emergency department visits or hospital admissions for IHD (U.S. EPA,
2019, section <IP_ADDRESS>) while studies conducted in the U.S. and Canada
reported positive associations between short-term PM2.5
exposures and emergency department visits for HF. Epidemiologic studies
conducted in single cities contribute some support, 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, 2019, 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.
    In addition, a number of more recent 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, 2019, 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. All but one of the available controlled human
exposure studies examining the potential for endothelial dysfunction
report an effect of PM2.5 exposure on measures of blood flow
(U.S. EPA, 2019, section <IP_ADDRESS>). 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). Some controlled human exposure studies using PM2.5
CAPs report evidence for small increases in blood pressure (U.S. EPA,
2019, section <IP_ADDRESS>). In addition, although not entirely consistent,
there is also some evidence across controlled human exposure studies
for conduction abnormalities/arrhythmia (U.S. EPA, 2019, section
<IP_ADDRESS>), changes in heart rate variability (HRV) (U.S. EPA, 2019,
section <IP_ADDRESS>), changes in hemostasis that could promote clot
formation (U.S. EPA, 2019, section <IP_ADDRESS>), and increases in
inflammatory cells and markers (U.S. EPA, 2019, section <IP_ADDRESS>).
Thus, when taken as a whole, controlled human exposure studies are
coherent with epidemiologic studies in that they provide evidence that
short-term exposures to PM2.5 may result in the types of
cardiovascular endpoints that could lead to emergency department visits
and hospital admissions 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 recent 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, 2019,
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, 2019,
section <IP_ADDRESS>). Studies in animals also provide evidence for changes
in a number of other cardiovascular endpoints following short-term
PM2.5 exposure. Although not entirely consistent, these
studies provide some evidence of conduction abnormalities and
arrhythmia (U.S. EPA, 2019, section <IP_ADDRESS>), changes in HRV (U.S. EPA,
2019, section <IP_ADDRESS>), changes in blood pressure (U.S. EPA, 2019,
section <IP_ADDRESS>), and evidence for systemic inflammation and oxidative
stress (U.S. EPA, 2019, section <IP_ADDRESS>).
    In summary, recent evidence supports the conclusions reported in
the 2009 ISA indicating relationships between short-term
PM2.5 exposures and hospital admissions and ED visits for
IHD and HF, along with cardiovascular mortality. Epidemiologic studies
reporting robust associations in copollutant models are supported by
direct evidence from controlled human exposure and animal toxicological
studies reporting independent effects of PM2.5 exposures on
endothelial dysfunction as well as endpoints indicating impaired
cardiac function, increased risk of arrhythmia, changes in HRV,
increases in BP, and increases in indicators of systemic inflammation,
oxidative stress, and coagulation (U.S. EPA, 2019, section 6.1.16).
Epidemiologic panel studies, although not entirely consistent, provide
some evidence that PM2.5 exposures are associated with
cardiovascular effects, including increased risk of arrhythmia,
decreases in HRV, increases in BP, and ST segment depression. 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 reporting positive
associations between short-term PM2.5 exposures and IHD and
HF, and ultimately cardiovascular mortality. The 2019 ISA concludes
that, overall, ``there continues to be sufficient evidence to conclude
that a causal relationship exists between short-term PM2.5
exposure and cardiovascular effects'' (U.S. EPA, 2019, p. 6-138).
c. Respiratory Effects
i. Long-Term PM2.5 Exposures
    The 2009 PM ISA concluded that ``a causal relationship is likely to
exist between long-term PM2.5 exposure and respiratory
effects'' (U.S. EPA, 2009c). 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 the 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.
    Recent cohort studies provide 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, 2019, section 5.2.13).
This relationship is further supported by a recent retrospective study
that reports an association between declining PM2.5
concentrations and improvements in lung function growth in children
(U.S. EPA, 2019, section 5.2.11). Epidemiologic studies also examine
asthma development in children (U.S. EPA, 2019, section 5.2.3), with
recent 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, 2019, section 5.2.13). A recent 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, 2019, 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, 2019, section 5.2.11). A
recent 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, 2019, 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'' (U.S. EPA, 2019, p. 1-
34). Additional epidemiologic evidence ``supports a relationship with
asthma development in children, increased bronchitic symptoms in
children with asthma, acceleration of lung function decline in adults,
and respiratory mortality, including cause-specific respiratory
mortality for COPD and respiratory infection'' (U.S. EPA, 2019, 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. Recent animal studies 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 ISA concludes that ``the collective evidence is sufficient
to conclude a likely to be causal relationship between long-term
PM2.5 exposure and respiratory effects'' (U.S. EPA, 2019, p.
5-220).
ii. Short-Term PM2.5 Exposures
    The 2009 PM ISA (U.S. EPA, 2009c) 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 emergency department
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 available 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 find respiratory effects following short-term
PM2.5 exposures.
    Recent epidemiologic studies provide evidence for a relationship
between short-term PM2.5 exposure and several respiratory-
related endpoints, including asthma exacerbation (U.S. EPA, 2019,
section <IP_ADDRESS>), COPD exacerbation (U.S. EPA, 2019, section <IP_ADDRESS>),
and combined respiratory-related diseases (U.S. EPA, 2019, section
5.1.6), particularly from studies examining emergency department visits
and hospital admissions. The generally positive associations between
short-term PM2.5 exposure and asthma and COPD emergency
department 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, 2019,
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, 2019, section 5.1.9).
    Building on the studies evaluated in the 2009 ISA, recent
epidemiologic studies 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, 2019, section <IP_ADDRESS>).
    Insight into whether there is an independent effect of
PM2.5 on respiratory health is provided by findings from
animal toxicological studies. Specifically, short-term exposure to
PM2.5 has been shown to enhance asthma-related responses in
an animal model of allergic airways disease and lung injury and
inflammation in an animal model of COPD (U.S. EPA, 2019, 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 controlled human exposure studies provide
limited evidence of respiratory effects (U.S. EPA, 2019, section
5.1.12).
    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, 2019, p. 5-155).
When taken together, the ISA concludes that this evidence ``is
sufficient to conclude a likely to be causal relationship between
short-term PM2.5 exposure and respiratory effects'' (U.S.
EPA, 2019, 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, 2009c). 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 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,
2019, section 10.2.5). Reanalyses 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, 2019, 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, 2019, section <IP_ADDRESS>.1). Although studies
that evaluate lung cancer incidence, including studies of people who
have never smoked, are limited in number, recent studies generally
report positive associations with long-term PM2.5 exposures
(U.S. EPA, 2019, 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, 2019, 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, 2019,
section <IP_ADDRESS>.2).
    The 2019 ISA evaluates the degree to which recent epidemiologic
studies have addressed the potential for confounding by copollutants
and the shape of the concentration-response 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. The 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, 2019, 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, 2019, section <IP_ADDRESS>.3). Compared
to total (non-accidental) mortality (discussed above), fewer studies
have examined the shape of the concentration-response curve for cause-
specific mortality outcomes, including lung cancer. Several studies
have reported no evidence of deviations from linearity in the shape of
the concentration-response 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, 2019, section
<IP_ADDRESS>.4).
    In support of the biological plausibility of an independent effect
of PM2.5 on cancer, the 2019 ISA notes evidence from recent
experimental 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, 2019,
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, 2019, 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, 2019,
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, 2019, section
10.2.3).
    Epidemiologic evidence for associations between PM2.5
exposure 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 there is a likely to be causal relationship
between long-term PM2.5 exposure and cancer'' (U.S. EPA,
2019, p. 10-77).
    In its letter to the Administrator on the draft ISA, the CASAC
states that ``the Draft ISA does not present adequate evidence to
conclude that there is likely to be a causal relationship between long-
term PM2.5 exposure and . . . cancer'' (Cox, 2019a, p. 1 of
letter). The CASAC specifically states that this causality
determination ``relies largely on epidemiology studies that . . . do
not provide exposure time frames that are appropriate for cancer
causation and that there are no animal studies showing direct effects
of PM2.5 on cancer formation'' (Cox, 2019a, p. 20 of
consensus responses).
    With respect to the latency period, it is well recognized that
``air pollution exposures experienced over an extended historical time
period are likely more relevant to the etiology of lung cancer than air
pollution exposures experienced in the more recent past'' (Turner et
al. 2011). However, many epidemiologic studies conducted within the
U.S. that examine long-term PM2.5 exposure and lung cancer
incidence and lung cancer mortality rely on more recent air quality
data because routine PM2.5 monitoring did not start until
1999-2000. An exception to this is the American Cancer Society (ACS)
study that had PM2.5 concentration data from two time
periods, 1979-1983 and from 1999-2000. Turner et al. (2011), conducted
a comparison of PM2.5 concentrations between these two time
periods and found that they were highly correlated (r >0.7), with the
relative rank order of metropolitan statistical areas (MSAs) by
PM2.5 concentrations being ``generally retained over time.''
Therefore, areas where PM2.5 concentrations were high
remained high over decades (or low remained low) relative to other
locations. Long-term exposure epidemiologic studies rely on spatial
contrasts between locations; therefore, if a location with high
PM2.5 concentrations continues to have high concentrations
over decades relative to other locations a relationship between the
PM2.5 exposure and cancer should persist. This was confirmed
in a sensitivity analysis conducted by

Turner et al. (2011), where the authors reported a similar hazard ratio
(HR) for lung cancer mortality for participants assigned exposure to
PM2.5 (1979-1983) and PM2.5 (1999-2000) in two
separate analyses.
    While experimental studies showing a direct effect of
PM2.5 on cancer formation were limited to an animal model of
urethane-induced tumor initiation, a large number of experimental
studies report that PM2.5 exhibits several key
characteristics of carcinogens, as indicated by genotoxic effects,
oxidative stress, electrophilicity, and epigenetic alterations, all of
which provide biological plausibility that PM2.5 exposure
can contribute to cancer development. The experimental evidence, in
combination with multiple recent and previously evaluated epidemiologic
studies examining the relationship between long-term PM2.5
exposure and both lung cancer incidence and lung cancer mortality that
reported generally positive associations across different cohorts,
exposure assignment methods, and in analyses of never smokers further
addresses uncertainties identified in the 2009 PM ISA. Therefore, upon
re-evaluating the causality determination for cancer, when considering
CASAC comments on the Draft PM ISA and applying the causal framework as
described (U.S. EPA, 2015; U.S. EPA, 2019, section A.3.2.1), the EPA
continues to conclude in the 2019 Final PM ISA that the evidence for
long-term PM2.5 exposure and cancer supports a ``likely to
be causal relationship'' (U.S. EPA, 2019, p. 10-77).
e. Nervous System Effects
    Reflecting the very limited evidence available in the last 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 last review, this body of evidence has grown
substantially (U.S. EPA, 2019, section 8.2). Recent studies in adult
animals 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, 2019, section 8.2.5). Further,
while the evidence is limited, early markers of Alzheimer's disease
pathology have been reported in rodents following long-term exposure to
PM2.5 CAPs. These findings support reported associations
with neurodegenerative changes in the brain (i.e., decreased brain
volume), all-cause dementia, and hospitalization for Alzheimer's
disease in a small number of epidemiologic studies (U.S. EPA, 2019,
section 8.2.6). Additionally, loss of dopaminergic neurons in the
substantia nigra, a hallmark of Parkinson disease, has been reported in
mice following long-term PM2.5 exposures (U.S. EPA, 2019,
section 8.2.4), though epidemiologic studies provide only limited
support for associations with Parkinson's disease (U.S. EPA, 2019,
section 8.2.6). Overall, the lack of consideration of copollutant
confounding introduces some uncertainty in the interpretation of
epidemiologic studies of nervous system effects, but this uncertainty
is partly addressed by the evidence for an independent effect of
PM2.5 exposures provided by experimental animal studies.
    In addition to the findings described above, which are most
relevant to older adults, several recent studies of neurodevelopmental
effects in children have also been conducted. Positive associations
between long-term exposure to PM2.5 during the prenatal
period and autism spectrum disorder (ASD) are observed in multiple
epidemiologic studies (U.S. EPA, 2019, section <IP_ADDRESS>), while studies
of cognitive function provide little support for an association (U.S.
EPA, 2019, section <IP_ADDRESS>). Interpretation of these epidemiologic
studies is limited due to the small number of studies, their lack of
control for potential confounding by copollutants, and uncertainty
regarding the critical exposure windows. Biological plausibility is
provided for the ASD findings by a study in mice that found
inflammatory and morphologic changes in the corpus collosum and
hippocampus, as well as ventriculomegaly (i.e., enlarged lateral
ventricles) in young mice following prenatal exposure to
PM2.5 CAPs.
    Taken together, the 2019 ISA concludes that the strongest evidence
of an effect of long-term exposure to PM2.5 on the nervous
system is provided by toxicological studies that show inflammation,
oxidative stress, morphologic changes, and neurodegeneration in
multiple brain regions following long-term exposure of adult animals to
PM2.5 CAPs. These findings are coherent with epidemiologic
studies reporting consistent associations with cognitive decrements and
with all-cause dementia. There is also initial, and limited, evidence
for neurodevelopmental effects, particularly ASD. The ISA determines
that ``[o]verall, the collective evidence is sufficient to conclude a
likely to be causal relationship between long-term PM2.5
exposure and nervous system effects'' (U.S. EPA, 2019, p. 8-61).
    In its letter to the Administrator on the draft ISA, the CASAC
states that ``the Draft ISA does not present adequate evidence to
conclude that there is likely to be a causal relationship between long-
term PM2.5 exposure and nervous system effects'' (Cox,
2019a, p. 1 of letter). The CASAC specifically states that ``[f]or a
likely causal conclusion, there would have to be evidence of health
effects in studies where results are not explained by chance,
confounding, and other biases, but uncertainties remain in the overall
evidence'' (Cox, 2019a, p. 20 of consensus responses). These
uncertainties in the eyes of CASAC reflect that animal toxicological
studies ``have largely been done by a single group'' (P.20), and for
epidemiologic studies that examined brain volume that ``brain volumes
can vary . . . between normal people'' and the results from studies of
cognitive function were ``largely non-statistically significant''.
    With these concerns in mind, the EPA re-evaluated the evidence and
note that animal toxicological studies were conducted in ``multiple
research groups [and show a range of effects including] inflammation,
oxidative stress, morphologic changes, and neurodegeneration in
multiple brain regions following long-term exposure of adult animals to
PM2.5 CAPs'' (U.S. EPA, 2019, p. 8-61). The results from the
animal toxicological studies ``are coherent with a number of
epidemiologic studies reporting consistent associations with cognitive
decrements and with all-cause dementia'' (U.S. EPA, 2019, p. 8-61).
Additionally, as discussed in the Preamble to the ISAs (U.S. EPA,
2015):

    ``. . . the U.S. EPA emphasizes the importance of examining the
pattern of results across various studies and does not focus solely
on statistical significance or the magnitude of the direction of the
association as criteria of study reliability. Statistical
significance is influenced by a variety of factors including, but
not limited to, the size of the study, exposure and outcome
measurement error, and statistical model specifications. Statistical
significance . . . is just one of the means of evaluating confidence
in the observed relationship and assessing the probability of chance
as an explanation. Other indicators of reliability such as the
consistency and coherence of a body of studies as well as other
confirming data may be used to justify reliance on the results of a
body of epidemiologic studies, even if results in individual studies
lack statistical significance . . . [Therefore, the U.S. EPA] . . .
does not limit its focus or consideration to statistically
significant results in epidemiologic studies.''

    Therefore, upon re-evaluating the causality determination, when
considering the CASAC comments on the Draft PM ISA and applying the
causal framework as described (U.S. EPA, 2015; U.S. EPA, 2019, section
A.3.2.1), the EPA continues to conclude in the 2019 Final PM ISA that
the evidence for long-term PM2.5 exposure and nervous system
effects supports a ``likely to be causal relationship'' (U.S. EPA,
2019, p. 8-61).
2. Populations at Risk of PM2.5-Related Health Effects
    The NAAQS are meant to protect the population as a whole, including
groups that may be at increased risk for pollutant-related health
effects. In the last review, based on the evidence assessed in the 2009
ISA (U.S. EPA, 2009c), the 2011 PA focused on children, older adults,
people with pre-existing heart and lung diseases, and those of lower
socioeconomic status as populations that are ``likely to be at
increased risk of PM-related effects'' (U.S. EPA, 2011, p. 2-31). In
the current review, the 2019 ISA cites 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, 2019, p. 12-1). For example, in support of its ``causal''
and ``likely to be causal'' determinations, the ISA cites substantial
evidence for:
     PM-related mortality and cardiovascular effects in older
adults (U.S. EPA, 2019, sections 11.1, 11.2, 6.1, and 6.2);
     PM-related cardiovascular effects in people with pre-
existing cardiovascular disease (U.S. EPA, 2019, section 6.1);
     PM-related respiratory effects in people with pre-existing
respiratory disease, particularly asthma exacerbations in children
(U.S. EPA, 2019, section 5.1); and
     PM-related impairments in lung function growth and asthma
development in children (U.S. EPA, 2019, sections 5.1 and 5.2;
<IP_ADDRESS>).
    The ISA additionally notes that stratified analyses (i.e., analyses
that directly compare PM-related health effects across groups) provide
support for racial and ethnic differences in PM2.5 exposures
and in PM2.5-related health risk (U.S. EPA, 2019, section
12.5.4). Drawing from such studies, the ISA concludes that ``[t]here is
strong evidence demonstrating that black and Hispanic populations, in
particular, have higher PM2.5 exposures than non-Hispanic
white populations'' and that ``there is consistent evidence across
multiple studies demonstrating an increase in risk for nonwhite
populations'' (U.S. EPA, 2019, p. 12-38). Stratified analyses focusing
on other groups also suggest that populations with pre-existing
cardiovascular or respiratory disease, populations that are overweight
or obese, populations that have particular genetic variants,
populations that are of low socioeconomic status, and current/former
smokers could be at increased risk for PM2.5-related adverse
health effects (U.S. EPA, 2019, Chapter 12).
    Thus, the groups at risk of PM2.5-related health effects
represent a substantial portion of the total U.S. population. In
evaluating the primary PM2.5 standards, an important
consideration is the potential PM2.5-related public health
impacts in these populations.
3. CASAC Advice
    In its review of the draft ISA, the CASAC provided advice on the
assessment of the scientific evidence for PM-related health and welfare
effects and on the process under which this review of the PM NAAQS is
being conducted (Cox, 2019b). With regard to the assessment of the
evidence, the CASAC recommended that a revised ISA should ``provide a
clearer and more complete description of the process and criteria for
study quality assessment'' and that it should include a ``[c]learer
discussion of causality and causal biological mechanisms and pathways''
(Cox, 2019b, p. 1 of letter). The CASAC further advised that the draft
ISA ``does not present adequate evidence to conclude that there is
likely to be a causal relationship between long-term PM2.5
exposure and nervous system effects; between long-term ultrafine
particulate (UFP) exposure and nervous system effects; or between long-
term PM2.5 exposure and cancer'' (Cox, 2019b, p. 1 of
letter).
    As discussed above in section I.C.5, and as detailed in the final
ISA, to address these comments the EPA: (1) Added text to the Preface
and developed a new Appendix to more clearly articulate the process of
ISA development; (2) added text to the Preface and to the health
effects chapters to clarify the discussion of biological plausibility
and its role in forming causality determinations; and (3) revised the
determination for long-term UFP exposure and nervous system effects to
suggestive of, but not sufficient to infer, a causal relationship. The
EPA's rationales for not revising the other causality determinations
questioned by the CASAC are discussed above in sections II.B.1.d (i.e.,
for cancer) and II.B.1.e (i.e., for nervous system effects).
    With regard to the process for reviewing the PM NAAQS, the CASAC
requested the opportunity to review a 2nd draft ISA (Cox, 2019b, p. 1
of letter) and recommended that ``the EPA reappoint the previous CASAC
PM panel (or appoint a panel with similar expertise)'' (Cox, 2019b, p.
2 of letter). As discussed above in section I.C.5, the Agency's
responses to these recommendations were described in a letter from the
Administrator to the CASAC chair.\40\
---------------------------------------------------------------------------

    \40\ Available at: https://yosemite.epa.gov/sab/sabproduct.nsf/
0/6CBCBBC3025E13B4852583D90047B352/$File/EPA-CASAC-19-
002_Response.pdf.
---------------------------------------------------------------------------

    In addition to the consensus advice noted above, the CASAC did not
reach consensus on some issues related to the assessment of the
PM2.5 health effects evidence. In particular, the CASAC
members ``had varying opinions on whether there is robust and
convincing evidence to support the EPA's conclusion that there is a
causal relationship between PM2.5 exposure and mortality''
(Cox, 2019b, p. 3 of letter). ``Some members of the CASAC'' concluded
that ``the EPA must better justify their determination that short-term
or long-term exposure to PM2.5 causes mortality'' (Cox,
2019b, p. 1 of consensus responses). These members recommended that the
ISA should specifically address the biological action of PM and how
exposures to low concentrations of PM2.5 could cause
mortality; the geographic heterogeneity in effect estimates between
PM2.5 exposure and mortality; concentration concordance
across epidemiologic, controlled human exposure and animal
toxicological studies (i.e., how the continuum of effects is impacted
by the concentrations at which different effects have been observed);
uncertainties in the shapes of concentration-response functions and in
the potential for thresholds to exist; how results compare between and
within studies; and whether PM2.5 exposures result in
mortality in animal studies (Cox, 2019b, pp. 1-2).
    In contrast, ``[o]ther members of the CASAC are of the opinion
that, although uncertainties remain, the evidence supporting the causal
relationship between PM2.5 exposure and mortality is robust,
diverse, and convincing'' (Cox, 2019b, p. 3 of consensus responses).
These members noted that epidemiologic observations ``have been
reproduced around the world in communities with widely varying
exposures'' and that ``the findings of many of the largest studies have
been repeatedly reanalyzed, with

confirmation of the original findings'' (Cox, 2019b, p. 3). These
committee members additionally stated that the ISA's causality
determinations consider ``a wide range of evidence from a variety of
sources, including human clinical exposure and animal toxicology
studies that have provided rational biological plausibility and
potential mechanisms'' (Cox, 2019b, p. 3). They highlighted the fact
that there is new evidence in the current review from epidemiologic
studies supporting associations between PM2.5 and mortality
and new evidence from toxicology studies informing the biological
plausibility of mechanisms that could lead to mortality (Cox, 2019b, p.
3).

C. Proposed Conclusions on the Current Primary PM2.5
Standards

    This section describes the Administrator's proposed conclusions
regarding the adequacy of the current primary PM2.5
standards. His approach to reaching these proposed conclusions draws
from the ISA's assessment of the scientific evidence for health effects
attributable to PM2.5 exposures (U.S. EPA, 2019) and the
analyses in the PA (U.S. EPA, 2020), including uncertainties in the
evidence and analyses. Section II.C.1 discusses the evidence- and risk-
based considerations in the PA. Section II.C.2 summarizes CASAC advice
on the current primary PM2.5 standards, based on its review
of the draft PA (Cox, 2019a). Section II.C.3 presents the
Administrator's proposed decision to retain the current primary
PM2.5 standards.
1. Evidence- and Risk-Based Considerations in the Policy Assessment
    The Administrator's proposed decision in this review draws from his
consideration of the PM2.5 health evidence assessed in the
ISA (U.S. EPA, 2019) and the evidence- and risk-based analyses
presented in the PA (U.S. EPA, 2020), including the uncertainties
inherent in the evidence and analyses. The sections below summarize the
consideration of the evidence-based information (II.C.1.a) and risk-
based information (II.C.1.b) in the PA.
a. Evidence-Based Considerations
    The PA considers the degree to which the available scientific
evidence provides support for the current and potential alternative
standards in terms of the basic elements of those standards (i.e.,
indicator, averaging time, form, and level). With regard to the current
indicator, averaging times, and forms, the PA concludes that the
available evidence continues to support these elements in the current
review. For indicator, the PA specifically concludes that available
studies provide strong support for health effects following long- and
short-term PM2.5 exposures and that the evidence is too
limited to support potential alternatives (U.S. EPA, 2020, section
<IP_ADDRESS>). For averaging time, the PA notes that epidemiologic studies
continue to provide strong support for health effects based on annual
(or multiyear) and 24-hour PM2.5 averaging periods and
concludes that the evidence does not support considering alternatives
(U.S. EPA, 2020, section <IP_ADDRESS>). For form, the PA notes that the
foremost consideration is the adequacy of the public health protection
provided by the combination of the form and the other elements of the
standard. It concludes that (1) the form of the current annual standard
(i.e., arithmetic mean, averaged over three years) remains appropriate
for targeting protection against the annual and daily PM2.5
exposures around the middle portion of the PM2.5 air quality
distribution, and (2) the form of the current 24-hour standard (98th
percentile, averaged over three years) continues to provide 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, 2020, section <IP_ADDRESS>).
    With regard to level, the considerations in the PA reflect analyses
of the PM2.5 exposures and ambient concentrations in studies
reporting PM2.5-related health effects (U.S. EPA, 2020). As
noted above, the focus is on health outcomes for which the ISA
concludes the evidence supports a ``causal'' or a ``likely to be
causal'' relationship with PM exposures.\41\ While the causality
determinations in the ISA are informed by studies evaluating a wide
range of PM2.5 concentrations, the PA considers the degree
to which the evidence supports the occurrence of PM-related effects at
concentrations relevant to informing conclusions on the primary
PM2.5 standards. Section II.C.1.a.i below summarizes the
PA's consideration of exposure concentrations that have been evaluated
in experimental studies and section II.C.1.a.ii summarizes the PA's
consideration of ambient concentrations in locations evaluated by
epidemiologic studies.
---------------------------------------------------------------------------

    \41\ As discussed above in II.A.2, such a focus recognizes that
standards set to provide protection based on evidence for ``causal''
and ``likely to be causal'' health outcomes will also provide some
measure of protection against the broader range of PM2.5-
associated outcomes, including those for which the evidence is less
certain.
---------------------------------------------------------------------------

i. PM2.5 Exposure Concentrations Evaluated in Experimental
Studies
    Evidence for a particular PM2.5-related health outcome
is strengthened when results from experimental studies demonstrate
biologically plausible mechanisms through which adverse human health
outcomes could occur (U.S. EPA, 2015, Preamble p. 20). Two types of
experimental studies are of particular importance in understanding the
effects of PM exposures: Controlled human exposure and animal
toxicology studies. In such studies, investigators expose human
volunteers or laboratory animals, respectively, to known concentrations
of air pollutants under carefully regulated environmental conditions
and activity levels. Thus, controlled human exposure and animal
toxicology studies can provide information on the health effects of
experimentally administered pollutant exposures under well-controlled
laboratory conditions (U.S. EPA, 2015, Preamble, p. 11). The sections
below summarize the PA's evaluation of the PM2.5 exposure
concentrations that have been examined in controlled human exposure
studies and animal toxicology studies.
Controlled Human Exposure Studies
    Controlled human exposure studies have reported that
PM2.5 exposures lasting from less than one hour up to five
hours can impact cardiovascular function (U.S. EPA, 2019, section 6.1).
The most consistent evidence from these studies is for impaired
vascular function (U.S. EPA, 2019, section <IP_ADDRESS>). In addition,
although less consistent, the ISA notes that studies examining
PM2.5 exposures also provide evidence for increased blood
pressure (U.S. EPA, 2019, section <IP_ADDRESS>), conduction abnormalities/
arrhythmia (U.S. EPA, 2019, section <IP_ADDRESS>), changes in heart rate
variability (U.S. EPA, 2019, section <IP_ADDRESS>), changes in hemostasis
that could promote clot formation (U.S. EPA, 2019, section <IP_ADDRESS>),
and increases in inflammatory cells and markers (U.S. EPA, 2019,
section <IP_ADDRESS>).
    Table 3-2 in the PA (U.S. EPA, 2020) summarizes information from
the ISA on available controlled human exposure studies that evaluate
effects on markers of cardiovascular function following exposures to
PM2.5. Most of the controlled human exposure studies in
Table 3-2 of the PA have evaluated average PM2.5 exposure
concentrations at or above about 100 [micro]g/m\3\, with exposure
durations typically up to about two hours. Statistically significant
effects on one or more indicators of

cardiovascular function are often, though not always, reported
following 2-hour exposures to average PM2.5 concentrations
at and above about 120 [micro]g/m\3\, with less consistent evidence for
effects following exposures to lower concentrations. Impaired vascular
function, the effect identified in the ISA as the most consistent
across studies (U.S. EPA, 2019, section <IP_ADDRESS>), is shown following
2-hour exposures to PM2.5 concentrations at and above 149
[micro]g/m\3\. Mixed results are reported in the few studies that
evaluate longer exposure durations (i.e., longer than 2 hours) and
lower PM2.5 concentrations (U.S. EPA, 2020, section
<IP_ADDRESS>).
    To provide some insight into what these studies may indicate
regarding the primary PM2.5 standards, analyses in the PA
examine monitored 2-hour PM2.5 concentrations at sites
meeting the current standards (U.S. EPA, 2020, section <IP_ADDRESS>). At
these sites, most 2-hour concentrations are below 11 [mu]g/m\3\, and
they almost never exceed 32 [mu]g/m\3\. Even the highest 2-hour
concentrations remain well-below the exposure concentrations
consistently shown to cause effects in controlled human exposure
studies (i.e., 99.9th percentile of 2-hour concentrations is 68 [mu]g/
m\3\ during the warm season). Thus, while controlled human exposure
studies support the plausibility of the serious cardiovascular effects
that have been linked with ambient PM2.5 exposures (U.S.
EPA, 2019, Chapter 6), the PA notes that the PM2.5 exposures
evaluated in most of these studies are well-above the ambient
concentrations typically measured in locations meeting the current
primary standards (U.S. EPA, 2020, section <IP_ADDRESS>.1).
Animal Toxicology Studies
    The ISA relies on animal toxicology studies to support the
plausibility of a wide range of PM2.5-related health
effects. While animal toxicology studies often examine more severe
health outcomes and longer exposure durations than controlled human
exposure studies, there is uncertainty in extrapolating the effects
seen in animals, and the PM2.5 exposures and doses that
cause those effects, to human populations.
    As with controlled human exposure studies, most of the animal
toxicology studies assessed in the ISA have examined effects following
exposures to PM2.5 concentrations well-above the
concentrations likely to be allowed by the current PM2.5
standards. Such studies have generally examined short-term exposures to
PM2.5 concentrations from 100 to >1,000 [mu]g/m\3\ and long-
term exposures to concentrations from 66 to >400 [mu]g/m\3\ (e.g., see
U.S. EPA, 2019, Table 1-2). Two exceptions are a study reporting
impaired lung development following long-term exposures (i.e., 24 hours
per day for several months prenatally and postnatally) to an average
PM2.5 concentration of 16.8 [mu]g/m\3\ (Mauad et al., 2008)
and a study reporting increased carcinogenic potential following long-
term exposures (i.e., 2 months) to an average PM2.5
concentration of 17.7 [mu]g/m\3\ (Cangerana Pereira et al., 2011).
These two studies report serious effects following long-term exposures
to PM2.5 concentrations close to the ambient concentrations
reported in some PM2.5 epidemiologic studies (U.S. EPA,
2019, Table 1-2), though still above the ambient concentrations likely
to occur in areas meeting the current primary standards. Thus, as is
the case with controlled human exposure studies, animal toxicology
studies support the plausibility of various adverse effects that have
been linked to ambient PM2.5 exposures (U.S. EPA, 2019), but
have not evaluated PM2.5 exposures likely to occur in areas
meeting the current primary standards.
ii. Ambient Concentrations in Locations of Epidemiologic Studies
    As summarized above in section II.B.1, epidemiologic studies
examining associations between daily or annual average PM2.5
exposures and mortality or morbidity represent a large part of the
evidence base supporting several of the ISA's ``causal'' and ``likely
to be causal'' determinations for cardiovascular effects, respiratory
effects, cancer, and mortality. The PA uses two approaches to consider
what information from epidemiologic studies may indicate regarding
primary PM2.5 standards (U.S. EPA, 2020, section <IP_ADDRESS>).
In one approach, the PA evaluates the PM2.5 air quality
distributions reported by key epidemiologic studies, with a focus on
overall mean PM2.5 concentrations (i.e., averages over the
study period of the daily or annual PM2.5 concentrations
used to estimate exposures) and the concentrations somewhat below these
overall means (i.e., corresponding to the lower quartiles of exposure
or health data) (U.S. EPA, 2020, section <IP_ADDRESS>.1). In another
approach, the PA calculates study area air quality metrics similar to
PM2.5 design values (i.e., referred to as pseudo-design
values) and considers the degree to which such metrics indicate that
study area air quality would likely have met or violated the current
standards during study periods (U.S. EPA, 2020, section <IP_ADDRESS>.2).
These approaches are discussed briefly below.
PM2.5 Air Quality Distributions Associated With Mortality or
Morbidity
    The PA evaluates the PM2.5 air quality distributions
over which epidemiologic studies support health effect associations and
the degree to which such distributions are likely to occur in areas
meeting the current standards. As discussed further in the PA (U.S.
EPA, 2020, section <IP_ADDRESS>.1), epidemiologic studies generally provide
the strongest support for reported health effect associations over the
part of the air quality distribution corresponding to the bulk of the
underlying data (i.e., estimated exposures and/or health events), often
falling in the middle part of the distribution (i.e., rather than at
the extreme upper or lower ends). Thus, in considering PM2.5
air quality data from epidemiologic studies, the PA evaluates study-
reported means (or medians) of daily and annual average
PM2.5 concentrations as proxies for the middle portions of
the air quality distributions that support reported associations. When
data are available, the PA also considers the broader PM2.5
air quality distributions around the overall mean concentrations, with
a focus on the lower quartiles of data to provide insight into the
concentrations below which data supporting reported associations become
relatively sparse.
    Based on its evaluation of study-reported PM2.5
concentrations, the PA notes that key epidemiologic studies conducted
in the U.S. or Canada report generally positive and statistically
significant associations between estimated PM2.5 exposures
(short- or long-term) and mortality or morbidity across a wide range of
ambient PM2.5 concentrations (U.S. EPA, 2020, section
<IP_ADDRESS>.1). With regard to these study-reported concentrations, the PA
makes a number of observations, including the following:
     For the large majority of key studies, the
PM2.5 air quality distributions that support reported
associations are characterized by overall mean (or median)
PM2.5 concentrations ranging from just above 8.0 [mu]g/m\3\
to just above 16.0 [mu]g/m\3\. Most of these key studies, including all
but one U.S. study, report overall mean (or median) concentrations at
or above 9.6 [mu]g/m\3\.
     Several U.S. studies report positive and statistically
significant health effect associations in analyses restricted to annual
average PM2.5 concentrations <12 [mu]g/m\3\ (Lee et al.
(2015); Shi et al. (2016); Di et al., 2017b). Studies also report
positive and statistically significant health effect associations in
analyses restricted to days with 24-hour average PM2.5
concentrations <35 [mu]g/m\3\

(Lee et al. (2015); Shi et al. (2016); Di et al. (2017a)).
     For some key studies, information on the broader
distributions of PM2.5 exposure estimates and/or health
events is available. In these studies, ambient PM2.5
concentrations corresponding to 25th percentiles of the underlying data
(i.e., estimated exposures or health events) are generally >6.0 [mu]g/
m\3\.
     A small group of studies report increased life expectancy,
decreased mortality, and decreased respiratory effects following past
declines in ambient PM2.5 concentrations. These studies have
examined ``starting'' annual average PM2.5 concentrations
(i.e., prior to the reductions being evaluated) ranging from about 13
to >20 [mu]g/m\3\ (i.e., U.S. EPA, 2020, Table 3-3).
    The PA concludes that the overall mean PM2.5
concentrations reported by several of these key epidemiologic studies
are likely below the long-term mean concentrations (i.e., averaged
across space and over time) in areas just meeting the current annual
PM2.5 standard (U.S. EPA, 2020, section <IP_ADDRESS>). The PA
also concludes that there are uncertainties in using study-reported
concentrations to inform conclusions on the primary PM2.5
standards (U.S. EPA, 2020, section <IP_ADDRESS>.1). For example, the overall
mean PM2.5 concentrations reported by key epidemiologic
studies are not the same as the ambient concentrations used by the EPA
to determine whether areas meet or violate the PM NAAQS. Overall mean
PM2.5 concentrations in key studies reflect averaging of
short- or long-term PM2.5 exposure estimates across
locations (i.e., across multiple monitors or across modeled grid cells)
and over time (i.e., over several years). In contrast, to determine
whether areas meet or violate the NAAQS, the EPA measures air pollution
concentrations at individual monitors (i.e., concentrations are not
averaged across monitors) and calculates ``design values'' at monitors
meeting appropriate data quality and completeness criteria. For the
annual PM2.5 standard, design values are calculated as the
annual arithmetic mean PM2.5 concentration, averaged over 3
years (described in appendix N of 40 CFR part 50). For an area to meet
the NAAQS, all valid design values in that area, including the highest
monitored values, must be at or below the level of the standard.
Additional uncertainties associated with using the PM2.5
concentrations reported by key epidemiologic studies to inform
conclusions on the primary PM2.5 standards result from the
fact that (1) epidemiologic studies do not identify specific
PM2.5 exposures that result in health effects or exposures
below which effects do not occur and (2) exposure estimates in some
recent studies are based on hybrid modeling approaches for which
performance depends on the availability of monitoring data and varies
by location. These results and uncertainties are discussed in detail in
the PA (U.S. EPA, 2020, section <IP_ADDRESS>.1).
PM2.5 Pseudo-Design Values in Epidemiologic Study Locations
    As noted above, a key uncertainty in using study-reported
PM2.5 concentrations to inform conclusions on the primary
PM2.5 standards is that they reflect the averages of daily
or annual PM2.5 air quality concentrations or exposure
estimates in the study population over the years examined by the study,
and are not the same as the PM2.5 design values used by the
EPA to determine whether areas meet the NAAQS. Therefore, the PA also
considers a second approach to evaluating information from
epidemiologic studies. In this approach, the PA calculates study area
air quality metrics similar to PM2.5 design values (i.e.,
referred to in the PA as pseudo-design values; U.S. EPA, 2020, section
<IP_ADDRESS>.2) and considers the degree to which such metrics indicate that
study area air quality would likely have met or violated the current
standards during study periods. When pseudo-design values in individual
study locations are linked with the populations living in those
locations, or with the number of study-specific health events recorded
in those locations, these values can provide insight into the degree to
which reported health effect associations are based on air quality
likely to have met or violated the current (or alternative) primary
PM2.5 standards. The results of these analyses are
summarized below in Table 1 (from U.S. EPA, 2020, Appendix B, Tables B-
5 and B-6).

 Table 1--Summary of Results from Analysis of PM2.5 Pseudo-Design Values
         in Locations of Key U.S. and Canadian Multicity Studies
                    [From U.S. EPA, 2020, Table B-5]
------------------------------------------------------------------------
  Percent of population/health events in     Number of studies  (of the
   locations meeting  current standards             29 evaluated)
------------------------------------------------------------------------
> 25%.....................................  17
> 50%.....................................  9
> 75%.....................................  4
< 25%.....................................  12
------------------------------------------------------------------------

    Given the results of these analyses, the PA concludes that several
key epidemiologic studies report positive and statistically significant
PM2.5 health effect associations based largely, or entirely,
on air quality likely to be allowed by the current primary
PM2.5 standards (U.S. EPA, 2020, section <IP_ADDRESS>). The PA
also concludes that there are important uncertainties to consider when
using this information to inform conclusions on the primary
PM2.5 standards. For example, for most key multicity
studies, some study locations would likely have met the current primary
standards over study periods while others would likely have violated
one or both standards, complicating the interpretation of these
analyses. In addition, pseudo-design values are averaged over multiyear
study periods of varying lengths, rather than reflecting the three-year
averages of actual design values; analyses necessarily focus on
locations with at least one PM2.5 monitor, while unmonitored
areas are not included; and recent changes to PM2.5
monitoring requirements are not reflected in analyses of pseudo-design
values. These results and uncertainties are discussed in greater detail
in the PA (U.S. EPA, 2020, section <IP_ADDRESS>.2).
b. Risk-Based Considerations
    In addition to evaluating PM2.5 concentrations in
locations of key epidemiologic studies, the PA includes a risk
assessment that estimates population-level health risks associated with
PM2.5 air quality that has been adjusted to simulate air
quality scenarios of policy interest (e.g., ``just meeting'' the
current standards). The general approach to estimating
PM2.5-associated health risks combines concentration-
response functions from epidemiologic studies with model-based
PM2.5 air quality surfaces, baseline health incidence data,
and population demographics for forty-seven urban study areas (U.S.
EPA, 2020, section 3.3, Figure 3-10 and Appendix C).
    The risk assessment estimates that the current primary
PM2.5 standards could allow a substantial number of
PM2.5-associated deaths in the U.S. For example, when air
quality in the 47 study areas is adjusted to simulate just meeting the
current standards, the risk assessment estimates from about 16,000 to
17,000 long-term PM2.5 exposure-related deaths from ischemic
heart disease in a single year (i.e., confidence intervals range from
about 12,000 to

21,000 deaths).\42\ Compared to the current annual standard, meeting a
revised annual standard with a lower level is estimated to reduce
PM2.5-associated health risks by about 7 to 9% for a level
of 11.0 [micro]g/m\3\, 14 to 18% for a level of 10.0 [micro]g/m\3\, and
21 to 27% for a level of 9.0 [micro]g/m\3\.
---------------------------------------------------------------------------

    \42\ For the only other cause-specific mortality endpoint
evaluated (i.e., lung cancer), substantially fewer deaths were
estimated (U.S. EPA, 2020, section 3.3.2, e.g., Figure 3-5). Risk
estimates were not generated for other ``likely to be causal''
outcome categories (i.e., respiratory effects, nervous system
effects).
---------------------------------------------------------------------------

    Limitations in the underlying data and risk assessment approaches
lead to uncertainty in these estimates of PM2.5-associated
risks (e.g., in the size of risk estimates). Uncertainty in risk
estimates results from a number of factors, including assumptions about
the shape of the concentration-response relationship with mortality at
low ambient PM concentrations, the potential for confounding and/or
exposure measurement error in the underlying epidemiologic studies, and
the methods used to adjust PM2.5 air quality. The PA
characterizes these and other sources of uncertainty in risk estimates
using a combination of quantitative and qualitative approaches (U.S.
EPA, 2020, Appendix C, section C.3).
2. CASAC Advice
    As part of its review of the draft PA, the CASAC has provided
advice on the adequacy of the public health protection afforded by the
current primary PM2.5 standards.\43\ Its advice is
documented in a letter sent to the EPA Administrator (Cox, 2019a). In
this letter, the committee recommends retaining the current 24-hour
PM2.5 standard but does not reach consensus on whether the
scientific and technical information support retaining or revising the
current annual standard. In particular, though the CASAC agrees that
there is a long-standing body of health evidence supporting
relationships between PM2.5 exposures and various health
outcomes, including mortality and serious morbidity effects, individual
CASAC members ``differ in their assessments of the causal and policy
significance of these associations'' (Cox, 2019a, p. 8 of consensus
responses). Drawing from this evidence, ``some CASAC members'' express
support for retaining the current annual standard while ``other
members'' express support for revising that standard in order to
increase public health protection (Cox, 2019a, p.1 of letter). These
views are summarized below.
---------------------------------------------------------------------------

    \43\ The CASAC also provided advice on the draft ISA's
assessment of the scientific evidence (Cox, 2019b) and on the
analyses and information in the draft PA (Cox, 2019a), which drew
from the draft ISA. That advice, and the resulting changes made in
the final ISA and final PA, are summarized above in sections I.C.5,
II.B.1.d, II.B.1.e and II.B.3, and in the final ISA (U.S. EPA, 2019,
ES-3 to ES-4) and the final PA (U.S. EPA, 2020, section 1.4).
---------------------------------------------------------------------------

    The CASAC members who support retaining the current annual standard
express the view that substantial uncertainty remains in the evidence
for associations between PM2.5 exposures and mortality or
serious morbidity effects. These committee members assert that ``such
associations can reasonably be explained in light of uncontrolled
confounding and other potential sources of error and bias'' (Cox,
2019a, p. 8 of consensus responses). They note that associations do not
necessarily reflect causal effects, and they contend that recent
epidemiologic studies reporting positive associations at lower
estimated exposure concentrations mainly confirm what was anticipated
or already assumed in setting the 2012 NAAQS. In particular, they
conclude that such studies have some of the same limitations as prior
studies and do not provide new information calling into question the
existing standard. They further assert that ``accountability studies
provide potentially crucial information about whether and how much
decreasing PM2.5 causes decreases in future health effects''
(Cox, 2019a, p. 10), and they cite recent reviews (i.e., Henneman et
al., 2017; Burns et al., 2019) to support their position that in such
studies, ``reductions of PM2.5 concentrations have not
clearly reduced mortality risks'' (Cox, 2019a, p. 8 of consensus
responses). Thus, the committee members who support retaining the
current annual standard advise 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 of consensus responses).
    These members of the CASAC further conclude that the
PM2.5 risk assessment does not provide a valid basis for
revising the current standards. This conclusion is based on concerns
that (1) ``the risk assessment treats regression coefficients as causal
coefficients with no justification or validation provided for this
decision;'' (2) the estimated regression concentration-response
functions ``have not been adequately adjusted to correct for
confounding, errors in exposure estimates and other covariates, model
uncertainty, and heterogeneity in individual biological (causal)
[concentration-response] functions;'' (3) the estimated concentration-
response functions ``do not contain quantitative uncertainty bands that
reflect model uncertainty or effects of exposure and covariate
estimation errors;'' and (4) ``no regression diagnostics are provided
justifying the use of proportional hazards . . . and other modeling
assumptions'' (Cox, 2019a, p. 9 of consensus responses). These
committee members also contend that details regarding the derivation of
concentration-response functions, including specification of the beta
values and functional forms, are not well-documented, hampering the
ability of readers to evaluate these design details. Thus, these
members ``think that the risk characterization does not provide useful
information about whether the current standard is protective'' (Cox,
2019a, p. 11 of consensus responses).
    Drawing from their evaluation of the evidence and the risk
assessment, these committee members conclude that ``the Draft PM PA
does not establish that new scientific evidence and data reasonably
call into question the public health protection afforded by the current
2012 PM2.5 annual standard'' (Cox, 2019a, p.1 of letter).
    In contrast, ``[o]ther members of CASAC conclude that the weight of
the evidence, particularly reflecting recent epidemiology studies
showing positive associations between PM2.5 and health
effects at estimated annual average PM2.5 concentrations
below the current standard, does reasonably call into question the
adequacy of the 2012 annual PM2.5 [standard] to protect
public health with an adequate margin of safety'' (Cox, 2019a, p.1 of
letter). The committee members who support this conclusion note that
the body of health evidence for PM2.5 includes not only the
repeated demonstration of associations in epidemiologic studies, but
also includes support for biological plausibility established by
controlled human exposure and animal toxicology studies. They point to
recent studies demonstrating that the associations between
PM2.5 and health effects occur in a diversity of locations,
in different time periods, with different populations, and using
different exposure estimation and statistical methods. They conclude
that ``the entire body of evidence for PM health effects justifies the
causality determinations made in the Draft PM ISA'' (Cox, 2019a, p. 8
of consensus responses).
    The members of the CASAC who support revising the current annual
standard particularly emphasize recent findings of associations with
PM2.5 in areas with average long-term PM2.5
concentrations below the level of the

annual standard and studies that show positive associations even when
estimated exposures above 12 [mu]g/m\3\ are excluded from analyses.
They find it ``highly unlikely'' that the extensive body of evidence
indicating positive associations at low estimated exposures could be
fully explained by confounding or by other non-causal explanations
(Cox, 2019a, p. 8 of consensus responses). They additionally conclude
that ``the risk characterization does provide a useful attempt to
understand the potential impacts of alternate standards on public
health risks'' (Cox, 2019a, p. 11 of consensus responses). These
committee members conclude that the evidence available in this review
reasonably calls into question the protection provided by the current
primary PM2.5 standards and supports revising the annual
standard to increase that protection (Cox, 2019a).
3. Administrator's Proposed Decision on the Current Primary
PM2.5 Standards
    This section summarizes the Administrator's considerations and
conclusions related to the current primary PM2.5 standards
and presents his proposed decision to retain those standards, without
revision. As described above (section II.A.2), his approach to
considering the adequacy of the current standards focuses on evaluating
the public health protection afforded by the annual and 24-hour
standards, taken together, against mortality and morbidity associated
with long- or short-term PM2.5 exposures. This approach
recognizes that changes in PM2.5 air quality designed to
meet either the annual or the 24-hour standard would likely result in
changes to both long-term average and short-term peak PM2.5
concentrations and that the protection provided by the suite of
standards results from the combination of all of the elements of those
standards (i.e., indicator, averaging time, form, level). Thus, the
Administrator's consideration of the public health protection provided
by the current primary PM2.5 standards is based on his
consideration of the combination of the annual and 24-hour standards,
including the indicators (PM2.5), averaging times, forms
(arithmetic mean and 98th percentile, averaged over three years), and
levels (12.0 [mu]g/m\3\, 35 [mu]g/m\3\) of those standards.
    In establishing primary standards under the Act that are
``requisite'' to protect public health with an adequate margin of
safety, the Administrator is seeking to establish standards that are
neither more nor less stringent than necessary for this purpose. He
recognizes that the requirement to provide an adequate margin of safety
was intended to address uncertainties associated with inconclusive
scientific and technical information and to provide a reasonable degree
of protection against hazards that research has not yet identified.
However, the Act does not require that primary standards be set at a
zero-risk level; rather, the NAAQS must be sufficiently protective, but
not more stringent than necessary.
    Given these requirements, the Administrator's final decision in
this review will be a public health policy judgment drawing upon
scientific and technical information examining the health effects of
PM2.5 exposures, including how to consider the range and
magnitude of uncertainties inherent in that information. This public
health policy judgment will be based on an interpretation of the
scientific and technical information that neither overstates nor
understates its strengths and limitations, nor the appropriate
inferences to be drawn, and will be informed by the Administrator's
consideration of advice from the CASAC and public comments received on
this proposal document.
    With regard to the CASAC, the Administrator recognizes that while
the committee supports retaining the current 24-hour PM2.5
standard, it does not reach consensus on the annual standard (Cox,
2019a, pp. 1-3 of letter). In particular, some members of the CASAC
conclude that the new scientific evidence and data do not reasonably
call into question the public health protection afforded by the current
annual standard, while other members conclude that the weight of the
evidence does reasonably call into question the adequacy of that
standard (Cox, 2019a, p. 1 of letter).
    As discussed above (II.C.2), the CASAC members who support
retaining the annual standard emphasize their concerns with available
PM2.5 epidemiologic studies. They assert that recent studies
``mainly confirmed what had already been anticipated or assumed in
setting the 2012 NAAQS'' (Cox, 2019a, p. 8 consensus responses) and do
not provide a basis for revising the current standards. They also
identify several key concerns regarding the associations reported in
PM2.5 epidemiologic studies and conclude 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).
    One of the methodological limitations highlighted by these
committee members is that associations reported in epidemiologic
studies are not necessarily indicative of causal relationships and such
associations ``can reasonably be explained in light of uncontrolled
confounding and other potential sources of error and bias'' (Cox,
2019a, p. 8). Thus, these committee members do not think that recent
epidemiologic studies reporting health effect associations at
PM2.5 air quality concentrations likely to have met the
current primary standards support revising those standards.
    Consistent with the views expressed by these CASAC members, the
Administrator recognizes that epidemiologic studies examine
associations between distributions of PM2.5 air quality and
health outcomes, and they do not identify particular PM2.5
exposures that cause effects (U.S. EPA, 2020, section 3.1.2). In
contrast, he notes that experimental studies (i.e., controlled human
exposure, animal toxicology) do provide evidence for health effects
following particular PM2.5 exposures under carefully
controlled laboratory conditions (e.g., U.S. EPA, 2015, Preamble
Chapters 5 and 6). He further notes that the evidence for a given
PM2.5-related health outcome is strengthened when results
from experimental studies demonstrate biologically plausible mechanisms
through which such an outcome could occur (e.g., U.S. EPA, 2015,
Preamble p. 20). Thus, when using the PM2.5 health evidence
to inform conclusions on the adequacy of the current primary standards,
the Administrator is most confident in the potential for
PM2.5 exposures to cause adverse effects at concentrations
supported by multiple types of studies, including experimental studies
as well as epidemiologic studies.
    In light of this approach to considering the evidence, the
Administrator recognizes that controlled human exposure and animal
toxicology studies report a wide range of effects, many of which are
plausibly linked to the serious cardiovascular and respiratory outcomes
reported in epidemiologic studies (including mortality), though the
PM2.5 exposures examined in these studies are above the
concentrations typically measured in areas meeting the current annual
and 24-hour standards (U.S. EPA, 2020, section <IP_ADDRESS>). In the absence
of evidence from experimental studies that PM2.5 exposures
typical of areas meeting the current annual and 24-hour standards can
activate biological pathways that plausibly contribute to serious
health outcomes, the Administrator is cautious about placing too much
weight on reported PM2.5 health effect associations for air
quality

meeting those standards. He concludes that such associations alone,
without supporting experimental evidence at similar PM2.5
concentrations, leave important questions unanswered regarding the
degree to which the typical PM2.5 exposures likely to occur
in areas meeting the current standards can cause the mortality or
morbidity outcomes reported in epidemiologic studies. Given this
concern, the Administrator does not think that recent epidemiologic
studies reporting health effect associations at PM2.5 air
quality concentrations likely to have met the current primary standards
support revising those standards. Rather, he judges that the overall
body of evidence, including controlled human exposure and animal
toxicological studies, in addition to epidemiologic studies, indicates
continuing uncertainty in the degree to which adverse effects could
result from PM2.5 exposures in areas meeting the current
annual and 24-hour standards.
    The Administrator additionally considers the emerging body of
evidence from studies examining past reductions in ambient
PM2.5, and the degree to which those reductions have
resulted in public health improvements. As an initial matter, he notes
the observation from some CASAC members (i.e., those who support
retaining the current annual standard) that in accountability studies,
``reductions of PM2.5 concentrations have not clearly
reduced mortality risks, especially when confounding was tightly
controlled'' (Cox, 2019a, p. 8). The Administrator recognizes that
interpreting such studies in the context of the current primary
PM2.5 standards is also complicated by the fact that some of
the available studies have 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 have not been
able to disentangle health impacts of the interventions from background
trends in health (U.S. EPA, 2020, section 3.5.1). He further recognizes
that the small number of available studies that do report public health
improvements following past declines in ambient PM2.5 have
not examined air quality meeting the current standards (U.S. EPA, 2020,
Table 3-3). This includes recent U.S. studies that report increased
life expectancy, decreased mortality, and decreased respiratory effects
following past declines in ambient PM2.5 concentrations.
Such studies have examined ``starting'' annual average PM2.5
concentrations (i.e., prior to the reductions being evaluated) ranging
from about 13 to > 20 [mu]g/m\3\ (i.e., U.S. EPA, 2020, Table 3-3). It
also includes a recent study conducted in Japan that reports reduced
mortality following reductions in ambient PM2.5 due to the
introduction of diesel emission controls (Yorifuji et al., 2016). As in
the U.S. studies, ambient PM2.5 concentrations in this study
were above those allowed by the current primary PM2.5
standards. Given the lack of studies reporting public health
improvements attributable to reductions in ambient PM2.5 in
locations meeting the current standards, together with his broader
concerns regarding the lack of experimental studies examining
PM2.5 exposures typical of areas meeting the current
standards (discussed above), the Administrator judges that there is
considerable uncertainty in the potential for increased public health
protection from further reductions in ambient PM2.5
concentrations beyond those achieved under the current primary
PM2.5 standards.
    In addition to the evidence, the Administrator considers the
potential implications of the risk assessment for his proposed
decision. In doing so, he notes that all risk assessments have
limitations and that, in previous reviews, these 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 3128,
January 15, 2013). Such limitations in risk estimates can result from
uncertainty in the shapes of concentration-response 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, 2020,
section <IP_ADDRESS>).
    In addition to these general uncertainties with risk assessments,
the Administrator notes the concerns expressed by members of the CASAC
who support retaining the current standards. Their concerns largely
reflect their overall views on the limitations in the PM2.5
epidemiologic evidence, which provides key inputs to the risk
assessment. These committee members assert that ``the conclusions from
the risk assessment do not comprise valid empirical evidence or grounds
for revising the current NAAQS'' (Cox, 2019a, p. 9 consensus
responses). As discussed above, the Administrator agrees with the broad
concerns expressed by these members of the CASAC regarding associations
at PM2.5 concentrations meeting the current standards. He
further notes their concerns regarding the characterization of
uncertainty in the risk assessment and the evaluation of modeling
assumptions (Cox, 2019a). In light of these concerns, together with the
more general uncertainty in risk estimates summarized above, the
Administrator judges it appropriate to place little weight on
quantitative estimates of PM2.5-associated mortality risk in
reaching conclusions on the primary PM2.5 standards.
    When the above considerations are taken together, the Administrator
proposes to conclude that the scientific evidence that has become
available since the last review of the PM NAAQS, together with the
analyses in the PA based on that evidence, does not call into question
the public health protection provided by the current annual and 24-hour
PM2.5 standards. In particular, the Administrator judges
that there is considerable uncertainty in the potential public health
impacts of reductions in ambient PM2.5 below the
concentrations achieved under the current primary standards and,
therefore, that standards more stringent than the current standards
(e.g., with lower levels) are not supported. That is, he judges that
such standards would be more than requisite to protect the public
health with an adequate margin of safety. As described above, this
judgment reflects his consideration of the uncertainties in the
potential implications of recent 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 current standards.
    For the 24-hour standard, he notes that this judgment is consistent
with the consensus advice of the CASAC (Cox, 2019). For the annual
standard, this judgment is consistent with the advice of some CASAC
members and reflects the Administrator's disagreement with the
``[o]ther members of CASAC'' who recommend revising the current annual
standard based largely on evidence from recent epidemiology studies
(Cox, 2019a, p. 1 of letter).
    In addition, based on the Administrator's review of the science,
including experimental and accountability studies conducted at levels
just above the current standard, he judges that the degree of public
health protection provided by the current standard is not greater than
warranted. This judgment, together with the fact that no CASAC member
expressed support for a less stringent standard, leads the
Administrator to conclude that standards less stringent

than the current standards (e.g., with higher levels) are also not
supported.
    When the above information is taken together, the Administrator
proposes to conclude that the available scientific evidence and
technical information continue to support the current annual and 24-
hour PM2.5 standards. This proposed conclusion reflects the
fact that important limitations in the evidence remain. The
Administrator proposes to conclude that these limitations lead to
considerable uncertainty regarding the potential public health
implications of revising the existing suite of PM2.5
standards. Given this uncertainty, and the advice from some CASAC
members, he proposes to conclude that the current suite of primary
standards, including the current 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, remain requisite to protect the
public health. Therefore, the Administrator proposes to retain the
current suite of primary PM2.5 standards, without revision,
in this review. He solicits comment on this proposed decision and on
the supporting rationale described above.

III. Rationale for Proposed Decisions on the Primary PM10 Standard

    The current primary PM10 standard is intended to protect
the public health against exposures to PM10-2.5 (78 FR 3164,
January 15, 2013). This section provides the rationale supporting the
Administrator's proposed decision to retain the current primary
PM10 standard. Section III.A summarizes the Agency's
approach to reaching a decision on the primary PM10 standard
in the last review and presents the general approach to reaching a
proposed decision in this review. Section III.B summarizes the
scientific evidence for PM10-2.5-related health effects.
Section III.C presents the Administrator's proposed conclusions
regarding the adequacy of the current primary PM10 standard.

A. General Approach

1. Approach Used in the Last Review
    The last review of the PM NAAQS was completed in 2012 (78 FR 3086,
January 15, 2013). In that review the EPA retained the existing primary
24-hour PM10 standard, with its level of 150 [mu]g/m\3\ and
its one-expected-exceedance form on average over three years, to
continue to provide public health protection against exposures to
PM10-2.5. In support of this decision, the prior
Administrator emphasized her consideration of three issues: (1) The
extent to which it was appropriate to maintain a standard that provides
some measure of protection against all PM10-2.5 (regardless
of composition or source or origin), (2) the extent to which a standard
with a PM10 indicator can provide protection against
exposures to PM10-2.5, and (3) the degree of public health
protection provided by the existing PM10 standard. Her
consideration of each of these issues is summarized below.
    First, the prior Administrator judged that the evidence provided
``ample support for a standard that protects against exposures to all
thoracic coarse particles, regardless of their location or source of
origin'' (78 FR 3176, January 15, 2013). In support of this, she noted
that epidemiologic studies had reported positive associations between
PM10-2.5 and mortality or morbidity in a large number of
cities across North America, Europe, and Asia, encompassing a variety
of environments where PM10-2.5 sources and composition are
expected to vary widely. Though most of the available studies examined
associations in urban areas, she noted that some studies had also
linked mortality and morbidity with relatively high ambient
concentrations of particles of non-urban crustal origin. In light of
this body of available evidence, and consistent with the CASAC's
advice, the prior Administrator concluded that it was appropriate to
maintain a standard that provides some measure of protection against
exposures to all thoracic coarse particles, regardless of their
location, source of origin, or composition (78 FR 3176, January 15,
2013).
    In reaching the conclusion that it was appropriate to retain a
PM10 indicator for a standard meant to protect against
exposures to ambient PM10-2.5, the prior Administrator noted
that PM10 mass includes both coarse PM (PM10-2.5)
and fine PM (PM2.5). As a result, the concentration of
PM10-2.5 allowed by a PM10 standard set at a
single level declines as the concentration of PM2.5
increases. Because PM2.5 concentrations tend to be higher in
urban areas than rural areas, she observed that a PM10
standard would generally allow lower PM10-2.5 concentrations
in urban areas than in rural areas. She judged it appropriate to
maintain such a standard given that much of the evidence for
PM10-2.5 toxicity, particularly at relatively low particle
concentrations, came from study locations where thoracic coarse
particles were of urban origin, and given the possibility that
PM10-2.5 contaminants in urban areas could increase particle
toxicity. Thus, in the last review the prior Administrator concluded
that it remained appropriate to maintain a standard that allows lower
ambient concentrations of PM10-2.5 in urban areas, where the
evidence was strongest that exposure to thoracic coarse particles was
associated with morbidity and mortality, and higher concentrations in
non-urban areas, where the public health concerns were less certain.
The prior Administrator concluded that the varying concentrations of
coarse particles that would be permitted in urban versus non-urban
areas under the 24-hour PM10 standard, based on the varying
levels of PM2.5 present, appropriately reflected the
differences in the strength of evidence regarding coarse particle
health effects.
    Finally, in specifically evaluating the degree of public health
protection provided by the primary PM10 standard, with its
level of 150 [mu]g/m\3\ and its one-expected-exceedance form on average
over three years, the prior Administrator recognized that the available
health evidence and air quality information was much more limited for
PM10-2.5 than for PM2.5. In particular, the
strongest evidence for health effects attributable to
PM10-2.5 exposure was for cardiovascular effects,
respiratory effects, and/or premature mortality following short-term
exposures. For each of these categories of effects, the 2009 ISA
concluded that the evidence was ``suggestive of a causal relationship''
(U.S. EPA, 2009c, section 2.3.3). These determinations contrasted with
those for PM2.5, as described in Chapter 3 above, which were
determined in the ISA to be either ``causal'' or ``likely to be
causal'' for mortality, cardiovascular effects, and respiratory effects
(U.S. EPA, 2009c, Tables 2-1 and 2-2).
    The prior Administrator judged that the important uncertainties and
limitations associated with the PM10-2.5 evidence and
information raised questions as to whether additional public health
improvements would be achieved by revising the existing PM10
standard. She specifically noted several uncertainties and limitations,
including the following:
     The number of epidemiologic studies that have employed
copollutant models to address the potential for confounding,
particularly by PM2.5, was limited. Therefore, the extent to
which PM10-2.5 itself, rather than one or more copollutants,
contributes to reported health effects remained uncertain.
     Only a limited number of experimental studies provided
support for the associations reported in epidemiologic studies,
resulting in

further uncertainty regarding the plausibility of the associations
between PM10-2.5 and mortality and morbidity reported in
epidemiologic studies.
     Limitations in PM10-2.5 monitoring data (i.e.,
limited data available from FRM/FEM sampling methods) and the different
approaches used to estimate PM10-2.5 concentrations across
epidemiologic studies resulted in uncertainty in the ambient
PM10-2.5 concentrations at which the reported effects occur,
increasing uncertainty in estimates of the extent to which changes in
ambient PM10-2.5 concentrations would likely impact public
health.
     While PM10-2.5 effect estimates reported for
mortality and morbidity were generally positive, most were not
statistically significant, even in single-pollutant models. This
included effect estimates reported in some study locations with
PM10 concentrations above those allowed by the current 24-
hour PM10 standard.
     The composition of PM10-2.5, and the effects
associated with various components, were also key uncertainties in the
available evidence. Without more information on the chemical speciation
of PM10-2.5, the apparent variability in associations across
locations was difficult to characterize.
    In considering these uncertainties and limitations, the prior
Administrator particularly emphasized the considerable degree of
uncertainty in the extent to which health effects reported in
epidemiologic studies are due to PM10-2.5 itself, as opposed
to one or more co-occurring pollutants. This uncertainty reflected the
relatively small number of PM10-2.5 studies that had
evaluated copollutant models, particularly copollutant models that
included PM2.5, and the very limited body of controlled
human exposure evidence supporting the plausibility of
PM10-2.5-attributable adverse effects at ambient
concentrations.
    When considering the evidence as a whole, the prior Administrator
concluded that the degree of public health protection provided by the
current PM10 standard against exposures to
PM10-2.5 should be maintained (i.e., neither increased nor
decreased). Her judgment that protection did not need to be increased
was supported by her consideration of uncertainties in the overall body
of evidence. Her judgment that the degree of public health protection
provided by the current standard is not greater than warranted was
supported by the observation that positive and statistically
significant associations with mortality were reported in some single-
city U.S. study locations likely to have violated the current
PM10 standard. Thus, the prior Administrator concluded that
the existing 24-hour PM10 standard, with its one-expected
exceedance form on average over three years and a level of 150 [mu]g/
m\3\, was requisite to protect public health with an adequate margin of
safety against effects that have been associated with
PM10-2.5. In light of this conclusion, the EPA retained the
existing PM10 standard.
2. Approach in the Current Review
    The approach for this review builds on the last review, taking into
account the more recent scientific information now available. The
approach summarized below draws from the approach taken in the PA (U.S.
EPA, 2020) and is most fundamentally based on using the ISA's
assessment of the current scientific evidence for health effects of
PM10-2.5 exposures (U.S. EPA, 2019).
    As discussed above for PM2.5 (II.A.2), the approach in
the PA places the greatest weight on effects for which the evidence has
been determined to demonstrate a ``causal'' or a ``likely to be
causal'' relationship with PM exposures (U.S. EPA, 2019). This approach
focuses policy considerations and conclusions on health outcomes for
which the evidence is strongest. Unlike for PM2.5, the ISA
does not identify any PM10-2.5-related health outcomes for
which the evidence supports either a ``causal'' or a ``likely to be
causal'' relationship. Thus, for PM10-2.5 the PA considers
the evidence determined to be ``suggestive of, but not sufficient to
infer, a causal relationship,'' recognizing the greater uncertainty in
such evidence.
    The preamble to the ISA states that ``suggestive'' evidence is
``limited, and chance, confounding, and other biases cannot be ruled
out'' (U.S. EPA, 2015, Preamble Table II). In light of the additional
uncertainty in the evidence for PM10-2.5-related health
outcomes, compared to the evidence supporting ``causal'' or ``likely to
be causal'' relationships for PM2.5, the approach to
evaluating the primary PM10 standard in this review is more
limited than the approach to evaluating the primary PM2.5
standards (discussed in II.A.2). Specifically, the approach for
PM10 does not include evaluations of air quality
distributions in locations of individual epidemiologic studies,
comparisons of experimental exposures with ambient air quality, or the
quantitative assessment of PM10-2.5 health risks. The
substantial uncertainty in such analyses, if they were to be conducted
based on the currently available PM10-2.5 health studies,
would limit their utility for informing conclusions on the primary
PM10 standard. Therefore, as discussed further below, the
focus of the evaluation of the primary PM10 standard is on
the overall body of evidence for PM10-2.5-related health
effects. This includes consideration of the degree to which
uncertainties in the evidence from the last review have been reduced
and the degree to which new uncertainties have been identified.

B. Health Effects Related to Thoracic Coarse Particle Exposures

    This section briefly outlines the key evidence for health effects
associated with PM10-2.5 exposures. This evidence is
discussed more fully in the ISA (U.S. EPA, 2019) and the PA (U.S. EPA,
2020, Chapter 4).
    While studies conducted since the last review have strengthened
support for relationships between PM10-2.5 exposures and
some health outcomes (discussed below), several key uncertainties in
the evidence from the last review have, to date, ``still not been
addressed'' (U.S. EPA, 2019, section 1.4.2, p. 1-41). For example,
epidemiologic studies available in the last review relied on various
methods to estimate PM10-2.5 exposures, and these methods
had not been systematically compared to evaluate spatial and temporal
correlations in exposure estimates. Methods included (1) calculating
the difference between PM10 and PM2.5
concentrations at co-located monitors, (2) calculating the difference
between county-wide averages of monitored PM10 and
PM2.5 based on monitors that are not necessarily co-located,
and (3) direct measurement of PM10-2.5 using a dichotomous
sampler (U.S. EPA, 2019, section 1.4.2). In the current review, more
recent epidemiologic studies continue to use these approaches to
estimate PM10-2.5 concentrations. Additionally, some recent
studies estimate long-term PM10-2.5 exposures as the
difference between PM10 and PM2.5 concentrations
based on information from spatiotemporal or land use regression (LUR)
models, in addition to monitors. As in the last review, the various
methods used to estimate PM10-2.5 concentrations have not
been systematically evaluated (U.S. EPA, 2019, section <IP_ADDRESS>),
contributing to uncertainty regarding the spatial and temporal
correlations in PM10-2.5 concentrations across methods and
in the PM10-2.5 exposure estimates used in epidemiologic
studies (U.S. EPA, 2019, section <IP_ADDRESS>.3 and section <IP_ADDRESS>.3).
Given the greater spatial and temporal variability of
PM10-2.5 and fewer PM10-2.5 monitoring sites,
compared to PM2.5,

this uncertainty is particularly important for the coarse size
fraction.
    Beyond uncertainty associated with PM10-2.5 exposure
estimates in epidemiologic studies, the limited information on the
potential for confounding by copollutants and the limited support
available for the biological plausibility of serious effects following
PM10-2.5 exposures also continue to contribute broadly to
uncertainty in the PM10-2.5 health evidence. Uncertainty
related to potential confounding stems from the relatively small number
of epidemiologic studies that have evaluated PM10-2.5 health
effect associations in copollutants models with both gaseous pollutants
and other PM size fractions. Uncertainty related to the biological
plausibility of serious effects caused by PM10-2.5 exposures
results from the small number of controlled human exposure and animal
toxicology \44\ studies that have evaluated the health effects of
experimental PM10-2.5 inhalation exposures. The evidence
supporting the ISA's ``suggestive'' causality determinations for
PM10-2.5, including uncertainties in this evidence, is
summarized below in sections III.B.1 to III.B.7.
---------------------------------------------------------------------------

    \44\ Compared to humans, smaller fractions of inhaled
PM10-2.5 penetrate into the thoracic regions of rats and
mice (U.S. EPA, 2019, section 4.1.6), contributing to the relatively
limited evaluation of PM10-2.5 exposures in animal
studies.
---------------------------------------------------------------------------

1. Mortality
a. Long-Term Exposures
    Due to the dearth of studies examining the association between
long-term PM10-2.5 exposure and mortality, the 2009 PM ISA
concluded that the evidence was ``inadequate to determine if a causal
relationship exists'' (U.S. EPA, 2009c). Since the completion of the
2009 ISA, some recent cohort studies conducted in the U.S. and Europe
report positive associations between long-term PM10-2.5
exposure and total (nonaccidental) mortality, though results are
inconsistent across studies (U.S. EPA, 2019, Table 11-11). The
examination of copollutant models in these studies remains limited and,
when included, PM10-2.5 effect estimates are often
attenuated after adjusting for PM2.5 (U.S. EPA, 2019, Table
11-11). Across studies, PM10-2.5 exposure concentrations are
estimated using a variety of approaches, including direct measurements
from dichotomous samplers, calculating the difference between
PM10 and PM2.5 concentrations measured at
collocated monitors, and calculating difference of area-wide
concentrations of PM10 and PM2.5. As discussed
above, temporal and spatial correlations between these approaches have
not been evaluated, contributing to uncertainty regarding the potential
for exposure measurement error (U.S. EPA, 2019, section <IP_ADDRESS> and
Table 11-11). The 2019 ISA concludes that this uncertainty ``reduces
the confidence in the associations observed across studies'' (U.S. EPA,
2019, p. 11-125). The ISA additionally concludes that the evidence for
long-term PM10-2.5 exposures and cardiovascular effects,
respiratory morbidity, and metabolic disease provide limited biological
plausibility for PM10-2.5-related mortality (U.S. EPA, 2019,
sections 11.4.1 and 11.4). Taken together, the 2019 ISA concludes that,
``this body of evidence is suggestive, but not sufficient to infer,
that a causal relationship exists between long-term PM10-2.5
exposure and total mortality'' (U.S. EPA, 2019, p. 11-125).
b. Short-Term Exposures
    The 2009 ISA concluded that the evidence is ``suggestive of a
causal relationship between short-term exposure to PM10-2.5
and mortality'' (U.S. EPA, 2009c). Since the completion of the 2009
ISA, multicity epidemiologic studies conducted primarily in Europe and
Asia continue to provide consistent evidence of positive associations
between short-term PM10-2.5 exposure and total
(nonaccidental) mortality (U.S. EPA, 2019, Table 11-9). Although these
studies contribute to increasing confidence in the PM10-2.5-
mortality relationship, the use of a variety of approaches to estimate
PM10-2.5 exposures continues to contribute uncertainty to
the associations observed. In addition, the 2019 ISA notes that an
analysis by Adar et al. (2014) indicates ``possible evidence of
publication bias, which was not observed for PM2.5'' (U.S.
EPA, 2019, section 11.3.2, p. 11-106). Recent studies expand the
assessment of potential copollutant confounding of the
PM10-2.5-mortality relationship and provide evidence that
PM10-2.5 associations generally remain positive in
copollutant models, though associations are attenuated in some
instances (U.S. EPA, 2019, section <IP_ADDRESS>, Figure 11-28, Table 11-
10). The 2019 ISA concludes that, overall, the assessment of potential
copollutant confounding is limited due to the lack of information on
the correlation between PM10-2.5 and gaseous pollutants and
the small number of locations in which copollutant analyses have been
conducted. Associations with cause-specific mortality provide some
support for associations with total (nonaccidental) mortality, though
associations with cause-specific mortality, particularly respiratory
mortality, are more uncertain (i.e., wider confidence intervals) and
less consistent (U.S. EPA, 2019, section 11.3.7). The ISA concludes
that the evidence for PM10-2.5-related cardiovascular and
respiratory effects provides only limited support for the biological
plausibility of a relationship between short-term PM10-2.5
exposure and cardiovascular mortality (U.S. EPA, 2019, Section 11.3.7).
Based on the overall evidence, the 2019 ISA concludes that, ``this body
of evidence is suggestive, but not sufficient to infer, that a causal
relationship exists between short-term PM10-2.5 exposure and
total mortality'' (U.S. EPA, 2019, p. 11-120).
2. Cardiovascular Effects
a. Long-term Exposures
    In the 2009 PM ISA, the evidence describing the relationship
between long-term exposure to PM10-2.5 and cardiovascular
effects was characterized as ``inadequate to infer the presence or
absence of a causal relationship.'' The limited number of epidemiologic
studies reported contradictory results and experimental evidence
demonstrating an effect of PM10-2.5 on the cardiovascular
system was lacking (U.S. EPA, 2019, section 6.4).
    The evidence relating long-term PM10-2.5 exposures to
cardiovascular mortality remains limited, with no consistent pattern of
associations across studies and, as discussed above, uncertainty
stemming from the use of various approaches to estimate
PM10-2.5 concentrations (U.S. EPA, 2019, Table 6-70). The
evidence for associations with cardiovascular morbidity has grown and,
while results across studies are not entirely consistent, some
epidemiologic studies report positive associations with IHD and
myocardial infarction (MI) (U.S. EPA, 2019, Figure 6-34); stroke (U.S.
EPA, 2019, Figure 6-35); atherosclerosis (U.S. EPA, 2019, section
6.4.5); venous thromboembolism (VTE) (U.S. EPA, 2019, section 6.4.7);
and blood pressure and hypertension (U.S. EPA, 2019, Section 6.4.6).
PM10-2.5 cardiovascular mortality effect estimates are often
attenuated, but remain positive, in copollutants models that adjust for
PM2.5. For morbidity outcomes, associations are inconsistent
in copollutant models that adjust for PM2.5, NO2,
and chronic noise pollution (U.S. EPA, 2019, p. 6-276). The lack of
toxicological evidence for long-term PM10-2.5 exposures
represents a substantial data gap (U.S. EPA, 2019, section 6.4.10),
resulting in the 2019

ISA conclusion that ``evidence from experimental animal studies is of
insufficient quantity to establish biological plausibility'' (U.S. EPA,
2019, p. 6-277). Based largely on the observation of positive
associations in some high-quality epidemiologic studies, the ISA
concludes that ``evidence is suggestive of, but not sufficient to
infer, a causal relationship between long-term PM10-2.5
exposure and cardiovascular effects'' (U.S. EPA, 2019, p. 6-277).
b. Short-Term Exposures
    The 2009 ISA found that the available evidence for short-term
PM10-2.5 exposure and cardiovascular effects was
``suggestive of a causal relationship.'' This conclusion was based on
several epidemiologic studies reporting associations between short-term
PM10-2.5 exposure and cardiovascular effects, including IHD
hospitalizations, supraventricular ectopy, and changes in heart rate
variability (HRV). In addition, dust storm events resulting in high
concentrations of crustal material were linked to increases in total
cardiovascular disease emergency department visits and hospital
admissions. However, the 2009 ISA noted the potential for exposure
measurement error and copollutant confounding in these epidemiologic
studies. In addition, there was only limited evidence of cardiovascular
effects from a small number of experimental studies (e.g. animal
toxicological studies and controlled human exposure studies) that
examined short-term PM10-2.5 exposures (U.S. EPA, 2009c,
section <IP_ADDRESS>). In the last review, key uncertainties included the
potential for exposure measurement error, copollutant confounding, and
limited evidence of biological plausibility for cardiovascular effects
following inhalation exposure (U.S. EPA, 2019, section 6.3.13).
    The evidence for short-term PM10-2.5 exposure and
cardiovascular outcomes has expanded since the last review, though
important uncertainties remain. The 2019 ISA notes that there are a
small number of epidemiologic studies reporting positive associations
between short-term exposure to PM10-2.5 and cardiovascular-
related morbidity outcomes. However, there is limited evidence to
suggest that these associations are biologically plausible, or
independent of copollutant confounding. The ISA also concludes that it
remains unclear how the approaches used to estimate PM10-2.5
concentrations in epidemiologic studies may impact exposure measurement
error. Taken together, the 2019 ISA concludes that ``the evidence is
suggestive of, but not sufficient to infer, a causal relationship
between short-term PM10-2.5 exposures and cardiovascular
effects'' (U.S. EPA, 2019, p. 6-254).
3. Respiratory Effects--Short-Term Exposures
    Based on a small number of epidemiologic studies observing
associations with some respiratory effects and limited evidence from
experimental studies to support biological plausibility, the 2009 ISA
(U.S. EPA, 2009c) concluded that the relationship between short-term
exposure to PM10-2.5 and respiratory effects is ``suggestive
of a causal relationship.'' Epidemiologic findings were consistent for
respiratory infection and combined respiratory-related diseases, but
not for COPD. Studies were characterized by overall uncertainty in the
exposure assignment approach and limited information regarding
potential copollutant confounding. Controlled human exposure studies of
short-term PM10-2.5 exposures found no lung function
decrements and inconsistent evidence for pulmonary inflammation. Animal
toxicological studies were limited to those using non-inhalation (e.g.,
intra-tracheal instillation) routes of PM10-2.5 exposure.
    Recent epidemiologic findings consistently link PM10-2.5
exposure to asthma exacerbation and respiratory mortality, with some
evidence that associations remain positive (though attenuated in some
studies of mortality) in copollutant models that include
PM2.5 or gaseous pollutants. Studies provide limited
evidence for positive associations with other respiratory outcomes,
including COPD exacerbation, respiratory infection, and combined
respiratory-related diseases (U.S. EPA, 2019, Table 5-36). As noted
above for other endpoints, an uncertainty in these epidemiologic
studies is the lack of a systematic evaluation of the various methods
used to estimate PM10-2.5 concentrations and the resulting
uncertainty in the spatial and temporal variability in
PM10-2.5 concentrations compared to PM2.5 (U.S.
EPA, 2019, sections <IP_ADDRESS>.3 and <IP_ADDRESS>). Taken together, the 2019
ISA concludes that ``the collective evidence is suggestive of, but not
sufficient to infer, a causal relationship between short-term
PM10-2.5 exposure and respiratory effects'' (U.S. EPA, 2019,
p. 5-270).
4. Cancer--Long-Term Exposures
    In the last review, little information was available from studies
of cancer following inhalation exposures to PM10-2.5. Thus,
the 2009 ISA determined the evidence was ``inadequate to assess the
relationship between long-term PM10-2.5 exposures and
cancer'' (U.S. EPA, 2009c). Since the 2009 ISA, the assessment of long-
term PM10-2.5 exposure and cancer remains limited, with a
few recent epidemiologic studies reporting positive, but imprecise,
associations with lung cancer incidence. Uncertainty remains in these
studies with respect to exposure measurement error due to the use of
PM10-2.5 predictions that have not been validated by
monitored PM10-2.5 concentrations (U.S. EPA, 2019, sections
<IP_ADDRESS> and 10.3.4). Relatively few experimental studies of
PM10-2.5 have been conducted, though available studies
indicate that PM10-2.5 exhibits two key characteristics of
carcinogens: Genotoxicity and oxidative stress. While limited, such
experimental studies provide some evidence of biological plausibility
for the findings in a small number of epidemiologic studies (U.S. EPA,
2019, section 10.3.4).
    Taken together, the small number of epidemiologic and experimental
studies, along with uncertainty with respect to exposure measurement
error, contribute to the determination in the 2019 ISA that, ``the
evidence is suggestive of, but not sufficient to infer, a causal
relationship between long-term PM10-2.5 exposure and
cancer'' (U.S. EPA, 2019, p. 10-87).
5. Metabolic Effects--Long-Term Exposures
    The 2009 ISA did not make a causality determination for
PM10-2.5-related metabolic effects. Since the last review,
one epidemiologic study shows an association between long-term
PM10-2.5 exposure and incident diabetes, while additional
cross-sectional studies report associations with effects on glucose or
insulin homeostasis (U.S. EPA, 2019, section 7.4). As discussed above
for other outcomes, uncertainties with the epidemiologic evidence
include the potential for copollutant confounding and exposure
measurement error (U.S. EPA, 2019, Tables 7-15 and 7-15). The evidence
base to support the biological plausibility of metabolic effects
following PM10-2.5 exposures is limited, but a cross-
sectional study that investigated biomarkers of insulin resistance and
systemic and peripheral inflammation may support a pathway leading to
type 2 diabetes (U.S. EPA, 2019, sections 7.4.1 and 7.4.3). Based on
the expanded, though still limited evidence base, the 2019 ISA
concludes that, ``[o]verall, the evidence is

suggestive of, but not sufficient to infer, a causal relationship
between [long]-term PM10-2.5 exposure and metabolic
effects'' (U.S. EPA, 2019, p. 7-56).
6. Nervous System Effects--Long-Term Exposures
    The 2009 ISA did not make a causality determination for
PM10-2.5-related nervous system effects. In the current
review, newly available epidemiologic studies report associations
between PM10-2.5 and impaired cognition and anxiety in
adults in longitudinal analyses (U.S. EPA, 2019, Table 8-25, section
8.4.5). Associations of long-term exposure with neurodevelopmental
effects are not consistently reported in children (U.S. EPA, 2019,
sections 8.4.4 and 8.4.5). Uncertainties in these studies include the
potential for copollutant confounding, as no studies examined
copollutants models (U.S. EPA, 2019, section 8.4.5), and for exposure
measurement error, given the use of various model-based subtraction
methods to estimate PM10-2.5 concentrations (U.S. EPA, 2019,
Table 8-25). In addition, there is only limited animal toxicological
evidence supporting the biological plausibility of nervous system
effects (U.S. EPA, 2019, sections 8.4.1 and 8.4.5). Overall, the 2019
ISA concludes that, ``the evidence is suggestive of, but not sufficient
to infer, a causal relationship between long-term PM10-2.5
exposure and nervous system effects (U.S. EPA, 2019, p. 8-75).

C. Proposed Conclusions on the Current Primary PM10 Standard

    This section describes the Administrator's proposed conclusions
regarding the adequacy of the current primary PM10 standard.
The approach to reaching these proposed conclusions draws from the
ISA's assessment of the scientific evidence for health effects
attributable to PM10-2.5 exposures (U.S. EPA, 2019). Section
III.C.1 discusses the evidence-based considerations from the PA.
Section III.C.2 summarizes CASAC advice on the current primary
PM10 standard, based on its review of the draft PA. Section
III.C.3 presents the Administrator's proposed conclusions on the
current primary PM10 standard.
1. Evidence-Based Considerations in the Policy Assessment
    In the last review, the strongest evidence for PM10-2.5-
related health effects was for cardiovascular effects, respiratory
effects, and premature mortality following short-term exposures. For
each of these categories of effects, the ISA concluded that the
evidence was ``suggestive of a causal relationship'' (U.S. EPA, 2009c,
section 2.3.3). As summarized in the sections above, key uncertainties
in the evidence resulted from limitations in the approaches used to
estimate ambient PM10-2.5 concentrations in epidemiologic
studies, limited examination of the potential for confounding by co-
occurring pollutants, and limited support for the biological
plausibility of the serious effects reported in many epidemiologic
studies. Since 2009, the evidence base for several PM10-2.5-
related health effects has expanded, broadening our understanding of
the range of health effects linked to PM10-2.5 exposures
(U.S. EPA, 2020, Chapter 4). This includes expanded evidence for the
relationships between long-term exposures and cardiovascular effects,
metabolic effects, nervous system effects, cancer, and mortality.
However, key limitations in the evidence that were identified in the
2009 ISA persist in studies that have become available since the last
review. As discussed in the PA, these limitations include the
following:
     The use of a variety of methods to estimate
PM10-2.5 exposures in epidemiologic studies and the lack of
systematic evaluation of these methods, together with the relatively
high spatial and temporal variability in ambient PM10-2.5
concentrations and the small number of monitoring sites, results in
uncertainty in exposure estimates;
     The limited number of studies that evaluate
PM10-2.5 health effect associations in copollutant models,
together with evidence from some studies for attenuation of
associations in such models, results in uncertainty in the independence
of PM10-2.5 health effect associations from co-occurring
pollutants;
     The limited number of controlled human exposure and animal
toxicology studies of PM10-2.5 inhalation contributes to
uncertainty in the biological plausibility of the PM10-2.5-
related effects reported in epidemiologic studies.
    Thus, while new evidence is available for a broader range of health
outcomes in the current review, including an increase in the number of
studies that report effects related to long-term PM10-2.5
exposure, that evidence is subject to the same types of uncertainties
that were identified in the last review of the PM NAAQS. As in the last
review, these uncertainties contribute to the conclusions in the 2019
ISA that the evidence for the PM10-2.5-related health
effects discussed in this section is ``suggestive of, but not
sufficient to infer'' causal relationships.
2. CASAC Advice
    As part of its review of the draft PA, the CASAC has provided
advice on the adequacy of the public health protection afforded by the
current primary PM10 standard. As for PM2.5
(section II.C.2), the CASAC's advice is documented in a letter sent to
the EPA Administrator (Cox, 2019a).
    In its comments on the draft PA, the CASAC concurs with the draft
PA's overall preliminary conclusions that it is appropriate to consider
retaining the current primary PM10 standard without
revision. The CASAC finds the more limited approach taken for
PM10, compared with the approach taken for PM2.5,
to be ``reasonable and appropriate'' given the less certain evidence
and the conclusion that ``key uncertainties identified in the last
review remain'' (Cox, 2019a, p. 13 of consensus responses). To reduce
these uncertainties in future reviews, the CASAC recommends
improvements to PM10-2.5 exposure assessment, including a
more extensive network for direct monitoring of the PM10-2.5
fraction (Cox, 2019a, p. 13 of consensus responses). The CASAC also
recommends additional human clinical and animal toxicology studies of
the PM10-2.5 fraction to improve the understanding of
biological causal mechanisms and pathways (Cox, 2019a, p. 13 of
consensus responses). Overall, the CASAC agrees with the EPA that ``. .
. the available evidence does not call into question the adequacy of
the public health protection afforded by the current primary
PM10 standard and that evidence supports considering of
retaining the current standard in this review'' (Cox, 2019a, p. 3 of
letter).
3. Administrator's Proposed Decision on the Current Primary
PM10 Standard
    This section summarizes the Administrator's considerations and
proposed conclusions related to the current primary PM10
standard and presents his proposed decision to retain that standard,
without revision. As discussed above for PM2.5 (II.C.3), in
establishing primary standards under the Act that are ``requisite'' to
protect the public health with an adequate margin of safety, the
Administrator is seeking to establish standards that are neither more
nor less stringent than necessary for this purpose. He recognizes that
the Act does not require that primary standards be set at a zero-risk
level; rather, the NAAQS must be sufficiently protective, but not more
stringent than necessary.
    Given these requirements, and consistent with the primary
PM2.5

standards discussed above (II.C.3), the Administrator's final decision
in this review will be a public health policy judgment that draws upon
the scientific information examining the health effects of
PM10-2.5 exposures, including how to consider the range and
magnitude of uncertainties inherent in that information. His decision
will require judgments based on an interpretation of the science that
neither overstates nor understates its strengths and limitations, nor
the appropriate inferences to be drawn.
    As an initial matter, the Administrator notes that the decision to
retain the primary PM10 standard in the last review
recognized that epidemiologic studies had reported positive
associations between PM10-2.5 and mortality or morbidity in
cities across North America, Europe, and Asia. These studies
encompassed a variety of environments where PM10-2.5 sources
and composition were expected to vary widely. Although most of these
studies examined PM10-2.5 health effect associations in
urban areas, some studies had also linked mortality and morbidity with
relatively high ambient concentrations of particles of non-urban
crustal origin. Drawing from this evidence, the EPA judged it
appropriate to maintain a standard that provides some measure of
protection against exposures to PM10-2.5, regardless of
location, source of origin, or particle composition (78 FR 3176,
January 15, 2013). The Agency further judged it appropriate to retain a
PM10 standard to provide such protection given that the
varying concentrations of PM10-2.5 permitted in urban versus
non-urban areas under a PM10 standard, based on the varying
levels of PM2.5 present (i.e., lower PM10-2.5
concentrations allowed in urban areas, where PM2.5
concentrations tend to be higher), appropriately reflected differences
in the strength of PM10-2.5 health effects evidence.
    Since the last review, the Administrator notes that the evidence
for several PM10-2.5-related health effects has expanded,
particularly for long-term exposures. Recent epidemiologic studies
continue to report positive associations with mortality and morbidity
in cities across North America, Europe, and Asia, where
PM10-2.5 sources and composition are expected to vary
widely. While the Administrator recognizes that important uncertainties
remain, as described below, he also recognizes that the expansion in
the evidence since the last review has broadened the range of effects
that have been linked with PM10-2.5 exposures. Such studies
provide an important part of the body of evidence supporting the ISA's
strengthened causality determinations (and new determinations) for
long-term PM10-2.5 exposures and mortality, cardiovascular
effects, metabolic effects, nervous system effects and cancer (U.S.
EPA, 2019; U.S. EPA, 2020, section 4.2). Drawing from his consideration
of this evidence, the Administrator proposes to conclude that the
scientific studies that have become available since the last review do
not call into question the decision to maintain a primary
PM10 standard that provides some measure of public health
protection against PM10-2.5 exposures, regardless of
location, source of origin, or particle composition.
    With regard to uncertainties in the evidence, the Administrator
notes that the decision in the last review highlighted limitations in
estimates of ambient PM10-2.5 concentrations used in
epidemiologic studies, the limited evaluation of copollutant models to
address the potential for confounding, and the limited number of
experimental studies supporting biologically plausible pathways for
PM10-2.5-related effects. These and other limitations in the
PM10-2.5 evidence raised questions as to whether additional
public health improvements would be achieved by revising the existing
PM10 standard.
    In the current review, despite the expanded body of evidence for
PM10-2.5-related health effects, the Administrator
recognizes that similar uncertainties remain. As summarized above
(III.B), these include uncertainties in the PM10-2.5
exposure estimates used in epidemiologic studies, in the independence
of PM10-2.5 health effect associations, and in support for
the biological plausibility of PM10-2.5-related effects
(e.g., from controlled human exposure and animal toxicology studies)