1 Comments for Consideration by the CASAC Ozone Review Panel on the Reconsideration of the 2008 NAAQS for its teleconference d eliberations on February 18, 2011 Milan Hazucha, M.D., Ph.D. Department of Medicine, School of Medicine and Center for Environmenta l Medicine, Asthma, and Lung Biology University of North Carolina Chapel Hill, NC 27599

- 7310
and Allen S. Lefohn, Ph.D. A.S.L. & Associates, 302 North Last Chance Gulch , Suite 410 Helena, Montana 59601 asl

- associates.com/

February 7, 2011

Last Marc h 19, 2010 we submitted Comments for Consideration by the US EPA for its deliberations on the re

- evaluation of the ozone ( O 3 ) standard entitled “Clarification to Some of the Scientific Issues Raise d by the EPA Concerning Human Laboratory Studies”, Docket ID No.EPA

- HQ

- OAR

- 2005

- 0172. In assessing the health effects, the proposed primary standard is based on the strength of evidence derived from human laboratory studies that, and as asserted by EPA, “provide data with the highest level of confidence” ( 75 FR , 2010, p.2945) because they provide human health effects data acquired under closely monitored conditions and can provide exposure

- response relationships. As asserted by EPA, we fully agree that the informed judgment and conclusions about the health effect s should be based on the nature and weight of the evidence, on biological plausibility, consistency, strength , and coherence of evidence. As indicated in the Federal Register ( 75 FR, 2010, p.2940), the reconsideration of the O 3 standards is based on the sc ientific and technical information and analyses on which the March 2008 O 3 NAAQS rulemaking was based. In the pages that follow, we have expressed concerns about some of the scientific issues summarized in the Federal Register (2010)

. We would also like t o expand on our March 19, 2010 comments with focus on the Charge Questions ( Wegman , 2011) to be discussed at the February 18 and March 3, 2011 CASAC teleconferences in the hope that our comments will provide more2 accurate input into the decision making pro cess associated with setting the level of the human health standard for O 3 . 1. Comments to C harge Q uestion 1
.

1.1 Controlled h uman e xposure s tudies. What is your advice on the overall strengths and limitations of the evidence from controlled human exposure and epidemiological studies and the re sults of the exposure and risk assessments, in the context of EPA's selection of a standard level within the proposed range that would be requisite to protect public health with an adequate margin of safety, including the need to protect susceptible popula tions, such as children and people with asthma?

T he first Charge Question on the overall strengths and limitations of the evidence from controlled human studies briefly summarizes the results of two Adams multi

- expos ure studies (2002, 2006) considered new for 2008 rulemaking. A point is made that these are “newly available in the 2008 rulemaking.... down to an exposure level of 0.060 ppm.” Actually, t hese studies discuss exposure levels down to 0.040 ppm.
A more rece nt study that was not available in 2008 provide s some guidance on the O 3 effects at 0.060 ppm level. It is a multi

- exposure study of Schelegle et al . ( 2009 ) which report s lung function data effects following 6.6

- hr exposure to 0.087, 0.080, 0.070, and 0.06 0 ppm

. The authors used several parametric and nonparametric tests to analyze the data and found the effects of 0.060 exposure to be not significant from filtered air by any of the tests. All other O 3 exposure effects were significant from filtered air. Ou r reanalyzes of Schelegle and colleagues ( 2009 ) data agreed with the authors ' findings (Lefohn et al

. , 2010). As reiterated in the Memorandum ( Wegman, 2011) , the current EPA ( 75 FR, 2010, p. 2950 ) approach in evaluating the “health effects” is placing th e emphasis in interpretation of effects on the number of individuals whose FEV 1 decrement at the end of exposure is greater than 10% ( more specifically FEV 1 decrements ≥ 10 % but <20% )

. The Memorandum ( Wegman, 2011) states that “7 to 20% of the subjects in the Adams studies experienced lung function decrements ( ≥ 10%) at the 0.060 ppm exposure level” (75 FR, 2010, p. 2986). The 7 % of the subjects represents 2 of 30 sub jects in the Adams (2006) study population that experienced FEV 1 decrements with ≥ 10 % with the square

- wave exposure pattern at the 0.060 ppm exposure level3 (comparing pre

- and post

- exposures ) when the results were adjusted for the effects of exercise alon e in filtered air (FA)

. This number disagrees with data presented in Fig. 8

- 1B (US EPA, 2006) showing that only 3 %, i.e., 1/30 subjects in Adams (2006) study experienced ≥ 10% decrement. Moreover , t he upper range value of 20% (6/30) perpetuated throughout the EPA documents may apparently come from the 0.080 pm face

- mask Adams (2002) study and, therefore, in this context is not relevant

. However, it may also be possible that the 20% value (6 of 30 subjects) , although cited as Adams (2002) by the EPA, origina ted from his earlier study in 1998 , which was not published in the peer
- reviewed literature and is neither referenced in the Criteria Document ( US EPA, 2006) nor Federal Register (75 FR, 2010) . In this face mask study , which according to Adams presented an “artificial burden” with minute ventilation 15% greater than used in his 2002 and 2006 studies and 0.060 ppm O 3 concentration, FEV 1 changes were not statistically significant

. We believe that it is inappropriate for EPA to use the non

- peer reviewed Adam s’ results from his 1998 report in its rulemaking considerations.
EPA subsequently states ( Wegman, 2011; 75 FR , 2010, p

. 2951) that such magnitude of lung function decrements is of concern because for active healthy people, moderate levels of functional r esponses ( e.g ., FEV 1 decrements of ≥ 10% but < 20%) and/ or moderate symptomatic responses would likely interfere with normal activity for a relatively few responsive individuals. Furthermore, CASAC indicated ( 75 FR , 2010, p.2973) that focus should be on t he lower end of the range of moderate levels of functional responses for estimating potentially adverse lung function decrements in people with lung disease

. The EPA then uses the concentration at which a small percentage of volunteers who responded with ≥ 10% decrement in FEV 1 to extrapolate to an entire population ( US EPA, 2007 )

. In the opinion of Prof. Smith 1 , 2

EPA’s approach overlooks numerous modulating/ confounding factors that will impact health effects assessment. The use of FA is not an appropriate control exposure because the 0 ppb O 3 with which we concur the 2 out of 30 subjects “is an extremely small number of individuals from which to conclude that the response is significa nt” (Smith, 2007). Moreover , to quote : “Given the large uncertainty in the probability of response at 0.06 ppm ozone , I do not believe tha t staff paper’s conclusi ons on this point are justified ” (Smith, 2007).

1 Prof. Richard L. Smith is Director of Statistical and Applied Mathematical Sciences Institute, University of North Carolin a

– Chapel Hill , NC.

2 Member of Health Effects Institute , Heal t h Research Committee4 “air ” that is generated in the laboratory does not exist under ambient or indoor air conditions. For example, the FA F EV 1 responses associated with the controlled human exposure experiments show an improvement of FEV 1 (Adams, 2006 ). Comparing changes across corresponding time intervals and expressing them as "corrected values" that take into consideration the absolute dif ference between the O 3 and FA responses may perhaps “artificially” enhance the magnitude of the O 3 response. Such enhanced responses may not be necessarily observed at relevant background levels of hourly average O 3 concentrations with the result that stat istically significant differences using FA may not be realized using actual ambient background levels . A comparison to a control that represents background O 3 concentrations is more appropriate. The selection of the background O 3 level to be used as a cont rol exposure is important. The EPA ( 75 FR , 2010, p.2980) has estimated, using a model that policy

- relevant background (PRB) O 3 concentrations are in the range of 15

- 35 ppb. Empirical O 3 data collected at an O 3 monitoring site where PRB conditions predomina te show that the O 3 concentration levels are frequently ≥ 50 ppb (Oltmans and Lefohn, 2005; Oltmans et al., 2008). The range of maximum hourly average concentrations for April for the period 2003 to 2010 is 54

– 65 ppb and the range of hourly average concentrations **≥** 50 ppb is 30

– 188 occurrences
. Eurasian emissions associated with biomass burning and their easterly transport enhance O 3 concentrations at west coast O 3 monitoring sites under PRB conditions, as well as inland O 3 monitoring sites in Montana, Wyoming, and North Dakota (Oltmans et al., 2010). Thus, the EPA's modeled estimates of policy

- relevant background O 3 concentrations in the range of 15 to 35 ppb is much lower than actual measured ambient values when PRB conditions predominate.
In assessing the relevance of the small number of individuals that experience moderate lung function decrements, important considerations that must be taken into account are: (1) lack of relevant background O 3 control profile in laboratory studies; (2) substantial intra

- individual vari ability; (3) lack of coherence between responses of some individuals to a range of O 3 concentrations; (4) post hoc statistical analyses; and (5) inadequate standard

- setting assessment when applying square

- wave exposure patterns.

1 .2 Questionable p ost - hoc s tatistical a nalyses of d ata . In considering the weight of the evidence gained from the two Adams studies EPA has commented that although the two studies are by one investigator the studi es are well designed5 (Wegman , 2011). The 0.040 ppm exposure showed non
- significant improvement of lung function (FEV 1 ) in both studies. The 0.060 ppm effects in 2006 study were also found to be non

significant by the author. The EPA, however, has considered statistical analyses of this study to be “inconclusive” and did i ts own reanalysis finding the not significant 0.060 ppm square

- wave exposure effects as statistically significant (Brown , 2007; Brown et al

. , 2008). This re

- analyses was done “because of potential regulatory implications of the presence or absence of effec ts” (Brown et al., 2008) , implicitly referring to statistical significance or no n
- significance of effects. C ommenting on the EPA’s criticism of Adams (2006) , Smith (2007) states that in considering the statistical aspect of Adams’ analysis “the evidence fo r a response at 0.06 ppm ozone level is still very uncertain”. Subsequently, Smith (2007) comment ed that “In my judgment, when all the comparisons are taken into account, there is insufficient evidence to conclude that there is any well

- defined response to ozone exposure below the 0.08 ppm level”. Surprisingly, the effects of average 0.060 ppm step

- wise exposure s reported in the same study , which were also found not to be significant by the author , were not reanalyzed by EPA

. The approach of Brown et al. ( 2008) is problematic

. The selection of statistical method to analyze data is closely tied to and dependent upon study hypotheses . In all of the relevant Adams studies , the key interest was in hourly changes and not solely the end

- exposure effects. Thus, Brown et al. (2008) reanalyzes of only end of exposure changes ignoring intermediate hourly changes is questionable. Our reanalyzes of Adams (2006) data using a statistical method different from both Adams (2006) and Brown (2008) found the effects of 0.040 and 0.060 ppm to be in agreement with Adams analyses, i.e., not significant from filtered air (Lefohn et al, 2010). It is apparent that s everal statistical approaches are claimed to be appropriate for analyses of the same data by different investigators , even though they result in conflicting statistical significance of reported changes. T he appropriate statistical test is the one that is in conformity with the study hypotheses and that would be Adams ’ analyses as well as that of Lefohn et al (2010)

. To re
- analyze data because the original statistical outcome did not produce desired results and expected “implications” of such outcome is inappropriate.6 1 .3 The risk assessment base d on infrequent square
- wave - like exposure profile and not on a typical diurn al concentration pattern is troubling
. The NAAQS (US EPA, 2006) document states that “the controlled exposure (or “clinical”) studies provide the clearest and most compelling evidence for human health effects directly attributable to acute exposures to O 3 per se” (page E

- 9). Implicitly , such acute O 3 exposure s
mean exposure s to diurnal ( i.e., variable) concentration encou ntered by general public in ambient air

. One of the key topics discussed in Chapter 3 of the same document entitled “Environmental Concentrations, Patterns, and Exposure Estimates” is characterization of ambient O 3 concentrations , particularly section 3.4 entitled “Diurnal and Seasonal variability of ozone”

. More than 25 pages including 13 figures each with 4

- 6 panel s show plots of a typical diurnal concentration pattern recorded across various US cities ( US EPA , 2006)

. In our perusal of Chapter 3 we have not found any reference to a square
- wave concentration profile occurring in the ambient atmosphere in the US. The figures and relat ed discussion in this Chapter leave no doubt that the diurnal O 3 profile across the US has a variable form with bell

- like concentration pattern reaching peak in the early afternoon ( see the Figure 3

- 12a

- d ). Therefore, one would expect that the health risk estimate would be based on real diurnal ambient atmosphere concentration profiles and not on an occasional occurrence of a near steady

- state concentration. Results from controlled laboratory exposures (e.g., variable concentration profile) of human volunte ers indicate that higher O 3 hourly average concentrations elicit a greater effect on hour

by

- hour physiologic response (i.e., F EV 1 ) than lower hourly average values, which implies a nonlinear dose

- response relationship (US EPA, 2006; Adams, 2006b; Hazucha and Lefohn, 2007). Thus, identical 8

- h average dose produces different responses, depending on the hour

- by

hour O 3 concentration pattern. The current 8

- h average human

- health O 3 standard is not adequate7 for describing this nonlinear FEV 1 hour

- by

- hour patte rn of response. For developing a consistent standard to protect human health, it is important to identify those ambient

- type concentration patterns that elicit adverse human health effects. The EPA appears to be focused on the square

wave regimes to establ ish the lower

- level of response although it is clear that a variable pattern is typical of outdoor ambient conditions (US EPA, 2006, page AX6

- 19). Diurnal patterns predominate in urban, suburban, and low

- elevation rural areas (US EPA, 2006). Using EPA AQS data for 2002, out of 28,148 8

- h sequences, only 426 (1.51%) were classified as a square

- wave ambient O 3 concentration profile (Lefohn et al., 2010 ). Consequently, the prevalence of a variable O 3 concentration profile in ambient air associated with greater spirometric effects should make the variable exposure studies “the highlights of evidence” and the key studies for standard setting. However, such is not the case; EPA has focused only on the 0.06 ppm square

- wave results from Adams (2006) and possibly the 1998 non peer reviewed report by Adams that is cited in Adams (2002)

. We are concerned that by omitting data from the variable profile studies, the EPA has provided an inadequate assessment for the human health considerations.

2. Comments to Charge Question 2 : Recognizing that controlled human exposure studies at 0.080 ppm O 3 and above have provided evidence of other health effects, including inflammation and increased airway responsiveness which may occur through different physiological mechanisms than the r eduction in FEV 1 , how should the results of these studies inform our understanding the health effects to

Human O 3 studies at concentration ≥ 0. 0 8 ppm exploring changes in i nflammatory variables show much greater intra

- and inter

- individual variance of measured endpoints than spirometric variables. At this time we do not have a sufficient number of human controlled studies exploring these endp oints to make a definitive statement concerning the importance of these observations in the standard

- setting process

. A recent study by Kim et al. (2011) reports on both spirometry and inflammatory cell changes to square
- wave 0.060 ppm and perhaps may prov ide some general guidance as to the magnitude and individual variability of inflammatory endpoints following square
- wave 0.060 exposure s . However, for future rulemaking activit i es , we believe that variable/stepwise exposures and the application of realisti c background O 3 levels as a control would be required to provide specific guidance to the EPA. healthy adults at exposures levels from 0.060 to 0.070 ppm?8 3. Comments to Charge Question 3. How should the results of the controlled human exposure studies at 0.060 ppm O 3 , showing effects on FEV 1 and respiratory symptom s, in the context of the larger body of evidence from controlled human exposure studies, mentioned above, inform our understanding of the health

EPA recognizes that the intra

- individual variability of various endpoints may be substantial but believes that the variability tends to be reproducible ( 75 FR , 2010, p. 2949). Although there is a tendency by the investigators to interpret their findings of repeated exposures to the same
concentr ation as “reproducible” since the group averages are similar and correlations between two separate exposures are high (i.e., for some spirometric endpoints), closer examination shows that for many individuals, the differences in FEV 1 response may be substa ntial and, in some cases, different by as much as 40 percentage points. Hazucha et al. (2003) noted that many individuals, who were initially classified as weak responders, became strong responders on the second exposure and vice versa. Such a shift in an individual’s O 3 responsiveness has a direct bearing on the current approach to data interpretation and usage by EPA in support of a lower O 3 standard. effects to healthy adults at exposure levels from 0.060 to 0.070 ppm?

Furthermore, there is a considerable intra

- individual inconsistency of response within an exposure period . Some individuals show no response during, for example, 6.6

- h exposure, but a sudden decrease in FEV 1 at the end of exposure. Others show an up and down response during exposure with a chance FEV 1 decrement of ≥ 10% at the end of exposure. Other individua ls may respond with ≥ 10 % or even 15% decrement at the first hour, but minimal or no response at the end. With such individual variability, the utility of using only individuals’ end exposure FEV 1 value for health assessment is questionable. These finding s illustrate the large individual variability of response. Thus, because of the large intra

- individual inconsistencies in response between and within exposures observed in the controlled health experiments, it is our opinion that the end of exposure value of an FEV 1 ≥ 10% decrement may not be indicative of a detrimental health effect. Adams (2006) reported no statistical significance at the 0.06 ppm level using both variable and square

- wave profiles . Similarly, Schelegle et al. (2009) reported similar results using a variable profile . Lefohn et al. (2010), using the data from Adams (2006) and Schelegle et al. (2009) and a different statistical approach, repo rted no statistical significance. Using almost9 double the number of subjects as Adams (2006) and Schelegle et al . (2009), Kim et al. (2011) reported statistical significance using 0.06 ppm square

- wave profiles. However, the resulting FEV 1 effects were compared with FA instead of realistic ambient variable exposure pattern that represented background O 3 concentration s. Actual PRB O 3 concentrations have been reported to frequently occur at some monitoring sites ≥ 50 ppb (Oltmans et al., 2008; Oltmans et al., 2010). An important issue to consider is whether Kim et al. (2011) would have observed a statistically significa nt difference between the square

- wave 0.06 ppm exposure and a control that reflected observed PRB O 3 concentrations (i.e., concentrations ≥ 50 ppb)

. No evidence is currently available to conclude that Kim et al. (2011) would have reported a statistically s ignificant difference between the enhanced treatment of 0.06 ppm and a control that represented observed PRB concentrations. 4. Comments to Charge Question 4. With respect to the information from controlled human exposure studies at 0.060 ppm O 3 , what is the scientific importance of the small, group mean FEV1 decrements relative to the findings that 7 to 20% of the subjects experienced FEV1 decrements ≥ 10%? Please consider this

To date EPA has used only selected data (square

- wave) from a few controlled human exposure studie s that have reported on the effects of O 3 at 0.060. The available database could be substantially enhanced if (1) the variable/stepwise concentration profile studies were included, and (2 ) the hourly responses data were considered as well. However , additio n of these data to the database may require a modified approach to risk estimation based on a cumulative approach as described in Lefohn et al. (2010). question from both a public health and a clinical perspective

.

As we already pointed out in comments to Charge Question 1, Adams (2006) and Fig. 8

- 1B (US EPA, 2006) r eported only 1/30 subjects (3%) show ing FEV 1 decrement ≥ 10% following exposure to 0.060 ppm O 3 . This becomes 7% (2/30) when adjusted for filtered air response by EPA (Brown et al., 2008) , which we do not necessarily consider appropriate because of enhance ments at FA, which is not a relevant background O 3 concentration

. The upper limit of 20% is misleading because it is either based on the 0.080 ppm results of face

- mask exposure (Adams, 2002) or on a non
- peer reviewed Adams (1998) report

. Consequently, the use of such data is highly questionable. Thus, f or 0.060 ppm exposure (square

- wave) , we do not have a range but 1 or p ossibly 2 subjects with ≥10% decrement. Considering “the large uncertainty in the10 probability of response at 0.06 ppm ozone” (Smith, 2007) and considering that 2/30 subjects “ is an extremely small number of individuals from which to conclude that the res ponse is significant” (Smith, 2007) , we find the available evidence of pulmonary function effects , based

on the Adams ( 2006) study , to be inadequate and believe that an extrapolation to a general population is inappropriate

. 5. Conclusions
EPA in its curren t approach in evaluating the “health effects” is placing the emphasis in interpretation of effects on the number of individuals whose FEV 1 decrement at the end of exposure is greater than 10%. The EPA states that this is of concern because for active healt hy people, moderate levels of functional responses ( e.g ., FEV 1 decrements of ≥ 10% but < 20%) and/ or moderate symptomatic responses would likely interfere with normal activity for a relatively few responsive individuals. However, in assessing the relevanc e of the small number of individuals that experience moderate lung function decrements, important considerations must be taken into account. Based on our analysis, we conclude:
1. The use of FA may not be an appropriate control exposure because the 0 ppb O 3 “ air’ that is generated in the laboratory does not exist under ambient or indoor air conditions. Actual PRB O 3 concentrations are greater the 15

- 35 ppb levels modeled by the EPA and PRB hourly average concentrations frequently occur at some sites ≥ 50 ppb. Comparing changes across corresponding time intervals and expressing them as "corrected values" that take in to consideration the absolute difference between the O 3 and FA responses may perhaps “artificially” enhance the magnitude of the O 3 response. 2. Intra

- individual variability of various endpoints may be substantial. Although there is a tendency by the investi gators to interpret their findings of repeated exposures as reproducible , closer examination shows that for many individuals the differences in FEV 1 response may be substantial and, in some cases, different by as much as 40 percentage points. With such ind ividuals, between and within exposure inconsistencies, the utility of using only individuals’ end exposure FEV 1 value for health assessment is questionable.
3. The lack of coherence between responses of many individuals to a range of O 3 concentrations furthe r reflects on instability of these effects.
4. Post hoc statistical analyses are questionable because they may violate a priori statistical design. Approaches based on the behavior of extreme responses within specific experiments, treatments, and measurement times have not been presented in a way to have any confidence in attempts to reinterpret the analysis in a meaningful statistical sense. 5. Focusing on square

- wave versus realistic variable exposures provides an inadequate assessment for the human health considerations.11 6. Inflammatory variables show much greater intra

- and inter

- individual variance of measured endpoints than spirometric variables. At this time we do not have a sufficient number of human controlled studies exploring these endpoints to make a definitive statement concerning the importance of these observations in the standard

- setting process.

5. References Adams, W. C., 2002. Comparison of chamber and face

- mask 6.6

- hour exposures to ozone on pulmonary function and symptoms responses. Inhalati on Toxicol. 14:745

- 764.
Adams W.C. , 2006 . Comparison of chamber 6.6

- h exposures to 0.04

- 0.08 ppm ozone via square

wave and triangular profiles on pulmonary responses. Inhal. Toxicol. 18:127

- 136. Adams W.C., 2006b. Human pulmonary responses with 30

- minute time intervals of exercise and rest when exposed for 8 hours to 0.12 ppm ozone via square

- wave and acute triangular profiles. Inhal. Toxicol. 18:413

- 422. Brown, J.S. The effects of ozone on lung function at 0.06 ppm in healthy adults. June 14, 2007. Memo to the Ozone NAAQS Review Docket. EPA

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- 0175. Available online at: http://www.epa.gov/ttn/naaqs/standards/ozone/s_o3_cr_td.html

. Brown, J.S., Bateson, T.F., McDonne ll, W.F., 2008. Effects of exposure to 0.06 ppm ozone on FEV 1 in humans: a secondary analysis of existing data. Environ. Health Perspect. 116 : 1023

- 1026. Federal Register , 2010. National Ambient Air Quality Standards for Ozone: Proposed rule. 40 CFR Parts 50 and 58 (EPA

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- 2005

- 0172; FRL

- 9102

- 1). RIN 2060

- AP98. Vol. 75, No. 11, p. 2938

- 3052. Hazucha, M., Lefohn, A.S., 2007. Nonlinearity in Human Health Response to Ozone: Experimental Laboratory Considerations Atmospheric Environment . 41 : 4559

- 4570.
Haz ucha, M., Lefohn, A.S., 2010. An alternative form and level of the human health ozone standard. Inhal Toxicol 22:999

- 1011. Kim, C.S., Neil E Alexis, Ana G Rappold, Howard Kehrl, Milan J Hazucha , John C Lay, Mike Schmitt, Martin Case, Robert B Devlin, Dav id B Peden, and David Diaz

- Sanchez. Lung Function and Inflammatory Responses in Healthy Young Adults Exposed to 0.06 ppm Ozone for 6.6 Hours

. Am J Respir Crit Care Med, prepubl . Jan, 7, 2011. Lefohn, A.S., Hazucha, M.J., Shadwick, D., Adams, W.C., 2010. A n Alternative Form and Level of the Human Health Ozone Standard. Inhalation Toxicology. 22:999

– 1011.12 Oltmans, S.J., Lefohn, A.S., 2005. Using empirical data to estimate policy relevant background for ozone exposures. Submitted to the U.S. EPA as part of t he comments on the second draft of the Ozone Criteria Document. Oltmans, S.J., Lefohn, A.S., Harris, J.M., Shadwick, D., 2008. Background ozone levels of air entering the west coast of the U.S. and assessment of longer

- term changes. Atmospheric Environmen t 42 : 6020

- 6038. Oltmans, S.J. , Lefohn, A.S. , Harris, J.M. , Tarasick, D.W. , Thompson, A.M. , Wernli, H. , Johnson, B.J. , Novelli, P.C. , Montzka, S.A. , Ray, J.D. , Patrick, L.C. , Sweeney, C. , Jefferson, A. , Dann, T. , Davies, J. , Shapiro, M. , Holben, B.N. , 20 10

. Enhanced ozone over western North America from biomass burning in Eurasia during April 2008 as seen in surface and p rofile observations. Atmos Environ 44 : 4497

- 4509. Smith, R.L. Public Comments to CASAC Ozone Review Panel, March 7, 2007.
U.S. Environme ntal Protection Agency, 2006. Air Quality Criteria for Ozone and Related Photochemical Oxidants. Environmental Protection Agency, Office of Research and Development, Research Triangle Park, NC. U.S. EPA report no. EPA/600/R

- 05/004bF.
U.S. Environmental P rotection Agency , 2007. Review of the National Ambient Air Quality Standards for Ozone: Policy A ssessment of Scientific and Technical Information. OAQPS Staff Paper, Report EPA

- 452/R

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- 007. Research Triangle Park, NC:Office of Air Quality Planning and Sta ndards, U.S. Environmental Protection Agency. Available online at : http://www.epa.gov/ttn/naaqs/standards/ozone/s_o3_cr_sp.html

. Wegman L.N. Memorandum: Solicitation of CASAC Ad vice on EPA’s Reconsideration of the 2008 Primary Ozone National Ambient Air Quality Standard, EPA, HEID, OAQPS, January 26, 2011.