UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
JSP SB,. WASHINGTON B.C. 20460
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0<> OFFICE OF THE ADMINISTRATOR
SCIENCE ADVISORY BOARD
July 20, 2012
EPA-C AS AC- 12-005
The Honorable Lisa P. Jackson
Administrator
U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, N.W.
Washington, D.C. 20460
Subj ect: CAS AC Review of the EPA' s Integrated Science Assessment for Lead (Second
External Review Draft - February 2012)
Dear Administrator Jackson:
The Clean Air Scientific Advisory Committee (CASAC) Lead Review Panel met on April 10-11, 2012,
to peer review the EPA' s Integrated Science Assessment for Lead (Second External Review Draft -
February 2012), hereafter referred to as the Second Draft ISA. The chartered CASAC conducted a
quality review of the Panel's draft review during a public teleconference on July 16, 2012. The
CAS AC'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 EPA for substantial revisions to the first draft ISA based upon its prior advice
(December 201 1). Nevertheless, the CASAC has further recommendations for improving the document
and recommends that EPA develop a third draft of the ISA and provide it to the CASAC for a review
focused on the key changes called for in this letter.
Overarching Comment
Much of the discussion throughout the document is still largely encyclopedic, where individual papers
on specific topics are summarized rather than assessed in an integrative manner. Additional integrative
synthesis in discussions throughout the document will improve readability.
Preamble, Preface, Executive Summary, and Integrative Summary
The organizational structure of the Second Draft ISA has been enhanced by the addition of a Preamble
containing the discussion on the causal framework and by the inclusion of an Executive Summary as
Chapter 1. However, the document still fails to consistently and transparently apply the causal
framework to the analysis of the health effects of lead (Pb). The CASAC previously recommended that a
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thorough appraisal of the strengths and limitations of the epidemiological data be performed in its
review of the First Draft ISA and finds that this appraisal has not yet been adequately executed. As per
prior CASAC recommendations, the causal determination analysis requires a substantial revision that:
(1) focuses on specific health endpoints as opposed to organ system effects, and (2) assesses the weight
of the evidence for causation after critically evaluating the data and systematically applying the
causation criteria set forth in the Preamble. The terms used for causal determination of ecological effects
in the integrative summary chapter should be consistently linked with the terms used in the ecological
effects chapter.
Source to Concentration
The addition of new material to Chapter 3 is an improvement, but there are still problems that need to be
addressed. There are many instances involving incorrect interpretation of the literature, especially in
Section 3.5. Adding an integrative synthesis, along with moving much of the detailed discussion of the
studies to an appropriate appendix, will improve the readability of the chapter. Although the discussion
of Pb sampling methods in this chapter is improved, the larger issue of the importance of sampling Pb
over a broad range of particle sizes is still not addressed. This omission points to the need for better
linkage between Chapters 3 and 4. More information on the role(s) of different Pb particle sizes in terms
of human exposure and uptake is needed.
Exposure, Toxicokinetics and Biomarkers
The additions and edits to Chapter 4 are generally responsive to the comments provided by the CASAC
on the First Draft ISA. These changes provide a more comprehensive overview of current modeling
approaches and available data that are relevant to understanding how air-related exposure can contribute
to total Pb exposure. However, the chapter should be improved by:
• Further synthesizing the presented information and data, as well as discussing their implications
on the overall exposure assessment and understanding of relationships between exposure and
biomarkers of effect;
• Providing table or figure summaries that convey information about uncertainty in the empirical
data and model-based estimates of blood Pb / air Pb slope factors. This information should
include demonstration of how the range of estimates translates into corresponding changes in the
distribution of blood Pb and should specifically address implications of errors associated with
estimates of particle size distributions from historical total suspended particulates (TSP)
measurements;
• Adding a discussion of the implications of the alternative mathematical approaches to fitting
blood Pb / air Pb relationships, focusing on the uncertainty in describing the relationship at low
air Pb levels; and
• Offering a critical assessment of the estimates of the blood Pb / air Pb slope factors that are most
appropriate and useful for risk assessment.
Integrated Health Effects of Lead
In general, the revisions made to Chapter 5 addressed several issues identified in the CASAC's review
of the First Draft ISA. These revisions include improved integration of the toxicologic and
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epidemiologic literature in terms of relevant outcomes and exposures, as well as acknowledgement that
contemporary blood Pb levels (especially in adults and older children) may not directly account for
observed health effects (due to the likely contribution of previously higher or longer term exposures).
For childhood IQ, adult nervous system effects, blood pressure, and other cardiovascular outcomes,
discussion of the evidence associating these outcomes with Pb, including analyses of consistency (or
lack thereof) across the literature, confounding, and study design issues were improved. However, for
many of the remaining health measures, a number of important concerns identified in the CASAC's
review of the First Draft ISA were not addressed, including:
• Inadequate critical assessment of each study reviewed to determine the strength of the observed
associations (e.g., analyses of the potential for confounding, bias, or study design limitations to
explain apparent Pb effects were incomplete);
• Lack of transparency, balance, and consistency regarding causal determination;
• Incomplete application of causal determination criteria outlined in the ISA's preamble; and
• Lack of clarity in the description and conceptualization of outcomes (particularly behavioral
outcomes).
The compelling evidence associating Pb exposure with childhood IQ decrements and adult
cardiovascular outcomes (e.g., blood pressure) is well documented in this chapter. However, the main
consequence of the above limitations is likely misclassification of the weight of evidence supporting
causal associations of low-level Pb exposures with other health endpoints, including childhood behavior
and adult renal function.
Potentially At-Risk Populations
The expanded discussion and revisions made to the First Draft ISA better capture the intricacies
associated with "at-risk" populations. The reorganization of the chapter into related factors also makes it
more cohesive and better integrated. The revised Chapter 6 adequately defines some factors as having
limited evidence based on the strength of available evidence. However, the extent to which these risk
factors actually modify the magnitude of the impacts of Pb exposure is not adequately discussed.
Additionally, the CASAC encourages the Agency to develop standard terminology and concepts for
populations at risk that can be broadly applied and consistently used across criteria pollutants.
Ecological Effects of Lead
Although new information has been added to Chapter 7, it is not summarized and integrated into a
meaningful synthesis and little technical evaluation of extant data is provided. Detailed data should be
provided in an appendix and summarized in tables in the text of the chapter. The CASAC also
recommends the following: consistent expression of exposure dose throughout the chapter; considering
survival, growth, and reproduction as the most relevant endpoints; discussing sub-organismal responses
in the context of secondary responses; and clarifying whether the causal determinations are based on air
deposition of Pb or laboratory exposures.
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EPA Presentation on Lead Air Sampling
During the meeting, the EPA made a presentation on the development of a new Pb air sampler. The
CASAC had previously, on numerous occasions, made the recommendation to replace the high-volume
total suspended particulates (TSP) air sampler and is encouraged by and supportive of the development
of a new Pb air sampler. The CASAC would be pleased to provide advice as the development of the
sampler progresses.
The CASAC appreciates the opportunity to provide advice on the ISA and looks forward to reviewing
the third draft of the ISA.
Sincerely,
/Signed/ /Signed/
Dr. Jonathan M. Samet, Chair Dr. H. Christopher Frey, Chair
Clean Air Scientific Advisory Committee CASAC Lead Review Panel
Enclosures
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NOTICE
This report has been written as part of the activities of the EPA's Clean Air Scientific Advisory
Committee (CASAC), a federal advisory committee independently chartered to provide extramural
scientific information and advice to the Administrator and other officials of the EPA. The CASAC
provides balanced, expert assessment of scientific matters related to issues and problems facing the
agency. This report has not been reviewed for approval by the agency and, hence, the contents of this
report do not necessarily represent the views and policies of the EPA, nor of other agencies within the
Executive Branch of the federal government. In addition, any mention of trade names or commercial
products does not constitute a recommendation for use. The CASAC reports are posted on the EPA
website at: http://www.epa.gov/casac.
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U.S. Environmental Protection Agency
Clean Air Scientific Advisory Committee
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
CASAC MEMBER
Mr. George A. Allen, Senior Scientist, Northeast States for Coordinated Air Use Management
(NESCAUM), Boston, MA
CONSULTANTS
Dr. Herbert Allen, Professor Emeritus, Department of Civil and Environmental Engineering,
University of Delaware, Newark, DE
Dr. Richard Canfield, Senior Research Associate, Division of Nutritional Sciences, Cornell University,
Ithaca, NY
Dr. Deborah Cory-Slechta, Professor, Department of Environmental Medicine, School of Medicine
and Dentistry, University of Rochester, Rochester, NY
Dr. Cliff Davidson, Professor, Civil and Environmental Engineering, Syracuse University, Syracuse,
NY
Dr. Philip E. Goodrum, Senior Consultant, Cardno ENTRIX, Syracuse, NY
Dr. Sean Hays, President, Summit Toxicology, Allenspark, CO
Dr. Philip Hopke, Bayard D. Clarkson Distinguished Professor, Department of Chemical and
Biomolecular Engineering, Clarkson University, Potsdam, NY
Dr. Chris Johnson, Professor, Department of Civil and Environmental Engineering, Syracuse
University, Syracuse, NY
Dr. Susan Korrick, Assistant Professor of Medicine, Department of Medicine, Brigham and Women's
Hospital, Channing Laboratory, Harvard Medical School, Boston, MA
Dr. Michael Kosnett, Associate Clinical Professor, Division of Clinical Pharmacology and Toxicology,
Department of Medicine, University of Colorado School of Medicine, Denver, CO
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Dr. Roman Lanno, Associate Professor and Associate Chair, Department of Evolution, Ecology, and
Organismal Biology, Ohio State University, Columbus, OH
Mr. Richard L. Poirot, Environmental Analyst, Air Pollution Control Division, Department of
Environmental Conservation, Vermont Agency of Natural Resources, Waterbury, VT
Dr. Joel G. Pounds, Laboratory Fellow, Cell Biology & Biochemistry, Biological Sciences Division,
Pacific Northwest National Laboratory, Richland, WA
Dr. Michael Rabinowitz, Geochemist, Marine Biological Laboratory, Newport, RI
Dr. William Stubblefield, Senior Research Professor, Department of Molecular and Environmental
Toxicology, Oregon State University, Corvallis, OR
Dr. Ian von Lindern, President, TerraGraphics Environmental Engineering, Inc., Moscow, ID
Dr. Gail Wasserman, Professor of Clinical Psychology in Child Psychiatry, Division of Child and
Adolescent Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY
Dr. Michael Weitzman, Professor, Pediatrics; Psychiatry, New York University School of Medicine,
New York, NY
SCIENCE ADVISORY BOARD STAFF
Mr. Aaron Yeow, Designated Federal Officer, U.S. Environmental Protection Agency, Science
Advisory Board (1400R), 1200 Pennsylvania Avenue, NW, Washington, DC, 20460
in
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U.S. Environmental Protection Agency
Clean Air Scientific Advisory Committee
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, Gary 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 20460
IV
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Consensus Responses to Charge Questions on
EPA's Integrated Science Assessment for Lead
(Second External Review Draft - February 2012)
Preface, Preamble, Chapters 1 (Executive Summary) and 2 (Integrative Summary)
The CASAC panel offered a number of recommendations to enhance the organization and presentation
of the evidence in the ISA. An Executive Summary has been prepared and is included as Chapter 1. As
part of the development of the Executive Summary and restructuring of the integrative overview chapter,
Chapter 1 materials have been revised and moved, specifically: (a) the more general sections on the
development of the ISA and the causality framework are being placed in a Preamble that can support all
ISAs; (b) the introductory sections specific to this ISA describing the ISA development and scope are
placed at the beginning of Chapter 2; and (c) sections on legislative background and history of previous
reviews are contained in a Preface in the front matter of the ISA. The intent was to bring the integrative
overview discussion to the front of the document, thus making it more accessible to the reader, and to
streamline the ISA organization.
Please review and comment on the effectiveness of these revisions. Please comment on the extent to
which Chapters 1 and 2 comprise a useful and effective approach for presenting this summary
information and conclusions. Please recommend any revisions that may improve the scientific accuracy
or presentation of these summary sections and the conclusions therein.
In addition, please comment the extent to which the discussion of the health effects evidence in Chapters
1 and 2 reflects the revisions to Chapter 5, which were designed to characterize the weight of the
evidence for specific endpoints as well as the strengths and limitations of the studies.
The organizational structure of the 2nd External Review Draft of the Integrated Science Assessment for
Lead (2nd Draft ISA) has been enhanced by movement of the general description of the ISA
development process and the causation framework to a Preamble, and by the inclusion of an Executive
Summary as Chapter 1.
Preface
The subsection within the Preface entitled "History of the NAAQS for Pb" should be improved by
adding a discussion of aspects of the pre-promulgation history, notably the contribution of public
interest lawsuits and court decisions to the initiation of the National Ambient Air Quality Standard
(NAAQS) process. It will also benefit from a discussion of lead (Pb) being a multimedia pollutant,
which is unlike other criteria pollutants. Hence, although regulating Pb air concentrations reduces total
Pb exposure, other sources and pathways can still affect Pb intake.
Chapter 1 (Executive Summary)
The revisions made to Chapter 1 (moving material to the Preface and Preamble) and making it an
Executive Summary are appropriate. Some further improvements that should be made to this chapter
include: mentioning that the main pathway of Pb intake for most people is Pb ingested from dietary
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sources; adding a statement to Section 1.3.1 that there is variability in the reversibility of health effects
across organ systems; and stating that Pb occurs naturally at a range of background levels in soil which
are not toxic to soil-dwelling biota that have evolved in the presence of Pb.
Chapter 2 (Integrative Summary)
Chapter 2 includes a summary of the other chapters of the ISA. The CASAC's comments and
recommendations for the respective chapters are detailed in the consensus responses and should also be
reflected in the summaries in Chapter 2.
A major conclusion of the CASAC's review of the 1st Draft ISA was that the document failed to
consistently and transparently apply EPA's established causal framework to the analysis of the health
effects of Pb. A thorough appraisal of the strengths and limitations of the epidemiological data was
recommended, and it was suggested that summary tables of the relevant literature include a column that
specifically highlighted these features. These same major concerns and shortcomings continue to apply
to the causal determination analysis that appears in the Executive Summary, Chapter 2, and Chapter 5 of
the 2nd Draft ISA. As per prior CASAC recommendations, the causal determination analysis will benefit
from a substantial revision that (1) focuses on specific health endpoints as opposed to organ system
effects, and (2) assesses the weight of the evidence for causation after systematically and critically
evaluating the data for:
• Strength of observational study designs (in accordance with the standard epidemiological
hierarchy: prospective cohort study, nested case control, case control, and cross-sectional);
• Consistency in terms of the nature and strength of the observed associations;
• The extent to which the possibility that associations arising from chance, bias, or confounding
have been considered and these alternatives to causation can be set aside;
• Demonstration of a dose-response relationship, focusing particularly on the presence of effects at
current or former environmental Pb doses (i.e., blood Pb levels < 25 |ig/dL);
• Biological plausibility of effects at low doses demonstrated by findings from toxicological
investigations; and
• Findings that might identify the cumulative Pb dose or temporal pattern of blood Pb
concentrations at which the causal impacts may occur.
As discussed below in the consensus response on Chapter 5 and the individual comments of several
panel members, particular concerns exist regarding the causal inference analysis of behavioral effects in
children, and renal effects in children and adults. With respect to behavioral effects in children, the
analysis summarized in the Executive Summary and Chapter 2 will benefit from a critical appraisal that
acknowledges: (1) inconsistency in findings observed within the published literature (particularly
notable if older, high quality, prospective studies omitted from the current ISA are considered); and (2)
the potential for observed associations to have been subject to confounding or bias as a consequence of
the limited extent to which many studies have been able to adjust for parental behavior or
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psychopathology. Behavioral outcomes in children should be distinguished from effects on cognitive
function, and the authors should reconsider the frequent tendency for the narrative to refer to the impact
of Pb on both of these endpoints as if they occur jointly or with equal causal weight.
With respect to renal effects, the narrative should offer a more balanced assessment in which the
strength of the evidence for causal inference is tempered by:
• Inconsistency in the literature (underscored by the existence of studies that observed no
significant relationship or a relationship in which increasing blood Pb levels were associated
with improved renal function);
• The potential contribution of reverse causation; and
• The paucity of toxicological studies that identify a nephrotoxic mode of action of Pb on the
kidney at the low doses in which a reciprocal relationship between blood Pb and glomerular
filtration rate may have been observed.
The uncertainty that characterizes the relationship between Pb exposure and asthma and allergy should
be acknowledged, as only one or two epidemiological studies of each of these endpoints have been
discussed in the document, and those are subject to methodological limitations.
The terminology utilized in the ISA to characterize causal relationships between Pb and various health
endpoints often merits revision. For example, in several instances the narrative states "the weight of the
evidence supports associations" (e.g., see Table 2-10 section on neurobehavioral effects; page 1-7, line
12; and many places in Chapter 5). This phraseology is ambiguous with respect to causal assessment,
because an epidemiological "association", however strong, is by itself insufficient to establish causation,
particularly if bias and confounding cannot be ruled out with reasonable confidence.
The new subsection in Chapter 2 on "Public Health Significance" (section 2.9.1) is a positive addition to
the document. This chapter appropriately notes that the magnitude of change observed in certain
parameters in epidemiological studies (e.g., decrements in IQ or increases in blood pressure) may be of
limited clinical impact in any one individual, yet nonetheless signify a substantial public health impact
on the population as a whole. It would be prudent for this section to focus on the impacts of Pb on
cognitive functions in children, and blood pressure and cardiovascular disease in adults, and to curtail or
eliminate discussion of other endpoints (such as behavior, immune dysfunction, and renal dysfunction)
for which the effect of Pb at low dose is less well established. With respect to the discussion of the
public health impact of Pb on IQ in children, it should be noted and discussed that the validity of Figure
2-1 is predicated on the incremental dose response of Pb on IQ being of similar magnitude in children
with low and high intelligence. The sentence on page 2-54 line 20 should be rephrased to note that there
is "no level of Pb exposure shown to be without deleterious effect" rather than refer to "no safe level of
exposure". A consideration of the level of exposure to a hazardous substance that is considered "safe"
involves risk management issues that are beyond the intended scope of the subsection.
For causal determinations of ecological effects, the document should clarify whether the effects are
based on air deposition of Pb or laboratory exposures. The terms used for causal determination of
ecological effects in this chapter should consistently linked with the terms used in the Chapter 7.
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Chapter 3 - Source to Concentration
Revisions made to Chapter 3 in response to CASAC comments include elaboration of changes to the
National Emissions Inventory between the 2006 Pb AQCD and the ISA (Section 3.2), discussion of the
limitations of the current total suspended particulate federal reference method sampler and available
alternatives (Section 3.4.1), removal of questionable data presented for particle size Pb comparisons
(Section 3.5.3), addition of a background Pb section (Section 3.5.5), and supplementation of studies to
elucidate the relationship between air Pb andPb in soil (Section 3.6.1).
Please comment on the adequacy of these and other changes to the chapter and recommend any
revisions to improve the discussion of key information. Is material clearly, succinctly, and accurately
provided? Where appropriate, please provide guidance that may refine the scientific interpretation
and/or improve the representation of the science.
This chapter is improved from the prior version with substantial new material, but there are still
problems that need to be addressed. There are many instances involving incorrect interpretation of the
literature, especially in Section 3.5. Much of the discussion is still largely encyclopedic, where
individual papers are summarized, rather than providing an integrated assessment of the science. Adding
an integrative synthesis, along with moving much of the detailed discussion of the studies to an
appropriate appendix, will improve the readability of the chapter (especially Section 3.5). In addition to
the information on the largest Pb source categories, it would be useful to add a list of the largest
individual Pb emission sources, along with contextual information comparing population exposures
from large individual sources, such as smelters, to exposures from large source categories, such as piston
aircraft. Additionally, EPA should review the recent Aucott and Caldarelli (2012) study on Pb in wheel
weights. Chapters 3 and 4 have some common elements that will benefit from more direct cross-chapter
linkage between exposures and Pb-air measurements. One example is wood smoke (3.2.2.5 and 4.1.3.1).
The expanded description of the Pb Total Suspended Particulates (TSP) Federal Reference Method
(FRM) and related Pb sampling methods in Section 3.4.1 has substantial new and helpful content in
response to comments on the 1st Draft ISA, especially on the current FRM high-volume (HiVol)
sampling method. A limited discussion on the possibilities of and need for a better alternative FRM has
been added, but still ends with "...there is a continued need to assess the feasibility of a revised TSP
sampler design..." without discussing how to move forward towards the promulgation of a revised FRM
TSP sampler. Although it may not be within the traditional scope of an ISA, an expanded discussion on
the state of the aerosol science supporting possible alternatives to the HiVol TSP FRM would be useful
to address the many and long-standing CASAC comments on this topic. EPA should consider
addressing what might be acceptable (from an exposure perspective) and practical for sampler
performance (e.g., cut size, cut curve shape and sharpness (geometric standard deviation), and wind
speed dependence). EPA should discuss whether the measurement of very large airborne particles is
meaningful, useful, or desired given the indirect nature of the dominant exposure pathways. EPA should
also discuss whether a modest decrease in design value concentrations from a robust larger particle FRM
sampler would be important, considering the relatively large uncertainty in all other aspects of the
relationship between air Pb concentrations and health outcomes. This topic is closely related to exposure
and dose. The Integrative Summary states that "the Pb-TSP indicator was retained in 2008 in recognition
of the role of all PM sizes in ambient air Pb exposures", but relatively little information is presented (in
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Chapter 4 or elsewhere) on what the role(s) of different Pb particle sizes are in terms of human exposure
and uptake.
In Section 3.5.3, Size Distribution of Lead-Bearing PM, EPA should consider further broadening the
scope of this topic beyond studies in the peer-reviewed literature; all data on Pb size above 10 jim are
useful given the limited literature on this topic. The summary of Air Quality System (AQS) data in
Table 3 A-13 (ambient air Pb particle size information) in the appendix of the first draft should be
revised (not removed) to include only concurrent, paired samples above the method detection limits
(MDLs). Again, improved linkage to Chapter 4 will be helpful; for example, Table 4-3 will benefit from
information about the size fractions measured in these studies.
In Section 3.5.4, Lead Concentrations in a Multipollutant Context, use of Spearman rank correlation
coefficient alone to describe associations with other pollutants may not be sufficiently informative. EPA
should consider also presenting or evaluating Pearson or another parametric correlation coefficient, and
should justify what approach was used. Some filtering of results to those that are meaningful for use in
source identification would make the material more accessible.
In Section 3.5.5, Background Pb Concentrations, the issue of how to define "background" should be
further discussed. In the first paragraph, the policy relevant background (PRB) is defined as "those
concentrations that would occur in the U.S. in the absence of anthropogenic emissions in continental
North America." This definition contrasts with the more scientific definition of a "natural" background,
unaffected by any anthropogenic sources. Both are difficult to assess, but the natural background is
probably easier to evaluate. In any event, the section does not come to a conclusion on what the
background levels might be; the section is comprised of several paragraphs explaining why it is difficult
to estimate PRB levels. It should be possible to bracket a range for background airborne, soil, and
aquatic Pb concentrations.
Chapter 4 - Exposure, Toxicokinetics and Biomarkers
The exposure section of Chapter 4 includes additional discussion of the relationship between airborne
Pb-particle size distribution and exposure by inhalation andingestion (e.g., hand-to-mouth). Cross-
referencing to Chapter 3 further emphasizes measurement errors and uncertainties that may affect
exposure assessment for air Pb. A new section on exposure assessment methodologies was added that
includes discussion of exposure representation within the 1EUBK model and exposure modeling
techniques.
The revised toxicokinetics section of Chapter 4 expands discussion on the effects of both past and
current Pb exposure on blood Pb levels. Studies that followed blood Pb levels in individuals following
cessation of high Pb exposure occupations and in children over the first several years of life were
added. The section on bone Pb measurement was expanded. Air to blood slopes were reevaluated across
the range of air Ph concentrations available in a given study with an emphasis on the central tendency
of air Pb concentrations in each study.
With consideration of these revisions, please comment on the accuracy of the interpretation of the
science. Are uncertainties and limitations of relevant data, methodologies and approaches adequately
discussed? Where appropriate, please provide specific recommendations to refine the scientific
interpretation and/or improve the representation of the science.
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The additions and edits to Chapter 4 are generally responsive to the comments provided by the CAS AC
on the 1st Draft ISA. These changes provide a more comprehensive overview of current modeling
approaches and available study data that are relevant to understanding how air-related exposure can
contribute to total Pb exposure. However, there are several areas where the chapter can be improved.
Additional synthesis and summary of information is needed on the following:
• Section 4.1- Section 4.1.3.3 (Dietary Lead Exposure) - The information is factual, but the
reader will benefit from more interpretation, context, and summary. The chapter should include
additional discussion to explain the importance and impact of the reviewed data to the ISA. This
recommendation can be generalized to all chapters of the ISA document - EPA should review
each section and determine if, in addition to summarizing the information and data available, the
implications of this information also are conveyed.
• Section 4.1.1, p. 4-6 - The additional paragraph is helpful at presenting quantitative estimates of
percent contribution of air Pb to blood Pb. A table that summarizes this information should be
included which distinguishes between estimates based on modeling (e.g., IEUBK) and empirical
studies. Text should be added to synthesize and summarize this information with specific focus
on the importance of changes in these percent contribution estimates over time, or as a function
of the low-end versus high-end blood Pb levels.
• A section should be added that relates estimates of air Pb to blood Pb slopes to the original goals
of the ISA as presented in the Integrated Review Plan, which called for an uncertainty analysis
that provides a foundation to review the NAAQS. For example, the ISA can demonstrate how a
particular slope factor translates into a corresponding change in blood Pb at the geometric mean
(GM) and 95* percentile of the distribution, assuming a lognormal distribution with geometric
standard deviation (GSD) of 1.6 (which is adopted in the IEUBK model).
Additional discussion and perspectives on the relevance of information as presented is needed:
• Chapter 4 leaves the impression that from a multipathway exposure perspective, direct inhalation
of air Pb is generally a relatively minor contributor to total dose compared to soil and dust
ingestion, diet, water ingestion and other routes of exposure (although some exceptions are
noted, such as populations living in the vicinity of an airport). This impression may raise
questions regarding the interpretation of the air Pb to blood Pb slopes, or the potential for a
reduction in NAAQS to have a meaningful effect on blood Pb. Chapter 3 provides a more
explicit discussion of the correspondence between air Pb and multiple exposure media (beyond
air itself). There needs to be a better linkage between Pb air concentration and exposure in
Chapters 3 and 4.
• The discussion in Section 4.2.1, p. 4-30, lines 24-28 needs to be expanded to include the concept
that time-integrated blood Pb reflects an aggregation of the biological processes that includes
both recent Pb bioavailability and absorption as well as inputs from soft tissue and bone.
• The simulations in Figures 4-8, 4-9, and 4-11 are very informative and help to illustrate the
temporal profile of Pb in blood, bone, and overall body burden. The text (p. 4-63) indicates that
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the simulations represent an exposure scenario in which a child experiences "a constant Pb intake
(from age 2-5) via ingestion.. .followed by an abrupt decline in intake." Additional details
regarding the exposure or dose will be useful - specifically what constant Pb intake was
administered, and when intake was abruptly reduced - was the intake set at zero or some non-
zero baseline? Further clarification on the relevance or interpretation of the time averaging
would be useful because it is unclear how the reduction in variance attributable to the averaging
can be related to the experimental data. The EPA should consider removing the time-weighted
average blood Pb panel.
• Figure 4-22 is a very helpful addition to demonstrate the various slopes, particularly to
emphasize the differences in the model selection (e.g., log-log, log-linear). The shapes of the
response curves are very divergent at low air concentrations. Given that the focus of the NAAQS
is at the low end of the air Pb range presented, EPA should (1) comment on the challenge of
estimating the low-end of the curves (i.e., < 0.2 |ig/m3) from data collected, and (2) comment
specifically on the magnitude of difference in estimates and representativeness of the statistical
models applied to empirical data. EPA should conduct an independent analysis of the underlying
studies and determine if a common model can be used to describe all the datasets. Then, the EPA
should relate the analysis back to estimates of expected change in blood Pb associated with
change in NAAQS (see third bullet under additional synthesis above).
• The ISA presents a range of air Pb to blood Pb slope factors without pinpointing a subset of
estimates that may be more relevant to the objectives of the REA. To the extent that the EPA has
already identified a "best estimate" of a slope factor, or a range of best estimates that are most
appropriate and useful for risk assessment, this information should be included in the ISA,
accompanied by a discussion of the rationale that supports the selection.
• The EPA should discuss the importance of errors associated with estimates of particle size
distributions from historical Pb TSP measurements. How does this uncertainty likely contribute
to (1) estimates of air Pb to blood Pb slopes; (2) estimates of predicted blood Pb from
epidemiological data; and (3) corresponding uncertainty in predicted change in blood Pb
associated with reduction in air Pb (see third bullet under additional synthesis above).
• Section 4.1.1 presents the conceptual model for a multi-pathway assessment. Page 4-6 (lines 8 to
34) discusses the relevance of particle size distributions for inhalation and soil and dust ingestion
exposure pathways. The first sentence (line 8) states that particle size of Pb-PM is relevant to
transport through various media leading to exposure. This sentence should be restated or the
introduction should be expanded to emphasize that different ranges of particle sizes are relevant
to different exposure pathways.
• The historical perspective on the change in Pb sources over time associated with the change in
blood Pb remains somewhat biased towards the phase-down of gasoline Pb (e.g., Section 3.7.1;
Section 4.4.1, p. 4-78, introductory paragraph). It should also emphasize the role of reductions in
emissions in the vicinity of point sources as presented subsequently (e.g., pp. 4-84 to 4-86).
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The following contradictions need to be addressed:
• The text on clearance rates for blood Pb (e.g., 4-62) suggests that the rate of change may be slow
following cessation of exposure, such that blood Pb will remain elevated years after exposure
ends. Yet, the narrative discussion at the top of page 4-67, and the model simulations in Figure 4-
11 (ICRP modeling) suggest exactly the opposite - a rapid decline in blood Pb following
cessation of exposure. EPA should provide more description regarding model assumptions (e.g.,
how baseline exposure was factored in), and comment on whether this relationship may differ for
higher blood Pb that corresponds with adult occupational exposure. If available, the document
should discuss literature that provides empirical observations for the change in blood Pb
following cessation of exposure that resulted in moderate elevations (e.g., blood Pb in the 10 to
25 |ig/dL range) for various time durations. There is concern regarding the external validity of
the simulation in Figure 4-11, in which blood Pb was shown to decline to baseline levels within
months of termination of exposure that had resulted in a blood Pb concentration more than 300%
above baseline for 25 years.
• Pages 4-39 (line 23) and 4-120 (line 22) report that 1% of the Pb body burden is in blood,
whereas page 4-49 (line 12) reports that 5% of the Pb body burden is in blood.
Chapter 5 - Integrated Health Effects of Lead
In Chapter 5, the integration/synthesis of evidence between epidemiologic and toxicological studies and
across related outcomes has been expanded throughout the text and in summaries of individual
endpoints. In the summary and causal determination sections, we have described more explicitly the
weight of evidence for each endpoint within a broad outcome category and specified the particular
endpoints that contribute most heavily to the determination of causality. We have noted, where
applicable, uncertainties regarding the specific Pb exposure periods, levels, frequency and duration that
contributed to epidemiologic observations and included additional details and discussion of study
limitations.
Please comment on the extent to which the revised discussion of the evidence and the causal
determinations accurately reflect the weight of evidence for endpoints within a major outcome category
and the strengths and limitations of studies (e.g., study design, control for potential confounding,
statistical analysis) that comprise the evidence base.
For childhood IQ, adult nervous system effects, blood pressure, and other cardiovascular outcomes,
discussion of the evidence, including analyses of consistency (or lack thereof) across the literature,
confounding, and study design issues were improved. However, for most of the remaining health
measures, a number of concerns identified in the CASAC's review of the 1st Draft ISA remain
unaddressed.
These unaddressed concerns include:
• Incomplete critical assessment of each study reviewed to determine the strength of the observed
associations. The review did not systematically address the adequacy with which epidemiologic
studies have ruled out the potential influence of bias, confounding, or other study design
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limitations on findings and the extent to which multiple high quality studies have reached
consistent and replicate findings. This critical approach would mean not necessarily accepting
study authors' conclusions for a number of studies; however, an appropriately critical approach
was taken infrequently, if at all. There was rarely a distinction made between associations
observed in cross-sectional versus longitudinal studies despite important differences in strength
of inferences possible from these two study types. Differential weighting of cross-sectional and
longitudinal studies should be done but generally was not. Most, if not all, of the epidemiology
studies of Pb and immune function were cross-sectional but the implications of the cross-
sectional design (such as reverse causality) were not acknowledged.
Lack of transparency and consistency regarding causal determination. A balanced analysis of the
strengths and weaknesses of the literature (see the previous bullet above), consistency (or lack
thereof) across the literature, and causal determination criteria outlined in this ISA's Preamble
were not applied consistently across the chapter's sections. For some outcomes, null studies or
studies that do not support the conclusions were not reviewed or were reviewed in a cursory
manner. For example, the null associations of Pb with child neurodevelopment noted after
adjustment for Home Observation for Measurement of the Environment (HOME) score and other
covariates in the Ernhart et al. (1987, 1988, 1999) prospective studies were briefly described in
the text but absent from relevant figures (Figure 5-2), tables (Tables 5-3, 5-4), and conclusions.
Similarly, two prospective studies of Pb and attention-related measures that did not show
consistent findings were not included in reviews of the Pb-behavior literature (Wasserman et al.,
2001; Canfield et al., 2003). As a final example, a recent review contending that the available
published literature does not support the conclusion that low level Pb exposure causes renal
dysfunction (Evans and Blinder, 2011) was not cited in the chapter. There might be good reasons
for excluding or down-weighting these studies but, absent any rationale for doing so, it appears
that non-confirming studies may have been given insufficient attention. As a consequence,
EPA's causation criteria pertaining to "consistency" and "replication" by multiple high quality
studies may not have been adequately addressed with respect to a number of endpoints.
For some outcomes, the approach to causal determination needs to be revisited to consistently
include the adequacy of study design (see the previous two bullets above), toxicologic support,
and biological plausibility. The phrase "the weight of evidence supports the association" is used
throughout the chapter primarily to describe consistently observed associations but the use of this
phrase does not address the requisite elements of a "weight-of-evidence" causal determination.
In the epidemiology literature, consistently observed associations, however strong, are not
sufficient to establish causation particularly if non-causal explanations for the associations (e.g.,
residual confounding or bias) cannot be ruled out with reasonable confidence. An example is the
possibility that confounding by maternal (parental) psychopathology, particularly an attention
deficit hyperactivity disorder (ADHD) diagnosis or subclinical deficits in attention, may explain
apparent associations of Pb with ADHD. This is a major limitation in studies of ADHD in
particular, where family history may reflect both heredity and parenting behaviors contributory
to ADHD risk. For studies of Pb and ADHD or ADHD-related behavior that were reviewed,
credible information about maternal (parental) diagnosis was not available.
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• Example consequences of the above limitations in the weight-of-evidence analysis include: (1)
the weight of evidence relating Pb with childhood cognition versus behavior is not the same but
the text implies it is; (2) this draft addresses some previous concerns and is more measured than
the 1st Draft ISA in its presentation of renal effects but still does not adequately address major
concerns with the Pb-renal epidemiologic literature. These include the potential for reverse
causation, inconsistencies and uncertainties among studies, and absence of a plausible
mechanism for renal effects at low blood Pb levels.
• For some health measures, the weight-of-evidence analysis was undermined by lack of clarity in
the description and conceptualization of outcomes, particularly behavioral outcomes. For
example, behavioral check lists or formal psychometric tests of attention should not be equated
with a clinical diagnosis of ADHD. The evidence associating Pb with ADHD is limited
(essentially all cross-sectional studies) whereas there is more substantial support for an
association of Pb with inattention. This important distinction is unclear in the document. In
general, behavioral outcomes were considered superficially without careful characterization of
differences among different study endpoints. Based on the review of the chapter, it was
sometimes difficult to determine the strength of Pb's associations with child behavior because
distinct outcome measures were often blurred or intermixed. Comparable behavioral assessments
are necessary for meaningful comparison of findings across human studies. If not done already,
consulting with experts in psychometric assessment (for both clinical diagnosis and research
purposes) and experts in animal behavioral testing might help promote a more rigorous approach
to interpreting and drawing comparisons among the complex and diverse behavioral measures in
the literature. For example, the assessment of the human behavioral literature should include a
clearer distinction between outcomes defined by behavior check lists and those defined by
clinical diagnosis. Similarly, a more robust approach to identifying homologies between animal
and human behavioral test measures is needed.
Please comment on the adequacy with which evidence has been integrated between toxicological and
epidemiologic studies, in particular: the increased emphasis on toxicological findings most relevant to
Pb-associated effects in humans; the discussion of results from homologous or parallel tests (e.g.,
response inhibition, blood pressure, renal function); and discussion of evidence describing modes of
action for Pb-associated health effects. Has the coherence of findings among related endpoints been
sufficiently described? Please comment on the effectiveness of the integration of scientific evidence both
within sections for specific endpoints and summary sections.
The revised Chapter 5 includes better integration of the epidemiology and toxicology literature with, in
most cases, a clearer focus on comparing (or acknowledging) homologous tests and exposure routes in
animal and human studies, an improved discussion of the relevance of mode of action studies to human
health effects, and a more explicit description of the relevance of exposure levels used in the toxicology
literature to human exposure and/or modes of action. However, in some cases, homologies between
animal and human tasks were over-extended or ambiguous. For example, in the section on nervous
system effects, homologies between the Morris Water Maze and Cambridge Neuropsychological Test
Automated Battery (CANTAB) were over-extended. Furthermore, the CANTAB is not a specific test so
stipulation of the relevant test in CANTAB is needed in any comparison with animal tests. Similarly, in
animal models where "overall FI rate" is designated "a hyperactive behavior" (see page 5-92), it is
unclear how this characterization might be homologous to ADHD-like behaviors in children which are
10
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largely related to issues of distractibility and impulsivity, rather than movement. Also, for some
outcomes (e.g., some immune effects), the most robust associations with Pb are seen in the toxicology,
but not the epidemiology literature. This distinction and its implications are not made clear. With respect
to renal endpoints, the fact that the experimental animal studies summarized in Chapter 5 utilized Pb
doses (e.g. in the tens to hundreds ppm of Pb in water or diet) that were many orders of magnitude
higher than recent community environmental exposures, and yielded blood Pb concentrations in the
animals considerably higher than recent general population levels merits clear acknowledgement in
section 5.5.6 (Summary and Causal Determination).
Please comment on the extent to which conclusions regarding the blood and bone Pb levels with which
various health effects are associated in epidemiologic studies accurately reflect the weight of evidence
given the study designs and statistical methods employed and populations examined (e.g., school-aged
children, adolescents, adults without occupational exposure, adults with occupational exposure). Are
inferences regarding the specific Pb exposure scenarios (e.g., level, timing, frequency, and duration)
that contributed to the observed associations consistent with the evidence?
The revised chapter is consistent in acknowledging that contemporary blood Pb levels in adults (and
older children) may not directly account for observed health effects because of the likely contribution of
previously higher or longer term exposures. In this context, the chapter is correct to note uncertainty
with respect to the precise Pb dose associated with an outcome. Nevertheless, for the endpoints of blood
pressure, hypertension, and cardiovascular mortality, secular trends in blood Pb and bone Pb data would
allow the EPA to reasonably conclude that decades of blood Pb concentration in the range of
10-25 ug/dL likely bears a causal relationship with elevated blood pressure and increased cardiovascular
mortality in susceptible populations. The epidemiological data support this finding by virtue of
consistent findings in multiple high quality studies that have adequately controlled for bias and
confounding. In addition, toxicological and clinical data offer evidence of plausible biochemical
mechanisms at this level of exposure. In contrast, among studies of children, acknowledging
".. .uncertainty regarding the frequency, timing, dose.. .of Pb" associated with an outcome may be
appropriate for a number of populations but is less of an issue for studies of most U.S. children growing
up in recent times when blood Pb levels have been lower and less variable. Nonetheless, even in certain
studies of the relation of blood lead to health effects in children, uncertainty may remain regarding the
independent contribution of prenatal exposure.
Some exposure characterizations need refinement. For example, characterizing prenatal or early infancy
exposures in humans as "short duration" could be misleading because short duration exposures during
critical periods of development (such as prenatally) can have profoundly deleterious, long term
consequences.
The document is inconsistent in its approach to exposure timing. For example, critical exposure periods
are discussed in detail in the nervous system section but, at least for human data, there is minimal, if
any, discussion of this issue for immune system effects.
Lastly, in discussions of non-linear dose-response relationships, the distinction between supralinear and
U-shaped dose-response curves is not always clear. Lack of effect at high levels may be observed with
U-shaped, but not supralinear, dose-response.
11
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Additional CASAC Comments
Additional comments on this revised Chapter 5 include:
• A new section on the public health significance of nervous system effects is informative and
adds to the weight of evidence presented. However, this discussion alludes to a figure on page 2-
55 that is based on a statistical model rather than observed data. This fact needs to be made clear
because, with all models, findings are predicated on assumptions that may or may not be true.
Specifically, the figure and related inferences are based on assumptions about both the baseline
distribution of population IQ values and expected changes in that distribution associated with Pb
exposure.
• In some places, the chapter is difficult to read due to run-on sentences, repeated text, lack of
transitional text, and factual errors. In the extreme cases, the intended meaning of some sections
of the chapter cannot be deciphered (as an example, see the discussion of the potential for
differential survival time to bias Pb's association with Amyotrophic Lateral Sclerosis on page 5-
164).
Chapter 6 - Potentially At-Risk Populations
The introduction to Chapter 6 has been revised with expanded discussion to better capture the
intricacies associated with characterizing populations potentially at greater risk for Pb-related health
effects. Please comment on the adequacy of these revisions to clarify the consideration of potential at-
risk populations, and recommend any revisions to improve the characterization of key findings and
scientific conclusions.
In addition, please comment on whether the designation of some factors as having limited evidence
adequately reflects the knowledge base considered and strength of evidence available.
In general, the expanded discussion in the revised chapter better captures the intricacies associated with
"at-risk" populations. The reorganization of the chapter into related factors also makes it more cohesive
and better integrated. The revised chapter adequately defines some factors as having limited evidence
based on strength of available evidence. Additionally, the CASAC encourages the Agency to develop
standard terminology and concepts for populations at risk that can be broadly applied and consistently
used across criteria pollutants.
Some issues still remaining include the extent to which these risk factors actually modify the magnitude
of the impacts of Pb exposure. As currently constructed, there is no way to discern which of these risk
factors is most critical and certainly a better understanding of magnitude of the impact would be of
assistance for risk assessment and management.
The CASAC has the following recommendations for improving the chapter:
• Given the differences between maternal self-esteem (how was it actually measured) vs. stress
imposed in rat models, such a homology should certainly be limited or at least qualified.
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• The statement regarding the impact of arsenic on Pb bioavailabity (p. 6-3, lines 33-35) should be
re-checked for accuracy because the cited study (Wang and Fowler, 2008) does not support the
statement.
• Section 6.3.6 (Race and Ethnicity) and Section 2.9.6.5 do not sufficiently discuss the potential
susceptibility of African Americans to Pb possibly arising from factors not mediated by
socioeconomic status (SES) or exposure.
• There are statements in Chapter 2 suggesting interactions between Pb and fluoride and co-
exposures. There appears to be additional information related to this, and a discussion of Pb and
fluoride should be added to Chapter 6, including limitations and uncertainty. The statement on
page 2-78, lines 29-31 regarding the influence of fluoridation on Pb in water is not supported by
the scientific studies presented elsewhere in the ISA, and it should not be included in its current
form.
Chapter 7 - Ecological Effects of Lead
The causal statements for ecological effects discussed in Chapter 7 have been reevaluated as advised by
CASAC. There are now separate causal determinations for terrestrial and aquatic biota for each
endpoint under consideration. In addition, the chapter now incorporates additional findings from the
2006 Pb AQCD on the effects ofPb on ecosystem receptors, an enhanced discussion of bioavailability
and bioaccessibility, and separate discussions of marine and freshwater toxicity in the aquatic
ecosystem section.
Please comment on the adequacy of these various revisions and other changes to the chapter and
recommend any revisions to improve the discussion of key information.
This chapter has been greatly improved by reorganization and the inclusion of additional material.
Sections have been clarified with the addition of concise introductions, by reference to previous Air
Quality Criteria Documents (AQCDs), and the inclusion of brief summaries of sections, where
appropriate. More recent information on Pb exposure, toxicity, and effects to ecological receptors has
been included in separate sections for terrestrial, freshwater, and marine ecosystems. Although the
revised ISA contains new information presented in an organized manner, the information is not
summarized and integrated into a meaningful synthesis and little technical evaluation of extant data is
provided. Summary tables listing media-based exposure concentrations (soil, freshwater, marine),
nominal or measured, with their respective responses and key abiotic modifying factors (e.g., pH,
organic carbon, cation-exchange capacity (soils), water hardness) will help in further organizing the data
to facilitate a synthesis. A detailed table should be provided in an appendix (e.g., 2006 Pb AQCD) with a
summary of the most relevant data presented in the ISA to guide the discussion. An initial discussion
should include the relevance of responses observed at very high Pb levels that may not be expected in
most environmental scenarios. In a similar manner, Pb exposures and effects related to very low levels
also should be addressed, especially where Pb levels appear to be below analytical detection limits.
Discussion could then conclude with an evaluation of how the ranges of Pb found in various media (see
Table 2-1) overlap with experimental concentrations. Although some discussion of bioavailability is
provided, integration of this concept into the discussion of observed effects of Pb exposure in different
media should be attempted.
13
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Throughout the chapter, the consistent expression of exposure dose will help facilitate comparisons of
exposures within and among studies. Exposure doses should be expressed on a mass basis (e.g., mg/kg,
mg/L) for all exposures, except for comparisons between or among metals, where exposure should be
expressed on a molar basis (e.g., jiM). Nominal concentrations and exposures in non-standard media
(e.g., hydroponic, agar) should be identified.
The EPA's Office of Water utilizes the endpoints of survival, growth, and reproduction for the
development of water quality criteria. Pb that is subject to atmospheric deposition and results in
ecological effects would ultimately be present in water, sediments, or soils. Survival, growth, and
reproduction should be considered the most relevant endpoints, and sub-organismal responses should be
discussed in the context of secondary responses.
The nature of the question that is asked in causal determinations as related to ecological responses needs
to be clarified, i.e., What is a "relevant pollutant exposure" (Preamble, page lv)? Are causal
determinations related to aerial deposition of Pb or are they only considered in relation to laboratory
exposures even though relevance to ecosystems is unclear?
There is a need for consistent linkage of terms for causal determination with chapter 2.
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REFERENCES
Aucott, M. and Caldarelli, A. (2012). Quantity of lead released to the environment in New Jersey in the
form of motor vehicle wheel weights. Water, Air, & Soil Pollution., 223:1743-1752.
Canfield, R.L., Kreher, D.A., Cornwell, C., and Henderson, C.R. (2003). Low-Level lead exposure,
executive functioning, and learning in early childhood. ChildNeuropsychology, 9(l):35-53.
Ernhart, C.B., Morrow-Tlucak, M., Marler, M.R., Wolf, A.W. (1987). Low level lead exposure in the
prenatal and early preschool periods: Early preschool development. Neurotoxicology and Teratology, 9:
259-270.
Ernhart, C.B., Morrow-Tlucak, M., Wolf, A.W. (1988). Low level lead exposure and intelligence in the
preschool years. Sci Total Environ, 71: 453-459.
Ernhart, C.B., Morrow-Tlucak, M., Wolf, A.W., Super, D., Drotar, D. (1989). Low level lead exposure
in the prenatal and early preschool periods: intelligence prior to school entry. Neurotoxicology and
Teratology, 11:161-170.
Evans, M. and Blinder, C.-G. G. (2011). Chronic renal failure from lead: myth or evidence-based fact?
Kidney international, 79(3): 272-279.
U.S. EPA (2006). Air quality criteria for lead: Volume I of II (EPA/600/R-05/144aF). Research Triangle
Park, NC: US EPA. http://cfpub.epa.gov/ncea/CFM/recordisplav.cfm?deid=158823
Wang, G.S., Fowler, B.A. (2008). Roles of biomarkers in evaluating interactions among mixtures of
lead, cadmium and arsenic. ToxicolApplPharmacol, 233: 92-99.
Wasserman, G.A., Liu, X., Pine, D.S., and Graziano, J.H. (2001). Contribution of maternal smoking
during pregnancy and lead exposure to early child behavior problems. Neurotoxicology and Teratology,
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Appendix A
Compendium of Individual Comments by CASAC Lead Review Panel Members on
EPA's Integrated Science Assessment for Lead
(Second External Review Draft - February 2012)
Mr. George A. Allen A-2
Dr. Herbert Allen A-5
Dr. Richard Canfield A-7
Dr. Deborah Cory-Slechta A-ll
Dr. Cliff Davidson A-13
Dr. Philip E. Goodrum A-15
Dr. Sean Hays A-20
Dr. Philip Hopke A-21
Dr. Chris Johnson A-23
Dr. Susan Korrick A-25
Dr. Michael Kosnett A-36
Dr. Roman Lanno A-46
Dr. Richard L. Poirot A-48
Dr. Joel G. Pounds A-60
Dr. Michael Rabinowitz A-64
Dr. William Stubblefield A-67
Dr. Ian von Lindern A-70
Dr. Gail Wasserman A-79
A-l
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Mr. George A. Allen
General Comments
Revisions to Chapter Three generally address the panel's comments on the first ISA draft. Some sections
have been reorganized and expanded, and there are several new subsections. Some of the new material,
especially in section 3.5, may not been carefully reviewed internally; there are many mistakes and issues
with interpretation (or lack thereof) of the literature discussed. Chapters 3 and 4 have some common
elements that would benefit from more direct cross-chapter linkage. Chapter 4, section 4.4.1 notes the
Miranda dx.doi.org/10.1289/ehp. 1003231) 2011 study of blood lead in children living in the vicinity of
GA airports. This study's results imply that inhalation may be a major pathway of exposure to GA
airport Pb, but there is no discussion of this in section 4.1.3.1, Airborne Lead Exposure.
HERO continues to be useful, especially for material that is not in the published literature.
Specific comments on Chapter 3:
Section 3.2.2.5, "Description of air Pb emissions from wood burning" discusses the contribution of this
source to air Pb, primarily from wildfires, as a "potentially uncontrollable source." There is still no
meaningful discussion of avoidable Pb exposures from residential space heating woodsmoke; this may
be the primary air exposure pathway for "new" Pb in rural or small valley towns where woodsmoke PM
concentrations can be high for much of the winter. Chapter four cites one limited study (Molnar, 18
woodsmoke samples) on these exposures with minimal discussion because p=0.06; despite the p-value,
this is a notable result given the small sample size.
Section 3.4.1, Ambient Lead Monitoring Techniques, has substantial new content in response to
comments on the first draft ISA, especially on the current FRM Hi-Vol TSP sampling method. A limited
discussion on the possibilities of and need for a better alternative FRM has been added. While it may not
be within the traditional scope of an ISA, an expanded discussion on the state of the (aerosol) science
supporting possible alternatives to the Hi-Vol FRM would be useful to address the many and long-
standing CASAC comments on this topic. It would be useful to have some discussion here and/or in
chapter 4 on an acceptable FRM particle size cut from an exposure perspective; is a "TSP" measurement
that has well characterized under-sampling of large particles at higher wind speeds sufficient to assess
exposures to Pb in the context of NAAQS-relevant exposure pathways? Is measurement of very large
particles meaningful or useful given the indirect nature of the dominant exposure pathways?
Section 3.5, Ambient Air Lead Concentrations, has been substantially expanded and revised in the
second draft. Overall the changes are an improvement, but some of the new material needs more careful
proofing and editing; this section can be difficult to read and understand at times. There is a tendency to
present material but not synthesize it in the larger context of this section or chapter. Sometimes data are
presented without noting the sampling method; this is difficult to interpret since measurement of larger
particles depends on the sampler. 3.5.1.2, Intra-urban Variability, has several new subsections: near-
roads, airports, and urban-rural that provide additional useful detail. Section 3.5.3, Size Distribution,
appears to be a nearly complete re-write of this important topic and would benefit from additional
editing to make the information more readily accessible. Section 3.5.4, Multipollutant Context, also has
A-2
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a large amount of new material that needs cleaning up. Section 3.5.5, Background Concentrations, is
new; although Pb background is not much of a factor relative to some other NAAQS (ozone for
example), this discussion is useful.
Specific comments follow (page, line[s]).
3.3.1.3, 3-27, 15-25. This discussion of maximum height above ground is confusing and doesn't seem to
be consistent. One cite has maximum height of 75 um particles as 0.4 m and another has it as 0.05 m.
There needs to be a discussion on this wide range of reported or modeled data if the cites are correct.
3-27, 27-32. "long range transport of dust" limited to particles < 10 um. If LRT here is meant in the
traditional sense (100s of km or more), 10 um is too large.
3.4.1.1, pg 3-58, table 3-3. The PM10 SSIHiVol FRM should be included here; it is mentioned in the
text.
3.4.1.6, pg 3-67, 6-7. Highly time-resolved measurements are also valuable for determining sources.
This section should mention the "on-line" Cooper/Pall Xact 620 XRF ambient sampler:
http://www.pall.com/main/OEM-Media-Membranes-and-Materials/Product.page?id=54499.
3.4.2.1, GA Airport monitoring. Although the results of the first year of GA airport monitoring won't be
available until spring 2013, there will be some useful information available by this fall. There are six
GA airports with 2008 NEI emissions over 1.0 tpy; the highest is Deer Valley (Phoenix) at 1.3 tpy. One
of the 15 airports in the 1-year pilot study has emissions during the summer similar to Deer Valley's tpy.
Nantucket (MA, ACK) has 0.76 tpy according to
http://www.epa.gov/ttn/chief/net/2008nei vl/lead facility_vl 5 final.xls, with much (more than 2/3?)
of this during four summer months. Thus the emissions during the 3-month rolling average form of the
Pb NAAQS from mid-June to mid-September are perhaps higher than any other GA airport. It would be
useful to have monthly airport activity information to better understand these seasonal emissions
patterns at Nantucket.
3.5.1.1, variability, pg 3-79, table 3-6. It may be worth noting that the "highest" values reported here are
not stable numbers due to the limited 6th day sampling and the strongly skewed distribution of the data.
Same for table 3-8, pg. 3-82.
3.5.3.2, airborne Pb near roadways.
3-99, 30-31: UF, fine and coarse Pb "roughly constant" - makes no sense; units are mg/kg [typo]
3-100, 5: units? Line 22: what size range/cut?
3-101, 4-5: the 1 to 10 um bin concentration should be reported too.
8: NOx reactivity cause of lower R2? NOx in the near-road context is conserved.
11-12: mean is lower than winter/summer concentrations
3.5.3.3, airborne Pb other urban/rural.
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3-102, 28-29. PM 1-2.5 is too large for a ~ 1:1 fine/course aerosol.
3-104 fig 3-28: correlation of 1.0 for 3 categories - is this real?
3-105, l-3:Rorrho?
3-107, table 3-10. Most of the reported correlations across sizes are implausible.
3.5.5, background Pb.
3-109, 23-25: sentence makes no sense.
Typos:
3-67 line 16
3-74 line 8
3-76 line 2
3-99 line 22, 28
3-103 line 14-21: awkward, hard to understand; punctuation error? "figures illustrates"
A-4
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Dr. Herbert Allen
Chapter 7 - Ecological Effects of Lead
This draft of the ISA represents a substantial improvement of the document. Chapter 7 is well-written
and comprehensive. The assessments are based on the studies presented and are easily followed.
p. 7-70. L. 6-16. This presents only the inorganic species that are present. To state that these are
the forms that are present is not true and is countered elsewhere. In addition to these inorganic forms,
lead humate is present in the solid phase and lead fulvate is present in solution.
p. 7-75. L. 5. and p. 7-134. L. 7. "commercially-derived humic acid" is a poor description. If this
was Aldrich Humic Acid, state that as this is a widely used material.
p. 7-75. L. 13. jimole is a unit of mass, not of concentration. If this was 1 (imole/liter, write 1 |iM. The
unit |iM means jimolar or jimole/liter. This error occurs in a number of other locations.
p. 7-85. L. 8. 2.9 and 6.6 mg Pb is not in the correct units. The mass of plant tissue considered must be
presented. Perhaps this should be mg Pb/ g plant. Likewise, in the next line, the mass of sediment must
be indicated. Perhaps this should be 0.3 mg/ g sediment.
p. 7-88. L. 16. The volume of water is not indicated. Perhaps this should be 0.05 jiM rather than 0.05
jimole.
p. 7-88.1. 34. Perhaps "rate" should be deleted as time is not a variable.
p. 7-92. L. 8. Report the concentration of Pb not of Pb-nitrate. An example of a good style is p. 7-93.1.
20.
p. 7-92. L. 24-26. This is not clear. Why is the average Pb in sediment given together with the range of
values for body burden? Why not provide ranges for both or use mean values for both? Is this whole
body?
p. 7-101. L. 18 jimole is a unit of mass, not of concentration.
p. 7-102. L. 8, 14 and 35. mmol is a unit of mass, not of concentration.
p. 7-102. L. 15. (imol is a unit of mass, not of concentration.
p. 7-103. L. 6. mmol is a unit of mass, not of concentration (twice).
p. 7-104. L. 2. Na+ notNa2+. Ca2+ not Ca+.
p. 7-110. L. 36 and 37. Ca2+ not Ca+.
p. 7-110. L. 38 Probably Ca2+ not Ca.
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p. 7-111. L. 1. Probably Zn2+, Cd2+, Na+, CF, Ag+, and Cu2+.
p. 7-1111. 2 and 4. Probably Ca2+ and Na+.
p. 7-1111. 17and23.Ca2+notCa+.
p. 7-113. L. 8. Were these exposure concentrations analytically verified? These are among the lowest
concentrations cited in this chapter and this are of importance in establishing the concentrations that can
elicit biological response. 10 nM Pb is approximately 2 |ig/L. Low concentrations of Pb are difficult to
maintain and, of course, the potential for contamination always exists.
p. 7-114. L. 9. The unit is not expressed clearly, but I take it to be 0.3-0.48 g Pb/ kg wet fish • day. This
value is HUGE. Is the unit for Pb mass correct?
p. 7-114. L. 26. The second value in the list should probably be 0.01 rather than 001.
p. 7-115. L. 6. These concentrations are even less than those in p. 7-113. L. 8. On a weight basis they
correspond to 0.02 to 0.2 jig Pb/L. That is a concentration below that found in most freshwaters. If
goldfish are representative of all fish, the conclusion is that most fish are affected by environmental lead
exposure. This is a very serious finding and the results should be very carefully assessed and the
discussion should be increased. In the next sentence of the ISA the results of an estrogenicity cell growth
assay in the same study are reported. The cited paper indicates that ECso value for lead was 1 x 10"14 M.
This is, I believe, the lowest effect concentration reported anywhere in the ISA. It is 4-5 orders-of-
magnitude below the effect value in the vitellogenin evaluation. I am greatly concerned about this entire
study. To maintain these low concentrations of lead is exceedingly difficult. Normally, I would expect to
find that the entire study had been carried out in a Class 100 clean room and would expect to find that
the nominal concentrations that are reported in the study had been confirmed analytically, e.g. ICP-MS.
The authors point out that result for cadmium chloride was 4 orders-of-magnitude below the value that
had been previously reported. This should have raised concern about the results.
p. 1-121. L. 16-22. Because the chemical reactions involved in considering critical load should be
expressed with molar units rather than weight units, the difference in critical loads for different metals
should also be compared on a molar basis. The atomic weight of Pb is more than 3 times that of Cu, Ni,
and Zn. Comparing moles a metal loading at the critical load, the value for lead is approximately a factor
of 3 greater than that for the other metals, not an order of magnitude greater.
p. 7-133. L. 20-25. The constancy of Na+, Ca2+, and Mg2+ concentrations is true for marine systems that
are little influenced by fresh water. However, very important saltwater systems are embayments and
estuaries. Saltwater systems encompass a range of salinities from just above that of freshwater to full
strength seawater.
p. 7-152. L. 21-25. This is not what is shown on the next page. Bioaccumulation does primarily occur
from uptake of Pb from water via the gills.
p. 7-166 1. 17. Is there a chlorophyll that contains Ca?
A-6
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Dr. Richard Canfield
In Chapter 5, the integration/synthesis of evidence between epidemiologic and toxicological studies and
across related outcomes has been expanded throughout the text and in summaries of individual
endpoints. In the summary and causal determination sections, we have described more explicitly the
weight of evidence for each endpoint within a broad outcome category and specified the particular
endpoints that contribute most heavily to the determination of causality. We have noted, where
applicable, uncertainties regarding the specific Pb exposure periods, levels, frequency and duration that
contributed to epidemiologic observations and included additional details and discussion of study
limitations.
Please comment on the extent to which the revised discussion of the evidence and the causal
determinations accurately reflect the weight of evidence for endpoints within a major outcome category
and the strengths and limitations of studies (e.g., study design, control for potential confounding,
statistical analysis) that comprise the evidence base.
1. Interpreting Bayley MDI results: The Bayley MDI test is nicely introduced (p. 5-65) but could
benefit from an explicit statement that although it statistically analogous to IQ, it is not an IQ test
and, when administered prior to about age 2 or 3 years, does not consistently correlate with
childhood IQ when measured during childhood or later in life. It is somewhat misleading to
lump together Bayley test results from 6 months to 3 years because many of the items on the 3
year MDI are quite similar to items that appear on the WPPSI, Stanford-Binet, and other IQ tests
when administered to the youngest age groups. Because children change so rapidly during
infancy and early childhood, there is not a single item on the 6 month MDI that also appears on
the 2 or 3 year MDI. It's still called the MDI, and that is a source of confusion. In reality, there
is little agreement on what the MDI measures, especially in the normal range of infant and child
developmental outcomes. When the MDI does predict later IQ it is typically a case in which an
at-risk sample (e.g., brain infarcts during delivery, vlbw)includes some infants that are severely
impaired and some that are normal and then the prediction is really more of a test of whether
those groups develop differently or reach different IQ endpoints. If I were to assess the strength
of the evidence for causality based on the PbB-MDI literature (not having reviewed it as recently
or as comprehensively as was done for this ISA), I would say that MDI data are not inconsistent
with the IQ results but that the measure is poorly suited for this purpose and the results are not
wholly consistent, yet they do not provide a basis for questioning the results seen with IQ testing
at later ages.
2. Confirmation bias: The concern about a confirmation bias stems from examples such as the
treatment of results from the Cleveland cohort study(Ernhart et al. studies). This is a prospective
longitudinal study that gave substantial attention to covariate control, yet found nonsignificant
effects of lead after adjustment. A key concern with the handling of this study is that it could
appear that it was considered not important solely because the findings did not agree with the
bulk of the research in this area (more so for IQ than for MDI). This impression is greatly
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amplified by noticing that although the study is briefly described in the text, alongside the other
studies, it does not appear in the summary tables and figures in both sections where it is relevant.
That is, in section 5.3.2.1 Ernhart et al. studies are absent from figure 5-2 and table 5-3 (p. 5-57
to 5-59). This is also true for the section describing MDI results on p. 5-66 to 5-68 where the
Ernhart studies are not included in table 5-4. As a result of these omissions, the figure and tables
contain only evidence that supports the conclusions of the document. There might be good
reasons for excluding those studies but in the absence of any rationale for giving them no
apparent weight in characterizing the strength of support for the conclusions raises the concern
that non-confirming studies were, in general, given insufficient attention.
3. Homology: In a number of instances the homology asserted to exist between performance of
animals in toxicology studies and children in epidemiological studies is at times overstated. For
example, the Morris Water Maze task, as typically administered, is a test of spatial navigation or
place learning using distal landmarks. However, it can be administered in a simplified form by
using local landmarks, and it can be administered such that the location of the platform is
different for each testing day. None of these versions can be considered directly homologous to
the CANTAB tests used in the Rochester study. On 5-73 the CANTAB is described as "sharing
homology" with MWM but on 5-88 it is stated that "The Morris Water Maze is homologous to
the spatial memory components of the CANTAB and WISC-R, which test the ability of subjects
to recall correctly a sequence of locations." The MWM typically involves only one location and
so here the homology is somewhat weak. On 5-100 MWM results are characterized as "These
animal observations provided strong coherence with associations in children with homologous
tests of spatial memory and rule learning and reversal." And on 5-102 ".. .tests of learning and
memory in animals that are directly homologous to tests conducted in children.."
Moreover, the CANTAB tests administered in the Rochester study are part of the working
memory and planning battery and is shown to depend heavily on frontal areas. On the other
hand, MWM is generally considered a hippocampal task. This would suggest that they are not
homologous.
a. Going deeper into the interpretation of CANTAB, several different tests were given and
each measures a somewhat distinct aspect of cognitive function. Thus, the spatial
working memory task (SWM) requires the subject to recall which of several boxes had
been visited previously on that trial to retrieve the reward. This is most homologous to a
radial arm maze task. The spatial span task (SSP) measures something slightly different.
It is designed to test the maximum number of locations that can be held in working
memory and then recalled to guide behavior (pointing). Because there is essentially no
delay imposed, these are measures of visual-spatial working memory that I would agree
"share homology" with
(note also that MWM is a stressful task, which could influence the cognitive and emotional functions
measured)
A-8
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1 Coherence/relating specific cognitive measures to IQ: on page 5-55 it is stated that "specific
indices of cognitive function are reflected in global measures of intelligence." It's unclear what
is being claimed here...correlations between specific tests and IQ are sometimes close to 0.. .for
example some executive function measures aren't well reflected in IQ and in the reviewed study
by Canfield et al. using the cantab some measures were associated Pb independent of IQ.
5-118 Decrements in cog function and behavior problems demonstrated within same population is not
direct evidence for cognitive underpinnings of behavior problems.. .have studies looked at assoc
between cogn and behavior in the same children???
5-102 and 5-191 and elsewhere.. ."relatively short durations of lead exposure" are considered to be
conception through birth or even into postnatal life. In tox studies short can be 1 hour or 24 hours in cell
cultures. The term is misleading in the context of continuous prenatal exposure and should be dropped.
On 5-213 (1. 27) frontal lobe and striatum are mentioned but not hippocampus
Interpreting dose-response curves: (p. 5-223 and elsewhere) U-shaped dose-response curves from
toxicology studies are clearly different from the supralinear concentration-response curves often seen in
epidemiological studies using IQ as the outcome. In the latter case it is always true that more Pb is
worse than less Pb, it is just that the adverse effect of a unit of exposure is greater at the lower levels. In
the former case there are groups for which a greater Pb dose is associated with less (or no) damage as
compared to the larger effects of a lesser dose.
Please comment on the adequacy with which evidence has been integrated between toxicological and
epidemiologic studies, in particular: the increased emphasis on toxicological findings most relevant to
Pb-associated effects in humans; the discussion of results from homologous or parallel tests (e.g.,
response inhibition, blood pressure, renal function); and discussion of evidence describing modes of
action for Pb-associated health effects. Has the coherence of findings among related endpoints been
sufficiently described? Please comment on the effectiveness of the integration of scientific evidence both
within sections for specific endpoints and summary sections.
Please comment on the extent to which conclusions regarding the blood and bone Pb levels with which
various health effects are associated in epidemiologic studies accurately reflect the weight of evidence
given the study designs and statistical methods employed and populations examined (e.g., school-aged
children, adolescents, adults without occupational exposure, adults with occupational exposure). Are
inferences regarding the specific Pb exposure scenarios (e.g., level, timing, frequency, and duration)
that contributed to the observed associations consistent with the evidence?
1. Frequent unevenness from paragraph to paragraph and section to section on whether there was
both an introductory statement about the health-relevance of an outcome and a summary
statement about what the reader should conclude from the review of studies in relation to that
outcome. This ranged from often-excellent to nonexistent.
2. "There is uncertainty regarding the frequency, duration, timing, and magnitude of exposure
contributing to the blood Pb levels among the adult [adolescent, child] population studied." (2-
74) This type of statement is frequently made in the integrative summary in relation to adult and
A-9
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adolescent cross-sectional data. It is also relevant for interpreting results of cross-sectional
studies in school-aged children and should be mentioned in chapter 5 Integrated Health Effects.
a. For example, BPb of 2 at 8-11 years is difficult to interpret regarding threshold or low-
level effects because we don't know what the earlier exposures were.
5-214 pub health significance: Might include issue of societal use of cut-off scores on IQ-like tests to
qualify for admission to college, grad school, etc. The loss of a few points could have substantial life-
long effects on the individual's opportunities, regardless of the absolute magnitude of the difference in
ability that is represented by a few point lower IQ score.
5-86 table 5-6 Beaudin et al. and Stangle et al. studies show most prominent effect in error reactivity,
which they characterize as an emotional effect. This interpretation should be considered in sections
5.3.3.2 (5-137) and/or 5.3.3.5 (5-145)
Chelation
Recent work in Strupp lab shows that chelation alone results in some cognitive impairment and so
interpretation of this literature depends on knowing this.
5-100 Methionine choline supplementation did not reduce brain Pb but did cause improved learning
and memory in rats. This could be due to an independent effect of choline supplementation during the
early postnatal period. Information about the ages period of choline supplementation should be included
in the writeup and a reference to work by Williams and Meek on choline effects in the rat.
5-112 MMSE is a screening test for cognitive impairment and NOT at test of general cognitive
function.
There is more diversity to associations between age of BLL and correlation with later outcome than is
made clear in the document. For example, in Boston, only 24-mo Pb correlated with 57 mo IQ whereas
in Rochester 24-mo lead showed the lowest correlation with 3 and 5 yr IQ.
SES- Good discussion of a complex issue. One instructive comparison could be considered for
inclusion.. .Rochester and Boston included children at near opposite ends of SES and IQ distribution,
but had very similar BLL profiles. They also showed very close estimates of effect size and
supralinearity of effect curve.
5-151 Differential effects in children and adults... should include mention that affectingapparently
different neuropsych processes operating at different ages could also be variation due to different ages of
exposure and exposure profiles in the various studies.
Should be some mention of "filedrawer problem" in which some studies fail to be published due to
nonsignificant results whereas results significant by chance association would more likely see
publication. This is a source of uncertainty.
5-259 5.4.3.3 Heart Rate Variability... .need intro on how to interpret the measure, why is it important?
Need introduction similar to 5.4.3.2 or 5.4.3.4.
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Dr. Deborah Cory-Slechta
Comments on Chapter 5
My comments on Chapter 5 are primarily editorial, with one exception. I am concerned about
associating lead with ADHD. All but one of these studies is based on teacher and/or parent report and
not a clinical diagnosis, hence the reliability of such a diagnosis is questionable. There is significant
support for an association of Pb with attention-related behaviors, and maybe this is the appropriate
terminology, unless there is some reference that can show reliability of teacher/parent reports to actual
clinical diagnosis.
p. 5-26; lines 16-20; are the increases vs. decreases related to Pb level and perhaps indicative of a non-
linear curve?
p. 5-27, lines 22-24; again, could it also be indicative of non-linear concentration-effect functions?
p. 5-47, lines 25-27: increased apoptosis of what?
p. 5-55, lines 11-12: I think significant caution needs to be exercised in ascribing Pb exposure to ADHD.
Most of the studies cited in support of this are based on parent and or teacher reports and not on an
actual clinical diagnosis, which makes them far less credible (albeit teacher reports are likely better than
parents).
p. 5-75, Figure 5-5: It would be helpful if the actual names of the tests were used here; they are for some
of the studies, but not others, e.g., for Chiodo the table lists 'perseverative errors', but on what test? The
specific tests are not listed in Table 5-5 either for many of the studies, just references to e.g., Cantab. It
would be particularly useful to somehow incorporate the specific test names (e.g., rule learning and
reversal is the IntraExtra Dimensional Shift Set).
p. 5-88 line 4: change mouse to rodent, the test is used with both rats and mice
p. 5-89, line 5-6: again, the name of the specific test being referred to should be included. To cite this as
'components of the Cantab' is confusing as there is not "the Cantab" but a menu of specific tests one can
use from Cantab.
p.5-91, line 14: should be two months not two weeks
p. 5-99, lines 4-7. Its not clear why this distinction is being made; for both humans and animals, the
subjects assess the ability to complete a task when the 'rules change'. That is the same thing as say
'changes in reinforcement'.
p. 5-114, lines 23-24. Not sure that it is really appropriate to say that the relevance of the plasma Pb
fraction is not clear; we know that this is the fraction that delivers Pb to soft tissue. For example, in
chelation studies, e.g., Korean workers after CaEDTA, it is the plasma Pb compartment that shows
A-ll
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increases in Pb even as blood Pb levels decline and in animal studies that same procedure results in
increases in tissue Pb levels, including brain.
p. 5-120, lines 9-20: it would be more appropriate to describe the test as "shift focus to another
dimension of the stimulus that defines correct responding (e.g., color to shape)"
pp. 5-128-132. Here again, I repeat the concern about linking Pb to ADHD specifically which is a
clinical diagnosis. All but one of the cited studies for this section relies on parent and or teacher reports,
which is far less confirmatory. Options include citing this significant limitation, looking at the literature
to see how predictive teacher reports of ADHD are relative to clinical diagnosis, or describing these as
'attention-related' deficits.
p. 5-138, lines 16: should change "absence of a fixed schedule of reinforcement" to something like "
time interval preceding the availability of reward opportunity".
p. 5-138, line 19: change 'interresponse rates' to 'interresponse times'
p. 5-138, line 27 change 'repeat-acquisition' to either 'repeated acquisition' or 'repeated learning'
p. 5-150, line 9, change "frontal striatum' to 'frontal cortex and striatum'
p. 5-150, line 10, delete space before period after 'density'
p. 5-151, line 6, change 'processed' to 'processes'
p. 5-207, lines 21-25. A reference needs to be added for this description of outcomes.
Comments on Chapter 6
I have no major comments for Chapter 6, the revised version of the draft has addressed my prior
comments. The only thing that I think would still be useful is some indication of magnitude of the
differences in Pb toxicity that can occur with some of the factors that confer susceptibility or risk. In
particular, while polymorphisms can induce differential risk, what is the magnitude of the differences
that they are associated with? It would seem that an understanding of the risk associated with such
factors would be useful for risk assessment and for the question of whether or not the current methods of
ascribing safety factors of 3 or 10, for example, actually accommodate those susceptibilities.
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Dr. Cliff Davidson
Preamble and Preface: The revised ISA does a good job of separating material that can support all IS As
and putting this in the Preamble. The Preamble and Preface read well, and contain appropriate material.
There are a few editorial comments:
Page xlv, line 19: "animal toxicological studies includes" should be "animal toxicological studies
include"
Page xlv, lines 25-26: the word "should" sounds prescriptive and doesn't match the rest of the section.
Should be modified.
Page xlvi, lines 22-24: remove "the health effects evidence from" and "evidence" as the last word of the
sentence.
Page xlvi, line 24: "first draft ISA" is confusing - should be this "second draft ISA"?
Page xlviii, lines 1-7: First sentence on the page is too long, and in any case it is a run-on sentence. Start
new sentence beginning :more generally.."
Page xlix, line 17: "Controlled human exposure studies" at the beginning of the sentence should be
"Such controlled studies..."
Page 1, lines 4-5: sentence has three negatives in it, difficult to read.
Page 1, lines 33-34: "this potential threat to inferential validity" should be "the potential for erroneous
inferences"
Page li, lines 34-36: This sentence should be revised as follows: "For example, an individual of low
socioeconomic status or with a pre-existing disease may have increased risk of effects related to air
pollution exposure; either of these factors may be an effect modifier."
Page Ivi, line 6: "Surgeon" is misspelled.
Page Ixi, line 9: revise after the semicolon to read: "for example, there is no established change in any
lung function measure that represents an adverse effect."
Page Ixi, line 14: delete "For example"
Page Ixix, line 14: change semicolon to a comma - currently incorrect grammar. "2" should be a
superscript.
Chapter 1. Chapter 1, as the Executive Summary, is a brief outline of the full ISA, and incorporates
enough background so that the reader will know whether to make the investment in moving on to
Chapter 2, which is a much more detailed integrative summary. The chapter reads well and there are
only a few very minor edits suggested:
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Page 1-5, line 14: sentence has grammatical problems.
Page 1-7, line 2: define AQCD
Page 1-7, line 12: define SES
Page 1-9, line 26: delete comma
Chapter 2. A reader should be able to read this chapter and come away with a good idea of what studies
are relevant to the NAAQS for Pb and how they fit together. As an integrative summary, Chapter 2 now
accomplishes that. The chapter reads well and contains the requisite information. The problem
remaining is to incorporate changes in the later chapters back in Chapter 2 so that it is consistent with
these changes. The CAS AC suggested a number of changes in Chapters 3 through 7, and those will be
summarized in the consensus report. Thus the substantive edits to Chapter 2 will come later.
Page 2-13, lines 24-26: sentence has grammatical problems.
Page 2-24, line 34: "association" should be "associations".
Page 2-60: the description of Table 2-61 is too brief. Some individuals will read Chapter 2 and never get
beyond this chapter. Table 2-61 is important and merits a bit of discussion.
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Dr. Philip E. Goodrum
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.
The pre-meeting memorandum to the Pb CASAC Panel notes that the following items were updated in
Chapter 4 of this second external draft:
Exposure
• Additional discussion of the relationship between airborne Pb-particle size distribution and
exposure by inhalation and ingestion (e.g., hand-to-mouth).
• Further emphasis on measurement errors and uncertainties that may affect exposure assessment
for air Pb.
• Addition of new section on exposure assessment methodologies that includes discussion of
exposure representation within the IEUBK model and exposure modeling techniques.
Toxicokinetics
• Expanded discussion on the effects of both past and current Pb exposure on blood Pb levels.
• Presentation of additional data from studies that followed blood Pb levels in individuals
following cessation of high Pb exposure occupations and in children over the first several years
of life.
• Expanded section on bone Pb measurement.
• Reevaluated air-to-blood slopes across the range of air Pb concentrations available in a given
study with an emphasis on the central tendency of air Pb concentrations.
Charge to CASAC committee:
Comment on the accuracy of the interpretation of the science:
1. Are uncertainties and limitations of relevant data, methodologies, and approaches adequately
discussed?
2. Provide specific recommendations to refine the scientific interpretation and/or improve the
representation of the science.
General Comments
The additions and edits to Chapter 4 are generally responsive to the comments provided by CASAC on
the first draft of the ISA. These changes provide a more comprehensive overview of current modeling
A-15
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approaches and available study data that are relevant to understanding how air-related exposure can
contribute to total Pb exposure.
The ISA presents a well organized and systematic overview of the key elements of exposure assessment
for Pb. The addition of cross references to other chapters and references to the 2006 Pb AQCD,
guidance documents, and risk assessment literature improves the overall readability. Important concepts
that help to describe the role of air-related lead exposure are more clearly introduced. However, the
synthesis of this information could be further improved so that the ISA provides a stronger foundation
for the review of the NAAQS. An important shortcoming of Chapter 4 is that it does not succinctly
address the key questions based on the evidence presented. According to the Integrated Review Plan for
NAAQS (November 2011, p. 4-9), the ISA is intended to address the following questions regarding Pb
exposure:
• Can air-related pathways be disentangled from water- and soil-related pathways using available
data (and modeling approaches)?
• How do new studies inform the assessment of exposure to air-related pathways?
The Summary and Conclusions (Section 4.7) ends by offering the following perspectives (with my
paraphrasing):
• Air-lead concentrations are decreasing, but it continues to be challenging to disentangle air-
related pathways from other exposure pathways.
• Extensive monitoring data exists and sampling errors contribute to uncertainty in exposure
assessment.
• Modeling approaches are available, but errors in measurements and assumptions can propagate
through to the model predictions of exposure and blood lead concentrations.
Toxicokinetics information can help us understand the complex relationship between a life history of
exposures, biomarkers of exposure, and predicted changes in biomarkers with changes in air lead
sources. But without sufficient long-term monitoring data, it is difficult to quantify these relationships
for specific populations.
• Air-lead / blood-lead relationships can be established by evaluating specific studies. Variability
in study designs and findings introduces uncertainty in extrapolating results to populations on a
broader scale.
While this is a thoughtful articulation of the uncertainties of both empirical and modeling approaches to
exposure assessment, the document seems to be missing an uncertainty analysis that more directly
informs the science-policy decisions. Given these uncertainties, what specifically can be said regarding
the assessment questions noted in the Integrated Review Plan?
A-16
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Specific Comments and Suggestions
Section 4.1.1 Pathways for Lead Exposure
• p. 4-2. Very good addition of the discussion on the importance of particle size in determining
relative contributions of inhalation vs. ingestion. This paragraph helps to set the stage for Figure 4-1
that follows. Further, it highlights an important uncertainty in available study data - "..no studies in
the literature have presented information on the relative contributions of Pb from different PM size
fractions to blood Pb concentrations"
• pp. 4-5 to 4-6. Good addition of how IEUBK can be used to address questions about pathway
contributions by using empirical data combined with modeling assumptions. Importantly, it
highlights the challenge in estimating the portion of soil/dust ingestion that derives from air Pb, and
how a sensitivity analysis was conducted to establish plausible ranges of pathway-specific
contributions to blood lead from recent air Pb exposures.
Section 4.1.2 Environmental Exposure Assessment Methodologies
• p. 4-7 to 4-8. This section provides a very useful transition between the conceptual model and the
discussion of exposure studies. It provides a balanced discussion of both monitoring and modeling
techniques, and sets the stage for using both to inform the exposure assessment.
• p. 4-8. AALM is introduced here. For consistency with subsequent reference on p. 4-119, state that
AALM is still in development.
Section 4.5.1. Air lead-Blood Led Relationships
• Figure 4-22 is an extremely helpful addition to accompany the slopes presented in Table 4-11. The
descriptive text on p. 4-101 is also well written.
Section 4.6. Biokinetic Models of Lead Exposure-Blood Lead Relationships
Earlier in Section 4.3.6, Figures 4-12 and 4-13 provide graphical summaries of blood-lead and tissue-
lead relationships based on simulations with the ICRP Pb biokinetics model (Leggett). In Section 4.6,
IEUBK is introduced as a tool for establishing relationships between exposure-blood lead relationships.
Consider adding a series of graphics that directly address the question of air-lead / blood-lead
relationships (as discussed above). For example, Figures 1 to 3 below were generated with IEUBK and
illustrate the potential changes in the GM and 95th percentiles (assuming lognormal distributions with
GSD =1.6) if the standard were reduced from 0.15 |ig/m3 to 0.10, 0.05, or 0.015 |ig/m3.
If the standard were reduced to 0.10 |ig/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 |ig/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 ug/dL. Presenting these calculations 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.
A-17
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A-18
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A-19
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Dr. Sean Hays
Comments on Chapter 4
I commend EPA for addressing the concerns I had with the previous version of Chapter 4. They have
improved the transparency in the discussion and documentation of the Pb air-Pb blood correlations.
They also expanded a discussion of the relative contributions of the various Pb sources/pathways
towards PbB. A few specific comments:
• Summary of air-blood lead correlations is a helpful addition. Table 4-11 and Figure 4-22 are very
helpful. It would be helpful for EPA to opine on which correlations will be most applicable for a
risk assessment for air concentrations at and below the current NAAQS. The shape of the
response curves are very divergent at low air concentrations, with the log-log models being the
most divergent. EPA should conduct an independent analysis of the underlying studies and
determine if a common model (linear, log-linear, or log-log model) can be used to describe all
the datasets equally well. I would expect this to be an important discussion in the Exposure and
Risk Assessment report released later this year.
• I appreciated the expanded discussion of the use of the IEUBK model to assess relative
contributions of exposure sources/pathways towards blood lead concentrations for various
percentiles of exposures (pages 4-5 - 4-6) and notations of expanded results available in
Appendix I of the 2007 Pb Risk Assessment. This type of analysis will be critical for the
Exposure and Risk Assessment report released later this year.
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Dr. Philip Hopke
Comments on Chapter 3
This chapter is improved from the prior version, but there remain some problems that need to be
addressed. However, much of the discussion is still largely encyclopedic where individual papers are
summarized rather than providing an integrated science assessment with references to these details in an
appropriate appendix. It made ready things like section 3.5 difficult since there was no integrating train
of thought.
If we are to have a two-tiered sampling system (hi-vol TSP and low vol PM10), then there has to be an
adequate discussion of the comparison of these two and the interrelationships that exist (to the extent
they do) that can be extracted from existing data. There was some of that in the prior version that now
has disappeared. Choi et al. (2011) is already in the ISA and can be used to inform this review of what
we do know of particle size and lead concentrations. It is strange that it is not used since coauthors
include ORD and OAQPS staff members. They need to lay the foundation for the FRM approach here.
There needs to be a greater attention paid to wheel weights. Very recent work in NJ, (Aucott and
Caldarelli, 2012) based on extrapolation of their results to the entire state, suggests that approximately
12 tons per year of lead in the form of wheel weights are deposited on New Jersey roadways, and that
approximately 40 kg of lead enters the environment in the form of small particles formed from the
abrasion and grinding action of traffic on weights deposited on roadways. George Allen has previously
commented on this issue, but the importance of this source has not yet been adequately reflected in the
ISA text.
Sampling/Analysis
One sampling approach that has not been included is passive samplers such as the UNC sampler
(Wagner and Leith, 2001a,b,c). Analysis of these samples is then conducted using computer-controlled
scanning electron microscopy (CCSEM) (Hopke and Casuccio, 1991). The resulting data can be
manipulated to provide quantitative assessment of microscale variability (Hopke, 2008). Given that the
interest in lead concentrations is on a long term average value, the passive sampler provides an
opportunity for dense spatial sampling designs to really explore the intra-urban variability of lead
exposures across a community.
Intra-Urban Spatial Variation in Non-Source Areas
There are two reports of the variability of coarse particles across urban areas (Rochester and Syracuse,
NY) where particle types that include Pb-bearing particles (Lagadu et al., 2011; Kumar et al., 2012).
Thus, it would be easy to carefully examine the variability of coarse Pb-bearing particles across these
urban areas relative to major roadways or other locations of interest and provide more information on
spatial and temporal variability than is available from the limited number of active samplers in the
locations that are reported.
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I still believe the presentation of the Spearman correlation coefficients provides absolutely no useful
information. Others on the panel think Spearman provides information, but given the extensive work I
have done on air quality data analysis methods, I do not agree. The fact that two variables are in the
same rank order does not provide the same level of information about their co-emission as a parametric
correlation like a Pearson correlation. It really tells us nothing about the likelihood that the Pb is related
to the other pollutants since it could be driven entirely by meteorology such as variations in the mixing
heights. It appears that they will be included, but if they are there, there certainly should be the inclusion
of the corresponding Pearson coefficients so we can see the differences. These results certainly should
not be emphasized in the chapter summary (section 3.7.4).
References
Aucott, M. and Caldarelli, A., 2012. Quantity of lead released to the environment in New Jersey in the
form of motor vehicle wheel weights. Water, Air, & Soil Pollution, 223:1743-1752.
Cho, S.-H. , Richmond-Bryant, J., Thornburg, J., Portzer, J., Vanderpool, R., Cavender, K., Rice, J., 2011. A
literature review of concentrations and size distributions of ambient airborne Pb-containing particulate
matter, Atmospheric Environment 45, 5005-5015.
Hopke, P. K., 2008. Quantitative Results from Single-Particle Characterization Data. Journal of
Chemometrics 22, 528-532.
Hopke, P.K., Casuccio, G.S., 1991. Scanning Electron Spectroscopy, ;, in Receptor Modeling for Air
Quality Management, P.K. Hopke, Editor. Elsevier Science: Amsterdam, p. 149-212.
Kumar, P., Raja, S., Hopke, P. K., Casuccio, G., Lersch, T. L., West, R. R., 2012. Characterization and
Heterogeneity of Coarse Particles across an Urban Area. Atmospheric Environment 46, 339-359.
Lagudu, U. R. K., Raja, S., Hopke, P. K., Chalupa, D. C., Utell, M. J., Casuccio, G., Lersch, T. L., West,
R. R., 2011. Heterogeneity of Coarse Particles in an Urban Area. Environmental Science and
Technology 45, 3288-3296.
Wagner, J., Leith, D., 2001a. Passive Aerosol Sampler. I: Principle of Operation. Aerosol Science and
Technology 34, 186-192.
Wagner, J., Leith, D., 2001b. Passive Aerosol Sampler. II: Wind Tunnel Experiments. Aerosol Science
and Technology 34,193-201.
Wagner, J., Leith, D., 2001c. Field Tests of a Passive Aerosol Sampler. Journal of Aerosol Science 32,
33-48
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Dr. Chris Johnson
In my review of the 2nd Draft ISA, I focused my attention on chapters 3 and 7.1 hope to have additional
comments, particularly on Chapters 1 and 2 at the CAS AC Review Panel meeting on April 10-11.
Comments on Chapter 3
Chapter 3 of the 2nd Draft ISA is generally well written, as was the first draft. The deficiencies in the
first draft have largely been addressed. While there are a few issues that panelists are likely to raise, this
is a very impressive summary of the sources, transport and fate of Pb in the environment.
Question: Please comment on the adequacy of... [the] changes to the chapter and recommend any
revisions to improve the discussion of key information?
The discussion of the limitations of current and alternative methods for measurement of total suspended
paniculate Pb is a good addition and strengthens the document. I will leave it to others with more
expertise in atmospheric physics and chemistry to comment on the quality of these amendments.
Similarly, the editing of questionable data appears to have made for a more cohesive discussion of
national trends.
The addition of section (3.5.5) on background Pb concentrations is a good idea. However, I think it
needs some work. The issue of how to define "background" is never fully resolved. In the first
paragraph, the policy relevant background (PRB) is defined as "those concentrations that would occur in
the U.S. in the absence of anthropogenic emissions in continental North America. This definition
contrasts with the more scientific definition of a "natural" background, unaffected by any anthropogenic
sources. Both are difficult to assess, but the natural background is probably easier. In any event, the
section never actually comes to a conclusion on what the background levels might be. The section is
comprised of several paragraphs explaining why it is so hard to estimate PRB levels. Surely it is possible
to bracket a range for background airborne, soil and aquatic Pb concentrations.
The additional work done on section 3.6.1, relating soil Pb to air Pb is very useful.
Question: Is material clearly, succinctly, and accurately provided?
The material presented in Chapter 3 was, I thought, generally accurate, complete and relevant. It is
clearly presented. It is hard to call a 200-page chapter "succinct," but this is a complicated topic, and to a
certain extent, the CASAC demanded the level of detail found in this second draft document.
Question: ...provide guidance that may refine the scientific interpretation and/or improve the
representation of the science.
In the areas of my expertise - soil and water chemistry - Chapter 3 does an excellent job in laying out a
clear conceptual model for the behavior of Pb. I have no recommendations for refinement at this time.
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Comments on Chapter 7
Chapter 7 of the 2nd Draft ISA is also nicely organized and well-written. I focused most my attention on
the areas of terrestrial systems and ecosystems-level issues. The changes made to these sections of
Chapter 7 add some valuable depth to what was already a generally good survey of the literature.
Question: Please comment on ... various revisions and other changes to the chapter and recommend any
revisions to improve the discussion of key information?
The two most notable additions to the terrestrial effects sections of Chapter 7 were: (1) additional
discussion of ecosystem receptors and the Biotic Ligand Model; and (2) increased discussion of
ecosystem services. These are welcome additions, though the application of the receptor concept in
terrestrial systems is difficult to generalize across biomes.
As I commented on the previous draft, the discussion of ecosystem services in the case of terrestrial Pb
is contextual. Terrestrial soils provide a service to aquatic ecosystems by sequestering Pb through
sorption and coprecipitation. At the same time, this very process potentially damages services that the
same systems provide, such as agricultural production. What is in the 2nd Draft ISA is valuable, but
only tells half of an admittedly complicated story.
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Dr. Susan Korrick
Overall Comments and Considerations:
In general, Chapter 5 of this 2nd draft Pb ISA addressed a number of the comments made in review of
the 1st draft. However, some key concerns from the 1st draft are either incompletely or inconsistently
addressed.
Specific areas of improvement include: (1) identifying the state-of-knowledge as of the 2006 AQCD as a
baseline upon which to build; (2) improving the integration of toxicologic and epidemiologic literature
both in terms of the relevance of outcomes (e.g., drawing parallels among homologous or related
measures in animal models and human studies) and exposure levels (e.g., identifying studies of animal
exposures within range of contemporary non-occupationally exposed populations and acknowledging
limitations to dose-response implications of exposure routes that are not representative of human
exposure as, e.g., intraperitoneal injection). Of note, in some cases, establishment of homologies among
animal and human studies was done well but, in some cases, this effort still needs revision; (3) more
explicitly discussing exposure timing and its implications; and (4) acknowledging limitations in
interpreting associations with current blood Pb levels (especially in adults and older children) as such
levels may not represent the exposure levels responsible for observed associations. In addition, some
sections of this revision have been re-organized to improve readability and interpretability - e.g.,
presenting data in some tables ordered by exposure level and cohort.
While assessing the overall quality of the Chapter and its responsiveness to previous substantive
concerns, it is challenging to follow-up on how the revision addresses more specific reviewer comments
from the 1st draft because of the tremendous breadth and detail of material presented (-500+ pages).
Also, where previous reviewer recommendations have not been followed, there appears to be no
mechanism for understanding why this was the case. Some previous recommendations based on factual
inaccuracies were not corrected (e.g., see summary of Kim et al. 2009b [p. 5-62 to 63, figure 5-3] where
blood Mn units are reported in ug/dL but should be ug/L. As currently reported, these Mn levels are
substantially higher than Kim et al. and higher than reasonable expectation and thus bring into question
the study's interpretation). Lastly, in a few sections, it appears there has been editing such that some text
has lost logical progression, material is out of order, phrases appear to be cut short, or inappropriate
terminology is used. In the extreme, sentences and content appear to have been re-arranged in such a
way that the text no longer makes sense (e.g., see the discussion of Pb and ALS on page 5-164, lines 20-
36).
Chapter 5 Charge Questions:
1. Please comment on the extent to which the revised discussion of the evidence and the causal
determinations accurately reflect the weight of evidence for endpoints within a major outcome category
and the strengths and limitations of studies (e.g., study design, control for potential confounding,
statistical analysis) that comprise the evidence base.
This revised (2nd) draft does a better job than the 1st draft reflecting the weight of evidence in causal
determinations but this effort still needs more work and the quality of the revision re. this issue varies
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widely by health outcome. For most sections of the Chapter, there is a synthesis of findings that are
consistent across the literature on a topic but it's often done without attention to variable quality among
studies. Instead, the "weight of evidence" analysis often seems to be based on the number of studies on a
topic or the predominant fmding(s) among available studies but does not consistently include design
critiques of those studies. Indeed, in much of the Chapter not only are analyses of strengths and
limitations absent but basic information such as study sample size is not mentioned in describing study
findings. In much of the Chapter, there are not analyses of which studies contribute the most robust
evidence and which do not with conclusions based on the more robust findings. Some new studies have
been added and weak ones (e.g., case reports) removed which are appropriate updates. However, in
other cases, null studies or studies that do not support the Chapter's conclusions are either not reviewed
or only reviewed cursorily. Although there is some discussion of strengths and limitations of studies for
some studies and some outcomes, in other instances (e.g. the description of Pb's associations with
puberty) there is essentially no discussion of study design issues despite the clear potential for
uncontrolled confounding, selection bias, or cross-sectional study design to impact the strength of
findings in many, if not all, studies reviewed for this outcome. Similarly, in the review of child
neurodevelopmental literature there is not much discussion of how study design limitations might
impact the weight of evidence (e.g., there is limited, if any, discussion of the relative value of cross-
sectional vs. longitudinal analyses or self-reported diagnosis in studies of ADHD or attention-related
measures) whereas the review of adult neurodegenerative disease more consistently acknowledges study
design issues (e.g., potential reverse causality in cross sectional or case-control studies).
2. Please comment on the adequacy with which evidence has been integrated between toxicological and
epidemiological studies, in particular: the increased emphasis on toxicological findings most relevant to
Pb-associated effects in humans; the discussion of results from homologous or parallel tests (e.g.,
response inhibition, blood pressure, renal function); and discussion of evidence describing modes of
action for Pb-associated health effects, (a) Has coherence of findings among related endpoints been
sufficiently described? (b) Please comment on the effectiveness of the integration of scientific evidence
both within sections for specific endpoints and summary sections.
In general, this revision integrates toxicology and human literature more effectively than the 1st draft by
having a clearer focus on homologous/parallel outcomes between the animal and epidemiologic
literature. E.g., in the discussion of nervous system effects, animal assessments are explicitly described
in terms of which human assessments they parallel (there's an example of this on p. 5-99 in the
discussion of cognitive flexibility). Similarly, mechanistic toxicity/mode of action studies are discussed
in terms of relevant human effects. Also, there is more discussion and explicit description of exposure
levels in the toxicology literature reviewed (e.g., inclusion of blood Pb and, in some cases, even bone Pb
levels in animals) so relevance to human exposures can be more clearly delineated. As per the above
general comments, coherence of findings across human and toxicologic literature has generally been
better specified than in the first draft. But, in a few instances, this still needs work. For some outcomes, a
number of the animal studies reviewed had exposures well in excess of those typical of current human
populations; the applicability of these findings to humans (e.g., to provide mechanistic insight vs. dose-
response information) was not consistently addressed. In some areas, homologies across animal and
human studies may have been identified incorrectly. In other instances, integration is incomplete. E.g.,
for some immune effects, the most robust associations are based on the toxicology literature, not the
human literature. This distinction is not clear in the text. Pb-associated changes in cytokines is listed as
an association supported by the literature (p. 5-389) whereas elsewhere (p. 5-386), the text states "... it
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is difficult to draw conclusions about.. .effects of Pb on cytokine[s].. .in human population^]. This is an
example of apparent inconsistencies across the two literature sources that need to be more clearly
acknowledged and their implications discussed. There are a number of design limitations in the
epidemiologic studies reviewed for immune system effects and these might account, in some part, for
lack of concordance with toxicologic data but these limitations are not reviewed. Apropos of this issue,
some discussion of whether or not animal and toxicology literatures are sufficient to support causality in
the absence of consistent findings in the human literature is needed
3. Please comment on the extent to which conclusions regarding the blood and bone Pb levels with
which various health effects are associated in epidemiologic studies accurately reflect the weight of
evidence given the study designs and statistical methods employed and populations examined (e.g.,
school-aged children, adolescents, adults without occupational exposure, adults with occupational
exposure), (a) Are inferences regarding the specific Pb exposure scenario (e.g., level, timing, frequency,
and duration) that contributed to the observed associations consistent with the evidence?
Generally, this revised draft is careful to distinguish between settings (based on study design, study
population, etc.) in which a given Pb exposure level (in blood or bone) is likely associated with a
particular health outcome and settings in which a given Pb exposure level may not directly account for
observed health effects because of the possible contribution of previously elevated or longer term
exposures. Likewise, there was clear acknowledgement that blood Pb in adults includes information
about past exposure (via bone Pb mobilization, e.g.). However, apropos of charge item #2 above, there
were some instances of an apparent disconnect between relevant exposures in human as compared to
animal data. E.g., for neurodevelopmental toxicities, there was a recurrent theme of prenatal/early life
exposures being key to Pb neurotoxicities in developing animals whereas a number of recent human
studies suggest that concurrent (later childhood) Pb exposure may be the most toxic. This seeming
discrepancy and the possible risk represented by concurrent childhood blood Pb (especially in the
context of early life exposure) was not addressed clearly.
Specific Comments:
NERVOUS SYSTEM EFFECTS
Page 5-79: How does "past exposure via maternal bone Pb" impact cord blood? Is this comment
assuming there were higher exposures in earlier pregnancy prior to delivery absent some exogenous
exposure source? Are there data to support this? E.g., calcium demands in pregnancy, especially early in
pregnancy, are relatively small (e.g., compared to lactation) so differential effects on Pb mobilization
across pregnancy seem unlikely.
Page 5-53: Removed case study from this section which is good but same concerns as with 1st draft.
MRI studies cited include children (ages 9-13), some cross-sectional analyses, so description of "young
adults with prior childhood Pb exposures" (Cecil et al. 2005) does not seem accurate.
Figures 5-2 & 5-3: BPb levels and effect estimates look different for some studies compared with 1st
draft, not clear what changed or why (e.g., used concurrent vs. lifetime exposure effect estimates for
Canfield et al., 2003a?)
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Page 5-63, figure 5-3: As with 1st draft, Mn units should be mcg/L not mcg/dL. This matters since,
otherwise, it looks as if Mn exposures were enormous in the population and interpretation of relative Pb
contribution is more complicated.
Page 5-64: Try to consistently provide Pb exposure levels, not done for some studies (Kordas et al,
2011; Roy et al., 2011)
Pages 5-66: Apparent and repeated emphasis on HOME as a key confounder throughout this section
seems misdirected (e.g., see page 5-102). Clearly HOME is important but a broader and more balanced
discussion of confounding overall would be more useful. HOME is just one component of a large
number of key potential confounders for child nervous system effects.
Page 5-68: Moffitt et al., 2001 should be Jedrychowski et al. 2009a; line 7 insert larger decrease in MDI
Page 5-69: It is unclear what text is saying about interaction between Pb and folate in determination of
MDI effects. Does folate lower blood Pb levels or decreased target tissue sensitivity to Pb's toxicity at
the same level of exposure? Importance of distinction between exposure modification and effect
modification seems blurred.
Page 5-78: Five Korean studies (should be citiesl) with null findings but didn't give reference or BPb
levels... .need reference Cho et al., 2010.
Page 5-100: No chelation discussion for humans? Is succimer trial in moderately exposed children too
old (main result NEJM 2001)?
Page 5-101: Weight of evidence "based on frequency of examination", what does this mean? In this
section and elsewhere, some discussion integrating what's known about critical exposure periods in
epidemiologic literature and what current thinking is re. the meaning of concurrent blood Pb and its
association with cognitive function in children would be helpful. E.g., is there some 'acute' blood Pb
effect postnatally? Is high concurrent blood Pb a proxy for identifying children with consistent high Pb
exposures over time? Or something else?
Page 5-117: PbxGene interaction commentary for adult cognitive function: "Results were NOT uniform
across... cognitive tests..."
Page 5-119/120: Recent studies looked at concurrent BPb - distinction between cross-sectional vs.
prospective designs not always clear. Cannot always infer that concurrent BPb is most potent if lack
information about earlier life BPb levels and their relationship with behavior outcomes. Text is unclear
on this point although this does not mitigate importance of concurrent exposure, always must consider
the possibility of reverse causation.
Page 5-120, lines 11 & 15: Should be increases in inattention, not attention.. .or "increasedinattention"
Table 5-10: Several NHANES analyses for ADHD diagnosis - ADHD diagnosis in NHANES from
parental report (+/- medication use). Limitations of this outcome measure should be mentioned. E.g.,
outcome reporting bias, outcome measurement error, and possible confounding by regional differences
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in diagnosis (there are differences in medical practice by regions in the U.S.) and regional differences in
Pb exposure risk.
Page 5-132: Do not understand logic of statements re. confounding for ADHD analyses. Specifically, for
parental ADHD to be a confounder of Pb-ADHD behavior, parental Pb does not have to be highly
associated with parental ADHD (which is in current text). Given the strong familial component of
ADHD risk, parental ADHD would only have to be correlated with child Pb to be a confounder.
Page 5-142: Opler et al. (2004, 2008) assessing schizophrenia using 5-ALA level as a proxy for BPb
(>15) is an important outcome but limitations of exposure assessment and how to integrate these studies
into the context of this document need to be clear.
Page 5-155: This page is one example of an issue that comes up elsewhere: units for bone Pb measures
in animals are incorrect. This impacts the interpretability of the exposure information. Units are reported
incorrectly as ug/dL whereas they should be ug/gm bone mineral.
Page 5-160: Pb effects on retina "are modified by dose of Pb" seems an odd way to describe the
literature. Was this meant to indicate that a number of the Pb-associated changes in vision in the
toxicology literature do not follow a monotonic (or even threshold) dose-response? If so, say so, and
then discuss what these atypical dose-response relationships might mean, if they are biologically
plausible, and, if not, if that undermines the robustness of any observed associations.
Page 5-165: The motor section, last paragraph looks as if it's been cut and pasted so it no longer makes
sense (plus punctuation problems). "The collective body of evidence demonstrates that within the same
population of children..." doesn't make sense. Where are the "observations that Pb exposure affects
development and function of ... [motor]... systems"?
Page 5-162: The description of findings re. seizures in animal models doesn't explain the basic
experimental study design/premise before jumping into results so the text is hard to follow- this happens
several times throughout descriptions of the animal literature for nervous system effects.
Page 5-164: For ALS, discussion of potential for differential survival time to bias Pb association is very
confusing. It is impossible to follow the argument, I suspect something was edited in a way that
muddled content.
Page 5-167: line 12 - replace PD with ET.
Page 5-168: The discussion of the toxicology literature's evidence of a possible role of of microglial
cells in neuro-inflammatory processes is confusing, talks about two cell types without specifying which
two cell types are intended. Was text cut and pasted into the wrong place?
Page 5-169: Toxicologic evidence of Pb-induced cell apoptosis is largely observed at very high
exposures; this issue is not acknowledged and its potential relevance, or lack of, to current population
exposures is not mentioned but should be.
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Page 5-170: Incongruities between epidemiology and animal studies of Pb and AD may not just be
because of wrong exposure time (i.e., developmental exposure matters most and epidemiology largely
relies on adult exposure measures). Even recent animal studies are largely conducted at doses well in
excess of expectation for current non-occupationally exposed aging adults. The potential role of
exposure level on incongruities is not discussed but should be. Are authors assuming a non-threshold
effect? If so this should be discussed and explained. This is an example where integration between
toxicology and epidemiology literature could be improved.
Page 5-191 (lines 20-21): comes up elsewhere in text, language is confusing re. meaning of "maternal
Pb exposures"; here presumably mean maternal pregnancy exposures/Pb levels, otherwise it is not clear
how maternal Pb exposures postnatally are contributory to offspring lower cognitive function.
Page 5-191 (lines 27-28): expected correlation between prenatal and postnatal blood Pb likely depends
on how far from birth measures are made - e.g., 3-month vs. 15-month old infant? See page 5-196 for an
apparently contradictory text describing example of weak correlation between prenatal and subsequent
blood Pb levels.
Page 5-212: Causal pathway usually refers to inter-related health outcomes, not over controlling for
exposure proxies.
Page 5-219: Clarify what's cross sectional and what's prospective for ADHD studies.
Page 5-221: For line 18 should "temporality" be "directionality"?
Page 5-224, lines 23-27: Cannot say weight of evidence supports concurrent exposure as most
deleterious and then in the next sentence indicate that considerable uncertainty exists on critical
exposure period. Latter seems the better conclusion.
CARDIOVASCULAR EFFECTS
Page 5-236: In description of findings in occupational cohort in Korea it may be worth noting that the
population is young and potential for bone Pb-BP (especially HTN) findings in older populations to, at
least in some part, reflect confounding by age (since bone Pb is generally strongly correlated with age) is
not discussed.
Page 5-244: acknowledge that injection Pb administered in animals may not be comparable to human
exposures
Page 5-265: It is true that there are few studies of Pb and CVD effects other than BP or HTN (e.g.,
HRV, PAD, IHD) but it is also the case that much of data is from only 2 population sources (NAS and
NHANES; see Tabel 5-19) which is another useful caveat.
Page 5-282, lines 36-37: Findings across studies are not as consistent as this sentence implies: e.g., Pb-
associated stroke mortality not elevated in SOF (Study of Osteoporotic Fractures)
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Table 5-21: Neuberger et al., Cocco et al. Not discussed in the text? Used SMRs and found protective
SMRs in latter study, a follow up of an occupational cohort of Pb smelter workers- some discussion
would be useful. Is this an appropriate study to include, i.e., how high were exposures and are design
issues including the potential for a healthy worker effect important limitations?
RENAL EFFECTS
Page 5-308: Issue of reverse causality is the same as before: especially in a cross-sectional analysis,
seeing a stable Pb-serum Cr relationship across the normal range of serum Cr does not rule out reverse
causalitiy as there can be substantial decrements in renal function with 'normal' serum Cr... .Also (see
Table 5-25) NAS longitudinal studies adjusted for baseline serum Cr which can bias results assessing
change in Cr.
General issue (but evident in renal section): Where susceptible subgroup analyses are done (e.g., by
genes like HFE or by health status/co-morbidities), although the interaction may be biologically
plausible, there's always the possibility that subgroup findings are by chance especially if the subgroup
is small. E.g., in Tsaih et al. the Pb-Cr findings in the NAS population are strongest in diabetics (n~26?).
It's important to consider this limitation in interpreting findings.
Page 5-327-28: Discussion of why reverse causality is unlikely to explain Pb-renal function associations
is a useful addition but it lacks balance; that is, it would be an even more useful addition to the chapter if
it acknowledged that reverse causality is still possible in epidemiologic studies of Pb and renal function.
Page 5-339 (section 5.5.5.1): Re. renal effects and the impact of 'treatment' with antioxidants is
presented in an awkward context - is this intended as a summary of 'treatment' interventions? Or as a
commentary on Pb MO A?
IMMUNE SYSTEM EFFECTS
Page 5-366: Cross-sectional studies in adults are not just limited because of uncertainty re. relevant Pb
exposure dose and time period. There are also important limitations due to potential confounding and
challenges with potential reverse causation. E.g., it's speculative but theoretically possible that adults
with inflammation may absorb Pb more efficiently.
Page 5-367: IgE and Pb: only at the end of this section is there acknowledgement of limitations in the
literature due to lack of control for confounding (especially important in childhood studies is failure to
account for potential confounding by SES or allergen exposure, e.g.). It would be useful to discuss this
issue more systematically during the literature review; otherwise, the relative value of different studies is
hard to judge. Also, where studies are cross-sectional (which is a common limitation of the immune
studies reviewed), this design limitation needs to be mentioned. (See above comment re. attendant
caveats with cross sectional designs including the possibility of reverse causality. E.g., as above, one
could speculate that children in a pro-inflammatory state might absorb Pb more efficiently such that
immune changes lead to higher blood Pb rather than the reverse).
Page 5-368: Here and elsewhere in the Chapter "lack of statistical analysis" is used, this phrase needs to
be defined.
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Page 5-372: This issue comes up in several places in this Chapter, that is, there is a caveat given that
higher past Pb exposure may have influenced maternal pregnancy Pb levels and resultant fetal
exposures. When looking at newborn outcomes, it's not clear what this means. Maternal pregnancy Pb
levels are what the infant experiences, not maternal past Pb exposures. Is the issue that, somehow, past
maternal Pb exposures influence variability in Pb levels during pregnancy? Whatever the issue, it needs
a clearer explanation.
Page 5-378: The title for section 5.6.5 - "Mode of Action for Lead Immune Effects" is confusing as
inflammation itself an "immune effect". Perhaps there needs to be a clearer distinction between Pb
effects believed to be mediated through immune toxicity (e.g., asthma) versus direct effects of Pb on
measures of immune function?
Page 5-383-84: In describing the relation of Pb with cytokines, studies which are concordant with a
particular conclusion (e.g., Pb-associated depressed Thl, enhanced Th2 response) are emphasized with
inconsistent findings cursorily described (e.g., "other studies found variable Pb-induced changes in IL-
2"). It is impossible to discern whether this was an oversight, a biased presentation of the available
literature, or an attempt to prioritize findings based on the quality of the studies reviewed since
quality/study design issues are not discussed.
Page 5-384: The need to make analysis of the literature as independent and balanced as possible is
illustrated here where authors conclude that differences in cytokine levels among healthy and allergic
children living near an oil refinery may have been due to differences in blood Pb levels. Presumably
there are other issues that could explain the observed associations in this study given limitations in its
design; perhaps most important of these is potential confounding by other exposures associated with
residence near a refinery which is not acknowledged in this discussion.
Page 5-386 (lines 26-27) What's "limited" about the investigation of Pb and cytokines? Number and/or
quality of epidemiologic studies? Or is it that findings are not consistent? This broad statement needs
better definition.
Page 5-389 (-line 18): Listing Pb-associated changes in cytokine production among associations
supported by the literature seems to contradict conclusion on p. 5-386, lines 27-28 that "it is difficult to
draw conclusions about .. .effects of Pb on cytokine(s).. .in human population(s)." In addition, a number
of epidemiologic studies reviewed in this section lacked adjustment for important potential confounders
and were often cross sectional, a design that limits inferences that can be made re. the direction of the
association. These are examples of substantial limitations in the human literature but these limitations
are not reflected in the summary. Similarly, some discussion of whether or not animal and toxicology
literatures are sufficient to support causality in the absence of consistent human literature is needed.
Page 5-391, lines 3-6: This section is an example of an important limitation that comes up throughout
this Chapter. That is, cross sectional studies are acknowledged for having "uncertainty regarding the
magnitude, timing, frequency, and duration of Pb exposures that contributed to the observed
associations" but rarely acknowledged as being limited regarding the direction of the association or,
depending on the design (e.g., case-control studies) being limited by potential sources of selection bias
or confounding. As above, in the case of immune function measures, it's theoretically possible that
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individuals in a pro-inflammatory state absorb Pb more efficiently. Thus immune changes could induce
higher blood Pb rather than the reverse; it is difficult, if not impossible, to distinguish these two possible
directions of effect in most cross sectional studies.
Page 5-392, lines 28+: Lack of confounding in one study design does not mean that failure to adjust for
potentially important (identified a priori) confounders in another study design is ok. Confounding
patterns, by definition, can be study specific (depending on study design and population).
HEME SYNTHESIS AND RBC FUNCTION
Page 5-398: It is important to acknowledge potential confounding by other occupational exposures in
occupational cohort studies (here re. heme synthesis/RBC toxicities) but similar attention to this issue is
not consistent in this Chapter (e.g., not done in immune function section).
Page 5-401, lines 14-16: Is the issue "equivocal findings" or inconsistent findings? It seems most studies
have unequivocal findings, they're just not all in the hypothesized direction. Differences among studies
of children could also have to do with residual confounding or other design limitations.
Page 5-411, lines 27-33: In vitro studies described as having "similar effects on indices of oxidative
stress" are presumably being compared to Conterato et al.? However, the latter observed some Pb
associations in the opposite direction (e.g., associations with SOD) of those described for in vitro
studies. Given the complex feedback among some of these measures, this needs clarification.
REPRODUCTIVE AND DEVELOPMENTAL EFFECTS
Page 5-431, -line 103: For epidemiologic studies of puberty reviewed here potential confounds of
associations are not discussed - e.g., nutritional confounding could be very important to these
associations especially in populations where malnutrition may be common (e.g., Tomoum et al.).
Page 5-431, lines 8+: Better clarity on the direction of described associations is needed. Presumably,
Naicker et al.'s positive association of blood Pb and age at menarche, etc. was a positive association
with delayed age at menarche. The current text implies the opposite association.
Page 5-437 (table 5-34): It is notable that in this table and elsewhere in section 5.8, information about
confounding adjustment and study sample size is rarely, if ever, provided. This should be included as
part of the balanced review of the strengths and limitations of the literature. E.g., statistically significant
findings from a small study are more likely due to chance than findings in a large population. Similarly,
wide confidence limits may reflect lack of power from a small n where moderate to large effect sizes are
observed.
Page 5-450: The same comment applies to studies in men and women - use of study populations being
treated for infertility is not just an issue of generalizeability of findings. It is also potentially the case that
bias (e.g., participation bias) and related design limitations could impact robustness of findings.
Page 5-454, lines 3-4: "delayed pubertal development" should be "delayed pubertal onset"
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Page 5-454, lines 4-5: Ages appear to be reversed.
Page 5-466: As is true of most, if not all, of this section, review of literature on Pb and pre-term birth
was done without any critiques so the conclusion that no patterns of findings were apparent seems
premature. E.g., it is possible that, among the studies reviewed, those with better design and higher Pb
exposures have more consistent associations with preterm birth. However, it is not possible to ascertain
this kind of pattern without more systematic assessment of each study's relevant strengths and
weaknesses as well as assessment of the potential for there to be a threshold for a Pb effect.
Page 5-472, linesl 1-12: "..the strongest associations observed at the lowest blood Pb level..." is a
confusing statement especially given the data presentation in Table 5-40. Is this statement meant to refer
to a supralinear dose-response? If so, it would be clearer if describe that way.
Page 5-476, Table 5-41: Afieche et al., effect estimates need a '-' sign.
Page 5-484: What does it mean to have decreased hepatic DNA?
Page 5-486: Not clear why authors conclude Pb-delayed puberty associations are stronger in girls than
boys. There are fewer studies among boys but their findings are relatively homogeneous and, although
not strictly comparable, effect estimates seem roughly comparable to those observed in girls.
EFFECTS ON OTHER ORGAN SYSTEMS
Page 5-489, lines 18-19: Previously described associations of increases in liver enzymes with
occupational Pb exposure but not "specifically with Pb exposures" does not make sense. Is this referring
to studies for which occupation rather than a biomarker of Pb exposure was used to estimate exposure?
If this is the case, as is described later in this section, the role of confounding by other occupational
exposures may be particularly relevant in interpreting such literature.
Page 5-493, lines 31-33: Is apparent differential effect on CAT activity (increase with Pb, decrease with
undernourishment) correct? Section as written implies the effects of Pb and malnutrition are similar;
additional explanation would be useful.
Page 5-506, lines 30-34: It is unclear what the meaning of this finding is vis-a-vis Pb's association with
periodontal disease as it is not based on assessing the relation of a biomarker or other indicator of Pb
exposure with the outcome. The value/context of including this study in the review needs to be made
clear.
Page 5-510 (and 5-503): As with studies of Pb and bone/joint turnover markers, NHANES analyses of
blood Pb and osteoporosis are also limited by cross sectional design so the direction of the association is
uncertain.
CANCER
Table 5-42: Need to provide explanation for effect estimates, e.g., SMR's, OR's, HR's or whatever
measure was used for each study. Only 2 studies in the entire table seem to have this information. Also,
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something is wrong with Lundstrom et al., units for median cumulative blood Pb index - |imol/Pb
cannot be correct.
Page 5-521, lines 1-2: As in above comment re. Page 5-437, study summaries for cancer outcomes
generally lack information about sample size. This should be part of the critical review.
Page 5-526: This is an example of an issue that comes up throughout the Chapter - acknowledgement of
one of the key limitations of studies in occupational cohorts, i.e. confounding by other occupational
exposures, is often not discussed. This should be part of the critical review
Page 5-530, lines 19-23: As was an issue mentioned in the review of the 1st draft, for studies of
chromosomal aberrations, it seems the most robustly designed and most consistent associations are with
lead chromate (not acetate or nitrate) and yet interpretation of such studies is limited because of
chromate's potential role in observed associations. This is mentioned in the section but should be
repeated in the summary paragraph as it is an important limitation of this literature. Limitations of using
Pb chromate for cancer-related studies are not consistently acknowledged throughout this cancer section
of the Chapter. However, it is appropriately discussed in some sections (e.g., page 5-535, lines 5-6 and
page 5-537).
Page 5-538: As per previous comment re. page 5-389, some discussion of how to characterize causality
when most evidence comes from the toxicology, not the human, literature is a challenge.
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Dr. Michael Kosnett
The following are comments on the 2n external draft Integrated Science Assessment for Lead (February
2012) prepared following the CASAC Lead Review Panel meeting of April 10 -11, 2012. These
comments focus on Chapter 2, the Integrative Summary, and Chapter 5, Health Effects.
Key elements of the CASAC Lead Review Panel report on the 1st External Review Draft of the
Integrated Science Assessment for Lead included a recommendation that the ISA improve its approach
to causation assessment for the health effects of lead. Specifically, the CASAC report (December, 2011)
recommended, "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" and "This
weight-of-the-evidence assessment should be applied to specific health endpoints, in addition to broadly
assessing impacts on whole organ systems." I respectfully feel that the 2nd draft ISA has failed to
satisfactorily address these major recommendations.
The "causation determinations" summarized in Chapter 2 continue to address broad organ system
findings, without specifically focusing on key health endpoints within those endpoints. For example, in
Section 2.6.2 (Cardiovascular Effects) page 2-18, the narrative states, "Collectively, the evidence
integrated across epidemiologic and toxicological studies as well as across the spectrum of other
cardiovascular endpoints examined is sufficient to conclude that there is a causal relationship between
Pb exposures and cardiovascular health effects." But the summary section on Cardiovascular Effects
does not specifically indicate whether the endpoints subsumed under "Cardiovascular Effects" with
respect to causality includes hypertension in adults, hypertension in children, cardiovascular mortality,
or cerebrovascular mortality.l Nor, for virtually all the organ systems, have these causation
determinations identified the magnitude of lead exposure that conclusively causes specific health effects.
For a risk characterization document such as the lead AQCD to have optimal utility to risk managers and
public health stakeholders, identification of specific health endpoints and the exposure (or dose)
associated with causation are necessary. This is well illustrated by the narratives supporting the
derivation of Reference Doses in EPA's ISIS database, which identify specific doses (e.g. LOAELs)
associated with specific health effects.2
In addition to the lack of focus on specific health endpoints, the causation assessments included in the
2nd ISA fail to systematically address the causation criteria set forth in Table II of the preamble (p Ivii).
1 In Summary Table 2-10, specific cardiovascular endpoints such as blood pressure, hypertension, and cardiovascular
mortality are addressed, but the conclusion is limited to stating that the evidence supports "an association" between lead and
these endpoints. As noted further in these comments, this terminology is ambiguous with respect to causal determination,
which requires more than a summary finding of 'association".
2 The summary discussion of cardiovascular endpoints in section 2.6.2, and the corresponding section in Chapter 5, note that
although some studies have found a significant association between blood lead < 5 ug/dL and cardiovascular endpoints in
adults, these adult cohorts experienced much higher blood lead concentrations earlier in life. It is further noted that bone lead
has been a strong predictor of cardiovascular endpoints in some studies in which current blood lead was not (e.g. the
Normative Aging Study cohort reported by Hu et al, 1996). While the ISA is correct to note current uncertainty with respect
to the precise cumulative lead dose associated with a given risk of hypertension, it would be reasonable to conclude that
longterm (e.g. decades) of lead exposure resulting in a blood lead across the range of 10 to 25 ug/dL likely bears a causal
relationship with an increased risk of hypertension in susceptible populations (cf Kosnett M et al, Recommendations for
Medical Management of Adult Lead Exposure, Environ Health Persp 115:463-471; 2007).
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As stated in that table, a conclusion that a causal relationship exists between lead exposure and a human
health effect requires that:
".. .the pollutant has been shown to result in health effects in studies in which chance, bias, and
confounding could be ruled out with reasonable confidence. For example: a) controlled human
exposure studies that demonstrate consistent effects; or b) observational studies that cannot be
explained by plausible alternatives or are supported by other lines of evidence (e.g., animal
studies or mode of action information). Evidence includes replicated and consistent high-quality
studies by multiple investigators."
The summary presentations in Chapter 2, and apparently most of those in Chapter 5, generally fail to
present a critical analysis, in narrative terms, that systematically addresses the adequacy with which the
human epidemiological studies have ruled out the influence of bias and confounding, and the extent to
which multiple high quality studies have reached consistent and replicate findings.
For example, with respect to "neurobehavioral effects" in children, Chapter 2 concludes, in Table 2-10:
Recent studies in children continue to support associations of Pb exposure with a range of
effects, largely inattention and hyperactivity, and also misconduct delinquent behavior. In new
studies, the weight of evidence supports associations with concurrent blood Pb in populations
with lower mean blood Pb levels (2-5 ug/dL) than those in previous studies. New evidence
indicates associations of concurrent blood Pb levels with ADHD diagnosis and contributing
diagnostic indices in populations with mean blood Pb levels 2-4 ug/dL. [emphasis added]
The terminology in the foregoing paragraph, which is repeated frequently in other parts of Chapter 2 and
Chapter 5, states that the "weight of evidence supports associations". This phraseology is ambiguous,
and fails to address the requisite elements of a "weight of the evidence" causation determination. A
finding of an "association", however strong, between lead exposure and a health endpoint in an
epidemiological study is by itself inadequate to establish causation, particularly if bias and confounding
cannot be ruled out with reasonable confidence. As was stated in the CAS AC report of December 2011:
"With respect to other [i.e. noncognitive CNS] 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."
The discussion of neurobehavioral endpoints in Chapter 2 and Chapter 5 in the 2n draft ISA continue to
lack a sufficient critical discussion of such limitations. Contrary to the recommendations of the CAS AC
report, the tables that describe key studies addressing specific health endpoints have not been expanded
to include a column that specifically addresses key limitations of each study. With respect to
neurobehavioral endpoints in children, the narrative sections of Chapter 2 fail to note that virtually all of
the studies of low level lead exposure have inadequately adjusted for parental psychopathology. This is a
major limitation in studies of inattention in general and ADHD in particular, where epidemiological
findings suggest that heredity accounts for 50 to 70 percent of the incidence. Accordingly, parental
psychopathology, particularly parental ADHD or subclinical deficits in attention, merit major
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consideration as potential confounders. In contrast to most studies of the effect of lead on cognitive
function in children, in which the influence of maternal intelligence is commonly adjusted for by
including maternal IQ as a covariate in regression models, the studies of low level lead exposure and
child behavior have been unable to include an acceptable measure of maternal or paternal inattentiveness
or ADHD.3 EPA's causation criterion requiring that confounding be ruled out with reasonable
confidence has therefore not been satisfied.
EPA's causation criterion pertaining to "consistency" and "replication" by multiple high quality studies
is likewise inadequately addressed in the narrative with respect to low-level lead exposure and
behavioral endpoints. For example, neither chapter 2 nor the section 5.3.3 note that two major
prospective studies of low lead level and child behavioral outcomes did not observe a significant
association between lead and measures of attention (Wasserman et al, 2001; Canfield et al, 2003). In the
prospective cohort study of Yugoslavian children in Pristina with BLL < 10 |ig/dL studied by
Wasserman et al (2001), blood lead was not significantly associated with either the attention subscale or
the aggregate "externalizing" behavior score. In the prospective Rochester cohort of 4 to 5 year old
children with mean BLL of 6.5 |ig/dL studied by Canfield et al (2003), there were no significant
associations in multivariable models between blood lead and performance on tasks of attention (see
Table 2 in Canfield et al). In contrast, different studies conducted in these same cohorts have reported
that low-level lead exposure was associated with decrements in cognitive function. Overall, the 2n draft
ISA has failed to present a critical review that distinguishes the well-validated causal relationship
between low level lead exposure and cognitive function with the comparatively smaller and limited body
of epidemiological evidence that has examined the relationship between lead and behavioral outcomes.
As noted by Bellinger et al (1994), compared to models of cognition, models of behavioral outcome in
children explain comparatively little of the overall variance (i.e. they have low R2), raising the likelihood
that even statistically significant associations may be relatively more vulnerable to residual
confounding.4 5
3 The narrative in Section 5.3.3.1 comments that several of the studies of child behavior listed inFigure 5-14 and Table 5-9
have controlled for potential confounders such as SES and maternal IQ, while inexplicably failing to note the lack of
adequate control for parental psychopathology. As demonstrated by Chen et al (2006), maternal IQ is not a significant
covariate for child behavior. On page 5-127, the ISA narrative states, "While none of the studies examined the potential for
confounding by HOME score, they did evaluate confounding by several other demographic and SES- related variables, as
well as parental history of psychopathology, including ADHD (Cho et al., 2010; Nicolescu et al., 2010)." However, a careful
assessment of these studies would raise substantial doubt as to the adequacy with which such potential confounding was in
fact addressed. In the Korean study by Cho et al (2010), which in fact failed to report a consistent positive association
between lead and indices of ADHD or attention in most of the measures that were examined, the adjustment for parental
psychology consisted of having the parents of 590 children note in a questionnaire whether they ever had ADHD or any other
neuropsychiatric disorder. Implausibly, less than 5 percent responded affirmatively. Moreover, the variable was not included
the multivariable models. In the Romanian study by Nicolescu, parents were asked by telephone interview whether either had
been diagnosed with "psychological/psychiatric problems." However, the extent of positive response was not reported, and
even though "family psychopathology" was the factor with the strongest bivariate correlation with child ADHD rating by the
parents, it was not included in the multivariable models of child attention or ADHD (see caption to Figure 2 in Nicolescu et
al, 2010). The statement on page 5-132 of the 2nd draft ISA that refers to Nicolescu et al by stating, "Higher blood Pb level
was associated with higher ADHD ratings in children in models with blood Pb level alone and in models that adjusted for
parental psychopathology plus other covariates" is puzzling and should be corrected, because it appears to be contradicted by
the details of the model reported inFigure 2 of that report. The narrative on page 5-132 also erroneously states, "It should be
noted that for parental ADHD to be a confounder, parental Pb levels would have to be highly associated with ADHD in the
parent and with blood Pb level in the child."
4 The summary narrative in Chapter 2 and the expanded narrative in Chapter 5 fail to note other major limitations of many of
the studies of the relationship between low-level lead exposure and behavioral problems in children. In contrast to the
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In accordance with recommendations in the first CAS AC report, sections of the 2n draft SA in chapter 2
and chapter 5 pertaining to adverse effects of lead in adults appropriately note the effects cannot
confidently be imputed to contemporary blood lead concentrations (i.e. < 10 |ig/dL) because the
populations in which they have been observed sustained higher blood lead concentrations in the past (i.e.
general population BLLs of 10 to 25 |ig/dL in the decades prior to 1980). Nevertheless for the endpoints
of blood pressure, hypertension, and cardiovascular mortality, secular trends in blood lead and bone lead
data would allow EPA to reasonably conclude that decades of blood lead concentration in the range of
10 to 25 |ig/dL can cause elevated blood pressure and increased cardiovascular mortality in susceptible
populations. The epidemiological data support this finding by virtue of consistent findings in multiple
high quality studies that have adequately controlled for bias and confounding. In addition, toxicological
and clinical data offer evidence of plausible biochemical mechanisms at this level of exposure.
The situation with respect to low level lead exposure and renal effects is quite different, and for this
endpoint the 2n draft ISA continues to lack a balanced and critical analysis of the strengths and
limitations of the data. In its consensus response to charge questions, the first CAS AC report (December
2011) noted with respect to the 1st draft ISA:
"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 |ig/dL... .Failure to temper
conclusions with study design limitations was particularly problematic for the review of the renal
effects of Pb."
These criticisms remain a major concern in the 2nd draft ISA. The summary section 2.6.3. "Renal
Effects" essentially fails to acknowledge these limitations and concerns regarding the relevant literature.
Chapter 5 addresses some of the concerns, albeit in a manner that would greatly benefit from a more
balanced approach. Specifically, the new section, "5.5.2.5 Reverse Causality" appears to exist less as a
critical analysis of the potential for reverse causation to explain (even partly) the inverse association of
blood lead concentration and glomerular filtration rate, and more as a pointed attempt to refute its
negative prospective studies of Wasserman et al (2001) and Canfield et al (2003), many of the "positive studies" are limited
by a cross-sectional study design, combined with the fact that the single measure of blood lead available was obtained in late
childhood. The cross-sectional design offers limited causal inference regarding low level lead exposure because it does not
rule out that the possibility that a behavior problem preceded the development of an elevated BLL, and/or that BLL in early
childhood may have exceeded the value measured in late childhood. The following sentence on page 5-127, line 4 is
misleading and should be replaced: "Recent studies consistently reported associations of blood Pb levels with ADHD in
children." First, it should be noted that many of the studies cited did not formally diagnose ADHD, but rather relied on
screening tests for ADHD or tests of attention, which is not the same as a clinical diagnosis. Second, it should be
acknowledged that not all the studies yielded consistent results using these limited testing methods. In the study by Cho et al
(2010), blood lead was no longer associated with measures of attention in the continuous perfomance test after adjustment for
covariates (see Cho et al, 2010, table 3). In the same study, blood lead was significantly correlated with the teachers grading
of ADHD, but not the parents' grading of ADHD. In a study by Kim et al (2010) [Sci Tot Environ 408:5737-5743; 2010 -
not cited in the ISA], teacher rating of ADHD behavior was not significantly correlated with blood lead after adjustment for
covariates in the entire population of children (see Kim et al, 2010 table 2, model 3). A positive finding (in boys only)
emerged in a post-hoc analysis that looked for differential effects by gender.
5 In view of the foregoing discussion concerning inadequate adjustment for confounding and inconsistency among studies,
statements such as the following that appear on page 2-15, line 11 should be revised to acknowledge limitations and
uncertainty: "Epidemiologic and toxicological evidence clearly demonstrates Pb-associated increases in behavioral problems,
in particular, inattention and impulsivity (prior symptoms of ADHD)."
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plausibility. This stands in contrast the comments on "reverse causation" put forth by authors of several
key studies that have reported a significant BLL - GFR association. For example, in the discussion
section of their longitudinal Normative Aging Study report on lead and serum creatinine, Kim et al
(1996) state: "Our findings do not necessarily exclude the existence of an effect of impaired renal
function on levels of blood lead. In line with epidemiologic and toxicologic evidence that low-level lead
exposure causes subclinical impairment of renal function is the physiologically plausible possibility that
decreased glomerular filtration or decreased tubular excretion results in decreased excretion of lead.
Further research is required to test the hypothesis of a bidirectional relationship."
Unfortunately, the new section on "Reverse Causality" in the 2n ISA offers no acknowledgement that
such a bidirectional component remains an unanswered question. Similarly to the 1st draft ISA, the 2n
draft ISA dismisses the possibility of reverse causation in part by repeating the assertion that reverse
causation is implausible because, ".. .the association was not limited to the segment of the population
with potentially significant renal dysfunction in whom reduced Pb excretion would be more likely" (p 5-
328). However, the 2n ISA, like the first ISA, offers no citation or other substantiation for the
supposition that there cannot be an inverse association between a filtered agent such as creatinine or lead
and GFR in individuals whose creatinine or renal function falls within the "normal range". The narrative
did respond to my comment in response to the 1st draft ISA that, "... 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." Two remaining points
offered in section 5.5.2.5 to dismiss the possible contribution of reverse causation should be revisited.
Two papers by Akesson et al (2005, 2006) were cited as finding no elevation of urinary lead in subjects
with lower creatinine clearance. The narrative then argues, (line 17, page 5-328) "If reverse causality
were the more likely hypothesis for these associations, lower creatinine clearance would be associated
with lower urinary Pb, which it is not." The citation of the studies by Akesson et al (2005, 2006) in this
context is puzzling, because in neither of these papers did the investigators either measure or report
values for lead in urine. The second point offered in Section 5.2.2.5 is that neither blood lead nor
chelated lead is elevated in patients with renal disease of known (i.e. non-lead related ) cause. However,
studies not cited in Section 5.2.2.5 (e.g Muntner et al, 2007 and others to be supplied) actually do show a
trend of increased blood lead in subjects with renal failure.
The sections of Chapter 2 and Chapter 5 pertaining to renal endpoints assert several times that the
literature is "consistent" in reporting a significant relationship between low blood lead levels and
markers of kidney dysfunction (e.g page 2-20, line 5; page 5-307, line 9: "studies consistently
demonstrate associations between higher blood Pb level and lower renal function in adults. The studies
in this category provided critical evidence that the effects of Pb on the kidney occur at much lower doses
than previously appreciated based on occupational exposure data"). On the contrary, as was pointed out
in the CAS AC consensus comments of December 2011, an inverse relationship between blood lead and
glomerular filtration has not been consistently observed. For example, in the large general population
study of de Burbure et al (2003) there was no significant association between blood lead and serum
creatinine or other biomarkers of renal function in multivariable regression models. In the normative
aging study (Tsai et al, 2004) there was no significant association between either blood lead or bone lead
and serum creatinine in subjects without hypertension or diabetes. A further inconsistency arises from
some studies of subjects with occupational lead exposure (Weaver et al, 2003a; Roels et al, 1994), in
which higher blood lead was associated with improved renal function. Although, as noted in the
comments supplied in the first CAS AC report, this might conceivably be a consequence of lead-induced
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hyperfiltration, the actual cause has not been determined, and the unexplained inconsistency, which
weakens causal inference, should be acknowledged. Instead, without justification, the 2n draft ISA, (p
2-21), dismisses these "paradoxical" observations as reflecting unspecified "limitations of the study
design." The observation by Evans et al, (2010) that individuals with low-level occupational lead
exposure had a significantly decreased risk of developing renal insufficiency is another striking
inconsistency. Evans and her co-author, C. Blinder, both of the Karolinska Instituet, wrote a review
article in Kidney International in 2011 in which they contend that the available published literature does
not allow the conclusion that low level lead exposure causes renal dysfunction. However, this important
article was not cited in the 2nd draft ISA.
Finally, the observation in the first CASAC consensus comments that the absence of a discernible
nephrotoxic mode of action of lead at low dose limits causal inference continues to lack
acknowledgement in the 2nd draft ISA. Instead, contrary to the recommendation in the first CASAC
report, the 2n draft ISA continues to cite numerous studies of lead nephrotoxicity in animal models in
which the lead dose greatly exceeded the much lower human exposure that is of interest with respect to
NAAQS and the AQCD. For example, on p 5-304, the narrative describes an animal study in which
exposure of rats to 100 ppm (-100,000 jig Pb/L) of lead acetate in water for 14 weeks is characterized as
"low dose" exposure, when this exposure level is 4 to 5 orders of magnitude higher than typical human
environmental lead exposure from water or diet.6
The sections of Chapter 2 and Chapter 5 in the 2nd draft ISA that discuss immunological effects of lead
have been improved by partially responding to concerns expressed in the CASAC December 2011 report
that certain studies were mischaracterized and that causal inference regarding some associations were
overstated in light of shortcomings in the database. However, the conclusion expressed in the sentence,
"Associations with asthma and allergy were observed after considering potential confounding by several
factors, including, SES and allergen exposure" (page 2-21, line 22, and page 5-393, line 26) remains
overstated, and should be revised. An appraisal of the epidemiological studies described in section
5.6.4.2 "Asthma and Allergy" would appear insufficient to infer a causal relationship. First, there is a
vast literature on childhood asthma, an illness that has notably been increasing over the past 30 years
contemporaneous with a dramatic decline in childhood lead exposure. Based upon the limited number of
investigations (five) presented in table 5-29, it is apparent that only a handful of the numerous studies
examining the etiology of childhood asthma and allergy have reported any positive association with lead
exposure. Second, of the studies listed in Table 5-29, only one, by Pugh Smith and Nriagu (2011),
reported a statistically significant association between blood lead (expressed as a categorical value BLL
6 There are additional instances in which the sections of the ISA pertaining to renal effects appear not to have acknowledged
comments offered in the CASAC report, even to the limited but still acceptable extent of disagreeing with them. The
limitations of the studies of Yu et al (2004) and the related studies of Lin et al are not mentioned in the relatively lengthy
discussion of these studies. On the contrary, without a detailed discussion of the major limitations of these studies, the 2nd
draft ISA continues to favor the explanation that lead chelation has salutary effects on renal function in subjects with low
level lead exposure. As noted in previous CASAC comments, EPA might prudently avoid offering an analysis of this
controversial pharmacologic intervention in this document. The CASAC consensus comments recommended that "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 ug/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. However, the 2nd draft ISA (p 5-343) continues to describe in the
narrative the implicit adverse renal effect of an increase in blood lead from 1 to 10 ug/dL, even though it was derived from a
study of older adult subjects who had higher blood lead concentrations earlier in life.
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> 10) and asthma after controlling for family income. The study by Joseph et al (2005) that adjusted
(albeit indirectly and ecologically) for family income as a confounder did not observe a statistically
significant association. The study by Jedrychowski et al (2011), which reported a significant odds ratio
for a positive skin prick test based on cord blood lead but not contemporaneous blood lead in 5 year old
children adjusted for maternal education, an incomplete surrogate for socioeconomic status. Overall, it is
recommended that the epidemiological evidence relating lead exposure to childhood asthma and/or
allergy best be regarded as limited and preliminary. The need for additional investigations of the
relationship that carefully adjust for important confounders such as SES and allergen exposure should be
acknowledged.
Section 5.7 contains an extensive discussion of the affects of lead on heme synthesis and red blood cell
function. However, the following sentence appearing in the summary section on heme effects in Table
2-10, page 2-82 should be deleted because it overstates the overall evidence regarding any impact of a
blood lead of ~ 5 |ig/dL on red cell function: "Associations were observed in populations with mean (or
median) blood Pb concentrations as low as approximately 5 ug/dL." It appears that only one study
referred to in the ISA examined the relationship of a blood lead concentration of ~ 5 |ig/dL on
hematological parameters (Olivero-Verbel et a, 2007). This study was equivocal, because blood lead
was positively correlated with rbc count, and nonsignificantly associated with hemoglobin. Moreover,
the validity of the study findings was diminished by the fact that there was no control for nutritional
factors including iron.
The December CASAC report (page A-5) recommended that the ISA offer a more detailed discussion of
the relative contribution of different sources of lead to total contemporary lead absorption and blood
lead concentrations. Although the presence of additional narrative on this topic at the bottom of page 4-6
in the 2nd draft ISA is welcome, it would be useful to include a graphical representation of this important
data that attempts to partition sources of lead exposure (e.g. a pie-chart or related figure). It is interesting
to note what seems to be a large contribution of lead from food and beverages (Table 4-1). In addition,
the findings of Manton et al (2005) regarding the contribution of housedust to dietary lead might be
worth mentioning.
The December CASAC report (bottom of page A-6) recommended that the section of the draft ISA
pertaining to the rate of decline in blood lead following cessation of lead exposure be revised to reflect
concerns that certain simulations utilizing the Leggett model depicted a more rapid decline in blood lead
than is frequently observed empirically. The CASAC report took specific issue with the sentence on
page 4-48, line 9 of the 1st external draft that stated, "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." Surprisingly, this identical sentence, which referred to cessation of lead exposure after an
exposure period of 20 years, still appears in the same context in the second draft ISA on page 4-67, line
11. The criticism raised in the first CASAC report remains to be addressed. There has been insertion of
language discussing alternative findings in the second paragraph on page 4-62 of the 2n draft ISA.
However, the presentation of different findings on different pages does not adequately clarify the issue.
The new section, 2.9.1 Public Health Significance, appropriately addresses the overall point that small
outcome changes evident on a population basis (e.g. a few point shift in IQ, a few mmHg increase in
blood pressure) may have limited clinical impact on any one individual yet nevertheless signify
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significant public health impact on the population as a whole. Several arguments in support of this are
made, such as the significant impact of a shift in mean IQ on the tails of the IQ distribution. A few
recommendations pertaining to this section are offered: 1) It might be noted that for some endpoints that
have multiple causes and are subject to strong gene-environment interaction (such as blood pressure), a
small change in the population mean may signify a relatively large change in some individuals, and no
change in others. 2) The sentence on page 2-55, line 11 would benefit from revision for increased
clarity; perhaps it could state: "Evan a small relative risk for an adverse health effect that is highly
prevalent in a population can translate into large increase in the number of clinical cases." Similar
revisions for increased clarity of this point are suggested for the narrative on page 2-56, lines 17- 28. 3)
The discussion of the bell-shaped curve distribution of IQ at the bottom of page 2-55 should not be
extended to "inattention", because unlike IQ, is not clearly established that the capacity for attention is
normally distributed. Here, and in the discussion that follows on page 2-56, the discussion of lead's
affect on cognitive function is appropriate, but the inclusion of behavioral endpoints could prudently be
removed because they are subject to more uncertainty.7
Overall, it is strongly recommended that the discussion about public health significance in this section
focus predominantly, if not exclusively, on health endpoints such as cognitive function and blood
pressure/cardiovascular disease, for which causation from environmental lead exposure has been
established. Discussion of the public health impact of lead on endpoints such as behavior, renal
dysfunction, asthma and allergy, and Alzheimer's disease, for which causal inference at low dose is
subject to considerably more uncertainty, may detract from the strong point that can be made in this
section with respect to cognition and cardiovascular disease.
The following sentence in Section 2.9, page 2-54, line 20 should be revised: "No safe level of Pb
exposure has been identified in current or previous assessments and any threshold for Pb neurotoxicity
would have to exist at distinctly lower levels than those associated with the lowest blood Pb
concentrations examined in the epidemiologic studies included in this assessment" [emphasis added].
This appears to be the only sentence in the entire ISA where the term "safe level" was employed. It
would be preferable and accurate to rephrase this sentence without use of the term "safe", instead noting
that "No level of lead exposure has been shown to be without deleterious effect..." "Safe" represents a
risk-management issue which is not the intended focus of this section.
The discussion in Section 2.9.2, Section 4.5.1 and Section 4.7.4 of the Air Lead - Blood Relationship
appropriately notes that studies have reported a range of slopes and modeled relationships (e.g. log-log
or linear). In its December 2011 report, the CAS AC lead review panel suggested with respect to the
discussion of this data (page A-8), "The narrative should consider offering a science-based judgment
regarding which relationship(s) are optimal for quantitative risk assessment....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
7 On page 2.56, line 5, the following statement should be revised: "In cohorts of children where Pb-associated decrements in
cognition and attention were observed, lower academic performance, antisocial behavior, or delinquent behavior assessed in
adolescence or in early adulthood were also observed in association with blood Pb levels." As noted above, a distinction
between academic performance and delinquent behavior as endpoints is indicated. While both has been observed in some
cohorts (notably the Cincinnati cohort studied by Wright and Dietrich and colleagues [2008]), increased delinquency has not
been reported in other cohorts in which cognitive effects have been found, such as the Boston prospective cohort studied by
Bellinger and colleagues.
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literature and selecting key studies, rather than simply compiling study results." It does not appear that
the 2n review draft has adequately addressed this specif
have examined the Air Lead - Blood Lead relationship.
the 2n review draft has adequately addressed this specific request regarding analysis of the studies that
Section 2.9.6.5 Race and Ethnicity (and Section 6.3.6) do not sufficiently discuss the potential
susceptibility of African-Americans to lead possibly arising from factors not mediated by SES or
exposure. For example, the document does not discuss the important recent article by Theppeang et al
[American Journal of Public Health. 98(7): 1248-55, 2008] that found that African Americans have
higher bone lead, after controlling for SES related variables. The document does not address other
articles that have found black children to have higher BLL after controlling for SES. It has been
suggested that genetic differences in calcium metabolism may contribute to higher lead stores in blacks.
Moreover, the document fails to note important earlier literature that has suggested that blacks may be at
higher risk of lead associated increases in blood pressure than nonblacks, e.g. (Vupputuri S, He J,
Muntner P, et al. Blood lead level is associated with elevated blood pressure in blacks. Hypertension
2003;41:463-8; Sharp DS, Benowitz NL, Osterloh JD, et al. Influence of race, tobacco use, and caffeine
use on the relation between blood pressure and blood lead concentration. Am J Epidemiol
1990; 131:845-54) However, this lead-race interaction has not been consistently observed, e.g. Martin et
al. Am JEpid 163:467-478; 2006).
Portions of the discussion of lead chelation in Section 5.3.2.3 (page 5-99) are misleading and subject to
serious misinterpretation, particularly as they pertain to the studies of Stangle et al, 2007 and Beaudin et
al, 2007. The following sentences on page 5-100 are misleading and require clarification and revision:
"In summary, succimer or chelation treatment appears to be able to restore Pb-dependent impairments of
learning and arousal and be neuroprotective in a concentration-dependent fashion. In these studies,
succimer use was more efficacious at lower doses ofPb exposure" [emphasis added]. First and foremost,
the ISA's description of lead chelation in the studies by Stangle et al and Beaudin et al (both of which
utilized the same study design) fails to explain that these studies examined only two lead dosing groups:
a medium lead dose that produced a peak blood lead prior to chelation of 40 to 60 |ig/dL, and a high
lead dose that yielded a peak blood lead of 100 to 140 |ig/dL (cf Beaudin et al, 2007, page 190). Second,
the use of succimer in the control rats, which had blood lead concentrations of approximately 1.5 |ig/dL,
produced deficits in cognitive function and behavior that were of the same magnitude of high lead
exposure alone. It is important to include this additional information in the narrative, lest it be
misinterpreted by some as supporting the value of lead chelation in children with low level
environmental lead exposure and low blood lead concentrations.
Additional comments and recommendations:
Page 2-14, line 8 (and the corresponding sentence elsewhere): Please reconsider the statement: "The
concentration of Pb in urine follows blood Pb concentration, in that it mainly reflects the exposure
history of the previous few months and therefore, is likely a relatively poor index of Pb body burden."
Urine lead more closely follows plasma lead than it does whole blood lead, and it changes more rapidly
and frequently in response to changes in exposure than does blood lead. Rather than reflecting lead
exposure in the past few months, urine lead is more a reflection of lead exposure within the past few
days. Urine lead responds more quickly to changes in external lead exposure than does blood lead (cf.
Gulson B et al, Blood Lead-Urine Lead Relationships in Adults and Children, Environ Res A 78:152-
160; 1998).
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Page 2-25, line 23: The first sentence of this paragraph requires revision for clarity.
Section 2.8.1. "Modes of Action Relevant to Downstream Health and Ecological Effects" is a well-
written summary.
Page 2-58, Table 2-6: The fourth row appears to have an erroneous entry that should be checked:
"Creatinine > 30 mg/g creatinine indicates albuminuria" [sic]
Page 2-70, line 7: The following sentence appears too general and should be revised: "Studies that found
associations with concurrent blood Pb levels also tended to find associations with prenatal cord or
maternal blood Pb levels." In some longterm prospective cohort studies of lead and IQ, e.g. the Boston
cohort studied by Bellinger and colleagues, the Port Pirie cohort reported by Tong et al (1996), and the
pooled analysis by Lanphear, the influence of cord blood lead on IQ in late childhood was not
significant. Conversely, the Mexico City Prospective study reported by Schnaas et al found only prenatal
BLL to be predictive of later childhood IQ. The Yugoslavia cohorts studied by Wasserman and
colleagues found concurrent effects of both prenatal and postnatal blood lead.
Section 2.9.6.7 Proximity to Pb Sources and Residential Factors, and the related sections of Chapter 6
should note that residential water service lines made of lead are a risk factor for elevated childhood BLL
(Brown MJ et al. Environ Res 111:67-74; 2011).
Section 2.9.6.1 Co-exposure of Lead with Metals and Chemicals. On page 2-78, line 22, the sentence
regarding the impact of As on Pb bioavailability should be checked, as a review of the cited reference in
Section 6.1 (Wang and Fowler, 2008) does not appear to support this contention. On page 2-78 line 29,
the following sentence appears to be speculative and should be deleted:
"Since Pb is acid soluble, fluoridation may increase Pb concentration in water through leaching from
pipes and Pb solder (Section 4.1.3.3)." In the ISA, this sentence appears to be entirely based on a single
in vitro study by Maas et al (2006) examining the impact of fluoride on lead leaching from brass
fixtures. This article did not address lead from pipes or solder. This statement should be eliminated in
the absence of any other data indicating that fluoridation increases the risk of lead exposure or elevates
blood lead concentrations. Alternatively, if studies of adequate quality do address the relationship
between fluoridation and lead in drinking water, the topic should be more critically and thoroughly
addressed.
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Dr. Roman Lanno
Comments on Chapter 7
The causal statements for ecological effects discussed in Chapter 7 have been re-evaluated as advised
by CASAC. There are now separate causal determinations for terrestrial and aquatic biota for each
endpoint under consideration. In addition, the chapter now incorporates additional findings from the
2006 Pb AQCD on the effects of Pb on ecosystem receptors, an enhanced discussion of bioavailability
and bioaccessibility, and separate discussions of marine and freshwater toxicity in the aquatic
ecosystem section.
Please comment on the adequacy of these various revisions and other changes to the chapter and
recommend any revisions to improve the discussion of key information.
Chapter 7 has been greatly improved with the addition of very good introductions to sections and also by
providing background reference to previous AQCD documents and concise summaries of sections where
appropriate. The US EPA has provided a complete coverage of the more recent additions to the
knowledge of Pb exposure, toxicity, and effects to ecological receptors in terrestrial, freshwater, and
marine ecosystems.
Although the revised ISA contains much new information presented in an organized manner, the
information is not summarized and integrated into a meaningful synthesis. Summary tables listing
media-based exposure concentrations (soil, freshwater, marine; nominal or measured) with their
respective responses and key abiotic modifying factors (e.g., pH, organic carbon, cation-exchange
capacity (soils), water hardness, etc.) would help in further organizing the data to facilitate a synthesis.
Detailed tables could be provided in an Appendix (e.g., as in the 2006 Pb AQCD) with summary tables
of the most relevant data presented in the text of the ISA to guide discussion.
An initial discussion should include the relevance of studies where responses were observed at very high
Pb levels that may not be expected in most environmental scenarios. In a similar manner, studies where
organisms were exposed to Pb at very low levels should also be carefully scrutinized as to the validity of
the studies (i.e., were Pb concentrations nominal or measured, did they approach detection limits).
Finally, studies where Pb exposures overlap actual expected environmental levels of Pb (see Table 2-1)
would comprise the main focus of the discussions.
Although some discussion of bioavailability is provided, integration of this concept into the discussion
of Pb effects (e.g., how water quality parameters affect Pb toxicity) observed in different media should
be attempted.
In the section on terrestrial toxicity tests, there are a number of paragraphs that refer to tests conducted
with plants in hydroponic systems. A clear distinction should be made between tests in hydroponic
solution and tests conducted in soil. There are physiological differences between plants in hydroponic
systems (e.g., reduced development of root hairs) and plants exposed in soils that make comparisons of
toxicity between these exposure systems difficult and extrapolation from hydroponic systems to soils
systems problematic. A similar situation arises when discussing nematode tests that are apparently
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conducted in agar or some other test medium with exposure concentrations reported in ug/L for soil
organisms. It would be important to note when toxicity tests are not conducted in actual soils and stress
that the comparison and extrapolation of this data to toxicity tests in real soils should be done with
extreme caution.
Throughout Chapter 7, it is often not clear when exposure doses are expressed as nominal or measured
concentrations. When round numbers (e.g., 100, 250, 5, 30 mg/L or mg/kg) are presented, I assume that
these are nominal concentrations. Often times it is stated that these are nominal concentrations, which is
excellent. However, if measured concentrations are available, these should be reported in lieu of
nominal concentrations. If only nominal concentrations are provided in the original research, then these
studies should be considered as secondary data and so noted since one of the major criteria for primary
data is actual measured exposure concentrations.
There are a number of paragraphs in the terrestrial section where Pb exposure concentrations are
presented but little information is provided regarding the physical and chemical characteristics of soil
that have the potential to modify Pb toxicity. Reporting this information would provide some means of
comparison of the effects of modifying factors of toxicity (see previous comment on bioavailability).
There are a number of paragraphs where the reporting of exposure doses are in different units (e.g., ug/L
and mg/L) where standardizing the expression of dose would greatly facilitate the comparison of
toxicity, both within a study and amongst different studies.
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Dr. Richard L. Poirot
Overall, Chapter 3 is much improved, with changes responsive to previous review comments. The
discussion of historical changes to emissions inventories is much more clearly presented. The expanded
discussions on natural and intercontinental background Pb and on air Pb/ soil/Pb relationships are
helpful. The HERO system works flawlessly and represents a major improvement to the review process.
I was disappointed that the comparison of collocated Pb measurements in different size fractions was
removed (rather than repaired - to include only concurrent, above-MDL, paired samples), as I think
there could be useful information content there. At a minimum, you might just append the Cavender &
Schmidt (2007) memo comparing Pb in different PM sizes prepared for the previous NAAQS review,
although hopefully this might be updated to include a few more years of data. You could also reproduce
the similar (table 3) information in the excellent Cho et al. (2011) literature review paper. Possibly you
could also summarize the size distribution results derived from the many studies you cite (and several
others listed below) using MOUDI samplers in a single table or graphic. Of particular interest would be
information about how Pb particle size distributions might change over time, by season, by proximity to
different source types, or as a function of concentration or chemical composition. It would also be
helpful if information on particle size, concentration and/or composition presented in Chapter 3 could be
more directly linked to the exposure and toxicokinetics information in Chapter 4.
The discussion of limitations of the current TSP FRM sampler has been much improved, and various
other Pb sampling (& analytical) methods are reviewed. However, there isn't really much discussion of
practical alternatives, such as the louvered lo-vol inlet - or scaled-up version of it (Kenny et al., 2005),
other than to indicate they "could be tested". There is also no discussion, in chapter 3 or 4, relating to
what particle cut size(s) would be most desirable in a Pb FRM. The "Integrative Summary" states (p 2-
6) that "the Pb-TSP indicator was retained in 2008 in recognition of the role of all PM sizes in ambient
air Pb exposures", but relatively little information is presented (in Chapter 4 or elsewhere) on what the
role(s) of different Pb particle sizes actually are in terms of human exposure and uptake. Arguably
inhalation (fine particle only) is more efficient than ingestion (Hodgkins et al., 1991); ingested fine
particles are absorbed more efficiently than coarse ones (Barltrop and Meek, 1979); and are composed
of more inherently soluble Pb compounds than coarse particles. Fine particles penetrate more efficiently
into indoor environments - by various transfer mechanisms, and once deposited to surfaces, are more
readily picked up and ingested (Juhasz et al., 2011). So arguably, a sampler (like the TSP hi-vol) that
excludes progressively larger fractions of progressively larger particles (and does so most effectively
when high wind speeds suspend the highest concentrations of ultra-coarse particles) - may not be so bad
after all...
Chapter 3 concludes that our understanding of TSP sampling errors, particle size distributions, and
possible alternative samplers has not changed much since the last review cycle. This is true enough, but
unless we plan to hear similar laments in each subsequent Pb NAAQS review cycle, we need to start
thinking more proactively about alternative sampling approaches. What are the desired particle cut size
characteristics for sampling Pb in the ambient air? If a sampler could be developed that would
consistently capture particles larger (or smaller) than those captured by the hi-vol under different wind
conditions, would that be an improvement? Are there practical upper particle cut size limits to what can
be consistently achieved for different wind conditions by filter sampling techniques, and might these
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size limits also be justified by the spatial (population) representativeness of the resulting measurements,
and/or by the decreasing bio-relevance of larger particle sizes? Is there a need to start routinely
collecting additional information on particle size distributions at sites with high Pb concentrations?
Specific Comments
P 3-1, lines 25-26: Maybe insert "a majority of before "ambient airborne lead", as you indicate on p 3-8
that organic Pb - which may comprise up to 20% of Pb emitted from piston aircraft - would remain
largely in vapor phase.
P 3-5, lines 4-5: It's not clear what "this category" refers to. Should there be some preceding statement
indicating what (relatively large) % of Pb was emitted from what (relatively small) % of the largest
emitting counties? Along similar lines, it might be helpful to include something like a list of the largest
point sources, at least summarized by category, if not by name. Given that there are 20,000 airports
contributing to the largest total emission category (with roughly half the Pb emitted at/near the airport),
it's hard to get a sense of how individual airports compare with other large Pb sources.
P 3-9, line 2: Can you indicate how far downwind of the smelter the concentrations were 35 x higher?
It's also not clear what "(0.625-0.880 jig/m3)" refers to. I assume it might be the range of measured
downwind concentrations. If so, you might move it to follow "downwind" - rather than "upwind".
P 3-9, lines 20-21:1 assume this estimate of "nationwide median fugitive emissions" is specific to
secondary Pb processing facilities? Also, in this section you use the terms "secondary", "smelting",
"processing" and "recovery". Do these have different meanings? If so, some explanation would help.
P 3-10, line 11: Is there any indication of what fraction of Pb from coal combustion is in the form of
relatively insoluble PbSO4? See for example Tan et al. (2006), Xie et al. (2009).
P 3-10, lines 15-19:1 wasn't aware that such large amounts of crude oil (Pb emissions similar to residual
oil) were being burned. Also, adding these estimates for coal (200 tons/yr), crude (100-500 tons/yr), and
residual oil (25-700 tons/yr), yields a range of 325 to 1400 tons/yr. This is a large range and a factor of 2
to 10 greater than the 149 tons from fuel combustion presented in Figure 3-3. Are emissions estimates
really this uncertain, and if so (or if not) some additional discussion seems warranted.
P 3-11, lines 16-18: Just citing West Virginia patterns for US seems simplistic. I think there's generally
a summer peak in US power demand due to air conditioning, but the summer peak in utility coal burning
is not much higher than a secondary winter peak, as much of the increased summer power demand is
supplied by seasonally cheap natural gas.
A-49
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150.000
Coal 2009 • Coal 2010 • Coal 2011 Nat Gas 2009 • Nat Gas 2010 • Nat Gas 2011
From: http://www.eia.gov/electricity/monthly/epm_table_grapher.cfm?t=epmt_l_2
P 3-11, lines 21-22: Maybe mention that this 63% Pb from incinerators was based on just 6 sample days.
P 3-12, lines 17-20: Again, it seems worth mentioning that this 20% Pb from Canadian wildfires was out
of 6 days, 1 or 2 of which included the highest wildfire smoke concentrations ever seen in that region.
P 3-14, line 12: This higher concentration of Pb in the 0.18 to 0.32 |im size mode does not seem
consistent with ground-up wheel weights (i.e. it's not the fine tail of the coarse mode). Can you offer
other explanations, or at least observe that there may be other roadway (or regional) sources of fine
mode Pb? See for example Thorpe and Harrison (2008), Maher et al. (2008).
P 3-16, line 14: Maybe change "comparison" to "difference".
P 3-16, lines 30-31: It's not clear what these percentages refer to. A month after demolition, was Pb 18%
higher, 18% higher and 29% higher in dust on alleys, sidewalks and roadways than it was in those
locations prior to demolition?
P 3-21, line 4: You might add something like "and systematic reductions in emissions from other lead
sources" after "motor vehicles". Over the past 20 years, most of the Pb emissions reductions and air
improvements have come from non-MV sources.
P 3-21, lines 8-12: [Seems like this paragraph belongs in section 3.3.1.2 (Deposition)]. I also think you
overstate the solubility argument. Particle size dynamics are a more important contributing factor to the
different removal mechanisms than solubility. Large particles will dry deposit relatively quickly whether
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they are soluble or not, nor would they tend to be removed predominantly by wet deposition processes if
they were more soluble. For example, the current GEOS-CHEM treatment of (soluble) sea salt aerosol
deposits % of small particles (<4|i) by wet deposition, and % of large particles (>4|i) by dry deposition.
(http://wiki.seas.harvard.edu/geos-chem/index.php/Sea salt aerosols).
Fine particles do not dry deposit efficiently in any case, and insoluble components of fine particles are
often coated/mixed with soluble species in internally mixed aerosols, and readily removed by wet
deposition processes. Freshly emitted (fine particle) black carbon, for example, is considered primarily
hydrophobic, but ages over time, becomes mixed with soluble species, becomes hydrophilic, and is
removed primarily by wet deposition (Reimer etal., 2010). An average of 47% of Pb in 2005 and 2006
wet deposition samples in the eastern Mediterranean was insoluble (Theodosi etal., 2010). This paper
also includes interesting observations of seasonal patterns in wet & dry Pb deposition, and changes in
solubility with precipitation pH.
P 3-24, lines 3-6: You could change "at" to "near" in line 3, as the upper bound Pb Vd reported in the
2006 CD was 1.3 cm/s. Also, the 12-17 mg/m2-year dry Pb deposition reported here for Tokyo Bay was
not more than 10 times the upper bound of the range reported in the 2006 CD - which included 8.4-14
mg/m -year dry Pb deposition reported by Yi et al, (2001) near Lake Michigan for 1993-1995 (see p. 2-
57 of the 2006 CD).
P 3-24, line 32: You could change "in locations near" to "at" or "from".
P 3-25, lines 6-11: I don't understand why a "smoothed" gradient indicates resuspension. With no
resuspension, I would still expect a relatively smooth gradient in deposition of pollutants away from
long-term emission sources - maybe declining with the log of distance from source. More detail is
needed to explain this. Also, any spatial pattern of lead in soil would likely reflect historical air
concentrations and sources (including resuspension), rather than influence from current sources.
P 3-28, lines 29-31: These measurements indicating relatively greater resuspension of fine Pb than
coarse are an interesting contrast with the model estimates of relatively greater suspension of coarse than
fine particles on preceding page (p 3-27, lines 11-19).
P 3-39, lines 11-12: Is this (1 |ig/l) the concentration of Pb (rather than DOC or Fe)?
P 3-46, line 17: What is "high quality deciduous litter"?
P 3-47, lines 32-37: You first refer to what Perdrial et al. "postulated", but then refer to it as "important
new evidence".
P 3-53, lines 23-24: This sentence needs work.
P 3-56, line 14: In discussing the TSP FRM sampling biases with wind speed, it might also be worth
noting that the lower collection efficiencies for larger particles at higher wind speeds coincide with
(windy) conditions most conducive to suspending large Pb containing particles and sustaining their
atmospheric presence over longer times and distances. Conversely, on days when samplers are not
running, the TSP FRMs are also susceptible to passive sampling artifacts, increasing with increasing
wind speed and particle size (McFarland et al., 1979).
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P 3-57, lines 6-7: ".. .have been thoroughly reviewed" (20 years ago). It would be helpful somewhere to
include some discussion of what particle size(s) it would be desirable to collect (are most relevant to
human exposure). Here or in Chapter 4, some discussion of how particle size characteristics relate to Pb
uptake would be helpful, along with a more proactive demonstration that coarse particle Pb - within
some size limits - is, in fact, of equal importance as fine Pb. How would we expect a given Blood Pb:
Air Pb ratio to shift, if the size distribution of Air Pb particles shifted to larger (or smaller) particles?
P 3-57, line 29: Don't you mean "low-volume" PMio?
p. 3-85, lines 4-5: While Pb compounds in PM may have relatively high densities, particle size is
typically a more important factor, and it's only the larger particles (regardless of their densities - within
limits) that tend to settle out quickly. Pb incorporated in small particles tends to be combined with other
(lower-density) compounds and/or is not efficiently deposited near its emission sources - hence the wide
spatial distribution of historical automotive Pb in remote locations.
P 3-86, line 6: Could you give an example of what you mean by high spatial variability? It might be
helpful to put this in context by comparing to the spatial variability of other pollutants.
O"
P 3-85, line 36: Add "m" after "z
P 3-88, Figure 3-20: This is a good example. It might be useful to have some other graphical depictions
of long-term Pb trends to help support the emission inventory trends - for example:
http://www.epa.gov/airtrends/lead.html.
P 3-93-96: There appears to be very little seasonal variability in the ambient Pb data as summarized here
(hard to see any), and only very slight summer peaks in some of the Appendix 3.8.1 tables. This seems
inconsistent with various recent analyses of Mielke, Laidlaw and others suggesting summer (or dry
season) peaks in both fine soil and Pb. There do seem to be relatively strong seasonal peaks in children's
blood lead in many studies. While several of these are mentioned in Chapter 4, there's not much
associated discussion of potential causal or contributing factors. Other older and newer studies that
might be considered include: Baghurst etal, 1992; US EPA, 1996; Yiin etal, 2000; Kemp etal, 2007;
Havlena et al., 2009; Mielke et a/., 2011; Laidlaw et a/., 201 la, b). It might be useful to include some
discussion of similarities & differences in seasonal patterns of air Pb and blood Pb, along with
explanations of mechanisms that may contribute to the seasonal blood Pb increases.
I also think the aggregated summary nature of Figures 3-24 through 3-26 may be masking some of the
unique seasonal patterns at individual sites - that may be revealing of source influences, or may affect
exposure patterns. Note for example, the (low concentration but) distinct April peak in PM2.5 Pb at
remote Western IMPROVE sites, which would be consistent with Asian transport (van Donkelaar et al.,
2008; Ewing et al. 2010, DePaolo, 2011). Note also the different seasonal patterns in other rural & urban
PM2.5 sites and at selected source-oriented TSP sites.
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0.0016
0.0014
"E 0.0012
1
•g 0.001
.3
Up 0.0008
QJ
•* 0.0006
I 0.0004
0.0002
0
0.02
0.018
0.016
-I. 0.014
&
-g 0.012
oi 0.01
S 0.008
-------
P 3-100, lines 22-24: How do the east & west directions relate to sampler orientation to the roadway,
and is there any indication of roadway influence - in the larger or smaller size fractions? Possibly the
review of this study could be deleted here as it's repeated in more detail in the following section - and is
more relevant to the "non-road influences at near-road sites" theme of that section.
P 3-100: Another possibly useful reference on roadway Pb influences on air & soil Pb, vertical soil
profiles and bioavailability is Preciado and Li (2006). Maher etal. (2008) present recent evidence of
vehicle exhaust fine particle Pb deposition on leaves of roadside trees. Several more recent publications
by Mark Laidlaw (201 la, b) make a persuasive case for the importance of resuspended roadside soils.
See also his extensive bibliography at http://www.urbanleadpoisoning.com .
P 3-104, lines 10-11: Could you give an explanation for the large decrease in collocated sites - from 129
in 2007-08 to only 16 in 2009. Intuitively one would expect an increase in sites with the tighter new
2008 Pb NAAQS.
P 3-104, Figures 3-28 & 3-29: I'm suspicious about the several perfect 1.0 correlations between Pb and
862, PM2.5 and CO in figure 3-28. Do all the "source" and "non-source" categories in these figures refer
to the associated pollutants or to the Pb (or both)? I would imagine it might be possible to have a source-
oriented PMio site where collocated Pb measurements were not considered source-specific. What would
be a "source" site for ozone?
P 3-105, line 32: So what's the implication of the Pb-humate observation?
P 3-107, Table 3-10: Considering PM2.5 is included in PMio, and PMio in TSP, some of the numbers and
huge differences in correlations for the different size fractions look very suspicious. For example the
correlation between Pb and Fe is 0.43 for TSP, 0.99 for PMio and -0.51 for PM2.5. For Pb vs. Ni the
correlations are 0.08 for TSP, 0.99 for PMio and -0.67 for PM2.5.1 don't believe it, and suggest double-
checking these numbers and either find a way to explain, comment critically, or delete the reference.
P 3-108, Figure 3-30: I like this figure! It might be instructive to show something similar for IMPROVE
data. Also, some discussion of the relatively high correlation between Pb and K seems warranted. K is
often a good tracer for wood smoke, although fireworks are also a large but only occasional source, and
K is also contributed by soil and sea spray. None of the above - with the possible exception of
woodsmoke (from forest fires) has been suggested as an important Pb source.
P 3-109, lines 23-25: Needs work.
P 3-110, line 1: Add "Pb" before "concentrations".
P 3-110, lines 7-14: The seasonal patterns of Pb at many remote western US IMPROVE sites show a
distinct (but very low concentration) Spring peak, which would be consistent with Asian transport. See
figure below p 3-106 comment.
P 3-112, line 1: I think you mean "contemporary", not "contemporaneous".
P 3-112, line 23: Is "debrided" the right word here? Maybe peeling, degrading, flaking...
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P 3-113 and generally: It's helpful to include sample depths when you report soil concentrations, which
you do in some cases but not in others.
P 3-113, lines 27-30: This indication of declining Pb concentrations in soils (is the only one discussed
here but) could be an important point suggesting that current Pb loading rates are insufficient to sustain
Pb concentrations at locations where resuspension of historically deposited Pb may be important. See
also the roadside soil Pb profiles in Preciado and Li (2006), which show highest Pb concentrations at
depths of 0.25 to 0.3 meters, decreasing substantially toward the surface.
P 3-114, lines 29-30: As indicated previously, some explanation would help understand why smooth
gradients imply resuspension.
P 3-117, line 28: Add "g" after "|i".
P 3-118: At some point in this section (or elsewhere), it would be helpful to discuss mechanisms like
resuspension and air movement vs. tracking on shoes, etc. by which soil Pb gets incorporated into indoor
dust (Layton and Beamer, 2009). Any information on the influence of particle size on these transport
mechanisms would be helpful.
P 3-122 & 3-123, Figures 3-33 and 3-34: I don't understand these figures and think additional
explanation is needed. Why is the 1992-94 pattern - showing a large increase at Atlanta with declining
concentrations downstream - so different from the closely overlapping 1990-1995 sediment pattern
which shows no increase at Atlanta for that period or for any other time period back to 1975? Is this just
because in the samples used to construct Figure 3-34, there were no samples near Atlanta (about 650
miles upstream) until you get to about 500 miles downstream? If this is the case, the lines between the 2
right-hand points are likely misleading as they suggest gradual increase from 750 to 500 miles, when in
fact we expect a large step up at 650 miles, followed by gradual decline downstream. Adding further
confusion, it looks like the largest concentrations in 3-34 at 500 miles occur where the Pb background
(shown only in 3-33 but included in the 3-34 caption) jumps up.
P 3-123, lines 10 & 13: Could you report the MDL?
P 3-124, lines 11-18: This paragraph seems unnecessary - or could be shortened to "There are no routine
measurements of Pb in precipitation in the US."
p 3-125, line 15:1 don't think "the greatest reductions occurred in late 1990s" is really correct for either
Europe or the US. In the US, I would think the greatest reductions in Pb emissions, air & deposition
likely occurred in the late 1970s and early 1980s (see Figures 3-1 & 3-20). Maybe you could say
something like "prior to 1990, with relatively smaller reductions in recent years". As indicated above,
some graphic illustrations showing long-term decreases in air Pb would be helpful.
P 3-129, line 75 (& Fig 3-37): A possible explanation for this extreme value at Noatack could be
fugitive emissions from (or similar bedrock ore deposits to) the relatively nearby Red Dog mine (one of
the largest Zn & Pb mines in the world). See: http://www.reddogseis.com , Hasselbach et al. 2005, and
http://dec.alaska.gov/air/reddog.htm.
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P 3-139, lines 8-18: As indicated in comment on p 3-29,1 think you overstate the importance of
solubility. Also, if coarse Pb is predominantly insoluble, then presumably it's less readily adsorbed
when ingested, and may be relatively less injurious than its (soluble, respirable) fine particle
counterparts.
P 3-139, line 21: You might add "most" before "surface waters". Surely there are some where current or
past mining or smelting operations or other sources are locally more important than atmospheric
deposition (for example Kurkjian et al. 2004; EPA Region 9 (2012); Coeur Alaska, inc. v. Southeast
Alaska Conservation Council). While it seems logical that atmospheric deposition has been the most
important source of Pb input to most surface waters historically, I wonder how current Pb deposition
rates compare to resuspension from sediments (p 3-140, lines 1-3), or urban runoff contaminated by Pb
wheel weights, historically deposited Pb, etc.? For example Davis et al. (2001) estimated that wet and
dry Pb deposition contributed less than 20% of total Pb loading in urban runoff.
P 3-140, lines 26: This may be true, although it seems like you haven't tried very hard. You could have
included some discussion of the excellent Cho et al. (2011) review paper, included a more carefully
conducted update of the comparison of Pb in different size fractions included in the last draft Pb ISA
(but dropped here), summarized the results from the various (at least 7) MOUDI studies you list here,
and added a few others such as Albuquerque et al. (2012), Csavina et al. (2011), Fang and Huang
(2011), Gao (2009), Lin et al. (2005) Wang et al. (2005), etc.
References
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the city of Sao Paulo, Brazil: comparisons between polluted and unpolluted periods, Environ. Monit.
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Baghurst, P.A., S.L. long, AJ. McMichael, E.F. Robertson, N.R. Wigg and G.V. Vimpani (1992)
Determinants of blood lead concentrations to age 5 years in a birth cohort study of children living in the
lead smelting city of Port Pirie and surrounding areas, Arch. Environ. Health, 47(3):203-10.
Barltrop D. and F. Meek (1979) Effect of particle size on lead absorption from the gut, Arch. Environ.
Health 34(4):280-285.
Cahill, T. A. et al. (2009) Deposition of coarse toxic particles in Wilmington, CA for the Department of
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Cavander, K.A. and M. Schmidt (2007 Memorandum on: Review of collocated Lead in total suspended
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(2011) A literature review of concentrations and size distributions of ambient airborne Pb-containing
parti culate matter, Atmos. Environ. 45: 5005-5015.
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Csavina, J. A. Landazuri, A. Wonaschiitz, K. Rine, P. Rheinheimer, B. Barbaris, W. Conant, A.E. Saez
and E. A. Betterton (2011) Metal and Metalloid Contaminants in Atmospheric Aerosols from Mining
Operations, Water, Air, & Soil Pollution 221: Numbers 1-4, 145-157. And see slides at:
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Davis A.P., Shokouhian M. and S. Ni (2001) Loading estimates of lead, copper, cadmium, and zinc in
urban runoff from specific sources, Chemosphere, 44(5):997-1009.
DePaolo, DJ. (2011) Using Pb and Sr isotopes to assess Asian aerosol impacts in urban and interior
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Ewing, S.A., J.N. Christensen, S.T. Brown, R.A. Vancuren, S.S. Cliff, and DJ. Depaolo (2010) Pb
isotopes as an indicator of the Asian contribution to particulate air pollution in urban California,
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Gao, Y. (2009) Monitoring of Air Toxic Particulate Pollutants from Heavily Trafficked New Jersey
Turnpike: An Urban Community-Wide Project, Result of Targeted Trace Metals,
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Hasselbach L., J.M. Ver Hoef, J. Ford, P. Neitlich, E. Crecelius, S. Berryman, B. Wolk and T. Bohle
(2005) Spatial patterns of cadmium and lead deposition on and adjacent to National Park Service lands
in the vicinity of Red Dog Mine, Alaska, Sci. Total Environ. 348(1-3):211-30.
Havlena J., Kanarek, M.S. and M. Coons (2009) Factors associated with the seasonality of blood lead
levels among preschool Wisconsin children, WMJ 108(3):151-5.
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effect of airborne lead particle size on worker blood-lead levels: an empirical study of battery workers,
J. Occup. Med. 33(12): 1265-1273.
Johnson, D.L., K. McDade and D. Griffith (1996) Seasonal variation in pediatric blood lead levels in
Syracuse, NY, USA, Environmental Geochemistry and Health, 18, No. 2: 81-88.
Juhasz, A.L., J. Weber and E. Smith (2011) Impact of soil particle size and bioaccessibility on children
and adult lead exposure in peri-urban contaminated soils, J. ofHaz. Mat., 186: 1870-1879.
Kemp, F.W., P.V.S.V. Neti, R.W. Howell, P. Wenger, D.B. Louria, and J. D. Bogden (2007) Elevated
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Kenny, L., G. Beaumont, A. Gudmundsson, A. Thorpe and W. Koch (2005) Aspiration and sampling
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Kurkjian,R., C. Dunlap, A. R. Flegal (2004) Long-range downstream effects of urban runoff and acid
mine drainage in the Debed River, Armenia: insights from lead isotope modeling, Applied
Geochemistry., 19, No. 10, pp. 1567-1580. http://www.pf-armenia.org/fileadmin/pfa uploads/Mining.pdf
LaidlawM.A., H.W. Mielke, G.M. Filippelli, D.L. Johnson and C.R. Gonzales (2005) Seasonality and
children's blood lead levels: developing a predictive model using climatic variables and blood lead data
from Indianapolis, Indiana, Syracuse, New York, and New Orleans, (USA). Environ. Health Perspect.,
113:793-800.
Laidlaw, M.A. and G.M. Filippelli (2008) Resuspension of urban soils as a persistent source of lead
poisoning in children: A review and new directions, Applied Geochemistry, 23: 2021-2039.
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Australia due to exposure to lead in soil dust, Environ. Pollut., 159(1): 1-9.
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lead contaminated urban soil as a dominant source of atmospheric lead in Birmingham, Chicago, Detroit
and Pittsburgh, USA, Atmos. Environ., 49: 302-310.
Layton, D.W., and P.I. Beamer (2009) Migration of contaminated soil and airborne particulates to
indoor dust, Environ. Sci Technol. 43(21):8199-205.
Lin, C.C., S.J. Chen, K.L. Huang, W.I. Hwang, G.P. Chang-Chien and W.V. Lin (2005) Characteristics
of metals in nano/ultrafine/fme/coarse particles collected beside a heavily trafficked road, Environ Sci
Technol. 39(21):8113-8122.
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identified by magnetic and elemental analysis of roadside tree leaves, Atmos. Environ. 42: 364-373.
Mielke, H.W., M.A.S. Laidlaw, C.R. Gonzales (2011) Estimation of leaded (Pb) gasoline's continuing
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air monitoring, 86th National Meeting, American Institute of Chemical Engineers.
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Tan, M.G GL. Zhang, X.L. Li, Y.X. Zhang, W.S. Yue, J.M. Chen, Y.S. Wang, A.G Li, Y. Li, Y.M.
Zhang, and Z.C. Shan (2006) Comprehensive Study of Lead Pollution in Shanghai by Multiple
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traffic: A review, Sci. Tot. Environ. 400: 270-282.
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Immediately Cease Illegal Discharge of Toxic Pollutants to San Francisco Bay,
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Zhang, E. J. Dunlea, J. L. Jimenez, J. E. Dibb, L. G. Huey, R. Weber, and M. O. Andreae (2008)
Analysis of aircraft and satellite measurements from the Intercontinental Chemical Transport
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Dr. Joel G. Pounds
Comments on Chapter 4
Comments on accuracy of the interpretation of the science:
In general, the literature results presented in Section 4.1 (dietary lead exposure) is clearly written and
faithfully presented. However, the text of individual paragraphs provide little interpretation, context, or
summary. That is data are merely presented without evaluation, thus the reader must guess the
importance and impact of the reviewed data to the ISA. For example, the point of paragraph beginning
on P4-20-L12 is unclear without inclusion of a summary sentence that helps the reader understand why
these two studies were reviewed. The paragraph identifies an "important problem" but does not
convince the reader as to the importance of the problem or the insights offered by the reviewed studies.
In contrast, most paragraphs of 4.2 are summarized with an evaluative sentence that places the reviewed
data in context of the ISA.
Are uncertainties and limitations of relevant data, methodologies and approaches adequately
discussed:
P4-30-L-23.
P4-33. Organic Lead Section. Suggest ISA include sentence or two that summarizes the importance, or
lack thereof, of organic lead compounds to the lead body burden or blood lead.
P4-50, L3. Very nice paraphagrh describing uses and limitations of mechanistic models. P4-100 is a
parallel nice paragraph describing the use and limitations of empirical models.
I have several comments related to blood Pb simulations P4-48; P4-8, 4-9, 4-11; and other figures and
text. The ISA authors are commended for their efforts to provide lucid simulations that collectively
illustrate relationships between blood Pb and selected tissue. These simulations are very helpful to
provide an interpretative context for blood lead and bone lead measurements in human individuals and
populations.
1. It would be helpful to include a little more information in the "Note" for each simulation. For
example, how much lead was "administered"? When Pb administration to the model was changed, was
input set to zero Pb or some baseline?
2. I'm unclear why "time-averaging" of urine Pb, blood Pb etc. was used in many of the Figures in this
Section. I think of time-averaging as a method to decrease variability of experimental in addition to
experimental error. However, the simulations have no variability in this sense. Over what time scale are
the data averaged? The time-averaged data could be more useful if compared and contrasted with
experimental data, yet this comparison is not provided.
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Specific recommendations to refine interpretation / representation of the science:
P4-30-L24-28. The text states "If properly measured (e.g. time-integrated blood Pb), under most
conditions Pb bioavailability is equivalent (or nearly equivalent) to Pb absorption". This statement
seems conceptually incorrect. Agreed, blood lead is the central compartment of biological reality and the
models that describe these biological processes. However, blood lead also includes inputs from soft
tissues and bone. Thus, time-integrated blood lead will over-estimate Pb bioavailability/absorption.
P4-34-35-> The role of "nutritional deficiencies" in lead metabolism is more complex than summarized
here. The papers reviewed are interpreted correctly but the review is necessarily superficial or not well
organized. Good summary however on P35-L20-24. It would be helpful to include a paragraph on the
ISA that summarizes the complexity of nutritional interactions as these interactions may be
physiological (deficiency programs homeostatic regulators to absorb and retain needed elements),
biochemical (competition between Pb and other elements for transport and binding sites),
macronutrients may alter Pb bioassessibility, genetic variants may modify all of the above.
P4-38,L36-37. "Factors that may affect in vitro predictions of RBA of interior dust Pb could include.
Suggest clarify sentence for potential ambiguity. The 'prediction' is for in vivo RBA. In vitro RBA is
measured. Secondly, while the in vitro measurements will be affected by factors such as particle size and
composition, etc. the 'predictions' should hold as the in vitro -> in vivo predictions are particle
dependent.
P4-46, L19-21. "Approximately 7-39% of the maternal Pb burden transferred to the fetus was derived
from the maternal skeleton..." The relative contribution of maternal skeletal lead stores and
contemporaneous environmental lead exposures to the fetal skeleton is not easily generalized as the
maternal skeletal burden on the environmental exposure may vary significantly - independent of each
other. Moreover, I believe the skeletal lead levels of these cynomologus monkeys were quite high
diminishing the human relevance of these studies.
P4-39,L23 vs. L4-49,L12. Contradiction -> Page 39 reports that 1% of body burden is in blood; Page 49
reports 5%.
P4-49,L15 vs. P4-54, L7. Contradiction -> variously report either hemoglobin or ALAD as the major
lead binding protein in blood.
P4-53,L22-30. Most proteomic and metabolomics data are highly left censored and statistical strategies
have been developed to deal with this issue, with and without imputation. It may be appropriate to
revisit this issue using newer methods.
P4-61,L9-18. Although Mitchell et al, and Hernberg et al. discussed blood Pb, and blood ALAD activity
in the context of lead exposure I suggest the their use as a "biomarker of lead exposure" (LI 1) is vague
and potentially mislead in the context of the ISA. This limitation is due to the effects of ALAD alleles
on Pb binding and ALAD activity that confound relationship to lead exposure.
P4-65, Figure 4-9, 4-11. Remove "upper", "middle" , lower" labels . Suggest remove panel with time-
averaged blood Pb
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Comments related to fluoride and lead:
The ISA briefly and superficially discusses the potential role and impact of fluoride on drinking water
lead following leaching from plumbing (p2-78; p4-21) or experimental skeletal lead accumulation in the
rat (p6-3). These brief citations suggest that fluoride may increase leaching and by implication lead
levels in drinking water. In contrast to the ISA's brief conclusion, Triantafyllidoua and Edwards do not
mention fluoride in their recent extensive review (Lead (Pb) in Tap Water and in Blood: Implications for
Lead Exposure in the United States. Critical Reviews in Environmental Science and Technology,
Volume 42(13), 2012 DOL10.1080/10643389.2011.556556).
Consistent with the ISA, Coplan et al. review numerous studies purporting to show the importance of
fluoride and blood lead levels. (Confirmation of and explanations for elevated blood lead and other
disorders in children exposed to water disinfection andfluoridation chemicals. NeuroToxicology 28
(2007) 1032-1042). However, this paper also includes sections titled, "4. EPA's refutation of SiF
adverse health effects" and "5. CDC's dismissal of an SiF/PbB linkage". Thus, the potential health
interactions of Fl and Pb may be charged with scientific and/or policy conflicts. Therefore, the ISA
should be revised to provide a careful, more nuanced review of this issue.
Comments related to clarification:
P4-21-L20. Define the model used my Miranda et al.
P4-30. Section 4.2. Consider moving (burying) the "dermal absorption" text at the end of 4.2.1 rather
than leading with the section with this less important route.
P4-32-L10-13.1 believe that "bioavailable' should be "bioaccessible"
P4-34, L14. Sentence "Eating breakfast..." is not clear. Is breakfast proportional to blood lead?
Inversely proportional? Is lead found in breakfast foods or is breakfast a bioavailability/bioassessibility
issue?
P4-36, L13. Relative bioavailability (RBA) is defined as fraction (L13) but presented as percentage.
P4-40, L28. 'lexicologically' -> kinetically
P4-41, L3 clarify to 'limited capacity of Pb-binding proteins in RBCs..."
P4-44, LI 3 - clarify to "nonexchangeable" (except by bone resorption/bone remodeling) pool of Pb in
bone..."
P4-45, LI 3. "A key factor affecting Pb uptake into bone the fraction of bone surface in trabecular and
cortical bone adjacent to active bone marrow." This paragraph does not convinceably describe why this
fraction is a "key factor".
P4-47, L32. "Estimates of urinary filtration of Pb from serum" -> Estimates of urinary filtration of
plasma
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P4-62,L28. "...measure of Pb dose." -> "...measure of long-term lead exposure.
P4-67,L25. ".. .the effects of bone Pb..." -> "the correlation of bone Pb..."
P4-99, Figure 4-20. Note is confusing. What is the solid line?
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Dr. Michael Rabinowitz
General Remarks in Response to Charge Question:
This draft is much improved, particularly with the inclusion of these summary chapters and by the
placing of the causation discussion in the Preamble. This allows a reader to get a clear picture with
sufficient, but not excessive, detail. I must assume some readers will only read Chapter 1, and a few
more might read Chapter 2. In that role it appears to be an effective and useful resource. Looking at
Chapter Five and how its content was captured by Chapter, it appears adequate.
Additional Specific Comments:
In that my pre-meeting comments contained many small corrections and suggestions to wording with
page and line citations, here I present only the more general and salient comments.
A: Some history could be added : It was recognized early that unlike other priority pollutants, such as
ozone, lead exposure is multi-media, and that regulating air exposure did reduce total exposure, but
other sources and pathways were at work.
Also, for background we should remind readers that most of us get most of our daily lead intake from
dietary sources.
Additionally, soil naturally contains some lead, soil and biota have evolved to accommodate this fact.
For example, many plants ( grasses) sequester large amounts.
Lead is not biomagnified nor bio-accumulated (to use a more accepted term). This is in contrast with
mercury, where fish achieve higher concentrations than algae, and carnivorous fish have more than algae
eaters.
B: Maybe, also add something about the uncertainty about the permanence or reversibility of lead
effects. Some effects are reversible, such as interruption of the heme pathway, while others such as
nerve conduction appear permanent.
C: Please, change the word "measurable" referring to lead levels. It is not helpful, and is only a tribute to
analytical chemists. "Elevated " concentrations would be suitable.
D: Looking at the slopes which summarize the air lead-blood lead relationship, Table 2-7 for example
and elsewhere, it was tempting for me to see how me own earlier experimental assessments of this slope
compare, both from clinical work in Los Angeles and epidemiological work in Boston. I mention the
Los Angeles experience because it is unique in measuring lead intake directly, not as a correlation, but
as a matter of laboratory medicine. Following the template of the table these two estimates follow:
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Adult Populations
Ref hero id 815254 Magnitude of lead intake from respiration
Location: West Los Angeles
Years: 1973-1975
Subjects: Adult Male Veterans (n=5)
Analysis: Long term metabolic balance ward with constant duplicate diets, stable isotope dietary tracer
with and without HEPA filtered air.
Model: linear changes in blood lead from changes in air, incomplete labeling of blood from dietary lead,
and urinary output exceeding dietary uptake
Blood Pb: mean 19, range 17 to 25 ug/dL
Air Lead: 0.07 to 1.9 ug/m3
Slope: 4.4
Children Populations
Ref hero id 093549 Lead in umbilical blood, indoor air, tap water and gasoline in Boston
Location: Boston
Years: 1980-1981
Subjects: Umbilical cord consecutive births n~7000
Analysis: Regression of 14 monthly mean cord blood (n~ 500) against mean indoor air lead (n~12)
Model: Linear
Blood Pb: 4.3-7.0 ug/dL (monthly mean)
Air Lead .02 to .2 ug/m3 (monthly mean)
Slope: 9.1 (est 7 to 10) r=0.71 p<01
Although there was a statistical relationship between monthly average air lead and monthly average cord
blood, many other factors were much more predictive of blood lead levels, including parity, smoking,
and indoor dust lead levels. Regarding subsequent childhood blood lead levels in this population, they
did not correlate with their indoor air lead levels. Soil lead, dust lead, lead paint and refmishing activity
were strong predictors.
We all recognize this blood lead slope is not a constant of nature, like the charge on an electron, where
successively better measurements will yield better estimates of a specific underlying value. Rather the
slope has a spread in values, reflecting variations seen among populations.
These two additional values, 4.4 and 9.1, with different populations at different air lead levels, add to the
picture. Taken with the other studies, there is real consistency, within a factor of two, but also variations
among populations and are evident. One would expect the slope would be steeper for children compared
to adults because of their higher metabolic rate.
The broader issue, which is not fully discussed, is how this slope uncertainty translates into uncertainty
in setting an air standard.
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E: Regarding confounder so lead's effects on child development, I had suggested displaying 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. We should be able to see the extent or strength of
confounding in the various studies, and see the effect size for Pb along with the whole model's
predictive power (r-sqr). That Pb can be shown to have a non-zero coefficient in multiple regression
models, for example, of children's mental performance, is insufficient. 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 ( Wilks criteria) 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 progressively lower Pb levels, where Pb effects are small, blood Pb 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. At these lower but measurable, Pb levels, Pb effects get lower, but the confounders relative
strength increases. For these reasons, at these low levels, effects attributed to Pb by statistically adjusting
for the other covariates, may overstate the case. For that reason showing models with and without the Pb
term would be useful. Also, it may help identify the more critical studies in terms of seeing a "clean" Pb
effect.
Now, let me suggest in tabulating the studies, show both the raw lead coefficient and the adjusted value.
The strength of the confounding in that study would be indicated by the difference between the raw and
adjusted vales. This would guide the reader in weighing the various studies so as to put less weight on
studies with extensive confounding.
F: The role of fluoride in drinking water in elevating blood lead levels needs more elucidation. The
effect may be from increasing the plumbo-solvency of the water, its ability to dissolve lead from metals,
as well as fluoride effect of skeletal metabolism of trace divalent metals. The form of the fluoride
additive and the relevant dosages are unclear.
G: About causation and our ability to make comments about degrees of certainty, I suggested turning to
the legal profession for some guidance or examples. In civil cases of money damages the level of proof
is "more likely than not", while in criminal cases "beyond a reasonable doubt" is the test. As EPA
evolves its considerations of causality something might be gained from the legal precedents.
H: Now that we are able to be concerned with progressively lower lead levels, it might well be time to
revisit the leach-ability of lead from glasses, ceramics, and tableware. Years ago when we getting more
than a hundred ug/day in our diet, the few ug from lead glazes were insignificant, but now with just a
few ug/day ingested from all sources, this might be a more weighty sources of exposure.
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Dr. William Stubblefield
General Comments
In preparing these comments I have reviewed the document, Integrated Science Assessment for Lead
(2nd External Review Draff), with specific attention given to Chapter 7: Ecological Effects of Lead.
Charge Questions Addressed:
Preface, Preamble, Chapters 1 (Executive Summary) and 2 (Integrative Summary)
The CASAC panel offered a number of recommendations to enhance the organization and presentation
of the evidence in the ISA. An Executive Summary has been prepared and is included as Chapter 1. As
part of the development of the Executive Summary and restructuring of the integrative overview chapter,
Chapter 1 materials have been revised and moved, specifically: (a) the more general sections on the
development of the ISA and the causality framework are being placed in a Preamble that can support all
ISAs; (b) the introductory sections specific to this ISA describing the ISA development and scope are
placed at the beginning of Chapter 2; and (c) sections on legislative background and history of previous
reviews are contained in a Preface in the front matter of the ISA. The intent was to bring the integrative
overview discu-ssion to the front of the document, thus making it more accessible to the reader, and to
streamline the ISA organization.
Please review and comment on the effectiveness of these revisions. Please comment on the extent to
which Chapters 1 and 2 comprise a useful and effective approach for presenting this summary
information and conclusions. Please recommend any revisions that may improve the scientific accuracy
or presentation of these summary sections and the conclusions therein.
In addition, please comment the extent to which the discussion of the health effects evidence in Chapters
1 and 2 reflects the revisions to Chapter 5, which were designed to characterize the weight of the
evidence for specific endpoints as well as the strengths and limitations of the studies.
Chapter 7 - Ecological Effects of Lead
The causal statements for ecological effects discussed in Chapter 7 have been reevaluated as advised by
CASAC. There are now separate causal determinations for terrestrial and aquatic biota for each
endpoint under consideration. In addition, the chapter now incorporates additional findings from the
2006 Pb AQCD on the effects ofPb on ecosystem receptors, an enhanced discussion ofbioavailability
andbioaccessibility, and separate discussions of marine and freshwater toxicity in the aquatic
ecosystem section.
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Please comment on the adequacy of these various revisions and other changes to the chapter and
recommend any revisions to improve the discussion of key information.
The following are my preliminary responses to the charge questions. I have focused most of my
attention on the Chapter 7 concerns, but many of the comments are equally applicable to Chapters 1 and
2.1 have also focused primarily on what I consider major concerns; greater detailed and editorial
comments will be provided at the meeting.
1. EPA staff and technical support contractors are to be congratulated for the improvements in
the overall document as a result of the revisions. The document is more readable and
comprehendible and the organizational revisions have improved the overall flow and
technical discussions in each of the chapters and subsections. Increased literature search
efforts have identified a number of studies that greatly improve the database and
understanding of potential effects on ecological receptors attributable to lead. It is noted,
however, that in some cases, industry data developed for the purposes of European REACH
regulation requirements have not been considered in the document. As previously pointed out
by this review panel, additional data are available that may or may not improve the overall
understanding of lead effects on ecological receptors. At a minimum the report should
acknowledge the existence of these data and state justification for not considering these data
in the preparation of the AQCD.
2. Causal relations: A great deal of effort and focus in this document go toward the review and
evaluation of whether lead exposure can result in a variety of effects to exposed terrestrial
and aquatic organisms. In each case, literature data are identified and a conclusion rendered
as to whether the observed effect can be causally linked to lead exposure. The results of these
analyses are contained in Table 7-2: Summary of lead causal determinations for plants,
invertebrates, invertebrates. These conclusions may be misleading, leaving the reader with
the impression that air quality exceedances are leading to adverse effects in exposed
terrestrial and aquatic systems. When in fact, what is actually presented is an array of
potential adverse effects, enzymatic responses, neurological or behavioral responses that an
organism may or may not exhibit depending on the concentration of lead that they are
exposed to. Little information about the exposure concentrations at which these endpoints are
affected and no discussion about the relationship between atmospheric lead concentrations
and observed adverse environmental effects is provided. In some cases, for example Section
7.4.2.6: Survival-aquatic biota, a risk assessment-based approach appears to have been
applied to the evaluation of potential effects. In this section it is noted that "Freshwater biota
that exhibit sensitivity to Pb in the range of Pb concentrations measured in US waters [...]
include some species of gastropods, amphipods, cladocerans, and rotifers although the
toxicity of Pb is highly dependent upon water quality variables as DOC, hardness and pH."
This suggests a comparison of reported toxicity values to measure environmental lead
concentrations and a conclusion that environmental lead concentrations may be sufficient to
cause adverse effects and exposed organisms. No discussion is offered as to whether these
environmental concentrations result from atmospheric deposition, point or nonpoint aquatic
discharges, or natural background concentrations. In most of the other endpoint discussions,
no reference whatsoever is provided to the concentrations at which adverse effects are
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observed and "real world" environmental exposure concentrations, thus leading the reader to
conclude that adverse effects are resulting from current exposure conditions [and by
inference to lead atmospheric discharge concentrations].
3. Nontraditional endpoints: Traditionally the US EPA has limited the use of potential
endpoints to those "higher order biological responses" (e.g., survival, growth, reproduction)
that can be directly related to "population level" effects. Alternative endpoints such as
physiological stress, hematological effects, biochemical and enzymatic responses, and
neurological and neurobehavioral alterations may be affected by lead exposure but the
interpretation of these observed responses and their meaning on a population level remains in
question. This document identifies these endpoints as important observations and attributes
these endpoints to lead exposure. This approach is appropriate if EPA has changed their
stated policy regarding the importance and use of these types of endpoints. And suggests that
in the future EPA should/will be considering these endpoints in the methods employed for
developing contaminant criteria/standards.
4. Prediction of environmental lead concentrations attributable to atmospheric deposition.
Although not specifically part of Chapter 7, this point is key to the interpretation of the entire
AQCD. Measured environmental lead concentrations are a result of a number of potential
inputs, e.g., atmospheric deposition [e.g., stack emissions and blown dust from contaminated
areas], point or nonpoint aquatic discharges, or natural background concentrations. Little use
can be made of environmental monitoring data if we do not have a firm understanding of the
sources that may have resulted in the measured concentrations. It is therefore critical that
EPA take steps to understand the role of atmospheric lead deposition and, if appropriate, to
develop atmospheric deposition models that will allow the prediction of terrestrial and
aquatic lead concentrations and attribute those concentrations to atmospheric sources.
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Dr. Ian von Lindern
Preface, Preamble, Chapters 1 and 2
Please review and comment on the effectiveness of these revisions. Please comment on the extent to
which Chapters 1 and 2 comprise a useful and effective approach for presenting this summary
information and conclusions. Please recommend any revisions that may improve the scientific accuracy
or presentation of these summary sections and the conclusions therein.
Addition of the Preamble and Executive Summary has markedly improved the readability and
comprehensiveness of the document. The previous draft was well-edited, as are the added sections. The
explanation and summaries progress from the most brief to a relatively full (but nevertheless) concise
presentation of the salient issues brought out in the ISA. The historic perspective incorporating the
findings of the previous AQCD findings are a particularly strong addition to the document.
In my opinion this is an excellent document that is both comprehensive and well presented as were the
AQCDs produced in 1977, 1986 and 2006. However, I believe there are three fundamental weaknesses
that detract from the tradition of EPA providing the seminal, scientifically sound review of the existing
knowledge of lead poisoning that was fundamental to developing and implementing effective lead health
policy and response throughout the world.
1. The scope of the review has been amended to an insular and less comprehensive
document that will have adverse effects on the ability of both the EPA and other parties,
who have historically relied on these reviews, to effect comprehensive and holistic
policy.
2. The failure to collect and or assess information relative to the use and disposition of lead
in US commerce, and the decision to exclude globally representative exposures,
precludes the Agency from considering the effects of policy decisions in media other than
air and beyond the boundaries of the US.
3. These factors, combined with diminished monitoring over the past two decades and
reliance on outdated emissions inventories, reduce the Agency's ability to assess risk
across the nation. As a result, EPA must rely on theoretical models, as opposed to
observed exposures, to conduct appropriate risk assessments. Because so little additional
information has been collected in the areas of use, consumption, emission factors, and
ambient monitoring, these models will be a repeat of those supporting the 2006
documents, and will be decades out of date.
General Comments
The fundamental premise underlying the relative weakness of the ISA, in contrast to earlier AQCDs, can
be found on page xlvi of the Preamble that states "... the intent of the ISA is to provide a concise review,
synthesis, and evaluation of the most policy-relevant science to serve as a scientific foundation for the
review of the NAAQS, not extensive summaries of all health, ecological and welfare effects studies for a
pollutant."
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EPA, subsequently, limits the ISA and the definition of "policy relevant science " to the "peer reviewed
literature " and to "exposures within one to two orders of magnitude of those currently observed in the
US".
These limits, nevertheless, have resulted in a massive document that does a masterful job of recounting
the findings of the 2006 AQCD and the state of knowledge with respect to the peer-reviewed literature
from 2006-2010 regarding the health and ecological effects of low-level lead exposure in the US,
Europe and Australia. An entire volume of 550 pages is dedicated to Chapter 5 the Integrated Health
Effects of Lead Exposure. The length and detail presented in Chapter 5 is justifiable, in a health-centric
sense, as a considerable amount of new information has accumulated in that relatively short amount of
time.
In contrast, however, only 18 pages are reserved for Sources of Lead of which relatively little of the
information is new. Moreover, virtually nothing is found in over 1100 pages of lead-related information
regarding the uses or rates of consumption of lead, the role of lead in US and international commerce,
lead production, the level of imports/exports of products and wastes, or the ultimate disposition,
recovery, recycling or disposal of lead-containing materials.
The same deficiency was noted in the last NAAQS review and the 2006 AQCD was admittedly bereft of
this information in comparison to the predecessor documents. It was clear at that time, as in previous
iterations of the AQCD, such information was not to be found in the peer-reviewed literature. In the
1977 and 1986 AQCDs, source, production, and fate information was provided by an active lead
industry in the US, and by EPA staff development and synthesis of trade, professional and commerce
data sources, or so-called grey literature. Among CASAC's responsibilities in those years was to review
the scientific credibility of those analyses and trade data, and its use in the criteria document, and
ultimate formulation of lead policy.
The EPA has, through its change in approach, conveniently both made its job less challenging and short-
changed the policy-makers (also making their job easier) by adopting a rule, exemplified in the ISA and,
pre-destined to similarly limit policy in a myopic and insular way that concludes: If it's not in US air, we
don't care.
The analyses then point out that air lead decreased by more than 90% from the 1970s to 2008. Similarly,
dramatic decreases in blood lead levels in the US population and other biota and environmental media
have also been observed. This is good news for the children, general population, and flora and fauna of
the US; and should be considered a remarkable success in environmental health regulation.
However, a couple of points remain that, perhaps, question the validity of an approach that ignores the
numerous areas of this planet that live two orders of magnitude above current US exposures.
i) In the last analyses of US commercial use of lead in the 2006 AQCD, domestic lead
consumption had increased to levels near the peak tetra-ethyl lead years, presumably for batteries
and the consumer electronics industry. However, domestic lead production had diminished as
drastically as ambient air levels. At the primary smelting level, production will soon be zero as
the last US smelter closes, and responsible recycling capacity in the US is limited.
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The absence of data or analyses in the ISA suggests that EPA, apparently, has little knowledge of
where all this lead comes from, how it is used, how much is recovered or recycled, or its ultimate
disposition. This is even though demand may likely increase as electric cars hit the markets.
Rather than find out, the agency has, through the ISA, devised a way to avoid either finding out
or admitting this deficiency.
ii) Beyond the US borders, in what can only be considered tragic, on a global basis today - more
children are lead-poisoned, at higher absorption levels, unprecedented mortality rates, or with
severe brain trauma doomed to lifetimes of stupidity and dependency - than has ever been
recorded in the peer-review literature.
For EPA to apply the - "If it's not in US air, we don't care " position to these children, the Agency is
seemingly convinced that US lead consumption and poisoned children in other countries are unrelated.
However, it seems naive to believe that a standard, with the policy implications of the NAAQS, has not
influenced the magnitude and associated costs of production, recycling, recovery and disposal of lead
and lead waste, and metals prices. There are numerous examples of poisoned children living in the
vicinity of smelters producing lead for the US market; of discarded US car batteries poisoning children
in Mexico, Latin America and the Caribbean; and of families poisoned from recovering metals from US
e-waste in Africa and Asia. Previous iterations of the AQCDs provided a sound scientific basis for
policy considerations in the US and were relied upon by other national and international entities to
assess, bring attention to, and effect health responses to these situations. EPA, in the past, has and should
continue to, take great pride in this laudable role. The ISA is silent on these issues.
Moreover, the substantial increases in both commodity and precious metals prices over the last five
years have lead to unprecedented increases in both formal and informal mining, smelting and waste
recovery across the globe. Yet the only mention of global lead in the ISA is in reference to "... only fine
particulate lead is of consequence on a global basis, as most large particles fall out near the sources."
This definition implies that only those particle emissions capable of dispersing into this country from
overseas are significant. It is quite possible that the US sends far more lead waste across the oceans in
container ships than the upper atmosphere delivers in small particles to the US.
It seems appropriate for the EPA through the ISA process to inform the Agency decision-makers, the
CAS AC, and eventual policy-makers and reviewers regarding the disposition of lead in US commerce,
the health and environmental effects playing out on the global stage, and any connections or interactions
that may be at play. It also seems incumbent on the Agency to develop the available information and
subject it to the same scrutiny and evaluation that has been so well done regarding low-level health
effects within the current insular viewpoint.
Two examples of current events in the outside world that could be of interest and value to a less myopic
ISA, and in providing a vetted information base for responsible policy development are discussed briefly
below, There are many more.
1. The USEPA has recently concluded Trustee Settlements with Responsible Parties to guarantee
cleanup of lead contaminated sites throughout the United States under CERCLA. These settlements
run to billions of dollars with multi-national corporations. These funds depend on profits made by
these companies producing metals largely in underdeveloped countries that do not subscribe to US
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pollution control standards. In these cases, the US standards and policies have contributed to the
export of the US national production capacity to foreign countries subject to health and
environmental exploitation. The concurrent need for these corporations to route profits to fund US
cleanups could be coming at the expense of pollution control, thus exacerbating the damage done to
children in these communities. Moreover, as the ISA demonstrates, human health risks in the US
have been substantially diminished. As a result, the vast majority of the cleanup activities being
undertaken in this country, with these trust monies, addresses ecological and water quality remedies.
However, these laudable improvements in US "ecological and welfare effects" may well be coming
at the cost of childhood lead poisoning in populations most vulnerable to those SES and concurrent
disease risk co-factors so well identified in the ISA.
2.) There are today sites in Africa where children are dying of lead encephalopathy, in at least one
case, at staggering rates. Some villages in northern Nigeria lost more than 25% of children under
five years of age. An estimated 400-500 children died of lead poisoning in less than one-year in an
overall population of 10,000. More than 2000 children, with blood lead levels averaging greater
than 130 ug/dl, at presentation to clinics, have received multiple rounds ofchelation treatment.
Another 20,000 people are likely lead poisoned and receiving no treatment. Among those are 1500
children under age 5 living in mud-hut homes with soil lead concentrations more than 1 % lead, with
blood lead levels greater than 70 ug/dl, who cannot be provided treatment. A cohort of more than
5000 women, expected to have 5-10 children in their reproductive life, have persisting blood lead
levels greater than 70 ug/dl. These populations live on less than $2 USD/day. More than 90% of the
children presented for chelation have malaria. Mumps, measles, polio and meningitis are endemic in
these communities. Last year more than 250 children under age 5, in hospital, were being
simultaneously treated for lead poisoning, malaria, malnutrition and cholera,
It seems inappropriate that these situations are not considered "policy relevant" and are excluded
from consideration in an "Integrated Science Assessment for Lead". It seems that, at least, a
scientific review of these situations be conducted to assess whether consideration of these
unprecedented case histories can contribute to the knowledge base regarding childhood lead
poisoning, Moreover, it would seem appropriate to provide a properly vetted information basis for
US policy-makers to assess whether regulation of lead in the US facilitates, contributes to, or
possibly could help alleviate these tragedies.
Specific Comments:
Preamble Page Ixvii, line 3: The History section for the NAAQS should also include (with similar
reference to the key decisions) the pre-promulgation history, particularly noting that the EPA initially
proposed regulating airborne lead through Best Available Technology (BAT) controls on point-source
emission sources in 1974-75. The EPA was subsequently sued by public interest groups and eventually
forced by the Courts to develop the NAAQS. Similarly, the promulgation was opposed and delayed by
suits brought by lead industry advocates. These lawsuits were not resolved until 1980 when the NAAQS
became effective. This history is important to underscore the point (well documented in the ISA
discussion that follows in the document) that outside intervention by litigation has routinely been
required to assist and provide guidance to the EPA in undertaking responsible review, assessment, and
promulgation of lead regulation.
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Preamble Page Ixviii, line 29: A brief description of the actual computational basis specifically
justifying the .15 ug/m3 standard, and the rationale for averaging times would be helpful.
Executive Summary Page 1-2: The Section 1.2 discussion refers to Figure to Figure 1.1. The Figure is
excellent and well described later in Chapter 4, but the discussion here seems overly brief and does not
convey to the uninitiated reader the complexity of the Figure, nor the pathways the Figure represents.
There seems to be a need for some transition language for the text immediately preceding and that
following Figure 1.1, which moves from environmental pathway discussion abruptly to blood lead.
Chapter 2 Page 2.5 line 19: Several times in the discussion the term 0 is used to refer to the Preamble.
This seems distractive and could be confusing to uninitiated readers.
Section 2.2.1 Page 2-6 line 9 and Page 2-10 line 6: These discussions refer to "... on a global scale lead
is primarily associated with fine PM." In this context, and in similar discussions throughout the
document, it seems that EPA by implication considers only those lead emissions that reach the US are
significant on a global basis. In turn, this seems to imply that EPA defines the global atmosphere as a
"source" rather than a transport mechanism, or exposure medium; that foreign populations are emitters
rather than co-receptors; and that "local" emissions beyond US borders are unrelated to US policy.
Table 2-1: Including earlier concentrations observed in the US over the past few decades and those
observed globally today would serve to put these relatively low exposures in an historic and
international context.
Page 2-11 line 31: Description of the term "personal cloud effect" would be helpful.
Table 2-7: This Table does not include the slope estimates, nor the supporting studies, used in
promulgation of the NAAQS in 1977-78. As this was the basis for EPA's NAAQS for over 25 years, it
seems it should be listed for contrast with those studies reviewed to support the more recent standard
and accumulating evidence.
Chapter 3 - Source to Concentration
Please comment on the adequacy of these and other changes to the chapter and recommend any
revisions to improve the discussion of key information. Is material clearly, succinctly, and accurately
provided? Where appropriate, please provide guidance that may refine the scientific interpretation
and/or improve the representation of the science.
Sections 3.2 and 3.3: The EPA seemingly knows little about the use, consumption and ultimate
disposition of lead in the US (see earlier general comments). These sections generally report the same
deficient information developed for the 2006 AQCD. The synthesis of this lack of information should
note the scarcity and the implications of being uninformed in this capacity.
Sections 3.4 and 3.5: This Section does a good job of describing the methods and network systems and
the results of the various monitoring efforts. However, it is difficult to get any real answers to important
questions in these sections. This in contrast to the health effects and ecological sections where the
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document provides synthesis analyses and draws significant conclusions with regard to causality, mode
of action, potential effects, etc. It is difficult in the air monitoring sections to determine:
Which sites are monitored for compliance or exposure characterization?
How representative are these sites of the remainder of the country?
How many observations exceed health significant exposures or criteria?
What are the sources of those high levels?
Are measures being undertaken to control those sources?
The most informative presentations are in Tables 3-7 through 3-9 and Figures 3-23 through 3-26. These
tables and figures seem to suggest that non-source- oriented lead TSP, lead-PMlO, lead-PM2.5 show no
lead problem with whatever is being monitored. Does this mean no lead problem for these sites, for
similar sites in the US, or that these techniques are inappropriate?
Source oriented TSP, however, seems to a cause for consternation, at least at those sites being
monitored. The mean concentration for all sites seems to be consistently well above the health
significant level, at least for these sites. What does this imply for the overall US? What confidence does
the EPA have that all significant sources are being monitored? This is particularly troublesome when it
seems the Agency has little idea where, how, or in what quantities lead is used, consumed, or disposed.
In summary, there continues to be no "take away" message with regard to these data and analyses. 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.
Page 3-13 line 2: spelling of "simualated"
Page 3-53 line 23: spelling of "were" where?
Section 3.6.8 and other locations: References to tissue lead concentrations should always indicate
whether these values are wet weight or dry weight basis.
Chapter 4 - Exposure, Toxicokinetics and Biomarkers
The exposure section of Chapter 4 includes additional discussion of the relationship between airborne
Ph-particle size distribution and exposure by inhalation andingestion (e.g., hand-to mouth). Cross-
referencing to Chapter 3 further emphasizes measurement errors and uncertainties that may affect
exposure assessment for air Pb. A new section on exposure assessment methodologies was added that
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includes discussion of exposure representation within the IEUBK model and exposure modeling
techniques.
The revised toxicokinetics section of Chapter 4 expands discussion on the effects of both past and
current Pb exposure on blood Pb levels. Studies that followed blood Pb levels in individuals following
cessation of high Pb exposure occupations and in children over the first several years of life were
added. The section on bone Pb measurement was expanded. Air to blood slopes were reevaluated across
the range of air Pb concentrations available in a given study with an emphasis on the central tendency
of air Pb concentrations in each study.
With consideration of these revisions, please comment on the accuracy of the interpretation of the
science. Are uncertainties and limitations of relevant data, methodologies and approaches adequately
discussed? Where appropriate, please provide specific recommendations to refine the scientific
interpretation and/or improve the representation of the science.
Chapter 4 is well organized, comprehensive and provides an understandable, accurate and balanced
interpretation of the science as related to exposure, toxicokinetics, and biomarkers. The material added
to this draft not only improves the readability of the material, but puts the information in the context of
how it might be used to assess exposure and alternative techniques. The cross reference to Chapter 3 is
an important addition, as uncertainties and insufficiencies in the database are key to reflect in any
attempt to assess exposures.
The addition of the historical perspective provides important insight as to 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. Both Chapters 3 and 4,
however, remain somewhat biased toward the gasoline phase down in this regard and would be better
served by noting that significant emission and air lead reductions achieved in the vicinity of point
sources. The major reductions in point source emissions were achieved through a combination of
pollution control and elimination / curtailment of the industry. Two important aspects of this
realignment go unmentioned. These sources were also significant with respect to other metals and
pollutant exposures that were similarly reduced. The export of the mineral processing operations also
had profound effects with respect to risk co-factors in the US and exposures and systemic effects both
here and abroad. Particularly important in the US were effects associated with numerous other metal-
related pollutant concentration decreases in other media and levels of ecological risk, both locally and
regionally. These effects were both attendant to and independent of the phase down and curtailments in
industrial emissions.
The addition of the IEUBK oriented discussion illustrates the interdependence of various exposure
routes. This is followed by an excellent discussion of other media that effectively summarizes the
current state of knowledge with respect to relative significance of these media in acting as sources, in
pathways, and as receptors. It is 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 US, Europe and Australia, where nearly all the
science has been developed. It might be noted, as a prelude to Section 6, that many foreign and
immigrant populations in the US engage in ethnic and cultural behaviors leaving them more susceptible
to lead intake and uptake.
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Chapter 4 provides a concise and well-developed discussion of the toxicokinetics that is reflective of the
current understanding and practice in risk assessment activities. The overall discussion of the health
significance and interrelationship of the toxicokinetics and biomarkers is informative and well
presented. This chapter also provides a concise summary of exposure / blood lead relationship
representative of the current scientific consensus for this important segment of risk assessment process.
Chapter 5 - Integrated Health Effects of Lead Exposure
In Chapter 5, the integration/synthesis of evidence between epidemiologic and toxicological studies and
across related outcomes has been expanded throughout the text and in summaries of individual
endpoints. In the summary and causal determination sections, we have described more explicitly the
weight of evidence for each endpoint within a broad outcome category and specified the particular
endpoints that contribute most heavily to the determination of causality. We have noted, where
applicable, uncertainties regarding the specific Pb exposure periods, levels, frequency and duration that
contributed to epidemiologic observations and included additional details and discussion of study
limitations.
Please comment on the extent to which the revised discussion of the evidence and the causal
determinations accurately reflect the weight of evidence for endpoints within a major outcome category
and the strengths and limitations of studies (e.g., study design, control for potential confounding,
statistical analysis) that comprise the evidence base.
Please comment on the adequacy with which evidence has been integrated between toxicological and
epidemiologic studies, in particular: the increased emphasis on toxicological findings most relevant to
Ph-associated effects in humans; the discussion of results from homologous or parallel tests (e.g.,
response inhibition, blood pressure, renal function); and discussion of evidence describing modes of
action for Ph-associated health effects. Has the coherence of findings among related endpoints been
sufficiently described? Please comment on the effectiveness of the integration of scientific evidence both
within sections for specific endpoints and summary sections.
Please comment on the extent to which conclusions regarding the blood and bone Pb levels with which
various health effects are associated in epidemiologic studies accurately reflect the weight of evidence
given the study designs and statistical methods employed and populations examined (e.g., school-aged
children, adolescents, adults without occupational exposure, adults with occupational exposure). Are
inferences regarding the specific Pb exposure scenarios (e.g., level, timing, frequency, and duration)
that contributed to the observed associations consistent with the evidence?
Chapter 5 is monumental and is an excellent and impressive summary and synthesis of a subject area in
which incredible advancements have been accomplished both in the last three decades and last five
years.
Chapter 6 - Potentially At-Risk Populations
The introduction to Chapter 6 has been revised with expanded discussion to better capture the
intricacies associated with characterizing populations potentially at greater risk for Ph-i-elated'health
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effects. Please comment on the adequacy of these revisions to clarify the consideration of potential at-
risk populations, and recommend any revisions to improve the characterization of key findings and
scientific conclusions.
In addition, please comment on whether the designation of some factors as having limited evidence
adequately reflects the knowledge base considered and strength of evidence available.
Chapter 6 does an outstanding job of synthesizing the information from the previous chapters and
identifying those populations potentially at risk due to lead exposure. However, it might be noted that
these are hypothetical populations, as an effective national risk assessment is not possible due to the lack
of appropriate exposure data.
Chapter 7 - Ecological Effects of Lead
The causal statements for ecological effects discussed in Chapter 7 have been reevaluated as advised by
CASAC. There are now separate causal determinations for terrestrial and aquatic biota for each
endpoint under consideration. In addition, the chapter now incorporates additional findings from the
2006 Pb AQCD on the effects ofPb on ecosystem receptors, an enhanced discussion ofbioavailability
andbioaccessibility, and separate discussions of marine and freshwater toxicity in the aquatic
ecosystem section.
Please comment on the adequacy of these various revisions and other changes to the chapter and
recommend any revisions to improve the discussion of key information.
Chapter 7 in and of itself is a major contribution to literature and understanding of this long-neglected
aspect of both the mechanisms and the adverse effects of lead on US ecosystems and public welfare.
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Dr. Gail Wasserman
Chapter 1:
1-15 Discussion of Public Health Significance. I found this to be informative and well done.
Chapter 2:
Substantive concerns:
2-55 Discussion at top of page. This figure still troubles me. To be most accurate , the ISA needs to
explicitly indicate that it is a model, for illustrative purposes. It's really not data-based; especially at the
low end, where the model would apply only if exposure/outcome relationship is the same, or of similar
magnitude, across all points on the exposure curve. This place where we lack data to confirm or
disconfirm the model needs to be explicitly stated.
2-66 and 2-67 This discussion, that refers to the non-linearity of the exposure/outcome association I
think has implications for that figure on page 2-55
Smaller edits:
2-15, L 12 I think there is a word added or missing in the parentheses "(prior symptoms of ADHD)"
2-48, Table 2-4 Another place remains where "neurological" remains, and should be ?
neurodevel opmental ? ? ? ?
2-54 L 15 Another place remains where "neurological" remains, and should be ?
neurodevel opmental ? ? ? ?
2-56 L 13 "It is shown " needs a citation
2-72 Table 2-8 I think that the entry should refer to "Exposure to cigarette smoke" rather than to
"Smoking"
2-80 Table 2-10 Under Neurobehavioral Effects, there is a word missing. Should read "and also
misconduct and delinquent behavior"
Chapter 4:
4-82 Figure 4-16. Title should read " among US children (1-5 years old at baseline)" otherwise it is
confusing.
Chapter 5:
Charge questions:
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1. Does the revised discussion of evidence and causal determinations accurately reflect the weight
of evidence for endpoints within a major outcome category and the strengths/weaknesses of studies that
comprise the evidence base.
Overall I think this version reads better, and is far more grounded. This version is more thorough
regarding where we lack definitive answers to questions about exposure characteristics and the weight of
the evidence.
5-62 to 5-64 In the presentation of the papers from Asia of the exposure/IQ association, when expectable
associations between social factors and intelligence do not appear to be significant, it is not clear WHAT
this means. Either this reflects likely cultural differences in which features of the social environment do
and do not contribute to intellectual functioning, or it means that one or another of the constructs (either
the measurement of intelligence or measurement of the social environment) is badly defined. To me, this
is a red flag that study results should be given less critical weight. Perhaps the nature of this limitation
could be better spelled out, as it is likely these studies are not capturing the constructs that should be
adjusted for in those settings.
Section beginning on 5-19. The discussion of ADHD needs to distinguish between (1) measurement that
relies on the cardinal symptoms of the disorder (ie inattention, impulsivity, symptoms are usually
indexed by parent- or teacher-report on a scale, such as Conners or CBCL) and (2) that which is based
on presence of the clinical disorder itself. I suggest that the authors specifically consult the DSM for
information supporting the distinction between symptoms and disorder. This is a conversation we
already had about measuring delinquency via items on a subscale that is labeled "delinquency" but that
may include a range of behaviors (as in the CBCL subscale of that name), and juvenile delinquency
(which is a legal term, referring to being identified, usually by juvenile justice authorities, as breaking a
law). Discussion of the underlying constructs in attention problems would allow for easier mapping onto
animal work. In the discussion of this outcome, the authors should clearly note which outcome they are
considering, and should provide some context about how this disordered is measured, both clinically and
non-clinically.
More broadly, in the section on behavior, it should be noted that there is commonly overlap across types
of behavioral problems. This overlap occurs both within a broad domain ("misconduct", or " attention
problems") as well as across domains (as when depressive symptoms are more common among
individuals who also show conduct symptoms). In this light, investigations that allow for examination of
hypothesized differences across domains in degree of association with lead exposure would seem to be
key. In other words, a higher degree of certainty is provided by studies which look at Pb associations
with both hypothesized and not-hypothesized outcomes, and which can demonstrate that exposure is
related to A (as hypothesized) but not related to B (which was not hypothesized, but which can be
measured in the same way). In our work in Yugoslavia, we did this, with different age-variations of the
CBCL at child age 3 and 4-5 years. In each case, using an instrument that assesses behavior in the same
way (parent report) across a range of types (with a range of subscales for different content areas of
behavior problems). Oddly, the ISA only cites the first study with preschoolers(Wasserman, GA;
Staghezza-Jaramillo, B; Shrout, P; Popovac, D; Graziano, J. (1998). The effect of lead exposure on
behavior problems in preschool children. Am J Public Health 88: 481-486.
http://dx.doi.Org/10.2105/AJPH.88.3.481) and does not refer to the more recent investigation with
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slightly older children at all (Wasserman GA, Liu X, Pine DS, Graziano JH.Contribution of maternal
smoking during pregnancy and lead exposure to early child behavior problems. Neuurotoxicol Teratol.
2001 Jan-Feb;23(l): 13-21). There were 2 studies because the CBCL offered one instrument for the
younger ages, and a somewhat different checklist for the older children.
Here is the abstract for the preschool study (1998): OBJECTIVES: Interpreting associations between
lead exposure and child behavior problems is difficult because studies have not controlled for
sociodemographic confounders or have used shed teeth to mark exposure. This study explored
associations between blood lead and preschool behavior. METHODS: Children from a smelter town and
a non-lead-exposed town in Yugoslavia were followed up prospectively from pregnancy through age 3.
The Child Behavior Checklist was used to assess behavior problems in 379 3-year-olds, controlling for
sociodemographic factors and difficult infant temperament. RESULTS: Multiple regression revealed the
expected significant associations between checklist subscales and sociodemographic factors, which
explained 7% to 18% of the variance on the subscales. Concurrent blood lead explained a significant 1%
to 4% of the variance on the Destructive and Withdrawn subscales. Earlier difficult temperament
explained an additional 2% to 5% of the checklist variance. Scores on the Destructive subscale were
consistently associated with blood lead. As blood lead increased from 10 to 20 micrograms/dL, subscale
scores increased by approximately 0.5 points. CONCLUSIONS: Lead/behavior associations are
significant but small compared with the effects of social factors.
And here is the abstract for the study with 4-5 year olds: Maternal smoking during pregnancy elevates
risk for later child behavior problems. Because prior studies considered only Western settings, where
smoking cooccurs with social disadvantage, we examined this association in Yugoslavia, a different
cultural setting. Mothers enrolled in pregnancy as the low-exposure group in a prospective study of lead
exposure were interviewed about health, including smoking history. A total of 199 children were
assessed on the Child Behavior Checklist (CBCL) at ages 4, 4 1/2, and 5 years. Average cumulative
blood lead (BPb) was determined from serial samples taken biannually since delivery. Longitudinal
analyses were derived from 191 children with available data on behavior and covariates. Smoking was
unrelated to social adversity. Controlling for age, gender, birthweight, ethnicity, maternal education, and
Home Observation for Measurement of the Environment (HOME) Acceptance, smoking was associated
with worse scores on almost all subscales; BPb concentration was related to small increases in the
Delinquency subscale. Daughters of smokers received significantly higher scores on Somatic
Complaints compared to daughters of nonsmokers, consistent with other work relating biological factors
and internalizing problems in young girls. Because the present smoking/child behavior associations
persist after control for individual and social factors also related to behavior problems, possible
biological mediators are considered.
To summarize, then, among 3-year olds, we found that, adjusting for sociodemographic features and
infant temperament, concurrent blood lead explained a significant 1% to 4% of the variance on the
Destructive and Withdrawn subscales (at this age, there is no subscale measuring attention problems,
and the Destructive subscale maps most closely onto misconduct). With the version of the CBCL that
does measure both attention and misconduct, at age 4-5, adjusting for sociodemographic features,
childrearing, and in utero exposure to smoking, we reported significant associations between Pb
exposure and misconduct (Delinquency) but not with Attention Problems, in the paper that was NOT
cited in the ISA. Neither study, then, found support for a specific association with attention problems,
although misconduct was related to exposure.
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2. How adequately has evidence been integrated between toxicological and epidemiological
studies, in particular the increased emphasis on toxicological findings most relevant to Pb-associated
effects in humans
Overall, I think there is far more integration across the modes of scientific inquiry (epidemiology and
toxicology). This makes interpretation much more accessible for the reader. Within the information
presented on cognitive and behavioral endpoints, I think there are two places where more should be
provided.
First, on 5-91 in the text at bottom of page. I think it is quite a leap to equate maternal self-esteem in
humans with maternal stress in animals. In other areas of investigation, for example, maternal stress in
animals has been used in models for maternal depression.
Second, on page 5-92 L 22, "overall FI rate" is designated "a hyperactive behavior". Do the authors
mean "overactive"? Do they mean to reference the disorder of ADHD? Would a mention of impulsivity
be more apt? So much of ADHD relates to issues of distractibility and impulsivity, rather than
movement, that this is confusing. We need the dots to be connected here.
3. How well does the document integrate scientific evidence both within sections for specific
endpoints and summary sections.
The authors have clearly expended effort to provide the cross-talk that this document needed, within and
across endpoints. I think it reads better and more forcefully now.
4. Do conclusions regarding the blood and bone Pb levels with which various health effects are
associated in epidemiologic studies accurately reflect the weight of evidence given the study designs and
statistical methods employed and the populations examined (e.g., school-aged children, adolescents,
adults with and without occupational exposure).
Overall, a fair and thorough presentation of the evidence.
5. Are inferences regarding the specific Pb exposure scenarios (e.g., level, timing, frequency, and
duration) that contributed to the observed associations consistent with the evidence?
5-52 L 21-27. It's not clear if second half of this paragraph is referring back to the Lanphear pooled
analysis or to the base of work reviewed in the 2006 document, or to something else.
Similarly, in the "most strongly indicated in children with " sentence, it should probably be clarified
that the differences in the exposure levels most commonly identified as promoting risk are related to the
distributions of exposures in the populations studied, and not really to identifying which exposure is
most risky.
Further substantive concerns:
5-63 Fig 5-3. In presenting this figure from its original source, considerable information was not carried
over in the figure legend, making this impossible to understand. Specifically, that the 3 lines reflect CI's,
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what is the meaning of "A" and "B", and what units are presented (both exposure and IQ are presented
with negative values, no units indicated). Figure 5-12 (on page 5-111) does a better job at explaining
what is being shown.
5-66 LI "MDI scores are... .[substitute for " not necessarily" instead "only modestly"] correlated with
IQ scores". It's not that this association appears sometimes, it is that it is of small magnitude. I think this
is an important distinction, as it speaks to the underlying construct, not just to variability across
investigations.
5-213-216 Overall, I think the discussion of public health significance adds considerably to the weight
of the evidence presented. On the other hand, there are still problems with the discussion that relates to
increasing the proportions of individuals in the clinical range for IQ. This relates back also to the figure
presented on p 2-55. It's noted on P 214 that these projections are based "on purely statistical grounds"
but I don't think the distinction between an illustrative model and actual data is really highlighted. And
these models are still based on the assumption that the impact of Pb is the same across all levels of
ability, which is something we don't know, and which should be explicitly indicated. Here in chapter 5
(and again in chapter 2) it should be clearly stated, if this figure is to be provided, that it is a model, for
illustration only, and it assumes that the impact of exposure is the same at every point on the ability
curve (for which there is little, or no, evidence).
The evidence that is provided, as in particular vulnerabilities of children at low SES, and the possibility
of earlier, accumulating deficits with some groups of children, supports the determination of public
health significance
Smaller edits:
5-60 L 24. In which one study ... [at a time]... was successively excluded" or something similar, for
clarity
5-72 L 8 "because several tests... [and their underlying functions]... .are interrelated". It's more
important that the constructs interrelate, rather than that the measures interrelate
5-77 L 1 and 3. Words missing: "Rochester cohort [at] age 5 years" and "same tests [of] executive
function"
5-78 L 21. Word missing "performance [on] a color-word"
5-79 L 17 Should read "blood Pb level, the decrease[s] in.
5-84 L 9 Maybe not 2 "demonstrate"s in same line?
5-91 Table 5-7. This table is a bit telegraphic. Hard to see what is being shown. At least define NS, OS,
and PS.
L8 Whose "ability to cope" are we talking about? Mom's? offspring's?
5-104 L 13.1 don't know if it was defined elsewhere, but this is a long chapter, and NAS should be
defined here, or redefined here, when it is discussed.
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5-131 L28 What is meant by indirect effects?
L 34 missing word, "out [of] the range of..."
5-136 L 8, More proximal to this discussion, suggest writing out what is the CLS cohort?
5-137 L 15 "may [lie] on the"
5-141 L4 "investigation[s]"
5-144 L9. I think these are meant to be "disorders" rather than "symptoms'"
Chapter 6- Potentially at-risk populations
Charge questions:
1. ... the adequacy of these revisions to clarify the consideration of potential at-risk populations,
and recommend any revisions to improve the characterization of key findings and scientific conclusions.
2. ... whether the designation of some factors as having limited evidence adequately reflects the
knowledge base considered and strength of evidence available.
I think the evidence base is presented in a full fair manner. For some individual factors, even within a
single outcome area, there are inconsistencies in the degree to which this factor relates to increased
vulnerability to Pb exposure across studies. For example, on page 6-20, first paragraph, some studies
find increased risk for males (as in frontal lobe grey matter loss in Brubaker and greater cognitive
deficits in a Polish cohort), while others (as in Port Pirie) report poorer cognitive scores in females.
These inconsistencies are mentioned as a reason for further research. Maybe there isn't any better way to
integrate these, but the fact that there are inconsistencies also speaks to the certainty with which we
weight these findings, and this needs to be made more clear.
Overall, the discussion of the dynamic nature of some of these associations (the declining race
differences in vulnerability in the US, for example) is informative.
6-34 L 4. Again, there is an equation suggested between maternal stress in animals and lower maternal
self-esteem in humans (point also made on 5-91), that I think needs to be more fully considered.
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