respiratory health outcomes. Limited evidence from recent long-term
morbidity studies have suggested in some cases that chronic exposure to
O3 may be associated with seasonal declines in lung function
or reduced lung function development, increases in inflammation, and
development of asthma in children and adults. Seasonal decrements or
smaller increases in lung function measures have been reported in
several studies; however, the extent to which these changes are
transient remains uncertain. While there is supportive evidence from
animal studies involving effects from chronic exposures, large
uncertainties still remain as to whether current ambient levels and
exposure patterns might cause these same effects in human populations.
The Criteria Document concludes that epidemiological studies of new
asthma development and longer-term lung function declines remain
inconclusive at present (EPA, 2006a, p. 7-134).
iii. Effects on the Cardiovascular System of O3 Exposure
    At the time of the 1997 review, the possibility of O3-
induced cardiovascular effects was largely unrecognized. Since then, a
very limited body of evidence from animal, controlled human exposure
and epidemiologic studies has emerged that provides evidence for some
potential plausible mechanisms for how O3 exposures might
exert cardiovascular system effects, however much needs to be done to
substantiate these potential mechanisms. Possible mechanisms may
involve O3-induced secretions of vasoconstrictive substances
and/or effects on neuronal reflexes that may result in increased
arterial blood pressure and/or altered electrophysiologic control of
heart rate or rhythm. Some animal toxicology studies have shown
O3-induced decreases in heart rate, mean arterial pressure,
and core temperature. One controlled human exposure study that
evaluated effects of O3 exposure on cardiovascular health
outcomes found no significant O3-induced differences in ECG
or blood pressure in healthy or hypertensive subjects but did observe a
significant O3-induced increase the alveolar-to-arterial
PO2 gradient and heart rate in both groups resulting in an
overall increase in myocardial work and impairment in pulmonary gas
exchange (Gong et al., 1998). In another controlled human exposure
study, inhalation of a mixture of PM2.5 and O3 by
healthy subjects increased brachial artery vasoconstriction and
reactivity (Brook et al., 2002).
    The evidence from a few animal studies also includes potential
direct effects such as O3-induced release from lung
epithelial cells of platelet activating factor (PAF) that may
contribute to blood clot formation that would have the potential to
increase the risk of serious cardiovascular outcomes (e.g., heart
attack, stroke, mortality). Also, interactions of O3 with
surfactant components in epithelial lining fluid of the lung may result
in production of oxysterols and reactive oxygen species that may
exhibit PAF-like activity contributing to clotting and also may exert
cytotoxic effects on lung and heart muscle cells.
    Epidemiologic panel and field studies that examined associations
between O3 and various cardiac physiologic endpoints have
yielded limited evidence suggestive of a potential association between
acute O3 exposure and altered heart rate variability,
ventricular arrhythmias, and incidence of heart attacks. A number of
epidemiological studies have also reported associations between short-
term exposures and hospitalization for cardiovascular diseases. As
shown in Figure 7-13 of the Criteria Document, many of the studies
reported negative or inconsistent associations. Some other studies,
especially those that examined the relationship when O3
exposures were higher, have found robust positive associations between
O3 and cardiovascular hospital admissions (EPA, 2006a, p. 7-
82). For example, one study reported a positive association between
O3 and cardiovascular hospital admissions in Toronto, Canada
in a summer-only analysis (Burnett et al.,

1997b). The results were robust to adjustment for various PM indices,
whereas the PM effects diminished when adjusting for gaseous
pollutants. Other studies stratified their analysis by temperature,
i.e., by warm days versus cool days. Several analyses using warm season
days consistently produced positive associations.
    The epidemiologic evidence for cardiovascular morbidity is much
weaker than for respiratory morbidity, with only one of several U.S./
Canadian studies showing statistically significant positive
associations of cardiovascular hospitalizations with warm-season
O3 concentrations. Most of the available European and
Australian studies, all of which conducted all-year O3
analyses, did not find an association between short-term O3
concentrations and cardiovascular hospitalizations. Overall, the
currently available evidence is inconclusive regarding an association
between cardiovascular hospital admissions and ambient O3
exposure (EPA, 2006a, p. 7-83).
    In summary, based on the evidence from animal toxicology, human
controlled exposure, and epidemiologic studies, from the Criteria
Document concludes that this generally limited body of evidence is
suggestive that O3 can directly and/or indirectly contribute
to cardiovascular-related morbidity, but that much needs to be done to
more fully integrate links between ambient O3 exposures and
adverse cardiovascular outcomes (EPA, 2006a, p. 8-77).
b. Mortality
i. Mortality and Short-Term O3 Exposure
    The 1996 Criteria Document concluded that an association between
daily mortality and O3 concentration for areas with high
O3 levels (e.g., Los Angeles) was suggested. However, due to
a very limited number of studies available at that time, there was
insufficient evidence to conclude that the observed association was
likely causal.
    The current Criteria Document includes results from numerous
epidemiological analyses of the relationship between O3 and
mortality. Additional single city analyses have also been conducted
since 1996, however, the most pivotal studies in EPA's (and CASAC's)
finding of increased support for the relationship between premature
mortality and O3 is in part related to differences in study
design--limiting analyses to warm seasons, better control for
copollutants, particularly PM, and use of multicity designs (both time
series and meta-analytic designs). Key findings are available from
multi-city time-series studies that report associations between
O3 and mortality. These studies include analyses using data
from 90 U.S. cities in the National Mortality, Morbidity and Air
Pollution (NMMAPS) study (Dominici et al., 2003) and from 95 U.S.
communities in an extension to the NMMAPS analyses (Bell et al., 2004).
    The original 90-city NMMAPS analysis, with data from 1987 to 1994,
was primarily focused on investigating effects of PM10 on
mortality. A significant association was reported between mortality and
24-hour average O3 concentrations in analyses using all
available data as well as in the warm season only analyses (Dominici et
al., 2003). The estimate using all available data was about half that
for the summer-only data at a lag of 1-day. The extended NMMAPS
analysis included data from 95 U.S. cities and included an additional 6
years of data, from 1987-2000 (Bell et al., 2004). Significant
associations were reported between O3 and mortality in
analyses using all available data. The effect estimate for increased
mortality was approximately 0.5 percent per 0.020 ppm change in 24-hour
average O3 measured on the same day, and approximately 1.04
percent per 0.020 ppm change in 24-hour average O3 in a 7-
day distributed lag model (EPA, 2006a, p. 7-88). In analyses using only
data from the warm season, the results were not significantly different
from the full-year results. The authors also report that O3-
mortality associations were robust to adjustment for PM (EPA, 2006a, p.
7-100). Using a subset of the NMMAPS data set, Huang et al. (2005)
focused on associations between cardiopulmonary mortality and
O3 exposure (24-hour average) during the summer season only.
The authors report an approximate 1.47 percent increase per 0.020 ppm
change in O3 concentration measured on the same day and an
approximate 2.52 percent increase per 0.020 ppm change in O3
concentration using a 7-day distributed lag model. These findings
suggest that the effect of O3 on mortality is immediate but
also persists for several days.
    As discussed below in section II.A.3.a, confounding by weather,
especially temperature, is complicated by the fact that higher
temperatures are associated with the increased photochemical activities
that are important for O3 formation. Using a case-crossover
study design, Schwartz (2005) assessed associations between daily
maximum concentrations and mortality, matching case and control periods
by temperature, and using data only from the warm season. The reported
effect estimate of approximately 0.92 percent change in mortality per
0.040 ppm O3 (1-hour maximum) was similar to time-series
analysis results with adjustment for temperature (approximately 0.76
percent per 0.040 ppm O3), suggesting that associations
between O3 and mortality were robust to the different
adjustment methods for temperature.
    An initial publication from APHEA, a European multi-city study,
reported statistically significant associations between daily maximum
O3 concentrations and mortality in four cities in a full
year analysis (Toulomi et al., 1997). An extended analysis was done
using data from 23 cities throughout Europe (Gryparis et al., 2004). In
this report, a positive but not statistically significant association
was found between mortality and 1-hour daily maximum O3 in a
full year analysis. Gryparis et al. (2004) noted that there was a
considerable seasonal difference in the O3 effect on
mortality; thus, the small effect for the all-year data might be
attributable to inadequate adjustment for confounding by seasonality.
Focusing on analyses using summer measurements, the authors report
statistically significant associations with total mortality,
cardiovascular mortality and with respiratory mortality (EPA, 2006a, p.
7-93, 7-99).
    Numerous single-city analyses have also reported associations
between mortality and short-term O3 exposure, especially for
those analyses using warm season data. As shown in Figure 7-21 of the
Criteria Document, the results of recent publications show a pattern of
positive, often statistically significant associations between short-
term O3 exposure and mortality during the warm season. In
considering results from year-round analyses, there remains a pattern
of positive results but the findings are less consistent. In most
single-city analyses, effect estimates were not substantially changed
with adjustment for PM (EPA, 2006a, Figure 7-22).
    In addition, several meta-analyses have been conducted on the
relationship between O3 and mortality. As described in
section 7.4.4 of the Criteria Document, these analyses reported fairly
consistent and positive combined effect estimates ranging from
approximately 1.5 to 2.5 percent increase in mortality for a
standardized change in O3 (EPA, 2006a, Figure 7-20). Three
recent meta-analyses evaluated potential sources of heterogeneity in
O3-mortality associations (Bell et al., 2005; Ito et al.,
2005; Levy et al., 2005). The

Criteria Document (p. 7-96) observes common findings across all three
analyses, in that all reported that effect estimates were larger in
warm season analyses, reanalysis of results using default convergence
criteria in generalized additive models (GAM) did not change the effect
estimates, and there was no strong evidence of confounding by PM. Bell
et al. (2005) and Ito et al. (2005) both provided suggestive evidence
of publication bias, but O3-mortality associations remained
after accounting for that potential bias. The Criteria Document
concludes that the ``positive O3 effects estimates, along
with the sensitivity analyses in these three meta-analyses, provide
evidence of a robust association between ambient O3 and
mortality'' (EPA, 2006a, p. 7-97).
    Most of the single-pollutant model estimates from single-city
studies range from 0.5 to 5 percent excess deaths per standardized
increments. Corresponding summary estimates in large U.S. multi-city
studies ranged between 0.5 to 1 percent with some studies noting
heterogeneity across cities and studies (EPA, 2006a, p. 7-110).
    Finally, from those studies that included assessment of
associations with specific causes of death, it appears that effect
estimates for associations with cardiovascular mortality are larger
than those for total mortality. The meta-analysis by Bell et al. (2005)
observed a slightly larger effect estimate for cardiovascular mortality
compared to mortality from all causes. The effect estimate for
respiratory mortality was approximately one-half that of cardiovascular
mortality in the meta-analysis. However, other studies have observed
larger effect estimates for respiratory mortality compared to
cardiovascular mortality. The apparent inconsistency regarding the
effect size of O3-related respiratory mortality may be due
to reduced statistical power in this subcategory of mortality (EPA,
2006a, p. 7-108).
    In summary, many single- and multi-city studies observed positive
associations of ambient O3 concentrations with total
nonaccidental and cardiopulmonary mortality. The Criteria Document
finds that the results from U.S. multi-city time-series studies provide
the strongest evidence to date for O3 effects on acute
mortality. Recent meta-analyses also indicate positive risk estimates
that are unlikely to be confounded by PM; however, future work is
needed to better understand the influence of model specifications on
the risk coefficient (EPA, 2006a, p. 7-175). A meta-analysis that
examined specific causes of mortality found that the cardiovascular
mortality risk estimates were higher than those for total mortality.
For cardiovascular mortality, the Criteria Document (Figure 7-25, p. 7-
106) suggests that effect estimates are consistently positive and more
likely to be larger and statistically significant in warm season
analyses. The findings regarding the effect size for respiratory
mortality have been less consistent, possibly because of lower
statistical power in this subcategory of mortality. The Criteria
Document (p. 8-78) concludes that these findings are highly suggestive
that short-term O3 exposure directly or indirectly
contribute to non-accidental and cardiopulmonary-related mortality, but
additional research is needed to more fully establish underlying
mechanisms by which such effects occur.\19\
---------------------------------------------------------------------------

    \19\ In commenting on the Criteria Document, the CASAC Ozone
Panel raised questions about the implications of these time-series
results in a policy context, emphasizing that ``* * * while the
time-series study design is a powerful tool to detect very small
effects that could not be detected using other designs, it is also a
blunt tool'' (Henderson, 2006b). They note that ``* * * not only is
the interpretation of these associations complicated by the fact
that the day-to-day variation in concentrations of these pollutants
is, to a varying degree, determined by meteorology, the pollutants
are often part of a large and highly correlated mix of pollutants,
only a very few of which are measured'' (Henderson, 2006b). Even
with these uncertainties, the CASAC Ozone Panel, in its review of
the Staff Paper, found ``* * * premature total non-accidental and
cardiorespiratory mortality for inclusion in the quantitative risk
assessment to be appropriate.'' (Henderson, 2006b).
---------------------------------------------------------------------------

ii. Mortality and Long-Term O3 Exposure
    Little evidence was available in the last review on the potential
for associations between mortality and long-term exposure to
O3. In the Harvard Six City prospective cohort analysis, the
authors report that mortality was not associated with long-term
exposure to O3 (Dockery et al., 1993). The authors note that
the range of O3 concentrations across the six cities was
small, which may have limited the power of the study to detect
associations between mortality and O3 levels (EPA, 2006a, p.
7-127).
    As discussed in section 7.5.8 of the Criteria Document, in this
review there are results available from three prospective cohort
studies: the American Cancer Society (ACS) study (Pope et al., 2002),
the Adventist Health and Smog (AHSMOG) study (Beeson et al., 1998;
Abbey et al., 1999), and the U.S. Veterans Cohort study (Lipfert et
al., 2000, 2003). In addition, a major reanalysis report includes
evaluation of data from the Harvard Six City cohort study (Krewski et
al., 2000).\20\ This reanalysis also includes additional evaluation of
data from the initial ACS cohort study report that had only reported
results of associations between mortality and long-term exposure to
fine particles and sulfates (Pope et al., 1995). This reanalysis was
discussed in the Staff Paper (section <IP_ADDRESS>) but not in the Criteria
Document.
---------------------------------------------------------------------------

    \20\ This reanalysis report and the original prospective cohort
study findings are discussed in more detail in section 8.2.3 of the
Air Quality Criteria for Particulate Matter (EPA, 2004).
---------------------------------------------------------------------------

    In this reanalysis of data from the previous Harvard Six City
prospective cohort study, the investigators replicated and validated
the findings of the original studies, and the report included
additional quantitative results beyond those available in the original
report (Krewski et al., 2000). In the reanalysis of data from the
Harvard Six Cities study, the effect estimate for the association
between long-term O3 concentrations and mortality was
negative and nearly statistically significant (relative risk = 0.87, 95
percent CI: 0.76, 1.00).
    The ACS study is based on health data from a large prospective
cohort of approximately 500,000 adults and air quality data from about
150 U.S. cities. The initial report (Pope et al., 1995) focused on
associations with fine particles and sulfates, for which significant
associations had been reported in the earlier Harvard Six Cities study
(Dockery et al., 1993). As part of the major reanalysis of these data,
results for associations with other air pollutants were also reported,
and the authors report that no significant associations were found
between O3 and all-cause mortality. However, a significant
association was reported for cardiopulmonary mortality in the warm
season (Krewski et al., 2000). The ACS II study (Pope et al., 2002)
reported results of associations with an extended data base; the
mortality records for the cohort had been updated to include 16 years
of follow-up (compared with 8 years in the first report) and more
recent air quality data were included in the analyses. Similar to the
earlier reanalysis, a marginally significant association was observed
between long-term exposure to O3 and cardiopulmonary
mortality in the warm season. No other associations with mortality were
observed in both the full-year and warm season analyses.
    The Adventist Health and Smog (AHSMOG) cohort includes about 6,000
adults living in California. In two studies from this cohort, a
significant association has been reported between long-term
O3 exposure and increased risk of lung cancer mortality
among males only (Beeson et al., 1998; Abbey

et al., 1999). No significant associations were reported between long-
term O3 exposure and mortality from all causes or
cardiopulmonary causes. Due to the small numbers of lung cancer deaths
(12 for males, 18 for females) and the precision of the effect estimate
(i.e., the wide confidence intervals), the Criteria Document discussed
concerns about the plausibility of the reported association with lung
cancer (EPA, 2006a, p. 7-130).
    The U.S. Veterans Cohort study (Lipfert et al., 2000, 2003) of
approximately 50,000 middle-aged males diagnosed with hypertension,
reported some positive associations between mortality and peak
O3 exposures (95th percentile level for several years of
data). The study included numerous analyses using subsets of exposure
and mortality follow-up periods which spanned the years 1960 to 1996.
In the results of analyses using deaths and O3 exposure
estimates concurrently across the study period, there were positive,
statistically significant associations between peak O3 and
mortality (EPA, 2006a, p. 7-129).
    Overall, the Criteria Document concludes that consistent
associations have not been reported between long-term O3
exposure and all-cause, cardiopulmonary or lung cancer mortality (EPA,
2006a, p. 7-130).
c. Role of Ground-Level O3 in Solar Radiation-Related Human
Health Effects
    Beyond the direct health effects attributable to inhalation
exposure to O3 in the ambient air discussed above, the
Criteria Document also assesses potential indirect effects related to
the presence of O3 in the ambient air by considering the
role of ground-level O3 in mediating human health effects
that may be directly attributable to exposure to solar ultraviolet
radiation (UV-B). The Criteria Document (chapter 10) focuses this
assessment on three key factors, including those factors that govern
(1) UV-B radiation flux at the earth's surface, (2) human exposure to
UV-B radiation, and (3) human health effects due to UV-B radiation. In
so doing, the Criteria Document provides a thorough analysis of the
current understanding of the relationship between reducing ground-level
O3 concentrations and the potential impact these reductions
might have on increasing UV-B surface fluxes and indirectly
contributing to UV-B related health effects.
    There are many factors that influence UV-B radiation penetration to
the earth's surface, including latitude, altitude, cloud cover, surface
albedo, PM concentration and composition, and gas phase pollution. Of
these, only latitude and altitude can be defined with small uncertainty
in any effort to assess the changes in UV-B flux that may be
attributable to any changes in tropospheric O3 as a result
of any revision to the O3 NAAQS. Such an assessment of UV-B
related health effects would also need to take into account human
habits, such as outdoor activities (including age- and occupation-
related exposure patterns), dress and skin care to adequately estimate
UV-B exposure levels. However, little is known about the impact of
these factors on individual exposure to UV-B.
    Moreover, detailed information does not exist regarding other
factors that are relevant to assessing changes in disease incidence,
including: Type (e.g., peak or cumulative) and time period (e.g.,
childhood, lifetime, current) of exposures related to various adverse
health outcomes (e.g., damage to the skin, including skin cancer;
damage to the eye, such as cataracts; and immune system suppression);
wavelength dependency of biological responses; and interindividual
variability in UV-B resistance to such health outcomes. Beyond these
well recognized adverse health effects associated with various
wavelengths of UV radiation, the Criteria Document (section <IP_ADDRESS>)
also discusses protective effects of UV-B radiation. Recent reports
indicate the necessity of UV-B in producing vitamin D, and that vitamin
D deficiency can cause metabolic bone disease among children and
adults, and may also increase the risk of many common chronic diseases
(e.g., type I diabetes and rheumatoid arthritis) as well as the risk of
various types of cancers. Thus, the Criteria Document concludes that
any assessment that attempts to quantify the consequences of increased
UV-B exposure on humans due to reduced ground-level O3 must
include consideration of both negative and positive effects. However,
as with other impacts of UV-B on human health, this beneficial effect
of UV-B radiation has not been studied in sufficient detail to allow
for a credible health benefits or risk assessment. In conclusion, the
effect of changes in surface-level O3 concentrations on UV-
induced health outcomes cannot yet be critically assessed within
reasonable uncertainty (Criteria Document, p. 10-36).
    The Agency last considered indirect effects of O3 in the
ambient air in its 2003 final response to a remand of the Agency's 1997
decision to revise the O3 NAAQS. In so doing, based on the
available information in the last review, the Administrator determined
that the information linking (a) Changes in patterns of ground-level
O3 concentrations likely to occur as a result of programs
implemented to attain the 1997 O3 NAAQS to (b) changes in
relevant exposures to UV-B radiation of concern to public health was
too uncertain at that time to warrant any relaxation in the level of
public health protection previously determined to be requisite to
protect against the demonstrated direct adverse respiratory effects of
exposure to O3 in the ambient air (68 FR 614). At that time,
the more recent information on protective effects of UV-B radiation was
not available, such that only adverse UV-B-related effects could be
considered. Taking into consideration the more recent information
available in this review, the Criteria Document and Staff Paper
conclude that the effect of changes in ground-level O3
concentrations, likely to occur as a result of revising the
O3 NAAQS, on UV-induced health outcomes, including whether
these changes would ultimately result in increased or decreased
incidence of UV-B-related diseases, cannot yet be critically assessed.
EPA requests comment on available studies or data that would be
relevant to conducting a critical assessment with reasonable certainty
of UV-induced health outcomes and how evidence of UV-induced health
outcomes might inform the Agency's review of the primary O3
standard.
3. Interpretation and Integration of Health Evidence
    As discussed below, in assessing the new health evidence, the
Criteria Document integrates findings from experimental (e.g.,
toxicological, dosimetric and controlled human exposure) and
epidemiological studies, to make judgments about the extent to which
causal inferences can be made about observed associations between
health endpoints and exposure to O3. In evaluating the
evidence from epidemiological studies, the EPA focuses on well-
recognized criteria, including: The strength of reported associations,
including the magnitude and precision of reported effect estimates and
their statistical significance; the robustness of reported
associations, or stability in the effect estimates after considering
factors such as alternative models and model specification, potential
confounding by co-pollutants, and issues related to the consequences of
exposure measurement error; potential aggregation bias in pooling data;
and the consistency of the effects associations as observed by looking
across results of multiple- and

single-city studies conducted by different investigators in different
places and times. Consideration is also given to evaluating
concentration-response relationships observed in epidemiological
studies to inform judgments about the potential for threshold levels
for O3-related effects. Integrating more broadly across
epidemiological and experimental evidence, the Criteria Document also
focuses on the coherence and plausibility of observed O3-
related health effects to reach judgments about the extent to which
causal inferences can be made about observed associations between
health endpoints and exposure to O3 in the ambient air.
a. Assessment of Evidence From Epidemiological Studies
    Key elements of the evaluation of epidemiological studies are
briefly summarized below.
    (1) The strength of associations most directly refers to the
magnitude of the reported relative risk estimates. Taking a broader
view, the Criteria Document draws upon the criteria summarized in a
recent report from the U.S. Surgeon General, which define strength of
an association as ``the magnitude of the association and its
statistical strength'' which includes assessment of both effect
estimate size and precision, which is related to the statistical power
of the study (CDC, 2004). In general, when associations are strong in
terms of yielding large relative risk estimates, it is less likely that
the association could be completely accounted for by a potential
confounder or some other source of bias, whereas with associations that
yield small relative risk estimates it is especially important to
consider potential confounding and other factors in assessing
causality. Effect estimates between O3 and some of the
health outcomes are generally small in size and could thus be
characterized as weak. For example, effect estimates for associations
with mortality generally range from 0.5 to 5 percent increases per
0.040 ppm increase in 1-hour maximum O3 or equivalent,
whereas associations for hospitalization range up to 50 percent
increases per standardized O3 increment. However, the
Criteria Document notes that there are large multicity studies that
find small associations between short-term O3 exposure and
mortality or morbidity and have done so with great precision due to the
statistical power of the studies (EPA, 2006a, p. 8-40). That is, the
power of the studies allows the authors to reliably distinguish even
weak relationships from the null hypothesis with statistical
confidence.
    (2) In evaluating the robustness of associations, the Criteria
Document (sections 7.1.3 and <IP_ADDRESS>) and Staff Paper (section 3.4.2)
have primarily considered the impact of exposure error, potential
confounding by copollutants, and alternative models and model
specifications.
    In time-series and panel studies, the temporal (e.g., daily or
hourly) changes in ambient O3 concentrations measured at
centrally-located ambient monitoring stations are generally used to
represent a community's exposure to ambient O3. In
prospective cohort or cross-sectional studies, air quality data
averaged over a period of months to years are used as indicators of a
community's long-term exposure to ambient O3 and other
pollutants. In both types of analyses, exposure error is an important
consideration, as actual exposures to individuals in the population
will vary across the community.
    Ozone concentrations measured at central ambient monitoring sites
may explain, at least partially, the variance in individual exposures
to ambient O3; however, this relationship is influenced by
various factors related to building ventilation practices and personal
behaviors. Further, the pattern of exposure misclassification error and
the influence of confounders may differ across the outcomes of interest
as well as in susceptible populations. As discussed in the Criteria
Document (section 3.9), only a limited number of studies have examined
the relationship between ambient O3 concentrations and
personal exposures to ambient O3. One of the strongest
predictors of the relationship between ambient concentrations and
personal exposures appears to be time spent outdoors. The strongest
relationships were observed in outdoor workers (Brauer and Brook, 1995,
1997; O'Neill et al., 2004). Statistically significant correlations
between ambient concentrations and personal exposures were also
observed for children, who likely spend more time outdoors in the warm
season (Linn et al., 1996; Xue et al., 2005). There is some concern
about the extent to which ambient concentrations are representative of
personal O3 exposures of another particularly susceptible
group of individuals, the debilitated elderly, since those who suffer
from chronic cardiovascular or respiratory conditions may tend to
protect themselves more than healthy individuals from environmental
threats by reducing their exposure to both O3 and its
confounders, such as high temperature and PM. Studies by Sarnat et al.
(2001, 2005) that included this susceptible group reported mixed
results for associations between ambient O3 concentrations
and personal exposures to O3. Collectively, these studies
observed that the daily averaged personal O3 exposures tend
to be well correlated with ambient O3 concentrations despite
the substantial variability that existed among the personal
measurements. These studies provide supportive evidence that ambient
O3 concentrations from central monitors may serve as valid
surrogate measures for mean personal exposures experienced by the
population, which is of most relevance for time-series studies. A
better understanding of the relationship between ambient concentrations
and personal exposures, as well as of the other factors that affect
relationship will improve the interpretation of concentration-
population health response associations observed.
    The Criteria Document (section <IP_ADDRESS>) also discusses the
potential influence of exposure error on epidemiologic study results.
Zeger et al. (2000) outlined the components to exposure measurement
error, finding that ambient exposure can be assumed to be the product
of the ambient concentration and an attenuation factor (i.e., building
filter) and that panel studies and time-series studies that use ambient
concentrations instead of personal exposure measurements will estimate
a health risk that is attenuated by that factor. Navidi et al. (1999)
used data from a children's cohort study to compare effect estimates
from a simulated ``true'' exposure level to results of analyses from
O3 exposures determined by several methods, finding that
O3 exposures based on the use of ambient monitoring data
overestimate the individual's O3 exposure and thus generally
result in O3 effect estimates that are biased downward (EPA,
2006a, p. 7-8). Similarly, in a reanalysis of a study by Burnett et al.
(1994) on the acute respiratory effects of ambient air pollution, Zidek
et al. (1998) reported that accounting for measurement error, as well
as making a few additional changes to the analysis, resulted in
qualitatively similar conclusions, but the effects estimates were
considerably larger in magnitude (EPA, 2006a, p. 7-8). A simulation
study by Sheppard et al. (2005) also considered attenuation of the risk
based on personal behavior, their microenvironment, and the qualities
of the pollutant in time-series studies. Of particular interest is
their finding that risk estimates were not further attenuated in time-
series studies even when the correlations between personal exposures
and ambient

concentrations were weak. In addition to overestimation of exposure and
the resulting underestimation of effects, the use of ambient
O3 concentrations may obscure the presence of thresholds in
epidemiologic studies (EPA, 2006a, p. 7-9).
    As discussed in the Criteria Document (section 3.9), using ambient
concentrations to determine exposure generally overestimates true
personal O3 exposures by approximately 2- to 4-fold in
available studies, resulting in attenuated risk estimates. The
implication is that the effects being estimated occur at fairly low
exposures and the potency of O3 is greater than these
effects estimates indicate. As very few studies evaluating
O3 health effects with personal O3 exposure
measurements exist in the literature, effect estimates determined from
ambient O3 concentrations must be evaluated and used with
caution to assess the health risks of O3. In the absence of
available data on personal O3 exposure, the use of routinely
monitored ambient O3 concentrations as a surrogate for
personal exposures is not generally expected to change the principal
conclusions from O3 epidemiologic studies. Therefore,
population health risk estimates derived using ambient O3
levels from currently available observational studies, with appropriate
caveats about personal exposure considerations, remain useful. The
Criteria Document recommends caution in the quantitative use of effect
estimates calculated using ambient O3 concentrations as they
may lead to underestimation of the potency of O3. However,
the Staff Paper observes that the use of these risk estimates for
comparing relative risk reductions between alternative ambient
O3 standards considered in the risk assessment (discussed
below in section II.B.2) is less likely to suffer from this concern.
    Confounding occurs when a health effect that is caused by one risk
factor is attributed to another variable that is correlated with the
causal risk factor; epidemiological analyses attempt to adjust or
control for potential confounders. Copollutants (e.g., PM, CO,
SO2 and NO2) can meet the criteria for potential
confounding in O3-health associations if they are potential
risk factors for the health effect under study and are correlated with
O3. Effect modifiers include variables that may influence
the health response to the pollutant exposure (e.g., co-pollutants,
individual susceptibility, smoking or age). Both are important
considerations for evaluating effects in a mixture of pollutants, but
for confounding, the emphasis is on controlling or adjusting for
potential confounders in estimating the effects of one pollutant, while
the emphasis for effect modification is on identifying and assessing
the effects for different modifiers. The Criteria Document (p. 7-148)
observes that O3 is generally not highly correlated with
other criteria pollutants (e.g., PM10, CO, SO2
and NO2), but may be more highly correlated with secondary
fine particles, especially during the summer months, and that the
degree of correlation between O3 and other pollutants may
vary across seasons. For example, positive associations are observed
between O3 and pollutants such as fine particles during the
warmer months, but negative correlations may be observed during the
cooler months (EPA, 2006a, p. 7-17). Thus, the Criteria Document
(section 7.6.4) pays particular attention to the results of season-
specific analyses and studies that assess effects of PM in potential
confounding of O3-health relationships. The Criteria
Document also discussed the limitations of commonly used multipollutant
models that include the difficulty in interpreting results where the
copollutants are highly colinear, or where correlations between
pollutants change by season (EPA, 2006a, p. 7-150). This is
particularly the situation where O3 and a copollutant, such
as sulfates, are formed under the same atmospheric condition; in such
cases multipollutant models would produce unstable and possibly
misleading results (EPA, 2006a, p. 7-152).
    For mortality, the results from numerous multi-city and single-city
studies indicate that O3-mortality associations do not
appear to be substantially changed in multipollutant models including
PM10 or PM2.5 (EPA, 2006a, p. 7-101; Figure 7-
22). Focusing on results of warm season analyses, effect estimates for
O3-mortality associations are fairly robust to adjustment
for PM in multipollutant models (EPA, 2006a, p. 7-102; Figure 7-23).
The Criteria Document concludes that in the few multipollutant analyses
conducted for these endpoints, copollutants generally do not confound
the relationship between O3 and respiratory hospitalization
(EPA, 2006a, p. 7-79 to 7-80; Figure 7-12). Multipollutant models were
not used as commonly in studies of relationships between respiratory
symptoms or lung function with O3, but the Criteria Document
reports that results of available analyses indicate that such
associations generally were robust to adjustment for PM2.5
(EPA, 2006a, p. 7-154). For example, in a large multi-city study of
asthmatic children (Mortimer et al., 2002), the O3 effect
was attenuated, but there was still a positive association; in Gent et
al. (2003), effects of O3, but not PM2.5,
remained statistically significant and even increased in magnitude in
two-pollutant models (EPA, 2006a, p. 7-53). Considering this body of
studies, the Criteria Document concludes: ``Multipollultant regression
analyses indicated that O3 risk estimates, in general, were
not sensitive to the inclusion of copollutants, including
PM2.5 and sulfate. These results suggest that the effects of
O3 on respiratory health outcomes appear to be robust and
independent of the effects of other copollutants (EPA, 2006a, p. 7-
154).''
    The Criteria Document observes that another challenge of time-
series epidemiological analysis is assessing the relationship between
O3 and health outcomes while avoiding bias due to
confounding by other time-varying factors, particularly seasonal trends
and weather variables (EPA, 2006a, p. 7-14). These variables are of
particular interest because O3 concentrations have a well-
characterized seasonal pattern and are also highly correlated with
changes in temperature, such that it can be difficult to distinguish
whether effects are associated with O3 or with seasonal or
weather variables in statistical analyses.
    The Criteria Document (section <IP_ADDRESS>) discusses statistical
modeling approaches that have been used to adjust for time-varying
factors, highlighting a series of analyses that were done in a Health
Effects Institute-funded reanalysis of numerous time-series studies.
While the focus of these reanalyses was on associations with PM, a
number of investigators also examined the sensitivity of O3
coefficients to the extent of adjustment for temporal trends and
weather factors. In addition, several recent studies, including U.S.
multi-city studies (Bell et al., 2005; Huang et al., 2005; Schwartz et
al., 2005) and a meta-analysis study (Ito et al., 2005), evaluated the
effect of model specification on O3-mortality associations.
As discussed in the Criteria Document (section <IP_ADDRESS>), these studies
generally report that associations reported with O3 are not
substantially changed with alternative modeling strategies for
adjusting for temporal trends and meteorologic effects. In the meta-
analysis by Ito et al. (2005), a separate multi-city analysis was
presented that found that alternative adjustments for weather resulted
in up to 2-fold difference in the O3 effect estimate.
Significant confounding can occur when strong seasonal cycles are
present, suggesting

that season-specific results are more generally robust than year-round
results in such cases. A number of epidemiological studies have
conducted season-specific analyses, and have generally reported
stronger and more precise effect estimates for O3
associations in the warm season than in analyses conducted in the cool
seasons or over the full year.
    (3) Consistency refers to the persistent finding of an association
between exposure and outcome in multiple studies of adequate power in
different persons, places, circumstances and times (CDC, 2004). In
considering results from multi-city studies and single-city studies in
different areas, the Criteria Document (p. 8-41) observes general
consistency in effects of short-term O3 exposure on
mortality, respiratory hospitalization and other respiratory health
outcomes. The variations in effects that are observed may be
attributable to differences in relative personal exposure to
O3, as well as varying concentrations and composition of
copollutants present in different regions. Thus, the Criteria Document
(p. 8-41) concludes that ``consideration of consistency or
heterogeneity of effects is appropriately understood as an evaluation
of the similarity or general concordance of results, rather than an
expectation of finding quantitative results with a very narrow range.''
    (4) The Staff Paper recognizes that it is likely that there are
biological thresholds for different health effects in individuals or
groups of individuals with similar innate characteristics and health
status. For O3 exposure, individual thresholds would
presumably vary substantially from person to person due to individual
differences in genetic susceptibility, pre-existing disease conditions
and possibly individual risk factors such as diet or exercise levels
(and could even vary from one time to another for a given person).
Thus, it would be difficult to detect a distinct threshold at the
population level below which no individual would experience a given
effect, especially if some members of a population are unusually
sensitive even down to very low concentrations (EPA, 2004, p. 9-43, 9-
44).
    Some studies have tested associations between O3 and
health outcomes after removal of days with higher O3 levels
from the data set; such analyses do not necessarily indicate the
presence or absence of a threshold, but provide some information on
whether the relationship is found using only lower-concentration data.
For example, using data from 95 U.S. cities, Bell et al. (2004) found
that the effect estimate for an association between short-term
O3 exposure and mortality was little changed when days
exceeding 0.060 ppm (24-hour average) were excluded in the analysis.
Bell et al. (2006) found no difference in estimated effect even when
all days with 24-hour O3 concentrations <0.020 ppm were
excluded (EPA, 2006a, p. 8-43). Using data from 8 U.S. cities, Mortimer
and colleagues (2002) also reported that associations between
O3 and both lung function and respiratory symptoms remained
statistically significant and of the same or greater magnitude in
effect size when concentrations greater than 0.080 ppm (8-hour average)
were excluded (EPA, 2006a, p. 7-46). Several single-city studies also
report similar findings of associations that remain or are increased in
magnitude and statistical significance when data at the upper end of
the concentration range are removed (EPA, 2006a, section 7.6.5).
    Other time-series epidemiological studies have used statistical
modeling approaches to evaluate whether thresholds exist in
associations between short-term O3 exposure and mortality.
As discussed in section 7.6.5 of the Criteria Document, one European
multi-city study included evaluation of the shape of the concentration-
response curve, and observed no deviation from a linear function across
the range of O3 measurements from the study (Gryparis et
al., 2004; EPA, 2006a, p. 7-154). Several single-city studies also
observed a monotonic increase in associations between O3 and
morbidity that suggest that no population threshold exists (EPA, 2006a,
p. 7-159).
    On the other hand, a study in Korea used several different modeling
approaches and reported that a threshold model provided the best fit
for the data. The results suggested a potential threshold level of
about 0.045 ppm (1-hour maximum concentration; < 0.035 ppm, 8-hour
average) for an association between mortality and short-term
O3 exposure during the summer months (Kim et al., 2004; EPA,
2006a, p. 8-43). The authors reported larger effect estimates for the
association for data above the potential threshold level, suggesting
that an O3-mortality association might be underestimated in
the non-threshold model. A threshold analysis recently reported by Bell
et al. (2006) for 98 U.S. communities, including the same 95
communities in Bell et al. (2004), indicated that if a population
threshold existed for mortality, it would likely fall below a 24-hour
average O3 concentration of 0.015 ppm (<0.025 ppm, 8-hour
average). In addition, Burnett and colleagues (1997a,b) plotted the
relationships between air pollutant concentrations and both respiratory
and cardiovascular hospitalization, and it appears in these results
that the associations with O3 are found in the concentration
range above about 0.030 ppm (1-hour maximum; < 0.025 ppm, 8-hour
average). Vedal and colleagues (2003) reported a significant
association between O3 and mortality in British Columbia
where O3 concentrations were quite low (mean 1-hour maximum
concentration of 0.0273 ppm). The authors did not specifically test for
threshold levels, but the fact that the association was found in an
area with such low O3 concentrations suggests that any
potential threshold level would be quite low in this data set.
    In summary, the Criteria Document finds that, taken together, the
available evidence from clinical and epidemiological studies suggests
that no clear conclusion can now be reached with regard to possible
threshold levels for O3-related effects (EPA, 2006a, p. 8-
44). Thus, the available epidemiological evidence neither supports nor
refutes the existence of thresholds at the population level for effects
such as increased hospital admissions and premature mortality. There
are limitations in epidemiological studies that make discerning
thresholds in populations difficult, including low data density in the
lower concentration ranges, the possible influence of exposure
measurement error, and interindividual differences in susceptibility to
O3-related effects in populations. There is the possibility
that thresholds for individuals may exist in reported associations at
fairly low levels within the range of air quality observed in the
studies but not be detectable as population thresholds in
epidemiological analyses.
b. Biological Plausibility and Coherence of Evidence
    The body of epidemiological studies discussed in the Staff Paper
emphasizes the role of O3 in association with a variety of
adverse respiratory and cardiovascular effects. While recognizing a
variety of plausible mechanisms, there exists a general consensus
suggesting that O3 could, either directly or through
initiation, interfere with basic cellular oxidation processes
responsible for inflammation, reduced antioxidant capacity,
atherosclerosis and other effects. Reasoning that O3
influences cellular chemistry through basic oxidative properties (as
opposed to a unique chemical interaction), other reactive oxidizing
species (ROS) in the

atmosphere acting either independently or in combination with
O3 may also contribute to a number of adverse respiratory
and cardiovascular health effects. Consequently, the role of
O3 should be considered more broadly as O3
behaves as a generator of numerous oxidative species in the atmosphere.
    In considering the biological plausibility of reported
O3-related effects, the Staff Paper (section 3.4.6)
considers this broader question of health effects of pollutant mixtures
containing O3. The potential for O3-related
enhancements of PM formation, particle uptake, and exacerbation of PM-
induced cardiovascular effects underscores the importance of
considering contributions of O3 interactions with other
often co-occurring air pollutants to health effects due to
O3-containing pollutant mixes. The Staff Paper summarizes
some examples of important pollutant mixture effects from studies that
evaluate interactions of O3 with other co-occurring
pollutants, as discussed in chapters 4, 5, and 6 of the Criteria
Document.
    All of the types of interactive effects of O3 with other
co-occurring gaseous and nongaseous viable and nonviable PM components
of ambient air mixes noted above argue that O3 acts not only
alone but that O3 also is a surrogate indicator for air
pollution mixes which may enhance the risk of adverse effects due to
O3 acting in combination with other pollutants. Viewed from
this perspective, those epidemiologic findings of morbidity and
mortality associations, with ambient O3 concentrations
extending to quite low levels in many cases, become more understandable
and plausible.
    The Criteria Document integrates epidemiological studies with
mechanistic information from controlled human exposure studies and
animal toxicological studies to draw conclusions regarding the
coherence of evidence and biological plausibility of O3-
related health effects to reach judgments about the causal nature of
observed associations. As summarized below, coherence and biological
plausibility are discussed for each of the following types of
O3-related effects: short-term effects on the respiratory
system, effects on the cardiovascular system, effects related to long-
term O3 exposure, and short-term mortality-related health
endpoints.
i. Coherence and Plausibility of Short-Term Effects on the Respiratory
System
    Acute respiratory morbidity effects that have been associated with
short-term exposure to O3 include such health endpoints as
decrements in lung function, increased airway responsiveness, airway
inflammation, increased permeability related to epithelial injury,
immune system effects, emergency department visits for respiratory
diseases, and hospitalization due to respiratory illness.
    Recent epidemiological studies have supported evidence available in
the previous O3 NAAQS review on associations between ambient
O3 exposure and decline in lung function for children. The
Criteria Document (p. 8-34) concludes that exposure to ambient
O3 has a significant effect on lung function and is
associated with increased respiratory symptoms and medication use,
particularly in asthmatics. Short-term exposure to O3 has
also been associated with more severe morbidity endpoints, such as
emergency department visits and hospital admissions for respiratory
cases, including specific respiratory illness (e.g., asthma) (EPA,
2006a, sections 7.3.2 and 7.3.3). In addition, a few epidemiological
studies have reported positive associations between short-term
O3 exposure and respiratory mortality, though the
associations are not generally statistically significant (EPA, 2006a,
p. 7-108).
    Considering the evidence from epidemiological studies, the results
described above provide evidence for coherence in O3-related
effects on the respiratory system. Effect estimates from U.S. and
Canadian studies are shown in Figure 1, where it can be seen that
mostly positive associations have been reported with respiratory
effects ranging from respiratory symptoms, such as cough or wheeze, to
hospitalization for various respiratory diseases, and there is
suggestive evidence for associations with respiratory mortality. Many
of the reported associations are statistically significant,
particularly in the warm season. In Figure 1, the central effect
estimate is indicated by a square for each result, with the vertical
bar representing the 95 percent confidence interval around the
estimate. In the discussions that follow, an individual study result is
considered to be statistically significant if the 95 percent confidence
interval does not include zero.\21\ Positive effect estimates indicate
increases in the health outcome with O3 exposure. In
considering these results as a whole, it is important to consider not
only whether statistical significance at the 95 percent confidence
level is reported in individual studies but also the general pattern of
results, focusing in particular on studies with greater statistical
power that report relatively more precise results.
---------------------------------------------------------------------------

    \21\ Results for studies of respiratory symptoms are presented
as odds ratios; an odds ratio of 1.0 is equivalent to no effect, and
thus is presented as equivalent to the zero effect estimate line.
---------------------------------------------------------------------------

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    Considering also evidence from toxicological, chamber, and field
studies, the Criteria Document (section 8.6) discusses biological
plausibility and coherence of evidence for acute O3-induced
respiratory health effects. Inhalation of O3 for several
hours while subjects are physically active can elicit both acute
adverse pathophysiological changes and subjective respiratory tract
symptoms (EPA, 2006a, section 8.4.2). Acute pulmonary responses
observed in healthy humans exposed to O3 at ambient
concentrations include: decreased inspiratory capacity; mild
bronchoconstriction; rapid, shallow breathing during exercise;
subjective symptoms of tracheobronchial airway irritation, including
cough and pain on deep inspiration; decreases in measures of lung
function; and increased airway resistance. The severity of symptoms and
magnitude of response depends on inhaled dose, individual O3
sensitivity, and the degree of attenuation or enhancement of response
resulting from previous O3 exposures. Lung function studies
of several animal species acutely exposed to relatively low
O3 levels (0.25 to 0.4 ppm) show responses similar to those
observed in humans, including increased breathing frequency, decreased
tidal volume, increased resistance, and decreased FVC. Alterations in
breathing pattern return to normal within hours of exposure, and
attenuation in functional responses

following repeated O3 exposures is similar to those observed
in humans.
    Physiological and biochemical alterations investigated in
controlled human exposure and animal toxicology studies tend to support
certain hypotheses of underlying pathological mechanisms which lead to
the development of respiratory-related effects reported in epidemiology
studies (e.g., increased hospitalization and medication use). Some of
these are: (a) Decrements in lung function, (b) bronchoconstriction,
(c) increased airway responsiveness, (d) airway inflammation, (e)
epithelial injury, (f) immune system activation, (g) host defense
impairment, and (h) sensitivity of individuals, which depends on at
least a person's age, disease status, genetic susceptibility, and the
degree of attenuation present due to prior exposures. The time
sequence, magnitude, and overlap of these complex events, both in terms
of development and recovery, illustrate the inherent difficulty of
interpreting the biological plausibility of O3-induced
cardiopulmonary health effects (EPA, 2006a, p. 8-48).
    The interaction of O3 with airway epithelial cell
membranes and ELF to form lipid ozonation products and ROS is supported
by numerous human, animal and in vitro studies. Ozonation products and
ROS initiate a cascade of events that lead to oxidative stress, injury,
inflammation, airway epithelial damage and increased epithelial damage
and increased alveolar permeability to vascular fluids. Repeated
respiratory inflammation can lead to a chronic inflammatory state with
altered lung structure and lung function and may lead to chronic
respiratory diseases such as fibrosis and emphysema (EPA, 2006a,
section 8.6.2). Continued respiratory inflammation also can alter the
ability to respond to infectious agents, allergens and toxins. Acute
inflammatory responses to O3 are well documented, and lung
injury can become apparent within 3 hours after exposure in humans.
    Taken together, the Criteria Document concludes that the evidence
from experimental human and animal toxicology studies indicates that
acute O3 exposure is causally associated with respiratory
system effects, including O3-induced pulmonary function
decrements, respiratory symptoms, lung inflammation, and increased lung
permeability, airway hyperresponsiveness, increased uptake of nonviable
and viable particles, and consequent increased susceptibility to PM-
related toxic effects and respiratory infections (EPA, 2006a, p. 8-48).
ii. Coherence and Plausibility of Effects on the Cardiovascular System
    There is very limited experimental evidence of animals and humans
that has evaluated possible mechanisms or physiological pathways by
which acute O3 exposures may induce cardiovascular system
effects. Ozone induces lung injury, inflammation, and impaired
mucociliary clearance, with a host of associated biochemical changes
all leading to increased lung epithelial permeability. As noted above
in section II.A.2.b, the generation of lipid ozonation products and ROS
in lung tissues can influence pulmonary hemodynamics, and ultimately
the cardiovascular system. Other potential mechanisms by which
O3 exposure may be associated with cardiovascular disease
outcomes have been described. Laboratory animals exposed to relatively
high O3 concentrations (>=0.5 ppm) demonstrate tissue edema
in the heart and lungs. Ozone-induced changes in heart rate, edema of
heart tissue, and increased tissue and serum levels of ANF found with
8-hour 0.5 ppm O3 exposure in animal toxicology studies
(Vesely et al., 1994a, b, c) also raise the possibility of potential
cardiovascular effects of acute ambient O3 exposures.
    Animal toxicology studies have found both transient and persistent
ventilatory responses with and without progressive decreases in heart
rate (Arito et al., 1997). Observations of O3-induced
vasoconstriction in a controlled human exposure study by Brook et al.
(2002) suggests another possible mechanism for O3-related
exacerbations of preexisting cardiovascular disease. One controlled
human study (Gong et al., 1998) evaluated potential cardiovascular
health effects of O3 exposure. The overall results did not
indicate acute cardiovascular effects of O3 in either the
hypertensive or control subjects. The authors observed an increase in
rate-pressure product and heart rate, a decrement for FEV1,
and a >10 mm Hg increase in the alveolar/arterial pressure difference
for O2 following O3 exposure. Foster et al.
(1993) demonstrated that even in relatively young healthy adults,
O3 exposure can cause ventilation to shift away from the
well-perfused basal lung. This effect of O3 on ventilation
distribution may persist beyond 24-hours post-exposure (Foster et al.,
1997). These findings suggest that O3 may exert
cardiovascular effects indirectly by impairing alveolar-arterial
O2 transfer and potentially reducing O2 supply to
the myocardium. Ozone exposure may increase myocardial work and impair
pulmonary gas exchange to a degree that could perhaps be clinically
important in persons with significant preexisting cardiovascular
impairment.
    As noted above in section II.A.2.b, a limited number of new
epidemiological studies have reported associations between short-term
O3 exposure and effects on the cardiovascular system. Among
these studies, three were population-based and involved relatively
large cohorts; two of these studies evaluated associations between
O3 and heart rate variability (HRV) and the other study
evaluated the association between O3 levels and the relative
risk of myocardial infarction (MI). Such studies may offer more
informative results based on their large subject-pool and design.
Results from these three studies were suggestive of an association
between O3 exposure and the cardiovascular endpoints
studied. In other recent studies on the incidence of MI and some more
subtle cardiovascular health endpoints, such as changes in HRV or
cardiac arrhythmia, some but not all studies reported associations with
short-term exposure to O3 (EPA, 2006a, section <IP_ADDRESS>).
From these studies, the Criteria Document concludes that the ``current
evidence is rather limited but suggestive of a potential effect on HRV,
ventricular arrhythmias, and MI incidence'' (EPA, 2006a, p. 7-65).
    An increasing number of studies have evaluated the association
between O3 exposure and cardiovascular hospital admissions.
As discussed in section 7.3.4 of the Criteria Document, many reported
negative or inconsistent associations, whereas other studies,
especially those that examined the relationship when O3
exposures were higher, have found positive and robust associations
between O3 and cardiovascular hospital admissions. The
Criteria Document finds that the overall evidence from these studies
remains inconclusive regarding the effect of O3 on
cardiovascular hospitalizations (EPA, 2006a, p. 7-83).
    The Criteria Document notes that the suggestive positive
epidemiologic findings of O3 exposure on cardiac autonomic
control, including effects on HRV, ventricular arrhythmias and MI, and
reported associations between O3 exposure and cardiovascular
hospitalizations generally in the warm season gain credibility and
scientific support from the results of experimental animal toxicology
and human clinical studies, which are indicative of plausible pathways
by which O3 may exert cardiovascular effects (EPA, 2006a,
section 8.6.1).

iii. Coherence and Plausibility of Effects Related to Long-Term
O3 Exposure
    Human chamber studies can not evaluate effects of long-term
exposures to O3; there is some evidence available from
toxicological studies. While early animal toxicology studies of long-
term O3 exposures were conducted using continuous exposures,
more recent studies have focused on exposures which mimic diurnal and
seasonal patterns and more realistic O3 exposure levels
(EPA, 2006a, p. 8-50). Studies of monkeys that compared these two
exposure scenarios found increased airway pathology only with the
latter design. Persistent and irreversible effects reported in chronic
animal toxicology studies suggest that additional complementary human
data are needed from epidemiologic studies (EPA, 2006a, p. 8-50).
    There is limited evidence from human studies for long-term
O3-induced effects on lung function. As discussed in section
8.6.2 of the Criteria Document, previous epidemiological studies have
provided only inconclusive evidence for either mortality or morbidity
effects of long-term O3 exposure. The Criteria Document
observes that the inconsistency in findings may be due to a lack of
precise exposure information, the possibility of selection bias, and
the difficulty of controlling for confounders (EPA, 2006a, p. 8-50).
Several new longitudinal epidemiology studies have evaluated
associations between long-term O3 exposures and morbidity
and mortality and suggest that these long-term exposures may be related
to changes in lung function in children; however, little evidence is
available to support a relationship between chronic O3
exposure and mortality or lung cancer incidence (EPA, 2006a, p. 8-50).
    The Criteria Document (p. 8-51) concludes that evidence from animal
toxicology studies strongly suggests that chronic O3
exposure is capable of damaging the distal airways and proximal
alveoli, resulting in lung tissue remodeling leading to apparent
irreversible changes. Such structural changes and compromised pulmonary
function caused by persistent inflammation may exacerbate the
progression and development of chronic lung disease. Together with the
limited evidence available from epidemiological studies, these findings
offer some insight into potential biological mechanisms for suggested
associations between long-term or seasonal exposures to O3
and reduced lung function development in children which have been
observed in epidemiologic studies (EPA, 2006a, p. 8-51).
iv. Coherence and Plausibility of Short-Term Mortality-Related Health
Endpoints
    An extensive epidemiological literature on air pollution related
mortality risk estimates from the U.S., Canada, and Europe is discussed
in the Criteria Document (sections 7.4 and 8.6.3). These single- and
multi-city mortality studies coupled with meta-analyses generally
indicate associations between acute O3 exposure and elevated
risk for all-cause mortality, even after adjustment for the influence
of season and PM. Several single-city studies that specifically
evaluated the relationship between O3 exposure and
cardiopulmonary mortality also reported results suggestive of a
positive association (EPA, 2006a, p. 8-51). These mortality studies
suggest a pattern of effects for causality that have biologically
plausible explanations, but our knowledge regarding potential
underlying mechanisms is very limited at this time and requires further
research. Most of the physiological and biochemical parameters
investigated in human and animal studies suggest that O3-
induced biochemical effects are relatively transient and attenuate over
time. The Criteria Document (p. 8-52) hypothesizes a generic pathway of
O3-induced lung damage, potentially involving oxidative lung
damage with subsequent inflammation and/or decline in lung function
leading to respiratory distress in some sensitive population groups
(e.g., asthmatics), or other plausible pathways noted below that may
lead to O3-related contributions to cardiovascular effects
that ultimately increase risk of mortality.
    The third National Health and Nutrition Examination Follow-up data
analysis indicates that about 20 percent of the adult population has
reduced FEV1 values, suggesting impaired lung function in
some portion of the population. Most of these individuals have COPD,
asthma or fibrotic lung disease (Manino et al., 2003), which are
associated with persistent low-grade inflammation. Furthermore,
patients with COPD are at increased risk for cardiovascular disease.
Also, lung disease with underlying inflammation may be linked to low-
grade systemic inflammation associated with atherosclerosis,
independent of cigarette smoking (EPA, 2006a, p. 8-52). Lung function
decrements in persons with cardiopulmonary disease have been associated
with inflammatory markers, such as C-reactive protein (CRP) in the
blood. At a population level it has been found that individuals with
the lowest FEV1 values have the highest levels of CRP, and
those with the highest FEV1 values have the lowest CRP
levels (Manino et al., 2003; Sin and Man, 2003). This complex series of
physiological and biochemical reactions following O3
exposure may tilt the biological homeostasis mechanisms which could
lead to adverse health effects in people with compromised
cardiopulmonary systems.
    Of much interest are several other types of newly available data
that support reasonable hypotheses that may help to explain the
findings of O3-related increases in cardiovascular mortality
observed in some epidemiological studies. These include the direct
effect of O3 on increasing PAF in lung tissue that can then
enter the general circulation and possibly contribute to increased risk
of blood clot formation and the consequent increased risk of MI,
cerebrovascular events (stroke), or associated cardiovascular-related
mortality. Ozone reactions with cholesterol in lung surfactant to form
epoxides and oxysterols that are cytotoxic to lung and heart muscles
and that contribute to atherosclerotic plaque formation in arterial
walls represent another potential pathway. Stimulation of airway
irritant receptors may lead to increases in tissue and serum levels of
ANF, changes in heart rate, and edema of heart tissue. A few new field
and panel studies of human adults have reported associations between
ambient O3 concentrations and changes in cardiac autonomic
control (e.g., HRV, ventricular arrhythmias, and MI). These represent
plausible pathways that may lead to O3-related contributions
to cardiovascular effects that ultimately increase the risk of
mortality.
    In addition, O3-induced increases in lung permeability
allow more ready entry for inhaled PM into the blood stream, and
O3 exposure may increase the risk of PM-related
cardiovascular effects. Furthermore, increased ambient O3
levels contribute to ultrafine PM formation in the ambient air and
indoor environments. Thus, the contributions of elevated ambient
O3 concentrations to ultrafine PM formation and human
exposure, along with the enhanced uptake of inhaled fine particles,
consequently may contribute to exacerbation of PM-induced
cardiovascular effects in addition to those more directly induced by
O3 (EPA, 2006a, p. 8-53).
c. Summary
    Judgments concerning the extent to which relationships between
various health endpoints and ambient O3

exposures are likely causal are informed by the conclusions and
discussion in the Criteria Document as discussed above and summarized
in section 3.7.5 of the Staff Paper. These judgments reflect the nature
of the evidence and overall weight of the evidence, and are taken into
consideration in the quantitative risk assessment discussed below in
section II.B.2.
    For example, there is a very high level of confidence that
O3 induces lung function decrements in healthy adults and
children due in part to the dozens of controlled human exposure and
epidemiological studies consistently showing such effects. The Criteria
Document (p. 8-74) states that these studies provide clear evidence of
causality for associations between short-term O3 exposures
and statistically significant declines in lung function in children,
asthmatics and adults who exercise outdoors. An increase in respiratory
symptoms (e.g., cough, shortness of breath) has been observed in
controlled human exposure studies of short-term O3
exposures, and significant associations between ambient O3
exposures and a wide variety of symptoms have been reported in
epidemiology studies (EPA, 2006a, p. 8-75). Aggregate population time-
series studies showing robust associations with respiratory hospital
admissions and emergency department visits are strongly supported by
human clinical, animal toxicologic, and epidemiologic evidence for
O3-related lung function decrements, respiratory symptoms,
airway inflammation, and airway hyperreactivity. The Criteria Document
(p. 8-77) concludes that, taken together, the overall evidence supports
the inference of a causal relationship between acute ambient
O3 exposures and increased respiratory morbidity outcomes
resulting in increased emergency department visits and hospitalizations
during the warm season. Further, recent epidemiologic evidence has been
characterized in the Criteria Document (p. 8-78) as highly suggestive
that O3 directly or indirectly contributes to non-accidental
and cardiopulmonary-related mortality.
4. O3-Related Impacts on Public Health
    The following discussion draws from chapters 6 and 7 and section
8.7 of the Criteria Document and section 3.6 of the Staff Paper to
characterize factors which modify responsiveness to O3,
subpopulations potentially at risk for O3-related health
effects, the adversity of O3-related effects, and the size
of the at-risk subpopulations in the U.S. These considerations are all
important elements in characterizing the potential public health
impacts associated with exposure to ambient O3.
a. Factors That Modify Responsiveness to Ozone
    There are numerous factors that can modify individual
responsiveness to O3. These include: influence of physical
activity; age; gender and hormonal influences; racial, ethnic and
socioeconomic status (SES) factors; environmental factors; and oxidant-
antioxidant balance. These factors are discussed in more detail in
section 6.5 of the Criteria Document.
    It is well established that physical activity increases an
individual's minute ventilation and will thus increase the dose of
O3 inhaled (EPA, 2006a, section 6.5.4). Increased physical
activity results in deeper penetration of O3 into more
distal regions of the lungs, which are more sensitive to acute
O3 response and injury. This will result in greater lung
function decrements for acute exposures of individuals during increased
physical activity. Research has shown that respiratory effects are
observed at lower O3 concentrations if the level of exertion
is increased and/or duration of exposure and exertion are extended.
Predicted O3-induced decrements in lung function have been
shown to be a function of exposure concentration, duration and exercise
level for healthy, young adults (McDonnell et al., 1997).
    Most of the studies investigating the influence of age have used
lung function decrements and symptoms as measures of response. For
healthy adults, lung function and symptom responses to O3
decline as age increases. The rate of decline in O3
responsiveness appears greater in those 18 to 35 years old compared to
those 35 to 55 years old, while there is very little change after age
55. In one study (Seal et al., 1996) analyzing a large data set, a 5.4%
decrement in FEV1 was estimated for 20 year old individuals exposed to
0.12 ppm O3, whereas similar exposure of 35 year old
individuals were estimated to have a 2.6% decrement. While healthy
children tend not to report respiratory symptoms when exposed to low
levels of O3, for subjects 18 to 36 years old symptom
responses induced by O3 tend to decrease with increasing age
(McDonnell et al., 1999).
    Limited evidence of gender differences in response to O3
exposure has suggested that females may be predisposed to a greater
susceptibility to O3. Lower plasma and NL fluid levels of
the most prevalent antioxidant, uric acid, in females relative to males
may be a contributing factor. Consequently, reduced removal of
O3 in the upper airways may promote deeper penetration.
However, most of the evidence on gender differences appears to be
equivocal, with one study (Hazucha et al., 2003) suggesting that
physiological responses of young healthy males and females may be
comparable (EPA, 2006a, section 6.5.2).
    A few studies have suggested that ethnic minorities might be more
responsive to O3 than Caucasian population groups (EPA,
2006a, section 6.5.3). This may be more the result of a lack of
adequate health care and socioeconomic status (SES) than any
differences in sensitivity to O3. The limited data
available, which have investigated the influence of race, ethnic or
other related factors on responsiveness to O3, prevent
drawing any clear conclusions at this time.
    Few human studies have examined the potential influence of
environmental factors such as the sensitivity of individuals who
voluntarily smoke tobacco (i.e., smokers) and the effect of high
temperatures. New controlled human exposure studies have confirmed that
smokers are less responsive to O3 than nonsmokers; however,
time course of development and recovery of these effects, as well as
reproducibility, was not different from nonsmokers (EPA, 2006a, section
6.5.5). Influence of ambient temperature on pulmonary effects induced
by O3 has been studied very little, but additive effects of
heat and O3 exposure have been reported.
    Antioxidants, which scavenge free radicals and limit lipid
peroxidation in the ELF, are the first line of defense against
oxidative stress. Ozone exposure leads to absorption of O3
in the ELF with subsequent depletion of antioxidant in the nasal ELF,
but concentration and antioxidant enzyme activity in ELF or plasma do
not appear related to O3 responsiveness (EPA 2006a, section
6.5.6). Controlled studies of dietary antioxidant supplements have
shown some protective effects on lung function decrements but not on
symptoms and airway inflammatory responses. Dietary antioxidant
supplements have provided some protection to asthmatics by attenuating
post-exposure airway hyperresponsiveness. Animal studies have also
supported the protective effects of ELF antioxidants.
b. At-Risk Subgroups for O3-Related Effects
    Several characteristics may increase the extent to which a
population group shows increased susceptibility or vulnerability.
Information on potentially susceptible and vulnerable groups is
summarized in section 8.7 of the

Criteria Document. As described there, the term susceptibility refers
to innate (e.g., genetic or developmental) or acquired (e.g., personal
risk factors, age) factors that make individuals more likely to
experience effects with exposure to pollutants. A number of population
groups have been identified as potentially susceptible to health
effects as a result of O3 exposure, including people with
existing lung diseases, including asthma, children and older adults,
and people who have larger than normal lung function responses that may
be due to genetic susceptibility. In addition, some population groups
have been identified as having increased vulnerability to
O3-related effects due to increased likelihood of exposure
while at elevated ventilation rates, including healthy children and
adults who are active outdoors, for example, outdoor workers, and
joggers. Taken together, the susceptible and vulnerable groups make up
``at-risk'' groups.\22\
---------------------------------------------------------------------------

    \22\ In the Staff Paper and documents from previous
O3 NAAQS reviews, ``at-risk'' groups have also been
called ``sensitive'' groups, to mean both groups with greater
inherent susceptibility and those more likely to be exposed.
---------------------------------------------------------------------------

i. Active People
    A large group of individuals at risk from O3 exposure
consists of outdoor workers and children, adolescents, and adults who
engage in outdoor activities involving exertion or exercise during
summer daylight hours when ambient O3 concentrations tend to
be higher. This conclusion is based on a large number of controlled-
human exposure studies and several epidemiologic field/panel studies
which have been conducted with healthy children and adults and those
with preexisting respiratory diseases (EPA 2006a, sections 6.2, 6.3,
7.2, and 8.4.4). The controlled human exposure studies show a clear
O3 exposure-response relationship with increasing
spirometric and symptomatic response as exercise level increases.
Furthermore, O3-induced response increases as time of
exposure increases. Studies of outdoor workers and others who
participate in outdoor activities indicate that extended exposures to
O3 at elevated exertion levels can produce marked effects on
lung function, as discussed above in section IIA.2 (Brauer et al.,
1996; H[ouml]ppe et al., 1995; Korrick et al., 1998; McConnell et al.,
2002).
    These field studies with subjects at elevated exertion levels
support the extensive evidence derived from controlled human exposure
studies. The majority of human chamber studies have examined the
effects of O3 exposure in subjects performing continuous or
intermittent exercise for variable periods of time. Significant
O3-induced respiratory responses have been observed in
clinical studies of exercising individuals. The epidemiologic studies
discussed above also indicate that prolonged exposure periods, combined
with elevated levels of exertion or exercise, may magnify O3
effects on lung function. Thus, outdoor workers and others who
participate in higher exertion activities outdoors during the time of
day when high peak O3 concentrations occur appear to be
particularly vulnerable to O3 effects on respiratory health.
Although these studies show a wide variability of response and
sensitivity among subjects and the factors contributing to this
variability continue to be incompletely understood, the effect of
increased exertion is consistent. It should be noted that this wide
variability of response and sensitivity among subjects may be in part
due to the wide range of other highly reactive photochemical oxidants
coexisting with O3 in the ambient air.
ii. People With Lung Disease
    People with preexisting pulmonary disease are likely to be among
those at increased risk from O3 exposure. Altered
physiological, morphological and biochemical states typical of
respiratory diseases like asthma, COPD and chronic bronchitis may
render people sensitive to additional oxidative burden induced by
O3 exposure. At the time of the last review, it was
concluded that this group was at greater risk because the impact of
O3-induced responses on already-compromised respiratory
systems would noticeably impair an individual's ability to engage in
normal activity or would be more likely to result in increased self-
medication or medical treatment. At that time there was little evidence
that people with pre-existing disease were more responsive than healthy
individuals in terms of the magnitude of pulmonary function decrements
or symptomatic responses. The new results from controlled exposure and
epidemiologic studies continue to indicate that individuals with
preexisting pulmonary disease are a sensitive subpopulation for
O3 health effects.
    Several clinical studies reviewed in the 1996 Criteria Document on
atopic and asthmatic subjects had suggested but not clearly
demonstrated enhanced responsiveness to acute O3 exposure
compared to healthy subjects. The majority of the newer studies
reviewed in Chapter 6 of the Criteria Document indicate that asthmatics
are as sensitive as, if not more sensitive than, normal subjects in
manifesting O3-induced pulmonary function decrements. In one
key study (Horstman et al., 1995), the FEV1 decrement observed in the
asthmatics was significantly larger than in the healthy subjects (19%
versus 10%, respectively). There was also a notable tendency for a
greater O3-induced decrease in FEF25-75 in
asthmatics relative to the healthy subjects (24% versus 15%,
respectively). A significant positive correlation in asthmatics was
also reported between O3-induced spirometric responses and
baseline lung function, i.e., responses increased with severity of
disease.
    Asthmatics present a differential response profile for cellular,
molecular, and biochemical parameters (Criteria Document, Figure 8-1)
that are altered in response to acute O3 exposure. Ozone-
induced increases in neutrophils, IL-8 and protein were found to be
significantly higher in the BAL fluid from asthmatics compared to
healthy subjects, suggesting mechanisms for the increased sensitivity
of asthmatics (Basha et al., 1994; McBride et al., 1994; Scannell et
al., 1996; Hiltermann et al., 1999; Holz et al., 1999; Bosson et al.,
2003). Neutrophils, or PMNs, are the white blood cell most associated
with inflammation. IL-8 is an inflammatory cytokine with a number of
biological effects, primarily on neutrophils. The major role of this
cytokine is to attract and activate neutrophils. Protein in the airways
is leaked from the circulatory system, and is a marker for increased
cellular permeability.
    Bronchial constriction following provocation with O3
and/or allergens presents a two-phase response. The early response is
mediated by release of histamine and leukotrienes that leads to
contraction of smooth muscle cells in the bronchi, narrowing the lumen
and decreasing the airflow. In people with allergic airway disease,
including people with rhinitis and asthma, these mediators also cause
accumulation of eosinophils in the airways (Bascom et al., 1990; Jorres
et al., 1996; Peden et al., 1995 and 1997; Frampton et al., 1997a;
Michelson et al., 1999; Hiltermann et al., 1999; Holz et al., 2002;
Vagaggini et al., 2002). In asthma, the eosinophil, which increases
inflammation and allergic responses, is the cell most frequently
associated with exacerbations of the disease. A study by Bosson et al.
(2003) evaluated the difference in O3-induced bronchial
epithelial cytokine expression between healthy and asthmatic subjects.
After O3 exposure the epithelial expression of IL-5 and GM-
CSF increased significantly in

asthmatics, compared to healthy subjects. Asthma is associated with
Th2-related airway response (allergic response), and IL-5 is an
important Th2-related cytokine. The O3-induced increase in
IL-5, and also in GM-CSF, which affects the growth, activation and
survival of eosinophils, may indicate an effect on the Th2-related
airway response and on airway eosinophils. The authors reported that
the O3-induced Th2-related cytokine responses that were
found within the asthmatic group may indicate a worsening of their
asthmatic airway inflammation and thus suggest a plausible link to
epidemiological data indicating O3-associated increases in
bronchial reactivity and hospital admissions.
    The accumulation of eosinophils in the airways of asthmatics is
followed by production of mucus and a late-phase bronchial constriction
and reduced airflow. In a study of 16 intermittent asthmatics,
Hiltermann et al. (1999) found that there was a significant inverse
correlation between the O3-induced change in the percentage
of eosinophils in induced sputum and the change in PC20, the
concentration of methacholine causing a 20% decrease in
FEV1. Characteristic O3-induced inflammatory
airway neutrophilia at one time was considered a leading mechanism of
airway hyperresponsiveness. However, Hiltermann et al. (1999)
determined that the O3-induced change in percentage
neutrophils in sputum was not significantly related to the change in
PC20. These results are consistent with the results of Zhang
et al. (1995), which found neutrophilia in a murine model to be only
coincidentally associated with airway hyperresponsiveness, i.e., there
was no cause and effect relationship. (Criteria Document, AX 6-26).
Hiltermann et al. (1999) concluded that the results point to the role
of eosinophils in O3-induced airway hyperresponsiveness.
Increases in O3-induced nonspecific airway responsiveness
incidence and duration could have important clinical implications for
asthmatics.
    Two studies (J[ouml]rres et al., 1996; Holz et al., 2002) observed
increased airway responsiveness to O3 exposure with
bronchial allergen challenge in subjects with preexisting allergic
airway disease. J[ouml]rres et al. (1996) found that O3
causes an increased response to bronchial allergen challenge in
subjects with allergic rhinitis and mild allergic asthma. The subjects
were exposed to 0.25 ppm O3 for 3 hours with IE. Airway
responsiveness to methacholine was determined 1 hour before and after
exposure; responsiveness to allergen was determined 3 hours after
exposure. Statistically significant decreases in FEV1
occurred in subjects with allergic rhinitis (13.8%) and allergic asthma
(10.6%), and in healthy controls (7.3%). Methacholine responsiveness
was statistically increased in asthmatics, but not in subjects with
allergic rhinitis or healthy controls. Airway responsiveness to an
individual's historical allergen (either grass and birch pollen, house
dust mite, or animal dander) was significantly increased after
O3 exposure when compared to FA exposure. In subjects with
asthma and allergic rhinitis, a maximum percent fall in FEV1
of 27.9% and 7.8%, respectively, occurred 3 days after O3
exposure when they were challenged with of the highest common dose of
allergen. The authors concluded that subjects with asthma or allergic
rhinitis, without asthma, could be at risk if a high O3
exposure is followed by a high dose of allergen. Holz et al. (2002)
reported an early phase lung function response in subjects with
rhinitis after a consecutive 4-day exposure to 0.125 ppm O3
that resulted in a clinically relevant (>20%) decrease in FEV1. Ozone-
induced exacerbation of airway responsiveness persists longer and
attenuates more slowly than O3-induced lung function
decrements and respiratory symptom responses and can have important
clinical implications for asthmatics.
    A small number of in vitro studies corroborate the differences in
the responses of asthmatic and healthy subject generally found in
controlled human exposure studies. In vitro studies (Schierhorn et al.,
1999) of nasal mucosal biopsies from atopic and nonatopic subjects
exposed to 0.1 ppm O3 found significant differences in
release of IL-4, IL-6, IL-8, and TNF-[alpha]. Another study by
Schierhorn et al. (2002) found significant differences in the
O3-induced release of the neuropeptides neurokinin A and
substance P for allergic patients in comparison to nonallergic
controls, suggesting increased activation of sensory nerves by
O3 in the allergic tissues. Another study by Bayram et al.
(2002) using in vitro culture of bronchial epithelial cells recovered
from atopic and nonatopic asthmatics also found significant increases
in epithelial permeability in response to O3 exposure.
    The new data on airway responsiveness, inflammation, and various
molecular markers of inflammation and bronchoconstriction indicate that
people with asthma and allergic rhinitis (with or without asthma)
comprise susceptible groups for O3-induced adverse effects.
This body of evidence indicates that human clinical and epidemiological
panel studies of lung function decrements and respiratory symptoms that
evaluate only healthy, non-asthmatic subjects likely underestimate the
effects of O3 exposure on asthmatics and other susceptible
populations. The effects of O3 on lung function,
inflammation, and increased airway responsiveness demonstrated in
subjects with asthma and other allergic airway diseases, provide
plausible mechanisms underlying the more serious respiratory morbidity
effects, such as emergency department visits and hospital admissions,
and respiratory mortality effects.
    A number of epidemiological studies have been conducted using
asthmatic study populations. The majority of epidemiological panel
studies that evaluated respiratory symptoms and medication use related
to O3 exposures focused on children. These studies suggest
that O3 exposure may be associated with increased
respiratory symptoms and medication use in children with asthma. Other
reported effects include respiratory symptoms, lung function
decrements, and emergency department visits, as discussed in the
Criteria Document (section <IP_ADDRESS>). Strong evidence from a large
multi-city study (Mortimer et al., 2002), along with support from
several single-city studies suggest that O3 exposure may be
associated with increased respiratory symptoms and medication use in
children with asthma. With regard to ambient O3 levels and
increased hospital admissions and emergency department visits for
asthma and other respiratory causes, strong and consistent evidence
establishes a correlation between O3 exposure and increased
exacerbations of preexisting respiratory disease for 1-hour maximum
O3 concentrations <0.12 ppm. As discussed in the Criteria
Document, section 7.3, several hospital admission and emergency
department visit studies in the U.S., Canada, and Europe have reported
positive associations between increase in O3 and increased
risk of emergency department visits and hospital admissions for asthma
and other respiratory diseases, especially during the warm season.
Finally, from epidemiological studies that included assessment of
associations with specific causes of death, some studies have observed
larger effects estimates for respiratory mortality and others have
observed larger effects estimates for cardiovascular mortality. The
apparent inconsistency regarding the effect size of O3-
related respiratory mortality may be due to reduced statistical power
in this

subcategory of mortality (EPA, 2006a, p. 7-108).
    Newly available reports from controlled human exposure studies (see
chapter 6 in the Criteria Document) utilized subjects with preexisting
cardiopulmonary diseases such as COPD, asthma, allergic rhinitis, and
hypertension. The data generated from these studies that evaluated
changes in spirometry did not find clear differences between filtered
air and O3 exposure in COPD subjects. However, the new data
on airway responsiveness, inflammation, and various molecular markers
of inflammation and bronchoconstriction indicate that people with
atopic asthma and allergic rhinitis comprise susceptible groups for
O3-induced adverse health effects.
    Although controlled human exposure studies have not found evidence
of larger spirometric changes in people with COPD relative to healthy
subjects, this may be due to the fact that most people with COPD are
older adults who would not be expected to have such changes based on
their age. However, in section 8.7.1, the Criteria Document notes that
new epidemiological evidence indicates that people with COPD may be
more likely to experience other effects, including emergency room
visits, hospital admissions, or premature mortality. For example,
results from an analysis of five European cities indicated strong and
consistent O3 effects on unscheduled respiratory hospital
admissions, including COPD (Anderson et al., 1997). Also, an analysis
of a 9-year data set for the whole population of the Netherlands
provided risk estimates for more specific causes of mortality,
including COPD (Hoek et al., 2000, 2001; reanalysis, Hoek, 2003); a
positive, but nonsignificant, excess risk of COPD-related mortality was
found to be associated with short-term O3 concentrations.
Moreover, as indicated by Gong et al. (1998), the effects of
O3 exposure on alveolar-arterial oxygen gradients may be
more pronounced in patients with preexisting obstructive lung diseases.
Relative to healthy elderly subjects, COPD patients have reduced gas
exchange and low SaO2. Any inflammatory or edematous responses due to
O3 delivered to the well-ventilated regions of the COPD lung
could further inhibit gas exchange and reduce oxygen saturation. In
addition, O3-induced vasoconstriction could also acutely
induce pulmonary hypertension. Inducing pulmonary vasoconstriction and
hypertension in these patients would perhaps worsen their condition,
especially if their right ventricular function was already compromised
(EPA, 2006a, section 6.10).
iii. Children and Older Adults
    Supporting evidence exists for heterogeneity in the effects of
O3 by age. As discussed in section 6.5.1 of the Criteria
Document, children, adolescents, and young adults (< 18 yrs of age)
appear, on average, to have nearly equivalent spirometric responses to
O3, but have greater responses than middle-aged and older
adults when exposed to comparable O3 doses. Symptomatic
responses to O3 exposure, however, do not appear to occur in
healthy children, but are observed in asthmatic children, particularly
those who use maintenance medications. For adults (>17 yrs of age)
symptoms gradually decrease with increasing age. In contrast to young
adults, the diminished symptomatic responses in children and the
diminished symptomatic and spirometric responses in older adults
increases the likelihood that these groups continue outdoor activities
leading to greater O3 exposure and dose.
    As described in the section <IP_ADDRESS> of the Criteria Document, many
epidemiological field studies focused on the effect of O3 on
the respiratory health of school children. In general, children
experienced decrements in pulmonary function parameters, including PEF,
FEV1, and FVC. Increases in respiratory symptoms and asthma
medication use were also observed in asthmatic children. In one German
study, children with and without asthma were found to be particularly
susceptible to O3 effects on lung function. Approximately
20% of the children, both with and without asthma, experienced a
greater than 10% change in FEV1, compared to only 5% of the
elderly population and athletes (Hoppe et al., 2003).
    The American Academy of Pediatrics (2004) notes that children and
infants are among the population groups most susceptible to many air
pollutants, including O3. This is in part because their
lungs are still developing. For example, eighty percent of alveoli are
formed after birth, and changes in lung development continue through
adolescence (Dietert et al., 2000). Children are also likely to spend
more time outdoors than adults, which results in increased exposure to
air pollutants (Wiley et al., 1991a,b). Moreover, children have high
minute ventilation rates and high levels of physical activity which
also increases their dose (Plunkett et al., 1992).
    Several mortality studies have investigated age-related differences
in O3 effects (EPA, 2006a, section <IP_ADDRESS>). Older adults
are also often classified as being particularly susceptible to air
pollution. The basis for increased O3 sensitivity among the
elderly is not known, but one hypothesis is that it may be related to
changes in the respiratory tract lining fluid antioxidant defense
network (Kelly et al., 2003). (EPA 2006a, p. 8-60) Older adults have
lower baseline lung function than younger people, and are also more
likely to have preexisting lung and heart disease. Increased
susceptibility of older adults to O3 health effects is most
clearly indicated in the newer mortality studies. Among the studies
that observed positive associations between O3 and
mortality, a comparison of all age or younger age (< =65 years of age)
O3-mortality effect estimates to that of the elderly
population (>65 years) indicates that, in general, the elderly
population is more susceptible to O3 mortality effects. The
meta-analysis by Bell et al. (2005) found a larger mortality effect
estimate for the elderly than for all ages. In the large U.S. 95
communities study (Bell et al., 2004), mortality effect estimates were
slightly higher for those aged 65 to 74 years, compared to individuals
less than 65 years and 75 years or greater. The absolute effect of
O3 on premature mortality may be substantially greater in
the elderly population because of higher rates of preexisting
respiratory and cardiac diseases. The Criteria Document concludes that
the elderly population (>65 years of age) appear to be at greater risk
of O3-related mortality and hospitalizations compared to all
ages or younger populations (EPA, 2006a, p. 7-177).
    The Criteria Document notes that, collectively, there is supporting
evidence of age-related differences in susceptibility to O3
lung function effects. The elderly population (>65 years of age) appear
to be at increased risk of O3-related mortality and
hospitalizations, and children (< 18 years of age) experience other
potentially adverse respiratory health outcomes with increased
O3 exposure (EPA, 2006a, section <IP_ADDRESS>).
iv. People With Increased Responsiveness to Ozone
    New animal toxicology studies using various strains of mice and
rats have identified O3-sensitive and resistant strains and
illustrated the importance of genetic background in determining
O3 susceptibility (EPA, 2006a, section 8.7.4). Controlled
human exposure studies have also indicated a high degree of variability
in some of the pulmonary physiological parameters. The variable effects
in individuals have

been found to be reproducible, in other words, a person who has a large
lung function response after exposure to O3 will likely have
about the same response if exposed again to the same dose of
O3. In human clinical studies, group mean responses are not
representative of this segment of the population that has much larger
than average responses to O3. Recent studies of asthmatics
by David et al. (2003) and Romieu et al. (2004) reported a role for
genetic polymorphism in observed differences in antioxidant enzymes and
genes involved in inflammation to modulate pulmonary function and
inflammatory responses to O3 exposure.\23\
---------------------------------------------------------------------------

    \23\ Similar to animal toxicology studies referred above, a
polymorphism in a specific proinflammatory cytokine gene has been
implicated in O3-induced lung function changes in
healthy, mild asthmatics and individuals with rhinitis. These
observations suggest a potential role for these markers in the
innate susceptibility to O3, however, the validity of
these markers and their relevance in the context of prediction to
population studies needs additional experimentation.
---------------------------------------------------------------------------

    Biochemical and molecular parameters extensively evaluated in these
experiments were used to identify specific loci on chromosomes and, in
some cases, to relate the differential expression of specific genes to
biochemical and physiological differences observed among these species.
Utilizing O3-sensitive and O3-resistant species,
it has been possible to identify the involvement of increased airway
reactivity and inflammation processes in O3 susceptibility.
However, most of these studies were carried out using relatively high
doses of O3, making the relevance of these studies
questionable in human health effects assessment. The genes and genetic
loci identified in these studies may serve as useful biomarkers and,
ultimately, can likely be integrated with epidemiological studies.
v. Other Population Groups
    There is limited, new evidence supporting associations between
short-term O3 exposures and a range of effects on the
cardiovascular system. Some but not all, epidemiological studies have
reported associations between short-term O3 exposures and
the incidence of MI and more subtle cardiovascular health endpoints,
such as changes in HRV and cardiac arrhythmia. Others have reported
associations with hospitalization or emergency department visits for
cardiovascular diseases, although the results across the studies are
not consistent. Studies also report associations between short-term
O3 exposure and mortality from cardiovascular or
cardiopulmonary causes. The Criteria Document concludes that current
cardiovascular effects evidence from some field studies is rather
limited but supportive of a potential effect of short-term
O3 exposure and HRV, cardiac arrhythmia, and MI incidence
(EPA, 2006a, p. 7-65). In the Criteria Document's evaluation of studies
of hospital admissions for cardiovascular disease (EPA 2006a, section
7.3.4), it is concluded that evidence from this growing group of
studies is generally inconclusive regarding an association with
O3 in studies conducted during the warm season (EPA 2006a,
p. 7-83). This body of evidence suggests that people with heart disease
may be at increased risk from short-term exposures to O3;
however, more evidence is needed to conclude that people with heart
disease are a susceptible population.
    Other groups that might have enhanced sensitivity to O3,
but for which there is currently very little evidence, include groups
based on race, gender and SES, and those with nutritional deficiencies,
which presents factors which modify responsiveness to O3.
c. Adversity of Effects
    In making judgments as to when various O3-related
effects become regarded as adverse to the health of individuals, the
Administrator has looked to guidelines published by the American
Thoracic Society (ATS) and the advice of CASAC. While recognizing that
perceptions of ``medical significance'' and ``normal activity'' may
differ among physicians, lung physiologists and experimental subjects,
the ATS (1985) \24\ defined adverse respiratory health effects as
``medically significant physiologic changes generally evidenced by one
or more of the following: (1) Interference with the normal activity of
the affected person or persons, (2) episodic respiratory illness, (3)
incapacitating illness, (4) permanent respiratory injury, and/or (5)
progressive respiratory dysfunction.'' During the 1997 review, it was
concluded that there was evidence of causal associations from
controlled human exposure studies for effects in the first of these
five ATS-defined categories, evidence of statistically significant
associations from epidemiological studies for effects in the second and
third categories, and evidence from animal toxicology studies, which
could be extrapolated to humans only with a significant degree of
uncertainty, for the last two categories.
---------------------------------------------------------------------------

    \24\ In 2000, the American Thoracic Society (ATS) published an
official statement on ``What Constitutes an Adverse Health Effect of
Air Pollution?'' (ATS, 2000), which updated its earlier guidance
(ATS, 1985). Overall, the new guidance does not fundamentally change
the approach previously taken to define adversity, nor does it
suggest a need at this time to change the structure or content of
the tables describing gradation of severity and adversity of effects
described below.
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    For ethical reasons, clear causal evidence from controlled human
exposure studies still covers only effects in the first category.
However, for this review there are results from epidemiological
studies, upon which to base judgments about adversity, for effects in
all of the categories. Statistically significant and robust
associations have been reported in epidemiology studies falling into
the second and third categories. These more serious effects include
respiratory events (e.g., triggering asthma attacks) that may require
medication (e.g., asthma), but not necessarily hospitalization, as well
as respiratory hospital admissions and emergency department visits for
respiratory causes. Less conclusive, but still positive associations
have been reported for school absences and cardiovascular hospital
admissions. Human health effects for which associations have been
suggested through evidence from epidemiological and animal toxicology
studies, but have not been conclusively demonstrated still fall
primarily into the last two categories. In the last review of the
O3 standard, evidence for these more serious effects came
from studies of effects in laboratory animals. Evidence from animal
studies evaluated in this Criteria Document strongly suggests that
O3 is capable of damaging the distal airways and proximal
alveoli, resulting in lung tissue remodeling leading to apparently
irreversible changes. Recent advancements of dosimetry modeling also
provide a better basis for extrapolation from animals to humans.
Information from epidemiological studies provides supporting, but
limited evidence of irreversible respiratory effects in humans than was
available in the prior review. Moreover, the findings from single-city
and multi-city time-series epidemiology studies and meta-analyses of
these epidemiology studies are highly suggestive of an association
between short-term O3 exposure and mortality particularly in
the warm season.
    While O3 has been associated with effects that are
clearly adverse, application of these guidelines, in particular to the
least serious category of effects related to ambient O3
exposures, involves judgments about which medical experts on the CASAC
panel and public commenters have expressed diverse views in the past.
To help frame such judgments, EPA staff have defined specific ranges of
functional responses

(e.g., decrements in FEV1 and airway responsiveness) and
symptomatic responses (e.g., cough, chest pain, wheeze), together with
judgments as to the potential impact on individuals experiencing
varying degrees of severity of these responses, that have been used in
previous NAAQS reviews. These ranges of pulmonary responses and their
associated potential impacts are summarized in Tables 3-2 and 3-3 of
the Staff Paper.
    For active healthy people, moderate levels of functional responses
(e.g., FEV1 decrements of >=10% but <20%, lasting up to 24
hours) and/or moderate symptomatic responses (e.g., frequent
spontaneous cough, marked discomfort on exercise or deep breath,
lasting up to 24 hours) would likely interfere with normal activity for
relatively few responsive individuals. On the other hand, EPA staff
determined that large functional responses (e.g., FEV1
decrements >=20%, lasting longer than 24 hours) and/or severe
symptomatic responses (e.g., persistent uncontrollable cough, severe
discomfort on exercise or deep breath, lasting longer than 24 hours)
would likely interfere with normal activities for many responsive
individuals. EPA staff determined that these would be considered
adverse under ATS guidelines. In the context of standard setting, CASAC
indicated that a focus on the mid to upper end of the range of moderate
levels of functional responses (e.g., FEV1 decrements >=15%
but < 20%) is appropriate for estimating potentially adverse lung
function decrements in active healthy people. However, for people with
lung disease, even moderate functional (e.g., FEV1
decrements >=10% but <20%, lasting up to 24 hours) or symptomatic
responses (e.g., frequent spontaneous cough, marked discomfort on
exercise or with deep breath, wheeze accompanied by shortness of
breath, lasting up to 24 hours) would likely interfere with normal
activity for many individuals, and would likely result in more frequent
use of medication. For people with lung disease, large functional
responses (e.g., FEV1 decrements >=20%, lasting longer than
24 hours) and/or severe symptomatic responses (e.g., persistent
uncontrollable cough, severe discomfort on exercise or deep breath,
persistent wheeze accompanied by shortness of breath, lasting longer
than 24 hours) would likely interfere with normal activity for most
individuals and would increase the likelihood that these individuals
would seek medical treatment. In the context of standard setting, the
CASAC indicated (Henderson, 2006c) that a focus on the lower end of the
range of moderate levels of functional responses (e.g., FEV1
decrements >=10%) is most appropriate for estimating potentially
adverse lung function decrements in active healthy people.
    In judging the extent to which these impacts represent effects that
should be regarded as adverse to the health status of individuals, an
additional factor that has been considered in previous NAAQS reviews is
whether such effects are experienced repeatedly during the course of a
year or only on a single occasion. While some experts would judge
single occurrences of moderate responses to be a ``nuisance,''
especially for healthy individuals, a more general consensus view of
the adversity of such moderate responses emerges as the frequency of
occurrence increases.
    The new guidance builds upon and expands the 1985 definition of
adversity in several ways. There is an increased focus on quality of
life measures as indicators of adversity. There is also a more specific
consideration of population risk. Exposure to air pollution that
increases the risk of an adverse effect to the entire population is
adverse, even though it may not increase the risk of any individual to
an unacceptable level. For example, a population of asthmatics could
have a distribution of lung function such that no individual has a
level associated with significant impairment. Exposure to air pollution
could shift the distribution to lower levels that still do not bring
any individual to a level that is associated with clinically relevant
effects. However, this would be considered to be adverse because
individuals within the population would have diminished reserve
function, and therefore would be at increased risk if affected by
another agent.
    Of the various effects of O3 exposure that have been
studied, many would meet the ATS definition of adversity. Such effects
include, for example, any detectible level of permanent lung function
loss attributable to air pollution, including both reductions in lung
growth or acceleration of the age-related decline of lung function;
exacerbations of disease in individuals with chronic cardiopulmonary
diseases; reversible loss of lung function in combination with the
presence of symptoms; as well as more serious effects such as those
requiring medical care including hospitalization and, obviously,
mortality.
d. Size of At-Risk Subpopulations
    Although O3-related health risk estimates may appear to
be small, their significance from an overall public health perspective
is determined by the large numbers of individuals in the subpopulations
potentially at-risk for O3-related health effects discussed
above. For example, a population of concern includes people with
respiratory disease, including approximately 11 percent of U.S. adults
and 13 percent of children who have been diagnosed with asthma and 6
percent of adults with chronic obstructive pulmonary disease (chronic
bronchitis and/or emphysema) in 2002 and 2003 (Table 8-4 in the
Criteria Document, section <IP_ADDRESS>). More broadly, individuals with
preexisting cardiopulmonary disease may constitute an additional
population of concern, with potentially tens of millions of people
included in each disease category. In addition, subpopulations based on
age group also comprise substantial segments of the population that may
be potentially at risk for O3-related health impacts. Based
on U.S. census data from 2003, about 26 percent of the U.S. population
are under 18 years of age and 12 percent are 65 years of age or older.
Hence, large proportions of the U.S. population are included in age
groups include those most likely to have increased susceptibility to
the health effects of O3 and or those with the highest
ambient O3 exposures.
    The Criteria Document (section <IP_ADDRESS>) notes that the health
statistics data illustrate what is known as the ``pyramid'' of effects.
At the top of the pyramid, there are approximately 2.5 millions deaths
from all causes per year in the U.S. population, with about 100,000
deaths from chronic lower respiratory diseases. For respiratory health
diseases, there are nearly 4 million hospital discharges per year, 14
million emergency department visits, 112 million ambulatory care
visits, and an estimated 700 million restricted activity days per year
due to respiratory conditions from all causes per year. Applying small
risk estimates for the O3-related contribution to such
health effects with relatively large baseline levels of health outcomes
can result in quite large public health impacts related to ambient
O3 exposure. Thus, even a small percentage reduction in
O3 health impacts on cardiopulmonary diseases would reflect
a large number of avoided cases. In considering this information
together with the concentration-response relationships that have been
observed between exposure to O3 and various health
endpoints, the Criteria

Document (section <IP_ADDRESS>) concludes that exposure to ambient
O3 likely has a significant impact on public health in the
U.S.

B. Human Exposure and Health Risk Assessments

    To put judgments about health effects that are adverse for
individuals into a broader public health context, EPA has developed and
applied models to estimate human exposures and health risks. This
broader context includes consideration of the size of particular
population groups at risk for various effects, the likelihood that
exposures of concern will occur for individuals in such groups under
varying air quality scenarios, estimates of the number of people likely
to experience O3-related effects, the variability in
estimated exposures and risks, and the kind and degree of uncertainties
inherent in assessing the exposures and risks involved.
    As discussed below there are a number of important uncertainties
that affect the exposure and health risk estimates. It is also
important to note that there have been significant improvements in both
the exposure and health risk model. CASAC expressed the view that the
exposure analysis represents a state-of-the-art modeling approach and
that the health risk assessment was ``well done, balanced and
reasonably communicated'' (Henderson, 2006c). While recognizing and
considering the kind and degree of uncertainties in both the exposure
and health risk estimates, the Staff Paper judged that the quality of
the estimates is such that they are suitable to be used as an input to
the Administrator's decisions on the O3 primary standard
(Staff Paper, p. 6-20--6-21).
    In modeling exposures and health risks associated with just meeting
the current and alternative O3 standards, EPA has simulated
air quality to represent conditions just meeting these standards based
on O3 air quality patterns in several recent years and on
how the shape of the O3 air quality distribution has changed
over time based on historical trends in monitored O3 air
quality data. As described in the Staff Paper (section 4.5.8) and
discussed below, recent O3 air quality distributions have
been statistically adjusted to simulate just meeting the current and
selected alternative standards. These simulations do not reflect any
consideration of specific control programs or strategies designed to
achieve the reductions in emissions required to meet the specified
standards. Further, these simulations do not represent predictions of
when, whether, or how areas might meet the specified standards.\25\
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    \25\ Modeling that projects whether and how areas might attain
alternative standards in a future year is presented in the
Regulatory Impact Analysis being prepared in connection with this
rulemaking.
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    As noted in section I.C above, around the time of the release of
the final Staff Paper in January 2007, EPA discovered a small error in
the exposure model that when corrected resulted in slight increases in
the simulated exposures. Since the exposure estimates are an input to
the lung function portion of the health risk assessment, this
correction also resulted in slight increases in the lung function risk
estimates as well. The exposure and risk estimates discussed in this
notice reflect the corrected estimates, and thus are slightly different
than the exposure and risk estimates cited in the January 31, 2007
Staff Paper.\26\
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    \26\ EPA plans to make available corrected versions of the final
Staff Paper, and human exposure and health risk assessment technical
support documents on or around July 16, 2007 on the EPA web site
listed in the Availability of Related Information section of this
notice.
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1. Exposure Analyses
a. Overview
    The EPA conducted exposure analyses using a simulation model to
estimate O3 exposures for the general population, school age
children (ages 5-18), and school age children with asthma living in 12
U.S. metropolitan areas representing different regions of the country
where the current 8-hour O3 standard is not met. The
emphasis on children reflects the finding of the last O3
NAAQS review that children are an important at-risk group. The 12
modeled areas combined represent a significant fraction of the U.S.
urban population, 89 million people, including 18 million school age
children of whom approximately 2.6 million have asthma. The selection
of urban areas to include in the exposure analysis took into
consideration the location of O3 epidemiological studies,
the availability of ambient O3 data, and the desire to
represent a range of geographic areas, population demographics, and
O3 climatology. These selection criteria are discussed
further in chapter 5 of the Staff Paper. The geographic extent of each
modeled area consists of the census tracts in the combined statistical
area (CSA) as defined by OMB (OMB, 2005).\27\
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    \27\ The 12 CSAs modeled are: Atlanta-Sandy Springs-Gainesville,
GA-AL; Boston-Worcester-Manchester, MA-NH; Chicago-Naperville-
Michigan City, IL-IN-WI; Cleveland-Akron-Elyria, OH; Detroit-Warren-
Flint, MI; Houston-Baytown-Huntsville, TX; Los Angeles-Long Beach-
Riverside, CA; New York-Newark-Bridgeport, NY-NJ-CT-PA;
Philadelphia-Camden-Vineland, PA-NJ-DE-MD; Sacramento-Arden-Arcade-
Truckee, CA-NV; St. Louis-St. Charles-Farmington, MO-IL; Washington-
Baltimore-N. Virginia, DC-MD-VA-WV.
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    Exposure estimates were developed using a probabilistic exposure
model that is designed to explicitly model the numerous sources of
variability that affect people's exposures. As discussed below, the
model estimates population exposures by simulating human activity
patterns, air conditioning prevalence, air exchange rates, and other
factors. The modeled exposure estimates were developed for three recent
years of ambient O3 concentrations (2002, 2003, and 2004),
as well as for O3 concentrations adjusted to simulate
conditions associated with just meeting the current NAAQS and various
alternative 8-hour standards based on the three year period 2002-
2004.\28\ This exposure assessment is more fully described and
presented in the Staff Paper and in a technical support document, Ozone
Population Exposure Analysis for Selected Urban Areas (US EPA, 2006b;
hereafter Exposure Analysis TSD). The scope and methodology for this
exposure assessment were developed over the last few years with
considerable input from the CASAC Ozone Panel and the public.\29\
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    \28\ All 12 of the CSAs modeled did not meet the current
O3 NAAQS for the three year period examined.
    \29\ The general approach used in the current exposure
assessment was described in the draft Health Assessment Plan (EPA,
2005a) that was released to the CASAC and general public in April
2005 and was the subject of a consultation with the CASAC
O3 Panel on May 5, 2005. In October 2005, OAQPS released
the first draft of the Staff Paper containing a chapter discussing
the exposure analyses and first draft of the Exposure Analyses TSD
for CASAC consultation and public review on December 8, 2005. In
July 2006, OAQPS released the second draft of the Staff Paper and
second draft of the Exposure Analyses TSD for CASAC review and
public comment which was held by the CASAC O3 Panel on
August 24-25, 2006.
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    The goals of the O3 exposure assessment were: (1) To
provide estimates of the size of at-risk populations exposed to various
levels associated with recent O3 concentrations, and with
just meeting the current O3 NAAQS and alternative
O3 standards, in specific urban areas; (2) to provide
distributions of exposure estimates over the entire range of ambient
O3 concentrations as an important input to the lung function
risk assessment summarized below in section II.B.2; (3) to develop a
better understanding of the influence of various inputs and assumptions
on the exposure estimates; and (4) to gain insight into the
distribution of exposures and patterns of exposure

reductions associated with meeting alternative O3 standards.
    EPA recognizes that there are many sources of variability and
uncertainty inherent in the inputs to this assessment and that there is
uncertainty in the resulting O3 exposure estimates. With
respect to variability, the exposure modeling approach accounts for
variability in ambient O3 levels, demographic
characteristics, physiological attributes, activity patterns, and