Draft

– Do Not Cite or Quote xlix September 2011 

## 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

- relevant science to serve as a scientific 

### 4

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

### 5

gen eral process for NAAQS reviews is described at 

### 6

http://www.epa.gov/ttn/naaqs/review.html ; information for individual NAAQS reviews is 

### 7

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

### 8

steps and criteria used in developing an ISA; for each ISA, specific details and 

### 9

considerations are included in the introductory section for that assessment. 

### 10

The fundamental process for developi ng an ISA includes: 

### 11

 literature searches; 

### 12

 study selection; 

### 13

 evaluation and integration of the evidence; and 

### 14

 development of scientific conclusions and causal judgments. 

### 15

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

### 16

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

### 17

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

### 18

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

### 19

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

### 20

Search strategies are designed for pollutants and scientific disciplines and iteratively 

### 21

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

### 22

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

### 23

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

### 24

independent identification of relevant literature by expert s cientists; review of citations in 

### 25

previous assessments and identification by the public and CASAC during the external 

### 26

review process. Publications considered for inclusion in the ISA are added to the Health 

### 27

and Environmental Research Online (HERO) database developed by EPA 

### 28

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

### 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, visi bility 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 l September 2011 Studies that have undergone scientific peer review and have been published or accepted 

### 1

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

### 2

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

### 3

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

### 4

toxicological, and ecological a nd welfare effects studies published since the last review 

### 5

are considered, including those related to exposure

- response relationships, mode(s) of 

### 6

action (MOA), and potentially at

- risk populations and lifestages . Studies on atmospheric 

### 7

chemistry, environmen tal fate and transport, dosimetry, toxicokinetics and exposure are 

### 8

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

### 9

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

### 10

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

### 11

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

### 12

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

### 13

the previous re view and on any new interpretations of previous literature, integrating the 

### 14

results of recent scientific studies with previous findings. Important older studies may be 

### 15

discussed in detail to reinforce key concepts and conclusions or for reinterpretation in 

### 16

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

### 17

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

### 18

definitive works available in the literature. 

### 19

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

### 20

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



### 21

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

### 22

describe the relationship between the criteria pollutant and effects, including studies that 

### 23

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

### 24

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

### 25

anal yses of concentration

- response or dose

- response relationships, or analyses related to 

### 26

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

### 27

associated with pollutant concentrations relevant to current population and ecosyst em 

### 28

exposures, and particularly those pertaining to concentrations currently found in ambient 

### 29

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

### 30

unreported effect or MOA for an observed effect, or examine multiple concentratio ns to 

### 31

elucidate exposure

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

### 32

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

### 33

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

### 34

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

### 35

are they sufficiently well defined to allow for meaningful comparisons 

### 36

between study or exposure groups? 

### 37Draft

– Do Not Cite or Quote li September 2011  Are the statistical analyses appropriate, properly performed, and prop erly 

### 1

interpreted? Are likely covariates adequately controlled or taken into account 

### 2

in the study design and statistical analysis? 

### 3

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

### 4

sufficiently representative of information regard ing ambient conditions? 

### 5

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

### 6

and reliable? 

### 7

 Do the analytical methods provide adequate sensitivity and precision to 

### 8

support conclusions? 

### 9

Considerations specific to particular disciplines include the following. In selecting 

### 10

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

### 11

associations with short

- or long

- term pollutant exposures at or near ambient conditions; 

### 12

(2) addresses potential confounding by oth er pollutants; (3) assesses potential effect 

### 13

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

### 14

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

### 15

the health evidence (e.g., lag or t ime period between exposure and effects, model 

### 16

specifications, thresholds, mortality displacement). 

### 17

Considerations for the selection of research evaluating controlled human exposure or 

### 18

animal toxicological studies includes a focus on studies conducted usi ng relevant 

### 19

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

### 20

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

### 21

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

### 22

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

### 23

Evaluation of controlled human exposure studies focuses on those that approximated 

### 24

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

### 25

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

### 26

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

### 27

potentially at

- risk populations and lifestages such as people with asthma or 

### 28

cardiovas cular diseases, children or older adults; (2) address issues such as concentration



### 29

response or time

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

### 30

findings. 

### 31

Review of the animal toxicological evidence focuses on studies that appr oximate 

### 32

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

### 33

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

### 34

Emphasis is placed on studies that: (1) investigate animal models of di sease that can 

### 35

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

### 36Draft

– Do Not Cite or Quote lii September 2011 issues such as concentration

- response or time

- course of responses; and (3) have sufficient 

### 1

statistical power to assess findings. Due to resource constra ints on exposure duration and 

### 2

numbers of animals tested, animal studies typically utilize high

- concentration exposures 

### 3

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

### 4

placed on studies using doses or concentrations gene rally within 1

- 2 orders of magnitude 

### 5

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

### 6

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

### 7

interspecies differences and potential differences between healthy and susceptible human 

### 8

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

### 9

mechanistic insight or further support for results demonstrated in vivo. 

### 10

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

### 11

policy

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

### 12

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

### 13

synthesis, and evaluation of the most policy

- relevant scie nce to serve as a scientific 

### 14

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

### 15

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

### 16

studies is whether they provide useful qualitative or qua ntitative information on 

### 17

exposure

- effect or exposure

- response relationships for effects associated with pollutant 

### 18

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

### 19

decisions on whether to retain or revise the standards. 

### 20

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

### 21

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

### 22

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

### 23

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

### 24

workshop in which EPA and non

- EPA experts review the scientific content of 

### 25

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

### 26

policy

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

### 27

disciplines. 

### 28

EPA integrates the evidence from across scientific disciplines or study types and 

### 29

characterizes the weight of evidence for relationships between the pollutant and va rious 

### 30

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

### 31

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

### 32

evaluation of health effects evidence would include the integration of the resul ts from 

### 33

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

### 34

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

### 35

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

### 36

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

### 37Draft

– Do Not Cite or Quote liii September 2011 draft causality determinations on the nature of the relationships. Causality determinations 

### 1

often entail an iterative process of review and evaluation of the evid ence. Two drafts of 

### 2

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

### 3

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

### 4

framework are carefully considered in revising and completin g the final ISA. 

### 5



## EPA Framework for Causal Determination

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

### 6

pollution

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

### 7

described below establis hes uniform language concerning causality and brings more 

### 8

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

### 9

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

### 10

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

### 11

Disability Decision

- Making Process for Veterans ( 2008 )

, a comprehensive report on 

### 12

evaluating causality. This framework: 

### 13

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

### 14

relationship between exposur e and health effects; 

### 15

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

### 16

of a causal relationship; 

### 17

 identifies issues and approaches related to uncertainty; and 

### 18

 provides a framework for classifying and characterizing the weight of 

### 19

evidence in support of a general causal relationship. 

### 20

Approaches to assessing the separate an d combined lines of evidence 

### 21

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

### 22

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

### 23

the NAS ( 2008 ) , International Agency for Research on Cancer ( 2006 )

, EPA Guidelines 

### 24

for Carcinogen Risk Assessment ( 2005 ) , and Centers for Disease Control and Prevention 

### 25

( 2004 ) . Causal inference criteria have also been described for ecological effects evidence 

### 26

( U.S. EPA, 1998 ; Fox, 1991 ) . These formalized approaches offer guidance for assessing 

### 27

causality. The frameworks are similar in nature, although adapted to different purpo ses, 

### 28

and have proven effective in providing a uniform structure and language for causal 

### 29

determinations. 

### 30Draft

– Do Not Cite or Quote liv September 2011 

## Evaluating Evidence for Inferring Causation

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

### 1

relationship between an agen t and an associated disorder or disease in the host ” ( HEW ) ; 

### 2

more generally, a cause is defined as an agent that brings about an effect or a result. An 

### 3

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

### 4

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

### 5

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

### 6

is, a claim about what the world would have been like under different or changed 

### 7

circumstances ( Samet and Bodurow, 2008 )

. 

### 8

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

### 9

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

### 10

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

### 11

genetic susceptibility, nutritional status, immune competence, and social factors ( Samet 

### 12

and Bodurow, 2008 ; Gee and Payne

- Sturges, 2004 )

. Effects on ecosystems are often also 

### 13

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

### 14

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

### 15

represent the net effect of many actions and coun teractions. 

### 16

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

### 17

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

### 18

as having limited knowledge to exactly describe an existing s tate or future outcome, 

### 19

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

### 20

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

### 21

analysis is qualitative, and can include professional judg ment or inferences based on 

### 22

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

### 23

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

### 24

analysis might progress to more complex measures and techni ques, if needed for decision 

### 25

support. Various approaches to evaluating uncertainty include classical statistical 

### 26

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

### 27

complexity and data requirements. However, data ma y not be available for all aspects of 

### 28

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

### 29

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

### 30

degrees of uncertainty. The ISA generally evaluates uncertainties qualitatively in 

### 31

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

### 32

approaches, such as meta

- regression, may be used. 

### 33

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

### 34

estima tes. It is well understood that studies reporting non

- null findings are more likely to 

### 35

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

### 36Draft

– Do Not Cite or Quote lv September 2011 overestimation of effect estimate sizes ( Ioannidis, 2008 ) . For example, effect estimates 

### 1

from single

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

### 2

from multicity studies ( Bell et al., 2005 )

. 

### 3



## Consideration of evidence from scientific disciplines

Moving from association to causation involves the elimination of alternative explanations 

### 4

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

### 5

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

### 6

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

### 7

evidence from across scientific di sciplines. The relative importance of different types of 

### 8

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

### 9

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

### 10

of human health ef fects: controlled human exposure, epidemiologic and toxicological 

### 11

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

### 12

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

### 13

(e.g., community ecol ogy, biogeochemistry and paleological/historical reconstructions). 

### 14

The most direct evidence of a causal relationship between pollutant exposures and human 

### 15

health effects comes from controlled human exposure studies. Controlled human 

### 16

exposure studies experi mentally evaluate the health effects of administered exposures in 

### 17

human volunteers under highly controlled laboratory conditions. Also referred to as 

### 18

human clinical studies, these experiments allow investigators to expose subjects to known 

### 19

concentrations o f air pollutants under carefully regulated environmental conditions and 

### 20

activity levels. In some instances, controlled human exposure studies can also be used to 

### 21

characterize concentration

- response relationships at pollutant concentrations relevant to 

### 22

ambi ent conditions. Controlled human exposures are typically conducted using a 

### 23

randomized crossover design, with subjects exposed both to the pollutant and a clean air 

### 24

control. In this way, subjects serve as their own controls, effectively controlling for many 

### 25

potential confounders. However, controlled human exposure studies are limited by a 

### 26

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

### 27

exposure patterns relevant to understanding real

- world exposures, especially long

- term 

### 28

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

### 29

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

### 30

hours and days preceding the controlled exposures may vary significantly betw een and 

### 31

within individuals. Finally, controlled human exposure studies require investigators to 

### 32

adhere to stringent health criteria for subjects included in the study, and therefore the 

### 33

results cannot necessarily be generalized to an entire population. Alt hough some 

### 34

controlled human exposure studies have included health

- compromised individuals such 

### 35

as those with respiratory or cardiovascular disease, these individuals must also be 

### 36Draft

– Do Not Cite or Quote lvi September 2011 relatively healthy and may not represent the most sensitive individuals in th e population. 

### 1

In addition, the study design is limited to exposures and endpoints that are not expected 

### 2

to result in severe health outcomes. Thus, not observing an effect in controlled human 

### 3

exposure studies does not necessarily mean that a causal relation ship does not exist. 

### 4

While controlled human exposure studies provide important information on the biological 

### 5

plausibility of associations observed in epidemiologic studies, observed effects in these 

### 6

studies may underestimate the response in certain populat ions. 

### 7

Epidemiologic studies provide important information on the associations between health 

### 8

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

### 9

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

### 10

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

### 11

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

### 12

e.g., cross

- sectional, prospective cohort, panel and time

- series studies

. “ Natural 

### 13

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

### 14

exposure, such as closure of a pollution source. 

### 15

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

### 16

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

### 17

consideration is evaluation of the potential contribution of the pollutant to a health 

### 18

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

### 19

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

### 20

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

### 21

pollution mixture; effects resulting from interactions between that pollutant and 

### 22

copollutants. 

### 23

In th e evaluation of epidemiologic evidence, one important consideration is potential 

### 24

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

### 25

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

### 26

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

### 27

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

### 28

confounders is to control for characteristics that may d iffer between exposed and 

### 29

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

### 30

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

### 31

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

### 32

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

### 33

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

### 34

associated with the same effect. 

### 35

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

### 36

with none of them being completely satisfactory. Multivariable regression models 

### 37Draft

– Do Not Cite or Quote lvii September 2011 constitute one tool for estimating the association between exposure and outcome after 

### 1

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

### 2

multipollutant regression models has been the prevailing approach for controlling 

### 3

potential confounding by copollutants in air pollution health effects studies. Finding th e 

### 4

likely causal pollutant from multipollutant regression models is made difficult by the 

### 5

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

### 6

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

### 7

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

### 8

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

### 9

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

### 10

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

### 11

prevailing approach employed in most air pollution epidemiologic studies and provides 

### 12

some insight into the potential for confounding or interaction amo ng pollutants. 

### 13

Confidence that unmeasured confounders are not producing the findings is increased 

### 14

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

### 15

exposures, each of which might eliminate another source of confounding fro m 

### 16

consideration. For example, multicity studies which use a consistent method to analyze 

### 17

data from across locations with different levels of covariates can provide insight on 

### 18

potential confounding in associations. Intervention studies, because of their qua si



### 19

experimental nature, can be particularly useful in characterizing causation. 

### 20

Another important consideration in the evaluation of epidemiologic evidence is effect 

### 21

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

### 22

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

- measure 

### 23

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

### 24

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

### 25

effect estimate, effect

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

### 26

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

### 27

estimate effect

- measure modification ” ( Rothm an and Greenland, 1998 )

. When a risk 

### 28

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

### 29

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

### 30

magnitude of the association between the exposur e and the outcome in stratified analyses. 

### 31

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

### 32

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

### 33

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

### 34

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

### 35

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

### 36

and different from the overall estimate, indicating a different exposure

- response 

### 37

relationship may exist in populations represented by these variables. 

### 38Draft

– Do Not Cite or Quote lviii September 2011 Another key consideration for epidemiologic evidence is exposure measurement error. 

### 1

There are several components that contribute to exp osure measurement error in 

### 2

epidemiologic studies, including the difference between true and measured ambient 

### 3

concentrations, the difference between average personal exposure to ambient pollutants 

### 4

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

### 5

exposure rather than individual exposure estimates. 

### 6

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

### 7

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

### 8

circumstances. Taking into account physiological differences of the experimental species 

### 9

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

### 10

exposure

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

### 11

determi nations of at

- risk or susceptible populations. These studies evaluate the effects of 

### 12

exposures to a variety of pollutants in a highly controlled laboratory setting and allow 

### 13

exploration of toxicological pathways or mechanisms by which a pollutant may cause 

### 14

effects. Understanding the biological mechanisms underlying various health outcomes 

### 15

can prove crucial in establishing or negating causality. In the absence of human studies 

### 16

data, extensive, well

- conducted animal toxicological studies can support determina tions 

### 17

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

### 18

under ambient exposure conditions. 

### 19

Interpretations of animal toxicological studies are affected by limitations associated with 

### 20

extrapolation between animal an d human responses. The differences between humans 

### 21

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

### 22

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

### 23

of a high degree of homolog y and the existence of a high percentage of orthologous 

### 24

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

### 25

alterations at the gene level is complicated by species

- specific differences in 

### 26

transcriptional regulation. Given these differences, there are uncertainties associated with 

### 27

quantitative extrapolations of observed pollutant

- induced pathophysiological alterations 

### 28

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

### 29

widely varying biochemical, e ndocrine, and neuronal factors. 

### 30

For ecological effects assessment, both laboratory and field studies (including field 

### 31

experiments and observational studies) can provide useful data for causality 

### 32

determination. Because conditions can be controlled in labora tory studies, responses may 

### 33

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

### 34

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

### 35

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

### 36

In addition, larger

- scale processes are difficult to reproduce in the laboratory. 

### 37Draft

– Do Not Cite or Quote lix September 2011 Field observational studies measure biological changes in uncontrolled situations, and 

### 1

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

### 2

provide important information for assessments of multiple stressors or where site

- specific 

### 3

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

### 4

geographic scales and higher lev els of biological organization. However, because 

### 5

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

### 6

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

### 7

and effect levels are meas ured concurrently. The presence of confounding factors can 

### 8

make it difficult to attribute observed effects to specific stressors. 

### 9

Intermediate between laboratory and field are studies that use environmental media 

### 10

collected from the field to examine respon se in the laboratory, and experiments that are 

### 11

performed in the natural environment while controlling for some environmental 

### 12

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

### 13

environments can be considered a hybrid between a fie ld experiment and laboratory study 

### 14

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

### 15

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

### 16

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

### 17

under more controlled conditions. 

### 18



## Application of Framework for Causal Determination

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

### 19

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

### 20

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

### 21

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

### 22

the concentration

- response relationships and the lo ads to ecosystems, exposure doses or 

### 23

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

### 24

To aid judgment, various “ aspects ” 2 of causality have been discussed by many 

### 25

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

### 26

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

### 27

strength, specificity, temporal relati onship, and coherence ( HEW, 1964 ) . Sir Austin 

### 28

Bradford Hill ( 1965 ) articulated aspects of causality in epidemiology and public health 

### 29

that have been widely used ( Samet and Bodurow, 2008 ; IARC, 2006 ; U.S. E PA, 2005 ; 

### 30

HHS, 2004 ) . These aspects ( Hill, 1965 ) have been modified (Table I ) for use in causal 

### 31

2 The “aspects” described by Hill ( 1965 ) have 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.Draft

– Do Not Cite or Quote lx September 2011 

### 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

subdi sciplines of ecology (e.g., community ecology, biogeochemistry and paleological/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 dem onstrating effects across multiple study designs or related health endpoints 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 so urces demonstrating plausible biological mechanisms. A proposed mechanistic linking between an effect and exposure to the agent is an important source of support for causality, especially when data establishing the existence and functioning of those mechan istic 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

relat ionships are also observed for duration of exposure (e.g., increasing 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 or frequency of health or

welfare effects.

Temporal relationship of

the observed association Evidence of a temporal sequence between the introduction of an agent, and appearance

of the ef fect, constitutes another argument in favor of causality.

Specificity of the

observed association Evidence linking an exposure to a specific outcome can provide a strong argument for causation. However, it must be recognized that rarely, if ever, does ex posure to a pollutant invariably predict the occurrence of an outcome, 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 assoc iation is causal. Similarly, information on mode of action for a chemical, as one of many structural analogs, can inform decisions regarding likely causality.

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

### 1

2009d )

. 3 Although these aspects provide a framework for assessing the evidence, they do 

### 2

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

### 3

evidence leading to conclusions about causality ( Hill, 1965 ) . For example, one cannot 

### 4

simply count the number of studies reporting statistically significant results or 

### 5

3 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 lxi September 2011 st atistically nonsignificant results and reach credible conclusions about the relative 

### 1

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

### 2

account with the goal of producing an objective appraisal of the evidence, inf ormed by 

### 3

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

### 4

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

### 5

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

### 6

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

### 7

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

### 8



## Determination of Causality

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

### 9

during previous NAAQS reviews, to draw conclusions on the causal relationships 

### 10

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

### 11

five

- level hierarchy that classifies the weight of evidence for causation 4 . In developing 

### 12

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

### 13

IOM ’ s Improving the Presumptive Disability Decision

- Making Process for Veterans 

### 14

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

### 15

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

### 16

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

### 17

environmental effects disciplines. These sepa rate judgments are integrated into a 

### 18

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

### 19

descriptors for causal determination are described in Table II

. 

### 20

Determination of causality involves the evaluation of evidence for d ifferent types of 

### 21

health, ecological or welfare effects associated with short

- and long

- term exposure 

### 22

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

### 23

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

### 24

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

### 25

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

### 26

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

### 27

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

### 28

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

### 29

characterizes the evidence on which the judgment is based, including strength of 

### 30

evidence for individual endpoints within the major outcome cate gor y

. 

### 31

4 It should be noted that the 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 Carcinogen Risk Assessment and to provide a more nuanced set of categories.Draft

– Do Not Cite or Quote lxii September 2011 

### 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

relation ship 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 b e ruled out with reasonable confidence. For example: a) controlled human exposure studies that demonstrate consistent effects; or b) observational studies that cannot be explained by plausible alternatives or are supported by other lines of evidence (e.g., animal studies or mode of action information). Evidence includes replica ted and consistent high

- quality studies by multiple investigators. Evidence is sufficient to conclude that there is a causal relationship with relevant pollutant exposures i.e., dose s

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 exposu re 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 eviden ce 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

relat ionship 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 ruled out with reasonable confidence but potenti al issues remain. For example: a) observational studies show an association,

but copollutant 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

- quality studies by multiple investigators. Evidence is sufficient to conclude that there is a likely causal association with relevant pollut ant exposures. That is, an association has been observed be tween the pollutant and the outcome in studies in which chance, bias and confounding are minimized, but unc ertainties 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 g roups.

Suggestive of

a causal relationship Evidence is suggestive of a causal relationship with relevant pollutant exposures, but is limited. For example, (a) at least one high

- quality epidemiologic study shows an association with a given health outcome b ut 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 studies are inconsistent.

Inadequate to

infer a causal relationship Evidence is inadequate to determine that a causal

relation ship exists with relevant pollutant exposures. The available studies are of insufficient quantity, quality, consistency or statistical power to permit a conclu sion regarding the presence or absence of an effect. The avail able 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, are mutually consisten t 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.

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

### 1

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

### 2

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

### 3

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

, 

### 4

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

### 5

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

### 6Draft

– Do Not Cite or Quote lxiii September 2011 category, but generally inclu des those with doses or exposures in the range of one to two 

### 1

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

### 2

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

### 3

inform our underst anding of mode of action, interspecies differences or factors that may 

### 4

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

### 5

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

### 6

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

### 7

orders of magnitude above current levels. 

### 8

In addition, EPA evaluates evidence relevant to understand the quantitative relationships 

### 9

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

### 10

evaluation of the form of concentration

- response or dose

- response relationships and, to 

### 11

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

### 12

ISA also draws scientific conclusions reg arding important exposure conditions for effects 

### 13

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

### 14

section. 

### 15



## Quantitative relationships : Effects on Human Populations

Once a determination is made regarding the causal rela tionship between the pollutant and 

### 16

outcome category, important questions regarding quantitative relationships include: 

### 17

 What is the concentration

- response, exposure

- response, or dose

- response 

### 18

relationship in the human population? 

### 19

 What is the interrelations hip between incidence and severity of effect? 

### 20

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

### 21

important? 

### 22

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

### 23

at risk of experiencing effects)? 

### 24

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

### 25

characterize pollutant concentrations and exposure durations at which effects were 

### 26

observed for exposed populations, including populations and lifestages potentially at 

### 27

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

### 28

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



### 29

response relationships between health outcomes and the pollutant may be identified. 

### 30

Con trolled human exposure studies provide the most direct and quantifiable exposure



### 31

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

### 32

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

### 33Draft

– Do Not Cite or Quote lxiv September 2011 characterize the form of relationships between the pollutant and health outcomes and 

### 1

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

### 2

evaluation of concentration

- response relationships, particularly relative to MOAs an d 

### 3

characteristics of susceptible populations. 

### 4

An important consideration in characterizing the public health impacts associated with 

### 5

exposure to a pollutant is whether the concentration

- response relationship is linear across 

### 6

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

### 7

Of particular interest is the shape of the concentration

- response curve at and below the 

### 8

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

### 9

data densit y in the lower concentration range, possible influence of exposure 

### 10

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

### 11

health effects, tend to smooth and “ linearize ” the concentration

- response function, and 

### 12

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

### 13

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

### 14

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

### 15

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

### 16

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

### 17

available human data at ambient concentrations for some environmental pollutants 

### 18

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

### 19

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

### 20

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

### 21

human population dose

- response relationships have been extensively discussed in the 

### 22

broader epidemiologic literature ( Rothman and Greenland, 1998 )

. 

### 23

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

### 24

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

### 25

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

- risk population ” is used to 

### 26

encompass populations variously described as susceptible, vulnerable, or sensitive. “ At



### 27

risk populations ” is defined here as those populations or lifestages that have a greater 

### 28

likelihood of experiencing health effects related to exposure to an air pollutant due to a 

### 29

variety of factors. These factor s may be intrinsic, such as genetic or developmental 

### 30

factors, race, gender, lifestage, or the presence of preexisting diseases, or they may be 

### 31

extrinsic, such as socioeconomic status (SES) , activity pattern and exercise level, reduced 

### 32

access to health care , low educational attainment, or increased pollutant exposures (e.g., 

### 33

near roadways). Epidemiologic studies can help identify populations potentially at 

### 34

increased risk of effects by evaluating health responses in the study population. Examples 

### 35

include test ing for interactions or effect modification by factors such as gender, age 

### 36

group, or health status. Experimental studies using animal models of susceptibility or 

### 37Draft

– Do Not Cite or Quote lxv September 2011 disease can also inform the extent to which health risks are likely greater in specific 

### 1

popula tion groups. 

### 2



## Quantitative relationships: Effects on Ecosystems or

Public Welfare

Key questions for understanding the quantitative relationships between exposure (or 

### 3

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

### 4

in clude: 

### 5

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

### 6

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

### 7

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

### 8

responses, such a s impaired visibility or materials damage? 

### 9

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

### 10

and pattern) are effects seen? 

### 11

 What is the shape of the concentration

- response or exposure

- response 

### 12

relationship? 

### 13

Evaluations of causal ity generally consider the probability of quantitative changes in 

### 14

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

### 15

of exposure

- response relationships for ecological effects is the great regional and local 

### 16

variabilit y in ecosystems. Thus, exposure

- response relationships are often determined for 

### 17

a specific ecological system and scale, rather than at the national or even regional scale. 

### 18

Quantitative relationships therefore are available site by site and may differ great ly 

### 19

between ecosystems. 

### 20



## Concepts in Evaluating Adversity of Health Effects

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

### 21

between adverse and nonadverse health effects resulting from exposure to air pollution

. 

### 22

Some heal th outcomes, such as hospitalization for respiratory or cardiovascular diseases, 

### 23

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

### 24

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

### 25

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

### 26

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

### 27

measures. The challenge is determining the magnitude of change in these mea sures when 

### 28

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

### 29

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

### 30Draft

– Do Not Cite or Quote lxvi September 2011 adverse health effect may vary between populations. Some changes that may not be 

### 1

considered adverse in healthy individuals would be potentially adverse in more 

### 2

susceptible individuals. 

### 3

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

### 4

by the American Thoracic Society (ATS) in an official s tatement titled What Constitutes 

### 5

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

. An air pollution

- induced shift in the 

### 6

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

### 7

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

. 

### 8

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

### 9

that no identifiable individual has a level associated with significant impairment. 

### 10

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

### 11

experiences clinic ally relevant effects. This shift toward decreased lung function, 

### 12

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

### 13

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

### 14

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

### 15

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

### 16

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

### 17

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

### 18

separate adverse from nonadverse effects. 

### 19

It is important to recognize that the more subtle health outcomes may be connected 

### 20

mechanistically to health events that are clearly ad verse. For example, air pollution may 

### 21

affect markers of transient myocardial ischemia such as ST

- segment abnormalities and 

### 22

onset of exertional angina. These effects may not be apparent to the individual, yet may 

### 23

still increase the risk of a number of cardi ac events, including myocardial infarction and 

### 24

sudden death. Thus, small changes in physiological measures may not appear to be 

### 25

clearly adverse when considered alone, but contribute to a coherent and biologically 

### 26

plausible group of related health outcomes, including responses that are very clearly 

### 27

adverse. 

### 28



## Concepts in Evaluating Adversity of Ecological Effects

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

### 29

cellular level to the individual organism and to the population, community and ecosystem 

### 30

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

### 31

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

### 32

with one another that inhabit an area. An ecosystem is the interactive system formed from 

### 33

all living organisms and their abiotic (physical and chemical) environment within a given 

### 34

area ( IPCC, 2007a ) . The boundaries of what could be called an ecosystem are somewhat 

### 35Draft

– Do Not Cite or Quote lxvii September 2011 arbitrary, depending on the focus of interest or study. Thus, the extent of an ecosystem 

### 1

may range from very small spatial scales to, ultimately, the entire Earth ( IPCC, 2007a )

. 

### 2

Effects on an individual organism are generally not considered to be adverse, however if 

### 3

effects occur to enough individuals within a population, communities and ecosystems 

### 4

may be disrupted. Changes to populations, communities and ecosystems can in turn result 

### 5

in an alteration of ecosystem processes. Ecosystem processes are defined as the metabolic 

### 6

functio ns of ecosystems including energy flow, elemental cycling, and the production, 

### 7

consumption and decomposition of organic matter ( U.S. EPA, 2002 ) . Growth, 

### 8

reproduction, and mortality are species

- level endpoints that can be cle arly linked to 

### 9

community and ecosystem effects and are considered to be adverse when negatively 

### 10

affected. Other endpoints such as changes in behavior and physiological stress can 

### 11

decrease ecological fitness of an organism, but are harder to link unequivoca lly to effects 

### 12

at the population, community and ecosystem level. The degree to which pollutant 

### 13

exposure is considered adverse may also depend on the location and its intended use (i.e. 

### 14

city park, commercial cropland). Support for consideration of adversity beyond the 

### 15

species level by making explicit the linkages between stress

- related effects at the species 

### 16

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

### 17

on Ecological Condition: an SAB report ( U.S. EPA, 2002 ) . Additionally, the National 

### 18

Acid Precipitation Assessment Program (NAPAP) uses the following working definition 

### 19

of adverse ecological effects in the preparation of reports to Congress mandated by the 

### 20

Clean Air Act: “ any injury (i.e. loss of chemical or physical quality or viability) to any 

### 21

ecological or ecosystem component, up to and including at the regional level, over both 

### 22

long and short terms. ” 

### 23

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

### 24

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

. 

### 25

According to the Millennium Ecosystem Assessment, ecosystem services include: 

### 26

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

### 27

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

### 28

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

### 29

other non material benefits. ” For example, a more subtle ecological effect of pollution 

### 30

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

### 31

population decline in a species that is recreationally or culturally important. 

### 32Draft

– Do Not Cite or Quote lxviii September 2011 

## PREFACE

L egislative Requirements for the NAAQS Review

Two sections of the Clean Air Act (CAA) govern the establishment and revision of 

### 1

the National Ambient Air Quality Standards (NAAQS). Section 108 (42 USC §7408) 

### 2

directs the Administrator to identify and list cert ain air pollutants and then to issue air 

### 3

quality criteria for those pollutants. The Administrator is to list those air pollutants 

### 4

that in her “ judgement; cause or contribute to air pollution which may reasonably be 

### 5

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

### 6

ambient air results from numerous or diverse mobile or stationary sources ” ( CAA, 

### 7

1990a ) . Air quality criteria are intended to “ accurately reflect th e latest scientific 

### 8

knowledge useful in indicating the kind and extent of identifiable effects on public 

### 9

health or welfare which may be expected from the presence of [a] pollutant in 

### 10

ambient air . . . [ 42 USC §7408(b) ]

. 

### 11

Section 109 ( CAA, 1990b ) directs the Administrator to propose and promulgate 

### 12

“ primary ” and “ secondary ” NAAQS for pollutants for which air quality criteria have 

### 13

been issued. Section 109(b)(1) defines a primary sta ndard as one “ the attainment and 

### 14

maintenance of which in the judgment of the Administrator, based on such criteria 

### 15

and allowing an adequate margin of safety, are requisite to protect the public 

### 16

health. ” 5 A secondary standard, as defined in section 109(b)(2 ), must “ specify a level 

### 17

of air quality the attainment and maintenance of which, in the judgment of the 

### 18

Administrator, based on such criteria, is required to protect the public welfare from 

### 19

any known or anticipated adverse effects associated with the prese nce of [the] 

### 20

pollutant in the ambient air. ” 6 

### 21

The requirement that primary standards include an adequate margin of safety was 

### 22

intended to address uncertainties associated with inconclusive scientific and technical 

### 23

information available at the time of stand ard setting. It was also intended to provide a 

### 24

reasonable degree of protection against hazards that research has not yet identified. 

### 25

See Lead Industries Association v. EPA, 647 F.2d 1130, 1154 (D.C. Cir 1980), cert. 

### 26

denied, 449 U.S. 1042 (1980); American P etroleum Institute v. Costle, 665 F.2d 

### 27

1176, 1186 (D.C. Cir. 1981), cert. denied, 455 U.S. 1034 (1982). Both kinds of 

### 28

uncertainties are components of the risk associated with pollution at levels below 

### 29

5 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 th e health of any [sensitive] group of the population,” and that for this purpose “reference should be made to a representative sample of persons comprising the sensitive group rather than to a single person in such a group” [S. Rep. No. 91

- 1196, 91 st Cong., 2d Sess. 10 (1970)].

6 Welfare effects as defined in section 302(h) include, but are not limited to, “effects on soils, water, crops, vegetation, ma n

- made materials, animals, wildlife, weather, visibility and climate, damage to and deterioration of proper ty, and hazards to transportation, as well as effects on economic values and on personal comfort and well

- bein g ” ( CAA, 2005 )

.Draft

– Do Not Cite or Quote lxix September 2011 those at which human health effects can be said to occu r with reasonable scientific 

### 1

certainty. Thus, in selecting primary standards that include an adequate margin of 

### 2

safety, the Administrator is seeking not only to prevent pollution levels that have 

### 3

been demonstrated to be harmful but also to prevent lower po llutant levels that may 

### 4

pose an unacceptable risk of harm, even if the risk is not precisely identified as to 

### 5

nature or degree. 

### 6

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

### 7

severity of the health effects involved, the s ize of the sensitive population(s) at risk, 

### 8

and the kind and degree of the uncertainties that must be addressed. The selection of 

### 9

any particular approach to providing an adequate margin of safety is a policy choice 

### 10

left specifically to the Administrator ’ s judgment. See Lead Industries Association v. 

### 11

EPA, supra, 647 F.2d at 1161

- 1162. 

### 12

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

### 13

provided in Section 109(b), EPA ’ s task is to establish standards that are neither more 

### 14

nor le ss stringent than necessary. In so doing, EPA may not consider the costs of 

### 15

implementing the standards. [ See generally Whitman v. American Trucking 

### 16

Associations, 531 U.S. 457, 465

- 472, 475

- 76. ] 

### 17

Section 109(d)(1) requires that “ not later than December 31, 1 980, and at 5

- year 

### 18

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

### 19

published under section 108 and the national ambient air quality standards ... and 

### 20

shall make such revisions in such criteria and standards and promul gate such new 

### 21

st andards as may be appropriate... ” Section 109(d)(2) requires that an independent 

### 22

scientific review committee “ shall complete a review of the criteria ... and the 

### 23

national primary and secondary ambient air quality standards ... and shall 

### 24

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

### 25

criteria and sta ndards as may be appropriate ... ” Since the early 1980 s, this 

### 26

independent review function has been performed by CASAC. 

### 27



## History of the NAAQS for Ozone

Tropospheric (ground

- level) O 3 is the indicator for the mix of photochemical 

### 28

oxidants (e.g., peroxyacetyl nitrate, hydrogen peroxide) formed from biogenic and 

### 29

anthropogenic precursor emissions. Naturally occurring O 3 in the troposphere can 

### 30

result from biogenic organic precursors reacting with naturally occurring nitrogen 

### 31

oxides (NO X ) and by stratospheric O 3 intrusion into the troposphere. Anthropogenic 

### 32

precursors of O 3 , especially NO X , and volatile organic compounds (VOCs), originate 

### 33

from a wide variety of stationary an d mobile sources. Ambient O 3 concentrations 

### 34Draft

– Do Not Cite or Quote lxx September 2011 produced by these emissions are directly affected by temperature, solar radiation, 

### 1

wind speed, and other meteorological factors. 

### 2

NAAQS are comprised of four basic elements: indicator, averaging time, level, and 

### 3

f orm. The indicator defines the pollutant to be measured in the ambient air for the 

### 4

purpose of determining compliance with the standard. The averaging time defines the 

### 5

time period over which air quality measurements are to be obtained and averaged or 

### 6

cumula ted, considering evidence of effects associated with various time periods of 

### 7

exposure. The level of a standard defines the air quality concentration used (i.e., an 

### 8

ambient concentration of the indicator pollutant) in determining whether the standard 

### 9

is ach ieved. The form of the standard specifies the air quality measurements that are 

### 10

to be used for compliance purposes (e.g., the annual fourth

- highest daily maximum 

### 11

8

- hour concentration, averaged over 3 years), and whether the statistic is to be 

### 12

averaged acro ss multiple years. These four elements taken together determine the 

### 13

degree of public health and welfare protection afforded by the NAAQS. 

### 14

Table III Summary of primary and secondary NAAQS promulgated for ozone during the period 1971

- 2008

Final Rule Indicato r Avg

Time Level (ppm) Form

1971 (36 FR 8186) Total photochemical

oxidants 1

- h 0.08 Not to be exceeded more than 1 hour per year

1979 (44 FR 8202) O 3 1

- h 0.12 Attainment is defined when the expected number of days per calendar year, with maximum hourly average concentration greater

than 0.12 ppm, is ≤ 1

1993 (58 FR 13008) EPA decided that revisions to the standards were not warranted at the time.

1997 (62 FR 38856) O 3 8

- h 0.08 Annual fourth

- highest daily maximum 8

- h concentration averaged over 3 years

2008 (73 FR 16483) O 3 8

- h 0.075 Form of the standards remained unchanged relative to the 1997

standard

Table III summarizes the O 3 NAAQS that have been promulgated to date. In each 

### 15

review, the secondary standard has been set to be identical to the primary standard. 

### 16

These reviews are briefly described below. 

### 17

EPA first established primary and secondary NAAQS for photochemical oxidants in 

### 18

1971 . Both primary and secondary standards were set at a level of 0.08 parts per 

### 19

million (ppm), 1

- h avg, total photochemical oxidants, not to be exceeded mor e than 

### 20

1 hour per year. The standards were based on scientific information contained in the 

### 21

1970 AQCD. 

### 22

In 1977, EPA announced the first periodic review of the 1970 AQCD in accordance 

### 23

with Section 109(d)(1) of the Clean Air Act. In 1978, EPA published an AQ CD. 

### 24Draft

– Do Not Cite or Quote lxxi September 2011 Based on the 1978 AQCD, EPA published proposed revisions to the original NAAQS 

### 1

in 1978 ( U.S. EPA, 1978b ) and final revisions in 1979 ( U.S. EPA, 1979 a )

. The level 

### 2

of the primary and secondary standards was revised from 0.08 to 0.12 ppm; the 

### 3

indicator was revised from photochemical oxidants to O 3 ; and the form of the 

### 4

standards was revised from a deterministic to a statistical form, which defined 

### 5

atta inment of the standards as occurring when the expected number of days per 

### 6

calendar year with maximum hourly average concentration greater than 0.12 ppm is 

### 7

equal to or less than one. 

### 8

In 1982 , EPA announced plans to revise the 1978 AQCD ( U.S. EPA, 1978a ) . In 1983, 

### 9

EPA announced that the second periodic review of the primary and secondary 

### 10

standards for O 3 had been initiated ( U.S. EPA, 1983 ) . EPA subsequently published 

### 11

the 1986 O 3 AQCD ( U.S. EPA, 19 86 ) and 1989 Staff Paper ( U.S. EPA, 1989 )

. 

### 12

Following publication of the 1986 O 3 AQCD, a number of scientific abstracts and 

### 13

articles were published that appeared to be of sufficient importance concerning 

### 14

potential health and welfare effects of O 3 to warrant preparatio n of a Supplement to 

### 15

the 1986 O 3 AQCD ( Costa et al., 1992 ) . Under the terms of a court order, on August 

### 16

10, 1992, EPA published a proposed decision ( U.S. EPA, 1992 ) stating that revisions 

### 17

to the existing primary and secondary standards were not appropriate at the time 

### 18

( U.S. EPA, 1992 ) . This notice explained that the proposed decision would complete 

### 19

EPA ’ s review of information on health and welfare effects of O 3 assembled over a 

### 20

7

- year per iod and contained in the 1986 O 3 AQCD ( U.S. EPA, 1986 ) and its 

### 21

Supplement to the 1986 O 3 AQCD ( Costa et al., 1992 ) . The proposal also annou nced 

### 22

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

### 23

quality criteria and standards for O 3 in light of emerging evidence of health effects 

### 24

related to 6

- to 8

- hour O 3 exposures. On March 9, 1993, EPA concluded the review 

### 25

by deciding that revisions to the standards were not warranted at that time ( U.S. EPA, 

### 26

1993 )

. 

### 27

In August 1992, EPA announ ced plans to initiate the third periodic review of the air 

### 28

quality criteria and O 3 NAAQS ( U.S. EPA, 1992 ) . On the b asis of the scientific 

### 29

evidence contained in the 1996 O 3 AQCD and the 1996 Staff Paper ( U.S. EPA, 

### 30

1996e ) , and related technical sup port documents, linking exposures to ambient O 3 to 

### 31

adverse health and welfare effects at levels allowed by the then existing standards, 

### 32

EPA proposed to revise the primary and secondary O 3 standards on December 13, 

### 33

1996 ( U.S. EPA, 1996d ) . The EPA proposed to replace the then existing 1

- hour 

### 34

primary and secondary standards with 8

- h avg O 3 standards set at a level of 0.08 ppm 

### 35

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

### 36

proposed, in the alternative, to establish a new distinct secondary standard using a 

### 37

biologically based cumulative seasonal form. The EPA completed the review on July 

### 38Draft

– Do Not Cite or Quote lxxii September 2011 18, 1997 by setting the pri mary standard at a level of 0.08 ppm, based on the annual 

### 1

fourth

- highest daily maximum 8

- h avg concentration, averaged over 3 years, and 

### 2

setting the secondary standard identical to the revised primary standard ( U.S. EPA, 

### 3

1997 )

. 

### 4

On May 14, 1999, in response to challenges to EPA ’ s 1997 decision by industry and 

### 5

others, the U.S. Court of Appeals for the District of Columbia Circuit (D.C. Cir

. ) 

### 6

rema nded the O 3 NAAQS to EPA, finding that Section 109 of the CAA, as 

### 7

interpreted by EPA, effected an unconstitutional delegation of legislative authority. In 

### 8

addition, the D.C. Cir. directed that, in responding to the remand, EPA should 

### 9

consider the potential beneficial health effects of O 3 pollution in shielding the public 

### 10

from the effects of solar ultraviolet (UV) radiation, as well as adverse health effects. 

### 11

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

### 12

constitutional issu e (and two other issues) but did not request review of the D.C. Cir

., 

### 13

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

### 14

the U.S. Supreme Court unanimously reversed the judgment of the D.C. Cir

. on the 

### 15

constitutional issu e, holding that Section 109 of the CAA does not delegate 

### 16

legislative power to the EPA in contravention of the Constitution, and remanded the 

### 17

case to the D.C. Cir

. to consider challenges to the O 3 NAAQS that had not been 

### 18

addressed by that Court ’ s earlier decisions. On March 26, 2002, the D.C. Cir. issued 

### 19

its final decision, finding the 1997 O 3 NAAQS to be “ neither arbitrary nor 

### 20

capricious, ” and denied the remaining petitions for review. On November 14, 2001, 

### 21

in response to the D.C. Cir. remand to consider the potential beneficial health effects 

### 22

of O 3 pollution in shielding the public from effects of solar (UV) radiation, EPA 

### 23

proposed to leave the 1997 8

- h O 3 NAAQS unchanged ( U.S. EPA, 2001 ) . After 

### 24

considering public comment on the proposed decision, EPA published its final 

### 25

response to this remand on January 6, 2003, reaffirming the 8

- h O 3 NAAQS se t in 

### 26

1997 ( U.S. EPA, 2003 ) . On April 30, 2004, EPA announced the decision to make the 

### 27

1

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

### 28

designation of those areas for the 8

- h NAAQS ( 2004 ) . For most areas, the date that 

### 29

the 1

- h NAAQS no longer applied was June 15, 2005. 

### 30

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

### 31

September 2000 with a call for information ( U.S. EPA, 2000 ) . The schedule for 

### 32

completion of that rulemaking later became governed by a consent decree resolving a 

### 33

lawsuit filed in March 2003 by a group of plaintiffs representing national 

### 34

environmental and public health organizations. Based on the 2006 O 3 AQCD ( U.S. 

### 35

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

### 36

technical support documents, the proposed decision was published in the Federal 

### 37

Register on July 11, 2007 ( U.S. EPA, 2007a ) . The EPA proposed to revise the level of 

### 38Draft

– Do Not Cite or Quote lxxiii September 2011 the primary standard to a level within the range of 0.075 to 0.070 ppm. Two options 

### 1

were proposed for the secondary standard: (1) replacing the current standard with a 

### 2

cumulative, seasonal standard, expressed as an index of the annual sum of weighted 

### 3

hourly concentrations cumulated over 12 daylight hours during the consecutive 

### 4

3

- month period within th e O 3 season with the maximum index value, set at a level 

### 5

within the range of 7 to 21 ppm

- h; and (2) setting the secondary standard identical to 

### 6

the revised primary standard. The EPA completed the rulemaking with publication of 

### 7

a final decision on March 27, 2008 ( U.S. EPA, 2008e ) , revising the level of the 

### 8

8

- hour primary O 3 standard from 0.08 ppm to 0.075 ppm and revising the secondary 

### 9

standard to be identical to the primary standard. 

### 10



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