UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C. 20460

OFFICE OF THE ADMINISTRATOR

SCIENCE ADVISORY BOARD

June 4, 2013

EPA-CASAC-13-004

The Honorable Bob Perciasepe

Acting Administrator

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, N.W.

Washington, D.C. 20460

Subject: CASAC Review of the EPA’s Integrated Science Assessment for Lead (Third External 

Review Draft – November 2012)

Dear Acting Administrator Perciasepe:

The Clean Air Scientific Advisory Committee (CASAC) Lead Review Panel met on February 5, 2013,

to peer review the EPA’s Integrated Science Assessment for Lead (Third External Review Draft –

November 2012), hereafter referred to as the Third Draft ISA. The charge questions from the agency, the 

CASAC’s consensus responses to the agency’s charge questions and the individual review comments 

from the CASAC Lead Review Panel are enclosed. The CASAC’s key points are highlighted below.

The CASAC commends the EPA for substantial revisions to the Second Draft ISA based upon its prior 

advice (July 2012). The CASAC believes that the ISA will serve as a scientifically sound foundation for 

the Lead (Pb) National Ambient Air Quality Standards (NAAQS) review. There is no need for the 

CASAC to review another draft of the ISA; however, the CASAC offers additional comments and 

recommendations on improving the document, as well as repeats some comments and recommendations 

that were not previously addressed.

The description in the ISA of the state of the science for measurement of particles greater than 10 

micrometers has been improved. The CASAC has previously recommended that the EPA develop a new 

Pb air sampler to replace the high-volume total suspended particulates sampler. Although it is 

understood that the EPA will not have completed work on design and characterization of an improved 

“larger particle” sampler for this cycle of the Pb NAAQS, the EPA is encouraged to continue this 

process.

The application of the causal framework is clearer and better documented in the revised ISA. In general, 

the new health endpoint groupings are appropriate and contribute to greater clarity of causal 

determinations for all major organ systems. This new approach has the greatest impact on improving the 

section describing health effects related to the nervous system; however, standard naming conventions 

(e.g. clinical terminology and classification) should be used in the description of behavioral outcomes. 

In addition, there are several errors of health or study outcome categorization for the nervous system 

review and there are a few instances where appropriate specific health endpoints are the focus of the 
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literature review but the causal determination is applied, inappropriately, to a more general organ 

system. 

The ISA should provide greater transparency in differentiating between the designations “likely to be 

causal relationship” between Pb exposures and health outcomes and “suggestive of a causal 

relationship.” The EPA should be explicit in discussing the uncertainties and limitations which 

contributed to the designation. Additionally, the ISA should be clear about whether human data or 

animal data contributed to the causal determination. The EPA should change the designation between 

low level Pb exposure and renal dysfunction from “likely to be a causal relationship” to “suggestive of a 

causal relationship.” The reasons for this change include: inconsistency of the epidemiological findings 

in large high-quality studies; absence of a demonstrated pathological mode of action for Pb

nephrotoxicity in humans or animals at blood Pb concentrations less than 10 micrograms per deciliter; 

and the plausibility of reverse causation as an explanation for the association.

In reviewing literature, the EPA raises particular study design concerns multiple times throughout the 

ISA (e.g., lack of adjustment for parenting quality and poor representativeness of the study population), 

but their relevance to interpretation of a given study is not discussed. The representativeness of study 

populations is emphasized as a limitation in a number of nervous system studies. However, the lack of 

generalizability does not impact the validity of a study (unless there is effect measure modification).

Therefore, in some cases, the findings of such studies may have been disproportionately discounted.

The EPA has integrated an extraordinary amount of information about at-risk populations and employs a

useful framework(s) for critically reviewing and integrating information. However, indication of the

relative magnitude of the effect modification from the risk factors is still missing. It would be extremely 

useful to add a table, with appropriate interpretive text, that summarizes the magnitude of effect 

modification that these various risk factors impose. 

Although the ISA provides a fair and balanced evaluation of the existing scientific information on the 

ecological effects of Pb, one major concern is the inability to relate ecosystem effects to the 

concentrations of Pb that exist in air, soil, and water. For ecosystems, an important source of the Pb in 

soil and water is atmospheric deposition and transport processes. A critical loads approach is needed to 

establish this relationship. Research should be conducted to develop, calibrate, and test models 

applicable to the development of critical loads for Pb and other metals in the United States.

Tables that summarize the key studies leading to the causal determinations of the ecological effects of 

Pb are an important addition to the ISA. In addition to these tables, it would be useful to include a graph 

showing the various effects as a function of the exposure concentration. The environmental 

concentration range also could be shown. Distinctions should be made on the graph between measured 

concentrations and nominal concentrations (if there are not measured concentrations). 
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The CASAC appreciates the opportunity to provide advice on the ISA and looks forward to the EPA’s

response to the advice provided here.

Sincerely,

/signed/

Dr. H. Christopher Frey, Chair

Clean Air Scientific Advisory Committee

Enclosures
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NOTICE

This report has been written as part of the activities of the EPA's Clean Air Scientific Advisory 

Committee (CASAC), a federal advisory committee independently chartered to provide extramural 

scientific information and advice to the Administrator and other officials of the EPA. The CASAC 

provides balanced, expert assessment of scientific matters related to issues and problems facing the 

agency. This report has not been reviewed for approval by the agency and, hence, the contents of this 

report do not necessarily represent the views and policies of the EPA, nor of other agencies within the 

Executive Branch of the federal government. In addition, any mention of trade names or commercial 

products does not constitute a recommendation for use. The CASAC reports are posted on the EPA 

website at: http://www.epa.gov/casac.
ii

U.S. Environmental Protection Agency

Clean Air Scientific Advisory Committee

CASAC Lead Review Panel (2010-2013)

CHAIR

Dr. H. Christopher Frey, Distinguished University Professor, Department of Civil, Construction and 

Environmental Engineering, College of Engineering, North Carolina State University, Raleigh, NC

OTHER CASAC MEMBER

Mr. George A. Allen, Senior Scientist, Northeast States for Coordinated Air Use Management 

(NESCAUM), Boston, MA

CONSULTANTS

Dr. Herbert Allen, Professor Emeritus, Department of Civil and Environmental Engineering, 

University of Delaware, Newark, DE

Dr. Richard Canfield, Senior Research Associate, Division of Nutritional Sciences, Cornell University, 

Ithaca, NY

Dr. Deborah Cory-Slechta, Professor, Department of Environmental Medicine, School of Medicine 

and Dentistry, University of Rochester, Rochester, NY

Dr. Cliff Davidson, Professor, Civil and Environmental Engineering, Syracuse University, Syracuse, 

NY

Dr. Philip E. Goodrum, Senior Consultant, Cardno ENTRIX, Syracuse, NY

Dr. Sean Hays, President, Summit Toxicology, Allenspark, CO

Dr. Philip Hopke, Bayard D. Clarkson Distinguished Professor, Department of Chemical and 

Biomolecular Engineering, Clarkson University, Potsdam, NY

Dr. Chris Johnson, Professor, Department of Civil and Environmental Engineering , Syracuse 

University, Syracuse, NY

Dr. Susan Korrick, Assistant Professor of Medicine , Department of Medicine, Brigham and Women's 

Hospital, Channing Laboratory, Harvard Medical School, Boston, MA

Dr. Michael Kosnett, Associate Clinical Professor, Division of Clinical Pharmacology and Toxicology, 

Department of Medicine, University of Colorado School of Medicine, Denver, CO
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Dr. Roman Lanno, Associate Professor and Associate Chair, Department of Evolution, Ecology, and 

Organismal Biology, Ohio State University, Columbus, OH

Mr. Richard L. Poirot, Environmental Analyst, Air Pollution Control Division, Department of 

Environmental Conservation, Vermont Agency of Natural Resources, Waterbury, VT

Dr. Joel G. Pounds, Laboratory Fellow, Cell Biology & Biochemistry, Biological Sciences Division, 

Pacific Northwest National Laboratory, Richland, WA

Dr. Michael Rabinowitz, Geochemist, Marine Biological Laboratory, Newport, RI

Dr. William Stubblefield, Senior Research Professor, Department of Molecular and Environmental 

Toxicology, Oregon State University, Corvallis, OR

Dr. Ian von Lindern, President, TerraGraphics Environmental Engineering, Inc., Moscow, ID

Dr. Gail Wasserman, Professor of Clinical Psychology in Child Psychiatry, Division of Child and 

Adolescent Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY

Dr. Michael Weitzman, Professor, Pediatrics; Psychiatry, New York University School of Medicine, 

New York, NY

SCIENCE ADVISORY BOARD STAFF

Mr. Aaron Yeow, Designated Federal Officer, U.S. Environmental Protection Agency, Science 

Advisory Board (1400R), 1200 Pennsylvania Avenue, NW, Washington, DC
iv

U.S. Environmental Protection Agency

Clean Air Scientific Advisory Committee

CASAC

CHAIR

Dr. H. Christopher Frey, Distinguished University Professor, Department of Civil, Construction and 

Environmental Engineering, College of Engineering, North Carolina State University, Raleigh, NC

MEMBERS

Mr. George A. Allen, Senior Scientist, Northeast States for Coordinated Air Use Management 

(NESCAUM), Boston, MA

Dr. Ana Diez-Roux, Professor of Epidemiology, School of Public Health, University of Michigan, Ann 

Arbor, MI

Dr. Jack Harkema, Professor, Department of Pathobiology, College of Veterinary Medicine, Michigan 

State University, East Lansing, MI

Dr. Helen Suh, Associate Professor, Bouve School of Health Sciences, Northeastern University, 

Boston, MA

Dr. Kathleen Weathers, Senior Scientist, Cary Institute of Ecosystem Studies, Millbrook, NY

Dr. Ronald Wyzga, Technical Executive, Air Quality Health and Risk, Electric Power Research 

Institute, Palo Alto, CA

SCIENCE ADVISORY BOARD STAFF

Dr. Holly Stallworth, Designated Federal Officer, U.S. Environmental Protection Agency, Science 

Advisory Board (1400R), 1200 Pennsylvania Avenue, NW, Washington, DC
1

Consensus Responses to Charge Questions on 

EPA’s Integrated Science Assessment for Lead

(Third External Review Draft – November 2012)

Preamble; Legislative and Historical Background

Please review and comment on the effectiveness of these revisions to the third draft Pb ISA. Please 

comment on the extent to which these sections of the ISA provide a useful and effective format for 

presenting introductory materials for this and future ISAs. Please recommend any revisions that may 

further improve the clarity of discussion.

The newly included flow diagrams in Figures I, II, and III of the Preamble in the Integrated Science 

Assessment for Lead (Third External Review Draft – November 2012), hereafter referred to as the Third 

Draft ISA, are helpful in summarizing the process employed to develop the ISA documents for criteria 

pollutants. However, it is not clear whether the strict criteria set forth in Figure II for a “study selected 

for inclusion in an ISA” reflects the actual process applied in the ISA for lead (Pb). As noted in the 

CASAC comments on the previous two Pb ISA documents, as well as in comments on this Third Draft 

ISA, the Pb ISA is an enormous document, unparalleled in the scope of its review of the vast literature 

on inorganic lead. By this very nature, it includes many studies that fall short of the ideal design and 

quality criteria presented in Figure II. For example, there are limitations in how particular studies of the 

effects of Pb on attention in children have adjusted for confounding by familial covariates, or how 

certain studies of the association of Pb on renal dysfunction have accounted for covariates that influence 

the course of chronic kidney disease (see the consensus responses to the Chapter 5 charge questions for 

further details). Contrary to the implication of Figure II, it is often acceptable to include such studies in 

the ISA, as long as the limitations are clearly identified and their contribution to the weight of evidence 

for causal inference is appropriately modulated. 

The revised approach to causal determination in the Third Draft ISA that now examines specific health 

endpoints within an organ system, rather than broad organ system effects, is a welcome improvement. 

As detailed in the consensus responses for the other chapters, the health effects criteria in Table II that 

distinguish “likely to be a causal relationship” from “suggestive of a causal relationship” are sometimes 

challenging to apply. In these circumstances, there should be an expanded discussion in Table II (or in 

the narrative) of the nature of the evidence that informed the judgment in favor of one category versus 

another.

Chapters 1 (Executive Summary) and 2 (Integrative Summary)

Please comment on the adequacy of these and other changes to the chapters and recommend any 

revisions to improve the discussion of key information. Please recommend any revisions that may 

further improve the clarity of discussion.

Section 1.2 (page 1-3) briefly notes that there are multiple pathways that ultimately result in human 

exposure to ambient (atmospheric) Pb. However, Chapters 1 and 2 should include an expanded 

discussion of the relative contributions of the direct and indirect air-related pathways to overall human 

Pb exposure. For example, as noted in Tables 4-1 and 4-2, direct inhalation of Pb in ambient air at 
2

currently prevalent levels makes a minor contribution to total exposure. The indirect contribution of 

ambient Pb to Pb in outdoor soil and indoor dust is more substantial, as might be the contribution of 

legacy air emissions to Pb in the current diet. Chapters 1 and 2 should have an expanded discussion of 

the challenges in characterizing air-related exposure, perhaps including Figure 3-2 that appears in the 

draft Policy Assessment (PA), and an explanation of “recent air” and “past air,” as well as dietary Pb

that appears in section 3.4.4 of the draft PA.

The revised approach to weight-of-the evidence causation determinations in the ISA represents a major 

improvement in that it separately assesses the findings for specific health endpoints rather than for major 

outcome categories/organ systems. 

Pb is distinguished from many other toxicants by the existence of an extensive database of human 

studies of relatively low-level environmental exposure. Therefore, human data have been of particular 

value in the assessment of adverse effects at low levels of Pb exposure. In instances where the ISA has 

relied predominantly on animal toxicology rather than human epidemiology to arrive at a weight-of-the 

evidence causation assessment, such as the “likely to be causal” determination for immune system 

effects and for cancer, this should be explicitly noted in the narrative and summary tables.

Choosing between the causal determinations of “likely to be a causal relationship” and “suggestive of a 

causal relationship” for health effects of Pb can be challenging. Different evaluators may reach 

reasonable but divergent decisions after reviewing the same set of data. A transparent causation 

assessment that acknowledges uncertainty and reasonable differences in judgment is needed. The EPA 

should consider a different causation determination for certain endpoints, such as reduced kidney 

function, and could also consider a different causation determination for certain endpoints such as 

attention-related behavioral problems at low Pb dose. It is unclear why the EPA concludes that the 

designation of low levels of Pb exposure and renal dysfunction is “likely to be a causal relationship” 

rather than “suggestive of a causal relationship” considering: (a) inconsistency of the epidemiological 

findings in large high quality studies; (b) absence of a demonstrated pathological mode of action for Pb

nephrotoxicity in humans or animals at blood Pb concentrations less than 10 μg/dL; and (c) the 

plausibility of reverse causation as an explanation for the association (See the response to the Chapter 5 

charge questions for further detail). With respect to Pb and attention-related behavioral problems, 

Chapters 1 and 2 should acknowledge that the evidence for a causal relationship is based predominantly 

on findings in human and animal studies where the Pb exposure has resulted in blood Pb concentrations 

≥ 10 μg/dL, and that additional study of the relationship at lower blood Pb concentrations is advisable.

The CASAC urges the EPA to acknowledge in the ISA that although primary production of Pb in the 

United States is decreasing, there are still global Pb environmental health issues due to increased U.S. 

Pb exports and increased global levels of Pb production.

The revision of section 2.9.1 (Public Health Significance) to focus on cognitive effects in children and 

cardiovascular effects in adults is appropriate, as these endpoints are characterized by well-established 

causal relationships and extensive downstream effects on public health and societal well-being. The 

discussion of the Weiss concept on page 2-63, line 9 should be edited from “in children with high and 

low intelligence” to “across the full range of IQ.” In like manner, the sentence on line 11, although

accurate, appears out of context since the Weiss concept does not involve changes in relative risk. For 

enhanced clarity, Figure 2-1 should be re-drawn to apply specifically to the hypothetical impact of 

change in mean population blood Pb on IQ (as intended by Weiss, 1988).
3

Section 2.9.5 (Reversibility and Persistence of Neurotoxic Effects of Lead) should note that, in addition 

to the cited study of Bellinger et al. (1990), other longitudinal studies have observed improved cognition 

in children with declining blood Pb concentrations (Ruff et al., 1993; Liu et al., 2002; Chen et al., 2005; 

Hornung et al., 2009). However, the extent to which such improvement represents biological 

reversibility of Pb-related effects, the influence of enrichment-related intervention, or the development 

of compensatory mechanisms remains uncertain.

Chapter 3 – Ambient Lead: Source to Concentration

Please comment on the adequacy of these and other changes in responding to the Panel’s comments. 

Please provide comment on revisions that may further improve the utility of this chapter for 

interpretation of health evidence in subsequent chapters.

The revisions to Chapter 3 are responsive to the CASAC’s comments on the Second Draft ISA. Many 

minor and some major changes have been made that improve the readability of the document and 

address specific weak points of the Second Draft ISA.

The additions to section 3.4.1.1, Sample Collection, are an improvement to the description of the “state 

of the science” for measurement of particles greater than 10 micrometers, clearly illustrating the 

challenges in designing a new Federal Reference Method (FRM) to replace the high-volume (Hi-Vol) 

sampler where sampling of larger particles is of interest. Although it is understood that EPA will not 

have completed work on design and characterization of an improved “larger particle” FRM for this cycle 

of the Pb National Ambient Air Quality Standards (NAAQS) review, the EPA is strongly encouraged to 

continue this process.

The presentation of available data showing the range of Pb concentrations with diameters larger than 10 

micrometers near sources is useful, and shows a very wide range of results. Much of the variation is due 

to the type of sampler being used or the wide range in near-source characteristics and other factors 

including wind speed. Overall for (non-airport) near-source sites, the amount of airborne Pb greater than 

10 micrometers is typically between 10-30%, with much of that less than 15 micrometers diameter. In 

the context of the NAAQS, this is not a large proportion given the uncertainty of linkage between air Pb 

and dose. The ISA also appropriately notes that particles larger than approximately 15 micrometers in 

aerodynamic diameter deposit close to the source. This may inform the process of developing a new 

FRM because the effort to validate a sampler with a 15 micrometer cut size is substantially less than for 

larger cut sizes (even at just 17 or 18 micrometers). This applies both to the sampler design and the FRM 

wind tunnel testing process. The EPA should consider whether the effort to develop a sampler for 

particles larger than 15 micrometers has value in terms of the data needs of the Pb monitoring network.

The Summary and Conclusions section (3.7) is well written, and covers the key points of the chapter. 

Section 3.7.3 (Ambient Monitoring) implies that a 15 micrometer sampler would be adequate. However, 

the end of section 3.4.4.1 considers the upper particle size range of interest to be as high as 20 

micrometers, but the need for data in the 15 to 20 micrometer particle diameter size range is not clear. 

Also, this section concludes with a sentence that is not fully supported by this chapter (section 3.4.1.1): 

“The existing samplers reasonably capture the airborne fraction of ambient Pb that is available for 

human exposure.” The Pb doses from inhalation and ingestion are highly uncertain, as are the transfer 

functions for airborne Pb in various particle sizes to surfaces from which hand-to-mouth uptake and 
4

ingestion are likely. Nasal deposition and subsequent ingestion can occur with some particles larger than 

15 micrometers. However, the chapter does not provide much discussion of what the desirable particle 

size characteristics of an atmospheric Pb sampler should be, nor does it strongly justify the 

“reasonableness” of the existing Hi-Vol Total Suspended Particulates (TSP) sampler in that regard.

The discussion of sampling issues, available technology, and relevant size for sampling larger particles 

makes clear that although there are promising candidates for evaluation (e.g., low-volume TSP inlets), 

they have not been fully characterized for wind speed effects as required for use as a FRM sampler. A 

goal for this effort would be convergence of what is both feasible and desirable.

There is a need for improved characterization of Pb emitted from use of aviation gasoline on ambient Pb 

concentration in areas near general aviation airports. If airborne Pb data from 15 pilot sites near general 

aviation airports are available in EPA’s Air Quality System (AQS), or even possibly preliminary data 

not in AQS, it would be useful to include them in the final version of the ISA with caveats, as needed. 

Recent and ongoing studies of the Pb air quality and effects associated with Pb emitted from general 

aviation operations should be considered for inclusion in the ISA both here and in other relevant 

chapters. For example, a recent study (Perugini et al., 2011) indicates that there are elevated levels of Pb 

in honeybees near general aviation airports.

Chapter 4 – Exposure, Toxicokinetics and Biomarkers

Please comment on the adequacy of these and other changes in responding to the Panel’s comments. 

Please provide comment on revisions that may further improve the utility of this chapter for 

interpretation of health evidence in subsequent chapters.

The CASAC commends EPA for clearly summarizing the information on exposures, toxicokinetics and 

biomarkers in Chapter 4. The lucid description of topic strengths, weaknesses, and limitations found in

the introductory and concluding sections are well done. Chapter 4 credibly explains and applies

mechanistic and empirical models, and provides illustrative figures of several Pb exposure scenarios and 

the impact on blood and bone Pb biomarkers. The EPA appropriately summarizes exposure data through 

a balanced use of tables and figures to convey complex information. However, in addition to the current 

summary of the phase-down of lead as a gasoline fuel additive, the chapter should also note the 

significant emission and air Pb reductions achieved in the vicinity of point sources. The major 

reductions in point source emissions were achieved through a combination of pollution control and 

relocation of industry. The summary of Pb in consumer products is helpful, but the discussion might 

include any conclusions on how exposure to Pb in consumer products might impact blood Pb levels 

(quantitatively if possible – for example, see VanArsdale et al., 2004).

The presentation and discussion of air-to-blood relationships is thorough, and the inclusion of potential 

biases and factors that possibly affect observed air-to-blood relationships improves the discussion.

Conclusions or summary statements regarding the utility of estimated or measured relationships for 

current Pb exposures (and even lower) would be helpful. Specifically, the EPA is encouraged to 

consider the comments on Chapter 4 provided by the individual panel members for examples relative to 

(1) potential limitations of current mechanistic models to predict blood Pb levels at low level exposure; 

(2) the uncertainty associated with extrapolation of lower bounds of blood Pb from figures that present 
5

empirical data on air-to-blood Pb relationships; and (3) adding discussion of estimates of percent 

contribution of air Pb to blood Pb associated with alternative slope factor estimates. 

Chapter 5 - Integrated Health Effects of Lead Exposure

In the revised draft, causal determinations for health effects were drawn for more specific groups of 

related outcomes instead of major organ systems. Please comment on the appropriateness of these new 

endpoint groupings. 

In general, the new health endpoint groupings are appropriate and contribute to greater clarity of causal 

determinations for all major organ systems. This new approach has the greatest impact on the section 

describing health effects related to the nervous system but there are revisions recommended for the 

approach used in this section. In the description of behavioral outcomes, use of a standard naming 

convention (e.g. clinical terminology and classification) is recommended. Specifically, behaviors 

currently listed as “attention-related” (inattention, impulsivity, hyperactivity, etc.)” and those related to 

conduct problems/disorders would be appropriately grouped under the label of “externalizing behavior.” 

Other domains (depressive symptoms, anxiety) should be maintained in a separate section on 

“internalizing behavior.” Schizophrenia is a psychotic disorder, and is neither internalizing nor 

externalizing. The literature on such behaviors can still be summarized for each behavior individually. 

For example, the ISA could summarize studies of attention, impulse control, hyperactivity, and 

oppositional behavior, one at a time. Then the causal assessment could be reorganized to look at the 

externalizing behaviors as a group and to acknowledge differences in Pb causality among the various 

categories of externalizing behaviors. 

In addition, there are several errors of health categorization or study outcome categorization for the 

nervous system review (see specific individual panel member comments by Drs. Canfield, Korrick, and

Wasserman). For example, schizophrenia is not a mood disorder, phobic anxiety is a subcategory of 

anxiety, and “opposition defiance” is not a meaningful term. 

Lastly, there are a few instances where appropriate specific health endpoints are the focus of the 

literature review but the causal determination is applied, inappropriately, to a more general organ 

system. For example, the relationship between Pb and sensory function is most consistent for audition,

not vision. But the causal framework was applied to all sensory function rather than focusing on the 

appropriate specific endpoint of auditory function. 

Further, please comment on the extent to which the text and new summary tables support the application 

of the causal framework in deriving causal determinations. 

This draft provides clearer and better documented support for the application of the causal framework 

than did the previous draft. The new summary tables, in combination with the text summaries, clearly 

demonstrate the causal framework that was applied. However, it is difficult to determine what degree 

and type of uncertainty informed the judgment to distinguish between “likely causal” versus 

“suggestive” determinations. As there is unlikely to be consensus even among experts in assigning this 

middle ground of causality, it is important that Chapter 5 explicitly identify the uncertainties that 

contribute to a less than causal association. For example, the chapter concludes that studies assessing the 

relationship of low level Pb exposure with renal function support a “likely causal” relationship whereas 
6

the previous draft deemed this relationship as “causal.” As noted in the consensus response to the 

Chapter 2 charge questions, the CASAC questions the designation of the association between low level 

Pb exposure and renal dysfunction as “likely to be a causal relationship” instead of “suggestive of a 

causal relationship.” As discussed further below, the CASAC considers the latter category to be more 

appropriate.

How consistently and appropriately was the causal framework applied across the endpoint groups? 

In general, the causal framework is consistently and appropriately applied across health endpoints. (See 

the response to the previous charge question). Several associations in the Second Draft ISA were

assigned as “causal,” yet the CASAC had concerns about those designations due to uncertainties in the 

literature. Except as noted below (e.g. renal dysfunction), these associations have now been 

appropriately revised in the Third Draft ISA to reflect these uncertainties.

Please comment on the adequacy of the discussion of the strengths and limitations of the evidence in the 

text and tables within Chapter 5 and in the evaluation of the evidence in the derivation of causal 

determinations. 

In general, this draft applies a balanced approach to reviewing the literature, including: giving 

prospective studies priority over those with cross-sectional designs; explicitly acknowledging potential 

for residual confounding where applicable; and commenting on the likelihood (or not) of participation 

bias affecting results. In addition, the generalizability of specific study populations to the U.S. general 

population is considered. In keeping with this approach, new summary tables provide detail regarding 

strengths and limitations of the evidence. However, there are some basic issues regarding the literature 

review that are vague. For example, summary tables reportedly list nervous system studies in order of 

strength of study design. Aside from prospective studies being listed before cross-sectional ones, the

additional ordering criteria are never explicitly given. In some cases, studies that confirmed an adverse 

effect of Pb appear to be given more weight than studies that revealed inconsistencies in the evidence,

but the rationale for that order is not provided.

Certain study design concerns are repeated multiple times throughout the chapter – lack of adjustment 

for parenting quality, poor representativeness of the study population – but their relevance to 

interpretation of a given study is not discussed. The narrative in section 5.3.3 repeatedly notes that a 

limitation of the studies of behavior in Pb-exposed children is the failure to control for “parental 

caregiving quality.” This feature should be more clearly explained (e.g., the extent to which it may be 

measured by the Home Observation for Measurement of the Environment [HOME] score). In addition, 

literature which establishes “parental caregiving quality” as a predictor of attention performance in 

children should be cited. Several relevant papers can aid in an independent search for the most 

appropriate papers (Matas et al., 1978; Jacobvich and Sroufe, 1987; Dunham and Dunham, 1995; Moore 

and Dunham, 1995; Bornstein et al., 1997; Evans et al., 1999). The representativeness of study 

populations is emphasized as a limitation in a number of nervous system studies; e.g., results of studies

with a high prevalence of maternal pregnancy alcohol consumption or drug use appeared to be 

downplayed on this basis. However, the lack of generalizability does not impact the validity of a study 

(unless there is effect measure modification). Thus, in some cases, these findings may have been 

disproportionately discounted.
7

For behavioral outcomes, there is repeated mention of uncertainties regarding the correlation of parental 

psychopathology with parenting quality. This commentary does not address the most relevant point 

concerning parental psychopathology as a potential confounder of some behavioral outcomes. Residual 

confounding by parental psychopathology is discussed as a substantial study design limitation in the 

CASAC’s prior review of the Second Draft ISA, given that many behavioral disorders (e.g., attention 

deficit hyperactivity disorder [ADHD]) have strong familial components (which may operate via 

parenting behavior, and/or genetic contributions to disorder type). Certain forms of parental 

psychopathology might be associated with increased Pb exposure risk through multiple direct and 

indirect mechanisms, including parental neglect, increased exposure to unremediated Pb hazards, and 

other pathways. The narrative in section 5.3.3 continues to characterize the studies by Cho et al. (2010)

and Nicolescu et al. (2010) as having controlled for “parental psychopathology.” However, the ISA 

should note that a critical examination of these studies calls into question the adequacy with which this 

was done in these investigations (please see Dr. Kosnett’s individual comments for further detail). 

The CASAC continues to recommend that the analysis of renal dysfunction in Chapter 5 (section 5.5) 

present a more balanced approach that adequately discusses the strengths and limitations of all of the 

relevant literature. In particular, aspects of this analysis that were of concern in the First and Second 

Draft ISA documents continue to be of concern in the current draft. Thus, in an effort to provide explicit 

guidance, the following text is a detailed exposition of the key issues. 

In the CASAC’s review of the Second Draft ISA (July 20, 2012, top of page 3) the consensus comments 

state, “With respect to renal effects, the narrative should offer a more balanced assessment in which the 

strength of the evidence for causal inference is tempered by inconsistency in the literature (underscored 

by the existence of studies that observed no significant relationship or a relationship in which increasing 

blood Pb levels were associated with improved renal function).” A similar concern over inconsistency in 

the literature is expressed in the CASAC review of the First Draft ISA (December 9, 2011, top of page 

A-10). It is therefore noteworthy that sections of the Third Draft ISA that address this topic continue to 

use virtually identical language to that which appeared in the Second Draft ISA. Page 2-24, line 6 et 

seq., section 2.6.3 of the Third Draft ISA reads:

The epidemiologic evidence from prospective and cross-sectional studies consistently [emphasis 

added] demonstrates a relationship between higher blood Pb level and reduced kidney function 

(e.g., lower creatinine clearance, higher serum creatinine, and lower GFR) in nonoccupationallyexposed adults with mean concurrent or baseline blood Pb levels of 2-10 μg/dL. Associations 

were observed after adjustment for multiple potential confounding factors such as age, sex, 

comorbid cardiovascular conditions, BMI, smoking, and alcohol use. 

In like manner, page 5-376, Line 17 et seq., reads: 

As illustrated in Figure 5-31 and Table 5-25, studies consistently [emphasis added] demonstrate 

associations between higher blood Pb level and lower renal function in adults. These general 

population studies provided critical evidence that the effects of Pb on the kidney occur at much 

lower doses than previously appreciated based on occupational exposure data. 

The foregoing discussion and tables in the Third Draft ISA do not acknowledge the lack of a statistically 

significant relationship between Pb and serum creatinine in the large population-based study by de 

Burbure et al. (2003). Although this study was mentioned in prior individual panel member comments, it 
8

is omitted from Table 5-25 (and elsewhere in the Third Draft ISA). Section 5.5 should further note in its 

repeated reference to the study by Tsaih et al. (2004) that a statistically significant relationship between 

blood Pb and change in serum creatinine was confined to post-hoc analyses of the relatively small subset 

of subjects who had diabetes or hypertension. Although Section 5.5 repeatedly refers to the two 

Normative Aging Study (NAS) investigations by Kim et al. (1996) and Tsaih et al. (2004) as offering 

“consistent” evidence (e.g., see page 5-422, line 18), the ISA should note that these NAS studies in fact 

did not replicate each other. The former study observed a statistically significant association between 

blood Pb and prospective decline in serum creatinine in the large NAS cohort, but the latter study did 

not. 

Elsewhere in Section 5.5, particularly in the summary subsections, the analysis would be improved by a 

more balanced discussion of other inconsistent observations in the literature. As recently reviewed by 

Evans and Elinder (2011) (a paper still not cited in the Third Draft ISA despite the CASAC’s prior 

consensus recommendation to do so), studies in cohorts with both environmental and occupational Pb

exposure have yielded markedly different results. Several investigations of satisfactory quality have not 

observed any association between low or moderate Pb exposure and renal dysfunction, and in some 

studies, such as Weaver et al. (2003), Roels et al. (1994) and deBurbure et al. (2006), blood Pb

concentration was associated with biomarkers of improved renal function. In the discussion of the study 

by Weaver et al. (2009) on page 5-392, a balanced analysis could clearly indicate that the study reported 

a positive correlation between baseline (blood and bone) Pb measurements and creatinine clearance, and

that in male workers, prospective increases in blood Pb were associated with a decline in serum 

creatinine. It is conceivable that the aforementioned observations may represent Pb-induced 

hyperfiltration, but this would be an uncertain and untested hypothesis. Overall, as emphasized in prior 

CASAC consensus comments and individual panel member comments, the epidemiology associating 

low to moderate level Pb exposure with renal dysfunction is not consistent. 

The opportunity for better balance in presentation of the renal literature’s strengths and weaknesses 

emerges in several other places in Section 5.5. The large population-based case-control study combined 

with a prospective component by Evans et al. (2010) is discussed on page 5-387. This study found that 

occupational Pb exposure had no association with the incidence or progression of chronic kidney disease 

(Evans et al., 2010). After enumerating nearly all the cases in Sweden, the odds ratio for incident severe 

chronic kidney disease (CKD) was 0.97 (95% C.I. 0.68 – 1.38) in Pb-exposed participants compared 

with non-exposed participants. In the study’s prospective component, Pb exposure was found to have no 

impact on the rate of decline of severe CKD. Yet when this entirely negative study is discussed on page 

5-387 of the Third Draft ISA, the analysis somewhat paradoxically remarks, “The results overall do not 

provide strong evidence that Pb exposure was associated with renal effects.” Limitations of the study are 

then presented. This approach to exposition and critique can be contrasted to that applied to the positive 

prospective studies of chronic kidney disease and Pb exposure reported by Lin and coworkers as well as

Yu and coworkers (works cited on pages 5-386 to 5-387). The nearly full-page discussion of these 

studies (further summarized in Table 5-26) omitted any mention of the studies’ limitations. However, as 

noted in past individual CASAC panel member comments on the Second Draft ISA, these studies are 

subject to major drawbacks that limit their causal inference, particularly inadequate blinding during the 

follow-up period, an important consideration in a condition such as chronic renal insufficiency in which 

medical treatment and medical and dietary compliance strongly influence change in renal function. 

Moreover the statistical models in these prospective studies did not account for how prospective changes 

in covariates that affect renal function, such as diet or blood pressure, may have influenced the outcome. 

In the chelation studies by Lin cited in the ISA, there was no indication that change in blood Pb or urine 
9

Pb excretion after calcium ethylenediaminetetraacetic acid (CaEDTA) chelation had any impact on any 

measure of renal function. Given the prominence with which these studies have been profiled in Section 

5.5, a more balanced discussion that details their limitations is recommended.

Possibly in response to the CASAC’s review of the First Draft ISA, a new subsection in chapter 5 of the 

Second Draft ISA entitled “Reverse Causality” was included to address the hypothesis that associations 

between blood Pb and renal function may be due, at least in part, to decreased Pb excretion as a 

consequence of renal dysfunction. The consensus comments of the CASAC’s review of the Second 

Draft ISA nevertheless suggested that a more balanced approach to consideration of the reverse causality 

hypothesis was warranted. This concern continues with respect to section 5.5.2.4 “Reverse Causality” in 

the Third Draft ISA. Rather than offering a balanced, neutral approach to this unresolved issue, section 

5.2.2.5 concludes on page 5-400, line 3 et seq.: 

In summary, several lines of evidence support that reverse causality does not contribute 

substantially to associations between higher blood Pb levels and worse kidney function. These 

lines of evidence include prospective data observing that baseline Pb measures are associated 

with subsequent declines in renal function, that associations in prospective studies persist among 

adults with normal renal function, that renal failure does not increase Pb biomarker levels and 

that reduction of Pb levels by chelation improves kidney function. However, this bidirectional 

relationship is still possible and additional research is needed to fully exclude [emphasis added] 

the hypothesis. In particular prospective data are required as is research to determine if normal 

kidney function influences blood Pb levels.

The CASAC considers reverse causation a completely plausible hypothesis, and it questions the validity 

and persuasiveness of each of the “lines of evidence” cited in the foregoing paragraph. Prospective 

studies may have observed an association between blood Pb concentration and a biomarker of renal 

dysfunction (such as serum creatinine) because the prospective development of renal dysfunction can 

prospectively result in diminished Pb excretion and higher blood Pb concentrations. The existence of the 

association in “adults with normal renal function” does not exclude reverse causation because even in 

individuals with “normal renal function,” pharmacokinetic clearance of a xenobiotic substance (whether 

Pb or a drug) that undergoes predominantly renal excretion, is inversely related to glomerular filtration 

rate. For example, this has been demonstrated for the renally-cleared organometal drug, carboplatin, 

where plasma levels correlate with glomerular filtration rate even in patients with normal renal function 

(Calvert et al., 1989). Contrary to the supposition in section 5.2.2.5, some studies have observed 

elevated blood Pb concentrations (Behringer et al., 1986; Colleoni et al., 1993; Davenport et al., 2009) 

and bone Pb concentration (Winterberg et al., 1990) in renal failure patients without any apparent 

history of elevated Pb exposure. Finally, as noted previously, the studies by Lin et al. purporting to 

associate chelation with improved renal function were subject to major design limitations, and in any 

case, failed to report a statistical association between any Pb exposure variable and any renal function 

measure.

The capacity of prolonged high dose Pb exposure to cause histopathologically demonstrable 

nephropathy is indisputable. However, in view of (a) the inconsistency of the epidemiological findings 

in large high quality studies of low to moderate Pb exposure; (b) the absence of a demonstrated 

pathological mode of action for Pb nephrotoxicity in humans or animals at low blood Pb concentrations;

and (c) the plausibility of reverse causation as an explanation for the association, the EPA should 

designate the association between low level environmental Pb exposure (e.g., blood Pb concentrations 
10

less than 10 μg/dL) and renal dysfunction as “suggestive of a causal relationship” rather than “likely to 

be a causal relationship.”

Please also comment on the extent to which the nervous system outcomes have been grouped into 

appropriate constructs and the extent to which appropriate parallels were drawn between nervous 

system endpoints examined in humans and animals.

In general, the nervous system outcomes have been grouped into appropriate outcomes and constructs 

with reasonable parallels drawn between human and animal endpoints. Also, pairing the toxicology 

summaries with the specific relevant epidemiology, rather than summarizing the two literature streams 

separately, is helpful for assessing coherence of findings across disciplines. Distinguishing between 

symptoms or formal psychometric test results versus clinical diagnoses is clearer in this draft and is 

important to maintain. (See the response to the first charge question of this chapter for more specific 

comments on areas that could be improved related to this question.)

Chapter 6 - Potentially At-Risk Populations

Please comment on the adequacy of these revisions to clarify the consideration of potential at-risk

populations and recommend any revisions to improve the characterization of key findings and scientific 

conclusions.

The chapter is improved over the prior version. Improvements include the more specific delineation of 

at-risk sources in terms of biological versus environmental, for example. In addition, the chapter better 

summarizes the strength of the evidence with respect to each of the factors that are considered. The EPA

has managed to integrate an extraordinary amount of information and to employ useful framework(s) for 

critically reviewing and integrating information.

However, any sense of the relative magnitude of the effect modification from the risk factors is still 

missing. It is stated that the magnitudes are discussed in Chapter 5, but it is not clear that they are 

actually discussed there. It would be extremely useful to have a summary table that summarizes the 

magnitude of the effects modification these various risk factors impose. There may be very consistent

effects of any given factor, but if the magnitude of the effect modification from the risk factor is 2%, for 

example, how important are they? It may not be feasible to find a common metric for the variety of 

comparisons that would need to be made, but some form of comparison in terms of magnitude of effect 

modification or other relevant metrics is critical to policy as it relates to how to utilize existing 

resources.

Sections on risk include multiple endpoints and different associations between risk factors and increased 

risk of Pb health effects (for example, sometimes for males and sometimes for females), which is 

confusing. Each section’s last paragraph draws this out concretely. However, it would be more helpful to 

the reader to provide a roadmap at the beginning of each section in the first paragraph with respect to the 

end points and associations between risk factors and increased risk of Pb health effects that are 

addressed within the section.

The EPA should acknowledge that there are many childhood conditions that collectively account for a 

substantial percentage of children for whom there might be hypothetical reasons to predict increased (or 
11

decreased) risk of Pb health effects, such as: low and very low birth weight; prenatal exposure to 

alcohol, cocaine, heroin, or tobacco; birth asphyxia; serious head trauma; and numerous genetic 

conditions associated with developmental delays. Also, children with sickle cell anemia are at increased 

risk for peripheral neuropathies.

Chapter 7 - Ecological Effects of Lead

Please comment on the adequacy, scientific soundness and usefulness of the material presented and 

recommend specific revisions to improve the discussion of key information in Chapter 7.

The revised Chapter 7 is greatly improved, and with minor modifications will be an adequate discussion 

of the literature and is suitable to provide the information necessary to support the PA.

Adequacy

The new information contained in the ISA is insufficient to reach significantly modified assessments 

compared to those made in the 2008 PA. There are studies on additional organisms that principally 

strengthen, but do not modify, the previous assessments. There has been important new information on 

the influence of modifying chemical factors and “aging” of Pb on bioavailability. Few deleterious 

ecological effects have been noted at Pb concentrations found in environments that have not been 

impacted by major point sources of Pb (i.e., within one to two orders of magnitude of background 

levels).

Scientific Soundness

The chapter provides a fair and balanced evaluation of the existing scientific information. However, one

major concern is the inability to relate ecosystem effects to the concentrations of Pb that exist in air, soil, 

and water. For ecosystems, an important source of the Pb in soil and water is atmospheric deposition and 

transport processes. A critical loads approach would be most appropriate to establish this relationship. 

Research should be conducted to develop, calibrate, and test models applicable to the development of 

critical loads for Pb and other metals in the United States.

Usefulness

The chapter presents a review of existing knowledge and new studies in terrestrial, freshwater, and 

marine systems, which is followed by a section presenting the causal determinations. Tables 7.4 to 7.6, 

which summarize the key studies leading to the causal determinations, are an important addition to the 

ISA. In addition to these tables, it would be useful to include a graph for each of the three system types, 

in which the various effects are shown as a function of the exposure concentration. The environmental 

concentration range also could be shown. Distinctions should be made on the graph between measured 

concentrations and nominal concentrations (if there are not measured concentrations). 
12

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(Hg, Cr, Cd, and Pb) contamination in urban areas and wildlife reserves: Honeybees as 

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and Chettle, D. (1994). Renal function and hyperfiltration capacity in lead smelter workers with 

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(2004). Lead, diabetes, hypertension, and renal function: the normative aging study. 

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K. K. (2009). Longitudinal associations between lead dose and renal function in lead workers. 

Environmental research, 109(1):101-107.

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A-1

Appendix A

Agency Charge

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

National Center for Environmental Assessment

OFFICE OF 

RESEARCH AND DEVELOPMENT

January 7, 2013

SUBJECT: CASAC Review of Third External Review Draft Integrated Science Assessment for Lead

FROM: John Vandenberg, Ph.D. /s/

Director

National Center for Environmental Assessment

Research Triangle Park Division (B243-01)

TO: Aaron Yeow, M.P.H.

Designated Federal Officer

Clean Air Scientific Advisory Committee

EPA Science Advisory Board Staff Office (1400R)

The Third External Review Draft Integrated Science Assessment for Lead (draft Pb ISA) prepared by 

the Environmental Protection Agency’s (EPA) National Center for Environmental Assessment –

Research Triangle Park Division (NCEA –RTP) as part of EPA’s ongoing review of the national 

ambient air quality standards (NAAQS) for lead (Pb) was released on November 27, 2012. This third 

external review draft ISA integrates the scientific evidence for review of the primary (health-based) and 

secondary (welfare-based) NAAQS for Pb and provides draft findings, conclusions and judgments on 

the strength, coherence and plausibility of the evidence. The ISA is intended to “accurately reflect the 

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

health which may be expected from the presence of [a] pollutant in ambient air” (Clean Air Act, Section 

108; 42 U.S.C. 7408). The draft ISA will be reviewed by the Clean Air Scientific Advisory Committee 

(CASAC) Pb NAAQS Review Panel (the Pb CASAC Panel) at a public meeting on February 5-6, 2013. 

We have distributed the draft Pb ISA to the Pb CASAC Panel. I am requesting that you forward our 

charge to the Pb CASAC Panel.

Following the review of the third external review draft ISA, NCEA-RTP staff will produce a final Pb 

ISA projected for release in the Spring of 2013 that addresses comments received from the CASAC Pb 

Panel and the public. The final Pb ISA, in conjunction with additional technical assessments, will 
A-2

provide the scientific basis for EPA’s decision regarding the adequacy of the current standards for Pb to 

protect human health, public welfare, and the environment.

We look forward to the Pb CASAC Panel review of the third draft ISA at the upcoming meeting. Should 

you have any questions regarding the draft Pb ISA, please feel free to contact Dr. Mary Ross (919-541-

5170, Ross.Mary@epa.gov) or Dr. Ellen Kirrane (919-541-1340, Kirrane.Ellen@epa.gov).
A-3

Charge to the Pb CASAC Panel 

This draft ISA includes revisions based on the comments and advice provided by the CASAC Pb Panel 

and public comments on the second external review draft ISA. Specific revisions to the third draft Pb 

ISA were described in EPA’s recent response (September 18, 2012) to the CASAC Pb Panel’s review 

letter (July 20, 2012) on the second draft Pb ISA. We have carefully considered all of the comments 

provided by the CASAC Pb Panel members and the public in creating this third draft ISA. In particular, 

we focused on several key overarching points raised by the CASAC Panel: 

integration of evidence across scientific disciplines; 

enhancing critical review of studies; 

improving transparency of the application of the framework for causal determination; 

reconsidering the health and ecological endpoints around which conclusions were formed and/or 

received emphasis.

Changes to the content and structure of the draft ISA are highlighted below together with the new charge 

questions for this CASAC Pb Panel review. These charge questions are not intended to limit the scope of 

the Panel’s review, rather these charge questions are intended to assist the Panel by highlighting specific 

areas where the Agency has responded to prior comments of the Panel or where the Agency raises 

emerging issues to the attention of the Panel for comment. 

Preamble; Legislative and Historical Background (formally Preface) 

The Ozone CASAC Panel recommended that flow diagrams be included in the Preamble of the third 

draft Ozone ISA to more effectively and clearly communicate the process of ISA development and the 

NAAQS review process. Thus, based on the CASAC support for these diagrams, they were also 

incorporated into the preamble of the third draft Pb ISA and will be further updated to reflect revisions 

made for the final Ozone ISA. In addition, the text of the preamble was revised to read, “In discussing 

the causal determination, EPA characterizes the evidence on which the judgment is based, including 

strength of evidence for individual endpoints within the major outcome category or group of related 

endpoints.” This change was introduced because, as recommended by the CASAC Pb Panel, 

conclusions were drawn for specific health endpoints, rather than major outcome categories, in the third 

draft of the Lead ISA.

The Ozone CASAC Panel also recommended renaming the Preface of the draft Ozone ISA to reflect its 

historical content. Consistent with this change, the Preface was renamed in the third draft Pb ISA and 

text describing pre-promulgation history of the Lead NAAQS was added. 

Please review and comment on the effectiveness of these revisions to the third draft Pb ISA. Please 

comment on the extent to which these sections of the ISA provide a useful and effective format for 

presenting introductory materials for this and future ISAs. Please recommend any revisions that may 

further improve the clarity of discussion. 

Chapters 1 (Executive Summary) and 2 (Integrative Overview) 

Consistent with CASAC recommendations, the language in Chapter 1 was simplified to improve the 

readability for a non-technical audience. Call-outs were added to Chapters 1 and 2 for ease of accessing 
A-4

more detailed discussions in the rest of the ISA. Both chapters were updated to reflect revisions in 

subsequent chapters. The public health significance section was revised to focus on cognitive effects in 

children and cardiovascular effects in adults. 

Highlights of revisions made to address CASAC comments on enhancing the critical review of the data 

and the systematic application of the framework for causal determination are discussed in greater detail 

under the charge question for Chapter 5. Revisions made to address the CASAC recommendation 

regarding specific health endpoints in the Pb ISA, rather than organ system effects, are evident in the 

following tables and text that appear in Chapters 1 and 2 of the third draft Pb ISA:

Table 1-1, Table 2-2

Section 2.6.1 Nervous System Effects

Section 2.6.1.1 Children: Cognitive Function Decrements, Attention-Related Behavior Problems, 

Internalizing Behaviors, Conduct Problems in Children and Young Adults, 

Sensory Function Decrements, Motor Function Decrements

Section 2.6.1.2 Adults: Cognitive Function, Psychopathological Effects, Sensory Function Decrements, 

Neurodegenerative Disease

Section 2.6.2 Cardiovascular Effects: Hypertension, Subclinical Atherosclerosis, Coronary Heart 

Disease, Cerebrovascular Disease

Section 2.6.3 Renal Effects: Reduced Kidney Function

Section 2.6.4 Immune System Effects: Atopic and Inflammatory Conditions, Decreases in Host 

Resistance, Autoimmunity

Section 2.6.5 Hematological Effects: Decreased Red Blood Cell Survival and Function, Heme Synthesis

Section 2.6.6 Reproductive and Developmental Effects: Development, Birth Outcomes, Male 

Reproductive Effects, Female Reproductive Effects

Section 2.6.7 Cancer

Although causal determinations for ecological effects are consistent between Chapters 2 and 7, in 

Chapter 7 causal determinations for reproductive, growth, survival, neurobehavioral, hematological, and 

physiological stress endpoints are presented separately for terrestrial, freshwater and saltwater organisms 

(Sections 7.3.12, 7.4.12 and 7.4.21, respectively). In Chapter 2 (Section 2.7.3) causal determinations for 

the same endpoints are further integrated across terrestrial, freshwater and saltwater taxa. Links are 

provided in the text to the corresponding sections. 

Please comment on the adequacy of these and other changes to the chapters and recommend any 

revisions to improve the discussion of key information. Please recommend any revisions that may 

further improve the clarity of discussion.

Chapter 3 – Ambient Lead: Source to Concentration

The integrative synthesis (Section 3.7 - Summary and Conclusions), was revised per CASAC 

recommendations. CASAC recommendations regarding additional synthesis were predominately related 

to Section 3.5 (Ambient Air Pb Concentrations). This section was made more concise with an eye 

towards synthesis of the relevant data. Information was moved to the Chapter 3 Appendix where 

appropriate. Additionally, integration was improved through expanded cross-referencing between 

Chapter 3 and the exposure section of Chapter 4 (Section 4.1). To further address CASAC comments, 
A-5

data describing the size distribution of PM containing Pb was restored (Section 3.5.3.2 and Appendix 

Section 3.8.4) with elimination of data below the limit of detection. Size distribution data from a recent 

literature review was also incorporated. A brief discussion and data regarding global disposition of Pb 

were added to Section 3.2. Information regarding alternate methods for measuring size-resolved Pb in 

PM was added to Section 3.4.

Please comment on the adequacy of these and other changes in responding to the Panel’s comments. 

Please provide comment on revisions that may further improve the utility of this chapter for 

interpretation of health evidence in subsequent chapters.

Chapter 4 – Exposure, Toxicokinetics, and Biomarkers

In response to CASAC comments, the discussion of differences in particle size distributions of airborne 

Pb laden particles from those in dust and soil was expanded. Clarification was provided to differentiate 

the size distribution of dust and soil particles from the size distribution of ambient air particulate matter. 

The influence of dust and the size of soil particles on Pb concentration and transport via tracking and 

adherence to hands was also clarified. As noted above, additional cross-referencing between Chapters 3 

and 4 was included in the current draft to enhance integration between sections on particle size 

distribution and exposure. Tables, figures, and sections that serve as illustrative examples of the 

revisions relating to particle size distribution are listed below:

Section 3.5.3.2 Studies of Pb-bearing PM size distribution in the literature

Table 3-9 Summary of studies reporting Pb Size distribution in the peer-reviewed literature

Figure 3-27 Size distribution of Pb-containing dust collected near busy (HWY 1) and low traffic 

(HWY 17) highways.

Section 3.8.4 Size Distribution of Pb-bearing PM

Table 3-26 Correlations and average of the concentration ratios for co-located monitors, TSP versus 

PM10, TSP versus PM2.5, and PM10 versus PM2.5

Table 3-27 Metadata for studies of Pb-PM size distribution

Table 3-28 Size distribution for various studies described in Table 3-27

Section 4.1.1.1 Particle Size Distributions for Airborne-Pb, Dust-Pb, and Soil-Pb

Factors affecting exposure were synthesized in Section 4.1.3. These factors include air-related pathways 

(e.g., Pb deposited to urban gardens or agricultural crops and ingested, exposure to outdoor soil or dust 

containing Pb) and non-air-related pathways (e.g., Pb in drinking water from pipe corrosion, 

occupational exposures, and exposures through consumer products). Some of these factors were also 

introduced in Section 4.1.1 during introduction of the conceptual model for air-related pathways of Pb 

exposure. 

Discussion of the relationship between biomarkers and exposure was expanded in Sections 4.3.5 

(Relationship between Pb in Blood and Pb in Bone) and 4.5 (Empirical Models of Pb Exposure-Blood 

Pb Relationships). Table 4-2 was added to exemplify IEUBK predictions of pathway contributions to 

concurrent blood Pb levels. Discussion of the contribution of Pb from ambient air and other pathways to 

blood Pb was augmented. Information on potential biases and factors that may affect observed air-toblood relationships was added. The discussion of the relationship between Pb in bone and blood was

expanded, in part, to clarify effects of long-term Pb clearance from bone. 
A-6

Please comment on the adequacy of these and other changes in responding to the Panel’s comments. 

Please provide comment on revisions that may further improve the utility of this chapter for 

interpretation of health evidence in subsequent chapters.

Chapter 5 – Integrated Health Effects of Lead Exposure

In the revised draft, causal determinations for health effects were drawn for more specific groups of 

related outcomes instead of major organ systems. Please comment on the appropriateness of these new 

endpoint groupings. Further, please comment on the extent to which the text and new summary tables 

support the application of the causal framework in deriving causal determinations. How consistently and 

appropriately was the causal framework applied across the endpoint groups? A listing of the summary 

tables is below:

Table 5-17 Summary of evidence supporting nervous system causal determinations

Table 5-24 Summary of evidence supporting cardiovascular causal determinations

Table 5-31 Summary of evidence supporting renal causal determinations

Table 5-34 Summary of evidence supporting immune causal determinations

Table 5-35 Summary of evidence supporting RBC survival and heme synthesis causal determinations

Table 5-48 Summary of evidence supporting reproductive and developmental causal determinations

Table 5-50 Summary of evidence supporting cancer and genotoxicity causal determinations

Clarity in the description and the conceptualization of behavioral outcomes was enhanced by soliciting 

advice from experts in the fields of neuropsychology and neurotoxicology on how to categorize 

individual nervous system outcomes into broader categories. For example, experts considered IQ, 

learning, memory, executive function, and academic performance as indicators of cognitive function 

(Section 5.3.2) and inattention, impulsivity, hyperactivity, and attention deficit hyperactivity disorder as 

indicators of attention-related behavioral problems (Section 5.3.3). Rather than discussing all of the 

epidemiologic evidence and then all of the toxicological evidence, we reorganized by outcome group 

and discussed the epidemiology and toxicology together (e.g. Section 5.3.2.3 Learning and Memory in 

Children [p. 5-94 of the redline version] and Section 5.3.2.4 Executive Function in Children [p. 5-114 of 

the redline version] integrates evidence from both disciplines).

To clarify the rationale for the conclusions drawn regarding the strength of evidence for particular health 

endpoint groupings, the discussions of the health effects of Pb were expanded with additional details on 

strengths and limitations of the evidence, with respect to issues such as study design, consideration of 

potential confounding factors, analytical methods, and potential for reverse causation in epidemiologic 

studies and Pb exposure route and concentration in toxicological studies. 

Specific revisions include prioritizing studies to emphasize those with the strongest design (e.g., 

prospective studies with serial measurements of lead biomarkers and health outcomes, analysis of 

several potential confounding factors) in both the text and conclusions. Some illustrative examples of 

such revisions are below:

Section 5.3.2 Cognitive Function: Revisions to clarify the approach to the assessment were made (pp. 

5-63 and 5-64 of the redline version). 

Section 5.3.2.1 Full Scale IQ in Children: Evidence from prospective studies discussed first (p. 5-64 of 

redline version) while cross-sectional studies are discussed later as supporting evidence 

(p. 5-81 of redline version).
A-7

Section 5.8.1 Effects on Development: Section reorganized to start with the strongest epidemiologic 

studies (i.e. NHANES analyses). Studies in Table 5-36 were reordered to follow the text 

discussion.

The potential for confounding and other biases, as they affected the body of literature contributing to the 

causal determinations, were highlighted in the summary tables referenced above. Additionally, revisions 

to the text and other tables in the document were made. Illustrative examples of such revisions are 

below:

Section 5.5 Renal Effects: Critical assessment of the influence of reverse causality expanded (i.e. 

Section 5.5.2.4 or 5.5.2.5, pp. 5-539 to 5-541 in redline version) 

Section 5.6.5 Immune-based Diseases (e.g. discussion of limitations to studies of viral or bacterial 

infection on p. 5-613 redline version)

Section 5.6.5.2 Asthma and Allergy: Discussion of confounding, selection bias and reverse causality 

expanded (e.g. pp. 5-614 to 5-624 of the redline version)

Please comment on the adequacy of the discussion of the strengths and limitations of the evidence in the 

text and tables within Chapter 5 and in the evaluation of the evidence in the derivation of causal 

determinations. Please also comment on the extent to which the nervous system outcomes have been 

grouped into appropriate constructs and the extent to which appropriate parallels were drawn between 

nervous system endpoints examined in humans and animals.

Chapter 6 – Potentially At-Risk Populations

The O3 CASAC panel encouraged the development of standard terminology and concepts for assessing 

populations at risk that could be applied broadly across the criteria pollutants. To help synthesize the 

evidence, a new classification system was created for considering risk factors and that system has been 

incorporated into the third draft Pb ISA. Similar to the approach used to determine causal relationships, 

each factor in the Pb ISA was evaluated and classified based on the weight of evidence within and 

across disciplines. 

In addition, staff evaluated whether there were adequate numbers of studies for a given health endpoint 

or group of related health endpoints within an at-risk factor to allow the magnitude of the modification 

by that potential at-risk factor to be evaluated across studies. Evidence from studies of genetic risk, 

race/ethnicity that may modify the effect of lead exposure on the cardiovascular system indicating 

increased risk of certain groups within the population was highlighted (Section 2.9.1). 

Please comment on the adequacy of these revisions to clarify the consideration of potential at-risk 

populations and recommend any revisions to improve the characterization of key findings and scientific

conclusions. 

Chapter 7 – Ecological Effects of Lead

The CASAC panel provided a number of comments that prompted focused revisions of Chapter 7. A 

new section on Pb fate and transport in ecosystems (Section 7.2) and summary tables for studies of 

reproduction, growth, and survival endpoints including key modifying factors were added (Section 7.6). 

Causal statements and their organization were revised to place greater emphasis on endpoints that are 
A-8

most clearly linked to effects at the population-level and higher (reproduction, growth, and survival) 

while additional organism- and sub-organism level responses (neurobehavior, hematological effects, and 

physiological stress) are now considered in the context of secondary responses (Sections 2.1, 2.7.3, 

7.3.12, 7.4.12, 7.4.21, and Tables 2-3 and 7-3). In addition, causal statements were further separated into 

freshwater and saltwater biota. Clarifying language was added to Sections 2.1 and 7.5 to indicate that 

causal determinations were based on various routes of exposures to Pb, often under controlled 

experimental conditions, and are not specific to air deposition. Throughout the chapter, more synthesis 

of effects on ecosystem receptors has been added and units have been standardized to express exposure 

dose consistently. Specifically, aqueous concentrations of Pb are reported as μg Pb/L, sediment and soil 

concentrations as mg Pb/kg, and concentration in solutions applied to soil or extracted from soil in mg 

Pb/L solution. 

Please comment on the adequacy, scientific soundness and usefulness of the material presented and 

recommend specific revisions to improve the discussion of key information in Chapter 7.
B-1

Appendix B

Compendium of Individual Comments by CASAC Lead Review Panel Members on

EPA’s Integrated Science Assessment for Lead

(Third External Review Draft – November 2012)

Mr. George A. Allen.............................................................................................................................. B-2

Dr. Herbert Allen.................................................................................................................................. B-4

Dr. Richard Canfield ............................................................................................................................ B-6

Dr. Deborah Cory-Slechta.................................................................................................................. B-11

Dr. Cliff Davidson............................................................................................................................... B-12

Dr. Philip E. Goodrum ....................................................................................................................... B-13

Dr. Sean Hays...................................................................................................................................... B-17

Dr. Philip Hopke ................................................................................................................................. B-19

Dr. Chris E. Johnson .......................................................................................................................... B-20

Dr. Susan Korrick............................................................................................................................... B-21

Dr. Michael Kosnett............................................................................................................................ B-30

Dr. Roman Lanno ............................................................................................................................... B-35

Mr. Richard L. Poirot......................................................................................................................... B-38

Dr. Joel G. Pounds.............................................................................................................................. B-43

Dr. Michael Rabinowitz...................................................................................................................... B-46

Dr. Ian von Lindern............................................................................................................................ B-48

Dr. Gail Wasserman ........................................................................................................................... B-51

Dr. Michael Weitzman........................................................................................................................ B-55
B-2

Mr. George A. Allen

General Comments

The revisions to Chapter Three are responsive to the panel’s comments on the second ISA draft. Many 

minor and some major changes have been made that improve the readability of the document and 

address specific weak points of the second draft.

The additions to section 3.4.1.1, Sample Collection, are an improvement to the description of the “state 

of the science” for measurement of particles greater than 10 microns, clearly illustrating the challenges 

in designing a new FRM to replace the Hi-Volume sampler where sampling of larger particles is of 

interest. While it is understood that EPA will not have completed work on design and characterization of 

an improved “larger particle” FRM for this cycle of the Pb NAAQS, I encourage the Agency to continue 

this process.

The presentation of available data showing the range of Pb concentrations larger than 10 microns 

diameter near sources is useful, and shows a very wide range of results. Some of this is related to the 

actual air concentrations, but given the very wide range of methods used for sampling this size range and 

near-source sites, it is possible that much of the variation is due to the type of sampler being used or the 

wide range in near-source characteristics and other factors including wind speed. Overall for [nonairport] near-source sites the amount of airborne Pb greater than 10 microns is typically between 10 and 

30%, with much of that less than 15 microns diameter. In the context of the NAAQS, this is not a large 

amount given the uncertainty of linkage between air Pb and dose. The ISA also appropriately notes that 

particles larger than ~15 microns deposit close to the source. This may inform the process of 

development of a new FRM since the effort to validate a sampler with a 15 micron size cut is 

substantially less than attempting to go higher – even to 17 or 18 microns. This applies both to the 

design and the FRM wind tunnel testing process. I urge the Agency to consider if the effort to go with a 

sampler for particles larger than 15 microns has value in terms of the data needs of the Pb monitoring 

network.

The Summary and Conclusions section (3.7) is well written, and covers the key points of the chapter. 

Section 3.7.3 (Ambient Monitoring) implies that a 15 micron sampler would be adequate, which I agree 

with. However, the end of section 3.4.4.1 considers the upper particle size range of interest as 15 to 20 

microns. As noted before, effective sampling of 20 micron particles is much more difficult if not 

completely impractical for a FRM sampler than for 15 microns. Also, this section concludes with a 

sentence that isn’t fully supported by this chapter (section 3.4.1.1): “The existing samplers reasonably 

capture the airborne fraction of ambient Pb that is available for human exposure”. The discussion of 

sampling issues, available technology, and relevant size for sampling larger particles is clear that while 

there are promising candidates for evaluation (the low-vol TSP louvered inlet for example), they have 

not been fully characterized for wind speed effects as required for use as a FRM sampler.

The topic of elevated air Pb near general aviation airports is discussed, but there are no data from the 15 

pilot sites that were scheduled to start sampling early in 2012. If any of these data are available (e.g., in 

AQS or even possibly preliminary data not in AQS), it would be useful to include it in the final version 

of the ISA.
B-3

Minor comments on Chapter 3

Pg 3-10, line 14: It may be worth noting here that the “solid particles” formed by condensation are 

(very) fine mode [sub-micron] Pb just to be clear.

Pg 3-15, line 6-7: this section describes wood burning other than for space heating, not just “wood 

burning”.

Section 3.2.2.6, pages 3-23 and 3-24: tire wear particle size is first described as sub-micron (Maher 

2008), and then as “coarser sizes” (Chon 2010). This discrepancy needs to be addressed or discussed.

Pg 3-54, line 10: “mor layer” needs to be defined on first use (O-horizon?)
B-4

Dr. Herbert Allen

Comments on Chapter 7 – Ecological Effects of Lead

Draft 3 of the ISA is greatly improved over earlier versions. The document is well written and, although 

lengthy, reasonably easy to follow. The authors have done an excellent job of summarizing and 

integrating a large amount of information. By reporting all concentrations in mass units (e.g. mg/kg or 

mg/L), rather than some in mass and others in molar units, it is much easier to make comparisons of 

results from different studies. 

I only have a few major comments which are followed by several more minor ones.

It is now very clear that the concentrations producing effects vary by many orders of magnitude. These 

ranges, and the effects attributed to them, are quite important in presenting the Synthesis of New 

Evidence (Section 7.3.11 and 7.4.11) and in the Causal Determination sections that follow these. A 

graphic for terrestrial and for aquatic effects that relates the various effects on the abscissa to 

concentration on the ordinate could serve to summarize the information in a useful manner. The 

environmental concentration range should be shown. Some effects, although real, have little or unproven 

applicability to environmental situations. The ISA discusses concentrations that vary more than 8 orders 

of magnitude, far more than the range of environmental concentrations.

A primary factor controlling bioavailability in both aquatic and terrestrial systems is the solubility of the 

tested material. Lead is typically added as either the chloride or the nitrate salt. Both dissociate 

completely to release lead ions, Pb2+. The lead ions can react with ligands in the solution to form 

soluble complexes and insoluble precipitates. For solutions of a near neutral pH the solubility of lead is 

low and many of the concentrations reported in the review likely exceed the solubility of lead hydroxide, 

cerrusite, PbCO3, or hydrocerrusite, Pb3(OH)2(CO3). Hydrocerrusite is not even mentioned as one of 

the important solids (page 7-91 lines 11-14). A paragraph should be added to the chapter discussing 

solubility, its importance, and its calculation, for example with the EPAs MINTEQ program. 

On page 7-124 and 7-125 the foliar proline concentrations in a macrophyte were reported to increase in 

a concentration-dependent manner as the Pb concentration increased from 20,720 to 1,036,000 μg Pb/L. 

The upper concentration of 1,036,000 μg Pb/L is over 1 g/L. Unless the pH was exceeding low, virtually 

all the Pb was in the form of a precipitate, not in a soluble form. It is interesting that biochemical and 

cytological effects such as this are found at high concentrations relative to traditional endpoints such as 

death and reproduction for which lower concentrations produce effects. 

The information on page 7-33 line 22 duplicates that on page 730 line 28.

Anecic earthworms reach depths of 6 feet, not 6 inches (page 7-36 line 8).

The observation on page 37 line 7 that honeybees collected near an airport have the highest 

concentration of Pb is very interesting and likely very important. Aviation fuel contains Pb.

On page 7-39 lines 21-22 the phrase “...with high absorption of cerussite and Mn-Pb oxides and poor 

absorption of galena and anglesite.” Should be changed to “...with high absorption of Pb from cerussite 

and Mn-Pb oxides and poor absorption of Pb from galena and anglesite.”
B-5

On page 7-44 lines 10-11 there is aan error in the concentration conversion. 10 mM Pb is 2072 mg/L not 

10,360 mg/L.

On page 7-44 line 34 “theses” should be “these”

On page 7-47 lines 24 and 25 mM, which means mmol/L, should be changed to mmol.

On page 7-47 line 26 “nitrite” should be “nitrate”.

The discussion of ionoregulation (page 7-134 lines 8-24) is particularly well written and helpful.

On page 7-136 lines 19-20. The value 0.08 nM/100 embryos is probably incorrect. This means 0.08 

nmoles/L/100embryos. Likely it should be 0.08 nmoles/100 embryos.

The summary on page 7-157 beginning at line 19 and the corresponding section for effects terrestrial 

systems are very good. This is where the figure that relates the various effects to exposure 

concentrations would be helpful.

On page 158 line 13 please do not advocate the use of LOEC. Many papers have discussed the reasons 

for this. The use of LC10 is fine.

On page 166 line 18-20 the LC50 value is derived because it is a stable value and is less dependent on 

the method used than are other computed values (e.g. LC10). It is not used to suggest that this value be 

used as a regulatory limit or as a value that is desirable for an ecosystem.
B-6

Dr. Richard Canfield

Comments on Chapter 5 – Integrated Health Effects of Lead Exposure

1. Appropriateness of new endpoint groupings

a. The new organization by endpoint groupings is a nice improvement. I would like to 

discuss the underlying conceptual scheme and also the wording during the meetings. My 

key question is why the term “externalizing behaviors” was not adopted whereas 

“internalizing behaviors” was adopted (e.g., table 2.2 and page 5-169 (line 7)). The term 

“attention-related behavior problems” is nonstandard and seems to imply a link between 

some broad definition of attention and child conduct. It also suggests a possible narrower 

interpretation in which it would be just another term for ADHD. The table below (from 

Behavioral, Social, and Emotional Assessment of Children and Adolescents , Whitcomb 

and Merrell, 2012) provides a categorization scheme and behavior descriptions that might 

be helpful for arriving at descriptors that accurately represent the behavior categories as 

they are pertinent to lead exposure studies. As I see it, one could use “externalizing 

behaviors” as the general term and then break it down into “attention/hyperactivity 

problems” and “conduct problems.” Of course, as the child leaves the protection of the 

school-based disciplinary structures then conduct problems become delinquency and

criminality.

b.

2. Extent to which the text and new summary tables support the application of the causal 

framework

a. The text and tables are now much more clearly and explicitly linked to the causal 

framework. What seems a bit inconsistent is the weight given to studies that confirm an 
B-7

adverse effect of lead as compared to studies that reveal inconsistencies in the evidence.

The paragraph-length descriptions of the levels of causal determination presented in 

PreambleTable II provide a nice balance of considering both confirmatory and nonconfirmatory or inconsistent evidence but in the summary tables (e.g., 5-17) there is a 

column for “Key Supporting Evidence” but not for “Key Opposing Evidence.” 

3. Consistency and accuracy of applying causal framework across endpoint groupings. [Still 

working on consistency and accuracy...will comment after going through all the tables.]

a. Table 5-17 (p. 5-281): This is a tremendously helpful table and the authors merit 

congratulations on a job well done. Suggestions:

i. On p. 5-282 under “Key Supporting Evidence” for the epidemiological findings 

from toxicology studies the descriptions of the effects on learning do not 

accurately reflect the findings in Stangle, et al., 2007. Those authors characterize 

their findings as a deficit in associative ability (on their page 206): “Pb-induced 

learning deficits and efficacy of succimer treatment. Both the High-Pb and ModPb groups learned the basic rules of the visual discrimination task and attention 

task 1 more slowly than the controls, indicating lasting impairment in the 

associative ability as a result of a short period of early Pb exposure, as previously 

reported (e.g. Garavan et al. 2000).”

ii. Also, I wonder if the Garavan paper is relevant to cite here (I don’t recall the 

exposure levels.)

iii. A minor formatting issue: for example, on page 5-282 consider adding a heading 

across the top to indicate that the contents of the table are a continuation of the 

previous page pertaining to cognitive function deficits in children. When going 

back and forth between the various tables it is easy to lose track of the endpoint 

grouping.

iv. The evidence for Pb effects on internalizing behaviors is very much weaker than 

for externalizing behaviors (“conduct problems”) but both reach the “likely 

causal” threshold. I would like CASAC and EPA to discuss this contrast as a tool 

for evaluating the model for causal determination and the accuracy and 

consistency of its application.

v. Evidence for sensory function deficits (page 5-286) seems to teeter on the Likely 

Causal/Suggestive of Causal edge. Is one (1) strong epidemiological study 

accompanied by one (1) cross sectional study sufficient evidence for Likely 

Causal? Also, the primate study had exposures from 33-170 ug/dL. Is that a 

relevant exposure range and were the effects a consequence of the higher 

exposure animals?

vi. For neurodegenerative diseases it is noted that, “occupational studies did not 

consider Mn co-exposures” but control or lack of control for Mn is not 

consistently mentioned with respect to occupational studies for other endpoint 

groupings (e.g., psychopathological effects in adults). In cognitive function 

decrements in adults it is noted that occupational studies did not consider other 
B-8

occupational exposures but Mn is not singled out in the way it is for 

neurodegenerative diseases.

b. Table 5-24

i. As for other tables, consider “continuation” headings when evidence relevant to a 

given outcome spills onto the back of a page (e.g., 5-370).

c. Table 5-31

i. This table summarizes a very complex area of research and it is very helpful to 

have entries in “Key Supporting Evidence” that explicitly identifies issues that 

add uncertainty to the causal determination.

d. Table 5-34

i. Maybe I missed the explanation for this but why is it that the outcome categories 

in this table do not match the outcome categories presented in figure 5-34 (page 5-

429)?

e. Table 5-35

i. I did not find an MOA section for heme synthesis.

f. Table 5-48

i. It could be misleading to have the bold heading “Effects on Development –

Causal” that corresponds only to delayed puberty and not to postnatal growth or 

impaired organ systems. Consider breaking those out as separate endpoints so 

there will be a more clear indication of the level of evidence for Pb effects on 

postnatal growth and impaired organ systems.

ii. Page 5-635 replace “spermatiogenesis” with “spermatogenesis”.

iii. Should there be headings for effects on hormone levels and fertility? Currently it 

jumps from mode of action on sperm to inconsistent evidence regarding hormone 

levels.

g. Table 5-50

i. Is it possible to include information about Pb exposure levels in the 

epidemiological studies?

4. Expanded discussion of strengths and limitations of evidence for health effects for individual 

endpoints

a. Renal (5.5)

i. This is very helpful, particularly the section summarizing Lin’s chelation studies.

ii. I suggest changing the word “prudent” to “parsimonious” or “plausible” on page 

5-392.

iii. On page 5-399 line 14 it would be helpful to link back to the excellent discussion 

of independent effects of EDTA on kidney function on pages 5-391 and 5-392.

b. Immune (5.6.5)

i. Nicely done.

c. Asthma and allergy (5.6.5.2)

i. Again, a very helpful section for interpreting the following studies.

ii. Page 5-457 line 29 delete the word “in”
B-9

iii. Page 5-458 line 2 change to ”direct causal” relationship with Pb exposure.

5. Prioritizing studies with strongest designs

a. 5.3.2 Cognitive function 

i. For the reader who is not very familiar with IQ testing, I fear they will come away 

with the notion that all IQ tests are divided into verbal and performance subscales 

and produce an overall FSIQ. That particular terminology derives from the 

Wechsler products and not all studies of Pb and IQ used those tests.

ii. I think it is important to make clear what the most important studies are and I also 

think great care must be taken to make sure the reader knows what are the 

attributes that go into the ranking. In particular, I caution against using any 

shortcuts when referring to the basis for ranking studies. For example, in this 

charge question only the strength of the design is noted whereas the 

representativeness of the study population is an extremely important criterion 

(hence the relatively low rankings of the Wasserman et al. and Tong et al. 

studies). Also, the sense of quality must be put into an appropriate context; i.e., 

some studies are “better” (more useful) than others for addressing the particular 

issues of concern for this ISA and at this time in history.

b. 5.3.2.1 FSIQ 

c. Another issue with the ranking -- some might see the pooled analysis as a version of the 

Rochester analysis but with a less consistent measure of FSIQ and a cobbling together of 

SES and other covariate measures, all of which introduces error variance. We tried to 

make the pooled analysis as “uniform” as possible but compromises are necessary when 

bringing together disparate data sets. One perspective is that the pooled analysis revealed 

the “true” concentration-response relationship for low level exposures. Another 

perspective is that the Rochester and Boston cohorts contributed nearly all the data to the 

analyses dealing with effects < 10 ug/dL and given that each of those studies achieved 

greater consistency in measurement of the outcome and the covariates than was possible 

in the pooled analysis, those studies should be considered more influential. I’m not sure 

this sort of issue rises to the level of a need for revision of the ISA but if others on 

CASAC or in EPA pick up on it then we should discuss it.

d. 5.8.1 Effect on development

i. It’s not clear to me why the Wu et al. study is listed first when the Selevan et al. 

study does a more nuanced analysis (stratified by ethnicity) and considered a 

broader array of covariates. Selevan also considered a broader age range (8-18 

rather than 8-16).

ii. I found it very difficult to extract the key information from Table 5-36. The data 

are inherently complicated but the outcomes (e.g., Breast development) are not 

easy to distinguish from other text in the column. Maybe they could be bolded.

Also, it would be much easier to read if the information in the adjusted effects 

estimate column did not word wrap.
B-10

Other wording issues, questions, queries

5-55 line 19: The word “substantiated” includes the connotation that the primary studies were somehow 

not as real or accurate as the pooled analysis, whereas compromises on covariate selection in the 

combined analysis makes it arguably weaker evidence. Possibly the term “is further supported 

by” would convey the idea that the pooled study adds to what we already knew rather than being 

the study that makes the original research “substantial.”

5-56 lines 32-37: The characterization of the empirical foundation of the supralinear concentrationresponse relationship is imprecise and the quality of the evidence varies widely among the 

studies cited. Kordas was a cross-sectional study that found weak evidence for a supralinear 

effect and was based on concurrent Pb in childhood whereas Canfield et al. used lifetime average 

blood lead and IQ tests at two different ages. I suggest dividing up the references into a stronger 

and weaker group with the Kordas paper (on which I am a co-author) in the weaker pile.

5-67 line 25: It could be noted that home cleanliness and pica are likely to be proxies for exposure. If so, 

including them in the regression model would control for the exposure itself.

5-72 line 23: Please check to see if a lack of variation in parental education and income is also a 

plausible explanation for the absence of an association with FSIQ.

5-73 line 3: “a large majority”

Lines 20-23: The logic of the sentence beginning, “The few weak or null associations...” is unclear to 

me. Wouldn’t the use of similar confounding factors strengthen the importance of these null 

findings? Is something different being said here as compared to what is said at the bottom of 

page 5-70 (and some other places) regarding how one evaluates the importance of the Cleveland 

study?

Paragraph beginning on line 28: This seems misplaced in the cross-sectional study section. Also, it 

seems mostly equivalent to the last paragraph on page 5-70.

5-74 line20: A primary reference for characterizing the Bayley test (which is done quite well in this 

ISA) and its status as a test of mental function is: McCall, R.B., P.S. Hogarty, and N. Hurlburt, 

Transitions in infant sensorimotor development and the prediction of childhood IQ, in American 

Psychologist, C.S. Gersoni and K.B. Little, Editors. 1972, American Psychological Association: 

Washington, D.C. p. 728-748.

5-532 line 6: For consistency, comment on covariate control for the Wu study (or list them). When the 

Selevan study is noted for including many potential confounders but no confounder information 

is given for Wu then the reader easily concludes that Wu had no covariate control.

5-533 Figure 5-37: Suggest changing “Puberty” to “Puberty onset”.

5-695 Check units for bone lead measures, g/g or ug/g?
B-11

Dr. Deborah Cory-Slechta

Comments on Chapter 6 – Potentially At Risk Populations

Please comment on the adequacy of these revisions to clarify the consideration of potential at-risk 

populations and recommend any revisions to improve the characterization of key findings and scientific 

conclusions. 

The chapter is improved over the prior version. Improvements include the more specific delineation of at 

risk sources in terms of biological vs. environmental for example. In addition, the Chapter better 

summarizes the strength of the evidence with respect to each of the factors that are considered.

What is missing is any sense of the relative magnitude/importance of the risk factors. It is stated that the 

magnitudes are discussed in Chapter 5, but its not clear that they are discussed there, and it makes it 

more difficult for the reader to have to go back and try to track them down. It would be extremely useful 

to have a summary table that summarizes the magnitude of effects these various factors impose. It may 

be the case that there are very consistent effects of any given factor, but if the magnitude of the risk 

modification is 2%, for example, how important are they?
B-12

Dr. Cliff Davidson

Comments on Chapter 3

The third version of Chap. 3 of the ISA has been revised according to CASAC comments. Pages 3-2 to 

3-22 appear to be a reasonable summary of the National Emission Inventory for Pb, and includes 

information on lead wheel weights from the Aucott and Caldarelli (2002) study, as requested by 

CASAC. 

Section 3.3 starting on page 23 discusses deposition of lead. While the information in this section seems 

reasonable, there could be a mention that lead deposition allows for a link between airborne lead and an

ingestion pathway, e.g., food from urban gardens (I didn’t see this written explicitly, although it might 

be in the document). 

In section 3.4.1, limitations of the FRM and alternative methods of sampling have been discussed on 

pages 3-60 to 3-68. The discussion of low volume samplers, saturation samplers, and passive samplers is 

good. It is unclear why the Andersen impactor reported concentrations 97% higher than the Texas A&M 

sampler for PM4 but only 14% higher for PM10 (page 3-66). One would expect better agreement as 

particle size decreases. (Why did EPA choose to highlight this specific difference?)

Revisions made to the airborne lead size distribution discussion in section 3.5.3 starting on page 3-96 are 

reasonable. The new discussion on background lead levels in section 3.5.5, page 3-109, is reasonable. 

The section concludes with an estimate of background airborne lead concentrations as requested by 

CASAC; the given estimate is 0.02 to 1 ng/m3, which is consistent with the literature values in remote 

areas. The given range varies by a factor of 50; it is probably difficult to decrease this spread. We know 

PM concentrations can vary by more than this depending on whether sampling is done in a remote area 

with vegetation and soil, or on an ice sheet far from exposed soil and seaspray. If PM total mass can 

vary greatly in geographically different remote areas, one could expect airborne lead to vary greatly as 

well.
B-13

Dr. Philip E. Goodrum

Comments on Chapter 4

Please comment on the adequacy of these and other changes in responding to the Panel’s comments. 

Please provide comment on revisions that may further improve the utility of this chapter for 

interpretation of health evidence in subsequent chapters.

In general, EPA was largely responsive to comments from the CASAC committee on Chapter 4, and 

suggestions to better integrate Chapters 3 and 4. Specific comments are given in the table below for each 

of the comments and recommendations that CASAC provided on ISA Version 2.

CASAC’s Comments on ISA Version 2 Comments on ISA Version 3

1 Additional synthesis and summary of information is needed on the following

1a Section 4.1 – example, Section 4.1.3.3 (Dietary Lead 

Exposure) – Information is factual, but the reader 

will benefit from more interpretation, context, and 

summary. Include additional discussion to explain 

the importance and impact of the reviewed data to 

the ISA. This recommendation can be generalized to 

all chapters of the ISA document – EPA should 

review each section and determine if, in addition to 

summarizing the information/data available, the 

implications of this information is also conveyed. 

Text was added to effectively convey the 

implications of the exposure pathwayspecific summaries. For example, Dietary 

Pb exposure is discussed in 4.1.3.3. A 

paragraph was added (p.4-28, lines 19-32) 

to tie together multi-source contributions to 

Pb in food items.

1b Section 4.1.1, p. 4-6 – The additional paragraph is 

helpful at presenting quantitative estimates of % 

contribution of air Pb to blood Pb. Include a table 

that summarizes this information, distinguishing 

between estimates based on modeling (e.g., IEUBK) 

and empirical studies. Then add text to 

synthesize/summarize this information with specific 

focus on the importance of changes in these % 

contribution estimates over time, or as a function of 

the low end vs high end blood leads.

Addition of Table 4-2 summarizes % 

contribution to median and 95th percentile 

blood Pb, assuming GSD = 2.1. The text 

should further discuss the implications of 

the modeling results presented in this table 

– specifically, increasing the air Pb from 

0.14 to 0.87 μg/m3(a factor of 0.7) yields 

an increase in blood Pb of 0.2 μg/L for the 

median (slope =0.27 μg/L per μg/m3) and 

0.7 μg/L (0.96 μg/L per μg/m3 ).

1c Add a section that relates estimates of blood Pb / air 

Pb slopes to the original goals of the ISA as 

presented in the Integrated Review Plan, which 

called for an uncertainty analysis that provides a 

foundation to review the NAAQS. For example, the 

ISA can demonstrate how a particular slope factor 

translates into a corresponding change in blood Pb at 

the GM and 95th percentile of the distribution 

assuming a lognormal distribution with GSD =1.6 (a 

model adopted in IEUBK).

See comments on 1b.

2 Additional discussion and perspectives on the relevance of information as presented is needed:
B-14

2a Chapter 4 leaves the impression that from a 

multipathway exposure perspective, direct inhalation 

of air Pb is generally a relatively minor contributor 

to total dose compared to soil/dust ingestion, diet, 

water ingestion and other routes of exposure 

(although some exceptions are noted, such as 

populations living in the vicinity of an airport). This 

may raise questions regarding the interpretation of 

the blood Pb / air Pb slopes, or the potential for a 

reduction in NAAQS to have a meaningful effect on 

blood Pb. Chapter 3 provides a more explicit 

discussion of the correspondence between air Pb and 

multiple exposure media (beyond air itself). Need 

better linkage between Chapter 3 and Chapter 4.

Pages 415-416, addition of new paragraphs 

explain some of the uncertainties associated 

with developing slope estimates from 

empirical data, appropriately concluding on 

a neutral tone “..[uncertainties] may lead to 

both positive and negative biases in the 

[slope factor] estimates from individual 

studies.

New sections on particle size help to make 

the point that particle size governs exposure 

routes and that inhalation is not the only 

exposure route for Pb in air.

2b Section 4.2.1, p. 4-30, lines 24-28 – expand this 

discussion to include the concept that time-integrated 

blood Pb reflects an aggregation of the biological 

processes that includes both recent Pb 

bioavailability/absorption as well as inputs from soft 

tissue and bone.

This points were added.

2c Figures 4-8; 4-9; and 4-11 – the simulations are very 

informative and help to illustrate the temporal profile 

of Pb in blood, bone, and overall body burden. The 

text (p. 4-63) indicates that the simulations represent 

an exposure scenario in which a child experiences 

“..a constant Pb intake (from age 2-5) via 

ingestion... followed by an abrupt decline in intake.” 

Additional details regarding the exposure/dose 

would be useful - specifically what constant Pb 

intake was administered, and when intake was 

abruptly reduced – was this set at zero or some nonzero baseline? Further clarification on the 

relevance/interpretation of the time averaging would 

be useful since it is unclear how the reduction in 

variance attributable to the averaging can be related 

to the experimental data. Consider removing the 

time-weighted average blood Pb panel.

These additional notes were added.

2d Figure 4-22 – very helpful addition to demonstrate 

the various slopes, particularly to emphasize the 

differences in the model selection (e.g., log-log, loglinear, etc). The shapes of the response curves are 

very divergent at low air concentrations. Given the 

focus of the NAAQS is at the low end of the air Pb 

range presented, EPA should 1) comment on the 

challenge of estimating the low-end of the curves 

(i.e., < 0.2 μg/m3) from data collected, and 2) 

comment specifically on the magnitude of difference 

The figures are still included, but I did not 

see this additional discussion included in 

Version 3.
B-15

in estimates and representativeness of the statistical 

models applied to empirical data. EPA should 

conduct an independent analysis of the underlying 

studies and determine if a common model can be 

used to describe all the datasets. Then, tie this back 

to estimates of expected change in blood Pb 

associated with change in NAAQS (see 1(c) above).

2e The ISA presents a range of blood Pb / air Pb slope 

factors without pinpointing a subset of estimates that 

may be more relevant to the objectives of the REA.

To the extent that EPA has already identified a “best 

estimate” of a slope factor, or a range of best 

estimates, this information should be included in the 

ISA, accompanied by a discussion for the rationale 

that supports the selection.

Paragraph added to p. 4-130

2f Comment on the importance of errors associated 

with estimates of particle size distributions from 

historical Pb TSP measurements. How does this 

uncertainty likely contribute to 1) estimates of air Pb 

/ blood Pb slopes; 2) estimates of predicted blood Pb 

from epidemiological data; and 3) corresponding 

uncertainty in predicted change in blood Pb 

associated with reduction in air Pb (see 1(c) above).

Additional discussion on TSP was added.

2g Section 4.1.1 presents the conceptual model for a 

multi-pathway assessment. Page 4-6 (lines 8 to 34) 

discusses the relevance of particle size distributions 

for inhalation and soil/dust ingestion exposure 

pathways. The first sentence (line 8) states: Particle 

size of Pb-PM is relevant to transport through 

various media leading to exposure. Restate this or 

expand the introduction to emphasize that all particle 

sizes are relevant to lead exposure assessment in 

general, and to understanding the air Pb / blood lead 

relationship specifically.

Chapter 3 and 4 include this overall 

message.

2h Historical perspective on change in Pb sources over 

time associated with change in blood Pb – Chapters 

3 and 4 remained somewhat biased towards gasoline 

Pb phase down (e.g., Section 3.7.1; Section 4.4.1, p. 

4-78, introductory paragraph); also emphasize the 

role of reductions in emissions in the vicinity of 

point sources as presented subsequently (e.g., pp. 4-

84 to 4-86).

Concepts are included on page 3-28.

3 The following contradictions need to be addressed:

3a Clearance rates for blood Pb – the text (e.g., 4-62) 

suggests that the rate of change may be slow 

following cessation, such that blood Pb will remain 

elevated years after exposure ends. Yet, the narrative 

Additional discussion was added on 

clearance rates.
B-16

discussion at the top of page 4-67, and the model 

simulations in Figure 4-11 (ICRP modeling) suggests 

exactly the opposite – a rapid decline in blood Pb 

following cessation. EPA should provide more 

description regarding model assumptions (e.g., how 

was baseline exposure factored in?), and comment 

on whether this relationship may differ for higher 

blood Pb that corresponds with adult occupational 

exposure. Literature that provides empiric 

observation for change in blood lead following

cessation of exposure that resulted in moderate 

elevations (e.g., blood Pb in the 10 to 25 ug/dL 

range) for various time durations should be discussed 

(if available).

% Pb in blood - Page 4-39 (line 23) and 4-120 (line 

22) report that 1% of body burden is in blood, 

whereas 4-49 (line 12) reports 5%.

In Section 4.3 (Biomarkers, page 4-52, line 

23), 5% was changed to 1% for consistency
B-17

Dr. Sean Hays

General Comments on Chapter 4

4.1.13.5 Exposure to lead from consumer products: Providing this data is extremely valuable.

Table 4-7 is especially helpful. However, the discussion of the importance of exposure to lead 

from consumer products is extremely sparse and seems inadequate. Surely there are studies 

available that provide some context on the impact of PbB due to lead exposures to consumer 

products. Consider discussing the study by VanArsdale (VanArsdale JL, Leiker RD, Kohn M, 

Merritt TA, Horowitz BZ. Lead poisoning from a toy necklace. Pediatrics. 2004 

Oct;114(4):1096-9.). While this is likely the worse case example, it may still be informative 

nonetheless. Other examples would be very helpful.

4.3.5 Relationship between Pb in blood and Pb in bone: This section was well written and some 

insightful conclusions were drawn.

I appreciate and liked the summary of data/studies that have investigated the relationship 

between lead in air and blood leads. In particular, the historical perspectives around the declines 

in the use of lead in gasoline and related decreases in blood leads in the US and other countries is 

helpful for establishing the context around setting a lead NAAQS.

The description of the empirical models, and their strengths and weaknesses, is good. Again, 

many of the empirical models were developed using data from smelter/mining communities, 

which are very different than the scenarios involving setting a NAAQS. These empirical models 

would be helpful for setting a SAAQS (Smelter Ambient Air QS), but not so much for setting a 

NAAQS.

Table 4-12 is very telling about how our understanding of blood-air relationship is shaped by 

high airborne lead exposures and/or high blood lead levels. Most studies had blood lead levels 

that exceeded 10. No studies have captured current exposures and the relationship (if any) 

between blood lead and air lead for the general population who are not exposed to point sources 

of air emissions.

Figure 4-22 & 4-24: These figures seem to imply that blood lead levels decline to zero at zero air 

Pb levels. I’m not sure the underlying data support this extrapolation. Consider truncating the 

figure at a higher blood lead levels (For Figure 4-24, truncate at the air [0.05] & blood level [10 

ug/dL]).

I still wish the agency would provide a summary of the sources of lead exposures for the general 

population and the general proportions as a function of age and blood lead levels. For instance, 

for children with blood lead levels above 5, 10, etc. ug/dL , what proportion of their lead 

exposure is coming from air, water, soil, dust, consumer products, paint, etc. Do these 

proportions change as a function of age and blood lead levels? This is what is needed to provide 

more informed decisions on how the NAAQS should/could be improved. I would love to see 

some pie charts for the following ages/PbB (even if they are educated guesses):

o Children < 2 yrs, 2-6 yrs of age, 6-18 yrs of age, 18-40, >60 yrs of age

 PbB <2 ug/dL

 PbB 2-5 ug/dL

 PbB 5-10 ug/dL

 PbB > 10 ug/dL

Specific Comments on Chapter 4
B-18

Page 4-68, Line 28: Reference to Figure 4-9 should instead be to Figure 4-10.

Figures 4-9, 11 & 12: Figures that mix Time-integrated Blood Pb and instantaneous 

concentrations are confusing. There is no need to reproduce the instantaneous bone or body 

burden when they are provided in the paired figure above.

Page 4-84, lines 20-33: The ISA presents an analysis of How was this analysis done? Was it 

modeled? Not enough detail is provided for the reader to follow.

Page 4-139: The paragraph from lines 21-31 is overly biased. The second to last sentence in 

particular. This sentence should be revised to read “Still, uncertainty may be expected to remain 

about parameters in complex exposure-biokinetic models.” 
B-19

Dr. Philip Hopke

In general, EPA has done a good job of responding to comments on the prior versions and this draft of 

the ISA is in good shape. 

Comments on Chapter 3

This version is quite well written and is pretty much ready to go. There are some useful new results that 

EPA may wish to take note of 

Sources

Wood Combustion - Lead concentrations in 132 samples of wood pellets and 23 samples of wood chips 

from the northeastern US were presented by Chandrasekaran et al. (2012). It appears that some of the 

commercially available pellets used waste wood that included lead-painted material. The actual 

compositions of the emissions measured in the effluent of two high efficiency, low emissions 

commercial scale wood pellet boilers burning virgin wood pellets were provide by Chandrasekaran et al. 

(2011). 

Analytical methods

There is now a semi-continuous field monitoring system for elements, the Cooper Environmental 

Services Ambient Metals Monitor (Xact 620) for Near‐Real Time PM10 Metals Monitoring that is now 

commercially available. It has been used in several field studies and deserves a mention as an approach 

that would permit near real-time monitoring of lead in ambient PM.

References cited

Chandrasekaran, S.R., J. Laing, T.M. Holsen, S. Raja, P.K. Hopke, (2011) Emission Characterization 

and Efficiency Measurements of High Efficiency Wood Boilers, Energy and Fuels 25, 5015–5021.

Chandrasekaran, S.R., P.K. Hopke, L. Rector, G. Allen, L. Lin, 2012. Chemical Composition of Wood 

Chips and Wood Pellets, Energy and Fuel 26: 4932−4937.
B-20

Dr. Chris E. Johnson

Comments on Chapter 7: Ecological Effects of Lead

Please comment on the adequacy, scientific soundness and usefulness of the material presented and 

recommend specific revisions to improve the discussion of key information in Chapter 7.

Several revisions were made to the Ecological Effects chapter of the Second Draft ISA to improve its 

organization and effectiveness. A new section (7.2) has been added on Pb fate and transport in 

ecosystems. While I have no objection to adding this section, much of this content is repeated from 

Chapter 3, and little of it is used in the following sections of Chapter 7. For example, section 7.2.2 

covers half-lives and time to achieve 95% of steady state, yet there appears to be no use of these 

concepts in the rest of the document.

An important criticism of this chapter of the Second Draft ISA was that information from individual 

studies was not well integrated into meaningful syntheses with sound technical interpretation. The 

terrestrial sections of this Third Draft (7.3.1 to 7.3.9) are much improved in this regard, with good 

summaries at the end of each section synthesizing the interpretations.

Perhaps the most important revision to this chapter of the ISA is the addition of Tables 7.4, 7.5 and 7.6. 

These helpful tables summarize the most relevant data leading to the conclusions regarding the causal 

determinations.

Finally, the discussion of bioavailability is much improved and integrated with the discussion of 

biomagnification. 

A persistent problem in the analysis of ecological effects, especially ecosystem effects, is the inability to 

develop meaningful relationships between Pb concentrations in air and Pb concentrations in soils and 

water. This disconnect ultimately limits our ability to set an ecosystem-based secondary standard for Pb 

despite clear indications of causal relationships between Pb exposure and most biotic responses. This is 

not a new problem. However, one may hope that in the near future there will be sufficient data to close 

this gap and develop an ecologically based secondary standard, perhaps using a critical loads approach.

With regard to terrestrial effects, Chapter 7 of this Third Draft ISA is a well-written and comprehensive 

summary of current scientific understanding.
B-21

Dr. Susan Korrick

Comments on Chapter 5: Integrated Health Effects of Lead Exposure

1. "....Causal determinations for health effects were drawn for more specific groups of related outcomes 

instead of major organ systems. Please comment on the appropriateness of new endpoint groupings..."

The Nervous System Effects section, in particular, has been re-organized into more specific outcomes. 

E.g., Cognitive function in children has been divided into sections focused on specific tests and/or 

cognitive domains such as "full scale IQ", Bayley Scales of Infant Development, Learning and Memory 

, Executive Function and Academic Performance and Achievement. Similarly, the previous draft's 

"Behavioral Effects" section has been divided according to behavioral phenotypes -- Attention-related 

behavioral problems, Conduct problems, Internalizing problems, etc. In general, this a much better 

approach than in the previous draft and facilitates a more focused and critical discussion of the literature. 

This, in turn, makes the causal determinations clearer and better justified. 

The only limitation of this approach is that some specific groups of related outcomes may not be optimal 

or appropriate. In addition, the choice of studies to include in each specific group was sometimes 

confusing. E.g., on p. 110 and Table 5-9, the summary of studies of academic achievement includes a 

study of the WRAML Verbal Learning test. This is an odd choice as it is a pure memory task (the child 

is asked to recite a simple word list from memory after hearing it read); this task is unrelated to 

vocabulary or other acquired verbal skill. These are not critical limitations but it is useful to keep in 

mind that there is still some misclassification among the health groupings. 

2. "...Further, please comment on the extent to which the text and new summary tables support the 

application of the causal framework in deriving causal determinations?"

This draft provides clearer and better documented support for the application of the causal framework 

than was the case in the previous draft. Especially helpful in this regard are the new summary tables that 

parallel the text summaries of causal determination for each health measure. 

3. "...How consistently and appropriately was the causal framework applied across endpoint groups?"

In general, this draft applied a more balanced approach to reviewing the literature than previous drafts. 

The approach included giving prospective studies priority over those with cross-sectional designs, 

explicitly acknowledging potential for residual confounding where applicable, and commenting on the 

likelihood (or not) of participation bias affecting results. In addition, the generalizablity of specific study 

populations to the U.S. general population was considered. In keeping with this approach, tables 

summarizing study findings provided more detail (study size, design, participation rates, confounders 

considered, modeling approach, etc.) than previously which is a valuable update. But there were a 

number of basic issues that were vague. E.g., summary tables indicated that nervous system studies were 

listed in order of strength of study design. Aside from prospective studies being listed before crosssectional ones, the additional 'ordering' criteria were unclear and never explicitly explained. E.g., large 

cross sectional studies were often listed as lower priority than very small ones. On p. 5-123 the BMS 

(Baltimore Memory Study) did not adjust for potential confounding by smoking and alcohol, a 

potentially important weakness in studies of adult cognitive function and Pb, yet BMS is 1st in Table 5-
B-22

10. Was adjustment for smoking and alcohol considered over-adjustment since these can be important 

correlates of exposure? Some discussion of this would have been useful. 

Lack of adjustment for parental caregiving quality seemed to play a disproportionately large role in 

prioritizing child nervous system outcomes although the role of this covariate in confounding for some 

nervous system outcomes was unclear. For behavioral outcomes, there was repeated emphasis on 

whether or not parental behavioral disorders were accounted for and whether parental psychopathology 

correlated with parenting quality. This was an issue of concern in the previous draft given that many 

behavioral disorders (e.g., ADHD) have strong familial components. Also, "representativeness" of study 

populations was emphasized as a limitation in a number of nervous system studies (e.g., studies with a 

high prevalence of maternal pregnancy alcohol consumption or drug use appeared to be downgraded 

because of this issue). Although generalizability is important in interpreting study findings, unless there 

is effect measure modification by the unique features of the study population, it should not impact the 

internal validity of a study's findings. Examples of studies down weighted because of this issue include 

IQ studies in cohorts in Detroit, MI (e.g., Chiodo et al., 2204; 2007) and null findings in the prospective 

Cleveland, OH cohort (e.g., Greene et al. 1992). In fact, the Cleveland cohort's null associations were 

described as having "weaker implications" because of its "lack of representativeness" (see p. 69-70,75, 

etc.) The reasoning here is presumably not based on the validity of the findings? It's a bit unclear. 

4. "Please comment on the adequacy of the discussion of the strengths and limitations of the evidence in 

the text and tables within Chapter 5 and in the evaluation of the evidence in the derivation of causal 

determinations..."

As in charge #3 above. There were a few cases, where causal determination needed refinement. E.g., (p. 

272), in nervous system effects, Pb's relationship with sensory findings are most consistent for hearing, 

not vision, but conclusions seem to encompass all sensory functions. Conclusions should be more 

clearly focused on hearing alone. The causal analysis for renal effects was updated to be more nuanced 

than in the previous draft, acknowledging uncertainties re. reverse causality and methodologic concerns 

in prospective epidemiologic studies in which change in serum creatinine was assessed after adjustment 

for baseline Cr as this analytic approach can be biased. Thus, the conclusion of "likely causal" (rather 

than "causal") is an improvement compared with the previous draft. Still, it is a challenge to determine 

how the distinction between causal determinations of “likely causal” or “suggestive” were made. 

5. "Please also comment on the extent to which the nervous system outcomes have been grouped into 

appropriate constructs and the extent to which appropriate parallels were drawn between nervous 

system endpoints examined in humans and animals..." 

In general, the nervous system outcomes have been grouped into appropriate outcomes and constructs 

with reasonable parallels drawn between human and animal endpoints. Also, pairing the toxicology 

summaries with the specific relevant epidemiology rather than summarizing the two literature streams 

separately, was helpful for assessing coherence of findings across disciplines. A few specifics could be 

clearer. E.g., on p. 92, Pb-associated impaired animal FI (Fixed Interval) operant conditioning is used to 

support effects of Pb on attention-related problems. Is FI attention, or impulse control? Also, as per 

charge question #1, there are some nervous system groupings for the human literature that could be 

improved. E.g., I agree with Dr. Canfield's suggestion that Externalizing Behavior would be a better 

umbrella to describe a number of the behaviors currently subsumed under attention-related outcomes. 
B-23

Specific Comments:

Mechanisms:

p 30: not sure why heterogeneity of species, exposure duration, and metrics precluded assessing role of 

non-linearities in dose-response as a source of inconsistent findings....is the issue whether or not the D-R 

is a threshold?

p 37: How do gonadal cells have decreased plasma IGF1?

p 39: It is good that Pb-chromate studies are reportedly not included for genotoxic effects although in 

the section on Cancer-related outcomes, these studies are still summarized and considered. 

Nervous system:

p 55: Description "attention-related behavioral problems" is good

p 57: This is a good overview of exposure across childhood (later periods as well as cumulative) likely 

being detrimental (FSIQ) in epidemiologic literature (not just focused on prenatal/perinatal periods per 

some animal literature). Also, acknowledged issue of correlation of exposures over time and persistence 

of effects is useful. 

p 68: Emphasis on attenuated adjusted effect estimates not "losing precision" (ie still statistically 

significant) doesn't preclude residual confounding given evidence of reasonably strong confounding 

among known/measured covariates considered in models. Text seems to imply otherwise. 

p. 75: Table 5-4: It would be good to indicate that Hu et al. is also the same Mexican study population 

(different subset?) as Telez-Rojo and Claus Henn.

p. 77 & 80: There is a comment re. the uncertainty of exposure scenarios’ contribution to associations 

between cord blood Pb and MDI since there is increased mobilization of Pb from bone to blood in 

pregnancy. What does this mean? How would a given cord blood Pb level mean something different 

because of bone Pb mobilization?

p. 84: Use of the WCST as a memory/learning task seems odd. It is an indicator of executive function 

and cognitive flexibility (e.g., set shifting).

p. 90: This seems an odd definition of working memory ("info that changes frequently and is not stored 

permanently")

p.101: line 23: “Stoop” should be “Stroop”

p. 103, Table 5-8: Bellinger et al. 1994a (need to adjust signs for 95% CI; scores reversed so negative is 

worse but 95% CI are all positive values)
B-24

p. 104, Table 5-8: For 3 studies on this page, can’t tell if test scores were ‘adjusted’ (as in 1st half of 

table on previous page) so negative effect estimate means worse performance. Otherwise, looks as if Pb 

is associated with better performance as, e.g., fewer WCST errors, shorter Stroop time?

p. 105: Can’t tell why some studies mentioned briefly in text but results not summarized in any table or 

specifics (Nelson and Espy 2009, e.g.)

p. 110: Table 5-9: WRAML Verbal Learning is not a test of academic performance or achievement. 

Other odd choices in this table which includes KABC at age 4 yrs (or PPVT at age 7 yrs), etc. 

Presumably these are more measures of innate intelligence rather than explicit school achievement 

especially in a 4-year-old? 

p. 110: Table 5-9: Fergusson – what does it mean to leave school with no qualifications?

p. 111: Table 5-9: Leviton for Reading/BTQ, what does RR estimate reflect? 

p. 116: Leviton did or did not adjust for SES/parenting quality?

p. 118-119: In summary language, text sometimes reverts back to using “cognitive function” effects 

while also discussing specifics such as FSIQ, memory/learning, executive function where available 

studies and strength of associations may be more variable....Unfortunately, this does not make full use 

of the outcome specificity that was addressed with new review organization. It is important to maintain 

specific and consistent terminology. 

p. 120: Bone Pb does not contribute to childhood blood Pb to the same degree as in adults because bone 

is such a rapidly growing compartment in children. Still, it is true that concurrent blood Pb may reflect 

past exposures in children but it’s perhaps a more subtle issue than in adults. Also, concurrent blood Pb 

may reflect past exposure in as much as exposures in childhood are correlated over time.

p. 5-128: Table 5-10: looks as if Gao et al. (2008) saw beneficial Pb effects?

p. 5-131: Tendency to be overly broad -- enhanced Pb effect on MMSE in NAS with HFE variant "firm 

conclusions are not warranted" means what? Conclusions about the mechanism behind effect 

modification by HFE cannot be made? Conclusions need to be cautious because of increased type 1 

error with subgroup analyses? These are very different interpretations so wording needs to be clearer on 

this issue.

p. 5-124, Table 5-10: Effect estimates expressed as SD scores are not always specified...it would be 

helpful to label these consistently. 

p. 5-140: Consider how to better categorize response inhibition/impulse and attention (see discussion 

from summary for this chapter re. recommendations for better organization of behavioral measures).

p. 5-148: ‘Not clear how adjustment for parental psychopathology self-report (in studies of attentionrelated behaviors) relates to caregiving quality...’ This was a recommended adjustment because of the 

familial component of some behaviors and the theoretical possibility that parental psychopathology 

could affect caregiving and thus not only be a predictor of outcome but a confounder of the Pb-behavior 
B-25

association. This same comment repeats throughout the sections on behavior-type outcomes (e.g., p157). It's not clear what it means.

p. 4-149: Per last review request, it's good that Wasserman and Canfield null attention studies are now 

included (lower BPb, smaller n, younger age kids; prospective cohorts but looked at concurrent 

exposure)

p. 5-150: Problem with using case-control design (ADHD cases) to study continuous measures of 

behavior is not related to the potential for biased participation by Pb exposure but to the nonrepresentativeness of the distribution of outcome measures. Specifically, it is biased to do analyses 

assessing continuous outcomes related to the outcome upon which case-control selection was based. One 

way to account for this problem and eliminate bias is to do analyses weighted by sampling probability. 

This study is listed relatively high among the cross-sectional ones despite this important limitation.

p. 5-158: There is the potential for reporting bias in parental report of ADHD diagnosis in NHANES. 

But text says, “however...examination of multiple risk factors and outcomes in NHANES 

reduces...likelihood of biased...reporting of ADHD by parents of children with higher Pb exposure”. 

This type of statement repeats throughout the chapter. Issue of parent-reported ADHD diagnosis in 

NHANES has potential biases that are completely unrelated to the breadth of the study’s outcomes and 

risk factors. E.g., regional/SES/cultural differences in dx may correspond to regional/SES/cultural 

differences in exposure risk. Indeed the text goes on to say, "states with higher Pb poisoning have lower 

ADHD rates...and these data reduce potential for confounding of associations in NHANES...by 

regional differences in BPb levels and ADHD prevalences...” The lower ADHD rates in more exposed 

states could be related to diagnostic bias, not true differences in rates. In this case, there could be 

negative confounding by region so that failure to adjust for region could lead to an underestimation of 

Pb-ADHD associations.

p. 179: Frequent comment that cross-sectional studies make “temporal sequence between Pb exposure 

and development of a health outcome uncertain” [approximate quote]. It's even a more basic issue than 

that since the direction of the association is potentially unclear or unknown in a cross sectional study. An 

indeterminant temporal sequence can be a problem in a longitudinal study too depending on frequency, 

timing, and type (blood vs bone, e.g.) of exposure assessment relative to outcome assessment. 

p. 183: “Epidemiologic evidence of Pb-associated schizophrenia is inconclusive...” I would say it’s 

almost non-existent. One cited study used δ-ALA levels, not Pb measures, making interpretation 

difficult. 

p.235: Schnaas et al. 2006 is not reported in Table 5-15 despite text referring to it there

p. 238: It's good that distinction betweem inverted U-shaped dose-response and supralinear D-R is made 

clear as, with the latter, one still sees adverse effects with increasing exposure

pp. 254-55: Public health significance does a good job explaining the hypothetical nature of this analysis 

and defining the assumptions made in estimating changes in proportions of individuals in tails of the IQ 

distribution with Pb-associated shifts in mean IQ. 
B-26

p. 256: In this public health analysis, one may even underestimate the adverse population effect given, 

e.g., at least some evidence of potentially greater Pb-related decrements in children with poorer 

performance (see Miranda et al. 2009 with greater Pb-related decrements in EOG achievement test 

results for kids with lower EOG scores).

p. 264: Use of parental history of psychopathology not intended to measure just caregiving quality (as 

text seems to imply) but is an important potential confounder based on the strong familial component of 

some behavioral disorders. Its role as a confounder would depend on its relation with Pb exposure risk 

which may not be completely clear....

p. 264+: Challenge with evidence for attention-related behaviors is that there may be stronger effects at 

higher Pb levels than relevant currently, more likely seen in older kids (e.g., null Canfield and 

Wasserman studies in younger children (4-5 yrs)). Evidence for ADHD itself is weaker (case-control 

studies)

p. 273: Motor seems smaller body of literature so inconsistencies are more noticeable; +/- agree with 

“likely causal association”

p. 278: Limited studies on adult psychopathology, +/- agree with “likely causal association”

p. 279: Evidence is suggestive for Pb and adult sensory function (limited past evidence now enhanced 

by just one NAS study and weak case-control study) – perhaps would consider it “inadequate to 

determine....”

Cardiovascular effects:

No new specific comments

Renal effects:

p. 421+: It is noted that "treatment" (with antioxidants & chelators) sections have been removed from 

Renal Effects section which is appropriate. (see detailed comments in summary statement)

Immune system effects:

p. 428: Acknowledgement of small epidemiologic evidence base is important to have included. 

However, the statement that recent findings in humans have contributed to increased understanding of 

Pb’s immunotoxicity seems an overstatement. Of the few human studies cited for this health outcome, a 

number were null, or there were substantial inconsistencies among study findings, or exposures were not 

representative of current population levels (in occupational cohorts), or available studies had substantial 

design limitations (e.g., no consideration of key potential confounders, including other occupational 

exposures in Pb exposed workers) or numbers of children in higher Pb-exposed categories was very 

small, or confidence limits on effect estimates were wide (e.g., pp. 462, 481). Thus, the contribution of 

the epidemiologic literature to understanding from the toxicological literature is, at best, limited. In fact 

for some outcomes (e.g., p. 439) even animal studies have limited applicability to human exposure either 

by virtue of exposure route (injection) or level (high). Throughout this section, limitations of the 
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epidemiologic literature is mentioned. Again, the basis for this summary statement at the beginning of 

the section is unclear.

p. 432: In critically reviewing this literature, the text does not clearly prioritize study strengths and 

weaknesses. E.g., perhaps one of the most notable issues with Karmaus et al., is lack of a monotonic or 

biologically plausible dose-response relationship. This observation is made but is enumerated as part of 

a list of other features (adjustment for confounders except SES, likelihood of participation bias, etc.) so 

its relative importance is not discussed. 

p. 433: Language here is unclear – what is meant by the statement that associations of Pb with T cell 

abundance among 6-35-month olds was influence by those with bood Pb > 15 μg/dL? Does it mean 

these more exposed children represented a few influential outliers or high leverage points thereby 

undermining the validity of the findings? Or is influence meant to imply the relationship was only seen 

at these higher exposure levels? These interpretations are very different and the reader is given no clear 

sense of which is meant. More specific analyses and interpretation of such literature is needed here. 

Otherwise, in reviewing the epidemiologic literature, this section provides a list of issues without 

integrating, prioritizing or interpreting the meaning of what’s listed. 

p. 440: It’s good that limitations of cross-sectional epidemiologic studies acknowledged.

p. 452: As per p. 428, to summarize evidence re. Pb and IgE as having “coherence [of evidence] 

between epidemiologic and toxicologic findngs” seems an overstatement especially given limitations of 

epidemiologic literature discussed (e.g., uncontrolled for potential key confounders, lack of mono-tonic 

dose-response, cross sectional design, etc.).

p. 460: A theme that recurs throughout this chapter (in fact, for all health outcomes, not just those 

related to immune function) is that “the potential for selection bias is reduced because multiple 

exposures and outcomes were examined...” Selection bias can arise in a number of ways many of which 

are independent of knowledge of the particular exposure or outcome of interest to a study. Thus, this 

type of argument cannot be used as the sole basis for eliminating possible selection bias. 

p. 480: As per above comments for the introduction to this section (p. 428) the role of collective 

epidemiologic evidence in supporting the causality determination for most immune function outcomes 

("likely causal") seems over-stated. There is some explanation on pp. 486-487 but the logic is unclear. 

E.g., is the determination "likely" because of uncertainty in the human epidemiologic data but certainty 

in the animal/experimental literature? E.g., for "atopic and inflammatory conditions", both 

epidemiologic and toxicologic literature are described as consistently supportive of associations and the 

association is deemed "likely causal". But the same level of causation was also applied to "decrease in 

host resistance" where epidemiologic data was considered "not sufficiently informative". It is unclear 

why these two scenarios are assigned the same degree of causation. 

Hematologic effects:

p. 508: One key characteristic of the epidemiologic literature associating Pb with RBC survival and 

function is that almost all, if not all, human studies involve relatively high exposure levels. E.g., there 

are few, if any, that observed effects with blood Pb < 10 μg/dL and many observe effects at substantially 
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higher levels. Whether this is a limitation of existing literature or reflects a likely threshold for certain of 

Pb's hematologic toxicities is not discussed but should be. 

p. 511: It is useful to point out the likely differential sensitivity of various hematologic parameters to Pb 

with, e.g., ALAD levels perhaps being more sensitive than other indices. 

p. 514: The majority of childhood studies reviewed had mean blood Pb<15 μg/dL (range 8-22); these all 

represent relatively high exposures by today's U.S. standards. 

p. 516: A causal relationship of Pb with decreased RBC survival and function seems appropriate; the 

challenge the ISA does not clearly address is whether that relationship is causal at typical current 

population blood Pb levels. 

Table 5-35: Blood Pb levels in many of the described epidemiologic studies are relatively high 

(children<15, occupational cohorts < 20 μg/dL); there are few studies in the current blood Pb range. Use 

of the term "relevant" levels could be misleading in this context.

Reproductive and developmental effects:

General: 

(1) It is good that table summaries of epidemiologic literature now include sample size and confounder 

information (some of which was missing from previous drafts). This applies to other sections as well.

(2) Analogous to hematologic effects, male reproductive effects in the epidemiologic literature are 

strongest at relatively high blood Pb levels. A clearer synthesis of findings specific to the few studies 

with low level blood Pb would be helpful. 

Other organ systems:

p. 656: The summary of Machida et al. (2009) is a bit confusing. As a cross-sectional analysis, this 

studied modeled predictors of blood Pb including biomarkers of bone turnover and bone density. 

Surprisingly, bone mineral density was positively associated with blood Pb, the opposite of the 

association observed in studies described earlier in this section. However, it is important to keep in mind 

that the modeled analysis was not looking at how well Pb predicted the bone measures but the reverse 

direction of association. This point is not clear in the paragraph and should be. 

p. 659: The "likely causal" determination for effects on bone and teeth may be a bit optimistic. For bone, 

there is only one reasonably strong epidemiologic study (Kahlil et al. 2008). The remaining referenced 

epidemiologic studies for adult bone measures are all cross sectional. The likelihood of reverse causality 

in a cross sectional analysis (with blood Pb as the exposure marker) is substantial for this health 

endpoint. Specifically, higher bone turnover and associated declines in bone density would cause 

increased Pb mobilization from bone and therefore higher blood Pb. Thus, inferences about causality for 

bone density/turnover-related health outcomes are based on only one study (there was not epidemiologic 

assessment of these associations for the 2006 Pb AQCD). Indeed, because of the unique nature of these 

bone outcome measures, even longitudinal studies are susceptible to reverse causality as bone 

metabolism changes gradually over time and thereby could affect blood Pb levels prior to outcome 
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assessment. A more conservative approach to causal determination, at least for this outcome within the 

"other organ system" section, is recommended. 

Cancer: 

p. 700: As in the 2nd draft ISA, the designation of "likely causal" is based on strong toxicologic 

evidence without consistent epidemiologic evidence. This determination is further complicated by two 

factors that are discussed in this section but not explicitly mentioned in the concluding statement. First, 

most of the supportive toxicologic evidence is likely (blood Pb equivalents are not given) at relatively 

high doses compared to current U.S. population exposures. Second, many of the mechanistic studies 

supportive of the toxicologic findings use Pb chromate so it is not possible to determine whether 

observed effects are secondary to Pb vs. chromate, a known human carcinogen. Thus the role of Pb as a 

probable human carcinogen (per IARC, e.g.) at exposure levels relevant to current population exposures 

is unclear. Some discussion/acknowledgement of these uncertainties in the concluding paragraph would 

be useful.
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Dr. Michael Kosnett

The following are comments on the 3rd external draft Integrated Science Assessment for Lead (February 

2012) prepared subsequent to CASAC Lead Review Panel meeting of February 5-6, 2013. These 

comments focus on the Preamble, Executive Summary (Chapter 1), and Integrative Summary (Chapter 

2), but also include comments on Health Effects (Chapter 5).

The revision to causation determination in the 3rd draft ISA that now separately weighs the evidence for 

specific health endpoints rather than for major outcome categories/organ systems as had been the case in 

the 2nd draft ISA is a major improvement. 

Two key summary tables in Chapter 2 are Table 2-2 (Summary of causal determinations between 

exposure to Pb and health outcomes) and Table 2-8 (Summary of evidence from epidemiologic, animal 

toxicological and ecological studies on the effects associated with exposure to Pb). Blood lead level 

(BLL) associated with the causal determination is not mentioned at all in Table 2-2, and only 

sporadically in Table 2-8, a less than optimal approach given that NAAQS are particularly concerned 

with the low levels of environmental exposure prevalent today. It would be desirable for Table 2-8 to 

consistently note the blood lead concentration associated with the health endpoint under consideration. 

In like manner, the blood lead range highlighted in the table should be consistent with those mentioned 

in the summary sections of Chapter 2. An important example of inconsistency in this regard involves the 

discussion of “Attention-Related Behavior Problems” on page 2-17, and the corresponding second row 

of Table 2-8 (page 2-78). The narrative on page 2-17 (Section 2.6.1.1) predominantly mentions BLLs 

>10 μg/dL (the lowest mentioned was 6.8 μg/dL). However, the second column of the second row of 

Table 2-8 focuses on lower blood lead levels, stating: 

Recent studies in children continue to support associations of blood Pb levels with inattention 

and hyperactivity in children ages 8-17 years. In several recent studies, associations were found 

with concurrent blood Pb in populations with mean blood Pb levels 1–5 μg/dL; however, the 

influence of higher past Pb exposures in these older children cannot be excluded. A few casecontrol studies found higher concurrent blood Pb levels in children with ADHD.

With respect to attention-related behavior problems in children, I think it would be prudent to revise or 

at least qualify the causal determination in Table 2-2 and page 2-17, to include additional relevant 

limitations in Table 2-8. Table 2-8 (in contrast to table 5-11) fails to note the inconsistency of the 

findings in studies conducted in children with BLL < 10 ug/dL. In particular, the important weight of the 

negative (i.e. nonsignificant) findings in prospective studies by Burns et al (1999, in boys), Wasserman 

et al (2001), Canfield et al (2003), and Chandramouli et al (2009) is not given adequate emphasis.1In 

addition, the summary narrative in Table 2-8 and the narrative in Section 2.6.1.1 (page 2-17) could note 

that an important caveat in derivation of a causal determination remains the inability of any study to date 

to effectively control for parental behavioral psychopathology. This is a major limitation, given that 

many aspects of behavior (such as attention disorders) are highly heritable traits.2This is acknowledged 

 

1 Wasserman et al (2001) is incorrectly classified as a cross-sectional study in Table 5-11. Canfield et al (2003) is classified 

as a cross-sectional study, although it is more likely a prospective study given its prospective design, and the observation that 

serial blood lead measurements conducted on the subjects averaged less than 10 ug/dL at multiple time points

2 The narrative in section 5.3.3 repeatedly notes that a limitation of the studies of behavior outcome in lead exposed children

is the failure to control for what is termed “parental caregiving quality.” This feature should be more clearly explained (e.g. 
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briefly in the narrative at the top of page 5-159, which represents an improvement over prior discussion 

of this aspect of confounding in the 2nd draft ISA. In like manner, the more detailed and balanced 

discussion in 5.3.16.2 (Evidence for Attention-related Behavioral Problems in Children, p 5-263) 

represents a considerable improvement over the shorter discussion of causation in section 5.3.13.2 of the 

2

nd draft ISA. For example, the paragraph beginning on page 5-265, line 25 specifically acknowledges 

the limitations of the studies that have associated lead exposure with ADHD, stating, “Because of the 

cross-sectional or case-control design of studies and lack of consideration for potential confounding by 

parental caregiving quality or attention-related problems, the ADHD evidence is not a major 

consideration in drawing conclusions about the relationship between Pb exposure and attention-related 

behavioral problems.” It is problematical, however, that mention of such limitations and inconsistencies 

does not appear in the integrated summary in Chapter 2. 

As currently written, the integrated summary in Chapter 2 concludes that there is a causal relationship 

regarding “attention related behavioral problems”, just as it concludes there is a causal relationship 

regarding cognitive function deficits. However, Chapter 2 lacks a succinct acknowledgement that the 

strength of the evidence for the latter is considerably stronger than it is for the former, and that with 

respect to BLLs < 10 of contemporary concern, the epidemiological data is consistent and adequately 

adjusted for confounding for cognition, but not for attention -related behavioral problems3. I recommend 

that the causal determination for this endpoint conclude that the weight of the evidence supports a causal 

relationship at BLL > 10, but is “suggestive of a causal relationship” at BLL < 10.

An entirely new section that appears on page 2-76 entitled “2.9.7 Ecological Effects and Corresponding 

Pb Concentrations” merits reappraisal and revision. The opening statement reads: 

“There is limited evidence to relate ambient air concentrations of Pb to levels of deposition onto 

terrestrial and aquatic ecosystems and to subsequent movement of atmospherically-deposited Pb 

through environmental compartments (e.g., soil, sediment, water, biota).” 

This would appear to be somewhat at odds with the paragraph on page 2-75 that reads:

“There is adequate evidence that proximity to areas with Pb sources, including areas with large 

industrial sources, is associated with increased Pb exposure. Relatively high concentrations of 

ambient air Pb have been measured near sources, compared with large urban areas without 

sources and high Pb exposures have been documented near Superfund sites.”

 

the extent to which it may be measured by the HOME score). In addition, literature which establishes “parental caregiving 

quality” as a predictor of attention performance in children should be cited. The narrative in section 5.3.3 continues to 

characterize the studies by Cho et al, 2010, and Nicolescu et al, 2010 as having controlled for “parental psychopathology.” 

However, as noted in my comments on the 2nd draft ISA, a critical review of these studies lends considerable doubt that these 

studies did so in an adequate manner. In the Korean study by Cho et al (2010), which in fact failed to report a consistent 

positive association between lead and indices of ADHD or attention in most of the measures that were examined, the 

adjustment for parental psychology consisted of having the parents of 590 children note in a questionnaire whether they ever 

had ADHD or any other neuropsychiatric disorder. Implausibly, less than 5 percent responded affirmatively. Moreover, the 

variable was not included the multivariable models. In the Romanian study by Nicolescu, parents were asked by telephone 

interview whether either had been diagnosed with “psychological/psychiatric problems.” However, the extent of positive 

response was not reported, and even though “family psychopathology” was the factor with the strongest bivariate correlation 

with child ADHD rating by the parents, it was not included in the multivariable models of child attention or ADHD (see 

caption to Figure 2 in Nicolescu et al, 2010).

3 The data linking BLL > 10 to an array of attention-related behavioral problems are more consistent.
B-32

Further discussion at the CASAC lead review panel meeting indicated that compared to the effect of 

lead on humans, the impact of lead on nonhuman biota and ecosystems is indeed limited. It might be 

worthwhile for the ISA to explicitly note that humans constitute the ecological receptors for which lead 

toxicity has been most extensively characterized.

Although the 3rd draft ISA has appropriately downgraded the determination in the 2nd draft ISA that 

reduced renal function is “causally associated” with low-level environmental lead exposure, the current 

classification of the relationship as a “likely causal relationship” may still represent an overstatement. 

The summary discussion of effects in section 2.6.3 (page 2-24) continues to include the statement: 

The epidemiologic evidence from prospective and cross-sectional studies consistently 

demonstrates a relationship between higher blood Pb level and reduced kidney function (e.g., 

lower creatinine clearance, higher serum creatinine, and lower GFR) in nonoccupationallyexposed adults with mean concurrent or baseline blood Pb levels of 2-10 μg/dL [emphasis 

added].

As was pointed out in the review of the 1st and 2nd draft of the ISA, this is incorrect and should be 

revised. The large general population study by de Burbure et al (2003) found no significant association 

between blood lead and serum creatinine or other biomarkers of renal function in multivariable 

regression models. In the Normative Aging Study (Tsai et al, 2004) there was no significant association 

between either blood lead or bone lead and serum creatinine in subjects without hypertension or 

diabetes. In addition, it is important to consider that many epidemiological studies of subjects with a 

range of occupational lead exposure have not observed an inverse relationship between blood lead and 

reduced renal function, including studies that have actually found a positive association between blood 

lead and renal function (Roels et al, 1994; Weaver et al, 2003a).

Section 2.6.3 also includes the statement: 

“Studies in animals with long-term exposure to Pb report mixed evidence for Pb-induced kidney 

dysfunction and histopathological changes, including tubular atrophy and sclerosis at relevant Pb 

blood and exposure levels. [Emphasis added].

However, as indicated in the studies cited in Chapter 5, that the animal evidence for toxicological effects 

of lead at doses comparable to human environmental exposure are limited. In no animal studies or 

human studies have lead-related pathological impacts or biomarkers of renal damage been observed 

when lifetime BLL has remained less than 10 ug/dL. The section on “Reverse Causality” (section 

5.5.2.4), would benefit from a more balanced presentation that gives more prominence to the plausibility 

of this hypothesis as an explanation for the association between low level lead exposure and markers of 

renal dysfunction. Given the inconsistent observations in environmental and occupational studies, the 

lack of a demonstrable pathological mode of action for lead on renal function at low dose, and the 

plausibility of reverse causation, I recommend that the association between low level environmental lead 

exposure and renal dysfunction be designated as “suggestive of a causal relationship” rather than “likely 

to be a causal relationship.”

Revision of section 2.9.1 (Public Health Significance) to focus on cognitive effects in children and 

cardiovascular effects in adults is appropriate and prudent, because these are two major public health 

endpoints for which the causal effect of low-level environmental lead exposure is well established. 
B-33

Regarding the sentence in section 2.9.1, page 2-63, line 11 that reads: “Even a small relative risk for a 

health effect that is highly prevalent in the population can translate into a large increase in the number of 

clinical cases”-- this sentence is correct, but it appears to be out of context, because the discussion by 

Weiss et al in that paragraph does not involve relative risk.

Re Section 2.9.2Air-Pb-to-Blood-Pb Relationships: The prior CASAC lead panel review had urged the 

draft ISA to critically identify which of the relationships identified in Table 2-6 were most optimal for 

quantitative risk assessment. It would be helpful if this assessment were specifically summarized in this 

section. Some of the critical analysis of these relationships in the draft Policy Assessment might be 

helpfully recapitulated in Chapter 2 of the ISA>

The discussion on reversibility and persistence of neurotoxic effects of Pb in section 2.9.5(page 2-71) 

might note that some prospective studies of lead exposed children have reported that concurrent blood 

lead is a better predictor of IQ than early childhood blood lead, and that declines in blood lead during 

childhood are associated with improved cognition (cf Bellinger et al, 1990; Ruff et al 1995; Liu et al 

2002; Chen et al 2005; Hornung et al, 2009). However, there is uncertainty regarding the extent to which 

such improvement represents biological reversibility of lead-related effects, the influence of enrichmentrelated intervention, or the development of compensatory mechanisms.

It is appropriate that the 3rd draft of the ISA has deleted reference (in Section 2) to fluoridation as a 

factor that potentially increases the risk of Pb-related health effects.

Section 5.4.2.2 (Toxicology) reviews studies in animals that have examined the relationship between 

blood lead and blood pressure. Only two studies purport to provide data on the blood lead / blood 

pressure relationship in animals whose peak blood lead concentration was less than 10 μg/dL – Tsao et 

al, (2000) and Nakhoul et al (1992). It is recommended that the narrative in this section express a note of 

caution in interpreting the mean blood lead concentrations reported for the low exposure groups in these 

studies, i.e. 2.15 μg/dL in Tsao et al (2000) and 5.3 μg/dL in these two studies, both of which were 

reportedly associated with exposing the rats to 100 ppm lead in drinking water for 8 weeks. These blood 

lead concentrations appear low in comparison to the dose of lead reported. In the case of Tsao et al, the 

value of 2.15 μg/dL implies a doubtful level of precision, given that the limit of quantitation of the 

authors’ analytical technique (electro-thermal atomic absorption spectroscopy) is generally 2 to 3 μg/dL. 

It may be noted that the laboratory of Cory-Slechta and colleagues at the University of Rochester, which 

has published numerous studies in lead exposed rats, has found that feeding rats 50 ppm in drinking 

water yields blood lead concentrations of 10 to 15 μg/dL (Virgolini et al, 2008a). 

Additional comments:

Page 1-2, line 20: A national “average” Pb concentration in soil of 18.9 mg/kg is cited. Given that the 

distribution is likely to be lognormal, can a geometric mean value be cited instead of (or in addition to)

an arithmetic mean?

Page 1-4, line 12: The statement, “Overall, blood Pb levels have been decreasing among U.S. children 

and adults for the past twenty years” could actually be revised to state that levels have been decreasing 

for the past 35 years.
B-34

Page 1-4, line 15: Among children age 1-5, 95th percentile BLL in NHANES 2009-10 is 3.4 ug/dL, not 

4.0 ug/dL. [See NCEH (CDC) Fourth National Exposure Report, Updated Tables, September 2012, 

p141]

Page 2-16, line 26: The following sentence needs editorial revision for better clarity:

The associations consistently found in prospective studies of children with adjustment for Social 

Economic Status (SES), parental education and caregiving quality for associations with various 

indicators of cognitive function and the biological plausibility provided by evidence in animals 

for impairments in learning, memory, and executive function with relevant Pb exposures and 

evidence describing modes of action is sufficient to conclude that there is a causal relationship 

between Pb exposure and decrements in cognitive function in children.

Page 2-21, line 16, and page 2-22 line 16: grammatically revise sentence for clarity.

Page 2-64, line 20: The following sentence could be revised to enhance clarity. It now reads: 

The high correlation between blood pressure and clinical cardiovascular outcomes combined 

with the high prevalence of cardiovascular disease in the U.S. adult population translate into a 

large increase in the prevalence of conditions in the population.

Page 2-69 The following sentence starting on line 18 should be corrected to indicate that HR is the 

abbreviation for “hazard ratio”, not “heart rate”:

In the NAS cohort, C-R relationships between bone Pb and mortality were approximately linear 

for patella Pb on the log (heart rate [HR]) scale for all cardiovascular disease (CVD), but appear 

nonlinear for IHD (Weisskopf et al. 2009).

Page 2-70: Sentences near bottom of page and continuing to top of next page require editing for clarity.

Page 5-376, line 9: Replacement of the word “concurrent” with the word “current”, as was the case in 

the 2nd draft ISA, is recommended, as the word “current” expresses the meaning more clearly and 

accurately. 
B-35

Dr. Roman Lanno

Comments on Chapter 7 – Ecological Effects of Lead

The 3rd draft of the Ecological Effects of Lead in the ISA is well written and an excellent improvement 

of the previous draft. In particular, the tables at the end of the chapter (Tables 7-3 to 7-6) organize a 

tremendous amount of data in a very accessible manner. This allows ready reference to the key data in 

each of the new manuscripts reviewed for this chapter. The standardization of units (e.g., mg/L, mg/kg) 

facilitates easier comparison of exposure doses in the studies. More importantly, it’s easy to see where 

exposure dose is only nominal and when it is actually measured. This makes it fairly simple to see which 

studies are of sufficient quality to actually use as primary data for causal analysis. 

The chapter is logically organized into terrestrial, freshwater, and saltwater sections, with consistent 

organization within sections. Breaking out freshwater and marine environments and justification re: 

bioavailability was very good. Although this leads to some repetition within sections, it is still easy to 

read and follow. 

Distinction between data used in causal determination and environmental relevance for determining the 

secondary standard. Nominal, hydroponic, culture medium, etc.

Addition of a figure summarizing the data available on exposure levels and responses, similar to that for 

the Pb EcoSSL. One problem would be standardizing the data without strict data quality criteria. 

Distinguish between nominal and measured.

How should hydroponic data be handled? I suppose it can be used in causal analysis but not in 

extrapolation to soils.

Page 7-9, line 4 – What is meant by “Pb evaporation”? Do you mean Pb volatilization? To my mind this 

is not an important fate process for Pb.

Page 7-14, Table 7-2 – In the Pb concentration column, under vegetation, what is meant by “Grasses: 

31% (percent of soil Pb in grass)”? Is this (Pb concentration in grass/Pb concentration in soil) x 100?

Page 7-18, line 15 – change “later” to “latter”

Line 31 – What is meant by “relative bioavailability”? Was bioavailability actually measured in this 

study or just sequential soil extracts? Relative bioavailability has a very specific meaning as defined in 

the bioavailability schematic, Fig 7-2. Please clarify.

Page 7-21, lines 7-8 – What are the simulated soils or soil components?

Page 7-22, line 19 – Change “). Modifying” to “) modifying”

Page 7-25, line 5 – What is meant by “organic content”? Is this organic matter content or organic carbon 

content? This needs to be specific since they are different measurements and needs to be addressed 

throughout the terrestrial section.
B-36

Line 29 – “near stationary sources” sounds like the sources are almost stationary. Perhaps “nearby 

stationary sources” would be better

Page 7-31, line 20 – Are these really metal-contaminated soils? These concentrations are around 

background levels for many soils.

Line 30 – Specific BCFs – Were these actually ratios of metal levels in plant tissues to soil pore water?

Page 7-33, line 12 – change “determined” to “observed”

Page 7-36, line 8 – Anecic worms usually burrow up to 2 m not 6 inches. Use SI units.

Page 7-40, line 22 – Change “vegetative” to “vegetation”

Line 35 – If godwits are insectivorous, then why are they eating worms? Perhaps vermivorous is more 

appropriate.

Page 7-46, lines 31-32 – How is it possible to compare hydroponic Pb concentrations to Pb 

concentrations in soil?

Page 7-50, lines 28-29 – This seems somewhat odd – Pb doesn’t usually induce metallothionein 

production.

Page 7-52, line 37 – Drosophila should be italicized (Drosophila). Genus names are always italicized. 

This needs to be checked throughout the chapter as there are many other places where genus names are 

not italicized.

Page 7-56, line 3 – change “2,2” to “2.2”

Page 7-60, lines 11-12 – What is meant by this sentence – “Because toxicity is influenced by 

bioavailability of soil biogeological and chemical characteristics”?

Page 7-63, line 17 – Change “type” to “types”

Line 18 – This is not clear as to what this soil Pb concentration is

Line 26 – Should the units be mg Pb/kg?

Page 7-67, line – “physiochemical” means physiological/chemical – should be physicochemical

Page 7-74, line 6 – change “rather a larger” to “rather than a larger”; “whole” to “entire”

Lines 15-16 – What is meant by “the presence of effects at elevated exposures implies effects at lower 

exposures”?

Page 7-77, line 15 – change 2,08 to 2.08

Page 7-79, lines 25-26 – What is a “10 day nominal exposure”? Do you mean exposed to nominal Pb 

concentrations?

Page 7-83, line 19 – change “were” to “was”

Line 22 – again, the “nominal” issue
B-37

Page 7-88, line 3 – change “estimate” to “estimates”

Line 7 – add parentheses – (Pb 0.001 and 0.01 mg Pb/L)

Page 7-95, line 26 – change “Kessleri” to “kessleri”

Page 7-96, line 26 – change “with” to “to”

Lines 28-34 – this section should be in the terrestrial section

Page 7-103, line 36 – delete “can”

Page 7-105, line 4 – What is meant by “saturation”?

Page 7-110, line 26 – change to “on the tissue distribution of Pb in freshwater organisms”

Page 7-114, line 18 – By “media” do you mean water?

Page 7-125, lines 18-19 – What is meant by “selective pressure on plants”? Is this in an evolutionary 

sense?

Page 7-151, line 18 – change “owing the” to “owing to the”

Page 7-153, line 1 – What are “high molecular weight cationic Pb species”? Is this Pb bound to 

proteins?

Page 7-219 – What medium were nematodes exposed in? Guo et al. 2009

Page 7-221 – change “quails” to “quail”
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Mr. Richard L. Poirot

Comments on Chapter 3

Chapter 3 is much improved, with revisions responsive to previous comments. The new discussion of 

alternative sampling methods (and desired and/or feasible Pb sampling characteristics), the additional 

presentation of Pb size distribution data, and a better synthesis between Chapter 3 and 4 - are all notable 

improvements. The red-line track-changes version was extremely helpful to the review process, as was 

the HERO database, although I encountered frequent “traffic delays” with the latter, which were 

irritating but not debilitating. All my comments are minor, and I don’t think it would be necessary to see 

another revised draft of this chapter.

P 3-1, lines 9-11: This sentence could be deleted since it doesn’t add any useful information, since you 

later provide a nice summary of chemical forms (Table 3-1) from the 2006 CD, and since you 

summarize many post-2006 studies that do provide added information on chemical forms (and/or 

chemical associations) from various emissions sources on pp 3-10 through 3-17, and elsewhere in the 

ISA.

P 3-2, line 33 and 3-3, line 1: Is resuspended soil Pb included in the “Miscellaneous” category (and if so 

could it be mentioned here)? 

P 3-6, lines 3, 4: Could these 182 sources and their emissions be listed in an appendix?

P 3-9, line 4: It might be informative to know the destinations and end uses of the increasing Pb exports. 

P 3-14, line 9: Change “vary” to “varies” or “can vary”.

P 3-15, lines 5-13: These large differences in Pb emissions (10% at 500 oC to 85% at 850 oC) have 

important implications for the partitioning of Pb in smoke vs. ash from residential wood stoves – for 

which maximum combustion temperatures typically only reach the middle of this range. Subsequent Pb 

exposure routes could also be quite different, as wood stove ash is often intentionally deposited in 

gardens or on icy driveways. Conversely, wild fires may reach much higher temperatures, burn the 

uppermost humic soil layers, etc.

P 3-16, line 33: If 2.7 to 5% of the mass of all wheel weights were deposited to the road daily (and 

assuming tires are periodically rebalanced), then 100% of wheel weights would be lost in a month or 

less. I don’t believe it.

P 3-17, line 5: Does “disbursed” mean emitted to the ambient air?

P 3-17, lines 18, 19: Fauser’s 90% of tire wear particles < 1 micron is not logical, although certain kinds 

of non-spherical particles may have aerodynamic properties that might be unexpected from their 

physical “diameters”.

P 3-17 and 3-18 in general: This is a very interesting discussion, but doesn’t provide much confidence 

that the most important source(s) of roadway-related Pb emissions (and particle sizes) are very well 
B-39

known (wheel weights, brake wear, tire wear, unleaded gas, diesel, road line paint, historically deposited 

roadside Pb, etc.).

P 3-20, line 13 – and elsewhere: The terms “loading” and “loading rate” can be somewhat confusing and 

might benefit from some explanation here or somewhere. I assume that in this case we’re talking about 

“loading” units something like μg Pb/m2in dust which is extracted from these various surfaces, while 

“loading rate” (used elsewhere) has units like μg Pb/m2/yr. How surface dust concentrations, loading 

loading rate, and flux are measured – and in particular what particle sizes are captured in such sampling 

– would be of interest.

P 3-24-3-28: The sections on transport and deposition are clearly written and informative. You make a 

compelling argument for the decreasing solubility of Pb (and importance of larger particles) as fine 

fraction Pb-containing particles interact with and are incorporated onto coarser (primarily crustal) 

particles. A potentially important but missing part of the story relates to the fate of soluble Pb in wet 

deposition as it percolates through soil. If Pb remains in solution, it would tend to pass through surface 

soil layers and thus be unavailable for re-suspension, but if it is quickly bound to surface organic matter 

or alkaline crustal compounds, it would be more readily available for re-suspension or direct uptake and 

ingestion. Potentially also historically deposited Pb on/near the soil surface may be removed after years 

of relatively Pb-free but still acidic precipitation. There is more detailed discussion of this later in 

section 3.3.3.3, but it isn’t focused at all on potential re-suspension from urban roadside or other nearsource soils. Some discussion of the fate of (previously) soluble Pb in soils would be informative in or 

prior to Section 3.3.1.3. See for example: Maclean and Bledsoe (1992), Yobouet et al. (2010).

McLean, J. E. and B. E. Bledsoe (1992) Behavior of Metals in Soils, U. S. EPA Ground Water 

Issue, EPA/540/S-92/018. http://www.epa.gov/superfund/remedytech/tsp/download/issue14.pdf

Yobouet Y. A., K. Adouby, A. Trokourey and B. Yao (2010) Speciation in contaminated soils, 

International Journal of Engineering Science and Technology, Vol. 2(5), 802-812.

In addition, details on spatial gradients in soil or dust or biota Pb (rates at which concentrations decline 

with distance) near current or historical sources could be informative for exposure assessments or to 

guide future air monitoring approaches.

P 3-27, line 1: Add “on” after “focused”. 

P 3-27, lines 15 and 16: You could delete “For example”, since it doesn’t follow the preceding sentence.

P 3-27, line 29: The sentence meaning and context are unclear.

P 3-27, lines 30-35: You could change “at” to “near” in line 3, as the upper bound Pb Vd reported in the 

2006 CD was 1.3 cm/s. Also, the 12-17 mg/m2-year dry Pb deposition reported here for Tokyo Bay was 

not more than 10 times the upper bound of the range reported in the 2006 CD - which included 8.4-14 

mg/m2-year dry Pb deposition reported by Yi et al., (2001) near Lake Michigan for 1993-1995 (see p. 2-

57 of the 2006 CD).

P 3-28, lines 12 and 13: You could delete “transition”, as Pb is not a “transition metal”.
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P 3-28, lines 15, 16: Emissions, concentration and deposition of coarse particles could be driven by

diurnal changes in wind speed – regardless of whether the source was anthropogenic or natural. 

Conversely, there are many anthropogenic sources that operate at night.

P 3-29, lines 7, 12 and 13: An increase of 0.84% in air Pb for each 1% increase in airborne soil is not 

necessarily “minor”, as it suggests that if airborne soil concentrations were doubled, airborne Pb 

concentrations would nearly double as well (increase 84%), and that soil is the predominant source of 

airborne Pb (I must be missing something here).

P 3-31, lines 30, 31: This has important implications for the spatial representativeness of “air” samples 

containing particles larger than 20 μm, as well as for the design of an alternative (to hi-vol TSP) Pb 

sampler.

P 3-34, lines 21-23: Although you refer to a “nominal dissolved phase”, you might put “dissolved 

phase” in quotes to emphasize that there may well be particles passing through a 0.45 μm filter – for 

example as you report from observations of McKenzie et al. (2008) on p 3-41, line 3.

P 3-40, lines 3-10: Its not clear what you mean by “uniform” size distribution. In line 3, do you mean 

“Pb in PM” or just “PM” in general, and do you mean that the Pb concentrations were similar (uniform) 

in particles of different sizes? If so, this implies that the Pb is present throughout the larger (and smaller) 

particles, rather than on the surface of the particles or more concentrated in/on the smaller particles.

P 3-40, line 22: This road paint contribution of 46% of Pb in heavy traffic dust sounds important, and 

should be mentioned in Section 3.2.2.6.

P 3-41, line 16: How is “dissolved” defined here?

P 3-60, line 1 and elsewhere: The term “TSP” is used inconsistently in this section - with several 

different meanings - and would benefit from clearer definition(s) or alternative nomenclature. In line 1 

the verbal definition (and origin of the acronym) is given as “total suspended particles”, a hypothetical 

and un-measurable concept. “TSP”, in the context of the Pb-TSP FRM basically means “whatever the 

Hi-Vol TSP sampler captures”. “TSP” is also used (incorrectly) to describe the “mass median 

aerodynamic diameter” in Table 3-3 and in subsequent discussion of several of the current alternative 

sampling methods to describe what the Texas A&M Lo-Vol TSP sampler, the UIUC Isokenetic TSP 

sampler, and the Airmetric MiniVol collect – although these samplers all have particle cut size 

characteristics which are different from each other and from Hi-Vol TSP sampler. A fourth different 

meaning of “TSP” is implied by the term “revised TSP sampler” – meaning a yet to be developed 

alternative to the Hi Vol , which if it were preferable, would clearly not collect the same TSP as the Hi 

Vol, or other currently available so-called TSP samplers.

What if you had a few lines or text box up front, (and made minor changes in the text and tables) 

something like: 

TSP is an acronym for Total Suspended Particles, an hypothetical and un-measurable concept. In 

this chapter, we use the term TSP to mean “particles with the size characteristics of those 

collected by the high volume (Hi Vol) TSP sampler” and Pb-TSP to mean “Pb in particles 

collected by the Hi Vol TSP sampler”. When referring to alternative existing or future samplers 
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with an upper 50% particle cut size larger than 10 microns, but not identical to the Hi Vol TSP 

sampler, we use the term “TSP” in quotes.

PP 3-63 and 3-64, Table 3-3: You could change the 4th column heading to something like “Particle Size 

Characteristics” and when TSP is indicated for samplers other than the hi-vol, put “TSP” in quotes.

P 3-68, lines 2-8: This (surrounding paragraph) is an excellent summary, and the points raised here - that

the relevant size distribution for ambient sampling is smaller than that of the settled dust, and that 

particles > 20 μm are too large to be transported more than a few seconds – indicate that there may be 

some convergence of “what’s desired” for Pb-PM sampling, and “what’s feasible” for filter-based 

sampling with size selective inlets.

P 3-91, lines 10-18: Could you add a bit more detail on how far upwind and downwind these sites are?

P 3-97, lines 15-18 (and Table 3-8): This is a good addition from last draft. The description on p 3-97 

(used data from sites with at least 30 paired, collocated samples where both were above MDL) is 

different from the note at bottom of Table 3-8, which says “... comparisons were limited to monitors 

where all samples were above the MDL...” The same note is also used in Table 3-26 in the appendix on 

page 3-205. I assume the Table notes aren’t quite what you mean, and what you do mean is something 

like “...comparisons were limited to samples from sites which had at least 30 pairs of collocated 

samples, with both samples above the MDL and where both monitors reported data at STP...”

P 3-107, lines 1-4 and Figure 3-25: I notice that Figure 3-25 has changed from the previous draft (in 

which K had the second highest correlation with Pb, after Zn, and am just curious why the figure 

changed? Also, in listing the elements with low to moderate correlations (p 3-107, lines 2-3), it seems 

somewhat arbitrary to exclude K which is barely lower than Br and is followed by a much larger step 

reduction in correlation with K+. It can also be noted in the seasonal correlation plots in Figures 3-66 

and 3-67 of the Chapter 3 Appendix, K exhibited the 2nd, 3rd, 4th and 2nd highest correlations with Pb (in 

Winter, Spring, Summer and Fall, respectively) – and so it seems odd that it would have only the 8th

highest correlation on an annual basis. 

These relatively high correlations of Pb with K and K+- as well as with EC & OC – suggest a possible 

influence from wood smoke. Fireworks are another occasional large source of K, OC and EC which 

have been identified as an occasional Pb source (more so in past years, but occasionally in recent 

measurements). See for example:

DePaolo, D.J. (2012) Using Pb and Sr Isotopes to Assess Asian Aerosol Impacts in Urban and 

Interior California, Final Report to the California ARB and the California EPA, Contract No. 07-

318. http://www.arb.ca.gov/research/apr/past/07-318.pdf

Licudine, J.A., H. Yee, W. L. Chang and A. C. Whelen (2012) Hazardous Metals in Ambient Air 

Due to New Year Fireworks During 2004–2011 Celebrations in Pearl City, Hawaii, Public 

Health Reports, Volume 127, 440-450. http://hawaii.gov/health/laboratories/sld-forms/np2012_PHR_127_4_Licudine.pdf
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Liu, D-Y. D. Rutherford, M. Kinsey and K.A. Prather (1997) Real-Time Monitoring of 

Pyrotechnically Derived Aerosol Particles in the Troposphere, Analytical Chemistry, 69 (10), 

1808-1814.

Perry, K. D. (1999): Effects of Outdoor Pyrotechnic Displays on the Regional Air Quality of 

Western Washington State, J. Air & Waste Manage. Assn., 49:2, 146-155.

In addition to wood smoke and fireworks, soil is another well-known source of K in PM2.5

measurements. The fact that K correlates better with Pb than other soil elements do suggests that other 

sources of K and Pb are important, but possibly the consistently high Pb:K correlations in all seasons 

indicates that soil, smoke and fireworks may all be occasional contributors.
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Dr. Joel G. Pounds

Comments on Chapter 4 – Exposure, Toxicokinetics, and Biomarkers 

General Comments

The third draft of this chapter is very well organized and well written. I am particularly pleased with the 

lucid description of topic strengths, weaknesses, and limitations found in the introductory and 

concluding paragraphs of many sections. The authors of Chapter 4 have done a very nice job of 

explaining and applying both mechanistic and empirical models to illustrate scenarios of changing 

exposure levels, duration of Pb exposure, and other Pb exposure scenarios to the interpretation of blood 

and bone Pb levels as biomarkers of Pb exposure. 

I believe the principle purpose of computational models is to organize existing data and knowledge. The 

current mechanistic models are out-dated and fail to organize much information that we know to 

modulate the relationship between exposure and blood Pb. The Chapter 4 authors should anticipate the 

next ISA iteration and the inadequacy of the current mechanistic model to accurately simulate Pb 

exposure levels appropriate to 21st century Pb exposure. All existing mechanistic models are 

parameterized based on blood, tissue, or skeletal Pb levels associated with Pb exposure during periods of 

much higher levels of Pb exposure. Moreover, the mechanistic models are poorly calibrated to growth, 

exposure patterns, etc. of adolescents. The last ten or fifteen years has seen numerous studies that 

incorporate blood or urine biomarkers of bone formation with dual energy x-ray absorptiometry 

(DEXA) characterization of bone mineral density, especially during ages of skeletal growth or aging. 

These data provide a significant opportunity to improve the biological accuracy and relevance of 

mechanistic models for individuals and populations. 

Page 58. The review and analysis of the potential contribution of ALAD alleles to blood Pb levels is fair 

and complete. However, this paragraph needs to draw a more explicit conclusion because ALAD 

polymorphisms are the most widely recognized genetic determinants of blood Pb. This conclusion may 

be little more than the contribution of ALAD alleles is inconclusive and the underlying causes of 

discrepancies among studies remains to be elucidated. 

Specific Comments

Page 4-41 – Bioaccessibility is a key factor in defining bioavailability of Pb. The ISA authors might 

consider speculating (I’m not aware of any data) on the potential role of the human microbiome in 

modulating Pb bioassessibility. There are many reports in the environmental microbiology literature of 

microbes oxidizing or reducing minerals and using diverse minerals as electron sources. 

Characterization of the role of the gut microbiome accessibility including the age- or diet- or ethnic-
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dependent differences in microbiome composition and function. Perhaps this issue should be identified 

as a data gap? 

Page 4-60. Figure 4-7 Legend is a little confusing. Is Child B “elevated” Pb intake of 5.5 μg per day on 

top of the baseline 10 μg/d? Should be 55μg/d? Is there a reason this simulation used a 10 μg/d baseline 

when several other simulations in this chapter used 3.2 μg/d?

Page 4-70 Figures 4-9. Is “bone” total skeletal Pb? See also comment on Figure 4-7 above. Blood Pb 

peaks at ~ 8 μg/dL with a simulated intake of ~38 μg/d, while Child B (Figure 4-7) peaks at ~20 μg/dL 

with a smaller simulated Pb intake? 

Figures 9-15. The plots which show time-dependent decreases in blood Pb are potentially misleading 

because they compress many decades, even a simulated lifetime blood Pb into a single plot. This time 

compression supports the conclusion that the decrease in blood Pb is “very rapid” especially when 

viewed in contrast to changes in blood Pb over a few months or a couple years human occupational 

studies. This potential confusion or interpretation could be minimized by (a) fitting the blood Pb curve 

(e.g. Figure 4-11 or 4-12) after reduction in intake to a three-term sum of exponential equation, (b) then 

calculating the size and half-time for each blood Pb kinetic pool, and (c) incorporating this information 

into the text. These calculated half-times for blood Pb will be consistent with half-time measurements in 

human populations and help mitigate these potential interpretation that model simulated decline in blood 

Pb is inappropriate rapid. 

Page 4-83. Figure 4-15 legend. This legend might also include the Leggett model inputs for this 

simulation. That is, that the “switch” for RBC saturation is turned on, and the RBC concentration used 

for saturation. Question, How was RBC saturation handled in Figure 12- (high exposure in adults)?

Page 4-88. Figure 4-17. Can you clarify the meaning of “at baseline” for this figure. 

Table 4-9. This table could be modified to note how the papers cited handled censored data. The related 

text includes a nice description of the issues related to the application of XRF measurements to 

population studies. But, how the authors dealt with frequent missing or negative data affects the readers’ 

inference of the distribution of bone Pb that might be drawn from this table using the tabulated mean and 

SD. Not a problem with data presented as quintiles. 

Add citations for Pb model papers from David Fleming and Anna Steen out for completeness?

Editorial comments

Consider renaming, “Exposure, Toxicokinetics, and Biomarkers” to “Exposure, Toxicokinetics, and 

Biomarkers of Exposure”.
B-45

P4-63 Teeth. I recall a couple papers describing the heterogeneity of Pb in longitudinal sections of teeth 

using PIXE or SRIXE. Joel will look for those papers. 

P4-65 Line 26. Contribute 40-  contribute as much as 40% (because relative contribution depends on 

all sources of Pb to blood, including soft tissue and skeletal Pb. 

P4-68 Line 28. by resorption  by bone resorption

P4-65 Line 29. This sentence, Half-times for the release of Pb in bone are dependent on age and 

intensity of exposure” is a little confusing. Bone Pb half-times depend on bone turnover rates, bone 

resorption, age. Why intensity? Perhaps, when Pb exposure is extremely high and osteoclast function is 

inhibited the bone half-time may be increased. In general, the bone Pb half-time will be far more 

dependent on the rates of bone formation and resorption than the ‘intensity’ of Pb exposure. 

Page 4-45. 

Line 14 this...  this limited binding capacity

Line 16. This...  This process...

Page 4-55 Line 22 This...  This uncertainty...

Page 4-69 line 4. This...  This concept...

Page 4-84 Line 84. This...  This observation...

Page 4-84 Title Studies of Pb Biomarker Levels  Studies of Biomarkers of Pb Exposure

Page 4-139 Line 18 They...  These models...

Page 4-139 Line 21 They...  These models 

Page 4-139 Line 23 confidence in...  confidence in individual...

Page 4-142 Line 12 diffuses to...  diffuse to kinetically... 

Page 4-142 Title for 4.7.3 Pb Biomarkers  Biomarkers of Pb Exposure
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Dr. Michael Rabinowitz

Comments on the Preamble

The general methodology and approach are clearly presented. The diagrams do help. Overall, in this 

draft, the Preamble does provide a more useful and effective introductory format. 

Page lvii line 13 This raises the issue of increased confidence from replicating studies, not only from 

using different subjects, but also different patterns of exposure. I suspect this is generally true,

particularly if the strength of un-measured confounders were some-how randomly distributed across 

studies. There always are un-measured confounder (micro-nutrient level such as iodine, zinc, iron, 

omega-3 fatty acids or educational opportunities, or exposure to co-pollutants, for example). If they are 

not measured in any study, using more studies will not remove their influence, particularly if the 

disadvantaged sub-groups are also the more lead exposed group. What is attributed to a lead-effect after 

adjustment for measured covariates, may still contain the effects of any un-measured covariates. We 

should not become over-confident. As stated in line 15, intervention studies avoid this issue.

Comments on Chapters 1 (Executive Summary) 

Regarding the relative strength of the air pathway compared to lead ingestion from water, food and other 

sources, perhaps on page 1-3 or in the figure 1-1, is there any way to show how small the air input is 

relative to these other inputs? I realize the figure is conceptual, but it might be taken too literally. I just 

want to stress more how relatively small current air inputs. 

page 1-2 two minor comments line 20, average lead in soil was about 20 ug/g. That would be accurate 

enough. line 26 maybe just 1 decade, 1970 and 1980

page 1-3 line 9 , to put air lead in perspective, why not offer a general summary statement something 

like: most of us get most of our lead not from air, but we get it from the ingestion of food, water, dust, 

and other consumer products. 

page 1-5 line 8, add fever as a factor that moves lead from bone to blood, it is fairly common.

page 1-12 lines 6 and 12 do you want to say here that these ( BP and IQ) were the driving basis of the 

earlier standards?

page 1-13 line 27 the source of the airborne Pb (combustion or smelting, for example) effects the 

chemical form and the particle size. maybe mention that... examined and the chemical and physical form 

of the airborne Pb, which varies according to its source ( leaded fuel, smelter, or re-suspended soil). It is 

the form of the lead, not the source, per se, that matters. 

page 1-14 line 3 "larger effect" may be misleading to some. The effect of lead is greater at higher doses. 

More lead equates to more badness. What you may want to say is that it is a larger rate of change, or 

larger bad effect from a small incremental increase in lead, at lower than at higher lead levels. again in 

line 10 .... larger incremental effect.....
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Comments on Chapter 2 (Integrative Overview)

page 2-8 line 5 please say measurable increase in lead concentrations ( or detectable lead pollution) , not 

just measurable lead. 

2-28 line 4 can you give an example or two of the potential confounding in this context

Table 2-8 I liked it, although it is massive, and not without room for improvement

page 2-63 Figure 2-1 Regarding population shifts and the magnified effects seen in the tails. I have some 

problems with this abstraction. Does health-outcome mean Pb level here? Is this about IQ or BP? In 

theory it is correct if the shape of the population does not change as different Pb groups are considered, 

but in practice that may not be the case. For example, different remediation measured will impact the 

curve differently. Lowering air or water Pb levels will move population curves more uniformly than Pbpaint remediation, which would affect the higher lead groups more, changing the shape of the curve. I 

would prefer a figure based on real data.

page 2-71 Regarding the reversibility of low-level lead induced neurotoxicity, we know from 

longitudinal studies that concurrent blood lead levels are often better predictors than earlier blood 

samples, in young children. So, some effects of earlier exposure can become un-detectable, much as 

heme-formation disruptions disappear when blood lead levels are lowered. The problem with relying on 

the failure of chelation to produce reversibility (line 25-26) may be related to chelation's change in the 

bodily distribution of lead. Any good from getting rid of the whole-body lead stores may well be offset 

by putting more lead into the brain.

Generally, I wish there were a place to express overall uncertainly or confidences in our ability to 

predict blood lead levels, let alone lead induced effects, at these exposure levels of interest.

Overall, this draft is adequate, and the suggested changes minor.
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Dr. Ian von Lindern

Comments on the Preamble; Legislative and Historical Background (formally Preface)

Please review and comment on the effectiveness of these revisions to the third draft Pb ISA. Please 

comment on the extent to which these sections of the ISA provide a useful and effective format for 

presenting introductory materials for this and future ISAs. Please recommend any revisions that may 

further improve the clarity of discussion.

Preamble: Inclusion of the flow diagrams from the Ozone document and discussion of the regulatory 

history in the in the Preamble is an improvement to the document and does enhance the effectiveness 

and clarity in communicating the ISA process in the NAAQS review. The diagrams are largely selfinformative and don’t necessarily rely on the text to interpret, and are congruent with the descriptions as 

well. Figure III is an exception, where the Term “Evergreen” Literature Search and Study Selection is 

not defined or discussed and seems to imply some proprietary or specialized criteria. The parenthetical 

in Figure III refers to Figure II, but no specific reference to this method is found there or in the text. 

Some of the text in the Preamble suggests that the discussion and figures may have been lifted from the 

Ozone document, and although appropriate could be edited to be more “lead friendly”. The discussions 

relative to controlled human exposure or animal toxicological studies are, perhaps, more pertinent to 

ozone than the lead review. The section on Concepts in Evaluating Adversity of Health Effects, for 

example, emphasizes lung function as opposed to a more common lead related adverse health effect.

The Preamble also seems to suggest that the principal objective of the document and outcome of the ISA 

process is to establish causation. Several terms are interchangeably used “causal determination, causal 

nature, causal relationship, inferring causation, causal claim, web of causation, determination of 

causality, evidence for causation” are all used within a few paragraphs. Is there a universal meaning or 

different definition for these terms? In either case, it was an improvement to more specifically relate 

these conclusions to individual endpoints, rather than major outcome categories. The addition of text 

describing pre-promulgation history of the Lead NAAQS is also an important addition to the document. 

However, the historic discussion does not emphasize that the review process for criteria pollutants was 

modified between the 2006 and 2011 five-year reviews for lead. The changes implemented markedly 

decreased the scope of the review, analyses, and conclusions available to those making policy 

determinations. This issue is discussed in more detail in my Policy Assessment (PA) comments.

Comments on Chapters 1 (Executive Summary) and 2 (Integrative Overview)

Please comment on the adequacy of these and other changes to the chapters and recommend any 

revisions to improve the discussion of key information. Please recommend any revisions that may 

further improve the clarity of discussion. 

The revisions to Chapter 1 have improved the readability for a non-technical audience. The call-outs 

added to Chapters 1 and 2 are a distinct improvement and convenience in reviewing the document. The 

updates are reflective of the critical revisions in the individual chapters. The introduction, however, 

could perhaps reflect a bit more of the Preamble, and the criteria for determining “Policy Relevant 

Considerations” if the Executive Summary is intended to be a stand-alone section. 
B-49

Chapter 2 “summarizes and synthesizes the recently available scientific evidence ... to best inform the 

review of the current NAAQS...”. The discussions and associated Tables provide an effective summary 

and pertinent discussion of the health effects endpoints that should be considered in the policy review. 

The analysis of health end points reflects the considerable knowledge base that has evolved regarding 

lead health effects over the past three decades. Nearly 74 pages in this chapter are dedicated to health 

effects in this summary. Conversely, 5 pages summarize sources, ambient concentrations, exposure, 

toxicokinetics and biomarkers. No pages discuss production, use, and disposition of lead in US 

commerce. 

The summary does indicate that lead is multimedia pollutant and that consideration of the behavior of 

lead in other media is important to understanding the sources, transport, exposure and integrative effects 

of lead toxicity. However, EPA has forgotten that lead, as opposed to other criteria pollutants, is a 

commodity ubiquitous in society. Lead continues to be mined, refined, produced, fabricated, utilized, 

disposed of, recycled and recovered, remanufactured and redistributed; and offers the opportunity for 

human exposure throughout this cycle. The EPA’s policy decisions with respect to regulating certain 

segments of the lead cycle will always have health significant effects somewhere else. The CDs and 

Staff Papers of the 1970s, 80s and 90s, and to a limited extent in 2006, addressed lead’s role in society 

and exposures and policies in regulating lead throughout this cycle. The decreases in US population’s 

blood lead levels and associated health effects were not achieved solely from the NAAQS. This public 

health success story was the result of integrated efforts across a number of regulatory programs and 

voluntary actions informed by multi-media multi-disciplinary, and multi-programmatic efforts.

There is little doubt the NAAQS was a key component in achieving these reductions, and had positive 

indirect effects on public health by inducing the substitution of non-lead alternatives for many of 

society’s uses. However, there were also negative impacts, often associated with the relocation of 

processes, emissions, exposures and disease beyond the jurisdiction of the NAAQS. The decisions to 

discontinue monitoring and assessment of lead’s behavior in US and global commerce deprives policymakers and critics the opportunity to assess and address these effects. In that regard, the synthesis fails 

to “best inform the review of the current NAAQS”.

Comments on Chapter 4 – Exposure, Toxicokinetics, and Biomarkers

Please comment on the adequacy of these and other changes in responding to the Panel’s comments. 

Please provide comment on revisions that may further improve the utility of this chapter for 

interpretation of health evidence in subsequent chapters.

Chapter 4 comprehensively provides an accurate interpretation of the science as related to exposure, 

toxicokinetics, and biomarkers that is reflective of the current understanding and practice in risk 

assessment activities. The overall discussion of the health significance and interrelationship of the 

toxicokinetics and biomarkers is informative and well presented. This chapter also provides a concise 

summary of exposure / blood lead relationship representative of the current scientific consensus for this 

important segment of risk assessment process. 

Both Chapters 3 and 4, however, remain biased toward the gasoline phase down in this regard and 

should note the significant emission and air lead reductions achieved in the vicinity of point sources. 

The major reductions in point source emissions were achieved through a combination of pollution 

control and relocation of the industry. The export of the mineral processing operations had profound 
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effects with respect to risk co-factors in the US and exposures abroad. Also important in the US were 

effects associated with decreases in other metal-related pollutant concentrations decreases in other media 

and levels of ecological risk, both locally and regionally. These effects were both attendant to and 

independent of the phase down and curtailments in industrial emissions. 

The addition of Table 4-2 to showing IEUBK predictions of pathway contributions to concurrent blood 

Pb levels is illustrative of the multimedia aspects of lead exposure. Presenting the potential biases and 

factors possibly affecting observed air-to-blood relationships improves the discussion.
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Dr. Gail Wasserman

Overall this reads very well, and is a sound document. Staff have managed to integrate an extraordinary 

amount of information and to employ useful framework(s) for critically reviewing and integrating 

information. Well done!

Preamble

This section reads well and is clearly presented.

Smaller edits:

P lvi L 32 perhaps should read: “methods is completely satisfactory”

P lxiv L 18 extra word? “the ISA evaluates results from across epidemiologic studies that characterize”

Chapter 2

(1) Highlighting the public health significance of cognitive and cardiac endpoints is an improvement.

P 63 The Weiss Hypothetical model. In a document that is so packed with actual real DATA, I don’t 

really agree that this hypothetical model needs to be presented here and then again in Chapter 5.

On the other hand, I very much appreciate this revision’s clarifying that this is not based on actual data.

These issues are addressed more fully in chapter 5. In this instance, however, it would be better to be 

consistently precise, so as to not lead to misinterpretation by a reader who does not take the time to get 

to Chapter 5. In particular, it would be better if:

L 9 use “across the full range of IQ” instead of “with high and low intelligence “

L 13 insert “in this model, a” : For example [in this model, a], small shift in the population mean 

IQ may result in a substantial increase in... 

(2) Other conclusions

P 70 L 19 Discussion of the timing of exposure: could insert “and in children”. The document should 

cite our comparisons in the Yugoslavia cohort of children whose exposure was stable and those for 

whom it increased, examining contribution of different developmental periods to intelligence: 

Wasserman, G.A., Liu, X., Popovac, D., Factor-Litvak, P., Kline, J., Waternaux, C., LoIacono, N. & 

Graziano, J.H. (2000) The Yugoslavia Prospective Lead Study: Contributions of prenatal and postnatal 

lead exposure to early intelligence, Neurotoxicology and Teratology, 22, 811-818. This paper was not 

mentioned in the section in Chapter 5 on the review of the timing of exposure. 

Smaller edits:

P 16 L 10 word missing “on tests [of]”

L 12 typo: omit “but”

L 27 SES refers to socio-economic status, not “Social Economic Status” 
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P 17 and P18 The sections on the various behavioral outcomes in children (attention problems, 

internalizing problems, conduct problems) correctly include mention of whether or not studies adjusted 

for parenting behavior. On the other hand, there is no mention of the contributions of parental 

psychopathology, which in most instances is contributory. See my discussion below of Chapter 5, 

charge point 4.

P 75 L 16 typo: increased[d]

Comments on Chapter 5

This chapter, which is so very extensive, works much better with the new framework.

(1) New system for organizing and inter-relating the cognitive and behavior outcomes into broader 

categories works very much better. The places that still need some work to be consistent with standard 

practice include: 

P 170 L 24-25 I think the text means to refer to the various ways “conduct problems” is measured, not 

to different kinds of problems. Oppositional behavior is the more general terms that encompasses 

Oppositional Defiant Disorder. “opposition defiance” is not a meaningful term. In that case, the text 

should read “ that examined different [measures of] conduct problems (i.e., opposition[al behavior], 

delinquency, externalizing problems

P 183 L1 I don’t know what distinction the text means to convey by parsing into “psychopathological 

effects” vs such things as “aggression and criminal behavior” (which would also denote 

psychopathology). Perhaps what is meant is disorder vs behavior, in which case this sentence should 

read “Studies of Pb exposure and behavior in adults have focused on [disorder? Mental health 

conditions?] rather than aggression and criminal behavior.

L 7-8 The measures are symptom checklists, so the sentence should read: “...Pb levels with [symptoms 

of] depression and anxiety “ 

P 221 L 27 schizophrenia is NOT a mood disorder

P 257 L 13 I think the text is referring here to “depressive [symptoms]”

P 277 L 15. I am not sure what the three constructs are supposed to be here, as “phobic anxiety” is a sub 

category of “anxiety”.

(2) Concerns about discussion of appropriate parallels across species for nervous system endpoints 

largely met.

(3) Merging discussion of epidemiologic and toxicologic evidence by outcome is a useful integration.

(4) Expanded discussions that provide additional details on strengths and limitations of the evidence is 

very helpful.

Two concerns about presentation of confounding remain:
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In several places ( P-154 L 34, and P 161 L17, and there are more) adjustment for parental 

psychopathology in models predicting child psychopathology is couched in text about the degree to 

which parental disorder does or does not relate to caregiving behavior, almost as a disclaimer. On the 

other hand, parental disorder is likely considered in these studies, not just a proxy for parenting 

behavior, but as a direct contributor. Most types of child behavior problems, including inattention, 

hyperactivity, conduct problems, and anxiety are highly heritable. There is a good discussion of these 

points on p 5-159, but perhaps this should come earlier and then that disclaimer would not have to 

reappear again and again. 

Subcategories within cognitive and behavioral functioning are usually substantially intercorrelated, 

making examination of specificity complicated, and this should be noted somewhere. For example P 174 

the text should point out that externalizing and internalizing (and indeed, most forms of mental health 

problems) are positively correlated. This is the case for cognitive outcomes as well, where intelligence is 

related to working memory, executive function, etc.

P 227 L 9 This is not a limitation of the prospective studies, but of studies, in general, that examine 

development 

(5) Revisions that prioritize studies to emphasize those with the strongest design: this is very helpful!!!

Other edits 

5-57 L 11. It is worth noting that in Wasserman et al 2000, we compared the impact (on intelligence at 

3,4,5 and 7y) of changes in BPb among those whose exposure was stable, vs not: and the results showed 

a stronger impact of prenatal exposure, although even adjusting for prenatal exposure, postnatal 

exposure still had significant negative associations.

5-60, as well as subsequent Table 5-3. This is a discussion of the findings from the Lanphear pooling of 

the prospective studies. The text refers to the findings that pertain to the full pooled sample of 1333 

children. The first row of Table 5-3, which provides supportive information for the Lanphear analyses 

refers only to the subset of 103 children with BPbs < 7.5. For clarity, perhaps information on both full 

and subset samples should be presented. Further, there should be some note that the Bellinger, 

Wasserman, and Dietrich data (and others) ALSO appear in the Lanphear report?

P 225 The section on the timing of exposure should include reference to Wasserman, G.A., Liu, X., 

Popovac, D., Factor-Litvak, P., Kline, J., Waternaux, C., LoIacono, N. & Graziano, J.H. (2000) The 

Yugoslavia Prospective Lead Study: Contributions of prenatal and postnatal lead exposure to early 

intelligence, Neurotoxicology and Teratology, 22, 811-818. In this paper, considering changes in blood 

lead levels measured during pregnancy and annually thereafter, we found that both prenatal levels as 

well as postnatal changes relative to prenatal levels adversely impacted child IQ. Associations with 

prenatal BPs were, however, stronger. 

P 253 The section on public health significance: Chapter is much improved by the inclusion of this 

section

Smaller edits
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5-74 L 26. Should read “not necessarily STRONGLY correlated” Bayley and later IQ are generally 

positively (and significantly) correlated, but the strength is less than for relationships across later ages.

5-101 L 23 should be STROOP test

5-139, last para: the decision about which studies of inattention were most weighted seems sound

5-140. L 22: should read “evidence in both”

L. 26 The proper spelling is Somerville

5-141 L 3: “responses”

P 160 L26 typo

P 170 L 34 provide citation for “the authors....”

P 181 L 15 what are the three self-reported disorders?

P 197 L 10 did

P 264 L 10 The proper spelling is Somerville 

Comments on Chapter 6

(1) How successful is the new classification system for considering risk factors that has been 

incorporated into the third draft Pb ISA, whereby each factor was evaluated and classified based on the 

weight of evidence within and across disciplines? 

This is clearly presented, and is a useful means of organizing the information presented. 

(2) How useful is new approach that evaluates the adequacy of numbers of studies for health endpoints 

for examining the magnitude of the modification by that potential at-risk factor across studies?

Sections on risk include multiple endpoints and different associations between risk and vulnerability 

(sometimes, for example, for males, sometimes for females), which is confusing. Each section’s last 

paragraph draws this out concretely, but perhaps this should be stated in the first paragraph for each 

section, so that the reader is not searching for common factors that are not there.

Smaller edits

P 1 L 27-28 not a sentence

P 5 L 13 confounders?

L 24-25 since this section considers both human and non-human studies, it would be clearer if for each 

point, the text could clarify which species is studied

P 8 provide units for Table

P 18 Section 6.2.6. It would be better if here the text mentioned the direction of associations

P 26 L 18 interaction(s)

P 26 L 13-14 species

The last paragraph on this page should reword its conclusions to be clearer.
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Dr. Michael Weitzman

Comments on Chapter 6 - Potentially At-Risk Populations

Overall this chapter is comprehensive and I have just a few suggestions:

6-1, line 31: I suggest that after “SES may affect...” please add “housing, proximity to increased sources 

outside the home and malnutrition, and altered levels of household stress and mental health problems 

among family members.” 

6-1, line 32 add “and diminished access may deprive families of lead prevention screening and 

counseling.” 

6-4, line 12: Please consider adding “Infants also absorb lead more efficiently from their gastrointestinal 

tracks than older children and adults.” There are multiple citations supporting this.

6-6, line 15: Please consider adding “respiratory rates” after “increased.”

6-21, line 25: after 12% please add “(a measure both of iron deficiency without accompanying anemia 

and of iron deficiency anemia)”.

6-22, just before Older Adulthood: I suggest that we discuss the fact that there is insufficient data to 

identify critical windows of exposure, or whether peak blood lead levels, or cumulative exposure over 

the preschool period or shorter periods of time before school age appear most predictive of IQ loss and 

neurocognitive problems.

6-30 Pre-Exisiting Conditions: I believe we should acknowledge that there are many childhood 

conditions, that collectively account for a substantial percentage of children, for whom there might be 

hypothetical reasons to predict increased (or decreased) vulnerability to lead exposure, such as low and 

very low birth weight; prenatal exposure to alcohol, cocaine, heroin and tobacco; birth asphyxia; serious 

head trauma; and numerous genetic conditions associated with developmental delays. Also, children 

with sickle cell anemia are at increased risk for peripheral neuropathies I believe.

6-33 Smoking Status: while we mention the one paper on prenatal tobacco smoke exposure and lead 

exposure being associated with higher odds of ADHD, I do not believe that there has been investigation 

of the relationship of SHS, either by parent report or biomarker measurement such as cotinine level, and 

IQ or neurocognitive problems.

6-34 Socioeconomic Status And Race/Ethnicity: We need 2010 census data...the demography of the 

US population has changed profoundly in the past 10 years with more children living in poverty and 

significantly increased absolute #s and percentages of children who themselves or whose parents have 

emigrated from Asia and the Middle East and we have no data about the lead exposure of these children 

or their parents.