the PA analysis compares the DI2019 and HA2020 surfaces. At the
national scale, the two surfaces generally produce similar average
annual PM2.5 concentrations, with the DI2019 surface being
slightly higher compared to the HA2020 surface. The average annual
PM2.5 concentrations are also slightly higher using the
DI2019 surface compared to the HA2020 surface when the analyses are
conducted for CBSAs. Also, regardless of which surface is used, the
average annual and 3-year average of the average annual
PM2.5 concentrations for the CBSA-only analyses are somewhat
higher than for the nationwide analyses (4-8% higher) (U.S. EPA, 2022b,
section <IP_ADDRESS>.4, Table 2-5).\42\ Overall, these analyses suggest that
there are only slight differences in the average PM2.5

concentrations depending on the hybrid modeling method employed, though
including other hybrid modeling methods in this comparison could result
in larger differences.
---------------------------------------------------------------------------

    \42\ For the national scale, 3-year averages of the average
annual PM2.5 concentrations generally range from about
5.3 [mu]g/m\3\ to 8.1 [mu]g/m\3\, compared to the CBSA scale, which
ranges from 5.7 [mu]g/m\3\ to 8.7 [mu]g/m\3\. (U.S. EPA, 2022b,
section <IP_ADDRESS>.4, Table 2-6).
---------------------------------------------------------------------------

    The PA next evaluates how the averages of the hybrid model surfaces
compare to regulatory design values using both the DI2019 and HA2020
surfaces and how population weighting influences the mean
PM2.5 concentration.\43\ As presented in the PA, the results
using the DI2019 and HA2020 surfaces are similar for the average annual
PM2.5 concentrations, for each 3-year period. When
population weighting is not applied, the average annual
PM2.5 concentrations generally range from 7.0 to 8.6 [mu]g/
m\3\. When population weighting is applied, the average annual
PM2.5 concentrations are slightly higher, ranging from 8.2
to 10.2 [mu]g/m\3\. As with CBSAs versus the national comparison above,
population weighting results in a higher average PM2.5
concentration than when population weighting is not applied (U.S. EPA,
2022b, section <IP_ADDRESS>.4, Table 2-7). For the CBSAs included in the
population weighted analyses, the average maximum annual design values
generally range from 9.5 to 11.7 [mu]g/m\3\. The results are similar
for both the DI2019 and HA2020 surfaces and the maximum annual
PM2.5 design values measured at the monitors are often 40%
to 50% higher than average annual PM2.5 concentrations
predicted by hybrid modeling methods when population weighting is not
applied. However, when population weighting is applied, the ratio of
the maximum annual PM2.5 design values to the predicted
average annual PM2.5 concentrations are lower than when
population weighting is not applied, with monitored design values
generally 15% to 18% higher than population-weighted hybrid modeling
average annual PM2.5 concentrations (U.S. EPA, 2022b,
section <IP_ADDRESS>.4, Table 2-7).
---------------------------------------------------------------------------

    \43\ For this analysis, the PA includes CBSAs with three or more
valid design values for the 3-year period. The regulatory design
values for the CBSAs were calculated for each 3-year period for the
CBSAs with 3 or more design values in each of the 3-year periods.
Using the maximum design value for each CBSA and by each 3-year
period, the ratio of maximum design values to modeled average annual
PM2.5 concentrations were calculated, for each 3-year
period. More details about the analytical methods used for this
analysis are described in section A.6 of Appendix A in the PA (U.S.
EPA, 2022b).
---------------------------------------------------------------------------

6. Background PM
    In this reconsideration, background PM is defined as all particles
that are formed by sources or processes that cannot be influenced by
actions within the jurisdiction of concern. U.S. background PM is
defined as any PM formed from emissions other than U.S. anthropogenic
(i.e., manmade) emissions. Potential sources of U.S. background PM
include both natural sources (i.e., PM that would exist in the absence
of any anthropogenic emissions of PM or PM precursors) and
transboundary sources originating outside U.S. borders. Background PM
is discussed in more detail in the PA (U.S. EPA, 2022b, section 2.4).
At annual and national scales, estimated background PM concentrations
in the U.S. are small compared to contributions from domestic
anthropogenic sources.\44\ For example, based on zero-out modeling in
the last review of the PM NAAQS, annual background PM2.5
concentrations were estimated to range from 0.5-3 [mu]g/m\3\ across the
sites examined. In addition, speciated monitoring data from IMPROVE
sites can provide some insights into how contributions from different
sources, including sources of background PM, may have changed over
time. Such data suggests the estimates of background concentrations
using speciated monitoring data from IMPROVE monitors are around 1-3
[mu]g/m\3\ and have not changed significantly since the 2012 review.
Contributions to background PM in the U.S. result mainly from sources
within North America. Contributions from intercontinental events have
also been documented (e.g., transport from dust storms occurring in
deserts in North Africa and Asia), but these events are less frequent
and represent a relatively small fraction of background PM in most of
the U.S. (U.S. EPA, 2022b, section 2.4).
---------------------------------------------------------------------------

    \44\ Sources that contribute to natural background PM include
dust from the wind erosion of natural surfaces, sea salt, wildland
fires, primary biological aerosol particles such as bacteria and
pollen, oxidation of biogenic hydrocarbons such as isoprene and
terpenes to produce secondary organic aerosols (SOA), and geogenic
sources such as sulfate formed from volcanic production of
SO2 and oceanic production of dimethyl-sulfide (U.S. EPA,
2022b, section 2.4). While most of these sources release or
contribute predominantly to fine aerosol, some sources including
windblown dust, and sea salt also produce particles in the coarse
size range (U.S. EPA, 2019a, section 2.3.3).
---------------------------------------------------------------------------

II. Rationale for Proposed Decisions on the Primary PM2.5 Standards

    This section presents the rationale for the Administrator's
proposed decision to revise the primary annual PM2.5
standard and retain the primary 24-hour PM2.5 standard. This
rationale is based on a thorough review of the scientific evidence
generally published through January 2018,\45\ as presented in the 2019
ISA (U.S. EPA, 2019a), on the human health effects of PM2.5
associated with long- and short-term exposures \46\ to PM2.5
in the ambient air. Additionally, this rationale is based on a thorough
evaluation of some studies that became available after the literature
cutoff date of the 2019 ISA, as evaluated in the ISA Supplement, that
could either further inform the adequacy of the current PM NAAQS or
address key scientific topics that have evolved since the literature
cutoff date for the 2019 ISA, generally through March 2021 (U.S. EPA,
2022b).\47\ The Administrator's rationale also takes into account: (1)
the PA evaluation of the policy-relevant information in the 2019 ISA
and ISA Supplement and presentation of quantitative analyses of air
quality and health risks; (2) CASAC advice and recommendations, as
reflected in discussions of the drafts of the ISA Supplement and PA at
public meetings and in the CASAC's letters to the Administrator; and
(3) public comments received during the development of these documents.
---------------------------------------------------------------------------

    \45\ In addition to the 2020 review's opening ``call for
information'' (79 FR 71764, December 3, 2014), the 2019 ISA
identified and evaluated studies and reports that have undergone
scientific peer review and were published or accepted for
publication between January 1, 2009, through approximately January
2018 (U.S. EPA, 2019a, p. ES-2). References that are cited in the
2019 ISA, the references that were considered for inclusion but not
cited, and electronic links to bibliographic information and
abstracts can be found at: https://hero.epa.gov/hero/particulate-matter.
    \46\ Short-term exposures are defined as those exposures
occurring over hours up to 1 month, whereas long-term exposures are
defined as those exposures occurring over 1 month to years (U.S.
EPA, 2019a, section P.3.1).
    \47\ The ISA Supplement represents an evaluation of recent
studies that are of greatest policy relevance to the reconsideration
of the 2020 final decision on the PM NAAQS. Specifically, the ISA
Supplement focuses on studies of health effects for which the
evidence in the 2019 ISA supported a ``causal relationship'' (i.e.,
short- and long-term PM2.5 exposure and mortality and
cardiovascular effects) because those were the health effects that
were most useful in informing conclusions in the 2020 PA. The ISA
Supplement does not include an evaluation of studies for other
PM2.5-related health effects (U.S. EPA, 2022b).
---------------------------------------------------------------------------

    In presenting the rationale for the Administrator's proposed
decisions and its foundations, section II.A provides background and
introductory information for this reconsideration of the primary
PM2.5 standards. It includes background on the 2020 final
decision to retain the primary PM2.5 standards (section
II.A.1) and also describes the general approach for this
reconsideration (section II.A.2). Section II.B summarizes the key
aspects of the currently available health effects evidence, focusing on
consideration of

the key policy-relevant aspects. Section II.C summarizes the risk
information for this reconsideration, drawing on the quantitative
analyses for PM2.5, presented in the PA. Section II.D
presents the Administrator's proposed conclusions on the current
primary annual and 24-hour PM2.5 standards (section II.D.3),
drawing on both the evidence-based and risk-based considerations
(section II.D.2) and advice from the CASAC (section II.D.1).

A. General Approach

    This reconsideration of the 2020 final decision on the primary
PM2.5 standards relies on using the EPA's assessment of the
current scientific evidence and associated quantitative analyses to
inform the Administrator's judgment regarding primary PM2.5
standards that protect public health with an adequate margin of safety.
The EPA's assessments are primarily documented in the 2019 ISA, ISA
Supplement, and PA, all of which have received CASAC review and public
comment (83 FR 53471, October 23, 2018; 83 FR 55529, November 6, 2018;
85 FR 4655, January 27, 2020; 86 FR 52673, September 22, 2021; 86 FR
54186, September 30, 2021; 86 FR 56263, October 8, 2021; 87 FR 958,
January 7, 2022; 87 FR 22207, April 14, 2022; 87 FR 31965, May 26,
2022). In bridging the gap between the scientific assessments of the
2019 ISA and ISA Supplement and the judgments required of the
Administrator in determining whether the current standards provide the
requisite public health protection, the PA evaluates policy
implications of the evaluation of the current evidence in the 2019 ISA
and ISA Supplement, and the risk information documented in the PA. In
evaluating the public health protection afforded by the current
standards, the four basic elements of the NAAQS (indicator, averaging
time, level, and form) are considered collectively.
    The final decision on the adequacy of the current primary
PM2.5 standards is a public health policy judgment to be
made by the Administrator. In reaching conclusions with regard to the
standards, the decision will draw on the scientific information and
analyses about health effects and population risks, as well as
judgments about how to consider the range and magnitude of
uncertainties that are inherent in the scientific evidence and
analyses. This approach is based on the recognition that the available
health effects evidence generally reflects a continuum, consisting of
levels at which scientists generally agree that health effects are
likely to occur, through lower levels at which the likelihood and
magnitude of the response become increasingly uncertain. This approach
is consistent with the requirements of the NAAQS provisions of the
Clean Air Act and with how the EPA and the courts have historically
interpreted the Act (summarized in section I.A above). These provisions
require the Administrator to establish primary standards that, in the
judgment of the Administrator, are requisite to protect public health
with an adequate margin of safety. In so doing, the Administrator seeks
to establish standards that are neither more nor less stringent than
necessary for this purpose. The Act does not require that primary
standards be set at a zero-risk level, but rather at a level that
avoids unacceptable risks to public health, including the health of
sensitive groups.\48\
---------------------------------------------------------------------------

    \48\ As noted in section I.A above, the legislative history
describes such protection for the sensitive group of individuals and
not for a single person in the sensitive group (see S. Rep. No. 91-
1196, 91st Cong, 2d Sess. 10 [1970]).
---------------------------------------------------------------------------

    The subsections below provide background and introductory
information. Background on the 2020 decision to retain the current
standards, including the rationale for that decision, is summarized in
section II.A.1. This is followed, in section II.A.2, by an overview of
the general approach for the reconsideration of the 2020 final
decision. Following this introductory section and subsections, the
subsequent sections summarize current information and analyses,
including that newly available in this reconsideration. The
Administrator's proposed conclusions on the primary PM2.5
standards, based on the current information, are provided in section
II.D.3.
1. Background on the Current Standards
    The current primary PM2.5 standards were retained in
2020 based on the scientific evidence and quantitative risk analyses
available at that time, as well as the Administrator's judgments
regarding the available scientific information, the appropriate degree
of public health protection for the standards, and the available risk
information regarding the exposures and risk that may be allowed by the
current standards (85 FR 82718, December 18, 2020). With the 2020 final
decision, the EPA retained the primary 24-hour PM2.5
standard, with its level of 35 [mu]g/m\3\, and the primary annual
PM2.5 standard, with its level of 12.0 [mu]g/m\3\, this
decision was informed by the scientific evidence evaluated in the 2019
ISA, the evidence and quantitative risk information in the 2020 PA, the
advice and recommendations of the CASAC, and public comments on the
proposed decision (85 FR 24094, April 30, 2020).
    The health effects evidence base available in the 2020 review
included extensive evidence from previous reviews as well as the
evidence that had emerged since the prior review had been completed in
2012. This evidence base, spanning several decades, documents the
relationship between short- and long-term PM2.5 exposure and
mortality or serious morbidity effects. The evidence available in the
2019 ISA reaffirmed, and in some cases strengthened, the conclusions
from the 2009 ISA regarding the health effects of PM2.5
exposures (U.S. EPA, 2009a). Much of the evidence came from
epidemiologic studies conducted in North America, Europe, or Asia
examining short-term and long-term exposures that demonstrated
generally positive, and often statistically significant,
PM2.5 health effect associations with a range of outcomes
including non-accidental, cardiovascular, or respiratory mortality;
cardiovascular or respiratory hospitalizations or emergency department
visits; and other mortality/morbidity outcomes (e.g., lung cancer
mortality or incidence, asthma development). Experimental evidence, as
well as evidence from panel studies, strengthened support for potential
biological pathways through which PM2.5 exposures could lead
to health effects reported in many population-based epidemiologic
studies, including support for pathways that could lead to
cardiovascular, respiratory, nervous system, and cancer-related
effects. Based on this evidence, the 2019 ISA concludes there to be a
causal relationship between long- and short-term PM2.5
exposure and mortality and cardiovascular effects, as well as likely to
be causal relationships between long- and short-term PM2.5
exposures and respiratory effects, and between long-term
PM2.5 exposures and cancer and nervous system effects (U.S.
EPA, 2019a, section 1.7).
    Epidemiologic studies reported PM2.5 health effect
associations with mortality and/or morbidity across multiple U.S.
cities and in diverse populations, including in studies examining
populations and lifestages that may be at increased risk of
experiencing a PM2.5-related health effect (e.g., older
adults, children). The 2019 ISA cited extensive evidence indicating
that ``both the general population as well as specific populations and
lifestages are at risk for PM2.5-related health effects''
(U.S. EPA, 2019a, p. 12-1). Some of the evidence that supported
conclusions on at-risk populations and lifestages also

contributed to the conclusions of causal and likely to be causal
relationships within the 2019 ISA, including:
     PM2.5-related mortality and cardiovascular
effects in older adults (U.S. EPA, 2019a, sections 11.1, 11.2, 6.1, and
6.2);
     PM2.5-related cardiovascular effects in people
with pre-existing cardiovascular disease (U.S. EPA, 2019a, section
6.1);
     PM2.5-related respiratory effects in people
with pre-existing respiratory disease, particularly asthma (U.S. EPA,
2019a, section 5.1);
     PM2.5-related impairments in lung function
growth and asthma development in children (U.S. EPA, 2019a, sections
5.1, 5.2, and <IP_ADDRESS>).
    The 2019 ISA also noted that stratified analyses (i.e., analyses
that allow for the comparison of PM-related health effects across
different populations) provided strong evidence for racial and ethnic
differences in PM2.5 exposures and PM2.5-related
health risk. Such analyses indicated that certain racial and ethnic
groups, specifically Hispanic and non-Hispanic Black populations have
higher PM2.5 exposures than non-Hispanic White populations,
thus contributing to risk of adverse PM2.5-related health
effects in minority populations (U.S. EPA, 2019a, section 12.5.4).
Stratified analyses focusing on other groups also suggested that
populations with pre-existing cardiovascular or respiratory disease,
populations that are overweight or obese, populations that have
particular genetic variants, and populations that are of low
socioeconomic status (SES) could be at increased risk for
PM2.5-related adverse health effects (U.S. EPA, 2019a,
chapter 12).
    The risk information available in the 2020 review included risk
estimates for air quality conditions just meeting the existing primary
PM2.5 standards, and also for air quality conditions just
meeting potential alternative standards. The general approach to
estimating PM2.5-associated health risks combined
concentration-response (C-R) functions from epidemiologic studies with
model-based PM2.5 air quality surfaces, baseline health
incidence data, and population demographics for 47 urban areas (U.S.
EPA, 2022b, section 3.3, Figure 3-10, Appendix C). The risk assessment
estimated that the existing primary PM2.5 standards could
allow a substantial number of PM2.5-associated deaths in the
U.S. Uncertainty in risk estimates (e.g., in the size of risk
estimates) can result from a number of factors, including assumptions
about the shape of the C-R relationship with mortality at low ambient
PM2.5 concentrations, the potential for confounding and/or
exposure measurement error, and the methods used to adjust
PM2.5 air quality.
    Consistent with the general approach routinely employed in NAAQS
reviews, the initial consideration in the 2020 review of the primary
PM2.5 standards was with regard to the adequacy of the
protection provided by the existing standards. Key aspects of the
consideration are summarized in section II.A.1.a below.
a. Considerations Regarding the Adequacy of the Existing Standards in
the 2020 Review
    With the 2020 final decision, the EPA retained the primary 24-hour
PM2.5 standard, with its level of 35 [micro]g/m\3\, and the
primary annual PM2.5 standard, with its level of 12.0
[micro]g/m\3\. The Administrator's conclusions regarding the adequacy
of the primary PM2.5 standards at the time of the 2020
review was based on consideration of the evidence, analyses and
conclusions contained in the 2019 ISA; the quantitative risk assessment
in the 2020 PA; advice from the CASAC; and public comments. Key
considerations informing the Administrator's decision to retain the
standards that were promulgated in the 2012 review are summarized
below.
    As an initial matter, the Administrator considered the range of
scientific evidence evaluating these effects, including studies of at-
risk populations, to inform his review of the primary PM2.5
standards, placing the greatest weight on evidence of effects for which
the 2019 ISA determined there to be a causal or likely to be causal
relationship with long- and short-term PM2.5 exposures (85
FR 82714-82715, December 18, 2020).
    With regard to indicator, the Administrator recognized that,
consistent with the evidence available in prior reviews, the scientific
evidence in the 2020 review continued to provide strong support for
health effects following short- and long-term PM2.5
exposures. He noted the 2020 PA conclusions that the information
continued to support the PM2.5 mass-based indicator and
remained too limited to support a distinct standard for any specific
PM2.5 component or group of components, and too limited to
support a distinct standard for the ultrafine fraction. Thus, the
Administrator concluded that it was appropriate to retain
PM2.5 as the indicator for the primary standards for fine
particles (85 FR 82715, December 18, 2020).
    With respect to averaging time and form, the Administrator noted
that the scientific evidence continued to provide strong support for
health effects associations with both long-term (e.g., annual or multi-
year) and short-term (e.g., mostly 24-hour) exposures to
PM2.5, consistent with the conclusions in the 2020 PA. In
the 2019 ISA, epidemiologic and controlled human exposure studies
examined a variety of PM2.5 exposure durations.
Epidemiologic studies continued to provide strong support for health
effects associated with short-term PM2.5 exposures based on
24-hour PM2.5 averaging periods, and the EPA noted that
associations with sub-daily estimates are less consistent and, in some
cases, smaller in magnitude (U.S. EPA, 2019a, section <IP_ADDRESS>; U.S.
EPA, 2020a, section <IP_ADDRESS>). In addition, controlled human exposure
and panel-based studies of sub-daily exposures typically examined
subclinical effects, rather than the more serious population-level
effects that have been reported to be associated with 24-hour exposures
(e.g., mortality, hospitalizations). Taken together, the 2019 ISA
concludes that epidemiologic studies did not indicate that sub-daily
averaging periods were more closely associated with health effects than
the 24-hour average exposure metric (U.S. EPA, 2019a, section <IP_ADDRESS>).
Additionally, while controlled human exposure studies provided
consistent evidence for cardiovascular effects following
PM2.5 exposures for less than 24 hours (i.e., < 30 minutes
to 5 hours), exposure concentrations in the studies were well-above the
ambient concentrations typically measured in locations meeting the
existing standards (U.S. EPA, 2020a, section <IP_ADDRESS>). Thus, these
studies also did not suggest the need for additional protection against
sub-daily PM2.5 exposures (U.S. EPA, 2020a, section
<IP_ADDRESS>). Therefore, the Administrator judged that the 24-hour
averaging time remained appropriate (85 FR 82715, December 18, 2020).
    With regard to the form of the 24-hour standard (98th percentile,
averaged over three years), the Administrator noted that epidemiologic
studies continued to provide strong support for health effect
associations with short-term (e.g., mostly 24-hour) PM2.5
exposures (U.S. EPA, 2020a, section <IP_ADDRESS>) and that controlled human
exposure studies provided evidence for health effects following single
short-term ``peak'' PM2.5 exposures. Thus, the evidence
supported retaining a standard focused on providing supplemental
protection against short-term peak exposures and

supported a 98th percentile form for a 24-hour standard. The
Administrator further noted that this form also provided an appropriate
balance between limiting the occurrence of peak 24-hour
PM2.5 concentrations and identifying a stable target for
risk management programs (U.S. EPA, 2020a, section <IP_ADDRESS>). As such,
the Administrator concluded that the available information supported
retaining the form and averaging time of the current 24-hour standard
(98th percentile, averaged over three years) and annual standard
(annual average, averaged over three years) (85 FR 82715, December 18,
2020).
    With regard to the level of the standards, in reaching his final
decision, the Administrator considered the large body of evidence
presented and assessed in the 2019 ISA (U.S. EPA, 2019a), the policy-
relevant and risk-based conclusions and rationales as presented in the
2020 PA (U.S. EPA, 2020a), advice from the CASAC, and public comments.
In particular, in considering the 2019 ISA and 2020 PA, he considered
key epidemiologic studies that evaluated associations between
PM2.5 air quality distributions and mortality and morbidity,
including key accountability studies; the availability of experimental
studies to support biological plausibility; controlled human exposure
studies examining effects following short-term PM2.5
exposures; air quality analyses; and the important uncertainties and
limitations associated with the information (85 FR 82715, December 18,
2020).
    As an initial matter, the Administrator considered the protection
afforded by both the annual and 24-hour standards together against
long- and short-term PM2.5 exposures and health effects. The
Administrator recognized that the annual standard was most effective in
controlling ``typical'' PM2.5 concentrations near the middle
of the air quality distribution (i.e., around the mean of the
distribution), but also provided some control over short-term peak
PM2.5 concentrations. On the other hand, the 24-hour
standard, with its 98th percentile form, was most effective at limiting
peak 24-hour PM2.5 concentrations, but in doing so also had
an effect on annual average PM2.5 concentrations. Thus,
while either standard could be viewed as providing some measure of
protection against both average exposures and peak exposures, the 24-
hour and annual standards were not expected to be equally effective at
limiting both types of exposures. Thus, consistent with previous
reviews, the Administrator's consideration of the public health
protection provided by the existing primary PM2.5 standards
was based on his consideration of the combination of the annual and 24-
hour standards. Specifically, he recognized that the annual standard
was more likely to appropriately limit the ``typical'' daily and annual
exposures that are most strongly associated with the health effects
observed in epidemiologic studies. The Administrator concluded that an
annual standard (as the arithmetic mean, averaged over three years)
remained appropriate for targeting protection against the annual and
daily PM2.5 exposures around the middle portion of the
PM2.5 air quality distribution. Further, recognizing that
the 24-hour standard (with its 98th percentile form) was more directly
tied to short-term peak PM2.5 concentrations, and more
likely to appropriately limit exposures to such concentrations, the
Administrator concluded that the current 24-hour standard (with its
98th percentile form, averaged over three years) remained appropriate
to provide a balance between limiting the occurrence of peak 24-hour
PM2.5 concentrations and identifying a stable target for
risk management programs. However, the Administrator recognized that
changes in PM2.5 air quality to meet an annual standard
would likely result not only in lower short- and long-term
PM2.5 concentrations near the middle of the air quality
distribution, but also in fewer and lower short-term peak
PM2.5 concentrations. The Administrator further recognized
that changes in air quality to meet a 24-hour standard, with a 98th
percentile form, would result not only in fewer and lower peak 24-hour
PM2.5 concentrations, but also in lower annual average
PM2.5 concentrations (85 FR 82715-82716, December 18, 2020).
    Thus, in considering the adequacy of the 24-hour standard, the
Administrator noted the importance of considering whether additional
protection was needed against short-term exposures to peak
PM2.5 concentrations. In examining the scientific evidence,
he noted the limited utility of the animal toxicological studies in
directly informing conclusions on the appropriate level of the standard
given the uncertainty in extrapolating from effects in animals to those
in human populations. The Administrator noted that controlled human
exposure studies provided evidence for health effects following single,
short-term PM2.5 exposures that corresponded best to
exposures that might be experienced in the upper end of the
PM2.5 air quality distribution in the U.S. (i.e., ``peak''
concentrations). However, most of these studies examined exposure
concentrations considerably higher than are typically measured in areas
meeting the standards (U.S. EPA, 2020a, section <IP_ADDRESS>). In
particular, controlled human exposure studies often reported
statistically significant effects on one or more indicators of
cardiovascular function following 2-hour exposures to PM2.5
concentrations at and above 120 [mu]g/m\3\ (at and above 149 [mu]g/m\3\
for vascular impairment, the effect shown to be most consistent across
studies). To provide insight into what these studies may indicate
regarding the primary PM2.5 standards, the 2020 PA (U.S.
EPA, 2020a, p. 3-49) noted that 2-hour ambient concentrations of
PM2.5 at monitoring sites meeting the current standards
almost never exceeded 32 [mu]g/m\3\. In fact, even the extreme upper
end of the distribution of 2-hour PM2.5 concentrations at
sites meeting the primary PM2.5 standards remained well-
below the PM2.5 exposure concentrations consistently shown
in controlled human exposure studies to elicit effects (i.e., 99.9th
percentile of 2-hour concentrations at these sites is 68 [mu]g/m\3\
during the warm season). Thus, the available experimental evidence did
not indicate the need for additional protection against exposures to
peak PM2.5 concentrations, beyond the protection provided by
the combination of the 24-hour and the annual standards (U.S. EPA,
2020a, section <IP_ADDRESS>; 85 FR 82716, December 18, 2020).
    With respect to the epidemiologic evidence, the Administrator noted
that the studies did not indicate that associations in those studies
were strongly influenced by exposures to peak concentrations in the air
quality distribution and thus did not indicate the need for additional
protection against short-term exposures to peak PM2.5
concentrations (U.S. EPA, 2020a, section 3.5.1 The Administrator noted
that this was consistent with CASAC consensus support for retaining the
current 24-hour standard. Thus, the Administrator concluded that the
24-hour standard with its level of 35 [mu]g/m\3\ was adequate to
provide supplemental protection (i.e., beyond that provided by the
annual standard alone) against short-term exposures to peak
PM2.5 concentrations (85 FR 82716, December 18, 2020).
    With regard to the level of the annual standard, the Administrator
recognized that the annual standard, with its form based on the
arithmetic mean concentration, was most appropriately meant to limit
the ``typical'' daily and annual exposures that were most strongly
associated with the health

effects observed in epidemiologic studies. However, the Administrator
also noted that while epidemiologic studies examined associations
between distributions of PM2.5 air quality and health
outcomes, they did not identify particular PM2.5 exposures
that cause effects and thus, they could not alone identify a specific
level at which the standard should be set, as such a determination
necessarily required the Administrator's judgment. Thus, consistent
with the approaches in previous NAAQS reviews, the Administrator
recognized that any approach that used epidemiologic information in
reaching decisions on what standards are appropriate necessarily
required judgments about how to translate the information from the
epidemiologic studies into a basis for appropriate standards. This
approach included consideration of the uncertainties in the reported
associations between daily or annual average PM2.5 exposures
and mortality or morbidity in the epidemiologic studies. Such an
approach is consistent with setting standards that are neither more nor
less stringent than necessary, recognizing that a zero-risk standard is
not required by the Clean Air Act (CAA) (85 FR 82716, December 18,
2020).
    The Administrator emphasized uncertainties and limitations that
were present in epidemiologic studies in previous reviews and persisted
in the 2020 review. These uncertainties included exposure measurement
error, potential confounding by copollutants, increasing uncertainty of
associations at lower PM2.5 concentrations, and
heterogeneity of effects across different cities or regions (85 FR
82716, December 18, 2020). The Administrator also noted the advice
given by the CASAC on this matter. As described in section I.C.5 above,
the CASAC did not reach consensus on the adequacy of the primary annual
PM2.5 standard. ``Some CASAC members'' expressed support for
retaining the primary annual PM2.5 standard while ``other
members'' expressed support for revising that standard in order to
increase public health protection (Cox, 2019a, p. 1 of consensus
letter). The CASAC members who supported retaining the annual standard
expressed their concerns with the epidemiologic studies, asserting that
these studies did not provide a sufficient basis for revising the
existing standards. They also identified several key concerns regarding
the associations reported in epidemiologic studies and concluded that
``while the data on associations should certainly be carefully
considered, this data should not be interpreted more strongly than
warranted based on its methodological limitations'' (Cox, 2019a, p. 8
consensus responses).
    Taking into consideration the views expressed by the CASAC members
who supported retaining the annual standard, the Administrator
recognized that epidemiologic studies examined associations between
distributions of PM2.5 air quality and health outcomes, and
they did not identify particular PM2.5 exposures that cause
effects (U.S. EPA, 2020a, section 3.1.2). While the Administrator
remained concerned about placing too much weight on epidemiologic
studies to inform conclusions on the adequacy of the primary standards,
he noted the approach to considering such studies in the 2012 review.
In the 2012 review, it was noted that the evidence of an association in
any epidemiologic study was ``strongest at and around the long-term
average where the data in the study are most concentrated'' (78 FR
3140, January 15, 2013). In considering the characterization of
epidemiologic studies, the Administrator viewed that when assessing the
mean concentrations of the key short-term and long-term epidemiologic
studies in the U.S. that use ground-based monitoring (i.e., those
studies where the mean is most directly comparable to the current
annual standard), the majority of studies had mean concentrations at or
above the level of the existing annual standard, with the mean of the
study-reported means or medians equal to 13.5 [mu]g/m\3\, a
concentration level above the existing level of the primary annual
standard of 12 [mu]g/m\3\. The Administrator further noted his caution
in directly comparing the reported study mean values to the standard
level given that study-reported mean concentrations, by design, are
generally lower than the design value of the highest monitor in an
area, which determines compliance. In the 2020 PA, analyses of recent
air quality in U.S. CBSAs indicated that maximum annual
PM2.5 design values for a given three-year period were often
10% to 20% higher than average monitored concentrations (i.e., averaged
across multiple monitors in the same CBSA) (U.S. EPA, 2020a, Appendix
B, section B.7). He further noted his concern in placing too much
weight on any one epidemiologic study but instead judged that it was
more appropriate to focus on the body of studies together and therefore
noted the calculation of the mean of study-reported means (or medians).
Thus, while the Administrator was cautious in placing too much weight
on the epidemiologic evidence alone, he noted that: (1) the reported
mean concentration in the majority of the key U.S. epidemiologic
studies using ground-based monitoring data were above the level of the
existing annual standard; (2) the mean of the reported study means (or
medians) (i.e., 13.5 [mu]g/m\3\) was above the level of the current
standard; \49\ (3) air quality analyses showed the study means to be
lower than their corresponding design values by 10-20%; and (4) these
analyses must be considered in light of uncertainties inherent in the
epidemiologic evidence. When taken together, the Administrator judged
that, even if it were appropriate to place more weight on the
epidemiologic evidence, this information did not call into question the
adequacy of the current standards (85 FR 82716-82717, December 18,
2020).
---------------------------------------------------------------------------

    \49\ The median of the study-reported mean (or median)
PM2.5 concentrations is 13.3 [mu]g/m\3\, which was also
above the level of the existing standard.
---------------------------------------------------------------------------

    In addition to the evidence, the Administrator also considered the
potential implications of the risk assessment. He noted that all risk
assessments have limitations and that he remained concerned about the
uncertainties in the underlying epidemiologic data used in the risk
assessment. The Administrator also noted that in previous reviews,
these uncertainties and limitations have often resulted in less weight
being placed on quantitative estimates of risk than on the underlying
scientific evidence itself (e.g., 78 FR 3086, 3098-99, January 15,
2013). These uncertainties and limitations included uncertainty in the
shapes of C-R functions, particularly at low concentrations;
uncertainties in the methods used to adjust air quality; and
uncertainty in estimating risks for populations, locations and air
quality distributions different from those examined in the underlying
epidemiologic study (U.S. EPA, 2020a, section <IP_ADDRESS>). Additionally,
the Administrator noted similar concern expressed by some members of
the CASAC who support retaining the existing standards; they
highlighted similar uncertainties and limitations in the risk
assessment (Cox, 2019b). In light of all of this, the Administrator
judged it appropriate to place little weight on quantitative estimates
of PM2.5-associated mortality risk in reaching conclusions
about the level of the primary PM2.5 standards (85 FR 82717,
December 18, 2020).
    The Administrator additionally considered an emerging body of
evidence from accountability studies that examined past reductions in

ambient PM2.5 and the degree to which those reductions
resulted in public health improvements. While the Administrator agreed
with public commenters that well-designed and conducted accountability
studies can be informative, he viewed the interpretation of such
studies in the context of the primary PM2.5 standards as
complicated by the fact that some of the available studies had not
evaluated PM2.5 specifically (e.g., as opposed to
PM10 or total suspended particulates), did not show changes
in PM2.5 air quality, or had not been able to disentangle
health impacts of the interventions from background trends in health
(U.S. EPA, 2020a, section 3.5.1). He further recognized that the small
number of available studies that did report public health improvements
following past declines in ambient PM2.5 had not examined
air quality meeting the existing standards (U.S. EPA, 2020a, Table 3-
3). This included U.S. studies that reported increased life expectancy,
decreased mortality, and decreased respiratory effects following past
declines in ambient PM2.5 concentrations. Such studies
examined ``starting'' annual average PM2.5 concentrations
(i.e., prior to the reductions being evaluated) ranging from about 13.2
to >20 [mu]g/m\3\ (i.e., U.S. EPA, 2020a, Table 3-3). Given the lack of
available accountability studies reporting public health improvements
attributable to reductions in ambient PM2.5 in locations
meeting the existing standards, together with his broader concerns
regarding the lack of experimental studies examining PM2.5
exposures typical of areas meeting the existing standards, the
Administrator judged that there was considerable uncertainty in the
potential for increased public health protection from further
reductions in ambient PM2.5 concentrations beyond those
achieved under the existing primary PM2.5 standards (85 FR
82717, December 18, 2020).
    When the above considerations were taken together, the
Administrator concluded that the scientific evidence assessed in the
2019 ISA, together with the analyses in the 2020 PA based on that
evidence and consideration of CASAC advice and public comments, did not
call into question the adequacy of the public health protection
provided by the existing annual and 24-hour PM2.5 standards.
In particular, the Administrator judged that there was considerable
uncertainty in the potential for additional public health improvements
from reducing ambient PM2.5 concentrations below the
concentrations achieved under the existing primary standards and that,
therefore, standards more stringent than the existing standards (e.g.,
with lower levels) were not supported. That is, he judged that more
stringent standards would be more than requisite to protect the public
health with an adequate margin of safety. This judgment reflected the
Administrator's consideration of the uncertainties in the potential
implications of the lower end of the air quality distributions from the
epidemiologic studies due in part to the lack of supporting evidence
from experimental studies and retrospective accountability studies
conducted at PM2.5 concentrations meeting the existing
standards (85 FR 82717, December 18, 2020).
    In reaching this conclusion, the Administrator judged that the
existing standards provided an adequate margin of safety. With respect
to the annual standard, the level of 12 [mu]g/m\3\ was below the lowest
``starting'' concentration (i.e., 13.2 [mu]g/m\3\) in the available
accountability studies that showed public health improvements
attributable to reductions in ambient PM2.5. In addition,
while the Administrator placed less weight on the epidemiologic
evidence for selecting a standard, he noted that the level of the
annual standard was below the reported mean (and median) concentrations
in the majority of the key U.S. epidemiologic studies using ground-
based monitoring data (noting that these means tend to be 10-20% lower
than their corresponding area design values which is the more relevant
metric when considering the level of the standard) and below the mean
of the reported means (or medians) of these studies (i.e., 13.5 [mu]g/
m\3\). In addition, the Administrator recognized that concentrations in
areas meeting the existing 24-hour and annual standards remained well-
below the PM2.5 exposure concentrations consistently shown
to elicit effects in human exposure studies (85 FR 82717-82718,
December 18, 2020).
    In addition, based on the Administrator's review of the science,
including controlled human exposure studies examining effects following
short-term PM2.5 exposures, the epidemiologic studies, and
accountability studies conducted at levels just above the existing
annual standard, he judged that the degree of public health protection
provided by the existing annual standard is not greater than warranted.
This judgment, together with the fact that no CASAC member expressed
support for a less stringent standard, led the Administrator to
conclude that standards less stringent than the existing standards
(e.g., with higher levels) were also not supported (85 FR 82718,
December 18, 2020).
    In reaching his final decision, the Administrator concluded that
the scientific evidence and technical information continued to support
the existing annual and 24-hour PM2.5 standards. This
conclusion reflected the Administrator's view that there were important
limitations and uncertainties that remained in the evidence. The
Administrator concluded that these limitations contributed to
considerable uncertainty regarding the potential public health
implications of revising the existing primary PM2.5
standards. Given this uncertainty, and noting the advice from some
CASAC members, he concluded that the primary PM2.5
standards, including the indicators (PM2.5), averaging times
(annual and 24-hour), forms (arithmetic mean and 98th percentile,
averaged over three years) and levels (12.0 [mu]g/m\3\, 35 [mu]g/m\3\),
when taken together, remained requisite to protect the public health.
Therefore, in the 2020 review, the Administrator reached the conclusion
that the primary 24-hour and annual PM2.5 standards,
together, were requisite to protect public health from fine particles
with an adequate margin of safety, including the health of at-risk
populations, and retained the standards, without revision (85 FR 82718,
December 18, 2020).
2. General Approach and Key Issues in This Reconsideration of the 2020
Final Decision
    To evaluate whether it is appropriate to consider retaining the
current primary PM2.5 standards, or whether consideration of
revision is appropriate, the EPA has adopted an approach in this
reconsideration that builds upon the general approach used in past
reviews. This includes the substantial assessments and evaluations
performed in those reviews, and also takes into account the more recent
scientific evidence and risk information now available to inform
understanding of the key policy-relevant issues in the reconsideration.
As summarized above, the Administrator's decisions in the 2020 review
were based on an integration of PM health effects information with the
judgments on the adversity and public health significance of key health
effects, policy judgments as to when the standard is requisite to
protect public health with an adequate margin of safety, and
consideration of CASAC advice and public comments.
    Similarly, in this reconsideration, we draw on the current evidence
and quantitative assessments of exposure

pertaining to the public health risk of PM in ambient air. In
considering the scientific and technical information here, we consider
both the information available at the time of the 2020 review and
information more recently available, including that which has been
critically analyzed and characterized in the 2019 ISA and ISA
Supplement. The quantitative risk analyses, including a newly conducted
at-risk analysis, provide a context for interpreting the evidence of
mortality and the potential public health significance of risks
associated with air quality conditions that just meet the current and
potential alternative standards. The overarching purpose of these
analyses is to inform the Administrator's conclusions on the public
health protection afforded by the current primary standards, with an
important focus on evaluating the potential for exposures and risks
beyond those indicated by the information available at the time the
current standards were established.

B. Overview of the Health Effects Evidence

    The information summarized here is an overview of the policy-
relevant aspects of the health effects evidence available in this
reconsideration; the assessment of this evidence is documented in the
2019 ISA and ISA Supplement and its policy implications are further
discussed in the PA. While the 2019 ISA provides the broad scientific
foundation for this reconsideration, additional literature has become
available since the cutoff date of the 2019 ISA that expands the body
of evidence related to mortality and cardiovascular effects for both
short- and long-term PM2.5 exposure that can inform the
Administrator's judgment on the adequacy of the current primary
PM2.5 standards. As such, the ISA Supplement builds on the
information presented within the 2019 ISA with a targeted
identification and evaluation of new scientific information (U.S. EPA,
2022a, section 1.2). The ISA Supplement focuses on PM2.5
health effects evidence where the 2019 ISA concludes a ``causal
relationship,'' because such health effects are given the most weight
in an Administrator's decisions in a NAAQS review. As such, the ISA
Supplement evaluates newly available evidence related to short- and
long-term PM2.5 exposure and mortality and cardiovascular
effects given the strength of the evidence available in the 2019 ISA
and past ISAs and AQCDs, as well as the clear adversity of these
endpoints. Specifically, U.S. and Canadian epidemiologic studies for
mortality and cardiovascular effects along with controlled human
exposure studies associated with cardiovascular effects at near ambient
concentrations, were considered to be of greatest utility in informing
the Administrator's conclusions on the adequacy of the current primary
PM2.5 standards. While the ISA Supplement does not include
information for health effects other than mortality and cardiovascular
effects, the scientific evidence for other health effect categories is
evaluated in the 2019 ISA, which in combination with the ISA Supplement
represents the complete scientific record for the reconsideration of
the 2020 final decision.
    The ISA Supplement also assessed accountability studies because
these types of epidemiologic studies were part of the body of evidence
that was a focus of the 2020 review. Accountability studies inform our
understanding of the potential for public health improvements as
ambient PM2.5 concentrations have declined over time.
Further, the ISA Supplement considered studies that employed
statistical approaches that attempt to more extensively account for
confounders and are more robust to model misspecification (i.e., used
alternative methods for confounder control),\50\ given that such
studies were highlighted by the CASAC and identified in public comments
in the 2020 review. Since the literature cutoff date for the 2019 ISA,
multiple accountability studies and studies that employ alternative
methods for confounder control have become available for consideration
in the ISA Supplement and, subsequently, in this reconsideration.
---------------------------------------------------------------------------

    \50\ As noted in the ISA Supplement (U.S. EPA, 2022a, p. 1-3):
``In the peer-reviewed literature, these epidemiologic studies are
often referred to as causal inference studies or studies that used
causal modeling methods. For the purposes of this Supplement, this
terminology is not used to prevent confusion with the main
scientific conclusions (i.e., the causality determinations)
presented within an ISA. In addition, as is consistent with the
weight-of-evidence framework used within ISAs and discussed in the
Preamble to the Integrated Science Assessments, an individual study
on its own cannot inform causality, but instead represents a piece
of the overall body of evidence.''
---------------------------------------------------------------------------

    The ISA Supplement also considered recent health effects evidence
that addresses key scientific issues where the literature has expanded
since the completion of the 2019 ISA.\51\ The 2019 ISA evaluated a
couple of controlled human exposure studies that investigated the
effect of exposure to near-ambient concentrations of PM2.5
(U.S. EPA, 2019a, section 6.1.10 and 6.1.13). The ISA Supplement adds
to this limited evidence, including a recent study conducted in young
healthy individuals exposed to near-ambient PM2.5
concentrations (U.S. EPA, 2022a, section 3.3.1). Given the importance
of identifying populations at increased risk of PM2.5-
related effects, the ISA Supplement also included epidemiologic or
exposure studies that examined whether there is evidence of exposure or
risk disparities by race/ethnicity or SES. These types of studies
provide additional information related to factors that may increase
risk of PM2.5-related health effects and provide additional
evidence for consideration by the Administrator in reaching conclusions
regarding the adequacy of the current standards. In addition, the ISA
Supplement evaluated studies that examined the relationship between
short- and long-term PM2.5 exposures and SARS-CoV-2
infection and/or COVID-19 death, as these studies are a new area of
research and were raised by a number of public commenters in the 2020
review.
---------------------------------------------------------------------------

    \51\ As with the epidemiologic studies for long- and short-term
PM2.5 exposure and mortality and cardiovascular effects,
epidemiologic studies of exposure or risk disparities and SARS-CoV-2
infection and/or COVID-19 death were limited to those conducted in
the U.S. and Canada.
---------------------------------------------------------------------------

    The evidence presented within the 2019 ISA, along with the targeted
identification and evaluation of new scientific information in the ISA
Supplement, provides the scientific basis for the reconsideration of
the 2020 final decision on the primary PM2.5 standards. The
subsections below briefly summarize the nature of PM2.5-
related health effects, with a focus on those health effects for which
the 2019 ISA concluded a ``causal'' or ``likely to be causal''
relationship.
1. Nature of Effects
    The evidence base available in the reconsideration includes decades
of research on PM2.5-related health effects (U.S. EPA,
2004b; U.S. EPA, 2009b; U.S. EPA, 2019a), including the full body of
evidence evaluated in the 2019 ISA (U.S. EPA, 2019a), along with the
targeted evaluation of recent evidence in the ISA Supplement (U.S. EPA,
2022a). In considering the available scientific evidence, the sections
below summarize the relationships between long- and short-term
PM2.5 exposures and mortality (II.B.1.a), cardiovascular
effects (II.B.1.b), respiratory effects (II.B.1.c), cancer (II.B.1.d),
and nervous system effects (II.B.1.e). For these outcomes, the 2019 ISA
concluded that the evidence supports either a ``causal'' or a ``likely
to be causal'' relationship.\52\
---------------------------------------------------------------------------

    \52\ In this reconsideration of the PM NAAQS, the EPA considers
the full body of health evidence, placing the greatest emphasis on
the health effects for which the evidence has been judged in the
2019 ISA to demonstrate a ``causal'' or ``likely to be causal''
relationship with PM2.5 exposures.

---------------------------------------------------------------------------

a. Mortality
i. Long-Term PM2.5 Exposures
    In the 2012 review, the 2009 ISA reported that the evidence was
``sufficient to conclude that the relationship between long-term
PM2.5 exposures and mortality is causal'' (U.S. EPA, 2009a,
p. 7-96). The strongest evidence supporting this conclusion was
provided by epidemiologic studies, particularly those examining two
seminal cohorts, the American Cancer Society (ACS) cohort and the
Harvard Six Cities cohort. Analyses of the Harvard Six Cities cohort
included evidence indicating that reductions in ambient
PM2.5 concentrations are associated with reduced mortality
risk (Laden et al., 2006) and increases in life expectancy (Pope et
al., 2009). Further support was provided by other cohort studies
conducted in North America and Europe that reported positive
associations between long-term PM2.5 exposure and mortality
(U.S. EPA, 2019a).
    Cohort studies, which have become available since the completion of
the 2009 ISA and evaluated in the 2019 ISA, continue to provide
consistent evidence of positive associations between long-term
PM2.5 exposures and mortality. These studies add support for
associations with all-cause and total (non-accidental) mortality,\53\
as well as with specific causes of mortality, including cardiovascular
disease and respiratory disease (U.S. EPA, 2019a, section 11.2.2).
Several of these studies conducted analyses over longer study durations
and periods of follow-up than examined in the original ACS and Harvard
Six Cities cohort studies and continue to report positive associations
between long-term exposure to PM2.5 and mortality (U.S. EPA,
2019a, section <IP_ADDRESS>; Figures 11-18 and 11-19). In addition to
studies focusing on the ACS and Harvard Six Cities cohorts, additional
studies examining other cohorts also provide evidence of consistent,
positive associations between long-term PM2.5 exposure and
mortality across a wide range of demographic groups (e.g., age, sex,
occupation), spatial and temporal extents, exposure assessment metrics,
and statistical techniques (U.S. EPA, 2019a, sections <IP_ADDRESS>, 11.2.5;
U.S. EPA, 2022a, Table 11-8). This includes some of the largest cohort
studies conducted to date, such as analyses of the U.S. Medicare cohort
that includes nearly 61 million enrollees and studies that control for
a range of individual and ecological covariates, including race, age,
SES, smoking status, body mass index, and annual weather variables
(e.g., temperature, humidity) (U.S. EPA, 2019a).
---------------------------------------------------------------------------

    \53\ The majority of these studies examined non-accidental
mortality outcomes, though some Medicare studies lack cause-specific
death information and, therefore, examine total mortality.
---------------------------------------------------------------------------

    In addition to those cohort studies evaluated in the 2019 ISA,
recent North American cohort studies evaluated in the ISA Supplement
continue to examine the relationship between long-term PM2.5
exposure and mortality and report consistent, positive and
statistically significant associations. These recent studies also
utilize large and demographically diverse cohorts that are generally
representative of the national populations in both the U.S. and Canada.
These ``studies published since the 2019 ISA support and extend the
evidence base that contributed to the conclusion of a causal
relationship between long-term PM2.5 exposure and
mortality'' (U.S. EPA, 2022a, section <IP_ADDRESS>.1, Figure 3-19, Figure 3-
20).
    Furthermore, studies evaluated in the 2019 ISA and the ISA
Supplement that examined cause-specific mortality expand upon previous
research that found consistent, positive associations between
PM2.5 exposure and specific mortality outcomes, which
include cardiovascular and respiratory mortality, as well as other
mortality outcomes. For cardiovascular-related mortality, the evidence
evaluated in the ISA Supplement is consistent with the evidence
evaluated in the 2019 ISA with recent studies reporting positive
associations with long-term PM2.5 exposure. When evaluating
cause-specific cardiovascular mortality, recent studies reported
positive associations for a number of outcomes, such as ischemic heart
disease (IHD) and stroke mortality (U.S. EPA, 2022a, Figure 3-23).
Moreover, recent studies also provide some initial evidence that
individuals with pre-existing health conditions, such as heart failure
and diabetes, are at an increased risk of PM2.5-related
health effects (U.S. EPA, 2022a, section <IP_ADDRESS>) and that these
individuals have a higher risk of mortality overall, which was
previously only examined in studies that used stratified analyses
rather than a cohort of people with an underlying health condition
(U.S. EPA, 2022a, section <IP_ADDRESS>). With regard to respiratory
mortality, epidemiologic studies evaluated in the 2019 ISA and ISA
Supplement continue to provide support for associations between long-
term PM2.5 exposure and respiratory mortality (U.S. EPA,
2019a, section 5.2.10; U.S. EPA, 2022a, Table 3-2).
    A series of epidemiologic studies evaluated in the 2019 ISA tested
the hypothesis that past reductions in ambient PM2.5
concentrations are associated with increased life expectancy or a
decreased mortality rate (U.S. EPA, 2022a, section <IP_ADDRESS>). Pope et
al. (2009) conducted a cross-sectional analysis using air quality data
from 51 metropolitan areas across the U.S., beginning in the 1970s
through the early 2000s, and found that a 10 [mu]g/m\3\ decrease in
long-term PM2.5 concentration was associated with a 0.61-
year increase in life expectancy. In a subsequent analysis, the authors
extended the period of analysis to include 2000 to 2007, a time period
with lower ambient PM2.5 concentrations (Correia et al.,
2013). In this follow-up study, a decrease in long-term
PM2.5 concentration continued to be associated with an
increase in life expectancy, though the magnitude of the increase was
smaller than during the earlier time period (i.e., a 10 [mu]g/m\3\
decrease in long-term PM2.5 concentration was associated
with a 0.35-year increase in life expectancy). Additional studies
conducted in the U.S. or Europe similarly report that reductions in
ambient PM2.5 are associated with improvements in longevity
(U.S. EPA, 2022a, section <IP_ADDRESS>). Since the literature cutoff date
for the 2019 ISA, a few epidemiologic studies were published that
examined the relationship between long-term PM2.5 exposure
and life-expectancy (U.S. EPA, 2022a, section <IP_ADDRESS>) and report
results that are consistent with and expand upon the body of evidence
from the 2019 ISA. For example, reported that PM2.5
concentrations above the lowest observed concentration (2.8 [mu]g/m\3\)
were associated with a 0.15 year decrease in national life expectancy
for women and 0.13 year decrease in national life expectancy for men
(U.S. EPA, 2022a, section <IP_ADDRESS>.4, Figure 3-25). Another study
compared participants living in areas with PM2.5
concentrations >12 [mu]g/m\3\ to participants living in areas with
PM2.5 concentrations <12 [mu]g/m\3\ and reported that the
number of years of life lost due to living in areas with higher
PM2.5 concentrations was 0.84 years over a 5-year period
(Ward-Caviness et al., 2020; U.S. EPA, 2022a, section <IP_ADDRESS>.4).
    Additionally, a number of accountability studies, which are
epidemiologic studies that evaluate whether an environmental policy or
air quality intervention resulted in reductions in ambient air
pollution concentrations and subsequent reductions in mortality, have
emerged

and were evaluated in the ISA Supplement (U.S. EPA, 2022a, section
<IP_ADDRESS>). For example, Sanders et al. (2020a) examined whether policy
actions (i.e., the first annual PM2.5 NAAQS implementation
rule in 2005 for the 1997 annual PM2.5 standard with a 3-
year annual average of 15.0 [mu]g/m\3\) reduced PM2.5
concentrations and mortality rates in Medicare beneficiaries between
2000-2013, and found that following implementation of the annual
PM2.5 NAAQS, annual PM2.5 concentrations
decreased by 1.59 [mu]g/m\3\ (95% CI: 1.39, 1.80) which corresponded to
a reduction in mortality rates among individuals 65 years and older
(0.93% [95% CI: 0.10%, 1.77%]) in non-attainment counties relative to
attainment counties.
    The 2019 ISA also evaluated a small number of studies that used
alternative methods for confounder control to further assess
relationship between long-term PM2.5 exposure and mortality
(U.S. EPA, 2019a, section <IP_ADDRESS>). In addition, multiple
epidemiologic studies that implemented alternative methods for
confounder control and were published since the literature cutoff date
of the 2019 ISA were evaluated in the ISA Supplement (U.S. EPA, 2022a,
section <IP_ADDRESS>). These studies used a variety of statistical methods
including generalized propensity score (GPS), inverse probability
weighting (IPW), and difference-in-difference (DID) to reduce
uncertainties related to confounding bias in the association between
long-term PM2.5 exposure and mortality. Studies that
employed these alternative methods for confounder control reported
consistent positive associations between long-term PM2.5
exposure and total mortality (U.S. EPA, 2022a, section <IP_ADDRESS>), and
provided further support for the associations reported in the cohort
studies referenced above.
    The 2019 ISA and ISA Supplement also evaluated the degree to which
recent studies examining the relationship between long-term
PM2.5 exposure and mortality addressed key policy-relevant
issues and/or previously identified data gaps in the scientific
evidence, including methods to estimate exposure, methods to control
for confounding (e.g., co-pollutant confounding), the shape of the C-R
relationship, as well as examining whether a threshold exists below
which mortality effects do not occur. For example, with respect to
exposure assessment, based on its evaluation of the evidence, the 2019
ISA concludes that positive associations between long-term
PM2.5 exposures and mortality are robust across recent
analyses using various approaches to estimate PM2.5
exposures (e.g., based on monitors, models, satellite-based methods, or
hybrid methods that combine information from multiple sources) (U.S.
EPA, 2019a, section <IP_ADDRESS>). Hart et al. (2015) report that
correction for bias due to exposure measurement error increases the
magnitude of the hazard ratios (confidence intervals widen but the
association remains statistically significant), suggesting that failure
to correct for exposure measurement error could result in attenuation
or underestimation of risk estimates.
    The 2019 ISA additionally concludes that positive associations
between long-term PM2.5 exposures and mortality are robust
across statistical models that use different approaches to control for
confounders or different sets of confounders (U.S. EPA, 2019a, sections
11.2.3 and 11.2.5), across diverse geographic regions and populations,
and across a range of temporal periods including periods of declining
PM concentrations (U.S. EPA, 2019a, sections <IP_ADDRESS> and <IP_ADDRESS>).
Additional evidence further demonstrates that associations with
mortality remain robust in copollutants analyses (U.S. EPA, 2019a,
section 11.2.3), and that associations persist in analyses restricted
to long-term exposures (annual average PM2.5 concentrations)
below 12 [mu]g/m\3\ (Di et al., 2017b) or 10 [mu]g/m\3\ (Shi et al.,
2016), indicating that risks are not disproportionately driven by the
upper portions of the air quality distribution. Recent studies
evaluated in the ISA Supplement further assess potential copollutant
confounding and indicate that while there is some evidence of potential
confounding of the PM2.5-mortality association by
copollutants in some of the studies (i.e., those studies of the
Mortality Air Pollution Associations in Low Exposure Environments
(MAPLE) cohort), this result is inconsistent with other recent studies
evaluated in the 2019 ISA that were conducted in the U.S. and Canada
that found associations in both single and copollutant models (U.S.
EPA, 2019a; U.S. EPA, 2022a, section <IP_ADDRESS>)
    Additionally, a few studies use statistical techniques to reduce
uncertainties related to potential confounding to further inform
conclusions on causality for long-term PM2.5 exposure and
mortality. For example, studies by Greven et al. (2011), Pun et al.
(2017), and Eum et al. (2018) completed sensitivity analyses as part of
their Medicare cohort study in which they decompose ambient
PM2.5 into ``spatial'' and ``spatiotemporal'' components in
order to evaluate the potential for bias due to unmeasured spatial
confounding. Pun et al. (2017) observed positive associations for the
``temporal'' variation model and approximately null associations for
the ``spatiotemporal'' variation model for all causes of death except
for chronic obstructive pulmonary disease (COPD) mortality. The
difference in the results of these two models for most causes of death
suggests the presence of unmeasured confounding, though the authors do
not indicate anything about the direction or magnitude of this bias. It
is important to note that the ``temporal'' and ``spatiotemporal''
coefficients are not directly comparable to the results of other
epidemiologic studies when examined individually and can only be used
in comparison with one another to evaluate the potential for unmeasured
confounding bias. Eum et al. (2018) and Wu et al. (2020) also attempted
to address long-term trends and meteorological variables as potential
confounders and found that not adjusting for temporal trends could
overestimate the association, while effect estimates in analyses that
excluded meteorological variables remained unchanged compared to the
main analyses. While results of these analyses suggest the presence of
some unmeasured confounding, they do not indicate the direction or
magnitude of the bias.\54\
---------------------------------------------------------------------------

    \54\ In public comments on the 2019 draft PA, the authors of the
Pun et al. (2017) study further note that ``the presence of
unmeasured confounding . . . was expected given that we did not
control for several potential confounders that may impact
PM2.5-mortality associations, such as smoking, socio-
economic status (SES), gaseous pollutants, PM2.5
components, and long-term time trends in PM2.5'' and that
``spatial confounding may bias mortality risks both towards and away
from the null'' (Docket ID EPA-HQ-OAR-2015-0072-0065; accessible in
https://www.regulations.gov/).
---------------------------------------------------------------------------

    An additional important consideration in characterizing the public
health impacts associated with PM2.5 exposure is whether C-R
relationships are linear across the range of concentrations or if
nonlinear relationships exist along any part of this range. Studies
evaluated in the 2019 ISA and the ISA Supplement examine this issue,
and continue to provide evidence of linear, no-threshold relationships
between long-term PM2.5 exposures and all-cause and cause-
specific mortality (U.S. EPA, 2019a, section 11.2.4; U.S. EPA, 2022a,
section <IP_ADDRESS>.7, Table 3-6). Across the studies evaluated in the 2019
ISA and the ISA Supplement, a variety of statistical methods have been
used to assess whether there is evidence of deviations in linearity
(U.S. EPA, 2019a, Table 11-7; U.S. EPA, 2022a, section <IP_ADDRESS>).
Studies have also

conducted cut-point analyses that focus on examining risk at specific
ambient PM2.5 concentrations. Generally, the evidence
remains consistent in supporting a no-threshold relationship, and in
supporting a linear relationship for PM2.5 concentrations >
8 [mu]g/m\3\. However, uncertainties remain about the shape of the C-R
curve at PM2.5 concentrations < 8 [mu]g/m\3\, with some
recent studies providing evidence for either a sublinear, linear, or
supralinear relationship at these lower concentrations (U.S. EPA,
2019a, section 11.2.4; U.S. EPA, 2022a, section <IP_ADDRESS>). There was
also some limited evidence indicating that the slope of the C-R
function may be steeper (supralinear) at lower concentrations for
cardiovascular mortality (U.S. EPA, 2022a, section <IP_ADDRESS>.6).
    The biological plausibility of PM2.5-attributable
mortality is supported by the coherence of effects across scientific
disciplines (i.e., animal toxicological, controlled human exposure
studies, and epidemiologic) when evaluating respiratory and
cardiovascular morbidity effects, which are some of the largest
contributors to total (nonaccidental) mortality. The 2019 ISA outlines
the available evidence for biologically plausible pathways by which
inhalation exposure to PM2.5 could progress from initial
events (e.g., pulmonary inflammation, autonomic nervous system
activation) to endpoints relevant to population outcomes, particularly
those related to cardiovascular diseases such as ischemic heart
disease, stroke and atherosclerosis (U.S. EPA, 2019a, section 6.2.1),
and to metabolic effects, including diabetes (U.S. EPA, 2019a, section
7.3.1). The 2019 ISA notes ``more limited evidence from respiratory
morbidity'' (U.S. EPA, 2019a, p. 11-101) such as development of chronic
obstructive pulmonary disease (COPD) (U.S. EPA, 2019a, section 5.2.1)
to support the biological plausibility of mortality due to long-term
PM2.5 exposures (U.S. EPA, 2019a, section 11.2.1).
    Taken together, epidemiologic studies evaluated in the 2019 ISA,
including recent studies evaluated in the ISA Supplement, consistently
report positive associations between long-term PM2.5
exposure and mortality across different geographic locations,
populations, and analytic approaches (U.S. EPA, 2019a; U.S. EPA, 2022a,
section <IP_ADDRESS>). As such, these studies reduce key uncertainties
identified in previous reviews, including those related to potential
copollutant confounding, and provide additional information on the
shape of the C-R curve. As evaluated in the 2019 ISA, experimental and
epidemiologic evidence for cardiovascular effects, and respiratory
effects to a more limited degree, supports the plausibility of
mortality due to long-term PM2.5 exposures. Overall, studies
evaluated in the 2019 ISA support the conclusion of a causal
relationship between long-term PM2.5 exposure and mortality,
which is supported and extended by evidence from recent epidemiologic
studies evaluated in the ISA Supplement (U.S. EPA, 2022a, section
<IP_ADDRESS>).
ii. Short-Term PM2.5 Exposures
    The 2009 ISA concluded that ``a causal relationship exists between
short-term exposure to PM2.5 and mortality'' (U.S. EPA,
2009a). This conclusion was based on the evaluation of both multi- and
single-city epidemiologic studies that consistently reported positive
associations between short-term PM2.5 exposure and non-
accidental mortality. These associations were strongest, in terms of
magnitude and precision, primarily at lags of 0 to 1 days. Examination
of the potential confounding effects of gaseous copollutants was
limited, though evidence from single-city studies indicated that
gaseous copollutants have minimal effect on the PM2.5-
mortality relationship (i.e., associations remain robust to inclusion
of other pollutants in copollutant models). The evaluation of cause-
specific mortality found that effect estimates were larger in
magnitude, but also had larger confidence intervals, for respiratory
mortality compared to cardiovascular mortality. Although the largest
mortality risk estimates were for respiratory mortality, the
interpretation of the results was complicated by the limited coherence
from studies of respiratory morbidity. However, the evidence from
studies of cardiovascular morbidity provided both coherence and
biological plausibility for the relationship between short-term
PM2.5 exposure and cardiovascular mortality.
    Multicity studies evaluated in the 2019 ISA and the ISA Supplement
provide evidence of primarily positive associations between daily
PM2.5 exposures and mortality, with percent increases in
total mortality ranging from 0.19% (Lippmann et al., 2013) to 2.80%
(Kloog et al.) \55\ at lags of 0 to 1 days in single-pollutant models.
Whereas many studies assign exposures using data from ambient monitors,
other studies employ hybrid modeling approaches, which estimate
PM2.5 concentrations using data from a variety of sources
(i.e., from satellites, land use information, and modeling, in addition
to monitors) and enable the inclusion of less urban and more rural
locations in analyses (Kloog et al., 2013, Lee et al., 2015, Shi et
al., 2016).
---------------------------------------------------------------------------

    \55\ As detailed in the Preface to the ISA, risk estimates are
for a 10 [mu]g/m\3\ increase in 24-hour avg PM2.5
concentrations, unless otherwise noted (U.S. EPA, 2019a).
---------------------------------------------------------------------------

    Some studies have expanded the examination of potential confounders
including long-term temporal trends, weather, and co-occurring
pollutants. Mortality associations were found to remain positive,
although in some cases were attenuated, when using different approaches
to account for temporal trends or weather covariates (e.g., U.S. EPA,
2019a, section <IP_ADDRESS>). For example, Sacks et al. (2012) examined the
influence of model specification using the approaches for confounder
adjustment from models employed in several multicity studies within the
context of a common data set (U.S. EPA, 2019a, section <IP_ADDRESS>). These
models use different approaches to control for long-term temporal
trends and the potential confounding effects of weather. The authors
report that associations between daily PM2.5 and
cardiovascular mortality were similar across models, with the percent
increase in mortality ranging from 1.5-2.0% (U.S. EPA, 2019a, Figure
11-4). Thus, alternative approaches to controlling for long-term
temporal trends and for the potential confounding effects of weather
may influence the magnitude of the association between PM2.5
exposures and mortality but have not been found to influence the
direction of the observed association (U.S. EPA, 2019a, section
<IP_ADDRESS>). Taken together, the 2019 ISA and the ISA Supplement conclude
that recent multicity studies conducted in the U.S., Canada, Europe,
and Asia continue to provide consistent evidence of positive
associations between short-term PM2.5 exposures and total
mortality across studies that use different approaches to control for
the potential confounding effects of weather (e.g., temperature) (U.S.
EPA, 2019a, section <IP_ADDRESS>.1; U.S. EPA, 2022a, section <IP_ADDRESS>).
    With regard to copollutants, studies evaluated in the 2019 ISA
provide additional evidence that associations between short-term
PM2.5 exposures and mortality remain positive and relatively
unchanged in copollutant models with both gaseous pollutants and
PM10-2.5 (U.S. EPA, 2019a, section 11.1.4). Additionally,
the low (r < 0.4) to moderate correlations (r = 0.4-0.7) between
PM2.5 and gaseous pollutants and PM10-2.5
increase the confidence in PM2.5 having an independent
effect on

mortality (U.S. EPA, 2019a, section 11.1.4). Consistent with the
studies evaluated in the 2019 ISA, studies evaluated in the ISA
Supplement that used data from more recent years also indicate that
associations between short-term PM2.5 exposure and mortality
remain unchanged in copollutant models. However, the evidence indicates
that the association could be larger in magnitude in the presence of
some copollutants such as oxidant gases (Lavigne et al., 2018; Shin et
al., 2021).
    The generally positive associations reported with mortality are
supported by a small group of studies employing alternative methods for
confounder control or quasi-experimental statistical approaches (U.S.
EPA, 2019a, section <IP_ADDRESS>). For example, two studies by Schwartz et
al. report associations between PM2.5 instrumental variables
and mortality (U.S. EPA, 2019a, Table 11-2), including in an analysis
limited to days with 24-hour average PM2.5 concentrations
<30 [mu]g/m\3\ (Schwartz et al., 2015; Schwartz et al., 2017). In
addition to the main analyses, these studies conducted Granger-like
causality tests as sensitivity analyses to examine whether there was
evidence of an association between mortality and PM2.5 after
the day of death, which would support the possibility that unmeasured
confounders were not accounted for in the statistical model. Neither
study reports evidence of an association with PM2.5 after
death (i.e., they do not indicate unmeasured confounding). Yorifuji et
al. (2016) conducted a quasi-experimental study to examine whether a
specific regulatory action in Tokyo, Japan (i.e., a diesel emission
control ordinance), resulted in a subsequent reduction in daily
mortality (Yorifuji et al., 2016). The authors reported a reduction in
mortality in Tokyo due to the ordinance, compared to Osaka, which did
not have a similar diesel emission control ordinance in place. In
another study, Schwartz et al. (2018) utilized three statistical
methods including instrumental variable analysis, a negative exposure
control, and marginal structural models to estimate the association
between PM2.5 and daily mortality (Schwartz et al., 2018).
Results from this study continue to support a relationship between
short-term PM2.5 exposure and mortality. Additional
epidemiologic studies evaluated in the ISA Supplement that employed
alternative methods for confounder control to examine the association
between short-term PM2.5 exposure and mortality also report
consistent positive associations in studies that examine effects across
multiple cities in the U.S. (U.S. EPA, 2022a).
    The positive associations for total mortality reported across the
majority of studies evaluated are further supported by analyses
reporting generally consistent, positive associations with both
cardiovascular and respiratory mortality (U.S. EPA, 2019a, section
11.1.3). Recent multicity studies evaluated in the ISA Supplement add
to the body of evidence indicating a relationship between short-term
PM2.5 exposure and cause-specific mortality, with more
variability in the magnitude and precision of associations for
respiratory mortality (U.S. EPA, 2022a; Figure 3-14. For both
cardiovascular and respiratory mortality, there has been a limited
assessment of potential copollutant confounding, though initial
evidence indicates that associations remain positive and relatively
unchanged in models with gaseous pollutants and PM10-2.5.
This evidence further supports the copollutant analyses conducted for
total mortality. The strong evidence for ischemic events and heart
failure, as detailed in the assessment of cardiovascular morbidity
(U.S. EPA, 2019a, Chapter 6), provides biological plausibility for
PM2.5-related cardiovascular mortality, which comprises the
largest percentage of total mortality (i.e., ~33%) (National Heart,
Lung, and Blood Institute (NHLBI), 2017). Although there is evidence
for exacerbations of COPD and asthma, the collective body of
respiratory morbidity evidence provides limited biological plausibility
for PM2.5-related respiratory mortality (U.S. EPA, 2019a,
Chapter 5).
    In the 2009 ISA, one of the main uncertainties identified was the
regional and city-to-city heterogeneity in PM2.5-mortality
associations. Studies evaluated in the 2019 ISA examine both city-
specific as well as regional characteristics to identify the underlying
contextual factors that could contribute to this heterogeneity (U.S.
EPA, 2019a, section <IP_ADDRESS>). Analyses focusing on effect modification
of the PM2.5 mortality relationship by PM2.5
components, regional patterns in PM2.5 components and city
specific differences in composition and sources indicate some
differences in the PM2.5 composition and sources across
cities and regions, but these differences do not fully explain the
observed heterogeneity. Additional studies find that factors related to
potential exposure differences, such as housing stock and commuting, as
well as city specific factors (e.g., land use, port volume, and traffic
information), may also explain some of the observed heterogeneity (U.S.
EPA, 2019a, section <IP_ADDRESS>). Collectively, studies evaluated in the
2019 ISA and the ISA Supplement indicate that the heterogeneity in
PM2.5 mortality risk estimates cannot be attributed to one
factor, but instead a combination of factors including, but not limited
to, PM composition and sources as well as community characteristics
that could influence exposures (U.S. EPA, 2019a, section 11.1.12; U.S.
EPA, 2022a, section <IP_ADDRESS>.1).
    A number of studies conducted systematic evaluations of the lag
structure of associations for the PM2.5-mortality
relationship by examining either a series of single day or multiday
lags and these studies continue to support an immediate effect (i.e.,
lag 0 to 1 days) of short-term PM2.5 exposures on mortality
(U.S. EPA, 2019a, section <IP_ADDRESS>; U.S. EPA, 2022a, section <IP_ADDRESS>).
Recent studies also conducted analyses comparing the traditional 24-
hour average exposure metric with a sub-daily metric (i.e., 1-hour
max). These initial studies provide evidence of a similar pattern of
associations for both the 24-hour average and 1-hour max metric, with
the association larger in magnitude for the 24-hour average metric.
    Multicity studies indicate that positive and statistically
significant associations with mortality persist in analyses restricted
to short-term (24-hour average PM2.5 concentrations)
PM2.5 exposures below 35 [mu]g/m\3\ (Lee et al., 2015),\56\
below 30 [mu]g/m\3\ (Shi et al., 2016), and below 25 [mu]g/m\3\ (Di et
al., 2017a), indicating that risks associated with short-term
PM2.5 exposures are not disproportionately driven by the
peaks of the air quality distribution. Additional studies examined the
shape of the C-R relationship for short-term PM2.5 exposure
and mortality and whether a threshold exists below which mortality
effects do not occur (U.S. EPA, 2019a, section 11.1.10). These studies
used various statistical approaches and consistently demonstrate linear
C-R relationships with no evidence of a threshold. Moreover, recent
studies evaluated in the ISA Supplement provide additional support for
a linear, no-threshold C-R relationship between short-term
PM2.5 exposure and mortality, with confidence in the shape
decreasing at concentrations below 5 [mu]g/m\3\ (Shi et al., 2016;
Lavigne et al., 2018). Recent analyses provide initial evidence
indicating that PM2.5-mortality associations persist and may
be stronger

(i.e., a steeper slope) at lower concentrations (e.g., Di et al.,
2017a; Figure 11-12 in U.S. EPA, 2019). However, given the limited data
available at the lower end of the distribution of ambient
PM2.5 concentrations, the shape of the C-R curve remains
uncertain at these low concentrations. Although difficulties remain in
assessing the shape of the short-term PM2.5-mortality C-R
relationship, to date, studies have not conducted systematic
evaluations of alternatives to linearity and recent studies evaluated
in the ISA Supplement continue to provide evidence of a no-threshold
linear relationship, with less confidence at concentrations lower than
5 [mu]g/m\3\.
---------------------------------------------------------------------------

    \56\ Lee et al. (2015) also report that positive and
statistically significant associations between short-term
PM2.5 exposures and mortality persist in analyses
restricted to areas with long-term concentrations below 12 [mu]g/
m\3\.
---------------------------------------------------------------------------

    Overall, epidemiologic studies evaluated in the 2019 ISA and the
ISA Supplement build upon and extend the conclusions of the 2009 ISA
for the relationship between short-term PM2.5 exposures and
total mortality. Supporting evidence for PM2.5-related
cardiovascular morbidity, and more limited evidence from respiratory
morbidity, provide biological plausibility for mortality due to short-
term PM2.5 exposures. The primarily positive associations
observed across studies conducted in diverse geographic locations is
further supported by the results from copollutant analyses indicating
robust associations, along with evidence from analyses examining the C-
R relationship. Overall, studies evaluated in the 2019 ISA support the
conclusion of a causal relationship between short-term PM2.5
exposure and mortality, which is supported by evidence from recent
epidemiologic studies evaluated in the ISA Supplement (U.S. EPA, 2022a,
section <IP_ADDRESS>, p. 3-69).
b. Cardiovascular Effects
i. Long-Term PM2.5 Exposures
    The scientific evidence reviewed in the 2009 ISA was ``sufficient
to infer a causal relationship between long-term PM2.5
exposure and cardiovascular effects'' (U.S. EPA, 2009a). The strongest
line of evidence comprised findings from several large epidemiologic
studies of U.S. and Canadian cohorts that reported consistent positive
associations between long-term PM2.5 exposure and
cardiovascular mortality (Pope et al., 2004; Krewski et al., 2009;
Miller et al., 2007; Laden et al., 2006). Studies of long-term
PM2.5 exposure and cardiovascular morbidity were limited in
number. Biological plausibility and coherence with the epidemiologic
findings were provided by studies using genetic mouse models of
atherosclerosis demonstrating enhanced atherosclerotic plaque
development and inflammation, as well as changes in measures of
impaired heart function, following 4- to 6-month exposures to
PM2.5 concentrated ambient particles (CAPs), and by a
limited number of studies reporting CAPs-induced effects on coagulation
factors, vascular reactivity, and worsening of experimentally induced
hypertension in mice (U.S. EPA, 2009b).
    Consistent with the evidence assessed in the 2009 ISA, the 2019 ISA
concludes that recent studies, together with the evidence available in
previous reviews, support a causal relationship between long-term
exposure to PM2.5 and cardiovascular effects. Additionally,
recent epidemiologic studies published since the completion of the 2019
ISA and evaluated in the ISA Supplement expands the body of evidence
and further supports such a conclusion (U.S. EPA, 2022a). As discussed
above (section II.B.1.a), results from U.S. and Canadian cohort studies
evaluated in the 2019 ISA conducted at varying spatial and temporal
scales and employing a variety of exposure assessment and statistical
methods consistently report positive associations between long-term
PM2.5 exposure and cardiovascular mortality (U.S. EPA, 2019,
Figure 6-19, section 6.2.10). Positive associations between long-term
PM2.5 exposures and cardiovascular mortality are generally
robust in copollutant models adjusted for ozone, NO2,
PM10-2.5, or SO2. In addition, most of the
results from analyses examining the shape of the C-R relationship
between long-term PM2.5 exposures and cardiovascular
mortality support a linear relationship and do not identify a threshold
below which mortality effects do not occur (U.S. EPA, 2019a, section
6.2.16, Table 6-52).
    The body of literature examining the relationship between long-term
PM2.5 exposure and cardiovascular morbidity has greatly
expanded since the 2009 ISA, with positive associations reported in
several cohorts evaluated in the 2019 ISA (U.S. EPA, 2019a, section
6.2). Though results for cardiovascular morbidity are less consistent
than those for cardiovascular mortality (U.S. EPA, 2019a, section 6.2),
studies in the 2019 ISA and the ISA Supplement provide some evidence
for associations between long-term PM2.5 exposures and the
progression of cardiovascular disease. Positive associations with
cardiovascular morbidity (e.g., coronary heart disease, stroke,
arrhythmias, myocardial infarction (MI), atherosclerosis progression)
are observed in several epidemiologic studies (U.S. EPA, 2019a,
sections 6.2.2 to 6.2.9; U.S. EPA, 2022a, section <IP_ADDRESS>).
Additionally, studies evaluated in the ISA Supplement report positive
associations among those with pre-existing conditions, among patients
followed after a cardiac event procedure, and among those with a first
hospital admission for heart attacks among older adults enrolled in
Medicare (U.S. EPA, 2022a, sections 3.1.1 and 3.1.2).
    Recent studies published since the literature cutoff date of the
2019 ISA further assessed the relationship between long-term
PM2.5 exposure and cardiovascular effects by conducting
accountability analyses or by using alternative methods for confounder
control in evaluating the association between long-term
PM2.5 exposure and cardiovascular hospital admissions (U.S.
EPA, 2022a, section <IP_ADDRESS>). Studies that apply alternative methods
for confounder control increase confidence in the relationship between
long-term PM2.5 exposure and cardiovascular effects by using
methods that reduce uncertainties related to potential confounding
through statistical and/or study design approaches. For example, to
control for potential confounding Wei et al. (2021) used a doubly
robust additive model (DRAM) and found an association between long-term
exposure to PM2.5 and cardiovascular effects, including MI,
stoke, and atrial fibrillation, among the Medicare population.
Additionally, an accountability study by Henneman et al. (2019a)
utilized a difference-in-difference (DID) approach to determine the
relationship between coal-fueled power plant emissions and
cardiovascular effects and found that reductions in PM2.5
concentrations resulted in reductions of cardiovascular-related
hospital admissions. Furthermore, several recent epidemiologic studies
evaluated in the ISA Supplement reported that the association between
long-term PM2.5 exposure with stroke persisted after
adjustment for NO2 but was attenuated in the model with
O3 and oxidant gases represented by the redox weighted
average of NO2 and O3 (U.S. EPA, 2022a, section
<IP_ADDRESS>.8). Overall, these studies report consistent findings that
long-term PM2.5 exposure is related to increased hospital
admissions for a variety of cardiovascular disease outcomes among large
nationally representative cohorts and provide additional support for a
relationship between long-term PM2.5 exposure and
cardiovascular effects.
    The positive associations reported in epidemiologic studies are
supported by toxicological evidence for increased

plaque progression in mice following long-term exposure to
PM2.5 collected from multiple locations across the U.S.
(U.S. EPA, 2019a, section <IP_ADDRESS>). A small number of epidemiologic
studies also report positive associations between long-term
PM2.5 exposure and heart failure, changes in blood pressure,
and hypertension (U.S. EPA, 2019a, sections 6.2.5 and 6.2.7).
Associations with heart failure are supported by animal toxicological
studies demonstrating decreased cardiac contractility and function, and
increased coronary artery wall thickness following long-term
PM2.5 exposure (U.S. EPA, 2019a, section <IP_ADDRESS>).
Similarly, a limited number of animal toxicological studies
demonstrating a relationship between long-term PM2.5
exposure and consistent increases in blood pressure in rats and mice
are coherent with epidemiologic studies reporting positive associations
between long-term exposure to PM2.5 and hypertension.
    Moreover, a number of studies evaluated in the ISA Supplement
focusing on morbidity outcomes, including those that focused on
incidence of MI, atrial fibrillation (AF), stroke, and congestive heart
failure (CHF), expand the evidence pertaining to the shape of the C-R
relationship between long-term PM2.5 exposure and
cardiovascular effects. These studies use statistical techniques that
allow for departures from linearity (U.S. EPA, 2022a, Table 3-3), and
generally support the evidence characterized in the 2019 ISA showing
linear, no-threshold C-R relationship for most cardiovascular disease
(CVD) outcomes. However, there is evidence for a sublinear or
supralinear C-R relationship for some outcomes (U.S. EPA, 2022a,
section <IP_ADDRESS>.9).\57\
---------------------------------------------------------------------------

    \57\ As noted above for mortality, uncertainty in the shape of
the C-R relationship increases near the upper and lower ends of the
distribution due to limited data.
---------------------------------------------------------------------------

    Longitudinal epidemiologic analyses also report positive
associations with markers of systemic inflammation (U.S. EPA, 2019a,
section 6.2.11), coagulation (U.S. EPA, 2019a, section 6.2.12), and
endothelial dysfunction (U.S. EPA, 2019a, section 6.2.13). These
results are coherent with animal toxicological studies generally
reporting increased markers of systemic inflammation, oxidative stress,
and endothelial dysfunction (U.S. EPA, 2019a, section <IP_ADDRESS> and
6.2.14).
    The 2019 ISA concludes that there is consistent evidence from
multiple epidemiologic studies illustrating that long-term exposure to
PM2.5 is associated with mortality from cardiovascular
causes. Epidemiologic studies evaluated in the ISA Supplement provide
additional evidence of positive associations between long-term
PM2.5 exposure and cardiovascular morbidity (U.S. EPA,
2022a, section <IP_ADDRESS>). Associations with coronary heart disease
(CHD), stroke and atherosclerosis progression were observed in several
additional epidemiologic studies providing coherence with the mortality
findings. Results from copollutant models generally support an
independent effect of PM2.5 exposure on mortality.
Additional evidence of the independent effect of PM2.5 on
the cardiovascular system is provided by experimental studies in
animals, which support the biological plausibility of pathways by which
long-term exposure to PM2.5 could potentially result in
outcomes such as CHD, stroke, CHF, and cardiovascular mortality.
Overall, studies evaluated in the 2019 ISA support the conclusion of a
causal relationship between long-term PM2.5 exposure and
cardiovascular effects, which is supported and extended by evidence
from recent epidemiologic studies evaluated in the ISA Supplement (U.S.
EPA, 2022a, section <IP_ADDRESS>).
ii. Short-Term PM2.5 Exposures
    The 2009 ISA concluded that ``a causal relationship exists between
short-term exposure to PM2.5 and cardiovascular effects''
(U.S. EPA, 2009a). The strongest evidence in the 2009 ISA was from
epidemiologic studies of emergency department (ED) visits and hospital
admissions for IHD and heart failure (HF), with supporting evidence
from epidemiologic studies of cardiovascular mortality (U.S. EPA,
2009a). Animal toxicological studies provided coherence and biological
plausibility for the positive associations reported with MI, ED visits,
and hospital admissions. These included studies reporting reduced
myocardial blood flow during ischemia and studies indicating altered
vascular reactivity. In addition, effects of PM2.5 exposure
on a potential indicator of ischemia (i.e., ST segment depression on an
electrocardiogram) were reported in both animal toxicological and
epidemiologic panel studies.\58\ Key uncertainties from the last review
resulted from inconsistent results across disciplines with respect to
the relationship between short-term exposure to PM2.5 and
changes in blood pressure, blood coagulation markers, and markers of
systemic inflammation. In addition, while the 2009 ISA identified a
growing body of evidence from controlled human exposure and animal
toxicological studies, uncertainties remained with respect to
biological plausibility.
---------------------------------------------------------------------------

    \58\ Some animal studies included in the 2009 ISA examined
exposures to mixtures, such as motor vehicle exhaust or woodsmoke.
In these studies, it was unclear if the resulting cardiovascular
effects could be attributed specifically to the fine particle
component of the mixture.
---------------------------------------------------------------------------

    Studies evaluated in the 2019 ISA provide additional support for a
causal relationship between short-term PM2.5 exposure and
cardiovascular effects. This includes generally positive associations
observed in multicity epidemiologic studies of emergency department
visits and hospital admissions for IHD, heart failure (HF), and
combined cardiovascular-related endpoints. In particular, nationwide
studies of older adults (65 years and older) using Medicare records
report positive associations between PM2.5 exposures and
hospital admissions for HF (U.S. EPA, 2019a, section <IP_ADDRESS>).
Moreover, recent multicity studies, published after the literature
cutoff date of the 2019 ISA and evaluated in the ISA Supplement, are
consistent with studies evaluated in the 2019 ISA that report positive
association between short-term PM2.5 exposure and ED visits
and hospital admission for IHD, heart attacks, and HF (U.S. EPA, 2022a,
section 3.1). Epidemiologic studies conducted in single cities
contribute some support to the causality determination, though
associations reported in single-city studies are less consistently
positive than in multicity studies, and include a number of studies
reporting null associations (U.S. EPA, 2019a, sections 6.1.2 and
6.1.3). When considered as a whole; however, the recent body of IHD and
HF epidemiologic evidence supports the evidence from previous ISAs
reporting mainly positive associations between short-term
PM2.5 concentrations and emergency department visits and
hospital admissions.
    The ISA Supplement also includes some epidemiologic studies,
published since the literature cutoff date for the 2019 ISA, including
accountability analyses and epidemiologic studies that employ
alternative methods for confounder control to evaluate the association
between short-term PM2.5 exposure and cardiovascular-related
effects (U.S. EPA, 2022a, section <IP_ADDRESS>). These studies report
positive associations across a number of statistical approaches,
providing additional support for a relationship between short-term
PM2.5 exposure and cardiovascular effects, while also

reducing uncertainties related to potential confounder bias.
    Consistent with the evidence assessed in the 2019 ISA, some studies
evaluated in the ISA Supplement report no evidence of an association
with stroke, regardless of stroke subtype. Additionally, as in the 2019
ISA, evidence evaluated in the ISA Supplement continues to indicate an
immediate effect of PM2.5 on cardiovascular-related outcomes
primarily within the first few days after exposure, and that
associations generally persisted in models adjusted for copollutants
(U.S. EPA, 2022a, section <IP_ADDRESS>).
    A number of controlled human exposure, animal toxicological, and
epidemiologic panel studies provide evidence that PM2.5
exposure could plausibly result in IHD or HF through pathways that
include endothelial dysfunction, arterial thrombosis, and arrhythmia
(U.S. EPA, 2019a, section 6.1.1). The most consistent evidence from
recent controlled human exposure studies is for endothelial
dysfunction, as measured by changes in brachial artery diameter or flow
mediated dilation. Multiple controlled human exposure studies that
examined the potential for endothelial dysfunction report an effect of
PM2.5 exposure on measures of blood flow (U.S. EPA, 2019a,
section <IP_ADDRESS>). However, these studies report variable results
regarding the timing of the effect and the mechanism by which reduced
blood flow occurs (i.e., availability vs sensitivity to nitric oxide).
In addition, some controlled human exposure studies using CAPs report
evidence for small increases in blood pressure (U.S. EPA, 2019a,
section <IP_ADDRESS>). Although not entirely consistent, there is also some
evidence across controlled human exposure studies for conduction
abnormalities/arrhythmia (U.S. EPA, 2019a, section <IP_ADDRESS>), changes in
heart rate variability (HRV) (U.S. EPA, 2019a, section <IP_ADDRESS>),
changes in hemostasis that could promote clot formation (U.S. EPA,
2019a, section <IP_ADDRESS>), and increases in inflammatory cells and
markers (U.S. EPA, 2019a, section <IP_ADDRESS>). A recent study by Wyatt et
al. (2020), evaluated in the ISA Supplement, adds to the limited
evidence base of controlled human exposure studies conducted at near
ambient PM2.5 concentrations. The study, completed in
healthy young adults subject to intermittent exercise, found some
significant cardiovascular effects (e.g., systematic inflammation
markers, including C-reactive protein (CRP), and cardiac
repolarization). Thus, when taken as a whole, controlled human exposure
studies are coherent with epidemiologic studies in that they
demonstrate that short-term exposures to PM2.5 may result in
the types of cardiovascular endpoints that could lead to emergency
department visits, hospital admissions and mortality in some people.
    Animal toxicological studies published since the 2009 ISA also
support a relationship between short-term PM2.5 exposure and
cardiovascular effects. A study demonstrating decreased cardiac
contractility and left ventricular pressure in mice is coherent with
the results of epidemiologic studies that report associations between
short-term PM2.5 exposure and heart failure (U.S. EPA,
2019a, section <IP_ADDRESS>). In addition, and as with controlled human
exposure studies, there is generally consistent evidence in animal
toxicological studies for indicators of endothelial dysfunction (U.S.
EPA, 2019a, section <IP_ADDRESS>). Some studies in animals also provide
evidence for changes in a number of other cardiovascular endpoints
following short-term PM2.5 exposure including conduction
abnormalities and arrhythmia (U.S. EPA, 2019a, section <IP_ADDRESS>),
changes in HRV (U.S. EPA, 2019a, section <IP_ADDRESS>), changes in blood
pressure (U.S. EPA, 2019a, section <IP_ADDRESS>), and evidence for systemic
inflammation and oxidative stress (U.S. EPA, 2019a, section <IP_ADDRESS>).
    In summary, evidence evaluated in the 2019 ISA extends the
consistency and coherence of the evidence base evaluated in the 2009
ISA and prior assessments. Direct evidence for an independent effect of
PM2.5 on cardiovascular effects can be found in a number of
controlled human exposure and animal toxicological studies, which
supports the results of epidemiologic studies reporting that
associations remain relatively unchanged in copollutant models. These
results concur with epidemiologic panel studies reporting that
PM2.5 exposure is associated with some of the same
cardiovascular endpoints reported in experimental studies. For some
cardiovascular effects, there are inconsistencies in results across
some animal toxicological, controlled human exposure, and epidemiologic
panel studies, though this may be due to substantial differences in
study design and/or study populations. Overall, the results from
epidemiologic panel, controlled human exposure, and animal
toxicological studies, in particular those related to endothelial
dysfunction, impaired cardiac function, ST segment depression,
thrombosis, conduction abnormalities, and changes in blood pressure
provide coherence and biological plausibility for the consistent
results from epidemiologic studies observing positive associations
between short-term PM2.5 concentrations and IHD and HF, and
ultimately cardiovascular mortality. Overall, studies evaluated in the
2019 ISA support the conclusion of a causal relationship between short-
term PM2.5 exposure and cardiovascular effects, which is
supported and extended by evidence from recent epidemiologic studies
evaluated in the ISA Supplement (U.S. EPA, 2022a, section <IP_ADDRESS>).
c. Respiratory Effects
i. Long-Term PM2.5 Exposures
    The 2009 ISA concluded that ``a causal relationship is likely to
exist between long-term PM2.5 exposure and respiratory
effects'' (U.S. EPA, 2009a). This conclusion was based mainly on
epidemiologic evidence demonstrating associations between long-term
PM2.5 exposure and changes in lung function or lung function
growth in children. Biological plausibility was provided by a single
animal toxicological study examining pre- and post-natal exposure to
PM2.5 CAPs, which found impaired lung development.
Epidemiologic evidence for associations between long-term
PM2.5 exposure and other respiratory outcomes, such as the
development of asthma, allergic disease, and COPD; respiratory
infection; and the severity of disease was limited, both in the number
of studies available and the consistency of the results. Experimental
evidence for other outcomes was also limited, with one animal
toxicological study reporting that long-term exposure to
PM2.5 CAPs results in morphological changes in nasal airways
of healthy animals. Other animal studies examined exposure to mixtures,
such as motor vehicle exhaust and woodsmoke, and effects were not
attributed specifically to the particulate components of the mixture.
    Cohort studies evaluated in the 2019 ISA provided additional
support for the relationship between long-term PM2.5
exposure and decrements in lung function growth (as a measure of lung
development), indicating a robust and consistent association across
study locations, exposure assessment methods, and time periods (U.S.
EPA, 2019a, section 5.2.13). This relationship was further supported by
a retrospective study that reports an association between declining
PM2.5 concentrations and improvements in lung function
growth in children (U.S. EPA, 2019a, section 5.2.11). Epidemiologic
studies

also examine asthma development in children (U.S. EPA, 2019a, section
5.2.3), with prospective cohort studies reporting generally positive
associations, though several are imprecise (i.e., they report wide
confidence intervals). Supporting evidence is provided by studies
reporting associations with asthma prevalence in children, with
childhood wheeze, and with exhaled nitric oxide, a marker of pulmonary
inflammation (U.S. EPA, 2019a, section 5.2.13). Additionally, the 2019
ISA includes an animal toxicological study showing the development of
an allergic phenotype and an increase in a marker of airway
responsiveness supports the biological plausibility of the development
of allergic asthma (U.S. EPA, 2019a, section 5.2.13). Other
epidemiologic studies report a PM2.5-related acceleration of
lung function decline in adults, while improvement in lung function was
observed with declining PM2.5 concentrations (U.S. EPA,
2019a, section 5.2.11). A longitudinal study found declining
PM2.5 concentrations are also associated with an improvement
in chronic bronchitis symptoms in children, strengthening evidence
reported in the 2009 ISA for a relationship between increased chronic
bronchitis symptoms and long-term PM2.5 exposure (U.S. EPA,
2019a, section 5.2.11). A common uncertainty across the epidemiologic
evidence is the lack of examination of copollutants to assess the
potential for confounding. While there is some evidence that
associations remain robust in models with gaseous pollutants, a number
of these studies examining copollutant confounding were conducted in
Asia, and thus have limited generalizability due to high annual
pollutant concentrations.
    When taken together, the 2019 ISA concludes that the
``epidemiologic evidence strongly supports a relationship with
decrements in lung function growth in children'' and ``with asthma
development in children, with increased bronchitis symptoms in children
with asthma, with an acceleration of lung function decline in adults,
and with respiratory mortality and cause-specific respiratory mortality
for COPD and respiratory infection'' (U.S. EPA, 2019a, p. 1-34). In
support of the biological plausibility of such associations reported in
epidemiologic studies of respiratory health effects, animal
toxicological studies continue to provide direct evidence that long-
term exposure to PM2.5 results in a variety of respiratory
effects. Animal studies in the 2019 ISA show pulmonary oxidative
stress, inflammation, and morphologic changes in the upper (nasal) and
lower airways. Other results show that changes are consistent with the
development of allergy and asthma, and with impaired lung development.
Overall, the 2019 ISA concludes that ``the collective evidence is
sufficient to conclude that a causal relationship is likely to exist
between long-term PM2.5 exposure and respiratory effects''
(U.S. EPA, 2019a, section 5.2.13).
ii. Short-Term PM2.5 Exposures
    The 2009 ISA (U.S. EPA, 2009a) concluded that a ``causal
relationship is likely to exist'' between short-term PM2.5
exposure and respiratory effects. This conclusion was based mainly on
the epidemiologic evidence demonstrating positive associations with
various respiratory effects. Specifically, the 2009 ISA described
epidemiologic evidence as consistently showing PM2.5-
associated increases in hospital admissions and ED visits for COPD and
respiratory infection among adults or people of all ages, as well as
increases in respiratory mortality. These results were supported by
studies reporting associations with increased respiratory symptoms and
decreases in lung function in children with asthma, though the
epidemiologic evidence was inconsistent for hospital admissions or
emergency department visits for asthma. Studies examining copollutant
models showed that PM2.5 associations with respiratory
effects were robust to inclusion of CO or SO2 in the model,
but often were attenuated (though still positive) with inclusion of
O3 or NO2. In addition to the copollutant models,
evidence supporting an independent effect of PM2.5 exposure
on the respiratory system was provided by animal toxicological studies
of PM2.5 CAPs demonstrating changes in some pulmonary
function parameters, as well as inflammation, oxidative stress, injury,
enhanced allergic responses, and reduced host defenses. Many of these
effects have been implicated in the pathophysiology for asthma
exacerbation, COPD exacerbation, or respiratory infection. In the few
controlled human exposure studies conducted in individuals with asthma
or COPD, PM2.5 exposure mostly had no effect on respiratory
symptoms, lung function, or pulmonary inflammation. Available studies
in healthy people also did not clearly demonstrate respiratory effects
following short-term PM2.5 exposures.
    Epidemiologic studies evaluated in the 2019 ISA continue to provide
strong evidence for a relationship between short-term PM2.5
exposure and several respiratory-related endpoints, including asthma
exacerbation (U.S. EPA, 2019a, section <IP_ADDRESS>), COPD exacerbation
(U.S. EPA, 2019a, section <IP_ADDRESS>), and combined respiratory-related
diseases (U.S. EPA, 2019a, section 5.1.6), particularly from studies
examining ED visits and hospital admissions. The generally positive
associations between short-term PM2.5 exposure and asthma
and COPD as well as ED visits and hospital admissions are supported by
epidemiologic studies demonstrating associations with other
respiratory-related effects such as symptoms and medication use that
are indicative of asthma and COPD exacerbations (U.S. EPA, 2019a,
sections <IP_ADDRESS> and <IP_ADDRESS>). The collective body of epidemiologic
evidence for asthma exacerbation is more consistent in children than in
adults. Additionally, epidemiologic studies examining the relationship
between short-term PM2.5 exposure and respiratory mortality
provide evidence of consistent positive associations, demonstrating a
continuum of effects (U.S. EPA, 2019a, section 5.1.9).
    Building off the studies evaluated in the 2009 ISA, epidemiologic
studies evaluated in the 2019 ISA expand the assessment of potential
copollutant confounding. There is some evidence that PM2.5
associations with asthma exacerbation, combined respiratory-related
diseases, and respiratory mortality remain relatively unchanged in
copollutant models with gaseous pollutants (i.e., O3,
NO2, SO2, with more limited evidence for CO) and
other particle sizes (i.e., PM10-2.5) (U.S. EPA, 2019a,
section <IP_ADDRESS>).
    In the 2019 ISA, the uncertainty related to whether there is an
independent effect of PM2.5 on respiratory health is also
partially addressed by findings from animal toxicological studies.
Specifically, short-term exposure to PM2.5 enhanced asthma-
related responses in an animal model of allergic airways disease and
enhanced lung injury and inflammation in an animal model of COPD (U.S.
EPA, 2019a, sections <IP_ADDRESS>.4 and <IP_ADDRESS>.3). The experimental
evidence provides biological plausibility for some respiratory-related
endpoints, including limited evidence of altered host defense and
greater susceptibility to bacterial infection as well as consistent
evidence of respiratory irritant effects. Animal toxicological evidence
for other respiratory effects is inconsistent and a recent study by
Wyatt et al. (2020) that was evaluated in the ISA Supplement, conducted
at near ambient PM2.5 concentrations, adds to the limited
evidence base of controlled human

exposure studies. The study, completed in healthy young adults subject
to intermittent exercise, found some significant respiratory effects
(including decrease in lung function), however these findings were
inconsistent with the controlled human exposure studies evaluated in
the 2019 ISA (U.S. EPA, 2019a, section <IP_ADDRESS>, <IP_ADDRESS>, and
<IP_ADDRESS>.1).
    The 2019 ISA concludes that ``[t]he strongest evidence of an effect
of short-term PM2.5 exposure on respiratory effects is
provided by epidemiologic studies of asthma and COPD exacerbation.
While animal toxicological studies provide biological plausibility for
these findings, some uncertainty remains with respect to the
independence of PM2.5 effects'' (U.S. EPA, 2019a, p. 5-155).
When taken together, the 2019 ISA concludes that this evidence ``is
sufficient to conclude that a causal relationship is likely to exist
between short-term PM2.5 exposure and respiratory effects''
(U.S. EPA, 2019a, p. 5-155).
d. Cancer
    The 2009 ISA concluded that the overall body of evidence was
``suggestive of a causal relationship between relevant PM2.5
exposures and cancer'' (U.S. EPA, 2009a). This conclusion was based
primarily on positive associations observed in a limited number of
epidemiologic studies of lung cancer mortality. The few epidemiologic
studies that had evaluated PM2.5 exposure and lung cancer
incidence or cancers of other organs and systems generally did not show
evidence of an association. Toxicological studies did not focus on
exposures to specific PM size fractions, but rather investigated the
effects of exposures to total ambient PM, or other source-based PM such
as wood smoke. Collectively, results of in vitro studies were
consistent with the larger body of evidence demonstrating that ambient
PM and PM from specific combustion sources are mutagenic and genotoxic.
However, animal inhalation studies found little evidence of tumor
formation in response to chronic exposures. A small number of studies
provided preliminary evidence that PM exposure can lead to changes in
methylation of DNA, which may contribute to biological events related
to cancer.
    Since the completion of the 2009 ISA, additional cohort studies
provide evidence that long-term PM2.5 exposure is positively
associated with lung cancer mortality and with lung cancer incidence,
and provide initial evidence for an association with reduced cancer
survival (U.S. EPA, 2019a, section 10.2.5). Re-analyses of the ACS
cohort using different years of PM2.5 data and follow up,
along with various exposure assignment approaches, provide consistent
evidence of positive associations between long-term PM2.5
exposure and lung cancer mortality (U.S. EPA, 2019a, Figure 10-3).
Additional support for positive associations with lung cancer mortality
is provided by recent epidemiologic studies using individual level data
to control for smoking status, by studies of people who have never
smoked (though such studies generally report wide confidence intervals
due to the small number of lung cancer mortality cases within this
population), and in analyses of cohorts that relied upon proxy measures
to account for smoking status (U.S. EPA, 2019a, section <IP_ADDRESS>.1).
Although studies that evaluate lung cancer incidence, including studies
of people who have never smoked, are limited in number, studies in the
2019 ISA generally report positive associations with long-term
PM2.5 exposures (U.S. EPA, 2019a, section <IP_ADDRESS>.2). A
subset of the studies focusing on lung cancer incidence also examined
histological subtype, providing some evidence of positive associations
for adenocarcinomas, the predominate subtype of lung cancer observed in
people who have never smoked (U.S. EPA, 2019a, section <IP_ADDRESS>.2).
Associations between long-term PM2.5 exposure and lung
cancer incidence were found to remain relatively unchanged, though in
some cases confidence intervals widened, in analyses that attempted to
reduce exposure measurement error by accounting for length of time at
residential address or by examining different exposure assignment
approaches (U.S. EPA, 2019a, section <IP_ADDRESS>.2).
    The 2019 ISA evaluates the degree to which epidemiologic studies
have addressed the potential for confounding by copollutants and the
shape of the C-R relationship. To date, relatively few studies have
evaluated the potential for copollutant confounding of the relationship
between long-term PM2.5 exposure and lung cancer mortality
or incidence. A small number of such studies have generally focused on
O3 and report that PM2.5 associations remain
relatively unchanged in copollutant models (U.S. EPA, 2019a, section
<IP_ADDRESS>.3). However, available studies have not systematically
evaluated the potential for copollutant confounding by other gaseous
pollutants or by other particle size fractions (U.S. EPA, 2019a,
section <IP_ADDRESS>.3). Compared to total (non-accidental) mortality (U.S.
EPA, 2019a, section <IP_ADDRESS>.4), fewer studies have examined the shape
of the C-R curve for cause-specific mortality outcomes, including lung
cancer. Several studies of lung cancer mortality and incidence have
reported no evidence of deviations from linearity in the shape of the
C-R relationship (Lepeule et al., 2012; Raaschou-Nielsen et al., 2013;
Puett et al., 2014), though authors provided only limited discussions
of results (U.S. EPA, 2019a, section <IP_ADDRESS>.4).
    In support of the biological plausibility of an independent effect
of PM2.5 on lung cancer, the 2019 ISA notes evidence from
experimental and epidemiologic studies demonstrating that
PM2.5 exposure can lead to a range of effects indicative of
mutagenicity, genotoxicity, and carcinogenicity, as well as epigenetic
effects (U.S. EPA, 2019a, section 10.2.7). For example, both in vitro
and in vivo toxicological studies have shown that PM2.5
exposure can result in DNA damage (U.S. EPA, 2019a, section 10.2.2).
Although such effects do not necessarily equate to carcinogenicity, the
evidence that PM exposure can damage DNA, and elicit mutations,
provides support for the plausibility of epidemiologic associations
with lung cancer mortality and incidence. Additional supporting studies
indicate the occurrence of micronuclei formation and chromosomal
abnormalities (U.S. EPA, 2019a, section <IP_ADDRESS>), and differential
expression of genes that may be relevant to cancer pathogenesis,
following PM exposures. Experimental and epidemiologic studies that
examine epigenetic effects indicate changes in DNA methylation,
providing some support for PM2.5 exposure contributing to
genomic instability (U.S. EPA, 2019a, section 10.2.3). Overall, there
is limited evidence that long-term PM2.5 exposure is
associated with cancers in other organ systems, but there is some
evidence that PM2.5 exposure may reduce survival in
individuals with cancer (U.S. EPA, 2019a, section 10.2.7; U.S. EPA,
2022a, section <IP_ADDRESS>.1).
    Epidemiologic evidence for associations between PM2.5
and lung cancer mortality and incidence, together with evidence
supporting the biological plausibility of such associations,
contributes to the 2019 ISA's conclusion that the evidence ``is
sufficient to conclude that a causal relationship is likely to exist
between long-term PM2.5 exposure and cancer'' (U.S. EPA,
2019, section 10.2.7).

e. Nervous System Effects
    Reflecting the very limited evidence available in the 2012 review,
the 2009 ISA did not make a causality determination for long-term
PM2.5 exposures and nervous system effects (U.S. EPA,
2009c). Since the 2012 review, this body of evidence has grown
substantially (U.S. EPA, 2019, section 8.2). Animal toxicological
studies assessed in in the 2019 ISA report that long-term
PM2.5 exposures can lead to morphologic changes in the
hippocampus and to impaired learning and memory. This evidence is
consistent with epidemiologic studies reporting that long-term
PM2.5 exposure is associated with reduced cognitive function
(U.S. EPA, 2019a, section 8.2.5). Further, while the evidence is
limited, the presence of early markers of Alzheimer's disease pathology
has been demonstrated in rodents following long-term exposure to
PM2.5 CAPs. These findings support reported associations