UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C. 20460

OFFICE OF THE ADMINISTRATOR
SCIENCE ADVISORY BOARD May 19, 2010

EPA-CASAC-10-012

The Honorable Lisa P. Jackson

Administrator U.S. Environmental Protection Agency 1200 Pennsylvania Avenue, N.W. Washington, D.C. 20460

Subject: Review of the Risk and Exposure Assessment for the Review of the Carbon Monoxide Primary National Ambient Ai r Quality Standards (NAAQS): Second External Review Draft

Dear Administrator Jackson:

The Clean Air Scientific Advisory Committee (CASAC or Committee) Carbon Monoxide (CO) NAAQS Review Panel me t on March 22-23, 2010 to review EPA’s Risk and Exposure Assessment for the Review of the Ca rbon Monoxide Primary National Ambient Air Quality Standards (NAAQS): Second External Review Draft . The Chartered CASAC held a public teleconference on April 19, 2010, to review and approve the report. This letter provides

CASAC’s overall comments and eval uation. We highlight the most important issues which need

to be addressed as the sec ond draft Risk and Exposure Assessment (REA) is finalized.

The Panel expressed appreciati on to EPA staff for the major improvements made in the second draft of the REA. The changes are respon sive to the suggestions and concerns expressed by the Panel in its review of the first draft. Nonetheless, CASAC offers several suggestions and

concerns to be considered as the second draft undergoes final revisions.

The Panel encourages a clearer distinction be tween the levels set for the CO NAAQS and the concentrations at which expos ures are currently experienced throughout the country. Current

levels of CO are far lower than historic levels a nd the risk for health eff ects associated with these current levels may be minimal or difficult to quantify with certainty. However, the degree of protection afforded to susceptibl e populations by the current NAAQS still needs to be considered by EPA. A greater degree of pr otection may be warranted.

As mentioned in its review of the first draft, the Panel felt strongly that the focus of the REA, and the associated Policy Assessment document, should be broader than cardiac ischemia (coronary artery disease or CAD). The Panel recognizes that compelling evidence comes from

clinical studies demonstrati ng a relationship between elevat ed levels of carboxyhemoglobin

1(COHb) and a reduced time to the onset of angina. These studies have been at the center of the evidence used to set the NAAQS for CO. Howe ver, there is increasing evidence that CO increases the frequency and sever ity of congestive heart failure a nd enhances susceptibility to arrhythmias. Consequently, we recommend that a broad set of health outcomes be considered, beyond cardiac ischemia. The susceptible populations might also include those with pulmonary disease and the fetus. The Allred et al. (1989) study should be more completely presented. While a reduction in time to onset of angina is an important and easily interpretable clinical outcome, this response is subjective. In contra st, the outcome of ST segment depression, as assessed by a blinded cardiologist , is an objective measure of m yocardial ischemia and should receive greater consideration. Moreover, ST segment depression has been validated, both as an outcome of inadequate delivery of oxygen to the myocardium and as a risk factor for more frequent arrhythmias.

The Panel recommends greater clarity rega rding the major contributors to COHb: ambient outdoor exposures, endogenous production of CO within the bod y, and finally indoor sources of CO from home cooking, heating, and passive smoking. The relative importance of

these contributors to COHb must be more cl early delineated. The REA should address how these multiple sources are used in modeling and contribute to variability and uncertainty in

model results.

We are concerned about two aspects of the adequacy of the current CO monitoring network. First, more sensitive and precise monitors need to be deployed to measure levels that are less than or equal to 1 ppm. Such monitors are needed to validate CO exposure models. Second, the approach for siting monitors needs gr eater consideration. More extensive coverage may be warranted for areas where concentrations may be more elevated, such as near roadway

locations. The Panel found that in some inst ances current networks underestimated carbon monoxide levels near roadways. Such underestima tion is a critical issue since populations with low social economic status (SES) are often overre presented in those areas. People with SES are more likely to smoke, a substantial source of CO . In addition, African Americans have a higher incidence of sickle cell disease, which affects oxygen transport.

In regard to the quantitative risk assessment, the Panel recommends greater clarity in describing the model that was used, along with in formation available about its validity. The profile of COHb in time with va rying CO exposures is complex since loading (increased COHb levels) is much more rapid than unloading of COHb levels as ambient CO levels drop. In an analysis that acknowledges multiple sources, it is essential to emphasize the increment which is

attributable to ambient CO.

2The CASAC and Panel membership are listed in Enclosure A. The Panel’s responses to EPA’s charge questions are presented in Enclosur e B. Finally, Enclosure C is a compilation of individual panel member comments. We l ook forward to the Agency’s response and the successful completion of the CO NAAQS review.

Sincerely,

/Signed/ /Signed/

Dr. Joseph D. Brain, Chair Dr. Jonathan M. Samet, Chair CASAC CO Review Panel Clean Air Scientific Advisory Committee

Enclosures

3NOTICE

This report has been written as part of the activ ities 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.

4Enclosure 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 Profe ssor of Environmental Physiology, Department of Environmental Health, Harvard School of Public Healt h, Harvard University, Boston, MA

MEMBERS

Dr. Paul Blanc , Professor and Chief, Department of Medicine, Endowed Chair, Occupational and Environmental Medicine, Division of Occupa tional and Environmental Medicine, University of California San Francisco, San Francisco, CA

Dr. Thomas Dahms , Professor and Director, Anesthesiol ogy 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 Civ il, Construction and Environmental Engineering, College of Engineering, No rth 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 Hi ll, Chapel Hill, NC

Dr. Joel Kaufman , Director, Occupational and Environmen tal 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 St ate University, Baton Rouge, LA

5Dr. Beate Ritz , Professor, Epidemiology, School of Public Health, University of California at Los Angeles, Los Angeles, CA

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

Dr. Armistead (Ted) Russell , Professor, Department of Civ il 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 H ealth 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, 1200 Pe nnsylvania Avenue, NW, Washington,

DC

6

### 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 Profe ssor of Environmental Physiology, Department of Environmental Health, Harvard School of Public Healt h, Harvard University, Boston, MA

Dr. H. Christopher Frey , Professor, Department of Civ il, Construction and Environmental Engineering, College of Engineering, No rth Carolina State University, Raleigh, NC

Dr. Donna Kenski , Data Analysis Director, Lake Mi chigan Air Directors Consortium,
Rosemont, IL

Dr. Armistead (Ted) Russell , Professor, Department of Civ il 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

7Enclosure B

CASAC’s Consensus Responses to EPA’s Charge Questions

1. Does the Panel find the summary of CO ex posure and discussion of ambient CO sources, exposures, dose, health effects and risk char acterization approach to be technically sound, clearly communicated, and appropriately characterized?

In general, the Panel found Chapter 2 to be well organized, technically sound and a good conceptual overview of the REA. The chapter provides a sound rationale for the decision to use

COHb level as the internal dose metric for assessing exposure to ambient levels of CO and for characterizing the potential for h ealth risks in the population of persons with coronary artery disease (CAD). While some Panel members supported a cautious approach to using epidemiological data in the risk assessment, overall there were concerns that the current presentation under-emphasized the epidemiologic fi ndings. Even if the epidemiological data are not used in the risk assessment, it is important to incorporate them into the discussion of risk. The epidemiological evidence provides information on non-hypoxia relevant mechanisms and

chronic outcomes that cannot be addre ssed by relying on COHb levels alone.

The Panel continued to be concerned with EP A’s designation of the at-risk population. The choice of modeling risk for the CAD population needs to be furthe r justified and/or expanded to include other susceptible populations. Again, the findings of epidemiological studies suggest several groups to be consider ed, especially the broader categ ory of cardiovascular disease (CVD). Since this chapter serves as the intr oduction to the REA, it should be edited as the Panel’s recommendations are incorporated into subsequent chapters.

2. Does the Panel find the considerations of current ambient carbon monoxide monitoring data, including specifically the data for the monito rs included in this draft of the assessment, and the discussion of the extent to which near ro adway concentrations are represented to be technically sound, clearly communicate d, and appropriately characterized?

The discussion is technically sound, clearly comm unicated, and appropriately characterized. The treatment of the CO monitoring data, the descripti on of the extent that these monitors represent near-roadway concentrations, and the data used in this iteration of the assessment are improved

over the first external draft REA. The curr ent monitoring network does not represent nearroadway concentrations very accurately, whic h is now well-documented in the REA. The

increased discussion of NCore and measurement characteristics is usef ul and appropriately placed.

Should there be additional monitoring for i ndoor and in-vehicle expos ures? Representative monitoring to evaluate emissions inventories or models may be different from monitoring to

assess exposure.

3. In recognition of CASAC comments of first draft REA, this draft REA is expanded from the previous assessment in a number of ways (summa rized in section 1.3 of the draft document). The assessment study areas are in the Den ver and Los Angeles study areas. We are

8interested in eliciting the views of the Panel on the usefulness of this approach in informing our review the NAAQS for CO. What are the P anel members’ views on the following aspects in which the assessment has been expanded from the previous draft?

a. An important change of this assessment from th e first draft is the ex pansion of each of the modeling domains to include a greater numbe r of ambient monitors used as input to APEX. Additionally, this draft assessment empl oys an algorithm that adjusts for temporal and spatial heterogeneity in ambient con centrations across each study areas.

An important improvement in this assessment fr om the first draft is the expansion of each modeling domain to include a greater number of ambient mo nitors for input to APEX. Additionally, this draft assessmen t employs an algorithm that adjusts for temporal and spatial heterogeneity in ambient concentrations across e ach study area. While use of a larger number of ambient air monitors may have improved exposure assessment, we are not convinced that spatial heterogeneity driven by proximity to sources ca n be adequately captured by the current ambient monitoring network. In fact, e xposures outdoor, in homes and in workplaces near roadways might be underestimated.

It would be helpful to describe with greater clarity how data from overlapping districts, zones and areas were treated for input into the APEX model. What approach was used to avoid duplication of input data from overlapping zones? For Los Angeles, was one of the areas designated as a dominant source or was each area considered separately in the assessment? These are all questions that should be addressed in future analyses.

In generating simulated individuals, demographi c variables should includ e socioeconomic status (SES) and race if possible. These variables will impact other APEX modules, particularly COHb. If not, future data collection e fforts should provide sufficient coverage.

We find the tables of exposure values vs. estim ated number and percentage of CHD persons affected at specific CO concentrations to be ve ry instructive. Tables showing estimated COHb levels vs. number of people with CHD and persons/days are similarly instructive. Additional

calculations and tabulation of endogenous COHb level using APEX and additional plots reflecting contribution of endogenous COHb to total COHb are illustrative.

b. The current draft assessment also in clude an increase in the number of

microenvironments modeled over that in the first draft (from two to eight) and improved the representation of variability in estim ated microenvironmental concentrations, including in-vehicles.

The Panel has no major issues with this approach.

c. This draft assessment has implemente d the mass-balance model for estimating

concentrations in indoor microenvironments.

We consider the selection of the mass-balan ce model for indoor air to be appropriate.

94. Does the Panel view the results of the draft exposure analyses to be technically sound,clearly communicated, and ap propriately characterized?

The Panel questions EPA’s assumption that it has captured spatial heterogeneity in homes and workplaces near busy roadways. We agree with the summary of findings (p. A-5) that the current physiology file data is obsolete and may ev en be incorrect for some variables. While some variables were already updated, others su ch as race, SES, total hemoglobin (THb) and DLco should be either added or replaced in th e input module. With these qualifications, the Panel answers affirmatively to question 4.

5. Does the Panel find the de rivation and presentation of th e modeling approach as a whole (chapters 4 and 5) to be technically s ound, clearly communicated, and appropriately
characterized?

The data added to the ambien t source inputs for the exposure modeling reflect commendable responsiveness to the feedback we provided in the previous review of the initial REA draft. The modeling appears to be technically sound.

The subject matter is complex and highly challenging to communi cate clearly, particularly the material in Chapter 4. The presentation of this material seems to be aimed at the exposure modeling community, which makes it difficult for ot hers to readily grasp. Nonetheless, the detailed description of the APEX model provides a helpful snaps hot of the extensive nature of the model. The derivation and presentation of the modeling approach as a whole are well presented. Moreover, the application of the “CHAD” database in modeling the physiological changes of simulated residents during their daily lives appears to be appr opriately handled. This approach has been applied and vetted for othe r regulated air pollutants. Nonetheless, the coupling of the non-linear CFK with the CHAD in the APEX model would be more convincing if this approach had been validated with actual field study measurements of delivered dose. We understand, however, that such va lidation is not possible on pr actical grounds. Moreover, previous approaches are less sophisticated from a modeling point of view and also lack field validation for the same reasons of feasibility.

Appendix C contains some helpful illustrations of the variability in time spent for a given individual in locations/activities throughout the ye ar. It might be helpful, additionally, to have

similar illustrations of:

1. Estimated %COHb levels for an individual duri ng a day with exposures that were near current criteria (maximum allowable) levels of atmospheric CO, and

2. An illustration of the potential va riability in peak levels of %COHb throughout the year.

Indeed, inclusion of such illustrative scenarios in the text, rather than in the Appendix, should be

considered. This material could assist the reader in understandi ng the variability in the modeled levels of CO exposure.

6. Does the Panel find the derivation and pr esentation of the COHb estimates (Chapters 5 and 6) to be technically sound, clearly co mmunicated, and appropriately characterized?

10The derivation and presentation of the %COHb estimates are clearly communicated and characterized. However, the final %COHb estimate s, as presented in the REA, are potentially problematic. This is related, in part, to thei r derivation and the basic assumptions made in arriving at these values, not the computationa l operations of the APEX system. Modeling %COHb, as a biological marker of ambient CO exposure, presents particular challenges stemming from the various sources of exposure, each of which can potentially contribute to the

final %COHb estimate. These sources include : endogenous production; ambient air pollution; and indoor air sources not accounted for by ambi ent pollution tracking indoors (e.g., combustion byproducts from home heating or cooking and se condhand smoking-associated CO). Extensive modeling in the REA appropriately deals with s cenarios of ambient CO contributions to the indoor exposure environments. It was only well into Chapter 6 that modeling including “Internal

Sources” of COHb was introduced. The Panel fu rther takes issue with the confusing word

choice since this does not mean internal in the sense of endogenous metabolism . As shown in Tables 6-15 and 6-16, excluding these indoor sources, modeled %COHb values (i.e., from ambient exposures levels) are similar between the 2000 model that also provides the indoor (“internal”) estimates and the current APEX model. Key is that inclusion of the indoor sources of exposure drives up exposure such that five pe rcent of the population hits a 3% COHb level and roughly two percent of the popula tion reaches a 4.0% COHb level.

The Panel appreciated the addi tional attention given to endogenous CO production (again, not the “Internal” metric above). There was concer n that this discussion co uld lead to confusion, because the modeled levels of endogenous %COHb are quite a bit lower than population means for non-smokers. This is because the actual data for the non-smoking population reflect the sum of ambient exposure, indoor exposure, and endog enous CO production. It might be useful to clarify these distinctions explic itly. Beyond issues of presenta tion, the modeled distribution of endogenous %COHb values seems too narrow. It appears to be based on “normal” healthy population estimates of endogenous production (alb eit with a variety of activity levels). Literature demonstrating elevated endogenous %COHb values in certain subpopulations (for example, in persons with sickle cell disease) may be difficult to account for in these models, but an attempt to address them is warranted. At a minimum, the REA shou ld directly acknowledge

this limitation of the model estimates.

Further confusion may be introduced through th e random subset estimations, given that the central tendency (mean) of this random sub-sample seems to differ from the larger modeling estimate (apparently a chance observation). The narrower distribution is produced by the limited intra-person variation since most of the data points are derived from multiple runs on a relatively small subset – (this should not explain the shift in the mean). It may even be relevant to acknowledge that certain groups at risk for higher endogenous production systematically may be more likely to have higher ambien t scenarios (e.g., persons with si ckle cell disease, low SES, and those living/working near a major roadway). The lack of transparen cy in the endogenous production model as applied may also contribut e to confusion. The description of what endogenous rates were used in the model is unclear and the information in Table B-3 on page B20 is poorly labeled. Despite these limitations , the material on endogenous production of CO

and its contribution to the overa ll %COHb in combination with ambient levels of CO is very informative and indeed necessary. In summary, the Panel is concerned that there is no modeling

11of %COHb that covers indoor non- ambient s ources and endogenous CO production, as well as ambient exposure.

The staff’s presentation at the meeting included additional analyses of the contribution of

ambient CO to the COHb% levels. The Panel found the analyses presen ted during the meeting represented an improvement of the discussions in the REA itself. Although the data were apparently computationally intens ive to develop, some Panel memb ers believe that the additional analyses could be an extremely useful avenue for further development of the standard. The specific increase in %COHb over the subjects’ pre-exposure or filtered air exposure was the focus of the influential Allred et al. papers and not on the magnitude of the final %COHb. It may well be that the ambient-attributable increment in %COHb is the most directly analogous

dose for consideration in a risk assessment. Using incremental %COHb as the metric for ambient-attributable dose could simplify the risk assessment because the i ssue of “overlap” with the endogenous range of final COHb% (let al one indoor non ambient contributions) would be parsed-out. This treatment coul d still delineate the other sources of exposure as above-noted and

would address the Panel’s concerns with regard to the continuity of the CO exposure-response in experimental studies. The presentation of incremental exposure data and estimated %COHb combined and separately would allow policy makers to consider ambient exposure alone, as well as in the context of other sources of exposure.

7. In the Panel’s view, to what extent does the modified assessmen t approach employed in this second draft assessment provide re sults that meaningfully inform the EPA’s consideration of the public health imp lications of the current standards.

The modified assessment approach has two key components: estimated exposure and estimated at-risk (susceptible) population. In terms of exposure, it should also be noted that the additional

information included in the current modification do es not relieve uncertainties from the use of a relatively limited data set (i.e., two case studie s in Denver and Los Ange les), even with the additional monitoring data. The REA could be improved by showing the impact, or lack of impact, on dose variability that resulted from the in clusion of data from more monitoring sites.

Data resolution from the two case studies and inclusion of data fr om more monitoring sites will be particularly relevant for national extrap olations. The Panel has provided additional suggestions to strengthen the exposure component in response to other ch arge questions. Such improvements could serve to better inform th e EPA’s consideration of the public health implications of the current CO standard.

There are serious potential data uncertainties in the estimates of the “at risk” population, many of which might lead to a systematic underestimation of the public health impact of CO exposure. The REA continues to rely singul arly on the National H ealth Interview Survey (NHIS) data to provide a population estimate of persons at ri sk. The “at risk” population has been narrowly defined as self-reported corona ry artery disease, which was the Panel’s primary point of contention and critique of the first draft REA. The revision now includes an estimate of “undiagnosed” disease that represents approxima tely 40% in addition to the base population. This is an important acknowledgment of one as pect of systematic underestimation, although the

American Heart Association source of the mathematical value used is far from convincing. It is

12recommended that EPA incorporat e a female>male differential to address the probable sex-based gap in CAD diagnosis.

Data from NHANES and the Beha vioral Risk Survey are eas ily accessible and will generally support the NHIS-based, restricted subset of susceptib le persons based on a CAD definition. However, the narrowly-defined CAD prevalence es timate, to the exclusion of all others with cardiac disease, misinterprets th e ISA (particularly Tables 4-9, 5-10, 5-11 and Figures 5-5 though 5-7). Revisiting the NHIS, the prevalence rates fo r “all heart disease” are considerably greater than those of narrowly defined CAD. It is very likely that most, if not all, of these persons are at

increased risk for adverse cardiovascular effect s from ambient CO in ways that cannot be distinguished epidemiologically fr om the CAD subset. It is certainly appropriate for the REA to present estimates, as indeed it did, using a narrow CAD definition of “at risk” to inform an EPA public health assessment. However, this approach alone is not sufficient. Much effort is spent on multiple scenarios of exposure, while falling s hort in the critical area of defining alternate measures of the vulnerable popula tion. As a consequence of th e approach suggested above, a population more broadly defined with cardiovascular disease is likely to overlap to a meaningful

extent with adults with chroni c obstructive lung disease (through sh ared risk factors), which may be another at risk group for adve rse CO exposure effects. This is not a determining factor, however, in the rationale for applying a more broadly-defined cardiac disease definition in modeling the at-risk population.

8. What are the views of the Panel regarding th e adequacy of the assessment of uncertainty and variability? To what extent have sources of uncertainty b een identified and the implications for the risk characterization been characterized? To what extent has variability adequately de scribed and represented?

In general, the incorporation of more monito rs in each area, more microenvironments, and variability in various variable s within APEX better addresses variability and thus general uncertainty in exposure and dose. However, th e use of the power 0.621 in equations 4-11 and 4- 22, reduces the CO concentration at an outdoor location, relative to the nearest central monitor, and thus possibly reduces the number of occu rrences of the highest CO concentrations.

In addition, all three contributors to COHb (ambient, endogenous production, and indoor sources, excluding smoking) should be considered in modeling and as contributing to variability and uncertainty in model results.

13

### Enclosure C

Review Comments from the CASAC CO Panel on the Second Draft Risk and

Exposure Assessment to Support the Review of the Carbon Monoxide Primary NAAQS

Comments received :

Dr. Paul Blanc ............................................................................................................................... 15

Dr. Thomas Dahms ....................................................................................................................... 18

Dr. Russell Dickerson ................................................................................................................... 21

Dr. Milan Hazucha ........................................................................................................................ 23

Dr. Francine Laden ....................................................................................................................... 29

Dr. Arthur Penn ............................................................................................................................. 30

Dr. Beate Ritz

............................................................................................................................... . 31

Dr. Paul T. Roberts ....................................................................................................................... 32 Dr. Anne Sweeney ........................................................................................................................ 34 Dr. Stephen Thom ......................................................................................................................... 35

14

### Dr. Paul Blanc

5. Does the Panel find the de rivation and presentation of th e modeling approach as a whole (Chapters 4 and 5) to be technically s ound, clearly communicated, and appropriately
characterized?

Insofar as the increase in puts to the ambient source inputs to th e models, this revision was quite responsive to the input that it received in review of its initial draft and is to be commended. This aspect of the approach appears to be techni cally sounds. This subjec t matter is complex and highly challenging to communicate clearly, in part icular the material in Chapter 4. .

6. Does the Panel find the derivation and pr esentation of the COHb estimates (Chapters 5 and 6) to be technically sound, clearly co mmunicated, and appropriately characterized?

The final COHb estimates in 6 are problem-ridde n. This is related in part to the derivation (including under this the basic assumptions made, not simply the mathematical operations of the APEX system). The presentation magnifies cert ain issues by potentially obscuring points presumed to be manifest but that may be to be more explicit.

Modeling COHb, as a biological marker of ambien t air pollution exposure, presents a particular challenge because there are 4 principal domai ns of exposure, each which can potentially

contribute to the end concentration measured. These 4 domains are: endogenous production; ambient air pollution; active cigarette smoking; and supplemental sources of carbon monoxide beyond these three. This fourth dom ain, for most persons, is drive by indoor air exposure to CO from combustion byproducts from home heati ng or cooking and secondhand smoking-associated CO [although other sources of exposure within this domain may be important for population subsets, e.g., occupationally-related CO exposure].

Chapter 5, in relation to CO exposure modeling leading to COHb is focused entirely on the domain of ambient CO, although extensive modeli ng deals with scenarios of contributions of ambient CO to indoor exposure environments. Th is can be a bit confus ing because internal combustion engine contributions to exposure in certain indoor scenarios are essentially point sources (service station and auto repair GM 2.97 [PPMs although not labeled]). Of note, another indoor facility group includes (Manufacturing facility) and is rather low – GM 0.089. One

assumes fork lifts or truck deliveries not c onsidered. The salient poi nt however is: these scenarios exclude other likely co ncomitant sources of exposure.

It is not until well into Chapter 6 that modeling that includes the domain of “Internal Sources” of

COHb is introduced. The term Internal as used here is unfortunate, since it ac tually is intended to

mean “indoor – not from ambient sources ” i.e., what I refer to as the 4 th domain above. If this also includes endogenous production it is by no means clear. As shown in Tables 6-15 and 6-16, excluding these indoor sources th ese estimated exposures levels are similar between a 2000

model and the current APEX model – but inclusion of this critical sour ce of exposure drives up exposure such that 5% of the population hits a 3% COHb level and roughly 2% a 4.0% COHb

15level. Remarkably there is no simulation or ot her estimation combining current indoor sources

with the ambient estimates.

Despite the short-shrift give the indoor exposure issue, a great deal of attention is then given to endogenous CO production. This, of cour se, is not “Internal” as used above, but rather refers to “normal” metabolic production of CO. This secti on is likely to lead to some confusion because, quite appropriately, the modeled levels of COHb% (population mean 0.255%) are quite a bit lower than population means for non-smokers. The reason of course if that observed nonsmoking population data reflect the sum of domains 1,2,and 4, no simply endogenous production (thus the baseline samples in the Allred study, etc) . This is a point of blurred presentation, not modeling. The modeling itself, however, could bene fit from more transparency. The reader is

told that a certain number of studies informed th e metabolic parameters as detailed in B but in

fact it is hard to tease-out whic h references there are the ones in question. These seem to be fairly dated (Coburn’s work from the 1960s) and this may be the best there is. Nonetheless, more recent literature exploring moderately elevated C OHb in certain conditions (for example, sickle cell disease) suggests that the model specifi cations and simulations yielding a maximum endogenous value of 1.54 is not likely to be refl ective of population variability. This may be driven by simulating 59 indivi duals only, albeit with 8,760 hours of modeled observation. To capture endogenous variability, within person hour to hour activity inputs is not nearly as important as between person variability. Moreover, it is likely that certain at risk groups may be more likely to have ambient scenarios (and i ndoor scenarios) of highe r exposure: eg. a low income resident of south-central LA dwelling near a freeway with sickle cell disease (and heating the home with a gas stove in the winter).

Integrating the comments above, there is no appa rent modeling of COHb that includes variable indoor not ambient sources (exclusive of dir ect cigarette smoking) + endogenous CO production (anticipation a possible bimodal distribution, with certain disease states contributing a sub-group of outliers) and ambient exposure.

7. In the Panel’s view, to what extent does the modified assessmen t approach employed in this second draft assessment provide re sults that meaningfully inform the EPA’s consideration of the public health imp lications of the current standards.

The modified assessment approach has two key components: estimated exposure and the estimated at risk (susceptible) population. All of the comments above (charge questions 5 and 6) relate to the exposure assessment. To the extent that the exposure issues raised above can be addressed, this would serve to better inform the EPA’s consideration of the public health implications of the current CO standard. Even as is, this portion of the Risk and Exposure Assessment is not fundamentally flawed.

Insofar as the at risk population estimates are concerned, the document as currently constituted is prone to several sources of data uncertainties , all of which would te nd to systematically underestimate the public health im pact of exposure. The document continues to rely on National Health Interview Survey (NHIS) to provide a population estimate of persons at risk, narrowly defined as self reported coronary artery disease. This was a matter of focused critiq ue of the first

draft document. The revision now includes an esti mate of “undiagnosed” disease (approximately

1640% in addition to the base population). Conceptu ally this is an impor tant acknowledgment of the one aspect of systematic underestimation, a lthough the American Heart Association source of

the mathematical value used is far from c onvincing (and whatever value is used should incorporate a female>male differential given the cl ear sex-based gap in diagnosis. In addition, in terms of the restricted subset of susceptible persons based on CAD, suppo rtive prevalence data

based on NHANES and the Behavioral Risk Surv ey are easily accessible and will generally support the NHIS-based values. More fundament ally, the narrowly de fined CAD prevalence estimate, to the exclusion of all others with ca rdiac disease misreads and misinterprets the ISA particularly Tables 4-9, 5- 10, 5-11 and Figures 5-5 though 5-7. Revisiting the NHIS, the prevalence rates for “all heart disease” are consider ably more than for narrowly defined CAD. It is very likely that most if not all of these are at risk as from adverse cardiac effects from ambient CO in ways that cannot be distinguished epid emiologically from the CAD subset (this includes in term of RR). It is certainly appropriate fo r the REA to present estimates, as it did, using a narrow definition of “at risk”; to inform an EPA public health assessment, this approach alone is unacceptable. It is ironic that so much effort is spent on multiple scenarios of exposure, while falling short in the critical area of the key vulnerable population.

17

### Dr. Thomas Dahms

5. Does the Panel find the de rivation and presentation of th e modeling approach as a whole (Chapters 4 and 5) to be technically s ound, clearly communicated, and appropriately
characterized?

The detailed description of the ap ex model provides a helpful snaps hot of the extensive nature of the model. The application of the CHAD databa se in modeling the physiological changes of simulated residents during their da ily lives seems to be appropriate ly handled. This approach has been applied and vetted for other regulated air po llutants. The presentation of the material seems to be aimed at the exposure modeling community which makes it difficult to assess for someone not in the modeling community.

Appendix C contains some helpful illustrations of the variability in time spent for an individual in locations/activities during a ye ar. It would be helpful to have a similar illustration of

estimated %COHb levels of %COHb in an individua l during a day with near criteria levels of atmospheric CO and also an illustration of th e variability in peak levels of %COHb thoughout the year. Additions of these illustrations to th e text rather than in the Appendix should be

considered. It would assist the reader in understanding the variability in th e modeled levels of

dose of CO.

The coupling of the non-linear CFK with the CHAD in the APEX model would be more convincing if there were references to validation of this model in studies where measurements of

dose were made. Without documentation of such va lidation, the reader is expected to accept this model based on years of improvements over other models.

Since the controlled human exposur e data is a major factor in se tting policy, it would be helpful to see how well the exposure model predicts the measured CO dose in these experiments. Although these exposures are for only 1 hour with s ubjects at rest, it w ould provide a means of validation of the exposure/dose modeling used for the general population. It might also provide a means of comparison of the various controlled human exposures.

6. Does the Panel find the de rivation and presentation of the COHb estimates (chapters 5 and 6) to be technically sound, clearly co mmunicated, and appropriately characterized?

The presentation of how the model arrives at estimates of %COHb in the population of Denver and Los Angeles is clear in that it follows a natural progressi on in this field over the past 40 years. It is clearly communicated and the improve ments in the modeling over the years is clearly presented and is very rational. There are concerns with the output of the model that leads to a level of uncertainty that could be so mewhat reduced as described below.

The primary goal of this section would be to de termine whether or not the estimated levels of %COHb (from the model) using the current as is data are lower or higher than those estimated levels of %COHb using the curren t standards. It is presumed th at the exposure to the current standards for CO results in a small but acceptable number of at risk persons for a given %COHb

18benchmark. If the current as is data results in a smaller number of persons at that benchmark, there would be little pressure to change the standards. Therefore the issue that needs to be

discussed/defined is : what is a small but ac ceptable number of persons who can be exposed at an acceptable benchmark. This discussion is absent.

It is not clear what background in modeling minutia the reader is expected to have to clearly understand and analyze the details of the material presented. The crux of the matter is that for carbon monoxide there is an agreed upon dose metr ic, %COHb, that can be used to evaluate exposure. This is not quite the case for the other regulated pollutants. There is no mention of any attempt to validate the model being used under any circumstances. No matter how sophisticated the model, without validation it is just a m odel with all of the attendant uncertainties.

The presentation of the information in section 6.4 on the influence of endogenous rates of CO production on dose estimates is potentially a probl em. The description of what endogenous rates

were used in the model is unclear and the info rmation on Table B-3 on page B-20 is very poorly labeled. The values used in this portion of the mo del need to be clearly documented and justified. This becomes and issue because this modeling da ta is used to justif y not including 1.0 %COHb in the Policy Assessment document. The modeling of all of the parameters that impact baseline %COHb into ‘endogenous rates of CO production’ as the primar y determinate of baseline (no CO exposure) %COHb. This comes to light in Table 6-17 on page 6-18 which shows the APEX

model to result in a median value of %C OHB somewhere between 0.25 and 0.50% COHb and the non-parametric distribution of values is considerable. The mode lers claim that this data can not be compared to any studies in the literature because of the time frame over which the data is modeled. Unfortunately there will always be skep ticism of any model that can not be validated practically with actual measuremen ts. The study by Allred et al ob served 63 subjects in 3 cities on 4 experimental days (repeated measurements on an individual occurred within 6 weeks) and all of the subjects were observed over less than a 2 year peri od ( 270 measurements of baseline levels of %COHb). The mean %COHb levels did not vary over this period of time. These values ranged between 0.62 and 0.64 %COHb with a sta ndard deviation of 0.16% COHb. The model results does not fit these results on the populat ion most at risk in this assessment. The search for a alternative formats for setting standards maybe statistically enticing but would present too many problems for implementation of public health measures when the standards have been exceeded. News readers have a difficult time with the current standards provided in PPM so I can only imagine how they would attemp t to explain any of the proposed alternative

methods.

There is also no attempt made to employ the model in the studies de aling with controlled exposures in subjects with CAD. I know that using APEX to m odel a 1 hour exposure to CO is akin to killing a slug with a sledge hammer, but wh at other data base is as relevant to validation of the model being so widely used?

7. In the Panel’s view, to what extent does the modified assessmen t approach employed in this second draft assessment provide results th at meaningfully inform EPA’s consideration of the public health implications of the current standards?

19The additional information included in the current modification does not re lieve the anxiety from the use of so little monitoring data to provide guidance for setting st andards. Perhaps it is in the way in which the information is presented: there is no data presented or referred to that shows that including more data adds nothing to the analysis. As a re sult of what has currently been presented, I am still uneasy with the use of so littl e of the available monitoring data for this risk

assessment. Does the use of data from a few mon itoring cites imply that we need fewer monitors

in our cities because we can accu rately predict what exists in the entire metro area based upon a

few monitors? How is the reader to interpret the use of data from so few sites. To state the above concern in another way, the document could be improved by showing the impact, or lack of impact, on the dose variability by including data from more monitoring site s. This could be previously published information and need not i nvolve re-running of the m odels with data from

these additional sites.

There is also mention of the lack of data resolution of the LA monitors vs the Denver monitors but the impact of the low resolution monitors in LA is not discussed. If it has no impact why was

the issue raised?

It is my impression that the estimates of risk due to exposure to CO are to apply to entire country and not just to Denver and Los Ange les. It is clear that the detail presented for these two cities can not be also presented for all of the major metropolitan areas of the country. However it is incumbent upon the authors to addr ess how these risk assessments for Denver and LA are to be applied to the entire pop ulation of the United States. After all the document goes to great lengths to describe how many people are in the at risk gr oup in the country and then applies some metric to determine how many of these indi viduals are in Denver and in LA.

20

### Dr. Russell Dickerson

2. Does the Panel find the considerations of current ambient carbon monoxide monitoring data, including specifically the data for the monito rs included in this draft of the assessment, and the discussion of the extent to which near ro adway concentrations are represented to be technically sound, clearly communicate d, and appropriately characterized?

The revised draft is much improved, and generall y meets expectations. EPA is faced with the

situation that ambient measurements are more accurate than emissions. This makes measurement/model comparisons difficult. Alth ough Chemical Transport Models (CTM’s) are not used in Chapter 3 or the REA, that chapter should point out that such tools should be used and continued evaluations and improvements (if necessary) in emissions are needed.

The increased discussion of NCore and Analytical Sensitivity are useful a nd appropriately placed

near the front.

Key Observations (page 3-18 and 3-19) are appr opriate, except I could not find much on the uncertainties in emissions (see also comments on ISA) and their impact on model output.

Chapter 5 appears to refl ect the state of knowledge.

Preliminary Comments on the ISA (relevant to REA)

In one last reading of the ISA, Chapter 2 doe s a thorough job of providi ng an overview of our

technical understa nding of CO.

A few comments: 1. Page 2-3 might mention HCHF’s are removed by OH 2. The caption to Figure 3-1 might include the word DIRECT so people don’t go looking for isoprene. 3. Section 3.2.2 looks really good, as does Figure 3-8. This makes an importa nt point that should appear in the PA. 4. The sections on ambient measurements, detection limits and NCore are all much improved. 5. Based on a quick read, S ection 3.5 looks solid now.

In poking around the literature I have found a few more papers that evaluate the emissions inventories of CO. Kuhns et al. (2004) a nd Yu et al. (2007; 2009) also found evidence of overestimates of CO emissions in Mobile6 or CMAQ. Marmur et al. (2009) in contrast seem to

find that the CO emissions are underestimated. Zhang and Batterman (2010) find that Mobile 6 matches plume dispersion models and a roadside monitor reasonably well. We are just about to submit a paper that evaluates Mobile6 CO emi ssions using about 100 altitude profiles and find that modeled emissions are high but not in gros s error. If the pape r is accepted soon enough I will send a preprint.

21Kuhns, H. D., et al. (2004), Remote sensing of PM, NO, CO and HC emission factors for onroad gasoline and diesel engi ne vehicles in Las Vegas, NV Science of the Total Environment

, 322 , 123-137. Marmur, A., et al. (2009), Evaluation of mode l simulated atmospheric constituents with observations in the factor projected space: CMAQ simulations of SEARCH measurements, Atmospheric Environment

, 43 , 1839-1849. Yu, S.C., et al. (2007), A detailed evaluation of the Eta-CMAQ forecast model performance for

O 3 , its related precursors, and meteorologi cal parameters during the 2004 ICARTT study, Journal of Geophysical Research

, 112 , D12S14. Yu, S.C., et al. (2009), Eta-CMAQ air quality forecasts for O 3 and related species using three different photochemical mechanisms ( CB4, CB05, SAPRC-99): comparisons with measurements during the 2004 ICARTT study, Atmospheric Chemistry and Physics

Discussions

, 9 , 22955-22992. Zhang, K., and S. Batterman, Near-road air po llutant concentrations of CO and PM2.5: A comparison of MOBILE6.2/CALINE4 a nd generalized additive models, Atmospheric
Environment, doi:10.1016/j.atmosenv.2010.02.008, in press 2010.

22

### Dr. Milan Hazucha

Background on assessing ambient CO exposure and risk (Chapter 2). Charge Question 1 : Does the Panel find the summary of CO exposure and discussion of ambient CO sources, exposures, dose, health eff ects and risk characteri zation approach to be technically sound, clearly communicated, and appropriately characterized?

Qualified yes in all respects.

In addition to already mentioned endogenous CO production and exogenous sources (p. 2-6, l. 11-13), additional source is metabolic production of CO due to inhalation of, e.g., dihalomethanes, other substan ces and certain medication.

Do we really consider people using recreat ional drugs to be at -risk population and be considered in risk assessment (p. 2-8, l.19)? If so we will have to consider smokers to be atrisk population as well.

Since Allred et al. studies provi de the key evidence for CO hea lth effects assessment it would be very helpful if the document, in addition to % changes of the critical endpoint, e.g., time to angina also reported the actual mean and CI (confidence interval) values in respective endpoint units (p.2-11, l.24-27 and p. 2-12, l. 10-13). How clinically significant is shorter by 22 seconds time to angina out of nearly 9 minutes? Besides reduced time to angina, was the duration and the intensity of angina affected as well? Did frequenc y of angina attacks increased because of CO exposure? If these endp oints were not reported by the investigators, it should be specifically stated so in REA.

I support very cautious approach to some epidem iology studies reports of the effects of CO on respiratory system (p.2-10, 2-13, 2-18). I fu lly agree with EPA assessment that the interpretation of CO-induced lung-related outcomes “is affe cted by uncertainties including with regard to the biological mechanism that could explain CO-induced outcomes” (p. 2-13, l. 8-11).

As far 1% COHb benchmark suggested by the Pane l, the staff correctly pointed out that “this level overlaps with the upper part of the range of endogenous levels” and decided not to focus on dose estimates (p.2-16, l. 26-34). I supp ort this approach since this complies with

the EPA’s task “to establish standards that are neither more nor less st ringent than necessary for these purposes”, .i.e. public health.

23Air Quality Consideratio ns (Chapter 3 and 5) Charge Question 2: Does the panel find the cons iderations of cu rrent ambient carbon monoxide monitoring data, including specifically the data for the monitors included in this draft of the assessment, and the discussion of the exte nt to which near road way concentrations are represented to be technically sound, clearly communicated, and appropriately characterized?

Yes in all respects.

Characterization of Exposure, Dose and Potential Risk (Chapter 4-6) Charge Question 3 : In recognition of CASA C comments of first draft REA, this draft REA is expanded from the previous assessment in a numbe r of ways (summarized in section 1.3 of the draft document). The assessment study areas are in the Denver and Los Angeles study areas. We are interested in eliciting the views of the Panel on the usefulness of this approach in informing our review the NAAQS for CO. What are the Panel members’ view s on the following aspects in which the assessment has been expanded from the previous draft?

The charge questions span across 3 chapters : Ch. 4 Overview of APEX modeling, Ch. 5 Application of APEX, and Ch. 6 Simula ted exposure and COHb dose results.

However, it is difficult to comment on the chap ters in general since the sub-questions are rather specific.

A. An important change of this assessment from the first draft is the expansion of each of the modeling domains to include a greater number of ambient monitors used as input to APEX. Additionally, this draft assessment employs an algorithm that adjusts for temporal and spatial heterogeneity in ambient c oncentrations across each study areas.

The bulleted list of modified/expanded sections is very helpful. Similarly, the flow chart showing input points and flow of data has been very helpful as well.

How does the expansion of modeling domain s in this REA compare to REA1? Were

the estimates about the same or diffe rent and how they were different?

Generally, larger number of monitors may improve exposure assessment. Figure 5.1 (p.5-5) shows a considerable overlay of air districts, meteorological zones and for Los Angeles study areas as well. Although the overlapping distri cts, zones and areas were adjusted for as far as exposure goes, how were they treated in terms of input data into other modules of APEX? What approach was used to avoid duplication of input data? For L. A., was one of the areas desi gnated as a dominant source or each area was considered separately in the assessment?

In generation of simulated individuals, de mographic variables should include socioeconomic status and race. These variab les will impact othe r APEX modules, particularly the COHb one.

Chapter 6: The tables tabulating exposure va lues vs estimated nu mber and percentage of CHD persons affected at specific CO concentrations are very instructive and

24revelatory. Tables showing estimated COHb levels vs number of CHD persons and persons/days are similarly instructive. Gene rally, these table show that the current level of both standards is prot ective as required by the legi slation, i.e., “standards that

are neither more nor less stringent than necessary.”

Additional calculations and tabulation of endogenous C OHb level using APEX has been also very helpful. Table 6-18 (p.6-19) shows that the endogenous contribution to a total COHb is “less than 0.5%, t hough for a limited number of hours, the endogenous contribution could be over 1.0% COHb.” The additional plots reflect contribution of endogenous COHb to a total COHb level essentially following physiologic laws of Haldane.

Section 6.5 Key Observations (p.6-24) summ arizes the main observations presented in this chapter. One of the important conclu sions is that more than 95% of simulatedat-risk population of L.A. study areas will experience an annual daily maximum endof-hours COHb level below 1.5%. Moreover, when considering a lternative standards “only 0.1% of the CHD population was estim ated to experience a maximum end-of

hour COHb at or above 2%. Simila r values are provided for Denver.

B. The current draft assessment also incl ude an increase in the number of

microenvironments modeled over that in the first draft (fro m two to eight) and improved the representation of variability in estimated microenvironmental concentrations, including in-vehicles.

Chapter 4: Table 4-4 (p. 5-21) and 4-5 (p. 4-29) lists 15 microenvironments used in estimates in pNEM/CO model in 2000, and the same number and type in APEX4.3. However, the number for this draft is re duced to 8. Did this change in any way

affected the estimates?

It would have been helpful instead of making a general statement on how better APEX is, to actually list in 4.5 Key Ob servations section(p. 4-35) specific enhancements of APEX over pNEM/CO.

The two important conclusions were that (1) the policy relevant background was negligible, and (2) the fixed site monito ring data could be ad justed. The tables provide sufficiently detailed data to evaluate all 5 scenarios.

In the current draft the nu mber of microenvironments was increased to 4 indoor, 3 outdoor and 1 in-vehicle. Such expansion may improve strategies and enhance the validity as well as credibility of the asse ssment. More realistic scenarios provide stronger and more representati ve base for decision making.

C. This draft assessment has implemented the mass-balance model for estimating

concentrations in indoor microenvironments.

I consider the selection of mass-bala nce model for indoor air appropriate.

25Charge Question 4 . Does the Panel view the results of the draft exposure analyses to be technically sound, clearly communicated, and appropriately characterized?

Qualified yes to all respects.

The various modules of APEX model are regularly upgraded to improve the simulation process making it as realistic as possible. Yet the COHb module to estimate venous blood COHb level, the ultimate endpoint remains th e same, i.e. based on CFKE (p.4-34, l.20-31). As already commented on this matter by several panel members including myself in the past why is EPA so adamant exploring more recen t and more sophisticated CFK equations? Replacing original CFK with an enhanced, e.g. Bruce and Bruce module should be simple enough. If there are no substantial differences, then no change is necessary. However, if there are differences in COHb estimates, then we may search and evaluate the factors that may have affected the change. Such informati on may potentially useful in standard setting.

Moreover, regardless of a mathematical m odel employed in COHb module, the COHb estimates can be improved by tuning some of the explicit input variables such as THb and

DLco.

Appendix A : I agree with the summary of findings ( p. A-5) that the curr ent physiology file data is obsolete and may even be incorrect fo r some variables. While some variables were already updated, others such as race, SES, THb and DLco s hould be either added to or replace the old data in the input module.

Charge Question 5: Does the Panel find the derivati on and presentation of the modeling approach as a whole (chapters 4 and 5) to be technically sound, cl early communicated, and appropriately characterized?

Yes in all respects. The staff did an excellent job of presenting and discussing APEX model. I agree with well reasoned ar guments and the conclusions.

Any concerns about the effect of missing concentration valu es on their distribution were cleared by addition of desc riptive statistics tables (5-7 th rough 5-10). The tables demonstrate that the missing values whether estimated a nd corrected for or not do not influence the distribution of hourly values either in Denver or Los Angeles. Similar approach to estimation of missing temperature values required by APEX likely resulted, as stated in the document, in negligible differences.

Charge Question 6 : Does the Panel find the derivation a nd presentation of the COHb estimates (chapters 5 and 6) to be technically s ound, clearly communicate d, and appropriately

characterized?

Qualified YES in all respects.

Section 6.3.1 referenced in the document is likely section 6.4.1.

26The section 6.4 on endogenous production of CO and its contribution to overall COHb in combination with ambient levels of CO is very informative. Table 6-17 clearly shows that even at 0 ppm CO in ambient air several hund red individuals will reach COHb level as high

as 1.8%. It would be instruc tive to identify group s of individuals (e.g. with anemia) who exceeded 1% COHb level due to endogenous production.

Figure 6-2 shows, as expected, that endogenous CO will not influence COHB level if the ambient CO concentration exceed the one produc ed endogenously (this needs to be stated more clearly on p. 6-21, l. 6-8). Figure 6-4 indeed confirms the above statement.

Appendix B. COHB module:

p. B-3: The P Ico , should be defined as a partial pressure.

p. B-5 In eq. B-11 and B-14 P co2 subscript should be corr ect to read not as CO 2 (carbon dioxide) but as c O2 (capillary O 2 ).

Suggest to move the second paragraph on page B-8 as the first para graph of the section, otherwise without the explanati on, the statement is misleading.

p. B-9- B-14. Section C4: The C OHb module seems to be the w eakest of the APEX modules. Primarily, it is because we do not have suffi cient data over the physiologic range for many variables. However, though still limited some physiologic data are available for healthy and at-risk groups and they should be integrated into data base for COHb module. From the

tables nor the text it does not look like that many critical variables such as Hb, DLco, endogenous CO and others were, besides age and gender, adjusted for other physical characteristics or disease conditions. For exampl e, the amount of Hb will determine the rate

of COHb formation and is a critical variable. There are substantial differences between blood

concentration of Hb in whites and blacks.

Charge Question 7 : In the Panel’s view, to what extent does the modified assessment approach employed in this second draft assessment provide results that meaningfully inform EPA’s consideration of the public health implications of the current standard?

I agree with the expanded approach and I beli eve that it will allow for more accurate

assessment and risk-characterization.

Characterization of Variability and Uncertainty (Chapter 7) Charge Question 8 : What are the views of the Panel re garding the adequacy of the assessment of uncertainty and variability? To what extent have sources of uncertainty been identified and the implications for risk characterization been ch aracterized? To what extent has variability adequately described and represented?

The staff adequately described uncertainty and va riability. However, from table 7-1 it appears

that CHD has been considered to be the onl y sources of variability and no other disease

27conditions were considered in the model. Why no other relevant diseases were considered? Was socio-economic status in any way c onsidered in estimating uncertainty?

Does APEX model has build in any internal c onsistency check between factors used in the calculations (p. 7-2)? For exam ple, randomly selected oxygen upt ake which may be high maybe assigned to an individual with CHD who is unable to achieve such uptake level.

Activity patterns of persons 30 years ago used as APEX input are very much different for current activity patterns (p. 7-8). Can CHAD data be limited only to more recent activity patterns??

28

### Dr. Francine Laden

1. Does the Panel find the summary of CO ex posure and discussion of ambient CO sources, exposures, dose, health effects and risk char acterization approach to be technically sound, clearly communicated, and appropriately characterized?

Chapter 2, background on assessing ambient CO exposure and risk, is well organized and technically sound. EPA appropriate ly characterized what they did do, as well as what they did not do. The discussion explaining th e uncertainties associated with directly using studies of the association of cardiovascular morbidity with m easurements of ambient CO is important for motivating the focus on COHb levels. It may not be immediately obvious to all readers why ambient CO exposures are not th e exposure of interest. One c oncern is that most of the monitoring data and the laboratory data crucial to the assessment is quite old and could thus

effect the determination of risk. Is EPA confid ent that current situations can be extrapolated appropriately from what was observed in the past ? Perhaps some statement to this uncertainty would be valuable, as well as acknowledgement that there are not any appropriate-m ore recent studies available. For the most part the chapte r is clearly communicated. However, the chapter

overall would benefit from some careful editing.

5. Does the Panel find the de rivation and presentation of th e modeling approach as a whole (chapters 4 and 5) to be technically s ound, clearly communicated, and appropriately
characterized?

The derivation and presentation of the modeling a pproach as a whole is very well presented. I had one trivial question: Could the prevalence of undiagnosed CHD be greater for women than

for men? The model assumes that the ratios of undiagnosed cases to diagnosed cases are identical for each gender and also that this rati o has not changed since 1990. The text should at least acknowledge that this might not be so.

6. Does the Panel find the de rivation and presentation of the COHb estimates (chapters 5 and 6) to be technically sound, clearly co mmunicated, and appropriately characterized?

The derivation and presentation of the COHb estimates are technically sound, clearly communicated and appropriately characterized.

7. In the Panel’s view, to what extent does the modified assessmen t approach employed in this second draft assessment provide results th at meaningfully inform EPA’s consideration of the public health implications of the current standards?

The draft assessment provides results that mean ingfully inform EPA’s consideration of the public health implications of the current standa rds. Given that CO levels have decreased significantly over the years, that leve ls rarely approach the standards, and that elevated levels of COHb estimated by the risk assessment are quite low, the usefulness of the current standards may need to be reassessed.

29

### Dr. Arthur Penn

1. Does the Panel find the summary of CO ex posure and discussion of ambient CO sources, exposures, dose, health effects and risk char acterization approach to be technically sound, clearly communicated, and appropriately characterized?

No major issues with this chapter. The summarie s are well-done and the health effects and risk characterization approach are presente d clearly and seem technically sound.

30

### Dr. Beate Ritz

3. What are the Panel members’ views on the fo llowing aspects in which the assessment has been expanded from the previous draft? A. An important change of this assessment from the first draft is the ex pansion of each of the modeling domains to include a greater number of ambient monitors used as input to APEX. Additionally, this dra ft assessment employs an algorithm that adjusts for temporal and spatial heterogeneity in ambient con centrations across each study area.

While the larger number of ambient air monitors may have improved exposure assessment, I am

not convinced that this in fact gives more correct estimates of exposure near roadways - mainly in homes since only one singular distribution was used for all ho mes and this distribution may not adequately reflect near roadways exposures in homes i.e. I am not convinced that spatial heterogeneity driven by proximity to sources can be adequately captured by the ambient monitoring network. In fact, the exposure both in homes and in work places closer to roadways might be underestimated.

B. The current draft assessment also includes an increase in the number of microenvironments modeled over that in the fi rst draft (from two to eight) and improved the representation of variability in estimated mi croenvironmental concentrations, including invehicles.

yes

C. This draft assessment has implemente d the mass-balance model for estimating

concentrations in indoor microenvironments.

yes

4. Does the Panel view the results of the draft exposure analyses to be technically sound,clearly communicated, and ap propriately characterized?

Yes, except for the assumption about having captur ed spatial heterogeneity in homes and work places near busy roadways.

31

### Dr. Paul T. Roberts

2. Does the Panel find the considerations of current ambient carbon monoxide monitoring data, including specifically the data for the monitors included in this draft of the assessment, and the discussion of the extent to which near roadway concentrations are represented to be technically sound, clearly communicated, and appropriately
characterized?

In general, the treatment of the CO monitoring data and the (admittedly poor) extent that these monitors represent near-roadway concentrations, including the data used for this version of the assessment, are improved over the 1 st external draft REA, technically sound, clearly communicated, and appropriately characterized. In addition, the use of data from more monitors as input to the exposure modeling is a significant improvement.

Characterization of Exposure (Chapters 4 and 5)

The following changes from the 1 st external draft REA are significant improvements and help the results from this REA do a much better job of informing our review of the CO NAAQS.

• Expansion of the modeling domain to include more monitors in both Denver and LA.

• Adjusting for both spatial and temporal heteroge neity in ambient CO concentrations in each study area.

• A significant increase in the modeled microenvironments.

• The use of a mass-balance model for estimating CO concentrations in indoor environments (factors are reasonable estimates fo r the other microenvironments).

However, I am concerned about the use of th e power of .621 in equations 4-11 and 4-22, which

reduces the CO concentration at an outdoor location, relative to th e nearest central monitor. The main justification for this is given on lines 33 to 35 of page 4-27 as a way to get the pNEM/CO and APEX models to agree, but I do not understand the physical ra tionale for this. On page 5- 23, lines 8-10, it is suggested that the resulting “compression effect” is consistent with Wilson et al (1995). However, even if we agree that this might be occurring near most residences, as in the Wilson study, it does not occur at near-roadway or in-v ehicle locations. In fact, the net result of using this as part of the factor calculation for estimated CO concentrations is that near-roadway

and in-vehicle concentrations are a fair amount lower than was documented in the 1 st REA, section 5.4.2 (in-vehicle concentrations) and in the ISA for near-roadway. Since these two microenvironments might be contributing a fair amount to total exposure, I think this is an important issue to resolve. In addition, the use of this factorfor near-road and in-vehicle microenvironments has probably decreased the percen t of people who experience the highest concentration exposures, for example in Chapter 6.

Table 5-16 is a good summary of the various cond itions in the 8 microenvironments, especially

with the distributions. I did not iced, however, in Appendix that a couple of locations codes are probably mis-assigned, although these are probably sm all contributions: bicycle should be 5, as shown in Table 5-16, and all the boat categories should be 8, since boats are uncontrolled for CO

32and produce significantly high CO concentrations (t hey should probably be much higher than 8, but again this is probably a small contributor).

8. What are the views of the Panel regarding th e adequacy of the assessment of uncertainty and variability? To what extent have sources of uncertainty b een identified and the implications for the risk characterization been characterized? To what extent has variability adequately de scribed and represented?

In general, the incorporation of more monito rs in each area, more microenvironments, and variability in various variables within APEX is an important method for addressing variability and thus general uncertainty in exposure and dose.

Although I still think that the mo st significant uncertainties fro m this table could be better quantified by using sensitivity runs of the model, I understand the time constraints on the current NAAQS process. I believe that the significant improvements in representing near-roadway and in-vehicle exposures has reduced the uncertainties a ssociated with that end of the exposued population, as represented in Table 7-2.

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### Dr. Anne Sweeney

1. Does the Panel find the summary of CO ex posure and discussion of ambient CO sources, exposures, dose, health effects and risk char acterization approach to be technically sound, clearly communicated, and appropriately characterized?

Overall, Chapter 2 is a very well-written compre hensive background that de scribes the issues and

considerations that were confronted in the e ffort to assess ambient air CO exposure and human

health risks. The contributions of the various sources of both am bient and indoor CO levels were clearly described and supported by numerous pub lished studies. Exposure pathways and the importance of the microenvironment were also well-documented.

The justification for the utilization of persons with CHD as the unit of anal ysis in the quantitative assessment is appropriate, given the lack of data on COHb levels in othe r potentially high risk groups. However, characteristics of this simula ted population that should be included in the modeling include the popul ation prevalence of income level (a surrogate for several important covariates, e.g., residence near congested tra ffic areas) and smoking (also related to income level).

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### Dr. Stephen Thom

1. Does the Panel find the summary of CO ex posure and discussion of ambient CO sources, exposures, dose, health effects and risk char acterization approach to be technically sound, clearly communicated, and appropriately characterized?

The summary is accurate and appropriate.

2. Does the Panel find the considerations of current ambient carbon monoxide monitoring data, including specifically the data for the monito rs included in this draft of the assessment, and the discussion of the extent to which near ro adway concentrations are represented to be technically sound, clearly communicate d, and appropriately characterized?

The discussion on current air quality m onitoring is accurate and appropriate.

3. In recognition of CASAC comments on first draft REA, this draft REA is expanded from the previous assessment in a number of ways (summarized in section 1.3 of the draft document). The assessment study areas are in the Denver and Los Angeles study areas.

We are interested in eliciti ng the views of the Panel on the usefulness of this approach in informing our review the NAAQS for CO. W hat are the Panel members’ views on the following aspects in which the assessment has been expanded from the previous draft?

A. An important change of this assessment fr om the first draft is the expansion of each of the modeling domains to include a greater number of ambient monitors used as input to APEX. Additionally, this draft a ssessment employs an algorithm that adjusts for temporal and spatial heterogeneity in ambient concentrations across each study

area.

B. The current draft assessment also includes an increase in the number of

microenvironments modeled over that in the first draft (fro m two to eight) and improved the representati on of variability in estim ated microenvironmental concentrations, including in-vehicles.

C. This draft assessment has implemente d the mass-balance model for estimating

concentrations in indoor microenvironments.

I found the document to be generally well wri tten. My one question pertains to the APEX modeling, as raised in my review of the Po licy Assessment document. The discussion in the

REA document includes information that most fixe d monitors have a 1 ppm CO lower detectable limit so the modelers added 0.5 ppm CO to all measured values to remove zeros and negative numbers thought to be related to monitor drift. It seems to me that this makes it exceedingly difficult to accept estimates of the at-r isk population and threshold COHb levels.

3536 4. Does the Panel view the results of the dr aft exposure analyses to be technically sound, clearly communicated, and appropriately characterized?

I am unsure if the draft exposure analys is is technically sound (see comment #3).