May 2011 i DRAFT – DO NOT CITE OR QUOTE

Chapter 1 Contents

Chapter 1. Introduction ______________________________________________________________________________ 1-1

1.1. Legislative Requirements_____________________________________________________________________ 1-4

1.2. History of Reviews of the NAAQS for Lead ______________________________________________________ 1-6

1.3. ISA Development___________________________________________________________________________ 1-9

Figure 1-1. Identification of studies for inclusion in the ISA. _______________ 1-10

1.4. Document Organization _____________________________________________________________________ 1-14

1.5. Document Scope __________________________________________________________________________ 1-15

1.6. EPA Framework for Causal Determination ______________________________________________________ 1-15

1.6.1. Scientific Evidence Used in Establishing Causality________________________________________ 1-16

1.6.2. Association and Causation ___________________________________________________________ 1-17

1.6.3. Evaluating Evidence for Inferring Causation _____________________________________________ 1-17

1.6.4. Application of Framework for Causal Determination ______________________________________ 1-21

Table 1-1. Aspects to aid in judging causality___________________________ 1-23

1.6.5. Determination of Causality __________________________________________________________ 1-23

Table 1-2. Weight of evidence for causal determination ___________________ 1-25

1.6.5.1. Effects on Human Populations _______________________________________________ 1-26

1.6.5.2. Effects on Ecosystems or Public Welfare_______________________________________ 1-28

1.6.6. Concepts in Evaluating Adversity of Health Effects _______________________________________ 1-28

1.7. Summary ________________________________________________________________________________ 1-29

Chapter 1 References ____________________________________________________________________________ 1-30
May 2011 1-1 DRAFT – DO NOT CITE OR QUOTE

Chapter 1. Introduction

1 This first external review draft Integrated Science Assessment (ISA) is a concise review, 

2 synthesis, and evaluation of the most policy-relevant evidence, and communicates critical science 

3 judgments relevant to the National Ambient Air Quality Standards (NAAQS) review. As such, the 

4 ISA forms the scientific foundation for the review of the primary (health-based) and secondary 

5 (welfare-based) NAAQS for lead (Pb). The ISA accurately reflects “the latest scientific knowledge 

6 useful in indicating the kind and extent of identifiable effects on public health which may be 

7 expected from the presence of [a] pollutant in ambient air” (42 U.S.C. 7408). Key information and 

8 judgments formerly contained in an Air Quality Criteria Document (AQCD) for Pb are incorporated 

9 in this assessment. This ISA thus serves to update and revise the evaluation of the scientific evidence 

10 available at the time of the previous review of the NAAQS for Pb that was concluded in 2008. 

11 The draft Integrated Review Plan for the National Ambient Air Quality Standards for Lead

12 (U.S. EPA, 2011) identifies a series of policy-relevant questions that provide a framework for this 

13 assessment of the scientific evidence. These questions frame the entire review of the NAAQS for Pb, 

14 and thus are informed by both science and policy considerations. The ISA organizes, presents, and 

15 integrates the scientific evidence which is considered along with findings from any risk analyses and 

16 policy considerations to help the U.S. Environmental Protection Agency (EPA) address these 

17 questions during the NAAQS review for Pb. In evaluating the health evidence, the focus of this 

18 assessment is on scientific evidence that is most relevant to the following questions taken directly 

19 from the Integrated Review Plan:

20  What new evidence is available on exposure to Pb through air-related pathways? Can air21 related pathways be disentangled from water- and soil-related pathways using available 

22 data?

23  What new evidence is available regarding observational studies of Pb exposure? How do 

24 these studies inform the assessment of exposure to air-related pathways?

25  What new evidence is available on biological and other factors that could affect the 

26 distribution and accumulation of Pb into blood and bone (e.g., age, diet, gender, race)? 

 

Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and 

Environmental Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of 

developing science assessments such as the Integrated Science Assessments (ISA) and the Integrated Risk Information System (IRIS).
May 2011 1-2 DRAFT – DO NOT CITE OR QUOTE

1  How and to what extent does previous or concurrent Pb exposure, including duration 

2 (e.g., acute, subchronic, chronic) and pattern (e.g., continuous low, extreme peak) impact 

3 blood and bone Pb?

4  What new evidence is available on the relationship between air Pb and blood Pb levels 

5 and uncertainties in that relationship? What new knowledge exists regarding the 

6 characterization of changes in this relationship when accounting for the multiple 

7 pathways of Pb exposure and body burden associated with Pb exposure? What does the 

8 current evidence indicate regarding variation in the relationship with variation in blood 

9 Pb levels or air Pb levels?

10  To what extent does new scientific evidence increase our understanding of the 

11 contributions of Pb from different sources and exposure pathways to blood Pb levels or 

12 to other indicators of Pb body burden (e.g., contributions from various air-related 

13 pathways, including diet and indoor dust pathways)?

14  How do results of recent epidemiologic studies and current or new interpretations of 

15 previous findings expand our understanding of the relationship between body burdens of 

16 Pb and neurological effects in children and adults, including deficits in IQ, behavior, 

17 learning, and motor skills, as well as risk of neurodegenerative diseases? What new 

18 evidence is available on the potential clinical relevance of these effects? Do recent 

19 studies expand the current understanding of concentration-response relationships 

20 pertinent to the range of Pb exposures currently experienced by the U.S. population?

21  For what Pb-induced health effects, is there sufficient evidence in multiple species to 

22 support a quantitative comparison of exposures that induce the effects?

23  To what extent are the health effects observed in epidemiological studies attributable to 

24 exposure to Pb rather than co-exposures to other toxic metals or environmental 

25 contaminants?

26  In epidemiologic studies, what are the uncertainties in Pb effect estimates due to 

27 potential confounding factors (e.g., demographic and lifestyle attributes, socioeconomic 

28 status [SES], genetic susceptibility factors, occupational exposure, and access to medical 

29 care)?

30  Based on the new body of evidence, what uncertainties remain regarding the nature and 

31 shape of concentration-response relationships (e.g., threshold, linear, nonlinear)? What 

32 evidence is newly available on the uncertainties related to other aspects of statistical 

33 model specification and how can it be used to assess the influence of these uncertainties 
May 2011 1-3 DRAFT – DO NOT CITE OR QUOTE

1 on the results of epidemiologic studies? What evidence is available from toxicological 

2 studies of dose-response relationships?

3  To what extent is key evidence now available regarding mechanisms for neurological 

4 effects associated with “lower” (<10 μg/dL or <5 μg/dL) blood Pb levels (e.g., oxidative 

5 stress)? What toxicological evidence is available on mechanisms and dose-response 

6 relationships for other health outcomes (e.g., cardiovascular, renal, or immunological 

7 effects), and is there coherence between this and epidemiologic findings for these 

8 endpoints?

9  To what extent is key new evidence available that could inform the understanding of 

10 populations that are particularly susceptible to Pb exposures? What is known about 

11 genetic traits, pre-existing conditions (obesity), or other factors that affect susceptibility 

12 (sex)? To what extent is the strength of epidemiologic or toxicological evidence driven 

13 by effects observed in populations with increased susceptibility? 

14  To what extent is key evidence now available to inform our understanding of 

15 developmental lifestages that are particularly susceptible to Pb exposures? What is 

16 known about critical windows of exposure for Pb with regard to their impact on 

17 concentration-response relationships and/or effects elicited?

18  What do the currently available studies indicate regarding the relationship between 

19 exposures to Pb and health effects in those with preexisting diseases (e.g., renal diseases) 

20 compared to healthy individuals? What medical conditions are identified as increasing 

21 susceptibility to Pb effects? What is the nature and time-course of the development of 

22 effects in previously healthy persons and in persons with pre-existing disease (e.g., 

23 cardiovascular disease)? What are the pathways and mechanisms through which Pb may 

24 be acting for these groups?

25 In evaluating evidence on welfare effects of Pb, the focus will be on evidence that can help 

26 inform these questions from the Integrated Review Plan:

27  What new information is available about the nature of the effects of Pb on terrestrial 

28 ecosystems, especially Pb that is relevant to air-related pathways? Is there new evidence 

29 of effects at current ecosystem loads? Is there new evidence that, in combination with the 

30 previously existing evidence, supports the development of critical loads for terrestrial 

31 ecosystems?

32  Is there new information available for establishing specific exposure levels at which 

33 terrestrial ecological receptors are expected to experience effects?
May 2011 1-4 DRAFT – DO NOT CITE OR QUOTE

1  Are there new empirical data or modeling results that would improve our understanding 

2 of the movement of Pb in or through terrestrial systems, or would improve our 

3 understanding of Pb bioavailability and pathways of exposure for terrestrial organisms?

4  Is there new evidence that contributes to a better understanding of the nature and 

5 magnitude of the potential effects of Pb on terrestrial ecosystem services?

6  What new information is available about the nature of the effects of Pb on aquatic 

7 ecosystems, especially Pb that is relevant to air-related pathways? Is there new evidence 

8 of effects at current ecosystem loads? Is there new evidence that, in combination with the 

9 previously existing evidence, supports the definition of critical loads for aquatic 

10 ecosystems?

11  Is there new information available for establishing specific exposure levels at which 

12 aquatic ecological receptors are expected to experience effects?

13  Are there new empirical data or modeling results that would improve our understanding 

14 of the movement of Pb in or through aquatic systems or would improve our 

15 understanding of Pb bioavailability and pathways of exposure for aquatic organisms?

16  Is there new evidence that contributes to a better understanding of the nature and 

17 magnitude of the potential effects of Pb on aquatic ecosystem services?

18 This introductory chapter (Chapter 1) of the Pb ISA presents: (1) background information on 

19 pertinent Clean Air Act legislative requirements, the air quality criteria and NAAQS review process, 

20 and the history of previous Pb NAAQS reviews; (2) an overview of the ISA development process 

21 and an orientation to the general organizational structure and content of this Pb ISA; and (3) the 

22 framework for causal determination used to evaluate the causal nature of air pollution-induced health 

23 and environmental effects in NAAQS reviews.

1.1. Legislative Requirements

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

25 NAAQS. Section 108 (42 USC §7408) directs the Administrator to identify and list certain air 

26 pollutants and then issue air quality criteria for those pollutants. The Administrator is to list those air 

27 pollutants that in her “judgment, cause or contribute to air pollution which may reasonably be 

28 anticipated to endanger public health and welfare;” “the presence of which in the ambient air results 

29 from numerous or diverse mobile or stationary sources;” and “for which....[the Administrator] plans 

30 to issue air quality criteria....” Air quality criteria are intended to “accurately reflect the latest 
May 2011 1-5 DRAFT – DO NOT CITE OR QUOTE

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

2 or welfare which may be expected from the presence of [a] pollutant in ambient air....” 42 USC 

3 §7408(b). Section 109 (42 USC §7409) directs the Administrator to propose and promulgate 

4 “primary” and “secondary” NAAQS for pollutants for which air quality criteria are issued. Section 

5 109(b)(1) defines a primary standard as one “the attainment and maintenance of which in the 

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

requisite to protect the public health.”1 7 A secondary standard, as defined in section 109(b)(2), must 

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

9 Administrator, based on such criteria, is requisite to protect the public welfare from any known or 

anticipated adverse effects associated with the presence of [the] pollutant in the ambient air.”2 10

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

12 address uncertainties associated with inconclusive scientific and technical information available at 

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

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

15 1154 (D.C. Cir 1980), cert. denied, 449 U.S. 1042 (1980); American Petroleum Institute v. Costle, 

16 665 F.2d 1176, 1186 (D.C. Cir. 1981), cert. denied, 455 U.S. 1034 (1982); American Farm Bureau v. 

17 EPA, 559 F. 3d 512, 533 (D.C. Cir. 2009); Coalition of Battery Recyclers Association v. EPA, 604 F. 

18 3d 613, 617-18 (D.C. Cir. 2010). Both kinds of uncertainties are components of the risk associated 

19 with pollution at levels below those at which human health effects can be said to occur with 

20 reasonable scientific certainty. Thus, in selecting primary standards that include an adequate margin

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

22 demonstrated to be harmful but also to prevent lower pollutant levels that may pose an unacceptable 

23 risk of harm, even if the risk is not precisely identified as to nature or degree. The CAA does not 

24 require the Administrator to establish a primary NAAQS at a zero-risk level or at background 

25 concentration levels, see Lead Industries v. EPA, 647 F.2d at 1156 n.51, but rather at a level that 

26 reduces risk sufficiently so as to protect public health with an adequate margin of safety.

27 In addressing the requirement for an adequate margin of safety, the EPA considers such factors 

28 as the nature and severity of the health effects involved, the size of sensitive population(s) at risk, 

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

30 approach to providing an adequate margin of safety is a policy choice left specifically to the 

 

1 The legislative history of section 109 indicates that a primary standard is to be set at “the maximum permissible ambient air level... which 

will protect the health of any [sensitive] group of the population,” and that for this purpose “reference should be made to a representative 

sample of persons comprising the sensitive group rather than to a single person in such a group” S. Rep. No. 91-1196, 91st Cong., 2d Sess. 

10 (1970).

2 Welfare effects as defined in section 302(h) (42 U.S.C. § 7602(h)) include, but are not limited to, “effects on soils, water, 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.”
May 2011 1-6 DRAFT – DO NOT CITE OR QUOTE

1 Administrator’s judgment. See Lead Industries Association v. EPA, 647 F.2d at 1161-62; Whitman v. 

2 American Trucking Associations, 531 U.S. 457, 495 (2001).

3 In setting primary and secondary standards that are “requisite” to protect public health and 

4 welfare, respectively, as provided in section 109(b), EPA’s task is to establish standards that are 

5 neither more nor less stringent than necessary for these purposes. In so doing, EPA may not consider 

6 the costs of implementing the standards. See generally, Whitman v. American Trucking Associations, 

7 531 U.S. 457, 465-472, 475-76 (2001). Likewise, “[a]ttainability and technological feasibility are not 

8 relevant considerations in the promulgation of national ambient air quality standards.” American 

9 Petroleum Institute v. Costle, 665 F. 2d at 1185.

10 Section 109(d)(1) requires that “not later than December 31, 1980, and at 5-year 

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

12 published under section 108 and the national ambient air quality standards...and shall make such 

13 revisions in such criteria and standards and promulgate such new standards as may be appropriate...”

14 Section 109(d)(2) requires that an independent scientific review committee “shall complete a review 

15 of the criteria... and the national primary and secondary ambient air quality standards... and shall 

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

17 as may be appropriate...” Since the early 1980s, this independent review function has been 

performed by the Clean Air Scientific Advisory Committee (CASAC).1 18

1.2. History of Reviews of the NAAQS for Lead

19 On October 5, 1978, EPA promulgated primary and secondary NAAQS for Pb under section 

20 109 of the Act (43 FR 46246). Both primary and secondary standards were set at a level of 1.5 μg 

micrograms per cubic meter (μg/m3 21 ), measured as Pb in total suspended particles (Pb-TSP), not to be 

22 exceeded by the maximum arithmetic mean concentration averaged over a calendar quarter. This 

23 standard was based on the 1977 AQCD for Pb (U.S. EPA, 1977). 

24 The first review of the Pb standards was initiated in the mid-1980s. The scientific assessment 

25 for that review is described in the 1986 Lead AQCD (U.S. EPA, 1986a), the associated Addendum

26 (U.S. EPA, 1986b), and the 1990 Supplement (U.S. EPA, 1990a). As part of the review, the Agency 

27 designed and performed human exposure and health risk analyses (U.S. EPA, 1989), the results of 

28 which were presented in a 1990 Staff Paper (U.S. EPA, 1990b). Based on the scientific assessment 

29 and the human exposure and health risk analyses, the 1990 Staff Paper presented recommendations 

30 for consideration by the Administrator (U.S. EPA, 1990b). After consideration of the documents 

 

1 Lists of CASAC members and of members of the CASAC Pb Review Panel are available at: 

http://yosemite.epa.gov/sab/sabproduct.nsf/WebCASAC/CommitteesandMembership?OpenDocument
May 2011 1-7 DRAFT – DO NOT CITE OR QUOTE

1 developed during the review and the significantly changed circumstances since Pb was listed in 

2 1976, the Agency did not propose any revisions to the 1978 Pb NAAQS. In a parallel effort, the 

3 Agency developed the broad, multi-program, multimedia, integrated U.S. Strategy for Reducing 

4 Lead Exposure (U.S. EPA, 1991). As part of implementing this strategy, the Agency focused efforts 

5 primarily on regulatory and remedial clean-up actions aimed at reducing Pb exposures from a variety 

6 of non-air sources judged to pose more extensive public health risks to U.S. populations, as well as 

7 on actions to reduce Pb emissions to air, such as bringing more areas into compliance with the 

8 existing Pb NAAQS (U.S. EPA, 1991). 

9 The most recent review of the Pb air quality criteria and standards was initiated in November, 

10 2004 (69 FR 64926) and the Agency’s plans for preparation of the AQCD and conduct of the 

11 NAAQS review were contained in two documents: Project Work Plan for Revised Air Quality 

12 Criteria for Lead (U.S. EPA, 2005b) and Plan for Review of the National Ambient Air Quality 

Standards for Lead (U.S. EPA, 2006c).

1 13 The schedule for completion of this review was governed by 

14 a judicial order in Missouri Coalition for the Environment v. EPA (No. 4:04CV00660 ERW, Sept. 14, 

15 2005; amended April 29, 2008 and July 1, 2008), which specified a schedule for the review of 

16 duration substantially shorter than five years.

17 The scientific assessment for the review is described in the 2006 AQCD for Pb(U.S. EPA, 

18 2006a), multiple drafts of which received review by CASAC and the public. EPA also conducted 

19 human exposure and health risk assessments and a pilot ecological risk assessment for the review, 

20 after consultation with CASAC and receiving public comment on a draft analysis plan (U.S. EPA, 

21 2006b). Drafts of these quantitative assessments were reviewed by CASAC and the public. The pilot 

22 ecological risk assessment was released in December 2006 (ICF, 2006) and the final health risk 

23 assessment report was released in November 2007 (U.S. EPA, 2007). The policy assessment based 

24 on both of these assessments, air quality analyses and key evidence from the AQCD was presented in 

25 the Staff Paper (U.S. EPA, 2006d), a draft of which also received CASAC and public review. The 

26 final Staff Paper presented OAQPS staff’s evaluation of the public health and welfare policy 

27 implications of the key studies and scientific information contained in the AQCD and presented and 

28 interpreted results from the quantitative risk/exposure analyses conducted for this review. Based on 

29 this evaluation, the Staff Paper presented OAQPS staff recommendations that the Administrator give

30 consideration to substantially revising the primary and secondary standards to a range of levels at or 

below 0.2 μg/m3 31 .

32 Immediately subsequent to completion of the Staff Paper, EPA issued an advance notice of 

33 proposed rulemaking (ANPR) that was signed by the Administrator on December 5, 2007 (72 FR 

 

1 In the current review, these two documents have been combined into an integrated plan (this document).
May 2011 1-8 DRAFT – DO NOT CITE OR QUOTE

71488).1 1 CASAC provided advice and recommendations to the Administrator with regard to the Pb 

2 NAAQS based on its review of the ANPR and the previously released final Staff Paper and Risk 

3 Assessment Report. The proposed decision on revisions to the Pb NAAQS was signed on May 1, 

4 2008 and published in the Federal Register on May 20, 2008 (73 FR 29184). In addition to public 

5 comments on the proposal received during the public comment period, both written and oral at two 

6 public hearings, the CASAC Pb Panel provided advice and recommendations to the Administrator 

7 based on its review of the proposal notice. The final decision on revisions to the Pb NAAQS was 

8 signed on October 15, 2008 and published in the Federal Register on November 12, 2008 (73 FR 

9 66964).

10 The November 2008 notice described EPA’s revisions to the primary and secondary NAAQS 

11 for Pb. In consideration of the much-expanded health effects evidence on neurocognitive effects of 

Pb in children, EPA substantially revised the primary standard from a level of 1.5 μg/m3 12 to a level of 

0.15 μg/m3 13 . EPA’s decision on the level for the standard was based on the weight of the scientific 

14 evidence and guided by an evidence-based framework that integrates evidence for relationships 

15 between Pb in air and Pb in children’s blood and Pb in children’s blood and IQ loss. The level of 

0.15 μg/m3 16 was estimated to protect against air Pb-related IQ loss in the most highly exposed 

17 children, those exposed at the level of the standard. Results of the quantitative risk assessment were 

18 judged supportive of the evidence-based framework estimates. The averaging time was revised to a 

19 rolling 3-month period with a maximum (not-to-be-exceeded) form, evaluated over a 3-year period. 

20 As compared to the previous averaging time of calendar quarter, this revision was considered to be

21 more scientifically appropriate and more health protective. The rolling average gives equal weight to 

22 all three-month periods, and the new calculation method gives equal weight to each month within 

23 each three-month period. Further, the rolling average yields 12 three-month averages each year to be 

24 compared to the NAAQS versus four averages in each year for the block calendar quarters pertaining 

25 to the previous standard. The indicator of Pb in total suspended particles (Pb-TSP) was retained, 

26 reflecting the evidence that Pb particles of all sizes pose health risks. The secondary standard was 

revised to be identical in all respects to the revised primary standards.2 27

28 Revisions to the NAAQS were accompanied by revisions to the data handling procedures, the 

29 treatment of exceptional events and the ambient air monitoring and reporting requirements, as well 

as emissions inventory reporting requirements.3 30 One aspect of the new data handling requirements is 

 

1 The ANPR was one of the features of the revised NAAQS review process that EPA instituted in 2006. :In 2009, this component of the 

process was replaced by reinstatement of the OAQPS policy assessment (previously termed the Staff Paper).

2 The 2008 NAAQS for Pb are specified at 40 CFR 50.16.

3 The 2008 federal regulatory measurement methods for Pb are specified in 40 CFR 50, Appendix G and 40 CFR part 53. Consideration of 

ambient air measurements with regard to judging attainment of the standards is specified in 40 CFR 50, Appendix R. The Pb monitoring 

network requirements are specified in 40 CFR 58, Appendix D, section 4.5. Guidance on the approach for implementation of the new 

standards was described in the Federal Register notices for the proposed and final rules (73 FR 29184; 73 FR 66964).
May 2011 1-9 DRAFT – DO NOT CITE OR QUOTE

1 the allowance for the use of Pb-PM10 monitoring for Pb NAAQS attainment purposes in certain 

2 limited circumstances at non-source oriented sites. Subsequent to the 2008 rulemaking, additional 

3 revisions were made to the monitoring network requirements.

1.3. ISA Development

4 EPA announced the initiation of the current periodic review of the air quality criteria for Pb 

5 and the Pb NAAQS in April 2010 and issued a call for information from the public (75 FR 20843). 

6 In addition to the call for information, publications were identified through an ongoing literature 

7 search process that includes extensive computer database mining on specific topics in a variety of 

8 disciplines. Literature searches were conducted to identify studies published since the last review, 

9 focusing on publications from January 2006 to March 2011. Search strategies were iteratively 

10 modified in an effort to optimize the identification of pertinent publications. Additional papers were 

11 identified for inclusion in several ways: review of pre-publication tables of contents for journals in 

12 which relevant papers may be published and independent identification of relevant literature by 

13 expert authors and peer reviewers. It is anticipated that further identification of studies will occur 

14 during the external review process by the public and CASAC. Publications considered for inclusion 

15 in the ISA were added to the Health and Environmental Research Online (HERO) database recently 

16 developed by EPA (http://hero.epa.gov); note that all citations in the ISA are electronically linked to 

17 the database. Typically, only information that underwent scientific peer review and was published or 

18 accepted for publication was considered. All relevant epidemiologic, animal toxicological, and 

19 ecological and welfare effects studies published since the last review were considered, including 

20 those related to exposure-response relationships, mode(s) of action (MOA), and susceptible 

21 populations. Additionally, air quality and emissions data, studies on atmospheric chemistry, 

22 environmental fate and transport, as well as issues related to Pb toxicokinetics and exposure were

23 considered for inclusion in the document. The process for identifying studies for consideration and 

24 inclusion in the Pb ISA is provided in Figure 1-1. All references that were considered for inclusion

25 can be found within the HERO website (http://hero.epa.gov/lead). This site contains HERO links to

26 lists of references that are cited in the ISA, as well as those that were considered for inclusion, but 

27 not cited in the ISA, with bibliographic information and abstracts.
May 2011 1-10 DRAFT – DO NOT CITE OR QUOTE

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

1 The ISA builds upon the conclusions of the previous review of the air quality criteria for Pb, 

2 presented in the 2006 Pb AQCD (U.S. EPA, 2006a), and focuses on peer reviewed literature 

3 published thereafter and on any new interpretations of previous literature. The 2006 Pb AQCD (U.S. 

4 EPA, 2006a) evaluated literature published through December 2005. In subsequent chapters, the 

5 results of recent scientific studies are integrated with previous findings. Important older studies may 

6 be discussed in detail to reinforce key concepts and conclusions or if they are open to 

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

8 document where research efforts have subsided, and these older studies remain the definitive works 

9 available in the literature. Emphasis is placed on studies that examine effects associated with Pb 
May 2011 1-11 DRAFT – DO NOT CITE OR QUOTE

1 concentrations relevant to current population and ecosystem exposures, and particularly those 

2 pertaining to Pb concentrations currently found in ambient air. Other studies are included if they 

3 contain unique data, such as a previously unreported effect or MOA for an observed effect, or 

4 examine multiple concentrations to elucidate exposure-response relationships. 

5 Discussions in the ISA primarily focus on scientific evaluations that can inform the key policy 

6 questions described in the Integrated Review Plan (U.S. EPA, 2011). Although emphasis is placed on 

7 discussion of health and welfare effects information, other scientific information is also presented 

8 and evaluated in order to provide a better understanding of the sources of Pb to ambient air, 

9 measurement and concentrations of Pb in ambient air, its subsequent fate and transport in the 

10 environment, pathways of human and ecological exposure, and toxicokinetic characteristics of Pb in 

11 the human body, as well as the measurement of population exposure to Pb. 

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

13 studies, the following considerations were taken into account when selecting studies for inclusion in 

14 the ISA. 

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

16 sufficiently well defined to allow for meaningful comparisons between study or exposure 

17 groups? 

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

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

20 statistical analysis? 

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

22  Are the health or welfare effect measurements meaningful and reliable? 

23 Studies published since the 2006 Pb AQCD are emphasized; however, evidence from studies 

24 described in previous assessment that are needed to characterize the current state of the science as 

25 well as new interpretations of older evidence is also considered. Among the studies EPA included in 

26 the ISA, particular focus is for the following areas:

27  New studies with adequate blood Pb data at the low end of the distribution (e.g., 

28 <10 μg/dL);

29  New studies that provide quantitative effect estimates for populations or lifestages and 

30 concentrations of interest;

31  Lead exposure or effects in susceptible populations and lifestages; 

32  Issues related to the potential for confounding of study effects/responses by non-Pb 

33 exposure-related factors or variables, and to the modification of Pb-related effects; 
May 2011 1-12 DRAFT – DO NOT CITE OR QUOTE

1  The timing (e.g., across/within specific lifestages) and duration of exposure associated 

2 with specific responses;

3  Concentration-response relationships for specific Pb-related effects;

4  The interpretation of Pb biomarkers in epidemiological studies; and air-to-blood Pb or

5 air-to-bone Pb relationships;

6  Studies that evaluate Pb as a component of a complex mixtures of pollutants. 

7 In selecting epidemiologic studies for inclusion in the present assessment, EPA has considered 

8 studies containing information on: (1) recent or cumulative exposures relevant to current population 

9 exposure levels of Pb; (2) health endpoints that repeat or extend findings from earlier assessments as 

10 well as those not previously extensively researched; (3) populations and lifestages that are 

11 susceptible to Pb exposures; (4) issues related to potential confounding, and modification of effects; 

12 and/or (5) important methodological issues (e.g., timing and duration of exposure, concentration13 response relationships, interpretation of biomarkers in epidemiological studies, and air-to-blood/bone 

14 relationships) related to Pb exposure effects. In selecting the most informative and policy-relevant 

15 epidemiologic studies on which to give particular focus in the Pb ISA, emphasis is placed on those 

16 most relevant to standard setting in the United States. Informative studies conducted in other 

17 countries are discussed, as appropriate (e.g., studies for which the mean blood Pb level in the 

18 population studied is comparable to the current mean blood Pb level in the corresponding U.S. 

19 population).

20 In reviewing new studies that evaluated the response of laboratory animals to Pb exposure, 

21 focus in on studies that reveal the effects of Pb exposure within the previously identified target 

22 biological systems (e.g., neurological, cardiovascular, renal, immune). Additionally, particular focus 

23 is on those studies that involve doses or blood Pb/bone Pb levels that approximate human doses or 

24 blood Pb/bone Pb levels relevant to current U.S. populations. Studies at higher exposure doses that 

25 result in body burdens above what is found in the current U.S. population are included when the 

26 study can provide information relevant to potential MOA, information on exposure-response 

27 relationships, or otherwise improve our understanding of susceptible populations. Studies of the 

28 efficacy of chelation as a treatment for Pb poisoning in humans and laboratory animals are excluded, 

29 except where they provide evidence for the reversibility of a given health effect.

30 In selecting informative studies of welfare effects, emphasis is placed on recent studies that: 

31 (1) evaluate the occurrence of effects associated with Pb exposure at current ambient concentrations, 

32 with a particular focus on ambient concentrations resulting from ambient air Pb; and/or (2) 

33 investigate the effects of Pb on ecosystems at any scale. Studies conducted in geographical areas 

34 outside the U.S. are included in the assessment if they contribute to the general knowledge of the 
May 2011 1-13 DRAFT – DO NOT CITE OR QUOTE

1 effects of Pb irrespective of species or locality. As in the selection of health-related scientific studies, 

2 welfare-related studies were selected that advance our understanding of MOA by which Pb directly 

3 affects terrestrial and aquatic biota. These MOAs, as they pertain to Pb exposures of short or longer 

4 duration, informs our understanding of indirect effects that Pb may exert more broadly on ecosystem 

5 structure, function and services. Key studies identified for welfare effects are integrated into the 

6 discussion to inform our interpretation of the ecological literature and our characterization of 

7 uncertainties.

8 The criteria described here provide generalized benchmarks to guide the inclusion in the ISA 

9 of the highest quality and most policy-relevant studies. Of most relevance for evaluation of studies is 

10 whether they provide useful qualitative or quantitative information on exposure-effect or 

11 exposure-response relationships for effects associated with current blood Pb or bone Pb levels likely 

12 to be encountered in the U.S. population. Detailed critical analysis of all studies of the effects of Pb 

13 on health and welfare, especially in relation to the above considerations, is beyond the scope of this 

14 document. Since the last AQCD was completed in 2006, a considerable portion of the current ISA is

15 devoted to summarizing previously available evidence that contributed to the basis for the last 

16 rulemaking.

17 As discussed previously, studies included in the text of the ISA are those deemed informative 

18 to the NAAQS review process (e.g., policy relevant) and of adequate quality. The ISA text, tables 

19 and figures highlight and summarize key study details that are needed to understand and interpret the 

20 results of a study. This information, which was described in the text as well as reiterated in the annex 

21 tables of previous documents, includes the air quality system (AQS) data; studies of fate and 

22 transport in air, water, and soil; human exposure and dosimetry studies; blood or tissue Pb levels 

23 corresponding to adverse health effects and dose and duration of exposure in toxicological studies; 

24 and, effect estimates, study location, population, exposure metric and time window, as well as the 

25 characteristics of the exposure/dose distribution for epidemiologic studies. In addition, 

26 supplementary materials are provided in the form of output from the HERO database. A key function 

27 of the HERO output is to document the base of evidence containing publications evaluated for the Pb 

28 review, including any publications considered but not included in the ISA. This information is

29 presented as links to lists of references in the HERO database, which include bibliographic 

30 information and abstracts and can be found at http://hero.epa.gov/lead. In addition, certain study 

31 characteristics of epidemiologic studies, including location, ages investigated, outcomes, and health 

32 endpoints, are summarized in tables included in Chapter 5.

33 In developing the Pb ISA, EPA began by reviewing and summarizing the evidence on: (1) 

34 atmospheric sciences and exposure; (2) the health effects evidence from in vivo and in vitro animal 

35 toxicological and epidemiologic studies; and (3) the welfare effects of Pb, including ecological 

36 effects. In December 2010, EPA held a peer-review input workshop to obtain review of the scientific 
May 2011 1-14 DRAFT – DO NOT CITE OR QUOTE

1 content of initial draft materials or sections for the ISA. The purpose of the peer-review input

2 workshop was to ensure that the ISA was up to date and focused on the most policy-relevant 

3 findings, and to assist EPA with integration of evidence within and across disciplines. Subsequently, 

4 EPA addressed comments from the peer-review input workshop and completed the initial integration 

5 and synthesis of the evidence.

6 The integration of evidence on health or welfare effects involves collaboration between 

7 scientists from various disciplines. As described in the section below, the ISA organization is based 

8 on health and welfare effect categories. As an example, an evaluation of health effects evidence 

9 would include summaries of findings from epidemiologic and toxicological studies, and integration 

10 of the results to draw conclusions based on the causal framework described below. Using the causal 

11 framework described in Section 1.6, EPA scientists consider aspects such as strength, consistency, 

12 coherence and biological plausibility of the evidence, and develop draft causality judgments on the 

13 nature of the relationships. The draft integrative synthesis sections and conclusions are reviewed by 

14 EPA internal experts and, as appropriate, by outside expert authors. In practice, causality 

15 determinations often entail an iterative process of review and evaluation of the evidence. The draft 

16 ISA is released for review by the CASAC and the public. Comments on the characterization of the 

17 science as well as the implementation of the causal framework are carefully considered in revising 

18 and completing the ISA.

1.4. Document Organization

19 This ISA is composed of seven chapters. This introductory chapter presents background 

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

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

22 toxicokinetics, MOA, important health effects of Pb, including neurological, cardiovascular, renal, 

23 immunological, reproductive and developmental, and cancer outcomes, and welfare effects of Pb, 

24 including terrestrial and aquatic ecosystem impacts. More detailed summaries, evaluations, and 

25 integration of the evidence are included in Chapters 3 through 7. Chapter 3 highlights key concepts 

26 or issues relevant to understanding the sources, ambient concentrations, atmospheric behavior, and 

27 fate of Pb in the environment. Chapter 4 summarizes key concepts and recent findings on exposures 

28 to Pb using a conceptual model that reflects the multimedia nature of Pb exposure, toxicokinetics, 

29 biomarkers of Pb exposure and body burden, and models. Chapter 5 presents a discussion of the 

30 MOA of Pb and evaluates and integrates epidemiologic and animal toxicological information on 

31 health effects related to Pb exposures, including neurological, cardiovascular, renal, immunological, 

32 reproductive and developmental, and cancer outcomes. Chapter 6 summarizes the evidence on 
May 2011 1-15 DRAFT – DO NOT CITE OR QUOTE

1 potentially susceptible populations for health effects of Pb exposure. Chapter 7 evaluates welfare 

2 effects evidence that is relevant to the review of the secondary NAAQS for Pb, including ecological 

3 effects. The chapter also presents key conclusions and scientific judgments regarding causality for 

4 welfare effects of Pb. 

1.5. Document Scope

5 For the current NAAQS review of the primary Pb standard, relevant scientific information on 

6 human exposures and health effects associated with exposure to ambient Pb has been assessed. 

7 Previous reviews have included an extensive body of evidence from the major health disciplines of 

8 toxicology and epidemiology on the health effects of Pb exposure (U.S. EPA, 1986a, 2006a). In this 

9 review, the conclusions from previous reviews are summarized at the beginning of each health 

10 outcome discussion to provide the foundation for consideration of evidence from recent studies. 

11 In some cases where no new information is available, the summary of key findings and conclusions 

12 from the previous Pb AQCDs serve as the basis for current key conclusions. Results of key studies 

13 from previous reviews are included in ISA discussions or tables and figures, as appropriate, and 

14 conclusions are drawn based on the synthesis of evidence from recent studies with the extensive 

15 literature summarized in previous reviews. 

16 The review also assesses scientific information associated with known or anticipated 

17 ecological and public welfare effects that is relevant to the review of the secondary Pb standard. 

18 Research on the ecological effects of Pb, including impacts on vegetation, has been discussed

19 extensively in previous AQCDs. This review incorporates and discusses findings of recent studies, 

20 building upon previous evaluations and conclusions. 

1.6. EPA Framework for Causal Determination

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

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

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

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

25 from the National Academy of Sciences (NAS) Institute of Medicine (IOM) document, Improving 

26 the Presumptive Disability Decision-Making Process for Veterans, (2008) the most recent 

27 comprehensive work on evaluating causality.
May 2011 1-16 DRAFT – DO NOT CITE OR QUOTE

1 This introductory section focuses on the evaluation of health effects evidence. While focusing 

2 on human health outcomes, the concepts are also generally relevant to causality determination for 

3 welfare effects. This section: 

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

5 relationship between exposure and health effects; 

6  defines causation, in contrast to statistical association; 

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

8 a causal relationship; 

9  highlights the issue of multifactorial causation; 

10  identifies issues and approaches related to uncertainty; and

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

12 support of a general causal relationship.

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

14 controlled human exposure, and animal toxicological studies) have been formulated by a number of 

15 regulatory and science agencies, including the IOM of the NAS (2008), International Agency for 

16 Research on Cancer (2006), EPA Guidelines for Carcinogen Risk Assessment (2005a), Centers for 

17 Disease Control and Prevention (2004), and National Acid Precipitation Assessment Program (1991). 

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

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

20 structure and language for causal determinations. Moreover, these frameworks have supported 

21 decision-making under conditions of uncertainty.

1.6.1. Scientific Evidence Used in Establishing Causality 

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

23 scientific disciplines; the type of evidence that is most important for such determinations will vary 

24 by assessment. The most direct evidence of a causal relationship between pollutant exposures and 

25 human health effects comes from controlled human exposure studies. This type of study 

26 experimentally evaluates the health effects of administered exposures in human volunteers under 

27 highly-controlled laboratory conditions. Controlled human exposure studies are not done for Pb, and 

28 thus, are unavailable for consideration.

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

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

31 associations between exposures and effects. In the case of Pb, most observational studies use 
May 2011 1-17 DRAFT – DO NOT CITE OR QUOTE

1 biomarkers of Pb (i.e., blood or bone Pb) rather than exposures to relate to effects. These studies fall 

2 into several categories: cross-sectional and longitudinal studies. “Natural experiments” offer the 

3 opportunity to investigate changes in health with a change in exposure; these include comparisons of 

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

5 source.

6 Experimental animal data can help characterize effects of concern, exposure-response 

7 relationships, susceptible populations, MOAs and enhance understanding of biological plausibility of 

8 observed effects. In the absence of human data, animal data alone may be sufficient to support a 

9 likely causal determination, assuming that similar responses are expected in humans. 

1.6.2. Association and Causation 

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

11 welfare. “Association” is the statistical dependence among events, characteristics, or other variables. 

12 An association is prima facie evidence for causation; alone, however, it is insufficient proof of a 

13 causal relationship between exposure and disease or health effect. Determining whether an observed 

14 association is causal rather than spurious involves consideration of a number of factors, as described 

15 below. Much of the newly available health information evaluated in this ISA comes from 

16 epidemiologic studies that report a statistical association between ambient exposure and health 

17 outcomes. 

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

19 etiologies. Diseases such as asthma, cardiovascular disease, Parkinson’s disease or cancer are 

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

21 genetic susceptibility, nutritional status, immune competence, and social factors (Gee & Payne22 Sturges, 2004; Samet & C. C. Bodurow, 2008). Effects on ecosystems are also multifactorial with a 

23 complex web of causation. Further, exposure to a combination of agents could cause synergistic or 

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

25 counteractions. 

1.6.3. Evaluating Evidence for Inferring Causation 

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

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

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

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

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

31 estimate. Uncertainty characterization and uncertainty assessment are two activities that lead to 
May 2011 1-18 DRAFT – DO NOT CITE OR QUOTE

1 different degrees of sophistication in describing uncertainty. Uncertainty characterization generally 

2 involves a qualitative discussion of the thought processes that lead to the selection and rejection of 

3 specific data, estimates, scenarios, etc. Uncertainty assessment is more quantitative. The process 

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

5 extent needed to support the decision for which the assessment is conducted, to more complex 

6 measures and techniques. Data will not be available for all aspects of an assessment and those data 

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

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

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

10 of uncertainty. Uncertainties commonly encountered in evaluating health evidence for the criteria air 

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

12 evaluating uncertainty include classical statistical methods, sensitivity analysis, or probabilistic 

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

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

15 situations, quantitative analysis approaches, such as meta-regression, may be used. 

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

17 body of studies. Blair et al. (1995) observe that meta-analysis can enhance understanding of 

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

19 study results and can be particularly useful for formally examining sources of heterogeneity. 

20 However, these authors note that meta-analysis may not be useful when the relationship between the 

21 exposure and outcome is obvious, when only a few studies are available for a particular exposure22 outcome relationship, where there is limited access to data of sufficient quality, or where there is 

23 substantial variation in study design or population. In addition, important differences in effect 

24 estimates, exposure metrics, or other factors may limit or even preclude quantitative statistical 

25 combination of multiple studies.

26 Epidemiologic studies provide important information on the associations between health 

27 effects and exposure of human populations to ambient air pollution. In the evaluation of 

28 epidemiologic evidence, one important consideration is potential confounding. Confounding is “...a 

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

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

31 may be null)” (Rothman & Greenland, 1998). One approach to remove spurious associations from 

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

33 persons; this is frequently termed “adjustment.” Appropriate statistical adjustment for confounders 

34 requires identifying and measuring all reasonably expected confounders. Deciding which variables 

35 to control for in a statistical analysis of the association between exposure and disease or health 

36 outcome depends on knowledge about possible mechanisms and the distributions of these factors in 
May 2011 1-19 DRAFT – DO NOT CITE OR QUOTE

1 the population under study. In addition, scientific judgment is needed regarding likely sources and 

2 magnitude of confounding, together with consideration of how well the existing constellation of 

3 study designs, results, and analyses address this potential threat to inferential validity. 

4 Another important consideration in the evaluation of epidemiologic evidence is effect 

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

6 difference is that, whereas confounding is a bias that the investigator hopes to prevent or remove 

7 from the effect estimate, effect-measure modification is a property of the effect under study... In 

8 epidemiologic analysis one tries to eliminate confounding but one tries to detect and estimate effect9 measure modification” (Rothman & Greenland, 1998). Examples of effect modifiers in some of the 

10 studies evaluated in this ISA include environmental variables, such as temperature or humidity, 

11 individual risk factors, such as education, cigarette smoking status, age in a prospective cohort study, 

12 and community factors, such as percent of population >65 years old. It is often possible to stratify 

13 the relationship between health outcome and exposure or biomarker by one or more of these risk 

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

15 different from one another and different from the overall estimate, indicating a different exposure16 response relationship may exist in populations represented by these variables. Effect modifiers may 

17 be encountered (1) within single-city time-series studies; or (2) across cities in a two-stage 

18 hierarchical model or meta-analysis.

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

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

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

22 participants that might confound the results. The use of multipollutant regression models has been 

23 the prevailing approach for controlling potential confounding by copollutants in air pollution health 

24 effects studies. Finding the pollutant likely responsible for the health outcome from multipollutant 

25 regression models is made difficult by the possibility that one or more air pollutants may be acting as 

26 a surrogate for an unmeasured or poorly-measured pollutant or for a particular mixture of pollutants. 

27 In addition, more than one pollutant may exert similar health effects, resulting in independently 

28 observed associations for multiple pollutants. Further, the correlation between the air pollutant of 

29 interest and various copollutants may make it difficult to discern associations between different 

30 pollutant exposures and health effects. Thus, results of models that attempt to distinguish gaseous 

31 and particle effects must be interpreted with caution. The number and degree of diversity of 

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

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

34 employed in most air pollution epidemiologic studies, and provides some insight into the potential 

35 for confounding or interaction among pollutants.
May 2011 1-20 DRAFT – DO NOT CITE OR QUOTE

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

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

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

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

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

6 causal association. Appropriate statistical adjustment for confounders requires identifying and 

7 measuring all reasonably expected confounders. Deciding which variables to control for in a 

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

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

10 study. Identifying these mechanisms makes it possible to control for potential sources that may result 

11 in a spurious association.

12 Adjustment for potential confounders can be influenced by differential exposure measurement 

13 error. There are several components that contribute to exposure measurement error in epidemiologic 

14 studies, including the difference between true and measured ambient concentrations, the difference 

15 between average personal exposure to ambient pollutants and ambient concentrations at central 

16 monitoring sites, and the use of average population exposure rather than individual exposure 

17 estimates. Previous AQCDs have examined the role of measurement error in time-series 

18 epidemiologic studies using simulated data and mathematical analyses and suggested that “transfer 

19 of effects” would only occur under unusual circumstances (i.e., “true” predictors having high 

20 positive or negative correlation; substantial measurement error; or extremely negatively correlated 

21 measurement errors) (U.S. EPA, 2004).

22 Confidence that unmeasured confounders are not producing the findings is increased when 

23 multiple studies are conducted in various settings using different subjects or exposures; each of 

24 which might eliminate another source of confounding from consideration. Thus, multicity studies 

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

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

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

28 In addition to controlled human exposure and epidemiologic studies, the tools of experimental 

29 biology have been valuable for developing insights into human physiology and pathology. 

30 Laboratory tools have been extended to explore the effects of putative toxicants on human health, 

31 especially through the study of model systems in other species. These studies evaluate the effects of 

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

33 MOAs or mechanisms by which a pollutant may cause effects. Background knowledge of the 

34 biological mechanisms by which an exposure might or might not cause disease can prove crucial in 

35 establishing or negating a causal claim. There are, however, uncertainties associated with 

36 quantitative extrapolations between laboratory animals and humans on the pathophysiological effects 
May 2011 1-21 DRAFT – DO NOT CITE OR QUOTE

1 of any pollutant. Animal species can differ from each other in fundamental aspects of physiology and 

2 anatomy (e.g., metabolism, airway branching, hormonal regulation) that may limit extrapolation. 

3 Interpretations of experimental studies of pollutant effects in laboratory animals, as in the case 

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

5 extrapolation models. The differences between humans and rodents with regard to pollutant 

6 absorption and distribution profiles based on metabolism, hormonal regulation, exposure dose, and 

7 differences in target organ structure and anatomy, all have to be taken into consideration. Also, in 

8 spite of a high degree of homology and the existence of a high percentage of orthologous genes 

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

10 level is complicated by species-specific differences in transcriptional regulation. Given these 

11 molecular differences, at this time there are uncertainties associated with quantitative extrapolations 

12 between laboratory animals and humans of observed pollutant-induced pathophysiological 

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

1.6.4. Application of Framework for Causal Determination

14 EPA uses a two-step approach to evaluate the scientific evidence on health or environmental 

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

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

17 evaluation of the quantitative evidence regarding the concentration-response relationships and the 

18 loads or levels, duration and pattern of exposures at which effects are observed. 

To aid judgment, various “aspects”1 19 of causality have been discussed by many philosophers 

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

21 general, were articulated by Sir Austin Bradford Hill (1965) and have been widely used (CDC, 2004; 

22 IARC, 2006; NRC, 2004; Samet & C. C. Bodurow, 2008; U.S. EPA, 2005a). Several adaptations of 

23 the Hill aspects have been used in aiding causality judgments in the ecological sciences (Adams, 

24 2003; Collier, 2003; Fox, 1991; Gerritsen et al., 1998). These aspects (Hill, 1965) have been 

25 modified (Table 1-1) for use in causal determinations specific to health and welfare effects or 

pollutant exposures.2 26 Some aspects are more likely than others to be relevant for evaluating evidence 

27 on the health or environmental effects of criteria air pollutants. For example, the analogy aspect does 

28 not always apply and specificity would not be expected for multi-etiologic health outcomes such as 

29 asthma or cardiovascular disease, or ecological effects related to acidification. Aspects that usually 

 

1 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.

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

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

with EPA’s Guidelines for Carcinogen Risk Assessment.
May 2011 1-22 DRAFT – DO NOT CITE OR QUOTE

1 play a larger role in determination of causality are consistency of results across studies, coherence of 

2 effects observed in different study types or disciplines, biological plausibility, exposure-response 

3 relationship, and evidence from “natural” experiments.

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

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

6 conclusions about causality (Hill, 1965). For example, one cannot simply count the number of 

7 studies reporting statistically significant results or statistically nonsignificant results and reach 

8 credible conclusions about the relative weight of the evidence and the likelihood of causality. Rather, 

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

10 appraisal of the evidence, informed by peer and public comment and advice, which includes 

11 weighing alternative views on controversial issues. In addition, it is important to note that the aspects 

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

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

14 preclude a determination of causality (CDC, 2004). 
May 2011 1-23 DRAFT – DO NOT CITE OR QUOTE

Table 1-1. Aspects to aid in judging causality

Aspect Decription

Consistency of the 

observed association An inference of causality is strengthened when a pattern of elevated risks is observed across several 

independent studies, conducted in multiple locations by multiple investigators. The reproducibility of findings 

constitutes one of the strongest arguments for causality. If there are discordant results among investigations, 

possible reasons such as differences in exposure, confounding factors, and the power of the study are 

considered.

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

(e.g., controlled human exposure and animal toxicological studies) that support a cause-and-effect 

interpretation of the association. Causality is also supported when epidemiologic associations are reported 

across study designs and across related health outcomes. Evidence on ecological or welfare effects may be 

drawn from a variety of experimental approaches (e.g., greenhouse, laboratory, and field) and subdisciplines 

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. The 

absence of other lines of evidence, however, is not a reason to reject causality

Biological plausibility An inference of causality tends to be strengthened by consistency with data from experimental studies or 

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

effect, and exposure to the agent, is an important source of support for causality, especially when data 

establishing the existence and functioning of those mechanistic links are available. A lack of biological 

understanding, however, is not a reason to reject causality.

Biological gradient 

(exposure-response 

relationship)

A well-characterized exposure-response relationship (e.g., increasing effects associated with greater 

exposure) strongly suggests cause and effect, especially when such relationships are also observed for 

duration of exposure (e.g., increasing effects observed following longer exposure times). There are, 

however, many possible reasons that a study may fail to detect an exposure-response relationship. Thus,

although the presence of a biological gradient may support causality, the absence of an exposure-response 

relationship does not exclude a causal relationship.

Strength of the 

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

or other factors. However, given a truly causal agent, a small magnitude in the effect could follow from a 

lower level of exposure, a lower potency, or the prevalence of other agents causing similar effects. While 

large effects support causality, modest effects therefore do not preclude it.

Experimental evidence The strongest evidence for causality can be provided when a change in exposure brings about a change in 

occurrence or frequency of health or welfare effects.

Temporal relationship 

of the observed

association

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

constitutes another argument in favor of causality.

Specificity of the

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

effect or disease (Hill, 1965). Based on the current understanding this is now considered one of the weaker 

guidelines for causality; for example, many agents cause respiratory disease and respiratory disease has 

multiple causes. At the scale of ecosystems, as in epidemiology, complexity is such that single agents 

causing single effects, and single effects following single causes, are extremely unlikely. The ability to 

demonstrate specificity under certain conditions remains, however, a powerful attribute of experimental 

studies. Thus, although the presence of specificity may support causality, its absence does not exclude it.

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

whether an association is causal. Similarly, information on mode of action for a chemical, as one of many 

structural analogs, can inform decisions regarding likely causality.

1.6.5. Determination of Causality

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

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

3 between relevant exposures or body burden, as measured by blood or tissue Pb levels, and health 
May 2011 1-24 DRAFT – DO NOT CITE OR QUOTE

1 effects and relevant Pb concentrations and environmental effects. This ISA uses a five-level 

hierarchy that classifies the weight of evidence for causation, not just association1 2 ; that is, whether 

3 the weight of scientific evidence makes causation at least as likely as not, in the judgment of the 

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

5 most prominently the IOM’s Improving the Presumptive Disability Decision-Making Process for 

6 Veterans (2008), EPA’s Guidelines for Carcinogen Risk Assessment (2005a), and the U.S. Surgeon 

7 General’s smoking reports (CDC, 2004). In the ISA, EPA uses a series of five descriptors to 

8 characterize the weight of evidence for causality. This weight of evidence evaluation is based on 

9 various lines of evidence from across the health and environmental effects disciplines. These 

10 separate judgments are integrated into a qualitative statement about the overall weight of the 

11 evidence and causality. The five descriptors for causal determination are described in Table 1-2.

12 For the Pb ISA, determination of causality involved the evaluation of evidence for different 

13 types of health effects associated with Pb biomarkers of exposure and body burden (i.e., blood and 

14 tissue). In making determinations of causality for Pb, evidence was evaluated for health outcome 

15 categories, such as neurological effects, and then conclusions were drawn based upon the integration 

16 of evidence from across disciplines (e.g., epidemiology and toxicology) and also across the suite of 

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

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

19 was determined by the type of study and methods of exposure or dose and response measurements. 

20 Results from different protocols were compared and contrasted. 

 

1 It should be noted that the CDC and IOM frameworks use a four-category hierarchy for the strength of the evidence. A five-level 

hierarchy is used here to be consistent with the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a) and to provide a more 

nuanced set of categories.
May 2011 1-25 DRAFT – DO NOT CITE OR QUOTE

Table 1-2. Weight of evidence for causal determination

Determination Health Effects Ecological and Welfare Effects 

Causal

relationship

Evidence is sufficient to conclude that there is a causal 

relationship with relevant blood or tissue Pb levels. That is, 

blood or tissue Pb levels have been shown to result in 

health effects in studies in which chance, bias, and 

confounding could be ruled out with reasonable 

confidence. For example: a) controlled human exposure 

studies that demonstrate consistent effects; or b) 

observational studies that cannot be explained by 

plausible alternatives or are supported by other lines of 

evidence (e.g., animal studies or mode of action 

information). Evidence includes replicated and consistent 

high-quality studies by multiple investigators.

Evidence is sufficient to conclude that there is a causal 

relationship with relevant pollutant exposures. That is, the 

pollutant has been shown to result in effects in studies in 

which chance, bias, and confounding could be ruled out 

with reasonable confidence. Controlled exposure studies 

(laboratory or small- to medium-scale field studies) provide 

the strongest evidence for causality, but the scope of 

inference may be limited. Generally, determination is 

based on multiple studies conducted by multiple research 

groups, and evidence that is considered sufficient to infer 

a causal relationship is usually obtained from the joint 

consideration of many lines of evidence that reinforce 

each other.

Likely to be a 

causal 

relationship

Evidence is sufficient to conclude that a causal 

relationship is likely to exist with relevant blood or tissue 

Pb levels, but important uncertainties remain. That is, 

blood or tissue Pb levels have 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 confounding factors are difficult to 

address and/or other lines of evidence (controlled human 

exposure, animal, or mode of action information) are 

limited or inconsistent; or b) animal toxicological evidence 

from multiple studies from different laboratories that 

demonstrate effects, but limited or no human data are 

available. Evidence generally includes replicated and 

high-quality studies by multiple investigators.

Evidence is sufficient to conclude that there is a likely 

causal association with relevant pollutant exposures. That 

is, an association has been observed between the 

pollutant and the outcome in studies in which chance, bias 

and confounding are minimized, but uncertainties remain. 

For example, field studies show a relationship, but 

suspected interacting factors cannot be controlled, and 

other lines of evidence are limited or inconsistent. 

Generally, determination is based on multiple studies in 

multiple research groups.

Suggestive 

of a causal 

relationship

Evidence is suggestive of a causal relationship with 

relevant blood or tissue Pb levels, but is limited because 

chance, bias and confounding cannot be ruled out. For 

example, at least one high-quality epidemiologic study 

shows an association with a given health outcome but the 

results of other studies are inconsistent.

Evidence is suggestive of a causal relationship with 

relevant pollutant exposures, but chance, bias and 

confounding cannot be ruled out. For example, at least 

one high-quality study shows an effect, but the results of 

other studies are inconsistent.

Inadequate 

to infer a 

causal 

relationship

Evidence is inadequate to determine that a causal 

relationship exists with relevant blood or tissue Pb levels. 

The available studies are of insufficient quantity, quality, 

consistency or statistical power to permit a conclusion 

regarding the presence or absence of an effect.

The available studies are of insufficient quality, 

consistency or statistical power to permit a conclusion 

regarding the presence or absence of an effect.

Not likely to 

be a causal 

relationship

Evidence is suggestive of no causal relationship with 

relevant blood or tissue Pb levels. Several adequate 

studies, covering the full range of levels of exposure that 

human beings are known to encounter and considering 

susceptible populations, are mutually consistent in not 

showing an effect at any level of exposure. 

Several adequate studies, examining relationships with 

relevant exposures, are consistent in failing to show an 

effect at any level of exposure.

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

2 on evidence of effects at relevant pollutant exposures. For making causality judgments for Pb health 

3 effects, the focus is on evidence of exposure or body burden as indicated by relevant (within one 

4 order of magnitude) blood or tissue Pb levels of the current U.S. population (median blood Pb level 
May 2011 1-26 DRAFT – DO NOT CITE OR QUOTE

1 = 1.3; 95th percentile = 4.1; 99th percentile = 7.2). Studies of the efficacy of chelation therapy in Pb2 poisoned children and toxicological studies in which Pb levels were sufficiently high to induce an 

3 overtly toxic response in the animals (e.g., mortality) were specifically excluded. Studies of workers 

4 exposed to Pb in occupational settings were generally considered in the causal determinations.

5 Building upon the determination of causality are questions relevant to quantifying health or 

6 environmental risks based on our understanding of the quantitative relationships between pollutant 

7 exposures or biomarkers and health or welfare effects. While the causality determination is based 

8 primarily on evaluation of health or environmental effects evidence, EPA also evaluates evidence 

9 related to the doses or biomarker levels at which effects are observed. Considerations relevant to 

10 evaluation of quantitative relationships for health and environmental effects are summarized below.

1.6.5.1. Effects on Human Populations

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

12 outcome category, important questions regarding quantitative relationships include: 

13  What is the concentration-response, exposure-response, or dose-response relationship in 

14 the human population?

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

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

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

18 To address these questions, the entirety of policy-relevant quantitative evidence is evaluated to 

19 best quantify those concentration-response relationships that exist. For Pb, evaluation of blood or 

20 tissue Pb concentrations at which effects were observed for exposed populations, including 

21 potentially susceptible populations, has been an important element of this process. The integration of 

22 evidence resulted in identification of a study or set of studies that best approximated the 

23 concentration-response relationships between blood Pb and various health outcomes, given the 

24 current state of knowledge and the uncertainties that surrounded these estimates. To accomplish this, 

25 evidence is considered from multiple and diverse types of studies. To the extent available, the ISA 

26 evaluates results from across epidemiologic studies that use various methods to evaluate the form of 

27 relationships between blood or tissue Pb concentrations and health outcomes and draws conclusions 

28 on the most well-supported shape of these relationships. Animal data may also inform evaluation of 

29 concentration-response relationships, particularly relative to MOAs and characteristics of susceptible 

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

31 risks.
May 2011 1-27 DRAFT – DO NOT CITE OR QUOTE

1 An important consideration in characterizing the public health impacts associated with 

2 exposure to a pollutant is whether the concentration-response relationship is linear across the full 

3 concentration range encountered or if nonlinear relationships exist along any part of this range. In 

4 general, the shape of the concentration-response curve varies, depending on the type of health 

5 outcome, underlying MOA and dose. At the human population level, however, various sources of 

6 variability and uncertainty, such as the low data density at the lowest blood Pb levels, possible 

7 influence of exposure measurement error, and individual differences in susceptibility to Pb health 

8 effects, tend to smooth and “linearize” the concentration-response function. In addition, many 

9 chemicals and agents may act by perturbing naturally occurring background processes that lead to 

10 disease, which also linearizes population concentration-response relationships (Clewell & Crump, 

11 2005; Crump et al., 1976; Hoel, 1980). These attributes of population dose-response may explain 

12 why the available human data at ambient concentrations for some environmental pollutants (e.g., Pb, 

13 PM, O3, environmental tobacco smoke [ETS], radiation) do not exhibit evident thresholds for cancer 

14 or noncancer health effects, even though likely mechanisms include nonlinear processes for some 

15 key events. These attributes of human population dose-response relationships have been extensively 

16 discussed in the broader epidemiologic literature (Rothman & Greenland, 1998). Of particular 

17 interest for Pb is the shape of the concentration- response curve at the low end (<10 μg/dL) of 

18 current blood Pb concentrations observed in the U.S. population.

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

20 is well understood that studies reporting non-null findings are more likely to be published than 

21 reports of null findings, and publication bias can also result in overestimation of effect estimate sizes 

22 (Ioannidis, 2008). For example, effect estimates from single-city epidemiologic studies have been 

23 found to be generally larger than those from multicity studies (Anderson et al., 2005). 

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

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

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

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

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

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

30 lifestage, lifestyle (e.g., smoking status and nutrition) or preexisting disease; as well as population31 level factors that can increase an individual’s exposure to an air pollutant (e.g., Pb) such as 

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

33 attainment, residential location, and other factors. Epidemiologic studies can help identify 

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

35 stratified analyses for subsets of the population under study or testing for interactions or effect 

36 modification by factors such as gender, age group, or health status. Experimental studies using 
May 2011 1-28 DRAFT – DO NOT CITE OR QUOTE

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

2 greater in specific population groups. Further discussion of these groups is presented in Chapter 6.

1.6.5.2. Effects on Ecosystems or Public Welfare

3 Key questions for understanding the quantitative relationships between exposure (or 

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

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

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

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

8 pattern) are effects observed? 

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

10 Evaluations of causality generally consider the probability of quantitative changes in 

11 ecological and welfare effects in response to exposure. A challenge to the quantification of exposure12 response relationships for ecological effects is the great regional and local variability in ecosystems. 

13 Thus, exposure-response relationships are often determined for a specific ecological system and 

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

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

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

17 studies are available, they may be used to aid in characterizing exposure-response relations, 

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

1.6.6. Concepts in Evaluating Adversity of Health Effects

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

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

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

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

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

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

25 not be considered adverse while those of a similar type and magnitude are potentially adverse in 

26 more susceptible individuals. 

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

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

29 Health Effect of Air Pollution? (2000). This statement updated the guidance for defining adverse 

30 respiratory health effects that had been published 15 years earlier (ATS, 1985), taking into account 
May 2011 1-29 DRAFT – DO NOT CITE OR QUOTE

1 new investigative approaches used to identify the effects of air pollution and reflecting concern for 

2 impacts of air pollution on specific susceptible groups. In the 2000 update, there was an increased 

3 focus on quality of life measures as indicators of adversity and a more specific consideration of 

4 population risk. Exposure to air pollution that increases the risk of an adverse effect to the entire 

5 population is viewed as adverse, even though it may not increase the risk of any identifiable 

6 individual to an unacceptable level. For example, a population of asthmatics could have a 

7 distribution of lung function such that no identifiable individual has a level associated with 

8 significant impairment. Exposure to air pollution could shift the distribution such that no identifiable 

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

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

11 diminished reserve function and therefore would be at increased risk to further environmental insult.

1.7. Summary

12 This draft ISA is a concise evaluation and synthesis of the most policy-relevant science for 

13 reviewing the NAAQS for Pb, and it is the chief means for communicating the critical science 

14 judgments relevant to that NAAQS review. It reviews the most policy-relevant evidence from 

15 atmospheric science, exposure, and health and environmental effects studies and includes 

16 mechanistic evidence from basic biological science. A framework for making critical judgments 

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

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

19 clarity to current and future assessments. Once complete, the ISA should assist EPA and others, now 

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

21 concerning the effects of Pb on human health and public welfare.
May 2011 1-30 DRAFT – DO NOT CITE OR QUOTE

Chapter 1 References

Adams, S. M. (2003). Establishing causality between environmental stressors and effects on aquatic ecosystems. Human 

and Ecological Risk Assessment, 9, 17-35. http://dx.doi.org/10.1080/713609850

Anderson, H. R., Atkinson, R. W., Peacock, J. L., Sweeting, M. J., & Marston, L. (2005). Ambient particulate matter and 

health effects: Publication bias in studies of short-term associations. Epidemiology, 16(2), 155-163. 

http://dx.doi.org/10.1097/01.ede.0000152528.22746.0f

ATS. (American Thoracic Society). (1985). Guidelines as to what constitutes an adverse respiratory health effect, with 

special reference to epidemiologic studies of air pollution. American Review of Respiratory Disease, 131, 666-

668. http://www.ncbi.nlm.nih.gov/pubmed/3994164

ATS. (American Thoracic Society). (2000). 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 1999. American 

Journal of Respiratory and Critical Care Medicine, 161, 665-673. 

Blair, A., Burg, J., Foran, J., Gibb, H., Greenland, S., Morris, R., . . . Zimmerman, R. (1995). Guidelines for application of 

meta-analysis in environmental epidemiology. Regulatory Toxicology and Pharmacology, 22, 189-197. 

http://dx.doi.org/10.1006/rtph.1995.1084

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 and Human Services.

Clewell, H. J., & Crump, K. S. (2005). Quantitative estimates of risk for noncancer endpoints. Risk Analysis, 25(2), 285-

289. http://dx.doi.org/10.1111/j.1539-6924.2005.00589.x

Collier, T. K. (2003). Forensic ecotoxicology: Establishing causality between contaminants and biological effects in field 

studies. Human and Ecological Risk Assessment, 9, 259-266. http://dx.doi.org/10.1080/713609862

Crump, K. S., Hoel, D. G., Langley, C. H., & Peto, R. (1976). Fundamental carcinogenic processes and their implications 

for low dose risk assessment. Cancer Research, 36(9 pt.1), 2973-2979. 

http://www.ncbi.nlm.nih.gov/pubmed/975067

Fox, G. A. (1991). Practical causal inference for ecoepidemiologists. Journal of Toxicology and Environmental Health, 

Part A: Current Issues, 33(4), 359-373. http://dx.doi.org/10.1080/15287399109531535

Gee, G. C., & Payne-Sturges, D. C. (2004). Environmental health disparities: A framework integrating psychosocial and 

environmental concepts. Environmental Health Perspectives, 112(17), 1645-1653. 

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

Gerritsen, J., Carlson, R. E., Dycus, D. L., Faulkner, C., Gibson, G. R., Harcum, J., & Markowitz, S. A. (1998). Lake and 

reservoir bioassessment and biocriteria: Technical guidance document. (Report No. EPA 841-B-98-007). 

Washington, DC: U.S. Environmental Protection Agency, Office of Water. Retrieved from 

http://www.epa.gov/owow/monitoring/tech/lakes.html.

Hill, A. B. (1965). The environment and disease: Association or causation? Proceedings of the Royal Society of Medicine, 

58(5), 295-300. http://www.ncbi.nlm.nih.gov/pubmed/14283879

Hoel, D. G. (1980). Incorporation of background in dose-response models. Federation Proceedings, 39(1), 73-75. 

http://www.ncbi.nlm.nih.gov/pubmed/7351247

IARC. (International Agency for Research on Cancer). (2006). IARC monographs on the evaluation of carcinogenic risks 

to humans: Preamble. Lyon, France: World Health Organization. Retrieved from 

http://monographs.iarc.fr/ENG/Preamble/CurrentPreamble.pdf.

ICF. (ICF International). (2006). Lead human exposure and health risk assessments and ecological risk assessment for 

selected areas: Pilot phase: External review draft technical report. Research Triangle Park, NC: U.S. 

Environmental Protection Agency, Office of Air Quality Planning and Standards.

Ioannidis, J. P. A. (2008). Why most discovered true associations are inflated. Epidemiology, 19(5), 640-648. 

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

NAPAP. (National Acid Precipitation Assessment Program). (1991). The experience and legacy of NAPAP: Report of the 

Oversight Review Board of the National Acid Precipitation Assessment Program. Washington, DC: Author.

NRC. (National Research Council). (2004). Research priorities for airborne particulate matter: IV: Continuing research 

progress. Washington, DC: National Academy Press.

Rothman, K. J., & Greenland, S. (1998). Modern epidemiology (2nd ed.). Philadelphia, PA: Lippincott-Raven Publishers.
May 2011 1-31 DRAFT – DO NOT CITE OR QUOTE

Samet, J. M., & C. C. Bodurow (Eds.). (Institute of Medicine). (2008). Improving the presumptive disability decisionmaking process for veterans. Washington, DC: National Academies Press.

U.S. EPA. (U.S. Environmental Protection Agency). (1977). Air quality criteria for lead. (Report No. EPA-600/8-77-017). 

Washington, DC: U.S. Environmental Protection Agency, Office of Research and Development. Retrieved from 

http://www.ntis.gov/search/product.aspx?ABBR=PB280411.

U.S. EPA. (U.S. Environmental Protection Agency). (1986a). Air quality criteria for lead. (Report No. EPA/600/8-83/028 

aF-dF). Washington, DC: Author.

U.S. EPA. (U.S. Environmental Protection Agency). (1986b). Lead effects on cardiovascular function, early development, 

and stature: An addendum to U.S. EPA Air Quality Criteria for Lead (1986). (Report No. EPA-600/8-83/028aF). 

Washington, DC: U.S. Environmental Protection Agency, Office of Research and Development.

U.S. EPA. (U.S. Environmental Protection Agency). (1989). Review of the national ambient air quality standards for lead: 

Exposure analysis methodology and validation: OAQPS staff report. (Report No. EPA-450/2-89-011). Research 

Triangle Park, NC: U.S. Environmental Protection Agency, Office of Air Quality Planning and Standards.

U.S. EPA. (U.S. Environmental Protection Agency). (1990a). Air quality criteria for lead: Supplement to the 1986 

addendum. (Report No. EPA/600/8-89/049F). Washington, DC: U.S. Environmental Protection Agency, Office of 

Research and Development.

U.S. EPA. (U.S. Environmental Protection Agency). (1990b). Review of the national ambient air quality standards for 

lead: Assessment of scientific and technical information: OAQPS staff paper. (Report No. EPA-450/2-89-022). 

Research Triangle Park, NC: U.S. Environmental Protection Agency, Office of Air Quality Planning and 

Standards.

U.S. EPA. (U.S. Environmental Protection Agency). (1991). Strategy for reducing lead exposures. Washington, DC: 

Author. Retrieved from http://www.epa.gov/ttn/naaqs/standards/pb/data/leadstrategy1991.pdf.

U.S. EPA. (U.S. Environmental Protection Agency). (2004). Air quality criteria for particulate matter. (Report No. 

EPA/600/P-99/002aF-bF). Research Triangle Park, NC: U.S. Environmental Protection Agency, National Center 

for Environmental Assessment. Retrieved from http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=87903.

U.S. EPA. (U.S. Environmental Protection Agency). (2005a). Guidelines for carcinogen risk assessment. (Report No. 

EPA/630/P-03/001F). Washington, DC: U.S. Environmental Protection Agency, Risk Assessment Forum. 

Retrieved from http://www.epa.gov/cancerguidelines/.

U.S. EPA. (U.S. Environmental Protection Agency). (2005b). Project work plan for revised air quality criteria for lead. 

(Report No. NCEA-R-1465). Research Triangle Park, NC: U. S. Environmental Protection Agency. Retrieved 

from http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=113963.

U.S. EPA. (U.S. Environmental Protection Agency). (2006a). Air quality criteria for lead. (Report No. EPA/600/R05/144aF-bF). Research Triangle Park, NC: U.S. Environmental Protection Agency, National Center for 

Environmental Assessment. Retrieved from http://cfpub.epa.gov/ncea/CFM/recordisplay.cfm?deid=158823.

U.S. EPA. (U.S. Environmental Protection Agency). (2006b). Analysis plan for human health and ecological risk 

assessment for the review of the lead national ambient air quality standards (draft). Research Triangle Park, NC: 

Author. Retrieved from http://www.epa.gov/ttn/naaqs/standards/pb/s_pb_cr_pd.html.

U.S. EPA. (U.S. Environmental Protection Agency). (2006c). Plan for review of the national ambient air quality standards 

for lead. Research Triangle Park, NC: Author. Retrieved from 

http://www.epa.gov/ttn/naaqs/standards/pb/s_pb_cr_pd.html.

U.S. EPA. (U.S. Environmental Protection Agency). (2006d). Review of the national ambient air quality standards for 

lead: Policy assessment of scientific and technical information: OAQPS staff paper - first draft. (Report No. EPA452/P-06-002). Research Triangle Park, NC: U.S. Environmental Protection Agency, Office of Air Quality 

Planning and Standards.

U.S. EPA. (U.S. Environmental Protection Agency). (2007). Lead: Human exposure and health risk assessments for 

selected case studies: Volume 1: Human exposure and health risk assessments - full-scale. (Report No. EPA452/R-07-014a). Research Triangle Park, NC: U.S. Environmental Protection Agency, Office of Air Quality 

Planning and Standards. Retrieved from http://www.ntis.gov/search/product.aspx?ABBR=PB2008102573.

U.S. EPA. (U.S. Environmental Protection Agency). (2011). Integrated review plan for the national ambient air quality 

standards for lead: External review draft. (Report No. EPA-452/D-11-001). Research Triangle Park, NC: U.S. 

Environmental Protection Agency, Office of Research and Development.