v>EPA
EPA/600/R-23/061
United States .. ,
Environmental Protection iviarcn zuzj
Agency www.epa.gov/isa
Integrated Science
Assessment for Lead
External Review Draft
March 2023
Health and Environmental Effects Assessment Division
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
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DISCLAIMER
This document is an external review draft for peer review purposes only. This information is
distributed solely for the purpose of predissemination peer review under applicable information quality
guidelines. It has not been formally disseminated by the Environmental Protection Agency. It does not
represent, and should not be construed to represent, any Agency determination or policy. Mention of trade
names or commercial products does not constitute endorsement or recommendation for use.
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DOCUMENT GUIDE
This Document Guide is intended to orient readers to the organization of the Lead (Pb) Integrated
Science Assessment (ISA) in its entirety and to the subsection of the ISA at hand (indicated in bold). The
ISA consists of the Front Matter (list of authors, contributors, reviewers, and acronyms), Executive
Summary, Integrated Synthesis, and 12 Appendices, which can all be found at
https://cfpub.cpa.gov/ncca/isa/rccordisplav.cfm 'Mcid=357282.
Front Matter
Executive Summary
Integrative Synthesis
Appendix 1. Lead Source to Concentration
Appendix 2. Exposure, Toxicokinetics, and Biomarkers
Appendix 3. Nervous System Effects
Appendix 4. Cardiovascular Effects
Appendix 5. Renal Effects
Appendix 6. Immune System Effects
Appendix 7. Hematological Effects
Appendix 8. Reproductive and Developmental Effects
Appendix 9. Effects on Other Organ Systems and Mortality
Appendix 10. Cancer
Appendix 11. Effects of Lead in Terrestrial and Aquatic Ecosystems
Appendix 12. Process for Developing the Pb Integrated Science Assessment
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CONTENTS
LIST OF TABLES vi
LIST OF FIGURES viii
INTEGRATED SCIENCE ASSESSMENT TEAM FOR LEAD ix
AUTHORS, CONTRIBUTORS, AND REVIEWERS xi
ACRONYMS AND ABBREVIATIONS xvii
EXECUTIVE SUMMARY ES-1
ES.1 Purpose and Scope of the Integrated Science Assessment for Lead (Pb) ES-1
ES.2 Pb in Ambient Air ES-2
ES.3 Fate and Transport ES-3
ES.4 Trends ES-4
ES.5 Exposure ES-5
ES.6 Health and Welfare Effects of Pb Exposure ES-7
ES.6.1 Health Effects of Pb Exposure ES-7
ES.6.2 Welfare Effects of Pb Exposure ES-11
ES.7 Key Aspects of Health and Welfare Effects Evidence ES-15
ES.7.1 Health Effects Evidence: Key Findings ES-16
ES.7.2 Welfare Effects Evidence: Key Findings ES-18
INTEGRATED SYNTHESIS FOR LEAD IS-1
15.1 Introduction IS-2
15.1.1 Purpose and Overview IS-2
15.1.2 Pb Integrated Science Assessment Process and Development IS-3
15.2 Pb Source to Concentration IS-8
15.2.1 Sources and Emissions IS-9
15.2.2 Fate and Transport IS-9
15.2.3 Sampling and Analysis IS-11
15.2.4 Ambient Air Pb Concentrations IS-12
15.3 Trends IS-12
15.4 Human Exposure to Ambient Pb IS-16
15.5 Toxicokinetics IS-17
15.6 Pb Biomarkers IS-19
15.7 Evaluation of the Health Effects of Pb IS-20
15.7.1 Connections Among Health Effects IS-20
15.7.2 Biological Plausibility IS-21
15.7.3 Summary of Health Effects Evidence IS-23
15.7.4 At-Risk Populations IS-57
15.8 Evaluation of Welfare Effects of Pb IS-70
15.8.1 Summary of Effects on Terrestrial Ecosystems IS-71
15.8.2 Summary of Effects on Freshwater Ecosystems IS-73
15.8.3 Summary of Effects on Saltwater Ecosystems IS-76
15.8.4 Summary of Welfare Effects Evidence IS-79
15.8.5 Summary of Causality Evidence for Ecological Effects of Pb IS-80
15.9 Policy-Relevant Issues IS-98
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15.9.1 Air Pb-to-Blood Pb Relationships IS
15.9.2 Concentration-Response Relationships for Human Health Effects IS-
15.9.3 Lifestages and Timing of Pb Exposure Contributing to Observed Nervous System
Effects IS-
15.9.4 Ecological Effects and Corresponding Pb Concentrations IS-
References IS-
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LIST OF TABLES
Table IS-1
Table IS-2A
Summary of causality determinations by health outcome.
IS-23
Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and nervous system effects ascertained during childhood, adolescent, and young adult
lifestages. IS-27
Table IS-2B Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and nervous system effects ascertained during childhood, adolescent, and young adult
lifestages. IS-29
Table IS-2C Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and nervous system effects ascertained during childhood, adolescent, and young adult
lifestages. IS-30
Table IS-2D Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and nervous system effects ascertained during childhood, adolescent, and young adult
lifestages. IS-32
Table IS-2E Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and nervous system effects ascertained during childhood, adolescent, and young adult
lifestages. IS-33
Table IS-2F Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and nervous system effects ascertained during childhood, adolescent, and young adult
lifestages. IS-35
Table IS-3A Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and nervous system effects ascertained during adult lifestages. IS-37
Table IS-3B Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and nervous system effects ascertained during adult lifestages. IS-39
Table IS-4 Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and cardiovascular effects. IS-42
Table IS-5 Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and renal effects. IS-43
Table IS-6A Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and immune system effects. IS-45
Table IS-6B Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and immune system effects. IS-47
Table IS-7 Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and hematological effects. IS-49
Table IS-8A Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and reproductive and developmental effects. IS-51
Table IS-8B Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and reproductive and developmental effects. IS-53
Table IS-9 Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and musculoskeletal effects. IS-54
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Table IS-10 Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and total (nonaccidental) mortality. IS-56
Table IS-11 Summary of evidence from epidemiologic and animal toxicological studies on Pb exposure
and cancer. IS-57
Table IS-12 Characterization of evidence for factors potentially increasing the risk for Pb-related health
effects. IS-58
Table IS-13 Summary of evidence for populations at increased risk to the health effects of Pb. IS-61
Table IS-14 Summary of causality determinations for welfare effects of Pb. IS-80
Table IS-15 Summary of evidence for effects of Pb on physiological stress endpoints in terrestrial and
aquatic biota. IS-81
Table IS-16 Summary of evidence for effects of Pb on hematological endpoints in terrestrial and
aquatic biota. IS-84
Table IS-17 Summary of evidence for effects of Pb on neurobehavioral endpoints in terrestrial and
aquatic biota. IS-86
Table IS-18 Summary of evidence for effects of Pb on survival of terrestrial and aquatic biota. IS-88
Table IS-19 Summary of evidence for growth effects of Pb in terrestrial and aquatic biota. IS-91
Table IS-20 Summary of evidence for reproductive effects of Pb in terrestrial and aquatic biota. IS-94
Table IS-21 Summary of evidence for community and ecosystem effects of Pb. IS-97
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LIST OF FIGURES
Figure ES-1 Conceptual model of multimedia Pb exposure. ES-6
Figure ES-2 Summary of causality determinations by exposure duration and health outcome. ES-8
Figure ES-3 Summary of causality determinations for ecological effects of Pb. ES-12
Figure IS-1 Maps of Pb sampled from A-horizon (A.) and C-horizon (B.) soils, the ratio of Pb observed
in A-horizon to C-horizon soils (C.), and population density (D.). IS-14
Figure IS-2 Illustrative figure for potential biological pathways for health effects following Pb exposure. IS-22
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INTEGRATED SCIENCE ASSESSMENT TEAM FOR LEAD
Executive Direction
Dr. John Vandenberg (Director)—former Health and Environmental Effects Assessment
Division, Center for Public Health and Environmental Assessment, Office of Research
and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Steven J. Dutton (Director)—Health and Environmental Effects Assessment Division,
Center for Public Health and Environmental Assessment, Office of Research and
Development, U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Emily Gibb Snyder (Associate Director)—Health and Environmental Effects
Assessment Division, Center for Public Health and Environmental Assessment, Office of
Research and Development, U.S. Environmental Protection Agency, Research Triangle
Park, NC
Dr. Scott Jenkins (Branch Chief)—Health and Environmental Effects Assessment Division,
Center for Public Health and Environmental Assessment, Office of Research and
Development, U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Jane Ellen Simmons (Branch Chief)—former Health and Environmental Effects
Assessment Division, Center for Public Health and Environmental Assessment, Office of
Research and Development, U.S. Environmental Protection Agency, Research Triangle
Park, NC
Dr. Christopher Weaver (Branch Chief)—Health and Environmental Effects Assessment
Division, Center for Public Health and Environmental Assessment, Office of Research
and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC
Technical Support Staff
Ms. Shannon Cassell—former Oak Ridge Associated Universities, Health and
Environmental Effects Assessment Division, Center for Public Health and Environmental
Assessment, Office of Research and Development, U.S. Environmental Protection
Agency, Research Triangle Park, NC
Ms. Amanda Haddock—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Mr. Max Hatala—Oak Ridge Associated Universities, Health and Environmental Effects
Assessment Division, Center for Public Health and Environmental Assessment, Office of
Research and Development, U.S. Environmental Protection Agency, Research Triangle
Park, NC
Ms. Danielle Moore—former Senior Environmental Employment Program, Health and
Environmental Effects Assessment Division, Center for Public Health and Environmental
Assessment, Office of Research and Development, U.S. Environmental Protection
Agency, Research Triangle Park, NC
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Mr. Sam Penry—Oak Ridge Associated Universities, Health and Environmental Effects
Assessment Division, Center for Public Health and Environmental Assessment, Office of
Research and Development, U.S. Environmental Protection Agency, Research Triangle
Park, NC
Ms. Karlee Shadle—Oak Ridge Associated Universities, Health and Environmental Effects
Assessment Division, Center for Public Health and Environmental Assessment, Office of
Research and Development, U.S. Environmental Protection Agency, Research Triangle
Park, NC
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
Authors
Mr. Evan Coffman1' (Health Assessment Team Lead, Integrated Science Assessment for
Lead)—Health and Environmental Effects Assessment Division, Center for Public Health
and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Meredith Lass iter' (Welfare Assessment Team Lead, Integrated Science Assessment for
Lead)—Health and Environmental Effects Assessment Division, Center for Public Health
and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Ms. Anna Champlin1' (Project Manager, Integrated Science Assessment for Lead)—Health
and Environmental Effects Assessment Division, Center for Public Health and
Environmental Assessment, Office of Research and Development, U.S. Environmental
Protection Agency, Washington, DC
Dr. Timothy Anderson—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Mr. Michael Beuthe—Technology Innovation and Field Services Division, Office of
Superfund Remediation and Technology Innovation, Office of Land and Emergency
Management, U.S. Environmental Protection Agency, Edison, NJ
Ms. Katie Boaggio—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. James Brown—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Barbara Buckley—former Health and Environmental Effects Assessment Division,
Center for Public Health and Environmental Assessment, Office of Research and
Development, U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Peter Byrlcy '—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Laura M. Carlson—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Catheryne Chiang—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Rebecca Dalton—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (Continued)
Dr. Stephanie DcFlorio-Barker'—Health and Environmental Effects Assessment Division,
Center for Public Health and Environmental Assessment, Office of Research and
Development, U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Jean-Jacques Dubois—Health and Environmental Effects Assessment Division, Center
for Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Parker F. Duffney—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Ms. Zahra Gohari—Oak Ridge Associated Universities, Health and Environmental Effects
Assessment Division, Center for Public Health and Environmental Assessment, Office of
Research and Development, U.S. Environmental Protection Agency, Research Triangle
Park, NC
Ms. Rebecca Gray—ICF, Durham, NC
Dr. Brooke L. Hemming—Health and Environmental Effects Assessment Division, Center
for Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Kirstin Hester—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Anthony Jones—Health and Environmental Impacts Division, Office of Air Quality
Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection
Agency, Research Triangle Park, NC
Dr. S. Douglas Kaylor—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Ms. Haesoo Kim— Oak Ridge Associated Universities, Health and Environmental Effects
Assessment Division, Center for Public Health and Environmental Assessment, Office of
Research and Development, U.S. Environmental Protection Agency, Research Triangle
Park, NC
Dr. Ellen Kirranc'—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Alison Krajcwski'—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Ms. Nichole Kulikowski—Health and Environmental Effects Assessment Division, Center
for Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Washington, D.C.
Dr. Archana Lamichhane—Health and Environmental Impacts Division, Office of Air
Quality Planning and Standards, Office of Air and Radiation, U.S. Environmental
Protection Agency, Research Triangle Park, NC
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (Continued)
Ms. Emma Leath—Oak Ridge Associated Universities, Health and Environmental Effects
Assessment Division, Center for Public Health and Environmental Assessment, Office of
Research and Development, U.S. Environmental Protection Agency, Research Triangle
Park, NC
Dr. David M. Lchmann '—Health and Environmental Effects Assessment Division, Center
for Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Cynthia Lin—ICF, Durham, NC
Dr. Qingyu Meng—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Stephen McDow'—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Leigh C. Moorhead—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Anuradha Mudipalli—Health and Environmental Effects Assessment Division, Center
for Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Natalia Neal-Walthall—Oak Ridge Associated Universities, Health and Environmental
Effects Assessment Division, Center for Public Health and Environmental Assessment,
Office of Research and Development, U.S. Environmental Protection Agency, Research
Triangle Park, NC
Dr. Kristopher Novak—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Nicole Olson—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Russell D. Owen—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Michael Pennino—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Washington, D.C.
Mr. R. Byron Rice—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Rachel M. Shaffer—Chemical Pollutant Assessment Division, Center for Public Health
and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Washington, D.C.
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (Continued)
Dr. Michael Stew art '—Research Planning & Implementation Staff, Center for Public Health
and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
fAppendix Lead.
Contributors
Ms. Meredith Clemons—ICF, Durham, NC
Dr. Sorina Eftim—ICF, Durham, NC
Ms. Julia Finver—ICF, Durham, NC
Ms. Alexandra Goldstone—ICF, Durham, NC
Ms. Tara Hamilton—ICF, Durham, NC
Mr. Anthony Hannani—ICF, Durham, NC
Ms. Michele Justice—ICF, Durham, NC
Ms. Afroditi Kastigiannakis—ICF, Durham, NC
Ms. Anna Kolanowski—ICF, Durham, NC
Ms. Madison Lee—ICF, Durham, NC
Dr. Nathan Lothrop—ICF, Durham, NC
Ms. Denyse Marquez Sanchez—ICF, Durham, NC
Dr. Michelle Mendez—ICF, Durham, NC
Ms. Melissa Miller—ICF, Durham, NC
Ms. Danielle Moore—ICF, Durham, NC
Mr. Kevin O'Donovan—ICF, Durham, NC
Ms. Emily Pak—ICF, Durham, NC
Ms. Sheerin Shirajan—ICF, Durham, NC
Ms. Swati Sriram—ICF, Durham, NC
Ms. Nkoli Ukpabi—ICF, Durham, NC
Dr. Janielle Vidal—ICF, Durham, NC
Ms. Connie Xiong—ICF, Durham, NC
Ms. Maricruz Zarco—ICF, Durham, NC
Reviewers
Dr. Britta Bierwagen—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Washington, DC
Dr. Joseph Braun—Brown University
Dr. Kevin Brix—University of Miami
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (Continued)
Mr. Halil Cakir—Air Quality Assessment Division, Office of Air Quality Planning and
Standards, Office of Air and Radiation, U.S. Environmental Protection Agency, Research
Triangle Park, NC
Mr. Kevin Cavender—Air Quality Assessment Division, Office of Air Quality Planning and
Standards, Office of Air and Radiation, U.S. Environmental Protection Agency, Research
Triangle Park, NC
Dr. Jasim Chowdhury—International Lead Association
Ms. Rebecca Daniels—Public Health and Integrated Toxicology Division, Center for Public
Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Cliff Davidson—Syracuse University
Dr. Rodney Dietert—Cornell University College of Veterinary Medicine
Dr. Aimen Farraj—Public Health and Integrated Toxicology Division, Center for Public
Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Gabriel Filippelli—Indiana University-Purdue University Indianapolis School of Science
Ms. Jessica Frank—Science Policy Division, Office of Science Advisor, Policy and
Engagement, U.S. Environmental Protection Agency, Washington, DC
Dr. Eliseo Guallar—Johns Hopkins University
Dr. Iman Hassan— Health and Environmental Impacts Division, Office of Air Quality
Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection
Agency, Research Triangle Park, NC
Ms. Beth Hassett-Sipple—Health and Environmental Effects Assessment Division, Center
for Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Erin Hines—Public Health and Integrated Toxicology Division, Center for Public Health
and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Andrew Hotchkiss—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Marion Hoyer—Assessment and Standards Division, Office of Transportation and Air
Quality, Office of Air and Radiation, U.S. Environmental Protection Agency, Ann Arbor,
MI
Dr. Mary Hutson—Health and Environmental Impacts Division, Office of Air Quality
Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection
Agency, Research Triangle Park, NC
Ms. Hali Kerr, Attorney-Advisor— Air and Radiation Law Office, Office of General
Counsel, U.S. Environmental Protection Agency, Washington, DC
Dr. Roman Lanno—Ohio State University
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (Continued)
Dr. Qingyu Meng1—Health and Environmental Effects Assessment Division, Center for
Public Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Ms. Leigh Meyer—Health and Environmental Impacts Division, Office of Air Quality
Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection
Agency, Research Triangle Park, NC
Dr. Deirdre Murphy—Health and Environmental Impacts Division, Office of Air Quality
Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection
Agency, Research Triangle Park, NC
Dr. Zachary Pekar—Environmental Impacts Division, Office of Air Quality Planning and
Standards, Office of Air and Radiation, U.S. Environmental Protection Agency, Research
Triangle Park, NC
Mr. Venkatesh Rao—Air Quality Assessment Division, Office of Air Quality Planning and
Standards, Office of Air and Radiation, U.S. Environmental Protection Agency, Research
Triangle Park, NC
Dr. Justin Richardson—University of Massachusetts Amherst
Dr. Jennifer Richmond-Bryant—North Carolina State University
Dr. Christina Sobin—University of Texas at El Paso
Dr. Aaron Specht—Purdue University
Dr. Jay Turner—Washington University - McKelvey School of Engineering
Dr. Rosalind Wright—Icahn School of Medicine at Mount Sinai
1 Dr. Meng was affiliated with CalEPA at the time of the exposure topic of the Peer Input Workshop that took place
on June 29, 2022.
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ACRONYMS AND ABBREVIATIONS
AD Alzheimer's disease
ADHD attention-deficit/hyperactivity disorder
AL allostatic load
ALAD S-aminolevulinic acid dehydratase
APOE apolipoprotein E
AQCD Air Quality Criteria Document
AQS Air Quality System
AWQC ambient water quality criteria
BAEP brainstem auditory evoked potentials
BLL blood lead level
BLM biotic ligand model
BMI body mass index
BMS Baltimore Memory Study
BP blood pressure
Ca2+ calcium ion
CAD coronary artery disease
CASAC Clean Air Scientific Advisory
Committee
Cd cadmium
CEC cation exchange capacity
CHD coronary heart disease
CI confidence interval
C-R concentration-response
CVD cardiovascular disease
d day(s)
DOC dissolved organic carbon
DTH delayed-type hypersensitivity
EC 10 effect concentration at 10% inhibition
EC50 half maximal effect concentration
Fe iron
FRM Federal Reference Method
FSIQ full-scale intelligence quotient
GABA gamma aminobutyric acid
GRIN glutamate ionotropic receptor N methyl
D aspartate-type subunit
GST glutathione S-transferase
HAZ height-for-age Z-score
Hb hemoglobin
HERO Health and Environmental Research
Online
HFE hemochromatosis gene
HISA Highly Influential Scientific
Assessment
HMOX1 heme oxygenase-1
hr hour(s)
HRV heart rate variability
IEUBK Integrated Exposure Uptake Biokinetic
IFN-y interferon gamma
Ig immunoglobulin
IHD ischemic heart disease
IL-4 interleukin-4
IQ intelligence quotient
IRP Integrated Review Plan
IS Integrated Synthesis
ISA Integrated Science Assessment
KNHANES Korea National Health and Nutrition
Examination Survey
LC lethal concentration
LECES Level of Biological Organization,
Exposure, Comparison, Endpoint, and
Study Design
LOEC lowest observed effect concentration
MDI Mental Development Index
Mg2+ magnesium ion
MI myocardial infarction
mo month(s)
mtDNA mitochondrial DNA
NAAQS National Ambient Air Quality
Standards
NAS Normative Aging Study
NASGLP North American Soil Geochemical
Landscapes Project
NEI National Emissions Inventory
NHANES National Health and Nutrition
Examination Survey
NOAA National Oceanic and Atmospheric
Administration
NOEC no observed effect concentration
OM organic matter
OMB Office of Management and Budget
Pb lead
PDI Psychomotor Developmental Index
PECOS Population, Exposure, Comparison,
Outcome, and Study
PHQ Patient Health Questionnaire
PM particulate matter
PP pulse pressure
PQAPP Program-level QA Project Plan
QA quality assurance
RBC red blood cell
SE standard error
SES socioeconomic status
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SHEDS Stochastic Human Exposure and Dose VDR vitamin D receptor
Simulation week(s)
SNP single nucleotide polymorphism yr year(s)
Th T helper
TSP total suspended particulate
TT tetanus toxoid
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EXECUTIVE SUMMARY
ES.1 Purpose and Scope of the Integrated Science Assessment for
Lead (Pb)
The federal Clean Air Act (CAA) requires the United States Environmental Protection Agency
(U.S. EPA) to set National Ambient Air Quality Standards (NAAQS) for criteria air pollutants that are
considered harmful to public health and the environment, including lead (Pb), and to periodically review
the science upon which the NAAQS are based. Pb emitted into air can be inhaled/ingested or can deposit
and accumulate in other environmental media (e.g., soil, water, sediment, biota), contributing to a wide
range of effects in humans and wildlife. This Integrated Science Assessment (ISA), prepared by the U.S.
EPA, is a synthesis and evaluation of the most policy-relevant science that forms the scientific foundation
for the review of the primary (health-based) and secondary (welfare-based) NAAQS for Pb. The Pb
primary NAAQS is established to protect public health, including at-risk populations, with an adequate
margin of safety. The Pb secondary NAAQS is intended to protect the public welfare from known or
anticipated adverse effects of Pb in the ambient air, and, in this regard, this ISA focuses specifically on
ecological effects.
This Executive Summary provides an overview of the important conclusions drawn in the ISA
across scientific disciplines, beginning with information on sources of Pb emissions in ambient air, the
fate and transport of Pb in the environment, concentration trends of Pb in air and non-air media, and
pathways of exposure, followed by the health and welfare effects of Pb. Health effects evidence evaluated
in the Pb ISA includes experimental animal studies and observational epidemiologic studies. Welfare
effects evidence evaluated in the Pb ISA includes studies examining the effects of Pb on terrestrial,
freshwater, and saltwater ecosystems and biota. A more extensive summary of the evidence and
conclusions of the Pb ISA is presented in the Integrated Synthesis, and detailed study-level information
and an in-depth characterization of the weight-of-evidence conclusions are included in individual
appendices for each topic area. Studies considered in the development of the ISAs are documented in the
U.S. EPA Health and Environmental Research Online (HERO) database. The publicly accessible HERO
project page for this ISA contains the references that were considered for inclusion and provides
bibliographic information and abstracts.
The previous ISA for Pb was published in 2013 (U.S. EPA. 2013a) and included peer-reviewed
literature published through September 2011. Prior Pb assessments include the 2006 Air Quality Criteria
Document (AQCD) for Pb (U.S. EPA. 2006a'). the 1986 Pb AQCD (U.S. EPA. 1986b) and its associated
addendum (U.S. EPA. 1986d). the 1990 Supplement to the 1986 addendum (U.S. EPA. 1990). and the
1977 Pb AQCD (U.S. EPA. 1977). The most recent review of the primary and secondary Pb NAAQS was
completed in 2016, at which time the existing standards from 2008 were retained without revision (81 FR
71906). In the 2008 review, the interpretation of the science in the 2006 AQCD led to a policy decision to
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lower the levels of the primary and secondary NAAQS for Pb by ten-fold, from the 1978 levels of
1.5 |ig/m3 to a level of 0.15 |ig/nr\ The averaging time was revised to a rolling three-month period with a
maximum (not-to-be-exceeded) form, evaluated over a three-year period. EPA's decision to revise the
primary standard in 2008 was based on the substantially expanded body of health effects evidence
available at that time, including evidence for cognitive effects of Pb exposure in children. The revised
2008 standard was established to increase protection against air Pb related human health effects, including
neurocognitive effects, for children and other at-risk populations. In 2016, the EPA Administrator
concluded that the existing primary standard provides health protection from air emissions for Pb for at-
risk groups, especially children, and the existing secondary standard provides protection against adverse
effects to public welfare from air emissions for Pb, including harm to aquatic and terrestrial ecosystems
(81 FR 71906).
This ISA focuses on synthesizing and integrating the evidence that has become available since the
2013 Pb ISA with the information and conclusions from previous assessments. Key policy-relevant
conclusions are intended to inform the EPA's review of the Pb NAAQS, including conclusions on the
populations at increased risk of Pb-related effects, the Pb exposure concentrations at which such effects
occur, and the overall strength of the evidence supporting relationships between Pb exposures and health
or welfare effects. Conclusions on the overall strength of evidence are described using a five-level
hierarchy that classifies the weight of evidence for causation into one of the following categories:
• Causal relationship
• Likely to be a causal relationship
• Suggestive of, but not sufficient to infer, a causal relationship
• Inadequate to infer a causal relationship
• Not likely to be a causal relationship
These causality determinations are made for broad health and welfare effect categories and are
informed by evaluating evidence across scientific disciplines for consistency, coherence, and biological
plausibility, as well as for uncertainties. The ISA's approach to evaluating the weight of evidence and
reaching causality determinations is described in more detail in the Preamble to the Integrated Science
Assessments (U.S. EPA. 2015).
ES.2 Pb in Ambient Air
Exposure to Pb can occur from contaminated air, water, soil and dust. When it is released from
industrial processes into the air, Pb is mainly emitted into the air in particulate form (IS.2.3). In general,
fine particulate Pb is mostly soluble and removed from the atmosphere by wet deposition, and coarse
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particulate Pb is mostly insoluble and removed from the atmosphere by dry deposition. Total Pb
emissions have steadily decreased for decades largely due to the elimination of leaded gasoline used in
automobiles before 1996, and, in later years, to reductions in emissions from metals processing sources
(U.S. EPA. 2022b. 2013a. 2006b). From 1990 to 2020, there was a steep decline in total U.S. Pb
emissions, from about 5 kton/year to less than 1 kton/year. Over this time period, industrial sources have
been replaced by non-road mobile sources as the dominant category of Pb emissions, with emissions from
aircraft that operate on leaded aviation fuel as the largest emissions source in this category (U.S. EPA.
2021). Total estimated national air emissions from the 2017 National Emissions Inventory (NEI) were
668 tons, with 70% from emissions associated with use of leaded aviation gasoline, 10% from smelting
and metals processing, 10% from other industrial sources, and 7.0% from fuel combustion. All other
sources of Pb air emissions combined were estimated to account for less than 4% of total U.S. Pb
emissions in the NEI. Not included in the NEI are Pb emissions estimates from wildland fires or
resuspended legacy Pb. Pb emissions from wildland fires were not estimated in the 2017 NEI, and the
complete 2020 NEI is not scheduled for release until March 2023. However, the national emissions
estimate of 18 tons per year from wildland fires was recently released by EPA in advance of the complete
NEI. Fire emissions vary considerably from year to year and are increasing, but this estimate is equivalent
to about 3% of total 2017 national Pb emissions, which would put wildfires as the fourth largest source of
Pb emissions, behind piston engine aircraft, industrial processes, and fuel combustion. In addition to
contemporary Pb emissions into the atmosphere, soil bound Pb near historical sources can potentially
become airborne under some wind or traffic conditions (IS.2.3).
Several recent studies indicated substantial spatial variability in urban ambient air Pb
concentrations influenced by proximity to local sources or industrial activities. Across urban and
neighborhood scales, these variations in ambient air Pb concentrations may not be captured by national
monitoring networks. Seasonal trends were reported in numerous recent studies, but results were mixed,
and no consistent national pattern of seasonality was apparent. Pb size distributions in ambient air appear
to have shifted since the 1980s from size distributions with a mass median diameter usually smaller than
2.5 |im to those with a mass median diameter between 2.5-10 |im. based on size distribution data from
samples collected near roads, near industrial sources, in rural locations, and in urban locations within the
U.S. and the European Union. No recent studies specifically investigated background Pb concentrations,
but a plausible range of 0.2 to 1 ng/m3 was proposed based on earlier studies in the 2013 Pb ISA (U.S.
EPA. 2013a).
ES.3 Fate and Transport
Pb emitted into the atmosphere can be distributed into soil, water, and other media (IS.2.4). The
fate and transport of Pb emitted into the air depends on particle size, which in turn depends largely on the
source emissions. Particle-bound Pb associated with fine particulate matter is transported long distances
and can be found in remote areas, while Pb associated with coarse particulate matter is more likely to
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deposit closer to its source. After deposition, resuspension of soil-bound Pb can contribute to airborne
concentrations near major Pb sources. Once deposited in soil, Pb is strongly retained in soil organic
material, and subsequent Pb fate and transport through the soil column is influenced by several
physicochemical factors, such as storage in leaf litter, amount and decomposition rates of organic matter,
composition of organic and inorganic soil constituents, microbial activity, and soil pH. These
physicochemical properties are based on soil forming factors (i.e., climate, organisms, parent material,
relief (shape of the landscape), time, and anthropogenic input). Soils that differ in these factors will
subsequently have different physicochemical properties and different trends in Pb transport. In water,
runoff from urban or historically industrial areas contains higher Pb concentrations than non-urban areas.
Recent studies have improved our understanding of soil fate and transport in many areas. These include
the relationships between street characteristics, population density, and land cover with runoff. Recent
research has also expanded on the influence of seasonality and precipitation events on runoff. In addition,
there have been advances in research on transport and sedimentation. While Pb deposition has decreased
in the last half century with the phase-out of leaded gasoline and stricter regulation of some Pb sources,
accumulated Pb-contaminated sediments in areas with a history of industry and urbanization are
vulnerable to resuspension and both down and upstream movement following a disturbance event. For
example, dam removal or other disturbances to water bodies can lead to resuspension and dissolution of
Pb-contaminated sediment that was previously deposited. With the predicted increase in drought
alongside less frequent but more severe precipitation patterns across most of the U.S., there may be a
potential for remobilization of legacy Pb.
Additional media besides air, water, and soil play a role in understanding how Pb moves and
changes overtime in the urban environment (IS.2.2). Urban soil, resuspended dust, road dust, and house
dust serve as urban compartments between which Pb can be transported or cycled. High Pb concentrations
are characteristic of urban soil in comparison to other soils and are often related to legacy sources. Studies
in several U.S. cities have explored the high spatial variability of urban soil Pb concentrations, with hot
spots related to income and racial disparities. In recent studies, associations between airborne Pb and
elemental indicators of airborne soil have been observed, suggesting the potential for contaminated soil to
be a source of airborne Pb locally in urban and industrial areas under some circumstances. Resuspension
of urban soil can also be a source of Pb in house dust.
ES.4 Trends
Pb concentrations in ambient air in the U.S. have decreased since the 1970s, mainly due to the
phase-out of Pb in gasoline (IS.3). For some monitors, there has also been a more recent period of
continued decline corresponding to reductions in Pb emissions from local and regional industrial sources.
Based on Pb monitoring network data, the national median of maximum 3-month average Pb
concentrations across monitoring sites declined by 89% from 1990 to 2010 for a mix of 74 source-
oriented and non-source-oriented monitors that operated continuously through this period (IS.3). For a
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smaller population of 37 monitors with a higher proportion of source-oriented monitors that operated
continuously from 2010 to 2021, the national median of maximum 3-month average Pb concentrations
across monitoring sites decreased by 88% over that period (IS.3). This recent decrease was driven by the
2008 Pb NAAQS revision and the steepest declines were observed over the period from 2012 to 2015
(IS.3).
Changes in the patterns of Pb emissions over time and between regions of the U.S. are also
detectable in non-air environmental media and biota (IS.3). Pb may be retained in soils, sediments, the
shells of long-lived bivalves, or trees, where it provides a historical record of Pb deposition over periods
of decreasing Pb emissions, such as the phase-out of Pb from on-road gasoline and reductions in
industrial releases. Overall, evidence from national and regional surveys of Pb in environmental media
and biota reflects a decline in anthropogenic emissions of Pb. However, Pb persists in environmental
media and is still observed in measurable concentrations within biota, particularly near historic and
current sources of Pb pollution. Long-term monitoring of Pb concentration trends in biota (e.g., the
National Oceanic and Atmospheric Administration Mussel Watch program) and soil surveys covering
large spatial extents (e.g., the U.S. Geological Survey North American Soil Geochemical Landscapes
Project) provide essential records of Pb concentrations in the environment observed across decades and
regions. Information on atmospheric Pb concentration trends can be difficult to interpret due to the
influence of other anthropogenic inputs of Pb and heterogeneity associated with natural environments.
Despite reductions in Pb pollution in recent decades, anthropogenic Pb persists in the environment.
ES.5 Exposure
The Venn diagram (Figure ES-1) below depicts the various pathways that Pb can take through
environmental media to reach plants, animals, and humans (IS.4). These exposures are considered air-
related if Pb passed through the air compartment at any point prior to plant, animal, or human contact. For
example, air-related Pb exposure may occur through direct inhalation with air that contains Pb or
ingestion of food, water, dust and soil, or other materials that have been contaminated by Pb originally in
ambient air, or inhalation of resuspended material contaminated with Pb originally in ambient air. Dust
and soil particles containing Pb are typically in the size range that is ingested rather than inhaled.
However, soil can act as a reservoir for deposited Pb, and exposure to soil contaminated with deposited
Pb can occur through resuspended PM as well as hand-to-mouth contact, which is the main pathway of
childhood exposure to Pb. The primary contribution of ambient air Pb to young children's blood Pb
concentrations is generally due to ingestion of Pb following its deposition in soils and dusts rather than
inhalation of ambient air. Non ambient air-related exposures include hand-to-mouth contact with Pb-
containing consumer goods, hand-to-mouth contact with dust or chips of peeling Pb-containing paint, or
ingestion of Pb in drinking water conveyed through Pb pipes. As a result of the multitude of possible
exposure pathways, the contribution from specific pathways (e.g., consumer products, diet, soil, ambient
air) to blood Pb concentrations is situation specific.
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Figure ES-1 Conceptual model of multimedia Pb exposure.
The majority of Pb in the body is stored in bone (roughly 90% in adults, 70% in children; IS.5).
Much of the remaining Pb is found in soft tissues; only about 1% of Pb is found in the blood. Pb in blood
is primarily (-99%) bound to red blood cells. The small fraction of Pb in blood plasma (<1% of Pb in
blood) may be the more toxicologically active fraction of the circulating Pb. The relationship between Pb
in blood and plasma is approximately linear at relatively low daily Pb intakes and at blood Pb
concentrations below -20-30 (ig/dL. Both Pb uptake to and elimination from soft tissues are much faster
than they are in bone. Pb accumulates in bone regions undergoing the most active calcification at the time
of exposure. Pb in bone becomes distributed in trabecular (e.g., patella) and the denser cortical bones
(e.g., tibia).
Blood Pb is the most common biomarker of Pb exposure in epidemiologic studies of Pb health
effects. Overall, blood Pb levels (BLLs) have been decreasing among U.S. children and adults for the past
45 years. For children aged 1-5 years, the 1976-1980 National Health and Nutrition Examination Survey
(NHANES) showed a geometric mean blood Pb level of 15.2 (95% CI: 14.3, 16.1) (ig/dL with nearly all
children (99.8%) exceeding 5 (ig/dL. By 2011-2016, geometric mean levels declined to 0.8 (95% CI: 0.8,
0.9) (ig/dL with only 1.3% exceeding 5 (ig/dL (IS.6). Other common Pb exposure metrics used in
epidemiologic studies are Pb in bone, which generally reflects cumulative exposure over long periods
(months to years), and Pb in cord blood, which is an indicator of prenatal and neonatal blood Pb
concentration.
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Blood Pb is dependent on the recent exposure history of the individual, as well as the long-term
exposure history that determines total body burden and the amount of Pb stored in the bone. The
contribution of bone Pb to blood Pb changes throughout an individual's lifetime and depends on the
duration and intensity of the exposure, age, and various other physiological stressors (e.g., nutritional
status, pregnancy, menopause, extended bed rest, hyperparathyroidism) that may affect bone remodeling,
which continuously occurs under normal conditions. In children, blood Pb is both an index of recent
exposure and, potentially, body burden, largely due to faster exchange of Pb to and from bone of children
relative to adults. Generally, bone Pb is an index of cumulative exposure and body burden. As described
previously, Pb is sequestered in two types of bone compartments: Pb in cortical bone, which is denser and
has a slower turnover rate, is a better marker of cumulative exposure than Pb in the more highly perfused
trabecular bone, which is more likely to be correlated with blood Pb concentration. During pregnancy, Pb
is transferred from the mother to the fetus. Transplacental transfer of Pb may be facilitated by an increase
in the plasma/blood Pb concentration ratio during pregnancy. Maternal-to-fetal transfer of Pb appears to
be related partly to the mobilization of Pb from the maternal skeleton.
ES.6 Health and Welfare Effects of Pb Exposure
The subsequent sections summarize the current evidence and causality determinations for health
and welfare effects in this ISA. These causality determinations appear in Figure ES-2 and Figure ES-3,
and are more fully discussed in the Integrated Synthesis and the respective health (Appendices 3-10) and
welfare effects (Appendix 11) appendices: httos://cfbub.epa.gov/ncea/isa/recordisplav.cfm?deid=357282.
ES.6.1 Health Effects of Pb Exposure
Pb exposure can disrupt important physiological pathways, triggering responses such as increased
oxidative stress and inflammation, and lead to a diverse array of health effects. In this ISA, the body of
evidence from toxicological and epidemiologic studies is evaluated for health effects that vary in severity
from minor subclinical effects to more serious effects that can lead to death. The integration of evidence
from these health studies, supported by the evidence from atmospheric chemistry, exposure assessment,
toxicokinetics, and exposure biomarker studies, contributes to the causality determinations made for the
various health outcomes. Building off the conclusions from the 2013 Pb ISA, a total of thirty causality
determinations were made for health outcomes in this ISA. These determinations are summarized in
Figure ES-2.
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Causality Determinations for Health Effects of Pb
Health Outcomes
2023 Pb ISA
Nervous System Effects Ascertained During Childhood, Adolescent, and Young Adult Lifestages
Cognitive Function Decrements in Children
Externalizing Behaviors: Attention. Impulsivity: and Hyperactivity
Externalizing Behaviors: Conduct Disorders in Children and Young Adults
Internalizing Behaviors: Anxiety and Depression
Sensory Function Decrements
1
Motor Function Decrements
Social Cognition and Behavior
+
Nervous System Effects Ascertained During Adult Lifestages
Cognitive Function Decrements
Psychopathological Effects
Sensory Function Decrements
Neurodegenerative Disease
t
Cardiovascular Effects
Cardiovascular Effects
Renal Effects
Renal Effects
t
Immune System Effects
Immunosuppression
Sensitization and Allergic Response
i
Autoimmunity and Autoimmune Disease
Hematological Effects
Altered Heme Synthesis and Decreased RBC Survival and Function
Reproductive and Developmental Effects
Pregnancy and Birth Outcomes
1
Development
Female Reproductive Function
1
Male Reproductive Function
Effects on Other Organ Systems
Hepatic Effects
t
Metabolic Effects
+
Gastrointestinal Effects
Endocrine System Effects
Musculoskeletal Effects
Effects on Ocular Health
Respiratory Effects
Total (Non-Accidental) Mortality
Total Mortality
+
Cancer
Cancer
| Causal (8) J Likely Causal (8) Q Suggestive (8) | | Inadequate (6)
+ New Causality Determination (3) tori Change in Causality Determination since 2013 ISA (5)
Figure ES-2 Summary of causality determinations by exposure duration and
health outcome.
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Recent evidence continues to support causal relationships between exposure to Pb and cognitive
function decrements in children, externalizing behaviors (i.e., attention, impulsivity, and hyperactivity) in
children, cardiovascular effects, effects on development, and effects on male reproductive function.
Expanded evidence also supports causal relationships between Pb exposure and renal effects and total
(nonaccidental) mortality. The evidence summarized in the 2013 Pb ISA was "suggestive of a causal
relationship" between Pb exposure and renal effects, whereas no determination was made for the
relationship between Pb exposure and mortality in the 2013 Pb ISA. Recent evidence also indicates that
Pb exposure is likely to cause conduct disorders, internalizing behaviors, and motor function decrements
in children; cognitive function decrements and depression and anxiety in adults; and immunosuppression,
musculoskeletal effects, and cancer. Additional evidence is suggestive of a causal relationship between Pb
exposure and sensory function decrements and effects on social cognition and behavior in children;
sensory function decrements in adults; neurodegenerative disease; sensitization and allergic response;
effects on female reproductive function, pregnancy, and birth outcomes; and hepatic effects, though there
are more uncertainties associated with the interpretation of the evidence for these effects.
ES.6.1.1 Effects of Pb Exposure on Health Outcomes Ascertained in Children,
Adolescents, and Young Adults
While Pb affects nearly every organ system, the nervous system appears to be one of the most
sensitive targets. Epidemiologic studies conducted in diverse populations continue to demonstrate the
harmful effects of Pb exposure on neurodevelopment in children. Given their limited exposure histories,
neurodevelopmental effects observed in young children are among the effects best substantiated as
occurring at the lowest blood Pb levels. Specifically, blood Pb-associated effects on cognitive function are
supported by studies in populations of children (ages 4-10) with mean or group blood Pb levels -
measured concurrently or earlier - in the range of 2-8 (ig/dL (ES.7.1.3). Notably, evidence suggests that
some Pb-related cognitive effects may be irreversible and that the neurodevelopmental effects of Pb
exposure may persist into adulthood (U.S. EPA. 2013a). In addition to cognitive effects, epidemiologic
studies also demonstrate that Pb exposure is associated with decreased attention, and increased
impulsivity and hyperactivity in children (i.e., externalizing behaviors). A small number of recent studies
also serve to extend the lower bound of the mean BLLs that were observed to be associated with
inattention, impulsivity, and hyperactivity in the 2013 Pb ISA. These prospective studies with mean
maternal and cord blood Pb levels <5 (ig/dL report associations with some measures of inattention and
impulsivity. The neurodevelopmental epidemiologic evidence is supported by findings in animal studies
demonstrating both analogous effects and biological plausibility at relevant exposure levels.
Pb exposure can also exert harmful effects on blood cells and blood producing organs (potentially
leading to anemia in children) and is likely to cause an increased risk of symptoms of depression and
anxiety and withdrawn behavior (i.e., internalizing behaviors), decreases in motor function, delayed
pubertal onset, as well as conduct disorders in children and young adults. There is continued uncertainty
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about the timing, frequency, and duration of Pb exposures contributing to the blood Pb levels and effects
observed in epidemiologic studies, though these uncertainties are greater in studies of older children and
adults than in studies of young children (ES.7.1.4). Despite these uncertainties, there is clear and
consistent evidence that Pb exposure leads to negative health effects in children; further, recently
available evidence does not provide evidence of a threshold for the observed neurodevelopmental effects
across the range of blood Pb levels examined (ES.7.1.3).
ES.6.1.2 Effects of Pb Exposure on Health Outcomes Ascertained in Adults
Recent experimental animal and epidemiologic studies expand an already large body of evidence
that demonstrates the effect of Pb exposure on the cardiovascular and renal systems. The evidence most
strongly contributing to a causal relationship between Pb exposure and cardiovascular effects includes
studies reporting Pb-related increases in blood pressure, hypertension, and cardiovascular mortality. The
extent to which the effects of Pb on the cardiovascular system are reversible is not well-characterized.
Recent evidence also addresses uncertainties related to reverse causality in studies examining the renal
effects of Pb exposure and provides strong support for Pb-induced kidney dysfunction that is independent
of baseline renal function. The cardiovascular and renal effects evidence, which includes coherence of
results from epidemiologic and animal toxicological studies, is also supported by animal toxicological
evidence providing biological plausibility for the observed health effects. In particular, Pb effects on the
renin-angiotensin system provide a biologically plausible pathway through which Pb is capable of
eliciting health effects in both organ systems.
Consistent with the evidence demonstrating blood and bone Pb-associated cardiovascular
mortality, recent studies also report that Pb exposure is associated with total (nonaccidental) mortality.
The strongest supporting evidence for Pb effects on mortality comes from studies of cardiovascular
effects, which provide extensive epidemiologic and experimental animal evidence indicating pathways by
which exposure to Pb could plausibly progress from initial events to events that could lead to
cardiovascular mortality, including exacerbation of ischemic heart disease and potential myocardial
infarction. There is also very limited evidence that Pb exposure may contribute to other causes of
mortality, including Alzheimer's disease and infection, although this evidence is less established and has
greater uncertainties.
Pb exposure can also lead to cognitive function decrements, symptoms of depression and anxiety,
and immune effects in adults. Notably, the frequency, timing, level, and duration of Pb exposure causing
the effects observed in adults remains an uncertainty in the evidence, and higher past exposures may
contribute to the development of health effects measured later in life. Despite these uncertainties, there is
clear and consistent evidence that Pb exposure can result in harm to an array of organ systems that is
evident in adulthood, with the strongest evidence for effects on the cardiovascular and renal systems.
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ES.6.2 Welfare Effects of Pb Exposure
There are effects associated with Pb exposure in terrestrial and aquatic organisms. Although Pb is
present in the natural environment, it has no biological function in plants or animals. The atmosphere and
terrestrial and aquatic ecosystems are interconnected, with transfer of Pb taking place between each of
these systems (IS.2). Uptake of Pb from soils, water, sediment, and biota (via diet), subsequent
bioaccumulation, and toxicity of Pb varies greatly between species and across taxa, as characterized in the
1977 AQCD (U.S. EPA. 1977). the 1986 Pb AQCD (U.S. EPA. 1986b). the 2006 Pb AQCD (U.S. EPA.
2006b). the 2013 Pb ISA (U.S. EPA. 2013a). and further supported in this ISA. As reported in the 2013
Pb ISA and preceding Pb AQCDs, effects of Pb are observed across endpoints common to terrestrial,
freshwater, and saltwater organisms. Those endpoints include reproduction, growth, survival,
neurobehavioral and hematological effects, and physiological stress, and occur at multiple scales of
biological organization, from the cellular to the ecosystem. For ecological endpoints in this ISA,
biochemical (e.g., enzymes and stress markers) responses at the suborganism level of biological
organization are grouped under the broad endpoint of "physiological stress." The effects of Pb at the
subcellular and cellular level may lead to effects on organism reproduction, growth, and survival. These
endpoints in turn have the potential to alter population, community, and ecosystem levels of biological
organization.
In the 2013 Pb ISA, a series of causality determinations were made for these effects of Pb on
plants, invertebrates, and vertebrates in terrestrial, freshwater, and saltwater ecosystems using biological
scale as an organizing principle (U.S. EPA. 2013a). Evidence published since that time supports or
slightly expands the evidence for causality in endpoints that were already established as causal in the
2013 Pb ISA (Figure ES-3). A few studies report effects at lower concentration of Pb than in the 2013 Pb
ISA. New evidence for terrestrial (IS.8.1) and freshwater (IS.8.2) biota continues to support the existing
causality determinations from the 2013 Pb ISA and there are no changes to these causality determinations.
At the time of the 2013 Pb ISA, there were fewer studies on effects of Pb in saltwater biota compared to
terrestrial and freshwater organisms, and evidence was inadequate to infer causality relationships for
many endpoints. Specifically, chronic toxicity data were lacking, and relatively few laboratory studies
measured Pb concentration in the exposure water or sediment. Since the 2013 Pb ISA, several newly
available studies verify Pb concentrations analytically and report effects on endpoints at lower
concentration than previously observed for saltwater biota; some of these studies are chronic exposure
bioassays (IS.8.3). This additional information supports a change in causality determinations for three
endpoints for saltwater organisms (IS.8.5). Specifically, the evidence is sufficient to conclude there is a
likely to be causal relationship between Pb exposure and reproductive and developmental effects in
saltwater invertebrates. Additionally, the evidence is suggestive of, but not sufficient to infer, a causal
relationship between Pb exposure and saltwater vertebrate survival, and, the evidence is suggestive of, but
not sufficient to infer, a causal relationship between Pb exposure and saltwater community and ecosystem
effects (Figure ES-3).
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Causality Determinations for Ecological Effects of Pb
Level
Effect
Terrestrial
Freshwater
Saltwater
Community-
and Ecosystem
Community and Ecosystem Effects
t
Population-Level Endpoints
Organism-Level Responses
Reproductive and Developmental Effects-Plants
Reproductive and Developmental Effects-
Invertebrates
1
Reproductive and Developmental Effects-
Vertebrates
Growth-Plants
G rowth-1 n vertebrates
Growth-Vertebrates
Survival-Plants
Survival-Invertebrates
Survival-Vertebrates
t
Neurobehavioral Effects-Invertebrates
N en ro be h aviora 1 Effects-Ve rte brates
Sub-organismal
Responses
Hematological Effects-Invertebrates
Hematological Effects-Vertebrates
Physiological Stress-Plants
PhysiologicalStress-lnvertebrates
Physiological Stress-Vertebrates
Based on the weight of evidence for causality determination in Table II of the Preamble. Ecological causality determinations are
based on doses or exposures generally within one to too orders of magnitude of the range of Pb currentfy measured in the
environment (Table 2-1 of the 2013 ISA for Pb).
¦ Causal (12) CD Likely Causal (16) ~ Suggestive (4) ~ Inadequate (19) 1 Change in Causality Determination since 2013 Pb ISA
Figure ES-3 Summary of causality determinations for ecological effects of Pb.
ES.6.2.1 Effects on Development and Reproduction
Evidence from invertebrate and vertebrate studies in the Pb AQCDs, the 2013 Pb ISA, and this
ISA indicates that Pb affects reproductive performance in multiple species (IS.8.5.6). Various endpoints
measured in multiple taxa of terrestrial and aquatic organisms show impaired reproduction or
development following Pb exposure. Decreased reproduction at the organism level of biological
organization can result in a decline in how widespread a species is; the disappearance of populations of a
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species; a decline in the variety of different species present; and changes in the mixture of species seen in
an ecological community. For freshwater invertebrates, recent evidence further supports previous
observations of Pb effects on reproductive endpoints at low concentrations in some sensitive species of
snails as well as zooplankton, such as cladocerans (group of small aquatic invertebrates belonging to the
subphylum Crustacea) and rotifers (small aquatic invertebrates that constitute the phylum Rotifera),
especially under chronic exposure scenarios (IS.8.5.6 and see Appendix 11. Table 11-5). Since the 2013
Pb ISA, the evidence base for Pb effects on reproductive and developmental endpoints in saltwater
invertebrates has expanded, primarily due to multiple new embryo-larval developmental assays in
mollusks and sea urchins (IS.8.5.6 and see Appendix 11. Table 11-7). This new evidence augments the
previous causality determination from the 2013 Pb ISA of suggestive of, but not sufficient to infer, a
causal relationship. This ISA concludes there is a likely to be causal relationship between Pb exposure
and reproductive and developmental effects in saltwater invertebrates.
ES.6.2.2 Effects on Growth
As reported in this ISA, the 2013 Pb ISA, and the Pb AQCDs, exposure to Pb has been shown to
have detrimental effects on growth in plants and in some species of invertebrates and vertebrates
(IS.8.5.5). Evidence for those effects of Pb on growth is strongest in terrestrial plants. Evidence
accumulated over several decades of research shows that Pb inhibits photosynthesis and respiration in
terrestrial plants, both of which reduce growth (U.S. EPA. 2013a. 2006b. 1977). Effects reported in plants
largely occur at concentrations that greatly exceed Pb concentrations typically found in U.S. soils and
surface waters, with studies that include multiple concentrations of Pb showing increased response with
increasing Pb in water, sediment, or soil. Evidence for detrimental effects of Pb on growth in
invertebrates has been gathered most extensively in freshwater species, with growth inhibition in a few
sensitive species occurring in the range of Pb concentration values available for U.S. surface waters. In
general, juvenile organisms are more sensitive than adults. Data on growth effects in vertebrates is
limited.
ES.6.2.3 Effects on Survival
Survival (IS.8.5.4) may have a direct impact on population size and can lead to effects at the
community and ecosystem levels of biological organization. Pb has generally not been found to affect
survival of aquatic or terrestrial plants at concentrations found in the environment away from stationary
sources. Freshwater invertebrates are generally more sensitive to Pb exposure than other types of
organisms, with survival reduced in laboratory studies of a few species at concentrations occasionally
encountered in the environment. Studies of some freshwater invertebrates reported in the 2006 Pb AQCD
and 2013 Pb ISA indicate decreased survival at <20 |ig Pb/L under some water quality conditions. Several
studies since the 2013 Pb ISA provide further characterization for known effects on survival in a few
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sensitive species of freshwater invertebrates, notably snails and amphipods (shrimp-like crustaceans), at
analytically verified chronic exposure <15 |ig Pb/L (IS.8.5.4). Limited studies with vertebrates showed
adverse effects of Pb on survival at concentrations higher than typical Pb levels in the environment,
although juvenile organisms are usually more sensitive than adults. In the 2013 Pb the causality
determination for survival in saltwater vertebrates was inadequate. Additional evidence in this ISA
(IS.8.5.4) from laboratory-based bioassays in a few saltwater fish species in which Pb exposure
concentration was analytically verified demonstrates effects on survival in chronic exposures to Pb
(Appendix 11. Table 11-7). Based on these new chronic studies in saltwater fish, the evidence is
suggestive of, but not sufficient to infer, a causal relationship between Pb exposure and saltwater
vertebrate survival.
ES.6.2.4 Neurobehavioral Effects
Pb is a known to cause impairments in the nervous system of invertebrates and vertebrates.
Historical and recent evidence of Pb effects on terrestrial and freshwater animals indicates that Pb
adversely affects behaviors, such as food consumption, locomotion, behavioral regulation of body
temperature, and prey capture. Additional evidence since the 2013 Pb ISA include studies quantifying
alterations in foraging and feeding behavior in bees and changes in locomotion in freshwater amphipods,
bivalves, and zebrafish (IS.8.5.3). The causality determinations for neurobehavioral effects of Pb in
terrestrial and freshwater organisms remain unchanged from the 2013 Pb ISA (Figure ES-3). The
causality determination between Pb exposure and neurobehavioral endpoints in saltwater invertebrates
and vertebrateswas inadequate in the 2013 Pb ISA and this continues to be the case.
ES.6.2.5 Hematological Effects
As reported in the Pb AQCDs and 2013 Pb ISA, hematological effects of Pb exposure in wildlife
include inhibition of ALAD (delta-aminolevulinic acid dehydratase, an important rate-limiting enzyme
needed for heme production) and altered blood cell counts and serum profiles. Decreased ALAD activity
is commonly recognized as an indicator of Pb exposure across a wide range of animals as shown in both
field and laboratory studies. Previous studies have indicated considerable species differences in ALAD
activity in response to Pb. Since the 2013 Pb ISA, new studies in terrestrial birds, amphibians, and
mammals have continued to support the connection between Pb exposure and hematological effects
(IS.8.5.2). In contrast, fewer studies were identified that quantified ALAD response in terrestrial or
freshwater invertebrates, freshwater vertebrates, or in saltwater organisms. The causality determinations
for hematological effects of Pb in biota remain unchanged from the 2013 Pb ISA (Figure ES-3).
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ES.6.2.6 Effects on Physiological Stress
Increased levels of antioxidant enzymes (in response to oxidative stress or altered cell signaling)
and increased lipid peroxidation (the process by which free radicals induce the oxidation of fatty acids,
leading to cell membrane damage) are reliable biomarkers of various stresses. Oxidative damage and
antioxidant activity have been observed in field studies in a wide range of species in terrestrial and
aquatic environments when Pb is present (often along with other chemical stressors), and also following
laboratory exposures to Pb without other stressors in plants, invertebrates and vertebrates (IS.8.5.1).
Changes in markers of physiological stress may indicate increased susceptibility to other stressors, as well
as diminished fitness of individual organisms. Causality determinations for physiological stress in
terrestrial, freshwater and saltwater organisms remain unchanged from the 2013 Pb ISA (Figure ES-3).
ES.6.2.7 Community and Ecosystem Effects
Uptake of Pb by terrestrial and aquatic organisms and subsequent adverse effects on survival,
growth, development, and reproduction at the organism level can lead to effects at higher levels of
biological organization including populations, communities, and ecosystems. In terrestrial habitats, soil
microbial, plant, and animal communities may be affected in locations where soil Pb concentration is
elevated, such as in the proximity to historic metal extracting and processing point sources. In freshwater
ecosystems, shifts in sediment-associated microbial and invertebrate communities and aquatic plant
communities are linked to the presence of Pb as well as other stressors. For terrestrial and freshwater
systems, the likely to be causal determinations remain unchanged from the 2013 Pb ISA. For saltwater
ecosystems, new experimental and observational studies have examined the relationship between Pb in
sediment, and microbial abundance and/or diversity and saltwater foraminifera (single-celled marine
organisms, usually with shells) communities (IS.8.5.7). These studies show that diversity and distribution
of these organisms varies with Pb concentration and co-stressors in the environment and at different
locations. This new evidence is suggestive of a causal relationship between Pb exposure and saltwater
community and ecosystem effects which is a change from the 2013 Pb ISA. Although the presence of Pb
is associated with shifts in biological communities, this metal rarely occurs as a sole contaminant in
natural systems, making the contribution of Pb to the observed effects difficult to isolate in many
locations. Furthermore, the variability of conditions in the environment affects Pb bioavailability and
organism response making it difficult to characterize effects of Pb at the ecosystem scale.
ES.7 Key Aspects of Health and Welfare Effects Evidence
In addition to causality determinations, this ISA also reaches conclusions on other policy-relevant
topics. These conclusions are drawn from a careful evaluation of the available evidence and the extent to
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which recent studies have addressed or reduced uncertainties from previous assessments. Conclusions on
key policy-relevant topics are summarized below.
ES.7.1 Health Effects Evidence: Key Findings
In addition to the causality determinations for health effects (ES.6.1), the evidence evaluated in
this ISA addresses some of the key policy-relevant issues of this NAAQS review, as outlined in Volume
II of the Pb IRP (U.S. EPA. 2022a). A summary of this health evidence and Pb ISA conclusions is
provided below and discussed in more detail in the Integrated Synthesis and supporting appendices.
ES.7.1.1 At-Risk Populations
The NAAQS are intended to protect public health with an adequate margin of safety, including
protection for those potentially at increased risk for health effects in response to exposure to a criteria air
pollutant [e.g., Pb; see Preamble (U.S. EPA. 2015)1. In addition to consideration of Pb-related health
effects observed among populations with diverse characteristics, this ISA also considers those studies that
examine specific populations or lifestages that may be at increased risk of Pb-related health effects, using
a pragmatic approach to characterize the strength of the evidence (U.S. EPA. 2015). The risk of health
effects from exposure to Pb may be modified as a result of intrinsic (e.g., pre-existing disease, genetic
factors) or extrinsic factors (e.g., sociodemographic or behavioral factors), differences in internal dose, or
differences in exposure to Pb in the environment. This ISA concludes that there is adequate evidence to
classify children; minority populations; individuals in close proximity to Pb sources; individuals living in
residences with factors contributing to increased house dust Pb levels; individuals with certain genetic
variants; individuals with high stress levels; and those with certain nutritional excesses or deficiencies as
populations at increased risk to the health effects of Pb exposure (IS.7.4). These conclusions are based on
the consistency in findings across studies, as well as on coherence of results from different scientific
disciplines. There is suggestive evidence for several other factors contributing to potentially increased risk
of Pb-related health effects: older age, sex, pre-existing diabetes, low socioeconomic status, and high
levels of exposure to other metals.
ES.7.1.2 Air-Pb-to-Blood-Pb Relationships
The relationship between air Pb and blood Pb is commonly characterized as a "slope factor,"
which describes the incremental change in blood Pb levels relative to a change in air Pb concentrations
(IS.9.1). A larger slope indicates a larger estimated incremental contribution of air Pb to the blood Pb
level in exposed populations. Epidemiologic studies evaluating air-to-blood slope factors include various
study locations, populations, and analytic methodologies (e.g., model form and other considerations, such
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as soil Pb, that are accounted for in the model), all of which contribute to variation in the estimated
slopes. Results described in the 2013 Pb ISA (U.S. EPA. 2013a) provide a range of air-to-blood slope
estimates from 4 to 9 (ig/dL per |ig/m3 in studies of children.
Newer studies after the phaseout of leaded gasoline and not focused on communities near
significant air Pb sources show increasing slope factors with decreasing air Pb concentrations. Although
slope factors increase with decreasing air Pb concentration, it is possible that the contribution from non-
air exposure pathways may lead to the higher slope factors at lower air concentrations. In other words, in
older studies in which leaded gasoline or local sources were a major contributor to air Pb, there may be a
greater likelihood of discerning the true effect of air Pb on blood Pb due to relatively less contribution
from non-air exposure pathways. However, overarching distinctions between old and new studies should
be made with caution given that Pb in all media, not just air, has decreased overtime.
ES.7.1.3 Concentration-Response Relationships for Human Health Effects
In assessing the relationship between Pb exposure and human health effects, evidence from each
previous assessment (U.S. EPA. 2013a. 2006b') demonstrates that progressively lower BLLs or Pb
exposures are associated with cognitive deficits in children. The evidence assessed in the 2013 Pb ISA
found that cognitive effects in children were substantiated to occur in populations with mean BLLs
between 2 and 8 (ig/dL. Recent studies generally include somewhat older children or employ modelling
strategies designed to answer relatively narrow research questions and consequently do not have the
attributes of the studies on which the conclusion of the 2013 Pb ISA was based (i.e., early childhood
BLLs, consideration of peak BLLs, or concurrent BLLs in young children). Therefore, the recently
available studies were not designed and may not have the sensitivity to detect the effect or hazard at these
very low BLLs, nor do they provide evidence of a threshold for the effects across the range of BLLs
examined.
Compelling evidence in the 2013 Pb ISA also supported a larger incremental negative effect of
Pb on children's IQ at lower BLLs compared to higher BLLs (for BLLs ranging from 2.5 to 33.2 (ig/dL;
Section IS.9.2). Only a few recent studies that evaluate the shape of the concentration-response (C-R)
function for the relationship between Pb exposure and cognitive effects in children, but recent evidence
continues to support the conclusions from the previous ISA. Possible explanations specific to nonlinear
relationships observed in studies of Pb exposure in children include a smaller incremental effect at higher
Pb concentrations due to covarying risk factors, though the evidence does not reveal a consistent set of
covarying risk factors that explain the differences in the blood Pb-IQ C-R relationship observed in
epidemiologic studies.
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ES.7.1.4 Lifestages and Timing of Pb Exposure Contributing to Observed Nervous
System Effects
As discussed in Section ES.5, blood Pb may reflect recent as well as past exposures because Pb is
both taken up by and released from the bone. The resulting uncertainty regarding the relative proportion
of blood Pb from recent versus past exposure is greater in adults and older children than in young children
who have shorter exposure histories. As a result, there is inherent uncertainty in the level, timing,
frequency, and duration of Pb exposures contributing to associations between adult and older children's
BLLs and health outcomes observed in epidemiologic studies. In epidemiologic studies of nervous system
effects with BLLs measured in younger children, recent evidence is consistent with findings from the
2013 Pb ISA, which consistently showed that blood Pb levels measured during various lifestages and time
periods (i.e., prenatal, early childhood, childhood average, and concurrent with the outcome) were
associated with nervous system effects in children. A notable uncertainty in the interpretation of this
evidence is the typically high correlation between blood Pb measurements at different ages in childhood,
making it difficult to discern the relative importance of the various exposure metrics (i.e., BLLs at
different ages) used in epidemiologic studies. Nonetheless, the epidemiologic evidence is supported by
experimental evidence in monkeys that indicates that Pb exposures during multiple lifestages and time
periods, including prenatal only, prenatal plus lactational, postnatal only, or lifetime starting during the
juvenile period, induce impairments in cognitive function when assessed between ages 6 and 10 years.
These findings are consistent with the understanding that the nervous system continues to develop
throughout childhood and into adolescence.
ES.7.2 Welfare Effects Evidence: Key Findings
Effects of Pb in ecosystems are primarily associated with Pb from deposition and other sources,
subsequent transport, and exposure through environmental media (soil, water, sediment, biota). Pb
bioaccumulates in plants and animals in terrestrial, freshwater, and saltwater environments; however, the
relative contribution of Pb from different sources is usually not known. Exposure of organisms to Pb can
be via one or more pathways (e.g., uptake from soil or water, ingestion). For Pb to interact with a
biological membrane and be taken up into an organism it must be bioavailable (IS.8). Generally, the
greater amount of Pb available as the free Pb ion, the greater bioavailability. Conditions in the
environment, such as soil composition and soil and water chemistry, modify Pb bioavailability and
subsequent toxicity to organisms. Once Pb uptake occurs, a variety of effects may occur in organisms,
including impaired reproduction, decreased growth, and reduced survival, as documented in this ISA, the
2013 Pb ISA and the Pb AQCDs. These effects on individual organisms may lead to effects at the
population, community, and ecosystem level of biological organization. In both terrestrial and aquatic
organisms, gradients in response are observed with increasing concentration of Pb in laboratory and field
studies. However, the level at which Pb elicits a specific effect is difficult to establish in natural systems
due to the influence of other environmental variables (e.g., pH and organic matter) on both Pb
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bioavailability and toxicity, and also because of substantial species differences in Pb sensitivity. Some
laboratory studies report effects within the range of Pb detected in environmental media over the past
several decades. Specifically, effects on reproduction, growth, and survival in sensitive freshwater
invertebrates are well-characterized from controlled studies at concentrations at or near Pb concentrations
occasionally encountered in U.S. fresh surface waters. There are considerable uncertainties associated
with generalizing effects observed in controlled studies to effects at higher levels of biological
organization. Furthermore, available studies on community and ecosystem-level effects are usually from
contaminated areas where Pb concentrations are much higher than typically encountered in the
environment. As in the 2013 Pb ISA, the contribution of atmospheric Pb to specific sites is not clear, and
the connection between air concentration of Pb and ecosystem exposure continues to be poorly
characterized.
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INTEGRATED SYNTHESIS FOR LEAD
Overall Conclusions of tlic Lead (I'h) Integrated Science. \ssessment (IS. I)
Human Health IJJec/s
• Recall studies support and e\pand upon I he siroim hods of e\ idence spainnim scientific disciplines,
real!iriiiiiiu c ,ius,il i\ /tiiiiiii>hi/,> hem con lJh exposure ;md se\ eral iicia oils s\ sieni elleels mi children,
iiicliicliiiu comnli\ e Iniiclkh 1 decrements ;md e\lern;ih/inu heh;i\ ioin tie. ;illenlK¦ .msiil re/.itioiishi/'s helween I'h exposure ;md ;i iinniherof
oilier health elleels. iiichidiimcardio\ascnlarcffccls. hein;iU>k>uic;iI elTecls. de\ elopnieiiial elTecls. ;md
el leels tin male reprodiicli\ e function
• I \panded c\ idence for lJh exposure ;md ren;il elleels supports ;i cliaime in cansahis delcrniiiialion from
suggestive of a causal relationship in the 2013 ISA to a causal relationship in this ISA.
• Recent experimental ;ind epidemiologic e\ idenee supports likely in he > iius.il rehiiiniisliips helween I'h
exposure ;md conduct disorder in ehildren ;ind \onim ;idnlls. iiilernali/iim heh;i\ iors in ehildren ;ind
adolescents. motor function deereinenis in ehildren. comiiti\c function deerenienis mi ;idnlis.
neiirodeueiieraliN e diseases. ininiiiiiosnpprcssioii. niiisenk)skelel;il elleels. total (iioiiaccideiilah mortality.
;nid e;11leer
• f or all oilier Iie;i11h effect categories. iiiieeri;iiniies ;md hniiialions in ihe scientific e\ idence coiiirihnie lo
causality determinations that the evidence is suggestive of hut not sufficient to infer, a causal relationship
or inadequate to infer the presence or absence of a causal relationship.
• \1an\ populations (e u . race elhnicilies. uenelic hackuroimdsi and lifesiaues ie u . children, older adults)
ha\ e heen slum n lo he at increased risk of health effects in response lo I'h exposure \nioiiu popnlalions
and hfesiaues e\ alnaled in ilns ISA. current scienlific e\ idence is adequate lo conclude lhal children,
people h\ iiiu in proxiimis lo I'h sources, people willi specific uenelic \arianis. people with increased
stress, and populations w iili ceriain iiniriiional or resideniial factors nia> he at disproportionale risk for I'h-
relaled health elleels I here is snuuesii\e e\ idence lhal older aue. sev pre-esisimu disease, socioeconomic
stains (SI :S). and exposure lo other nielals nia> increase risk for health effects of I'h e\posnre
H el/are li/Jccts
• I !ITecls iif I'h in ecos\ sienis are priniarih associated with I'h from deposition and oilier sources,
subsequent transport, and exposure ihronuh en\ ironmeiiial media (soil, water, sedimeni. Inoiai I'h
hioacciimnlales in plants aikI animals m terrestrial, freshwater, and saliwalcrcm ironmeiiis. howe\er. the
relali\ e coiiirihiiiion of I'h from dilfereiii sources is nsnalK not know n
• I ilTecls of I'h are ohsen ed in terrestrial, freshwater, and saltwater oruanisnis across se\ eral le\elsof
hiolouical oruam/alion 11 e . from the cellular le\ el of oruam/alion ihronuh mdi\ idnal oruanisnis io the
le\ el of coniniiimiies and ecos\ sienisi. \losi e\ idence is from loxicils hioassav s on mdi\ idnal oruanisnis.
ralherihaii field-hased studies
• In most cases, new research alfirnis the conclusions m the 2<> I ' I'h IS A for ihe eiidpomis of ph\ siolouical
stress, hematological el leels. iienrohcha\ lor. snr\ i\al. urowili. reproduction and de\ elopnieiii. and
coniniiimn and ecos\ siem elleels m terresirial and freshwaler hioia \ few studies report elleels at lower
conceiiiralioiis ilian in llie 2ul ' I'h ISA
• \ddilional studies in saliwaler oruamsnis address some (.if I he imceria nines identified mi I he 2d I ' lJh IS \.
There is snl'l'icieiii new e\ idence lo support a ULI\- /" he c ,ius,il i\ lniii>iisliii> helween I'h exposure and
reprodncliN e and de\ elopnienial elleels mi saltwater m\ eriehrales for iwo other eiidpoinis. snr\ i\ al in
saltwater \ eriehrales ihased on fish studies) and effects on saliwaler coniniiimiies and ecos\ sienis. new
evidence is suggestive of. hut not sufficient lo infer, a causa! relationship.
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IS.1
Introduction
IS.1.1 Purpose and Overview
The Integrated Science Assessments (ISAs), prepared by the U.S. Environmental Protection
Agency (EPA), serve as the scientific foundation of the National Ambient Air Quality Standards
(NAAQS) review process.1 The ISA is a comprehensive evaluation and synthesis of the policy-relevant
science "useful in indicating the kind and extent of all identifiable effects on public health or welfare,2
which may be expected from the presence of [a] pollutant in the ambient air," as described in Section 108
of the Clean Air Act (42 U.S. Code [U.S.C.] 7408).3 For this ISA, "policy-relevant" science is described
in Volume 2 of the Integrated Review Plan (IRP) for Lead (Pb) (U.S. EPA. 2022a) as referring to
"scientific information and analyses intended to address key questions related to the adequacy of the
standards." Those "key questions" are also laid out in Volume 2 of the IRP. As stated in the Preamble to
the ISAs (U.S. EPA. 2015). hereafter "Preamble," "[t]he key policy-relevant questions included in the
IRP serve to clarify and focus the NAAQS review on the critical scientific and policy issues, including
addressing uncertainties discussed during the previous review and newly emerging literature." This ISA
reviews and synthesizes the air quality criteria for the health and welfare effects of Pb. It draws on the
existing body of evidence to evaluate and describe the current state of scientific knowledge on the most
relevant issues pertinent to the current review of the Pb NAAQS, to identify changes in the scientific
evidence since the previous review, and to describe remaining or newly identified uncertainties and
limitations in the evidence.
This Integrated Synthesis (IS) is the main body of the Pb ISA. The following sections provide a
concise synopsis of the ISA conclusions and synthesize the key findings considered in characterizing Pb
exposure and relationships with health and welfare effects. The IS includes summaries of key information
for each topic area covered in 12 appendices to the Pb ISA, including atmospheric science, sources, and
environmental distribution; exposure, biomarkers, and toxicokinetics; the nature of health and welfare
effects associated with Pb exposure, including causality determinations for relationships between
exposure to Pb and specific types of health and welfare effects; and the human lifestages and populations
at increased risk of the effects of Pb. This IS also discusses the evidence related to other policy-relevant
1 Section 109(d)(1) of the Clean Air Act requires periodic review and, if appropriate, revision of existing air quality
criteria to reflect advances in scientific knowledge on the effects of the pollutant on public health and welfare. Under
the same provision, EPA is also to periodically review and, if appropriate, revise the NAAQS based on the revised
air quality criteria.
2 Under section 302(h) of the Clean Air Act, effects on welfare include, but are not limited to, "effects on soils,
water, crops, vegetation, manmade materials, animals, wildlife, weather, visibility, and climate, damage to and
deterioration of property, and hazards to transportation, as well as effects on economic values and on personal
comfort and well-being."
3 The general process for developing an ISA, including the framework for evaluating weight of evidence and
drawing scientific conclusions and causal judgments, is described in a companion document, the Preamble to the
ISAs.
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issues, such as the exposure durations, metrics, and concentrations eliciting health and welfare effects; the
concentration-response (C-R) relationships for specific effects, including the overall shape and
discernibility of thresholds in these relationships; and the public health and welfare impact of effects
associated with exposure to Pb.
When final, the Pb ISA will inform EPA decisions on the primary and secondary NAAQS for Pb.
The primary Pb NAAQS are established to protect public health with an adequate margin of safety,
including the health of at-risk populations such as children. The secondary Pb NAAQS are intended to
protect the public welfare from known or anticipated adverse effects associated with the presence of the
pollutant in ambient air. The current primary and secondary Pb NAAQS were established in 2008. In that
review, the levels of the primary and secondary standards were lowered tenfold, from the 1978 levels of
1.5 |ig/m3 to 0.15 |ig/m3. The averaging time was revised from a calendar quarter average to a rolling
three-month period with a maximum (not-to-be-exceeded) form, evaluated over a three-year period. The
revised primary standard was established to protect against air Pb-related human health effects, including
intelligence quotient (IQ) loss, in the most highly exposed children. The secondary standard was set equal
to the primary standard for requisite protection of organisms and ecosystems. The most recent review of
the Pb NAAQS was completed in 2016, at which time the standards set in 2008 were retained without
revision.
IS.1.2 Pb Integrated Science Assessment Process and Development
Each NAAQS review begins with a "Call for Information" published in the Federal Register that
announces the start of the review and invites the public to assist in this process by identifying relevant
research studies in the subject areas of concern. For this review of the Pb NAAQS, the Call for
Information was published in the Federal Register on July 7, 2020 (85 FR 40641). Following the Call for
Information, the planning phase of the review includes development of an IRP, which is made available
for public comment and provided to the Clean Air Scientific Advisory Committee (CASAC) for review or
consultation. Volume 2 of the IRP for Pb addresses the general approach for the review and planning for
the ISA (U.S. EPA. 2022a).
The process for developing this ISA is described in detail in Appendix 12 of this ISA, The
Process for Developing the Pb Integrated Science Assessment. Through iterative NAAQS reviews, ISAs
build on evidence and conclusions from previous assessments. The previous ISA for Pb was published in
2013 (U.S. EPA. 2013a) and included peer-reviewed literature published through September 2011. Prior
Pb assessments include the 2006 Air Quality Criteria Document (AQCD) for Pb (U.S. EPA. 2006a'). the
1986 Pb AQCD (U.S. EPA. 1986b) and its associated addendum (U.S. EPA. 1986d). the 1990
Supplement to the 1986 addendum (U.S. EPA. 1990). and the 1977 AQCD for Pb (U.S. EPA. 1977). This
ISA focuses on synthesizing and integrating the evidence that has become available since the 2013 Pb
ISA with the information and conclusions from previous assessments. Important older studies from the
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2013 ISA or from the Pb AQCDs may be drawn on to reinforce key concepts and conclusions. Older
studies also may be the primary focus in some subject areas or scientific disciplines where research efforts
have subsided, and/or where these older studies remain the definitive works available in the literature.
The general steps for ISA development include literature search and study selection; evaluating study
quality; developing initial draft materials for peer-input consultation; evaluating, synthesizing, and
integrating evidence; and developing scientific conclusions and causality determinations (U.S. EPA.
2015V
These steps are described in greater detail in the Preamble (U.S. EPA. 2015). which provides a
general framework for developing ISAs, and in the Process Appendix (Appendix 12). which supplements
the Preamble with additional details specific to this ISA including methods for documentation, literature
review, study quality evaluation, public engagement, and quality assurance (QA). As described in the
Preamble, EPA uses a structured and transparent process to evaluate scientific information and to
determine the causal nature of relationships between air pollution and health and welfare effects [see
Preamble (U.S. EPA. 2015)1. Development of the ISA includes approaches for literature searches,
application of criteria for selecting and evaluating relevant studies, and application of a framework for
evaluating the weight of evidence and forming causality determinations. As part of the external review
process, one or more drafts of the ISA are made available to the public and undergo formal review by the
CASAC, an independent scientific committee appointed by the EPA Administrator.
Studies considered in the development of the Pb ISA are documented in the EPA HERO
database. The publicly accessible HERO project page for this ISA contains the references that were
considered for inclusion and provides bibliographic information and abstracts. Within HERO, each
reference has a unique HERO ID number. References can be viewed individually or filtered by appendix,
discipline, or the draft in which they are referenced.
IS.1.2.1 Scope of the Pb ISA
Pb is a multimedia and persistent pollutant that contributes complexities to the review of the Pb
NAAQS. Pb emitted into ambient air may subsequently be found in multiple environmental media (i.e.,
soil, water, sediment, biota), contributing to multiple pathways of exposure for humans and ecological
receptors. This multimedia distribution of, and multipathway exposure to, air-related Pb has a key role in
the Agency's consideration of the Pb NAAQS. The Pb ISA includes research relevant to assessing the
health and welfare effects of Pb exposure. Health effects evidence evaluated in the ISA includes
experimental animal toxicological studies and observational epidemiologic studies. Welfare evidence
included in the Pb ISA focuses specifically on ecological effects. In addition to the human health and
welfare effects of Pb, the ISA also evaluates other scientific information on sources of Pb to ambient air,
measurement and concentrations of Pb in ambient air, fate and transport of Pb in the environment,
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pathways of human and ecological exposure, toxicokinetic characteristics of Pb in the human body, and
characterization of population exposures to Pb.
The scope of the health portions of the ISA are explicitly defined by scoping statements that
generally characterize the parameters for study inclusion to aid in identifying the most relevant evidence.
The use of scoping statements to define study relevance is consistent with recommendations by the
National Academies of Sciences, Engineering, and Medicine for improving the design of risk assessment
through planning, scoping, and problem formulation to better meet the needs of decision makers
(NASEM. 2018). The statement used to define the scope of the health effects portion of this ISA
comprises Population, Exposure, Comparison, Outcome, and Study Design (PECOS) components. There
are discipline-specific PECOS criteria for experimental and epidemiologic studies. For experimental
studies, the scope of the evidence used for this ISA encompassed studies of nonhuman mammalian animal
species with exposures that are relevant to the range of human exposures, with mean blood Pb levels
(BLLs) up to 30 (ig/dL, which is about one order of magnitude above the 95th percentile of the 2011—
2016 National Health and Nutrition Examination Survey (NHANES) distribution of BLLs in children
(Egan et al.. 2021). The evaluation of epidemiologic studies focused on the association between exposure
to Pb (as indicated by Pb levels in blood, bone, and teeth; validated environmental indicators of Pb
exposure; or intervention groups in randomized trials and quasi-experimental studies) and an ensemble of
health effects, including effects on the nervous system, cardiovascular effects, and reproductive and
developmental outcomes. Emphasis was placed on studies conducted in non-occupationally exposed
populations, but recent longitudinal studies of occupational exposure to Pb published since the literature
cutoff date for the 2013 Pb ISA were considered insofar as they addressed a topic that was of particular
relevance to the NAAQS review (e.g., longitudinal studies designed to examine recent versus historical
Pb exposure). Additionally, the following types of health studies are generally considered to fall outside
the scope and are not included in the ISA: review articles (which typically present summaries or
interpretations of existing studies rather than bringing forward new information in the form of original
research or new analyses); Pb poisoning studies or clinical reports (e.g., involving accidental exposures to
very high amounts of Pb described in clinical reports that may be extremely unlikely to be experienced
under ambient air exposure conditions); and risk or benefit analyses (e.g., that apply existing C-R
functions or effect estimates to exposure estimates for differing cases). For the health appendices, the
PECOS statement defines the scope of the studies considered in the assessment of health evidence and
establishes study inclusion criteria thereby facilitating identification of the most relevant literature to
inform the ISA for each health discipline.
Similarly, the statement used to define the scope of the ecological effects includes Level of
Biological Organization, Exposure, Comparison, Endpoint, and Study Design (LECES). The LECES
statement developed by EPA specifically for the purpose of scoping literature for the ISAs, was based on
the PECOS with some concepts substituted to provide a better fit with ecological science. In the LECES,
"population" (PECOS) is replaced with "level of biological organization" (LECES) and "outcome"
(PECOS) is replaced with "endpoint" (LECES). The LECES statement aids in identifying the relevant
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evidence in the literature for ecological effects of Pb. Other topics within scope, in addition to Pb effects
on biota described in the LECES criteria above, include effects of Pb biogeochemistry on bioavailability
in terrestrial, freshwater, and saltwater environments; subsequent vulnerability of particular organisms,
populations, communities, or ecosystems, as well as key uncertainties and limitations in the evidence
identified in the previous review. Concentrations relevant to the welfare effects of Pb consider the range
of Pb concentrations in the environment and the available evidence for concentrations at which effects are
observed in plants, invertebrates, and vertebrates. Effects observed at or near Pb concentrations measured
in ambient soil, sediment, and water for which local contamination is not thought to be a primary
contributor are emphasized. Concentration cutoff values were applied when evaluating the ecological
literature published since the 2013 Pb ISA (Appendix 12). For soil, the cutoff value for screening of
terrestrial studies of Pb exposure and effects was set at a concentration of approximately 230 mg Pb/kg of
soil. For aqueous exposures, the cutoff value for study screening was approximately 10 fxg Pb/L and, for
sediments, the literature cutoff value for study screening was approximately 300 mg Pb/kg dry weight
(Appendix 12. Table 12-4). Studies at higher concentrations were included only to the extent that they
informed mechanisms of action, exposure-response, or the wide range of sensitivity to Pb across taxa.
Areas outside of the scope for ecological effects in the Pb ISA included site-specific studies in non-U.S.
locations that did not contribute novel insights on Pb biogeochemistry or effects. Studies on mine tailings,
biochar, industrial effluent, sewage, ship breaking, bioremediation of highly contaminated sites, and
ingestion of Pb shot, fishing tackle or pellets were not within the scope of the ISA due to high
concentration of Pb and lack of a connection to an air-related source or process.
IS.1.2.2 Organization of the ISA
The ISA consists of the Front Matter (list of authors, contributors, and reviewers), Executive
Summary (ES), IS and 12 appendices: https://cfpub.epa.gov/ncea/isa/recordisplav.cfm?deid=357282. This
IS consolidates the key findings from the appendices considered in characterizing Pb exposure and
relationships with human and welfare effects. Subsequent appendices are organized by subject area and
include a detailed assessment and description of atmospheric science (Appendix 1), exposure
(Appendix 2), health evidence (Appendix 3-Appendix 10), welfare evidence (Appendix 11), and the ISA
development process (Appendix 12). Appendices for each broad health effect category (e.g., nervous
system effects) discuss potential biological pathways and conclude with a causality determination
describing the strength of the evidence between exposure to Pb and the outcome(s) under consideration.
Likewise, the appendix devoted to welfare evidence (Appendix 11) includes causality determinations for
multiple effects on ecosystems.
Organization of the 2023 External Review Draft Pb ISA:
• Front Matter
• Executive Summary
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• Integrative Synthesis
• Appendix 1. Lead Source to Concentration
• Appendix 2. Exposure, Toxicokinetics, and Biomarkers
• Appendix 3. Nervous System Effects
• Appendix 4. Cardiovascular Effects
• Appendix 5. Renal Effects
• Appendix 6. Immune System Effects
• Appendix 7. Hematological Effects
• Appendix 8. Reproductive and Developmental Effects
• Appendix 9. Effects on Other Organ Systems and Mortality
• Appendix 10. Cancer
• Appendix 11. Effects of Lead in Terrestrial and Aquatic Ecosystems
• Appendix 12. Process for Developing the Pb Integrated Science Assessment
15.1.2.3 Quality Assurance Summary
The use of QA and peer review helps ensure that EPA conducts high-quality science assessments
that can be used to help policymakers, industry, and the public make informed decisions. QA activities
performed by EPA ensure that environmental data are of sufficient quality to support the Agency's
intended use. EPA has developed a detailed Program-level QA Project Plan (PQAPP) for the ISA
Program to describe the technical approach and associated QA/quality control procedures associated with
the ISA Program. All QA objectives and measurement criteria detailed in the PQAPP have been
employed in developing this ISA. Furthermore, the Pb ISA is classified as a Highly Influential Scientific
Assessment (HISA), which is defined by the Office of Management and Budget (OMB) as a scientific
assessment that is novel, controversial, or precedent-setting, or has significant interagency interest
(Bolton. 2004). OMB requires a HISA to be peer reviewed before dissemination. To meet this
requirement, EPA engages CASAC as an independent federal advisory committee to conduct peer
reviews. Both peer-review comments provided by the CASAC panel and public comments submitted to
the panel during its deliberations about the external review draft will be considered in the development of
the final ISA. For a more detailed discussion of peer review and QA, see Appendix 12.
15.1.2.4 Evaluation of the Evidence
This ISA draws conclusions about the causal nature of relationships between exposure to Pb and
categories of related health and welfare effects, the concentrations at which effects are observed, and the
populations and organisms most affected by Pb, by integrating recent evidence across scientific
disciplines and building on the evidence from previous assessments. Determinations are made about
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causation, not just association, and are based on judgments of nine aspects of the evidence, including
consistency, coherence, and biological plausibility of observed effects, and on related uncertainties (U.S.
EPA. 2015). The ISA uses a formal causal framework to classify the weight of evidence using a five-level
hierarchy (i.e., "causal relationship"; "likely to be causal relationship"; "suggestive of, but not sufficient
to infer, a causal relationship"; "inadequate to infer the presence or absence of a causal relationship"; or
"not likely to be a causal relationship" as described in Table II of the Preamble (U.S. EPA. 2015)).
This framework for making causality determinations was recently reviewed by an ad hoc
committee of the National Academies of Sciences, Engineering, and Medicine (NASEM. 2022). The
committee broadly endorsed the framework, concluding that it "allows EPA to draw conclusions that
integrate scientific findings across multiple study designs and disciplines, as required by the [Clean Air
Act] page 111 of (NASEM. 2022)." The committee further provided recommendations on approaches to
increase transparency in how evidence is integrated and on other aspects of the ISA causality framework.
EPA is currently evaluating the committee's recommendations and anticipates incorporating appropriate
changes to the framework in future ISAs and documenting these changes in a future revision of the
Preamble.
IS.2 Pb Source to Concentration
This section characterizes the current state of atmospheric and environmental science relevant to
understanding Pb exposure and Pb-related health and ecological effects described in subsequent sections.
It builds on previous research reviewed in the 2013 Pb ISA (U.S. EPA. 2013a) and previous Pb AQCDs
(U.S. EPA. 2006a. 1986c. 1977). and it emphasizes relevant advances in sources and emissions, fate and
transport, sampling and analysis methods, and concentration observations discussed in greater detail in
Appendix 1 (Lead Source to Concentration). The scope is not limited to airborne Pb from contemporary
emission sources because non-atmospheric processes as well as legacy sources are also relevant for
understanding the effects of air-related Pb. For example, transport and transformation processes in soil
and water after deposition are also relevant. Therefore, current research in other media is also included to
promote understanding of air-related Pb in the context of non-atmospheric sources and media.
In previous ISAs, an up-to-date review of air emissions, monitoring, and concentration trends has
been accomplished through a combination of analysis of EPA monitoring network data and a synthesis of
observations reported in the peer-reviewed literature. Reference data such as estimates of total emissions,
coverage of network monitors, average concentrations, and concentration trends can become out of date
before the document is published because these data are so frequently updated. To facilitate provision of
the most current emissions and concentration data from the Pb monitoring network, a set of relevant maps
and graphics that have been routinely included in previous ISAs are now contained in a separate
document titled "Overview of Lead (Pb) Air Quality in the United States" (U.S. EPA. 2022b).
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Appendix 1 of the Pb ISA provides a literature-based synthesis of recent research on Pb sources, fate and
transport, measurement, and ambient air concentrations.
Section IS.2.1 provides an overview of sources and emissions of Pb in ambient air and other
environmental media. Section IS.2.2 gives descriptions of the fate and transport of Pb in air, soil, and
aqueous media. Section IS.2.3 describes advances in Pb measurement methods, and Section IS.2.4
describes ambient air Pb concentrations, including spatial and temporal variability and the size
distributions of Pb-bearing particulate matter (PM).
15.2.1 Sources and Emissions
Total estimated national Pb emissions to ambient air from the 2017 National Emissions Inventory
(NEI) were 668 tons, with 70% from emissions associated with use of leaded aviation gasoline, 20% from
industrial sources, and 7% from fuel combustion. All other sources combined were estimated to account
for less than 4% of total U.S. Pb emissions estimated by the NEI. Not included in the NEI are Pb
emissions estimates from wildland fires or resuspended legacy Pb. Pb emissions from wildland fires were
not estimated in the 2017 NEI but there are plans for including them in the 2020 NEI scheduled for
release in March 2023 (Appendix 1.2.4). A preliminary national emissions estimate for wildfires is
approximately 18 tons per year, which would put wildfires as the fourth largest source of Pb, behind
piston engine aircraft, industrial processes, and fuel combustion (Appendix 1.2.4). In addition to
contemporary Pb emissions into the atmosphere, historical sources of Pb can potentially contribute to
airborne Pb under some circumstances through the processes of suspension and resuspension
(Appendix 1.3.4). Details of recent research and results of individual studies of Pb emissions from
aviation, industrial sources, stationary fuel combustion, wildfires, automobile traffic and roads, volcanoes,
and legacy sources in the United States are presented in Appendix 1.2.
15.2.2 Fate and Transport
Pb emitted into the atmosphere can be distributed into soil, water, and other media. Pb is mainly
emitted into the air in particulate form. The fate and transport of Pb emitted into the air depends on
particle size, which in turn depends largely on the source. For example, Pb emitted by aircraft using
leaded aviation gas is mainly associated with ultrafine particles smaller than 0.1 |im diameter, while a
large fraction of airborne Pb produced by resuspension of contaminated soil near current or historic
sources can be associated with coarse particles, including particles larger than 10 |im. Pb-containing
particles are subject to the same atmospheric processes that transport and remove other forms of PM.
Particle-bound Pb associated with fine PM is transported long distances and found in remote areas, while
Pb associated with coarse PM is more likely to deposit closer to its source. As discussed in
Appendix 1.3.1. the dry deposition rate of particles increases with increasing particle size, effectively
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reducing transport distance and atmospheric lifetime. However, depending on the chemical counter-ion,
Pb compounds vary in water solubility, determining the degree to which Pb is removed by wet deposition.
After deposition, resuspension of soil-bound Pb can contribute to airborne concentrations near major Pb
sources (Appendix 1.3.4). There has been little recent research on transport of airborne Pb, beyond a few
individual studies outside the United States that showed agreement of Pb biomonitoring data with
dispersion modeling estimates and chemical transformations of Pb to a more soluble form in polluted air
under specific circumstances (Appendix 1.3.1.2).
In general, fine particulate Pb is mostly soluble and removed from the atmosphere by wet
deposition, and coarse particulate Pb is mostly insoluble and removed from the atmosphere by dry
deposition. Other factors also influence Pb deposition, however. The pH of precipitation can play a role
because Pb solubility increases with decreasing pH. Precipitation can also scavenge insoluble particulate
Pb as an aqueous suspension. Several U.S. studies, some of which have been published since the 2013 Pb
ISA, have reported substantially greater deposition rates in areas near industrial sources than in
nonindustrial areas. Recent studies have also filled in some details about the Pb deposition process,
including studies that indicated Pb deposition increased with elevation and that Pb is enriched in
atmospheric ice nuclei (Appendix 1.3.1.3).
Once deposited in soil, Pb is strongly retained in soil organic material with subsequent Pb fate
and transport through the soil column influenced by several physicochemical factors, including storage in
leaf litter, the amount and decomposition rates of organic matter (OM), composition of organic and
inorganic soil constituents, mobile colloid abundance and composition, microbial activity, and soil pH.
These physicochemical properties are based on soil forming factors: climate, organisms, parent material,
relief (shape of the landscape), time, and anthropogenic input. Soils that differ in these factors will
subsequently have different physicochemical properties and different trends in Pb transport. In general,
leaf litter, low rates of OM decomposition, neutral pH, and soil constituents rich in charged surfaces such
as OM, Fe and Mn oxides, and clay minerals will lead to increased Pb retention and sorption. Conversely,
thin organic layers, increased OM decomposition, acidic pH, increases in anthropogenic Pb, and less
reactive soil constituents such as quartz increase Pb leaching from soils.
In water, runoff from urban or historically industrial areas contains higher Pb concentrations than
runoff from nonurban areas. Recent studies have improved our understanding of relationships between Pb
runoff and street length and density, population density, and land cover, and expanded on the influence of
seasonality and precipitation events on runoff as well as transport and sedimentation. While Pb deposition
has decreased in the last half-century with the phase-out of leaded gasoline and stricter regulation,
accumulated Pb-contaminated sediments in areas with a history of industry and urbanization are
vulnerable to resuspension in water and both down and upstream movement following a disturbance
event. Dam removal or other disturbances to water bodies can lead to resuspension in water and
dissolution of Pb-contaminated sediment that was previously deposited. With the predicted increase in
future frequency of drought alongside less frequent but more severe precipitation patterns across most of
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the United States, the potential for remobilization of such legacy Pb in waterbodies is an area for
consideration.
Additional media besides air, water, and soil are useful for understanding how Pb moves and
changes over time in the urban environment. It is potentially useful to consider urban soil, resuspended
dust, road dust, and house dust as urban compartments between which Pb can be transported or cycled.
High Pb concentrations are characteristic of urban soil in comparison with other soils and are often related
to legacy sources. Studies in several U.S. cities have explored the high spatial variability of urban soil Pb
concentrations, with hot spots related to income and racial disparities. In recent studies, associations
between airborne Pb and elemental indicators of airborne soil have been observed, suggesting the
potential for contaminated soil to be a source of airborne Pb locally in urban and industrial areas under
some circumstances. Suspension of urban soil into the air can also be a source of Pb in house dust
(Appendix 1.3.4V
IS.2.3 Sampling and Analysis
There are two Federal Reference Methods (FRMs) for sample collection of airborne Pb. The
FRM for Pb in total suspended particulate (Pb-TSP) requires a high-volume sampler and is required for
all source-oriented NAAQS surveillance monitors. The FRM for Pb associated with PMio (Pb-PMio) is
acceptable for Pb NAAQS surveillance monitoring at locations where the expected Pb concentration does
not approach the NAAQS and in the absence of nearby sources of Pb associated with particles greater
than 10 |im diameter. Variability in high-volume TSP sampler collection efficiency associated with
effects of wind speed and sampler orientation for particles larger than 10 |im has been a serious concern
since the sampler was first implemented for TSP and Pb-TSP sampling. Recent research confirmed that
sampling effectiveness decreased with particle size for coarse particles and varied with wind speed and
sampler orientation. A number of alternative manufacturer-designated low-volume TSP samplers have
been developed, but recent studies showed that their sampling effectiveness also decreases with particle
size for coarse particles. The Pb-PMio FRM is not as vulnerable to sampling errors associated with the
Pb-TSP FRM because it is based on a strictly defined performance standard, but Pb associated with
particles larger than 10 |im in diameter can be an important contributor to airborne Pb exposure. Other
recent advances in ambient air Pb sampling and analysis included the development of a new Pb analysis
FRM based on inductively coupled plasma mass spectrometry, development of more relevant reference
materials for ambient air Pb sampling and analysis, and development of higher time resolution sampling
and analytical methods.
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IS.2.4
Ambient Air Pb Concentrations
Several recent studies indicated substantial spatial variability in urban ambient air Pb
concentrations influenced by proximity to local sources or industrial activities. Across urban and
neighborhood scales, these variations in ambient air Pb concentrations may not be captured by national
monitoring networks. Seasonal trends were reported in numerous recent studies, but results were mixed,
and no consistent national pattern was apparent. Size distribution data from samples collected near roads,
near industrial sources, in rural locations, and in urban locations within the United States and the
European Union suggest that Pb size distributions in ambient air have shifted in the 1980s from size
distributions with a mass median diameter usually smaller than 2.5 |im to those with a primary mode
between 2.5-10 |im. No recent studies specifically investigated background Pb concentrations, but a
plausible range of 0.2 to 1 ng/m3 was proposed based on earlier studies in the 2013 Pb ISA (U.S. EPA.
2013a).
IS.3 Trends
Total Pb emissions have steadily decreased for decades, largely due to the elimination of leaded
gasoline use in automobiles before 1996, and in later years because of reductions in emissions from
metals processing sources (U.S. EPA. 2022b. 2013a. 2006a'). From 1990 to 2020, there has been a steep
decline in total U.S. Pb emissions from about 5 kton/year to less than 1 kton/year (U.S. EPA. 2021). In
some cases, there have been more recent periods of continued decline corresponding to reductions in Pb
emissions from local and regional industrial sources. A quantitative description of the trend in ambient air
concentrations based on monitoring network data is problematic for two reasons. First, air Pb
concentration reporting requirements changed in 2010 from measured Pb concentration at standard
temperature and pressure to Pb concentration measured under local conditions. As a result, daily
concentration and design value data from before 2010 are not directly comparable to data from after 2010.
Second, as numerous monitors have been discontinued because of declining Pb concentrations, the
proportion of monitors located near sources has increased. Pb monitoring network data show that the
national median of maximum 3-month average Pb concentrations across monitoring sites declined by
89% from 1990 to 2010 for a mix of 74 source-oriented and non-source-oriented monitors that operated
continuously through this period (Appendix 1.5.1). For a smaller population of 37 monitors with a higher
proportion of source-oriented monitors that operated continuously from 2010 to 2021, the national
median of maximum 3-month average Pb concentrations across monitoring sites decreased by 88% over
that period (Appendix 1.5.1). This recent decrease was driven by the 2008 NAAQS revision and the
steepest declines were observed over the period from 2012 to 2015 (Appendix 1.5.1). Detailed maps and
graphics of changing ambient air Pb concentrations over time are available in U.S. EPA (2022b).
Changes in the patterns of Pb emissions over time and between regions of the United States are
also detectable in non-air environmental media and biota. Pb may be retained in soils, sediments, the
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shells of long-lived bivalves, or trees, where it provides a historical record of deposition such as phase-out
of Pb from on-road gasoline and reductions in industrial releases. However, information on Pb
atmospheric trends can be difficult to interpret due to the influence of other anthropogenic inputs of Pb
and heterogeneity associated with natural environments. The number of studies that examine trends in Pb
concentration in non-air media at national and regional scales is limited.
Concentrations of Pb in soils (Appendix 11.2.2.1) vary across the United States due to a variety
of natural and anthropogenic factors, including historical Pb deposition. The United States Geological
Survey North American Soil Geochemical Landscapes Project (NASGLP) provides the most
comprehensive and rigorous information on the distribution of Pb across the conterminous United States
(Smith et al.. 2013). In the NASGLP survey, soil samples were collected from multiple depths at 4,857
sites. In areas with historic depositional input of Pb, the concentration of Pb observed in upper-horizon
soils was often higher than that observed in the bedrock. Figure IS-1 C shows the ratio of A-horizon (the
uppermost mineral soil) to C-horizon (a deeper soil sample generally of partially weathered parent
material) Pb concentrations mapped in Woodruff et al. (2015). using inverse-distance weighting methods
derived from the NASGLP survey (Smith et al.. 2013). This map displays areas with increased
concentrations of Pb in A-horizon soils relative to lower horizons, hinting at the lasting effect of
depositional Pb pollution, where historical Pb deposition may have a relatively higher effect on people
and ecosystems. Patterns of elevated A- to C-horizon soil Pb concentrations in Figure IS-l.C are
conspicuous in areas with historical anthropogenic sources of Pb. This pattern is observed in the
northeastern United States, with a historically high population density and intensity of industrial
development. Likewise, mapping highlights former Pb smelting and mining sites, for instance in areas
near smelters in Everett and Tacoma, Washington or the Doe Run smelter in Herculaneum, Missouri (the
last Pb smelter in the United States, which closed in 2013). Areas near mining sites, including near
Leadville, Colorado, Cooke City, Montana, and northern Utah, also have a high ratio of A- to C-horizon
Pb. Woodruff et al. (2015) emphasized that no known natural geological process would otherwise explain
elevated A-horizon soils relative to the underlying layers.
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B. Lead (Pb) - C Horizon
D. Population density (per sq. mile) by county
A. Lead (Pb) - A Horizon
C. Lead (Pb) - Ratio of A Horizon/C Horizon
Source: Woodruff et al. (2015)
Figure IS-1 Maps of Pb sampled from A-horizon (A.) and C-horizon (B.) soils,
the ratio of Pb observed in A-horizon to C-horizon soils (C.), and
population density (D.).
In a regional survey of forest floor soils limited to the northeastern United States featuring
sequential sampling in 1980, 1990, 2002, and 2011, mean soil Pb concentrations decreased from 151 ± 29
(standard error [SE]) mg Pb/kg in 1980 to 68 ± 13 (SE) mg Pb/kg in 2011 and were estimated to decline
2.0 ± 0.3 % per year (Richardson et al.. 2015; Richardson et al.. 2014). A 2019 survey of peri-urban soil
Pb in several southern California counties is illustrative of the regional variability in U.S. soil Pb
concentrations. Soil Pb in the study (mean of 23 .9 ± 13 .8 mg Pb/kg) was elevated relative to the
southwestern U.S. region, but lower than concentrations found at contaminated sites near point sources of
Pb (iVIackowiak et al.. 2021). These recent national and regional surveys of soil Pb document the spatial
and temporal patterns of residual pollution resulting from decades of Pb emissions. In general, areas with
higher population density and intensity of industrial activity have higher soil Pb concentrations relative to
rural areas. Recent results from more local studies of individual cities and neighborhoods are consistent
with these results (Appendix 1.3.4).
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Quantification of Pb in tree rings can be used to reconstruct historical trends of Pb in air pollution
(U.S. EPA. 2006a. 1986b. 1977); however, radial transport of Pb, which may vary among species, can
occur within the tree, contributing uncertainty and reducing precision of such reconstructions.
Additionally, there may be a 10- to 15-year delay in tree ring Pb compared with air concentrations as Pb
deposition leaches through the soil and is absorbed by the tree (U.S. EPA. 2013a). Although trends varied
across tree species and regions in several North American studies published since the 2013 Pb ISA
(Appendix 11.2.2.2). studies identified a temporal pattern of Pb that increased after 1850-1900 and, in
some cases, peaked in 1970-1985, then decreased afterward. Tree ring studies with temporal patterns that
deviate from this pattern were conducted near active industrial point sources of Pb pollution.
Temporal trends of Pb deposition in sediment show distinct peaks associated with leaded gasoline
usage in the United States. These peaks are found globally, corresponding to the specific phase-out
periods for the contributing countries (Appendix 1.3.3.4). Patterns of increasing Pb concentration
occurring from the mid- 19th century through the mid-20th century due to early industry as well as
agriculture, weathering, and mining operations are identifiable in North American lake and reservoir
sediments. Following the peak deposition period in the 1960s due to leaded gasoline in North America,
widespread decreases in Pb concentration in sediments are seen over the following half-century, but
concentration values are still higher than pre-19th century levels showing continued deposition, nonpoint
contamination, and/or legacy Pb runoff contributions.
In freshwater environments, no recent studies were identified that examined spatial or temporal
trends in Pb concentration in fish or invertebrates from locations across the United States.
Appendix 11.3.2 summarizes several historical studies reviewed in earlier AQCDs or the 2013 Pb ISA.
Limited evidence from regional studies of temporal trends in freshwater aquatic ecosystems published
since the 2013 Pb ISA, including one of dissolved Pb in Appalachian streams and another of peat cores in
northern Alberta, Canada, suggests that modern atmospheric deposition of Pb is not a major contributor to
Pb concentrations in streams in remote locations (Appendix 11.3.2).
In long-term biomonitoring studies of saltwater biota (Appendix 11.4.2). there is some evidence
of declining Pb concentrations, particularly in studies that began sampling before the 1990s. However,
other studies provide mixed results, with some observations of insignificant change or even increases in
Pb concentrations, likely due to non-air anthropogenic sources. The National Oceanic and Atmospheric
Administration (NOAA) Mussel Watch program has monitored pollutant trends since 1986 via periodic
sampling of bivalve tissue (Mytilus spp. and Crassostrea virginica oysters) and sediment along the U.S.
coastline (Kimbrough et al.. 2008). In general, the highest concentrations of Pb are in bivalves in the
vicinity of urban and industrial areas. Metals concentrations in Mytilus californianus were sampled at
long-term biomonitoring sites off the coast of California from 1977 to 2010 (specific years vary by site)
(Melwani et al.. 2014). Decreasing trends were observed at some sites while others showed no significant
trend. In addition to tissues, quantification of chemical variation of elements taken up and deposited in
shells of marine organisms (sclerochronology) provides a temporal record of Pb deposition inputs to
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coastal environments. Several studies in bivalves collected off the coast of the eastern United States,
where Pb sources include atmospheric transport by easterly winds, show elevated Pb in shell
corresponding to the peak of Pb gasoline use in the United States and then declines after that time
(Krausc-Nchring et al.. 2012; Gillikin et al.. 2005). In a synthesis of data from 15 studies from different
geographic locations that quantified Pb in marine bivalves, shell concentrations tended to be higher in
areas near sources of Pb pollution (Cariou et al.. 2017). In addition to bivalves, heavy metals quantified in
horseshoe crab (Limulus polyphemus) eggs collected along Delaware Bay in 2012 showed a decline in Pb
overtime in a comparison with compiled data from earlier surveys conducted between 1993 and 2000
(Burger and Tsipoura. 2014) while, in contrast, a decade-long biomonitoring study of metals in the
muscle tissue of dolphinfish (Coryphaena hippurus) in the southern Gulf of California from 2006-2015
found no temporal trend in Pb conccntrations(Gil-Manriquc et al.. 2022).
Overall, evidence from surveys of Pb in environmental media and biota reflects a decline in
anthropogenic emissions of Pb. However, Pb pollution persists in environmental media and is still
observed in measurable concentrations within biota, particularly near sources of Pb pollution both
historical and current. Long-term monitoring of Pb concentration trends in biota (e.g., the NOAA Mussel
Watch program) and soil surveys covering large spatial extents (e.g., NASGLP) provide essential records
of Pb concentrations in the environment observed across decades and regions.
IS.4 Human Exposure to Ambient Pb
Human exposure to Pb derives from the multiple sources of Pb in the environment and the
various media through which it passes (Appendix 2.1). Air-related pathways of Pb exposure are the focus
of this assessment. However, most Pb biomarker studies do not indicate species or isotopic signature,
making it a challenge to link Pb exposures to specific sources. Air-related Pb exposure pathways include
inhalation of Pb in ambient air along with inhalation and ingestion of Pb in indoor dust and/or outdoor
soil that originated from recent or historic ambient air (e.g., air Pb that has penetrated into the residence
either via the air or tracking of soil), ingestion of Pb in drinking water drawn from surface water
contaminated from atmospheric deposition or contaminated from surface runoff of deposited Pb, and
ingestion of Pb in dietary sources after uptake by plants or livestock of Pb that originated from the
atmosphere. Soil can act as a reservoir for deposited Pb emissions. Exposure to soil contaminated with
deposited Pb can occur through inhalation of resuspended soil as well as ingestion via hand-to-mouth
contact. The primary contribution of ambient air Pb to young children's blood Pb concentrations is
generally due to ingestion of Pb following its deposition to soils and dusts (Appendix 2.1.3.2).
Nonambient air-related exposures include hand-to-mouth contact with dust or chips of peeling Pb-
containing paint or ingestion of Pb in drinking water leached by corroding pipes. Several studies indicate
that Pb-containing paint in the home (or home age used as a surrogate for the presence of Pb paint) are
important residential factors that increase risk of elevated blood Pb (Appendix 2.1.3.2).
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The size distribution of soil or dust particles containing Pb differs from the size distribution of
inhalable ambient Pb-bearing PM (Appendix 2.1.3.1). Airborne particles containing Pb tend to be small
(much of the distribution <10 |im) compared with soil or dust particles containing Pb (-50 |im to several
hundred |im). The size of particles containing Pb that someone may be exposed to can vary due to source
type and proximity to those sources. Ingestion through hand-to-mouth contact is the predominant
exposure pathway for the larger particles in soil and dust containing Pb.
A number of monitoring and modeling techniques have been employed for estimating Pb
exposures and associated BLLs. Environmental Pb concentration data can be collected from ambient air
Pb monitors, soil Pb samples, dust Pb samples, and dietary Pb samples to estimate human exposure.
Exposure estimation error depends, in part, on the collection efficiency of these methods. Models, such as
the Integrated Exposure Uptake Biokinetic (IEUBK) model, coupling of the Stochastic Human Exposure
and Dose Simulation (SHEDS) and IEUBK models (SHEDS-IEUBK), and the All Ages Lead Model,
simulate human exposure to Pb from multiple sources and through intake routes of inhalation and
ingestion. Children's exposure to Pb is modeled using inputs including soil Pb concentration, air Pb
concentration, dietary Pb intake including drinking water and Pb-dust ingestion, human activity, and
biokinetic factors. The relative contribution from specific exposure pathways (e.g., water, diet, soil,
ambient air) to blood Pb concentrations is situation specific. Measurements and/or assumptions can be
utilized when formulating the model inputs; errors in measurements and assumptions have the potential to
propagate through exposure models. Biomarkers, such as blood Pb, can also be used to provide
information about exposure (Appendix 2.3).
IS.5 Toxicokinetics
The majority of Pb in the body is found in bone (roughly 90% in adults, 70% in children); only
about 1% of Pb is found in the blood. Pb in blood is primarily (-99%) bound to red blood cells (RBCs). It
has been suggested that the small fraction of Pb in plasma (<1%) may be the more biologically labile and
toxicologically active fraction of the circulating Pb. The relationship between Pb in blood and plasma is
approximately linear at relatively low daily Pb intakes (i.e., <10 |ig/kg per day) and at blood Pb
concentrations <25 (ig/dL, and becomes curvilinear at higher blood Pb concentrations due to saturable
binding to RBC proteins. As BLL increases and the higher affinity binding sites for Pb in RBCs become
saturated, a larger fraction of the blood Pb is available in plasma to distribute to brain and other tissues.
See Appendix 2.2.2 for additional details.
The half-life of Pb in blood is approximately 20-30 days in adults and a half-life of
approximately 6 days has been estimated based on data for children under the age of 3 years. An abrupt
change in Pb uptake gives rise to a relatively rapid change in blood Pb, with a new quasi-steady state
achieved in approximately 75-100 days (i.e., 3-4 times the blood elimination half-life). A slower phase of
Pb clearance from the blood may become evident with longer observation periods following a decrease in
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exposure due to the gradual redistribution of Pb among bone and other compartments. See
Appendix 2.3.5 for additional details. Absorbed Pb is excreted primarily in urine and feces, with sweat,
saliva, hair, nails, and breast milk being minor routes of excretion. Approximately 30% of intravenously
injected Pb in humans (40-50% in beagles and baboons) is excreted via urine and feces during the first
20 days following administration (Leggett. 1993). The kinetics of urinary excretion following a single
dose of Pb is similar to that of blood (Chamberlain et al.. 1978). likely because Pb in urine derives largely
from Pb in plasma. See Appendix 2.2.3 for additional details.
The burden of Pb in the body may be viewed as divided between a dominant slow compartment
(bone) and smaller fast compartment(s) (soft tissues). Pb uptake to and elimination from soft tissues is
much faster than in bone. Pb accumulates in bone regions undergoing the most active calcification at the
time of exposure. Pb accumulation is thought to occur predominantly in cortical bone during childhood
and in both cortical and trabecular bone in adulthood. However, several considerations complicate the
dichotomy between Pb accumulation in trabecular versus cortical bone. For example, the tibia is generally
considered a cortical bone with less than 1% trabecular bone at its midshaft but is 55-75% trabecular
bone toward the ends of the bone. A high bone formation rate in early childhood results in the rapid
uptake of circulating Pb into mineralizing bone; however, in early childhood, bone Pb is also recycled to
other tissue compartments or excreted in accordance with a high bone resorption rate. Thus, much of the
Pb acquired early in life is not permanently fixed in the bone due to rapid bone formation and
reabsorption. See Appendix 2.2.2.2 for additional details.
The exchange of Pb from plasma to the bone surface is a relatively rapid process. Pb in bone
becomes distributed in trabecular bone and the denser cortical bone. The proportion of cortical to
trabecular bone in the human body varies by age, but on average is about 80% cortical to 20% trabecular.
Of the bone types, trabecular bone is more reflective of recent exposures than is cortical bone due to the
slower turnover rate and lower blood perfusion of cortical bone. Some Pb diffuses to kinetically deeper
bone regions where it is relatively inert, particularly in adults. These bone compartments are much more
labile in infants and children than in adults as reflected by half-times for movement of Pb from bone into
the plasma (e.g., cortical half-time = 0.23 years at birth, 3.7 years at 15 years of age, and 23 years in
adults; trabecular half-time = 0.23 years at birth, 2.0 years at 15 years of age, and 3.8 years in adults)
(Leggett. 1993). See Appendix 2.3.5 for additional details.
Evidence for maternal-to-fetal transfer of Pb in humans is derived from umbilical cord blood to
maternal blood Pb ratios (i.e., cord blood Pb concentration divided by mother's blood Pb concentration).
Group mean ratios range from about 0.7 to 1.0 at the time of delivery for mean maternal BLLs ranging
from 1.7 to 8.6 (ig/dL. Transplacental transfer of Pb may be facilitated by an increase in the plasma/blood
Pb concentration ratio during pregnancy. Maternal-to-fetal transfer of Pb appears to be related partly to
the mobilization of Pb from the maternal skeleton. See Appendix 2.2.2.4 for additional details.
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IS.6 Pb Biomarkers
Overall, BLLs have been decreasing among U.S. children and adults over the past 45 years. The
geometric mean BLL for the entire U.S. population was 0.753 (ig/dL (95% CI: 0.723, 0.784), based on the
2017-2018 NHANES data (CDC. 2021). Among children aged 1-5 years, the geometric mean was
slightly lower, at 0.670 (ig/dL (95% CI: 0.600, 0.748). By comparison, the 1976-1980 NHANES showed
a geometric mean blood Pb of 15.2 (ig/dL (95% CI: 14.3, 16.1) in children aged 1-5 years. In addition,
the gap in BLLs between non-Hispanic black children and children of different racial/ethnic groups, aged
1-5 and 6-10 years, has decreased overtime, as shown by 1999-2000 to 2015-2016 NHANES data. See
Appendix 2.4.1 for additional details.
Blood Pb is dependent on both the recent exposure history of the individual and the long-term
exposure history, which determines body burden and Pb in bone. The contribution of bone Pb to blood Pb
varies depending on the duration and intensity of the exposure, age, and various other physiological
stressors (e.g., nutritional status, pregnancy, menopause, extended bed rest, hyperparathyroidism) that
may affect bone remodeling, which occurs continuously under normal circumstances. In children, blood
Pb is both an index of recent exposure and potentially an index of body burden, largely due to faster
exchange of Pb to and from bone than in adults. In adults and children whose exposure to Pb has
effectively ceased or greatly decreased, there is a rapid decline in blood Pb over the first few months
followed by a more gradual, slow decline in blood Pb concentrations over the period of years due to the
gradual release of Pb from bone. Bone Pb is an index of cumulative exposure and body burden. Bone
compartments should be recognized as reflective of differing exposure periods, with Pb in trabecular bone
exchanging with the blood more rapidly than Pb in cortical bone. Consequently, Pb in cortical bone is a
better marker of cumulative exposure, while Pb in trabecular bone is more likely to be correlated with
blood Pb, even in adults. See Appendix 2.2.2 and 2.3.5 for additional details.
It is important to recognize that from a single measurement of blood Pb, it cannot be determined
the extent to which blood Pb reflects recent exposure, movement of Pb from bone into blood from
historical exposures, or both recent and historical exposures. Additionally, a single measurement of blood
Pb cannot inform whether an individual is at a steady-state blood Pb concentration or whether blood Pb is
changing because of a change in Pb exposure. In contrast, multiple blood Pb concentrations over time can
provide more insight into cumulative exposures and average Pb body burdens overtime. The degree to
which repeated sampling will reflect the actual long-term time-weighted average blood Pb concentration
depends on the sampling frequency in relation to variability in exposure. High variability in Pb exposures
can produce episodic (or periodic) oscillations in blood Pb concentration that may not be captured with
infrequent samples. Furthermore, similar blood Pb concentrations in two individuals (or populations),
regardless of their age, do not necessarily translate to similar body burdens or similar exposure histories.
The blood Pb measurement method (capillary or venous) may also influence measured blood Pb
concentrations because of a positive bias in capillary sample measurement and contamination of
fingertips where samples were collected. See Appendix 2.3.2 for additional details.
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The concentration of Pb in urine follows blood Pb concentration. There is added complexity with
Pb in urine because concentration is also dependent upon urine flow rate (see Appendix 2.2.3). which
requires timed urine samples that is often not feasible in epidemiologic studies. Other biomarkers have
been utilized to a lesser extent (e.g., Pb in teeth, hair, and saliva) because of complications with
environmental contamination or inconsistent associations with blood Pb. See Appendix 2.3 for additional
details.
IS.7 Evaluation of the Health Effects of Pb
IS.7.1 Connections Among Health Effects
Broad health effect categories organized by organ system are evaluated separately in the
appendices of this ISA, though the mechanisms underlying disease progression may overlap and are not
necessarily restricted to a single organ system. This section provides a brief overview of how the
relationship between Pb exposure and a variety of health outcomes may be related or affect one another.
Pb-induced injuries can take place via complex pathways within the body. The health effects of
Pb can be triggered by both direct and indirect actions within an organ but can also cause systemic
changes that can affect other areas of the body. Pb can directly bind to cellular proteins and in some
instances can displace biologically relevant enzymes leading both to ion imbalance and initiation of
inflammation and oxidative stress. Because the circulatory system is connected to all body systems,
effects of damage in one organ system may contribute to health effects in another. Pb-induced systemic
inflammation and oxidative stress can trigger systemic responses in multiple organs.
There is crosstalk between organ systems in the body. For example, the nervous system regulates
the development and function of many organs and thus, modulation of the nervous system by Pb exposure
(see Appendix 3) can have widespread effects. Pb has been shown to disrupt the network of signaling
between the hypothalamus, pituitary, and adrenal and gonadotropic axes, which have important
implications in the regulation of development, reproduction, cardiovascular function, and respiratory
function. This is of particular concern with Pb exposure early in life as proper organ development requires
proper hormonal and cell signaling cues. Disruption of these processes early in life can lead to lasting
changes in organ structure and function. In a similar manner, the function of the liver, kidneys, and
cardiovascular system are also linked. The liver plays a major role in the generation, trafficking, and
metabolism of fatty acids and cholesterol, which are trafficked throughout the body for use in other
organs. Alterations in cholesterol and fatty acid homeostasis by Pb can affect the organ systems that use
these resources. The renin-angiotensin system provides another means of crosstalk between the kidney,
liver, and cardiovascular systems. Renin, produced in the kidney, processes angiotensin, produced by the
liver, which can promote vascular contraction. Pb-induced increases in angiotensin processing can lead to
various effects including increased vascular constriction and increased blood pressure (BP). Chronic
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increases in BP can lead to kidney damage. Although these examples are not exhaustive, they highlight
means by which Pb-induced effects in one organ could lead to systemic effects capable of eliciting
multiple health effects.
While all systems of the body are connected intrinsically, most of the available research
examining the health effects of Pb exposures focuses on specific health endpoints. Thus, this ISA includes
separate supporting appendices for Nervous System Effects (Appendix 3). Cardiovascular Effects
(Appendix 4). Renal Effects (Appendix 5). Immune System Effects (Appendix 6). Hematological Effects
(Appendix 7). Reproductive and Developmental Effects (Appendix S). Effects on Other Organ Systems
and Mortality (Appendix 9). and Cancer (Appendix 10).
IS.7.2 Biological Plausibility
Biological plausibility can strengthen the basis for causal inference (U.S. EPA. 2015). In this
ISA, biological plausibility is part of the weight-of-evidence analysis that considers the totality of the
health effects evidence, including consistency and coherence of effects described in experimental and
observational studies. Each of the human health appendices (Appendix 3-Appendix 10) includes a
biological plausibility section that summarizes the evidence for potential pathways by which Pb
exposures could result in adverse health outcomes at the population level. Although there is some overlap
in the potential pathways between the appendices, each biological plausibility section is tailored to the
specific health outcome category for which causality determinations are made.
Each of the biological plausibility sections includes a figure illustrating possible pathways that
connect Pb exposures with health outcomes. Pathways are based on evidence evaluated in previous
assessments, both AQCDs and IS As, as well as evidence from more recent studies. The accompanying
text characterizes the evidence upon which the figures are based, including results of studies
demonstrating specific effects related to Pb exposure and considerations of physiology and
pathophysiology. Together, the figure and text portray the available evidence that supports the biological
plausibility of Pb exposure leading to specific health outcomes. Gaps in the evidence base (e.g., health
endpoints for which studies have not been conducted) are represented by corresponding gaps in the
figures and are identified in the accompanying text.
In the model figure below (Figure IS-2), each box represents evidence demonstrated in a study or
group of studies for a particular effect related to Pb exposure. While most of the studies used to develop
the figures are experimental studies (i.e., animal toxicological and in vitro studies), some observational
epidemiologic studies also contribute to the pathways. These epidemiologic studies generally comprise
effects observed at the population level. The boxes are arranged horizontally, with boxes on the left side
representing initial effects that reflect early biological responses and boxes to the right representing
intermediate (i.e., subclinical or clinical) effects and effects at the population level. The boxes are color
coded according to their position in the exposure to outcome continuum.
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1
3
Pb
'¦¦¦~
Exposure
V. J
Intermediate
Effect 2
'
Intermediate
Effect 3
1HHH
Note: The boxes above represent the effects for which there is experimental or epidemiologic evidence related to Pb exposure, and
the arrows indicate a proposed relationship between these effects. Solid arrows denote evidence of essentiality as provided, for
example, by an inhibitor of the pathway or a genetic knockout model used in an experimental study involving Pb exposure. Shading
around multiple boxes is used to denote a grouping of these effects. Arrows may connect individual boxes, groupings of boxes, and
individual boxes within groupings of boxes. Progression of effects is generally depicted from left to right and color coded (white,
exposure; green, initial effect; blue, intermediate effect; orange, effect at the population level or a key clinical effect). Here,
population-level effects generally reflect results of epidemiologic studies. When there are gaps in the evidence base, there are
complementary gaps in the figure and the accompanying text below.
Figure IS-2 Illustrative figure for potential biological pathways for health
effects following Pb exposure.
The arrows that connect the boxes indicate a progression of effects resulting from exposure to Pb
In most cases, arrows are dotted (arrow 1), denoting a possible relationship between the effects. While
most arrows point from left to right, some arrows point from right to left, reflecting progression of effects
in the opposite direction or a feedback loop (arrow 2). In a few cases, the arrows are solid (arrow 2),
indicating that progression from the upstream to downstream effect has been shown to occur as a direct
result of Pb exposure. This relationship between the boxes, where the upstream effect is necessary for
progression to the downstream effect, is termed essentiality (OECD. 2018). Evidence supporting
essentiality is generally provided by experimental studies using pharmacologic agents (i.e., inhibitors) or
animal models that are genetic knockouts. The use of solid lines, as opposed to dotted lines, reflects the
availability of specific experimental evidence that Pb exposure results in an upstream effect which is
necessary for progression to a downstream effect.
In the figures, upstream effects are sometimes linked to multiple downstream effects. To illustrate
this proposed relationship using a minimum number of arrows, downstream effects are grouped together
within a larger shaded box and a single arrow (arrow 3) connecting the upstream effect represented by a
single box to the outside of the downstream shaded box containing the multiple effects. Multiple
upstream effects may similarly be linked to a single downstream effect using an arrow (arrow 4) that
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originates from the outside of a shaded box, which contains multiple effects, to an individual downstream
box. In addition, arrows sometimes connect one individual upstream effect to an individual downstream
effect that is contained within a larger shaded box (arrow 2) or two individual effects both contained
within separate larger shaded boxes (arrow 5). Thus, arrows may connect individual boxes, groupings of
boxes, and individual boxes within groupings of boxes depending on the proposed relationships between
effects represented by the boxes.
IS.7.3 Summary of Health Effects Evidence
Results from health studies, supported by the evidence from atmospheric chemistry and exposure
assessment studies, contribute to the causality determinations made for the health outcomes evaluated in
this ISA. Recent evidence is considered in combination with the evidence presented in the 2013 Pb ISA.
This ISA evaluates the available health effects evidence and presents causality determinations for 30 health
effect categories. In addition to updated causality determinations for the various health outcomes that were
evaluated in the 2013 Pb ISA, this ISA includes three new causality determinations for social cognition and
behavior in children, metabolic effects, and total (nonaccidental) mortality. The causality determinations
from this ISA and their relation to the conclusions from the 2013 Pb ISA are summarized in Table IS-1.
Table IS-1 Summary of causality determinations by health outcome.
Outcome Group
Health Outcome
Causality Determination
Cognitive function decrements in children
Causal
Externalizing behaviors: attention,
impulsivity, and hyperactivity
Causal
Nervous System Effects
Externalizing behaviors: conduct disorders
in children and young adults
Likely to be causal
Ascertained During Childhood,
Adolescent, and Young Adult
Lifestages
Internalizing behaviors: anxiety and
depression
Likely to be causal
Sensory function decrements
^Suggestive
Motor function decrements
Likely to be causal
Social cognition and behavior
+Suggestive
Cognitive function decrements
Likely to be causal
Nervous System Effects
Psychopathological effects
Likely to be causal
Ascertained During Adult
Lifestages
Sensory organ function
Suggestive
Neurodegenerative disease ^Suggestive
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Outcome Group
Health Outcome
Causality Determination
Cardiovascular Effects3
Cardiovascular effects
Causal
Renal Effects
Renal effects
^Causal
Immunosuppression
Likely to be causal
Immune System Effects'5
Sensitization and allergic response
^Suggestive
Autoimmunity and autoimmune disease
Inadequate
Hematological Effects
Altered heme synthesis and decreased
RBC survival and function
Causal
Pregnancy and birth outcomes
Suggestive
Reproductive and Developmental
Effects
Development
Causal
Female reproductive function
Suggestive
Male reproductive function
Causal
Hepatic effects
^Suggestive
Metabolic effects
+ lnadequate
Gastrointestinal effects
Inadequate
Effects on Other Organ Systems
Endocrine system effects
Inadequate
and Mortality
Musculoskeletal effects
Likely to be causal
Effects on ocular health
Inadequate
Respiratory effects
Inadequate
Total (nonaccidental) mortality
+Causal
Cancer
Cancer
Likely to be causal
RBC = red blood cell.
+ Denotes new causality determination.
| or | Denotes change in causality determination from 2013 Pb ISA.
aThe 2013 Pb ISA made four causality determinations with respect to cardiovascular disease (CVD), including BP and
hypertension (causal), subclinical atherosclerosis (suggestive), coronary heart disease (CHD; causal), and cerebrovascular
disease (inadequate). This ISA follows the precedent set by the 2019 Particulate Matter and 2020 Ozone ISAs (U.S. EPA. 2020.
2019) by making a single causality determination for cardiovascular effects.
bThe evidence for immune system effects in this ISA is organized based on the World Health Organization's Guidance for
Immunotoxicity Risk Assessment for Chemicals (IPCS. 2012). For comparison with the causality determinations issued in the 2013
Pb ISA, the evidence considered for "sensitization and allergic response" maps closely with "atopic and inflammatory disease," the
"immunosuppression" section largely overlaps with "decreased host resistance," and the evaluation of "autoimmunity and
autoimmune disease" includes consideration of the same endpoints as "autoimmunity."
1 There is substantial evidence across scientific disciplines (i.e., animal toxicology and
2 epidemiology) demonstrating that Pb exposure can result in a range of health effects, including nervous
3 system effects in children and adults, cardiovascular effects, and reproductive and developmental effects.
4 The evidence that supports these causality determinations includes studies examining the potential
5 biological pathways that provide evidence of biological plausibility; studies examining the broader health
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effects evidence spanning scientific disciplines; and studies examining issues related to exposure
assessment, toxicokinetics, and biomarkers of Pb exposure. The subsequent sections focus on health
outcome categories for which the health effects evidence indicates a "causal relationship" or a "likely to
be causal relationship" and outcome categories for which a previous "causal relationship" or a "likely to
be causal relationship" has been changed (i.e., "likely to be causal" changed to "suggestive of, but not
sufficient to infer a causal relationship"). The evidence for Pb exposure and health effects that is
"suggestive of, but not sufficient to infer, a causal relationship" or "inadequate to infer the presence or
absence of a causal relationship" is noted in Table IS-1 and discussed more fully in the respective health
effects appendices (Appendix 3-Appendix 10).
IS.7.3.1 Nervous System Effects Ascertained During Childhood, Adolescent, and
Young Adult Lifestages
While Pb affects nearly every organ system, the nervous system appears to be one of the most
sensitive targets. The collective body of recent epidemiologic and toxicological evidence, along with
evidence detailed in the 2013 Pb ISA (U.S. EPA. 2013a). demonstrates effects of Pb exposure on a range
of nervous system effects ascertained during childhood, adolescent, and young adult lifestages. These
effects include cognitive function (Appendix 3.5.1). externalizing behaviors (Appendix 3.5.2 and
Appendix 3.5.3). internalizing behaviors (Appendix 3.5.4). and motor function (Appendix 3.5.5). Tables
at the end of each subsection provide a summary of the evidence from epidemiologic and animal
toxicological studies, highlighting the state of the science in the 2013 Pb ISA and summarizing the recent
evidence (Table IS-2A through Table IS-2F).
IS.7.3.1.1 Cognitive Function in Children
The epidemiologic and toxicological evidence evaluated in the 2013 Pb ISA was sufficient to
conclude that there is a "causal relationship" between Pb exposure and decrements in cognitive function
in children. The strongest evidence supporting this determination came from multiple prospective studies
conducted in diverse populations that consistently reported associations between increases in blood and
tooth Pb levels and decreases in full-scale IQ (FSIQ), executive function, and academic performance and
achievement. Most studies examined representative populations and had moderate to high follow-up
participation without indication of selective participation among children with higher BLLs and lower
cognitive function (i.e., no evidence of selection bias). Associations between BLL and cognitive function
decrements were found with adjustment for several potential confounding factors, most commonly
socioeconomic status (SES), parental IQ, parental education, and parental caregiving quality. In children
ages 4-11 years, associations were found with prenatal, early childhood, childhood average, and
concurrent BLLs in populations with mean or group BLLs in the range of 2-8 (ig/dL. At the time of the
previous review, neither epidemiologic nor toxicological evidence had identified an individual critical
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lifestage or duration of Pb exposure within childhood that is associated with cognitive function
decrements. Several epidemiologic studies found a supralinear C-R relationship. Additionally, a threshold
for cognitive function decrements is not discernible from the available evidence (i.e., examination of early
childhood blood Pb or concurrent blood Pb in the range of <1 to 10 (.ig/dL). Epidemiologic evidence in
children was coherent with toxicological studies that observed consistent evidence of Pb-induced
impairments in learning, memory, and executive function in juvenile animals. Several studies in animals
indicated learning impairments with prenatal, lactational, postlactational and lifetime (with or without
prenatal) Pb exposures that resulted in BLLs of 10-25 (ig/dL. The biological plausibility for Pb-
associated cognitive function decrements was supported by observations of Pb-induced impairments in
neurogenesis, synaptogenesis, synaptic pruning, long-term potentiation, and neurotransmitter function in
the hippocampus, prefrontal cortex, and nucleus accumbens.
Recent studies support the conclusion from the 2013 Pb ISA that Pb-associated cognitive effects
in children occur in populations with mean BLLs between 2 and 8 (ig/dL (Appendix 3.5.1.6.1). This
conclusion continues to be based on studies that examined early childhood BLLs (i.e., age <3 years),
considered peak BLLs in their analysis (i.e., peak <10 (.ig/dL). or examined concurrent BLLs in young
children aged 4 years. Some recent studies find associations of Pb exposure with cognitive effects among
children with mean BLLs <2 (ig/dL; however, those studies do not have the aforementioned attributes and
there is heterogeneity in both the magnitude and direction of the associations at the lowest blood Pb
concentrations. The observed heterogeneity may be explained in part by the distribution of at-risk factors
among the populations studied, including sex, maternal stress, and co-exposures to other metals and
neurotoxic chemicals. Additionally, the available studies do not generally have the sensitivity (Cooper et
al.. 2016) to detect the effect or hazard at these very low BLLs. Therefore, the heterogeneity does not
weaken the larger body of evidence supporting the association of Pb exposure with cognitive effects in
children at BLLs <5 (ig/dL. Considering the collective body of epidemiologic studies, there is no
evidence of a threshold for cognitive effects in children across the range of BLLs examined.
Epidemiologic and toxicological studies also continue to strongly support the finding that Pb exposure
during multiple lifestages (prenatal through adolescence/early adulthood) is associated with cognitive
function decrements in children and young adults. Recent toxicological studies extend the evidence
indicating that early-life exposures are associated with cognitive effects that persisted later into
adolescence and adulthood. Biological plausibility is provided by studies that describe pathways
involving the interaction of Pb with cellular proteins, in some cases competing with and displacing other
biologically relevant cations, leading to increased oxidative stress and the presence of inflammation,
which can have widespread impacts on brain structure and function, as well as disruptions of calcium ion
(Ca2+) signaling that can result in alteration in brain signaling and contribute to the development of
neurological impairments. Given consistency of the results from epidemiologic studies of FSIQ, Bayley
Mental Development Index (MDI), and academic performance and achievement, as well as the coherence
of evidence across epidemiologic and toxicological studies of learning and memory, the overall evidence
remains sufficient to conclude that there is a causal relationship between Pb exposure and
decrements in cognitive function in children.
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Table IS-2A Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and nervous system effects ascertained
during childhood, adolescent, and young adult lifestages.
Cognitive Function in Children: Causal Relationship (IS.7.3.1.1 and Appendix 3.5.1)
Evidence from the 2013 Pb ISA
Clear evidence of cognitive function decrements (as
measured by FSIQ, academic performance, and executive
function) was reported in young children (4 to 11 yr old) with
mean or group BLLs measured at various lifestages and
time periods between 2 and 8 [jg/dL. Clear support from
animal toxicological studies that demonstrate decrements in
learning, memory, and executive function with dietary
exposures.
Evidence from the 2023 Pb ISA
Recent longitudinal epidemiologic studies with group
or population means <5 [jg/dL add to the evidence,
generally supporting conclusions from the 2013 Pb
ISA. Heterogeneity in the magnitude and direction of
the associations with FSIQ, which was potentially
explained by modeling choices or modification of the
association by exposure to other metals, sex, or
maternal stress, did not weaken inference from the
large body of supporting evidence. Recent
experimental animal studies provide consistent
evidence that Pb exposure results in learning and
memory impairments, with developmental periods
potentially representing a more sensitive window for
exposure.
BLL = blood lead level; FSIQ = full-scale intelligence quotient; ISA = Integrated Science Assessment; Pb = lead; yr = year(s).
IS.7.3.1.2 Externalizing Behaviors: Attention, Impulsivity, and Hyperactivity in Children
The evidence presented in the 2013 Pb ISA was sufficient to conclude that there is "a causal
relationship" between Pb exposure and effects on attention, impulsivity, and hyperactivity in children.
Several prospective studies demonstrated associations between blood or tooth Pb levels measured years
before outcomes with attention decrements and hyperactivity in children 7-20 years old, as assessed using
objective neuropsychological tests and/or parent and teacher ratings. Most of these prospective studies
examined representative populations without indication of selection bias. The results from prospective
studies were adjusted for potential confounding by SES as well as parental education and caregiving
quality, with some studies also considering parental cognitive function, birth outcomes, substance abuse,
and nutritional factors. BLLs were associated with attention decrements and hyperactivity in populations
with prenatal (maternal or cord), age 3-60 month average, age 6 year, or lifetime average (to age 11-
13 years) mean BLLs of 7 to 14 (ig/dL, and groups with age 30 month BLLs >10 (ig/dL. Most well-
conducted cross-sectional studies that adjusted for potential confounding factors supported these findings,
noting associations of attention decrements, impulsivity, and hyperactivity in children ages 5-7.5 years
with concurrent BLLs with means of 5-5.4 (ig/dL. There were a small number of studies of diagnosed
attention-deficit/hyperactivity disorder (ADHD), which were limited by cross-sectional or case-control
study designs, inconsistent adjustment for SES and parental education, and lack of consideration for
potential confounding by parental caregiving quality. Animal toxicological studies reported increases in
impulsivity or impaired response inhibition in animals with postweaning and lifetime Pb exposures that
resulted in BLLs of 11 to 30 (ig/dL. There was biological plausibility for Pb-associated attention
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decrements, impulsivity, and hyperactivity provided by observations of Pb-induced alterations in
neurogenesis, synaptic pruning, and dopamine transmission in the prefrontal cerebral cortex, cerebellum,
and hippocampus.
The largest uncertainty addressed by the recent evidence base is the previous lack of prospective
studies examining ADHD (Appendix 3.5.2.4-3.5.2.5). The bulk of the recent evidence comprises
prospective studies that establish the temporality of the association between Pb exposure and parent or
teacher ratings of ADHD symptoms and clinical ADHD. Across studies, associations were observed with
tooth Pb concentrations, childhood BLLs (<6 (.ig/dL). and with maternal or cord BLLs (2-5 (ig/dL).
Studies of caregiver-reported ADHD symptoms generally report associations of BLLs with composite
indices, but there is some support to indicate that the associations with impulsivity and hyperactivity
symptoms are stronger than the associations with inattention symptoms. Some studies addressed the
validity of caregiver-assessed outcomes by evaluating internal consistency, and one study addressed
reliability/validity concerns by using structural equation modeling to create latent factors for inattention
and hyperactivity-impulsivity for each informant. Confounder adjustment has also become more
consistent across recent studies of ADHD. Another recent prospective epidemiologic study examined
clinical ADHD diagnoses after adjusting for parental education and SES, although not quality of parental
caregiving. In this study, children with BLLs between 5 and 10 (ig/dL (measured <4 years old) had
increased odds of clinically diagnosed ADHD at approximately 6 years of age compared with children
with BLLs <2 (ig/dL. Additionally, a small number of recent studies also serve to extend the lower bound
of the mean BLLs that were observed to be associated with attention, impulsivity, and hyperactivity in the
previous ISA. These prospective studies with mean maternal and cord BLLs <5 (ig/dL report associations
with some measures of inattention and impulsivity (Appendix 3.5.2.1-3.5.2.3). Across studies, there is
uncertainty regarding the patterns of exposure that are associated with maternal and cord BLLs and BLLs
in older children, because they may be influenced by higher past exposures. In summary, the total body
of evidence evaluated is sufficient to conclude that there is a causal relationship between Pb
exposure and attention decrements, impulsivity, and hyperactivity.
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Table IS-2B Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and nervous system effects ascertained
during childhood, adolescent, and young adult lifestages.
Externalizing Behaviors: Attention, Impulsivity, and Hyperactivity in Children:
Causal Relationship (IS.7.3.1.2 and Appendix 3.5.2)
Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
Clear evidence of attention decrements, impulsivity, and
hyperactivity (assessed using objective neuropsychological
tests and parent and teacher ratings) was observed in
children 7-20 yr. The strongest evidence for blood Pb-
associated increases in these behaviors was found in
prospective studies examining prenatal (maternal or cord),
age 3-60 mo, age 6 yr, or lifetime average (to age 11-13 yr)
mean BLLs of 7 to 14 [jg/dL and groups with early childhood
(age 30 mo) BLLs >10 [jg/dL. Biological plausibility was
provided by animal toxicological studies demonstrating
impulsivity or impaired response inhibition with relevant
prenatal, lactational, postrotational, and lifetime Pb
exposures.
A small number of recent studies of children with
population or group mean BLLs <5 [jg/dL contribute
to the body of evidence, supporting and extending
conclusions from the 2013 Pb ISA. The majority of
recent studies rely on parent and teacher ratings of
ADHD symptoms; notably, confounder adjustment
remained inconsistent across these studies.
However, prospective studies of ADHD, including a
study of clinical ADHD that controlled for parental
education and SES, although not quality of parental
caregiving reported positive associations. Findings
from studies of rodents and nonhuman primates
indicate that Pb exposure changes behavior in ways
consistent with increased impulsivity while
experimental animal studies of hyperactivity remain
inconsistent, potentially due to differential exposure
and testing windows (hyperactivity was consistently
observed with lactational exposure).
ADHD = attention-deficit/hyperactivity disorder; BLL = blood lead level; ISA = Integrated Science Assessment; mo = month(s);
Pb = lead; SES = socioeconomic status; yr = year(s).
IS.7.3.1.3 Externalizing Behaviors: Conduct Disorders in Children, Adolescents, and Young
Adults
The 2013 Pb ISA concluded that "a causal relationship is likely to exist" between Pb exposure
and conduct disorders in children and young adults. This determination was based on several prospective
cohort studies that consistently indicated that increases in earlier childhood (e.g., age 30 months, 6 years)
or lifetime average (to age 11-13 years) BLLs or tooth (from ages 6-8 years) Pb levels are associated
with criminal offenses in children and young adults ages 19-24 years and with higher parent and teacher
ratings of behaviors related to conduct disorders in children ages 7-17 years. Pb-associated increases in
conduct disorders were found in populations with mean BLLs of 7-14 (ig/dL. Associations with lower
BLLs that are not influenced by higher earlier Pb exposures were not well characterized. These
associations were found without indication of strong selection bias and with adjustment for SES, parental
education and IQ, parental caregiving quality, family functioning, smoking, and substance abuse.
Toxicological evidence for Pb-induced aggression in animals is inconsistent, with increases in aggression
found in some studies of adult animals with gestational and lifetime Pb exposure, but not juvenile
animals.
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Recent epidemiologic studies support and extend the findings from the previous ISA
(Appendix 3.5.3.1). The strongest evidence comes from recent prospective cohort studies of 1) self-
reported conduct and aggression-related outcomes, and 2) external measures of delinquency (e.g.,
criminal arrests, school suspensions). These studies evaluated outcomes among individuals ages 7-
33 years in relation to earlier (or cumulative) blood and bone Pb levels. Mean and/or median BLLs ranged
from 2.3 to 8.7 (ig/dL (measured 6.5 to 13 years) in studies reporting positive associations with self-
reported conduct and aggression-related outcomes, though were higher in studies reporting positive
associations with external measures of delinquency (mean: 14.4 (ig/dL; measured prenatal to 6 years).
There are no recent animal toxicological studies at BLLs relevant to humans; thus, the central uncertainty
present in the 2013 Pb ISA database remains: there is limited and inconsistent supporting evidence from
animal toxicological studies. Despite the lack recent studies examining aggression in animals exposed to
Pb, Pb-induced changes on many neurochemical endpoints that contribute to aggressive behaviors have
been reported in experimental animal studies (Appendix 3.3). which provides biological plausibility for
Pb-related conduct disorders and aggression. Given the consistent positive associations observed across
various populations and based on multiple outcome assessment approaches at relevant Pb exposure levels,
there is sufficient evidence to conclude that there is likely to be a causal relationship between Pb
exposure and conduct disorders, aggression, and criminal behavior.
Table IS-2C Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and nervous system effects ascertained
during childhood, adolescent, and young adult lifestages.
Externalizing Behaviors: Conduct Disorders in Children, Adolescents, and Young Adults:
Likely to be Causal (IS.7.3.1.3 and Appendix 3.5.3)
Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
Prospective epidemiologic studies demonstrated that early
childhood (age 30 mo, 6 yr) or lifetime average (to age 11-
13 yr) BLLs or tooth Pb levels (from ages 6-8 yr) are
associated with criminal offenses in young adults ages 19-
24 yr and with higher parent and teacher ratings of
behaviors related to conduct disorders in children ages 8-
17 yr. Pb-associated increases in conduct disorders were
found in populations with mean BLLs 7 to 14 [jg/dL;
associations with lower BLLs as observed in cross-sectional
studies were likely to be influenced by higher earlier Pb
exposures. There is coherence in epidemiologic findings
among related measures of conduct disorders. Evidence of
Pb-induced aggression in animals was mixed, with
increases in aggression found in some studies of adult
animals with gestational plus lifetime Pb exposure, but not
juvenile animals. The lack of clear biological plausibility
produces some uncertainty.
Several prospective studies add to the evidence,
particularly in providing evidence of positive
associations between Pb exposure and direct
aggressive measures, such as physical violence. A
limited number of recent studies examine crime or
delinquency and generally observed positive
associations. Studies evaluated the associations
among individuals ages 7-33 yr in relation to earlier
(or cumulative) Pb levels. In the studies of self-
reported conduct and aggression-related outcomes,
mean BLLs were 2.3 to 8.7 [jg/dL (ages 6.5 to 13 yr),
while in studies of external measures of delinquency,
they were higher (e.g., mean 14.4 [jg/dL; prenatal to
6 yr). Studies generally controlled for most relevant
confounders. There were no recent experimental
animal studies of aggression; thus, toxicological
evidence remains limited and inconsistent.
BLL = blood lead level; ISA = Integrated Science Assessment; Pb = lead; yr = year(s).
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IS.7.3.1.4 Internalizing Behaviors: Anxiety and Depression
The evidence evaluated in the 2013 Pb ISA was sufficient to conclude that "a causal relationship
is likely to exist" between Pb exposure and internalizing behaviors in children. Prospective studies in a
few populations demonstrated associations between increases in early lifetime average blood (mean:
-14 (ig/dL) or childhood tooth (from ages 6-8 years) Pb levels with higher parent and teacher ratings of
internalizing behaviors, such as withdrawn behavior and symptoms of depression and anxiety in children
ages 8-13 years. The available evidence of study participation by BLL and parental and teacher ratings do
not suggest a high likelihood of selection bias in these studies. The results from a few cross-sectional
studies in populations with mean concurrent BLLs of 5 (ig/dL were inconsistent. Pb-associated increases
in internalizing behaviors were reported in models that adjusted for maternal education and SES-related
variables, though consideration of potential confounding by parental caregiving quality was inconsistent.
Despite some uncertainty in the epidemiologic evidence regarding potential confounding and
inconsistency in the supporting cross-sectional studies, biological plausibility for the effects of Pb on
internalizing behaviors was provided by a few studies in animals with dietary lactational Pb exposure,
with some evidence at BLLs relevant to humans. Biological plausibility findings included Pb-induced
changes in the hypothalamic-pituitary-adrenal axis and dopaminergic and gamma aminobutyric acid
(GABA)-ergic systems.
Several recent longitudinal epidemiologic studies with high to moderate participation rates used
an expanded array of instruments to assess internalizing behaviors and continue to provide support for
associations with BLLs (childhood average, prenatal, and postnatal BLLs <7 (ig/dL; Appendix 3.5.4.1).
The majority of analyses controlled for important potential confounders including the quality of parental
caregiving, which was less frequently considered by studies included in the previous ISA. A limited
number of studies aimed to distinguish between the types of internalizing behaviors associated with Pb
exposure and demonstrated stronger support for Pb-associated anxiety compared with depression. Recent
animal toxicological studies are coherent with the epidemiologic evidence and largely support and expand
evidence of increases in anxiety-like behavior in Pb-exposed rodents with peak BLLs ranging from 3 to
greater than 30 (ig/dL, the lower end of which is lower than evidence from the previous ISA. Overall, the
evidence is sufficient to conclude that there is likely to be a causal relationship between Pb exposure
and internalizing behaviors in children.
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Table IS-2D Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and nervous system effects ascertained
during childhood, adolescent, and young adult lifestages.
Internalizing Behaviors: Anxiety and Depression: Likely to be Causal (IS.7.3.1.4 and Appendix 3.5.4)
Evidence from the 2013 Pb ISA
Prospective epidemiologic studies reported associations of
higher lifetime average blood (mean: -14 |jg/dL) or
childhood tooth (from ages 6-8 yr) Pb levels with higher
parent and teacher ratings of internalizing behaviors such as
symptoms of depression or anxiety and withdrawn behavior
in children ages 8-13 yr. Consideration of potential
confounding by parental caregiving was not consistent and
findings from cross-sectional studies in populations ages 5
and 7 yrwith mean BLLs of 5 [jg/dL were mixed. Animal
toxicological studies demonstrate depression-like behaviors
and increases in emotionality with relevant lactational
exposures.
Evidence from the 2023 Pb ISA
Recent longitudinal studies report consistent
associations between BLLs and internalizing in
multiple countries with mean blood Pb concentrations
typically <7 [jg/dL (prenatal, early childhood, lifetime
average). Recent studies used parent or teacher
ratings to assess internalizing behaviors, i.e., the
Child Behavior Checklist, Strengths and Difficulties
Questionnaire, Behavioral Assessment System for
Children, and Caregiver-Teacher Report Form.
Increased anxiety-like behaviors in rodents were
demonstrated at lower exposure levels (3-30 |jg/dL)
following developmental Pb exposure.
BLL = blood lead level; ISA = Integrated Science Assessment; mo = month(s); Pb = lead; yr = year(s).
IS.7.3.1.5 Motor Function
The evidence presented in the 2013 Pb ISA was sufficient to conclude that "a causal relationship
is likely to exist" between Pb exposure and decrements in motor function in children. This determination
was based on strong evidence from prospective studies that reported that increases in neonatal,
concurrent, and lifetime average BLLs were associated with decrements in fine and gross motor function
among children ages 4.5-6 years and that increases in earlier childhood (ages 0-5 year average; age
78 months) BLLs were associated with decrements in fine and gross motor function among children ages
15-17 years. The means for these blood Pb metrics ranged from 4.8 to 12 (ig/dL. These studies included
adjustment for several potential confounding factors, including SES, parental caregiving quality, and
child health, and did not have indications of substantial selection bias. Evidence from cross-sectional
studies was less consistent. The biological plausibility for associations observed in children is provided by
a study that found poorer balance in male mice with relevant gestational to early postnatal (postnatal day
10) Pb exposures.
Several recent birth cohort studies observed consistently lower scores on the Bayley Psychomotor
Developmental Index (PDI) in association with maternal Pb exposure (no clear pattern by trimester of
pregnancy; means or geometric means: 1.4 to 6.5 (.ig/dL). cord BLL (means: 1.2 to 5.6 (.ig/dL). and
postnatal concurrent BLL (2.85-4.87 (ig/dL). Pb-associated decrements in motor function were also
observed in neonates and in some, but not all studies of toddlers that assessed motor function using the
Gesell scale or children's abilities to perform certain tasks indicative of gross motor function. Evidence
from recent toxicological studies is coherent with the epidemiologic evidence, indicating that
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developmental Pb exposure in rodents induces deficits in motor function at mean BLLs <30 (ig/dL. These
new studies illustrate effects of Pb exposure across a range of gross and fine motor development in novel
paradigms. In addition to the effect on rotarod performance described in the previous ISA, recent studies
observed Pb-induced decrements in righting reflex, negative geotaxis reflex, ascending wire mesh, and
forelimb hang tests. The available studies demonstrate consistent effects on motor function, but given the
disparate effects examined do not provide evidence of consistent results for any specific test. Overall, the
evidence is sufficient to conclude that there is likely to be a causal relationship between Pb exposure
and motor function in children.
Table IS-2E Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and nervous system effects ascertained
during childhood, adolescent, and young adult lifestages.
Motor Function: Likely to be Causal (IS.7.3.1.5 and Appendix 3.5.5)
Evidence from the 2013 Pb ISA
Prospective epidemiologic studies provided evidence of
associations of fine and gross motor function decrements in
children ages 4-17 yr with lifetime average BLLs and with
BLLs measured at various time periods with means
generally ranging from 4.8 to 12 [jg/dL. Results were
inconsistent in cross-sectional studies with concurrent BLL
means 2-5 [jg/dL. Limited evidence in animal toxicological
studies with relevant Pb exposures.
Evidence from the 2023 Pb ISA
Several recent birth cohort studies report lower
scores on the Bayley PDI at ages 12 to 36 mo in
association with maternal Pb exposure, cord BLL,
and postnatal concurrent BLL. Limited biological
plausibility is provided by a small number of recent
toxicological studies showing various effects on motor
function in rodent models with developmental Pb
exposure resulting in BLLs <30 [jg/dL.
BLL = blood lead level; ISA = Integrated Science Assessment; mo = month(s); Pb = lead; PDI = Psychomotor Developmental
Index; yr = year(s).
IS.7.3.1.6 Sensory Organ Function
The 2013 Pb ISA presented two causality determinations relating to sensory function in children:
auditory function and visual function. The evidence was sufficient to conclude that "a causal relationship
is likely to exist" between Pb exposure and auditory function decrements in children, while the evidence
was "inadequate to determine that a causal relationship exists" between Pb exposure and visual function
in children. In this ISA, recent studies inform a single causality determination for sensory organ function.
A prospective epidemiologic study, as well as a few cross-sectional studies, reported associations between
BLLs and hearing loss and auditory processing deficits with BLLs measured at various time periods,
including prenatal maternal, neonatal (10 day, mean 4.8 |ig/dL). lifetime average (to age 5 years), and
concurrent (ages 4-19 years; median 8 (ig/dL). Evidence for Pb-associated increases in hearing thresholds
or latencies of auditory evoked potentials was found in adult monkeys with lifetime dietary Pb exposure.
However, these effects in adult animals were found with higher peak or concurrent BLLs (i.e., 33-
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150 jxg/dL); thus, the biological plausibility for epidemiologic observations is unclear. Studies examining
visual effects were of limited quantity and relevance.
Recent cross-sectional and case-control studies have continued to demonstrate associations
between BLLs and hearing loss in young children (aged 3-7, BLLs ~3 to 6 (ig/dL) and adolescents (aged
12-19, BLLs ~1 to 8 (.ig/dL). particularly at higher frequencies. This is coherent with previously noted
evidence in adult monkeys. Recent experimental animal studies have not further evaluated hearing
thresholds in nonhuman primates at more relevant BLLs, but a recent study reported a 8-12 dB upward
shifts in brainstem auditory evoked potentials (BAEPs) between 4 and 32 kHz in young adult mice
exposed during adolescence (peak BLLs 29 (.ig/dL). Similar studies did not detect differences in BAEP in
rodents with lower peak BLLs (3 to 8 (.ig/dL): however, decrements in auditory processing (e.g., sound
discrimination and localization) were demonstrated at these lower BLLs (8 (ig/dL). A few recent
epidemiologic studies also evaluated BAEP with inconsistent results. Evidence of visual function remains
limited and inconsistent.
In conclusion, recent evidence is generally consistent with the evidence presented in the 2013 Pb
ISA. Cross-sectional and case-control epidemiologic studies provide some support for positive
associations between Pb exposure and impaired hearing/auditory processing. Toxicological evidence for
Pb-induced auditory functioning, particularly in studies with BLLs relevant to humans, remains limited.
Taken together, the evidence is suggestive of, but not sufficient to infer, a causal relationship between
Pb exposure and sensory function in children.1
1 The Preamble to the ISA, which was published after the release of the 2013 Pb ISA, included some minor changes
to the weight-of-evidence descriptors for the five-level causality hierarchy (U.S. EPA. 20151. These changes
resulted in the evidence for Pb exposure and effects on sensory organ function being more consistent with examples
of evidence that is "suggestive of, but not sufficient to infer, a causal relationship. " Therefore, the change from
"likely to be causal" to "suggestive of, but not sufficient to infer, a causal relationship " reflects minor changes to
the causal framework, rather than a weakening of the evidence base. See Appendix 3.5.6.4 of the Nervous System
Effects Appendix for further discussion.
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Table IS-2F Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and nervous system effects ascertained
during childhood, adolescent, and young adult lifestages.
Sensory Function: Suggestive of, but not sufficient to infer, a causal relationship
(IS.7.3.1.6 and Appendix 3.5.6)
Evidence from the 2013 Pb ISA
A prospective epidemiologic study and large cross-sectional
studies indicated associations between BLLs and increased
hearing thresholds at ages 4-19 yr. Across studies,
associations were found with BLLs measured at various time
periods, including prenatal maternal, neonatal (10 d, mean
4.8 |jg/dL), lifetime average, and concurrent (ages 4-19 yr)
BLLs (median 8 |jg/dL). The lack of biological plausibility in
animals with relevant exposures produces some uncertainty.
The available epidemiologic and toxicological evidence for
visual function is of insufficient quantity, quality, and
consistency.
Evidence from the 2023 Pb ISA
Recent cross-sectional and case-control studies have
continued to demonstrate positive associations
between BLLs and hearing loss in young children
(aged 3-7, BLLs ~3 to 6 |jg/dL) and adolescents
(aged 12-19, BLLs ~1 to 8 |jg/dL). Experimental
animal studies evaluating young adult rodents found
increases in BAEP thresholds at mean BLLs of
29 [jg/dL but not at lower mean BLLs (3 to 8 pg/dL);
however, mice with mean peak BLLs of 8 [jg/dL had
deficits in auditory processing, The epidemiologic and
toxicological evidence for visual function was not
extended.
BAEP = brainstem auditory evoked potentials; BLL = blood lead level; d = day(s); ISA = Integrated Science Assessment;
Pb = lead; yr = year(s).
IS.7.3.2 Nervous System Effects Ascertained During Adult Lifestages
This ISA presents causality determinations for four nervous systems outcomes ascertained during
adult lifestages, including cognitive function, psychopathological effects, sensory organ function, and
neurodegenerative diseases. The available evidence is "suggestive of, but not sufficient to infer, a causal
relationship" between Pb exposure and: (1) sensory organ function (Appendix 3.6.3) and (2)
neurodegenerative disease (Appendix 3.6.4). Evidence related to these outcomes is discussed in the
Nervous System Effects Appendix. Cognitive effects (IS.7.3.2.1) and psychopathological effects
(IS.7.3.2.2), for which evidence supports likely to be causal relationships with Pb exposure, are discussed
in more detail in the ensuing sections. Table IS-3A and Table IS-3B provides a summary of the evidence
from epidemiologic and animal toxicological studies related to these outcomes, highlighting the recent
evidence in comparison with the evidence available in the 2013 Pb ISA.
IS.7.3.2.1 Cognitive Function in Adults
The 2013 Pb ISA concluded that "a causal relationship is likely to exist between" long-term
cumulative exposure to Pb and cognitive function decrements in adults. This causality determination was
supported by prospective studies in the Normative Aging Study (NAS) and Baltimore Memory Study
(BMS) cohorts that reported associations of higher baseline tibia (means 19, 20 jxg/g) or patella (mean
25 jxg/g) Pb levels with declines in cognitive function in adults (age >50 years) over 2- to 4-year periods.
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These associations were noted in models adjusted for a range of potential confounding factors, including
age, education, SES, current alcohol use, and current smoking. Supporting evidence was provided by
cross-sectional analyses of the NAS, BMS, and the Nurses' Health Study, which observed larger
decrements in cognitive function in association with bone Pb level compared with concurrent BLL.
Cross-sectional studies also considered more potential confounding factors, including dietary factors,
physical activity, medication use, and comorbid conditions. The range of exposures and health outcomes
examined in many of these studies reduced the likelihood of participation bias, specifically by adults with
higher Pb exposure and lower cognitive function. The specific timing, frequency, duration, and magnitude
of Pb exposures contributing to the associations observed with bone Pb levels was not discernible from
the evidence. There was also potential for residual confounding by age because of the strong correlation
between increasing bone Pb levels and increasing age. The effects of recent Pb exposures on cognitive
function decrements in adults were indicated in Pb-exposed workers by associations found with BLLs,
although these studies did not consider potential confounding by other workplace exposures. Biological
plausibility for the observed associations was provided by animal toxicological studies demonstrating that
relevant lifetime Pb exposures from gestation, birth, or after weaning induced learning impairments in
adult animals, as well as evidence the Pb exposure altered neurotransmitter function in hippocampus,
prefrontal cortex, and nucleus accumbens.
Recent prospective cohort studies with longer follow-up periods, multiple and repeatedly
measured cognitive outcomes, and adjustment for multiple risk factors and confounders reduce
uncertainties and strengthen the overall evidence related to the association of Pb exposure with cognitive
function in adulthood. Specifically, recent cohort studies indicate that increases in adult bone Pb levels
(tibia mean range: 10.5to21.6 |ig/g. patella mean range: 12.6to30.6 jxg/g) were associated with
decrements in cognitive function/performance during young-, mid- or older-adulthood periods
(Appendix 3.6.1). A few recent prospective studies also observed associations between childhood BLLs
(mean range: 3.4 (ig/dL to 10.99 (ig/dL at 7-12 years of age) and decrements in IQ and cognitive domains
during late adolescence (18-19 years) and mid-adulthood (38-45 years) after adjustment for demographic
and socioeconomic factors, maternal IQ, and childhood IQ scores. These findings provide new insight
into the persistence of Pb-associated cognitive function decrements. There was some variability in the
associations across the various domains of cognitive function tested within studies; however, higher Pb
levels were associated with decrements in full-scale IQ (verbal comprehension, perceptual reasoning,
working memory, and processing speed IQs), global cognitive function, executive function, visuospatial
skills, attention, learning, and memory. In addition to potential confounders considered in studies
evaluated in the 2013 Pb ISA, recent studies control for additional behavioral, clinical, and neighborhood
level factors. Results from recent toxicological studies are coherent with the epidemiologic evidence and
provide evidence that exposure to Pb during adulthood impairs learning and memory function in rodents
with exposure resulting in mean BLLs <30 (ig/dL (means BLLs: 8-8.8 (ig/dL; peak BLLs: 11-28 (ig/dL).
While these studies are consistent with one another and evidence from the 2013 Pb ISA, toxicological
evidence for effects of Pb on cognitive function in adults remains limited. Additionally, a few recent
studies in juvenile rodents provide some support for the association between Pb exposure during
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adolescence and cognitive impairment, but the evidence is less consistent. Overall, the collective
evidence is sufficient to conclude that there is likely to be a causal relationship between Pb exposures
and cognitive effects in adults.
Table IS-3A Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and nervous system effects ascertained
during adult lifestages.
Cognitive Function in Adults: Likely to be Causal (IS.7.3.2.1 and Appendix 3.6.1)
Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
Prospective studies in the NAS and BMS cohorts indicated
associations of higher baseline tibia (means 19, 20 pg/g) or
patella (mean 25 pg/g) Pb levels with declines in cognitive
function in adults (age >50 yr) over 2- to 4-yr periods. While
the specific covariates differed between studies, these bone
Pb-associated cognitive function decrements were found
with adjustment for potential confounding factors such as
age, education, SES, current alcohol use, and current
smoking. Supporting evidence is provided by cross-sectional
analyses of the NAS, BMS, and the Nurses' Health Study,
which found stronger associations with bone Pb level than
concurrent BLL. Cross-sectional studies also considered
more potential confounding factors, including dietary factors,
physical activity, medication use, and comorbid conditions.
Biological plausibility for the effects of Pb exposure on
cognitive function decrements in adults is provided by
findings that relevant lifetime Pb exposures from gestation,
birth, or after weaning induce learning impairments in adult
animals and by evidence for the effects of Pb altering
neurotransmitter function in hippocampus, prefrontal cortex,
and nucleus accumbens.
Recent longitudinal epidemiologic studies with longer
follow-up periods, multiple and repeatedly measured
cognitive outcomes, and consideration of multiple risk
factors/confounders provide additional evidence of
associations between cumulative and early childhood
exposure to Pb and cognitive decrements in adults.
These studies reduce uncertainties and strengthen
the overall evidence related to the association of Pb
exposure with cognitive function in adulthood. Some
uncertainties related to the frequency, duration, and
magnitude of Pb exposures associated with cognitive
decrements remain. Several recent studies of rodents
with exposure resulting in mean BLLs <30 [jg/dL add
to the evidence informing the association of Pb
exposure with measures of learning and memory in
rodents exposed throughout adulthood.
BMS = Baltimore Memory Study; ISA = Integrated Science Assessment; NAS = Normative Aging Study; Pb = lead;
SES = socioeconomic status.
IS.7.3.2.2 Psychopathological Effects in Adults
The evidence presented in the 2013 Pb ISA was sufficient to conclude that "a causal relationship
is likely to exist" between Pb exposures and psychopathological effects in adults. This causality
determination was based on a small body of epidemiologic evidence that demonstrated consistent positive
associations between concurrent blood or bone Pb levels and self-reported symptoms of depression,
anxiety, and panic disorder in large studies of adults (i.e., NHANES, NAS). Epidemiologic associations
were observed in study populations of young (20-39 years old) and older (44-98 years old) adults.
Because of the cross-sectional design of the epidemiologic studies, there was uncertainty regarding the
temporal sequence between Pb exposure and psychopathological symptoms in adults. This uncertainty is
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somewhat reduced with results for tibia Pb because it is an indicator of cumulative Pb exposure. Still,
because these studies included adults with likely higher past Pb exposures, uncertainty exists as to the Pb
exposure level, timing, frequency, and duration contributing to the associations observed with blood or
bone Pb levels. The epidemiologic evidence was supported by coherence in animal toxicological studies
that demonstrated depression-like behavior and emotionality in rodents exposed to dietary lactational Pb
with or without additional postlactational exposure. An uncertainty in the toxicological evidence base was
the limited number of studies that administered exposures resulting in BLLs that are relevant to humans.
Recent evidence from prospective epidemiologic studies provides further support for positive
associations between Pb exposures and pathological effects, including increased internalizing symptoms.
A strength of the recent evidence is that two of the prospective studies reported increased internalizing
symptoms in association with childhood BLLs, providing more information on the timing of Pb exposure
associated with psychopathological effects. Notably, supporting evidence from recent cross-sectional
epidemiologic studies conducted in diverse populations is largely inconsistent. However, these studies, as
well as the recent prospective analyses described previously, do not adjust for potential confounding by
antidepressant medication. The epidemiologic evidence is supported by coherence with results from an
expanded number of toxicological studies conducted at BLLs relevant to humans. In addition to recent
toxicological studies that continue to provide strong support for Pb-induced anxiety-like behaviors, and
persistence of these behaviors, following developmental and cumulative exposures, there is some novel
evidence for an increase in anxiety-like behavior following adult exposures. Overall, the collective
evidence is sufficient to conclude that there is likely to be a causal relationship between Pb exposure
and psychopathological effects in adults.
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Table IS-3B Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and nervous system effects ascertained
during adult lifestages.
Psychopathological Effects in Adults: Likely to be Causal (IS.7.3.2.2 and Appendix 3.6.2)
Evidence from the 2013 Pb ISA Evidence from the 2023 Pb ISA
Cross-sectional studies in a few populations
demonstrate associations of higher concurrent blood
or tibia Pb levels with self-reported symptoms of
depression and anxiety in adults. Pb-associated
increases in depression and anxiety among adults
were found with adjustment for age, SES, and in the
NAS, daily alcohol intake. The biological plausibility for
epidemiologic evidence is provided by observations of
depression-like behavior in animals with dietary
lactational Pb exposure.
Recent prospective analyses provide additional support for
a positive association between bone and BLLs and
psychopathological effects in older adults, although results
from cross-sectional studies are inconsistent. Recent
toxicological studies in rodents with developmental
exposure continue to provide evidence of anxiety-like
behaviors. Multiple studies demonstrate the persistence of
these effects into adulthood. Additionally, a few recent
studies in rodents demonstrated effects of adult-only Pb
exposures on anxiety-like behavior after 42-126 d of
exposure (BLLs: 7.1 to 28.4 pg/dL), but not following a 30-d
exposure (BLLs: 6.8 to 8.8 |jg/dL).
BLL = blood lead level; d = day(s); NAS = Normative Aging Study; Pb = lead; SES = socioeconomic status.
IS.7,3.3 Cardiovascular Effects
The 2013 Pb ISA made four causality determinations with respect to cardiovascular disease
(CVD), using the U.S. Surgeon General's Report on Smoking as a guideline to group evidence into health
outcome categories (CDC. 2004). The outcome categories evaluated included BP and hypertension,
subclinical atherosclerosis, coronary heart disease (CHD), and cerebrovascular disease. This ISA follows
the precedent set by the 2019 Particulate Matter and 2020 Ozone ISAs (U.S. EPA. 2020. 2019) by making
a single causality determination for cardiovascular effects. This approach allows for a more holistic
evaluation of inter-related health endpoints (e.g., atherosclerosis, endothelial dysfunction, and increased
BP).
The strongest evidence for cardiovascular effects of Pb exposure in the 2013 ISA came from
studies of BP and hypertension, which supported a causal relationship. Several epidemiologic studies
evaluated in the 2013 Pb ISA (U.S. EPA. 2013a) and previous AQCD documents (U.S. EPA. 2006d.
1990) indicated positive associations between biomarkers of Pb exposure in adults and increases in BP
and hypertension risk (Table IS-4). Previous studies do not identify an apparent threshold below which
blood Pb was not significantly associated with changes in BP, for mean adult BLLs ranging from
<2 (ig/dL to 34 (ig/dL. Meta-analyses evaluated in the 2013 Pb ISA underscore the consistency and
reproducibility of the Pb-associated increases in BP and hypertension. However, the studies available at
the time represented populations historically exposed to higher levels of Pb, raising uncertainty regarding
the level, timing, frequency, and duration of Pb exposure contributing to the observed associations. In
addition to epidemiologic evidence, the 2013 Pb ISA described a large body of animal toxicological
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studies that provided evidence that long-term Pb exposure (>4 weeks), resulting in BLLs less than
10 |ig/dL. could result in the onset of hypertension (after a latency period) in experimental animals that
persists long after the cessation of Pb exposure.
The 2013 Pb ISA also presented a large body of evidence indicating a relationship between Pb
exposure and cardiovascular mortality, which helped support a causal relationship in the 2013 Pb ISA for
CHD. Specifically, prospective epidemiologic studies conducted in a number of locations reported that
biomarkers of Pb exposure were associated with risk of mortality from myocardial infarction (MI),
ischemic heart disease (IHD), and CHD. In addition, epidemiologic studies reviewed in the 2013 Pb ISA
included some evidence of a positive association between exposure to Pb and changes in cardio
electrophysiology (e.g., changes in heart rate variability [HRV] and QT interval) and atherosclerotic
plaque formation. These studies, along with animal toxicological studies demonstrating the production of
oxidative stress species that could inactivate the vasodilator nitric oxide, contribute to the biological
plausibility of Pb-induced cardiovascular morbidity and mortality.
Recent studies greatly expand the evidence base from the 2013 Pb ISA and strengthen support for
the relationship between exposure to Pb and cardiovascular effects in adults. Numerous epidemiologic
studies published since the literature cutoff date for the previous ISA reported positive associations
between Pb biomarkers and increases in BP and hypertension risk (Appendix 4.3). Specifically, nationally
representative cross-sectional studies in the United States, Canada, and South Korea observed positive
associations between BLLs and systolic BP and/or diastolic BP in adult populations with mean BLLs
ranging from -1.5 to 3 (ig/dL. Notably, in these studies of adult populations, uncertainty remains
regarding the influence of higher past exposures on the level, timing, frequency, and duration of Pb
exposure contributing to the observed associations. The majority of recent analyses consider a wide range
of confounders including demographics, comorbid conditions, antihypertensive medication use, and other
co-exposures to metals such as cadmium (Cd). In addition, there was also an extensive amount of
literature that considered effect measure modifiers including, sex, age, and race, among others (Section
IS.7.4). Recent animal toxicological studies are coherent with the epidemiologic evidence of associations.
In several recent studies with exposures resulting in BLLs <30 (ig/dL, animals exposed to Pb had
consistent increases in BP when compared with control treated animals. Combined with results from the
previous ISA and AQCDs, there is clear and substantial evidence that exposure to Pb results in increases
in measures of BP.
A number of recent prospective cohort studies, including extended analyses of previous
NHANES cohorts, reported consistent positive associations between BLLs and CVD-related mortality
that are of similar magnitude to results from studies evaluated in the 2013 Pb ISA (Section 4.10). These
more recent studies also reported that associations persisted after accounting for risk factors such as
physical activity, serum cholesterol, and Cd levels in blood or urine. Once again, there were consistent
positive associations between BLLs and mortality in populations with low mean BLLs, but the specific
level, timing, frequency, and duration of Pb exposure contributing to CVD mortality in adult populations
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with higher past than recent exposure is not discernible from this evidence. Epidemiologic studies of
mortality are consistent not only with the large amount of evidence for changes in BP and hypertension
described above, but also with evidence of associations between blood or bone Pb levels and other
cardiovascular outcomes. Past and recent analyses of the NAS cohort of older adult men indicate positive
associations between bone Pb levels and incident IHD and prolonged QT interval. Additionally, a series
of recent Korea National Health and Nutrition Examination Survey (KNHANES) studies observed
increased 10-year CVD risk with increasing BLLs. These results are coherent with a toxicological study
evaluated in the 2013 Pb ISA demonstrating increased incidence of arrhythmia, atrioventricular block,
and a prolonged ST segment interval in Pb-exposed animals. In general, animal and in vitro toxicological
evidence provides plausible pathways by which exposure to Pb could lead to serious CVD-related
outcomes such as IHD and MI (Appendix 4.11). A notable pathway includes Pb resulting in oxidative
stress and systemic inflammation that could potentially lead to impaired vascular function, a pro-
atherosclerotic environment, and increases in BP. These effects, in particular atherosclerosis and increases
in BP, can lead to MI or stroke that could result in mortality.
Taken together, the recent evidence supports and extends the evidence base reported in the 2013
Pb ISA. Consistent epidemiologic associations reported between body Pb concentrations and
cardiovascular outcomes such as increased BP, hypertension, and cardiovascular mortality are coherent
with evidence from animal toxicological studies, and further supported by experimental animal and in
vitro studies demonstrating biologically plausible pathways through which exposure to Pb could lead to
these outcomes. Thus, there is sufficient evidence to conclude that there is a causal relationship
between Pb exposure and cardiovascular effects.
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Table IS-4 Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and cardiovascular effects.
Cardiovascular Effects: Causal (IS.7.3.3 and Appendix 4)
Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
Hypertension'. Prospective epidemiologic studies
consistently reported associations of blood and bone Pb
levels with hypertension incidence and increased BP. These
findings were replicated across multiple high-quality studies
comprising large and diverse populations. Further support
was provided by multiple cross-sectional analyses. While the
adjustment for specific factors varied by study, the collective
body of epidemiologic evidence included adjustment for
multiple potential key confounding factors. Although
epidemiologic studies in adults observed associations in
populations with relatively low mean concurrent BLLs, the
majority of individuals in these adult populations were likely
to have had higher levels of Pb exposure earlier in life. Thus,
there is uncertainty concerning the specific Pb exposure
level, timing, frequency, and duration contributing to the
associations observed in the epidemiologic studies. A causal
relationship of Pb exposure with hypertension is supported
by evidence from experimental animal studies that
demonstrate effects on BP after long-term Pb exposure
resulting in mean BLLs of 10 [jg/dL or greater.
CHD\ Prospective epidemiologic studies of cohorts of adults
during the period 1976-1994 consistently reported positive
associations between BLLs and riskofCVD mortality,
including Ml and IHD. Several other studies reported
associations between Pb biomarkers and incidence of CHD-
related outcomes, including a prospective analysis reporting
increased incidence of IHD (physician confirmed Ml, angina
pectoris) in association with increasing blood and bone Pb
levels.
Recent studies strengthen support for the relationship
between exposure to Pb and cardiovascular effects in
adults. In particular, the strongest evidence continues
to come from studies demonstrating the effect of Pb
on increases in BP. The majority of recent analyses
examining BP consider a wide range of potential
confounders, including demographics, comorbid
conditions, antihypertensive medication use, and
other co-exposures to metals such as Cd. There is
also an extensive amount of literature that considered
effect measure modifiers, including sex, age, and
race, among others. Recent animal toxicological
studies provide additional evidence that exposure to
Pb resulting in BLLs <30 [jg/dL lead to increases in
measures of BP. In addition to recent evidence on BP
and hypertension, there is substantially more
evidence for cardiovascular-related mortality, as well
as some epidemiologic and toxicological evidence for
effects such as changes in cardiac electrophysiology
(e.g., electrocardiography measures of cardiac
depolarization, repolarization, and HRV), arrythmia,
and markers of atherosclerosis. There continues to
be uncertainty regarding the specific Pb exposure
level, timing, frequency, and duration contributing to
the associations observed in the epidemiologic
studies.
BLL = blood lead level; BP = blood pressure; Cd = cadmium; CHD = coronary heart disease; CVD = cardiovascular disease;
HRV = heart rate variability; IHD = ischemic heart disease ; Ml = myocardial infarction; Pb = lead.
IS.7.3.4 Renal Effects
1 The 2013 Pb ISA concluded that evidence was "suggestive of a causal relationship" between Pb
2 exposure and renal effects. Recent epidemiologic and toxicological studies extend the body of evidence
3 presented in the 2013 Pb ISA indicating that Pb exposure is associated with reduced kidney function and
4 kidney damage (Table IS-5). The causality determination in the 2013 Pb ISA was primarily limited by
5 uncertainty due to the potential for reversal causality, as kidney damage could lead to increased BLLs
6 through reduced excretion, rather than increased Pb exposure (e.g., elevated BLLs) being a causative
7 factor of kidney impairment. A number of recent epidemiologic studies address this uncertainty with
8 prospective study designs that control for baseline kidney function (Appendix 5.6). These studies
9 demonstrate associations between biomarkers of Pb exposure and incident markers in kidney function in
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adults that are independent of baseline kidney function. Additionally, recent animal toxicological studies
provide further evidence for Pb-induced kidney damage and dysfunction (e.g., morphological changes in
kidney structure, increased glomerular filtration rate, increased serum and urine creatinine, and increased
blood urea nitrogen), supporting the directionality of effects. Combined, the toxicological and
epidemiologic evidence indicates that reverse causality is highly unlikely to explain the epidemiologic
associations between higher BLLs and decreased kidney function in adults. Toxicological studies also
indicate plausible biological pathways connecting Pb exposure to renal effects, including Pb-induced
oxidative stress and increases in BP (Appendix 5.9). Recent epidemiologic evidence of associations
between BLLs and reduced kidney function in adults are observed at BLLs <5 (ig/dL, and a number of
recent toxicological studies extend the evidence base to include effects in rodents with BLLs <20 (ig/dL.
Despite the evidence for associations at relatively low BLLs in adults, these renal outcomes were most
often examined in adults who have been exposed to higher levels of Pb earlier in life, and uncertainty
remains concerning the Pb exposure level, timing, frequency, and duration contributing to the observed
associations. Collectively, there is sufficient evidence to conclude that there is a causal relationship
between Pb exposure and renal effects.
Table IS-5 Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and renal effects.
Renal Effects: Causal (IS.7.3.4 and Appendix 5)
Evidence from the 2013 Pb ISA
Longitudinal studies reported Pb-associated decrements in
renal function in populations with mean BLLs of 7 and
9 [jg/dL. However, the contributions of higher past Pb
exposures could not be excluded. Additionally, there was
uncertainty due to potential reverse causality in
epidemiologic studies. Animal toxicological studies provided
clear biological plausibility with evidence for Pb-induced
kidney dysfunction at BLLs greater than 30 [jg/dL; however,
evidence in animals with BLLs <20 [jg/dL was generally not
available.
Evidence from the 2023 Pb ISA
Recent toxicological and prospective epidemiologic
studies support and extend conclusions from the
2013 Pb ISA. Notably, prospective studies with
baseline measures of renal function reduce
uncertainty regarding potential reverse causality,
providing additional evidence of Pb-associated
decrements in renal function in adult populations with
mean BLLs <5 [jg/dL. The contribution of higher past
Pb exposures remains an uncertainty. Recent animal
toxicological studies include evidence for renal effects
observed at concentrations <20 [jg/dL.
BLL = blood lead level; ISA = Integrated Science Assessment; Pb = lead.
IS.7.3.5 Immune System Effects
The 2013 Pb ISA issued causality determinations for the effects of Pb exposure on different
aspects of the immune system including atopic and inflammatory responses, decreased host resistance,
and autoimmunity. The evidence in this ISA is organized based on the World Health Organization's
Guidance for Immunotoxicity Risk Assessment for Chemicals (IPCS. 2012). As proposed in this guidance,
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this ISA restructures the available evidence into slightly different outcome groups than those in the 2013
Pb ISA, which include immunosuppression, sensitization and allergic responses, and autoimmunity and
autoimmune disease. For comparison with the causality determinations issued in the 2013 Pb ISA, the
evidence considered for "sensitization and allergic response" maps closely with "atopic and inflammatory
disease," the "immunosuppression" section largely overlaps with "decreased host resistance," and the
evaluation of "autoimmunity and autoimmune disease" includes consideration of the same endpoints as
"autoimmunity." The recent evidence for autoimmunity and autoimmune disease remains "inadequate to
determine the presence or absence of a causal relationship" (Appendix 6.7). The following sections focus
on the evidence for immunosuppression (IS.7.3.5.1) and sensitization and allergic response (IS.7.3.5.2),
which is also summarized in Table IS-6A and Table IS-6B.
IS.7.3.5.1 Immunosuppression
The 2013 Pb ISA concluded that "a causal relationship is likely to exist" between Pb exposures
and decreased host resistance. This causality determination was based primarily on consistent evidence
that exposure to relevant BLLs suppresses the delayed-type hypersensitivity (DTH) response and
increases bacterial titers and subsequent mortality in rodents. Suppressed DTH response is one of the
most consistently reported immune effects associated with Pb exposure in animals and has been reported
following gestational and postnatal exposures to Pb acetate resulting in BLLs ranging from 6.75 to
>100 (ig/dL in rats, mice, and chickens. A limited number of epidemiologic studies reviewed in the 2013
Pb ISA (U.S. EPA. 2013a) indicated an association between BLLs and increased viral and bacterial
infections in children. None of the studies considered potential confounders, however, and most analyzed
populations with higher BLLs (means >10 (ig/dL). Cross-sectional studies of cell-mediated immunity
reported consistent associations between BLL and lower T cell abundance in children, while results from
other studies on lymphocyte activation, macrophages, neutrophils, and natural killer cells were generally
inconsistent or not sufficiently informative (e.g., cross-sectional study designs with limited or no
consideration of potential confounding, and a lack of information on C-R relationship). Biological
plausibility was provided by a number of studies demonstrating Pb-induced suppression of T helper (Th)l
cytokines production (e.g., interferon gamma [IFN-y]), and decreased macrophage function, both of
which may lead to decreased DTH response and increased incidence of viral and bacterial infection.
Recent toxicological studies provide additional evidence for immunosuppression, including
decreased serum levels of anti-tetanus toxoid (TT) specific immunoglobulin M (IgM) (but not IgG)
antibodies in iron (Fe)-deficient rats exposed to Pb in drinking water (BLL =16.1 (.ig/dL). Consistent with
findings reported in the previous ISA, recent studies show that Pb exposure suppresses the DTH response
(BLL = 18.48 (ig/dL). Recent epidemiologic studies investigating aspects of immunosuppression include
populations with wider age-ranges and much lower mean and median BLLs than studies evaluated in the
previous ISA. Recent studies also adjust for a wide range of potential confounders, including extensive
consideration of SES factors. Cross-sectional and case-control studies are coherent with the toxicological
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evidence, providing consistent evidence of associations between Pb exposure (mean, median, or
geometric mean BLLs: 1.4-3.15 (ig/dL) and increased viral and bacterial infections or susceptibility to
antibiotic resistance in children and adults. Notably, epidemiologic studies of viral and bacterial infection
used concurrent blood Pb measures, raising uncertainty regarding the temporal sequence between Pb
exposure and immunosuppression and the level, timing, frequency, and duration of Pb exposures that
contributed to the observed associations. Vaccine antibody response, an endpoint that was not examined
in studies evaluated in the previous ISA, was evaluated in a birth cohort study and a few cross-sectional
studies that demonstrate generally consistent evidence of an association between BLLs (mean or median
<2 (ig/dL) and decreased virus-neutralizing antibodies in children. Biological plausibility for the observed
associations is provided by recent and previously evaluated toxicological and epidemiologic studies
demonstrating (1) skewing of T cell populations, promoting Th2 cell formation and cytokine production,
(2) decreased IFN-y production, (3) decrements in macrophage function, (4) production of inflammatory
mediators, and (5) disruption of the microbiome. Collectively, there is sufficient evidence to conclude
that there is likely to be a causal relationship between Pb exposure and immunosuppression.
Table IS-6A Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and immune system effects.
Immunosuppression: Likely to be Causal (IS.7.3.5.1 and Appendix 6.3)
Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
Animal toxicological studies were the primary contributors to
the evidence for Pb-induced immunosuppression. Several
studies in rodents show that dietary Pb exposure producing
relevant BLLs (7-25 |jg/dL) results in increased
susceptibility to bacterial infection and suppressed DTH. A
few cross-sectional epidemiologic studies indicate Pb-
associated increases in respiratory infections, but these
studies are limited by a lack of rigorous methodology or
consideration for potential confounding.
Recent toxicological studies demonstrate the ability of
Pbto alter antibody responses, providing additional
evidence for the immunosuppressive effects of Pb.
The relationship between Pb exposure and
immunosuppression is further supported by recent
epidemiologic studies, which expand the quantity and
quality of the observational evidence base evaluated
in the 2013 Pb ISA. A mix of recent prospective
cohort, case-control, and cross-sectional studies that
include more robust consideration for potential
confounding report associations between low BLLs
(<3.5 |jg/dL) and susceptibility to viral and bacterial
infection, reduced antibiotic resistance, and reduced
vaccine antibodies in children.
BLL = blood lead level; DTH = delayed-type hypersensitivity; ISA = Integrated Science Assessment; Pb = lead.
IS.7.3.5.2 Sensitization and Allergic Response
The 2013 Pb ISA concluded that "a causal relationship is likely to exist" between Pb exposures
and an increase in atopic and inflammatory conditions. This causality determination was supported by a
prospective analysis reporting associations between BLLs and increased asthma incidence in children and
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another longitudinal study that observed a positive association between cord BLLs and immediate-type
allergic responses in children that were detected clinically using skin prick tests. Both studies had small
sample sizes, however, and lacked precision (i.e., had wide 95% CIs), which increases the likelihood of
chance findings. The associations observed in the prospective analyses were supported by a cross-
sectional study of BLL-associated parental-reported asthma in children and population-based cross-
sectional studies in children that reported associations between BLL and elevated serum IgE. Notably,
many of the serum IgE studies had limited adjustment for potential confounders and included population
mean BLLs >10 (ig/dL. The epidemiologic findings were coherent with a large body of toxicological
studies that reported physiological responses in animals consistent with the development of allergic
sensitization, including increased lymph node cell proliferation, increased production of Th2 cytokines
such as interleukin 4 (IL-4), increased total serum IgE antibody levels, and misregulated inflammation.
Recent animal toxicological studies relevant to sensitization and allergic response are limited in
number. The available studies report effects of Pb on production of cytokines relevant to immediate-type
hypersensitivity. However, the utility of these data for hazard identification is limited because changes in
cytokine levels (particularly when measured in blood) can be associated with many different types of
tissues and toxicities and may reflect an immune response to tissue injury but not necessarily an impact
on or impairment of immune function. Recent epidemiologic evidence is inconsistent with studies
evaluated in the 2013 Pb ISA. Specifically, results from recent epidemiologic studies of atopic disease,
including prospective cohort studies examining of asthma, eczema, and food allergies were generally
consistent in reporting a lack of an association in populations with low BLLs (mean or median BLLs
<2 (ig/dL). Similar to cohort studies evaluated in the 2013 Pb ISA, recent longitudinal analyses are
limited in number and have limited statistical power because of low case numbers. Among other things,
limited statistical power results in the reduced likelihood of detecting a true effect and a reduced
likelihood that an observed result reflects a true effect. Notably, recent cross-sectional NHANES analyses
also reported null associations between children's BLLs and asthma, eczema, and food allergies in much
larger study populations. Additionally, recent studies provide inconsistent evidence for Pb-associated
changes in immunological biomarkers involved in hypersensitivity and allergic response. Whereas there
was coherence between the animal toxicological and epidemiologic evidence evaluated in the previous
ISA, the recent evidence is less coherent given the inconsistencies and null findings across epidemiologic
studies. Overall, given the strong body of toxicological evidence, but inconsistent results across
epidemiologic studies, the collective evidence is suggestive of, but not sufficient to infer, a causal
relationship between Pb exposure and sensitization and allergic responses.
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Table IS-6B Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and immune system effects.
Sensitization and Allergic Response: Suggestive (IS.7.3.5.2 and Appendix 6.4)
Evidence from the 2013 Pb ISA
A limited number of prospective studies in a few populations
of children ages 1-5 yr reported associations of asthma and
allergy with BLLs prenatal cord BLLs or BLLs. These studies
had small sample sizes and lacked precision (i.e., had wide
95% CIs). The epidemiologic findings are coherent with a
large body of toxicological studies that reported
physiological responses in animals consistent with the
development of allergic sensitization, including increased
lymph node cell proliferation, increased production of Th2
cytokines such as IL-4, increased total serum IgE antibody
levels, and misregulated inflammation.
Evidence from the 2023 Pb ISA
Several recent epidemiologic studies of sensitization
and allergic response, including prospective birth
cohorts and cross-sectional studies with mean or
median BLLs <2 |jg/d, provide little evidence of an
association between exposure to Pb and atopic
disease, including asthma, eczema, and food
allergies. Similar to the evidence in the 2013 Pb ISA,
a considerable uncertainty in the evidence base is the
limited number of children with asthma in the cohort
studies evaluated. Recent toxicological evidence for
effects of Pb exposure on biomarkers of allergic
disease is sparse but provides some evidence of Pb-
induced changes in IFN-y, a Th1 cytokine known to
play a role in the resolution of asthma.
BLL = blood lead level; CI = confidence interval; IgE = immunoglobulin E; IL-4 = interleukin 4; ISA = Integrated Science
Assessment; Pb = lead; Th = T helper; yr = year(s).
IS.7.3,6 Hematological Effects
The effects of Pb exposure on RBC function and heme synthesis have been extensively studied
over several decades in both human and animal studies. The 1978 NAAQS for Pb were established to
prevent BLLs in most children from exceeding 30 (ig/dL as such levels were associated with impaired
heme synthesis, evidenced by accumulation of protoporphyrin in erythrocytes (U.S. EPA. 1978). The
2013 Pb ISA issued causality determinations for two hematological outcomes: RBC survival and function
and altered heme synthesis. The evidence for both outcomes was "sufficient to conclude that there is a
causal relationship" with Pb exposure. Given the interconnectedness of the effects of Pb on RBC survival
and function and altered heme synthesis, this assessment presents a single causality determination for the
combination of these outcomes. This approach allows for a more holistic evaluation of inter-related health
endpoints, including a discussion of how all individual lines of evidence contribute to the overall
hematological effects causality determination. The evidence available in the 2013 Pb ISA as well as
evidence from recent studies is discussed in the ensuing subsections and summarized in Table IS-7.
Taken together, there is sufficient evidence to conclude that there is a causal relationship between
Pb exposure and hematological effects, including altered heme synthesis and decreased RBC
survival and function.
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15.7.3.6.1 Red Blood Cell Survival and Function
A strong body of evidence from experimental animal studies reviewed in the 2013 Pb ISA
demonstrated that Pb exposures alter several hematological parameters (e.g., hemoglobin [Hb],
hematocrit, mean corpuscular volume, mean corpuscular Hb), induce oxidative stress (e.g., alter
antioxidant enzyme activities [superoxide dismutase, catalase, glutathione peroxidase], decrease cellular
glutathione, and increase lipid peroxidation), and increase cytotoxicity in RBC precursor cells in rodents
exposed to various forms of Pb via drinking water and gavage resulting in BLLs <30 (ig/dL. Consistent
results were observed in several additional studies in rodents that did not report BLLs. Results from
epidemiologic studies were coherent with the toxicological evidence, including associations between
BLLs and altered hematological endpoints, increased measures of oxidative stress, altered hematopoiesis,
and anemia. Notably, the epidemiologic evidence consisted of cross-sectional studies that were conducted
in populations with higher mean Pb exposures (i.e., BLLs >10 (.ig/dL). did not thoroughly consider
potential confounders, and lacked rigorous statistical methodology.
Recent toxicological evidence is limited, but studies continue to support the findings from the last
review. The most consistent evidence comes from studies that report decreased Hb levels in rodents
following Pb exposures (BLLs ranging from 7.5 to 14.7 (ig/dL) (Appendix 7.3.2). Recent epidemiologic
studies expand on the evidence presented in the 2013 Pb ISA and are coherent with the experimental
evidence. Although the recent studies are also cross-sectional, they include populations with much lower
BLL means (<10 (ig/dL) and include more robust adjustment for potential confounding, addressing
important uncertainties from the last review. The most consistent epidemiologic evidence indicates an
association between higher BLLs and decreased Hb levels in children (Appendix 7.3.1). which is in line
with the evidence from recent experimental animal studies. While the clinical relevance of small mean
decrements in Hb across exposure quintiles is unclear, a few of the recent epidemiologic studies observed
increases in the odds of prevalent anemia in children associated with increasing quantiles of BLLs.
15.7.3.6.2 Altered Heme Synthesis
As described in the 2013 Pb ISA, a small but consistent body of studies in adult animals reported
that Pb exposures via drinking water and gavage for 15 days to 9 months (resulting in BLLs <30 (ig/dL)
decreased ALAD and ferrochelatase activities. The relationship between Pb exposure and altered heme
synthesis was further supported by several toxicological studies that observed decreased Hb levels in
laboratory animals exposed to Pb. Decreased Hb levels can be a direct indicator of decreased heme
synthesis. Cross-sectional epidemiologic studies provided supporting evidence that concurrent elevated
BLLs are associated with decreased ALAD and ferrochelatase activities and decreased Hb levels in both
adults and children. However, the majority of these studies are limited by the lack of consideration of
potential confounding. Although there were limitations in the epidemiologic evidence, some studies in
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1 children did control for or consider potential confounding, and effects in adults and children in these
2 studies are coherent with effects observed in animal toxicological studies.
3 Recent PECOS-relevant studies are limited in number and focus mainly on Hb levels, but
4 continue to provide support for Pb-related alterations in heme synthesis. Notably, recent epidemiologic
5 studies indicate an inverse association between BLLs and Hb levels in children. These studies include
6 more robust statistical methods, expanded consideration of potential confounders, and populations with
7 much lower BLLs than the studies included in the previous reviews (mean or median BLLs ranging from
8 3.04 to 8.38 (ig/dL; Appendix 7.3.1). The recent epidemiologic evidence is coherent with recent
9 toxicological studies, which observed Hb decrements in Pb-exposed mice with BLLs relevant to humans.
Table IS-7 Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and hematological effects.
Altered Heme Synthesis and Decreased Red Blood Cell (RBC) Survival and Function: Causal
(IS.7.3.6.2 and Appendix 7)
Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
RBC Survival and Function'. Experimental animal studies
demonstrate that exposures resulting in BLLs relevant to
humans alter several hematological parameters, increase
measures of oxidative stress, and increase cytotoxicity in
RBC precursor cells. Epidemiologic studies find associations
in both adults and children between BLLs and altered
hematological endpoints, increased measures of oxidative
stress, altered hematopoiesis, and increased prevalence of
anemia. The epidemiologic evidence consisted of cross-
sectional studies that were conducted in populations with
high mean Pb exposures and did not thoroughly consider
potential confounders. Additional support for these findings
was provided by toxicological and epidemiologic studies
demonstrating increased intracellular Ca2+ concentrations,
decreased Ca2+/Mg2+ adenosine triphosphatase activity, and
increased phosphatidylserine exposure, establishing
biologically plausibility for Pb-induced changes in RBC
survival.
RBC Survival and Function'. Recent animal
toxicological studies are limited in number, but
consistent with evidence in the 2013 Pb ISA. The
most consistent evidence comes from studies that
report decreased Hb levels in rodents following Pb
exposures (BLLs of 7.5 to 14.7 |jg/dL). Recent
epidemiologic studies include populations with much
lower BLL means than studies in the 2013 Pb ISA
(3.04 to 8.38 |jg/dL) and more robust adjustment for
potential confounding. The most consistent
epidemiologic evidence indicates an association
between increased BLLs and decreased Hb levels
and increased prevalence of anemia in children (birth
to 11 yr).
Heme Synthesis'. Altered heme synthesis (e.g., decreased
ALAD and ferrochelatase activities, and decreased Hb
levels) was demonstrated by a small, but consistent, body of
epidemiologic and toxicological studies with relevant Pb
exposures. Epidemiologic studies were all cross-sectional
and the majority lacked consideration for potential
confounding. Evidence for altered heme synthesis is also
provided by a large body of toxicological and epidemiologic
studies that report decreased Hb concentrations in
association with Pb exposure or BLLs.
Heme Synthesis'. Recent epidemiologic studies
indicate an association between increased BLLs and
decreased Hb levels in children. These studies
expanded consideration of potential confounders and
include populations with lower BLLs (mean or median
BLLs ranging from 3.04 to 8.38 |jg/dL). The recent
epidemiologic evidence is coherent with recent
toxicological studies, which also observed Hb
decrements in Pb-exposed mice with BLLs relevant to
humans.
ALAD = 6-aminolevulinic acid dehydratase; BLL = blood lead level; Ca2+ = calcium ion; Hb = hemoglobin; ISA = Integrated Science
Assessment; Mg2+ = magnesium ion; Pb = lead; RBC = red blood cell; yr = year(s).
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IS.7.3.7 Reproductive and Developmental Effects
This ISA organizes the reproductive and developmental effects of Pb exposure into four outcome
categories: effects on pregnancy and birth outcomes, effects on development, effects on female
reproductive function, and effects on male reproductive function. The collective evidence is "suggestive
of, but not sufficient to infer, a causal relationship" between Pb exposure and: 1) effects on pregnancy and
birth outcomes, and 2) effects on female reproductive function. Evidence related to these outcomes is
described in Appendix 8 (Sections 8.3 and 8.5, respectively). Effects on development (IS.7.3.7.1) and
effects on male reproductive function (IS.7.3.7.2), for which evidence supports causal relationships with
Pb exposure, are discussed in more detail in the ensuing sections. Table IS-8A and Table IS-8B provide a
summary of the evidence from epidemiologic and animal toxicological studies related to these outcomes,
highlighting the recent evidence in comparison with the evidence available in the 2013 Pb ISA.
IS.7.3.7.1 Effects on Development
The 2013 Pb ISA determined that the collective evidence was "sufficient to conclude that there is
a causal relationship between Pb exposures and developmental effects." This determination was based on
a strong body of evidence demonstrating delayed pubertal onset among males and females exposed to Pb.
Cross-sectional epidemiologic studies reported consistent associations between BLLs and delayed
pubertal onset (measured by age at menarche, pubic hair development, and breast development) among
girls (ages 6-18 years) with mean and/or median concurrent BLLs of 1.2-9.5 (ig/dL. Although fewer
studies were conducted in boys, associations between BLLs and delayed puberty onset in boys (ages 8-
15 years) were observed in a longitudinal study and a few supporting cross-sectional studies (mean and/or
median BLLs of 3-9.5 (ig/dL). Limitations across most of the epidemiologic studies of BLLs and delayed
puberty included a lack of adjustment for nutritional factors as a potential confounder and the use of
cross-sectional study designs, which do not establish temporality. Additionally, because studies included
older children and adolescents who likely had higher earlier childhood Pb exposures, there is uncertainty
regarding the level, timing, frequency, and duration of Pb exposure that contributed to the observed
associations. Experimental animal studies demonstrate that puberty onset in both males and females is
delayed following exposure to Pb. Evidence for effects on postnatal growth was inconsistent.
Recent epidemiologic evidence continues to support an association between BLLs and delayed
pubertal onset in girls (Appendix 8.4.2) and boys (Appendix 8.4.3V Notably, recent studies observe more
consistent associations between Pb exposure and effects on puberty in girls. Although associations are
reported in populations with lower mean BLLs (0.65-6.57 (.ig/dL). uncertainty regarding the role of
potentially higher past exposures remains. Recent epidemiologic studies consider a wide range of
confounders, including height, weight, and body mass index (BMI), and some studies were conducted
among established longitudinal cohorts. No recent PECOS-relevant toxicological studies reported on the
effects of Pb on male or female puberty, though some studies provide evidence for the biological
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plausibility of delayed pubertal onset. Specifically, Pb-induced disruptions of the hypothalamic-pituitary-
gonadal axis, steroidogenic enzymes, and their sex steroid products provide plausible pathways through
which Pb exposure could lead to the observed delays in pubertal onset reported in epidemiologic and
toxicological studies. Recent toxicological and epidemiologic evidence for effects on postnatal growth is
largely inconsistent, though epidemiologic studies that examined BLLs, as opposed to other biomarkers,
provide more consistent patterns of inverse associations between Pb exposure and height and weight in
children (8 months to 11 years). Because of the strong body of evidence demonstrating delayed pubertal
onset among males and females exposed to Pb, the collective evidence is sufficient to conclude that
there is a causal relationship between Pb exposure and effects on development.
Table IS-8A Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and reproductive and developmental effects.
Effects on Development: Causal Relationship (IS.7.3.7.1 and Appendix 8.4)
Evidence from the 2013 Pb ISA
Epidemiologic studies reported associations between
concurrent BLLs and delayed pubertal onset in boys and
girls. Associations were observed in children and
adolescents (6-18 yr) with low mean and/or median BLLs
(1.2-9.5 |jg/dL). A limitation across most of these studies is
their cross-sectional design, which does not establish
temporality between the exposure and outcome.
Additionally, there is uncertainty with regard to the exposure
frequency, timing, duration, and level that contributed to the
associations observed in these studies. Experimental animal
studies demonstrated that puberty onset in both males and
females is delayed with Pb exposure.
BLL = blood lead level; mo = month(s); Pb = lead; yr = year(s).
Evidence from the 2023 Pb ISA
Recent epidemiologic and toxicological evidence
continues to support Pb-related delays in pubertal
onset in boys and girls, including associations at
lower BLLs in the epidemiologic studies (0.65-
6.57 |jg/dL). Results from recent studies examining
the relationship between Pb exposure and postnatal
growth are inconsistent, though epidemiologic studies
that examined BLLs, as opposed to other biomarkers,
provide more consistent patterns of inverse
associations between Pb exposure and height and
weight in children (8 mo to 11 yr).
IS.7.3.7.2 Male Reproductive Function
In the 2013 Pb ISA, the evidence was "sufficient to conclude that there is a causal relationship
between Pb exposures and male reproductive function." Key evidence was provided by toxicological
studies in rodents, nonhuman primates, and rabbits showing detrimental effects on semen quality, sperm,
and fecundity/fertility with supporting evidence in epidemiologic studies of associations between BLLs
and detrimental effects on sperm. Animal exposures resulting in BLLs from 5-43 (ig/dL induced lower
sperm quality and sperm production rate, sperm DNA damage, and histological or ultrastructural damage
to the male reproductive organs. These effects were found in animals exposed to Pb for 1 week to 3
months during peripuberty or as adults. Pb exposure of male rats also resulted in subfecundity in female
mates and lower fertilization of eggs in vitro. Detrimental effects of Pb on sperm were observed in
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epidemiologic studies with concurrent BLLs of 25 (ig/dL and greater among occupationally exposed men;
however, these studies were limited because of their lack of consideration of potential confounding
factors, including occupational exposures other than Pb. A smaller number of epidemiologic studies
among men with lower Pb biomarker levels were limited to fertility clinic studies that may lack
generalizability. Additionally, because of uncertainty regarding greater exposure to Pb earlier in life in
these populations, the specific timing, frequency, duration, and level of Pb exposure associated with the
BLLs and effects observed is not discernible from the epidemiologic evidence. Biological plausibility for
the observed associations was provided by animal toxicological studies that demonstrated Pb-induced
oxidative stress within the male sex organs, increase apoptosis of spermatocytes and germ cells, and
impaired germ cell structure and function.
Recent epidemiologic evidence continues to support an association between BLLs and decreased
sperm/semen production, quality, and function. Results from analyses using other Pb biomarkers,
including plasma, semen, and seminal fluid, were inconsistent. The evaluated studies were cross-sectional
and conducted in males attending fertility clinics, which may have resulted in selection bias and limits the
generalizability of the results. The studies were also limited by concurrent measurement of exposure and
outcome, examination of different seminal parameters, and small sample sizes. Despite these limitations,
a wide variety of potential confounders were considered, including adjustment for hormone levels, which
could potentially impact sperm/semen production, quality, and function. Recent toxicological studies
generally report that Pb exposure alters some aspects of sperm or semen quality, such as sperm density,
motility, morphology, and viability, especially studies that include dosing during developmental periods
or for periods 30 days or longer. The strongest line of evidence, including potential biologically plausible
pathways, were reported for effects on sperm/semen production, quality, and function, while evidence for
other effects on male reproductive function, including hormone levels, male fertility, and morphology and
histology of male sex organs is either limited in quantity and/or inconsistent. Overall, the collective
evidence is sufficient to conclude that there is a causal relationship between Pb exposure and male
reproductive function.
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Table IS-8B Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and reproductive and developmental effects.
Male Reproductive Function: Causal Relationship (IS.7.3.7.2 and Appendix 8.6)
Evidence from the 2013 Pb ISA
Animal toxicological studies in rodents, nonhuman primates,
and rabbits reported that Pb exposures resulting in BLLs
from 5-43 [jg/dL induced lower sperm quality and sperm
production rate, sperm DNA damage, and histological or
ultrastructural damage to the male reproductive organs.
These effects were found in animals exposed to Pb for 1 wk
to 3 mo during peripuberty or as adults. There was some
supporting epidemiologic evidence, but most studies
examined occupational^ exposed men with high BLLs
(>25 |jg/dL) and included limited control for potential
confounders.
Evidence from the 2023 Pb ISA
Recent epidemiologic studies reported consistent
associations between BLLs and decreased
sperm/semen production and quality. Results were
inconsistent in studies that measured Pb in seminal
fluid or seminal plasma. Epidemiologic studies also
provided initial evidence of an association between
BLLs and increased testosterone and morphological
changes in male sex organs. The epidemiologic
studies evaluated include non-occupationally
exposed men with lower Pb exposures than studies
included in the previous ISA. Recent toxicological
evidence is consistent with findings from the 2013 Pb
ISA.
BLL = blood lead level; ISA = Integrated Science Assessment; mo = month(s); Pb = lead; wk = week(s); yr = year(s).
IS.7.3.8 Musculoskeletal Effects
The 2013 Pb ISA concluded that "a causal relationship is likely to exist between Pb exposure and
effects on bone and teeth." In order to be more inclusive of other health effects related to bone and teeth
(e.g., muscles, joints, and cartilage), this ISA expands the considered health outcomes to include effects
on the entire musculoskeletal system. A summary of the evidence available in the 2013 Pb ISA as well as
evidence from recent studies is provided in Table IS-9. Recent epidemiologic evidence continues to
support an association between Pb exposure and effects on bone (e.g., increased prevalence of
osteoporosis) and teeth (i.e., increased prevalence and incidence of dental caries and tooth loss in children
and adults). There is also an emerging area of research on osteoarthritis, an endpoint that was not
discussed in the 2013 Pb ISA. A few recent cross-sectional studies reported positive associations between
BLLs and symptomatic and radiographic osteoarthritis and some biomarkers of joint tissue metabolism.
The epidemiologic evidence base includes a larger number of studies and adult populations with lower
mean, median, or geometric mean BLLs than studies included in the 2013 Pb ISA (1.03 to 4.44 (.ig/dL).
Despite the evidence for associations at relatively low BLLs, these musculoskeletal outcomes were most
often examined in adults who have been exposed to higher levels of Pb earlier in life, and uncertainty
remains concerning the Pb exposure level, timing, frequency, and duration contributing to the observed
associations. Additionally, recent epidemiologic evidence is mostly from cross-sectional study designs
and does not thoroughly address the temporality of exposure and outcome. This may be particularly
relevant for health outcomes that correlate with bone turnover rates that could lead to higher BLLs. The
toxicologic data support Pb-induced alterations in multiple aspects of bone, teeth, and joint maintenance.
For skeletal bones, shift in the balance between bone building osteoblasts and bone resorbing osteoclasts
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could be responsible for delayed bone growth and increased bone degeneration seen in epidemiologic
studies. In teeth and joints, Pb appears to suppress the synthesis of cellular matrix proteins important for
joint maintenance and enamel formation which could plausibly contribute to the osteoarthritic and dental
effects seen in some epidemiologic studies. Overall, the collective evidence is sufficient to conclude
that there is likely to be a causal relationship between Pb exposure and musculoskeletal effects.
Table IS-9 Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and musculoskeletal effects.
Musculoskeletal Effects: Likely to be Causal (IS.7.3.8 and Appendix 9.5)
Evidence from the 2013 Pb ISA
Strong toxicological evidence evaluated in the 2013 Pb ISA
and the 2006 Pb AQCD (U.S. EPA. 2006a) demonstrates
effects in bone and teeth in animals following Pb exposure.
Exposure of animals to Pb during gestation and the
immediate postnatal period was reported to significantly
depress early bone growth with concentration-dependent
trends. Systemic effects of Pb exposure included disruption
of bone mineralization during growth, alterations in bone cell
differentiation and function due to alterations in plasma
levels of growth hormones and calcitropic hormones such as
1,25-dihydroxyvitamin D3, effects on Ca2+- binding proteins,
and increases in Ca2+ and phosphorus concentrations in the
bloodstream. As in bone, Pb was found to easily substitute
for Ca2+ in the teeth following exposure and was taken up
and incorporated into developing teeth in experimental
animals. These findings were coherent with results from a
small body of epidemiologic studies that provided consistent
evidence of associations between Pb biomarker levels and
various effects on bone and teeth after adjusting for potential
confounding by age and SES-related factors.
Evidence from the 2023 Pb ISA
Recent epidemiologic studies continue to support
associations between Pb exposure and effects on
bone in adults and teeth in children and adults. The
recent epidemiologic evidence is mostly from cross-
sectional studies and does not thoroughly address
the temporality of exposure and outcome.
Additionally, uncertainty remains concerning the Pb
exposure level, timing, frequency, and duration
contributing to the observed associations in adult
populations. Recent toxicological evidence is limited,
but consistent with findings from the 2013 Pb ISA and
coherent with the epidemiologic evidence.
AQCD = Air Quality Criteria Document; Ca2+ = calcium ion; ISA = Integrated Science Assessment; Pb = lead;
SES = socioeconomic status.
IS.7.3.9 Mortality
In the 2013 Pb ISA (U.S. EPA. 2013a). the strongest evidence for Pb-associated mortality was
from studies examining cardiovascular mortality. The evidence did not provide strong support for Pb-
associated mortality other than through cardiovascular pathways, and very few studies examined total
(nonaccidental) mortality. For these reasons, the 2013 Pb ISA evaluated studies of all-cause mortality
together with studies examining cardiovascular mortality, and these studies were all included within the
CVD chapter. Although this evidence contributed to the "causal relationship" between Pb exposure and
CHD, there was no distinct causality determination for total or cause-specific mortality. A small number
of studies evaluated in the 2013 Pb ISA reported consistently positive associations between Pb
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biomarkers and total mortality. This evidence was further supported by consistent evidence of positive
associations between BLLs and cardiovascular mortality in NHANES cohorts, including some studies
that controlled for a wide range of potential confounders, tested for interactions between confounders and
BLL, included evaluations of C-R relationships and extensive analysis of model evaluations, and
examined specific causes of CVD mortality. In addition, an analysis of the NAS reported an association
between bone Pb, a metric of cumulative Pb exposure, and increased total and cardiovascular mortality in
older male veterans.
Several recent epidemiologic studies build upon evidence from the 2013 Pb ISA and provide
largely consistent evidence of an association between biomarkers of Pb exposure and total and
cardiovascular mortality (Table IS-10). Recent studies include nationally representative adult populations
with low BLLs (mean <2.5 (.ig/dL). including an extended analysis of the NHANES III cohort. Notably,
all of these analyses include study populations that were born prior to the phase-out of leaded gasoline
and therefore likely had much higher past Pb exposures, making it difficult to characterize the specific
timing, duration, frequency, and level of Pb exposure that contributed to the observed associations.
Studies that examined multiple causes of mortality in the same cohort generally reported effect estimates
that were notably smaller in magnitude for total mortality compared to cardiovascular mortality. This
suggests that the total mortality results may in large part be driven by the association between BLLs and
cardiovascular mortality. There is extensive epidemiologic and toxicological evidence indicating
pathways by which exposure to Pb could plausibly progress from initial events to endpoints relevant to
the cardiovascular system, such as hypertension, exacerbation of IHD, and potential MI or stroke.
Because cardiovascular morbidity, which comprises 33% of total (nonaccidental) mortality, is the most
common contributor to total mortality (NHLBI. 2017). the progression demonstrated in the available
evidence for cardiovascular morbidity supports potential biological pathways by which Pb exposure could
result in cardiovascular mortality. There is also very limited evidence that Pb exposure is positively
associated with other causes of mortality, including Alzheimer's disease (AD) and infection. Biological
plausibility for these outcomes is demonstrated by pathways leading from Pb exposure to
neurodegenerative disease (Appendix 3.3) and immunosuppression (Section IS.7.3.5), respectively.
However, although there is toxicological evidence that developmental exposure to Pb increases the
expression of proteins related to AD, the epidemiologic evidence relating Pb exposure to incident AD
remains limited. A few uncertainties remain in the evidence base, including a limited number of
independent studies (i.e., from non-overlapping study populations), and uncertainty regarding to the
specific timing, duration, frequency, and level of Pb exposure that contributed to the observed
associations. Given the evidence for Pb-associated all-cause and cardiovascular mortality and strong
supporting evidence for Pb-associated cardiovascular effects, there is sufficient evidence to conclude
that there is a causal relationship between Pb exposure and total (nonaccidental) mortality.
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Table IS-10 Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and total (nonaccidental) mortality.
Total Mortality: Causal (IS.7.3.9 and Appendix 9.8)
Evidence from the 2013 Pb ISA
Consistent evidence of positive associations between BLLs
and total and cardiovascular mortality observed in NHANES
cohorts, including some studies that controlled for a wide
range of potential confounders. In addition, an analysis of
the NAS reported an association between bone Pb, a metric
of cumulative Pb exposure, and increased total and
cardiovascular mortality in older male veterans.
Evidence from the 2023 Pb ISA
Recent epidemiologic studies build upon evidence
from the 2013 Pb ISA and provide largely consistent
evidence of an association between biomarkers of Pb
exposure and total and cardiovascular mortality.
Recent studies include nationally representative
populations with low BLLs (mean <2.5 |jg/dL).
Uncertainties remain regarding the specific timing,
duration, frequency, and level of Pb exposure that
contributed to the observed associations.
BLL = blood lead level; ISA = Integrated Science Assessment; NAS = Normative Aging Study; NHANES = National Health and
Nutrition Examination Survey; mo = month(s); Pb = lead; yr = year(s).
IS.7.3.1Q Cancer
The 2013 Pb ISA concluded that "a causal relationship is likely to exist between Pb exposure and
cancer." This determination was based on strong evidence from animal toxicological studies
demonstrating effects of Pb on cancer, genotoxicity, or epigenetic modification (Table IS-11).
Carcinogenicity in animal toxicological studies with relevant routes of Pb exposure were reported in the
kidneys, testes, brain, adrenals, prostate, pituitary, and mammary gland, albeit at high doses of Pb.
Epidemiologic studies of cancer incidence and mortality reported inconsistent results; one strong
epidemiologic study demonstrated an association between BLLs and increased cancer mortality, but other
studies reported weak (i.e., small magnitude and/or imprecise 95% CIs) or null associations. The
consistent evidence indicating Pb-induced carcinogenicity in animal models was substantiated by the
mode of action findings from multiple high-quality toxicological studies in animal and in vitro models
from different laboratories.
There are no recent toxicological studies conducted at concentrations deemed relevant to this ISA
(i.e., BLLs <30 (.ig/dL). Recent in vitro studies add to our understanding of how Pb exposures may
activate the mechanistic pathways that can result in cancer, including evidence for Pb activation of
mechanistic pathways mediated by oxidative stress, genotoxicity, and inflammation, as well as changes in
cell cycle regulatory genes, epigenetics, apoptosis, and necrosis (Appendix 10.3). Additionally, new areas
of research involving matrix metalloproteinases and metallothioneins have emerged and provide evidence
of other potential mechanistic pathways through which Pb exposure could contribute to cancer. In the
absence of any new cancer bioassay studies using animal models, uncertainty remains regarding the
carcinogenic potential of low levels of Pb exposure. Recent epidemiologic evidence does little to address
this uncertainty. Similar to the epidemiologic evidence evaluated in the 2013 Pb ISA, recent
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epidemiologic studies observed inconsistent associations between Pb exposure and overall cancer
mortality (Appendix 10.4.2). A limited number of recent studies evaluating Pb exposure and site-specific
cancers is also inconsistent. The small body of evidence across various site-specific cancer endpoints
limits the ability to judge coherence and consistency across these studies. In general, recent studies
control for a wide range of potential confounders, but studies were limited by a small number of cases
resulting in limited power to detect an association, a relatively short time period between exposure and
outcome, potential differences in Pb exposure histories based on study location, and the use of different
biomarkers of exposure. Additionally, when associations were observed, study populations most often
included adults who have been exposed to higher levels of Pb earlier in life, which produces uncertainty
regarding the Pb exposure level, timing, frequency, and duration contributing to the observed
associations. Strong support from animal toxicological studies suggests that the collective evidence is
sufficient to conclude that there is likely to be a causal relationship between Pb exposure and cancer
incidence and mortality.
Table IS-11 Summary of evidence from epidemiologic and animal toxicological
studies on Pb exposure and cancer.
Cancer: Likely to be Causal (IS.7.3.10 and Appendix 10)
Evidence from the 2013 Pb ISA
Toxicological studies consistently reported cancer incidence
following chronic exposure (i.e., 18 mo or 2 yr) to high
concentrations of Pb, such as 10,000 ppm Pb acetate in diet
or 2,600 ppm Pb acetate in drinking water. High-quality
toxicological studies in animal and in vitro models from
different laboratories also provided a biologically plausible
pathway through which Pb exposure could lead to cancer.
Epidemiologic studies of cancer incidence and mortality
reported inconsistent results.
Evidence from the 2023 Pb ISA
No recent cancer bioassay studies using animal
models with relevant exposure levels are available. In
vitro studies provide additional evidence supporting
the Pb-induced activation of diverse mechanistic
pathways that are typically associated with
carcinogenesis. Recent epidemiologic studies add to
the inconsistent evidence of an association between
Pb exposure and cancer mortality.
ISA = Integrated Science Assessment; mo = month(s); Pb = lead; yr = year(s).
IS.7.4 At-Risk Populations
Interindividual variation in exposure or human responses to ambient air pollution can result in
some groups or lifestages being at increased risk for health effects. The NAAQS are intended to protect
public health with an adequate margin of safety. In so doing, protection is provided for both the
population as a whole and those at increased risk for health effects in response to exposure to a criteria air
pollutant [e.g., Pb; see Preamble (U.S. EPA. 2015)1. There is interindividual variation in both
physiological responses and exposure to Pb in the environment. The scientific literature has used a variety
of terms to identify factors and subsequently populations or lifestages that may be at increased risk of an
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air pollutant-related health effect, including susceptible, vulnerable, sensitive, at-risk, and response-
modifying factors (U.S. EPA. 2015). Acknowledging the inconsistency in definitions for these terms
across the scientific literature and the lack of a consensus on terminology in the scientific community, "at-
risk" is the all-encompassing term used in ISAs for groups with specific factors that increase the risk of an
air pollutant (e.g., Pb)-related health effect in a population, as initially detailed in the 2013 Pb ISA (U.S.
EPA. 2013a). Therefore, this ISA takes an inclusive and all-encompassing approach and focuses on
identifying those populations or lifestages potentially "at risk" of a Pb-related health effect.
As discussed in the Preamble (U.S. EPA. 2015). the risk of health effects from exposure to Pb
may be modified as a result of intrinsic (e.g., pre-existing disease, genetic factors) or extrinsic factors
(e.g., sociodemographic or behavioral factors), differences in internal dose, or differences in exposure to
Pb in the environment. Some factors may lead to a reduction in risk and are recognized as such during the
evaluation. However, to inform decisions on the NAAQS, this ISA focuses on identifying those
populations or lifestages at greater risk. While a combination of factors (e.g., residential location and
SES) may increase the risk of Pb-related health effects in portions of the population, information on the
interaction among factors remains limited. Thus, this ISA characterizes the individual factors that
potentially result in increased risk for Pb-related health effects [see Preamble (U.S. EPA. 2015)1.
IS.7.4.1 Approach to Evaluating and Characterizing the Evidence for At-Risk Factors
The ISA identifies and evaluates factors that may increase the risk of a population or specific
lifestage to a Pb-related health effect; this approach is described in detail in the Preamble (U.S. EPA.
2015) and is illustrated in Table IS-12. Whereas Appendices 3-10 include a discussion of some
populations and lifestages in order to explicitly characterize the causal nature between Pb biomarkers of
exposure and health effects based on the body of evidence (e.g., children, minority populations), this
section focuses on summarizing evidence that can inform the identification of such populations and
lifestages.
Table IS-12 Characterization of evidence for factors potentially increasing the
risk for Pb-related health effects.
Classification Health Effects
Adequate evidence There is substantial, consistent evidence within a discipline to conclude that a factor results
in a population or lifestage being at increased risk of air pollutant-related health effect(s)
relative to some reference population or lifestage. Where applicable, this evidence includes
coherence across disciplines. Evidence includes multiple high-quality studies.
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Classification
Health Effects
Suggestive evidence The collective evidence suggests that a factor results in a population or lifestage being at
increased risk of air pollutant-related health effect(s) relative to some reference population
or lifestage, but the evidence is limited due to some inconsistency within a discipline or,
where applicable, a lack of coherence across disciplines.
Inadequate evidence The collective evidence is inadequate to determine whether a factor results in a population
or lifestage being at increased risk of air pollutant-related health effect(s) relative to some
reference population or lifestage. The available studies are of insufficient quantity, quality,
consistency, and/or statistical power to permit a conclusion to be drawn.
Evidence of no effect There is substantial, consistent evidence within a discipline to conclude that a factor does
not result in a population or lifestage being at increased risk of air pollutant-related health
effect(s) relative to some reference population or lifestage. Where applicable, the evidence
includes coherence across disciplines. Evidence includes multiple high-quality studies.
The evidence evaluated in this section includes relevant studies discussed in Appendix 3-
Appendix 10 of this ISA and builds on the evidence presented in the 2013 Pb ISA (U.S. EPA. 2013a).
Using the approach developed in previous ISAs, (U.S. EPA. 2020. 2016a. 2013a. b) recent evidence is
integrated across scientific disciplines and health effects, and where available, with information on
exposure and dosimetry. In evaluating factors and population groups, greater emphasis is placed on the
evidence for those health outcomes for which a "causal" or "likely to be causal" relationship is concluded
in Appendix 3-Appendix 10 of this ISA (see Section IS.7.3).
As discussed in the Preamble (U.S. EPA. 2015). consideration of at-risk populations includes
evidence from epidemiologic and animal toxicological studies, in addition to relevant exposure-related
information. Regarding epidemiologic studies, the evaluation focuses on those studies that include
stratified analyses to compare populations or lifestages exposed to similar air pollutant concentrations
within the same study design along with consideration of the strengths and limitations of each study.
Other epidemiologic studies that do not stratify results but instead examine a specific population or
lifestage can provide supporting evidence for the pattern of associations observed in studies that formally
examine effect measure modification. Similar to the characterization of evidence in
Appendix 3-Appendix 10. the greatest emphasis is placed on patterns or trends in results across studies.
Experimental studies in animals that focus on factors, such as genetic background or pre-existing disease,
are evaluated because they provide coherence and can support the biological plausibility of effects
observed in epidemiologic studies. Also evaluated are studies examining whether factors may result in
differential exposure to Pb and subsequent increased risk of Pb-related health effects. Additionally,
physiologic factors that may influence the internal distribution of Pb are also considered. Conclusions are
made with respect to whether a specific factor increases the risk of a Pb-related health effect based on the
characterization of evidence using the framework detailed in Table III of the Preamble (U.S. EPA. 2015).
and presented in Table IS-12.
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IS.7.4.2 Summary of At-Risk Populations
The 2013 Pb ISA (U.S. EPA. 2013a) concluded that there was adequate evidence to classify
children, minority populations, individuals in proximity to Pb sources, individuals living in residences
with factors contributing to increased house dust Pb levels, and those with a certain nutritional status as
populations at increased risk of Pb-related health effects. These conclusions were based on the
consistency in findings across studies, as well as on coherence of results from different scientific
disciplines. Some populations may be at increased risk of Pb-related health effects mostly due to
increased Pb exposure. Recent studies provide additional evidence that minority populations, children,
those in proximity to Pb sources, and those with certain nutritional excesses or deficiencies are at
increased risk for Pb-related health effects. There is relatively little recent evidence to add to the evidence
presented in the 2013 Pb ISA regarding individuals living in areas with certain residential factors
(Table IS-13).
Several recent large epidemiologic studies, including some longitudinal studies, evaluated health
effects among certain racial/ethnic groups or stratified results by race/ethnicity. Results from these studies
expand the current knowledge base from the 2013 Pb ISA to provide further support of the relationship
between Pb biomarkers and health effects (mainly increased concurrent BP and hypertension) among
black and Asian populations. However, there remains uncertainty regarding the level, timing, frequency,
and duration of Pb exposure contributing to the observed associations. Similarly, recently available
evidence among children further elucidates the increased risk children can experience from elevated
exposures to Pb. Additionally, those living in proximity to a Pb sources (e.g., industrial sources of Pb) are
not only at increased risk of elevated Pb biomarker levels, due to increased Pb exposure, but also
increased risk of negative Pb-related health outcomes, as was demonstrated in the 2013 Pb ISA. Lastly,
the recent evidence further supports and adds to the collective evidence presented in the 2013 Pb ISA that
the presence of absence of certain nutrients may increase Pb-related health effects, while other nutrient
deficiencies or surpluses may decrease the risk of a Pb-related health effect among certain populations.
Since the 2013 Pb ISA, recent research has expanded the evidence bases for several factors,
which were originally classified as providing suggestive evidence of a population or lifestage that
increases the risk of Pb-related health effects. Specifically, at the time of the 2013 Pb ISA there were a
limited number of studies that evaluated genetic variants in relation to the effects of Pb exposure on a
population. However, recent studies consider several additional genetic variants, and evidence collected
as a whole further elucidates differential effects among certain segments of the population with genetic
variants. Additionally, more evidence is available related to the impacts of stress on the health effects of
Pb exposure. Taken together, recent studies, in combination with studies evaluated in the 2013 Pb ISA,
provide adequate evidence that high stress levels modifies the associations between Pb exposure and
health effects.
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Table IS-13 Summary of evidence for populations at increased risk to the health
effects of Pb.
Conclusions from 2013 Pb ISA
Conclusions from the 2023 Pb ISA
Adequate evidence (2023 Pb ISA)
Race/ethnicity Compared with white populations,
minority populations were observed to
be more at risk of Pb-related health
effects. Studies of race/ethnicity
provide adequate evidence that
race/ethnicity is an at-risk factor based
on the higher exposure observed
among minority populations and some
modification observed in studies of
associations between Pb levels and
health effects.
Recent exposure studies demonstrate that non-
Hispanic black children consistently have higher
than average BLLs, particularly when compared
with Hispanic and non-Hispanic white children,
even though overall BLLs are dropping. Recent,
large epidemiologic studies conducted in the
United States expand upon previous evidence
indicating that race/ethnicity is an effect measure
modifier for Pb-related health outcomes.
Childhood
In consideration of the evidence base
(e.g., stratified and longitudinal
analyses) and integrating across
disciplines of toxicokinetics, exposure,
and health, there is adequate evidence
to conclude that children are an at-risk
population.
Recent evidence supports previous conclusions
and extends findings among different childhood
age groups.
Proximity to Pb
sources
Epidemiologic studies report consistent
positive associations between
increased Pb exposure and associated
health effects among those in proximity
to Pb sources, including areas with
large industrial sources.
Recent epidemiologic evidence further supports
prior conclusions for both increased exposure and
increased risk of health effects in proximity to Pb
sources.
Nutrition
Epidemiologic and toxicologic studies
provide consistent evidence that
certain nutritional factors can increase
or decrease the association between
Pb exposure and certain Pb-related
health effects.
Epidemiologic and toxicologic studies provide
consistent evidence that certain nutritional factors
can increase or decrease the association
between Pb exposure and certain Pb-related
health effects.
Residential factors
Findings suggest positive associations
between increased blood Pb and
increased house dust Pb levels.
Recent information does not inform or change
prior conclusions.
Genetics
Few genetic variants have been
observed in epidemiologic and
controlled human exposure studies to
affect the risk of Pb-related health
outcomes and support is provided by
animal toxicological studies of genetic
factors.
Additional genetic variants, epigenetic
modifications, and gene expression factors have
been found to interact with Pb-related health
outcomes.
Stress
Stress was evaluated as a factor that
potentially increases the risk of Pb-
related health effects (e.g., cognitive
function in adults and hypertension),
and while limited by the small number
of epidemiologic studies, increased
stress was observed to exacerbate the
effects of Pb. Toxicological studies
supported this finding.
Recent evidence informs prior conclusions and
extends the results to children. Studies observed
that high levels of maternal stress exacerbated
the effect of prenatal Pb exposure on several
neurodevelopmental domains, including
language. Toxicological studies provide support
for the interaction between maternal stress and
Pb-related cognitive effects by sex.
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Conclusions from 2013 Pb ISA
Conclusions from the 2023 Pb ISA
Suggestive evidence (2023 Pb ISA)
Older adulthood Evidence, based on limited
epidemiologic evidence but support
from toxicological studies and
differential exposure studies, is
suggestive that older adults are
potentially at risk of Pb effects.
However, there are uncertainties
related to the exposure profile
associated with the effects in older
populations.
Recent information does not inform or change
prior conclusions.
Sex
Potential evidence suggests that
adolescent and adult males typically
demonstrate higher BLLs, although
evidence regarding health outcomes is
limited due to inconsistencies in
whether males or females are at
greater risk of certain outcomes in
relation to Pb
Recent evidence informs prior conclusions, but
still contains inconsistencies in presented results.
Pre-existing disease
There are a limited number of
epidemiologic studies that suggest pre-
existing diabetes modifies Pb effects
on specific health effects (e.g., renal
function or cardiovascular outcomes)
Recent information does not inform or change
prior conclusions.
Studies ofSES and its relationship with
Pb-related health effects are few and
report inconsistent findings regarding
low SES as a potential at-risk factor.
Overall, the evidence is suggestive that
low SES is a potential at-risk factor for
Pb-related health effects.
Recent information does not inform or change
prior conclusions.
Other metals
High levels of other metals, such as Cd
and Mn, were observed to result in
greater effects for the associations
between Pb and various health
endpoints (e.g., renal function,
cognitive function in children), but
overall, the evidence was limited.
Limited recent evidence informs prior conclusions.
Hg and As were also found to interact with Pb-
related cognitive functions.
Inadequate evidence (2023 Pb ISA)
Smoking status
There are a limited number of studies
and insufficient coherence for
differences in Pb-related health effects
by smoking status.
Recent information does not inform or change
prior conclusions.
BMI
A small number of studies provide
inadequate evidence that there may be
BMI-related increase in risk of Pb-
related health effects for some
outcomes.
Recent evidence suggests modification of Pb-
related health effects by overweight status.
Alcohol consumption
A small number of studies provide
inadequate evidence that there may be
alcohol-related increases in Pb-related
health effects for some outcomes.
Recent information does not inform or change
prior conclusions.
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Conclusions from 2013 Pb ISA
Conclusions from the 2023 Pb ISA
Maternal self-esteem
A small number of studies related to
the relationship between Pb exposure
and infant development suggested that
maternal self-esteem modified the
association, but the results were
inconsistent, especially across other
health outcomes.
Recent information does not inform or change
prior conclusions.
Cognitive reserve
Limited epidemiologic evidence
suggests that cognitive reserve may
differentially impact the association
between Pb exposure and Pb-related
health outcomes. No additional
evidence from the 2013 Pb ISA
expanded the assessment of this
factor.
Recent information does not inform or change
prior conclusions.
BLL = blood lead level; BMI = body mass index; ISA = Integrated Science Assessment; Pb = lead; SES = socioeconomic status.
IS.7.4.2.1 Race/Ethnicity
Race is widely acknowledged to be a social construct, not a fixed biological trait (Pavnc-Sturgcs
et al.. 2021). Observed differences in exposures and/or outcomes across racial groups, therefore, are likely
to reflect race as a proxy measure for a complex set of factors that result from these societal constructs
(e.g., nutrition, housing opportunity, access/barriers to health care). This ISA evaluates and synthesizes
existing research on the health and welfare effects of exposure to Pb, and many studies evaluated herein
examine racial disparities in environmental exposure and human health, but do not empirically assess the
underlying complexities that contribute to said disparities. Identifying racial disparities is an important
step in recognizing populations at increased risk to the health effects of Pb but should also be considered
in the context of the specific underlying factors that might explain these differences in exposures and/or
outcomes. This section describes racial and ethnic disparities in Pb exposure and health effects, while
some of the ensuing sections address other factors that may be impacted by social constructs of race (i.e.,
proximity to sources, nutrition, and stress).
Historically, racial and ethnic differences in exposures to environmental Pb have been evident.
Both the 2006 Pb AQCD and the 2013 Pb ISA presented consistent evidence that black populations have
historically had relatively higher blood and bone Pb levels compared with white and other minority
populations. While the 2013 Pb ISA reported that racial and ethnic gaps in mean blood and bone Pb levels
have gradually narrowed over time, black populations continue to typically have higher Pb exposures and
body burdens compared with white populations. Recent evidence from 2011-2018 NHANES cycles
indicates that non-Hispanic black populations generally had BLLs higher than the national average, but in
more recent years, average BLLs in non-Hispanic black populations were lower than in non-Hispanic
white populations (Appendix 2.4). Moreover, in some years, Asian populations had the highest mean
BLLs when compared with other racial/ethnic groups. Nonetheless, non-Hispanic black children are
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consistently the group with the highest BLLs, although both overall differences and differences among
groups are declining.
The 2013 Pb ISA concluded that minority populations, specifically non-Hispanic black
populations, are at an increased risk of health effects related to Pb exposure, compared with white
populations. This conclusion is supported by several longitudinal and cross-sectional analyses. Recent
large epidemiologic studies conducted in the United States expand on evidence from the 2013 Pb ISA and
provide further support for an association between Pb exposure and health outcomes among minority
populations. Specifically, several analyses using NHANES data reported increases in BP among non-
Hispanic white individuals and non-Hispanic black individuals (Appendix 4.3.1.1.1'). However, increases
in BP and hypertension prevalence were consistently larger among non-Hispanic black individuals. These
findings held true across several nationally representative cross-sectional and longitudinal analyses.
Taken together, the evidence suggests that in addition to having higher BLLs, associations between blood
Pb and BP and hypertension are larger among non-Hispanic black populations when compared with
Hispanic or non-Hispanic white populations. These racial differences may also reflect a history of greater
exposure to Pb among non-Hispanic black populations. Racial differences were also noted for
associations of Pb exposure and neurodevelopmental outcomes in children, but the evidence was limited
to a single study. Overall, recent evidence confirms and extends the previous ISA's findings, indicating
increases in Pb biomarker levels and a differential association between Pb exposure biomarkers and
changes in BP or hypertension status, and potentially neurodevelopmental outcomes in children based on
race/ethnicity.
IS.7.4.2.2 Childhood
Historically, children have been known to be at particularly higher risk for Pb-related health
effects. The 2013 Pb ISA provided a plethora of evidence indicating a greater likelihood of Pb-related
health outcomes among children. Previous toxicokinetic studies established that Pb can cross the placenta
and disrupt the developing nervous system of the fetus. Additionally, studies have shown that children's
behaviors and activities (including increased hand-to-mouth contact, crawling, and poor handwashing),
differences in diets, and biokinetic factors may place them at greater risk for exposure. There was strong
evidence for Pb-related cognitive deficits and behavioral problems across gestation, childhood, and into
adolescence. Among adolescents, Pb exposure was linked to delinquent or criminal behavior, delays in
pubertal onset, and renal effects. However, uncertainty exists regarding the timing and duration of Pb
exposure on observed health effects because of the high levels of Pb in the adolescent populations
studied. Several studies reported evidence for Pb-related increases in immunosuppression, immune
sensitization, and allergic responses in children. Associations were also found for increased anemia and
reduced RBC function and survival. Children with higher BLLs were also reported to be at higher risk for
dental caries.
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Recent evidence extends support for Pb-related decrements in FSIQ, infant neurodevelopment,
learning, memory, executive function, and academic performance/achievement in children. Several recent
studies assessed timing of exposure by comparing associations between health outcomes and Pb levels
measured during different exposure windows, including during gestation, birth, early-life, and concurrent
exposures. There is no consistent pattern for critical exposure windows in the recent evidence base, which
is consistent with the heterogeneity of results observed for different timing and duration of exposures in
studies evaluated in the 2013 Pb ISA. Toxicological studies and epidemiologic studies examining
modification by genetic/epigenetic factors, coexposure to other metals, or maternal stress indicate that
time window sensitivities may be linked with biological, environmental, and psychosocial variables that
operate at different timepoints during development. A few studies provide evidence for the persistence of
effects of prenatal or early-life Pb exposure, noting early childhood cognitive deficits that continue into
late adolescence. Furthermore, two animal studies reported Pb-induced cognitive function effects with
longer exposure durations that spanned multiple developmental periods. Additionally, several
epidemiologic studies indicated nonlinear C-R relationships between BLLs and cognitive function in
children, which may be explained by unmeasured confounding or interaction by sex, genetics, underlying
conditions, sociodemographics, and timing or duration of exposure. Most studies, however, generally
supported dose-dependent cognitive function decrements at BLLs <30 (ig/dL.
Additional recent studies find strong evidence for Pb affecting externalizing behaviors in
children, including through influence on attentional deficits, impulsivity, hyperactivity, conduct disorders,
aggression, and criminal behavior. Similarly, gestational, postnatal, adolescent, and average childhood
(from birth to ages 4-5 or 11-13 years) Pb biomarker concentrations are associated with internalizing
behaviors, such as anxiety and depression. Both gross and fine motor function are also affected, in line
with previous findings involving oxidative stress, inflammation and Ca2+ signaling, impaired neuron
development, synaptic changes, and neurotransmitter changes with increased Pb exposure. No clearly
defined pattern exists regarding a specific sensitive exposure window regarding these health effects,
although a few toxicological studies report greater decrements in motor function in association with
gestational Pb exposure.
Although the 2013 Pb ISA found support for Pb-related immune effects in children, recent
evidence was less consistent. Results for immunosuppression are consistent with previous findings, but
the body of literature regarding immune sensitization and allergic responses was generally null. On the
other hand, recent evidence supports results from previous studies, reporting associations between Pb
exposures and decreased RBC survival and function, including increased prevalence of anemia among
children with mean BLLs <10 (ig/dL.
Recent epidemiologic studies also continue to report consistent associations between BLLs and
delayed puberty among male and female adolescents. Some studies suggest that as BLLs decline, the
association between blood Pb and age of menarche may be attenuated by potential confounders such as
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1 body weight and adiposity. Of note, there is some evidence that childhood BLLs may affect the function
2 of insulin-like growth factor, which could lead to delays in growth and pubertal onset in adolescent boys.
3 Although no recent toxicological studies have examined the relationship between Pb exposure
4 and teeth, several recent epidemiological studies among large populations reinforce previous conclusions
5 of increased dental caries in association with higher BLLs in early childhood.
6 Overall, substantial toxicokinetic, exposure, and health evidence continues to support the
7 previous conclusion that children are at increased risk for the health effects of Pb.
IS.7.4.2.3 Proximity to Pb Sources
8 Studies from the 2013 Pb ISA provided sufficient evidence that living near Pb sources, including
9 large industrial sources and urbanized areas with Pb-contaminated soils, is associated with increased Pb
10 exposure. Additionally, aviation fuel was highlighted as a major source of Pb emissions in ambient air
11 (Appendix 1.2). A study in North Carolina reported inverse associations of children's BLLs with
12 proximity of their residence to airports (where leaded aviation fuel may be used). Recent evidence
13 continues to support increased Pb biomarker levels associated with proximity to airports and other Pb
14 sources. Additionally, recent evidence also implies that a reduction in environmental Pb at a particular
15 source (e.g., superfund site) is associated with decreases in the BLLs of children in proximity to the
16 original source.
17 In addition to increased biomarker Pb levels being associated with proximity to Pb sources,
18 several recent epidemiologic analyses have reported increased Pb-related health effects among those in
19 proximity to industrial sources of Pb. Specifically, studies comparing populations within certain distances
20 of a Pb source indicated increases in BP and decreases in renal function, though they did not control for
21 additional metals in their analyses. Additionally, recent studies have assessed child IQ and observed small
22 reductions in child intelligence in closer proximity to Pb sources.
IS.7.4.2.4 Nutrition
23 The 2013 Pb ISA and prior AQCDs concluded that by limiting or outcompeting Pb for absorption
24 in the gastrointestinal tract, diets rich in minerals including Ca2+, Fe, and zinc give some protection from
25 increased BLLs. Additionally, previous epidemiologic and toxicological investigations indicated that
26 people with Fe deficits are at increased risk for Pb-related health consequences. Therefore, there are
27 sufficient data from several fields showing certain nutritional factors affect the risk of Pb exposure and
28 health effects in a population.
29 Several recent epidemiologic studies continue to explore other modifications of Pb-related health
30 effects by diet or nutritional intake. Diets rich in curcumin (curry) reduced the likelihood of Pb-associated
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prevalent hypertension in a single study. Additionally, another study evaluated the impact of two different
diet types (Prudent: high amounts of fruit, legumes, whole grains, tomatoes, seafood, poultry, cruciferous
vegetables, dark-yellow vegetables, leafy vegetables, and other vegetables; Western: high intake of
processed meat, red meat, refined grains, butter, high-fat dairy products, eggs, and fries) on the
relationship between bone Pb levels and cardiovascular outcomes. In this study, patella Pb measurements
among those with low prudent diets were associated with a higher risk of coronary artery disease (CAD)
compared with those with a high prudent diet. This difference was not evident when assessing tibia Pb
measurements.
Recent toxicological studies investigated the impact of various dietary factors on the effects of Pb
on neurological outcomes. A recent study reported that in comparison with a standard diet, a high-fat diet
exacerbated the effect of Pb on learning deficits during the first stages of learning. Another study, which
supplemented Pb exposure in mice with green tea extract, reported that green tea ameliorated the negative
impact of Pb exposure on both learning and memory. Additionally, one study reported probiotic
supplementation partially mitigates the cognitive deficits observed in an active avoidance paradigm.
Given the disparate dietary factors examined across these studies, conclusions on the modifying potential
of any individual factor remains uncertain. However, when considered more generally, there is consistent
toxicological evidence that dietary factors modify the cognitive effects of Pb exposure.
Adding on to previous evidence from the 2013 Pb ISA, recent studies have connected Fe
deficiency to immune system effects in a few toxicological studies. A few studies that focused on
different outcomes reported decreases in anti-TT-specific IgM and mucosal IgA levels in rats that were
fed an Fe-deficient diet for 4 weeks and administered Pb acetate in drinking water for 4 weeks after
confirming Fe deficiency. Taken together, these studies support a role for dietary factors in the
immunotoxicity of Pb, but the diversity of nutritional factors investigated among a small number of
studies makes it difficult to determine their relative importance. In summary, the evidence continues to
indicate increased risk for populations with reduced intake of Ca2+ and Fe, and potential risk associated
with other dietary factors.
IS.7.4.2.5 Genetics
Evidence from the 2013 Pb ISA suggested that various genetic variants may modify the
relationship between Pb and various health effects. According to these previous epidemiologic and
toxicological studies, populations with specific ALAD variants may have increased risk of Pb-related
health effects. Variants of vitamin D receptor (VDR), dopamine receptor D4, glutathione S-transferase
(GST) Mu 1, tumor necrosis factor a, endothelial nitric oxide synthase, and hemochromatosis (HFE) were
other genes studied, and presence of their variants may also affect the risk of Pb-related health effects.
Overall, the potential for genetic variants to modify Pb-related health outcomes were investigated in a
small number of studies. Therefore, despite some evidence that certain genetic variants may modify Pb-
related health effects, there are still some uncertainties in the evidence.
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Several recent studies in children add to the small body of previous evidence. The effect of Pb
exposure on children's IQ was reported to be weaker (i.e., smaller magnitude) among those with the
ALAD1 genotype (median BLL: 1.0 (ig/dL). This study identified unique glutamate ionotropic receptor
N methyl D aspartate-type subunit (GRIN)2A and GRIN2B variations that exacerbated Pb-related
deficiencies in learning, memory, and executive function, with a greater impact observed in boys.
Another recent study observed that prenatal Pb exposure was linked to DNA methylation in regions
including genes involved in neurodevelopment. Overall, there is limited evidence of interactions and
increased risk of relationships between genes and Pb exposure in children.
Several recent studies in adults have shown that certain genetic polymorphisms can be important
in assessing the potential for increased risk of Pb biomarker levels and of Pb-related health effects.
Specifically, VDR was evaluated in a longitudinal study examining the association between pulse
pressure (PP) and bone and BLLs. Variations in VDR genes have the potential to influence Pb
accumulation, absorption, and retention in the body. At the initial visit (baseline), an interquartile range
increase in either tibia or patella Pb was associated with an increased PP among those with the variant
(opposed to ancestral) genotype (single nucleotide polymorphisms [SNPs] in Bsml, Taql,Apal, or
Fokl). While the strength of the association between PP and tibia Pb diminished overtime (10-year
follow-up), the three-way interaction terms between bone Pb, VDR receptor type, and time-since-baseline
was almost null, indicating that VDR consistently modifies the association between bone Pb and PP. In
another recent study, several other genes and proteins were also evaluated as effect measure modifiers of
the relationship between bone Pb measurements and incident CHD, including: ALAD, HFE, heme
oxygenase-1 (HMOX1), VDR, apolipoprotein E (APOE), GSTs, and renin-angiotensin. These genes and
the proteins they encode appear to play a role in influencing Pb uptake and retention, as well as altering
Pb toxicity. The authors constructed two sets of genetic risk scores summing either all of the measured
SNPs or a subset of SNPs that were observed to modify the relationship between Pb exposure and CHD.
The association between patella Pb levels and incident CHD was notably stronger in participants in the
highest tertiles of the two genetic risk scores compared with those in the lowest, suggesting that genetic
loci may modify Pb-related CHD risk.
Recent epidemiologic studies on gene regulation during pregnancy are limited but provide insight
on potential mechanistic pathways through which Pb may impact pregnancy. In one study, the association
between maternal Pb levels in blood, patella, and tibial bone and microRNA (miRNA) expression in the
cervix during the second trimester of pregnancy was assessed. Expression of two of the miRNAs were
associated with maternal second trimester BLLs. Another study assessed the association of BLLs during
pregnancy with mitochondrial DNA (mtDNA) content in cord blood, which is a sensitive marker of
mitochondrial function and oxidative stress. Maternal Pb levels during the second trimester were
associated with higher mtDNA content. As BLLs may differ by ALAD (aminolevulinic acid dehydratase)
genotype, one study compared growth outcomes in children with ALAD I-1 and ALAD 1-2/2-2. There
were negative associations between baseline BLLs and height, knee height, and height-for-age z-score
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(HAZ). The observed associations between BLLs and height, knee height, and HAZ were stronger (i.e.,
larger magnitude) in children with ALAD1-2/2-2 compared with ALAD1-1.
Overall recent studies have added to the body of evidence on genetic variants previously found to
modify the risk of Pb-related health effects. Recent studies have also identified other variants - including
but not limited to ALDA1, N-methyl D aspartate, HFE, VDR, HMOX1, and APOE - that may modify the
relationship of Pb exposure and human health effects and predispose certain populations to greater risk of
Pb-related health effects.
IS.7.4.2.6 Stress
The 2013 Pb ISA evaluated stress as a factor that could modify the association with Pb-related
health outcomes. Specifically, these effects were most commonly evaluated within studies evaluating
cognitive function and hypertension. More recent evidence expands the knowledge base for stress as a
factor that can increase the risk of Pb-related health effects.
Recent epidemiologic studies have evaluated the effect of stress as a modifying factor in the
relationship between Pb biomarker exposure and certain health effects. Specifically, a large amount of
recent evidence points to stress as being an effect measure modifier of the relationship between Pb
biomarkers and cardiovascular outcomes among both adults and children. Allostatic load (AL), a measure
of cumulative stress, was reported to modify the association between biomarkers of Pb exposure and
CVD mortality, BP, and hypertension, with markers of increased AL being associated with stronger
associations (i.e., larger magnitude) between Pb biomarkers and cardiovascular outcomes. Another study
relied on the Patient Health Questionnaire (PHQ-9) to assess psychosocial stress and indicated that
increased PHQ-9 score (>3; representing greater psychosocial stress) was associated with stronger
associations between blood Pb and increases in BP. Toxicological studies supported these findings,
particularly studies evaluating maternal stress.
Several recent studies among children evaluated cardiovascular outcomes associated with Pb
biomarkers as a response to acute stressors. One study indicated that a higher level of Pb exposure during
early childhood (mean age of 2.6 years) was related to a greater total peripheral resistance response to
acute stress years later (at 9.5 years of age). Another study indicated significant decreases in HRV
associated with BLLs, following an acute stressful stimulus in young (aged 3-5) children.
Maternal stress has also been evaluated within studies assessing the relationship between
biomarkers of Pb exposure and neurologic and developmental outcomes among offspring. Maternal stress
appeared to substantially modify the associations between Pb exposure biomarkers and neurodevelopment
among children. Specifically, high maternal stress appeared to exacerbate the effect of prenatal Pb
exposure on neurodevelopment in several domains, including language. However, epidemiologic and
toxicological studies assessing birth outcomes did not observe an effect of maternal stress on relationships
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between Pb and adverse birth outcomes. Overall, the majority of recent evidence strengthens the previous
conclusion that increased stress exacerbates the effects of Pb.
IS.8 Evaluation of Welfare Effects of Pb
Effects of Pb relevant to the secondary NAAQS are observed across ecological endpoints
common to terrestrial, freshwater, and saltwater biota. Those endpoints include reproduction, growth,
survival, neurobehavioral effects, hematological effects, and physiological stress, and occur at multiple
scales of biological organization from the cellular to the ecosystem. The atmosphere and terrestrial and
aquatic ecosystems are interconnected, with transfer of Pb taking place between each of these systems
(Appendix 11.1.2). Although Pb is present in the natural environment, it has no biological function in
plants or animals. In some instances, depending on the form of Pb and prevailing environmental
chemistry at a particular geographic location, Pb is taken up by biota where it can lead to a biological
response. Pb exposure to organisms can be via one or more pathways (e.g., uptake from soil or water,
ingestion). For Pb to interact with a biological membrane and be taken up into an organism it must be
bioavailable (Appendix 11.1.6). Generally, the greater amount of Pb available as the free Pb ion, the
greater bioavailability. Factors such as pH, dissolved organic carbon (DOC) or water hardness in aquatic
environments, and pH, cation exchange capacity (CEC), or aging in terrestrial environments often interact
strongly with Pb concentration to modify its effects, primarily through their influence on bioavailability,
but also sometimes through direct modification of biotic effects. Uptake, subsequent bioaccumulation,
and toxicity of Pb varies greatly between species and across taxa, as characterized in the 1977 AQCD
(U.S. EPA. 1977). the 1986 Pb AQCD (U.S. EPA. 1986b). the 2006 Pb AQCD (U.S. EPA. 2006a). the
2013 Pb ISA (U.S. EPA. 2013a). and further supported in this ISA. The welfare effects of Pb summarized
in the following sections are presented in greater detail in Appendix 11. Effects of Lead in Terrestrial and
Aquatic Ecosystems. Appendix 11 includes an overview of concepts related to ecosystem effects of Pb
(Appendix 11.1) and evidence for effects of Pb on organisms inhabiting terrestrial (Appendix 11.2),
freshwater (Appendix 11.3) and saltwater (Appendix 11.4) environments, especially since the 2013 Pb
ISA.
Initial perturbations associated with exposure to Pb such as cytological or biochemical changes
may cascade to effects at higher levels of biological organization (i.e., from the subcellular and cellular
level through the individual organism and up to ecosystem-level processes). The alteration of cellular ion
status (including disruption of Ca2+ homeostasis, altered ion transport mechanisms, and perturbed protein
function through displacement of metal cofactors) appears to be the major unifying mode of action
underlying all subsequent modes of action of Pb toxicity in plants, animals, and humans (Lassiter et al..
2015; U.S. EPA. 2013a). Molecular mechanisms linked to oxidative stress may induce DNA damage and
generation of reactive oxygen species leading to protein modification, lipid peroxidation, and altered
enzyme response. For ecological endpoints in this ISA, biochemical (e.g., enzymes, stress markers)
responses at the suborganism-level of biological organization are grouped under the broad endpoint of
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"physiological stress," while organism-level effects include reproduction, growth, and survival. These
endpoints in turn have the potential to alter population, community, and ecosystem levels of biological
organization (Sutcr et al.. 2004). The definition of an ecosystem used in this ISA is "a functional unit
consisting of living organisms, their nonliving environment, and the interactions within and between
them" (Allwood et al.. 2014). Ecosystems can be natural, cultivated, or urban (U.S. EPA. 1986b) and may
be defined on a functional or structural basis (Appendix 11.1.4). Biotic structure includes species
abundance, richness, distribution, diversity, evenness, and composition measured at the population,
species, community, ecosystem, or global scale. Pollutants, such as Pb, can affect the ecosystem structure
at any of these levels of biological organization (Sutcr etal.. 2005). Causality determinations for
ecological effects of Pb in this ISA use biological scale as an organizing principle to summarize effects on
vegetation, invertebrates, and vertebrates in terrestrial, freshwater, and saltwater environments.
IS.8.1 Summary of Effects on Terrestrial Ecosystems
In terrestrial ecosystems, non-air media can receive Pb from atmospheric deposition or other
sources. Once deposited, Pb can be resuspended into the air or transferred among other environmental
media (Appendix 1.3). Since the 2013 Pb ISA (U.S. EPA. 2013a). evidence has continued to accrue for
many of the effects of Pb on terrestrial ecosystems reported in that ISA and previous EPA assessments. In
particular, effects previously documented were observed at exposures lower than in previous studies. This
additional supporting evidence includes investigations of effects on species and communities that had not
been previously studied, but none of the additional evidence is sufficient to change any of the causality
determinations for terrestrial ecosystems that were reached in the 2013 Pb ISA.
Studies published since the 2013 Pb ISA (U.S. EPA. 2013a) continue to support previous findings
that plants generally sequester larger amounts of Pb in roots as compared with shoots and that there are
species, ecotype, and cultivar-dependent differences in the uptake of Pb from soil and the atmosphere, and
in the translocation of sequestered Pb (Appendix 11.2.1). In the 2013 Pb ISA and previous assessments,
Pb exposure was found to result in plant physiological stress and deficits in plant growth, whereas
evidence of effects on plant survival and reproduction was mixed. Recent studies have continued to
demonstrate various deleterious physiological effects of Pb exposure on plants, particularly oxidative
stress. Strong uncertainties also remain regarding the concentrations at which these effects would be
observed in the environment. Recent studies have examined the protective effects of mycorrhizae and of
some plant nutrients when added in excess of the minimal requirements of the plants.
In terrestrial invertebrates, the 2013 Pb ISA (U.S. EPA. 2013a) and previous assessments
reported evidence of effects on invertebrates that included responses of antioxidants, reductions in growth
and survival, as well as decreased fecundity. Neurobehavioral aberrations and endocrine impacts were
also found, as well as incomplete evidence of hematological effects. Second-generation effects were also
observed. Evidence published since then provides additional support for the effects of Pb exposure on
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organismal and suborganismal responses including a decrease in survival as well as decreased growth and
fecundity (Appendix 11.2.4.3). Recently published studies on physiological responses to Pb include
decreases in protein and lipid content and increases in malondialdehyde in earthworms.
Acetylcholinesterase activity decreased in response to Pb in snails and honeybees while the effects on
protein, glycogen, other enzymes, and GST responses were variable depending on the site or species
examined. Several new studies quantified changes in feeding and foraging behavior in bees following Pb
exposure. Evidence also suggests that in earthworms, Pb exposure can have lasting effects on growth
even postexposure and slow the time to maturation. Pb exposure delayed onset of the breeding season and
shortened duration in isopods, as well as influenced mate selection in fruit flies. Evidence published after
the 2013 Pb ISA (U.S. EPA. 2013a) includes new organisms as well as modifying factors of organism
response such as habitat, exposure history, and seasonality.
Effects of Pb observed in terrestrial vertebrates include decreased survival and reproduction, as
well as neuro-behavioral effects and effects on development (U.S. EPA. 2006a). The 2013 Pb ISA (U.S.
EPA. 2013a) also provided evidence for Pb effects on hormones, blood, and other physiological and
biochemical variables (U.S. EPA. 2013a). Evidence of effects on growth was limited. Studies published
since the 2013 Pb ISA provide additional evidence for effects on suborganism- and organism-level
endpoints, and specifically on hematological and physiological endpoints (Appendix 11.2.4.4). New
studies have expanded upon the relationship between Pb exposure and ALAD activity by adding more
species of birds, amphibians, and mammals to the evidence base. Additional evidence of oxidative stress
has been gathered, as well as evidence of effects on corticosterone levels and immunity in birds. Recent
literature continues to add to evidence relating to reproductive effects at both the organism and
suborganism levels including effects on lifetime breeding success and some specific secondary sexual
traits. New findings of behavioral effects of Pb included increased aggression in mockingbirds.
Systematic studies of the validity of using results of experiments with addition of soluble salts of
Pb to soil for estimating effects of Pb exposure under field conditions have continued since the 2013 Pb
ISA. As in previous work, recent experiments showed that the form of Pb, pH, CEC, organic carbon, Fe
and Mn oxides, percolation, aging, and soil composition are all strong modifiers of toxicity. Recent
studies demonstrated additional interactions among those variables and showed that their effects are at
times mediated by additional variables, such as salinity. Those studies add support to the conclusion that
data from exposure-response experiments in terrestrial environments conducted using spiking of soils
with soluble salts of Pb are unlikely to generate accurate estimates of effects in contaminated natural
environments (Appendix 11.2.5). However, Ports et al. (2021) suggested that two corrections to the
results of exposure-response experiments conducted with additions of soluble salts of Pb to soil may be
sufficient to derive predicted no-effect concentrations according to the European Registration, Evaluation,
Authorisation and Restriction of Chemicals Regulation (Parliament and Council. 2006).
According to the 2013 Pb ISA (U.S. EPA. 2013a) and previous assessments, effects on terrestrial
communities and ecosystems observed in contaminated natural environments have included decreased
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species diversity, changes in floral and faunal community composition, and decreasing vigor of terrestrial
vegetation. In addition to impacts on soil microbial community function alone, interconnection of effects
of Pb contamination among soil bacterial and fungal community structure, earthworms, and plant growth,
have also been systematically documented. Some new evidence of the effects of Pb at the terrestrial
community and ecosystem levels of biological organization has since been added. Many studies on the
effects of Pb on microbial communities were reported in the 2013 Pb ISA (U.S. EPA. 2013a). Additional
observational studies published since then (Appendix 11.2.4.1). many of which were anthropogenic
environmental gradient studies, have continued linking Pb exposure and effects on microbial community
structure (e.g., abundance, diversity) and function (e.g., enzyme activities, respiration rates). Many found
mixed (negative, positive, or null) relationships between total or bioavailable Pb soil concentration and
the abundance of bacterial and fungal taxa. It remains difficult to disentangle the effects of Pb exposure
on microbial communities from the effects of other soil contaminants using anthropogenic environmental
gradients, as other heavy metals and soil physicochemical properties are significantly correlated with soil
Pb concentration, and many of these factors also influence microbial processes. In addition to microbial
communities, species interactions between tree species and their pests, and between herbaceous plants
and nectar robbers, worms, and lepidopteran consumers were among the new community and ecosystem
endpoints for which effects of Pb were observed (Appendix 11.2.6). Several studies found inverse
relationships between Pb concentration along a pollution gradient and community structure of soil mites,
potworms, nematodes, and kale-associated invertebrates. Although evidence for effects on growth,
reproduction, and survival at the individual organism level and in simple trophic interactions makes the
existence of effects at higher levels of organization likely, direct evidence is relatively sparse and difficult
to quantify. The presence of multiple stressors, especially other metals, continues to introduce
uncertainties in attributing causality to Pb at higher levels of organization.
IS.8.2 Summary of Effects on Freshwater Ecosystems
Freshwater organisms including algae, aquatic plants, microbes, invertebrates, vertebrates, and
other biota with an aquatic lifestage (e.g., amphibians) may be exposed to Pb in aquatic environments.
Inputs of Pb to freshwater ecosystems include air-related sources and non-air sources. Atmospherically
derived Pb can enter aquatic systems through direct wet or dry deposition and erosional transport or
resuspension of Pb from terrestrial systems (Appendix 11.1.2). Receiving water bodies include lakes
(lentic systems) and rivers and streams (lotic systems). Freshwater wetlands, some of which may be
inundated occasionally or constantly, also provide habitat for aquatic biota. Uptake of Pb by aquatic biota
may occur via multiple exposure routes including direct absorption from the water column, ingestion of
contaminated food and water, uptake from sediment porewater, or incidental ingestion of sediment (U.S.
EPA. 2013a. 2006a).
As described in previous EPA reviews of Pb, sensitivity to this metal can vary by several orders
of magnitude across freshwater biota. Pb elicits responses in some freshwater invertebrate species at
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concentrations below 5 to 10 jxg Pb/L (under some water conditions) while other freshwater organisms
appear to be unaffected at concentrations greatly exceeding 1,000 |ig Pb/L. Most of the available studies
of Pb exposures in freshwater biota are laboratory toxicity tests on single species in which an organism is
exposed to a known concentration of Pb, and the effect on a specific endpoint is evaluated. Concentration-
response data from freshwater organisms indicate that there is a gradient of response to increasing Pb
concentration and that some effects in sensitive species are observed at or near the upper limit of Pb
concentrations quantified in U.S. surface waters (Appendix 11. Table 11-1). Freshwater invertebrate taxa
that exhibit sensitivity to Pb include some species of gastropods, amphipods, cladocerans, and rotifers,
although the toxicity of Pb is highly dependent upon water quality variables such as DOC, hardness, and
pH.
Physicochemical properties of surface waters such as hardness, DOC, and pH can be quantified,
are directly related to the toxic effects, and are used in bioavailability models to predict acute and chronic
toxicity (Appendix 11.1.6). As described in prior AQCDs, the 2013 Pb ISA, and this document
(Appendix 11.3.2.1.1). the effect of water hardness is variable; generally, both the acute and chronic
toxicity of Pb increases with decreasing water hardness as Pb becomes more soluble and bioavailable and
less Ca2+ and Mg2+ ions are available to compete with Pb for binding sites. DOC has a protective effect on
Pb toxicity in freshwater invertebrates and fish; newer studies generally continue to support these
observations with some exceptions (Appendix 11.3.2.1.2). Since the 2013 Pb ISA, studies have further
elucidated the relationship between the characteristics of humic substances and Pb bioavailability. As
described in prior AQCDs and the 2013 Pb ISA, uptake and subsequent toxicity of Pb to freshwater biota
can also be affected by pH, either directly or indirectly (Appendix 11.3.2.1.3). Generally, at low pH, there
is more Pb2+ available to bind to the biotic ligand. As pH increases, there is increased formation of Pb
organic (DOC) and inorganic (OH-, CO,2 ) complexes, which decrease Pb bioavailability. Since the 2013
Pb ISA, several studies have further characterized Pb complexation and adsorption under changing pH
conditions, recent studies generally support the previous understanding that higher pH is protective; these
findings vary by the duration of the toxicity bioassays and by taxa, however.
Biological factors that may influence freshwater organism response to Pb exposure include
lifestage, genetics, and nutrition (see Section 7.2.3, 2006 AQCD, Section 6.4.9, 2013 Pb ISA, and
Appendix 11.3.2 of this ISA). These factors are more difficult to link quantitatively to toxicity than water
chemistry variables. Often, species' differences in metabolism, sequestration, and elimination rates
influence the relative sensitivity and vulnerability of exposed organisms. Uptake studies generally show
that aquatic invertebrates and vertebrates accumulate Pb from water in a concentration-dependent manner
and may reach an equilibrium depending on the organism's ability to eliminate or store Pb. Since the
2013 Pb ISA, several studies have examined how the activities of sediment-associated benthic
invertebrates (sometimes called "bioturbators" because of the biological role they play in water column
turbidity) influence Pb transfer to the water column and subsequent bioavailability to other aquatic
organisms (Appendix 11.3.2.1.11). Overall, presence of these bioturbators can enhance Pb availability to
organisms in the water column and potentially cause toxic effects in those organisms.
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For freshwater plants and algae, studies on bioavailability and toxicity of Pb published since the
2013 Pb ISA (Appendix sections 11.3.2.2 and 11.3.4.2) continue to support previous findings that plants
tend to sequester larger amounts of Pb in roots as compared with shoots and that there are species-specific
differences in uptake of Pb, compartmentalization of that sequestered Pb, and plant response (U.S. EPA.
2013a. 2006a'). Most studies on effects of Pb in freshwater algal species reviewed in the 2013 Pb ISA and
the AQCDs were conducted with nominal media exposures and effect concentrations greatly exceeded Pb
reported in surface water. In the 1977 Pb AQCD, differences in sensitivity to Pb among different species
of algae were observed, and concentrations of Pb within the algae varied among genera and within a
genus (U.S. EPA. 1977). The 1986 Pb AQCD (U.S. EPA. 1986b) reported that some algal species (e.g.,
Scenedesmus sp.) were found to exhibit physiological changes when exposed to high Pb concentrations in
situ. Effects of Pb on algae reported in the 2006 Pb AQCD included decreased growth, deformation, and
disintegration of algae cells, and blocking of the pathways that lead to pigment synthesis, thus affecting
photosynthesis. New information since the 2013 Pb ISA includes studies on common reed (Phragmites
australis) showing significant decreases in total biomass, photosynthesis, and rhizome growth as well as
alterations in growth form and propagation strategy under Pb exposure and a study in freshwater algae
based on analytically verified concentration of Pb (Appendix 11.3.4.2 and Table 11-5).
Freshwater aquatic invertebrates are generally more sensitive to Pb exposure than other taxa.
Controlled studies at concentrations near the upper range of representative concentrations of Pb available
from surveys of U.S. surface waters (median: 0.50 |ig Pb/L; range 0.04 to 30 |ig Pb/L, 95th percentile
1.1 Mg Pb/L) (U.S. EPA. 2006a). reviewed in the 1986 AQCD, the 2006 Pb AQCD, the 2013 Pb ISA, and
this document provide evidence for the effects of Pb on reproduction, growth and survival in sensitive
freshwater invertebrates, notably gastropods, cladocerans, rotifers, and amphipods. In studies reviewed in
the 2013 Pb ISA the freshwater snail (Lymnaea stagnalis) was identified as one of the most sensitive
species to Pb exposure, and more recent studies support these observations. Recent evidence further
characterizes Pb effects on growth and reproduction at concentrations below 10 fxg Pb/L in sensitive
species of freshwater gastropods, cladocerans, rotifers, and amphipods, especially under chronic exposure
scenarios (Appendix 11.3.5 and Table 11-5).
For freshwater vertebrates, early studies on waterfowl investigated exposure to Pb via accidental
poisoning or ingestion of Pb shot (U.S. EPA. 1977). Studies on aquatic vertebrates reviewed in the 1986
Pb AQCD were limited to hematological, neurological, and developmental responses in fish (U.S. EPA.
1986b). In the 2006 Pb AQCD, effects on freshwater vertebrates included consideration of the role of
water quality parameters on toxicity to fish, as well as limited information on the sensitivity of turtles and
aquatic stages of frogs to Pb (U.S. EPA. 2006a). Evidence in the 2013 Pb ISA supported the 2006 Pb
AQCD conclusions that the gill is a major site of Pb uptake in fish and that there are species differences in
the rate of Pb accumulation and distribution of Pb within the organism. Several studies in fish in which Pb
concentration was analytically verified provide additional evidence for reproductive and developmental
effects for freshwater vertebrates (Appendix 11.3.4.4.1.2). New studies continue to show distinct patterns
of Pb tissue distribution in water versus dietary exposures (Appendix 11.3.2.4).
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Reductions in species abundance, richness, and diversity associated with the presence of Pb in
freshwater habitats are reported in the literature, usually in heavily contaminated sites where Pb (and
other metal) concentrations are higher than typically observed environmental concentrations. Most
evidence is from sediment-associated macroinvertebrate communities. New studies generally confirm
findings in the 2006 Pb AQCD (U.S. EPA. 2006a) and 2013 Pb ISA (U.S. EPA. 2013a) that transfer of Pb
through the food web is generally low (Appendix 11.3.2.5). Observational and experimental studies
published since the 2013 Pb ISA continue to show negative associations between sediment and/or
porewater Pb concentration and macroinvertebrate communities (Appendix 11.3.6). The evidence is
expanded somewhat with studies reporting associations with Pb and periphyton abundance.
Approaches for characterizing the toxicity of Pb to freshwater biota since the 2013 Pb ISA
include a proposal for updating aquatic life water quality criteria (Appendix 11.1.7.3). The existing EPA
ambient water quality criteria (AWQC) for Pb for the protection of aquatic life are a criterion maximum
concentration of 65 |ig Pb/L (for acute exposure) and criterion continuous concentration of 2.5 |ig Pb/L
(for chronic exposure) at a hardness of 100 mg/L (U.S. EPA. 1985). Using the biotic ligand model (BLM)
(Appendix 11.1.6) (Deforest et al.. 2017) proposed acute BLM-based freshwater criteria ranging from
18.9 to 998 |ig Pb/L and chronic BLM-based Pb freshwater criteria ranging from 0.37 to 41 |ig Pb/L. The
lowest criteria were for water with low DOC (1.2 mg/L), pH (6.7) and hardness (4.3 mg/L as CaC03),
and the highest criteria were for water with high DOC (9.8 mg/L), pH (8.2) and hardness (288 mg/L as
CaC03), which encompasses varying water quality conditions of North American surface waters. The
updated data sets in Deforest et al. (2017) incorporated toxicity information for L. stagnalis, the
cladoceran, Ceriodaphnia dubia, the amphipod, Hyalella azteca, and the rotifer, Philodina rapida;
freshwater invertebrates that are relatively sensitive to Pb exposure. Compared to the number of genera
used to develop the existing U.S. EPA AWQC for Pb (1984) for the protection of aquatic life, the number
of genera with acute toxicity data for Pb increased from 10 to 32, and for chronic toxicity, from 4 to 13,
which enabled the proposed chronic criteria to be based on bioassay data rather than an acute-to-chronic
ratio. Additional advances in freshwater research since the 2013 Pb ISA have included development and
evaluation of bioavailability models to predict the toxicity of acute and chronic metal mixtures, of which
Pb is one component (Appendix 11.3.2.1.5). Considerable research beyond the scope of this document
(Appendix 11.1.1) has focused on metal mixture assessment, including how uptake and bioaccumulation
are affected in freshwater biota in the presence of multiple metals.
IS.8.3 Summary of Effects on Saltwater Ecosystems
Saltwater ecosystems encompass a range of salinities from just above that of freshwater (<1 ppt)
to that of seawater (generally described as 35 ppt). These ecosystems may receive Pb from multiple
sources such as contributions from direct atmospheric deposition and via inputs from terrestrial systems
including runoff and riverine transport (Appendix 1). Habitats associated with coastal areas include salt
marshes, estuaries, shallow open waters, sandy beaches, mud and sand flats, rocky shores, oyster beds,
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coral reefs, mangrove forests, river deltas, tidal pools, and seagrass beds (U.S. EPA. 2016b). Estuaries,
where freshwater inflows gradually mix with salt water, are dynamic, heterogeneous environments
characterized by physicochemical gradients of salinity. The Pb2+ ion, which is the most bioavailable form
of Pb, is not common in seawater; rather, Pb primarily exists as a carbonate complex and to a lesser extent
as a chloride complex (Appendix 11.4. IV
Factors affecting bioavailability of Pb to saltwater organisms (Appendix 11.4.2) are many of the
same factors affecting bioavailability to freshwater biota, notably OM and pH. Since the 2013 Pb ISA,
studies have further explored the effects of varying dissolved OM composition and changing pH on Pb
uptake and bioaccumulation in saltwater biota. In contrast to freshwater, OM in saltwater systems does
not necessarily demonstrate a protective effect and in some cases exacerbated toxicity of Pb to
invertebrates (Appendix 11.4.2.1). Other factors, such as salinity, play a greater role in Pb fate, transport,
and bioavailability in marine and estuarine systems, especially in dynamic estuarine environments
characterized by physicochemical gradients of salinity (Appendix 11.4.2.3). Other factors that affect
uptake and toxicity of Pb, such as biological adaptations by organisms, and the role of seasonality,
metabolism, diet, and lifestage, are more difficult to link quantitatively to toxicity (Appendix 11.4.2).
For saltwater plants, there is relatively little information on biouptake and toxicity at
concentrations of Pb typically encountered in the environment. Limited data on marine algae and
saltwater plants reviewed in the 1986 Pb AQCD, 2006 Pb AQCD, the 2013 Pb ISA and a few new studies
(Appendix 11. sections 11.4.2.10 and 11.4.4.2) provide evidence for species differences in Pb uptake,
bioaccumulation rates and toxicity. In the 2013 Pb ISA, evidence was inadequate to establish causality
relationships for Pb exposure and any endpoints relevant to effects of Pb in saltwater plants and algae
(i.e., growth, survival, physiological stress) and this continues to be the case. As in freshwater plants, Pb
is concentrated in root tissue, but sensitivity is species specific. Understanding of Pb effects in saltwater
plants has not changed appreciably since the 2013 Pb ISA; observed effects occur at much higher Pb
exposures than are found in the natural environment.
The majority of available studies of Pb effects on saltwater organisms are for invertebrate species.
Uptake and subsequent bioaccumulation of Pb in marine invertebrates varies greatly between species and
across taxa (U.S. EPA. 2006a) (U.S. EPA. 2013a) and Appendix 11.4.2.11. In the 2006 Pb AQCD, a few
effects were noted in saltwater invertebrates including differences in sensitivity to Pb in copepods,
increasing toxicity of Pb with decreasing salinity in mysids, and effects on embryogenesis in bivalves
(U.S. EPA. 2006a'). In the 2013 Pb ISA, several studies reported concentrations associated with
reproductive effects in saltwater invertebrates including in a marine amphipod, a polychaete, and clams
(U.S. EPA. 2013a). Several field monitoring studies with marine bivalves in the 2013 Pb ISA used ALAD
as a biomarker for Pb exposure and correlated ALAD inhibition to increased Pb tissue content. Field and
laboratory studies provide evidence for antioxidant response to Pb exposure; however, most effects are
observed at concentrations of Pb that are higher than concentrations detected in marine environments. At
that time available evidence was sufficient to be suggestive of a causal relationship between Pb exposure
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and the endpoints of physiological stress, hematological effects, and reproduction and development in
saltwater invertebrates, for all other effects evidence was inadequate to assess causality (Appendix 11.
Table 11-6). New information for saltwater invertebrates since the 2013 Pb ISA includes additional
studies that report physiological perturbations associated with Pb exposure, including a few observations
in previously untested taxa. Recent exposure-response data for saltwater invertebrates (Appendix 11.4.5
and Table 11-7) include reproductive and developmental bioassay results based on analytically verified
concentration for mollusks and echinoderms, with effects reported at lower concentrations than studies
included in the 2013 Pb ISA. Specifically, several embryo development bioassays for bivalves (48-hr
exposure) and sea urchin (72-hr exposure) found effects at concentrations <50 |ig Pb/L with no effects at
concentrations <10 (ig Pb/L for a few species (Markich. 2021; Romero-Murillo et al.. 2018; Nadella etal..
2013V
For saltwater vertebrates, available information is largely for fish, with a few field-based studies
in birds and turtles (Appendix 11.4.4.4). Studies published since the 2013 Pb ISA provide chronic toxicity
data for several fish species, information that was previously lacking for evaluating longer-term effects of
Pb on these organisms. Calculated chronic no observed effect concentrations (NOECs) for three saltwater
fish species are <15 |ig Pb/L with effects reported in the range of 15 to 30 |ig Pb/L for survival (Appendix
11. Table 11-7). These studies in fish were conducted with juvenile lifestages.
For community- and ecosystem-level effects evidence from field studies in saltwater
environments in the 2006 Pb AQCD and the 2013 Pb ISA, studies found either negative or null
relationships between Pb and species abundance, richness, and diversity in saltwater macroinvertebrates;
Pb is not the only contaminant in most observational studies, however, thereby making it difficult to
separate the effects of Pb alone from other metal pollutants. Several experimental and observational
studies since the 2013 Pb ISA reported negative relationships between sediment or saltwater Pb
concentration and microbial abundance and diversity, while other studies found no relationship
(Appendix 11.4.4.1). Additionally, new mesocosm and observational studies since the 2013 Pb ISA find
reductions in foraminiferal and/or meiofaunal community richness, diversity, and/or abundance associated
with higher concentrations of Pb in sediment and water, while others find positive or null correlations
(Appendix 11.4.6). New observational studies in saltwater systems generally confirm findings in the 2006
Pb AQCD (U.S. EPA. 2006a) and 2013 Pb ISA (U.S. EPA. 2013a) of little transfer of Pb through the
food web, with Pb concentration decreasing with increasing trophic level (Appendix 11.4.2.13).
Since the 2013 Pb ISA, there are new toxicity data for saltwater biota that address some of the
uncertainties at that time. There are new studies reporting effects of Pb on survival in saltwater
vertebrates (Appendix 11.4.5) and additional evidence for reproductive and developmental effects in
saltwater invertebrates (Appendix 11.4.5). Furthermore, in many of the studies supporting these effects,
the concentration of Pb in the exposure media is analytically verified. This information reduces
uncertainties identified in the previous review concerning a lack of exposure-response data for saltwater
organisms, especially for chronic toxicity, and enables calculations of effect levels for saltwater biota
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based on experimental data. An increase in toxicological data for saltwater organisms over the last several
years and availability of studies that analytically verify Pb exposure concentration has led to a study
proposing updates to the acute and chronic AWQC for Pb (Church ct al.. 2017). For the acute criterion,
the newly proposed value of 100 |ig Pb/L is less than the current acute criterion of 210 |ig Pb/L due to
more recent acute toxicity data from relatively sensitive early lifestages of echinodermata and mollusca.
Finally, there is additional evidence for Pb association with changes in benthic invertebrate, microbial,
and foraminiferal communities in coastal environments (Appendix 11.4.4.1 and 11.4.6).
IS.8.4 Summary of Welfare Effects Evidence
In the 2013 Pb ISA (U.S. EPA. 2013a). a series of causality determinations were made for effects
of Pb on plants, invertebrates, and vertebrates in terrestrial, freshwater, and saltwater ecosystems (U.S.
EPA. 2013a). Evidence published since that time supports or slightly expands the evidence for endpoints
that were already established as causal in the 2013 Pb ISA (Table IS-14). A few studies report effects at
lower effect concentration than in the 2013 Pb ISA. The new evidence is not sufficient to change any of
the previous causality determinations for terrestrial and freshwater organisms and ecosystems. New
evidence for terrestrial (Appendix 11-2) and freshwater (Appendix 11-3) biota continue to support
the existing causality determinations from the 2013 Pb ISA summarized in Table IS-14.
At the time of the 2013 Pb ISA there were fewer studies on effects of Pb in saltwater biota
compared with terrestrial and freshwater organisms and evidence was inadequate to infer causality
relationships for many endpoints. Specifically, there was a lack of chronic toxicity data, and relatively
few studies reported analytically verified Pb concentration in the experimental media. Several newer
studies quantify Pb in water and/or sediment and report effects on endpoints at lower concentration than
previously observed for saltwater biota, some of these studies are chronic exposure bioassays. Since the
2013 Pb ISA, the additional research for saltwater organisms supports a change in causality
determinations for three endpoints (Table IS-14). Specifically, the evidence is sufficient to conclude
there is likely to be a causal relationship between Pb exposure and reproductive and developmental
effects in saltwater invertebrates. In addition, the evidence is suggestive of, but not sufficient to infer,
a causal relationship between Pb exposure and saltwater vertebrate survival, and, the evidence is
suggestive of, but not sufficient to infer, a causal relationship between Pb exposure and saltwater
community and ecosystem effects. Previous causality determinations for the remaining saltwater
endpoints shown in Table IS-14 remain unchanged from the 2013 Pb ISA.
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Table IS-14 Summary of causality determinations for welfare effects of Pb.
Level
Effect
Terrestrial3
Freshwater3
Saltwater3
Community-
and
Ecosystem
Community and Ecosystem Effects
Likely Causal
Likely Causal
TSuggestive
Reproductive and Developmental Effects - Plants
Inadequate
Inadequate
Inadequate
(0
+-»
Reproductive and Developmental Effects -
Invertebrates
Causal
Causal
TLikely
Causal
0
Q.
-o
C
LU
o3
>
0)
-1
1
c
o
0)
C
Reproductive and Developmental Effects -
Vertebrates
Causal
Causal
Inadequate
O
Q.
0)
Growth - Plants
Causal
Likely Causal
Inadequate
Od
o3
Growth - Invertebrates
Likely Causal
Causal
Inadequate
J2
3
0
_i
1
E
w
"c
(5
Growth - Vertebrates
Inadequate
Inadequate
Inadequate
Q.
0
Q_
Survival - Plants
Inadequate
Inadequate
Inadequate
S5
O
Survival - Invertebrates
Causal
Causal
Inadequate
Survival - Vertebrates
Likely Causal
Causal
TSuggestive
Neurobehavioral Effects - Invertebrates
Likely Causal
Likely Causal
Inadequate
Neurobehavioral Effects - Vertebrates
Likely Causal
Likely Causal
Inadequate
Hematological Effects - Invertebrates
Inadequate
Likely causal
Suggestive
E «
.2 8>
Hematological Effects - Vertebrates
Causal
Causal
Inadequate
c c
as o
u> a.
« 10
Physiological Stress - Plants
Causal
Likely Causal
Inadequate
o a,
w
Physiological Stress - Invertebrates
Likely Causal
Likely Causal
Suggestive
Physiological Stress - Vertebrates
Likely Causal
Likely Causal
Inadequate
aBased on the weight of evidence for causal determination in Table II of the Preamble (U.S. EPA. 2015).
Directional arrows denote a change in causality determination from 2013 Pb ISA.
IS.8.5 Summary of Causality Evidence for Ecological Effects of Pb
1 Evidence used in determining causality for effects of Pb is presented below, with the order of
2 effect categories reflecting an increasing scale of biological organization. In the presentation of the
3 causality determinations below, rather than grouping determinations by ecosystem type, the sections are
4 organized by endpoint (physiological stress, hematological effects, neurobehavioral effects, survival,
5 growth, reproduction) and then community and ecosystem scale of biological organization.
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IS.8.5.1 Physiological Stress
Physiological stress endpoints considered in the 2013 Pb ISA and previous AQCDs included
changes in markers of enzyme function and oxidative stress. Although stress responses are correlated with
Pb exposure, they are nonspecific and may be altered with exposure to any number of environmental
stressors. There are no changes in this ISA to the causality conclusions from the 2013 ISA for
physiological stress in terrestrial, freshwater, or saltwater biota (Table IS-15) At the time of the 2013 Pb
ISA, evidence was sufficient to conclude that there is a causal relationship between Pb exposures and
physiological stress in terrestrial plants, and new evidence has reinforced this conclusion. Evidence is
sufficient to conclude that a causal relationship is likely to exist between Pb exposures and physiological
stress in terrestrial invertebrates and vertebrates as well as freshwater plants, invertebrates, and
vertebrates. Further evidence in saltwater invertebrates is suggestive of a causal relationship between Pb
exposures and physiological stress. Evidence is inadequate to conclude that there is a causal relationship
between Pb exposure and physiological stress responses in saltwater plants and vertebrates. Recent
literature supports the previous evidence for Pb effects on enzymes and antioxidant activity in freshwater
invertebrates (Appendix 11.3.4.3.1). New studies on physiological stress endpoints in freshwater
invertebrates include changes in the activities of antioxidant defense enzymes such as superoxide
dismutase, catalase, and glutathione peroxidase with aqueous exposure to Pb. A large body of evidence
supports sublethal biomarker perturbations with Pb exposure in freshwater vertebrates; however, few
studies were identified for this ISA that reported physiological response at more environmentally relevant
concentrations of Pb (<10 (ig Pb/L; Appendix 11.1.1) or concurrently assessed response at organism-level
endpoints (i.e., from the cellular and subcellular level to effects on growth, reproduction, or survival).
Table IS-15 Summary of evidence for effects of Pb on physiological stress
endpoints in terrestrial and aquatic biota.
Evidence from the 2013 Pb ISA Evidence from the 2023 Pb ISA
Terrestrial Plant Physiological Stress: Causal
Several studies from the 2006 Pb AQCD report lipid
peroxidation in plants; however, exposures in these studies
were higher than would be found generally in the
environment (U.S. EPA. 2006c). Building on the body of
evidence presented in the 2006 Pb AQCD, studies in the
2013 Pb ISA provide evidence of upregulation of antioxidant
enzymes and increased lipid peroxidation associated with
Pb exposure in many species of plants. Increased
antioxidant enzymes with Pb exposure occur in some
terrestrial plant species at concentrations approaching the
average Pb concentrations in U.S. soils.
Recent studies continue to confirm increased
antioxidant activity in plants in response to Pb stress
as well as genotoxic effects of Pb exposure
(Appendix 11.2.4.2)
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Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
Freshwater Plant Physiological Stress: Likely to be Causal
Increases of antioxidant enzymes with Pb exposure occur in
algae, mosses, and floating and rooted aquatic
macrophytes. Most available evidence for antioxidant
responses in aquatic plants are from laboratory studies
lasting from 2 to 7 d and at concentrations higher than
typically found in the environment. However, data from
transplantation experiments from nonpolluted to polluted
sites indicate that elevated enzyme activities are associated
with Pb levels measured in sediments.
Physiological stress response in freshwater
vegetation is typically observed at much higher Pb
exposures than are found in the natural environment.
Studies reporting antioxidant processes upregulated
in algae support previous findings of a likely to be
causal relationship (Appendix 11.3.4.2).
Saltwater Plant Physiological Stress: Inadequate
Insufficient evidence to assess causality
Insufficient evidence to assess causality
Terrestrial Invertebrate Physiological Stress: Likely to be Causal
Changes in enzyme activities and oxidative stress markers
were reported in terrestrial invertebrates, including
earthworms, snails, and nematodes.
Additional studies in a few terrestrial invertebrate
species, notably earthworms, report altered enzyme
activity and perturbations in other biomarkers of
physiological stress associated with Pb exposure
(Appendix 11.2.4.3.1).
Freshwater Invertebrate Physiological Stress: Likely to be Causal
Stress responses associated with exposure to Pb in aquatic
invertebrates reported in previous AQCDs include elevated
heat shock proteins, osmotic stress, lowered metabolism
and decreased glycogen levels. Although these stress
responses are correlated with Pb exposure, they are
nonspecific and may be altered with exposure to any
number of environmental stressors. Evidence in the 2013 Pb
ISA included upregulation antioxidant enzymes, production
of reactive oxygen species, and increased lipid peroxidation
associated with Pb exposure.
Recent literature (Appendix 11.3.4.3.1) supports
previous findings of Pb effects on enzymes and
antioxidant activity in freshwater invertebrates with
several studies reporting effects at <20 |jg Pb/L.
Physiological stress response was also observed in
several invertebrates in chronic sediment bioassays
conducted within the range of sediment Pb
concentration measured in the environment.
Saltwater Invertebrate Physiological Stress: Suggestive
Changes in antioxidant activity with Pb exposure are
reported in some saltwater invertebrates. The 2013 Pb ISA
included some evidence of invertebrate antioxidant
responses in bivalves and crustaceans at Pb concentrations
that are detected in the marine environment. Additional
evidence from environmental monitoring studies that
compared biomarker responses between reference and
contaminated sites indicated a correlation between the
amount of Pb with changes in antioxidant enzyme activity.
Studies published since the 2013 Pb ISA in saltwater
invertebrates, primarily mollusks, continue to show
perturbations to biomarkers of oxidative stress with
Pb exposure, albeit at concentrations of Pb higher
than typically countered in the environment.
(Appendix 11.4.4.3.1)
Terrestrial Vertebrate Physiological Stress: Likely to be Causal
Markers of oxidative damage are observed in terrestrial
mammals in response to Pb exposure.
The evidence since the 2013 Pb ISA
(Appendix 11.2.4.4.1) continues to support a likely to
be causal relationship between Pb exposure and
response in biomarkers of physiological stress. Most
new studies are in birds.
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Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
Freshwater Vertebrate Physiological Stress: Likely to be Causal
Markers of oxidative damage are observed in fish and
amphibians in laboratory studies. Across freshwater
vertebrates, there are differences in the induction of
antioxidant enzymes with Pb exposure that appear to be
species-dependent.
Sublethal biomarker perturbations are associated with
Pb exposure in freshwater vertebrates
(Appendix 11.3.4.4.1.1). Few studies were identified
that reported physiological stress response at <10 |jg
Pb/L or concurrently assessed response at organism-
level endpoints.
Saltwater Vertebrate Physiological Stress: Inadequate
Insufficient evidence to assess causality Insufficient evidence to assess causality
AQCD = Air Quality Criteria Document; ISA = Integrated Science Assessment; Pb = lead.
IS.8.5.2 Hematological Effects
As reported in the 2013 Pb ISA, inhibition of ALAD enzyme activity, an important rate-limiting
enzyme needed for heme production, is a recognized biomarker of Pb exposure (U.S. EPA. 2013a). The
causality determinations for Pb effects on hematological endpoints in terrestrial, freshwater and saltwater
organisms are unchanged from the 2013 Pb ISA (Table IS-16). Previous studies have indicated
considerable species differences in ALAD activity in response to Pb. At the time of the 2013 Pb ISA
evidence was sufficient to conclude that there is a causal relationship between Pb exposures and
hematological effects in terrestrial vertebrates and inadequate to assess causality between Pb exposures
and hematological effects in terrestrial invertebrates. Since the 2013 Pb ISA, additional species of birds,
amphibians and mammals have been shown to experience decreased ALAD activity following exposure
to Pb further supporting the existing causal relationship. For freshwater vertebrates, the evidence
evaluated in the 2013 Pb ISA and Pb AQCDs was sufficient to conclude that there is a causal relationship
between Pb exposures and hematological effects. Hematological effects of Pb on fish reported in the 2013
Pb ISA and AQCDs include a decrease in RBCs and inhibition of ALAD with elevated Pb exposure
under various test conditions. Inhibition of ALAD is also reported in environmental assessments of metal-
impacted habitats. In the 2013 Pb ISA it was determined that a causal relationship is likely to exist
between Pb exposures and hematological effects in freshwater invertebrates. Limited evidence from
saltwater invertebrates was suggestive of a causal relationship between Pb exposures and hematological
effects while evidence for saltwater vertebrates was insufficient to assess causality. Evidence for
hematological effects in saltwater invertebrates in previous AQCDs and the 2013 Pb ISA were primarily
from field monitoring studies of marine bivalves that used ALAD as a biomarker for Pb exposure and
correlated ALAD inhibition to increased Pb tissue content. Few new studies were identified since the
2013 Pb ISA that quantified ALAD response in terrestrial invertebrates or aquatic invertebrates or
vertebrates; hence causality relationships for hematological effects of Pb are unchanged.
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Table IS-16 Summary of evidence for effects of Pb on hematological endpoints in
terrestrial and aquatic biota.
Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
Terrestrial Invertebrate Hematological Effects: Inadequate
Insufficient evidence to assess causality
Insufficient evidence to assess causality
Freshwater Invertebrate Hematological Effects: Likely to be Causal
In metal-impacted habitats, ALAD is a recognized biomarker
of Pb exposure. Laboratory studies with freshwater
invertebrates have indicated considerable species
differences in ALAD activity in response to Pb. Field studies
in freshwater bivalves report a correlation between Pb and
ALAD activity.
No recent studies quantifying ALAD activity in
freshwater invertebrates at environmentally relevant
concentration of Pb were identified for inclusion in this
ISA.
Saltwater Invertebrate Hematological Effects: Suggestive
Field studies in saltwater bivalves report a correlation
between Pb and ALAD activity.
Few additional studies have reported inhibition of
ALAD activity in Pb-exposed saltwater invertebrates
and the concentrations at which enzyme activity is
affected appear to be much higher than Pb typically
encountered in seawater (Appendix 11.4.4.3.1).
Terrestrial Vertebrate Hematological Effects: Causal
In the 1986 Pb AQCD, decreases in RBC ALAD activity
were documented in birds and mammals near a smelter
(U.S. EPA. 1986b). Additional evidence for effects of Pb
blood parameters and their applicability as biomarkers of Pb
exposure in terrestrial birds and mammals were presented in
the 2005 Ecological Soil Screening Levels for Lead (U.S.
EPA. 2005). the 2006 Pb AQCD (U.S. EPA. 2006c). and the
2013 ISA. Field studies include evidence for elevated BLLs
correlated with decreased ALAD activity in songbirds and
owls living in historical mining areas.
New evidence (Appendix 11.2.4.4.1) continues to
support a causal relationship between Pb exposure
and hematological effects in terrestrial vertebrates
with most new evidence in birds. ALAD inhibition
correlated with increased blood Pb concentrations in
waterfowl, passerines, and scavengers as well as
livestock and toads.
Freshwater Vertebrate Hematological Effects: Causal
In the 1986 Pb AQCD, hematological effects of Pb exposure
in fish included decrease in RBCs and inhibition of ALAD
(U.S. EPA. 1986b). In fish, Pb effects on blood chemistry
have been documented with Pb concentrations ranging from
100 to 10,000 |jg Pb/L in studies cited in the 2006 AQCD
(U.S. EPA. 2006c).
Few laboratory studies were identified since the 2013
Pb ISA that quantify ALAD response in freshwater
fish in laboratory exposure at concentrations
considered for this ISA. There is limited information
from field studies (Appendix 11.3.4.4.1).
Saltwater Vertebrate Hematological Effects: Inadequate
Insufficient evidence to assess causality
Insufficient evidence to assess causality
AQCD = Air Quality Criteria Document; ALAD = 6-aminolevulinic acid dehydratase; BLL = blood lead level; ISA = Integrated
Science Assessment; RBC = red blood cell; Pb = lead.
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IS.8.5.3 Neurobehavioral Effects
Organism-level endpoints include effects on behavior linked to Pb neurotoxicity. The causality
determinations for neurobehavioral effects of Pb in terrestrial, freshwater and saltwater organisms remain
unchanged from the 2013 Pb ISA. Evidence for causality determinations for neurobehavioral endpoints
are summarized in Table IS-17. The 2013 Pb ISA concluded that the neurobehavioral effects of effects Pb
exposure on terrestrial, freshwater and saltwater invertebrates are likely causal. In terrestrial invertebrates,
the 2013 Pb ISA (U.S. EPA. 2013a') reported evidence of neurobehavioral aberrations such as impaired
locomotion in nematode Caenorhabditis elegans that persisted over several generations while limited
studies in freshwater invertebrates provided evidence of decreased ability to escape or avoid predation in
worms and snails. Additional evidence since the 2013 Pb ISA in support of the likely to be causal
relationship between Pb exposure and neurobehavioral effects in terrestrial invertebrates include studies
quantifying alterations in foraging and feeding behavior in bees (Appendix 11.2.4.3.2). A few new studies
including effects on locomotion in amphipods and bivalves, and alternation of neurotransmitter activity in
bivalves and gastropods further support the 2013 finding of a likely to be causal relationship between Pb
exposure and neurobehavioral endpoints in freshwater invertebrates (Appendix 11.3.4.3.2V Evidence is
inadequate to assess causality between Pb exposure and neurobehavioral endpoints in saltwater
invertebrates.
In the 2013 Pb ISA, the evidence was sufficient to conclude that the relationship between Pb
exposure and neurobehavioral effects in terrestrial and freshwater vertebrates is likely to be causal. Diet
and injection studies in gull chicks and in lizards, designed to obtain Pb blood levels comparable to
organisms exposed in the wild, resulted in a variety of abnormal behaviors. For aquatic vertebrates,
evidence in prior AQCDs included behavioral impairment of a conditioned response in goldfish (U.S.
EPA. 1977) and several studies in which Pb was shown to affect predator-prey interactions in fathead
minnows (U.S. EPA. 2013a. 2006a'). Since the 2013 Pb ISA, there are additional studies on
neurobehavioral response particularly in zebrafish (Appendix 11.3.4.4.1.2). which are used as an animal
model for human health outcomes associated with Pb exposure such as neurogenerative disease and
developmental and neurobehavioral alterations (Li et al.. 2019). Endpoints assessed in zebrafish assays,
such as decreased locomotor activity and altered social interactions used as surrogates for autistic
behaviors in humans, can affect organism fitness in natural environments. Furthermore, many of these
studies link changes in gene expression, neurotransmitter levels or other molecular and cellular responses
to the observed behavioral outcomes. These new studies continue to support the likely to be causal
relationship between Pb exposure and effects on neurobehavior in aquatic vertebrates.
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Table IS-17 Summary of evidence for effects of Pb on neurobehavioral endpoints
in terrestrial and aquatic biota.
Evidence from the 2013 Pb ISA Evidence from the 2023 Pb ISA
Terrestrial Invertebrate Neurobehavioral Effects: Likely to be Causal
A few studies reported altered feeding rates in snails while
others reported no effects. In limited studies available on
nematodes, there is evidence that Pb may affect the ability
to escape or avoid predation. Additional evidence of
changes in the morphology of GABA motor neurons was
also found in nematodes (C. elegans).
Nematode studies reported food preference, food
finding ability, and feeding activity were altered by Pb
exposure. New evidence in additional taxa include
findings that Pb negatively affects foraging and
feeding behavior as well as cognitive flexibility in bees
(Appendix 11.2.4.3.2).
Freshwater Invertebrate Neurobehavioral Effects: Likely to be Causal
In the 2006 Pb AQCD, several studies were reviewed in
which Pb was shown to affect predator-prey interactions. In
limited studies available on worms and snails, there is
evidence that Pb may affect the ability to escape or avoid
predation.
A few studies in amphipods and bivalves further
support the finding of a likely to be causal relationship
between Pb exposure and neurobehavioral endpoints
(Appendix 11.3.4.3.2). These endpoints include
effects on locomotion in amphipods and alteration of
neurotransmitter activity and foot movement in a
freshwater bivalve.
Saltwater Invertebrate Neurobehavioral Effects: Inadequate
Insufficient evidence to assess causality Insufficient evidence to assess causality
Terrestrial Vertebrate Neurobehavioral Effects: Likely to be Causal
Limited behavioral studies in gull chicks experimentally
exposed to Pb reported abnormal behaviors such as
decreased walking, learning deficits, erratic behavioral
thermoregulation, and food begging that could make them
more vulnerable in the wild (Burger and Gochfeld. 2005).
Lizards exposed to Pb through diet exhibited abnormal
coloration and posturing behaviors. These results also
cohere with findings in laboratory animals that show that Pb
induces changes in learning and memory.
A few additional studies in birds since the 2013 Pb
ISA reported a relationship between Pb exposure and
neurobehavior or reported no effects
(Appendix 11.2.4.4.2). In one study in mockingbirds,
higher BLLs were correlated with increased levels of
aggressive behavior (McClelland etal.. 2019).
Freshwater Vertebrate Neurobehavioral Effects: Likely to be Causal
In the 2006 AQCD, exposure to Pb was shown to affect
brain receptors in fish and may alter avoidance behaviors
and predator-prey interactions. Studies cited in the 2013 Pb
ISA included those that provided additional evidence for Pb
effects on behaviors that may impact predator avoidance
(swimming) and prey capture ability.
Several studies with larval zebrafish (Danio rerio)
bolster the finding of a likely to be causal relationship
from the 2013 Pb ISA. Some effects on behavioral
endpoints such as locomotion and social interactions
were reported at <20 |jg Pb/L; for a subset of these
studies, Pb was analytically verified
(Appendix 11.3.4.4.1.2).
Saltwater Vertebrate Neurobehavioral Effects: Inadequate
Insufficient evidence to assess causality Insufficient evidence to assess causality
AQCD = Air Quality Criteria Document; BLL = blood lead level; GABA = gamma aminobutyric acid; Pb = lead.
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IS.8.5.4 Survival
Survival may have a direct impact on population size and can lead to effects at the community
and ecosystem level of biological organization. Survival is commonly assessed in laboratory bioassays
and reported as a toxicological dose descriptor (e.g., 50% lethal concentration [LC50], LC20) to facilitate
comparison of effects across species and test conditions. In the 2013 Pb ISA the evidence was inadequate
to conclude that there is a causal relationship between Pb exposure and survival in terrestrial, freshwater,
or saltwater plants and this continues to be the case (Table IS-18). For invertebrates, the causality
determinations for survival remain unchanged from the 2013 Pb ISA (Table IS-18). At that time, the
evidence was sufficient to conclude that there is a causal relationship between Pb exposures and survival
in terrestrial and freshwater invertebrates and inadequate for saltwater invertebrates.
Terrestrial invertebrates typically tolerate high concentrations of Pb relative to concentrations
found in most uncontaminated soils. For freshwater invertebrates, key studies in amphipods reported in
the 2006 Pb AQCD and 2013 Pb ISA indicate a response to Pb at <10 |ig Pb/L under some water
conditions. Several studies since the 2013 Pb ISA provide further characterization for known effects on
survival in a few sensitive species of freshwater invertebrates, notably gastropods and amphipods, at
<15 (ig Pb/L in chronic exposures in which the concentration of Pb was analytically verified
(Appendix 11.3.5).
Evidence is sufficient to conclude that a causal relationship is likely to exist between Pb exposure
and survival in terrestrial vertebrates, with most of the direct evidence coming from studies of waterfowl
and birds of prey conducted throughout the last 50 years. For freshwater vertebrates, studies in fish
provided the basis for causal relationship for survival in the 2013 Pb ISA. Additional fish bioassays
conducted in varying water chemistry conditions report effects on survival at Pb concentrations similar to
those reported in the 2013 Pb ISA further supporting the causal relationship between Pb exposure and
survival in freshwater vertebrates (Table IS-18). Several additional studies have considered the effects of
Pb on native fish species including white sturgeon (Acipenser transmontanus), and westslope cutthroat
trout (Oncorhynchus clarkii lewisi) (Appendix 11.3.5). Other recent studies on freshwater vertebrates
have further characterized the response to Pb under varying water conditions.
In the 2013 Pb ISA and previous assessments, the evidence for Pb effects on survival of saltwater
vertebrates was inadequate. New evidence (Appendix 11.4.5) is limited to laboratory-based bioassays in a
few fish species, toxicity data for other saltwater vertebrates remains lacking. Several recent chronic
bioassays conducted with early lifestages of three saltwater fish species report NOEC in the range of 11-
14 |ig Pb/L (Appendix 11. Table 11-7). Furthermore, Pb in these bioassays was analytically verified. In
the larval fish Topsmelt (Atherinops affinis), an LC50 = 15.1 |ig Pb/L; NOEC <13.8 |ig Pb/L was observed
at a salinity of 14 ppt (Reynolds et aL 2018). Calculated chronic values for additional saltwater fish
species that are consistent with the range reported above include grey mullet (Mugil cephalus) fingerling
survival and Tiger perch (Terapon jarbua) fingerling survival (Hariharan et al.. 2016). Given these new
chronic studies in saltwater fish, the causality determination for this endpoint has changed since the 2013
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Pb ISA and the evidence is suggestive of, but not sufficient to infer, a causal relationship between Pb
exposure and saltwater vertebrate survival (Table IS-18).
Table IS-18 Summary of evidence for effects of Pb on survival of terrestrial and
aquatic biota.
Evidence from the 2013 Pb ISA Evidence from the 2023 Pb ISA
Terrestrial Plant Survival: Inadequate
Insufficient evidence to assess causality Insufficient evidence to assess causality
Freshwater Plant Survival: Inadequate
Insufficient evidence to assess causality Insufficient evidence to assess causality
Saltwater Plant Survival: Inadequate
Insufficient evidence to assess causality Insufficient evidence to assess causality
Terrestrial Invertebrate Survival: Causal
Survival of soil-associated invertebrates is adversely
affected by Pb exposure, albeit at Pb concentrations
associated with contaminated sites. In nematodes, the 2006
Pb AQCD reported LCso values varying from 10 to 1,550 mg
Pb/kg dry weight dependent upon soil OM content and soil
pH (U.S. EPA. 2006c). In earthworms, 14 and 28-d LCso
values typically fell in the range of 2,400-5,800 mg Pb/kg
depending upon the species tested. More recent evidence
has been consistent with these values and showed
concentration-dependent decreases in survival in
collembolans and earthworms under various experimental
conditions.
Freshwater Invertebrate Survival: Causal
Most of the evidence for Pb effects on survival in freshwater
invertebrates is from sensitive species of gastropods,
amphipods, cladocerans, and rotifers. In the 2006 Pb
AQCD, Pb impacted the survival of some aquatic
invertebrates at <20 |jg/L dependent upon water quality
variables (i.e., DOC, hardness, pH). Evidence in the 2013
Pb ISA also showed effects on survival in a few additional
freshwater invertebrates at <20 |jg Pb/L. Toxicity testing with
amphipods under various water conditions indicate these
organisms are sensitive to Pb at <10 |jg Pb/L.
Evidence continues to support a causal relationship
between Pb exposure and invertebrate mortality,
although most reported effects occurred at
concentrations that greatly exceed environmental
concentrations. Additional bioassays include studies
in garden snails and earthworms
(Appendix 11.2.4.3.2).
Several studies provide further characterization for
known effects on survival in a few sensitive species of
freshwater invertebrates at <20 |jg Pb/L. In the
gastropod L. stagnalis, survival was significantly
decreased at 8.4 |jg Pb/L after 21-d exposure and
decreased survival was observed up to the end of a
56-d full life cycle assessment (Munlev et al.. 2013).
In a chronic 42-d bioassay with the amphipod H.
azteca, survival was similar under two different
experimental diets conducted concurrently
(LC20 = 15 |jg Pb/L and LC20 = 13 |jg Pb/L) (Besser et
al.. 2016). and the results supported the previous
findings of effects in amphipods in the low |jg/L range
(Appendix 11.3.5 and Table 11-5).
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Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
Saltwater Invertebrate Survival: Inadequate
Limited evidence suggests that effects on survival are not
observed in most saltwater invertebrates unless Pb
concentrations greatly exceed those typically detected in
seawater.
Evidence continues to show that effects on survival
are typically not observed in bioassays unless Pb
concentrations greatly exceed those typically
detected in seawater.
Terrestrial Vertebrate Survival: Likely to be Causal
In terrestrial avian and mammalian species, toxicity is No new studies were available within the scope of
observed in laboratory studies over a wide range of doses ^is reporting effects of Pb exposure on the
(<1 to >1,000 mg Pb/kg body weight per day) as reviewed survival of terrestrial vertebrates.
for the development of ecological soil screening levels (U.S.
EPA. 2005), and subsequently reported in the 2006 Pb
AQCD (U.S. EPA. 2006a). The no-observed-adverse-effect
level for survival ranged from 3.5 to 3,200 mg Pb/kg per day.
Freshwater Vertebrate Survival: Causal
There is considerable historic information on Pb toxicity to
freshwater fish. Early observations from highly impacted
mining areas where Pb and other metals were present
indicated local extinction offish from streams (U.S. EPA.
1977). Several studies in the 2013 Pb ISA reported effects
at <100 [jg/Pb L in juvenile lifestages of a few fish species.
In the 2013 Pb ISA, 96-hr LCso values in fathead minnow
tested in natural waters across the United States were as
low as 41 |jg Pb/L (Esbauqh etal., 2011).
Additional fish bioassays conducted in varying water
chemistry conditions report effects on survival at Pb
concentrations similar to those in the 2013 Pb ISA
(Appendix 11.3.5 and Table 11-5). For larval
zebrafish (D. rerio), 96-hr LCso values varied with
water hardness; in soft water LCso = 52.9 |jg Pb/L
and in hard water LCso=>590 |jg Pb/L (Alsop and
Wood. 2011). In 96-hr acute tests conducted with two
lifestages of white sturgeon (Acipenser
transmontanus), the lowest 96-hr LCso was 177 |jg
Pb/L in 8-d post hatch larvae (Vardv et al.. 2014).
Saltwater Vertebrate Survival: Suggestive (Inadequate in the 2013 Pb ISA)
Insufficient evidence to assess causality
Additional evidence since the 2013 Pb ISA includes
chronic bioassays with analytically verified
concentrations of Pb conducted with early lifestages
in three saltwater fish species that report NOECs in
the range of 11-14 |jg Pb/L (Appendix 11.4.5 and
Table 11-7). In the larval fish Topsmelt (Atherinops
affinis), survival was impacted to a greater extent at
lower salinity (LCso = 15.1 |jg Pb/L; NOEC <13.8 |jg
Pb/L) than higher salinity (LCso = 79.8 |jg Pb/L;
NOEC = 45.5 |jg Pb/L) (Reynolds et al.. 2018).
Calculated chronic values for additional saltwater fish
species include an NOEC = 14 |jg Pb/L and
LOEC = 29 |jg Pb/L for grey mullet (Mugil cephalus)
fingerling survival and an NOEC = 11 [jg Pb/L and
LOEC = 22 |jg Pb/L for Tiger perch (Terapon jarbua)
fingerling survival following 30 d exposure to Pb
(Hariharan etal.. 2016).
AQCD = Air Quality Criteria Document; d = day(s); DOC = dissolved organic carbon; hr = hour(s); ISA = Integrated Science
Assessment; LC50 = 50% lethal concentration; LOEC = lowest observed effect concentration, NOEC = no observed effect
concentration; OM = organic matter; Pb = lead.
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IS.8.5.5 Growth
Alterations in the growth of an organism can impact population, community, and ecosystem-level
variables. In plants, the 2013 Pb ISA concluded that the relationship between Pb exposure and reduced
growth is causal in terrestrial plants and likely to be causal in freshwater aquatic plants. New evidence
continues to support these findings (Table IS-19). Evidence was inadequate for growth endpoints for
saltwater plants and algae in 2013 and this continues to be the case. There is evidence over several
decades of research that Pb inhibits photosynthesis and respiration in terrestrial plants, both of which
reduce growth (U.S. EPA. 2013a. 2006a. 1977). Effects reported in plants are typically observed in
laboratory or greenhouse settings with high exposure concentrations or in field studies near stationary
sources and heavily contaminated sites, but studies that include multiple concentrations of Pb show
increased response with increasing concentration. In the 2006 Pb AQCD, half maximal effect
concentration (EC50) values for growth inhibition in various freshwater algal and aquatic plant species
were between approximately 1000 and >100,000 |ig Pb/L, and were mostly based on nominal
concentration data (U.S. EPA. 2006c). An important advancement since the 2013 Pb ISA is the
availability of bioassay data for algal growth rate in several freshwater species based on measured Pb
concentration instead of nominal concentration, which strengthens confidence in the findings for the
concentrations assessed (Appendix 11.3.5). In conclusion, most primary producers experience EC50
values for growth at concentrations that greatly exceed Pb concentrations typically found in U.S. soils and
surface waters.
The 2013 Pb ISA concluded that the relationship between Pb exposure and decreased growth in
freshwater invertebrates is causal, and likely to be causal in terrestrial invertebrates. Building upon the
evidence for growth effects reported in the draft Ambient Aquatic Life Water Quality Criteria for Lead
(U.S. EPA. 2008) and the 2006 Pb AQCD (U.S. EPA. 2006a). studies reviewed in the 2013 Pb ISA
reported some effects at <10 (ig Pb/L for growth endpoints in aquatic invertebrates (U.S. EPA. 2013a').
The growth of the freshwater snail L. stagnalis was identified as one of the most sensitive organisms and
endpoints for Pb toxicity. Since then, additional studies have supported previous findings of Pb effects on
the growth of this species at <10 (ig Pb/L lYCremazv et al.. 2018; Munlev et al.. 2013; Brix et al.. 2012;
Esbaugh et al.. 2012); Appendix 11. Table 11-5], The evidence remains inadequate to infer a causality
relationship for Pb exposure and reduced growth in saltwater invertebrates, and terrestrial and aquatic
vertebrates.
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Table IS-19 Summary of evidence for growth effects of Pb in terrestrial and
aquatic biota.
Evidence from the 2013 Pb ISA Evidence from the 2023 Pb ISA
Terrestrial Plant Growth: Causal
Effects of Pb on plant growth are typically observed in
laboratory studies with high exposure concentrations or in
field studies near stationary sources. In terrestrial plants,
there is evidence over several decades of research that Pb
inhibits photosynthesis and respiration, all ofwhich can
reduce the growth of the plant (U.S. EPA. 2006c. 1986a.
1977). The 2006 Pb AQCD relied principally on evidence
assembled in the Ecological Soil Screening Levels for Lead
document (U.S. EPA. 2005), which concluded that growth
(biomass) was the most sensitive and ecologically relevant
endpoint for plants. In the 2013 Pb ISA, there was some
evidence for exposure-dependent decreases in the biomass
of some plant species grown in Pb-amended or Pb-
contaminated soil.
Recent studies have continued to demonstrate
growth effects, albeit at concentrations that greatly
exceed Pb measured in soils. Growth endpoints
include decreases in photosynthetic performance,
damage to chlorophyll, increased antioxidant activity
in response to Pb stress, as well as genotoxic effects
of Pb. Studies of the effects of Pb on terrestrial plants
published since the last ISA continue to support the
previous known findings of declines in plant growth
under controlled exposures of Pb
(Appendix 11.2.4.2).
Freshwater Plant Growth: Likely to be Causal
There is a large body of evidence to support growth effects
in plants at higher Pb concentrations. As reported in the
2013 Pb ISA and earlier AQCDs, there are documented
effects on growth in algae and aquatic plants in laboratory
studies. Most primary producers experience ECso values for
growth in the range of 1,000 to 100,000 |jg Pb/L,
concentrations that greatly exceed Pb concentrations
typically found in U.S. surface waters.
Additional studies in algae and macrophytes continue
to support a likely to be causal relationship
(Appendix 11.3.4.1). A few new studies assessed the
sensitivity of freshwater algal growth to Pb exposure
and found a significantly negative effect in certain
species. New information on Pb effects on common
reed (P. australis) shows significant decreases in total
biomass, photosynthesis, and rhizome growth as well
as alterations in growth form and propagation
strategy under Pb exposure.
Saltwater Plant Growth: Inadequate
Saltwater species are historically underrepresented in
toxicity testing. In studies reviewed in the 2013 Pb ISA,
marine algae exhibited a range of sensitivity to Pb with a 72-
hr ECso reported for Chaetorceros sp. of 105 |jg Pb/L. Other
tested species were considerably less sensitive (72-hr
EC50 = 740 |jg Pb/L or higher).
Limited evidence for growth inhibition for marine algal
species published since the 2013 Pb ISA, including a
few longer-term studies, generally show effects at
concentrations that greatly exceed environmental
concentrations (Appendix 11.4.4.2).
Terrestrial Invertebrate Growth: Likely to be Causal
A few studies cited in the 1986 Pb AQCD, the 2006 AQCD,
and the 2013 Pb ISA reported growth effects in terrestrial
invertebrates and that effects were more pronounced in
juvenile organisms, underscoring the importance of lifestage
to overall Pb susceptibility. Some studies also showed
concentration-dependent inhibition of growth in earthworms
raised in Pb-amended soil.
Recent evidence continues to show growth-rate
effects in organisms associated with soil and food Pb
contamination including earthworms, snails, and
nematodes, as well as new evidence for tobacco
cutworm and fruit flies (Appendix 11.2.4.3.2).
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Evidence from the 2013 Pb ISA Evidence from the 2023 Pb ISA
Freshwater Invertebrate Growth: Causal
Some studies in sensitive freshwater invertebrates reported
inhibition of growth at or below 20 |jg Pb/L. The lowest
reported LOEC for growth in the 2006 Pb AQCD (16 |jg
Pb/L) was in amphipods (H. azteca) (Besser et al.. 2005). In
the 2013 Pb ISA, there was evidence for growth inhibition in
one species of snail (L. stagnalis) at <4 |jg Pb/L (Grosell and
Brix. 2009: Grosell et al.. 2006). The lowest genus mean
chronic toxicity value for Pb was 10 |jg Pb/L in a freshwater
mussel (Wang et al.. 2010).
Saltwater Invertebrate Growth: Inadequate
Insufficient evidence to assess causality Insufficient evidence to assess causality
Terrestrial Vertebrate Growth: Inadequate
In AQCDs, growth effects of Pb have been reported in birds
(changes in juvenile weight gain) at concentrations typically
higher than currently found in the environment away from
heavily exposed sites.
Freshwater Vertebrate Growth: Inadequate
Evidence for growth effects of Pb is limited to a few studies
in amphibians and fish. Reports of Pb-associated growth
effects in freshwater fish are inconsistent; some studies
have shown no effects. Growth effects of Pb were reported
in frogs at concentrations typically higher than currently
found in the environment.
Saltwater Vertebrate Growth: Inadequate
Insufficient evidence to assess causality Few studies were identified since the 2013 Pb ISA
that assessed growth in saltwater vertebrates.
AQCD = Air Quality Criteria Document; EC50 = half maximal effect concentration; ISA = Integrated Science Assessment;
LOEC = lowest observed effect concentration; Pb = lead.
IS.8.5.6 Reproduction
1 Evidence from invertebrate and vertebrate studies from Pb AQCDs, the 2013 Pb ISA and in this
2 review indicates that Pb is affecting reproductive performance in multiple species (Table IS-20). Various
3 endpoints have been measured in multiple taxa of terrestrial and aquatic organisms to assess the effect of
4 Pb on development, fecundity, and hormone homeostasis, and they have demonstrated the presence of
5 adverse effects. Reproductive effects are important when considering effects of Pb because impaired
6 fecundity at the organism level of biological organization can result in a decline in abundance and/or
7 extirpation of populations, decreased taxa richness, and decreased relative or absolute abundance at the
8 community level (Suteretal.. 2004). The evidence is inadequate to conclude that there is a causal
9 relationship between Pb exposures and developmental and reproductive effects in either terrestrial or
Additional studies support previous findings of Pb
effects on growth of the snail (L. stagnalis) <10 |jg
Pb/L (Cremazv et al.. 2018) (Munlev et al.. 2013; Brix
et al.. 2012: Esbauah et al.. 2012) and a few other
invertebrates at or near 25 |jg Pb/L (Appendix 11.3.5
berand Table 11-5).
No new studies were available within the scope of
this ISA reporting growth effects in terrestrial
vertebrates from Pb exposure.
A few additional fish studies assessed growth
endpoints, with some reporting no effect
(Appendix 11.3.4.4.1.2).
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aquatic plants. In the 2013 Pb ISA the evidence was sufficient at that time to conclude that there is a
causal relationship between Pb exposures and developmental and reproductive effects in terrestrial and
freshwater invertebrates. New evidence suggests that in earthworms, Pb exposure slows the time to
maturation and that in isopods, it delays onset of the breeding season and shortens its duration, and that it
influences mate selection in fruit flies (Appendix 11.2.4.3.2). For freshwater invertebrates, recent
evidence further supports previous observations of Pb effects on reproductive endpoints at low
concentrations in sensitive species of gastropods, cladocerans and rotifers, especially under chronic
exposure scenarios (Appendix 11.3.5 and see Table 11-5).
In the 2013 Pb ISA, evidence was suggestive of a causal relationship between Pb exposure and
reproductive and developmental effects in saltwater invertebrates based on endpoints including delay in
onset to reproduction in amphipods, impaired larval development and embryogenesis inhibition in
bivalves, and a decrease in fertilization rate of eggs in a marine polychaete (U.S. EPA. 2013a). Since the
2013 Pb ISA, the evidence base for Pb effects on reproductive and developmental endpoints in saltwater
invertebrates has expanded, primarily due to multiple new embryo-larval developmental assays in
mollusca and echinodermata (Appendix 11.4.5 and Table 11-7). Several of these acute exposure bioassays
analytically verify the concentration of Pb at which effects were observed (Markich. 2021; Romero-
Murillo et al.. 2018; Nadella et al.. 2013) and report effects at lower concentrations than reported in the
2013 Pb ISA. Considering coherence of reproductive and developmental effects of Pb across species,
observations in saltwater invertebrates are consistent with terrestrial and freshwater invertebrates (both
"causal" in the 2013 Pb ISA). As a result of the newly available evidence since the 2013 Pb ISA the
causality determination for this endpoint has changed and the evidence is sufficient to infer a likely to be
causal relationship between Pb exposure and reproductive and developmental effects in saltwater
invertebrates.
In the 2013 Pb ISA, the evidence was sufficient to conclude that there is a causal relationship
between Pb exposures and developmental and reproductive effects in terrestrial and freshwater
vertebrates, and this continues to be the case. For reproduction and development in freshwater vertebrates,
the weight of evidence for the causal relationship in the 2013 Pb ISA was primarily from studies with
fish. Previous Pb AQCDs have reported reproductive and developmental effects in fish, including brook
trout (Salvelinus fontinalis), rainbow trout (Oncorhynchus mykiss), and fathead minnow (Pimephales
promelas) (U.S. EPA. 2013a. 2006a. 1977). Other supporting evidence for the causal determination in the
2013 Pb ISA for reproductive effects in aquatic vertebrates included alteration of steroid profiles and
additional reproductive variables, although most of the available studies were conducted using nominal
concentrations of Pb. New early lifestage fish studies, including several in zebrafish (D. rerio) in which
the concentration of Pb in exposure water was analytically verified (Appendix 11.3.4.4.1.2) add to the
existing evidence for Pb effects on endocrine and developmental endpoints. These studies at analytically
verified concentration of Pb are bolstered by additional fish studies conducted at nominal concentrations
and several developmental studies in amphibians (Appendix 11.3.4.4.3).
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Table IS-20 Summary of evidence for reproductive effects of Pb in terrestrial and
aquatic biota.
Evidence from the 2013 Pb ISA Evidence from the 2023 Pb ISA
Terrestrial Plant Reproduction: Inadequate
Insufficient evidence to assess causality Insufficient evidence to assess causality
Freshwater Plant Reproduction: Inadequate
Insufficient evidence to assess causality Insufficient evidence to assess causality
Saltwater Plant Reproduction: Inadequate
Insufficient evidence to assess causality Insufficient evidence to assess causality
Terrestrial Invertebrate Reproduction: Causal
The 2006 Pb AQCD reported effects on reproduction in
collembolans and earthworms, with LOECs and NOECs
typically well above Pb soil concentrations observed away
from stationary sources of contamination. In the 2013 Pb
ISA, studies in a fewtaxa expanded the evidence for Pb
effects on developmental and reproductive endpoints for
invertebrates at concentrations that generally exceed Pb
levels in U.S. soils. Evidence of multi-generational toxicity
effects of Pb is also present in terrestrial invertebrates,
specifically springtails, mosquitoes, carabid beetles, and
nematodes in which decreased fecundity in the progeny of
Pb-exposed individuals was observed.
Freshwater Invertebrate Reproduction: Causal
Reproductive effects of Pb in freshwater aquatic
invertebrates are well-characterized in previous Pb AQCDs
and the 2013 Pb ISA and have been observed at or near
current ambient concentrations in some species in
laboratory exposures. Results under controlled conditions
have consistently shown reproductive effects of Pb in
sensitive taxa, especially amphipods and cladocerans, at
concentrations near Pb quantified in freshwater
environments.
Studies published since the 2013 Pb ISA continue to
support a causal relationship between Pb exposure
and invertebrate reproductive endpoints including
time to maturation and brood size
(Appendix 11.2.4.3.2). In addition to new studies in
earthworms and nematodes, additional new taxa
demonstrating reproductive effects associated with
Pb exposure include isopods and fruit flies. Several
multi-generational fruit fly studies together report that
Pb exposure influences female mate selection,
oviposition site, and tolerance to Pb contamination is
greater in populations with a history of Pb exposure.
Recent evidence (Appendix 11.3.5) further
characterizes Pb effects on reproductive endpoints at
low (<10 |jg Pb/L) concentrations in sensitive species
of gastropods, cladocerans, and rotifers (Appendix
11. Table 11-5), especially under chronic exposure
scenarios.
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Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
Saltwater Invertebrate Reproduction: Likely to be Causal (Suggestive of, but Not Sufficient to Infer Causality
in the 2013 Pb ISA)
For saltwater invertebrates, there is limited evidence for
effects on reproduction and early development. Reported
effects included a delay in the onset to reproduction in
amphipods (Ringenarv et al.. 2007). impaired larval
development (Wang et al.. 2009) and embryogenesis
inhibition (Wang et al.. 2009: Beiras and Albentosa. 2004) in
bivalves and a decrease in the fertilization rate of eggs
(marine polycheate annelid) (Gopalakrishnan et al.. 2008).
These effects were observed for Pb concentrations higher
than typically detected in marine environments.
Multiple new embryo-larval developmental assays in
mollusca (mussels, oysters) and echinodermata (sea
urchin) (Appendix 11.4.5 and Table 11-7) have
expanded the evidence for reproductive effects since
the 2013 Pb ISA. Several of these acute exposure
bioassays analytically verified the concentration of Pb
at which effects were observed (Markich, 2021;
Romero-Murillo et al.. 2018; Nadella et al.. 2013) and
reported effects at lower effect concentrations than
those reported in the 2013 Pb ISA. For example, the
48-hr EC10 was 9-10 |jg Pb/L in two mussel species,
and 72-hr EC10 was 19 |jg Pb/L in sea urchin
Strongylocentrotus purpuratus (Nadella et al.. 2013).
Terrestrial Vertebrate Reproduction and Development: Causal
Effects reported in the 2006 Pb ISA included declines in
clutch size, number of young hatched, number of young
fledged, decreased fertility, and decreased eggshell
thickness observed in birds near areas of Pb contamination
and in birds with elevated Pb tissue concentration
regardless of location (U.S. EPA. 2006c). In the 2013 Pb
ISA, studies in a few taxa expand the evidence for Pb
effects on mammalian developmental and reproductive
endpoints.
Recent studies, although limited, continue to support
a causal relationship between Pb exposure and
reproductive effects in terrestrial vertebrates. New
studies provide additional evidence of Pb exposure
causing decreased lifetime breeding success, lower
nestling weight at birth, decreased eggshell
thickness, and decreases in egg yolk antioxidant
levels in birds (Appendix 11.2.3.4.2).
Freshwater Vertebrate Reproduction and Development: Causal
The weight of evidence for reproductive and developmental
effects in freshwater vertebrates is from fish. Pb AQCDs
have reported developmental effects in a few fish species at
or near 120 pg Pb/L (U.S. EPA. 1977) (U.S. EPA. 1986b)
and reported effects on other reproductive endpoints
including decreased spermatocyte development (U.S. EPA.
2006a). Reproductive effects in fish are influenced by water
chemistry.
Several studies in fish further support previous
findings of Pb effects on reproductive endpoints in
freshwater vertebrates (Appendix 11.3.4.4.1.2). A few
of these studies report effects at lower concentrations
than the 2013 Pb ISA or prior AQCDs. Specifically,
hatching success rates in zebrafish embryos were
reduced at 4.5, 9.6 and 18.6 pg Pb/L aqueous
exposure; (Zhao et al.. 2020). Endocrine disruption
(significant reduction in thyroid hormones
triiodothyronine (T3) and thyroxine (T4)) was
observed in zebrafish larvae following exposure to
30 |jg Pb/L (Zhu etal.. 2014).
Saltwater Vertebrate Reproduction and Development: Inadequate
Insufficient evidence to assess causality Insufficient evidence to assess causality
AQCD = Air Quality Criteria Document; EC10 = effect concentration at 10% inhibition; hr = hour(s); ISA = Integrated Science
Assessment; LOEC = lowest observed effect concentration; NOEC = no observed effect concentration; Pb = lead
IS.8.5.7 Community and Ecosystem Effects
Endpoints relevant to assessing effects of Pb on communities and ecosystems include the
alteration of species richness, species composition, and biodiversity. Uptake of Pb into aquatic and
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terrestrial organisms and subsequent effects on mortality, growth, development, and reproduction at the
organism level can cascade to effects on populations and communities and lead to ecosystem-level
consequences. Although the evidence is strong for the effects ofPb on growth, reproduction, and survival
in certain species in experimental settings, considerable uncertainties exist in generalizing effects
observed under experimental conditions and at a smaller scale to predicted effects at the community and
ecosystem levels of biological organization. In many cases, it is difficult to characterize the nature and
magnitude of ecosystem-level effects and to quantify relationships between environmental concentrations
of Pb and ecosystem response due to the presence of multiple stressors, variability in field conditions, and
differences in Pb bioavailability. In addition, although the presence of Pb is associated with shifts in
biological communities, this metal rarely occurs as a sole contaminant in natural systems, making the
contribution of Pb to the observed effects difficult to ascertain.
In the 2013 Pb ISA, the body of evidence was sufficient to conclude there is a likely to be causal
relationship between Pb exposure and terrestrial and freshwater-community and ecosystem effects, and
recent evidence continues to support this determination (Appendix sections 11.2.6. 11.3.6. 11.2.4.1. and
11.3.4.1 and Table IS-21). In terrestrial habitats, communities and ecosystems exposed to elevated Pb
concentration, typically from proximity to historically active metal extracting and processing point
sources, have been shown to suffer from decreased species diversity and changes in species composition.
These changes affect microbial, floral, and faunal communities. Since the 2013 Pb ISA, effects of Pb
exposure on the interactions between trees and their pests, between herbaceous plants and insects, and
plants, worms, and soils invertebrates have been added to the evidence (Appendix 11.2.6). Reductions in
species abundance, richness, or diversity associated with the presence of Pb in freshwater habitats are
reported in the literature, usually in heavily contaminated sites where Pb (and other metal) concentrations
are higher than typically observed environmental concentrations. Most evidence is from sediment-
associated microbial and macroinvertebrate communities. Since the 2013 Pb ISA (U.S. EPA. 2013a).
several experimental and observational studies have examined the relationship between Pb concentration
in the sediment and effects on freshwater microbes (Appendix 11.3.4.1). Several of these studies report
negative relationships between sediment Pb concentration and microbial abundance or community
structure, while some report no relationship or positive associations. Observational and experimental
studies published since the 2013 Pb ISA continue to show negative associations between sediment and/or
porewater Pb concentration and macroinvertebrate communities (Appendix 11.3.6).
For saltwater ecosystems, evidence was inadequate in the 2013 Pb ISA to assess causality
between Pb exposures and community and ecosystem effects. Reduced species abundance and
biodiversity of protozoan and meiofauna communities were observed in laboratory microcosm studies
with marine water and marine sediments reviewed in the 2006 Pb AQCD as summarized in Table AX7
2.5.2 (U.S. EPA. 2006c). In the 2013 Pb ISA, there were a few additional studies including effects on
community structure and nematode diversity (U.S. EPA. 2013a). Since that time, there are new
experimental and observational studies (Table IS-21) examining the relationship between Pb in sediment,
and microbial abundance and/or diversity (Appendix 11.4.4.1). and Pb associations with saltwater
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foraminiferal communities (Appendix 11.4.6'). Several of the benthic foraminifera studies report effects
on community richness, diversity, and abundance. In other studies with foraminifera, there were changes
in abundance of certain taxa associated with Pb, but not diversity metrics. Considering the new evidence,
Pb quantified in sediment is a factor explaining variation in microbial diversity and foraminiferal species
distributions and abundance in a variety of distinct geographic locations. In these studies, Pb is often
correlated with other heavy metals. In addition to the available studies assessing Pb effects on saltwater
communities, primarily foraminifera, the effects of Pb on reproduction and survival of early lifestages in
sensitive saltwater invertebrates, especially when considered cumulatively, could impact populations, and
community and ecosystem structure and function. Population, community, or ecosystem-level studies are
typically conducted at sites that have been contaminated or adversely affected by multiple stressors
(several chemicals alone or combined with physical or biological stressors), which increase the
uncertainty of attributing observed effects to Pb. Therefore, additional evidence available since the 2013
Pb ISA indicates the evidence is suggestive of, but not sufficient to infer, a causal relationship between
Pb exposure and community and ecosystem effects.
Table IS-21 Summary of evidence for community and ecosystem effects of Pb.
Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
Terrestrial Community and Ecosystem Effects: Likely to be Causal
Independent effects of Pb are difficult to interpret because of
the presence of other stressors, including metals. The 1986
Pb AQCD (U.S. EPA. 1986a) reported shifts toward Pb-
tolerant communities at 500 to 1,000 mg Pb/kg soil. In the
2006 AQCD (U.S. EPA. 2006c), decreased species diversity
and changes in community composition were observed in
ecosystems surrounding former smelters. In the 2013 Pb
ISA, there was additional evidence for Pb effects on soil
microbial communities.
Experimental studies have shown that trophic transfer
of Pb can affect species interactions, nematode
community composition, and bacterial abundance
and/or activity (Appendix 11.2.4.1). Additional
observational studies reported negative or null
relationships between soil Pb concentration and
microbial and invertebrate abundance and diversity
(Appendix sections 11.2.4.1 and 11.2.6).
Freshwater-Community and Ecosystem Effects: Likely to be Causal
Effects of Pb are difficult to interpret because of the
presence of other stressors, including metals. Most evidence
of community and ecosystem-level effects is from near Pb
sources, usually mining effluents. In the 2013 Pb ISA
evidence for Pb effects on sediment-associated and
freshwater aquatic plant communities added to the existing
body of evidence of effects of Pb at higher levels of
biological organization.
Several studies reported negative correlations
between sediment Pb concentration and invertebrate
community composition or ecosystem processes
(Appendix 11.3.6). Additionally, observational and
experimental studies have reported negative
relationships between sediment and/or porewater Pb
concentration and microbial abundance and/or
community structure, while some reported no
relationship or positive associations
(Appendix 11.3.4.1)
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Evidence from the 2013 Pb ISA
Evidence from the 2023 Pb ISA
Saltwater Community and Ecosystem Effects: Suggestive of, but Not Sufficient to Infer, a Causal
Relationship (Inadequate in the 2013 Pb ISA)
No studies on community and ecosystem-level effects of Pb
in marine systems were reviewed in the 1977 Pb AQCD
(U.S. EPA. 1977). or the 1986 Pb AQCD (U.S. EPA. 1986a).
Observations from field studies reviewed in the 2006 Pb
AQCD (U.S. EPA. 2006c) included findings of a negative
correlation between Pb and species richness and diversity
indices of macroinvertebrates associated with estuary
sediments. Evidence for community and ecosystem-level
effects of Pb in saltwater ecosystems in the 2013 Pb ISA
included a few laboratory microcosm studies as well as
observations from field-collected sediments, biofilm and
plants in which changes in community structure were
observed; however, evidence was inadequate to make a
causality determination at the time.
Additional studies since the 2013 Pb ISA provide
sufficient evidence for effects on saltwater
communities and ecosystems to be suggestive of a
causal relationship. Mesocosm and observational
studies found reductions in foraminiferal and/or
meiofaunal community richness, diversity, and/or
abundance associated with higher concentrations of
Pb in sediment and water, while others found positive
or null correlations (Appendix 11.4.6). In addition,
several experimental and observational studies
reported negative relationships between sediment
and/or saltwater Pb concentrations and microbial
abundance and/or diversity, while other studies found
no relationship (Appendix 11.4.4.1).
AQCD = Air Quality Criteria Document; ISA = Integrated Science Assessment; Pb = lead.
IS.9 Policy-Relevant Issues
In the process of evaluating the current state of the science with respect to the effect of Pb
exposure on health and welfare, studies that conducted analyses that address some of the key policy-
relevant questions of this review were identified, as detailed in Volume II of the Pb IRP (U.S. EPA.
2022a). such as:
• To what extent has new information altered scientific conclusions regarding the relationships
between Pb in ambient air and Pb in children's blood?
• To what extent does the newly available evidence alter our understanding of the C-R relationships
between Pb in children's blood and reduced IQ?
• To what extent is there new scientific evidence available to improve our understanding of the
health effects associated with various time periods of Pb exposures at various stages of life?
• Has new information altered our understanding of human populations that are particularly
sensitive to the current low environmental Pb exposures, including air-related exposures?
• Does the newly available evidence identify new endpoints or indicate new exposure levels at
which ecological systems or receptors are expected to experience effects?
The following sections summarize the evidence that can inform consideration of these policy-
relevant questions, specifically: air Pb-to-blood Pb relationships (Section IS.9.1); C-R relationship
between BLLs and IQ (Section IS.9.2); the level, timing, duration, and frequency of Pb exposure
contributing to observed health effects (Section IS.9.3), and populations potentially at increased risk of a
PM-related health effect (Section IS.9.4). A summary of recent evidence related to at-risk populations is
provided in Section IS.7.4.
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IS.9.1
Air Pb-to-Blood Pb Relationships
Multivariate regression models, commonly used in epidemiology, provide estimates of the
variability in BLLs (or other biomarkers) explained by various exposure pathways (e.g., air Pb
concentration, surface-dust Pb concentration). Models can provide estimates of the rate of change of
blood or bone Pb concentration in response to an incremental change in exposure level (i.e., slope factor).
Within the literature and EPA documents, the relationship between air Pb and blood Pb is commonly
characterized in terms of a "slope factor" or "air-to-blood ratio." An air-to-blood ratio of 1:5 indicates that
for every 1 |ig/m3 of air Pb, there is a 5 (ig/dL increase in blood Pb. Synonymously, this is characterized
by a slope factor of 5 (ig/dL per |ig/nr\ Air Pb-blood Pb relationships in children, described in
Appendix 2.5.1. are summarized below.
The 1986 Pb AQCD (U.S. EPA. 1986a) described epidemiologic studies of relationships between
air Pb and blood Pb. Drawing from the studies examined, the aggregate blood Pb-air Pb slope factor
(when considering both air Pb and Pb in other media derived from air Pb) was estimated to be
approximately double the slope estimated from the contribution due to inhaled air alone (U.S. EPA.
1986a). Much of the pertinent earlier literature (e.g., prior to 1984, when air Pb was dominated by the use
of leaded gasoline in on-road motor vehicles) on children's BLLs was summarized by Brunekreef (1984)
and found that the blood Pb versus air Pb slope was smaller at high blood and air levels. Most studies
have empirically modeled the air Pb-to-blood Pb relationship using nonlinear regression (i.e., log-log),
which itself gives an increasing slope with decreasing air Pb concentration.
In the 2008 final rule for the Pb NAAQS (73 FR 66964-67062), the Administrator's decision on
the revised level for the new primary standard was informed by an evidence-based framework for
considering air-related IQ loss for children living near Pb sources. EPA, recognizing uncertainty and
variability in the air-to-blood relationships, reported that estimates of 1:5 and 1:7 were supported by the
evidence (and pertained to the population of U.S. children at the time), with 1:5 at the lower end and 1:10
at the upper end of a range reflective of current conditions (73 FR 67001-67002).
At the time of the 2013 Pb ISA (U.S. EPA. 2013a'). there was uncertainty, due to the limited
evidence, in projecting the magnitude of the air Pb-blood Pb relationship to ambient air Pb below
0.2 |ig/m3. There are studies since the 2013 Pb ISA that evaluate the air Pb-to-blood Pb relationship that
are more reflective of current conditions. As was the case for older data in the 1986 Pb AQCD (U.S. EPA.
1986a). newer data also show slope factors increasing with decreasing air Pb. It is possible that the
contribution from non-air exposure pathways may lead to the high slope factors at low air concentrations.
In other words, in older studies in which leaded gasoline or local sources were a major contributor to air
Pb, there may be a greater likelihood of discerning the true effect of air Pb on blood Pb due to relatively
less contribution from non-air exposure pathways. However, overarching distinctions between old and
new studies should be made with caution given that Pb in all media, not just air, has decreased over time.
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In general, longitudinal studies conducted after phasing out leaded gasoline would best inform the
current relationship of blood Pb to air Pb. Ideally, such studies would compare two populations for which
all Pb sources but air Pb concentrations are unchanged. Such a nearly ideal study, Hilts (2003) reported
the change in blood Pb from 1996 to 2001 for children under 5 years old associated with the emission
reduction from a local smelter in Trail, BC, Canada. However, even in this study, the reduction in
exposure from pathways other than air cannot be ruled out because of the "comprehensive education and
case management programs." An advancement in understanding the blood Pb-air Pb association came
from leveraging the EPA Air Quality System (AQS) with NHANES surveys. The blood Pb-air Pb
associations across different NHANES periods should reflect the change in this association for the U.S.
population over time (Richmond-Bryant et al.. 2014; Richmond-Bryant et al.. 2013) because each
NHANES is a representative sample of the U.S. population. However, merging blood Pb results from
multiple NHANES periods with the EPA AQS could introduce exposure measurement errors as well as
uncertainties in terms of population representativeness and availability of covariates. Each single study
presented in Table 2-13 (Appendix 2.5.1) deviates from the ideal design in one or more aspects.
Collectively, all of these studies contribute to our understanding of how air Pb impacts blood Pb.
IS.9.2 Concentration-Response Relationships for Human Health Effects
In assessing the relationship between Pb exposure and human health effects, an important
consideration is the shape of the C-R relationship across the full range of Pb biomarker levels and
whether there is a threshold concentration below which there is no evidence of an effect. As described
elsewhere in the document (Appendix 2.3). the interpretation of the epidemiologic study findings depends
on the exposure history of the study populations and the choice of the biomarker in the context of what is
known about that exposure history. Many of the adult populations examined in older and more recent
epidemiologic studies are likely to have had higher past than recent Pb exposure. Given their longer
exposure histories, there is uncertainty regarding the frequency, duration, timing, and level of exposure
contributing to the blood Pb or bone Pb levels measured in adult and adolescent populations. Therefore,
this section summarizes evidence relevant to thresholds and C-R relationships in studies of childhood Pb
exposure. A summary of previous evidence regarding C-R relationships for exposure biomarkers in
adolescents and adults is presented in Section 1.9.3 of the 2013 Pb ISA (U.S. EPA. 2013a). and a
summary of recent evidence can be found within the health effects appendices.
With each previous assessment (U.S. EPA. 2013a. 2006b). the epidemiologic and toxicological
evidence demonstrated that progressively lower BLLs or Pb exposures are associated with cognitive
deficits in children. The 2006 AQCD found that cognitive effects in children were observed in association
with BLLs of 10 (ig/dL and lower, while the evidence assessed in the 2013 Pb ISA found that an
association between BLLs and cognitive effects in children was substantiated to occur in populations with
mean BLLs between 2 and 8 (ig/dL. The conclusion of the 2013 Pb ISA was based on studies that
examined early childhood BLLs (i.e., age <3 years), considered peak BLLs in their analysis (i.e., peak
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<10 jxg/dL), or examined concurrent BLLs in young children (i.e., age 4 years). Although some recent
studies report associations between Pb exposure and cognitive effects in children with mean BLLs
<2 (.ig/dL. recent studies generally include somewhat older children, or employ modeling strategies
designed to answer relatively narrow research questions (e.g., the effect of joint exposure to Pb and other
metals, or the effect of concurrent Pb exposure independent from prenatal exposure) and consequently do
not have the attributes of the studies on which the conclusion of the 2013 Pb ISA was based (i.e., early
childhood BLLs, consideration of peak BLLs, or concurrent BLLs in young children). Furthermore,
studies that might extend the evidence related to exposure-response relationships (i.e., recent studies that
reflect the lower early childhood Pb exposures now more common in the United States with an adequate
range of Pb exposure [i.e., studies of subjects with BLLs <1 to 2 (ig/dL measured during relevant time
periods]) are generally lacking. Overall, the recently available studies were not designed, and may not
have the sensitivity, to detect (Cooper et al.. 2016) the effect or hazard at these very low BLLs, nor do
they provide evidence of a threshold for the effects across the range of BLLs examined.
Epidemiologic studies evaluated in the 2013 Pb ISA provided evidence of a larger decrement in
cognitive function per unit increase in blood Pb among children with lower mean BLLs compared with
children with higher mean BLLs. Key evidence was provided by an international pooled analysis of seven
prospective cohort studies (Lanphear et al.. 2019. 2005). as well as studies that examined prenatal or early
childhood BLLs or considered peak BLLs in school-aged children or concurrent BLLs in young children
(i.e., 2 years old). Recent studies that evaluate the shape of the C-R function for the relationship between
Pb exposure and cognitive effects in children are limited in number, but continue to support the
conclusions from the previous ISA. In particular, a re-analysis of the pooled data set of Lanphear et al.
(2005). Crump et al. (2013) corroborated the finding that there was evidence of a nonlinear C-R function
overthe range of the BLLs evaluated (e.g., 2.5-33.2 (ig/dL, as 5th to 95th percentile concurrent BLLs) -
i.e., a larger incremental effect of Pb exposure on IQ at lower blood Pb concentrations as indicated by a
log-linear C-R function. Lanphear et al. (2005) also fit linear functions over stratified BLL ranges (e.g., <
7.5 (ig/dL and >7.5 (ig/dL) that similarly indicated statistically significantly larger Pb-associated
cognitive function decrements across the lower range compared to the higher range. Individual studies
also support this finding, showing greater decrements in cognitive function per unit increase in BLL
among children in lower strata of BLLs compared with children in higher strata of BLLs [Figure 4-15,
and Table 4-16 of U.S. EPA (2013a)l. Notably, uncertainty in the shape of the C-R relationship increases
at lower BLLs due to a smaller number of observations. Previous assessments also noted attenuation of C-
R relationships at higher exposure or dose levels in the occupational literature. Reasons proposed to
explain the attenuation include greater exposure measurement error and saturation of biological
mechanisms at higher levels, as well depletion of the pool of susceptible individuals at higher exposure
levels (Stavncr et al.. 2003). Possible explanations specific to nonlinear relationships observed in studies
of Pb exposure in children include a lower incremental effect of Pb due to covarying risk factors such as
low SES, poor caregiving environment, and higher exposure to other environmental factors (Schwartz.
1994). differential activity of mechanisms at different exposure levels, and confounding by omitted or
misspecified variables (U.S. EPA. 2013a'). Review of the evidence did not reveal a consistent set of
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covarying risk factors to explain the differences in the blood Pb-IQ C-R relationship across high and low
Pb exposure groups observed in epidemiologic studies. Additionally, although evidence indicates a larger
incremental effect of Pb exposure on IQ at lower BLLs, consistent findings of higher mean IQ at lower
BLLs indicates that the absolute magnitude of the effect of Pb exposure on cognitive function declines
with decreasing BLL.
IS.9.3 Lifestages and Timing of Pb Exposure Contributing to Observed
Nervous System Effects
As discussed in Appendix 2.3.5. blood Pb may reflect both recent as well as past exposures
because Pb is both taken up by and released from the bone. The relative proportion of BLLs resulting
from recent versus past exposure is uncertain in the absence of specific information about the pattern of
exposure contributing to observed BLLs, which is generally not ascertainable in epidemiologic studies.
This uncertainty is greater in adults and older children, than in young children who do not have lengthy
exposure histories. As a result, stronger conclusions can be reached regarding the timing of exposures that
result in health effects in children. Several lines of evidence, which are summarized below, inform the
interpretation of epidemiologic studies of young children with regard to the patterns of exposure that
contribute to observed health effects.
The collective body of epidemiologic evidence reviewed in the 2013 Pb ISA did not provide
strong evidence to identify an individual critical lifestage or timing of Pb exposure with regard to
neurodevelopmental effects in children (U.S. EPA. 2013a). Specifically, epidemiologic studies reviewed
in the 2013 Pb ISA consistently showed that BLLs measured during various lifestages and time periods
(i.e., prenatal, early childhood, childhood average, and concurrent with the outcome) were associated with
nervous system effects in children. Recent studies generally support this conclusion, though several
studies indicate that increases in postnatal (earlier childhood, lifetime average, concurrent) BLLs were
associated with larger cognitive function decrements in children ages 4-10 years than increases in
prenatal BLLs. These results suggest that per unit increase, postnatal Pb exposures that are reflected in
concurrent or cumulative BLLs or tooth Pb levels may have a larger magnitude of effect on cognitive
function decrements as children age. Notably, however, exposure metrics that are based on blood Pb
measurements at different ages in childhood are typically highly correlated. Consequently, the relative
importance of various exposure metrics, which are measured during different lifestages and time periods,
is difficult to discern in epidemiologic studies. Evidence in rodents and monkeys, however, indicates that
Pb exposures during multiple lifestages and time periods, including prenatal only, prenatal plus
lactational, postnatal only, and lifetime are observed to induce impairments in learning (Rice, 1992b,
1990; Rice and Gilbert, 1990b). These findings are consistent with the understanding that the nervous
system continues to develop (i.e., synaptogenesis and synaptic pruning remains active) throughout
childhood and into adolescence.
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IS.9.4
Ecological Effects and Corresponding Pb Concentrations
Pb that is released into air, soil, or water is then cycled through any, or all, of these media before
reaching an ecological receptor. When a plant, invertebrate, or vertebrate is exposed to Pb, the proportion
of observed effects attributable to Pb from atmospheric sources is difficult to assess because of a lack of
information not only on deposition but also on bioavailability, as affected by specific characteristics of the
receiving ecosystem and on kinetics of Pb distribution in long-term exposure scenarios. Although long-
term trends in declining anthropogenic emissions are detected in some non-air media and biota, the
connection between air concentration and ecosystem exposure continues to be poorly characterized for
Pb, and the contribution of atmospheric Pb to specific sites is not clear. Current evidence indicates that Pb
is bioaccumulated in biota; however, the sources of Pb in biota have only been identified in a few studies,
and the relative contribution of Pb from all sources is usually not known.
No new endpoints were identified for Pb effects in terrestrial, freshwater, or saltwater biota since
the 2013 Pb ISA. However, a few effects were reported at lower concentration than the 2013 Pb ISA,
primarily in chronic laboratory-based bioassays for endpoints that were already established as causal in
the 2013 Pb ISA. However, the level at which Pb elicits a specific effect is difficult to establish in
terrestrial and aquatic systems due to the influence of other environmental variables on both Pb
bioavailability and toxicity and also to substantial species differences in Pb susceptibility. There are large
differences in species sensitivity to Pb, and many environmental variables (e.g., pH, OM) determine the
bioavailability and toxicity of Pb.
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References
Allwood. JM; Bosetti. V; Dubash. NK; Gomez-Echeverri. L; von Stechow. C. (2014). Annex 1: Glossary,
acronyms and chemical symbols. In Climate Change 2014: Mitigation of Climate Change
Contribution of Working Group III to the Fifth Assessment Report of the Intergovernmental
Panel on Climate Change. Cambridge, United Kingdom: Cambridge University Press.
https://www.ipcc.ch/site/assets/uploads/2018/02/ipcc wg3 ar5 annex-i.pdf
Alsop. D; Wood. CM. (2011). Metal uptake and acute toxicity in zebrafish: Common mechanisms across
multiple metals. Aquat Toxicol 105: 385-393. http://dx.doi.Org/10.1016/i.aquatox.2011.07.010
Beiras. R; Albentosa. M. (2004). Inhibition of embryo development of the commercial bivalves Ruditapes
decussatus and Mytilus galloprovincialis by trace metals; implications for the implementation of
seawater quality criteria. Aquaculture 230: 205-213. http://dx.doi.org/10.1016/S0Q44-
8486(03)00432-0
Besser. JM: Brumbaugh. WG; Brunson. EL: Ingersoll. CG. (2005). Acute and chronic toxicity of lead in
water and diet to the amphipod Hyalella azteca. Environ Toxicol Chem 24: 1807-1815.
http://dx.doi.org/10.1897/04-480R. 1
Besser. JM: Ivev. CD: Brumbaugh. WG: Ingersoll. CG. (2016). Effect of diet quality on chronic toxicity
of aqueous lead to the amphipod Hyalella azteca. Environ Toxicol Chem 35: 1825-1834.
http: //dx.doi .org/10.1002/etc .3341
Bolton. JB. (2004). Issuance of OMB's "Final Information Quality Bulletin for Peer Review"
[Memorandum], (M-05-03). Washington, DC: U.S. Office of Management and Budget, Executive
Office of the President.
https://www.whitehouse.gov/sites/whitehouse.gov/files/omb/memoranda/2005/m05-Q3.pdf
Brix. KV: Esbaugh. AJ: Munlev. KM: Grosell. M. (2012). Investigations into the mechanism of lead
toxicity to the freshwater pulmonate snail, Lymnaea stagnalis. Aquat Toxicol 106-107: 147-156.
http://dx.doi.Org/10.1016/i.aquatox.2011.ll.007
Brunekreef. B. (1984). The relationship between air lead and blood lead in children: A critical review
[Review], Sci Total Environ 38: 79-123. http://dx.doi.org/10.1016/0048-9697(84)90210-9
Burger. J: Gochfeld. M. (2005). Effects of lead on learning in herring gulls: An avian wildlife model for
neurobehavioral deficits. Neurotoxicology 26: 615-624.
http://dx.doi.Org/10.1016/i.neuro.2005.01.005
Burger. J: Tsipoura. N. (2014). Metals in horseshoe crab eggs from Delaware Bay, USA: Temporal
patterns from 1993 to 2012. Environ Monit Assess 186: 6947-6958.
http://dx.doi.org/10.1007/slQ661-014-3901-8
Cariou. E: Guivel. C: La. C: Lenta. L: Elliot. M. (2017). Lead accumulation in oyster shells, a potential
tool for environmental monitoring. Mar Pollut Bull 125: 19-29.
http://dx.doi.Org/10.1016/i.marpolbul.2017.07.075
CDC (Centers for Disease Control and Prevention). (2004). The health consequences of smoking: A
report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services.
http://www.cdc.gov/tobacco/data statistics/sgr/2004/index.htm
CDC (Centers for Disease Control and Prevention). (2021). Fourth national report on human exposure to
content/uploads/2021/04/FourthReport
External review draft
UpdatedTables
IS-104
8.pdf
Do not cite or quote
-------
Chamberlain. AC; Heard. MJ; Little. P; Newton. D; Wells. AC; Wiffin. RD. (1978). Investigations into
lead from motor vehicles. (AERE-R9198). Berkshire, England: Transportation and Road
Research Laboratory.
Church. BG; Van Sprang. PA; Chowdhurv. MJ; DeForest. DK. (2017). Updated species sensitivity
distribution evaluations for acute and chronic lead toxicity to saltwater aquatic life. Environ
Toxicol Chem 36: 2974-2980. http://dx.doi.org/10.1002/etc.3863
Cooper. GS; Lunn. RM; Agerstrand. M; Glenn. BS; Kraft. AD; Luke. AM; Ratcliffe. JM. (2016). Study
sensitivity: Evaluating the ability to detect effects in systematic reviews of chemical exposures.
Environ Int 92-93: 605-610. http://dx.doi.Org/10.1016/i.envint.2016.03.017
Cremazv. A; Brix. KV; Wood. CM. (2018). Chronic toxicity of binary mixtures of six metals (Ag, Cd,
Cu, Ni, Pb, and Zn) to the great pond snail Lymnaea stagnalis. Environ Sci Technol 52: 5979-
5988. http://dx.doi.org/10.1021/acs.est.7b06554
Crump. KS; Van Landingham. C; Bowers. TS; Cahov. D; Chandalia. JK. (2013). A statistical
reevaluation of the data used in the Lanphear et al. (2005) pooled-analysis that related low levels
of blood lead to intellectual deficits in children [Review]. Crit Rev Toxicol 43: 785-799.
http://dx.doi.org/10.3109/10408444.2Q13.832726
Deforest. DK; Santore. RC; Ryan. AC; Church. BG; Chowdhurv. MJ; Brix. KV. (2017). Development of
biotic ligand model-based freshwater aquatic life criteria for lead following US Environmental
Protection Agency guidelines. Environ Toxicol Chem 36: 2965-2973.
http: //dx.doi .org/10.1002/etc .3861
Egan. KB; Cornwell. CR; Courtney. JG; Ettinger. AS. (2021). Blood lead levels in U.S. children ages 1-
11 years, 1976-2016. Environ Health Perspect 129: 37003. http://dx.doi.org/10.1289/EHP7932
Esbaugh. AJ; Brix. KV; Mager. EM; De Schamphelaere. K; Grosell. M. (2012). Multi-linear regression
analysis, preliminary biotic ligand modeling, and cross species comparison of the effects of water
chemistry on chronic lead toxicity in invertebrates. Comp Biochem Physiol C Toxicol Pharmacol
155: 423-431. http://dx.doi.org/10.1016/i.cbpc.2011.11.005
Esbaugh. AJ; Brix. KV; Mager. EM; Grosell. M. (2011). Multi-linear regression models predict the
effects of water chemistry on acute lead toxicity to Ceriodaphnia dubia and Pimephales promelas.
Comp Biochem Physiol C Toxicol Pharmacol 154: 137-145.
http://dx.doi.Org/10.1016/i.cbpc.2011.04.006
Gil-Manrique. B; Ruelas-Inzunza. J; Meza-Montenegro. MM; Ortega-Garcia. S; Garcia-Rico. L; Lopez-
Duarte. AL; Vega-Sanchez. B; Vega-Millan. CB. (2022). A ten-year monitoring of essential and
non-essential elements in the dolphinfish Coryphaena hippurus from the southern Gulf of
California. Mar Pollut Bull 174: 113244. http: //dx. doi .org/10.1016/i .marpolbul .2021.113244
Gillikin. DP; Dehairs. F; Baevens. W; Navez. J; Lorrain. A; Andre. L. (2005). Inter- and intra-annual
variations of Pb/Ca ratios in clam shells (Mercenaria mercenaria): A record of anthropogenic lead
pollution? Mar Pollut Bull 50: 1530-1540. http://dx.doi.Org/10.1016/i.marpolbul.2005.06.020
Gopalakrishnan. S; Thilagam. H; Raja. PV. (2008). Comparison of heavy metal toxicity in life stages
(spermiotoxicity, egg toxicity, embryotoxicity and larval toxicity) of Hydroides elegans.
Chemosphere 71: 515-528. http://dx.doi.Org/10.1016/i.chemosphere.2007.09.062
Grosell. M; Brix. KV. (2009). High net calcium uptake explains the hypersensitivity of the freshwater
pulmonate snail, Lymnaea stagnalis, to chronic lead exposure. Aquat Toxicol 91: 302-311.
http: //dx.doi .org/10.1016/i .aquatox.2008.10.012
External review draft
IS-105
Do not cite or quote
-------
Grosell. M; Gerdes. RM: Brix. KV. (2006). Chronic toxicity of lead to three freshwater invertebrates—
Brachionus calyciflorus, Chironomus tentans, and Lymnaea stagnalis. Environ Toxicol Chem 25:
97-104. http://dx.doi.org/10.1897/04-654R. 1
Hariharan. G; Purvaia. R; Ramesh. R. (2016). Environmental safety level of lead (Pb) pertaining to toxic
effects on grey mullet (Mugil cephalus) and tiger perch (Terapon jarbua). Environ Toxicol 31:
24-43. http://dx.doi.org/10.1002/tox.22019
Hilts. SR. (2003). Effect of smelter emission reductions on children's blood lead levels. Sci Total Environ
303: 51-58. http://dx.doi.org/10.1016/S0048-9697(02)00357-l
IPCS (International Programme on Chemical Safety). (2012). Guidance for immunotoxicity risk
assessment for chemicals. (Harmonization Project Document No. 10). Geneva, Switzerland:
World Health Organization, https://apps.who.int/iris/handle/10665/330098
Kimbrough. KL: Lauenstein. GG; Christensen. JD: Apeti. DA. (2008). An assessment of two decades of
contaminant monitoring in the nation's coastal zone. (NOAA Technical Memorandum NOS
NCCOS 74). Silver Spring, MD: National Centers for Coastal Ocean Science.
https://repositorv.librarv.noaa.gov/view/noaa/2499
Krause-Nehring. J: Brev. T: Thorrold. SR. (2012). Centennial records of lead contamination in northern
Atlantic bivalves (Arctica islandica). Mar Pollut Bull 64: 233-240.
http://dx.doi.Org/10.1016/i.marpolbul.2011.11.028
Lanphear. BP: Hornung. R: Khourv. J: Yolton. K: Baghurst. P; Bellinger. DC: Canfield. RL; Dietrich.
KN: Bornschein. R: Greene. T: Rothenberg. SJ: Needleman. HL: Schnaas. L: Wasserman. G:
Graziano. J: Roberts. R. (2005). Low-level environmental lead exposure and children's
intellectual function: An international pooled analysis. Environ Health Perspect 113: 894-899.
http://dx.doi.org/10.1289/ehp.7688
Lanphear. BP: Hornung. R; Khourv. J: Yolton. K; Baghurst. P; Bellinger. DC: Canfield. RL: Dietrich.
KN: Bornschein. R; Greene. T; Rothenberg. SJ: Needleman. HL: Schnaas. L; Wasserman. G:
Graziano. J: Roberts. R. (2019). Erratum: "Low-level environmental lead exposure and children's
intellectual function: An international pooled analysis" [Erratum], Environ Health Perspect 127:
099001. http://dx.doi.org/10.1289/EHP5685
Lassiter. MG: Owens. EO: Patel. MM: Kirrane. E: Madden. M: Richmond-Bryant. .1: Hines. E: Davis. A:
Vinikoor-Imler. L: Dubois. JJ. (2015). Cross-species coherence in effects and modes of action in
support of causality determinations in the U.S. Environmental Protection Agency's Integrated
Science Assessment for lead [Review]. Toxicology 330: 19-40.
http://dx.doi.Org/10.1016/i.tox.2015.01.015
Leggett. RW. (1993). An age-specific kinetic model of lead metabolism in humans [Review]. Environ
Health Perspect 101: 598-616. http://dx.doi.org/10.1289/ehp.93101598
Li. X: Zhang. B: Li. N: Ji. X: Liu. K: Jin. M. (2019). Zebrafish neurobehavioral phenomics applied as the
behavioral warning methods for fingerprinting endocrine disrupting effect by lead exposure at
environmentally relevant level. Chemosphere 231: 315-325.
http://dx.doi.Org/10.1016/i.chemosphere.2019.05.146
Mackowiak. TJ: Mischenko. IC: Butler. MJ: Richardson. JB. (2021). Trace metals and metalloids in peri-
urban soil and foliage across geologic materials, ecosystems, and development intensities in
Southern California. Journal of Soils and Sediments 21: 1713-1729.
http://dx.doi.org/10.1007/sll368-021-Q2893-3
External review draft
IS-106
Do not cite or quote
-------
Markich. SJ. (2021). Comparative embryo/larval sensitivity of Australian marine bivalves to ten metals:
A disjunct between physiology and phylogeny. Sci Total Environ 789: 147988.
http://dx.doi.Org/10.1016/i.scitotenv.2021.147988
McClelland. SC; Duraes Ribeiro. R; Mielke. HW: Finkelstein. ME; Gonzales. CR; Jones. JA; Komdeur.
J; Derrvberrv. E; Saltzberg. EB; Karubian. J. (2019). Sub-lethal exposure to lead is associated
with heightened aggression in an urban songbird. Sci Total Environ 654: 593-603.
http: //dx.doi .org/10.1016/i. scitotenv.2018.11.145
Melwani. AR; Gregorio. D; Jin. Y; Stephenson. M; Ichikawa. G; Siegel. E; Crane. D; Lauenstein. G;
Davis. JA. (2014). Mussel Watch update: Long-term trends in selected contaminants from coastal
California, 1977-2010. Mar Pollut Bull 81: 291-302.
http://dx.doi.Org/10.1016/i.marpolbul.2013.04.025
Munlev. KM: Brix. KV: Panlilio. J: Deforest. DK: Grosell. M. (2013). Growth inhibition in early life-
stage tests predicts full life-cycle toxicity effects of lead in the freshwater pulmonate snail,
Lymnaea stagnalis. Aquat Toxicol 128-129: 60-66.
http://dx.doi.Org/10.1016/i.aquatox.2012.ll.020
Nadella. SR: Tellis. M: Diamond. R: Smith. S: Bianchini. A: Wood. CM. (2013). Toxicity of lead and
zinc to developing mussel and sea urchin embryos: Critical tissue residues and effects of
dissolved organic matter and salinity. Comp Biochem Physiol C Toxicol Pharmacol 158: 72-83.
http://dx.doi.Org/10.1016/i.cbpc.2013.04.004
NASEM (National Academies of Sciences, Engineering, and Medicine). (2018). Progress toward
transforming the Integrated Risk Information System (IRIS) program: A 2018 evaluation.
Washington, DC: National Academies Press, http://dx.doi.org/10.17226/25086
NASEM (National Academies of Sciences, Engineering, and Medicine). (2022). Advancing the
framework for assessing causality of health and welfare effects to inform National Ambient Air
Quality Standards reviews. Washington, DC: National Academies Press.
http://dx.doi.org/10.17226/26612
NHLBI (National Institutes of Health, National Heart Lung and Blood Institute). (2017). NHLBI fact
book, fiscal year 2012: Disease statistics. Available online at
https ://web .archive .org/web/20170711012213/http ://www.nhlbi .nih.gov/about/documents/factboo
k/2012/chapter4 (accessed August 23, 2017).
OECD (Organisation for Economic Co-operation and Development). (2018). Users' Handbook
supplement to the Guidance Document for developing and assessing Adverse Outcome Pathways
(AOPs). In Series on Testing & Assessment No 233; Series on Adverse Outcome Pathways No 1.
(ENV/JM/MONO(2016) 12). Paris, France: OECD Publishing.
http://dx.doi.org/10.1787/5ilvlm9dlg32-en
Ports. K: Smolders. E: Lanno. R: Chowdhurv. MJ. (2021). Bioavailability and ecotoxicity of lead in soil:
Implications for setting ecological soil quality standards. Environ Toxicol Chem 40: 1948-1961.
http://dx.doi.org/10.1002/etc.5051
Parliament. E: Council. (2006). Regulation (EC) No 1907/2006 of the European Parliament and of the
Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and
Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending
Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission
Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission
Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC. Available online at https ://eur-
lex.europa.eu/eli/reg/2006/1907 (accessed August 16, 2022).
External review draft
IS-107
Do not cite or quote
-------
Pavnc-Sturgcs. DC; Gee. GC; Corv-Slechta. DA. (2021). Confronting Racism in Environmental Health
Sciences: Moving the Science Forward for Eliminating Racial Inequities Comment. Environ
Health Perspect 129. http://dx.doi.org/10.1289/ehp8186
Reynolds. EJ; Smith. DS; Chowdhurv. MJ; Hoang. TC. (2018). Chronic effects of lead exposure on
topsmelt fish (Atherinops affinis): Influence of salinity, organism age, and relative sensitivity to
other marine species. Environ Toxicol Chem 37: 2705-2713. http://dx.doi.org/10.1002/etc.4241
Richardson. JB; Donaldson. EC; Kaste. JM; Friedland. AJ. (2015). Forest floor lead, copper and zinc
concentrations across the northeastern United States: Synthesizing spatial and temporal
responses. Sci Total Environ 505: 851-859. http://dx.doi.org/10.1016/i.scitotenv.2014.10.023
Richardson. JB; Friedland. AJ; Kaste. JM; Jackson. BP. (2014). Forest floor lead changes from 1980 to
2011 and subsequent accumulation in the mineral soil across the Northeastern United States. J
Environ Qual 43: 926-935. http://dx.doi.org/10.2134/ieq2013.10.0435
Richmond-Bryant. J; Meng. O; Davis. A; Cohen. J; Lu. SE; Svendsgaard. D; Brown. JS; Tuttle. L;
Hubbard. H; Rice. J; Kirrane. E; Vinikoor-Imler. LC; Kotchmar. D; Hines. EP; Ross. M. (2014).
The influence of declining air lead levels on blood lead-air lead slope factors in children. Environ
Health Perspect 122: 754-760. http://dx.doi.org/10.1289/ehp.1307072
Richmond-Bryant. J; Meng. O; Davis. JA; Cohen. J; Svendsgaard. D; Brown. JS; Tuttle. L; Hubbard. H;
Rice. J; Kirrane. E; Vinikoor-Imler. L; Kotchmar. D; Hines. E; Ross. M. (2013). A multi-level
model of blood lead as a function of air lead. Sci Total Environ 461-462: 207-213.
http: //dx.doi .org/10.1016/i. scitotenv.2013.05.008
Ringenarv. MJ; Molof. AH; Tanacredi. JT; Schreibman. MP; Kostarelos. K. (2007). Long-term sediment
bioassay of lead toxicity in two generations of the marine amphipod Elasmopus laevis, S.I. Smith,
1873. Environ Toxicol Chem 26: 1700-1710. http://dx.doi.org/10.1897/06-303R1.1
Romero-Murillo. P; Espeio. W; Barra. R; Orrego. R. (2018). Embryo-larvae and juvenile toxicity of Pb
and Cd in Northern Chilean scallop Argopecten purpuratus. Environ Monit Assess 190: 16.
http://dx.doi.org/10.1007/slQ661-017-6373-9
Schwartz. J. (1994). Low-level lead exposure and children's IQ: A meta-analysis and search for a
threshold. Environ Res 65: 42-55. http://dx.doi.org/10.1006/enrs.1994.102Q
Smith. DB: Cannon. WF; Woodruff. LG; Solano. F; Kilburn. JE; Fev. PL. (2013). Geochemical and
mineralogical data for soils of the conterminous United States. (Data Series 801). Reston, VA:
U.S. Department of the Interior, U.S. Geological Survey, http ://pubs .usgs. gov/ds/801/
Stavner. L; Steenland. K; Dosemeci. M; Hertz-Picciotto. I. (2003). Attenuation of exposure-response
curves in occupational cohort studies at high exposure levels. Scand J Work Environ Health 29:
317-324. http://dx.doi.org/10.5271/siweh.737
Suter. GW. II; Norton. SB; Fairbrother. A. (2005). Individuals versus organisms versus populations in the
definition of ecological assessment endpoints. Integr Environ Assess Manag 1: 397-400.
http://dx.doi.org/10.1002/ieam.56300104Q9
Suter. GW; Rodier. DJ; Schwenk. S; Trover. ME; Tyler. PL; Urban. DJ; Wellman. MC; Wharton. S.
(2004). The U.S. Environmental Protection Agency's generic ecological assessment endpoints.
Hum Ecol Risk Assess 10: 967-981. http://dx.doi.org/10.1080/108070304908871Q4
U.S. EPA (U.S. Environmental Protection Agency). (1977). Air quality criteria for lead [EPA Report].
(EPA-600/8-77-017). Washington, DC.
http://nepis.epa.gov/Exe/ZvPURL.cgi?Dockev=20013GWR.txt
External review draft
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U.S. EPA (U.S. Environmental Protection Agency). (1978). National ambient air quality standard for
lead: final rules and proposed rulemaking. Fed Reg 43: 46246-46263.
U.S. EPA (U.S. Environmental Protection Agency). (1985). Ambient water quality criteria for lead - 1984
[EPA Report], (EPA 440/5-84-027). Washington, DC.
https://nepis.epa.gov/Exe/ZvPURL.cgi?Dockev=9100MJ9L.txt
U.S. EPA (U.S. Environmental Protection Agency). (1986a). Air quality criteria for lead [EPA Report].
(EPA/600/8-83/028aF-dF). Research Triangle Park, NC.
http://cfpub. epa.gov/ncea/cfm/recordisplav. cfm?deid=32647
U.S. EPA (U.S. Environmental Protection Agency). (1986b). Air quality criteria for lead: Volume I of IV
[EPA Report]. (EPA-600/8-83/028aF). Research Triangle Park, NC.
http://cfpub. epa.gov/ncea/cfin/recordisplav. cfm?deid=32647
U.S. EPA (U.S. Environmental Protection Agency). (1986c). Air quality criteria for lead: Volume II of IV
[EPA Report]. (EPA-600/8-83/028bF). Research Triangle Park, NC.
http://cfpub.epa.gov/ncea/cfin/recordisplav.cfin?deid=32647
U.S. EPA (U.S. Environmental Protection Agency). (1986d). Lead effects on cardiovascular function,
early development, and stature: An addendum to U.S. EPA Air Quality Criteria for Lead (1986)
[EPA Report], (EPA-600/8-83/028aF). Washington, DC.
U.S. EPA (U.S. Environmental Protection Agency). (1990). Air quality criteria for lead: Supplement to
the 1986 addendum [EPA Report]. (EPA/600/8-89/049F). Washington, DC.
https://nepis.epa.gov/Exe/ZvPDF.cgi?Dockev=30001IKR.PDF
U.S. EPA (U.S. Environmental Protection Agency). (2005). Ecological soil screening levels for lead:
Interim final. (OSWER Directive 9285.7-70). Washington, DC.
https://www.epa.gov/sites/default/files/2015-09/documents/eco-ssl lead.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2006a). Air quality criteria for lead [EPA Report].
(EPA/600/R-05/144aF-bF). Research Triangle Park, NC.
https://cfpub.epa.gov/ncea/risk/recordisplav.cfrn?deid=158823
U.S. EPA (U.S. Environmental Protection Agency). (2006b). Air quality criteria for lead (Final report,
2006): Volume I of II [EPA Report], (EPA/600/R-05/144aF). Washington, DC.
http: //cfpub. epa.gov/ncea/ CFM/recordisplav. cfin ?deid= 158823
U.S. EPA (U.S. Environmental Protection Agency). (2006c). Air quality criteria for lead (Final report,
2006): Volume II of II [EPA Report], (EPA/600/R-05/144bF). Washington, DC.
https://cfpub.epa.gov/ncea/risk/recordisplav.cfin?deid=158823
U.S. EPA (U.S. Environmental Protection Agency). (2006d). Air quality criteria for ozone and related
photochemical oxidants. (EPA/600/R-05/004aF-cF). Research Triangle Park, NC.
http://cfpub. epa.gov/ncea/cfm/recordisplav. cfin?deid= 149923
U.S. EPA (U.S. Environmental Protection Agency). (2008). Ambient aquatic life water quality criteria for
lead (draft). Washington, DC.
U.S. EPA (U.S. Environmental Protection Agency). (2013a). Integrated science assessment for lead [EPA
Report], (EPA/600/R-10/075F). Washington, DC.
https://nepis.epa.gov/Exe/ZvPURL.cgi?Dockev=P100K82L.txt
External review draft
IS-109
Do not cite or quote
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U.S. EPA (U.S. Environmental Protection Agency). (2013b). Integrated science assessment for ozone and
related photochemical oxidants [EPA Report]. (EPA/600/R-10/076F). Research Triangle Park,
NC: U.S. Environmental Protection Agency, Office of Research and Development, National
Center for Environmental Assessment-RTP Division.
http://cfpub.epa.gov/ncea/isa/recordisplav.cfm?deid=247492
U.S. EPA (U.S. Environmental Protection Agency). (2015). Preamble to the Integrated Science
Assessments [EPA Report]. (EPA/600/R-15/067). Research Triangle Park, NC: U.S.
Environmental Protection Agency, Office of Research and Development, National Center for
Environmental Assessment, RTP Division.
https://cfpub.epa.gov/ncea/isa/recordisplav.cfm?deid=310244
U.S. EPA (U.S. Environmental Protection Agency). (2016a). Integrated science assessment (ISA) for
oxides of nitrogen: Health criteria (Final report, Jan 2016) [EPA Report]. (EPA/600/R-15/068).
Washington, DC. https://cfpub.epa.gov/ncea/isa/recordisplav.cfm?deid=310879
U.S. EPA (U.S. Environmental Protection Agency). (2016b). National coastal condition assessment 2010
[EPA Report]. (EPA 841-R-15-006). Washington, DC: U.S. Environmental Protection Agency,
Office of Water, Office of Research and Development.
https://nepis.epa.gov/Exe/ZvPURL.cgi?Dockev=P100NZ64.txt
U.S. EPA (U.S. Environmental Protection Agency). (2019). Integrated Science Assessment (ISA) for
particulate matter (final report, Dec 2019) [EPA Report]. (EPA/600/R-19/188). Washington, DC.
https://cfpub. epa.gov/ncea/isa/recordisplav. cfm?deid=347534
U.S. EPA (U.S. Environmental Protection Agency). (2020). Integrated Science Assessment (ISA) for
ozone and related photochemical oxidants (final report, Apr 2020) [EPA Report]. (EPA/600/R-
20/012). Washington, DC. https://nepis.epa.gov/Exe/ZvPURL.cgi?Dockev=P1011 lKI.txt
U.S. EPA (U.S. Environmental Protection Agency). (2021). 2017 National Emissionslinventory: January
2021 updated release, technical support document [EPA Report]. (EPA-454/R-21-001). Research
Triangle Park, NC. https://www.epa.gov/sites/default/files/2021-
02/documents/nei2017 tsd full ian2021.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2022a). Integrated review plan for the National
Ambient Air Quality Standards for lead. Volume 2: Planning for the review and the Integrated
Science Assessment [EPA Report]. (EPA-452/R-22-003b). Research Triangle Park, NC: U.S.
Environmental Protection Agency, Office of Air Quality Planning and Standards and Office of
Research and Development. https://nepis.epa.gov/Exe/ZvPURL.cgi?Dockev=P10148PX.txt
U.S. EPA (U.S. Environmental Protection Agency). (2022b). Overview of lead (Pb) air quality in the
United States, 2021. Washington, DC.
Vardv. DW; Santore. R; Ryan. A; Giesv. JP; Hecker. M. (2014). Acute toxicity of copper, lead, cadmium,
and zinc to early life stages of white sturgeon (Acipenser transmontanus) in laboratory and
Columbia River water. Environ Sci Pollut Res Int 21: 8176-8187.
http://dx.doi.org/10.1007/sll356-014-2754-6
Wang. N: Ingersoll. CG: Ivev. CD: Hardestv. DK; May. TW: Augspurger. T; Roberts. AD; van
Genderen. E: Barnhart. MC. (2010). Sensitivity of early life stages of freshwater mussels
(Unionidae) to acute and chronic toxicity of lead, cadmium, and zinc in water. Environ Toxicol
Chem 29: 2053-2063. http://dx.doi.org/10.1002/etc.250
Wang. O: Liu. B: Yang. H: Wang. X: Lin. Z. (2009). Toxicity of lead, cadmium and mercury on
embryogenesis, survival, growth and metamorphosis of Meretrix meretrix larvae. Ecotoxicology
18: 829-837. http://dx.doi.org/10.1007/slQ646-009-0326-l
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Woodruff. L; Cannon. WF; Smith. DB; Solano. F. (2015). The distribution of selected elements and
minerals in soil of the conterminous United States. J Geochem Explor 154: 49-60.
http://dx.doi.Org/10.1016/i.gexplo.2015.01.006
Zhao. J; Zhang. Q; Zhang. B; Xu. T; Yin. D; Gu. W; Bai. J. (2020). Developmental exposure to lead at
environmentally relevant concentrations impaired neurobehavior and NMDAR-dependent BDNF
signaling in zebrafish larvae. Environ Pollut 257: 113627.
http://dx.doi.Org/10.1016/i.envpol.2019.113627
Zhu. B; Wang. Q; Wang. X; Zhou. B. (2014). Impact of co-exposure with lead and decabromodiphenyl
ether (BDE-209) on thyroid function in zebrafish larvae. Aquat Toxicol 157: 186-195.
http://dx.doi.Org/10.1016/i.aquatox.2014.10.011
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