# Chapter 1. Introduction

This Integrated Science Assessment (ISA) is a review, synthesis, and evaluation of the most policy-relevant evidence, and communicates criti cal science judgments relevant to the National Ambient Air Quality Standards (NAAQS) review. As such, the ISA forms the scientific foundation for the review of the primary (health-based) and secondary (welfare-based) NAAQS for particulate matter (PM). The ISA accurately reflects “the late st scientific knowledge useful in indicating the kind and extent of identifiable effects on public he alth which may be expected from the presence of [a] pollutant in ambient air” (42 U.S.C. 7408). Key information and judgments formerly contained in an Air Quality Criteria Document (AQCD) for PM are incorporated in this assessment. Additional details of the pertinent literature published since th e last review, as well as selected older studies of particular interest, are included in a series of anne xes. This ISA thus serves to update and revise the
evaluation of the scientific evidence available at the time of the previous review of the NAAQS for
PM that was concluded in 2006.
The Integrated Review Plan for the National Ambi ent Air Quality Standards for Particulate

Matter identifies a series of policy-relevant questions that provide a framework for this assessment of the scientific evidence (U.S. EPA, 2008, 157072 ). These questions frame the entire review of the NAAQS for PM, and thus are informed by both science and policy considerations. The ISA organizes and presents the scientific evidence such that, when considered along with findings from risk analyses and policy considerations, will help the EPA address these questions during the NAAQS review for PM. In evaluating the health evidence, the focus of this assessment will be on
scientific evidence that is most relevant to the following questions that have been taken directly from the Integrated Review Plan:

 Has new information altered the body of scien tific support for the occurrence of health effects following short- and/or long-term exposure to levels of fine and thoracic coarse particles found in the ambient air?

 Has new information altered conclusions from previous reviews regarding the plausibility of adverse health effects associated with exposures to PM 2.5 , PM 10 , PM 10-2.5 , or alternative PM indicators that might be considered?

 What evidence is available from recent st udies focused on specific size fractions, chemical components, sources, or environmen ts (e.g., urban and non-urban areas) of PM to inform our understanding of the nature of PM exposures that are linked to various
health outcomes?

 To what extent is key scientific evidence becoming available to improve our understanding of the health effects associated with various time periods of PM exposures, including not only short-term (daily or multi-day) and chronic (months to years) exposures, but also peak PM exposures (<24 hours)? To what extent is critical research becoming available that could improve our understanding of the relationship between various health endpoints and different lag periods (e.g., <1 day, single day, multi-day distributed lags)?

 What data are available to improve our understanding of spatial and/or temporal heterogeneity of PM exposures considering di fferent size fractions and/or components?

 At what levels of PM exposure do health effects of concern occur? Is there evidence for
the occurrence of adverse health effects at levels of PM lower than those observed previously? If so, at what levels and what are the important uncertainties associated with

Note: Hyperlinks to the reference citations throughout this doc ument will take you to the NCEA HERO database (Health and Environmental Research Online) at http://epa.gov/hero . HERO is a database of scientific literature used by U.S. EPA in the process of developing science assessments such as the Integrated Science Assessments (ISA) and the Integrated Risk Information System (IRIS)

.

December 2009 1-1that evidence? What is the nature of the dose-response relationships of PM for the
various health effects evaluated?

 What evidence is available linking particle number concentration with adverse health effects of UF particles?

 Do risk/exposure estimates suggest that exposures of concern for PM-induced health effects will occur with current ambient levels of PM or with levels that just meet the current standards? If so, are these risks/e xposures of sufficient magnitude such that the health effects might reasonably be judged to be important from a public health perspective? What are the important uncer tainties associated with these risk/exposure
estimates?

 To what extent is key evidence becoming available that could inform our understanding of subpopulations that are particularly sensitive or vulnerable to PM exposures? In the last review, sensitive or vulnerable subpopulations that appeared to be at greater risk for
PM-related effects included individuals with pre-existing heart and lung diseases, older adults, and children. Has new evidence become available to suggest additional sensitive subpopulations should be given increased focus in this review (e.g., fetuses, neonates, genetically susceptible subpopulations)?

 To what extent is key evidence becoming available to inform our understanding of populations that are particularly vulnerable to PM exposures? Specifically, is there new or emerging evidence to inform our understanding of geographical, spatial, SES, and environmental justice considerations?

 To what extent have important uncertainties identified in the last review been reduced and/or have new uncertainties emerged?

 To what extent is new information available to inform our understanding of non-PMexposure factors that might influence the a ssociations between PM levels and health effects being considered (e.g., weather-relate d factors; behavioral factors such as heating/air conditioning use; driving patterns; and time-activity patterns)?

In evaluating evidence on welfare effects of PM, the focus will be on evidence that can help inform these questions from the Integrated Review Plan:

 What new evidence is available on the relationship between PM mass/size fraction and/or specific PM components and visibility impairment and climate-related and other
welfare effects?

 To what extent has key scientific evidence now become available to improve our understanding of the nature and magnitude of visibility, climate, and ecosystem responses to PM and the variability associated with those responses (including ecosystem type, climatic conditions, environmental effects and interactions with other environmental factors and pollutants)?

 Do the evidence, the air quality assessment, and the risk/exposure assessment provide support for considering alternative averaging times?

 At what levels of ambient PM do visibility impairment and/or environmental effects of concern occur? Is there evidence for the occurrence of adverse visibility and other welfare-related effects at levels of PM lower than those observed previously? If so, at what levels and what are the important uncertainties associated with the evidence?

 Do the analyses suggest that PM-induced visi bility impairment and/or other welfareeffects will occur with current ambient levels of PM or with levels that just meet the current standards? If so, are these effects of sufficient magnitude and/or frequency such

December 2009 1-2that these effects might reasonably be judged to be important from a public welfare perspective? What are the uncertainties associated with these estimates?

 What new evidence and/or techniques are available to quantify the benefits of improved visibility and/or other welfare-related effects?

 To what extent have important uncertainties identified in the last review been reduced and/or have new uncertainties emerged?



# 1.1. Legislative Requirements

Two sections of the United States (U.S.) Clean Air Act (CAA, the Act) govern the
establishment and revision of the NAAQS. Section 108 of the Act (42 U.S.C. 7408) directs the Administrator to identify and list “air pollutants” that “in his judgment, may reasonably be anticipated to endanger public health and welfare” and whose “presence... in the ambient air results from numerous or diverse mobile or stationary sources” and to issue air quality criteria for those that are listed (42 U.S.C. 7408). Air quality criteria are in tended to “accurately reflect the latest scientific knowledge useful in indicating the kind and extent of identifiable effects on public health or welfare which may be expected from the presence of [a] pollutant in ambient air...” 42 U.S.C. 7408(b). Section 109 of the Act (42 U.S.C. 7409) direct s the Administrator to propose and promulgate “primary” and “secondary” NAAQS for pollutants li sted under Section 108. 42 U.S.C. 7409(a). Section 109(b)(1) defines a primary standard as one “the attainment and maintenance of which in the judgment of the Administrator, based on such criteria and allowing an adequate margin of safety, are requisite to protect the public health.” 1 42 U.S.C. 7409(b)(1). A secondary standard, as defined in Section 109(b)(2), must “specify a level of air quality the attainment and maintenance of which, in the judgment of the Administrator, based on such criteria, is required to protect the public welfare from any known or anticipated adverse effects associated with the presence of [the] pollutant in the
ambient air.” 2 42 U.S.C. 7409(b)(2). The requirement that primary standards include an adequate margin of safety was intended to
address uncertainties associated with inconclusive scientific and technical information available at the time of standard setting. It was also intended to provide a reasonable degree of protection against hazards that research has not yet identified. See Lead Industries Association v. EPA , 647 F.2d 1130, 1154 (D.C. Cir 1980), cert. denied, 449 U.S. 1042 (1980); American Petroleum Institute v. Costle

, 665 F.2d 1176, 1186 (D.C. Cir. 1981), cert. denied, 455 U.S. 1034 (1982); American Farm Bureau
Federation v. EPA , 559 F. 3d 512, 533 (D.C. Cir. 2009). Both kinds of uncertainties are components of the risk associated with pollution at levels below those at which human health effects can be said to occur with reasonable scientific certainty. Thus, in selecting primary standards that include an adequate margin of safety, the Administrator is seeking not only to prevent pollution levels that have been demonstrated to be harmful, but also to prevent lower pollutant levels that may pose an unacceptable risk of harm, even if the risk is not precisely identified as to nature or degree. In selecting a margin of safety, the EPA considers such factors as the nature and severity of the health effects involved, the size of the sensitive population(s) at risk, and the kind and degree of the uncertainties that must be addressed. The selection of any particular approach to providing an adequate margin of safety is a policy choice left specifically to the Administrator’s judgment. See
Lead Industries Association v. EPA , supra, 647 F.2d 1161-62. In setting standards that are “requisite” to prot ect public health and welfare, as provided in Section 109(b), the Administrator’s task is to esta blish standards that are neither more nor less

1 The legislative history of Section 109 indicates that a primary st andard is to be set at “the maximum permissible ambient air

level...which will protect the health of any [sensitive] group of the population,” and that for this purpose “reference should be made to a representative sample of persons comprising the sensitive group rather than to a single person in such a group” [S. Rep. No. 91 -1196, 91st Cong., 2d Sess. 10 (1970)].

2 Welfare effects as defined in Section 302(h) [42 U.S.C. 7602( h)] include, but are not limited to, “effects on soils, water, cr ops, vegetation,

man-made materials, animals, wildlife, weather, visibility and climate, damage to and deterioration of property, and hazards to transportation, as well as effects on economic values and on personal comfort and well-being.”

December 2009 1-3stringent than necessary. In so doing, EPA may not consider the costs of implementing the standards. See generally Whitman v. American Trucking Associations , 531 U.S. 457, 465-472, 475-76 (2001). Section 109(d)(1) requires that “not late r than December 31, 1980, and at 5-yr intervals thereafter, the Administrator shall complete a thorough review of the criteria published under Section 108 and the national ambient air quality standards...and shall make such
revisions in such criteria and standards and promulgate such new standards as may be appropriate...” 42 U.S.C. 7409(d)(1). Section 109( d)(2) requires that an independent scientific review...committee “shall complete a review of the criteria and the national primary and secondary ambient air quality standards...and shall recommen d to the Administrator any new standards and revisions of existing criteria and standards as may be appropriate...” 42 U.S.C. 7409(d)(2). Since the early 1980s, this independent review function ha s been performed by the Clean Air Scientific Advisory Committee (CASAC).



# 1.2. History of Reviews of the NAAQS for PM

PM is the generic term for a broad class of chemically and physically diverse substances that exist as discrete particles (liquid droplets or solids) over a wide range of sizes. Particles originate from a variety of anthropogenic stationary and mobile sources, as well as from natural sources. Particles may be emitted directly or formed in the atmosphere by transformations of gaseous emissions such as sulfur oxides (SO X ), nitrogen oxides (NO X ), and volatile organic compounds (VOC). The chemical and physical properties of PM vary greatly with time, region, meteorology, and source category, thus complicating the assessment of health and welfare effects. Table 1-1 summarizes the NAAQS that have been promulgated for PM to date. These reviews are briefly described below, and further details are provided in the Integrated Review Plan (U.S. EPA, 2008,

157072 ). EPA first established NAAQS for PM in 1971 (36 FR 8186, April 30, 1971), based on the original criteria document (NAPCA, 1969, 014684 ). The reference method specified for determining attainment of the original st andards was the high-volume sampler, which collects PM up to a nominal size of 25-45 micrometers (μm) (referred to as total suspended particulates [TSP]). The primary standards (measured by the indicator TSP) were 260 μg/m 3 , 24-h avg, not to be exceeded more than once per year, and 75 μg/m 3 , annual geometric mean. The secondary standard was 150 μg/m 3 , 24-h avg, not to be exceeded more than once per year. In October 1979 (44 FR 56730, October 2, 1979), EPA announced the first periodic review of the air quality criteria and NAAQS for PM, and significant revisions to the original standards were promulgated in 1987 (52 FR 24634, July 1, 1987). In that decision, EPA changed the indicator for particles from TSP to PM 10 , the latter including particles with a mean aerodynamic diameter 1 ≤ 10 μm, which delineated that subset of inhalable particles small enough to penetrate to th e thoracic region (including the tracheobronchial and alveolar regions) of the respiratory tract (referr ed to as thoracic particles). EPA also revised the level and form of the primary standards by (1) replacing the 24-h TSP standard with a 24-h PM 10 standard of 150 μg/m 3 with no more than one expected exceedence per year; and (2) replacing the
annual TSP standard with a PM 10 standard of 50 μg/m 3 , annual arithmetic mean, averaged over 3 yr.

1 The more precise term is 50% cut point or 50% diameter (d50). This is the aerodynamic particle diameter for which the efficiency of

particle collection is 50%. Larger particles are not excluded a ltogether, but are collected with substantially decreasing effic iency and smaller particles are collected with increasing (up to 100%) efficiency.

December 2009 1-4

### Table 1-1. Summary of NAAQS promulgated for PM, 1971-2006.

Year (Final Rule) Indicator Avg Time Level Form

24 h 260 μg/m 3 (primary) 150 μg/ m 3 (secondary) Not to be exceeded more than once per yr 1971 (36 FR 8186) TSP (Total Suspended Particulates) Annual 75 μg/m 3 (primary) Annual geometric mean

24 h 150 μg/m 3 Not to be exceeded more than once per yr on average over a 3-yr period 1987 (52 FR 24634) PM 10 Annual 50 μg/m 3 Annual arithmetic mean, averaged over 3 yr

24 h 65 μg/m 3 98th percentile, averaged over 3 yr PM 2.5 Annual 15 μg/m 3 Annual arithmetic mean, averaged over 3 yr 1

24 h 150 μg/m 3 Initially promulgated 99th percentile, averaged over 3 yr; when 1997 standards were vacated in 1999, the form of 1987 standards remained in place (not to be exceeded more than once per yr on average over a 3-yr period) 1997 (62 FR 38652)

PM 10

Annual 50 μg/m 3 Annual arithmetic mean, averaged over 3 yr

24 h 35 μg/m 3 98th percentile, averaged over 3 yr PM 2.5 Annual 15 μg/m 3 Annual arithmetic mean, averaged over 3 yr 2 2006 (71 FR 61144)

PM 10 24 h 150 μg/m 3 Not to be exceeded more than once per yr on average over a 3-yr period

Note: When not specified, primary and secondary standards are identical.

The secondary standard was revised by replacing it with 24-h and annual standards identical in all respects to the primary standards. The revisions also included a new reference method for the
measurement of PM 10 in the ambient air and rules for determining attainment of the new standards. On judicial review, the revised standa rds were upheld in all respects. See Natural Resources Defense
Council v. Administrator , 902 F. 2d 962 (D.C. Cir. 1990), cert. denied, 498 U.S. 1082 (1991). In April 1994, EPA announced its plans for th e second periodic review of the air quality criteria and NAAQS for PM, and promulgated significant revisions to the NAAQS in 1997 (62 FR 38652, July 18, 1997). In that decision, EPA re vised the PM NAAQS in several respects. Most significantly, EPA determined that the fine and coarse 3 fractions of PM 10 should be considered separately. The Administrator’s decision to modify the standards was based on evidence that serious health effects were associated with short- and long-t erm exposure to fine particles in areas that met the existing PM 10 standards. EPA accordingly added new standards, using PM 2.5 as the indicator for fine particles (with PM 2.5 referring to particles with a no minal mean aerodynamic diameter

≤ 2.5 μm), and PM 10 as the indicator for thoracic coarse particles or coarse-fraction particles (generally including particles with a nominal mean aerodynamic diameter >2.5 μm and ≤ 10 μm, or

PM 10-2.5 ). The EPA established two new PM 2.5 standards: an annual standard of 15 μg/m 3 , based on the 3-yr avg of annual arithmetic mean PM 2.5 concentrations from single or multiple community-oriented monitors; and a 24-h standard of 65 μg/m 3 , based on the 3-yr avg of the 98th percentile of 24-h PM 2.5 concentrations at each population-oriented monitor within an area. Also, EPA established a new reference method for measuring PM 2.5 in the ambient air and adopted protocols for determining attainment of the new sta ndards. To continue to address thoracic coarse particles, EPA retained the annual PM 10 standard, while revising the form, but not the level, of the

1 The level of the 1997 annual PM 2.5 standard was to be compared to measurements made at the community-oriented monitoring site

recording the highest level, or, if specific constraints were me t, measurements from multiple community-oriented monitoring sit es could be averaged (“spatial averaging”). This approach was judged to be consistent with the short-term epidemiologic studies on which the

annual PM 2.5 standard was primarily based, in which air quality data were generally averaged across multiple monitors in an area or were taken from a single monitor that was select ed to represent community-wide exposures, not localized “hot spots” (62 FR 38672). T hese

criteria and constraints were intended to ensure that spatial averaging would not re sult in inequities in the level of protecti on afforded by

the PM 2.5 standards. Community-oriented monitoring sites were specified to be consistent with the intent that a spatially averaged annua l standard provide protection for persons living in smaller co mmunities, as well as those in larger population centers.

2 In the revisions to the PM NAAQS finalized in 2006, EPA tightened the constraints on the spatial averaging criteria by further limiting

the conditions under which some areas may average measurements from multiple community-oriented mo nitors to determine complianc e (71 FR 61165-61167, October 17, 2006).

3 See definitions of “fine” and “coarse” particles in Section 3.2.

December 2009 1-524-h PM 10 standard to be based on the 99th percentile of 24-h PM 10 concentrations at each monitor in an area. The EPA revised the secondary standards by making them identical in all respects to the primary standards. Following promulgation of the 1997 PM NAAQS, petitions for review were filed by a large number of parties, addressing a broad range of issues. In May 1999, a three-judge panel of the U.S. Court of Appeals for the District of Columbia Circuit issued an initial decision that upheld EPA’s decision to establish fine particle standards, holding that “the growing empirical evidence demonstrating a relationship between fine partic le pollution and adverse health effects amply justifies establishment of ne w fine particle standards.” American Trucking Associations v. EPA (175 F. 3d 1027, 1055-56 (D.C. Cir. 1999); rehearing granted in part and denied in part, 195 F. 3d 4 (D.C. Cir. 1999), affirmed in part and reversed in part, Whitman v. American Trucking Associations 531 U.S. 457 (2001). The panel also found “ample support ” for EPA’s decision to regulate coarse particle pollution, but vacated the 1997 PM 10 standards, concluding that EPA had not provided a reasonable explanation justifying use of PM 10 as an indicator for coarse particles (175 F. 3d at 1054-55). Pursuant to the court’s decision, EPA removed the vacated 1997 PM 10 standards from the Code of Federal Regulations. The pre-existing 1987 PM 10 standards remained in place (65 FR 80776, December 22, 2000). The Court also upheld EPA’s de termination not to establish more stringent secondary standards for fine particles to addr ess effects on visibility (175 F. 3d at 1027). More generally, the panel held (over one judge’s dissent) that EPA’s approach to establishing the level of the standards in 1997, both for the PM and ozone (O 3 ) NAAQS promulgated on the same day, effected “an unconstitutional delegati on of legislative authority” (Id. at 1034-40). Although the panel stated that “the factors EPA use s in determining the degree of public health
concern associated with different levels of ozon e and PM are reasonable,” it remanded the rule to EPA, stating that when EPA considers these factors for potential non-threshold pollutants “ lacks is any determinate criterion for drawing lines ” to determine where the standards should be set. Consistent with EPA’s long-standing interpretati on and D.C. Circuit precedent, the panel also reaffirmed its prior holdings that in setting NAAQS EPA is “not permitted to consider the cost of implementing those standards” (Id what EPA

. at 1040-41). On EPA’s petition for rehearing, the panel adhered to its position on these points. American Trucking Associations v. EPA , 195 F. 3d 4 (D.C. Cir. 1999). The full Court of Appeals denied EPA’s suggestion for rehearing en banc, with five judges dissenting (Id. at 13). Both sides filed cross appeals on these issues to the U.S. Supreme Court, and the Court granted certiorari . In February 2001, the Supreme Court issued a unanimous decision upholding EPA’s position on both the constitutional and cost issues. Whitman v. American Trucking

Associations , 531 U.S. 457, 464, 475-76. On the constitutiona l issue, the Court held that the statutory requirement that NAAQS be “requisit e” to protect public health with an adequate margin of safety sufficiently guided EPA’s discretion, affirming EPA’s approach of setting standards that are neither more nor less stringent than necessary. The Su preme Court remanded the case to the Court of Appeals for resolution of any remaining issues that had not been addressed in that court’s earlier rulings (Id. at 475-76). In March 2002, the Court of Ap peals rejected all remaining challenges to the standards, holding under the traditional standard of judicial review that PM 2.5 standards were reasonably supported by the administrative r ecord and were not “arbitrary and capricious” American Trucking Associations v. EPA , 283 F. 3d 355, 369-72 (D.C. Cir. 2002). In October 1997, EPA published its plans for the th ird periodic review of the air quality criteria and NAAQS for PM (62 FR 55201). After CASAC an d public review, EPA finalized the 2004 PM AQCD (U.S. EPA, 2004, 056905 ) and 2005 Staff Paper (U.S. EPA, 2005, 090209 ). For the primary fine particle standards, most CASAC PM Panel me mbers favored the option of revising the level of
the 24-h PM 2.5 standard in the range of 35 to 30 μg/m 3 with a 98th percentile form, in concert with revising the level of the annual PM 2.5 standard in the range of 14 to 13 μg/m 3 (Henderson, 2005,

188316 ). Most of the members of the CASAC PM Pa nel also strongly supported establishing a new, secondary PM 2.5 standard to protect urban visibility and recommended establishing a sub-daily (4- to 8-h averaging time) PM 2.5 standard within the range of 20 to 30 μ g/m 3 with a form within the range of the 92nd to 98th percentile (Henderson, 2005, 188316 ). For thoracic coarse particles, there was general concurrence among CASAC PM Panel members to revise the PM 10 standards by establishing a primary standard specifically targeted to address particles in the size range of 2

μ m (PM .5 to 10

10-2.5 ) . The CASAC PM Panel was also in general ag reement “that coarse particles in urban or industrial areas are likely to be enriched by anthropogenic pollutants that tend to be inherently more toxic than the windblown crustal material which typically dominates coarse particle mass in

December 2009 1-6arid rural areas.” Based on its review of the Staff Paper, there was general agreement among the
CASAC PM Panel members that a 24-h PM 10-2.5 standard with a level in the range of 50 to 70 μg/m 3 with a 98th percentile form, was reasonably justified and that a PM ,

10-2.5 standard with an annual averaging time was not warranted (Henderson, 2005, 156537 ). On January 17, 2006, EPA proposed to revise the NAAQS for PM (71 FR 2620). For fine particles, EPA proposed to retain PM

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for 2.5 as the indicator, to retain standards for 24-h and annual exposures, and to revise the form of the annual standard to tighten conditions for demonstrating compliance using spatially averaged monitoring EPA also proposed to revise the level of the 24-h PM 2.5 standard to 35 μg/m 3 to provide increased protection against health effects associated with short-term PM 2.5 exposures, including premature mortality and increased hospital admission and emergency room visits, but proposed to retain th
level of the annual PM 2.5 standard at 15 μg/m 3 , continuing protection against health effects associated with long-term exposure including premature mortality and development of chronic respiratory disease. With regard to the primary st andards for thoracic coarse particles, EPA proposed
to revise the 24-h PM 10 standard in part by establishing a new indicator for thoracic coarse particles (particles generally between 2.5 and 10 μm in diam eter), qualified so as to include any ambient mix
of PM 10-2.5 that was dominated by resuspended dust from high density traffic on paved roads an generated by industrial sources and construction sources, and proposed to exclude any ambient mi
of PM 10-2.5 that was dominated by rural windblown dust and soils and PM 10-2.5 generated by agricultural and mining sources. EPA also proposed a detailed monitoring regime in conjunction wit this proposed indicator (71 FR 2710, 2731-42). The EPA proposed to set a 24-h standard (using proposed indicator) at a level of 70 μg/m 3 to continue to provide a level of protection against healt effects associated with short-term exposure (including hospital admissions for cardiopulmonary diseases, increased respiratory symptoms and possibl y premature mortality) in those areas where the proposed indicator was found, generally equivalent to the level of protection provided by the exist
24-h PM 10 standard. Also, EPA proposed to revoke, upon finalization of a primary 24-h standard thoracic coarse particles, the 24-h PM 10 standard as well as the annual PM 10 standard. EPA proposed to revise the secondary standards by making them identical to the suite of proposed primary standards for fine and coarse particles, providing protection against PM-related public welfare effects including visibility impair ment, effects on vegeta tion and ecosystems, and materials damage and soiling. EPA also solicited comment on adding a new sub-daily PM 2.5 secondary standard to address visibility impairment in urban areas. CASAC provided additional advice to EPA in a letter to the Administrator requesting
reconsideration of CASAC’s recommendati ons for both the primary and secondary PM 2.5 standards, as well as standards for thoracic coarse particles (Henderson, 2006, 156538 ). On September 21, 2006, EPA announced its final decisions to revise the primary and secondary NAAQS for PM to provide increased protection of public health and welfare, respectively (71 FR 61144). With regard to the primary and se condary standards for fine particles, EPA revised
the level of the 24-h PM 2.5 standard to 35 μg/m 3 , retained the level of the annual PM 2.5 standard at 15 μg/m 3 , and revised the form of the annual PM 2.5 standard by narrowing the constraints on the optional use of spatial averaging. EP A established the secondary standard for fine particles identical to the primary standards. With regard to the primary and secondary standards for thoracic coarse particles, EPA retained PM 10 as the indicator for coarse particles, retained the level and form of the
24-h PM 10 standard (so the standard remains 150 μg/m 3 with a one expected exceedence form) and
revoked the annual standard because available ev idence generally did not support a link between long-term exposure to current ambient levels of coar se particles and health or welfare effects. Following promulgation of the revised PM NAAQS in 2006, several parties filed petitions for review with respect to: (1) selecting the level of the annual primary PM 2.5 standard; (2) setting the secondary PM 2.5 standards identical to the primary standards; (3) retaining PM 10 as the indicator for coarse particles and retaining the level and form of the PM 10 24-h standard; and (4) revoking the

PM 10 annual standard. On judicial review, the D.C. Circuit remanded the annual standard for fine particles to EPA because EPA failed to adequately explain why the annual PM 2.5 standard provided the requisite protection from both short- and l ong-term exposures to fine particles including protection for vulnerable subpopulations. With respect to protection from short-term exposures, in 1997 EPA determined that the annual standard was the generally controlling standard for lowering both short- and long-term PM 2.5 concentrations and the 24-h standard was set to “provide an adequate margin of safety against infrequent or isolated peak concentrations that could occur in areas that attain the annual standard” (62 FR 38676-77, July 18, 1997). In the 2006 decision, the Administrator considered it appropriate to use a somewhat different evidence-based approach from

December 2009 1-7that used in 1997 to set the level of the 24-h and annual PM 2.5 standards. In that decision, the Administrator relied upon evidence from the short-term exposure PM 2.5 studies as the principal basis for selecting the proposed level of the 24-h standard and relied upon evidence from the long-term exposure PM 2.5 studies as the principal basis for selecting the level of the annual standard. The court found EPA failed to adequately explain this cha nge in approach in light of CASAC and staff’s recommendations to do otherwise. The court also found that EPA had failed to adequately explain why a short-term 24-h standard by itself would provide the protection needed from short-term

exposures. American Farm Bureau Federation v. EPA , 559 F. 3d 512, 520-24 (D.C. Cir. 2009). With respect to protection from long-term exposure, the cour t found that EPA failed to adequately explain how the current standard provided “an adequate margin of safety for vulnerable subpopulations, such as children, the elderly, or those with conditions that exposure them to greater risk from fine particles”. Specifically, EPA did not provide a reasonable explanation of why certain studies, including a study of children in Southern California showing lung damage from long-term exposure, did not call for a more stringent a nnual standard (Id. at 522-23). The court also remanded the secondary standard for fine particles, based on EPA’s failure to adequately explain why setting the secondary NAAQS equivalent to the pr imary standards provided the required protection for public welfare including protection from visibility impairment. The court found that EPA failed to identify a target level of visibility impairment that would be requisite to protect public welfare. This was contrary to the statute and resulted in a lack of a reasoned basis for the final decision. In addition, EPA’s near exclusive reliance on a comparison of numbers of counties that would be in nonattainment under various types of standards was an inadequate basis for making
a decision. It did not take into account the relative visibility protection of different standards, as well as the failure of a 24-h standard to address regional differences in humidity and its effect on visibility (Id. at 528-31). The court upheld EPA’s decision to retain the 24-h PM 10 standard to provide protection for coarse particle exposures and to revoke the annual PM 10 standard. The court found that EPA reasonably included all coarse PM within the standard, both urban and non-urban, to provide nationwide protection for exposure to coarse PM. It rejected arguments that the evidence showed there are no risks from exposure to non-urban coarse PM (Id. at 531-33). The court further found that EPA had a reasonable basis to not set separate st andards for urban and non-urban coarse PM, namely the inability to reasonably define what ambient mixes would be included under either “urban” or “non-urban.” In addition, the court found that record evidence supported EPA’s cautious decision to provide “some protection from exposure to thoracic coarse particles... in all areas.” The court also upheld EPA’s decision to use PM 10 as the indicator for coarse partic les and to retain the level of the standard at 150 μg/m 3 . EPA’s final rule acknowledged that evidence of harm from urban-type coarse PM is stronger than for other types, and targeted protection at areas where urban-type coarse PM is most likely present. The targeting is done by using the indicator PM 10 for coarse particles. PM 10 includes both coarse PM and fine PM. Urban and indust rial areas tend to have higher levels of fine PM than rural areas, so that in those areas less coarse PM is allowed – the desired targeting. Conversely, fine PM levels tend to be lower in ru ral areas, so more coarse particles are allowed in those areas – again the desired targeting. Likewise, the court concluded that the EPA’s choice of the
level for the PM 10 standard was reasonable for many of the same reasons (Id. at 533-36). The court also upheld EPA’s decision to revoke the annual PM 10 standard (Id. at 537-38).



# 1.3. ISA Development

EPA initiated the current formal review of the NAAQS for PM on June 28, 2007 with a call for information from the public (72 FR 35462). In additi on to the call for information, publications were identified through an ongoing literature search pr ocess that includes extensive computer database mining on specific topics. Literature searches were conducted routinely to identify studies published since the last review, focusing on publications from 2002 to May 2009. Search strategies were iteratively modified in an effort to optimize the identification of pertinen t publications. Additional papers were identified for inclusion in several ways : review of pre-publication tables of contents for journals in which relevant papers may be published; independent identification of relevant literature by expert authors; and identification by the public and CASAC during the external review process. Generally, only information that had undergone sc ientific peer review and had been published or

December 2009 1-8accepted for publication was considered. All releva nt epidemiologic, controlled human exposure, animal toxicological, and welfare effects studies p ublished since the last review were considered, including those related to exposure-response relatio nships, mode(s) of action (MOA), or susceptible populations. In general, in assessing the scientific quality a nd relevance of health and environmental effects studies, the following considerations have been taken into account when selecting studies for inclusion in the ISA or its annexes. The selection process for studies included in this ISA is shown in Figure 1-1

.

 Are the study populations, subjects, or animal models adequately selected and are they sufficiently well defined to allow for meaningful comparisons between study or exposure groups?

 Are the statistical analyses appropriate, pr operly performed, and properly interpreted? Are likely covariates adequately controlled or taken into account in the study design and statistical analysis?

 Are the PM aerometric data, exposure, or dose metrics of adequate quality and sufficiently representative of information regarding ambient PM?

 Are the health or welfare effect measurements meaningful and reliable?

In selecting epidemiologic studies, EPA considered whether a given study contained information on associations with short- or long-term PM exposures at or near ambient levels of PM; evaluated health effects of PM size fractions, components or source-related indicators; considered approaches to evaluate issues related to potential confounding by other pollutants; assessed potential effect modifiers; and evaluated important metho dological issues (e.g., lag or time period between exposure and effects, model specifications, thresholds, mortality displacement) related to interpretation of the health evidence. Among the ep idemiologic studies selected, particular emphasis was placed on those studies most relevant to the review of the NAAQS. Specifically, studies
conducted in the U.S. or Canada were discussed in more detail than those from other geographical regions. Particular emphasis was placed on: (1) re cent multicity studies that employ standardized analysis methods for evaluating effects of PM and that provide overall estimates for effects based on combined analyses of information pooled across multiple cities; (2) studies that help understand quantitative relationships between exposure concentrations and effects; (3) recent studies (published since the last PM NAAQS review) that provide ev idence on effects in susceptible populations; and (4) studies that consider and report PM as a co mponent of a complex mixture of air pollutants.

December 2009 1-9

### Figure 1-1. Identification of st udies for inclusion in the ISA.

December 2009 1-10Criteria for the selection of research ev aluating controlled human exposure or animal toxicological studies included a focus on studies conducted using relevant pollutant exposures. For both types of studies, relevant pollutant exposures ar e considered to be those generally within one or two orders of magnitude of ambient PM concentrations. Studies in which higher doses were used may also be considered if they provide information relevant to understanding MOAs or mechanisms,
as noted below. Evaluation of controlled human exposure studies focused on those that approximated expected human exposure conditions in terms of concentrati on and duration. In the selection of controlled human exposure studies, emphasis is placed on studi es that: (1) investigate potentially susceptible populations such as people with cardiovascular dise ases or asthmatics, particularly studies that compare responses in susceptible individuals with those in age-matched healthy controls; (2) address issues such as concentration-response or time-cou rse of responses; (3) investigate exposure to PM separately and in combination with other pollutants such as O 3 ; (4) include control exposures to filtered air; and (5) have sufficient statistical power to assess findings. For selecting toxicological studies for highlighti ng in the text, emphasis is placed on inhalation studies conducted at concentrations <2 mg/m 3 and those studies that approximate expected human dose conditions in terms of concentration, size dist ributions, and duration, which will depend on the toxicokinetics and biological sensitivity of the par ticular laboratory animals examined. Studies that elucidated MOAs and/or susceptibility, particularly if the studies were conducted under atmospherically relevant conditions, were emphas ized whenever possible. A limited number of toxicological studies were included that employed intratracheal (IT) instillation techniques, mainly
for PM 10-2.5 studies in rodents, that explored new emerging areas of investigation (e.g., vasomotor function), or that evaluated specific potential MOA or mechanisms of response. The sources, transport, and fate of fibers and unique nano-mater ials (viz., dots, hollow spheres, rods, fibers, tubes) are not reviewed herein because the in vivo disposition of these unique nanomaterials is not necessarily relevant to the behavior of ultrafine (UF) aerosols in the urban environment that are created by combustion sources and photochemical formation of secondary organic aerosols. In considering the potential effects of different components of PM, EPA has focused on studies that have assessed effects for a range of PM sources or components, including those using source apportionment methods or comparing effects for numerous PM components, and not on studies of individual constituents or species. Studies of ubiquit ous PM sources as part of a mixture (i.e., diesel exhaust, gasoline exhaust, wood smoke) are includ ed, provided they meet the other remaining
selection criteria. Those studies of mixtures that are not a significant source of ambient PM, such as environmental tobacco smoke (ETS), are not included. These criteria provide benchmarks for evalua ting various studies and for focusing on the policy relevant studies in assessing the body of health and welfare effects evidence. Detailed critical analysis of all PM health and welfare effects studies, especially in relation to the above considerations, is beyond the scope of this document. Of most relevance for evaluation of studies is whether they provide useful qualitative or quantitative information on exposure-effect or exposure-response relationships for effects associated with current ambient air concentrations of PM
that can inform decisions on whether to retain or revise the standards. In developing the PM ISA, EPA began by reviewing and summarizing the evidence on (1) atmospheric sciences and exposure; (2) the health effects evidence from in vivo and in vitro animal toxicological, controlled human exposure, and epidemiologic studies; and (3) the welfare effects of PM, including visibility, climate, and ecological effects. In June 2008, EPA held a workshop to
obtain review of the scientific content of initial dr aft materials or sections for the draft ISA and its annexes, that primarily contain summary informa tion. The purpose of the initial peer review workshop was to ensure that the ISA is up to date and focused on the most policy-relevant findings, and to assist EPA with integration of evidence within and across disciplines. Following the peer review workshop, EPA addressed comments from the peer review workshop and completed the initial integration and synthesis of the evidence. The integration of evidence on health or welfare effects involves collaboration between scientists from various disciplines. As described in the section below, the ISA organization is based on health or welfare effect categories. As an example, an evaluation of health effects evidence would include summaries of findings from epidemiologic, controlled human exposure, and toxicological studies, and integration of the results to draw conclusions based on the causal framework described below. Using the causal framework described in Section 1.5 , EPA scientists consider aspects such as strength, consistency, coherence and biological pl ausibility of the evidence, and develop draft

December 2009 1-11causality judgments on the nature of the relationshi ps. The draft integrative synthesis sections and conclusions are reviewed by EPA internal experts and, as appropriate, by outside expert authors. In practice, causality determinations often entail an iterative process of review and evaluation of the evidence. The draft ISA is released for review by the CASAC and the public. Comments on the characterization of the science as well as the implementation of the causal framework are carefully considered in revising and completing the ISA.

PM 10 health studies are included in this assessment because they provide important evidence regarding the health effects of PM in general. However, the ISA draws no conclusions regarding causality for short- or long-term exposure to PM , as 10 PM 10 is comprised of both fine and thoracic coarse particles. As a result, causa lity determinations are limited to PM 2.5 , PM 10-2.5 , and UF particle (UFP) size fractions. In the cases where it was determined that PM 10 is dominated by fine or thoracic coarse PM in specific study locations, these health studies are used in supporting the causality
determinations for PM 2.5 or PM 10-2.5 . Epidemiologic studies of short-term exposure to PM 10 are also relied upon to examine potential effect modifier s, potential confounding by copollutants, and the influence of different modeling approaches on PM-mortality risk estimates, as well as the concentration-response relationship between PM and mo rtality. Therefore, to the extent possible, the findings of PM 10 studies are considered insofar as they provi de information relevant to the review of the NAAQS for fine and thoracic coarse particles.



# 1.4. Document Organization

This ISA is composed of nine chapters. This introductory chapter presents background information, and provides an overview of EP A’s framework for making causal judgments. Key findings and conclusions for consideration in the review of the NAAQS for PM from the atmospheric sciences, ambient air data analyses, exposure assessment, dosimetry, health and welfare effects, including judgments on causality for the he alth and welfare effect s of PM exposure, are presented in Chapter 2. More detailed summaries, evaluations and integration of the evidence are included in Chapters 3 through 9. Chapter 3 highlights key concepts or issues relevant to understanding the atmospheric chemistry, sources, and exposure of and to PM following a “source-to-exposure” paradigm. Chapter 4 summarizes key concepts and recen t findings on the dosimetry of PM, and Chapter 5 discusses possible pathways and MOA for the effects of PM. Chapters 6 and 7 evaluate and integrate epidemiologic, controlled human exposure, and an imal toxicological information relevant to the review of the primary NAAQS for PM. Health effects related to short-term exposures (hours to days) to PM are the focus of Chapter 6. Chapter 7 eval uates health evidence related to long-term exposures (months to years) to PM. Chapters 6 and 7 are or ganized by health outcome categories, such as cardiovascular or respiratory effects, and each s ection includes effects of the various types of PM studied. For each health outcome category, summary sections then integrate the findings to draw conclusions on the evidence for the main size classes of PM (i.e., PM 2.5 , PM 10-2.5 , and UFP). Chapter 6 also includes a summary and synthesis of the recent health evidence that uses systematic approaches to assess health effects of sources and constituents of ambient PM; most such studies have evaluated effects of short-term exposure. Chap ter 8 evaluates evidence related to populations potentially susceptible to PM-related effects. Chapter 9 evaluates welfare effects evidence that is relevant to the review of the secondary NAAQS for PM. This chapter incl udes consideration of effects of PM on visibility impairment, materials damage, effects of PM on climate, and ecological effects of PM that were not addressed in the Integrated Science Assessment for Oxides of Nitrogen and Sulfur

― Ecological Criteria (NO X SO X ISA) (U.S. EPA, 2008, 157074 ). The chapter also presents key conclusions and scientific judgments regarding causality for welfare ef fects of PM. In 2008, EPA completed the NO X SO X ISA (U.S. EPA, 2008, 157074 ), that focused on ecological effects related to the deposition of nitrogen (N)- and sulfur (S)-containing compounds. The 2008 NO X SO X ISA included ecological effects from particle-phase compounds (e.g., nitrates and sulfates), primarily effects from acidification a N-nutrient enrichment and eutrophication. In this IS A, the focus is on recent data for direct welfare effects of particle-phase NO nd

amage

o X and SO X in the ambient air – primarily visibility impairment, d to materials, and positive and negative climate in teractions – not the welfare effects related t deposition of particle-phase NO X and SO X

.

December 2009 1-12A series of annexes supplement this ISA. The annexes provide additional details of the pertinent literature published since the last review, as well as selected older studies of particular
interest. These annexes contain information on:

 atmospheric chemistry of PM, sampling and analytic methods for measurement of PM, concentrations, emissions, sources and human exposure to PM (Annex A);

 studies on the dosimetry of PM (Annex B);

 controlled human exposure studies of health effects related to exposure to PM (Annex C);

 toxicological studies of health effects rela ted to exposure to PM in laboratory animals and cell cultures (Annex D);

 epidemiologic studies of health effects from short- and long-term exposure to PM (Annex E); and

 studies that evaluate PM-induced health eff ects attributable to specific constituents or sources (Annex F).

Within Annexes B through F, detailed informati on about methods and results of health studies is summarized in tabular format, and generally in cludes information about: concentrations of PM and averaging times; study methods employed; re sults; and quantitative results for relationships between effects and exposure to PM. As noted in the section above, the most pertinent results of this body of studies are brought into the ISA.



# 1.5. EPA Framework for Causal Determination

The EPA has developed a consistent and transparent basis to evaluate the causal nature of air pollution-induced health or environmental effect s. The framework described below establishes uniform language concerning causality and brings more specificity to the findings. It drew standardized language from across the federal government and wider scientific community, especially from the recent National Academy of Sciences (NAS) Institute of Medicine (IOM) document, Improving the Presumptive Disability Decision-Making Process for Veterans (IOM, 2008,

156586 ), the most recent comprehensive work on evaluating causality. This introductory section focuses on the evaluation of health effects evidence; while focusing on human health outcomes, the con cepts are also generally relevant to causality determination for
welfare effects. This section:

 describes the kinds of scientific eviden ce used in establishing a general causal relationship between exposure and health effects;

 defines cause, in contrast to statistical association;

 discusses the sources of evidence necessary to reach a conclusion about the existence of a causal relationship;

 highlights the issue of multifactorial causation;

 identifies issues and approaches related to uncertainty; and

 provides a framework for classifying and characterizing the weight of evidence in support of a general causal relationship.

Approaches to assessing the separate and combined lines of evidence (e.g., epidemiologic, controlled human exposure, and animal toxicological studies) have been formulated by a number of

December 2009 1-13regulatory and science agencies, including the IOM of the NAS (IOM, 2008, 156586 ), International Agency for Research on Cancer (IARC, 2006, 093206 ), EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005, 086237 ), Centers for Disease Control and Prevention (CDC, 2004,

056384 ), and National Acid Precipitation Assessment Program (NAPAP, 1991, 095894 ). These formalized approaches offer guidance for assessing causality. The frameworks are similar in nature, although adapted to different purposes, and have proven effective in providing a uniform structure and language for causal determinations. Moreover, these frameworks have supported decision-making under conditions of uncertainty.



## 1.5.1.

1.5.2. Scient ific Evidence Used in Establishing Causality

Causality determinations are based on the eval uation and synthesis of evidence from across scientific disciplines; the type of evidence that is most important for such determinations will vary by assessment. The most direct evidence of a ca usal relationship between pollutant exposures and human health effects comes from controlled human exposure studies. This type of study experimentally evaluates the health effects of administered exposures in human volunteers under highly-controlled laboratory conditions. In most epidemiologic or observational studies of humans, the investigator does not control exposures or intervene with the study population. Broadly, observational studies can describe associations between exposures and effects. Th ese studies fall into several categories: cross-sectional, prospective cohort, and time-serie s studies. “Natural experiments” offer the opportunity to investigate changes in health with a change in exposure; these include comparisons of health effects before and after a change in population exposures, such as the closure of a pollution

source. Experimental animal data can help charact erize effects of concern, exposure-response relationships, susceptible populations, MOAs and enhanc e understanding of biological plausibility of
observed effects. In the absence of controlled hu man exposure or epidemiologic data, animal data alone may be sufficient to support a likely causal determination, assuming that similar responses are expected in humans.



## Associ ation and Causation

“Cause” is a significant, effectual relationship between an agent and an effect on health or public welfare. “Association” is the statistical de pendence among events, characteristics, or other
variables. An association is prima facie evidence for causation; alone, however, it is insufficient proof of a causal relationship between exposure and di sease or health effect. Determining whether an observed association is causal rather than spurious involves consideration of a number of factors, as described below. Much of the newly available heal th information evaluated in this ISA comes from epidemiologic studies that report a statistical association between ambient exposure and health

outcomes. Many of the health and environmental outcomes reported in these studies have complex etiologies. Diseases such as asthma, coronary artery disease or cancer are typically initiated by a web of multiple agents. Outcomes depend on a variety of factors, such as age, genetic susceptibility, nutritional status, immune competence, and soc ial factors (Gee and Payne-Sturges, 2004, 093070 ; IOM, 2008, 156586 ). Effects on ecosystems are also multifactor ial with a complex web of causation. Further, exposure to a combination of agents coul d cause synergistic or antagonistic effects. Thus, the observed risk represents the net effect of many actions and counteractions.



## 1.5.3. Evalua ting Evidence for Inferring Causation

Moving from association to causation involves elimination of alternative explanations for the association. In estimating the causal influence of an exposure on health or environmental effects, it is recognized that scientific findings include uncertainty. Uncertainty can be defined as a state of having limited knowledge where it is impossible to exactly describe an existing state or future outcome; the lack of knowledge about the correct value for a specific measure or estimate. Uncertainty characterization and uncertainty assess ment are two activities that lead to different degrees of sophistication in describing uncertainty . Uncertainty characterization generally involves a

December 2009 1-14qualitative discussion of the thought processes that lead to the selection and rejection of specific data, estimates, scenarios, etc. Uncertainty assess ment is more quantitative. The process begins with simpler measures (e.g., ranges) and simpler analy tical techniques and progresses, to the extent needed to support the decision for which the assessment is conducted, to more complex measures and techniques. Data will not be available for all aspects of an assessment, and those data that are available may be of questionable or unknown qualit y. In these situations, evaluation of uncertainty can include professional judgment or inferences based on analogy with similar situations. The net result is that the assessments will be based on a number of assumptions with varying degrees of uncertainty. Uncertainties commonly encountered in evaluating health evidence for the criteria air pollutants are outlined below for epidemiologic an d experimental studies. Various approaches to characterizing uncertainty include classical statistical methods, sensi tivity analysis, or probabilistic uncertainty analysis, in order of increasing comp lexity and data requirements. The ISA generally evaluates uncertainties qualitatively in assessing the evidence from across studies; in some situations quantitative analysis approaches, such as meta-regression may be used. It is important to note here that, although the following discussion refers primarily to health effect studies, many parallels exist with welfare effects studies. Controlled exposure studies have been conducted in which plant species have been directly exposed to air pollutants, and the strengths and limitations of that body of studies mirror those of the controlled human exposure studies discussed below. Ecological field or natural gradient studies are similar to epidemiologic studies, for example, in the study of free-living populations and in the challenges faced in distinguishing effects of pollutants within a mixture. Controlled human exposure studies evaluate the ef fects of exposures to a variety of pollutants in a highly-controlled laboratory setting. Also referred to as human clinical studies, these experiments allow investigators to expose subjects to fixed concentrations of air pollutants under carefully regulated environmental conditions and ac tivity levels. Controlled human exposures to PM typically involve exposing subjects either at rest or while engaged in intermittent exercise in a whole-body exposure chamber, although mouthpiece and facemask systems can also be used. A variety of different types of particles are used in these studies including ambient outdoor particles, concentrated ambient particles (CAPs), diesel exhaust (DE) from a diesel engine, wood smoke generated in a wood stove, laboratory generated m odel particles (e.g., elemental carbon [EC] or zinc oxide [ZnO]), or particles collected on a filter, resuspended in saline, and administered either through IT instillation or inhalation. The recovery of particles on filters is variable and some components, such as organics, may be too volatile to be collected. Exposures to artificially generated particles may provide important information on the health effects of PM, but are not truly representative of ambient air pollution particles. The direct exposure of humans to ambient air pollution particles may be complicated by factors that cannot be controlled such as coexposures to other air pollutants (e.g., O 3 , SO 2 , and NO 2 ). In concentrating ambient particles, gaseous copollutants are not proportionately concentrated and interactions between PM and the copollutant cannot be investigated unless the latter are re-introduced. These limitations as well as daily variability in concentration and composition ca n make it difficult to compare the results from controlled human exposure studies employing particles from s

different sources. In some instances, controlled human exposure studies can also be used to characterize concentration-response relationships at pollutant con centrations relevant to ambient conditions. Controlled human exposures are typically conducted using a randomized crossover design with subjects exposed both to PM and a clean air control. In this way, subjects serve as their own controls, effectively controlling for many potential confound ers. However, controlled human exposure studies are limited by a number of factors including a small sample size and short exposure times. These laboratory studies are often conducted at PM co ncentrations much higher than those typically observed under ambient conditions, which may result in an overestimate of the acute response to exposure in the general population. Although the repetitive nature of ambient PM exposures may lead to cumulative health effects, this type of ex posure is not practical to replicate in a laboratory setting. In addition, while subjects do serve as their own controls, personal exposure to pollutants in the hours and days preceding the controlled exposures may vary significantly between and within individuals. Finally, controlled human exposure studies require investigators to adhere to stringent health criteria for a subject to be included in the st udy, and therefore the results cannot necessarily be generalized to an entire population. Although some controlled human exposure studies have included health comprised individuals such as asthmatics or individuals with chronic obstructive pulmonary disease (COPD) or coronary artery disease, these individuals must also be relatively healthy and do

December 2009 1-15not represent the most sensitive individuals in the population. Thus, a lack of observation of effects from controlled human exposure studies does not necessarily mean that a causal relationship does not exist. While controlled human exposure studies provide important information on the biological plausibility of associations observed between air pollutant exposure and health outcomes in epidemiologic studies, observed effects in these studies may underestimate the response in certain subpopulations. Epidemiologic studies provide important information on the associations between health effects and exposure of human populations to ambient air pollution. In the evaluation of epidemiologic evidence, one important consideratio n is potential confounding. Confounding is “...a confusion of effects. Specifically, the apparent effect of the exposure of interest is distorted because
the effect of an extraneous factor is mistaken fo r or mixed with the actual exposure effect (which may be null)” (Rothman and Greenland, 1998, 086599 ). One approach to remove spurious associations from possible confounders is to control for characteristics that may differ between exposed and unexposed persons; this is frequently termed “adjustment.” Appropriate statistical adjustment for confounders requires identifying and measuring all reasonably expected confounders. Deciding which variables to control for in a statis tical analysis of the association between exposure and disease or health outcome depends on kno wledge about possible mechanisms and the distributions of these factors in the population under study. In addition, scientific judgment is needed regarding likely sources and magnitude of confounding, together with consideration of how well the existing constellation of study designs, results, and analyses address this potential threat to inferential validity. One key consideration in this re view is evaluation of the potential contribution of PM to health effects when it is a component of a complex air pollutant mixture. Reported PM effect estimates in epidemiologic studies may reflect independent PM effects on respiratory and cardiovascular health. Ambient PM may also be serving as an indicator of complex ambient air pollution mixtures that share the same source as PM (i.e., combustion of S-containing fuels or motor vehicle emissions). Alternatively, copollutants may mediate the effects of PM or PM may influence the toxicity of copollutants. Another important consideration in the evaluation of epidemiologic evidence is effect
modification. “Effect-measure modification diff ers from confounding in several ways. The main difference is that, whereas confounding is a bias that the investigator hopes to prevent or remove from the effect estimate, effect-measure modification is a property of the effect under study . . . Inepidemiologic analysis one tries to eliminate confounding but one tries to detect and estimate effectmeasure modification” (Rothman and Greenland, 1998, 086599 ). Examples of effect modifiers in some of the studies evaluated in this ISA include environmental variables (e.g., temperature or humidity), individual risk factors (e.g., education, cigarette smoking status, age), and community factors (e.g., percent of population > 65 years old) . It is often possible to stratify the relationship between health outcome and exposure by one or more of these risk factor variables. Effect modifiers may be encountered (a) within single-city time-se ries studies; or (b) across cities in a two-stage hierarchical model or meta-analysis.
Several statistical methods are available to de tect and control for potential confounders, with none of them being completely satisfactory. Multiv ariable regression models constitute one tool for estimating the association between exposure and ou tcome after adjusting for characteristics of participants that might confound the results. The use of multipollutant regression models has been the prevailing approach for controlling potential confounding by copollutants in air pollution health effects studies. Finding the pollutant likely responsi ble for the health outco me from multipollutant regression models is made difficult by the possibility that one or more air pol lutants may be acting as a surrogate for an unmeasured or poorly-measured pollu tant or for a particular mixture of pollutants. In addition, more than one pollutant may exert si milar health effects, resulting in independently observed associations for multiple pollutants. Furthe r, the correlation between the air pollutant of interest and various copollutants may make it di fficult to discern associations between different pollutant exposures and health effects. Thus, resu lts of models that attempt to distinguish gaseous and particle effects must be interpreted with ca ution. The number and degree of diversity of covariates, as well as their relevance to the pot ential confounders, remain matters of scientific judgment. Despite these limitations, the use of multipollutant models is still the prevailing approach employed in most air pollution epidemiologic studies, and provides some insight into the potential for confounding or interaction among pollutants. Adjustment for potential confounders can be infl uenced by differential exposure measurement error. There are several components that contribut e to exposure measurement error in epidemiologic

December 2009 1-16studies, including the difference between true and measured ambient concentrations, the difference between average personal exposure to ambient pollutants and ambient concentrations at central monitoring sites, and the use of average popul ation exposure rather than individual exposure estimates. Previous AQCDs have examined the role of measurement error in time-series epidemiologic studies using simulated data and math ematical analyses and suggested that “transfer of effects” would only occur under unusual circ umstances (i.e., “true” predictors having high positive or negative correlation; substantial measu rement error; or extremely negatively correlated measurement errors) (U.S. EPA, 2004, 056905 ). Confidence that unmeasured confounders are not producing the findings is increased when multiple studies are conducted in various setti ngs using different subjects or exposures; each of which might eliminate another source of confoundi ng from consideration. Thus, multicity studies which use a consistent method to analyze data from across locations with different levels of covariates can provide insight on potential confound ing in associations. Intervention studies, because of their quasi-experimental nature, can be particularly useful in characterizing causation. In addition to controlled human exposure and epid emiologic studies, the tools of experimental biology have been valuable for developing insights into human physiology and pathology. Animal toxicological studies explore the effects of pollu tants on human health, especially through the study of model systems in other species. These studies ev aluate the effects of exposures to a variety of pollutants in a highly controlled laboratory setting, and allow exploration of MOAs or mechanisms by which a pollutant may cause effects. Backgro und knowledge of the biological mechanisms by which an exposure might or might not cause disease ca n prove crucial in establishing, or negating, a causal claim. There are, however, uncertainties associated with quantitative extrapolations between laboratory animals and humans on the pathophysiological effects of any pollutant. Animal species
can differ from each other in fundamental a spects of physiology and anatomy (e.g., metabolism, airway branching, hormonal regulation) that ma y limit extrapolation. The differences between humans and rodents with regard to pollutant a bsorption and distribution profiles based on breathing pattern, exposure dose, and differences in lung structure and anatomy all have to be taken into
consideration. A relatively new tool available for experimental studies of PM exposure is the particle
concentrator. Particle concentrators enable human subjects, animals, or cell culture systems to be exposed to atmospheric PM at concentrations greater than that observed under ambient conditions. As ambient PM is just one component of a comp lex mixture that interacts with gases and other aerosols, CAPs systems provide a method of expos ing subjects to the particle phase. There are several instrument systems used to concentrate am bient PM in controlled human or animal exposure studies (Gordon et al., 1999, 001176 ; Maciejczyk and Chen, 2005, 087456 ; Sioutas et al., 1995,

001629 ; Sioutas et al., 1999, 001633 ). Gases (such as O 3 and SO 2 ) are not concentrated nor is

PM 10 -2.5 (except for the coarse particle concentr ator) and only certain systems are capable of concentrating UFPs. In UF CAPs systems, increas ed number fraction of organic carbon and PAHs, along with decreased relative percentage of EC pa rticles have been reported in concentrated PM compared to ambient PM (Su et al., 2006, 157021 ). These data suggest that for UF concentrators, the CAPs do not accurately reflect atmospheric UFP composition. The ability to extrapolate between species has not generally changed since the 2004 PM AQCD but some considerations related to coarse part icles merit attention. The inhalability of particles >2.5 μ m in diameter is considerably lower in ra ts than in humans; however, once inhaled, deposition in the extrathoracic region is near 100% percent for particles >5 μ m for most laboratory animal species (rat, mouse, hamster, guinea pig, and dogs). By contrast, penetration of thoracic coarse particles into the lower respiratory tract is greater in humans than rodents due to the moderately less efficient nasal deposition of humans and oronasal breathing (especially during exercise). The extent to which coarse particle deposition in the lower respiratory tract differs between the species is highly dependent on the activity level of the human exposure scenario in contrast with the resting exposure conditions co mmon to rodent exposures. Endotracheal exposures of rodents may be needed to achieve coarse partic le tissue doses in the lower respiratory tract of rodents similar to those experien ced by humans. For particles <1 μ m, including UFPs, deposition is expected to be relatively similar between the species. There are also differences between species in both the rates of particle clearance from and retention in the lung. The clearance rate of particles from the ciliated airways of rats is considerably greater than humans. There is also evidence of prolonged particle retention in the smaller bronchioles of humans that does not appear to exis t or has not been observed in rats. Under most

December 2009 1-17circumstances, clearance from the alveolar region of rats is also more rapid than observed in humans. Thus, these combined effects contribute to a greater particle burden in the lower respiratory tract of humans relative to rats. An important consideration in studies where are rats chronically exposed to high concentrations of insoluble particles, is the potential for “overload conditions.” Rats, unlike other laboratory animals or humans, may experience a reduction in their alveolar clearance rates and an accumulation of interstitial particle burden and under these conditions, the relevance of tissue burdens and responses to humans is questionable. Considering interspecies differences in both deposition and clearance, greater exposure concentrat ions are required to achieve coarse particle tissue doses in the lower respiratory tract of rodents similar to those experienced by humans.



## 1.5.4. Applic ation of Framework for Causal Determination

EPA uses a two-step approach to evaluate the sc ientific evidence on health or environmental effects of criteria pollutants. The first step determines the weight of evidence in support of causation and characterizes the strength of any resulting causa l classification. The second step includes further evaluation of the quantitative evidence regardi ng the concentration-response relationships and the loads or levels, duration and pattern of exposures at which effects are observed. To aid judgment, various “aspects” 1 of causality have been discussed by many philosophers and scientists. The most widely cited aspects of causality in epidemiology, and public health, in general, were articulated by Sir Austin Bradford Hill (1965, 071664 ) and have been widely used (CDC, 2004, 056384 ; IARC, 2006, 093206 ; IOM, 2008, 156586 ; NRC, 2004, 156814 ; U.S. EPA, 2005, 086237 ). Several adaptations of the Hill aspects ha ve been used in aiding causality judgments in the ecological sciences (Adams, 2003, 156192 ; Collier, 2003, 155736 ; Fox, 1991, 156444 ; Gerritsen et al., 1998, 156465 ). These aspects (Hill, 1965, 071664 ) have been modified ( Table 1-2 ) for use in causal determinations specific to health and welfare effects or pollutant exposures. 2 Some aspects are more likely than others to be relevant for evaluating evidence on the health or environmental effects of criteria air pollutants. For example, the analogy aspect does not always apply and specificity would not be expected for multi-etiologic health outcome s such as asthma or cardiovascular disease, or ecological effects related to acidification. Aspects that usually play a larger role in determination of causality are consistency of results across studies, coherence of effects observed in different study types or disciplines, biological plausibility , exposure-response relationship, and evidence from “natural” experiments. Although these aspects provide a framework fo r assessing the evidence, they do not lend themselves to being considered in terms of simple formulas or fixed rules of evidence leading to conclusions about causality (Hill, 1965, 071664 ). For example, one cannot simply count the number of studies reporting statistically significant results or statistically nonsignificant results and reach credible conclusions about the relative weight of the evidence and the likelihood of causality. In addition, it is important to note that the aspects in Table 1-2 cannot be used as a strict checklist, but rather to determine the weight of the evidence for inferring causality. While these aspects are particularly salient in this assessment, it is also im portant to recognize that no one aspect is either necessary or sufficient for drawing inferences of causality.

1 The “aspects” described by Hill (1965, 071664 ) have become, in the subsequent literature, more commonly described as “criteria.” The original term “aspects” is used here to avoid confusion with ‘c riteria’ as it is used, with diff erent meaning, in the Clean Air Act.

2 The Hill aspects were developed for interpretation of epidemiologi c results. They have been modified here for use with a broad er array of data, i.e., epidemiologic, controlled human exposure, and animal toxicological studies, as well as in vitro data, and to be mor e consistent with EPA’s Guidelines for Carcinogen Risk Assessment.

December 2009 1-18

### Table 1-2. Aspects to aid in judging causality.

Aspect Description

CONSISTENCY OF THE OBSERVED ASSOCIATION An inference of causality is strengthened when a pattern of elevated risks is observed across several independent studies, conducted in multiple locations by multiple investigators. The reproducibility of findings constitutes one of the strongest arguments for causality. If there are discordant results among investigations, possible reasons such as differences in exposure, confounding factors, and the power of the study are considered.

COHERENCE An inference of causality from epidemiologic as sociations may be strengthened by other lines of evidence (e.g., controlled human exposure and ani mal toxicological studies) that support a cause-and-effect interpretation of the association. Causality is also su pported when epidemiologic associations are reported across study designs and across related health outcomes. Evidence on ecological or welfare effects may be drawn from a variety of experimental approaches (e.g., greenhouse, laboratory, and field) and subdisciplin es of ecology (e.g., community ecology, biogeochemistry and paleological/ hi storical reconstructions). The coherence of evidence from various fields greatly adds to the strength of an inference of causality. The absence of other lines of evidence, however, is not a reason to reject causality

BIOLOGICAL PLAUSIBILITY An inference of causality tends to be strengthened by consistency with data from experimental studies or other sources demonstrating plausible biological mechanisms. A proposed mechanistic linking between an effect, and exposure to the agent, is an important source of support for causality, especially when data establishing the existence and functioning of those mechanistic links are available. A lack of biologica l understanding, however, is not a reason to reject causality.

BIOLOGICAL GRADIENT (EXPOSURE-RESPONSE RELATIONSHIP) A well characterized exposure-response relationship (e.g., increasing effects associated with greater exposure) strongly suggests cause and effect, especially when such relationships are also observed for duration of exposure (e.g., increasing effects observed following longer exposure times). There are, however, many possible reasons that a study may fail to detect an exposure-response relationship. Thus, although the presence of a biological gradient may support causality, the absence of an exposure-response relationship does not exclude a causal relationship.

STRENGTH OF THE OBSERVED ASSOCIATION The finding of large, precise risks increases confi dence that the association is not likely due to chance, bias, or other factors. However, given a truly causal agent, a small magnitude in the effect could follow from a lower level of exposure, a lower potency, or the prevalence of other agents causing similar effects. While large effects support causality, modest effects therefore do not preclude it.

EXPERIMENTAL EVIDENCE The strongest evidence for causality can be provided when a change in exposure brings about a change in occurrence or frequency of health or welfare effects.

TEMPORAL RELATIONSHIP OF THE OBSERVED ASSOCIATION Evidence of a temporal sequence between the introduction of an agent and appearance of the effect constitutes another argument in favor of causality.

SPECIFICITY OF THE OBSERVED ASSOCIATION As originally intended, this refers to increased in ference of causality if one cause is associated with a single effect or disease (Hill, 1965, 071664 ). Based on the current understanding this is now considered one of the weaker guidelines for causal ity; for example, many agents cause respiratory disease and respiratory disease has multiple causes. At the scale of ecosystems, as in epidemiology, complexity is such that single agents causing single effe cts, and single effects following single causes, are extrem ely unlikely. The ability to demonstrate specificity under certain conditions remains, however, a powerful attribute of experimental studies. Thus, although the presence of specificity may support causality, its absence does not exclude it.

ANALOGY Structure activity relationships and information on the agent’s structural analogs can provide insight into whether an association is causal. Similarly, information on mode of action for a chemical, as one of many structural analogs, can inform decisions regarding likely causality.



## 1.5.5. First Step—Determination of Causality

In the ISA, EPA assesses the results of rece nt relevant publications, building upon evidence available during the previous NAAQS review, to draw concl usions on the causal relationships between relevant pollutant exposures and health or e nvironmental effects. This ISA uses a five-level

December 2009 1-19hierarchy that classifies the weight of evidence for causation, not just association 1 . In developing this hierarchy, EPA has drawn on the work of previous evaluations, most prominently the IOM’s Improving the Presumptive Disability Decision-Making Process for Veterans (IOM, 2008, 156586 )

, EPA’s Guidelines for Carcinogen Ri sk Assessment (U.S. EPA, 2005, 086237 ) and the U.S. Surgeon General’s smoking reports (CDC, 2004, 056384 ). This weight of evidence evaluation is based on
various lines of evidence from across the health and environmental effects disciplines. These separate judgments are integrated into a qualitati ve statement about the overall weight of the evidence and causality. The five descriptor s for causal determination are described in Table 1-3

. For PM, this determination of causality step i nvolved a rather complex evaluation of evidence for different PM indices, different types of health or environmental effects, and for short- and longterm exposure periods. There were insufficient data on peak (i.e., <24 h) exposures for any PM size fraction with health effects to make causality de terminations for this exp osure category. Causality determinations were made for the PM measure ( PM 2.5, PM 10-2.5 , and UFPs, to the extent evidence was available for each measure), the overall effect category, and the exposure duration. As noted above, to the extent possible, results of PM 10 studies are considered in causality determinations for

PM )

to ht of 2.5 and PM 10-2.5 . In the evaluation of health effects fi ndings in Chapter 6 (for short-term exposure and Chapter 7 (for long-term exposure), evidence wa s evaluated for health outcome categories, such as cardiovascular effects, and then conclusions we re drawn based upon the integration of evidence from across disciplines (e.g., epidemiology, cont rolled human exposure, and toxicology) and also
across the suite of related individual health outco mes. Chapters 6 and 7 initially summarize and evaluate findings for individual health outcomes, then integrate the results in summary sections draw conclusions on causality for each PM indicator . The causality narratives present the weig evidence that highlights the quality and brea dth of the data, including any limitations or uncertainties. In the integrative synthesis and co nclusions in Chapter 2, the ISA presents causality determinations and a summary of the underlying basis for those determinations for the PM indicator (e.g., PM 2.5 ), for the exposure time period (e.g., short- and long-term exposure) and for the major health effect categories.

1 It should be noted that the CDC and IOM frameworks use a four- category hierarchy for the strength of the evidence. A five-leve l hierarchy is used here to be consistent with the EPA Guidelines for Carcinogen Risk Assessment and to provide a more nuanced se t of categories.

December 2009 1-20

### Table 1-3. Weight of evidence for causal determination.

Determination Health Effects Ecological and Welfare Effects

CAUSAL RELATIONSHIP Evidence is sufficient to conclude that there is a causal relationship with relevant pollutant exposures. That is, the pollutant has been shown to result in health effects in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. For example: a) controlled human exposure studies that demonstrate consistent effects; or b) observational studies that cannot be explained by plausible alternatives or are supported by other lines of evidence (e.g., animal studies or mode of action information). Evidence includes replicated and consistent high-quality studies by multiple investigators. Evidence is sufficient to conclude that there is a causal relationship with relevant pollutant exposures. That is, the pollutant has been shown to result in effects in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. Controlled exposure studies (laboratory or small- to medium-scale field studies) provide the strongest evidence for causality, but the scope of inference may be limited. Generally, determination is based on multiple studies conducted by multiple research groups, and evidence that is considered sufficient to infer a causal relationship is usually obtained from the joint consideration of many lines of evidence that reinforce
each other.

LIKELY TO BE A CAUSAL RELATIONSHIP Evidence is sufficient to conclude that a causal relationship is likely to exist with relevant pollutant exposures, but important uncertainties remain. That is, the pollutant has been shown to result in health effects in
studies in which chance and bias can be ruled out with reasonable confidence but potential issues remain. For example: a) observational studies show an association, but copollutant exposures are difficult to address and/or other lines of evidence (controlled human exposure, animal, or mode of action information) are limited or inconsistent; or b) animal toxicological evidence from multiple studies from different laboratories that demonstrate effects, but limited or no human data are available. Evidence generally includes replicated and high-quality studies by multiple investigators. Evidence is sufficient to conclude that there is a likely causal association with relevant pollutant exposures. That is, an association has been observed between the pollutant and the outcome in studies in which chance, bias and confounding are minimized, but uncertainties remain. For example, field studies show a relationship, but suspected interacting factors cannot be controlled, and
other lines of evidence are limited or inconsistent. Generally, determination is based on multiple studies in multiple research groups.

SUGGESTIVE OF A CAUSAL RELATIONSHIP Evidence is suggestive of a causal relationship with relevant pollutant exposures, but is limited because chance, bias and confounding cannot be ruled out. For example, at least one high- quality epidemiologic study shows an association with a given health outcome but the results of other studies are inconsistent. Evidence is suggestive of a causal relationship with relevant pollutant exposures, but chance, bias and confounding cannot be ruled out. For example, at least one high-quality study shows an effect, but the results of
other studies are inconsistent.

INADEQUATE TO INFER A CAUSAL RELATIONSHIP Evidence is inadequate to determine that a causal relationship exists with relevant pollutant exposures. The available studies are of insufficient quantity, quality, consistency or statistical power to permit a conclusion regarding the presence or absence of an effect. The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of an effect.

NOT LIKELY TO BE A CAUSAL RELATIONSHIP Evidence is suggestive of no causal relationship with relevant pollutant exposures. Several adequate studies, covering the full range of levels of exposure that human beings are known to encounter and considering susceptible populations, are mutually consistent in not showing an effect at any level of exposure. Several adequate studies, examining relationships with relevant exposures, are consistent in failing to show an effect at any level of exposure.



## 1.5.6.

1.5. 

## Second Step—Evaluation of Response

Beyond judgments regarding ca usality are questions relevant to quantifying health or
environmental risks based on our understanding of the quantitative relationships between pollutant exposures and health or welfare effects.



## 6.1. Eff ects on Human Populations

Once a determination is made regarding the causal relationship between the pollutant and outcome category, important questions rega rding quantitative relationships include:

December 2009 1-21 What is the concentration-response or dose-response relationship in the human population?

 What exposure conditions (dose or exposure, duration and pattern) are important?

 What subpopulations appear to be differen tially affected (i.e., more susceptible to effects)?

To address these questions, in the second step of the EPA framework, the entirety of quantitative evidence is evaluated to best quan tify those concentration-response relationships that exist. This requires evaluation of pollutant c oncentrations and exposure durations at which effects were observed for exposed populations includi ng potentially susceptible populations. This integration of evidence results in identification of a study or set of studies that best approximates the concentration-response relationships between health outcomes and PM indicators for the U.S. population or subpopulations, given the current state of knowledge and the uncertainties that
surrounded these estimates. To accomplish this, evidence from multiple and di verse types of studies is considered. To the extent available, the ISA evaluates results from across epidemiologic studies that use various methods to evaluate the form of relationships between PM and health outcomes, and draws conclusions on the most well-supported shape of th ese relationships. Controlled human exposure studies can also provide data on the concentrati on-response relationship. Animal data may inform evaluation of concentration-response relationships, par ticularly relative to MOAs, and characteristics of susceptible populations. For some health outcomes, the probability and severity of health effects and associated uncertainties can be characterized. Chapter 2 presents the integrated findings informative for evaluation of population risks. An important consideration in characterizing the public health impacts associated with exposure to a pollutant is whether the concentration-response relationship is linear across the full concentration range encountered, or if nonlinear relationships exist along any part of this range. Of particular interest is the shape of the concentration-response curve at and below the level of the current standards. The shape of the concentra tion-response curve varies, depending on the type of health outcome, underlying biological mechanisms and dose. At the human population level, however, various sources of variability and uncertainty tend to smooth and “linearize” the concentration-response function (such as the low da ta density in the lower concentration range, possible influence of measurement error, and indivi dual differences in susceptibility to air pollution health effects). In addition, many chemicals and agents may act by perturbing naturally occurring background processes that lead to disease, wh ich also linearizes population concentration-response relationships (Clewell and Crump, 2005, 156359 ; Crump et al., 1976, 003192 ; Hoel, 1980, 156555 ). These attributes of population dose-response may expl ain why the available human data at ambient concentrations for some environmental pollutants (e.g., PM, O 3 , lead [Pb], ETS, radiation) do not exhibit evident thresholds for health effects, even though likely mechanisms include nonlinear processes for some key events. These attributes of human population dose-response relationships have been extensively discussed in the broader ep idemiologic literature (Rothman and Greenland, 1998, 086599 ). Publication bias is a source of uncertainty regard ing the magnitude of health risk estimates. It is well understood that studies reporting non-null fi ndings are more likely to be published than reports of null findings, and publication bias can al so result in overestimation of effect estimate sizes (Ioannidis, 2008, 188317 ). For example, effect estimates from single-city epidemiologic studies have been found to be generally larger than those from multicity studies (Anderson et al., 2005, 087916 ). Finally, identification of the susceptible population groups contributes to an understanding of the public health impact of pollutant exposures. Epid emiologic studies can help identify susceptible populations by evaluating health responses in the study population. Examples include stratified analyses for subsets of the population under study, or testing for interactions or effect modification by factors such as gender, age group, or health stat us. Experimental studies using animal models of susceptibility or disease can also inform the extent to which health risks are likely greater in specific population subgroups. Further discussion of these groups is in Chapter 8.

December 2009 1-22

## 1.5.



## 1.5.7. 6.2. Eff ects on Public Welfare

Key questions for understanding the quantitative relationships between exposure (or concentration or deposition) to a pollutant and risk to the public welfare (e.g., ecosystems, visibility, materials, climate):

 What elements of the ecosystem (e.g., types, regions, taxonomic groups, populations, functions, etc.) appear to be affected, or are more sensitive to effects?

 Under what exposure conditions (amount de posited or concentration, duration and pattern) are effects seen?

 What is the shape of the concentration-response or exposure-response relationship?

Evaluations of causality typically consider the probability of welfare effects changing in response to exposure. A challenge to the quantification of exposure-response relationships for ecological effects is the variability across ecosyst ems. Ecological responses are evaluated within the range of observations, so a quantitative relationship may be determined for a given ecological system and scale. However, there is great regional a nd local variability in ecosystems. Thus, exposureresponse relationships are often available site by site, rather than at the national or even regional scale. For example, an ecological response to de position of a given pollutant can differ greatly between ecosystems. Where results from greenhou se or animal ecotoxicological studies are available, they may be used to aid in char acterizing exposure-response relationships, particularly relative to mechanisms of action, and characteristics of sensitive biota.



## Concep ts in Evaluating Adver sity of Health Effects

In evaluating the health evidence, a number of factors can be considered in determining the
extent to which health effects are “adverse” for health outcomes such as changes in lung function.
What constitutes an adverse heal th effect may vary between populations. Some changes in healthy individuals may not be considered adverse while those of a similar type and magnitude are potentially adverse in more susceptible individuals. The American Thoracic Society (ATS) published an official statement titled What Constitutes an Adverse Health Effect of Air Pollution? (ATS, 2000, 011738 ). This statement updated the guidance for defining adverse respiratory health effects that had been published 15 years earlier (ATS, 1985, 006522 ), taking into account new investigative approaches used to identify the effects of air pollution and reflecting concern for impact s of air pollution on specific susceptible groups. In the 2000 update, there was an increased focus on quality of life measures as indicators of adversity and a more specific consideration of population risk. Exposure to air pollution that increases the risk of an adverse effect to the entire population is viewed as adverse, even though it may not increase the risk of any identifiable individual to an unacceptable level; estimated mean population effects do
not reflect more severe effects in individuals. Fo r example, a population of asthmatics could have a distribution of lung function such that no identifiable individual has a level associated with significant impairment. Exposure to air pollution could shift the distribution such that no identifiable individual experiences clinically-relevant effects; th is shift toward decreased lung function, however, would be considered adverse because individuals within the population would have diminished reserve function and, therefore, would be at increased risk to further environmental insult.



# 1.6. Summary

This ISA is a review, synthesis, and evaluation of the most policy-relevant science, and communicates critical science judgments relevant to the NAAQS review. It reviews the most policy-relevant evidence from environmental effects studies and includes information on atmospheric chemistry, PM sources and emissions, exposure, and dosimetry. This ISA incorporates
clarification and revisions based on advice and co mments provided by EPA’s CASAC (Samet, 2009,

190992 ; Samet, 2009, 199522 ). Annexes to the ISA provide additional details of the literature published since the last review. A framework for making critical judgments concerning causality

December 2009 1-23appears in this chapter. It relies on a widely accept ed set of principles and standardized language to express evaluation of the evidence. This approach can bring rigor and clarity to current and future assessments. This ISA should assist EPA and others, now and in the future, to accurately represent what is presently known—and what remains unknown—concerning the effects of PM on human health and public welfare.

December 2009 1-24

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