population-level metrics that CASAC advised were most useful to
consider in identifying the PM2.5 concentrations

most influential in generating the health effect estimates reported in
the epidemiological studies.\23\ Consistent with CASAC advice, the most
relevant information was the distribution of health events (e.g.,
deaths, hospitalizations) occurring within a study population in
relation to the distribution of PM2.5 concentrations.
However, in recognizing that access to health event data can be
restricted, the Policy Assessment also considered the number of study
participants within each study area as an appropriate surrogate for
health event data.
---------------------------------------------------------------------------

    \23\ The second draft Policy Assessment focused on the
distributions of ambient PM2.5 concentrations and
associated population data across areas included in several multi-
city studies for which such data were available in seeking to
identify the most influential range of concentrations (U.S. EPA,
2010f, section <IP_ADDRESS>). In its review of the second draft Policy
Assessment, CASAC advised that it ``would be preferable to have
information on the concentrations that were most influential in
generating the health effect estimates in individual studies''
(Samet, 2010d, p.2). Therefore, in the final Policy Assessment, the
EPA considered population-level data (i.e., area-specific health
event data and study area population data) along with corresponding
PM2.5 concentrations to generate a cumulative
distribution of the population-level data relative to long-term mean
PM2.5 concentrations to determine the most influential
part of the air quality distribution (U.S. EPA, 2011a, Figure 2-7
and associated text).
---------------------------------------------------------------------------

    The Policy Assessment recognized that an approach considering
analyses of confidence intervals around concentration-response
functions was intrinsically related to an approach that considered
different distributional statistics. Both of these approaches could be
employed to understand the broader distribution of PM2.5
concentrations which correspond to the health events reported in
epidemiological studies. In applying these approaches, the Policy
Assessment, consistent with CASAC advice (Samet, 2010d, p. 3),
considered PM2.5 concentrations from long- and short-term
PM2.5 exposure studies using composite monitor
distributions.
    In reaching staff conclusions on alternative standard levels that
were appropriate to consider, the Policy Assessment also included a
broader consideration of the uncertainties and limitations of the
current scientific evidence. Most notably, these uncertainties are
related to the heterogeneity observed in the epidemiological studies in
the eastern versus western parts of the U.S., the relative toxicity of
PM2.5 components, and the potential role of co-pollutants
(U.S. EPA, 2011a, pp. 2-25 to 2-26). The limitations and uncertainties
associated with the currently available scientific evidence, including
the availability of fewer studies toward the lower range of alternative
annual standard levels being considered in this proposal, are
summarized in section III.B below and further discussed in section
III.B.2 of the proposal.
    The Policy Assessment recognized that the level of protection
afforded by the NAAQS relies both on the level and the form of the
standard. The Policy Assessment concluded that a policy approach that
used data based on composite monitor distributions to identify
alternative standard levels, and then compared those levels to
concentrations at maximum monitors to determine whether an area meets a
given standard, inherently has the potential to build in some margin of
safety (U.S. EPA, 2011a, p. 2-14).\24\ This conclusion was consistent
with CASAC's comments on the second draft Policy Assessment, in which
CASAC expressed its preference for focusing on an approach using
composite monitor distributions ``because of its stability, and for the
additional margin of safety it provides'' when ``compared to the
maximum monitor perspective'' (Samet, et al., 2010d, pp. 2 to 3).
---------------------------------------------------------------------------

    \24\ Statistical metrics (e.g., means) based on composite
monitor distributions may be identical to or below the same
statistical metrics based on maximum monitor distributions. For
example, some areas may have only one monitor, in which case the
composite and maximum monitor distributions will be identical in
those areas. Other areas may have multiple monitors that may be very
close to the monitor measuring the highest concentrations, in which
case the composite and maximum monitor distributions could be
similar in those areas. As noted in Hassett-Sipple et al. (2010),
for studies involving a large number of areas, the composite and
maximum concentrations are generally within 5 percent of each other
(77 FR 38905, fn. 30). Still other areas may have multiple monitors
that may be separately impacted by local sources in which case the
composite and maximum monitor distributions could be quite different
(U.S. EPA, 2011a, p. 2-14). See further discussion of this issue in
section III.E.4.c.i below.
---------------------------------------------------------------------------

    In reaching staff conclusions on alternative 24-hour standard
levels that are appropriate to consider for setting a 24-hour standard
intended to supplement the protection afforded by a generally
controlling annual standard, the Policy Assessment considered currently
available short-term PM2.5 exposure studies. The evidence
from these studies informed our understanding of the protection
afforded by the suite of standards against effects associated with
short-term exposures. In considering the short-term exposure studies,
the Policy Assessment evaluated both the distributions of 24-hour
PM2.5 concentrations, with a focus on the 98th percentile
concentrations (to the extent such data were available) to match the
form of the current 24-hour PM2.5 standard, as well as the
long-term mean PM2.5 concentrations reported in these
studies. In addition to considering the epidemiological evidence, the
Policy Assessment also considered air quality information based on
county-level 24-hour and annual design values \25\ to understand the
policy implications of the alternative standard levels supported by the
underlying science. In particular, the Policy Assessment considered the
extent to which different combinations of alternative annual and 24-
hour standards would support the policy goal of focusing on a generally
controlling annual standard in conjunction with a 24-hour standard that
would provide supplemental protection. In so doing, the Policy
Assessment discussed the roles that each standard might be expected to
play in the protection afforded by alternative suites of standards.
---------------------------------------------------------------------------

    \25\ Design values are the metrics (i.e., statistics) that are
compared to the NAAQS levels to determine compliance.
---------------------------------------------------------------------------

    Beyond these evidence-based considerations, the Policy Assessment
also considered the quantitative risk estimates and the key
observations presented in the Risk Assessment. This assessment included
an evaluation of 15 urban case study areas and estimated risk
associated with a number of health endpoints associated with long- and
short-term PM2.5 exposures (U.S. EPA, 2010a). As part of the
risk-based considerations, the Policy Assessment considered estimates
of the magnitude of PM2.5-related risks associated with
recent air quality levels and air quality simulated to just meet the
current and alternative suites of standards using alternative
simulation approaches. The Policy Assessment also characterized the
risk reductions, relative to the risks remaining upon just meeting the
current standards, associated with just meeting alternative suites of
standards. In so doing, the Policy Assessment recognized the
uncertainties inherent in such risk estimates, and took such
uncertainties into account by considering the sensitivity of the
``core'' risk estimates to alternative assumptions and methods likely
to have substantial impact on the estimates. In addition, the Policy
Assessment considered additional analyses characterizing the
representativeness of the urban study areas within a broader national
context to understand the roles that the annual and 24-hour standards
may play in affording protection against effects related to both long-
and short-term PM2.5 exposures.
    Based on the approach discussed above, the Policy Assessment
reached conclusions related to the primary PM2.5 standards
that reflected an

understanding of both evidence-based and risk-based considerations to
inform two overarching questions related to: (1) The adequacy of the
current suite of PM2.5 standards and (2) revisions to the
standards that were appropriate to consider in this review to protect
against health effects associated with both long- and short-term
exposures to fine particles. When evaluating the health protection
afforded by the current or any alternative suites of standards
considered, the Policy Assessment took into account the four basic
elements of the NAAQS: The indicator, averaging time, form, and level.
    The general approach for reviewing the primary PM2.5
standards described above provided a comprehensive basis that helped to
inform the Administrator's judgments in reaching her proposed and final
decisions to revise the current suite of primary fine particle NAAQS
and in responding to the remand of the 2006 primary annual
PM2.5 standard.

B. Overview of Health Effects Evidence

    This section outlines the key information presented in section
III.B of the proposal (77 FR 38906 to 38911, June 29, 2012) and
discussed more fully in the Integrated Science Assessment (Chapters 2,
4, 5, 6, 7, and 8) and the Policy Assessment (Chapter 2) related to
health effects associated with fine particle exposures. Section III.B.
of the proposal discusses available information on the health effects
associated with exposures to PM2.5, including the nature of
such health effects (section III.B.1) and associated limitations and
uncertainties (section III.B.2), at-risk populations (section III.B.3),
and potential PM2.5-related impacts on public health
(section III.B.4). As was true in the last two reviews, evidence from
epidemiological, controlled human exposure and animal toxicological
studies played a key role in the Integrated Science Assessment's
evaluation of the scientific evidence.
    The 2006 PM NAAQS review concluded that there was ``strong
epidemiological evidence'' for linking long-term PM2.5
exposures with cardiovascular-related and lung cancer mortality and
respiratory-related morbidity and for linking short-term
PM2.5 exposures with cardiovascular-related and respiratory-
related mortality and morbidity (U.S. EPA, 2004, p. 9-46; U.S. EPA,
2005, p. 5-4). Overall, the evidence from epidemiological,
toxicological, and controlled human exposure studies supported ``likely
causal associations'' between PM2.5 and both mortality and
morbidity from cardiovascular and respiratory diseases, based on ``an
assessment of strength, robustness, and consistency in results'' (U.S.
EPA, 2004, p. 9-48).\26\
---------------------------------------------------------------------------

    \26\ The term ``likely causal association'' was used in the 2004
Criteria Document to summarize the strength of the available
evidence available in the last review for PM2.5. However,
this terminology was not based on a formal framework for evaluating
evidence for inferring causation. Since the last review, the EPA has
developed a more formal framework for reaching causal determinations
with standardized language to express evaluation of the evidence
(U.S. EPA, 2009a, section 1.5).
---------------------------------------------------------------------------

    In this review, based on the expanded body of evidence, the EPA
finds that:

    (1) In looking across the extensive new scientific evidence
available in this review, our overall understanding of health
effects associated with fine particle exposures has been greatly
expanded. The currently available evidence is largely consistent
with evidence available in the last review and substantially
strengthens what is known about the effects associated with fine
particle exposures.
    (2) A number of large multi-city epidemiological studies have
been conducted throughout the U.S., including extended analyses of
long-term exposure studies that were important to inform decision-
making in the last review. The body of currently available
scientific evidence has also been expanded greatly by the
publication of a number of new multi-city, time-series studies that
have used uniform methodologies to investigate the effects of short-
term PM2.5 exposures on public health. This body of
evidence provides a more expansive data base and considers multiple
locations representing varying regions and seasons that provide
evidence of the influence of different air pollution mixes on
PM2.5-associated health effects. These studies provide
more precise estimates of the magnitude of effects associated with
short-term PM2.5 exposure than most smaller-scale single-
city studies that were more commonly available in the last review.
These studies have reported consistent increases in morbidity and/or
premature mortality related to ambient PM2.5
concentrations, with the strongest evidence reported for
cardiovascular-related effects.
    (3) In addition, the findings of new toxicological and
controlled human exposure studies greatly expand and provide
stronger support for a number of potential biological mechanisms or
pathways for cardiovascular and respiratory effects associated with
long- and short-term PM exposures. These studies provide coherence
and biological plausibility for the effects observed in
epidemiological studies.
    (4) Using a more formal framework for reaching causal
determinations than used in prior reviews,\27\ the EPA concludes
that a causal relationship exists between both long- and short-term
exposures to PM2.5 and premature mortality and
cardiovascular effects and a likely causal relationship exists
between long- and short-term PM2.5 exposures and
respiratory effects. Further, there is evidence suggestive of a
causal relationship between long-term PM2.5 exposures and
other health effects, including developmental and reproductive
effects (e.g., low birth weight, infant mortality) and carcinogenic,
mutagenic, and genotoxic effects (e.g., lung cancer mortality).\28\
---------------------------------------------------------------------------

    \27\ The causal framework draws upon the assessment and
integration of evidence from across epidemiological, controlled
human exposure, and toxicological studies, and the related
uncertainties that ultimately influence our understanding of the
evidence. This framework employs a five-level hierarchy that
classifies the overall weight of evidence and causality using the
following categorizations: causal relationship, likely to be causal
relationship, suggestive of a causal relationship, inadequate to
infer a causal relationship, and not likely to be a causal
relationship (U.S. EPA, 2009a, Table 1-3). The development of the
causal framework reflects considerable input from CASAC and the
public, with CASAC concluding that, ``The five-level classification
of strength of evidence for causal inference has been systemically
applied [for PM]; this approach has provided transparency and a
clear statement of the level of confidence with regard to causation,
and we recommend its continued use in future ISAs'' (Samet, 2009f,
p. 1).
    \28\ These causal inferences are based not only on the more
expansive epidemiological evidence available in this review but also
reflect consideration of important progress that has been made to
advance our understanding of a number of potential biologic modes of
action or pathways for PM-related cardiovascular and respiratory
effects (U.S. EPA, 2009a, chapter 5).
---------------------------------------------------------------------------

    (5) The newly available evidence significantly strengthens the
link between long- and short-term exposure to PM2.5 and
premature mortality, while providing indications that the magnitude
of the PM2.5-mortality association with long-term
exposures may be larger than previously estimated. The strongest
evidence comes from recent studies investigating long-term exposure
to PM2.5 and cardiovascular-related mortality. The
evidence supporting a causal relationship between long-term
PM2.5 exposure and mortality also includes consideration
of new studies that demonstrated an improvement in community health
following reductions in ambient fine particles.
    (6) Several new studies have examined the association between
cardiovascular effects and long-term PM2.5 exposures in
multi-city studies conducted in the U.S. and Europe. While studies
were not available in the last review with regard to long-term
exposure and cardiovascular-related morbidity, recent studies have
provided new evidence linking long-term exposure to PM2.5
with an array of cardiovascular effects such as heart attacks,
congestive heart failure, stroke, and mortality. This evidence is
coherent with studies of short-term exposure to PM2.5
that have observed associations with a continuum of effects ranging
from subtle changes in indicators of cardiovascular health to
serious clinical events, such as increased hospitalizations and
emergency department visits due to cardiovascular disease and
cardiovascular mortality.
    (7) Extended analyses of studies available in the last review as
well as new epidemiological studies conducted in the U.S. and abroad
provide stronger evidence of respiratory-related morbidity effects
associated with long-term PM2.5 exposure. The strongest
evidence for respiratory-related

effects is from studies that evaluated decrements in lung function
growth, increased respiratory symptoms, and asthma development. The
strongest evidence from short-term PM2.5 exposure studies
has been observed for increased respiratory-related emergency
department visits and hospital admissions for chronic obstructive
pulmonary disease (COPD) and respiratory infections.
    (8) The body of scientific evidence is somewhat expanded from
the 2006 review but is still limited with respect to associations
between long-term PM2.5 exposures and developmental and
reproductive effects as well as cancer, mutagenic, and genotoxic
effects. The strongest evidence for an association between
PM2.5 and developmental and reproductive effects comes
from epidemiological studies of low birth weight and infant
mortality, especially due to respiratory causes during the post-
neonatal period (i.e., 1 month-12 months of age). With regard to
cancer effects, ``[m]ultiple epidemiologic studies have shown a
consistent positive association between PM2.5 and lung
cancer mortality, but studies have generally not reported
associations between PM2.5 and lung cancer incidence''
(U.S. EPA 2009a p. 2-13).
    (9) Efforts to evaluate the relationships between PM composition
and health effects continue to evolve. While many constituents of
PM2.5 can be linked with differing health effects, the
evidence is not yet sufficient to allow differentiation of those
constituents or sources that may be more closely related to specific
health outcomes nor to exclude any individual component or group of
components associated with any source categories from the fine
particle mixture of concern.
    (10) Specific groups within the general population are at
increased risk for experiencing adverse health effects related to PM
exposures. The currently available evidence expands our
understanding of previously identified at-risk populations (i.e.,
children, older adults, and individuals with pre-existing heart and
lung disease) and supports the identification of additional at-risk
populations (e.g., persons with lower socioeconomic status, genetic
differences). Evidence for PM-related effects in these at-risk
populations has expanded and is stronger than previously observed.
There is emerging, though still limited, evidence for additional
potentially at-risk populations, such as those with diabetes, people
who are obese, pregnant women, and the developing fetus.
    (11) The population potentially affected by PM2.5 is
large. In addition, large subgroups of the U.S. population have been
identified as at-risk populations. While individual effect estimates
from epidemiological studies may be small in size, the public health
impact of the mortality and morbidity associations can be quite
large given the extent of exposure. Taken together, this suggests
that exposure to ambient PM2.5 concentrations can have
substantial public health impacts.
    (12) While the currently available scientific evidence is
stronger and more consistent than in previous reviews, providing a
strong basis for decision making in this review, the EPA recognizes
that important uncertainties and limitations in the health effects
evidence remain. Epidemiological studies evaluating health effects
associated with long- and short-term PM2.5 exposures have
reported heterogeneity in responses between cities and geographic
regions within the U.S. This heterogeneity may be attributed, in
part, to differences in the fine particle composition or related to
exposure measurement error, which can introduce bias and increased
uncertainty in associated health effect estimates. Variability in
the associations observed across PM2.5 epidemiological
studies may be due in part to exposure error related to measurement-
related issues, the use of central fixed-site monitors to represent
population exposure to PM2.5, models used in lieu of or
to supplement ambient measurements, and our limited understanding of
factors that may influence exposures (e.g., topography, the built
environment, weather, source characteristics, ventilation usage,
personal activity patterns, photochemistry). In addition, where
PM2.5 and other pollutants (e.g., ozone, nitrogen
dioxide, and carbon monoxide) are correlated, it can be difficult to
distinguish the effects of the various pollutants in the ambient
mixture (i.e., co-pollutant confounding).\29\
---------------------------------------------------------------------------

    \29\ A copollutant meets the criteria for potential confounding
in PM-health associations if: (1) It is a potential risk factor for
the health effect under study; (2) it is correlated with PM; and (3)
it does not act as an intermediate step in the pathway between PM
exposure and the health effect under study (U.S. EPA, 2004, p. 8-
10).
---------------------------------------------------------------------------

    While uncertainties and limitations still remain in the available
health effects evidence, the Administrator judges the currently
available scientific data base to be stronger and more consistent than
in previous reviews providing a strong basis for decision making in
this review.

C. Overview of Quantitative Characterization of Health Risks

    In addition to a comprehensive evaluation of the health effects
evidence available in this review, the EPA conducted an expanded
quantitative risk assessment for selected health endpoints to provide
additional information and insights to inform decisions on the primary
PM2.5 NAAQS.\30\ As discussed in section III.C of the
proposal, the approach used to develop quantitative risk estimates
associated with PM2.5 exposures was built on the approach
used and lessons learned in the last review and focused on improving
the characterization of the overall confidence in the risk estimates,
including related uncertainties, by incorporating a number of
enhancements, in terms of both the methods and data used in the
analyses.
---------------------------------------------------------------------------

    \30\ The quantitative risk assessment conducted for this review
is more fully described and presented in the Risk Assessment (U.S.
EPA, 2010a) and summarized in detail in the Policy Assessment (U.S.
EPA, 2011a, sections 2.2.2. and <IP_ADDRESS>). The scope and methodology
for this risk assessment were developed over the last few years with
considerable input from CASAC and the public as described in section
II.B.3 above.
---------------------------------------------------------------------------

    The goals of this quantitative risk assessment were largely the
same as those articulated in the risk assessment conducted for the last
review. These goals included: (1) To provide estimates of the potential
magnitude of premature mortality and/or selected morbidity effects in
the population associated with recent ambient levels of
PM2.5 and with simulating just meeting the current and
alternative suites of PM2.5 standards in 15 selected urban
study areas,\31\ including, where data were available, consideration of
impacts on at-risk populations; (2) to develop a better understanding
of the influence of various inputs and assumptions on the risk
estimates to more clearly differentiate among alternative suites of
standards; and (3) to gain insights into the distribution of risks and
patterns of risk reductions and the variability and uncertainties in
those risk estimates. In addition, the quantitative risk assessment
included nationwide estimates of the potential magnitude of premature
mortality associated with long-term exposure to recent ambient
PM2.5 concentrations to more broadly characterize this risk
on a national scale and to support the interpretation of the more
detailed risk estimates generated for selected urban study areas.
---------------------------------------------------------------------------

    \31\ The Risk Assessment concluded that these 15 urban study
areas were generally representative of urban areas in the U.S.
likely to experience relatively elevated levels of risk related to
ambient PM2.5 exposure with the potential for better
characterization at the higher end of that distribution (U.S. EPA,
2011a, p. 2-42; U.S. EPA, 2010a, section 4.4, Figure 4-17). The
representativeness analysis also showed that the 15 urban study
areas do not capture areas with the highest baseline morality risks
or the oldest populations (both of which can result in higher
PM2.5-related mortality estimates). However, some of the
areas with the highest values for these attributes had relatively
low PM2.5 concentrations (e.g., urban areas in Florida)
and, consequently, the Risk Assessment concluded failure to include
these areas in the set of urban study areas was unlikely to exclude
high PM2.5-risk locations (U.S. EPA, 2010a, section
4.4.1).
---------------------------------------------------------------------------

    The expanded and updated risk assessment conducted in this review
included estimates of risk for: (1) All-cause, ischemic heart disease-
related, cardiopulmonary-related, and lung cancer-related mortality
associated with long-term PM2.5 exposure; (2) non-
accidental, cardiovascular-related, and respiratory-related mortality
associated with short-term PM2.5 exposure; and (3)
cardiovascular-related and respiratory-related hospital admissions and
asthma-related emergency department visits

associated with short-term PM2.5 exposure.\32\
---------------------------------------------------------------------------

    \32\ The evidence available for these selected health effect
endpoints generally focused on the entire population, although some
information was available to support analyses that considered
differences in estimated risk for at-risk populations including
older adults and persons with pre-existing cardiovascular and
respiratory diseases.
---------------------------------------------------------------------------

    The Risk Assessment included a core set of risk estimates
supplemented by an alternative set of risk results generated using
single-factor and multi-factor sensitivity analyses. The core set of
risk estimates was developed using the combination of modeling elements
and input data sets identified in the Risk Assessment as having higher
confidence relative to inputs used in the sensitivity analyses. The
results of the sensitivity analyses provided information to evaluate
and rank the potential impacts of key sources of uncertainty on the
core risk estimates. In addition, the sensitivity analyses represented
a set of reasonable alternatives to the core set of risk estimates that
fell within an overall set of plausible risk estimates surrounding the
core estimates.
    The EPA recognized that there were many sources of variability and
uncertainty inherent in the inputs to its quantitative risk
assessment.\33\ The design of the risk assessment included a number of
elements to address these issues in order to increase the overall
confidence in the risk estimates generated for the 15 urban study
areas, including using guidance from the World Health Organization
(WHO, 2008) as a framework for characterizing uncertainty in the
analyses.\34\
---------------------------------------------------------------------------

    \33\ Variability refers to the heterogeneity of a variable of
interest within a population or across different populations.
Uncertainty refers to the lack of knowledge regarding the actual
values of inputs to an analysis (U.S. EPA, 2010a, p. 3-63).
    \34\ The extent to which key sources of potential variability
were (or were not) fully captured in the design of the risk
assessment are discussed in section 3.5.2 of the Risk Assessment
(U.S. EPA, 2010a, pp. 3-67 to 3-69).
---------------------------------------------------------------------------

    With respect to the sources of variability, the Risk Assessment
considered those that contributed to differences in risk across urban
study areas, but did not directly affect the degree of risk reduction
associated with the simulation of just meeting current or alternative
standard levels (e.g., differences in baseline incidence rates,
demographics and population behavior). The Risk Assessment also focused
on factors that not only introduced variability into risk estimates
across study areas, but also played an important role in determining
the magnitude of risk reductions upon simulation of just meeting
current or alternative standard levels (e.g., peak-to-mean ratios of
ambient PM2.5 concentrations within individual urban study
areas and the nature of the rollback approach used to simulate just
meeting the current or alternative standards). Key sources of potential
variability that were likely to affect population risks included the
following: (1) Intra-urban variability in ambient PM2.5
concentrations, including PM2.5 composition; (2) variability
in the patterns of reductions in PM2.5 concentrations
associated with different rollback approaches when simulating just
meeting the current or alternative standards; (3) co-pollutant
exposures; (4) factors related to demographic and socioeconomic status;
(5) behavioral differences across urban study areas (e.g., time spent
outdoors); (6) baseline incidence rates; and (7) longer-term temporal
variability in ambient PM2.5 concentrations reflecting
meteorological trends as well as future changes in the mix of
PM2.5 sources, including changes in air quality related to
future regulatory actions.
    With regard to uncertainties, single and multi-factor sensitivity
analyses were combined with a qualitative analysis to assess the impact
of potential sources of uncertainty on the core risk estimates. Key
sources of uncertainty included: (1) Characterizing intra-urban
population exposure in the context of epidemiological studies linking
PM2.5 to specific health effects; (2) statistical fit of the
concentration-response functions for short-term exposure-related health
endpoints; (3) shape of the concentration-response functions; (4)
specifying the appropriate lag structure for short-term exposure
studies; (5) transferability of concentration-response functions from
study locations to urban study area locations for long-term exposure-
related health endpoints; (6) use of single-city versus multi-city
studies in the derivation of concentration-response functions; (7)
impact of historical air quality on estimates of health risk associated
with long-term PM2.5 exposures; and (8) potential variation
in effect estimates reflecting compositional differences in
PM2.5.
    Beyond characterizing uncertainty and variability, a number of
design elements were included in the risk assessment to increase the
overall confidence in the risk estimates generated for the 15 urban
study areas (U.S. EPA, 2011a, pp. 2-38 to 2-41). These elements
included: (1) Use of a deliberative process for specifying components
of the risk model that reflects consideration of the latest research on
PM2.5 exposure and risk (U.S. EPA, 2010a, section 5.1.1);
(2) integration of key sources of variability into the design as well
as the interpretation of risk estimates (U.S. EPA, 2010a, section
5.1.2); (3) assessment of the degree to which the urban study areas are
representative of areas in the U.S. experiencing higher
PM2.5-related risk (U.S. EPA, 2010a, section 5.1.3); and (4)
identification and assessment of important sources of uncertainty and
the impact of these uncertainties on the core risk estimates (U.S. EPA,
2010a, section 5.1.4). Further, additional analyses examined potential
bias and overall confidence in the risk estimates. Greater confidence
is associated with risk estimates based on simulated annual mean
PM2.5 concentrations that are within the region of the air
quality distribution used in deriving the concentration-response
functions where the bulk of the data reside (e.g., within one standard
deviation around the long-term mean PM2.5 concentration)
(U.S. EPA, 2011a, p. 2-38).
    Key observations and insights from the PM2.5 risk
assessment, together with important caveats and limitations, were
discussed in section III.C.3 of the proposal. In general, in
considering the set of quantitative risk estimates and related
uncertainties and limitations related to long- and short-term
PM2.5 exposure together with consideration of the health
endpoints which could not be quantified, the Policy Assessment
concluded this information provided strong evidence that risks
estimated to remain upon simulating just meeting the current suite of
PM2.5 standards are important from a public health
perspective, both in terms of severity and magnitude of effects.
Patterns of increasing estimated risk reductions were generally
observed as either the annual or 24-hour standard level, or both, were
reduced over the ranges considered in the Risk Assessment.
    The magnitude of both long- and short-term exposure-related risk
estimated to remain upon just meeting the current suite of standards as
well as alternative standard levels was strongly associated with the
simulated change in annual mean PM2.5 concentrations.
Although long- and short-term exposure-related mortality rates have
similar patterns in terms of the subset of urban study areas
experiencing risk reductions for the current suite of standard levels,
the magnitude of risk remaining is higher for long-term exposure-
related mortality and substantially lower for short-term exposure-
related mortality. Short-term exposure-related morbidity risk estimates
were greater for cardiovascular-related than respiratory-related events
and emergency

department visits for asthma-related events were significant:
Furthermore, most of the aggregate risk associated with short-term
exposures was not primarily driven by the small number of days with
PM2.5 concentrations in the upper tail of the air quality
distribution, but rather by the large number of days with
PM2.5 concentrations at and around the mean of the
distribution, that is, the 24-hour average concentrations that are in
the low- to mid-range, well below the peak 24-hour concentrations (U.S.
EPA, 2011a, p. 2-3).
    With regard to characterizing estimates of PM2.5-related
risk associated with simulation of alternative standards, the Policy
Assessment recognized that greater overall confidence was associated
with estimates of risk reduction than for estimates of absolute risk
remaining (U.S. EPA, 2011a, p. 2-94). Furthermore, the Policy
Assessment recognized that estimates of absolute risk remaining for
each of the alternative standard levels considered, particularly in the
context of long-term exposure-related mortality, may be
underestimated.\35\ In addition, the Policy Assessment observed that in
considering the overall confidence associated with the quantitative
analyses, the Risk Assessment recognized that: (1) Substantial
variability existed in the magnitude of risk remaining across urban
study areas and (2) in general, higher confidence was associated with
risk estimates based on PM2.5 concentrations near the mean
PM2.5 concentrations in the underlying epidemiological
studies providing the concentration-response functions (e.g., within
one standard deviation of the mean PM2.5 concentration
reported). Furthermore, although the Risk Assessment estimated that the
alternative 24-hour standard levels considered (when controlling) would
result in additional estimated risk reductions beyond those estimated
for alternative annual standard levels alone, these additional
estimated reductions were highly variable. Conversely, the Risk
Assessment recognized that alternative annual standard levels, when
controlling, resulted in more consistent risk reductions across urban
study areas, thereby potentially providing a more consistent degree of
public health protection (U.S. EPA, 2010a, p. 5-17).
---------------------------------------------------------------------------

    \35\ Based on the consideration of both the qualitative and
quantitative assessments of uncertainty, the Risk Assessment
concluded that it is unlikely that the estimated risks are over-
stated, particularly for premature mortality related to long-term
PM2.5 exposures. In fact, the Policy Assessment and the
Risk Assessment concluded that the core risk estimates for this
category of health effects may well be biased low based on
consideration of alternative model specifications evaluated in the
sensitivity analyses (U.S. EPA, 2011a, p. 2-41; U.S. EPA, 2010a, p.
5-16; Figures 4-7 and 4-8). In addition, the Policy Assessment
recognized that the currently available scientific information
included evidence for a broader range of health endpoints and at-
risk populations beyond those included in the quantitative risk
assessment, including decrements in lung function growth and
respiratory symptoms in children as well as reproductive and
developmental effects (U.S. EPA, 2011a, section 2.2.1).
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D. Conclusions on the Adequacy of the Current Primary PM2.5
Standards

1. Introduction
    The initial issue to be addressed in the current review of the
primary PM2.5 standards is whether, in view of the advances
in scientific knowledge and other information reflected in the
Integrated Science Assessment, the Risk Assessment, and the Policy
Assessment, the existing standards should be retained or revised. In
considering the adequacy of the current suite of PM2.5
standards, the Administrator has considered the large body of evidence
presented and assessed in the Integrated Science Assessment (U.S. EPA,
2009a), the quantitative assessment of risks, staff conclusions and
associated rationales presented in the Policy Assessment, views
expressed by CASAC, and public comments. The Administrator has taken
into account both evidence- and risk-based considerations \36\ in
developing final conclusions on the adequacy of the current primary
PM2.5 standards.
---------------------------------------------------------------------------

    \36\ Evidence-based considerations include the assessment of
epidemiological, toxicological, and controlled human exposure
studies evaluating long- or short-term exposures to
PM2.5, with supporting evidence related to dosimetry and
potential pathways/modes of action, as well as the integration of
evidence across each of these disciplines, as assessed in the
Integrated Science Assessment (U.S. EPA, 2009a) and focus on the
policy-relevant considerations as discussed in section III.B above
and in the Policy Assessment (U.S. EPA, 2011a, section 2.2.1). Risk-
based considerations draw from the results of the quantitative
analyses presented in the Risk Assessment (U.S. EPA, 2010a) and
focus on the policy-relevant considerations as discussed in section
III.C above and in the Policy Assessment (U.S. EPA, 2011a, section
2.2.2).
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a. Evidence- and Risk-based Considerations in the Policy Assessment
    In considering the available epidemiological evidence in this
review, the Policy Assessment took a broader approach than was used in
the last review. This approach reflected the more extensive and
stronger body of evidence available since the last review on health
effects related to both long- and short-term exposure to
PM2.5. As discussed in section III.A.3 above, this broader
approach focused on setting the annual standard as the ``generally
controlling'' standard for lowering both short- and long-term
PM2.5 concentrations and so providing requisite protection
to public health. In conjunction with such an annual standard, this
approach focused on setting the 24-hour standard to provide
supplemental protection against days with high peak PM2.5
concentrations.
    In addressing the question whether the evidence now available in
this review supports consideration of standards that are more
protective than the current PM2.5 standards, the Policy
Assessment considered whether: (1) Statistically significant health
effects associations with long- or short-term exposures to fine
particles occur in areas that would likely have met the current
PM2.5 standards [see American Trucking Associations, 283 F.
3d at 369, 376 (revision of level of PM NAAQS justified when health
effects are observed in areas meeting the existing standard)], and (2)
associations with long-term exposures to fine particles extend down to
lower air quality concentrations than had previously been observed.
With regard to associations observed in long-term PM2.5
exposure studies, the Policy Assessment recognized that extended
follow-up analyses of the ACS and Harvard Six Cities studies provided
consistent and stronger evidence of an association with mortality at
lower air quality distributions than had previously been observed (U.S.
EPA, 2011a, pp. 2-31 to 2-32). The original and reanalysis of the ACS
study reported positive and statistically significant effects
associated with a long-term mean PM2.5 concentration of 18.2
[mu]g/m\3\ across 50 metropolitan areas for 1979 to 1983 (Pope et al.,
1995; Krewski et al., 2000).\37\ In extended analyses, positive and
statistically significant effects of approximately similar magnitude
were associated with declining PM2.5 concentrations, from an
aggregate long-term mean in 58 metropolitan areas of 21.2 [micro]g/m\3\
in the original monitoring period (1979 to 1983) to 14.0 [micro]g/m\3\
for 116 metropolitan areas in the most recent years evaluated (1999-
2000), with an overall average across the two study periods in 51
metropolitan areas of 17.7 [micro]g/m\3\ (Pope et al., 2002; Krewski et
al., 2009). With regard to the Harvard Six Cities Study, the original
and reanalysis reported positive and statistically significant effects
associated

with a long-term mean PM2.5 concentration of 18.0 [mu]g/m\3\
for 1980 to 1985 (Dockery et al., 1993; Krewski et al., 2000). In an
extended follow-up of this study, the aggregate long-term mean
concentration across all years evaluated was 16.4 [mu]g/m\3\ for 1980
to 1988 \38\ (Laden et al., 2006). In an additional analysis of the
extended follow-up of the Harvard Six Cities study, investigators
reported that the concentration-response relationship was linear and
``clearly continuing below the level'' of the current annual standard
(U.S. EPA, 2009a, p. 7-92; Schwartz et al., 2008).
---------------------------------------------------------------------------

    \37\ The study periods referred to in the Policy Assessment
(U.S. EPA, 2011a) and in this final rule reflect the years of air
quality data that were included in the analyses, whereas the study
periods identified in the Integrated Science Assessment (U.S. EPA,
2009a) reflect the years of health event data that were included.
    \38\ Aggregate mean concentration provided by study author
(personal communication from Dr. Francine Laden, 2009).
---------------------------------------------------------------------------

    Cohort studies conducted since the last review provided additional
evidence of mortality associated with air quality distributions that
are generally lower than those reported in the ACS and Harvard Six
Cities studies, with effect estimates that were similar or, in some
studies, significantly greater in magnitude than in the ACS and Harvard
Six Cities studies (see also, section III.D.1.a of the proposal, 77 FR
38918 to 28919; U.S. EPA, 2011a, pp. 2-32 to 2-33). The Women's Health
Initiative (WHI) study reported positive and most often statistically
significant associations between long-term PM2.5 exposure
and cardiovascular-related mortality as well as morbidity effects, with
much larger relative risk estimates for mortality than in the ACS and
Harvard Six Cities studies, at an aggregate long-term mean
PM2.5 concentration of 12.9 [mu]g/m\3\ for 2000 (Miller et
al., 2007).\39\
---------------------------------------------------------------------------

    \39\ The Policy Assessment noted that in comparison to other
long-term exposure studies, the Miller et al. (2007) study was more
limited in that it was based on only one year of air quality data
(U.S. EPA, 2011a, p. 2-82). The proposal further noted that the air
quality data considered were extrapolated from that one single year
of air quality data (2000) to the whole study, and that the air
quality data post-dated the years of health events considered (i.e.,
1994 to 1998) (77 FR 38918, fn 62).
---------------------------------------------------------------------------

    Using the Medicare cohort, Eftim et al. (2008) reported somewhat
higher effect estimates than in the ACS and Harvard Six Cities studies
with aggregate long-term mean concentrations of 13.6 [mu]g/m\3\ and
14.1 [mu]g/m\3\, respectively, for 2000 to 2002. Zeger et al. (2008)
reported associations between long-term PM2.5 exposure and
mortality for the eastern region of the U.S. at an aggregated long-term
PM2.5 median concentration of 14.0 [mu]g/m\3\, although no
association was reported for the western region with an aggregate long-
term PM2.5 median concentration of 13.1 [mu]g/m\3\ (U.S.
EPA, 2009a, p. 7-88).\40\
---------------------------------------------------------------------------

    \40\ Zeger et al. (2008) also reported positive and
statistically significant effects for the central region, with an
aggregate long-term mean PM2.5 concentration of 10.7
[mu]g/m\3\. However, in contrast to the eastern and western risk
estimates, the central risk estimate increased with adjustment for
COPD (used as a proxy for smoking status). Due to the potential for
confounding bias influencing the risk estimate for the central
region, the Policy Assessment did not focus on the results reported
in the central region to inform the adequacy of the current suite of
standards or alternative annual standard levels (U.S. EPA, 2011a, p.
2-32).
---------------------------------------------------------------------------

    Premature mortality in children reported in a national infant
mortality study as well as mortality in a cystic fibrosis cohort
including both children and adults reported positive but statistically
nonsignificant effects associated with long-term aggregate mean
concentrations of 14.8 [mu]g/m\3\ and 13.7 [mu]g/m\3\, respectively
(Woodruff et al., 2008; Goss et al., 2004).
    With respect to respiratory morbidity effects associated with long-
term PM2.5 exposure, the across-city mean of 2-week average
PM2.5 concentrations reported in the initial Southern
California Children's Health Study was approximately 15.1 [micro]g/m\3\
(Peters et al., 1999). These results were found to be consistent with
results of cross-sectional analyses of the 24-Cities Study (Dockery et
al., 1996; Raizenne et al., 1996), which reported a long-term cross-
city mean PM2.5 concentration of 14.5 [mu]g/m\3\.\41\ In
this review, extended analyses of the Southern California Children's
Health Study provide stronger evidence of PM2.5-related
respiratory effects, at lower air quality concentrations than had
previously been reported, with a four-year aggregate mean concentration
of 13.8 [mu]g/m\3\ across the 12 study communities (McConnell et al.,
2003; Gauderman et al., 2004, U.S. EPA, 2009a, Figure 7-4).
---------------------------------------------------------------------------

    \41\ See American Farm Bureau Federation v. EPA, 559 F. 3d at
525 (noting the importance of these studies, as well as EPA's
failure to properly take them into account).
---------------------------------------------------------------------------

    In also considering health effects for which the Integrated Science
Assessment concluded evidence was suggestive of a causal relationship,
the Policy Assessment noted a limited number of birth outcome studies
that reported positive and statistically significant effects related to
aggregate long-term mean PM2.5 concentrations down to
approximately 12 [mu]g/m\3\ (U.S. EPA, 2011a, p. 2-33).
    Collectively, the Policy Assessment concluded that currently
available evidence provided support for associations between long-term
PM2.5 exposure and mortality and morbidity effects that
extend to distributions of PM2.5 concentrations that are
lower than those that had previously been associated with such effects,
with aggregate long-term mean PM2.5 concentrations extending
to well below the level of the current annual standard.
    The Policy Assessment also considered the long-term mean
PM2.5 concentrations in short-term exposure studies in
assessing the appropriateness of the level of the current annual
standard. See American Farm Bureau Federation v. EPA, 559 F. 3d at 522,
523-24 (remanding 2006 standard because the EPA had not adequately
explained its choice not to consider long-term means of short-term
exposure studies in assessing adequacy of primary annual
PM2.5 standard). In light of the mixed findings reported in
single-city, short-term exposure studies, the Policy Assessment placed
comparatively greater weight on the results from multi-city studies in
considering the adequacy of the current suite of standards (U.S. EPA,
2011a, pp. 2-34 to 2-35).
    With regard to associations reported in short-term PM2.5
exposure studies, the Policy Assessment recognized that long-term mean
concentrations reported in new multi-city U.S. and Canadian studies
provided evidence of associations between short-term PM2.5
exposure and mortality at similar air quality distributions to those
that had previously been observed in an 8-cities Canadian study
(Burnett and Goldberg, 2003; aggregate long-term mean PM2.5
concentration of 13.3 [mu]g/m\3\). In a multi-city time-series analysis
of 112 U.S. cities, Zanobetti and Schwartz (2009) reported a positive
and statistically significant association with all-cause,
cardiovascular-related (e.g., heart attacks, stroke), and respiratory-
related mortality and short-term PM2.5 exposure, in which
the aggregate long-term mean PM2.5 concentration was 13.2
[mu]g/m\3\ (U.S. EPA, 2009a, Figure 6-24). Furthermore, city-specific
effect estimates indicated the association between short-term exposure
to PM2.5 and total mortality and cardiovascular- and
respiratory-related mortality was consistently positive for an
overwhelming majority (99 percent) of the 112 cities across a wide
range of air quality concentrations (long-term mean concentrations
ranging from 6.6 [mu]g/m\3\ to 24.7 [mu]g/m\3\; U.S. EPA, 2009a, Figure
6-24, p. 6-178 to 179). The EPA staff noted that for all-cause
mortality, city-specific effect estimates were statistically
significant for 55 percent of the 112 cities, with long-term city-mean
PM2.5 concentrations ranging from 7.8 [mu]g/m\3\ to 18.7
[mu]g/m\3\ and 24-hour PM2.5 city-mean 98th percentile
concentrations ranging from 18.4 to 64.9

[mu]g/m\3\ (personal communication with Dr. Antonella Zanobetti,
2009).\42\
---------------------------------------------------------------------------

    \42\ Single-city Bayes-adjusted effect estimates for the 112
cities analyzed in Zanobetti and Schwartz (2009) were provided by
the study authors (personal communication with Dr. Antonella
Zanobetti, 2009; see also U.S. EPA, 2009a, Figure 6-24).
---------------------------------------------------------------------------

    With regard to cardiovascular and respiratory morbidity effects, in
the first analysis of the Medicare cohort conducted by Dominici et al.
(2006a) across 204 U.S. counties, investigators reported a
statistically significant association with hospitalizations for
cardiovascular and respiratory diseases and short-term PM2.5
exposure, in which the aggregate long-term mean PM2.5
concentration was 13.4 [mu]g/m\3\. Furthermore, a sub-analysis
restricted to days with 24-hour average concentrations of
PM2.5 at or below 35 [mu]g/m\3\ indicated that, in spite of
a reduced statistical power from a smaller number of study days,
statistically significant associations were still observed between
short-term exposure to PM2.5 and hospital admissions for
cardiovascular and respiratory diseases (Dominici, 2006b).\43\ In an
extended analysis of this cohort, Bell et al. (2008) reported a
positive and statistically significant increase in cardiovascular
hospitalizations associated with short-term PM2.5 exposure,
in which the aggregate long-term mean PM2.5 concentration
was 12.9 [mu]g/m\3\. These results, along with the observation that
approximately 50 percent of the 204 county-specific mean 98th
percentile PM2.5 concentrations in the study aggregated
across all years were below the 24-hour standard of 35 [mu]g/m\3\, not
only indicated that effects are occurring in areas that would meet the
current standards but also suggested that the overall health effects
observed across the U.S. are not primarily driven by the higher end of
the PM2.5 air quality distribution (Bell, 2009a, personal
communication from Dr. Michelle Bell regarding air quality data for
Bell et al., 2008 and Dominici et al., 2006a).
---------------------------------------------------------------------------

    \43\ This sub-analysis was not included in the original
publication (Dominici et al., 2006a). The study authors provided
sub-analysis results for the Administrator's consideration as a
letter to the docket following publication of the proposed rule in
January 2006 (personal communication with Dr. Francesca Dominici,
2006b). As noted in section III.A.3, this study is part of the basis
for the conclusion that there is no evidence suggesting that risks
associated with long-term exposures are likely to be
disproportionately driven by peak 24-hour concentrations.
---------------------------------------------------------------------------

    Collectively, the Policy Assessment concluded that the findings
from short-term PM2.5 exposure studies provided evidence of
PM2.5-associated health effects occurring in areas that
would likely have met the current suite of PM2.5 standards
(U.S. EPA, 2011a, p. 2-35). These findings were further bolstered by
evidence of statistically significant PM2.5-related health
effects occurring in analyses restricted to days in which 24-hour
average PM2.5 concentrations were below 35 [mu]g/m\3\
(Dominici, 2006b).
    In evaluating the currently available scientific evidence, as
summarized in section III.B of the proposal, the Policy Assessment
first concluded that there was stronger and more consistent and
coherent support for associations between long- and short-term
PM2.5 exposures and a broad range of health outcomes than
was available in the last review, providing the basis for fine particle
standards at least as protective as the current PM2.5
standards (U.S. EPA, 2011a, p. 2-26). Having reached this initial
conclusion, the Policy Assessment addressed the question of whether the
available evidence supported consideration of standards that were more
protective than the current standards. In so doing, the Policy
Assessment considered whether there was now evidence that health effect
associations have been observed in areas that likely met the current
suite of PM2.5 standards. As discussed above, long- and
short-term PM2.5 exposure studies provided evidence of
associations with mortality and cardiovascular and respiratory effects
both at lower ambient PM2.5 concentrations than had been
observed in the previous review and at concentrations allowed by the
current standards (U.S. EPA, 2011a, p. 2-35).
    In reviewing this information, the Policy Assessment recognized
that important limitations and uncertainties associated with this
expanded body of scientific evidence, as discussed in section III.B.2
of the proposal, needed to be carefully considered in determining the
weight to be placed on the body of studies available in this review.
Taking these limitations and uncertainties into consideration, the
Policy Assessment concluded that the currently available evidence
clearly calls into question whether the current suite of primary
PM2.5 standards protects public health with an adequate
margin of safety from effects associated with long- and short-term
exposures. Furthermore, the Policy Assessment concluded this evidence
provides strong support for considering fine particle standards that
would afford increased protection beyond that afforded by the current
standards (U.S. EPA, 2011a, p. 2-35).
    In addition to evidence-based consideration, the Policy Assessment
also considered the extent to which health risks estimated to occur
upon simulating just meeting the current PM2.5 standards may
be judged to be important from a public health perspective, taking into
account key uncertainties associated with the quantitative health risk
estimates. In so doing, the Policy Assessment first noted that the
quantitative risk assessment addresses: (1) The core PM2.5-
related risk estimates; (2) the related uncertainty and sensitivity
analyses, including additional sets of reasonable risk estimates
generated to supplement the core analysis; (3) an assessment of the
representativeness of the urban study areas within a national context;
\44\ and (4) consideration of patterns in design values and air quality
monitoring data to inform interpretation of the risk estimates, as
discussed in section III.C above.
---------------------------------------------------------------------------

    \44\ Based on analyses of the representativeness of the 15 urban
study areas in the broader national context, the Policy Assessment
concludes that these study areas are generally representative of
urban areas in the U.S. likely to experience relatively elevated
levels of risk related to ambient PM2.5 exposures (U.S.
EPA, 2011a, p. 2-42).
---------------------------------------------------------------------------

    In considering the health risks estimated to remain upon simulation
of just meeting the current suite of standards and considering both the
qualitative and quantitative assessment of uncertainty completed as
part of the assessment, the Policy Assessment concluded these risks are
important from a public health standpoint and provided strong support
for consideration of alternative standards that would provide increased
protection beyond that afforded by the current PM2.5 (U.S.
EPA, 2011a, pp. 2-47 to 2-48). This conclusion reflected consideration
of both the severity and the magnitude of the effects. For example, the
Risk Assessment indicated the possibility that premature deaths related
to ischemic heart disease associated with long-term PM2.5
exposure alone would likely be on the order of thousands of deaths per
year in the 15 urban study areas upon simulating just meeting the
current standards \45\ (U.S. EPA, 2011a, pp. 2-46 to 2-47). Moreover,
additional risks were anticipated for premature mortality related to
cardiopulmonary effects and lung cancer associated with long-term
PM2.5 exposure as well as mortality and cardiovascular- and
respiratory-related morbidity effects (e.g., hospital admissions,
emergency department visits) associated with short-term
PM2.5 exposures. Based on the consideration of both
qualitative and

quantitative assessments of uncertainty completed as part of the
quantitative risk assessment, the Risk Assessment concluded that it was
unlikely that the estimated risks are over-stated, particularly for
mortality related to long-term PM2.5 exposure, and may well
be biased low based on consideration of alternative model
specifications evaluated in the sensitivity analyses (U.S. EPA, 2010a,
p. 5-16; U.S. EPA, 2011a, p. 2-41). Furthermore, the currently
available scientific information summarized in section III.B of the
proposal provided evidence for a broader range of health endpoints and
at-risk populations beyond those included in the quantitative risk
assessment (U.S. EPA, 2011a, p. 2-47).
---------------------------------------------------------------------------

    \45\ Premature mortality for all causes attributed to
PM2.5 exposure was estimated to be on the order of tens
of thousands of deaths per year on a national scale based on 2005
air quality data (U.S. EPA, 2010a, Appendix G, Table G-1).
---------------------------------------------------------------------------

b. CASAC Advice
    The CASAC, based on its review of drafts of the Integrated Science
Assessment, the Risk Assessment, and the Policy Assessment, provided an
array of advice both with regard to interpreting the scientific
evidence and quantitative risk assessment, as well as with regard to
consideration of the adequacy of the current PM2.5 standards
(Samet, 2009a,b,c,d,e,f; Samet 2010a,b,c,d). With regard to the
adequacy of the current standards, CASAC concluded that the ``currently
available information clearly calls into question the adequacy of the
current standards'' (Samet, 2010d, p. i) and that the current standards
are ``not protective'' (Samet, 2010d, p. 1). Further, in commenting on
the first draft Policy Assessment, CASAC noted:

    With regard to the integration of evidence-based and risk-based
considerations, CASAC concurs with EPA's conclusion that the new
data strengthens the evidence available on associations previously
considered in the last round of the assessment of the
PM2.5 standard. CASAC also agrees that there are
significant public health consequences at the current levels of the
standard that justify consideration of lowering the PM2.5
NAAQS further (Samet, 2010c, p. 12).

c. Administrator's Proposed Conclusions Concerning the Adequacy of the
Current Primary PM2.5 Standards

    At the time of the proposal, in considering the body of scientific
evidence, the Administrator concluded there was stronger and more
consistent and coherent support for associations between long- and
short-term PM2.5 exposure and a broader range of health
outcomes than was available in the last review, providing the basis for
fine particle standards at least as protective as the current
PM2.5 standards. In particular, the Administrator recognized
in section III.D.4 of the proposal that the Integrated Science
Assessment concluded that the results of epidemiological and
experimental studies form a plausible and coherent data set that
supports a causal relationship between long- and short-term
PM2.5 exposures and mortality and cardiovascular effects and
a likely causal relationship between long- and short-term
PM2.5 exposures and respiratory effects. Furthermore, the
Administrator reflected that effects had been observed at lower ambient
PM2.5 concentrations than what had been observed in the last
review, including at ambient PM2.5 concentrations in areas
that likely met the current PM2.5 NAAQS. With regard to the
results of the quantitative risk assessment, the Administrator noted
that the Risk Assessment concluded that the risks estimated to remain
upon simulation of just meeting the current standards were important
from a public health standpoint in terms of both the severity and
magnitude of the effects.
    At the time of the proposal, in considering whether the current
suite of PM2.5 standards should be revised to provide
requisite public health protection, the Administrator carefully
considered the staff conclusions and rationales presented in the Policy
Assessment, the advice and recommendations from CASAC, and public
comments to date on this issue. In so doing, the Administrator placed
primary consideration on the evidence obtained from the epidemiological
studies and provisionally found the evidence of serious health effects
reported in long- and short-term exposure studies conducted in areas
that would have met the current standards to be compelling, especially
in light of the extent to which such studies are part of an overall
pattern of positive and frequently statistically significant
associations across a broad range of studies that collectively
represent a strong and robust body of evidence.
    As discussed in the Integrated Science Assessment and Policy
Assessment, the Administrator recognized that much progress has been
made since the last review in addressing some of the key uncertainties
that were important considerations in establishing the current suite of
PM2.5 standards. For example, progress made since the last
review provides increased confidence in the long- and short-term
exposure studies as a basis for considering whether any revision of the
annual standard is appropriate and increased confidence in the short-
term exposure studies as a basis for considering whether any revision
of the 24-hour standard is appropriate.\46\
---------------------------------------------------------------------------

    \46\ The EPA notes that this increased confidence in the long-
and short-term associations generally reflects less uncertainty as
to the likely causal nature of such associations, but does not
address directly the question of the extent to which such
associations remain toward the lower end of the range of ambient
PM2.5 concentrations. This question is central to the
Agency's evaluation of the relevant evidence to determine
appropriate standards levels, as discussed below in section III.E.4.
---------------------------------------------------------------------------

    Based on her consideration of these conclusions, as well as
consideration of CASAC's conclusion that the evidence and risk
assessment clearly called into question the adequacy of the public
health protection provided by the current PM2.5 NAAQS and
public comments on the proposal, the Administrator provisionally
concluded that the current primary PM2.5 standards, taken
together, were not requisite to protect public health with an adequate
margin of safety and that revision was needed to provide increased
public health protection. The Administrator provisionally concluded
that the scientific evidence and information on risk provided strong
support for consideration of alternative standards that would provide
increased public health protection beyond that afforded by the current
PM2.5 standards.
2. Comments on the Need for Revision
    This section addresses general comments based on relevant facts
that either support or oppose any change to the current suite of
primary PM2.5 standards. Comments on specific long- and
short-term exposure studies that relate to consideration of the
appropriate levels of the annual and 24-hour standards are addressed in
section III.E.4 below. Many public comments asserted that the current
PM2.5 standards are insufficient to protect public health
with an adequate margin of safety and that revisions to the standards
are therefore appropriate, indeed necessitated.
    Among those calling for revisions to the current standards were the
Children's Health Protection Advisory Committee (CHPAC); major medical
and public health groups including the American Heart Association
(AHA), American Lung Association (ALA), American Public Health
Association (APHA), American Thoracic Society (ATS); the Physicians for
Social Responsibility (PSR); major environmental groups such as the
Clean Air Council, Clean Air Task Force, Earthjustice, Environmental
Defense Fund (EDF), National Resources Defense Council (NRDC), and
Sierra Club; many environmental justice organizations as

well as medical doctors, academic researchers, health professionals,
and many private citizens. For example, the American Heart Association
and other major national public health and medical organizations stated
that, ``[o]ur organizations are keenly aware of the public health and
medical threats from particulate matter'' and called on the EPA to
``significantly strengthen'' both the annual and 24-hour
PM2.5 standards ``to help us protect the health of our
patients and our nation'' (AHA et al., 2012, pp. 1 and 13). AHA et al.
and ALA et al., as well as a group of more than 350 physicians,
environmental health researchers, and public health and medical
professionals articulated similar comments on the available evidence:

    Ample scientific evidence supports adopting tighter standards to
protect the health of people who are most susceptible to the serious
health effects of these pollutants. More than 10,000 peer-reviewed
scientific studies have been published since 1997 when EPA adopted
the current annual standard. These studies validate and extend
earlier epidemiologic research linking both acute and chronic fine
particle pollution with serious morbidity and mortality. The newer
research has also expanded our understanding of the range of health
outcomes associated with PM and has identified adverse respiratory
and cardiovascular health effects at lower exposure levels than
previously reported. As discussed and interpreted in the EPA's 2009
Integrated Science Assessment for Particulate Matter, the new
evidence reinforces already strong existing studies and supports the
conclusion that PM2.5 is causally associated with
numerous adverse health effects in humans at exposure levels far
below the current standard. Such a conclusion demands prompt action
to protect human health. (AHA et al., 2012, pp. 1 to 2; ALA et al.,
pp. 4 to 5; similar comment submitted by Rom et al., 2012, p. 1).

    All of these medical and public health commenters stated that the
current PM2.5 standards need to be revised, and that even
more protective standards than those proposed by the EPA are needed to
adequately protect public health, particularly for at-risk populations.
Many environmental justice organizations and individual commenters also
expressed such views.
    The National Association of Clean Air Agencies (NACAA), the
Northeast States for Coordinated Air Use Management (NESCAUM), and many
State and local air agencies and health departments who commented on
the PM2.5 standards supported revision of the suite of
current PM2.5 standards, as did five state attorneys general
(Schneiderman et al., 2012) and the National Tribal Air Association
(NTAA).
    These commenters based their views chiefly on the body of evidence
and technical analyses presented and discussed in the Integrated
Science Assessment, the Risk Assessment, and the Policy Assessment
finding the available scientific information to be stronger and more
compelling than in the last review. These commenters generally placed
much weight on CASAC's recommendation to revise the PM2.5
standards to provide increased public health protection and on the EPA
staff conclusions presented in the final Policy Assessment.
    Some of these commenters specifically mentioned extended analyses
of seminal long-term exposure studies--the ACS (Krewski et al., 2009),
Harvard Six Cities (Laden et al., 2006), and Southern California
Children's Health (Gauderman et al., 2004) studies. These commenters
also highlighted the availability of additional long-term exposure
studies in this review, specifically a study of premature mortality in
older adults (Eftim et al., 2008) and the WHI study of cardiovascular
morbidity and mortality effects in women (Miller et al., 2007)
providing stronger evidence of mortality and morbidity effects
associated with long-term PM2.5 exposures at lower
concentrations than had previously been observed, including studies of
effects in at-risk populations. For example, some commenters asserted:

    Evidence during the last review showed clearly that the annual
average standard needed to be much lower than the standard of 15
[micro]g/m\3\ that was first set in 1997. The evidence has only
grown since then. Multiple, multi-city studies over long periods of
time have shown clear evidence of premature death, cardiovascular
and respiratory harm as well as reproductive and developmental harm
at contemporary concentrations far below the level of the current
(annual) standard (ALA et al., 2012, p. 39; AHA et al., 2012, p.
10).

    These commenters also highlighted the availability of a number of
short-term PM2.5 exposure studies as providing evidence of
mortality and morbidity effects at concentrations below the level of
the current 24-hour PM2.5 standard. Specifically, these
commenters made note of multi-city studies of premature mortality
(Zanobetti and Schwartz, 2009) and increased hospitalizations for
cardiovascular and respiratory-related effects in older adults (Bell et
al., 2008). These commenters also asserted the importance of many of
the single-city studies, arguing that these studies ``provide valuable
information regarding impacts on susceptible populations and on health
risk in areas with high peak to mean concentration ratios'' (ALA, et
al., 2012, p. 65). Collectively, considering the multi- and single-city
short-term exposure studies, these commenters asserted ``the record
clearly supports a more stringent 24-hour standard of 25 [micro]g/m\3\
to provide uniform protection in all regions of the country
particularly from short-term spikes in pollution and from the sub-daily
exposures that trigger heart attacks and strokes'' (ALA et al., 2012,
p. 62). A group of more than 350 physicians, environmental health
researchers, and public health and medical professionals argued,
``[s]tudies of short-term exposure demonstrate that PM2.5
air pollution increases the risk of hospital admissions for heart and
lung problems even when you exclude days with pollution concentrations
at or above the current daily standard of 35 [micro]g/m\3\. Daily
concentrations must be capped at lower levels to protect against peak
exposure days that occur due to local and seasonal sources of
emissions'' (Rom et al., 2012, p. 2).
    In addition, many of these commenters generally concluded that
progress had been made in reducing many of the uncertainties identified
in the last review, in better understanding mechanisms by which
PM2.5 may be causing the observed health effects, and in
improving our understanding of at-risk populations. Further, a number
of commenters argued that by making the standards more protective, the
PM2.5 NAAQS would be more consistent with other existing
standards (e.g., California's annual average standard of 12 [micro]g/
m\3\) (CARB, 2012; CA OEHHA, 2012). Other commenters argued that
revising the primary PM2.5 standards would be more
consistent with the recommendations of the World Health Organization
(WHO) and/or Canada (e.g., ALA et al., 2012, p. 62; ISEE, 2012, p. 2;
MOE-Ontario, 2012, p. 1).
    With regard to the scope of the literature reviewed for
PM2.5-related health effects, some commenters asserted that
the EPA inappropriately narrowed the scope of the review by excluding a
number of categories of relevant studies, specifically related to
studies of diesel pollution and traffic-related pollution (ALA, et al.,
2012, p. 17). These commenters argued that, based upon the exclusion of
these types of studies, the Integrated Science Assessment ``came to the
erroneous conclusion that the causal relationship between PM and cancer
is merely suggestive. This conclusion does not square with the
International Agency Research on Cancer (IARC) finding that diesel
emissions are a known human carcinogen nor with the conclusions of

the extended analyses of the [Harvard] Six Cities and ACS cohort
studies that report positive and statistically significant associations
between PM2.5 and lung cancer.'' Id.
    Some of these commenters also noted the results of the EPA's
quantitative risk assessment, concluding that it showed that the risks
estimated to remain when the current standards are met are large and
important from a public health perspective and warrant increased
protection. For example, ALA et al., noted that the Risk Assessment
indicated the quantitative risk analyses likely underestimated
PM2.5-related mortality (U.S. EPA, 2010a, p. 5-16) and
argued that ``the measurements of risk should be treated
conservatively'' (ALA, et al., 2012, p. 73). These commenters also
summarized an expanded analysis of alternative PM2.5
standard levels that they argued documented the need for more
protective standards (McCubbin, 2011).
    In general, all of these commenters agreed on the importance of
results from the large body of scientific studies reviewed in the
Integrated Science Assessment and on the need to revise the suite of
PM2.5 standards as articulated in the EPA's proposal, while
generally differing with the EPA's proposed judgments about the extent
to which the standards should be revised based on this evidence,
specifically for providing protection for at-risk populations.
    The EPA generally agrees with these commenters' conclusion
regarding the need to revise the current suite of PM2.5
standards. The scientific evidence noted by these commenters was
generally the same as that assessed in the Integrated Science
Assessment and the Policy Assessment, and the EPA agrees that this
evidence provides a strong basis for concluding that the current
PM2.5 standards, taken together, are not requisite to
protect public health with an adequate margin of safety, and they need
to be revised to provide increased protection. For reasons discussed in
section III.E.4.c below, however, the EPA disagrees with aspects of
these commenters' views on the level of protection that is appropriate.
    The EPA disagrees with these commenters' views that diesel exhaust
studies were excluded from the Integrated Science Assessment and were
not considered when making the causality determination for cancer,
mutagenicity, and genotoxicity. As discussed in section 7.5 of the
Integrated Science Assessment, diesel exhaust studies were integrated
within the broader body of scientific evidence that was considered in
reaching the causality determination for these health endpoints.
Additionally, as discussed in section 1.5.3 of the Integrated Science
Assessment, the evidence from diesel exhaust studies was also
considered as part of the collective evidence evaluated when making
determinations for other, noncancer health outcomes (e.g.,
cardiovascular and respiratory effects).\47\ Specifically, when
evaluating this evidence, the focus was on understanding the effects of
diesel exhaust particles.
---------------------------------------------------------------------------

    \47\ In developing the second draft Integrated Science
Assessment, the EPA reexamined the controlled human exposure and
toxicological studies of fresh diesel and gasoline exhaust. This
information, in addition to other considerations, supported a change
in the causal determinations for ultrafine particles. Specifically,
in reevaluating the causal determinations for short-term ultrafine
particle exposures and cardiovascular and respiratory effects, the
EPA changed the classification from ``inadequate'' to ``suggestive''
for both categories of health outcomes (Vandenberg, 2009, p. 3).
CASAC agreed with the EPA's rationale for revising these causal
determinations (Samet, 2009f, p. 10).
---------------------------------------------------------------------------

    It is important to recognize that the Integrated Science Assessment
focused on experimental studies of diesel exhaust that evaluated
exposures that were relevant to ambient concentrations, i.e., ``within
one or two orders of magnitude of ambient PM concentrations'' (U.S.
EPA, 2009a, section 1.3). The causal determination for cancer,
mutagenicity, and genotoxicity presented in the Integrated Science
Assessment represents an integration of experimental and observational
evidence of exposures to ambient PM concentrations. The EPA fully
considered the findings of studies that assessed these and other health
effects associated with exposure to diesel particles in reaching
causality determinations regarding health outcomes associated with
PM2.5 exposures. Furthermore, CASAC supported the EPA's
change to the causal determination for cancer and long-term
PM2.5 concentrations from ``inadequate'' to ``suggestive''
(Samet, 2009f, p. 2).
    With regard to traffic studies, the EPA disagrees with the
commenters' views that traffic studies that focused on exposure
indicators such as distance to roadways should have been included in
the Integrated Science Assessment. These studies were excluded from
consideration because they did not measure ambient concentrations of
specific air pollutants, including PM2.5, but instead were
studies evaluating exposure to the undifferentiated ``traffic related
air pollution'' mixture (ALA et al., 2012, p. 17) (U.S. EPA, 2009a,
section 1.3). As a result, these studies do not add to the collective
body of evidence on the relationship between long- or short-term
exposure to ambient concentrations of PM2.5 and health
effects.
    Some of these commenters also identified ``new'' studies that were
not included in the Integrated Science Assessment as providing further
support for the need to revise the primary PM2.5 standards.
As discussed in section II.B.3 above, the EPA notes that, as in past
NAAQS reviews, the Agency is basing the final decisions in this review
on the studies and related information included in the PM air quality
criteria that have undergone CASAC and public review and will consider
the ``new'' studies for purposes of decision making in the next PM
NAAQS review. Nonetheless, in provisionally evaluating commenters'
arguments (see Response to Comments document), the EPA notes that its
provisional assessment of ``new'' science found that such studies did
not materially change the conclusions in the Integrated Science
Assessment (U.S. EPA, 2012b).
    Another group of commenters opposed revising the current
PM2.5 standards. These views were most extensively presented
in comments from the Utility Air Regulatory Group (UARG), representing
a group of electric generating companies and organizations and several
national trade associations; the American Petroleum Institute (API)
representing more than 500 oil and natural gas companies; the National
Association of Manufacturers (NAM), the American Chemistry Council
(ACC), the American Fuel & Petroleum Manufacturers (AFPM), the Alliance
of Automobile Manufacturers (AAM), and other manufacturing
associations; the Electric Power Research Institute (EPRI); and the
Texas Commission on Environmental Quality (Texas CEQ). These commenters
generally mentioned many of the same studies that were cited by the
commenters who supported revising the standards, as well as other
studies, but highlighted different aspects of these studies in reaching
substantially different conclusions about their strength and the extent
to which progress has been made in reducing uncertainties in the
evidence since the last review. Furthermore, they asserted that the
evidence that has become available since the last review does not
establish a more certain risk or a risk of effects that are
significantly different in character to those that provided a basis for
the current standards, nor does the evidence demonstrate that the risk
to public health upon attainment of the current standards would be
greater than was

understood when the EPA established the current standards in 2006.
    These commenters generally expressed the view that the current
standards provide the requisite degree of public health protection. In
supporting their view, these commenters generally argued that the EPA's
conclusions are inconsistent with the current state of the science and
questioned the underlying scientific evidence including the causal
determinations reached in the Integrated Science Assessment. More
specifically, this group of commenters argued that: (1) The EPA did not
apply its framework for causal determination consistently across
studies or health outcomes and, in the process, the EPA relied on a
selective group of long- and short-term exposure studies to reach
conclusions regarding causality; (2) toxicological and controlled human
exposure studies do not provide supportive evidence that the health
effects observed in epidemiological studies are biologically plausible;
(3) uncertainties in the underlying health science are as great or
greater than in 2006; (4) there is no evidence of greater risk since
the last review to justify tightening the current annual
PM2.5 standard; and (5) ``new'' studies not included in the
Integrated Science Assessment continue to increase uncertainty about
possible health risks associated with exposure to PM2.5.
These comments are discussed in turn below.
    (l) Some of these commenters asserted that the EPA did not apply
its framework for causal determinations consistently across studies or
health outcomes (e.g., ACC, 2012, Attachment A, pp. 1 to 2; API, 2012,
Attachment 1, p. 30; NAM et al., 2012, pp. 22 to 25; Texas CEQ, 2012,
pp 2 to 3).\48\ These commenters argued that the EPA downplayed
epidemiological studies with null or inconsistent results,
inappropriately used the Hill criteria when evaluating the
epidemiological evidence, and used the same study and the same
underlying database to conclude that there was a causal association
between mortality and multiple criteria pollutants.
---------------------------------------------------------------------------

    \48\ The EPA notes that the same concerns about the causal
determinations presented in the Integrated Science Assessment were
raised in comments to CASAC on the draft Integrated Science
Assessments (e.g., UARG, 2009; API, 2009; ACC, 2012, Appendix B).
CASAC, therefore, had the opportunity to consider these comments in
reaching consensus conclusions on this issue.
---------------------------------------------------------------------------

    The EPA disagrees with these commenters' views. First, the EPA
recognizes that the evaluation of the scientific evidence and its
application of the causal framework used in the current PM NAAQS review
was the subject of exhaustive and detailed review by CASAC and the
public. As summarized in section II.B.3 above, prior to finalizing the
Integrated Science Assessment, two drafts were released for CASAC and
public review to evaluate the scientific integrity of the documents.
Evidence related to the substantive issues raised by CASAC and public
commenters with regard to the content of the first and second draft
Integrated Science Assessments were discussed at length during these
public CASAC meetings and considered in developing the final Integrated
Science Assessment. CASAC supported the development of the EPA's
causality framework and its use in the current PM NAAQS review and
concluded:

    The five-level classification of strength of evidence for causal
inference has been systematically applied; this approach has
provided transparency and a clear statement of the level of
confidence with regard to causation, and we recommend its continued
use in future Integrated Science Assessments (Samet 2009f, p. 1).

    These commenters asserted that during the application of the causal
framework the EPA inappropriately relied on a selective group of long-
and short-term exposure studies in reaching causal inferences (API,
2012, pp 12 to 17; ACC, 2012, Attachment A, pp 1 to 2; NAM et al.,
2012, pp. 22 to 25; Texas CEQ, 2012, pp 2 to 3). Additionally, these
commenters expressed the view that the EPA focused on a subset of
epidemiological studies that reported positive and statistically
significant results while ignoring other studies, especially those that
reported no statistically significant associations, those that reported
potential thresholds, or those that highlighted uncertainties and
limitations in study design or results. Furthermore, some of these
commenters argued that epidemiological studies are observational in
nature and cannot provide evidence of a causal association.
    The EPA disagrees with these commenters' views on assessing the
health effects evidence and on the conclusions regarding the causality
determinations reached in the Integrated Science Assessment. In
conducting a comprehensive evaluation of the evidence in the Integrated
Science Assessment, the EPA recognized the distinction between the
evaluation of the relative scientific quality of individual study
results and the evaluation of the pattern of results within the broader
body of scientific evidence and considered both in reaching causality
determinations. The more detailed characterizations of individual
studies included an assessment of the quality of the study based on
specific criteria as described in the Integrated Science Assessment
(U.S. EPA, 2009a, section 1.5.3).
    In developing an integrated assessment of the health effects
evidence for PM, the EPA emphasized the importance of examining the
pattern of results across various studies and did not focus solely on
statistical significance \49\ as a criterion of study strength. This
approach is consistent with views clearly articulated throughout the
epidemiological and causal inference literature, specifically, that it
is important not to focus on results of statistical tests to the
exclusion of other information.\50\ The concepts underlying the EPA's
approach to evaluating statistical associations have been discussed in
numerous publications, including a report by the U.S. Surgeon General
on the health consequences of smoking (Centers for Disease Control and
Prevention, 2004). This report cautions against over-reliance on
statistical significance in evaluating the overall evidence for an
exposure-response relationship. Criteria characterized by Hill (1965)
also addressed the value, or lack thereof, of statistical tests in the
determination of cause:
---------------------------------------------------------------------------

    \49\ Statistical significance is an indicator of the precision
of a study's results, which is influenced by a variety of factors
including, but not limited to, the size of the study, exposure and
measurement error, and statistical model specifications. Studies
typically calculate ``p-values'' to determine whether the study
results are statistically significant or whether the study results
are likely to occur simply by chance. In general practice, effects
are considered statistically significant if p values are less than
0.05.
    \50\ For example, Rothman (1998) stated, ``Many data analysts
appear to remain oblivious to the qualitative nature of significance
testing [and that] * * * statistical significance is itself only a
dichotomous indicator. As it has only two values, significant or not
significant * * *. Nevertheless, p-values still confound effect size
with study size, the two components of estimation that we believe
need to be reported separately.'' As a result, Rothman recommended
that p-values be omitted as long as point and interval estimates are
available.

    No formal tests of significance can answer those [causal]
questions. Such tests can, and should, remind us of the effects the
play of chance can create, and they will instruct us in the likely
magnitude of those effects. Beyond that, they contribute nothing to
---------------------------------------------------------------------------
the `proof' of our hypothesis (Hill, 1965, p. 299).

    The statistical significance of individual study findings has
played an important role in the EPA's evaluation of the study's results
and the EPA has placed greater emphasis on studies reporting
statistically significant results. However, in the broader evaluation
of the evidence from many

epidemiological studies, and subsequently during the process of forming
causality determinations in integrating evidence across
epidemiological, controlled human exposure, and toxicological studies,
the EPA has emphasized the pattern of results across epidemiological
studies, and whether the effects observed were coherent across the
scientific disciplines for drawing conclusions on the relationship
between PM2.5 and different health outcomes. Thus, the EPA
did not limit its focus or consideration to just studies that reported
positive associations or where the results were statistically
significant.
    In addition, some commenters asserted that the EPA inappropriately
used the Hill criteria by failing to consider the limitations of
studies with weak associations, thereby overstating the consistency of
the observed associations (API, 2012, Attachment 1, pp. 30 to 35).
These commenters argued that risk estimates greater than 3 to 4 reflect
strong associations supportive of a causal link, while smaller risk
estimates (i.e., 1.5 to 3) are considered to be weak and require other
lines of evidence to demonstrate causality.
    As discussed in section 1.5.3 of the Integrated Science Assessment,
the EPA thoroughly considered the limitations of all studies during its
evaluation of the scientific literature (U.S. EPA,, 2009a, p. 1-14).
This collective body of evidence, including known uncertainties and
limitations of the studies evaluated, were considered during the
process of forming causality determinations as discussed in chapters 6
and 7 of the Integrated Science Assessment. For example, the EPA
concluded that ``a causal relationship exists between short-term
PM2.5 exposure and cardiovascular effects,'' however, in
reaching this conclusion, the Agency recognized and considered
limitations of the current evidence that still requires further
examination (U.S. EPA, 2009a., in section <IP_ADDRESS>). Therefore, the EPA
disagrees with these commenters' views that the Hill criteria were
inappropriately used in that the limitations of studies were not
considered.
    The EPA also disagrees with the commenters' assertion that the
magnitude of the association must be large to support a determination
of causality. As discussed in the Integrated Science Assessment, the
strength of the observed association is an important aspect to aid in
judging causality and ``while large effects support causality, modest
effects therefore do not preclude it'' (U.S. EPA, 2009a, Table 1-2,
section 1.5.4). The weight of evidence approach used by the EPA
encompasses a multitude of factors of which the magnitude of the
association is only one component (U.S. EPA, 2009a, Table 1-3). An
evaluation of the association across multiple investigators and
locations supports the ``reproducibility of findings [which]
constitutes one of the strongest arguments for causality'' (U.S. EPA,
2009a, Table 1-2). Even though the risk estimates for air pollution
studies may be modest, the associations are consistent across hundreds
of studies as demonstrated in the Integrated Science Assessment.
Furthermore, the causality determinations rely on different lines of
evidence, by integrating evidence across disciplines, including animal
toxicological studies and controlled human exposure studies.
    Furthermore, as summarized in section III.B above and discussed
more fully in section III.B.3 of the proposal, the EPA recognizes that
the population potentially affected by PM2.5 is
considerable, including large subgroups of the U.S. population that
have been identified as at-risk populations (e.g., children, older
adults, persons with underlying cardiovascular or respiratory disease).
While individual effect estimates from epidemiological studies may be
modest in size, the public health impact of the mortality and morbidity
associations can be quite large given that air pollution is ubiquitous.
Indeed, with the large population exposed, exposure to a pollutant
causally associated at a population level with mortality and serious
illness has significant public health consequences, virtually
regardless of the relative risk. Taken together, this information
indicates that exposure to ambient PM2.5 concentrations has
substantial public health impacts.
    In addition, these commenters believed that the EPA downplayed null
or inconsistent findings in numerous long-term mortality studies with
reported PM2.5 concentrations above and below the level of
the current annual standard. The EPA disagrees that studies with null
or inconsistent findings were not accurately presented and considered
in the Integrated Science Assessment. For example, as discussed
throughout section 7.6 and depicted in Figures 7-6 and 7-7 of the
Integrated Science Assessment, the EPA presented the collective
evidence from all studies that examined the association between long-
term PM2.5 exposure and mortality. Overall, across these
studies there was evidence of consistent positive associations in
different cohorts. That evidence, in combination with the biological
plausibility provided by experimental and toxicological studies
evaluated in sections 7.1 and 7.2 of the Integrated Science Assessment,
supported a causal relationship exists between long-term
PM2.5 exposure and mortality.
    Lastly, some of these commenters argued that in some cases, the EPA
used the same study and the same underlying database to conclude that
there is a causal association between mortality and multiple criteria
pollutants. These commenters argued, ``[i]n doing so, EPA attributes
the cause of the mortality effects observed to whichever criteria
pollutant it is reviewing at the time'' (API, 2012, pp. 14 to 16).
    The EPA strongly disagrees that the Agency ``attributes the cause
of mortality effects observed to whichever criteria pollutant it is
reviewing at the time.'' The EPA consistently recognizes that other
pollutants are also associated with health outcomes, as is reflected in
the fact that the EPA has established regulations to limit emissions of
particulate criteria pollutants as well as other gaseous criteria
pollutants. Epidemiological studies often examine the association
between short- and long-term exposures to multiple air pollutants and
mortality within a common dataset in an attempt to identify the air
pollutant(s) of the complex mixture most strongly associated with
mortality. In evaluating these studies, the EPA employs specific study
selection criteria to identify those studies most relevant to the
review of the NAAQS. In its assessment of the health evidence regarding
PM2.5, the EPA has carefully evaluated the potential for
confounding, effect measure modification, and the role of
PM2.5 as a component of a complex mixture of air pollutants
(U.S. EPA, 2009a, p. 1-9). The EPA used a rigorous weight of evidence
approach to inform causality that evaluated consistency across studies
within a discipline, evidence for coherence across disciplines, and
biological plausibility. Additionally, during this process, the EPA
assessed the limitations of each study in the context of the collective
body of evidence. It was the collective evidence, not one individual
study that ultimately determined whether a causal relationship exists
between a pollutant and health outcome. In the Integrated Science
Assessment, the combination of epidemiological and experimental
evidence formed the basis for the Agency concluding for the first time
that a causal relationship exists between short- or long-term exposure
to a criteria pollutant and mortality (U.S. EPA, 2009, sections <IP_ADDRESS>
and <IP_ADDRESS>).

    Additionally, while the EPA has evaluated some of the studies used
to inform the causality determination for PM in the Integrated Science
Assessments for other criteria air pollutants, the Agency has done so
in the context of examining the collective body of evidence for each of
the respective criteria air pollutants. As such, the body of evidence
to inform causality has varied from pollutant to pollutant resulting in
the association between each criteria air pollutant and mortality being
classified at a different level of the five-level hierarchy used to
inform causation (e.g., U.S. EPA, 2008e, U.S. EPA, 2008f, U.S. EPA,
2010k).
    The EPA notes that the final causality determinations presented in
the Integrated Science Assessment reflected CASAC's recommendations on
the second draft Integrated Science Assessment (Samet, 2009f, pp. 2 to
3). Specifically, CASAC supported the EPA's changes (in the second
versus first draft Integrated Science Assessment) from ``likely
causal'' to ``causal'' for long-term exposure to PM2.5 and
cardiovascular effects and for cancer and PM2.5 (from
``inadequate'' to ``suggestive''). Id. Furthermore, CASAC recommended
``upgrading'' the causal classification for PM2.5 and total
mortality to ``causal'' for both the short- and long-term timeframes.
Id. With regard to mortality, the ``EPA carefully reevaluated the body
of evidence, including the collective evidence for biological
plausibility for mortality effects, and determined that a causal
relationship exists for short- and long-term exposure to
PM2.5 and mortality, consistent with the CASAC comments''
(Jackson, 2010).
    (2) With regard to toxicological and controlled human exposure
studies, these commenters argued that the available evidence does not
provide coherence or biological plausibility for health effects
observed in epidemiological studies (API, 2012, pp. 21 to 22,
Attachment 1, pp. 25 to 29; AAM, 2012, pp. 15 to 16; Texas CEQ, 2012,
p. 3). With regard to the issue of mechanisms, these commenters noted
that although the EPA recognizes that new evidence is now available on
potential mechanisms and plausible biological pathways, the evidence
provided by toxicological and controlled human exposure studies still
does not resolve all questions about how PM2.5 at ambient
concentrations could produce the mortality and morbidity effects
observed in epidemiological studies. More specifically, for example,
some of these commenters argued that:

    A review of the Integrated Science Assessment, however, suggests
that the experimental evidence is inconsistent and not coherent with
findings in epidemiology studies. Specifically, the findings of mild
and reversible effects in most experimental studies conducted at
elevated exposures are not consistent with the more serious
associations described in epidemiology studies (e.g., hospital
admissions and mortality). Also, both animal studies and controlled
human exposure studies have identified no effect levels for acute
and chronic exposure to PM and PM constituents at concentrations
considerably above ambient levels. EPA should consider the
experimental findings in light of these higher exposure levels and
what the relevance may be for ambient exposures (API, 2012,
Attachment 1, p. 25).

    The EPA notes that in the review completed in 1997, the Agency
considered the lack of demonstrated biological mechanisms for the
varying effects observed in epidemiological studies to be an important
caution in its integrated assessment of the health evidence upon which
the standards were based (71 FR 61157, October 17, 2006). In the review
completed in 2006, the EPA recognized the findings from additional
research that indicated that different health responses were linked
with different particle characteristics and that both individual
components and complex particle mixtures appeared to be responsible for
many biologic responses relevant to fine particle exposures. Id. Since
that review, there has been a great deal of research directed toward
advancing our understanding of biologic mechanisms. While this research
has not resolved all questions, and further research is warranted (U.S.
EPA, 2011a, section 2.5), it has provided important insights as
discussed in section III.B.1 of the proposal (77 FR at 38906 to 38909)
and discussed more fully in the Integrated Science Assessment (U.S.
EPA, 2009a, Chapter 5).
    As noted in the proposal, toxicological studies provide evidence to
support the biological plausibility of cardiovascular and respiratory
effects associated with long- and short-term PM exposures observed in
epidemiological studies (77 FR 38906) and provide supportive
mechanistic evidence that the cardiovascular morbidity effects observed
in long-term exposure epidemiological studies are coherent with studies
of cardiovascular-related mortality (77 FR 38907). The Integrated
Science Assessment concluded that the new evidence available in this
review ``greatly expands'' upon the evidence available in the last
review ``particularly in providing greater understanding of the
underlying mechanisms for PM2.5 induced cardiovascular and
respiratory effects for both short- and long-term exposures'' (U.S.
EPA, 2009a, p. 2-17). The mechanistic evidence now available, taken
together with newly available epidemiological evidence, increases the
Agency's confidence that a causal relationship exists between long- and
short-term exposure to PM2.5 and cardiovascular effects and
mortality.\51\ In addition, CASAC supported the Integrated Science
Assessment approach and characterization of potential mechanisms or
modes of action (Samet, 2009e, pp. 7 to 8; Samet, 2009f, p. 11), as
well as the findings of a causal relationship at the population level
between exposure to PM2.5 and mortality and cardiovascular
effects (Samet, 2009f, pp. 2 to 3).\52\
---------------------------------------------------------------------------

    \51\ See American Trucking Associations v. EPA, 175 F. 3d 1027,
1055-56 (DC Cir. 1999) reversed in part and affirmed in part sub
nom, Whitman v. American Trucking Associations, 531 U.S. 457 (2001)
holding that the EPA could establish NAAQS without identifying a
biological mechanism (``To begin with, the statute itself requires
no such proof. The Administrator may regulate air pollutants
``emissions of which, in his judgment, cause or contribute to air
pollution which may reasonably be anticipated to endanger public
health or welfare.'' (emphasis added by the court). Moreover, this
court has never required the type of explanation petitioners seek
from EPA. In fact, we have expressly held that EPA's decision to
adopt and set air quality standards need only be based on
`reasonable extrapolations from some reliable evidence'* * *.
Indeed, were we to accept petitioners' view, EPA (or any agency for
that matter) would be powerless to act whenever it first recognizes
clear trends of mortality or morbidity in areas dominated by a
particular pathogen.'').
---------------------------------------------------------------------------

    Additionally, the EPA disagrees with commenters that the mild and
reversible effects observed in controlled human exposure studies are
inconsistent with the more serious effects observed in epidemiological
studies. Ethical considerations regarding the types of studies that can
be performed with human subjects generally limit the effects that can
be evaluated to those that are transient, reversible, and of limited
short-term consequence. The relatively small number of subjects
recruited for controlled exposure studies should also be expected to
have less variability in health status and risk factors than occurring
in the general population.\53\ Consequently, the severity

of health effects observed in controlled human exposure studies
evaluating the effects of PM should be expected to be less than
observed in epidemiologic studies. Nonetheless, that effects are
observed in relatively healthy individuals participating in controlled
exposure studies serves as an indicator that PM is initiating health
responses and that more severe responses may reasonably be expected in
a more diverse population.
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    \53\ For example, the EPA excludes from its controlled human
exposure studies involving exposure to PM2.5 any
individual with a significant risk factor for experiencing adverse
effects from such exposure. Thus, the EPA excludes a priori the
following categories of persons: those with a history of angina,
cardiac arrhythmias, and ischemic myocardial infarction or coronary
bypass surgery; those with a cardiac pacemaker; those with
uncontrolled hypertension (greater than 150 systolic and 90
diastolic); those with neurogenetive diseases; those with a history
of bleeding diathesis; those taking beta-blockers; those using oral
anticoagulants; those who are pregnant, attempting to become
pregnant, or breastfeeding; those who have experienced a respiratory
infection within four weeks of exposure; those experiencing eye or
abdominal surgery within six weeks of exposure; those with active
allergies; those with a history of chronic illnesses such as
diabetes, cancer, rheumatologic diseases, immunodeficiency state,
known cardiovascular disease, or chronic respiratory diseases;
smokers. The EPA ``Application for Independent Review Board Approval
of Human Subjects Research: Cardiopulmonary Effects of healthy Older
GSTM1 Null and Sufficient individuals to Concentrated Ambient Air
Particles (CAPTAIN)'', Nov. 9, 2011, p. 9.
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    It should also be noted that there is a small body of toxicological
evidence demonstrating mortality in rodents exposed to PM (e.g.,
Killingsworth et al. 1997). Overall it is not surprising that lethality
is not induced in more toxicological research, as these types of
studies do not readily lend themselves to this endpoint.
Epidemiological studies have observed associations between PM and
mortality in communities with populations in the range of many
thousands to millions of people. Clearly, it is not feasible to expose
hundreds (if not thousands) of animals to ambient PM (potentially over
many years) in a laboratory setting to induce enough lethalities to
distinguish between natural deaths and those attributable to PM.
Furthermore, the heterogeneous human populations sampled in
epidemiological studies are comprised of individuals with different
physical, genetic, health, and socioeconomic backgrounds which may
impact the outcome. However, in toxicological studies, the rodent
groups are typically inbred, such that inter-individual variability is
minimized. Thus, if the rodent strain used is quite robust, PM-induced
effects may not be observed at low exposure concentrations.
    (3) In asserting that the uncertainties in the underlying health
science are as great or greater than in the last review and therefore
do not support revision to the standards at this time, commenters in
this group variously discussed a number of issues related to: (a)
Confounding, (b) heterogeneity in risk estimates, (c) exposure
measurement error, (d) model specification, (e) the shape of the
concentration-response relationship, and (f) understanding the relative
toxicity of components within the mixture of fine particles. Each of
these issues is addressed below and some are discussed in more detail
in the Response to Comments document.
    In summary, these commenters concluded that the substantial
uncertainties present in the last review have not been resolved and/or
that the uncertainty about the possible health risks associated with
PM2.5 exposure has not diminished. As discussed below, the
EPA believes that the overall uncertainty about possible health risks
associated with both long- and short-term PM2.5 exposure has
diminished to an important degree since the last review. While the EPA
agrees that important uncertainties remain, and that future research
directed toward addressing these uncertainties is warranted, the EPA
disagrees with commenters' views that the remaining uncertainties in
the scientific evidence are too great to warrant revising the current
PM2.5 NAAQS.
(a) Confounding
    Some commenters have criticized the EPA for not adequately
addressing the issue of confounding in both long- and short-term
exposure studies of mortality and morbidity. This includes confounding
due to copollutants, as well as unmeasured confounding.\54\
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    \54\ The Integrated Science Assessment defines confounding as
``a confusion of effects. Specifically, the apparent effect of the
exposure of interest is distorted because the effect of an
extraneous factor is mistaken for or mixed with the actual exposure
effect (which may be null) (Rothman and Greenland, 1998)'' (U.S.
EPA, 2009a, p. 1-16). Epidemiological analyses attempt to adjust or
control for these characteristics (i.e., potential confounders) that
differ between exposed and non-exposed individuals (U.S. EPA, 2009a,
section 1.5.3). Not all risk factors can be controlled for within a
study design/model and are termed ``unmeasured confounders.'' An
unmeasured confounder is a confounder that has not previously been
measured and therefore is not included in the study design/model.
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    With regard to copollutant confounding, these commenters asserted
that the EPA has not adequately interpreted the results from studies
that examined the effect of copollutants on the relationship between
long- and short-term PM2.5 exposures and mortality and
morbidity outcomes. These commenters contend that the EPA has
inappropriately concluded that PM2.5-related mortality and
morbidity associations are generally robust to confounding. The
commenters stated that statistically significant PM2.5
associations in single-pollutant models in epidemiological studies do
not remain statistically significant in copollutant models.
    The loss of statistical significance or the reduction in the
magnitude of the effect estimate when a co-pollutant model is used may
be the result of factors other than confounding. These changes do not
prove either the existence or absence of confounding. These impacts
must be evaluated in a broader context that considers the entire body
of evidence. The broader examination of this issue in the Integrated
Science Assessment included a focus on evaluating the stability of the
size of the effect estimates in epidemiological studies conducted by a
number of research groups using single- and copollutant models (U.S.
EPA, 2009a, sections <IP_ADDRESS>, <IP_ADDRESS>, and 6.5, Figures 6-5, 6-9, and
6-15). This examination found that, for most epidemiological studies,
there was little change in effect estimates based on single- and
copollutant models, although the Integrated Science Assessment
recognized that in some cases, the PM2.5 effect estimates
were markedly reduced in size and lost statistical significance.
Additionally, the EPA notes that these comments do not adequately
reflect the complexities inherent in assessing the issue of copollutant
confounding. As discussed in the proposal (77 FR 38907, 38909, and
38910) and more fully in the Integrated Science Assessment (U.S.EPA,
2009a, sections 6.2, 6.3, and 6.5), although copollutant models may be
useful tools for assessing whether gaseous copollutants may be
potential confounders, such models alone cannot determine whether
copollutants are in fact confounders. Interpretation of the results of
copollutant models is complicated by correlations that often exist
among air pollutants, by the fact that some pollutants play a role in
the atmospheric reactions that form other pollutants such as secondary
fine particles, and by the statistical power of the studies in question
inherent in the study methodology. For example, the every-third or
sixth-day sampling schedule often employed for PM2.5
measurements compared to daily measurements of gaseous copollutants
drastically reduces the overall sample size to assess the effect of
copollutants on the PM2.5-morbidity or mortality
relationship, such that the reduced sample size can lead to less
precise effect estimates (e.g., wider confidence intervals).
    The EPA recognizes that when PM2.5 is correlated with
gaseous pollutants it can be difficult to identify the effect of
individual pollutants in the ambient mixture (77 FR 38910). However,
based on the available evidence, the EPA

concludes epidemiological studies continue to support the conclusion
that PM2.5 associations with mortality and morbidity
outcomes are robust to the inclusion of gaseous copollutants in
statistical models. The EPA evaluated the potential confounding effects
of gaseous copollutants and, although it is recognized that
uncertainties and limitations still remain, the Agency concluded the
collective body of scientific evidence is ``stronger and more
consistent than in previous reviews providing a strong basis for
decision making in this review'' (77 FR 38910/1).
    Several commenters offered detailed comments on the long-term
PM2.5 exposure studies arguing that associations from
mortality studies are subjected to unmeasured confounding and as a
result are not appropriately characterized as providing evidence of a
causal relationship between long-term PM2.5 exposure and
mortality (e.g., UARG, 2012, pp. 10 to 11, Attachment A, pp. 17 to 23;
API, 2012, pp. 13 to 14, Attachment 1, pp. 11 to 14, Attachment 7, pp.
2-10; ACC, 2012, p. 18 to 21; AFPM, 2012, p. 8; Texas CEQ, 2012, p. 4).
Specifically, commenters cited two studies (i.e., Janes et al., 2007
and Greven et al., 2011) that used a new type of statistical analysis
to examine associations between annual (long-term) and monthly (sub-
chronic) PM2.5 exposure and mortality. The commenters
interpreted the results of these analyses as evidence of unmeasured
confounding in the long-term PM2.5 exposure-mortality
relationship. These commenters interpreted these studies as raising
fundamental questions regarding the EPA's determination that a causal
relationship exists between long-term PM2.5 exposure and
mortality. In addition to the commenters mentioned above, all of the
authors of the publications by Janes et al. (2007) and Greven et al.
(2011) (i.e., Francesca Dominici, Scott Zeger, Holly Janes, and Sonja
Greven) submitted a joint comment to the public docket in order to
clarify specific points regarding these two studies (Dominici et al.,
2012).
    The first study, Janes et al. (2007), was evaluated in the
Integrated Science Assessment (U.S. EPA, 2009a, p. 7-88). The second
study, Greven et al. (2011), an extension of the Janes et al. (2007)
study adding three more years of data, is a ``new'' study discussed in
the Provisional Science Assessment (U.S. EPA, 2012). Both studies used
nationwide Medicare mortality data to examine the association between
monthly average PM2.5 concentrations over the preceding 12
months and monthly mortality rates in 113 U.S. counties and examined
whether community-specific trends in monthly PM2.5
concentrations and mortality declined at the same rate as the national
rate. The investigators examined this by decomposing the association
between PM2.5 and mortality into two components: (1)
National trends, defined as the association between the national
average trend in monthly PM2.5 concentrations averaged over
the previous 12 months and the national average trend in monthly
mortality rates, and (2) local trends, defined as county-specific
deviations in monthly PM2.5 concentrations and monthly
mortality rates from national trends.
    The EPA does not question the results of the national trends
analyses conducted by Janes et al. (2007) and Greven et al. (2011).\55\
Both Janes et al. (2007) and Greven et al. (2011) observed positive and
statistically significant associations between long-term exposure to
PM2.5 and mortality in their national analyses. However,
Janes et al. (2007) and Greven et al. (2011) eliminated all of the
spatial variation in air pollution and mortality in their data set when
estimating the national effect, focusing instead on both chronic
(yearly) and sub-chronic (monthly) temporal differences in the data
(Dominici et al. 2012). Janes et al. (2007) (Table 1) highlighted that
over 90 percent of the variance in the data set used for the analyses
conducted by both Janes et al. (2007) and Greven et al. (2011) was
attributable to spatial variability, which the authors chose to
discard. As noted above, the focus of the analyses by Janes et al.
(2007) and Greven et al. (2011) was on two components: (1) A temporal
or time component, i.e., the ``national'' trends analysis, which
examined the association between the national average trend in monthly
PM2.5 concentrations averaged over the previous 12 months
and the national average trend in monthly mortality rates and (2) a
space-by-time component, i.e., the ``local'' trends analysis, which
examined county-specific deviations in monthly PM2.5
concentrations and monthly mortality rates from national trends. These
two components combined comprised less than 10 percent of the variance
in the data set. The authors included a focus on the space-by-time
component, which represented approximately 5 percent of the variance in
the data set, in an attempt to identify, absent confounding, if
PM2.5 was associated with mortality at this unique exposure
window. Thus, these studies are not directly comparable to other cohort
studies investigating the relationship between long-term exposure to
PM2.5 and mortality, which make use of spatial variability
in air pollution and mortality data.\56\ This point was highlighted by
the study authors who stated that ``when one considers that this wealth
of information is not accounted for in [Janes 2007], it is not as
surprising that * * * vastly different estimates of the
PM2.5/mortality relationship [were observed] than in other
studies that do exploit that variability'' (Dominici et al., 2012, p.
2).
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    \55\ In its evaluation of Janes et al. (2007) in the Integrated
Science Assessment, the EPA did not identify limitations in the
statistical methods used per se (U.S. EPA, 2009a, p. 7-88) and
included the results of the national-scale analyses in that study in
the body of evidence that supported the determination that there is
a causal relationship between long-term PM2.5 exposure
and mortality.
    \56\ Though not directly comparable, the national effect
estimates for mortality reported by Janes et al. (2007) and Greven
et al. (2011) are coincidentally similar in magnitude to those
previously reported. It is important to note that previous cohort
studies have focused on identifying spatial differences in
PM2.5 concentrations between cities, while Janes et al.
(2007) and Greven et al. (2011) focus primarily on temporal
differences in PM2.5 concentrations. In fact, Greven et
al. (2011) state ``We do not focus here on a third type [of
statistical approach] used in cohort studies, measuring the
association between average PM2.5 levels and average age-
adjusted mortality rates across cities (purely spatial or cross-
sectional association).''
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    The EPA notes that the results of the local trends analyses
conducted by Janes et al. (2007) and Greven et al. (2011) are limited
by the monthly timescale used in these analyses. This view is
consistent with comments on the Janes et al. (2007) study articulated
in Pope and Burnett (2007),\57\ which noted that an important
limitation of the local scale analysis conducted by Janes et al. (2007)
and subsequently by Greven et al. (2011) was the subchronic exposure
window considered in these analyses. Both studies used annual average
PM2.5 concentrations to characterize long-term national
trends which was consistent with exposure windows considered in other
studies of long-term exposure to PM2.5 and mortality.\58\
However, the local scale analyses used monthly average PM2.5
concentrations to characterize county-specific deviations from national
trends (the local scale). The use of monthly average data likely does
not provide

enough exposure contrast to observe temporal changes in mortality at
the local scale. It also represents a different exposure window than
considered in the large body of evidence of health effects related to
short-term (from less than one day to up to several days) and chronic
(one or more years) measures of PM2.5.
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    \57\ Some commenters argued that there were flaws in the
criticisms offered by Pope and Burnett (2007) on the paper by Janes
et al. (2007) (UARG, 2012, Attachment A, pp. 19 to 23). The EPA