UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

 WASHINGTON D.C. 20460 

 OFFICE OF THE ADMINISTRATOR 

 SCIENCE ADVISORY BOARD

January 20, 2010

EPA-CASAC-10-005 

The Honorable Lisa P. Jackson 

Administrator 

U.S. Environmental Protection Agency 

1200 Pennsylvania Avenue, N.W. 

Washington, D.C. 20460 

Subject: Review of Integrated Science Assessment for Carbon Monoxide (Second 

External Review Draft)

Dear Administrator Jackson: 

The Clean Air Scientific Advisory Committee (CASAC) Carbon Monoxide (CO) Review 

Panel met on November 16-17, 2009 to review EPA’s Integrated Science Assessment (ISA) for 

Carbon Monoxide (Second External Review Draft, September 2009). The Panel’s report was 

reviewed and approved by the chartered CASAC on a December 22, 2009 public teleconference. 

This letter begins with CASAC’s overall comments and evaluation. We highlight the most 

important issues which need to be addressed as the ISA is finalized. The Panel and CASAC 

membership is listed in Enclosure A. The Panel’s consensus responses to the Agency’s charge 

questions are presented in Enclosure B. Finally, Enclosure C is a compilation of individual panel 

member comments. 

We appreciate the responsiveness of EPA staff to our previous comments. The issues 

that we targeted as important in our previous review were addressed. Both the revised 

document, as well as statements by staff in response to our comments at the meeting, was 

responsive to our concerns. CASAC commends the EPA staff for the development of a 

comprehensive and readable second draft of the Integrated Science Assessment for Carbon 

Monoxide. The document integrates relevant evidence from the past decades while emphasizing 

newer evidence and a deeper understanding of mechanisms by which CO affects health. The 

extensive literature on CO is thoughtfully summarized and presented effectively in tables and 

appendices. 
We are comfortable with the process used by the EPA to produce this document. The 

EPA has implemented a process that is consistent with current approaches to evidence review 

and synthesis. It has progressively refined this process in recent NAAQS reviews. The process, 

which is being applied across the criteria pollutants, will enhance the quality and transparency of 

CASAC’s reviews. 

Some additional major comments follow: 

• CASAC previously noted that the terms “sensitive, susceptible, and vulnerable” are 

sometimes used interchangeably in EPA’s various review documents. We reiterate the 

need for these terms to be used in a consistent manner. We recommend that the EPA 

develop a glossary of terms to be used across documents related to all criteria 

pollutants. Such a glossary would promote consistency in the ISAs and REAs. The 

definitions presented in the recently released final ISA for PM (December 2009, 

EPA/600/R-08/139F) may address some of CASAC’s concerns. 

• The Panel expresses concern about the existing CO monitoring network, both for its 

spatial coverage and for its utility in estimating human exposure. CO exposures may 

not be adequately characterized for populations that may be exposed to higher CO 

levels because of where they live and work. Moreover, because CO levels are often 

below the limit of detection of current monitors, both exposure assessment and model 

calculations may be limited. The Panel recommends that monitoring for CO should be 

improved. 

• The Panel approves the broadening of the evidence base considered in the ISA. For 

example, the discussion of CO in relation to atmospheric chemistry and climate change 

is useful. Although such considerations do not drive the current standard, it is 

important to acknowledge climate change. While we agree that this topic merits 

discussion, the influence of climate change on a secondary standard is minimal because 

of the high level of uncertainty at present. 

• Although EPA regulations for most pollutants are weighted heavily by information 

provided from epidemiologic studies, in the case of CO, information from welldesigned clinical exposure studies has received emphasis. We agree with the weight 

that they are given in the current document. 

• The problem of co-pollutants serving as potential confounders is particularly 

problematic for CO. Since exposure levels for CO are now low, consideration needs to 

be given to the possibility that in some situations CO may be a surrogate for exposure 

to a mix of pollutants generated by fossil fuel combustion. A better understanding of 

the possible role of co-pollutants is relevant to regulation and to the design, analysis, 

and interpretation of epidemiologic studies on the health effects of CO. 

2
• Some of the challenges in interpreting and reviewing the evidence on CO in the ISA 

(and Risk and Exposure Assessment) reflect the great progress in reducing ambient 

concentrations of CO. Control measures taken over the past decades have led to greatly 

reduced emissions and concentrations. Notable progress has been made in reducing 

exposure of the public to CO. CASAC notes that the ISA documents a substantial 

decline in CO levels in urban areas over the past two decades, which has undoubtedly 

benefited public health. 

CASAC agrees that the Draft CO ISA will be adequate for rulemaking with the 

incorporation of changes in response to the Panel’s major comments and recommendations. 

We thank the Agency for the opportunity to provide advice on the Draft CO ISA. 

Sincerely, 

 /Signed/ /Signed/ 

Dr. Joseph D. Brain, Chair Dr. Jonathan M. Samet, Chair 

Clean Air Scientific Advisory Committee Clean Air Scientific Advisory Committee 

 Carbon Monoxide Review Panel 

Enclosures 

3
Enclosure A 

Rosters of the CASAC CO Panel and CASAC 

U.S. Environmental Protection Agency 

Clean Air Scientific Advisory Committee Carbon Monoxide Review Panel 

CHAIR 

Dr. Joseph Brain, Cecil K. and Philip Drinker Professor of Environmental Physiology, 

Department of Environmental Health, Harvard School of Public Health, Harvard University, 

Boston, MA 

MEMBERS 

Dr. Paul Blanc, Professor and Chief, Department of Medicine, Endowed Chair, Occupational 

and Environmental Medicine, Division of Occupational and Environmental Medicine, University 

of California San Francisco, San Francisco, CA 

Dr. Thomas Dahms, Professor and Director, Anesthesiology Research, School of Medicine, St. 

Louis University, St. Louis, MO 

Dr. Russell R. Dickerson, Professor and Chair, Department of Meteorology, University of 

Maryland, College Park, MD 

Dr. Laurence Fechter, Senior Career Research Scientist, Department of Veterans Affairs, Loma 

Linda VA Medical Center, Loma Linda , CA 

Dr. H. Christopher Frey, Professor, Department of Civil, Construction and Environmental 

Engineering, College of Engineering, North Carolina State University, Raleigh, NC 

Dr. Milan Hazucha, Professor, Department of Medicine, Center for Environmental Medicine, 

Asthma and Lung Biology, University of North Carolina - Chapel Hill, Chapel Hill, NC 

Dr. Joel Kaufman, Director, Occupational and Environmental Medicine Program, University of 

Washington, Seattle, WA 

Dr. Michael T. Kleinman, Professor, Department of Medicine, Division of Occupational and 

Environmental Medicine, University of California, Irvine, Irvine, CA 

Dr. Francine Laden, Professor, Channing Laboratory, Harvard University, Boston, MA 

Dr. Arthur Penn, Professor LSU School of Veterinary Medicine, Department of Comparative 

Biomedical Sciences, Louisiana State University, Baton Rouge, LA 

4
Dr. Beate Ritz, Professor, Epidemiology, School of Public Health, University of California at 

Los Angeles, Los Angeles, CA 

Dr. Paul Roberts, Executive Vice President, Sonoma Technology, Inc., Petaluma, CA 

Dr. Armistead (Ted) Russell, Professor, Department of Civil and Environmental Engineering, 

Georgia Institute of Technology, Atlanta, GA 

Dr. Anne Sweeney, Professor of Epidemiology, Department of Epidemiology and Biostatistics, 

School of Rural Public Health, Texas A&M Health Science Center, College Station, TX 

Dr. Stephen R. Thom, Professor, Institute for Environmental Medicine, University of 

Pennsylvania, Philadelphia, PA 

SCIENCE ADVISORY BOARD STAFF 

Ms. Kyndall Barry, Designated Federal Officer, Washington, DC 

5
U.S. Environmental Protection Agency 

Clean Air Scientific Advisory Committee 

CHAIR 

Dr. Jonathan M. Samet, Professor and Flora L. Thornton Chair, Department of Preventive 

Medicine, University of Southern California, Los Angeles, CA 

MEMBERS 

Dr. Joseph Brain, Cecil K. and Philip Drinker Professor of Environmental Physiology, 

Department of Environmental Health, Harvard School of Public Health, Harvard University, 

Boston, MA 

Dr. H. Christopher Frey, Professor, Department of Civil, Construction and Environmental 

Engineering, College of Engineering, North Carolina State University, Raleigh, 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. Helen Suh, Associate Professor, Department of Environmental Health, School of Public 

Health, Harvard University, Boston, MA 

Dr. Kathleen Weathers, Senior Scientist, Cary Institute of Ecosystem Studies, Millbrook, NY 

SCIENCE ADVISORY BOARD STAFF 

Dr. Holly Stallworth, Designated Federal Officer, Washington, DC 

6
NOTICE 

This report has been written as part of the activities of the EPA’s Clean Air Scientific Advisory 

Committee (CASAC), a federal advisory committee independently chartered to provide extramural 

scientific information and advice to the Administrator and other officials of the EPA. CASAC 

provides balanced, expert assessment of scientific matters related to issues and problems facing the 

Agency. This report has not been reviewed for approval by the Agency and, hence, the contents of 

this report do not necessarily represent the views and policies of the EPA, nor of other agencies 

within the Executive Branch of the federal government. In addition, any mention of trade names of 

commercial products does not constitute a recommendation for use. CASAC reports are posted on 

the EPA website at http://www.epa.gov/CASAC.

7
Enclosure B 

CASAC’s Consensus Responses to EPA’s Charge Questions

1. Chapter 1 has been revised in response to comments from the CO Panel, as well as 

related comments from the CASAC PM Panel, to add information regarding criteria for 

study selection and evaluation, to add more CO-specific information to the framework for 

causal determination, and to more clearly describe the process of integrating evidence 

from various disciplines to classify the overall weight of evidence relating to causality. 

What are the views of the Panel on the extent to which this revised Chapter 1 provides 

necessary and sufficient background information for review of the subsequent chapters of 

the CO ISA? 

Chapter 1 is an important but challenging chapter. It is responsive to the comments and 

suggestions provided previously by CASAC. The chapter establishes a solid background to 

subsequent chapters of the CO ISA. The integration of Tables 1-1 and 1-2 provides a concise 

summary of the aspects used in epidemiology to assess causality. Section 1.6, EPA Framework 

for Causal Determination, now incorporates a detailed description of the criteria for causal 

determination. The introductory sentence to Section 1.6.3 clearly describes the process of 

moving from association to causation, requiring the elimination of alternative explanations for 

the association. In order to illustrate the criteria used to assess the quality of a study, it would be 

helpful to include: the definitions of confounding and effect measure modification and the 

criteria for determining if a factor (covariate) is a confounder; the process utilized to identify 

confounders and effect measure modifiers; available methods to control for confounding in the 

design and analysis phase of a study; and the most appropriate ways to interpret effect measure 

modification. In general, the ISA would greatly benefit from an improved presentation of 

epidemiologic concepts. 

More detail on the scope of the critical review of ecological effects (in the sense of effects on the 

ecosystem, not ecological associations) is requested. Specifically, what literature databases were 

searched, using what keywords, for what time period, and for what geographic scope? Given the 

scant literature on the ecological effects of CO, EPA should nonetheless comment on hypotheses 

for ecological effects and identify key data gaps. Such information would be useful for setting a 

research agenda to inform the next revision of the CO NAAQS. 

The terms “sensitive,” “susceptible,” and “vulnerable” are often used interchangeably or at least 

with potentially overlapping meanings. In regard to the final CO ISA, CASAC reiterates its 

expectation that the terminology will be consistent with the definitions in the final PM ISA and 

used uniformly throughout the entire document. EPA should develop a glossary of terms that are 

used across criteria pollutants, to ensure consistency of terminology in the ISAs and REAs for all 

NAAQS reviews. The term “sensitive” is in the statutory language (see footnote 1 on p. 1-3) and 

thus may have special regulatory significance, which should be explained. The role of 

identifying “susceptible” and “vulnerable” groups with respect to characterization of “sensitive” 

groups should be explained as well. Although a table giving definitions of these terms appears 

later in the document, clarification earlier would be better. 

8
Finally, given that the epidemiologic literature on CO has grown over the past decade, the Panel 

recommends that EPA assess the applicability of performing quantitative meta-analyses when 

appropriate. Such analyses would better inform quantitative effect estimates, and allow the 

Agency to refine further its inferences from the scientific literature. 

2. Chapter 3 has been revised and expanded in response to Panel comments regarding climate, 

monitoring, spatial variability, and exposure. 

a. Evidence reviewed in Chapter 3 of the ISA indicates that the direct contribution of 

CO to greenhouse warming is very small, while the role of CO in atmospheric 

chemistry cycles involving other species makes a larger contribution to radiative 

forcing. This combined evidence leads to the conclusion in Chapter 2 that a causal 

relationship exists between current atmospheric concentrations of CO and effects on 

climate. What are the Panel’s opinions related to this causal statement and the 

evidence provided to support it? 

b. Additional detail has been provided regarding the detection limits of CO monitors 

in the regulatory network, the number of monitors reporting at each horizontal 

spatial measurement scale and comparison of monitoring data at each scale, and 

spatial variability of CO concentrations near major sources, particularly roadways. 

Please comment on the usefulness of these revisions in characterizing the information 

provided by the CO monitoring network. 

c. The section on exposure assessment has been reorganized to provide information 

on exposure assessment at different spatial scales and to create a subsection 

containing information regarding exposure error and its implications for 

interpretation of epidemiologic studies. Does the Panel consider that the sources of 

exposure error have been appropriately characterized, and agree with the revised 

conclusions regarding the impact of exposure error due to spatial variability and the 

presence of CO as part of a combustion-related mixture on health effect estimates 

from time-series epidemiologic studies? 

Substantial information has been added to both Chapters 2 and 3 as well as to Annex A. The ISA has 

been strengthened by these additions. The review of the literature appears to be thorough, and the 

analysis of the scientific evidence systematic. In discussion of non-anthropogenic CO emissions (pages 

3-3 to 3-5), emissions from biogenic sources, and CO generation from the oxidation of volatile organic 

compounds (VOCs), isoprene, and other biogenic VOCs should be added to the caption of Figure 3-1. 

Additionally, the discussion would benefit from the inclusion of information on the range of motor 

vehicle operations which favor CO emissions, such as operation under high load, emissions during coldstarts, and emissions from gross-polluting vehicles. 

The addition of information on the potential impact of CO on climate is very helpful. It appears 

that the direct impact of CO is small, but the indirect impact of CO may be substantial. 

However, the estimates of the impacts of CO on climate are uncertain. This current high level of 

uncertainty does not favor the development of a secondary standard.

9
The expanded discussions on CO detection limits, monitoring details, and spatial CO characteristics 

better characterizes the information provided by the CO monitoring network and helps to qualify the 

data used in exposure estimations. Specifically, the expanded discussions on monitor detection limits 

and monitoring locations in Section 3.4 and the respective Annex figures and tables are critical to 

understanding CO concentrations. They are an important addition to the ISA. Although the limitations 

of insensitive existing monitors are provided in the text (page 3-43, lines 13-18), these limitations need 

to be added at numerous other places in the ISA that also address CO concentrations. The relaxation of 

CO monitoring requirements and the continued use of older, less sensitive monitors with high detection 

limits the use of monitoring data for current exposure assessments. 

 

In general, the expanded discussions of sources of exposure and resulting exposure assessment in 

Section 3.6 are a great improvement and are useful in characterizing the potential impacts of exposure 

error. The section on Land Use Regression Models (page 3-94, lines 6-23) is limited in scope. It does 

not represent the wide range of modeling methods nor exposure results from the literature. Additional 

discussions should help characterize the spatial concentrations of CO between monitoring locations and 

particularly near roads where concentrations are usually much higher than in general area locations. 

Admittedly, much of the modeling work in the literature is on pollutants other than CO, but the 

conclusions regarding what methods work and how they relate to estimating pollutant concentrations 

should be directly applicable to CO. 

3. In response to comments from the CASAC CO Panel, material has been added to Chapter 

4 describing comparisons among predictive COHb models, the relative influence of 

differing exposure scenarios on COHb concentration, and endogenous CO production 

rates in individuals with various diseases and conditions. Please comment on the 

usefulness of this information in illustrating the factors influencing COHb kinetics and 

potential COHb levels under various scenarios. 

Generally, we found the revised and substantially expanded Chapter 4 of the second draft ISA to 

be comprehensive and very useful in illustrating various physiologic factors and disease states 

that influence blood levels of COHb and/or their potential adverse affects. Section 4.2 describes 

in adequate detail various COHb predictive models. However, despite the addition of section 

4.2.3 on Model Comparison and its discussions of the respective models’ strengths and 

limitations, questions remain. It is unclear to the Panel: (1) how these different models will 

perform under the same simulated temporal exposure scenario of 30-60 minute duration with 

occasional peak CO concentrations, and (2) which model is the most accurate in predicting 

COHb levels? Several models seem to be most suitable for an inter-model comparison and 

evaluation, e.g., Smith et al., 1994, Bruce and Bruce, 2008, Gosselin et al., 2009, as well as the 

non-linear Coburn-Forster-Kane equation (CFKE) used by EPA in the Agricultural Policy 

EXtender (APEX ) model. This comparison may help to establish whether the CFKE is the best 

model given that activity levels are evaluated on a minute-by-minute basis and ambient CO 

shows transient peaks. The physiological parameters (e.g., VA and DLCO) used in both Denver 

and Los Angeles COHb calculations should be spelled out, since DLCO and ventilation rates 

vary by altitude. 

10
There are some inconsistencies among the tables, figures and text presented in the discussion of 

the Quantitative Circulatory Physiology (QCP) model in section 4.2.4, which need to be 

reconciled. The section could be shortened by dropping less relevant material. 

The addition of section 4.3.4 COHb Analysis Methods in this draft is very helpful in pointing to 

limitations and inaccuracies of some of the instruments used to measure COHb. Since the 

differences in COHb determination among methods may be substantial, we suggest indicating 

the method/instruments used to determine COHb in the tabulated studies as well as in other key 

studies discussed in the text. 

In addition to people with cardiovascular disease there are other large population groups 

potentially at-risk from CO exposure, such as those having various forms of anemia or COPD. 

Although there are no experimental studies on the effects of CO exposure on these groups at 

ambient concentrations, these individuals may be more vulnerable to CO because their disease 

state amplifies the action of CO. The application of COHb predictive models with the inclusion 

of appropriate pathophysiological parameters representing such disease states, if feasible, might 

be helpful in determining the extent of risk in such populations. Especially, if available, 

additional details should be provided and discussed regarding the fetus as an at-risk individual. 

Identification of CO-specific associations with health endpoints in epidemiologic studies often 

requires complex, multivariate analyses. Utilization of appropriate COHb predictive models can 

help in interpreting the biological plausibility of associations of CO with health endpoints and 

will likely provide further insight into the pathophysiological basis of responses. 

4. The cardiovascular effects section has been expanded to: 

• evaluate key uncertainties in the health evidence, particularly regarding the 

biological plausibility of effects at low ambient CO concentrations and 

distinguishing independent effects of CO in multipollutant ambient mixtures; 

• provide more detail on the design and findings of a multicenter controlled human 

exposure study to clarify the levels at which effects were observed; 

• add description of new epidemiologic studies, including a large U.S. multicity 

study and studies on associations between blood markers and ambient CO 

concentrations; and 

• more clearly describe the integration of controlled human exposure and 

epidemiologic evidence to reach a causal determination. 

Please comment on these revisions to Chapter 5 and the conclusions for each of the 

health outcomes evaluated in this chapter. In particular, we are requesting CASAC 

comment on the interpretation of the evidence and the causal determination for shortterm exposure to CO and cardiovascular morbidity. 

The EPA staff is to be commended for the expanded, wide-ranging and comprehensive 

presentation in Chapter 5 of the ISA. They have added relevant material to the earlier version of 

this chapter and included updates from articles that appeared as late as September, 2009. The 

Panel offers the following suggestions for Chapter 5 of the final ISA: additional Forest plots to 

11
summarize CO effects on blood markers and heart rate variability, and a meta-analysis of health 

effects studies for selected outcomes. 

Cardiovascular Morbidity. The most compelling CO-related cardiovascular results remain those 

from the controlled human exposure studies of Allred et al; Kleinman et al; and Sheps et al. The 

1991 Allred report contains dose-response information, including responses at COHb 

concentrations <2%, based on the air-exposed COHb levels. More recent epidemiological 

studies of morbidity at ambient CO levels, including data on hospital admissions, are consistent 

with and reinforce the observations from the earlier controlled human studies. A large at-risk 

population includes people with CVD who have not yet been formally diagnosed with this 

condition. This undiagnosed group will likely grow in size and importance as our population 

ages. Many individuals that have had acute myocardial infarctions do not have already 

diagnosed coronary artery disease (CAD). 

Although those with diagnosed CAD are the largest CVD group and may represent the most 

easily quantifiable highly-susceptible group for CO-related outcomes, CASAC notes that EPA’s 

singular focus on CAD will underestimate the at-risk population. Other CVD patients, 

regardless of whether they carry a diagnosis of CAD or not, are at increased risk for CO-related 

hospital admissions. Further, limited data from people suffering myocardial infarctions (MIs), 

who had recently experienced high acute CO exposures, indicate that those MIs were associated 

with vasospasm, rather than with complications of CAD. This further indicates that CAD need 

not be a final common pathway to designate adverse CV outcomes. Finally, the association of 

stroke with small increases in ambient CO levels also supports a more broadly defined risk group 

going beyond those with established CAD. 

In conclusion, it is CASAC’s recommendation that EPA broaden the definition of the at-risk 

population beyond people with CAD. The Panel members concur with the ISA’s conclusion that 

a causal relationship is likely to exist between relevant short-term CO exposure and CV 

morbidity. We note that data are inadequate to establish a relationship between either chronic 

CO exposure or transient elevations in ambient CO and morbidity. 

Stroke. The Panel finds there is a strong association between elevated ambient CO levels and 

hospital admissions for stroke, distinct from other neurological outcomes (see above). 

Consideration might be given to changing the title of the neurological outcomes section to “CO 

and non-stroke CNS morbidity”. 

Respiratory Morbidity. Positive associations have been demonstrated between short-term 

exposure to CO and respiratory-related outcomes including effects on pulmonary function, 

respiratory symptoms, medication use, hospital admissions, and emergency department visits. 

However, there were no convincing data in which these relationships were consistently observed 

after adjusting for multiple co-pollutants, which are also risk factors for adverse respiratory 

outcomes. The Panel was divided, and while the majority view was in favor of “evidence 

suggestive of a causal relationship” others favored a designation of “inadequate to infer a causal 

relationship.” The evidence on associations between long-term exposure to CO and respiratoryrelated outcomes is even more uncertain than for short-term exposures and were appropriately 

categorized as “inadequate.” Finally, the point was made that allergy and allergic responses 

12
should be considered separately from respiratory outcomes and that this distinction should be 

noted in the final ISA. 

“Therapeutic” Applications of CO. There is a growing literature regarding possible therapeutic 

applications of CO at levels of ~250 ppm. These studies have been carried out in some animal 

models and in cell culture. CO is a pro-oxidant and has profound extended pro-inflammatory 

effects. However, in specific scenarios with distinct organ systems or specific cell types, CO 

may have short-term anti-inflammatory effects. Clinical trials thus far have not supported health 

benefits of CO administration. Further, there is no evidence that the hypothetical therapeutic 

results provide any insight into health effects of acute or chronic ambient exposures in the 

general population, and especially in subpopulations susceptible to CO effects. 

5. The section on susceptible populations has been revised substantially in response to 

comments from the CASAC CO Panel and in consideration of similar comments from the 

CASAC PM Panel. The definition of a susceptible population has been clarified, and 

each subsection describing a susceptibility characteristic has been revised to emphasize 

specific evidence from controlled human exposure studies of individuals with underlying 

disease, epidemiologic studies that conducted stratified analyses to examine effect 

modification, and toxicological studies using animal disease models. Does this revised 

section provide appropriate characterization of populations potentially susceptible to 

CO-induced health effects? 

The discussion of populations susceptible to carbon monoxide has been greatly improved. The 

data are now presented in a logical framework providing a clear and concise summary. Section 

5.7 begins with Table 5-25, which provides a useful context for understanding the historical use 

of the terms vulnerability and susceptibility. A question was raised during the Panel’s 

deliberations regarding whether level of exposure should be considered a “vulnerability” factor. 

It was suggested that the term “at risk” may be useful in some instances to distinguish 

individuals who are truly more susceptible owing to some specific subject characteristic rather 

than to a difference in level of exposure. 

Cardiovascular Disease. As indicated in the previous charge question, the Panel finds that the 

discussion of vulnerable subpopulation is focused too narrowly on coronary artery disease 

(CAD). It has been noted that arrhythmias and congestive heart failure should also be discussed 

in this section. Further, CAD represents a continuous progression with many more individuals at 

risk than those carrying a doctor diagnosis. 

Anemia. A susceptible subpopulation is individuals with anemia from a diverse range of disease 

states. A key mechanism by which anemia may put individuals at increased risk is the reduction 

in the capacity to carry oxygen. Hemoglobinopathies, including sickle cell disease, should be 

distinguished from anemia in general, as these disorders are likely to have a different 

susceptibility relationship with carbon monoxide. 

Diabetes. Diabetes was identified as another factor condition might increase susceptibility to 

carbon monoxide. During the Panel’s deliberations, it was noted that the ISA does not mention 

the high rate of obesity and metabolic syndrome as risk factors in addition to diabetes itself or 

13
the high correlation between diabetes and cardiovascular disease. In particular, the Panel cited 

the results of a recent South Korean study (not included in the report) in which the effects of 

carbon monoxide were investigated in individuals having both diabetes and cardiovascular 

disease1

. 

Gestational Development. The focus on altered gestational development included both the 

mother and fetus. Limited data suggest the possibility of paternally mediated effects of carbon 

monoxide owing to altered sperm production2

. These effects cannot be ruled out as a potential 

contributor to the effects of carbon monoxide in gestational development, but there is currently 

no compelling evidence for this concern. 

6. Chapter 2 has been revised and expanded to provide more information on atmospheric 

science and exposure assessment, policy relevant considerations, and integration of CO 

health effects. 

a. The section on policy-relevant considerations was revised to present additional 

detail on the concentration-response relationship observed in a multi-center 

controlled human exposure study, present results from a new U.S. multicity 

epidemiologic study investigating the potential presence of a threshold and 

departure from linearity, and summarize the evidence for susceptible populations. 

Please comment on these revisions. 

b. A section and summary figure have been added to the end of Chapter 2 to 

summarize the main conclusions of the ISA regarding the health effects of CO and 

the range of concentrations at which effects are observed, along with 

uncertainties that complicate the interpretation of the evidence. We would 

appreciate CASAC comment on the material in this section and its effectiveness in 

presenting the conclusions of the ISA. 

The inclusion and analysis of data from a multi-site epidemiological study 3

 is commendable, 

given that it was published only recently. In addition, there are multiple points in which these 

data could have been presented in Chapter 5, which is the basis of the presentation in Chapter 2 

(see also comments to that charge question). Greater detail should be provided here in Chapter 2 

because the data are particularly relevant. For example, limiting the analysis to those days with 1 

ppm values or less resulted in the point estimate for the increased hospitalization actually 

increasing to approximately 1.75%. 

Figure 2-1 is new to this revision, and is appropriate and helpful. The Panel offers the following 

suggestions for improving Figure 2-1. The effect estimate metric as presented in the far right 

 

1

 Min JY, Paek D, Cho SI, and Min KB (2009). “Exposure to environmental carbon monoxide may have a greater 

negative effect on cardiac autonomic function in people with metabolic syndrome,” Science of the Total 

Environment, 407(17), 4807-4811. 

2

 Rubes J, Rybar R, Prinosilova P, Vesnick Z, Chvatalova I, Solansky I, and Sram RJ. 2009. Genetic polymorphisms 

influence the susceptibility of men to sperm DNA damage associated with exposure to air pollution. Mutat. Res. Oct. 

2. 

3 Bell ML, Peng RD,Dominici F, Samet JM (2009). "Emergency admissions for cardiovascular disease and ambient 

levels of carbon monoxide: Results for 126 U.S. urban counties, 1999–2005," Circulation, 120 (11), 924–927. 

14
column of Figure 2-1 should be more understandable. For example, because the lower bound of 

the CI and the point estimate are of far more interest than the upper bound, adjusting the scale is 

appropriate and would help the presentation visually. Also, the effects could be grouped by 

endpoint, not by study, with total CVD top, then IHD, CHF, and stroke. Finally, the 99th

percentile of exposure may be of less interest than the 95th. 

Although the CVD endpoint of Bell is included in Figure 2-1, the other specific endpoint of Bell 

is left out. This is related to the tree plot consisting of unadjusted CO effects only. A clarifying 

note with text emphasizing that there are co-pollutant adjusted values from Bell et al. should be 

added. These critical endpoints include ischemic heart disease (IHD), congestive failure, and 

stroke. The data in Figure 2-1 could be summarized with a formal meta-analysis or, if this 

proves inappropriate due to heterogeneity, a comment as to the rationale for not having such an 

analysis should be included. The ISA should also explain why the data in Figure 2-1 are limited 

to findings from North America. 

 

We draw attention to the concluding paragraph in Chapter 2. Before addressing uncertainties 

that remain, it might be more straightforward to first catalogue the uncertainties that have been 

substantially addressed since the 2000 CO AQCD. (In the present text this is stated first in the 

negative: “some of these uncertainties remain.”) The argument with regard to the lack of 

biological plausibility runs counter to the rich series of recent studies that indicate the potential 

modulatory effects of CO at low levels on a number of systems (pages 5-5 to 5-17). A separate 

section should summarize this central point of improved data that has reduced much of the 

uncertainty previously encountered. Moreover, the phrase in the last sentence “biological 

plausibility provided by CO’s role in limiting O2 availability” seems to diminish the rich data on 

other mechanisms and their possible role (e.g., cell signaling independent of heme moiety 

binding). 

The concluding paragraph refers to the “many new epidemiological studies adding to the body of 

evidence showing associations.” The EPA could modify this statement to include the adjective 

convincingly, to be consistent with the next sentence regarding definitive cardiovascular effects 

in controlled exposures. At various points, but most importantly in the very last sentence, the 

phrase “relevant... exposures” is used. If this means exposure at or below the current EPA CO 

NAAQS, this should be explicitly stated. Relevant could imply that other exposure levels are 

irrelevant to the assessment of health effects, which of course is not intended as they may be 

relevant through the mechanistic insights they provide. The Panel found the focus on 

cardiovascular endpoints in the concluding paragraph appropriate. Nonetheless, an additional 

sentence acknowledging that there is at least a suggestive relationship with several other 

endpoints is warranted. Also, a restatement of the association with global warming would be 

appropriate in this concluding paragraph. 

There is agreement among the Panel with the ISA’s conclusion that there is a likely causal 

association between acute ambient CO exposures in the range of the current air quality standard 

and adverse cardiovascular endpoints. In contrast, there is scant evidence in the health effects 

section related to chronic CO exposure effects on cardiovascular morbidity. Even though these 

data may be categorized as “inadequate,” this category appears to have been omitted from Table 

15
2-1 and should be added. Also, the 2006 publication by Hedblad et al. 4

 seems to be missing 

from the discussion. It is relevant to Chapter 5. 

There is heterogeneity of views among the Panel regarding the summary statement that acute CO 

exposure has a suspected association with adverse respiratory outcomes. The Panel recommends 

tempering the narrative by explicitly indicating that for this association the evidence borders 

between suggestive and inadequate. In particular, the epidemiological evidence was limited by 

an absence of co-pollutant data. We lack studies showing substantive attenuation of CO risk 

estimates when co-pollutant modeling is performed. 

There is a consensus of the Panel that the evidence on the relationship between chronic CO 

exposure and mortality should be categorized as inadequate. This view is based in large part on 

the difficulty in epidemiologically differentiating between mortality due to multiple acute effects 

compared to prolonged lower level effects without peaks. Also, we believe that chronic 

outcomes in myocardial infarction and stroke can be presumed to include excess mortality. 

 

4 Hedblad B, Engstrom G, Janzon E, et al. COHb% as a marker of cardiovascular risk in never smokers: results 

from a population-based cohort study. Scand J Public Health 2006; 34:609–615

16
Enclosure C 

Compendium of Review Comments from CASAC Carbon Monoxide Review Panel on 

EPA’s Integrated Science Assessment for Carbon Monoxide: Second External Review Draft 

(September 2009)

Comments received: 

Dr. Paul Blanc ............................................................................................................................. 18 

Dr. Thomas Dahms ..................................................................................................................... 23 

Dr. Russell Dickerson ................................................................................................................. 27 

Dr. Laurence Fechter.................................................................................................................. 31 

Dr. H. Christopher Frey............................................................................................................. 32 

Dr. Milan Hazucha...................................................................................................................... 37 

Dr. Michael Kleinman ................................................................................................................ 40 

Dr. Francine Laden..................................................................................................................... 41 

Dr. Arthur Penn.......................................................................................................................... 42 

Dr. Beate Ritz .............................................................................................................................. 45 

Dr. Paul T. Roberts..................................................................................................................... 48 

Dr. Armistead Russell................................................................................................................. 53 

Dr. Anne Sweeney ....................................................................................................................... 54 

Dr. Stephen Thom....................................................................................................................... 56

17
Dr. Paul Blanc 

Comments on Charge Question #6 

a. Please comment on these revisions: The section on policy-relevant considerations was 

revised to present additional detail on the concentration-response relationship observed in a 

multi-center controlled human exposure study, [to] present results from a new U.S. multicity 

epidemiologic study investigating the potential presence of a threshold and departure from 

linearity, and [to] summarize the evidence for susceptible populations. 

It is appropriate to include the Allred concentration (exposure) response data and to point out 

(as is done in the text) that this study was far larger and more powerful than any previous 

controlled exposure study. In terms of exposure (concentration) response, the key Allred study 

appeared in 1991 (the current document refers the reader to the 1989 Allred paper, although the 

subsequent 1991 paper provides details of the exposure [concentration]; clarifying this point in 

the text would be advisable). The Allred data could be presented to better effect if the point is not 

only the linear relationship, but also the presence of a threshold. In this regard, the Allred 

analysis of time until angina (from the actual paper, Figure 12, page 112, 1991 and related text) 

indicates that there was an intercept value (at 0% carboxyHb) of a 1% decrease (± 2.1%; not 

different from zero) in time until angina onset. This is based on an analysis of room air not as 

“zero,” but as the actual post-exercise room air COHb value (which varied by site and among 

subjects). The ST depression intercept, of note, was significantly in the positive direction, which 

could be argued in favor of a threshold for that endpoint. This can be discussed more explicitly 

than as it appears in the current draft. Also in regard to threshold, the analysis by Somoli, in 

which the deviance from linearity was associated with a p value of > 0.9, should not be described 

as “weak evidence in favor of a threshold” – this would be better described as a finding that does 

not support the presence of a threshold. Moreover, there is an overextended discussion here as to 

why this analysis was poorly powered to observe a threshold, including wording such as “an 

inability to draw conclusions.” This could give the appearance of trying too hard to leave open 

the possibility of a threshold effect where none was no threshold observed. 

No attempt was made to perform an integrated analysis of the experimental data for low-level 

CO exposure and time until onset of angina from multiple studies (for example, using the data in 

Table 27 of Allred of multiple studies on this subject, taking into account baseline room air 

carboxyhemoglobin and post exposure levels). It may be that the data, ultimately, so not permit 

this. If so, a brief statement in this regard in the text would nonetheless be useful. 

The concluding statement of this section reads: “Although the C-R relationship has not been 

explicitly evaluated in human clinical studies with exposures resulting in COHb concentrations 

< 2.0%, the findings of Allred et al. provide some evidence of a significant C-R relationship over 

a range of COHb concentrations relevant to the NAAQS.” This sentence is overly weak, 

somewhat confusing, and inexact. Allred, in fact, did explicitly analyze the concentration 

response including those resulting from air (ambient CO +metabolism). Many of these 

observations included in that regression were less than 2% COHb (see above, re: threshold). The 

wording “some evidence” operates to undermine the findings – it is “evidence,” which could be 

argued to be substantial or strong (as opposed to the indeterminant “some”). If “significant” as 

18
used in this text means statistically significant, then this should be explicit as well. Also on this 

topic of concentration response, a comment voiced in the meeting was that, in addition the 

potential differences between concentration response and delivered dose response based on 

biological monitoring should be acknowledged, either here or elsewhere in the document. 

The summary of evidence regarding “susceptible” populations (2.6.1) actually precedes the 

discussion of concentration response (2.6.2). This section does a fair job of summarizing lengthy 

text elsewhere in the document, but also suffers from the organizational issues of that text. The 

most substantive issue here is the usage of the term “susceptible” to refer to two entirely different 

concepts, operationally. The first usage is consistent with the way in which susceptible is 

typically applied: subgroups in which an exposure identical to the general population could be 

expected to have a greater adverse effect. Examples of this include, and are documented: those 

with pre-existing cardiovascular disease, diabetics, those with pre-existing anemia, those with 

pre-existing hypoxemia, and the fetus. In contradistinction to this classic construct of 

susceptibility, the document lumps together with this individuals who are susceptible because 

either they are more likely to experience higher ambient exposures (living near roads, greater 

commute times) or because the ambient exposure they receive will be superimposed on a higher 

baseline value secondary to greater than average exposure to exogenous CO or due to greater 

metabolic production of CO. Susceptibility by both routes are important, but the presentation 

would be more lucid if the distinction were spelled out explicitly. 

The concluding sentence “Overall the controlled human exposure, epidemiologic, and 

toxicological studies evaluated in this assessment provide evidence for increased susceptibility 

among various populations” is overly weak. By saying that the evidence for those with CAD is 

“strongest” in the next sentence, the implication could be drawn that the other “evidence” is 

somehow weak. It could be argued that the strongest evidence of susceptibility to CO, per se, is 

for fetal exposure, on kinetic grounds of a longer half-life. The evidence of susceptibility is 

certainly strong to convincing in a number of other scenarios. Also in the sentence in question, if 

toxicological means animal toxicology this should be stated and a fourth category of human 

clinical toxicology cases added, or toxicology be clarified to mean both.. 

Overall in the document there seems to have been little use made of human toxicology case 

reports insofar as the implications that might be drawn from such data. One specific example: 

human case reports clearly have shown that coronary artery spasm appears to mediate COinduced MI in some individuals (post CO-caused MI coronary vessels without underlying CAD 

consistent with MI). [See for example: Marius Nunez AL, Myocardial infraction with normal 

coronary arteries after acute exposure to carbon monoxide. Chest 1990; 97:491-4 and related 

case reports]. There was, however, another minority view presented by a panel member that 

argued against consideration of any data in which high levels of exposure had occurred as being 

irrelevant to lower level scenarios. 

The various scenarios of susceptibility seem to ignore indoor air sources of supplemental CO 

exposure. Most glaringly, secondhand smoke exposure is missing [it can also be argued that this 

can be an outdoor ambient issue in areas with heavy concentrations of smokers at the threshold 

of edifices. This is also relevant to secondhand smoke exposure to vehicular passengers in 

automobiles, already exposure to higher roadway levels of CO. Related to this issue, term 

19
secondhand smoke (SHS) should be substituted for “ETS” where currently used in the document. 

Paralleling the SHS issue, deficient home heating which may also be a risk and is likely to run 

with lower socioeconomic status and or living in colder parts of the US in the winter months, 

also relevant to susceptibility. In the same vein, occupational exposures superimposed on 

ambient exposure should be taken into account as a potential susceptibility factor. Further, the 

metabolism of “dihalomethanes” is mentioned as an enteric source of CO, but this would be 

better stated a predominantly methylene chloride (which has also been in some consumer 

products). In regard to metabolism, there could be further clarification of data gaps in the overlap 

or non-overlap of similar systemic levels of carboxyhemoglobin from internal metabolism 

compared to extrinsic exposure. Finally, diabetics are mentioned, but a recent relatively large 

study (n=986) from Korea (Min PY et al, Sci Total Environ Aug 2009) with effect modification 

for autonomic dysfunction [decreased heart rate variability] from CO by fasting blood glucose 

was not cited or discussed. Many of these points are also relevant to the more detailed 

presentation of susceptibility in Chapter 5. 

 

b. We would appreciate CASAC comment on the material in this section and its 

effectiveness in presenting the conclusions of the ISA: “A section and summary figure have 

been added to the end of Chapter 2 to summarize the main conclusions of the ISA regarding 

the health effects of CO and the range of concentrations at which effects are observed, along 

with uncertainties that complicate the interpretation of the evidence.”

Figure 2-1 (page 2-21) is new to this revision. The Figure, in principal, is appropriate and 

helpful, but it could be improved upon in ways delineated in the points below. The effect 

estimate (far right of Figure 2-1) should have the metric presented more clearly graphically. For 

example, because the lower bound of the CI and the point estimate are far more of interest than 

the upper bound – scaling so that the scale is bigger would help the presentation visually. Also, 

the effects could be grouped by endpoint, not by study, with total CVD top, then IHD, CHF and 

stroke. Finally, the 99th percentile of exposure may be of less interest than the 95th. 

The inclusion and analysis of data from the multi-site epidemiological study (Bell et. al.) is 

commendable in the text and to a limited extent in the Figure, given that it was published only 

recently. There are multiple points in which these data could have been presented in Chapter 5 

(which is the basis of the presentation in Chapter 2 – see also comments to that charge question) 

beyond the limited places where the paper is cited). Greater detail should be provided here in 

Chapter 2 because the data are so relevant (for example: that limiting the analysis to those days 

with 1 PPM values or less, the point estimate for the increased hospitalization actually increased 

to approximately 1.75% [95% interval excludes 0)] or that a re-analysis excluding any days over 

the 1 hour 35 ppm standard had no impact on the estimated of 0.55%). 

In terms of the new Figure, although the CVD endpoint of Bell is included the other specific 

endpoint of Bell are left out. This is related to the tree plot being of unadjusted CO effects only, 

but this could be addressed with clarifying notes and with test emphasizing that there are copollutant adjusted values from Bell et al. These critical endpoints include IHD, congestive 

failure, and stroke. 

20
The data in Figure 2-1 could benefit from a formal meta-analysis or, if this proves 

inappropriate (for example, due to heterogeneity) a comment as to the rationale to forgo the 

presentation of such an analysis should be included. (Also in regard to Figure 2-1, a compelling 

rationale as to why the data are limited to findings from North America is not provided and 

should be inserted). 

 

The concluding paragraph (pages 2-24 and 2-25) is hampered by the logic of its presentation. 

Before addressing uncertainties that remain, it might be more straightforward to first catalogue 

the uncertainties that have now been substantially addressed since the 2000 CO AQCD. (In the 

present text this is stated first in the negative: “some of these uncertainties remain.”) The 

argument re: lack of biological plausibility runs counter to the rich series of recent studies 

indicating the potential modulatory effects of CO at low levels on a number of systems (see 

pages 5-5 to 5-17). Indeed, a separate section as part of the policy section should summarize and 

address this central point of an improved data that has reduced much of the uncertainty 

previously encountered. Moreover the phrase “biological plausibility provided by CO’s role in 

limiting O2 availability” [last sentence] basically cuts out the rich data on other mechanisms 

from any plausible mechanistic role [e.g., cell signaling independent of heme moiety binding). 

Earlier in the text, this same paragraph refers to the “many new epidemiological studies 

adding to the body of evidence showing associations..” This could be modified to include the 

adjective convincingly, consistent with the next sentence re: definitive cardiovascular effects in 

controlled exposures. 

At various points, but most importantly in the very last sentence, the phraseology 

“relevant....exposures” is used. Where this means exposure at or below the current EPA CO 

NAAQS, this should be so stated. “Relevant” could imply that other exposure levels are 

irrelevant to the assessment of health effects, which of course is not intended (they are relevant 

through mechanistic insights they provide, etc). 

In summary, there was a consensus of the Panel agreeing with the conclusion that there was a 

likely causal association between acute ambient CO exposures in the range of the current air 

quality standard and adverse cardiovascular endpoints. In contrast to this, there is only scant 

evidence in the health effects section re: chronic CO exposure effects on cardiovascular 

morbidity. Even though these data may be categorized as “inadequate,” this category appears to 

have been dropped from Table 2-1 and this row should be added [note: Hedblad B. et al, Scand J 

Public health, 2006 seems to be missing from that discussion and seems on topic; this would be 

relevant to Chapter 5]. 

In terms of the summary that acute CO exposure has a suspected association with adverse 

respiratory outcomes, there was a heterogeneity of views on the Panel, with a suggestion that this 

might be tempered in the narrative with explication indicating that this association was 

borderline between suggestive and “insufficient data.” In particular, the epidemiological 

evidence was limited by an absence of co-pollutant data or was marked by CO risk estimates 

were substantively attenuated when co-pollutant modeling was performed. 

21
 In terms of chronic CO exposure and mortality, there was a consensus view that this would 

be better categorized as “Insufficient data” rather than “unrelated.” This view is based in large 

part on the difficulty in epidemiologically differentiating between mortality due to multiple acute 

effects compared to prolonged lower level effects without peaks and the fact that, logically, 

chronic outcomes in myocardial infarction and stroke can be presumed to include excess 

mortality. 

In summary, it is appropriate to focus on cardiovascular endpoints in the concluding 

paragraph as written. Nonetheless, an additional sentence acknowledging that there is at least a 

suggestive relationship with several other endpoints is warranted and also a restatement of the 

association with global warming would be appropriate in this concluding paragraph. 

22
Dr. Thomas Dahms 

Statement: In response to comments from the CASAC CO Panel, material has been added 

to Chapter 4 describing comparisons among predictive COHb models, the relative 

influence of differing exposure scenarios on COHb concentration, and endogenous CO 

production rates in individuals with various diseases and conditions. 

Q: Please comment on the usefulness of this information in illustrating the factors influencing 

COHb kinetics and potential COHb levels under various scenarios. 

General comments: This section provides an excellent review of the modeling of CO uptake and 

release. It provides the essential information needed to understand most of the variables involved 

in relating CO exposure and CO dose. What follows are suggestions/questions that may lead to 

further improvement and clarification of the material presented. 

I. With the increasing amount of epidemiology data being considered in this database changes in 

atmospheric CO levels with various adverse health effects, the exposure models need to provide 

guidance to the reader regarding likely levels of exposure in some of these studies. The evidence 

from the atmospheric data demonstrates a steady fall in monitored levels of atmospheric levels of 

CO yet significant relationships with seemingly small changes in environmental CO continue to 

be identified. How can the exposure models provide insight into what might be occurring? I 

presume that this would include a discussion of the limitations of the use of the current 

atmospheric monitoring data to estimate exposure? I realize that there is data in the RFA and in 

the 2000 CO ACQD pertaining to this situation but it is scattered and it would help the reader if 

the salient issues were summarized as they pertain to the epidemiologic studies. 

II.. The modeling discussion in most of chapter 4 is based on factors influencing equilibrium 

values for COHb given different exposure conditions. In Section 4.2.3 (Model Comparison), the 

brief mention of the Bruce and Bruce model for predicting COHb levels with transient CO 

uptake conditions , page 4.9 lines14-20 or the QCP model deserves much greater consideration 

based upon what we know from real life exposure scenarios. If the primary exposures to CO 

occur during periods of commuting, which model more accurately predicts the CO uptake during 

the 30 to 60 minutes of exposure? Section 4.2.3. mentions the value of the Bruce and Bruce 

model but then proceeds to use the QCP model in the following section 4.2.4.without discussion 

or examples as to how ithe QCP compares to the other models. If the models in section 4.2.3 

were all compared to observed data, this distinction needs to be made. Otherwise the use of 

untested mathematical modeling in section 4.2.4. does not make sense. 

III.. Given that adverse health effects have been demonstrated at 2% COHb, the discussion on 

page 4-5 lines 23-26 report that application of unspecified scenarios in some form of the CFK 

model yield ranges of exposure levels required to reach 2% COHb. For the 1 hour (transient) 

exposure, these atmospheric levels of CO are 24-48 ppm which encompases the 35 ppm hourly 

criteria. However for the 8 hour exposure (equilibrium) the required exposure values are 11 to 13 

ppm which is above the 9 ppm standard. This data needs to be better referenced since it applies 

so directly to the standards. 

23
IV. Use of modeling information: 

1. With the paucity of actual measurements of COHb distributions in the population 

(nothing since NHANES II), modeling is proposed to provide data relevant exposure 

data. 

2. Since there are other pieces of missing data from the ideal data base from which to make 

assumptions regarding risks from CO exposure, I would propose that modeling be used 

to provide guidance for identified at risk groups for which there is little or no data. These 

groups would include those frequently mentioned: 

a. anemia. 

For the past 30 years patients with anemia has been identified as being an at risk group for 

adverse health effects due to CO exposure. It is discussed again in this document in Section 

5.7.1.3. This would be a particularly sensitive subset of patients with CAD since both 

elevated COHb and reduced hemoglobin concentrations reduce oxygen delivery to the 

myocardium. It should be noted that anemia is a significant risk factor for development of 

angina. Yet there appear to be no studies available addressing this issue. The extent of 

exposure risk for this sizable group of people (approximately 4 million over 65 with anemia) 

needs to be addressed. 

The treatment of anemia in this document focuses on the increased risk due to elevated 

endogenous production of CO. It is unclear what influence the elevated endogenous rates 

have on adverse health effects. One would suppose that in the four-element (Section 4.2. 

page 4-2 lines 28-29) CFK model that when the largest element changed would be the 

storage compartment (total body hemoglobin) that exposure conditions would be reduced in 

order to result in the same measures of effective dose (%COHb). One would expect an 

increase in the transfer interface with the hyperdynamic state due to the anemia, but the 

impact of this component would be less clear. It is likely that the lack of a sizeable storage 

compartment in anemic individuals would result in reaching levels of COHb of concern at 

lower atmospheric levels during 1 hour or 8 hour exposures. The relative importance of 

endogenous production, reduced storage capacity and increased transfer rates could be 

determined through the use of modeling. 

(The number of individuals in the USA with anemia is significant. According to NHANES 

III, 10-12% of the population over 65 yrs of age (40 million) has anemia. 

The number of individuals with CAD and anemia is more difficult to estimate but the 

numbers range from 8-15% of those patients with CAD also have anemia.) 

b. COPD and Emphysema

According to NHANESIII there are 24 million individuals in the US with some amount of 

COPD. This is such a sizable at risk group that application of various models of CO exposure 

using the impaired pulmonary function parameters would be helpful in determining the 

extent of risk in this population. 

24
V. Section 4.5. 

Whenever COHb is mentioned the method of analysis should also be indicated otherwise the 

reader would be misled assuming that all of the values were equivalent when they are not. This is 

particularly relevant when discussion the impact of endogenous CO production because the 

resultant COHb levels are very low. 

The limitations of the easy to use and reproducible CO-oximeter data was outlined in section 

2.6.1 of the 2000 CO AQC D. There are many assays with sufficient sensitivity available for use 

as used by Coburn et al to produce the data shown in Figure 4-12. However much of the other 

data in this Figure was collected with instruments not designed for accurate measurements of low 

levels of COHb (De las Heras et al used a CO-Oximeter). 

Additional major concern: 

Section 5.7.1.3. The primary concern for individuals with anemia when exposed to CO is that 

the tissue hypoxia due to the anemia will be exacerbated by the additional reduction in oxygen 

delivered to the tissues due to COHb. This should be the common theme for many of the preexisting diseases. Insufficient oxygen delivery making the heart tissue more susceptible to any 

increase in oxygen demand as occurs during exercise from the underlying disease should be the 

primary reason for concern. This is the case for the current state of our knowledge in the area of 

tissue effects of CO as stated multiple times in this document. The only reference to the 

pathophysiology of anemia is in line 31 on page 5-170 and the information is not correct. By 

convention hypoxia implies a reduced oxygen supply. The blood does not have the reduced 

oxygen supply in the lungs in anemia, only the tissues have a reduced supply of oxygen. The 

information provided could be: ....and result in a reduced arterial oxygen content due... The 

focus of this section should not be on the etiology of anemias but on the combined effects of two 

different causes of tissue hypoxia. 

25
Editorial and minor comments: 

1. The use of deoxyhemoglobin is probably a carry over from the assumptions used in the 

CFK modeling of McCartney (013162) which should be ignored because it is not correct. . 

2. Section 4.2. page 4-2, line 17. altitude should read exposure time and altitude. 

3. Section 4.2.1. page 4-3, line 29. Vco is not shown in Figure 4-1. 

4. Section 4.2.1 page 4-4, lines 11-14. The discrepancy between arterial and venous blood 

CO levels is mentioned without any interpretation as to why this is important. Also in this 

section the absolute errors in COHb are mentioned without providing any sense of what the 

mean increase in COHb was under these conditions. 

5. Section 4.2.1. page 4-5, lines 23-26. A reference is needed. 

6. Section 4.2.4, page 4-5.,lines 27-28. No explanation is given for reduced uptake by 

babies which appears to contradict information given in section 4.1. lines 20-22. 

7. Section 4.2.3. page 4-9, line7. ‘differ ±0.5%’ needs clarification. 0.5% COHb or of the 

value obtained? 

8. Section 4.2.4, page 4-9, line 21. Population data for COHb are available in (Radford and 

Drizd, 1982) so this statement needs to be clarified. 

9. Section 5.7.1.1. In this section the distinction between the terms CAD and IHD needs to 

be spelled out probably according to ICD-9 codes since these disease codes are the basis for 

most of the epidemiology studies. The term CHD should be dropped or noted as being of 

historic value only. 

26
Dr. Russell Dickerson 

Carbon monoxide, as the major sink for OH in the global troposphere has a substantial role in the 

oxidizing capacity of the atmosphere. For example Shindell et al. (2006) and [Isaksen et al., 

2009] show that the lifetime of methane can change by a factor of two depending on the range of 

tropospheric CO mixing ratios. Uncertainties in the budget of OH are such that the current state 

of the science is insufficient to establish the safe level of CO based for example on a 1oC 

temperature rise. The ISA should reflect this uncertainty and point out the need for further 

experiments and theory to inform the EPA. Because CO (like SO2 and NOx) is both a local 

pollutant and contributor to global climate change, a standard based only on the local maximum 

concentration is inappropriate for protecting welfare. Reduction of total emissions is appropriate 

for pollutants such as CH4 and CO2 with adverse effects on a global scale. The ISA should 

discuss the scientific basis for emissions-based standards or guidelines for CO. 

Comments on ISA Charge Question 2a 

In reference to ISA Chapters 2&3 that discuss a causal relationship between current atmospheric 

concentrations of CO and effects on Climate. “What are the Panel’s opinions related to this 

causal statement and the evidence to support it?” 

Substantial additional information has been added to both Chapters 2 and 3 as well as in Annex 

A, and the ISA is much stronger for it. The review of the literature appears to be thorough, and 

the analysis of the science systematic. One substantive comment I would make is that the 

evidence all points to the need for new regulations for the climate effects of CO. The current 

ambient concentration-based standards are not appropriate for large-scale global atmospheric 

concentration concerns aimed at protecting welfare. This will have to be emissions-based 

regulations similar to those being planned for CO2. I suspect that the state of the science not yet 

adequate to establish a specific CO emissions cap, and if that is the judgment of the EPA authors 

then the Integrated Science Assessment should clearly state that further research is needed to 

establish a numerical value for American CO emissions. Do we know what the safe level of CO 

in the atmosphere is? If not then the ISA should so state. 

The review of satellite measurements for establishing PRB concentrations is fair –existing 

instruments lack sensitivity in the PBL. Remote sensing is already useful for model evaluation 

and may some day be helpful for low-altitude measurements, and is 

There is one more relevant paper that came out in Science after the draft was finished; it shows 

gas/aerosol interactions can amplify the effects of non-CO2 trace gases on radiative forcing 

[Shindell et al., 2009]. 

Comments on ISA Charge Question 2b 

27
In reference to Chapters 2&3 that additional detail has been added on detection limits, number 

and spatial variability of CO monitors etc. “Please comment on the usefulness of theses 

revisions....” 

Table A-1 is a great addition. This shows that highly sensitive instruments are commercially 

available. Page 3-20. The LOD is given as 0.04 ppm, but Table A-1 shows 0.02 ppm. The ISA 

should say the replacement monitors should have the lower LOD’s. 

Page 3-12 Figure 3-8 is hard to read, perhaps a scatter plot. 

Page 3-22 The ISA should state the revoking the CO monitoring requirements impedes our 

scientific understanding of air quality and climate. The paragraph on NCORE is a great addition. 

Page 3-33. The bar has a black stripe on top that looks like it should be a red stripe. 

The additional detail in 3.5.1.2 is great. Page 3-45. The tale on top with E C A B D does not 

seem to correspond to the columns below. 

Comments on ISA Charge Question 6b 

A section and summary figure have been added to the end of Chapter 2. “We would appreciate 

CASAC comments....”

Figure 2.1 gives a good demonstration of the morbidity risks associated with CO, and is 

understandable by non-specialists in epidemiology. 

General Comments on ISA Chapters 2 & 3. 

There is some redundancy between Chapters 2 & 3 as well as within the chapters that could be 

eliminated without loss of coherence. 

Section 3.2 There is a need for a bottom line here: substantial uncertainties in emissions 

continue to exist. On page 3-4 is states that the reviewed literature is consistent in determining a 

decrease of 5% per year in on-road CO emissions. Does that agree with Figure 3.2? It might be 

but it would be nice to see it explicitly compared. 

Page 3-10. CH3OOH is not really soluble; the Henry’s Law coefficient is about 300 M/atm, 

much less that H2O2. 

Page 3-13. OH does not react with the major CFC’s that are fully halogenated (such as CFC-11 

and 12). There needs to be a hydrogen atom bound to the carbon somewhere. 

The Summary and Conclusions should state that: 

1. There are substantial uncertainties in the emissions inventories. 

 

28
2. The current state of the science is insufficient to determine what level of CO emissions is 

adequate to protect welfare from adverse changes in global or local climate and in the oxidizing 

capacity of the atmosphere. 

Minor points on ISA 

1. Page 2-20 line 14 space. 

2. Page 3-14 line 22 semicolon where a comma should be. 

3. The caption to Figure 3-10 and other similar figures should say that the circles indicate 

the position of the monitors. 

4. AADT is not in the table of acronyms. 

5. The word ‘fraught’ on page 3-85 seems odd to my ear.

29
Reference and some additional papers that may be of value to EPA. 

[Clements et al., 2009; El-Fadel and Abi-Esber, 2009; Saide et al., 2009; Tomlin et al., 2009; 

Wang and Zhang, 2009; Zhu et al., 2009] 

Clements, A. L., Y. L. Jia, A. Denbleyker, E. McDonald-Buller, M. P. Fraser, D. T. Allen, D. R. 

Collins, E. Michel, J. Pudota, D. Sullivan, and Y. F. Zhu (2009), Air pollutant 

concentrations near three Texas roadways, part II: Chemical characterization and 

transformation of pollutants, Atmospheric Environment, 43, 4523-4534. 

El-Fadel, M. and L. Abi-Esber (2009), In-vehicle Exposure to Carbon Monoxide Emissions from 

Vehicular Exhaust: A Critical Review, Critical Reviews in Environmental Science and 

Technology, 39, 585-621. 

Isaksen, I. S. A., C. Granier, G. Myhre, T. K. Berntsen, S. B. Dalsoren, M. Gauss, Z. Klimont, R. 

Benestad, P. Bousquet, W. Collins, T. Cox, V. Eyring, D. Fowler, S. Fuzzi, P. Jockel, P. 

Laj, U. Lohmann, M. Maione, P. Monks, A. S. H. Prevot, F. Raes, A. Richter, B. 

Rognerud, M. Schulz, D. Shindell, D. S. Stevenson, T. Storelvmo, W. C. Wang, M. van 

Weele, M. Wild, and D. Wuebbles (2009), Atmospheric composition change: ClimateChemistry interactions, Atmospheric Environment, 43, 5138-5192. 

Saide, P., R. Zah, M. Osses, and M. O. de Eicker (2009), Spatial disaggregation of traffic 

emission inventories in large cities using simplified top-down methods, Atmospheric 

Environment, 43, 4914-4923. 

Shindell, D. T., G. Faluvegi, D. M. Koch, G. A. Schmidt, N. Unger, and S. E. Bauer (2009), 

Improved Attribution of Climate Forcing to Emissions, Science, 326, 716-718. 

Shindell, D.T., et al. J. Geophys., Res., (2006) 111 D19306. doi :10.1029/2006JD007100. 

Tomlin, A. S., R. J. Smalley, J. E. Tate, J. F. Barlow, S. E. Belcher, S. J. Arnold, A. Dobre, and 

A. Robins (2009), A field study of factors influencing the concentrations of a trafficrelated pollutant in the vicinity of a complex urban junction, Atmospheric Environment, 

43, 5027-5037. 

Wang, Y. J. and K. M. Zhang (2009), Modeling Near-Road Air Quality Using a Computational 

Fluid Dynamics Model, CFD-VIT-RIT, Environmental Science & Technology, 43, 7778-

7783. 

Zhu, Y. F., J. Pudota, D. Collins, D. Allen, A. Clements, A. DenBleyker, M. Fraser, Y. L. Jia, E. 

McDonald-Buller, and E. Michel (2009), Air pollutant concentrations near three Texas 

roadways, Part I: Ultrafine particles, Atmospheric Environment, 43, 4513-4522. 

30
Dr. Laurence Fechter 

Comments on ISA question 5 

The discussion of susceptible populations to carbon monoxide has been dramatically improved. 

The data are now presented in a logical framework providing a clear and concise summary. The 

only minor change I would propose on page 5-167 2nd complete sentence is to revise as follows: 

"These analyses require the proper identification of confounders and their subsequent 

adjustment in statistical models, which helps eliminate spurious associations.” 

31
Dr. H. Christopher Frey

Review of Carbon Monoxide Second Draft of Integrated Science Assessment 

Charge Question 1: Chapter 1 has been revised in response to comments from the CO Panel, as 

well as related comments from the CASAC PM Panel, to add information regarding criteria for 

study selection and evaluation, to add more CO-specific information to the framework for causal 

determination, and to more clearly describe the process of integrating evidence from various 

disciplines to classify the overall weight of evidence relating to causality. What are the views of 

the Panel on the extent to which this revised Chapter 1 provides necessary and sufficient 

background information for review of the subsequent chapters of the CO ISA? 

Response to Charge Question 1: 

Chapter 1 is generally very good. 

The chapter should define the terms “sensitive,” “susceptible,” and “vulnerable” when they are 

first introduced. The term “sensitive” seems to be in the statutory language (see footnote 1 on p. 

1-3) and thus may have special regulatory significance. This should be explained. The role of 

identifying “susceptible” and “vulnerable” groups with respect to characterization of “sensitive” 

groups should be explained. Furthermore, these terms should be used consistently throughout 

the chapter. Moreover, EPA should develop a glossary of terms that are used across criteria 

pollutants, just to ensure consistency of terminology for ISAs and REAs for each criteria 

pollutant. 

Figure 1-1 should be revised. The current figure is unclear with respect to what it is depicting. It 

would be helpful if this figure follows the flow of an individual study or paper that is identified 

in the literature review. (will provide an alternative diagram). 

EPA has explained the criteria for study selection and evaluation. However, some additional 

explanation as to why the focus of the literature review is on studies conducted in the U.S. and 

Canada is needed. In particular, given the scarcity of literature on welfare effects, have studies 

from other countries been considered? 

In Section 1.4, the topic of welfare effects should be discussed more fully. EPA should 

explicitly comment on welfare effects or lack of information about welfare effect, so that the 

reader can understand the decision process that leads to lack of treatment of this topic in the ISA, 

and that the omission is intentional and well-reasoned. 

In Section 1.5, the text on page 1-10, line 22 refers to “the extensive body of literature” but only 

four references are cited. The text could be more clear as to the scope of the literature review 

and how it was narrowed to the four references cited. 

The scope of the critical review of ecological effects needs more detail. Specifically, what 

literature databases were searched, using what keywords, for what time period, geographic 

32
scope, and so on. Given the scarcity of literature on ecological effects of CO, can EPA 

nonetheless comment on hypotheses for ecological effects and identify what are the key data 

gaps. Such information would be useful for setting a research agenda to inform the next revision 

of the CO NAAQS. 

Page 1-11, line 4, the term “necessarily” seems out of place. 

The discussion of the framework for causality determination is much improved from the first 

draft, and nicely addresses CO-specific examples. 

Page 1-12, line 7, what is meant by “assessment?” Does this refer to “endpoint”? 

Page 1-13, line 3, the term “susceptible” is used. Here is unclear as to whether this is meant to 

inform a determination of “sensitive” groups. 

Section 1.6.3. The term “measure” is unclear. Does this refer to an empirical quantity that is 

measured, estimated, or predicted? Or does it refer to a metric for a quantity? Suggest that the 

term “measure” should be replaced with more specific or descriptive terms. 

Should avoid use of “etc.” (e.g., p. 1-13, line 16) and attempt to enumerate all items in a list. 

P. 1-13, line 22. An “assumption” is essentially an untested hypothesis. For example, an 

assumption that an interior indoor space is well-mixed is a hypothesis. More critical discussion 

of assumptions would be helpful. 

p. 1-13, line 25. Earlier, the term uncertainty “characterization” is defined as qualitative, but 

here it is implied to be quantitative. Use terminology consistently. 

p. 1-13, line 27. “assessing the evidence from across studies” – does “evidence” here refer to 

evidence for causality, or does it refer to empirical information from which scenarios, models, 

and model inputs are inferred? 

p. 1-16, line 5, please define “transfer of effects” 

Table 1-2 on p. 1-20 is very useful. Another table would also be useful. Recommend that a table 

be added that relates “aspects” to the “Weight of Evidence” categories. Example: 

Aspect Causal Likely to be 

Causal 

Suggestive of 

Causal 

Inadequate to 

Infer 

Not Likely to 

be Causal 

Consistency 

Coherence 

Biological 

Plausibility 

Biological 

Gradient 

33
Strength of 

observed 

association 

Experimental 

Evidence 

Temporal 

Resolution 

Specificity 

Analogy 

The entries in each row could either be text descriptions specific to each case, or some 

combination of graphics and text. A table such of this could be used in ISAs for all criteria 

pollutants. 

Page 1-21, line 9-10. Missing here is “exposure-response.” Dose and exposure are not the same 

thing, nor are exposure and concentration. Some discussion on these points would be helpful. 

Page 1-21, line 13-14. Here again, terms “susceptible” and “vulnerable” are used but not 

defined. How do these relate to “sensitive”? 

Page 1-21, line 29-31. Should also mention the role of exposure misclassification if ambient 

concentration is used instead of exposure. 

Page 1-22, line 5: it is not entirely self-evident that averaging will “linearize” a signal, and 

assumption such as this might introduce error. If the goal of a model is to predict individual 

incidences of adverse health effects (e.g., number of individuals affected), then averaging as 

discussed here might be problematic. 

Charge Question 6: Chapter 2 has been revised and expanded to provide more information on 

atmospheric science and exposure assessment, policy relevant considerations, and integration of 

CO health effects. 

a. The section on policy‐relevant considerations was revised to present additional detail on the

concentration‐response relationship observed in a multi‐center controlled human exposure

study, present results from a new U.S. multicity epidemiologic study investigating the potential

presence of a threshold and departure from linearity, and summarize the evidence for

susceptible populations. Please comment on these revisions.

b. A section and summary figure have been added to the end of Chapter 2 to summarize the main

conclusions of the ISA regarding the health effects of CO and the range of concentrations at

which effects are observed, along with uncertainties that complicate the interpretation of the

evidence. We would appreciate CASAC comment on the material in this section and its

effectiveness in presenting the conclusions of the ISA.

Response to Charge Question 6: 

There should be more clear discussion and justification of the absence of treatment of ecological 

effects. 

34
Page 2-2, line 11-12; it may not be entirely correct to state that CO is formed by photochemical 

reactions. While there is a role of photochemistry in secondary CO formation, CO can also be 

formed from chemistry involving radical attack on various hydrocarbon species. Hence, suggest 

splitting this sentence into one for primary emissions of CO, and one for secondary formation of 

CO. 

Page 2-3, line 7, please state what is the inferred PRB for CO for CONUS. 

Page 2-5, it should be stated that correlation in ambient CO concentration between monitors may 

not imply the same spatial correlation in CO exposure. 

Page 2-5, line 15. Exposure assessment is not complicated by multipollutant mixtures that 

include CO. The epidemiological inferences may be. 

Page 2-5, line 18, does “spatial and temporal variability” refer to exposure here? 

Page 2-5, line 31, define “pCO” 

Page 2.6, line 4, lack of definition of “susceptibility” in Chapter 1 leads to lack of clarity as to 

what are the various categories of susceptibility that are not listed here. 

Page 2-8, line 21-23. A policy question is whether NAAQS should be protective of incremental 

health effects to smokers from exposure to ambient pollution, and whether the concentrationresponse, exposure-response, or dose-response relationship for effects associated with ambient 

CO are linear or not. These points should be clarified. 

Page 2-9, line 1: do the increases refer to smokers, or nonsmokers? 

Page 2-14, line 6-7. Could clarify that the interaction is for CO as part of a mixture. 

Page 2-14, should bring up exposure misclassification issues here and how they affect the weight 

of evidence discussion and inferences regarding possibility of health effects. 

Section 2.6, policy-relevant considerations. 

Please add a table that defines and lists attributes of “susceptible,” “vulnerable,” and “sensitive” 

Page 2-16, line 21, is the 10-15% increase on a relative basis or in terms of COHb percentage 

points? Reader infers the former, but this could be more clear. 

Section 2.6.2 concentration-response 

The chapter would benefit from a discussion somewhere of the difference between 

concentration, exposure, and dose. Terms should be used consistently. For example, p. 2-18, line 

32 refers to “dose-response” but might actually be based on potential dose or exposure. 

Similarly, top of page 2-19, isn’t it the case that clinical studies deal with potential dose and not 

merely concentration? 

35
Table 2-1, label the number scale at the bottom of the last column – i.e. define “effect estimate.” 

Page 2-22 seems repetitive of Section 2.5 

Page 2-22 and 2-23. There seems to be contradictory text to the effect that exposure 

misclassification leads to bias (see p 3-113, lines 2-4) and then later that it would only widen 

confidence intervals (p-23, lines 17-18). 

Page 2-25, line 14 – seems to presume a linear dose-response relationship. This should be stated 

and discussed. 

What about ecological effects? Health effects associated with climate change? 

36
Dr. Milan Hazucha

Revised Comments on Chapter 4: Dosimetry and Pharmacokinetics of Carbon Monoxide 

of the Second External Review Draft of the ISA for Carbon Monoxide 

Charge: “In response to comments from the CASAC CO Panel, material has been added to 

Chapter 4 describing comparisons among predictive COHb models, the relative influence of 

differing exposure scenarios on COHb concentration, and endogenous CO production rates in 

individuals with various diseases and conditions. Please comment on the usefulness of this 

information in illustrating the factors influencing COHb kinetics and potential COHb levels 

under various scenarios”.

This chapter of the Second Draft is much more comprehensive in discussing the respective 

material. The Chapter has been expanded by more than one third. New subsections were added 

(4.2.3, 4.3.4, 4.4.3.1) and most of the old subsections were expanded, some substantially (4.2.4, 

4.5). This is mostly to the benefit by facilitating better understanding of the section topics. 

In general, the authors adequately addressed CASAC’s CO panel comments by appropriate 

revisions and addition of relevant material discussed in sufficient detail. One question, however, 

which in my view was not satisfactorily answered, is “Which COHb model is the best in 

estimating venous COHb”? 

Section 4.2.1 The Coburn-Forster-Kane and Other Models 

The discussion of various models has been slightly expanded and a most recent model by 

Gosselin et al, 2009 is discussed as well. This model has been developed for and commissioned 

by Health Canada, Air Health Effects Division. It is a comprehensive model based on CFKE and 

it seems to estimate experimental data very well under a variety of environmental and 

occupational conditions. 

Section 4.2.3 Model Comparison” 

This is a new very helpful section. It discusses strengths and weaknesses of various models 

reviewed in previous sections. However, at the end, there is no conclusion, no recommendation 

as to which model is the best in estimating venous COHb. With so many different COHb 

prediction models it will be difficult for most of the readers to select the best model. If not here, 

maybe section 4.6 Summary and Conclusions could be more specific. 

Section 4.2.4 Mathematical Model Usage 

This is a substantially expanded section by discussing comprehensively The Quantitative 

Circulatory Physiology (QCP) model supported by several plots. Extensive discussion of this 

model seems to suggest that this is another “preferred” model for COHb estimation. So it 

appears that we now have two “preferred” models, Gosselin et al, 2009 and QCP. Again, which 

one gives the best estimation of venous COHb? Since these models have been described in a 

considerable detail, why not to compare COHb estimates utilizing one of exposure profiles, e.g., 

like in fig. 4-2. Moreover, all of the discussed models are predicting venous COHb. Is it possible 

to use these two or any other models to estimate transient arterial COHb level? It would be 

helpful to have a one paragraph discussion of utility of these models, if any, in estimating 

transient arterial COHb level if such data exist. 

37
Section 4.3.2.4 Other Tissues 

Although this is only a page long section with two tables, I was (in the first draft) and am still 

struggling with presented material. There is a substantial discussion of animal studies. However, 

the data were based on CO exposures with COHb levels as high as 80%. I do not think that these 

data are relevant. Maybe, table 4-2 showing human data, though some at very high COHb would 

be sufficient, and drop table 4-3. 

Section 4.3.4 COHb Analysis Methods 

This new section gives a very good discussion of current methods used for COHb analyses. It 

discusses advantages and limitations of various methods which is helpful in interpretation of 

data. 

Section 4.4.3.1 Fetal Pharmacokinetics 

Short and concise new subsection with a figure, pointing out to maternal-fetal differences in 

COHb buildup and elimination. However, there are more recent studies published on 

maternal/fetal COHb correlation that should be briefly discussed as well ( Hayde et al., Early 

Human Development 58:205-212, 2000 and other articles from this group., Ziaei et al, Paediat 

Perinat Epidemiol 19:27-30, 2005). Although these studies are concerned with specific diseases 

they have used healthy controls. 

Section 4.5 Endogenous CO Production and Metabolism 

Substantially expanded and quite comprehensive. The authors went beyond CASAC’s CO panel 

suggestions for revisions and discuss in detail, including very helpful tables, various health 

conditions and diseases that can increase endogenous CO production and subsequently elevated 

COHb. This is all supported with abundance of references. It is an excellent review. 

More specific comments: 

Reference list needs to be updated. 

Page 4-3, lines 1-9: It would be easier to follow parameter and variable description if they were 

listed in two columns. 

Page 4-3, line 17 and p.4-9, line 7: Clarify. Do you mean ±0.5% of the nominal value? 

Page 4-5, l. 9: Which two parameters? Be more specific. 

Page 4-9, l.13 Clarify. Is it Gosselin’s model? 

Page 4-9, l.14: Clarify. Is it linear or non-linear CFK model? 

Page 4-10, l. 6: There is no 4 ppm value in table 4-1. 

Page 4-10, table: increase font size for VA

Page 4-10, l. 16: This study was done in police cars which are regularly maintained and tuned. 

So the real CO value is somewhere between 5 and 50 ppm. 

Page 4-14, l.14: insert after “interface” the words “into plasma and subsequently into RBC” 

Page 4-15, fig. 4-7. Unusual referencing of the source. Why not simply say that the source is 

U.S.EPA 2000. 

Page 4-16, l. 22: The value for Haldane constant M is reported to be 218. However, some 

sections report the use of other values, like 230. The M value should be used uniformly, 

whenever possible. 

Page 4-17, l. 17: Suggest replacing “quickly” with “2-10 min”. 

38
Page 4-20, table 4-3; I am not sure that we need this table. For most of exposure conditions listed 

in the table COHb levels are well beyond the scope of this document. Suggest deleting. 

The three sentences in the text (line11-14) are sufficient. 

Page 4-21, l. 2-15: Similarly, the discussion of rodent’s data does not seem to be too relevant. In 

some referenced studies, though not on the list, %COHb levels were as high as 80%. 

Page 4-23, l.17: “distribution” might be a better word than “uptake”. 

Page 4-28, l. 27-29: Delete, not relevant. 

Page 4-31, l 6: Suggest replacing “processes” with “function” 

Page 4-31, l.8: Suggest replacing “combat” with “compensate for” 

Chapter 5: Integrated Health Effects of the Second External Review Draft of the ISA for 

Carbon Monoxide (sections 5.1 and 5.5). 

Section 5.1 Mode of Action of CO toxicity. This revised section covers in adequate depth 

various mechanisms of CO effects at a cellular level, including NO and CO signaling, redox 

status and modulation of kinase activity. I would highlight very important but easily overlooked 

determination stated on p.5-16, line 7-8 which says that “...the situation of increased 

endogenous CO production and of exogenous CO exposure are not equivalent.” This 

distinction is critical to understanding the cellular mechanisms of action of CO from different 

sources. Thus, exogenous CO tissue effects at low concentration are more general and the 

pathways of action are not necessarily the same as that of endogenous CO. 

In contrast, the summary statement on p. 5-31, l.25-26, over interprets the reviewed studies in 

this subsection (5.2.1.8). Considering all the caveats these studies report, there is a lack of 

coherence between the endpoints and the evidence of the effects is of uncertain significance. 

Section 5.5 Respiratory Effects. The author(s) of this section should have been more critical 

evaluating the studies discussed in this section, particularly when summarizing the findings. For 

example, on p.5-118, l.13-17 how can the Asthma study findings, to quote “suggest a potential 

effects of CO on lung function at relatively low CO concentration..” when CO is 3.8 ppm? This 

is a concentration which will result in <1% COHb. Moreover, in asthmatics the endogenous 

production is higher than 3.8 ppm (section 4.5)! At this level CO has no effects on lung function! 

Similarly, contrary what is stated on p.5-120, l.7-9 European studies do not provide stronger 

evidence than the US studies. Their findings are also full of caveats which make the conclusions 

uncertain. 

Page 5-143, l.13-14 state that “epidemiologic studies provide evidence of positive 

association.....” However, statements on l.18-23 which is a correct summary of available 

evidence contradict this assertion. 

Page 5-143, l.29-30 statement should be reconciled with subsequent statement on l.31-32 which 

correctly summarizes the available evidence. 

39
Dr. Michael Kleinman 

Charge question 3: Material has been added to Chapter 4 describing differences among models 

that predict COHb concentrations as a function exposure and physiological parameters. This is 

useful however the summary and conclusions do not make it apparent which model will be 

preferred for health risk assessments and why. 

Specific Comments: The new illustrative material could be better coordinated. Table 4-1 for 

example demonstrates that COHb concentrations increase with increasing ventilation rates after 

1- and 8-hr of exposure but begin to decrease at 24 hr. The explanation may come later in the 

chapter but it would be useful to mention the rationale in the description of the Table. 

Figure 4-4 does not seem to agree numerically with Table 4-1 for the higher exposure 

concentrations. Also COHb levels for exposures at 20 ppm seem to be increasing during the first 

8 hours and those at 50 ppm are decreasing. The curves appear to be show them approaching the 

same concentration if the subject continued to sleep. It would be helpful to add a graph of Va 

used for the model keyed to the right Y axis. 

Figure 4-5 data for endogenous production 0.007 does not appear to be consistent with Table 4-

1. 

Figure 4-6 seems unnecessary since the scenario it presents is not related to any real-world case 

and its importance is not explained in the text. 

The Bruce and Bruce model is claimed to better predict COHb levels when inspired CO levels 

change rapidly, as might occur during start-up conditions in some combustion emission scenario 

and is said to better predict CO washout than does the CFK. However the previous examples 

seem to have been calculated using the CFK. Some reason for why the Bruce and Bruce model 

is not selected would be useful. 

40
Dr. Francine Laden 

Section 5.1.3.2. Recent Studies of Non-Hypoxic Mechanisms, is an excellent summary and I 

agree with its conclusions. The multicenter controlled human exposure study is well described 

and the levels at which effects were observed are now clear. 

One editorial comment, the definitions of Hb and Mb should be repeated at the beginning of each 

chapter 

The descriptions of the epidemiologic studies and the studies of the associations between blood 

markers and ambient CO concentrations are good. The following reference should be added to 

5.2.1.8: 

Delfino RJ, Staimer N, Tjoa T, Gillen DL, Polidori A, Arhami M, Kleinman MT, Vaziri 

ND, Longhurst J, Sioutas C. Air pollution exposures and circulating biomarkers of effect 

in a susceptible population: clues to potential causal component mixtures and 

mechanisms. Environ Health Perspect. 2009 Aug;117(8):1232-8. 

A table or figure summarizing the results from the blood markers studies (much like the ones 

included later in the chapter) would be very helpful. 

A similar table or figure summarizing the results of the HRV, ECG abnormalities, arrhythmias, 

blood pressure (Sections 5.2.1.1. through 5.2.1.7. would be helpful as well. 

In Figure 5.6. it should be made clearer that the other pollutants, used as separators, are included 

as co-pollutants in the models of CO with the different cardiovascular outcomes. 

I agree with the conclusions of each of the other health outcomes: CNS, birth outcomes, 

respiratory effects, mortality , and of susceptible populations. 

41
Dr. Arthur Penn 

Initial response to CO ISA, 2nd external review draft

Many of the conclusions presented in the 2nd external review of the ISA, are retained 

(understandably) from the 1st ISA, My focushere is on areas of CVD-related outcomes on which 

less emphasis has so far been placed and which I believe deserve additional attention since they 

deal with biological plausibility of CVD outcomes in response to elevations in low daily ambient 

CO levels. These outcomes also are consistent with the statement at the top of p. 5-67 “It is 

conceivable that the most sensitive individuals respond to levels of COHb lower than 2%” as 

well as with the “causal relationship” statement at the bottom of that page. 

Ambient CO Effects on CVD

The most impressive CO-related CVD results remain the 20+-year-old controlled human 

exposure studies of Allred et al; Kleinman et al; Sheps et al; however, a direct 

connectionbetween these results and the predictions for CO effects on CVD morbidity/mortality 

at CO levels close to ambient has yet to be made. The effective CO exposure levels in those 3 

studies were > 2 orders of magnitude above ambient levels and resulted in COHb levels of 2-

4%.With ambient CO levels at 0.5-0.6 ppm and associated COHb levels well below 2%, the gap 

between a) the controlled studies with small numbers of high-risk volunteers exposed 

to>100ppm CO and b) real-life,large population exposures to small increases (<1 ppm) in daily 

max [CO] is too large to discount at present. Further, other studies (Adir et al, 1999; Kizakevich 

et al, 2000) with healthy volunteers suggest little or no major responses to elevated (as high as 

3000 ppm) CO exposure levels. In those studies there were no reported arrhythmias, no changes 

in lactate/pyruvate, no effects on ST-segment changes or on cardiac rhythm. 

The focus on possible CO effects in patients with major artery occlusion and MI history is 

understandable from the perspective of a potentially highly susceptible population, but moves 

attention away from other populations that may be more likely at risk to elevations in ambient 

CO. 

Alternative populations meriting attention are the groups suffering from CHF (pp. 5-43 to 5-45) 

and arrhythmias (pp. 5-24 to 5-26). While most of the evidence here is carried over from the 1st

ISA Draft, some of the reports summarized in this section + others noted in other sections of 

Chapter5 are worthy of further consideration. In addition I have added some studies from the 

past 12 years that were not mentioned in the 2nd ISA Draft. 

Results reported by Yang(JTEH, 2008) on Taipei data for the years 1996-2004--while CHF 

hospital admissions (HAs) were associated with all 5 major air pollutant groups for warm days, 

the only association on cold days was withincreases in ambient CO. 

Mann et al (EHP, 2002) reported that a 1ppm increase in 8-hr average CO in So. California was 

associated with a 3.6% increase in same-day IHD HAs for patients with a 2o

diagnosis of CHF 

and 2.99% increase for those with a 2o

 diagnosis of arrhythmias. 

42
Peel et al, (Am J Epidemiol, 2007) reported an association between a 1 ppm elevation in 1 hr 

max CO and HAs for patients with dysrhythmias and CHF who had hypertension as a co-morbid 

condition. This was an 8-year study with > 4.4 million patient visits to 31 Atlanta area hospitals. 

Other relevant CO/CHF studies include: 

a) Morris et al (AJPH, 1995)--elevated ambient CO levels in 7 US cities were associated with 

increased HAs for CHF in elderly patients; 

b) Burnett et al (Epidemiology, 1997)--daily high hour ambient CO levels on day of HA had the 

strongest association of any of the 5 major air pollutants with HAs for CHF; 

c) Morris and Naumova (EHP, 1998)--HAs in Chicago for CHF were most strongly associated 

with increases in ambient CO-effect was strongest at lowest temperature (see Yang, above); 

d) Stieb et al (Environ Hlth, 2004)--in a multicity study in Canada (1980s & early 1990s), for 

every 0.7 ppm increase in 24-hr mean [CO], there was a 2.6% increase in ED visits for 

MI/angina, but a 3.8% increase in visits for CHF; 

e) most recently, Bell et al (EHP, 2009- in ISA reference list, but not discussed??) in a study of 

emergency HAs for CVD and their association with 1 hr max. CO levels in 126 US urban 

counties (av. max CO level=1.6 ppm) found the highest % increase in CO-related risk for HAs 

(~1%) was for heart failure in patients > 65 yrs of age. HAs for 9.3 million patients over 7 years 

were examined. 

The downside of these studies-that they are association/correlation studies—is countered by the 

large #s of patient records screened in each of these independent studies and the similarity of the 

findings for urban CHF/arrhythmia patients in the US, Canada & Taiwan. 

Blood Markers of CO Exposure-Coagulation (but not inflammation)

A few recent studies (Baccarelli et al, 2007; Delfino et al, 2008; Rudez et al, 2009) point to 

increased platelet activation and pro-coagulation effects associated with elevations in ambient 

CO. In these and other studies (Ruckerl et al, 2006, 2007; Steinvil et al, 2008) elevations in 

fibrinogen in response to elevated CO are largely absent. Many of these studies note that 

elevations in ambient CO were not associated with any inflammatory responses (see question to 

Panel members below). One exception was the recent report of Ljungman et al, (EHP, 2009). 

Among 955 MI survivors, the 16% with specific polymorphisms in both IL-6 & fibrinogen genes 

showed larger IL-6 responses to elevated CO than did MI survivors without these 

polymorphisms. 

Q. for Panel members: In light of the EPA’s interest both in controlled human studies with 

responses to exposures to> 100 ppm CO and responses of large populations to 1 ppm increases 

in peak ambient CO, are there any Panel members concerned (intrigued?) by the growing interest 

in therapeutic uses of CO as an anti-inflammatory agent? A number of recent studies on animal 

models of injury/disease (sickle cell disease, I/R injury, lung injury associated with 

43
cardiopulmonary bypass) have reported on the therapeutic value of treatment with “low”, i.e., 

250 ppm, doses of CO. 

44
Dr. Beate Ritz 

 

1. The framework for causal determination presented in Chapter 1 was developed and 

refined in other ISAs (e.g., the PM ISA). During previous reviews, CASAC generally 

endorsed this framework in judging the overall weight of the evidence for health effects. 

Please comment on the extent to which Chapter 1 provides necessary and sufficient 

background information for review of the subsequent chapters of the CO ISA. 

This chapter has improved but still does not adequately address and present methodologic 

concepts in epidemiology and, thus, lacks clarity in how epidemiologic studies are evaluated and 

determined to be “high or low quality studies” as necessary for applying the criteria listed in 

Table 1.2 (i.e. for assessing the weight of evidence for causal determination). 

A minor point: I previously recommended using the more appropriate term ‘effect measure 

modification’ instead of ‘effect modification’ but the wording in this chapter has not been 

corrected. More importantly, however, while there is some improvement, the authors of this 

chapter still seem to not be fully understanding nor formulating adequately some of the issues 

involved in confounding and confounder control. They claim on page 1-15 that “deciding which 

variables to control for in a statistical analysis of the association between exposure and disease or 

health outcome depends on knowledge about possible mechanisms and the distribution of these 

factors in the population under study. Identifying these mechanisms ...”. Knowledge of 

‘mechanisms’ may help, but such knowledge is not needed to decide whether a covariate is a 

potential confounder neither is it necessary to know mechanisms to assess confounding. It is 

furthermore completely obscure what the authors mean by the following sentence on page 1-15 

“adjustment for potential confounders can be influenced by differential exposure measurement 

error”; here they seem to confuse error in measuring confounding variables with error in 

exposure assessment? Finally on page 1-13 the second sentence under 1.6.3. “Uncertainty can be 

defined....” seems to confuse precision and validity or at least does not acknowledge that these 

are two different concepts that have a different place in judging study results. These confusions 

of concepts does not instill much confidence in the ability of staff who wrote this chapter to 

judge epidemiologic studies adequately according to established criteria for study validity and 

precision (both contributing to accuracy); this is further confirmed by the chapter 5 qualitative 

reviews that are still grossly lacking in consistency and interpretation of epidemiologic results. 

The criteria for causal determination detailed in table 1-2 are similar to those used by the 

IOM and the International Agencies for Research on Cancer. Yet, they leave open what the 

criteria are for deciding that a study is high quality (for example, confounding is a bias, so why 

list bias and confounding apart from chance?) and it is also unclear what is meant by “replicated” 

results and why this would be a criterion. Again, without a standardized approach to the review 

of epidemiologic studies or a quantitative meta-analysis based review, these criteria remain 

ambiguous. Since the epidemiologic literature on criteria air pollution health effects has 

multiplied greatly in the past decade, it would be appropriate if EPA staff abandoned qualitative 

reviews in favor of quantitative effect estimates based on meta-analytic procedures to draw 

inferences about the scientific literature and used standardized and transparent rules for data 

abstraction. Such a systematic and quantitative procedure requires making the authors’ 

45
assumptions explicit rather than allowing authors to emphasize studies they agree or disagree 

with and to pick the results they like to emphasize over others. Such quantitative reviews could 

be contracted out to entities that are able to conduct meta- or pooled analyses. 

5. Chapter 5 presents information on cardiovascular, central nervous system, 

developmental, respiratory, and mortality outcomes following exposure to CO. To what 

extent are the discussion and integration of toxicological, clinical, and epidemiologic 

evidence for these health effects scientifically sound, appropriately balanced, and clearly 

communicated? Are the tables and figures presented in Chapter 5 appropriate, 

adequate, and effective in advancing the interpretation of these health studies? 

In Chapter 5, the qualitative description of epidemiologic studies improved somewhat but is 

still inadequate; the level of detail devoted to each study in the text seems still arbitrary and the 

information provided in tables and figures selective without being systematic; for example why 

did the authors decide to present in Figure 5-8 the citywide and negative associations for the 

Australian CO study of PTB (Jalaludin) and not the positive associations for births within a 5km 

radius of a monitor. The review of birth weight and air pollution is lacking a discussion of the 

difference between LBW and term LBW sorely needed since LBW includes preterm birth 

outcomes that are then discussed separately and studies examining LBW are possibly more 

comparable in their results to those examining PTB; only term LBW is a mutually exclusive 

outcome. Also the measure of birthweight as a continuous outcome compared to the 

dichotomous variables LBW and PTB deserve some more general introduction about their 

general value (similar to the discussion of SGA versus IUGR), i.e. do we really expect the whole 

birthweight distribution to shift according to ambient air pollution exposures or only the most 

susceptibly infants to be affected. 

Surprisingly, there is still a lot of information I requested in my first review missing from this 

new draft. This includes the following: no information is provided in the tables concerning the 

type of study design employed (e.g. Table 5-12). I also already mentioned previously that many 

of tables report mean CO levels and mention 24 hrs or 8 hrs in brackets; this is misleading for 

pregnancy outcome studies in which the averages are for trimesters, weeks, or months (e.g. the 

Ritz et al. (2000) study of PTB is listed in table 5-12 as having a Mean CO of 2.7 ppm for the 6-

9 am period – however this mean represents a mean over the whole first month of pregnancy and 

the Wilhelm and Ritz (2005) study mentions a 1.4 ppm mean for 24 hrs but this is in fact a first 

trimester mean of 24 daily measurements; the way this data is shown now the bracketed 24 hour 

mention seems to imply similar averaging period and comparability in effect estimates. I also 

mentioned already previously that while the Ritz et al 2007 study is listed in table 5-12 no results 

for this study are presented in figure 5-6. I had also recommended to rescale quartiles to a 

continuous estimates rather than leaving results from important papers out of a figure that gives 

an overview over all study results. 

Also I mentioned previously that according to the text accompanying the figures, the 

estimated increase in CO presented have been ‘standardized’, however, how this might have 

been done across so many different study types and averages for differing exposure periods 

(rather than 24 hour averages as the authors of these chapters seem to imply) has not been 

46
explained. Also, in figure 5.1 the title says that the effect estimates have been standardized to a 

1ppm increase in ambient CO for 1-hr max CO concentrations, 0.75 ppm for 8-h max CO 

concentrations and 0.5 ppm for 24 hrs avg CO concentrations, but the figure does not tell us 

which scale has originally been used in which study and it might be questionable whether effect 

estimate sizes based on these different scales and based on different length lag periods are 

comparable to each other (indicating which study used which scale would be informative. 

There are also sentences in this review chapter that are plainly wrong, e.g. on page 5-71 and 

OR of 1 (95% CI 0.96-1.04) is called a positive association. 

47
Dr. Paul T. Roberts 

Revised Comments on 2nd draft ISA

ISA Charge Question 2. Chapter 3 has been revised and expanded in response to Panel comments 

regarding climate, monitoring, spatial variability, and exposure. 

2b. Additional detail has been provided regarding ..... Please comment on the usefulness of these 

revisions in characterizing the information provided by the CO monitoring network. 

In general, the expanded discussions in the 2nd draft ISA Chapter 3 on CO detection limits, monitoring 

details, and spatial CO characteristics are very useful in characterizing the information provided by the 

CO monitoring network and in qualifying the data for use in exposure estimations. My detailed 

comments are provided below. 

In discussion of non-anthropogenic CO emissions on page 3-5: it is confusing in the first paragraph 

(starting on line 3) to have fire emissions of about 13% (14.5 MT) shown in Figure 3-1, but biogenic 

emissions of about 5% not shown in Figure 3-1, and the text implies that the geogenic emissions are 

included (in the miscellaneous category?). This is confusing to the reader and makes it difficult to 

compare these smaller, but still important sources. Please add biogenics to Figure 3-1 and make it clear 

what is included. 

Comments on discussion of Hudman et al and Figures 3-3 and 3-4, starting on page 3-5 at line 21: 

First, I suggest that this be a new paragraph; it is a different topic from the non-anthropogenic emissions. 

In addition, the CO from oxidation of VOCs, of isoprene, and of other biogenic VOCs (see lines 27-29), 

which are apparently huge in this simulation, relative to the anthropogenic CO emissions, have not been 

discussed before. These secondary emissions sources needed to be discussed in the overall context of 

CO emissions first (or put the general discussion in with the Climate text, Chapter 3.3.1). In addition, 

the potential influence of this huge source of CO on the results of the simulation and the conclusion 

needs to be discussed. I also suggest that Figure 3-3 be dropped, since I find it hard to compare these 

colored spatial plots. In contrast, Figure 3-4, as an example of the results, gets the point across that 

reducing the anthropogenic emissions by 60 % made significantly better comparisons with 

measurements. Maybe also add a statement saying that other results in the paper support this general 

conclusion. 

Additional comment on the paragraph on page 3-5, lines 21-29: I suggest that a sentence be added 

translating the Tg amounts to MT, so that these emissions can be placed in context with the rest of the 

emissions discussion. 

Comments on page 3-7, lines 13-15: I suggest that a comment be added (either in the text or the figure 

caption) about general transport winds being from west to east at this latitude, thus carrying the 

emissions from the Alaska fires across Canada and the northern US and into the north Atlantic, as shown 

in Figure 3-5 (assuming the data support this). 

48
Page 3-11, lines 9-10: The comment on the significant quantities of aromatics in gasoline is likely no 

longer true, since regulations have significantly reduced aromatics in gasoline (and these references are 

old). I suggest that these comments be modified to say that this used to be the case, but less so with 

current fuel content. 

Page 3-12, lines 8-9: The comments on limited mixing between the hemispheres would benefit from an 

additional comment that northern hemisphere CO emissions are significantly larger than the emissions 

in the southern hemisphere, plus a representative reference. 

In general, the expanded discussions on monitor detection limits and monitoring locations in 

Chapter 3.4 (pages 3-18 to 3-31 and associated Annex figures and tables) are critical to 

understanding CO concentrations and are an important addition to the ISA. However, these 

limitations are still often left out of the discussions on CO concentrations in Chapter 3.5. In 

general, the relaxation of CO monitoring requirements and the continued use of older, less 

sensitive, monitors with poor levels of detection impedes the use of monitoring data for exposure 

assessments and climate, especially in the future as CO concentrations decrease. See my detailed 

comments below. 

Page 3-19, lines 20-23: This discussion on the needs for trace-level CO measurements should include 

the use of low-level CO data for improved exposure estimates at current ambient concentrations in many 

locations in the US. 

Table 3-2: Please fix the first row of the table. I think there should be a header row labeling the 

columns as “Parameter” and “Specification”, for example, plus the current first row should be part of the 

body of the table and left justified in each column. 

Page 3-20 lines 3, 12, and 18: The LODs listed on these lines are not the same as listed in the 

referenced Table A-1 in the Annex, which lists the LOD of the trace-level monitor as 0.02, not 0.04. 

Thus, the value listed as 50% of the LOD on line 6 should be 0.01. Note also that several of the LOD 

levels listed in slide 10 of the presentation should be 0.02, not 0.04. 

Page 3-20, line 5: I suggest that this line start with “When the monitored value is below the LOD, some 

states... 

Page 3-20, line 14, page 3-21 and Figure 3-8: This discussion on a comparison of older and newer 

monitors with specific quantifications is a good one, and important to include here. However, the last 

sentence of the paragraph (lines 6-8) does not make sense to me. Also, the CO axis of the figure needs 

to be labeled and the units of the time axis needs to be added (hours since some start time, or?). The 

similar figure in slide 10 of the presentation is much better at showing the data, plus the axis are labeled; 

these are good modifications and address my comments on the figure. 

The limitation of the LOD issues discussed in Chapter 3.4 need to be added in several places in Chapter 

3.5, including at the beginning of the sentence that starts on line 11 of page 3-36, in Figures 3-7, 3-8, 

and 3-9. In particular, statements similar to the paragraph at lines 13-18 on page 3-43 (good job there!) 

could be added to address this issue at these locations in the text and in the conclusions (3.7.3) and the 

summary of conclusions (2.1). 

49
Page 3-41, lines 1-3: What was the cause of the 10.9 ppm CO measured at the Newkirk, OK site? This 

seems like an unusual concentration. 

Page 3-43, lines 13-18: This is a good qualifying paragraph which is needed here and other places. On 

line 15, I suggest the following wording: “...in large part very near or below the detection ...” 

Figure 3-18 on page 3-45 (and Figure 3-20): How is the data below LOD treated for this and similar 

figures? Might this influence the lower ends of the box-whisker plots? I suggest that a comment on this 

be added. 

Chapter 3.5.1.2: Add a note that all of these monitors in LA and Denver are older, higher LOD, 

monitors, and add some comments similar to the comments at lines 13-18 on page 3-43. 

Page 3-60, lines 14-15: I don’t see how the data shown in Figure 3-24 can lead to a statement that 

includes the following words “...near-road CO concentrations..” . 

Page 3-76, lines 5-6: I suggest this sentence be moved to the end of the paragraph at lines 12-21 on 

page 3-77. In addition, the sentence should read “....analogous to Figures 3-36 and 3-37 for ....in Annex 

A, Figures A.44 to A.48.” 

Page 3-77, line 11: I suggest these are meteorological, not micrometeorological factors. 

2c. The section on exposure assessment has been reorganized to provide information on ..... Does 

the Panel consider that the sources of exposure error have been appropriately characterized, and 

agree with the revised conclusions regarding the impact of exposure error due to spatial 

variability and the presence of CO as part of a combustion-related mixture on health effect 

estimates from time-series epidemiological studies? 

In general, the expanded discussions in the 2nd draft ISA Chapter 3.6 on sources of exposure and 

exposure assessment are a great improvement and are very useful in characterizing the potential impacts 

of exposure error. My detailed (minor) comments are provided below. 

Page 3-93, lines 18 and 29: Please explain or modify the terms “driven cavity” and “posterior 

probability distribution function”. 

Page 3-94, lines 6-23, section on Land Use Regression Models: This section is still very limited in 

scope and does not represent the wide range of results from the literature. Admittedly, much of the LUR 

work in the literature is on pollutants other than CO, but the types of conclusions regarding what 

methods work and how they relate to estimating pollutant concentrations are directly applicable to CO. 

See the list of references I suggested last time (re-listed at the end of my comments), plus there must be 

many more than I could easily find. 

50
Page 3-98, line 11: How can a regression coefficient be 1.99 (greater than 1.0)? Also, the results in 

lines 9-11 and in lines 13-14, although from the same reference, seem inconsistent; please explain how 

they are consistent or different. 

Page 3-114, line 26: Table A-1 says the LOD for trace-level FRMs is 0.02, not 0.04 as stated here. 

Page 3-115, lines 13-17: Please add the limitation statement on LOD to this section regarding 

characteristic concentrations. 

Page 3-117, line 15: I suggest that the word “nearby” be added, so that the sentence would read “...at a 

location with few nearby CO sources could...”. 

In summary, Chapter 3 of this 2nd External Review Draft of the ISA clearly conveys and 

appropriately characterizes the atmospheric science and air quality analyses. The information 

provided regarding CO source characteristics, CO chemistry, policy-relevant background CO, 

and spatial and temporal patterns of CO concentrations accurate are relevant to the review of the 

CO NAAQS. 

Minor edits and typos in the 2nd draft ISA: 

- page 3-2, line 22: word near end of the line should be “inherent” 

- Page 3-41, line 16: suggest that “medians” be replaced with “median correlation coefficients (r)” 

- Figures 3-17 and 3-19: I can barely make out the lines for the highways (whereas the ones in the 

Annex are fine); lease make darker. 

- Make bolder the lines separating the scales in Tables 3-10 and 3-11; it is currently difficult to 

read. 

- Page 3-72, line 2 should read: “...as shown in Figure 3-6.” not in Figure 3-32. 

- It is very hard to see the 95th and 5th percentile lines in Figures 3-33 and 3-34; please make 

darker or bolder. 

- Page 3-85, lines 17 and 24-25: I suggest that you use words other than “fidelity” in line 17 (and 

line 4 of page 3-86) and “fraught” in line 25; maybe “accurately” and “are difficult”. Also, add a 

comma after troposphere in line 24. 

Selected, easy for me to find, references for Land Use Regression and spatial mapping (see above 

discussion on Chapter 3.6.3): 

Gauderman, Avol, Lurmann, Kuenzli, Filliland, Peters, and McConnell “Childhood Asthma and 

Exposure to Traffic and Nitrogen Dioxide, Epidemiology 2005; 16, 737-743. 

Ross, Jerrett, Ito, Tempalski, and Thurston “A land use Regression for predicting fine particulate matter 

concentrations in the New York City region”, Atmospheric Environment 41 (2007) 2255-2269. 

Hoek, Beelen, Hoogh, Vienneau, Gulliver, Fischer, and Briggs “A review of land-use regression models 

to assess spatial variation of outdoor air pollution” Atmospheric Environment 42 (2008) 7561-7578. 

51
Henderson, Beckerman, Jerrett, and Brauer “Application of Land Use Regression to Estimate LongTerm Concentrations of Traffic-Related Nitrogen Oxides and Fine Particulate Matter ES&T 2007, 41, 

2422-2428. 

Molitor, Jerrett, Chang, Molitor, Gauderman, Berhane, McConnel, Lurmann, Wu, Winer, and Thomas 

“Assessing Uncertainty in Spatial Exposure Models for Air Pollution Health Effects Assessment EHP 

vol 115,no 8, August 2007. 

Popawski, Gould, Setton, Allen, Su, Larson, Henderson, Brauer, Hystad, Lightowlers, Keller, Cohen, 

Silva, and Buzzelli “Intercity transferability of land use regression models for estimating ambient 

concentrations of nitrogen dioxide” J Exposure Science & Environmental Epidemiology (2008), 1-11. 

52
Dr. Armistead Russell 

Review of CO ISA 2nd Draft 

In general, I am pleased with the modifications to the ISA, and believe that the 2nd draft is 

stronger in general. It provides the level of information needed to support the REA and policy 

analyses. 

In response to specific Charge Questions: 

2. Chapter 3 has been revised and expanded in response to Panel comments regarding 

climate, monitoring, spatial variability, and exposure. 

I appreciate the substantial information added in regards to the potential impact of CO on 

climate. As noted, the impact is likely small, and highly uncertain, though the physics are such 

that it almost has to have an impact, even if unknown or not soon knowable. While this lack of 

certainty may inhibit developing a related secondary standard, it should motivate the appropriate 

research to assess the likely magnitude of the impact. The section on monitoring and 

instrumental capabilities is likewise strengthened. This section should continue to stress the 

utility of CO as an indicator for gasoline-powered automobile emissions, and the CO monitoring 

network has tremendous value beyond just demonstrating attainment. 

a. Evidence reviewed in Chapter 3 of the ISA indicates that the direct contribution of CO 

to greenhouse warming is very small, while the role of CO in atmospheric chemistry 

cycles involving other species makes a larger contribution to radiative forcing. This 

combined evidence leads to the conclusion in Chapter 2 that a causal relationship exists 

between current atmospheric concentrations of CO and effects on climate. What are the 

Panel’s opinions related to this causal statement and the evidence provided to support it? 

A causal statement is appropriate, though it should also note that the extent of the impact 

is highly uncertain which inhibits using a causal determination to develop a secondary 

standard at this time. 

b. Additional detail has been provided regarding the detection limits of CO monitors in 

the regulatory network, the number of monitors reporting at each horizontal spatial 

measurement scale and comparison of monitoring data at each scale, and spatial 

variability of CO concentrations near major sources, particularly roadways. Please 

comment on the usefulness of these revisions in characterizing the information provided 

by the CO monitoring network. 

This addition strengthens the document. Further discussion of the adequacy of the 

current monitoring network and the potential implementation of a near-road network 

should be considered. 

53
Dr. Anne Sweeney 

Legislative Requirements: Page 1-3. Lines 25-28 (selecting a margin of safety): include a 

reference to the EPA’s Supplemental Guidance for Assessing Cancer Susceptibility from EarlyLife Exposure to Carcinogens (2005) 

Identification of studies for inclusion in the ISA: Page 1-7, line 4: “included approaches to 

evaluate issues related to confounding and effect modification by other pollutants”---add “and/or 

host characteristics”; i.e., the level of control for all potential confounding/effect measure 

modification. 

Page 1-7, line 5: “Addressed health points and populations not previously extensively 

researched”: a word of caution in that new evidence can alter previously accepted results. 

Scientific Evidence Used in Establishing Causality (1.6.1) Page 1-12, lines 10-13: Add case 

control design to types of observational studies 

Page 1-7, lines 7-10 (and elsewhere): need to discuss volunteer bias in human clinical studies 

Application of framework for causal determination: (1.6.4) Page 1-17: Add to line 21: 

Strength of the association” 

Effects on Human Populations: (1.6.5.1) Page 1-22, lines 26-32: Include references to articles 

published regarding critical windows of susceptibility (from the 2000 EPA workshop on same) 

I strongly agree with Dr. Ritz’s suggestion to conduct meta-analyses on the growing number of 

studies assessing air pollution and adverse human health effects. 

Additional references on Gestational Development 

Jensen TK, Bonde JP, and Joffee M. 2006. The influence of occupational exposure on male 

reproductive function. Occup. Med. (Lond.) 56(8):544-553. 

Hauser R, Meeker JD, Duty S, Silva MJ, and Calafat AM. 2006. Altered semen quality in 

relation to urinary concentrations of phthalate monoester and oxidative metabolites. 

Epidemiol. 17(6):682-691. 

Hauser R. 2006. The environment and male fertility: recent research on emerging chemicals and 

semen quality. Semin. Reprod. Med. 24(3):156-167. 

Hauser R. 2008. Urinary phthalate metabolites and semen quality: a review of a potential marker 

of susceptibility. Int. J. Androl. 31:112-117. 

De Rosa M, Zarrilli S, Paesano L, Carbone U, Boggia B, Petretta M, Maisto A, Cimmino F, Puca 

G, Colao A, and Lombardi G. 2003. Traffic pollutants affect fertility in men. Hum. Reprod. 

18(5):1055-1061. 

Guven A, Kayikci A, Cam K, Arbak P, Balbay O, and Cam M. 2008. Alterations in semen 

54
parameters in toll collectors working at motorways: does diesel exposure induce detrimental 

effects on semen? Andrologia 40:346-351. 

Hammoud A, Carrell DT, Gibson M, Sanderson M, Parker-Jones K, and Peterson CM. 2009. 

Decreased sperm motility is associated with air pollution in Salt Lake City. Fertil. Steril. 

[Epub ahead of print]:19217100. 

Hsu PC, Chen I-Y, Pan CH, Wu KY, Pan MH, Chen JR, Chen CJ, Chien G-C, Hsu CH, Liu CS, 

and Wu MT. 2006. Sperm DNA damage correlates with polycyclic aromatic hydrocarbons 

biomarker in coke-oven workers. Int. Arch. Occup. Environ. Health 79(5):349-356. 

Rubes J, Rybar R, Prinosilova P, Vesnick Z, Chvatalova I, Solansky I, and Sram RJ. 2009. 

Genetic polymorphisms influence the susceptibility of men to sperm DNA damage 

associated with exposure to air pollution. Mutat. Res. Oct. 2. 

Sokol RZ, Kraft P, Fowler IM, Mamet R, Kim E, and Berhane KT. 2006. Exposure to 

environmental ozone alters semen quality. Environ. Health Perspect 114(3):360-365. 

Xia Y, Han Y, Zhu P, Gu A, Wang L, Lu C, Fu G, Song L, and Wang X. 2009. Relation between 

urinary metabolites of polycyclic aromatic hydrocarbons and human semen quality. Environ. 

Sci. Technol. 43(12):4567-4573. 

55
Dr. Stephen Thom 

Modifications in the second draft are well done and improve the Integrated Science Assessment 

(ISA) for carbon monoxide. It was a good idea to include sections that integrate health effects 

risks, but there seem to be some internal contradictions in reviews of pulmonary injury outlined 

in chapters 2 (starting on page 2-12) and 5 (starting on page 5-144). The ISA may be open to 

criticism because conclusions pertinent to short term and long-term CO exposures differ, but the 

discussions outline similar limitations in the data. The statements below are mostly excerpts 

taken directly from the ISA, but they were put in a different order than in the actual document. 

Morbidity assessments for short and long term CO exposure:

Animal toxicological studies provide evidence that short-term exposure to CO (50-100 ppm) can 

cause oxidative injury and inflammation and alter pulmonary vascular remodeling. Controlled 

human exposure studies have not extensively examined the effect of short-term exposure to CO 

on respiratory morbidity. Positive associations between short-term exposure to CO and 

respiratory-related outcomes include effects on pulmonary function, respiratory symptoms, 

medication use, hospital admissions, and ED visits. The problem is that the majority of this 

literature does not report results of extended analyses to examine the potential influence of model 

selection, effect modifiers, or confounders on the association between CO and respiratory 

morbidity. In particular, the lack of co-pollutant models prevents assessment of which effects are 

due to CO versus other combustion-related pollutants. Yet, the ISA conclusion is that evidence is 

suggestive of a causal relationship between short-term exposure to relevant CO concentrations 

and respiratory morbidity. 

The ISA outlines limitations in studies that have examined the association between long-term 

exposure to CO and respiratory morbidity including the lack of replication and absence of 

validation studies to evaluate some of the epidemiological statistical methodologies, whether 

health effects observed can be explained by the known biological mechanisms and an absence of 

co-pollutant analyses to disentangle the respiratory effects from CO versus other combustionrelated pollutants. The conclusion was that the evidence is inadequate to conclude that a causal 

relationship exists between long-term exposure to relevant CO concentrations and respiratory 

morbidity. 

Mortality assessments for short and long term CO exposure:

Epidemiological evidence was reviewed from multi- and single-city studies which suggest that 

there is an association between short-term exposure to CO and mortality. The limitations in the 

data were highlighted along with the observation that CO risk estimates were attenuated in copollutant models. Despite the uncertainty as to whether CO was acting alone or as an indicator of 

effects related to other combustion-related pollutants the ISA concluded that evidence suggests 

there is a causal relationship between short-term exposure to relevant CO concentrations and 

mortality from respiratory disorders (page 5-158). 

56
57

With regard to pulmonary-related mortality from long-term CO exposure, the ISA outlines the 

consistent null and negative associations observed across epidemiologic studies which included 

cohort populations encompassing potentially susceptible subpopulations. The discussion includes 

an assessment that there is a lack of evidence for respiratory and cardiovascular morbidity 

outcomes following long-term exposure to CO (Note that page 5-56 discusses long-term 

cardiovascular effects observed in epidemiological studies. A conclusion is offered that there is a 

direct effect of short term exposure and cardiovascular disease morbidity – see page 5-67, but no 

summary statements are made regarding long term exposures). These assessments, along with an 

absence of specific mechanisms to explain the progression from morbidity to mortality, are used 

to conclude that it is unlikely that there is a causal relationship between long-term exposure to 

CO and mortality (page 5-166). 

To conclude, my impression is that similar limitations exist in the data for pulmonary effects 

from short term and long term CO exposure. Despite this similarity, short term effects on 

morbidity and mortality are given a stronger summary assessment of risk (evidence suggests 

there is a causal relationship) whereas long-term CO exposure is said to be unlikely to be 

causally linked to respiratory morbidity and mortality.