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# Chapter 1. Introduction

1 The Int egrated Science Assessment (ISA) is a concise evaluation and synthesis of the most



### 2 policy- relevant science for reviewing the national ambient air quality standards (NAAQS). Because



### 3 t he ISA communicates critical science judgments relevant to the NAAQS revie w, it forms the



### 4 scientific foundation for the review of the NAAQS for ozone (O 3 ). The existing primary O 3 standard

include s an 8- hour (h) average (avg) standard se t at 75 parts per billion (ppb) and not to be exceeded



### 6 more than once per year. The secondary standard for O 3 is set equal to the primary standard

.



### 7 The ISA accurately reflects “the latest scientific knowledge useful in indicating the kind and



### 8 extent of identifiable effects on public health which may be expected from the presence of [a]



### 9 pollutant in ambient air” (1990, 080701 ). Key information and judgments formerly contained in the

Air Quality Criteria Document (AQCD) for O 3 are inc orporated in this assessment. Additional



### 11 details of the pertinent scientific literature published since the last review, as well as selected older



### 12 stu dies of particular interest, are included . This ISA thus serves to update and revise the evaluation of



### 13 the scientific evidence available at the time of the completion of the 2006 O 3 AQCD (U.S. EPA,



### 14 2006, 088089 ).

The draft I ntegrated Review Plan for the Ozone National Ambient Air Quality Standards (IRP)



### 16 (U.S. EPA, 2009, 684024 ) identified key policy

- relevant questions that provide d a framework for



### 17 this assessment of the scientific evidence. These questions frame the entire review of t he NAAQS for



### 18 O 3 and thus are informed by both science and policy considerations. The ISA organizes , presents

,



### 19 and integrates the scientific evidence which is considered along with findings from risk analyses and

policy considerations to help the U.S. Envir onmental Protection Agency (EPA) address these



### 21 questions during the NAAQS review

. In evaluating the health evidence, t he focus of this assessment



### 22 is on scientific evidence that is most relevant to the following questions taken directly from the



### 23 Integrated Review Plan:



### 24  To what extent has new scientific information become available that alters or

substantiates our understanding of the health effects associated with various time periods



### 26 of exposure to ambient O 3 , including short

- term (1 -3 hour s), prolonged (6 -8 hour s), and



### 27 chronic (months to years) exposures?



### 28  To what extent has new scientific information become available that alters or



### 29 substantiates our understanding of the health effects of O 3 on at

- risk populations,

including those with potentially increased susceptibility such as children and



### 31 disadvantaged populations?

Note: Hyperlinks to the reference citations throughout this document 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)

.

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1  To what extent has new scientific information become available that alters or



### 2 substantiates conclusions from previous reviews regarding the plausibility of adverse



### 3 health effects caused by O 3 exposure?



### 4  At what levels of O 3 exposure are health effects observed? Is there evidence of effects at

exposure levels lower than those previously observed, and what are the important



### 6 uncertainties associated with that evidence? What is the nature of the exp osure- response



### 7 relationships of O 3 for the various health effects evaluated?



### 8  To what extent has new scientific information become available that alters or



### 9 substantiates our understanding of non -O 3 - exposure factors that might influence the

associations betw een O 3 levels and health effects being considered (e.g., weather

- related



### 11 factors; behavioral factors such as heating/air conditioning use; driving patterns; and



### 12 time

- activity patterns)?



### 13  To what extent do risk and/or exposure analyses suggest that exposures of concern for



### 14 O 3 - related health effects are likely to occur with current ambient levels of O 3 or with

levels that just meet the O 3 standard? Are these risks/exposures of sufficient magnitude



### 16 such that the health effects might reasonably be judged to be i mportant from a public



### 17 health perspective? What are the important uncertainties associated with these



### 18 risk/exposure estimates?



### 19  To what extent have important uncertainties identified in the last rulemaking been

addressed and/or have new uncertainties emerge d?



# 1.1. Legis lative Requirements

21 Two sections of the Clean Air Act (CAA) (2011, 013410 ) govern the establishment and



### 22 revision of the NAAQS. Section 108 (42 USC §7408) directs the Administrator to identify and list



### 23 certain air pollutants and then to issue air qu ality criteria for those pollutants. The Administrator is to



### 24 list those air pollutants that in her “judgement; cause or contribute to air pollution which may

reasonably be anticipated to endanger public health or welfare” and whose “presence...in the



### 26 ambient air results from numerous or diverse moble or stationary sources.” (1990, 080701 ) . Air



### 27 quality criteria are intended to “accurately reflec t the latest scientific knowledge useful in indicating



### 28 the kind and extent of identifiable effects on public health or welfare which may be expected from



### 29 the presence of [a] pol lutant in ambient air . . . (42 USC §7408(b)).

Section 109 (1990, 037658 ) directs the Administrator to propose and promulgate “primary”



### 31 and “secondary” NAAQS for pollutants for which air quality criteria have been issued. Section

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### 1 109(b)(1) defines a primary standard as one “the attainment and maintenance of which in the



### 2 judgment of the Administrator, based on such criteria and allowing an adequate margin of safety, are



### 3 requisite to pro tect the public health.”. 1 A secondary standard, as defined in section 109(b)(2), must



### 4 “specify a level of air quality the attainment and maintenance of which, in the judgment of the



### 5 Administrator, based on such criteria, is required to protect the public welfare from any known or



### 6 anticipated adverse effects associated with the presence of [the] pollutant in the ambient air.”. 2



### 7 The requirement that primary standards include an adequate margin of safety was intended to



### 8 address uncertainties associated with inconclusive scientific and technical information available at



### 9 the time of standard setting. It was also intended to provide a reasonable degree of protection against



### 10 hazards that research has not yet identified. See Lead Industries Association v. EPA, 647 F.2d 1130,



### 11 1154 (D.C. Cir 1980) (1980, 090977 ) , cert. denied, 449 U.S. 1042 (1980); American Petroleum



### 12 Institute v. Costle , 665 F.2d 1176, 1186 (D.C. Cir. 1981) (1981, 090978 ) , cert. denied, 455 U.S. 1034



### 13 (1982). Both kinds of uncertainties are components of the risk associated with pollution at levels



### 14 below those at which human health effects can be said to occur with reasonable scientific certainty.



### 15 Thus, in selecting primary standards that include an adequate margin of safety, the Administrator is



### 16 seeking not only to prevent pollution levels that have been demonstrated to be harmful but also to



### 17 prevent lower pollutant levels th at may pose an unacceptable risk of harm, even if the risk is not



### 18 precisely identified as to nature or degree.



### 19 In selecting a margin of safety, the EPA considers such factors as the nature and severity of the



### 20 health effects involved, the size of the sensitive population(s) at risk, and the kind and degree of the



### 21 uncertainties that must be addressed. The selection of any particular approach to providing an



### 22 adequate margin of safety is a policy choice left specifically to the Administrator’s judgment. See



### 23 Lea d Industries Association v. EPA , supra, 647 F.2d at 1161

- 11 62 (1980, 090977 ).



### 24 In setting standards that are “requisite” to protect public health and welfare, as provided in



### 25 Section 109(b), EPA’s task is to establish standards that are neither more nor less stringent than



### 26 necessary. In so doing, EPA may not consider the costs of implementing the standards. See generally



### 27 Whitman v. American Trucking Associations , 531 U.S. 457, 465

- 472, 475

- 76 (2001, 043004 ).



### 28 Section 109(d)(1) requires that “not later than December 31, 1980, and at 5

- year



### 29 intervals thereafter, the Administrator shall complete a thorough review of the criteria



### 30 published under section 108 an d the national ambient air quality standards

... and shall make such



### 31 revisions in such criteria and standards and promulgate such new standards as may be



### 32 appropriate ...”. Section 109(d)(2) requires that an independent scientific review committee “shall



### 33 complet e a review of the criteria

... and the national primary and secondary ambient air quality



### 34 standards

... and shall recommend to the Administrator any new . . . standards and revisions of

1 The legislative history of section 109 indicates that a primary standard 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 mad e to a

representative sample of persons comprisi ng the sensitive group rather than to a single person in such a group” [S. Rep. No. 91

- 1196, 91 st

Cong., 2d Sess. 10 (1970)].

2 Welfare effects as defined in section 302(h) include, but are not limited to, “effects on soils, water, crops, vegetation, man -m ade

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.” (2005, 090976 ).

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### 1 existing criteria and standards as may be appropriate ...”

. Since the early 1980's, this independent



### 2 review function has been performed by CASAC.



# 1.2. His tory of the NAAQS for O zone

3 Tropospheric (ground

- level) O 3 is the indicator for the mix of photochemical oxidants (e.g.,



### 4 peroxyacetyl nitrate, hydrogen peroxide) formed from biogenic and anthropogenic precursor



### 5 emissions. Naturally occurring O 3 in the troposphere can result from biogenic organic precursors



### 6 reacting with naturally occurring nitrogen oxides ( NO X ) and by stratospheric O 3 intrusion into the



### 7 troposphere. Anthropogenic precu rsors of O 3 , especially NO X , and volatile organic compounds



### 8 (VOCs), originate from a wide variety of stationary and mobile sources. Ambient O 3 concentrations



### 9 produced by these emissions are directly affected by temperature, solar radiation, wind speed, and



### 10 other meteorological factors.



### 11 NAAQS are comprised of four basic elements: indicator, averaging time, level , and form. The



### 12 indicator defines the pollutant to be measured in the ambient air for the purpose of determining



### 13 compliance with t he standard. T he av eraging time defines the time period over which air quality



### 14 measurements are to be obtained and averaged or cumulated, considering evidence of effects



### 15 associated with various time periods of exposure. The level of a standard defines the air quality



### 16 concent ration used (i.e., an ambient concentration of the indicator pollutant) in determining whether



### 17 the standard is achieved. The form of the standard specifies the air quality measurements that are to



### 18 be used for compliance purposes (e.g., the annual fourth -hi ghest daily maximum 8

- hour



### 19 concentration, averaged over 3 years), and whether the statistic is to be averaged across multiple



### 20 years. These four elements taken together determine the degree of public health and welfare



### 21 protection afforded by the NAAQS.



### Tabl e 1

- 1. Summary of primary and secondary NAAQS promulgated for ozone during the period

1971

- 2008

Final Rule Indicator Avg Time Level (ppm) Form

Total 1971 (36 FR 8186) photochemical 1-h 0.08 Not to be exceeded more than 1 hour per year (1971, 039176 ) oxidants

Attainment is defined when the expected number of 1979 (44 FR 8202) O 3 1-h 0.12 days per calendar year, with maximum hourly average (1979, 039177 ) concentration greater than 0.12 ppm, is ≤ 1

1993 (58 FR 13008) EPA decided tha t revisions to the standards were not warranted at the time. (1993, 043977 )

1997 (62 FR 38856) Annual fourth

- highest daily maximum 8

- h concentration O 3 8-h 0.08 (1997, 083356 ) averaged over 3 years

2008 (73 FR 16483) Form of the standards remained unchanged relative to O 3 8-h 0.075 (2008, 684051 ) the 1997 standard

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39 Table 1

- 1 summarizes the O 3 NAAQS that have been promulgated to date. In each review, the

secondary standard has been set to be identical to the prim ary standard. These reviews are briefly

described below.

EPA first established primary and secondary NAAQS for photochemical oxidants in 1971

(U.S. EPA, 1971, 039176 ) . Both primary and secondary standards were set at a level of 0.08 parts

per million (ppm), 1- h avg, total photochemical oxidants, not to be exceeded more than 1 hour per

year. The standards were based on scientific information contained in the 1970 AQCD (U.S. EPA,

1970, 014681 )

.

In 1977, EPA announced the first periodic review of the 1970 AQCD (U.S. EPA, 1970,

014681 ) in accordance with Section 109(d)(1) of the Clean Air Act. In 1978, EPA published a n

AQCD (U.S. EPA, 1978, 040586 ) . Based on the 1978 AQ CD, EPA published proposed revisions to

the original NAAQS in (1978, 684050 ) and final revisions in 1979 (1979, 039177 ) . The level of the

primary and secondary standards w as revised from 0.08 to 0.12 ppm ; the indicator was revised from

photochemical oxidants to O 3 ; and the form of the standards w as revised from a deterministic to a

statistical form, which defined attainment of the standards as occurring when the expected number of

days per calendar year wit h maximum hourly average concentration greater than 0.12 ppm is equal

to or less than one.

In 1982 (Air quality criteria document for ozone and other photochemical oxidants, 1982,

043971 ) , EPA announced plans to revise the 1978 AQCD (U.S. EPA, 1978, 040586 ) . In 1983, EPA

announced that the second periodic review of the primary and secondary standards for O 3 had been

initiated (Rev iew of the national ambient air quality standards for ozone, 1983, 043972 ) . EPA

subsequently published the 1986 O 3 AQCD (U.S. EPA, 1986, 017607 ) and 1989 Staff Paper

(U.S. EPA, 1989, 041919 ) . Following publication of the 1986 O 3 AQ CD, a number of scientific

abstracts and articles were published that appea red to be of sufficient importance concerning

potential health and welfare effects of O 3 to warrant preparation of a Supplement to the 1986 O 3

AQCD (U.S. EPA, 1992, 042599 ) . Under the terms of a court order, on August 10, 1992, EPA

published a proposed decision (1992, 043976 ) stating that revisions to the existing primary and

secondary standards were not appropriate at the time (1992, 043976 ) . This notice explained that the

proposed decision would complete EPA’s review of information on health and welfare effects of O 3

assembled over a 7

- year period and contained in the 1986 O 3 AQCD (U.S. EPA, 1986, 017607 ) and

its Supplement to the 1986 O 3 AQCD (U.S. EPA, 1992, 042599 ) . The proposal also announced

EPA’s intention to proceed as rapidly as possible with the next review of the air quality criteria and

standards for O 3 in light of emerging evidence of health effects related to 6

- to 8

- hour O 3 exposures.

On March 9, 1993, EPA concluded the review by deciding that revisi ons to the standards were not

warranted at that time (1993, 043977 ).

In August 1992, EPA announced plans to initiate the third periodic review of the air quality

criteria and O 3 NAAQS (1992, 043976 )

. O n the basis of the scientific evidence contained in the

1996 O 3 AQCD (U.S. EPA, 1996, 017831 ) and the 1996 Staff Paper (U.S. EPA, 1996, 039046 ) , and

related technical support documents, linking exposures to ambient O 3 to adverse health and welfare

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39 effects at levels allowed by the then existing standards , EPA proposed to revise the primary and

secondary O 3 standards on December 13, 1996 (U.S. EPA, 1996, 031951 ). The EPA proposed to

r eplac e the then existing 1

- hour primary and secondary standards with 8

- h avg O 3 standards set at a

level of 0.08 ppm ( equivalent to 0.084 ppm using standard rounding conventions ). The EPA also

pro posed, in the alternative, to establish a new distinct secondary standard using a biologically based

cumulative seasonal form . The EPA completed the review on July 18, 1997 by setting the primary

standard at a level of 0.08 ppm, based on the annual fourth

- highest daily maximum 8

- h avg

concentration, averaged over 3 years, and setting the secondary standard identical to the revised

primary standard (U.S. EPA, 1997, 083356 ).

On May 14, 1999, in response to challenges to EPA’s 1997 decision by industry and ot hers , t he

U.S. Court of Appeals for the District of Columbia Circuit (D.C . Circuit Court) remanded the O 3

NAAQS to EPA, finding that Section 109 of the CAA , as interpreted by EPA, effected an

unconstitutional delegation of legislative authority. In additio n, the D.C. Circuit Court directed that,

in responding to the remand, EPA should consider the potential beneficial health effects of O 3

pollution in shielding the public from the effects of solar ultravi olet (UV) radiation, as well as

adverse health effect s. On January 27, 2000, EPA petitioned the U.S. Supreme Court for certiorari on

the constitutional issue (and two other issues) but did not request review of the D.C. Circuit Court

ruling regarding the potential beneficial health effects of O 3 . On February 27, 2001, the U.S.

Supreme Court unanimously reversed the judgment of the D.C. Circuit Court on the cons titutional

issue, holding that Section 109 of the CAA does not delegate legislative power to the EPA in

contravention of the Constitution, and remanded the case to the D.C. Circuit Court to consider

challenges to the O 3 NAAQS that had not been addressed by that Court’s earlier decisions. On

March 26, 2002, the D.C. Circuit Court issued its final decision, finding the 1997 O 3 NAAQS to be

“neither arbitrar y nor capricious,” and denied the remaining petitions for review. In response to the

D.C. Circuit Court remand to consider the potential beneficial health effects of O 3 pollution in

shielding the public from effects of solar (UV) radiation, on November 14, 2001, EPA proposed to

leave the 1997 8 -h O 3 NAAQS unchanged (2001, 684026 )

. After considering public comment on the

proposed decision, EPA published its final response to this remand on January 6, 2003, reaffirming

the 8 -h O 3 NAAQS set in 1997 (National ambient air quality standards for ozone: Final response to

remand; final rule, 2003, 015702 )

. Finally, on April 30, 2004, EPA announced the decision to make

the 1 -h O 3 NAAQS no longer applicable to areas 1 year after the effective date of the designation of

those areas for the 8 -h NAAQS (2004, 684054 ) . For most areas, the date that the 1

- h NAAQS no

longer applied was June 15, 2005.

EPA initiated the next periodic review if the air quality criteria and O 3 standards in Septe mber

20 00 with a call for information (2000, 080678 ) . The schedule for completion of that rulemaking

later became governed by a consent decree resolving a lawsuit filed in March 2003 by a group of

plaintiffs representing national environmental and public health organizations. Based on the 2006 O 3

AQCD (U.S. EPA, 2006, 088089 ) published in March 2006, and the Staff Paper (U.S. EPA, 2007,

090207 ) and related technical support documents, the proposed decision was published in the

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1 Federal Register on July 11, 2007 (2007, 684055 ) . The EPA proposed to revise the level of the



### 2 primary standard to a level within the range of 0.075 to 0.070 ppm . Two options were proposed for



### 3 the secondary standard: (1) replacing the current standard with a cumulative, seasonal standard,



### 4 expressed as an index of the annual sum of weighted hourly concentrations cumulated over

12 day light hours during the consecutive 3

- mo n th period within the O 3 season with the maximum



### 6 index value, set at a lev el with in the range of 7 to 21 ppm -h; and (2) setting the secondary standard



### 7 identical to the revised primary standard. The EPA completed the rulemaking with publication of a



### 8 final decision on March 27, 2008 (2008, 684051 ) , revising the level of the 8

- hour primary O 3



### 9 standard from 0.08 ppm to 0.075 ppm and revising the secondary standard to be identical to the

primary standard.



### 11 O n September 16, 2009, the EPA Administrator announced her decision to reco nsider the



### 12 March 2008 decisions on revisions to the primary and secondary O 3 NAAQS.



# 1.3. ISA Development

13 EPA initiated the current review of the NAAQS for O 3 on September 29, 2008, with a call for



### 14 information from the public (2008, 684057 ) . In addition to the call for information, publications

were identified through an ongoing literature search process that includes extensive computer



### 16 database mining on spec ific topics. Literature searches were conducted routinely to identify studies



### 17 published since the last review , focusing on publications since 2005

. S earch strategies were



### 18 iteratively modified to optimize identification of pertinent publ ications . Additional papers are



### 19 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



### 21 authors ; and identification by the public and CASAC during the external review process

.



### 22 Publications considered for inclusion in the ISA were added to the Health and Environmental



### 23 Research Online (HERO) database recently developed by EPA ( http://hero.epa.gov/ ) ; note that the



### 24 references in the ISA include a HERO ID that p rovides a link to the database. All references that a re

considered for inclusion in each chapter, organized by discipline, will be found through the HERO



### 26 links provided at the beginning of the i ndividual chapter reference sections. The HERO link provides



### 27 the list of ref e rences that a re included

, as well as those that a re considered and not included in the



### 28 ISA, with bibliographic information and abstracts.



### 29 Typically , only information that had unde rgone scientific peer review and had been published

or accepted for publication was considered for inclusion , along with analyses conducted by EPA



### 31 using publicly available data

. This review has attempted to evaluate a ll relevant data published since



### 32 the la st review pertaining to the atmospheric science of O 3 , human exposure to ambient O 3 , and



### 33 epidemiologic, controlled human exposure , and animal toxicological studies on O 3 , including those



### 34 related to exposure

- response relationships, mode(s) of action (MOA), or susceptible populations , and

literature on the ecological or welfare effects of ambient O 3 . Added to the body of research on O 3

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1 effects were EPA’s analyses of air quality and emissions data, studies on atmospheric chemistry,



### 2 transport, and fate of these emissions, as well as issues related to exposure to O 3

.



### 3 In general, in assessing the scientific quality and relevance of health and environmental effects



### 4 studies, the following considerations have been taken into account when selecting studies for

inclus ion in the ISA. The selection process for studies included in this ISA is shown in Figure 1 -1.



### 6  Are the study populations, subjects, or animal models adequately selected, and are they



### 7 sufficiently well defined to allow for meaningful comparisons between stu dy or exposure



### 8 groups?



### 9  Are the statistical analyses appropriate, properly performed, and properly interpreted?

Are likely covariates adequately controlled or taken into account in the study design and



### 11 statistical analysis?



### 12  Are the air quality data, exposure, or dose metrics of adequate quality and sufficiently



### 13 representative of information regardin g ambient O 3 ?



### 14  Are the health , ecological or welfare effect measurements meaningful and reliable?

In selecting epidemiologic studies, EPA considered whether a gi ven study presented



### 16 information on associations with short

- or long

- term O 3 exposures at or near ambient levels of O 3 ;



### 17 considered approaches to evaluate issues related to potential confounding by other pollutants;



### 18 assessed potential effect modifiers; addre ssed health endpoints and populations not previously



### 19 extensively researched; and evaluated important methodological issues (e.g., lag or time period

between exposure and effects, model specifications, thresholds, mortality displacement) related to



### 21 interpre tation of the health evidence. Among the epidemiologic studies selected, particular emphasis



### 22 was placed on those studies most relevant to the review of the NAAQS. Specifically, studies



### 23 conducted in the United States (U.S.) or Canada were discussed in more detail than those from other



### 24 geographical regions. Particular emphasis was placed on: (1) recent multicity studies that employ

standardized analysis methods for evaluating effects of O 3 and that provide overall estimates for



### 26 effects, based on combined anal yses of information pooled across multiple cities; (2) studies that



### 27 help understand quantitative relationships between exposure concentrations and effects; (3) new



### 28 studies that provide evidence on effects in susceptible populations; and (4) studies that co nsider and



### 29 report O 3 as a component of a complex mixture of air pollutants.

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9 Figure 1-1. Identification of studies for inclusion in the ISA.

Criteria for the selection of research evaluating controlled hum an exposure or animal

toxicological studies included a focus on studies conducted using relevant pollutant exposures. For

both types of studies, relevant pollutant exposures are considered to be those generally within one or

two orders of magnitude of ambi ent O 3 concentrations. Studies in which higher doses were used may

also be considered if they provide information relevant to understanding modes of action or

mechanisms, as noted below.

Evaluation of controlled human exposure studies focused on those that approximated expected

human exposure conditions in terms of concentration and duration. In the selection of controlled

human exposure studies, emphasis is placed on studies that: (1) investigate potentially susceptible

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39 populations such as people with card iovascular diseases; (2) address issues such as concentration

response or time

- course of responses; (3) include control exposures to filtered air; and (4) have

sufficient statistical power to assess findings.

Review of the animal toxicological evidence fo cused on studies that approximate expected

human dose conditions, which will vary depending on the toxicokinetics and biological sensitivity of

the particular laboratory animal species or strains studied. Due to resource constraints on exposure

duration an d numbers of animals tested, animal studies typically utilize high -concentration

exposures to acquire data relating to mechanisms and assure a measurable response. Such studies

were considered to the extent that they provided useful information to inform o ur understanding of

interspecies differences and potential sensitivity differences between healthy and susceptible human

populations.

Evaluation of the ecological impact of O 3 focused on studies of vegetation and effects on

ecosystems that occur in the U. S. and report endpoints or processes most relevant to the review of

the secondary standard. Many studies have been published about vegetation and ecosystems outside

of U.S. and North America, largely in Europe and Asia. This document includes discussion of studies

of vegetation and ecosystems outside of North America if those studies contribute to the

understanding of O 3 effects across species and ecosystems. For example, studies outside North

America that deal with physiological and biochemical processes t hat contribute to the effects of O 3

across species are discussed . Also, ecosystem studies outside of North America that contribute to the

understanding of O 3 effects on ecosystem processes are discussed. In addition, the specific role that

tropospheric O 3 plays in the earth's radiation budget and how perturbations in tropospheric O 3 might

affect (1 ) climate through its role as a greenhouse gas and (2 ) health, ecology and welfare through its

role in shielding ultraviolet radiation are assessed.

These criteri a provide benchmarks for evaluating 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 O 3 health, ecological and welfare effects studies, especiall y 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 ef fects associated with current ambient air concentrations of O 3

that can inform decisions on whether to retain or revise the standards.

In developing the O 3 ISA, EPA began by reviewing and summarizing the evidence on

atmospheric sciences and exposure and t he health effects evidence from in viv o and in vitro

toxicological studies

, controlled human exposure studies, and epidemiologic studies. In August 2010,

EPA held a public workshop, in which EPA experts and several non

- EPA experts were asked to

review the scientific content of preliminary draft materials for the draft ISA . The purpose of the

initial 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.

Subsequently, EPA addressed comments and completed the initial integration and synthesis of the

evidence.

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1 The integration of evidence on health, and ecological or welfare effects

, involves collaboration



### 2 between scientists from vari ous disciplines. As described in the section below, the ISA organization



### 3 is based on health and ecological effect categories. As an example, an evaluation of health effects



### 4 evidence would include summaries of findings from epidemiologic, controlled human e xposure, and

toxicological studies, and integration of the results to draw conclusions

– based on the causal



### 6 framework described below. Using the causal framework described in Section 1.6 , EPA scientists



### 7 consider aspects such a s strength, consistency, coherence

, and biological plausibility of the evidence,



### 8 and develop draft causality judgments on the nature of the relationships. The draft integrative



### 9 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



### 11 review and evaluation of the evidence. The draft ISA is released for review by the CASAC and the



### 12 public, and comments received on the charac terization of the science as well as the implementation



### 13 of the causal framework are carefully considered in revising and completing the ISA.



# 1.4. Document Organization

14 The ISA is composed of 10 chapters. This introductory chapter presents background

information and provides an overview of EPA’s framework for making causal judgments. Chapter 2



### 16 is an integrated summary of key findings and conclusions regarding the source to dose paradigm,



### 17 MOA, important health effects of O 3 , including respiratory, cardiovascular, nervous system,



### 18 perinatal/developmental, and mortality outcomes , and ecological or welfare effects. Chapter 3



### 19 highlights key concepts and evidence relevant to understanding the sources, ambient concentrations,

and atmospheric beh avior of ambient O 3

. Chapte r 4 evaluates the evidence on human exposure to



### 21 ambient O 3 . Chapter 5 describes the dosimetry of O 3 as well as a discussion of the MOA of O 3

.



### 22 Chapter 6 reviews, evaluates and integrates epidemiologic, human clinical, and animal toxicological



### 23 information on health effects related to short

- term exposures (i.e., hours, days, or weeks) to O 3 ,



### 24 including respiratory effects, cardiovascular and systemic effects, central nervous system (CNS)

effects, effects on the liver and cutaneous/ocular tissues , and mortality. Chapter 7 is similar to



### 26 Chapter 6, but focuses on health effects related to long

- term exposures (i.e., months or years) to O 3

.



### 27 Chapter 8 summarizes the evidence on potentially susceptible populations for health effects of O 3



### 28 exposure. Chapter 9 reviews, e valuates and integrates evidence on the ecological effects of ambient



### 29 O 3 , including crop and forest productivity, visible foliar injury, and ecosystem processes. Chapter 10

presents relevant evidence on the welfare effects of O 3 , focusing primarily on the effects on climate



### 31 and UV exposure. As noted above, these discussions focus on the most policy

- relevant studies, and



### 32 the broader body of literature considered is included in HERO; and additional HERO links are



### 33 provided at the beginning of the individual ch apter reference sections

.

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# 1.5. Document Scope

1 For the current review of the primary O 3 standard, relevant scientific information on human



### 2 exposures and health effects associated with exposure to ambient O 3 has been assessed. Previous



### 3 reviews have included an e xtensive body of evidence from all three major health disciplines

–



### 4 toxicology, controlled human exposure studies and epidemiology

– on the health effects of O 3

exposure (U .S. EPA, 2006, 088089 ) . In this ISA, the conclusions from previous reviews are



### 6 summarized at the beginning of each health outcome discussion to provide the f oundation for



### 7 consideration of evidence from recent studies. Results of key studies from previous reviews are



### 8 included in discussions or tables and figures, as appropriate, and conclusions are drawn based on the



### 9 synthesis of evidence from recent studies wi th the extensive literature summarized in previous

reviews.



### 11 The ISA also includes the assessment of scientific information associated with known or



### 12 anticipated ecological and public welfare effects that is relevant to the review of the secondary O 3



### 13 standa rd

. Research on the ecological effects of O 3 , including impacts on vegetation, have been



### 14 discussed extensively in previous AQCDs (U.S. EPA, 2006, 088089 )

. T he welfare effects of O 3 ,

particularly focusing on climate forcing effects and shielding of UV light, are discussed. The current



### 16 document incorporates findings of recent stu dies, building upon previous evaluations and



### 17 conclusions.



# 1.6. EPA Framework for Caus al Determination

18 The EPA has developed a consistent and transparent basis to evaluate the causal nature of air



### 19 pollution

- induced health or environmental effects. The framework described below establishes

uniform language concerning causality and brings more specificity to the findings. This standardized



### 21 language was drawn from across the federal government and wider scientific community, especially



### 22 from the recent National Acad emy of Sciences (NAS) Institute of Medicine (IOM) document,



### 23 Improving the Presumptive Disability Decision

- Making Process for Veterans

, (2008, 156586 ) the



### 24 most recent comprehensive work on evaluating causality.

The introductory portion of this section fo cuses on the evaluation of health effects evidence.



### 26 While focusing on human health outcomes, the concepts are also generally relevant to causality



### 27 determination for welfare effects. This section:



### 28  describes the kinds of scientific evidence used in establis hing a general causal



### 29 relationship between exposure and health effects;

 defines cause, in contrast to statistical association;



### 31  discusses the sources of evidence necessary to reach a conclusion about the existence of



### 32 a causal relationship;

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1  highlights the issue of multifactorial causation;



### 2  identifies issues and approaches related to uncertainty; and



### 3  provides a framework for classifying and characterizing the weight of evidence in



### 4 support of a general causal relationship.

Approaches to assessing the separate and combined lines of evidence (e.g., epidemiologic,



### 6 human clinical, and animal toxicological studies) have been formulated by a number of regulatory



### 7 and science agencies, including the IOM of the NAS (2008, 156586 ) , International Agency for



### 8 Research on Cancer (2006, 093206 )

, EPA Guidelines for Carcinogen Risk Assessment (2005,



### 9 086237 )

, and Centers for Disease Control and Prevention (2004, 056384 ) . These formalized

appro aches offer guidance for assessing causality. The frameworks are similar in nature, although



### 11 adapted to different purposes, and have proven effective in providing a uniform structure and



### 12 language for causal determinations. Moreover, these frameworks have supported decision -making



### 13 under conditions of uncertainty.



## 1.6.1. Scien tific Evide n ce Us ed in Es tablis hin g Cau s ality

14 Causality determinations are based on the evaluation and synthesis of evidence from across

scientific disciplines; the type of evidence that is mo st important for such determinations will vary



### 16 by pollutant or assessment. The most compelling evidence of a causal relationship between pollutant



### 17 exposures and human health effects comes from human clinical studies. This type of study



### 18 experimentally evalu ates the health effects of administered exposures in human volunteers under



### 19 highly controlled laboratory conditions.

In epidemiologic or observational studies of humans, the investigator does not control



### 21 exposures or intervene with the study population. Broadly, observational studies can describe



### 22 associations between exposures and effects. These studies fall into several categories:



### 23 cross

- sectional, prospective cohort, and time

- series studies. “Natural experiments” offer the



### 24 opportunity to investigate chan ges in health with a change in exposure; these include comparisons of

health effects before and after a change in population exposures, such as closure of a pollution



### 26 source.



### 27 Experimental animal data can help characterize effects of concern, exposure

- response



### 28 relationships, susceptible populations and MOAs. I n the absence of controlled human exposure or



### 29 epidemiologic data, animal data alone may be sufficient to support a likely causal determination,

assuming that humans respond similarly to the experimental species.

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## 1.6.2. As s o ciation an d Ca us a tio n

1 “Cause” is a significant, effectual relationship between an agent and an effect on health or



### 2 public welfare. “Association” is the statistical dependence among events, characteristics, or other



### 3 variables. An association is prima facie evidence for causation; alone, however, it is insufficient



### 4 proof of a causal relationship between exposure and disease. Unlike an association, a causal claim

supports the creation of counterfactual claims; that is, a claim about what the wo rld would have been



### 6 like under different or changed circumstances (IOM, 2008, 156586 ) . Much of the newly available



### 7 health information evaluated in this ISA comes from epidemiologic studies that report a statistical



### 8 association between ambient exposure and health outcome.



### 9 Many of the health and environmental outcomes reported in these studies have complex

etiologies. Diseases such as asthma, coronary heart disease (CHD) or cancer are typically initiated



### 11 by multiple agents. Outcomes depend on a variety of factors, such as age, genetic susceptibility,



### 12 nutritional status, immune competence, and social factors (Gee and Payne

- Sturges, 2004, 093070 ;



### 13 IOM, 2008, 156586 ) . Effects on ecosystems are oft en also multifactorial with a complex web of



### 14 causation. Further, exposure to a combination of agents could cause synergistic or antagonistic

effects. Thus, the observed risk represents the net effect of many actions and counteractions.



## 1.6.3. Evalu a tin g Evid en c e fo r In fe rrin g Cau s a tio n

16 Moving from association to causation involves the elimination of alternative explanations for



### 17 the association. In estimating the causal influence of an exposure on health or environmental effects,



### 18 it is recognized that scientific findings incorporate uncertainty. “ Uncertainty ” can be defined as a



### 19 state of having limited knowledge where it is impossible to exactly describe an existing state or

future outcome

, e.g., the lack of knowledge about the correct value for a specific measure or



### 21 estimate. Uncertainty characterization and uncertainty assessment are two activities that lead to



### 22 different degrees of sophistication in describing uncertainty. Uncertainty characterization generally



### 23 involves a qualitative discussion of the thought pro cesses that lead to the selection and rejection of



### 24 specific data, estimates, scenarios, etc. U ncertainty assessment is more quantitative. The process

begins with simpler measures (e.g., ranges) and simpler analytical techniques and progresses, to the



### 26 exten t needed to support the decision for which the assessment is conducted, to more complex



### 27 measures and techniques. Data may not be available for all aspects of an assessment and those data



### 28 that are available may be of questionable or unknown quality. In these situations, evaluation of



### 29 uncertainty can include professional judgment or inferences based on analogy with similar situations.

The ne t result is that the assessment will be based on a number of assumptions with varying degrees



### 31 of uncertainty. Uncertaint ies commonly encountered in evaluating health evidence for the criteria air



### 32 pollutants are outlined below for epidemiologic and experimental studies. Various approaches to



### 33 evaluating uncertainty include classical statistical methods, sensitivity analysis, or probabilistic



### 34 uncertainty analysis, in order of increasing complexity and data requirements. The ISA generally

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39 evaluates uncertainties qualitatively in assessing the evidence from across studies; in some situations

quantitative an alysis approaches, such as meta regression

, may be used.

Meta

- analysis may be a valuable tool for evaluating evidence by combining results from a

body of studies. Blair et al. (1995, 079190 ) observe d that meta

- analysis can enhance understanding

of associations between exposures and effects that are not readily apparent in examination of

individual study results a nd can be particularly useful for formally examining sources of

heterogeneity. However, these authors note d that meta

- analysis may not be useful when the

relationship between the exposure and outcome is obvious, when only a few studies are available for

a particular exposure

- outcome relationship , where there is limited access to data of sufficient quality

,

or where there is substantial variation in study design or population. In addition, important

differences in effect estimates, exposure metrics, or other factors may limit or even preclude

quantitative statistical combination of multiple studies.

Controlled human exposure studies evaluate the effects of exposures to a variety of pollutants

in a highly controlled laboratory setting. Also referred to as huma n clinical studies, these

experiments allow investigators to expose subjects to known concentrations of air pollutants under

carefully regulated environmental conditions and activity levels. In some instances, controlled

human exposure studies can also be used to characterize concentration

- response relationships at

pollutant concentrations relevant to ambient conditions. Controlled human exposures are typically

conducted using a randomized crossover design

, with subjects exposed both to O 3 and a clean air

c ontrol. In this way, subjects serve as their own controls, effectively controlling for many potential

confounders. However, human clinical studies are limited by a number of factors

, including a small

sample size and short exposure time s . The repetitive na ture of ambient O 3 exposures at levels that

can vary widely may lead to cumulative health effects, but this type of exposure is not practical to

replicate in a laboratory setting. In addition, although subjects do serve as their own controls,

personal expo sure to pollutants in the hours and days preceding the controlled exposures may vary

significantly between and within individuals. Finally, human clinical studies require investigators to

adhere to stringent health criteria for a subject to be included in the study, and therefore the results

cannot necessarily be generalized to an entire population. Although some human clinical studies

have included health

- compromised individuals such as those with respiratory or cardiovascular

disease, these individuals must also be relatively healthy and do not represent the most sensitive

individuals in the population. Thus, a lack of observation of effects from human clinical studies does

not necessarily mean that a causal relationship does not exist. While human clinica l 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 populat ions.

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 consideration is potential confounding. Confounding is “... a

confusion of effects. Specifically, the apparent effect of the exposure of interest is distorted because

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39 the effect of an extraneous factor is mistaken for or mixed with the actual exposure effect (which

may be null)” (Rothman and Greenland, 1998, 086599 ) . One approach to remove spurious

associations due to possible confounders is to control for characteristics that may differ between

exposed and unexposed persons; this is frequently termed “adjustment.” Scien tific 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 consi deration in this review is evaluation of the potential contribution of O 3 to health

effects when it is a component of a complex air pollutant mixture. Reported O 3 effect estimates in

epidemiologic studies may reflect independent O 3 effects on health outcom es. Ambient O 3 may also

be serving as an indicator of complex ambient air pollution mixtures, particularly the photochemical

oxidant mixture. Alternatively, co -pollutant s may mediate the effects of O 3 , or O 3 may influence the

toxicity of co -pollutant s.

Ano ther important consideration in the evaluation of epidemiologic evidence is effect

modification . “Effect

- measure modification differs from confounding in several ways. The main

difference is that, whereas confounding is a bias that the investigator hopes t o prevent or remove

from the effect estimate, effect

- measure modification is a property of the effect under study . . . In

epidemiologic analysis one tries to eliminate confounding but one tries to detect and estimate effect

measure modification” (Rothman and Greenland, 1998, 086599 )

. When a risk factor is a confounder,

it is the true cause of the association observed between the exposure and the outcome; when a risk

factor is an effect modifier, it changes the magnitude of the association between the exposure and the

outcome in stratified analyses. Examples of potential effect modifiers in some of the studies

evaluated in this ISA may include environmental variables

, such as temperature or humidity,

individual risk factors

, such as e ducation, cigarette smoking status, age in a prospective cohort study,

and community factors

, such as 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 potenti al effect

modifiers

. For variables that modify the association, effect estimates in each stratum will be different

from one another and different from the overall estimate, indicating a different exposure

- response

relationship may exist in populations repr esented by these variables. Effect modifiers may be

encountered ( 1 ) within single

- city time

- series studies ; or ( 2 ) across cities in a two

- stage hierarchical

model or meta -analysis.

Several statistical methods are available to detect and control for potential confounders, with

none of them being completely satisfactory. Multivariable regression models constitute one tool for

estimating the association between exposure and outcome after adjusting for characteristics of

participants that might confound the res ults. The use of multi -pollutant regression models has been

the prevailing approach for controlling potential confounding by co

- pollutant s in air pollution health

effects studies. Finding the likely causal pollutant from multi

- pollutant regression models i s made

difficult by the possibility that one or more air pollutants may be acting as a surrogate for an

unmeasured or poorly measured pollutant or for a particular mixture of pollutants. In addition, more

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38 than one pollutant may exert similar health effects , resulting in independently observed associations

for multiple pollutants. For example, O 3 , NO 2 and SO 2 have each been linked to respiratory effects in

epidemiologic studies. C orrelation between O 3 concentrations and various co -pollutants makes it

difficu lt to quantitatively interpret associations between different pollutant exposures and health

effects. Thus, results of models that attempt to distinguish O 3 effects from those of co

- pollutant s

must be interpreted with caution. The number and degree of dive rsity of covariates, as well as their

relevance to the potential confounders, remain matters of scientific judgment. Despite these

limitations, the use of multi -pollutant models is still the prevailing approach employed in most air

pollution epidemiologic studies and provide s some insight into the potential for confounding or

interaction among pollutants

.

Another way to adjust for potential confounding is through stratified analysis, i.e., examining

the association within homogeneous groups with respect to the confounding variable. The use of

stratified analyses has an additional benefit: it allows examination of effect modification through

comparison of the effect estimates across different groups. If investigators successfully measured

characteristics that distort the results, adjustment of these factors help separate a spurious from a true

causal association. Appropriate statistical adjustment for confounders requires identifying and

measuring all reasonably expected confounders. Deciding which variables t o control for in a

statistical analysis of the association between exposure and disease or health outcome depends on

knowledge about possible mechanisms and the distributions of these factors in the population under

study. Identifying these mechanisms make s it possible to control for potential sources that may result

in a spurious association.

Adjustment for potential confounders can be influenced by differential exposure measurement

error. There are several components that contribute to exposure measuremen t error in epidemiologic

studies, 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 avera ge population exposure rather than individual exposure

estimates. Consideration of issues important for evaluation of exposure to ambient O 3 include the

relationship between O 3 measured at central site monitors with exposure to ambient O 3 in indoor

environ ments, since penetration of O 3 into buildings may be limited. Previous AQCDs have

examined the role of measurement error for non

- reactive pollutants in time

- series epidemiologic

studies using simulated data and mathematical analyses and suggested that tran sfer of effects from

the “ causal” variable to the confounder would only occur under unusual circumstances (i.e., “true”

predictors having high positive or negative correlation; substantial measurement error; or extremely

negatively correlated measurement e rrors) (U.S. EPA, 2004, 056905 )

.

Confidence that unmeasured confounders are not producing the f indings is increased when

multiple studies are conducted in various settings using different subjects or exposures

, each of

which might eliminate another source of confounding from consideration. Thus, multi city studies

which use a consistent method to analyze data from across locations with different levels of

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1 covariates can provide insight on potential confounding in associations. Intervention studies, because



### 2 of their quasi- experimental nature, can be particularly useful in characterizing causation.



### 3 In addition to clinical and epidemiologic studies, the tools of experimental biology have been



### 4 valuable for developing insights into human physiology and pathology. Laboratory tools have been

extended to explore the effects of putative toxicants on human heal th, especially through the study of



### 6 model systems in other species. These studies evaluate the effects of exposures to a variety of



### 7 pollutants in a highly controlled laboratory setting and allow exploration of MOAs or mechanisms



### 8 by which a pollutant may ca use effects. Understanding the biological mechanisms underlying



### 9 various health outcomes can prove crucial in establishing or negating causality. T here are , however,

uncertainties associated with quantitative extrapolations between laboratory animals and hu mans o n



### 11 the pathophysiologi cal effects of any pollutant. Animal species can differ from each other in



### 12 fundamental aspects of physiology and anatomy (e.g., metabolism, airway branching, hormonal



### 13 regulation) that may limit extrapolation

.



### 14 Interpretations of experimental studies of air pollution effects in laboratory animals, as in the

case of environmental comparative toxicology studies, are affected by limitations associated with



### 16 extrapolation models. The differ ences between humans and other species with reg ard to pollutant



### 17 absorption and distribution profiles based on metabolism, hormonal regulation, breathing pattern,



### 18 exposure dose, and differences in lung structure and anatomy

, all have to be taken into consideration.



### 19 Also, in spite of a high degree of hom ology and the existence of a high percentage of orthologous

genes across humans and rodents (particularly mice), extrapolation of molecular alterations at the



### 21 gene level is complicated by species

- specific differences in transcriptional regulation. Given th ese



### 22 molecular differences, at this time there are uncertainties associated w ith quantitative extrapolations



### 23 b etween laboratory animals and humans of observed pollutant

- induced pathophysiological



### 24 alterations under the control of widely varying biochemical, endocrine, and neuronal factors.



## 1.6.4. Ap plic ation o f Fra me work fo r Ca us al De te rmin ation

EPA uses a two

- step approach to evaluate the scientific evidence on health or ecological



### 26 effects of criteria pollutants. The first step determines the weight of evidence in support of causation



### 27 and characterizes the strength of any resulting causal classification. The second step includes further



### 28 evaluation of the quantitative evidence regarding the concentration

- response relationships and the



### 29 loads or levels, duration and pa ttern of exposures at which effects are observed.

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

An inference of causality is strengthened when a pattern of elevated risks is observed across sever al

Consistency of the independent studies. The reproducibility of findings constitutes one of the strongest arguments for

observed association 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.

An inference of causality from epidemiologic associations may be strengthened by other lines of

evidence (e.g., clinical and animal studies) that support a cause

- and

- effect interpretation of the

association. Evidence on ecological or welfare effects may be drawn from a variety of experimental

Coherence approaches (e.g., greenhouse, laboratory, and field) and subdisciplines of ecology (e.g., community

ecology, biogeochemistry and paleological/historical reconstructions). The cohere nce 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.

An inference of causality tends to be strengthene d by consistency with data from experimental studies or

other sources demonstrating plausible biological mechanisms. A proposed mechanistic linking between

Biological plausibility. 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 biologic

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 biologic gradient may support causality, the absence of an

exposure

- response relationship does not exclud e a causal relationship.

The finding of large, precise risks increases confidence that the association is not likely due to chance,

Strength of the observed bias, or other factors. However, given a truly causal agent, a small magnitude in the effect could follow

association 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.

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

Temporal relationship of Evidence of a temporal sequence between the introduction of an agent , and appearance of the effect,

the observed association constitutes another argument in favor of causality.

Specificity of the

observed association As originally intended, this refers to increased inference of causality if one cause is associated with a

single effect or disease (Hill, 1965, 071664 ) . Based on our current understanding, this is now considered

one of the weaker guidelines for causality; for example, many agents cause respiratory d isease and

respiratory disease has multiple causes. At the scale of ecosystems, as in epidemiology, complexity is

such that single agents causing single effects, and single effects following single causes, are extremely

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.

Structure activity relationships and informati on on the agent’s structural analogs can provide insight into

Analogy 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 To aid judgmen t, various “aspects” 1 of causality have been discussed by many philosophers



### 2 and scientists. The most widely cited aspects of causality in epidemiology, and public health, in



### 3 general, were articulated by Sir Austin Bradford Hill (1965, 071664 ) and have been widely used



### 4 (CDC, 2004, 056384 ; IARC, 2006, 093206 ; IOM, 2008, 156586 ; U.S. EPA, 2005, 086237 ). These



### 5 aspects (Hill, 1965, 071664 ) have been modified (Table 1

- 2) for use in causal determinations



### 6 specific to health and welfare effects or pollutant exposures (U.S. EPA, 2009, 179916 ). 2 Some



### 7 aspects are more likely than others to be relevant for evaluating evide nce on the health or ecologic al



### 8 effects of criteria air pollutants. For example, the " analogy " aspe ct does not always apply, especially



### 9 for the gaseous criteria pollutants, and specificity would not be expected for multi

- etiologic health

1 The “aspects” described by Hill (1965, 071664 ) have become, in the subsequent literature, more commonly described as “criteria.” Th e

original term “aspects” is used here to avoid confusion with ‘criteria’ as it is used, with different meaning, in the Clean A ir Act.

2 The Hill aspects were developed for interpretation of epidemiologic results. They have been modified here for use with a broader array of

data, i.e., epidemiologic, controlled human exposure , ecological, and animal toxicological studies, as well as in vitro data, and to be more

consistent with EPA’s Guidelines for Carcinogen Risk Assessment.

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### 1 outcomes, such as asthma or cardiovascular disease, or ecological effects related to acidification.



### 2 Aspects that usua lly play a larger role in determination of causality are consistency of results across



### 3 studies, coherence of effects observed in different study types or disciplines, biological plausibility,



### 4 exposure

- response relationship, and evidence from “natural” expe riments.



### 5 Although these aspects provide a framework for assessing the evidence, they do not lend



### 6 themselves to being considered in terms of simple formulas or fixed rules of evidence leading to



### 7 conclusions about causality (Hill, 1965, 071664 ) . For example, one cannot simply count the number



### 8 of studies reporting statistically significant results or statistically nonsignificant results and reach



### 9 credible conclusions about th e relative weight of the evidence and the likelihood of causality. Rather,



### 10 these important considerations are taken into account with the goal of producing an objective



### 11 appraisal of the evidence, informed by peer and public comment and advice, which includ es



### 12 weighing alternative views on controversial issues. In a ddition, it is important to note that the aspects



### 13 in Table 1-2 cannot be used as a strict checklist, but rather to determine the weight of the evidence



### 14 for inferring causa lity. In particular, not meeting one or more of the principles does not automatically



### 15 preclude a determination of causality (See discussion in CDC, 2004, 056384 ).



## 1.6.5. De termin a tio n o f Cau s ality

16 In the ISA, EPA assesses the results of recent relevant publications, building upon evidence



### 17 available during the previous NAAQS review, to draw conclusions on the causal relationships



### 18 between relevant pollutant exposures and health or environmental effects. This ISA uses a five

- level



### 19 hierarchy that classifies the weight of evidence for causation, not just association 1 ; that is, whether



### 20 the weight of scientific evidence makes causation at least as likely as no t, in the judgment of the



### 21 reviewing group. In developing this hierarchy, EPA has drawn on the work of previous evaluations,



### 22 most prominently the IOM’s Improving the Presumptive Disability Decision

- Making Process for



### 23 Veterans (2008, 156586 ) , EPA’s Guidel ines for Carcinogen Risk Assessment (2005, 086237 ) , and the



### 24 U.S. S urgeon General’s smoking report (CDC, 2004, 056384 ) . In the ISA, EPA uses a series of five



### 25 descriptors to characterize the weight of evidence for causality. This weight of evidence evaluation is



### 26 based on various li nes of evidence from across the health and environmental effects disciplines.



### 27 These separate judgments are integrated into a qualitative statement about the overall weight of the



### 28 evidence and causality. The five descriptors for causal determination are des cribed in Table 1 -3.

1 It should be noted that the CDC and IOM frameworks use a four

- category hierarchy for the strength of the evidence. A five

- level

hierarchy is used here to be consistent with the EPA Guidelines for Carcinogen Risk Assessment and to provide a more nuanced set of

categories.

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

Health Effects Ecological and Welfare Effects

Evidence is sufficient to conclude that there is a causal

Causal

relationship Evidence is sufficient to conclude that there is a causal

relation ship with relevant polluta nt 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 e ffects; 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 replica ted and

consistent high

- quality studies by mu ltiple investigators. 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 pollu tant has been shown to result in health effects in

studies in which chance and bias can be rul ed out with

reasonable confidence but potential issues remain. For

example: a) observational studies show an association,

but co

- pollutant exposures are diffi cult 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

- qualit y 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 chanc e, 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 ba sed 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

exampl e, 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

con founding cannot be ruled out. For example, at least

one high

- quality study shows an effect, but the results of

other studies are inconsistent.

Evidence is inadequate to determine that a causal

Inadequate to relation ship exists with relevant pollutant exposures. The The available studies are of insufficient quality,

infer a causal available studies are of insufficient quantity, quality, con sistency or statistical power to permit a conclusion

relationship consistency or statistical power to permit a conclu sion regarding the presence or absence of an effect.

regarding the presence or absence of an effect.

Evidence is suggestive of no causal relationship with

relevant pollutant exposures. Several adequate studies, Not likely to Several adequate studies, examining relationships with

cover ing the full range of levels of exposure that human be a causal re levant exposures, are consistent in failing to show an beings are known to encounter and considering relationship effect at any level of exposure. susceptible populations, are mutually consistent in not

showing an effect at any level of exposure.



### 1 For the O 3 ISA, determination of causality involved the evaluation of evidence for different



### 2 types of health effects associated with short

- and long

- term exposure pe riods. In making



### 3 determinations of causality

, evidence was evaluated for health outcome categories, such as



### 4 respiratory effects, and then conclusions were drawn based upon the integration of evidence from



### 5 across disciplines (e.g., epidemiology, clinical st udies and toxicology) and also across the suite of



### 6 related individual health outcomes. To accomplish this integration, evidence from multiple and



### 7 various types of studies was considered. Response was evaluated over a range of observations which



### 8 was determi ned by the type of study

, methods of exposure or dose

, and response measurements.



### 9 Results from different protocols were compared and contrasted. EPA focuses on health outcome



### 10 categories, rather than very specific endpoints, since the coherence of evidence across a spectrum of



### 11 related endpoints (e.g., effects ranging from inflammatory effects to respiratory mortality) is an



### 12 important aspect for drawing conclusions regarding causality.

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### 1 In drawing judgments regarding causality for the criteria air pollutants, EPA focuses on



### 2 evidence of effects at relevant pollutant exposures. To best inform reviews of the NAAQS, these



### 3 evaluations go beyond a determination of causality at any dose or concentration to emphasize the



### 4 relationship apparent at relevant pollutant exp osures. Concentrations generally within an order of



### 5 magnitude or two of ambient pollutant measurements are considered to be relevant for this



### 6 determination. Building upon the determination of causality are questions relevant to quantifying



### 7 health or enviro nmental risks based on our understanding of the quantitative relationships between



### 8 pollutant exposures and health or welfare effects. While the causality determination is based



### 9 primarily on evaluation of health or environmental effects evidence, EPA also e valuates evidence



### 10 related to the doses or levels at which effects are observed. Considerations relevant to evaluation of



### 11 quantitative relationships for health and environmental effects are summarized below.



## 1.6.5.1. Effe c ts o n Huma n P op ula tio ns

12 Once a determination is made regarding the causal relationship between the pollutant and



### 13 outcome category, i mportant questions regarding quantitative relationships include:



### 14  What is the concentration

- response , exposure

- response, or dose

- response relationship in



### 15 the human popu lation?



### 16  What is the interrelationship between incidence and severity of effect?



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



### 18  What populations appear to be differentially affected (i.e., more susceptible to effects)?



### 19 To a ddress these questions

, the entirety of policy

- relevant quantitative evidence is evaluated to



### 20 best quantify th ose concentration

- response relationships that exist. This requires evaluation of



### 21 pollutant concentrations and exposure durations at which effects were observed for exposed



### 22 populations, including potentially susceptible population s . This integration of evidence resulted in



### 23 identification of a study or set of studies that best approximated the concentration

- response



### 24 relationship s between health outcom es and O 3 , given the current state of knowledge and the



### 25 uncertainties that surrounded these estimates. To accomplish this, evidence is considered from



### 26 multiple and diverse types of studies. To the extent available, the ISA evaluates results from across



### 27 epi demiologic studies that use various methods to evaluate the form of relationships between O 3 and



### 28 health outcomes and draws conclusions on the most well

- supported shape of these relationships

.



### 29 Animal data may also inform evaluation of concentration

- response relationships, particularly relative



### 30 to MOAs and characteristics of susceptible populations. Controlled human exposure studies have



### 31 provided the strongest and most quantifiable exposure

- response data on the human health effects of



### 32 O 3

. Chapter 2 presents the integrated findings informative for evaluation of population risks.

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### 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39 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 fu ll

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 concentration

- res ponse 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

, such as the low data density in the lower

concentration range, p ossible influence of exposure measurement error, and individual differences in

susceptibility to air pollution health effects

, tend to smooth and “linearize” the concentration

response function. In a ddition, many chemicals and agents may act by perturbing naturally occurring

background processes that lead to disease, which also linearizes population concentration

- response

relationships (Clewell and Crump, 2005, 156359 ; Crump et al., 1976, 003192 ; Hoel, 1980, 156555 )

.

T hese attributes of population dose

- response may explain why the available human data at ambient

concentrations for some environmental pollutants (e.g., PM, O 3 , lead [Pb], environmental tobacco

smoke [ETS] , radiation ) do not exhibit evident thresholds for cancer or noncancer 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 t he broader

epidemiologic literature (Rothman and Greenland, 1998, 086599 )

.

Publication bias is a source of uncertainty regarding the magnitude of health risk estimates. It

is well understood that studies reporting non

- null findings are more likely to be published than

reports of null findings, and publication bias can also 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 )

Although publication b ias commonly exists for many research areas, it may be present to a lesser

degree for epidemiologic studies on O 3 . Many epidemiologic studies have focused on the effects of

PM, and O 3 was largely considered as a potentially confounding co

- pollutant of PM. Thus, O 3 - effect

estimates may have been presented in these studies regardless of the statistical significance of the

results.

Finally, identification of the susceptible population groups contributes to an understanding of

the public health impact of pollu tant exposures. In this ISA, the term “ susceptible population” will

be used as an overarching concept to encompass populations variously described as susceptible,

vulnerable, or sensitive. “ Susceptible populations” is defined here as those p opulations that have a

greater likelihood of experiencing health effects related to exposure to an air pollutant (e.g., O 3 ) due

to a variety of factors including but not limited to: genetic or developmental factors, race, gender,

lifestage, lifestyle (e.g., smoking statu s and nutrition) or preexisting disease; as well as population

level factors that can increase an individual's expos ure to an air pollutant (e.g., O 3 ) such as

socioeconomic status [SES], which encompasses reduced access to health care, low educational

atta inment, residential location, and other factors. Epidemiologic studies can help identify

susceptible populations by evaluating health responses in the study population. Examples include

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### 5

10

15

20

25

30

1 stratified analyses for subsets of the population under study or testi ng for interactions or effect



### 2 modification by factors such as gender, age group, or health status. Experimental studies using



### 3 animal models of susceptibility or disease can also inform the extent to which health risks are likely



### 4 greater in specific populat ion groups. Further discussion of these groups is presented in Section 5.7.



## 1.6.5.2. Effe c ts o n Ec os ys te ms or Pu blic We lfa re

Key questions for understanding the quantitative relationships between exposure (or



### 6 concentration or deposition) to a pollutant and risk to ecosystems or the public welfare include:



### 7  What elements of the ecosystem (e.g., types, regions, taxonomic groups, populations,



### 8 functions, etc.) appear to be affected, or are more sensitive to effects?



### 9  Under what exposure conditions (amount deposited or co ncentration, duration and

pattern) are effects seen?



### 11  What is the shape of the concentration

- response or exposure

- response relationship?



### 12 Evaluations of causality generally consider the probability of quantitative changes in



### 13 ecological and welfare effects in response to exposure. A challenge to the quantification of exposure



### 14 response relationships for ecological effects is the great regional and local variability in ecosystems.

Thus, exposure

- response relationships are often determined for a specific ecolog ical system and



### 16 scale , rather than at the national or even regional scale. Quantitative relationships therefore are



### 17 available site by site. For example, an ecological response to deposition of a given pollutant can



### 18 differ greatly between ecosystems. Where results from greenhouse or animal ecotoxicological



### 19 studies are available, they may be used to aid in characterizing exposure

- response relations,

particularly relative to mechanisms of action, and characteristics of sensitive biota.



## 1.6.6. Concepts in Evaluating Ad vers ity of He a lth Effec ts

21 In evaluating the health evidence, a number of factors can be considered in determining the



### 22 extent to which health effects are “adverse” for health outcomes such as changes in lung function or



### 23 in cardiovascular health measures. Some health outcome events, such as hospitalization for



### 24 respiratory or cardiovascular diseases, are clearly considered adverse; what is more difficult is

determining the extent of change in the more subtle health measures that is adverse. What constitutes



### 26 an adverse health effect may vary between populations. Some changes in healthy individuals may



### 27 not be considered adverse ; while those of a similar type and magnitude are potentially adverse in



### 28 more susceptible individuals.



### 29 For example, the extent to which changes in lung function are adverse has been discussed by

the American Thoracic Society (ATS) in an official statement titled What Constitutes an Adverse



### 31 Health Effect of Air Pollution? (2000, 011738 ) . This statement updated the guidance for defining

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### 5

10

15

20

25

1 adverse respiratory health effects that had been published 15 years earlier (ATS, 1985, 006522 )

,



### 2 taking into account new investigative approaches used to identify the effects of air pollution and



### 3 reflecting concern for impacts of air pollution on specific susceptible groups. In the 2000 update,



### 4 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



### 6 adverse effect to the entire population is viewed as adverse, even though it may not increase the risk



### 7 of any identifiable individual to an unacceptable level. For example, a population of asthmatics



### 8 could have a distribution of lung function such that no identifiable individual has a level associated



### 9 with significant impairment. Exposure to air pollution could sh ift the distribution such that no

identifiable individual experiences clinically relevant effects . T his shift toward decreased lung



### 11 function, however, would be considered adverse because individuals within the population would



### 12 have diminished reserve function and therefore would be at increased risk to further environmental



### 13 insult.



### 14 It is important to recognize that the more subtle health outcomes may be linked to health

events that are clearly adverse. For example, air pollution has been shown to affect mar kers of



### 16 transient myocardial ischemia such as ST

- segment abnormalities and onset of exertional angina. In



### 17 some cases, these effects are silent yet may still increase the risk of a number of cardiac events,



### 18 including MI and sudden death.



# 1.7. Summary

19 This draft ISA is a concise evaluation and synthesis of the most policy

- relevant science for

reviewing the NAAQS for O 3 , and it is the chief means for communicating the critical science



### 21 judgments relevant to that NAAQS review. It reviews the most policy

- relevant evi dence from



### 22 atmospheric science, exposure, health , and ecological and welfare effects studies ; and includ es



### 23 mechanistic evidence from basic biological science

. A framework for making critical judgments



### 24 concerning causality was presented in this chapter. It relies on a widely accepted set of principles and

standardized language to express evaluation of the evidence. This approach can bring rigor and



### 26 clarity to curr ent and future assessments. Once complete, the ISA should assist EPA and others, now



### 27 and in the future, to accurately represent what is presently known and what remains unknown



### 28 concerning the effects of O 3 on human health and public welfare.

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