### Draft

– Do Not Cite or Quote liv June 2012 

## PREAMBLE

Process of ISA Development

This preamble outlines the general process for developing an Integrated Science 

### 1

Assessment (ISA) including the framework for evaluating weight of evidence and 

### 2

drawing scientific conclusions and causal judgments. The ISA provides a concise review, 

### 3

synthesis, and evaluation of the most policy

- releva nt science to serve as a scientific 

### 4

foundation for the review of the National Ambient Air Quality Standards (NAAQS). The 

### 5

general process for NAAQS reviews is described at 

### 6

http://www.epa.gov/ttn/naaqs/r eview.html . Figure I depicts the general NAAQS review 

### 7

process and information for individual NAAQS reviews is available at 

### 8

www.epa.gov/ttn/naaqs . This preamble is a general discussion of the basic steps and 

### 9

criter ia used in developing an ISA; for each ISA, specific details and considerations are 

### 10

included in the introductory section for that assessment. 

### 11

The fundamental process for developing an ISA includes: 

### 12

 literature searches; 

### 13

 study selection; 

### 14

 evaluation and integ ration of the evidence; and 

### 15

 development of scientific conclusions and causal judgments. 

### 16

An initial step in this process is publication of a call for information in the Federal 

### 17

Register that invites the public to provide information relevant to the assessment, such as 

### 18

new publications on health or welfare 1 effects of the pollutant, or from atmospheric and 

### 19

exposure sciences fields. EPA maintains an ongoing literature search process for 

### 20

identification of relevant scientific studies published since the last review of the NAAQS. 

### 21

Search strategies are designed for pollutants and scientific disciplines and iteratively 

### 22

modified to optimize identification of pertinent publications. Papers are identified for 

### 23

inclusion in several additional ways: specialized se arches on specific topics; independent 

### 24

review of tables of contents for journals in which relevant papers may be published; 

### 25

independent identification of relevant literature by expert scientists; review of citations in 

### 26

previous assessments and identificati on by the public and CASAC during the external 

### 27

review process. This literature search and study selection process is depicted in Figure II. 

### 28

Publications considered for inclusion in the ISA are added to the Health and 

### 29

1 Welfare effects as defined in Clean Air Act section 302(h) [42 U.S.C. 7602(h)] include, but are not limited to, “effects on soils, water, crops, 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.”

### Draft

– Do Not Cite or Quote lv June 2012 Environmental Research Online (HERO) da tabase developed by EPA 

### 1

( http://hero.epa.gov/ ); the references in the ISA include a hyperlink to the database. 

### 2

Studies that have undergone scientific peer review and have been published or accepted 

### 3

for publication and re ports that have undergone review are considered for inclusion in the 

### 4

ISA. Analyses conducted by EPA using publicly available data are also considered for 

### 5

inclusion in the ISA. All relevant epidemiologic, controlled human exposure, 

### 6

toxicological, and ecolog ical and welfare effects studies published since the last review 

### 7

are considered, including those related to exposure

- response relationships, mode(s) of 

### 8

action (MOA), and potentially at

- risk populations and lifestages. Studies on atmospheric 

### 9

chemistry, envi ronmental fate and transport, dosimetry, toxicokinetics and exposure are 

### 10

also considered for inclusion in the document, as well as analyses of air quality and 

### 11

emissions data. References that were considered for inclusion in a specific ISA can be 

### 12

found usin g the HERO website ( http://hero.epa.gov ). 

### 13

Figure I Illustration of the key steps in the process of the review of National Ambient Air Quality Standards. Workshop on science

policy issue

EPA final
decision on
standards Interagency review CASAC review and public comment Peer

- reviewed scientific studies

Agency decision making and draft
final notice Public hearings and comments

on proposal Integrated Review Plan : timeline and key policy

- relevant issues and scientific questions Integrated Science Assessment (ISA) : concise evaluation and synthesis of most policy

- relevant studies

Clean Air Scientific Advisory Committee (CASAC) review and public comment

Agency decision making and draft proposal notice Interagency review Policy Assessment: staff analysis of policy options based

on integration and

interpretation of information in the ISA and REA Risk/Exposure Assessment (REA): concise quantitative assessment focused on key results, observations, and uncertainties

EPA proposed
decision on
standards 

## National Ambient Air Quality Standard Review Process

### Draft

– Do Not Cite or Quote lvi June 2012 Figure II Illustration of processes for literature search and st udy selection used for development of ISAs.

Each ISA builds upon the conclusions of previous assessments for the pollutant under 

### 1

review. EPA focuses on peer reviewed literature published following the completion of 

### 2

the previous review and on any new interp retations of previous literature, integrating the 

### 3

results of recent scientific studies with pr evious findings. Important earlier studies may 

### 4

be discussed in detail to reinforce key concepts and conclusions or for reinterpretati on in 

### 5

light of newer data. Earlier studies also are the primary focus in some areas of the 

### 6

document where research efforts have subsided, or if these earlier studies remain the 

### 7

definitive works available in the literature. 

### 8

Selection of studies for inclusion in the ISA is based on t he general scientific quality of 

### 9

the study, and consideration of the extent to which the study is informative and policy



### 10

relevant. Policy relevant and informative studies include those that provide a basis for or 

### 11

describe the relationship between the crite ria pollutant and effects, including studies that 

### 12

offer innovation in method or design and studies that reduce uncertainty on critical issues, 

### 13

such as analyses of confounding or effect modification by copollutants or other variables, 

### 14

analyses of concentrat ion

- response or dose

- response relationships, or analyses related to 

### 15

time between exposure and response. Emphasis is placed on studies that examine effects 

### 16

associated with pollutant concentrations relevant to current population and ecosystem 

### 17 Screened Considered Included

Title

No A bstract F ull text

No No

Recommendations
during P eer Review Literature

Search
Strategies Yes Yes Yes

Citations from

Past Assessments Criteria for study evaluation

include:

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

 Are the air quality data, exposure, or dose metrics of adequate quality and sufficiently representative of information regarding ambient

conditions?

 Are the health, ecological or welfare effect measurements meaningful,

valid and reliable?

 Do the analytical methods provide adequate sensitivity and precision to support conclusions?

### Draft

– Do Not Cite or Quote lvii June 2012 exposures, and particularly those pertaining to concentrations currently found in ambient 

### 1

air. Other studies are included if they contain unique data, such as a previously 

### 2

unreported effect or MOA for an observed effect, or examine multiple concentrations to 

### 3

elucidate ex posure

- response relationships. In general, in assessing the scientific quality 

### 4

and relevance of health and welfare effects studies, the following considerations have 

### 5

been taken into account when selecting studies for inclusion in the ISA. 

### 6

 Are the study pop ulations, subjects, or animal models adequately selected, and 

### 7

are they sufficiently well defined to allow for meaningful comparisons 

### 8

between study or exposure groups? 

### 9

 Are the statistical analyses appropriate, properly performed, and properly 

### 10

interpreted? Are likely covariates adequately controlled or taken into account 

### 11

in the study design and statistical analysis? 

### 12

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

### 13

sufficiently representative of information regarding ambient condit ions? 

### 14

 Are the health, ecological or welfare effect measurements meaningful, valid 

### 15

and reliable? 

### 16

 Do the analytical methods provide adequate sensitivity and precision to 

### 17

support conclusions? 

### 18

Considerations specific to particular disciplines include the follo wing. In selecting 

### 19

epidemiologic studies, EPA considers whether a given study: (1) presents information on 

### 20

associations with short

- or long

- term pollutant exposures at or near conditions relevant to 

### 21

ambient exposures; (2) addresses potential confounding by other pollutants; (3) assesses 

### 22

potential effect modifiers; (4) evaluates health endpoints and populations not previously 

### 23

extensively researched; and (5) evaluates important methodological issues related to 

### 24

interpretation of the health evidence (e.g., lag or time period between exposure and 

### 25

effects, model specifications, thresholds, mortality displacement). 

### 26

Considerations for the selection of research evaluating controlled human exposure or 

### 27

animal toxicological studies includes a focus on studies conducted using relevant 

### 28

pollutant exposures. For both types of studies, relevant pollutant exposures are 

### 29

considered to be those generally within one or two orders of magnitude of ambient 

### 30

concentrations. Studies in which higher doses were used may also be considere d if they 

### 31

provide information relevant to understanding MOA or mechanisms, as noted below. 

### 32

Evaluation of controlled human exposure studies focuses on those that approximated 

### 33

expected human exposure conditions in terms of concentration and duration. Studies 

### 34

should include control exposures to filtered air, as appropriate. In the selection of 

### 35

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

### 36

### Draft

– Do Not Cite or Quote lviii June 2012 potentially at

- risk populations and lifestages such as people with asthma or 

### 1

cardi ovascular diseases, children or older adults; (2) address issues such as concentration



### 2

response or time

- course of responses; and (3) have sufficient statistical power to assess 

### 3

findings. 

### 4

Review of the animal toxicological evidence focuses on studies that approximate 

### 5

expected human dose conditions, which vary depending on the dosimetry, toxicokinetics 

### 6

and biological sensitivity of the particular laboratory animal species or strains studied. 

### 7

Emphasis is placed on studies that: (1) investigate animal models o f disease that can 

### 8

provide information on populations potentially at increased risk of effects; (2) address 

### 9

issues such as concentration

- response or time

- course of responses; and (3) have sufficient 

### 10

statistical power to assess findings. Due to resource con straints on exposure duration and 

### 11

numbers of animals tested, animal studies typically utilize high

- concentration exposures 

### 12

to acquire data relating to mechanisms and assure a measurable response. Emphasis is 

### 13

placed on studies using doses or concentrations generally within 1

- 2 orders of magnitude 

### 14

of current levels. Studies with higher concentration exposures or doses are considered to 

### 15

the extent that they provide useful information to inform understanding of interspecies 

### 16

differences and potential differences between healthy and potentially at

- risk human 

### 17

populations. Results from in vitro studies may also be included if they provide 

### 18

mechanistic insight or further support for results demonstrated in vivo. 

### 19

These criteria provide benchmarks for evaluating various studies and for focusing on the 

### 20

policy

- relevant studies in assessing the body of health, ecological and welfare effects 

### 21

evidence. As stated initially, the intent of the ISA is to provide a concise review, 

### 22

synthesis, and evaluation of the most policy

- relev ant science to serve as a scientific 

### 23

foundation for the review of the NAAQS, not extensive summaries of all health, 

### 24

ecological and welfare effects studies for a pollutant. Of most relevance for inclusion of 

### 25

studies is whether they provide useful qualitativ e or quantitative information on 

### 26

exposure

- effect or exposure

- response relationships for effects associated with pollutant 

### 27

exposures at doses or concentrations relevant to ambient conditions that can inform 

### 28

decisions on whether to retain or revise the stand ards. 

### 29

In developing an ISA, EPA reviews and summarizes the evidence from: studies of 

### 30

atmospheric sciences and exposure; the health effects evidence from toxicological, 

### 31

controlled human exposure and epidemiologic studies; and ecological and welfare effects 

### 32

evidence. In the process of developing the first draft ISA, EPA may convene a public 

### 33

workshop in which EPA and non

- E PA experts review the scientific content of 

### 34

preliminary draft materials to ensure that the ISA is up to date and focused on the most 

### 35

policy

- relevant findings, and to assist EPA with integration of evidence within and across 

### 36

disciplines. The general process for ISA development is illustrated in Figure III. 

### 37

### Draft

– Do Not Cite or Quote lix June 2012 EPA integrates the evidence from across scientific disciplines or study types and 

### 1

chara cterizes the weight of evidence for relationships between the pollutant and various 

### 2

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

### 3

involves collaboration between scientists from various disciplines. As an example, an 

### 4

ev aluation of health effects evidence would include the integration of the results from 

### 5

epidemiologic, controlled human exposure, and toxicological studies, and application of 

### 6

the causal framework (described below) to draw conclusions. Using the causal 

### 7

frame work described in the following section, EPA scientists consider aspects such as 

### 8

strength, consistency, coherence, and biological plausibility of the evidence, and develop 

### 9

causality determinations on the nature of the relationships. Causality determination s often 

### 10

entail an iterative process of review and evaluation of the evidence. Two drafts of the ISA 

### 11

are typically released for review by the CASAC and the public, and comments received 

### 12

on the characterization of the science as well as the implementation of the causal 

### 13

framework are carefully considered in revising and completing the final ISA. 

### 14

### Draft

– Do Not Cite or Quote lx June 2012 Figure III Characterization of the general process of ISA development. 

### Evergreen Literature Search and Study Selection

(See Figure II) 

## Integrated Science Assessment Development Process

Characterization of Evidence Develop initial sections or “building blocks” of scientific evidence for assessment: review and summarize new study results, by outcome/effect category and discipline, for example, toxicological studies of lung function. Summarize findings and conclusions from previous assessment. As appropriate, develop initial conclusions about the available evidence.

Development of Conclusions and Causal Determinations Evaluate weight of evidence and develop judgments regarding causality for health or welfare effect categories, integrating health or welfare effects evidence with information on mode of action and exposure assessment. Develop conclusions regarding concentration

- or dose

- response relationships, potentially at

- risk populations or ecosystems. Peer Input Review of initial draft materials for scientific quality and to facilitate integration.

Draft Integrated Science Assessment released for review Clean Air Scientific Advisory Committee review in public meeting; anticipated review of two drafts of ISA

Final Integrated Science Assessment Evaluation, Synthesis, and Integration of Evidence Integrate evidence from scientific disciplines or study types

– for example, toxicological, controlled human exposure and epidemiologic study findings for particular health outcome. Evaluate evidence for related groups of endpoints or outcomes to draw conclusions regarding health or welfare effect categories.

### Draft

– Do Not Cite or Quote lxi June 2012 

## EPA Framework for Causal Determination

EPA has developed a consistent and transparent basis t o evaluate the causal nature of air 

### 1

pollution

- related health or welfare effects for use in developing ISAs. The framework 

### 2

described below establishes uniform language concerning causality and brings more 

### 3

specificity to the findings. This standardized langu age was drawn from sources across the 

### 4

federal government and wider scientific community, especially the National Academy of 

### 5

Sciences (NAS) Institute of Medicine (IOM) document, Improving the Presumptive 

### 6

Disability Decision

- Making Process for Veterans ( 2008 ) , a comprehensive report on 

### 7

evaluating ca usality. This framework: 

### 8

 describes the kinds of scientific evidence used in establishing a general causal 

### 9

relationship between exposure and health effects; 

### 10

 characterizes the evidence necessary to reach a conclusion about the existence 

### 11

of a causal relationship; 

### 12

 identifies issues and approaches related to uncertainty; and 

### 13

 provides a framework for classifying and characterizing the weight of 

### 14

evidence in support of a general causal relationship. 

### 15

Approaches to assessing the separate and combined lines of evidence 

### 16

(e.g., epidemiologic, controlled human exposure, and animal toxicological studies) have 

### 17

been formulated by a number of regulatory and science agencies, i ncluding the IOM of 

### 18

the NAS ( 2008 )

, International Agency for Research on Cancer ( 2006 )

, U.S. EPA ( 2005 )

, 

### 19

and Centers for Disease Contr ol and Prevention ( 2004 ) . Causal inference criteria have 

### 20

also been described for ecological effects evidence ( U. S. EPA, 1998a ; Fox, 1991 ) . These 

### 21

formalized approaches offer guidance for assessing causality. The frameworks are similar 

### 22

in nature, although adapted to different purposes, and have proven effective in providing 

### 23

a uniform structure and language for causal determinations. 

### 24



## Evaluating Evidence for Inferring Caus ation

The 1964 Surgeon General’s report defined “cause” as a “ significa nt, effectual 

### 25

relationship between an agent and an associated disorder or disease in the host” ( HEW, 

### 26

1964 ) ; more generally, a cause is defined as an agent that brings about an effect or a 

### 27

result. An association is the statistical relationship among variables; alone, however, it is 

### 28

insufficient proof of a causal relationship between an exposure and a health out come. 

### 29

Unlike an association, a causal claim supports the creation of counterfactual claims, that 

### 30

### Draft

– Do Not Cite or Quote lxii June 2012 is, a claim about what the world would have been like under different or changed 

### 1

circumstances ( Samet and Bodurow, 2008 )

. 

### 2

Many of the health and environmental outcomes repo rted in these studies have complex 

### 3

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

### 4

initiated by multiple agents. Outcomes depend on a variety of factors, such as age, 

### 5

genetic susceptibility, nutritional status, imm une competence, and social factors ( Samet 

### 6

and Bodurow, 2008 ; Gee and Payne

- Sturges, 2004 ) . Effects on ecosystems are often also 

### 7

multifactorial with a complex web of causation. Further, exposure to a combination of 

### 8

agents could cause synergistic or antagonistic effects. Thus, the observed risk may 

### 9

represent the net effect of many acti ons and counteractions. 

### 10

In estimating the causal influence of an exposure on health or environmental effects, it is 

### 11

recognized that scientific findings incorporate uncertainty. “Uncertainty” can be defined 

### 12

as having limited knowledge to exactly describe a n existing state or future outcome, 

### 13

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

### 14

Uncertainty analysis may be qualitative or quantitative in nature. In many cases, the 

### 15

analysis is qualitative, and can include profe ssional judgment or inferences based on 

### 16

analogy with similar situations. Quantitative uncertainty analysis may include use of 

### 17

simple measures (e.g., ranges) and analytical techniques. Quantitative uncertainty 

### 18

analysis might progress to more complex measure s and techniques, if needed for decision 

### 19

support. Various approaches to evaluating uncertainty include classical statistical 

### 20

methods, sensitivity analysis, or probabilistic uncertainty analysis, in order of increasing 

### 21

complexity and data requirements. Howe ver, data may not be available for all aspects of 

### 22

an assessment and those data that are available may be of questionable or unknown 

### 23

quality. Ultimately, the assessment is based on a number of assumptions with varying 

### 24

degrees of uncertainty. The ISA general ly evaluates uncertainties qualitatively in 

### 25

assessing the evidence from across studies; in some situations quantitative analysis 

### 26

approaches, such as meta

- regression, may be used. 

### 27

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

### 28

estimates. It is well understood that studies reporting non

- null findings are more likely to 

### 29

be published than reports of null findings, and publication bias can also result in 

### 30

overestimation of effect estimate sizes ( Ioannidis, 2008 ) . For example, effect estima tes 

### 31

from single

- city epidemiologic studies have been found to be generally larger than those 

### 32

from multicity studies ( Bell et al., 2005 )

. 

### 33

### Draft

– Do Not Cite or Quote lxiii June 2012 

## Consideration of Evidence from Scientific Disciplines

Moving from association to causation involves the elimination of alternative explanations 

### 1

for the association. The ISA focuses on evaluation of the findings from the body of 

### 2

evidence, drawin g upon the results of all studies determined to meet the criteria described 

### 3

previously. Causality determinations are based on the evaluation and synthesis of 

### 4

evidence from across scientific disciplines. The relative importance of different types of 

### 5

evidenc e varies by pollutant or assessment, as does the availability of different types of 

### 6

evidence for causality determination. Three general types of studies inform consideration 

### 7

of human health effects: controlled human exposure, epidemiologic and toxicologica l 

### 8

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

### 9

experimental approaches (e.g., greenhouse, laboratory, field) and numerous disciplines 

### 10

(e.g., community ecology, biogeochemistry and paleontological/historical 

### 11

reconstructi ons). 

### 12

Direct evidence of a relationship between pollutant exposures and human health effects 

### 13

comes from controlled human exposure studies. Controlled human exposure studies 

### 14

experimentally evaluate the health effects of administered exposures in human volun teers 

### 15

under highly controlled laboratory conditions. Also referred to as human clinical studies, 

### 16

these experiments allow investigators to expose subjects to known concentrations of air 

### 17

pollutants under carefully regulated environmental conditions and activ ity levels. In some 

### 18

instances, controlled human exposure studies can also be used to characterize 

### 19

concentration

- response relationships at pollutant concentrations relevant to ambient 

### 20

conditions. Controlled human exposures are typically conducted using a ra ndomized 

### 21

crossover design, with subjects exposed both to the pollutant and a clean air control. In 

### 22

this way, subjects serve as their own controls, effectively controlling for many potential 

### 23

confounders. However, controlled human exposure studies are limite d by a number of 

### 24

factors, including small sample size and short exposure time. For example, exposure 

### 25

patterns relevant to understanding real

- world exposures, especially long

- term exposures, 

### 26

are generally not practical to replicate in a laboratory setting. In addition, although 

### 27

subjects do serve as their own controls, personal exposure to pollutants in the hours and 

### 28

days preceding the controlled exposures may vary significa ntly between and within 

### 29

individuals. Finally, controlled human exposure studies requir e investigators to adhere to 

### 30

stringent health criteria for subjects included in the study, and therefore the results often 

### 31

cannot be generalized to an entire population. Although some controlled human exposure 

### 32

studies have included health

- compromised indiv iduals such as those with respiratory or 

### 33

cardiovascular disease, these individuals must also be relatively healthy and may not 

### 34

represent the most sensitive individuals in the population. In addition, the study design is 

### 35

limited to exposures and endpoints t hat are not expected to result in severe health 

### 36

outcomes. Thus, not observing an effect in controlled human exposure studies does not 

### 37

### Draft

– Do Not Cite or Quote lxiv June 2012 necessarily mean that a causal relationship does not exist. While controlled human 

### 1

exposure studies provide important info rmation on the biological plausibility of 

### 2

associations observed in epidemiologic studies, observed effects in these studies may 

### 3

underestimate the response in certain populations. 

### 4

Epidemiologic studies provide important information on the associations betwe en health 

### 5

effects and exposure of human populations to ambient air pollution. In epidemiologic or 

### 6

observational studies of humans, the investigator generally does not control exposures or 

### 7

intervene with the study population. Broadly, observational studies can describe 

### 8

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

### 9

e.g., cross

- sectional, prospective cohort, panel and time

- series studies. “Natural 

### 10

experiments” offer the opportunity to investigate changes in health rela ted to a change in 

### 11

exposure, such as closure of a pollution source. 

### 12

In evaluating epidemiologic studies, consideration of many study design factors and 

### 13

issues must be taken into account to properly inform their interpretation. One key 

### 14

consideration is eva luation of the potential contribution of the pollutant to a health 

### 15

outcome when it is a component of a complex air pollutant mixture. Reported effect 

### 16

estimates in epidemiologic studies may reflect: independent effects on health outcomes; 

### 17

effects of the pol lutant acting as an indicator of a copollutant or a complex ambient air 

### 18

pollution mixture; effects resulting from interactions between that pollutant and 

### 19

copollutants. 

### 20

In the evaluation of epidemiologic evidence, one important consideration is potential 

### 21

co nfounding. Confounding is “... a confusion of effects. Specifically, the apparent effect 

### 22

of the exposure of interest is distorted because the effect of an extraneous factor is 

### 23

mistaken for or mixed with the actual exposure effect (which may be null)” ( Rothman 

### 24

and Greenland, 1998 ) . One approach to remove spurious associations due to possible 

### 25

confounders is to control for characteristics that may differ between exposed and 

### 26

unexposed persons; this is frequently termed “adjustment.” S cientific judgment is needed 

### 27

to evaluate likely sources and extent of confounding, together with consideration of how 

### 28

well the existing constellation of study designs, results, and analyses address this 

### 29

potential threat to inferential validity. A confounde r is associated with both the exposure 

### 30

and the effect; for example, confounding can occur between correlated pollutants that are 

### 31

associated with the same effect. 

### 32

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

### 33

wi th none of them being completely satisfactory. Multivariable regression models 

### 34

constitute one tool for estimating the association between exposure and outcome after 

### 35

adjusting for characteristics of participants that might confound the results. The use of 

### 36

m ultipollutant regression models has been the prevailing approach for controlling 

### 37

### Draft

– Do Not Cite or Quote lxv June 2012 potential confounding by copollutants in air pollution health effects studies. Finding the 

### 1

likely causal pollutant from multipollutant regression models is made difficult by t he 

### 2

possibility that one or more air pollutants may be acting as a surrogate for an unmeasured 

### 3

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

### 4

than one pollutant may exert similar health effects, resulting in indepe ndently observed 

### 5

associations for multiple pollutants. The number and degree of diversity of covariates, as 

### 6

well as their relevance to the potential confounders, remain matters of scientific 

### 7

judgment. Despite these limitations, the use of multipollutant mo dels is still the 

### 8

prevailing approach employed in most air pollution epidemiologic studies and provides 

### 9

some insight into the potential for confounding or interaction among pollutants. 

### 10

Confidence that unmeasured confounders are not producing the findings i s increased 

### 11

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

### 12

exposures, each of which might eliminate another source of confounding from 

### 13

consideration. For example, multicity studies can provide insight on potential 

### 14

confo unding through the use of a consistent method to analyze data from across locations 

### 15

with different levels of copollutants and other covariates . Intervention studies, because of 

### 16

their quasi

- experimental nature, can be particularly useful in characterizing causation. 

### 17

Another important consideration in the evaluation of epidemiologic evidence is effect 

### 18

modification, which occurs when the effect differs between subgroups or strata; for 

### 19

example, effect estimates that vary by age group or potential risk factor. “Effect

- measure 

### 20

modification differs from confounding in several ways. The main difference is that, 

### 21

whereas confounding is a bias that the investigator hopes to prevent or remove from the 

### 22

effect estimate, effect

- measure modification is a property of the e ffect under study

... In 

### 23

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

### 24

estimate effect

- measure modification” ( Rothman and Greenland, 1998 ) . When a risk 

### 25

factor is a confounder, it is the true cause of the association observed between the 

### 26

exposure and the outcome; when a risk factor is an effect modifier, it changes the 

### 27

magnitude of the association between the exposure and the outcome in stratified analyses. 

### 28

For example, the presence of a p reexisting disease or indicator of low socioeconomic 

### 29

status may be an effect modifier in causing increased risk of effects related to air 

### 30

pollution exposure. It is often possible to stratify the relationship between health outcome 

### 31

and exposure by one or mo re of these potential effect modifiers. For variables that 

### 32

modify the association, effect estimates in each stratum will be different from one another 

### 33

and different from the overall estimate, indicating a different exposure

- response 

### 34

relationship may exist in populations represented by these variables. 

### 35

Exposure measurement error, which refers to the uncertainty associated with using 

### 36

exposure metrics to represent the actual exposure of an individual or population, can be 

### 37

### Draft

– Do Not Cite or Quote lxvi June 2012 an important contributor to variabilit y in air pollution epidemiologic study results. 

### 1

Exposure error can under

- or over

- estimate epidemiologic associations between ambient 

### 2

pollutant concentrations and health outcomes by biasing effect estimates toward or away 

### 3

from the null, and tends to widen confidence intervals around those estimates. There are 

### 4

several components that contribute to exposure measurement error in air pollution 

### 5

epidemiologic studies, including the difference between true and measured ambient 

### 6

concentrations, the difference betwee n average personal exposure to ambient pollutants 

### 7

and ambient concentrations at central monitoring sites, and the use of average population 

### 8

exposure rather than individual exposure estimates. Factors that could influence exposure 

### 9

estimates include nonambie nt sources of exposure, topography of the natural and built 

### 10

environment, meteorology, measurement errors, time

- location

- activity patterns and extent 

### 11

to which ambient pollutants penetrate indoor environments. The importance of exposure 

### 12

misclassification var ies with study design and is dependent on the spatial and temporal 

### 13

aspects of the design. 

### 14

The third main type of health effects evidence, animal toxicological studies, provides 

### 15

information on the pollutant’s biological action under controlled and monitored exposure 

### 16

circumstances. Taking into account physiological differences of the experimental species 

### 17

from humans, these studies inform characterization of health effects of concern, 

### 18

exposure

- response relationships and MOAs. Further, animal models can inform 

### 19

determinations of at

- risk populations. These studies evaluate the effects of exposures to a 

### 20

variety of pollutants in a highly controlled laboratory setting and allow exploration of 

### 21

toxicological pathways or mechanisms by which a pollutant may cause effects

. 

### 22

Understanding the biological mechanisms underlying various health outcomes can prove 

### 23

crucial in establishing or negating causality. In the absence of human studies data, 

### 24

extensive, well

- conducted animal toxicological studies can support determinations of 

### 25

causality, if the evidence base indicates that similar responses are expected in humans 

### 26

under ambient exposure conditions. 

### 27

Interpretations of animal toxicological studies are affected by limitations associated with 

### 28

extrapolation between animal and human responses. The differences between humans 

### 29

and other species have to be taken into consideration, including metabolism, hormonal 

### 30

regulation, breathing pattern, and differences in lung structure and anatomy. Also, in spite 

### 31

of a high degree of homology and th e existence of a high percentage of orthologous 

### 32

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

### 33

alterations at the gene level is complicated by species

- specific differences in 

### 34

transcriptional regulation. Given these differen ces, there are uncertainties associated with 

### 35

quantitative extrapolations of observed pollutant

- induced pathophysiological alterations 

### 36

between laboratory animals and humans, as those alterations are under the control of 

### 37

widely varying biochemical, endocrine , and neuronal factors. 

### 38

### Draft

– Do Not Cite or Quote lxvii June 2012 For ecological effects assessment, both laboratory and field studies (including field 

### 1

experiments and observational studies) can provide useful data for causality 

### 2

determination. Because conditions can be controlled in laboratory stu dies, responses may 

### 3

be less variable and smaller differences easier to detect. However, the control conditions 

### 4

may limit the range of responses (e.g., animals may not be able to seek alternative food 

### 5

sources), so they may not reflect responses that would o ccur in the natural environment. 

### 6

In addition, larger

- scale processes are difficult to reproduce in the laboratory. 

### 7

Field observational studies measure biological changes in uncontrolled situations, and 

### 8

describe an association between a disturbance and an e cological effect. Field data can 

### 9

provide important information for assessments of multiple stressors or where site

- specific 

### 10

factors significa ntly influence exposure. They are also often useful for analyses of larger 

### 11

geographic scales and higher levels of b iological organization. However, because 

### 12

conditions are not controlled, variability is expected to be higher and differences harder 

### 13

to detect. Field surveys are most useful for linking stressors with effects when stressor 

### 14

and effect levels are measured con currently. The presence of confounding factors can 

### 15

make it difficult to attribute observed effects to specific stressors. 

### 16

Intermediate between laboratory and field are studies that use environmental media 

### 17

collected from the field to examine response in th e laboratory, and experiments that are 

### 18

performed in the natural environment while controlling for some environmental 

### 19

conditions (i.e., mesocosm studies). This type of study in manipulated natural 

### 20

environments can be considered a hybrid between a field expe riment and laboratory study 

### 21

since some aspects are performed under controlled conditions but others are not. They 

### 22

make it possible to observe community and/or ecosystem dynamics, and provide strong 

### 23

evidence for causality when combined with findings of stud ies that have been made 

### 24

under more controlled conditions. 

### 25



## Application of Framework for Causal Determination

In its evaluation of the scientific evidence on health or welfare effects of criteria 

### 26

pollutants, EPA determines the weight of evidence in support o f causation and 

### 27

characterizes the strength of any resulting causal classification. EPA also evaluates the 

### 28

quantitative evidence and draws scientific conclusions, to the extent possible, regarding 

### 29

the concentration

- response relationships and the loads to ec osystems, exposure doses or 

### 30

concentrations, duration and pattern of exposures at which effects are observed. 

### 31

### Draft

– Do Not Cite or Quote l xviii June 2012 Table I Aspects to aid in judging causality

Consistency of the

observed association An inference of causality is strengthened when a pattern of elevated risks is observed across several independent studies. 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 one line of evidence (e.g., epidemiologic, clinical or animal studies) may be strengthened by other lines of evidence that support a cause

- and

- effect interpretation of the association. Evidence on ecological or welfare effects may be drawn from a variety of experimental approaches (e.g., greenhouse, laboratory, and field) and subdisciplines of ecology (e.g., community ecology, biogeochemistry and paleo ntological/historical reconstructions). The coherence of evidence from various fields greatly adds to the strength of an inference of causality. In addition, there may be coherence in demonstrating effects across multiple study designs or related health en dpoints within one

scientific line of evidence.

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 mecha nistic 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.

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., increasin g effects observed following longer exposure times).

Strength of the observed

association The finding of large, precise risks increases confidence that the association is not likely due to chance, bias, or other factors. However, it is noted that a small magnitude in an effect estimate may represent a substantial effect in a population.

Experimental evidence Strong evidence for causality can be provided through “natural experiments” when a change in exposure is found to result in a change in occurrence o r 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.

Specific ity of the

observed association Evidence linking a specific outcome to an exposure can provide a strong argument for causation. However, it must be recognized that rarely, if ever, does exposure to a pollutant invariably predict the

occurrence of an outcom e, and that a given outcome may have multiple causes.

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 r egarding likely causality.

To aid judgment, various “aspects” 1 of causality have been discussed by many 

### 1

philosophers and scientists. The 1964 Surgeon General’s report on tobacco smoking 

### 2

discussed criteria for the evaluation of epidemiologic studies, focusing on consistency, 

### 3

strength, specificity, temporal relationshi p, and coherence ( HEW, 1964 )

. Sir Austin 

### 4

Bradford Hill ( Hill, 1965 ) articulated aspects of causality in epidemio logy and public 

### 5

health that have been widely used ( Samet and Bodurow, 2008 ; IARC, 2006 ; U.S. EPA, 

### 6

2005 ; CDC, 2004 ) . These aspects ( Hill, 1965 ) have been modified (Table I) for use in 

### 7

causal determinations specific to health and welfare effects for pollutant exposures ( U.S. 

### 8

EPA, 2009d )

. 2 Although these aspects provide a framework for assessing the evidence, 

### 9

they do not lend themselves to being considered in terms of simple formulas or fixed 

### 10

1 The “aspects” described by Sir Austin Bradford Hill ( Hill, 1965 ) h ave become, in the subsequent literature, more commonly described as “criteria.” The original term “aspects” is used here to avoid confusion with “ criteria ” as it is used, with different meaning,

in the Clean Air Act.

2 The Hill aspects were developed for inte rpretation 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 E PA’s Guidelines for Carcinogen Risk Assessment.

### Draft

– Do Not Cite or Quote lxix June 2012 rules of evidence leading to conclusions about causality ( Hill, 1965 ) . For example, one 

### 1

cannot simply count the number of studies reporting statistically significa nt results or 

### 2

stati stically non significa nt results and reach credible conclusions about the relative 

### 3

weight of the evidence and the likelihood of causality. Rather, these aspects are taken into 

### 4

account with the goal of producing an objective appraisal of the evidence, inform ed by 

### 5

peer and public comment and advice, which includes weighing alternative views on 

### 6

controversial issues. In addition, it is important to note that the aspects in Table I cannot 

### 7

be used as a strict checklist, but rather to determine the weight of the ev idence for 

### 8

inferring causality. In particular, not meeting one or more of the principles does not 

### 9

automatically preclude a determination of causality [see discussion in ( CDC, 2004 ) ]. 

### 10



## Determination of Causality

In the ISA, EPA assesses the body of relevant literature, building upon evidence available 

### 11

during previous NAAQS reviews, to dr aw conclusions on the causal relationships 

### 12

between relevant pollutant exposures and health or environmental effects. ISAs use a 

### 13

five

- level hierarchy that classifies the weight of evidence for causation 1 . In developing 

### 14

this hierarchy, EPA has drawn on the w ork of previous evaluations, most prominently the 

### 15

IOM’s Improving the Presumptive Disability Decision

- Making Process for Veterans 

### 16

( Samet and Bodurow, 2008 ) , EPA’s Guidelines for Carcinogen Risk Assessment ( U.S. 

### 17

EPA, 2005 ) , and the U.S. Surgeon General’s smoking report ( CDC, 2004 ) . This weight 

### 18

of evidence evaluation is based on various lines of evidence from across the health and 

### 19

environmental effects disciplines. These separate judgments are integrated into a 

### 20

qualitative s tatement about the overall weight of the evidence and causality. The five 

### 21

descriptors for causal determination are described in Table II. 

### 22

Determination of causality involves the evaluation of evidence for different types of 

### 23

health, ecological or welfare ef fects associated with short

- and long

- term exposure 

### 24

periods. In making determinations of causality, evidence is evaluated for major outcome 

### 25

categories and then conclusions are drawn based upon the integration of evidence from 

### 26

across disciplines and also ac ross the spectrum of related endpoints. In making causal 

### 27

judgments, the ISA focuses on major outcome categories (e.g., respiratory effects, 

### 28

vegetation growth), by evaluating the coherence of evidence across a spectrum of related 

### 29

endpoints (e.g., health eff ects ranging from inflammatory effects to respiratory mortality) 

### 30

to draw conclusions regarding causality. In discussing the causal determination, EPA 

### 31

1 T he Center for Disease Control ( 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 Carci nogen Risk Assessment and to provide a more nuanced set of categories.

### Draft

– Do Not Cite or Quote lxx June 2012 characterizes the evidence on which the judgment is based, including strength of 

### 1

evidence for individual e ndpoints within the major outcome category. 

### 2

In drawing judgments regarding causality for the criteria air pollutants, the ISA focuses 

### 3

on evidence of effects in the range of relevant pollutant exposures or doses, and not on 

### 4

determination of causality at any dose. Emphasis is placed on evidence of effects at doses 

### 5

(e.g., blood lead concentration) or exposures (e.g., air concentrations) that are relevant to, 

### 6

or somewhat above, those currently experienced by the population. The extent to which 

### 7

studies of higher concentrations are considered varies by pollutant and major outcome 

### 8

category, but generally includes those with doses or exposures in the range of one to two 

### 9

orders of magnitude above current or ambient conditions. Studies that use higher doses or 

### 10

exposur es may also be considered to the extent that they provide useful information to 

### 11

inform understanding of mode of action, interspecies differences, or factors that may 

### 12

increase risk of effects for a population. Thus, a causality determination is based on 

### 13

wei ght of evidence evaluation for health, ecological or welfare effects, focusing on the 

### 14

evidence from exposures or doses generally ranging from current levels to one or two 

### 15

orders of magnitude above current levels. 

### 16

In addition, EPA evaluates evidence relevan t to understand the quantitative relationships 

### 17

between pollutant exposures and health, ecological or welfare effects. This includes 

### 18

evaluation of the form of concentration

- response or dose

- response relationships and, to 

### 19

the extent possible, drawing conclus ions on the levels at which effects are observed. The 

### 20

ISA also draws scientific conclusions regarding important exposure conditions for effects 

### 21

and populations that may be at greater risk for effects, as described in the following 

### 22

section. 

### 23

### Draft

– Do Not Cite or Quote lxxi June 2012 Table II Weight of evidence for causal determination

Health Effects Ecological and Welfare Effects

Causal relationship Evidence is sufficient to conclude that there is a causal relationship with relevant pollutant exposures (i.e., doses or exposures generally within one to two orders of magnitude of current levels). 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 stu dies 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 multiple high

- quali ty studies Evidence is sufficient to conclude that there is a causal relationship with relevant pollutant exposures i.e., doses or exposures generally within one to two orders of magnitude of current levels). 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 inf erence 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

hu man data are available. Evidence generally includes multiple high

- quality studies. 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 polluta nt 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. For example, (a) at lea st one high

- quality epidemiologic study shows an association with a given health outcome but the results of other studies are inconsistent; or (b) a

well

- conducted toxicological study, such as those conducted in the National Toxicology Program (NTP),

shows effects in animal species. 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 stud ies 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 statistic al 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 at

- risk populations, ar e 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.

### Draft

– Do Not Cite or Quote lxxii June 2012 

## Quantitative Relationships: Effec ts on Human Populations

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

### 1

outcome category, important questions regarding quantitative relationships include: 

### 2

 What is the concentration

- response, exposure

- response, or dose

- response 

### 3

relationship in the human population? 

### 4

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

### 5

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

### 6

important? 

### 7

 What populations and lifestages appear to be differentially affected (i.e., more 

### 8

at risk of experiencing effects)? 

### 9

To address these questions, the entirety of quantitative evidence is evaluated to 

### 10

characterize pollutant concentrations and exposure durations at which effects were 

### 11

observed for exposed populations, including populations and lifestages potentially at 

### 12

increased risk. To accomplish this, evidence is considered from multiple and diverse 

### 13

types of studies, and a study or set of studies that best approximates the concentration



### 14

response relation ships between health outcomes and the pollutant may be identified. 

### 15

Controlled human exposure studies provide the most direct and quantifiable exposure



### 16

response data on the human health effects of pollutant exposures. To the extent available, 

### 17

the ISA evalua tes results from across epidemiologic studies that use various methods to 

### 18

characterize the form of relationships between the pollutant and health outcomes and 

### 19

draws conclusions on the shape of these relationships. Animal data may also inform 

### 20

evaluation of concentration

- response relationships, particularly relative to MOAs and 

### 21

characteristics of at

- risk populations. 

### 22

An important consideration in characterizing the public health impacts associated with 

### 23

exposure to a pollutant is whether the concentration

- res ponse relationship is linear across 

### 24

the range of concentrations or if nonlinear relationships exist along any part of this range. 

### 25

Of particular interest is the shape of the concentration

- response curve at and below the 

### 26

level of the current standards. Vario us sources of variability and uncertainty, such as low 

### 27

data density in the lower concentration range, possible influence of exposure 

### 28

measurement error, and variability between individuals in susceptibility to air pollution 

### 29

health effects, tend to smooth an d “linearize” the concentration

- response function, and 

### 30

thus can obscure the existence of a threshold or nonlinear relationship. Since individual 

### 31

thresholds vary from person to person due to individual differences such as genetic level 

### 32

susceptibility or pre existing disease conditions (and even can vary from one time to 

### 33

another for a given person), it can be difficult to demonstrate that a threshold exists in a 

### 34

population study. These sources of variability and uncertainty may explain why the 

### 35

### Draft

– Do Not Cite or Quote lxxiii June 2012 available human data at ambient concentrations for some environmental pollutants 

### 1

(e.g., particulate matter [PM], O 3 , lead [Pb], environmental tobacco smoke [ETS], 

### 2

radiation) do not exhibit thresholds for cancer or noncancer health effects, even though 

### 3

likely mechanisms in clude nonlinear processes for some key events. These attributes of 

### 4

human population dose

- response relationships have been extensively discussed in the 

### 5

broader epidemiologic literature ( Rothman and Greenland, 1998 )

. 

### 6

Finally, id entification of the population groups or lifestages that may be at greater risk of 

### 7

health effects from air pollutant exposures contributes to an understanding of the public 

### 8

health impact of pollutant exposures. In the ISA, the term “at

- risk population” is used to 

### 9

encompass populations or lifestages that have a greater likelihood of experiencing health 

### 10

effects related to exposure to an air pollutant due to a variety of factors ; other terms used 

### 11

in the literature include susceptible, vulnerable, and sensitive . These factors may be 

### 12

intrinsic, such as genetic or developmental factors, race, gender, lifestage, or the presence 

### 13

of preexisting diseases, or they may be extrinsic, such as socioeconomic status (SES), 

### 14

activity pattern and exercise level, reduced access to health care, low educational 

### 15

attainment, or increased pollutant exposures (e.g., near roadways). Epidemiologic studies 

### 16

can help identify populations potentially at increased risk of effects by evaluating health 

### 17

responses in the study population. Example s include testing for interactions or effect 

### 18

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

### 19

using animal models of susceptibility or disease can also inform the extent to which 

### 20

health risks are likely greater in s pecific population groups. 

### 21



## Quantitative Relationships: Effects on Ecosystems or Public

Welfare

Key questions for understanding the quantitative relationships between exposure (or 

### 22

concentration or deposition) to a pollutant and risk to ecosystems or the pub lic welfare 

### 23

include: 

### 24

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

### 25

populations, functions, etc.) appear to be affected, or are more sensitive to 

### 26

effects? Are there differences between locations or materials in welfare effects 

### 27

res ponses, such as impaired visibility or materials damage? 

### 28

 Under what exposure conditions (amount deposited or concentration, duration 

### 29

and pattern) are effects seen? 

### 30

 What is the shape of the concentration

- response or exposure

- response 

### 31

relationship? 

### 32

Evaluat ions of causality generally consider the probability of quantitative changes in 

### 33

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

### 34

### Draft

– Do Not Cite or Quote lxxiv June 2012 of exposure

- response relationships for ecological effects is the great regional and lo cal 

### 1

spatial variability, as well as temporal variability, in ecosystems. Thus, exposure



### 2

response relationships are often determined for a specific ecological system and scale, 

### 3

rather than at the national or even regional scale. Quantitative relationships t herefore are 

### 4

available site by site and may differ greatly between ecosystems. 

### 5



## Concepts in Evaluating Adversity of Health Effects

In evaluating health evidence, a number of factors can be considered in delineating 

### 6

between adverse and nonadverse health eff ects resulting from exposure to air pollution

. 

### 7

Some health outcomes, such as hospitalization for respiratory or cardiovascular diseases, 

### 8

are clearly considered adverse. It is more difficult to determine the extent of change that 

### 9

constitutes adversity in more subtle health measures. These include a wi de variety of 

### 10

responses, such as alterations in markers of inflammation or oxidative stress, changes in 

### 11

pulmonary function or heart rate variability, or alterations in neurocognitive function 

### 12

measures. The challenge is determining the magnitude of change i n these measures when 

### 13

there is no clear point at which a change become adverse; for example, what percentage 

### 14

change in a lung function measure represents an adverse effect. What constitutes an 

### 15

adverse health effect may vary between populations. Some change s that may not be 

### 16

considered adverse in healthy individuals would be potentially adverse in more at

- risk 

### 17

individuals. 

### 18

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

### 19

by the American Thoracic Society (ATS) in an off icial statement titled What Constitutes 

### 20

an Adverse Health Effect of Air Pollution? ( 2000b )

. An air pollution

- induced shift in the 

### 21

population distribution of a given risk factor for a health outcome was viewed as adverse, 

### 22

even though it may not increase the risk of any one individual to an unacceptable level

. 

### 23

For example, a population of asthmatics could have a distribution of lung function such 

### 24

that no identifiable individual has a level associated with significa nt impairment. 

### 25

Exposure to air pollution could shift the distribution such that no identifiable individ ual 

### 26

experiences clinically relevant effects. This shift toward decreased lung function, 

### 27

however, would be considered adverse because individuals within the population would 

### 28

have diminished reserve function and therefore would be at increased risk to furthe r 

### 29

environmental insult. The committee also observed that elevations of biomarkers, such as 

### 30

cell number and types, cytokines and reactive oxygen species, may signal risk for ongoing 

### 31

injury and clinical effects or may simply indicate transient responses that can provide 

### 32

insights into mechanisms of injury, thus illustrating the lack of clear boundaries that 

### 33

separate adverse from nonadverse effects. 

### 34

### Draft

– Do Not Cite or Quote lxxv June 2012 The more subtle health outcomes may be connected mechanistically to health events that 

### 1

are clearly adverse. For e xample, air pollution may affect markers of transient myocardial 

### 2

ischemia such as ST

- segment abnormalities and onset of exertional angina. These effects 

### 3

may not be apparent to the individual, yet may still increase the risk of a number of 

### 4

cardiac events, i ncluding myocardial infarction and sudden death. Thus, small changes in 

### 5

physiological measures may not appear to be clearly adverse when considered alone, but 

### 6

may be a part of a coherent and biologically plausible chain of related health outcomes 

### 7

that rang e up to responses that are very clearly adverse, such as hospitalization or 

### 8

mortality. 

### 9



## Concepts in Evaluating Adversity of Ecological Effects

Adversity of ecological effects can be understood in terms ranging in scale from the 

### 10

cellular level to the individ ual organism and to the population, community, and 

### 11

ecosystem levels. In the context of ecology, a population is a group of individuals of the 

### 12

same species, and a community is an assemblage of populations of different species 

### 13

interacting with one another th at inhabit an area. An ecosystem is the interactive system 

### 14

formed from all living organisms and their abiotic (physical and chemical) environment 

### 15

within a given area ( IPCC, 2007a ) . The boundaries of wha t could be called an ecosystem 

### 16

are somewhat arbitrary, depending on the focus of interest or study. Thus, the extent of an 

### 17

ecosystem may range from very small spatial scales to, ultimately, the entire Earth 

### 18

( IPCC, 2007a )

. 

### 19

Effects on an individual organism are generally not considered to be adverse to public 

### 20

welfare. However if effects occur to enough individuals within a population, then 

### 21

communities and ecosystems may be disrupted. Changes to populations , communities 

### 22

and ecosystems can in turn result in an alteration of ecosystem processes. Ecosystem 

### 23

processes are defined as the metabolic functions of ecosystems including energy flow, 

### 24

elemental cycling, and the production, consumption and decomposition of organic matter 

### 25

( U.S. EPA, 2002 ) . Growth, reproduction, and mortality are species

- level endpoints that 

### 26

can be clearly linked to community and ecosystem effects and are considered to be 

### 27

adverse when negatively affected. Other endpoints such as changes in behavior and 

### 28

physiological stress can decrease ecological fitness of an organism, but are harder to link 

### 29

unequivocally to effects at the population, community, and ecosystem level. The degree 

### 30

to which pollutant exposure is considered adverse may also depend on the location and its 

### 31

intended use (i.e., city park, commercial

, cropland). Support for consideration of 

### 32

adversity beyond the species level by making explicit the linkages between stress

- related 

### 33

effects at the species and effects at the ecosystem level is found in A Framework for 

### 34

Assessing and Reporting on Ecological C ondition: an SAB report ( U.S. EPA, 2002 )

. 

### 35

Additionally, the National Acid Precipitation Assessmen t Program (NAPAP) uses the 

### 36

### Draft

– Do Not Cite or Quote lxxvi June 2012 following working definition of “ adverse ecological effects ” in the preparation of reports 

### 1

to Congress mandated by the Clean Air Act: “any injury (i.e., loss of chemical or physical 

### 2

quality or viability) to any ecological or ecos ystem component, up to and including at the 

### 3

regional level, over both long and short terms.” 

### 4

On a broader scale, ecosystem services may provide indicators for ecological impacts. 

### 5

Ecosystem services are the benefits that people obtain from ecosystems ( UNEP, 2003 )

. 

### 6

According to the Millennium Ecosystem Assessment, ecosystem services include: 

### 7

“provisioning services such as food and water; regulating services such as regulation of 

### 8

floods, dro ught, land degradation, and disease; supporting services such as soil formation 

### 9

and nutrient cycling; and cultural services such as recreational, spiritual, religious and 

### 10

other nonmaterial benefits.” For example, a more subtle ecological effect of pollutio n 

### 11

exposure may result in a clearly adverse impact on ecosystem services if it results in a 

### 12

population decline in a species that is recreationally or culturally important

. 

### 13

### Draft

– Do Not Cite or Quote lxxvii June 2012 

### References

ATS (American Thoracic Society). (2000b). What constitutes an adverse health effect of air pollution? This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July

1 999. Am J Respir Crit Care Med 161: 665

- 673.
Bell, ML; Dominici, F; Samet, JM. (2005). A meta

- analysis of time

- series studies of ozone and mortality with compa rison to the national morbidity, mortality, and air pollution study. Epidemiology 16: 436

- 445. http://dx.doi.org/10.1097/01.ede.0000165817.40152.85

CDC (Centers for Disease Control and Prevention). (2004). The health consequences of smoking: A report of the Surgeon General. Washington, DC: U.S. Department of Health a nd Human Services. http://www.surgeongeneral.gov/library/smokingconsequences/
Fox, GA. (1991). Practical causal inference for ecoepidemiologists. J Toxicol Environ Health A 33: 359

- 373. http://dx.doi.org/10.1080/15287399109531535 Gee, GC; Payne

- Sturges, DC. (2004). Environmental health disparities: A framework integrating psychosocial and environmental concepts. Environ Health Perspect 112: 1645

- 1653. http://dx.doi.org/10.1289/ehp.7074

HEW (U.S. Department of Health, Education and Welfare). (1964). Smoking and health: Report of the advisory committe e to the surgeon general of the public health service. Washington, DC: U.S. Department of Health, Education, and Welfare. http://profiles.nlm.nih.gov/ps/retrieve/ResourceMetadata /NNBBMQ
Hill, AB. (1965). The environment and disease: Association or causation? Proc R Soc Med 58: 295

- 300.

IARC (International Agency for Research on Cancer). (2006). Preamble to the IARC monographs. Lyon,

France. http://mo nographs.iarc.fr/ENG/Preamble/
Ioannidis, JPA. (2008). Why most discovered true associations are inflated. Epidemiology 19: 640

- 648. http://dx.doi.org/10.1097/EDE.0b013e31818131e7

IPCC (Intergovernmental Panel on Climate Change). (2007a). Climate change 2007: Impacts, adaptation and vulnerability. Cambridge, UK: Cambridge University Press.

Roth man, KJ; Greenland, S. (1998). Modern epidemiology (2nd ed.). Philadelphia, PA: Lippincott, Williams,

& Wilkins.
Samet, JM; Bodurow, CC. (2008). Improving the presumptive disability decision

- making process for veterans. In JM Samet; CC Bodurow (Eds.). Washington, DC: National Academies Press. http://www.nap.edu/openbook.php?record_id=11908

U.S. EPA (U.S. Environmental Protection Agency). (1998a). Guidelines for ecological risk assessment [EPA Report]. (EPA/630/R

- 95/002F). Washington, DC. http://www.epa.gov/raf/publications/guidelines

ecological

- risk

- assessment.htm

U.S. EPA (U.S. Environmental Protection Agency). (2002). A framework for assessing and reporting on ecological condition: An SAB report [EPA Report]. Washington, DC. http://www.ntis.gov/sear ch/product.aspx?ABBR=PB2004100741

U.S. EPA (U.S. Environmental Protection Agency). (2005). Guidelines for carcinogen risk assessment [EPA Report]. (EPA/630/P

- 03 /001F). Washington, DC. http://www.epa.gov/cancerguidelines/

U.S. EPA (U.S. Environmental Protection Agency) . (2009d). Integrated science assessment for particulate matter [EPA Report]. (EPA/600/R

- 08/139F). Research Triangle Park, NC. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=2165 46

UNEP (United Nations Environment Programme). (2003). Millennium Ecosystem Assessment: Ecosystems

and human well

- being: A framework for assessment. Washington , DC: Island Press.