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i. Evidence from Controlled Human Exposure Studies

As noted in the overview of health effects evidence, section II.A.2 above, two new controlled human-exposure studies (Adams 2002, 2006) are now available that examine respiratory effects associated with prolonged O 3 exposures at levels at and below 0.080 ppm, which was the lowest exposure
level that had been examined in the last review. One group of commenters that included national medical (e.g., ATS, AMA, ACCP) and national environmental and public health organizations (e.g., ALA in a joint set of comments with Environmental Defense, Sierra Club), agreed with EPA ’ s reanalysis of the Adams ’data while disagreeing with EPA ’ s characterization
of the evidence from the Adams studies

as ‘‘ very limited ’’(72 FR 37870). These commenters expressed the view that the Adams studies provide evidence of
effects at lower concentrations than had previously been reported. They noted that Adams, while finding small group mean changes at 0.060 ppm, reported total subjective symptom scores reachedstatistical significance (relative to preexposure) at 5.6 and 6.6 hours, with the triangular exposure scenario, and that pain on deep inspiration values followed a similar pattern to total subjective symptoms scores. In addition, Adams (2002) reports that ‘‘ some sensitive subjects experience notable effects at 0.060 ppm, ’’based on a greater than 10% reduction in FEV 1 . These commenters made the point that the responses of individuals are more important than group mean responses and that when the Adams (2002, 2006) study data are corrected for the effects of exercise in clean air, 7 percent of subjects experience FEV 1 decrements greater than 10% at the 0.040 and 0.060 ppm exposure levels. They expressed
the view that while 2 of 30 tested subjects responding at the 0.060 ppm level may seem like a small number, a 7 percent response rate is far from trivial. Seven percent of the U.S. population is 21.2 million people (ALA
et al. , p. 51). Noting that the subjects in
the Adams ’studies were all healthy adults, these groups expressed concern
that ‘‘ in some vulnerable populations the magnitude of the response would be greater and the exposure level at which responses are observed to occur would
be lower ’’(ATS, p. 4).

These commenters generally supported EPA ’ s reanalysis of the
Adams ’data, stating that EPA has undertaken a careful reanalysis of the underlying data in the Adams studies to assess the change in FEV 1 following exposure to 0.060 ppm O 3 and filtered air, and concluding that ‘‘ the reanalysis employs the standard approach used by other researchers, and supported by

CASAC ’’ (ALA et al. , p. 49), and ‘‘ we believe that the Adams study shows significant health effects at 0.06 ppm exposure levels ’’(ATS, p. 5). The American Thoracic Society, AMA and other medical organizations conclude:

The Adams study confirms our understanding that in healthy populations, an important fraction of the population will experience larger-than-average decrements in

FEV 1 when exposed to low levels of ozone.
It is reasonable to assume that these effects would be even greater when extrapolated to other populations known to have sensitivities to ozone (children, asthmatics, COPD patients). We feel the correct conclusion to draw from the Adams study is that there is a significant fraction of the population that will express significant responses to low levels of ozone. [ATS, p. 5]

EPA generally agrees with most of the comments summarized above, while placing more emphasis on the limited nature of the evidence addressing O 3 - related lung function and respiratory symptom responses at the 0.060 and

0.040ppm exposure levels. As characterized in the proposal notice,

EPA ’ s reanalysis of the data from the most recent Adams study shows small group mean decrements in lung function responses to be statistically significant at the 0.060 ppm exposure level, while acknowledging that the
author ’ s analysis did not yield statistically significant lung function responses. The Adams studies report a small percentage of subjects experiencing lung function decrements (≥ 10 percent) at the 0.060 ppm exposure level. EPA disagrees with these commenters that the percent of subjects that experienced FEV 1 decrements greater than 10% in this study of 30 subjects can appropriately be generalized to the U.S. population. The
Administrator concludes that these studies provide very limited evidence of

O 3 -related lung function decrements and respiratory symptoms at this lower exposure level.

The second group of commenters, who opposed revision of the standard, raised many concerns about the role of
the Adams studies and EPA ’ s reanalysis
of the Adams data in the decision. With regard to the results reported by Adams, these commenters expressed the view that the group mean FEV 1 decrement measured at 0.060 ppm was small, less than 3%, which is within the 3 to 5% range of normal measurement variability for an individual (UARG, p. 12). Moreover even the reported group mean

FEV 1 decrements in Adams subjects when exposed to an O 3 concentration of

0.080ppm were described as quite minimal, likely non-detectable by the subjects and within the range that the
EPA would consider to be normal or mild (UARG, p. 13); With respect to the larger decrements in FEV 1 (≥ 10%) experienced by some subjects in the Adams studies, these commenters stated
the view that such decrements would not be considered adverse in healthy individuals, and that ‘‘ reliance on the individual responses of such a miniscule number of subjects (2 of 30) is woefully inadequate as any basis for
a nationwide O 3 standard ’’ (UARG, p.14). Some of these commenters put the results of the Adams studies (2002, 2006) in the context of the 1997
decision on the O 3 standard to reach the
conclusion that there is no basis for revising that standard. They stated that the data from Adams (2002, 2006) on O 3 levels below 0.080 ppm was too limited to support a revised standard, and noted that responses reported in the Adams studies at 0.080 ppm were similar to responses reported previously (Horstmann et al. , 1990 and McDonnell
et al. , 1991), and therefore, provided no
new information on O 3 that was not
known at the time of EPA ’ s last review (Exxon Mobil, pp. 5

–6).

These commenters raised one or more of the following concerns about EPA ’ s reanalysis of the Adams data: (1) EPA ’ sre-analysis was not published or peerreviewed, and therefore neither the scientific community nor the public was afforded opportunity to appropriately review the analysis (Exxon Mobil, p. 6); (2)EPA has misinterpreted the studies of Dr. Adams, and over his objections used a different analytical methodology to reach a different conclusion; (3)

EPA ’ s reanalysis did not employ an appropriate statistical test; the ANOVA statistical test employed by Adams was preferred over the statistical test used in

EPA ’ s reanalysis (paired t-test); and (4) the reanalysis of the Adams data is evidence that EPA interpreted and presented scientific information in a systematically biased manner, reflecting purposeful bias because the reanalysis supported staff policy recommendations
and Adams ’own analysis did not, and the 10% decrement in FEV 1 was a posthoc threshold chosen for compatibility with EPA staff policy recommendations (NAM, p. 19).

First, EPA agrees that the group mean lung function decrement observed in the Adams study at the 0.060 ppm exposure level is relatively small. However, EPA
and the CASAC Panel observed that the study showed some individuals experienced lung function decrements

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important finding from this study in terms of public health implications. The magnitude of changes in the group mean
do not address whether a subset of the population is at risk of health effects.
The clinical evidence to date makes it clear that there is significant variability in responses across individuals, so it is important to look beyond group mean to the response of subsets of the group to evaluate the potential impact for sensitive or susceptible parts of the population. The Administrator also agrees with both EPA staff and CASAC ’ s views that this level of response may not represent an adverse health effect in healthy individuals but does represent a
level that should be considered adverse
for asthmatic individuals.

Second, EPA notes that its reanalysis of the Adams (2006) study was prepared in response to the issues and analysis raised by a public commenter who made a presentation to the CASAC Panel at its March 5, 2007 teleconference. EPA replicated the analysis and addressed issues raised in these public comments concerning the statistical significance of

0.060ppm O 3 exposure on lung function response in the Adams (2006) publication. EPA documented its response in a technical memorandum (Brown, 2007), which was placed in the rulemaking docket prior to publication of the proposal. EPA has clearly stated that the additional statistical analyses conducted by both the public commenter and by EPA staff do not
contradict or undercut the statistical analysis presented by Dr. Adams in his published study, as EPA and the author were addressing different questions. While the author of the original study was focused on determining whetherthe changes observed on an hour-byhour basis were statistically significant for different exposure protocols, EPA ’ s reanalysis was focused on the different question of whether there was a statistically significant difference in lung function decrement before and after the entire 6.6 hour exposure period between the 0.060 ppm exposure protocol and filtered air.

Third, with respect to the concerns raised by Dr. Adams and other
commenters that EPA had used an inappropriate statistical approach to address the question regarding statistical significance of the average lung function response at 0.060 ppm,
members of the CASAC Panel noted on the March 5, 2007 teleconference the very conservative nature of the approach used by Adams to evaluate the research questions posed by the author.
These same CASAC Panel members also supported the use of the statistical approach (i.e., paired-t test) used in the analysis prepared by the public commenter, which was the same approach later used in EPA ’ s reanalysis, as the preferred method for analyzing the pre-minus post-exposure lung function responses reported in this study. EPA agrees with the characterization of the Adams (2006) study in the Rochester Report, which stated, ‘‘ Although these findings have not been confirmed or replicated, the responses to 0.06 ppm ozone in this [Adams] study are consistent with the presence of an exposure-response curve with responses that do not end abruptly below 0.08 ppm. ’’This same report also concluded,

The statistical test used in Adams (2006) did not identify the response of the 0.06 ppm exposure as statistically different from that of the filtered air exposure. However, alternative statistical tests suggest that the observed small group mean response in FEV 1 induced by exposure to 0.06 ppm compared
to filtered air is not the result of chance alone. [Rochester Report, p. 56].

Fourth, EPA rejects the contention that the conduct and presentation of its reanalysis of the Adams (2006) study to address issues raised by public commenters represents purposeful bias and was developed only to support a pre-determined policy position. As discussed above, EPA ’ s reanalysis addressed a different question than the
author ’ s analysis contained in the publication. Other controlled human exposure studies had routinely examined the same question EPA ’ s reanalysis addressed, whether or not there was a statistically significant group mean response for the entire exposure period compared to filtered

air.

ii Evidence from Epidemiological
Studies

This section contains major comments

on EPA ’ s assessment of epidemiological studies in the proposal and the Agency ’ s general responses to those comments. Many of the issues discussed below are
addressed in more detail in the Response to Comments document.

Comments on EPA ’ s interpretation and assessment of the body of epidemiological evidence are discussed
first and then comments on methodological issues and particular study designs are discussed. EPA notes
here that most of the issues and concerns raised by commenters on the interpretation of the epidemiological evidence and methodological issues are essentially restatements of issues raised during the review of the Criteria Document and Staff Paper. EPA presented and the CASAC Panel reviewed the interpretation of the epidemiological evidence in the Criteria Document and the integration of the evidence with policy considerations in the development of the policy options presented in the Staff Paper for consideration by the Administrator.
CASAC reviewed both the O 3 Criteria
Document and O 3 Staff Paper and approved of the scientific content and accuracy of both documents. The
CASAC chairman sent to the Administrator one letter (Henderson, 2006a) for the O 3 Criteria Document and
another letter for the O 3 Staff Paper (Henderson, 2006c) indicating that these documents provided an appropriate basis for use in regulatory decision making regarding the O 3 NAAQS.

As with evidence from controlled human exposure studies, sharply divergent comments were received on the evidence from epidemiological studies, including EPA ’ s interpretation of the evidence. One group of commenters from medical, public health and environmental organizations, in general, supported EPA ’ s interpretation of the epidemiological evidence (72 FR 37838, section II.a.3.a

–c) with regard to
whether the evidence for associations is
consistent and coherent and whether there is biological plausibility for judging whether exposure to O 3 is causally related to respiratory and cardiovascular morbidity and mortality effects. Comments of public health and environmental groups, including a joint
set of comments from ALA and several environmental groups, note that more than 250 new epidemiological studies, published from 1996 to 2005, were
included in the Criteria Document and point to a figure from the Staff Paper and proposal (72 FR 37842, Figure 1) of
short-term O 3 exposures and respiratory health outcome showing consistency in an array of positive effects estimates and health endpoints observed in multiple
locations in Canada and the U.S. Medical commenters, including ATS and AMA, stated that these ‘‘ real world ’’ studies support the findings of chamber studies to show adverse respiratory
health effects at levels below the current
8-hour O 3 standard. These commenters generally expressed agreement with the weight of evidence approach taken by
the Criteria Document and the conclusions reached, which were reviewed by CASAC, that the effects of

O 3 on respiratory symptoms, lung function changes, emergency department visits for respiratory and cardiovascular effects, and hospital
admissions can be considered causal.

EPA generally agrees with this interpretation of the epidemiological
evidence. The Criteria Document concludes that positive and robust