Exponent, Inc. February 10, 2011

1 COMMENTS ON MEMORANDUM FROM LYDIA N. WEGMAN TO HOLLY STALLWORTH: SOLICITATION OF CASAC ADVICE ON EPA’S RECONSIDERATION OF THE 2008 PRIMARY OZONE

NATIONAL AM B IENT AIR QUALITY STANDARD. JANUARY 25, 2011

After reconsidering the scientific literature support ing the current 8

- hour primary ozone National Ambient Air Quality Standard (NAAQS) level of 0.075 ppm , EPA in January 2010 proposed to lower the level to within the range of 0.060 to 0.070 ppm in order to provide increased protection for children an d other ‘‘at risk’’ populations

.

On January 25, 2010 , EPA sent a m emorandum to the CASAC Ozone Reconsideration Panel soliciting additional advice prepa ra tory to EPA ’s decision on a final primary ozone standard (the “Memorandum”). The American Petroleum Institu te asked Exponent, Inc. to review and
comment on important issues raised by the Memorandum.

W e find that the Memorandum is deficient in a number of ways. It asks CASAC for guidance on matters that are not within CASAC’s purview, namely on policy judgments that should be made at the sole discretion of the EPA Administrator. It asks CASAC to provide assistance in areas in which CASAC has already taken unequivocal positions and in which its responses are predictable. Perhaps most importantly, it asks CASAC t o base its response to the charge questions posed in the Memorandum to literature that appeared before 2006, despite the fact that much directly relevant peer

- reviewed new literature has appeared after that cut

- off date

. Overall, the purpose of the Memora ndum appears to be to ask CASAC to rubber

- stamp decision s that EPA has already made.

O ur further thoughts on each of these items are given below

.Exponent, Inc. February 10, 2011

2 CASAC is being asked to comment on policy decisions that should made by the EPA Administrator

EPA ’s M emorandum makes clear that the upper and lower bound s on the range of levels on an

ozone standard that EPA proposed in its January 2010 reconsideration reflect two approaches to judging the scientific data available on the health effects of ozone. The up per end of the range places significant weight on the uncertainties and limitations inherent in the scientific information while the lower end places less weight on the strength of the information , with more concern shown for the need to avoid underestimat ing adverse effects on the public health. Another way of viewing these approaches is as follows. An ozone level set at the upper end is consistent with one of the fundamental tenet s of scientific inquiry, namely the need to embrace a theory only if the e vidence for it is extremely strong in the face of competing theories. A level set at the lower level, on the other hand, acknowledges the existence of data limitations but recognizes that EPA’s mission under the Clean Air Act to protect the public health with an adequate margin of safety may require it to accept scientific information of questionable certainty in order to avoid the possibility of subjecting a portion of the population to adverse health effects

.

Thus, in deciding on the final form of the ozone standard, EPA will have to judge the weight to place on information that is characterized by a high degree of scientific certainty and the weight to give to information that is marked by a greater degree of uncertainty and is perhaps subject
to addit ional limitations

. The significance of the role that subjective judgment play s i s clearly shown by the fact that although both the NAAQ S current level of 0.075 ppm set in 2008 and the
range of levels of 0.060 to 0.070 ppm proposed in EPA’s re consideration of 2010 were based

u pon identical scientific information embodied in the ozone Criteria Document of 2006. The differen ce in the levels were simply a reflection of the policy judgments made by different Administrators on interpr etation of the data , with t heir uncertainties and limitations, which in turn reflected different understandings of EPA’s mission. In 2008, the Administrator apparentlyExponent, Inc. February 10, 2011

3 gave more weight to data with a greater degree of certainty while i n 2010 a new Administrator decided to give more weight to data with more uncertainty.

Given the large role played in the decision

- making process by subjective judgment, it is questionable what EPA can hope to gain from soliciting further advice from CASAC , a committee that was established to provide independent advice to the EPA Administrator on the technical basis for EPA’s NAAQS

. The charge questions in large part extend beyond a solicitation for advice on the technical basis for an ozone NAAQS; they ask CASAC to respond to questions that can be answered only by making policy judgments on the weight to be given to studies that are marked by varying degrees of uncertainty. For example, charge questions 2 and 3 in the Memorandum ask whether results of controlled human studies at ozone levels at
0.0 80 and 0.060 ppm can contribute to an understanding of the effects from exposure levels to healthy adults between 0.060 and 0.080 ppm. As we discuss below, the significance of the results at the 0.060 ppm level are uncertain. These questions can only be answered on the basis of policy judgments on the weights to apply to the studies, judgments that must be left to the EPA A dministrator , and not to CASAC

.

The Memorandum asks CASAC to respond to questions on which CASAC has already taken strong and unequi vocal positions.

In the past, CASAC has made abundantly clear its position on the range in which the ozone primary NAAQS level should be set. In commenting on the 2007 2 nd draft EPA Staff Paper, th e 2007 Final Rule and the 2010 proposed r econsideration, CASAC has consistently and forceful ly let EPA know that an ozone level in the of 0.060 to 0.070 ppm was appropriate. In fact, EPA has made clear that it relied heavily upon this series of recommendation s by CASAC to propose changing the 200 8 primary stand ard to a level within those limit s. One can only question whether CASAC can render an unbiased opinion on the charge questions , especially if they were
to lead the Ad ministrator to consider an ozone 8

- hour primary NAAQS that is outside the 0.060
to 0.070 ppm level range.Exponent, Inc. February 10, 2011

4 This is put into sharp focus by the first “overall” charge question , by which EPA solicits advice from CASAC on “the overall strengths and limitations of the evidence from controlled human exposure and epidemiological studies and the res ults 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 populat ions, such as children and people with asthma.” Certainly both EPA , as stated in its proposed reconsideration, and CASAC , as stated in its series of advisory letters to the EPA Administrator, already believe that the evidence is sufficient to establish a level within the range of 0.060 to 0.070 ppm. Beyond that, however , the precise nature of advice that EPA is requesting from CASAC is not at all clear

. Does EPA expect CASAC to o ffer an opinion on whether the evidence is strong enough to support a specif ic level within that range? As indicated above that subjective decision must be left to the Administrator and not an outside scientific advisory panel. Other than endorsing decisions already made, the only purpose that we can see in such a charge questio n is to p aint a veneer of scientific respectability on a ny final ozone primary NAAQS set by the Administrator

.

CASAC is asked to respond to charge questions on the basis of literature appearing before 2006 despite the fact that highly relevant literatu re has appeared since then.

The Memorandum explicitly asks CASAC “to consider only the information that has become available in the record of the 2008 O 3 NAAQS review, as information that has become available since the 2008 is not relevant to EPA’s recons ideration of the 2008 O 3 standard.” Since the
2008 NAAQS review was based on the scientific literature compiled in the March 2006 Criteria Document, CASAC is being asked to confine its response to the charge questions to literature published not later tha n early 200 6

. We are puzzled by EPA’s imposition of a restriction on CASAC to provide advice without benefit of information that appeared in the scientific literature beyond that date

. As we point out in our comments below, new and highly relevant litera ture is available that calls into question s ome of the results of studies that appeared before 2006. Si nce any new standard that EPA may decide upon will presumably remai n inExponent, Inc. February 10, 2011

5 place during the next five

- year NAAQS r eview cycle, EPA runs the serious risk of imposing a standard based upon outdated scientific information

. Our further comments below review EPA’s line of reasoning that led to its proposed range of
0.060 to 0.070 ppm
. We point out areas where EPA either glossed over or misinterpreted results of s tudies it relied upon, with an emphasis on how new published data can lead to a deeper understanding of the technical basis for an ozone standard.

Basis for EPA’s Proposed Decision on a Range of Primary Ozone NAAQS Levels Upon reconsidering the data avai lable through 2006, EPA proposed to reduce the 2008 standard based on the following evidence :

1. Two controlled exposure studies (Adams 2002, 2006), in which healthy subjects were exposed to ozone for 6.6 hours down to a level of 0.060 ppm. Pulmonary funct ion decrements were observed at 0.080 ppm and some subjects showed moderate decrements at 0.060 ppm.

2. EPA’s understanding that the evidence from controlled human exposure and epidemiological studies indicate that “people with asthma are likely to experienc e larger and more serious effects than healthy people.”

3. A body of epidemiological evidence indicating associations for a wide range of serious health effects across distributions of ambient ozone concentrations that extend beyond 0.075 ppm

In addition, EPA took into account the results of exposure and risk assessments it conducted to arrive at its proposed range on the levels of a primary ozone standard. The remainder of this section focuses on the evidence

- based information relied upon by EPA

.Exponent, Inc. February 10, 2011

6 The Ada ms Studies Three of the eight charge questions in the Memorandum deal with the interpretation of results of controlled human exposure studies, with particular attention paid to two studies conducted by Adams in 2002 and 2006. The importance of these latte r studies stems from the low ozone levels to which subjects were exposed. They are the only controlled exposure studies that examined respiratory effects associated with ozone exposures less than 0.080 ppm.

EPA states in its 2010 reconsideration that the Adams studies provide “limited but important evidence” of the range of levels defining where a primary ozone standard should be set. Despite EPA’s contention that the evidence provided by the Adams studies was “limited,” EPA relied on the studies to recom mend that the primary ozone standard should be set in the range of 0.070 to 0.060 ppm. In fact, the 2007 Staff Paper concluded that the Adams papers “provide evidence of a lowest

- observed effect of 0.060 ppm for potentially adverse lung function decrement s and respiratory symptoms in some healthy adults wile at prolonged moderate exertion.” EPA cited this conclusion numerous times in its proposed reconsideration. T he charge questions EPA poses to CASAC in this regard are at least partially directed to wha t weight the Administrator should ultimately give to the Adams studies.

A number of issues have already been raised by commenters on EPA’s interpretation of the results of the Adam’s studies , two of which are especially relevant. The first issue relates to the response of subjects to ozone at a level of 0.060 ppm. Although Adams observed a group mean FEV 1.0 decrement of 1.5% at the 0.06 ppm level, his paper concluded that this decrement was not statistically different from the mean FEV 1.0 incr ease of 1.5% in those exposed to filter ed air. Based on a reevaluation of the data by Brown using a different statistical method than Adams, EPA concluded to the contrary that a statistically significant group mean decrease in FEV 1.0 occurred at the 0.060 ppm level.Exponent, Inc. February 10, 2011

7 Brown et al. (2008) have now published their reanalyses of the Adams data. The Adams studies were designed as longitudinal studies with repeated measures. As such, that is how they should be analyzed. An appropriate approach would be to us e mixed effects models for longitudinal studies. Neither Adams nor Brown et al. (2008) used this approach. In fact, Brown et al. used only the data points at the end of the study at 6.6 hours after examining the data. A glance at their figure 1 shows that , while there is a clear difference in the response at 0.08 ppm ozone and filtered air over the entire period of the study, this is not true of 0.06 ppm group. For this group only the results at 6.6 hours are significantly different from the filtered air g roup. Brown et al. do not report whether the difference at 5.6 hours reached significance. Because Brown et al. (2008) did not analyze the entire data and because of the post

- hoc nature of their analyses, their result should at best be thought of as a hyp othesis requiring further investigation. In particular, a chamber study in which exposure extends beyond 6.6 hours would be needed to see whether the apparent trend in 0.06 ppm group starting at 5.6 hours continued beyond 6.6 hours.

The second issue revo lves about whether decrem ents ≥ 10 ppm in FEV 1.0 should be considered adverse in the absence of symptoms. Adams found that 7 to 20 % of the subjects experienced
FEV 1.0 decrements ≥ 10 % without accompanying symptoms and concluded that these were adverse, contrary to the Americ an Thoracic Society guidelines that stip ulated that such a response should not be considered adverse.

Numerous comments were submitted in response to EPA’s proposed reconsideration, which among other things questioned the validity of EPA’s interpretation of the Adams’ studies. The comments of the National A ssociation of Manufacturers in particular provid e an extensive review of the relevant scientific issues including a detailed critique of the Brown study show ing that a large number of prominent research ers in the field favored Adams’ met hod of statistical analysis over Brown’ s method of analysis . Yet EPA’ s solicitation memorandum does not discuss any of these contrary comments in its discussion of the charge questions. Admittedly, CASACExponent, Inc. February 10, 2011

8 had the opportun ity to review public comments at the time they were submitted about one
year ago , but a summary of the arguments that were taken opposing the position advocated by EPA would have presented a more balanced view of this important subject. At the very least, if CASAC agrees with EPA’ s on its interpretation of the results of the Adams studies, it is obligated to address in detail the questions raised by commenters, specifically on the validity of the statistical methods used by Brown and on the definition of p ulmonary system adversity that
EPA relied upo n
.

The Gent et al. (2003) , Mortimer et al. (2002) , Schildcrout et al. (200 6 ) and O’Connor et al. (2008 ) studies The Gent et al. (2003) and Mortimer et al. (2002) studies were viewed by EPA as providing substant ial evidence that people with asthma are among those that are at increased risk from
ozone exposure. EPA ignored the results of the Schildcrout (200 6 ) study, which found no associations with ozone. A new study by O’ Connor et al. (2008 ) , cosponsored by EPA, likewise finds no as sociations with ozone.

The Gent et al. (2003) study includes a number of significant limitations. It investigated the association of ambient fine particles and ozone with respiratory symptoms in children with asthma. The study included 271 children (<12 years old) in southern New England. Daily respiratory symptoms and medication use were prospectively recorded over the six

- month study period of April 1, 2001 to September 30, 2001. The authors stratified the subjects into a group of 130 that used maint enance asthma medications during the follow

- up period and 141 who did not use asthma medications. In joint pollutant modeling with PM 2.5 , risks for ozone were elevated and sometimes statistically significant while PM 2.5 risks were generally not elevated a nd not significant. As noted below , Schildcrout et al. (2006) found that the highest risks were attributable to carbon monoxide and nitrogen dioxide, not ozone.

Another limitation of the Gent et al. (2003) study is its treatment of potential meteorologic al confounders. Although limited control for temperature is reported in the paper, relative humidityExponent, Inc. February 10, 2011

9 does not appear to have been controlled. Additionally, it is puzzling that while the results clearly suggest a dose related increase in respiratory sympt oms, there is little indication of increased use of bronchodilators, which would have been expected. In this regard, EPA’s summary of this study in the Staff Paper (p. 3

- 10) is misleading. The Staff Paper states:

“Effects of O 3 , but not PM 2.5 , remained significant and even increased in magnitude in
two

- pollutant models. Some of the associations were noted at 1

- hr max O 3 levels below 60 ppb. In contrast, no effects were observed among asthmatics not using maintenance medication.”

The odds ratios in Tabl e 5 of the Gent et al. study, which show that results for maintenance medication users for wheeze, persistent cough, chest tightness, shortness of breath and bronchodilator use, are quite similar in magnitude to the results in Table 6 for those who did not use maintenance medication. However, the confidence intervals are wider for the later group. Also, only a handful of the odds ratios for maintenance medication users were statistically significant. A more judicious interpretation of these results would be that the odd ratios were similar in magnitude for users and non

- users of maintenance medication, but that the odd ratios were sometimes statistically significant for maintenance medication users. The Staff Paper should be more balanced in its discussio n of these results.

The second study relied on by the Staff Paper was conducted by Mortimer et al. (2002). This study examined the effects of summer air pollution on 846 asthmatic children residing in eight urban areas in the U.S. EPA uses this study not only as evidence that exposure to ozone results in decreased lung function among asthmatics, but also suggests that this study provides evidence of increased symptoms and medication use associated with exposure to ozone. However, ozone was not the only p ollutant associated with health effects. The authors state, “In conclusion, summertime air pollution is associated with increased asthma morbidity and decreased pulmonary function among inner

- city children with asthma in the USA ... Nitrogen dioxide, sulfur dioxide, and particles with a 50% cut

- off aerodynamic diameter of 10 μm were associated with increases in symptoms, with nitrogen dioxide exhibiting the strongest influence. OzoneExponent, Inc. February 10, 2011

10 was most influential in peak expiratory flow rate.” Moreover, the peak ex piratory flow rate (PEFR) results are inconsistent in the study. For an incidence of greater than or equal to a 10% decline in PEFR, the associations for ozone were not significant for 1, 2, and 3

- day lags, but were significant for a 4

- day lag, a result f or which there is no plausible biological explanation. More significantly, when SO 2 , NO 2 , PM 10 , and O 3 were included in multi

- pollutant modeling for morning asthma symptoms, ozone was not elevated (RR=1.00; CI, 0.75

- 1.34). The risks for SO 2 , NO 2 , and PM 10 were not significant; but, in contrast to O 3 , were all elevated. This result contradicts EPA’s conclusion that the ozone effects were “robust” in this study. If the ozone effects vanish in a multi

- pollutant analysis, the ozone effects were, by definitio n, not robust. The Staff Paper should add a discussion of the multi

- pollutant modeling results in Mortimer et al. (2002) and discuss how their results cast doubt on the associations with ozone.

The Schildcrout et al. (2006) study included 990 children in eight North American cities during the pre

- randomization phase of the Childhood Asthma Management Program (CAMP). The authors evaluated associations with CO, NO 2 , PM 10 , SO 2 , and warm season O 3 during the period November 1993

– September 1995. The cities consisted of Albuquerque, NM; Baltimore, MD; Boston, MA; Denver, CO; San Diego, CA; Seattle, WA; St. Louis, MO; and Toronto, Canada. Many of these cities would have likely exceeded the current O 3 standard, particularly back in the early to mid

- 1990s. Th e endpoints in the study included asthma symptoms and rescue inhaler uses. The authors concluded: “Lags in carbon monoxide and nitrogen dioxide were positively associated with both measures of asthma exacerbation, and the 3

- day moving sum of sulfur dioxid e levels was marginally related to asthma symptoms. PM 10 and ozone were unrelated to exacerbations.” The results were particularly clear for rescue inhaler uses. For ozone, the relative risks ranged from 0.99

- 1.01 depending on the lag and none were clos e to statistical significance. However, the relative risks were 1.06 (1.01

- 1.10) and 1.04 (1.01

- 1.07) for CO for a 2

- day lag and a 3

- day moving average lag, respectively. They were 1.05 (1.01

- 1.09) and 1.03 (1.01

- 1.05) for NO 2 for a 2

- day lag and a 3

- day moving average lag, respectively.

The O’Connor et al. (2008) study examined the association between air pollutants and pulmonary functions ( specifically FEV 1 and PEFR ) and asthma symptoms among 861 inner

- cityExponent, Inc. February 10, 2011

11 children with “persistent asthma .” They report their results thus, “In si ngle

- pollutant models, higher 5

- day average concentrations of NO 2 , sulfur dioxide, and particles smaller than 2.5 μm were associated with significantly lower pulmonary function. Higher pollutant levels were independently associated with reduced lung funct ion in a 3

- pollutant model. Higher concentrations of NO 2 and particles smaller than 2.5 μm were associated with asthma

- related missed school days, and higher NO 2 concentrations were associated with asthma symptoms. ” Most relevant, no associations with ozone were reported.

Taken together, the longitudinal studie s evaluating asthma effects are inconsistent and not robust. There were assoc iations with ozone in the Gent et al. and the Mortimer et al. studies but not the Schildcrout et al. and O’Connor studies using single

- pollutant models. For the Mortimer et al. (2002) study, the association of ozone with the incidence of morning asthma symptoms disappeared in multi

- pollutant modeling. Across the studies, there were associations of asthma

related variables with SO 2 , NO 2 , particles and CO for different endpoints, but these associations were inconsistent, as they were with ozone. Therefore, these studies do not provide a clear picture of how air pollution affects asthmatics and which pollutants are responsible.

Other epidemiological evidence Other substantial epid emiological studies of the health impacts of ambient ozone have appeared as well after 2006 that are highly relevant to the setting of an ozone standard. In particular there are two comprehensive time

- series studies by Smith et al. (2009) and Katsouyanni e t al. (2009) that should certainly be considered in the setting of revised standards. For example, in a reanalysis of the NMMAPS data, Smith et al. (2009) reported strong effect modification of the short

- term impact of ozone on mortality by a number of fac tors. This finding raises questions regarding the estimation of a national effect estimate for ozone in the
US. The Katsouyanni et al. (2009) study reported that the association of ozone with mortality in NMMAPS was sensitive to the model used, particula rly the degrees of freedom used for smoothing of trends and the inclusion of co

- pollutants.Exponent, Inc. February 10, 2011

12 Conclusions

EPA has already proposed to replace the current primary ozone standard of 0. 0 75 ppm w ith a standard in the range of 0.060 to 0.070 ppm

. Rather than asking CASA C to provide advice on whether this range is supported by the available scientific literature , EPA appears to be looking to CASAC to support a decision that EPA has already made. The nature of the charge questions is inappropriate given CASAC’ s mandate to provide technical guidance only. Moreover, CASAC is being asked to provide fresh insight on matters in which its stance has been made very clear since 2006. Finally, EPA’s placement of restrictions on the n ew information that can be consider ed threatens to result in the setting of an ozone NAAQS that has limited scientific validity.Exponent, Inc. February 10, 2011

13 References

Adams (2002). Comparison of chamber and face

- mask 6.6

- hour exposures to ozone on pulmonary function and symptoms responses. Inhal Tox14:745

- 764.

Ada ms (2006). Comparison of chamber 6.6

- hour exposure to 0.04

- 0.08 ppm ozone via square
wave and triangular profiles on pulmonary responses. Inhal Tox 18:127

- 136.

Brown et al . (2008). Effects of exposure to 0.06 ppm o zone on FEV 1 in h umans: a secondary anal ysis of existing d ata . Environ Health Perspect 116: 1023

- 1026.
EPA, Air Quality Criteria Document for Ozone and Related Photochemical Oxidants , EPA/600/R

05/004cF, Feb . 2006.
EPA, Review of the National Ambient Air Quality Standards for Ozone: Policy Ass essment of Scientific and Technical Information , OAQPS Staff Paper

- Second Draft, EPA

- 452/D

- 05

- 002, July 2006.

Gent et al . (2003). Association of low level ozone and fine particles with respiratory symptoms in children with asthma. JAMA 290:1859

- 1867.

K atsouyanni et al. (2009). Air Pollution and Health: P A European and North American Approach (APHENA). Research Report 142, Health Effects Institute.

Mortimer et al. (2002). The effect of air pollution on inner

- city children with asthma. Eur Respir J. 19 :699

- 705.

O’Conn or G. et al. (2008). Acute respiratory health effects of air pollution on children with asthma in US inner cities. J. Allergy Clin Immunol 121:1133

- 9.

Schildcrout et al . (2006). Ambient air pollution and asthma exacerbations in children: an eight

- city analysis. Am. J. Epid. 164: 505

- 17.

Smith et al. (2009). Reassessing the relationship between ozone and short

- term mortality in U.S. urban communities . Inhal Tox: 29(S2): 37

- 61.