UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C. 20460

 

OFFICE OF THE ADMINISTRATOR

 SCIENCE ADVISORY BOARD

December 9, 2011

EPA-CASAC-12-002

The Honorable Lisa P. Jackson

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 (First External 

Review Draft – May 2011)

Dear Administrator Jackson:

The Clean Air Scientific Advisory Committee (CASAC) Lead Review Panel met on July 20 - 21, 2011,

and September 15, 2011, to peer review the EPA’s Integrated Science Assessment for Lead (First 

External Review Draft – May 2011), hereafter referred to as, ISA. The chartered CASAC approved this 

report during a public teleconference on November 28, 2011. 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 a well-written, comprehensive and well-organized document. 

However, the CASAC has specific comments and recommendations for improving the document.

General Comments

A summary chapter, such as Chapter 2, is very useful for readers, and should be located early in the ISA. 

The ISA should consistently contain summaries of the state of science as it stood prior to this review, 

critical evaluation of the literature since the last review, and conclusions regarding what has been 

learned since the last review. The framework for causal determination should be applied consistently 

and transparently. The document would benefit from discussion of the public health significance of 

observed lead (Pb) effects as well as a discussion of the distinction between public health consequences 

and clinically significant effects. In several places, terms need to be defined and applied consistently. 

Study Selection

The criteria used to consider studies for review and analysis are reasonable. Studies of people who have 

blood lead (Pb) concentrations within one order of magnitude of the general U.S. population are 

appropriate given the focus on risks associated with environmental Pb exposure. With respect to 

epidemiological studies, it appears that these criteria are consistently and appropriately applied. 
2

However, the ISA highlights many toxicological studies for which the Pb dose is far in excess of what 

might be relevant to environmental exposure to humans. The Health and Environmental Research 

Online (HERO) system is very useful and functions well as a means to retrieve studies that were cited in 

the document.

Integrative Health and Ecological Effects Overview

Overall, this chapter summarizes a substantial body of knowledge and the effort to integrate the 

ecological effects literature and human health effects literature is commendable. However, this 

important “overview” chapter should undergo substantial revision to address several shortcomings. With 

respect to human health endpoints, a rigorous weight-of-the-evidence assessment is needed that 

transparently applies the criteria for the strength of evidence for causation, set forth in section 1.6 and 

Table 1-2. This weight-of-the-evidence assessment should be applied to specific health endpoints, in 

addition to broadly assessing impacts on whole organ systems (e.g., “neurological effects”, 

“cardiovascular effects”, “renal effects” and other effects identified in Table 2-1). Further, the analysis 

in this chapter would benefit from a more careful interpretation of the use and validity of an adult’s 

contemporaneous blood Pb as a biomarker of Pb exposure. Key tables that summarize the effects of low 

level Pb exposure in children and adults, such as Table 2-2, 2-3, and 2-8, require substantial revision to 

reflect different levels of the strength of evidence for causal inference for specific health endpoints. 

Discussion of these tables also should reflect the components of past and current Pb exposure that 

influence the utility of blood Pb as a biomarker.

Ambient Lead

The chapter on ambient Pb provides a clearly written, detailed and comprehensive summary that focuses

primarily and appropriately on new studies since the last NAAQS review. In some sections, the 

presentation of recent results is not adequately prefaced by a clear summary of the state of the scientific 

understanding prior to the current review cycle. Thus, it is difficult to infer how or if the new results add 

to, modify, or conflict with the previous state of the science in ways that are relevant to a potential 

revision to the Pb National Ambient Air Quality Standard (NAAQS).

During the previous (2008) Pb NAAQS review, the CASAC strongly recommended that the agency 

specify or develop a sampler for Pb compliance monitoring that is better than the currently deployed 

high-volume total suspended particulate (TSP) sampler. CASAC strongly reiterates this 

recommendation. The ISA should address the state of science with regard to monitoring technology and 

fixed site monitor siting criteria for representation of population exposures. Errors in existing 

measurements and implications for comparison of Pb in different particulate matter (PM) size fractions 

should be discussed.

These errors raise doubts about the accuracy of the reported comparisons of Pb in the different particle 

size fractions. The EPA should screen the particle size data for very low concentrations that may have 

poor precision and re-check the calculations. Several aspects of the reported Pb emissions inventory data

need further review and interpretation. For example, the decision to exclude published information on

several Pb emissions sources should be reconsidered, specifically regarding (1) the relative importance 

of resuspended Pb from soils near historical sources (including roadways) and (2) emissions from 

aviation gasoline combustion from airports versus from elevated flight paths. Further, the discussion of 

Pb emissions inventory data should document changes in emission inventory assumptions from the 2006 

Air Quality Criteria Document (AQCD), as well as the temporal trends, precision and accuracy, and 
3

relevance to human exposure of the emissions inventory data. More information should be provided on 

the relationship between Pb in air (in various particle size ranges) and Pb in other environmental media. 

Transboundary transport and policy-relevant background should be discussed further. 

Exposure, Toxicokinetics and Biomarkers

The selections of topics and material emphasized in the chapter on Pb exposure, toxicokinetics, and 

biomarkers are appropriate, but the document should provide additional comparison of the relative 

contributions of Pb in air versus contemporaneous exposures from other media. The state of science 

around exposure measurements and modeling, including multipathway exposure, should be discussed.

Descriptions and scientific assessments of available exposure models are needed, as well as a 

description of empirical data available for evaluating the modeling efforts. The chapter should more 

clearly explain that a series of scenarios are developed to represent a range of plausible exposure 

conditions at a community level and that, collectively, the results provide perspective on how the 

distribution of blood Pb concentrations may vary among communities that share similar exposure 

profiles. This analysis will help to explain the relevance of various empirical data sets to the overall 

evaluation.

The kinetics and biomarkers sections are well written. Additional discussion is recommended regarding: 

biokinetic modeling assumptions and model validation by comparison to empirical biomarker data; and 

the definition, application, and limitations of biomarkers. A summary of precision, accuracy and 

variability in bone Pb measurements similar to that in the previous AQCD would be helpful. Sharper 

definitions of and distinctions between the terms “absorption,” “bioavailability,” and “bioaccessibility”

are needed. Distinctions between biomarkers for Pb exposure, body burden, internal dose and risk

should be discussed. The validation and application of these biomarkers also should be considered. 

The inclusion of additional studies from which to estimate air Pb to blood Pb slope factors is a useful 

addition from the previous NAAQS, which relied on just one or two studies. More clarity is needed, 

however, regarding how the range of empirical data compares with environmental concentrations. The 

CASAC is unaware of any additional studies that could be added to the list.

Integrated Health Effects of Lead Exposure

In general, the discussion of the potential modes of action underlying the health effects of Pb exposure is

thorough and inclusive of the current scientific literature. No known modes of action have been omitted. 

However, in some cases, studies are not presented in sufficient detail to support the presumed 

mechanism of action for reported effects and in some cases, the mode of action information might be 

considered misleading or over-interpreted.

The discussion of specific health endpoints in this chapter is sufficiently broad in scope and inclusion of 

additional health endpoints is not required. However, integration of associations within and across 

endpoints should be increased, especially with regard to mechanisms. The ISA offers a satisfactory 

discussion of the causal relationship between low blood Pb levels and decrements in IQ and adverse 

neurocognitive development in children. With respect to other endpoints in children and adults, a more 

rigorous and transparent weight-of-the-evidence analysis is recommended to establish the extent of any 

causal relationship. This analysis should devote more attention to the limitations of the existing studies

with respect to consistency, reproducibility, bias, control for potential confounders, and shortcomings in 

statistical methodology.
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This chapter provides a comprehensive review of the human epidemiologic and toxicological evidence 

of the health effects of Pb and this approach provides useful support for integration across the two 

disciplines. Such integration is encouraged and should be expanded if possible. A number of specific 

modifications to the chapter and several ways to improve the application of causal determination criteria 

are recommended, as detailed in the consensus response (Enclosure A).

The issue of non-linearity of the dose-response for IQ was a critical issue in the previous NAAQS 

review. The additional evidence since 2006 is appropriately cited and provides further support for the 

non-linearity of the dose-response curve. These findings also are supported by an animal literature that 

dates back to the 1970s-80s, which should be discussed.

Susceptible Populations and Lifestages

For Pb, issues related to susceptibility across the life course are critical for public health protection. 

While the chapter covers relevant studies, the conceptual framework for interpreting them needs to be 

modified to more sharply address factors that may lead to increased risk and to increased exposure or

dose. The ISA lays out an ambiguous set of terms and a conceptual model that does not adequately 

support interpretation of the literature. The CASAC had similar concerns with regard to the first draft 

ISA for ozone and voiced them in its letter to Administrator Jackson, dated August 10, 2011. Those 

comments are applicable to the lead ISA as well, and we recommend revisions that parallel those made 

in Chapter 8 of the second draft ISA for ozone. 

As revisions are made, the CASAC also notes that there are many sections with only a few citations. The 

EPA should be very clear on the strength of evidence in the literature and cautious in inferring causality

if the knowledge base is weak. The ISA would be strengthened by more discussion of nutritional aspects 

that serve to increase susceptibility, differences in effects by gender, gene-environmental interactions, 

and epigenetic implications. There are other factors that could be better described, such as age of 

housing stock, and percentage of homes with Pb-free windows and that have grass cover or bare soil in 

yards and playgrounds. Although early development is a vulnerable time period, research shows that Pb 

exposures during later periods in life also are associated with significant adverse effects.

Ecological Effects of Lead

The chapter on the ecological effects of Pb is well written, effectively organized, and adequately 

addresses “new” published data (post-2006). However, the chapter does not address pre-2006 

information, making it difficult to understand the context and contribution of more recent data to the 

body of knowledge on Pb toxicity and how they may or may not inform a decision to revise the 

secondary NAAQS for Pb. There may be substantial additional toxicity data available from nonpublished sources, such as data generated for the European Registration, Evaluation, Authorisation and 

Restriction of Chemicals (REACH) regulations. The EPA should explore how the quality of the data 

was assessed and if acceptable, determine how easily these data could be incorporated into the ISA 

framework.

The importance of bioavailability and bioaccessibility in assessing the toxicity of Pb to environmental 

receptors should be stressed throughout the chapter. The aquatic and terrestrial Biotic Ligand Models 

(BLMs) should be considered when evaluating possible environmental effects. Marine and freshwater 

toxicity data should be treated separately due to differences in Pb speciation and bioavailability and 
5

possible differences in the sensitivity of freshwater and marine organisms. The terms “bioconcentration 

factor” (BCF) and “bioaccumulation factor” (BAF) should be carefully defined and consistently applied. 

BCF and BAF are inappropriate measures to assess the hazard of Pb, and thus a better assessment of the 

utility (or lack thereof) of these values is needed. Causal conclusions are only weakly supported by 

limited exposure data and thus should be reevaluated. Additionally, since bioaccumulation is not a true 

“effect” and due to the occurrence of biodilution during trophic transfer, a causal determination for the 

bioaccumulation of Pb as it affects ecosystem services is not warranted at this time.

The CASAC appreciates the opportunity to provide advice on this issue and looks forward to receiving 

the agency’s response.

Sincerely,

 Dr. H. Christopher Frey, Chair Dr. Jonathan M. Samet, Chair 

CASAC Lead Review Panel Clean Air Scientific Advisory Committee

Enclosures
i

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

CHAIR

Dr. H. Christopher Frey, 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. 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 Health Sciences Center, Denver, CO

Dr. Roman Lanno, Associate Professor and Associate Chair, Department of Evolution, Ecology, and 

Organismal Biology, Ohio State University, Columbus, OH
iii

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, Phone: 202-564-2050, 

Fax: 202-565-2098, (yeow.aaron@epa.gov)

*Did not participate in the review.
iv

U.S. Environmental Protection Agency

Clean Air Scientific Advisory Committee (CASAC)

CHAIR

Dr. Jonathan M. Samet, Professor and Flora L. Thornton Chair, Department of Preventive Medicine, 

Keck School of Medicine, University of Southern California, Los Angeles, CA

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. H. Christopher Frey, Professor, Department of Civil, Construction and Environmental 

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

Dr. Armistead (Ted) Russell, Professor, Department of Civil and Environmental Engineering, Georgia 

Institute of Technology, Atlanta, GA

Dr. Helen Suh, Program Area Director, Environmental Health, Public Health Division, National 

Opinion Research Corporation (NORC) at the University of Chicago, West Newton, MA

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

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, Phone: 202-564-2073, 

Fax: 202-565-2098, (stallworth.holly@epa.gov)

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

Advisory Board (1400R), 1200 Pennsylvania Avenue, NW, Washington, DC, Phone: 202-564-2050, 

Fax: 202-565-2098, (yeow.aaron@epa.gov)
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Enclosure A

Consensus Responses to Charge Questions on EPA’s Integrated Science Assessment for Lead (First 

External Review Draft – May 2011)

1. The legislative history of Pb NAAQS reviews and the framework for causal determination and judging 

the overall weight of evidence is presented in Chapter 1. Selection criteria used to identify studies for 

inclusion in the ISA are also described in Chapter 1. Please comment on the consistency and 

appropriateness of the application of these criteria and the appropriateness of the decision to consider 

studies within approximately one order of magnitude of current exposure levels (e.g. was the 

determination of “informative” occupational studies and their subsequent inclusion in the document 

appropriate and consistently applied across endpoints?) Please comment on the application of the 

Health and Environmental Research Online (HERO) system to support a more transparent assessment 

process. 

The discussion in Chapter 1 of the criteria used to consider studies for review and analysis in the ISA is 

reasonable. Studies of people who have blood lead (Pb) concentrations within one order of magnitude of 

the general U.S. population equates to cohorts with blood Pb concentrations approximately less than 40 

μg/dL. This is appropriate for a document intended to focus on risks associated with environmental 

rather than occupational Pb exposure. With respect to human epidemiology studies, these criteria have 

been consistently and appropriately applied. However, the ISA highlights many toxicological studies in 

animals or in vitro systems in which the dose of Pb was far in excess of what might be relevant to low 

level environmental exposure to humans. The document should make clear that toxicological studies 

involving animals or in vitro systems are generally in one of three categories: exposures comparable to 

environmental exposures to humans and therefore of clear relevance, exposures far in excess of these 

exposures but relevant for various reasons that can be explained, and exposures far in excess of these 

exposures and not as relevant to establishing an ambient air quality standard. The Health and 

Environmental Research Online (HERO) system functions well as a means to retrieve studies that were 

cited in the document. 

2. Chapter 2 presents the integrative summary and conclusions from the Pb ISA with a discussion of 

evidence presented in detail in subsequent chapters. Is this a useful and effective summary presentation? 

Is the framework for causal determination appropriately applied? Please comment on approaches that 

may improve the communication of key ISA findings to varied audiences. The health and ecological 

effects of Pb are mediated through multiple interconnected modes of action and there is substantial 

overlap between the ecological and health endpoints considered in the causal determinations. Since the 

mechanism of Pb toxicity is likely conserved from invertebrates to vertebrates to humans in some organ 

systems, the scientific evidence was integrated across the disciplines of health and ecology. Please 

comment on this approach e.g., is this a useful and effective integration of the scientific evidence? 

Chapter 2 summarizes a huge body of knowledge, including a summary of the ecological effects 

literature and the human health effects literature. The chapter attempts to summarize which health and 

ecological effects are 1) caused by Pb; 2) likely causal; 3) suggestive of causal associations; or 4) 

inadequate to infer a causal relationship. However, in this chapter (and elsewhere), the document fails to 

consistently or adequately apply this causal framework, despite its critical importance to the ISA. 
A-2

Specifically, the causal analysis is not applied systematically or in a transparent way. In assessing 

studies related to a particular human health outcome, a critical analysis of the strength of evidence is 

often not done in the more detailed chapters upon which this summary is based (e.g., Chapters 5 and 7). 

Limitations of the data concerning selected endpoints are inadequately characterized. As a consequence, 

the summaries in this chapter fail to capture important distinctions in the strength of evidence for a 

particular level of causal association. A critical analysis should review the number of studies available 

on a topic; the strengths and limitations of study design, data, and analyses; and the distinction between 

short-term and chronic Pb exposure effects. Such a review is necessary for a defensible causality 

determination. For example, the epidemiologic literature supporting a Pb-childhood IQ association is 

much more robust and consistent than studies of Pb and childhood attention deficit hyperactivity 

disorder (ADHD) or adult essential tremor (ET). Distinguishing among neurologic outcomes for which 

the literature supports a likely causal association from those less robustly associated with Pb needs to be 

part of any conclusion about Pb’s causal relationship with neurological health. Instead, the text 

addresses the weight of evidence for causation for “neurological effects” as a broad category; a similar 

approach is used for other health endpoints, e.g., “cardiovascular effects” or “reproductive effects”. 

Additionally, since bioaccumulation is not a true “effect”, and due to the occurrence of biodilution 

during trophic transfer, a causal determination for the bioaccumulation of Pb as it affects ecosystem 

services is not warranted (Chapter 7).

Per the above discussion, key tables such as 2-2 and 2-3 need major revision to reflect differences in the 

strength of evidence supporting a potential relationship of Pb with each specific outcome. Currently, 

these tables incorrectly imply equal levels of the strength of evidence for causality across outcomes. As 

above, e.g., the epidemiologic evidence associating low-level Pb exposure with childhood ADHD, adult 

ET, or even adult neurocognitive function is weaker than that associating low-level Pb exposure with 

reduction of childhood IQ. In many of the epidemiologic studies of the impact of Pb on adverse health 

effects in adults, the contemporaneous blood Pb concentration of study cohort members likely differed 

substantially from blood Pb concentrations earlier in life when average population blood Pb levels were 

higher. Thus, key tables (e.g., 2-2, 2-3, 2-8) that summarize the impact of current low level Pb exposure 

also need revision to recognize the role of likely higher past blood Pb concentrations (and cumulative Pb 

exposure) in determining the risk of current adult disease. 

Several panel members also have specific concerns about the ISA’s analysis of a causal relationship of 

low level Pb exposure to specific health endpoints. These concerns are described in individual 

committee members’ detailed comments.

Recognizing that some practitioners and policymakers may focus on Chapter 2, rather than on the more 

substantive work on which it is based (e.g., Chapter 5), it is recommended that key features in Chapter 5 

be presented, albeit summarily in Chapter 2. For example, Pb has been shown to impact growth in 

humans (as described in Chapter 5) but this important outcome is missing from Chapter 2. More care is 

needed to be certain that the content of this chapter is consistent with the remainder of the document that 

is summarized. For example, Chapter 5 discusses the likelihood that contemporaneous child blood Pb 

may be the most relevant to neurodevelopmental outcomes whereas, in Chapter 2, the text indicates that 

there is uncertainty regarding the most susceptible Pb exposure period in childhood. Such apparent 

contradictions within the document need to be reconciled. 

In addition to a more critical assessment of the literature, an appraisal of the public health significance of 

observed Pb effects should be included in this chapter. Public health significance (i.e., for populations)

should be distinguished from clinical significance (i.e., for individuals). The ISA should make clear that: 
A-3

(1) individual risks may vary from the point estimates of effect observed in population-based 

epidemiologic studies and (2) depending on the outcome, small effect sizes may have important impacts 

on health at the population level (see Bellinger D.C. Interpretation of small effect sizes in occupational 

and environmental neurotoxicology: individual versus population risk. Neurotoxicology 2007;28:245-

251).

There is a lack of consistency in the amount of detail across all sections of the chapter, and in the 

citations of later chapters. Some sections have no citations to later chapters, while others, e.g., 2.8.4.1, 

include too many citations, making it difficult to read. Throughout Chapter 2 enough citations should be 

included to enable the reader to find the information in the later chapters, but not so many citations as to 

make the chapter difficult to read. 

In Section 2.6.10, page 2-40, a cited study (Mahmoudi et al., 2007) involves laboratory observations of 

aquatic organisms exposed to sediments contaminated with varying amounts of Pb. The conclusions that 

are drawn cannot be extrapolated to the real-world environment, which includes many complexities 

absent from the lab experiments. This lack of generalizability should be pointed out in the chapter.

In general, where in vitro and in vivo study results are described, the exposure media need to be 

explicitly defined and, as much as possible, standardized exposure units should be used to facilitate 

comparison and interpretation of findings across studies and systems. For example, in Table 2-6, the 

discussion of endocrine disruption at 20 ppm Pb does not list the environmental medium in which Pb 

was measured. Furthermore, the CASAC suggests that equivalent mg/liter be included rather than 

merely listing the concentration in ppm. 

There is only one sentence in the entire chapter mentioning the correlation between Pb in paint and Pb in 

blood, an important topic needing further development. 

At the end of Section 2.1.2, the document states that there is a strong correlation between airborne Pb 

and zinc concentrations, and moderate correlations between concentrations of airborne Pb and bromine, 

copper, and potassium. Since 49% of total Pb emissions are from piston engine aircraft, which probably

do not emit large amounts of copper, potassium, and zinc, the correlations are surprising and suggest 

that there may be data issues.

During the July 2011 meeting, the agency proposed combining part of Chapter 1 with Chapter 2, and the 

CASAC finds that change to be acceptable.

3. Chapter 3 provides a wide range of information to inform the exposure and health sections of the ISA. 

To what extent are the atmospheric science and air quality analyses presented in Chapter 3 clearly 

conveyed and appropriately characterized? Is the information provided regarding Pb source 

characteristics, fate and transport of Pb in the environment, Pb monitoring, and spatial and temporal 

patterns of Pb concentrations in air and non-air media accurate, complete, and relevant to the review of 

the Pb NAAQS? Does the ISA adequately characterize the available evidence on the relationship 

between ambient air Pb concentrations and concentrations of Pb in other environmental media?

Chapter 3 provides a clearly written, detailed and comprehensive summary focused primarily on new 

studies available since the last NAAQS review. In some sections, the presentation of recent results is not 

adequately prefaced by a clear summary of the state of the scientific understanding prior to the current
A-4

review cycle, so it is difficult to see how or if the new results add to, modify, or conflict with the 

previous state of the science in ways which would result in revisions to the NAAQS.

For the most part, the information presented on these topics appears to be accurate, complete, and 

relevant. There was a detailed and informative discussion of the various existing, and in some cases 

developing, analytical methods employed for total Pb or Pb species. However, the summary of methods 

for collecting Pb in different particle sizes is much more limited. The substantial sampling biases with 

wind speed and direction for particles larger than 10 microns associated with the current high-volume 

total suspended particulates (TSP) sampler are noted, but no information is provided on currently 

available or developing methods that might reduce these sampling biases. There is also no information 

provided here or drawn from other chapters on what the ideal or acceptable particle size characteristics 

of a Pb Federal Reference Method (FRM) sampler should be. It is unclear whether the ratio of blood Pb 

to air Pb is likely to be the same for air Pb in particles greater 15 microns as for air Pb in particles less 

than 1 micron.

The accuracy of some of the particle size Pb comparisons summarized in section 3.5.3.1 and presented 

in more detail in Table 3A-13 of the Appendix needs further evaluation. There appears to be an 

implausibly-high frequency of sites with more Pb in smaller size ranges than in collocated samples with 

larger particle cut sizes. The EPA should screen the data for very low concentrations that may have poor 

precision and re-check the calculations. If these possibly incorrect particle size ratios persist, the 

CASAC recommends providing additional details on the filter blank, extraction and analytical methods 

employed, or other factors that may explain these results.

Several aspects of the reported Pb emissions inventory data require further evaluation, including 

revisiting the decision to exclude published information on the relative importance of resuspended Pb 

from soils near historical sources (including roadways), emissions from aviation gasoline combustion 

from airports vs. from elevated flight paths, and changes in emission inventory assumptions from the 

2006 Air Quality Criteria Document (AQCD) to the current ISA – especially for aviation gasoline use.

Relatively little information is provided on the relationship between Pb in air (in various particle size 

ranges) and Pb in other environmental media. While a high proportion of the Pb content in soils, 

sediments and surface waters can be associated with historical emissions of Pb to the ambient air, there 

is very limited information available on the changes in these environmental concentrations that would be 

expected to result from changes in current air Pb concentrations. 

It is unclear whether the ratio of Pb in surface waters to air Pb is likely to be the same for air Pb in 

particles greater than 15 microns as for air Pb in particles less than 1 micron.

4. Chapter 4 describes the multimedia nature of Pb exposure, toxicokinetics of Pb in humans, 

biomarkers of Pb exposure and body burden, as well as models of the relationship between Pb 

biomarkers and environmental Pb measurements.

4a. How well do the choice and emphasis of topics provide a useful context for the evaluation of human 

health effects of Pb in the ISA? Is the current organization of the chapter clear and logical? Are there 

ways that information on exposure and toxicokinetics can be more clearly integrated throughout the 

chapter? Does the ISA adequately describe and balance air-related and non-air related pathways of Pb 

exposure?
A-5

The selection of topics and material emphasized in Chapter 4 are appropriate. The opening section 

provides a summary of the sources and exposure pathways, both directly and indirectly related to Pb in 

air. Important points that should be emphasized early in the discussion are that Pb is a multiple-media 

contaminant, and that blood and bone Pb levels are the biomarkers generally used to integrate exposure 

for risk assessment and management purposes. It should be pointed out that the relative significance of 

the source media has varied historically, site-specifically, and by the behavioral and socioeconomic 

status (SES) of the affected populations.

A historical perspective is needed to set the context. The air Pb discussion does an adequate job of 

describing the large decreases in exposure noted with the lead-in-gasoline phase down. It is also 

important to note that the air Pb reductions are associated with changes in point source emissions over 

the same time frame, particularly with respect to smelting, mineral processing and secondary recycling. 

The ambient air Pb decreases in the vicinity of these sources were significantly greater than those 

achieved in urban areas through the phase down. 

It should be noted that these emission reductions resulted in significant decreases in Pb concentrations in 

other media. The document would benefit from a quantitative description of these historical decreases, 

as well. An introductory paragraph describing the range and central tendencies of media concentration 

for each of the three previous criteria documents could be provided for each media. It would also be 

important to note and provide comparative data regarding exposure reduction from Pb in non-air 

exposure media achieved in the same time frame. These include paint, solder, drinking water, food, and 

consumer items. This information would help provide perspective regarding the significance of 

uncertainties in the exposure assessment used in the current evaluation, particularly the extent to which 

blood Pb concentration can be related to average air Pb emissions. 

This discussion should be followed with best estimates of contemporaneous concentrations in these 

media today, i.e. the new information. There seems to be little new data, at least in the peer-reviewed 

literature, and the document should indicate that the adequacy of the databases and studies available to 

characterize contemporaneous Pb exposure is extremely limited, relative to the new Pb NAAQS.

The document provides little contrast of the relative contribution of air Pb to contemporaneous 

exposures from other media. The lack of contemporaneous monitoring and surveillance data, suggests 

that such comparisons will, necessarily, be achieved by modeling. As such, the chapter would benefit 

from a description, and a scientific assessment, of the exposure models available and applied to 

undertake such analyses, and the empirical data available to inform or verify the modeling efforts.

Specifically, it would be informative to include a brief description of the default assumptions regarding 

modeling assumptions that apply to the Integrated Exposure Uptake Biokinetic (IEUBK) model:

• Multiple source analysis for estimating indoor dust Pb concentration (% contributions from 

various sources)

• Contribution of soil Pb to indoor dust Pb (MSD)

• Contribution of outdoor airborne Pb to outdoor soil (indicate this is not part of the model)

• Contribution of outdoor airborne Pb to indoor dust Pb

• Final breakdown of % contribution to average daily intake by exposure pathway

The chapter should more directly discuss the extent to which empirical data are (or are not) available to 

tailor these assumptions to evaluate specific scenarios.
A-6

There is a potential for confusion regarding the intended utility of the mechanistic models for evaluating 

risks at the national scale. The chapter should more clearly emphasize that a series of scenarios be

developed to represent a range of plausible exposure conditions at a community level and that, 

collectively, this provides a perspective on how the distribution of blood Pb concentrations may vary 

among communities that share similar exposure profiles. This strategy contrasts with developing a single 

model run, for example, that represents all children in the United States. With this introduction, it will be 

easier to explain the relevance of various empirical data sets for the overall evaluation. For example, the 

air Pb to blood Pb relationships reported in the literature generally reflect studies in various 

communities. Rather than attempting to consolidate the results into a single summary statistic, the range 

of slope factors needs to be characterized and presented. Similarly, this explains why the summary 

statistics of blood Pb distributions reported by the National Health and Nutrition Examination Survey 

(NHANES) are not used to adjust or otherwise update the default geometric standard deviation (GSD)

term in the IEUBK model. 

The EPA’s Technical Review Workgroup has periodically updated estimates of average daily Pb uptake 

from food as data from the Food and Drug Administration’s (FDA’s) Total Diet Study become 

available. This time course of changes over time by age group would be informative to include in the 

chapter and the overall assessment.

4b. Biological markers of Pb exposure and body burden are discussed in Section 4.3. How well does this 

section reflect the current state of knowledge of Pb biomarkers and their interpretation as it relates to 

exposure and dose? Is the focus on blood Pb and bone Pb appropriate, given that the epidemiologic 

literature largely assesses exposure through these two biomarkers? Is there sufficient and accurate 

discussion of the relationship between blood Pb and bone Pb? Are relationships between blood Pb and 

Pb in soft tissues and urine Pb adequately described?

The biomarkers section is well written. The CASAC panel comments generally relate to topics that 

should be added or receive additional or clarifying discussions. Although there is little ‘new’ 

information on Pb biomarkers, the discussion of Pb biomarkers and the interplay between Pb in blood 

and bone, and the impact of a short duration or discontinuous exposure on the various dose metrics 

(concurrent, maximum, integrated, etc.) is helpful. 

In general, figures showing the Pb in blood and bone profiles generated using the Leggett model were 

useful. The figures could be more useful to a broader audience if the discussion was extended to include 

the modeling assumptions, and to describe how the model predictions are validated by or compared to 

empirical biomarker data. In particular, it would be useful to help the reader understand the apparent 

differences in rate of blood Pb decline depicted in Figures 4-6, 4-8, and 4-10 vs. empirical data which 

sometimes show a slower rate of blood Pb decline. It could be helpful to match, or at least compare and 

contrast Pb exposure histories in the Leggett model simulations vs. data from comparable empirical 

studies. The narrative should note that other models, such as that of O’Flaherty et al. (1998), would 

often predict a slower decline in blood Pb concentration following cessation of exposure than several of 

the Leggett model simulations depicted in section 4.3. On page 4-48, line 9, the document states: 

“Based on this hypothetical simulation, a blood Pb concentration measured 1 year following cessation of 

a period of increased Pb uptake would show little or no appreciable change from prior to the exposure 

event whereas, the body burden would remain elevated.” The discussion in this paragraph should be 

expanded to reflect the fact that in many exposure scenarios, the decline in blood Pb following cessation 

of exposure would proceed at a slower rate, requiring far longer than one year for blood Pb

concentration to return to pre-exposure levels.
A-7

Many paragraphs in the biomarker section reviewing new literature would be improved by evaluative, 

judgmental conclusions in paragraphs, i.e. why is a reviewed paper important, what does it add to 

existing knowledge, etc.

Although it is not necessary to repeat detailed information on precision, accuracy, and variability in 

bone Pb reviewed in the 2006 AQCD, summarizing data here would be useful, particularly as these 

technologies can have relatively poor reproducibility especially in populations with lower bone Pb 

content or low bone density. (For example, Hoppin et al., Environ Health Perspect 2000;108:239-42; 

Hoppin et al., Environ Health Perspect 1995;103:78-83). An important consequence (not mentioned 

here) of expressing bone Pb measures relative to bone mineral content is that lower bone mineral density 

is associated with greater measurement uncertainty in bone Pb. This density dependent uncertainty can 

have important implications for studies in older women for whom low bone mineral density is more 

common than in other populations including men and younger adults. 

The working definitions of absorption and bioavailability do not make the terms very distinct. 

Absorption refers to the fraction of Pb absorbed from respiratory or gastrointestinal tract while 

bioavailability refers to the amount of Pb ingested or inhaled that enters systemic circulation. Is it the 

units (fraction vs. amount) or the specificity of absorption into ‘systemic circulation’ that distinguishes 

the two terms? This ambiguity is furthered by the apparent interchangeable (or incorrect by these 

definitions) use of the absorption and bioavailability. Most of these inconsistent uses probably result 

from carry-over usage from the original paper. These definitions should be revisited and the entire ISA 

document be reviewed for use consistent with the clarified definitions. 

The section on the definition, application, and limitations of biomarkers should be expanded (and carried 

into section 4.7.3). The section introduction would be well served by defining the distinction between, 

validation and application of, biomarkers for Pb exposure, body burden, internal dose, and risk. The ISA 

recognizes that the Pb biomarkers are not equally valid when applied to different exposure scenarios but 

does not consistently apply this principle in assessing the epidemiologic literature. E.g., blood Pb in 

older adults reflects not only current but likely past exposure and this is not clear in the ISA. Similarly,

where bone Pb appears to be a stronger predictor of outcome than blood Pb (see blood pressure 

literature), acknowledgement that this difference in biomarker sensitivity may reflect differences in 

chronic vs. short-term Pb exposure effects is not consistently done. 

Pb biomarkers are not equally valid when applied to different exposure scenarios, so it is important, 

when using and interpreting biomarkers, to clearly describe the exposure scenarios and their limitations. 

The Chapter 4 text contains cogent, but scattered discussions (including figures) illustrating this point. 

Because blood and bone Pb levels are used for risk assessment and management, this discussion is 

important enough to bring up to section 4.0 or at least 4.3 and the summary. 

The sections on kinetics and Pb biomarkers should recognize that adolescents are poorly defined by all 

existing physiologically based pharmacokinetic (PBPK) and biokinetic models. Individuals undergo 

rapid changes in sexual development, growth, food and water intake, bone growth and turnover, 

behavior, etc. during adolescence. There is a paucity of experimental measurements of Pb biomarkers 

during this time developmental window. The individual biological and kinetic parameters for 

adolescents are largely interpolated rather than based on solid experimental and toxicological 

measurements. These deficiencies limit the validity of model predictions in this age group. 
A-8

The relationship between air Pb and blood Pb is not completely described. The literature review is good, 

but not complete and generalizations (conclusions) are not clearly made and on a firm basis. Respiratory 

tract deposition and clearance are reported in the context of a specific study, but the ISA does not give a 

sense of the breadth of the issue or the scientific context for this information. Perhaps a table abstracted 

from Chapter 3 that summarizes relationships between PM size, Pb content, blood Pb, etc. would be 

helpful. 

4c. Section 4.5.1 discusses empirical models of air Pb-blood Pb relationships from new and old studies. 

This was an important policy issue in the last Pb NAAQS review. Does this section accurately reflect 

what is known about air Pb-blood Pb relationships? Are there particular studies that should receive less 

or greater emphasis?

The inclusion of additional studies from which to estimate air Pb to blood Pb slope factors is a positive 

advancement from the previous NAAQS, which relied on just one or two studies. The CASAC is 

unaware of any additional studies that could be added to the list. The ISA should critically discuss and 

evaluate the finding in several studies that the slope between air Pb and blood Pb changes (typically 

increases) at low air Pb values. The narrative should consider offering a science-based judgment 

regarding which relationship(s) are optimal for quantitative risk assessment.

Useful summary information is presented regarding the empirical data available to estimate the blood Pb 

to air Pb slopes. Table 4-11 should include additional information: 1) parameters of the models; 2) air Pb

intervals used to calculate each slope; 3) description of the study conditions such as ambient urban, 

adjacent to smelter, and phase-out of Pb; and 4) type of air sampling and PM cut points. 

The text that references the table should highlight the subset of studies that are particularly useful for the 

NAAQS evaluation and explain why they are useful. This approach would adhere to the goal of 

critically evaluating the literature and selecting key studies, rather than simply compiling study results. 

An error was identified in the presentation of the Brunekreef (1984) study – the lower bound on the air 

Pb interval should be changed from 0.15 to 0.50 μg/m3

. 

The EPA appropriately emphasizes that the slope factors vary, in part, due to the form of the equation. 

For example, the log-log equations yield higher slope factors at lower air Pb concentrations. Given this 

observation, it is even more important that readers can easily see how the range of empirical data may 

compare with alternative NAAQS standards. A figure can be generated that presents results from each 

study on one chart (as a separate series), showing how the calculated slopes vary as a function of 

discrete intervals of air Pb concentrations. This will help the reviewer understand which slopes are valid 

in the air concentration of interest (e.g., 0.1 – 2 μg/m3). 

Figures should also be generated to illustrate the potential change (reduction) in blood Pb concentrations

in relationship to scenarios of reducing the current NAAQS. Examples can be found in individual 

comments from Dr. Goodrum. 

5. Chapter 5 presents assessments of the health effects of Pb, with evidence organized by health effect 

category, endpoint and scientific discipline.
A-9

5a. To what extent are the discussion and integration of the potential modes of action underlying the 

health effects of Pb exposure presented accurately and in sufficient detail? Are there additional modes 

of action that should be included in order to characterize fully the underlying mechanisms of Pb?

In general, discussions of the potential modes of action underlying the health effects of Pb exposure are 

thorough and inclusive of the current scientific literature. The document has done a very good job of 

attempting to, in some respects, prioritize the mechanisms in an integrative fashion so as to explain their 

potential relationships to observed health effects. The inclusion of prior data from past Pb reviews in this 

particular section is appropriate as it is important to the full presentation of known mechanisms. No 

known modes of action have been left out.

The CASAC notes, however, that in some cases, studies are not presented in sufficient detail to conclude 

that the presumed mechanism of action is the basis for reported effects. In the case of studies of 

antioxidant treatments, for example, experimental designs are not adequately outlined. Thus, it could be 

possible that providing an antioxidant contiguously with Pb exposure in an animal model results in a 

decrease in Pb uptake from the gastrointestinal (GI) tract or enhanced excretion or some other 

toxicokinetic change that therefore results in a lower “effective” dose of Pb and lower risk for the health 

effect. Such a scenario would not be consistent with an “antioxidant” mechanism but rather a 

toxicokinetic amelioration of Pb effect.

Some information with respect to the mode of action might be considered misleading or overlyinterpreted. For example, Table 5-2 presents all endpoints and modes of action and the lowest level at 

which the MOA is observed, suggesting that cancer, e.g., is an equally potent endpoint for Pb as is 

neurological effects, which does not seem consistent with the collective evidence.

5b. Does the ISA adequately describe the evidence with regard to the range of exposure concentrations 

(and/or blood or bone levels) associated with the identified endpoints? What are the views of the panel 

regarding the clarity and effectiveness of figures and tables in conveying information about the 

consistency of evidence for a given health endpoint, lifestage of exposure, or biomarker of exposure 

(e.g., blood versus bone Pb levels)?

The extent to which the ISA satisfactorily characterizes the magnitude of Pb exposure that bears a causal 

relationship to various human health endpoints varies according to the health endpoint. 

The ISA offers a satisfactory discussion of recent findings that address and support a conclusion that Pb

exposure associated with blood Pb concentrations less than 5 μg/dL is causally associated with 

decrements in IQ and adverse neurocognitive development in children. With respect to other endpoints 

in children, such as attention deficit hyperactivity disorder (ADHD), a more rigorous and transparent 

“weight of the evidence” analysis is recommended to establish the extent of any causal relationship. This 

analysis should devote more attention to the limitations of the existing studies with respect to 

consistency, reproducibility, bias, control for confounders, and shortcomings in statistical methodology.

With respect to health endpoints in adults, there is uncertainty regarding the extent to which blood Pb

concentrations ≤ 5 μg/dL bear a causal relationship to any health endpoints, particularly because the 

adult populations in which such associations were noted sustained considerably higher blood Pb

concentrations in the past. In several of the study cohorts finding a relationship between Pb exposure 

and blood pressure elevation or hypertension, bone Pb concentration was usually a stronger predictor 

than blood Pb concentration, consistent with the importance of the subject’s cumulative Pb exposure, 
A-10

rather than their current low level exposure, for any causal relationship. The subjects in these cohorts 

may have been experienced unique developmental effects of Pb at exposure levels higher than indicated 

by contemporary adult blood Pb values. In addition to the ubiquitous concern regarding the influence of 

higher blood Pb concentrations experienced earlier in life, other limitations apply to causal assessments 

made for other health endpoints in adults. In the case of renal effects, causal inferences are limited by 

the potential for reverse causation, inconsistency in the epidemiological observations, and the absence of 

a demonstrable nephrotoxic mode of action at a blood Pb concentrations ≤ 5 μg/dL. For immune effects 

in both adults and children, the discussion should devote greater attention to the paucity of and the 

biostatistical shortcomings of the epidemiological studies that have reported effects of Pb at low dose. 

For every health endpoint, animal models that establish an adverse effect of Pb where the blood Pb

concentration in utero or postnatal never exceeded 5 μg/dL are virtually nonexistent, and statements to 

the contrary in the narrative merit careful review and reappraisal. A detailed “weight of the evidence” 

analysis, including critical appraisal of the strengths and limitations of the supporting studies, is 

recommended in order to establish the strength of evidence for a causal relationship at specific levels of

adult Pb exposure.

The many tables in Chapter 5 that summarize the design and outcomes of epidemiological and 

toxicological studies could be expanded to include a column that allows the inclusion of short comments 

on a study’s notable strengths and weaknesses. In certain tables and figures, the practice of relying on 

extrapolation to characterize a dose-response relationship at a low blood Pb concentration (e.g., renal 

effects at a blood Pb concentration of 1 μg/dL in Figure 5-43) should be used sparingly, if at all, 

particularly when none of the studies included significant numbers of subjects with such a low blood Pb

concentration, or when the validity of such extrapolation may be subject to considerable uncertainty. It 

would be helpful for summary figures such as Figure 5-29 to include study citations, and to distinguish 

among the endpoints with respect to the strength of the evidence. In like manner, summary tables such 

as Tables 2-2 and 2-3 should be substantially revised to distinguish among specific health endpoints for 

which a causal effect of Pb at a particular dose is established, versus those for which a causal 

relationship (in the terminology of Table 1-2) may be only “likely” or “suggestive”. 

Several sections of the narrative would benefit from an expanded discussion of the significance of the 

observed effect sizes. Some guidance to the reader in appraising the public health significance of 

observed Pb effects should be included here. Public health significance (i.e., for populations) should be 

distinguished from clinical significance (i.e., for individuals). The ISA should make clear that: (1) 

individual risks may vary from the point estimates of effect observed in population-based epidemiologic 

studies and (2) depending on the outcome, small effect sizes may have important impacts on health at 

the population level (see Bellinger DC Interpretation of small effect sizes in occupational and 

environmental neurotoxicology: individual versus population risk. Neurotoxicology 2007;28:245-251 

and Kraemer HC, Epidemiological methods: about time. Int J Environ Res Public Health 2010;

7:29-45).

5c. Should discussion of specific endpoints be expanded to provide a more comprehensive assessment of 

health effects associated with current Pb exposures in the U.S. population overall or in susceptible 

groups?

The discussion of specific health endpoints in chapter 5 is sufficiently broad in scope, and inclusion of 

additional health endpoints is not required. Rather than any expansion of the proposed endpoints, 

integration of associations within and across endpoints might be enhanced, especially with respect to 

mechanisms. Many neurodevelopmental outcomes are not independent, but rather bear expectable 
A-11

associations to each other; disturbances in one system might have downstream consequences for 

functioning in another system. Explicating these connections would be useful. The review presents 

evidence for differences in behavioral outcomes in different age groups upon exposure (so that 

symptoms of disruptive behavior are found in children, while symptoms of depression are found in 

adults); since these reflect quite different features of psychopathology, some discussion of those 

differences, and the implications of detection differential associations should be explicated.

5d. What are the views of the panel on the integration of epidemiologic and toxicological evidence, in 

particular, on the balance of emphasis placed on each discipline and the accuracy with which the 

evidence is presented? Considering the Pb exposure concentrations and durations in toxicological 

studies and the potential for confounding in epidemiological studies, please comment on the conclusions 

drawn about the coherence of the evidence and biological plausibility.

Chapter 5 provides a comprehensive review of the human epidemiologic and toxicological evidence on 

the health effects of Pb. The chapter is organized by health effects with results from human and related 

toxicological (both in vitro and in vivo) studies presented in tandem for each outcome. Overall, the 

approach works for integration across the two disciplines. However, the CASAC recommends a number 

of modifications to the chapter and identifies several ways to improve the application of causal 

determination criteria to the chapter’s conclusions:

1) An introductory section should be included that reviews homologies between animal and human 

assessments.

2) Where possible, to improve organization of the toxicological data presentation, specific outcome 

measures within a given health effect should be organized into broad conceptual groups (e.g., 

learning, attention, hearing) to maximize comparability between measures from human and 

animal studies. For example, studies of learning in animals (the Morris water maze, among 

others) should be described in parallel to findings from learning and memory tests in humans. 

Studies of animal attention or impulse control can be described in parallel to tests of the 

analogous behaviors in humans, e.g., studies of ADHD or CPT.

3) For each health measure, there should be a critical discussion of the strengths and limitations of 

the available literature. Those studies with more robust designs and methods should be explicitly 

acknowledged and contribute greater weight to inferences and conclusions. In addition, a column 

of study limitations (and strengths) should be added to the tables summarizing findings from the 

literature reviewed. The summarized information should also note negative findings (e.g. the 

notable absence of a predictive effect of blood Pb in studies that reveal a predictive effect of 

bone Pb). The chapter would benefit from a more rigorous presentation of a weight of the 

evidence analysis for each health measure.

4) As an extension of item #3, the application of the causal determination criteria often lacks 

transparency, and would benefit by a more specific and structured approach. For example, within 

a given category of health outcome such as “neurological effects”, the analysis should better 

differentiate the weight of evidence as it applies to divergent outcomes (e.g., childhood IQ, 

ADHD, adult ET) for which the strength of findings for low-level Pb associations is highly 

variable.
A-12

5) Animal studies with exposures most relevant to human health effects should be emphasized. This 

means focusing on doses relevant to low level human exposure, critical consideration of 

exposure route (e.g., oral, intravenous, and intraperitoneal) and Pb form (Pb acetate, Pb 

chromate, etc.), and the relevance of temporal patterns of exposure to health effects with long 

latencies. For example, direct injection of Pb into the hippocampus may not be informative for 

human neurobehavioral effects, exposing animals to Pb-chromate has limited utility in assessing 

Pb’s potential carcinogenicity, and short-term exposure and outcome measures are unlikely to be 

applicable to Pb-associated hypertension or renal disease in human populations.

6) As an extension of item #5, the Chapter includes toxicological data that, in a number of cases, 

involve Pb exposures substantially higher (e.g., an order of magnitude or greater) than would be 

characteristic of U.S. non-occupationally exposed populations and thus findings from these 

studies are of uncertain relevance to an assessment of low-level Pb effects in people. In many of 

the epidemiologic studies of adults’ adverse health effects, the contemporaneous blood Pb 

concentration of participants likely differed substantially from blood Pb concentrations earlier in 

life when average population blood Pb levels were higher. Tables (e.g., 2-2, 2-3, 2-8) that 

summarize the impact of current low level Pb exposure need revision to reflect likely higher past 

blood Pb concentrations (and cumulative exposure) in determining the risk of current adult 

disease. 

7) Similarly, providing some context relating in vitro exposure levels to low-level human exposures 

would be helpful. In general, in describing in vitro and in vivo study results exposure media need 

to be explicitly defined and, as much as possible, standardized exposure units should be used to 

facilitate comparison and interpretation of findings across studies and systems.

8) In seeking coherence between plausible modes of action and many of the chronic human health 

outcomes discerned in epidemiological studies, such as hypertension, renal insufficiency, and 

possible neurodegenerative changes in adults, the narrative should highlight evidence for modes 

of action that are consistent with the insidious and latent development of these endpoints. Such 

modes of action may include, but not be limited to, epigenetic impacts on gene expression, 

remodeling of tissue structure or responsiveness (e.g. in brain, kidney or vascular endothelium), 

and genotoxic and nongenotoxic effects of chronic oxidative stress.

9) Effect modification should be consistently addressed (including potential sexual dimorphisms in 

Pb toxicokinetics or effects), particularly as, dependent on the context, it can result in Pb effects 

at lower levels than occur in the absence of the modifier. The magnitude of the interaction should

be explicitly described as part of assessing its biological relevance.

10) If studies are restricted to males (e.g., the Normative Aging Study (NAS) and a large proportion 

of animal models), potential limited generalizability to females should be acknowledged.

11) For a number of health measures the conclusions regarding health effects of low-level Pb 

exposures are not well justified by careful consideration of the literature reviewed, e.g., lack of 

robust justification of conclusions was particularly notable for the review of immunologic effects 

of Pb. Failure to temper conclusions with study design limitations was particularly problematic 

for the review of the renal effects of Pb.
A-13

12) Examples of specific issues that undermine the robustness of some conclusions include:

(a) a failure to accurately assign Pb exposures, including assigning a lower level Pb exposure 

than comprehensive consideration of the experimental design or the population's 

characteristics justified; 

(b) a failure to acknowledge limitations to findings that were, e.g., only evident in a subset of the 

study population (e.g., subsetting by phenotype or hormone use status) or only evident in 

conjunction with other risk factors (e.g., low-level Pb effects only seen in conjunction with 

relatively high level manganese exposure);

(c) a failure to temper the strength of observed associations in studies for which control for 

potential confounding was not well addressed (as was often the case for occupational cohort 

studies);

(d) a failure to explain limitations regarding the implications of observed associations in 

epidemiologic studies where direct biomarkers of exposure were not used (e.g., in a number 

of occupational studies); 

(e) particularly in studies of chronic disease risk in adults (e.g., cardiovascular disease), the 

chapter does not consistently or carefully acknowledge the likely importance of historical 

(and relatively high) long-term, chronic Pb exposure in determining both current blood Pb 

levels and serving as a surrogate for past levels in estimates of associations of current levels 

with health outcomes.

13) The review of the literature regarding Pb and childhood IQ was, with few exceptions, robust and 

appropriate conclusions were drawn.

14) There were a number of areas of inconsistencies between Chapter 5 and conclusions described in 

Chapter 2 that need to be reconciled.

15) The term “neurological” should be consistently changed to the term “neurodevelopmental”

throughout the document.

(Please see attached individual comments from the panel members regarding specific examples of the 

above issues, including, extensive detailed comments from Dr. Michael Kosnett). 

5e. The 2006 AQCD described a nonlinear dose-response relationship between blood Pb levels and 

cognitive function in children. The ISA presents evidence from epidemiologic and toxicological studies 

to further evaluate potential explanations for the nonlinear shape (e.g., differential proportions of 

susceptible populations in different segments of the blood Pb level distribution, differential activation of 

mechanisms). Please comment on the extent to which the expanded discussion is informative and 

consistent with the available evidence.

The issue of non-linearity of the dose-response for IQ was clearly a critical issue in the previous 

NAAQS deliberations. Additional evidence supportive of the dose-response observed in the Lanphear et 

al., 2005 meta-analysis has been reported since 2006, as appropriately cited here, providing further 

support for the non-linearity of the dose-response curve defining the association between blood Pb and 

IQ, specifically the greater slope at blood Pb levels less than 10 ug/dl than above 10 ug/dl. These 

findings are supported, as indicated, by an animal literature that has similarly reported evidence for nonlinearity of Pb effects that dates back even to the 1970s-80s.
A-14

The CASAC notes that not all human studies will provide evidence for this non-linearity for reasons 

such as lack of sufficient power and /or use of less sensitive outcome measures. In addition, animal 

studies are not likely to fully duplicate the parameters of the IQ slopes seen in studies of 

children. Animal studies commonly employ behavioral measures that are not analogous to the often 

broad skills reflected in IQ scores, but rather make use of more pinpointed behavioral measures that 

likely map onto one or another subcomponent of IQ. Further, animal studies focus on individual 

molecular actions that are components of integrated physiological responses underlying behavioral 

functions.

6. Chapter 6 is a discussion of potential susceptibility factors. Are the characteristics included within 

the broad susceptibility categories appropriate and consistent with the definitions used? Are there any 

key susceptibility factors that were not included and need to be added? Is it appropriate to include 

material on susceptibility factors related to Pb exposure and dose, or should the chapter focus solely on 

susceptibility factors as they influence Pb-induced health effects? Susceptibility to Pb associated effects 

is also discussed in sections of the ISA other than Chapter 6. Does the ISA adequately cover and 

appropriately distinguish lifestage-dependent differences (e.g. differences between children and adults) 

as they relate to the modes of action of Pb, potential exposures to Pb, toxicokinetics and Pb biomarkers, 

health effects of Pb and susceptibility to Pb induced effects?

For lead, issues related to susceptibility across the life course are critical for public health protection. 

While the chapter covers relevant studies, the conceptual framework for interpreting them needs to be 

modified to more sharply address factors that may lead to increased risk and to increased exposure or 

dose. The ISA lays out an ambiguous set of terms and a conceptual model that does not adequately 

support interpretation of the literature. The CASAC had similar concerns with regard to the first draft 

ISA for ozone and voiced them in its letter to Administrator Jackson dated August 10, 2011. Those 

comments are applicable to the lead ISA as well, and we recommend revisions that parallel those made 

in Chapter 8 of the second draft ISA for ozone.

The title is perhaps inaccurate—while the chapter discusses variations in blood Pb levels by age, this is 

NOT a major focus of the chapter, which discusses genetics, nutrition, soil exposure and other variables. 

There also are quite a few places where literature is discussed in what seems the wrong section, that is, 

much discussion of factors that are risks for Pb exposure/absorption are discussed in the section on 

susceptibility to Pb effects. This editing problem should be relatively easy to address.

In many places in this chapter, there are sections with only a few citations, in some cases discussing only 

a single article (i.e., the article on Pb’s association with ADHD being stronger among those exposed to

secondhand smoke). The CASAC recommends that the EPA be very clear on the strength of evidence in 

the literature and cautious in inferring causality in this chapter based upon the limited number of studies 

available.

Throughout the chapter specific topics that are mentioned are discussed in more detail elsewhere in the 

report. The CASAC concludes that it would be very useful to point the reader to the relevant section, or 

better still, to the exact page, and for the electronic version, to provide relevant hyperlinks. Given the 

size and comprehensiveness of this review, such linking would greatly facilitate the use of the entire 

document.

The CASAC finds that this chapter would be strengthened with more discussion of nutritional aspects 

that serve to increase susceptibility, and more discussion is warranted for differences in effects by 
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gender (or the need for more research in this area), more discussion of gene-environmental interactions 

(with the provision of the magnitude of associations/effects) and epigenetic implications.

Insufficient emphasis is given to the findings that even older children and adolescents are vulnerable to 

neurocognitive effects as is clear from findings showing the sometimes even stronger associations of 

concurrent blood Pb levels with IQ scores. It also was noted that there are other factors that could be 

better described, such as age of housing stock, percentage of homes with Pb-free windows, having grass 

cover or bare soil in yards and playgrounds.

7. Chapter 7 is a discussion of the ecological effects of Pb. Effects on terrestrial and aquatic ecosystems 

are first considered separately. They are then integrated by classes of endpoints (bioaccumulation, 

growth, mortality, hematological effects, development and reproduction, neurobehavior, community and 

ecosystem effects). Does the panel consider this approach appropriate? Is it appropriate to derive a 

causal determination for bioaccumulation as it affects ecosystem services? Has the ISA adequately 

characterized the available information on the relationship between Pb exposure and effects on 

individual organisms and ecosystems, as well the range of exposure concentrations for the specific 

endpoints? Are there subject areas that should be added, expanded upon, shortened or removed? If the 

ISA was expanded to consider dose-response in terrestrial systems, should we limit data to field soils? If 

the ISA were expanded to consider dose-response in aquatic systems, how might we most efficiently 

present toxicity data that varies greatly by organism, and environmental parameters that influence 

bioavailability (pH, dissolved organic carbon etc.)?

Chapter 7 is well written, effectively organized, and does an adequate job of addressing “new” published

data (post-2006). However, the chapter did not address pre-2006 information, so it is difficult to 

understand the context and contribution of more recent data to the body of knowledge on Pb toxicity and 

how they may or may not inform a decision to revise the secondary NAAQS for Pb. This is particularly 

important given that the extant regulatory values (e.g., Ambient Water Quality Criteria and the terrestrial 

ecological soil screening level values) that are relied upon are somewhat dated, 1985 and 2003, 

respectively. The document would be greatly improved by providing a short summary of the status of 

relevant knowledge at the time of the 2006 AQCD at the beginning of each section, followed by the 

present review of the literature for the topic. Sections could then be summarized with short statements 

indicating which significant new findings would be relevant to revising the secondary NAAQS and why 

other studies were not.

The separation of terrestrial and aquatic ecosystem data is appropriate and the subsequent organization 

by endpoints and levels of biological complexity is good. Marine and freshwater toxicity data should be 

segregated in the chapter due to differences in Pb speciation and bioavailability and the possibility of 

differences in the sensitivity of freshwater and marine organisms.

Is it appropriate to derive a causal determination for bioaccumulation as it affects ecosystem services?

This is a difficult question since the process of bioaccumulation, i.e., the uptake and accumulation of 

environmental pollutants by organisms, may or may not have any effects on ecosystem services. The 

process of bioaccumulation itself should not necessarily be thought of as an adverse or toxic effect. 

Bioaccumulation of Pb in select tissues is a normal metabolic process by which an organism is able to 

sequester and ultimately detoxify or eliminate Pb, e.g. metal-rich granule formation in mollusks and 

earthworms. Only when the rate of bioaccumulation exceeds the capacity of the organism to detoxify or 

excrete Pb are toxic effects evident. It may very well be possible to derive a “causal” relationship 
A-16

between exposure and the presence of metals in tissues. However, due to the non-linear relationship 

between exposure concentration and tissue concentration with metals, developing a quantitative 

relationship would be difficult.

Similar concerns exist when evaluating possible food chain related effects. Available data suggest that 

little tissue bound Pb is bioaccessible when consumed by predators, thus leading to “biodilution” of Pb

concentrations as one moves up food webs. If sufficient substantive evidence exists that trophic transfer 

results in toxicity, then a causal assessment may be appropriate. Most of the available data suggest that 

biodilution is the predominant fate of Pb during trophic transfer, but some studies suggest moderate

effects. As a regulating ecosystem service, bioaccumulation may provide a mechanism for decreasing 

bioaccessible Pb, but this would likely be minor compared to other fate processes. Overall, a causal 

determination for the bioaccumulation of Pb as it affects ecosystem services is not warranted at this 

time.

Has the ISA adequately characterized the available information on the relationship between Pb 

exposure and effects on individual organisms and ecosystems, as well the range of exposure 

concentrations for the specific endpoints? 

The ISA has done an excellent job of synthesizing and discussing the relationship between Pb exposure 

and effects on individual organisms and ecosystems with the new information available since 2006. 

Since the document relies on data that existed prior to 2006 and does not provide a summary of the 

extant data it is somewhat difficult to assess how adequately the document characterizes all of the 

available information. Summarization of all of the available data would be helpful; however, 

presentation of all of the available data would make the document unwieldy. Presentation of the 

available data in the form of a species sensitivity distribution (SSD) that identifies new versus old data 

would be helpful to the reader. Also, the ISA relies solely on published toxicity data available in the 

open literature. Additional unpublished, toxicity information may be available from the Pb industry 

given all of their efforts over the past 5+ years in developing data for compliance with the European 

Union Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulations. This 

data may be very useful pending review and acceptance by the EPA and should be expressed as a 

separate SSD, if used, to facilitate comparison with existing data.

Are there subject areas that should be added, expanded upon, shortened or removed?

The ISA does a good job of covering most post-2006 published data relating to Pb effects on aquatic and 

terrestrial organisms. It is interesting, however, that a number of endpoints such as physiological stress, 

hematological effects, and neurobehavioral effects are considered in this document. Traditionally the 

EPA has limited their interpretation of environmental effects to those effects that can be directly related 

to population and community level concerns. This approach has limited endpoints considered for criteria 

and standards to those associated with organism survival, growth, and reproduction. Alternative 

biochemical or physiological level endpoints are considered only when they can be linked directly to 

population or community level concerns. Therefore, since no direct linkages can be made between an 

observation of a biochemical, behavioral, or physiological endpoint and a population or community 

level concern, it may be appropriate to eliminate discussion of these types of endpoints from the ISA. If 

these endpoints are judged not to be germane to this effort, they should be moved to an appendix.

In addition to the issue of endpoint application, there is also the issue of relevance to organisms, 

populations, and ultimately, application in the revision of the secondary NAAQS. As an example, 
A-17

consider Pb-induced hypometabolism under conditions of environmental hypoxia in crayfish (Morris et 

al., 2005). Pb may not be the sole causal agent in this study since it is combined with reduced oxygen 

levels. Glycogen levels in the freshwater snail B. glabrata were significantly decreased at near 

environmentally relevant concentrations of Pb (50 μg/L) (Ansaldo et al., 2006). Glycogen levels in 

organisms decrease with exposure to any number of environmental stressors. In both these studies and 

others related to sub-organismal endpoints, the direct relevance of Pb exposure to organism survival, 

growth, or reproduction needs to be established. 

The ISA treats terrestrial and aquatic ecosystems separately and for clarity of understanding and this is a 

good separation. However, one casualty of this approach is that the linkage between the two media is 

lost. Pb loadings to aquatic ecosystems, especially freshwater systems, are primarily derived from the 

runoff of terrestrial systems. It would be useful to include a discussion of the linkages of watershed 

processes between terrestrial and aquatic systems.

If the ISA was expanded to consider dose-response in terrestrial systems, should we limit data to field 

soils?

Data selection should be limited to field soils. Artificial soil is not a soil, but is a standardized test 

substrate, and data generated using artificial soil have no relevance to any application in real soils. 

Artificial soil is used as a reference condition in standardized laboratory bioassays with soils and as a 

standardized test matrix for conducting “proof of concept”-type bioassays with soil invertebrates. In the 

development of the ecological soil screening levels, the EPA did not consider data generated using 

artificial soil as acceptable. For plants, hydroponic test systems may be convenient, but not for 

examining the effects of Pb in soil since the matrix (actually lack of a soil matrix) itself has a 

tremendous effect on plant physiology and hence Pb uptake and metabolism. Also, given the clear effect 

of “aging” and soil physical/chemical characteristics on the biological cycling of Pb in terrestrial 

ecosystems, it would be best to limit dose-response data to studies utilizing field soils.

If the ISA were expanded to consider dose-response in aquatic systems, how might we most efficiently 

present toxicity data that varies greatly by organism, and environmental parameters that influence 

bioavailability (pH, dissolved organic carbon etc.)? 

The best approach for presenting wide differences in sensitivity among organisms is through a species 

sensitivity distribution (SSD) approach. Physical and chemical parameters that influence Pb 

bioavailability are best discussed in terms of a description of the biotic ligand model (BLM). The BLM 

approach would allow standardization of exposure in the SSD to the concentration of free Pb ion and 

important ligands. Application of the BLM to natural waters is best described by presenting the results 

of calculations using a series of natural waters or waters that exhibit a range of composition and 

chemical/physical parameters found across the United States. By presenting the data in this fashion the 

reader can easily ascertain the relative importance of each of the parameters on assessing Pb toxicity. 

This applies to both the aquatic environment as well as to the terrestrial environment.

Bioavailability and bioaccessibility are extremely important in assessing the toxicity of Pb to 

environmental receptors. Total concentrations of Pb in soil and water are inappropriate expressions of 

exposure and better effects relationships are found with respect to the soil pore water concentrations and 

free Pb ion in water. Aquatic and terrestrial BLMs are the state-of-the-science and must be considered 

when evaluating possible environmental effects.
A-18

The terms bioconcentration factor (BCF) and bioaccumulation factor (BAF) are used somewhat 

inconsistently, this should be revised to reflect proper use. The CASAC notes that BCF and BAF are

inappropriate measures to assess the hazard of Pb. The CASAC recommends providing a better 

assessment of the utility (or lack thereof) of BCF values, rather than simply reporting the data from the 

literature.
B-1

Enclosure B

Compendium of Individual Comments by CASAC Lead Review Panel Members on 

EPA’s Integrated Science Assessment for Lead 

(First External Review Draft – May 2011)

Mr. George A. Allen...................................................................................................................... 2

Dr. Herbert E. Allen ..................................................................................................................... 5

Dr. Deborah Cory-Slechta.......................................................................................................... 10

Dr. Cliff Davidson....................................................................................................................... 15

Dr. Philip Goodrum.................................................................................................................... 21

Dr. Sean Hays.............................................................................................................................. 25

Dr. Philip Hopke ......................................................................................................................... 27

Dr. Chris E. Johnson .................................................................................................................. 29

Dr. Susan Korrick....................................................................................................................... 35

Dr. Michael Kosnett.................................................................................................................... 44

Dr. Roman Lanno ....................................................................................................................... 54

Mr. Richard Poirot ..................................................................................................................... 63

Dr. Joel Pounds........................................................................................................................... 70

Dr. Michael Rabinowitz.............................................................................................................. 75

Dr. William Stubblefield ............................................................................................................ 80

Dr. Ian von Lindern.................................................................................................................... 82

Dr. Gail Wasserman ................................................................................................................... 89

Dr. Michael Weitzman................................................................................................................ 92
B-2

Mr. George A. Allen

General Comment: The Health and Environmental Research Online (HERO) system is a wonderful 

resource for panel members. While there have been a few problems with access, those were resolved. I 

encourage continued use of this approach for future National Ambient Air Quality Standard (NAAQS)

review documents.

Comments on Chapter 3 - Ambient Lead: Source to Concentration

Charge Question 3: To what extent are the atmospheric science and air quality analyses presented in 

Chapter 3 clearly conveyed and appropriately characterized? Is the information provided regarding Pb 

source characteristics, fate and transport of Pb in the environment, Pb monitoring, and spatial and 

temporal patterns of Pb concentrations in air and non-air media accurate, complete, and relevant to the 

review of the Pb NAAQS? Does the ISA adequately characterize the available evidence on the 

relationship between ambient air Pb concentrations and concentrations of Pb in other environmental 

media?

Overall, the document is well written, comprehensive, and reflects a very detailed review by EPA staff 

of all aspects the state of the science. As with the ozone Integrated Science Assessment (ISA), it may be 

too comprehensive in some areas, and could benefit from editing to reduce the overall length and 

improve the focus of the chapter.

The discussion of lead (Pb) source characteristics and the fate and transport of Pb in the environment are 

relevant and adequate. The section on the sampling aspect of Pb monitoring is brief, while the review of 

analysis methods is detailed. The substantial limitations of the present Hi-Vol FRM sampler for Pb are 

noted, but the document doesn’t suggest anything better other than PM10, which can underestimate Pb 

in some near-source scenarios (but not GA airports). There is no clear discussion of the exposure/health 

implications of changing the FRM sampler to PM10; in that sense this chapter needs to be linked to later 

chapters on exposures.

There is a substantial history of CASAC recommendations to not use the Hi-Vol sampler as the FRM 

sampler. The CASAC letter of July 18, 2008 states on pages 7 and 8:

“In several rounds of previous comments, the CASAC Panel recommended that a revised (and 

substantially-lowered) Lead NAAQS should be accompanied by a transition of the sampling 

indicator from total suspended particulates (TSP) to a low-volume ambient air monitor for lead 

in particulate matter (PM) less than 10 micrometers in diameter (PM10) in ambient air. In the 

CASAC’s advice dated January 22, 2008 (EPA-CASAC-08-007), the CASAC noted that the 

CASAC Panel "unanimously supported the selection of an [PM10] indicator that can be more 

robustly measured and thus would be more representative of actual population exposures," 

adding that "a more accurate and precise Pb-PM10 indicator would provide a more stable 

determination of compliance with the new lower Lead NAAQS." With regard to concerns over a 

potential loss of ultra-coarse lead particles by PM10 samplers, the CASAC Panel further noted 

that "it would be well within EPA’s range of discretionary options to accept a slight loss of ultracoarse lead at some monitoring sites by selecting an appropriately conservative level for the 

revised Lead NAAQS." In a subsequent teleconference consultation by the CASAC Ambient Air 

Monitoring and Methods (AAMM) Subcommittee held on March 25, 2008, a majority of the 
B-3

subcommittee members also supported a transition from TSP to low-volume PM10 sampling for 

lead (see EPA-CASAC-08-010 dated April 14, 2008). "

Since then, the topic has been discussed in the CASAC AAMMS letter of Nov. 30, 2010 on review of 

the Pb FRM, and also during the May 5, 2011 consultation on the Draft IRP.

Despite these CASAC communications to EPA, the agency has not yet taken meaningful action to 

address these concerns. While this discussion doesn’t directly fit into the framework of the ISA, this is 

the only part of the current NAAQS review process that could address this issue in an exposure/healthoutcome context and still allow sufficient time for ORD to evaluate potential replacements to the Hi-Vol 

sampler other than the existing PM10 low-volume FRM sampler (by the time the review of the PAD 

starts, it is too late to start any such evaluation for inclusion in any revision to the NAAQS). The 

uncertainty of air-related Pb exposures is much much larger than the modest (~20-30% on average but 

wildly variable) change in ambient Pb measurements between the Hi-Vol and Pb-PM10. A very recent 

review article on Pb concentrations and size distributions was just published in Atmospheric 

Environment by Cho et al., 45 (2011) 5005-5015, DOI 10.1016/j.atmosenv.2011.05.009 . The overall 

impression from this paper is that there are few robust studies of Pb size distribution that would be 

relevant to NAAQS exposure issues. The agency could evaluate the existing PM10 inlet aspiration 

efficiency as a function of wind speed as an expeditious approach to a “larger than PM10" Pb sampler 

for this round of the NAAQS review.

Another area of general concern is that there is no meaningful discussion of Pb in wildfire and 

residential space heating woodsmoke. There is Pb in woodsmoke (WS), and especially for valley towns 

where WS concentrations can be high for much of the winter, this could be the primary air exposure 

pathway for “new” Pb. Page 3-102, line 28 notes that fine mode Pb is fairly soluble and thus would be 

expected to be present in wood just as Hg and sulfur are, especially in the eastern US.

The document notes that relevant data for spatial and temporal characterization of Pb in air and non-air 

media are very limited. It is likely to remain limited given current resource constraints. Similarly, there 

are limited data to adequately characterize the relationship between ambient air Pb concentrations and 

concentrations of Pb in other environmental media; the document’s discussion of this topic is adequate 

given these constraints.

Specific comments follow (page, line[s]).

3-2, 14-16: The 2008 NEI reports GA aircraft as 49% of all Pb emissions, but the % that is relevant to 

human exposure is likely much much less, since most of those emissions are at altitude and are in the 

fine mode; thus deposition is widely dispersed, and a significant amount may deposit as wet Pb. Thus 

the impact on “new” ground level air Pb is likely to be much less than the emission inventory suggests. 

The way it is stated here may be confusing in this context. I fully support the phase-out of Pb in AvGas 

on general principle, but I am not convinced that AvGas Pb is a significant exposure in the context of the 

current Pb NAAQS.

3-4, 8 and 15-16: it may be worth noting that this smelter (Herculaneum MO, the largest single point 

source of Pb in this country) is closing by the end of 2013 -- sooner than the binding 2016 date. This 

event would present a rare opportunity to study the changes in both soil and vegetation Pb over time

before and after the smelter closes. EPA should consider funding an extra-mural multi-media study 

(STAR?) that starts sampling a year before the smelter shuts down, and insures that near-field soil 
B-4

sampling areas are isolated from potential site cleanup efforts. (Note: a new Pb ore processing facility is 

planned for that site using cleaner technologies.)

3-5, 5: same issue as pg 3-2, above.

3-7, 3: The median Pb value should be reported here, since the data are highly log-normal. The 0.3 

ug/m3 value shown here is an outlier in this study; this should be noted. There is also substantial 

uncertainty in the data quality for this sample; given the lack of runtime data, this sample would be 

voided in AQS. For the very first sample day to be much higher than all subsequent samples makes the 

sample further suspect. The second highest sample for the study is from site A for the same day.

3.2.2.5 [Roadway sources]: While Pb wheel weights are currently a major source, it should be noted 

here that several [at least 7] states have already banned their use, and EPA is planning a NPRM in 2012 

to ban them. Once banned, their use will drop rapidly. Pb in tires is approximately 15 ppm w/w, and the 

mass of tire mass from road wear is very large. More quantitative information on Pb in tires and tire 

wear emission rates would be helpful to better understand their contribution to NR Pb.

3-14, 6: The discussion abruptly switches from Pb-PM to PM concentrations. Is it intended to be “PbPM” on this line?

3-17, 10-13: Pb in WS, and 3-22, 26-29: these cites seem to contradict each other re: Pb in wildfire 

WS. See general comments above.

3-53, 22-26: It should be noted that the dichotomous sampler is a preferred way to measure Pb-coarse in 

areas where the fine to coarse Pb ratio is greater than 1. There is a commercial dichot sampler currently 

approved as an FEM for PM-coarse.

3-56, 10: says 9 elements from Improve, but there are up to 24 reported. Some may be of use in this 

analysis.

3-60, 19-22: Can the single particle mass spec method measure large Pb without substantial losses in 

the sample train?

3-69, 8-14: should tires as a source of near-road (NR) Pb be noted here? As Pb wheel weights are 

phased out, tire wear may become [one of] the largest NR Pb sources of “new” Pb. Tires are 

approximately 15 ppm w/w Pb. Has an inventory estimate ever been made of tire wear as a near-road Pb 

source?

3-69, 29-32: 8 ng/m3 Pb isn’t much of an industrial source value; this needs clarification. Was the 

SEAS Pb measurement validated in any way? The other 2 sites from that study are 1 and 2 ng/m3 Pb, 

levels that are so low as to be unlikely in urban areas.

3-104, 3: “lower rate of error” -- a different term [precision?] should be used here.

3-104, 28-31: it is unclear what dataset is being summarized on line 31.
B-5

Dr. Herbert E. Allen

Comments on Chapter 2 - Integrative Health and Ecological Effects Overview

The authors have prepared a very well-written overview of the health and ecological effects of Pb. There 

are several items that should be modified and there is some recent literature that could be incorporated. 

The items in this review are presented in the order they appear within the chapter.

It would be very helpful for each of the discussions to refer to the exact location in the following 

chapters in which the relevant information is presented.

2-7 line 8. The correlations of Pb with Zn, Br, Cu, and K should be further investigated. Page 2-2 line 28 

indicates that ~49% of total atmospheric Pb emissions come from piston engine aircraft. With such a 

high percentage of the emissions arising from a single source, for the correlations of Zn, Br, Cu, and K 

indicated in page 2-5 line 8, the emissions of these elements from piston engine aircraft would 

necessarily need to be high relative to other sources. Certainly, this is likely for Br (in the absence of a 

significant sea salt input). However, is it also reasonable for the other elements? Emission factor data 

and very simple modeling should be used to resolve this rather than just providing a speculation. Also, 

in line 7 “metals” should be replaced by “elements” as Br is not a metal.

2-7 lines 23-25. Even in areas not near smelters the smelters in operation prior to modern control 

technologies were responsible for a large amount of the emissions of metals to the atmosphere. How 

important are historic mining and smelting as the origins of Pb in soil and sediment?

2-10 Section 2.5.1. Neurological Effects is very well presented. It does an excellent job of integrating 

the information.

2-30 lines 14-16. Aging of lead and other metals in soil is an important phenomenon that greatly affects 

bioavailability. The fundamental physicochemical processes involved in sorption must be understood 

and formulated into appropriate kinetic models of sorption that incorporate chemical speciation.

2-34 lines 17-19. The LC50 is a poor measure to compare to environmental concentrations. Most LC50 

values are for acute, not chronic, exposures. Consequently, if the environmental concentration were to 

reach the LC50 value it is unlikely that there would be a sustainable population. A lower toxicity, such 

as LC5 or LC10, is more reasonable to compare to environmental concentrations.

2-34 lines 29-30. This 50-fold range in the LC50 value for larval fathead minnows for differing pH and 

concentrations of DOC and CaSO4 clearly demonstrates the importance of the chemistry of the exposure 

medium to the effect. The importance of these factors that modify toxicity and are accounted for by the 

Biotic Ligand Model (Di Toro et al., 2001).

2-35 lines 13-14. Many of these Pb concentrations exceed its solubility. Such data have historically 

confounded the literature and have necessitated additional studies of toxicity.

2-38 lines 2-9. Do the adverse effects of Pb on reproduction in invertebrates and vertebrates occur at 

environmental concentrations of Pb?
B-6

2-40 lines 1-4. The sediments used in this study were oxidized by the sample treatment process. This 

would have eliminated acid volatile sulfide from the sample and modified the bioavailability of the 

added Pb. Thus, the sediments cannot be considered to be in their natural state and caution should be 

applied to the interpretation of this and to other studies in which the sediment chemistry has likewise 

been modified. Of course, there is always a great difficulty in relating laboratory results to those in the 

field. However, in this instance one of the major factors known to affect the results has been modified. 

The results appear to be valid, but the extrapolation from laboratory to field may not be.

2-40 line 31. Sulfide should be added to pH and organic matter as an important environmental variable 

that affects Pb bioavailability and toxicity.

2-41 lines 4-16. The EPA Equilibrium Partitioning Sediment Benchmarks (Hansen et al., 2005) should 

be mentioned. These provide a means to evaluate which sediments will not exhibit toxicity.

2-43 lines 13-16. I do not understand the sentence “The level at which Pb elicits a specific effect is more 

difficult to establish in terrestrial and aquatic systems due to the influence of environmental variables on 

Pb bioavailability and toxicity and substantial species differences in Pb susceptibility.” What is implied 

in the phrase “more difficult to establish in terrestrial and aquatic systems”? Is this a comparison to 

human health? These and other environmental variables affect the bioavailability for humans.

References

Di Toro, D.M., H.E. Allen, H.L. Bergman, J.S. Meyer, P.R. Paquin, and R.C. Santore. 2001. Biotic 

Ligand Model of the Acute Toxicity of Metals. 1. Technical Basis. Environ. Toxicol. Chem. 20: 2383-

2396.

Hansen, D.J., D.M. Di Toro, W.J. Berry, W. S. Boothman, R. M. Burgess, G.T. Ankley, D.R. Mount, 

J.A. McGrath, H.E. Bell, and C.S. Zarba. 2005. Procedures for the Derivation of Equilibrium 

Partitioning Sediment Benchmarks (ESBs) for the Protection of Benthic Organisms: Metal Mixtures 

(Cadmium, Copper, Lead, Nickel, Silver, and Zinc). Office of Research and Development. Washington, 

DC. EPA/600/R-02/011

Comments on Chapter 7 - Ecological Effects of Lead

The authors have prepared a very well-written and comprehensive review of recent literature on the 

ecological effects of lead. 

The HERO database and excess ability greatly facilitated the review. This excellent system is a pleasure 

to work with.

There are several items that should be modified and there is some recent literature that could be 

incorporated. 

My greatest concern regards the lack of clarity regarding which reports lead to modification of the 2006 

assessment. It would greatly improve the reader’s understanding of the basis for the assessments if the 

sections first presented a short summary of the status of relevant knowledge at the time of the 2006 

assessment. This could then be followed by the present review of the literature for the topic. Finally, a 

short statement indicating what significant new findings had been included and the reasons that other 
B-7

studies were not included. In this regard it is most important that the review not be simply a recitation of 

the author’s claims within the cited paper. The review should be critical and should point out alternative 

conclusions to those presented by the authors when appropriate. I will illustrate that by a discussion of 

the paper of Ettler et al. discussed in the next paragraph.

7-9 line 28 through 7-10 line 4. Great care should be exercised in the use of selective extraction data 

such as the results of Ettler et al. (2005) cited in the ISA. The assignment of specific geochemical 

associations to the results of these extractions has been demonstrated not to be valid by a number of 

researchers (e.g., Tipping et al., 1985; Rapin et al., 1986; Kheboian and Baur, 1987; Martin et al., 1987; 

and Qing et al., 1994). Not only are metals released from the indicated geochemical phases indicated, 

but they are also released from other phases. Although Ettler et al. (2005) assumed the extracted 

fractions were related to bioavailability, no bioavailability was actually determined. The lack of any 

toxicity or metal uptake data in their paper does not provide the necessary level of assurance that the 

results of these extraction procedures can be used to infer relative bioavailability. Indeed, there is not 

even a citation to any published study in which such a relationship has been demonstrated. I believe that 

the lack of measurement of any biological effect, or even of citation that this methodology can be related 

to biological effect, should be noted in the review. This assessment is directly contrary to that of the 

authors. 

7-11 line 28 through 7-12 line 3. What this and other studies actually show is that relating effects to total 

concentrations of metal in soil (mg/kg) is inappropriate. The better effects relationships that were found 

with respect to the soil pore water concentrations are because the pore water represents the equilibrium 

partitioning and thus bioavailability.

7-35 lines 20-21. New exposure-response data are presented in several papers (Chen et al., 2010; and 

Kopittke et al. 2011).

7-36 line 31. ISO is the International Standards Organization. It is not a European methodology.

7-65 lines 14-18. Here and in a number of other places, BCF and BAF factors have been used. However, 

BCF is a poor factor to use in the hazard assessment of metals. Bioaccumulation factors are used as an 

important aspect in the hazard assessment for hydrophobic organic compounds (e.g. PCBs and DDT). 

For such compounds the BCF for a biological species is approximately constant and the concentration in 

the organism is proportional to the concentration in the environment (Chapman et al., 1996). Thus, high 

BCF values indicate highly bioaccumulated materials that warrant consideration for regulation as a 

consequence of the biological effects that these materials may cause in the organism or to the food 

chain. However, this is not the case for metals (with the possible exception of mercury). The BCF for an 

organism is not a constant, but is highly dependent on exposure conditions, including the concentration 

of the metal in the environment. A very extensive study of the relationship of bioaccumulation to 

exposure concentration of metals, including lead, has been published by McGeer et al., 2003). They 

found that in almost all cases the BCF decreased with increased exposure concentration. Thus, if one 

considers a high BCF as a predictor of hazard, increasing the environmental concentration of the metal 

would then lead to a lower anticipated hazard. Clearly, this is not the case. The error lies in 

consideration of BCF values for metals as anything more than the ratio of two values, the concentration 

in the organism and the concentration in the environment. As this ratio is not a constant, it not only lacks 

any predictive or assessment value. 
B-8

Problems with the BCF can be further seen in the present document. Consider the data for BCF for 

aquatic plants. In the 2006 report the range of BCF values was from 840 to 20,000. The new data in 

Table 7-3 has a range 0.01 to 1500. The maximum value for the new data is less than a factor of 2 

greater than the minimum value in the older report. The total range of BCF values is now 0.01 to 20,000. 

This is a range of 2,000,000. Furthermore, the range of BCF values for duckweed (Lemna sp.) is now 

0.01 to 3,560. This is a range of 356,000 which clearly is too great to be of any use in assessments. 

Furthermore, if the maximum and minimum values are considered, very different conclusions can be 

drawn regarding the potential hazard of lead. The low BCF value of 0.01 indicates that there is no 

hazard of Pb. The high BCF value of 3,560 is above a commonly used assessment criterion of 1,000 and 

suggests that Pb is a hazard. Clearly, BCF is an inappropriate measure to assess the hazard of Pb. The 

document needs to provide a better assessment of the utility (or lack thereof) of BCF values rather than 

simply reporting the data from the literature.

That organisms can have high concentrations of metals is true and important. The consequences of these 

high metal concentrations can be discussed without use of BCF and BAF.

References

Chapman, P.M., Allen, H.E., Godtfredsen, K., and Z’Graggen, M.N.. Evaluation of Bioaccumulation 

Factors in Regulating Metals. Environmental Science and Technology 30: 448A-452A (1996).

Chen, Z., Zhu, L. and Wilkinson, K.J.. 2010. Validation of the biotic ligand model in metal mixtures: 

Bioaccumulation of lead and copper. Environ. Sci. Technol. 44: 3580-3586.

Ettler, V., Vanek, A., Mihaljevic, M., & Bezdicka, P. (2005). Contrasting lead speciation in forest and 

tilled soils heavily polluted by lead metallurgy. Chemosphere, 58(10), 1449-1459.

Kheboian, C. and C.F. Bauer. 1987. Accuracy of selective extraction procedures for metal speciation in 

model aquatic sediments. Anal. Chem. 59: 1417-1423.

Kopittke, P.M., Kinraide, T.B., Wang, P., F. Blamey, P.C., Reichman, S.M. and Menzies, N.W. 2011. 

Alleviation of Cu and Pb Rhizotoxicities in Cowpea (Vigna unguiculata) as Related to Ion Activities at 

Root-Cell Plasma Membrane Surface. Environ. Sci. Technol. 45: 4966–4973.

Martin, J.M., P. Nirel and A.J. Thomas. 1987. Sequential Extraction Techniques: Promises and 

Problems. Marine Chemistry 22:313-341.

McGeer, J.C., Brix, K.V., Skeafe, J.M., Deforest, D.K., Brigham, S.I., Adams, W.J., and Green, A. 

2003. Inverse Relationship Between Bioconcentration Factor and Exposure Concentration for Metals: 

Implications for Hazard Assessment of Metals in the Aquatic Environment. Environ. Toxicol. Chem. 22: 

1017-1037.

Qiang, T., Xiao-Quan, S., Jin, Q. and Zhe-Ming, N. 1994. Trace metal redistribution during extraction of 

model soils by acetic acid/sodium acetate. Anal. Chem. 66: 3562-3568.

Rapin, F., Tessier, A., Campbell, P.G.C. and Carignan, R. 1986. Potential artifacts in the determination 

of metal partitioning in sediments by a sequential extraction procedure. Environ. Sci. Technol. 20: 836-

840.
B-9

Tipping, E., Hetherington, N.B., Hilton, J., Thompson, D.W., Bowles, E. and Hamilton-Taylor, J. 1985. 

Artifacts in the use of selective chemical extraction to determine distributions of metals between oxides 

of manganese and iron. Anal. Chem. 57: 1944-1946.
B-10

Dr. Deborah Cory-Slechta

Comments on Chapter 5 - Integrated Health Effects of Lead Exposure

Charge Question 5a

1. Several places in the text refer, especially in describing in vitro studies, of the use of ‘levels as 

low as’ or ‘to as little as’ and then cite concentrations that are not considered low. Certainly 1 

uM is not a low concentration. And in some cases (e.g., p. 5-6), a level of 5 uM is listed as low. 

It would be useful to provide some context about the relationship of in vitro exposure levels to 

human exposures and blood Pb levels. 

2. In cases of interaction effects, i.e., effect modification, it is not always possible to rule out the 

fact that the interaction was due to altered lead toxicokinetics. For example, numerous studies are 

cited in which anti-oxidants are stated to reverse effects of Pb. The description of these studies is 

generally not sufficient to fully understand the methodological details. But it was not always 

clear that some anti-oxidant, for example, co-administered with lead did not reverse its effects 

per se, but instead, altered its toxicokinetics. This would significantly alter the presumed (and 

often stated) interpretation of anti-oxidant mechanisms.

3. Comments related to mechanistic studies that suggest therapeutic approaches are debatable and 

do not belong in the scope of this document.

Charge Question 5e

1. Additional evidence has accumulated since 2006 supporting the non-linearity of the dose 

response curve defining the association between blood Pb and IQ, specifically the greater slope 

at blood Pb <10 ug/dl than above 10 ug/dl. These are supported by a substantial animal literature 

that has reported non-linear effects of Pb over the years. It is important to note that not all human 

studies will provide evidence for this non-linearity for reasons such as lack of sufficient power 

and/or insensitivity of outcome measures. In addition, animal studies are not likely to exactly 

duplicate the parameters of the slopes in children given that other physiological processes will be 

invoked as well.

Charge Questions 5b and 5c

1. The implications to changes in auditory brainstem evoked responses, observed in both the human 

and animal studies, are under-appreciated in the document. While they are indicative of 

alterations in auditory acuity, changes in the latencies between peaks have also been related to 

changes in brain myelination and in synaptic maturation.

2. A significant number of studies, both human and animal have examined the specific components 

of attention that are disrupted by Pb exposure and this topic does not appear to have been 

sufficiently covered in the Toxicology section or in the human studies. 

3. In regard to the neurocognitive outcomes, the Toxicology section seems somewhat disorganized 

and not consistent with behavioral domains. Why is the morris water maze study cited not 

included under learning? Changes in schedule-controlled behavior are also consistent with 

learning impairments as lead alters the prototypical patterns of responding. Response inhibition 

should be considered under the domain of attention. 
B-11

Charge Question 5d

1. While this Section does a fairly good job of integration, it is also somewhat superficial. More 

specific examples of direct correspondence between human and animal studies would be highly 

supportive. For example, there are very parallel studies of specific domains of neurocognitive 

dysfuntion (e.g., learning, reversal learning, planning, executive function) in humans (e.g., 

Canfield et al. , 2004) and in animal studies. Deficits in glucocorticoid negative feedback (i.e., 

HPA axis dysfunction) are found in low level exposures in both humans (Gump studies) and 

animal studies (Rossi-George studies). Studies of attention have looked at sustained attention in 

humans and animals, etc. There are direct correspondences in auditory brainstem evoked 

responses in human and animal studies. Since these are such direct correspondences, they carry 

particular weights.

Other General Comments on Chapter 5

1. In some human studies, the population described as controls have blood lead levels in the range 

that are now considered to be associated with effects, even in some adult studies. This should be 

pointed out and the effects of the study qualified accordingly. 

2. There are many examples of studies of gene-Pb exposure interactions throughout Chapter 5 

describing the health effects of Pb. None of these describe the magnitude of the effect of this 

interactions. Are these actually biologically relevant or of such small magnitude as to not be 

pertinent? Here too context is important. All such interaction outcomes where cited should 

include information on the extent/magnitude of the effect.

3. It would be far preferable and facilitate comparisons if all blood lead measures used the same 

units, preferably ug/dl; this may mean converting the units used in some of the cited studies.

4. The importance of effect modification is included in some places in the document, but it would 

be useful to address it in the summary of health effects as well, particularly as, dependent upon 

the context, it can result in effects of lead at even lower levels of exposure than when lead 

occurred in the absence of that modifier. Gender is also an important effect modifier and it is 

particularly astounding, given the size of the lead literature, how little we know about gender 

differences, but they are, when examined, far reaching.

Specific Comments

1. p. 5-44, lines 16-36. One interpretation that has to be considered with respect to studies of life 

stages of vulnerability is that the early effects of lead exposure on intellectual function cause 

early academic retardation that by itself, above and beyond subsequent lead exposure, would 

itself lead to later academic problems. Clearly, children who do not learn the basics early in 

school will have increasing problems later on because of that.

2. P. 5-51. It would be helpful and easier for the reader to have the same y axis values on all 4 plots 

in Figure 5-3 as it allows direct comparison of the magnitude of effects across conditions. 

3. P. 5-52 and 5-53, Specific Indices of Cognitive Function. It is surprising that no mention is 

included here of the Canfield et al., 2004 study. 

4. P. 5-61 lines 27-29. Albeit limited, the brain does generate stem cells as well, which this 

statement ignores. 

5. P. 5-62, lines 32-35. This statement is a gross over-generalization as it is already clear that 

different environmental toxicants/insults differ in their impacts on males vs. females. 

6. P. 5-68, lines 1-19. The point of the paragraph is not really clear.
B-12

7. P. 5-73, lines 1-16. It is important to continue to point out that questions regarding differences in

sensitivity of different developmental periods of exposure in human studies will always be 

complicated by the problem that the measures at different stages differ in their sensitivity. 

8. The section beginning on Toxicological studies is confusingly organized. For example, why are 

studies of morris water maze on p. 5-75 lines 1-2 and 5-76 lines 1-21separated out; these are 

essentially studies of learning as are studies subsequently described on p. 5-77 lines 12-28 and 

subsequently.

9. The statement on p. 5-77 lines 1-2 stating that deficits in working memory are thought to 

underlie the associations between blood Pb levels and ADHD in humans is highly simplistic and 

not reflective of the literature in general on ADHD.

10. P. 5-79 Figure 5-13; it is important to point out that offspring stress was actually PS followed by 

OS, not OS alone.

11. P. 5-83; the word water appears to be a mistake in the title for Table 5-8

12. P. 5-84; there was a prior study by Brockel and Cory-Slechta in 1998 where postweaning Pb 

exposures associated with blood Pbs of 9 ug/dl were likewise not affected in a sustained attention 

task. 

13. P. 5-85, lines 27-32. This summary seems highly overstated and over-generalized based on what 

is a very small literature. 

14. P. 5-94, Figure 5-17. The magnitude of effect in this study was very small and this figure 

provides an artificial amplification that is misleading.

15. P. 5-98 and 5-99. It is not clear why Canfield et al. 2004 is not included in this section.

16. P. 5-108, lines 24-26; Toxicological Studies of Neurobehavioral Outcomes. What references 

support statements such as cerebellum as a target of Pb?

17. P. 5-11-, lines 15-16; again, this is an over-generalization.

18. P. 5-112, line 18, please note psychological stress is not necessarily a negative factor. Indeed, a 

growing literature documents the ability of early stress to promote resiliency.

19. P. 5-113, lines 3-5; the original reference is not White et al., but Cory-Slechta, 2004.

20. P. 5-114 and p. 5-119, lines 3-13. The changes that occur in auditory brainstem evoked response, 

found in both human and animal studies, seem to be suggested only as related to hearing deficits. 

In fact, however, alterations in interpeak latencies are clearly indicative of myelination status as 

well as impairments in synapse formation. This is never mentioned. 

21. P. 5-117. The use of the phrase gestational Pb exposure in a rodent model is likely over-stated; it 

is impossible to turn off exposure to the offspring specifically at PND10 given the kinetics of Pb.

22. P. 5-123, line 21. The use of the adjective ‘old’ in referring to 12-14 week old rats is a misstatement; that adjective is used for animals that are significantly older, e.g., 18 mos of age.

23. P. 5-125, line 28. It should be noted that no dementia has ever been established in these models, 

however.

24. P. 5-135, lines 2-4. The notion that strategies involving glial transmission or D-serine 

supplementation might be used for Pb exposure is premature and also not realistic for low level 

Pb exposure, particularly given that it is likely to have multiple other effects. It is not clear that 

this statement belongs in the document.

25. P. 5-138, lines 11-12 suffer from the same issue described in #24 above.

26. P. 5-143, comparisons of magnitude of lead effects across sociodemographic groups may well be 

confounded by floor effects, i.e., it would be difficult to pick up as great an effect in low SES 

communities, where average IQ score, for example, may already be quite low.

27. P. 5-147, lines 21-23. This seems like an overstatement of the animal literature and is very likely 

to depend upon the outcome measures that are used; postweaning rats are very sensitive to lead 

and in fact effect in that model have been reported at blood Pbs of 9 ug/dl, the lowest levels 
B-13

examined to date. Unless some specific references can be provided demonstrating actual 

comparisons across more than one endpoint, this statement should be qualified.

28. P. 5-178, lines 1-8. What is the magnitude of the change caused by the polymorphisms?

29. P. 5-189, line 11, no year for the reference

30. P. 5-228, lines 21-31. Since the actual exposures protocols are not explicitly described, it is not 

evident that the antioxidants worked not by reversing oxidative stress, but by toxicokinetic 

mechanisms, decreasing lead uptake for example, which would lead to quite a different 

interpretation of the results. This issue applies to other sections describing reversal of Pb effects 

by e.g., antioxidants, chelators, etc.

31. P. 5-229, lines 1-16. This paragraph again underscores the importance of breaking out gender in 

both toxicological and epidemiological studies.

32. P. 5-229, lines 24-26. It isn’t clear how this interpretation relates to this study, since lead is not 

‘metabolized’.

33. P. 5-231, Figure 5-46. It would be very helpful if additional tics could be added to the x axis.

34. P. 5-232, Section 5.5.4 Effects of Exposure to Lead Mixtures. An important study by Mejia et al. 

1997 is relevant and should be cited here as it appears to show that lead content in brain tissue 

can be increased by co-exposure to arsenic.

35. P. 5-233, line 33, the year is missing for the reference.

36. P. 5-267, line 9, reference is missing the year.

37. P. 5-272, line 19, seems to be inconsistent with p. 5-271.

38. P. 5-287, lines 21-23, what is the magnitude of the effect of the polymorphism?

39. P. 5-317, line 12, missing the reference.

40. P. 5-360, line 9 and line 29, missing reference.

Charge Question 6

1. In relation to genetic background, there are many examples of studies of gene-Pb exposure 

interactions throughout Chapter 5 describing the health effects of Pb. None of these describe the 

magnitude of the effect of this interactions. Are these actually biologically relevant or of such 

small magnitude as to not be pertinent? Here too context is important. All such interaction 

outcomes where cited should include information on the extent/magnitude of the effect.

2. It is important not to oversell earliest development as the most sensitive period of exposure. 

While there are toxicokinetic factors that increase exposure, there are also multiple examples in 

the human studies of current blood lead associated with IQ reductions and in some cases these 

occur even when earlier exposure blood leads are not significant. This has also led to 

reconsideration of the impacts of effects in adolescence. In addition, in the animal literature, 

there are many examples of effects of lead even when exposures do not occur until after 

weaning. Indeed, for long-term potentiation, a physiological substrate of learning and memory, 

this was among the most sensitive periods for this effect. It is also important to continue to point 

out that questions regarding differences in sensitivity of different developmental periods of 

exposure in human studies will always be complicated by the problem that the measures at 

different stages differ in their sensitivity. 

3. The potential for gender differences in lead effects deserves far more emphasis. It is now found 

routinely in the animal studies and unfortunately, despite years of literature and human studies 

that frequently statistically control for gender, where examined, there are reported differences in 

the human studies as well. One could also consider the fact that blood lead levels of females are 

typically lower than those of males across the distribution. If one considers the greater slope of 

IQ reductions at the lower blood lead levels, the lower blood leads should be represented to a 
B-14

greater extent by female subjects than males, and could suggest their greater sensitivity than 

males, although this has never been examined in the human studies. 
B-15

Dr. Cliff Davidson

Comments on Chapter 1 – Introduction

The selection criteria for inclusion of studies seem reasonable. The decision to focus on exposures 

within one order of magnitude of current exposures also seems reasonable. There are some specific 

comments regarding Chapter 1, as follows.

1. Figure 1-1 states that studies not addressing exposure and/or effects of air pollutants under review are 

excluded. But the text states (on page 1-9, lines 18-23) the following:

“All relevant epidemiologic, animal toxicological, and ecological and welfare effects studies 

published since the last review were considered, including those related to exposure-response 

relationships, mode(s) of action (MOA), and susceptible populations. Additionally, air quality 

and emissions data, studies on atmospheric chemistry, environmental fate and transport, as well 

as issues related to Pb toxicokinetics and exposure were considered for inclusion in the 

document.”

Thus it appears that studies addressing emissions, atmospheric chemistry, and fate and transport, in 

addition to exposure and effects, were included in the document.

2. Typo on page 1-13, lines 3-5 (“informs” should be “inform”):

3. Also on page 1-13, the text states:

“These MOAs, as they pertain to Pb exposures of short or longer duration, informs our 

understanding of indirect effects that Pb may exert more broadly on ecosystem structure, 

function and services.”

What are “MOAs”? This abbreviation is not in the list at the front of Chapter 1.

4. Page 1-16, lines 22-28 deal with causality for direct human exposure in controlled chambers. This is 

irrelevant for Pb, since there are no human chamber studies for this pollutant, so this paragraph may be 

considered unnecessary. The paragraph is as follows:

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

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

vary by assessment. The most direct evidence of a causal relationship between pollutant 

exposures and human health effects comes from controlled human exposure studies. This type of 

study experimentally evaluates the health effects of administered exposures in human volunteers 

under highly-controlled laboratory conditions. Controlled human exposure studies are not done 

for Pb, and thus, are unavailable for consideration.”

5. Section 1.6.2 begins by defining “causality” and “association” on page 1-17. It might be better to 

move these definitions earlier – for example, section 1.6 starts on page 1-15 and starts using the terms 

well before they are defined.
B-16

6. The following sentence on page 20, lines 22-24, is grammatically incorrect:

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

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

which might eliminate another source of confounding from consideration.”

Comments on Chapter 2 - Integrative Health and Ecological Effects Overview

This chapter appears to be a useful summary of the rest of the document. The key challenge in 

communicating the ISA results to varied audiences is that there is a lot of information included in the 

ISA, and it will take some effort for readers to track down what they are looking for. Is it possible to 

develop an alphabetical index by topic areas? The framework for causal determination seems 

reasonable, and it appears to have been applied in a reasonable way. The integration of findings in the 

literature across health and ecological studies also appears to be reasonable. There are some specific 

comments with regard to Chapter 2, as follows.

1. On page 2-3, lines 8-9, the text states: 

“Global atmospheric Pb deposition peaked in the 1970s, followed by a more recent decline.”

What is the purpose of “more recent” in this sentence? Shouldn’t this be simply “followed by a 

decline”?

2. On page 2-4, lines 1-2, the text states:

“The FRM is based on flame AAS. ICPMS is under consideration as a new FRM for Pb-TSP.”

Perhaps the reasons for the delay in obtaining acceptance of ICP-MS could be mentioned.

3. On page 2-4, line 11. Typo: “network” appears twice.

4. On page 2-4, lines 16-17: The following sentence seems obvious – not sure why it is needed:

“Non-source oriented monitors were those monitors not considered to be source oriented.”

5. On page 2-10, lines 11-14, the text states:

“Both epidemiologic studies (in children) and toxicological studies, demonstrated neurocognitive 

deficits in association with blood Pb levels at and below 10 μg/dL, and evidence from both 

disciplines supported a nonlinear exposure-response relationship, with greater effects estimated 

for lower blood Pb levels.”

Why are there greater effects estimated for lower blood levels? This is confusing.

6. Some sections of Chapter 2 summarizing important results do not refer to the sections of later 

chapters where the details are found. But some sections of Chapter 2 do refer to the later chapters, such 

as this part of Section 2.8.4.1 on page 2-50:
B-17

“2.8.4.1. Children 

Children may be more highly exposed to Pb compared to adults without occupational exposure 

to Pb, through their behaviors (e.g., hand-to-mouth contact). Blood Pb levels are highest among 

the youngest children and decrease with increasing age of the child (Table 6-1). Biokinetic 

factors that vary by age, including bone turnover and absorption, also affect blood Pb levels. 

Childhood, as a susceptibility factor related to Pb exposure and dose, is discussed in more detail 

in sectin 6.1.1.1. The kinetics of Pb, and how absorption, distribution, and elimination may vary 

depending on lifestage, is discussed in Section 4.2. 7 

It is recognized that Pb can cross the placenta to affect the developing nervous system of the 

fetus (Sections 4.2.2.4, 5.3.2.1) and there is evidence of increased susceptibility to the 

neurocognitive effects of Pb exposure during several lifestages throughout childhood and into 

adolescence (for more detail, see Section 5.3.2.1). Further, Pb exposure is associated with effects 

on the renal (Section 5.5.2.3), immune (Section 5.6) and heme synthesis and RBC function 

(Section 5.7) of children. A limited number of studies of immune parameters, transferring 

saturation, and iron-deficiency anemia that stratified children by age report stronger associations 

among the youngest children. Childhood, as a susceptibility factor related to Pb-induced health 

effects, is discussed in more detail in Section 6.2.1.1.”

Note that there is a typo on the seventh line above (“sectin”).

These referrals to later chapters are helpful, but listing so many sections such as in the paragraph above 

for all of Chapter 2 may be too time-consuming, and makes it difficult to read. In any case, there is 

currently an inconsistency in that some sections of Chapter 2 do not include any referrals to later 

chapters, while others do. Perhaps referring to major sections in later chapters would be a good 

compromise to apply throughout Chapter 2 (e.g., refer to sections 3.1 and 3.1.2, etc., but not 3.1.2.3).

7. On page 2-46, bottom of the page, the text states:

“The Schnaas (2004) had a particularly strong experimental design in that is the only 

longitudinal study in which blood Pb concentration was monitored repeatedly in individual 

children from age 6 months to 10 years.”

It appears that a word or words are missing. Perhaps the intended sentence begins “The Schnaas (2004) 

study had a particularly strong experimental design....”

8. On page 2-49, the text states:

“This body of with the addition of more recent studies is presented Figure 2-2.”

Again, a word or words are missing.

9. On page 2-50, the text states:

“Menke et al. (2006), reporting a non-linear relationships”

Note that “relationships” should be “relationship”.
B-18

Comments on Chapter 3 - Ambient Lead: Source to Concentration

The information on atmospheric sciences and air quality in this chapter appear to be a good summary. 

They are, in general, clearly conveyed. The information on sources, fate and transport, monitoring, and 

spatial and temporal patterns seem relevant and thoroughly researched. The discussion of relationships 

between air Pb and concentrations in other environmental media also appear to be reasonable. There are 

some specific comments on Chapter 3, as follows.

1. On page 3-7, the text states:

“Gidney et al. (2010) point out that, where tetraethyl Pb is used as an additive in piston engine 

aircraft fuel, the fuel also contains ethylene dibromide to act as a Pb “scavenging agent.” When 

ethylene dibromide reacts with Pb, it forms Pb bromide and Pb oxybromides, which are more 

volatile.”

It is not clear why the scavenging agent is used. If ethylene dibromide reacts to form more volatile 

species, then there will be more Pb emitted (in gaseous form). How is that helpful?

2. On page 3-9, the text states:

“Tan et al. (2006) compared several emissions sources in Shanghai, China. They estimated 

emission values for on-road exhaust from use of Pb-free gasoline (238 ± 5 mg/kg), vehicle 

exhaust from leaded on-road gasoline (7,804 ± 160 mg/kg), coal combustion (1,788 ± 37 mg/kg), 

metallurgic dust (6,140 ± 130 mg/kg), soil (11.7 ± 0.3 mg/kg), and cement (103 ± 2 mg/kg). Pbfree automobile gasoline has been in use in Shanghai since 1997. The isotope ratios for each of 

these emission sources were determined. Based on the 4.4 × 107 tons of coal combusted annually 

in Shanghai, an average coal Pb concentration of 13.6 ± 6.6 mg/kg, and an emission factor of 

0.5, approximately 300 tons Pb was being emitted annually in association with fine PM. They 

concluded that a major priority should be to reduce Pb emissions from coal combustion now 

that the contribution from vehicle exhaust emissions has decreased.”

Why did the authors conclude that Pb reduction from coal should be a major emphasis, considering that 

Pb from leaded gasoline is four times greater? Should the last sentence state “now that the contribution 

from vehicle exhaust is expected to decrease in the future”?

3. On page 3-11, the text states:

“The 2006 Pb AQCD (U.S. EPA, 2006) cited an estimate by Harris and Davidson (2005) that 

more than 90% of airborne Pb emissions in the South Coast Basin of California were from soil 

resuspension. Since publication of the 2006 Pb AQCD (U.S. EPA, 2006), further analysis of the 

Harris and Davidson (2005) paper has revealed that the contributions of Pb from piston engine 

aircraft were underestimated compared with the 2002 NEI. Assumptions of spatial uniformity 

incurred by the “continuously stirred reactor” mass balance model and for mixing layer height 

used by Harris and Davidson (2005) were also not valid because Pb concentrations are spatially 

heterogeneous at the urban scale; see Section 3.5. Therefore, the estimate of 90% of airborne Pb 

from resuspension is not employed in the current assessment.”
B-19

The paper by Harris and Davidson is being discredited here, but why? The reasons do not appear to be 

based on sound science. If the NEI estimates of 2002 are used, the mass balance changes very little. 

Furthermore, many mass balances in the literature use the “continuously stirred reactor” model, and it is 

acknowledged in the paper as merely an estimate. There was very good agreement between the estimates 

cited from measurements and estimates cited from emissions data. So why exclude this value of 90% by 

discrediting the paper? It is the only estimate available, and this is a high ranking peer reviewed journal. 

I suggest the following revised paragraph which says the same thing without discrediting the paper:

“The 2006 Pb AQCD (U.S. EPA, 2006) cited an estimate by Harris and Davidson (2005) that 

more than 90% of airborne Pb emissions in the South Coast Basin of California were from soil 

resuspension. This value was obtained by constructing mass balances rather than direct 

measurements of lead alongside roads, and hence is merely an estimate. Currently, measured 

data are not available with sufficient spatial resolution to discern the specific contribution of soil 

Pb resuspension to air Pb concentration, but resuspended soil Pb cannot be eliminated as a 

potential major source of airborne Pb.”

4. On page 3-42, the text states:

“Additional research highlighted the importance of taking forest cycling and litter throughput 

account in estimating input by deposition.”

The word “into” is missing after “throughput”.

5. On page 3-52, the text discusses the rationale for choosing the TSP sampler over the PM10 sampler, 

and states:

“The rationale for this decision included recognition of exposure due to Pb-TSP that would not 

be captured by PM10 sampling, the paucity of information documenting the relationship 

between Pb-PM10 and Pb-TSP at the broad range of Pb sources in the U.S., and uncertainty 

regarding the effectiveness of a Pb-PM10-based NAAQS in controlling ultracoarse Pb-PM near 

sources where Pb concentrations are highest (73 FR 66991).”

It is not clear why a measurement method with such a high variability is preferred – we won’t know how 

much of the Pb is associated with particle diameters greater than 5 micrometers, or even what the true 

concentration of particles with diameters above 5 micrometers is. I feel this is a weak justification that 

could be strengthened.

6. On page 3-64, the text reads:

“Non-source oriented monitors were those monitors in the system not designated to be source 

oriented”

I don’t see why this sentence is needed – the definition appears obvious.

7. On page 3-76, the text reads:

“For both Pb-PM10 (Figure 3-21) and Pb-PM2.5, (Figure 3-22) monthly average concentrations 

are considerably higher in the fall than in other seasons, with lowest the three highest monthly 
B-20

average concentrations observed in September, October, and November, and the average 

September concentration more than double the average December concentration.”

It appears that the word “lowest” in the third line should be deleted.

8. On page 3-84, the text states:

“The strongest association was with Zn (median R = 0.51).”

As part of the ISA, was there any attempt to look at the literature for other chemical species, e.g., Zn, in 

an effort to understand the Pb data?

9. On page 3-103, the text states:

“In contrast, Pb associated with coarse PM is usually insoluble, and removed by dry deposition.”

It should be noted in the text that dry deposition may not be an “ultimate sink” because particles which 

dry deposit are often subsequently resuspended and redeposited many times before reaching a site where 

further transport is unlikely. The same is, of course, true for any deposition mechanism, but it is 

especially true for dry deposition onto dry ambient surfaces.
B-21

Dr. Philip Goodrum

Section 4.5.1 was fairly well organized, and it was particularly useful to begin with reiterating the 

analysis and findings of Brunekreef et al (1984) based a meta-analysis of multiple studies. It is not 

obvious upon first reading how the slope term was calculated from the parameters of the log-log 

regression. Several short examples should be added:

1. Brunekreef et al (1984) - the equations presented in the title of Figure 4-19 should be carried 

over to the main text and example calculations should be provided. There are errors in lines 9 

and 11 on page 4-79 – the slopes presented for both data groups are based on an increase in air 

Pb concentration from 0.50 to 1.5 μg/m3

, rather than 0.15 to 1.5 μg/m3. Text and tables 

throughout the section should be closely reviewed for similar typographical errors.

2. Table 4-11: I’d suggest re-orienting the table to landscape view, and expanding the “Model 

Description” from 1 column into 3, with the following headers: Model (e.g., log-log), 

Parameters (provide BOTH slope and intercept terms), Description (the remaining information)

3. Table 4-11: Slope calculations – references to footnotes suggest that either the slope was 

calculated by integration, or more likely some interval of air lead concentrations was used. It is 

not clear how the slopes were calculated, nor can the values presented be readily identified from 

the cited literature. In the text or table footnotes, provide a few additional example calculations 

to demonstrate how the slopes were determined.

It is unclear if the increase in blood lead concentration that is referred to in discussion of the slopes is 

actually predictive of a change in the geometric mean (GM) or arithmetic mean. Given the reliance on 

log-transformed variables in the regressions and based on a cursory review of the primary literature, it 

appears more supportable to interpret these deltas as changes in the GM. A short discussion of the 

difference between arithmetic mean and GM for lognormal distributions should be added and, if there 

are differences in interpretation – either provide both the AM and GM, or describe how the conversion 

to GM was conducted.

The descriptions of the key new studies is helpful and the summary provides sufficient detail to 

understand the advantages and limitations of the new data. Clearly there are many uncertainties 

associated with any single study, but collectively the estimates provide a useful basis for understanding 

the extent to which air lead (PbA) may contribute to exposure. With this concept in mind, EPA may 

want to consider recasting the section in a broader context that presents the historic and new data in a 

way that informs a key objective of the ISA – to evaluate the scientific developments and determine if 

changes to the NAAQS may be warranted. To accomplish this, it would be helpful to present a series of 

graphics that illustrate how a range of plausible blood-air slopes (consistent with the available literature) 

can be used to understand how alternative (lower) standards may change the blood lead distribution 

(both the GM and 95th percentile). Figures 1 to 3 below provide such examples, illustrating the potential 

changes in the GM and 95th percentiles (assuming lognormal distributions with GSD =1.6) if the 

standard were reduced from 0.15 μg/m3 to 0.10, 0.05, or 0.015 μg/m3. For example, if the standard were 

reduced to 0.10 μg/m3 (Figure 1), blood-air slopes in the range of 3 to 9 would be expected to shift the 

distribution down by less than 1 ug/dL for both the GM and 95th percentile. Similarly, if the standard 

were reduced by an order of magnitude to 0.015 μg/m3 and the slope is expected to be no greater than 7, 

the GM would be reduced by ≤1 ug/dL and the corresponding 95th percentile would be reduced by ≤2 
B-22

ug/dL. Presenting these calculations first would frame the discussion of the supporting data as falling 

within a range that would be expected to yield changes in blood leads within a quantifiable interval.

The CASAC committee discussed the challenge of isolating the relative contribution of air lead to blood 

lead when lead exposure is a multi-media phenomenon, and the mass contribution of lead in outdoor air 

contributes in some way to the reservoir of lead in nearly every exposure medium. A few points can be 

emphasized in the document:

• At the relatively low blood lead concentrations under consideration, it is likely that lead in diet 

contributes a substantially higher fraction of the average daily lead intake than lead in air (even 

after accounting for fate and transport processes that suggest air Pb contributes some fraction to 

soil and dust Pb). Present the FDA dietary exposure estimates and show how changes in lead in 

diet correspond to changes in population parameters of the blood lead distribution. Also present 

the assumptions in the IEUBK and ALM models regarding relative contributions of diet, water, 

air, soil, and dust as well as the air-to-dust partitioning assumptions.

• The graphical summary of the regression models used to define the blood-air slopes should be 

accompanied by a more in-depth overview of the information provided: 1) overall variance 

explained by the models used to derive the slope (e.g., what is the importance of a low 

coefficient of determination?); 2) range of blood lead concentrations in the empirical study –

particulary if it is representative of individuals with relatively high blood lead concentrations; 3) 

consistency of slope from each new study with comparable studies presented previously (i.e., is 

the new study within the same range?); 4) relevance of the new slope estimates the key decision 

points regarding the standard. As noted in the graphics below, these decision points include: a) 

the change in the GM and 95th percentile blood lead concentrations that are considered 

significant at the population level; and b) the plausible range of slope factors that could trigger an 

exceedance of the thresholds established in (a).

• While historically, much attention is given to predicted (and measured) blood lead 

concentrations in the fetus and developing child, older age groups also warrant concern because 

the association between average air Pb concentrations and health outcomes may be stronger for 

older age groups, and available studies / empirical data on older age groups can be more directly 

included in the assessment. Currently, the assessment is restricted by the tools that are publically 

available. Specifically, the IEUBK and ALM models restrict the assessment to data on children 

and adults of child-bearing age. A concerted effort to finalize the All Ages Model would break 

down this barrier and allow for a more comprehensive evaluation of lifetime exposures to be 

conducted.
B-23

Fig 1. Change from PbA = 0.15 to 0.10 ug/m3

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0 1 2 3 4 5 6 7 8 9

Slope (change in PbB per 1 ug/m3 change in PbA)

PbB (ug/dL)

delta GM PbB delta 95th %ile

GSD = 1.6

Fig 2. Change from PbA = 0.15 to 0.05 ug/m3

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0 1 2 3 4 5 6 7 8 9

Slope (change in PbB per 1 ug/m3 change in PbA)

PbB (ug/dL)

delta GM PbB delta 95th %ile

GSD = 1.6
B-24

Fig 3. Change from PbA = 0.15 to 0.015 ug/m3

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0 1 2 3 4 5 6 7 8 9

Slope (change in PbB per 1 ug/m3 change in PbA)

PbB (ug/dL)

delta GM PbB delta 95th %ile

GSD = 1.6
B-25

Dr. Sean Hays

Comments on Chapter 4 - Exposure, Toxicokinetics, and Biomarkers

Charge Question 4a:

I found chapter 4 to be the chapter that adhered to the ‘what’s new information since previous AQCD’ 

format better than any of the other chapters. I found this useful. One piece of information that I would 

like to see is how lead exposures from air compare to lead exposures from other sources. Ideally this 

would be handled through pie charts or tables and would help the reader to understand the relative 

contribution that lead in air has on total lead exposure or PbB. And this would ideally be done for a 

range of PbB and/or exposure scenarios (child living in urban environment, child living near smelter, 

etc.). This exercise will help the reviewer better assess whether changes in the NAAQS for lead would 

meaningfully impact PbB among the US population and/or among specific population sub-groups.

Charge Question 4b Biological Markers:

I first could not appreciate how a discussion of lead biomarkers was ‘new information’. However, I can 

appreciate how a discussion of lead biomarkers and the interplay between lead in blood and bone, and 

the impact a short duration exposure has on the various dose metrics (concurrent, maximum, integrated, 

etc.) could be helpful, especially for epidemiologists who don’t appreciate toxicokinetics as much as the 

PK modelers. I very much liked the figures in section 4.3 showing the lead in blood and bone profiles.

Charge Question 4c – Empirical Modeling: 

I found the review of the PbA – PbB relationships to be very helpful. The previous NAAQS relied on 

empirical models, but only one or two. This more expanded review and discussion is very helpful. It 

would be best to compare the various slope factors by creating a figure (linear, log or log-linear) that 

shows the slopes of the various relationships. Each curve should only be shown for the range of air lead 

concentrations for which the relationship is valid (i.e., the range (or some percentile range) of air 

concentrations that were included in the underlying study). This will help the reviewer understand which 

slopes are valid in the air concentration of interest (e.g., 0.1 – 2 ug/m3

). Furthermore, there needs to be 

more transparency with regard to the characteristics of the study for each slope factor, specifically the 

type of population exposures (ambient urban, phasing out of lead, living near a smelter, etc.) and the 

sampling type and PM cut-points.

Comments on Chapter 5 - Integrated Health Effects of Lead Exposure

Charge Question 5a & e Modes of Action and Dose-Response:

Modes of Action

Chapter 5 did not adhere to the ‘what’s new since last NAAQS’ model. The review of the modes of 

action is quite thorough. The summary of the mode of action information is quite misleading. In 

particular, Table 5-2 is misleading. In Table 5-2 all endpoints and modes of action have similar 

potencies (e.g., ‘lowest level at which MOA observed’). As far as I’m concerned, cancer is not as 

equally potent for lead as is neurological effects. This issue needs to be fixed.
B-26

I appreciate the dose-response section and the discussion of additional lines of evidence that might 

support the non-linear dose-response observed in the Lanphear et al. 2005 meta-analysis. The issue of 

non-linearity in the dose-response for IQ was an important issue in the previous NAAQS deliberations. 

Having this expanded discussion on supporting evidence is helpful.

Dose-Response
B-27

Dr. Philip Hopke

Comments on Chapter 3 - Ambient Lead: Source to Concentration

Chapter 3 provides a wide range of information to inform the exposure and health sections of the ISA. 

To what extent are the atmospheric science and air quality analyses presented in chapter 3 clearly 

conveyed and appropriately characterized? Is the information provided regarding Pb source 

characteristics, fate and transport of Pb in the environment, Pb monitoring, and spatial and temporal 

patterns of Pb concentrations in air and non-air media accurate, complete, and relevant to the review of 

the Pb NAAQS? Does the ISA adequately characterize the available evidence on the relationship 

between ambient air Pb concentrations and concentrations of Pb in other environmental media?

The chapter provides considerable information but harkens back to the encyclopedic nature of Criteria 

Documents. It may be overly detailed and certainly does not provide a concise overview of the critical 

information needed for informing risk assessments and the ultimate policy assessment. It would seem 

that with the use of some additional appendices, the information could be better summarized and 

presented in a manner that makes it easier to read and more useful for its ultimate purpose.

There is some discussion of long-range transport of submicron Pb-bearing particles, but there were no 

analyses of the available data from high elevation rural sites in the Western US to observe if there was 

any significant Pb transport along with the Asian dust that has been observed. Liu et al. (Liu, W., P. K. 

Hopke, and R. A. VanCuren, Origins of fine aerosol mass in the western United States using positive 

matrix factorization, J. Geophys. Res., 108(D23), 4716, doi:10.1029/2003JD003678, 2003) suggested no 

enrichment in lead at Lassen Volcano or Crater Lake National Parks, but it would be good to discuss the 

evidence for little or not transported background lead from trans-Pacific sources.

Similarly, the ISA points out a paper describing transport of Saharan dust to Israel where it is suggested 

that the enrichment in Pb observed in Israel is the result of transport through regions in which leaded 

fuels are still used. Since we see significant impacts of Saharan dust in the eastern US, it would be 

useful to analyze the dust episodes (June to August) at CSN and eastern IMPROVE sites to preclude Pb 

impacts from transported Saharan dust. 

The number of PM10/TSP and PM2.5/TSP and even PM2.5/PM10 ratios raise some serious questions 

about the sampling and analysis methods. The number of PM2.5/PM10 ratios greater than 1 raises a 

serious question regarding the application of XRF to coarse particle samples. There are no particle-size 

or loading corrections applied to the PM10 data and it is quite possible that the mass of collected 

material is attenuating the Pb L X-rays resulting in an underestimation of the Pb in PM10. These data 

raise continuing questions of basing the determination of speciation data for coarse particles on a 

difference method and the need for an effective coarse particle speciation sampler. 

The TSP data suggests that if we want to continue to look at TSP as an indicator, we need to find an 

inlet that is not directionally or wind speed sensitive. There is a commercially available unit, but I am 

unaware of any published characterization of its properties.

In the section in which the relationships with other measured pollutants are explored, the primary tool is 

Spearman rank correlation. I do not think that such an analysis really tells us much regarding the 

relationships. This approach will likely be much more subject to meteorological influence. The fact that 
B-28

the concentrations are in the same order, but are not really linearly related as would be shown using a 

Pearson correlation coefficient provides a false impression of the degree of covariance between Pb and 

the other pollutants. Given the wide and successful use of factor analysis methods to explore the 

correlative structure of such data, it is not clear what this section is supposed to tell us since it really is 

not helpful in source attribution or atmospheric chemistry. Thus, either there should be a change to 

Pearson coefficients (if there is anything there) or eliminate the section altogether as irrelevant. The 

current section provides no useful information relevant to setting a NAAQS or understanding the pattern 

of measured concentrations

Comments on Chapter 4 - Exposure, Toxicokinetics, and Biomarkers

Chapter 4 describes the multimedia nature of Pb exposure, toxicokinetics of Pb in humans, biomarkers 

of Pb exposure and body burden, as well as models of the relationship between Pb biomarkers and 

environmental Pb measurements.

a. How well do the choice and emphasis of topics provide a useful context for the evaluation of human 

health effects of Pb in the ISA? Is the current organization of the chapter clear and logical? Are there 

ways that information on exposure and toxicokinetics can be more clearly integrated throughout the 

chapter? Does the ISA adequately describe and balance air-related and non-air related pathways of Pb 

exposure?

This chapter seems to be in reasonably good shape as best I can tell. Given the multiple pathway 

exposure for lead, it would seem appropriate to have a discussion of exposure models like TRIM. Will 

there not be an effort to assess the nature of the exposure pathways particularly in areas near major Pb 

sources? It would seem logical to make TRIM runs to suggest the relative influence of the various 

exposure pathways as part of the policy assessment and thus, exposure modeling should be discussed. It 

is said that Pb exposure is hard to assess because of the multiple pathways, but was that not why tools 

like TRIM were developed? Is this not an appropriate place to try it out?

Specific issues

Several years ago there were considerable problems with lead in toys coming from China, but there 

seems to be no reference to these problems in Table 4.6. Given that this incident led to substantial action 

by the CPSC, it should be noted here. 
B-29

Dr. Chris E. Johnson

Comments on Chapter 3 - Ambient Lead: Source to Concentration

Chapter 3 of the ISA document is generally well written. The treatment of Pb sources, characterization 

of emitted Pb, and fate and transport were informative, relevant, and sufficient. The other sections were 

more uneven, often relying heavily on very few studies, or presenting data that were confusing or offtarget. Further details may be found in my responses to the specific charge questions, and some other 

review comments that follow.

Specific Charge Questions:

Question: To what extent are the atmospheric science and air quality analyses presented in Chapter 3 

clearly conveyed and appropriately characterized? 

Others on the CASAC are better prepared to answer this question that I am. For my part, as a non-expert 

in the atmospheric sciences area, I found the information to be generally clearly conveyed and 

understandable. I do have some concerns about some of the data analyses presented in section 3.5, 

however. The major concerns are presented here, and a minor concern in the “Additional Review 

Comments” below.

The data for Pb concentration in air is cobbled together from four networks, which were set up for 

different purposes. None of them appear to be particularly well suited to the assessment of the level of 

attainment of the current NAAQS for Pb. Nor does there appear to be an obvious way to use the data 

from these networks to model, with high confidence, attainment of the NAAQS. This is a serious 

concern, and needs to be addressed, if not now, by the time of the next NAAQS review.

Section 3.5.3.1 includes a statistical analysis of the AQS data to understand the particle-size distribution 

of lead-bearing particulate matter. The data appear to be fraught with problems. For example, in several 

cases, the content of PM2.5 is greater than the total suspended particle content, which is clearly 

impossible. Similarly, some of the data indicate that the PM2.5 content is greater than the PM10 content, 

which is also impossible. The document tries to draw some conclusions from these data, but I wonder if 

this analysis is really productive. Given the concerns that exist in the scientific community about the 

performance of the high-volume samplers (that are the basis of the Pb-TSP measurement), and the 

impossible particle-size ratios that come from the data, it might be best to scrap this analysis entirely and 

use the literature observations (section 3.5.3.2).

Question: Is the information provided regarding Pb source characteristics, fate and transport of Pb in 

the environment, Pb monitoring, and spatial and temporal patterns of Pb concentrations in air and nonair media accurate, complete, and relevant to the review of the Pb NAAQS?

Chapter 3 of the ISA generally does a good job in the areas of source characterization and the fate and 

transport of Pb. The material in these sections was, I thought, generally accurate, complete and relevant.

The discussion of Pb monitoring suffered some weaknesses related to the ad hoc nature of the 

monitoring network from which nation-wide data were gathered. This issue was discussed in the 

previous charge question.
B-30

The presentation of Pb monitoring and the spatial and temporal patterns of Pb in air and non-air media 

was somewhat lacking in the areas of soil, rain, and natural waters.

Soil. The section on soil (3.6.1) focused entirely on urban/suburban soils, smelter-impacted soils, and 

soils affected by Pb shot. There are good, long-term studies of spatial and temporal variation in trace 

metals in forest soils as well which could and should be discussed here. One is the Kaste (2006) work, 

already cited in the chapter. Another is the work of Evans et al. (Evans, G.C., S.A. Norton, I.J. 

Fernandez, J.S. Kahl, and D. Hanson. 2005. Changes in concentrations of major elements and trace 

metals in northeastern US-Canadian sub-alpine forest floors. Water Air Soil Pollut. 163:245–267).

Rain. The only recent information cited in section 3.6.3 are from studies in Canada and Europe. Are 

there truly no recent data on the spatial and/or temporal changes in precipitation Pb concentrations from 

monitoring in the United States?

Natural Waters.

3-38, lines 27-28: “...anthropogenic acidification of upland waters is likely to continue due to nitrogen 

leaching from the surrounding catchment...” This is highly debatable, especially in areas of the United 

The section on natural waters is exclusively about one study in Ontario, Canada. Is no 

one in the United States monitoring Pb concentrations in streams and rivers? Is no one looking at lakes?

Question: Does the ISA adequately characterize the available evidence on the relationship between 

ambient air Pb concentrations and concentrations of Pb in other environmental media?

The ISA does not adequately address the relationship between ambient air Pb and concentrations in 

other media. Having said that, one must admit that with the possible exception of precipitation, such 

relationships are nearly impossible to develop. This issue, perhaps more than any other, confounds 

efforts to develop a secondary, welfare-based standard for Pb. One exception to this criticism is the 

discussion in section 3.6.1 on the relationship between Pb-TSP and soil Pb in a study near El Paso, TX.

Additional Review Comments:

3-25, lines 12-31: One factor that should be discussed in this paragraph about wet deposition is the pH 

of the rain. Large reductions in sulfur emissions have resulted in steadily increasing precipitation pH, 

especially in the Midwest and Northeast, which experienced chronic acid rain for decades. Presumably, 

increasing pH in water vapor will reduce Pb solubility and therefore affect wet deposition.

3-28, lines 7-9: This sentence contains and incomplete thought – “...concentrations in surface waters are 

highest near sources of pollution before substantial Pb by flushing, evaporation and sedimentation.”

3-39, line 33 to 3-40, line 1: “This was likely due to the presence of organic-bound colloids smaller than 

0,45 um rather than true Pb dissolution.” Is this a hypothesis, or is there evidence for these “dissolved” 

colloids?

3-34, line 24: Some words are missing from this sentence.

3-37, lines 29-30: “The generally high dissolved Pb stores and high stream water DOC concentrations.” 

is an incomplete sentence.
B-31

States which are demonstrating recovery of surface water pH and alkalinity after decades of elevated 

acid rain.

3-73, lines 24-27: Do the data really support the generalizations made here about seasonal patterns? 

Looking at Figure 3-19, it looks to me like the seasonal pattern is

Spring > Fall> Summer > Winter

Have appropriate statistical tests been carried out to “prove” this pattern?

3-88, Table 3-9: Is this table complete? Some lines have no Min, Med, or Max (see for example Chicago 

2008 and 1987).

3-90, Figure 3-27: The figure legend should indicate what the numbers in the map itself represent. I 

would guess that they are the number of samples collected in each neighborhood zone?

Comments on Chapter 7 - Ecological Effects of Lead

In reviewing Chapter 7 of the Draft Integrated Science Assessment for Lead, and reflecting on the 

charge questions, I focused most my attention on the areas of terrestrial systems and ecosystems-level 

issues. Chapter 7 of the ISA document is extremely well written, especially the sections on terrestrial 

systems. Summaries of relevant studies are deftly written and informative, without being overly long. 

This chapter of the ISA pretty religiously restricted itself to literature published since the 2006 Air 

Quality Criteria Document (AQCD), and there is a lot to cover. There is almost no mention of data 

published before 2005, aside from comments that the recent literature confirms and expands on 

conclusions made in the 2006 AQCD. Presumably, this means that the authors found no reasons to reinterpret the older literature. For the most part I would agree, with exceptions noted later in these 

remarks.

It was sobering to see how much of the literature discussed in Chapter 7 was not done in the United 

States. Even European studies seem to be getting rarer. The review was heavily dependent on work done 

in south Asia (i.e. India) and southeastern Asia (i.e. China). This probably reflects growing concerns in 

those areas about metal pollution, and (generally) declining concerns in North America.

Specific Charge Questions:

Question: Effects on terrestrial and aquatic ecosystems are first considered separately. They are then 

integrated by classes of endpoints (bioaccumulation, growth, mortality, hematological effects, 

development and reproduction, neurobehavior, community and ecosystem effects). Does the panel 

consider this approach appropriate?

There is no perfect way to organize an integrated assessment of effects in complex systems. This seems 

to me to be a reasonable way to construct the assessment.

Question: Is it appropriate to derive a causal determination for bioaccumulation as it affects ecosystem 

services?

This is a tricky issue because bioaccumulation is at once an “effect” and a regulating ecosystem service. 

The mussels that accumulate Pb, for example, provide a valuable service to coastal and estuarine 
B-32

ecosystems, perhaps to their own detriment and the detriment of their predators. Counter-intuitively, the 

value of this service actually increases with increased Pb loading. This goes against the spirit of the risk 

assessment being attempted here, and I would suggest that it is not appropriate.

Question: Has the ISA adequately characterized the available information on the relationship between 

Pb exposure and effects on individual organisms and ecosystems, as well the range of exposure 

concentrations for the specific endpoints?

This is an impossible question to answer. The literature on terrestrial effects is not deep, and I was very 

pleasantly surprised at the ability of the authors to uncover relevant studies in the global scientific 

literature. It is certainly possible that they missed some valuable studies, but I am not aware of them.

Question: Are there subject areas that should be added, expanded upon, shortened or removed?

The ISA treats terrestrial and aquatic ecosystems separately. This editorial decision is expedient for a 

number of reasons, and I would not suggest changing it. However, one casualty of this approach is that 

the linkage between the two is lost. Loadings to aquatic ecosystems, especially freshwater systems, are 

primarily derived from the runoff of terrestrial systems. There is no discussion in Chapter 7 of the ISA 

of watershed processes as they influence aquatic systems. This is, in my view, a key omission.

Question: If the ISA was expanded to consider dose-response in terrestrial systems, should we limit data 

to field soils?

Given the clear effect of “aging” on the biological cycling of Pb in terrestrial ecosystems, it would 

probably be best to limit such an analysis to field soils. However, if the literature is not deep enough to 

come to any conclusions based on field soils alone, it may be necessary to use results from artificial soils 

(i.e., growth media).

Question: If the ISA were expanded to consider dose-response in aquatic systems, how might we most 

efficiently present toxicity data that varies greatly by organism, and environmental parameters that 

influence bioavailability (pH, dissolved organic carbon etc.)?

The effects sub-sections of the aquatic ecosystems section of Chapter 7 are already organized by major 

organism type (plants, invertebrates, vertebrates). The vertebrates sections are further divided into fish, 

mammals, etc. If the decision is made to include dose-response studies, emphasis should be placed on 

studies showing effects at the lowest levels, with some statistical tools (e.g., histograms, box plots) used 

to characterize overall variability.

Additional Review Comments:

7-9, lines 22-23: “...Pb adsorption to sandy loam clay was a function of both (1) Fe and Mn oxide 

interactions...” This is ambiguous. Interactions between what and what?

7-10, lines 3-4: This final sentence stands in stark contrast to pre-2005 literature on Pb in forest soils, 

which demonstrated that in virtually all studies the exchangeable Pb was a very small fraction of total 

soil Pb. 
B-33

7-10, lines 23-25: What is the “humified bottom layer”? Also, the contrast set up by “whereas” isn’t 

really a logical contrast, from a soils perspective. This should be clarified.

7-11, lines 7-8: “...with aging defined primarily as leaching following initial influx, but also as binding 

and complexation.” This is not a sufficient or satisfactory definition of “aging.” Leaching is a physical 

process, binding and complexation are chemical processes. Pb in soils subjected to these processes is not 

“aged” but rather is undergoing physic-chemical transformation to new fractionation.

7-14, lines 11-12: It would be useful to know how Klaminder et al. (2005) measured “direct adsorption” 

from the atmosphere.

7-14, lines 16-21: “...correlated with Pb in the litter layer, where Pb comes from atmospheric 

deposition...” Pb in litter may be derived from geological sources, and returned to the soil through 

recycling. Also, in most forests, the litter layer and the fermented layer below are active rooting zones, 

possible sources of Pb uptake.

7-15, lines16-22: If spruce is not a reliable species for metal dendrochronology (discussed on pp. 7-14 

and 7-15), then can these results be trusted?

7-16, lines 20-22: The final sentence of this section is important and should be emphasized earlier, and 

in summary sections of the chapter. Cycling of Pb in forest vegetation is very minimal in a wide range of 

ecosystem types.

7-21, lines 27-29: Based on the Coeurdassier et al. (2007) study, it would appear that snails increase Pb 

bioavailability.

7-25, Table 7-2: Is it possible to assess, semi-quantitatively at least, the confidence level for a hypothesis 

that the bioaccumulation factor for terrestrial species is less than 1?

7-29, lines 7-10: The lack of a response in soils spiked with smelter ash indicates that the added Pb must 

be in a soluble form to affect growth.

7-34, lines 7-8: “...mean nestling mortality was 2.5 and 1.7 higher...” This doesn’t make sense. First, 

should this be “2.5 and 1.7 times

7-41 to 7-42, section 7.2.7.: The section on critical loads is disappointing. After the second paragraph, it 

does not deal with critical loads. The message seems to be that we lack too much critical information to 

higher...”? Second, why are there two numbers for only one contrast 

(after vs. before)? Please clarify.

7-36, lines 8-14: No effect with spiked soils, but an effect with soil leachate. Once again, the importance 

of soluble Pb.

7-39, lines 4-8: Soil microbial activity declined for two weeks, then recovered. Is this adaptive behavior, 

or a change in community structure?

7-40, lines 16-18: “...exposure...can alter the structure of soil decomposer communities, which could in 

turn decrease decomposition rates.” I do not see the evidence for making the connection between 

structure and function here.
B-34

compute critical loads adequately. This section needs to review the major components of critical loads 

estimation and discuss where we have good information, and where we lack good information.

7-43, lines 2-4: Given the many studies highlighted in this ISA, should the Pb Eco-SSLs be updated?

7-45, lines 1-3: Afforestation of agricultural land normally leads to organic matter accumulation over 

time. Thus, “old fields” would appear to be low vulnerability ecosystems.

7-48, lines 10-12: The evidence in this ISA would seem to be quite clear that Pb is attenuated in 

terrestrial food webs. I think that the document could be much more forceful than “...no consistent 

evidence of trophic magnification was found.”

7-61, lines 11-13: Units must be wrong here. 145 ug Pb/mg would be 14.5% Pb!

7-61, line 29: “...exposed to water concentrations of up to 100 umol Pb...” Presumably this is umol per 

liter

Section 7.4: On the whole I would agree with the causality determinations presented in this section of 

the ISA. The one exception is section 7.4.1. (“...there is a causal relationship between Pb exposures and 

bioaccumulation of Pb that affects ecosystem services associated with terrestrial and aquatic biota.”) 

First, I don’t think that the case has been made for a causal relationship between Pb exposures and 

bioaccumulation in terrestrial systems. Second, I would not agree that there is evidence that any such 

bioaccumulation has had a substantial impact on ecosystem services.

.

7-65, lines 14-18, Table 7-3: The BCFs in the previous AQCD were much, much higher than (most) of 

the BCFs in Table 7-3. What explains the sudden drop in reported bioaccumulation? A re-assessment of 

the pre-2005 studies would seem to be in order. 

7-98, line 26: There is no context for “study sites 2 and 3.”

7-101, lines 31-33, Section 7.3.7.: As with the terrestrial section, the half-hearted attempt to look at 

critical loads is highly disappointing. Even if no studies have been published, it would be useful for EPA 

to know the state of the science. What information do we have and what do we lack for the construction 

of critical loads models for aquatic systems?

7-110, lines 1-7: The aquatic effects section of Chapter 7 has waffled on the issue of Pb transfer up the 

food chain. The data presented in this ISA for aquatic fauna seem to indicate that Pb is transferred up the 

food chain pretty well.
B-35

Dr. Susan Korrick

Charge Question 2: 

Is this a useful and effective summary presentation?

Generally, yes. 

Is the framework for causal determination appropriately applied? 

Causal determination framework seems reasonable. 

Comment on approaches that may improve the communication of key ISA findings to varied audiences. 

Comment on the approach used (integrating scientific evidence across disciplines of health and 

ecology); e.g., is this a useful and effective integration of scientific evidence? 

Application of mechanistic studies (from in vitro and animal experimentation) to ecologic outcomes 

optimizes the use of available data which is commendable. As a number of biological processes 

relevant to Pb toxicity are well conserved across human systems, ecologic systems, and experimental 

animal models, integrating across disciplines makes sense as it can address at least some data gaps and 

uncertainties that would be present if only one discipline was assessed in isolation. 

Page-specific comments:

Page 2-11, lines 17-21: The logic behind an apparent differential relationship of blood vs. cumulative 

(bone?) Pb measures and neurocognitive outcomes in adults is unclear to me in the following text: 

“Studies of adults without occupational Pb exposure have not provided consistent evidence for 

associations between blood Pb and...neurological effects...[as] cognitive reserve may compensate for 

the effects of Pb...Compensatory mechanisms may become less effective with increasing age, 

explaining the consistent associations between measures of cumulative Pb exposure and neurocognitive 

deficits.” It seems as if bone Pb is being equated with older age; although age and bone Pb are 

correlated, both blood and bone Pb measures can be obtained in both young and elderly adults. This 

statement needs substantial clarification. 

Page 2-13, Fig 2-1: What’s the blood Pb at which decreased neurite outgrowth is seen in rodents?

Page 2-15, lines 3-4: “...concentration-response relationships of blood Pb with BP or 

mortality....information is inconclusive (Section 2.8.2)” Does this refer to uncertainty about the shape 

of the dose-response (e.g., linear vs. non-linear) or uncertainty about the general association? It seems to 

imply the latter but I believe intends the former. This needs clarification. 

Page 2-16, lines 6-7: Prospective studies are key evidence against reverse causality as an explanation 

for observed Pb-renal function associations. Creatinine can be ‘normal’ even in the context of declining 

renal function; observing consistent Pb effects on renal function across a range of creatinine values is 

therefore not the most robust way to rule out reverse causality.
B-36

Page 2-26, table 2-3: Delayed puberty is a health outcome in children, not adults. Why does decreased 

hematocrit occur at 30 mcg/dL vs. decreased hemoglobin at 10 mcg/dL? If hemoglobin is decreased, so 

is hematocrit and vice versa.

Page 2-42, table 2-5: Childhood growth is covered in the human health review in Chapter 5 (e.g., page 

5-344) and should be included in this table as an important and basic health measure.

Charge Question 4b:

How well does Section 4.3 reflect the current state of knowledge of Pb biomarkers and their 

interpretation as it relates to exposure and dose?

The section reflects current knowledge. However, see page-specific comments for areas that could be 

expanded or clarified. 

Is the focus on blood Pb and bone Pb appropriate, given that the epidemiologic literature largely 

assesses exposure through these two biomarkers?

This focus is appropriate.

Is there sufficient and accurate discussion of the relationship between blood Pb and bone Pb? Are 

relationships between blood Pb and Pb in soft tissues and urine Pb adequately described?

Section 4.3 relies heavily on the ICRP Pb biokinetics model to demonstrate relationships among 

biomarkers of Pb exposure under different exposure scenarios and at different ages. This is useful for 

demonstrating the theoretical kinetic differences between, and relationships among, bone and blood/soft 

tissue compartments. However, an explicit discussion of the context in which these models are useful, 

and their limitations, would be helpful. As an extension of this point, a better explanation of model 

assumptions is needed. E.g., does Pb decrease to 0 at the end of the exposure period? What are the 

assumptions that result in no net increase in blood Pb after a 3-year constant Pb exposure despite a net 

increase in bone Pb? Based on observational epidemiology data, once relatively long-term Pb exposure 

ends, blood Pb increases above the baseline as bone and blood reach a new equilibrium. In addition to 

better explaining the utility and assumptions behind these theoretical descriptors, more empiric 

information about the relationship among markers (e.g., estimated correlations, prediction models, halflives, etc.) from epidemiologic studies of non-occupationally exposed populations, including children 

and adult men and women would be useful. E.g., see: Nie et al., J Occup Environ Med 2009;51:848-57; 

Korrick et al., Am J Epidemiol 2002;156:335-43 ; Kim et al., Am J Epidemiol 1997;146:586-91. Lastly, 

although reviewed in the previous AQCD, a summary of the limitations of Pb biomarkers, such as the 

reproducibility of bone Pb and sources of measurement error for bone Pb, would be useful to the 

subsequent interpretation of literature using such biomarkers (see page-specific comment 4-35, lines 11-

12 below). 

Page-specific comments:

Page 4-35, lines 3-4: The patella may be preferred over the calcaneous as a trabecular bone site but the 

tibia has advantages over both in terms of likely measurement error and is the most commonly used 

bone Pb measurement site in the literature.
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Page 4-35, lines 5-9: The mix of technologies described for measuring bone Pb seem to include both 

non-invasive in vivo measures like XRF but also ex-vivo chemical measures. Making this distinction 

explicit would be helpful since the use of non-invasive in vivo measures is applicable to most 

epidemiologic (human health) studies.

Page 4-35, lines 11-12: Although it is not necessary to repeat detailed information on precision, 

accuracy, and variability in bone Pb reviewed in the 2006 Pb AQCD, summarizing the data here would 

be useful especially as this technology can have relatively poor reproducibility especially in populations 

with lower bone Pb content or low bone density (For example, Hoppin et al., Environ Health Perspect 

2000;108:239-42; Hoppin et al., Environ Health Perspect 1995;103:78-83).

Page 4-35, lines 20-23: An important consequence (not mentioned here) of expressing bone Pb 

measures relative to bone mineral content is that lower bone mineral density is associated with greater 

measurement uncertainty in bone Pb. This can have important implications for studies in older women 

for whom low bone mineral density is more common than in other populations including men and 

younger adults. 

Page 4-50, lines 10-11: I think it’s important to acknowledge that the NAS is an all male cohort; the 

relationship of bone Pb with blood Pb can be very different in women, especially across an age range 

that includes menopause. 

Page 4-50, lines 32-33: If applicable, the increased calcium demands of lactation (relative to pregnancy) 

may explain the significantly greater %change in blood Pb observed post pregnancy vs. in the 2nd/3rd

trimesters. 

Page 4-54, lines 4-5: I do not understand the logic behind the simulation showing slower brain Pb 

accumulation in children. Perhaps this is because I do not have toxicokinetic expertise. To make the 

document accessible to a wider audience, this should be clarified. 

Charge Question 5d:

What are the views of the panel on the integration of epidemiologic and toxicologic evidence, in 

particular, on the balance of emphasis placed on each discipline? And on the accuracy with which the 

evidence is presented? Considering the Pb exposure concentrations and durations in toxicological 

studies and the potential for confounding in epidemiologic studies, please comment on the conclusions 

drawn about the coherence of the evidence and biological plausibility.

General comments:

Chapter 5 provides a comprehensive review of the human epidemiologic and toxicologic evidence of 

lead’s health effects with the addition of studies published since the last AQCD (January 2006 forward). 

The Chapter is organized by health outcome with human and related toxicologic studies for a given 

outcome presented in tandem. The approach generally works well and, depending on the health 

outcome, there is more or less emphasis on epidemiologic vs. toxicologic evidence. However, the 

Chapter was inconsistent in its approach to causal inference and would benefit from a clear and explicit 

plan for weight of evidence assessment and then consistent application of the plan to each health 

outcome. For some sections of the review, the encyclopedic nature of the research summaries fails to 

provide the reader with any perspective or prioritization of data vis-à-vis its quality. For example, some 

studies have more robust designs than others but this distinction is not always made clear. Similarly, 
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numbers of epidemiologic studies on a topic are often enumerated but without commenting on their 

relative value. Oftentimes there is an appearance of multiple studies on a topic when, in fact, studies 

represent slight variants on analyses in the same population such as NHANES or the Normative Aging 

Study (NAS). In these cases, most information on a particular topic may actually be coming from a 

relatively limited set of study populations. This is generally not discussed or acknowledged but should 

be. 

The juxtaposition of epidemiologic and toxicologic data on a given health outcome is useful but often 

the two data streams are not well integrated. For example, section 5.3 reviews Neurological Effects. The 

epidemiologic review focuses on enumerating effect estimates associating biomarkers of Pb exposure 

with specific neurologic outcomes ranging from childhood IQ and behavior to neurodegenerative 

disease in the elderly. But for studies relating to childhood cognition and behavior, e.g., the toxicologic 

evidence does not review complementary (where relevant) effect estimates in animal models. Instead, 

the emphasis is on the interaction between Pb exposure and stress in animal models. This provides a 

reasonable basis for discussion about mechanisms whereby Pb might affect neuropsychological 

functions but means there is minimal direct overlap with the epidemiologic review. Although Figure 5-

29 provides some dose-response comparisons between animal and human data, toxicologic studies 

described in the text, tables, and other figures are often not directly analogous to the human studies 

described. 

Admittedly, the lack of animal data that more directly parallels human data is, at least in part, a 

consequence of differences in study design (and necessary differences in outcomes) between the 

epidemiologic and toxicologic literature. Given these differences, providing additional synthesis 

(beyond Figure 5-29) of the two information streams would be helpful. E.g., a table listing 

neurobehavioral outcomes studied in humans and, where applicable, their animal analogue with an 

indication of the general pattern of Pb associations observed in the two disciplines would be useful. 

Also, the integration between the two disciplines would benefit from summary statements discussing: 

(1) exposure dose (level and chronicity) comparability between animal and human studies; (2) the doseresponse relationship in animal models (e.g., is there a threshold?). This is discussed in the 

“Neurological Effects” section as its own topic (p. 5-139 to 146) but not integrated into the description 

of specific studies; (3) animal exposure route (oral, iv, ip, etc.) and its implications for relevance of 

toxicological studies to human exposures; (4) choice of Pb form for animal dosing (Pb acetate, Pb 

chromate, Pb nitrate, or Pb chloride, e.g.). This is important in a number of ways to interpretation of 

findings (as happens in carcinogenicity studies where Pb chromate was used and findings attributable to 

Cr but not Pb could be discerned); and (5) specific outcomes that are roughly comparable between 

animal models and human studies. Otherwise, there is minimal discussion of issues of exposure 

comparability between human and animal studies and how this may, or may not, impact the integration 

of information from the two fields. Although the animal studies often have discrete dosing regimens that 

make it difficult to assess thresholds, where possible, noting threshold for effects, where relevant, would 

be helpful to integrating the two data sources and applying results for risk assessment. 

In addition to generally higher exposures (higher blood Pb levels) in animal models compared with 

contemporary U.S. population levels, there are also differences in the route of exposure which may be 

particularly important to consideration of population Pb exposure from air pollution which likely 

involves multiple pathways. Acknowledgement of this issue is lacking. Similarly, discussion of studies 

with exposure routes unrelated to human circumstances (studies in which Pb is injected directly into the 

hippocampus of an animal – e.g., page 5-76, Jett et al., 1997 or Pb is administered via intraperitoneal 
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(IP) bolus, page 5-110, lines 4-5) should be done with caveats regarding generalizeability to humans. In 

mechanistic study reviews, acknowledgement of potential differences between in vitro and in vivo 

mechanisms would be useful. E.g., the Cardiovascular Effects section seems to assume that in vitro 

mechanistic studies are applicable to the in vivo setting but, where in vivo and in vitro study findings are 

in conflict, does not acknowledge that the difference in study type can result in apparently conflicting 

results (e.g., page 5-182, lines 12-20). 

The Chapter (and its conclusions) would benefit from more consistent attention to potential thresholds 

for effect. E.g., for outcomes with mixed findings in the literature, careful consideration of sources of 

variability across epidemiologic studies is often not reviewed. In some cases, this variability may, at 

least in part, relate to Pb dose, e.g., adverse Pb effects are evident at higher rather than lower Pb levels. 

Depending on the outcome, this issue is, at best, incompletely considered in the Chapter.

Also, introducing each health outcome with a brief (1-2 sentence) summary of the state-of-the-art 

conclusions as of the 2006 AQCD would be helpful. Then the new literature would build on this. This 

approach is applied in some sections but not all in the Chapter.

Additional issues for Neurological Effects: (1) emphasis on stress/Pb interactions in animal toxicologic 

literature raises issue of how stress of animal handling (for purposes of neurocognitive/neurobehavioral 

assessments) may be impacting demonstrated Pb associations in animal models. Although handling 

stress is mentioned, its role as a modifier of experimental systems is not. (2) how to interpret findings for 

areas with primarily animal data and ~no human data (e.g., vision effects?) where animal models 

generally have relatively high exposure (e.g., blood Pb 25 mcg/dL). (3) how to interpret findings with 

supportive mechanistic toxicologic data but inconclusive or null human studies (e.g., Pb related neuronal 

plaque formation in prenatally exposed animals vs. AD in aging humans). (4) how to identify 

meaningful susceptibility factors (sex perhaps more consistent in animal models, genotypes inconsistent 

findings for ALAD & VDR, e.g.). 

Issues for Cardiovascular Effects: the data for non-BP-related CVD outcomes is limited and largely 

based on either NHANES or NAS (men only). Some acknowledgement of the limited variation in study 

populations would be useful. 

Issues for Immune System Effects: This section lacked clarity regarding a weight of evidence approach

to inference. For a number of immune parameters, conclusions regarding Pb’s potential impact are often 

primarily based on toxicologic data (animal and in vitro studies) and heavily exposed occupational 

populations. Some of the occupational studies are limited by lack of adjustment for confounding 

(including failure to account for co-occurring occupational exposures) and lack of a biomarker of Pb 

exposure to assess effects. For many immune parameters, there are relatively limited data (and often 

inconsistent or subgroup-dependent findings) in Pb-exposed general population samples for this topic. 

As a consequence, concluding that there is coherence among epidemiologic and toxicologic data seems 

over-stated for a number of immune measures reviewed. Given this context, the potential ‘causal’ 

relationship of low-level Pb exposure with most indices of immune function in the general population is 

difficult to address with certainty. However, the section does not adequately account for these data 

limitations and uncertainties in its summary statements. 

Page-specific comments:

Throughout: There are a number of tables/figures in which the footnotes appear to be mis-labeled.
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Page 5-44, lines 2-5: in describing the relation of Pb with neuroimaging, references are summarized as 

showing “...associations of childhood blood Pb levels with decreased neuronal density and neuronal 

loss measured in adulthood, as assessed by magnetic resonance imaging techniques...”. One of the 

referenced studies is a case-control assessment of 9-13-year-olds, another is a case report in a young boy 

and thus these do not address adult outcomes. Furthermore, two of the referenced studies used functional 

MRI to measure regional neuronal activity and lateralization of activity which is not the same as either 

neuronal density or loss but is an important phenomenon in understanding Pb effects on 

neuroanatomical functional correlates. The summary text does not appear to accurately describe what it 

references. 

Page 5-48-49, figure 5-2, table 5-3: What do Baghurst exposure measures mean (21.7 (25-50%))? In 

table 5-3, 25-50% is given as 17. 4 (vs. 50-75% is 21.7)? Are there no exposure measures available 

(‘NR’) for Dietrich 1993 and Ris 2004? It seems footnotes a and b are reversed? 

Page 5-51, figure 5-3: the original manuscript being referenced is inconsistent on this point but it seems 

the Mn threshold should be in units of mcg/L so the cut point would be 1.4 mcg/dL rather than 14 

mcg/dL; similarly, the blood Pb concentrations are log transformed (it would be helpful to say so in the 

figure). 

Page 5-77, lines 1-2: the statement that ‘Deficits in working memory are thought to underlie 

associations between blood Pb levels and ADHD in humans’ is an unfamiliar concept to this reader. 

Unless there is a reference to support this statement, it should be deleted. 

Page 5-76, lines 19-20: it is unclear what ‘new study’ is being referred to as the apparent reference is 

from 1997. 

Throughout the “Neurologic Effects” section, table and figure footnotes have errors in them and some of 

the figure graphic symbols are incorrect (e.g. wrong color coding for exposure periods). 

Also, it is common throughout this section for associations to be described without indicating the 

direction of effect, direction needs to be consistently indicated, e.g.:

Page 5-77, line 8: “...early life Pb...contributes to response inhibition...” – does this mean that it 

contributes to impaired response inhibition? 

Page 5-101, lines 2-3: “They found positive associations, suggesting that blood Pb...may have an 

independent effect on behavior.” Because higher scores on behavioral indices typically indicate worse 

behavior, making this explicit would be useful, e.g., by adding, “may have an independent adverse

effect on behavior”. 

Page 5-105, lines 8-9: “...DRD4.7 also has been associated with sustained attention, response inhibition, 

and quicker response time...” Shouldn’t this be “...DRD4.7 also has been associated with better

sustained attention, better response inhibition, and quicker response time”? 

Page 5-109: lines 33+: How does rodent performance on the rotarod (endurance, balance & coordination 

measure) relate to human neurobehavior? 
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Page 5-122, line 2: PD should be ET?

Page 5-147, lines 22-31: This is a recurring theme mentioned in the Neurological Effects section that 

for animals in utero/early postnatal period is the most sensitive for Pb-related neurologic effects but that 

stronger effect estimates are generally observed for concurrent blood Pb in epidemiologic studies of 

children. Can this observation be related to mechanistic issues and dose-response relationships? 

Page 5-167, Figure 5-33: where’s the “arrow line”?

Page 5-177, lines 10-11: discussion of heart rate variability (HRV) is important but out of place in this 

section otherwise entirely devoted to BP and hypertension. Should be placed in the following paragraph 

(page 5-178).

Page 5-191, lines 1-2: Weisskopf (2009) null blood Pb relationship with mortality “could have been 

affected if the majority of the hypothesized non-linear effect was contained...in the...(reference) blood 

Pb tertile” Is this referring to an hypothesized ‘superlinear’ dose-response between Pb and mortality? 

Needs to be clearer.

Page 5-197, line 9: 5th-9th percentile should be 5th -95th

Page 5-248, table 5-23: Blood Pb levels presented for occupational exposures are not clearly labeled. 

E.g., Mishra et al (2010), presumably “132 (103)” refer to the mean (SD) but this is not specified 

anywhere. Similarly, for Yucesoy et al. (1997b), e.g., “59.4, 58.4” presumably refers to the 2 different 

Pb exposed workers assessed but, again, that’s not clear in the table. And it looks as if Fischbein et al. 

(1993) firearms instructors blood Pb’s are mislabeled – should ≥15 be ≥25? Of note, levels in Mishra 

et al (2010) are clearly out of range for current non-occupationally exposed populations. 

Page 5-274, lines 21+: This section seems too speculative re. the implications of biomarker findings on 

“immune-based disease”; more careful qualification is needed as per the subsequent discussion on page 

5-275, lines 4-7.

Page 5-296: Results for Change et al. 2006, reported in the Table 5-27, is OR for ‘fertility’ or 

‘infertility’? 

Page 5-298, lines 3-4: More information about potential sources, if any, of differences across infertility 

studies would be useful here. E.g., it appears dose may play a role; that is, there is a more consistent 

association of Pb with infertility at higher Pb doses. Some discussion of this issue would be relevant 

here. Some Pb-associated health effects may have dose-response thresholds and this is important to 

consider throughout Chapter 5. 

Pages 5-298 to 5-299, Table 5-28: Essentially all of the epidemiologic studies discussed here are crosssectional. Some discussion of how this may impact the integration of epidemiologic findings with 

animal model findings (in which primarily prenatal/early postnatal exposures are assessed) is important 

to better integrating findings across these two disciplines. 

Page 5-312: Some inconsistencies regarding relations of Pb with hormone levels in epidemiologic 

literature may relate to dose and cohorts studied (e.g., low dose vs. occupationally exposed). This 
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distinction is relevant to the discussion of mixed outcomes in the literature but is not mentioned (lines 

11-12).

Page 5-318 (birth defects): This is an example of incomplete consideration of exposure in comparing 

and integrating results among studies. E.g., the two studies cited from the 2006 AQCD demonstrating 

possible associations between parental Pb exposure and neural tube defects assessed exposure via 

drinking water or occupation, respectively. Neither had a biomarker of exposure and, in both cases, 

uncontrolled confounding may have played a role in any observed associations (e.g., other risk factors 

may have varied by household location and or by occupation). It’s not clear from the discussion that the 

lack of an evident association of Pb with neural tube defects in more recent literature (in which direct 

biomarkers of exposure were used) is at odds with the earlier studies given their design limitations. 

Page 5-321: The same issue applies here as was mentioned previously -- inconsistency among findings 

across studies of Pb and preterm birth may, in part, be related to thresholds for effect. Consideration of 

this issue would be helpful to conclusions; e.g., adverse associations may be more consistent among 

more exposed populations. 

Page 5-324, Table 5-36: Zentner et al (2006) reference is confusing. The results presented in the table 

are based on blood Pb as the outcome, not birth weight and length which are used to predict blood Pb. 

This should be made clear. 

Page 5-326, line 9: “Inverse relationship” doesn’t make sense based on description of findings 

associating increasing Pb exposure with heavier weight; term should be “positive relationship”.

Page 5-327, lines 20-21: In this study of rats, the 5-month exposure was before pregnancy, not during 

gestation. The current wording is very confusing. (This same study is discussed again on page 5-336).

Page 5-328, line 15: Seems to be missing punctuation? Needs a period between retina and Pbexposure?

Page 5-328, line 26: Needs a comma between birth defects and spontaneous abortion.

Page 5-330, lines 9-13: Including ecologic literature is of interest but seems out-of-place as this may be 

the only instance in Chapter 5 where such literature is referenced. Is this because there is no relevant 

ecologic literature for other sections of the Chapter?

Pages 5-331-332: Both studies cited as providing evidence of associations of occupational Pb exposure 

with decrements in liver function and markers of oxidative stress (Patil et al., 2007 & Kahn et al., 2008) 

did not account for the possibility that other occupational exposures may have been important to 

observed associations. It is probably no coincidence that elevated liver enzymes were seen among spray 

painters but not other Pb exposed occupations despite the other occupational groups having higher Pb 

levels (Patil et al., 2007). Painters are likely exposured to known hepatotoxins (e.g., solvents). There is 

no discussion/mention of the possibility of uncontrolled confounding by other occupational exposures in 

this section. This makes it difficult, if not impossible, to accurately interpret the reported findings. 

Page 5-336: It is somewhat confusing that toxicologic data re. gestational Pb exposure’s possible 

hepatoxicities is presented both here and as an example of “developmental effects of Pb” a few pages 

before. The distinction seems somewhat arbitrary. E.g., prenatal Pb exposure’s neurotoxcity is not 
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mentioned under “developmental effects”. How is “developmental effects” defined for this document (as 

compared to organ or organ-system specific effects)? 

Page 5-348, line 8: Another example of the possibility that uncontrolled confounding by other 

exposures (association of Pb with TSH among contaminated fish eaters with organochlorine and 

mercury exposure) may affect reported associations. Again, would be useful to include such limitations 

in the review. 

Page 5-348, line 22: Presumably meant to say ‘osteoporosis-related fractures” not falls?

Page 5-349, Cancer: Throughout this section, there is inconsistent acknowledgement of limitations of 

study design. E.g., occupational cohort studies lacking biomarkers of exposure and lacking adjustment 

for potential confounding by other occupational exposures should be clearly identified as having 

substantial limitations that impact inferences. 

Page 5-361 to 5-362 (Chromosomal Aberrations): This is another example of the above issue. Here the 

relevance of toxicologic studies using PbCrO4 is unclear since Cr may have similar effects to those 

being assessed. It’s unclear whether these studies contribute meaningfully to this review. At a minimum, 

a more explicit discussion of the limitations of such studies to understanding Pb effects is needed as the 

studies are reviewed (Cr concerns are mentioned under Mechanisms of Action section, page 5-365 and 

in the Summary, pages 5-368 to 5-369). PbCrO4 is used in other studies in the Cancer section.

Page 5-367 (Epigenetics): Some discussion of the predictive/mechanistic relevance of global measures 

of DNA methylation in blood vis-à-vis cancer risk would be useful here. This is a relatively new area, 

DNA methylation in blood may not reflect levels in other tissues, e.g., so its relevance to nonhematologic malignancy risk may be limited. 
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Dr. Michael Kosnett

The following are my comments on the draft Integrated Science Assessment for Lead (May 2011)

prepared following the CASAC Lead Review Panel meeting of July 2011. 

The discussion in Chapter 1 of the criteria used to consider studies for review and analysis in the ISA is 

reasonable. Studies of subjects who have blood lead concentrations within one order of magnitude of the 

general US population equates to cohorts with blood lead concentrations approximately less than 40 

μg/dL. This is appropriate for a document intended to focus on risks associated with environmental 

rather than occupational lead exposure. With respect to human epidemiology, it appears that these 

criteria has been consistently and appropriately applied. However, as discussed further below, the ISA 

included many toxicological studies that employed lead dosages far higher than those relevant to low 

level human exposure to lead from environmental sources. The HERO system functioned well as a 

means to retrieve studies that were cited in the document. 

In chapter 2, a summary statement on lead biomarkers appearing on page 2-8, line 22 read, “Blood lead 

in adults is typically more an index of recent exposures than body burden.” In my opinion, as a general 

finding, this statement is incorrect and should be revised. For example, in many of the important cohort 

studies of middle-aged to elderly adults used to assess the impact of lead exposure on cardiovascular and 

cognitive function (e.g. the Normative Aging Study [NAS], or the Baltimore Memory Study [BMS]) the 

mean and median blood lead concentration was approximately 5 μg/dL. This was 3 to 4 fold higher than 

the median or mean blood lead concentration of the overall US population, and more than 4 fold higher 

than the median or mean blood lead concentration of teenagers. Teenagers have the highest intake per 

body weight of food and beverages, the predominant source of contemporaneous lead exposure to the 

general population. It is clear that the blood lead concentration of the adults participating in the NAS and 

BMS, as well as most adults greater than 60 years of age, largely reflects higher skeletal lead stores 

accumulated earlier in life, as opposed to their current external lead intake. 

The application of the causal determination criteria in Chapter 2 and Chapter 5 often lacks transparency, 

and would benefit by a more specific and structured approach. It is problematic that the narrative takes 

the approach of opining on the weight of evidence for causation for broad categories such as 

“neurological effects” or “cardiovascular effects” or “reproductive effects and birth outcomes”, rather 

than evaluating more specific health outcomes within each category. For example, although the 

causation assessments in Section 2.5.1 and Section 5.3.8 conclude that “there is a causal relationship 

between Pb exposures and neurological effects”, the analysis in these subsections does little to 

differentiate the weight of the evidence as it applies to such widely divergent neurological effects as 

cognitive function in children, essential tremor in adults, cognitive function in adults, and ADHD in 

children. The summary Tables 2-2 and 2-3, which imply that there is evidence for a causal impact for 

lead on cognitive function in both children and adults at a blood lead of 5 μg/dL, belie the fact that 

while there is ample evidence to establish cognitive impacts in children, the evidence for a similar 

impact on adults is nowhere near as compelling. It is puzzling how Table 2-3 singles out the NHANES 

III study by Krieg et al (1990) to support the conclusion that a blood lead of 5 μg/dL has a “causal” 

impact on diminished cognitive function in adults, when in fact this study reported no significant impact 

of blood lead on cognitive tests in adults age 20 to 59 or ≥ 60 years of age. Moreover, Section 5.3.2.4 

“Epidemiological studies of cognitive function in adults” concluded, “In summary, among adults 

without occupational exposures to Pb, there is weak evidence for an association between blood lead 

levels and cognitive function” (emphasis added). Indeed, the relatively few studies that have found an 
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association between low blood lead concentrations and aspects of cognitive function in adults, such as 

Muldoon et al, 2006, Payton et al, 1998, and Wright et al, 2003, (surprisingly not discussed in Section 

5.3.2.4) were conducted in elderly populations who sustained prolonged periods of much higher blood 

lead concentrations (e.g. 10 to 25 μg/dL) earlier in life.

With respect to other “neurological effects”, such as essential tremor in adults and ADHD, the ISA 

would also benefit from a more rigorous presentation of a weight of the evidence analysis that Tables 2-

2 and 2-3 imply yields a “causal relationship” at a blood lead concentration of ≤ 5 μg/dL. While 

intriguing, the epidemiological evidence that supports the relationship between lead exposure and 

essential tremor is limited to two cross-sectional studies conducted in middle aged to elderly adults. By 

virtue of their age, these subjects sustained decades of much higher blood lead concentrations earlier in 

life. Moreover, the pathogenesis of essential tremor is poorly understood, and there is no experimental 

animal or in vitro data that provide a model of lead induced essential tremor at low dose, or that 

establish a particular mode of action. With respect to the implicit finding of a “causal” relationship 

between blood lead concentration less than 5 μg/dL and ADHD, the narrative would benefit from a 

critical evaluation of limitation in the epidemiological studies that should temper the certainty of this 

conclusion, including a) the lack of control for parental ADHD in all the studies; b) the cross-sectional 

nature of the studies; c) the sole reliance on blood lead in late childhood and the lack of information on 

blood lead level as toddlers; and d) incomplete ascertainment in some studies of covariates such as 

prenatal tobacco exposure. The analysis might also address the implications for lead causation of ADHD 

of the observation that a marked rise in ADHD incidence has occurred during a period of dramatic 

decline in population lead exposure.

Section 5.4 of the ISA reviews recent epidemiological studies that demonstrate an association between 

lead exposure and blood pressure and/or hypertension, as well as cardiovascular mortality. This topic is 

exceedingly important, because hypertension and related cardiovascular diseases are pre-eminent causes 

of morbidity and mortality in the United States. While the evidence presented in the prior 2006 lead air 

criteria document (AQD) and the current draft ISA convincingly establish that environmental lead 

exposure is a cause of hypertension and cardiovascular morbidity and mortality, there is considerable 

uncertainty regarding the dose of lead at which these endpoints emerge. Knowledge of this dose, 

including evidence of any potential threshold, would be of paramount importance in the establishment of 

a NAAQS based on these endpoints. The statement in Section 5.4.1 “Both human and animal studies 

provide consistent evidence for an association of increased BP and arterial hypertension with chronic 

exposure to Pb resulting in adult blood Pb levels below 5 μg/dL” is not supported by the available data. 

All of the epidemiological studies cited in the past AQCD and the current ISA that demonstrate an 

association between blood lead and blood pressure, hypertension, or cardiovascular morbidity or 

mortality have been conducted in populations that likely experienced blood lead concentrations > 5 

μg/dL for a significant proportion of their lifetimes. The epidemiological studies have been mainly 

conducted in middle aged to elderly adults who, notwithstanding their current low blood levels, lived a 

substantial proportion of their lives prior to 1980, when background blood lead concentration was 

typically in the range of 10 to 25 μg/dL. As noted in the narrative, in several of these cohorts (such as 

those examined in the Normative Aging Study), the association of lead to blood pressure or hypertension 

is more strongly predicted by bone lead than by blood lead, consistent with the influence of cumulative 

lead exposure accrued in part during these earlier decades. In addition to receiving a substantial 

contribution to cumulative lead exposure in early life, these cohorts were subject to what may have been 

unique developmental impacts of blood lead concentrations > 10 μg/dL on their cardiovascular system. 
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At the present time, there appear to be no human or animal1

Section 5.2 of the document offers an extensive discussion of various modes of action of lead observed 

in toxicological studies (mainly conducted in cellular preparations or whole animal experiments) across 

a wide range of exposure concentrations. Table 5.2 seeks to relate the “dose” of lead (in vitro or ex vivo) 

associated with various modes of action to human health effects. The table suggests that of all the modes 

of action listed, only altered ion status might be expected to be relevant to human health effects observed 

studies that demonstrate the effect of lead 

on blood pressure, hypertension, or cardiovascular disease in subjects whose blood lead concentration 

never exceeded 5 μg/dL. The ISA would benefit from a revision that reflects this unresolved and 

important issue. 

A somewhat similar problem has occurred with respect to the ISA’s assessment of renal effects in 

Section 5.4 and Section 2.5.3. The draft ISA’s assessment is that blood lead concentrations as low as 2 

μg/dL are associated, on a causal basis, with renal insufficiency demonstrated by a low calculated GFR 

(glomerular filtration rate). In my opinion, a conclusion of causal assessment at that blood lead 

concentration is not supported by the scientific literature for several reasons. First, many of the studies 

that associated blood lead concentrations of this magnitude with diminished GFR were conducted in 

cohorts in which most of the members lived a substantial proportion of their lives with much higher 

blood lead concentrations (in the range of 10 to 25 μg/dL). Second, the epidemiological evidence that 

associates blood lead and GFR is subject to reverse causation. Since lead undergoes substantial renal 

excretion, elevations in blood lead concentration can be a consequence of decreased GFR, rather than a 

cause of reduced GFR. The explanation against reverse causation offered in the ISA that “...the 

association between blood Pb and serum creatinine occurred over the entire serum creatinine range, 

including the normal range where reverse causality would not be expected” has no apparent 

experimental support and is unpersuasive. On the contrary, steady state serum creatinine is inversely 

proportional to GFR, and in any person, decrements in GFR are associated with increases in serum 

creatinine even when the serum creatinine remains in the normal range. Third, the epidemiological data 

has not yielded consistent findings, and in some cohorts with low level environmental lead exposure, 

blood lead concentration was associated with biomarkers consistent with improved renal function (e.g. 

lower serum creatinine, de Burure et al, 2006). It is conceivable, but unknown, whether this represents 

lead induced hyperfiltration. Fourth, the toxicological literature reviewed in the ISA offers no evidence, 

in either human or animal studies, of a demonstrable nephrotoxic lesion or mechanism induced by a 

blood lead concentration of 2 μg/dL. On the contrary, early biomarkers of tubular damage have not 

consistently emerged in occupational cohorts or animal studies until blood lead concentrations are 

generally higher by an order of magnitude. 

In general, the numerous tables in Chapter 5 that offer details (“characteristics and quantitative data”) of 

selected epidemiological studies pertaining to broad health endpoints should include a column that 

comments on the strengths and limitations of each study in terms of causal assessment. The summarized 

information should also note negative findings (e.g. the notable absence of a predictive effect of blood 

lead in studies that reveal a predictive effect of bone lead). For ease of reference, abbreviations should 

be explained in the caption to each table.

 1 Regarding animal studies, the statement on page 5-165, “An array of studies have provided evidence that extended exposure 

to low levels of Pb (<5 μg/dL) can result in delayed onset of hypertension in experimental animals that persists long after the 

cessation of Pb exposure” is not supported by data presented in the ISA. Section 5.4.2.2, and Figure 5-167 refer to two animal 

studies, Chang et al, 2005 and Tsao et al 2000, that the document implies show an effect of lead on increased blood pressure 

at blood lead concentrations < 5 μg/dL. However, neither of these studies reaches such conclusions nor do they present data 

that establishes such a finding. 
B-47

at blood lead concentrations in the range of current environmental interest (i.e. 1 to 10 μg/dL). A whole 

blood lead concentration of 1 to 10 μg/dL corresponds to a plasma blood lead concentration of 

approximately 0.01 to 0.1 μg/dL, or 0.1 to 1 μg/L2

In view of the foregoing, the document could be shortened by omitting the frequent discussion of 

toxicological studies that have examined lead doses and/or modes of action that are not relevant to the 

actions of lead plausibly associated with insidious or latent low-dose human health effects. Those 

toxicological studies that by virtue of dose and temporal pattern are relevant to these human endpoints 

should be summarized in tables that identify key aspects of dose and study design, and that comment on 

, which is approximately 0.5 to 5 nM (nanomolar). 

Since it is lead in plasma that is available for uptake into cells of key target organs such as the brain, 

kidney, gonads, and vascular endothelium, the narrative might consider emphasizing only those modes 

of action for which there is evidence of action at cellular concentrations of 5 nM or less. Lead’s 

interaction with protein kinase C and calmodulin mediated processes, demonstrable in the subnanomlar 

range in vitro, are particularly relevant in this regard. By contrast, studies of the effect of lead on cells in 

culture where the culture medium contained lead at micromolar concentrations are of doubtful relevance 

and could be omitted from the ISA.

The narrative should highlight and emphasize toxicological findings from animal studies in which the 

animal’s exposure and/or blood lead concentration approximates that which occurs to humans with low 

level environmental lead exposure. For example, in the United States, the median lead concentration of 

the human diet is approximately 3 ppb, the median blood lead concentration is approximately 1.6 μg/dL, 

and daily intake of lead is on the order of 10 micrograms (or 0.00014 mg/kg/day; see Table 4-1). 

However, the document extensively discusses experiments in which laboratory animals were fed diets 

containing on the order of 100 to 2000 ppm lead, received lead doses on in the range of 1 to 10 

mg/kg/day or higher, or had blood lead concentrations on the order of 15 to 150 μg/dL (or higher), 

without considering the relevance of these relatively high values to the potential health impact of much 

lower environmental lead exposure to humans. 

From a temporal standpoint, it appears that some of the key health impacts associated with 

environmental lead exposure in humans, such as hypertension and cardiovascular disease, renal 

insufficiency, and adverse neurological outcomes (such as cognitive dysfunction or possible 

neurodegeneration in adults) are the consequence of longterm cumulative exposure. For example, days 

to weeks of exposure to lead resulting in blood lead concentrations in the range of 10 to 25 μg/dL do not 

appear to induce contemporaneous elevations in blood pressure or hypertension in humans that is 

observable in that time frame. Instead, evidence suggests that the risk emerges after years of such 

exposure. Lead exposure in childhood has not been associated with elevated blood pressure or 

hypertension in childhood (cf Chen et al, 2006; Gump et al 2005; Factor-Litvak et al, 1996), although it 

has been associated with the latent development of increased blood pressure in early adulthood (Gerr et 

al, 2002). Accordingly, the likely modes of action underlying the development of lead-induced 

hypertension are not those associated with acute or subacute pharmacological action, but rather those 

compatible with slow, insidious onset and/or long latency. Therefore, in seeking coherence between 

many of the chronic human health outcomes discerned in epidemiological studies and plausible mode(s) 

of action supported by toxicological studies, the narrative should focus on slow or latent processes, such 

as, but not limited to, epigenetic impacts on gene expression, or remodeling of tissue structure or 

responsiveness (e.g. in brain, kidney or vascular endothelium).

 2 As noted in Section 4.2.2.1, ≤ 1% of lead in blood is present in the plasma in individuals with low level environmental 

exposure; the value of 6% implied in line 7 of 5.2.3.3 should be corrected.
B-48

strengths and limitations. Figures such as Figure 5-29 which omit the study citation and other key data 

are relatively unhelpful. Toxicological studies that exposed animals or cells to massive doses of lead not 

relevant to low level human exposure should be omitted from the document, or confined to subsections 

that clearly note their questionable utility with respect to NAAQS development.

Additional comments on the ISA’s discussion of specific health endpoints:

Neurocognitive function

b) Section 5.3.2.1 addresses the important and challenging issue of age-based susceptibility to leadassociated neurodevelopmental deficits by noting that while adverse impacts of lead on the entire range 

of development (in utero, early childhood, and late childhood) have been observed in epidemiological 

studies, “...concurrent blood Pb level appears to be the best predictor of neurodevelopmental effects in 

children.... Thus, the course of cognitive development may be modified in children, depending on 

concurrent blood Pb levels or positive caregiving environment” (page 5-73, lines 12-16, emphasis 

added). It is unclear how this important conclusion is mirrored in Chapter 2, which states, “Collectively, 

the epidemiological evidence has not identified one unique time window of exposure that poses the 

greatest risk to cognitive function in children (Figure 2-3)” (Section 2.8.3, line 28). Figure 2-3, which is 

the same as Figure 5-10 

. The ISA’s discussion of recent studies that demonstrate an effect of in utero 

and childhood low level lead exposure on cognitive function are of particular interest, because this 

endpoint formed the basis of the last revision of the NAAQS for lead. The comprehensive review of 

recent studies provided in the narrative and the tables supports and extends the observations and 

conclusions reached in the 2006 assessment. A few relatively minor points warrant comment: 

a) In section 5.3.2.1, the discussion of the study by Kim et al (2009) highlights its importance as a study 

that demonstrated an impact of lead on full scale IQ in a population with blood lead < 5 μg/dL, (thus 

representing a cohort with the lowest blood lead for which FSIQ was the primary endpoint). However, 

the narrative, including the caption to Figure 5-3, should provide a clearer indication that the value of 

this study is tempered by the finding that a statistically significant impact of lead on FSIQ was confined 

to subjects with relatively high blood manganese (>14 μg/dL). In like manner it appears misleading for 

the findings of this study to be referred to, without citation and qualification, in Section 5.3.8 Summary 

and Causal Determination, which states (page 5-147, line 13), “In the cumulative body of evidence, 

negative associations between blood Pb level and IQ are best substantiated at mean blood Pb levels in 

the range of 5-10 μg/dL; however, an association was observed in a recent study with a mean blood Pb 

level of 1.73 μg/dL. [emphasis added] 

3

, provides data abstracted from Table 2 of Bellinger et al (1990) in support of 

the primary importance of concurrent blood lead, and the improvement in IQ that may ensue with 

declining blood lead in childhood. However, it would appear that data from Table 3 of Bellinger et al 

(1990), rather than Table 2, is more suited to this point. 

Renal effects

On page 5-129, the prospective study of renal function in patients with chronic renal insufficiency 

reported by Yu et al (2004) is described as a “hallmark” study illustrating the impact of low blood lead 

. Table 5-43 depicts “the change in kidney metric [e.g. biomarkers of renal function such as 

serum creatinine or estimated GFR] per μg/dL blood Pb, at 1 μg/dL.” This is misleading, because in 

virtually all of these studies, most of the subjects had blood lead concentrations considerably higher than 

1 μg/dL, and the validity of extrapolation of the study findings to a blood lead concentration of 1 μg/dL 

is not established. 

 3 The beginning of the caption to Figure 5-10 omits the superscript “a” that is found in the caption of Figure 2-3.
B-49

concentration (< 5 μg/dL) on renal function. Given the multiple limitations of this study, such an 

endorsement seems unwarranted. The study’s limitations include, in part: a) sparse information 

regarding subject recruitment; b) the unacknowledged likelihood, based on the range of blood lead 

concentration and EDTA provoked urine lead excretion, that many study subjects had substantially 

higher blood lead concentrations prior to enrollment; c) lack of 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; d) statistical analysis 

using a Cox proportional hazards model that adjusted the hazard ratio for renal function deterioration 

only on baseline covariates, rather than an alternative survival analysis that adjusted for changes in key 

covariates, such as blood pressure or protein intake, during the extensive period of follow-up; e) failure 

to report possible interactions between lead biomarkers and other covariates in the proportional hazards 

analysis. Similar unacknowledged major limitations exist for the chelation studies conducted by these 

same investigators that are discussed on pages 5-223 to 5-224, including the crucial finding that change 

in renal function in the chelated subjects was not related to any lead biomarker. The statement in the 

draft ISA suggesting that if these observations are replicated, “chelation could yield important public 

health benefits” appears to be premature. In any case, it would be highly inadvisable to retain even this 

qualified endorsement of an unproven therapy in the ISA document, whose principal purpose is to 

review the association between lead exposure and health effects. 

Immune system effects

“One of the most salient findings collectively was that DTH [delayed type hypersensitivity] was 

suppressed in animals with blood Pb levels ranging from <2 to 5 μg/dL (Bunn, Ladics, et al., 2001; 

Bunn, Parsons, et al., 2001a, 2001b; Miller et al., 1998; Muller et al., 1977)”. However, in every one of 

these citations, the suppression observed in delayed type hypersensitivity followed in utero or postnatal 

lead exposure associated with blood lead concentrations greatly in excess of 5 μg/dL. Specifically, in 

“Bunn, Ladics et al, 2001”, and “Bunn, Parsons et al, 2001a” changes in DTH were observed only in 

young female (but not male) rats whose in utero lead exposure resulted in a postnatal day 1 blood lead 

concentration of 35 (thirty-five) μg/dL. In “Bunn, Parsons et al, 2001a”, the effects occurred only in 

young female rats whose postnatal day 1 blood lead concentration averaged 51 μg/dL. In “Miller et al, 

1998” in utero lead exposure associated with postnatal changes in DTH in the offspring appeared in 

pregnant dams who had a blood lead concentration of 71 μg/dL. Decrements in DTH were not detected

in the offspring of pregnant dams with blood lead concentrations of 39 μg/dL. In Muller et al, 1977, 

which studied DTH in adult rats, the lowest blood lead concentration studied was 20 μg/dL. 

Accordingly, the narrative was misleading in implying that lead exposure associated with a blood lead 

concentration of “<2 to 5 μg/dL” was sufficient to suppress delayed type hypersensitivity in animal 

models.

. In certain sections of the ISA, there was a troubling mischaracterization of the 

blood lead concentrations associated with immunotoxic effects in animal models. A striking example 

occurred on page 5-250, line 3-4, where the narrative stated:

4

 4 In some of the studies described in this paragraph, the blood lead concentration in the rats may have declined to less than 5

μg/dL at the time DTH was tested, even though they were much higher in utero or early in life. It would be disingenuous to 

imply that these studies demonstrate an effect of lead exposure associated with a blood lead concentration of < 5 μg/dL. In 

the context of the ISA, which seeks to examine the health impact of low level environmental lead exposure, an 

epidemiological or animal study should be identified as demonstrating an effect of lead exposure associated with a blood lead

concentration less than 5 μg/dL if and only if the subjects’ blood lead concentration never exceeded 5 μg/dL. 

Not every article cited in support of conclusive statements such as that on page 5-250 line 3-4 

could be reviewed at the time these comments were prepared, and the extent of similar 

mischaracterizations elsewhere in the ISA has not been comprehensively investigated. However, a 

careful re-checking of the literature cited in support of conclusive statements pertaining to low-level lead 

exposure throughout the ISA may be prudent at this point in the revision process.
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The manner in which the draft ISA has summarized findings of the 2006 Pb AQCD often merits 

revision. For example, in the first sentence of section 5.6.4.1 “Host Resistance” (page 5-258), the 

narrative states, “The capacity of Pb to reduce host resistance to bacteria has been known for almost 40 

years and was supported by several toxicological studies described in the 2006 Pb AQCD (U.S. EPA, 

2006).” This sentence implies that the 2006 document concluded that impaired human resistance to 

bacteria was well known to be caused by lead exposure and found support from toxicological studies in 

animals. However, a reading of the 2006 document reveals conclusions that are quite to the contrary. 

Specifically, page 6-196 of the 2006 Pb AQCD stated, “Associations between Pb exposure and host 

resistance have not been rigorously examined in humans. Two analyses of illness surveys in children 

(Rabinowitz et al., 1990) and Pb workers (Ewers et al., 1982) have been reported....Collectively, these 

studies do not provide convincing evidence for a strong association between Pb exposure and altered 

disease resistance in humans.”

Latter in that same paragraph, (page 5-258, Line 7), the narrative states, “Gupta et al. (2002) 

demonstrated that elevated Pb exposure 6 of mice (>125 mg/kg Pb, 13.0 μg/dL blood Pb) reduced host 

resistance to viral infections as indicated by an increased viral titre and increased mortality.” This 

represents both a numerical error and a mischaracterization. In Gupta et al (2002) lead exposure of 125 

mg/kg for 28 days, yielding a blood lead concentration of 130 (one hundred thirty) μg/dL, was not

associated with increased mortality, which was observed only at a lead dose of 250 mg/kg x 28 days and 

a blood lead concentration of 210 μg/dL. Aside from the draft ISA’s mistaken description of the study 

findings, the question remains of the utility of even mentioning this study at all, given that it employed 

massive doses of lead irrelevant to low level environmental lead exposure.

Overall, sections of the ISA in Chapter 2 and Chapter 5 devoted to “immune system effects” appear to 

overstate the significance and conclusiveness of the evidence that suggests a causal link to low level 

environmental lead exposure. For example, on page 5-242, the narrative states that the 2006 ACQD 

found “strong evidence that the immune system was one of the more sensitive systems affected by Pb 

exposure.” In section 5.6.7 “Summary and Causal Determination”, the narrative states, “The collective 

body of evidence integrated across epidemiologic and toxicological studies consistently demonstrates 

that the immune system is a major target of Pb.” On the contrary, the toxicological and epidemiological 

evidence linking low level environmental lead exposure with immune system effects is sparse, often 

inconsistent, and subject to considerable uncertainty arising from weak study design and inadequate 

statistical analysis. Sections 5.6 and 2.5.4 in particular would benefit from a substantive revision that 

critically acknowledges the tentative nature of the findings and discusses the many uncertainties 

pertaining to their validity and clinical and public health significance. 

In tables and the narrative, Section 5.6 highlights epidemiological studies by Karamaus et al (2005) and 

Sarasua et al (2002) as “demonstrating” immune system effects of lead at blood lead concentrations less 

than 10 μg/dL. With what appears to be an implicit reliance on the reports of Karamaus et al and 

Sarasua et al, the narrative states, “...epidemiological evidence in children consistently links elevated 

blood lead levels (as low as 2.2 to 3.4 μg/dL) with decreases in T cell abundance” [page 5-274, line 16-

17). In fact, in its analysis of the effect of lead on T cell subsets, (confined to a supplemental file 

“Additional File 1”), Karamaus et al (2005) reported no statistically significant effect of lead exposure 

by ANOVA or linear regression. In an analysis highly susceptible to Type I error from multiple 

comparisons, two t-test contrasts found that the number of CD3+ T cells and B cells in children with 

blood lead between 2.2 to 2.8 were lower than that in children with blood lead < 2.2 μg/dL. (Note: for 

this analysis, the number of cells was log transformed and then analyzed in quartiles, instead of as 
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continuous data). Effects were not seen at blood lead concentrations in two higher quartiles 2.8 to 3.4, 

and > 3.4 μg/dL, and no plausible basis for an apparent U-shaped dose response was offered. A similarly 

inexplicable U shaped dose response was also found for log transformed IgE levels by blood lead 

quartiles. In a separate analysis, the impact of blood lead on IgE revealed an interaction with levels of 

the organochlorine DDE, such that no impact of lead was found in the subjects with serum levels of 

DDE above the median. In what constitutes a major inconsistency, there was no effect of lead 

whatsoever when IgE associated with basophils was the dependent variable. Page 5-254, line 31 refers 

to a “strength” of Karamaus et al that arose from its control of potential confounders. On the contrary, 

the study failed to adjust for socioeconomic status, rural versus urban residence, housing condition, or 

ethnicity, key covariates associated with pediatric immunological status that could readily confound any 

effect of lead. In like manner, the study by Sarasua et al (2000), highlighted in the ISA as demonstrating 

an effect of low level lead exposure on immunological parameters, did not adjust for these same 

potential confounders. In that study, an association between lead and the percentage of T or B cells 

emerged only in the subset of children age 6 to 35 months, and not in the older children, an unexplained 

interaction with age. With respect to the impact of lead on immunological markers in this age subset, the 

authors of Sarasua et al noted that the statistically significant findings were principally due to data 

obtained in children with blood lead concentrations over 15 μg/dL.

On page 5-255, the narrative highlights the study by Pizent et al (2008) as offering evidence of an 

association between lead exposure and total IgE at blood lead concentrations less than 10 μg/dL in 

adults. However, the discussion in the ISA failed to point out that this association only emerged after an 

undisclosed number of female subjects not taking hormone replacement therapy or oral contraceptives 

were excluded from the analysis. The authors did not disclose the final statistical model or display a 

graph of the results. The methodology of subject recruitment was not disclosed, and there was no 

adjustment for key potential confounders such as socioeconomic status, residential factors, or 

occupation. In discussing the findings of Songdej et al (2010) another study focusing on adults, the 

narrative cites changes in inflammatory markers among subjects with low blood lead concentrations, 

without noting that the subjects experienced much higher blood lead concentrations earlier in life. In the 

study of young adults by Kim et al (2007), associations between low blood lead concentration and 

certain cytokines were limited to subjects with specific phenotypes, and were not adjusted for the key 

potential confounders of socioeconomic status or residential history. 

Finally, it should be noted that even if it could be demonstrated that low levels of environmental lead 

exposure (i.e. at blood lead concentrations less than 10 μg/dL) caused perturbations in certain 

immunological parameters such as T or B cell prevalence, cytokine level, or immunoglobulin 

concentration, the clinical or public health significance of changes of the magnitude observed is 

uncertain at this point in time. Sweeping and unreferenced statements in the narrative, such as 

“Suppression of Th1 function by Pb places individuals at greater risk of certain infectious diseases and 

cancer” (page 5-275, line 8 to 9) are speculative, and should be deleted. From the standpoint of clinical 

or public health significance, a significant impact of low-level environmental lead exposure on the 

immune system has not yet been established. It is perhaps noteworthy that several recent clinical and 

public health oriented reviews of the human health effects of low level lead exposure do not discuss any 

immunological effects of lead (CDC, 2005; CDC 2010; Kosnett et al, 2007; Henretig, 2011)5

 5 CDC. Centers for Disease Control and Prevention. Preventing lead poisoning in young children. A statement by the Centers 

for Disease Control and Prevention. Atlanta: CDC, 2005

CDC. Centers for Disease Control and Prevention. Guidelines for the identification and management of lead exposure in 

pregnant and lactating women. Atlanta: CDC, 2010

.
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Comment on lead biomarkers and lead biokinetics: Section 4.3

First, features of the Leggett model that may serve to predict a relatively rapid decline in blood lead 

should be critically evaluated. It should be noted that the Leggett model is a compartmental model in 

which lead in bone moves over time from an exchangeable to a nonexchangeable subcompartment; lead 

in the nonexchangeable bone subcompartment can be returned to the plasma only by bone resorption 

(O’Flaherty 1998; EPA 2001

. Several modeling simulations based on 

the Leggett lead model feature prominently in section 4.3, e.g. Figure 4-6, Figure 4-8, and Figure 4-10. 

These figures depict a rapid decline in blood lead concentration in both children and adults following 

cessation of one or more years of elevated lead exposure. In Figure 4-6, after a year of elevated blood 

lead exposure associated with an increase in blood lead from approximately 3 μg/dL to 21 μg/dL, a 

young child’s blood lead concentration declined with a half-time of approximately 3 months. In Figure 

4-6, a similar half-time for lead in blood appeared to apply to a young child after a 3 year period of 

elevated lead exposure during which the blood lead level increased from 1 to 9 μg/dL. In Figure 4-10, a 

simulation of adult blood lead dose-response, blood lead abruptly increased from approximately 2 to 9 

μg/dL, where it remained for 20 years. Then, following cessation of exposure, the blood lead abruptly 

declined to 2 μg/dL within one year; a pattern consistent with a blood lead half-time of approximately 6 

months. The narrative describing Figure 4-10, (page 4-48, Line 9 to 11) states, “Based on this 

hypothetical simulation, a blood Pb concentration measured 1 year following cessation of a period of 

increased Pb uptake would show little or no appreciable change from prior to the exposure event 

whereas, the body burden would remain elevated.” These simulations based on the Leggett model 

appear to be variance with empirical data revealing a slower pattern of decline in blood lead 

concentration in children and adults following prolonged periods of elevated lead exposure. 

Accordingly, the discussion in Section 4.3 of the change in blood lead following diminution or cessation 

of lead exposure merits reappraisal and revision. 

6

Second, Section 4.3 should review and integrate the findings of empiric studies that have observed a 

decline in blood lead concentrations following cessation of exposure that is slower than that suggested 

by the simulations presented in the ISA using the Leggett model. Specifically, Manton et al (2000)

). This is in contrast to the O’Flaherty physiologically based kinetic 

model, which allows for diffusion of lead in all bone compartments to plasma in an age-dependent rate. 

Section 4.3 of the ISA should review how the O’Flaherty model, in comparison to the Leggett model, 

might predict a slower decline in blood lead concentration following cessation of extended periods of 

elevated lead exposure. 

7

 

Henretig F, “Lead”, chapter 94, in Goldfrank’s Toxicologic Emergencies, 9th ed, Nelson L et al (eds); New York: McGraw 

Hill; 2011

Kosnett MJ, Wedeen RP, Rothenberg SJ, Hipkins KL, Materna BL, Schwartz BS, Hu H, Woolf A. Recommendations for 

medical management of adult lead exposure. Environ Health Perspect 115:463-471; 2007 6 EPA. Adult Lead Risk Assessment Committee of the Technical Review Workgroup for Lead. Review of Adult Lead 

Models. Evaluation of Models for Assessing Human Health Risks Associated with Lead Exposures at Non-Residential Areas 

of Superfund and Other Hazardous Waste Sites. Final Draft: August 2001

7 Manton WI, Angle CR, Stanek KL et al. Acquisition and retention of lead by young children. Environmental Research. 

Section A. 82:60-80; 2000

Other articles cited in this paragraph:

Hodgkins DG, Hinkamp DL, Robins TG et al. Influence of high past lead-in-air exposures on the lead-in-blood levels of

lead-acid battery workers with continuing exposure. J Occup Med 33:797-803; 1991

Schutz A, Skerfving S, Ranstam J et al. Kinetics of lead in blood at the end of occupational exposure. Scand J Work Environ 

Health 13:221-231; 1987

Hryhorczuk DO, Rabinowitz MB, Hessl SM et al. Elimination kinetics of blood lead in workers with chronic lead 

intoxication. Am J Ind Med 8:33-42; 1985
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published data that demonstrated blood lead half-times between 20 to 38 months in young children 

exposed to lead dust from residential home remodeling. In the case of adults with occupational lead 

exposure, Hodgkins et al (1991) presented data that demonstrated an impact of past air lead levels on 

contemporaneous blood lead concentration more than 5 years after large reductions in air lead exposure 

had been achieved. Schutz et al (1987) presented data on former lead workers indicating that the decline 

in blood lead following cessation of exposure followed a two compartment model – a fast compartment 

with a half-time of 1 to 2 months, and a slow compartment with a median half-time of 5 years. 

Hryhorczuk et al (1985) observed that for workers with chronic lead intoxication and normal renal 

function, the median blood lead elimination half-time was 619 days. 
B-54

Dr. Roman Lanno

Comments on Chapter 2 - Integrative Health and Ecological Effects Overview

Chapter 2 presents the integrative summary and conclusions from the Pb ISA with a discussion of 

evidence presented in detail in subsequent chapters. 

Is this a useful and effective summary presentation? 

The structure and presentation of Chapter 2 is logical and provides a good summary of the approach and 

the rationale behind causal determinations for human health and welfare. Leaving out many specific 

references is fine here since this summary is intended for a broader audience and a completely scientific 

format may prove distracting for many readers. Figure 2-1 provides particularly good synopsis of 

spectrum of scientific evidence for human health effects of Pb. The tables within sections summarizing 

data for causal determinations are good, as is the final summary table, 2-8.

Is the framework for causal determination appropriately applied? 

Please comment on approaches that may improve the communication of key ISA findings to varied 

audiences. The health and ecological effects of Pb are mediated through multiple interconnected modes 

of action and there is substantial overlap between the ecological and health endpoints considered in the 

causal determinations. Since the mechanism of Pb toxicity is likely conserved from invertebrates to 

vertebrates to humans in some organ systems, the scientific evidence was integrated across the 

disciplines of health and ecology. Please comment on this approach e.g., is this a useful and effective 

integration of the scientific evidence?

The discussion of commonalities in modes of toxic action across varied taxa is an important step in 

highlighting the connection between human and ecological receptors and is a bold step for the EPA to 

attempt. Overall, the argument for various general modes of toxic action is strengthened by presenting 

similar findings from many taxonomic groups and this is captured very well in section 2.7.1, Modes of 

Action Relevant to Downstream Health and Ecological Effects.

One way of increasing the readability of this section (and the entire ISA document) would be the 

standardization of units used in expressing concentrations for measured parameters and especially for Pb 

dose. Blood Pb levels are consistently expressed as ug/dL and there is some useful discussion about 

expressing blood Pb levels using ug/L if we were to consider even lower blood Pb levels in assessments. 

However, Pb doses are expressed in a number of ways which make interpretation for the reader very 

difficult, especially if they are not scientists. For example, consider Table 2-6 which deals strictly with 

human data. Blood Pb levels are clearly expressed in ug/dL, but Pb dose is presented in pM, nM, uM, 

and ppm. Although it may be difficult to standardize M expressions due to the many orders of 

magnitude difference, ppm is not a very meaningful expression of dose. This should at least be 

converted to SI units, mg/L, but more usefully, expressed as a molar value, so as to facilitate comparison 

with other Pb dose measurements in the table. 

Following up on Table 2-6, I checked Krieg (2007) and it was not very clearly stated what the Pb dose 

was, so where did the 20 ppm come from? (HERO was great for making these comparisons very 

quickly, very slick!) In Wiebe and Barr (1988), the dose was 20 ppm in drinking water, not air, so this 
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should at least be expressed in mg/L. In Huel et al. (2008), Pb and As were measured in hair samples of 

women as exposure dose and correlated with Ca pump activity in RBCs from umbilical cord blood. In 

Kern et al. (2000), in vitro tests were conducted examining the conformation of calmodulin in the 

presence of Ca and Pb and dose was expressed as pM of free metal ion, Pb2+ or Ca2+. In order to make 

the interpretation of dose easier, it would be good to include additional information regarding the 

medium in which Pb dose was measured (e.g., hair, in vitro test solution, drinking water). This would 

reduce confusion in the interpretation of Pb dose. Additionally, it would be important to include the 

form of Pb that was measured as dose (e.g., total Pb, modeled Pb2+), so as to incorporate the concept of 

bioavailability into the measurement of dose. This may be less applicable in human health exposures, 

but is very important when examining ecological data. To summarize, effective comparisons of 

exposure dose can be mediated by:

1) Expressing exposure dose consistently in SI units (e.g., ug/L, mg/kg, etc.), preferably as molar 

concentrations, where possible. Dose as ppm is not acceptable. Dose expressed on a molar basis 

makes sense since it is not the mass of Pb at the site of toxic action that causes effects, rather the 

number of moles of Pb. 

2) Observed effects could be discussed in the order of “policy relevance”, discussing the context of 

the exposure. For example, in soil ecological exposures, tests conducted in natural soils, with 

measured Pb concentrations, using organism reproduction as an endpoint would have the highest 

relevance for assessing the effects of Pb on welfare. Experiments conducted with nematodes, 

using Pb added to agar or solutions, with unmeasured Pb concentrations, and endpoints of 

behavior and non-specific developmental anomalies would have little policy relevance.

With respect to the ecological effects section of Chapter 2, a summary of the various endpoints used to 

assess Pb toxicity are presented, but unlike the human health section, very few measures of dose are 

presented. As discussed above, the comparison of modes of toxic action among taxa is a good idea, but 

at least some measures of dose should be provided for ecological exposures. Even though ecological 

exposure measures may not translate directly into human exposure values, for those readers that would 

like to try and make a comparison, the values would be available. Summary tables of responses and 

doses (as in Table 2-6) would provide a good summary and make interpretation of the ecological data 

somewhat clearer.

Additional comments related to specific sections of Chapter 2 are provided below.

Page 2-13 – Figure 2-1 is great! Wonderful summary – a similar figure for ecological effects would be 

striking.

Page 2-19, line 13 – change “Pb levels in as low” to “Pb levels as low”

Page 2-22, lines 9-10 – What is meant by “target”? Is this a site of toxic action or simply a site for the 

absorption of Pb from the GIT, or both?

Page 2-24, line 21 – closing bracket needs to be added

Page 2-26, Table 2-3 – This could be a very powerful table if another column was added that provided

an exposure dose level, especially if exposure dose could be expressed in terms of air Pb levels
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Page 2-28, line 3 – What is meant by “dissolved Pb”? Is that Pb2+ or operationally-defined as Pb in a 

solution passed through a 0.45 um filter?

Page 2-28, line 31 – The rate of Pb accumulation in earthworms is also affected by the feeding biology 

of the different species

Page 2-29, lines 34-36 – It is completely expected that responses will differ when organisms are exposed 

to Pb in different soils due to the effects of soil type on Pb bioavailability, so unless, the soil is the same 

identical soil in terms of physical/chemical characteristics, the phrase “the same medium, e.g., soil” is 

not correct. This should be reworded.

Page 2-30, line 12 – change “physiochemical” to “physicochemical”. Physiochemical refers to 

physiological and chemical while physicochemical refers to physical and chemical.

Page 2-35, lines 5-6 – The reason evidence for Pb effects on growth is strongest in plants is that growth 

is the primary endpoint measured in plant tests, while reproduction is the primary endpoint measured in 

tests with soil invertebrates. Growth is rarely measured in soil invert tests, so perhaps this could be 

captured somewhere in these sentences.

Page 2-40, lines 13-15 – These concentrations of Pb are not very different. Is there another reason for 

differences in numbers of resident aquatic plants?

Page 2-40, line 27 – change “though” to “through”

Page 2-47, line 7 – insert “fuel” after “fossil”

Page 2-49, line 6 – Insert “evidence” after “body of” and “in” after “presented”

Page 2-55, line 5 – Change “sectin” to “section”

Page 2-56, line 13 – insert “to” after “continue”

Page 2-57, line 5 – insert “of” after “modifiers”; line 16 – remove “i”

Page 2-58, line 27 – Write out Fluorine in full at beginning of sentence; line 28 – insert “study” after 

“toxicological”

Page 2-59, line 23 – What is meant by this sentence? How does Pb bioaccumulation by aquatic 

organisms change the aquatic environment? Either provide specifics or remove.

Comments on Chapter 7 - Ecological Effects of Lead

Chapter 7 is a discussion of the ecological effects of Pb. Effects on terrestrial and aquatic ecosystems are 

first considered separately. They are then integrated by classes of endpoints (bioaccumulation, growth, 

mortality, hematological effects, development and reproduction, neurobehavior, community and 

ecosystem effects). 
B-57

Does the panel consider this approach appropriate? 

This approach is complete but involves some redundancy as some data sets can be used in more than one 

topic area. Overall, the reiteration is useful and this structure is easy to follow. 

Is it appropriate to derive a causal determination for bioaccumulation as it affects ecosystem services? 

This is a grey area question. Of itself, the bioaccumulation of Pb is not a toxic effect, but the normal 

adaptation of an organism to maintain homeostasis when challenged by a stressor. The magnitude of the 

stressor determines whether there is an effect (see schematic of bioavailability below). At low levels of 

Pb exposure, the rate of uptake of Pb is such that organisms that can bioaccumulate Pb will do so in a 

manner that partitions or detoxifies Pb within the normal range of physiological functions. This can be 

termed benign bioaccumulation. Once the rate of uptake of Pb exceeds the capacity of the organism to 

detoxify Pb, toxic effects become evident within the exposed organism, so at this point, bioaccumulation 

is no longer benign, but toxic. However, the effect is the mode of toxic action mediated through the 

interaction with some biological molecule in the organism, not the phenomenon of bioaccumulation. In 

terms of ecosystem services, there will be a level of bioaccumulation at a lower trophic level (benign or 

toxic) that will be ingested by a higher trophic level. If this level of Pb bioaccumulation in the lower 

trophic level results in a toxic effect in the higher trophic level, then a causal determination is warranted 

for bioaccumulation. If there is enough substantive evidence that trophic transfer results in toxicity, then 

a causal assessment is appropriate. Most of the available data suggests that biodilution is the 

predominant fate of Pb during trophic transfer, but some studies suggest some effects, so a causal

determination is probably warranted. 

Has the ISA adequately characterized the available information on the relationship between Pb 

exposure and effects on individual organisms and ecosystems, as well the range of exposure 

concentrations for the specific endpoints?

I guess this depends upon one’s perspective. Since this document focuses on new data since 2006, the 

range of exposure concentrations presented in text and tables covers that time period. In the context of 

all available information, the newer data may not be adequately characterized. The newer data should be 

adequately characterized by providing some information on the relevance of this data to existing data. 

This could be accomplished by providing all-inclusive tables or figures (e.g., species sensitivity 

distribution) with all the other relevant data from previous ISAs that could be used to make a decision 

regarding a secondary NAAQS for Pb. For example, data on chronic toxicity from the current ISA could 

be plotted on an existing SSD for Pb from previous ISA documents using different color symbols so it is 

immediately evident where the new data lie, similar to the presentation for human data in Figures 2-2 

and 2-3.

Are there subject areas that should be added, expanded upon, shortened or removed?

Page 7-8: A summary of background Pb levels in soils, similar to what is presented on page 7-50 for the 

Aquatic Ecosystem Effects section, would be useful in the interpretation of the relative Pb levels used in 

soil toxicity tests. A reasonable presentation of background Pb levels in US soils is available in the US 

EPA EcoSSL guidance document for Pb (US EPA 2005). 

Another useful addition would be background schematics on the concept of bioavailability to ecological 

receptors and one for specifics of the biotic ligand model (BLM). The bioavailability schematic can be 
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found in the US EPA Framework for Metals Risk Assessment (2007) and is similar to the schematic 

below. The BLM schematic can be found in any number of papers that describe the model. Both these 

diagrams can form a focus when discussing the bioaccessibility, bioavailability, bioaccumulation, and 

toxicity of metals in aquatic, sediment, and soil media. They would also provide a graphic illustration of 

the concepts central to any discussion of metal toxicity to ecological receptors. 

Environmental availability

Bioaccessibility

Exposure ================================================ Effects

Bioavailability

Physiological membrane

uptake Toxicological 

Accumulation

Site of 

Toxic 

Action

Bioaccumulated chemical

Benign 

Accumulation

Detoxification 

Storage

Essentiality -

enzymes

Elimination

Uptake

efficiency

Uptake

efficiency

Cationic 

competition

Predation

foraging

Soluble species A

Soluble species B

Soluble species C

Other dissolved 

species

Non-available 

chemical Dietary intake

Uptake

efficiency

ADME

Total chemical concentration

Soluble fraction Solid phase

Low Bioaccumulation of chemical High

One point of clarification that would be useful is distinguishing between bioconcentration and 

bioaccumulation and ensuring that these terms are used in the proper context throughout the document 

in the discussion of Pb bioavailability to ecological receptors. Bioconcentration and bioconcentration 

factor (BCF) refer to uptake of a compound strictly from water and are usually constructs of laboratory 

exposures. Bioaccumulation and bioaccumulation factor (BAF) refer to the summative uptake of a 

compound from all possible media (e.g., water and/or air + diet), so if organisms are being fed in the lab 

during tests or for almost all field exposures, bioaccumulation is the proper term to use. 

The concept of bioavailability should be incorporated into the discussion of Pb exposure by clearly 

defining the chemical measure of exposure. Measurements of exposure can be total Pb (a vigorous acid 

digest of the medium), dissolved (total Pb in solution passed through a 0.45 um filter), solvent extracted 

(total Pb in a weak acid or weak salt extract of a sediment or soil), solid-phase extract (total Pb in 

diffusion gradient thin films (DGTs) or cation-exchange resin that diffuse through a membrane and 

hydrogel layer), free ion can be measured directly (maybe not for Pb), or based upon models such as 

WHAM, the Pb2+ concentration can be estimated from total dissolved Pb and other water chemistry 

parameters such as pH, DOC, carbonates, etc. Various combinations of these techniques can be used to 

estimate free Pb ion in water, sediment pore water, and soil solution.

In order to have any idea of how all the modifying factors of Pb bioavailability alter bioaccumulation 

and toxicity in various environmental media, Pb concentrations must be measured in some way. Data 

from any studies only expressing exposure as nominal concentrations is excluded from EcoSSL or 

Water Quality Criterion development data sets. There appear to be a number of references in the ISA 
B-59

where this is the case, so care must be taken in describing the relevance of these studies if they are to be 

included in the ISA. 

If the ISA was expanded to consider dose-response in terrestrial systems, should we limit data to field 

soils? 

Absolutely, artificial soil (AS) is not a soil, but a standardized test substrate, and data generated using 

AS has no relevance to any application in real soils. Artificial soil is used as a reference condition (not 

necessarily a good one) in standardized laboratory bioassays with soils and as a standardized test matrix 

for conducting “proof of concept”-type bioassays with soil invertebrates. In the development of 

EcoSSLs, the US EPA did not consider data generated using AS as acceptable for the development of 

EcoSSLs. For plants, hydroponic tests may serve a purpose, but not really for examining the effects of 

Pb in soil since the matrix itself has a tremendous effect on plant physiology.

If the ISA were expanded to consider dose-response in aquatic systems, how might we most efficiently 

present toxicity data that varies greatly by organism, and environmental parameters that influence 

bioavailability (pH, dissolved organic carbon etc.)?

Probably the best way to present dose-response data for aquatic systems would be to standardize dose to 

the free Pb ion using an aquatic metal speciation model such as WHAM. The next step would be to 

standardize further with a biotic ligand and effect to create a Pb BLM, but I’m not familiar with how far 

this has been developed. 

Another approach may be to “bin” values in a more qualitative way and construct species sensitivity 

distributions (SSDs) for a certain range of conditions. By selecting the most important water quality 

parameters that modify Pb bioavailability (e.g., hardness, DOC) within the range of these parameters 

normally found in US waters, toxicity data could be examined under conditions of high (e.g., low pH, 

hardness, DOC), moderate (e.g., intermediate pH, hardness, DOC), and low (e.g., high pH, hardness, 

DOC) bioavailability. This would be similar to using a water hardness regression to determine sitespecific guidelines for Pb and also to the approach used for the development of Ecological Soil 

Screening Levels for soil.

Additional comments on Chapter 7

Page 7-10, line 8-9 – “Pb had been removed by resident plant species” – does removed imply that the 

plants took up Pb and the plants were harvested, to completely remove the Pb? Otherwise, Pb will 

simply be recycled into the system via plant residues.

Page 7-14, lines 11-12 – “direct adsorption from the atmosphere” – does this mean that the Pb was then 

absorbed by the tree or was it measured as surficial, adsorbed Pb?

Line 16 – “incidental processing” should be defined here

Page 7-17, line 23 – these are low levels of Pb in soil and represent background concentrations in many 

soils. Data from experiments with low levels of Pb in soils must be interpreted carefully and raises the 

question of how to consider data from organisms exposed to low levels of Pb.
B-60

Page 7-19, lines 24-27 – If no evidence for a regulatory mechanism for Pb was observed, (i.e., no 

saturation of uptake mechanisms?) why would snails have to grow additional soft tissue to retain 

additional Pb? Please clarify.

Page 7-20, line 5 – What were the correlation coefficients?

Page 7-21, lines 24-26 – Worms increasing soil pH via mucous secretions seems highly unlikely and soil 

pH is very stable? If soil pH were increasing then why would Pb bioavailability increase? The needs 

rewording or removal.

Page 7-24, line 12 – What are Rumex K-1 plants?

Page 7-25, lines 10-12 – These statements require references

Page 7-27, lines 4-6 – Exactly what is stated here? Is it being implied that photosystem II effects of Pb 

would be expected in all plants? That would only be if Pb is translocated to or absorbed by leaves and 

shoots. If Pb doesn’t get to the chlorophyll (e.g., by physiological exclusion mechanisms) then toxicity 

would not be observed. I think this sentence needs to be reworded.

Page 7-29, line 28 – What is the relevance of hydroponically grown plants to the toxicity of metals in 

soils. This is a huge extrapolation and no hydroponics data was used in the development of EcoSSLs.

Page 7-30, lines 10-28 – Are these tests conducted in agar? If so, they have little relevance to soil 

toxicology. Are these developmental and behavioural effects specific to Pb?

Page 7-31, lines 9-14 – Is an increase in cellulase activity actually a negative effect on the worms? 

Seems to me that would enhance digestion of plant material.

Page 7-31, lines 22-26 – Topical application to snails – this is not a standard methodology applied to soil 

organisms. Was the 500-2,000 ug Pb applied to the snails the mass of Pb applied or the concentration of 

the topical solution and how was dose ensured? Was the LD50 and internalized dose or was it still 

surficial?

Page 7-35, lines 6-8 – I don’t see the relevance of in vitro oocyte exposure to NAAQS development.

Page 7-36, 1st paragraph – What type of soil was used?

Page 7-36, 3rd paragraph – Were these LC50s incipient lethal levels or just 28-day exposures? Since 

there were no differences in Pb content between species, it’s possible that an ILL had been reached.

Page 7-36, 4th paragraph, line 34 – P. kimi populations would be extirpated in Artificial Soil? The 

relevance here is not clear.

Page 7-37, 1st paragraph – Nominal concentrations in an undefined soil type is not information that can 

be used.
B-61

Page 7-40, 2nd paragraph – This interpretation is unclear. If species composition of microbial 

communities changed, the authors cannot state that decomposition rates may decrease unless they 

measured decomposition. This is due to functional redundancy of microbial communities in soil.

Page 7-47, line 22 – change “layer” to “horizon”

Page 7-52, line 2 – change “qualities” to “quantities”

Page 7-63, line 3 – I think Lemna are free-floating and not rooted macrophytes

Page 7-66, line 36 – What does “significant amounts of metal” mean? Statistically significant relative to 

controls or reference organisms?

Page 7-67, line 21 – Should this be “exoskeleton > mid-gut gland > muscle > hemolymph”?

Page 7-68, lines 9-11 – Are these values actually different? They don’t seem to be unless the precision 

of the measurements is really high?

Page 7-68, last paragraph and Table 7-4 – BCF and BAF appear to be used interchangeably and their use 

should be consistent.

Throughout the text, the statements “accumulated significant amounts of metal”, “significantly 

increased”, or “detected at elevated levels” are used, but the relevance of these statements is often 

missing. Were Pb levels higher than in controls or reference organisms, higher than in organisms 

exposed to different concentrations, etc.? These need to be clarified.

Page 7-73, line 27 – remove “internally”

Page 7-87, line 24 – change “aspirate” to “aspartate”

In terms of quality assurance/quality control (QA/QC) of the experimental design and data 

measurements, what determines whether data from recent studies is used in the assessment or 

development of a NAAQS for Pb? As I’ve noted in many cases for soil toxicity tests, many of these 

studies would be excluded from EcoSSL development since they do not meet QA/QC criteria for soil 

toxicity data and have no relevance to assessing the toxicity of Pb in soil. How are data used where Pb 

exposures are very high by an exposure pathway that has low relevance to environmental exposures 

(e.g., in vitro exposures)?

Page 7-92, line 26 – Should this be “epidermal absorption” to gain an internal dose?

Page 7-92, line 32 – Xenopus laevis is the African Clawed Frog (not a toad)

Page 7-94, line 23 – This is a low EC20 but it is also unbounded? What is the preferred method for 

expressing this type of data?

Page 7-95, lines 9-13 – This is a comparison of toxicity in between freshwater and marine bivalves

Page 7-95, lines 34-35 – How many molts actually occur in 10 days and is this a realistic parameter?
B-62

Page 7-104, section on Species Sensitivity

Bioaccumulation may not be a toxic effect if it’s in the realm of normal homeostasis of an organism, so 

differences in Pb bioaccumulation by different species does not necessarily have anything to do with 

sensitivity to Pb. 

Page 7-105, lines 10-11 – Aren’t exoskeleton and hardened exterior tissue the same thing?

Page 7-110, line 5 – replace “bioconcentrated” with “bioaccumulated”

Page 7-110, line 7 and page 7-61, line 16 – The term “biodilution” is used to describe two different 

processes. Page 7-61 is “growth dilution” in relation to bioaccumulation studies

Page 7-114, line 8 – It’s unclear to me which routes of entry actually occur in plants. Stomata are on the 

undersides of leaves and aerial Pb can enter the leaf through the stomatal openings. What about Pb that 

is deposited on the upper surface of the leaf? Does this enter the leaf as well or does it only remain 

adsorbed to the surface?

Page 7-116, lines 17-18 – Limited information is available on growth effects on in invertebrates since 

growth is not a measured endpoint in most standardized invertebrate tests since it’s too variable and 

often organisms lose weight during tests due to substrate effects.

Page 7-117, line 27 – Heat shock proteins are a non-specific stress response and it’s not clear to me how 

they are relevant to Pb exposure.
B-63

Mr. Richard Poirot

Comments on Chapter 3 - Ambient Lead: Source to Concentration

Charge Question: Chapter 3 provides a wide range of information to inform the exposure and health 

sections of the ISA. To what extent are the atmospheric science and air quality analyses presented in 

Chapter 3 clearly conveyed and appropriately characterized? Is the information provided regarding Pb 

source characteristics, fate and transport of Pb in the environment, Pb monitoring, and spatial and 

temporal patterns of Pb concentrations in air and non-air media accurate, complete, and relevant to the 

review of the Pb NAAQS? Does the ISA adequately characterize the available evidence on the 

relationship between ambient air Pb concentrations and concentrations of Pb in other environmental 

media?

Chapter 3 generally provides an adequate review of the most recently available information on 

atmospheric emission sources, transport, ambient air concentrations, size distributions, spatial and 

temporal patterns, deposition and fate of lead in the environment. Many of the studies cited focus on Pb 

in a single environmental media, and there is relatively little information indicating how concentrations 

of Pb in soils (or wet or dry deposition, surface waters, sediments, indoor surfaces, etc.) would be 

expected to change in relation to future changes in air emissions and ambient air concentrations. I think 

this is primarily a limitation in the available literature, rather than a shortcoming of the ISA.

The authors stick closely to the assignment of focusing on “the latest scientific information” (1/06-3/11) 

available since the 2008 Pb NAAQS review, and this makes at times for uneven “recent literature 

review” discussions that seem to provide a paragraph summarizing the details of each new paper, 

without demonstrating how or why the new information advances or re-directs the state of scientific 

understanding in ways that would support or challenge the current NAAQS. I’m not a fan of the “only 

what’s new” approach and think that at a minimum, there should be a clearly-stated summary of the 

existing conceptual (model) understanding at the start of each new section. If this summarizes the last 

ISA (or in this case CD), it won’t work very well if the previous ISA or CD was itself just a summary of 

what was new 5 years earlier. One possible approach would be to have introductory sections 

summarizing the “existing conceptual understanding”, with a following section (or appendix) 

documenting the “new literature” that simply summarizes the relevant new publications, and a 

concluding section that indicates specifically how the existing conceptual understanding has been 

modified (if at all). Another approach might be to have a standing “state of the scientific understanding” 

document (more like the original CDs) that is periodically modified where and if the new information 

warrants changes. A “track changes” view would be a good way for reviewers to see what’s both new 

and important.

The Chapter 3 appendix provides interesting and useful information reflecting on spatial patterns and

particle size distributions from the (limited) available ambient measurement data. As indicated in 

specific comments below, Table 3A-13 reveals uncomfortably high incidences of illogical particle size 

results where there was apparently more Pb measured in PM10 than TSP (1/5 of sites), in PM2.5 than in 

TSP (1/5 of sites) and in PM2.5 than in PM10 (2/5 of sites). Collectively, these illogical results suggest 

either widespread prevalence of poor quality Pb measurements, or errors in processing the data used for 

this comparison. Additional information is needed on the different sampling methods, filter media and 

blank characteristics, analytical and sample extraction methods, accuracy and precision characteristics, 

and the screening/processing methods for the measurement data employed in these Pb size comparison 
B-64

studies. This is especially important given the wide range of acceptable FEM analytical methods for Pb 

and continuing concerns over the highly variable cut size characteristics of the current hi-vol TSP FRM. 

While the chapter provides a detailed and informative discussion of the various existing, and in some 

cases developing, analytical methods employed for total Pb or Pb species, the discussion of methods for 

collecting Pb in different particle sizes is much more limited. The substantial sampling biases with wind 

speed and direction for particles larger than 10 microns associated with the current high volume TSP 

sampler are noted, but no information is provided on currently available or developing methods that 

might reduce or eliminate these sampling biases. Nor is any information provided in Chapter 3, or drawn 

from other chapters, on what the ideal particle size characteristics of a Pb FRM sampler should be. 

During the course of the previous (2008) Pb NAAQS review, the CASAC Pb NAAQS Review Panel 

and AAMMS subcommittee strongly encouraged the Agency to develop and/or evaluate alternatives to 

the antiquated, imprecise hi-vol TSP samplers. The need for such alternatives is also clearly recognized 

in the “ambient air monitoring” section (6) of the March, 2011 Integrated Review Plan for the National 

Ambient Air Quality Standards for Lead, but the topic is not discussed in the current ISA. Developing 

and evaluating such alternative samplers should be a high priority during the current Pb NAAQS review, 

and should not be postponed (again) until the end of the review cycle.

Specific Comments

p. 3-2, lines 15-16 (and p. 3-1, line 22): Some additional explanation seems warranted to account for 

how Pb emissions from piston aircraft engines increased from < 10% of total in 2006 AQCD (based on 

2002 NEI) to 49% of total in 2008. Did everything else decrease a lot (I doubt it), or was there a 

difference in inventory methodologies? In Figure 3-2, it looks like 2002 piston aircraft emissions were 

about 33% of total (not < 10%).

p. 3-3, Figure 3-2: Is there an explanation for the increase in miscellaneous Pb emissions from 2005 to 

2008? 

p. 3-4, line 2 and elsewhere: Piston aircraft emissions are referred to here as “direct point source 

emissions”. Are individual planes (or airports) considered to be “point sources”? What fraction of the 

590 tons of aircraft Pb is emitted at/near airports, vs. along the flight paths?

p. 3-4, lines 14, 15: The “upper 0.1% of stationary emissions came from 33 counties” doesn’t sound 

right. I think there are about 3,100 counties (or equivalent jurisdictions) in the US, so 33 counties would 

be about 1% of counties (emitting only the upper 0.1% of stationary source Pb emissions?).

p. 3-10, Subheading under “Roadway-Related Sources”: I think you probably mean “Contemporary” 

(not “Contemporaneous”).

p. 3-11, lines 15-27: This is not especially helpful – re-suspended soil lead contributes somewhere 

between 90% of total and “can’t be ruled out”.

p. 3-14, line 2: So what happens to the 25% of Pb in fuel which is not emitted in auto exhaust?

p. 3-15 to 3-18: The discussion on Pb source apportionment is rambling and not especially helpful, 

switching focus from the chemical composition of Pb-containing compounds from sources to receptor 
B-65

model attribution of total Pb to sources, to composition of Pb-containing particles in the atmosphere. 

Many of the summarized studies – from Beijing, Shanghai, Mexico City, etc. may not be very relevant 

to current US sources. Conversely, no information is presented showing any source attribution to, or 

expected or measured chemical composition of Pb emitted from piston engine aviation fuel use.

p. 3-18, line 7: You might refer to “Pb-Zn-Cl-containing” particles to make it clear that 73% of PM2.5

particles were not composed entirely of these 3 elements.

p. 3-22, line 16: It’s not clear why Pb in re-suspended road dust should exhibit a bimodal distribution. 

Can some explanation be provided to indicate the different sources expected to be contributing to this 

bimodal size distribution?

p. 3-26, lines 1, 2: The Pb dry deposition flux in new measurements was considerably greater in 

industrialized urban areas than it was in the 2006 Pb CD? What does this mean? Is this based on just 1 

study in Tokyo Bay, and are you sure the units are right (see below)? 

p. 3-26, line 11: Is it possible you mean 12-17 mg/m2

/yr (rather than μg/m2/yr)? Otherwise it seems 

inconsistent with the (30x higher) 0.49 mg/m2/yr bulk wet deposition at an a rural forested central 

Ontario site, and with the dry deposition flux ranges of 0.04 to 4 mg/m2

/yr and 2 to 3 mg/m2/yr 

attributed on p. 3-22 (lines 4 and 11) to the 2006 Pb CD. A range 12-15 μg/m2/yr wouldn’t be “more 

than 10 times the upper bound” (of 4 mg/m2/yr or 4000 μg/m2/yr) from the 2006 CD.

p. 3-27, line 6: Not clear what is 0.002 to 0.3% of what?

p. 3-28, line 1: “under” what?

p. 3-28, line2: You could change “substantial” to something like “important” or “relatively large”, since 

the size of the resuspension contribution would be at least as large (and likely larger) in the vicinity of 

current major sources.

p. 3-28, line 28: Delete either “is” or “originates”.

p. 3-31, line 1: Is this “TSP” in water? If so, please define. If it’s in the air, more explanation is needed.

pp. 3-33 to 3-40: This lengthy review of Pb in runoff and associated transport and deposition 

mechanisms is detailed and occasionally interesting, but it’s not clear how this “new” information 

(mostly pertaining to transport of historically deposited Pb, is relevant to the review of an ambient air Pb 

NAAQS. Possibly here or elsewhere you could include some discussion of the relatively extensive 

sampling an analysis of flood-deposited Pb-containing sediments in post-Katrina New Orleans. This 

(flood water transport) mechanism could be a potentially important transport pathway for re-distribution 

and re-emission of historically deposited Pb to the ambient air. See for example: Plumlee et al. (2006) 

USGS environmental characterization of flood sediments left in the New Orleans area after Hurricanes 

Katrina and Rita, 2005—Progress Report: U.S. Geological Survey Open-File Report 2006-1023, 74 p. 

http://pubs.usgs.gov/of/2006/1023/pdf/OFR-2006-1023.pdf . 

p. 3-37, lines 29-30: Part of this sentence (“The generally high...DOC concentrations”) must be 

missing.
B-66

p. 3-42, line 33: Add “into” before “account”.

p. 3-56, line 1: The objective of IMPROVE isn’t “to protect visibility” per se, but rather “to monitor 

visibility and the pollutants which impair it”.

p. 3-56, line 10: There are more than 9 XRF elements; more like 24 for IMPROVE.

p. 3-66 or elsewhere: Other than the Figure 3-13, there doesn’t seem to be a clear presentation of the 

names, locations, monthly and 3-month maxima and variability of sites exceeding 2007-09 Pb design 

values. Could a table providing that information be provided here or in the appendix?

p. 3-68 or elsewhere in this section: It might be informative to present some summary spatial and 

temporal patterns of PM2.5 Pb from IMPROVE sites, to convey general background patterns and to show 

how low these rural, fine particle concentrations are – relative to standards. Also these could be more 

directly compared to the occasionally much higher urban CSN PM2.5 Pb data – hopefully using 

something other than the dreaded “county plots”, which I just don’t find very informative. The figure 

below shows an example of recent 5-year averages from the two PM2.5 networks, for which the Pb data 

from collocated sites appear to be quite comparable. You could also show temporal trends for nearly 10 

years from CSN and 20 years from some IMPROVE sites.

Figure 1. Five-Year Average PM2.5 Pb from Rural IMPROVE and Urban CSN sites: 2004-08

p. 3-68 & 3-69: I don’t like the approach here of describing information in the chapter which is only 

displayed in the appendices. At least provide an example or illustration of what you’re describing here in 

the chapter. 
B-67

p. 3-76, line 2: Delete “lowest”. Also, you might indicate if the observed seasonal differences are 

statistically significant or if similar seasonal patterns were apparent in other time periods.

p. 3-77, line 18 and elsewhere: It isn’t clear (to me) why you are using a ρ (rho) correlation metric, 

rather than the more familiar r or r2. Sometimes ρ is used to denote the population correlation, rather 

than the sample correlation, but ρ is also often used to connote the Spearman’s rank-order (nonparametric) correlation. If you are intentionally using a non-parametric method, you might indicate this, 

explain why, and include an illustration that Pb data (in all size ranges) are not normally distributed.

p. 3-78: It might be helpful to include some mention of the analytical (and extraction) methods generally 

employed for quantifying Pb in the different size fractions which are compared here, as those differences 

may help explain some of the (occasionally illogical) differences in concentrations. See below.

p. 3-78, lines 12, 13: An average PM2.5 Pb/ PM10 Pb ratio > 1 warrants additional discussion. Looking at 

Table 3A-13 on p. 3-166 & 167 of the Chapter 3 Appendix, it is disconcerting to note that: 

PM10 Pb > TSP Pb at nearly 20% (5/27) of collocated TSP and PM10 Pb sites, 

PM2.5 Pb > TSP Pb at nearly 20% (8/45) of collocated TSP and PM2.5 Pb sites, and 

PM2.5 Pb > PM10 Pb at nearly 40% (19/49) of collocated PM10 and PM2.5 Pb sites. 

These high incidences of illogical results raise concerns about the quality of all Pb measurements, and 

call for further analysis and explanation. In addition, I note that many of the collocated Pb data sets 

utilized in Table 3.8.2 in the Appendix appear to be identical to those employed in a similar analysis 

conducted for the previous Pb NAAQS review, reported in a 4/22/08 memo from Mark Schmidt and 

Kevin Cavender (http://www.epa.gov/ttn/naaqs/standards/pb/data/20080428_scalingfactors.pdf ). The 

correlation metric in that previous analysis was different (r2 vs. the current ρ) although I would expect 

the r2 to generally be more stringent (a lower number), but at a number of sites the former r2 was higher 

than the current ρ. There was also an “average ratio” (of PM10 Pb to TSP Pb) reported for each site in the 

Schmidt & Cavender memo, which is different for than the “average ratio” reported in the current Table 

3.8.2 for many of those sites and data periods of record which were presumably the same in both 

analyses. Some explanation for these differences seems warranted.

There is a fairly substantial database of Pb (and other XRF elements) from a Canadian dichotomous 

sampler network, where analytical methods were consistent for fine and coarse fractions, and where 

relevance to current/recent US concentrations and size distributions would be high.

p. 3-80, lines 24, 25: Was Pb highly correlated with As in both the coarse and ultrafine fractions in the 

Hays et al. study?

p. 3-80, line 32: Do you mean Pb in PM0.1 was 15 times higher in the tunnel than by the roadside?

pp. 3-80 – 3-81: The Figure 3-23 results summarized from Sabin et al. (2006) raise questions about (a) 

What were the particle cut size characteristics of the samplers used in that study? and (b) How well 

would the current TSP sampler capture the different particle sizes observed in that study?

pp. 3-80 – 3-82: This is an interesting discussion. Possibly some of the results you cite from other 

countries might not be directly relevant to US if Pb sources and historical trends are different. 

pp. 3-83 – 3-84: Is there an explanation for the large reduction in the number of sites with collocated Pb 

and other pollutants in 2009, compared to 2007-2008?
B-68

P 3-86, Figure 3-26: It might convey information more clearly if the co-pollutants were sorted by 

highest to lowest median or average correlations with Pb, rather than alphabetically. 

p. 3-87, lines 6-7: Is the more rapid Pb accumulation in soils from Pb salts than from sewage sludge or 

fly ash due to higher Pb concentrations in the salts, or from better retention in soils or from both 

concentration and retention? 

p. 3-88, line 14: Explain the meaning of “TSP” in soil samples.

p. 3-88 – 3-95: In discussing Pb concentrations in soils or sediments, it would be helpful to indicate or at 

least generally summarize the depth of the soil and sediment samples for which you report 

concentrations.

p. 3-92, lines 16, 17: I don’t agree that “these results suggest that soil Pb concentration tends to be 

spatially heterogeneous in the absence of a source”. In the absence of any Pb sources, there would be no 

Pb. In the absence of strong anthropogenic Pb emission sources contributing to Pb deposition, the soil 

Pb concentrations would be determined by natural soil Pb content, which would not tend to exhibit 

especially high spatial variability.

p. 3-92, line 29: Although Pb air monitoring was not formally conducted as part of the WACAP study, 

fine particle Pb was measured at IMPROVE sites at about 3⁄4 of the national parks included in the 

WACAP study.

p. 3-93, line 18: You could insert “average” after “highest”, as it appears from Table 3-10 that the 

highest peak Pb concentration was observed in Baltimore.

p. 3-95, Figure 3-29: There is no “background” displayed in this figure, as indicated in the caption.

p. 3-98, lines 4, 20 and elsewhere: Could you use consistent units to describe Pb concentrations in rain, 

snow, surface waters, etc. – rather than switching from μg/l to pg/g to ng/l?

p. 3-98, line 22: the reference (collated in 2008) works electronically, but not in hard copy. You could 

change this to (Lee et al., 2008).

p. 3-99, lines 28-30: Some additional explanation of 206Pb/207Pb ratios would be helpful. Otherwise its 

hard to see that a ratio of 1.16 is “far from” 1.19. In general, this entire paragraph, extending onto p. 3-

100, is not very informative and could be clarified.

p. 3-102, lines 17-21: This summary of Pb speciation, including the statement that Pb speciation was 

“fairly well characterized” in the 2006 CD, is not especially informative. What are the predominant Pb 

compounds that we expect to find in the current ambient air in the vicinity of various Pb sources? Does 

20% of Pb emitted from piston aviation engines persist as gaseous organic compounds (unmeasured by 

PM samplers) or is this just 20% of Pb bromide and dibromide compounds (and are they in gas or 

particle phase)?

p. 3-102, line24: This may be true, but I don’t recall mention in the chapter that “global” Pb deposition 

peaked in the 1970s, and think that might be a difficult thing to document with confidence. 
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p. 3-103, line 24: Delete “that”.

p. 3-134, line3: The text indicates that “the comparison tables include the Pearson correlation coefficient 

(r)” but the table legends indicate ρ (rho), which is presumably the Spearman rank-ordered correlation. 

So which is it, and if it’s Pearson r, why is this different than the metric used to correlate Pb in different 

size fractions?

p. 3-134, lines 11-18: Can you indicate how means were calculated where (sometimes high) fractions of 

the samples were below MDL?

p. 3-140, Table 3A-7 and elsewhere in Appendix: It’s difficult to understand the 3 separate values (rows) 

showing “correlations” between each pair of sites without flipping back several pages in the text. 

Perhaps you could provide a clearer legend, an explanatory note at bottom of each table, or add a 

column repeating ρ, P90 and COD for each row. Possibly also rename these “Comparisons...” rather 

than “Correlations...” in the table captions, since it’s not just correlations that are presented.

p. 3-165: The table above indicates that monitors A, B and C are all “source-oriented”, while the figure 

caption refers to source and non-source-oriented monitors.
B-70

Dr. Joel Pounds

General Comments

Chapter 4, like other parts of the ISA is well written. Information is provided within the chapters in a 

logical fashion. The detailed table of contents provides a useful roadmap for the reader to follow the 

flow of information and to look for location of specific information. 

Chapter 4’s focus on blood and bone Pb is appropriate given the wealth of experimental and 

epideomolgical reports and the state of experimental and conceptual linkage between the two 

biomarkers. The Leggett model simulations nicely illuminate the complex relationship between blood 

and bone lead levels. The discussion describing the relationship between blood Pb and soft tissues is 

adequately presented. The absence of new data or insights limits the 

Chapter 4, as other chapters, often needs more evaluative, judgmental conclusions in paragraphs 

reviewing data. In Chapter 4, the results of published literature are generally summarized in a single 

paragraph. The summary is judged complete and accurate. Missing from these paragraphs however, is 

the evaluation. Why were these papers included? What is the new information that extends knowledge 

beyond the last document? Does the paper confirm previous findings? Does this paper identify new 

knowledge or data gaps? What are the limitations of the new information? To include, where 

appropriate, this critical evaluations is important to creating a compelling ISA document. 

The following comments identify topics that should be added or receive additional or clarifying 

discussions

Page 21. Section 4.2.1. Absorption. This section defines the terms “absorption”, “bioavailability”, and 

“bioaccessibility”. The working definitions of absorption and bioavailability do not make these terms 

very distinct. Absorption “refers to the fraction of Pb absorbed from respiratory or gastrointestinal tract” 

while bioavailability” refers to the amount of lead ingested or inhaled that enters systemic circulation”. 

Is it the units (fraction vs. amount or the specificity of absorption into “systemic circulation” that 

distinguishes the two terms? This ambiguity is furthered by the apparent interchangeable use (or 

incorrect by these definitions) of the absorption and bioavailability in Chapter 4 and elsewhere in the 

ISA. I suspect that most of these inconsistent uses result from carry-over usage from the original 

literature cited. I also don’t understand why the ISA is not using well accepted jargon of uptake and 

intake. Some of the inconsistent uses are identified below in my “editorial suggestions” I recommend 

that these definitions be revisited and that the entire ISA document be reviewed for use consistent with 

the clarified definitions. 

Sections 4.3 and 4.7.3. The definition, application, and limitations of biomarkers. Like other clinical 

biomarkers, Pb biomarkers (blood and bone) are applied to both individuals and to populations for a 

variety of purposes. Blood and bone Pb levels are used as biomarkers for (a) Pb exposure, (b) body 

burden, (c) diagnosis of toxicity, (d) internal dose, and (e) risk for a plethora of adverse outcomes. The 

individuals and populations include broad age range, gender, genotype, and diverse exposure scenarios. 

Moreover, blood Pb in particular, is also used to benchmark animal studies to human studies. The 

approach and requirements for experimental validation of blood and bone Pb biomarkers for these 

applications is different according to the specific application. Thus, blood or bone Pb measurements are 
B-71

not equally valid for all applications listed above and limitations are associated with each biomarker and 

application. 

The ISA clearly recognizes that the Pb biomarkers are not equally valid when applied to different 

exposure scenarios. The Chapter 4 text contains cogent, but scattered discussions of the limitations of 

blood Pb with complex temporal exposures. The model simulations provided in Figures 4.4-12 provide 

very nice conceptual illustration of this point. Nonetheless, it is very easy (and common) to use and 

interpret Pb biomarkers in a facile manner without clearly communicating the ‘biomarker for what’ and 

limitations of the application. Because blood and bone Pb levels are used for risk assessment and 

management, this discussion is important enough to bring up to section 4.0 or at least 4.3 and the 

Chapter 4 Summary, 4.7.3. 

The ISA and Chapter 4 would be well served by defining the conceptual and practical distinction 

between applications of Pb biomarkers for exposure, body burden, internal dose, diagnosis and risk. In 

addition, I believe that a scientific paper that discusses the topics above would be a very useful 

contribution to the lead field. I encourage EPA staff to consider authoring such a paper. 

Sections 4.2 and 4.3 (Kinetics and lead biomarkers) should recognize that adolescents are poorly in 

existing mechanistic and empirical models. Individuals undergo rapid changes in sexual dimorphism, 

body growth, food and water intake, bone growth and turnover, diet, behavior, etc. during adolescence. 

Although there are some case-control studies suggesting that manifestations of early Pb exposure are 

observed, there is a paucity of experiment measurements of Pb biomarkers during this time. The lack of 

good data results in a deficiency of biokinetic models. Moreover, the individual biological and kinetic 

parameters are largely interpolated rather than based on solid experimental and toxicological 

measurements. These deficiencies limit the validity and use of model predictions to link exposure 

history with blood and bone Pb levels.

4.b. Relationship between Air Pb and PbB is not completely described. Literature review is good, but 

not complete and generalizations (conclusions) are not clearly made. Respiratory tract deposition and 

clearance are reported in the context of a specific study, but the ISA does not give a sense of the breath 

of the issue or the scientific context for this information. Perhaps a table abstracted from Chapter 3 that 

summarizes relationships between PM size, Pb content, PbB, etc would be helpful. Section needs takehome conclusion. 

Page 34. 4.3. Biomarkers. This section nicely introduces the topic but could be improved by slightly 

more extended rationale for selection of the Leggett model over the other available biokinetic models. 

4.2.2.3. Soft tissues. (Comment). While the statement that soft tissue Pb “exists predominately bound to 

protein” may be true and may be logical, the state of Pb in tissues is more conjecture than 

experimentally derived conclusion. Pb is no doubt, in equilibrium with proteins and complexed with 

many other ligands including glutathione, amino acids and small organic acids. Pb bound to extracted 

proteins supports the conclusion that this binding occurs in vivo but does not well describe the fraction 

of total Pb bound in intact cell/tissues as the experimental data reflect binding in diluted proteins in 

buffer without the pH and ion gradients and compartmentalization of ions, proteins and other compting 

ligands. 

Question 5. I agree with Drs. Cory-Slechta and Kosnett that it is very important to evaluate the 

experimental design of in vitro studies to judge their relevance to elucidate mode of action. This difficult 
B-72

evaluation is deceptively simple. Arithmetic conversion of Pb M in cell culture media to blood or 

plasma Pb concentrations is simple, straight forward, and unambiguous; 1 μM Pb cell culture medium is 

arithmetically equivalent to ~21 μg /dL whole blood. Similar calculations can compare medium Pb to 

plasma Pb. Unfortunately, this simple comparison is inadequate for several reasons. The critical question 

is wether the in vitro and in vivo experiments have comparable Pb levels in the cells, tissues, and 

biological processes. First, for the purposes of these extrapolations, medium and blood Pb levels are akin 

to exposure rather than dose. We know from autopsy studies, animal studies, and biokinetic model 

simulations that blood Pb poorly correlates with tissue lead concentrations. Thus the simple 

extrapolation of medium Pb concentration to blood Pb is not appropriate. Rather to evaluate the 

relevance of an in vitro study, one should consider (a) comparison of the Pb level in the in vitro model 

(cells) to the Pb level of the comparable cells in vivo, (b) the specificity/sensitivity of the in vitro

outcome vs. non-specific outcomes in vitro. That is, do the in vitro studies show effects that appear 

distinct from non-specific, overt stress response? And (c) are the cellular / molecular processes targeted 

in vitro consistent or plausible with toxicologic modes of action to produce the related toxicity in vivo.

Table 5.2. Related health effects... I suggest it is not appropriate to use the cell culture medium Pb 

concentration as “dose” as this value is much more equivalent to an exposure. The exposure duration, 

composition of the culture media, cell type, etc. modify the actual cellular dose given the identical 

exposure level. 

Editorial Suggestions. 

xxiv Abbreviations. Pb++ redundant with Pb2+ (search and replace Pb++ with Pb2+)

P 4-1, L6. It was reported in  The 2006

P 4-1, L7. 2006) that  2006) reported that

P4.1, L10. It was also observed that Pb  Pb

P4-3, L3. Could you list a couple susceptibility factors that influence exposure? 

P4.3, L8-10. Sentence beginning “it is plausible” is not clear

P4-4, L4. Delete ‘shown to be’

P4.8, L1. Studies have demonstrated  studies demonstrated

P4-9, L4. This indicates  This result indicates

P4-9, L23. Delete ‘found to be’

P4-9, L24. Change ‘It was’  Sill surface was...

P4-10, L20. in Pb  in water Pb” 

P4-10, L24. To what does “This” refer? 

P4-11, L15. this would  this substitution would

P4-11, L16. To what does “this” refer? 

P4-11, L22. Delete “potentially”

P4-11, L35. It was found that blood Pb level was  Blood Pb levels were

P4-12, L11 & 13. Does “Pb(II)” in line 13 meant to convey information distinct from line 11? 

P4-13, L10. “enriched the Pb content...” of what? 

P4-13, L19. median Pb  median fertilizer Pb...

P4-13, L22. this remains  this source remains... 

P4-13, L26. Delete ‘found to be’

P4-13, L28. was observed to have  had

P4-14, L6-7. were demonstrated to have high  had high

P4-15, L6. delete3 ‘have’

P4-15, L9. maximum Pb  maximum sediment (?) Pb 
B-73

P4-15, L19-20. There has also been evidence  There is also evidence

P4-19. 4.2.1. Clarify definitions for absorption and bioavailability. (see comment above)

P4-20, L3. activity median particle diameter  aerodynamic...?

P4-20, L14. Delete “heavy”

P4-20, L25-28. Ultrafine-sized is defined as <100 nm (L25) while L28 mentioned nano-size ranges. Are 

these size categories different or are the different words used to describe the identical sample size 

range. 

P4-20, L32. This indicated  this result indicated

P4-21, L10, L10-11. Is “bioavailability” used here as defined on page 19? That is, the fraction absorbed 

into systemic circulation. 

P4-23, L12-26. Is the use of the terms bioaccessible and bioavailability in this paragraph consistent with 

the definitions on page 19? 

P4-23, L16. based measurements  based on measurements

P4-25, L11. Comparisons of outcomes in in vitro  Comparisons of outcomes in different in vitro...

P4-25, L19. Soil has been reported to be...  soil was reported...

P4-25, L20. Pb dust maybe  Pb dust reaching the gastrointestinal tract maybe...

P4-25, L33. expectations would be that...  expectations are that...

P4-25, L34. this has...  This validation has...

P4-26, L29. capacity has been estimated...  capacity was estimated

P4-28, Figure 4-4. This figure doesn’t clearly show the pseudo-linear relationships in the blood Pb and 

intake range described in Lines 4-5. 

P4-30, L11. about 80 to 20 (...  about 80 to 20 percent...

P4-31, L18. liver, and brain) exists  liver, and brain) presumably exists [although it is plausible that 

tissue Pb is “predominately bound to protein” this conclusion is not supported by direct 

experimental observations.] See comment above. 

P4-33, L9. Concentration has been shown to be...  concentration was...

P4-33, L12. This contributes...  This relationships contributes...

P4-34, L4. Pb have shown that... Pb showed that...

P4-35, L20. This may...  This unit may...

P4-35, L31. It has not...  ICP-MS has not...

P4-36, L14. Although, this would be...  Although, this interpretation would be...

P4-36, L18-19. I believe this sentence has been misplaced. “Both analyses reported”... (which 

analyses?). “little difference... large difference” not sure which data differences is referring to. 

P4-36, L28. studies have found...  studies found...

P4-36, L35. This is illustrated...  This concept is illustrated... 

P4-39, L17-24. Urinary Pb concentration reflects, mainly, the exposure history... As correctly discussed 

elsewhere in Chapter 4, urine Pb reflects filterable plasma Pb. Plasma Pb reflects input from all 

sources i.e. intake, RBC, soft tissues, bone. The relative input to plasma from these sources along 

with renal function determine urine Pb. Concurrent Plasma Pb, not historyxxx

P4-41, L17. This may allow...  This difference may allow...

P4-41, L20. was able to discern differences...  discerned differences...

P4-42, L4. Delete ‘possibly’

P4-42, L8. at low levels...  at low blood Pb levels...

P4-43, L19. Slow bone volume compartments  Slow bone turnover compartments...

P4-43, L20. movement into...  movement back into...

P4-44, L21. this comes...  this conclusion comes...

P4-45, L2. This is expected  This result is expected... 

P4-48, L11. This illustrates...  This (what?) illustrates... 
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P4-48, L14-24. Good paragraph. 

P4-49, L1. Pb has been shown to be correlated...  Pb is correlated...

P4-50, L3. This has been observed...  This divergence was observed...

P4-50, L20-21. Increased blood Pb... This sentence is unclear. Increased blood Pb is characterized as 

patter of lower blood Pb...? 

P4-11, L11. This is in contrast...  This reduction is in contrast...

P4-51, L18. category, women...  category, pregnant women???

P4-51, L22. remobilization  mobilization 

P4-54, L4. This is reflected...  This (what??) is reflected...

P4-58, L3. data have shown a...  data showed a...

P4-63, L23. among various study populations...  among selected study populations...

P4-65 and P73. I did not recognize any L-XRF studies in these tables. If this observation is correct, 

suggest edit table title to read, “...bone Pb measurement by K-XRF...”

P4-78, Figure 4-18 legend. 50%  Pb

P4-79, L8. This corresponds... This (what?) corresponds... 

P4-82, L3. These include...  These factors include... 

P4-85, L6. This corresponds to...  This slope corresponds to...

P4-86, L6-8. The Pb concentrations were corrected by... It is not clear how these concentrations were 

corrected if authors did not report respirator protection factors. 

P4-86, L14-15. This corresponds...  This (what?) corresponds...

P4-90, L1. analyzed data on blood Pb and soil Pb concentration...  analyzed blood Pb and soil Pb 

concentration data...

P4-93, L2. They include...  Biokinetic models include... 

P4-95, L1 and L2. compartments...  compartment(s)

P4-95, L14. deeper bone regions...  deeper kinetic bone regions...

P4-95, L18. rapid turnover...  rapid formation and turnover...

P4-96, 4.7.3. Lead Biomarkers  Lead Biomarkers for Pb Exposure and body burden
B-75

Dr. Michael Rabinowitz

What follows are comments prompted by the text of the documents, arranged by page, and responses to 

the general and specific charge questions. Which topics to add or subtract, emphasize, shorten, or reenforce as key concepts, are addressed. 

Specific Charge Question 2. 

Is this a useful and effective summary?

Yes. It frames the right questions and presents adequate answers.

Is the framework for causal determination appropriately applied?

Yes, but I'd like to see nested models to help show the extent to which Pb is an independent risk factor 

in the epidemiological modeling, where so much variance is shared. For more, see p 1-19.

Approaches that may improve the communications of key findings?

Among my comments arranged by page are several minor editorial changes to help clarify some points, 

such as Table 3-1, or Figure 4, for example. 

Also, efforts should be made to show the extent or strength of the confounding, in the context of the 

effect size for lead and for the whole model's predictive power (r-sqr).

Also, see comments at the end about host factors being important, but environmental Pb is a far biggest 

predictor of PbB. Looking at these host factors helps us identify sub-populations at risk, whose 

protection drives our calculations, and may offer ideas about mitigation. Still, the more that can be done 

to lower environmental Pb levels, the less important these other concerns become. 

Is combining the health and the ecological effects of lead a useful and effective integration of the 

scientific evidence?

I strongly concur that combining health and ecological effects of lead yields a more useful and effective 

integration of the scientific evidence. We are obligated to protect both realms, and MOAs can be 

clarified. My only real concern is direct conversion of doses and concentrations among species. Because 

humans and animals occupy different environments and have different eating habits, our sensitivities to 

environmental lead may be more or less than some other animals. We have seen marine animals take up 

more lead if they live in the sediments versus animals that live in the water column. Furthermore, the 

fraction of the whole body burden that is in blood most likely varies among animals. Fish, birds, bovine, 

and human hemoglobin likely bind Pb with somewhat different strengths, which would profoundly 

affect their biokinetc distributions. That could be very useful. We have cases of Pb poisoned, nectar 

feeding birds and, and in another setting, meadow grazed horses, each being a sentinel species, their 

particular sensitivities proving useful for eventual human protection.
B-76

Comments Arranged by Page:

Page xxii, Acronyms and Abbreviations - These 17 pages demonstrate the wide range of disciples 

tapped by the authors of this document: Biology, psychology, medicine, chemistry, physics, geology and 

mathematics, but add MOA, mode of action, from page 1-9, line 20.

Page 1-1, line 2 - remove second comma. This is a long but not compound sentence. 

consider......evidence, and it communicates....

Page 1-14 - clear exposition of organization

Page 1-19, line 20 - "detect and control". Also, efforts should be made to show the extent or strength of 

the confounding, in the context of the effect size for lead and for the whole model's predictive power (rsqr). The presentation, and the researchers they cite and the journal reviewers they must satisfy seem 

content to show that Pb has a non-zero coefficient in multiple regression models, for example, of 

children's mental performance. But, because of the extent of the confounding, this is different than 

showing that Pb is an independent risk factor. Pb and these other risk factors share considerable 

variances, particularly in some of the higher risk populations, where Pb exposure and other risk factors 

often coexist. The relative size of this non-zero coefficient, the size of the Pb effect, should be shown in 

terms of the model r-sqr, or goodness of fit. How good is that model's fit with and without a Pb term in a 

series of nested models? Does the r-sqr increase significantly when a Pb term is offered? How much do 

the confounders' strength shift towards the Pb term, with which it shares variance, when Pb term is 

introduced? This would help a reader see how much is caused by Pb compared to other risk factors, 

preventable and otherwise. 

My concern is that at increasing low lead levels, where the lead effects is small, blood lead can still be 

measured relative accurately (often to 2 significant figures) but other, stronger variables, such as 

maternal education or richness of the child's home environment can be more difficult to measure, subject 

to reporting errors, and are often entered as broadly categorical variables, while lead is a continuous 

variable. For these reasons some may be a bit skeptical that at these low levels, effects that have been 

attributed to lead are fully caused by lead. 

Page 1-20, line 1 - Might you want to say anything here about how sample sizes often limit how much 

stratification can be done.

Page 2-6, line 22 - perhaps.....related to the re-suspension of the Pb

Page 2-6, line 28 - I would like to see the reference of the change in ratios and sources. Does this mean 

the sources changed their isotopic composition or the relative importance of various sources has 

changed? Fuel additive Pb isotopes varied among markets and over time. Was a change in food Pb IC 

seen? The document does not really need reference to isotopes at this point, unless further clarification 

proves useful. 

Page 2-6, line 36 - how about “after ingestion occurs" 

Page 2-7, line 2 - in vivo is a function of the co-presence or absence of food, host factors such as 

anemia, iron and calcium status, in vitro particle size and reagents 
B-77

Page 2-8, line 2 - lactation, fever (more likely), fractures, menopause

Page 2-8, line 16 - indicating higher recent exposures...

Page 2-9, line 17 -...burden, but not practical. Actually urinary output after chelation challenge has been 

a useful measure of labile body pools of Pb.

Also, on the topic of urinary Pb, the IC of urine tracks plasma Pb on a hourly basis. Urine reflects the 

filterable fraction of PbB, which equilibrates with the larger pool of RBC-bound Pb over an hourly time 

scale.

Page 2-11, line 27 - Some proto- porphyrins themselves are behavioral neurotoxins (recall King George 

III's porphyria ) and the amount of Pb needed to induce ALAD elevations are typically above 15 ug/dL 

in humans, anemic or not.

Page 2-15, line 15 - but what about the fact that PbB has fallen >10 fold, from > 20 to < 2 ug/dL, but 

BP has not. It seems like an insensitive relationship. I appreciate the historical significance. The BP-PbB 

relationship was a selling point for the removal of Pb fuel additives in the 1970's because the target 

population was middle aged to older males (congressmen worried about their blood pressure).

Page 2-16, line 17 - I liked this

Page 2-18, line 32 - for humans, the values are much higher, so these rats seem much more sensitive to 

Pb

Page 2-20, lines 15-16 - The trends here are a bit confusing to me. PbB levels have dropped, and age of 

puberty have dropped, If inverse, the PbB goes up, then delays goes down. 

Page 2-20, line 25 - Were these in occupational settings?

Page 2-24, line 30 - true, and maybe 1000 times lower than in circa 1980.

Page 2-25, line 2 – No, this type of axis scaling axis will not change the shape of curve. Also, ppm is not 

ug/L (that's ppb). This type of error is troubling.

Page 2-46, line 29 and whole section - Just a summary reminder that the slope will be steeper for 

children. 

The contribution of air Pb to soil and hence to humans is real, but much less efficient than direct 

inhalation.

Page 2-51, line 8 - In other words, decline attributed to Pb could be accounted for by the extent to which 

the confounders are harder to separate from a Pb effect at lower Pb levels.

Page 2-51, line 15 - Is this difference statistically significant? The ranges certainly overlap. 

Page 3-4 - A question: all of the sources except aircraft emit Pb close to ground level where we live, 

while aircraft emissions are largely high in the troposphere, aside from take-offs. Does this matter or is 

this factored in somehow? So, is Figure 3-5 based on sales of fuels or where it was emitted? 
B-78

Page 3-7, line 11 - 2 gr / gal for an automobile fuel would have been mid-range, high-lead high-test back 

in the day.

Page 3-7, line 19 - ....which are make the Pb combustion products (Pb halides) more volatile. (but they 

are not more volatile than TEL)

Page 3-8 - If we compare line 32, China's 122 kt/yr with US values of about 1 kt/yr from pages 3-3 and 

3-4, and knowing that China is upwind of the US, and knowing China's increasing reliance on coal, 

rapidly building new coal burning power plants at the rate of about one per month. Therefore, I wonder 

how much of our air Pb values are under our national control. We could have zero domestic emissions, 

but measurable airborne Pb.

Page 3-9, Section 3.2.2.4 - I'm not sure the first example is that useful. The European example is better.

Page 3-11, line 14 - Can you make a stronger statement? Not major, maybe minor, or maybe currently 

on-road usage of gasoline contributes at most X % 

Page 3-12, line 31 - maybe say: The potential for widespread dust lead pollution following demolition or 

sand-blasting depends on the actual site practices, such as hazardous material collection and disposal. 

Page 3-13, Figure 3-6 and text - It may be noteworthy to compare current emissions' from aircraft 600 or 

Mainland China's 120,000 tons/yr with this old data. 

Page 3-16 - In Table 3-1, maybe add the Pb ore cerrusite. Pb carbonate PbCO3, which is the most toxic, 

occasionally becoming newsworthy, as in the Esperance episode. It is a rare ore, absent from most major 

deposits, but predominant in a few mining areas.

 

Page 3-16 - Is lawn mower exhaust a concern?

Page 3-86 - Figure 3-26, why is this important?

Page 4-12, line 26 - Dietary Pb from contaminated soil - tea strikes me as an untypical example, since 

we do not eat tea. The Pb must be trans-located to the lead from the soil and then infused to the 

beverage. To grow tea, the soils must be fairly acidic pH 4.5 to 6, which aids metal solubility, and Al 

rich. There is a vast literature on plant uptake of lead from soil, even prior to 1980, for a wide variety of 

edible crops and indicators of air pollution. For example, the response of rice crops to Pb amended 

paddy soils has been well documented. See: Hseu ZY, Su, SW, Lai HY, Guo HY, Chen TC, Chen ZS; 

Remediation techniques and heavy metal uptake by different rice varieties in metal-contaminated soils 

of Taiwan. Soil Science and Plant Nutrition 56; p31-52 Feb 2010.

Page 4-13, line 15 - What is sub-proportionally?

Page 4-15, line 16 - Can this be expressed up to 25% as much as drinking water... or % of the total, or 

ug/day. % of water as a source is not that easily understood by me. 

Page 4-16, line 11 - Maybe should be Pb-Zn mining (Tar Creek?)
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Page 4-17, line 11 - Do we need this example of Nigerian sawdust? Are the values that high? Do we 

have similar situation anywhere in US?

Page 4-18, Table 4-6 - Why did Mainland Chinese toys and jewelry and venetian blinds not make the 

list?

Page 4-21 - Organic Pb - In 2nd para the combustion products of Pb+4 (TEL) are Pb+2 so Arthur's work 

on this topic does not go into this section about organic (Pb+4). Also, the change in PbB for each ug/cu 

M would yield 1000. it is closer to 3 ( see 4-80). You may want to give the volume of distribution for 

TEL. For Pb+2, it is about 10L for adult human.

Page 4-24, Figure 4-2 - May I suggest showing only Pb compounds, drop groups 2, 5 and 8. Also, I am 

surprised phosphate ( pyromorphite ) is so high since the solubility constant is many orders of 

magnitude lower than anything else shown, even galena. 

Page 4-26, line 13 - felt need for summary such as- no chemical form of Pb is safe, i.e. un-absorbable.

Page 4-26, line 18 - in this context, say only ...Pb in whole blood exchanges with both these 

compartments via the blood plasma. 

Page 4-41, line 9 - maybe say ...Each tooth in the mouth has a somewhat different anatomy and period 

of growth. Further complicating the matter, teeth are composed of enamel, dentine and pulp. Teeth are 

not like blood, which is a uniform liquid, making dental sampling and interpretation more complex. The 

ease of collection and the concentration difference (ppm in teeth vs. ppb in blood) at times overrides 

these concerns.

Page 4-41, line 26 - Some prenatal Pb is still found in the dentine found under the crown rather than 

down the root

Page 4-42, line 10 - I do concur in that hair is really not well suited as a biomarker for Pb, but hair 

plays a small role in the body's loss of Pb. Some human kinetic work has been done 

see7- my article with George Wetherill and Joel Kopple (1976) Delayed appearance of tracer lead in 

facial hair. Arch Environ Hth 31: 220 - 3.

4 end - A lot has been written about individual factors that modify uptake and susceptibility to 

environmental Pb ( genetics, gender, nutrition, age...). However, the major predictor of PbB is how 

much Pb is, I need to emphasize, how much Pb is in the environment, not any of the many host factors. 

Other remarks:

In an effort to explore the relationship between exposures and outcomes, a variety of models have been 

tried. My sense is it that the natural variations in Pb and IQ are much greater than the differences among 

the predictions of the various models. I am satisfied with the empirical models. Any uncertainty caused 

by model selection is smaller than the variation in the data. 
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Dr. William Stubblefield

Comments on Chapter 7 - Ecological Effects of Lead

Chapter 7 is a discussion of the ecological effects of Pb. Effects on terrestrial and aquatic ecosystems 

are first considered separately. They are then integrated by classes of endpoints (bioaccumulation, 

growth, mortality, hematological effects, development and reproduction, neurobehavior, community and 

ecosystem effects). 

Does the panel consider this approach appropriate? 

Chapter 7 provides an excellent synthesis of the available toxicity data for lead. The chapter is wellwritten and well-organized and does an adequate job of addressing “new” published data (post-2006). 

The separation of terrestrial and aquatic ecosystem data is appropriate and the subsequent organization 

by endpoints and levels of biological complexity is good. Some questions may be raised regarding the 

inclusion of some data and endpoints; however, this will be discussed in greater detail below.

Is it appropriate to derive a causal determination for bioaccumulation as it affects ecosystem services? 

This question is a bit difficult to address as posed. The process of bioaccumulation, i.e., the uptake and 

accumulation of environmental pollutants, may or may not have any effects on ecosystem services. 

Therefore, bioaccumulation should not necessarily be thought of as an adverse or toxic effect. 

Bioaccumulation as a result of environmental exposure can result in adverse effects to the exposed 

organism or to consumers of the organism but only if concentrations of the contaminant are sufficient to 

elicit a toxic response at a given “site of action.” In many cases bioaccumulation of metals, such as lead, 

in select tissues is a normal metabolic process by which an organism is able to sequester and ultimately 

eliminate metals, e.g. metal granule formation in mollusks. It may very well be possible to derive a 

“causal” relationship between exposure and the presence of metals in tissues. However, due to the non—

linear relationship between exposure concentration and tissue concentration with metals, developing a 

quantitative relationship would be doubtful. Similar concerns exist when evaluating possible food chain 

related effects. Available data suggest that little tissue bound lead is bio-accessible when consumed by 

predators, thus leading to “biodilution” of lead concentrations as one moves up the food chain.

Has the ISA adequately characterized the available information on the relationship between Pb 

exposure and effects on individual organisms and ecosystems, as well the range of exposure 

concentrations for the specific endpoints?

The ISA has done an excellent job of synthesizing and discussing the relationship between lead 

exposure and effects on individual organisms and ecosystems since 2006. Since the document relies on 

data that existed prior to 2006 and does not provide a summary of the extant data it is somewhat difficult 

to assess how adequately the document characterizes all of the available information. Summarization of 

all of the available data would be helpful; however, presentation of all of the available data would make 

the document unwieldy. Presentation of the available data in the form of a species sensitivity distribution 

(SSD) that identifies new versus old data would be helpful to the reader. Also, the ISA relies solely on 

published toxicity data available in the open literature. Additional unpublished toxicity information may 

be available from the lead industry given all of their efforts over the past 5+ years in developing data for 

compliance with the European REACH regulations. This information is likely to be available either 
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directly from the lead industry or from the European Chemicals Agency. It should also be pointed out 

that the US EPA Ambient Water Quality Criteria for lead is based on 1985 or older science. In 1999 the 

US EPA Office of Water announced its intent to revise the existing lead criteria to reflect newer science; 

to date this has not been done. Clearly, based on the data summarized in the ISA, there is substantial 

“new” information available upon which to revise the criteria document. In moving forward with the 

lead air quality criteria it will be necessary for the Office of Air to consider the available new science in 

deriving their assessment of possible effects to organisms in the aquatic environment.

Are there subject areas that should be added, expanded upon, shortened or removed?

The ISA does a good job of covering the vast majority of post-2006 published data relating to let effects 

on aquatic and terrestrial organisms. It is interesting, however, that a number of endpoints such as 

physiological stress, hematological effects, and neurobehavioral effects are considered in this document. 

Traditionally the US EPA has limited their interpretation of environmental effects to those effects that 

can be directly related to population and community level concerns. This approach has limited endpoints 

considered for criteria and standards to those associated with organism survival, growth, and 

reproduction. Alternative biochemical or physiological level endpoints are considered only when a 

direct link can be made to population or community level concerns. Therefore, since no direct linkages 

can be made between an observation of a biochemical, behavioral, or physiologic endpoint and a 

population or community level concern it may be appropriate to eliminate discussion of these types of 

endpoints from the ISA.

If the ISA was expanded to consider dose-response in terrestrial systems, should we limit data to field 

soils? 

I would recommend the data should be limited to “natural” soil data. Testing can be conducted under 

either laboratory or field conditions but the test matrix should be a “true soil.”

If the ISA were expanded to consider dose-response in aquatic systems, how might we most efficiently 

present toxicity data that varies greatly by organism, and environmental parameters that influence 

bioavailability (pH, dissolved organic carbon etc.)?

The best approach for presenting wide differences in sensitivity among organisms is through a species 

sensitivity distribution (SSD) approach. 

Environmental parameters that influence bioavailability are best discussed in terms of a description of 

the biotic ligand model. Application of the BLM to natural waters is best described by presenting the 

results of calculations using a series of natural waters or waters that exhibit a range of composition and 

chemical/physical parameters found across the United States. By presenting the data in this fashion the 

reader can easily ascertain the relative importance of each of the parameters on assessing lead toxicity. 

This applies to both the aquatic environment as well as to the terrestrial environment.
B-82

Dr. Ian von Lindern

Overview: The draft Integrated Science Assessment (ISA) is organized, comprehensive, and presented 

in a logical, transparent manner. It is an impressive well-edited document that is convenient to read and 

digest, despite its size. The document is structured as a follow up to the EPA 2006 criteria review

document and presents many of the conclusions as affirmations or supplements to the 2006 edition. The 

questions outlined in Section 1 are all keyed to the implications of new evidence that has evolved since 

the last review and how those studies inform the Agency in meeting its responsibilities. 

This is an appropriate approach in light of the EPA ISA strategy, which seems to be to examine whether 

any new information developed since 2006 provides justification for modifying the earlier analyses. 

This works well for those familiar with the previous review. However, this format i) may be 

challenging for uninitiated readers and reviewers, ii) does not inform the reviewer as to the historic 

conditions and accomplishments (in some areas), and iii) does not address weaknesses (in some areas) in 

the information base identified or analyses conducted in the last review.

Historic Perspective: There were challenges encountered in the previous review that indicated 

significant gaps in the knowledge base. These information gaps introduced uncertainties into the process 

that should be revisited. The last NAAQS review showed that EPA had, in maintaining the irrelevant 

standard from 1978-2007, “lost track” of key parameters necessary to effectively assess the health and 

ecological risks of airborne lead in the U.S. Relatively little data were available in several key areas for 

performing a responsible risk assessment.

It seems EPA intends to conclude in the Risk Assessment Planning document that, although substantive 

information has accumulated, little of this information changes the analyses or conclusions developed 

and presented in 2006. Based on the information presented, this conclusion does appear to be justified. 

However, there seems to be a disconnect in that i) significant data deficiencies were identified in 2006, 

ii) EPA is the Agency responsible to collect the data to fill these data gaps, iii) now EPA concludes the 

data continue to be unavailable to appropriately assess lead exposure in the country, and iv) the old risk 

analyses will be continued to be relied upon for another five years. 

The current exposure and risk assessment strategy evaluates pilot examples representing real situations 

prevalent in the country. These analyses are modeling exercises based on outdated empirical 

relationships and little concurrent ambient data. These situations show substantial probability of 

exceeding the new NAAQS and attendant levels of excess risk to surrounding populations. The major 

problem with respect to current exposure and risk analyses is that EPA is unable to estimate how much 

of the country is subject to these excessive levels. 

The ISA should point this deficiency out and ascertain whether there are technological or scientific 

barriers to developing the requisite information from existing sources, or through new program 

activities. The subsequent policy analyses should examine whether relevant databases are being 

developed, both internal and external to the EPA. Should EPA be developing, supporting, or 

implementing programmatic activities to make it possible to move from the near total reliance on risk 

modeling to observational and empirical analysis of contemporaneous data? 
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Several questions should be answered with respect to monitoring and surveillance. What data base is 

accumulating with respect to compliance with the new standard? Is a network established, is it adequate 

and effective, and are there detectable blood lead levels associated with any gradient in exposure? Have 

there been excursions? Certain U.S. sub-populations (e.g. immigrants and inner city children) are at 

substantially greater risk of exposure due to co-factors associated with different cultures, climates, 

dietary and nutritional regimes, as are being encountered in the global lead poisoning epidemic. Are 

these venues being monitored?

ISA Exposure Assessment Review: Evaluation of the Exposure Assessment portion of the document 

begins with Chapter 1 and extends through Chapter 4.

Chapters 1 and 2 Introduction and Integrative Health and Ecological Overview, respectively, are 

well organized, edited to provide a clear and transparent presentation of the intent and structure, and 

effectively summarize the document. Section 1.6 on causality and EPA’s Framework for Causal 

Determination is particularly strong and organized to clearly present EPA’s conclusions and 

justifications with respect to health issues. Section 2.7 and 2.8 are also especially pertinent additions and 

improvements to the Criteria Document process. Overall, the causation and health effects sections are 

impressive, comprehensive, and well-supported. 

In contrast, there is little discussion and few conclusions presented regarding sources, uses, ambient 

concentrations, exposure or populations at risk. Only 4 of 72 pages in the summary Chapter 2 discuss 

Ambient Lead and Exposure, followed by 2 pages of Toxicokinetics and Biomarkers, compared to 16 

pages of Human Health Effects and 15 pages of Ecological Effects summary. This is followed by an 18 

page summary dedicated to Integration of Human Health and Ecological Effects. 

The latter is a particularly good presentation and the Agency should be commended for beginning to 

make these connections formally in policy support documents. It is a step forward in environmental 

regulatory approach that will well serve both the environment and U.S. health and ecological policy. 

Table 2.8 in the Chapter 2 summary is particularly strong in making this point. 

Unfortunately, the relative amount of attention paid to exposure in the summary is appropriate to the 

makeup of the document as a whole, with more than 70% of the ISA dedicated to health effects and 

causality. This is also likely reflective of where research and monitoring attention and publication 

resources have been focused in recent years. With regard to the AQCD it is also points out the greatest 

deficiencies in the last NAAQS process have not been addressed and are perhaps being compounded and 

extended in this revision. 

Developing effective exposure estimates was the weakest point in the analyses that supported the current 

NAAQS. This was due to the lack of monitoring data available to assess contemporary exposures in the 

U.S., or to support the modeling analyses relied on in subsequent development of the NAAQS. 

Unfortunately, in the last review, the EPA was challenged in effectively estimating the extent of 

potential damage in the general population; the relationship between air lead levels, emissions and 

absorption; a safe air lead concentration; or the number of citizens exposed to potentially dangerous 

levels. 

This weakness was identified in the 2006 AQCD and the OAQPS made the best of a poorly 

characterized situation. There were insufficient data to characterize active emissions and emission rates, 

ambient concentrations and the degree, extent and severity of ongoing redistribution of residual lead in 
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the nation’s environment. As a result, EPA relied on modeling and decades-old empirical relationships 

to quantify exposures. This resulted in considerable uncertainty inherent in the overall process. 

Chapter 3 Ambient Lead: Source to Concentration: Chapter 3 addresses the areas identified as data 

gaps in the last review, and presents the information that will eventually be relied upon in developing 

exposure risk assessments for the U.S. population. There has been some additional ambient monitoring 

conducted since 2007 that better informs the Agency with respect to population exposure.

Formal and Informal Uses of Lead in the U.S.: Prior to discussing the adequacy of available ambient 

lead data, it is critical to note that there is no information relative to trends of commercial use and 

disposition of lead in U.S. commerce in the entire document. That 2006 AQCD indicated that use and 

consumption of lead in the U.S. were approaching levels near the peak utilization seen before the 

gasoline additive phase down. Yet, it seems the EPA has little or no information on the current life-cycle 

of lead in either the formal or informal industrial sector in the U.S. Does the Agency know how much or 

where this lead is being produced, used, consumed, recycled, recovered, reused, disposed of, or if it is 

being exported as waste? Is this information obtainable? Are any data bases available? Is the 

information reliable? It seems these data would inform the Agency as to where appropriate monitoring 

and testing should be undertaken. 

Sources of Atmospheric Lead: Sections 3.1 and 3.2 discuss sources of lead and summarize the National 

Emissions Inventory and discuss other anthropogenic sources of airborne lead. This discussion provides 

a good overview of the larger airborne sources in the U.S. and provides a county-by-county database to 

characterize the magnitude and extent of these sources across the country. These sections indicate that 

there are some quantitative data regarding larger point sources in the country and a basic understanding 

of source behavior with respect to numerous smaller lead sites in which the airborne pathway plays a 

significant role in human and ecologic exposure. However, there does not seem to be an inventory of the 

latter sites. How many are there? Where are these located? Is the list complete? Are there populations 

nearby? Are health risks in these areas addressed in other regulatory programs? 

Fate and Transport: Section 3.3 provides good discussion of lead fate and transport in the environment 

and recognizes that the majority of environmental lead is potentially air lead in waiting, or once was air 

lead, and can easily be transferred to other environmental compartments of exposure significance. 

Air Quality Monitoring / Surveillance: Section 3.4 is an informative discussion of lead monitoring 

techniques and appropriately covers the available technology to effectively monitor air lead in the U.S.

Section 3.5 does provide some new information to address the data gaps identified in 2006. There have 

been additional monitoring data collected in the interim that provide some concurrent information 

regarding airborne exposures in the U.S. Although a fair quantitative discussion and an extensive

Appendix are provided, no conclusions are drawn with regard to the quality, representativeness and 

degree of compliance with the NAAQS as currently implemented. 

With regard to compliance or implied risk, this information is confusing. It seems that “Source Oriented 

TSP monitors” indicate the NAAQS is being exceeded in 14 of 22 counties being monitored across the 

U.S. Conversely, non-source oriented monitors show levels generally well below the new NAAQS 

standard. Additional discussion is provided with regard to PM10 and PM2.5 monitors analyzed for lead. 

These networks generally seem to show overall compliance with the new NAAQS, even when TSP 

monitoring shows the same areas at-risk.
B-85

However, there seems to be no “take away” message with regard to these data and analyses. This is in 

stark contrast to the health issues presented and discussed in the document that are clearly conclusion 

oriented. Questions that come to mind include: 

What is the appropriate monitoring technique? One method shows 2/3rds of all source oriented sites are 

out of compliance across the U.S.; the other method shows 3 of 323 sites exceed the criteria, but does 

not specify source type. Does the latter method appropriately reflect the risk associated with these 

sources? 

If 2/3rds of source oriented sites are out of compliance, how many of these sites are there in the country? 

Are there only 22 that are being effectively monitored, or hundreds or thousands not being monitored? 

What populations are exposed by these sites? How do these sites relate to the National Emissions 

Inventory presented earlier in the Chapter, or are these the other anthropogenic sites, for which there is 

no inventory? It seems there should either be answers provided to these questions to support a national 

risk assessment, or an indication that the problem is not appropriately characterized by current source 

inventory and monitoring efforts. 

Particle Size: Section 3.5.3 addresses particle size distribution of lead-bearing particulate and seems to 

be oriented toward eventual monitoring and health risk assessment of lead particulate. Doubtless particle 

size is a critical parameter with respect to collection efficiency and transport, solubility, chemicaltransformation and toxicological properties. However, it must be remembered that lead in any particle 

size seen within these discussions is, or soon can be, hazardous to children and other receptors. 

Concentrations in Other Media: The remainder of Chapter 3 is dedicated to summarizing lead 

concentrations observed in various environmental media. These are good and informative discussions. 

The air lead discussion does a good job of describing the large decreases noted with the gasoline phase 

down. It would also be important to note the decreases associated with point sources in the same time 

frame, particularly with respect to smelting, mineral processing and secondary recycling. The ambient 

air lead decreases in the vicinity of these sources were significantly greater than those achieved in urban 

areas through the phase down. Moreover, many of these industries were shutdown and were replaced in 

the global sense outside the U.S.

The document would also benefit from a larger historic perspective to the other media similar to that 

developed for air. Other media and biota have seen significant concentration decreases since the phase 

down and industry shutdown and cleanups. However, the pattern, length of time, relative magnitude and 

toxicological significance of these declines vary by media. It would be beneficial to note these patterns, 

particularly in light of the increasing interest in ecological response and potential secondary standard 

considerations.

Chapter 3 should develop a conclusion oriented format similar to that employed for the causality 

associations made in Chapter 2 and the other subject areas of the document. 

Chapter 4 Exposure, Toxicokinetics and Biomarkers: 

Pathways and Exposure Parameters: Chapter 4 addresses Exposure Assessment in Section 4.1 and 

begins with an appropriate discussion of pathways. There appears to be a typo on line 4 regarding the 

gasoline phase down date, but the text notes the associated historic reductions in air lead exposures. It is 
B-86

always good to note that significant air lead reductions also were noted in the vicinity of point sources, 

and other media concentration decreases were observed, both attendant to and independent of the phase 

down and curtailments in industrial emissions. 

This is followed by a discussion of indoor versus outdoor versus personal exposure that does not quite 

reach a conclusion. It seems that personal exposures are generally higher than the ambient exposures, 

which is important to note, and indoor versus outdoor tends to vary with site specifics and season and 

cannot be generalized. Soils and dusts are discussed next. The complexity and interrelationship of these 

variables and the role of air media in the continual exchange between these media is emphasized, but it 

might be noted that a clear empirical relationship between soil and dust has yet to be demonstrated, as it 

also likely tends to vary with specific site conditions, seasonality, etc.

The remainder of this section discusses other media and effectively summarizes the current state of 

knowledge with respect to relative significance of these media in acting as sources in pathways common 

to North America, Europe and Australia, where almost all of these studies have derived. A limited 

amount of discussion is provided for China. However, it should be noted that exposure sources and 

pathways are moderated by behavior, housing, lifestyle and cultural patterns. These patterns vary 

immensely for developing and middle-income countries and cultures, as compared to the U.S. Also 

many immigrant populations in the U.S. may engage in ethnic and cultural behaviors leaving them more 

susceptible to lead intake and uptake. 

All of these sections would benefit from a brief description of how the concentrations and relative 

intakes have decreased in association with the phase down, industrial source curtailment, and decrease in 

lead content of consumer goods over the past three decades. Table 4.5 could benefit from some 

additional description of dry weight versus wet weight considerations for dietary crops and how that 

relates to ingestion of lead from soils versus foodstuff. Description of how concentrations and intakes 

from these same media can vary dramatically in cultural, ethnic and socio-economic situations differing 

from Europe and North America would be a benefit to the document.

In Table 4.6, one study shows lead content in ug as opposed to a concentration. A footnote would be 

appropriate to allow comparison to other entries in the Table. 

Toxicokinetics: The toxicokinetics discussion is concise and well-developed and reflective of the 

current understanding and practice in risk assessment activities. The discussion could be amplified with 

respect to the uncertainties associated with uptake and excretion in populations outside of North 

America and European populations.

Biomarkers: The discussion in Section 4.3.2 Blood Lead measurements has a confusing transition from 

analytical techniques to ALAD from page 4-35 to 4-36. Perhaps the analytical discussion could be 

expanded and some transition language be inserted, or the discussion of the significance of ALAD be 

moved or combined with Section 4.3.4.4.

Relationship of Lead in Blood and Lead in Bone: The overall discussion of the health significance and 

interrelationship of these biomarkers is informative and well presented. It might be useful to discuss the 

relevance of these biomarkers in terms of internal exposure to organs and tissue and the relevance to 

immediate toxic health effects.
B-87

Exposure-Blood Lead Relationships: Section 4.5 through the Summary in Section 4.7 provides a 

concise summary of this topic area that has been well vetted in several previous SAB reviews and 

represents the current scientific consensus for this important segment of risk assessment process. 

Chapter 4 should develop a conclusion oriented format similar to that employed for the causality 

associations made in Chapter 2 and the other subject areas of the document. 

Policy Implications: The ISA is reflective of a long history of lead health and risk assessment and 

attendant regulatory programs. These actions have reduced lead exposures and health effects in the U.S. 

and other developed countries by orders of magnitude over the past four decades. As the populations in 

these countries attain ever lower blood lead levels and body burdens, investigators are observing 

previously undetected adverse outcomes. In the last decade, lead-related research has continued to 

concentrate on investigating and defining adverse effects at ever-lower exposure levels. Similarly the 

ISA is heavily weighted toward assessing and characterizing new information regarding health effects. 

However, during this time, the EPA and other environmental regulators have diminished the monitoring 

and programmatic attention paid to lead, as the overt health risks have subsided. This has occurred 

because the ambient exposures have decreased dramatically to levels unimaginable in previous decades, 

and other health risks have taken priority. 

Nevertheless, the demand for and consumption of lead in the U.S. have increased markedly in this 

century, accompanied by substantial price increases in the domestic and world market. As noted above, 

other general exposure considerations related to market and use factors; (i.e. emission sources, 

commercial uses, waste, recovery, recycling and disposition and fate of lead) in the U.S. today are 

poorly understood, nor have exposure parameters been quantified. There is no treatment of these factors 

in the ISA. It is unclear if there are any data, or whether EPA sought such information. Several other 

issues, generally considered in policy decisions, not included in the ISA are advancements in pollution 

control capacity, best available technologies, and best practices for source control. 

Data Sources: Unfortunately, the best information for production data, emission information, industry 

transition and economic indicators is more likely to be found in the trade literature and government 

agency records. Much of the practical knowledge that has been developed in applying scientific findings 

and methods to remedial and regulatory activities is generated and housed in programmatic activities 

within EPA and the States. 

In 2006, the CASAC urged the Agency to mine these data sources in the last review. The sources cited 

in the ISA review seem to have been limited to the peer reviewed literature and the national air quality 

monitoring network. Perhaps in developing the attendant policy recommendations, the Agency will 

explore the life cycle and economic impacts of lead regulation in both this country and overseas.

Global Considerations: Although U.S. lead demand has increased, domestic production and recycling 

and recovery of many discarded lead products have been diverted to developing countries. Much of this 

is diversion results from EPA policies. On the international scene, the increased price and demand 

observed in the last five years has had devastating effects, substantially more severe than those observed 

in the 1970s. Environmental exposures and lead poisoning are increasing with several incidences of 

severe morbidity and substantial mortality associated with the increased demand and high price of 

metals. Hundreds of children have died at some sites and thousands suffer irreversible health effects that 

their families and communities must cope with for decades. 
B-88

More children in the world die and suffer irreversible, dysfunctional brain damage due to lead poisoning 

today than in the last fifty years. Although air lead levels in the U.S. are at an all time low, the 

implications for regulation of lead releases and the impact of U.S. policies in the global environment and 

human health are substantial. If not in the ISA, it seems the EPA has an obligation to inform the policy 

makers of the global consequences of lead regulation, or lack thereof. Similarly the U.S. has an 

obligation to export the scientific knowledge base, consequences of irresponsible practices, and 

information regarding mitigation of adverse effects. The subsequent regulatory policies when 

implemented have ramifications, not only beyond ambient air lead levels, but throughout the world.
B-89

Dr. Gail Wasserman

Comments on Chapter 2 - Integrative Health and Ecological Effects Overview

1. I disagree with the use of the conceptual heading “neurological” to encompass what are functional (ie 

neuropsychological or neurocognitive deficits; neurobehavioral problems) as well as structural and 

mechanistic components. The super-ordinate heading would be better cast as “central and peripheral 

nervous system” effects (at the level of cardio-vascular, or immune-system effects). Neurological is too 

narrow a term for the array of functional, mechanistic, and structural problems considered under this 

heading. In point of fact, those of us studying neurocognitive or neurobehavioral problems are rarely 

neurologists, and our work is not published in neurology journals. 

2. I found the framework for designating the strength of the causal evidence to be very helpful. The 

characterization of the minimal BLL at which effects are noted is clear.

3. Many practitioners may read the integrated summary (Chapter 2) rather than the longer, more detailed 

presentation of the evidence (Chapter 5). There is no mention of effect sizes or clinical significance for 

the neuropsychological and neurobehavioral outcomes summarized in Chapter 2. This would be 

essential for a cost-benefit discussion.

4. The integration of associations across human and animal species was clear and useful. 

Comments on Chapter 5 - Integrated Health Effects of Lead Exposure

General points:

1. See point 1, raised for Chapter 2. 

2. In some places, more cross-talk inter-relating commonalities (or their lack) between content areas 

reviewed would help. As examples, see specific points made below for pages 5-53, 5-57, 5-58, 5-105.

3. There is little provided in this chapter, or elsewhere, about the clinical significance of the effect sizes 

noted, which is important for policy-making and cost-benefit analysts. I think this holds for the effect 

sizes for other outcomes as well.

Also, the point I made for the REA holds here as well: there needs to be a discussion of the metrics of 

IQ scoring and the clinical significance of small deficits. As a practicing psychologist, I find the parsing 

of IQ scores into “points lost” that translates into fractions of a single point very uncomfortable, 

especially given that the standard error of measurement for most IQ tests is 5 points. There needs to be 

some risk/benefit awareness of the policy implications of interventions at very low blood lead levels. 

4. Regarding the expansion of endpoints, I think there is already a wide array. Integration of associations 

within and across endpoints could be increased, though, especially concerning mechanisms. In other 

words, are there evaluated (or not yet evaluated) models that interrelate mechanistic impacts across 

several systems? 

More specific points: 
B-90

P 5-45. There is inconsistency across age in behavioral effects (depression in adults, ADHD in kids). 

Some attempt should be made to explain this.

Table 5-2 and 5-3 The Factor-Litvak paper is a secondary summary; it would be better to reference the 

original source, which is not cited in this chapter. That citation is: 

Wasserman, G.A., Liu, X., Lolacono, N.,J., Factor-Litvak, P., Kline, J. K., Popovac, D., Morina, N., 

Musabegovic, A., Vrenezi, N., Capuni-Paracka, S., Lekic, V., Pretini-Redjepi, E., Hadzialjevic, S., 

Slavkovich, V., & Graziano, J.H. (1997). Lead exposure and intelligence in 7 year old children. 

Environmental Health Perspectives, 105, 956-962. 

In another report, we noted differential impact on Visual Motor, rather than language, skill, significantly 

so: 

Wasserman, G.A., Graziano, J.H., Factor-Litvak, P., Popovac, D., Morina, N., Musabegovic, A., Vrenzi, 

N., Capuni-Paracka, S., Lekic, V., Pretini-Redjepi, E., Hadzialevic, S., Slavkovich V., Kline, J., Shrout, 

P. & Stein, Z. (1994). Consequences of lead exposure and iron supplementation on childhood 

development at age four years. Neurotoxicology & Teratology, 16, 233-240.

P 5-52, L 29. In fact, MOST tests of neurocognitive function are interrelated, not “several”.

P 5-53 and 54 and Table 5-4. Specific Indices of Cognitive Function. It should be pointed out that these 

other functions contribute to intelligence, so these effects are more by way of explaining the IQ 

associations than additional functions impacted. It would helpful to point out if some functions are 

consistently more impacted than others (for example, the prospective studies often reported stronger 

associations with visual motor than with verbal skills). The inclusion of the Bayley MDI results in this 

section represents somewhat of an organizational anomaly, as this assessment is an infant developmental

test, and not one that measures the differentiated areas presented in the table. Tests of “intelligence” do 

not generally measure skills in the early age range tapped on the Bayley, so it is often seen as an 

analogue to overall intelligence, appropriate to its age-range. On the other hand, developmental research 

consistently documents reduced stability and predictive validity for tests of abilities measured for infants 

(as opposed to preschoolers) so that the generally stronger effects shown for MDI relative to the other 

items in Table 5-4 should be seen in this context. Finally, the discussion of specific indices should 

include Canfield RL, Gendle MH, Cory-Slechta DA. Impaired neuropsychological functioning in leadexposed children. Dev.Neuropsychol. 2004;26:513-40, which used the CANTAB battery.

P 5-57. In the discussion of the Surkan study, the point should be made that maternal self-esteem (like 

depression) is likely related to many components of childrearing that are commonly measured by an 

instrument such as the HOME Scale (for which most studies of children’s neurocognitive or 

neurobehavioral function often adjust).

P 5-58. It should not be a surprise that academic performance reveals adverse associations with lead 

exposure, since these probably result from more primary impacts on both neurocognitive (IQ, 

processing) and behavioral (attention problems) functions. 

P 5-62. In a section on timing of exposure and cognition, the report cites our 1998 paper, which is a 

study of behavior problems. We looked at timing of exposure in the paper above, in preschoolers. The 

accompanying table (5-7) has the correct reference. This section, on the timing of exposure, beginning 
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on p 5-61, appears in a section on cognition, but then Table 5.5 also considers behavior problems. There 

is a separate later section on behavior problems, and shouldn’t that section precede a discussion of the 

duration of exposure? Or consider the timing of behavioral effects separately when those effects are 

discussed, later.

P 5-69. The Wasserman et al 2000 paper compared different trajectories of lead exposure across ages 4-

7y, finding independent prenatal and postnatal associations, as well as a sharply increased slope of 

BL/IQ association in the 0-10 ug/dl range. 

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.

P 5-99. The text notes that non-cognitive effects are more complex to study than are IQ tests. I do not 

disagree, but the report should indicate why.

P5-101, L2, also Figs 5-20 and 5-21. Text should point out that while an adverse association with BPb is 

generally reflected in negative associations (lower IQ with increasing BPb), for behavior problems, this 

association is positive (more problems with increasing BPb). Otherwise the use of the word “positive” 

may be confusing to some readers.

P5-105 (and others in this section). The review should consistently note what features (if any) were 

adjusted for in these analyses, or other ways to weight the array of evidence. Also, as noted, the section 

on adults reports associations for mood problems, while in children, externalizing (conduct, attention) 

problems are most commonly noted. Is there any way to make sense of these developmental differences 

in content areas? 

P5-121. In discussing PD and tremor, some mention should be made of the importance of adjusting for 

co-exposures, particularly Mn, with commonly reported associations. 

P5-127, L 29. I believe this should read “associated”, and not “association”.

There is a new paper following up the New England sample into adulthood: Mazumdar et al. 

Environmental Health 2011, 10:24
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Dr. Michael Weitzman

Comments on Chapter 2 – Integrative Health and Ecological Effects Overview

EPA has done a remarkable job in synthesizing a vast literature and presenting it scientifically and 

comprehensibly.

I have one concern and one additional suggestion:

1. The only mention of lead-based paint as a source of children’s exposure was on page 2-6, in 

the third paragraph: “Studies have suggested that blood Pb is associated with exposure to Pb 

paints in older homes.....” It has been my understanding for quite a long time that household 

lead in dust, primarily from deteriorated lead based paint, is the major source of children’s 

exposure. I believe that this is central to most pediatric and federal and local efforts to 

prevent childhood lead exposure. Is this deserving of more discussion?

2. While Chapter 2, 5 and 6 mention lead and delinquent behavior, there is a literature, albeit 

small, that shows an association between blood lead levels and violent behaviors (e.g. several 

studies by R. Nevin. Should these be discussed for the purposes of thoroughness?

Comments on Chapter 6 - Susceptible Populations and Lifestages

EPA is to be truly congratulated for a remarkably comprehensive and cogent review of the literature on 

Susceptibility Factors and Lifestages Related to (a) Lead Exposure and Dose and (b) Lead Induced 

Health Effects. I do think that the characteristics included are appropriate and consistent and I do 

believe it appropriate to include material on susceptibility factors related to Pb exposure and dose.

The following comments and suggestions are offered with the intention of improving an already 

excellent document:

1. There are a fair number of places in the Section concerning Lead Induced Health Effects that 

better belong in the Section concerning Lead Exposure and Dose, as this is often confusing as 

written. A few examples include (possibly) sentence 1, last paragraph, pg 6-11; sentence 2, 

paragraph 1, pg 6-12; paragraph one under Hormones, pg 6-16 and 6-17 and paragraph 2 

under Vitamin D Receptor, pg 6-18 and 6-19.

2. Similarly, throughout this chapter there is mention that specific topics are discussed in more 

detail elsewhere in the overall document and it would be extremely useful to point the reader 

to those sections in which specific topics are discussed in more detail.

3. For areas of discussion that rely on a small number of studies I urge caution comparable to 

that so well utilized elsewhere to explicitly identify the level within the five level hierarchy 

classifying the weight of evidence for causation.

4. In discussing Susceptibility to Lead Exposure and Dose I suggest adding discussion of:

a. housing—one could use various cut points, such as pre-1950 housing or pre-1970 

housing—data are available on how housing stock age relates to blood lead levels. 
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There also are data about numbers of housing units in the USA that have had 

windows replaced or lead related abatements or renovations (repairs) and how these 

relate to lead exposure and these data have, I believe, been well summarized by the 

National Center for Healthy Housing and HUD. Similarly, household dust lead levels 

clearly represent a (the) major risk factor for lead exposure, at least of children, and I 

suggest considering a related section on what is known about soil lead levels and 

coverings with grass and foundation shrubbery and blood lead levels 

b. nutritional status-while briefly mentioned in the section on Lead Induced Health 

Effects, there is no parallel section on diet and lead exposure: iron deficiency is well 

documented to increase lead absorption from the GI tract, with a less robust literature 

on dietary calcium and fat intake. Given the obesity epidemic, with its associated 

epidemic of low Serum Vitamin D levels (as a fat soluble vitamin it is not yet clear 

that low serum Vitamin D levels in overweight individuals manifest comparable 

effects to low Vitamin D levels in the general population)

c. immigrant groups from countries with high lead exposure 

d. users of folk remedies from multiple countries such as India, Mexico and those in 

Southeast Asia.

5. Susceptibility Factors and Lifestages and Lead Induced Health Effects - This section, again, I 

believe to be excellent, but would benefit from extensive cross referencing to other chapters. 

Several things that I think deserve some discussion include:

a. are children and adults with ongoing exposure at more risk than those whose 

exposure is more limited, and does intermittent repeated increased exposures cause 

additional, cumulative or multiplicative damage?

b. the use of low birthweight in many studies of lead effects on children is very nonspecific, very low birthweight, extremely low birthweight, intraventricular 

hemorrhages all may (or may not) characterize vulnerable populations, as may

c. children who have repeated head tramua (i.e repeat concussions)

d. those from bilingual homes

e. those whose mothers OR fathers are depressed or suffer from other mental illnesses

f. pg 6-21: are the associations with lead different for Type 1 and Type 2 Diabetes? 

g. are there no studies of lead exposure and obesity, or of lead leading to increased rates 

of co-morbidities of those who are obese (elevated cholesterol/triglycerides, 

hypertension, central obesitiy, hepatitis, hypertension) or of asthma and lead 

exposure?