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16454 Federal Register / Vol. 73, No. 60 / Thursday, March 27, 2008 / Rules and Regulations 

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 O3 

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 reached 

statistical 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 FEV1. 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 FEV1 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 FEV1 following 

exposure to 0.060 ppm O3 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 

FEV1 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 O3-

related lung function and respiratory 

symptom responses at the 0.060 and 

0.040 ppm 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 FEV1 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 

O3-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 FEV1 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 

FEV1 decrements in Adams subjects 

when exposed to an O3 concentration of 

0.080 ppm 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 FEV1 (≥ 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 O3 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 O3 standard to reach the 

conclusion that there is no basis for 

revising that standard. They stated that 

the data from Adams (2002, 2006) on O3 

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 O3 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’s 

re-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 FEV1 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 

≥ 10 percent, which is the most 

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Federal Register / Vol. 73, No. 60 / Thursday, March 27, 2008 / Rules and Regulations 16455 

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 

0.060 ppm O3 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 whether 

the 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 FEV1 

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 O3 Criteria 

Document and O3 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 O3 Criteria Document and 

another letter for the O3 Staff Paper 

(Henderson, 2006c) indicating that these 

documents provided an appropriate 

basis for use in regulatory decision 

making regarding the O3 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 O3 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 O3 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 O3 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 

O3 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