed here.

On Page 4-12, developmental and birth outcomes are mentioned as chronic
effects. Why are they only considered chronic effects? Surely such
effects might occur with shorter-term exposures during critical
developmental periods.

On Page 4-12, the authors raise the issue as to whether CO might stand
as a surrogate for exposure to the mixture of pollutants from vehicles.
I could not find any explanation as to why they might want to know this.
The CO NAAQS doesn't stand as a surrogate for control on exposures to
these other pollutants.

On that same page, the authors mention the exposure-response curve for
CO. They formulate the question as one of determining the shape of that
curve. But they don't formulate it as an issue of uncertainty ABOUT the
shape of that curve, or how different curves would produce different
NAAQS results. That bullet needs to be rethought.

At the bottom of Page 4-14, the authors ask for any medical conditions
or medications that make an individual susceptible. I suspect that there
might also be activities (e.g. running near roadways) that make them
susceptible.

On Page 4-15, the authors ask about the extent to which the elderly and
fetuses are more susceptible. This seems to me to beg the question,
which should be about the extent to which they DIFFER in susceptibility
one way or the other. If the authors want to restrict the question to
increased susceptibility, they need to include a justification for this
(perhaps in past literature suggesting increased susceptibility in these
groups).

On Page 5-3, the authors first introduce the idea of using 2.1 % COHb as
an effects threshold. But no justification is given for this. I realize
it is analogous to the approach in Pb exposures, and that the figure of
2.1 % is based on past decisions at the EPA, but this needs to be
explained so the reader has some context for the decision here.

On Page 5-4, it would be good to know why the CO NAAQS review in 1999
was put on hold and never completed.

Some material is missing in the incomplete bullet at the top of Page
5-6.

The final bullet on that page considers the relationship between the 1
and 8 hour exposures. But no explanation is given as to why this is of
interest (I agree it is, but the document should state the reason).

On Page 5-8, it is not clear whether temporal variability will be used
to estimate a rolling average for exposures, or whether the timeline
will be discretized and averages calculated only in the discrete
intervals. These generally give slightly different results with
differing degrees of variability.

On the bottom of Page 5-10, the authors ask whether a given factor
contributes to uncertainty in a way that over-or-under-states the
risk/exposure. But a given factor could be neutral on average, neither
systematically under-or-over-stating the risk/exposure.

On Page 5-11, the authors state that the ideal way to assess uncertainty
due to model formulation is to compare model results against data. No
further clarification of this comment is given. I note first that such
an approach requires assumptions as to the validity of the data,
especially in geographic areas with high degrees of spatial variability.
And I can see how this can be used to assess the quality of one model,
but don't see how it is to be used to compare the degrees of belief in
competing models in characterizing uncertainty due to model formulation.

In that same paragraph, the authors speak of partitioning uncertainty
into model components. Is some form of contribution to variance intended
here? I assume it is, but this is not stated.

Section 6 is too generic to justify any further statements here. It
would be of interest only if the reader were provided a succinct
statement of the policy questions to be addressed and how these are
related to the answers to specific questions asked in the previous
sections.

The Morgan and Henrion 1990 reference appears to be missing from the
References section even though it is called out in the text.

# Dr. Thomas Dahms

Two of the main areas of evidence of health effects of Carbon Monoxide
seem to be 1) on the cardiovascular system in susceptible adults based
both on acute controlled effects (time to onset of angina/ischemia) and
on population studies of infarction rates, arrhythmias etc. and 2) on
the respiratory system as shown by effects in fetuses/infants based on
population studies. It is not clear whether the fetus/infant is
susceptible to cardiovascular effects of Carbon Monoxide. If this effect
requires underlying cardiovascular disease, then the lack of a
cardiovascular effect in infants would be understandable. This issue
should be raised somehow as part of page 4-11 lines 17-20.

The respiratory health effects of CO need to be raised based on recent
evidence rather than the concern identified on page 4-11 lines 7-9.

The absence of any acute effect of CO on the respiratory system in adult
humans and animals was a conclusion of the data in the 1990 AQC document
which was supported by the 2000 AQC document. The question then becomes:
what conditions make the fetal/infant lung more susceptible to carbon
monoxide? (This is obviously the case given the relationship between
atmospheric CO and respiratory deaths). Understanding the potential
predisposing factors in fetal death due to respiratory problems would be
essential in determining risk.

Since many of the other regulated air pollutants have measurable effects
directly on the lungs, the distinct effects of CO alone need to be
carefully assessed. This is especially the case with populations living
and working next to highly traveled roadways where CO is part of the
multi-pollutant mixture.

In addition, one of the consistent findings relates to the
anti-inflammatory effects of both exogenous and endogenous effects of
CO. However, many of the identified respiratory causes of infant death
appear to involve inflammation. It is not clear how to ensure that this
issue is part of the item identified on page 4-11, line 25-28.

***Section 3***

What is not clear to me from an organizational standpoint is how the
issues identified in Section 3 relate to the more specific issues in the
following sections. First, are they supposed be over-arching issues,
i.e., less specific? Also, it appears as though some of these identified
issues in the Draft Plan are asking questions that would require new
research and that the requested endpoints are not clearly linked to the
identified issues. I have commented on these issues. Following past
reviews, summary sessions were held where such issues were identified as
needs for addressing areas of uncertainty.

It is not clear how the writers of the ISA and those of us on the panel
are to deal with multi-pollutant data. Some direction as to its relative
importance should be clearly spelled out in the Plan as some attention
to this issue may provide insight into future use of such data even
though it may not be possible to use this information for this review.

Page 3-1, lines 22-23: The words short- and long-term probably refer to
1-hr and 8-hr exposures (primary standard). However given the newer
population exposure data in fetuses/infants, these terms need to be more
narrowly defined.

Page 3-2, lines 10-12: This issue of alternate dose indicators other
than carboxyhemoglobin (COHb) levels probably requires future research
and therefore should be eliminated from this section. As pointed out by
Dr. Hazucha, this is not an easy task because the current pulse
oximeters would provide erroneous data as they can not account for COHb
or metHb by design. That is the easily obtained non-invasive data would
be incorrect.

Page 3-2, lines 13-14: How is this issue different from the one
presented on page 3-1, lines 22-23? If the issue is different, the
question needs to be restated.

If there is felt to be any evidence that would support a secondary
standard, should this issue be raised directly in section 3? I assume
that this would include effects of exposures beyond 24 hrs and have
public health consequences as is indicated in Section 4 under long-term
exposures.

***Section 4***

Page 4-1, lines 29-30: *"Emphasis will be placed on studies conducted at
or near CO concentrations found in ambient air."* Given the uncertainty
in CO dosimetry and the falling atmospheric levels of CO, should this
statement provide better guidance?

Page 4-2, line 1: Multiple studies have been carried out in the most
sensitive population for CO. This language does not provide the ISA
authors' clear direction.

Literature Search: Will only peer reviewed material be included in the
database? The previous AQC documents in this field have unreferenced
material in them. It is not clear how this material should be used by
the authors of the ISA.

It is not clear how this data base will be made available to the authors
of the ISA. Will articles not referred to by the authors be in this
literature data base? This is implied by the way it is written.

Page 4-5, line 1: This statement implies that if the data is unique that
the paper(s) should be included even though they do meet the other
stringent criteria? It also implies that confirmatory data is of less
importance which is clearly not the case.

Page 4-6, lines 4-10: The toxicology experiments and the health effects
experiments often used exposures that result in relatively rapid
increases in concentrations of COHb. Hardly any of these experimental
exposures would meet the guidelines as written in the draft. Alternate
guidance should be provided.

Page 4-7, line 21: What do current atmospheric levels of CO have to do
with setting levels of acceptable human exposure? It should not matter
if atmospheric levels have decreased, there should remain a level(s)
that should not be exceeded. If atmospheric levels are decreasing, the
issue becomes one of how to alter enforcement not alter criteria
setting. Perhaps I have read too much into this language

Page 4-8, lines 15-19: Given the concern about near roadway exposure,
the following questions should be considered for inclusion. What are the
uncertainties when extrapolating between stationary CO monitoring
instruments and concentrations near roadways? What is the spatial effect
of roadway traffic on stationary CO monitoring?

Page 4-9, line 14: The original CFK model includes endogenously produced
CO in the factors considered for predicting increments in COHb.

Page 4-10, line 26-31: Angina does not occur in healthy individuals even
at maximal exercise. Therefore this question needs to be restated.

Page 4-11, lines 1-6: Delete since it is a repeat of previous question
on page 4-10, lines 26-31.

Page 4-11, lines 7-9: This issue probably requires future research and
therefore should be eliminated from this section. Lung diffusion
capacity is routinely measured using CO. This is potentially an
important issue because if it were true, it would cause a re-evaluation
of basic assumptions regarding oxygen transfer in the lung. However
there does not seem to be any support for this issue in the literature,
prior to 2000 nor since that review.

Page 4-11, lines 23-24: Since there is no guidance for consideration of
multi-pollutant air quality standards, how should this information be
dealt with in the ISA and how are we to consider such data? It is not
clear that the population is ever exposed to CO alone in the
environment. The only data possible seems to be from multi-variant
statistics.

Page 4-14, lines 5-6: I believe that this question is based upon the
presumed mechanism by which CO has its primary effect: through a
relative hypoxemia. This is demonstrated in patients who have coronary
artery disease and have lost the ability to dilate their coronary
arteries to meet increased oxygen demands of the heart that occur during
progressive exercise. However, the decrease in time to onset of angina
or time to ischemic changes in the ECG appears to occur when estimates
of oxygen delivery to the heart predict an adequate supply of oxygen in
the arterial blood. Therefore the mechanism of action of CO in this
susceptible population remains unidentified as does a marker of its
action. So to raise the issue that oxygen saturation which can be
estimated non-invasively might be a surrogate for COHb is based on a
false assumption.

Page 4-14, lines 25-29 through page 4-15, lines 1-3: An important part
of this question should be how does the pathophysiologic changes in this
population alter the normal compensatory responses to low levels of CO
observed in healthy individuals?

# Dr. Russell R. Dickerson

Comments EPA's *Draft Plan for Review of the Primary National Ambient
Air Quality Standard for Carbon Monoxide* for the teleconference on
April 8, 2008.

Three noteworthy topics: The current monitoring program is inadequate
but could easily be improved; CO plays an major role in the budgets of
other criteria pollutants and other environmental problems and thus a
secondary standard warrants serious consideration; the process by which
the scientific judgment of the CASAC and its focus groups is used in
forming policy needs careful consideration - especially in light of the
recent problems with PM2.5 and ozone standards.

On page 4-7, we may be asking the wrong questions. It might be better to
ask "how can current monitoring methods for CO be modified to provide
information adequate to determine CO exposure, statistics of ambient
concentrations, to evaluate models, etc?" CO, even at concentrations
well below the NAAQS, is responsible for a large fraction of the OH
reactivity and thus production of HO~2~, H~2~O~2~, and O~3~ over the US,
but emissions inventories and monitoring methods are inadequate. Direct
investigation of HOx chemistry has quantified the role of CO as
responsible for 10's of percents of the total OH reactivity (e.g., Ren
et al., 2005; Ren et al., 2008). The ratio of emissions of CO/NOx (based
on road-side research grade measurements) has decreased dramatically,
but MOBILE6 CO/NOx emission ratios have not followed this trend - they
are too high now. MOBILE6 indicates a ratio of 15:1 while current
measurements show 5-8 (Bishop and Stedman, 2008; Parrish*,* 2006). In
other words, current CO monitors as employed can not determine the
concentration of CO much of the time, but with relatively minor
modifications, these monitors can be improved such that the detections
limits are essentially always sufficient for ambient CO mixing ratios
*\[Dickerson and Dela*ny, 1988; Parrish et al. 2000). The Maryland Dept.
of the Environment operates one at Piney Run, MD. The manufactures of CO
analyzers have indicated a willingness to improve the instruments for
commercial sales.

The atmospheric chemistry and physics of CO are relatively simple and
well understood, making it enormously useful as a tracer. Improved
monitors would provide data useful to

-   evaluate emissions inventories

-   investigate the epidemiology of CO

-   evaluate chemical transport models (such as CMAQ) for ozone and
    PM2.5

-   determine the impact of CO emissions on the large scale composition
    of the atmosphere and climate.

Although the EPA did not complete the review which started in 1997, a
revised CD was prepared and reviewed. That CO CD recommended changes in
monitoring technique to provide data useful to models. Ambient
concentrations are typically below 300 ppb and commercial CO analyzers
can be easily modified to improve the resolution from 200 to 20 ppb.
While current monitors are adequate to demonstrate compliance with the
NAAQS, ambient concentrations are frequently below detection limits.

Global atmospheric composition, the oxidizing capacity of the
troposphere, and climate forcing should be considered in formulating a
secondary standard for CO to protect public welfare. In addition to its
direct health effects, the environmental effects of CO include:

-   A core precursor to ozone.

-   As a precursor to the oxidants that form PM2.5.

-   An impact on the large-scale composition, and oxidizing capacity of
    the atmosphere.

-   A role in global radiative balance and climate.

I am not clear on the new review procedures, but the comment by Dr.
Henderson "The CASAC is a science advisory body and we cannot give the
EPA our advice if the scientific analyses of the EPA staff are obscured
from us," needs substantial discussion.

**References**

Bishop, G. A., and D. H. Stedman, A Decade of On-road Emissions
Measurements, *Environ Sci. Technol*., 2008.

Dickerson, R. R., and A. C. Delany (1988), Modification of a commercial
gas filter correlation

CO detector for enhanced sensitivity, *J. Atmos. Ocean Technol.*, *5*,
424-431.

Parrish*,* D.D., Critical evaluation of US on-road vehicle emission
inventories, *Atmospheric*

*Environment,* 40, 2288-2300, 2006.

Parrish, D.D., and F. C. Fehsenfeld, Methods for gas-phase measurements
of ozone, ozone

precursors, and aerosol precursors, *Atmospheric Environment*, 34,
1921-1957, 2000.

Ren, X.R., et al., Hydroxyl and Peroxy Radical Chemistry in a Rural Area
of Central

Pennsylvania: Observations and Model Comparisons, *J. Atmos. Chem*.,
2005.

Ren, X.R., et al., HOx chemistry during INTEX-A 2004: Observation, model
calculation, and

comparison with previous studies, *J. Geophys. Res.,* 2008.

# Dr. Milan Hazucha

The Plan for Review (Plan) is structured around a series of critical
activities/tasks clustered into four key components that have to be
accomplished in developing the ISA and Annexes for CO. Generally, the
ISA and supporting Annex documents approach has been successfully used
in the development of recent NAAQS documents. The Plan review schedule
as proposed is reasonable.

One of the changes from the previous approaches to NAAQS reviews is the
proposed elimination of a staff paper. The staff paper served as a
compendium, identifying supporting evidence and providing rationale for
decision making. It was an extended summary of the ISA, generally
incorporating answers to questions raised in a review plan. In the
absence of staff paper the ISA should include a Chapter where each of
the questions raised in the Plan will be briefly, in a couple of
sentences or a short paragraph, answered. This will help to quickly
identify the areas which may have not been addressed or overlooked as
well as identify the gaps in the current scientific knowledge and
database(s).

Apart from eliminating the staff paper, I think that only minor
adjustments, most likely specific in nature, will be required to the
proposed Plan. My suggestions for changes/modifications in Chapters 3
and 4 are listed below.

Page 3-2: One of the issues that should be considered in this section is
the interaction between high altitude and CO. Both result in hypoxia,
however, CO at altitude may have additional detrimental effects.
Moreover, idle emissions are supposedly much higher at altitude which
may increase exposure load. Consequently, health risk may be greater.

Page 3-2, line 1-2: After "near-roadway" insert the words "and hot-spots
such as bus stops, city-intersections, etc,". These are the places where
ambient CO concentration may transiently reach high levels exposing
substantial population including individuals with compromised health.

Page 3-2, line 10-12: Percent of oxygen saturation as typically measured
would be a misleading indicator of CO exposure. Great majority of O2
saturation measurements are done by pulse oximeters that are known to be
unreliable for COHb estimation. Only when O2 saturation is determined by
specialized blood gas instruments the COHb level can be reasonably
approximated. But, in such setting, one may as well measure COHb level
directly by CO-oximeter.

Page 4-4, line 5: Include ISI Web of Knowledge database in the search
list. Of all mentioned databases, ISI is the most comprehensive database
and includes publications not found in other databases.

Page 4-4, line 19: Delete "pertinent". We do not know yet how pertinent
those studies are. All potentially pertinent studies will have to be
assessed first using study selection criteria listed in subsequent
section.

Page 4-4: Will EPA consider potentially pertinent studies published in a
foreign language? Will they be translated by EPA if they satisfy
selection criteria?

Page 4-5 line 4: List of conditions should be expanded to add
"Sufficient statistical power". Surprisingly high number of studies is
statistically deficient. Particularly the lack of statistical power is a
frequent deficiency of published studies. This criterion should be
specifically stated in the criteria list.

Page 4-5, line 9: The cons and pros of potentially pertinent studies,
i.e. design strength or deficiencies, poor statistics, etc., should be
discussed in respective Annexes. Studies that did not pass the muster
should still be discussed. Insert after the word "issues" following the
text "fully discussed in Annexes".

Page 4-5. Change the subtitle to read "Criteria for Selecting Field and
Epidemiological Studies." The design of field studies is different and
some selection criteria may differ as well.

Page 4-5, line 24-27: The argument for more detailed discussion of US
and Canadian studies is a concern "the potential impact of differing
health care systems" or other geographic regions may have on the
assessment. Well, Canada has substantially different health care system.
Suggest changing the sentence to read: "Certain findings of the studies
conducted in the U.S. may generally be discussed \...\....".

Page 4-6, line 4: Change subtitle to "Criteria for Selecting Human
Laboratory, Clinical and Animal Toxicological Studies." Each type of
studies should have its own criteria, particularly animal toxicological
studies.

Page 4-6, 2^nd^ para: There is no discussion about the selection
criteria for animal studies. Many animal toxicological studies may not
be relevant because of very high CO concentration used, exposure
duration, extrapolation difficulties, or other experimental conditions.

Page 4-6, line 8-10: It is highly unlikely that any of the mechanisms
can be elucidated under atmospherically relevant conditions, which
should be defined. Studies of mechanisms require more severe exposure
conditions so that the mechanisms are easier to identify and study. The
sentence should be reworded.

Page 4-7, l. 24: Insert "and temporal " between the words spatial and
variability. Both temporal and spatial variability will influence
averaging time.

Page 4-8: One of the questions that should be included in this section
is: "What is the effect of averaging time and methodology on health risk
assessment?" Peak ambient CO concentrations in hot-spot areas are
blunted by the current averaging method. But it is the peak CO
concentrations that will increase the health risk to individuals. It
would be desirable to weigh the peak or hourly peak concentrations when
calculating averages.

Page 4-9, line14-15: The models estimating COHb should be capable of
including endogenously produced CO as a variable endpoint and not a
constant. Several diseases, such as asthma or COPD, or transient airway
inflammation are known to increase production of endogenous CO to the
level that may exceed ambient concentration of CO.

Page 4-10, line 28: Reword. The time to onset of angina is not an
endpoint for healthy individuals.

Page 4-11, lines 1-6: This aim is identical to the preceding one on
p.10, line26-31. Delete.

Page 4-11, line 7-9: The effects of CO on respiratory gas exchange have
been studied extensively in the past. At ambient CO concentrations these
effects are of no clinical relevance even in at-risk population. A
simple statement to this fact should be sufficient.

Page 4-13, line 10: Change to read "\... human laboratory, clinical and
toxicological\..." The evaluation should include human laboratory and
relevant clinical studies as well.

Page 4-15, line 28-29: The first goal should be "to comprehensively and
critically review the literature and subsequently identify\...\...." as
stated on p.1-2, line 11-13. I also suggest adding a Chapter at the end
of the ISA discussing commonalities and differences, if any, of key
factors and studies that have led to and determined the current WHO, EU
and the NAAQS for CO.

# Dr. Rogene Henderson

Comments on Section 6. Policy Assessment/Rulemaking of the US EPA Draft
Plan for Review of the Primary NAAQS for Carbon Monoxide.

In a letter to the Administrator dated January 23, 2008, the CASAC
expressed their opposition to the use of an ANPR as a Policy Assessment
document at the end of the NAAQS review process and that opposition
still exists. As pointed out in that letter, the ANPR is a document that
belongs at the beginning of the review process, not at the end, because
the ANPR (Advance Notice of Proposed Rulemaking) is meant to describe
every possible choice that might be considered.

In a memo from Assistant Administrator Marcus Peacock of December 7,
2006, the ANPR/Policy Assessment Document was described as containing
essentially the analyses that had been in the former staff paper plus
modifications related to EPA management concerns. The ANPR that was
presented to CASAC at the end of the lead review process was NOT such a
document, but was the standard ANPR with all options described but with
no scientific justification for the options. It is **not acceptable** to
CASAC to remove from the review process the scientific analyses of the
data that was formerly provided in the Staff Paper and substitute an
ANPR that provides little or no scientific justifications.

The CASAC is a science advisory body and we cannot give the EPA our
advice if the scientific analyses of the EPA staff is obscured from us.

# Dr. Donna Kenski

This draft plan puts forward a logical framework for the coming review
of the CO NAAQS. It is very similar to the plans for NOx and SOx and,
because the work hasn't been done yet, it's hard to find any serious
flaws. I have two general comments. First, a potentially significant
problem with respect to ambient CO data in both the ISA and subsequent
risk assessment. Past efforts to control CO have been remarkably
successful and thus ambient concentrations are very low \-- as with NOx
and SOx, well below the NAAQS almost everywhere. Consequently many
monitors have been removed from state networks, since there is little
incentive for states to bear the cost of running monitors in areas where
there is no reasonable expectation of nonattainment. Where monitors
remain, concentrations are frequently at or below the detection limit.
With few monitors and a significant fraction of data below the detection
limit, the adequacy of the ambient data for assessing population
exposure and risk is severely limited. It would be helpful to have EPA
discuss these limitations and their expected impact on the exposure and
risk assessment in particular.

Second, as we discovered in the review of the lead NAAQS, the use of the
ANPR as a tool to present EPA's policy assessment was not successful in
communicating EPA's views on NAAQS revision. I saw no indication in this
document that the process had been changed to incorporate CASAC's
concerns. Perhaps it is too early and EPA is still contemplating how to
use the ANPR more appropriately as a policy assessment vehicle? In any
case, I look forward to an ANPR that makes genuine assessments of the
science and presents rational policy options for consideration.

p\. 5-6 is missing text at the top.

# Dr. Michael T. Kleinman

**[Section 3]{.underline}**

A policy relevant issue that is not explicitly addressed is the
non-uniformity of CO exposures in various environments. This has a
profound effect on the adequacy of our ability to judge health effects
as a function of high local exposures, i.e. near heavily trafficked
roads. Monitoring plans for CO should take this into account. Perhaps
this could be folded into the question*: "What do recent studies focused
on the near-roadway environment tell us about high-exposure
subpopulations and the health effects of CO?"*

Alternatively, it might be advisable to raise the issue of whether the
current network of air sampling monitors adequately represents
population exposures to CO as an explicit charge question.

**[Section 4]{.underline}**

4.1 SCOPE AND ORGANIZATION

Vis-à-vis the issue stated above, if "emphasis will be placed on studies
conducted at or near CO concentrations found in ambient air." Some
guidance should be provided with respect to ranges of exposures measured
near areas of unusually high concentration that are not always
represented by the placement of monitors for other criteria pollutants.

4.2 ASSESSMENT APPROACH

[Literature Search]{.underline}

The suggested search terms are rather limited. An important aspect of
the current literature relates to long-term sequelae which include
neurological as well as cardiovascular endpoints. While this may be
subsumed in the guidance to look at specific health outcomes, it might
be useful to state this explicitly. It might be useful to specifically
include terms related to the possible effects of co-pollutants both from
the effects standpoint and from the mechanistic area (i.e. pollutants
that induce inflammatory effects could up regulate HO-1 activity which
would increase endogenous CO production).

[General Criteria for Study Selection]{.underline}

The criteria are well thought out. In keeping with my previous comments
I suggest that we discuss the following criterion: "*To what extent are
the aerometric data, exposure, or dose metrics of adequate quality and
sufficiently representative to serve as indicators of exposure to
ambient CO?"*

This should be placed into a context of the exposure range for
populations with exceptional exposures since this criteria might be
interpreted to exclude some studies near CO sources that use measured
values that are in excess of those seen at central site monitoring
stations.

[Criteria for Selecting Animal and Human Toxicological
Studies]{.underline}

*"Criteria for the selection of research evaluating animal toxicological
or controlled*

*exposure studies will focus primarily on those studies conducted within
about an order of magnitude of ambient CO concentrations and those
studies that approximate expected human exposure conditions in terms of
concentration and duration."*

There are seasonal and site-specific factors that contribute to the
non-homogeneity of CO exposures. The order of magnitude requirement may
be too restrictive.

Many toxicological studies are limited with respect to exposure
durations and amounts of time subjects can be kept in the experimental
setting. Perhaps criteria should assess whether the study was performed
to assess subjects with reasonable levels of some biomarker even when
the exposure concentrations are greater than ambient rather than putting
too tight limitations on the acceptable concentration ranges.

One important factor that should be considered for assessing the
acceptability of human toxicological studies is whether the study was
appropriately blinded.

**[Section 5]{.underline}**

Page 5-5, line29: incomplete sentence

Page 5-6, line17: This area should be expanded to include issues related
to inhomogeneity of exposures. A key question is "What is the
relationship between peak 1 and 8 hr levels near roads and other
hotspots vs. levels measured near central sites?"

Page 5-7, line19: The manner in which the health, risk and exposure
assessments will deal with the issue of non-homogeneous concentrations
should be more clearly described and considered. This is a cross-cutting
problem that brings into play considerations of environmental justice as
well as the critical distinction between "compliance" monitoring and
monitoring for the purpose of providing the information needed to assess
the adequacy of health protection afforded by the NAAQS.

# Dr. Arthur Penn

Page 1-3, lines 7-8: Why was the staff paper omitted? By putting the
information into the Federal Register notice (not the most "reader
friendly" of document formats) rather than providing the historical
perspective within the IP could essentially make it more difficult,
especially for members of the general public, to find important, clearly
presented information?

Page 3-1, line 29: Are there sufficient data available from fetal
monitoring to allow assessment of fetal sensitivity?

Page 4-2, line 14: Please define "welfare effects". What else does this
describe besides "ecosystem effects"?

Page 4-4, line 27: "sufficiently representative"\--of CO levels?

Page 4-4, line 30: "meaningful and reliable". "Meaningful" is vague. Is
this independent of "statistically significant"? What are the specific
criteria that determine "reliability"?

Page 4-6, lines 8-10: Should studies that elucidate mechanisms be a
major part of the data to be analyzed? This seems like a major goal of a
possibly related, but distinct set of analyses.

Page 4-8, lines 12-13 (also see Page 4-13, lines 12-14): Interactions
between CO and these other factors will likely be very important. A
large amount of data from diverse sources will have to be examined and
analyzed. Who will do this?

Page 4-11, line 18: "Other systems"\--genito-urinary? digestive?
endocrine? By what criteria would any of these, or other systems, be
selected?

Page 4-15, lines 5-6: "Older adults and fetuses". No neonates? How are
effects on fetuses assessed?

Page 5-2, line 6: "Four scenarios"-Is there a summary of these scenarios
available so that people, especially members of the public, do not have
to find and wade through the 1992 document?

Page 5-2, line 6: Why was the CO NAAQS review put on hold? Why, 9 years
later, has the exposure analysis not been completed? Has there been a
public inquiry about this and a formal response?

Page 5-6, lines 1-4: Is there a missing paragraph, or is this just a
spacing error?

Page 5-11, lines 3-17: During the teleconference, a couple of the
discussants noted that the distribution of CO monitors was uneven and
that the monitors might be completely absent from certain communities
within a large monitoring zone. It was also noted that "the emissions
history was a disaster" and that in general, ambient CO measurements
were inadequate. Other committee members supported these comments. Given
these concerns, how reliable are the primary sources of the data (see
lines 4-5) that will be included in the APEX model inputs?

Page 5-11, line 14: The specific reference to Morgan &Henrion, 1990, was
not included in pages 7-1 or 7-2 in the draft plan. There are multiple
publications listed for them in 1990.

# Dr. Beate Ritz

Chapter 4:

page 4-4 \"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 provide overall estimates for effects
based on combined analyses of information pooled across multiple cities;
\"

The emphasis on pooled results from multi-city studies that use
standardized methods might be misplaced i.e. it is not clear that such
approaches will be informative. The problem with CO is its
intra-community heterogeneity due to local sources, heterogeneity may
not be reflected in ambient monitoring station measurement data.
Depending on how ambient monitoring is used to derive exposure estimates
in different communities, this could lead to differences in measurement
errors depending on how dense the network is. Concerning standardized
exposure modeling approaches, if different sources contribute to high CO
in different cities, a \'standardized model\' for different cities might
not work or be appropriate e.g. in some cities CO may depend more on
vehicular traffic and in others on power plant emissions etc.

Similarly questionable is the emphasis on \"studies that consider CO as
a component of a complex mixture of air pollutants.\" It is unclear
whether this means only multi-pollutant models will be taken into
consideration and how the expected (and possibly strong) correlational
pattern with particles and NO2 will be dealt with in such models. It
might be impossible to adjust for (highly) correlated pollutants in the
model, and it is not clear how this may be addressed and/or evaluated in
the report.

Furthermore, it is unclear what the emphasis on \"new studies that
provide quantitative effect estimates for populations of interest\"
means. For pregnancy outcomes, the issue of scaling according to a
(susceptible) time period is essential and it is not clear that 1ppm
exposure on average during a trimester is comparable to a 1ppm average
exposure during a month or week of pregnancy.

Chapter 5, page 5-4

\"For this current review, EPA staff will build upon the 1999 work and
subsequent improvements to the exposure model (now called APEX) in
developing its plan for CO exposure assessment. \" It is unclear what
this work will be i.e. what kind of data will be used to develop these
models and whether the data already exist and/or will be retrieved from
existing research (e.g. the LA RIOPA study that monitored CO).

Given that the highest CO exposures might occur inside cars during
commute, it is unclear how this will be integrated into the [stated
goals]{.underline} for CO exposure assessment (page 5-5), even though
the Apex model uses in-vehicle microenvironments and this is also
mentioned on page 5-10.

# Dr. Paul T. Roberts

Note that this document outlines a plan for the several year review
process for the CO NAAQS and thus includes little or no technical
detail. In general, this plan is well-written, is adequate to meet its
objectives, and (presumably) matches the review process currently
ongoing for sulfur dioxide and nitrogen oxides, which are both further
along than the process for CO. Overall, I am concerned about the
elimination of the EPA staff paper from the process, since I am not sure
how the summary and integrative aspects of the staff paper will be
handled in the new process (within the ISA and the Scope and Methods
Plan). Maybe this should be addressed directly in the "Plan".

In Section 1.3, I think that there should be some discussion of why the
previous 1997-2000 CO NAAQS review process was not completed (see page
1-6, lines 23-24).

Table 2-1 seems to have a duplicate listing for the first draft of the
risk and/or exposure assessments in January 2010 (see 3^rd^ and last
entry under Risk/Exposure Assessment in the table).

Specific comments on Sections 4 and 5:

-   The introduction to Section 4 mentions that a formal framework for
    the integration of health effects evidence was developed in the NOx
    ISA (see page 4-1, lines 13-16); I think this should be summarized
    here in the draft plan.

-   As far as I can tell, the WHO guidelines referenced on page 5-5,
    lines 3-4 do not include CO; information on CO was not updated from
    the earlier WHO Air Quality Guidelines for Europe, 2^nd^ edition
    published 2000.

-   I do think that a comparison and explanation of the different
    standards (and studies supporting them) published by WHO and others
    for CO should be discussed in summary form in this plan and in more
    detail in the ISA and/or the Scope and Methods Plan. This
    specifically could help on the short-term issues discussed on pages
    4-10 to 4-12 etc., since short-term standards is one major area of
    difference.

-   Text is missing from the bullet that begins on page 5-5 and
    continues onto the top of page 5-6.

-   There are several potential CO ambient exposure environments which
    are not mentioned in this document, but should be mentioned here and
    information for them explored during the development of the ISA and
    the Scope and Methods Plan. Existing study data may be useful for
    determining levels and averaging times, as well as relevant to
    future exposure environments. These ambient exposure environments
    include other near-source environments such as near ship loading and
    unloading ports (potential exposure from trucks and other vehicles
    plus potential exposure from the ships themselves) and exposures
    near recreational boats. Both of these environments cover locations
    where people live, work, and play. Recreational boat engines,
    including both 2-stroke and 4-stroke engines, do not have exhaust
    controls and several potential environments can result in very high
    CO concentrations in the near-source environment. Even with coming
    emissions controls on new boats, fleet turnover is extremely slow
    and such exposures will likely persist for 10-20 years. Places in
    the draft plan where these additional environments might be
    mentioned include: page 3-2, lines 1-2; page 4-8, lines 3 and 28-29;
    page 4-10 subsection on short-term exposure; and page 5-3, lines
    23-26.

-   There should be some discussion of the types of CO monitoring sites
    and how data from all types of sites will be used to characterize CO
    air quality and exposures (specifically mentioned in Section 5.3,
    pages 5-5 to 5-7). In particular, there are official CO monitoring
    sites, "hot-spot" sites, and data from special purpose monitoring
    sites which all might inform the analysis being undertaken. This
    section of the plan should discuss these additional data sets and
    how they might be used to further the objectives of the exposure
    assessment (note that this is also of importance for the discussions
    on pages 4-7 and 4-8 regarding spatial and temporal analyses). In
    addition, the appropriateness of current monitoring sites, relative
    to their purposes, should be discussed in the ISA and/or the Scope
    and Methods Plan. Also, existing sites should be evaluated in some
    consistent manner in order to ensure that the CO data being
    collected is appropriate for the stated purposes, both for the
    current review and for future uses relative to the NAAQS.

-   Based on discussions I heard on the April 8^th^ call, I was
    wondering how the binding time of COHb might be related to potential
    averaging time of the CO data? In particular, might the COHb binding
    time lead to a short-term standard that has otherwise been ignored?

-   In addition to these comments, I support the following comments by
    others on the Panel:

    -   Interest in having a short discussion of why the secondary CO
        standard was revoked in 1985.

    -   The need for the Draft Plan to specifically address the issue
        whether the existing monitoring methods and network are adequate
        to address the questions outlined in Section 3.

    -   Potential upgrading of present CO monitors to high-sensitivity
        monitors, which have been tested and evaluated by OAQPS staff in
        the recent past.

    -   The notion that CO characteristics might be different in
        different cities, especially as it relates to 'hot spots', thus
        requiring different types of data analysis approaches and
        methods.

    -   The concern that co-pollutants might also have an affect on the
        impact of CO concentrations on health.

    -   How will the CO ANPR show the results of the assessment of the
        full range of potential science and policy questions which will
        have been address by that time?

# Dr. Armistead Russell

Similar to past draft plans provided to CASAC, this draft plan lays out
a well thought out approach to reviewing the CO NAAQS. I was pleased to
see that they plan to organize the CO ISA similar to that for the NOx
and SOx primary NAAQS, which I found to be a very good approach. In
particular, what I liked about the NOx and SOx primary NAAQS ISA's was
having an initial chapter going from source to dose, then the future
chapters dealing with health endpoints, with a conclusion/summary
chapter at the end. (However, the bullet points do not follow this
order.) This worked well, and communicated the needed information in a
more integrated and briefer fashion. In so doing, however, EPA staff
should continue to provide the information necessary to review the
science that is most pertinent to reviewing the various aspects of the
NAAQS.

In regards to the atmospheric dynamics of CO, and the distribution of
the primary sources (automobile exhaust), CO is somewhat unique compared
to the other criteria pollutants. It is chemically reactive, both being
destroyed and formed in the atmosphere. CO exposures of most concern are
from primary emission, with the highest levels being near the source,
and dropping off rapidly as one moves away, though policy relevant
background (PRB) levels are from secondary formation. Thus, the type of
model used to estimate PRB CO levels is very different from the type
that would be used to estimate exposures. Indeed, as suggested in the
Draft Plan, PRB levels will appropriately be estimated using chemical
transport models. On the other hand, the model(s) used to help estimate
exposures may be quite different, e.g., dispersion models. This is not
well spelled out in the Draft Plan. What type of dispersion models, or
chemical transport models, should be more thoroughly discussed and
assessed. Indeed, one of the driving questions down the road as to the
exposure assessment may be the modeling approach. A further question
will be how to evaluate the model, particularly if a case study (or
studies) is used for which such an evaluation is not done. This is going
to be particularly important as one of the possible susceptible
populations is rather unique in regards to how air quality models have
been employed when estimating exposures, as discussed below. The Draft
Plan refers to consideration being made for confounding. The
Source-to-Dose chapter (and associated Annex) will need to address this
is detail. It will be critical.

The Draft Plan identifies APEX as the likely model to be used for
conducting the exposure modeling. This is a reasonable choice. It should
be noted, again, that the continued use of APEX in NAAQS assessments
should continue to motivate EPA to further enhance and evaluate APEX,
and that evaluation should consider subpopulations of interest. In this
case, what I think is a rather new and unique subpopulation is the
target, that being pregnant women. What population specific information
exists for APEX to use for this target, and when insufficient
information is not available, how is EPA going to modify APEX for this
group? Further, how are they going to integrate results from the air
quality modeling for use in APEX? On page 5-6, it notes that they will
include various types of exposures... how, in a probabilistic framework,
will you consider pregnancy in the matrix.

I would have liked to see more information on the planned use of case
studies. This has been a critical issue in past reviews. This Draft
discussed the Denver case study, and mentions a Los Angeles study. Both
would be of interest, still, along with, possibly, an Alaskan city
(Fairbanks or Anchorage). Los Angeles would provide an interesting
contrast to Denver due to the different magnitude in the variation
between seasons and temporal distributions, and, possibly, the
population distributions. This might be of particular interest if the
exposure period of interest is long... multi-day/week/month (e.g., for
fetal exposures). Alaskan cities might be extreme in the other
direction, and also may have the most extreme short term exposures.
Perhaps the analyses discussed on pages 5-5 to 5-6 (that is missing on
mine) covers this.

Other minor issues:

Pages 4-7 to 4-8 There seems to be an over-reliance on chemical
transport models verses dispersion models or other micro-scale modeling
approaches. There should be a fairly major section on various modeling
approaches for estimating CO concentrations and how they can be used to
assess exposure and dose.

Page 4-8, line 23: Pet peeve (though I make this mistake as well):
"particle" is not a phase, "condensed" can be used.

Page 4-9, line 7: This bullet asks a simple question, though the real
question is how does one evaluate the models being employed, and how
does one interpret those results.

Page 4-9: A similar bullet point for exposure models as above.

Page 5-6: You may want to consider what other procedures one might use
to rollback levels as part of an uncertainty assessment. Further, you
note on page 5-6 about assessing exposures for levels just meeting the
standard... that means you also have to rollup levels, too. The methods
should be consistent. Also, given that the methods likely used to reduce
CO emissions may rely on automotive standards, consideration as to how
exposure reductions are linked between cities may be appropriate.

Page 5-6: You note that you will evaluate the relationships between 1-
and 8-hour peaks... you should look to other averaging times.

Pages 5-5 to 5-7: Something is missing. (Maybe this is where other case
studies are identified.)

Summary: The Draft Plan provides a suitable map for going forward,
though given the introduction of a rather unique susceptible population
not treated previously (fetus's) and exposure route (pregnant women) how
exposure and dose will be linked to ambient concentrations and forms of
the standard requires greater discussion and detail as to how this will
be accomplished.

# Dr. Jonathan M. Samet

[General Comments:]{.underline}

-   This *Draft Plan* follows the model that is now coming into place
    for developing a primary National Ambient Air Quality Standard
    (NAAQS). As such, the plan draws on approaches taken already over
    the last several years. The overall plan and approach is
    appropriate.

-   However, the new plan appears to draw little on "lessons learned" to
    date from dealing with nitrogen oxides and sulfur oxides. The plan
    suffers from an overall lack of specificity and vagueness of wording
    that will undoubtedly become a limitation during its implementation.
    Additionally, there has been little advance in the EPA's formulation
    of such critical concepts as causality, confounding, effect
    modification, and susceptibility. On reading over the questions that
    will guide the review, problems arising from this vagueness are
    abundant. I highlight a number of examples in my specific comments.

**[Specific Comments:]{.underline}**

+------+-----+--------------------------------------------------------+
| **   | **L | **Comment**                                            |
| Page | ine |                                                        |
| \#** | \   |                                                        |
|      | #** |                                                        |
+======+=====+========================================================+
| 4-4  | 27  | "\...sufficiently representative" Of what?             |
|      |     | Representative in what regard?                         |
+------+-----+--------------------------------------------------------+
| 4-4  | 29  | Not clear at all                                       |
+------+-----+--------------------------------------------------------+
| 4-4  | 30  | "meaningful" From what perspective? Reliable means     |
|      |     | repeatable. Is the concern about misclassification?    |
+------+-----+--------------------------------------------------------+
| 4-5  | 5   | "potential confounders..." Specify criteria for these  |
+------+-----+--------------------------------------------------------+
| 4-8  | 20  | This needs greater specificity                         |
+------+-----+--------------------------------------------------------+
| 4-8  | 24  | Temporal and spatial?                                  |
+------+-----+--------------------------------------------------------+
| 4-9  | 19  | What does variability mean here?                       |
+------+-----+--------------------------------------------------------+
| 4-10 | 7   | Lines 7-10 are sweeping. What is this saying?          |
|      | -10 |                                                        |
+------+-----+--------------------------------------------------------+
| 4-11 | 18  | All other systems?                                     |
+------+-----+--------------------------------------------------------+
| 4-11 | 23  | "...nature of health effects..." Effect modification?  |
+------+-----+--------------------------------------------------------+
| 4-12 | 20  | What is meant by evidence [against]{.underline} a      |
|      | -22 | causal association? Could more be said about EPA's     |
| 4-13 |     | approach to causal inference?                          |
|      | 1-2 |                                                        |
+------+-----+--------------------------------------------------------+
| 4-13 | 9   | "evaluate uncertainty..." Any attempt to quantify?     |
+------+-----+--------------------------------------------------------+
| 4-13 | 17  | What does this mean? Is this in reference to potential |
|      | -19 | effect modification?                                   |
+------+-----+--------------------------------------------------------+
| 4-15 | 6   | Reference to fetuses not clear.                        |
+------+-----+--------------------------------------------------------+
| 4-15 | 10  | What results?                                          |
+------+-----+--------------------------------------------------------+
| 4-15 | 19  | Not clear in the formulation of attributable risk      |
|      | -21 |                                                        |
+------+-----+--------------------------------------------------------+

# Dr. Stephen R. Thom

**Approach & format for the integrated science assessment section are
well organized and logical.**

**Specific comments I suggest be included in the EPA document are:**

**A. Human exposure studies**: Environmental pollution causes a variety
of disorders, although not all studies have documented CO *per se* as
the etiologic agent.

1\. Neonates/infants:

a\) Preterm labor/delivery - association with environmental CO and also
particulates (PM) (as separate risk factors & also in combination)

b\) Infant mortality - association with CO plus PM

c\) Neonate hospitalizations for respiratory diseases - association with
CO

d\) Intra-uterine growth retardation/low birth weight (risks with CO, PM
and NO~2~)

e\) No relation between SIDS and CO, but a link has been established
with NO~2~ and SO~2~

2\. Children

a\) Childhood respiratory symptoms (wheezing) - association with CO and
also PM.

3\. Adults

a\) Correlations between ambient CO and ischemic heart disease ED visits
(CO and also NO~2~)

b\) Cardiovascular mortality (esp. elderly) - associations with CO and
CO/PM & O~3~

c\) Respiratory-related ED visits - association with CO and CO+O~3~

d\) Depression-related ED visits

e\) Pneumonia hospitalizations (CO + O~3~)

f\) No link between CO and tachyarrhythmias (but + link with ultra-fine
particulates)

g\) Risk of CVA elevated with CO, PM, NO~x~

h\) Cardiac irregularity (HR variability) and CO (+ link in some but not
all trials)

i\) Plasma markers of inflammation - atmospheric CO contamination only
linked with altered albumin. PM and O~3~ showed additional changes in
plasma levels of vWF, Factor VIII, fibrinogen. Higher CO concentrations
(& shorter exposure times) linked to elevated plasma myeloperoxidase.

**B. Issues of CO dose-response, as well as time-course of responses,
are not clear.** The weight of the scientific findings probably does not
warrant an alteration in EPA CO guidelines (1 hr 35 ppm; 8 hr 9 ppm).
Also, the variability among findings in some trials indicates that
combinations of CO with co-pollutants can yield disparate results,
leaving the issue of pathophysiological mechanisms unclear.

**C. Dosimetry questions persist**, and there needs to be some focus on
mechanisms unrelated to CO-O~2~ competition for hemoproteins (e.g. the
CFK equation alone is not adequate to 'predict' biological stresses).
These include pro-inflammatory processes such as intravascular
platelet-neutrophil interactions, and a growing body of information on
oxidative stress/free radical mediated mechanisms (some linked to
'therapeutic' pathways such as activation of MAPKs, NFκB inactivation,
caspase 8 inactivation). Endogenous CO production impacts mitochondrial
respiration but whether environmental CO will compound this effect is
unknown (current kinetic modeling suggests this is unlikely).