UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON D.C. 20460

OFFICE OF THE ADMINISTRATOR SCIENCE ADVISORY BOARD
October 24, 2006

EPA-CASAC-07-001

Honorable Stephen L. Johnson Administrator U.S. Environmental Protection Agency 1200 Pennsylvania Avenue, NW Washington, DC 20460

Subject: Clean Air Scientific Advisory Committee’s (CASAC) Peer Review of the Agency’s 2 ndDraft Ozone Staff Paper

Dear Administrator Johnson:

EPA is in the process of re viewing the national ambient ai r quality standards (NAAQS) for ozone (O 3 ) and related photochemical oxidants, whic h the Agency most recently revised in July 1997. As part of its ongoing review of the ozone NAAQS, EPA’s Office of Air Quality Planning and Standards (OAQPS) developed a 2 ndDraft Ozone Staff Paper, entitled, Review of the National Ambient Air Quality Standards fo r Ozone: Policy Assessmen t of Scientific and Technical Information (July 2006). At the request of the Agency, EPA’s Clean Air Scientific Advisory Committee (CASAC or Committee), s upplemented by subject-matter-expert panelists

— collectively referred to as the CASAC Ozone Review Panel (O zone Panel) — met in a public meeting in Durham, NC, on August 24-25, 2006, to conduct a peer review of this draft Ozone Staff Paper and three related draf t technical support documents.

In its summary of EPA staff conclusions on the primary (health-related) ozone NAAQS found in Chapter 6 of the 2 ndDraft Ozone Staff Paper, OAQPS se t-forth two options with regard to revising the level and the form of the standard: (1) retain the current pr imary eight-hour (8-hr) NAAQS of 0.08 parts per million (ppm); or (2) cons ider a reduction in the level of the primary O 3 NAAQS within the range of alternative 8-hr standards incl uded in Staff’s exposure and risk assessments (which included a range from 0.064 to 0.084 ppm) with primary focus on an O 3 level of 0.07 ppm with a range of forms from third- through fift h-highest daily maximum. The Ozone Panel unanimously concludes that:

1. There is no scientific justification for reta ining the current primar y 8-hr NAAQS of 0.08 parts per million (ppm), and

12. The primary 8-hr NAAQS needs to be substa ntially reduced to pr otect human health, particularly in sensitive subpopulations.

Therefore, the CASAC unanimously recommends a range of 0.060 to 0.070 ppm for the primary ozone NAAQS . With regard to the secondar y (welfare-related) ozone NAAQS, t he Ozone Panel is in strong agreement with the scientific and technical evidence presented in the summary of EPA staff conclusions on the sec ondary ozone NAAQS found in Chapter 8 of the draft Staff Paper in support of the alternative secondar y standard of cumulative form that extends over an entire growing season.

The Ozone Panel members agree that this letter adequately represents their views. The chartered Clean Air Scientific Advisory Committ ee fully endorses the Pa nel’s letter and hereby forwards it to you as the Committee’s consensus report on this subject. A discussion of each chapter in the 2 ndDraft Ozone Staff Paper follows this letter, and the comme nts of individual Panel members on the 2 ndDraft Ozone Staff Paper and thr ee related draft technical support documents are attached as Appendix D.

1. Background

2 Section 109(d)(1) of the CAA requires that the Agency periodically review and revise, as appropriate, the air quality criteria and the NAAQS for the “criteria” ai r pollutants, including ambient ozone. Pursuant to sections 108 and 109 of the Act, EPA is in the process of reviewing the ozone NAAQS. OAQPS, within the Office of Air and Radiation (OAR), developed the 2 nd Draft Ozone Staff Paper as part of this activity. In February 2006, the Ag ency’s National Center for Environmental Assessment, Research Triangle Park, NC (NCEA-RTP), within the Agency’s Office of Research and Developm ent (ORD), released its final Air Quality Criteria for Ozone and Related Photochemical Oxidants
, Volumes I, II, and III , (EPA/600/R-05/004aF-cF, Final Ozone Air Quality Criteria Document) for this current review cycle for the ozone NAAQS. The

ndDraft Ozone Staff Paper evaluates the policy imp lications of the key scientific and technical information contained in the Final Ozone AQCD and identifies critical elements that the Agency believes should be considered in its review of the ozone NAAQS. The Ozone Staff Paper is intended to “bridge the gap” be tween the scientific review c ontained in the Ozone AQCD and the public health and welfare pol icy judgments required of the EP A Administrator in reviewing the ozone NAAQS.

The Ozone Panel met in a public meeting on December 8, 2005 to conduct a consultation on EPA’s 1 st Draft Ozone Staff Paper and two related technical support documents. However, given that the OAQPS’ first draft Staff Paper di d not contain Agency st aff conclusions about whether to retain or revise the existing prim ary and secondary Ozone standards, the CASAC’s activity only amounted to a technical assessment of that document. The Committee’s letter to you from that meeting (EPA-CASAC-CON-06-003), dated February 16, 2006, is posted at URL: http://www.epa.gov/sab/pdf/casac_con_06_003.pdf

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22. CASAC Ozone Review Pane l’s Peer Review of the 2 nd Draft Ozone Staff Paper and Related Technical Support Documents

The Ozone Panel reviewed the 2 ndDraft Ozone Staff Pape r and found it improved over the earlier version that had been reviewed as part of a consultation process. However, the Panel did not agree with the EPA staff conclusions t hat it was appropriate to consider retaining the current NAAQS as an option that would be protective of public health and welfare. The Ozone Panel’s recommendations for reducing the level of the primary ozone standard, and its rationale for these recommendations, are provided immedi ately below. Following a detailed discussion on the primary and secondary NAAQS ar e the Panel’s major, chapter-specific comments. Finally, the individual written comments of Ozone Panel members on the 2 ndDraft Ozone Staff Paper and the three related draft technical support documen ts are attached in Appendix D. Panelists’ responses to the Agency’s charge questions are included in thes e individual review comments.

Primary Ozone NAAQS

New evidence supports and build-upon key, health-related conclusions drawn in the 1997 Ozone NAAQS review. Indeed, in the 2 ndDraft Ozone Staff Paper, EP A staff themselves arrived at this same conclusion:

“Based on the above considerations and findi ngs from the [Final Ozone AQCD], while being mindful of important remaining uncertainties, staff concludes that the newly available information generally reinforces our judgme nts about causal relationships between O 3 exposure and respiratory effects observed in the lastreview and broadens the evidence of O 3 -relatedassociations to include additional respiratory-related endpoints, newly identified cardiovascularrelated health endpoints, and mortality. Newly available evidence also has identified increased susceptibility in people with asthma. While recognizing that important uncertainties and research questions remain, we also conclude that progr ess has been made since the last review in advancing our understanding of potentia l mechanisms by which ambient O 3 , alone and in combination with other pollutants, is causally li nked to a range of respiratory- and cardiovascularrelated health endpoints.” (Pages 6-6 and 6-7)

2 Several new single-city studies and large multi-city studies designed specifically to examine the effects of ozone and other pollutants on both morbidity and mortality have provided more evidence for adverse health effects at concen trations lower than the current standard. (See the numerous ozone epidemiological single-city studies shown in Figure 3-4 on page 3-53 of the

ndDraft Staff Paper and, in addition, Appendix 3B of the staff paper, which contains the summary of effect estimates and air quality data for these studies and multi-city epidemiological studies.) These studies are b acked-up by evidence from contro lled human exposure studies that also suggest that the current primary ozone NAAQS is not adequate to protect human health (Adams, 2002; McDonnell, 1996).

Furthermore, we have evidence from recently reported controlled clinical studies of healthy adult human volunteers exposed for 6.6 hours to 0.08, 0.06, or 0.04 ppm ozone, or to filtered air alone during moderate exercise (Ada ms, 2006). Statistically-significant decrements in lung function were observed at the 0.08 ppm exposure level. Importantly, adverse lung function effects were also observed in so me individuals at 0.06 ppm (Adams, 2006). These

3results indicate that the current ozone standard of 0.08 ppm is not sufficie ntly health -protective with an adequate margin of safety. It should be noted these findi ngs were observed in healthy volunteers; similar studies in se nsitive groups such as asthmatic s have yet to be conducted. However, people with asthma, and particularly children, have been found to be more sensitive and to experience larger decrements in lung func tion in response to ozone exposures than would healthy volunteers (Mortimer et al. , 2002).

Going beyond spirometric decrements, adverse health effects due to low-concentration exposure to ambient ozone (that is, below th e current primary 8-hour NAAQS) found in the broad range of epidemiologic and controlled expo sure studies cited above include: an increase in school absenteeism; increases in respiratory hospital emergency department visits among asthmatics and patients with othe r respiratory diseases; an increase in hospitalizations for respiratory illnesses; an increase in symptoms a ssociated with adverse health effects, including chest tightness and medication usage; and an increase in mortal ity (non-accidental, cardiorespiratory deaths) reported at exposure levels well below the current standard. The CASAC considers each of these findings to be an important indicator of ad verse health effects. As demonstrated in Chapter 5 of the 2 ndDraft Ozone Staff Paper (specifically, Figures 5.5, 5.7, 5.8, and 5.9), a significant decrease in adverse eff ects due to ozone exposures can be achieved by lowering the exposure concentrations below th e current standard, which is effectively 0.084 ppm. Beneficial effects in term s of reduction of adverse health e ffects were calculated to occur at the lowest concentration considered ( i.e. , 0.064 ppm). (See also Fi gure 3-4, “Effect estimates (with 95% confidence intervals) for associa tions between short-term ozone exposure and respiratory health outcomes,” on page 3-53.)

The justification provided in the 2 ndDraft Ozone Staff Paper for retaining the current level of the primary ozone standa rd as an option for the Admini strator was based on results of controlled human exposure studies m easuring modest declines in FEV 1 after exposures to 0.08 ppm ozone. However, as stated in the Staff Paper (page 3-6), while average decrements in the FEV 1 were relatively small, 26% of the subjects had greater than 10% decrements, which can be clinically significant. Also, while measures of FEV 1 are quantitative and readily obtainable in humans, they are not the only measures — and perhaps not the most sensitive measures — of the adverse health effects induced by ozone exposure. As stated on page 6-32 of the Final Ozone AQCD, “Spirometric responses to ozone are i ndependent from inflammatory responses and markers of epithelial injury (Balmes et al. , 1996; Bloomberg et al. , 1999; Hazucha et al. , 1996; Torres et al. , 1997). Significant inflammatory responses to ozone exposures that did not elicit significant spirometric responses have been reported (Holz et al. , 2005; McBride et al. , 1994).” Agency staff’s analyses placed most emphasis on spirometric evidence and not enough emphasis on serious morbidity ( e.g. , hospital admissions) and mortality observed in epidemiology studies (see page 6-44).

Therefore, on the basis of the large amount of recent data evaluating adverse health effects at levels at and below the current N AAQS for ozone, it is the unanimous opinion of the CASAC that the current primary ozone NAAQS is not adequate to protect human health. Furthermore, the Ozone Panel is in complete agreement both that: the EPA staff conclusion in Section 6.3.6 arguing that “consideration could be given to retaining the current 8-hr ozone standard” is not supported by the relevant scien tific data; and that the current primary 8-hr

4standard of 0.08 ppm needs to be substantially reduced to be protective of human health, particularly in sensitive subpopulations.

Additionally, we note that the understanding of the associated science has progressed to the point that there is no longer significant scienti fic uncertainty regar ding the CASAC’s conclusion that the current 8-hr primary NAAQS must be lowered. A large body of data clearly demonstrates adverse human health effects at the current level of th e 8-hr primary ozone standard. Retaining this standard would continue to put large numb ers of individuals at risk for respiratory effects and/or significant impact on quality of life including asthma exacerbations, emergency room visits, hospital admissions and mort ality. (Scientific uncertainty does exist with regard to the lower level of ozone exposure that would be fully-protective of human health. The Ozone Panel concludes that it is possible that there is no thres hold for an ozone-induced impact on human health and that some adverse events may occur at policy-relevant background.)

Moreover, EPA staff concluded that changes in the concentration- based form of the standard ( i.e. , whether to use the third-, fourth-, or fifth-highest daily maximum 8-hr average concentration) should also be consid ered. The analysis found in the 2 ndDraft Ozone Staff Paper indicates that modest changes in the form of the standard can have substantial impacts on the frequency of adverse health effects. Theref ore, the CASAC recommends that the Agency conduct a broader evaluation of alternative concen tration-based forms of the primary 8-hr ozone standard and the implications of those alternat ive forms on public-health protection and stability ( i.e. , with respect to yearly variability to ensu re a stable target for control programs).

The CASAC further recommends that the ozone NAAQS should reflect the capability of current monitoring technology, which allows accu rate measurement of ozone concentrations with a precision of parts per billion , or equivalently to the thir d decimal place on the parts-permillion scale. In addition, given that setting a level of the ozone standard to only two decimal places inherently reflects upward or downward “rounding,” e.g. , 0.07 ppm includes actual measurements from 0.0651 ppm to 0.0749 ppm, the CASAC chooses to express its recommended level, immediately below, to the third decimal place.

Accordingly, the CASAC unanimously recommends that the current primary ozone NAAQS be revised and that the leve l that should be considered fo r the revised standard be from 0.060 to 0.070 ppm, with a range of concentration- based forms from the third- to the fifthhighest daily maximum 8-hr average concentration. While data exist that adverse health effects may occur at levels lower than 0.060 ppm, these data are less certain and achievable gains in protecting human health can be accomplished through lowering the ozone NAAQS to a level between 0.060 and 0.070 ppm.

Secondary Ozone NAAQS

An important difference between the effects of acute exposures to ozone on human health and the effects of ozone exposures on welfare is that vegetation effects are more dependent on the cumulative exposure to, and uptake of, ozone over th e course of the en tire growing season (defined to be a minimum of at least three months). Therefore, there is a clear need for a

5secondary standard which is distinctly different from the primary standar d in averaging time, level and form. Developing a biologically-relevant ozone air quality index would be directly responsive to the 2004 National Research C ouncil (NRC) recommendations on Air Quality Management in the United States (NAS, 1994) and will help support important new Agency initiatives to enhance ecosystem-rela ted program tracki ng and accountability.

In its 1996 review of the ozone NAAQS, EPA staff proposed several cumulative seasonal ozone exposure indices, including SUM06, the concentration-weighted metric ( i.e. , the seasonal sum of all hourly average concentrations > 0.06 ppm), and W126, the integrated exposure index with a sigmoidal weighting function, as candidate s for a secondary standard. The Administrator considered a three-month, 12-hr SUM06 secondar y standard at a level of 25 ppm-hr as an appropriate, biologically-relevant s econdary standard, but ultimately rejected this option in favor of simply setting the secondary stan dard equal to the primary. It was rationalized that efforts to attain the new 8-hr primary standard would al so eliminate most adverse effects on vegetation, and at that time there were uncertainties in how cumulative seasonal exposures would change with efforts to reduce peak 8-hour concentratio ns. Additionally, it was assumed that future ozone/vegetation effects research over the co ming years would clarif y the very uncertain quantitative relationships betw een ozone exposures and vegeta tion/ecological responses under ambient field conditions.

Unfortunately, however, the Agency has supporte d very little new vegetation/ecological ozone effects research over the past decade. The net result is that the quantitative evidence linking specific ozone con centrations to specific vegetation/ecological effects must continue to be characterized as having high uncertainties due to the lack of data for verification of those relationships. It is not surprisi ng that substantial research need s remain, as indicated both in Chapter 8 and in individual re viewer comments. The quantitative evidence linking specific ozone concentrations to specific vegetation effects — especially at the complex ecosystem level

2 — must continue to be characte rized as having high uncertainties due to the lack of data for verification of those relationships . To a large extent, this is an unavoidable consequence of the inherent complexities of ecosystem structure an d function, interactions among biotic and abiotic stressors and stimuli, variabili ty among species and genotype, de toxification and compensatory mechanisms, etc. Nevertheless, the compelling weight of evidence provided in Chapter 7 of the
ndDraft Ozone Staff Paper results from the c onvergence of results from many various and disparate assessment methods including chambe r and free air exposure, crop yield and tree seedling biomass experimental studies, foliar injury data from biomonitoring plots, and modeled mature tree growth.

Despite limited recent research, it has become clear since the last review that adverse effects on a wide range of vegeta tion including visible foliar injury are to be expected and have been observed in areas that are below the leve l of the current 8-hour primary and secondary ozone standards. Such effects are observed in areas with seasonal 12-hr SUM06 levels below 25 ppm-hr (the lower end of the range of a SU M06 secondary standard suggested in the 1996 review and the upper end of the rang e suggested in Chapter 8 of the 2 ndDraft Ozone Staff Paper). Seasonal SUM06 (or equivalent W126) ranges well below 25 ppm-hr were recommended for protecting various managed an d unmanaged crops and tree seedlings in the1997 workshop on secondary ozone standards (Heck and Cowling, 1997). The absence of clear6cut lower effects thresholds for sensitive vegetation combined with the lower recent estimates of policy-relevant background (typi cal range of 0.015 to 0.035 ppm ) emphasizes the importance of efforts to reduce low- to mid-range environmental exposures below 0.060 ppm.

Based on the Ozone Panel’s review of Chapters 7 and 8, the CASAC unanimously agrees that it is not appropriate to try to protect vegetation from the substan tial, known or anticipated, direct and/or indirect, adverse effects of ambi ent ozone by continuing to promulgate identical primary and secondary standards for ozone. Moreover, the members of the Committee and a substantial majority of the Ozone Panel agrees with EPA staff conclusions and encourages the Administrator to establish an alternative cu mulative secondary standard for ozone and related photochemical oxidants that is di stinctly different in averaging time, form and level from the currently existing or potentially revised 8-hour primary standard. The suggested approach to the secondary standard is a cumulative seasonal grow ing standard such as the indices SUM06 or W126 aggregated over at least the three summer months exhibiting the highest cumulative ozone levels and includes the ozone exposures from at least 12 daylight hours. The CASAC suggests a range of 10 to 20 ppm-hours for the three-mont h growing season SUM06 index for agricultural crops rather than the 15-25 ppm- hours proposed in Chapter 8.

However, the Ozone Panel views the thre e-month growing season W126 index as a potentially more biologically-r elevant index than the 3-mont h growing season SUM06 index. This is because the W126 index has no absolu te minimum ozone concentration threshold and only lightly weights the lower oz one concentrations. Therefore, a three-month seasonal W126 that is the approximate equivalent of the SUM 06 at 10 to 20 ppm-hr is preferred. As shown by the references cited at the e nd of Chapter 8, the consensus vi ew among expert persons in the ecological communities of both this country and elsewhere around the world is that a secondary standard of cumulative form and extending over an entire growing season will be far more effective than a secondary standard that is not cumulative in fo rm and does not include the whole growing season.

In conclusion, the Clean Air Scientific A dvisory Committee is pl eased to provide its scientific advice and recommendations to th e Agency on the primary and secondary ozone NAAQS. We recognize that ou r recommendation of lowering of the current primary ozone standard would likely result in a large portion of the U.S. being in non-attainment. Nevertheless, we take very seriously the statut ory mandate in the Clean Air Act not only for the Administrator to establish, but also for the CASAC to recommend to the Administrator, a primary standard that provides for an “adequate margin of safety ... requisite to protect the public health.”

Finally, as announced during the Ozone Pa nel’s August meeting, once the Agency releases the Final Ozone Staff Paper in early January 2007, the CASAC intends to hold a public teleconference in late January or early Februa ry 2007 for the members of the Ozone Panel to review — and, prospectively, to offer additional, unsolicited advi ce to the Agency concerning — Chapter 6 (Staff Conclusions on Primary O 3 NAAQS) and Chapter 8 (Staff Conclusions on Secondary O 3 NAAQS) in that final Agency document. The purpose of such advice would be to

7inform EPA’s efforts as it develops the fort hcoming, proposed rule for ozone and related photochemical oxidants. As always, the CASAC wishes EPA well in this important endeavor.

Sincerely,

/ S igned/

Dr. Rogene Henderson, Chair Clean Air Scientific Advisory Committee

Appendix A – Clean Air Scientific A dvisory Committee Roster (FY 2006) Appendix B – CASAC Ozone Review Panel Roster Appendix C – Charge to the CASAC Ozone Review Panel Appendix D – Review Comments from Indivi dual CASAC Ozone Review Panel Members

8

### CASAC Chapter-Specific Di scussion Comments on EPA’s 2 nd 

### Draft Ozone Staff Paper

Sub-groups of the CASAC Ozone Review Pane l who led the discussion on individual chapters of the Staff Paper summarized their comments in the following paragraphs:

Chapter 2 (Air Quality Characterization): A better introduction to the central role of photochemical oxidation reactions as the key reactions governing the behavi or of air pollutants in the atmosphere would improve this chapter. Ozone is the key indicator of the extent of oxidative chemistry and serves to integrate multiple pollutants. Oxidation in the atmosphere leads to the formation of particulate matter from SO 2 , NO X , and volatile organic compounds (VOCs) as well as gas phase irritants (formalde hyde, acrolein, etc). Thus, although ozone itself has direct effects on human health and ecosystems, it can also be considered as indicator of the mixture of photochemical oxidants and of the oxidizing potency of the atmosphere. Section 2.2.6 only briefly covers the relationship of ozone to other photochemical oxidants. It would be beneficial to add a short paragraph outlining th e role of ozone and other photochemical oxidants in the atmospheric transformation processes that may results in the formation of more toxic products (both in an outdoor a nd indoor environment), as prov ided in the individual comments appended to this letter.

The section on policy-relevant background (2.7) continues to have problems. Although the section briefly cites the results of comparis on of different models and measurements, it does not adequately address the un certainties of the global GE OS-CHEM model, and how these uncertainties are reflected in the health risk an alysis. Since ozone health effects are observed down to concentrations of the order of 0.04–0.05 ppm, it is impor tant to know how the PRB is related to the considered primar y ozone standard and what uncerta inties there are in the risk attributed to controllable sources.

Chapter 3 (Policy-Relevant Assessmentof Health Effects Evidence): The latest draft of Chapter 3 is much improved over the previous dr aft. Efforts to respond to some of the earlier concerns expressed by the CASAC ar e appreciated. While in general this chapter is well written, and is a credible basis for the risk analyses thatfollow, there are inconsistencies and inaccuracies that still need to be addressed. Typically, there is appropriate use of cautionary phrases when the data are not as strong as they mi ght be, but this use is inconsiste nt across the chapter, and there are instances where EPA staff appear to be stretching to infer that data support their statement. While the individual comment s of Ozone Panel members attached to this letter provide specifics on these points, some of the Panel’s more signi ficant concerns are discussed briefly below.

Discussion of measurement error is convoluted , confusing, and contains some mistakes. The primary issue in the use of central am bient monitors for ozone in time-series epidemiological studies is whethe r they provide any information atall that reflects daily personal ozone exposure in susceptible populations. The di scussion on p. 3-37 of the impact of various types of exposure measurement error is incorre ct; the difference between true and measured ambient concentrations is an example of classical measurement error that results in bias of effect

9estimates to the null, not just an increase in standard error. Cl aiming that the difference between average personal exposure and ambient concentra tions results in “attenua tion of risk” is not appropriate.

The Ozone Panel does not completely agree wi th staff’s conclusion that “the use of routinely monitored ambient ozon e concentrations as a surrogat e for personal exposures is not generally expected to change th e principal conclusions from oz one epidemiological studies.” Indeed, Panel members have little insight as to what we would find if we had actual exposure measurements. Personal exposures most likely correla te better with central site values for those subpopulations that spend a good deal of time outdoors, which coincides, for example, with children actively engaged in out door activities, and which happens to be a group that the ozone risk assessment focuses upon.

Some statements about which individuals are at greatest risk of ozone -induced effects are not adequately supported by the information discusse d in the chapter. Individuals with chronic obstructive pulmonary disease (COPD) and cardiova scular disease (CVD) are likely to be at increased risk, but the hypothesis that such “ hyper-responsiveness” can be used to identify individuals with COPD or CVD wh o are at greatest risk of O 3 -induced health effects has not been confirmed. A more appropria te conclusion would be that individuals with COPD and CVD are at increased risk of O 3 -induced health effects.

The discussion of the ranges for changes in FEV 1 that are considered to be small, moderate, or large for persons with impaired resp iratory systems is not consistent. While EPA staff state that the table values for the range s do not need to be ch anged, staff indirectly acknowledge that a 10% reducti on in this variable in as thmatics could have serious consequences, an interpretation that is used in Chapters 4-6.

The 30 subjects studied by Adams had a great influence on the analyses presented in Chapters 5 and 6. While the discussion of the lo w-level exposures used in the controlled human studies by Adams and colleagues is technically co rrect that no statistically significant changes were found in FEV 1 for ozone at 40 to 60 ppb compared to filtered air, there were clearly a few individuals who experienced declines in lung func tion at these lower concentrations. These were healthy subjects, so the percenta ge of asthmatic subjects, if th ey had been studied, would most likely be considerably greater.

The lack of statistical power is consistently offered in Chapter 3 for why there appears to be an inconsistent effect seen for COPD morta lity. Coherence of respir atory effects for ozone suffers from neither no more nor no less power considerations that do those for particulate matter (PM). Yet the Agency did not argue a lack of po wer when assessing PM risks, so consistency is needed here relative to ozone eff ect estimates for COPD mortality.

The relatively strong and relatively consistent effect of ozone on emergency department visits for respiratory disease, especially asthma, as evidenced in Figure 3-4 is misrepresented in several places in the Chapter (and in Chapters 5 a nd 6) as “inconclusive” or “inconsistent.” This should be corrected.

10Chapter 4 (Characterization of Human Exposure to Ozone): The second draft of Chapter 4 has responded to many of the comments made on the first draft, and is thus clearer than before. The panel was pleased to s ee the reanalysis for 2002 in addition to 2004.

It would be helpful to have the estimated exposures for current (2002 and 2004) levels displayed in Tables 4-8 & 4-9 ( p. 4-32) and Figures 4-4 to 4-21 ( pp. 4-33 to 4-41), in addition to only those for just meeting the current standard a nd alternative more stringent standards. This would be analogous to the way estimated effects ar e displayed in Chapter 5 (Figures 5-5 to 5-9 [pp.5-58 to 5-65]).

On the whole, Chapter 4 provides a clear “roa d map” for what was done to characterize available knowledge about human exposure to oz one in the framework of generally accepted modeling approaches of appropriate ly selected populations in 12 urban areas of the U.S. Much of the text reads lik e a basic textbook on human exposure as sessment using state-of-the-art modeling approaches, such as the Air Pollutant s Exposure Model (APEX), including adjustments for lung ventilation of delivered ozone dose. This extension, beyond e xposure characterization, is particularly important for ozone where the ex tent of measurable human responses is very sensitive to the amount of ozone inhaled and to where it deposits along the respiratory tract. Further extension of the methodology to estimate dose would have important implications and should be discussed.

There is an explicit discussion of the lim itations of the APEX model in terms of variability and the quality of the i nput data, which is appropriate and fine as far as it goes. There are good reasons presented for selection of urba n areas and the time periods to be modeled. However, there was inadequate consideration of the populations selected for modeling. Those selected were appropriate, but the omission of th e elderly, the population most at risk for ozoneassociated premature daily mortality, was notable and not even mentioned in terms of why it was not considered.

The chapter was very good at exposition and clear presentation of mode ling results, but was deficient it its discussion of seemingly counterintuitive resu lts, and of a potentially large influence of measurement biases. As an example of the first of these issues, the children in LA & Houston are estimated to have far fewer expos ures above 0.07 ppm (8-hr) than in most other cities with lower ozone concentr ations and fewer children. This was likely due to the greater within-day and sampler-to-sampler variations in c oncentration within these two cities than in the others, the fact that the entire year was modeled while for other sites the winter was not included and/or the greater extent of ai r conditioning, especially in Houst on. Whatever the reasons, there should have been some discussion of the cause s. The quadratic ro llback methodology should have been better described sin ce this strategy has important consequences for the modeled results.

The second issue that was presented, but left ha nging without an adequa te discussion is at the bottom of page 4-47, where it was simply stat ed that “in general, APEX systematically under-predicts the measured values by 0.001 to 0.02 ppm (zero to 50 percent).” If this is so, is it due to a really serious failure of the APEX m odel, or to unreliable measurements? The measurements at issue were six-day average concentrations based on the use of passive

11(diffusion) samplers, which are known to be subject to significant errors when the air velocity across the inlet is variable. The comparison of m easured and modeled concen trations depicted in Figure 4-22 is certainly worthy of furt her analysis and discussion.

Chapter 5 (Characterizati on of Health Risks): Generally the panel found Chapter 5 and its accompanying risk assessment to be we ll done, balanced and reasonably communicated. Additional text is needed at the beginning and end of the chapter to put the limited risk assessment into the context of the much larger body of evidence of ozone health effects. The discussion of uncertainty in these risk estimates is expa nded in section 5.3.2.5. Although a number of issues are raised, th eir impacts on the estimates have not been thoroughly explored. Additional sensitivity analyses seem warranted. In particular, it is essential that the sensitivity of the risk assessment to the shape of the dose-response curve for FEV 1 be evaluated. Although the 3 parameter logistic (3PL) model em ulates the pattern seen in the five “data points,” these points are aggregates of the original data, and may give a misleadingly optimistic picture of the quality of the fit. More importantly, a lthough the problem of m odel uncertainty is noted it has not been addressed even though methods exist for doing so. Even if only the linear and logistic models were included in the analysis, the error bands around the estimated res ponse probabilities would likely increase to better reflect that uncertaint y. In addition, a sugges tion to deal with the uncertainties surrounding estimation of PRB, pa rticularly as related to Table 5.5 (for lung function) and Table 5.11 (mortality), would be to change the form of the analyses to assess the impact of the concentration change in the expe cted number of health effects relative to the current standard. The key advantage of estimating the effect of concentration change is that it does not depend on the choice of the PRB.

With regard to the controlled human exposure studies, Ozone Panel members believe that the selection of changes in pulmonary func tion expressed as percent change in FEV 1 in children is a fair indicator of an advers e effect at 15% change in all active children; and, in asthmatic children, a 10% change is indicative of adverse effects. However, the presentation of the figures showing these effects needs to be revised to indicate the uncertainties in the results used, particularly at the lower levels of exposure. The potential mechanisms whereby these changes are a reflection of both pain on breathing, partial inflammation of smaller airways, other effects on airways, and potentially triggers for more si gnificant respiratory morbidity, particularly in asthmatic children, are not adequately discu ssed. In addition, some added discussion is necessary to indicate that these measures ar e generally taken in areas with relatively high background levels of ozone exposure, and that the role that tolera nce may play in minimizing the degree of adverse effect observe d needs to be considered.

From the perspective of the epidemiologica l data, the Ozone Panel judged the selection of: respiratory symptoms in moderate/severe asthmatic children (ages zero [birth] to 12); hospital admissions for respiratory illness among asthmatic children; and premature total non-accidental and cardiorespiratory mortality for inclusion in the quantitative risk assessment to be appropriate. However, the CASAC believes that several othe r endpoints should be disc ussed qualitatively to support the findings that these endpo ints indicate that significant adverse effects are occurring at exposure concentrations well below the current standard. Other endpoints deemed worthy of additional discussion included respiratory emer gency department visits among asthmatics and patients with other respiratory diseases, increased medication usage, and increased

12symptomatology reported at exposure levels well below the current standard. Taken together, members of the Ozone Panel felt strongly that these findings preclude including the current standard as a scientifically defensible option for the Administrator (see discussion about Chapter 6 found in the main portion of the letter above).

Another problem in the health effects calcula tions (see Table 5-5 and 5-11) is that they are based on computations of the form R x – RPRB , where R x is the risk at a given concentration x of O 3 and R PRB is the corresponding risk at pol icy-relevant background (PRB) for O 3 . As discussed at the Ozone Panel’s August meeting, the PRB is highl y-problematic to calculate and is, in some sense, “unknowable.” One can avoid this problem by calculating the ∆ = R 0.8 – R x for various concentrations x. This form woul d allow focus on the question, “What is the difference in the expected number of health effects that will occu r at various concentrations of O 3 , relative to the current standard of 0.08?” A key advantage of ∆ is that it does not depend on the choice of PRB, and thus is free of the un certainties surrounding estimation of PRB.

Chapter 6 (Staff Conclusions on Primary O 3 NAAQS): See the discussion on Chapter 6 found in the main portion of the letter above. It would also be helpful to have the estimated exposures for current (2002 and 2004) levels displayed in figures 6-1 to 6-6 (pp. 6-34 to 6-39), in addition to only those for just meeting the current standard and alternative more stringent standards. This would be analogous to the wa y estimated effects are displayed in Chapter 5 (Figures 5-5 to 5-9 [pp.5-58 to 5-65]).

Chapters 7 (Policy-Relevant Assessment of Welfare Effects Evidence) and 8 (Staff Conclusions on Secondary O 3 NAAQS): Chapter 7 is a well-developed and persuasively presented assessment of the welf are effects of ozone on vegetation, which forms the technical basis for the range of secondary standards recommended in Chapter 8. That having been said, the potential for significant pr opagation of error/uncertaintyin the underlying technical documentation draws into question the conclusion s drawn by EPA Staff. As observed in the Agency’s 1989 and 1996 Ozone Staff Papers, oz one remains the most prevalent phytotoxic compound in the ambient air “impairing crop production and injuring native vegetation and ecosystems more than any other air pollutant” (USEPA 1989, 1996). Furthermore, as has been noted in the current assessment of human health effects, there also appears to be no safe threshold concentration below which ozone effect s on sensitive vegetation are eliminated. See the additional discussion on Chapter 8 found in the main portion of the letter above.

13

### Appendix A – Clean Air Scientific Advisory Committee Roster (FY 2006)

U.S. Environmental Protection Agency Science Advisory Board (SAB) Staff Office Clean Air Scientific Advi sory Committee (CASAC)

CHAIR Dr. Rogene Henderson , Scientist Emeritus, Lovelace Re spiratory Research Institute, Albuquerque, NM

MEMBERS Dr. Ellis Cowling , University Distinguished Professo r-at-Large, North Carolina State University, Colleges of Natural Resources and Agriculture and Life Sciences, North Carolina State University, Raleigh, NC

Dr. James D. Crapo , Professor, Department of Medi cine, National Jewish Medical and Research Center, Denver, CO

Dr. Frederick J. Miller , Consultant, Cary, NC

Mr. Richard L. Poirot , Environmental Analyst, Air Pollutio n Control Division, Department of Environmental Conservation, Vermont Agencyof Natural Resources, Waterbury, VT

Dr. Frank Speizer , Edward Kass Professor of Medicine, Channing Laboratory, Harvard Medical School, Boston, MA

Dr. Barbara Zielinska , Research Professor, Division of At mospheric Science, Desert Research Institute, Reno, NV

SCIENCE ADVISORY BOARD STAFF
Mr. Fred Butterfield , CASAC Designated Federal Officer , 1200 Pennsylvania Avenue, N.W., Washington, DC, 20460, Phone : 202-343-9994, Fax: 202-233-0643 ( butterfield.fred@epa.gov ) (Physical/Courier/FedEx Address: Fred A. Butterf ield, III, EPA Science Advisory Board Staff Office (Mail Code 1400F), Woodies Building, 1025 F Street, N.W., Room 3604, Washington, DC 20004, Telephone: 202-343-9994)

A-1

### Appendix B – CASAC Ozone Review Panel Roster

U.S. Environmental Protection Agency Science Advisory Board (SAB) Staff Office Clean Air Scientific Advi sory Committee (CASAC) CASAC Ozone Review Panel

CHAIR Dr. Rogene Henderson *, Scientist Emeritus, Lovelace Respiratory Research Institute, Albuquerque, NM

MEMBERS
Dr. John Balmes , Professor, Department of Medicine, University of California San Francisco, University of California – San Fr ancisco, San Francisco, California

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

Dr. James D. Crapo *, Professor, Department of Medi cine, National Jewish Medical and Research Center, Denver, CO

Dr. William (Jim) Gauderman , Associate Professor, Prev entive Medicine, Medicine, University of Southern California, Los Angeles, CA

Dr. Henry Gong , Professor of Medicine and Preventiv e Medicine, Medicine and Preventive Medicine, Keck School of Medi cine, University of Southe rn California, Downey, CA

Dr. Paul J. Hanson , Senior Research and Development Scientist, Environmental Sciences Division, Oak Ridge National Labor atory (ORNL), Oak Ridge, TN

Dr. Jack Harkema , Professor, Department of Pathobiol ogy, College of Veterinary Medicine, Michigan State University, East Lansing, MI

Dr. Philip Hopke , Bayard D. Clarkson Distinguished Pr ofessor, Department of Chemical Engineering, Clarkson University, Potsdam, NY

Dr. Michael T. Kleinman , Professor, Department of Commu nity & Environmental Medicine, University of Californi a – Irvine, Irvine, CA

Dr. Allan Legge , President, Biosphere Soluti ons, Calgary, Alberta, Canada

B-1Dr. Morton Lippmann , Professor, Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY

Dr. Frederick J. Miller *, Consultant, Cary, NC

Dr. Maria Morandi , Assistant Professor of Environmen tal Science & Occupational Health, Department of Environmental Sciences, School of Public Health, University of Texas – Houston Health Science Center, Houston, TX

Dr. Charles Plopper , Professor, Department of Anatom y, Physiology and Cell Biology, School of Veterinary Medicine, University of California – Davis, Davis, California

Mr. Richard L. Poirot *, Environmental Analyst, Air Pollut ion Control Division, Department of Environmental Conservation, Vermont Agencyof Natural Resources, Waterbury, VT

Dr. Armistead (Ted) Russell , Georgia Power Distinguished Professor of Environmental Engineering, Environmental Engineering Group, School of Civil and Environmental Engineering, Georgia Institute of Technology, Atlanta, GA

Dr. Elizabeth A. (Lianne) Sheppard , Research Professor, Biostatistics and Environmental & Occupational Health Sciences, Public Health and Community Medici ne, University of Washington, Seattle, WA

Dr. Frank Speizer *, Edward Kass Professor of Medicine, Channing Laboratory, Harvard Medical School, Boston, MA

Dr. James Ultman , Professor, Chemical Engineering, Bioengineering Program, Pennsylvania State University, University Park, PA

Dr. Sverre Vedal , Professor of Medicine, Departmentof Environmental and Occupational Health Sciences, School of Public Health and Community Medicine, University of Washington, Seattle, WA

Dr. James (Jim) Zidek , Professor, Statistics, Science, University of British Columbia, Vancouver, BC, Canada

Dr. Barbara Zielinska *, Research Professor, Division of A tmospheric Science, Desert Research Institute, Reno, NV

SCIENCE ADVISORY BOARD STAFF
Mr. Fred Butterfield , CASAC Designated Federal Officer , 1200 Pennsylvania Avenue, N.W., Washington, DC, 20460, Phone : 202-343-9994, Fax: 202-233-0643 ( butterfield.fred@epa.gov )

* Members of the statutory Clean Air Scientific Advisory Committee (CASAC) appointed by the EPA

Administrator (FY 2006)

B-2

### Appendix C – Charge to the CASAC Ozone Review Panel

O 3 air quality information and analyses (Chapter 2) :

1. To what extent are the air quality characterizations and analyses clearly communicated, appropriately characterized, and relevant to the review of the primary and secondary O 3 NAAQS?

2. Does the information in Chapter 2 provide a sufficient air quality-related basis for the exposure, human health and environmental effects, health risk assessment, and environmental assessment presented in later chapters?

O 3 -related health effects (Chapter 3) :

1. To what extent is the presentation of evid ence from the health studi es assessed in the AQCD and the integration of information from acro ss the various health-related research areas drawn from the O 3 AQCD technically sound, appropria tely balanced, and clearly communicated?

2. What are the views of the Panel on the appropr iateness of staff’s discussion and conclusions in Chapter 3 on key issues related to quantitat ive interpretation of animal toxicology and controlled-exposure human experimental studies and epidemiologic study results, including, for example, exposure error, the influence of alternative model specification, potential confounding or effect modification by co-pollutants, and lag structure?

3. What are the Panel’s view on the adequacy a nd clarity of staff disc ussion on the issue of potential thresholds in concentration-res ponse relationships discussed in Chapter 3?

Exposure Analysis (Second Draft Chapter 4 of the O 3 Staff Paper, draft Exposure Analysis technical support document, and OAQPS Staf f Memorandum on Uncertainty Analysis) :

1. To what extent are the assessment, interpre tation, and presentation of the results of the exposure analysis as presented in Chapter 4 (and in the second draft Exposure Analysis technical support document) technically s ound, appropriately bala nced, and clearly communicated?

2. Are the methods used to conduct the exposure analysis technically sound? Does the Panel have any comments on the methods used?

3. To what extent are the uncertainties associated with the exposure analysis clearly and appropriately characterized in Chapter 4, the Exposure Analysis technical support document, and the uncertainty memorandum?

C-14. To what extent is the plan for the remaini ng uncertainty assessment technically sound? Are there other important uncertainties which are not covered? What are the views of the Panel on sensitivity analyses conducted to evaluate th e influence of uncertainties in the exposure analysis?

Heath Risk Assessment (Second Draft Chapter 5 of the O 3 Staff Paper and draft Health Risk Assessment technical support document) :

1. To what extent are the assessment, interpre tation, and presentation of the results of the revised exposure analysis as presented in Ch apter 5 (and in the second draft Risk Assessment technical support document) technically s ound, appropriately bala nced, and clearly communicated?

2. In general, is the set of health endpoints and concentration-respons e and exposure-response functions used in this risk asse ssment appropriate for this review?

3. Are the methods used to conduct the health risk assessment technically sound? Does the Panel have any comments on the methods used?

4. To what extent are the uncertainties associated with the health risk assessment clearly and appropriately characterized in both the second draft Chapter 5 and th e second draft Health Risk Assessment technical support documents?

Staff Conclusions and Standard Options for the Primary O 3 NAAQS (Chapter 6) :

1. What are the views of the Panel on the approach taken by staff (as discussed in Chapter 6) of using both evidence-based and quantitative expo sure- and risk-based considerations in drawing conclusions and identify ing options as to a range of standards to protect against health effects associated with exposure to O 3 , alone and in combination with the ambient mix of photochemical oxidants, for considera tion in this review of the primary O 3 NAAQS?

2. Does the Panel generally agree that the range of alternative primary O 3 standards identified in Chapter 6 is generally consistent with the available scientific information and is appropriate for consideration by the Administrator?

3. What are the views of the Pa nel on the key uncertainties and O 3 research recommendations discussed in Chapter 6?

O 3 -related welfare effects and second ary standard options (Chapters 7) :

1. To what extent is the presentation of evid ence drawn from the vegetation effects studies assessed in the O 3 AQCD technically sound, appropria tely balanced, and clearly communicated?

C-22. What are the views of the Panel on the appropriateness of staff’s weight-of-evidence approach which assesses information from acr oss the various vegetation-related research areas described in the O 3 AQCD, including chamber and free air exposure crop yield and tree seedling biomass experimental studies, foliar injury data from biomonitoring plots, and modeled mature tree growth?

3. To what extent are the methods used to conduct the exposure assessment and the interpretation and presentation of the results of the exposure assessment in the second draft Chapter 7 and the draft Environmental Asse ssment technical support document technically sound, appropriately balance d, and clearly communicated?

4. To what extent are the uncertainties associated with the exposure analysis clearly and appropriately characterized in the second dr aft Chapter 7 and the draft Environmental Assessment technical support document?

5. To what extent are the uncertainties associat ed with the vegetation risk assessment clearly and appropriately characterized in both th e second draft Chap ter 7 and the draft Environmental Assessment technical support document?

6. Staff recognizes that grad ients can exist between O 3 levels measured at monitor probe heights and those measured over low vegetation ca nopies. What are the Panel’s views on the appropriateness of applying a single adjustment factor to hourly monitoring data to account for the range of potential grad ients that can exist across sites and crop and tree seedling canopy structures? Are there alte rnative approaches or adjustment values the Panel would suggest? Are staff’s planned sensitivity analyses appropriate and sufficient?

7. To what extent do the figures aid in clarifyi ng the text? Should more or less information of this type be included in the fina l Chapter 7 or its Appendices?

8. Given the lack of quantitative information on O 3 -related ecosystem effects, what are the Panel’s views on the appropriateness of how th is topic is addresse d in the second draft Chapter 7?

Staff Conclusions and Standard Options for the Secondary O 3 NAAQS (Chapter 8) :

1. Does the Panel generally agree that the s econdary standard options identified by staff (including indicator, averaging time, form, and level) are generally consistent with the available scientific and technical information and are appropriate for consideration by the Administrator?

C-3

### Appendix D – Review Comments from Individual CASAC Ozone Review Panel Members

This appendix contains the preliminary a nd/or final written review comments of the individual members of the Clean Air Scientific Advisory Committee (CASAC) Ozone Review Panel on the 2 ndDraft Ozone Staff Paper and three related draft technical support documents — Ozone Health Risk Assessment fo r Selected Urban Areas: Draft Report (2 ndDraft Ozone Health Risk Assessment, July 2006); Ozone Population Exposure Analysis for Selected Urban Areas: Draft Report (2 ndDraft Ozone Exposure Assessment, July 2006); and Draft Ozone Environmental Assessment: Exposure, Risk and Benefits Assessment (Draft Ozone Environmental Assessment, July 2006) — who submitted such comments electronically. The comments are included here to provide both a full perspective and a range of i ndividual views expressed by Panel members during the review process. These comments do not represent the views of the CASAC Ozone Review Panel, the CASAC, the EPA Sc ience Advisory Board, or the EPA itself. The views of the CASAC Ozone Review Pane l and the CASAC as a whole are contained in the text of the report to which this appe ndix is attached. Pane lists providing review comments are listed on the next page, and their individual comments follow.

D-1Panelist Page #

Dr. John Balmes ......................................................................................... D-3

Dr. Ellis Cowling ....................................................................................... D-6

Dr. James D. Crapo ..................................................................................... D-11

Dr. William (Jim) Gauderman .......................................................................... D-12

Dr. Henry Gong .......................................................................................... D-13

Dr. Paul J. Hanson ........................................................................................ D-16

Dr. Jack Harkema ......................................................................................... D-24

Dr. Philip K. Hopke...................................................................................... D-26

Dr. Michael T. Kleinman............................................................................... D-28

Dr. Allan Legge .......................................................................................... D-34

Dr. Morton Lippmann .................................................................................. D-36

Dr. Frederick J. Miller ...................................................................................D-39

Dr. Maria Morandi ........................................................................................D-43

Mr. Charles Plopper......................................................................................D-46

Dr. Armistead (Ted) Russell ...........................................................................D-47

Dr. Elizabeth A. (Lianne) Sheppard .................................................................. D-52

Dr. Frank Speizer ........................................................................................D-62

Dr. James Ultman .......................................................................................... D-68

Dr. Sverre Vedal ......................................................................................... D-69

Dr. James (Jim) Zidek .................................................................................. D-76

Dr. Barbara Zielinska ................................................................................... D-91

D-2

### Dr. John Balmes

Review of Chapter 3 of the 2 nddraft Ozone staff paper – John Balmes

Overall, I find this draft of Chap ter 3 much improved over the previous draft. In particular, the efforts to respond to the some of the concer ns expressed in the le tter written by CASAC subsequent to the publication of the CD are appreciated.

In general, the chapter provides careful interpre tation of the available da ta in the controlled human exposure, epidemiological, and animal toxico logical literature. Ho wever, I do think that several of the statements about wh ich individuals are at greatest risk of ozone-induced effects in the concluding paragraph of the chapter are not adequately supported by the information discussed in the chapter. Fi rst, we do not know that individuals “with cardiorespiratory impairment (e.g., those with COPD or cardiovasc ular disease) who are “hyperresponsive” to O 3 exposure (i.e., exhibit much higher than normal lung function decrements and/or respiratory symptoms) would be consider ed at greatest risk of O 3 exposure.” While I agree that individuals with COPD and cardiovascular disease (CVD) are li kely to be at increased risk, I do not believe that the hypothesis that such “ hyperresponsiveness” can be used to identify individuals with COPD or CVD who are at greatest risk of O 3 -induced health effects has been confirmed. The hypothesis is certainly plausible, but for the purpose of this chapter, I suggest that it simply be stated in the conclusion that individuals with cardiorespirato ry impairment (e.g., those with COPD or CVD) are at increased risk of adverse effects of O 3 exposure.

Second, the final sentence of the chapter states that “those with genetic polymorphisms for antioxidant enzymes and inflammatory genes ma y be at heightened risk of effects of O 3 .” While I concur with this statement, the chapter provides no supportin g evidence from human studies (either controlled exposure or ep idemiological). The only relevant supporting information that is discussed in the previous secti ons of the chapter is that muri ne studies have used strain differences in O 3 -induced responses to identify candidate ge nes that are likely to be involved in determining susceptibility. These studies have involved genes in th e early inflammatory response rather than antioxidant enzymes. The previous discussi on also includes the caveat that the relevant murine studies used relatively high-dose exposure protocols. Unless, the limited human data suggesting that pol ymorphisms of certain antioxidant enzyme genes (e.g., GSTM1 and NQO1) are discussed in the chapter, I would revise the final sentence.

Specific Comments

3-6-21 and 22 The Adams et al. studies were not done in southern CA. They were done at UC Davis.

3-9-1 I would add “short-term” before declines in lung function in this sentence to be absolutely clear.

D-33-9-4 and 5 For both clarity and consistency, I would revise this sentence as follows: “...pulmonary function in asthma , which included increased nonspecific airway responsiveness secondary to airway inflammation due to O 3 exposure.”

3-12-7 and 8 This sentence is misleading as curren tly written. It should be revised as follows: “Both human and animal studies indicate that AHR is not associated with airway inflammation...”

3-34-2 This sentence overstates the limitations of the data on ED visits for respiratory disease, especially asthma. For example, in Figure 3-4 ED visits for asthma, only one study did not show an increased risk. I would revise the sentence as follows: “...positive but somewhat less robust evidence for associations with respiratory ED visits.”

3-36-9 and 10 This sentence is a bit unclear as written. I would revi se this sentence to end after “...studies.”

3-48-11 Spirometry cannot be done in an imals so “measures of lung function” should be substituted.

3-56-33 Controlled human exposure stud ies cannot evaluate effects of long-term O 3 exposures.
3-57-15 through 17 In my view, this sentence misrepresents the status of the available evidence. I would favor a statement that used “inconclusive” or “limited” to describe the evidence on long-term O 3 -induced effects on lung function.

3-60-35 Change “don’t” to do not

. 3-60-32 through 34 This sentence is poorly wr itten and should be revised as follows: “Controlled studies of dietary antioxidant supplements have s hown some protective effects on lung function decrements but not on symptoms and airway inflammatory responses.”

3-64-16 through 18 The Vagaggini study cited e xposed subjects to allergen before O 3 and obtained samples of respirat ory tract lining fluid by sput um induction rather than by bronchoalveolar lavage.

3-65-3 This sentence is simply untrue re garding asthmatic subjects . I would revise the sentence to delete the words “and asthmatic”.

3-67-11 This sentence is poorly written. I would revise the sentence as follows: “...the involvement of specific genes or genetic loci in O 3 -induced airway hyperresponsiveness and inflammation.”

Table 3-3 For consistency, I woul d replace “bronchial” with “airway”.

3-75-3 through 5 These bullets should be revised to “... O 3 after ... ”

D-43-81-16 Use “ ours ” here rather than “our.”

3-82-27 through 29 This statement is again too strong in my view. I would suggest wording to the effect that the data from epidemiological studies is “limited” or “inconclusive” while data from clinical studies is “lacking”.

3-82-30 and 31 This sentence is poorly written. I would revise the sentence as follows: “...of O 3 -induced effects with a clean air recovery period ...”

References The Mortimer reference listed is a secondary paper for the study. In addition to the 2002 Eur Respir J citation, the primary paper for th is study published in 2000 in the Am J Respir Crit Care Med should also be cited.

D-5

### Dr. Ellis Cowling

Dr. Ellis Cowling North Carolina State University August 17, 2006

General Comments on Chapters 7 and 8 of the “Second Draft OAQPS Staff Paper on Ozone: Policy Assessment of Scientific and Technical Information” and the draft technical support document titled “Technical Report on Ozone Exposure, Risk , and Impacts Assessments for Vegetation: Draft Report”

The following General and Specific comments are focused almost entirely on the CASAC “Charge Questions” raised in Ka ren Martin’s letter to Fred Butterfield dated July 17, 2006. Please note in the paragraphs below, that Karen Martin’s questions are written in bold-faced non-indented paragraphs , whereas my responses are written in indented paragraphs without bold type.

Comments in Response to the Charge Questi ons for Chapter 7 in the Second Draft Staff Paper on Ozone and the draft technica l support document mentioned above:

1. To what extent is the presentation of evid ence drawn from the vegetation effects studies assessed in the ozone Criteria Document tech nically sound, appropriately balanced, and clearly communicated?

I find the evidence drawn from the vegetation e ffects text and figures of Chapter 7 to be technically sound, appropriately bala nced, and clearly communicated.

2. What are the views of the Panel on the a ppropriateness of staff’s weight-of-evidence approach which assesses information from acro ss various vegetation-related research areas described in the ozone Criteria Document, including chamber and free air exposure crop yield and tree seedling biomass experimental studies, foliar injury data from biomonitoring plots , and modeled mature tree growth?

I find the weight-of evidence approach used by EPA staff appropr iate and reasonably thorough with regard to chamber and free air exposure crop yield and tree seedling biomass experimental studies, foliar in jury data from bio-monitoring plots, and modeled mature tree growth.

3. To what extent are the methods used to conduct the exposu re assessment and the interpretation and presentation of results of the exposure assessment in the second draft Chapter 7 and the draft Environmental Assessme nt technical support document technically sound, appropriately balanced, and clearly communicated?

D-6I find these methods, their interpretation, and pr esentation of results to be technically sound, appropriately balanced, and cl early communicated in both Chap ter 7 and the technical support document mentioned above.

4. To what extent are the uncertainties associ ated with the exposure analysis clearly and appropriately characterized in both the second draft Chapter 7 and the draft Environmental Assessment te chnical support document?

I find these uncertainties to be both clearly a nd appropriately characterized in both the second draft Chapter 7 and the draft Environmen tal Assessment technical support document.

5. To what extent are the uncertainties associ ated with the vegetation risk assessment clearly and appropriately characterized in bo th the second draft Chapter 7 and the draft Environmental Assessment te chnical support document?

Similarly, I find these additional uncertainties with re gard to the vegetation risk assessment to be both clearly and appropriate ly characterized in both the sec ond draft Chapter 7 and the draft Environmental Assessment technical support document.

6. Staff recognizes that gradients can exist be tween ozone levels meas ured at monitoring probe heights and those measured over low ve getation canopies. What are the Panel’s views on the appropriateness of applying a sing le adjustment factor to hourly monitoring data to account for the range of potential gr adients that can exist across sites and crop and tree seedling canopy structures? Are there al ternative approaches or adjustment values that the Panel would suggest? Are staff sens itivity analyses appropriate and sufficient?

I agree that these gradients in ambient air c oncentrations within ve getation canopies can and do exist and also find that the idea of applying a single adjustment fact or to account for these gradients is satisfactory. I thi nk the approach used in these documents is as reasonable as any other that could be considered a nd that the sensitivity analyses used by staff are both appropriate and sufficient.

7. To what extent do the figures aid in clarif ying the text? Should more or less information of this type be included in the final Chapter 7 or its appendices?

As indicated in my General Comments on th e First Draft Staff Paper on Ozone on December 17, 2005, lack of figures -- and especially pictur es and charts displaying the important and sometimes very severe impacts of ozone on crops, forest and shade trees, and natural ecosystems -- is a major shortcoming of Chapter 7 in th is Second Draft Staff Paper on Ozone effects on vegetation. Pictures are indeed worth a thousand words (or more!)

I assert once again that it is very important that the final draft of Chapter 7 in this Staff Paper on Ozone should include illustrations that show: a) The distribution of stomata on leaf surfaces, ideally also a paired set showing stomata open and stomata closed, and a diagram showing the structure of the stomata within the palisade layer of a leaf,

D-7b) Crop plants or floral plants grown under different concentrations of ozone, c) Differences in grain yield wi th and without exposure to inju rious concentrations of ozone, d) The greater effect of ozone exposure on root growth than on shoot growth, c) A collage of pictures showing foliar injury that decreases economic value of various leafy vegetables like spinach, cut flowers, and Chri stmas trees, and most important of all: 1) Widespread ozone-induced mortality or ozone -and-biotic-pathogen induced mortality of different species trees exposed to ozone in some of the national parks, state parks, and/or wilderness areas in various parts of the US. 2) A picture of the cross-section of the stem of a tree showing differences in width of annual rings in trees grown with and without exposur e to injurious concentr ations of ozone, and, if possible, also, a cross-section showing the differential width of annual rings on the same tree during years when ozone exposures were high and ozone e xposures were low.

8. Given the lack of quantitative Information on ozone-related ecosyst em effects, what are the Panel’s views on the appropriateness of ho w this topic is addressed in the second draft Chapter 7?

I think the staff have done about as well as can be expected with this question under the present circumstances of substa ntial scientific and technical ignorance about whole-ecosystem effects.

Comments in Response to the single Charge Question for Chapter 8 in the the Second Draft Staff Paper on Ozone:

1. Does the Panel generally agree that the seco ndary standard options identified by staff (including indicator, averaging time, form, an d level) are generally consistent with the available scientific and technical information and are appropriate for consideration by the Administrator?

I believe that EPA staff ha ve done precisely what should be done with regard to recommending firmly and persuasively to the Admi nistrator of EPA that the time has come to formulate and implement a Secondary (Welfare-Based) National Ambient Air Quality Standard for Ozone that is distinct in averaging tim e, form, and level from the Primary Standard

.

The scientific and technical evidence in support of the staff recommendations for serious consideration of the alternativ e cumulative SUM06 and/or W126 Secondary Standards is welldeveloped and persuasively presented.

As shown by the references cited at the end of Chapter 8, the consensus view among expert persons in the ecological communities of this co untry and elsewhere around the world is that a Secondary Standard of cumulative form and ex tending over a whole growing season -- will be far more effective than a Secondary Standard that is not cumulative in form and does not include the whole growing season. Thus, it is simply NOT appropriate to continue to try to protect

D-8vegetation from the substantial, known or anticipated, direct and/or indirect, adverse effects of ozone by continuing to promulgate identical Pr imary and Secondary Standards for ozone.

This generalization is true fo r a wide variety of commercially important crop plants. But it also is true for the vegetation in: a) both intensively managed and wild-land forests, b) scenic vistas in natural parks and wilderness areas, c) ornamental shrubs and shade trees in urba n, suburban, and rural areas, as well as d) the vegetation in natural grasslands, ra ngelands, and other natural ecosystems all over the United States.

A few final comments on the relationship between Chapter 2 and Chapters 7 and 8 in this Second Draft Staff Paper on Ozone and the Na me of the Standard to which this Second Draft Staff Paper is addressed:

1. Relationship between Chapter 2 titled “ Air Quality Characterization ” and Chapter 7 titled Policy Relevant Assessment of Welfare Effects Evidence and Chapter 8 titled Staff Conclusions on Secondary Ozone NAAQS

. There are several important parts of the Air Quality Characterization (Chapter 2) of this Second Draft Staff Paper on Ozone that are highly re levant to the conclusions drawn in Chapters 7 and 8. Thus, in my General Comments on the First Draft Staff Paper on Ozone, I recommended that maps be included in either Ch apter 2 or Chapter 7 (or both) (and possibly also in Chapter 8) that would show the distribution of counties in various parts of the US where exceedances of various alternative Primary and S econdary standards have occurred in the past and/or would be expected to occur in the future. I had in mind that these maps would show th e distribution of countie s that exceed: a) the present identical primary and secondary ozone standards (8-hour) and b) and c) -- the two distinctive cumulative secondarystandards that were propos ed for consideration by the Administrator of EPA in 1996 a nd again in this Second Draft Staff Paper in 2006 [b) SUM06 and c) W126]. At present, page 7-15 in Chapter 7 is the onl y place in this Second Draft Staff Paper where I could find all three of these al ternative existing and proposed ozone standards defined in way that allows ready comparison am ong these three alternatives: a) the existing identical Primar y and Secondary Standards, b) the proposed alternative cumulative SUM06 Secondary Standard, and c) the proposed alternative cumulative W126 Secondary Standard. But these definitions are now presented in Chapte r 7 – which is a very long way away from the maps that are presented in Chapter 2! A map showing the distribution of counties acr oss the US where exceedances of the existing identical Primary and Secondary Standards we re exceeded in 2002-2004 is shown in Figure 2-6 on page 2-20 in Chapter 2. And several diffe rent maps (based on two different sets of

D-9monitoring sites in 2001 and 2002) are shown in Chapter 2 for the SUM06 proposed cumulative Secondary Standard. But no maps at all are shown in either Chapte r 2 or chapters 7 or 8 for the W126 alternative proposed cumulative Secondary Standard. I know (and maybe some readers of the Final Staff Paper on Ozone will also know) that the SUM06 and W126 maps will be much the same, but that very similarity is good reason for showing how very si milar they are (or by chance are not so similar in one or another part of the US).

I believe the value of various parts of Chapter 2 for understanding the major conclusions in Chapters 7 and 8 will be enhanced if more inte r-chapter linkages and cross-references regarding exposures of crops, forests and natural ecosystems are included in the text of both chapters.

I believe it also will be valuable to include in Chapter 2 or Chapter 7, a chart similar to those on pages 2-28 and 2-32 in the First Draft Staff Paper on Ozone showing the diurnal patterns of ozone concentrations at a high-el evation forest site where ozone concentrations during nighttime hours frequently remain relatively high. These ni ghttime concentrations of ozone are important because of their injurious effects on high-elevation forests as discussed on page 7-22 of the First Draft Staff Paper on Ozone.

2) Title of this Draft Staff Paper on Ozone In my General Comments on the First Staff Paper on December 17, 2005, I agreed with Philip Hopke’s assertion that the title of this St aff Paper should be changed so it will be faithful to the title of the National Ambient Air Quality Standards to which this Staff Paper applies. Since the Standards dealt with in this Staff Paper on Ozone bear the name “Ozone and Related Photochemical Oxidants,” both Philip Hopke and I advised that the title of the staff paper should also include “Ozone and Relate d Photochemical Oxidants.” Apparently, either both Philip and I were wr ong in believing that “Related Photochemical Oxidants” are a part of the present name of these NAAQS, or the authors of the Second Draft Staff Paper considered our recommendation not to be relevant to the job they had at hand. Section 1.2.2 is titled “History of Ozone NAAQS Reviews.” But it does not explain when the NAME of these Standards (as opposed to th e specific “indicator” for these standards) was changed. Thus, I recommend that Section 1.2.2 be re vised to avoid the conf usion that at least Philip Hopke and I have had (and continue to ha ve) about the NAME of the standards to which this Staff Paper is relevant.

D-10

### Dr. James Crapo

Comments on Second Draft of the Ozone Staff Paper Chapter 6, "Staff Conclusions on Primary Ozone NAAQS"

Dr. James Crapo, CASAC August 22, 2006

This chapter is in general well written and describes the substantial progress that has occurred in the science underlying our understand ing of potential health effects from exposures to ozone at levels near or below the current primary stan dard of 0.08 PPM on an 8 hour average. In the interval since the current standa rd was set, a variety of studies have found that measurable lung function and/or other health effects occur, particularly in sensitive populations, for exposures to ozone that are at or below the current standard and possibly as low as 0.04 PPM. Uncertainties increase as the level of ozone e xposure decreases and the staff are appropriate in considering this in making final recommendations.

The summary recommendations in Section 6.3.6 provide a rationale fo r both retaining the current 8 hour ozone standard and for decreasing the standard to a level of 0.07 PPM with a range of forms from the third to the fifth highest daily ma ximum 8 hour average concentration. Given the consistency of data from multiple sources demonstr ating adverse health effects at levels at and below the current 0.08 PPM 8 hour standard, the reas onableness of retaining the current standard should be re-assessed. In my opinion, this posi tion is not well justified by the CD or by the arguments in the staff paper. Clear health bene fits are estimated by the EPA staff analysis to occur if the standard were lowered to 0.07 PPM and, although uncertainty increases, further benefit is demonstrated to occur by the staff anal ysis if the standard is lowered to 0.06 PPM. Based on staff analysis that enhanced benefit occurs by lowering the st andard as low as 0.06 PPM, I would recommend that the range of consid eration for modification of the standard be expanded to include a full analysis of the poten tial benefit of lowering the standard to 0.06 PPM.

The staff paper should also furthe r consider the form of the sta ndard. The staff paper analysis indicates that modest changes in the form of the standard can have profound impacts on the frequency of adverse health events. This woul d justify a more thorough evaluation of the form of the standard and a possible recommended ch ange. This is an area where research recommendations should emphasize the uncertainties and opportunity to more rigorously test the local and regional impacts of di fferent choices for the form of the primary ozone standard.

Overall, Section 6 is excellent and provides a stro ng rational basis for rule setting with regard to the ozone NAAQS.

D-11

### Dr. William (Jim) Gauderman

Comments on Staff Paper, post meeting Gauderman 8/25/06

The health-effects calculations given for lung f unction (e.g. Table 5-5) an d mortality (e.g. Table 5-11) are based on computations of the form R x – R PRB where R x is the risk at a given concentration x of O 3 and RPRB is the corresponding risk at policy relevant background for O 3
. As discussed at the Panel meeting, a pr eferable alternativ e is to compute ∆ = R 0.8 – R x for various concentrations x. This form would allow focu s on the question “What is the difference in the expected number of health effects that wi ll occur at various concentrations of O 3 , relative to the current standard of 0.08? ” A key advantage of ∆ is that it does not depend on the choice of PRB, and thus is free of the uncertainti es surrounding estimation of PRB.

D-12

### Dr. Henry Gong

Post-Meeting Comments on Chapter 6 (Staff Co nclusions on Primary O3 NAAQS) in Second Draft of Ozone Staff Paper (July 2006). Henry Gong, Jr., M.D. August 30, 2006

I did not present pre-meeting comments for this chapter. The discussion of Chapter 6 by the Committee as a whole helped me with my evaluati on of this chapter. My comments about this important chapter are as follows: 1. I believe that most of my comments rega rding Chapter 5 also apply to Chapter 6, especially in terms of the foundation for Staff decision-maki ng about clinical endpoints and their public health releva nce. The essential points ar e that many clinical endpoints (e.g., see Figure 3-4, page 3-53) may not be suffi ciently evaluated with quantitative risk assessment but nonetheless constitute highly relevant evidence-based ozone-related health effects. Such evidence and its cons istency “trumps” models, according to many clinicians. 2. The “adversity” of the health effects may be described using guide lines developed by the American Thoracic Society for healthy peopl e and people with respiratory impairment (see Tables 3-2 and 3-3, pages 3-70 and 3- 71). These tables may be somewhat misleading when comparing exposure responses of healthy people versus respiratory patients. People with pre-ex isting respiratory disease have varying pulmonary reserves; small percent decrements in lung function may result in more symptoms, interference or limitation of function, use of medications, et c., than anticipated. Even pulmonary patients with “mild” or “moderate” responses may require significantly more therapy (e.g., medications) and/or emergency department visits or hospitaliz ation. The exposure to ambient ozone is typically recurrent (since ozone episodes ge nerally persist over several days), and adverse effects are likely experienced repeatedly in sensitive groups. 3. The weight of the scientific evidence that was compiled and summarized in the Ozone Criterion Document and Ozone Staff Paper cl early indicates that the current ozone standard is inadequate to protect human heal th. Although more data is desirable such as at low ozone concentrations, we see advers e health effects below the current 0.08 ppmstandard. My reading of the numerous tables and figures indicate that thousands of sensitive children will conti nue to experience ozone exposur es of concern and resulting lung function decrements (and othe r health effects) at or belo w 0.07 ppm. [I note that the use of percentages can be confusing and misl eading in many of the ta bles (see Dr. Lianne Sheppard’s Final Comments, 8/28/06).] Thus, my overall gestalt is to support a reduction of the 8-hour standard to 0.060-0.070 ppm (to three decimal places) to achieve greater protection of public health. I am still concerne d that even this range does not build in an adequate margin of safety for sensitive groups, such as asthmatics. Thus, I favor a standard in the lower end of the proposed range. I anticipate that future research studies will demonstrate evidence of adverse effects in sensitive groups at lower ozone concentrations.

D-13Post-Meeting Comments on Chapter 5 (Characterization of Health Risks) in Second Draft of Ozone Staff Paper (July 2006). Henry Gong, Jr., M.D. August 28. 2006

My pre-meeting comments (dated 8/22/06) remain active. The discussion by the Committee as a whole helped me extend my eval uation of this chapter. My fu rther comments are as follows: 4. As I discussed during the meeting (August 24-25 ), I am concerned that a great deal of emphasis is given to the quantitative risk assessment of lung function decrements in school-age children. The concern about this vulnerable group is appropriate and well supported. Nonetheless, I conclude fromthis chapter that the emphasis is disproportionate in the sense that numerous other clinical endpoint s are down-graded or considered less than optimal, and, thus, should not be effectively or appropriately used to support the adverse health ri sks from contemporary ozone exposures. These ozonerelated endpoints are respiratory sympto ms among asthmatic children, increased medication usage, emergency department vi sits and hospitalizati ons for respiratory illnesses, and non-accidental, cardiorespirato ry deaths. The discussion is up and down regarding their respective causality by ozone, sufficiency of exposure-response data, data consistency, etc. I cannot see how such a large volume of s upporting evidence of clinically relevant information can be masked and not even considered in some type of qualitative risk assessment. Figure 3-4: “E ffect estimates (with 95%) for associations between short-term ozone exposure and respir atory health outcomes” (Chapter 3, page 3­ 53) is the best overall visually convincing clinical summary of this argument. This figure should be prominently and effectively used in subsequent communi cations regarding the adverse respiratory effects of ambient ozone exposure. I believe that the clinicians (physicians) on the CASAC Ozone Review Pane l recognize and agree to this point as well. As someone stated during the meeting, th e formal risk assessment process is only a piece of the evidence and not the entire argument for ozone-induced adverse health effects. 5. Lung function at low ozone concentrations (0.04, 0.06, and 0.08 ppm): This type of clinical data is very impo rtant to obtain and understand. I appreciated and supported the inclusion of Dr. Adams’ data into the Ozone Criterion Document and Staff Ozone Paper. Nonetheless, his data (n=30 subjects) must be carefully understood and interpreted. The probabilistic exposure-response relationships for FEV1 decr ements (Figures 5-2a,b,c) show a logistic modeled sigmoid curve that is weighted by relativel y few data points at the lower ozone concentrations. Are the FEV1 responses normal variations or real ozone responses? Are these responses reproducible in the same subjects? How confident can we be at this time about the lower risk estimat es for lung function response with the limited data points? Thus, I am expre ssing cautious review and inte rpretation of the small amount of lung function data at these low ozone levels. 6. Page 5-56. The “ozone season” in different study areas appe ars to be a “moving target” and is not identical from regi on to region. I am concerned he re that we are not comparing comparable ozone seasons. Changing meteorolo gy is another influential factor that alters ozone levels from year to year as well as spatially. 7. A recently published paper (Triche EW et a l: Low-level ozone exposure and respiratory symptoms in infants. Environ Health Pers pect 2006.114:911-916) did not make it into the

D-14current CASAC ozone review process. Nonethel ess, I would like to cal l attention to it as another indication that resp iratory symptoms occur at or below the current EPA Standards.

Pre-Meeting Review Comments on Chapter 5 (Charact erization of Health Risks) of Second Draft of Ozone Staff Paper (July 2006) ∗ Henry Gong, Jr., M.D. August 22, 2006

Responses to Four Queries from Dr. Martin et al. (OAQPS): 1. I generally found the assessment, interpretati on, and presentation of the results of the revised exposure analysis in the two documents to be technically sound, balanced, and adequately communicated. The progression of discussion appears logical. I specifically found the presentation on exposure-response func tions (section 5.3.1.3) to be reasonable. 2. The set of health endpoints and concentra tion-response and exposur e-response functions used in the risk assessment appear appropriate, given the limited information available for other potentially important endpoints , e.g., airways hyperreactivity, respiratory hospital admissions. As such, it seems that we are underplaying and understating the biological and health impacts of the non-analyzed endpoints of ambient ozone exposures. 3. As far as I can tell, the methods used to c onduct the health risk assessment are technically sound and appropriate. I look forward to hearing other reviewers comment on the methods used. 4. The major uncertainties associated with the health risk assessment appear clearly and appropriately characterized.

Other Comments about the Documents: 1. The value for policy relevant background such be stated early to set a reference point. 2. Page 5-12/line 3: “FEV1i.” must be a typo? 3. Why are there negative numbers for incidences of mortality (3 columns) in Table 5-11, page 5-51? 4. I cannot find Figure 5-12 (see page 5-71). 5. I do not understand the signi ficance of the statement that “the 8-hr maximum concentrations are on average twice the 24-hour average level.” I read it on page 5-73 (lines 37-38) and I believe that it was also stated pr eviously in the chapter.

∗ Also includes supporting Chapter 3 (Assessment of Risk Based on Controlled Human Exposure Studies) of the Draft Ozone Health Risk Assessment for Sel ected Urban Areas: Draft Report (June 2006).

D-15

### Dr. Paul J. Hanson

Dr. Paul J. Hanson August 27, 2006

Review of Chapters 7 and 8 of the Second Draft OAQPS Staff Paper on Ozone: Po licy Assessment of Scientific and Technical Information and the Technical Report on Ozone Exposure, Risk, a nd Impact Assessments for Vegetation: Draft Report July 13, 2006

Final Comments from Dr. Paul J. Hanson: August 27, 2006

The staff has done a credible job of summarizi ng the important issues of crop and forest tree species responses to troposphe ric ozone. Statements of the uncertainties surrounding their conclusions are presented, but some improvements could be made. I do, how ever, recognize that based on the nature of the available data the statem ents of uncertainty will default to qualitative statements in some cases (e.g., projected mature tree responses).

A. Responses to the Panel’s Charge Questions on Chapter 7

1. To what extent is the presentation of evid ence drawn from the ve getation effects studies assessed in the O 3 AQCD technically sound, appropriately balanced, and clearly communicated?

I was generally pleased with th e technical content, balance, and presentation of scientific details contained in the second draft st aff paper and the associated technical documentation. Comments and suggested chan ges for specific items are detailed after the responses to the charge questions.

2. What are the views of the Panel on the appropri ateness of staff’s weight-of-evidence approach which assesses information from across the vari ous vegetation-related research areas described in the O 3 AQCD, including chamber and free air expos ure crop yield and tree seedling biomass experimental studies, foliar in jury data from biomonitoring plots, and modeled mature tree growth?

I support this approach and was impressed thata variety of disparate methods could be used to develop a consistent picture of the sensitivity of vegetati on to ozone uptake. I have listed a number of concerns that the Staff should consider in the preparation of a final document.

3. To what extent are the methods used to conduc t the exposure assessmen t and the interpretation and presentation of the results of the exposure assessment in th e second draft Chapter 7 and the draft Environmental Assessment technical suppo rt document technically sound, appropriately balanced, and clearly communicated?

D-16The methods are appropriate to the appointed tasks, but my comments point to areas where details were missing and where the clarity might be improved.

4. To what extent are the uncertainties associ ated with the exposure analysis clearly and appropriately characterized in the second dr aft Chapter 7 and the draft Environmental Assessment technical support document?

Uncertainties related to the cal culation and enumeration of exposure values and statistics are covered in the document (Page 7-29), but more attention should be paid to the uncertainties of the biological input data with respect to how well they characterize the full breadth of genetic variation within cr ops and natural species. The document does a reasonable job of characterizing the variability of the available data for cultivated crops (pages 7-42 and 7-43), however, no similar disc ussion is provided for the response of tree species and the vegetation of ecosystems.

The document should acknowledge that availa ble studies on non-cr op species target a combination of species of commercial impor tance and species known to be sensitive to ozone. That is, much of what we know about the response of non-cr op-plant response to ozone results from work to understand why particular sp ecies or within-species genotypes exhibited their obvious sensitivity to oz one. The fact that they were sensitive to ozone caused them to be studied more th an species that did not exhibit measurable responses. The document should indicate that we have an inadequate quantitative understanding of the full range of ozone sensi tivity in natural vegeta tion. Available data could represent either an ove r or an underestimate of ve getation response throughout the United States. A dearth of information exis ts for key species present in many areas. Research is needed to understand the true range of ozone sensitivity of species and within-species genotypes distribut ed across the landscape.

5. To what extent are the uncertainties associated with the vegetation risk assessment clearly and appropriately characterized in both the second draft Chapter 7 and the draft Environmental Assessment technical support document?

No comment.

6. Staff recognizes that gradients can exist between O 3 levels measured at monitor probe heights and those measured over low vegetation ca nopies. What are the Panel’s views on the appropriateness of applying a single adjustment f actor to hourly monitoring data to account for the range of potential gradient s that can exist across sites and crop and tree seedling canopy structures? Are there alternative appr oaches or adjustment values the Panel would suggest? Are staff’s planned sensitivity analyses appropriate and sufficient?

This issue is discussed in mo re detail and with much greater clarity within Chapter 7 (pages 7-47 to 7-48) than in the supporting technical report. Th e authors did a good job of characterizing the desirability of adjusting measured ozone concentrations to relevant crop heights and they clearly recognize that su ch a procedure “Ideally should account for

D-17the exact height of each monitor, canopy roughness for each crop, and the seasonal and diurnal nature of turbulence.” Nevertheless, in their attempt to adjust ozone exposure levels for monitor vs. crop heights they may have improved the reality of ozone exposure for some crop species but degraded the appl icability for others (e.g., tall maize crops). Correction factors for crop species growing in windy environments with lower boundary layers would be different than correction factors for crops growing in areas with more stagnant air masses.

I do not suggest that Staff eliminate the co mpleted analysis, but rather include an additional analysis based on the POES data without the 10% adju stment. Having both data sets available will provide a bracket of responses within which the reality probably lies for all crops. Based on their presentation at the public meeting, I see that the Staff has indeed begun to make these calculations, a nd understand that they wi ll be included in the final document.

7. To what extent do the figures aid in clarifying the text? Shoul d more or less information of this type be included in the fi nal Chapter 7 or its Appendices?

The figures were generally ap propriate and helpful, but I made some recommendations on specific figures and tables in th e detailed comments listed below.

8. Given the lack of quantitative information on O 3 -related ecosystem effects, what are the Panel’s views on the appropriateness of how this topic is addressed in the second draft Chapter 7?

The document provides a concise summary of the important issues to be considered at the ecosystem scale, but appropriately concludes, “it is difficult to qua ntify the contribution of O 3 due to the combination of st resses present in ecosystems”.

B. Responses to the Panel’s Charge Questions on Chapter 8

1. Does the Panel generally agree that the s econdary standard options identified by staff (including indicator, averaging time, form, and leve l) are generally consistent with the available scientific and technical in formation and are appropriate for consideration by the Administrator?

Given the reality of the available data and th e status of our understanding of the response of vegetation to ozone exposure and uptake, the proposed indicators, averaging times, and forms are appropriate. I recognize that speci fying the level or leve ls to be applied to the new form of the secondary standard is a difficult task underscored by substantial uncertainties in the data. Nevertheless, I encourage the Staff to propose a level specific to the protection of vegetation independent of the primary stan dard. This is an important distinction. By providing an independent ju stification for the aver aging time, form and level for the secondary standard the Administ rator will have the opt ion of considering a change to the secondary standard even if the primary standard were to be left as is.

D-18The Staff’s recommendation for changing the fo rm of the secondary standard and a range of proposed levels should be accompanied by doc umented statements of the benefits that society would gain by achieving the proposed st andard. Tangible benefits that might be calculated include incr eased crop yield, forest production, and tree seedling survival. Conclusions regarding the benef its to be gained by a change in the secondary standard should be accompanied by acknowledgement of the uncertainties involved. The resulting summary would demonstrate to policy makers and the public the utility of considering a new secondary NAAQS for ozone.

In the future, alternate approaches based on mechanistic models of plant and ecosystem ozone uptake and subsequent response can and should be developed and discussed. However, the application of such detailed a pproaches to the combin ation of species and biomes present across the United States is not possible with current da ta (see page 7-4).

C. Specific comments and editor ial suggestions by document

In the following section I provide comments on the items that I questioned or for which I would like to point out possible editorial modifications. Reader s of these comments should not view the list as a negative refl ection on the document as a whole. Overall, I found that Chapters 7 and 8 and the associated technical docume nt contained many excellent conclusions and statements. I have simply not taken the tim e to enumerate and point out the positive.

Chapter 7

Page 7-7 lines 21 to 30: The aut hors fall into the trap of using teleological concepts to describe active rather than reactive plant responses to stress. Pl ants do not think ab out responding to ozone stress (they can’t). On line 22 the phr ase “plants have a variety of compensatory mechanisms” should probably be changed to ‘plants exhibit a variety of compensatory mechanisms’. What looks like or appears to be variable repair capacity among species or genotypes could be an induced response to wounding, but it could also be the result of inherently different membrane or protein turnover within those same tissues.

Page 7-7 line 4: One might replace “reallocation” with ‘translocation’.

Page 7-8 last paragraph: Pleas e reword as “...with the exception of a few clones of the genera Populus , which can be highly sensitive and in some cases are as sensitive to O3 as annual plants.” Some Populus clones are also very insensitive to ozone.

Page 7-9 line 9: I would prefer that “cause a” be changed to ‘result in a’.

Page 7-9 line 32: Replace this line with ‘...in vigor may be plant death for sensitive plant species’. The response discussed woul d not be general to all plants.

Page 7-12 line 16: Change “...which diseases are likely...” to ‘...the disease-ozone interactions likely...’.

D-19Page 7-12 line 27: Would it be appropriate to in dicate that the competitive response is driven indirectly by changes in plan t species ability to compete for water and nutrients?

Page 7-13: Change “increasing ozon e flux” to ‘foliar ozone uptake’.

Page 7-14 line 16: The authors might a dd a new heading at this location: Climatic Change

. Page 7-14 lines 24 to 28: The authors could cons ider citing a few modeling papers that have dealt with offsetting CO 2 and ozone responses.

Page 7-14 lines 30 to 34: Suggested rewording: ‘...simulations will be important in specifying hypotheses to be tested for the many complex intera ctions of ozone and various combinations of environmental factors. The results obtained will, of course, only be as reli able as the input data for their parameterization, and additional data from organized, systematic study will be needed to judge the efficacy of such model runs.’

Page 7-15 lines 1 to 3: A reference or the name of the EPA program should be provided.

Page 7-16 line 25: Delete the word ‘plots’.

Page 7-19: Figures 7-1 and 7-2 ha ve inadequate captions. They don’t stand on their own. I was unable to follow these figures until th ey were explained at the meeting.

The caption for Figure 7-3 was inadvertently spl it by the figure and “Smoke” should be ‘Smoky’.

Page 7-28 line 26: What are the criteria for the statement that the current NAAQS may not provide adequate protection at this point in the text? At this point , all that has been discussed are the exposure metrics. They have yet to be conn ected to biological response or a discussion of risk. The authors are associating attainment of ozone atmospheres above the current standard with a negative biological response. Although this may be true for some plant species (perhaps even many plant species), it won’t be true for a ll plant species. I would reserve the statements regarding levels of protec tion for later discussion.

Page 7-41: Exposure response information can be developed from FACE exposure systems, but one must recognize the potential for significant gradients of exposure gas concentrations throughout the exposure rings. While the FACE protocols minimize exposure concentration gradients, plants near the gas emitters will be exposed to larger concentrations than centrally located plants near the air monitori ng/sampling point. In the case of CO 2 studies this has often been considered a minor point, but in the c ontext of ozone response studies where peak concentrations are known to disproportionately affect plant function, subtle gradients could be very important. If growth data are averaged ac ross the entire ring, the mean response associated with ozone concentrations measured only at the ce nter of the ring will l ead to overestimates of plant response when extrapolated di rectly to other field locations.

Page 7-43: The authors shoul d delete the comparison of the SoyFACE results with the CRfunctions. The hail damage totally confounds th e desired comparison to the point that the

D-20comparison should not have been attempted. The Morgan et al. (2006) article is missing from the reference list.

Page 7-44 figure 7-13 versus Figure 7D-1 in the annex: When response surface data such as these are interconverted, how is it done? That is, how exactly is the x-axis based on 12 hour SUM06 altered to derive the exact or approximate equivalent for the “4 th highest daily 8-h average”? Is an approximate multiplier applied or are the values recalculated from raw hourly ozone values collected at the time of the original experiment? I asked a similar question at the public meeting and wasn't sure that I got my mess age across. I hope that this alternate wording of the question helps.

Page 7-51 line 17: Should ”Taylor et al. 1993” be listed as ‘Taylor 1993’.

Page 7-57: What Populus clonal data were used as th e base response function for the development of this map? Can the authors ch aracterize the extent to which that response function is appropriate and app licable for the full range of Populus distributed nationwide?

Page 7-58 to 7-60: This secti on starts out with so many qualif ying statements about the limited use of foliar injury responses I began to wonde r why the authors bothere d to include it in the document. Further reading of th is section, however, suggested that the FIA foliar injury data has real value as qualitative indicator of ozone exposure. If carefully measured and interpreted in the context of available ozone concentration measurem ents, I believe foliar injury data may have found a useful role as a semi-quantitative assessm ent of exposure. The authors do an excellent job of characterizing the limitations of this an alysis. Such data will likely never be refined enough to help characterize appropria te levels for future standard s, but they demonstrate nicely the relative magnitude and regional natu re of vegetation responses to ozone.

Appendix 7A Page 3 and 4: I believe that item number one leaves the reader with an inappr opriate conclusion. The real issue is that for flux-base d indices to work they would need to be based on perhaps hourly time step models to ensure that ozone c oncentration and foliar conductance data are appropriately matched. I don’t be lieve that a flux-based approach can be reduced to a simple mathematical index. The full mechanistic m odel based on a 24-hour calculation would be essential for success. In addition, a flux based model of ozone response would also need to include model components necessary to account for the transient development of soil water deficits that would lead to stomatal closure and result in reduced ozone uptake by foliage.

Appendix 7D Page 16: Tables 7E-1, 7E-2, 7E-3 and similar Table in the technical report (pages 5-6 and 5-7) would be more useful for future reference if the parameter estimates for each regression analysis (mean and perhaps max and min) were accompanie d by their respective standard deviations. Future probabilistic estimates of response, as apposed to the de terministic approach provided in the tables, would be made possible by the inclusion of these estimates of parameter error. In fact, if only the parameter estimates for those curves characterizing the mean response data were provided with the appropriate estimates of erro r, calculated max and min estimates could be reproduced for defined confidence limits around the mean.

D-21Providing such data in thes e key documents could very well be the basis for new and independent analyses by other researchers.

Chapter 8

Page 8-5 lines 4 to 16: The predicted value of anticipated loss would be greater if the ozone concentration reduction of 10% had not been applied to the POES data prior to this analysis. For reasons stated earlier, one might consider these es timates of loss to therefore be too low. Please include a discussion of the unadjusted values as presented by Staff during the public meeting.

Page 8-11: Please include an explanation and justification for why the cumulative exposure indices are limited to a 3-mont h window? Vegetation grows for much longer than 3 months in many regions of the United States. There may be an obvious answer apparent to those associated with the standard setting proce ss, but I believe it should be sp elled out in the Staff paper.

Page 8-14: As discussed and c oncluded during the public discussi on, I agree that the Staff paper should not recommend keeping the secondary standa rd identical to the primary. Such an option remains a default that the Administrator could consid er. It need not be listed and certainly is not supported by the weight-of-evidence.

Research needs: All of the proposed research needs listed on pages 8-14 to 8- 16 are justified, but they are not prioritized and therefore repr esent a simple wish list of de sired research. To move ozone effects research ahead at an optimum pace, any list of proposed research needs focus, prioritization and integration. Limited financia l resources underscore the need for making tough choices regarding the order of co mpletion of research objectives. A long wish list is a very scary budget prospect, but a prioritized research program to be addressed over time represents a palatable option for sustained progress in times of limited financial resources. My personal opinion is that baseline mechanistic research for the identification of the role of antioxidants and tissue replacement (i.e., repa ir) in conveying species or species genotype specific ozone resilience has received inadequate attention in recent years. The physics of ozone transport to and into foliage is reasonably well understood, but improved models may be required to characterize this phenomenon with in complex canopies of mixed vegetation. Development and implementation of a plan to characterize the full range of natural plant sensitivity to ozone for plant species with importa nt commercial and/or ae sthetic value to society is needed. Such data will ultimately be needed to translate plant specific responses to the monetary or intangible values they have throughout the United States. Notwithstanding excellent past suggestions for research to improve health and ecological risk assessments for ozone (EPA December 2001), the EPA has made very limited investment in ozone research since the last CD was produced. As I understand the situation, reduced emphasis on ozone was driven by the need to refocus funds and effort on other criteria pollutants (e.g., PM). To advance the science in time for the ne xt periodic evaluation of the Ozone and Related Photochemical Oxidants Standards, however, a f undamental change in the manner in which EPA funds research must be considered. Because such a plan must be rea listic and consider the distribution of limited fiscal resources, I reco mmend that EPA consider a two phase research concept consisting of sustained funding for mech anistic investigations whereby ozone damages

D-22tissues and their functions, to be supplemented periodically by field- scale, exposure-response campaigns to provide tangible em pirical data for testing models of plant response to ozone exposure. The timing of new expensive field campa igns could be determined or initiated when major shifts in cultivar use are evident, are currently needed fo r many dominant tree species, and might be applied to other ecosystem indicator species as their relationship to ecosystem net production is better understood. Whether my specific recommendations are follo wed is not important. It is critical, however, that EPA make plans for sustained invest ment in criteria pollu tant research. Without sustained research investment we stand to lo se critical institutional knowledge both within and outside EPA necessary to make the periodic evaluation of NAAQS work. Without new research results and sustained monitoring of indicator po llutants at relevant sc ales the legislated requirement for periodic evaluation of air quality standards could become a pointless exercise.

Technical report

The draft Technical Report on Ozone Exposure, Risk, and Impact Assessments for Vegetation dated July 13, 2006 contains useful information in s upport of Chapters 7 and 8 of the Staff paper.

Page 5-7: The 10% downward adjustment of oz one values is not fully explained in this document, but appropriate text for this issue is included in Chapter 7. If the technical report is intended to act as a stand-alone document as well as a supplem ent, it should contain some of those details.

I personally found Figures 5-5 to 5-9 to be very instructive regarding the yield losses for crops and one or more of these figures might be moved forward into Chapter 7. The analogous figures for tree seedling responses were al so very useful (Figures 5-10 to 5-14). Including such figures in Chapter 7 would provide the policy makers with visual information about the species-tospecies variation.

The mature tree growth discussion on pages 7- 1 and 7-2 should be expanded to include the details for the western tree speci es simulations discussed in Chap ter 7 (i.e., ponderosa pine).

D-23

### Dr. Jack Harkema

Comments on Second Draft of the Ozone Staff Paper Chapter 3, "Policy-Relevant Assessme nt of Health Effects Evidence"

Dr. Jack R. Harkema CASAC Ozone Review Panel August 25, 2006

General Comments: In general this chapter is very well written and adequately summarizes the health effects evidence presented in Chapters 4 through 7 of the CD. The authors have done a good job of integrating the most relevant health-effects data from epidemiologic and human/animal controlled exposure studies in this summary chapter. Emphasis on new reports in the peerreviewed, scientific literature regarding subpopulations with el evated susceptibility to ozone exposures, effects of ozone exposure on the card iovascular system, and epidemiology studies concerning the effects of acute exposure of ozone on mortality are most appropriate and adequately presented in this document. The new da ta presented in the CD and summarized in this chapter is strongly supportive of the current ozone standard, but al so suggests that the current standard may not be adequate to protect susceptible populations such as those with cardiopulmonary disease, children and the elderly from adverse health effects. This needs to be more strongly and clearly stated in this chapter.

The revised summary tables and figures in body of the text and appendix are excellent and nicely complement the text. For the most pa rt, more interpretation of the results of key studies has been provided in this revised draft compared to the previous draft. There are, however, areas in this chapter that still need more interpretation of results to help the reader understand the plausible reasons underlying the principle health -effects findings. For example, additional statements are needed on biological m echanisms that may be responsible for seasonal and individual variations in re sponse to ozone exposure in the subsections of 3.4. Numerous animal and human controlled exposure studies have documented that individual exposure history to ozone (or other oxid ant pollutants) determines an indi vidual’s response to short-term exposure. A person living in an ozone-polluted city will likely develop some form of tolerance to ozone and may respond differently than a person w ho lives in a relatively clean city and who has not built up a tolerance to ozone. The latter person may be at gr eater risk for developing adverse health effects in response to acu te ozone exposure than the former person. This concept needs to be presented more clearly in the document and how it relate s to the issue of threshold determination.

Specific Comments:

P3-1, L29-31 Authors need to state the key findings not just what was examined.

P3-6, L7 Define “BSA” and “triangular exposure.”

D-24P3-15, L15 Epithelial cell pro liferation (hyperplasia) is a more prominent and welldocumented ozone-induced CAR lesion after acut e exposure than is intramural fibrosis.

P3-21, L13 Monkeys exposed to 0.15 pp m (not 0.2) ozone developed airway remodeling (Harkema et. al., Am J Pathol. 1993 Sep;143(3):857-66).

P3-23-24, L35-2 This is an exampl e of “tolerance” in an animal study.

P3-44-45, L34-2 Study by Vedal et al. is a good ex ample of a population w ith a low level of oxidant air pollution that have a significant associati on between exposure and mortality at a low ozone concentration (see general comments).

P3-46, L21 Change “inflex” to “influx.”

Overall, Chapter 3 is excellent and provides strong supportive documentation for setting the ozone NAAQS.

D-25

### Dr. Philip K. Hopke

Comments on Chapter 2 P.K. Hopke

Ozone is of key importance in the atmosphere be cause it is the easily measured indicator of photochemical oxidation and oxidative chemistry. Th is chemistry leads to particle formation and the production of oxidize products that serve as irritants (acrolein, ca rbonyl compounds) and materials that can produce other effects. T hus, this chapter should take the opportunity to indicate the broader role of ozone and related photochemical oxidants on the overall production of air pollution in both the ga s and particle phases.

I still believe the role of other ambient photochemical oxidants in producing both health and ecosystem effects has been underestimated in this document. The short rationale provided in Chapter 2 for using ozone as the indicator basica lly dismisses the role of other oxidants, but clearly is written with the concep t that the other oxidants are in th e gas phase. There should be at least a mention of the role of ozone in partic le formation and the formation of particle bound ROS. We currently know little about the concentr ations and potential health effects of these species, but a placeholder for future better understa nding of this issue should be added through a few sentences addressing this issue.

One aspect of ozone chemistry and exposure that has not been noted in the staff paper is the formation of indoor particles from ozone that ha s infiltrated into the i ndoor environment reacting with organic compounds of indoor origins. I s uggest a paragraph someth ing along the lines of that which follows be added to Chapter 2.

Formation of new PM by nucleation has been obse rved indoors as a result of infiltrated ambient O 3 interaction with terpenes (S arwar et al., 2003; Weschler, 2004) . One class of compounds that are active ingredients of indoor ai r is terpenes (Wesch ler and Shields, 1997). Terpenes such as α

pinene, and β -pinene are also found in emissions from building material such as pine, hardwood, southern pine etc., (Baumann et al. , 1999). The terpene system (Fan et al. , 2003; Weschler & Shields, 2003; Weschler, 2003; Sarwar et al ., 2003) has been studied and known to produce aerosols with ozone levels normally observed in doors from exchange with outdoor air. Thus, another route of exposure to ai r pollutants is indoor exposure to particles resulting from infiltrated ambient ozone.

Baumann, G. D. M., Batterman, S.A., Zhang, G., Terpene emissions from particleboard and medium-density fiberboard products, Forest Products Journal 49, 49-56, 1999. Fan, Z., Lioy, P., Weschler, C.J. , Fielder, N., Kipen, H., Zhang, J., Ozone initiated reactions with mixtures of Volatile organic compounds under simulated indoor conditions”, Environmental Science and Technology37, 1811-1821, 2003. Sarwar G, Corsi R, Allen D, Weschler C, The significance of sec ondary organic aerosol formation and growth in buildings: expe rimental and computational evidence, Atmospheric Environment 37, 1365-1381, 2003

D-26Weschler CJ, Indoor/outdoor connections exemp lified by processes that depend on an organic compound's saturation vapor pressure, Atmospheric Environment 37, 5455-5465, 2003 Weschler, C. J., Chemical react ions among indoor pollutants: wh at we’ve learned in the new millenium, Indoor Air 14 (suppl 7): 184-194, 2004. Weschler CJ, Shields HC, Potential reactions among indoor pollutants, Atmospheric Environment 31, 3487-3495, 1997. Weschler CJ, Shields HC, Experiments probing the influence of air exchange rates on secondary organic aerosols derived from indoor chemistry, Atmospheric Environment 37, 5621­ 5631, 2003.

Otherwise, this chapter provides an adequate background on the atmospheric background for the standard

D-27

### Dr. Michael T. Kleinman

Chapter 4: Characteri zation of Human Exposure

Comments: M. Kleinman

General comments: This chapter is well writte n however there are some specific points that could be addressed better to strengthen it.

Page Line Comment 4-1 18 The criteria for selec ting the 12 locations should be summarized or at least a pointer to pg 4-18 (where this is somewhat discussed) should be inserted. 4-2 29 Briefly discuss why dose esti mation is not necessary in this exercise. 4-5 29 Is the 180 ppb an average for a room? Perhaps the room size, air exchange and other key pa rameters could be discussed since neither of the sources ci ted are primary peer reviewed literature. 4-5 30 A clear statement of the impact of outdoor O3 on indoor O3 concentration should be inse rted here to provide the foundation for statements made on pg 4-6, L 3 4-6 3 The basis for this needs clarification given the earlier statement that people spend most of their time indoors. 4-6 10 Explain why it is not nece ssary to go further and estimate dose. 4-11 31-32 Is this double-counting, or is the penetration factor computed sans inside source contributions? 4-12 31-32 This could be a problematical concept the way it is phrased. Isn’t this moderated by the pr obabilistic func tion? i.e the likelihood of one person getting th e entire sum of occurrences is vanishingly small. 4-13 25 Among the improvements should be an extension to actual computation of dose. 4-14 17 The degree to which the mode led 12 sites are representative of US populations should be described. 4-15 18 Were the AERs derived from the 12 modeled sites? If not the uncertainty engendered by not matching the sites should be discussed. 4-18 3-4 This should be rephrased since the meaning is not clear. 4-18 Table 4-2 The lack of consistency in periods modeled among the sites is a limitation on the generalization of the model. Some additional justificati on for the partial data coverage should be included. 4-19 6 Change “particularly” to “potentially”?

D-2814 Change “ section 4.3.1” to “section 4.3.4.7” 4-32 Tables 4-8 There is an apparent logical inconsistency when children in and 4-9 LA and Houston have fewer exposures above 0.07 ppm-8hr cities with lower average O3 levels and fewer children.

Technical Support Document:

The modeling efforts are well supported in the document. The method by which the attainment scenarios and the calculations of base cases in Chapter 5 is no t obvious. There seems to be a logical inconsistency in finding more person-days of excessive exposures in Boston than in Houston and some explanation needs to be provided.

Additional Comments Chapter 2

The issue of policy relevant background should be more extensively described. However, the use of PRB as a modifier for the risk assessments leads to increased uncertainty in the estimates. The PRB is very important in how states will develop implementation plans to achieve the O3 NAAQS, but the issue is very complex. Perhaps it would best be handled on a local level given the key factors such as source of background O3, precursors, reduc ing agents that may degrade O3 and many others will vary from locale to locale.

Chapter 3 Pg 3-39 L 1-4 Document states: “As disc ussed in the CD, Section 3.9, using ambient concentrations to determine exposure ge nerally overestimates true personal O 3 exposures by approximately 2- to 4-fold in available studies , resulting in biased de scriptions of underlying concentration-response relationshi ps and attenuated risk estimate s.” Given this more emphasis should be given to the large number of epidemio logical studies summarize d in Figure 3-4 that show clinically important adverse outcomes associated with O3 exposures where most of the exposures are at ambient concentrations BELOW the current NAAQS. This data, in concert with risk estimates in Chapter 5, pr oves that the current NAAQS does not provide adequate protection and in fact affords no margin of safety. This sh ould be carried forward in Chapter 6 to support a recommendation for setting a standa rd below the current 0.08 8hr NAAQS.

Chapter 4 General comments: This chapter is well writte n however there are some specific points that could be addressed better to strengthen it.

Page Line Comment 4-1 18 The criteria for selec ting the 12 locations should be summarized or at least a pointer to pg 4-18 (where this is somewhat discussed) should be inserted. 4-2 29 Briefly discuss why dose esti mation is not necessary in this exercise.

D-294-5 29 Is the 180 ppb an average for a room? Perhaps the room size, air exchange and other key pa rameters could be discussed since neither of the sources ci ted are primary peer reviewed literature. 4-5 30 A clear statement of the impact of outdoor O3 on indoor O3 concentration should be inse rted here to provide the foundation for statements made on pg 4-6, L 3 4-6 3 The basis for this needs clarification given the earlier statement that people spend most of their time indoors. 4-6 10 Explain why it is not nece ssary to go further and estimate dose. 4-11 31-32 Is this double-counting, or is the penetration factor computed sans inside source contributions? 4-12 31-32 This could be a problematical concept the way it is phrased. Isn’t this moderated by the pr obabilistic func tion? i.e the likelihood of one person getting th e entire sum of occurrences is vanishingly small. 4-13 25 Among the improvements should be an extension to actual computation of dose. 4-14 17 The degree to which the mode led 12 sites are representative of US populations should be described. 4-15 18 Were the AER’s derived from the 12 modeled sites? If not the uncertainty engendered by not matching the sites should be discussed. 4-18 3-4 This should be rephrased since the meaning is not clear. 4-18 Table 4-2 The lack of consistency in periods modeled among the sites is a limitation on the generalization of the model. Some additional justificati on for the partial data coverage should be included. 4-19 6 Change “particularly” to “potentially”? 14 Change “ section 4.3.1” to “section 4.3.4.7” 4-32 Tables 4-8 and 4-9 There is an apparent logical inconsistency when children in LA and Houston have fewer exposures above 0.07 ppm-8hr cities with lower average O3 levels and fewer children.

Chapter 5 This Chapter is well written and provides a us eful description of the exposure characterization process. The chapter does l ean heavily on the hu man exposure data at 0.04 and 0.06 ppm to seemingly justify the findings that there ar e measurable effects below the currant NAAQS. There is a tendency in the document to downplay the epidemiological fi ndings of important health effects in cities with aver age concentrations at or below the NAAQS. The point that could be made is that the limiting the studies to days that were below the NAAQS did not change the outcome. Also a more precise description of the f act that the average exposures (used in the epi. Studies) might be below the NAAQS but that at so me location an individual sampler could be above (putting the city out of compliance) a lthough very few people in the population would actually have received an excessive exposure, ne eds to be addressed. A quantitative assessment

D-30of the sensitivity of average exposure to the “p eak” exposure might help to put some concrete values on margin of safety.

Chapter 6 Pg 6-2, L18 Document states: “For the purpose of evaluating the level of the O 3 standard in this review, we have placed greater weight on U.S. and Canadian studies, taking into account the extent to which such studies have reported statis tically significant associations. This is because findings of U.S. and Canadian studies are more di rectly applicable for quantitative considerations in this review as studies conducted in other countries ma y well reflect quite different populations, exposure characteristic s, and air pollution mixtures.” Was the Canadian activities data used in CHAD?

Pg 6-8, L 7-10 Doc. States: “however, when correct ed for the effects of exercise in clean air a small percentage (7%) of healt hy adult subjects experi enced moderate lung function decrements ( ≥ 10% FEV 1 ) with exposure to 0.06 and 0.04 ppm O 3 .” Some indication that this finding has public health significance in context with the confidence limits around the concentration response function should be added to the paragraph.

Pg 6-11, L 29 Doc States:[in reference to ED vis its] ” These studies prov ide evidence of effects in areas that likely would not ha ve met the current standard bu t do not address the likelihood of effects occurring in areas that likely would have met the curr ent standard.” Should be amended to reflect that in several cases, restricting th e analyses to days with concentrations below 0.08 ppm still resulted in significant effects on health.

Pg 6-13 to 6-15 Table 6-1: This table is based on the exposure assessment modeling used previously in Chap 4 which provides “artifactua l” low values for key cities such as LA and Houston. The low values are due to the non-uni form O3 distribution with specific samplers having exceptionally high values causing an “inf lated” design value. When the rollback is performed, the O3 levels for most of the region is pushed to unreal istically low values leading to an inflated estimate of the reduced numbers of cases at the current standard. This leads up to the statement on Pg 6-16 L22 “When 2004 air quality is adjusted to just meet the current 8-hr standard, there are an estimated 50,000 person da ys of 8-hr, moderate exertion exposures of concern experienced by about 50,000 school age ch ildren, which means that there are very few occasions where there are multiple occurrences of exposures of concern.” Inclusion of these atypical cities in this analysis has provided a bi ased view of the value of possible alternative standards. This analysis should be rerun after excluding the “peaky” cities or with some other roll-back scenario that more r ealistically predicts effects of controls. Another improvement might be to present the percent of the children that still show adverse effects (as presented in Table 5-5) because this would highlight the fact that even when meeting the current standard substantial numbers (amounting to about 10%) of these sensitive children will still experience adverse effects.

Pp 6-23-25, Tables 6-4 and 5. These tables s hould be expanded to in clude the alternative scenarios that will be discussed. This is wher e one could provide some idea of the magnitude of excess effects that could be removed if one adopt ed a more stringent standard. Some statement

D-31should also be made that these tabl es show that there is not an ad equate margin of safety in the current NAAQS.

Pg 6-28 L31: Doc. States: “Only a few studies presented results for different O 3 averaging periods using the same data set. Two of the recent multi-city mortality studies reported associations for multiple averag ing times (Bell et al., 2004; Grypa ris et al., 2004). Both reported that the effect estimates for different averagi ng times were not statistic ally different, though the effect estimates for associati ons with 1-hr daily maximum O 3 concentrations were somewhat larger than those for longer averag ing times, especially 24-hr average O 3 .” The 1 hr standard is important for those anomalous cities with greater non-uniformity in O3 exposure. There should be some mention that states such as California have a dopted a 1 hr standard to provide a margin of safety not afforded by the 8 hr standard.

Pg 6-31 L10: Doc states “Collectively, the epid emiologic studies are inconclusive.” This is inconsistent with the Figure 3-4.

Pg 6-40 L10 Doc states “In conclusion, as disc ussed in the previous section addressing the adequacy of the current standard, ju st meeting the current 0.08 ppm, 4 th daily max standard substantially reduces estimates of exposures of concern and risks of various health effects” An additional statement that even when meeting th e standard substantial numbers of sensitive individuals are still expected to experience adverse effects, hence it is unlikely that the present standard provides the required margin of safety.

D-32Pg6-44 L 17 Doc States: “Such a view might pla ce more limited weight on evidence of more serious morbidity (e.g., associations with hospita l admissions) and mortality effects derived from time-series epidemiological studies” Again referri ng to fig 3-4 these strongly suggest that there is not an adequate margin of safety in the current standard.

Pg6-44 It would be appropriate to restate the current standard to 3 significant figures which is consistent with the precision of current monitori ng devices and which will improve the margin of safety by eliminating “rounding up” to 0.084.

D-33

### Dr. Allan Legge

FINAL REVIEW COMMENTS: Allan H. Legge “Review of the National Ambient Air Quality Standards for Ozone: Policy Assessment of Scientific and Technical Info rmation ( Second Draft ) - OAQPS Staff Paper, July 2006".

Chapter 7: Policy-Relevant Assessmen t of Welfare Effects Evidence and Chapter 8: Staff Conclusions on Secondary Ozone NAAQS

Overall Comment:

It is extremely unfortunate that the state of the science regard ing ambient ozone and vegetation has not significantly changed since 1996 with the last O 3 AQCD. The Agency has essentially done little in the interv ening years from 1996 to the present to help solve this problem. The Agency must be strongly criticized for this lack of action. The underlying science to be able to confidently set a meaningful biologically base d secondary NAAQS for ozone simply does still not exist. This is especially unfortunate when there is evidence of foliar injury from ozone exposure at the current primary NAAQS for ozone. One can only make scientific advancement with investment and for some reason the Agency has chosen not to make that investment with respect to the science ne eded to be able to establish a viable and protectiv e secondary NAAQS for ozone.

General Comments:

Despite the above comments, Staff is to be congratulated for atte mpting such a monumental task. This is especially true given that there has been essentially little new science carried out which has addressed the uncertainties which were evident in the last iteration of the O 3 AQCD in 1996. While the presentation of the evidence wh ich Staff has drawn from the current O 3 AQCD is as technically sound as the evidence wo uld allow, the large scientific uncertainties remain. Some of these uncertainties are recognized by Staff while ot hers are downplayed as not being important.

Staff, for example, have placed major emphasis on the results of the ozone exposure research experiments carried out in open-top chamber (OTC) under the National Crop Loss Assessment Network (NCLAN) Program for selected agricultura l crop species cultivars and for selected tree species seedlings by EPA’s National Environm ental Effects Research Laboratory-Western Ecology Division (NHEERL-WED) in the 1980's. It has never been shown that the concentration-response (C-R) func tions derived from these OTC expe riments realistically reflect the response(s) of these plant species cu ltivars under ambient field conditions.

The argument that one can use the same C-R functions developed during the NCLAN Program on crop species cultivars developed in the middle to late 1970's is highly questionable. This assumes, for example, that the current crop spec ies cultivars in use in 2002 have the same ozone sensitivity 25-30 years later as the crop speci es cultivars developed in the 1970's. Further, agricultural crop breeders do not directly bred for O 3 tolerance, it happens indirectly as a result

D-34of selection for the highest yielding disease resistant plants because the ambient O 3 present will be one of the selective factors.

The argument that one can use the same C-R functions developed by NHEERL-WED for selected tree species seedlings grown in pots and exposed to O 3 in OTC’s and that these data can then extrapolated to mature trees growing under fi eld conditions is highly questionable. Further, one cannot assume that tree species seedli ngs will have the same sensitivity to O 3 as mature trees.

Another very important point is that ozone exposure indices such as SUM06 and W126 which have been used by Staff do not have a biological basis as has been implied. It is ozone uptake by plants which is critical and not the ozone exposure.

While the Staff Paper (SP) is very logical in it’s presentation, Staff does not appear to be aware of the very real potential for si gnificant propagation of error and hence significant uncertainty in the analysis prepared for OAQPS by Abt Associat es Inc., (2006) [ “Tec hnical Report on Ozone Exposure, Risk, and Impact Assessments for Vege tation: Draft Report - July 13, 2006]. This is a critically important point because the analysis in the Abt Asso ciates Inc. (2006) draft report provides much of the foundation for conclusions drawn by Staff regardi ng potential secondary standards for O 3 . Put another way, the analyses provided by Abt Associates Inc. (2006) while quite elegant is essentially a ‘house of cards’ with an unstable S foundation.

Each chapter builds on the previ ous chapter with the uncertaintie s in each chapter being carried forward to the next chapter. These data are then used to generate an economic assessment for agriculture crop loss on a national scale. With respect to the forest trees the seedling data are scaled up to mature trees using the TREGRO Mo del which includes ozone as a stress factor to estimate yield loss. In the end of all of this one is not sure whether any of this is realistic or that it would be better describe d as science fiction.

D-35

### Dr. Morton Lippmann

M. Lippmann – Review Comments on Second Draft of Ozone Staff Paper, Chapter 2

Specific Comments

Page Line(s) Comment

2-47 5+ Policy-relevant background (PRB) n eeds to be discussed in a much broader context, with recognition that it is influenced by long-range tr ansport and scavenging processes (PRB of 40 ppb over the Pacific Ocean and less ove r nearby land areas due to reactions with vegetation and with background NO). The uncertain ties that PRB creates in apportioning ozone to PRB and North American anthropogenic sources are not relevant to un certainties in exposureresponse relationships at concentrations be ing considered for a revised ozone NAAQS.

M. Lippmann – Review Comments on Second Draft of Ozone Staff Paper, Chapter 3

Specific Comments

Page Line(s) Comment

3-8 15-19 The concentrations that produced the effects described need to be stated. 3-8 21 insert “routine” after “with”. 3-8 29-35 The concentrations that produced the effects described need to be stated. 3-9 2 add ”and that they occurred at conc entrations below those used in chamber studies using exercise.” at end of line. 3-10 29 insert “and” before “particularly.” 3-11 34 insert “at rest” after “exposure”. 3-12 14 insert “engaged in moderate ly high exercise” after “adults”. 3-15 24 insert the duration of the exposure 3-16 16 insert “pattern” after “temporal”. 3-21 18 insert “an association between O3 and” before “acute”. 3-26 17 provide a reference for the cited study. 3-57 27 insert “Short-Term” before “Mortality” 3-59 19,20 change “which” to “that”. 3-61 27 insert “relatively low concentrations of” after “to”. 3-63 7 Continue with a brief discussion of the O3 being part of a mixture. 3-66 20 change “effects” to “mortality”. 3-67 2 change “health” to “lung function”.

D-36M. Lippmann – Review Comments on Second Draft of Ozone Staff Paper, Chapter 4

Specific Comments

Page Line(s) Comment

4-1 30 Say something here about other impo rtant at-risk groups, such as seniors for excess daily mortality.

4-3 12 change “NOx” to “NO”. 4-4 11 add “, respectively” at end of line. 4-5 24 change “NOx” to “NO”. 4-13 11 add “elderly” as another population at risk (for premature mortality). 4-16 6 change “until we have sufficient inform ation characterizing” to “insofar as other variables have greater effects, for example”

4-18 19 clarify what the New York urban area covers, specifically how far it extends into PA.

4-30 5 change “city’ to “urban area”.

4-47 9,10 Sacramento is not an inla nd portion of the Los Angeles area.

4-47 2-25 The text says Apex was under-predi cting. This is a rare case where I would suspect the measurements rather than the model. The measurements were made with ozone passive monitors, which are notoriously sensitive to ambient air velocity across the inlet, and these velocities were likely to be very different across the inlets of th e personal, indoor, and outdoor units.

M. Lippmann – Review Comments on Second Draft of Ozone Staff Paper, Chapter 5

Specific Comments

Page Line(s) Comment

5-1 26 change “or” to “, or are”.

5-3 27 add “It is also important to consider th at O3 in ambient air is present in a complex mixture of air pollutants, and th at some other components of the mixture may play some role in the health-related effects”. At end of line

5-6 11 add “as well as similar responses in outdoor workers and others engaged in recreational outdoor activ ities” at end of line.

D-375-6 14 insert “young” before “adults”. 5-21 7 insert”, but larger than” after “to”. 5-26 28 change “which are not st atistically significant” to “that did not yield statistically significant results”.

5-27 22 change “nitrogen dioxide, sulfur diox ide, or carbon monoxide” to “NO2, SO2, or CO”.

M. Lippmann – Review Comments on Second Draft of Ozone Staff Paper, Chapter 6

Specific Comments

Page Line(s) Comment

6-3 4 insert “of O3 exposures” after “associations”. 6-3 15 insert “O3” before “air” 6-3 16 change “quality” to “concentration”. 6-3 22 change “an” to “a photochemical oxidant”. 6-3 32 insert “and other photochemical oxidants” after “O3”. 6-4 12 insert “indices of pulmonary function, such as” before “forced.” 6-4 12,13 delete “also known as lung function decrements” 6-4 24 insert”, who were judged to be a sensitive subgroup of concern” after “children”.

6-8 33 change “may” to “generally”.

D-38

### Dr. Frederick J. Miller

Dr. Fred J. Miller August 29, 2006

Policy-Relevant Assessment of Health Effects Evidence Chapter 3, OAQPS Staff Paper – Second Draft

General Comments Overall, Chapter 3 now represents a good assessment of the health effects evidence to serve as the basis for characterizing the health risks in humans from exposure to ozone. The material is well written and organized. For the most part, th e interpretation of inferences the data may support are reasonable; however, there are a few in stances where this review er considers staff to have “stretched” to infer the data support their statement (see specific comments below).

Probably my major points of disagreement w ith the material in this chapter are:

• Discussion of a policy relevant assessment of the evidence for health effects concerning the ranges for changes in FEV1 that are cons idered to be small, moderate, or large for persons with impaired respiratory systems. Discussion of this issue during the August 24-25 th meeting yielded an agreement to not ch ange the table values but to emphasize that a 10% reduction in asthmatics or pers ons with COPD could have more serious consequences than a similar reduction in a person without a compromised lung.

• The chapter comes across with th e view that central monitors in time series epi studies are giving the true picture. Yet we know from material contained in the CD that personal monitors consistently show lower levels. Staff seem to write this off but it has tremendous implications for Chapter 6 relative to the case for lowering the O 3 standard and for margin of safety considerations.

• While the discussion of the low level exposures used in the controlled human studies by Adams and colleagues is technically correct th at no statistically signi ficant changes were found in FEV1 compared to filtere d air, the fact that a reason able percent of the subjects had large decrements is glossed over. These we re healthy subjects, so the percentage of asthmatic subjects, if they had been studied, would be considerably greater. The fact that asthmatics respond with greater differences is shown in other studies discussed in the chapter.

• The lack of statistical power is offered for w hy there appears to be an inconsistent effect seen for COPD mortality. While the same arguments applied for PM, I don’t recall an emphasis on a lack of power. You can’t have it both ways – yes for PM and no for O 3 using many of the same studies.

Specific Comments
p. 3-15, l. 14 It is incorrect to claim that short-term ozone exposures cause fibrosis. The wording needs to be changed here. I believe the authors are intending to convey that fibrotic changes occur with short-term
exposure. P. 3-17, l. 14 Consistently, the authors seem to push the false negative possibility for

D-39explaining discrepancies when the fi nding they are defending could just as well be a false positive. Bette r balance here and throughout the chapter is needed. p. 3-18, l.24 In this sectio n, an Austrian study is cited as showing growth-related increases in lung function over the summer as being reduced with exposures ranging from 32.5 to 37.3 ppb. This study begs the question how low can you go and what is really being measured as growth related increases. This reviewer questions whether confounders are present and whether this kind of study can really be interpreted as growth-related. p. 3-32, l. 6 The authors state that a positive association was seen between longterm O 3 concentrations in the warm mont hs, but this association is not statistically significant. The wr iting comes across biased. If the association had been slightly negative with no statistical significance, I doubt the authors would have writte n about this. Caution against over stressing weak associations as ther e is more than enough positive data on other endpoints to carry the da y that the current standard is inadequate to protect public hea lth with a margin of safety. p. 35, l. 9 The rationale and accuracy of this sentence escapes me. Please clarify why the assumption that the chemical reactivity of O 3 does not induce strong temporal correlations is needed or is correct. p. 3-47, l. 2 The Sexton et al. (2004) reference cited here doe s not appear in the list of references. p. 3-55, ¶ 3 The authors seem to be stretchi ng how far the data can be interpreted to imply that O 3 can have a role in produci ng effects on the cardiovascular system. The current paragraph is highly speculative and should be rewritten. p. 3-57 This section on mortality-related health endpoints includes a number of sentences that are a stretch of the ava ilable data or that need to be made more factual if they are to be use d. For example, on p. 3-58, l. 9 there is a sentence that says the NHNE follow up data have 20% of adults with a reduced FEV 1 value that suggests impaired lung function. What is the % reduction being referred to? The react ions of O3 with cholesterol in lung surfactant are stated to ge nerate products responsible for atherosclerotic plaque formation in arterial walls. Where are the data to support this statement? p. 3-61, l. 36 In the description of the FEV 1 change in berry pickers in Canada, the adjective “large” is used to descri be a 5% decrease. I seriously doubt that pulmonary clinicians would cl assify this decrease as large. Table 3-3 This reviewer does not agree th at the same levels of FEV 1 decrements as for healthy individuals should be used to describe the degree of change in this variable for those with impaired respiratory symptoms. The statement is made in the text that there is no need to change the criteria from the previous NAAQS review. However, staff acknowledge on p. 3-72 that a 5 to 15% change in FEV1 is considered

D-40to have clinical importance to asthma morbidity.
p. 3-81, l. 14 Strike “our” from this sentence.
p. 3-84, l. 1 What is meant by this sentence ? Provide references for the statement.

Chapter 4 OAQPS Staff Paper – Second Draft

There are numerous places in Chapter 4 where only part of the data is presented with the reader being required to go to technical support documents for the “rest of the story”. This should not be the case. If the data for one alternative scenario are presented, the data for other scenarios that were considered should also be presented. The number of cases expected for a given health endpoint and a given exposure scenario is helpful but staff need to also describe what percent of the population is represented by these cases. The reader should not have to dig this out of supporting documents.

As part of the sensitivity analyses associated with using the APEX model, staff have provided some information on the number of children expe riencing at least 3 or more exposures above various ozone levels for Boston and Huston with changes in the activity database, ozone decay rate, air exchange rate, etc (pag es 4-44 to 4-46). This reviewer appreciates finally receiving this type of information, but staff have not gone far enough. One has to go to one of the supporting documents (Ozone Population Exposure Analysis fo r Selected Urban Areas) to find that, when considering exceedances above 70 ppb, for Boston the number of children having these events with moderate exercise represents 7% of the chil dren and about 1-2% of the children in Houston. Moreover, the figures on pages 50-52 of that doc ument show large numbers of children with 5 or more exceedances.

The frequency of exceedance is at the heart of th e question about the leve l of the standard in order to protect against adverse health effect s. This reviewer woul d submit that a child experiencing only one exceedance to an ozone leve l slightly above the current standard is not likely to be of significant concern from a public health perspective. However, the same child having 3 to 5 exceedances would be of great concern due to the repetitive injury to the lungs and the increased chance for more serious health outcomes to be experienced. Thus, for every scenario for potential alternative standards, this reviewer wants to see the percentage of children that will have 3 or more, 5 or more, etc exceedances.

Specific Comments

p. 4-2, l. 28 The statement is made that staff are modeling intake of O 3 and not dose, which is correct. However, staff fail to make use of the dosimetry models that are available. This reviewer has heard that after the last NAAQS review staff were told to forget about using dosimetry models because certain “scientists” did not believ e they could be used. Significant improvements in ozone dosimetry modeli ng have been made over the last decade. This reviewer would be glad to debate the merits of the dosimetry models and their uncertainties compared to the uncertainties present in

D-41various biological endpoint s and epidemiology studies.

More importantly, by not considering the actual dose of ozone to the centriacinar region, we may well be pu tting all our eggs in the “asthmatic child basket” when outdoor workers, who inhale much larger amounts of ozone over longer time periods each day and over the entire ozone season may well be the most affected s ubpopulation. As Dr. Charles Plopper pointed out during the O3 CD discu ssions, the frequency and duration are important determinants of the type of injury and the pr obability for the development of serious pulmonary di sease. Discussions with EPA staff during the August 24-25 th CASAC meeting indicate that there are not sufficient data available to be able to model risk to outdoor workers, and staff agreed to emphasize this po int in the final staff paper. p. 4-5, l. 26 Information is given on how ol der photocopiers and laser printers run under highly unlikely scenarios can generate 150-180 ppb of ozone. Can staff provide any data on how many su ch older copiers and printers are still in use? This reviewer highly do ubts than many such machines are still in use. P. 4-14, l. 15 Why do staff contend that a source of uncertainty results from modeling more than one ozone season? Having more seasonal data simply provides data on the variability over years, which is a good thing to know. p. 4-16, l. 19 The age of the diary informati on is a significant sour ce of uncertainty for the exposure analysis. About 50% of th e diary data are more than 15 years old. This reviewer strongly feels that the extent of computer and video game availability and popularity ma kes the use of these older data meaningless. p. 4-19, l. 16 Classifying 45% of the childre n as “active” seems too high. How much of this classification depends upon the outdated diary studies? p. 4-21, l. 10 More and more communities are going to year-round schools, so not including school commuting may have more of an impact than staff have supposed. p. 4-47, l. 18 The APEX model is shown to have a negative bias, which is 30 to 50% most of the time. The paragraph disc ussing this minimizes the potential impact of this bias. Material in th e technical support document should be brought forward for an expanded discussion of the bias. This review considers the bias to be a major w eakness in the risk assessment if the implication that significantly more exceedances than predicted are actually occurring due to APEX always under predicting exposure

.

D-42

### Dr. Maria Morandi

POST-MEETING COMMENTS ON THE 2ND DRAFT OF THE OZONE STAFF PAPER Maria Morandi

Comments on Chapter 6

Charge Question 1: What are the views of the Panel on the approach taken by staff (as discussed in Chapter 6) of using both evidence-based and quantitative exposure- and risk-based considerations in drawing conc lusions and identifying options as to a range of standards to protect against health effects associated with exposure to O3, alone and in combination with the ambient mix of photochemical oxidants, for consid eration in this review of the primary O3 NAAQS?

Answer: In general, Chapter 6 delineates cl early the rationale of the staff for the recommendations to be proposed to the Administ rator, with appropriate referencing to the relevant sections of the CD and/or Chapters 3-5 of the staff document. Using both evidencebased and quantitative exposure and risk consider ations is a reasonable approach. The available scientific evidence since the la st CD overwhelmingly supports the staff’s recommendation that any new primary standard should be at least as pr otective as the current on e. Clearly, there is no evidence that the current standard is too conser vative. The evidence also supports the staff’s decision that, while there is some evidence for chronic effects on lung f unction growth, there is insufficient data for establishing a quantitative st andard directed at this chronic effect at the present time.

Chapter 6 elaborates in detail on the additional evidence for effects for which the evidence was very limited at the time the current standard wa s set - specifically cardio vascular and mortality outcomes and effects on asthmatics, especially children. My sense upon reading this discussion, which reflects the CD but not the Review Pa nel’s general sense on the robustness of these studies, is that evidence for cardiovascular/mor tality outcomes is still limited and based on approaches that raise methodological and other questions. There is a c ontrast between these concerns and the weight the mort ality studies receive in this Chapter, and elsewhere in the document, although, in the end, they are not included in the formulation of the various standards.

Charge question 2. Does the Panel generally agre e that the range of alternative primary O3 standards identified in Chapter 6 is generally cons istent with the available scientific information and is appropriate for consid eration by the Administrator?

On balance, the scientific eviden ce for effects on asthmatic children and the risk analysis in the Draft document does not support th e recommendation that the current standard is sufficiently protective of this sensitive populat ion, so that a lowering of the 8-hour standard appears justified on this basis. However, it is not clear to me that the evidence for supporting 8-hour standard would be protective of for this group without co nsideration of a shorter-duration standard is presented in a convincing manner as indicated in conclusion stat ement (2) on page 6-43 (also lines 14-22 on page 6-30). Clearly, this statemen t is appropriate for effects observed in healthy, adult volunteers, but the evidence presented in th e document does not shows that it would be as

D-43protective of sensitive asthmatic children withou t a shorter-duration standa rd in locations where such excursions occur (i.e., cities such as Hous ton and LA). There is a somewhat “waving of the hands” feel to the discussion in the Chapter that one side describes the evidence for effects on this sensitive subgroup below the 1-hour or 8-h our standard, but appears not to follow through in the recommendations to the Administrator (eit her for the 0.08/4 or 0.07/7 ppb/8hr standard). The evidence and risk analysis presented in Chapter 6 do not support keeping the current standard as an option.

Charge question 3. What are the views of the Panel on the key uncertainties and O3 research recommendations discussed in Chapter 6?

Answer: The extensive discussion of the 0.08 ppm vs. 80 ppb concentration appears excessive in light of the uncertainties inhe rent in the exposure and risk evaluation. The significance of the concentration rounding can only be evaluated in li ght of an uncertainty analysis that includes both exposure and risk uncertainty, and it should be placed in that context.

Other issues include:

1. Adequacy of ozone as a surrogate for effects from other oxidants: it is co rrect to say that there is no evidence to support other indi cator for airborne oxidants at th is time. However, actual data to support this statement are limited very limited (i.e., lack of evidence may be the reflection of lack or research). The lack of data available to support the us e of ozone as the only and best indicator for photochemical oxidant s can be linked directly to recommendation (3) on page 6-46 under research needs.

2) Addition to research needs: Past and curr ent evidence shows that there are especially more susceptible subgroups among otherwise healthy indi viduals or those with compromised health such as asthmatics. These subgroups are generally called “responders” but the factors associated with such increased susceptibility remain unknown and, consequently, they may still be at risk even with a more restrictive standard. Studies are needed that can identify the underlying causes that make a subgroup among susceptible individuals pa rticularly sensitive to the effects of ozone (or other agents). It would appear that there are different phenotypes w ithin subpopulations with specific chronic diseases, such as asthma, and that each phenotype may be more sensitive to different specific agents, one of them being ozone. Understanding the underlying characteristics that make, for example, a subgroup of asthmatic children especially sens itive to ozone would provide more robust information for setting a protective standard.

Other general comments

In general, the 2nd draft reflects the scientif ic evidence presented in the AQCD. There are editorial issues that can be corrected (some of th ese corrections have been made already) that the Staff can address through a thorough editorial review.

Chapter 2 presents the air quality characterization and analyses in a clear manner that reflects the AQCD. However, there is a strenuous effort th at drives the analyses for supporting a higher

D-44PRB. As discussed by the Panel during the meeti ng, the uncertainties in model estimates of PRB for the 12 cities included in the study remain large undetermined. Ozone levels monitored at Trinidad Head are probably indi cative of extracontinen tal background at that site and perhaps along the western seaboard, but not for areas well within the continent to the eastern seaboard. Quite clearly, the PRB has implications for complia nce with the standard and, therefore, is an important consideration, but evalua tion of commonality in temporal patterns of concentrations at the Trinity Head site and else where in the continen t without more fundamental support basic on basic principles is not warranted for a reactive pollutant such as benzene.

Chapter 3 also presents the available evidence in a manner that reflects the AQCD descriptively, but there is fussiness in the presentation as to 1) which are the more robus t studies and end points that will form the basis for supporting the standard, and 2) which is the specific sensitive subgroup the standard is meant to protect. While the AQCD presents the plethora of studies and their results without engaging in a critical review, the Draft document needs to be more purposive and clear on its descriptio n of the key scientific findi ngs (as compared to the prior AQCD) that will form the basis for the NAAQS reco mmendation. As indicated in the review of the AQCD and by Panel members in the review of the 1st and 2nd Draft, the time series mortality studies raise a numb er of methodological questions beyond just ozone, but they are discussed extensively with lim ited critical evaluation. Given th e methodological uncertainties, apparent consistency of results may not necessarily be evidence for the strength of an association but perhaps reflect the similarity of assumptions inherent in the models (and which are typically never stated in an explicit manner). Given th e more robust evidence for effects found in the human chamber studies and the more epi evidence indicating effects on asthmatic children, it would appear that the extensive discussion of the mortality effects and the comparatively speculative nature of the proposed mechanis ms are not warranted at this time.

Chapter 4 presents a fairly reasonable assessment of exposures under a variety of scenarios. As with any model, evaluation of internal/external consistency and model pred ictions is critical, but there are very few personal exposure da ta available for this purpose.

D-45

### Mr. Charles Plopper

Comments Regarding Chapter 3-Charles G. Plopper

This chapter is a very satisfactory summation of the health effects evidence evaluated in Chapters 4 through 7 of the CD. In almost all case s, the description of th e materials is accurate and provides strong substantiating evidence for th e determinations of the subpopulations with elevated susceptibility th at may be of greatest public health interest and the understanding of the health-related effects associated w ith exposures. There are two asp ects of this anal ysis which are germane to understanding health eff ects evidence that need some expansion. The first of these is the phenomena of tolerance. What this refers to is that the exposure history for an individual will modify their response to subse quent exposure. This is a scientifically well-documented biological aspect of the response to repeated oz one exposures over a period of time. This will have a tremendous impact on such issues as the determination of threshol d in both epidemiologic studies and experimental studies using controlled exposures. It is therefore difficult to address the issue of threshold, because the threshold will vary depending on the air quality of the city in which a study population resides. Seasonal variati ons in 03 levels in th e environment will also modify the determination of no effect level in the same study population depending on the time of the season when testing is done. While this issue is emphasized, es pecially in section 3.4.2.3, the discussion could use clarification in terms of the biological reasons behind the seasonal variation in responses. This may explain some of the lack of strong positive associations between short-term ozone exposure and respiratory mortality, such as discussed in section 3.5 .2. An example of the impact of exposure history on an alysis of response is the Vedal, et al. (2003) study which was carried out in a region with ve ry low 03 concentrations and found significant associations with mortality at very low concen trations. Studies conducted in such low pollution environments may be stronger indicators of th e level of risk and th e threshold for effect, especially in more susceptible populations.

As an editorial note, in some portions of Chapter 3 there is reference to a lack of data from the experimental animal studies on long-term exposure affects. However, in other portions of the chapter, there is discussion of long-term e xposure studies, of which there have been an abundance.

The authors should not be hesitant about making st rong inferences from the data available. The new data is accurately summarized in the CD and in Chapter 3. It is more strongly supportive of the current standard than was the data when the previous standard was se t and indicates that the current standard may be too high to be protectiv e of susceptible populations such as children and the aging. Further, there is a growing body of evidence, well documented by the CD and summarized in Chapter 3, for cardiovascular he alth effects which must be taken into consideration for evaluating a new, lower standard.

D-46

### Dr. Armistead (Ted) Russell

Expanded Review of the OAQPS Staff Paper – Second Draft

Armistead (Ted) Russell

The comments below deal primarily with th e Second Draft of Chapter 4 dealing with Characterization of Human E xposure to Ozone, as well as the related Ozone Population Exposure Analysis for Selected Urban Areas re port, the Analysis of Uncertainty in Ozone Population Exposure Modeling memo, and the Un certainty in Ozone Measurements Memo.

This document includes prior comments, additio nal comments after the August 24-25 meeting ( provided in italic ), clarifying prior comments ( provided in italic ), and additional remarks ( also in italic ).

Response to Charge Questions: 1. To what extent are the assessment, interpre tation, and presentation of the results of the exposure analysis as presented in Chapter 4 (and in the second draft Exposure Analysis technical support document) technically sound, appropria tely balanced, and clearly communicated? The chapter is more clear this time around, and is reasonably balanced. It draws on the associated report well, bringing forward the ma in topics and findings. It should, however, be more clear as to how the APEX model and quadratic role-back are specifically used in the impacts analysis.

2. Are the methods used to conduct the exposure analysis technically so und? Does the Panel have any comments on the methods used? For the most part, they have used appropriat e methods. The addition of using 2002 is appreciated.

3. To what extent are the uncertainties associ ated with the exposure analysis clearly and appropriately characterized in Chapter 4, the Exposure Analysis technical support document, and the uncertainty memorandum? I appreciate all of the work they have done and are doing on the uncertainty assessment. Specific comments are found below.

4. To what extent is the plan for the remaini ng uncertainty assessment technically sound? Are there other important uncertainties which are not covered? What are the views of the Panel on sensitivity analyses conducted to evaluate the influence of uncertain ties in the exposure analysis? They are heading in the right directions, though I recommend that they also conduct an uncertainty apportionment as part of their studies . Try not to get too caught up in details and aspects that are so poorly defined that it will slow down the overall assessment. They have done well to state that they w ill not include some uncertainties.

D-47Remarks on the second draft of Chapter 4 : The second draft of Chapter 4 has responded to many of the comments made on the first draft, and is thus more clear than before. I was pleased to see the reanalysis for 2002 in addition to 2004.

Specific comments:

Page 4-47: They show a bias from APEX, but do not provide informa tion on how that impacts their analyses, and also tend to downplay the magn itude of the bias. 50% is big, and the bias, while smaller in other cases, is consistent. The bias shown continues to concern me, suggesting that the risks/exposures to le vels of concern based upon the exposures found by APEX are low. If staff can address th is, it would be good.

4-46: I might refrain from calling the uncertain ty analysis as bei ng results just yet.

Chapter 2 : I am pleased to see the measurement and design value uncertainty added to this chapter. They should add to this chapter the possible bias in the measurements as presented, noting that this may mean that in past analys es (particularly those depending upon routine monitoring data), the levels of ozone experienced may have been less than measured, thus increasing the risk at lower exposure levels. They should also suggest that future instruments be designed to address this issue.

In regards to PRB, given the contentious natur e of the issue, the use of the PRB should be discussed in Chapter 2, along with other measur es. However, their current approach has been peer-reviewed, and is appropriate. They should, be fore the next analyses, continue to refine and evaluate their approach to setting the PRB, and how it is used in the assessments. For example, might they use the PRB in the roll-back formul a? This could be done by analyzing CMAQ simulations where the boundary conditions are se t to those conditions representative of PRB conditions.

Chapter 6 : This chapter should deal not only with th e recommended standard, but also with the precision of the standard. They have done an anal ysis of the uncertainty in the observations, and find that most of the uncertainty is due to instru ment bias. They have also looked at the impact of the precision chosen on results. It is apparent that the exposure is sens itive to the choice of not only the standard, but also th e precision chosen. It would seem unlikely that given the large number of monitors used in th e various health studies upon whic h the standard is based, it is unlikely that the bias identified for a single monito r is appropriate, and this should be reflected in the precision of the standard. This chapter shou ld discuss this issue and make an appropriate recommendation.

I was pleased to hear that they are planning to suggest that the standar d be given to three decimal places (e.g., 0,080 or 0.070 ppm) as this is st rongly suggested by their analyses. This should not be just recommende d, but strongly recommended.

As an engineer, I can not speak so directly about the interpretation of the health data, but they very specifically note that (page 6-16) dependi ng upon the year rolled back to meet the current standard , 20,000-600,000 children are estimated to experience exposures of concern. Thus, the

D-48current standard is not protective, and would leave a large number of children at risk. It should be noted that the range should not be interprete d as that the number of children experience exposures of concern will vary depending upon year, e.g., from 20,000-600,000, so maintaining the current standard will lead to a very large number of exposures of concern in some years. On page 6-32, the SP notes that lowering the standa rd to 0.07 would still have, relative to just meeting the standard, 0-10% of the population experiencing expos ures of concern, suggesting that there is a strong likelihood of continued exposure to exposur es of concern. Such an analysis argues that the maximum standard in the future should be 0.07(0). No data presented suggest that the current standard is adequate.

Remarks on the second draft of Ozone Population Exposure Analysis for Selected Urban Areas: Again, the draft is more clear: thanks. Ho wever, they have not “corrected” some of the mathematical presentation (e.g., the del operato r) is still used in appropriately (why? ).

Page 2: Sec. 1.2: Update year.

Page 19: Eq. 2-15: Need to correct subscripting.

Page 20: You switch units between hours and minutes in the analysis.

Page 27: I still think it should be “... differentiate between people...”

Page 28: Are you able to correlate betw een meteorology, ozone and activity together?

Page 44, Pare 1: Awkward.

Page 64: Needs a bit more explanation.

Chapter 7: They really need to explain what the low bias from APEX really means and how it will be accounted for. Also, why use ug/m 3 in this section, ppm/ppb in others?

Specific Comments:

Page 2: Section 1.2: They still ha ve just 2004 as the application year.

Remarks on the Draft Analysis of Uncertaint y in Ozone Population Exposure Analysis for Selected Urban Areas:

Overall: This is a nice start, but obviously is not a fi nal product, so the co mments are on what is currently available. As a gene ral question, are you pl anning to attribute uncertainty to specific parameters and inputs? If not, why not? I would strongly recommend conducting a first order (or higher) analysis on c ontributor attribution.

Page 2: Add “Bias” to the list of important concepts in the list.

D-49Page 8: Paragraph 1 is a repeat.

Page 15: Using the ratio approach will give a “bias” and it is not surprising that the central value is 1.065 (what would appear to be a 6.5% bias). Instead, use absolute values, unless you plan to use the ratio to scale your exposures . The last line of this paragra ph is opaque, and they need to come up with a better explanation/reasoning. I would recommend that they not sue the ratio approach, but use the absolute differ ences in magnitudes, as this wi ll likely show much less bias, and should lead to less skewness late r in their analyses. If they wish, they can calculate the relative bias as the (average absolute bias)/(average concentration).

Page 16 (et al.): Please label all axis of the graph. Also, the last sentence needs to be better justified. The figure caption for Figure 7 (and similar figures) is insufficient.

Page 15: No need to use additional methods fo r spatial interpolation... they will give different, possibly slightly better, estimates, (they picked two of the easiest appro aches, not best) but the difference will likely be quite minor.

Page 18: Table 7 mixes uncerta inty units, likely unnecessarily.

Page 19: Fig. 10: Are the standard devi ations available? Is the trend for O 3 significant?

Page 21: Is the ratio really 0.12-0.16? This strikes me as a very low number for locations outside of street canyons.

Pages 22- 27: The rollback process and the resul ting Figures need to be better explained in the
text.

Page 39: If you are really going to do what is shown in Diagram 1, you can do some uncertainty apportionment. Not sure why this would be done just to find influential st atistics separate of a complete uncertainty analysis.

Page 43 et seq.: I am not sure I grab why th ey are saying that averag ing together a set of simulations is not as accurate as having a si ngle simulation with the same net number of “people”. Also, it is not obvious why you need 60,000 given the trend of Fig. 20.

Page 45: The spread shown rea lly is not very big (i.e., why do they say that the spread is significant?).

Figs. 21 and 22: Labels on all axes.

Page 55: The statement is made that the f actor model parameters have no uncertainty by definition. Please explain. I have trouble with this statement. They could have a more sophisticated set of factors (e.g., more than two, not all multiplicative), that would allow for more careful uncertainty assessment. They can make the statement that they are not examining the impact of having the current form on the results and the uncertainty assessment.

D-50Page 59... We await the results.

As presented at the meeting: I was pleased with what I saw at the meeting, and rather than attempt to be exhaustive, and not complete all of the analyses, continue as planned to examine the most influential. They should concentrat e on the uncertainties in the “differences” in exposures (this was presented, and one notes that the differences are small). They need to be ready to explain the skewed results, and a figure would help.

Comments on the Cox and Camlier memo: First, thanks for doing this. I was disappointed that a bottom line recommendation was not given as how to treat the calculated uncertainty in terms of the precision of the standard. This w ould indicate that the pr ecision of the standard should be to the nearest 1 ppb.

Other: As discussed with staff (Langstaff), a si mple diagram of the rollback approach would help significantly.

D-51

### Dr. Elizabeth A. (Lianne) Sheppard

Review of the Ozone Staff Paper Second Draft

Staff Paper Chapter 5

Response to charge questions – Overall comments

Heath Risk Assessment (Second Draft Chapter 5 of the O 3 Staff Paper and draft Health Risk Assessment technical support document):

1. To what extent are the assessment, interpreta tion, and presentation of the results of the revised exposure analysis as presented inChapter 5 (and in the second draft Risk Assessment technical support document) tec hnically sound, appropria tely balanced, and clearly communicated?

I found generally the work in this chapter and the accompanying risk assessment to be well done, balanced, and reasonably communicated. Th ere are a few places where I suggest improvements and I have included these in my detailed comments. Most important, the presentation and summarization of the clinical evidence for the FEV 1 decrement doseresponse implies far greater certa inty than I believe is warran ted by the data. Figure 5-2 must be completely revised to reflect the uncertainty in the data. A new table summarizing the derived study results used for this figure should be added to the Staff Paper. The method for deriving the dose-respon se calculation, and the use of the logistic function must be re-evaluated. Furthermore the sensitivity of the results to the doseresponse assumption must be assessed. The apparent certainty of the FEV 1 decrement dose-response has major implications, particularly since the estimated O 3 -induced decreases in lung function are lower than were estimated in the last review. Because of the currently hidden uncertainties, this conc lusion may not be correct and should be revisited after gaining new perspective on th e certainty of the es timated dose-response function.

2. In general, is the set of health endpoi nts and concentration -response and exposureresponse functions used in this risk assessment appropriate for this review?

Given the literature to date, the set of health e ndpoints are appropriate. I find it more difficult to infer causality from the epidemiological studi es than the staff, but I agree that the endpoints and estimates used are reasonable choices given the current stat e of the science. It is important to state clearly in both Chapters 5 and 6 that there are many endpoints with good evidence of effects cited in Chapter 3 that are not in corporated into the risk assessment in Chapter 5.

3. Are the methods used to conduct the health ri sk assessment technica lly sound? Does the Panel have any comments on the methods used?

D-52My main concern is the use of the 3-paramete r logistic function for the derived lung function response results. Not only is the function pr oblematic, but also the summarization of the data prior to selecting this function allows the perception of greater certainty than is warranted by the data to prevail. Because it has a large impact on the use of the clinical study estimates from the risk assessment, the approach to fitting this function and its sensitivity must be evaluate d. See my detailed comments.

4. To what extent are the uncertainties associated with the health risk assessment clearly and appropriately characterized in both the s econd draft Chapter 5 and the second draft Health Risk Assessment t echnical support documents?

I was pleased with the effort to document the uncertainties. While it is difficult to know whether or not all uncertainties are well enough unders tood to even document, the lists appear thorough and it is clear that this issue was thoughtfully consid ered. In terms of risk communication, be careful that thoughtful scie ntific consideration of the uncertainties doesn’t dilute the overall message.

Detailed comments

Please review all tables and fi gures (including captions) with an eye towards better labeling, particularly of figure axes and table columns. Always include units and enough details so the figure or table can stand alone out of context. For instance ther e are a number of figures that have the ozone concentrations/standards listed and also include “Recent (2004)” as one of the items. This is confusing out of context. It also may be helpful to give a detailed key of the first figure in a series.

Thorough cross-referencing with the technical Health Risk Assessment document would be helpful.

My concern is that focus on the risk assessmen t demotes in importance all other evidence in favor of O 3 health effects. Highlight a better in this chapter that the eff ects and endpoints used for the risk assessment are a small subset of the effects that were summarized in Chapter 3, as well as a subset of populations, locations, etc. An aspect of this is noted briefly on 5-7 9-12. It is too easy to focus only on the risk assessmen t results and overlook th e other large body of evidence that is not included in the risk asse ssment. The write-up should help readers avoid doing this. This point also needs to be brought forward into Chapter 6.

Make sure percentages are clearly defined. Avoi d whenever possible using number of events in the denominator. Instead use total population. If events are needed for some purposes, take care that counter-intuitive comparisons and results don’t get highlighted.

5-4 lines 1-11: I’m not convinced that we can ch aracterize the uncertainty of risk assessment in epidemiological studies as “consid erably” greater due to location. I don’t think we have great enough understanding of the sources of uncertainty to quantify its relative magnitude. Similar comment for the use of “considerably” in line 18.

D-535-5 and throughout: While observing consistent re sults across epidemiological studies may be a necessary condition for inferring a causal effect, I don’t think that it is a sufficient condition. While it may only be semantic, I find the judgments about causality as stated in this document, particularly with respect to the epidemiological studies, difficult to accept. One reason is that the epidemiological study relative risk estimates come from the time series study design and we have limited understanding of the effect of this study design, particularly for such a highly reactive pollutant such as ozone that doe s not penetrate well indoors. Ho wever, based on the perspective of the precautionary principle, I do not object to the selection of endpoints and their use in the risk assessment.

5-12 and throughout: Notation in this document is at times confusing. Anything staff can do to minimize the variants of notation through the whol e document, clarify the definitions, and unify the presentation, would be helpful. One suggestion is to prepare a gl ossary of symbols for Chapter 5 and/or for the TSD. (Note: eventually I found a glossa ry for some terms in Appendix B.2. However B is not defined there. At a minimum refe r readers to this appendix in Chapter 5.) In the process of preparing the glossary, inst ances of redundant and confusing notation will be more readily identified and can then be corrected.

5-14: It is unclear to me why the categor ies for “as is” and “bac kground” would ever be different (i.e. why distinguish between i and j ?). Is it possible to simp lify the equations from the most general forms and still captu re all of the work that was done ? Or are there examples where this isn’t possible?

5-16: I have difficulty with the use of the 3- parameter logistic function for estimating the doseresponse curve. While from the existing figure it appears to be better th an the previously used linear dose-response curve, it is not apparent to me how sensitive the results are to this assumption and how necessary it is to make a parametric assumption, particularly from a 3­ parameter model fit using only 5 data points. Th e biggest problem with the logistic function is that it is parametric so that a small change a nywhere on the curve may have a large impact in the region of primary interest – at the low ozone concen trations. In particular , note that the threshold response rate is estimated from these data although there are no study results at the higher exposures to verify this estimate. (As an additi onal point, I don’t recommend excluding data that could be informative for fitting this model and thus suggest the dataset be expanded to include studies conducted at higher con centrations – e.g., th e Follinsbee studies ci ted in the 1996 CD, particularly if the logistic f unction will continue to be used. Take heed from the O-ring data analysis on a restricted dataset used to justify the decision to launch prior to the Challenger disaster.) The logistic function is by defin ition symmetric, so small changes to the threshold estimate could have a large impact on the shap e of the curve at low concentrations and consequently on the risk assessment estimates that are so heavily weighted towards the smaller concentrations. I have several follow-up sugges tions: 1. Consider using a more non-parametric approach to smoothing as the main analysis, and cer tainly at a minimum as a sensitivity analysis. I suggest considering a natural cubic spline with one knot or pur e linear interpolation. 2. Consider weighting the contributi ons of each data point by their un certainties. Better yet, start from the raw data, not data averaged at each expos ure level. 3. Particularly if a parametric function is to be used, include ad ditional studies to bett er pin down the height of the curve. 4.

D-54Conduct a sensitivity analysis for a few different cu rves, including a linear function if indeed that function is consistent with the data when the unc ertainties are included. If the risk assessment isn’t particularly sensitive to changes in the ap proach to smoothing, then it will be less important to focus additional attention on the approach to smoothing at this late date. Based on the comparison of these new results to the previous review, the risk assessment is very sensitive to the shape of the selected dose-re sponse function. Therefore more needs to be done to address that sensitivity.

Figure 5-2 (and 3-3): Completely revise this figure. Show study- specific data, not summarized data. Include uncertainty estimat es on the figures. Show the poi nt estimates and uncertainties for all the studies (by e.g. jitteri ng around the target concentrations). Also add a table that gives all the results used to create the data in these fi gures (or cite the appropria te table in the CD). Chapter 3 (Appendix Table C-2) has the data, but it is not in the same form as the data used in this figure. There are no counts given in the table. Thus a new table needs to be developed and included in Chapter 5 to show the data used in the figure.

5-18: The “Bayesian” approach appears to be only Bayesian in flavor. For one thing the “data” in the “Bayesian” analysis are no t data, but predictions from the logistic curves. While it is a commendable effort to quantify uncertainty in these dose-response curves, there is no recognition of the uncertainty due to the selection of the function itself. Also the data are not used directly.

5-22 13-23: This is a place where including the notation along with the words will help the reader immensely. I’m still not sure I’m completely straight in this section as to when “baseline incidence rate” refers to B (the more typical use outside of this document) and when it refers to y

. On first reading it was only on page 5-29 line 30 that I finally bega n to understand that y is the baseline incidence.

5-24 17-30: Drop all this and just give the definition of notation, i.e. exp( β ∆ x )=RR ∆ x . 5-35 16-18: I suggest star ting that sentence with “One” rather than “The”. I think this is one possible explanation but not the only possi ble explanation as is currently implied.

5-49 21-22: The reason to use the highest 8- hour monitor when comparing to the 24-hour average is not clear. Epidemiological time se ries studies with 8-hour average ozone as the exposure do not use the highest monitor over a spatial region. Thes e appendix plots are examples of plots that need to be more clearly labeled and de scribed in the caption. Also the distribution of the maximum is re lated to the total number of monitors. Include this information (the number of possible monitors) in each plot.

5-56 21-23: It is helpful to know that the risk estimates are based on the accumulation of events over seasons that are different lengths. This means from one perspective, comparisons across cities are “unfair”. I think this information be longs in the table as a footnote or extra column (summarizing the percent of year for the ozone season) as well . Another idea is to add an additional table in the TSD to allow cross-c ity comparisons for the single highest average

D-55exposure month (or some other reasonable choice that would make the estimates from all cities temporally comparable).

5-71 9-11 and 31-34: This comment elevates the importance of my concerns regarding choice of the logistic function.

5-71 15: Figure 5-12 missing. Clarification: This is a typo; should be Figure 5-2.

5-73 8-10: It is unclear to me why New York was singled out for discussion.

5-76: I think there are also un certainties due to the f eatures/behavior of particular study designs, particularly the time series st udy design that relies on aggregate data and does not incorporate a one-to-one link between exposure an d outcome on individuals.

Minor comments :
5-12 3: Why is there an i subscript included for FEV 1 ?

5-24 13: Replace this line by: subtraction equa tion (5-3) from equation (5-2) and multiplying by y/y which yields:

5-33: An asterisk appears in th e table without a matching footnote.

5-36 and throughout: I would prefer the term “sampling variability” over “sample size considerations”.

5.57 16, 17; 5-73 22: Periods missing.

5-76 43: Replace line with: model uncertainty (i.e ., uncertainty about the selected model, e.g., the shape and magnitude of the

5-78 25-27: More information is needed to easily access this paper.

Staff Paper Chapter 6

General comments :

I found this chapter less well done than chapter 5. I found several errors, suggesting to me this chapter contains more than an acceptable number of errors. I felt that the composite body of evidence of O 3 effects summarized in chapter 3 was discounted, perhaps because many of the results cited in Chapter 3 aren’t easily quantified in a risk assessment. The force of scientific evidence should not be lost with focus on a limited risk assessment. In contrast, a few studies (e.g. the Peters et al 2001 pilot st udy results) were given inappropria te attention relative to other evidence in the literature.

D-56Most important, I did not find the evaluation of the risk assessment well grounded in public health considerations. I think th e first order of business for this chapter is to clearly define and justify the rationale for criteria fo r public health benefits of any st andard. I suggest public health significance should be based on absolu te rather than rela tive criteria. While the risk assessment is admittedly restricted to a subset of e ndpoints, population groups, and geographic locations, numbers from the risk assessment can be used for quantifiable estimates of public health benefits.

The second problem with the focus in this chapter is that it gives relatively too much weight to the necessarily restricted risk assessment (restricted to specifi c populations, endpoints, locations) compared to the full body of scientific evidence for O 3 health effects summarized in Chapter 3. This problem starts in Chapter 5 and is carried into Chapter 6.

One of the effects of the focus of this chapter is that the conclusion of possibly maintaining the current standard was presented as defensible fr om some points of view . I think the body of evidence only supports lowering the current standard. The chapter should be revised to focus on a vision for acceptable public health impact. Th en all the evidence should be brought to bear on this vision without overweighting those results that have an acco mpanying risk assessment. This will produce different conclusions.

I found the reliance on relative comparisons usin g cases as the denominators misleading (e.g. see Table 6-3; also Figures 6-1 through 6-6). Percen ts based on number of cases are sensitive to variation in the number of cases from year to y ear and this creates appa rent differences between percentages that are not real.

• For instance for incidence in Table 6-3 (see also 6-21 lines 17-18) the incidence differences for recent vs. just meets the sta ndard are identical but the percentages make it appear that it is better to reduce O 3 in a clean than a dirty year when in fact the absolute improvement is identical in both years.

• The figures show percent changes re lative to the current standard.

o It does have value in normalizing the data and allowing comparisons between locations. However, since many loca tions already don’t meet the current standard, this point of reference can be questioned. At a minimum keep the point of reference the same but also include the actual data as an additional exposure on the figure.

o Percents can also mask the public he alth significance by magnifying small absolute differences and the converse. For instance, going back to Table 3-11 in the TSD and comparing FEV decremen ts in Atlanta, note that the relative change for 0.084/4 to 0.80/4 is 11% for FEV greater than 10% and 24 % for FEV greater than 15%. However, for FEV greater than 15% affects 11,000 occurrences while for FEV greater than 10% affects 65,000 occu rrences. This is so much larger in absolute magnitude that it cannot be ignored. See page 6-33 lines 13-15 for an example of where the relative compar ison ignores the large differences in absolute effects.

Add some discussion in this chapter about atmo spheric chemistry and the importance of reducing oxidants on reducing overall pollution. Incorpor ate recognition that O3 is an indicator.

D-57Review the language used in this chapter for clarity.

Details :

6-10 30: The O 3 data used in Sheppard 2003 and the original 1999 paper are predominantly for the warm season. Only one year of 8 years of da ta included winter measurements. Also correct the reference.

6-11 8-10: This conclusion is confusing. Based on the 98 th percentile ppb averages, clearly most or all of the monitors in the Burn ett et al 1997b paper met the standard.

6-11 29-31: Since the epidemio logical studies estimate a linear dose-response relationship, and most when they check this assumption find thatit is well supported by the data, does it really make a difference whether the areas in which the st udies were done met the st andard? Is this an opportunity to incorporate th e concept of tolerance?

6-12 22-23: Can this be stated more clearly? Define the re levant air quality statistics.

6-12 27: Revise/add to the sentence as follows : “...likely to produce di fferent estimates for reasons such as seasonal differe nces in pollution or confounding...”

6-15, Table 6-1: Here is an exam ple of where the percentages are defined and their use is helpful for the interpretation.

6-17 15: Drop “for”

6-18 Table cell “just meeting” and “occurrences for FEV >20” the percent should be 90% not 85%.

6-21 17-18: Note that the absolu te changes here are identical while the relative changes are different! From a public health point of view, there is no difference between the reductions in the two years.

6-22 17-18: Note that the estimate from Bell et al is for all ye ar even though the exposure data are restricted to the O 3 season.

6-22 Table 6-3: Does it make sense the 2002 in cidence per 100,000 is higher than the recent air quality incidence rate?

6-28 11-12: Improve wording, e .g. drop the second “important”.

6-30 4: Citing only the pilot st udy results ignores the main study results which should be viewed as scientifically better grounded.

D-586-32 1-3: This sentence is unclear. Would this argument benefit from the evidence in the most recent Bell et al paper (2006) that shows the same effect estimate as days are excluded at progressively lower exposure cut-offs.

6-32 20-27: Here is an exampl e where the relative values may not give a full perspective.

6-33 12-15: As noted above, the relative comparis ons hide some important information. At a minimum make it clear these comparisons are relativ e by e.g. adding “relativ e” after “greater” in line 13. Better yet, revise to acknowledge the abso lute impacts as well. Incorporating absolute changes will also force the discussion to be more mindful of the very limited subsets on which the risk assessments were done.

6-33 29: Define reduction. Reductio n in what? This is an exampl e of a more pervasive issue in this chapter.

6-42 13: Figures 6-1 and 6-2 don’t have a and b.

6-49 36: Line missing.

Staff Paper Chapter 3

Specific comments :

Exposure error section 3.4.2.1, partic ularly page 3-37: This page needs improvement to convey a clear message. As a preamble, it can be help ful conceptually to partition total personal exposure into ambient and non-ambient sources. The ambient source can be simply assumed to be a product of ambient concentration and atte nuation due to the build ing filter (call this α ). Absent residual measurement error and conf ounding, an individual study such as a panel study using personal exposure to a pollutant w ill estimate toxicity of the pollutant (e.g. β ). Assuming measurable exposure, a panel study using ambient source exposure, will al so estimate toxicity ( β ). The same panel study using ambient concentr ation instead of ambien t source exposure will estimate attenuated toxicity (toxicity times α = βα ). Similarly, a time series study using ambient concentration instead of personal exposure will also estimate attenuated toxicity ( βα ). This is the point being made in Sheppard et al (2005). Lines 5-9 don’t clea rly summarize Sheppard et al.’s simulation study results. A time series study does not estimate the same effect as an individual study with personal exposure would estimate. Sheppard et al (2005) showed no further attenuation as one might anticipate be presen t due to the poor corre lation between personal exposure and ambient concentration. Their resu lts showed that when total personal exposure was the true exposure, a time series study estimat es the effect of concentration, which is the product of toxicity of the exposure and attenuation due to the building filter.

3-37 24-25: I note that point (2) fr om the Zeger et al paper also results in the point made above (i.e. that estimates of β aren’t the same as estimates of αβ ). The way this page is written it appears that these two points conflict.

D-593-38 10: The Brauer et al. reference is missing.

3-39 lines 1-4: Drop the rest of the sentence after the comma. Not only does this confuse the reader, but it is irrelevant to the Staff Paper si nce the epidemiological risk assessments always use concentrations as the exposure. Line 5: change “these” to “t he epidemiologic study”. It is correct that the health effect parameter in air pollution time series studies doesn’t estimate toxicity (called potency in line 5). However, th e relative risks for increm ents of concentration, while not directly interp retable as potency of O 3 , are interpretable.

3-43 2: This Peters pilot study result shoul d not be cited over th e primary study result.

AX6-4: The >6 hr exposure results are not summari zed in a way that is used later in the SP. This should be rectified here or in a later table in Chapter 5.

General Staff Paper Comments

Where possible, enhance the document with comme nts to help the reader navigate and look forward and backward in the document. Add cr oss-references whenever possible. To look forward, mention planned uses of calculations. To look backward, mention source numbers from previous chapters. Make sure every figure a nd table has a thorough capti on and good labeling so it can stand alone out of context as much as is feasible. Mostreaders will notdigest this document from start to finish. Th erefore anything that can be done to help a reader starting in the middle find relevant information and assumptions from other parts of the document will be very helpful.

Health Risk Assessment TSD

Comments that weren’t completely covered above in SP Chapter 5 comments :

3-4, section 3.1.3: This secti on does not adequately document the details used for the calculations. The raw data must be presented . If the averages for each exposure are to be used for deriving the dose-response function, then the calculations and intermediate steps taken to obtain those averages must be presented. (I would prefer that the an alysis be redone using only the raw data presented as estimated probabili ties of response at the different exposures.)

3-4: Document that the logist ic function fits clearly better than a linear function once the uncertainty in the data is included. Once the uncer tainties in the study resu lts are incorporated, I suspect this conclusion is not correc t. If the logistic function is to be retained, extending the plots (Figure 3-3) to include higher e xposures in order to show the th reshold level would help with physical interpretation of the dose-response function. 4-40: I agree the lack of daily incidence data shouldn’t be a problem, but can’t you use the cityspecific mortality or admissions data compar able to those used in the epi studies?

D-60References : Here is one study I found from a web s earch that includes >6 hr exposure above 0.12 ppm. I understand from my clinical colleague s that such studies we re reviewed in the previous CD.

Kehrl HR, Peden DB, Ball B, Folinsbee LJ, Horstman D. Increased specific airway reactivity of persons with mild allergic asthma after 7.6 hour s of exposure to 0.16 ppm ozone. J Allergy Clin Immunol. 1999 Dec;104(6):1198-204.

D-61

### Dr. Frank Speizer

Review of second draft of sta ff paper on Ozone Dated July 2006 Submitted by: Frank E. Speizer, CASAC

Chapter 1 Notably on page 1-3, line 25-30 the readi ng of Section 109(d)(2) states that an independent committee .... shall recommend to th e Administrator and new ....or change in the standard. That committee si nce the early 1980s has been CASAC and it therefore seems to be more than an advisory committee that only ap proves or rejects what EPA staff does.

Chapter 2 Page 2-5, line 17-19, in describing the findings in table 2.1 for NOx emissions it is clear that emissions have come down, in the face of increasing cars on the roads, and it probably worth indicating the reasons,, e.g. Better controls, catalytic converters, fuel processing, change in reference methods??? Say something. Same applies to table 2.2.

The box plots in Figures 2.2-2.4 of the 1, 8 and 24 hours show striking uniformity across the country. This is indicated by suggestion in the text that th e expected excesses in California are not localized to California alone , but it might be more explicit to state that the average levels are similar and for the 8 hour the levels above .0 7 represent 10% of the le vels recorded in all parts of the country. (I note this is roughly seen in Figure 2.6).

Text to page 2.40, mostly describes what is in figures, without providing much in the way of interpretation. If one just focuses on the 8 hou r data it seems pretty clear that in many of the cities, and for many of the time trends there are a substantial number of excedences each year (
e.g. Figure 2.17 shows monthly averages of 8 hr 4 th largest over .08 ppm with no particular improvement with temporal trend. This is not di scussed (maybe it is discussed elsewhere). Even if it is, it should be mentioned here.

Page 2.48, last sentence. Would it not be wort h a statement that each of the cities have remarkably consistent finding for both month and time of day? Again this might be discussed further in later chapters, but cer tainly no reason not to say it here since the subject is raised.

With regard to Martin Questions: See above. Although it appears that the data are presented and br ief descriptive analyses are presented in the tables and figures, some in terpretation needs to be added to text.

Chapter 3 The set of appendix tables (Appendix 3B and 3C) are excellent. They are laid out in a logical fashion, and should be a model for the future.

D-62Page 3.6, lines 7-12. The terms triangular e xposure and square wave exposure represent jargon of the field, and may not be understood by most readers. S uggest definitions be supplied.

Page 3.9, line 27-28: For clarity the odds ratio of 1.37 should be indicate d in this sentence to be per 30ppb (if it is).

Page 3.12, line 7-8. Need to reconcile this st atement with the first paragraph of section 3.3.1.1.3 on same page. It seems inconceivable that inflammation is not involved in airways responsiveness and is involved in exposure in the lung. Certainl y some part of the airway system, albeit smaller airways, which contribut e less to responsiveness, are involved in the inflammatory response of the lung. In fact rest of page and next goes on to indicate that some inflammation must be pr esent in the airways.

Section 3.4 starting on page 3.34-4.47, title is a little confusing. Certainly what has come before is much of the epidemiological as well as other evidence and I wo uld have called it an assessment thereof. To label this section “A ssessment of ...” seems odd. After reading it I come away with the feeling that it is an attempt to justify what has come before on the basis of Hill’s postulates. That’s ok, and maybe a little mo re thought to make the t itle of the section more appropriate is in order. There is also a style issue in this se ction. Each of the subsections concludes with essentially a quote from the CD. Th is really isn’t an interpretive statement but more a restating of what the CD states.

Page 3.62, line 14: Suggest change for cl arity to: ... 2 fold greater decline in...

Martin Questions 1. The evidence is presented in a sound effectiv e manner. In fact it is not clear to me what will be different in the subsequent chap ters on health as much of the information that will be contained can only be what is here in greater detail. 2. The discussion of key issue is also well presented. It is organized effectively, however, if anything toxicology and contro lled human exposure studies seem to be played down somewhat. Other ep i issues are well discussed. 3. Threshold is adequately discussed.

Chapter 4 The data in table 4.4 suggest that a relatively small number of diary-days, particularly for the children aged 5-18, were actua lly obtained. In addition, the range of days varies from 42 to 4332. Yet, as far as I can tell when these data are used each city is given equal weight. When these data are used shouldn’t the results be weighted by something like an inverse s quare term to take into account the rela tive uncertainty of the data? Maybe this is done in the generation of values but it needs to be specified somewhere.

There is mislabeling of the Figures in the text (Figure 4.1 and Figure 4.2 in text on page 4.30, line8 instead of 4.2 and 4.3. This continues as a problem on line 16. Martin questions I found this chapter relatively easy to read and quite inform ative in its use of the other related documents from which it draws its informa tion. However, I have a problem in that much

D-63of the information used is not from the CD but from the other documents, some of which are still called drafts. I know that we recommended the us e of “grey literature” but I would not consider the ancillary documents here that grey literature. This is an issue I think we need to discuss as a group and choose and go on record as endorsing the approach. I thi nk it is ok but I think CASAC needs to sign on. The methods used are reasonably sound. Uncer tainty is referred to, in citing another document, but probably needs to be explored furt her. For example there are no error bars on any of the later figures that give estimates of population exposed to specific levels. I do not think these must be calculated for each point but some general examples need to be given. Because there are such differences in the data by each ci ty, are there ways they can be combined that would allow for more robust assessments, perh aps by using dummy variables for city while considering all data together. Other more sophisticated stat istical approaches might be considered.

Chapter 5

Page 5.7, lines 10-12: This is an important caveat. The suggestion is that the current quantitative risk assessment gives only a minimum es timate of true short term risk. This needs to be discussed further.

Page 5.8, Para beginning line 8: This suggests that by not using emergency room visits and school absences in current risk assessment, the risk assessment is leaving out large potentially important health as well as economic impact of exposures.

Page 5.20, Figure 5.3a, b, c: In contrast to Figure 5.2, each of these components extend the curves beyond the data (0.12ppm) and seem to imply the exposur e-response curve is approaching an asymptote. I do not think this is justified and suggest curves be truncated at 0.12ppm.

Martin questions Assessment seems technically sound and methods seem appropriate. The question that comes up is to what degree is the concern about uncertainty a reflection of the lack of data on endpoints that are in fact not used in the assessment. E.g. all mightagree that cardiovascular end points lack specificity and lead to uncertainty but in fact they are not used in the calculations of the assessment. With regard to the technology used, to the degree it is dependent on the Draft Risk Assessment technical support document, I w ould think that a critic al evaluation of that report and its final status will need to be doc umented somewhere in the process before it can officially be used as a basis of the assessment. Another point of concern is the details on th e suggestion that the effective mortality is related to tolerance. The issue is raised but not adequately discussed.

D-64Chapter 6

The chapter is reasonably well written and e ssentially summarizes what comes before. One issue mentioned below seems to me not adequately addressed.

Page 6.6, sentence beginning line 23. This needs rephrasing or could simply be left out. One could just as easily argue that the no threshold was found as to neither supports or refutes, as it is all a matter of the level of expos ure used in measures of effects. The rest of the paragraph discusses this issue adequately.

Page 6.17, line 6, typo: 2004

Page 6.30, end of paragraph at line 13. Two issu es that are not adequately mentioned in this chapter but might be important modifiers in a discussion of the averaging time 1) are the quenching of O3 by NOx, that may be occurring in heavily traffic situations and 2) the natural night time drop of O3 that occurs as sea le vel sites (thus making the 24 hour measure an underestimate of high exposure for shorter periods) . Surely these are pa rt of the logic of selection of 8 hours as the measure of choice.

6.47, line 16, typo: microenvironments

Martin questions The combination of evidence-based and quantit ative exposure-and risk -based consideration seems appropriate, but as mentioned in discussion of chapter 3, much of the risk assessment is based on draft documents that have not had adequate peer review. I know that a request has been made to have CASAC review (and some of us will clearly get to that) but I am not sure that will be adequate and we will need to discuss the issue.

The presentation on Page 6.44 on whether to retain or change the current st andard is appropriate but as presented results in anunbalanced form. Paragraph a indicates the standard could be retained but bases this decision on a very narrow view of the data. This could be interpreted as saying that only controlled human study data with a 15% decrement in lung function is an adverse effect that should be considered. (The paragraph goes on to say that this would ignore much other evidence, which the administrator c ould choose to do). However, there must be a way to indicate some of the rele vance of the other disc iplines that need to be considered in making a decision to retain the exis ting standard. Whereas paragraph b is more thorough in considering the data, and emphasizes the potential importance of albeit less precise but perhaps as relevant, population based data.

One way out of this dilemma would be to reve rse the order of the presentation and give the alternatives for changing the sta ndard before the idea of retaini ng the standard. (I recognize that this would be different than the way this is done in the past, but the logic of not using all of the data seems inappropriate otherwise).

With regard to the key uncertainties and resear ch recommendations it is disappointing to realize that we have made so little progress since 1997, although I am not so sure I would totally agree

D-65in that conclusion. In fact, because of the work that has been done, particularly in working out the methodologies for PM, a lot of the methods que stions have been answered. New issues have arisen, and these have been summarized reasonabl y well. Perhaps more could be made of the approaches that might be used to explore mechanisms and potential gene-environmental interactions that may be important in identify ing subgroups of susceptible populations.

Review of Analysis of Uncertainty in O3 population exposure modeling Dated July 24, 2006 Submitted by Frank Speizer, 8/23/06

General Comment: This document claims that in its next iterati on it be included in its final form to inform the final Ozone Staff Paper. It seems clear th at unless a substantially revised document already exists (and this one claims it is waiting for in put from CASAC and the public) that this will be an impossible task. Much of the document is a pr omissory note of what th e author is planning to do. Simply reviewing the existing literature can not be accomplished without a Herculean task to have some thing ready in the next month that will be informative for the final staff paper. This is another example of too little t oo late and my suggestion would be to put this aside and find something more useful to do with the remaini ng time before the court ordered deadline is upon us. I certainly would not be ab le to sign off on this document a nd certainly there will be no time to review the next iteration.

Specific comments: Page 5, para 4, line 5: Recognizing that the auth or is referring to another document, it is not clear where these SD are coming from. Need to indicate that these are simulated models with arbitrary selection (if th at is what they are).

Page 8, first para: Editing: This says the same thing with the same words as that on the top of page 4

Page 11, para 2, end: If 2003 a nd 2004 are not correlated, then what is the meaning of indicating the averages from the table (I assume author m eans all the numbers) have average values as given? Further what does it mean that th e range of bias for 2003 is -7.35 to +11.28!?!

Page 13, first paragraph. It is not clear how these statements will be used. In fact meaning is not clear.

From here on out the promissory nature of the discussion becomes increasing frustrating and indicates to me that the tasks suggested will ne ver be completed in association with the time frame proposed. Page 15, end of first paragraph. What is the use of indication of what is said and is it logical to assume that the interpolation will be unbiased?

D-66Next paragraph: We plan to perform...It hasn’t been done, will it be done for this report or future reports? Figures 6-8: Should there be error bars on these curves?

Page 19, Table 8: Not clear why all upper bounds are equal to 1.0

Figure 10, error bars? Page 20, Table 9: Does this make sense that all values save in-vehicle, interstates are virtually the same?

Bottom of page 20, top of page 21, first 2 para. Too much work is being planned for an October deadline.

Because the remainder of the document suggest s that work will be done, I see no way to integrate this into the staff paper at this time.

D-67

### Dr. James Ultman

Chapter 6 in the OAQPS Staff Paper for Ozone (2 nddraft) Reviewer: JS Ultman Date: 8-25-06 (revised)

This chapter is well-writtenand logically presented.

Based on the scientific evidence, exposure analys is and risk assessment, I conclude that the current 0.08/4 standard does not adequately protec t asthmatic children from respiratory adversity due to ozone exposure. In addition to exposures above the “level-of-concern” and adverse FEV decrements predicted to occur when just-meeting the current standard, a number of independent studies indicate a signifi cant increase in emergency department visits and hospitalizations due to the exacerbation of asthma (fig. 3-4, pg 3-53).

Inflammatory processes are an important marker of tissue remodeling an d potential long-term lung injury due to ozone inhalati on. The use of 0.08 ppm as a “level -of-concern” in this chapter is consistent with the ozone concentration at which inflammatory mediators have so-far been observed in human studies. Clearly the selection of this level-of -concern has an important effect on the number of individuals and the number of acci dences per individual that is predicted by the exposure-activity model, and therefore the ra tionale of using 0.08 ppm should be better explained in this chapter.

The chapter summary states that the quantitative risk assessment is now appreciably lower than in the last review (pg. 6-44, lin es 13-16). This conclusion is based on an exposure-response curve for FEV 1 that is my view has a great deal of uncertainty. Thus, this statement is misleading and should be highly qualified, or entirely removed from the chapter.

Some other comments:

Page, line

6-4, 10 Delete first “human 6-7, 24 Delete “also” 6-13, 35 It would be useful to give your rationale for choosing these subgroups of the population for analysis. 6-22 In table 6-3 and tables that follow, it is not clear what incidence means in the context of “incidence per 100,000” and “per cent of total incidence.” 6-27,10-15 What are the “less serious” lung function effects you referring to? Why are they “less serious?” 6-40, 18-21 This sentence asse rts that there is a 90-100% reduction in exposures-of- concern estimate d at the 0.07/4 standard. Are these percent reductions obtained by rolli ng back the actual air qualityfor 2002 and/or 2004 to the 0.07/4 standard. If so, it appears from table 6-1 that similar reductions are possible using the 0.08/4 standard. I find this hard to believe.

D-68

### Dr. Sverre Vedal

August 2006 Critique of 2nd Ozone Staff Paper draft (chapters 3-6 ) Sverre Vedal

Chapter 3 (Health effects evidence) While in general this chapter is a credible basi s for the risk analysis that follows, there are inconsistencies and some inaccuracies, some of which are due to the necessary reliance on a too hastily prepared CD. There is a ppropriate use of cautions when the data are not as strong as they might be, but this is inco nsistent. A few points:

1. Measurement error discussion is convoluted and confusing, and contains some mistakes. The primary issue in the use of central am bient monitors for ozone in time series epidemiological studies is whether they provide any information at al l in reflecting daily personal ozone exposure in the susceptible populations , especially that of the debilitated elderly in the case of the mortality findings. The evidence on this issue is split, but as opposed to what is claimed in this chapter (p. 3-38, lines 26-29), th ere is information on this. The two Sarnat papers, one from Baltimore and the other from Boston, assessed relationships between personal and central ambient concentrations in elderly subjects with COPD. The discussion on the impact of various types of exposure measurement error is incorrect (p. 3-37, lines 22-30) or confusing. The diffe rence between true and measured ambient concentrations is an example of classical measur ement error and hence resu lts in bias of effect estimates to the null, not just an increase in standard error. Further, claiming that the difference between average personal exposure and ambient concentrations resu lts in “attenuation of risk” (line 29) is confusing (also p. 3-38, line 2 and 8, and p. 3-39, line 4 and 18). This statement is generally used when, due to classical exposure m easurement error, the eff ect estimate is biased downwards, and hence attenuated or underestima ting true risk. The effect of ambient concentrations themselves is underestimated. Here , as in the case of PM, the effect estimate is estimating effects of changes in ambient concentra tions. But, what is be ing referred to here is the difference between ambient a nd personal concentrations, with personal concentrations often being substantially lower. In this case, the effect of ambient concen trations is not being attenuated, at least not in the same sense. They are only attenuated if one is trying to estimate the effect of personal exposures for concentrations that are sim ilar to ambient concentrations, which is in fact not the case. This is not, therefore, a reason why we might be “underestimating true public health ri sk” (p. 3-39, line18). The assessment of plausibility st ill does not adequately discuss the issue of ozone exposure in the mortality time series studies (referred to on p. 3-35, but does not come up again). It is again claimed that central monitoring c oncentrations “may serve as ad equate surrogate measures for mean personal exposures experien ced by the population” (p. 3-38, lines 21-22). How can this be if in some settings there is no relationship betwee n individual personal con centrations and central concentrations? If mean personal concentrations correlate with central concentrations, and individual personal concentrations do not, then I presume some sort of ecologic error is at play here. I dispute the conclusion that “the use of routinely monitored ambient ozone concentrations as a surrogate for personal exposures is not generally expected to change the principal

D-69conclusions from ozone epidemio logical studies” (p.3-39, line 10-11). On the contrary, we have little insight as to what we would fi nd had we actual exposure measurements. The argument that central monitoring sites provi de more valid measures of personal exposure in respiratory admission time series studies, specifically, because most such admissions are due to asthma admissions, most asthmatics are child ren and children spend more time outdoors, is especially convoluted and unconvincing.

2. Cardiovascular mechanisms and effects. The discussion on plausibility of potential m echanisms underlying cardiovascular effects should begin with an acknowledgement that we don’t know much about these. The current presentation (p. 3-55) comes o ff as a hodgepodge of “the usual suspects,” some of which are a real stretch and serve largely to undermine credib ility of the more realis tic possibilities. The discussion on the role of ozone in PM-related cardiovascular effects is hypothetical (note the ultrafine discussion, in particular), yet are pres ented as though these in teractions are actually playing a role (p.3-59, lines 4-7).

3. Low concentration ozone effects on lung function. First, Adams (2002, 2006) concludes that 0.04 and 0.06 ppm responses were no different than filtered air responses. It is necessary to ma ke it clear (especially in Ch. 6) that the estimated effects in Fig. 3-1 (p. 3-7) are derived from Adams’ data, but are not in fact reported in his paper. It now becomes clear that the percent of the relevant populati on estimated to experience FEV1 declines at these low concentrations, estimates that are central to the risk analyses in chapters 5 and 6, are based on a total of the 30 subjects in Adams’ papers (i.e., 3 subjects for 10%). This area of low concentration responses is an area that clearly ne eds more research. Because these low-level effects have a very promin ent role in the risk analysis in chapters 5 and 6, the summary table (p. 3-78, table 3-4) should include them in some fashion.

4. Chronic effects on lung function: overstatements and inconsistencies. The conclusion on p. 3-20 (lines 16 and 32) is co rrect: we have “little evidence” for these. Why then do we get statements such as, “these lo ng-term exposures may be related to changes in lung function in children” (p. 3-56, line 30), “r educed lung function development in children which have been observed in epidemiologic stud ies” (p.5-56, line 25), and “recent studies of lung function changes in children living in cities with high ozone levels support the conclusion that long-term ozone exposure may play a role in causing irreversible lung damage” (p. 3-84, lines 6-8)?

5. Coherence of respiratory effects. It is repeatedly claimed that th e lack of consistently seen in the increased effect estimates for COPD mortality may be due to inadequate power (e.g., p. 3-29 [line16], p.3- 52 [line 18]). Note that this is in stark contrast to the case for PM where such relatively la rger effects are almost always seen; and the data used for the PM analyses have no better power than these for ozone. Also note that the large meta-a nalysis (Bell 2005) found smaller e ffect estimates for respiratory causes than for total mortality (p. 3-30). This ha s implications for the argument for plausibility based on coherence of the respiratory findings. Pa renthetically, why are not the studies used in the Bell meta-analysis (2005) included in the respiratory mortalit y studies in Figure 3-4 (p.3-53)?

D-70Smaller or detailed points : Page 3-7 (Figures 3-1A Æ C). These do not indicate “the porti on of subjects tested having FEV1 decrements in excess of 10%,” but rather give the distributions of % decrement. Also, clearly the findings are somewh at dependent on the subjects included, since the distribution of decrements in the McDonnell subjects for filtered air is about the same as that in the Adams subjects for 0.04 ppm ozone. 3-24 (line 12) and 3-79 (line18). Note that Gong did in fact find an effect on increased heart rate, as stated correctly on p. 3-25 Correct the referencing in the last paragrap h – the extension to NMMAPS analyses is only in the Bell 2004 reference 3-26 Regarding adequate control for temperature, control for single-day effects or matching on a day (as in the case-crossover approach, lines 28- 31) is probably not an adequate assessment of the adequacy of temperature control. 3-27 Effects using 1-hr and 8-hr averages in NMMAPS are not “distinctly” larger (line 13) than those for 24-hr averages; “slightly” la rger would be more descriptive. 3-32 The ozone effect in the ACS II study are not always nil (line 18). For one of the two ozone monitoring periods, the eff ect was clearly positive. 3-35 (line 18) There is an interesting allusion to the utility of time series studies here which doesn’t seem to come up subsequently in the SP. 3-38 Reference to Brauer 2002 (line10) is needed in the reference list, if it has not already been added. 3-44 (line 6) Note that Bell (2006) found no differe nce in estimated effect even when all days with 24-hr ozone concentrations < 20 ppb were excluded. 3-45 (lines 3-5) Note that the evidence of no cl ear threshold comes largely from epidemiological studies, and partly from clinical studie s, but not from t oxicological studies. 3-56 (lines 26-27) Another possibility, of course, is that in fact there ar e no effects on humans of long-term exposure. 3-61 (line25) These (5% decrease per 40 ppb increase) are not large decrements in lung function.

Chapter 4 (Human exposure) 1. It would be helpful to have the estimated exposures for current (2002 & 2004) levels displayed in Tables 4-8 & 4- 9 (p. 4-32) and Figures 4-4 Æ 4-21 (pp. 4-33 Æ 4-41), in addition to only those for just meeting the current standard a nd alternative more stringent standards. This would be analogous to the way estimated ef fects are displayed in Ch.5 (Figures 5-5 Æ 5-9 [pp.5- 58 Æ 5-65]).

Small points: Page 4-30 (line 8 and 16) Correct th e figure reference numbers. 4-31 (figure 4-3) It is still not entirely clear why the estimated exposures are so low in Los Angeles.

D-71Chapter 5 (Risk analysis) 1. Multi-city mortality estimates vs. single-city hospitalization estimates. Note that estimated multi-city mortality effects are qualitatively different from hospitalization effects, which are largely single city estimates ( p. 5-28, table 5-1). Not only is there the well known phenomenon of publication bias to contend with in using single-city estimates, but, the Bell (2004) estimates for a si ngle city are Bayesian shrunk estimates which are not the same as crude estimates of single- city effects, even from a multi-city study. Therefore, in using the mortality and hospitaliza tion effect estimates in a parallel manner, it should be made clear that these are in fact qualitative ly (and therefore quan titatively) different.

2. Confusion on the effect of exposure measurement error. Because ambient concentrations are two- to four-fold higher than personal exposures does not mean risk estimates are attenuated (p. 5-36) (see my comments on this point for Ch. 3 [point 1]). Yes, potency is underestimated, but underestim ation of risk is due to classical measurement error, not this type of differential measurement error. Risk would only be underestimated if exposure were to equivalent ambient concentratio ns of correct potency, which is not the case. The confusion occurs in making use of the analogy with PM.

3. Striking findings. It is striking how much all of the estimated health impacts (from lung function decline to mortality) are due to exposures at concentratio ns below 80 ppb. Obviously this is due to the predominance of days with these concentrations.

4. Relationship between 24-hr average concentrat ions and those from the monitor with highest maximum 8-hr average (p.5-73 [ lines 38-40] and Appendix 5A.2). I’m not sure what point is being made here. While it is true that thes e are about half as high, it is likely that 8-hr and 1-hr averages are not nearly so different from the 24-hr average. Of more importance, the estimates of effect from the mortality time series studies using these different ozone metrics are not much different , as demonstrated in the Bell study (2004).

Small points: Page 5-32 (table5-3) Note that “respiratory” as a single category is defi ned differently from “respiratory” in “cardio-respiratory”; also, this restricted definition of “cardiovascular” (limited number of ICD-9 categor ies) probably explains the rela tively smaller percentage of total deaths due to cardiovascul ar causes than is typical.

Ch. 6 (Conclusions on primary ozone NAAQS) This is generally a well-reasoned ch apter in its attempt to ultimately motivate specific alternative recommendations for revisions to the ozone NAAQS. It is appropriately cautious when necessary. A few points merit comment.

1. Suggestion for more informative graphs. In order to provide a more complete pers pective to help judge the relative estimated impacts of alternative standards, I would like to see figures 6-1 Æ 6-6 (pp. 6-34 Æ 6-39) display the estimated decrease in effects of the progressi vely more stringent stan dards relative to recent

D-72levels for 2002 and 2004, rather than only compared to just meeting the curre nt standard (84/4). Exposures for many in the population are estimated to be reduced dramatically from recent exposure scenarios by just meeting the current standard.

2. Apparently puzzling (but probably corre ct) results of the ri sk-based approach. Some of the results of the ri sk-based approach seem para doxical and could benefit from some further explanation. For example, in Tabl e 6-2 (p. 6-18) it is stra nge that twice as many individuals as are exposed to > 80 ppb are estimated to experience a 10% fall in FEV1, when only 10% of population reacts this much at 60 ppb (vs. 25% at 80 ppb); theref ore, most of these estimated falls in FEV1 must be due to exposure to <80 ppb. But, this is not what is shown by the “just meeting the standard” estimates, sinc e these only result in decreasing the number estimated to have these FEV1 falls in half. Als o, in Table 6-1 (p. 6-15), it seems strange that the % reduction in exposure due to more stringent standards is less in the worst case scenario (2002) than in the cleaner year (2004).

3. The form of the standard. While it is painful to seriously consider substa ntially different forms of the standard, they might nevertheless be worthy of consideration. I have been impressed by the differences in population ozone exposures across cities (more so th an for PM, for example) that have either always or sometimes been out of compliance with the ozone standard. For example, Denver has infrequent and relatively brief summertime episodes when concentrations skirt the ozone standard, sometimes resulting in Denver being out of compliance. In contrast, some cities experience sustained and repeated periods of elev ated ozone concentrations resulting in chronic noncompliance. These contrasting patterns are not distinguished by the current form of the standard, yet likely have substant ially different implications for the health of the populations in these cities. Why not at least consider some incremental form of the standard? Another issue of relevance in considering a change in the fo rm of the standard is the anomalies in estimated impacts on population expos ures produced by meeting the current form of the standard (Table 4-9 [p. 4- 32]). Specifically, there are marked disparities across cities, with dramatic effects on reducing estimated exposures in Houston and Los Angeles compared to those on other cities, simply due to the particular form of the standard. On a small point, it is unclear to me how, in distinguishing it from the earlier form, the current form of the standard also “is not just whether the concentrati on is above a specified level” (p. 6-41).

4. Concentration-respon se and thresholds. Evidence for thresholds based on controll ed human experiments and epidemiological studies is qualitatively a nd quantitatively different, as reflected in the different ways of using this evidence in the risk-based approach. At one extreme, it is argued (p.6-7 [line 18]) that it is difficult to find epidemiological studies that demonstrate associations at levels below the current standard, implying a threshold at levels that are only experienced in settings just in compliance with the current standard. On the contrary, I think it is easy to fi nd studies that provide evidence that effects are estimated to occur in settings where the current standard would be met (most notably, see the Bell 2006 paper that is cited). Further, it appears that an attempt is be ing made to argue that be cause studies are done in areas that would likely not have been in compliance with the ozone standard (pp.6-9 Æ 6-11),

D-73we can’t know whether the findings of these stud ies would have been s een if the studies had been done when the standard was met. In fact, it is almost certain that most of the data that is responsible for estimating the effects seen is from days when ozone concentrations are far below the standard. When analyses are done on subsets of data that seem to have clearly met the standard, results are unchanged (again, see Bell 2006). Further, there are in fact studies that have been carried out when the current standard wa s not exceeded: for example, the Vedal et al (2003) mortality time series study from Vancouver, the Brauer et al studies of berry pickers (1996 and 1999 [J Environ Med]), and some respir atory hospitalizations st udies (alluded to in Ch. 3-17 [lines 13-14]). And, likel y there are years in some of th e time series studies when the standard is met, even though, using the full st udy period, the standard would not be met. Therefore, there is ample evidence that associ ations in observational studies are present below the current standard. The real issue is one of how we interpret these associations, not whether they are present. At the other extreme, it is stated (p.6-6 [line 31]) that the human experimental data provide evidence for a threshold at “near the lower limit [my italics] of ambient ozone concentrations in the US (CD, p. 8-44).” This is not correct. The stat ement needs to be dropped, or at least clarified if so mething else is intended.

5. The level of the standard and the level of certainty. An argument is made that we are less certain of the findings of effects at lower ozone concentrations, and that this uncertainty should info rm our choice of alternative standards. It is clearly true for the human experimental findings that we are less certain of effects at lower concentrations (e.g., 40 – 60 ppb vs. 80 ppb and above). This is not necessarily the case for the epidemiological findings, at least based on the epidemiological stud ies alone. That is, we are not less certain because the studies th emselves are less certain. I find little difference in the certainty expressed about findings in studie s done in higher vs. lower ozone concentration settings. Our level of certainty concerning epidemiological findings is base d on information largely from outside of these studies, and th erefore takes on a Bayesian fla vor. Specifically, there are many reasons for being uncertain about epidemiological findings at lo w concentrations that are not directly related to the findings of the studies themselves. Two of the most important are: 1) there is justifiable concern that there is li ttle relevance of central site ambient ozone concentrations to individual exposures, with exposure concentrations being much lower and poorly (or at least variably) corr elated with monitored concentra tions, a problem that is likely more acute in low concentration settings, and 2) there is questionabl e plausibility to the contention that the concentra tions to which people are actua lly exposed in these lower concentrations studies can be responsible for si gnificant (or any, for that matter) adverse effects, most notably death. My recommendation for the level of the standard is in the range of 0.060 to 0.070 ppm. This recommendation is informed by clear demonstration, both experimentally and observationally, of effects below the level of the current standard. In 1997, we were aware of effects in experimental setti ngs at concentrations of 0.080, c oncentrations already below the current level of 0.084. My lower limit is informed by my level of certainty in study findings, both experimental and observational, of effects at lower concentrations. Within my preferred range, I would select a standard closer to 0.070 than 0.060. The basis fo r this preference is twofold: 1) the impracticability of imposing a standard where th e vast majority of the country would be out of compliance, and 2) the risk analyses demonstrating the relative impacts of

D-74meeting the current standard and of lower proposed standards, with the majo rity of the benefits to public health achieved merely by meeting th e current level of the standard. After all, standards that result in achievable benefits to public health are much pr eferred to those that might achieve these benefits only in an imaginary world.

6. Suggestions for uncertainties/research needs. The overwhelming deficiency is the paucity of experimental huma n data on lung function decline at concentrations below 80 ppb. Since these data are very in fluential in both the exposure analysis and the risk an alysis, increasing the number of subjects in such experiments, and assessing the reproducibility of such res ponses in individuals, should be a priority. In regard to point 3 (p. 6-46) of the uncerta inties and recommendations for future research, which touches on exposure, I would emphasize the n eed to have better exposure estimates for the population potentially at risk of dying from ozone exposure. Currently, a case can be made that exposures here are too low to plau sibly be responsible for the dire effects estimated in the time series studies mortality studies. Point 6 expands on this point well. On point 2, I would like to see more specific recommendations for figuring out how and whether exposure measurement error is having an effect on the shape of the concentration-re sponse relationship.

7. Minor points
page 6-13. What of exposure measurement error in influencing our le vel of certainty? 6-30. Reference to the Peters p ilot study on very short term eff ects of ozone on MI gives it too much play. Remember that the more prominent very short term effect s of PM in the pilot study were not seen in a larger and better de signed study by these same investigators (HEI report 2004), although they did not specifically report estimates of very short term effects of ozone in this later study. 6-42. Figure references need correcting.

D-75

### Dr. James (Jim) Zidek

Revised Comments of the Staff Report 2nd Draft James V Zidek, August, 2006

CHARGE QUESTIONS My detailed comments respond to a number of th e issues raised below and only summaries are provided here.

O3 air quality information and analyses (Chapter 2): 1. To what extent are the air quality charac terizations and analyses clearly communicated, appropriately characterized, and relevant to the review of the primary and secondary O3 NAAQS? The results are generally clear and very we ll communicated. In particular, the Report provides a good characterization of the concentr ation field of the cur rent criteria metrics.

2. Does the information in Chapter 2 provide a sufficient air quality-related basis for the exposure, human health and environmental effect s, health risk assessment, and environmental assessment presented in later chapters? I remained concerned about the le vel of level of uncertainty asso ciated with the estimates of the PRB field. A sensitivity analysis of the estimated levels would be desirable. In a statistical context, a coefficient of variation of 10% would be considered a realistic target for accuracy and if it were assumed that the GEOS-CHEM model me t this standard, it would mean varying that background by 10%, gu ided by estimates of that accuracy in the AQCD.

O3-related health effects (Chapter 3):

2. What are the views of the Panel on the appropri ateness of staff’s discu ssion and conclusions in Chapter 3 on key issues related to quantita tive interpretation of animal toxicology and controlled-exposure human experimental studies and epidemiologic study results, including, for example, exposure error, the influence of a lternative model specifica tion, potential confounding or effect modification by co- pollutants, and lag structure? My earlier concerns here have been adequately addressed.

Exposure Analysis (Second Draft Chapter 4 of the O3 Staff Paper, draft Exposure Analysis technical support document, and OAQPS St aff Memorandum on Un certainty Analysis): 1. To what extent are the assessment, interpre tation, and presentation of the results of the exposure analysis as presented in Chapter 4 (and in the second draft Exposure Analysis technical support document) technically sound, appropria tely balanced, and clearly communicated? Generally the results are clearly communicated and well presented although the interpretation for setting standards of some of the APEX outputs is difficult. A number of specific concerns appear in the comments below.

D-762. Are the methods used to conduct the exposure analysis technically so und? Does the Panel have any comments on the methods used? Based on my experience with a similar mode l, I believe APEX to be a sound methodology although too little assessment of its predictive accuracy has been carried out, especially given its central role in scenario anal ysis for standard setting.

3. To what extent are the uncertainties associ ated with the exposure analysis clearly and appropriately characterized in Chapter 4, the Exposure Analysis technical support document, and the uncertainty memorandum? Overall, a very thorough well-ba lanced account of poten tial sensitivities and weaknesses of the models used has been given. In so far as these can be checked they seem correct and comprehensive. In some instances a quantification of uncertainty estimates is needed as indicated in my comments. More discussion and in terpretation of the outputs is needed.

4. To what extent is the plan for the remaini ng uncertainty assessment technically sound? Are there other important uncertainties which are not covered? What are the views of the Panel on sensitivity analyses conducted to evaluate the influence of uncertain ties in the exposure analysis? This sensitivity analysis has been well done with in the limitations of available data and the obvious sensitivity to AER has been discovered. However, the whole analysis of output uncertainty could have been carried out within the framework of a fractio nal factorial design to look for interaction effects between the different parameters. That might have been informative.

Heath Risk Assessment (Second Draft Chapter 5 of the O3 Staff Paper and draft Health Risk Assessment techni cal support document): 1. To what extent are the assessment, interpreta tion, and presentation of the results of the revised exposure analysis as presented in Ch apter 5 (and in the second draft Risk Assessment technical support document) technically s ound, appropriately bala nced, and clearly communicated? These are generally sound and very well communicated.

4. To what extent are the uncertainties associated with the health risk assessment clearly and appropriately characterized in both the second dr aft Chapter 5 and the se cond draft Health Risk Assessment technical support documents? The uncertainties are very well characterized. A central problem here and elsewhere derives from the problem of quantifying qualitative unc ertainties such as model uncertainty.

D-77GENERAL COMMENTS

1 Overall the Second Draft St aff Report is well written.

2 Some early general discussion of the id eas underlying the APEX approach should be included in the Staff document, given its central role in this exercise

. After all, it is a big leap from the regulation of ambient levels to personal exposures. That discussi on should in particular describe how later in Chapter 5 it is used in conjunction with an exposure response function and used in scenario analysis.

3 Some concerns that need to be highlighted:

• The lack of assessment of APEX’S predictive accuracy. This seems surprising, given that this methodology along with its predecessor, pNEM, have b een under development for well over a decade and a principal tool for such analysis.

• APEXs assumption that reducing ozone concen trations would not l ead to behavioral changes. The Langstaff memorandum raises the same concern ( Langstaff page 56 ).

• Uncertainty of accuracy of APEX predictions. Providing estimates of the uncertainty for things such as person-days of overexposur e should be straightfo rward as APEX is a predictive probability distribution and “error bars” could have been generated and included in figures such as 5-11. Note: page 6-16, line 31 promises such estimates in the Final draft.

4. The quadratic rollback procedure is not ve ry well described in the AQCD, the Staff Reports or the supplementary material. Consideri ng its vital role in the scenario analyses and exposure response modeling, I suggest expanding lines 22-28, page 4-28 to include the formula, how it is used and the material on page 5-10. As now written, the reader learns for the first time in this document that it shri nks the actual ambient hourly co ncentration measurements into attainment.

5 While the discussion of APEX uncertainties is remarkably thorough and comprehensive, they can only be partially quantified leaving concerns about the accuracy of the eventual predictions of such things as person – hours of exposure above a prescribed threshold. However, I see no practical solutio n with present knowledge. In futu re much more model assessment should be done to get a be tter handle on its accuracy.

D-78DETAILED COMMENTS

Chapter 2:

2-2 line 16: The sentence beginning on this line should be the last sentence in its paragraph following the sentence defining NO y.
Appendix 2-A: July (month 7) and August seem to have the lowest PRB and Sacramento has a large month to month variation. Some rationale should be included for what some reviewers of this document might find curious findings.

CHAPTER 3

3-36 Line 9: Is 40ppb the “standardized unit” of change referred to in line 10 ? If so that same unit should be used again because th e sentence is ambiguous as it stands. 3-37 Line 3: Should not this be “exposures to ambient concentrations”? Line 18: This goes to a comment below and the 3 rdconcern above about APEX which assumes behavior would not change if ambient ozone concentrations were lowered. 3-39 Line 8: Some emphasis should be placed in futu re epidemiological studies in using a model like APEX to reduce erro rs in estimated population leve l exposures to the criteria pollutants, given the critical role APEX is playin g in setting standards and given that it is freely available. Line 19: I remain concerned about the observation reporte d in this line and ask that the rationale for it be included in the Report.

CHAPTER 4

4-1 Line 21: The report should say something like “based on 2002 and 2004, for reasons given below in Section 4.3.4.1,...”. However, two seem s like too few years to really characterize the “year-to-year varia tion and more importantly bias, sin ce 2004 had lower than typical O3 concentration levels. Line 24: No doubt lowering ozone levels would lead pe ople, especially susceptibles, to spend more time out of doors and thereby to sustain hi gher rather than lower exposures to ozone, a point not discussed in limitations of the APEX approach. (Runs condition on outdoor temperatures, not ozone levels, there by missing this important interaction.)

4-2 Line 28: Something should be said here about “d ose” (or a reference given). The text leaves the impression without explicitly saying so, that dose is important. Exposure (intake) is then estimated because it is an “important determ inant” of dose. Why not estimate dose itself? If dose cannot be estimated, does the science at leas t say qualitative about th e relationship between the surrogate (intake) and the thing it represen ts (dose) other than th at the relationship is monotonic? For example is the relationship line ar? That is would a 10% reduction in exposure lead to a 10% reduction in dose regardless of the level of that exposure?

D-794-3 Line 8: To avoid ambiguity, AQDC would be better than CD here and elsewhere in the report.

4-4 Line 17 : Generally monitors are sited primarily to detect non-compliance and therefore, tend to overestimate ozone concentrations. Nevert heless the data they pr oduce are used for other purposes as noted here in the report. However, it seems doubtful that th ey could be used to determine their own “representat iveness” without the help of Line 27. Therefore these sentences should be linked in the text for clarity. Line 20: For consistency the same units of measur ement should be used throughout the report. Preferably, this should be ppb since numbers like 0.085 ppm for ex ample, seem so small that seem unimportant.

4-6 As noted in my earlier comments, APEX is a valuable tool for exposure assessment as well as predicting the benefits of a pollution abatement program. In particular, it can answer “what if” questions under roll b ack scenarios. However, APEX is only a model, an analogue of the real world therefore its output s need to be assessed. I was pl eased to see on page 4-13 Line 23 some recognition of this fact and a plan to do something about it in the future and at least a crude assessment on page 4-47.

4-11 Line 12: The sentence added here in the revision seems to be a partial response to my comment on the first draft: “randomness of model parameters needs some expl anation in the Report. Their distributions could be interpreted by readers as Bayesian priors, reflecting (epistemic) model uncertainty, albeit with an empirical Bayes twist. In that interpretation, variability of the predictive output distribution would reflect that ep istemic uncertainty as it propag ates through the model, rather than only process (aleatory) uncertainty. It mi ght be worth stating that these parameters are actually random effects so that variability in the predictive distributi on represents aleatory uncertainty. Of course, that then pushes the issu e of model uncertainty to a higher level on that staircase of infinite regress, that Mosteller and Tukey famously referred to. (See my comments below re Table 5.5.)” Consider for example, the model in Equati on (2-15) of “Exposur e Analysis” technical attachment. The stdev’s for it in Table 2-4 do refl ect “uncertainties in th e parameter estimates”. In fact they are the standard errors of the estim ates computed in a regression analysis of data from 32 clinical trials contrary to the asserti on of that sentence. Moreover the issue of model uncertainty has been ignored even though it could we ll be the dominant source. In that model, for example, it seems quite plausible that a gender* age interaction term should be added. (In other words the coefficient b2 should be di fferent from women than for men.)

4-12 Line 7: My earlier suggestion to interpret m odel outputs in terms of predictive probabilities and expected values has not been implemented. However that would make them easier to understand and make in ter-city comparisons straightforw ard. Moreover, this approach would be more natural since APEX is a joint predictive probabil ity distribution expressed as the product of various conditional distributions. Finally the use of probabilities and expectations in quantitative risk analysis is standard.

In any case the value of the city specific number of “person hours” in standards setting needs to

D-80be clarified and their sta ndard errors stated as they may not be negligible even if the number of APEX runs is large. (See comments on page 53 below.)

4-14 Line 9: No mention is made of the possibl e bias that might arise in the

characterization of urban ambient ozone fields due to monitor placement for noncompliance detection. How were the moni tors placed in the selected cities?

Line 21. Using the multivariate spatial predictive distributions now available in modern space time process modeling, the variability of the ra ndom ozone field over the USA for a single or multiple years could well be captured and used in conj unction with APEX. (See Le and Zidek 2006. “Statistical analysis of environmental space- time processes.” Springer.) This would overcome the difficulty associated withrelying only on specified years.

That would not address the other kinds of uncertainties there regarding say changing demographic patterns and hence time activity pa tterns. This difficulty might be addressed partially by running APEX conditional on the demogr aphic group as is done in pCNEM (referred to in my earlier comments). The predictive population estimates at that level could then be combined with different weights to determine th e possible effects of de mographic trends. Users of APEX could then predict exposures for population subgroups such as commuters or individuals with heart disease, by representing them probabilistically as a combination of demographic groups and combining the predictive estimates appropriately.

4-15 Line 6: The meaning of the sentence beginning on this line should be clarified. To many, “uncertainty” means “variability”. Only things that do not vary are certain.

4-18 Line 16: As noted above, two is too few years to characterize variability due to year.

4-21 Line 30: Using LM=1 and LA =0 would seem more realistic than se tting both equal to 0 as has been done. Anyway, rerunn ing with these alternatives would give some idea of the sensitivity of results to these choices.

4-29 Line 4. The caption could be misleading since “d esign value” commonly refers to a specified cut-off criterion. “The measured values of the current design metric for the modeled areas” would avoid the interpretation that differentcriteria are imposed on the different cities. By the way, I am not sure why the ratio in the last column was included. Would not the difference be preferable, if anything was really needed th ere? (By the way, notice how much simpler this table would be if ppb were used instead of ppm.) Line 11: The graphs do not show the numbers but rather the percentages right in line with my suggestion above for page 4-12. These can be inte rpreted as the chances of the specified event occurring for a randomly selected indivi dual from the specified sup-population.

4-30 Line 5: The figure captions are really complicate d. How about inserting an example in the text to help the reader interpret them: “For example, Figure 4-2, shows a 42% chance that a randomly selected asthmatic child in Clevel and experienced repeated 8 hour exposures

D-81exceeding 70ppb (Scenario 74/4) during 2002-2004 while undergoing moderate or greater levels of exertion. In contrast....”

4-44 Line 20: The sensitivity observed here poses a dilemma for developing an optimum National air quality standard sinc e any one standard would result in varying exposures across the Country due to varying human behavior patterns. How should a National standard compromise between competing local optimum standards?

4-45 Line 14: the conclusion of “moderately sensitive” may need to be more clearly explained, given the –57% change we see in Ta ble 4-15. The fundamental issue here is the reliability of the stochastic decay rate model. If it is deemed to be valid, choosing the 10 th and 90 th percentiles (the worst case scenarios) in pla ce of the randomly distributed decay rate seems unduly severe. More natural: shift the center of the decay rate distribution to the 25 th and 75 th percentiles, thus preserving the uncertainty being expressed by that distribution while making it stochastically larger and smaller, respectively.

4-47 Line 8: Tailoring the model to fit the California situation assesses whether the model is ideally capable of accurately forecasting exposure. However, APEX as used to set National standards is a different model a nd it too should be assessed. Ma ybe it’s AERs are higher than those in Sacramento and it does not underestim ate exposure like its tailored counterpart. Line 18: The shifty unit again, this time going from the μ g/m 3 to ppm.

ATTACHMENT: “Ozone population exposure analysis for selected urban areas”.

10 Available predictive distribution methodologi es (and software) would enable ambient levels to be randomly generated down to the trac t level and thereby reflect the uncertainty in some urban areas about the ozone concentrations in the outside air being exchanged by the APEX model. Staff should consider this refineme nt. The result would be in line with the way APEX has been developed.

12 The claim about the stability of A “ove r cohorts” seems surprising if this means “between” rather than “within cohorts”. For example, one would have thought the autocorrelation for institutionalized seniors woul d be far higher than for young, working persons. Page C-S12 states that auto-correlations within cohor ts “may differ greatly” among its members. Some clarification is needed here. (I note th at the model outputs are insensitive to “small changes” whatever that means exactly.)

18 This page suggests, seem ingly in contraction to page 4-2, that dose is being simulated in addition to inhalation. Some reconciliation of language would seem desirable.

21 Clock hour “I” rather than “I” seems correct.

22 Can some estimate be made of the effect of using the school children’s D and A for all individuals? In particular is this path more liberal or conservative than that of drawing the sequence of daily time activ ity patterns at random?

D-8223 See the comment about page 10 above re the imputation of local concentrations from those at the monitoring sites.

40 There does not seem to be a Section 3.8.2 so it was not clear what fractions were actually taken from Appendix A and used.

46 Some discussion of the results in this section would have b een helpful. How are the plots shown here to be interpreted and used, especially those about “person – days”? The same can be said about the next section, a lthough there at least some discu ssion of the findings is given.

53 It is not clear how to interp ret the person-day estimates. Mo re discussion is needed about how exactly these person-day m easures of population impact are to be interpreted for setting standards.

No explicit statement is given about how the a ggregates were computed. In the case of persondays, was this done by: first cal culating the expected number of days of exposure per person based on a number of APEX runs; and then multiplying by sub-populatio n size? If so the standard error of these estimates could be quite large even if a large num ber of APEX runs were made. Some statement of the reliability of these estimates needs to be given. A very relevant analysis of this reliability is given in the Langstaff memorandum.

73 While this assessment is valuable and en couraging, nevertheless the suggestion that APEX underestimates true exposure is of concern. So is the use of weekly the aggregation of exposures. These could give quite a misleading impression of hourly exposures because of the ecologic effect.

84 The technical appendices that follow on from this page seem very comprehensive and thorough. Where I was able to check the details, I found them correct. More over, relative to the complexity of their content, they seemed commendably clear.

A-1 No information is given about the design of the survey used to select the 37 residences in the (smallest) RTP study. Nothing is said about the weights if any used in the estimates to adjust for unequal selection probabilities . Could the eventual estimate s of population parameters be biased?

E-6 I would have thought the regression model on this page should have been fitted after logarithm transformation and the resulting model on this page expressed at a product. That would have had the advantage of insuring amongs t other things that the predicted AER is positive, whereas it could in principle be negative as presented.

D-83DRAFT MEMORANDUM: “Analysis of uncertai nty in ozone population exposure modeling” by John Langstaff

This memorandum is a generally clear and well-written account of some very technical issues. Some specific comments fo r the specified pages follow:

2 “ Variability” also leads to “uncertainty” so nowadays these two are commonly referred to as “aleatory uncertainty” and “epistemic uncertainty ”. The first represents the uncertainty that derives from the various random sampling processe s built into the APEX simulator. The second, the more subtle of the two, repr esents lack of knowledge about the underlying stochastic models. In APEX this means uncertainty about the stochastic model parameters such as the one reflecting the variation in AERs. However, it should also reflect uncertainty about that model, say whether it is lognormal or any of the logstudents-t distri butions with their varyi ng degrees of freedom.

Why include model uncertainty? The answer: to buy in surance against model mis-specification that can lead to APEX outputs that are biased away from the actual exposures. Better to have a heavier tailed distribution that covers the exposures the m odel aspires to predict than an optimistically narrow one that misses the boat.

Incidentally, a proper assessment would determ ine the calibration of the APEX prediction intervals. Too much uncertainty would mean these say 95% intervals would be too broad relative to the observatio ns and hence cover more than 95% of the observed exposures. That would point to the need for additional knowledge and hence reduction in epistemic uncertainty. Pages 4 and 8 provide good discussion on this ge neral issue about uncertainty.

3 2 nd last paragraph: Shouldn’t this be “between input unc ertainty” rather than “between model input uncertainty”?

8 Log-normal distribution. Analysts usually log – transf orm data that are lognormally distributed, perform inference on th at scale and then transform ba ck. This leads immediately to confidence intervals for the GM and GS D since these are by definition, monotonic transformations or their transf ormed counterparts: GM = exp (A M) and GSD = exp (SD). This fact would lead to asymmetric confidence in tervals for both. For the geometric mean for example, the 95% confidence limits would be (GM/GSD 2, GM*GSD 2 ).

Since the normal theory estimates, AM and SD, ar e stochastically independent, I am puzzled by Figures 17 and 18 that show them to be correlate d. Is a different definition of GSD being used? (The mean and standard deviation of the lognorm al distribution are related in a mathematically explicit way.) If so that defi nition should be stated for clar ity. Or could this mean the lognormality assumption is inappropriate?

On this page and elsewhere bias in the ambi ent monitoring measurements in urban areas has been ignored.

D-849 Indeed spatial variation in ozone concentrations can be considerable. For that reason, SHEDS has been applied with the pollution field interpolated down to the tract level. Obviously that would be impractical for APEX however.

10 As noted above, the quadratic roll back process is not very well described anywhere in the documentation including the Staff paper.

13 First line: Typo: “at a given monitor as uncorrelated”.

The imputations of missing values have quantifiable erro rs that could be qua ntified and reflected in the uncertainty distribution for APEX outputs. However, the method proposed as an alternative seems satisfactory.

Incidentally, that method is the “cross-valida tion” approach rather than the “jack-knife” approach. The latter and its competitor, the “boot-st rap” are used to correct bias in estimators and estimate their standard errors. That term shoul d be changed on this and subsequent pages.

14 Would not including all the monitors lead to an underestimation not overestimation of the prediction errors? As noted in the la st line some of these will be zero. 15 Why is the ratio rather than difference used as a measure of prediction accuracy. The former unlike that latter would ha ve a very non-normal distribution.

The cross-validatory assessment should have been made by removing and not using the target site in constructing the spatial interpolator to get a better indicator of prediction error.

The basis for the assumption made at the end of the first paragraph on this page seems tenuous. Further analysis would e liminate the need for it.

A well-tested method for spatial prediction ha s been developed for space time fields and software is freely available online ( http://enviro.stat.ubc.caalso includes a demo). The method overcomes the deficiency in geostatistical methods that ignore the stream of temporal data available for estimating the various parameters requi red for the interpolator. It also avoids the assumption of covariance stati onarity made in kriging.

Incidentally, kriging, being a linear method, de facto assumes the underlying field is Gaussian. Its performance for ozone can therefore be impr oved by taking a square root transformation of the field and transforming back af ter completing the interpolation.

21 APEX averages the working and home distri ct ambient levels only in as much the microenvironments through which the sampled composite commuters go from home to work to home districts during weekdays. The first paragraph in the su bsection beginning on this page gives a misleading impression that the two ozone fields are directly av eraged. Furthermore the claim about ambient levels used for commuters who work outside the study area disagrees with what is claimed on page 4-21 of the Staff Report. Reconciliation is needed here.

22 The section beginning on this page does not make clear what uncertainties associated

D-85with roll - back are being assessed. Presumably the reductions called by the quadratic formula are not uncertain. Is it the quadr atic method? Is the uncertainty about how well this approach actual replicates what woul d happen under a real rollback?

First sentence, 2 nd paragraph of section. Shouldn’t “reflect” be change d to “attain”? In this same sentence, two sentences address how uncertain ty is to be assessed by the proposed method. Is one redundant? Should they be merged? In any case, I could not understand why the first one is true. Why do the differences between them reflect the uncertainty that is being considered in this section?

3 rd paragraph of section. If I understand its intended meaning correctly, the sentence beginning “A 3-year..” should be rewritten as: “A 3-year period with wide range ozone concentrations will typically have higher population exposures th an one with a narrow range even though both periods have the same design value (o r both are just in attainment).”

34 Why are these values constrained to lie between 0.95 and 8.05? Why is that even mentioned at this point since the actual estimates are well within that range?

CHAPTER 5

5-18 Line 20 - : This imaginative but somewhat ad hoc approach is not quite Bayesian because of the way in which synthetic data are created. A likeli hood based alternative:

D-86D-87D-88D-895-21 Line 28. A very good description of variability or what is commonly referred to as aleatory uncertainty. 5-22 Line 20: Word missing here.

CHAPTER 6

6-13 Line 6: A potentially important bias could arise from the changes in the time-activity patterns of members of the suscep tible groups, such as those usedto characterize the exposure – response function and as noted a bove, this source should be include d in the list of uncertainties.

6-34 Figure 6-1: In this and the falling figures we se e a surprising amount of variability between cities for 74/5 compared with 74/4 and th at is less than 74/3. That seems curious. In any case, it would argue for 74/4 on the basis of ro bust of the predicted benefits across cities.

6-47 Line 1: Environmental epidemiologist could well use APEX – type models in their assessments of association of health risks and pollution. Such models in conjunction with interpolation of ambient fields to local areas could help overcome the measurement error effect in the use of ambient concentration fields as su rrogates for exposure. It would also provide an estimate of the exposure response as against the concentration response. Moreover, based on my research work with an APEX relative (pCNEM) non- significant associations can be turned into significant associations through the de-a ttentuation of the relative risk.

D-90

### Dr. Barbara Zielinska

Comments of the 2 nd Draft Ozone Staff Paper Chapter 2

Barbara Zielinska DRI

1 In overall, this second draft of the ozone Staff Paper represents significant improvement over the

st

version. Below are my responses to the charge questions to the CASAC O 3 panel from Dr. Martin’s memo (July 17, 2006), regarding Chapter 2.

1. To what extend are the air quality characte rizations and analyses clearly communicated, appropriately characterized and relevant to the review of the pr imary and secondary O 3 NAAQS?

In my opinion, Chapter 2 is well written and pr esents a concise summary of the information contained in Chapter 2 and 3 of the final O 3 AQCD. The ambient ozone levels, O 3 precursors, their sources and emissions, temporal and spatial variability, l ong-term trends, and characterization of ozone episodes are adequately summarized in this chapter. This information is relevant to the review of primary and secondary O 3 standards.

2. Does the information in Chapter 2 provide a sufficient air quality- related basis for the exposure, human health and environmental effects, health risk assessment, and environmental assessment presented in later chapters?

Section 2.2.6 covers briefly the relationship of oz one to other photochemical oxidants. However, there is no information in this chapter regarding the role of ozone and other photochemical oxidants in the atmospheric transformation processe s that may results in the formation of more toxic products (both in outdoor and indoor environments), either in gas or particle phases. This topic, covered in O 3 AQCD, seems to be relevant to humanhealth and environmental effects.

The policy relevant background (PRB) section (2.7) continues to have problems. Although this section very briefly cites the results of the co mparison of different models and measurements, it does not adequately address the uncertainties of the global GEOS-CHEM model and how these uncertainties are reflected in the health risk anal ysis. The authors say (page 2-48, line 1-4) that the GEOS-CHEM model overestimates PRB ozone values for afternoon surface air over southeast in summer and it is accurate within 5 ppbv in other regions and seasons. If the PRB concentrations are predicted to be generall y in 15 to 35 ppb range, 10 ppb overestimation is substantial. Besides, it is not clear how this information was derived. Since ozone health effects are observed down to concentrations of the orde r of 0.04 – 0.05 ppm, it is important to know how the PRB compares to the considered primary ozone standard and what uncertainties there are in the risk attributed to controllable sources.

D-91Minor comments:

1. Page 2-2, lines 16 -21. The order of sentences should be changed. The sentence “NOx is considered a good surrogate for NOy” should be the last sentence, after NOy is defined. 2. Table 2-1. “Total without fire” for 2 003 and 2004 should be moved up one line. 3. Page 2-5, line 30. Formaldehyde should be spelled out (H2CO may not be clear to everybody) 4. Page 2-15, lines 27-29. Transport is not evident from Figure 2-6 5. Page 2-48, line 8: The text comments very brie fly that the PRB O3 concentrations are the highest during spring and decline into summer. However, as evident from Appendix 2A, diurnal ozone PRB profiles are very different for some city, for example for Houston or Sacramento. Any explanation?

D-92

### NOTICE

This report has been written as part of the activities of the U.S. Environmental Protection Agency’s (EPA) Clean Air Scie ntific Advisory Committee (CASAC), a Federal advisory committee administratively located under the EP A Science Advisory Board (SAB) Staff Office that is chartered to provide extramural sc ientific information and advice to the Administrator and other officials of the EPA. The CASAC is structured to provide balance d, expert assessment of scien tific matters related to issue and problems facing the Agency. This report has not been reviewed for approval by the Agency and, hence, the contents of this repo rt do not necessarily represent the views and policies of the EPA, nor of other agencies in the Executive Branch of the Federal government, nor does mention of trade names or commercial products constitute a recommendation for use. CASAC reports are posted on the SAB Web site at: http://www.epa.gov/sab

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