October 2006 

EPA/600/R-05/144bF 

Air Quality Criteria for Lead 

Volume II of II 
EPA/600/R-05/144bF 

October 2006 

Air Quality Criteria for Lead 

Volume II 

National Center for Environmental Assessment-RTP Division 

Office of Research and Development 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 
PREFACE

National Ambient Air Quality Standards (NAAQS) are promulgated by the United States 

Environmental Protection Agency (EPA) to meet requirements set forth in Sections 108 and 109 

of the U.S. Clean Air Act. Those two Clean Air Act sections require the EPA Administrator 

(1) to list widespread air pollutants that reasonably may be expected to endanger public health or 

welfare; (2) to issue air quality criteria for them that assess the latest available scientific 

information on nature and effects of ambient exposure to them; (3) to set “primary” NAAQS to 

protect human health with adequate margin of safety and to set “secondary” NAAQS to protect 

against welfare effects (e.g., effects on vegetation, ecosystems, visibility, climate, manmade 

materials, etc); and (5) to periodically review and revise, as appropriate, the criteria and NAAQS 

for a given listed pollutant or class of pollutants. 

Lead was first listed in the mid-1970’s as a “criteria air pollutant” requiring NAAQS 

regulation. The scientific information pertinent to Pb NAAQS development available at the time 

was assessed in the EPA document Air Quality Criteria for Lead; published in 1977. Based on 

the scientific assessments contained in that 1977 lead air quality criteria document (1977 Lead 

AQCD), EPA established a 1.5 μg/m3

 (maximum quarterly calendar average) Pb NAAQS in 

1978. 

To meet Clean Air Act requirements noted above for periodic review of criteria and 

NAAQS, new scientific information published since the 1977 Lead AQCD was later assessed in 

a revised Lead AQCD and Addendum published in 1986 and in a Supplement to the 1986 

AQCD/Addendum published by EPA in 1990. A 1990 Lead Staff Paper, prepared by EPA’s 

Office of Air Quality Planning and Standards (OPQPS), drew upon key findings and conclusions 

from the 1986 Lead AQCD/Addendum and 1990 Supplement (as well as other OAQPSsponsored lead exposure/risk analyses) in posing options for the EPA Administrator to consider 

with regard to possible revision of the Pb NAAQS. However, EPA chose not to revise the Pb 

NAAQS at that time. Rather, as part of implementing a broad 1991 U.S. EPA Strategy for 

Reducing Lead Exposure, the Agency focused primarily on regulatory and remedial clean-up 

efforts to reduce Pb exposure from a variety of non-air sources that posed more extensive public 

health risks, as well as other actions to reduce air emissions. 

The purpose of this revised Lead AQCD is to critically assess the latest scientific 

information that has become available since the literature assessed in the 1986 Lead 

II-iii 
AQCD/Addendum and 1990 Supplement, with the main focus being on pertinent new 

information useful in evaluating health and environmental effects of ambient air lead exposures. 

This includes discussion in this document of information regarding: the nature, sources, 

distribution, measurement, and concentrations of lead in the environment; multimedia lead 

exposure (via air, food, water, etc.) and biokinetic modeling of contributions of such exposures 

to concentrations of lead in brain, kidney, and other tissues (e.g., blood and bone concentrations, 

as key indices of lead exposure).; characterization of lead health effects and associated exposureresponse relationships; and delineation of environmental (ecological) effects of lead. This final 

version of the revised Lead AQCD mainly assesses pertinent literature published or accepted for 

publication through December 2005. 

The First External Review Draft (dated December 2005) of the revised Lead AQCD 

underwent public comment and was reviewed by the Clean Air Scientific Advisory Committee 

(CASAC) at a public meeting held in Durham, NC on February 28-March 1, 2006. The public 

comments and CASAC recommendations received were taken into account in making 

appropriate revisions and incorporating them into a Second External Review Draft (dated May, 

2006) which was released for further public comment and CASAC review at a public meeting 

held June 28-29, 2006. In addition, still further revised drafts of the Integrative Synthesis 

chapter and the Executive Summary were then issued and discussed during an August 15, 2006 

CASAC teleconference call. Public comments and CASAC advice received on these latter 

materials, as well as Second External Review Draft materials, were taken into account in making 

and incorporating further revisions into this final version of this Lead AQCD, which is being 

issued to meet an October 1, 2006 court-ordered deadline. Evaluations contained in the present 

document provide inputs to an associated Lead Staff Paper prepared by EPA’s Office of Air 

Quality Planning and Standards (OAQPS), which poses options for consideration by the EPA 

Administrator with regard to proposal and, ultimately, promulgation of decisions on potential 

retention or revision, as appropriate, of the current Pb NAAQS. 

Preparation of this document has been coordinated by staff of EPA’s National Center for 

Environmental Assessment in Research Triangle Park (NCEA-RTP). NCEA-RTP scientific 

staff, together with experts from academia, contributed to writing of document chapters. Earlier 

drafts of document materials were reviewed by scientists from other EPA units and by non-EPA 

experts in several public peer consultation workshops held by EPA in July/August 2005. 

II-iv 
NCEA acknowledges the valuable contributions provided by authors, contributors, and 

reviewers and the diligence of its staff and contractors in the preparation of this document. The 

constructive comments provided by public commenters and CASAC that served as valuable 

inputs contributing to improved scientific and editorial quality of the document are also 

acknowledged by NCEA. 

DISCLAIMER 

Mention of trade names or commercial products in this document does not constitute 

endorsement or recommendation for use. 

. 

II-v 
Air Quality Criteria for Lead 

(Second External Review Draft) 

VOLUME I 

EXECUTIVE SUMMARY .........................................................................................................E-1 

1. INTRODUCTION ........................................................................................................... 1-1 

2. CHEMISTRY, SOURCES, AND TRANSPORT OF LEAD.......................................... 2-1 

3. ROUTES OF HUMAN EXPOSURE TO LEAD AND OBSERVED

ENVIRONMENTAL CONCENTRATIONS.................................................................. 3-1 

4. TOXICOKINETICS, BIOLOGICAL MARKERS, AND MODELS OF LEAD 

BURDEN IN HUMANS.................................................................................................. 4-1 

5. TOXICOLOGICAL EFFECTS OF LEAD IN LABORATORY ANIMALS

AND IN VITRO TEST SYSTEMS................................................................................. 5-1 

6. EPIDEMIOLOGIC STUDIES OF HUMAN HEALTH EFFECTS 

ASSOCIATED WITH LEAD EXPOSURE .................................................................... 6-1 

7. ENVIRONMENTAL EFFECTS OF LEAD ................................................................... 7-1 

8. INTEGRATIVE SYNTHESIS OF LEAD EXPOSURE/HEALTH 

EFFECTS INFORMATION............................................................................................ 8-1 

VOLUME II 

CHAPTER 4 ANNEX (TOXICOKINETICS, BIOLOGICAL MARKERS, AND 

MODELS OF LEAD BURDEN IN HUMANS) ............................................. AX4-1 

CHAPTER 5 ANNEX (TOXICOLOGICAL EFFECTS OF LEAD IN 

LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS) ................ AX5-1 

CHAPTER 6 ANNEX (EPIDEMIOLOGIC STUDIES OF HUMAN HEALTH 

EFFECTS ASSOCIATED WITH LEAD EXPOSURE) ................................. AX6-1 

CHAPTER 7 ANNEX (ENVIRONMENTAL EFFECTS OF LEAD).................................. AX7-1 

II-vi 
Table of Contents 

Page

PREFACE .................................................................................................................................. II-iii 

DISCLAIMER ............................................................................................................................ II-v 

List of Tables .............................................................................................................................. II-x 

Authors, Contributors, and Reviewers..................................................................................... II-xxi

U.S. Environmental Protection Agency Project Team for Development of Air 

Quality Criteria for Lead................................................................................................. II-xxvii 

U.S. Environmental Protection Agency Science Advisory Board (SAB) Staff 

Office Clean Air Scientific Advisory Committee (CASAC)........................................... II-xxix 

Abbreviations and Acronyms ................................................................................................ II-xxxi

AX4. CHAPTER 4 ANNEX (TOXICOKINETICS, BIOLOGICAL MARKERS, 

AND MODELS OF LEAD BURDEN IN HUMANS) ................................... AX4-1 

 REFERENCES ...................................................................................................... AX4-44 

II-vii 
List of Tables 

Page

AX4-1 Analytical Methods for Determining Lead in Blood, Urine, and Hair ............ AX4-2 

AX4-2 Summary of Selected Measurements of PbB Levels in Humans .................... AX4-4 

AX4-3 Bone Lead Measurements in Cadavers............................................................ AX4-7 

AX4-4 Bone Lead Measurements in Environmentally-Exposed Subjects .................. AX4-9 

AX4-5 Bone Lead Measurements in Occupationally-Exposed Subjects................... AX4-12 

AX4-6 Bone Lead Contribution to PbB..................................................................... AX4-19 

AX4-7 Bone Lead Studies in Pregnant and Lactating Subjects................................. AX4-22 

AX4-8 Bone Lead Studies of Menopausal and Middle-aged to Elderly Subjects..... AX4-30 

AX4-9 Lead in Deciduous Teeth from Urban and Remote Environments................ AX4-36 

AX4-10 Lead in Deciduous Teeth from Polluted Environments................................. AX4-38 

AX4-11 Summary of Selected Measurements of Urine Lead Levels in Humans ....... AX4-39 

AX4-12 Summary of Selected Measurements of Hair Lead Levels in Humans ......... AX4-42 

II-x 
Authors, Contributors, and Reviewers 

CHAPTER 4 ANNEX (TOXICOKINETICS, BIOLOGICAL MARKERS, AND 

MODELS OF LEAD BURDEN IN HUMANS) 

Chapter Managers/Editors 

Dr. James Brown—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Principal Authors 

Dr. Brian Gulson—Graduate School of the Environment, Macquarie University 

Sydney, NSW 2109, Australia 

Contributors and Reviewers 

Dr. Lester D. Grant—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

CHAPTER 5 ANNEX (TOXICOLOGICAL EFFECTS OF LEAD IN HUMANS 

AND LABORATORY ANIMALS) 

Chapter Managers/Editors 

Dr. Anuradha Mudipalli—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Srikanth Nadadur—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Lori White—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Principal Authors 

Dr. Anuradha Mudipalli—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Sections 5-2, 5-10) 

II-xxi 
Authors, Contributors, and Reviewers 

(cont’d) 

Principal Authors 

(cont’d) 

Dr. Stephen Lasley—Dept. of Biomedical and Therapeutic Sciences, Univ. of Illinois College of 

Medicine, PO Box 1649, Peoria, IL 61656 (Section 5.3) 

Dr. Lori White—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Section 5.3) 

Dr. Gary Diamond— Syracuse Research Corporation, 8191 Cedar Street, Akron, NY 14001 

(Section 5.4) 

Dr. N.D. Vaziri—Division of Nephrology and Hypertension, University of California – Irvine 

Medical Center, 101, The City Drive, Bldg 53, Room #125. Orange, CA 92868 (Section 5.5) 

Dr. John Pierce Wise, Sr.—Maine Center for Toxicology and Environmental Health, 

Department of Applied Medical Sciences, 96 Falmouth Street, PO Box 9300, Portland, ME 

04104-9300 (Section 5.6) 

Dr. Harvey C. Gonick—David Geffen School of Medicine, University of California at 

Los Angeles, 201 Tavistock Ave, Los Angeles, CA 90049 (Sections 5.7, 5.11) 

Dr. Gene E. Watson—University of Rochester Medical Center, Box 705, Rochester, NY 14642 

(Section 5.8) 

Dr. Rodney Dietert—Institute for Comparative and Environmental Toxicology, College of 

Veterinary Medicine, Cornell University, Ithaca, NY 14853 (Section 5.9) 

Contributors and Reviewers 

Dr. Lester D. Grant—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Paul Reinhart—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Michael Davis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. David A. Lawrence—Dept of Environmental and Clinical Immunology, Empire State Plaza 

P.O. Box 509, Albany, NY 12201 

II-xxii 
Authors, Contributors, and Reviewers 

(cont’d) 

Contributors and Reviewers 

(cont’d) 

Dr. Michael J. McCabe, Jr.—Dept of Environmental Medicine, University of Rochester, 

575 Elmwood Avenue, Rochester, NY 14642 

Dr. Theodore I. Lidsky—New York State Institute for Basic Research, 1050 Forest RD, 

Staten Island, NY 10314 

Dr. Mark H. Follansbee—Syracuse Research Corporation, 8191 Cedar St. Akron, NY 14001 

Dr. William K. Boyes—National Health and Environmental Effects Research Laboratory, 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Philip J. Bushnell—National Health and Environmental Effects Research Laboratory, 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Ms. Beth Hassett-Sipple—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Zachary Pekar—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

CHAPTER 6 ANNEX (EPIDEMIOLOGICAL STUDIES OF AMBIENT LEAD 

EXPOSURE EFFECTS) 

Chapter Managers/Editors 

Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

II-xxiii 
Authors, Contributors, and Reviewers 

(cont’d) 

Principal Authors 

Dr. David Bellinger—Children’s Hospital, Farley Basement, Box 127, 300 Longwood Avenue, 

Boston, MA 02115 (Section 6.10) 

Dr. Margit Bleecker—Center for Occupational and Environmental Neurology, 2 Hamill Road, 

Suite 225, Baltimore, MD 21210 (Section 6.3) 

Dr. Gary Diamond— Syracuse Research Corporation, 8191 Cedar Street. 

Akron, NY 14001 (Section 6.8, 6.9) 

Dr. Kim Dietrich—University of Cincinnati College of Medicine, 3223 Eden Avenue, 

Kettering Laboratory, Room G31, Cincinnati, OH 45267 (Section 6.2) 

Dr. Pam Factor-Litvak—Columbia University Mailman School of Public Health, 722 West 

168th Street, Room 1614, New York, NY 10032 (Section 6.6) 

Dr. Vic Hasselblad—Duke University Medical Center, Durham, NC 27713 (Section 6.10) 

Dr. Stephen J. Rothenberg—CINVESTAV-IPN, Mérida, Yucatán, México & National Institute 

of Public Health, Cuernavaca, Morelos, Mexico (Section 6.5) 

Dr. Neal Simonsen—Louisiana State University Health Sciences Center, School of Public Health 

& Stanley S Scott Cancer Center, 1600 Canal Street, Suite 800, New Orleans, LA 70112 

(Section 6.7) 

Dr. Kyle Steenland—Rollins School of Public Health, Emory University, 1518 Clifton Road, 

Room 268, Atlanta, GA 30322 (Section 6.7) 

Dr. Virginia Weaver—Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe 

Street, Room 7041, Baltimore, MD 21205 (Section 6.4) 

Contributors and Reviewers 

Dr. J. Michael Davis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Lester D. Grant—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Kazuhiko Ito—Nelson Institute of Environmental Medicine, New York University School of 

Medicine, Tuxedo, NY 10987 

II-xxiv 
Authors, Contributors, and Reviewers 

(cont’d) 

Contributors and Reviewers 

(cont’d) 

Dr. Kathryn Mahaffey—Office of Prevention, Pesticides and Toxic Substances, 

U.S. Environmental Protection Agency, Washington, DC 20460 

Dr. Karen Martin—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Zachary Pekar—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Ms. Beth Hassett-Sipple—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

CHAPTER 7 ANNEX (ENVIRONMENTAL EFFECTS OF LEAD) 

Chapter Manager/Editor 

Dr. Timothy Lewis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Principle Authors 

Dr. Ruth Hull—Cantox Environmental Inc., 1900 Minnesota Court, Suite 130, Mississauga, 

Ontario, L5N 3C9 Canada (Section 7.1) 

Dr. James Kaste—Department of Earth Sciences, Dartmouth College, 352 Main Street, Hanover, 

NH 03755 (Section 7.1) 

Dr. John Drexler—Department of Geological Sciences, University of Colorado, 1216 Gillespie 

Drive, Boulder, CO 80305 (Section 7.1) 

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

365 Link Hall, Syracuse, NY 13244 (Section 7.1) 

Dr. William Stubblefield—Parametrix, Inc. 33972 Texas St. SW, Albany, OR 97321 

(Section 7.2) 

II-xxv 
Authors, Contributors, and Reviewers 

(cont’d) 

Principle Authors 

(cont’d) 

Dr. Dwayne Moore—Cantox Environmental, Inc., 1550A Laperriere Avenue, Suite 103, 

Ottawa, Ontario, K1Z 7T2 Canada (Section 7.2) 

Dr. David Mayfield—Parametrix, Inc., 411 108th Ave NE, Suite 1800, Bellevue, WA 98004 

(Section 7.2) 

Dr. Barbara Southworth—Menzie-Cura & Associates, Inc., 8 Winchester Place, Suite 202, 

Winchester, MA 01890 (Section 7.3) 

Dr. Katherine Von Stackleberg—Menzie-Cura & Associates, Inc., 8 Winchester Place, Suite 

202, Winchester, MA 01890 (Section 7.3) 

Contributors and Reviewers 

Dr. Jerome Nriagu—Department of Environmental Health Sciences, 109 South Observatory, 

University of Michigan, Ann Arbor, MI 48109 

Dr. Judith Weis—Department of Biology, Rutgers University, Newark, NJ 07102 

Dr. Sharon Harper—National Exposure Research Laboratory (D205-05), U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Karen Bradham—National Research Exposure Laboratory (D205-05), U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Ginger Tennant—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Ms. Gail Lacey—Office of Air Quality Planning and Standards, U.S. Environmental Protection 

Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

II-xxvi 
U.S. Environmental Protection Agency Project Team 

for Development of Air Quality Criteria for Lead 

Executive Direction 

Dr. Lester D. Grant (Director)—National Center for Environmental Assessment-RTP Division, 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Scientific Staff 

Dr. Lori White (Lead Team Leader)—National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. James S. Brown—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Robert Elias—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Retired) 

Dr. Brooke Hemming—National Center for Environmental Assessment (B243-01), U.S. 

Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Timothy Lewis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Anuradha Muldipalli—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Srikanth Nadadur—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Paul Reinhart—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Mary Ross— National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

II-xxvii 
U.S. Environmental Protection Agency Project Team 

for Development of Air Quality Criteria for Lead 

(cont’d) 

Technical Support Staff 

Mr. Douglas B. Fennell—Technical Information Specialist, National Center for Environmental 

Assessment (B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 

27711 (Retired) 

Ms. Emily R. Lee—Management Analyst, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Ms. Diane H. Ray—Program Specialist, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Ms. Donna Wicker—Administrative Officer, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Retired) 

Mr. Richard Wilson—Clerk, National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Document Production Staff 

Ms. Carolyn T. Perry—Task Order Manager, Computer Sciences Corporation, 2803 Slater Road, 

Suite 220, Morrisville, NC 27560 

Mr. John A. Bennett—Technical Information Specialist, Library Associates of Maryland, 

11820 Parklawn Drive, Suite 400, Rockville, MD 20852 

Mr. William Ellis—Records Management Technician, InfoPro, Inc., 8200 Greensboro Drive, 

Suite 1450, McLean, VA 22102 

Ms. Sandra L. Hughey—Technical Information Specialist, Library Associates of Maryland, 

11820 Parklawn Drive, Suite 400, Rockville, MD 20852 

Dr. Barbara Liljequist—Technical Editor, Computer Sciences Corporation, 2803 Slater Road, 

Suite 220, Morrisville, NC 27560 

Ms. Michelle Partridge-Doerr—Publications/Graphics Specialist, TEK Systems, 1201 Edwards 

Mill Road, Suite 201, Raleigh, NC 27607 

Mr. Carlton Witherspoon—Graphic Artist, Computer Sciences Corporation, 2803 Slater Road, 

Suite 220, Morrisville, NC 27560 

II-xxviii 
U.S. Environmental Protection Agency 

Science Advisory Board (SAB) Staff Office 

Clean Air Scientific Advisory Committee (CASAC) 

Chair 

Dr. Rogene Henderson*—Scientist Emeritus, Lovelace Respiratory Research Institute, 

Albuquerque, NM 

Members 

Dr. Joshua Cohen—Faculty, Center for the Evaluation of Value and Risk, Institute for Clinical 

Research and Health Policy Studies, Tufts New England Medical Center, Boston, MA 

Dr. Deborah Cory-Slechta—Director, University of Medicine and Dentistry of New Jersey and 

Rutgers State University, Piscataway, NJ 

Dr. Ellis Cowling*—University Distinguished Professor-at-Large, North Carolina State 

University, Colleges of Natural Resources and Agriculture and Life Sciences, North Carolina 

State University, Raleigh, NC 

Dr. James D. Crapo [M.D.]*—Professor, Department of Medicine, National Jewish Medical and 

Research Center, Denver, CO 

Dr. Bruce Fowler—Assistant Director for Science, Division of Toxicology and Environmental 

Medicine, Office of the Director, Agency for Toxic Substances and Disease Registry, U.S. 

Centers for Disease Control and Prevention (ATSDR/CDC), Chamblee, GA 

Dr. Andrew Friedland—Professor and Chair, Environmental Studies Program, Dartmouth 

College, Hanover, NH 

Dr. Robert Goyer [M.D.]—Emeritus Professor of Pathology, Faculty of Medicine, University of 

Western Ontario (Canada), Chapel Hill, NC 

Mr. Sean Hays—President, Summit Toxicology, Allenspark, CO 

Dr. Bruce Lanphear [M.D.]—Sloan Professor of Children’s Environmental Health, and the 

Director of the Cincinnati Children’s Environmental Health Center at Cincinnati Children’s 

Hospital Medical Center and the University of Cincinnati, Cincinnati, OH 

Dr. Samuel Luoma—Senior Research Hydrologist, U.S. Geological Survey (USGS), 

Menlo Park, CA 

II-xxix 
U.S. Environmental Protection Agency 

Science Advisory Board (SAB) Staff Office 

Clean Air Scientific Advisory Committee (CASAC) 

(cont’d) 

Members 

(cont’d) 

Dr. Frederick J. Miller*—Consultant, Cary, NC 

Dr. Paul Mushak—Principal, PB Associates, and Visiting Professor, Albert Einstein College of 

Medicine (New York, NY), Durham, NC 

Dr. Michael Newman—Professor of Marine Science, School of Marine Sciences, Virginia 

Institute of Marine Science, College of William & Mary, Gloucester Point, VA 

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

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

Dr. Michael Rabinowitz—Geochemist, Marine Biological Laboratory, Woods Hole, MA 

Dr. Joel Schwartz—Professor, Environmental Health, Harvard University School of Public 

Health, Boston, MA 

Dr. Frank Speizer [M.D.]*—Edward Kass Professor of Medicine, Channing Laboratory, Harvard 

Medical School, Boston, MA 

Dr. Ian von Lindern—Senior Scientist, TerraGraphics Environmental Engineering, Inc., 

Moscow, ID 

Dr. Barbara Zielinska*—Research Professor, Division of Atmospheric Science, Desert Research 

Institute, Reno, NV 

SCIENCE ADVISORY BOARD STAFF 

Mr. Fred Butterfield—CASAC Designated Federal Officer, 1200 Pennsylvania Avenue, N.W., 

Washington, DC, 20460, Phone: 202-343-9994, Fax: 202-233-0643 (butterfield.fred@epa.gov) 

(Physical/Courier/FedEx Address: Fred A. Butterfield, III, EPA Science Advisory Board Staff 

Office (Mail Code 1400F), Woodies Building, 1025 F Street, N.W., Room 3604, Washington, 

DC 20004, Telephone: 202-343-9994) 

*Members of the statutory Clean Air Scientific Advisory Committee (CASAC) appointed by the 

U.S. EPA Administrator 

II-xxx 
Abbreviations and Acronyms 

αFGF α-fibroblast growth factor 

AA arachidonic acid 

AAL active avoidance learning 

AAS atomic absorption spectroscopy 

ABA β-aminoisobutyric acid 

ACBP Achenbach Child Behavior Profile 

ACE angiotensin converting enzyme 

ACh acetylcholine 

AChE acetylcholinesterase 

ACR acute-chronic ratio 

AD adult 

ADC analog digital converter 

ADP adenosine diphosphate 

AE anion exchange 

AEA N-arachidonylethanolamine 

AFC antibody forming cells 

2-AG 2-arachidonylglycerol 

A horizon uppermost layer of soil (litter and humus) 

AHR aryl hydrocarbon receptor 

AI angiotensin I 

ALA *-aminolevulinic acid 

ALAD *-aminolevulinic acid dehydratase 

ALAS aminolevulinic acid synthetase 

ALAU urinary δ-aminolevulinic acid 

ALD aldosterone 

ALS amyotrophic lateral sclerosis 

ALT alanine aminotransferase 

ALWT albumin weight 

AMEM Alpha Minimal Essential Medium 

AMP adenosine monophosphate 

ANCOVA analysis of covariance 

ANF atrial natriuretic factor 

Ang II angiotensin II 

ANOVA analysis of variance 

II-xxxi 
ANP atrial natriuretic peptide 

AP alkaline phosphatase 

AP-1 activated protein-1 

ApoE apolipoprotein E 

AQCD Air Quality Criteria Document 

Arg arginine 

AS52 cells derived from the CHO cell line 

ASGP-R aceyl glycoprotein receptor 

AST aspartate aminotransferase 

ASV anode stripping voltammetry 

3-AT 3-aminotriazole; 3-amino triazide 

ATP adenosine triphosphate 

ATP1A2 sodium-potassium adenosine triphosphase α2 

ATPase adenosine triphosphatase 

ATSDR Agency for Toxic Substances and Disease Research 

AVCD atrioventricular conduction deficit 

AVS acid volatile sulfide 

AWQC ambient water quality criteria 

$ beta-coefficient; slope of an equation 

$FGF $-fibroblast growth factor 

17$–HS 17$-hydroxysteriod 

3$-HSD 3$-hydroxysteriod dehydrogenase 

17$-HSDH 17$-hydroxysteriod dehydrogenase 

6$-OH-cortisol 6-$-hydroxycortisol 

B both 

BAEP brainstem auditory-evoked potentials 

BAER brainstem auditory-evoked responses 

BAF bioaccumulation factor 

B cell B lymphocyte 

BCFs bioconcentration factors 

BCS bovine calf serum 

BDNF brain derived neurotrophic factor 

BDWT body weight changes 

BEI biological exposure index 

BFU-E blood erythroid progenitor 

II-xxxii 
BLL blood lead level 

BLM biotic ligand model 

BM basement membrane 

BMI body mass index 

BDNF brain-derived neurotrophic factor 

BOTMP Bruinicks-Oseretsky Test of Motor Proficiency 

BP blood pressure 

BPb blood lead concentration 

BSA bovine serum albumin 

BSI Brief Symptom Inventory 

BTQ Boston Teacher Questionnaire 

BUN blood urea nitrogen 

bw, b. wt., BW body weight 

C3H10T/12 mouse embryo cell line 

C3, C4 complement proteins 

CA chromosome aberration 

CA3 cornu ammonis 3 region of hippocampus 

45Ca calcium-45 radionuclide 

Ca-ATP calcium-dependent adenosine triphosphate 

Ca-ATPase calcium-dependent adenosine triphosphatase 

CaCO3 calcium carbonate 

CaEDTA calcium disodium ethylenediaminetetraacetic acid 

CAL calcitonin 

CaM calmodulin 

Ca-Mg-ATPase calcium-magnesium-dependent adenosine triphosphatase 

cAMP cyclic adenosinemonophosphate 

CaNa2 EDTA calcium disodium ethylenediaminetetraacetic acid 

CANTAB Cambridge Neuropsychological Testing Automated Battery 

CAT catalase; Cognitive Abilities Test 

CBCL Achenbach Child Behavior Checklist 

CBCL-T Total Behavior Problem Score 

CBL cumulative blood lead 

CBLI cumulative blood lead index 

CCB cytochalasin B 

CCD charge-coupled device 

II-xxxiii 
CCE Coordination Center for Effects 

CCL carbon tetrachloride 

CCS cosmic calf serum 

C-CVRSA coefficient of component variance of respiratory sinus 

arrhythmia 

Cd cadmium 

109Cd cadmium-109 radionuclide 

CdU urinary cadmium 

CEC cation exchange capacity 

CESD, CES-D Center for Epidemiologic Studies Depression (scale) 

GFAP glial fibrillary acidic protein 

CFU-E colony forming unit blood-erythroid progenitor (cell count) 

CFU-GEMM colony forming unit blood-pluripotent progenitor (cell count) 

CFU-GM blood granulocyte/macrophage progenitor (cell count) 

cGMP cyclic guanosine-3',5'-monophosphate 

ChAT choline acetyltransferase 

CHD coronary heart disease 

CHO Chinese hamster ovary cell line 

CI confidence interval 

CLE-SV competitive ligand-exchange/stripping voltammetry 

CLRTAP Convention on Long-Range Transboundary of Air Pollution 

CLS Cincinnati Lead Study 

CMC criterion maximum concentration 

CMI cell-mediated immunity 

CNS central nervous system 

COH cation-osmotic hemolysis 

ConA concanavalin A 

COR cortisol 

CoTx cotreatment 

COX-2 cyclooxygenase-2 

CP coproporphryn 

CPT current perception threshold 

cr creatinine 

CRAC calcium release activated calcium reflux 

CREB cyclic AMP-response element binding protein 

CRF chronic renal failure 

II-xxxiv 
CV 

CRI chronic renal insufficiency 

CSF cerebrospinal fluid 

CuZn-SOD copper and zinc-dependent superoxide dismutase 

conduction velocity 

CVLT California Verbal Learning Test 

CVR-R coefficient of variation of the R-R interval 

CYP cytochrome (e.g., CYP1A, CYP-2A6, CYP3A4, CYP450) 

CYP3a11 cytochrome P450 3a11 

D D-statistic 

DA dopamine; dopaminergic 

dbcAMP dibutyryl cyclic adenosine-3',5'-monophosphate 

DCV distribution of conduction velocities 

DEAE diethylaminoethyl (chromatography) 

DET diffusive equilibrium thin films 

DEYO death of young 

DFS decayed or filled surfaces, permanent teeth 

dfs covariate-adjusted number of caries 

DG dentate gyrus 

DGT diffusive gradient thin films 

DL DL-statistic 

DMEM Dulbecco’s Minimal Essential Medium 

DMEM/F12 Dulbecco’s Minimal Essential Medium/Ham’s F12 

DMFS decayed, missing, or filled surfaces, permanent teeth 

DMPS 2,3-dimercaptopropane 1-sulfonate 

DMSA 2,3-dimercaptosuccinic acid 

DMT Donnan membrane technique 

DMTU dimethylthiourea 

DNA deoxyribonucleic acid 

DO distraction osteogenesis 

DOC dissolved organic carbon 

DOM dissolved organic carbon 

DOPAc 3,4-dihydroxyphenylacetic acid 

DPASV differential pulse anodic stripping voltammetry 

dp/dt rate of left ventricular isovolumetric pressure 

DPPD N-N-diphenyl-p-phynylene-diamine 

II-xxxv 
DR drinking water 

DSA delayed spatial alternation 

DTC diethyl dithiocarbomate complex 

DTH delayed type hypersensitivity 

DTPA diethylenetriaminepentaacetic acid 

DTT dithiothreitol 

dw dry weight 

E embryonic day 

E2 estradiol 

EBE early biological effect 

EBV Epstein-Barr virus 

EC European Community 

EC50 effect concentration for 50% of test population 

eCB endocannabinoid 

ECG electrocardiogram 

Eco-SSL ecological soil screening level 

EDS energy dispersive spectrometers 

EDTA ethylenediaminetetraacetic acid 

EEDQ N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinone 

EEG electroencephalogram 

EG egg 

EGF epidermal growth factor 

EGG effects on eggs 

EGPN egg production 

EKG electrocardiogram 

electro electrophysiological stimulation 

EM/CM experimental medium-to-control medium (ratio) 

EMEM Eagle’s Minimal Essential Medium 

eNOS endothelial nitric oxide synthase 

EP erythrocyte protoporphyrin 

EPA U.S. Environmental Protection Agency 

Epi epinephrine 

EPMA electron probe microanalysis 

EPO erythropoietin 

EPSC excitatory postsynaptic currents 

II-xxxvi 
EPT macroinvertebrates from the Ephemeroptera (mayflies), 

Plecoptera (stoneflies), and Trichoptera (caddisflies) group 

ERG electroretinogram; electroretinographic 

ERL effects range – low 

ERM effects range – median 

EROD ethoxyresorufin-O-deethylase 

ESCA electron spectroscopy for chemical analysis 

ESRD end-stage renal disease 

EST estradiol 

ESTH eggshell thinning 

ET endothelein; essential tremor 

ETOH ethyl alcohol 

EXAFS extended X-ray absorption fine structure 

EXANES extended X-ray absorption near edge spectroscopy 

F F-statistic 

F344 Fischer 344 (rat) 

FAV final acute value 

FBS fetal bovine serum 

FCS fetal calf serum 

FCV final chronic value 

FD food 

FEF forced expiratory flow 

FEP free erythrocyte protoporphyrin 

FERT fertility 

FEV1 forced expiratory volume in one second 

FGF fibroblast growth factor (e.g., βFGF, αFGF) 

FI fixed interval (operant conditioning) 

FIAM free ion activity model 

FMLP N-formyl-L-methionyl-L-leucyl-L-phenylalanine 

fMRI functional magnetic resonance imaging 

FR fixed-ratio operant conditioning 

FSH follicle stimulating hormone 

FT3 free triiodothyronine 

FT4 free thyroxine 

FTES free testosterone 

II-xxxvii 
FTII Fagan Test of Infant Intelligence 

FTPLM flow-through permeation liquid membranes 

FURA-2 1-[6-amino-2-(5-carboxy-2-oxazolyl)-5-benzofuranyloxy]-2-

(2-amino-5-methylphenoxy) ethane-N,N,N',N'-tetraacetic acid 

FVC forced vital capacity 

(-GT (-glutamyl transferase 

G gestational day 

GABA gamma aminobutyric acid 

GAG glycosaminoglycan 

G12 CHV79 cells derived from the V79 cell line 

GCI General Cognitive Index 

GD gestational day 

GDP guanosine diphosphate 

GEE generalized estimating equations 

GFAAS graphite furnace atomic absorption spectroscopy 

GFR glomerular filtration rate 

GGT (-glutamyl transferase 

GH growth hormone 

GI gastrointestinal 

GIME-VIP gel integrated microelectrodes combined with voltammetric 

in situ profiling 

GIS geographic information system 

GLU glutamate 

GMAV genus mean acute value 

GMCV genus mean chronic value 

GMP guanosine monophosphate 

GMPH general morphology 

GnRH gonadotropin releasing hormone 

GOT aspartate aminotransferase 

GP gross productivity 

G6PD, G6PDH glucose-6-phosphate dehydrogenase 

GPEI glutathione S-transferase P enhancer element 

gp91phox NAD(P)H oxidase 

GPT glutamic-pyruvic transaminase 

GPx glutathione peroxidase 

GRO growth 

II-xxxviii 
GRP78 glucose-regulated protein 78 

GSD geometric standard deviation 

GSH reduced glutathione 

GSIM gill surface interaction model 

GSSG glutathione disulfide 

GST glutathione-S-transferase 

GSTP placental glutathione transferase 

GTP guanosine triphosphate 

GV gavage 

H+

 acidity 

3

H hydrogen-3 radionuclide (tritium) 

HA humic acid; hydroxyapatite 

Hb hemoglobin 

HBEF Hubbard Brook Experimenatl Forest 

HBSS Hank’s Balanced Salt Solution 

HCG; hCG human chorionic gonadotropin 

Hct hematocrit 

HDL high-density lipoprotein (cholesterol) 

HEP habitat evaluation procedure 

HET Binghamton heterogeneous stock 

HFPLM hollow fiber permeation liquid membranes 

Hgb hemoglobin 

HGF hepatocyte growth factor 

HH hydroxylamine hydrochloride 

H-H high-high 

HHANES Hispanic Health and Nutrition Examination Survey 

H-L high-low 

HLA human leukocyte antigen 

H-MEM minimum essential medium/nutrient mixture–F12-Ham 

HMP hexose monophosphate shunt pathway 

HNO3 nitric acid 

H2O2 hydrogen peroxide 

HOME Home Observation for Measurement of Environment 

HOS TE human osteosarcoma cells 

HPLC high-pressure liquid chromatography 

II-xxxix 
H3PO4 phosphoric acid 

HPRT hypoxanthine phosphoribosyltransferase (gene) 

HR heart rate 

HSI habitat suitability indices 

H2SO4 sulfuric acid 

HSPG heparan sulfate proteoglycan 

Ht hematocrit 

HTC hepatoma cells 

hTERT catalytic subunit of human telomerase 

HTN hypertension 

IBL integrated blood lead index 

IBL H WRAT-R integrated blood lead index H Wide Range Achievement 

Test-Revised (interaction) 

ICD International Classification of Diseases 

ICP inductively coupled plasma 

ICP-AES inductively coupled plasma atomic emission spectroscopy 

ICP-MS, ICPMS inductively coupled plasma mass spectrometry 

ID-MS isotope dilution mass spectrometry 

IFN interferon (e.g., IFN-() 

Ig immunoglobulin (e.g., IgA, IgE, IgG, IgM) 

IGF-1 insulin-like growth factor 1 

IL interleukin (e.g., IL-1, IL-1$, IL-4, IL-6, IL-12) 

ILL incipient lethal level 

immuno immunohistochemical staining 

IMP inosine monophosphate 

iNOS inducible nitric oxide synthase 

i.p., IP intraperitoneal 

IPSC inhibitory postsynaptic currents 

IQ intelligence quotient 

IRT interresponse time 

ISEL in situ end labeling 

ISI interstimulus interval 

i.v., IV intravenous 

IVCD intraventricular conduction deficit 

JV juvenile 

II-xl 
KABC Kaufman Assessment Battery for Children 

KTEA Kaufman Test of Educational Achievement 

KXRF, K-XRF K-shell X-ray fluorescence 

LA lipoic acid 

LB laying bird 

LC lactation 

LC50 lethal concentration at which 50% of exposed animals die 

LC74 lethal concentration at which 74% of exposed animals die 

LD50 lethal dose at which 50% of exposed animals die 

LDH lactate dehydrogenase 

LDL low-density lipoprotein (cholesterol) 

L-dopa 3,4-dihydroxyphenylalanine (precursor of dopamine) 

LE Long Evans (rat) 

LET linear energy transfer (radiation) 

LH luteinizing hormone 

LHRH luteinizing hormone releasing hormone 

LN lead nitrate 

L-NAME L-NG-nitroarginine methyl ester 

LOAEL lowest-observed adverse effect level 

LOEC lowest-observed-effect concentration 

LOWESS locally weighted scatter plot smoother 

LPO lipoperoxide 

LPP lipid peroxidation potential 

LPS lipopolysaccharide 

LT leukotriene 

LT50 time to kill 50% 

LTER Long-Term Ecological Research (sites) 

LTP long term potentiation 

LVH left ventricular hypertrophy 

μPIXE microfocused particle induced X-ray emission 

μSXRF microfocused synchrotron-based X-ray fluorescence 

MA mature 

MA-10 mouse Leydig tumor cell line 

MANCOVA multivariate analysis of covariance 

MAO monoamine oxidase 

II-xli 
MATC maximum acceptable threshold concentration 

MDA malondialdehyde 

MDA-TBA malondialdehyde-thiobarbituric acid 

MDCK kidney epithelial cell line 

MDI Mental Development Index (score) 

MDRD Modification of Diet in Renal Disease (study) 

MEM Minimal Essential Medium 

MG microglobulin 

Mg-ATPase magnesium-dependent adenosine triphosphatase 

MiADMSA monoisamyl dimercaptosuccinic acid 

Mi-DMSA mi monoisoamyl dimercaptosuccinic acid 

MK-801 NMDA receptor antagonist 

MLR mixed lymphocyte response 

MMSE Mini-Mental State Examination 

MMTV murine mammary tumor virus 

MN micronuclei formation 

MND motor neuron disease 

MNNG N-methyl-N'-nitro-N-nitrosoguanidine 

MPH morphology 

MRI magnetic resonance imaging 

mRNA messenger ribonucleic acid 

MROD methoxyresorufin-O-demethylase 

MRS magnetic resonance spectroscopy 

MS mass spectrometry 

MSCA McCarthy Scales of Children’s Abiltities 

mSQGQs mean sediment quality guideline quotients 

MT metallothionein 

MVV maximum voluntary ventilation 

MW molecular weight (e.g., high-MW, low-MW) 

N, n number of observations 

N/A not available 

NAAQS National Ambient Air Quality Standards 

NAC N-acetyl cysteine 

NAD nicotinamide adenine dinucleotide 

NADH reduced nicotinamide adenine dinucleotide 

II-xlii 
NADP nicotinamide adenine dinucleotide phosphate 

NAD(P)H, NADPH reduced nicotinamide adenine dinucleotide phosphate 

NADS nicotinamide adenine dinucleotide synthase 

NAF nafenopin 

NAG N-acetyl-$-D-glucosaminidase 

Na-K-ATPase sodium-potassium-dependent adenosine triphosphatase 

NAWQA National Water-Quality Assessment 

NBT nitro blue tetrazolium 

NCBP National Contaminant Biomonitoring Program 

NCD nuclear chromatin decondensation (rate) 

NCS newborn calf serum 

NCTB Neurobehavioral Core Test Battery 

NCV nerve conduction velocity 

ND non-detectable; not detected 

NDI nuclear divison index 

NE norepinephrine 

NES Neurobehavioral Evaluation System 

NF-κB nuclear transcription factor-κB 

NGF nerve growth factor 

NHANES National Health and Nutrition Examination Survey 

NIOSH National Institute for Occupational Safety and Health 

NIST National Institute for Standards and Technology 

NK natural killer 

NMDA N-methyl-D-aspartate 

NMDAR N-methyl-D-aspartate receptor 

NMR nuclear magnetic resonance 

NO nitric oxide 

NO2 nitrogen dioxide 

NO3 nitrate 

NOAEC no-observed-adverse-effect concentration 

NOAEL no-observed-adverse-effect level 

NOEC no-observed-effect concentration 

NOEL no-observed-effect level 

NOM natural organic matter 

NORs nucleolar organizing regions 

II-xliii 
NOS nitric oxide synthase; not otherwise specified 

NOx nitrogen oxides 

NP net productivity 

NPSH nonprotein sulfhydryl 

NR not reported 

NRC National Research Council 

NRK normal rat kidney 

NS nonsignificant 

NSAID non-steroidal anti-inflammatory agent 

NT neurotrophin 

NTA nitrilotriacetic acid 

O2 oxygen 

ODVP offspring development 

OH hydroxyl 

7-OH-coumarin 7-hydroxy-coumarin 

1,25-(OH)2-D, 1,25-(OH)2 D3 1,25-dihydroxyvitamin D 

24,25-(OH)2-D3 24,25-dihydroxyvitamin D 

25-OH-D3 25-hydroxyvitamin D 

8-OHdG 8-hydroxy-2'-deoxyguanosine 

O horizon forest floor 

OR odds ratio; other oral 

OSWER Office of Solid Waste and Emergency Response 

P, p probability value 

P300 event-related potential 

P450 1A1 cytochrome P450 1A1 

P450 1A2 cytochrome P450 1A2 

P450 CYP3a11 cytochrome P450 3a11 

PAD peripheral arterial disease 

PAH polycyclic aromatic hydrocarbon 

PAI-1 plasminogen activator inhibitor-1 

PAR population attributable risk 

Pb lead 

203Pb lead-203 radionuclide 

204Pb, 206Pb, 207Pb, 208Pb stable isotopes of lead-204, -206, -207, -208, respectively 

210Pb lead-210 radionuclide 

II-xliv 
Pb(Ac)2 lead acetate 

PbB blood lead concentration 

PbCl2 lead chloride 

Pb(ClO4)2 lead chlorate 

PBG-S porphobilinogen synthase 

PBMC peripheral blood mononuclear cells 

Pb(NO3)2 lead nitrate 

PbO lead oxides (or litharge) 

PBP progressive bulbar paresis 

PbS galena 

PbU urinary lead 

PC12 pheochromocytoma cell 

PCR polymerase chain reaction 

PCV packed cell volume 

PDE phosphodiesterase 

PDGF platelet-derived growth factor 

PDI Psychomotor Development Index 

PEC probable effect concentration 

PEF expiratory peak flow 

PG prostaglandin (e.g., PGE2, PGF2); prostate gland 

PHA phytohemagglutinin A 

Pi inorganic phosphate 

PIXE particle induced X-ray emission 

PKC protein kinase C 

pl NEpi plasma norepinephrine 

PMA progressive muscular atrophy 

PMN polymorphonuclear leucocyte 

PMR proportionate mortality ratio 

PN postnatal (day) 

P5N pyrimidine 5'-nucleotidase 

PND postnatal day 

p.o., PO per os (oral administration) 

POMS Profile of Mood States 

ppb parts per billion 

ppm parts per million 

II-xlv 
PPVT-R Peabody Picture Vocabulary Test-Revised 

PRA plasma renin activity 

PRL prolactin 

PROG progeny counts or numbers 

PRR prevalence rate ratio 

PRWT progeny weight 

PST percent transferrin saturation 

PTH parathyroid hormone 

PTHrP parathyroid hormone-related protein 

PVC polyvinyl chloride 

PWM pokeweed mitogen 

PRWT progeny weight 

QA/QC quality assurance/quality control 

Q/V flux of air (Q) divided by volume of culture (V) 

r Pearson correlation coefficient 

R2

 multiple correlation coefficient 

2

r correlation coefficient 

226Ra most stable isotope of radium 

R/ALAD ratio of ALAD activity before and after reactivation 

RAVLT Rey Auditory Verbal Learning Test 

86Rb rubidium-86 radionuclide 

RBA relative bioavailablity 

RBC red blood cell; erythrocyte 

RBF renal blood flow 

RBP retinol binding protein 

RBPH reproductive behavior 

RCPM Ravens Colored Progressive Matrices 

REL rat epithelial (cells) 

REP reproduction 

RHIS reproductive organ histology 

222Rn most stable isotope of radon 

RNA ribonucleic acid 

ROS reactive oxygen species 

ROS 17.2.8 rat osteosarcoma cell line 

RPMI 1640 Roswell Park Memorial Institute basic cell culture medium 

II-xlvi 
RR 

RT 

RSEM 

RSUC 

RT 

∑SEM 

SA7 

SAB 

SAM 

SBIS-4 

s.c., SC 

SCAN 

SCE 

SCP 

SD 

SDH 

SDS 

SE 

SEM 

SES 

sGC 

SH 

SHBG 

SHE 

SIMS 

SIR 

SLP 

SM 

SMAV 

SMR 

SNAP 

SNP 

SO2

SOD 

relative risk; rate ratio 

reaction time 

resorbed embryos 

reproductive success (general) 

reproductive tissue 

sum of the molar concentrations of simultaneously extracted 

metal 

simian adenovirus 

Science Advisory Board 

S-adenosyl-L-methionine 

Stanford-Binet Intelligence Scale-4th edition 

subcutaneous 

Test for Auditory Processing Disorders 

selective chemical extraction; sister chromatid exchange 

stripping chronopotentiometry 

Spraque-Dawley (rat); standard deviation 

succinic acid dehydrogenase 

sodium dodecyl sulfate; Symbol Digit Substitution 

standard error; standard estimation 

standard error of the mean 

socioeconomic status 

soluble guanylate cyclase 

sulfhydryl 

sex hormone binding globulin 

Syrian hamster embryo cell line 

secondary ion mass spectrometry 

standardized incidence ratio 

synthetic leaching procedure 

sexually mature 

species mean acute value 

standardized mortality ratio 

Schneider Neonatal Assessment for Primates 

sodium nitroprusside 

 sulfur dioxide 

superoxide dismutase 

II-xlvii 
SOPR sperm-oocyte penetration rate 

SPCL sperm cell counts 

SPCV sperm cell viability 

SQGs sediment quality guidelines 

SRA Self Reported Antisocial Behavior scale 

SRD Self Report of Delinquent Behavior 

SRIF somatostatin 

SRM Standard Reference Material 

SRT simple reaction time 

SSADMF Social Security Administration Death Master File 

SSB single-strand breaks 

SSEP somatosensory-evoked potential 

StAR steroidogenic acute regulatory protein 

STORET STOrage and RETrieval 

SVC sensory conduction velocity 

SVRT simple visual reaction time 

T testosterone 

TA tail 

TABL time-averaged blood lead 

T&E threatened and endangered (species) 

TAT tyrosine aminotransferase 

TB tibia 

TBARS thiobarbituric acid-reactive species 

TBPS Total Behavior Problem Score 

TCDD methionine-choline-deficient diet 

T cell T lymphocyte 

TCLP toxic characteristic leaching procedure 

TE testes 

TEC threshold effect concentration 

TEDG testes degeneration 

TEL tetraethyl lead 

TES testosterone 

TEWT testes weight 

TF transferrin, translocation factor 

TG 6-thioguanine 

II-xlviii 
TGF transforming growth factor 

TH tyrosine hydroxylase 

232Th stable isotope of thorium-232 

TLC Treatment of Lead-exposed Children (study) 

TNF tumor necrosis factor (e.g., TNF-α) 

TOF time-of-flight 

tPA plasminogen activator 

TPRD total production 

TRH thyroid releasing hormone 

TRV toxicity reference value 

TSH thyroid stimulating hormone 

TSP triple-super phosphate 

TT3 total triiodothyronine 

TT4 serum total thyroxine 

TTES total testosterone 

TTR transthyretin 

TU toxic unit 

TWA time-weighted average 

TX tromboxane (e.g., TXB2) 

U uriniary 

235U, 238U uranium-234 and -238 radionuclides 

UCP urinary coproporphyrin 

UDP uridine diphosphate 

UNECE United Nations Economic Commission for Europe 

Ur urinary 

USFWS U.S. Fish and Wildlife Service 

USGS United States Geological Survey 

UV ultraviolet 

V79 Chinese hamster lung cell line 

VA Veterans Administration 

VC vital capacity; vitamin C 

VDR vitamin D receptor 

VE vitamin E 

VEP visual-evoked potential 

variable-interval 

II-xlix 

VI 
vit C vitamin C 

vit E vitamin E 

VMA vanilmandelic acid 

VMI Visual-Motor Integration 

VSM vascular smooth muscle (cells) 

VSMC vascular smooth muscle cells 

WAIS Wechsler Adult Intelligence Scale 

WDS wavelength dispersive spectrometers 

WHO World Health Organization 

WISC Wechsler Intelligence Scale for Children 

WISC-R Wechsler Intelligence Scale for Children-Revised 

WO whole organism 

WRAT-R Wide Range Achievement Test-Revised 

WT wild type 

WTHBF-6 human liver cell line 

ww wet weight 

XAFS X-ray absorption fine structure 

XANES X-ray absorption near edge spectroscopy 

XAS X-ray absorption spectroscopy 

XPS X-ray photoelectron spectroscopy 

X-rays synchrotron radiation 

XRD X-ray diffraction 

XRF X-ray fluorescence 

ZAF correction in reference to three components of matrix effects: 

atomic number (Z), absorption (A), and fluorescence (F) 

ZnNa2 DTPA zinc disodium diethylenetriaminepentaacetic acid 

ZnNa2 EDTA zinc disodium ethylenediaminetetraacetic acid 

ZPP zinc protoporphyrin 

II-l 
 AX4-1 

AX4. CHAPTER 4 ANNEX 

ANNEX TABLES AX4 
 AX4-2 Table AX4-1. Analytical Methods for Determining Lead in Blood, Urine, and Hair Sample Matrix Preparation Method Analytical Method Sample Detection Limit Accuracy (percent recovery

Blood Wet ashing with acid mixtures; residue dissolution in dilute HClO4 ASV with mercury- graphite electrode (NIOSH Method 195) 40 μg/L 95B105 Blood Wet ashing with HNO3; residue dissolution in dilute HNO3 GFAAS (NIOSH Method 214) 100 μg/L No data 

Blood Dilution with Triton X-100®; addition of nitric acid and diammonium phosphate GFAAS 2.4 μg/L 93B105 

Blood Dilution of sample with ammonium solution containing Triton X-100 ICP/MS 15 μg/L 96B111 

Blood Dilution of sample in 0.2% Triton X-100 and water GFAAS .15 μg/L 97B150 Blood Wet ashing, dilution ICP-MS 0.1 ppb 94B100 

GFAAS 4 ppb 90B108 

Blood and urine 

Mixing of urine sample with HNO3; filtration, 

chelation of lead in whole blood or filtered urine with APDC, extraction with MIBK 

AAS (NIOSH Method 8003) 

0.05 μg/g (blood); 

50 μg/L (urine) 

99 (±10.8%) 

Blood and urine 

Wet ashing of sample with HNO3, complexation 

with diphenylthio-carbazone, and extraction with chloroform 

Spectrophotometry (NIOSH Method 102) 

30 μg/L (blood); 

12 μg/L (urine) 

97 97 

Blood and urine 

206Pb addition and sample acid digestion; lead coprecipitation by addition of Ba(NO3)2, followed by 

electrodeposition on platinum wire 

IDMS No data 98B99 

Blood and tissue 

Digestion of sample with HNO3/HClO4 /H2SO4; heat ICP-AES (Method 8005) 0.01 μg/g (blood); 

0.2 μg/g (tissue) 

113 
 AX4-3 Table AX4-1 (cont’d). Analytical Methods for Determining Lead in Blood, Urine, and H

Sample Matrix Preparation Method Analytical Method Sample Detection Limit Accuracy (percent recoveryBlood Addition of 50 μL of blood into reagent, mixing, and transferring to sensor strip (commercial test kit) Gold electrode sensor 1.4 μg/dL No data Urine Collect 50 mL urine sample and add 5 mL concentrated HNO3 as preservative; filter samples through cellulose membrane, adjust pH to 8, ash filters and resins in low temperature oxygen plasma for 6 hours ICP-AES (Method 8310) 5 μg/L 100 

Serum, blood, and urine Filtration of sample if needed; blood requires digestion in a Parr bomb; dilution of serum or urine with acid or water ICP-AES 10B50 μg/L 85 (serum) >80 (urine, blood) 

Urine Wet ashing of sample with acid mixture and dissolution in dilute HClO4 ASV with mercury- graphite electrode (Method 200) 4 μg/L 90B110 

Hair Cleaning of sample with acetone/ methanol; digestion 

with acid mixture and heat; diammonium phosphate addition as matrix modifier 

GFAAS 0.16 μg/g 99 

Hair Cleaning with lauryl sulfate and water; digestion with 

heated nitric acid 

ICP-AES 1 μg/g No data 

Hair Cleaning with water; digestion with heated nitric acid 

and H2O2 

ET-AAS <0.026 μg/g >90 

Hair Cleaning with acetone/water XRF 0.5 μg/g No data AAS, atomic absorption spectroscopy; APDC, ammonium pyrrolidine dithiocarbamate; ASV, anode stripping voltammetry; Ba(NO3)2, barium nitrat

atomic absorption spectrometry; GFAAS, graphite furnace atomic absorption spectroscopy; H2O2, hydrogen peroxide; H2SO4, sulfuric acid; HClO4, 

nitric acid; ICP-AES, inductively coupled plasma/atomic emission spectroscopy; ICP-MS, inductively coupled plasma-mass spectrometry; IDMS, isspectrometry; MIBK, methyl isobutyl ketone; NIOSH, National Institute for Occupational Safety and Health; 206Pb, lead 206; XRF, X-ray fluorescen
 AX4-4 Table AX4-2. Summary of Selected Measurements of PbB Levels in Humans Reference, Study Location, and Period Study Description PbB Measurement 

United States CDC (2005) U.S. 1999-2002 Design: National survey (NHANES IV) stratified, multistage probability cluster design Subjects: Children and adults ($1 yrs, n = 16, 915) in general population Biomarker measured: PbB Analysis: ICP-MS Units: μg/dL Geometric mean (95% CI) Age (yr) 1999-2000 2001-2002 1-5: 1.66 (1.60, 1.72) 1.45 (1.39, 1.40) n: 7, 970 8, 945 6-11: 1.51 (1.36, 1.66) 1.25 (1.14, 1.36) n: 905 1,044 12-19: 1.10 (1.04, 1.17) 0.94 (0.90, 0.99) n: 2, 135 2, 231 

$20: 1.75 (1.68, 1.81) 1.56 (1.49, 1.62) 

 n: 4, 207 4, 772 Males: 2.01 (1.93, 2.09) 1.78 (1.71, 1.86)  n: 3, 913 4, 339 Females: 1.37 (1.32, 1.43) 1.19 (1.14, 1.25)  n: 4,057 4, 606 

Data from N(1999-2000

Brody et al. (1994) Pirckle et al. (1998) U.S. 1988-1994 

Design: National survey (NHANES III) stratified multistage probability cluster design. Subjects: Children and adults ($1 yrs, n = 29, 843) 

in general population Biomarker measured: PbB Analysis: GFAAS 

Units: μg/dL Geometric mean (95% CI) 

Age (yr) 1988-1991 1991-1994 1-5: 3.6 (3.3, 4.0) 2.7 (2.5, 3.0)  n: 2, 234 2, 392 6-11: 2.5 (2.2, 2.7) 1.9 (1.8, 2.1)  n: 1, 587 1, 345 12-19: 1.6 (1.4, 1.9) 1.5 (1.4, 1.7)  n: 1, 376 1, 615 20-49: 2.6 (2.5, 2.8) 2.1 (2.0, 2.2)  n: 4, 320 4, 716 50-69 4.0 (3.8, 4.2) 3.1 (2.9, 3.2)  n: 2,071 2,026 $70 4.0 (3.7, 4.3) 3.4 (3.3, 3.6)  n: 1, 613 1, 548 Males: 3.7 (3.5, 3.9) 2.8 (2.6, 2.9)  n: 6,051 6, 258 Females: 2.1 (2.0, 2.2) 1.9 (1.8, 2.)  n: 6,068 7, 384 

Comparison Phase 1 (19(1991-1994concentratio
 AX4-5 Table AX4-2 (cont’d). Summary of Selected Measurements of PbB Levels in Humans Reference, Study Location, and Period Study Description PbB Measurement 

United States (cont’d) Nash et al. (2003) U.S. 1988-1994 Design: National survey (NHANES III) stratified, multistage probability cluster design Subjects: Women(n = 2, 575), age range: 40-59 yrs, in general population Biomarker measured: PbB Analysis: GFAAS Units: μg/dL Geometric mean (95% CI, n) Premenopausal: 1.9 (1.7, 2.0, 1, 222) Surgically menopausal: 2.7 (2.4, 3.2, 139) Naturally menopausal: 2.9 (2.5, 3.2, 653) Geometric m

were signifipremenopauPbB concenassociated wdensity. Pirkle et al. (1994) U.S. 1976-1980 Design: National survey (NHANES II, III) stratified, multistage probability cluster design Subjects: Children and adults ($1 yrs, n = 29, 843) in general population Biomarker measured: PbB Analysis: GFAAS Units: μg/dL Geometric mean (95% CI) Age (yr) 1976-1980 1988-1991 1-5: 15.0 (14.2, 15.8) 3.6 (3.3, 4.0) n: 2, 271 2, 234 

 6-19: 11.7 (11.2, 12.4) 1.9 (1.7, 2.2)  n: 2,024 2, 963  20-74: 13.1 (12.7, 13.7) 3.0 (2.8, 3.2)  n: 5, 537 6, 922  Males: 15.0 (14.5, 15.5) 3.7 (3.5, 3.9)  n: 4, 895 6,051  Females: 11.1 (10.6, 11.5) 2.1 (2.0, 2.2)  n: 4, 937 6,068 

Comparison (1976-1980III (1988-19PbB concen

Symanski and HertzPicciotto (1995) U.S. 1982-1984 

Design: National survey (HHANES) multistagearea probability sample Subjects: Adults, females (n = 3, 137), age range 20-60 yrs, in general Hispanic population Biomarker measured: PbB Analysis: GFAAS 

Units: μg/dL Arithmetic mean (SE, n) All Premenopausal: 7.5 (0.07, 1, 984) Menopausal: 8.9 (0.11, 1, 152) Mexican-American: Premenopausal: 7.2 (0.13, 1, 219) Menopausal: 8.4 (0.20, 624) 

Mean differpremenopau(#4 yrs) wa(95% CI: 0
 AX4-6 Table AX4-2 (cont’d). Summary of Selected Measurements of PbB Levels in Humans Reference, Study Location, and Period Study Description PbB Measurement 

United States (cont’d) Yassin et al. (2004) U.S. 1988-1994 Design: National survey (NHANES III) stratified, multistage probability cluster design Subjects: Adults (n = 11, 126) in general population, age range: 18-64 yr), stratified by occupational category Biomarker measured: PbB Analysis: GFAAS Units: μg/dL Occupation GM GSD 

Vehicle mechanics 4.80 3.88 Food service workers 2.00 2.69 Management, professional technical, and sales workers 2.13 4.05 Personal service workers 2.48 4.52 Agricultural workers 2.76 4.02 

Production workers: machine operators, material movers, etc. 2.88 4.24 

Laborers other than in construction 3.47 3.36 Transportation workers 3.49 5.19 Mechanics other than vehicle  mechanics 3.50 4.91 Construction trades people 3.66 4.64 Construction laborers 4.44 7.84 Health service workers 1.76 2.24 All 2.42 6.93 

Mexico Hernandez-Avila et al. (2002) Mexico 1993-1995 

Design: Cross-sectional Subjects: Adults females (n = 903) in general population, age range: 36-70 yr Biomarker measured: PbB Analysis: GFAAS 

Units: μg/dL 

Arithmetic mean (SD, n) Premenopausal: 10.63 (5.46, 463) Menopausal: 11.39 (2.65, 437) Surgically menopausal: 10.23 (4.92, 115) Naturally menopausal: 11.30 (5.88, 322) 

Mean differpremenopau0.76 μg/dL (

PbB, blood lead; GFAAS, graphite furnace atomic absorption spectroscopy; ICP-MS, inductively coupled plasma-mass spectrometry; NR, not repor
 AX4-7 Table AX4-3. Bone Lead Measurements in Cadavers Reference, Study Location, and Period Study Description Lead Measurement 

United States Wittmers et al. (1988) Minnesota 1976-82 Lead in tibia, skull, iliac crest, rib, and vertebrae. 81 Caucasian males and 53 male cadavers ranging in age from 0 to 98 yr. Ashing, nitric acid, AAS. Mean and SEM (μg/g bone ash) >75 yr: Tibia 29.0 

±3.4 (n = 28), ilium 

17.0 

± 2.6 (n = 29), rib 20.5 

± 2.4 (n = 31), vertebra 18.8 

± 2.6 (n = 30), 

skull 26.1 

± 3.2 (n = 28) 

51-75 yr: Tibia 24.2 

± 2.3 (n = 38), ilium 19.2 

± 2.4 (n = 15), rib 22.3 

± 2.6 

(n = 40), vertebra 22.4 

± 2.6 (n = 41), skull 22.8 

± 2.9 (n = 29) 

36-50 yr: Tibia 16.6 

±4.1 (n = 14), ilium 9.9 

± 1.6 (n = 15), rib 9.7 

± 1.7 

(n = 15), vertebra 11.9 

± 2.1 (n = 15), skull 15.2 

± 3.3 (n = 15) 

21-35 yr: Tibia 5.9 

±1.2 (n = 18), ilium 5.3 

± 1.2 (n = 16), rib 5.0 

± 1.2 

(n = 18), vertebra 6.3 

± 1.3 (n = 17), skull 4.9 

± 1.1 (n = 17) 

14-20 yr: Tibia 2.3 

±1.0 (n = 13), ilium 2.3 

± 0.9 (n = 13), rib 2.9 

± 1.4 

(n = 12), vertebra 3.8 

± 1.4 (n = 12), skull 3.2 

± 1.7 (n = 10) 

0-2 yr: Tibia 0.3 

±0.2 (n = 11), ilium 0.0 

± 0.0 (n = 11), rib 0.7 

± 0.4 

(n = 12), vertebra 0.6 

± 0.6 (n = 12), skull 0.6 

± 0.4 (n = 12) 

Rsk<1 >1 grof ameadutravesith

Saltzman et al. (1990) Cincinnati, OH 1970-71 

29 tissues from 55 cadavers, mean age 50 yrs. Muffle furnace ashing. Pb concentrations by dithazone method. 

Higher concentrations of Pb in tibia compared with rib and vertebrae and higher values for males compared with females. Males (n = 46): Ribs 6.70 

± 3.96 (μg/g, wet weight), tibia 12.55 

± 10.65, vertebrae 4.12 

± 2.49. 

Females (n = 8): Ribs 3.17 

± 0.91 (μg/g, wet weight), tibia 4.54 

± 2.04, 

vertebrae 2.01 

± 0.72. 

BReof et 

Canada 

Samuels et al. (1989) Canada 1965-69 

Ashed vertebral bones from male and female cadavers from three Canadian cities. AAS method. 

Changes for different age ranges in Pb concentration for the period 1965-1969: 0-11 months: 3.98 μg/g (n = 28) 

1-4 yrs: 10.02 μg/g (n = 32) 

5-11 yrs: 12.91 μg/g (n = 26) 12-19 yrs: 7.11 μg/g (n = 26) $20 yrs: 14.77 μg/g (n = 25) 

Fole(p litthWapth
 AX4-8 Table AX4-3 (cont’d). Bone Lead Measurements in Cadavers Reference, Study Location, and Period Study Description Lead Measurement Find

Europe Drasch et al. (1987) Germany 1983-85 Bone Pb in temporal bone, cortical part of the mid-femur, and pelvic bone from 120 female and 120 male adult cadavers. AAS. Geometric means: Males: Pelvic 1.95 ± 1.00 (μg/g, wet weight), mid-femur 4.75 ± 2.53, temporal 6.24 ± 3.17. Females: Pelvic 1.41 ± 0.74 (μg/g), mid-femur 3.14 ± 1.89, temporal 5.00 ± 2.66. F

trdmh>w

Age 0-1 yrs 1-6 yrs 10-20 yrs 0-20 yrs Sex Male Female Male Female Male Female Male Female n 9 16 9 9 18 16 39 42 

Temporal 0.331 0.334 0.530 0.732 1.770 1.740 0.858 0.749 Pelvic bone 

0.230 0.278 0.461 0.522 0.748 0.511 0.455 0.404 

Mid-femur 0.333 0.327 0.642 0.858 1.342 1.010 0.768 0.632 

Drasch and Ott (1988) Germany 1984 

Bone Pb in temporal bone, cortical part of the mid femur, and pelvic bone from 82 child cadavers. Nitric acid digestion, AAS. 

 (values in μg/g wet weight) 

N1 c1fohtrthbda

Hac et al. (1997) Poland 

Pb in rib bone and hair from 59 cadavers, aged 1-87 yrs. Perchloric acid digestion, AAS. 

Bone Pb 3.0 (±1.5) μg/g (n = 54). S

in sn

AsiaNoda et al. (1993) Japan 1976, 1981, and 1986 

76 cadavers, age range 0 to 83 yrs. 

Age 0 yrs (1.25 μg/g wet weight) to 59 yrs (4.5 μg/g) after which there was a decrease (~2.5 μg/g). For the age range 10-49 yrs, there was no significant difference in mean values of 2.8 to 3.1 μg/g. 

Fdwin 
 AX4-9 Table AX4-4. Bone Lead Measurements in Environmentally-Exposed Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Finding

United States Kim et al. (1996) Boston, MA 1989-90 Examination of the relationship between tooth Pb in children and bone Pb levels in young adults. Members of a cohort of young adults (n = 63, ~20 yr of age) were reassessed 13 yr after initial examination. Dentine Pb by anodic stripping voltammetry. Bone K-shell XRF. LOWESS smoothing, multiple linear regression. No PbB. Tibia Pb 1.3 (

± 4.4), patella Pb 5.4 (

±8.4). 

Dentine Pb 13.4 (

±10.7). 

Approximately one-third of tibia and one-fourth of patella estimates were negative values. 

A 10 μg/g increase childhood was predin tibia Pb levels apatella PbB levels, mean bone Pb leveThey concluded thmay be used to preup to 13 yr later. 

Hu et al. (1990) Boston, MA Unknown 

To evaluate if K-shell XRF can be used to assess low-level Pb burdens in 34 employees (26 males, 8 females) ranging in age from 21 to 58 yr of a biomedical company with no known history of excessive Pb exposure. Medical environmental history questionnaire. Multiple linear regression. 

18 (53%) of subjects had bone Pb levels included 0 or less within the estimate of uncertainty. Highest bone Pb 21 

± 4 μg/g bone mineral. 

For 16 young adults, age and year of home construction had a positive but statistically insignificant effect (p > 0.05) on bone Pb. 

K-shell XRF may level Pb burdens in 

Hu et al. (1996) Boston, MA 1991+

Normative Aging Study. Subjects were middle-aged and elderly men who had community (nonoccupational) exposures to lead. Cross-sectional. Backwards elimination multivariate regression models that considered age, race, education, retirement status, measures of both current and cumulative smoking, and alcohol consumption.

47-59 yrs (n = 116): PbB 5.8 (

±3.7), tibia 14.6 

(±8.3), patella 23.6 (

±12.4) 

60-69 yrs (n = 360): PbB 6.3 (

±4.2), tibia 21.1 

(±11.4), patella 30.5 (

±16.9) 

>70 yrs (n = 243): PbB 6.5 (

±4.5), tibia 27 

(±15.6), patella 38.8 (

±23.5)

Factors that remainhigher levels of bohigher age and mesmoking, and loweAn increase in patethe lowest to the mquintiles (13-56 μg

in PbB of 4.3 μg/dcomprised the maj

in these men.

Campbell et al. (2004) New York Unknown 

Investigated the relationship between bone mineral density and environmental Pb 

exposure in 35 African American children. 

High Pb exposure: PbB levels (mean 23.6 μg/dL; n = 19); low Pb exposure (mean 6.5 μg/dL; n = 16). 

Unexpectedly, they high Pb exposure hbone mineral densiPb exposure. They arises from the effebone maturation by hormone-related p
 AX4-10 Table AX4-4 (cont’d). Bone Lead Measurements in Environmentally-Exposed Subject

Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Finding

United States (cont’d) Rosen et al. (1989) Bronx, NY Unknown Comparison of L-shell XRF measures and EDTA provocation test in lead-toxic children 1-6 yr old. Eligible if PbB 25- 55 μg/dL and erythrocyte protoporphyrin >35 μg/dL. Negative EDTA test results (n = 30): PbB 30 

± 5 

μg/dL, tibia Pb 12 

± 2 μg/g (range 7-52). 

Positive EDTA test results (n = 29): PbB 39 

± 8 

μg/dL, tibia Pb 37 

± 3 μg/g (range 7-200). 

From PbB and LXchildren were correEDTA-positive or capable of replacin

Kosnett et al. (1994) Dickson City, PA 1991 

Aim to determine the influence of demographic, exposure and medical factors on the bone Pb concentration of subjects with environmental Pb exposure. 101 subjects (49 males, 52 females; aged 11 to 78 yrs) recruited from 49 of 123 households geographically located in a suburban residential neighborhood. Tibia. Multiple regression. 

Mean (SD) bone Pb12.7 (14.6). Log-transformed bone Pb highly correlated with age (r = 0.71; p # 0.0001). Gender differences in log-transformed bone Pb values were insignificant up until the 6th decade. 

Bone Pb showed nage 20 yr, increasemen and women band then increased than 55 yrs. 

Rosen et al. (1993) Moosic and Throop, PA 1989-91 

Suburban population (Throop, n = 269) exposed to unusually high emissions during 1963-81 from nearby battery recycling/secondary smelter. Moosic served as control community. Approximately 9% children aged 5-12 yr, 15% 13-17 yr, 40% 

≥ 18 yr. Soil and 

PbB, L-shell XRF. 

No significant differences in tibia Pb found among three age groups in Moosic or Throop. Mooaic: means 5-12 yr, 6 μg/g; 13-17 yr, 8 μg/g; $18 yr, 7 μg/g Throop: means 5-12 yr, 12 

± 1 μg/g; 13-17 yr, 

15 

± 2 μg/g; $18 yr, 12 

± 1 μg/g. 

No change in bone values for bone Pb exposed population reference baseline levels in similar co

Stokes et al. (1998) Bunker Hill, ID; Spokane, WA 1994 

Examined whether environmental exposure to Pb during childhood was associated with current adverse neurobehavioral effects. K-shell XRF. Formerly exposed as children 19-30 yr (n = 238, age 19-30 yr). Referents (n = 258) 

Exposed group: PbB 2.9 μg/dL; tibia Pb 4.6 μg/g. 

Referent group: PbB 1.6 μg/dL; tibia Pb 0.6 μg/g. 
 AX4-11 Table AX4-4 (cont’d). Bone Lead Measurements in Environmentally-Exposed Subject

Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral FindingUnited States (cont’d) McNeill et al. (2000) Idaho and Washington 1994 To determine if high Pb exposure in childhood persisted until adulthood. 262 exposed subjects and 268 age and sex matched controls aged 19 – 29 yr. Tibia bone Pb, cumulative PbB index. Inverse weighted group mean data, linear regressions. Group inverse weighted mean (SEM). Males: Exposed 4.54 (0.31); controls 0.03 (0.31) μg Pb/g bone mineral. Females: Exposed 5.61 (0.43); controls 1.67 (0.43) μg Pb/g bone mineral. Lead from exposur

persisted in the bonBone Pb significanexposed groups. Nregressions for conExposed subjects hsignificantly highesubjects in 7 of 11 subjects had increaconcentrations that with bone Pb valueinto bone 0.039 (0mineral)/ μg/dL yr

Mexico 

Farias et al. (1998) Mexico City and suburbs 1995-96 

Examined the relation of blood and tibia bone Pb levels to Pb determinants in 100 adolescents aged 11 to 21 yr. LOWESS smoothing, multivariate regressions. 

Females (n = 62): PbB 6.4 (

±3.2), tibia 5.5(

±8.6). 

Males (n = 36): PbB 9.1 (

±5.5), tibia 3.8 (

±5.5). 

25 subjects had bone Pb < 0. Bone Pb accounted for 4.1% of variation in PbB. Increase in bone Pb of 21.6 μg/g was associated with an increase in PbB of 1.2 μg/dL. 

Predictors of bone density near the hohistory, and time sof log-transformed levels, male sex, uand living in Mexiaccumulated over tsource of circulatin

PbB = blood lead. 
 AX4-12 Table AX4-5. Bone Lead Measurements in Occupationally-Exposed Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Finding

United States Hu et al. (1994) U.S. 1991 Construction workers aged 23 to 67 yr (n = 19). Examination of Bone Pb and PbB as predictors of blood pressure in construction workers. Multivariate linear regression, LOWESS smoothing. PbB 8.3 (

±4.0), tibia Pb 9.8 (

±9.5), patella Pb 

13.9 (

±13.6). 

Schwartz et al. (2000b) U.S. 1995 

Retired organolead employees (n = 543). Aim to determine influence of PbB, chelatable Pb, and tibial Pb on systolic and diastolic blood pressure. 

PbB 4.6 (

±2.6), tibia Pb14.4 (

±9.3). Tibia Pb was not a

pressure measures

Popovich et al. (2005) Idaho 

108 former female smelter employees and 99 referents to assess the PbB versus bone Pb relationship. 

Exposed: PbB 2.73 (

±2.39), tibia 14.4 (

±0.5) 

Referents: PbB 1.25 (

±2.10), tibia 3.22 (

±0.50) 

Pb concentrations in tibia and blood significantly higher in the exposed group. Endogenous release rate (μg Pb per dL blood/μg Pb/g bone) in postmenopausal women was double the rate found in premenopausal women (0.132 

± 0.019 vs. 0.067 

±

0.014). 

Higher tibia bone Passociated with use former) in both the postmenopausal w

Canada 

Fleming et al. (1997) Canada 1994 

Primary smelter workers, 367 active and 14 retired. PbB in 204 workers returning after a 10-mo strike ended in 1991. Cumulative PbB index, K-shell measures with 109Cd source. 

Active (1975-81) median PbB 16.0, (1987-92) median PbB 8.0, tibia range 0-150, calcaneus 0-250. Retired tibia range 20-120, calcaneus 40-220. Bone Pb-cumulative PbB index slopes larger for retired compared with active workers, but not significant. 

Nonlinearities in ctibia and calcaneus Pb transfer from wsmelter employeesbone stores at any all occupationally or retired. Age-related variatinot a dominant facof male lead workeof Pb in calcaneus 
 AX4-13 Table AX4-5 (cont’d). Bone Lead Measurements in Occupationally-Exposed Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Findin

Canada (cont’d) Fleming et al. (1998) Canada 1994 Primary smelter. ALAD 1-1 (n = 303) and ALAD1-2, 2-2 (n = 65). PbB, serum Pb, cumulative PbB index, ALAD genotype, K-shell measures with 109Cd source. 1-1: PbB 22.9, tibia 41.2, calcaneus 71.6 1-2, 2-2: PbB 25.2, tibia 42.7, calcaneus 72.3. Slopes of linear relations of bone Pb to cumulative PbB index were greater for workers homoallelic for ALAD 1, indicating more efficient uptake of lead from blood into bone; effect most significant in calcaneus bone and for workers hired since improved safety measures enacted in 1977 [ALAD1-1: 0.0528 

± 0.0028 and ALAD1-2 or 2-2: 0.0355 

± 0.0031 

(p < 0.001)]. 

Decreased transindividuals exprcontrasted with genotype affectpotentially modorgans includingenotype did noaccumulation of 

Brito et al. (2000) Canada 1993-98

Aims were to: (i) investigate the long-term human Pb metabolism by measuring the change of Pb concentration in the tibia and calcaneus between 1993 and 1998; and (ii) assess whether improved industrial hygiene was resulting in a slow accumulation of Pb in an exposed workforce. 101 workers in a secondary lead smelter, 51 subjects had similar bone Pb measurements in 1993. Most other subjects had been hired since 1993. Cumulative PbB index. Linear regressions. 

Repeats (n = 51) 1993: Tibia 39 (±19), calcaneus 64 (±36). 1998: Tibia 33 (±18), calcaneus 65 (±38). Non-repeats (n = 50) 1998: Tibia 15 (±16), calcaneus 13 (±18). Tibia Pb decreased significantly (p < 0.001) in the 51 subjects with repeated bone Pb measurements. Tibia Pb in 1993 and changes in cumulative PbB index were significant predictors of changes in tibia Pb. An overall half-life of 15 yr (95% CI: 9, 55 yr) was estimated. Adding continuing lead exposure and recirculation of bone lead stores to the regression models produced half-life estimates of 12 and 9 yr, respectively, for release of lead from the tibia. Repeat subjects showed no net change in calcaneus Pb after 5 yr. 

The decrease in release of previoin a significant drepeat subjects. from the tibia of more rapid end lack of a significPb was surprisinhave implicationmetabolism. 
 AX4-14 Table AX4-5 (cont’d). Bone Lead Measurements in Occupationally-Exposed Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Findin

Canada (cont’d) Brito et al. (2002) Canada 1994, 1999 Evaluated endogenous release of Pb from bone to blood in 204 exposed subjects resuming their duties after a 10-mo strike in a primary lead smelter in 1991. Bone Pb (109Cd source) measured in the tibia and calcaneus in 1994 (Fleming et al., 1997) and 1999. A linear model used to predict the current PbB upon the level of lead in bone. 327 subjects available on both occasions. Group H higher PbB and Group L lower PbB. Group H: PbB 22.0, tibia 19.2 (n = 120) Group L: PbB 20.6, tibia 82.8 (n = 45) Group H: PbB 24.2, calcaneus 41.4 (n = 90) Group L: PbB 20.2,calcaneus 138.2 (n = 45) Structural analysis of data gave slopes for tibia (2.0, 95% CI: 1.66-2.54) and calcaneus (0.19, 95% CI: 0.16-0.23) that were significantly higher than those predicted by the commonly used simple linear regression method, for tibia (0.73, 95%, CI: 0.58-0.88) and calcaneus (0.08, 95% CI: 0.06-0.09). Suggested that m

predicted by regfrom bone to bl

Europe Somervaille et al. (1988) 

England 

K-shell measures with 109Cd source on 

diverse Pb workers and controls Crystal glass (n = 87); Battery plant (n = 88); Precious metals (n = 15); Laboratory (n = 20). Cumulative PbB index. 

Crystal glass: PbB 48.1, tibia 31.0 Battery plant: PbB 32.3, tibia 32.3 Precious metals: PbB 51.4, tibia 54.8 Laboratory: PbB 13.1, tibia 16.7 

Correlation coeand duration of consistently higrespectively (r = p < 0.0001; r = relation between PbB index amofrom which PbB 

Christoffersson et al. (1984) Sweden Unknown 

Lead smelter employees Active (n = 75); Former plant (n = 32) Finger bone measurement with 57Co 

source. 

Active: median PbB 53.8 (15.5), mean tibia 43 (<20, 122) Former: median PbB 24.9 (7.0), mean tibia 59.0 (<20, 135) 

Increase of bonemployment, no Pb and current Pretired workers bone Pb. 

Christoffersson et al. (1986) Sweden 1978-84 

Retired lead workers. Group 1: 7 smelter, 1 storage battery monitored for 2-5 yr directly after end of exposure. Group 2: 6 battery, bone Pb measured 7-13 yr after end of exposure. Finger bone measurement with 57Co source from 4 to 

9 times. 

Group 1: mean initial bone Pb 97 (61, 131), decreasing bone Pb with time half-life 6.7 yr (3.4, 15) Group 2: mean initial bone Pb 72 (37, 96), mean half-life 8.2 yr (2.4,

∞) 

Decrease of leaexposure considearlier from varmetabolism. 
 AX4-15 Table AX4-5 (cont’d). Bone Lead Measurements in Occupationally-Exposed Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Findin

Europe (cont’d) Hanninen et al. (1998) Finland Unknown Storage battery workers Grouped into those whose PbB exceeded 50 μg/dL [High PbB (n = 28; 21 males)], and never [Low PbB (n = 26; 22 males)]. Evaluation of neuropsychological dysfunction. High PbB: average PbB 39.3 (

±8.3), tibia 35.3 

(±16.6), calcaneus 100.4 (

±43.1) 

Low PbB: average PbB 29.0 (

±6.2), tibia 19.8 

(±13.7), calcaneus 78.6(

±62.4) 

No relation was neuropsychologPb. 

Erkkilä et al. (1992) Finland Unknown 

K-shell measures with 109Cd source on acid 

battery employees and controls Active (n = 91); Former plant (n = 16); Office (n = 38); Laboratory (n = 26). Kshell XRF. 

Active: PbB 30.0 (9.5), tibia 21.1 (17), calcaneus 76.6 (55.3) Former plant: PbB 12.2 (6.2), tibia 32.4 (34.9), calcaneus 73.5 (57.7) Office: PbB 6.4 (3.3), tibia 7.7 (11.3), calcaneus 14.2 (15.6) Laboratory: PbB 3.7 (1.7), tibia 3.5 (10.8), calcaneus 1.2 (10.6) 

Tibia Pb concenconsistently botof exposure and Calcaneal Pb codependent on thduration of expoof Pb in calcanewhich the duratRetired workersPb arising from accumulated oveasily produce tsystemic Pb conoccupational ex

Nilsson et al. (1991) Sweden 1980s 

Group A: 7 retired smelter workers and 1 battery worker monitored for ~10 yr with 11-17 finger bone measurements with 

57Co. 

Group B: 6 retired battery workers monitored for up to 18.5 yr with 7-13 finger bone measurements. 

Bone Pb values decreased over time. A mono-exponential retention model was used. Group A: estimated half-life for bone Pb was 6.2-27 yr. Group B: half-life was 11-470 yr. 

The “shared” ha(CI: 12, 23) yr. than ones of Chfor the same twvalues were sub
 AX4-16 Table AX4-5 (cont’d). Bone Lead Measurements in Occupationally-Exposed Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Findin

Europe (cont’d) Gerhardsson et al. (1993) Sweden Unknown Pb smelter and truck assembly (referent) workers; Active smelter (n = 70); Retired smelter (n = 30); Truck assembly (n = 31); Retired truck assembly (n = 10). K-shell measures with 109Cd source. Median values presented. Active smelter: PbB 31.9 (5.0, 47.4), tibia 13.0 

(!4.1, 72.8), calcaneus 48.6 (0.4, 217.8) Retired smelter: PbB 9.9 (3.3, 21), tibia 39.3 (2.9, 73.4), calcaneus 100.2 (34.8, 188.9) Truck: PbB 4.1 (1.7, 12.4), tibia 3.4 (!9.4, 13.3), calcaneus 12.2 (!12.7, 43.0) 

Retired truck: PbB 3.5 (2.2, 12.2), tibia 12.0 (!6.7, 23.7), calcaneus 30.2 (!7.1, 56.7) 

Higher calcaneulead workers suabsorption over trabecular bonetimes were 16 y11, 29 yr) and 298 yr). Strong pbone Pb and cum

Börjesson et al. (1997) Sweden 1992 

Pb smelter and referent male metal workers Active smelter (n = 71); Retired smelter (n = 18); Referent active (n = 27); Referent retired (n = 8). Similar cohort to Gerhardsson et al. (1993). Finger bone measurement with 57Co source. 

Cumulative PbB index. 

Median values presented. Active smelter: PbB 33.1 (8.3, 93), bone Pb 23.0 (!13, 99) Retired smelter: PbB 17.2 (8.9, 33.1), bone Pb 55 (3, 88) Active referent: PbB 3.7 (0.8, 7.0), bone Pb 3 (!21, 16) Retired referent: PbB 3.9 (3.1, 6.2), bone Pb 1.5 (!3, 12) 

Multiple regresPb was best desPbB index, whiobserved varianin active workeworkers. Estimbone Pb among 5.2 yr (95% CI: 

Bergdahl et al. (1998) Sweden 1986 

Secondary Pb smelter Exposed (n = 77); Referents (n = 24). Kshell measures with 109Cd source. 

Cumulative PbB index and (calculated) plasma Pb. 

Exposed: PbB 35.0 (14, 57), tibia 25 (5, 193), calcaneus 52 (!20, 458) Referents: PbB 5.0 (2.9, 16). tibia 10 (!6, 36), calcaneus 11(!12, 61) 

Strong relations(r2 = 0.78) and c

cumulative PbB tibia 13-24 yr an

Erfurth et al. (2001) Sweden 

Secondary smelter Active (n = 62); Retired (n = 15); Referents (n = 26). Evaluation of effects of Pb on the endocrine system. Finger bone measures with 57Co source. 

Median values presented. Active: PbB 33.2 (8.3, 93.2), tibia 21 (!13, 99) Retired: PbB 18.6 (10.4, 49.7), tibia 55 (3, 88) Referents: PbB 4.1 (0.8, 6.2), tibia 2 (!21, 14) 

No significant aPb and pituitary serum testosterohormone and th
 AX4-17 Table AX4-5 (cont’d). Bone Lead Measurements in Occupationally-Exposed Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Findin

Europe (cont’d) Roels et al. (1995) Belgium Pb smelter and others. Active production (n = 73); Other departments (n = 50). K-shell measures with 109Cd source. Cumulative PbB index. Active: PbB 42.0, tibia 66.5 Others: PbB 14.5, tibia 31.4 Strong relations

cumulative PbB populations (r = explained #9.5% regression equalog cumulative doubling of cumcorresponds to d

Mexico Juarez-Perez et al. (2004) Mexico City 1996-7 Lithographic print shop workers; Males, n = 59, 10 females; mean age 47 yrs Plasma Pb by ultraclean ICP-MS methods. K-shell measures with 109Cd source. PbB 11.9 (

±5.8), tibia 27.6 (

±18.1; ND-73.8), 

patella 46.8 (

±29.3; ND-139) 

Statistically signbetween: plasmtibia Pb, age, edceramics but noindex at work. models with patpredictors and ahygiene index ein plasma Pb. Nbetween plasma suggest oral expuptake of Pb prexposure in thes

Asia 

Schwartz et al. (2001) Korea 1997-99 

Korean Pb workers (798, 639 male, 164 female) and controls (135, 124 male, 1 female). Evaluation of associations between PbB, tibia Pb, chelatable Pb, and neurobehavioral functions. K-shell measures with 109Cd source. 

Active: PbB 32 (

±15), tibia 37.2 (

±40.4) 

Controls: PbB 5.3 (

±1.8), tibia 5.8 (

±7.0). 

After adjustmenwas not associatest scores. 
 AX4-18 Table AX4-5 (cont’d). Bone Lead Measurements in Occupationally-Exposed Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Findings, Inter

Asia (cont’d) Todd et al. (2001) Korea Korean Pb workers active (n = 723), retired (n = 79), controls (n = 135). Evaluation of associations between PbB, tibia Pb, chelatable Pb. K-shell measures with 109Cd source. Active: median PbB 31.7, tibia 24.4 

(−7.4, 337.6) Retired: median PbB 13.5, tibia 26.4 (−6.7, 196.7) Controls: median PbB 5.1, tibia 5.0 (−10.9, 26.6) 

Control women Job duration, bowere positive prof increase in tiincreased with istores in older sand may contribstores in younge

PbB = blood lead.
 AX4-19 Table AX4-6. Bone Lead Contribution to PbB Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Finding

United States Korrick et al. (2002) Boston, MA 1990-95 Nurses’ Health Study. Cross- sectional study of 264 elderly women; 46-54 yr (n = 80) 55-64 yr (n = 102), 65-74 yr (n = 82). Tibia and patella Pb. Multivariate linear regression models. 46-54 yr: PbB 2.7 (SE 

±0.3), tibia 10.5 (

±1.0), patella 

14.9 (

±1.2) 

55-64 yr: PbB 3.4 (

±0.2), tibia 12.7 (

±0.9), patella 17.0 (

±1.1) 

65-74 yr: PbB 3.3 (

±0.3), tibia 16.4 (

±0.9), patella 19.8 (

±1.2). 

An increase from the first to the fifth quintile of tibia Pb level (19 μg/g) was associated with a 1.7 μg/dL increase in PbB (p 0.0001). 

Tibia and patella Pand positively assoamong postmenopausing estrogens. Owere associated wiwas associated with suggested the obsewith estrogen statusupports the hypothresorption, as occubecause of decreasresults in heighteneinto blood. 

Popovic et al. (2005) Bunker Hill, ID 1994 

108 former female smelter employees and 99 referents to assess the PbB versus bone Pb relationship 

Exposed: PbB 2.73 (

±2.39), tibia 14.4 (

±0.5) 

Referents: PbB 1.25 (

±2.10), tibia 3.22 (

±0.50) 

Pb concentrations in tibia and blood significantly higher in the exposed group. Endogenous release rate (μg Pb per dL blood/μ Pb/g bone) in postmenopausal women was double the rate found in premenopausal women (0.132 

± 0.019 vs. 0.067 

± 0.014). 

Higher tibia bone Pwith use of estrogeboth the whole refepostmenopausal wo
 AX4-20 Table AX4-6 (cont’d). Bone Lead Contribution to PbB Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Finding

Canada Brito et al. (2000) Canada 1993-98 Aims were to: (i) investigate the long term human Pb metabolism by measuring the change of Pb concentration in the tibia and calcaneus between 1993 and 1998; and (ii) assess whether improved industrial hygiene was resulting in a slow accumulation of Pb in an exposed workforce. 101 workers in a secondary lead smelter, 51 subjects had similar bone Pb measurements in 1993. Most other subjects had been hired since 1993. Cumulative PbB index. Linear regressions. Repeats (n = 51) 1993: Tibia 39 (±19), calcaneus 64 (±36). 1998: Tibia 33 (±18), calcaneus 65 (±38). Non-repeats (n = 50) 1998: Tibia 15 (±16), calcaneus 13 (±18). Tibia Pb decreased significantly (p <0.001) in the 51 subjects with repeated bone Pb measurements. Tibia Pb in 1993 and changes in cumulative PbB index were significant predictors of changes in tibia Pb. An overall half-life of 15 yr (95% CI: 9, 55 yr) was estimated. Adding continuing lead exposure and recirculation of bone lead stores to the regression models produced half-life estimates of 12 and 9 yr, respectively, for release of lead from the tibia. Repeat subjects showed no net change in calcaneus Pb after 5 yr. The decrease in new 

release of previousla significant decreasubjects. The rate otibia of 9 to 15 yr is of previous estimatchange in the calcanif confirmed would models of Pb metab

Brito et al. (2002) Canada 1994, 1999 

Evaluated endogenous release of Pb from bone to blood in 204 exposed subjects resuming their duties after a 10-mo strike in a primary lead smelter in 1991. Bone Pb (109Cd 

source) measured in the tibia and calcaneus in 1994 (Fleming et al., 1997) and 1999. A linear model used to predict the current PbB upon the level of lead in bone. 327 subjects available on both occasions. Group H higher PbB and Group L lower PbB. 

Group H: PbB 22.0, tibia 19.2 (n = 120) Group L: PbB 20.6, tibia 82.8 (n = 45) Group H: PbB 24.2, calcaneus 41.4 (n = 90) Group L: PbB 20.2,calcaneus 138.2 (n = 45) Structural analysis of data gave slopes for tibia (2.0, 95% CI: 1.66, 2.54) and calcaneus (0.19, 95% CI: 0.16, 0.23) that were significantly higher than those predicted by the commonly used simple linear regression method, for tibia (0.73, 95% CI: 0.58, 0.88) and calcaneus (0.08, 95% CI: 0.06, 0.09). 

Suggested that morpredicted by regresfrom bone to blood
 AX4-21 Table AX4-6 (cont’d). Bone Lead Contribution to PbB Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Finding

Mexico Brown et al. (2000) Mexico City 1994-5 Investigated determinants of bone Pb and PbB of 430 lactating Mexican women during the early postpartum period and contribution of bone Pb to PbB. Linear regression analyses. PbB 9.5 (±4.5), tibia 10.2 (±10.1), patella 15.2 (±15.1). Older age, use of P

proportion of life smain predictors of Women in the 90th had an untransformμg/dL higher than 

Téllez-Rojo et al. (2002) Mexico City 1994-95 Evaluated the hypothesis that lactation stimulates Pb release from bone to blood. Cross–sectional examination of breastfeeding patterns and bone Pb as determinants of PbB among 425 lactating women (mean age 24.8 ± 5.3 yr) for 7 mo after delivery. Bone Pb at 1 mo postpartum. Maternal blood samples 

and questionnaire information collected at delivery and at 1, 4, and 7 mo postpartum. Generalized estimating equations. 

Mean PbB decreased with time postpartum: 1 mo 9.4 (±4.4), 4 mo 8.9 (±4.0), 7 mo 7.9 (±3.3). Tibia 10.6 (11.6 after correction for negative values), patella 15.3 (16.9 after correction). After adjustment for bone Pb and environmental exposure, women who exclusively breastfed their infants had PbB levels that were increased by 1.4 μg/dL and women who practiced mixed feeding had levels increased by 1.0 μg/dL, in relation to those who had stopped lactation. A 10 μg Pb/g increment in patella and tibia bone Pb increased PbB by 6.1% (95% CI: 4.2, 8.1) and 8.1% (95% CI: 5.2, 11.1), respectively. 

They concluded thhypothesis that lactthe amount of Pb r

Garrido-Latorre et al. (2003) Mexico City 1995 

Aim was to examine the relationship of PbB levels to menopause and bone lead levels in 232 perimenopausal and postmenopausal women from Mexico City. Measured bone mineral density in addition to bone Pb. Information regarding reproductive characteristics and known risk factors for PbB was obtained using a standard questionnaire by direct interview. Mean age of the population was 54.7 yrs (±9.8). Linear regression analyses. 

PbB 9.2 (±4.7), tibia 14.85 (±10.1), patella 22.73 (±14.9). A change of 10 μg Pb/g bone mineral in postmenopausal subjects was associated with an increase in PbB of 1.4 μg/dL, whereas a similar change in bone lead among premenopausal women was associated with an increase in PbB of 0.8 μg/dL. 

Found that postmenhormone replacemlevels and higher tilevels than non-usegreatest part of varassociation with Pbdescribe any relatioand bone density. 

PbB = blood lead.
 AX4-22 Table AX4-7. Bone Lead Studies in Pregnant and Lactating Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral F

United States Hu et al. (1996) Boston, MA 1990 Cord PbB measured in 223 women, 41 bone Pb measured at 1-4 postpartum. ANOVA. Values omitted if measurement uncertainty was >10 μg/g for tibia and 15 μg/g for patella. Cord PbB 1.19 (±1.32), maternal PbB 2.9 (±2.6), tibia 4.5 (±4.0) patella 5.8 (±4.5). Maternal age was the only factor marginally associated with combined bone Pb (p = 0.08) but not individually with tibia or patella Pb. Umbi

womehospifrom 

Rothenberg et al (2000) Los Angeles, CA 1995-98 Examined bone Pb contribution to PbB in a group of 311 immigrant women (mean age 27.8 ±7.5 yr), 99% from Latin America, during the 3rd trimester of pregnancy, and 1 to 2 mo after delivery. Multiple 

regression, variance-weighted least squares regression, structural equation modeling. 

Prenatal PbB 2.2 (+4.8/!1.0, geometric mean), postnatal PbB 2.8 (+4.9/!1.2) (p < 0.0001), tibia 6.7(±12.5), calcaneus 8.4 (±13.2). Varianceweighted multiple regression and structural equation models showed that both calcaneus and tibia Pb were directly associated with prenatal PbB but only calcaneus Pb was associated with postnatal PbB. Increasing natural log yrs in the United States independently predicted decreasing calcaneus and 3rd trimester PbB. 

Suggexogemoduof Pbin the durinendogexposcontinin thi

Rothenberg et al. (2002) Los Angeles, CA 1995-2001 

Examined the effects of blood and bone PbB on hypertension and elevated blood pressure in the 3rd trimester and postpartum among 1,006 mostly Latina and AfroAmerican women. Multiple and logistic regression. 

Returned and eligible: 3rd trimester PbB (n = 720) 1.9 (+3.6/!1.0), postpartum PbB (n = 704) 2.3 (+4.3/!1.2), tibia (n = 700) 8.0 (±11.4), calcaneus (n = 700) 10.7 (±11.9). Returned but ineligible: 3rd trimester PbB (n = 279) 1.9 (+4.2/!0.8), postpartum PbB (n = 274) 2.3 (+4.7/!1.1), tibia (n = 263) 8.7 (±13.9), calcaneus (n = 262) 11.2 (±15.1). For each 10 μg/g increase in calcaneus Pb level, the odds ratio for 3rd trimester 

hypertension (systolic blood pressure $140 mmHg or diastolic blood 

pressure $90 mmHg) was 1.86 (95% CI: 1.04, 3.32). In normotensive subjects, each 10 μg/g increase in calcaneus Pb level was associated with a 0.70 mmHg (95% CI: 0.04, 1.36) increase in 3rd trimester systolic blood pressure and a 0.54 mmHg (95% CI: 0.01, 1.08) increase in diastolic blood pressure after adjusting for postpartum hypertension, education, immigration status, current smoking, current alcohol use, parity, age, and body mass index. Tibia bone Pb was not related to hypertension or elevated blood pressure either in the 3rd trimester or postpartum, nor was calcaneus Pb related to postpartum hypertension or elevated blood pressure. 

The aPb exhyper

presscontrrequilong 
 AX4-23 Table AX4-7 (cont’d). Bone Lead Studies in Pregnant and Lactating Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral F

Mexico Hernandez-Avila et al. (1996) Mexico City Cross-sectional investigation of the interrelationships between environmental, dietary, and lifestyle histories, blood and bone Pb levels, among 98 recently postpartum women. Multivariate linear regression. Age 25.6 (±6.8) yr. 14-20 yr (n = 24): PbB 10.4 (±4.1), tibia 11.8 (±14.9), patella 14.1 (±13.3). 21-29 yr (n = 44): PbB 10.3 (±4.8), tibia 10.7 (± 10.9), patella 17.1 (±13.4) 30-43 yr (n = 27): PbB 7.8 (± 3.7), tibia 16.3 (±8.4), patella 18.1 (±12.7). A 34 μg/g increase in patella Pb (from the medians of the lowest to the highest quartiles) was associated with an increase in PbB of 2.4 μg/dL. Significant predictors of bone Pb included years living in Mexico City, lower consumption of high calcium content foods, and nonuse of calcium supplements for the patella and years living in Mexico City, older age, and lower calcium intake for tibia bone. Low consumption of milk and cheese, as compared to the highest consumption category (every day), was associated with an increase in tibia Pb of 9.7 μg/g. Sugg

signifdurinconsuconteagainin on

González-Cossío et al. (1997) Mexico City Unknown 

Examined relationship of Pb levels in cord blood and maternal bone to birth weight. Umbilical cord and maternal venous blood samples and anthropometric and sociodemographic data were obtained at delivery and 1 mo postpartum. Bone Pb at 1 mo postpartum. Multiple regression, LOWESS. Background information for calcium supplementation study 

Hernandez-Avila et al. (2003). Mother-infant pairs (n = 272). 

Maternal PbB 8.9 (±4.1), cord PbB 7.1 (±3.5), tibia 9.8 (±8.9), patella 14.2 (±13.2). After adjustment for other determinants of birth weight, tibia Pb was the only Pb biomarker clearly related to birth weight. The decline in birth weight associated with increments in tibia Pb was nonlinear and accelerated at the highest tibia Pb quartile. In the upper quartile, neonates were on average, 156 g lighter than those in the lowest quartile. 

Bonerelate
 AX4-24 Table AX4-7 (cont’d). Bone Lead Studies in Pregnant and Lactating Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral F

Mexico (cont’d) Brown et al. (2000) Mexico City 1994-5 Investigated determinants of bone Pb and PbB of 430 lactating Mexican women during the early postpartum period and contribution of bone Pb to PbB. Linear regression analyses. PbB 9.5 (±4.5), tibia 10.2 (±10.1), patella 15.2 (±15.1). Older 

potterlife spmain and p90th an unmean those 

Chuang et al. (2001) Mexico City 1994-95 Aim to estimate the contribution of maternal whole PbB and bone Pb, and environmental Pb to umbilical cord PbB (as a measure of fetal Pb exposure). Maternal 

and umbilical cord blood samples within 12 hr of each infant's delivery. Structural equation modeling. 

Bone Pb measured within 1 mo after delivery. PbB 8.45 (±3.94, n = 608), tibia 9.67 (±9.21, n = 603), patella 14.24 (±14.19, n = 575). Tibia and patella Pb, use of Pb glazed ceramics, and mean air Pb level contributed significantly to plasma Pb. An increase in patella Pb and tibia Pb was associated with increases in cord PbB of 0.65 and 0.25 μg/dL, respectively. 

SuggPb vamaterContr(bone(enviappro(Plasm

Ettinger et al. (2004) Mexico City 1994-95 

Aim to quantify the relation between maternal blood and bone Pb and breast-feeding status among 310 lactating women in Mexico City, Mexico, at 1 mo postpartum. Breast milk measured. Multiple linear regression, LOWESS smoothing. 

Breastfeeding: PbB 9.3 (±4.4, n = 310), tibia 9.6 (±10.1, n = 303), patella 14.5 (±14.9, n = 294). Non breastfeeding: PbB 9.3 (±4.9, n = 319), tibia 10.5 (±10.2, n = 306), patella 15.2 (±16.1, n = 289). Breast milk geometric mean 1.1 (range 0.21-8.02) μg/L. Breast milk Pb significantly correlated with umbilical cord Pb and maternal PbB at delivery and with maternal PbB and patella Pb at 1 mo postpartum. An interquartile range increase in patella Pb (20 μg/g) was associated with a 14% increase in breast milk lead (95% CI: 5, 25%). An IQR increase in tibia Pb (12.0 μg/g) was associated with a 5% increase in breast milk lead (95% CI: !3, 14). 

Suggpopulrelatiexposare locurreredistaccumenvir
 AX4-25 Table AX4-7 (cont’d). Bone Lead Studies in Pregnant and Lactating Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral F

Mexico (cont’d) Sanín et al. (2001) Mexico City 1994-95 Examined early postnatal growth in a cohort of healthy breastfed newborns in relation to maternal bone Pb burden. 329 mother- infant pairs sampled for umbilical cord blood at birth and maternal and infant venous blood at 1 mo postpartum. Maternal evaluations at 1 mo postpartum included Pb measures in blood and bone. Primary endpoints were attained weight 1 mo of age, and weight gain from birth to 1 mo of age. Linear regression. Included in analyses (n = 329): Infant: cord PbB 6.8 (±3.9), PbB 1 mo 5.7 (±3.0) Maternal: PbB 9.7 (±5.2), tibia Pb 10.1 (±10.3), patella Pb 15.2 (±15.2) Excluded from analyses (n = 276): Infant: cord PbB 6.3 (±3.0), PbB 1 mo 5.5 (±3.3) Maternal: PbB 8.8 (±3.9), tibia Pb 9.75 (±10.3), patella Pb 14.2 (±17.3). Infant PbB were inversely associated with weight gain, with an estimated decline of 15.1 g/μg/dL of PbB. Children who were exclusively breastfed had significantly higher weight gains; however, this gain decreased significantly with increasing levels of patella Pb. Multivariate regression analysis predicted a 3.6 g decrease in weight at 1 mo of age/μg Pb/g bone mineral increase in maternal patella Pb levels. The a

materassocweighpostnto 1 m

Gomaa et al. (2002) Mexico City Unknown 

Aim to compare umbilical cord PbB and maternal bone Pb as independent predictors of infant mental development (n = 197). Prospective design. At 24 mo of age, each infant was assessed using the Bayley Scales of Infant Development-II (Spanish Version). Multiple linear regression. 

Cord PbB 6.7 (±3.4), tibia 11.5 (±11.0), patella 17.9 (±15.2). After adjustment for confounders, Pb levels in umbilical cord blood and patella bone were significantly, independently, and inversely associated with the Mental Development Index (MDI) scores of the Bailey Scale. In relation to the lowest quartile of patella Pb, the 2nd, 3rd, and 4th quartiles were associated with 5.4-, 7.2-, and 6.5-point decrements in adjusted MDI scores. A 2-fold increase in cord PbB (e.g., from 5-10 μg/dL) was associated with a 3.1-point decrement in MDI score. 

Suggpatell

an indimpaiinfaneffect mobistores
 AX4-26 Table AX4-7 (cont’d). Bone Lead Studies in Pregnant and Lactating Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral F

Mexico (cont’d) Hernandez-Avila et al. (2002) Mexico City 1994 Aim to evaluate the effects of maternal bone Pb stores on anthropometry at birth in 223 mother-infant pairs. Anthropometric data were collected within the first 12 hr following delivery. Maternal information was obtained 1 mo after delivery (mean age 24.4 ± 5.4 yr). Transformed anthropometric measurements to an ordinal 5- category scale, and association of measurements with other factors evaluated with ordinal logisticregression models. Cumulative 

Odds Model. 

Cord blood 7.01 (±3.5), maternal PbB 8.82 (± 4.0), tibia 10.70 (±7.58, adjusted for negative values), patella 15.39 (±11.18, adjusted for negative values). Maternal PbB increased linearly by 0.096/μg of tibia Pb and 0.078/μg patella Pb. Umbilical cord PbB increased by 0.111/μg tibia Pb and 0.061/μg patella Pb. Birth length of newborns decreased as tibia Pb levels increased (odds ratio of 1.03/μg/g bone mineral [95% CI: 1.01, 1.06]). 

Complower of tibquintrisk olength 95% was pof a lscoreunaffweigh1.02/ CI: 1not vauthoand oof he

Téllez-Rojo et al. (2002) Mexico City 1994-95 

Evaluated the hypothesis that lactation stimulates Pb release from bone to blood. Cross-sectional examination of breastfeeding patterns and bone Pb as determinants of PbB among 425 lactating women (mean age 24.8 ±5.3 yr) for 7 mo after delivery. Bone Pb at 1 mo postpartum. Maternal blood samples and questionnaire information collected at delivery and at 1, 4, and 7 mo postpartum. Generalized estimating equations. 

Mean PbB decreased with time postpartum: 1 mo 9.4 (±4.4), 4 mo 8.9 (±4.0), 7 mo 7.9 (±3.3). Tibia 10.6 (11.6 after correction for negative values), patella 15.3 (16.9 after correction). After adjustment for bone Pb and environmental exposure, women who exclusively breastfed their infants had PbB levels that were increased by 1.4 μg/dL and women who practiced mixed feeding had levels increased by 1.0 μg/dL, in relation to those who had stopped lactation. A 10 μg Pb/g increment in patella and tibia bone Pb increased PbB by 6.1% (95% CI: 4.2, 8.1) and 8.1% (95% CI: 5.2, 11.1), respectively. 

They suppolactatamoubone. 
 AX4-27 Table AX4-7 (cont’d). Bone Lead Studies in Pregnant and Lactating Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral F

Mexico (cont’d) Hernandez-Avila et al. (2002) Mexico City 1994 Evaluated the effects that maternal bone Pb has on anthropometry at birth in 223 mother-infant pairs. Anthropometric data (birth length, head circumference) collected within the first 12 hr following delivery. Maternal information was obtained 1 mo postpartum. Transformed anthropometric measurements to an ordinal 5- category scale, ordinal logistic- regression models. Participants (n = 223) Cord blood 7.01 (±3.5), maternal PbB 8.82 (±4.0), tibia 9.83 (±8.9), patella 14.14 (±13.0). Nonparticipants (n = 494): Cord blood 6.75 (±3.50), PbB 8.47 (±4.19). Birth length of newborns decreased as tibia Pb levels increased. Compared with women in the lower quintiles of the distribution of tibia Pb, those in the upper quintile had a 79% increase in risk of having a lower birth length newborn (odds ratio 1.79; 95% CI: 1.10, 3.22). The effect was attenuated– but nonetheless significant- even after adjustment for birth weight. Patella Pb was positively and significantly related to the risk of a low head circumference score; this score remained unaffected by inclusion of birth weight. The a

increhead-1.02/ CI: 1not vauthoand oof he

Hernandez-Avila et al. (2003) Mexico City 1994-95 

Tested the hypothesis that in a randomized trial of lactating women a dietary calcium supplement will lower PbB levels. Lactating women (mean age 24 yr) were randomly assigned to receive either calcium carbonate (1200 mg of elemental calcium daily) or placebo in a double-blind trial. Blood samples were obtained at baseline, and 3 and 6 mo after the trial began. Primary endpoint was change in maternal PbB in relation to supplement use and other covariates with multivariate generalized linear models for longitudinal observations. 

Lactating calcium group (n = 296): PbB 9.2 (±4.2), tibia 10.7 (±9.8), patella 16.2 (±15.7) Lactating placebo (n = 321): PbB 9.4 (± 5.0), tibia 9.6 (±10.3), patella 13.5 (± 15.1) Women randomized to the calcium supplements experienced a small decline in PbB of 0.29 μg/dL (95% CI: !0.85, !0.26). The effect was more 

apparent among women who were compliant with supplement use and had high patella Pb of $5 μg/g. Among this subgroup, supplement use was associated with an estimated reduction in mean PbB of 1.16 μg/dL (95% CI: !2.08, !0.23), an overall reduction of 16.4%. 

Amonrelaticalciuassocreduc
 AX4-28 Table AX4-7 (cont’d). Bone Lead Studies in Pregnant and Lactating Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral F

Mexico (cont’d) Téllez-Rojo et al. (2004) Mexico City 1997-99 Tested the hypotheses that maternal bone Pb burden is associated with increasing maternal whole PbB and plasma Pb over the 3 trimesters of pregnancy and that this association is modified by rates of maternal bone resorption. Urine was analyzed for cross-linked N- telopeptides (NTx) of type I collagen, a biomarker of bone resorption. Patella and tibia Pb at 1 mo postpartum. Mixed models. Participants (n = 193): PbB (μg/dL): initial 7.10 (±1.72), 1st trimester 6.47 (± 0.17), 2nd trimester5.80 (± 0.17), 3rd trimester 6.05 (± 0.17). Plasma (μg/L): 1st trimester 0.13 (±1.88), 2nd trimester 0.12 (± 1.95), 3rd trimester 0.12 (± 1.88) (geometric means and SD) Bone Pb during pregnancy: Tibia 11.35 (±8.82, adjusted for negative values), patella 13.82 (±10.97, adjusted for negative values). Nonparticipants (n = 134): PbB 6.82 (±1.75), tibia 13.71 (±9.17, adjusted for negative values), patella 11.79 (±9.75, adjusted for negative values). 

Found an increasing trend for plasma Pb among women with the highest bone Pb ($median level of 12.1 μg/g) but a decreasing trend among lessexposed women(below the median level). The observed increase reached its maximum among women with both the highest bone Pb and the highest bone resorption. In comparison with women with a low bone Pb and a high NTx level, those with a high bone Pb and a high NTx level had, on average, an 80% higher mean plasma Pb. In the cross-sectional analyses for each trimester of pregnancy, there was an increasingly stronger association between bone Pb and plasma Pb (log-transformed) as pregnancy progressed. An increase in patella lead of 10 μg/g would be associated with 9% (p = 0.07), 24% (p < 0.01), and 25% (p < 0.01) increases in plasma Pb in the 1st, 2nd, and 3rd trimesters of pregnancy, respectively. The corresponding values for tibia lead were 8% (p = 0.16), 19% (p < 0.01), and 13% (p = 0.01), respectively. Dietary calcium intake was inversely associated with plasma lead. 

They suppobiolobone resorpthat abone incre
 AX4-29 Table AX4-7 (cont’d). Bone Lead Studies in Pregnant and Lactating Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral F

Mexico (cont’d) Moline et al. (2000) Morelos, Mexico 1999 Pilot study to assess the body burden of lead in 24 Mexican women (age 21-34 yr) who were lactating. Demographic and reproductive characteristics of women and potential sources of lead exposure were gathered by a direct interview. Multiple regression. Average time of lactation 22 (±17) months. PbB 4.6 (± 2.0, geometric mean), tibia 9.2 (±4.2), patella 14.8 (±8.0), calcaneus 11.7 (±11.2). An inverse relationship was noted between months of lactation and age-adjusted calcaneus lead level (p = 0.001). No association was observed between age-adjusted patella or tibia lead level and months of lactation (p = 0.15). This 

limitehypotoccur

PbB = blood lead.
 AX4-30 Table AX4-8. Bone Lead Studies of Menopausal and Middle-aged to Elderly Subjects Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Findings, 

United States Hu et al. (1996) Boston, MA 1991+ Normative Aging Study. Subjects were middle-aged and elderly men who had community (nonoccupational) exposures to lead. Cross-sectional. Backwards elimination multivariate regression models that considered age, race, education, retirement status, measures of both current and cumulative smoking, and alcohol consumption. 47-59 yr: (n = 116): PbB 5.8 (

±3.7), tibia 14.6 (

±8.3), 

patella 23.6 (

±12.4) 

60-69 yr: (n = 360): PbB 6.3 (

±4.2), tibia 21.1 

(±11.4), patella 30.5 (

±16.9) 

>70 yr: (n = 243): PbB 6.5 (

±4.5), tibia 27 (

±15.6), 

patella 38.8 (

±23.5) 

Factors that remained silevels of both tibia and and measures of cumulalevels of education. An the median of the loweshighest quintiles (13-56 rise in PbB of 4.3 μg/dLcomprised the major sothese men. 

Kim et al. (1997) Boston, MA 1991-95 

Normative Aging Study (n = 70). Aim to examine age and secular trends in bone and PbB levels of community-exposed men aged 52-83 yr. Bone and PbB levels measured twice, with a 3-yr interval. 

PbB 6.7 (

±1.8), tibia 17.5 (

±2.0), patella 29.1 (

±1.8) 

3 yr later: PbB 5.1 (

±1.4), tibia 17.9 (

±1.7), patella 

22.2 (

±1.8) 

Cross-sectional analysis measurements indicated older individual would higher levels of Pb in parespectively. Secular trdecreasing for patella PPb levels. 

Cheng et al. (1998) Boston, MA 1991-95 

Normative Aging Study (n = 747). Aim to examine relationships of nutritional factors to body Pb burden. Cross-sectional. Multiple regression models adjusting for age, education level, smoking, and alcohol consumption. 

PbB 6.2 (± 4.1), tibia 21.9 (± 13.3), patella 32.0 (±19.5). Multiple regression models men in the lowest quintile of total dietary intake levels of vitamin D (including vitamin supplements) (<179 i.u./day) had mean tibia and patella Pb levels 5.6 μg/g and 6.0 μg/g/ higher than men with intake in the highest quintile ($589 

i.u./day). Higher calcium intake was associated with lower bone Pb levels, but this relation became 

insignificant when adjustment was made for vitamin D. Subjects in the lowest vitamin C intake quintile (<109 mg/day) had a mean PbB level 1.7 μg/dL higher than men in the highest quintile ($339 mg/day), while men in the lowest iron intake quintile (<10.9 mg/day) had a mean PbB level 1.1 μg/dL higher than men in the highest quintile ($23.5 mg/day). 

Also observed inverse awith total dietary intake Suggested that low dietmay increase Pb accumlower dietary intake of vincrease PbB. 
 AX4-31 Table AX4-8 (cont’d). Bone Lead Studies of Menopausal and Middle-aged to Elderly Sub

Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Findings, InterpretatioUnited States (cont’d) Hu et al. (2001) Boston, MA 1991+ Normative Aging Study. Aim to determine if ALAD polymorphism is associated with altered levels of lead in bone and blood. Multivariate linear regression models controlling for age, education, smoking, alcohol ingestion, and vitamin D intake. ALAD 1-1 (n = 608): PbB 6.3(

±4.1), tibia 22.2 

(±13.9), patella 32.2 (

±19.9) 

ALAD 1-2/2-2 (n = 118): PbB 5.7 (

±4.2), tibia 21.2 

(±10.9), patella 30.4 (

±17.2) 

ALAD 1- 1 genotype was associated with cortical bone lead levels that were 2.55 μg/g (95% CI: 0.05, 5.05) higher than those of the variant allele carriers. 

No significant differencto Pb levels in trabeculastratified analyses and a model that tested for intof trabecular bone Pb to significantly modified bvariant allele carriers haonly when trabecular boThe authors suggest thamodifies lead kinetics puptake into cortical bonmobilization of lead fro

Oliveira et al. (2002) Boston, MA 1991-98 

Normative Aging Study. To determine if seasonal fluctuations in PbB levels are related to increased mobilization of bone Pb stores during the winter months. Measurements of blood and bone Pb during the high sun exposure months of May-August (summer; n = 290); the intermediate sun exposure months of March, April, September, and October (spring/fall; n = 283); and the low sun exposure months of November-February (winter; n = 191). 

Mean PbB levels were slightly lower in summer (5.8 ± 3.4 μg/dL) compared with winter (6.6 ± 4.7 μg/dL). Mean bone Pb levels were higher during the 

summer than the winter months: 23.9 (±15.2) and 20.3 (±11.3) μg/g respectively for the tibia and 34.3 (±22.8) and 29.0 (±16.2) μg/g respectively for patella. 

Found a significant intebone Pb with bone Pb dexerting an almost 2-follevels than during the suauthors attributed this to endogenous bone Pb stodecreased exposure to sactivated vitamin D and 
 AX4-32 Table AX4-8 (cont’d). Bone Lead Studies of Menopausal and Middle-aged to Elderly Sub

Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Findings, United States (cont’d) Korrick et al. (2002) Boston, MA 1990-95 Nurses’ Health Study. Cross-sectional study of 264 elderly women; 46-54 yr (80) 55-64 yr (102), 65-74 yr (82). Tibia and patella Pb. Multivariate linear regression models. 46-54 yr: PbB 2.7 (SE 

±0.3), tibia 10.5 (

±1.0), patella 

14.9 (

±1.2) 

55-64 yr: PbB 3.4 (

±0.2), tibia 12.7 (

±0.9), patella 

17.0 (

±1.1) 

65-74 yr: PbB 3.3 (

±0.3), tibia 16.4 (

±0.9), patella 

19.8 (

±1.2). 

An increase from the first to the fifth quintile of tibia Pb level (19 μg/g) was associated with a 1.7 μg/dL increase in PbB (p = 0.0001). 

Tibia and patella Pb valpositively associated wipostmenopausal women estrogens. Older age anassociated with higher tassociated with patella Pobserved interaction of status in determining Pbthat increased bone resopostmenopausally becauproduction, results in hestores into blood. 

Tsaih et al. (1999) Boston, MA 1991-97 

Normative Aging Study. Aim to evaluate hypothesis that bone and erythrocyte Pb make independent contributions to urine Pb excreted over 24 hour. Urine used as a proxy for plasma Pb. Age range 53-82 yr (n = 71). Generalized additive model. 

PbB: 5.94 (±3.0), tibia 21.7 (±10.9), patella 31.1 (±15.1), urinary Pb 5.69 (±1.9) 

Fg/day. Both 

erythrocyte Pb and bone Pb variables remained independently and significantly associated with urinary Pb. 

Finding suggests that boa manner that is indepenerythrocytic lead on plasuperiority of bone Pb ochronic forms of toxicitbone's influence on plasbe useful as a proxy for 

Wright et al. (2004) Boston, MA 1991-97 

Normative Aging Study. Aim to evaluate if hemochromatosis gene (HFE) was associated with body lead burden. Tibia and patella bone Pb. DNA samples genotyped. Multivariate linear regression analyses. 

Of 730 subjects, 94 (13%) carried the C282Y variant and 183 (25%) carried the H63D variant. In multivariate analyses that adjusted for age, smoking, and education, having an HFE variant allele 

was an independent predictor of significantly lower patella Pb levels (p < 0.05). 

Suggested that HFE varof Pb accumulation aftemay be mediated by altvia iron metabolic pathwgene product and body 
 AX4-33 Table AX4-8 (cont’d). Bone Lead Studies of Menopausal and Middle-aged to Elderly Sub

Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Findings, United States (cont’d) Lin et al. (2004) Boston, MA 1999-2000 Community Lead Study. Measured PbB and bone Pb levels among minority individuals from Boston. Compared with earlier studies of predominantly white subjects, the 84 volunteers in this study (33:67 male to female ratio; 31-72 yrs of age) had similar educational, occupational, and smoking profiles and mean blood, tibia, and patella Pb levels. LOWESS smoothing curves. Multiple linear regression analyses to predict blood, tibia and patella Pb. <45 yr (n = 28): PbB 2.0 (±1.2), tibia 8.3 (±8.4), patella 8.9 (±14.3) 46-60 yr (n = 41): PbB 2.8 (±1.7), tibia 10.8 (±11.5), patella 11.8 (±11.4) 61-75 yr (n = 15): PbB 5.3 (±3.2),tibia 21.7 (±8.6), patella 30.9 (±15.7) Slopes of the univariate regressions of blood, tibia, and patella lead versus age were 0.10 μg/dL/yr (p < 0.001), 0.45 μg/g/yr (p <0.001), and 0.73 μg/g/yr (p < 0.001), respectively. Analyses of smoothing 

for tibia and patella Pb point at 55 yr of age, wi≥55 yr of age that were of younger subjects but than those observed for studies of predominantl

Berkowitz et al. (2004) New York 1994-99 

Longitudinal study of 91 premenopausal and perimenopausal women aged $ 30 yrs of age from New York who were undergoing surgical menopause (baseline; n 84) to determine if bone Pb values decrease and PbB values increase during menopause. Tibia Pb concentrations measured at baseline, 6 mo (70) and 18 mo (62) post surgery. 

Baseline: Median PbB 2.5 (0.3, 11.7), tibia 6.1 (!22.2, 36.4) 6 mo: PbB 3.2 (0.4, 12.0), tibia 6.8 (!14.2, 29.0) 18 mo: PbB 3.1 (0.5, 9.1), tibia 5.8 (!15.4, 24.2) 

Marginal decline in tibi18 mo post surgery for replacement therapy (ERdid not take ERT. They no substantial mobilizatduring menopause but cmasked this effect, the awere too low to detect isubjects was too small t

Schafer et al. (2005) Baltimore, MD 

Evaluated the relations among PbB, tibia Pb, and homocysteine levels by crosssectional analysis among subjects in the Baltimore Memory Study, a longitudinal study of 1, 140 randomly selected residents in Baltimore, MD, aged 50-70 yr and 66.0% female, 53.9% white, and 41.4% black or African American. Multiple linear regression analyses. 

PbB 3.5 (±2.4) μg/dL, tibia 18.9 (±12.5) μg/g, homocysteine 10.0 (±4.1) 

Fmol/L. Tibia lead was 

modestly correlated with PbB (Pearson r = 0.12, p < 0.01) but was not associated with homocysteine levels. 

Suggested that homocymechanism that underlicardiovascular and centpossibly offering new taprevent the long-term cexposure. 
 AX4-34 Table AX4-8 (cont’d). Bone Lead Studies of Menopausal and Middle-aged to Elderly Sub

Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Findings, Interpretatio

United States (cont’d) Kosnett et al. (1994) Dickson City, PA Aim to determine the influence of demographic, exposure and medical factors on the bone Pb concentration of subjects with environmental Pb exposure. 101 subjects (49 males, 52 females; aged 11 to 78 yrs) recruited from 49 of 123 households geographically located in a suburban residential neighborhood. Log-transformed bone Pb highly correlated with age (r = 0.71; p # 0.0001). Bone Pb showed no sig

20 yr, increased with thwomen between ages 20 increased at a faster rate 

Popovic et al. (2005) Bunker Hill, ID 1994 108 former female smelter employees and 99 referents to assess the PbB versus bone Pb relationship. Exposed: PbB 2.73 (

±2.39), tibia 14.4 (

±0.5) 

Referents: PbB 1.25 (

±2.10), tibia 3.22 (

±0.50) 

Pb concentrations in tibia and blood significantly higher in the exposed group. Endogenous release rate (μg Pb per dL blood/ μg Pb/g bone) in postmenopausal women was double the rate found in premenopausal women (0.132 

± 0.019 versus 

0.067 

± 0.014). 

Higher tibia bone Pb (awith use of estrogen (prwhole referent group anin the referent group. 

Canada 

Webber et al. (1995) Canada Unknown 

Tested hypothesis that women on hormone replacement therapy should have higher bone Pb content and lower plasma Pb as hormone replacement therapy would suppress the transfer of endogenous Pb to the circulation. 56 women, some using hormone replacement therapy over ~4 yrs. 

Low dose hormone replacement therapy (n = 15): PbB 4.08 (±1.60), tibia 19.37 (±8.62), calcaneus 24.02 (±10.88) Moderate dose hormone replacement therapy (n = 11): PbB 5.22 (±3.36), tibia 16.80 (±11.68), calcaneus 23.83 (±14.18) Calcium only (n = 22): PbB 4.6 (±1.59), tibia 11.13 (±6.22), calcaneus 21.12 (±13.55) 

Women not taking hormlower Pb values in cortiall women on hormone (p = 0.007). Showed hiincrease in calcaneus Pb 
 AX4-35 Table AX4-8 (cont’d). Bone Lead Studies of Menopausal and Middle-aged to Elderly Sub

Reference, Study Location, and Period Study Description Lead Measurement (SD or range) PbB in μg/dL, Bone Pb in μg/g Bone Mineral Findings, Mexico Garrido-Latorre et al. (2003) Mexico City 1995 Aim was to examine the relationship of PbB levels to menopause and bone lead levels in 232 perimenopausal and postmenopausal women from Mexico City. Measured bone mineral density in addition to bone Pb. Information regarding reproductive characteristics and known risk factors for PbB was obtained using a standard questionnaire by direct interview. Mean age of the population was 54.7 yrs (±9.8). Linear regression analyses. PbB 9.2 (±4.7), tibia 14.85 (±10.1), patella 22.73 (±14.9). A change of 10 μg Pb/g bone mineral in postmenopausal subjects was associated with an increase in PbB of 1.4 μg/dL, whereas a similar change in bone lead among premenopausal women was associated with an increase in PbB of 0.8 μg/dL. Found that postmenopa

replacement therapy hahigher tibia and patella users; patella Pb explainvariations in PbB. Founlevels and did not descrbetween bone lead and 

Australia Gulson et al. (2002) Sydney, Australia 2000 

Environmentally exposed females (n = 7) and males (n = 3) aged 44-70 yr. Treated for 6 mo with the bisphosphonate alendronate. PbB and isotopic ratios measured by TIMS for 6 mo prior to treatment and 12 mo post-treatment. Bone mineral density and bone markers including NTx measured. 

Found a decrease in PbB concentrations and changing PbB isotopic composition in the direction predicted during treatment. Upon cessation of treatment, PbB increased and the isotopic compositions changed. 

Results consistent with associated with bisphos

PbB = blood lead.
 AX4-36 Table AX4-9. Lead in Deciduous Teeth from Urban and Remote Environments Reference, Study Location, and Period Study Description Lead Measurement Finding

Canada Tsuji et al. (2001) Ontario, Canada Dentine chips from schoolchildren living in a remote area. Mean value of 9.2 μg/g dry weight (n = 61) Attributed the high 

lead contaminated 

Europe Tvinnereim et al. (1997) Norway 1990-94 2,746 deciduous whole teeth. Mean 1.27 ± 1.87 μg/g of dry tooth substance Observed an ~50% 

concentrations sinc

Lyngbye et al. (1991) Denmark In 2,033 teeth from 1, 848 children. Geometric mean for the largest group from Arhus to be 8.4 μg/g (wet weight) with similar values from Copenhagen suburbs with a secondary lead smelter (9.6 μg/g) and a lead battery factory (9.9 μg/g). Concluded tha

exhausts and iexposure were for the lead in 

Gil et al. (1996) Coruna, Spain 

220 whole deciduous and permanent teeth (one per subject). 

Permanent teeth showed higher mean values (13.1 ±1.1 μg/g) than deciduous teeth (4.0 ± 1.1 μg/g) 

Found no gender d

Nowak and Chmielnicka (2000) Poland 

Compared permanent teeth from two cohorts, one from the highly polluted Katowice district and a control town of Beskid. 

In the control teeth, they observed decreases in lead for incisors (41.8 μg/g) to canines (37.5 μg/g) to molars (35.3 μg/g) to premolars (32.0 μg/g). However, there was no difference in the mean values for the two centers: Katowice 36.5 ± 16.3 μg/g and Beskid 36.3 ± 11.5 μg/g. 

These values are vmost other studies
 AX4-37 Table AX4-9 (cont’d). Lead in Deciduous Teeth from Urban and Remote Environmen

Reference, Study Location, and Period Study Description Lead Measurement FindingMexico Hernandez-Guerrero et al. (2004) Mexico City 100 healthy deciduous teeth collected from 2 to 13 yr old children. Higher mean concentrations of lead in the 10-13 yr old group (7.7 μg/g) than in other age groups and the mean concentrations were higher in girls (7.3 μg/g) than boys (6.3 μg/g). No association bet

and tooth lead. Frank et al. (1990) Alsace, Mexico Circular biopsies 500 

Fm in diameter 

punched in the vertical sections of the crown and cervical third of each root. The age of the European subjects ranged from 10 to 80 yrs in Europe and 12 to 29 yrs in Mexico City. Energy-dispersive X-ray fluorescence method to compare lead in enamel and dentine of premolars and permanent molars. 

Compared with the European values, there were ~6 times higher inner coronal dentine and 7 to 9 times higher pulpal root dentine concentrations for samples from Mexico City. 

The authors found the relationship bevalues for enamel communities but a concentration in redifferences were at

Asia 

Karakaya et al. (1996) Ankara, Turkey 

103 whole deciduous teeth from primary school aged children aged 7 to 12 yrs. 

Significant differences in lead for urban (4.99 ± 0.46 μg/g dry weight) compared with suburban children (1.69 ± 0.25 μg/g). 
 AX4-38 Table AX4-10. Lead in Deciduous Teeth from Polluted Environments Reference, Study Location, and Period Study Description Lead Measurement Findi

Europe Begerow et al. (1994) Germany 1991 790 children aged 6 yrs old living in urban and rural areas in western and eastern Germany. Incisors sampled. Lead levels of 1.50 to 1.74 μg/g from the western sector and from 1.51 to 2.72 μg/g in the eastern sector. Major decreasCikrt et al. (1997) Czech Republic Compared tooth (n = 162) and PbB levels in children living at various distances from a lead smelter. Significant difference in the mean tooth lead for children from the most contaminated zone less than 0.5 km from the smelter (6.44 μg/g; n = 13) and those >5 km from the smelter (1.45 μg/g; n = 36). PbB levels varied from 15.42 μg Pb/100 ml (n = 6; 95% CI: 7.17, 33.17) close to the smelter to 4.66 μg/100 ml (n = 165, 95% CI: 4.30, 5.04) at larger distances. No descriptio

available. Australia Gulson (1996) Broken Hill, Australia 36 exposed and nonexposed children from Broken Hill lead-zinc mining 

community. Sectioned teeth into mainly enamel (incisal section) and mainly dentine (cervical section). Lead isotope ratios and lead concentrations by TIMS with isotope dilution. 

For subjects with low exposure (n = 13), lead concentrations in the incisal section ranged from 0.4 to 3.5 μg/g with a mean and standard deviation of 1.2 ± 0.8 μg/g (n = 13). For the cervical sections in low exposure children, the values ranged from 0.8 to 8.3 and mean 3.7 ± 2.4 μg/g. For subjects with high exposure (n = 23), lead concentrations in the incisal section ranged from 1.0 to 8.9 μg/g with a mean and standard deviation of 2.6 ± 1.8 μg/g. For the cervical sections in high exposure children the values ranged from 1.5 to 31.5 μg/g and mean 13.7 ± 8.0 μg/g. 

The isotopic rinterpreted to exposure from orebody durinassociated wi

Gulson et al. (2004) Lake Macquarie, Australia

10 children from six houses in a primary zinc-lead smelter community at North Lake Macquarie, New South Wales, Australia. Sectioned deciduous teeth compared with environmental samples. Lead isotope ratios and lead concentrations by TIMS with isotope dilution.

PbB levels in the children ranged from 10 to 42 μg/dL and remained elevated for a number of years. Median lead level in the enamel section of the teeth was 2.3 μg/g with a range from 0.6 to 7.4 μg/g; in dentine the median value was 5.3 μg/g with a range from 1.4 to 19.9 μg/g.

Approximatelbe derived fro

PbB = blood lead. 
 AX4-39 Table AX4-11. Summary of Selected Measurements of Urine Lead Levels in Humans Reference, Study Location, and Period Study Description Urine Lead Measurement 

United States CDC (2005) U.S. 1999-2002 Design: national survey (NHANES IV) stratified, multistage probability cluster design Subjects: children and adults ($6 yrs, n = 5140) in general population Biomarker measured: urine lead Analysis: ICP-MS Units: μg/g creatinine Geometric mean (95% CI) Age (yr) 1999-2000 2001-2002 

$6: 0.72 (0.70, 0.74) 0.64 (0.60, 0.68)  n: 2465 2689 6-11: 1.17 (0.98, 1.41) 0.92 (0.84, 1.00)  n: 340 368 12-19: 0.50 (0.46, 0.54) 0.40 (0.38, 0.43)  n: 719 762 $20: 0.72 (0.68, 0.76) 0.66 (0.621, 0.70)  n: 1406 1559 Males: 0.72 (0.68, 0.76) 0.64 (0.61, 0.67)  n: 1227 1334 Females: 0.72 (0.68, 0.76) 0.64 (0.59, 0.69)  n: 1238 1355 

Geometric in age strat1.51 μg/dL

Schwartz et al. (1999, 2000b) U.S. 1993-1997 

Design: prospective Subjects: adult male (n = 543) former TEL manufacture workers (age range: 42-74 yrs) Biomarker measured: DMSA (10 mg/kg)-provoked urine lead Analysis: GFAAS 

Units: μg/4 hr Arithmetic mean (SD): $2 yr exposure: 17.1 (15.7) <2 yr exposure: 20.4 (17.9) 

Arithmetic was 5.0 (2.$2 yr and 2exposed <2predictor olead. Arithmetic XRF) was exposed $2 workers ex

Rabinowitz et al. (1976) New York NR 

Design: experimental study Subjects: adult (n:5) males, age range 25-53 yrs, ingested 300 μg Pb/day (~50% as 204Pb) for 

10-210 days Biomarker measured: urine lead Analysis: MS 

Units: μg/day Arithmetic mean (range): 36 (36-41) 

Arithmetic was 19.4 (1Blood-to-u0.19 (range Diamond, 
 AX4-40 Table AX4-11 (cont’d). Summary of Selected Measurements of Urine Lead Levels in Hum

Reference, Study Location, and Period Study Description Urine Lead Measurement United States (cont’d) Berger et al. (1990) Ohio 1983-1986 Design: cross-sectional, convenience sample Subjects: children (n = 39), age range not reported. Biomarker measured: timed urine lead Analysis: AAS Units: μg/day range: 5-70 PbB range w

urine clearan(from Diamo

Europe Chamberlain et al. (1978) United Kingdom 1975-1976 Design: experimental Subjects: adult males (n = 6), intravenous injection of 203Pb tracer Biomarker: urinary lead clearance Analysis: gamma spectrometer (203Pb) Units: L/day Arithmetic mean (range) Blood-to-urine: 0.09 (0.08-0.10) Plasma-to-urine: 20 Brockhaus et al. (1988) Germany 

1982-1986 

Design: cross-sectional Subjects: children (n = 184), age range 4-11 yrs residing in 2 areas impacted by smelting operationsBiomarker measured: urine lead Analysis: GFAAS 

Units: μg/g creatinine Geometric mean (GSD, range) Stolberg (n = 106): 9.6 (2.3, 0.2-43.0) Dortmund (n = 78): 6.7 (2.0, 1.6-41.0) 

Geometric m~7 μg/dL. 

Koster et al. (1989) Germany NR 

Design: cross-sectional Subjects: adult (n = 46, 40 males) hospital workers, age range 20-78 yr. Biomarker measured: urine lead Analysis: GFAAS 

Units: μg/24 hr-1.73 m2 (adult body surface area) 

Arithmetic mean (range): 6.8 (2.3-18.9) 

Arithmetic mwas 7.6 (2.6Blood-to-uri0.15 L/day (

Australia 

Gulson et al. (2000) Australia 

Design: longitudinal Subjects: women (n = 58) during pregnancy, age range 18-35 yrs Biomarker measured: blood-to-urine clearance Analysis: TIMS 

Units: μg/h Arithmetic mean (SD, range): 3.2 (0.8-10.2) Geometric mean: 2.7 

Reported blocorresponds 
 AX4-41 Table AX4-11 (cont’d). Summary of Selected Measurements of Urine Lead Levels in Hum

Reference, Study Location, and Period Study Description Urine Lead Measurement Asia Araki et al. (1986, 1990) Japan NR Design: cross-sectional Subjects: adult (n = 19) male, gun metal foundry workers, age range 34-59 yr. Biomarker measured: urine lead Analysis: AAS Units: μg/24 hr Arithmetic mean (range): 94 (37-171) Arithmetic m

was 0.67 μgPlasma-to ur22 L/day. Blood-to-uri0.33 L/day (

Lee et al. (1990) Korea NR Design: cross-sectional Subjects: adults (n = 95) male workers in lead smelting, battery manufacture, PVC-stabilizer manufacture facilities, age range: 19-64 yrs; reference subjects (n = 13), age range 22-54 yr. Biomarker measured: DMSA (10 mg/kg)- provoked urine lead Analysis: GFAAS Units: μg/4 hr Arithmetic mean (SD, range) Lead workers: 288.7 (167.7, 32.4-789) Reference: 23.7 (11.5, 10.5-43.5) Arithmetic m

concentratio21.4-78.4) in 4.0-7.2) in rPbB was strprovoked ur

Schwartz et al. (2000a), Lee et al. (2001) Korea 1997-1999 

Design: Cross-sectional Subjects: Adult lead (inorganic) workers (n = 798, 634 males), age range 18-65 yrs. Biomarker measured: MSA (10 mg/kg)-provoked urine lead Analysis: GFAAS 

Units: μg/4 hr Arithmetic mean (SD, range) 186 (208, 4.8-2100) 

Arithmetic m(μg/dL) was strongest preurine lead. Arithmetic m(μg/g, XRF) 

AAS - atomic absorption spectroscopy; PbB = blood lead; ET-AAS - electro-thermal atomic absorption spectrometry; GFAAS - graphite furnace ato

spectroscopy; ICP-AES - inductively coupled plasma/atomic emission spectroscopy; ICP-MS - inductively coupled plasma-mass spectrometry; MS 

NR - not reported; Pct - percentile; TEL -tetraethyl lead; TIMS - thermal ionization mass spectrometry. 
 AX4-42 Table AX4-12. Summary of Selected Measurements of Hair Lead Levels in Humans Reference, Study Location, and Period Study Description Hair Lead Measurement Co

United States DiPietro et al. (1989) GA, SC, TX, VA 1976-1980 Design: Cross-sectional (random sample from NHANES II, HHANES Stands) Subjects: adults (n = 270, 200 males; age range: 20-73 yrs) from general population Biomarker measured: Hair lead Analysis: ICP-AES Units: μg/g Geometric mean (10-90th Pct range) 2.42 (<1.0-10.8) Hair lead level varied w

shampoo, coloring). Tuthill (1996) MA NR Design: Cross-sectional Subjects: children (n = 277, 141 males, age range 6.5-7.5 yrs) Biomarker measured: Hair lead Analysis: ICP-AES Units: μg/g <0.1-0.9 : 13.5% 1-1.9: 40.8% 2-2.9: 25.6% 3-3.9: 9.0% 

$4: 11.1% 

Study examined associalevels and attention-def

Europe 

Annesi-Maesano et al. (2003) France 1985, 1991-1992 

Design: cross-sectional Subjects: mother (mean age 29 yr)-infant pairs (n:374) Biomarker measured: hair lead Analysis: ICP-AES 

Units: μg/g Arithmetic mean (SD): Infant: 1.38 (1.26) Mother: 5.16 (6.08) 

Mean PbB concentratioin mothers and 67 (SD 4Infant hair-cord PbB cowas 0.21 (p < 0.01). 

Drasch et al. (1997) Germany 1993-1994 

Design: cross-sectional Subjects: adults (n = 150, 75 males; age range: 16-93 yrs) from general population with no known occupational exposure Biomarker measured: hair lead (post-mortem) Analysis: ET-AAS 

Units: μg/g Median (range): 0.76 (0.026-20.6) 25-75th Pct range: 0.45-1.48 

Median PbB (μg/dL) wMedian temporal bone l0.25-22.3), Hair lead co0.35 (p < 0.001) for blotemporal bone, and 0.16 burden.0.512 for liver ((p = 0.001) for kidney. 

Gerhardsson et al. (1995b) Sweden NR 

Design: cross-sectional Subjects: adult male smelter workers (n = 32) and referents (n = 10) Biomarker measured: hair lead (post-mortem) Analysis: XRF 

Units: μg/g Median (range): Active workers: 8.0 (1.5-29,000) Retired workers: 2.6 (0.6-9.3) Reference: 2.05 (0.3-96) 

Based on reported a cumof 1,374 μg/dL and aveemployment of 31.4 yrsbeen ~44 μg/dL in work(Spearman, r). 
 AX-43 Table AX4-12 (cont’d). Summary of Selected Measurements of Hair Lead Levels in Hum

Reference, Study Location, and Period Study Description Hair Lead Measurement CoEurope (cont’d) Esteban et al. (1999) Russia 1996 Design: cross-sectional Subjects: children (n = 189, 110 females; age rage 1.9-10.6 yr) living in the vicinity of lead battery and leaded glass manufacture facilities. Biomarker measured: hair lead Analysis: ICP-AES Units: ng/g Geometric mean (range): 5.4 (1-39.2) 90th Pct: ~15 Geometric mean PbB w

(range 3.1-35.7); log Pb(log hair) + 0.24 (gende

AAS - atomic absorption spectroscopy; PbB = blood lead; ET-AAS - electro-thermal atomic absorption spectrometry; GFAAS - graphite furnace atospectroscopy; HHANES - Hispanic Health and Nutrition Examination Survey; ICP-AES - inductively coupled plasma/atomic emission spectroscopycoupled plasma-mass spectrometry; NR - not reported; Pct - percentile. 
AX4-44 

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Abadin, H. G.; Wheeler, J. S. (1997) Guidance for risk assessment of exposure to lead: a site-specific, multi-media 

approach. In: Andrews, J. S.; Frumkin, H.; Johnson, B. L.; Mehlman, M. A.; Xintaras, C.; Bucsela, J. A., 

eds. Hazardous waste and public health: international congress on the health effects of hazardous waste. 

Princeton, NJ: Princeton Scientific Publishing Co.; pp. 477-485. 

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October 2006 

EPA/600/R-05/144bF 

Air Quality Criteria for Lead 

Volume II of II 
EPA/600/R-05/144bF 

October 2006 

Air Quality Criteria for Lead 

Volume II 

National Center for Environmental Assessment-RTP Division 

Office of Research and Development 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 
PREFACE

National Ambient Air Quality Standards (NAAQS) are promulgated by the United States 

Environmental Protection Agency (EPA) to meet requirements set forth in Sections 108 and 109 

of the U.S. Clean Air Act. Those two Clean Air Act sections require the EPA Administrator 

(1) to list widespread air pollutants that reasonably may be expected to endanger public health or 

welfare; (2) to issue air quality criteria for them that assess the latest available scientific 

information on nature and effects of ambient exposure to them; (3) to set “primary” NAAQS to 

protect human health with adequate margin of safety and to set “secondary” NAAQS to protect 

against welfare effects (e.g., effects on vegetation, ecosystems, visibility, climate, manmade 

materials, etc); and (5) to periodically review and revise, as appropriate, the criteria and NAAQS 

for a given listed pollutant or class of pollutants. 

Lead was first listed in the mid-1970’s as a “criteria air pollutant” requiring NAAQS 

regulation. The scientific information pertinent to Pb NAAQS development available at the time 

was assessed in the EPA document Air Quality Criteria for Lead; published in 1977. Based on 

the scientific assessments contained in that 1977 lead air quality criteria document (1977 Lead 

AQCD), EPA established a 1.5 μg/m3

 (maximum quarterly calendar average) Pb NAAQS in 

1978. 

To meet Clean Air Act requirements noted above for periodic review of criteria and 

NAAQS, new scientific information published since the 1977 Lead AQCD was later assessed in 

a revised Lead AQCD and Addendum published in 1986 and in a Supplement to the 1986 

AQCD/Addendum published by EPA in 1990. A 1990 Lead Staff Paper, prepared by EPA’s 

Office of Air Quality Planning and Standards (OPQPS), drew upon key findings and conclusions 

from the 1986 Lead AQCD/Addendum and 1990 Supplement (as well as other OAQPSsponsored lead exposure/risk analyses) in posing options for the EPA Administrator to consider 

with regard to possible revision of the Pb NAAQS. However, EPA chose not to revise the Pb 

NAAQS at that time. Rather, as part of implementing a broad 1991 U.S. EPA Strategy for 

Reducing Lead Exposure, the Agency focused primarily on regulatory and remedial clean-up 

efforts to reduce Pb exposure from a variety of non-air sources that posed more extensive public 

health risks, as well as other actions to reduce air emissions. 

The purpose of this revised Lead AQCD is to critically assess the latest scientific 

information that has become available since the literature assessed in the 1986 Lead 

II-iii 
AQCD/Addendum and 1990 Supplement, with the main focus being on pertinent new 

information useful in evaluating health and environmental effects of ambient air lead exposures. 

This includes discussion in this document of information regarding: the nature, sources, 

distribution, measurement, and concentrations of lead in the environment; multimedia lead 

exposure (via air, food, water, etc.) and biokinetic modeling of contributions of such exposures 

to concentrations of lead in brain, kidney, and other tissues (e.g., blood and bone concentrations, 

as key indices of lead exposure).; characterization of lead health effects and associated exposureresponse relationships; and delineation of environmental (ecological) effects of lead. This final 

version of the revised Lead AQCD mainly assesses pertinent literature published or accepted for 

publication through December 2005. 

The First External Review Draft (dated December 2005) of the revised Lead AQCD 

underwent public comment and was reviewed by the Clean Air Scientific Advisory Committee 

(CASAC) at a public meeting held in Durham, NC on February 28-March 1, 2006. The public 

comments and CASAC recommendations received were taken into account in making 

appropriate revisions and incorporating them into a Second External Review Draft (dated May, 

2006) which was released for further public comment and CASAC review at a public meeting 

held June 28-29, 2006. In addition, still further revised drafts of the Integrative Synthesis 

chapter and the Executive Summary were then issued and discussed during an August 15, 2006 

CASAC teleconference call. Public comments and CASAC advice received on these latter 

materials, as well as Second External Review Draft materials, were taken into account in making 

and incorporating further revisions into this final version of this Lead AQCD, which is being 

issued to meet an October 1, 2006 court-ordered deadline. Evaluations contained in the present 

document provide inputs to an associated Lead Staff Paper prepared by EPA’s Office of Air 

Quality Planning and Standards (OAQPS), which poses options for consideration by the EPA 

Administrator with regard to proposal and, ultimately, promulgation of decisions on potential 

retention or revision, as appropriate, of the current Pb NAAQS. 

Preparation of this document has been coordinated by staff of EPA’s National Center for 

Environmental Assessment in Research Triangle Park (NCEA-RTP). NCEA-RTP scientific 

staff, together with experts from academia, contributed to writing of document chapters. Earlier 

drafts of document materials were reviewed by scientists from other EPA units and by non-EPA 

experts in several public peer consultation workshops held by EPA in July/August 2005. 

II-iv 
NCEA acknowledges the valuable contributions provided by authors, contributors, and 

reviewers and the diligence of its staff and contractors in the preparation of this document. The 

constructive comments provided by public commenters and CASAC that served as valuable 

inputs contributing to improved scientific and editorial quality of the document are also 

acknowledged by NCEA. 

DISCLAIMER 

Mention of trade names or commercial products in this document does not constitute 

endorsement or recommendation for use. 

. 

II-v 
Air Quality Criteria for Lead 

(Second External Review Draft) 

VOLUME I 

EXECUTIVE SUMMARY .........................................................................................................E-1 

1. INTRODUCTION ........................................................................................................... 1-1 

2. CHEMISTRY, SOURCES, AND TRANSPORT OF LEAD.......................................... 2-1 

3. ROUTES OF HUMAN EXPOSURE TO LEAD AND OBSERVED

ENVIRONMENTAL CONCENTRATIONS.................................................................. 3-1 

4. TOXICOKINETICS, BIOLOGICAL MARKERS, AND MODELS OF LEAD 

BURDEN IN HUMANS.................................................................................................. 4-1 

5. TOXICOLOGICAL EFFECTS OF LEAD IN LABORATORY ANIMALS

AND IN VITRO TEST SYSTEMS................................................................................. 5-1 

6. EPIDEMIOLOGIC STUDIES OF HUMAN HEALTH EFFECTS 

ASSOCIATED WITH LEAD EXPOSURE .................................................................... 6-1 

7. ENVIRONMENTAL EFFECTS OF LEAD ................................................................... 7-1 

8. INTEGRATIVE SYNTHESIS OF LEAD EXPOSURE/HEALTH 

EFFECTS INFORMATION............................................................................................ 8-1 

VOLUME II 

CHAPTER 4 ANNEX (TOXICOKINETICS, BIOLOGICAL MARKERS, AND 

MODELS OF LEAD BURDEN IN HUMANS) ............................................. AX4-1 

CHAPTER 5 ANNEX (TOXICOLOGICAL EFFECTS OF LEAD IN 

LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS) ................ AX5-1 

CHAPTER 6 ANNEX (EPIDEMIOLOGIC STUDIES OF HUMAN HEALTH 

EFFECTS ASSOCIATED WITH LEAD EXPOSURE) ................................. AX6-1 

CHAPTER 7 ANNEX (ENVIRONMENTAL EFFECTS OF LEAD).................................. AX7-1 

II-vi 
Table of Contents 

Page

PREFACE .................................................................................................................................. II-iii 

DISCLAIMER ............................................................................................................................ II-v 

List of Tables .............................................................................................................................. II-x 

Authors, Contributors, and Reviewers..................................................................................... II-xxi

U.S. Environmental Protection Agency Project Team for Development of Air 

Quality Criteria for Lead................................................................................................. II-xxvii 

U.S. Environmental Protection Agency Science Advisory Board (SAB) Staff 

Office Clean Air Scientific Advisory Committee (CASAC)........................................... II-xxix 

Abbreviations and Acronyms ................................................................................................ II-xxxi

AX5. CHAPTER 5 ANNEX (TOXICOLOGICAL EFFECTS OF LEAD IN 

LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS ................. AX5-1 

ANNEX TABLES AX5-2 ....................................................................................... AX5-1 

ANNEX TABLES AX5-3 ..................................................................................... AX5-15 

ANNEX TABLES AX5-4 ..................................................................................... AX5-37 

ANNEX TABLES AX5-5 ..................................................................................... AX5-60 

ANNEX TABLES AX5-6 ..................................................................................... AX5-75 

ANNEX TABLES AX5-7 ................................................................................... AX5-111 

ANNEX TABLES AX5-8 ................................................................................... AX5-121 

ANNEX TABLES AX5-9 ................................................................................... AX5-146 

ANNEX TABLES AX5-10 ................................................................................. AX5-156 

ANNEX TABLES AX5-11 ................................................................................. AX5-186 

REFERENCES .................................................................................................... AX5-190 

II-vii 
List of Tables 

Page

AX4-1 Analytical Methods for Determining Lead in Blood, Urine, and Hair ............ AX4-2 

AX4-2 Summary of Selected Measurements of PbB Levels in Humans .................... AX4-4 

AX4-3 Bone Lead Measurements in Cadavers............................................................ AX4-7 

AX4-4 Bone Lead Measurements in Environmentally-Exposed Subjects .................. AX4-9 

AX4-5 Bone Lead Measurements in Occupationally-Exposed Subjects................... AX4-12 

AX4-6 Bone Lead Contribution to PbB..................................................................... AX4-19 

AX4-7 Bone Lead Studies in Pregnant and Lactating Subjects................................. AX4-22 

AX4-8 Bone Lead Studies of Menopausal and Middle-aged to Elderly Subjects..... AX4-30 

AX4-9 Lead in Deciduous Teeth from Urban and Remote Environments................ AX4-36 

AX4-10 Lead in Deciduous Teeth from Polluted Environments................................. AX4-38 

AX4-11 Summary of Selected Measurements of Urine Lead Levels in Humans ....... AX4-39 

AX4-12 Summary of Selected Measurements of Hair Lead Levels in Humans ......... AX4-42 

AX5-2.1 Effect of Lead on Erythrocyte Morphology, Mobility, and Other 

Miscellaneous Parameters................................................................................ AX5-2 

AX5-2.2 Lead, Erythrocyte Heme Enzymes, and Other Parameters.............................. AX5-6 

AX5-2.3 Lead Binding and Transport in Human Erythrocytes ...................................... AX5-9 

AX5-2.4 Lead Effects on Hematological Parameters ................................................... AX5-10 

AX5-2.5 Lead Interactions with Calcium Potassium in Erythrocytes .......................... AX5-12 

AX5-2.6 Lead, Heme, and Cytochrome P–450 ............................................................ AX5-13 

AX5-2.7 Lead, Erythrocyte Lipid Peroxidation, and Antioxidant Defense.................. AX5-14 

AX5-3.1 Summary of Key Studies on Neurochemical Alterations .............................. AX5-16 

AX5-3.2 Summary of Key Studies on Neurophysiological Assessments .................... AX5-20 

II-x 
List of Tables 

(cont’d) 

Page

AX5-3.3 Summary of Key Studies on Changes in Sensory Function .......................... AX5-21 

AX5-3.4 Summary of Key Studies on Neurobehavioral Toxicity................................ AX5-22 

AX5-3.5 Summary of Key Studies on Cell Morphology and Metal Disposition ......... AX5-31 

AX5-3.6 Key Studies Evaluating Chelation of Pb in Brain.......................................... AX5-33 

AX5-4.1 Effect of Lead on Reproduction and Development in Mammals Effects 

on Offspring ................................................................................................... AX5-38 

AX5-4.2 Effect of Lead on Reproduction and Development in Mammals Effects 

on Males......................................................................................................... AX5-45 

AX5-4.3 Effect of Lead on Reproduction and Development in Mammals Effects 

on Females ..................................................................................................... AX5-55 

AX5-5.1 In Vivo and In Vitro Studies of the Effects of Lead Exposure on 

Production and Metabolism of Reactive Oxygen Species, 

Nitric Oxide, and Soluble Guanylate Cyclease.............................................. AX5-61 

AX5-5.2 Studies of the Effects of Lead Exposure on PKC Activity, NFkB 

Activation, and Apoptosis.............................................................................. AX5-66 

AX5-5.3 Studies of the Effects of Lead Exposure on Blood Pressure and 

Adrenergic System......................................................................................... AX5-67 

AX5-5.4 Studies of the Effects of Lead Exposure on Renin-angiotensin System, 

Kallikrein-Kinin System, Prostaglandins, Endothelin, and Atrial 

NatriureticPeptide (ANP)............................................................................... AX5-69 

AX5-5.5 Studies of Effect of Lead on Vascular Contractility ...................................... AX5-70 

AX5-5.6 Effects of Lead on Cultured Endothelial Cell Proliferation, Angiogenesis, 

and Production of Heparan Sulfate Proteoglycans and tPA .......................... AX5-71 

AX5-5.7 Studies of the Effect of Lead on Cultured Vascular Smooth Muscle Cells... AX5-74 

AX5-6.1 Genotoxic/Carcinogenic Effects of Lead—Laboratory Animal Studies ....... AX5-76 

AX5-6.2 Genotoxic/Carcinogenic Effects of Lead—Human Cell Cultures................. AX5-78 

II-xi 
List of Tables 

(cont’d) 

Page 

AX5-6.3 Genotoxic/Carcinogenic Effects of Lead—Carcinogenesis Animal 

Cell Cultures .................................................................................................. AX5-79 

AX5-6.4 Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Laboratory 

Animal Studies............................................................................................... AX5-81 

AX5-6.5 Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Human Cell 

Cultures Mutagenesis..................................................................................... AX5-85 

AX5-6.6 Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Human Cell 

Cultures Clastogenicity.................................................................................. AX5-86 

AX5-6.7 Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Human Cell 

Cultures DNA Damage .................................................................................. AX5-88 

AX5-6.8 Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Animal Cell 

Cultures Mutagenicity.................................................................................... AX5-90 

AX5-6.9 Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Animal Cell 

Cultures Clastogenicity.................................................................................. AX5-92 

AX5-6.10 Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Animal Cell 

Cultures DNA Damage .................................................................................. AX5-95 

AX5-6.11 Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Non-mammalian 

Cultures .......................................................................................................... AX5-97 

AX5-6.12 Genotoxic/Carcinogenic Effects of Lead—Genotoxicity as it Pertains 

to Potential Developmental Effects ............................................................... AX5-98 

AX5-6.13 Genotoxic/Carcinogenic Effects of Lead—Genotoxicity as it Pertains 

to Potential Developmental Effects—Children ............................................. AX5-99 

AX5-6.14 Genotoxic/Carcinogenic Effects of Lead—Epigenetic Effects and Mixture 

Interactions—Animal................................................................................... AX5-100 

AX5-6.15 Genotoxic/Carcinogenic Effects of Lead—Epigenetic Effects and Mixture 

Interactions—Human ................................................................................... AX5-101 

AX5-6.16 Genotoxic/Carcinogenic Effects of Lead—Epigenetic Effects and Mixture 

Interactions—DNA Repair—Human........................................................... AX5-102 

II-xii 
List of Tables 

(cont’d) 

Page

AX5-6.17 Genotoxic/Carcinogenic Effects of Lead—Epigenetic Effects and Mixture 

Interactions—DNA Repair—Animal .......................................................... AX5-103 

AX5-6.18 Genotoxic/Carcinogenic Effects of Lead—Mitogenesis—Animal ............. AX5-104 

AX5-6.19 Genotoxic/Carcinogenic Effects of Lead—Mitogenesis Human and 

Animal Cell Culture Studies ........................................................................ AX5-107 

AX5-6.20 Genotoxic/Carcinogenic Effects of Lead—Mitogenesis Other ................... AX5-110 

AX5-7.1 Light Microscopic, Ultrastructural, and Functional Changes...................... AX5-112 

AX5-7.2 Lead and Free Radicals................................................................................ AX5-114 

AX5-7.3 Chelation with DMSA ................................................................................. AX5-117 

AX5-7.4 Effect of Chelator Combinations ................................................................. AX5-118 

AX5-7.5 Effect of Other Metals on Lead ................................................................... AX5-119 

AX5-8.1 Bone Growth in Lead-exposed Animals...................................................... AX5-122 

AX5-8.2 Regulation of Bone Cell Function in Animals—Systemic Effects 

of Lead ......................................................................................................... AX5-126 

AX5-8.3 Bone Cell Cultures Utilized to Test Effects of Lead ................................... AX5-129 

AX5-8.4 Bone Lead as a Potential Source of Toxicity in Altered Metabolic 

Conditions .................................................................................................... AX5-136 

AX5-8.5 Uptake of Lead by Teeth.............................................................................. AX5-142 

AX5-8.6 Effects of Lead on Enamel and Dentin Formation ...................................... AX5-143 

AX5-8.7 Effects of Lead on Dental Pulp Cells........................................................... AX5-144 

AX5-8.8 Effects of Lead on Teeth—Dental Caries .................................................... AX5-145 

AX5-9.1 Studies on Lead Exposure and Immune Effects in Humans........................ AX5-147 

AX5-9.2 Effect of Lead on Antibody Forming Cells (In Vitro Stimulation) ............. AX5-150 

II-xiii 
List of Tables 

(cont’d) 

Page

AX5-9.3 Studies Reporting Lead-induced Suppression of Delayed Type 

Hypersensitivity and Related Responses ..................................................... AX5-151 

AX5-9.4 Effect of Lead on Allogeneic and Syngeneic Mixed Lymphocyte 

Responses..................................................................................................... AX5-152 

AX5-9.5 Effect of Lead on Mitogen-induced Lymphoid Proliferation ...................... AX5-153 

AX5.9.6 Pattern of Lead-induced Macrophage Immunotoxicity ............................... AX5-155 

AX5-10.1 Hepatic Drug Metabolism............................................................................ AX5-157 

AX5-10.2 Biochemical and Molecular Perturbations in Lead-induced 

Liver Tissue ................................................................................................. AX5-162 

AX5-10.3 Effect of Lead Exposure on Hepatic Cholesterol Metabolism .................... AX5-165 

AX5-10.4 Lead, Oxidative Stress, and Chelation Therapy........................................... AX5-166 

AX5-10.5 Lead-induced Liver Hyperplasia: Mediators and Molecular 

Mechanisms ................................................................................................. AX5-171 

AX5-10.6 Effect of Lead Exposure on Liver Heme Synthesis..................................... AX5-177 

AX5-10.7 Lead and In Vitro Cytotoxicity in Intestinal Cells....................................... AX5-180 

AX5-10.8 Lead and Intestinal Uptake—Effect on Ultrastructure, Motility, 

Transport, and Miscellaneous ...................................................................... AX5-181 

AX5-10.9 Lead, Calcium, and Vitamin D Interactions, and Intestinal Enzymes ......... AX5-184 

AX5-11.1 Lead-binding Proteins.................................................................................. AX5-187 

II-xiv 
Authors, Contributors, and Reviewers 

CHAPTER 4 ANNEX (TOXICOKINETICS, BIOLOGICAL MARKERS, AND 

MODELS OF LEAD BURDEN IN HUMANS) 

Chapter Managers/Editors 

Dr. James Brown—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Principal Authors 

Dr. Brian Gulson—Graduate School of the Environment, Macquarie University 

Sydney, NSW 2109, Australia 

Contributors and Reviewers 

Dr. Lester D. Grant—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

CHAPTER 5 ANNEX (TOXICOLOGICAL EFFECTS OF LEAD IN HUMANS 

AND LABORATORY ANIMALS) 

Chapter Managers/Editors 

Dr. Anuradha Mudipalli—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Srikanth Nadadur—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Lori White—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Principal Authors 

Dr. Anuradha Mudipalli—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Sections 5-2, 5-10) 

II-xxi 
Authors, Contributors, and Reviewers 

(cont’d) 

Principal Authors 

(cont’d) 

Dr. Stephen Lasley—Dept. of Biomedical and Therapeutic Sciences, Univ. of Illinois College of 

Medicine, PO Box 1649, Peoria, IL 61656 (Section 5.3) 

Dr. Lori White—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Section 5.3) 

Dr. Gary Diamond— Syracuse Research Corporation, 8191 Cedar Street, Akron, NY 14001 

(Section 5.4) 

Dr. N.D. Vaziri—Division of Nephrology and Hypertension, University of California – Irvine 

Medical Center, 101, The City Drive, Bldg 53, Room #125. Orange, CA 92868 (Section 5.5) 

Dr. John Pierce Wise, Sr.—Maine Center for Toxicology and Environmental Health, 

Department of Applied Medical Sciences, 96 Falmouth Street, PO Box 9300, Portland, ME 

04104-9300 (Section 5.6) 

Dr. Harvey C. Gonick—David Geffen School of Medicine, University of California at 

Los Angeles, 201 Tavistock Ave, Los Angeles, CA 90049 (Sections 5.7, 5.11) 

Dr. Gene E. Watson—University of Rochester Medical Center, Box 705, Rochester, NY 14642 

(Section 5.8) 

Dr. Rodney Dietert—Institute for Comparative and Environmental Toxicology, College of 

Veterinary Medicine, Cornell University, Ithaca, NY 14853 (Section 5.9) 

Contributors and Reviewers 

Dr. Lester D. Grant—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Paul Reinhart—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Michael Davis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. David A. Lawrence—Dept of Environmental and Clinical Immunology, Empire State Plaza 

P.O. Box 509, Albany, NY 12201 

II-xxii 
Authors, Contributors, and Reviewers 

(cont’d) 

Contributors and Reviewers 

(cont’d) 

Dr. Michael J. McCabe, Jr.—Dept of Environmental Medicine, University of Rochester, 

575 Elmwood Avenue, Rochester, NY 14642 

Dr. Theodore I. Lidsky—New York State Institute for Basic Research, 1050 Forest RD, 

Staten Island, NY 10314 

Dr. Mark H. Follansbee—Syracuse Research Corporation, 8191 Cedar St. Akron, NY 14001 

Dr. William K. Boyes—National Health and Environmental Effects Research Laboratory, 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Philip J. Bushnell—National Health and Environmental Effects Research Laboratory, 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Ms. Beth Hassett-Sipple—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Zachary Pekar—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

CHAPTER 6 ANNEX (EPIDEMIOLOGICAL STUDIES OF AMBIENT LEAD 

EXPOSURE EFFECTS) 

Chapter Managers/Editors 

Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

II-xxiii 
Authors, Contributors, and Reviewers 

(cont’d) 

Principal Authors 

Dr. David Bellinger—Children’s Hospital, Farley Basement, Box 127, 300 Longwood Avenue, 

Boston, MA 02115 (Section 6.10) 

Dr. Margit Bleecker—Center for Occupational and Environmental Neurology, 2 Hamill Road, 

Suite 225, Baltimore, MD 21210 (Section 6.3) 

Dr. Gary Diamond— Syracuse Research Corporation, 8191 Cedar Street. 

Akron, NY 14001 (Section 6.8, 6.9) 

Dr. Kim Dietrich—University of Cincinnati College of Medicine, 3223 Eden Avenue, 

Kettering Laboratory, Room G31, Cincinnati, OH 45267 (Section 6.2) 

Dr. Pam Factor-Litvak—Columbia University Mailman School of Public Health, 722 West 

168th Street, Room 1614, New York, NY 10032 (Section 6.6) 

Dr. Vic Hasselblad—Duke University Medical Center, Durham, NC 27713 (Section 6.10) 

Dr. Stephen J. Rothenberg—CINVESTAV-IPN, Mérida, Yucatán, México & National Institute 

of Public Health, Cuernavaca, Morelos, Mexico (Section 6.5) 

Dr. Neal Simonsen—Louisiana State University Health Sciences Center, School of Public Health 

& Stanley S Scott Cancer Center, 1600 Canal Street, Suite 800, New Orleans, LA 70112 

(Section 6.7) 

Dr. Kyle Steenland—Rollins School of Public Health, Emory University, 1518 Clifton Road, 

Room 268, Atlanta, GA 30322 (Section 6.7) 

Dr. Virginia Weaver—Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe 

Street, Room 7041, Baltimore, MD 21205 (Section 6.4) 

Contributors and Reviewers 

Dr. J. Michael Davis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Lester D. Grant—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Kazuhiko Ito—Nelson Institute of Environmental Medicine, New York University School of 

Medicine, Tuxedo, NY 10987 

II-xxiv 
Authors, Contributors, and Reviewers 

(cont’d) 

Contributors and Reviewers 

(cont’d) 

Dr. Kathryn Mahaffey—Office of Prevention, Pesticides and Toxic Substances, 

U.S. Environmental Protection Agency, Washington, DC 20460 

Dr. Karen Martin—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Zachary Pekar—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Ms. Beth Hassett-Sipple—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

CHAPTER 7 ANNEX (ENVIRONMENTAL EFFECTS OF LEAD) 

Chapter Manager/Editor 

Dr. Timothy Lewis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Principle Authors 

Dr. Ruth Hull—Cantox Environmental Inc., 1900 Minnesota Court, Suite 130, Mississauga, 

Ontario, L5N 3C9 Canada (Section 7.1) 

Dr. James Kaste—Department of Earth Sciences, Dartmouth College, 352 Main Street, Hanover, 

NH 03755 (Section 7.1) 

Dr. John Drexler—Department of Geological Sciences, University of Colorado, 1216 Gillespie 

Drive, Boulder, CO 80305 (Section 7.1) 

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

365 Link Hall, Syracuse, NY 13244 (Section 7.1) 

Dr. William Stubblefield—Parametrix, Inc. 33972 Texas St. SW, Albany, OR 97321 

(Section 7.2) 

II-xxv 
Authors, Contributors, and Reviewers 

(cont’d) 

Principle Authors 

(cont’d) 

Dr. Dwayne Moore—Cantox Environmental, Inc., 1550A Laperriere Avenue, Suite 103, 

Ottawa, Ontario, K1Z 7T2 Canada (Section 7.2) 

Dr. David Mayfield—Parametrix, Inc., 411 108th Ave NE, Suite 1800, Bellevue, WA 98004 

(Section 7.2) 

Dr. Barbara Southworth—Menzie-Cura & Associates, Inc., 8 Winchester Place, Suite 202, 

Winchester, MA 01890 (Section 7.3) 

Dr. Katherine Von Stackleberg—Menzie-Cura & Associates, Inc., 8 Winchester Place, Suite 

202, Winchester, MA 01890 (Section 7.3) 

Contributors and Reviewers 

Dr. Jerome Nriagu—Department of Environmental Health Sciences, 109 South Observatory, 

University of Michigan, Ann Arbor, MI 48109 

Dr. Judith Weis—Department of Biology, Rutgers University, Newark, NJ 07102 

Dr. Sharon Harper—National Exposure Research Laboratory (D205-05), U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Karen Bradham—National Research Exposure Laboratory (D205-05), U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Ginger Tennant—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Ms. Gail Lacey—Office of Air Quality Planning and Standards, U.S. Environmental Protection 

Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

II-xxvi 
U.S. Environmental Protection Agency Project Team 

for Development of Air Quality Criteria for Lead 

Executive Direction 

Dr. Lester D. Grant (Director)—National Center for Environmental Assessment-RTP Division, 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Scientific Staff 

Dr. Lori White (Lead Team Leader)—National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. James S. Brown—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Robert Elias—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Retired) 

Dr. Brooke Hemming—National Center for Environmental Assessment (B243-01), U.S. 

Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Timothy Lewis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Anuradha Muldipalli—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Srikanth Nadadur—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Paul Reinhart—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Mary Ross— National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

II-xxvii 
U.S. Environmental Protection Agency Project Team 

for Development of Air Quality Criteria for Lead 

(cont’d) 

Technical Support Staff 

Mr. Douglas B. Fennell—Technical Information Specialist, National Center for Environmental 

Assessment (B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 

27711 (Retired) 

Ms. Emily R. Lee—Management Analyst, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Ms. Diane H. Ray—Program Specialist, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Ms. Donna Wicker—Administrative Officer, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Retired) 

Mr. Richard Wilson—Clerk, National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Document Production Staff 

Ms. Carolyn T. Perry—Task Order Manager, Computer Sciences Corporation, 2803 Slater Road, 

Suite 220, Morrisville, NC 27560 

Mr. John A. Bennett—Technical Information Specialist, Library Associates of Maryland, 

11820 Parklawn Drive, Suite 400, Rockville, MD 20852 

Mr. William Ellis—Records Management Technician, InfoPro, Inc., 8200 Greensboro Drive, 

Suite 1450, McLean, VA 22102 

Ms. Sandra L. Hughey—Technical Information Specialist, Library Associates of Maryland, 

11820 Parklawn Drive, Suite 400, Rockville, MD 20852 

Dr. Barbara Liljequist—Technical Editor, Computer Sciences Corporation, 2803 Slater Road, 

Suite 220, Morrisville, NC 27560 

Ms. Michelle Partridge-Doerr—Publications/Graphics Specialist, TEK Systems, 1201 Edwards 

Mill Road, Suite 201, Raleigh, NC 27607 

Mr. Carlton Witherspoon—Graphic Artist, Computer Sciences Corporation, 2803 Slater Road, 

Suite 220, Morrisville, NC 27560 

II-xxviii 
U.S. Environmental Protection Agency 

Science Advisory Board (SAB) Staff Office 

Clean Air Scientific Advisory Committee (CASAC) 

Chair 

Dr. Rogene Henderson*—Scientist Emeritus, Lovelace Respiratory Research Institute, 

Albuquerque, NM 

Members 

Dr. Joshua Cohen—Faculty, Center for the Evaluation of Value and Risk, Institute for Clinical 

Research and Health Policy Studies, Tufts New England Medical Center, Boston, MA 

Dr. Deborah Cory-Slechta—Director, University of Medicine and Dentistry of New Jersey and 

Rutgers State University, Piscataway, NJ 

Dr. Ellis Cowling*—University Distinguished Professor-at-Large, North Carolina State 

University, Colleges of Natural Resources and Agriculture and Life Sciences, North Carolina 

State University, Raleigh, NC 

Dr. James D. Crapo [M.D.]*—Professor, Department of Medicine, National Jewish Medical and 

Research Center, Denver, CO 

Dr. Bruce Fowler—Assistant Director for Science, Division of Toxicology and Environmental 

Medicine, Office of the Director, Agency for Toxic Substances and Disease Registry, U.S. 

Centers for Disease Control and Prevention (ATSDR/CDC), Chamblee, GA 

Dr. Andrew Friedland—Professor and Chair, Environmental Studies Program, Dartmouth 

College, Hanover, NH 

Dr. Robert Goyer [M.D.]—Emeritus Professor of Pathology, Faculty of Medicine, University of 

Western Ontario (Canada), Chapel Hill, NC 

Mr. Sean Hays—President, Summit Toxicology, Allenspark, CO 

Dr. Bruce Lanphear [M.D.]—Sloan Professor of Children’s Environmental Health, and the 

Director of the Cincinnati Children’s Environmental Health Center at Cincinnati Children’s 

Hospital Medical Center and the University of Cincinnati, Cincinnati, OH 

Dr. Samuel Luoma—Senior Research Hydrologist, U.S. Geological Survey (USGS), 

Menlo Park, CA 

II-xxix 
U.S. Environmental Protection Agency 

Science Advisory Board (SAB) Staff Office 

Clean Air Scientific Advisory Committee (CASAC) 

(cont’d) 

Members 

(cont’d) 

Dr. Frederick J. Miller*—Consultant, Cary, NC 

Dr. Paul Mushak—Principal, PB Associates, and Visiting Professor, Albert Einstein College of 

Medicine (New York, NY), Durham, NC 

Dr. Michael Newman—Professor of Marine Science, School of Marine Sciences, Virginia 

Institute of Marine Science, College of William & Mary, Gloucester Point, VA 

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

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

Dr. Michael Rabinowitz—Geochemist, Marine Biological Laboratory, Woods Hole, MA 

Dr. Joel Schwartz—Professor, Environmental Health, Harvard University School of Public 

Health, Boston, MA 

Dr. Frank Speizer [M.D.]*—Edward Kass Professor of Medicine, Channing Laboratory, Harvard 

Medical School, Boston, MA 

Dr. Ian von Lindern—Senior Scientist, TerraGraphics Environmental Engineering, Inc., 

Moscow, ID 

Dr. Barbara Zielinska*—Research Professor, Division of Atmospheric Science, Desert Research 

Institute, Reno, NV 

SCIENCE ADVISORY BOARD STAFF 

Mr. Fred Butterfield—CASAC Designated Federal Officer, 1200 Pennsylvania Avenue, N.W., 

Washington, DC, 20460, Phone: 202-343-9994, Fax: 202-233-0643 (butterfield.fred@epa.gov) 

(Physical/Courier/FedEx Address: Fred A. Butterfield, III, EPA Science Advisory Board Staff 

Office (Mail Code 1400F), Woodies Building, 1025 F Street, N.W., Room 3604, Washington, 

DC 20004, Telephone: 202-343-9994) 

*Members of the statutory Clean Air Scientific Advisory Committee (CASAC) appointed by the 

U.S. EPA Administrator 

II-xxx 
Abbreviations and Acronyms 

αFGF α-fibroblast growth factor 

AA arachidonic acid 

AAL active avoidance learning 

AAS atomic absorption spectroscopy 

ABA β-aminoisobutyric acid 

ACBP Achenbach Child Behavior Profile 

ACE angiotensin converting enzyme 

ACh acetylcholine 

AChE acetylcholinesterase 

ACR acute-chronic ratio 

AD adult 

ADC analog digital converter 

ADP adenosine diphosphate 

AE anion exchange 

AEA N-arachidonylethanolamine 

AFC antibody forming cells 

2-AG 2-arachidonylglycerol 

A horizon uppermost layer of soil (litter and humus) 

AHR aryl hydrocarbon receptor 

AI angiotensin I 

ALA *-aminolevulinic acid 

ALAD *-aminolevulinic acid dehydratase 

ALAS aminolevulinic acid synthetase 

ALAU urinary δ-aminolevulinic acid 

ALD aldosterone 

ALS amyotrophic lateral sclerosis 

ALT alanine aminotransferase 

ALWT albumin weight 

AMEM Alpha Minimal Essential Medium 

AMP adenosine monophosphate 

ANCOVA analysis of covariance 

ANF atrial natriuretic factor 

Ang II angiotensin II 

ANOVA analysis of variance 

II-xxxi 
ANP atrial natriuretic peptide 

AP alkaline phosphatase 

AP-1 activated protein-1 

ApoE apolipoprotein E 

AQCD Air Quality Criteria Document 

Arg arginine 

AS52 cells derived from the CHO cell line 

ASGP-R aceyl glycoprotein receptor 

AST aspartate aminotransferase 

ASV anode stripping voltammetry 

3-AT 3-aminotriazole; 3-amino triazide 

ATP adenosine triphosphate 

ATP1A2 sodium-potassium adenosine triphosphase α2 

ATPase adenosine triphosphatase 

ATSDR Agency for Toxic Substances and Disease Research 

AVCD atrioventricular conduction deficit 

AVS acid volatile sulfide 

AWQC ambient water quality criteria 

$ beta-coefficient; slope of an equation 

$FGF $-fibroblast growth factor 

17$–HS 17$-hydroxysteriod 

3$-HSD 3$-hydroxysteriod dehydrogenase 

17$-HSDH 17$-hydroxysteriod dehydrogenase 

6$-OH-cortisol 6-$-hydroxycortisol 

B both 

BAEP brainstem auditory-evoked potentials 

BAER brainstem auditory-evoked responses 

BAF bioaccumulation factor 

B cell B lymphocyte 

BCFs bioconcentration factors 

BCS bovine calf serum 

BDNF brain derived neurotrophic factor 

BDWT body weight changes 

BEI biological exposure index 

BFU-E blood erythroid progenitor 

II-xxxii 
BLL blood lead level 

BLM biotic ligand model 

BM basement membrane 

BMI body mass index 

BDNF brain-derived neurotrophic factor 

BOTMP Bruinicks-Oseretsky Test of Motor Proficiency 

BP blood pressure 

BPb blood lead concentration 

BSA bovine serum albumin 

BSI Brief Symptom Inventory 

BTQ Boston Teacher Questionnaire 

BUN blood urea nitrogen 

bw, b. wt., BW body weight 

C3H10T/12 mouse embryo cell line 

C3, C4 complement proteins 

CA chromosome aberration 

CA3 cornu ammonis 3 region of hippocampus 

45Ca calcium-45 radionuclide 

Ca-ATP calcium-dependent adenosine triphosphate 

Ca-ATPase calcium-dependent adenosine triphosphatase 

CaCO3 calcium carbonate 

CaEDTA calcium disodium ethylenediaminetetraacetic acid 

CAL calcitonin 

CaM calmodulin 

Ca-Mg-ATPase calcium-magnesium-dependent adenosine triphosphatase 

cAMP cyclic adenosinemonophosphate 

CaNa2 EDTA calcium disodium ethylenediaminetetraacetic acid 

CANTAB Cambridge Neuropsychological Testing Automated Battery 

CAT catalase; Cognitive Abilities Test 

CBCL Achenbach Child Behavior Checklist 

CBCL-T Total Behavior Problem Score 

CBL cumulative blood lead 

CBLI cumulative blood lead index 

CCB cytochalasin B 

CCD charge-coupled device 

II-xxxiii 
CCE Coordination Center for Effects 

CCL carbon tetrachloride 

CCS cosmic calf serum 

C-CVRSA coefficient of component variance of respiratory sinus 

arrhythmia 

Cd cadmium 

109Cd cadmium-109 radionuclide 

CdU urinary cadmium 

CEC cation exchange capacity 

CESD, CES-D Center for Epidemiologic Studies Depression (scale) 

GFAP glial fibrillary acidic protein 

CFU-E colony forming unit blood-erythroid progenitor (cell count) 

CFU-GEMM colony forming unit blood-pluripotent progenitor (cell count) 

CFU-GM blood granulocyte/macrophage progenitor (cell count) 

cGMP cyclic guanosine-3',5'-monophosphate 

ChAT choline acetyltransferase 

CHD coronary heart disease 

CHO Chinese hamster ovary cell line 

CI confidence interval 

CLE-SV competitive ligand-exchange/stripping voltammetry 

CLRTAP Convention on Long-Range Transboundary of Air Pollution 

CLS Cincinnati Lead Study 

CMC criterion maximum concentration 

CMI cell-mediated immunity 

CNS central nervous system 

COH cation-osmotic hemolysis 

ConA concanavalin A 

COR cortisol 

CoTx cotreatment 

COX-2 cyclooxygenase-2 

CP coproporphryn 

CPT current perception threshold 

cr creatinine 

CRAC calcium release activated calcium reflux 

CREB cyclic AMP-response element binding protein 

CRF chronic renal failure 

II-xxxiv 
CV 

CRI chronic renal insufficiency 

CSF cerebrospinal fluid 

CuZn-SOD copper and zinc-dependent superoxide dismutase 

conduction velocity 

CVLT California Verbal Learning Test 

CVR-R coefficient of variation of the R-R interval 

CYP cytochrome (e.g., CYP1A, CYP-2A6, CYP3A4, CYP450) 

CYP3a11 cytochrome P450 3a11 

D D-statistic 

DA dopamine; dopaminergic 

dbcAMP dibutyryl cyclic adenosine-3',5'-monophosphate 

DCV distribution of conduction velocities 

DEAE diethylaminoethyl (chromatography) 

DET diffusive equilibrium thin films 

DEYO death of young 

DFS decayed or filled surfaces, permanent teeth 

dfs covariate-adjusted number of caries 

DG dentate gyrus 

DGT diffusive gradient thin films 

DL DL-statistic 

DMEM Dulbecco’s Minimal Essential Medium 

DMEM/F12 Dulbecco’s Minimal Essential Medium/Ham’s F12 

DMFS decayed, missing, or filled surfaces, permanent teeth 

DMPS 2,3-dimercaptopropane 1-sulfonate 

DMSA 2,3-dimercaptosuccinic acid 

DMT Donnan membrane technique 

DMTU dimethylthiourea 

DNA deoxyribonucleic acid 

DO distraction osteogenesis 

DOC dissolved organic carbon 

DOM dissolved organic carbon 

DOPAc 3,4-dihydroxyphenylacetic acid 

DPASV differential pulse anodic stripping voltammetry 

dp/dt rate of left ventricular isovolumetric pressure 

DPPD N-N-diphenyl-p-phynylene-diamine 

II-xxxv 
DR drinking water 

DSA delayed spatial alternation 

DTC diethyl dithiocarbomate complex 

DTH delayed type hypersensitivity 

DTPA diethylenetriaminepentaacetic acid 

DTT dithiothreitol 

dw dry weight 

E embryonic day 

E2 estradiol 

EBE early biological effect 

EBV Epstein-Barr virus 

EC European Community 

EC50 effect concentration for 50% of test population 

eCB endocannabinoid 

ECG electrocardiogram 

Eco-SSL ecological soil screening level 

EDS energy dispersive spectrometers 

EDTA ethylenediaminetetraacetic acid 

EEDQ N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinone 

EEG electroencephalogram 

EG egg 

EGF epidermal growth factor 

EGG effects on eggs 

EGPN egg production 

EKG electrocardiogram 

electro electrophysiological stimulation 

EM/CM experimental medium-to-control medium (ratio) 

EMEM Eagle’s Minimal Essential Medium 

eNOS endothelial nitric oxide synthase 

EP erythrocyte protoporphyrin 

EPA U.S. Environmental Protection Agency 

Epi epinephrine 

EPMA electron probe microanalysis 

EPO erythropoietin 

EPSC excitatory postsynaptic currents 

II-xxxvi 
EPT macroinvertebrates from the Ephemeroptera (mayflies), 

Plecoptera (stoneflies), and Trichoptera (caddisflies) group 

ERG electroretinogram; electroretinographic 

ERL effects range – low 

ERM effects range – median 

EROD ethoxyresorufin-O-deethylase 

ESCA electron spectroscopy for chemical analysis 

ESRD end-stage renal disease 

EST estradiol 

ESTH eggshell thinning 

ET endothelein; essential tremor 

ETOH ethyl alcohol 

EXAFS extended X-ray absorption fine structure 

EXANES extended X-ray absorption near edge spectroscopy 

F F-statistic 

F344 Fischer 344 (rat) 

FAV final acute value 

FBS fetal bovine serum 

FCS fetal calf serum 

FCV final chronic value 

FD food 

FEF forced expiratory flow 

FEP free erythrocyte protoporphyrin 

FERT fertility 

FEV1 forced expiratory volume in one second 

FGF fibroblast growth factor (e.g., βFGF, αFGF) 

FI fixed interval (operant conditioning) 

FIAM free ion activity model 

FMLP N-formyl-L-methionyl-L-leucyl-L-phenylalanine 

fMRI functional magnetic resonance imaging 

FR fixed-ratio operant conditioning 

FSH follicle stimulating hormone 

FT3 free triiodothyronine 

FT4 free thyroxine 

FTES free testosterone 

II-xxxvii 
FTII Fagan Test of Infant Intelligence 

FTPLM flow-through permeation liquid membranes 

FURA-2 1-[6-amino-2-(5-carboxy-2-oxazolyl)-5-benzofuranyloxy]-2-

(2-amino-5-methylphenoxy) ethane-N,N,N',N'-tetraacetic acid 

FVC forced vital capacity 

(-GT (-glutamyl transferase 

G gestational day 

GABA gamma aminobutyric acid 

GAG glycosaminoglycan 

G12 CHV79 cells derived from the V79 cell line 

GCI General Cognitive Index 

GD gestational day 

GDP guanosine diphosphate 

GEE generalized estimating equations 

GFAAS graphite furnace atomic absorption spectroscopy 

GFR glomerular filtration rate 

GGT (-glutamyl transferase 

GH growth hormone 

GI gastrointestinal 

GIME-VIP gel integrated microelectrodes combined with voltammetric 

in situ profiling 

GIS geographic information system 

GLU glutamate 

GMAV genus mean acute value 

GMCV genus mean chronic value 

GMP guanosine monophosphate 

GMPH general morphology 

GnRH gonadotropin releasing hormone 

GOT aspartate aminotransferase 

GP gross productivity 

G6PD, G6PDH glucose-6-phosphate dehydrogenase 

GPEI glutathione S-transferase P enhancer element 

gp91phox NAD(P)H oxidase 

GPT glutamic-pyruvic transaminase 

GPx glutathione peroxidase 

GRO growth 

II-xxxviii 
GRP78 glucose-regulated protein 78 

GSD geometric standard deviation 

GSH reduced glutathione 

GSIM gill surface interaction model 

GSSG glutathione disulfide 

GST glutathione-S-transferase 

GSTP placental glutathione transferase 

GTP guanosine triphosphate 

GV gavage 

H+

 acidity 

3

H hydrogen-3 radionuclide (tritium) 

HA humic acid; hydroxyapatite 

Hb hemoglobin 

HBEF Hubbard Brook Experimenatl Forest 

HBSS Hank’s Balanced Salt Solution 

HCG; hCG human chorionic gonadotropin 

Hct hematocrit 

HDL high-density lipoprotein (cholesterol) 

HEP habitat evaluation procedure 

HET Binghamton heterogeneous stock 

HFPLM hollow fiber permeation liquid membranes 

Hgb hemoglobin 

HGF hepatocyte growth factor 

HH hydroxylamine hydrochloride 

H-H high-high 

HHANES Hispanic Health and Nutrition Examination Survey 

H-L high-low 

HLA human leukocyte antigen 

H-MEM minimum essential medium/nutrient mixture–F12-Ham 

HMP hexose monophosphate shunt pathway 

HNO3 nitric acid 

H2O2 hydrogen peroxide 

HOME Home Observation for Measurement of Environment 

HOS TE human osteosarcoma cells 

HPLC high-pressure liquid chromatography 

II-xxxix 
H3PO4 phosphoric acid 

HPRT hypoxanthine phosphoribosyltransferase (gene) 

HR heart rate 

HSI habitat suitability indices 

H2SO4 sulfuric acid 

HSPG heparan sulfate proteoglycan 

Ht hematocrit 

HTC hepatoma cells 

hTERT catalytic subunit of human telomerase 

HTN hypertension 

IBL integrated blood lead index 

IBL H WRAT-R integrated blood lead index H Wide Range Achievement 

Test-Revised (interaction) 

ICD International Classification of Diseases 

ICP inductively coupled plasma 

ICP-AES inductively coupled plasma atomic emission spectroscopy 

ICP-MS, ICPMS inductively coupled plasma mass spectrometry 

ID-MS isotope dilution mass spectrometry 

IFN interferon (e.g., IFN-() 

Ig immunoglobulin (e.g., IgA, IgE, IgG, IgM) 

IGF-1 insulin-like growth factor 1 

IL interleukin (e.g., IL-1, IL-1$, IL-4, IL-6, IL-12) 

ILL incipient lethal level 

immuno immunohistochemical staining 

IMP inosine monophosphate 

iNOS inducible nitric oxide synthase 

i.p., IP intraperitoneal 

IPSC inhibitory postsynaptic currents 

IQ intelligence quotient 

IRT interresponse time 

ISEL in situ end labeling 

ISI interstimulus interval 

i.v., IV intravenous 

IVCD intraventricular conduction deficit 

JV juvenile 

II-xl 
KABC Kaufman Assessment Battery for Children 

KTEA Kaufman Test of Educational Achievement 

KXRF, K-XRF K-shell X-ray fluorescence 

LA lipoic acid 

LB laying bird 

LC lactation 

LC50 lethal concentration at which 50% of exposed animals die 

LC74 lethal concentration at which 74% of exposed animals die 

LD50 lethal dose at which 50% of exposed animals die 

LDH lactate dehydrogenase 

LDL low-density lipoprotein (cholesterol) 

L-dopa 3,4-dihydroxyphenylalanine (precursor of dopamine) 

LE Long Evans (rat) 

LET linear energy transfer (radiation) 

LH luteinizing hormone 

LHRH luteinizing hormone releasing hormone 

LN lead nitrate 

L-NAME L-NG-nitroarginine methyl ester 

LOAEL lowest-observed adverse effect level 

LOEC lowest-observed-effect concentration 

LOWESS locally weighted scatter plot smoother 

LPO lipoperoxide 

LPP lipid peroxidation potential 

LPS lipopolysaccharide 

LT leukotriene 

LT50 time to kill 50% 

LTER Long-Term Ecological Research (sites) 

LTP long term potentiation 

LVH left ventricular hypertrophy 

μPIXE microfocused particle induced X-ray emission 

μSXRF microfocused synchrotron-based X-ray fluorescence 

MA mature 

MA-10 mouse Leydig tumor cell line 

MANCOVA multivariate analysis of covariance 

MAO monoamine oxidase 

II-xli 
MATC maximum acceptable threshold concentration 

MDA malondialdehyde 

MDA-TBA malondialdehyde-thiobarbituric acid 

MDCK kidney epithelial cell line 

MDI Mental Development Index (score) 

MDRD Modification of Diet in Renal Disease (study) 

MEM Minimal Essential Medium 

MG microglobulin 

Mg-ATPase magnesium-dependent adenosine triphosphatase 

MiADMSA monoisamyl dimercaptosuccinic acid 

Mi-DMSA mi monoisoamyl dimercaptosuccinic acid 

MK-801 NMDA receptor antagonist 

MLR mixed lymphocyte response 

MMSE Mini-Mental State Examination 

MMTV murine mammary tumor virus 

MN micronuclei formation 

MND motor neuron disease 

MNNG N-methyl-N'-nitro-N-nitrosoguanidine 

MPH morphology 

MRI magnetic resonance imaging 

mRNA messenger ribonucleic acid 

MROD methoxyresorufin-O-demethylase 

MRS magnetic resonance spectroscopy 

MS mass spectrometry 

MSCA McCarthy Scales of Children’s Abiltities 

mSQGQs mean sediment quality guideline quotients 

MT metallothionein 

MVV maximum voluntary ventilation 

MW molecular weight (e.g., high-MW, low-MW) 

N, n number of observations 

N/A not available 

NAAQS National Ambient Air Quality Standards 

NAC N-acetyl cysteine 

NAD nicotinamide adenine dinucleotide 

NADH reduced nicotinamide adenine dinucleotide 

II-xlii 
NADP nicotinamide adenine dinucleotide phosphate 

NAD(P)H, NADPH reduced nicotinamide adenine dinucleotide phosphate 

NADS nicotinamide adenine dinucleotide synthase 

NAF nafenopin 

NAG N-acetyl-$-D-glucosaminidase 

Na-K-ATPase sodium-potassium-dependent adenosine triphosphatase 

NAWQA National Water-Quality Assessment 

NBT nitro blue tetrazolium 

NCBP National Contaminant Biomonitoring Program 

NCD nuclear chromatin decondensation (rate) 

NCS newborn calf serum 

NCTB Neurobehavioral Core Test Battery 

NCV nerve conduction velocity 

ND non-detectable; not detected 

NDI nuclear divison index 

NE norepinephrine 

NES Neurobehavioral Evaluation System 

NF-κB nuclear transcription factor-κB 

NGF nerve growth factor 

NHANES National Health and Nutrition Examination Survey 

NIOSH National Institute for Occupational Safety and Health 

NIST National Institute for Standards and Technology 

NK natural killer 

NMDA N-methyl-D-aspartate 

NMDAR N-methyl-D-aspartate receptor 

NMR nuclear magnetic resonance 

NO nitric oxide 

NO2 nitrogen dioxide 

NO3 nitrate 

NOAEC no-observed-adverse-effect concentration 

NOAEL no-observed-adverse-effect level 

NOEC no-observed-effect concentration 

NOEL no-observed-effect level 

NOM natural organic matter 

NORs nucleolar organizing regions 

II-xliii 
NOS nitric oxide synthase; not otherwise specified 

NOx nitrogen oxides 

NP net productivity 

NPSH nonprotein sulfhydryl 

NR not reported 

NRC National Research Council 

NRK normal rat kidney 

NS nonsignificant 

NSAID non-steroidal anti-inflammatory agent 

NT neurotrophin 

NTA nitrilotriacetic acid 

O2 oxygen 

ODVP offspring development 

OH hydroxyl 

7-OH-coumarin 7-hydroxy-coumarin 

1,25-(OH)2-D, 1,25-(OH)2 D3 1,25-dihydroxyvitamin D 

24,25-(OH)2-D3 24,25-dihydroxyvitamin D 

25-OH-D3 25-hydroxyvitamin D 

8-OHdG 8-hydroxy-2'-deoxyguanosine 

O horizon forest floor 

OR odds ratio; other oral 

OSWER Office of Solid Waste and Emergency Response 

P, p probability value 

P300 event-related potential 

P450 1A1 cytochrome P450 1A1 

P450 1A2 cytochrome P450 1A2 

P450 CYP3a11 cytochrome P450 3a11 

PAD peripheral arterial disease 

PAH polycyclic aromatic hydrocarbon 

PAI-1 plasminogen activator inhibitor-1 

PAR population attributable risk 

Pb lead 

203Pb lead-203 radionuclide 

204Pb, 206Pb, 207Pb, 208Pb stable isotopes of lead-204, -206, -207, -208, respectively 

210Pb lead-210 radionuclide 

II-xliv 
Pb(Ac)2 lead acetate 

PbB blood lead concentration 

PbCl2 lead chloride 

Pb(ClO4)2 lead chlorate 

PBG-S porphobilinogen synthase 

PBMC peripheral blood mononuclear cells 

Pb(NO3)2 lead nitrate 

PbO lead oxides (or litharge) 

PBP progressive bulbar paresis 

PbS galena 

PbU urinary lead 

PC12 pheochromocytoma cell 

PCR polymerase chain reaction 

PCV packed cell volume 

PDE phosphodiesterase 

PDGF platelet-derived growth factor 

PDI Psychomotor Development Index 

PEC probable effect concentration 

PEF expiratory peak flow 

PG prostaglandin (e.g., PGE2, PGF2); prostate gland 

PHA phytohemagglutinin A 

Pi inorganic phosphate 

PIXE particle induced X-ray emission 

PKC protein kinase C 

pl NEpi plasma norepinephrine 

PMA progressive muscular atrophy 

PMN polymorphonuclear leucocyte 

PMR proportionate mortality ratio 

PN postnatal (day) 

P5N pyrimidine 5'-nucleotidase 

PND postnatal day 

p.o., PO per os (oral administration) 

POMS Profile of Mood States 

ppb parts per billion 

ppm parts per million 

II-xlv 
PPVT-R Peabody Picture Vocabulary Test-Revised 

PRA plasma renin activity 

PRL prolactin 

PROG progeny counts or numbers 

PRR prevalence rate ratio 

PRWT progeny weight 

PST percent transferrin saturation 

PTH parathyroid hormone 

PTHrP parathyroid hormone-related protein 

PVC polyvinyl chloride 

PWM pokeweed mitogen 

PRWT progeny weight 

QA/QC quality assurance/quality control 

Q/V flux of air (Q) divided by volume of culture (V) 

r Pearson correlation coefficient 

R2

 multiple correlation coefficient 

2

r correlation coefficient 

226Ra most stable isotope of radium 

R/ALAD ratio of ALAD activity before and after reactivation 

RAVLT Rey Auditory Verbal Learning Test 

86Rb rubidium-86 radionuclide 

RBA relative bioavailablity 

RBC red blood cell; erythrocyte 

RBF renal blood flow 

RBP retinol binding protein 

RBPH reproductive behavior 

RCPM Ravens Colored Progressive Matrices 

REL rat epithelial (cells) 

REP reproduction 

RHIS reproductive organ histology 

222Rn most stable isotope of radon 

RNA ribonucleic acid 

ROS reactive oxygen species 

ROS 17.2.8 rat osteosarcoma cell line 

RPMI 1640 Roswell Park Memorial Institute basic cell culture medium 

II-xlvi 
RR 

RT 

RSEM 

RSUC 

RT 

∑SEM 

SA7 

SAB 

SAM 

SBIS-4 

s.c., SC 

SCAN 

SCE 

SCP 

SD 

SDH 

SDS 

SE 

SEM 

SES 

sGC 

SH 

SHBG 

SHE 

SIMS 

SIR 

SLP 

SM 

SMAV 

SMR 

SNAP 

SNP 

SO2

SOD 

relative risk; rate ratio 

reaction time 

resorbed embryos 

reproductive success (general) 

reproductive tissue 

sum of the molar concentrations of simultaneously extracted 

metal 

simian adenovirus 

Science Advisory Board 

S-adenosyl-L-methionine 

Stanford-Binet Intelligence Scale-4th edition 

subcutaneous 

Test for Auditory Processing Disorders 

selective chemical extraction; sister chromatid exchange 

stripping chronopotentiometry 

Spraque-Dawley (rat); standard deviation 

succinic acid dehydrogenase 

sodium dodecyl sulfate; Symbol Digit Substitution 

standard error; standard estimation 

standard error of the mean 

socioeconomic status 

soluble guanylate cyclase 

sulfhydryl 

sex hormone binding globulin 

Syrian hamster embryo cell line 

secondary ion mass spectrometry 

standardized incidence ratio 

synthetic leaching procedure 

sexually mature 

species mean acute value 

standardized mortality ratio 

Schneider Neonatal Assessment for Primates 

sodium nitroprusside 

 sulfur dioxide 

superoxide dismutase 

II-xlvii 
SOPR sperm-oocyte penetration rate 

SPCL sperm cell counts 

SPCV sperm cell viability 

SQGs sediment quality guidelines 

SRA Self Reported Antisocial Behavior scale 

SRD Self Report of Delinquent Behavior 

SRIF somatostatin 

SRM Standard Reference Material 

SRT simple reaction time 

SSADMF Social Security Administration Death Master File 

SSB single-strand breaks 

SSEP somatosensory-evoked potential 

StAR steroidogenic acute regulatory protein 

STORET STOrage and RETrieval 

SVC sensory conduction velocity 

SVRT simple visual reaction time 

T testosterone 

TA tail 

TABL time-averaged blood lead 

T&E threatened and endangered (species) 

TAT tyrosine aminotransferase 

TB tibia 

TBARS thiobarbituric acid-reactive species 

TBPS Total Behavior Problem Score 

TCDD methionine-choline-deficient diet 

T cell T lymphocyte 

TCLP toxic characteristic leaching procedure 

TE testes 

TEC threshold effect concentration 

TEDG testes degeneration 

TEL tetraethyl lead 

TES testosterone 

TEWT testes weight 

TF transferrin, translocation factor 

TG 6-thioguanine 

II-xlviii 
TGF transforming growth factor 

TH tyrosine hydroxylase 

232Th stable isotope of thorium-232 

TLC Treatment of Lead-exposed Children (study) 

TNF tumor necrosis factor (e.g., TNF-α) 

TOF time-of-flight 

tPA plasminogen activator 

TPRD total production 

TRH thyroid releasing hormone 

TRV toxicity reference value 

TSH thyroid stimulating hormone 

TSP triple-super phosphate 

TT3 total triiodothyronine 

TT4 serum total thyroxine 

TTES total testosterone 

TTR transthyretin 

TU toxic unit 

TWA time-weighted average 

TX tromboxane (e.g., TXB2) 

U uriniary 

235U, 238U uranium-234 and -238 radionuclides 

UCP urinary coproporphyrin 

UDP uridine diphosphate 

UNECE United Nations Economic Commission for Europe 

Ur urinary 

USFWS U.S. Fish and Wildlife Service 

USGS United States Geological Survey 

UV ultraviolet 

V79 Chinese hamster lung cell line 

VA Veterans Administration 

VC vital capacity; vitamin C 

VDR vitamin D receptor 

VE vitamin E 

VEP visual-evoked potential 

variable-interval 

II-xlix 

VI 
vit C vitamin C 

vit E vitamin E 

VMA vanilmandelic acid 

VMI Visual-Motor Integration 

VSM vascular smooth muscle (cells) 

VSMC vascular smooth muscle cells 

WAIS Wechsler Adult Intelligence Scale 

WDS wavelength dispersive spectrometers 

WHO World Health Organization 

WISC Wechsler Intelligence Scale for Children 

WISC-R Wechsler Intelligence Scale for Children-Revised 

WO whole organism 

WRAT-R Wide Range Achievement Test-Revised 

WT wild type 

WTHBF-6 human liver cell line 

ww wet weight 

XAFS X-ray absorption fine structure 

XANES X-ray absorption near edge spectroscopy 

XAS X-ray absorption spectroscopy 

XPS X-ray photoelectron spectroscopy 

X-rays synchrotron radiation 

XRD X-ray diffraction 

XRF X-ray fluorescence 

ZAF correction in reference to three components of matrix effects: 

atomic number (Z), absorption (A), and fluorescence (F) 

ZnNa2 DTPA zinc disodium diethylenetriaminepentaacetic acid 

ZnNa2 EDTA zinc disodium ethylenediaminetetraacetic acid 

ZPP zinc protoporphyrin 

II-l 
 AX5-1

AX5. CHAPTER 5 ANNEX 

 ANNEX TABLES AX5-2 
 AX5-2 Table AX5-2.1. Effect of Lead on Erythrocyte Morphology, Mobility, and Other Miscellaneous P

Dose and Route of Exposure Duration Species Blood lead Effect Pb nitrate 0–100 μM, Free Pb2+ 0–20 μM, In vitro (a) Pb recovery studies, 10 min (b) Relationship of free Pb2+ to added Pb, 20 min Erythrocyte cell lysates from humans — Uptake and transport of Pb in erythrocyte and across erythrocyt

membrane under the influence of varying buffers and ions. a. Pb can cross the membrane passively in either direction. Influx and efflux show similar properties b. Passive transport of Pb is strongly stimulated by HCO3

!

(bicarbonate) 

c. Pb uptake is unaffected by varying the external concentratio

Na+, K+, and Ca2+

d. In RBC, Pb binds mainly to hemoglobin. The ratio of bound 

to free Pb2+ in the cytosol is estimated 6000:1 

Pb nitrate 1.5 mM In vitro 

1 h Human erythrocytes — Pb uptake and transport are studied in resealed erythrocyte ghos

a. Transport of Pb across erythrocyte membranes is passive b. 90% of Pb uptake by erythrocytes is inhibited by drugs that 

anion transport, indicating the involvement of anion exchang

c. Pb transport depends upon the presence of a second anion. I

presence of HCO3

!, the rate is stimulated in the order of ClO

<NO3

! and CH3CO2

! <F! <Cl! <Br! <I!

10 μM Pb, as Pb acetate, In vitro 

20 min Erythrocyte ghosts and 

unsealed erythrocytes 

— In erythrocytes, the anion exchange mechanisms and internal thi

groups are critical factors that affect the stimulation of a Ca2+-dependent process by Pb2+. 

100 μg/dL Pb, 1 h Plasma Pb uptake was at the rate of 0.17 μ moles/h. 10 mg/dL, Pb, In vitro 

24 h 

Human erythrocytes — 

Uptake comparable in erythrocyte ghosts and in intact cells. No association of Pb with membranes at 24 h. 

0–1 h MDCK Kidney epithelial cell 

line, In vitro 

2 μM Pb acetate 2 μM Pb 

0–2 h Human erythrocytes, in vitro 

— Anion exchange (AE) plays a critical role in regulating intracellu

pH in erythrocytes and epithelial cells and facilitates Pb uptake. 

10 or 20 mM Pb acetate, i.p. once a week (100 or 200 μmoles)/ kg b.wt. 

5 wks Albino rats Control: 

1-12 μg/100 mLExposed: 100-800 μg/dL 

Exposure to Pb significantly decreased the erythrocyte mobility. The decreases in mobility were either simultaneous or prior to thdecreases in hemoglobin (Hb) or hematocrit (Ht). In exposed rasignificant negative correlation was found between mobility and blood Pb levels. Decreases in ALAD (*-aminolevulinic acid), walso apparent in exposed animals. 
 AX5-3 Table AX5-2.1 (cont’d). Effect of Lead on Erythrocyte Morphology, Mobility, and Other Miscellane

Dose and Route of Exposure Duration Species Blood lead Effect 20 mM Pb acetate, i.p. once a week (200 μmoles/kg b.wt) 5 wks Male Wistar Albino rats Control: 1–12 μg/100 mL Exposed: 100–800 :g/dL Exposure to Pb significantly decreased RBC membrane sialic ac

content, erythrocyte survival, hemoglobin, and hematocrit. This evident to a minor extent below blood Pb levels 100 μg/100 mL was generally present from 100 μg/100 mL and higher. 

200 μM of Pb acetate, i.p. Once a week for 5 wks Rat 0–600 μg/dL Pb exposure significantly decreases RBC count, Hb values, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin, decreases erythrocyte mobility, membrane sialic ac

content, and deformability. 

Pb, i.p. 20 mg/ kg b.wt. 14 consecutive days Male Albino rat Acetyl choline esterase (AchE), NADH dehydrogenase, and Na+

ATPase activities in rat erythrocyte membranes were inhibited bexposure. Erythrocyte membrane sialic acid, hexose, hexosaminwere inhibited by Pb exposure. Membrane phospholipids and cholesterol were increased. 

1 μM Pb nitrate 1 h Erythrocytes from Pb-exposed healthy humans Controls: 8.3 μg/dL Exposed: 70.5 μg/dL Pb exposure in healthy human RBC membranes resulted in incre

levels of arachidonic acid (AA). The increase in AA correlated dose dependent manner with elevation in Pb and with serum ironOn the other hand, a negative correlation was found between Aa serum calcium. It is inferred that substitution of Pb to calcium, which is essential for the release of phospholipase A2 for AA remay be the reason for increased RBC membrane AA. 

1 h Erythrocytes from healthy human volunteers — Pb inhibits Gordos effect in human erythrocytes; electron spin labeling studies indicated cell shrinkage and decreased volume. 

1 μM Pb nitrate, In vitro 6 and 12 mo Erythrocytes from Pb-exposed rats Cation-osmotic hemolysis (COH) in 12 mo Pb-exposed rats was lower in the areas of lower ionic strength on erythrocyte membr

0.1–200 :M, Pb nitrate in the reaction buffer 1–6 h In vitro, human erythrocytes — Pb crosses the erythrocyte membrane by the anion exchanger an

can also leave erythrocytes by a vanadate–sensitive pathway, identified with the calcium pump. The high ratio of erythrocyte plasma Pb seen in vivo appeared to be due to the presence of a lPb2+- binding component present in erythrocyte cytoplasm. 

0.1–10 μM Pb ions from 10 mM Pb(NO3)2 solution, In vitro 24 h Erythrocytes from healthy human volunteers — Pb activates erythrocyte K+ channels, Ca2+ sensitive erythrocyte Scramblase, triggers Phosphatidyl serine receptors and result in 

shrinkage and decreased life span. 
 AX5-4 Table AX5-2.1 (cont’d). Effect of Lead on Erythrocyte Morphology, Mobility, and Other Miscellane

Dose and Route of Exposure Duration Species Blood lead Effect 

— Pb attenuates prolytic effect on neonatal erythrocytes in iso-or hypotonic low ionic strength media. 20 μM Pb ion, 

In vitro 2 min–2 h Erythrocytes from human umbilical cord Hemolytic activity of Organo Pbs increases with their hydrophobicity: triethyl Pb chloride < tri-n-propyl Pb chloride < tributyl tin chloride. 

20 μM Pb ions, In vitro 1 h Human umbilical cord erythrocytes — Pb ions increase the resistance to lysis in media of diminishing tonicity. These changes might be mediated by changes in memb

structure. 

Erythrocytes from Pb-exposed workers 24–45 yr old white males Duration of exposure not given. RBCs were isolated. Experiments were performed in ghosts and resealed membranes Humans 1.17–1.54 μM Increased blood Pb in exposed workers was associated with a significant decrease in the average microviscosity of resealed an

unsealed erythrocyte membranes. Alterations in the microviscoof the lipid regions of the hydrophobic core of the erythrocyte membrane bilayer and in the phospholipid composition of the membrane may be defects that contribute to the clinical and biochemical alterations/effects. 

0.1 mM Pb final concentration, In vitro 1 h Erythrocytes from healthy humans — Pb particles adhere to the external and internal surfaces of the hu

erythrocyte membrane and disturb the lamellar organization of lbilayers. 

1–10 μM Pb acetate, In vitro 3 h Erythrocytes from healthy humans — Low concentrations of Pb alter the physicochemical properties o

proteins and lipids in erythrocyte membranes. 

0–1200 nM Pb, In vitro 1 h Erythrocytes from healthy humans — Significant increase in the phosphorylation of membrane cytosk

proteins in Pb treated human erythrocytes at concentrations abov100 nM mediated by enhanced PKC activity. 
 AX5-5 Table AX5-2.1 (cont’d). Effect of Lead on Erythrocyte Morphology, Mobility, and Other Miscellane

Dose and Route of Exposure Duration Species Blood lead Effect 

— — a. 24 adult healthy controls (humans) b. 12 patients with Pb poisoning (plumbism) symptoms (Pb controls) c. Patients with chronic renal failure (CRF) Divided into: 1. Normal urinary blood Pb levels 2. High urinary blood Pb levels Controls: 

!17.1 μg/dL Pb controls: 80.5 μg/dL CRF !1: 

18.4 μg/dL CRF !2: 

18.0 μg/dL Urinary Pb CRF 1: !322 μg/72 h CRF 2: 1785 μg/72 h 

Increased erythrocyte Zn protoporphyrin to free protoporphyriratio in Pb controls and remained in the normal range in CRF 

patients. CRF patients showed minor abnormalities of erythroheme metabolism, such as low ALAD activity. 

Occupational, Human exposure 

— a. 28 male workers in a Pb 

refining factory 

b. Controls 

Exposed: !35.97 μg/100 g Controls: 5.23 μg/100 g 

SDS polyacrylamide electrophoresis for erythrocyte membranproteins showed bands at 3 and 4.1, that significantly decreasewhile bands 2.3, 6, and 7 significantly increased in the Pb worcompared with controls. 

RBC—Red blood cells; Hb—Hemoglobin; NADH—Nicotinamide adenine dinucleotide dehydrogenase; PKC—Protein kinase C; AchE—Acetyl choline esterase 
 AX5-6 Table AX5-2.2. Lead, Erythrocyte Heme Enzymes, and Other Parameters Dose and Route of Exposure Duration Species Blood lead Effect 

Dietary, 0–100 μg/g dry wt. of the diet 35 days Adult male Zebra finches 0–1.5 μg/mL Significant negative correlation was observed between blood-P

concentration and log ALAD activity. RBC ALAD activity raa sensitive indicator of dietary Pb concentration regardless of tmode of exposure. 

Pb acetate, oral gavage, 1.5 mg/kg b.wt, Pb acetate 3 or 11 wks Red-tailed Hawks 0.195– 0.752 μg/dL Erythrocyte phorphobilinogen synthetase was depressed significantly with in the 1st wk of treatment. Rapid but brief increase in free protoporphyrin. Hematocrit, erythrocyte coun

were all decreased and blood viscosity increased in exposed gr

20 μg/mL as Pb acetate in drinking water 5 wks Female Wistar Albino rats 37.8 μg/dL Pb exposure decreases hematocrit, hemoglobin, and the numbe

erythrocytes and enhances blood viscosity. 

17 μM Me/kg Pb acetate, Per OS 5 days Female Rabbits — Pb causes a significant decrease in blood ALAD activity, incre

free erythrocyte protoporphyrins, increases aminolevulinic aciand coporphyrin excretion in urine. 

1.5 mg Pb/kg body wt, oral dose 8 yrs Cynomolgus Monkey, in vitro — Kinetic analyses of erythrocyte *- aminolevulinic acid reveale

differences in PH optimum and Michaelis constants with Pb exposure. The ALAD enzyme kinetics of Pb exposed monkey

and humans are similar. 

Dogs from urban and rural areas of Greece 326, 97–68 μg/L Significant negative correlation existed between blood-Pb leve

and ALAD activity. 807–992 μmol/PBG/LRBC/h is establishthe normal erythrocyte ALAD range for dogs. 

Occupational exposure 11–22 yrs Human erythrocytes from exposed populations 1.39–1.42 μmol/l Liquid chromatography with inductively coupled plasma spectrometry had revealed ALAD to be the principle Pb bindin

protein. The percentage of Pb bound to ALAD was influenced a common polymorphism in the ALAD gene. 

0–20 mg Pb liter !1 29 days Juvenile Rainbow trout erythrocytes 

— Significant decreases in the erythrocyte ALAD activity after a 

days exposure to 121 and 201 mg Pb liter !1. 
 AX5-7 Table AX5-2.2 (cont’d). Lead, Erythrocyte Heme Enzymes, and Other Parameters Dose and Route of Exposure Duration Species Blood lead Effect 

8 wks Wistar rats $20!$40 μg/dL Pb increases blood and liver Pb, erythrocyte porphyrin content, hypoactivity of both hepatocytic and erythrocytic ALAD. Pb acetate 160 mg/L 

in water — Fish from regions close to the smelters and down stream — Smelter site fish had elevated Pb concentrations, decreased ALA

activity and species differences in this inhibitory activity were apparent that could be attributed to Zn levels. 

1.46 μmol/liter, In vitro 48 h Human whole blood erythrocyte hemolysates, normal and Pb intoxicated individuals — The effects of various divalent cations on erythrocyte porphobilinogen are concentration and PH dependent. Zn restor

the Pb inhibited activity. 

Pb 0.34 μM/L– 1.17 μM/L, subcutaneous injection 1 h Male albino New Zealand rabbits — Pb causes the most inhibition and Zn activation of rabbit Erythro

porphobilinogen activity.Cu2+, Cd2+, and Hg2+ are intermediary. Each divalent ion has a characteristic effect on the PH- activity relationship of PBG-S. 

0–60 pM Pb ion, In vitro 20 min Human erythrocyte lysates — Human erythrocyte lysate porphobilinogen activity is increased 

Zn2+ with a Km of 1.6 pM and inhibited by Pb with a Ki of 0.07 

Pb reduced the affinity for the substrate 5- aminolevulinate, noncompetitively. 

200–500 ppm Pb in drinking water 14 or 30 days Male ddY mice 24–51 μg/100 mL Pb inhibits erythrocyte and bone marrow P5’N activity. Erythro

ALAD activity was inhibited by 90%. Elevation of Urinary excretion of ALA with no change in erythrocyte protoporphyrin urinary co porphyrin as against in the Pb exposed humans indicathat protoporphyrin metabolism might be more resistant to Pb in mice than humans. 

0.1–100 μM Pb ion, In vitro 5 min Human erythrocyte ghosts — Under normal incubation conditions Pb inhibits, Ca2+ -Mg2+ ATP

with an IC50 of 6.0μM. Pb inhibits Ca2+- Mg2+ ATPase related 

sulphahydryl groups above 1.0 μM Pb and by direct action of Pb upon Calmodulin below 1.0 μM. 

20–5 μg/kg body wt 1 mg/ kg body wt Pregnancy through lactation Erythrocytes from Sprague- Dawley rats — Na2+- K+- ATPase and Ca2+- Mg+- ATPase of erythrocyte memb

from Pb-depleted animals did not change in P0 generation as compared to 1 mg/kg b.wt Pb animals, where as in F1 generatiodepleted rats showed reduced activity. 
 AX5-8 Table AX5-2.2 (cont’d). Lead, Erythrocyte Heme Enzymes, and Other Parameters Dose and Route of Exposure Duration Species Blood lead Effect 

20 mg Pb acetate/kg b.wt, i.p, In vivo 14 days Male Albino rats erythrocytes — Pb significantly decreases erythrocyte membrane acetyl choline este

NADH dehydrogenase, membrane sialic acid, hexose, and hexosam

Pb ions inhibit aerobic glycolysis and diminish ATP level in human erythrocytes in vitro. Magnesium partly abolishes these effects by stimulating Magnesium dependent enzymes. Effect is seen both by direct addition of Pb acetate to erythrocyte ghosts as well as in the gobtained after preincubation of erythrocytes with Pb acetate. Ca2+, M

ATPase is less sensitive and Mg ATPase is practically insensitive to under these conditions. 

10–200 μg/dL Pb ions (Pb acetate), In vitro 20 h Human umbilical cord erythrocytes — Pb significantly decreased the concentration of ATP, ADP, AMP, adenosine, GTP, GDP, GMP, Guanosine, IMP, inosine, hypoxanthin

NAD and NADP concentrations. 

Pb acetate through water or i.p. 1 or 2 mg/Kg b.wt. Every 4th day for 1 mo Wistar rats 1.51– 35.31 μg/dL The concentrations of adenosine tri phosphate (ATP), Guanosine triphosphate (GTP), Nicotinamide adenine dinucleotide NAD+, nicotinamide adenine dinucleotide phosphate NADP+ adenylate and Guanylate (AEC and GEC) were significantly reduced in erythrocyt

exposed animals. Results indicate Pb ions disrupt erythrocyte energpathway. 

ALAD — Aminolevulinic acid; Cu2+—Copper; Cd2+—Cadmium; Hg2+—Mercury; PBG-S Porphobilinogen synthetase; Zn—Zinc; ATP—Adenosine triphosphate; AD

AMP—Adenosine monophosphate; GTP—Guanosine tri phosphate; GDP—Guanosine diphosphate; GMP—Guanosine monophosphate; IMP—Inosine monophosphat

adenine dinucleotide; NADP—Nicotinamide adenine dinucleotide phosphate.
 AX5-9 Table AX5-2.3. Lead Binding and Transport in Human Erythrocytes Dose and Route of Exposure Duration Species Blood lead Effect 

0–60 pM Pb ion, In vitro 20 min Human erythrocyte lysates — Human erythrocyte lysate porphobilinogen activity is increased by Z

with a Km of 1.6 pM and inhibited by Pb with a Ki of 0.07 pM, Pb reduced the affinity for the substrate 5- aminolevulinate, non- competitively. 

Zn—Zinc 
 AX5-10 Table AX5-2.4. Lead Effects on Hematological Parameters Dose and Route of Exposure Duration Species Blood lead Effect 

4-6 mg/Kg b.wt, i.p., daily 15 and 30 days Intact and splenctamized rats — Pb increases urinary *-amino levulinic acid (ALA) excretion

depletion in RBC hemoglobin content, and more number of reticulocytes in peripheral blood, and results in accumulation immature erythrocytes both in intact and splenctomized rats

0.82 mg Pb/kg b.wt./d, oral gavage 3 or 11 wks Red-tailed hawks erythrocytes 0.195–0.375 mg/mL Activity of porphobilinogen synthase/ALAD was depressed significantly in Pb exposed rats and did not return to normal values until 5 wks after the termination of the treatment. A r

and relatively brief increase in erythrocyte free proto porphyand a slower, prolonged increase in Zn complex. 

17 μM Me/Kg b.wt Pb acetate or 3.5 mg of Pb/kg body wt, i.p 5 days Female Rabbits 17.5 μg/dL Pb causes a significant inhibition of ALAD in the blood , increases free erythrocyte protoporphyrin, and urinary excre

of Aminolevulinic acid and coporphyrin. 

17 μM Me/Kg b.wt Pb acetate or 3.5 mg of Pb/ kg body wt, i.p. or per OS 17.5 mg/kg b.wt single injection 5 days i.p. Female Rabbits — Pb induced ALAS activity in liver and kidney, both after i.p 

p.o. administration; i.p. administration of Pb also induced kiheme oxygen levels. 

Cu deficient 1 mg Cu/Kg Marginal deficient 2 mg/kg Control 5 mg Cu/Kg High Zn 60 mg/kg. 4 wks Rat — Moderately high Zn in the diet reduces plasma copper but no

plasma ceruloplasmin. Does not affect the recovery of plasma Cu or activity after ocopper sulphate in Cu deficient diets. Does not influence RBC Super oxide dismutase activity. 

0.02–40 ppm Pb, dietary 90 days Male and female Swiss mice 0.7–13.0 μg/dL Increased RBC number and increased hemoglobin and decre

hematocrit up on Pb exposure. 

20 μg/mL, Pb acetate in drinking water 5 wks Female Wistar Albino rats 37.8 μg/dL Erythrocyte count, hematocrit and hemoglobin were all decr

and blood viscosity increased in Pb exposed workers. 
 AX5-11 Table AX5-2.4 (cont’d). Lead Effects on Hematological Parameters Dose and Route of Exposure Duration Species Blood lead Effect 

Erythrocytes from humans of occupational Pb exposure and controls In vivo and in vitro — Male Pb workers and 13 normal volunteers Range 20.6– 71.3 μg/dL Nicotinamide adenine dinucleotide synthetase activity in the Pb wor

ranged from 0.08 to 1.1 μmol/h per g of hemoglobin. 50% of enzyminhibition was observed at 40 μg/dL. Aminolevulinic acid dehydratactivity decreased rapidly and reached a plateau at Pb-B levels 40-6μg/dL. 50% of enzyme activity inhibition was observed at 20 μg/dL

In vivo; exposure In vitro assays on erythrocytes from exposed populations — 1. Workers exposed to manganese (Mn) and 2. Workers exposed to Pb without clinical manifestations of intoxication — Erythrocyte concentrations of adenyl nucleotides (ADP and ATP) w

elevated in both groups of workers and that of AMP in Pb-exposed workers. The ratio of ATP/ADP significantly increased in Pb-expoworkers. 

ALA—Aminolevulinic acid; ALAS—Aminolevulinic acid synthetase; ALAD—Aminolevulinic acid dehydratase, RBC—Red blood cells. 
 AX5-12 Table AX5-2.5. Lead Interactions with Calcium Potassium in Erythrocytes Dose and Route of exposure Duration Species Blood lead Effect 

0–325 μM, Pb nitrate, In vitro 0–60 min In vitro — Pb modifies the threshold sensitivity of individual K+channels to 

with a biphasic time course. The increase of Pb concentration inthe extent of the initial inhibition and decreased the duration. Thinhibitory effect was not observed when addition of Calcium prethe addition of Pb. Pb decreased the rate of uptake of 86Rb. 

0 μM–5 mM Pb, In vitro 0–100 min Human erythrocyte hemolysates — Pb and Ca transport was carried out by a passive transport system 

two kinetic components (Michaelis- Menten and Hill) Pb and Ca capable of inhibiting the transport of the other metals in a non- competitive way. 

1–4 μM Pb acetate, In vitro 0–30 min Rabbit reticulocytes — Pb at low concentrations inhibits the uptake of Fe (II) into all thre

(heme, cytosolic and stromal) fractions. The saturable componeninhibited at lower concentrations of Pb than the non- saturable components. 

1–50 μM Pb ion, In vitro 20 min Marine fish erythrocytes — Pb activates Ca2+ activated potassium channels. Treatment of erythrocytes with 1-2 μM Pb led to a minor intra cellular K loss a

Pb concentrations of 20-50 μM 70% of potassium was lost. 

Pb depleted rats Pb concentration <20 μg/kg Diet, oral Pb controls 200,800 μg/kg Pb2+ in the form of supra pure Pb acetate. Diet, oral Gestation through to 15 days of lactation Sprague-Dawley rats — The concentration of CA2+ ions in erythrocytes of Pb-depleted ra

elevated in F1 generation, without changes in P0 generation. The elevation observed in depleted rats could be because of a reductio

CA2+-Mg2+ ATPase. 

Intact or erythrocyte ghosts 0–100 μM Pb ion or Pb nitrate in the reaction mix, In vitro 10 min Healthy human erythrocytes — Modulation of CA2+-activatable K+ permeability was compared w

modulation of a membrane-bound oxidoreductase activity in humerythrocytes. Pb, anitrion, and menadione had parallel effects on channel protein and the enzyme. The results demonstrate that the 

channel and the enzyme are distinct membrane proteins and the eactivity may influence channel gating. 

Pb—Lead; K+—Potassium; Na2+- K+ ATPase—sodium potassium ATPase; Ca2+- Mg2+ ATPase—Calcium, Magnesium ATPase. 
 AX5-13 Table AX5-2.6. Lead, Heme, and Cytochrome P–450 Dose and Route of exposure Duration Species Blood lead Effect 

0–75 mg of Pb2+/Kg b. wt. i.p., Single injection 0–30 h C57 BL/6 male mice — Pb causes an increase in *-amino levulinic acid levels in plasma 

decrease in the heme saturation of hepatic tryptophan -2,3 dioxygP-450- dependent activities, EROD and O-dealkylation of alkoxyresorufins decreased progressively. Pb exposure decreasemRNA levels of the P450 CYp3a11. The decrease in P450 transwas a mechanism dependent on heme by inhibition of heme syntand also by a mechanism independent of heme in which Pb decre450 transcription. 

EROD—Ethoxy resorufin-O-dealkylase. CYp3a11—Cytochrome P-450 3a11. 
 AX5-14 Table AX5-2.7. Lead, Erythrocyte Lipid Peroxidation, and Antioxidant Defense Dose and Route of exposure Duration Species Blood lead Effect 

7.5 mg of Pb acetate or 4.09 mg of Pb Kg-1 b.wt, oral 28 days, multiple analyses at day 7, 14, 21, and 28 Erythrocytes from male Calves 0.1–1.6 ppm Pb exposure significantly reduced erythrocyte super oxide dismu

activity until day 21 followed by a marginal increase by day 28. protein-bound and non protein- bound –SH content of erythrocytdeclined. 

5.46 mg Pb as Pb acetate, oral 14 days, multiple analyses at day 0, 7, and 14 Erythrocytes from female goats 0.09–1.12 ppm Pb exposure caused a significant increase of erythrocytic GPx, S

CAT activities, total thiol groups and total antioxidant status. 

10 mg/kg b.wt Pb acetate, intra muscular, daily Pre treatment with melatonin 7 days Rat — Pb significantly decreased heme synthesis, decreased Hb, decrea

*- ALAS and erythrocyte ALAD. Markedly elevates hepatic lipiperoxidation, reduced anti oxidant enzymes such as total sulphahgroups and Glutathione. Pre Treatment with melatonin reduced tinhibitory effect of Pb on both enzymatic and non enzymatic antioxidants and reduced the iron deficiency caused by Pb. 

A. ALA 40 mg/kg b.wt every other day and/or B. Melatonin 10 mg/kg 

Every other day 3 times daily for 2 wks 

Male Sprague- Dawley rats — Melatonin effectively protects nuclear DNA and lipids in rat lung 

spleen against the oxidative damage caused by the carcinogen AL

Pb acetate 0.2%, in drinking water, followed by individual or combined treatment of lipoic acid (25 mg/Kg b.wt and DMSA 20 mg/kg b.wt, i.p.) 

5 wks Male Albino rats 97.5 μg/dL Pb exposure results in decreased blood hemoglobin, hematocrit, 

enhanced erythrocyte membrane lipid peroxidation, decline in thactivities of erythrocyte membrane Na+-K+ ATPase, Ca2+ ATPase

Mg2+ ATPase. Treatment with lipoic acid and/or DMSA reduced 

induced adverse changes in the biochemical parameters. 

*-Aminolevulinic acid, 1-5 mM, In vitro 

10 days CHO cells — *- Aminolevulinic acid treatment induces oxidative stress in Chin

hamster ovary cells by inducing Glutathione, Glutathione disulphMalandialdehyde equivalents, and Catalase. N-acetyl cysteine administration reverses the decrease in cell survival and colony formation induced by *- ALA. 

SOD—Super oxide dismutase; CAT—Catalase; ALAS—Aminolevulinic acid synthatase, ALAD—Aminolevulinic acid dehydratase; ALA—Aminolevulinic acid; GPx
 AX5-15

ANNEX TABLES AX5-3 
 AX5-16 Table AX5-3.1. Summary of Key Studies on Neurochemical Alterations Subject Exposure Protocol Peak Blood Pb or [Pb] used Observed Effects 

Rat PND 16–18 Hippocampal cultures 0.1 and 1.0 μM Pb Cl2 Pb blockage of IPSCs were partially reversible while EPSCs were noRat PND 50 1500 ppm Pb(Ac)2 chow 10 days before breeding and maintained to sacrifice 31.9 μg/dL Decreases the NR1 subunit splice variant mRNA in hippocampus. 

Rat PND 7, 14, 21, 28, and 50 1500 ppm Pb(Ac)2 chow 10 days before breeding and maintained to sacrifice — Alters NMDAR subtypes and reduces CREB phosphorylation. 

Rat PND 21 750 ppm Pb(Ac)2 chow from GD 0 to PND 21 46.5 μg/dL Increased expression of nicotinic receptors. 

Cultured PC12 cells 0.03–10 μM Pb(NO3)2 Pb acts as a high affinity substitute for calcium in catecholamine release. 

Adult rat Water—0.1–1.0% Pb(Ac)2 from GD 15 to adult 61.8 μg/100 mL Hippocampal GLU and GABA release exhibits biphasic effects from chronic Pb. 

Adult rat Water—0.1–1.0% Pb(Ac)2 from GD 15 to adult 117.6 μg/100 mL NMDA receptor function is upregulated. 

Cultured PC12 cells 0.53 μM Pb(Ac)2 PKC is involved in TH upregulation but not downregulation of ChAT

Embryonic rat Hippocampal neurons 100 fM–100 nM Decreases [Ca2+]i and increases Ca2+ efflux by a calmodulin-depende

mechanism. 

Rat 750 or 1500 ppm Pb(Ac)2 chow from 10 days pre-mating to PND 14, 21, and 28 61.1 μg/dL Dose-response effect between level of Pb and expression of NR1 gen

Cultured PC 12 cells 5–20 μM Pb(Ac)2 Induces expression of immediate early genes but requires PKC. 
 AX5-17 Table AX5-3.1 (cont’d). Summary of Key Studies on Neurochemical Alterations Subject Exposure Protocol Peak Blood Pb or [Pb] used Observed Effects 

Rat PND 50 750 or 1500 ppm Pb(Ac)2 chow from 10 days pre-mating to PND 50 31.9 μg/dL Reductions in NMDAR receptors result in deficits in LTP and spatia

learning. 

Calcineurin in mixture 10–2000 pM Pb(NO3)2 Has a stimulatory (low) and inhibitory (high) effect on calcineurin. 

Adult rat Cerebrocortical membranes 0.01–4 μM free Pb(Ac)2 Pb binds to the NMDA receptor channel in a site different from zinc

Adult rat PND 2 0.2% Pb(Ac)2 in water and chow 52.9 μg/100 mL GLU and GABA release are inhibited independent of Pb exposure period. 

Rat Cultured hippocampal neurons 0.01–10 μM Pb Cl2 Inhibits glutamatergic and GABAergic transmission via calcium channel. 

Rat PND 17 Cultured hippocampal neurons 0.1–10 μM Pb Cl2 Increases tetrodotoxin-insensitive spontaneous release of GLU and GABA. Rat PND 7, 14, 21, 28 750 ppm Pb(Ac)2 chow from 14 days pre-mating to experimental use 59.87 μg/dL NMDAR-2A subunit protein expression is reduced in the hippocampus. 

Rat PND 7, 14, 21, 28 750 ppm Pb(Ac)2 chow from 14 days pre-mating to experimental use 59.87 μg/dL Alters the levels of NMDA receptor subunits mRNA in hippocampu

Rat PND 22-adult Water—0.2% Pb(Ac)2 from GD 16 to PND 21 — Induces loss of septohippocampal cholinergic projection neurons in neonates lasting into young adulthood. 

Rat PND 28 56, 112 Water—1000 ppm Pb(Ac)2 from GD 4-use 39.6 μg/dL Significant increase in [3H]MK-801 binding after chronic exposure. 
 AX5-18 Table AX5-3.1 (cont’d). Summary of Key Studies on Neurochemical Alterations Subject Exposure Protocol Peak Blood Pb or [Pb] used Observed Effects 

Rat PND 21–adult 50 or 150 ppm Pb(Ac)2 water for 2 wks–8 mo 28.0 μg/dL Differential effects in [3H]MK-801 binding with dopamine and D1 agonists. Adult rat Water—0.2% Pb(Ac)2 from PND 0–adult 37.2 μg/100 mL Presynaptic glutamatergic function in dentate gyrus is diminished. 

Rat 4 mo Water—0.2% Pb(Ac)2 from GD 16 to PND 28 22.0 μg/dL Developmental Pb results in long-lasting hippocampal cholinergic deficit. Rat PND 111 Water at 50 ppm Pb(Ac)2 for 90 days; start at PND 21 18 μg/dL Decreases in vivo release of dopamine in the nucleus accumbens. 

Cultured bovine chromaffin cells Variable kind and concentration Exerts dual stimulatory and inhibitory effects on adrenal PKC. 

Rat Homogenized cortex Ranging Pb(Ac)2 Pb activates PKC in the range of 10−11 to 10−8 M. 

Cultured bovine chromaffin cells Variable kind and concentration Pb and calcium activate the exocytotic release of norepinephrine. 

Review paper discussing Pb-calcium interactions in Pb toxicity. 

Review paper exploring Pb as a calcium substitute. 

Rat PND 14 or 56 Neuronal membranes Chow containing 750 ppm Pb(Ac)2 Inhibitory effect on [3H]MK-801 binding and loss of binding sites in neonates. 

Rat Cortical synaptosomes 1–50 nM free Pb or 1 μM Pb(NO3)2 Triggers acetylcholine release more effectively than calcium. 
 AX5-19 Table AX5-3.1 (cont’d). Summary of Key Studies on Neurochemical Alterations Subject Exposure Protocol Peak Blood Pb or [Pb] used Observed Effects 

Rat Hippocampal neurons 2.5–50 μM Pb Cl2 Pb has a blocking effect on the NMDA subtype of glutamate receptors. Rat Brain protein kinase C 10−10 M Pb salts Stimulates brain protein kinase C and diacylglycerol-activated calcium. 

Abbreviations GD—gestational day 
 AX5-20 Table AX5-3.2. Summary of Key Studies on Neurophysiological Assessments Subject Exposure Protocol Peak Blood Pb or [Pb] used Observed Effects 

Rat PND 22 250 ppm Pb(Ac)2 3–6 wks (electro) or 7-13 wks (immuno) 30.8 μg/dL Reduces midbrain dopamine impulse flow and decreases dopamine D

receptor sensitivity in nucleus accumbens. 

Rat PND 42–64 100, 250, or 500 ppm Pb(Ac)2 in chow for 3-6 wks 54.0 μg/dL Decrease in number of spontaneously active midbrain dopamine neu

Review paper examining glutamatergic components contributing to impairments in synaptic plasticity. 

Rat PND 130–210 0.2% Pb(Ac)2 in water 75.4 μg/dL Deficits in synaptic plasticity in the dentate gyrus from early exposur

Adult rat Water—0.1-1.0% Pb(Ac)2 from GD 16 to adult 117.6 μg/dL Biphasic dose-dependent inhibition of hippocampal LTP. Adult rat 0.2% Pb(Ac)2 in water 30.1 μg/dL Chronic Pb exposure significantly decreases range of synaptic plastic

Adult rat 0.2% Pb(Ac)2 in water PND 0-21 30.1 μg/dL Impairments in LTP and paired-pulse facilitation in the hippocampal 

Rat PND 90–130 750 ppm Pb(Ac)2 chow from 50 days pre-mating to experimental use 16.04 μg/100 mL NMDA-dependent forms of synaptic plasticity are more vulnerable t

NMDA-independent potentiation or paired pulse-facilitation. 

Rat 7–18 mo Water—0.2% Pb(Ac)2 from GD 16 to experimental use — Impairs ability to maintain LTP over time in the dentate gyrus. 

Rat PND 13–140 750 ppm Pb(Ac)2 chow from 50 days pre-mating to experimental use 28.5 μg/dL Paired-pulse stimulation of CA3 region shows inhibitory mechanism

Adult rat Water—0.2% Pb(Ac)2 from PND 0–adult — Chronic Pb increases the threshold for LTP in dentate gyrus in vivo. 

Rat PND 4–30 Hippocampal neurons 1–100 μM Pb Cl2 Identified the nicotinic acetylcholine receptor as a target for Pb. 

Rat 750 ppm Pb(Ac)2 chow from 50 days pre-mating to experimental use 16.2 μg/100 mL LTP and learning are impaired if exposed to Pb in the immature brai

Abbreviations

GD—gestational day 
 AX5-21 Table AX5-3.3. Summary of Key Studies on Changes in Sensory Function Subject Exposure Protocol Peak Blood Pb or [Pb] used Observed Effects 

Mice PND 7–90 0.15 % Pb(Ac)2 in dams water from PND 0–21 26 μg/dL Produces a rod photoreceptor-selective apoptosis inhibited by Bcl-xl overexpression. 

Rat retinas 0.01–10 μM Pb Cl2 Pb and calcium produce rod photoreceptor cell apoptosis via mitochondria

Rat PND 21 or 90 0.02% and 0.2% Pb(Ac)2 in dams water PND 0–21 and 

3 wks as adult 

59.0 μg/dL Functional alterations and apoptotic cell death in the retina. 

Monkey 13 yrs 

2 mg/kg/d Pb(Ac)2 

in capsule for 13 y 

168.0 μg/dL Mild increase in detection of pure tones outside of threshold. 

Monkey 350 or 600 mg Pb(Ac)2 

for 9.75 yrs 

55 μg/dL Consistent prolongations of latencies on the brain stem auditory evoked 

potential. 

Bovine retinas 50 pM–100 nM 

Pb(Ac)2

Direct inhibition of purified rod cGMP PDE, magnesium can reverse effe

 Rat retinas 10−9 to 10−4 M Alters several physiological and biochemical properties of rod photorecep

Review paper examining effects upon auditory and visual function. 

Adult rat 0.02% and 0.2% Pb(Ac)2 

in dams water PND 0–21 

59.4 μg/dL Inhibits adult rat retinal, but not kidney, Na+, K+-ATPase. 

Monkey 6 yr Glycerine capsule with 25 or 

2000 μg/kg/d Pb(Ac)2

220 μg/dL Morphological damage in the visual cortical area V1 and V2. 

Rat PND 90 

0.2% Pb(Ac)2 

in dams water PND 0–21 

0.59 ppm Long-term selective deficits in rod photoreceptor function and biochemist
 AX5-22 Table AX5-3.4. Summary of Key Studies on Neurobehavioral Toxicity Subject Exposure Protocol Peak Blood Pb or [Pb] Used Observed Effects 

Rat, female, 22 wks 75 or 300 ppm Pb(Ac)2 39 μg/dL Significantly impaired on the alteration task with variable intertrial delaysRat Wistar 750 ppm Pb(Ac)2 15 μg/dL Pb-induced deficits in AAL in rats exposed to Pb either during pre-weanin

or pre- and postweaning: postweaning-only exposure caused reduced def

in AAL. 

Rat, LE, postweaning 50 ppm Pb(Ac)2 15.1 μg/dL Quinpirole at 0.05 mg/kg reversed the effects of Pb on FI performance; eticlopride had no effect on response rates in Pb-treated animals. 

Rat, LE, male Postweaning 50 or 150 ppm Pb for 3 mo 10.8 and 28.5 μg/dL FR: 150-ppm rats—significantly higher response rates and component re

than the low dose group and controls. Waiting behavior: wait time was lin both treated groups. 150-ppm rats—increased number of reinforcers an

higher response to reinforcement ratio than low dose and controls. 

Rat, LE, male Postweaning 50 or 150 ppm Pb for 3 mo 9.7 and 26.2 μg/dL after 3 and 7 mo 

D2 agonist quinpirole reversed the Pb-induced effects on FR-response rate

FR resets, wait reinforcers, and wait time. 

Rat, LE, male Postweaning 

50 or 150 ppm Pb for 3 mo 16.0 and 

28.0 μg/dL 

No Pb-induced effects on sustained attention. 

Rat, SD, adult 500 ppm Pb(Ac)2 20.9 μg/dL Chronic Pb exposure attenuated the reinforcing effect of brain stimulation

Rat, SD 0.2% Pb(Ac)2 during gestation 

and lactation, postweaning only, or continuously 

PND 56: 3.8, 25.3, and 29.9 μg/dL 

No Pb-associated effects in learning performance with just maternal or postweaning exposure. Continually exposed rats tended to avoid less frequently and in two-way active avoidance training, did not respond more frequently. 
 AX5-23 Table AX5-3.4 (cont’d). Summary of Key Studies on Neurobehavioral Toxicity Subject Exposure Protocol Peak Blood Pb or [Pb] Used Observed Effects 

Rat, SD 0.2% Pb(Ac)2 during gestation and lactation, postweaning only, or continuously PND 56: 3.8, 25.3, and 29.9 μg/dL All Pb-treated groups: impaired learning acquisition but unimpaired mem

retention; possible alterations in AMPA receptor binding. 

Rat, LE, male 50 or 250 ppm Pb(Ac)2 chronically from PND 21 25.1 and 73.5 μg/dL Pb-induced decrements in accuracy on the learning component, but not on 

performance component compared; Pb exposure impaired learning by increasing preseverative responding on a single lever, even though such repetitive responding was not directly reinforced. 

Rat, LE, male 50 or 250 ppm Pb(Ac)2 chronically from PND 21 25.1 and 73.5 μg/dL Pb exposure: attenuated the decline in learning accuracy and the increase

preseverative responding produced by MK-801; dose-effect curves relatinMK-801 dose to changes in rates of responding were shifted to the right. 

Rat, LE, male 50 or 250 ppm Pb(Ac)2 in water PND 21-use 73.5 μg/dL Pb-induced potentiation of the accuracy-impairing effects of NMDA by fu

increasing the frequencies of errors and likewise potentiated the drug’s rasuppressing effect; learning impairments are not caused by changes in dopaminergic function. 

Rat, LE, male 50 or 500 ppm from weaning 30.3 and 58– 94 μg/dL 50-ppm group: no effects. 500-ppm group: response rates initially decre

then reached control levels, primarily due to longer interresponse times. FI response rates are more sensitive to perturbation by Pb than FR. 

Rat, LE, male, PND 21 50 ppm PbS 8–11 mo ~20 μg/dL Decreased FI response rates (i.e., longer IRTs and lower running rates) compared to controls. 

6–8.5 mo 50 or 500 ppm 3–5 mo Demonstrated no consistent changes in FI performance, suggesting that o

behavior has been acquired, it may be resistant to the adverse effects of subsequent Pb exposure. Rat, LE, male, PND 21 50 or 250 ppm Pb(Ac)2 73.2 μg/dL Increased sensitivity to the stimulus properties of dopamine D1 and D2 ag

Rat, F344, PND 21 8 mo, 16 mo 2 or 10 mL/kg/d Pb(Ac)2 for 9.5 mo 13–18 μg/dL steady state Young and old rats: increased VI and FI response rates; adult rats: decre

response rates on both schedules. Effects on FI seen with 2-mg dose and with only the 10-mg dose. 
 AX5-24 Table AX5-3.4 (cont’d). Summary of Key Studies on Neurobehavioral Toxicity Subject Exposure Protocol Peak Blood Pb or [Pb] Used Observed Effects 

Rat, F344, male 2 or 10 mg/kg Pb(Ac)2 2 mg: 23; 10 mg: 42 (adult), ~48 (old), ~58 μg/dL (young) Aging caused impaired accuracy: In both young and old rats: Pb-induced increase in accuracy, at the longest delay periods (12 s) in young rats, and 

short delay periods in old rats. Adults: not affected by Pb exposure. 

Rat, LE, male 100 or 350 ppm Pb(Ac)2 in dam’s water PND 0–21 34 μg/dL Induced functional D2-D3 supersensitivity to the stimulus properties of ag

Rat, LE, male 50 or 150 ppm Pb(Ac)2 from weaning 

C Altered cholinergic sensitivity due to Pb and several agonists. 

Rat, LE, male 50 or 150 ppm Pb(Ac)2 35.7 μg/dL Postweaning Pb exposure resulted in an MK-801 subsensitivity. 

Rat, LE, male 50 or 150 ppm Pb(Ac)2 

in water PND 21-use 

30.6 μg/dL (1) Enhances the stimulus properties of NMDA via a possible 

 dopaminergic path. 

(2) Low level Pb exposure is associated with D1 subsensitivity. 

Rat, LE, male 50 or 150 ppm Pb(Ac)2

from weaning 

15–25 30–50 μg/dL 

Pb exposures attenuated the decrements in rates produced by the two D1

agonists SKF38393 and SKF82958, and at 150 ppm, Pb exposure altered rate change associated with the low dose (0.033 mg/kg) of quinpirole. 

Rat, LE, male 100 or 350 ppm Pb(Ac)2 

from weaning 

35.0 μg/dL Post-washout decrease in sensitivity to MK-801. 

Rat, LE, male 50 or 500 ppm Pb(Ac)2 

from weaning 

49.1 μg/dL Increases FI schedule-controlled behavior in nucleus accumbens. 

Rat, LE, male 50 or 500 ppm Pb(Ac)2 

from weaning 

49.1 μg/dL Both DA and EEDQ, microinjected into the dorsomedial striatum, caused 

increases or decreases in FI response rates, which depended on baseline Foverall rates. 
 AX5-25 Table AX5-3.4 (cont’d). Summary of Key Studies on Neurobehavioral Toxicity Subject Exposure Protocol Peak Blood Pb or [Pb] Used Observed Effects 

Hamster, Golden 100 ppm Pb(Ac)2 GD8–PND 42 PND 42: 10–15 μg/d PND 19–20: Pb-exposed hamsters smaller, exhibited less play fighting. PND 45: Pb-induced increase in aggression. Rat, Wistar, female 8, 16, or 24 mg/mL Pb(Ac)2 during pregnancy, pregnancy and lactation, or lactation. 5.7–36.6 μg/dL PND 7: dose-dependent decrease in ultrasonic vocalization. PND 14: increased vocalization, and higher activity levels. 

BK:W mice, male and female 0.13% Pb(Ac)2 chronically started before breeding Brain and femur: 18 wks: 27.6 and 998 34 wk: 445 and 5, 364 (M) 34 wk: 787 and 4, 026 (F) Young Pb-exposed female mice habituated more slowly. Young Pb-expo

males habituated more rapidly. Adults: Pb-induced enhancement of social and sexual investigation. 

BK:W mice, male and female 0.25% Pb(Ac)2 chronically started before breeding 3–4 wks: Pb-induced increase in exploratory behavior and social investig

in exploratory behavior. 15–16 wks: Pb-induced decrease in nonsocial acin females, increase in males. 17–18 wks: Pb-induced shorter latencies to aggression in males. 

Monkey, rhesus, 4 yrs 10 mg/kg/d pulses (2) and chronic 0.7 for first yr of life 5 wks: 55 μg/dL first yr: ~36 yr 4: <5 Pb-induced longer latency to enter the open area, increased durations of environmental exploration and activity, and resulted in a failure to habitua

Rat, SD 350 ppm Pb(Ac)2 from birth until weaning 46 μg/dL No Pb-related effects in play, burrowing, dominance, residential running w

residential figure-8 maze, complex maze, acoustic startle, emergence, preinhibition. 

Rat LE, PND 53 300 or 600 ppm Pb(Ac)2 during gestation and lactation or lactation only 16, 12, and 18 μg/dL Two-choice olfactory serial reversal task: Pb-treated groups took more tr

reach the point where repeated responding to the previously correct cue en
 AX5-26 Table AX5-3.4 (cont’d). Summary of Key Studies on Neurobehavioral Toxicity Subject Exposure Protocol Peak Blood Pb or [Pb] Used Observed Effects 

Monkey, cynomolgus, 9–10 yrs of age 50 or 100 μg/kg/d Pb(Ac)2 15.4 and 25.4 μg/dL; 10.9 and 13.1 μg/dL, steady state Pb-induced impairment in the presence, but not the absence, of irrelevant 

in the lower-dose group monkeys, impairment ended when the irrelevant stimuli became familiar. 

Rat, male, adult 500 ppm Pb(Ac)2 in chow for 105 days 28 μg/dL Chronic Pb exposure attenuates cocaine-induced behavioral activation. 

Rat, LE 1500 ppm Pb(Ac)2 gestation and lactation 3.9 μg/dL at PND 50 Pb + enriched environment: enhanced performance in water maze; increa

gene expression in the hipppocampus of NMDAR subunit 1 and BDNF. 

Rat, Wistar, male 100 mg/kg/body weight by injection Not reported Pb-induced deficits in memory component of the radial arm maze test and 

retention of passive avoidance learning. 

Rat, LE, female 75 or 300 ppm Pb(Ac)2 in water GD0 experimental use 51 μg/dL Impairment of reversal learning as an associative deficit. 

Rat, LE, male and female 500 ppm Pb choride during lactation 42 μg/dL PND 11: no Pb-induced sex differences, effects on pup activity, and differences in pup retrieval by dams. PND 26: Pb treatment influenced all social behavior tested (i.e., investiga

duration and frequency, crossover frequency, pinning) but did not change activity levels. PND 36: Pb-treated pups demonstrated increased crossover frequencies bchange in activity levels compared to controls. 

Rat, LE 250 ppm Pb(Ac)2 chronically from gestation Hippocampal Pb levels PND 21: 1.73; PND 56: 1.02; PND 91: 0.91 μg/g Pb-exposure had no effect on working memory at any age tested, but did 

reference memory (significant in females and nearly significant in males) PND 21 rats. 
 AX5-27 Table AX5-3.4 (cont’d). Summary of Key Studies on Neurobehavioral Toxicity Subject Exposure Protocol Peak Blood Pb or [Pb] Used Observed Effects 

Rat, LE, male 750 ppm Pb(Ac)2 maternally, permanently, or postweaning only At PND 100 1.8, 21.3, 22.8, and 26.3 μg/dL Maternal and permanent exposure: impaired water maze performance, wi

maternal exposure producing both the greatest escape latency and longest escape path length. No effects on performance in the postweaning exposugroups. 

Monkey, rhesus Pb(Ac)2 testing first 4 wks of life 35 μg/dL Pb-induced greater agitation, climbing, fear, and exploration of the periph

Monkey, rhesus 1 mg/kg/d Pb(Ac)2 PND 5–PND 365 First yr ~70 μg/dL 16-mo PE: ~35 μg/dL First yr: Pb-induced disruption of social play, and increases in both self- stimulation and fearful behavior were observed. 16 mo: continued disruption. 

Monkey, rhesus Pb(Ac)2 testing first 4 wks of life 35 μg/dL Few differences between control and Pb-exposed monkeys were seen; les

stability in SNAP performance. 

Monkey, rhesus, 5–6 yrs 10 mg/kg/d pulses (2) and chronic 0.7 for first yr of life 250–300 μg/dL peak 80 for rest of yr Pb-induced deficits occurred most commonly with short intertrial delays; lose-shift errors, possibly due to perseveration. 

Monkey, rhesus, 7–9 yrs 10 mg/kg/d pulses (2) and chronic 0.7 for first yr of life 1–4 wk: 63 μg/dL 5–6 wk: 174 4 yrs: 4 7 yrs: 2 Chronic L-dopa ameliorated the Pb-induced DSA deficits, which returned following cessation of L-dopa administration: implicates DA mechanism

these impairments. 

Monkey, rhesus 10 mg/kg/d pulses (2) and chronic 0.7 for first yr of life wk 5: 56 during; remainder of first 6 mo: 33– 43 μg/dL First 6 wks: Pb-induced lowered muscle tonus and greater agitation, no effects on sensorimotor measures. PND 14: no Pb-related effects on obje

permanence task. 2 mo: Pb-induced decreased visual attentiveness in visual exploration tas

Monkey, rhesus 350 or 600 ppm in utero 50 and 110 μg/dL At age 12 to 15 mo, the high-dose group exhibited deficits in simple discrimination learning: both groups showed impairments in the more complex learning set formation trials; activity at 12–15 mo showed no Pb-related effects. 
 AX5-28 Table AX5-3.4 (cont’d). Summary of Key Studies on Neurobehavioral Toxicity Subject Exposure Protocol Peak Blood Pb or [Pb] Used Observed Effects 

Rat, SD, male, PND 60 8 or 16 mg Pb(Ac)2 6.8 μg/dL Long-lasting changes in drug responsiveness to cocaine and related drugsRat, Wistar 500 ppm Pb(Ac)2 through pregnancy and lactation 41.24 μg/dL (dams), 21.24 μg/dL (PND 23), <0.1 μg/dL (PND 70) PND 23: Pb-induced increased ambulation in the open-field tests, decrea

exploratory behavior in the holeboard tests, and no differences from contrthe elevated maze tests. PND 70: Pb-induced increase in head dipping in the holeboard test, decrein social interaction time. No differences in the rotarod tests. 

Rat, LE 75 or 300 ppm Pb(Ac)2 continuously 36 μg/dL Impaired learning of a visual discrimination task. 

Rat LE, PND 53 300 or 600 ppm during gestation or gestation and lactation PND 8: 36–43; PND 24: 27–34; PND 53: 131– 158 No Pb-induced differences in learning rate, motivation, or response latenc

for correct or incorrect responses. Pb-induced: increases in errors of omission when a delay was imposed prior to cue presentation, trials that followed an incorrect response, and response initiation. 

Rat, Wistar tested at PND 100 and PND 142 750 ppm though PND 16 maternal exposure or chronically PND 110: maternally exposed: <3; chronic: 34 μg/dL Both Pb-treated groups learned the original discrimination comparably to controls, but showed a deficit in retention; Pb-treated female rats took lon

to reach criterion in the acquisition learning and longer to eat the pellets in retention phase. 

Rat, Wistar, female 750 ppm Pb(Ac)2 17.3 μg/dL at PND 16 32–39 μg/dL continuous exposure Pb-induced deficits in acquisition of learning, but not with concurrent hippocampal lesions. Four wks later, both lesioned and Pb-treated anima

showed impaired retention. 

Rat, Wistar, female 750 ppm Pb(Ac)2 17.3 μg/dL at PND 16 32–39 μg/dL continuous exposure Pb and lesions of amygdala showed impairments in the acquisition phase 

the maze and impaired passive avoidance; neither treatment affected locomotor activity. Continuously exposed rats showed greater deficits. 

Rat, Wistar, PND 80 400 mg/L Pb Cl2 in dam’s water PND 1–30 PND 8: 10–15 μg/dL; PND 21: ~45; PND 80: 2–4 48 h PE: no Pb-induced changes in recall; 5 days PE: decline in recall latency. 
 AX5-29 Table AX5-3.4 (cont’d). Summary of Key Studies on Neurobehavioral Toxicity Subject Exposure Protocol Peak Blood Pb or [Pb] Used Observed Effects 

Rat, SD, male, adult 500 ppm Pb(Ac)2 28.91 μg/dL Decreases sensitization to the locomotor-stimulating effects of cocaine. Rat, SD, PND 120 16 mg Pb(Ac)2 via gavage 30 days pre-pregnancy to PND 21 38.0 μg/dL Self-administering rats prenatally exposed to Pb demonstrate and increase

sensitivity to the relapse phase of cocaine abuse. 

Rat, SD, PND 70 16 mg Pb(Ac)2 via gavage 30 days pre-pregnancy to PND 21 53.24 μg/dL Increased sensitivity to cocaine in rats perinatally exposed to Pb. 

Rabbit, Dutch Belted, male Pb(Ac)2 20, 40, and 80 μg/dL Exposed males mated with nonexposed females. Offspring at PND 25 showed Pb-induced effects on exploratory behavior. 

Monkey, squirrel Mother's blood Pb from gestation week 5–birth 21–79 μg/dL Reduced sensitivity to changes in reinforcement contingencies during behavioral transitions and in steady state. 

Monkey, squirrel In utero exposure 21–70 μg/dL maternal Pb-induced increase in the number of responses that failed to adequately displace the bar in the FR schedule and possible subtle motor impairment

Monkey, cynomolgus 2 mg/kg/d of Pb(Ac)2 continuously 115 μg/dL at PND 100 33 μg/dL by PND 270 At PND 60: Pb-induced increased mean FR pause times, and, decreased 

pause times. At 3 yrs of age: Pb-induced increased FI run rate, pause timand index of curvature. At both ages, Pb-induced increased variability of performance. 

Monkey, cynomolgus 50 or 100 μg/kg/d Pb(Ac)2 chronically beginning at PND 1 PND 100: 15.4 and 25.4 PND 300: 10.9 and 13.1 μg/dL Delayed alternation at 7–8 yrs of age: Pb-induced impairment of initial acquisition of tasks; longer delays between alternations resulted in poorer performance and perseverative behavior, sometimes lasting for hours. 

Monkey, cynomolgus, 7–8 yr 1500 μg/kg/d Pb(Ac)2 36 μg/dL Pb exposure in infancy only impaired spatial discrimination reversal tasks

Monkey, cynomolgus, 7–8 yr 1500 μg/kg/d Pb(Ac)2 continuously from birth, during infancy only, or beginning after infancy 36 μg/dL All Pb-treated groups: same impairments of initial acquisition, indiscrimi

responding, greater impairment with longer delays, and preseverative responses. 
 AX5-30 Table AX5-3.4 (cont’d). Summary of Key Studies on Neurobehavioral Toxicity Subject Exposure Protocol Peak Blood Pb or [Pb] Used Observed Effects 

Monkey, cynomolgus, 5–6 yr 1500 μg/kg/d Pb(Ac)2 continuously from birth, during infancy only, or beginning after infancy 36 μg/dL Post-infancy exposure impairs nonspatial discrimination reversal while exposure during infancy exacerbates the effect. Monkey, cynomolgus, 3 or 7 yr 1500 μg/kg/d Pb(Ac)2 36 μg/dL Pb exposure during different developmental periods produce different effe

on F1 performance in juveniles versus adults. 

Monkey, cynomolgus, 8–9 yr 1500 μg/kg/d Pb(Ac)2 continuously from birth, during infancy only, or beginning after infancy 36 μg/dL Pb-treated monkeys in all three exposure groups learned more slowly, wit

less impairment in infancy-only exposures, and showed perseverative behavior. 

Monkey, cynomolgus, 0.5 or 3 yr 2000 μg/kg/d Pb(Ac)2 115 μg/dL Decreased interresponse times and a greater ratio of responses per reinforcement on the differential reinforcement of low rate schedule. 

Rat, adult 16 mg Pb(Ac)2 via gavage 30 days pre- pregnancy to PND 21 83.2 μg/dL Developmental Pb exposure results in enhanced acquisition of cocaine sel

administration. 

Rat 0.5, 2.0, or 4.0 mM Pb(Ac)2 in drinking water 11–50 μg/dL Pb-induced decreased retention in shuttle avoidance task. Pb-associated increase in locomotor activity. 

Rat, F344 ~42 μg/dL Pb-induced better performance using extra-maze spatial cues; Pb-treated r

spent less time on the periphery of the maze. 

Rat, LE, male 0.2% Pb(Ac)2 from PND 25 until testing at PND 100 ~30 in Pb Pb-exposure + isolation: spatial learning deficits. Pb-exposure + enrichm

performed better than the isolated Pb group. Pb-induced decreases in hippocampal levels of BDNF, NGF-β, NT-3, and basic FGF. 

Rat, Wistar 750 ppm Pb(Ac)2 gestation and lactation PND 30: 25 μg/dL PND 90: 0.113 μg/dL At PND 30 and 90: no Pb-associated changes in elevated maze behavior. PND 30: decreased freezing, increased ambulation, and increased groom

PND 90: Pb-induced decreased freezing and increased ambulation. Offspring of Pb-treated females mated with nonexposed males. F2 generation at PND 30 and 90: increased ambulation and decreased grooming. 

Rat, Wistar 0.03%, 0.09%, or 0.27% 

Pb(Ac)2

gestationally 

~30, ~33, and ~42 μg/dL at PND 0, tested at PND 49 

Male offspring: all three doses impaired memory retrieval. Female offsponly the low dose affected memory retrieval. Motor performance and vis

were not affected by Pb. 
 AX5-31 Table AX5-3.5. Summary of Key Studies on Cell Morphology and Metal Disposition Subject Exposure Protocol Peak Blood Pb or [Pb] Used Observed Effects 

Rat, PND 110 Water—0.2% Pb(Ac)2 from GD 16-PND 21 or use 

C Reduction in hippocampal neurogenesis with no spatial learning 

impairments. 

Rat C6 glioma cells and human astrocytoma cells 

5–10 μM Pb(Ac)2 Directly targets GRP78 and induces its compartmentalized 

redistribution. GRP78 plays a protective role in Pb neurotoxicity

Rat pup astroglial cell culture 10 μM Pb(Ac)2 Oxidative stress in astroglia results from Pb impairment of the Cu 

transporter Atpase (Atp7a). 

Rat, PND 60 1500 ppm Pb(Ac)2 for 30–35 days 20.0 μg/dL Significant deleterious effects on progenitor cell proliferation. 

Rat, embryos 

Cultured neurospheres 0.1–100 μM 

Pb(Ac)2

Differentially affects proliferation and differentiation of embryonneural stem cells originating from different brain regions. 

Young rat PND 0–20 = 600 μg/dL 

PND 20–40 = 20–60 μg/dL 

131.3 μg/dL Blood Pb during succimer chelation are not an immediate indicat

of brain. Brain Pb values are slower to respond even though blooPb is normal. 

 Cultured oligodendrite progenitor 

cells—PND 2 

1 μM Pb(Ac)2 Pb inhibition of proliferation and differentiation of oligodendrocy

cells requires PKC. 

Cultured oligodendrite progenitor cells—PND 2 

0.1–100 μM 

Pb(Ac)2

Interferes with maturation of oligodendrocyte progenitor cells. 

Cultured cerebellar granule neurons 5–50 μM Pb(NO3)2

or Pb(ClO4)2

Specific transport systems carry Pb into neurons. 

Rat Cultured C6 glioma cells 1 μM Pb(Ac)2 Induces GRP78 protein expression and GRP78 is a strong Pb 

chelator. 

Human, 1–4 yr 

 Half-life of blood Pb was dependent upon exposure duration, 

ranging 10–38 mo. 

Rat and human Cultured rat astroglial, 

human neuroblastoma 

1 μM Pb(Ac)2 Immature astroglia vs. neuronal cells are most likely to bind Pb in 

the brain. 

Review paper addressing Pb-binding proteins in the brain and kidney. 

Cultured GH3, C6, and HEK293 cells 

1–10 μM Pb(NO3)2 Cellular uptake of Pb is activated by depletion of intracellular 

calcium. 

Rat 2 g/l Pb(Ac)2 in weanlings for 3 mo 39 μg/dL Chronic low Pb levels induces blood brain barrier dysfunction. 
 AX5-32 Table AX5-3.5 (cont’d). Summary of Key Studies on Cell Morphology and Metal Disposi

Subject Exposure Protocol Peak Blood Pb or [Pb] Used Observed Effects Rat 50 or 250 μg/mL Pb(Ac)2 for 30, 60, or 90 days 48.9 μg/dL Low dose, long-term exposure significantly decreases cerebral spinal fluid concentrations of TTR. Frog tadpoles Elvax implantation for 6 wks 10!10 to 10!6 M Pb Cl2 Stunted neuronal growth from low Pb levels are reversible with chelator. 

Rat Cultured hippocampal neurons 100 nM Pb Cl2 Possible neurite development inhibition via hyperphosphorylation

Human Pb-binding proteins isolated from cortex 10–2000 nM Pb(Ac)2 Characterizes two cytosolic Pb-binding proteins-thymosin beta 4 and an unidentified protein. 

Rats PND 7–60 100–2000 ppm Pb(Ac)2 in water for adult rats 72.5 μg/dL Elimination half-life of Pb from all regions of the brain was abou

20 days. There was no evidence of selective regional accumulatiof Pb. 

Rat, adult Radiolabeled Pb perfused across whole brain 9.7 mL/100 g Review paper examining the passage of Pb across the blood-brain barrier. Suggests it is actively transported via Ca-ATP pump. 

Review paper indicating that Pb either structurally alters nuclear protein p32/6.3 or inhibits a protease for which it is a substrate. 

Review paper discussing Pb removal from bone; the half-life of P

in bone is about 20 yr while in blood it is 1 mo. 

Rat, adult Radiolabeled albumin 

C Discovered that albumin rarely enters brain from blood. 

Guinea pig, chicken, and rat 

Mouse neuroblastoma 2a cell line 

C Results indicate a positive correlation between p32/6.3 levels and 

neuronal maturation. 

Dog and rat Mouse neuroblastoma 

2a cell line 

50–100 μM Pb Examined the relationship between Pb and nuclear protein p32/6.

and its abundance in intranuclear inclusion bodies. 

Adult rat Pb binding protein of kidney 

and brain 

0.1–1.6 μM Attenuation of Pb inhibition of ALAD involves sequestration of P

and a donation of zinc to the enzyme. 

Rat Perfusion of 0.5 MBq of Pb-203 

isotope for 0.5–4 h 

615 μg/dL Injections of Pb-203 showed a linear uptake into three regions of 

the brain, suggesting that the blood-brain barrier is rate-limiting. 

Human 

C 160 μg/100 mL Blood Pb half-life is affected by duration of exposure, age, and 

length of follow-up. 

Human 

C >60 μg/dL Blood Pb half-life is dependent upon the length of exposure. 
 AX5-33 Table AX5-3.6. Key Studies Evaluating Chelation of Pb in Brain Subject Exposure Protocol Chelator Observed Effects 

Rat, male, LE, PND 21 Group 1: 50 ppm Pb acetate in drinking water from PND 21 for 3–4 mo, after which they were given i.p. injections of 75 or 150 mg/kg CaEDTA for either 1, 2, 3, 4, or 5 days. Group 2: 25 or 500 ppm Pb acetate followed by a single injection of either 75 or 150 mg/kg CaEDTA. Twenty- four hour urine samples were collected following CaEDTA injections. CaEDTA Group 1: Blood Pb declined after the first CaEDTA injection, but did not dro

further with subsequent CaEDTA and never dropped below control levels (5 μg/dL). Pb levels in urine increased similarly with both doses of CaEDTA

Pb was found to be mobilized from both bone and kidney and initially redistributed to brain and liver. Subsequent CaEDTA injections caused declines in brain and liver Pb levels, but no net loss of Pb. Group 2: a single injection of 150 mg/kg CaEDTA caused marked elevation of brain Pb, which called into question use of injections of CaEDTA in clinical diagnostic procedures. 

Rat, male, LE, PND 21 50 ppm Pb acetate from weaning until testing 3–4 mo later. The rats received either 25 or 50 mg/kg DMSA for 1, 2, 3, 4, or 5 days and tissues were evaluated 24 h following the last injection. DMSA Blood Pb was decreased by DMSA dose-dependently, with levels dropping t

<5 μg/dL after 3 injection of the higher dose and 4 injections of the lower dose. Pb levels dropped in brain and kidney immediately, and in liver following a delay. Bone Pb did not decline, which contrasts with earlier studies showing mobilization from bone following DMSA chelation. Anothegroup in this study received the same 5 days of DMSA injections, but was evaluated 4 mo later. Pb concentrations in all tissues were comparable to those seen in the first group, indicating that chelation therapy must be continued to lower tissue Pb levels. 

Rat, female, Wistar Given 206Pb-enriched drinking water at 210 ng Pb/mL for 36 h. Following an overnight fast, the rats were injected with one 0.25 mL i.p. injection of 0.11 mmol/kg DMSA. Pb levels in blood, kidney, brain, and tibia assessed 24 h later. DMSA Blood Pb declined 40%, Pb in urine increased 1500%, and changes in kidney and brain tissue Pb levels varied inconsistently. Chelation did not result in increased excretion of skeletal Pb compared to controls, nor did it show a redistribution of Pb to brain. 
 AX5-34 Table AX5-3.6 (cont’d). Key Studies Evaluating Chelation of Pb in Brain Subject Exposure Protocol Chelator Observed Effects 

Rat, female, Albino 100 ppm Pb acetate in drinking water for 4 wks. During the last 2 days of that exposure, the rats were administered two i.p. injections of 1 μg stable 204Pb tracer. Animals then received 1 to 5 consecutive days of 150 mg/kg CaEDTA ; assayed 24 h following the last injection. CaEDTA No redistribution of endogenous Pb into the brain following one CaEDTA dose, no measurable reduction in brain or bone Pb levels, an

reductions in both kidney and blood Pb levels. Additionally, over the first day of treatment, CaEDTA reduced the 204Pb tracer more effectively than the Pb from chronic exposure, indicating greater biologically availability of Pb from recent exposures. 

Rat, male, SD rats at 6–7 wks Chelation with ongoing Pb exposure; blood Pb were ~45 μg/dL; 550 ppm Pb acetate in drinking water for 35 days. Group 1: continued on Pb only for 21 days. Group 2: received continued Pb plus oral DMSA at 16, 32, 120, or 240 mg/kg/d for 21 days. Group 3: discontinued on Pb after the first 35 days and received oral DMSA (16, 32, or 240 mg/kg/d). DMSA DMSA treatment increased urinary Pb and decreased levels of Pb in blood, brain, bone, kidney, and liver, even with continued Pb exposure

Rat, male, Wistar Dosed with 1000 ppm Pb in drinking water for 4 mo, then treated for 5 days with: saline; 25 mg/kg DMSA orally, twice daily; 75 mg/kg CaEDTA i.p. once daily; or 25 mg/kg DMSA twice daily plus 75 mg/kg CaEDTA i.p. once daily. Blood Pb resulting from these treatments were 46, 22, 28, and 13 μg/dL, respectively and brain Pb levels were 49, 38, 26, and 22 μg/g, respectively. CaEDTA and DMSA The combined treatments produced an additive response in urinary Pb elimination and elimination from blood, liver, kidney, brain, and femu
 AX5-35 Table AX5-3.6 (cont’d). Key Studies Evaluating Chelation of Pb in Brain Subject Exposure Protocol Chelator Observed Effects 

Rat, female, LE Group 1: 325 μg/mL Pb acetate maternally through weaning, and then to 30 μg/mL until PND 30. Chelation treatment consisted of 7 days of 30 or 60 mg/kg/d DMSA. Group 2: 325 μg/dL maternally and through PND 40 and then treated to DMSA for 7 or 21 days. DMSA Seven days of DMSA effectively removed Pb from both blood and brain. Treatment beyond 7 days further reduced brain Pb, but not blood Pb. Reductions in Pb were greater in the second group, which the authors attribut

to the higher exposures used. The authors also hypothesize that DMSA- mediated reduction in blood Pb are a poor indicator of reductions in brain Pb

Rat, LE Exposed gestationally to 600 μg/mL Pb acetate, then split into high and low dose groups. Low dose group: 20 μg/mL from PND 21–28, followed by 30 μg/mL from PND 29–40. High dose group: 40 μg/mL from PND 21–28, followed by 60 μg/mL from PND 29–40. DMSA treatment consisted of 50 mg/kg/d for 1 wk, then 25 mg/kg/d for 2 wks. Rats received either 1 or 2 treatments at PND 40 or 40 and 70. DMSA One treatment lowered both blood Pb and brain Pb, but the brain reductions lagged the blood reductions both temporally and in magnitude. Following th

second DMSA treatment, they observed a rebound in blood, but not brain Pb levels. 
 AX5-36 Table AX5-3.6 (cont’d). Key Studies Evaluating Chelation of Pb in Brain Subject Exposure Protocol Chelator Observed Effects 

Monkey, Rhesus, 11-yr-old with history of testing for effects of housing and rearing and which were used in drug challenge studies, were used after at least 1.5 yrs had elapsed since the last testing ~50 mg/kg/d Pb acetate, and then doses were adjusted to produce a target blood Pb of 35–40 μg/dL. Following 5 wks of Pb exposure, the monkeys were administered 204Pb tracer starting 4 days before chelation. DMSA was administered for 5 days at 30 mg/kg/d, followed by 14 days at 20 mg/kg/d. DMSA Brain levels of Pb and tracer, measured in prefrontal cortex, hippocampus, an

striatum, were not different from controls, indicating that DMSA was not effective in reducing brain Pb levels. They also found a poor correlation between brain and blood Pb levels. 

Rat, male, LE, PND 55 At PND 55, rats were started on an FI schedule, where a Pb- induced increase in interresponse time was observed. Pb exposure was then terminated and daily injections of 75 or 150 mg/kg CaEDTA were given for 5 consecutive days. CaEDTA Chelation treatment failed to reverse the learning deficits in Pb-exposed animals and further increased the proportion of short interresponse times. Th

authors suggest that this effect may be due to the CaEDTA-mediated redistribution of Pb from bone to brain. 

Rat, male, F344, 7-wk- old male 150 or 2000 ppm Pb for 21 days, then distilled water for the next 21 days. Blood Pb peaked at 37 and 82 μg/dL, respectively. Chelation: 50 mg/kg by oral gavage, 3 times a week for up to 21 days; reduced blood Pb to 22 and 56 μg/dL, respectively. DMSA Pb-induced increase in rearing behavior was observed. DMSA reduced the Pb-induced effects on activity. Levels of brain glial fibrillary acidic protein (GFAP) were also assessed in these animals. A Pb-induced dose-dependent increase in GFAP was observed in hippocampus, cortex, and cerebellum, which was reversed by DMSA treatment. 
 AX5-37

ANNEX TABLES AX5-4 
 AX5-38 Table AX5-4.1. Effect of Lead on Reproduction and Development in Mammals Effects on Of

Citation Species/ Strain/Age Dose/Route/ Form/Duration Endpoint BAl-Hakkak et al. (1988) Mouse/BALB/c, weaning 0, 25, 50 mg Pb monoxide alloy/kg in chow for 35– 70 days Reduced number of spermatogenia and spermatocytes in the 50 mg group after 70 days; reduced number of implantations after mating (after 35 days exposure). PAppleton (1991) Rat/Long-Evans hooded, adult Pb acetate single dose by i.v. at 30 mg/kg Increase in serum calcium and phosphorous; SEM analysis revealed ‘Pb line’ in tooth that was composed of hypomineralized interglobular dentine. PBataineh et al. (1998) Rat/Sprague- Dawley, adult 1000 ppm Pb acetate in drinking water for 12 wks Fertility was reduced; total number of resorptions was increased in female rats impregnated by males. PBerry et al. (2002) Rat/Sprague- Dawley, 21 days old Pb nitrate (1000 ppm Pb) in drinking water for 6 wks Mean plasma growth hormone levels decreased by 44.6%; reduced mean growth hormone amplitude by 37.5%, mean nadir concentration by 60%, and growth hormone peak area by 35%; findings are consistent with decreased hypothalamic growth hormone-releasing factor secretion or reduced somatotrope responsiveness; exogenous growth hormone in Pb-treated and control rats, this response was blunted by the Pb treatment; plasma IGF1 concentration was not significantly affected by Pb treatment. P

Bogden et al. (1995) Rat/Sprague- Dawley, 12 wks old 250 mg/L of Pb acetate in drinking water from GD 1 until after 1 wk after weaning Dam and pup hemoglobin concentrations, hematocrit, and body weights and lengths were reduced. PCamoratto et al. (1993) Rat/Sprague- Dawley, adult 0.02% Pb nitrate in drinking water from gestation day 5 of dams until PND 4 of offspring Female pups exposed to Pb beginning in utero were smaller, no corresponding effect in males; pituitary responsiveness to a hypothalamic stimulus. PCorpas (2002a) Rat/Wistar, adult Pb acetate 0 or 300 mg/L in drinking water during gestation and lactation Alterations in hepatic system of neonates (PND 12) and pups (PND 21); reductions in hemoglobin, iron, alkaline and acid phosphatase levels, and hepatic glycogen, and elevated blood glucose. PCorpas (2002b) Rat/Albino (NOS), adult Pb acetate 0 or 300 mg/L in drinking water during gestation and lactation Effects energy metabolism; decrease in testis and seminal vesicle weights, and an increase in DNA and RNA levels on PN day 21; protein was significantly decreased, alkaline and acid phosphatase levels of the gonads were reduced; reduction of the thickness of the epithelium and seminiferous tubule diameter. P
 AX5-39 Table AX5-4.1 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects o

Citation Species/ Strain/Age Dose/Route/ Form/Duration Endpoint BCory-Slechta et al. (2004)† Rat/Long-Evans, adult Pb acetate in drinking water (150 ppm); 2 mo before breeding until the end of lactation 14 rats no maternal stress Pb exposure, 15 rats no maternal stress with Pb exposure, 18 rats maternal stress without Pb exposure, 23 rats maternal stress and Pb exposure Pb alone (in male) (p < 0.05) and Pb plus stress (in females) (p < 0.05) permanently elevated corticosterene levels in offspring. PDey et al. (2001) Mouse/Albino (NOS), ~100 g Pb citrate 5 μg/kg-d p.o. from early pregnancy (NOS) until birth Perforations, tissue damage, cell deformity, disordered organization of collagen bundles found in offspring; reduction in the symmetry of sulphate group of skin pups of mice exposed to Pb citrate (5 μg/kg-d) throughout gestation exhibited a variety of skin anomalies, including perforations, tissue damage, cell deformity, and disordered collagen bundles Pb was found to affect initial genomic expression in embryos fathered by male rats. P

Flora and Tandon (1987) Rat/Albino (NOS), adult Pb nitrate dissolved in water 2– 20 mg/kg-d i.v. on day 9, 10, 11 of gestation; 6 rats in each group (0, 5, 10, 20, 40 mg/kg Pb) Dose-dependant increase in external malformations at all doses (p < 0.001), particularly tail defects; dose dependant decrease in number of live births at 20 and 400 mg/kg (p < 0.001); dose-dependent increase in number of resorptions per dam at #10 mg/kg (p < 0.01). P

Fox et al. (1991a) Rat/Long-Evans hooded, adult Lactation exposure via dams exposed to 0.02 or 0.2% Pb in drinking water from PND 1 through weaning (PND 21) 8 female pups per litter (number of litter unspecified) control pups, 8 pups for litter (number of litter unspecified) low level exposure pups, 8 pups per litter (number of litter unspecified) moderate level exposure pups Long-term, dose-dependent decreases retinal Na/K ATPase activity in the female offspring (only female pups were used) (!11%; !26%) (p < 0.05). P

w
 AX5-40 Table AX5-4.1 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects o

Citation Species/ Strain/Age Dose/Route/ Form/Duration Endpoint BFox et al. (1997)† Rat/Long-Evans hooded, adult 0.02 or 0.2% Pb acetate in drinking water from PND 0– PND 21; 8 female pups per litter control pups; 8 pups per litter low level exposure; 8 pups per litter moderate level exposure (number of litters per dose unspecified) Developmental and adult Pb exposure for 6 wks produced age and dose-dependent retinal degeneration such that rods and bipolar cells were selectively lost; at the ultrastructural level, all dying cells exhibit the classical morphological features of apoptotic cell death; decrease in the number of rods was correlated with the loss of rhodopsin content per eye confirming that rods were directly affected by Pb (p < 0.05); single-flash rod ERGs and cone ERGs obtained from Pb-exposed rats demonstrated that there were age- and dose-dependent decreases in the rod a-wave and b-wave sensitivity and maximum amplitudes without any effect on cones; in adult rats exposed to Pb for 3 wks, qualitatively similar ERG changes occurred in the absence of cell loss or decrease in rhodopsin content (p < 0.05); developmental and adult Pb exposure for three and 6 wks produced age- and dose-dependent decreases in retinal cGMP phosphodiesterase (PDE) activity resulting in increased CGMP levels (p < 0.05); retinas of developing and adult rats exposed to Pb exhibit qualitatively similar rod mediated ERG alterations as well as rod and bipolar apoptotic cell death (p < 0.05); similar biochemical mechanism such as the inhibition of rod and bipolar cell cGMP PDE, varying only in degree and duration, underlies both the Pb-induced ERG rod-mediated deficits and the rod and bipolar apoptotic cell death (p < 0.05). P

e(7 

Gandley et al. (1999) Rat/Sprague- Dawley, adult Male rats exposed to 25 or 250 ppm acetate Pb in drinking water for at least 35 days prior to breeding Fertility was reduced in males with PbB in range 27–60 μg/dL, Pb was found to affect initial genomic expression in embryos fathered by male rats with blood Pb levels as low as 15–23 μg/dL; dose-dependant increases were seen in an unidentified set of proteins with a relative molecular weight of ~70 kDa. P

Govoni et al. (1984) Rat/Sprague- Dawley, adult 2.5 mg/mL Pb acetate in drinking water from GD 16 to postnatal week 8 Decreased sulpiride binding in the pituitary is consistent with the elevated serum PRL concentrations previously described in Pb-exposed rats; DOPAc concentrations were reduced by 21% in Pb-treated rats. P

Hamilton et al. (1994) Rat/Sprague- Dawley, 25 days old Pb acetate in drinking water at 250, 500 or 1000 ppm; 8 wks prior to mating through GD 21 Altered growth rates; reduced early postnatal growth; decreased fetal body weight. P

Han et al. (2000) Rat/Sprague- Dawley, 5 wks old 250 mg/mL Pb acetate in drinking water for 5 wks followed by 4 wks no exposure (mated at end of 4-wk no exposure period) Pups born to Pb-exposed dams had significantly (p < 0.0001) lower mean birth weights and birth lengths. P

Hanna et al. (1997) Mouse/Swiss ICR preimplantation embryos In vitro incubation of two- and four-cell embryos with 0.05– 200 μM Pb acetate for 72 hr (time required for blastocyst formation) Exposure of embryos to Pb was only toxic at 200 μM, which reduced cell proliferation and blastocyst formation. P
 AX5-41 Table AX5-4.1 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects o

Citation Species/ Strain/Age Dose/Route/ Form/Duration Endpoint BIavicoli et al. (2003) Mouse/Swiss, adult Pb acetate in food (0.02, 0.06, 0.11, 0.2, 2, 4, 20, 40 ppm) exposure began 1 day after mating until litter was 90 days old one litter of mice exposed to each dietary concentration Low-level exposure (PbB 2–13 μg/dL) reduced red cell synthesis (p < 0.05); high-level exposure (PbB 0.6–2 μg/dL) enhanced red cell synthesis (p < 0.05). P

>

Iavicoli et al. (2004) Mouse/Swiss, adult Pb acetate in feed; exposure began 1 day after mating until litter was 90 days old In females: accelerated time to puberty at PbB <3 μg/dL; delayed time to puberty at 3–13 μg/dL. P

>

Lögdberg et al. (1987) Monkey/ Squirrel, adult Pb acetate p.o. exposure of gravid squirrel monkeys from week 9 of gestation through PND 0 Increase in pre- and perinatal mortality among squirrel monkeys receiving Pb acetate p.o. during the last two-thirds of pregnancy (45% vs. 7–8% among controls); mean maternal PbB was 54 μg/dL (39–82 μg/dL); statistically significant reductions in mean birth weight were observed in Pb-exposed monkeys as compared to controls; effects occurred without clinical manifestation of toxic effects in the mothers. PLögdberg et al. (1998) Monkey/ Squirrel, adult Pb acetate (varying concentrations #0.1% in diet); maternal dosing from 5– 8.5 wks pregnant to PND 1; 11 control monkeys, 3 low-Pb exposure group (PbB 24 μg/dL), 7 medium Pb group (PbB 40 μg/dL, 5 high-Pb group (PbB 56 μg/dL) Dose-dependent reduction in placental weight (p < 0.0007); various pathological lesions were seen in the placentas (n = 4), including hemorrhages, hyalinization of the parenchyma with destruction of the villi and massive vacuolization of chorion epithelium; effects occurred without clinical manifestation of toxic effects in the mothers. M

(245

McGivern et al. (1991)† Rat/Sprague- Dawley, adult 0.1% Pb acetate in drinking water from GD 14 to parturition Male offspring of dams exhibited reduced sperm counts, altered male reproductive behavior, and enlarged prostates later in life; females exhibited delayed puberty, menstrual irregularities, and an absence of observable corpora lutea; males and females exhibited irregular release patterns of both FSH and LH later in life. P

Nayak et al. (1989a) Mouse/Swiss Webster, adult Pb nitrate dissolved in NaCl solution, administered intravenously, via caudal vein at dose levels of 100, 150, 200 mg/kg; one time exposure on GD 9 Chemical analysis showed Pb was readily transferred across placenta; Pb caused moderate, statistically significant, increase in frequency of SCEs in maternal bone marrow cells and significant reduction in NORs at the 2 highest dose levels (150 and 200 mg/kg); animals showed several specific chromosomal aberrations, mostly deletions, in maternal bone, marrow, and fetal cells; aneupoidy was found to be frequently associated with the lowest dose levels of Pb nitrate (100 mg/kg); increased embryonic resorption and reduced placental weights. P

es

Piasek and Kostial (1991) Rat/Wistar, 10 wks old 7500 ppm Pb acetate in drinking water for 9 wks Decrease in litter size, pup survival, and birth weight; food consumption, body weight, and fertility were not altered in 20 wk exposure period. M

O
 AX5-42 Table AX5-4.1 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects o

Citation Species/ Strain/Age Dose/Route/ Form/Duration Endpoint BPinon- Lataillade et al. (1995) Mouse/NMRI, adult 0–0.5% Pb acetate in drinking water exposed to Pb during gestation until post- GD 60 Pb exposure during gestation reduces litter size; reduced birth weight and growth rates. PbPillai and Gupta (2005) Rat/Charles Foster, 200–220 g Subcutaneous injection of 0.05 mg/kg-d Pb acetate for 5–7 days prior to mating through PND 21 Long term exposure of rats (premating, gestational, and lactational) to moderate levels of Pb acetate (s.c.) resulted in reduced activities of hepatic steroid (E2) metabolizing enzymes (17-ß-hydroxy steroid oxidoreductase and UDP glucuronyl transferase) and decreased hepatic CYP450 content. Pb

Ronis et al. (1996)† Rat/Sprague- Dawley, 22, 55 days or plug- positive time- impregnated 0.6% Pb acetate in drinking water for various durations: PND 24–74 (pubertal exposure), PND 60–74 (post pubertal exposure); 11 males and females in pubertal exposure group (10 each in control pubertal group); 6 males and females post- pubertal exposure and control groups Reduction in serum testosterone levels in male, not female; in female suppression of circulating E2 (p < 0.05) and LH (p < 0.05); reduction in male secondary sex organ weight (p < 0.0005); delayed vaginal opening and disrupted diestrous in females (p < 0.005); increased incidence of stillbirth (2% control vs. 19% Pb) (p < 0.005). In 

PrPoPbin >2

Ronis et al. (1998a)† Rat/Sprague- Dawley, various ages 0.6% Pb acetate in drinking water ad libitum for various durations: GD 5 to PND 1, GD 5 to weaning, PND 1 to weaning 3 control litters, 2 gestation exposure litters, 2 lactation exposure litters, 2 gestation and lactation exposure litters, 2 postnatal litters, 2 chronic litters (4 male and 4 female pups per litter) Dose-dependent delay in sexual maturation (delayed vaginal opening) (p < 0.0002) following prenatal Pb exposure that continued until adulthood (85 days old); reduced birth weight (p < 0.05), more pronounced among male pups. Gr

NaCoGeLaGePoCh

Ronis et al. (1998b)† Rat/Sprague- Dawley, adult Pb acetate in drinking water (0.05% to 0.45% w/v); dams exposed until weaning, exposure of pups which continued until PND 21, 35, 55, or 85; 5 control litters (0%), 10 low-dose litters (0.05%), 8 mid-dose litters 

(0.15%), 9 high-dose litters (0.45%); 4 male and 4 female pups per litter 

Prenatal Pb exposure that continues until adulthood (85 days old) delays sexual maturation in female pups in a dose-related manner (p < 0.05); birth weight reduced (p < 0.05), more pronounced among male pups; decreased growth rates (p < 0.05) in both sexes accompanied by decrease in plasma concentrations of IGF1 through puberty (p < 0.05) and a significant increase in pituitary and growth hormone during puberty (p < 0.05). 

Pbag>138
 AX5-43 Table AX5-4.1 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects o

Citation Species/ Strain/Age Dose/Route/ Form/Duration Endpoint BRonis et al. (1998c) Rat/Sprague- Dawley, adult Pb acetate 0.05, 0.15, or 0.45% in drinking water beginning GD 5 continuing until PND 21, 35, 55, or 85; 5 control litters (0%), 10 low-dose litters (0.05%), 8 mid-dose litters (0.15%), 9 high-dose litters (0.45%); 4 male and 4 female pups per litter Dose-responsive decrease in birth weight (p < 0.05), and crown-to-rump length (p < 0.05); dose-responsive delay in sexual maturity in male (p < 0.05) and female (p < 0.05); neonatal decrease in sex steroids (p < 0.05); pubertal decrease in testosterone (male) (p < 0.05) and E2 (female) (p < 0.05); decrease estrous cyclicity at high dose (p < 0.05). Da

Pu>1Pu~2Pu>2Pu~3Pu>2

Ronis et al. (2001)† Rat/Sprague- Dawley, neonate, male (100 days) and female pup Pb acetate in drinking water to 825 or 2475 ppm ad libitum from G'D 4 to GD 55 postpartum; 1 male and female pup/litter (5 litters per group) control group, 1 male and female pup/litter (5 litters per group) 825 ppm Pb acetate group, 1 male and female pup/litter (5 litters per group) 2475 ppm Pb acetate group Dose-dependent decrease of the load of failure in male (p < 0.05); no difference in plasma levels of vitamin D metabolites; reduced somatic growth (p < 0.05), longitudinal bone growth (p < 0.05), and bone strength during the pubertal period (p < 0.05); sex steroid replacement did not restore skeletal parameters in Pb exposed rats; L-Dopa increased plasma IGF1 concentrations, rates of bone growth, and bone strength measures in controls while having no effect in Pb exposed groups; DO gap x- ray density and proximal new endostreal bone formation were decreased in the distration gaps of the Pb-treated animals (p < 0.01); distraction initiated at 0.2 mm 30 to 60 days of age. Pb

19Pb38

Sant'Ana et al. (2001) Rat/Wistar, 90 days old 0.1 and 1% Pb in drinking water 7 days 1% Pb exposure reduced offspring body weight during treatment, no changes observed after 0.1% exposure; no altered offspring sexual maturation, higher Pb improved sexual behavior, while 0.1% reduced it; 0.1% Pb caused decrease in testis weight, an increase in seminal vesicle weight, and no changes in plasma testosterone levels, hypothalamic VMA levels were increased compared to control group; reduced birth weight and growth rates. Pb

13

Singh et al. (1993b) Rat/ITRC, albino (NOS), 6 wks old 250, 500, 1000, and 2000 ppm Pb nitrate in drinking water from GD 6 to GD 14 Significantly reduced litter size, reduced fetal weight, and a reduced crown-to-rump length, increased resorption and a higher blood-Pb uptake in those groups receiving 1000 and 2000 ppm Pb; these also had a higher placental uptake; however the level was the same in both groups; fetal Pb uptake remained the same whether or not 2000 ppm Pb was given to an iron-deficient or normal iron groups of mothers. Pb

Watson et al. (1997) Rat/Sprague- Dawley, adult Pb in drinking water at 34 ppm from weaning of mothers through gestation and weaning of offspring until birth; 6 pups control group, 6 pups experimental 

group 

Reduced body weight (p = 0.04); parotid function was decreased by nearly 30% (p = 0.30); higher mean caries scores than the control pups (p = 0.005); pre- and perinatal Pb exposure had significantly increased susceptibility to dental caries (p = 0.015). 

Pb
 AX5-44 Table AX5-4.1 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects o

Citation Species/ Strain/Age Dose/Route/ Form/Duration Endpoint BWiebe et al. (1998) Rats/Sprague- Dawley, adult 20 or 200 ppm Pb chloride in drinking water; prior to pregnancy, during pregnancy, lactation Exposure to Pb did not affect tissue weights but did cause a significant decrease in gonadotropin-receptor binding in the prepubertal, pubertal, and adult females; conversion of progesterone to androstenedione and dihydrotestosterone was significantly decreased in 21-day old rats, in 150-day old females, the exposure to Pb resulted in significantly increased conversion to the 5-alpha-reduced steroids, normally high during puberty. Pb*Not including effects on the nervous or immune systems. † Candidate key study. cGMP, cyclic guanosine—3',5'-monophosphate; DO, distraction osteogenesis; DOPAc, 3,4-dihydroxyphenylacetic acid; E2, estradiol; ERG, electroretinographic; FSH

GD, gestational day; IGF1, insulin-like growth factor 1; i.v., intravenous; kDA, kilodalton; LH, luteinizing hormone; NOS, not otherwise specified; PbB, blood Pb conc

phosphodiesterase; PND, post-natal day; p.o., per os (oral administration); s.c., subcutaneous; SEM, standard error mean; UDP, uridine diphosphate; VMA, vanilmande
 AX5-45 Table AX5-4.2. Effect of Lead on Reproduction and Development in Mammals Effects on 

Citation Species/ Strain/Age Dose/Route/Form/Duration Endpoint Acharya et al. (2003) Mouse/Swiss, 6–8 wks old 200 mg/kg Pb acetate through i.p. injection of Pb; one time injection Testicular weight loss with constant increase in the incidence of abnormal sperm population; decrease in sperm count; testicular ascorbic acid also declined significantly; significant rise in LPP of tissue; LPP is indicative of oxidative stress in treated mice testes. NoAdhikari et al. (2000) Rat/Druckrey, 28 days old 0.0, 0.4, 4.0, 40.0 μM Pb acetate in vitro for 24 and 48 hr Germ cells progressively detached from Sertoli cell monolayer into medium in a concentration and duration dependent manner Viability of the detached cells showed a decrease with increase in time and concentration of Pb; leakage of LDH recorded at higher dose of 4.0 and 40.0 μM. Pb

Adhikari et al. (2001) Rat/Druckrey, 28 days old 5, 10, and 20 mg/kg Pb in distilled water by gavage for 2 wks Induced significant numbers of germ cells to undergo apoptosis in the semiferous tubules of rats treated with highest dose; DNA fragmentation was not detected at any of the doses; level of Pb accumulation in testes increased in a dose-dependent manner. Pb

Alexaki et al. (1990) Bulls/Holstein, 3–5 yrs old In vitro fertilization 2.5 or 0.25 μg/mL Sperm motility reduced significantly at 2.5 μg/mL; lower concentration had no effect on sperm motility. Pb

Al-Hakkak et al. (1988) Mouse/ BALB/c, weaning 0, 25, 50 mg Pb monoxide alloy/kg in chow for 35– 70 days Reduced number of spermatogenia and spermatocytes in the 50 mg group after 70 days; reduced number of implantations after mating (after 35 days exposure). Pb

Barratt et al. (1989) Rat/Wistar, 70 days old 0, 0.3, 33, 330 mg Pb acetate/kg-d in drinking water, by gavage for 63 days Increased number of abnormal post-testicular sperm in the highest exposure group; reduced number of spermatozoa at PbB >4.5 μg/dL. Pb

Pb

Bataineh et al. (1998) Rat/Sprague- Dawley, adult 1000 ppm Pb acetate in drinking water for 12 wks Fertility was reduced in males. Pb

Batra et al. (2001) Rat/Portan, 8 wks old 10, 50, 200 mg/kg Pb acetate orally for 3 mo Pb in testis and epididymis increased with dose; administration of zinc reduced Pb levels; dose related changes in activities of enzyme alkaline phosphatase and Na+-K+- ATPase, which decreased with increased dose of Pb; improvement in activities of enzymes was seen in groups given Pb and zinc; disorganization and disruption of spermatogenesis with accumulation of immature cells in lumen of tubule; highest dose of Pb resulted in arrest of spermatogenesis, and decrease in germ cell layer population; highest dose levels, damage of basement membrane, disorganization of epithelium and vacuolization cells; tubules were found almost empty, indicating arrest of spermatogenesis. Pb

Batra et al. (2004) Rat/Portan, 8 wks old 10, 50, 200 mg/kg Pb acetate orally for 3 mo LH and FSH concentrations were decreased at 200 mg/kg; decrease in fertility status at 200 mg/kg; decline in various cell populations at 200 mg/kg; 50 mg/kg group hormone levels, cell numbers, and fertility status were found close to normal. Pb

Bizarro et al. (2003) Mouse/CD-1, adult 0.01 M Pb acetate twice a week for 4 wks Dose-time relationship was found; ROS role. Pb

Boscolo et al. (1988) Rat/Sprague- Dawley, weanling 60 mg Pb acetate/mL in drinking water for 18 mo Increased vacuolization in Sertoli cells; no other ultrastructural modifications; no impairment of spermatogenesis. Pb
 AX5-46 Table AX5-4.2 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/ Strain/Age Dose/Route/Form/Duration Endpoint Chowdhuri et al. (2001) Mouse/ BALB/c, 3 mo old 0.0, 0.2, 0.5, 1.0, 2.0 μg/mL Pb acetate in culture medium for 2 hr (superovulated ova and sperm) Significant dose dependent decrease in the number of sperm attaching to the ova in both exposed groups; decrease in the incorporation of radio-labeled thymdine, uridine, and methionine. PbChowdhury et al. (1984) Rat/Albino, (NOS), adult Dietary concentrations of 0.25, 0.50, or 1.0 g/L Pb acetate for 60 days Testicular atrophy along with cellular degeneration was conspicuous at 1 g/L; high cholesterol concentration and significantly low ascorbic acid concentration were found in the testes at 1 g/L; lowest dose (0.25 g/L) had no significant morphological and biochemical alterations, whereas as 0.5 g/L resulted in partial inhibition of spermatogenesis. Pb

Chowdhury et al. (1986) Rat/NOS, adult 0, 1, 2, 4, 6 mg Pb acetate/kg-d i.p. for 30 days Dose-related decrease of testis weight; at 187 μg/dL: degenerative changes in testicular tissues; at 325 μg/dL: degenerative changes and inquiry of spermatogenetic cells; edematous dissociation in interstitial tissue. Pb

32

Chowdhury et al. (1987) Rat/Charles Foster, 150 ± 5 g 0, 1, 2, 4, 6 mg Pb acetate/kg-d/i.p. for 30 days Dose related decrease of testis weight at 56 μg of spermatoids; at 91 μg/dL: inhibition of post-meiotic spermatogenic cell; at 196 μg/dL: decreased spermatogenic cell count (6), detachment of germinal call layers; at 332 μg/dL: Decreased spermatogenic cell count, degenerative changes, Interstitial edema, and atrophy of Leydig cells. Pb

Coffigny et al. (1994)† Rat/Sprague- Dawley, adult Inhalation exposure to 5 mg/m3 Pb oxide daily for 13 days during gestation (GD 2, 3, 6–10, 13–17, 20) Adult male offspring exhibit no change in sperm parameters or sex hormones T, FSH, and LH (because of duration or timing). Pb

Pb

Corpas et al. (1995) Rat/Wistar, adult 300 mg/L Pb acetate via drinking water beginning GD 1 through 5 days postnatal or throughout gestation and early lactation Testicular weight and gross testicular structure were not altered; seminiferous tubule diameter and the number of prospermatogonia were reduced; total DNA, RNA, and protein content of the testes in treated rats was significantly reduced, DNA:RNA ratio remained unaltered. Pb

Corpas et al. (2002a) Rat/Wistar, adult 300 mg/L acetate Pb in drinking water beginning at mating until PND 12 and 21 Neither abnormalities in the liver structure nor depositions of Pb, toxicant produced biochemical alterations; pups exhibited decrease in hemoglobin, iron and alkaline, and acid phosphatase levels and an increase in Pb content; protein, DNA, and lipid total amounts were reduced, and hepatic glycogen content was diminished at 12 and 21 PN, with a higher dose of glucose in blood; decrease in alkaline phosphatase in liver of pups at day 21 PN, but acid phosphatase was unaltered. Pb

Corpas et al. (2002b) Rat/Wistar, adult 300 mg/L acetate Pb in drinking water beginning at mating until PND 12 and 21 Neither abnormalities in the liver structure nor depositions of Pb, toxicant produced biochemical alterations; pups exhibited decrease in hemoglobin, iron and alkaline, and acid phosphatase levels and an increase in Pb content; protein, DNA, and lipid total amounts were reduced, and hepatic glycogen content was diminished at 12 and 21 PN, with a higher dose of glucose in blood; decrease in alkaline phosphatase in liver of pups at day 21 PN, but acid phosphatase was unaltered. Pb
 AX5-47 Table AX5-4.2 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/ Strain/Age Dose/Route/Form/Duration Endpoint 

Cory-Slechta et al. (2004)† Rat/Long-Evans, adult Pb acetate in drinking water beginning 2 mo before breeding until the end of lactation Observed potential effects of Pb and stress in female; Pb alone (in male) and Pb plus stress (in females) permanently elevated corticosterene levels in offspring. PbFoote (1999) Rabbit/Dutch- belted, adult 0, 0.005, 0.01, and 0.025 mM PbCl2 in vitro; one time dose Six out of 22 males tested showed appreciable spontaneous hyperactivation, Pb did not affect hyperactivation, or associated capacitation. Pb

Foster et al. (1993) Monkey/ Cynomolgus, adult 0–1500 μg Pb acetate/kg-d in gelatin capsules p.o. for various durations: 9 control monkeys, 4 monkeys in lifetime group (birth to 9 yrs), 4 in infancy group (first 400 days of life), 4 in post- infancy exposure (from 300 days to 9 yrs) Suppressed LH response to GnRH stimulation in the lifetime group (p = 0.0370); Sertoli cell function (reduction in the inhibin to FSH ratio) (p = 0.0286) in lifetime and post-infancy groups. Li

4–

5–

3–

inf

Foster et al. (1996a) 

Monkey/ Cynomolgus, adult 

0–1500 μg Pb acetate/kg-d in 

gelatin capsules p.o. from birth until 9 yrs of age: 8 control monkeys, 4 monkeys in low group (6-20 μg/dL), 7 monkeys in high group (22–148 μg/dL) 

Mean PbB of 56 μg/dL showed no significant alterations in parameters of semen quality (count, viability, motility, or morphology). 

Pb

Foster et al. (1998) 

Monkey/ Cynomolgus, adult 

0–1500 μg Pb acetate/kg-d in 

gelatin capsules p.o. for various durations: birth to 10 yrs (lifetime); PND 300 to 10 yrs (post-infancy); birth to 300 days (infancy); 3 control monkeys, 4 lifetime, 4 infancy, 5 post-infancy 

Circulating concentrations of FSH, LH, and testosterone were not altered by treatment; semen characteristics (count, motility, morphology) were not affected by treatment possibly because not all Sertoli cells were injured; degeneration of seminiferous epithelium in infancy and lifetime groups (no difference in severity between these groups); ultrastructural alterations in seminal vesicles, most prominent in infancy and post-infancy groups. 

Pb

Gandley et al. (1999) 

Rat/SpragueDawley, adult Male rats received Pb acetate 25 or 250 ppm in drinking 

water for 35 days prior to mating 

High dose reduced fertility; low dose altered genomic expression in offspring. Pb

27

Gorbel et al. (2002) 

Rat/(NOS), 90 days old 

3 mg (P1) or 6 mg (P2) Pb acetate in drinking water for 15, 30, 45, 60, or 90 days 

Male rats, absolute and relative weights of testis, epididymis, prostate and seminal vesicles were found to significantly decrease at day 15 in P2 group and at day 45 in P1 group, at day 60 these absolute values and relative weights returned to control values; at day 15 arrest of cell germ maturation, changes in the Sertoli cells, and presence of apoptotic cells were observed; serum testosterone level was found to be lowered at day 15 in both P1 and P2, and peaked at day 60, then returned to normal values. 

Pb
 AX5-48 Table AX5-4.2 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/ Strain/Age Dose/Route/Form/Duration Endpoint Graca et al. (2004) Mouse/CD-1, 2 mo old Subcutaneous injection of 74 mg/kg-d of Pb chloride for 1 to 3 days Reversible changes in sperm (count) and ultrastructural changes in testes (reduced diameter of seminiferous tubules). PbHsu et al. (1997) Rat/Sprague- Dawley, 7 wks old 10 mg/kg Pb acetate through i.p. injection to males for 6 or 9 wks Six-week group had unchanged epididymal sperm counts, percent of motile sperms, and motile epididymal sperm counts compared with control group; 9-wk group showed statistically lower epididymal sperm counts, and lower motile epididymal sperm counts; good correlation between blood Pb and sperm Pb; significantly higher counts of chemiluminescence, they were positively associated with sperm Pb level; epididymal sperm counts, motility, and motile epididymal sperm counts were negatively associated with sperm chemiluminescence; SOPR were positively associated with epididymal sperm counts, motility and motile epididymal sperm counts, sperm chemiluminescence was negatively associated with SOPR. Pb

9 w

Hsu et al. (1998a) Rat/Sprague- Dawley, 100–120 g 20 or 50 mg Pb acetate via i.p. route weekly to males for 6 wks Serum testosterone levels were reduced; percentage of capacitation and the chemiluminescence were significantly increased in fresh cauda epididymal spermatozoa; serum testosterone levels were negatively associated with the percentage of acrosome-reacted spermatozoa; sperm chemiluminescence was positively correlated with the percentage of both capacitated and acrosome-reacted spermatozoa; SOPR was negatively associated with the percentage of both capacitated and acrosome-reacted spermatozoa. Pb

Hsu et al. (1998b) Rat/Sprague- Dawley, 7 wks old 10 mg/kg Pb acetate weekly via i.p. injection to males for 6 wks Intake of VE and/or VC in Pb exposed rats prevented the Pb associated sperm ROS generation, increased the epididymal sperm motility, enhanced the capacity of sperm to penetrate eggs harvested from unexposed female rats in vitro; protective effect of VE and VC not associated with reduced blood or sperm Pb levels. Pb

Pb

Huang et al. (2002) Mouse MA-10 cells 10−8 to 10−5 M Pb incubated for 3 hr Higher decreases in human chorionic gonadotropin (hCG)-stimulated progesterone production, expressions of StAR protein, and the activity of 3ß-HSD compared to 2 hr; no affect on P450scc enzyme activity. Pb

Johansson (1989) Mouse, 9 wks old 0–1 g Pb chloride/L in drinking water for 112 days No effects on frequency of motile spermatozoa, nor on swimming speed; decreased fertilizing capacity of the spermatozoa by in vitro fertilization; premature acrosome reaction . Pb

Johansson and Pellicciari (1988) Mouse/NMRI, 9 wks old 1 g/L Pb chloride in drinking water for 16 wks Decreased uptake of PI was found in spermatozoa from the vas deferens of the Pb- exposed mice; after thermal denaturation of the DNA, the spermatozoa showed a higher uptake of PI in comparison to those of the controls; after reductive cleavage of S-S bonds with DTT and staining with a thiol-specific reagent significantly fewer reactive disulfide bonds were also observed in the spermatozoa; significant delay in the capacity for NCD was noted. Pb

Johansson and Wide (1986) Mouse/NMRI, 9 wks old 0–1 g/L Pb chloride in drinking water for 84 days No effects on sperm count; no effects on serum testosterone; reduced number of implantations after mating. Pb

Mdifan(epPb
 AX5-49 Table AX5-4.2 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/ Strain/Age Dose/Route/Form/Duration Endpoint Johansson et al. (1987) Mouse/NMRI, 9–10 wks old 1 g/L Pb chloride in drinking water for 16 wks Spermatozoa had significantly lower ability to fertilize mouse eggs; morphologically abnormal embryos were found. PbKempinas et al. (1988) Rat/Wistar, adult 0.5 g/L and 1.0 g/L Pb acetate in drinking water for 90 days PbB exhibited a significant increase in both groups; decrease in hematocrit and hemoglobin, together with a rise in glucose levels; no signs of lesion were detected upon histological examination of testes, caput, and cauda epididymidis; an increase in ductal diameter, and a decrease in epithelial height were observed in the cauda epididymidis; concentration of spermatozoa stored in the caudal region of the epididymis exhibited a significant increase in Pb-treated animals. Pb

(1.0 g/L) Pb acetate in drinking water in addition to i.v. injections of Pb acetate (0.1 mg/100 g bw) every 10 days, 20 days Kempinas et al. (1990) Rat/NOS, pubertal (1.0 g/L) Pb acetate in drinking water in addition to i.v. injections of Pb acetate (0.1 mg/100 g bw) every 15 days, 9 mo Basal levels of testosterone were higher both in the plasma and in the testes of acutely intoxicated animals; levels of LH were not affected in either group, nor was the LHRH content of the median eminence; density of LH/hCG binding sites in testicular homogenates was reduced by saturnism in both groups, apparent affinity constant of the hormone-receptor, complex significantly increased. Pb0–1 g Pb acetate/L in drinking water + 0.1 mg/kg i.v. every 10 days for 20 days Kempinas Pb

et al. (1994) Rat/Wistar, 50 days old 0–1 g Pb acetate/L in drinking water + 0.1 μg/kg i.v. every 15 days for 270 days Increased plasma and testicular testosterone concentrations; no effects on testicular weight; reduced weight of prostate; increased weight of seminal vesicle and seminal secretions. Pb

Klein et al. (1994) Rat/Sprague- Dawley, 100 days old 0.1, 0.3, or 0.6% Pb acetate in distilled water for 21 days 

2–3-fold enhancement of mRNA levels of GnRH and the tropic hormone LH; 3-fold 

enhancement of intracellular stores of LH; mRNA levels of LH and GnRH and pituitary levels of stored LH are proportional to blood levels of Pb. 

Pb

Liu et al. (2001) 

Mouse, MA-10 cells 

10−8 to 10−5 Pb acetate in 

vitro for 2 hr 

Significantly inhibited hCG- and dbcAMP-stimulated progesterone production in MA-10 cells; steroid production stimulated by hCG or dbcAMP were reduced by Pb; expression of StAR protein and the activities of P450 side-chain cleavage (P450) and 3ß-HSD enzymes detected; expression of StAR protein stimulated by bdcAMP was suppressed by Pb at about 50%; progesterone productions treated with 22Rhydroxycholesterol or pregnenolone were reduced 30–40% in Pb treated MA-10 cells. 

Pb

Liu et al. (2003) 

Mouse, MA-10 cells 

10−8 to 10−5 Pb acetate in 

vitro for 6 hr incubated 

Pb significantly inhibited hCG- and dbcAMP-stimulated progesterone production from 20 to 35% in MA-10 cells at 6 hr; Pb suppressed the expression of steriodogenesis acute regulatory (StAR) protein from 30 to 55%; activities P450 side-chain cleavage (P450scc) enzyme and 3ß-HSD were reduced by Pb from 15 to 25%. 

Pb
 AX5-50 Table AX5-4.2 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/ Strain/Age Dose/Route/Form/Duration Endpoint Marchlewicz et al. (1993) Rat/Wistar, 90 days old 0–1% Pb acetate in drinking water for 270 days No histological or weight changes in testicle or epididymis; fever spermatozoa in all zones of the epididymis. PbMcGivern et al. (1991)† Rat/Sprague- Dawley, adult 0.1% Pb acetate in drinking water from GD 14 to parturition: 8 control litters; 6 Pb acetate litters (5 males per litter) Decreased sperm count (21% at 70 days and 24% at 165 days; p < 0.05); reduced male behavior (p < 0.05); enlarged prostate (25% increase in weight; p < 0.07); irregular release patterns of both FSH and LH (p < 0.05). Co

MPu

McMurry et al. (1995) Rat/Cotton, adult 0, 100, or 1000 ppm Pb in drinking water for 7 or 13 wks Immune function was sensitive to Pb exposure; spleen mass was reduced in cotton rats receiving 100 ppm Pb; total leukocytes, lymphocytes, neutrophils, eosinophils, total splenocyte yield, packed cell volume, hemoglobin, and mean corpuscular hemoglobin were sensitive to Pb exposure; reduced mass of liver, seminal vesicles, and epididymis in males after 7 wk exposure. Pb

Mishra and Acharya (2004) Mouse/Swiss, 9–10 wks old 10 mg/kg Pb acetate in drinking water for 5 to 8 wks Stimulates lipid peroxidation in the testicular tissue, associated with increased generation of noxious ROS; reduced sperm count, increased sperm abnormality Pb

Moorman et al. (1998) Rabbit/NOS, adult 3.85 mg/kg Pb acetate subcutaneous injection for 15 wks Increased blood levels associated with adverse changes in the sperm count, ejaculate volume, percent motile sperm, swimming velocities, and morphology; hormonal responses were minimal; dose-dependent inhibition of sperm formation; semen quality, threshold estimates ranged from 16 to 24 μg/dL. Pb

11

Murthy et al. (1991) Rat/ITRC, (NOS), weanling 0–250 ppm Pb acetate in drinking water for 70 days At 20 μg/dL no impairment of spermatogenesis; vacuolization of Sertoli cell cytoplasm and increase in number and size of lysosomes. Pb

Murthy et al. (1995) Rat/Druckrey, adult Pb 5 mg/kg i.p. Pb acetate in drinking water for 16 days Swelling of nuclei and acrosomes round spermatids; in Sertoli cells, nuclei appeared fragmented, whereas the cytoplasm exhibited a vacuolated appearance and a few structures delimitated by a double membrane that contains microtubules arranged in parallel and cross-striated fin fibrils, cell tight junction remain intact; no significant change in epididymal sperm motility and counts, testicular blood levels were found to be elevated after Pb exposure. Pb

Nathan et al. (1992) Rat/Sprague- Dawley, adult 0, 0.05, 0.1, 0.5, or 1% Pb acetate in drinking water for 70 days No effects on spermatogenesis in all groups; at 124 μg/dL: decreased seminal vesicle weight; decreased serum testosterone in the 0.5% group at 10 wks; no effects in the other exposure categories; no effects on serum FSH, LH, nor pituitary LH content. Pb

Pace et al. (2005) 

Mouse/BALB/c, 

adult 

0.1 ppm Pb acetate in drinking water (lactational exposure as neonates and drinking water from PND 21 to PND 42) 

Reduction in fertility when mated with unexposed females; no change in sperm count; increase in number of apoptotic cells in testes. 

NePo

Piasecka et al. (1995) 

Rat/Wistar, adult 

1% aqueous solution of Pb acetate for 9 mo 

Pb-loaded (electron dense) inclusions were found in the cytoplasm of the epididymal 

principal cells, especially in the caput of epididymis, also present, but smaller, in smooth muscle cells; inclusions were located in the vacuoles, rarely without any surrounding membrane; similar Pb-containing structures were found in the epididymal lumen. 

Pb
 AX5-51 Table AX5-4.2 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/ Strain/Age Dose/Route/Form/Duration Endpoint Piasek and Kostial (1987) Rat/Albino, (NOS), adult 1500, 3500, and 5500 ppm of Pb acetate in drinking water for 18 wks No overt signs of general toxicity in adult female rats, only at the end of the exposure period the mean body weight of males exposed to two higher levels was slightly lower; no effect of Pb exposure on male fertility either after first or after second mating; values in the pups did not differ from control group. Pb

0–0.3% Pb acetate in drinking water for 70 days Pinon- Lataillade et al. (1993) Rat/Sprague- Dawley, 90 days old 5 mg/m2 Pb oxide in aerosol for 6 hr/day, 5 days/wk, 90 days Decreased weight of seminal vesicles in inhalation study; no effects on spermatogenesis (epididymal sperm count, spermatozoal motility or morphology) or plasma testosterone, LH, and FSH; no effects on fertility; decrease in epididymal sperm count of progeny of sires of the inhalation group, however without effect on their fertility. Pb

Pb(in

Pinon- Lataillade et al. (1995) Mouse/NMRI, adult 0–0.5% Pb acetate in drinking water, day 1 of gestation until 60 days of age No effects on testicular histology, nor on number and morphology of epididymal spermatozoa; no effects on plasma FSH, LH, and testosterone, nor on testicular testosterone; decreased weight of testes, epididymis, seminal vesicles, and ventral prostate; no effects on fertility. Pb

Rodamilans et al. (1988) Mouse/BALB/c, 63 days old 0–366 mg Pb acetate/L in drinking water for 30, 60, 90, 120, 150, 180 days Reduction of intratesticular testosterone concentrations after 30 days; reduction of and renostenedione concentrations after 150 days; no changes in intratesticular progesterone and hydroxy-progesterone. Pb

Ronis et al. (1996)† Rat/Sprague- Dawley, adult 0.6% Pb acetate in drinking water for various durations: PND 24–74 (pubertal exposure); PND 60–74 (post pubertal exposure); 11 males and females in pubertal exposure group (10 each in control pubertal group); 6 males and females post- pubertal exposure and control groups PbB > 250 μg/dL reduced circulating testosterone levels in male rats 40–50% (p < 0.05); reduction in male secondary sex organ weight (p < 0.005); delayed vaginal opening (p < 0.0001); disrupted estrous cycle in females (50% of rats); increased incidence of stillbirth (2% control vs. 19% Pb) (p < 0.005). Pu

Po

M

60 

Ronis et al. (1998a) Rat/Sprague- Dawley, adult 0.6% Pb acetate in drinking water ad libitum for various durations as follows: GD 5 to PND 1; GD 5 to weaning; PND 1 to weaning; 3 control litters, 2 gestation exposure litters, 2 lactation exposure litters, 2 gestation and lactation exposure litters, 2 postnatal exposure litters, 2 chronic exposure litters; 4 male and 4 female pups 

per litter. 

Suppression of adult mean serum testosterone levels was only observed in male pups exposed to Pb continuously from GD 5 throughout life (p < 0.05). 

GrNaCoGeLaGePoCh
 AX5-52 Table AX5-4.2 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/ Strain/Age Dose/Route/Form/Duration Endpoint BRonis et al. (1998b) Rat/Sprague- Dawley, adult Pb acetate in drinking water (0.05% to 0.45% w/v); dams exposed until weaning, exposure of pups which continued until PND 21, 35, 55, or 85; 5 control litters (0%), 10 low-dose litters (0.05%), 8 mid-dose litters (0.15%), 9 high-dose litters (0.45%); 4 male and 4 female pups per litter Dose-response reduction in birth weight (p < 0.05), more pronounced in male pups; decreased growth rates in both sexes (p < 0.05) were accompanied by a statistically significant decrease in plasma concentrations of IGF1 through puberty PND 35 and 55 (p < 0.05); increase in pituitary growth hormone during puberty (p < 0.05). M

(wM(wM(w

Ronis et al. (1998c)† Rat/Sprague- Dawley, adult Pb acetate 0.05, 0.15, or 0.45% in drinking water beginning GD 5 continuing until PND 21, 35, 55, or 85; 5 control litters (0%), 10 low- dose litters (0.05%), 8 mid- dose litters (0.15%), 9 high- dose litters (0.45%); 4 male and 4 female pups per litter Dose-responsive decrease in birth weight (p < 0.05); dose-responsive decrease in crown-to-rump length (p < 0.05); dose-dependent delay in sexual maturity (p < 0.05); decrease in prostate weight (p < 0.05); decrease in plasma concentration of testosterone during puberty (p < 0.05); decrease in plasma LH (p < 0.05); elevated pituitary LH content (p < 0.05); decrease in plasma testosterone/LH ratio at high dose (p < 0.05). Da

Pu12Pu23Pu27Pu37Pu21

Sant'Ana et al. (2001) Rat/Wistar, 90 days old 0.1 and 1% Pb acetate in drinking water for 7 days 0.1% Pb caused decrease in testis weight, an increase in seminal vesicle weight and no changes in plasma testosterone levels, hypothalamic VMA levels were increased compared to control group. Pb

13

Saxena et al. (1984) Rat/ITRC, albino (NOS), 12 wks old 8 mg/kg Pb acetate i.p. for 15 days Histoenzymic and histological alterations in the testes; degeneration of seminiferous tubules; patchy areas showing marked loss in the activity of succinic dehydrogenase and adenosine triphosphatase, whereas alkaline phosphatase activity showed only slight inhibition. Pb

Saxena et al. (1986) Rat/ITRC, albino (NOS), 40–50 g 5, 8, or 12 mg Pb+2/kg Pb acetate i.p. for 15 days Increasing dose of Pb resulted in significant loss of body weight, as well as testicular weight in groups 3 and 4; cholesterol in the testis of rats markedly decreased at all given doses of Pb and was statistically significant in groups 3 and 4; in phospholipid contents, the significant decrease was observed only at two highest doses, while at the lowest dose the decrease was not significant; activity of ATPase remained unaffected at all three doses of Pb; no significant increase in Pb content in the testis was noticed at lower dose levels as compared to control; however, significant increase was found in groups 3 and 4 which was dose dependent. Pb

Saxena et al. (1987) Rat/Wistar, 40–50 g 8 mg Pb2/kg-d Pb acetate i.p. for 100 days (from PND 21 to 

PND 120) 

Disturbed spermatogenesis; Leydig cell degeneration; altered enzyme activity (G6PDH). 

Pb
 AX5-53 Table AX5-4.2 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/Strain/Age Dose/Route/ Form/Duration Endpoint Saxena et al. (1990) ITRC albino, (NOS), adult 8 mg/kg/d Pb acetate for 45 days Alterations in SDH, G6PDH activity, cholesterol, and ascorbic acid contents and reduced sperm counts associated with marked pathological changes in the testis, after combined treatment with Pb and immobilization stress in comparison to either alone. Pb

Monkey/ Cynomolgus, birth Birth: Singh et al. (1993a) 300 days: 0–1500 μg Pb acetate/kg-d in gelatin capsules for various durations: 3 control monkeys, 4 monkeys in infancy group (exposure first 400 days), 5 in post-infancy group (exposure 300 days to 9 yrs of age), 4 in lifetime group (exposure from birth until 9 yrs) Degeneration of seminiferous epithelium in all exposed groups (frequency not specified); ultrastructural alterations in seminal vesicles, most prominent in infancy and post-infancy groups (frequency not specified). Ch

Sokol (1987) Rat/Wistar, 52 days old 

0–0.3% Pb acetate in 

drinking water for 30 days 

Hyper-responsiveness to stimulation with both GnRH and LH (10); blunted response to naloxone stimulation (10). 

Pb

Rat/Wistar, 27 days old 

0–0.6% Pb acetate in drinking water for 30 days + 30 days recovery 

<3re

Sokol (1989) 

52 days old 0–0.6% Pb acetate in 

drinking water for 30 days + 30 days recovery 

Suppressed intratesticular sperm counts, sperm production rate, and serum testosterone in both Pb treated groups (10–10); sperm parameters and serum 

testosterone normalized at the end of the recovery period in the pre-pubertal animals (27 days at start) (10) but not in the pubertal animals (52 days at start) (5). B1 

af

Sokol (1990) Rat/Wistar, 52 days 

old 

0–0.6% Pb acetate in 

drinking water for 7, 14, 30, 60 days 

Decreased sperm concentration, sperm production rate and suppressed serum testosterone concentrations after 14 days of exposure; not dose related (NS). 

Coexafre

0

Sokol and Berman (1991) 

Rat/Wistar, NOS 0, 0.1, or 0.3% Pb acetate in 

drinking water for 30 days beginning at 42, 52, or 70 days old; 8–11 control rats 

for each age, 8–11 rats for 

each age in 0.1% group, 8–

11 rats for each age in 0.3% group 

Dose-related suppression of spermatogenesis (decreased sperm count and sperm 

production rate) in the exposed rats of the two highest age groups (p < 0.05); doserelated suppression of serum testosterone in 52-day old rats (p = 0.04) and in 70-day old rats (p < 0.003). 

0
 AX5-54 Table AX5-4.2 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/ Strain/Age Dose/Route/Form/Duration Endpoint Sokol et al. (1985)† Rat/Wistar, 52 days old 0.1 or 0.3% Pb acetate in drinking water for 30 days Negative correlations between PbB levels and serum and intratesticular testosterone values; dose-dependent reduction in intratesticular sperm count; FSH values were suppressed; no change in LH; decrease in ventral prostatic weight; no difference in testicular or seminal vesicle weights. Pb

Pb

Sokol et al. (1994) Rat/Sprague- Dawley, 100 days old 0.3% Pb acetate in drinking water for 14, 30, or 60 days Pb exposed fertilized fewer eggs; increased duration of exposure did not result in more significant percentage of eggs not fertilized; no ultrastructural changes were noted in the spermatozoa of animals; no difference in histogram patterns of testicular cells. Pb

Sokol et al. (2002) Rat/Sprague- Dawley, adult Pb acetate in water for 1 wk Dose-related increase in gonadotropin-releasing hormone (GnRH) mRNA; no effect on the serum concentrations of hypothalamic gonadotropin-releasing hormone (GnRH) or LH. Pb

Thoreux- Manlay et al. (1995a) Rat/Sprague- Dawley, 97 days old 0–8 mg Pb acetate/kg i.p. for 5 days/wk, 35 days No effects on spermatogenesis; decreased plasma and testicular testosterone by 80%; decreased plasma LH by 32%, indications for impaired Leydig cell function, no effects on fertility. Pb

Thoreux- Manlay et al. (1995b) Rat/Sprague- Dawley, adult 8 mg/kg-d Pb for 5 days/wk, 35 days Germ cells and Sertoli cells were not major target of Pb, accessory sex glands were target; epididymal function was unchanged; plasma and testicular testosterone dropped about 80%, plasma LH only dropped 32%. Pb

Wadi and Ahmad (1999) Mouse/CF-1, adult 0.25 and 0.5% Pb acetate in drinking water for 6 wks Low dose significantly reduced number of sperm within epididymis; high dose reduced both the sperm count and percentage of motile sperm and increased the percentage of abnormal sperm within the epididymis; no significant effect on testis weight, high dose significantly decreased the epididymis and seminal vesicles weights as well as overall body weight gain; LH, FSH, and testosterone were not affected. Pb

Wenda- Rózewicka et al. (1996) Rat/Wistar, adult 1% aqueous solution of Pb acetate for 9 mo Electron microscopic studies did not reveal any ultrastructural changes in the semiferous epithelium or in Sertoli cells; macrophages of testicular interstitial tissue contained (electron dense) Pb-loaded inclusions, usually located inside phagolisosome- like vacuoles; x-ray micro-analysis revealed that the inclusions contained Pb. Pb

Yu et al. (1996) Rat/Sprague- Dawley, neonates Neonatal and lactational exposure to 0.3% Pb acetate in drinking water beginning PND 1 to PND 21 Neonatal exposure to Pb decreased cold-water swimming endurance (a standard test for stress endurance) and delayed onset of puberty in males and female offspring, which was exacerbated by swimming stress. Pb

*Not including effects on the nervous or immune systems. † Candidate key study. 3ß-HSD, 3ß-hydroxysteriod dehydrogenase; dbcAMP, dibutyryl cyclic adenosine-3',5'-monophosphate; DTT, dithiothreitol; FSH, follicle stimulating hormone; G6PDH

dehydrogenase; GD, gestational day; GnRH, gonadotropin releasing hormone; hCG, human chorionic gonadotropin; IGF1, insulin-like growth factor 1; i.p., intraperiton

dehydrogenase; LH, luteinizing hormone; LHRH, luteinizing hormone releasing hormone; LPP, lipid peroxidation potential; NCD, nuclear chromatin decondensation rspecified; PbB, blood lead concentration; PND, post-natal day; p.o., per os (oral administration); ROS, reactive oxygen species; SDH, succinic acid dehydrogenase; SOrate; StAR, steroidogenic acute regulatory protein; VC, vitamin C; VE, vitamin E; VMA, vanilmandelic acid 
 AX5-55 Table AX5-4.3. Effect of Lead on Reproduction and Development in Mammals Effects on F

Citation Species/ Strain/Age Dose/Route/ Form/Duration Endpoint BBurright et al. (1989) Mouse/HET, neonates 0.5% Pb acetate solution via milk, or drinking water chronic beginning PND 1 Plasma prolactin levels implied that Pb exposure alone decreased circulating prolactin in primiparous; low prolactin levels in non-behaviorally tested females suggests that dietary Pb alone may alter plasma-hormone in these lactating HET dams; pattern of plasma prolactin appear to be inconsistent with the observation that Pb exposure decreases dopamine; prolactin levels of Pb exposed dams were very low. PbCoffigny et al. (1994)† Rat/Sprague- Dawley, adult Inhalation exposure to 5 mg/m3 Pb oxide daily for 13 days during gestation (GD 2, 3, 6–10, 13–17, 20) No effects on the incidence of pregnancy, prenatal death, or malformations when male and female rats from mothers who had been exposed. Pb

Pb

Corpas et al. (2002a) Rat/Wistar, adult 300 mg/L acetate Pb in drinking water from mating until PND 12 or PND 21 Neither abnormalities in the liver structure nor depositions of Pb, toxicant produced biochemical alterations; pups exhibited decrease in hemoglobin, iron and alkaline, and acid phosphatase levels and an increase in Pb content; protein, DNA, and lipid total amounts were reduced, and hepatic glycogen content was diminished at 12 and 21 PN, with a higher dose of glucose in blood; decrease in alkaline phosphatase in liver of pups at day 21 PN, but acid phosphatase was unaltered. Pb

Cory-Slechta et al. (2004)† Rat/Long-Evans, adult Pb acetate in drinking water beginning 2 mo before breeding through weaning Observed potential effects of Pb and stress in female; Pb alone (in male) and Pb plus stress (in females) permanently elevated corticosterene levels in offspring. Pb

Dearth et al. (2002)† Rat/Fisher 344, 150–175 g 12 mg/mL Pb acetate gavage from 30 days prior breeding until pups were weaned 21 days after birth; 10– 32 litters per group, control group, gestation and lactation exposure, gestation only exposure, lactation only exposure Delay in onset of puberty (p < 0.05); reduced serum levels of IGF1 (p < 0.001), LH (p < 0.001), and E2 (p < 0.001). M

PuGeGeGeGeGeGeLaLaLa

Dearth et al. (2004) Rat/Sprague- Dawley and Fisher-344, adult 12 mg/mL Pb acetate by gavage 30 days prior to breeding through PND 21 (gestation and lactation exposure) Pb delayed the timing of puberty in PbB 37.3 μg/dL Pb group and suppressed serum levels of LH and E2, these effects did not occur in PbB 29.9 μg/dL Pb group, when doubling dose to 29.9 μg/dL group the PbB levels rose to 62.6 μg/dL, yet no effect was noted; results indicate that offspring are more sensitive to maternal Pb exposure with regard to puberty related insults than are 29.9 μg/dL rats. Pb

DaPb
 AX5-56 Table AX5-4.3 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/ Strain/Age Dose/Route/ Form/Duration Endpoint BFoster (1992) Monkey/ Cynomolgus, 

0–10 yrs old 

Daily dosing for up to 10 yrs with gelatin capsules containing Pb acetate (1.5 mg/kg); 8 control group monkeys, 8 lifetime exposure (birth–10 yrs), 8 childhood exposure (birth–400 days), and 8 adolescent exposure (postnatal day 300–10 yrs of age) 

Statistically significant reductions in circulating levels of LH (p < 0.042), FSH (p < 0.041), and E2 (p < 0.0001) during menstrual cycle; progesterone concentrations were unchanged and menstrual cycle was not significantly affected. 

Pb

Foster et al. (1992) 

Monkey/ Cynomolgus, 10 yrs old 

Daily dosing for up to 10 yrs with gelatin capsules containing Pb acetate (1.5 mg/kg); 8 control group monkeys, 8 childhood (birth–

400 days), 7 adolescent (postnatal day 300–10 yrs), 

7 lifetime (birth–10 yrs) 

No effect on endometrial response to gonadal steroids as determined by ultrasound. Pb

Foster et al. (1996b) 

Monkey/ Cynomolgus, 15–20 yrs old 

Chronic exposure to Pb acetate 50 to 2000 μg/kg-d p.o. beginning at birth for 15–20 yrs; 20 control 

monkeys, 4 monkeys in 50 μg/kg-d group, 3 monkeys in 100 μg/kg-d, 2 monkeys in 500 μg/kg-d group, and 3 monkeys in 2000 μg/kg-d group 

Reduced corpora luteal production of progesterone (p = 0.04), without alterations in E2, 20alpha-hydroxyprogesterone, or menstrual cyclicity. 

Pb

(5Pbgr

Franks et al. (1989) 

Monkey/Rhesus, adult 

Pb acetate in drinking water (2–8 mg/kg-d) for 33 mo; 7 control and 10 Pb monkeys 

Reduced circulating concentration of progesterone (p < 0.05); treatment with Pb did not prevent ovulation, but produced longer and more variable menstrual cycles and shorter menstrual flow. 

Pb

Fuentes et al. (1996) 

Mouse/Swiss, adult 

14, 28, 56, and 112 mg/kg Pb acetate via i.p; one time exposure on GD 9 

Absolute placental weight at 112 mg/kg and relative placental weight at 14, 56, and 112 mg/kg were diminished significantly; most sections of placenta showed vascular congestion, and increase of intracellular spaces, and deposits of hyaline material of perivascular predominance; trophoblast hyperplasia was also observed, whereas there was a reinforcement of the fibrovascular network in the labyrinth 

Pb

Gorbel et al. (2002) 

Rat/NOS, 3 mo old 

3 mg (P1) or 6 mg (P2) Pb acetate in drinking water for 15, 30, 45, 60, or 90 days 

Female rats absolute and relative weights of ovary and uterus were unchanged, vaginal smears practiced in females revealed the estrus phase; fertility was found to be reduced; Pb level in blood was poorly correlated with the level of poisoning. 

Pb
 AX5-57 Table AX5-4.3 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/ Strain/Age Dose/Route/ Form/Duration Endpoint BIavicoli et al. (2004) Mouse/Swiss, 33–37 days old 0.02, 0.06, 0.11, 0.20, 2.00, 4.00, 20.00, 40.00 ppm in food Pb acetate concentration beginning GD 1 to 3 mo after birth Increase in food consumption; however, did low-dose group increase food consumption because of sweet nature of Pb. Body weight may contribute to delay in onset of puberty and confound results. Pb

3.8

Junaid et al. (1997) Mouse/Swiss, adult 0, 2, 4, or 8 mg/kg-d Pb acetate, subchronic exposure, 5 days/wk, 60 days Altered follicular development. Pb

Laughlin et al. (1987) Monkey/Rhesus, adult Pb acetate in drinking water at 3.6, 5.9, or 8.1 mg/kg-d for 1–2 yrs; 7 control and 10 experimental monkeys per group Reductions in cycle frequency (p < 0.01); fewer days of flow (p < 0.01); longer and more variable cycle intervals (p < 0.025). Pb

518088

Lögdberg et al. (1987) Monkey/ Squirrel, adult Pb acetate in drinking water from 9th week of gestation to PND 1; per oral exposure similar to Laughlin et al. (1987) Increase in pre- and perinatal mortality during the last two-thirds of pregnancy; statistically significant reduction in mean birth weight was observed in Pb exposed monkeys as compared to controls. M

(3

Lögdberg et al. (1988) Monkey/ Squirrel, adult Pb acetate maternal dosing from 5–8.5 wks pregnant to PND 1 11 control monkeys, 3 low- Pb exposure group (PbB 24 μg/dL), 7 medium Pb group (PbB 40 μg/dL, 5 high- Pb group (PbB 56 μg/dL) Dose-dependent reduction in placental weight (p < 0.0007); various pathological lesions were seen in the placentas, including hemorrhages, hyalinization of the parenchyma with destruction of the villi, and massive vacuolization of chorion epithelium. Pb

24 40 56 

McGivern et al. (1991)† Rat/Sprague- Dawley, adult 0.1% Pb acetate in drinking water from GD 14 to parturition Female rats showed delay in vaginal opening; 50% exhibited prolonged and irregular periods of diestrous and lack observable corpora lutea; both sexes showed irregular release patterns of both FSH and LH. Pb

Nilsson et al. (1991) Mouse/NMRI, adult 75 μg/g bw Pb chloride via i.v.; one time injection on GD 4 Electron microscopy showed that the uterine lumen, which was closed in control mice, was opened in Pb-injected mice; suggested that Pb caused increase in uterine secretion; study suggested Pb could have a direct effect on the function of the uterine epithelium and that Pb was secreted into the uterine lumen and affect the blastocysts. Pb

Piasek and Kostial(1991) Rat/Wistar, 10 wks old 7500 ppm Pb acetate in drinking water for 9 wks Decrease in litter size, pup survival, and birth weight; food consumption, body weight, and fertility were not altered in 20 wk exposure period. M

Of

Pinon- Lataillade et al. (1995) 

Mouse/NMRI, adult 

0–0.5% Pb acetate in drinking water exposed to Pb during gestation until postGD 60 

Exhibited reduced fertility as evidenced by smaller litters and fewer implantation sites. Pb
 AX5-58 Table AX5-4.3 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/ Strain/Age Dose/Route/ Form/Duration Endpoint BPriya et al. (2004) Rat/Charles Foster, 6–9 mo old 0.03 μM Pb in vitro for 1 h LH binding was dropped to 84% in Pb treated cells; Pb exposed cells showed 31% reduction in the enzymes 17ß-HSDH and 17ß-HS; Pb can cause a reduction in LH and FSH binding, which significantly alters steroid production in vitro and exerts a direct influence on granulose cell function. PbRonis et al. (1996) Rat/Sprague- Dawley, various ages Pb acetate in the drinking water or male and female rats for the following durations: PND 24–74 (pubertal exposure); PND 60–74 (post pubertal exposure) Data suggest that both the temporary and the long-lasting effects of Pb on reproductive endpoints in male and female experimental animals are mediated by the effects of Pb on multiple points along the hypothalamic-pituitary-gonad axis; exposure of male and female Sprague-Dawley rats pre-pubertally (age 24–74 days) to Pb acetate in the drinking water resulted in significant reduction in testis weight and in the weight of secondary sex organs in males; these effects were not observed in rats exposed post- pubertally (day 60–74); there is convincing evidence that pre-pubertal female rats exposed in utero and during lactation have reduced levels of circulating E2 and LH. M

Of

Ronis et al. (1998a)† Rat/Sprague- Dawley, adult 0.6% Pb acetate in drinking water; ad libitum for various durations as follows: GD 5 to PND 1, GD 5 to weaning, PND 1 to weaning Female pups exposed to Pb from birth through adulthood or from GD 5 through adulthood were observed to have significantly delayed vaginal opening and disrupted estrus cycling; these effects on female reproductive physiology were not observed in animals where Pb exposure was confined only to pregnancy or lactation. Pu

22

Ronis et al. (1998b) Rat/Sprague- Dawley, adult Ad libitum intake of Pb acetate (0.05 to 0.45% w/v); Pb exposure of dams until weaning, exposure of pups until day 21, 35, 55, 85 Prenatal Pb exposure that continues until adulthood (85 days old) delays sexual maturation in female pups in a dose-related manner; dose-dependent delay in sexual maturation (delayed vaginal opening) among female rats following prenatal Pb exposure that continued until adulthood (85 days old); a growth hormone-mediated effect on growth that differs depends upon the developmental state of the animal birth weight was significantly reduced and more pronounced among male pups; decreased growth rates in both sexes were accompanied by a statistically significant decrease in plasma concentrations of IGF1 through puberty and a significant increase in pituitary growth hormone during puberty; growth suppression of male and female rats involves disruption of growth hormone secretion during puberty. M

(wM(wM(w

Ronis et al. (1998c) Rat/Sprague- Dawley, adult 0.05, 0.15, or 0.45% Pb acetate in drinking water beginning GD 5 for 21, 35, 55, 85 days Dose-responsive decrease in birth weight and crown-to-rump length was observed in litters; dose-dependent delay in sexual maturity (delay in vaginal opening); decrease in neonatal sex steroid levels and suppression of E2 during puberty; elevation in pituitary LH content was observed during early puberty; E2 cycle was significantly disrupted at the highest Pb dose; data suggests that the reproductive axis is particularly sensitive to Pb during specific developmental periods, resulting in delayed sexual maturation produced by sex steroid biosynthesis. Pb

Pb82 wi

Sierra and Tiffany- Castiglioni (1992) Guinea pig/NOS, adult 0, 5.5, or 11 mg/kg Pb acetate, oral dose from GD 22 until GD 52 or 62 Hypothalamic levels of SRIF; lower serum concentrations of progesterone at higher dose only; hypothalamic levels of GnRH and SRIF were reduced in a dose-dependent manner by Pb treatment in both dams and fetuses; reduction of SRIF levels in 52-days old fetus was particularly severe (92%) in the 11 mg group. Pb

Srivastava et al. (2004) 

Rat/Fisher 344, adult 

12 mg/mL Pb acetate by gavage for 30 days prior to breeding until weaning 

Pb decreased StAR protein expression and lowered E2 levels; suggested that the primary action of Pb to suppress E2 is through its known action to suppress the serum levels of LH and not due to decreased responsiveness of StAR synthesizing machinery. 

Pbμg

0.2
 AX5-59 Table AX5-4.3 (cont’d). Effect of Lead on Reproduction and Development in Mammals Effects 

Citation Species/ Strain/Age Dose/Route/ Form/Duration Endpoint BTaupeau et al. (2001) Mouse/C57blxC BA, 8 wks old 10 mg/kg-d Pb nitrate via i.v. for 15 days Low Pb concentration in the ovary caused dysfunction of folliculogenesis, with fewer primordial follicles and an increase in atretic antral follicles. PTchernitchin et al. (1998a) Rat/Sprague- Dawley, 14 days old 172 μg/g bw Pb from day 14 every 2nd day until day 20 Pb inhibits estrogen-induced uterine eosinophilia at 6 and 24 hr after treatment; Pb also inhibits estrogen-induced edema in deep and superficial endometrial stoma at 24 hr but not 6 hr after treatment; myometrial hypertrophy is inhibited under the effect of exposure at 24 hr of treatment. P

Tchernitchin et al. (1998b) Rat/Sprague- Dawley, 20 or 21 days old (75 mg/g bw) Pb via i.v. one time exposure at 1 or 24 before hormone stimulation Enhanced some parameters of estrogen stimulation and inhibited other estrogenic responses; interaction with responses to estrogen was different depending on whether Pb pretreatment was 1 or 24 hr before hormone stimulation; estrogenic responses mostly affected were uterine eosinophilia, endometrial edema, uterine liminal epithelial, hypertrophy, and mitosis in various, but not all, uterine cell types, in some cell types, estrogen-induced mitotic response developed earlier under the effect of Pb exposure. P

Wide (1985) Mouse/NMRI, 10 wks old 20 μg/dL/g bw Pb chloride via i.v. single exposure on days 8, 12, or 16 after mating Litter size and fetal survival varied significantly; small litters and increased numbers of fetal deaths were observed in mice exposed to Pb on day 8 of intrauterine life; live fetuses were normal with respect to weight and morphological appearance; ovarian follicle counts revealed a significantly smaller number of primordial follicles in the latter group, it suggested that the exposure to Pb at a time of early organogenesis caused the observed fertility decrease by interfering with the development of the female germ cells. P

Wide and D'Argy (1986) Mouse/NMRI, adult 20 μg/g bw by i.v. single injection on GD 8 Primordial germ cells showed a normal body distribution but were significantly fewer at all four stages compared with those of control embryos of corresponding age; Pb had interfered with the production or activity of alkaline phosphatase. P

Wiebe and Barr (1988) Rat/Sprague- Dawley, adult 20 or 200 ppm Pb chloride in drinking water; 3 exposure durations; prior to mating through weaning, GD 7 to weaning, PND 21 to PND 35 Treatment with Pb prior to mating resulted in significant increase in E2-receptor affinity in 21-day old offspring without a change in E2 receptor number; treatment from day 7 of pregnancy until weaning of the pups resulted in ~35% decrease in E2 receptors per mg uterine protein when these offspring reached 150 days of age; Pb treatment from 21–35 days old or until 150 days resulted in a significant decrease in uterine E2 receptor number at 35 and 150 day, respectively. P

W

Wiebe et al. (1988) Rat/Sprague- Dawley, adult 20 or 200 ppm Pb chloride in drinking water; 4 exposure durations; prior to mating through weaning, GD 7 to weaning, PND 21 to PND 35, prior to mating only Exposure to Pb did not affect tissue weights but did cause a significant decrease in gonadotropin-receptor binding in the pre-pubertal, pubertal, and adult females; conversion of progesterone to androstenedione and dihydrotestosterone was significantly decreased in 21-day old rats and in 150-day old females; significantly increased conversion to the 5-alpha-reduced steroids, normally high during puberty. P

2

Yu et al. (1996) Rat/Sprague- Dawley, adult Neonatal and lactational exposure to 0.3% Pb acetate in drinking water (PND 30) Neonatal exposure to Pb decreased cold-water swimming endurance (a standard test for stress endurance); delayed onset of puberty in males and female offspring, which was exacerbated by swimming stress. P

*Not including effects on the nervous or immune systems. 

† Candidate key study. 

E2, estradiol; FSH, follicle stimulating hormone; GD, gestational day; GnRH, gonadotropin releasing hormone; HET, Binghamton Heterogeneous Stock; IGF1, insulin-

i.p., intraperitoneal; LH, luteinizing hormone; NOS, not otherwise specified; PbB, blood lead concentration; PND, post-natal day; p.o., per os (oral administration); SR

steroidogenic acute regulatory protein. 
 AX5-60

ANNEX TABLES AX5-5 
 AX5-61 Table AX5-5.1. In Vivo and In Vitro Studies of the Effects of Lead Exposure on Production and Metab

Oxygen Species, Nitric Oxide, and Soluble Guanylate Cyclease Pb Exposure Measured Parameters Reference Species/ Tissue Age/Weight n Dosage Duration Pb Level CVS Other Intervention

Khalil- Manesh et al. (1994) Male SD rats 200 g N/A Pb-acetate, 100 ppm in water 6 mo 7 ± 3.6 μg/d BP, tail art. ring response to NE ET-3, cGMP DMSA RX Gonick et al. (1997) 

Male SD rats 

2 mo 

200 g 

6 Pb-acetate, 

100 ppm in water 

3 mo 12.4 ± 1.8 μg/dL BP cGMP, NO2 + 

NO3, ET-1, 

ET-3, MDA, eNOS, iNOS 

— 

Ding et al. (1998) 

Male SD rats 

2 mo N/A Pb-acetate, 

100 ppm in water 

3 mo 3.2 ± 0.2 μg/dL BP Urine NO2 + 

NO3, plasma 

MDA 

DMSA (0.5% H

H 2 wks, i.v. infusions of L. Arg., SOD and S

Vaziri (1997) Male SD 

rats 

190 g 12 Pb-acetate, 

100 ppm in water 

3 mo 17 ± 9 μg/dL BP Plasma MDA 

urine NO2 + 

NO3

Antioxidant Rx 

(Lazaroid) 

Dursun (2005) 

Male SD rats 

 24 Pb acetate 

8 mg/kg IP 

2 wks BP, RBF Ur Na, Ur 

NO2 + NO3, 

24 hr UrNa (Na+ intake 

Not given ) 
 AX5-62 Table AX5-5.1 (cont’d). In Vivo and In Vitro Studies of the Effects of Lead Exposure on Production an

Reactive Oxygen Species, Nitric Oxide, and Soluble Guanylate Cyclease Pb Exposure Measured Parameters Reference Species/ Tissue Age/Weight n Dosage Duration Pb Level CVS Other Interventio

Vaziri et al. (1999b) Male SD rats 200 g 6 per group per time point Pb-acetate, 100 ppm in water 3 mo 8.2 ± .8 and 10.8 ± 1 μg per g. Kidney tissue in untreated and antiox-treated groups BP Aorta and kidney eNOS protein abundance, Ur NO2 + NO Subgroups treated with h

dose vitamin 

Vaziri et al. (2001) Male SD rats 200 g 6 per group Pb acetate 3 mo N/A BP Aorta, heart, kidney and brain NOS isoforms, urine NO2 + NO3 Subgroups studied after 2 wks of Rx w/tempol and those studied 

wks after cessation of tempol Rx 

Vaziri and Ding (2001) Human coronary endothelial cells N/A $4 per experiment 0 and 1 ppm Pb acetate 24 hrs w/Pb or Na acetate followed by 24 hrs w/tempol or vehicle 1 ppm medium N/A eNOS expression Co-treatment w/O2• scaveng

tempol 
 AX5-63 Table AX5-5.1 (cont’d). In Vivo and In Vitro Studies of the Effects of Lead Exposure on Production an

Reactive Oxygen Species, Nitric Oxide, and Soluble Guanylate Cyclease Pb Exposure Measured Parameters Reference Species/ Tissue Age/Weight n Dosage Duration Pb Level CVS Other Interventio

Vaziri et al. (1999a) Male SD rats 200 g 6 per group 100 ppm in water 3 mo 8.3–10.8 μg/g kidney tissue BP Urine NO2 + NO3, tissue and plasma nitrotyrosine (marker of NO-ROS interaction). Antioxidant R

(Vit E) 

Vaziri et al. (2003) 

Male SD rats 200 g 6 per group 100 ppm in 

water 

3 mo N/A BP Urine NO2 + 

NO3, kidney, 

heart, brain SOD, catalase, GPX, NAD(P)H oxidase abundance 

Tempol (O2

•

scavenger infusion) 

Ni et al. (2004) 

Cultured human coronary endothelial and VSM cells. 

N/A $4 per 

experiment 

0,1 and 10 ppm Pb acetate 

Short exposure (5–30 min) 

and long exposure (60 hr) 

0, 1, 10 ppm N/A O2

• and H2O2

productions SOD, catalase, GPX and NAD(P)H oxidase (gp91phox) 

None 
 AX5-64 Table AX5-5.1 (cont’d). In Vivo and In Vitro Studies of the Effects of Lead Exposure on Production an

Reactive Oxygen Species, Nitric Oxide, and Soluble Guanylate Cyclease Pb Exposure Measured Parameters Reference Species/ Tissue Age/Weight n Dosage Duration Pb Level CVS Other Interventio

Ding et al. (2001) Male SD rats 2 mo 200 g N/A 100 ppm 3 mo Blood Pb 12.4 ± 1.8 μg/dL vs. 1 mg/dL in controls BP Response to DMTU administration, tissue nitrotyrosine, hydroxyl radical i.v. infusion o

DMTU 

Ding et al. (2000) 

Cultured rat aorta endothelial cells 

N/A $4 

experiment 

0–1 ppm 1, 2, 24, 84 hr 0–1 ppm culture 

media 

N/A Hydroxyl radical 

production using the following reaction (Na Salicylate + OH → 2,3dihydroxy benzoic acid), MDA 

None 

Attri (2003) Male Wistar 

Kyoto rats 

150–200 g 10 per 

group 

Pb acetate, 100 ppm in water ±Vit C 20 mg/d/rat 

1–3 mo Blood Pb 

1.5 mg/dL at 1 mo 2.4 mg/dL at 2 mo 4.1 mg/dL at 3 mo 

BP Total antioxidant 

capacity, ferricreducing antioxidant power, NO metabolites, MDA, 8-hydroxyguanosine 

Response to vitamin C. 

Malvezzi (2001) 

Male Wistar rats 

5–6 wks 

(170 g) 

4–10 per 

group 

Pb acetate 750 ppm in water 

100 days Blood, bone, 

kidney, aorta, liver 

BP — Response to L

arg, DMSA, Larg .+ DMSA (given togethw/Pb in last 30 days 
 AX5-65 Table AX5-5.1 (cont’d). In Vivo and In Vitro Studies of the Effects of Lead Exposure on Production an

Reactive Oxygen Species, Nitric Oxide, and Soluble Guanylate Cyclease Pb Exposure Measured Parameters Reference Species/ Tissue Age/Weight n Dosage Duration Pb Level CVS Other Interven

Khalil- Manesh et al. (1993b) Male SD rats 8 wks N/A Pb acetate 100 or 5000 ppm in water 

1–12 mo 29 ± 4 μg/dL BP, vascular 

contractility to NE in vitro 

cGMP, ET-3, ANP — 

Marques et al. (2001) 

Male Wistar rats 

3 mo 20 Pb acetate 5 ppm 

± Vit C (3 mmol/L) in water 

30 days N/A BP, arch-, SNPvasorelaxation 

response in aorta rings 

sGC protein mRNA and activity. cGMP production, eNOS protein 

CoTx with 

Farmand et al. (2005) 

Male SD rats 

200 g 8 Pb acetate 100 

ppm in water 

3 mo N/A BP Aorta sGC, SOD, 

catalase, glutathione peroxidase 

— 

Courtois et al. (2003) 

Rat thoracic aorta 

N/A 6/ 

experiment 

0–1 ppm 24 hr 0–1 ppm cGMP 

production 

sGC expression, superoxide production, COX-2 

Vit C, COXinhibitor 
 AX5-66 Table AX5-5.2. Studies of the Effects of Lead Exposure on PKC Activity, NFkB Activation, and 

Pb Exposure Measured Parameters Reference Species/ Tissue Age/ Weight n Dosage Duration Pb Level CVS Other Interven

Watts et al. (1995) Isolated rabbit mesenteric artery N/A 5–6 sets per experiment Pb acetate 10−10−10−3M Immediate (contraction) 

5−10−10−3M 

medium 

Vascular contraction 

 Preincubat

w/PKC activators, inhibitor overapamil 30–60 min 

endotheliudenudation 

RodríguezIturbe et al. (2005) 

Male SD rats 200 g 8 Pb group 

9 controls 

Pb acetate 100 ppm in drinking water 

3 mo N/A NFkB activation, 

apoptosis, Ang II positive cells, macrophage/T cell infiltration and nitrotyrosine staining in renal tissue 

 
 AX5-67 Table AX5-5.3. Studies of the Effects of Lead Exposure on Blood Pressure and Adrenergic S

Pb Exposure Measured Parameters Reference Species/ Tissue Age/ Weight n Dosage Duration Pb Level CVS Other Refere

Chang et al. (1997) Wistar rats 190–200 g 20 Pb acetate 0.5% in drinking water 2 mo Blood 29.1 ± 1.9 μg/dL aorta; 1.9 ± 0.2 μg/g BP Plasma catecholamines + aorta; β receptor binding assay and cAMP generation — Tsao et al. (2000) 

Wistar rats 190–200 g 70 Pb acetate 

0–2% in 

drinking water 

2 mo Blood, heart, 

aorta, kidney 

BP, β agoniststimulated cAMP production (10 μM isoproterenol in vitro) 

pl NEpi, cAMP β

receptor densities 

— 

Carmignani et al. (2000) 

Male SD rats 3 mo 24 60 ppm 10 mo Blood 22.8 ±

1.2 μg/dL 

BP, HR, cardiac contractility (dP/dt), blood flow 

Plasma NE, Epi, dopamine, monoamine oxidase (MAO) activity, histology 

— 
 AX5-68 Table AX5-5.3 (cont’d). Studies of the Effects of Lead Exposure on Blood Pressure and Adrener

Pb Exposure Measured Parameters Reference Species/ Tissue Age/ Weight n Dosage Duration Pb Level CVS Other Interven

Lai et al. (2002) Male SD rats 300 g Acute response In vivo: Intrathecal injection of PbCl2, 10– 100 μM. In vitro: Thoracic cord slices exposed to 5–50 μM PbCl2 — — BP, HR, (In vivo) w/without ganglionic blockade (Hexomethonium) Electophysiologi c measures (In vitro) before/after saline washout — Chang et al. (2005) Male Wistar rats 10 wks 70 2% Pb acetate (drinking water) 2 mo, observed for 7 mo after cessation Blood: 85 μg/dL Aorta: 8 μ/g/g Heart: 1 μg/g Kidney: 60 μg/g BP Plasma NE, β recaptor density (aorta, heart, kidney) Cessation 

exposure 
 AX5-69 Table AX5-5.4. Studies of the Effects of Lead Exposure on Renin-angiotensin System, Kallikrein-K

Prostaglandins, Endothelin, and Atrial Natriuretic Peptide (ANP) Pb Exposure Measured Parameters Reference Species/ Tissue Age/ Weight n Dosage Duration Pb Level CVS Other Interventio

Carmignani et al. (1999) Male SD rats Weaning 16 Pb acetate 60 ppm drinking water 10 mo Blood 24.2 ± 1.8 μg/dL BP, HR, carotid blood flow Plasma ACE, Kininase Kallikrein activities dp/dt — Sharifi et al. (2004) Male SD rats 200 g 32 Pb acetate 100 ppm drinking water 

2–8 wks — BP ACE activity in 

plasma, aorta, heart, kidney 

— 

Gonick at al. (1998) 

Male SD rats 2 mo 21 Pb acetate 

100 ppm drinking water 

12 wks — BP Urinary Tx B2, 6-

keto PGF1 

— 

Dorman and Freeman (2002) 

VSMC (rat aorta) 

— — 0.0, 0.02, 0.2, 

2.0 mg/dL 

up to 48 hrs 0.0 to 2 

mg/dL 

— Arachidonic acid 

(AA), DNA synthesis, cell proliferation + cell viability 

Ang II, FC

Giridhar and Isom (1990) 

Male SD rats 150–175 g 20 Pb acetate 0.01, 

0.01, 0.5, 1.0 mg/Kg, BiW, IP 

30 days — — ANF — 
 AX5-70 Table AX5-5.5. Studies of Effect of Lead on Vascular Contractility Pb Exposure Measured Parameters Reference Species/ Tissue Age/ Weight n Dosage Duration Pb Level CVS Other Interventi

Shelkovnikov and Gonick (2001) Rat aorta rings Pb acetate 10−8 to 10−4 Short incubations — Vasoconstriction/ vasodilation Purdy et al. (1997) Male SD rats 8 wks Pb acetate 100 ppm in water 3 mo — BP Aorta ring response to NE, phenylephrine, acetylcholine, and nitroprusside 

Oishi et al. (1996) Male Wistar rats Pb acetate 1–3 mo Mesenteric art and aorta response to acetylcholine in presence or absence of NOS inhibitor (L- NAME) 

Valencia et al. (2001) Wistar rat thoracic aorta rings 7 wks 6 sets/ experiment Pb acetate 0.1–3.1 mM Rapid response in vitro — In vitro contractile response 
 AX5-71 Table AX5-5.6. Effects of Lead on Cultured Endothelial Cell Proliferation, Angiogenesis, 

Production of Heparan Sulfate Proteoglycans and tPA Pb Exposure Measured Parameters Reference Species/ Tissue Age/ Weight n Dosage Duration Pb Level CVS Other Interventi

Kaji et al. (1995a) — 4 sets per experiment Pb nitrate 

5–50 μM 

24 hrs 

— Endothelial 

damage 

Co-incubatiowith cadmiu

Kaji et al. (1995b) 

Bovine aorta endothelial cells 

— 4–5 sets per 

experiment 

Pb nitrate 0.5–5 μM 

24 hrs 

— 3H-thymidine 

incorporation, cell count, morphology, LDH release 

Stimulation w/βFGF and αFGF 

Fujiwara et al. (1998) 

Bovine aorta endothelial cells 

— 6 set per 

experiment 

Pb nitrate 5 and 10 μM 

48 hrs 

— Appearance of 

cells in denuded areas of monolayer, DNA synth 

Stimulation w/Zn 

Kishimoto et al. (1995) 

Humanumbilical vein endothelia cells 

— 3 sets per 

experiment 

Pb acetate 1–100 

FM 

24 hrs 

— Formation of 

tube-like structures (angiogenesis assay, on Matrigel (BM) 

— 

Ueda D. et al. (1997) 

Human umbilical vein endothelial cells 

— 3 sets per 

experiment 

Pb acetate 1–100 μM 

24 hrs — Tube formation 

on Matrigel matrix 

PKC activatand inhibito
 AX5-72 Table AX5-5.6 (cont’d). Effects of Lead on Cultured Endothelial Cell Proliferation, Angiogen

Production of Heparan Sulfate Proteoglycans and tPA Pb Exposure Measured Parameters Reference Species/ Tissue Age/ Weight n Dosage Duration Pb Level CVS Other Interventi

Fujiwara and Kaji (1999) Bovine aorta endothelial cells 

— 4 sets per 

experiment 

Pb nitrate 0.5, 1, 2 μM 

12–48 hrs βFGF production/ 

distribution Heparan sulfate production (sulfate incorporation) DNA synthesis (cell proliferation) βFGF binding assay 

Heparin, AnβFGF antibo

Kaji et al. (1991) 

Bovine aorta endothelial cells 

— 4–5 sets per 

experiment 

Pb nitrate 0, 1–20 μM 

24–48 hrs Glycosaminoglycan 

(GAG) synthesis (sulfate incorporation) 

Kaji et al. (1997) 

Bovine aorta endothelial cells (confluent) 

— N/A Pb chloride 

10 M 

24 hrs N/A Synthesis of heparan 

sulfate proteoglycans (HSPGs) and their core proteins 
 AX5-73 Table AX5-5.6 (cont’d). Effects of Lead on Cultured Endothelial Cell Proliferation, Angiogen

Production of Heparan Sulfate Proteoglycans and tPA Pb Exposure Measured Parameters Reference Species/ Tissue Age/ Weight n Dosage Duration Pb Level CVS Other Interventi

Fujiwara and Kaji (1999) Bovine aorta endothelial cells (growing 10% BCS) 

— 4 sets per 

experiment 

Pb nitrate 0.1 μM 

48 hrs Sulfate and 

glucosamine incorporation in GAGs, quantification of high and low MW-HSPG, identification of perlecan core protein 

Kaji et al. (1992) 

Human umbilical vein endothelial cells (confluent) 

— 5 sets per 

experiment 

0.01–1 μM t-PA release, DNA 

synth, protein synth (leucine incorporation) 

Thrombin anET-1 stimulations 
 AX5-74 Table AX5-5.7. Studies of the Effect of Lead on Cultured Vascular Smooth Muscle Cel

 Pb Exposure Measured Parameters Reference Species/ Tissue Age/ Weight n Dosage Duration Pb Level CVS Other ReferenFugiwara et al. (1995) Bovine aorta vascular smooth muscle cell 4 sets per experiment Pb nitrate 0.5–10 μM 24 hrs — DNA synthesis Coincubat

w/βFGF, αFGF. pDG

Carsia et al. (1995) 

Rat aorta VSMC cells (80–90% 

confluent) 

$3 sets per experiment 

Pb citrate 100 and 500 μg/L 

Time to confluence (~90% for control experiments) 

Cell density (cell #/Cm2), cell 

morphology, membrane lipid analysis, receptor densities (Ang-II, α, β, ANP 

Yamamoto et al. (1997) 

Human aorta VSMC and fetal lung fibroblasts (confluent) 

5 sets per experiment 

Pb chloride 0.5–10 μM 

24 hrs t-PA and PAI-1 

release 
 AX5-75

ANNEX TABLES AX5-6 
 AX5-76 Table AX5-6.1. Genotoxic/Carcinogenic Effects of Lead—Laboratory Animal Studies Compound Dose and Duration Cell Type Co-exposure Effects 

Pb acetate 0.5, 5, or 25 ppm given in drinking water–duration not given. Number of animals per group was not given. Female C3HSt mice infected with MMTV (Murine mammary tumor virus)–age not given Selenium, 0.15– 1 ppm (duration not given) in diet ( Se prevents spontaneous tumors in these mice) Pb acetate exposed mice exhibited greater mortality un

the tumor formation. 25 ppm suppressed tumor formation, but increased the aggressiveness of the tumors. 5 ppm increased tumor formation, but had no effect on rates. 0.5 ppm with low selenium exhibited 80% tumor formreduced weight gains that recovered. 0.5 ppm with high selenium exhibited normal weight gtumor incidence still reached 80%. Control data described as “significantly lower” but not 

Methods poorly described and data not shown. 

Pb acetate 0–4000 ppm given in drinking water for 104 wks. Wild type (WT) and metallothionine null (MT null) mice None Renal proliferative lesions were much more common a

in MT null mice than WT mice. MT null mice could nrenal inclusion bodies even with prolonged Pb exposur

could have contributed to increase in the carcinogenic of Pb. 

Pb acetate 50, 250, or 1000 ppm given in drinking water for 15 wks. Number of mice per group in initial exposures not given. Number of mice at analysis ranged from 19–25. Female albino Swiss Mice–3 wks old Urethane 1.5 mg/g given i.p. No signs of Pb poisoning. No Pb effects on growth or 

gain. Urethane added to induce lung tumors. Pb did not affect urethane metabolism. Pb did not affect number of tumors or affect tumor sizePb alone was not evaluated. Pb levels did increase in tissues. 
 AX5-77 Table AX5-6.1 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Laboratory Animal Stu

Compound Dose and Duration Cell Type Co-exposure Effects Pb acetate 50 or 1000 ppm 50 or 1000 ppm given in drinking water for 280 days. Number of mice pre group in initial exposures not given. Number of mice at end were 50 per dose. Female albino Swiss Mice–8 wks old None Mice have high rate of spontaneous leukemia from end

infection. No signs of Pb poisoning. No Pb effects on growth or gain. Pb did increase leukemia-related mortality possibly duimmunosuppression. Pb levels did increase in tissues. Data indicate that Pb may be immunosuppressive, thouexact mechanism is not understood. 

Pb acetate 60 mg/kg injected s.c. weekly for 5 wks followed by observation for 80 wks. 13 treated and 14 control rats. Fisher F344/NSle rats– 3 wks old None Pb induced tumors at the site of injection in 42% of rat

though data was not shown. Control data not indicated or shown. Pb accumulated in tumor tissue, tooth, and bone. This was shown. 

Pb acetate 1 or 100 μg/L given in the drinking water for 31 wks 8 animals per group Male Wistar Rats— weanlings 0.2–4 % calcium carbonate given in the diet for 31 wks. No differences in drinking water or food consumption. High Pb and high calcium reduced growth. No deaths in low calcium groups. 10/24 rats from high calcium diet died (4 from controls 

each from Pb groups). All 10 had kidney or bladder st0/8 rats in low calcium no Pb had kidney pathology 2/8 rats in low calcium low Pb had nephrocalcinosis. 7/8 rats in low calcium high Pb had nephrocalcinosis. 3/4 rats in high calcium no Pb had nephrocalcinosis. 1/5 rats in high calcium low Pb had a renal pelvic carci3/5 rats had nephrocalcinosis. 3/5 rats in high calcium high Pb had transitional cell hyperplasia. 2/5 rats had invasive renal pelvic carcinomPb tissue levels were same regardless of dietary calcium levels. 
 AX5-78 Table AX5-6.2. Genotoxic/Carcinogenic Effects of Lead—Human Cell Cultures Compound Dose and Duration Cell Type Co-exposure Effects 

Pb chromate Anchorage Independence (0.1–1 μM for 48 h) Human Foreskin Fibroblasts In H-MEM +15% FCS None Pb chromate-induced concentration-dependent increase i

anchorage independence. 

Pb chromate Anchorage Independence (0.1–1 μM for 48 h) Human Foreskin Fibroblasts In H-MEM +15% FCS None Pb chromate-induced concentration-dependent increase i

anchorage independence. 

Pb chromate Morphological Transformation (2 μg/mL for 24 h, performed 3 times immediately after passage) Anchorage Independence (0.2– 2 μg/mL or cells isolated during morphological transformation) Neoplastic Transformation (cells isolated during morphological transformation) HOS TE 85 in DMEM + 10% FBS None Pb chromate induced foci of morphological transformati

after repeated exposure and passaging. Pb chromate did not induce anchorage independence, bucells from the foci obtained during morphological transformation. Pb chromate did not induce neoplastic transformation in cells from the foci obtained during morphological transformation. Studied as a chromate compound. Role of Pb not mentioor considered. 

Pb acetate Anchorage Independence (500–2000 μM for 24 h) Human Foreskin Fibroblasts (Chinese) In DMEM +10% FCS 3-aminotriazole (3-AT) (80 mM to inhibit catalase) Pb acetate-induced concentration-dependent increase in anchorage independence. Anchorage independence not affected by 3-AT. 
 AX5-79 Table AX5-6.3. Genotoxic/Carcinogenic Effects of Lead—Carcinogenesis Animal Cell Cul

Compound Dose and Duration Cell Type Co-exposure Effects Pb acetate Morphological Transformation (10–50 μM for 48 h) Primary SHE cells in AMEM + 10% FBS None Pb acetate was weakly positive inducing a 0.19–1.6% increase in transformation. There was a weak dose response. There were no statistical analyses of these dPb chloride Morphological Transformation (doses not given) C3H10T1/2 cells in EMEM +10% FBS None Pb chloride did not induce morphological transformatiPb chromate Enhancement of Simian Adenovirus (SA7) induced morphological transformation. (80–1,240 μM for 20 h) Primary SHE cells in DMEM + 10% FBS None Pb chromate enhanced SA7-induced morphological transformation. Studied as a chromate compound. Role of Pb not mentioned or considered. 

Pb chromate Morphological Transformation (10–50 μM for 24 h) Anchorage Independence for cells isolated during morphological transformation Neoplastic Transformation for cells isolated during morphological transformation. C3H10T1/2 cells in EMEM + 10% FBS None Pb chromate induced morphological and neoplastic transformation. Cells exhibiting morphological transformation grew in 

agar and grew in nude mice. Studied as a chromate compound. 

Pb chromate (and pigments containing Pb chromate) Morphological Transformation (0.04–8 μg/mL as Cr for 7 days) Anchorage Independence for cells isolated during morphological transformation Neoplastic Transformation for cells isolated during morphological transformation Primary SHE cells in DMEM + 10% FCS None Pb chromate induced morphological and neoplastic transformation. Cells exhibiting morphological transformation grew in 

agar and grew in nude mice. Studied as a chromate compound. 

Pb chromate Morphological Transformation (0.02–0.88 μg/mL as Cr for 7 days) Primary SHE cells in DMEM + 10% FCS None Pb chromate induced morphological transformation mo

potently (9-fold) than other chromate compounds. 
 AX5-80 Table AX5-6.3 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Carcinogenesis Animal Cell 

Compound Dose and Duration Cell Type Co-exposure Effects Pb nitrate Morphological Transformation (0.04–8 μg/mL as Cr for 7 days) Primary SHE cells in DMEM + 10% FCS Calcium chromate Pb nitrate alone did not induce significant levels of transformation. Pb nitrate plus calcium chromate increased the potency 

calcium chromate to that of Pb chromate. Data suggesions are synergistic with chromate ions in inducing neoplastic transformation. 

Abbreviations Cells SHE—Syrian hamster embryo; C3H10T/12 cells are a mouse embryo cell line Medium and Components AMEM—Alpha Minimal Essential Medium; DMEM—Dulbecco’s Minimal Essential Medium; EMEM—Eagle’s Minimal Essential Medium; FBS—Fetal Bovine Serum FCS—Fetal Calf Serum H-MEM—Minimum essential medium/nutrient mixture–F12-Ham HOS TE—Human osteosarcoma cell line TE Differences between the serum are unclear as insufficient details are provided by authors to distinguish.
 AX5-81 Table AX5-6.4. Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Laboratory Animal S

Compound Dose and Duration Species Co-exposure Effects Pb acetate 2.5 mg/100 g given i.p. as daily injection for 5– 15 days or 10–20 mg/100 g given i.p. as single injection and animals studied after 15 days 5 animals per group. Chromosome damage in bone marrow Female Norway Rat Selenium (0.012– 0.047 mg/100g or 0.094–0.188 mg/100 g given i.p. with Pb) Pb induced chromosome damage after chronic treatme

was not dose dependent as only 1 dose was studied. Theffects of selenium on Pb effects are unclear as seleniualone induced substantial chromosome damage. The single dose exposure also induced chromosome dabut untreated controls were not done in this regimen. Tis some mention that this dose regimen is toxic to the aas selenium modulated the lethal effects, but no explanof how many animals died. 

Pb acetate 25–400 mg/kg given i.p. as single injection and animals studied after 24 h For some chromosome damage studies animals were treated with 25– 200 mg/kg given i.p. as a series of 3, 5, or 7 daily injections and animals studied after 24 h after the last injection. 5 animals per group. Chromosome damage, sister chromatid exchange, in bone marrow and spermatocytes. Male Swiss Mice, 

9–12 wks old 

None Pb induced chromosome damage in a dose dependent m

at 100–400 mg/kg after a single dose or repeated does 

exposure in bone marrow cells. In spermatocytes, Pb also induced chromosome damagdose dependent manner at 50–400 mg/kg after a single 

or repeated dose exposure in bone marrow cells. Pb induced SCE at 50 and 100 mg/kg. A lower dose wnegative and higher doses were not done. 

Pb acetate 200 or 400 mg/kg given by 

gavage daily for 5 days 5 animals per group Chromosome aberrations in bone marrow and spermatocytes. 

Male Swiss Mice, 9–12 wks old 

Calcium chloride (40 or 80 mg/kg by gavage daily for 3 days given 2 wks after Pb exposure) 

Pb induced chromosome damage at both 200 and 400 min bone marrow cells and spermatocytes. Calcium appto block this effect. 
 AX5-82 Table AX5-6.4 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Laboratory Anim

Compound Dose and Duration Species Co-exposure Effects Pb nitrate 100–200 mg/kg given i.v. on 9th day of gestation onwards for 9 days. Mothers and fetuses analyzed on G18. Group size not given. Resorptions, fetal viability and chromosome damage, SCE and NOR in the mother and fetus were examined. Mother–bone marrow; fetus liver or lung 3 mothers and fetuses per dose were analyzed. ICR Swiss Webster Mice, 

6–8 wk old 

None Pb levels were found in both mother and fetus indicatin

problems crossing the placenta. All doses indicated increased resorption and decreased placental weights. No effects on fetal weight. Significant increase in SCE in mothers at 150 and 200 No increase in SCE in fetuses. Significant decrease in NOR in both mother and fetuseNo gaps or breaks in mothers or fetuses. Some weak aneuploidy at lowest dose. Some karyotypic chromosome damage was seen. No explanation of how many cells analyzed per anima(3 animals per dose were analyzed) as only 20– 40 cell

analyzed. There was no dose response and no statistical analyses chromosome damage. No details on how many animalanalyzed for metaphase damage or how many cells per animal. Data interpretation is also complicated as too few metawere analyzed 10–25 for SCE. Not given for CA. 

No detail on potential maternal toxicity. 

Pb nitrate 10, 20, or 40 mg/kg given 

i.p. 24 h 6 animals per group. Chromosome damage and Mitotic Index in bone marrow 

Swiss Albino Mice, 8 wks old 

Phyllanthus fruit extract (685 mg/kg) or ascorbic acid (16.66 mg/kg) given by gavage for 7 days 

Pb nitrate increased the amount of chromosome damageach dose. But there was no dose response and a simillevel of damage was seen for each dose. Phyllanthus fruit extract reduced the amount of damageach dose. Ascorbic acid reduced the damage at the lodose but increased it at the higher doses. Higher concentrations of Pb nitrate reduced the mitotic This effect was reversed by ascorbate and Phyllanthus the moderate dose. 

Pb nitrate 5, 10, or 20 mg/kg given 

i.p. 24 h 6 animals per group. Chromosome damage in bone marrow. 50 metaphases per animal for a total of 300 (X6). 

Swiss Albino Mice, 8 wks old 

Ferric chloride (18 mg/kg) given i.p. for 24 h administered 1 h before, 1 h after, or together with Pb nitrate 

Pb nitrate increased the amount of chromosome damagdose-dependent manner. Iron exhibited some modifications of Pb induced damaIf administered 1 h before Pb plus simultaneously it rethe damage. If administered with Pb only at same time reduced damage in the lower doses. If Pb was started before iron there was no effect. Thus iron may antagonize Pb perhaps by blocking upta
 AX5-83 Table AX5-6.4 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Laboratory Anim

Compound Dose and Duration Species Co-exposure Effects Pb nitrate 5 or 10 mg/kg given by gavage for 24 h 6 animals per group. Chromosome aberrations in bone marrow Swiss Albino Mice, 

7–8 wks old 

Zirconium oxychloride (110 or 220 mg/kg) given by gavage for 24 h administered 2 h before, 2 h after or together with Pb nitrate 

Pb nitrate increased the amount of chromosome damagdose-associated manner. Zirconium induced a dose-associated increase in chromosome damage. Zirconium exhibited minimal modification of Pb nitratinduced damage when administered 2 h before or after nitrate. Administering the two together increased the damage. 

Pb nitrate 10, or 20 mg/kg given i.p. 

48 h 12 animals per group. Micronucleus formation in bone marrow 

Swiss Albino Mice, 6 wks old 

Phyllanthus fruit extract (685 mg/kg) or ascorbic acid (16.66 mg/kg) given by gavage for 7 days 

Pb nitrate increased the amount of micronuclei at both in a dose-associated manner. The 48 h recovery time wlower than 24 h but still elevated. Phyllanthus fruit extract reduced the amount of damagboth doses. Ascorbic acid reduced the damage at the lodose but increased it at the higher dose. 

Pb nitrate 10, 20, or 40 mg/kg given 

i.p. 24 h 5 animals per group. SCE in bone marrow 

Swiss Albino Mice, 6–8 wks old 

Phyllanthus fruit extract (685 mg/kg) or ascorbic acid (16.66 mg/kg) given by gavage for 7 days 

Pb nitrate increased the amount of SCE in a dose-depemanner. Pb nitrate had no effect of the proliferative raindex (consideration of metaphases in different divisionumbers) Phyllanthus fruit extract and ascorbic acid reduced the amount of damage at each dose. 

Pb nitrate 0.625–80 mg/kg given i.p. 

for 12, 24 or 36 h 12 animals per group Micronucleus formation in bone marrow. 4000 erythorocytes scored per animal 

Swiss Albino Mice, 6–8 wks old 

None Pb nitrate induced micronuclei but they did not increas

dose. Pb induced more micronuclei in males than in femalesThe ratio of polychromatic to normochromatic erythrowas elevated in Pb nitrate treated cells, but again did nincrease with dose. 

Pb nitrate 0.7–89.6 mg/kg given by 

gavage for 24, 48, or 72 h, or 1 or 2 wks 5 animals per group. Cell viability by trypan blue Single strand breaks in white blood cells 

Swiss Albino Mice, 4 wks old 

None Viability was high (92–96%) at all doses. 

Pb nitrate induced single strand breaks but they did not increase with dose. In fact the 3 highest doses were all similar in magnitude and less than the 5 lowest doses. The 5 lowest doses were also similar in magnitude. 
 AX5-84 Table AX5-6.4 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Laboratory Anim

Compound Dose and Duration Species Co-exposure Effects Pb acetate 10 mg/kg given by gavage 5 times a week for 4 wks. 10 animals per group Chromosome Aberrations with 20 metaphases scored per animal Male Wistar rats, 30 days old Cypermethrin No effects on weight gain. Pb acetate induced an increase in aneuploidy, and the p

of cells with damage, but did not increase structural daor alterations in organ weight. Cypermethrin and Pb together increased structural aberrations that were predominately acentric fragmentsHowever, this was compared to untreated controls and individual treatments. Considering the individual treatthe two together are less than additive. 
 AX5-85 Table AX5-6.5. Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Human Cell Cultures M

Compound Dose and Duration Cell Type Co-exposure Effects Pb acetate, In vitro Cytotoxicity–tritium incorporation (0.1– 100 μM/mL for 2–24 h) Mutagenesis–HPRT modified to labeling of 6-thioguanine resistant cells (0.1–100 μM/mL for 

2–24 h) 

Human Keratinocytes pooled in MEM and low calcium MEM + 2% FBS 

None Decrease in tritium incorporation at 10–100 μM/mL. 

6 μM/L was selected as the concentration to study as trincorporation was highest and greater than control. Tritium incorporation in the presence of 6-thioguanine was optimal after 4 h Pb acetate exposure and 5 days oexpression time. It was concluded that the significant increase relative to control indicated mutations. The argument made was that because these cells are TG resthey must be mutated. However, this argument was noproven by sequencing or colony formation in TG. 

Pb acetate Cytotoxicity (500–

2,000 μM for 24 h) Mutagenicity–HPRT assay (500–2,000 μM for 24 h) 

Human Foreskin Fibroblasts (Chinese) in DMEM +10% FCS 

3-aminotriazole (3-AT) (80 mM to inhibit catalase) 

LC50 = 500 μM. Cytotoxicity not affected by 3-AT. Pb acetate was not mutagenic. Mutagenicity not affected by 3-AT. 

Pb chromate Mutagenicity as 6-

thioguanine resistance (0.25–1 μM for 24 h) 

Human Foreskin Fibroblasts In EMEM +15% FCS 

None Pb chromate was not mutagenic. 

Abbreviations

Medium and Components MEM—Minimal Essential Medium; DMEM—Dulbecco’s Minimal Essential Medium; EMEM—Eagle’s Minimal Essential Medium; FBS—Fetal Bovine Serum FCS—Fetal Calf Serum Differences between the serum types are unclear as insufficient details are provided by authors to distinguish. 
 AX5-86 Table AX5-6.6. Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Human Cell Cultures Cl

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb chromate Chromosome aberrations (0.08–2 μg/cm2 for 24 h) Human Foreskin Fibroblasts (Caucasian) in EMEM + 15% FBS None Pb chromate induced chromosome damage in a concentration dependent manner. This study was focused on chromate. Pb chromate Chromosome aberrations (0.1–5 μg/cm2 for 24 h) Primary Human Lung Cells in DMEM/F12 + 15% FBS None Pb chromate induced chromosome damage in a concentration dependent manner. This study was focused on chromate. 

Pb chromate Chromosome aberrations (0.1–5 μg/cm2 for 24 h) Primary Human Lung Cells and WTHBF-6—human lung cells with hTERT in DMEM/F12 + 15% FBS None Pb chromate induced chromosome damage in a concentration dependent manner. Effects were si

both cell types establishing the WTHBF-6 cells amodel. This study was focused on chromate. 

Pb chromate Chromosome aberrations (0.1–5 μg/cm2 for 24 h) WTHBF-6—human lung cells with hTERT in DMEM/F12 + 15% CCS Vitamin C (2 mM co-exposure for 24 h) Pb chromate induced chromosome damage in a concentration dependent manner. Vitamin C blocked Cr ion uptake and the chromo

damage after Pb chromate exposure. This study was focused on chromate. 

Pb chromate Chromosome aberrations (0.05–5 μg/cm2 for 24 h) WTHBF-6—human lung cells with hTERT in DMEM/F12 + 15% CCS Vitamin C (2 mM co-exposure for 24 h) Pb chromate induced chromosome damage in a concentration dependent manner. This study was focused on showing chromate and 

ions were the clastogenic species. 

Pb chromate Chromosome aberrations (0.05–5 μg/cm2 for 24 h) WTHBF-6—human lung cells with hTERT in DMEM/F12 + 15% CCS None Pb chromate induced chromosome damage in a concentration dependent manner. This study was focused on comparing particulate 

compounds. 
 AX5-87 Table AX5-6.6 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Human Cell Culture

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb glutamate Pb ion uptake–ICPMS (250–2,000 μM for 24 h) Chromosome Aberrations (250–2,000 μM for 24 h) WTHBF-6—human lung cells with hTERT in DMEM/F12 + 15% CCS None Pb glutamate induced a concentration-dependent 

intracellular Pb ions. Pb glutamate did not induce chromosome damag

Pb glutamate Pb ion uptake–ICPMS (250–2,000 μM for 24 h) Mitotic Index (250–2,000 μM for 24 h) Growth Curve (250–2,000 μM for 24 h) Cell cycle Analysis (250–2,000 μM for 24 h) WTHBF-6—human lung cells with hTERT in DMEM/F12 + 15% CCS None Pb glutamate induced a concentration-dependent 

intracellular Pb ions. Pb glutamate increased the mitotic index, but inhgrowth and did not induce chromosome damage. Radioactive Pb ions No further specification LET = 13,600keV/μM Fluence of 2 H 106 particles/ cm2 Chromosome Aberrations Human Foreskin Fibroblasts in DF-12 + 10% FCS None Pb induced chromosome damage that recurred with time and cell passaging. Analysis limited to ~25 metaphases. Focused on radioactive effects of Pb 

Abbreviations hTERT is the catalytic subunit of human telomerase Medium and Components EMEM—Eagle’s Minimal Essential Medium DMEM/F12—Dulbecco’s Minimal Essential Medium/Ham’s F12 CCS—Cosmic Calf Serum FBS—Fetal Bovine Serum FCS—Fetal Calf Serum Differences between the serum types are unclear as insufficient details are provided by authors to distinguish. 
 AX5-88 Table AX5-6.7. Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Human Cell Cultures DN

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb acetate DNA strand breaks as nucleiod sedimentation (500 μM for 20– 25 h) HeLa Cells in AMEM + 5% FBS None See also Table AX5-6.16 Pb acetate alone did not induce single strand breaks. Pb acetate DNA strand breaks as nucleoid sedimentation assay (100 μM for 30 min–4 h) HeLa Cells in HEPES/ glucose buffer Buthionine sulfoximine (BSO) to deplete cells of thiols Pb acetate did not induce DNA strand breaks. 

Pb chromate DNA adducts (0.4–0.8 μg/cm2 for 24 h) Primary Human Small Airway Cells in Clonetics growth medium None Pb chromate induced Pb inclusion bodies and Cr-DNA add

Pb-DNA adducts in a concentration-dependent manner. 

Pb chromate DNA double strand breaks (0.1–5 μg/cm2 for 24 h) by Comet assay and H2A.X foci formation WTHBF-6—human lung cells with hTERT in DMEM/F12 + 15% CCS None Pb chromate induced DNA double strand breaks in a conce

dependent manner. This study showed the damage was due to chromate and n

Pb acetate DNA strand breaks and DNA protein crosslinks and oxidative lesions by comet assay (1– 100 μM for 1 h) Primary lymphocytes in RPMI 1640 without serum Vitamins A (10 μM), C (10 μM), E (25 μM), calcium chloride (100 μM) magnesium chloride (100 μM) or zinc chloride (100 μM) Pb acetate induced an increase in DNA single strand break

that went down with increasing dose. The highest concentsignificantly less than the damage in untreated controls. Fstrand breaks, all concentrations had more damage than the but there was less damage in the highest concentrations thalower ones. Pb only induced a slight increase in the amou

protein crosslinks at the highest concentration. Co-exposure to magnesium had no effect. Co-exposure to C, and E or zinc exacerbated the DNA single strand break highest concentration. Co-exposure to calcium exacerbatestrand break effect at all concentrations. 
 AX5-89 Table AX5-6.7 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Human Cell Culture

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb nitrate DNA-protein crosslinks by SDS precipitation (1–10 mM for 6 h) Human Burkitt’s lymphoma cells–EBV transformed in RPMI 1640 + 10% FCS None Pb nitrate did not induced DNA protein crosslinks. Indepe

samples were analyzed by 5 different laboratories. 

Abbreviations hTERT is the catalytic subunit of human telomerase. Medium and Components AMEM—Alpha Minimal Essential Medium; EMEM—Eagle’s Minimal Essential Medium; DMEM/F12—Dulbecco’s Minimal Essential Medium/Ham’s F12; FBS—Fetal Bovine Serum FCS—Fetal Calf Serum Differences between the serum types are unclear as insufficient details are provided by authors to distinguish. 
 AX5-90 Table AX5-6.8. Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Animal Cell Cultures M

Compound Assay and Duration Cell Type Co-exposure Effects Pb acetate Cytotoxicity (1–25 μM for 24 h) Mutagenesis—HPRT (0.5–5 μM for 44 h) V79 in AMEM + 10% FBS None See also Table AX5-6.16 LC50 = 3 μM Pb acetate alone was not mutagenic. Pb acetate —insoluble precipitate at high dose. Cytotoxicity (0.5–2000 μM for 5 days) Mutagenesis—gpt (0.5–1700 μM for 5 days) G12–CHV79 cells with 1 copy gpt gene in Ham’s F12 + 5% FBS See also Table AX5-6.17 LC50 = 1700 μM Pb acetate was mutagenic, but only at toxic concentration (1700 μM) where precipitate 

not at lower concentrations (500 or 1000 μMThere were no statistical analyses of these d

Pb chloride Cytotoxicity (0.1–1 μM for 1 h) Mutagenicity—gpt assay (0.1–1 μM for 1 h) AS52-CHO-gpt, lack hprt in HBSS followed by Ham’s F12 + 5% FBS None LC74 = 1 μM (maximum concentration test

Pb chloride induced a dose-dependent increthe number of 6 thioguanine resistant mutanDid not adjust and compare as previous stud

Pb chloride Cytotoxicity (0.1–1 μM for 1 h) Mutagenicity—gpt assay (0.1–1 μM for 1 h) AS52-CHO-gpt, lack hprt in HBSS followed by Ham’s F12 + 5% FBS Allopurinol (50 μM) to inhibit xanthine oxidase LC74 = 1 μM. Allopurinol had no effect on cytotoxicity. Pb chloride was mutagenic (0.8 and 1 μM). Allopurinol reduced mutagenesis. Pb chloride Mutagenicity—gpt assay (0.1–1 μM for 1 h) PCR/Southern to analyze mutants for sequence AS52-CHO-gpt, lack hprt in HBSS followed by Ham’s F12 + 5% FBS None Pb chloride (0.1–0.4 μM) caused mostly po

mutations. Higher concentrations (0.5–1 μ

caused more deletions. There were no statistical analyses of these dUsually examined fewer mutations than con

Pb chromate Cytotoxicity (10–100 μM for 24 h) HGPRT assay (10–100 μM for 24 h) V79 CHL–HPRT low clone in MEM + 10% FCS NTA Mutagenesis was assessed with HGPRT ass

chromate was not mutagenic. Co-exposure to NTA caused Pb chromate to become mutagenic through increased solubThis mutagenic effect was completely attribthe Cr(VI) ions. 

Pb chromate Mutagenicity as Sodium/potassium ATPase (ouabain resistance) or 6-thioguanine resistance (25–100 μM for 5 h) C3H10T1/2 cells in EMEM + 10% FBS None Pb chromate was not mutagenic. 
 AX5-91 Table AX5-6.8 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Animal Cell Culture

Compound Assay and Duration Cell Type Co-exposure Effects Pb nitrate Precipitate at 1000 μM and higher. Cytotoxicity (50–5,000 μM for 5 days) Mutagenesis at HPRT locus (50–2,000 μM for 5 days) V79 CHL–HPRT low clone in Ham’s F12 +10% FBS None LC50 = 2950 μM Pb nitrate was mutagenic at 500 μM, but th

no dose response as higher doses less mutagthough still 2–4-fold higher. There were no statistical analyses of these data. 

Pb nitrate -no insoluble precipitate Cytotoxicity (0.5–2000 μM for 5 days) Mutagenesis—gpt (0.5–1700 μM for 5 days) G12–CHV79 cells with 1 copy gpt gene in Ham’s F12 + 5% FBS See also Table AX5-6.17 LC 50 = 1500 μM Pb nitrate was not mutagenic. There were n

statistical analyses of these data. 

Pb sulfide Cytotoxicity (100–1,000 μM for 24 h) Mutagenicity at HPRT locus (100–1,000 μM for 24 h) V79 CHL–HPRT low clone in Ham’s F12 +10% FBS None LC50 = 580 μM; did not increase with long

exposures. Mutagenic at 376 and 563 μM. Not mutagelower or higher. Suggested cytotoxicity premutagenesis at higher concentrations. Therno statistical analyses of these data. 

Abbreviations V79 are a Chinese Hamster Lung Cell Line; G12–CHV79 are derived from V79; CHO are a Chinese Hamster Ovary Cell Line ; AS52 are derived from CHO; C3H10T/12 cells are a mouse embryo cell line Medium and Components AMEM—Alpha Minimal Essential Medium; EMEM—Eagle’s Minimal Essential Medium; HBSS—Hank’s Balanced Salt Solution FBS—Fetal Bovine Serum FCS—Fetal Calf Serum Differences between the serum types are unclear as insufficient details are provided by authors to distinguish. 
 AX5-92 Table AX5-6.9. Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Animal Cell Cultures Cla

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb chromate Chromosome Aberrations (0.4–8 μg/cm2 for 24 h) Chinese Hamster Ovary AA8 cells in AMEM + 10% FBS None Pb chromate induced chromosome damage 

concentration dependent manner. This study was focused on chromate. 

Pb chromate Chromosome Aberrations (0.8–8 μg/cm2 for 24 h) Chinese Hamster Ovary AA8 cells in AMEM + 10% FBS Vitamin C (1 mM for 24 h as co-exposure to block Cr uptake) Pb chromate induced chromosome damage 

concentration dependent manner. This effeof Cr ions were blocked by vitamin C. This study was focused on chromate. 

Pb chromate Chromosome Aberrations (0.8 or 8 μg/cm2 for 24 h) Chinese Hamster Ovary AA8 cells in AMEM + 10% FBS Vitamin E (25 μM as pretreatment for 24 h) Pb chromate induced chromosome damage 

concentration dependent manner. Vitamin 

clastogenic activity of Pb chromate, but had other Pb compounds. This study found that the chromosome dammediated by chromate ions and not Pb ions 

Pb chromate Chromosome Aberrations (0.8–8 μg/cm2 for 24 h) Chinese Hamster Ovary AA8 cells in AMEM + 10% FBS Vitamin C (1 mM as pretreatment for 24 h) Vitamin E (25 μM as pretreatment for 24 h) Pb chromate induced chromosome damage 

concentration dependent manner. Vitamins 

blocked clastogenic activity of Pb chromateThis study was focused on chromate. 

Pb glutamate Chromosome Aberrations (500–2,000 μM for 24 h) Chinese Hamster Ovary AA8 cells in AMEM + 10% FBS Vitamin E (25 μM as pretreatment for 24 h) Pb glutamate induced chromosome damage 

not at higher or lower concentrations. Vitamin E did not modify this effect. 

Pb nitrate Chromosome Aberrations (500–2,000 μM for 24 h) Insoluble precipitate at all concentrations Chinese Hamster Ovary AA8 cells in AMEM + 10% FBS Vitamin E (25 μM as pretreatment for 24 h) Pb nitrate did not induce chromosome damaPb nitrate Chromosome Aberrations (3–30 μM for 2 h +16 h recovery) Chinese Hamster Ovary cells in EMEM + 10% FBS None Pb nitrate did not induce chromosome dama

Pb nitrate Chromosome aberrations (0.05–1 μM for 3–12 h) Chinese Hamster Ovary AA8 cells in DMEM +10% NCS Crown ethers to modify effect through chelation and uptake Pb nitrate did not induce chromosome dama
 AX5-93 Table AX5-6.9 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Animal Cell Culture

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb acetate SCE (1–10 μM for 26 h+) V79 in AMEM + 10% FBS None See also Table AX5-6.17 Pb acetate alone did not induce SCE. Only 

treatment analyzed. 

Pb acetate Micronucleus assay (0.01–10 μM for 18 h) Chinese Hamster V79 cells in DMEM + 10% FCS None Pb acetate induced an increase in micronuc

increased with concentration and reached a Two experiments were done and presented Figure and a Table. The magnitude of the esmall to modest and statistics were not done

Pb nitrate SCE Formation (500–3,000 μM for 24 h) Precipitate at 1000 μM and higher. V79 CHL–HPRT low clone in Ham’s F12 +10% FBS None No SCE. Only 30 cells analyzed per treatm

Pb nitrate Micronucleus formation (3–30 μM for 2 h +16 h recovery) SCE (3–30 μM for 2 h +16 h recovery) CHO cells in EMEM + 10% FBS None Pb nitrate did not induce micronuclei forma

Pb nitrate induces a concentration-dependenSCE (3, 10, 30 μM). 

Pb nitrate SCE (0.05–1 μM for 3–12 h) CHO AA8 in DMEM +10% NCS Crown ethers to modify effect through chelation and uptake Pb nitrate caused a weak concentration-dep

increase in SCE. These data were not statisanalyzed. The effect was reduced by a crowprobably because a similar reduction was sespontaneous SCE. 
 AX5-94 Table AX5-6.9 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Animal Cell Culture

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb sulfide SCE Formation (100–1,000 μM for 24 h) V79 CHL–HPRT low clone in Ham’s F12 +10% FBS None No SCE. Only 30 cells analyzed per treatmeAbbreviations V79 are a Chinese Hamster Lung Cell Line; CHO are a Chinese Hamster Ovary Cell Line ; Medium and Components AMEM—Alpha Minimal Essential Medium; DMEM—Dulbecco’s Minimal Essential Medium; EMEM—Eagle’s Minimal Essential Medium; HBSS—Hank’s Balanced Salt Solution FBS—Fetal Bovine Serum FCS—Fetal Calf Serum NCS—Newborn Calf Serum Differences between the serum types are unclear as insufficient details are provided by authors to distinguish. 
 AX5-95 Table AX5-6.10. Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Animal Cell Cultures D

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb acetate DNA damage as alkaline elution (exposure time and dose not given) Precipitate at 1000 μM and higher. V79 CHL–HPRT low clone in Ham’s F12 +10% FBS None No DNA damage (Single strand breaks, DN

protein crosslinks or DNA-DNA crosslinksHowever, the data was not shown 

Pb acetate DNA strand breaks as nick translation (1700 μM for 5 days) Or supercoiled relaxation (1000 μM for 5 days) Insoluble precipitate at high dose. G12–CHV79 cells with 1 copy gpt gene in Ham’s F12 + 5% FBS See also Table AX5-6.17 Pb acetate did not induce SSB. Pb acetate (1700 μM) did increase nick translation wh

exogenous polymerase was added. There wstatistical analyses of these data. 

Pb chromate DNA damage as alkaline elution (0.4–8 μg/cm2 for 24 h plus 24 recovery) Chinese Hamster Ovary AA8 cells in AMEM + 10% FBS None Pb chromate induced DNA single strand br

a concentration dependent manner, which wrepaired by 24 h post-treatment. Pb chromate induced DNA protein crosslinconcentration dependent manner, which per

at 24 h post-treatment. Pb chromate did not induce DNA-DNA crosslinks. This study was focused on chromate. 

Pb chromate DNA adducts (0.8 or 8 μg/cm2 for 24 h) Chinese Hamster Ovary AA8 cells in AMEM + 10% FBS Vitamin C (1 mM as pretreatment for 24 h) Vitamin E (25 μM as pretreatment for 24 h) Pb chromate induced DNA adducts in a concentration dependent manner. Vitamins 

E blocked DNA adducts induced by Pb chroThis study was focused on chromate. 

Pb nitrate DNA Protein Crosslinks as SDS precipitation (50–5,000 μM for 4 h) Novikoff ascites hepatoma cells None Pb nitrate induced DNA protein crosslinks 

concentration dependent manner. 
 AX5-96 Table AX5-6.10 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Animal Cell Cultur

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb nitrate DNA strand breaks as nick translation (1700 μM for 5 days) G12–CHV79 cells with 1 copy gpt gene in Ham’s F12 + 5% FBS See also Table AX5-6.17 Pb nitrate (1700 μM) did increase nick translation whe

exogenous polymerase was added. There were no statanalyses of these data. 

Abbreviations G12–CHV79 are derived from V79; V79 are a Chinese Hamster Lung Cell Line; CHO are a Chinese Hamster Ovary Cell Line ; Medium and Components AMEM—Alpha Minimal Essential Medium; FBS—Fetal Bovine Serum FCS—Fetal Calf Serum Differences between the serum types are unclear as insufficient details are provided by authors to distinguish. 
 AX5-97 Table AX5-6.11. Genotoxic/Carcinogenic Effects of Lead—Genotoxicity Non-mammalian C

Compound Assay and Concentration Cell Type Co-exposure Effects Pb chromate (and 13 pigments containing Pb chromate) Mutation Frequency (50–500 μg/plate) Anchorage Independence for cells isolated during morphological transformation Neoplastic Transformation for cells isolated during morphological transformation Salmonella typhimurium +/- S9 fraction Nitrilotriacetic acid (NTA to dissolve insoluble compounds) and Silica Encapsulation Pb chromate and its related pigments did not in

mutagenicity. A few did when dissolved in NTA. Encapsulation prevented mutagenesis in those twere positive when dissolved in NTA. S9 had no effect. Studied as a chromate compound. 
 AX5-98 Table AX5-6.12. Genotoxic/Carcinogenic Effects of Lead—Genotoxicity as it Pertains to Potential Deve

Compound Assay and Concentration Species Co-exposure Effects Pb acetate 25–400 mg/kg given i.p as single injection and animals studied after 24 h Sperm morphology Male Swiss Mice—

9–12 wks old 

None Pb induced sperm head abnormalities at 50–

100 mg/kg. A lower dose was negative and higdoses were not done. 

Pb acetate 200 or 400 mg/kg given by gavage daily 

for 5 days 5 animals per group Sperm Morphology 

Male Swiss Mice—9–12 wks old 

Calcium chloride (40 or 80 mg/kg by gavage daily for 3 days given 2 wks after Pb exposure) 

Pb induced sperm abnormalities at 200 and 400 mg/kg. A lower dose was negative and higher were not done. Calcium appeared to block this 
 AX5-99 Table AX5-6.13. Genotoxic/Carcinogenic Effects of Lead—Genotoxicity as it Pertains 

Potential Developmental Effects—Children Compound Exposure Regimen Species Co-exposure Effects 

Pb chloride Administered in drinking water 1.33 g/L for 6 wks Male NMRI Mice—9 wks old Cyclophosphamide— 120 mg/kg b.w. given i.p 7 days prior to start of breeding Pb did not increase resorptions indicating no dominant le

mutagenic effect. Pb appeared to have a small, but statisinsignificant reduction in the number of resorptions. Cyclophosphamide reduced live implants in female mice

Pb nitrate 12.5–75 mg/kg given i.v. on 9th day of gestation for 9 days. Mothers and fetuses analyzed on G18. 5 animals per group Resorptions, fetal viability, and chromosome damage in the mother and fetus were examined. ICR Swiss Webster Mice—6–8 wks old None 12.5–50 mg/kg had no effect on resorption or fetal viabil

75 mg/kg demonstrated some increased resorption thougstatistics were not done. No chromosome damage was seen in untreated controls. 

level 1-3 and 2-5 aberrations were seen in mothers and ferespectively. There was no dose response and no statistical analyses. interpretation is also complicated as too few metaphases analyzed 20–40 total. No descriptions of potential effects on maternal health pa

or fetal weights. No indication of how many animals included in the chroanalysis. 

Pb nitrate 100–200 mg/kg given i.v. on 9th day of gestation for 9 days. Mothers and fetuses analyzed on G18. Group size not given. Resorptions, fetal viability and chromosome damage, SCE and NOR in the mother and fetus were examined. Mother–bone marrow; fetus liver or lung 3 mothers and fetuses per dose were analyzed. ICR Swiss Webster Mice—6–8 wks old None Pb levels were found in both mother and fetus indicating 

problems crossing the placenta. All doses indicated increased resorption and decreased pweights. No effects on fetal weight. Significant increase in SCE in mothers at 150 and 200 mNo increase in SCE in fetuses. Significant decrease in NOR in both mother and fetuses. No gaps or breaks in mothers or fetuses. Some weak aneuploidy at lowest dose. Some karyotypic chromosome damage was seen. No exof how many cells analyzed per animal (3 animals per doanalyzed) as only 20–40 cells were analyzed. There was no dose response and no statistical analyses fo

chromosome damage. No details on how many animals for metaphase damage or how many cells per animal. Data interpretation is also complicated as too few metaphwere analyzed 10–25 for SCE. Not given for CA. 

No detail on potential maternal toxicity. 
 AX5-100 Table AX5-6.14. Genotoxic/Carcinogenic Effects of Lead—Epigenetic Effects and Mixture Interact

Compound Exposure Regimen Species Co-exposure Effects Pb acetate Administered as an i.p. injection of 100 μl/kg. Animals were studied either 24 h after a daily dose for 3 days or for various times (5 min–48 h) after a single dose. Male Wistar Rats— 10 wks old Actinomycin D (0.8 mg/kg) administered i.p. for 4 h before a single dose of Pb acetate. Pb acetate induced GST-P, which required the cis eleme

(GST-P enhancer I). Actinomycin D blocked the effects indicating that regulaat the mRNA level. Pb acetate induced c-jun, which exhibited three peaks of over 48 h. Pb acetate was more potent than Pb nitrate. 

Pb nitrate Administered as an i.p. injection of 100 μmol/kg. Animals were studied either 24 h after a daily dose for 3 days or for various times (5 min–48 h) after a single dose. Male Wistar Rats— 10 wks old Actinomycin D (0.8 mg/kg) administered i.p. for 4 h before a single dose of Pb acetate. Pb nitrate induced GST-P, which required the cis elemen

(GST-P enhancer I). Actinomycin D blocked the effects indicating that regulathe mRNA level. Pb nitrate induced c-jun, which exhibited three peaks of over 48 h. Pb nitrate was less potent than Pb acetate. 

Pb nitrate Administered as an i.p. injection of 100 μmol/kg. Some rats were partially hepatectomized. Animals were studied 48 h after injection. Male Sprague Dawley rats Partial Hepatectomy Pb nitrate induced GSH and GST 7-7 activity. Partial hepatectomy did not induce GSH or GST 7-7. 

Pb nitrate Administered as an i.v. injection of 20, 50, or 100 μmol/kg. Animals were studied 24 h after injection. Male Fisher 344 rats—7 wks old 2-methoxy- 4-aminobenzene to induce P4501A2 or 3-methylcholanthrene to induce 4501A1 Pb nitrate selectively inhibited P4501A2 and its inductio

methoxy-4-aminobenzene at the mRNA and protein levedose-dependent manner. Pb nitrate had minimal effect on P4501A1 and its inductmethyl cholanthrene. Pb nitrate did not affect microsomal activity. Pb nitrate induced GST-P in a dose-dependent manner. 
 AX5-101 Table AX5-6.15. Genotoxic/Carcinogenic Effects of Lead—Epigenetic Effects and Mixture Interact

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb acetate Tyrosine aminotransferase expression and activity (0.3–10 μM for 24–48 h) PKC activity: 10 μM for 48 h H4-IIE-C3— human hepatoma cells in DMEM + 2.5% FCS Dexamethasone (0.1 μM for 16 h), or calcium chloride (10 μM) or genistein (100 μM to block PKC activity) Pb acetate inhibited glucocorticoid –induction of tyrosine aminotransferase in a time- and dose-dependent manner. Co-treatment with calcium reduced the effects of Pb. Co-treatment with genistein increased the effects of Pb. Pb acetate decreases PKC activity and its translocation from the cytosol to the particulate cellular fraction. Pb nitrate EROD/MROD activity (10–100 μM for 24 h) NAD(P)H: quinone oxidoreductase activity (10–100 μM for 24 h) Glutathione-S-transferase Ya activity (10–100 μM for 24 h) Hepa 1c1c7 wild type cells in DMEM + 10% FBS TCDD (0.1 nM), 3-methyl cholanthrene (0.25 μM), beta- naptflavone (10 μM), benzo(a)pyrene (1 μM) Pb did not affect EROD/MROD activity. Pb reduced CYP1A1 induction by TCDD, 3-methyl cholanthren

beta-naptflavone, benzo(a)pyrene. Pb increased NAD(P)H: quinone oxidoreductase activity Pb increased NAD(P)H: quinone oxidoreductase activity inductTCDD, 3-methyl cholanthrene, beta-naptflavone, benzo(a)pyren10 μM increased Glutathione-S-transferase Ya activity. 25 and 100 μM increased Glutathione-S-transferase Ya activity. Pb nitrate did not affect Glutathione-S-transferase Ya induction TCDD, 3-methyl cholanthrene, beta-naptflavone, benzo(a)pyren

Pb nitrate NAD(P)H: quinone oxidoreductase activity (25 μM for 24 h) Glutathione-S-transferase Ya activity (25 μM for 24 h) C12- AHR- deficient Hepa 1c1c7 cells in DMEM + 10% FBS TCDD (0.1 nM), 3-methyl cholanthrene (0.25 μM), beta- naptflavone (10 μM), benzo(a)pyrene (1 μM) Pb nitrate did not increase NAD(P)H: quinone oxidoreductase a

Glutathione-S-transferase Ya activity Pb increased NAD(P)H: quinone oxidoreductase activity inductTCDD, 3-methyl cholanthrene, beta-naptflavone, benzo(a)pyrenPb did not affect Glutathione-S-transferase Ya induction by TCDmethyl cholanthrene, beta-naptflavone, benzo(a)pyrene. 

Abbreviations Medium and Components DMEM—Dulbecco’s Minimal Essential Medium; FBS—Fetal Bovine Serum FCS—Fetal Calf Serum Differences between the serum types are unclear as insufficient details are provided by authors to distinguish. 
 AX5-102 Table AX5-6.16. Genotoxic/Carcinogenic Effects of Lead—Epigenetic Effects and Mixtu

Interactions—DNA Repair—Human Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects 

Pb acetate DNA strand breaks as nucleoid sedimentation (500 μM for 20–25 h) HeLa Cells in AMEM + 5% FBS UV (5 J/m2) Pb acetate alone did not induce single strand breaks. UV did ind

strand breaks. Co-exposure of Pb and UV cause DNA strand brpersist longer suggesting an inhibition of repair. 

Abbreviations Medium and Components AMEM—Alpha Minimal Essential Medium; FBS—Fetal Bovine Serum 
 AX5-103 Table AX5-6.17. Genotoxic/Carcinogenic Effects of Lead—Epigenetic Effects and Mixtu

Interactions—DNA Repair—Animal Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects 

Pb acetate Cytotoxicity (0.5–5 μM for 24 h) Mutagenesis—HPRT (0.5–5 μM for 44h) SCE (1–10 μM for 26 h+) V79 in AMEM + 10% FBS UV (5 J/m2) Pb acetate ( 3 and 5 μM) increased UV-induced increased cytoto

with no dose response (plateau). There were no statistical analythese data. Pb acetate (0.5–5 μM) increased UV mutagenicity though with 

dose response (plateau). There were no statistical analyses of thdata Pb acetate (1–10 μM) increased UV-induced SCE. Significant a

p < 0.01. Only 25 cells per treatment analyzed. 

Pb acetate Mutagenesis—gpt (0.5–1700 mM for 24 h) DNA strand breaks as supercoiled relaxation (1000 mM for 24 h) G12–CHV79 cells with 1 copy gpt gene in Ham’s F12 + 5% FBS UV (2 J/m2), or MNNG (0.5 μg/L) Pb acetate was co-mutagenic with UV and MNNG increasing frequency 2-fold. Pb acetate does not increase strand breaks induced by UV. 

Abbreviations G12–CHV79 are derived from V79; V79 are a Chinese Hamster Lung Cell Line; Medium and Components AMEM—Alpha Minimal Essential Medium; FBS—Fetal Bovine Serum 
 AX5-104 Table AX5-6.18. Genotoxic/Carcinogenic Effects of Lead—Mitogenesis—Animal Compound Exposure Regimen Species Co-exposure Effects 

Pb acetate Administered Pb acetate (12.5 mg/kg) i.p. Animals studied 24 h after injection. Male B6 Mice None Pb acetate induced TNF-alpha in glial and neuronal cells in the cerebral cortex and subcortical white matter and on Purkinje ce

the cerebellum, but did not induced apoptosthese areas 

Pb nitrate Liver initiation induced by the resistant hepatocyte model Initiation followed by i.v. injection of Pb nitrate (100 μM/kg ) or partial hepatectomy Studied DNA synthesis (30 h after injection) and preneoplastic nodule formation (5 wks after injection) Male Wistar Rats—4 per group Partial Hepatectomy Pb nitrate stimulated DNA synthesis and liv

proliferation Pb nitrate did not induce preneoplastic noduPartial hepatectomy did. 

Pb nitrate Liver initiation induced by the resistant hepatocyte model (diethylnitrosamine followed by 2- acetylaminofluorene plus carbon tetrachloride) Initiation followed by i.v. injection of 4 doses of Pb nitrate (100 μM/kg ) given once every 20 days or partial hepatectomy, ethylene dibromide, or nafenopine Animal were evaluated for preneoplastic foci at 75 or 155 days after initiation. Male Wistar Rats—4 per group Diethylnitrosamine Pb nitrate, partial hepatectomy, ethylene dibromide, or nafenopine all stimulated DN

synthesis and liver cell proliferation Pb nitrate, ethylene dibromide, or nafenopinnot induce preneoplastic nodule. Partial hepatectomy did. 

Pb nitrate Liver initiation induced by the orotic acid model (diethylnitrosamine plus orotic acid) Initiation followed by i.v. injection of Pb nitrate (100 μM/kg) or partial hepatectomy, or by gavage: ethylene dibromide, or cyproterone DNA synthesis was examined at various time intervals (24 h–5 days) after injection. Male Wistar Rats—4 per group Diethylnitrosamine Pb nitrate, partial hepatectomy, ethylene dibromide, or cyproterone all stimulated DN

synthesis within 30 min. Pb nitrate induced DNA synthesis for 5 day
 AX5-105 Table AX5-6.18 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Mitogenesis—Anim

Compound Exposure Regimen Species Co-exposure Effects Pb nitrate Liver initiation induced by the resistant hepatocyte model (diethylnitrosamine followed by 2- acetylaminofluorene plus carbon tetrachloride) or the phenobarbital model (diethylnitrosamine plus orotic acid), or the orotic acid model (diethylnitrosamine plus orotic acid) Initiation followed by i.v. injection of Pb nitrate (100 μM/kg ) or partial hepatectomy, or carbon tetrachloride by gavage Animals were studied 6 wks after initiation. Male Wistar rats—4 per group Partial Hepatectomy, carbon tetrachloride Pb nitrate, partial hepatectomy, carbon tetrachloride all stimulated DNA synthesis 

liver cell proliferation Pb nitrate, did not induce preneoplastic nodPartial hepatectomy and carbon tetrachlorid

Pb nitrate Liver initiation induced by the resistant hepatocyte model (diethylnitrosamine followed by 2-acetylaminofluorene plus carbon tetrachloride) Initiation followed by i.v. injection of Pb nitrate (100 μM/kg ) or partial hepatectomy, or by gavage: ethylene dibromide, or cyproterone, or nafenopine Also tried either 1 or 2 additional i.v. injections of Pb over 3-day intervals. Animals were studied at various intervals (1–6 days) after injection Male Wistar rats—4 per group Diethylnitrosamine, 2-AAF This study aimed to determine if mitogens i

nodules at different time points. Pb nitrate, ethylene dibromide, cyproteronenafenopine did not induce preneoplastic nodat all. Partial hepatectomy did within 3 dayMultiple injections of Pb nitrate did not indpreneoplastic lesions. 

Pb nitrate Administered as i.v. injection of Pb nitrate (100 μM/kg ) or partial hepatectomy, or by gavage: carbon tetrachloride, or ethylene dibromide, or cyproterone, or nafenopine Animals were studied at various time intervals (0.25–24 h) after injection. Male Wistar rats—4 per group Partial Hepatectomy, carbon tetrachloride Pb nitrate, ethylene dibromide, cyproterone

nafenopine induced c-jun and c-myc but did induce c-fos. Partial hepatectomy and carbon tetrachloridinduced c-jun, c-fos, and c-myc. 

Pb nitrate Administered as i.v. injection of Pb nitrate (100 μM/kg) or partial hepatectomy, or nafenopine by gavage. Animals were studied at various time intervals (24–96 h) after injection. Male Wistar rats—4 per group, 8 wks old None Pb nitrate induced a high incidence of polyp

and binucleated cells. These changes were irreversible after 2 wks. Many of these cellthe newly synthesized cells. Partial hepatectomy and carbon tetrachloridinduced tetraploid and octaploid mononuclecells. 

Pb nitrate Administered as i.v. injection of Pb nitrate (10 μM/100 g) Studies for apoptosis at 12, 24, 36, 48, 72, 96, 120, 168, 336 h after injection Male Wistar rats—4 rats per group None Liver weight increased until day 5 then retu

control levels. DNA synthesis peaked at 36 h Apoptosis peaked at day 4 and then decreasgradually. 
 AX5-106 Table AX5-6.18 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Mitogenesis—Anim

Compound Exposure Regimen Species Co-exposure Effects Pb nitrate Administered as i.v. injection of Pb nitrate (100 μM/kg) or TNF-alpha. Animals were studied at various time intervals (12–48 h) after injection. Male Wistar Rats—4 per group, 5–6 wks old None Pb nitrate and TNF-alpha induced similar proliferative responses. Pb nitrate Administered after diethylnitrosamine (200 mg/kg given i.p) as i.v. injection of Pb nitrate (100 μM/kg ) or instead carbon tetrachloride by gavage Animals were studied at various time intervals (3–21 days) after injection. Male Wistar Rats—4 per group Carbon tetrachloride Pb nitrate induced apoptosis affects both new

synthesized cells and non-replicative cells. Pb nitrate decreased the number and had no eon the size of placental glutathione-S-transferlesions. Carbon tetrachloride substantially increased these lesions both in number and in 

Pb nitrate Administered as i.v. injection of Pb nitrate (100 μM/kg ) or partial hepatectomy, or by gavage: carbon tetrachloride, or cyproterone, or nafenopine Animals were studied at various time intervals (0.5–24 h) after injection. Male Wistar Rats—8 wks old Partial Hepatectomy, ethylene dibromide, nafenopine, or cyproterone Pb nitrate induced NF-kB, TNF-alpha and iN

but not AP-1. Carbon tetrachloride induced and activated NTNF-alpha iNOS, and AP-1. Nafenopine and cyproteone did not induce or activate NF-kB,TNF-alpha iNOS, or AP-1. 
 AX5-107 Table AX5-6.19. Genotoxic/Carcinogenic Effects of Lead—Mitogenesis Human and Animal Cell C

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb acetate Cell Proliferation (0.1–100 μM for 2–6 days) DNA synthesis (1–100 μM for 72 h) Tyrosine aminotransferase expression and activity (0.3–10 μM for 24– 48 h) H4-II-C3—human hepatoma cells in DMEM + 2.5% FCS Dexamethasone (0.1 μM for 16 h) Pb acetate inhibited cell growth in a time- and dose

dependent manner. Pb acetate inhibited DNA synthesis in a dose-depenmanner. Pb acetate alone did not inhibit tyrosine aminotransPb acetate inhibited glucocorticoid–induction of tyraminotransferase in a time- and dose-dependent ma

Pb acetate Cell proliferation (10 μM–1mM for 24 h–7 days) REL cells—Rat Epithelial cells in Ham’s F10 medium + 10% FBS None Pb acetate inhibited cell growth at all concentration

24 h–7 days. Pb acetate did not affect gap junction capacity, whicoften inhibited by tumor promoters. 

Pb acetate Cell growth (0.01–10 μM for 12-72 h) Expression of genes in cytokine pathways (0.01–10 μM for 24 h) U-373MG—human glioma cell line in DMEM + 10 or 20% FBS None Pb acetate did not inhibit or enhance cell growth. Pb acetate enhanced the expression of TNF-alpha, b

decreased interleukin-1 beta, interleukin-6, gamma- aminobutyric acid transaminase, and glutamine synunder 10% FBS. Pb acetate further enhanced the expression of TNF-under 20% serum, but had no effect at all on expresthe other genes. 

Pb acetate Cell proliferation (0.078–320 μM for 48 h) Apoptosis (1.25–80 μM) Cell cycle analysis Rat-1 fibroblasts in EMEM +10% FBS None Pb acetate inhibited cell growth at 0.635–320 μM. Pb acetate induced apoptosis from 2.5–10 μM. Pb acetate caused GS/M and S-phase arrest. Pb acetate DNA synthesis (1–50 μM for 24 h) Expression of genes in mitogen activated pathways (1–50 μM for 5 min–4 h) 1321N1–human astrocytoma cells in DMEM + 0.1% BSA None Pb acetate induced DNA synthesis. Pb acetate induced activation of MAPK, ERK1. ER

MEK1 , MEK2, PKC, and p90RSK. Pb acetate did not activate PI3K or p70s6k. 

Pb acetate Cell proliferation (1 μM for 24 h) Cell differentiation (1 μM for 48 h) PKC activation (1 μM for 24 h) Primary oligodendrocyte progenitor cells–in DMEM + 1% FBS None Pb acetate inhibited basal and growth factor stimula

growth. Pb acetate inhibited cell differentiation in a PHC-demanner. Pb acetate redistributes PKC from the cytosol to the membrane, but did not increase PKC activity. 
 AX5-108 Table AX5-6.19 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Mitogenesis Human and Animal Ce

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb acetate Expression of TNF-alpha (0.1–10 μM for 24 h) U-373MG—human glioma cell line in DMEM + 20% FBS None Pb acetate did not induce apoptosis. Pb acetate increased the expression of TNF-alpha i

dependent manner. TNF-alpha was not involved in Pb-induced apopto

Pb chloride Cell proliferation (10 μM–1mM for 24–48 h) REL cells—Rat Epithelial cells in Ham’s F10 medium + 10% FBS None Pb chloride inhibited cell growth at all concentratio

24–48 h. Pb chloride did not affect gap junction capacity, whoften inhibited by tumor promoters. 

Pb oxide Cell proliferation (10 μM–1mM for 24 h–7 days) REL cells—Rat Epithelial cells in Ham’s F10 medium + 10% FBS None Pb oxide inhibited cell growth at all concentrations 

24 h–7 days. Pb oxide did not affect gap junction capacity, whicinhibited by tumor promoters. 

Pb sulfate Cell proliferation (10 μM–1mM for 24–48 h) REL cells—Rat Epithelial cells in Ham’s F10 medium + 10% FBS None Pb sulfate inhibited cell growth at all concentration

48 h. Pb sulfate did not affect gap junction capacity, whioften inhibited by tumor promoters. 

Pb chromate Apoptosis (350 μM for 24 h) Chinese Hamster Ovary AA8 cells in AMEM + 10% FBS None Pb chromate induced apoptosis. This study was focused on chromate. 

Pb chromate Apoptosis (0.4–2 μg/cm2 for 24 h) Primary Human Small Airway Cells in Clonetics growth medium None Pb chromate induced apoptosis in a concentration- dependent manner. 

Pb chromate Growth Curve (0.5–5 μg/cm2 24 h) WTHBF-6—human lung cells with hTERT in DMEM/F12 + 10% CCS None Pb chromate inhibited cell growth. 

Pb glutamate Growth Curve (250–1,000 μM for 24 h) WTHBF-6—human lung cells with hTERT in DMEM/F12 + 10% CCS None Pb glutamate had no effect on growth. 

Pb glutamate Mitotic Index (250–2,000 μM for 24 h) Growth Curve (250–2,000 μM for 24 h) Cell cycle Analysis 

(250–2,000 μM for 24 h) 

WTHBF-6—human lung cells with hTERT in DMEM/F12 + 10% CCS 

None Pb glutamate induced a concentration-dependent in

intracellular Pb ions. Pb glutamate increased the mitotic index, but eitheeffect or inhibited growth and induced mitotic arre
 AX5-109 Table AX5-6.19 (cont’d). Genotoxic/Carcinogenic Effects of Lead—Mitogenesis Human and Animal Ce

Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects Pb nitrate Mitotic Index (3–30 μM for 2h +16 h recovery) CHO cells in EMEM + 10% FBS None Lower concentrations (1 and 3 μM) of Pb nitrate significantly increased the mitotic index. Higher concentrations (10 and 30 μM) had no effect. Pb nitrate Mitotic Index (0.05–1 μM for 3–12 h) CHO AA8 in DMEM +10% NCS Crown ethers to modify effect through chelation and uptake Pb nitrate dramatically reduced the mitotic index at 

though this was not statistically analyzed. There weffect on mitotic index at lower concentrations. Crethers had no modifying effect. 

Pb nitrate Apoptosis (15–240 μM for 3 h) Rat Alveolar Macrophages in DMEM + 10% FBS None Pb nitrate induced apoptosis in a dose-dependent mAbbreviations G12–CHV79 are derived from V79; V79 are a Chinese Hamster Lung Cell Line; hTERT is the catalytic subunit of human telomerase Medium and Components AMEM—Alpha Minimal Essential Medium; DMEM—Dulbecco’s Minimal Essential Medium; DMEM/F12—Dulbecco’s Minimal Essential Medium/Ham’s F12; EMEM—Eagle’s Minimal Essential Medium; BSA—Bovine Serum Albumin CCS—Cosmic Calf Serum FBS—Fetal Bovine Serum FCS—Fetal Calf Serum NCS—Newborn Calf Serum Differences between the serum types are unclear as insufficient details are provided by authors to distinguish. 
 AX5-110 Table AX5-6.20. Genotoxic/Carcinogenic Effects of Lead—Mitogenesis Other Compound Assay (Concentration and Exposure Time) Cell Type and Culture Medium Co-exposure Effects 

Pb acetate Production of reactive oxygen species (1 mM for 180 min) Glutathione levels (1 mM for 0–180 min) SH-SY5Y—Human neuroblastoma cells in DMEM + 7% FCS Glutamate (1 mM) or PKC inhibitor (1 μM) Pb acetate alone did not produce reactive oxygen species

alone did. Pb acetate plus glutamate increase glutamate induced increactive oxygen species. Pb acetate alone did not deplete glutathione. Glutamate Pb acetate plus glutamate decreased glumate-induced deglutathione. 

Pb acetate Catalase Activity (500–2,000 μM for 24 h) Human Foreskin Fibroblasts (Chinese) in DMEM +10% FCS 3-aminotriazole (3-AT) (80 mM to inhibit catalase) Pb acetate had no effect on catalase activity. Pb acetate Thiol Levels (100 μM for 30 min–4 h) HeLa in HEPES/glucose buffer Buthionine sulfoximine (BSO) to deplete cells of thiols Pb acetate only lowered thiols marginally 

Pb chloride Oxidative Metabolism (0.1–100 μM for 20 h) Phagocytosis (0.1–100 μM for 20 h) Macrophages from NMRI mice in EMEM (serum not given) Zymosan and latex particles as substrates for phagocytosis Pb inhibited oxidative metabolism. Pb inhibited phagocytosis, but only significantly at the hPb chloride Oxidative Enzyme Levels (0.1–1 μM for 1 h) AS52-CHO-gpt, lack hprt in HBSS followed by Ham’s F12 + 5% FBS Allopurinol (50 μM) to inhibit xanthine oxidase Pb chloride at low concentrations produced H2O2 at 1 h a

24 h. Pb chloride at high concentrations produced no chand increased H2O2 at 24 h. Allopurinol inhibited H2O2 

high Pb concentrations. Pb chloride had no effect on catalase, glutathione peroxiglutathione reductase. Pb chloride inhibited glutathione-transferase, CuZn-superoxide dismutase, and xanthine ox

Abbreviations AS52 are derived from CHO; CHO are a Chinese Hamster Ovary Cell Line; Medium and Components DMEM—Dulbecco’s Minimal Essential Medium; EMEM—Eagle’s Minimal Essential Medium; HBSS—Hank’s Balanced Salt Solution FBS—Fetal Bovine Serum FCS—Fetal Calf Serum 

Differences between the serum types are unclear as insufficient details are provided by authors to distinguish. 
 AX5-111

ANNEX TABLES AX5-7 
 AX5-112 Table AX5-7.1. Light Microscopic, Ultrastructural, and Functional Changes Author Animal Species Lead Dosage Blood Lead Finding

Khalil-Manesh et al. (1992a) Sprague-Dawley rat 0.5% Pb acetate in drinking water for 12 mo Max 125.4 μg/dL Mean 55 μg/dL Hyperfiltration at 3 mo. Decreased 

NAG and GST elevated. Nuclear inclusion bodies at all timeTubulointerstitial scarring from 6 mNo arterial or arteriolar pathology. Khalil-Manesh et al. (1992b) Sprague-Dawley rat 0.5% Pb discontinued after 6 mo 0.01% Pb discontinued after 6 mo DMSA 0.5% used in 1/2 Hi Pb @12 mo Disc 30.4 μg/dL Disc + DMSA 19.1 μg/dL Ctrl 3.1 μg/dL Lo Pb@12mo Disc 6.9 μg/dL DMSA5.5 μg/dL High Pb: Nuclear inclusion bodies prominenTubulointerstitial disease severe bucontinuous DMSA caused reductiobodies and tubuloint decrease, and Low Pb: Neg pathology and increase in GFR 

Khalil-Manesh et al. (1993a) Sprague-Dawley rat 0.01% Pb acetate for 12 mo Max 29.4 μg/dL Range 9–34 μg/dL GFR increased at 1 and 3 mo. NAG increased but GST normal. Pathology neg except at 12 mo—m

interstitial fibrosis seen. Sanchez- Fructuoso et al. (2002a) Wistar rat 500 ppm (0.05%) Pb acetate for 2 mo, then EDTA Max 52.9 μg/dL Day 90: 33.2 Day 137: 22.8 Ctrl: 5.90 μg/dL Rats given Pb to day 90, then treate

to day 137. Marked decrease in kidney, liver, a

no change in femur Pb Sanchez- Fructuoso et al. (2002b) Wistar rat 500 ppm (0.05%) Pb acetate for 2 mo, then EDTA Max 52.9 μg/dL Day 90: 33.2 Day 137: 22.8 Ctrl: 5.90 μg/dL Hypertrophy and vacuolization of m

mucoid edema and muscular hyperbodies and fibrosis. EDTA slowed progression. Papaioannou et al. (1998) Dogs 12 mg Pb acetate i.p. H 10 — Pb includes bodies intracytoplasmic

giant cells of peritoneum and in intcells of kidney. None in prox tubul
 AX5-113 Table AX5-7.1 (cont’d). Light Microscopic, Ultrastructural, and Functional Changes Author Animal Species Lead Dosage Blood Lead Finding

Vyskocil et al. (1989) Wistar rat 0.5%, 1%, and 2% Pb acetate for 

2–3 mo 

0.5%–105 μg/dL 

1%–196 μg/dL 

2%–320 μg/dL 

0.5%—no morphologic or function1%—Incr in β-2 microglobulin exc

2%—Incr in β2micr, glucose, prote

Hyperplasia and include bodies of p1% and 2%. 

Vyskocil et al. (1995) 

Wistar rat 1% or 0.1% Pb acetate for 2–4 mo 1%–173 μg/dL 

0.1%–37.6 μg/dL 

1% caused increase in β-2 microgloto proximal tubule. 0.1% caused no changes. 

Vyskocil and Cizkova (1996) 

Wistar rats Unleaded petrol vapor (4mg/m3) 

8 hrs/day for 60 days 

—

Β-2 microglobulin excretion increa

Sanchez et al. (2001) 

Sprague-Dawley rat 

0.06% Pb acetate for 4 mo 13.9 μg/dL vs. <0.5 μg/dL 

in ctrl 

Decrease in expression of laminin-of fibronectin in kidneys. 

HerakKramberger et al. (2001) 

Rat brush border membranes 

500 μM Pb 

—

58% loss of sealed brush border meloss of sealed basolateral membrane 

Fujiwara et al. (1995), Kaji et al. (1995b) 

Bovine cultured vascular smooth muscle and endothelial cells 

0.5–10 μM Pb nitrate 

—

Stimulated proliferation in smooth proliferation in endothelial cells No 
 AX5-114 Table AX5-7.2. Lead and Free Radicals Author Animal Species Lead Dosage Blood Lead Finding

Pereira et al. (1992) Rats ALA-treated (40 mg/kg every 2 days for 15 days) 

—

Fatigued earlier than controls. Increase of CuZn SOD in brain, mu

Somashekaraiah et al. (1992) 

Chick embryos 1.25 and 2.5 momol/kg of Pb acetate 

—

Lipoperoxides maximal at 9 hrs and 72 hrs. GSH depleted. GST, SOD and catabrain and heart at 72 hrs. 

Bondy and Guo (1996) 

Sprague-Dawley rat cerebral synaptosomes 

0.5 mM Pb acetate 

—

Generation of ROS not increased by when 50 μM iron sulfate added. 

Blazka et al. (1994) 

Mouse brain microvascular endothelial cell culture 

10, 100, and 1,000 nM Pb acetate 

—

Constitutive production of nitrite, bby Pb. Extracellular calcium abolis

Quinn and Harris (1995) 

Rat cerebellum homogenates 

17–80 nM Pb nitrate 

—

Constitutive NOS activity inhibited 100% by 80 nM Pb. Reversed by in

Ercal et al. (1996) C57BL/6 mice 1300 ppm Pb acetate for 5 wks, 

Nac, 5.5 mmol/kg, or DMSA, 1 mmol/kg, given in 6th week. 

36.5 μg/dL in Pb-treated; 13.7 μg/dL in Pb + DMSA-treated 

Liver and brain GSH depleted by PBoth were restored by either DMSA DMSA reduced blood, liver, and brdid not. 

Vaziri and coworkers (1997–

2004) 

Sprague-Dawley rats 

See Section 5.5 for details Variable See Section 5.5 for details. 

Farmand et al. (2005) 

Sprague-Dawley rats 

100 ppm Pb acetate for 3 mo 

—

CuZnSOD activity increased in kidincreased in aorta whereas protein aGuanylate cyclase protein abundanc

Gurer et al. (1999) 

Fischer 344 rats 1100 ppm Pb acetate for 5 wks, 

Captopril for 6th wk 

24.6μg/dL in Pb-treated. 23.8 μg/dL in Pb + Captopril-treated 

MDA in liver, brain, and kidney incdecreased. Captopril reversed these 
 AX5-115 Table AX5-7.2 (cont’d). Lead and Free Radicals Author Animal Species Lead Dosage Blood Lead Finding

Acharya and Acharya (1997) Swiss mice 200 mg/kg Pb acetate i.p. H 1 

—

MDA-TBA increased H 4 in liver, b

end of 1st wk and persisted for 4 wk

Upasani et al. (2001) 

Rats 100 ppm Pb acetate for 30 days, 

Groups given vit C, vit E, or algae 

—

MDA, conj dienes, and H2O2 increa

kidney by Pb. Treatment with vit Creversed these findings. 

Pande et al. (2001) 

Wistar rats Pb nitrate 50 mg/kg i.p. H 5 

Pb + DMSA,MiADMSA,NAC, DMSA + NAC,DMSA + MiADMSA 

—

DMSA most effective in blocking iZPP, and inhib of GSH. Combined effective when given during or post

Pande and Flora (2002) 

Wistar rats 2000 ppm Pb acetate H 4 wks, 

DMSA,MiADMSA, DMSA + LA,MiADMSA + LA H 5 days 

—

Pb caused decrease in ALAD, GSHacid (LA) did not chelate Pb in conagents increased ALAD and GSH. 

Flora et al. (2003) Wistar rats 1000 ppm Pb acetate H 3 mo, 

DMSA or MiADMSA + vit C or vit E H 5 days 

13.3 μg/dL Pb Rx 3 μg/dL DMSA Rx <1μg/dL DMSA+ vit E 

Both thiol chelators and 2 vitamins increase only after thiol chelators. chelators reduced blood Pb further. 

Saxena and Flora (2004) 

Wistar rats 2000 ppm Pb acetate H 6 wks, 

CaNa2EDTA + DMPS or 

MiADMSA H 5 days 

15.1μg/dL Pb Rx 9.8 μg/dL EDTA Rx 6 μg/dL EDTA + MiADMS 

Pb caused inhib of ALAD and GSH kidney, ALAS in liver, GSH in braiand GST. Combined Rx with CaNmost effective in reducing oxidative burden. 

Tandon et al. (2002) 

Rats 2000 ppm Pb acetate H 9 wks, 

DMSA, MiADMSA, or NAC or combo H 6 days 

—

Pb raised MDA, inhibited ALAD, idepleted GSH. DMSA plus NAC wreversing these changes. 
 AX5-116 Table AX5-7.2 (cont’d). Lead and Free Radicals Author Animal Species Lead Dosage Blood Lead Finding

Sivaprasad et al. (2002) Wistar rats 2000 ppm Pb acetate H 5 wks LA and DMSA during 6th week. 

—

Pb caused red in kidney GGT and Ncatalase, SOD, GPx and Glut reducLipoic acid +DMSA restored these changes. 

Senapati et al. (2000) 

Rats 1% sol of 5 mg/kg 

Pb acetate H 43 days Thiamine 25 mg/kg 

—

Thiamine reduced Pb content and Mand kidney and improved pathology

Patra et al. (2001) IVRI 2CQ rats 1 mg/kg Pb acetate for 4 wks 

Vit E, vit C or methionine in 5th wk. Vit E + EDTA. 

6.8 μg/dL Pb-Rx 6.3 μg/dL Pb, vit E +EDTA 

Pb in liver, kidney and brain reducetreatment. MDA increased by Pb in by vit E + EDTA. 

McGowan and Donaldson (1987) 

Chicks 2000 ppm Pb acetate H 3 wks 

—

GSH, non-protein SH, lysine and mand non-prot SH, glycine, cysteine kidney. Cysteine reduced in plasm
 AX5-117 Table AX5-7.3. Chelation with DMSA Author Animal Species Lead Dosage Blood Lead Finding

Cory-Slechta (1988) Rats 50 ppm Pb acetate for 3–4 mo 20 μg/dL-Pb 1 μg/dL-Pb+25 mg/kg DMSA DMSA 25–50 mg/kg i.p. for 1–5 da

blood, brain, kidney and liver, but n

Pappas et al. (1995) Sprague-Dawley rats 550–1100 ppm Pb acetate for 35 days 52 μg/dL @ 550 ppm Pb 65 μg/dL @ 1100 ppm Pb DMSA @16–240 mg/kg/d p.o. for 2

without concurrent Pb exposure. Rreduction in Pb content of blood, brliver with or without concur Pb. Smith and Flegal (1992) Wistar rats 206Pb 210 ng/mL for 1.5 days DMSA 20 mg/kg i.p. 5.1 ng/g-ctrl 3.0 ng/g-DMSA Rats on low Pb diet given DMSA d

skeletal Pb. Pb redistributed to ske

Varnai et al. (2001) Wistar rats (suckling) 2 mg/kg/d for 8 days DMSA 0.5 mmol/kg 6x/d on d1-3 and 6–8 — DMSA reduced Pb concentration in 

brain by ~50%. 
 AX5-118 Table AX5-7.4. Effect of Chelator Combinations Author Animal Species Lead Dosage Blood Lead Finding

Flora et al. (2004) Wistar rats 1000 ppm Pb acetate for 4 mo 46 μg/dL-Pb 12.8 μg/dL-combined Rx 5 days Rx with DMSA. CaNa2EDT

CaNa2EDTA. Comb Rx resulted in 

decreased Pb in blood, liver, brain, 

Jones et al. (1994) Mice 10 i.p. injections of Pb acetate, 5.0 mg/kg — Mice Rx’ed with DMSA, CaNa2ED

ZnNa3DTPA 1.0 mmol/kg/d 4–8 da

effective in removing brain Pb; DMand bone Pb. Kostial et al. (1999) Wistar rats (suckling) 5 mg Pb/kg i.p. H 1 Chel agents days 2 and 3 — EDTA, DMSA, racemic DMSA, ED

rac DMSA given. EDTA reduced ZDMSA reduced Zn in kidneys. DMaffecting Zn. Flora et al. (2004) Wistar rats 1000 ppm Pb acetate H 2 mo — DMSA, taurine or DMSA + taurine 

taurine and DMSA restored GSH. increased RBC SOD and decreased effectively depleting blood, liver, a

Sivaprasad et al. (2004) Wistar rats 2000 ppm Pb acetate H 5 wks — DMSA, lipoic acid or combination 

Renal enzymes, kidney Pb and renacombined Rx. Malvezzi et al. (2001) Wistar rats 750 ppm Pb acetate H 70 days DMSA, arginine, DMSA + arg or 

H2O H 30 days 

67.8 μg/dL to 11.2 μg/dL in H2O Rx’ed to 6.1 

μg/dL in DMSA + arg 

Pb increased BP and Pb levels in bl

and aorta. DMSA + L-arginine moand mobilizing Pb from tissues. 

Tandon et al. (1997) 

Rats 1000 ppm Pb acetate for 7 wks. 

Dithiocarbamate H 4 days 

105.3 μg/dL in Pb 86 μg/dL in dithiocarbamate. 

Two dithiocarbamates were comparand N-(4-methoxybenzyl)-D-glucampartially effective in restoring ALAkidney, but not brain Pb. They dep
 AX5-119 Table AX5-7.5. Effect of Other Metals on Lead Author Animal Species Lead Dosage Blood Lead Finding

Maldonado-Vega et al. (1996) Wistar rats (pregnant and nonpregnant) 100 ppm Pb acetate for 144– 158 days 5.2 (ctrl) to 27.3 μg/dL in Pb-exposed 8 (non-preg) to 17 μg/dL in rats exposed only during lactation Pb administered to period before la

mid-lactation (158 days).Pb in blooincreased. ALAD decreased and FEP incr. LaBlood Pb from 24.7 to 31.2 μg/dL a83.4 to 65.2 nmol/g. Olivi et al. (2002) MDCK canine kidney cells 1 μM — In response to agonists ADP or brad

intracellular Ca increased 3-fold anresponse. Bogden et al. (1991) Wistar rats 0,1,100 ppm Pb for 31 wks 0.2% or 4.0% Ca diet 1.9 to 39.1 μg/dL on low Ca diet and 2.0 to 53.3 μg/dL on high Ca diet At 100 ppm Pb high Ca diet producrenal cancers than low Ca diet and hliver, bone, heart, and testis but lowCa on high Ca diet was 13.2 mg/dL

Skoczyńska et al. (1994) Buffalo rats Pb 70 mg/kg 2x/wk for 7 wks Cd 20 mg/kg 1x/wk for 7 wks. All intragastric. 5.1 to 29.6 μg/dL in Pb- exposed. 37.4 μg/dL in Pb + Cd Simultaneous Pb and Cd administra

decreased Pb in liver and kidneys aadministration alone. Othman and El-Missiry (1998) Albino rats Pb acetate 100 momol/kg I.M. H 1 Se 10 momol/kg I.M. 2 hrs before Pb — Sodium selenite (Se is a well-knowlipid peroxidation (TBARS) and redPb. SOD and glut reductase also no

Tandon et al. (1992) Albino rats Pb acetate 10 mg/kg/d p.o. H 6 wks. EDTA or DTPA given for 5 days w/ or w/o Se 17 to 138 μg/dL after Pb 58 μg/dL after EDTA. 50 μg/dL after EDTA + Se Selenium had no additional benefit 

higher ALAD and lower ZPP in blokidney. Flora et al. (1989) Albino rats Pb acetate 10 mg/kg/d p.o. H 6 wks Thiamine, Zn or thiamine + Zn H 6 wks 6.2 to 120.9 μg/dL after Pb 44.1 μg/dL after thiamine + Zn Thiamine given as 25 mg/kg/d and 

ALAD restored by combined Rx. Laffected to a minor degree but brain 

Flora et al. (1994) Wistar albino rats Pb acetate 10 mg/kg/d H 56 days p.o. EDTA or EDTA + Zn H 5 days p.o. 4.6 to 43.0 μg/dL in Pb. 22.5 μg/dL in EDTA 16.5 μg/dL in EDTA + Zn. CaNa2 EDTA given as 0.3 mmol/k

or 50 mg/kg/d. ALAD partially resnot after EDTA. EDTA reduced Pb but not in brain. Zn conc increased by 50 mg Zn dosage. 
 AX5-120 Table AX5-7.5 (cont’d). Effect of Other Metals on Lead Author Animal Species Lead Dosage Blood Lead Finding

Satija and Vij (1995) Albino rats Pb acetate 20 mg/kg/d i.p. H 3 days Zn acetate 5 mg/kg/d i.p. H 3 days — Pb caused a decrease in Hgb, ALAD

synthetase, partially restored by ZnSH reduced by Pb, partially restore

Munoz et al. (1993) Wistar rats Pb acetate 60 ppm H 90 days, Zn or methionine given simultaneously <60 μg/dL-Pb SAM reduces to average of 7.3 μg/dL S-adenosyl-l-methionine (SAM) red

uroporphyrinogen I synthetase. RBand 2 Rx. Liver ALAD decreased b

Tandon et al. (1997) Albino rats Pb acetate 10 mg/kg/d H 8 wks p.o. Ethanol, Zn and lysine H 8 wks 1.8 to 47.2 μg/dL w Pb. Decreased to 34.2 μg/dL w Zn + lysine. Ethanol reduced blood but not liver 

Zn + lysine partially restored ALADreduced Pb in kidney. Hashmi et al. (1989) Rats Pb acetate 1000 ppm H 6 wks Fe-deficient or norm diet — Fe deficiency increased Pb in liver, 

increased femur Pb at 3 wks and de

Tandon et al. (1993) Rats Pb acetate 400 momol/kg i.p. H 1 Fe deficient and Fe-sufficient diets 

H 6 wk 

— 

Pb induced hepatic metallothionein Pb restored kidney and intestinal Mby Fe def. Pb in liver and kidney e

Crowe and Morgan (1996) 

 Wistar rat pups Pb acetate 2000 ppm H 15, 21, and 

63 days Fe def and Fe suff diets 

At 63 days Fe def410 μg/dL Fe suff rats 170 μg/dL 

Fe deficiency increased blood and kbrain or liver Pb. Fe levels in brain unaffected by Pb intoxication. 

Singh et al. (1991) 

Pregnant female albino rats 

Pb acetate 250–2000 ppm from 

15–20 days of gestation. 

At 2000 ppm Pb, Fe def 220 μg/dL Fe suff 160 μg/dL 

Fe def and Fe suff diets given to daremoved on 21st day. At 2000 ppmplacenta, and fetus higher in Fe deffetal kidney. 

Shakoor et al. (2000) 

Albino rats Pb acetate 125 mg/kg H 90 days 

Al chloride 50–100 mg/kg H 90 days — 

Plasma creat 1.88 mg/dL in Pb-Rx’Pb + Al-Rx’ed Kidney Pb increased 220 μg/g in Pb-Rx’ed, decreased to 
AX5-121 

ANNEX TABLES AX5-8 
 AX5-122 Table AX5-8.1. Bone Growth in Lead-exposed Animals Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level 

Pb acetate 41.7 mg Pb/l 83.3 mg Pb/l 166.6 mg Pb/l 12 to 16 wks Drinking water Rat Pb level in bone of control animals Wk 0 = 1.3 ± 0.83 μg Pb/g; Wk 4 = 1.2 ± 0.99 μg Pb/g; Wk 8 = 1.3 ± 1.08 μg Pb/g; Wk 12 = 0.8 ± 0.13 μg Pb/g; Wk 16 = 1.3 ± 0.95 μg Pb/g Pb level in bone of animals receiving 41.7 mg Pb/l Wk 0 = 1.0 ± 0.50 μg Pb/g; Wk 4 = 5.9* ± 1.76 μg Pb/g; Wk 8 = 2.9* ± 1.15 μg Pb/g; Wk 12 = 6.2* ± 1.01 μg Pb/g; Wk 16 = 6.0* ± 0.75 μg Pb/g Pb level in bone of animals receiving 83.3 mg Pb/l Wk 0 = 2.0 ± 0.97 μg Pb/g; Wk 4 = 11.7* ± 3.56 μg Pb/g; Wk 8 = 8.8* ± 3.37 μg Pb/g; Wk 12 = 14.3* ± 4.29 μg Pb/g Pb level in bone of animals receiving 166.6 mg Pb/l Wk 0 = 0.9 ± 0.23 μg Pb/g; Wk 4 = 17.0* ± 3.89 μg Pb/g; Wk 8 = 35.7* ± 3.64 μg Pb/g; Wk 12 = 21.7* ± 5.11 μg Pb/g; *significantly higher than control animals at corresponding time point Not given Pb aerosol 77, 249, or 1546 μg/m3 for 50 to 70 days Inhalation Rat 16.9 ± 6.6 μg Pb/g bone taken up in animals exposed to 77 μg/m3 for 70 days versus 0.2 ± 0.2 μg Pb/g in control animals; 15.9 ± 4.3 μg Pb/g bone in rats exposed to 249 μg/m3 for 50 days; 158 ± 21 μg Pb/g bone in rats exposed to 1546 μg/m3 for 50 days Control: 2.6 μg/dL 77 μg/m3: 11.5 μg/dL 249 μg/m3: 24.1 μg/dL 1546 μg/m3: 61.2 μg/dL 

Pb acetate 250 ppm or 1000 ppm 7 wks to females prior to mating, continuing through gestation and lactation Drinking water Rat Offspring body weight was depressed relative to controls during suckling (Day 11) and after weaning (Day 24) in high dose and continuously Pb-exposed groups. Continuous Pb exposure caused a greater decrease in offspring body weight than Pb exposure only prior to or after parturition. Decreased tail length growth suggested possible effects of Pb on tail vertebral bone growth. Dams prior to mating: Control = 2.7 ± 0.6 μg/dL 250 ppm = 39.9 ± 3.5 μg/dL 1000 ppm = 73.5 ± 9.3 μg/dL 
 AX5-123 Table AX5-8.1 (cont’d). Bone Growth in Lead-exposed Animals Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level 

Pb acetate Hi Pb animals 5000 ppm for 6 mo, reduced to 1000 ppm; Lo Pb animals 100 ppm Drinking Water Rat In male rats exposed to 100 ppm Pb in drinking water and a low calcium diet for up to one yr, bone density was significantly decreased after 12 mo, while rats exposed to 5000 ppm Pb had significantly decreased bone density after 3 mo. Pb content of femurs was significantly elevated over the content of control rats at all time points (1, 3, 6, 9, 12 mo). Trabecular bone from the low dose animals was significantly decreased from 3 mo forward. Low Pb (μg%): 1 mo Control = 2 ± 1; Exp = 19 ± 10* 3 mo Control = 2 ± 1; Exp = 29 ± 4* 6 mo Control = 3 ± 1; Exp = 18 ± 2* 9 mo Control = 1 ± 1; Exp = 17 ± 3* 12 mo Control = 3 ± 1; Exp = 21 ± 3* Hi Pb (μg%): 1 mo Control = 3 ± 1; Exp = 45 ± 13* 3 mo Control = 3 ± 1; Exp = 90 ± 15* 6 mo Control = 4 ± 1; Exp = 126 ± 10* 9 mo Control = 4 ± 1; Exp = 80 ± 39* 12 mo Control = 3 ± 1; Exp = 59 ± 18* *p < 0.001 Pb acetate 17 mg per kg of feed 50 days In diet Rat No differences in the length of the femurs, but the mean length of the 5th lumbar vertebra was significantly decreased. The mean length of the femur growth plate cartilage was also significantly decreased in Pb- exposed animals. Not given Pb acetate 17 mg per kg of feed 50 days In diet Rat No differences in the length of the femurs, but the mean length of the 5th lumbar vertebra was significantly decreased. The mean length of the femur growth plate cartilage was also significantly decreased in Pb- exposed animals. Not given 
 AX5-124 Table AX5-8.1 (cont’d). Bone Growth in Lead-exposed Animals Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level 

Pb acetate 0.6% GD 5 to Adulthood (various) In drinking water Rat Early bone growth was significantly depressed in a dose-dependent fashion in pups of Pb-exposed pups, with growth suppression in male offspring considerably greater than females. Significant decreases in plasma insulin-like growth factor and plasma sex steroids and increased pituitary growth hormone were also observed. Groups: DDW = Dams and pups received distilled deionized water entire study Ac/Ac = Dams and pups received acetic acid solution entire study Preg = Dams received 0.6% Pb water from GD 5 to parturition Lact = Dams received 0.6% Pb water during lactation only P + L = Dams received 0.6% Pb water from GD 5 through lactation Postnatal = Dams and pups received 0.6% Pb water from parturition through adulthood Pb/Pb = Dams and pups received 0.6% Pb water from GD 5 through adulthood Whole blood Pb (μg/dL) in male/female offspring at age Day 85: DDW = 5.5 ± 2.0/6.8 ± 1.5; Ac/Ac = 1.9 ± 0.2/1.4 ± 0.3; Preg = 9.1 ± 0.7*/11.6 ± 4.6*; Lact = 3.3 ± 0.4/3.4 ± 0.8; P + L = 16.1 ± 2.3*/10.4 ± 1.8*; Postnatal = 226.0 ± 29.0*/292.0 ± 53.0*; Pb/Pb = 316.0 ±53.0*/264.0 ± 21.0* *p < 0.05 compared to Ac/Ac group. Pb acetate 0.05% to 0.45% GD 5 through sacrifice of pups at 21, 35, 55, and 85 days In drinking water Rat Early bone growth was significantly depressed in a dose-dependent fashion in pups of all Pb-exposed groups, with growth suppression in male offspring considerably greater than females. Significant decreases in plasma insulin-like growth factor and plasma sex steroids and increased pituitary growth hormone were also observed. Between age 57 and 85 days growth rates were similar in control and Pb-exposed pups, suggesting exposure at critical growth periods such as puberty and gender may account for differences in growth reported by various investigators. Offspring: 0.05% Pb = 49 ± 6 μg/dL; 0.15% Pb = 126 ± 16 μg/dL; 0.45% Pb = 263 ± 28 μg/dL Pb nitrate 0.02% (125 ppm) GD5 to 1 day before sacrifice In drinking water Rat Exposure to 0.02% Pb nitrate (125 ppm Pb) did not significantly affect growth, though males weighed significantly less than females. Rat Pups 5 days old: 43.3 ± 2.7 μg/dL 49 days old: 18.9 ± 0.7 μg/dL (females: 19.94 ± 0.8 μg/dL; males: 17.00 ± 1.1 μg/dL) 
 AX5-125 Table AX5-8.1 (cont’d). Bone Growth in Lead-exposed Animals Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level 

Pb acetate 0.15% or 0.45% GD 4 until Day 55 In drinking water Rat A dose-dependent decrease in load to failure in tibia from Pb-exposed (0.15% and 0.45% Pb acetate in drinking water) male pups only. Hormone treatments (L-dopa, testosterone or dihydrotestosterone in males, or estradiol in females) failed to attenuate Pb deficits during the pubertal period. Distraction osteogenesis experiments performed after stabilization of endocrine parameters (at 100 days of age) found decreased new endosteal bone formation and gap x-ray density in the distraction gaps of Pb-exposed animals. Offspring: 0.15% Pb = 67–192 μg/dL; 0.45% Pb = 120–388 μg/dL Pb acetate 1000 ppm 22–26 days In drinking water Rat Pb disrupted mineralization during growth in demineralized bone matrix implanted subcutaneously into male rats. In the matrix that contained 200 micrograms Pb/g of plaque tissue, alkaline phosphatase activity and cartilage mineralization were absent, though calcium deposition was enhanced. Separate experiments found enhanced calcification and decreased alkaline phosphatase activity in rats implanted with a control (no Pb) matrix and given 1000 ppm Pb in drinking water for 26 days. Blood Pb (μg/dL) Control: Implantation Day 0 = 1.3 ± 0.6; Day 8 = 2.2 ± 0.9; Day 12 = 2.1 ± 0.7. Pb added to matrix: Implantation Day 0 = 1.5 ± 0.8; Day 8 = 5.7 ± 0.8a,b; Day 12 = 9.5 ± 0.5a,b. Pb in drinking water: Implantation Day 0 = 129.8 ± 6.7a; Day 8 = 100.6 ± 6.8a,b Day 12 = 96.4 ± 5.3a,b. a Significant (p # 0.05) difference from control. 

b Significance (p # 0.05) 

difference from corresponding value at implantation (Day 0). 

AbbreviationsMg—milligram μg—microgram ppm—parts per million GD—gestational day Pb—lead g—gram μg%—microgram percent 

l—liter m3 -—cubic meter 

Exp—experimental group wk—week dL—deciliter %—percent 
 AX5-126 Table AX5-8.2. Regulation of Bone Cell Function in Animals—Systemic Effects of Lea

Compound Dose/Concentration Duration Exposure Route Species Effects Blood Lev

Pb acetate 30 mg/kg Single i.v. injection Rat Groups of male rats were killed 0.5, 5, 15, and 30 min and 1, 2, 6, and 12 h after the single Pb injection. Serum calcium and phosphorus levels both initially increased after Pb injection with serum phosphorus reaching a maximum value (13.5 mg%) after 30 min and calcium (17 mg%) after 1 h. Calcium and phosphorus levels decreased after 1 h and returned to baseline levels after 12 h. Not given 

Ingestion of 0.82% Pb in male rats fed either a low phosphorus or low calcium diet reduced plasma levels of 1,25-(OH)2CC, while Pb had no effect in rats fed either a high calcium diet or a normal phosphorus diet. Effect of Pb on serum 1,25-(OH)2CC levels in rats fed low P or normal P diet Dietary Phosphorus 0.1% 0.1% 0.1% 0.3% 0.3% 0.3% Supplement Control Cholecalciferol 0.82% Pb+Cholecalciferol Control Cholecalciferol 0.82% Pb+Cholecalciferol Serum 1,25-(OH)2CC <10 pg/mL 248 ± 7 pg/mL 94 ± 13 pg/mL <10 pg/mL 285 ± 44 pg/mL 245 ± 46 pg/mL μg/100mL 3 ± 1 9 ± 8 352 ± 40 <3 <3 284 ± 36 Effect of Pb on serum 1,25-(OH)2CC levels in rats fed low Ca or high Ca diet Pb acetate 0.82% 1 wk In diet Rat Dietary Calcium 0.02% 0.02% 0.02% 1.2% 1.2% 1.2% Supplement Control Cholecalciferol (50ng/day) 0.82% Pb+Cholecalciferol Control Cholecalciferol (50ng/day) 0.82% Pb+Cholecalciferol Serum 1,25-(OH)2CC <10 pg/mL 754 ± 18 pg/mL 443 ± 79 pg/mL <10 pg/mL 285 ± 44 pg/mL 245 ± 46 pg/mL μg/100mL <3 <3 284 ± 36 

Pb acetate 0.15% or 0.45% GD 4 until Day 55 In drinking water Rat No effects of Pb on plasma concentrations of vitamin D metabolites, 25-OH D3 or 1,25- (OH2)D3, in pubertal male rats exposed to either 0.15% or 0.45% Pb acetate in drinking water and maintained on an adequate diet. Offspring: 0.15% Pb = 6

192 μg/dL; 0.Pb = 120– 388 μg/dL 
 AX5-127 Table AX5-8.2 (cont’d). Regulation of Bone Cell Function in Animals—Systemic Effects of 

Compound Dose/Concentration Duration Exposure Route Species Effects Blood LevPbCl2 0, 0.2, or 0.8% 1 or 2 wks In diet Chicks Compared with control animals, Pb exposure significantly increased intestinal calbindin protein and mRNA levels in addition to plasma 1,25-dihydroxyvitamin D concentration. The effect was present after 1 wk of exposure and continued through the second week. In calcium-deficient animals increased plasma 1,25-dihydroxyvitamin D and calbindin protein and mRNA were significantly (p < 0.05) inhibited by Pb exposure in a dose dependent fashion over the 2 wk experimental period. None given PbCl2 0, 0.2, or 0.8% 1 or 2 wks In diet Chicks Dose dependent increases in serum 1,25-(OH2)D3 levels (and Calbindin-D protein and mRNA) with increasing dietary Pb exposure (0.1% to 0.8%) in experiments performed on Leghorn cockerel chicks fed an adequate calcium diet. None given 

Short term administration of 1% Pb resulted in significant increases in bone Pb. Total serum calcium and ionized serum calcium were significantly decreased, as compared to controls. Circulating levels of 1,25-(OH2)D3 were also decreased, though the rats were maintained on a normal calcium diet (0.95%). In the long term study, a dose-dependent increase in parathyroid weight occurred with increasing exposure to Pb in drinking water. Short term (10 wks) exposure Serum Calcium (mM) Ionized Calcium (mM) 1,25(OH)2D3 (pM) Parathyroid Weight (μg/gland) *p < 0.01 Controls 2.42 ± 0.03 1.25 ± 0.03 232 ± 18.9 96 ± 34 Pb-exposed 2.32 ± 0.02* 1.15 ± 0.03* 177 ± 10.8* 178 ± 25* Long term (24 wks) exposure Pb in water Normalized Parathyroid Weight (μg/g body wt) 1,25(OH)2D3 (pM) Pb acetate 1% for 10 wks or 0.001–1% for 24 wks In drinking water Rat 0% 0.001% 0.01% 0.1% 1.0% p < 0.01 0.50 ± 0.06 0.72 ± 0.25 0.81 ± 0.28 0.94 ± 0.27 0.81 ± 0.29* 241 ± 32 188 ± 27 163 ± 17 206 ± 24 144 ± 33* Short term (10 

study: Control: < 0.02 μg/l Pb-exposed: > 5μg/l 
 AX5-128 Table AX5-8.2 (cont’d). Regulation of Bone Cell Function in Animals—Systemic Effects of 

Compound Dose/Concentration Duration Exposure Route Species Effects Blood LevPb nitrate 0.02% (125 ppm) GD5 to 1 day before sacrifice In drinking water Rat Basal release of growth hormone from control and Pb-exposed pups at age 49 days was not significantly different. Growth hormone releasing factor-stimulated release of growth hormone from pituitaries of Pb-exposed pups was smaller than the stimulated release of growth hormone from pituitaries of control animals (75% increase over baseline vs. 171% increase, respectively), but the difference did not achieve significance (P = 0.08). Growth hormone content of the pituitary glands was also not influenced by Pb exposure. Rat Pups 5 days old: 4

2.7 μg/dL 49 days old: ± 0.7 μg/dL (females: 19.0.8 μg/dL; ma17.00 ± 1.1 μ

Pb acetate 0.05% to 0.45% GD 5 through sacrifice of pups at 21, 35, 55, and 85 days In drinking water Rat Pituitary GH content (μg/mg) at postnatal day 55: Control Male Pups = 56.6 ± 8.0; Female Pups = 85.6 ± 9.3 0.05% Pb Male Pups = 107.2 ± 10.5*; Female Pups = 116.2 ± 9.1 0.15% Pb Male Pups = 96.8 ± 5.0*; Female Pups = 105.1 ± 7.3 0.45% Pb Male Pups = 106.0 ± 9.8*; Female Pups = 157.0 ± 9.9* *significantly different from control, p < 0.05 Offspring: 0.05% Pb = 4

μg/dL; 0.15% 126 ± 16 μg/d0.45% Pb = 228 μg/dL 

Abbreviations mg—milligram h—hour 1,25-(OH)2CC—1,25-dihydroxycholecalcigerol μg—microgram 25-OH D3—25-hydroxycholecalciferol PbCl2—lead chloride 1,25-(OH)2 D3—vitamin D3 kg—kilogram mg%—milligram percent pg—picogram GD—gestational day mM—millimolar Pb—lead pM—picomolar i.v.—intravenous %—percent mL—milliliter dL—deciliter mRNA—messenger ribonucleic acid ppm—parts per million GH—growth hormone min—minute 
 AX5-129 Table AX5-8.3. Bone Cell Cultures Utilized to Test Effects of Lead Compound Dose/Concentration Duration Exposure Route Species Effects Blood Lev

Stable “Pb” 5 mg/mL in drinking water given during gestation. On GD 18, 50 μCi 210Pb given i.v. to pregnant dams Rat (fetal bone organ culture) PTH (3885 IU/mg bone) enhanced cell-mediated release of 210Pb from bone. Release of 210Pb was accompanied by proportional loss of stable Pb and calcium from treated bones. Time: Release of 210Pb (EM/CM ratio) 0 min 1.00 10 min 0.82 ± 0.05 2 hr 1.12 ± 0.04 6 hr 1.59 ± 0.08* 24 hr 3.69 ± 0.15* 48 hr 3.75 ± 0.09* 48 hr 0.78 ± 0.14* (in presence of 30 mU/mL salmon calcitonin) *Different from 1.00, p < 0.01. Not given/not applicable 210Pb nitrate 6.5 to 65 μM 5 min to 2 h In medium Mice (bone cell isolation from calvaria) Uptake of 210Pb by OC cells rapid. OC cells have greater avidity for Pb compared to OB cells. OC cell uptake of Pb almost linear vs. little increase in Pb uptake by OB cells with increasing Pb concentrations in media. 15–30% release of 210Pb label occurred in OC cells over 2 h time period. Physiological concentrations of PTH resulted in marked increase in 210Pb and 45Ca uptake by OC cells. 210Pb uptake linear over PTH concentrations of 50 to 250 ng/mL). Media concentrations of Pb $26 μM enhanced calcium uptake by cells. Not applicabl210Pb nitrate 5 μM 20 hours In medium Mice (osteoclastic bone cell isolation from calvaria) Three readily exchangeable kinetic pools of intracellular Pb identified, with the majority (~78%) associated with the mitochondrial complex. Not applicablPb acetate 0 to 50 μM 20 h In medium Mice (osteoclastic bone cell isolation from calvaria) Cultures were labeled with 45Ca (25 μCi/mL) for 2 or 24 h and kinetic parameters were examined by analysis of 45Ca washout curves. In kinetic analysis using dual-label (1–2 μCi/mL 210Pb and 25 μCi/mL 45Ca) wash out curves, the Ca:Pb ratios of the rate constants were ~1:1, suggesting similar cellular metabolism. Not applicabl
 AX5-130 Table AX5-8.3 (cont’d). Bone Cell Cultures Utilized to Test Effects of Lead Compound Dose/Concentration Duration Exposure Route Species Effects Blood Lev

Pb acetate and 210Pb label 0–100 μM 20 hr In medium Mice (osteoclastic bone cell isolation from calvaria) and Rat Osteosarcoma Cells (ROS 17/2.8) Concentrations as high as 100 μM did not cause toxicity in either cell culture. There was a slight decrease in growth of ROS cells at 5 μM Pb concentration and a 50% decrease in growth at 25 μM Pb at day 9. 210Pb washout experiments with both cell cultures indicated similar steady-state Pb kinetics and intracellular Pb metabolism. Both cell cultures exhibited one large, slowly exchanging pool of Pb, indicative of the mitochondrial pool. Not applicablPb acetate 5 or 25 μM Up to 5 hr In medium Rat Osteosarcoma Cells (ROS 17/2.8) Used 19F NMR in combination with 1,2-bis(2-amino-5-fluorophenoxy)ethane- N,N,N’,N’-tetraacetic acid (5F-BAPTA) to distinguish and measure concentrations of Pb2+ and Ca2+ in aqueous solution. Basal concentration of [Ca2+]i was 128 ± 24 nM. Treatment of cells with 5 and 25 μM Pb2+ produced sustained 50% and 120% increases in [Ca2+]i, respectively, over a 5 hour exposure period. At a medium concentration of 25 μM Pb2+ a measurable entry of Pb2+into the cells ([Pb2+]i of 29 ± 8 pM) was noted. Not applicabl

Pb nitrate 5 μM 20 min In medium Rat (osteoblastic bone cell isolation from calvaria) Pb (5 μM) linearly raised the emission ratio of FURA-2 loaded cells 2-fold within 20 min of application, most likely due to increase in [Pb2+]i rather than increase in [Ca2+]i. Intracellular calcium increased even in the absence of extracellular calcium. Not applicablPb2+ 5 or 12.5 μM Up to 100 min In medium Rat (osteoblastic bone cell isolation from calvaria) 5 or 12.5 μM Pb2+ applied simultaneously with re-added calcium reduced immediate CRAC to 70% or 37% of control value, respectively. During CRAC a large influx of Pb2+ occurred, leading to a 2.7-fold faster increase in the FURA-2 excitation ratio. These effects were exclusive of any inhibitory action of Pb2+on calcium ATPase activity. Not applicabl
 AX5-131 Table AX5-8.3 (cont’d). Bone Cell Cultures Utilized to Test Effects of Lead Compound Dose/Concentration Duration Exposure Route Species Effects Blood Lev

Pb nitrate 0–150 μM Up to 72 hr In medium Mice (bone cell isolation from parietal bones) Pb2+ concentrations of 50 μM and above stimulated release of hydroxyproline and previously incorporated 45Ca from organ culture. This did not occur in bone inactivated by freezing and thawing. Eel calcitonin, bafilomycin A1, and scopadulcic acid B significantly inhibited Pb mediated 45Ca release. There was a high correlation between 45Ca and PGE2 release (p < 0.001), inferring Pb-induced bone resorption mediated by PGE2. This was further supported by the significant depression of Pb- stimulated 45Ca release that occurred with concurrent exposure to 10 μM of either indomethacin or flurbiprofen, both inhibitors of cyclooxygenase. Not applicablPb acetate 0–25 μM 48 hr In medium Rat Osteosarcoma Cells (ROS 17/2.8) Osteocalcin production in cells treated with 100 pg 1,25-dihydroxyvitamin D3/mL of medium and 0 μM Pb2+ for 16, 24, or 36 h was 20.1 ± 2.1, 23.5 ± 3.4, 26.1 ± 2.5 in cell digests, and 87.2 ± 3.3, 91.6 ± 6.7, 95.1 ± 5.2 in the medium, respectively. The presence of 25 μM Pb2+in the medium, reduced osteocalcin levels to as low as 30% of control levels. Cells treated with 0, 5, 10, or 25 μM Pb acetate for 24 h, followed by an additional 24 h exposure to 0 or 100 pg of 1,25-dihydroxyvitamin D3 and continued Pb2+ exposure, resulted in a concentration-dependent reduction of 1,25-dihydroxyvitamin 

D3-stimulated osteocalcin secretion. 10 μM Pb resulted in medium osteocalcin levels 

similar to control levels, however, 25 μM Pb resulted in about a 30% decrease. Cellular osteocalcin levels were unaffected.

Not applicabl

Pb glutamate 4.5 H 10−5 to 

4.5 H 10−7 M 2, 4, or 6 days In medium 

Rat Osteosarcoma Cells (ROS 17/2.8) 

In the presence of serum in the cultures, concentrations of Pb2+ less than 4.5 H 10−5 M 

had no effect on cell proliferation. In the absence of serum, 4.5 H 10−7 M Pb2+

increased proliferation at Day 4 and 4.5 H 10−6 M Pb2+ inhibited proliferation at Day 6.

Pb exposure for 48 h (4.5 H 10−6 M) significantly (p < 0.01) increased total protein 

production in cells and media of cultures labeled with [3H] proline, but did not 

increase collagen production. Protein synthesis and osteonectin were enhanced in cells following Pb2+ exposure. 

Not applicabl

Pb glutamate 4.5 H 10−5M–10−7M 

1,3, or 5 days incubation In medium 

Human Dental Pulp Cells 

All concentrations significantly increased cell proliferation on Day 1, 3, and 5 of 

exposure in serum free conditions. Pb exposure resulted in dose-dependent decrease in intracellular protein and procollagen I production over 5 days. In presence of serum only, 4.5 H 10−5M Pb2+ significantly increased protein production, however, at that 

same concentration Pb significantly decreased osteocalcin production (i.e., reduced the level of osteocalcin by 55% at 12 hr). 

Not applicabl
 AX5-132 Table AX5-8.3 (cont’d). Bone Cell Cultures Utilized to Test Effects of Lead Compound Dose/Concentration Duration Exposure Route Species Effects Blood Lev

Pb glutamate 5–20 μM 48 hr In medium Rat Osteosarcoma Cells (ROS 17/2.8) Cells treated with 0, 5, 10, or 20 μM Pb acetate for 24 h, followed by an additional 24 h exposure to 0 or 100 pg of 1,25-dihydroxyvitamin D3 and continued Pb2+ exposure, resulted in a significant (p < 0.05 or less) reduction of osteocalcin secretion, both in the presence and absence of 1,25-dihydroxyvitamin D3 at all Pb2+ concentrations. This effect is not mediated by PKC. Not applicablPb 0.5 to 5 μM 40 min In medium Rat Osteosarcoma Cells (ROS 17/2.8) 1 and 5 μM Pb2+ significantly increased [Ca2+]i in the absence of 1,25- dihydroxyvitamin D3 and significantly reduced the peak elevation in [Ca2+]i induced by 1,25-dihydroxyvitamin D3. Simultaneous treatment of previously unexposed cells to Pb2+and 1,25- dihydroxyvitamin D3 produced little reduction in the 1,25-dihydroxyvitamin D3- induced 45Ca uptake, while 40 min of treatment with Pb2+ before addition of 1,25- dihydroxyvitamin D3 significantly reduced the 1,25-dihydroxyvitamin D3-induced increase in 45Ca influx. Not applicabl

Pb nitrate 5 H 10−4 to 5 H 10−15 M 24 h In medium Rat Osteosarcoma Cells (ROS 17/2.8) Osteocalcin secretion significantly reduced below control values by culture with 1 μM Pb2+ in the presence or absence of added 1,25-dihydroxyvitamin D3 or 1,25- dihydroxyvitamin D3 and IGF-I. Inhibition of osteocalcin secretion was almost complete in either hormone-stimulated or basal cultures with the addition of 100 μM Pb2+. Cellular alkaline phosphatase activity paralleled those of osteocalcin, though there was no response to IGF-I alone or in combination with 1,25-dihydroxyvitamin 

D3. Pb2+at 10−15, 10−12, and 10−9 to 10−7 M did not influence DNA contents of cell 

cultures, but 1 μM significantly (p < 0.05) inhibited basal cultures and those with IGFI + D3. Cell cultures exposed to 1,25-dihydroxyvitamin D3 and Pb2+ were inhibited at 

10 μM Pb2+. 

Not applicabl

Pb acetate 2 to 200 μM 72 h In medium 

Rat Osteosarcoma Cells (ROS 17/2.8) 

Pb (2 to 200 μM) had no effect on cell number or DNA and protein synthesis. Alkaline phosphatase activity was significantly reduced (p < 0.001) by Pb in a doseand time-dependent manner. Pb Concentration. Alkaline Phosphatase Inhibition 2 μM. 10.0 ± 1.1% 20 μM. 22.0 ± 6.4% 200 μM. 57.8 ± 8.8% Reductions in alkaline phosphatase mRNA levels mirrored Pb2+ -induced inhibition of 

enzyme activity. 

Not applicabl
 AX5-133 Table AX5-8.3 (cont’d). Bone Cell Cultures Utilized to Test Effects of Lead Compound Dose/Concentration Duration Exposure Route Species Effects Blood Lev

Unidentified Pb2+ Various incubation times Not applicable Bovine (Bovine- derived osteocalcin) Binding studies of Ca2+ to osteocalcin suggested a single binding site with a dissociation constant (Kd) of 7 ± 2 μM for Ca-osteocalcin. Competitive displacement experiments by addition of Pb2+ indicated the Kd for Pb-osteocalcin is 1.6 ± 0.42 nM, ~3 orders of magnitude higher. Not applicablUnidentified Pb2+ Various incubation times Not applicable Bovine (Bovine- derived osteocalcin) Circular dichroism indicated Pb2+ binding induced a structural change in osteocalcin similar to that found in Ca2+ binding, but at 2 orders of magnitude lower concentration. Pb2+ has 4 orders of magnitude tighter binding to osteocalcin (Kd = 0.085 μM) than Ca2+ (Kd = 1.25 mM). Hydroxyapatite binding assays showed similar increased adsorption of Pb2+ and Ca2+ to hydroxyapatite, but Pb2+ adsorption occurred at a concentration 2–3 orders lower than Ca2+. Not applicabl

Pb acetate 10 μM 2 h In medium Rat Osteosarcoma Cells (ROS 17/2.8) Pb2+ treatment reduced the unidirectional rate of ATP synthesis (Pi to ATP) by a factor of 6 or more (

∆M/Mo: Control = 0.18 ± 0.04, Pb2+ < 0.03). Intracellular free Mg2+ 

concentration decreased 21% after 2 h of 10 μM Pb2+ treatment (0.29 ± 0.02 mM prior 

to Pb2+ treatment and 0.23 ± 0.02 mM after 2 h of Pb2+ treatment, p < 0.05). 

Not applicabl

Pb acetate 5 or 25 μM Up to 24 h In medium 

Rat Osteosarcoma Cells (ROS 17/2.8) 

5 μM Pb2+ significantly altered effect of EGF on intracellular calcium metabolism. 

In cells treated with 5 μM Pb2+ and 50 ng/mL EGF, there was a 50% increase in total 

cell calcium over cells treated with 50 ng/mL EGF alone. 

Not applicabl

Pb acetate 5 or 25 μM 20 h In medium 

Rat Osteosarcoma Cells (ROS 17/2.8) 

Treatment with 400 ng/mL culture medium for 1 h or with 25 μM Pb2+ for 20 h increased total cell calcium: Treatment Cell Calcium

Control 7.56 ± 1.05 nmol/mg protein PTH (400 ng/mL) 23.28 ± 1.40* nmol/mg protein Pb (25 μM) 11.37 ± 0.57* nmol/mg protein PTH + Pb 37.88 ± 4.21* nmol/mg protein * p # 0.05 from control 

Not applicabl
 AX5-134 Table AX5-8.3 (cont’d). Bone Cell Cultures Utilized to Test Effects of Lead Compound Dose/Concentration Duration Exposure Route Species Effects Blood Lev

Pb acetate 10−11 to 10−7 M 3 min In medium Rat Osteosarcoma Cells (ROS 17/2.8) Treatment of ROS cells with Pb at 1 or 5 μM concentrations produced a rise in [Ca2+]i to 170 nM and 230 nM, respectively, over the basal level of 125 nM. An elevation in [Ca2+]i to 210 nM occurred during treatment with an activator of PKC, phorbol 12- myristate 13-acetate (10 μM). Pretreatment with a selective inhibitor of PKC, calphostin C, did not change basal [Ca2+]i, but prevented the Pb-induced rise in [Ca2+]i. Free Pb2+activated PKC in a range from 10−11 to 10−7 M, with a Kcat (activation constant) of 1.1 H 10−10 M and a maximum velocity (Vmax) of 1.08 nmol/mg/min compared with Ca activation of PKC over a range of 10−8 to 10−3 M, with a Kcat of 3.6 H 10−7 M, and a Vmax of 1.12 nmol/mg/min. Not applicablPb acetate 0.5 to 60 μM 24 to 48 h In medium Human Osteosarcoma Cells (HOS TE 85) and Rat Osteosarcoma Cells (ROS 17/2.8) HOS TE 85 Cells Inhibition of proliferation (IC50) = 4 μM Pb Cytotoxicity = 20 μM Pb ROS 17/2.8 Cells Inhibition of proliferation (IC50) = 6 μM Pb Cytotoxicity = 20 μM Pb Highest Pb concentration in both cell types found in mitochondrial fraction. Not applicabl

Pb acetate or Pb chloride 0.1 to 200 μM 24 h to 6 days In medium Chick growth plate chondrocytes Growth plate chondrocytes were exposed to 3 or 30 μM for up to 6 days. Maximal inhibition of cell proliferation as measured by thymidine incorporation occurred after a 3-day exposure to Pb. A similar 40% inhibition was found at both concentrations. Higher concentrations (up to 100 μM) did not produce further inhibition. In cultures treated for 24 h, Pb produced a dose-dependent inhibition of alkaline phosphatase, with 10 μM producing maximal inhibition (40–50% inhibition). Effects of Pb on proteoglycan synthesis were not found until after 48 h of exposure, with maximal effect after 72 h of exposure (twofold, 30 μM). Pb exposure (10 to 200 μM) for 24 h produced a dose-dependent inhibition of both type II and type X collagen synthesis. Not applicabl
 AX5-135 Table AX5-8.3 (cont’d). Bone Cell Cultures Utilized to Test Effects of Lead Compound Dose/Concentration Duration Exposure Route Species Effects Blood Lev

Pb acetate 0.1 to 30 μM 24 h In medium Chicken growth plate and sternal chondrocytes A dose-dependent inhibition of thymidine incorporation into growth plate chondrocytes was found with exposure to 1–30 μM Pb for 24 h. A maximal 60% reduction occurred at 30 μM. Pb blunted the stimulatory effects on thymidine incorporation produced by TGF-β1 (24% reduction) and PTHrP (19% reduction), however, this effect was less than with Pb alone. Pb (1 and 10 μM) increased type X collagen in growth plate chondrocytes ~5.0-fold and 6.0-fold in TGF-β1 treated cultures and 4.2-fold and 5.1-fold in PTHrP treated cultures when compared with controls, respectively. Pb exposure alone reduced type X collagen expression by 70–80%. Not applicablAbbreviations Pb—lead μCi—microCurie IU—international units hr—hour OB—osteoblast 5F-BAPTA—1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N’,N’-tetraacetic acid [Pb2+]i—free intracellular lead FURA-2—1-[6-Amino-2-(5-carboxy-2-oxazolyl)-5-benzofuranyloxy]-2-(2-amino-5- methylphenoxy) ethane-N,N,N',N'-tetraacetic acid M—molar DNA—deoxyribonucleic acid 

∆M—decrease in magnetization of intracellular Pi upon prolonged saturation of gammaphosphate of ATP 

mM—millimolar Kcat—activation constant IC50—inhibitory concentration 50% 

mg—milligram 

210Pb—lead-210 radionuclide 

EM—experimental medium mU—milliunits 

45Ca—calcium-45 radionuclide 

CRAC—calcium release activated calcium reflux pg—picogram mRNA—messenger ribonucleic acid ng—nanogram 

Vmax—maximum velocity

TGF-β1—transforming growth factor-beta 1 mL—milliliter i.v.—intravenous CM—control medium μM—micromolar ng—nanogram [Ca2+]i —free intracellular calcium 

PGE2—prostaglandin E2

PKC—protein kinase C Kd—dissociation constant nmol—nanomole HOS TE 85 cells—human osteosarcoma cells PTHrP—parathyroid hormone-related protein GD—gestational day PTH—parathyroid hormone min—minute OC—osteoclast ROS 17/2.8—rat osteosarcoma cells nM—nanomolar h—hour IGF-I—insulin growth factor I ATP—adenosine triphosphate EGF—epidermal growth factor 
 AX5-136 Table AX5-8.4. Bone Lead as a Potential Source of Toxicity in Altered Metabolic Condit

Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level Pb acetate 200 μg/mL 105 days prior to mating or 105 days prior to mating and during gestation and lactation (160 days) In drinking water Mice Results suggested very little Pb was transferred from mother to fetus during gestation, however, Pb transferred in milk and retained by the pups accounted for 3% of the maternal body burden of those mice exposed to Pb prior to mating only. The amount of Pb retained in these pups exceeded that retained in the mothers, suggesting lactation effectively transfers Pb burden from mother to suckling offspring. Transfer of Pb from mothers was significantly higher when Pb was supplied continuously in drinking water, rather than terminated prior to mating. Not given Pb acetate 12 mM 8 wks prior to mating and during gestation In drinking water Rat Considerably higher lactational transfer of Pb from rat dams compared to placental transfer was reported. Continuous exposure of rat dams to Pb until day 15 of lactation resulted in milk Pb levels 2.5 times higher than in whole blood, while termination of maternal Pb exposure at parturition yielded equivalent blood and milk levels of Pb, principally from Pb mobilized from maternal bone. Concentration (μg/l) 

whole blood at day 1lactation: Controls = 14 ± 4; Pbexposed until parturit320 ± 55; Pb-exposed until day 15 of lactati1260 ± 171* *p < 0.001 compared dams at parturition. 

Pb acetate 100 ppm (A) Exposure for 158 ± 2 days from 21 days of age to midlactation; (B) Exposure 144 ± 2 days from day 21 up to delivery; (C) Exposure only during lactation; (D, E, and F) groups of nonpregnant rats exposed for periods equivalent to groups A, B and C, respectively. In drinking water 

Rat In rats exposed to Pb 144 days prior to lactation (B), the process of lactation 

itself elevated blood Pb and decreased bone Pb, indicating mobilization of Pb from bone as there was no external source of Pb during the lactation process. 

Rats exposed to Pb for 158 days (A)(144 days prior to lactation and 14 days during lactation) also experienced elevated blood Pb levels and loss of Pb from bone. Pb exposure only during the 14 days of lactation was found to significantly increase intestinal absorption and deposition (17 fold increase) of 

Pb into bone compared to nonpregnant rats, suggesting enhanced absorption of 

Pb takes place during lactation. The highest concentration of Pb in bone was found in nonpregnant, nonlactating control animals, with significantly decreased bone Pb in lactating rats secondary to bone mobilization and transfer 

via milk to suckling offspring. 

Concentration (μg/dLwhole blood at day 1lactation or equivalenGroup A = 31.2 ± 1.1Group B = 28.0 ± 1.7Group D = 27.3 ± 2.2Group E = 24.7 ± 1.2 
 AX5-137 Table AX5-8.4 (cont’d). Bone Lead as a Potential Source of Toxicity in Altered Metabolic Co

Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level Pb acetate 100 ppm (A) Exposure for 158 ± 2 days from 21 days through 14 days of lactation; (B) Nonpregnant control Group A; (C) Exposure 144 ± 2 days from day 21 up to delivery; (D) Nonpregnant control Group C; (E) Lactating rats not exposed to Pb; (F) Nonpregnant rats not exposed to Pb. In drinking water Rat When dietary calcium was reduced from the normal 1 to 0.05%, bone calcium concentration decreased by 15% and bone Pb concentration decreased by 30% during the first 14 days of lactation. In nonlactating rats on the 0.05% calcium diet, there were also decreases in bone calcium, but no incremental bone resorption nor Pb efflux from bone, suggesting the efflux from bone during lactation was related to bone resorption. Enhancement of calcium (2.5%) in the diet of lactating rats increased calcium concentration in bone by 21%, but did not decrease bone resorption, resulting in a 28% decrease in bone Pb concentration and concomitant rise in systemic toxicity. Concentration (μg/dL

whole blood at day 1lactation or equivalenGroup B = 26.1 ± 2.1Group A = 32.2 ± 2.7Group D = 23.8 ± 2.1Group C = 28.2 ± 2.2Groups E and F = 5.1 0.4. * p < 0.01, compared appropriate control 

Pb acetate 250 mg/mL Beginning at 5 wks of age, rats exposed to Pb for 5 wks, followed by no additional exposure. In drinking water Rat Demonstrated adverse effects in rat offspring born to females whose exposure to Pb ended well before pregnancy. Five wk-old-female rats given Pb acetate in drinking water (250 mg/mL) for five wks, followed by a one mo period without Pb exposure before mating. To test the influence of dietary calcium on Pb absorption and accumulation, some pregnant rats were fed diets deficient in calcium (0.1%) while others were maintained on a normal calcium (0.5%) diet. All Pb-exposed dams and pups had elevated blood Pb levels; however, pups born to dams fed the diet deficient in calcium during pregnancy had higher blood and organ Pb concentrations compared to pups from dams fed the normal diet. Pups born to Pb-exposed dams had lower mean birth weights and birth lengths than pups born to non-Pb-exposed control dams (p < 0.0001), even after confounders such as litter size, pup sex, and dam weight gain were taken into account. Blood Pb concentrati

pups (μM): Low calcium/no Pb = 0.130.030C; Low calcium

1.160 ± 0.053A; Norm

calcium/No Pb = 0.030.003C; Normal calcium/Pb = 0.771 ± 0.056B. Values that are not marked by the same lare significantly diffe(p < 0.05). 
 AX5-138 Table AX5-8.4 (cont’d). Bone Lead as a Potential Source of Toxicity in Altered Metabolic Co

Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level Pb acetate 1500 μg/Common Pb/kg/d ~10 yrs, replaced by a 204Pb-enriched dose (50 days), then 206Pb-enriched dose (50 days), and finally a 207Pb-enriched dose (50 days, with reduced concentration) Orally, in gelatin capsule Nonhuman Primate Sequential doses of Pb mixes enriched in stable isotopes ( 204Pb, 206Pb, and 207Pb) were administered to a female cynomolgus monkey (Macaca fascicularis) that had been chronically administered a common Pb isotope mix. The stable isotope mixes served as a marker of recent, exogenous Pb exposure, while the chronically administered common Pb served as a marker of endogenous (principally bone) Pb. From thermal ionization mass spectrometry analysis of the Pb isotopic ratios of blood and bone biopsies collected at each isotope change, and using end-member unmixing equations, it was determined that administration of the first isotope label allowed measurement of the contribution of historic bone stores to blood Pb. Exposure to subsequent isotopic labels allowed measurements of the contribution from historic bone Pb stores and the recently administered enriched isotopes that incorporated into bone. In general the contribution from the historic bone Pb (common Pb) to blood Pb level was constant (~20%), accentuated with spikes in total blood Pb due to the current administration of the stable isotopes. After cessation of each sequential administration, the concentration of the signature dose rapidly decreased. Total blood Pb range

31.2 to 62.3 μg/100g

Pb acetate 1300 to 1500 μg/Common Pb/kg/d ~10 yrs, replaced by a 204Pb-enriched dose (47 or 281 days), then 206Pb-enriched dose (50 or 105 days), and finally a 207Pb-enriched dose (50 days, with 650 μg concentration in only one primate) Orally, in gelatin capsule Nonhuman Primate Initial attempts to apply a single bone physiologically based model of Pb kinetics were unsuccessful until adequate explanation of these rapid drops in stable isotopes in the blood were incorporated. Revisions were added to account for rapid turnover of the trabecular bone compartment and slower turnover rates of cortical bone compartment, an acceptable model evolved. From this model it was reported that historic bone Pb from 11 yrs of continuous exposure contributes ~17% of the blood Pb concentration at Pb concentration over 50 μg/dL, reinforcing the concept that the length of Pb exposure and the rates of past and current Pb exposures help determine the fractional contribution of bone Pb to total blood Pb levels. The turnover rate for cortical (~88% of total bone by volume) bone in the adult cynomolgus monkey was estimated by the model to be ~4.5% per yr, while the turnover rate for trabecular bone was estimated to be 33% per yr. Various 
 AX5-139 Table AX5-8.4 (cont’d). Bone Lead as a Potential Source of Toxicity in Altered Metabolic Co

Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level Pb acetate 1100 to 1300 μg/Common Pb/kg/d ~14 yrs, replaced by a 204Pb-enriched dose, 206Pb-enriched dose, and/or finally a 207Pb-enriched dose of varied durations and concentrations. Orally, in gelatin capsule Nonhuman primate Using the method of sequential stable isotope administration examined flux of Pb from maternal bone during pregnancy of 5 female cynomolgus monkeys. Blood Pb levels in maternal blood attributable to Pb from mobilized bone were reported to drop 29 to 56% below prepregnancy baseline levels during the first trimester of pregnancy. This was ascribed to the known increase in maternal fluid volume, specific organ enlargement (e.g., mammary glands, uterus, placenta), and increased metabolic activity that occurs during pregnancy. During the second and third trimesters, when there is a rapid growth in the fetal skeleton and compensatory demand for calcium from the maternal blood, the Pb levels increased up to 44% over pre-pregnancy levels. With the exception of one monkey, blood Pb concentrations in the fetus corresponded to those found in the mothers, both in total Pb concentration and proportion of Pb attributable to each isotopic signature dose (common = 22.1% vs. 23.7%, 204Pb = 6.9% vs. 7.4%, and 206Pb = 71.0% vs. 68.9%, respectively). Between 7 and 25% of Pb found in fetal bone originated from maternal bone, with the balance derived from oral dosing of the mothers with isotope during pregnancy. In offspring from a low Pb exposure control monkey (blood Pb <5 μg/100 g) ~39% of Pb found in fetal bone was of maternal origin, suggesting enhanced transfer and retention of Pb under low Pb conditions Various, with total bl

Pb as high as ~65 μg

Pb acetate 250 mg/L Exposure began either at 5, 10, or 15 wks of age and continued for a total of 5 wks. Drinking water Rat Exposed rats for 5 wks to 250 mg/l Pb as acetate in drinking water beginning at 5 wks of age (young child), 10 wks of age (mid-adolescence), or 15 wks of age (young adult), followed by a 4 wk period of without Pb exposure. An additional group of rats were exposed to Pb beginning at 5 wks, but examined following an 8 or 20 wk period after cessation of Pb. Significantly lower blood and bone Pb concentrations were associated with greater age at the start of Pb exposure and increased interval since the end of exposure. Young rats beginning exposure to Pb at 5 wks and examined 20 wks after cessation of exposure still, however, had bone Pb concentrations higher than those found in older rats only 4 wks after cessation of exposure. Pb concentration (μM

4 wks after cessation exposure: Exposure started at 5 of age = 1.39 ± 0.09; Exposure started at 1of age = 1.18 ± 0.12; Exposure started at 1of age = 0.82 ± 0.05. 
 AX5-140 Table AX5-8.4 (cont’d). Bone Lead as a Potential Source of Toxicity in Altered Metabolic Co

Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level Pb acetate 50 ppm 11 mo Drinking water Rat Studied differences in tissue distribution of Pb in adult and old rats. Adult (8 mo old) and old (16 mo old) rats were exposed to 50 ppm Pb acetate in drinking water for 11 mo at which time the experiment was completed. Bone (femur) Pb levels in older rats were found to be less than those in younger rats, however, blood Pb levels were higher in the older rats. Brain Pb concentration in the older rats exposed to Pb were significantly higher, and brain weight significantly less than the brain Pb concentration and weights of unexposed older control rats or adult rats exposed to Pb, suggesting a potential detrimental effect. Authors suggested that a possibility for the observed differences in tissue concentrations of Pb was due to changes in the capacity of bone to store Pb with advanced age. Approximate median values after 6 mo of exposure: Adult rats : 23 μg/dL Old rats: 31 μg/dL After 11 mo of expos

Adult rats: 16 μg/dL Old rats: 31 μg/dL 

Pb acetate 0, 2, or 10 mg/kg/d 9.5 mo Drinking water Rat Examined kinetic and biochemical responses of young (21 days old), adult (8 mo old), and old (16 mo old) rats exposed to Pb at 0, 2, or 10 mg Pb acetate/kg/d over a 9.5 mo experimental period. Results suggested older rats may have increased vulnerability to Pb due to increased exposure of tissues to Pb and greater sensitivity of the tissues to the effects of Pb. Various from ~1 μg/d

up to 45 μg/dL 

Pb acetate 7 yrs total Drinking water Nonhuman primate In studies of bone Pb metabolism in a geriatric, female nonhuman primates exposed to Pb ~10 yrs previously, there were no significant changes in bone Pb level over a 10 mo observation period as measured by 109CD K X-ray fluorescence. The mean half-life of Pb in bone of these animals was found to be 3.0 ± 1.0 yrs, consistent with data found in humans, while the endogenous exposure level due to mobilized Pb was 0.09 ± 0.02 μg/dL blood. Historic concentratio

during exposure: 44 89 μg/100 mL. 

Pb (type unidentified) occurring naturally in diet (0.258 ng/mg dry wt) and water (5.45 ppb). Exposure from age 1 mo up to 958 days. Drinking water and diet Mice The Pb content of femurs increased by 83% (values ranged from 0.192 to 1.78 ng Pb/mg dry wt), no significant relationship was found between Pb and bone density, bone collagen, or loss of calcium from bone. The results suggest against low levels of bone Pb contributing to the osteopenia observed normally in C57BL/6J mice. None given 
 AX5-141 Table AX5-8.4. (cont’d). Bone Lead as a Potential Source of Toxicity in Altered Metabolic Co

Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level Pb acetate 250 mg/l Exposure for 5 wks Drinking water Rat Rats were exposed to Pb for 5 wks, followed by a 4 wk washout period without Pb to allow primarily accumulation in the skeleton. Rats were then randomly assigned to a weight maintenance group (WM), a moderate weight loss (MWL) group (70% of maintenance diet), or a substantial weight loss (SWL) group (40% of maintenance diet) for a 4 wk period. At the end of this experimental period the blood and bone levels of Pb did not differ between groups, however, the amount and concentration of Pb in the liver increased significantly. Treatment Group Pb (nmol/g) Femur WM 826 ± 70 MWL 735 ± 53 SWL 935 ± 84 Spinal Column Bone WM 702 ± 67 MWL 643 ± 59 SWL 796 ± 59 WM = 1.25 ± 0.10 μM

MWL = 1.16 ± 0.10 μWM = 1.32 ± 0.10 μM

Pb acetate 250 μg/l 14 days Drinking water Rat Study was undertaken to determine the effect of weight loss and exercise on the distribution of Pb. Weight loss secondary to dietary restriction was a critical factor elevating organ Pb levels and, contrary to prior study (Han et al. (1996)), elevated blood levels of Pb. No significant difference in organ or blood Pb concentrations were reported between the exercise vs. no exercise groups. Graphs indicate concentrations rangin

from 0.20 to 2.00 μM

Abbreviations μg—microgram mL—milliliter %—percent mM—millimolar l—liter ppm—parts per million dL—deciliter mg—milligram μM—micromolar Pb—lead kg—kilogram g—gram 204Pb, 206Pb, 207Pb—Stable isotopes of lead 204, 206, 207, 

wt—weight ppb—parts per billion 
 AX5-142 Table AX5-8.5. Uptake of Lead by Teeth Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level 

Pb acetate 1 μg/kg body weight Single IP injection Rat Uptake of Pb label into incisors of suckling rats: 0.7% of injected dose in 4 incisors of suckling rat after 24 h, 1.43% after 192 h. 0.6% of injected dose in 4 incisors of adult after 24 h, 0.88% after 192 h. Mean percent of dose af

time: Suckling: 3.04% after 24 h 1.71% after 72 h 1.52% after 144 h 1.18% after 192 h Adult: 6.40% after 24 h 3.41% after 24 h 1.92% after 24 h 1.04% after 72 h 0.72% after 144 h 0.48% after 192 h 

Pb aerosol 77, 249, or 1546 μg/m3 for 50 to 70 days Inhalation Rat 11 micrograms Pb/g incisor taken up in animals exposed to 77 μg/m3 for 70 days vs. 0.8 μg Pb/g in control animals 13.8 μg Pb/g incisor in rats exposed to 249 μg/m3 for 50 days 153 μg Pb/g incisor in rats exposed to 1546 μg/m3 for 50 days Control: 2.6 μg/dL 77 μg/m3: 11.5 μg/dL 249 μg/m3: 24.1 μg/dL 1546 μg/m3: 61.2 μg/d

Pb acetate 0, 3, or10 ppm During pregnancy and 21 days of lactation Drinking water Rat Pb concentration in teeth of offspring: 0 ppm group–Incisors (1.3 ppm), 1st molars (0.3 ppm) 3 ppm group–Incisors (1.4 ppm), 1st molars (2.7 ppm) 10 ppm group–Incisors (13.3 ppm), 1st molars (11.4 ppm) Not given 

Abbreviations μg—microgram kg—kilogram IP—intraperitoneal %—percent h—hour 

m3—cubic meter 

Pb—lead g—gram ppm—parts per million 
 AX5-143 Table AX5-8.6. Effects of Lead on Enamel and Dentin Formation Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level 

Pb “salt” 0.075 mM/100 g , 0.15 mM/100 g or 1.5 mM/100 g Single, SC injection Rat 0.075 mM dose, no disruption of dentin and enamel. 0.15 mM dose, mild mineralization disruption of dentin and enamel. 1.5 mM dose, mild to moderate disruption of dentin and enamel. Not given Pb acetate 30 mg/kg Single, i.v. injection Rat Rapid rise in serum calcium and phosphorus after injection. Formation of a “Pb line” in growing dentin within 6 hr after injection. Not given 

Pb acetate 3 mg/kg Single, i.v. injection Rat Production of a hypomineralized band in dentin. Not given 

Pb acetate 0 mg/l, 34 mg/l, or 170 mg/l 70 days Drinking water Rat Increased in relative amount of protein in enamel matrix. Significant (p < 0.05) decrease in microhardness values of groups exposed to Pb in regions of maturation enamel, but not fully mature enamel. Delay in enamel mineralization in animals exposed to Pb. 0 mg/l group: 0 ppm 34 mg/l group: 18.1 ppm 170 mg/l group: 113.3 ppm 

Pb acetate 40 mg/kg Single, IP injection Rat Significantly (p < 0.05) reduced eruption rates at various time points (days 8, 14, 16, 22, 24, 28) under hypofunctional conditions. Days after injection 0 days: 48 μg/dL 10 days: 37 μg/dL 20 days: 28 μg/dL 30 days: 16 μg/dL (Values estimated from graph) 

Abbreviations Pb—lead mM—millimolar g—gram SC—subcutaneous 

mg—milligram kg—kilogram 

i.v.—intravenous l—liter ppm—parts per million IP—intraperitoneal μg—microgram dL—deciliter 
 AX5-144 Table AX5-8.7. Effects of Lead on Dental Pulp Cells Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level 

Pb glutamate 4.5 H 10−5M–10−7M 1,3, or 5 days incubation Human Dental Pulp Cells All concentrations significantly increased cell proliferation on Day 1, 3 and 5 of exposure in serum free conditions. Pb exposure resulted in dose- dependent decrease in intracellular protein and procollagen I production over 5 days. In presence of serum only 4.5 H 10−5M significantly increased protein production. Pb significantly decreased osteocalcin production. Not applicable Abbreviations Pb

—lead 

M

—molar 
 AX5-145 

Table AX5-8.8. Effects of Lead on Teeth—Dental Caries 

Compound Dose/Concentration Duration Exposure Route Species Effects Blood Level Pb acetate 0.5 mEq 84 days males 98 days females Drinking water 

Hamster Significant increase in dental caries in male hamsters only 

(85 mean molar caries score control vs. 118 for Pb exposed). No significant difference in dental caries in female hamsters (68 mean molar caries score control vs. 85 for Pb exposed). 

Not given Wisotz

Pb acetate 34 ppm Pre- and perinatal Drinking water 

Rat Pb exposure resulted in an almost 40% increase in the 

prevalence of caries and nearly 30% decrease in stimulated parotid salivary gland function. 

Control: <5 μg/dL 34 ppm Pb: 48 ± 13 μg/dL 

Wat

Pb acetate 10 or 25 ppm Pb 3 wks Drinking water 

Rat When 15 ppm fluoride was concurrently given in diet, Pb did 

not increase prevalence of caries. 

Not given Tabch

Abbreviations

mEq—milliequivalents d—days ppm—parts per million %—percent μg—microgram dL—deciliter 
 AX5-146 

ANNEX TABLES AX5-9 
 AX5-147 Table AX5-9.1. Studies on Lead Exposure and Immune Effects in Humans Nature of Exposure Dose or Blood Lead Levels (BLLs) Sample Population Reported Effects 

Environmental 10.1–48.2 μg/L (BLL) 2nd grade children living near industrial waste incinerator or other industries causing pollution Increased blood Pb concentration associated w/ increased IgE, especi

28 μg/dL. Also decreased T-cells, cytotoxic T-cells, and B-cells (non-linear rela

Occupational 22 μg/dL: <30 yrs old 23.0 μg/dL: 30–39 yrs old 24.1 μg/dL: $40 yrs old Employees of Pb storage battery factories in Korea 554 Men 52 Women Serum IgE higher when BLL >30 μg/dL—Correlation of BLL with s

For employees less than 30 yrs old, IL-4 was lower when BLL >30 μ

Environmental 3.47–49.19 μg/dL Children 6–11 yrs of age 30 girls 35 boys Proximity to smelter Indirect (PHA) macrophage activation. NO production negatively associated with BLL. With proximity closest to smelter monocytes had increased superoxid

production by indirect and direct activation (positive correlation with stronger for boys than girls). 

Environmental 2.56–43.69 μg/dL (mean 9.52 μg/dL) 38 preschool children (3–6 yrs of age); 35 controls Percent of CD4+ and CD4+CD+ cells decreased while CD8+ increased

Occupational Range of 10.0–400.9 μg/dL Mean = 88.3 μg/dL Controls all below 10 μg/dL Male Pb-exposed workers PHA-mitogen response decreased; and IFN-gamma production increa

No effect on NK cytotox. 

Environmental 2.56–43.69 μg/dL (BLL mean of 9.52 μg/dL) 96 females 121 males (3–6 yrs old) IgG and IgM lower in high BLL group ($9.52 μg/dL). IgE greater in high BLL group (P < 0.10). No difference among males but females exposed to higher Pb had sig

decreases in IgG and IgM and increased in IgE. Correlation of BLL and serum IgE r = 0.48; P = 0.002. 

Occupational 10–20 yr exposure (original BLL mean 60 μg/dL; at time of study BLL mean = 30 μg/dL) 30 Pb workers from battery manufacturing plant (43 males and 21 females) Increased percentage of monocytes while percentage of B-cells, numb

lymphocytes, monocytes, and granulocytes decreased. 

Occupational 74.8 ± 17.8 μg/dL vs. 16.7 ± 5.0 μg/dL for controls 25 male storage battery workers exposed >6 mo; age 33 ± 8.5 yrs Decreased blood hemoglobin, TCD4+ cells, IgG, IgM, C3 and C4 com

proteins. Increased zinc protoporphyrin. Impaired neutrophil chemotaxis and random migration. 
 AX5-148 Table AX5-9.1 (cont’d). Studies on Lead Exposure and Immune Effects in Humans Nature of Exposure Dose or Blood Lead Levels (BLLs) Sample Population Reported Effects 

Environmental 1.7–16.1 μg/dL (Range in <3 yr old group) 1561 children and adults in high Pb community 480 controls 

6–35 mo: 

increased IgA, IgG, IgM, number and proportion of B lymphocytes decreased proportion of T-lymphocytes especially true when BLL > 1>3 yrs of age–no differences. 

Epidemiological study 

Blood Pbs from 1–45 μg/dL Urban Children population in 

Missouri; 56% male 279 children 9 mo–6 yr of age 

Correlation of blood Pb levels and serum IgE levels in Missouri child

Occupational BLL=39 

Range 15–55 μg/dL 

145 Pb exposed workers 84 controls 

No major effects; only subtle effects. Elev. B cells elevated CD4+/CD45RA+ cells. Decr. Serum IgG. 

Occupational Pb workers with BLL between 

7–50 μg/dL; mean 19 μg/dL 

71 male chemical plant workers vs. 29 controls 

T cell populations, Naïve T cells correlated positively with blood PB levels. Memory T reduced with Pb. 

Occupational Exposed—Range of 38–

100 μg/dL mean = 74.8 μg/dL; Controls 11–30 μg/dL mean = 

16.7 μg/dL (high controls!) 

25 Male battery plant workers vs. 25 controls 

Absolute and relative numbers of CD4+ T cells reduced in exposed grIgG, IgM C3 and C4 serum levels all lower in workers. 

Occupational BLL 12–80.0 μg/dL 33 male workers in a storage 

battery plant 

No changes in serum Igs of PHA response of PBMC. 

Occupational Males 

high BLL $25 μg/dL 

lower BLL <25 μg/dL control BLL #10 μg/dL 

51 Firearms instructors (high and lower) vs. controls 

T cell phenotypes and response—Pb reduced relative CD3+ cells and 

absolute CD4+ cells also reduced PHA (high Pb)and PWM mitogen rreduced MLR also(high Pb). 

Occupational >60 μg/dL for group showing 

best IgE effect 

2 groups of male workers occupationally exposed 

IgE positively correlated with BLL. 

Occupational BLL 14.8–91.4 μg/dL 39 male workers of storage battery 

plant (4 yr mean exposure) 

Impaired neutrophil migration. Impaired nitroblue tetrazolium positive neutrophils. Greater for those exposed up to 1 yr than those with longer exposure “of Pb can still cause immunosuppression. 

In vitro 207–1035 μg/L Human lymphocytes from adults 

25–44 yrs of age 

Pb associated with greater IgG production after stimulation with PWM

dependent. 
 AX5-149 Table AX5-9.1 (cont’d). Studies on Lead Exposure and Immune Effects in Humans Nature of Exposure Dose or Blood Lead Levels (BLLs) Sample Population Reported Effects 

Occupational 33.2 μg/dL in Pb-exposed group 2.7 μg/dL in controls 10 Male workers in scrap metal refinery vs. 10 controls PMN chemotaxis reduced to 2 different chemoattractants. Occupational 10 Pb exposure workers vs. controls Worker BLLs of 41–50 μg/dL No controls >19 μg/dL ConA-generated suppressor cell production—increased. Some other cellular parameters unchanged. 

Occupational Blood Pbs 64 μg/dL Range 21–90 39 male workers in Pb exposed group PHA response of lymphocytes from workers decreased. 

Occupational Comparison of workers with 25–53 μg/dL vs. controls with 

8–17 μg/dL 

Workers exposure to Pb No change in serum Ig levels PHA response of cells or NK activity. 

Environmental Near smelter BLLs varied 

seasonally 25–45 μg/dL 

Control area BLLs varied seasonally 10–22 μg/dL 

Boys and girls ~11.5 yrs old living near Pb smelting plant 

Higher BLL associated with: decreased 

)-amino levulinic acid dehyd

Decreased IgM and secretory IgA. Inversely related to IgG. 

Occupational Workers (18–85.85.2 μg/dL 

BLL) controls (6.6–20.8 μg/dL BLL) 

73 workers vs. 53 controls Negative correlation of BLL and serum IgG and C3. 

Positive correlation of BLL and saliva IgA. 

Environmental 12 Afr.- American children 

BLLs 41–51μg/dL; 

7 controls BLLs 14–30 μg/dL 

12 African American preschool children vs. 7 controls 

No difference in anti-tetanus antibody levels or in complement levels. 
 AX5-150 Table AX5-9.2. Effect of Lead on Antibody Forming Cells (In Vitro Stimulation) Species Strain/Gender Age Effect In Vivo/ Ex Vivo Lead Dose/ Concentration Durat

of Expo

Mouse Various Adult ↑AFC No 10 μM 5 days Mouse Various Adult AFC No change Yes 10 mM in water 8 wks 

Mouse CBA/J females Adult ↑AFC primary response No 100 μM 5 days 

Mouse BDF1 females Adult ↑AFC—T dependent antigen AFC—T independent antigen, no change 50 μg Pb acetate in water 3 wks 

Mouse CBA/J females Adult ↑AFC Yes 0.08 mM and 0.4 mM 4 wks 

Mouse CBA/J Adult ↑AFC No 10−5 M 5 days 

Mouse CBA/J females Adult ↑AFC No 10−4 M 1 hr preincuMouse Swiss males Adult ↓AFC Yes 0.5 ppm tetraethyl Pb 3 wks 

Mouse Swiss Adult ↓AFC Yes 1300 ppm 10 wks 

Rat SD Neonate– Juvenile 

↓AFC (IgM) Yes 25 ppm and 50 ppm 3 wks prena

6 wks postn

Mouse Swiss Adult ↑AFC–IgM 

↓AFC–IgG 

Yes 4 mg i.p. or oral Single dose 

Mouse Swiss Adult ↓AFC–IgM 

↓AFC–IgG 

Yes 13.75 ppm–1,375 ppm 8 wks 
 AX5-151 Table AX5-9.3. Studies Reporting Lead-induced Suppression of Delayed Type Hypersensitivity and R

Species Age Strain/Gender Route Lowest Effective Dose Durat

of Expo

Rat Embryo SD females Oral to Dam 250 ppm (BLL at 4 wk = 6.75 μg/dL) 5 wks Chicken Embryo Cornell K females in ovo 200 μg Single injec

Rat Fetal CD females Oral to Dam 500 ppm 6 days 

Rat Embryo–fetal F344 and CD females Oral to Dam 250 ppm 3 wks Rat Embryo–fetal F344 females Oral to Dam 250 ppm (BLL = 34.8μg/dL at birth) 3 wks 

Chicken Embryo Cornell K females in ovo 200 μg (BLL = 11 μg/dL) Single injecMouse Adult BALB/c females Oral 512 ppm (BLL = 87 μg/dL) 3 wks Rat Embryo-fetal F344 females Oral to Dam 250 ppm Pb acetate 5 wks (2 be

during gesta

Rat Embryo-fetal F344 females Oral to Dam 250 ppm Pb acetate 5 wks (2 be

during gesta

Goat Adult Females Gastric intubation 50 mg/kg Pb acetate 6 wks 

Rat Adult Wistar males Oral 6.3 m mol kg -1 8 wks 

Mouse Adult Swiss s.c. 0.5 mg/kg/d Shortest = 3 

just prior to challenge 

Rat Neonatal/ Juvenile CD females Oral 25 ppm Pb acetate (BLL= 29.3 μg/dL) 6 wks 

Mouse Adult BALB/c i.p. 0.025 mg Pb acetate 30 days 
 AX5-152 Table AX5-9.4. Effect of Lead on Allogeneic and Syngeneic Mixed Lymphocyte Respon

Species Strain/Gender Age Proliferation Effects In Vivo/ Ex Vivo Lead Dose/Concentration Duration of Exposure Mouse C57Bl/6 and BALB/c Adult ↑Allo-MLR No 0.1 μM 4 days MRat Lewis males Adult ↑Allo-MLR 

↑Syngeneic-MLR 

No 50 ppm Pb acetate 4 days R

(

Mouse CBA/J females Adult ↑Allo-MLR No 10−6–10−4 M 5 days L

Mouse CBA/J females Adult ↑Allo-MLR Yes 0.08 mM and 0.4 mM 4 wks L

Mouse DBA/2J males Adult Allo-MLR no 

significant change 

Yes 13, 130 and 1300 ppm 10 wks K
 AX5-153 Table AX5-9.5. Effect of Lead on Mitogen-induced Lymphoid Proliferation Species Strain/ Gender Age Proliferation Effects In Vivo/ Ex Vivo Lead Dose/ Concentration Duration of Exposure 

Human 

C Adult ↓PHA Yes Not available Occupational M

Mouse TO males Adult ↓ConA 

↓LPS 

Yes 1 mg/kg daily 2 wks F

(

Mouse Several Adult PHA stimulation No 

change 

No 25 μM 3 days M

Rat Lewis and F344 

males 

Adult ↑ConA 

↑LPS 

No 25 ppm 3 days R

Mouse CBA/J Adult LPS No change No 10 μM 3 days MRat AP strain males Adult PHA No change Yes 100 ppm and 1,000 ppm 2–20 wks K

Mouse CBA/J females Adult ConA 

LPS No change 

No 10−4 M 2 days W

Mouse BDF1 females Adult ↑ConA 

↑PHA ↑Staph A enterotoxin LPS no change 

Yes 0–1,000 ppm 3 wks B

Rat SD males Adult ↑ConA 

↑PHA ↑LPS 

Yes 1% Pb acetate in diet 2 wks B

Mouse CBA/J females Adult PHA no change 

↓LPS (high doses only) 

Yes 10 mM 4 wks L

Mouse CBA/J females Adult ConA, PHA no change 

↑LPS 

No 10−6

–10−4 M 2.5 days L

Mouse CBA/J females Adult ConA, PHA no change 

↑LPS 

No 10−6

–10−4 M 2–5 days L
 AX5-154 Table AX5-9.5 (cont’d). Effect of Lead on Mitogen-induced Lymphoid Proliferation Species Strain/ Gender Age Proliferation Effects In Vivo/ Ex Vivo Lead Dose/ Concentration Duration of Exposure 

Mouse C57 Bl/6 males Adult ↓PHA 

↓ConA LPS No change 

Yes 1,300 ppm 8 wks N

Rat SD females Neonatal–

Juveniles 

↓PHA ↓ConA 

Yes 25 ppm 6 wks F

Mouse BALB/c Adult ↑LPS No 10−5

–10−3 M 3 days G

Mouse Swiss males Adult ↓PHA 

↓PWM 

Yes 2,000 ppm 30 days G

Mouse Swiss males Adult ↑PHA 

↑PWM 

No 0.1 mM–1.0 mM 2–3 days G

(

Mouse CBA/J Adult ↑LPS Yes 13 ppm 18 mo K

Mouse BALB/c Adult ↑LPS No 10−5–10−3 M 2–3 days S
 AX5-155 Table AX5.9.6. Pattern of Lead-induced Macrophage Immunotoxicity Species Strain/ Gender Age Function In Vivo/ Ex Vivo Lowest Effective Dose Duration of Exposure 

Nitric Oxide Human Both genders Juvenile ↓NO Yes NK P

(

Rat CD males Embryo ↓NO Yes 500 ppm 6 days BChicken Cornell K strain females Embryo ↓NO Yes 10 μg One injection (E5) L

Mouse BALB/c females Adult ↓NO No 20 μg/mL one lower dose ↑NO 2 hrs KChicken HD-11 cell line - ↓NO No 4.5 μg 18 hrs C

Mouse CBA/J females Adult ↓NO No 1.0 μg 4 days TMouse CBA/J females Adult ↓NO No 0.625 μM 4 days T

Reactive Oxygen Intermediates Human Associated in males Juvenile ↑ROI Yes NK NK P

(

Rat Not indicated NK ↑ROI No 240 μM 3 hrs S

(

Mouse BALB/c females Adult ↑ROI Yes 1.5 mg/kg diet 30 days B

Rabbit New Zealand white males Adult ↑ROI Yes 31 μg/m3 inhaled 3 days Z
 AX5-156

ANNEX TABLES AX5-10 
 AX5-157 Table AX5-10.1. Hepatic Drug Metabolism Concentration Duration Species Blood Lead Effectsa 

2 days In vitro, rat microsomes Triethyl Pb — chloride, 0–3.0 mg/kg b. wt. In vitro, 0.0–3.0 mM triethyl Pb Not specified In vivo, rat microsomes — Triethyl Pb increased microsomal N-oxygenation in vivo and decreased microsomal C oxygenation by in vitro treatment. E

treatment thus gave rise to an increase in the N-oxygenation/Coxygenation ratio, which may lead to tumor potentiation. 

5 or 10 μmol/100g b. wt. Pb nitrate; i.v. 36 h Male Fischer 344 rats — Pb decreases phase I components (liver microsomal cyt.P-450

increases Phase II components (GST, DT diaphorase etc). Livcytosol in treated animals had a polypeptide that cross-reacted GSTP. 

5, 10, 50 mg Pb acetate kg!1 b. wt. Multiple durations (15 days, 2 and 3 mo) Female albino rats — Over all induction of cyt-p—450 and b5 in liver, long-term in

in liver GST and GSH. 

100 μmol/kg; i.v. Pb acetate 24 h Male Fischer 344 rats — Decrease in total CYP amount, selective inhibition of CYP1A

decrease in the expression at m-RNA and protein level, inductplacental form of glutathione s-transferase (GST-P). 

100 μmol/kg Pb nitrate; i.v. 9 h before or 6 h after 2-methoxy-4- aminoazobenzene (2-Meo-AAB) Male Fischer 344 rats — Male fisher rats treated with different metal ions 

CPb nitrate, 

chloride, cobalt chloride or cadmium chloride exhibited decretotal CYP amount in liver microsomes. However, only Pb redthe levels of the mRNA and protein of CYP 1A2 induced with methoxy-4-aminoazobenzene (2-Meo-AAB) and decreased thmicrosomal activity (Per CYP), Pb also induced placental form Glutathione, a marker enzyme for preneoplastic lesion. 

100 μmol/kg; i.v. Pb acetate 

24 h Male F 344 rats — Inhibition of CYP1A mRNA(s) by Pb nitrate is by aromatic am

not by aryl hydrocarbons. 

100 μmoles /kg; i.v. 

Multiple durations (3, 6, 12, 24, and 36 h) 

Male Wistar rats 

— Stimulation of TNF

α preceding hepatocyte DNA synthesis 

indicates a role for it in liver cell proliferation. Pb nitrate enhances sensitivity to bacterial LPS, in hepatocyte
 AX5-158 Table AX5-10.1 (cont’d). Hepatic Drug Metabolism Concentration Duration Species Blood Lead Effectsa 

Single 0.33 mg/kg- 1 Pb nitrate Multiple durations Male Wistar rats — Pb confers protection against the CCL4 induced hepatotoxicit

evident by marked reduction in serum Alanine aminotransfera(AST) and aspartate aminotransferase (AST) and this protectionot associated with the mitotic response of Pb. 

Pb acetate, 75 mg of Pb2+/kg, intraperitonial Multiple analyses up to 30 h C57BL/6 male mice — The decrease in P-450 as a result of Pb poisoning occurs at tw

levels. (1) A mechanism unrelated to heme, where Pb interferwith P-450 in 2 ways. (2) A mechanism dependent on heme, which Pb inhibits heme synthesis. 

0–10!6 M Pb nitrate 3 days Fish hepatoma cell line PLHC-1 — Effect of heavy metals Cu(II), Cd(II), Co(II), Ni(II), Pb(II), an

Zn(II), on Cytochrome induction (CYP1A) induction response Ethoxy resorufin-o-deethylase (EROD) activity. All metals had a more pronounced effect on EROD activity thCyp1 A protein. The rank order of the metal inhibition on ERCd(II) > Ni(II) > Cu(II) > Co(II) = Zn(II), Pb(II), Cd(II) and (May affect Cyp1 A system of the fish liver at low concentratiothrough the direct inhibition of CYP 1A enzyme activity. 

DT Diaphorase activity 0–125 mg/kg Pb acetate, Pb nitrate Time course experiments 100 mg/kg Pb acetate, i.p. 24 h–120 h Male Wistar rats — Pb acetate and nitrate induce DT diaphorase activity which is inhibited significantly by Dil a calcium antagonist, showing th

these changes are mediated by intracellular calcium changes. acetate induces DT diaphorase activity with out thymus atrophhence was suggested to be a monofunctional inducer as againsMethyl cholanthrene induced DT diaphorase activity. 

Cell viability assays 0–30 μM, for all other As , Pb, Hg, 5 μM, Cd, 1 μM 24 h in general and for EROD assays by PAHs 24–72 h Primary human hepatocytes — The effect of metals on PAH induced CYP1A and 1A2 as pro

by Ethoxy resorufin o- deethylase activity has demonstrated, m-Arsenic, Pb, mercury and cadmium decreased CYP1A1/ A2 expression by polycyclic aromatic hydrocarbons depending on dose, metal and the PAH. Arsenic was most effective, followPb, cadmium, and mercury. Cell viability was decreased by 228% by metals. 
 AX5-159 Table AX5-10.1 (cont’d). Hepatic Drug Metabolism Concentration Duration Species Blood Lead Effectsa 

10–100 μM, in vitro 24 h Murine hepatoma cell line — Effect of heavy metals on Aryl hydrocarbon regulated genes— metals alone did not induce a significant change in the cyp1a1 activity and protein levels but increased its m-RNA expression

AHR ligand-mediated induction of cyp1a1 activity and protein observed by all the metals. Pre and post translational modulatthis regulation have been implicated. These results demonstrathat the heavy metals differentially modulate the constitutive athe inducible expression of AHR regulated genes. 

5 and 10 μmoles/100 g of b.wt, single i.p — Wistar Rat — Pb nitrate induced the expression of Placental form of Glutath

transferase along with liver cell proliferation. The biochemicalesions induced by Pb under these conditions were similar to thepatic nodules. 

100 μmoles/100 g b. wt. Pb nitrate, single injection, i.v. Animals were sacrificed at 1, 2, 3, 4, and 15 days Wistar rats — Acute Pb treatment results in induced activity of Gamma-glut

transpeptidase, induced GSTP, a typical marker of pre neoplaslesion in most hepatocytes. Pb also inhibited liver adenylate cyclase activity 24 h postexposure. 

100 mg/kg i.p., single exposure Multiple analyses 0–96 h Male DDY strain mice — Pb decreased Glutathione content and decreased Glutathione s

transferase activity that is independent of Glutathione levels. 

100 μmol/kg body wt, i.v 70 h Male Sprague Dawley rats — Acute Pb nitrate treatment caused a significant increase of GS

activity in liver and kidney. While in liver the activity increasmainly due to isozyme GST 7-7, in kidney it is through the induction of all the isozymes. 

100 μmol/kg b. wt., intra cardiac Multiple time point analyses starting 6 days to 5 mo Male and female Wistar rats — Intracardiac administration of Pb acetate results in elevation o

glutathione transferase (GST) in Kupffer cells, the early respoGST.Yp was observed in sinusoidal cells and had a later patchresponse in the expression of GST.Yp Yp in hepatocytes 

10 μmol/100g b. wt., Pb nitrate, i.v. single dose Analyses at multiple time points 0–10 days Male Fischer 344 young adult rats — Glutathione transferase P1-1 is induced significantly by a sing

intravenous dose of Pb nitrate through increased transcription modulations at post transcription and translational levels. 
 AX5-160 Table AX5-10.1 (cont’d). Hepatic Drug Metabolism Concentration Duration Species Blood Lead Effectsa 

Pb nitrate, 100 μm/kg i.p, 3 times every 24 h 48 h — Pb acetate 100 μM/kg. 0.5–24 h Transgenic rats with 5 different constructs having GST-P and/or chloromphenica l acetyl transferase coding sequence. — GSTP (placental GST), is regulated by Pb at transcriptional le

GST-P enhancer (GPEI), is an essential cis-element required factivation of the GST-P gene by Pb and is involved in the actiregardless of the trans-activators involved. GPEI element conof two AP-1 binding sites. Activation of GST-P gene by Pb is mediated in major part by enhancer GPEI, which may involve activation partially. 10 nM Pb nitrate 24 h before transfection with ECAT deletion mutant, every 24 h there after till 48 h after transfection NRK Kidney fibroblasts — Pb induces GST-P in NRK normal rat kidney fibroblast cell li

10 mg Triethyl Pb, i.p. single dose Analyses at multiple durations (3, 4, 7, 10, or 14 days) Fischer 344 rats — Decreased liver Glutathione s-transferase (GST) activity and l

levels of several hepatic GST. Increase in quinone reductase activity by day 14 in liver. 

114 mg Pb acetate/kg b. wt. i.p Single (0.5–12 h group) or multiple (72 h and 7 days group) exposure Sprague Dawley — Pb exposure resulted in hepatic Glutathione (GSH) depletion a

increased malondialdehyde (MDA) production. 

A. 1.5–3.0 mg/kg wt Triethyl Pb (TEL) i.p. 2 exposures for 48 h Female Wistar — Pretreatment of rats did not affect the liver microsomal Oestra

17β metabolism or the content of cytochrome P-450 and cytochrome b5. B. 0.05–0.5, TEL to liver microsomal fractions 30 min incubations Liver microsomes from female Wistar rats — TEL at 0.05 mM significantly reduced 17β-hydroxy steroid oxidation and at concentration of 0.05 mM decreased 16α- hydroxylation. 
 AX5-161 Table AX5-10.1 (cont’d). Hepatic Drug Metabolism Concentration Duration Species Blood Lead Effectsa 

50 mg/kg, intragastric 8 wks Male Albino Wistar rats — Accentuation of liver membrane lipid peroxidation. significan

inhibition of liver antioxidant enzymes. Reduced ratio of reduglutathione(GSH) to oxidized glutathione (GSSG), 

Abbreviations b. wt.—body weight aCYP—Cytochrome P-450 

GSH—Glutathione GSSG—Oxidized glutathione TEL—Triethyl lead CCL—Carbon tetrachloride GSTP—Placental glutathione transferase MDA—Malondialdehyde Cu—Copper Cd—Cadmium Al—Aluminum Zn—Zinc Pb—Lead Ni—Nickel TNF

α—Tumor necrosis factor 

ALA—Alanine aminotransferase PAH—Polycyclic aromatic hydrocarbons LPS—Lipopolysaccharides 
 AX5-162 Table AX5-10.2. Biochemical and Molecular Perturbations in Lead-induced Liver Tiss

Concentration Duration Species Blood Lead Effectsa Pb-diethyl dithiocarbomate complex, Pb (DTC) 2, or Pb acetate 0.033– 10 μM 0.5–20 h Primary hepatocytes — Effect of interactions between Pb and diethyl dithiocarbomate (DTC) 

enzyme δ amino levulinic acid dehydratase in primary hepatocytes. Lipophilic Pb (DTC)2 caused a more rapid and stronger inhibition of activity than Pb acetate. Pb uptake is higher and more rapid with Pb (2 than Pb acetate. This increased inhibition of ALAD activity by Pb (2 might be due to facilitated cellular transport in the complexed form resulting in higher cellular concentrations of Pb. 

— — Primary rat hepatocytes — DTC decreases cellular effects of Pb and Cd despite unchanged/ even slightly increased concentrations of the metals. Hepatic ALAD was significantly inhibited in cells treated with Pb Ac and Pb (DTC)2. — — DBA and C57 mice — DBA mice(with a duplication of the ALAD gene accumulated twice t

amount of Pb in their blood and had higher Pb levels in liver and kidnthan mice with the single copy of the gene (C57), exposed to the same doses of the Pb during adult hood. Blood Zinc protoporphyrin (ZPP) increased with Pb exposure in C57 mice and were not affected in DBA mice. 

100 μmol/kg b. wt. i.v. single dose Single dose, analyses performed 12, 24, 48, 72, 96 and 168 h Male Wistar Albino Rats — First in vivo report showing association between Pb induced liver hyperplasia, Glucose-6-phosphate levels, and cholesterol synthesis. Pb treatment increased hepatic de novo synthesis of cholesterol as evi

by increased cholesterol esters and increase of G-6-PD to possibly supthe reduced equivalents for de novo synthesis of cholesterol. Changethese biochemical parameters were accompanied by liver hyperplasia

Pb nitrate, Single dose 100 μmol/kg b. wt. 0–168 h Male Wistar rats — Pb nitrate induces hepatic cell proliferation followed by reabsorption 

excess tissue with in 10–14 days. The proliferation was correlated wihepatic denovo synthesis of cholesterol, stimulation of hexose monophosphate shunt pathway and alterations in serum lipo proteins. 

Pb nitrate — Wistar rats — Pb nitrate induces multiple molecular forms of Glucose-6- phosphate dehydrogenase with an increase of band 3 and a concomitant increase 

band 1, shifting from the pattern induced by fasting with an increase iband 1. 
 AX5-163 Table AX5-10.2 (cont’d). Biochemical and Molecular Perturbations in Lead-induced Liver 

Concentration Duration Species Blood Lead Effectsa Pb nitrate, single i.v. 10 μM/100 g b. wt. Multiple time points 24–72 h and 20 days Male Wistar rats — Pb nitrate exposure results in complete loss of liver glycogen between 

and 48 h, which was replenished and was found in excess in treated lihepatocytes by 20 days. Glycogen synthase and glycogen phosphoryl

activities were diminished by 24 h and return to normal values by day The pentose phosphate enzymes were upregulated, which coincided hwith the increase in mitotic rate. Overall Pb nitrate induces drastic alterations in hepatic carbohydrate metabolism along with increased hcell proliferation. 

— — Rats — Pb acetate induced mitotic response much more effectively in renal epithelial cells than liver cells (675 fold less). 

10 or 20 mg/kg as Pb acetate, subcutaneous Once a wk for 5 wks Occupationally exposed workers Rats Pb-exposed workers: 0.24–30 nM/mL Control rats: 0.18 nM/mL 10 mg Pb/kg: 2.42 nM/mL: 20 mg Pb/kg: 3.82 nM/mL Pb induces lipid peroxidation in serum of manual workers, while bloo

superoxide dismutase (SOD) activity decreased. Similar phenomenon observed with rats that were subcutaneously injected with Pb acetate. At higher than 20 μM concentration, Pb in untreated microsomes incrNADPH dependent lipid peroxidation. 

100 μM/kg b. wt Pb nitrate, i.v 36 h postexposure Male Wistar Albino rats — Endogenous source of newly synthesized cholesterol together with inc

of HMP shunt enzyme activities is essential for hepatic cell proliferatiPb nitrate. 

2000 ppm Pb acetate in diet. 3 wks Arbor Acres male chicks — Liver non protein sulphahydryl (NPSH) and glutathione (GSH) were increased upon Pb exposure. The concentrations of liver glutamate, g

and methionine were also elevated upon Pb exposure. 

0–4000 ppm Pb acetate, oral 21 days Arbor Acre broiler chicks — Pb increases tissue peroxidation via a relative increase of 20:4 fatty ac

Decrease in the hepatic ratio of 18:2/20:4 might be specific to Pb toxi
 AX5-164 Table AX5-10.2 (cont’d). Biochemical and Molecular Perturbations in Lead-induced Liver 

Concentration Duration Species Blood Lead Effectsa Sodium vanadate, 30 mg/kg subcutaneous in mice 30 mg/kg b.wt, i.p. in rats 0.5 mM Acute studies, 24 h — Vanadium sulphate in drinking water for chronic treatment Chronic studies 10 wks Male Swiss- Webster mice Male Sprague Dawley Rat — Sodium orthovandate increases lipid peroxidation in kidneys of mic

rats. Malondialdehyde (MDA) formation increased 100%, with in 1 after injection. In both rat and mice, no significant increase in lipid peroxidation wobserved in brain, heart, lung, and spleen. Chronic exposure to vanadium, through maternal milk and drinking 

for 10 wks increased MDA formation and lipid peroxidation in kidn

250–2000 ppm Pb acetate in diet 19 days Arbor Acre broiler chicks — Dietary Pb consistently increased liver arachidonic acid, the arachidonate/linoleate ratio and hepatic non-protein sulfhydryl concentration. Hepatic microsomal fatty acid elongation activity w

decreased by Pb over all. These results demonstrate that changes in precursors and mechanisms involved with eicosanoid metabolism aalways reflected in tissue concentrations of leukotriens and prostagl

1.25–20.00 mg/L Pb nitrate, oral 30 days Fresh water fish — Pb accumulation in the liver and other tissue increased in a dose dep

manner up to 5mg/L, exposure to sublethal concentration (5 ppm) oreduced the total lipids, phospholipids, and cholesterol levels in the and ovary. Pb nitrate may affect the fecundity of fish by altered lipimetabolism. 

250 mg/L of Pb as Pb acetate, oral 5 wks of exposure followed by 4 wks of recovery Weanling female SD rats — Effect of weight loss on body burden of Pb: weight loss increases t

quantity and concentration of Pb in the liver even in the absence of continued exposure. 

35–70 mg, Pb intra gastric One or two times a wk/7 wks Male Buffalo rats Control: 4.6 μg/dL Pb 35 mg/kg: 16.8 μg/dL Pb 70 mg/kg: 32.4 μg/dL Decrease in plasma cholesterol, and HDL fraction, increase in serum triglyceride, atrophy of the elastic fibers in the aorta. 

Abbreviations

aCYP—Cytochrome P-450 

ALAD—Aminolevulinic acid dehydratas GSH—Reduced Glutathione 

ZPP—Zinc protoporphyrin HMP—Hexose monophosphate shunt pathway b. wt.—body weight 
 AX5-165 Table AX5-10.3. Effect of Lead Exposure on Hepatic Cholesterol Metabolism Concentration Duration Species Blood Lead Effectsa 

100 μmol/kg body wt, i.v. Pb nitrate Multiple durations 0, 3, 6, 12, 24, and 48 h Male Sprague Dwaley (SD) rats — Pb nitrate, activates the expression of the SREBP-2 and CYP 51 gen

with out decreasing the serum cholesterol level. 

100 μmol/kg body wt, i.v. Pb nitrate Multiple durations 0, 1, 3, 6, 12, 18, 24, 48, and 72 h Male Sprague Dawley (SD) rats — Pb nitrate effects on hepatic enzymes involved in cholesterol homeo

Demonstrated for the first time sterol independent gene regulation o

cholesterol synthesis in Pb nitrate treatment. 

0.05 mg/kg body wt/d. Pb acetate, subcutaneous, with or without cadmium acetate 0.025 mg Pb acetate/kg body wt/d Preexposure for 5–7 days, gestation through lactation Female Charles Foster rats — Pb and cadmium accumulated in the livers of metal treated pregnan

lactating rats. Hepatic steroid metabolizing enzyme 17-β-hydroxy 

oxidoreductase and UDP glucaronyl transferase were decreased and hepatic Cytochrome P-450 content was reduced by the metal exposuPb and cadmium alter liver biochemical parameters, however, combexposure had no intensifying effect on liver parameters. When administered together on similar concentration basis, the major effeare mediated by cadmium. 

300 mg/L Pb acetate, oral Gestation through lactation analyses done at day 12 and day 21 postnatal Female Wistar rats Control: 1.13 μg/dL Pb-exposed 12 days PN: 22.01 μg/dL 21d PN: 22.77 μg/dL In neonates, decrease in liver Hb, iron, alkaline and acid phosphatas

levels. Protein, DNA and lipid total amounts were reduced and hepglycogen content was reduced. Pb intoxication of mothers in gestatand lactation results in alterations in the hepatic system in neonates and pups. 

a CYP—Cytochrome P-450 b wt.—body weight 
 AX5-166 Table AX5-10.4. Lead, Oxidative Stress, and Chelation Therapy Concentration and Compound Duration Species Blood Lead Effects 

Pb acetate, 50 mg/kg b.wt, intragastric 8 wks Male Albino Wistar rats — Pb induces accentuation of membrane lipid peroxidation in liver by 

changes (decrease) in the activities of several antioxidant enzymes sSOD, Catalase, GPx and Glutathione reductase. Pb exposure also ca reduction in GSH/GSSG ratio (reduced to oxidized Glutathione). 

2,000 ppm, Pb acetate, Diet 5 wks Male Fisher 344 rats, young and old Young control: <1 μg/dL Young Pb-exposed: 38.8 μg/dL Old control: <1 μg/dL Old Pb-exposed: 21.7 μg/dL Effect of Pb on lipid peroxidation in young vs. adult rats– Liver GS

malondialdehydehyde levels were significantly higher in young rats adult rats. Blood Pb levels were higher in young exposed animals acompared to adults. In young, Pb exposed animals, Pb induced oxidstress was more pronounced particularly in liver tissue. 

0.1–1.0 μM — Lipid peroxidation as indicated by Malondialdehyde accumulation upon exposure to various redox-sensitive metals in cultured rat hepatocytes and hepatocytes loaded with α-linolenic acid indicated 

Al, Cr and Manganese, Ni, Pb and tin did not effectively induce lipi

peroxidation in these cells. – The induction was the highest in ferrous iron treated cells comp

to other metals (Cu, Cd, V, Ni). FeSO4, VCl3, CuSO4, CdCl2, CoCl2, AlCl3, CrCl3, MnCl2, NiSO4, Pb(NO3)2, SnCl2, culture medium 9 h — LAN—bovine serum complex 0.8 mM in culture medium Additional 12 h incubation Rat liver hepatocytes. Normal and LAN loaded — With any metal, the induction was higher in α-linolenic acid treated 

Iron and V induced cell injury in LAN loaded cells was prevented baddition of DPPD. Cd was a weak inducer of lipid peroxidation undthese conditions. 

5 mg kg−1, Pb acetate, i.p., single dose followed by therapy with chelating agents Analyses after 6 days of treatment DMSA, Mi- ADMSA at multiple times (0.5, 24 hr, 4th and 5th day after Pb treat Wistar 6 days old suckling rats — Treatment with DMSA and Mi- ADMSA showed Mi-ADMSA to b

more effective in reducing the skeletal, kidney and brain content of However there was no difference in reducing the liver Pb content between the two compounds. 
 AX5-167 Table AX5-10.4 (cont’d). Lead, Oxidative Stress, and Chelation Therapy Concentration and Compound Duration Species Blood Lead Effects 

550 ppm Pb acetate, oral DMSA treatment. (A) Pb for 35 + 21 days (B) Pb 35 days and Pb and DMSA for 21 days (C) Pb 35 days and DMSA for 21 days (D) Acedified Di H2O for 35 days and Di water for 21 days 6–7 Wk old male Sprague-Dawley rats Pb-exposed: 50 μg/dL Pb 35 days: Ranged from 5–20 μg/dL + DMSA from 0– 240 μg/kg/d DMSA reversed the hematological effects of Pb, decreased the bloo

brain , bone, kidney and liver concentration and produced marked P

diuresis, even when challenged with ongoing Pb exposure. 

Pb acetate Dose to achieve blood Pb levels of 35– 40 μg/dL. Biweekly dose adjustments, oral followed by treatment with chelator. 1 yr, chelator for two successive 19 day period following Pb exposure. Infant rhesus monkeys Pb-exposed: 35–40 μg/dL Specific emphasis on the beneficial effects of succimer treatment to cessation of Pb exposure. These data demonstrated that succimer efficiently reduces blood Pb levels which does not persist beyond th

completion of treatment. They also demonstrate the relative benefit eliminating Pb exposures , which serves to underscore the importanprimary prevention of Pb exposure. Neither DMSA treatment nor thcessation of Pb exposure were beneficial in reducing skeletal Pb lev

5 mg Pb kg−1, i.p Pb acetate followed by chelators for various time points. Analyses at Day 5 Suckling Wistar rats — Meso—DMSA is the treatment of choice for acute Pb poisoning in 

compared to EDTA and Rac-DMSA. 

50 mg/kg Pb as Pb nitrate, i.p, two injections, 16h apart 50% Ethanol, 0.5 mL, two injections, 16 h apart 24 h Male Albino rats — S-Adenosyl methionine confers protection against alterations in sev

parameters (ALAD, GSH, MDA) indicative of lipid peroxidation in liver and brain in Pb and acute Pb and ethanol exposed animals as wthe organ concentration of Pb. 

0.1% Pb acetate in drinking water with and without Sodium Molybdate, i.p 4 wks Male Albino rats Pb-exposed: 39 μg/dL Pb + chelators: 4.6–13.1 μg/dL Sodium molybdate significantly protected the uptake of Pb in blood

and kidney. The treatment with molybdate also restored the Pb induinhibited activity of blood δ-aminolevulinic acid dehydratase and th

elevation of blood Zn protoporphyrin , hepatic lipid peroxidation anserum ceruloplasmin. 
 AX5-168 Table AX5-10.4 (cont’d). Lead, Oxidative Stress, and Chelation Therapy Concentration and Compound Duration Species Blood Lead Effects 

20 mg/kg Pb acetate, i.p. 3 days treatment Male Albino rats — Significant Pb induced inhibition of hepatic heme synthesis associat

with decline of mixed function oxidases, depletion in anti oxidants s

as vitamin C. Oral supplementation with vitamin C confers protectiagainst toxic insult by reversing these parameters. 

1.5 mg/per bird /d 30 days Broiler chicken — Pb-induced inhibition of 5' mono deiodinase (5'- D) activity in chick

appeared to be mediated through the lipid peroxidative process. 

1. Pb acetate 10 mg/mL/kg (a) 2. Ethanol 1 g/ 4 mL/kg (b) 3. a + b = (c) 4 a + zinc 10 mg/ 4 mL/kg + lysine 25 mg/4 mL/kg (d) 5. b + 2n + lysine as in days, oral 6. a + b + Zn + lysine as in days 5 days/wk/8 wk Male Albino rats Control: 1.75 μg/dL 1. 47.23 μg/dL 2. 2.08 μg/dL 3. 45.37 μg/dL 4. 34.19 μg/dL 5. 1.84 μg/dL 6. 46.69 μg/dL Influence of lysine and zinc administration on the Pb-sensitive biochemical parameters and the accumulation of Pb during exposur

Pb. (1) Pb exposure inhibited blood ALAD activity. Serum enzymincreased blood and tissue Pb levels. (2) Decreased blood and hepaglutathione. Some of these effects were enhanced with co-exposure ethanol. Simultaneous administration of lysine and zinc reduced tisaccumulation of Pb and most of the Pb-induced biochemical alteratiirrespective of exposure to Pb alone or Pb and ethanol. 

1300 ppm Pb acetate in drinking water 5 wks C57BL/6 mice — Pb treatment resulted in depletion of GSH, increased GSSG and pro

Malondialdehyde (MDA) production in both liver and brain sampleDMSA or N- acetyl cysteine (NAC) treatment resulted in reversion these observations. DMSA treatment resulted in reduced Pb levels blood, liver and brain, where as treatment with NAC did not reduce levels. 

2000 ppm of Pb acetate in drinking water 5 wks followed by treatment with succimer DMSA, or thiol agent NAC Fisher 344 male rats — Pb induces oxidative stress in RBC and these biochemical alteration

reversed by both a thiol antioxidant (NAC) as well as a chelating ag

DMSA. 

500 μM Pb acetate in cells 2000 ppm of Pb acetate in drinking water Cells—20 h Animals 5 wks followed by treatment with 

α-lipoic acid 

Male fisher rats and Chinese hamster ovary cells 

— Pb induces oxidative stress. α-lipoic acid (LA)treatment significant

increased thiol capacity of cells and animals via increasing glutathiolevels and reducing Malondialdehyde levels, increased cell survivalLA was not effective against reducing blood or tissue Pb levels. 
 AX5-169 Table AX5-10.4 (cont’d). Lead, Oxidative Stress, and Chelation Therapy Concentration and Compound Duration Species Blood Lead Effects 

0–500 μM Pb acetate 6 h CHO cells and — 2000 ppm of Pb acetate in drinking water for 5 wks 5 wks Taurine 1.1 kg/d 6th wk Fischer 344 rats Controls: 0.43 μg/dL Pb-exposed: 36.4 μg/dL Pb + Taurine: 33.8 μg/dL Antioxidant Taurine reversed the abnormalities associated with lipid peroxidation parameters such as increased. Malondialdehyde forma

and decreased Glutathione and enhanced CHO cell survival. Howevwas not effective in reducing cell and tissue Pb burden in CHO cells Pb exposed Fischer rats. 

1 mg Pb2+/kg B.wt , i.p. Pb acetate 4 wks, treatment with various antioxidant in the 5th wk IVRI 2 CQ rats — Pb exposure resulted in increased lipid peroxidation, with tissue spe

changes in liver. Treatment of exposed rats with ascorbic acid and tocopherol lowered the lipid peroxidation. 

Pb as acetate, 400 mg Pb2+/mL, drinking water 10 days — 0.5 mg/mL L-methionine 4 wks post-Pb exposure Kunming mice — L- methionine has an ameliorative effect on Pb toxicity–Methionine reduced the decrease in Hb content and depressed body growth caus

Pb. Treatment with dietary methione along with Pb decreased the Mformation as opposed to Pb, moderately reversed the decreased iron content of the organs and decreased organ Pb content. 

100 μM/kg b.wt. Pb acetate, intramuscular, single 3 and 24 h Male Albino rats — Pb exposure resulted in significant increases in acid and alkaline phosphatases, serum GOT and GPT, elevated liver and kidney lipid peroxidation and decreased antioxidant enzymes at 3 and 24 h after exposure. Selenium administration prior to Pb exposure produced pronounced prophylactic effects against Pb exposure by enhancing endogenous anti oxidant capacity. 

100 μg/ Pb acetate, intra gastric, oral and intraperitoneal, treated with or with out thiamin (25, 50 mg/kg b.wt) and or Ca EDTA (50 mg/kg B.wt 3 days CD-1 mice — Two times more whole body Pb was retained by intraperitoneal inje

as compared to intragastric administration. Thiamin treatment increthe whole body retention of both intragastric and intraperitoneal Pb about 10%. Calcium EDTA either alone or in combination with thireduced the whole body retention of Pb by about 14% regardless of route of exposure. Regardless of the route Ca EDTA in the combintreatment reduced the relative retention of Pb in both in liver and kiThese studies indicate the combination treatment with thiamin and CEDTA alters the distribution and retention of Pb in a manner which have therapeutic application. 
 AX5-170 Table AX5-10.4 (cont’d). Lead, Oxidative Stress, and Chelation Therapy Concentration and Compound Duration Species Blood Lead Effects 

2000 ppm Pb acetate, oral I chelators LA, DMSA, MiADMSA LA + DMSA + LA+ MiADMSA 4 wks, 5 days of treatment with antioxidant or chelators Male Wistar albino rats Normal: 1.42 μg/dL Pb: 40.93 μg/dL Pb + chelators: 38.5– 4.27 μg/dL Treatment with all the chelators reduced hepatic GSH and reduced G

levels. Significant beneficial role of Alpha-lipoic acid (LA), in recothe altered biochemical parameters, however showed no chelating properties in lessening body Pb burden either from blood, liver, or kMost beneficial effects against Pb poisoning was observed with comtreatment of lipoic acid and either DMSA (meso 2,3-dimercaptosucacid) or MiADMSA (Mono isoamyl DMSA). 

0.1% Pb as acetate in drinking water DMSA—50 mg/kg, i.p./d MiADMSA—50 mg/kg, i.p./d 3 mo — Vitamin E 5 mg/kg and vitamin C 25 mg/kg/d, i.v. and oral 5 days post-Pb exposure Male Wistar rats — Single or combined administration of vitamin C, α-tocopherol and t

chelators DMSA and Mi ADMSA against the Parameters of Pb induoxidative stress– thiol chelators and the vitamins could bring the bloALAD to normal levels, most significantly by combined administraMi ADMSA with vitamin C. Vitamin C and E were effective againreducing oxidized glutathione ( GSSG), and thibarbituric acid reactisubstance(TBARS) and increasing catalase activity. MiADMSA anDMSA with vitamin C were effective in increasing hepatic GSH levIn summary combined treatment regimens with thiol chelators and vitamins seem very effective in reducing the Pb induced oxidative s

500 mg/kg Pb acetate daily, oral treatment with chelators Multiple durations (2, 4, and 6 wks) Male Albino rats Control: 0.32 μg/dL Pb-exposed: 0.48–0.56 μg/dL Pb + chelators: 0.32–0.36 μg/dL Impact of combined administration of vitamin C and Sylimarin on P

toxicity. Combined treatment of Pb-exposed animals with vitamin C Silymarin showed marked improvement of the adverse biochemicalmolecular and histopathological signs associated with Pb toxicity. 

Pb as acetate 0.2% in drinking water LA 25 mg/kg b.wt and DMSA 20 mg/kg b.wt 5 wks followed by a 6th wk administration of LA and or DMSA Male Albino rats — Pb treatment for 5 wks resulted hepatic enzymes alanine transamina

aspartate transaminase, and alkaline phosphatase, increased lipid peroxidation, and decreased hepatic anti oxidant enzymes. LA or Dalone, partially abrogated these effects, however, in combination completely reversed the lipid oxidative damage. 

Abbreviations b. wt.—body weight 

aCYP—Cytochrome P-450 

SOD—Super oxide dismutase GSH—Glutathione GSH/GSSG Ratio—Reduced Glutathione/Oxidized Glutathione MDA—Malondialdehyde Al—Aluminum As—Arsenic MiDMSA—Mi monoisoamyl DMSA 

Cr—Cromium V—Vanadium Pb—Lead NAC—N acetyl cysteine FeSO4—Ferrous sulphate

AlCl3—Aluminum chlorideVCl3—Vanadium chlorideCdCl2,—Cadmium chloride 

CuSO4—Copper sulphate 

CrCl3—Cromium chloride

MnCl2—Manganese chlorideNiSO4—Nickel sulphateCoCl2—Cobalt chlorideLAN—" Linolenic acid DPPD—DPPD,N-N Diphenyl –p-phyny

LA—Lipoic acid DMSA—Monoisoamyl DMSA 
 AX5-171 Table AX5-10.5. Lead-induced Liver Hyperplasia: Mediators and Molecular Mechanis

Concentration Duration Species Blood Lead Effectsa 

— — Rat — Apoptosis plays a major role in the regressive phase of Pb nitrate in

hepatic hyperplasia as detected by the apoptotic bodies by in situ enlabeling and HandE sections of the hepatic tissue. HandE scores mocells in apoptosis phase II, ISEL (in situ end labeling) scores for celphase I. Combination of these two methods is suggested for the betunderstanding of the extent and nature of apoptotic process in liver treated with chemicals. 

A. Pb nitrate, 100 μM/kg b.wt, intra-gastric B. Diethyl nitrosoamine 200 mg/kg b.wt, i.p. 3 and 15 days Male Wistar Albino rats — Mitogenic stimuli (3 days Pb nitrate treatment) and complete regres

(15 days after the treatment), affected the apoptosis differentially. Influence of apoptosis Vs necrosis on the growth of hepatocytes initby diethyl nitrosamine followed by Pb nitrate treatment indicated thregenerative response elicited by a necrogenic dose of CCL4 promoGSTP (Placental glutathione), a pre-neoplastic marker positive cells against the Pb nitrate that induced the apoptosis. 

0–100 μM Pb sulphate, Pb monoxide, Pb chloride and Pb acetate up to 1 mM, culture media. Multiple time points ranging from 24 h up to 7 days REL liver cells — Pb compounds showed a dose and time related effect on REL liver c

proliferation with varying potencies specific to the different Pb saltsPb acetate was the most effective and Pb monoxide, the least effectiOn 1 hr treatment none of the compounds tested affected the intracecommunication. 

Choline 1g/kg/d in drinking water 0, 20, and 24 h Male and female rats , partial hepatectomy — PKC isozymes during liver cell regeneration— PKC δ showed a pronounced increase 20h after partial hepatectomy. 

α, β, and Zeta a

corresponding with S-phase. Sexual dimorphism matching with sexdifferences in DNA synthesis was evident. Administration of cholinable to modulate the protein kinase C isozyme pattern in females in relation to DNA synthesis and c-myc expression. Taken together thpositively implicates α, β, and Zeta in growth after partial hepatecto

and δ in negative regulation. 

Pb nitrate, 75 μM/kg b.wt, single i.v. 

6 h–4 wks Adult male Albino 

rats 

— Pb induced significant increase in liver weight. Increased 3H Thym

incorporation. Pb induces extensive hypomethylation in treated rat 

Site-specific effect on methylation was confirmed at Hpa II, Msp I, Hae III. 

75 μmol/kg b. wt. Pb nitrate in adult and 20 μg/mL in the young, i.v.; single dose 

Analyses at 72 h Male Wistar 

Albino rats 

— Effect of Pb nitrate on the 5- methyl deoxy cytidine (5-mdcyd) cont

the HpaII, MSPI, Hae III restriction patterns of hepatic DNA from ymiddle aged and senescent rats. The results indicated that the methypattern of genomic DNA changed significantly with age and the methylation patterns were differentially affected in all the three populations. 
 AX5-172 Table AX5-10.5 (cont’d). Lead-induced Liver Hyperplasia: Mediators and Molecular Mech

Concentration Duration Species Blood Level Effectsa 10 μmol/100 g body weight Pb nitrate, i.v. Multiple analyses up to 40 h Male Wistar rats, hepatocytes from partial hepatectomy and Pb nitrate treatment. — The kinetics of DNA synthesis and expression of Proto oncogenes i

partially hepatectamized liver cells and Pb nitrate treated hepatic ceindicated peak DNA synthesis after 24 h in the formal and after 36 h later case. Both proliferative stimuli induced c-fos, c-myc and c-Ha expression. Induced c-myc expression persisted for up to 40h durinPb nitrate- induced liver cell proliferation. Pb induces hepatic hypethrough changes in proto-oncogene expression. 

100 μmol/kg, b. wt. Pb nitrate, i.v. Analyses at multiple time points, 0.25–24 h Male Wistar Albino rats — Proliferative stimuli by means of Pb nitrate exposure resulted in inc

expression of c-jun m-RNA where as compensatory regeneration in partially hepatectamized cells occurred through increased expressiofos and c-jun. Different mitogenic stimuli induced differential exprof these protooncogenes, in addition had a different profile than cellpartial hepatectomy despite the cell cycle timings being the same in cases. 

100 μmol/kg b. wt. 8 h Male Sprague Dawley rats — In rat liver, in addition to a few hepatocytes four types of non paren

cells namely, fibroblasts, macrophages, bile ducts and periductular cproliferate in response to Pb nitrate treatment. This growth is not re

to adaptive response secondary to parenchymal enlargement. Howesuch growth in parenchymal cells seems dormant and does not play functional role in adult liver epithelial growth. 

100 μmol/kg b. wt., i.v. Multiple analyses time points, 1–120 h Male Wistar rats — Both mRNA levels and enzyme activity of DNA polymerase β mark

increased before and/or during DNA synthesis in proliferating hepatin Pb nitrate treated and partially hepatectomized rats. 5 fold increa

the enzyme activity was observed 8 h after Pb nitrate administrationthe regenerative liver cells a 3 fold increase was observed 24–48h apartial hepatectomy. 

100 μ mol/kg b. wt., i.v. Pb nitrate Analyses at multiple time points, 8 h to 15 days Male Wistar rats — Pb nitrate induced Poly (ADP-ribose) polymerase mRNA 24 hr afte

exposure. A 2 fold increase in the mRNA levels of the enzyme occu2 days after the exposure. Such changes were also observed in hepacells from livers of partial hepatectomy. These changes preceded thincrease in DNA synthesis and remained high during the time of extDNA synthesis. 
 AX5-173 Table AX5-10.5 (cont’d). Lead-induced Liver Hyperplasia: Mediators and Molecular Mech

Concentration Duration Species Blood Lead Effectsa 30 mg/kg b. wt. Pb nitrate Multiple time points up to 8 days Adult male and female rats — Pb nitrate induced liver hyperplasia exhibited sexual dimorphism w

mitogenic action was less effective and was delayed in females as compared with males. Pre administration with choline partially fillethese sexual differences. 

30 mg/kg b. wt. Pb nitrate Multiple time point up to 60 h Adult male and female rats — Pb nitrate induced liver hyperplasia exhibited sexual dimorphism. Pre-administration with choline partially filled these sexual differen

Significant down regulation of PKC β and PKC 

α activities occurre

during Pb induced proliferation. 

100 μmol/kg b. wt. Pb nitrate, i.v., single dose. 

Multiple time point analyses ranging from 12–168 h 

Male Wistar rats Serum Pb 

concentrations peaking to 50–60 μg/dL between 12–24 h and remaining up to 40 μg/dL up to 108 h 

Effect of Pb nitrate on protein kinase C (PKC) activity. A single doPb nitrate resulted in enhanced activity of PKC in the purified particfraction of the rat liver, reached its peak activity by 24 h which laste48 h. This was accompanied by increased frequency of mitotic cellThese results indicate, Pb nitrate induced PKC activity may play a rliver cell proliferation. 

A. Mitosis—  Pb nitrate 

100 μM/kg, i.v. 

 Ethylene 

dibromide 100 mg/kg , intra gastric 

 Cyproterone 

acetate, 60 mg/kg intra gastric. 

B. Hepatocyte 

nodules diethyl nitrosamine 200 mg/kg 

30'–3 h Adult male Wistar 

rats 

— Liver cell proliferation by enhanced DNA synthesis was observed w

mitogens Cyproterone acetate, ethylene dibromide, and Pb nitrate as 

as 30 mints after treatment and persisted even after 5 days of treatmPb nitrate administration. hepatocytes isolated from pre neoplastic liver nodules have also exhenhanced cell proliferation. 

Pb nitrate, single i.v. 100 μm/kg b.wt LPS—12.5 μg/rat, post Pb nitrate treatment. 

Multiple analyses at 3, 6, 12, 24, and 36 h 

Male Wistar rats — Stimulation of hepatocyte cell proliferation by Pb nitrate was not 

accompanied by changes in liver levels of Hepatocyte growth factor (HGF), Transforming growth factorα (TGFα), or TGF-β1 m-RNA

nitrate treatment resulted in the enhancement of Tumor necrosis fac

a time preceding the onset of hepatocyte DNA synthesis, indicating in Pb induced hepatic cell proliferation. The survival of Pb nitrate t

rats decreased significantly with an after treatment of LPS (lipopolysaccharide). 
 AX5-174 Table AX5-10.5 (cont’d). Lead-induced Liver Hyperplasia: Mediators and Molecular Mech

Concentration Duration Species Blood Lead Effectsa 15 mg/kg b. wt. Pb acetate Pb+ LPS group analyzed after 14 h and the rest after 24 h after Pb administration Male Sprague Dawley rat — Pb augments the lethality of endotoxin lipopolysaccharide (LPS) in 

and enhances liver injury, which is further enhanced by TNF. Pb + treatment increased both serum TNF concentrations and TNF area acompared to LPS alone. simultaneous administration of Pb with eitLPS or TNF, serum aspartate transaminase, alanine transaminase, alphosphatase, glutamyl trans peptidase and plasma triglyceride levelmarkedly increased. 

Pb nitrate 100 μM/kg b. wt. i.v. single dose Multiple time points of analyses extending up to 48 h after treatment Male Wistar rats — Pb nitrate and ethylene bromide induce liver cell proliferation via induction of TNF

α. Dexa methasone, a known TNF inhibitor, decre

TNF expression and liver cell proliferation by these mitogens. Thesstudies support the fact that TNF might mediate hepatic cell proliferby Pb nitrate and ethylene bromide. 

100 μmol/kg b. wt Pb nitrate, single, i.v. 

Multiple time points of analyses up to 48 h 

— Pb nitrate (LN) treatment resulted in increased Brdu incorporation o

hepatocytes and non parenchymal cells at 12 h after treatment and rthe peak index at 36 h. Rats given a single i.v. of recombinant TNF

enhanced proliferation in non parenchymal cells after 24 h, the labehepatocytes at 36 h. NAF, Nafenopin another mitogen which does ninduce liver TNF

α, increased the number of labeled hepatocytes wi

increasing the labeling of non parenchymal cells indicating that only nitrate induced proliferation is mediated by TNF

α and these mitoge

initiate proliferation in different cells based on their capacity to stimTNF

α production. 

100 μmol/kg b. wt. single i.v. 

Multiple time points of analyses up to 80 h 

Male Sprague Dawley rats 

— Pb nitrate induces liver cell proliferation in rats without accompany

liver cell necrosis. This proliferation involves enhanced TNF mRNlevels but not hepatocyte growth factor. The role of TNF in Pb nitra

induced liver cell proliferation is supported by the inhibition of TNF reduced hepatocyte proliferation by several TNF inhibitors. 

100 μmol/kg b. wt. i.v. single dose 

Multiple time points of analyses up to 24 h 

Male Wistar rats — Pb nitrate induced liver cell proliferation involves TNF α production

enhanced NF-κB activation increased hepatic levels of iNos mRNA 

opposed to other mitogens such as Cyproterone acetate or Nafenopi

100 μmol/kg b. wt. i.v., single dose 

Multiple time point analyses up to 96 h 

Male Sprague Dawley rats 

— The role of neurotrophins, the nerve growth factor (NGF), the brain 

derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in Pnitrate treated liver cells was studied. LN, treatment resulted in incrin the levels of NGF, BDNF and NT-3. The increase in neurotrophireceptors and the gene expression were correlate with liver weights. study demonstrates that Pb nitrate induced hyperplasia may be mediby neurotrophins. 
 AX5-175 Table AX5-10.5 (cont’d). Lead-induced Liver Hyperplasia: Mediators and Molecular Mech

Concentration Duration Species Blood Lead Effectsa Multiple doses 0–50 μM, culture medium Multiple time points up to 24 h Hepatocytes from Adult male Swiss- mice, primary — Interaction between Pb and cytokines in hepatotoxicity– Pb potentia

cytokine-induced oxidative stress by decreasing GSH and increased of Oxidized glutathione (GSSG). Combined treatment resulted in a decline in intra cellular ATP concentration. 

50 μM Pb acetate, culture medium 24 h Rat hepatocyte and Kupffer cell and granulocyte co-cultures — Pb stimulates intercellular signaling between Kupffer cells and hepatocytes which increased synergistically at low lipopolysacchari

levels. These signals promote proteolytic hepatocyte killing in combination with a direct cellular interaction between the granulocyand hepatocytes. 

10 μM/110 g b. wt., single i.v. Multiple time point analyses up to 5 days Adult male Wistar rats — Pb nitrate induced hepatocyte apoptosis was prevented by pre-treatm

with gadolinium chloride, a Kupffer cell toxicant—Role for Kuffer hepatocyte apoptosis. 

10 μmol/100 g b. wt. single i.v. Multiple time points up to 9 days Male Wistar rats — Pb nitrate-induced liver hyperplasia in rats results in a significant in

in the expression of aceyl glycoprotein receptor (ASGP-R) during thinvolutive phase of Pb nitrate induced hyperplasia in rat-liver, which coincided with the massive death by apoptosis of the same cells. A significant rise in the galactose-specific receptors was also observ3 days after the treatment. These studies demonstrate that carbohydreceptors regulate Pb nitrate induced liver cell apoptosis. 

10 mmol/100 g, Pb nitrate, i.v. Multiple time points Male Wistar rats — Demonstration of the expression of carbohydrate receptors on Kupf

cells. Pb nitrate induced apoptosis in Kupffer cells and internalizatiapoptotic cells (Phagocytes) is mediated by both Mannose and Galareceptors. 
 AX5-176 Table AX5-10.5 (cont’d). Lead-induced Liver Hyperplasia: Mediators and Molecular Mech

Concentration Duration Species Blood Lead Effectsa Pb (No3)2, , i.v. 100 μM/110 g .b. wt 1, 3, and 5 days In vivo Adult male Wistar rats — GdCl3 0.75 mg/100 g. b. wt, i.v. 2, 4, or 24 h before Pb nitrate injection. — In vitro, 10 mM Pb nitrate Analyses at multiple time points up to 24 h in Hep G2 cells and at 24 and 48 h in Kupffer cells Hep G2 cells — Hepatic apoptosis induced by Pb nitrate in vivo is abolished by gado

chloride, a Kupffer cell toxicant that suppresses Kupffer cell activity reduces to half the apoptotic rate. Pb nitrate treatment also deprives hepatic cells from reduced glutathione and this process is reversed bGadolium chloride. Pb nitrate induces apoptosis in Kupffer cells, anHepG2 cells in vitro. 

Multiple concentrations varying from 300 nM–10 μM, up to 100 μM in certain in vitro expts 1, 2, 4 and 6 days Hepatoma cell line, H4-II-C3 — Acute effect of Pb on glucocorticoid regulation of Tyrosine aminotransferase (TAT) in hepatoma cells. Pb treatment does not significantly alter initial glucocorticoid receptor number or ligand b

Pb may perturb PKC mediated phosphorylations in the glucocorticoTAT signal transduction system. Pb also may be increasing the turnof TAT by actions at transcription, translation and /or post translatio

0–10 μM Pb acetate in the culture medium 24 and 48 h H4-IIE—C3 hepatoma cell culture model — In HTC cells glucocarticoid signal transduction pathways involve ca

mediated events and PKC isoforms, Pb exposure interferes with calmediated events and aberrant modulation of PKC activities and may contribute to the over all toxicity of Pb. 

aCYP—Cytochrome P-450 

b. wt.—body weight 
 AX5-177 Table AX5-10.6. Effect of Lead Exposure on Liver Heme Synthesis Concentration Duration Species Blood Lead Effectsa 

75 mg Pb/kg b. wt., i.p. Multiple time point analyses 0–30 h C57 BL/6 mice — Pb poisoning decreases P-450 as a consequence of two different mechanisms, a mechanism unrelated to heme where P-450 transcrip

inhibited (reduces the synthesis and activity), and a second mechaniwhere by inhibition of heme synthesis occurs decreasing the heme saturation of P450 and/or apo-P450 content. 

10−5 ppm Pb nitrate Multiple analyses up to 24 h RLC-GA1 Rat liver cell line — Pb increases heme synthesis in RLC-GA1 in rat liver cell line, when measured by the amount of 59 Fe incorporated into heme fraction. Increased incorporation of 59 Fe into the heme fraction of the Pb trea

cells was the result of increased uptake of iron 59 Fe into the heme fr

of Pb treated cells. Cellular degradation of Pb was not significantly affected by Pb. 

A. Triethyl Pb-3.5 and 8.0 mg/kg b.wt. Pb nitrate 3.5, 25, and 100 mg/kg Single Subcutaneous Multiple analyses up to 28 days Control: 5.2 μg/dL Triethyl Pb 8.0 mg/kg b.wt.: 19.6 μg/dL Pb nitrate 25 mg/kg b.wt.: 19.6 μg/dL Pb nitrate 100 mg/kg b.wt.: 27.2 μg/dL B. In vitro, 10−3–10−9 M triethyl Pb or Pb nitrate 30 min Adult male Fischer rats — Triethyl Pb chloride has a similar potency to inorganic Pb nitrate in inhibiting ALAD both in vitro and in vivo. Liver and blood ALAD 

similar sensitivities to Pb compounds. Inhibition is reduced in the presence of Zn. 

5 μM Pb acetate or Pb diethyldithio- carbomate Pb uptake studies 0.33–10 μM Multiple analyses from 0–20 h Rat primary hepatocyte cultures — Effect of Pb and diethyl dithiocarbomates on rat primary hepatocyte

studied with Pb acetate and or Pb-diethyldithiocarbomate complex (DTC2l) labeled with 203Pb indicated that (Pb DTC2l) complex caused 

more rapid and stronger inhibition of ALAD activity than Pb acetateUptake of Pb was rapid and higher with the complex than Pb acetateThe complex also inhibited the ALAD activity in vitro when incubawith purified ALAD enzyme. 

Per OS eqimolar doses (17 μM Me/kg) of SnCl2 or Pb (CH3COO)2 every day 5 days Female rabbits Control: 3.48 μg/100 cm3 Pb: 17.50 μg/100 cm3 Pb decreased liver and bone marrow ALAD, but had no change in th

Aminolevulinic acid synthetase (ALA-S) and increased erythrocyte 

protoporphyrin. 
 AX5-178 Table AX5-10.6 (cont’d). Effect of Lead Exposure on Liver Heme Synthesis Concentration Duration Species Blood Lead Effectsa 

Pb 500 ppm in drinking water 14 days Male ddY mice — Urinary excretion of β-Aminoisobutyric acid (ABA) and δ-aminolev

acid (ALA) increased significantly in mice exposed to Pb in drinkinwater for 14 days. The degree of increasing excretion for ALA was than urinary ABA. Liver and kidney ALA dehydratase was inhibitewhile ALA synthatase was not affected. 

0.5 or 2.4 μM Pb acetate in culture medium Analyses at multiple time points, 0–28 days Hepatocyte cultures on 3T3 cells — Hepatocyte cultures on 3T3 cells produce and excrete porphyrins fo

28 days. Pb exposure for 4 wks alters cell morphology and producecytotoxic effects that could be monitored by altered porphyrin excre

500 ppm Pb in drinking water Rat exposure 62 days Human occupational exposure 0.3–38 yrs. A. Male Wistar rats B. Pb smelt workers, males — Pb exposure significantly increases the urinary ALA (Aminolevulin

acid) and Coproporphyrins (CP-III>CP-I in rats and exposed workeUrinary 5-hydroxy indole acetic acid was not influenced by Pb expo

A. Cu deficient diet: 1 mg/kg Cu in the diet B. Moderately deficient: 2 mg/kg C. High Zn diet: 60 mg/kg b. wt. 4 wks Weanling Sprague Dawley rats — High Zn in the diet reduces plasma copper, but not plasma cerulopla

activity or the recovery of plasma copper or ceruloplasmin activity aoral copper sulphate of Cu-deficient rats. High dietary Zn also modthe response of plasma SOD activity to dietary copper , but does noinfluence RBC SOD activity. 

1200 mg/kg b. wt. Pb acetate in diet, Sub acute toxic studies 400 mg/Pb 4 wks Broiler chickens — Liver porphyrin levels increased during Pb toxicosis. Concurrent administration of selenium or monensin in the feed further enhances 

process. 

0–100 μM Pb acetate in the culture medium 19 h Primary Rat and chick embryo hepatocyte cultures — Formation of Zn protoporphyrins in cultured hepatocytes. Pb did no

specifically increase Zinc protoporphyrin accumulation or alter iron availability in cultured hepatocytes. 
 AX5-179 Table AX5-10.6 (cont’d). Effect of Lead Exposure on Liver Heme Synthesis Concentration Duration Species Blood Lead Effectsa 

Pb acetate, 160 mg/L, semi liquid diet, oral 8 wks Male Wistar rats — Rats exposed to Pb had a higher blood and liver Pb, increased eryth

protoporphyrin. Pb exposure also resulted in hypoactivity of aminolevulinate dehydrase. Rats exposed to ethanol and Pb had altered abnormalities in heme sito animals exposed to Pb alone. Hepatic levels of Zn decreased significantly only in animals exposeboth. Hepatic GSH, urinary ALA and porphyrin levels were maintained similarly in all the groups. Transferrin bound iron uptake by Pb was also inhibited by Pb at higconcentrations such as 4 μM. 

Pb acetate, 0.0625 μM–32 μM, in vitro 10 min pre incubation and 20 minute incubation Rabbit reticulocytes — The effect of Pb on ferrous iron transport is similar between Pb chlo

acetate, and nitrate and reversible. Uptake of ferrous iron into all (heme, cytosolic and stromal fractioninhibited by low concentrations of Pb. 50% inhibition in the uptake by cytosol occurred at 1 μM Pb. 

A. Transgenic mice carrying chimeric human TF gene — These studies present evidence for the modulation of the synthesis o

human transferrin by Pb. In transgenic mouse with chimeric human chloromphenical acetyl transferase Pb regulates human Transferrin transgenes at the m RNA level. Liver catalase (CAT) enzyme activCAT protein, and TF-CAT m-RNA levels were all suppressed. Pb d

alter other liver proteins, mouse TF and Albumin. 1, 5, or 10 mg/kg b. wt. Pb acetate or nitrate, i.p. 10−4 M Pb acetate for Hep G2 cells 3 days B. Hep G2 cells — Pb suppressed synthesis of Transferrin protein in cultured human hepatoma Hep G2 cells. 

10 mg Pb/kg b. wt. as Pb acetate , i.p., single injection 10 and 100 μM Pb acetate Analyses at multiple time points up to 72 h Transgenic mice and Hep G 2 cells — Pb suppresses human transferrin synthesis by a mechanism differen

acute phase response. Common proteins such as C3 and albumin associated with acute phase response were not altered by Pb. Pb acesuppresses 35S-transferrin protein synthesis and m-RNA levels in He

cells and transgenic mice, while LPS altered only protein levels. 

aCYP—Cytochrome P-450 

b. wt = body weight 
 AX5-180 Table AX5-10.7. Lead and In Vitro Cytotoxicity in Intestinal Cells Compound and Concentration Duration Species Blood Lead Effectsa 

HgCl2, CdCl2, Ti2 SO4, Pb(NO3)2– concentration not given clearly, Butathionine, up to 1 mM Glutathione 1 mM N-Acetyl cysteine, 1 mM Cell proliferation assays 48 h Glutathione depletion assays 48 h Sulphahydryl repletion studies. I-407, Intestinal epithelial cell line. — Rank order cytotoxicity of various metal salts in I-407 intestinal epi

cells in terms of LC50 values—HgCl2 (32 μM) > CdCl2 (53 μM), Cu

(156 μM) > Ti2SO4 (377 μM) > Pb (NO3)2 (1.99 mM) Role of Glutathione, in the cytotoxicity of these metals by the asses

of GSH depletion by Butathionine sulfoxamine pretreatment at non cytotoxic concentration increased the toxicity of HgCl2 (5.7-fold), a

CuCl2 (1.44-fold). Administration of glutathione, with either HgCl2 or CdCl2 did not pr

the cells against the toxicity. N-acetyl cysteine reduced the cytotoxicity of mercury. 

aCYP—Cytochrome P-450 
 AX5-181 Table AX5-10.8. Lead and Intestinal Uptake—Effect on Ultrastructure, Motility, Transport, and M

Compound and Concentration Duration Species Blood Lead Effectsa Pb acetate, 0.1%, in drinking water Multiple analyses at 2, 30, and 60 days after Pb exposure Male Wistar rats — Small intestinal goblet cells are involved in Pb detoxification. Pb treatment for 30 days produces characteristic goblet cells in the intestine and Pb appears in conjunction with goblet cell membrane. Prolonged exposure to Pb more than 30 days caused silver sulphide deposition (indicative of heavy metal deposition) in the mucus drop

of cytoplasmic goblet cells. 

100 mg/Pb acetate/kg b. wt. Multiple analyses at 2, 30 and 60 days Male Wistar rats — Pb poisoning changes the ultra structure of intestine. 30 days Pb exposed rat intestinal enterocytes showed numerous, sm

rough-membraned vesicles and prominent, dilated golgi complexes, their cytoplasm. By 60th day, Pb-exposed rats had a vacuolated cytoplasm and promi

golgi filled with vacuoles. 

Added Pb concentration in the milk—0–80 μg/mL — Adult and Infant rats (16 days) Fresh or frozen rat or Avian milk — 90% of Pb in rat and bovine milk was found associated with caseine micelles regardless of whether the milk is labeled in vitro or in vivo 

203 Pb. Similarly Pb in infant milk formula was also predominantly associated with casein, however, to a much lower extent than rat and bovine milk formulae. Pb tracer studies indicated that in infant rats, as the milk traversed th

the intestine, in the collected luminal fluid, Pb was primarily associawith casein curd and remained as a nonprecipitable, nondialyzable fas it moved to the small intestine, indicating that Pb remains with prfraction as it traverses through the stomach and small intestine fract

Pb as Pb acetate, for 0.5– 10.0 μM, Zn as Zn acetate 0, 5, 10, or 50 μM Temperature variation Expts, 5 μM Pb, and incubated for 10 min at 4, 22, or 37 °C 5, 10, 30 or 60 min, Simultaneously with Pb for 10 min Incubation time 10 min IEC-6 normal rat intestinal epithelial cells — Pb uptake by IEC-6 cells depends on the extracellular Pb concentrat

Pb transport in IEC-6 cells is time and temperature dependent, involsulphahydryl groups, and is decreased by the presence of Zn. 
 AX5-182 Table AX5-10.8 (cont’d). Lead and Intestinal Uptake—Effect on Ultrastructure, Motility, Transport, a

Compound and Concentration Duration Species Blood Lead Effectsa OECD (Organisation for Economic Co-operation and Development) medium was artificially contaminated at 1, 3, 5, or 10 times the Dutch intervention value of 530 mg/Pb/kg dry wt. Pb containing medium was presented at the apical surface of the cells in 2 mL DMEM/chyme. Neutral red uptake studies had DMEM/chime with low 5 μM and high 50 μM Pb content Cell viability studies—24 h incubation. Pb transport studies, 1, 3, 5, and 24 h — Transport of bioaccessible Pb across the intestinal epithelium—In C

cells exposed to artificial chime, with in 24 hrs. App. 27% of the Pb associated with the cells and 3% were transported across the cell monolayer. Pb associated with cells showed a linear relationship wPb available in the system. Results indicate that only a fraction of the bioavailable Pb is transpoacross the intestinal epithelium. On the basis of Pb speciation in chime, It could be attributed that dissociation of labile Pb species, such as Pb phosphate, and Pb bile complexes and subsequent transport of the released free metal ions toward the intestinal membrane. 

44 mg/kg/d Pb as 53 mmol/L Pb acetate 4 wks Rat — Pb exposure significantly decreases the amplitude of contraction in 

duodenum. 

2.5 mg/mL Pb acetate in drinking water 55 days Colonic segments taken from chronically exposed guinea pigs Exposed: 80 μg/dL Colonic propulsive activity as measured by the velocity of the displacement of the balloon, from the oral to the aboral end, did not 

affected significantly by Pb treatment. In longitudinal muscle-myenplexus preparations of distal ileum, addition of Pb nitrate (100 μm) slight increase in cholinergic contractions. 100 μM Pb nitrate, in vitro Duration not specified Muscle–myenteric plexus preparations of distal ileum of controlled animals — Moderate decrease of electrically induced cholinergic contractions. 
 AX5-183 Table AX5-10.8 (cont’d). Lead and Intestinal Uptake—Effect on Ultrastructure, Motility, Transport, a

Compound and Concentration Duration Species Blood Lead Effectsa 40 μM–240 μM Tri ethyl Pb added in a cumulative manner in vitro to mid- ileal portion. 7.5 sec–2 min Swiss mice JVI1 ileum — 1. Peristaltic contractile activity of ileum as measured as a change i

period duration and force amplitude indicated that tri ethyl Pb (TELconcentrations of <40 μM had no obvious effects on these paramete2. In the concentration range between 40 μM–120 μM, tri ethyl Pb affected the rhythm of contraction in a concentration dependent manwith elongation in period and reduction in force amplitude. 3. At concentrations above 120 μM, TEL induced irreversible dramchanges in the ileal contractile activity. 

aCYP—Cytochrome P-450 
 AX5-184 Table AX5-10.9. Lead, Calcium, and Vitamin D Interactions, and Intestinal Enzymes Compound and Concentration Duration Species Blood Lead Effectsa 

Ca—0.5% in diet (low calcium) 1.2% in diet (high calcium) Pb—0.8% in the diet as Pb chloride 10 days White Leghorn Cockerels — Dietary Pb affects intestinal Ca absorption in two different ways depending on the dietary Ca status. A. In chicks fed low Ca diet (0.05%), ingested Pb inhibited intestin

47Ca absorption, intestinal Calbindin D, and alkaline phosphata

synthesis in a dose dependent fashion. B. In normal calcium diets (1.2%) Pb exposure had no bearing on intestinal Ca absorption, or Calbindin D, or Alkaline phosphatasynthesis and in fact elevated their levels at higher Pb concentraThese results indicate that the primary effects of Pb in both casoccur at or prior to intestinal protein synthesis involving Cholecalciferol endocrine system. 

Ca—0.1% or 1.2% in the diet with Pb—0.1–0.8% as Pb chloride in the diet 1 or 2 wks Leghorn Cockerels — —Dietary Ca deficiency, initially (1st week) stimulates Ca absorption and Calbindin D levels regard

dietary Pb intake. —At 2 wks, this response is reversed by Pb. —Intestinal Pb absorption was enhanced by Ca deficiency initially awas inhibited by prolonged dietary Pb intake. —Intestinal Pb absorption was increased in adequate Ca situation, bonly after 2 wks at the lower levels of dietary Pb. 

Ca—0.1–1.2% Pb—0.8% 2 wks White Leghorn Cockerels — Interactions between dietary Pb and Ca-influence on serum vitamin 

levels. —Pb ingestion and Ca deficiency alone or in combination generally increased serum 1,25 (OH)2 D levels over the most of the range odietary Pb and Ca. —In severe Ca deficiency, Pb ingestion resulted in significant decrehormone concentration. —Similarities in response profiles for 1,25 ( OH)2 D, intestinal Ca absorption and Calbindin- D suggested major interactions between 

and calcium mediated changes via circulating1,25(OH)2 D concentration. 
 AX5-185 Table AX5-10.9 (cont’d). Lead, Calcium, and Vitamin D Interactions, and Intestinal Enzy

Compound and Concentration Duration Species Blood Lead Effectsa Pb, Alkaline phosphatase and Ca2+ ATPase 2.0–10.0 mM Pb, Sucrase 0.5 mM–6.0 mM Pb, (-glutamyl transpeptidase1.0–10 mM Pb, Acetyl choline esterase 10.00–35.00 mM Incubation time not specified Male Albino rats Pb inhibited the activity of several intestinal brush border enzymes 

Ca2+- ATPase, Sucrase, (-glutamyl-transpeptidase and acetyl cholin

esterase with the exception of alkaline phosphatase. Inhibition of C

ATPase was competitive and that of the other enzymes is by non- competitive means. 

Oral Pb in Similac or apple juice adjusted for attainment of blood Pb levels 35–40 μg/dL. Succimer 30 mg/kg/d 204 Pb 24.5 nM followed by 206 Pb 352 nM, Single dose Administered from 8th day post partum, until age 26 wks Two successive 19 days at age 53 wks and 65 wks Administered immediately before chelation Female infant Rhesus Monkeys Pb-exposed: 35–40 μg/dL Effect of oral succimer chelation on the Gastro intestinal absorption 

the whole body retention of Pb Radio isotope Pb tracer technique Succimer significantly reduced Gastro intestinal absorption of Pb anincreased urinary excretion of Pb The initial decrease in whole body Pb by 10% was over come when majority of administered tracer was retained in the body after 5 daytreatment. 

aCYP—Cytochrome P-450 
 AX5-186 

ANNEX TABLES AX5-11 
 AX5-187 Table AX5-11.1. Lead-binding Proteins Source Organ Species Molecular Weight Protein Properties Inducible Sep

Goyer (1968) Kidney Rat Intranuclear Pb inclusion bodies Yes Goyer et al. (1970a,b) Kidney Rat Pb is concentrated in the intranuclear inclusion body Yes Choie and Richter (1972) Kidney Rat Initial inclusion bodies in cytoplasm Yes Moore et al. (1973) Kidney Rat Protein in inclusion bodies is acidic, with high levels of aspartic a, glutamic a, glycine and cystine Yes Moore and Goyer (1974) Kidney Rat Inclusion body protein is 27.5 kDa Yes Acrylamide 

Shelton and Egle (1982) Kidney Rat Inclusion body is 32 kDa with pI of 6.3 Named p32/6.3 Yes Two-dimen

Egle and Shelton (1986) Brain Rat, mouse, dog, guinea pig, and chicken p32/6.3 found No Oskarsson et al. (1982) Kidney cytosol and brain Rat 11.5 and 63 kDa No 203Pb bindin

G-75 or G-2SDS-PAGE Mistry et al. (1985) Kidney cytosol Rat 11.5 kDa, 63 kDa, > 200 kDa Respective Kd values: 13, 40, 123 nM No 203Pb bindin6B column 

Fowler and DuVal (1991) Kidney cytosol Rat Cleavage product of alpha-2 microglobulin No Chromatogr

phase HPLCantibodies K
 AX5-188 Table AX5-11.1 (cont’d). Lead-binding Proteins Source Organ Species Molecular Weight Protein Properties Inducible Sep

Smith et al. (1998) Kidney cortex Human 9 kDa and 5 kDa ACBP and thymosin B4 No Sephadex G

Sephadex A

Goering et al. (1986) Brain Rat 12 kDa No Labeled (203

Sephadex G

DuVal and Fowler (1989) Brain Rat 23 kDa Glutamic a, aspartic a, cysteine. Not MT No Labeled cyt

75, DEAE, f

Fowler et al. (1993) Kidney and brain Monkey Brain Pb-binding protein larger than kidney aspartic a, glutamic a, glycine, serine No Sephadex GQuintanilla-Vega et al. (1995) Brain Human 5 kDa and 20 kDa Thymosin B4 and unidentified protein No Sephadex G

phase HPLC Raghavan and Gonick (1977) RBC Human Pb- workers 10 kDa Yes 210Pb bindin

followed by 

Raghavan et al. (1980) RBC Human Pb- workers 10 kDa Pb-binding protein absent in controls, low in symptomatic, high in asymptomatic Yes 210Pb bindinRaghavan et al. (1981) RBC Human Pb workers 10 kDa Pb in membrane fraction correlates inversely with Na- K-ATPase Yes 210Pb bindinGonick et al. (1985) RBC Human Pb workers 12 kDa, pI 5.3, and 30 kDa Glycine, histidine, aspartic a, leucine Yes Sephadex G

focusing, SD

Ong and Lee (1980) RBC Normal human 67 kDa Thought to be hemoglobin Yes 203Pb bindin

Lolin and O'Gorman (1988) RBC Human Pb workers Low molecular weight Pb-binding protein correlates with restored ALAD Yes Sephadex G

absorption 
 AX5-189 Table AX5-11.1 (cont’d). Lead-binding Proteins Source Organ Species Molecular Weight Protein Properties Inducible Sep

Church et al. (1993a) RBC Human Pb workers, one asymptomatic and one symptomatic 

6–7 kDa First pt had 67% of RBC Pb 

bound to protein. Second pt had 22% of RBC Pb in protein 

Yes RBC hemol

Amicon YM 12 column. 

Church et al. (1993b) RBC Human Pb 

workers 

5, 7 and 12 kDa, pI 4.7–4.9 

30 % cysteine Thought to be MT on basis of greater UV abs at 254 nm than 280 nm 

Yes Superose 12

YM 2, HPL

Xie et al. (1998) RBC Human Pb 

workers 

240 ~ 260 kDa, <30 kDa 

High M.Wt. peak identified as ALAD. Low M.Wt. peak seen after adding Pb in vitro 

Yes Bio-gel A c

A.A. 

Goering and Fowler, (1987a) 

Kidney Rat Pre-treatment with zinc 

before injecting 203Pb leads to 

zinc-thionein binding Pb 

No 203Pb bindin

Goering and Fowler, (1987b) 

Kidney and 

liver 

Rat Pre-Rx with Zn or Cd induces 

Zn or Zn, Cd-MT. The MT decreases Pb inhibition of ALAD 

No 203Pb bindin

Qu et al. (2002); Waalkes et al. (2004) 

Kidney MT-null 

phenotypic mice 

 Pb-exposed MT-null 

developed no Pb inclusion bodies, accumulated less renal Pb than WT 
AX5-190 

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October 2006

EPA/600/R-05/144bF 

Air Quality Criteria for Lead 

Volume II of II 
EPA/600/R-05/144bF 

October 2006 

Air Quality Criteria for Lead 

Volume II 

National Center for Environmental Assessment-RTP Division 

Office of Research and Development 

U.S. Environmental Protection Agency 

Research Triangle Park, NC
 II-iii

PREFACE 

National Ambient Air Quality Standards (NAAQS) are promulgated by the United States 

Environmental Protection Agency (EPA) to meet requirements set forth in Sections 108 and 109 

of the U.S. Clean Air Act. Those two Clean Air Act sections require the EPA Administrator 

(1) to list widespread air pollutants that reasonably may be expected to endanger public health or 

welfare; (2) to issue air quality criteria for them that assess the latest available scientific 

information on nature and effects of ambient exposure to them; (3) to set “primary” NAAQS to 

protect human health with adequate margin of safety and to set “secondary” NAAQS to protect 

against welfare effects (e.g., effects on vegetation, ecosystems, visibility, climate, manmade 

materials, etc); and (5) to periodically review and revise, as appropriate, the criteria and NAAQS 

for a given listed pollutant or class of pollutants. 

Lead was first listed in the mid-1970’s as a “criteria air pollutant” requiring NAAQS 

regulation. The scientific information pertinent to Pb NAAQS development available at the time 

was assessed in the EPA document Air Quality Criteria for Lead; published in 1977. Based on 

the scientific assessments contained in that 1977 lead air quality criteria document (1977 Lead 

AQCD), EPA established a 1.5 μg/m3 (maximum quarterly calendar average) Pb NAAQS in 

1978. 

To meet Clean Air Act requirements noted above for periodic review of criteria and 

NAAQS, new scientific information published since the 1977 Lead AQCD was later assessed in 

a revised Lead AQCD and Addendum published in 1986 and in a Supplement to the 1986 

AQCD/Addendum published by EPA in 1990. A 1990 Lead Staff Paper, prepared by EPA’s 

Office of Air Quality Planning and Standards (OPQPS), drew upon key findings and conclusions 

from the 1986 Lead AQCD/Addendum and 1990 Supplement (as well as other OAQPSsponsored lead exposure/risk analyses) in posing options for the EPA Administrator to consider 

with regard to possible revision of the Pb NAAQS. However, EPA chose not to revise the Pb 

NAAQS at that time. Rather, as part of implementing a broad 1991 U.S. EPA Strategy for 

Reducing Lead Exposure, the Agency focused primarily on regulatory and remedial clean-up 

efforts to reduce Pb exposure from a variety of non-air sources that posed more extensive public 

health risks, as well as other actions to reduce air emissions. 
 II-iv

The purpose of this revised Lead AQCD is to critically assess the latest scientific 

information that has become available since the literature assessed in the 1986 Lead 

AQCD/Addendum and 1990 Supplement, with the main focus being on pertinent new 

information useful in evaluating health and environmental effects of ambient air lead exposures. 

This includes discussion in this document of information regarding: the nature, sources, 

distribution, measurement, and concentrations of lead in the environment; multimedia lead 

exposure (via air, food, water, etc.) and biokinetic modeling of contributions of such exposures 

to concentrations of lead in brain, kidney, and other tissues (e.g., blood and bone concentrations, 

as key indices of lead exposure).; characterization of lead health effects and associated exposureresponse relationships; and delineation of environmental (ecological) effects of lead. This final 

version of the revised Lead AQCD mainly assesses pertinent literature published or accepted for 

publication through December 2005. 

The First External Review Draft (dated December 2005) of the revised Lead AQCD 

underwent public comment and was reviewed by the Clean Air Scientific Advisory Committee 

(CASAC) at a public meeting held in Durham, NC on February 28-March 1, 2006. The public 

comments and CASAC recommendations received were taken into account in making 

appropriate revisions and incorporating them into a Second External Review Draft (dated May, 

2006) which was released for further public comment and CASAC review at a public meeting 

held June 28-29, 2006. In addition, still further revised drafts of the Integrative Synthesis 

chapter and the Executive Summary were then issued and discussed during an August 15, 2006 

CASAC teleconference call. Public comments and CASAC advice received on these latter 

materials, as well as Second External Review Draft materials, were taken into account in making 

and incorporating further revisions into this final version of this Lead AQCD, which is being 

issued to meet an October 1, 2006 court-ordered deadline. Evaluations contained in the present 

document provide inputs to an associated Lead Staff Paper prepared by EPA’s Office of Air 

Quality Planning and Standards (OAQPS), which poses options for consideration by the EPA 

Administrator with regard to proposal and, ultimately, promulgation of decisions on potential 

retention or revision, as appropriate, of the current Pb NAAQS. 

Preparation of this document has been coordinated by staff of EPA’s National Center for 

Environmental Assessment in Research Triangle Park (NCEA-RTP). NCEA-RTP scientific 

staff, together with experts from academia, contributed to writing of document chapters. Earlier 
 II-v

drafts of document materials were reviewed by scientists from other EPA units and by non-EPA 

experts in several public peer consultation workshops held by EPA in July/August 2005. 

NCEA acknowledges the valuable contributions provided by authors, contributors, and 

reviewers and the diligence of its staff and contractors in the preparation of this document. The 

constructive comments provided by public commenters and CASAC that served as valuable 

inputs contributing to improved scientific and editorial quality of the document are also 

acknowledged by NCEA. 

DISCLAIMER 

Mention of trade names or commercial products in this document does not constitute 

endorsement or recommendation for use. 

. 
 II-vi

Air Quality Criteria for Lead 

(Second External Review Draft) 

VOLUME I 

EXECUTIVE SUMMARY .........................................................................................................E-1 

1. INTRODUCTION ........................................................................................................... 1-1 

2. CHEMISTRY, SOURCES, AND TRANSPORT OF LEAD.......................................... 2-1 

3. ROUTES OF HUMAN EXPOSURE TO LEAD AND OBSERVED 

ENVIRONMENTAL CONCENTRATIONS.................................................................. 3-1 

4. TOXICOKINETICS, BIOLOGICAL MARKERS, AND MODELS OF LEAD 

BURDEN IN HUMANS.................................................................................................. 4-1 

5. TOXICOLOGICAL EFFECTS OF LEAD IN LABORATORY ANIMALS 

AND IN VITRO TEST SYSTEMS................................................................................. 5-1 

6. EPIDEMIOLOGIC STUDIES OF HUMAN HEALTH EFFECTS 

ASSOCIATED WITH LEAD EXPOSURE.................................................................... 6-1 

7. ENVIRONMENTAL EFFECTS OF LEAD ................................................................... 7-1 

8. INTEGRATIVE SYNTHESIS OF LEAD EXPOSURE/HEALTH 

EFFECTS INFORMATION............................................................................................ 8-1 

VOLUME II 

CHAPTER 4 ANNEX (TOXICOKINETICS, BIOLOGICAL MARKERS, AND 

MODELS OF LEAD BURDEN IN HUMANS)..................................................... AX4-1 

CHAPTER 5 ANNEX (TOXICOLOGICAL EFFECTS OF LEAD IN 

LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS)................ AX5-1 

CHAPTER 6 ANNEX (EPIDEMIOLOGIC STUDIES OF HUMAN HEALTH 

EFFECTS ASSOCIATED WITH LEAD EXPOSURE)................................. AX6-1 

CHAPTER 7 ANNEX (ENVIRONMENTAL EFFECTS OF LEAD).................................. AX7-1 
II-vii

Table of Contents 

Page

PREFACE......................................................................................................................................iii 

DISCLAIMER ................................................................................................................................ v 

List of Tables ...............................................................................................................................viii 

Authors, Contributors, and Reviewers........................................................................................... xi 

U.S. Environmental Protection Agency Project Team for Development 

 of Air Quality Criteria for Lead............................................................................................. xvii 

U.S. Environmental Protection Agency Science Advisory Board (SAB) 

 Staff Office Clean Air Scientific Advisory Committee (CASAC)......................................... xix 

Abbreviations and Acronyms ...................................................................................................... xxi 

AX6. CHAPTER 6 ANNEX (EPIDEMIOLOGIC STUDIES OF HUMAN 

HEALTH EFFECTS ASSOCIATED WITH LEAD EXPOSURE ......................... AX6-1 

ANNEX TABLES AX6-2 ....................................................................................... AX6-2 

ANNEX TABLES AX6-3 ..................................................................................... AX6-29 

ANNEX TABLES AX6-4 ..................................................................................... AX6-69 

ANNEX TABLES AX6-5 ................................................................................... AX6-129 

ANNEX TABLES AX6-6 ................................................................................... AX6-168 

ANNEX TABLES AX6-7 ................................................................................... AX6-182 

ANNEX TABLES AX6-8 ................................................................................... AX6-206 

ANNEX TABLES AX6-9 ................................................................................... AX6-220 

 REFERENCES .................................................................................................... AX6-260 
II-viii

List of Tables 

Number Page

AX6-2.1 Prospective Longitudinal Cohort Studies of Neurocognitive Ability in 

Children............................................................................................................ AX6-3 

AX6-2.2 Meta- and Pooled-Analyses of Neurocognitive Ability in Children ............... AX6-9 

AX6-2.3 Cross-Sectional Studies of Neurocognitive Ability in Children.................... AX6-11 

AX6-2.4 Effects of Lead on Academic Achievement in Children ............................... AX6-14 

AX6-2.5 Effects of Lead on Specific Cognitive Abilities in Children — 

Attention/Executive Functions, Learning, and Visual-spatial Skills............. AX6-17 

AX6-2.6 Effects of Lead on Disturbances in Behavior, Mood, and Social 

Conduct in Children....................................................................................... AX6-19 

AX6-2.7 Effects of Lead on Sensory Acuities in Children........................................... AX6-23 

AX6-2.8 Effects of Lead on Neuromotor Function in Children................................... AX6-24 

AX6-2.9 Effects of Lead on Direct Measures of Brain Anatomical 

Development and Activity in Children.......................................................... AX6-25 

AX6-2.10 Reversibility of Lead-related Deficits in Children......................................... AX6-27 

AX6-3.1 Neurobehavioral Effects Associated with Environmental 

Lead Exposure in Adults................................................................................ AX6-30 

AX6-3.2 Symptoms Associated with Occupational Lead Exposure in Adults............. AX6-33 

AX6-3.3 Neurobehavioral Effects Associated with Occupational Lead 

Exposure in Adults......................................................................................... AX6-36 

AX6-3.4 Meta-analyses of Neurobehavioral Effects with Occupational 

Lead Exposure in Adults................................................................................ AX6-49 

AX6-3.5 Neurophysiological Function and Occupational Lead 

Exposure in Adults......................................................................................... AX6-51 

AX6-3.6 Evoked Potentials and Occupational Lead Exposure in Adults..................... AX6-56 

AX6-3.7 Postural Stability, Autonomic Testing, Electroencephalogram, 

Hearing Thresholds, and Occupational Lead Exposure in Adults................. AX6-59 
II-ix

List of Tables 

(cont’d) 

Number Page

AX6-3.8 Occupational Exposure to Organolead and Inorganic Lead in Adults .......... AX6-63 

AX6-3.9 Other Neurological Outcomes Associated with Lead Exposure in Adults.... AX6-66 

AX6-4.1 Renal Effects of Lead in the General Population........................................... AX6-70 

AX6-4.2 Renal Effects of Lead in the Occupational Population.................................. AX6-81 

AX6-4.3 Renal Effects of Lead in the Patient Population .......................................... AX6-104 

AX6-4.4 Renal Effects of Lead on Mortality ............................................................. AX6-120 

AX6-4.5 Renal Effects of Lead in Children ............................................................... AX6-122 

AX6-5.1 Effects of Lead on Blood Pressure and Hypertension ................................. AX6-130 

AX6-5.2 Effects of Lead on Cardiovascular Morbidity ............................................. AX6-159 

AX6-5.3 Effects of Lead on Cardiovascular Mortality............................................... AX6-162 

AX6-5.4 Cardiovascular Effects of Lead on Children................................................ AX6-166 

AX6-6.1 Placental Transfer of Lead from Mother to Fetus........................................ AX6-169 

AX6-6.2 Lead Exposure and Male Reproduction: Semen Quality............................ AX6-174 

AX6-6.3 Lead Exposure and Male Reproduction: Time to Pregnancy ..................... AX6-178 

AX6-6.4 Lead Exposure and Male Reproduction: Reproductive History................. AX6-180 

AX6-7.1 Recent Studies of Lead Exposure and Genotoxicity.................................... AX6-183 

AX6-7.2 Key Occupational Studies of Lead Exposure and Cancer ........................... AX6-186 

AX6-7.3 Key Studies of Lead Exposure and Cancer in the General Population........ AX6-192 

AX6-7.4 Other Studies of Lead Exposure and Cancer ............................................... AX6-194 

AX6-8.1 Effects of Lead on Immune Function in Children ....................................... AX6-207 

AX6-8.2 Effects of Lead on Immune Function in Adults........................................... AX6-211 
II-x

List of Tables 

(cont’d) 

Number Page

AX6-9.1 Effects of Lead on Biochemical Effects in Children ................................... AX6-221 

AX6-9.2 Effects of Lead on Biochemical Effects in Adults....................................... AX6-223 

AX6-9.3 Effects of Lead on Hematopoietic System in Children ............................... AX6-231 

AX6-9.4 Effects of Lead on Hematopoietic System in Adults................................... AX6-234 

AX6-9.5 Effects of Lead on the Endocrine System in Children................................. AX6-241 

AX6-9.6 Effects of Lead on the Endocrine System in Adults.................................... AX6-243 

AX6-9.7 Effects of Lead on the Hepatic System in Children and Adults .................. AX6-251 

AX6-9.8 Effects of Lead on the Gastrointestinal System........................................... AX6-253 

AX6-9.9 Effects of Lead on Bone and Teeth in Children and Adults........................ AX6-255 

AX6-9.10 Effects of Lead on Ocular Health in Children and Adults........................... AX6-258 
II-xi

Authors, Contributors, and Reviewers 

CHAPTER 4 ANNEX (TOXICOKINETICS, BIOLOGICAL MARKERS, AND 

MODELS OF LEAD BURDEN IN HUMANS) 

Chapter Managers/Editors

Dr. James Brown—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Principal Authors

Dr. Brian Gulson—Graduate School of the Environment, Macquarie University 

Sydney, NSW 2109, Australia 

Contributors and Reviewers

Dr. Lester D. Grant—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

CHAPTER 5 ANNEX (TOXICOLOGICAL EFFECTS OF LEAD IN HUMANS 

AND LABORATORY ANIMALS) 

Chapter Managers/Editors

Dr. Anuradha Mudipalli—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Srikanth Nadadur—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Lori White—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

 
II-xii

Authors, Contributors, and Reviewers 

(cont’d) 

Principal Authors

Dr. Anuradha Mudipalli—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Stephen Lasley—Dept. of Biomedical and Therapeutic Sciences, Univ. of Illinois College of 

Medicine, PO Box 1649, Peoria, IL 61656 

Dr. Lori White—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Gary Diamond— Syracuse Research Corporation, 8191 Cedar Street, Akron, NY 14001 

Dr. N.D. Vaziri—Division of Nephrology and Hypertension, University of California – Irvine 

Medical Center, 101, The City Drive, Bldg 53, Room #125. Orange, CA 92868 

Dr. John Pierce Wise, Sr.—Maine Center for Toxicology and Environmental Health, 

Department of Applied Medical Sciences, 96 Falmouth Street, PO Box 9300, Portland, ME 

04104-9300 

Dr. Harvey C. Gonick—David Geffen School of Medicine, University of California at 

Los Angeles, 201 Tavistock Ave, Los Angeles, CA 90049 

Dr. Gene E. Watson—University of Rochester Medical Center, Box 705, Rochester, NY 14642 

Dr. Rodney Dietert—Institute for Comparative and Environmental Toxicology, College of 

Veterinary Medicine, Cornell University, Ithaca, NY 14853 

Contributors and Reviewers

Dr. Lester D. Grant—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Paul Reinhart—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Michael Davis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. David A. Lawrence—Dept of Environmental and Clinical Immunology, Empire State Plaza 

P.O. Box 509, Albany, NY 12201 
II-xiii

Authors, Contributors, and Reviewers 

(cont’d) 

Contributors and Reviewers

(cont’d) 

Dr. Michael J. McCabe, Jr.—Dept of Environmental Medicine, University of Rochester, 

575 Elmwood Avenue, Rochester, NY 14642 

Dr. Theodore I. Lidsky—New York State Institute for Basic Research, 1050 Forest RD, 

Staten Island, NY 10314 

Dr. Mark H. Follansbee—Syracuse Research Corporation, 8191 Cedar St. Akron, NY 14001 

Dr. William K. Boyes—National Health and Environmental Effects Research Laboratory, 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Philip J. Bushnell—National Health and Environmental Effects Research Laboratory, 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Ms. Beth Hassett-Sipple—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Zachary Pekar—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

CHAPTER 6 ANNEX (EPIDEMIOLOGICAL STUDIES OF AMBIENT LEAD 

EXPOSURE EFFECTS) 

Chapter Managers/Editors

Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 
II-xiv

Authors, Contributors, and Reviewers 

(cont’d) 

Principal Authors

Dr. David Bellinger—Children’s Hospital, Farley Basement, Box 127, 300 Longwood Avenue, 

Boston, MA 02115 

Dr. Margit Bleecker—Center for Occupational and Environmental Neurology, 2 Hamill Road, 

Suite 225, Baltimore, MD 21210 

Dr. Gary Diamond— Syracuse Research Corporation, 8191 Cedar Street. 

Akron, NY 14001 

Dr. Kim Dietrich—University of Cincinnati College of Medicine, 3223 Eden Avenue, 

Kettering Laboratory, Room G31, Cincinnati, OH 45267 

Dr. Pam Factor-Litvak—Columbia University Mailman School of Public Health, 

722 West 168th Street, Room 1614, New York, NY 10032 

Dr. Vic Hasselblad—Duke University Medical Center, Durham, NC 27713 

Dr. Stephen J. Rothenberg—CINVESTAV-IPN, Mérida, Yucatán, México & National Institute 

of Public Health, Cuernavaca, Morelos, Mexico 

Dr. Neal Simonsen—Louisiana State University Health Sciences Center, School of Public Health 

& Stanley S Scott Cancer Center, 1600 Canal Street, Suite 800, New Orleans, LA 70112 

Dr. Kyle Steenland—Rollins School of Public Health, Emory University, 1518 Clifton Road, 

Room 268, Atlanta, GA 30322 

Dr. Virginia Weaver—Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe 

Street, Room 7041, Baltimore, MD 21205 

Contributors and Reviewers

Dr. J. Michael Davis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Lester D. Grant—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Kazuhiko Ito—Nelson Institute of Environmental Medicine, New York University School of 

Medicine, Tuxedo, NY 10987 
II-xv

Authors, Contributors, and Reviewers 

(cont’d) 

Contributors and Reviewers

(cont’d) 

Dr. Kathryn Mahaffey—Office of Prevention, Pesticides and Toxic Substances, 

U.S. Environmental Protection Agency, Washington, DC 20460 

Dr. Karen Martin—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Zachary Pekar—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Ms. Beth Hassett-Sipple—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

CHAPTER 7 ANNEX (ENVIRONMENTAL EFFECTS OF LEAD) 

Chapter Manager/Editor

Dr. Timothy Lewis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Principle Authors

Dr. Ruth Hull—Cantox Environmental Inc., 1900 Minnesota Court, Suite 130, Mississauga, 

Ontario, L5N 3C9 Canada 

Dr. James Kaste—Department of Earth Sciences, Dartmouth College, 352 Main Street, 

Hanover, NH 03755 

Dr. John Drexler—Department of Geological Sciences, University of Colorado, 

1216 Gillespie Drive, Boulder, CO 80305 

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

365 Link Hall, Syracuse, NY 13244 

Dr. William Stubblefield—Parametrix, Inc. 33972 Texas St. SW, Albany, OR 97321 
II-xvi

Authors, Contributors, and Reviewers 

(cont’d) 

Principle Authors

(cont’d) 

Dr. Dwayne Moore—Cantox Environmental, Inc., 1550A Laperriere Avenue, Suite 103, 

Ottawa, Ontario, K1Z 7T2 Canada 

Dr. David Mayfield—Parametrix, Inc., 411 108th Ave NE, Suite 1800, Bellevue, WA 98004 

Dr. Barbara Southworth—Menzie-Cura & Associates, Inc., 8 Winchester Place, Suite 202, 

Winchester, MA 01890 

Dr. Katherine Von Stackleberg—Menzie-Cura & Associates, Inc., 8 Winchester Place, 

Suite 202, Winchester, MA 01890 

Contributors and Reviewers

Dr. Jerome Nriagu—Department of Environmental Health Sciences, 109 South Observatory, 

University of Michigan, Ann Arbor, MI 48109 

Dr. Judith Weis—Department of Biology, Rutgers University, Newark, NJ 07102 

Dr. Sharon Harper—National Exposure Research Laboratory (D205-05), U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Karen Bradham—National Research Exposure Laboratory (D205-05), U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Ginger Tennant—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Ms. Gail Lacey—Office of Air Quality Planning and Standards, U.S. Environmental Protection 

Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 
II-xvii

U.S. Environmental Protection Agency Project Team 

for Development of Air Quality Criteria for Lead 

Executive Direction

Dr. Lester D. Grant (Director)—National Center for Environmental Assessment-RTP Division, 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Scientific Staff

Dr. Lori White (Lead Team Leader)—National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. James S. Brown—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Robert Elias—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Retired) 

Dr. Brooke Hemming—National Center for Environmental Assessment (B243-01), U.S. 

Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Timothy Lewis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Anuradha Muldipalli—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Srikanth Nadadur—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Paul Reinhart—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Mary Ross— National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 
II-xviii

U.S. Environmental Protection Agency Project Team 

for Development of Air Quality Criteria for Lead 

(cont’d) 

Technical Support Staff

Mr. Douglas B. Fennell—Technical Information Specialist, National Center for Environmental 

Assessment (B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 

27711 (Retired) 

Ms. Emily R. Lee—Management Analyst, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Ms. Diane H. Ray—Program Specialist, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Ms. Donna Wicker—Administrative Officer, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Retired) 

Mr. Richard Wilson—Clerk, National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Document Production Staff

Ms. Carolyn T. Perry—Task Order Manager, Computer Sciences Corporation, 2803 Slater Road, 

Suite 220, Morrisville, NC 27560 

Mr. John A. Bennett—Technical Information Specialist, Library Associates of Maryland, 

11820 Parklawn Drive, Suite 400, Rockville, MD 20852 

Mr. William Ellis—Records Management Technician, InfoPro, Inc., 8200 Greensboro Drive, 

Suite 1450, McLean, VA 22102 

Ms. Sandra L. Hughey—Technical Information Specialist, Library Associates of Maryland, 

11820 Parklawn Drive, Suite 400, Rockville, MD 20852 

Dr. Barbara Liljequist—Technical Editor, Computer Sciences Corporation, 2803 Slater Road, 

Suite 220, Morrisville, NC 27560 

Ms. Michelle Partridge-Doerr—Publications/Graphics Specialist, TEK Systems, 1201 Edwards 

Mill Road, Suite 201, Raleigh, NC 27607 

Mr. Carlton Witherspoon—Graphic Artist, Computer Sciences Corporation, 2803 Slater Road, 

Suite 220, Morrisville, NC 27560 
II-xix

U.S. Environmental Protection Agency 

Science Advisory Board (SAB) Staff Office 

Clean Air Scientific Advisory Committee (CASAC) 

Chair

Dr. Rogene Henderson*—Scientist Emeritus, Lovelace Respiratory Research Institute, 

Albuquerque, NM 

Members

Dr. Joshua Cohen—Faculty, Center for the Evaluation of Value and Risk, Institute for Clinical 

Research and Health Policy Studies, Tufts New England Medical Center, Boston, MA 

Dr. Deborah Cory-Slechta—Director, University of Medicine and Dentistry of New Jersey and 

Rutgers State University, Piscataway, NJ 

Dr. Ellis Cowling*—University Distinguished Professor-at-Large, North Carolina State 

University, Colleges of Natural Resources and Agriculture and Life Sciences, North Carolina 

State University, Raleigh, NC 

Dr. James D. Crapo [M.D.]*—Professor, Department of Medicine, National Jewish Medical and 

Research Center, Denver, CO 

Dr. Bruce Fowler—Assistant Director for Science, Division of Toxicology and Environmental 

Medicine, Office of the Director, Agency for Toxic Substances and Disease Registry, U.S. 

Centers for Disease Control and Prevention (ATSDR/CDC), Chamblee, GA 

Dr. Andrew Friedland—Professor and Chair, Environmental Studies Program, Dartmouth 

College, Hanover, NH 

Dr. Robert Goyer [M.D.]—Emeritus Professor of Pathology, Faculty of Medicine, University of 

Western Ontario (Canada), Chapel Hill, NC 

Mr. Sean Hays—President, Summit Toxicology, Allenspark, CO 

Dr. Bruce Lanphear [M.D.]—Sloan Professor of Children’s Environmental Health, and the 

Director of the Cincinnati Children’s Environmental Health Center at Cincinnati Children’s 

Hospital Medical Center and the University of Cincinnati, Cincinnati, OH 

Dr. Samuel Luoma—Senior Research Hydrologist, U.S. Geological Survey (USGS), 

Menlo Park, CA 
II-xx

U.S. Environmental Protection Agency 

Science Advisory Board (SAB) Staff Office 

Clean Air Scientific Advisory Committee (CASAC) 

(cont’d) 

Members

(cont’d) 

Dr. Frederick J. Miller*—Consultant, Cary, NC 

Dr. Paul Mushak—Principal, PB Associates, and Visiting Professor, Albert Einstein College of 

Medicine (New York, NY), Durham, NC 

Dr. Michael Newman—Professor of Marine Science, School of Marine Sciences, Virginia 

Institute of Marine Science, College of William & Mary, Gloucester Point, VA 

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

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

Dr. Michael Rabinowitz—Geochemist, Marine Biological Laboratory, Woods Hole, MA 

Dr. Joel Schwartz—Professor, Environmental Health, Harvard University School of Public 

Health, Boston, MA 

Dr. Frank Speizer [M.D.]*—Edward Kass Professor of Medicine, Channing Laboratory, 

Harvard Medical School, Boston, MA 

Dr. Ian von Lindern—Senior Scientist, TerraGraphics Environmental Engineering, Inc., 

Moscow, ID 

Dr. Barbara Zielinska*—Research Professor, Division of Atmospheric Science, Desert Research 

Institute, Reno, NV 

SCIENCE ADVISORY BOARD STAFF 

Mr. Fred Butterfield—CASAC Designated Federal Officer, 1200 Pennsylvania Avenue, N.W., 

Washington, DC, 20460, Phone: 202-343-9994, Fax: 202-233-0643 (butterfield.fred@epa.gov) 

(Physical/Courier/FedEx Address: Fred A. Butterfield, III, EPA Science Advisory Board Staff 

Office (Mail Code 1400F), Woodies Building, 1025 F Street, N.W., Room 3604, Washington, 

DC 20004, Telephone: 202-343-9994) 

*Members of the statutory Clean Air Scientific Advisory Committee (CASAC) appointed by the 

 U.S. EPA Administrator 
II-xxi

Abbreviations and Acronyms 

αFGF α-fibroblast growth factor

AA arachidonic acid 

AAL active avoidance learning 

AAS atomic absorption spectroscopy 

ABA β-aminoisobutyric acid 

ACBP Achenbach Child Behavior Profile 

ACE angiotensin converting enzyme 

ACh acetylcholine 

AChE acetylcholinesterase 

ACR acute-chronic ratio 

AD adult 

ADC analog digital converter 

ADP adenosine diphosphate 

AE anion exchange 

AEA N-arachidonylethanolamine 

AFC antibody forming cells 

2-AG 2-arachidonylglycerol 

A horizon uppermost layer of soil (litter and humus) 

AHR aryl hydrocarbon receptor 

AI angiotensin I 

ALA ∗-aminolevulinic acid 

ALAD ∗-aminolevulinic acid dehydratase 

ALAS aminolevulinic acid synthetase 

ALAU urinary δ-aminolevulinic acid 

ALD aldosterone 

ALS amyotrophic lateral sclerosis 

ALT alanine aminotransferase 

ALWT albumin weight 

AMEM Alpha Minimal Essential Medium 

AMP adenosine monophosphate 

ANCOVA analysis of covariance 

ANF atrial natriuretic factor 

Ang II angiotensin II 
II-xxii

ANOVA analysis of variance 

ANP atrial natriuretic peptide 

AP alkaline phosphatase 

AP-1 activated protein-1 

ApoE apolipoprotein E 

AQCD Air Quality Criteria Document 

Arg arginine 

AS52 cells derived from the CHO cell line 

ASGP-R aceyl glycoprotein receptor 

AST aspartate aminotransferase 

ASV anode stripping voltammetry 

3-AT 3-aminotriazole; 3-amino triazide 

ATP adenosine triphosphate 

ATP1A2 sodium-potassium adenosine triphosphase α2 

ATPase adenosine triphosphatase 

ATSDR Agency for Toxic Substances and Disease Research 

AVCD atrioventricular conduction deficit 

AVS acid volatile sulfide 

AWQC ambient water quality criteria 

∃ beta-coefficient; slope of an equation 

∃FGF ∃-fibroblast growth factor

17∃–HS 17∃-hydroxysteriod 

3∃-HSD 3∃-hydroxysteriod dehydrogenase 

17∃-HSDH 17∃-hydroxysteriod dehydrogenase 

6∃-OH-cortisol 6-∃-hydroxycortisol 

B both 

BAEP brainstem auditory-evoked potentials 

BAER brainstem auditory-evoked responses 

BAF bioaccumulation factor 

B cell B lymphocyte 

BCFs bioconcentration factors 

BCS bovine calf serum 

BDNF brain derived neurotrophic factor 

BDWT body weight changes 

BEI biological exposure index 
II-xxiii

BFU-E blood erythroid progenitor 

BLL blood lead level 

BLM biotic ligand model 

BM basement membrane 

BMI body mass index 

BDNF brain-derived neurotrophic factor 

BOTMP Bruinicks-Oseretsky Test of Motor Proficiency 

BP blood pressure 

BPb blood lead concentration 

BSA bovine serum albumin 

BSI Brief Symptom Inventory 

BTQ Boston Teacher Questionnaire 

BUN blood urea nitrogen 

bw, b. wt., BW body weight 

C3H10T/12 mouse embryo cell line 

C3, C4 complement proteins 

CA chromosome aberration 

CA3 cornu ammonis 3 region of hippocampus 

45Ca calcium-45 radionuclide 

Ca-ATP calcium-dependent adenosine triphosphate 

Ca-ATPase calcium-dependent adenosine triphosphatase 

CaCO3 calcium carbonate 

CaEDTA calcium disodium ethylenediaminetetraacetic acid 

CAL calcitonin 

CaM calmodulin 

Ca-Mg-ATPase calcium-magnesium-dependent adenosine triphosphatase 

cAMP cyclic adenosinemonophosphate 

CaNa2 EDTA calcium disodium ethylenediaminetetraacetic acid 

CANTAB Cambridge Neuropsychological Testing Automated Battery 

CAT catalase; Cognitive Abilities Test 

CBCL Achenbach Child Behavior Checklist 

CBCL-T Total Behavior Problem Score 

CBL cumulative blood lead 

CBLI cumulative blood lead index 

CCB cytochalasin B 
II-xxiv

CCD charge-coupled device 

CCE Coordination Center for Effects 

CCL carbon tetrachloride 

CCS cosmic calf serum 

C-CVRSA coefficient of component variance of respiratory sinus arrhythmia 

Cd cadmium 

109Cd cadmium-109 radionuclide 

CdU urinary cadmium 

CEC cation exchange capacity 

CESD, CES-D Center for Epidemiologic Studies Depression (scale) 

GFAP glial fibrillary acidic protein 

CFU-E colony forming unit blood-erythroid progenitor (cell count) 

CFU-GEMM colony forming unit blood-pluripotent progenitor (cell count) 

CFU-GM blood granulocyte/macrophage progenitor (cell count) 

cGMP cyclic guanosine-3',5'-monophosphate 

ChAT choline acetyltransferase 

CHD coronary heart disease 

CHO Chinese hamster ovary cell line 

CI confidence interval 

CLE-SV competitive ligand-exchange/stripping voltammetry 

CLRTAP Convention on Long-Range Transboundary of Air Pollution 

CLS Cincinnati Lead Study 

CMC criterion maximum concentration 

CMI cell-mediated immunity 

CNS central nervous system 

COH cation-osmotic hemolysis 

ConA concanavalin A 

COR cortisol 

CoTx cotreatment 

COX-2 cyclooxygenase-2 

CP coproporphryn 

CPT current perception threshold 

cr creatinine 

CRAC calcium release activated calcium reflux 

CREB cyclic AMP-response element binding protein 
II-xxv

CRF chronic renal failure 

CRI chronic renal insufficiency 

CSF cerebrospinal fluid 

CuZn-SOD copper and zinc-dependent superoxide dismutase 

CV conduction velocity 

CVLT California Verbal Learning Test 

CVR-R coefficient of variation of the R-R interval 

CYP cytochrome (e.g., CYP1A, CYP-2A6, CYP3A4, CYP450) 

CYP3a11 cytochrome P450 3a11 

D D-statistic 

DA dopamine; dopaminergic 

dbcAMP dibutyryl cyclic adenosine-3',5'-monophosphate 

DCV distribution of conduction velocities 

DEAE diethylaminoethyl (chromatography) 

DET diffusive equilibrium thin films 

DEYO death of young 

DFS decayed or filled surfaces, permanent teeth 

dfs covariate-adjusted number of caries 

DG dentate gyrus 

DGT diffusive gradient thin films 

DL DL-statistic 

DMEM Dulbecco’s Minimal Essential Medium 

DMEM/F12 Dulbecco’s Minimal Essential Medium/Ham’s F12 

DMFS decayed, missing, or filled surfaces, permanent teeth 

DMPS 2,3-dimercaptopropane 1-sulfonate 

DMSA 2,3-dimercaptosuccinic acid 

DMT Donnan membrane technique 

DMTU dimethylthiourea 

DNA deoxyribonucleic acid 

DO distraction osteogenesis 

DOC dissolved organic carbon 

DOM dissolved organic carbon 

DOPAc 3,4-dihydroxyphenylacetic acid 

DPASV differential pulse anodic stripping voltammetry 

dp/dt rate of left ventricular isovolumetric pressure 
II-xxvi

DPPD N-N-diphenyl-p-phynylene-diamine 

DR drinking water 

DSA delayed spatial alternation 

DTC diethyl dithiocarbomate complex 

DTH delayed type hypersensitivity 

DTPA diethylenetriaminepentaacetic acid 

DTT dithiothreitol 

dw dry weight 

E embryonic day 

E2 estradiol 

EBE early biological effect 

EBV Epstein-Barr virus 

EC European Community 

EC50 effect concentration for 50% of test population 

eCB endocannabinoid 

ECG electrocardiogram 

Eco-SSL ecological soil screening level 

EDS energy dispersive spectrometers 

EDTA ethylenediaminetetraacetic acid 

EEDQ N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinone 

EEG electroencephalogram 

EG egg 

EGF epidermal growth factor 

EGG effects on eggs 

EGPN egg production 

EKG electrocardiogram 

electro electrophysiological stimulation 

EM/CM experimental medium-to-control medium (ratio) 

EMEM Eagle’s Minimal Essential Medium 

eNOS endothelial nitric oxide synthase 

EP erythrocyte protoporphyrin 

EPA U.S. Environmental Protection Agency 

Epi epinephrine 

EPMA electron probe microanalysis 

EPO erythropoietin 
II-xxvii

EPSC excitatory postsynaptic currents 

EPT macroinvertebrates from the Ephemeroptera (mayflies), 

Plecoptera (stoneflies), and Trichoptera (caddisflies) group 

ERG electroretinogram; electroretinographic 

ERL effects range – low 

ERM effects range – median 

EROD ethoxyresorufin-O-deethylase 

ESCA electron spectroscopy for chemical analysis 

ESRD end-stage renal disease 

EST estradiol 

ESTH eggshell thinning 

ET endothelein; essential tremor 

ETOH ethyl alcohol 

EXAFS extended X-ray absorption fine structure 

EXANES extended X-ray absorption near edge spectroscopy 

F F-statistic 

F344 Fischer 344 (rat) 

FAV final acute value 

FBS fetal bovine serum 

FCS fetal calf serum 

FCV final chronic value 

FD food 

FEF forced expiratory flow 

FEP free erythrocyte protoporphyrin 

FERT fertility 

FEV1 forced expiratory volume in one second 

FGF fibroblast growth factor (e.g., βFGF, αFGF) 

FI fixed interval (operant conditioning) 

FIAM free ion activity model

FMLP N-formyl-L-methionyl-L-leucyl-L-phenylalanine 

fMRI functional magnetic resonance imaging 

FR fixed-ratio operant conditioning 

FSH follicle stimulating hormone 

FT3 free triiodothyronine 

FT4 free thyroxine 
II-xxviii

FTES free testosterone 

FTII Fagan Test of Infant Intelligence 

FTPLM flow-through permeation liquid membranes 

FURA-2 1-[6-amino-2-(5-carboxy-2-oxazolyl)-5-benzofuranyloxy]-2-(2-

amino-5-methylphenoxy) ethane-N,N,N',N'-tetraacetic acid 

FVC forced vital capacity 

(-GT (-glutamyl transferase 

G gestational day 

GABA gamma aminobutyric acid 

GAG glycosaminoglycan 

G12 CHV79 cells derived from the V79 cell line 

GCI General Cognitive Index 

GD gestational day 

GDP guanosine diphosphate

GEE generalized estimating equations 

GFAAS graphite furnace atomic absorption spectroscopy 

GFR glomerular filtration rate 

GGT (-glutamyl transferase 

GH growth hormone 

GI gastrointestinal 

GIME-VIP gel integrated microelectrodes combined with voltammetric 

in situ profiling 

GIS geographic information system 

GLU glutamate 

GMAV genus mean acute value 

GMCV genus mean chronic value 

GMP guanosine monophosphate 

GMPH general morphology 

GnRH gonadotropin releasing hormone 

GOT aspartate aminotransferase 

GP gross productivity 

G6PD, G6PDH glucose-6-phosphate dehydrogenase 

GPEI glutathione S-transferase P enhancer element 

gp91phox NAD(P)H oxidase 

GPT glutamic-pyruvic transaminase 

GPx glutathione peroxidase 
II-xxix

GRO growth 

GRP78 glucose-regulated protein 78 

GSD geometric standard deviation 

GSH reduced glutathione 

GSIM gill surface interaction model 

GSSG glutathione disulfide 

GST glutathione-S-transferase 

GSTP placental glutathione transferase 

GTP guanosine triphosphate 

GV gavage 

H+

 acidity 

3

H hydrogen-3 radionuclide (tritium) 

HA humic acid; hydroxyapatite 

Hb hemoglobin 

HBEF Hubbard Brook Experimenatl Forest 

HBSS Hank’s Balanced Salt Solution 

HCG; hCG human chorionic gonadotropin 

Hct hematocrit 

HDL high-density lipoprotein (cholesterol) 

HEP habitat evaluation procedure 

HET Binghamton heterogeneous stock 

HFPLM hollow fiber permeation liquid membranes 

Hgb hemoglobin 

HGF hepatocyte growth factor 

HH hydroxylamine hydrochloride 

H-H high-high 

HHANES Hispanic Health and Nutrition Examination Survey 

H-L high-low 

HLA human leukocyte antigen 

H-MEM minimum essential medium/nutrient mixture–F12-Ham 

HMP hexose monophosphate shunt pathway 

HNO3 nitric acid 

H2O2 hydrogen peroxide 

HOME Home Observation for Measurement of Environment 

HOS TE human osteosarcoma cells 
II-xxx

HPLC high-pressure liquid chromatography 

H3PO4 phosphoric acid 

HPRT hypoxanthine phosphoribosyltransferase (gene) 

HR heart rate 

HSI habitat suitability indices 

H2SO4 sulfuric acid 

HSPG heparan sulfate proteoglycan 

Ht hematocrit 

HTC hepatoma cells 

hTERT catalytic subunit of human telomerase 

HTN hypertension 

IBL integrated blood lead index 

IBL Η WRAT-R integrated blood lead index Η Wide Range Achievement 

Test-Revised (interaction) 

ICD International Classification of Diseases 

ICP inductively coupled plasma 

ICP-AES inductively coupled plasma atomic emission spectroscopy 

ICP-MS, ICPMS inductively coupled plasma mass spectrometry 

ID-MS isotope dilution mass spectrometry 

IFN interferon (e.g., IFN-() 

Ig immunoglobulin (e.g., IgA, IgE, IgG, IgM) 

IGF-1 insulin-like growth factor 1 

IL interleukin (e.g., IL-1, IL-1∃, IL-4, IL-6, IL-12) 

ILL incipient lethal level 

immuno immunohistochemical staining 

IMP inosine monophosphate 

iNOS inducible nitric oxide synthase 

i.p., IP intraperitoneal 

IPSC inhibitory postsynaptic currents 

IQ intelligence quotient 

IRT interresponse time 

ISEL in situ end labeling 

ISI interstimulus interval 

i.v., IV intravenous 

IVCD intraventricular conduction deficit 
II-xxxi

JV juvenile 

KABC Kaufman Assessment Battery for Children 

KTEA Kaufman Test of Educational Achievement 

KXRF, K-XRF K-shell X-ray fluorescence 

LA lipoic acid 

LB laying bird 

LC lactation 

LC50 lethal concentration at which 50% of exposed animals die 

LC74 lethal concentration at which 74% of exposed animals die 

LD50 lethal dose at which 50% of exposed animals die 

LDH lactate dehydrogenase 

LDL low-density lipoprotein (cholesterol) 

L-dopa 3,4-dihydroxyphenylalanine (precursor of dopamine) 

LE Long Evans (rat) 

LET linear energy transfer (radiation) 

LH luteinizing hormone 

LHRH luteinizing hormone releasing hormone 

LN lead nitrate 

L-NAME L-NG-nitroarginine methyl ester 

LOAEL lowest-observed adverse effect level 

LOEC lowest-observed-effect concentration 

LOWESS locally weighted scatter plot smoother 

LPO lipoperoxide 

LPP lipid peroxidation potential 

LPS lipopolysaccharide 

LT leukotriene 

LT50 time to kill 50% 

LTER Long-Term Ecological Research (sites) 

LTP long term potentiation 

LVH left ventricular hypertrophy 

μPIXE microfocused particle induced X-ray emission 

μSXRF microfocused synchrotron-based X-ray fluorescence 

MA mature 

MA-10 mouse Leydig tumor cell line 

MANCOVA multivariate analysis of covariance 
II-xxxii

MAO monoamine oxidase 

MATC maximum acceptable threshold concentration 

MDA malondialdehyde 

MDA-TBA malondialdehyde-thiobarbituric acid 

MDCK kidney epithelial cell line 

MDI Mental Development Index (score) 

MDRD Modification of Diet in Renal Disease (study) 

MEM Minimal Essential Medium 

MG microglobulin 

Mg-ATPase magnesium-dependent adenosine triphosphatase 

MiADMSA monoisamyl dimercaptosuccinic acid 

Mi-DMSA mi monoisoamyl dimercaptosuccinic acid 

MK-801 NMDA receptor antagonist 

MLR mixed lymphocyte response 

MMSE Mini-Mental State Examination 

MMTV murine mammary tumor virus 

MN micronuclei formation 

MND motor neuron disease 

MNNG N-methyl-N'-nitro-N-nitrosoguanidine 

MPH morphology 

MRI magnetic resonance imaging 

mRNA messenger ribonucleic acid 

MROD methoxyresorufin-O-demethylase 

MRS magnetic resonance spectroscopy 

MS mass spectrometry 

MSCA McCarthy Scales of Children’s Abiltities 

mSQGQs mean sediment quality guideline quotients 

MT metallothionein 

MVV maximum voluntary ventilation 

MW molecular weight (e.g., high-MW, low-MW) 

N, n number of observations 

N/A not available 

NAAQS National Ambient Air Quality Standards 

NAC N-acetyl cysteine 

NAD nicotinamide adenine dinucleotide 
II-xxxiii

NADH reduced nicotinamide adenine dinucleotide 

NADP nicotinamide adenine dinucleotide phosphate 

NAD(P)H, NADPH reduced nicotinamide adenine dinucleotide phosphate 

NADS nicotinamide adenine dinucleotide synthase 

NAF nafenopin 

NAG N-acetyl-∃-D-glucosaminidase 

Na-K-ATPase sodium-potassium-dependent adenosine triphosphatase 

NAWQA National Water-Quality Assessment 

NBT nitro blue tetrazolium 

NCBP National Contaminant Biomonitoring Program 

NCD nuclear chromatin decondensation (rate) 

NCS newborn calf serum 

NCTB Neurobehavioral Core Test Battery 

NCV nerve conduction velocity 

ND non-detectable; not detected 

NDI nuclear divison index 

NE norepinephrine 

NES Neurobehavioral Evaluation System 

NF-κB nuclear transcription factor-κB 

NGF nerve growth factor 

NHANES National Health and Nutrition Examination Survey 

NIOSH National Institute for Occupational Safety and Health 

NIST National Institute for Standards and Technology 

NK natural killer 

NMDA N-methyl-D-aspartate 

NMDAR N-methyl-D-aspartate receptor 

NMR nuclear magnetic resonance 

NO nitric oxide 

NO2 nitrogen dioxide 

NO3 nitrate 

NOAEC no-observed-adverse-effect concentration 

NOAEL no-observed-adverse-effect level 

NOEC no-observed-effect concentration 

NOEL no-observed-effect level 

NOM natural organic matter 
II-xxxiv

NORs nucleolar organizing regions 

NOS nitric oxide synthase; not otherwise specified 

NOx nitrogen oxides 

NP net productivity 

NPSH nonprotein sulfhydryl 

NR not reported 

NRC National Research Council 

NRK normal rat kidney 

NS nonsignificant 

NSAID non-steroidal anti-inflammatory agent 

NT neurotrophin 

NTA nitrilotriacetic acid 

O2 oxygen 

ODVP offspring development 

OH hydroxyl 

7-OH-coumarin 7-hydroxy-coumarin 

1,25-OH-D, 1,25-OH D3 1,25-dihydroxyvitamin D 

24,25-OH-D3 24,25-dihydroxyvitamin D

25-OH-D3 25-hydroxyvitamin D

8-OHdG 8-hydroxy-2'-deoxyguanosine 

O horizon forest floor 

OR odds ratio; other oral 

OSWER Office of Solid Waste and Emergency Response 

P, p probability value 

P300 event-related potential 

P450 1A1 cytochrome P450 1A1 

P450 1A2 cytochrome P450 1A2 

P450 CYP3a11 cytochrome P450 3a11 

PAD peripheral arterial disease 

PAH polycyclic aromatic hydrocarbon 

PAI-1 plasminogen activator inhibitor-1 

PAR population attributable risk 

Pb lead 

203Pb lead-203 radionuclide 

204Pb, 206Pb, 207Pb, 208Pb stable isotopes of lead-204, -206, -207, -208, respectively 
II-xxxv

210Pb lead-210 radionuclide 

Pb(Ac)2 lead acetate 

PbB blood lead concentration 

PbCl2 lead chloride 

Pb(ClO4)2 lead chlorate 

PBG-S porphobilinogen synthase 

PBMC peripheral blood mononuclear cells 

Pb(NO3)2 lead nitrate 

PbO lead oxides (or litharge) 

PBP progressive bulbar paresis 

PbS galena 

PbU urinary lead 

PC12 pheochromocytoma cell 

PCR polymerase chain reaction 

PCV packed cell volume 

PDE phosphodiesterase 

PDGF platelet-derived growth factor 

PDI Psychomotor Development Index 

PEC probable effect concentration 

PEF expiratory peak flow 

PG prostaglandin (e.g., PGE2, PGF2); prostate gland 

PHA phytohemagglutinin A 

Pi inorganic phosphate 

PIXE particle induced X-ray emission 

PKC protein kinase C 

pl NEpi plasma norepinephrine 

PMA progressive muscular atrophy 

PMN polymorphonuclear leucocyte 

PMR proportionate mortality ratio 

PN postnatal (day) 

P5N pyrimidine 5'-nucleotidase 

PND postnatal day 

p.o., PO per os (oral administration) 

POMS Profile of Mood States 

ppb parts per billion 
II-xxxvi

ppm parts per million 

PPVT-R Peabody Picture Vocabulary Test-Revised 

PRA plasma renin activity 

PRL prolactin 

PROG progeny counts or numbers 

PRR prevalence rate ratio 

PRWT progeny weight 

PST percent transferrin saturation 

PTH parathyroid hormone 

PTHrP parathyroid hormone-related protein 

PVC polyvinyl chloride 

PWM pokeweed mitogen 

PRWT progeny weight 

QA/QC quality assurance/quality control 

Q/V flux of air (Q) divided by volume of culture (V) 

r Pearson correlation coefficient 

R2 multiple correlation coefficient 

r

2 correlation coefficient 

226Ra most stable isotope of radium 

R/ALAD ratio of ALAD activity before and after reactivation 

RAVLT Rey Auditory Verbal Learning Test 

86Rb rubidium-86 radionuclide 

RBA relative bioavailablity 

RBC red blood cell; erythrocyte 

RBF renal blood flow 

RBP retinol binding protein 

RBPH reproductive behavior 

RCPM Ravens Colored Progressive Matrices 

REL rat epithelial (cells) 

REP reproduction 

RHIS reproductive organ histology 

222Rn most stable isotope of radon 

RNA ribonucleic acid 

ROS reactive oxygen species 

ROS 17.2.8 rat osteosarcoma cell line 
II-xxxvii

RPMI 1640 Roswell Park Memorial Institute basic cell culture medium 

RR relative risk; rate ratio 

RT reaction time 

RSEM resorbed embryos 

RSUC reproductive success (general) 

RT reproductive tissue 

∑SEM sum of the molar concentrations of simultaneously extracted metal 

SA7 simian adenovirus 

SAB Science Advisory Board 

SAM S-adenosyl-L-methionine 

SBIS-4 Stanford-Binet Intelligence Scale-4th edition 

s.c., SC subcutaneous 

SCAN Test for Auditory Processing Disorders 

SCE selective chemical extraction; sister chromatid exchange 

SCP stripping chronopotentiometry 

SD Spraque-Dawley (rat); standard deviation 

SDH succinic acid dehydrogenase 

SDS sodium dodecyl sulfate; Symbol Digit Substitution 

SE standard error; standard estimation 

SEM standard error of the mean 

SES socioeconomic status 

sGC soluble guanylate cyclase 

SH sulfhydryl 

SHBG sex hormone binding globulin 

SHE Syrian hamster embryo cell line 

SIMS secondary ion mass spectrometry 

SIR standardized incidence ratio 

SLP synthetic leaching procedure 

SM sexually mature 

SMAV species mean acute value 

SMR standardized mortality ratio 

SNAP Schneider Neonatal Assessment for Primates 

SNP sodium nitroprusside 

SO2 sulfur dioxide 

SOD superoxide dismutase 
II-xxxviii

SOPR sperm-oocyte penetration rate 

SPCL sperm cell counts 

SPCV sperm cell viability 

SQGs sediment quality guidelines 

SRA Self Reported Antisocial Behavior scale 

SRD Self Report of Delinquent Behavior 

SRIF somatostatin 

SRM Standard Reference Material 

SRT simple reaction time 

SSADMF Social Security Administration Death Master File 

SSB single-strand breaks 

SSEP somatosensory-evoked potential 

StAR steroidogenic acute regulatory protein 

STORET STOrage and RETrieval 

SVC sensory conduction velocity 

SVRT simple visual reaction time 

T testosterone 

TA tail 

TABL time-averaged blood lead 

T&E threatened and endangered (species) 

TAT tyrosine aminotransferase 

TB tibia 

TBARS thiobarbituric acid-reactive species 

TBPS Total Behavior Problem Score 

TCDD methionine-choline-deficient diet 

T cell T lymphocyte 

TCLP toxic characteristic leaching procedure 

TE testes 

TEC threshold effect concentration 

TEDG testes degeneration 

TEL tetraethyl lead 

TES testosterone 

TEWT testes weight 

TF transferrin, translocation factor 

TG 6-thioguanine 
II-xxxix

TGF transforming growth factor 

TH tyrosine hydroxylase 

232Th stable isotope of thorium-232 

TLC Treatment of Lead-exposed Children (study) 

TNF tumor necrosis factor (e.g., TNF-α) 

TOF time-of-flight 

tPA plasminogen activator 

TPRD total production 

TRH thyroid releasing hormone 

TRV toxicity reference value 

TSH thyroid stimulating hormone 

TSP triple-super phosphate 

TT3 total triiodothyronine 

TT4 serum total thyroxine 

TTES total testosterone 

TTR transthyretin 

TU toxic unit 

TWA time-weighted average 

TX tromboxane (e.g., TXB2) 

U uriniary 

235U, 238U uranium-234 and -238 radionuclides 

UCP urinary coproporphyrin 

UDP uridine diphosphate 

UNECE United Nations Economic Commission for Europe 

Ur urinary 

USFWS U.S. Fish and Wildlife Service 

USGS United States Geological Survey 

UV ultraviolet 

V79 Chinese hamster lung cell line 

VA Veterans Administration 

VC vital capacity; vitamin C 

VDR vitamin D receptor 

VE vitamin E 

VEP visual-evoked potential 

VI variable-interval 
II-xl

vit C vitamin C 

vit E vitamin E 

VMA vanilmandelic acid 

VMI Visual-Motor Integration 

VSM vascular smooth muscle (cells) 

VSMC vascular smooth muscle cells 

WAIS Wechsler Adult Intelligence Scale 

WDS wavelength dispersive spectrometers 

WHO World Health Organization 

WISC Wechsler Intelligence Scale for Children 

WISC-R Wechsler Intelligence Scale for Children-Revised 

WO whole organism 

WRAT-R Wide Range Achievement Test-Revised 

WT wild type 

WTHBF-6 human liver cell line 

ww wet weight 

XAFS X-ray absorption fine structure 

XANES X-ray absorption near edge spectroscopy 

XAS X-ray absorption spectroscopy 

XPS X-ray photoelectron spectroscopy 

X-rays synchrotron radiation 

XRD X-ray diffraction 

XRF X-ray fluorescence 

ZAF correction in reference to three components of matrix effects: 

atomic number (Z), absorption (A), and fluorescence (F) 

ZnNa2 DTPA zinc disodium diethylenetriaminepentaacetic acid 

ZnNa2 EDTA zinc disodium ethylenediaminetetraacetic acid 

ZPP zinc protoporphyrin 
 AX6-1 

AX6. CHAPTER 6 ANNEX 
 AX6-2 

ANNEX TABLES AX6-2 
 AX6-3 Table AX6-2.1. Prospective Longitudinal Cohort Studies of Neurocognitive Ability in Chi

Reference, Study Location, and Period Study Description Pb Measurement Findings, InteUnited States Bellinger et al. (1992) U.S. 148 subjects from the Boston Prospective Study were re-evaluated at 10 yrs of age. The WISCR was used to index intellectual status. Extensive assessment of medical and sociodemographic covariates. Cord and serial postnatal blood Pb assessments Cord blood Pb grouping <3, 6-7, >10 μg/dL Blood Pb at 2 yrs 6.5 (SD 4.9) μg/dL Increase of 10 μg/dL in blood P

associated with a decrement of was stronger for verbal comparPrenatal exposure to Pb as indewas unrelated to psychometric 

Dietrich et al. (1991, 1992, 1993a); Ris et al. (2004) U.S. 253-260 children followed since birth in the Cincinnati Pb Study were re-evaluated at 4, 5, and 6.5 yrs of age. At 4 and 5 yrs, the KABC was used to index intellectual status. At 6.5 yrs, the WISCR was administered. At 15-17 yrs of age, 195 Cincinnati Pb Study subjects were re-evaluated by use of a comprehensive neuropsychological battery that yielded a “Learning/IQ” factor in a principal components analysis. Extensive assessment of 

medical and sociodemographic covariates. 

Prenatal (maternal) and serial postnatal blood Pb assessments Prenatal blood Pb 8.3 (SD 3.7) μg/dL Blood Pb at 2 yrs 17.4 (SD 8.8) μg/dL 

Few statistically significant relaindices and covariate-adjusted Kof age. One KABC subscale thskills was associated with late pfollowing covariate adjustmentadjustment, avg postnatal blood associated with WISCR performPb concentrations >20 μg/dL win performance IQ on the order children with mean blood Pb coAt 15-17 yrs, late childhood blosignificantly associated with loLearning/IQ factor scores. 

Canfield et al. (2003a) U.S. 

172 predominantly African-American, lower socioeconomic status children in Rochester, NY followed since they were 5 to 7 mos were evaluated at 3 and 5 yrs. An abbreviated form of the Stanford-Binet Intelligence Scale-4 (SBIS-4) was used to index intellectual status. Extensive assessment of medical and sociodemographic covariates. 

Serial postnatal blood Pb Blood Pb at 2 yrs 9.7 μg/dL 

Following covariate adjustmentinverse relationship between blages. Overall estimate indicatelifetime blood Pb concentration with a loss of 1⁄2 IQ point. Effesubjects whose blood Pb levels Semiparametric analysis indicapoints for a lifetime avg blood 10 μg/dL, while for levels betwmore gradual decrease in IQ waconcluded that the most importwas that effects below 10 μg/dL cross-sectional studies have now rigorous prospective study. 
 AX6-4 Table AX6-2.1 (cont’d). Prospective Longitudinal Cohort Studies of Neurocognitive Ability in 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InteUnited States (cont’d) Bellinger and Needleman (2003) U.S. Reanalysis of data from the Boston Prospective Study focusing on 48 subjects at 10 yrs of age whose blood Pb levels never exceeded 10 μg/dL. WISCR was used to index intellectual status. See also Bellinger et al. (1992) Serial postnatal blood Pb Blood Pb at 2 yrs 6.5 (SD 4.9) μg/dL IQ was inversely related to two

following covariate adjustment(!1.56) was greater than that deincluding children with concen(!0.58). Authors conclude that reduced at Pb levels still preval

Chen et al. (2005) U.S. 

Repeat measure psychometric data on 780 children enrolled in Treatment of Pb-Exposed Children (TLC) clinical trial were analyzed to determine if blood Pb concentrations at 2 yrs of age constitute a 

critical period of exposure for expression of later neurodevelopmental deficits. Data for placebo and active drug groups were combined in these analyses, which spanned ~2 to 7 yrs of age. Measures of intellectual status included the Bayley Mental Development Index (MDI) and full scale IQ derived from age-appropriate Wechsler scales. 

Blood Pb Range 20-44 μg/dL Baseline blood Pb 26 (SD 26.5) μg/dL in both drug and placebo groups Blood Pb at 7 yrs 8.0 (SD 4.0) μg/dL 

Association between blood Pb intelligence increased in strengwhereas the relation between bIQ attenuated. Peak blood Pb cfully account for the observed abetween their lower blood Pb ceffect of concurrent blood Pb othan currently believed. Autho(a) support the idea that Pb expto children as they reach school support to the interpretation thadone by the time the child reach
 AX6-5 Table AX6-2.1 (cont’d). Prospective Longitudinal Cohort Studies of Neurocognitive Ability in 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InteEurope Wasserman et al. (1992, 1994, 2003); Factor- Litvak et al. (1999) Yugoslavia Birth cohort of ~300-400 infants followed since birth residing in two towns in Kosovo, Yugoslavia, one group near a longstanding Pb smelter and battery manufacturing facility and another in a relatively unexposed location 25 miles away. Intellectual status was monitored from 2 to 10-12 yrs of age with the Bayley Scales of Infant Development, McCarthy Scales of Children’s Abilities, and WISCIII. Extensive assessment of medical and sociodemographic covariates. Maternal prenatal, umbilical cord, and serial postnatal blood Pb Maternal blood Pb in exposed area 19.9 (SD 7.7) μg/dL, unexposed area 5.6 (SD 2.0) μg/dL Umbilical cord blood Pb in exposed area 22.2 (SD 8.1) μg/dL, unexposed area 5.5 (SD 3.3) μg/dL Blood Pb at 2 yrs in exposed area 35.4 μg/dL, 

unexposed area 8.5 μg/dL 

Postnatal blood Pb increment frof age associated with covariatepoints in Bayley MDI. Maternconsistently associated with Baprenatal and cord blood Pb conlower McCarthy General Cogn4 yrs. Scores on the Perceptualparticularly affected. After covof mothers with prenatal blood a full standard deviation below exposure group (<5 μg/dL prenblood Pb also associated with pIncrease in blood Pb level from with a reduction of 3.8 points in adjustment. Effects even more Perceptual-Performance subscainverse associations between lifWISCIII IQ were observed, incassociations with Performance measures. Adjusted intellectuaincrease in lifetime avg blood Pover 4 points in WISCIII Full-SAt 10-12 yrs, subjects were agaWISCIII. Following covariate-blood Pb was associated with aWISCIII, with effect sizes simi7 yrs. In most instances, bone Pstronger than those for blood Pb near the Pb smelter. 
 AX6-6 Table AX6-2.1 (cont’d). Prospective Longitudinal Cohort Studies of Neurocognitive Ability in 

Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

Latin America Schnaas et al. (2000) Mexico 112 children followed since birth with complete psychometric data from the Mexico City Prospective Study were examined. Intellectual status indexed by General Cognitive Index (GCI) from McCarthy Scales of Children’s Abilities (MSCA). Purpose of the study was to determine if magnitude of the effect of postnatal blood Pb levels on cognition varies with time between blood Pb and cognitive assessments. Serial postnatal blood Pb Avg blood Pb 24-36 mos 9.7 (range 3-48) μg/dL A number of significant interac

blood Pb levels and age of asseobserved at 48 mos, when a 5.8 scores was observed for each nblood Pb. Authors concluded tappears to be a critical period fpostnatal blood Pb level effects 

Schnaas et al. (2006) Mexico From the Mexico City Prospective Study, 150 children followed since birth with complete data for all covariates were examined. Intelligence from age 6 to 10 yrs was assessed using the WISC-R. Blood Pb measurements from various time points, starting from maternal blood Pb levels during the 

2nd trimester to postnatal Pb levels at age 10 yrs. 

Serial prenatal (maternal) and postnatal blood Pb  Geometric mean blood Pb  During pregnancy 8.0 (range 1-33) μg/dL  Age 1-5 yrs 9.8 (range 2.8-36.4) μg/dL  Age 6-10 yrs 6.2 (range 2.2-18.6) μg/dL 

Among all the Pb variables at thlog-transformed blood Pb levelwere significantly associated w10 yrs, after adjusting for potenpoint deficit in full scale IQ walog increment in blood Pb. The authors note that, given the relatively low power of this stuPb exposure from other developon child IQ. 

Gomaa et al. (2002) Mexico 

197 two yr-old children residing in Mexico City followed since birth. Bayley Scales of Infant Development Mental Development Index (MDI) used to index intellectual status. Extensive assessment of medical and sociodemographic covariates. 

Umbilical cord and serial postnatal blood Pb  Umbilical cord blood Pb 6.7 (SD 3.4) μg/dL  Blood Pb at 2 yrs 8.4 (SD 4.6) μg/dL Maternal tibial and patellar bone Pb  Patellar (trabecular) bone Pb 17.9 (SD 15.2) μg/g 

Umbilical cord blood Pb and pasignificantly associated with loMaternal trabecular bone Pb levsensorimotor functioning at two concentration Pb measured in cblood Pb level from 5 to 10 μg/3.1 point decrement in adjusted lowest quartile of trabecular boquartiles were associated with 5in MDI following covariate adjconcluded that higher maternal constitute an independent risk fdevelopment in infancy, likely maternal bone Pb stores over ge
 AX6-7 Table AX6-2.1 (cont’d). Prospective Longitudinal Cohort Studies of Neurocognitive Ability in 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InteLatin America (cont’d) Téllez-Rojo et al. (2006) Mexico 294 one and two yr-olds residing in Mexico City followed since birth. The Bayley Scales of Infant Development-II (MDI and PDI) were used to index developmental status. There was extensive assessment of medical and sociodemographic covariates. Umbilical cord blood Pb and postnatal blood Pb at 12 and 24 mos Umbilical cord blood Pb 4.8 (SD 3.0) μg/dL Blood Pb at 1 yr 4.27 (SD 2.1) μg/dL Blood Pb at 2 yrs 4.3 (SD 2.2) μg/dL Blood Pb at 12 mos was not ass

age. Blood Pb at 24 mos was s24 mo MDI. An increase of onblood Pb level was associated win MDI. Findings for PDI were a supplemental subsample of 90 levels >10 μg/dL, the coefficiensignificantly larger for infants nof internal dose. A steeper inveover the blood Pb range up to 5 1 μg/dL increase in blood Pb, p range between 5 and 10 μg/dL however, these slopes were not (p = 0.34). In conclusion, a maprospective study was that a sigrelationship between blood Pb neurodevelopment was observeblood Pb levels did not exceed 

AustraliaBaghurst et al. (1992); McMichael et al. (1994); Tong et al. (1996) Australia

400-500 subjects residing in and near Port Pirie, Australia and followed since birth were re-evaluated 

at 7 to 8 and 11-13 yrs of age. WISCR was used to index intellectual status at both ages. Extensive assessment of medical and sociodemographic covariates. 

Maternal prenatal, umbilical cord and serial postnatal blood Pb  Antenatal avg blood Pb 10.1 (SD 3.9) μg/dL  Umbilical cord blood Pb 9.4 (SD 3.9) μg/dL  Blood Pb at 2 yrs geometric mean 21.3 (SD 1.2) μg/dL Deciduous central incisor whole tooth Pb  Tooth Pb geometric 8.8 (SD 1.9) μg/g 

Significant decrements in covarwere observed in relationship to at both ages. At 7 to 8 yrs of agassociated with an increase in b30 μg/dL. At 11-13 yrs, mean points for an increase in lifetimconcentrations from 10 to 20 μupper incisors were also associfollowing covariate adjustmentdecline in IQ across the range o22 ppm was 5.1 points. 
 AX6-8 Table AX6-2.1 (cont’d). Prospective Longitudinal Cohort Studies of Neurocognitive Ability in 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InteAustralia (cont’d) Cooney et al. (1991) Australia 175 subjects from the Sydney, Australia Prospective Study were assessed at 7 yrs of age. The WISCR was used to index intellectual status. Extensive assessment of medical and sociodemographic characteristics. Maternal and cord blood Pb Cord blood Pb 8.4 μg/dL (SD not given) Blood Pb at 2 yr 15.8 μg/dL (SD not given) Blood indices of Pb exposure w

measure of psychometric intellithat the evidence from their studevelopmental deficits do occu<25 μg/dL, the effect size is likSydney results are difficult to inpresentation in their report. It iwere entered into regression anor substantive basis for their co

Asia Shen et al. (1998) China Pregnant women and newborns in Shanghai, China recruited from health care facilities in the community on the basis of cord blood Pb concentration percentiles (30th and 70th) yielding a total N of 173 subjects. The Bayley Scales of Infant Development 

Mental Development Index (MDI) and Psychomotor Development Index (PDI) were used to index sensorimotor/intellectual status at 3, 6, and 12 mos. Extensive assessment of medical and sociodemographic characteristics. 

Cord blood Pb “High group” 13.4 (SD 2.0) μg/dL “Low group” 5.3 (SD 1.4) μg/dL Blood Pb at 1 yr “High group” 14.9 (SD 8.7) μg/dL “Low group” 14.4 (SD 7.7) μg/dL 

At all ages the Bayley MDI wablood Pb groupings following aPostnatal blood Pb unrelated to Differences in MDI between prgroupings generally in accord win Boston, Cincinnati, and Clevthat the adverse effects of prenadiscernible and stable over the 
 AX6-9 Table AX6-2.2. Meta- and Pooled-Analyses of Neurocognitive Ability in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

Lanphear et al. (2005) Pooled analysis of seven international prospective studies involving 1,333 school-age children. Primary outcome measure was full-scale IQ as assessed by age-appropriate Wechsler scale. Measures of exposure were concurrent, peak, avg lifetime and “early” blood Pb (i.e. mean blood Pb from 6-24 mos). Cord blood Pb was also investigated for those studies that collected these samples at birth. Multivariate regression models were developed adjusting for site as well as 10 common covariates. Blood Pb measure with the largest adjusted R2 was nominated a priori as the preferred index for relating Pb exposure to IQ in subsequent analyses. Results evaluated by applying a random-effects model. Umbilical cord blood Pb Serial postnatal blood Pb Lifetime avg blood Pb 12.4 (range 4.1-34.8) μg/dL Concurrent blood Pb level exhib

relationship with IQ, although refor all blood Pb variables were s

IQ were at blood Pb concentratithe entire pooled data set, a declCI: 3.8, 8.6) was estimated for a

from 1 to 10 μg/dL. Needleman and Gatsonis (1990) Meta analysis of 12 studies chosen on the basis of quality—covariate assessment and application of 

multiple regression techniques. Studies weighted on basis of sample size. Studies divided according to tissue analyzed (blood or teeth). Joint p-values and avg effect sizes calculated using two different 

methods. 

Blood Pb Tooth Pb 

Joint p-values for blood Pb studmethods, whereas joint p-values were obtained for teeth. Partial –0.27 to –0.0003. No single stusignificance of the final findingsthe hypothesis that Pb lowers chdose is strongly supported by rereview. 

Schwartz (1994) Meta analysis of 7 recent studies relating blood Pb to 

IQ were reviewed, three longitudinal and four crosssectional. Measure of effect was estimated decrease in IQ for an increase in blood Pb from 10 to 20 μg/dL. Studies were weighted by the inverse of the variances using random 

Blood Pb Estimated decrease in IQ per blo

20 μg/dL was –2.6 points (SE 0determined by any individual stusimilar for longitudinal and crosFor studies with mean blood Pb effect sizes were larger. When texposures was examined alone usmoothing (Boston), no evidencobserved down to a blood Pb levconcludes that these data provideffects on cognition at levels bel
 AX6-10 Table AX6-2.2 (cont’d). Meta- and Pooled-Analyses of Neurocognitive Ability in Childr

Reference, Study Location, and Period Study Description Pb Measurement Findings, IntePocock et al. (1994) Meta-analysis of five prospective and fourteen cross- sectional studies (including tooth and blood tissues) were included. The fixed effect method of Thompson and Pocock (1992) was employed. Only blood Pb at or near two yrs of age was considered for the prospective studies. Blood Pb Tooth Pb Overall conclusion was that a d

from 10 to 20 μg/dL, or tooth Passociated with an avg estimatepoints. Authors caution interprPb literature in general, citing qrepresentativeness of the samplselection bias, and reverse caus
 AX6-11 Table AX6-2.3. Cross-Sectional Studies of Neurocognitive Ability in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

United States Lanphear et al. (2000) U.S. 4,853 U.S. children ages six to 16 yrs enrolled in NHANES-III. Two subtests of the WISC-R (Block Design and Digit Span) used to assess intellectual status. Medical and sociodemographic covariates were assessed Blood Pb at time of testing Geometric blood Pb 1.9 (SE 0.1) μg/dL 2.1% with blood Pb 

∃10 μg/dL 

Multivariate analyses revealed between blood Pb levels and boAssociations remained statisticanalyses were restricted to childbelow 10 μg/dL. Authors cautiparental intelligence and variabshould temper any conclusions 

Emory et al. (2003) U.S. 

77 healthy, lower-risk African-American infants age 7 mos. The Fagan Test of Infant Intelligence (FTII) was administered to assess intellectual status. Birth weight and gestational age examined as potential covariates/confounders. 

Maternal blood Pb Blood Pb 0.72 (SD 0.86) μg/dL 

Infants scoring in the upper 5th FTII had mother with significanPb levels when compared to tho5th or 15th percentile. Findingconsidered preliminary due to sof covariate assessment or cont

Chiodo et al. (2004) U.S. 

237 African-American inner-city children assessed at 7.5 yrs of age. Cohort was derived from a larger study of the effects of prenatal alcohol exposure on child development. 83% of children in Pb study had little or no gestational exposure to alcohol. WISC-III was administered to assess intellectual status. Medical and sociodemographic covariates were assessed. 

Blood Pb at time of testing Blood Pb 5.4 (SD 3.3) μg/dL 

Following covariate adjustment relationships between blood Pb performance IQ were observedon full-scale and performance Iconcentrations below 7.5 μg/dL

Europe 

Walkowiak et al. (1998) Germany 

384 six-yr-old children in three German cities. Two subtests of the WISC (Vocabulary and Block Design) used to estimate IQ. Both subscales were combined to form a “WISC Index.” Medical and sociodemographic covariate covariates were assessed. 

Blood Pb at time of testing Blood Pb 4.2 μg/dL 95th percentile 8.9 μg/dL 

Following covariate-adjustmensignificantly associated with blindex was borderline. Authors roughly correspond with those effects below 10 μg/dL but cauimportant covariates such as HOcontrolled. 

Prpic-Majic et al. (2000) Croatia 

275 3rd and 4th grade students in Zagreb, Croatia. WISC-R was administered to assess intellectual status. Covariate factors limited to parents’ educational status and gender of child. 

Blood Pb at time of testing Blood Pb 7.1 (SD 1.8) μg/dL 

Following covariate adjustmentassociations were observed for toxicity (ALAD, EP) on WISCstudy had sufficient power and threshold for Pb must be in the study’s range of exposures. 
 AX6-12 Table AX6-2.3 (cont’d). Cross-Sectional Studies of Neurocognitive Ability in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

Latin America Kordas et al. (2004, 2006) Mexico 602 1st grade children in public schools in a highly industrialized area of northern Mexico. Premise of study was that effects of Pb could be explained by correlated nutritional factors such as iron status, anemia, and growth. Peabody Picture Vocabulary Test-Revised (PPVT-R), Cognitive Abilities Test (CAT), and an abbreviated form of the WISC-R were administered to assess intellectual status. Medical and sociodemographic covariates were assessed. Blood Pb at time of testing Blood Pb 11.5 (SD 6.1) μg/dL Following covariate adjustment 

significantly associated with po

PPVT-R, WISC-R Coding, and Sequencing, a Math AchievemeMemory Test. Authors concludwith iron deficiency anemia or not explain relationship betweeperformance. Non-linear analyneurocognitive outcomes reveacurves were steeper at lower thlevels. Moreover, the slopes apPb levels below 10 μg/dL, abovplateau. Effects of Pb on neuroappeared to be greatest among members of the cohort. Counter et al. (1998) Ecuador 77 chronically Pb-exposed children living in Ecuadorian villages where Pb is used extensively in 

commercial ceramics production. Ravens Colored Progressive Matrices (RCPM) used to index intellectual status. Only half of the sample was assessed. No assessment of medical or sociodemographic covariates. 

Blood Pb at time of testing Blood Pb 47.4 (SD 22) μg/dL 

Simple regression analysis reveblood Pb and RCPM of only boResults difficult to interpret becto age-adjust. When analysis re11 yrs of age, a highly significaobtained. Study has little relevhazards in the U.S. because of uexposure. 

Asia 

Rabinowitz et al. (1991) Taiwan

443 children in grades one to three in Taipei City and three schools near Pb smelters. Ravens Colored Progressive Matrices (RCPM) used to index intellectual status. Medical and sociodemographic covariate factors were assessed. 

Dentin tooth Pb Taipei City 4.3 (SD 3.7) μg/g Smelter areas 6.3 (SD 3.3) μg/g 

Scores on the RCPM were negaPb concentrations. In multivarieducation was the most importascores, but tooth Pb concentratipredicted lower scores in femalfamilies. 

Bellinger et al. (2005) India 

74 four to fourteen yr-old children residing in Chennai, India were enrolled in the study, 31 of which were assessed with the Binet-Kamath Intelligence test. Data were collected on sociodemographic features of subjects’ families. 

Blood Pb at time of testing Blood Pb 11.1 (SD 5.6) μg/dL 

Covariate-adjusted blood Pb cononsignificant, perhaps due to shighly variable performance of elevated blood Pb concentration
 AX6-13 Table AX6-2.3 (cont’d). Cross-Sectional Studies of Neurocognitive Ability in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

Middle East Al-Saleh et al. (2001) Saudi Arabia 533 Riyadh, Saudi Arabian girls (6-12 yrs of age) were administered a variety of standardized tests including the TONI, and the Beery VMI. Extensive data were collected on potentially confounding variables including sociodemographic variables, early developmental milestones and child health status. Blood Pb at time of testing Blood Pb 8.1 (SD 3.5) μg/dL Blood Pb levels had no impact 

has limited evidence of validity Significant negative associationblood Pb levels and the Beery Vassociation between impairmenSaudi children with blood Pb le27.4 μg/dL. 
 AX6-14 Table AX6-2.4. Effects of Lead on Academic Achievement in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

United States Lanphear et al. (2000) U.S. Design: Cross-sectional. 4,853 U.S. children ages six to 16 yrs enrolled in NHANES-III. Subjects were administered the Arithmetic and Reading subtests of the Wide Range Achievement Test- Revised (WRATR). A number of medical and sociodemographic covariates were assessed and entered into multivariable models. Blood Pb at time of testing Geometric blood Pb 1.9 (SE 0.1) μg/dL 2.1% with blood Pb 

∃10 μg/dL 

Following covariate adjustmentrelationship between blood Pb awas found. A 0.70 point decremand a 1 point decrement in Rea1 μg/dL increase in blood Pb coStatistically significant inverse Pb levels and performance for bArithmetic subtests were found concentrations <5 μg/dL. Authof these analyses suggest that dare associated with blood Pb co5 μg/dL. They cautioned, howethat have been shown to be imp(i.e., parental IQ and HOME scThis may have over or under esacademic skills related to Pb. Twith all cross-sectional studies index of dose it is not clear wheskills were due to Pb exposure during early childhood or due tNevertheless, concurrent blood ongoing exposure and preexisti

Needleman et al. (1990) U.S. 

Design: Prospective cohort. Re-examination of the Chelsea and Somerville cohort recruited in the 1970’s (Needleman et al., 1979). 132 adolescents were recalled. Large battery of tests was administered to examine neurobehavioral deficits and academic achievement in high school and shortly following graduation. Extensive assessment of medical and sociodemographic covariates. 

Tooth (dentin) Pb Tooth Pb median 8.2 μg/g 

Subjects with dentin Pb levels >of dropping out of high school CI: 1.4, 40.7]) and of having a OR = 5.8 [95% CI: 1.7, 19.7]). were also significantly associatstanding, increased absenteeismgrammatical reasoning scores oEvaluation System (NES). Autexposure to Pb has enduring anobjective parameters of success 
 AX6-15 Table AX6-2.4 (cont’d). Effects of Lead on Academic Achievement in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

United States (cont’d) Bellinger et al. (1992) U.S. Design: Prospective longitudinal. 148 children in the Boston Pb Study cohort were examined at 10 yrs of age. The short-form of the Kaufman Test of Educational Achievement (KTEA) was used to assess academic achievement. Primary outcome was the Battery Composite Score. Extensive assessment of medical and sociodemographic covariates. Cord and serial postnatal blood Pb assessments. Cord blood Pb grouping <3, 6-7, >10 μg/dL Blood Pb at 2 yrs 6.5 (SD 4.9) μg/dL After covariate-adjustment, blood 

significantly predictive of lower a(∃ = !0.51, SE 0.20). Battery Com8.9 points for each 10 μg/dL increassociation was significant after aconclude that Pb-sensitive neuroplearning factors not reflected in mmay contribute to deficits in acad

Leviton et al. (1993) U.S. 

Design: Prospective cohort. Teachers of ~2000 eight yr-old children born in 1 hospital in Boston between 1979 and 1980 filled out the Boston Teachers Questionnaire (BTQ) to assess academic performance and behavior. Limited information is provided on the assessment of covariate factors but a number were considered and controlled for in multivariable analyses. 

Cord blood Pb Cord blood Pb 6.8 μg/dL Tooth (dentin) Pb Tooth Pb 2.8 μg/g 

Following adjustment for potentiaelevated dentin Pb concentrations statistically significant reading anassessed by the BTQ among girls conclude that their findings suppolearning problems at levels that wthe general population. Howeverto assess child-rearing quality in tlimits the inferences that can be d

Australia 

Fergusson et al. (1993, 1997); Fergusson and Horwood (1993) New Zealand 

Design: Prospective cohort. Academic performance was examined in a birth cohort of 1200 New Zealand children enrolled in the Christchurch Health and Development Study. Measures of academic performance at 12-13 yrs included the Brut Reading Test, Progressive Achievement Test, Test of 

Scholastic Abilities, and teacher ratings of classroom performance in the areas of reading, writing, and mathematics. The growth of word recognition skills from 8 to 12 yrs was also examined using growth curve modeling methods. Academic achievement in relationship to Pb was re-examined in this cohort at 18 yrs. Measures of academic achievement included the Burt Reading Test, number of yrs of secondary education, number of certificates passed (based on national examinations), and leaving school without 

formal qualifications (failing to graduate). Extensive assessment of medical and social covariates. 

Tooth (dentin) Pb Tooth Pb 6.2 (SD 6.2) μg/g 

Following covariate adjustment, dsignificantly associated with virtuacademic skills and teacher ratingin 12-13 yr-olds. After adjustmenlevels greater than 8 μg/g were asslow growth in word recognition catch up. At 18 yrs, tooth Pb leveassociated with lower reading test level of less than 12 yrs, failing to school, leaving school without qunumber of School Certificates pasearly exposure to Pb is independedetectable and enduring deficits in abilities. They further conclude tparticularly significant in that theNeedleman (1990), albeit in a cohexposure to environmental Pb. 
 AX6-16 Table AX6-2.4 (cont’d). Effects of Lead on Academic Achievement in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

Asia Wang et al. (2002a) Taiwan Design: Cross-sectional. 934 3rd graders living in an urban industrial area of Taiwan. Outcome variables were grades for Chinese (reading, writing), mathematics, history, and natural science. Grades were converted into individual class rankings to avoid teacher bias. Limited data on medical and sociodemographic covariates. Blood Pb at time of evaluation Blood Pb 5.5 (SD 1.9) μg/dL Following covariate adjustment

associated with lower class ranksubjects. Major shortcoming of control for potentially importanparental IQ. However, the relatexposure in this sample and strereported relationships suggest trole in lowering academic perfo

Rabinowitz et al. (1992) Taiwan Design: Cross-sectional. Teachers of 493 children in grades 1-3 filled out the Boston Teachers Questionnaire (BTQ) to assess academic performance and behavior. Sociodemographic and medical covariate factors were assessed. Tooth (dentin) Pb Tooth Pb 4.6 (SD 3.5) μg/g Prior to adjustment for covariat

exposures to Pb evinced a bordreading difficulties while byes dincreased difficulties with respetask attentiveness. In logistic reinclude significant covariate facfailed to achieve statistical signthat Pb levels found in the teeth Taiwanese sample are not assocproblems as assessed by the BT

Middle East Al Saleh et al. (2001) Saudi Arabia 

Class rank, as assessed by the teacher, was examined in conjunction with blood Pb levels in 533 Riyadh, Saudi Arabian girls (6-12 yrs of age). Extensive data were collected on potentially confounding variables including sociodemographic variables, early developmental milestones and child health status. 

Blood Pb at time of testing Blood Pb 8.1 (SD 3.5) μg/dL 

A significant inverse relationshand rank percentile scores was a number of demographic and sWhen multiple regression modestudents with blood Pb levels bpercentile continued to show a association with blood Pb level
 AX6-17 Table AX6-2.5. Effects of Lead on Specific Cognitive Abilities in Children — Attention/Executive Funct

Visual-spatial Skills Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

United States Bellinger et al. (1994a) U.S. Design: Prospective cohort. 79 subjects from the original Chelsea and Somerville, MA Pb study were re-evaluated at 19-20 yrs of age with the Mirsky battery of attentional measures. Extensive measures of medical and sociodemographic covariates. Tooth (dentin) Pb Tooth Pb 13.7 (SD 11.2) μg/g KXRF Bone Pb Tibial bone Pb (range <1 - >10) μg/g Patellar bone Pb (range <1 - >15) μg/g Higher tooth Pb concentrations 

associated with poorer scores oShift factors of the Mirsky batteassociations were observed betwperformance. Authors conclude may be associated with poorer pexecutive/regulatory functions, depend on the frontal or prefron

Stiles and Bellinger (1993) U.S. Design: Prospective longitudinal. 148 subjects from the Boston Pb Study were re-evaluated at 10 yrs of age with an extensive neuropsychological battery. Tests included the California Verbal Learning Test, Wisconsin Card Sorting Test, Test of Visual-Motor Integration, Rey-Osterieth Complex Figure, Story 

Recall, Finger Tapping, and Grooved Pegboard. Extensive measures of medical and sociodemographic covariates. 

Cord and serial postnatal blood Pb assessments Cord blood Pb grouping <3, 6-7, >10 μg/dL Blood Pb at 2 yrs 6.5 (SD 4.9) μg/dL 

Authors point out that the numbassociations was about equal to expected by chance. However, behaviors and executive functiofor which Pb was a significant pFollowing covariate adjustmentconcentrations at two yr were silower scores on Freedom from Wechsler scales, increase in pererrors on the Wisconsin Card SCalifornia Verbal Learning Tes

Canfield et al. (2003b, 2004) U.S. 

Design: Prospective longitudinal. 170-174 children from the Rochester Pb Study were administered a number of learning and neuropsychological functioning at 48, 54, and 66 mos of age. At 48 and 54 mos the Espy Shape School Task was administered while at 66 mos the Working Memory and Planning assessment protocols of the Cambridge Neuropsychological Test Automated Battery (CANTAB) was given. Extensive measures on medical and sociodemographic covariates. 

Serial postnatal blood Pb Blood Pb at 2 yrs 9.7 μg/dL Lifetime avg blood Pb 7.2 (range 0-20) μg/dL 

Following covariate adjustmentwas negatively associated with while performing the Shape Schnaming colors, and inhibition oChildren with higher blood Pb ccompleted fewer phases of the Ecolor and shape names. On the with higher lifetime avg blood Pperformance on spatial working span, and cognitive flexibility aconclude that the effects of pedrestricted to global measures of executive processes may be at p
 AX6-18 Table AX6-2.5 (cont’d). Effects of Lead on Specific Cognitive Abilities in Children — Attention/Exec

Learning, and Visual-spatial Skills Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

United States (cont’d) Ris et al. (2004) U.S. Design: Prospective longitudinal. 195 subjects from the Cincinnati Pb Study were administered an extensive and comprehensive neuropsychological battery at 16-17 yrs of age. Domains assessed included Executive Functions, Attention, Memory, Achievement, Verbal Skills, Visuoconstructional, and Fine Motor. Factor scores transformed to ranks derived from a principal components factor analysis of the neuropsychological test scores were the primary outcome variables. Extensive measures on medical and sociodemographic covariates. Prenatal (maternal) and serial postnatal blood Pb assessments Prenatal blood Pb 8.3 (SD 3.7) μg/dL Blood Pb at 2 yrs 17.4 (SD 8.8) μg/dL Following covariate adjustment

between Pb exposure and perfofactor scores derived from the Aincluded high loadings on variaContinuous Performance Test. strongest in males. Authors speincidence of Attention Deficit/Hgreater in males in general, earlexacerbate a latent potential for 
 AX6-19 Table AX6-2.6. Effects of Lead on Disturbances in Behavior, Mood, and Social Conduct in C

Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

United States Sciarillo et al. (1992) U.S. Design: Cross-sectional. 150 2-5 yr-old children in Baltimore separated into “high” (2 consecutive blood Pb levels >15 μg/dL) and “low” groups. Mothers filled out the Achenbach Child Behavior Checklist (CBCL). The Center for Epidemiologic Studies Depression Scale (CESD) was administered to mothers as a control measure. Screening blood Pbs at various times before assessment High group 28.6 (SD 9.3) μg/dL Low group 11.3 (SD 4.3) μg/dL When compared to lower expos

high group had a significantly hBehavior Problems Score (TBPExternalizing scores. After adjudepression, blood Pb concentraassociated with an increase in thgroup were nearly 3 times more the clinical range. A significanchildren in the high group scoreCBCL subscales measuring aggbehavioral tendencies. Bellinger et al. (1994b) U.S. Design: Prospective cohort: 1782 children born within a 1-yr period at a single Boston hospital were examined at 8 yrs of age. Teachers filled out the Achenbach Child Behavior Profile (ACBP). Medical and sociodemographic characteristics assessed by 

questionnaire and chart review. 

Umbilical cord blood Pb Cord blood Pb 6.8 (SD 3.1) μg/dL Tooth (dentin) Pb Tooth Pb 3.4 (SD 2.4) μg/g 

Cord blood Pb levels were not aprevalence or nature of behavioteachers. Tooth Pb levels were with ACBP Total Problem BehStatistically significant tooth Pbboth Externalizing and InternaliEach log unit increase in tooth P1.5-point increase in T scores focaution that residual confoundinbecause of the lack of informatipsychopathology or observationenvironment. However, these rother studies that social and eman important expression of elev

childhood. 

Denno (1990) U.S. 

Design: Prospective cohort. Survey of 987 Philadelphia African-American youths enrolled in the Collaborative Perinatal Project. Data available from birth through 22 yrs of age. Analysis considered 100 predictors of violent and chronic delinquent behavior. 

Blood Pb Values not provided 

Repeat offenders presented conmaternal education, prolonged munemployment, frequent movesintoxication. In male subjects, was among the most significant and adult criminality. 
 AX6-20 Table AX6-2.6 (cont’d). Effects of Lead on Disturbances in Behavior, Mood, and Social Conduct 

Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

United States (cont’d) Needleman et al. (1996) U.S. Design: Prospective cohort. 850 boys enrolled in the Pittsburgh Youth Study were prescreened to assess delinquent behavioral tendencies. Subjects who scored in the 30th percentile on the risk score and an equal number randomly selected from the remainder form the sample of 530 subjects. Measures of antisocial behavior were administered at 7 and 11 yrs of age including the Self Reported Antisocial Behavior scale (SRA), Self Report of Delinquent Behavior (SRD), and parents’ and teachers’ versions of the Achenbach Child Behavior Profile (CBCL). Extensive assessment of medical and sociodemographic covariates. Bone Pb by K-XRF Bone Pb (exact concentrations not reported) Negative values treated categorically as 1 and positive values grouped into quintiles. Following covariate-adjustment

higher Pb levels in bone reportesomatic complaints, more delinbehavior, and higher Internaliziscores. Teachers reported signisomatic complaints, anxious/deattention problems, delinquent b

behavior, internalizing and extehigher bone Pb subjects. At 11 were also significantly related thigh Pb subjects had CBCL T sfor attention, aggression, and deconclude that Pb exposure is asfor antisocial and delinquent be

Dietrich et al. (2001) U.S. Design: Prospective longitudinal. 195 subjects from the Cincinnati Pb Study were examined at 16-17 yrs of 

age. Parents were administered a questionnaire developed specifically for the study while CLS subjects were given the Self Report of Delinquent Behavior. Extensive assessment of medical and sociodemographic covariates. 

Prenatal (maternal) and serial postnatal blood Pb assessments. Prenatal blood Pb 8.3 (SD 3.7) μg/dL Blood Pb at 2 yrs 17.4 (SD 8.8) μg/dL 

Prenatal (maternal) blood Pb wwith a covariate-adjusted increaparent-reported delinquent and and measures of postnatal Pb exassociated with self-reported debehaviors. Authors concluded tmeasurable role in the developmin inner-city children independeand biomedical cofactors. 

Needleman et al. (2002) U.S. 

Design: Case-control. 194 adjudicated delinquents and 146 non-delinquent controls recruited from high schools in the City of Pittsburgh and Allegheny 

County, PA. Covariate assessments were not extensive but did include race, parental 

sociodemographic factors, and neighborhood crime rates. 

Bone Pb by KXRF Cases 11.0 (SD 32.7) μg/g Controls 1.5 (SD 32.1) μg/g 

Cases had significantly higher atibia than controls. Following cadjudicated delinquents were 4 bone Pb concentration >25 μg/g level was the second strongest fregression models, exceeded onstratified by race, bone Pb was only by single parent status. Au

elevated body Pb burdens are arisk for adjudicated delinquency
 AX6-21 Table AX6-2.6 (cont’d). Effects of Lead on Disturbances in Behavior, Mood, and Social Conduct 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterEurope Wasserman et al. (1994) Yugoslavia Design: Prospective longitudinal. Birth cohort of ~300-400 infants followed since birth residing in two towns in Kosovo, Yugoslavia, one group near a longstanding Pb smelter and battery manufacturing facility and another in a relatively unexposed location 25 miles away. 379 children at 3 yrs of age were examined. Parents were interviewed with the Achenbach Child Behavior Checklist (CBCL). Extensive assessment of medical and sociodemographic covariates. Maternal prenatal, umbilical cord and serial postnatal blood Pb Maternal blood Pb in exposed area 19.9(SD 7.7) μg/dL, unexposed area 5.6 (SD 2.0) μg/dL Umbilical cord blood Pb in exposed area 22.2 (SD 8.1) μg/dL, unexposed area 5.5 (SD 3.3) μg/dL Blood Pb at 2 yrs in exposed area 35.4 μg/dL, unexposed area 

8.5 μg/dL 

Following covariate adjustment, cwere associated with increased DCBCL subscale, although the variwas small compared to sociodemPb increased from 10 to 20 μg/dLby 0.5 points. The authors conclusignificant, the contribution of Pb problems in this cohort was small correlated social factors. 

Australia 

Burns et al. (1999) Australia 

Design: Prospective longitudinal. 322 subjects 

residing in and near Port Pirie, Australia and followed since birth were re-evaluated at 11-13 yrs of age. Parents completed the Achenbach Child Behavior Checklist. Extensive assessment of medical and sociodemographic characteristics. 

Maternal prenatal, umbilical cord and serial postnatal blood Pb  Antenatal avg blood Pb 10.1 (SD 3.9) μg/dL  Umbilical cord blood Pb 9.4 (SD 3.9) μg/dL  Blood Pb at 2 yrs geometric mean 21.3 (SD 1.2) μg/dL 

After adjustment for covariates, rthat for an increase in avg lifetimfrom 10 to 30 μg/dL, the Externascore increased by 3.5 points in bonly 1.8 points (95% CI: !0.1, 11behavior problems were predicted CI: 0.0, 4.2) in girls by only 0.8 (Authors concluded that Pb exposuincrease in externalizing (underco

Fergusson et al. (1993) New Zealand 

Design: Prospective cohort. 690-891 children ages 12 and 13 yrs from the Christchurch Child and Health Study, New Zealand were examined. Mothers and teachers were asked to respond to a series of items derived from the Rutter and Conners parental and teacher questionnaires. Extensive assessment of sociodemographic and medical covariates. 

Tooth (dentine) Pb  Tooth Pb range 3–12 μg/g 

Statistically significant dose-effecobserved between tooth Pb levels inattention/restlessness variable aconclude that this evidence is conmildly elevated Pb levels are assoterm deficits in attentional behavi
 AX6-22 Table AX6-2.6 (cont’d). Effects of Lead on Disturbances in Behavior, Mood, and Social Conduct 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterAustralia Silva et al. (1988) New Zealand As part of the 11-yr follow-up of the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of a birth cohort of children born in Dunedin’s only obstetric hospital, blood Pb levels were measured in 579 children at age 11 yrs old. The study sample was over-representative of higher SES, but was found to be representative of Dunedin children in educational attainment. Blood Pb levels were examined in association with intelligence assessed using the WISC-R and behavioral problems as assessed by both parents and teachers. Blood Pb at time of testing Blood Pb at age 11 yrs 11.1 (SD 4.91, range 4-50) μg/dL Log blood Pb levels were signific

measures of behavioral problems, Teachers’ Rutter Behavioral ScaleTeachers’ Hyperactivity Scale, anScale, after adjustment for various associations were observed betweIQ. Authors concluded that exposincreases in children’s’ general beespecially in inattention and hype
 AX6-23 Table AX6-2.7. Effects of Lead on Sensory Acuities in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Int

United States Schwartz and Otto (1991) U.S. Design: Cross-sectional. 3545 subjects 6-19 yrs old who participated in the Hispanic Health and Nutrition Examination Survey. Pure tone audiometric evaluations were performed at 500 Hz, 2000 Hz, and 4000 Hz. Extensive measures on medical and sociodemographic covariates. Blood Pb at the time of testing Blood Pb 50th percentile 8 μg/dL Following covariate adjustment

concentrations were associated whearing thresholds that were elereference level at all four frequeassociated higher hearing threshcontinuous outcome. These relaPb levels below 10 μg/dL. An i18 μg/dL was associated with a Authors conclude that HHANES earlier for NHANES-II. Dietrich et al. (1992) U.S. Design: Prospective/longitudinal. 215 subjects drawn from the Cincinnati Pb Study at the age of 5 yrs. Children were administered the SCAN-a standardized test of central auditory processing. Extensive measurement of medical and sociodemographic covariates Prenatal (maternal) and serial postnatal blood Pb assessments Prenatal blood Pb 8.3 (SD 3.7) μg/dL Blood Pb at 2 yrs 17.4 (SD 

8.8) μg/dL 

Higher prenatal (maternal), neonconcentrations were associated widentification of common monounder conditions of muffling. Fadjustment, avg childhood blood significantly associated with imSCAN subtest. Authors concludhearing and auditory processing mechanism by which an increaschild’s learning. 

Europe

Osman et al. (1999) Poland 

Design: Cross-sectional. 155 children 4-14 yr-old living in an industrial region of Poland. Pure tone audiometric evaluations were performed at 500 Hz, 1000 Hz, 2000 Hz, 4000 Hz, 6000Hz, and 8000 Hz. Basic data on medical history, limited information on sociodemographic covariates such as family structure and income. 

Blood Pb at the time of testing  Blood Pb median 7.2 (range 1.9-28) μg/dL 

Higher blood Pb concentrations with increased hearing thresholdThis relationship remained signilimited to subjects with blood PAuthors conclude that auditory impaired at blood Pb concentrat
 AX6-24 Table AX6-2.8. Effects of Lead on Neuromotor Function in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Inter

United States Dietrich et al. (1993b); Bhattacharya et al. (1995); Ris et al. (2004) U.S. Design: Prospective longitudinal. Relationship between Pb exposure and neuromotor function has been examined in several studies on the Cincinnati Pb Study Cohort from 6 to 17 yrs of age. At 6 yrs of age 245 subjects were administered the Bruininks- Oseretsky Test of Motor Proficiency (BOTMP); at 6- 10 yrs of age subjects were assessed for postural instability using a microprocessor-based strain gauge platform system and at 16-17 yrs of age the fine- motor skills of study subjects were assessed with the grooved pegboard and finger tapping tasks (part of a comprehensive neuropsychological battery). Extensive measurement of medical and sociodemographic factors. Prenatal (maternal) and serial postnatal blood Pb assessments Prenatal blood Pb 8.3 (SD 3.7) μg/dL Blood Pb at 2 yrs 17.4 (SD 8.8) μg/dL Following covariate adjustment, p

significantly associated with poormeasures of bilateral coordinationupper-limb speed and dexterity aComposite score. Low-level neoconcentrations were also significascores on the aforementioned subof visual-motor control. Postnatasignificantly associated with grea10 yr-old subjects and poorer fineexamined at 16-17 yrs. Authors conclude that effects of einto a number of dimensions of n

Europe

Wasserman et al. (2000a) Yugoslavia 

Design: Prospective longitudinal. Birth cohort of ~300-400 infants followed since birth residing in two towns in Kosovo, Yugoslavia, one group near a longstanding Pb smelter and battery manufacturing facility and another in a relatively unexposed location 25 miles away. 283 children at age 54 mos were administered the Beery Developmental Test of Visual-Motor Integration (VMI) and the BruininksOseretsky Test of Motor Proficiency (BOTMP). Extensive measurement of medical and sociodemographic factors. 

Maternal prenatal, umbilical cord and serial postnatal blood Pb Maternal blood Pb in exposed area 19.9 (SD 7.7) μg/dL, unexposed area 5.6 (SD 2.0) μg/dL Umbilical cord blood Pb in exposed area 22.2 (SD 8.1) μg/dL, unexposed area 5.5 (SD 3.3) μg/dL Blood Pb at 2 yrs in exposed area 35.4 μg/dL, unexposed area 8.5 μg/dL 

Following covariate-adjustment, Pb assessments to 54 mos was asMotor Composite and VMI scoreunrelated to gross motor performadjustment, an increase in avg blowas associated with a loss of 0.62 respectively, in Fine Motor Compnoted that other factors such as instimulation in the home make a ladevelopment than Pb. 
 AX6-25 Table AX6-2.9. Effects of Lead on Direct Measures of Brain Anatomical Development and Activit

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterUnited States Trope et al. (1998) U.S. Design: Case-control. One 10 yr-old subject with history of Pb poisoning and unexposed 9 yr-old cousin. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) were used to assess differences in cortical structures and evidence of neuronal loss. This was the first study to attempt to determine in vivo structural and/or metabolic differences in the brain of a child exposed to Pb compared with a healthy control. Blood Pb Pb poisoned case 51 μg/dL at 38 mo Unexposed control not reported. Both children presented with nor

revealed a significant alteration in reduction in N-acetylaspartate:creand white matter compared to the conclude that results suggest neurPb exposure. Trope et al. (2001) U.S. Design: Case-control. 16 subjects with a history of elevated blood Pb levels before 5 yrs of age and 5 age-matched siblings or cousins were evaluated. Avg age at time of evaluation was 8 yrs. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) were used to assess differences in cortical structures and 

evidence of neuronal loss. 

Blood Pb  Range in Pb-exposed 23 to 65 μg/dL  Controls <10 μg/dL 

All children had normal MRI exasubjects exhibited a significant reN-acetylaspartate:creatine and pofrontal gray matter compared to cthat Pb has an effect on brain metmatter suggestive of neuronal los

Cecil et al. (2005) U.S. 

Design: Prospective/longitudinal. 48 young adults ages 20 to 23 yrs were re-examined. Functional 

MRI (fMRI) was used to examine the influence of childhood Pb exposure on language function. Subjects performed a verb generation/fingertapping paradigm. Extensive measurement of medical and sociodemographic covariates 

Blood Pb  Avg childhood blood Pb 13.9 (SD 6.6, range 4.8-31.1) μg/dL 

Higher avg childhood blood Pb leassociated with reduced activatiohemisphere and increased activatlobe, the homologue of Wernickehemisphere. Authors conclude thexposure strongly influences neulanguage function on normal langconcomitant recruitment of contra striking dose-dependent atypicafunction. 
 AX6-26 Table AX6-2.9 (cont’d). Effects of Lead on Direct Measures of Brain Anatomical Development and Ac

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterLatin America Rothenberg et al. (2000) Mexico Design: Prospective/longitudinal. 113 5-7 yr-old children from the Mexico City Prospective Study were re-examined. Brain stem auditory evoked potentials were recorded to assess the impact of prenatal and postnatal Pb exposure on development of auditory pathways. Results adjusted for gender and head circumference. Blood Pb Prenatal (20 wks) 8.1 (SD 4.1) μg/dL Cord 8.7 (SD 4.3) μg/dL Postnatal 18 mo 10.8 (SD 5.2) μg/dL Prenatal blood Pb at 20 wks was 

interpeak intervals. After fitting data, I-V and III-V interpeak interose from 1 to 8 μg/dL and increa8 to 30 μg/dL. Increased blood Prelated to decreased conduction iacross the entire blood Pb range seffects. Asia Meng et al. (2005) China Design: Case-control. 6 subjects with blood Pb concentrations ∃27 μg/dL and 6 controls with blood Pb concentrations <10 μg/dL were evaluated with Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy to evaluate structural abnormalities and differences in Nacetylaspartate, creatine, and choline in frontal 

lobes and hippocampus of cases and controls. 

Blood Pb  Cases 37.7 (SD 5.7) μg/dL  Controls 5.4 (SD 1.5) μg/dL 

All children presented with normacetylaspartate, choline, and creawere reduced in Pb exposed child

Authors conclude that reduced brcases may be related to decreased Reduced choline signal may indicmembrane turnover or myelin altcreatine may indicate reduced neu
 AX6-27 Table AX6-2.10. Reversibility of Lead-related Deficits in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Inter

United States Ruff et al. (1993) U.S. Design: Intervention study, non-randomized. 126 children with complete data age 13 to 87 mos and with blood Pb levels between 25 and 55 μg/dL were given chelation with ETDA and/or therapeutic iron where indicated. At baseline and follow-up, patients were evaluated with the Bayley Scales of Infant Development, Mental Development Index, or Stanford Binet Scales of Intelligence depending upon age. Blood Pb at time of treatment Blood Pb 31.2 (SD 6.5) μg/dL Without respect to treatment regim

performance on cognitive measursignificantly related to changes in control for confounding factors. Sincreased 1 point for every 3 μg/d

Rogan et al. (2001); Dietrich et al. (2004) U.S. Design: Double blind, placebo-controlled randomized clinical trial. The Treatment of Pb- Exposed Children (TLC) clinical trial of 780 children in 4 centers was designed to determine if children with moderately elevated blood Pb concentrations given succimer would have better neuropsychological outcomes than children given 

placebo. Children between 12 and 33 mos of age were evaluated 3 yrs following treatments and again at 7 and 7.5 yrs of age. A wide range of neurological, neuropsychological, and behavioral tests was administered. Assessment of potentially confounding factors included sociodemographics and parental IQ. 

Blood Pb  Baseline blood Pb 26 (SD 26.5) μg/dL in both drug and placebo groups 

Succimer was effective in lowerinsubjects on active drug during the However, after 1 yr differences in succimer and placebo groups had 3 yrs following treatment, no statidifferences between active drug aobserved for IQ or other more focand behavioral measures. When eage, TLC could demonstrate no bon an extensive battery of cognitiand neuromotor endpoints. Authoregimen of chelation therapy is noneurodevelopmental benefits in chbetween 20 and 44 μg/dL and thathe importance of taking environmexposure to Pb in light of the appaassociated neurodevelopmental de
 AX6-28 Table AX6-2.10 (cont’d). Reversibility of Lead-related Deficits in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Inter

United States (cont’d) Liu et al. (2002) U.S. Design: Prospective longitudinal clinical trial. Data from the Treatment of Pb-Exposed Children (TLC) used to examine prospective relationships between falling blood Pb levels and changes in cognitive functioning. 741 children recruited between 13 and 33 mos of age were assessed at baseline and 6 mos later with the Bayley Mental Development Index (MDI) and 36 mos post- randomization with the Wechsler Preschool and Primary Scales of Intelligence-Revised to obtain IQ. Blood Pb Baseline blood Pb 26.2 (SD 5.1) μg/dL 36 mos post-randomization blood Pb 12.2 (SD 5.2) μg/dL TLC found no overall effect of ch

change in cognitive test scores frSlope estimated to be 0.0 points p

blood Pb. From baseline to 36 mfalling blood Pb levels were signincreased cognitive test scores, bassociation in the placebo group. because improvements were not data do not provide support that Pimpairments are reversible. Althneurotoxicity of succimer cannot 

Latin America Kordas et al. (2005); Rico et al. (2006) Mexico Design: Double-blind, placebo-controlled nutritional supplementation clinical trial conducted among 602 1st grade children ages 6-8 yrs in Torreón, Mexico. Subjects received iron, zinc, 

both or placebo for 6 mos. Parents and teachers 

filled out the Conners Rating Scales at baseline and follow-up six mos following the end of supplementation to index behavioral changes following therapy. In addition, 11 cognitive tests of memory, attention, visual-spatial abilities, and learning were administered, including WISCR-M at baseline and follow-up 6 mos later. 

Blood Pb  Baseline blood Pb 11.5  (SD 6.1) μg/dL 

No significant effects of treatmencould be detected with any consithat this regimen of supplementaimprovements in ratings of behavperformance. 

Australia

Tong et al. (1998) Australia 

Design: Prospective longitudinal. 375 children from the Port Pirie Prospective Study were followed from birth to the age of 11-13 yrs. Bayley Mental Development Index (MDI) at 2 yrs, the McCarthy Scales General Cognitive Index (GCI) and IQs from the Wechsler Intelligence Scale served as the primary indicators of intellectual status. The purpose of the study was to assess the reversibility of Pb effects on cognition in relationship to declines in blood Pb over time. 

Postnatal blood Pb  Mean blood Pb at 2 yrs 21.2 μg/dL declining to 7.9 μg/dL at 11-13 yrs 

Although blood Pb levels declineadjusted scores on standardized mattainment administered at 2, 4, 7unrelated to declining body burdeeffects of early exposure to Pb dureversed by a subsequent decline 
 AX6-29 

ANNEX TABLES AX6-3 
 AX6-30 Table AX6-3.1. Neurobehavioral Effects Associated with Environmental Lead Exposure in 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretaUnited States Krieg et al. (2005) 1988-1994 U.S. 4,937 adults aged 20-59 yrs from NHANES III completed three neurobehavioral tests. Regression analyses of neurobehaqvioral test and log of blood Pb concentration adjusted for sex, age education, family income, race/ethnicity, computer or video game familiarity, alcohol use, test language, and survey phase. Mean blood Pb 3.3 μg/dL Range 0.7 to 41.7 μg/dL No statistically significant relationship betw

and mean simple reaction time, symbol-digierrors and serial digit learning trials to criteradjustments for covariates. Muldoon et al. (1996) U.S. 325 women from rural location (mean age 71) and 205 women from a city location (mean age 69) participants in the Study for Osteoporotic Fractures had the association of nonoccupational Pb exposure and cognitive function examined. Logistic regression determined effect of blood Pb on neuropsychological performance. Rural group Blood Pb 5 μg/dL Urban group Blood Pb 5 μg/dL Groups were significantly different with the 

and smoked and drank more. Performance iexposure into three groups (low <4 μg/dL, m>7 μg/dL rural and >8 μg/dL) — no significpresent in the urban group but the rural grouperformance with increasing blood Pb for T1.04, 6.49]), Digit Symbol (OR = 3.73 [95% Reaction Time in the lower (OR = 2.84 [95% upper extremities (OR = 2.43 [95% CI: 1.0marked differences exist between the low Pb (the lowest 15th percentile) suggests the diffgroups are unrelated to Pb. Response time fgroups increased for the rural group and decsame for the urban group. As response time this raises question whether factors not meadifference. Namely MMSE for the whole pwith poorer performance in the rural group. for MMSE is 24 suggesting the presence of Even though this is a simple neuropsychologunable to perform some of the tests includin
 AX6-31 Table AX6-3.1 (cont’d). Neurobehavioral Effects Associated with Environmental Lead Exposur

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretaUnited States (cont’d) Payton et al. (1998) U.S. 141 healthy men in VA normal aging study evaluated every 3 to 5 yrs with cognitive battery and blood Pb and once a measurement of patella and tibia bone Pb. Statistics are confusing as it is not clear when ANCOVA is used and how the groups are created. Mean blood Pb 6 μg/dL Mean patella bone Pb 32 μg/g Mean tibia bone Pb 23 μg/g bone mineral Regressions adjusted for age and education 

relationship of blood Pb with Pattern CompaVocabulary, Word List Memory, ConstructiNaming Test, and Verbal Fluency Test. Onwere bone Pb and blood Pb significantly asssensitive to low levels Pb exposure believed Vocabulary is significantly associated with bnegatively correlated to bone and blood Pb. comparisons were handled Rhodes et al. (2003) U.S. 526 participants with mean age 67 yrs, 47% had education level of high school or less. Mood symptoms evaluated with Brief Symptom Inventory (BSI). Use of logistic regression adjusting for covariates examined association of BSI scales and blood Pb and bone Pb levels. Mean blood Pb 6 μg/dL Mean tibia Pb 22 μg/g Mean patella Pb 32 μg/g BSI found mood symptoms for anxiety and associated with bone Pb levels. Education wbone Pb and high school graduates had signGlobal Severity Index and Positive Symptom 

Wright et al. (2003) U.S. 

736 healthy men (mean age 68) in Normative Aging Study examined every 3 to 5 yrs were administered the MiniMental State Exam (MMSE). Linear regression examined relationship of MMSE and blood Pb, patella and tibia bone Pb measurements after adjusting for covariates. 

Mean blood Pb 5 μg/dL, Mean patella bone Pb 30 μg/g Mean tibia bone Pb 22 μg/g 

Mean MMSE score 27. Relation of MMSE blood Pb by logistic regression found OR = and for patella Pb OR = 1.21 (95% CI: 1.001.02 (95% CI: 1.00, 1.04). Risk of MMSE lowest and highest quartiles of patella Pb wafor tibia Pb was 2.2 (95% CI: 1.1, 3.8) and 1.6, 7.2). Interaction between patella Pb and in predicting MMSE found steeper decrease age in the higher quartiles of patella Pb and MMSE very sensitive to yrs of education besubjects had less than high school educationdwelling population had older individuals wareas with higher past pollution the confounsort out. Initially at beginning of NAS subjechronic medical problems or blood pressure addressed how the development of medical duration of the study are handled. 
 AX6-32 Table AX6-3.1 (cont’d). Neurobehavioral Effects Associated with Environmental Lead Exposur

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretUnited States (cont’d) Weisskopf et al. (2004b) U.S. 466 men, mean age 70 yrs, in the VA Normative Aging Study had 2 MMSE tests 3.5 yrs apart. Mean blood Pb 4 μg/dL Mean patella bone Pb 23 μg/g Mean tibia bone Pb 19 μg/g Baseline mean MMSE score was 27 and m

score over 3.5 yrs was 0.3. Change in MMinterquartile range increment for bone Pb arelationship between patella Pb and changwhen patella Pb is ∃90 μg/g bone mineral. below this level found a greater inverse aslower Pb concentrations (∃ = !0.25 [95% Cbut weaker association existed for tibia Pb bone mineral were removed (∃ = !0.19 [95

was no association of MMSE change and bCI: !0.13, 0.11]). There was no interactioThese are very high bone Pb levels for envbiological plausibility of change in the MMhave been reinforced if the change by funcMMSE was provided. Europe 

Nordberg et al. (2000) Sweden 

762 participants, mean age 88 yrs, in a study of aging and dementia examined MMSE. Used blood Pb as dependent and examined contribution of covariates and MMSE. 

Mean blood Pb 3.7 μg/dL Mean MMSE 25 found no relation of bloo

population was fairly homogenous, all eldlikelihood of prior exposure to elevated Pb 
 AX6-33 Table AX6-3.2. Symptoms Associated with Occupational Lead Exposure in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpret

Canada Lindgren et al. (1999) Canada Smelter workers (n = 467) with a mean age of 40 yrs completed the Profile of Mood Scale. Factor structure of POMS validated in this occupational population. Regression analysis determined association with Pb exposure. Mean (SD, range) blood Pb 28 (8.5, 4-62) μg/dL Mean (SD, range) IBL 711 (415.5, 1-1537) μg·yr/dL Factor analysis found one factor labeled “g

of POMS subscales anger, confusion, deprand a second factor labeled ‘psychological significantly associated with ‘general distrcovariates (∃ = 0.28 [SE 1.51 

Η 10!4], p = 

relation with blood Pb. The factor structurvalidated in a clinical population had six mfactor structure in this occupational populaonly two subscales. 

Holness et al. (1988) Canada 

47 demolition workers with acute Pb intoxication - Phase 1 - were followed with blood Pb and symptoms during engineering modifications to control exposure – Phases 2-4. Workers stratified by blood Pb and symptom frequency was analyzed. 

Phase I - Mean blood Pb 59 μg/dL Phase 2 - Mean blood Pb 30 μg/dL Phase 3 - Mean blood Pb 19 μg/dL Phase 4 - Mean blood Pb 17 μg/dL 

Below blood Pb <50 μg/dL, workers repor(25%), headache (14%), dizzy (9%), sleep (8%), muscle ache (8%), paresthesiae (8%constipation (6%), and weakness (6%). Asignificantly lower except for paresthesiae with blood Pb >70 μg/dL. Of interest, at bmean blood Pb was 13 μg/dL, no symptomend of Phase 4, mean blood Pb was 17 μg/complained of fatigue. 

Europe Lucchini et al. (2000) Italy 

66 workers in Pb manufacturing, mean age 40 (8.7) yrs and 86 controls mean age 43 (8.8) yrs were administered a questionnaire with neuropsychological (14 items), sensorymotor (3 items), memory (4 items) and extrapyramidal (8 items), 10 Parkinson symptoms and the Mood Scale. Group comparisons and linear regression examined relationship of symptoms and Pb exposure. 

Pb workers Mean (SD, range) blood Pb 27 (11.0, 6-61) μg/dL Mean (SD, range) TWA 32 (14.1, 6-61) μg/dL Mean (SD, range) IBL 410 (360.8, 8-1315) μg·yr/dL Controls Mean (SD, range) blood Pb 8 (4.5, 2-21) μg/dL 

Pb exposed worker reported confusion, somfatigue, irritability, and muscular pain morThere were no group differences for the paMood Scale. Linear regression combing efound neurological symptoms significantly r = 0.22, p = 0.006). Neuropsychological significantly higher in the High-IBL compThe estimated threshold for a significant inof a high score for neurological symptoms 12 μg/dL. 
 AX6-34 Table AX6-3.2 (cont’d). Symptoms Associated with Occupational Lead Exposure in Adu

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretLatin America Maizlish et al. (1995) Venezuela 43 workers from a Pb smelter, mean age 34 (9) yrs and 47 nonexposed workers, mean age 35 (11) yrs completed the profile of mood states (POMS) questionnaire and a questionnaire of symptoms of the central and peripheral nervous system, and gastrointestinal. Prevalence ratios used to examine symptoms and Pb. ANCOVA and linear regression adjusting for potential confounders examined relationship of Pb exposure and POMS. Pb workers Mean (SD) blood Pb 43 (12.1) μg/dL Mean (SD) peak blood Pb 60 (20.3) μg/dL Mean (SD) TWA 48 (12.1) μg/dL Controls Mean (SD) blood Pb 15 (6) μg/dL Mean (SD) peak blood Pb 15 (6) μg/dL Mean (SD) TWA 15 (SD 6) μg/dL Significantly increased relative risks found 

concentrating (RR = 1.8 [95% CI: 1.0, 3.1upset without reason (RR = 2.2 [95% CI: abnormally tired (RR = 2.2 [95% CI: 0.9, (RR = 1.8 [95% CI: 1.0, 3.3]). The six sunot significantly different between the expHowever dose-related analysis found signitension-anxiety and blood Pb (p = 0.009), (p = 0.01) and TWA (p = 0.04), and depre(p = 0.003) and peak Pb (p = 0.003) and T

Asia Schwartz et al. (2001a) Korea 

803 Pb-exposed Korean workers, mean age 40 yrs completed the Center for Epidemiologic Studies Depression Scale. Linear regression examined for association of CES-D and Pb biomarkers after adjusting for the covariates. 

Mean (SD) blood Pb 32 (15.0) μg/dL Mean (SD) tibia Pb 37 (40.3) μg/g bone mineral 

After adjustment for age, gender and educassociations found for CES-D and tibia Pb p < 0.01) but not with blood Pb. This occupopulations had higher past Pb exposure cmean blood Pb of 32 μg/dL. 

Lee et al. (2000) Korea 

95 Korean Pb exposed workers, mean age 43 yrs, completed questionnaire of Pb-related symptoms present over last three mos. Relationship between symptom score and measures of Pb exposure assessed by linear regression. Logistic regression use to model presence or absence of symptoms for gastrointestinal, neuromuscular, and general. 

DMSA-chelatable Pb Mean (SD) 289 (167.7) μg Mean (SD) ZPP 108 (60.6) μg/dL Mean (SD) ALAU3 (2.8) mg/L Mean(SD) blood Pb 45 (SD 9.3) μg/dL 

Workers with DMSA-chelatable Pb above 6.2 (95% CI: 2.4, 17.8) times more likely numbness in their extremities, 3.3 (95% Clikely to experience muscle pain and 3.2 (9more likely to feel irritable. The workers wwere 7.8 (95% CI: 2.8, 24.5) times more lneuromuscular symptoms compared to woPb. In this study ZPP predicted weakness (OR = 2.9 [95% CI: 1.1, 8.1]) and fatigue 1.1, 8.7]) while ALAU predicted inability CI: 1.2, 33.2]) and blood Pb was not signisymptoms. A measure of Pb in bioavailabstrongest predictor of symptoms particular
 AX6-35 Table AX6-3.2 (cont’d). Symptoms Associated with Occupational Lead Exposure in Adu

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretAsia (cont’d) Niu et al. (2000) China 44 Pb-exposed workers (17 men, 27 women) from Pb printing houses, mean age 35 (4.9) and education 9.3 (no SD) yrs and 34 controls (19 men and 15 women), mean age 33 (7.4) yrs and education 9.5 (no SD) yrs completed the profile of mood state as part of the NCTB. ANCOVA controlling for age, sex and education examined group differences and linear regression for dose- response relationship. Mean blood Pb 29 (SD 26.5) μg/dL (8 workers blood Pb exceeded 50 μg/dL) Controls Mean blood Pb 13 (SD 9.9) μg/dL (1 control blood Pb exceeded 50 μg/dL) POMS subscales for confusion (F = 3.02, p 

p < 0.01), and tension (F = 2.82, p < 0.01) in the Pb exposed group. Regression analy(data not shown). 
 AX6-36 Table AX6-3.3. Neurobehavioral Effects Associated with Occupational Lead Exposure in A

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretUnited States Fiedler et al. (2003) New Jersey 40 workers with Pb exposure, mean age 48 (9.5) yrs completed a neurobehavioral battery and was compared to 45 Pb/solvent workers, mean age 47 (10.2), 39 solvent exposed workers, mean age 43 (9.4), and 33 controls, mean age 44 (10.2). Group differences and dose-effect relationships were assessed after adjusting for potential confounding. Mean (SD) blood Pb μg/dL; mean (SD) bone Pb ppm (dry weight) Pb workers 14 (11.7); 2.7 (0.7) Pb/Solvent workers 12 (11.6); 2.8 (0.6) Solvent workers 5 (4.1); !1.8 (1.8) Controls 4 (1.4); !1.1 (1.6) Of nineteen outcomes, significant differen

verbal learning test (CVLT) (p = 0.05) and index on the Symptom checklist-90-R. On performed significantly better on trials 2 aefficiency of verbal learning. Symbol digiapproached significance (p = 0.09) with Pb slower on latency of response but not accusignificant predictor of latency of response paced auditory serial addition task and simpreferred hand. Bone Pb and SRT, preferrsignificance. This is a confusing study despredictor in workers both with and withou

Canada Lindgren et al. (1996) Canada 

467 Canadian former and current, French and English speaking Pb smelter workers, mean age 43 (11.0) yrs and education 10 (3.2) yrs were administered a neuropsychological battery in English or French. Data analyses used MANCOVA adjusting for age, education, measure of depressive symptoms and self reported alcohol use. 

Mean (SD) yrs employment 18 (7.4) Mean (SD) blood Pb 28 (8.4) μg/dL Mean (SD) TWA 40 (4-66) μg/dL Mean (SD) IBL 765 (1-1626) μg·yr/dL 

Fourteen neuropsychological variables exawith the grouping variable exposure (highcovariates, age, education, CES-D, and alcterm significant until yrs of employment, a added as a covariate. IBL exposure group2,417) on digit symbol (F = 3.03, p = 0.05P = 0.04), Purdue dominant hand (F = 4.89(F = 3.89, p = 0.02) and B (F = 3.2, p = 0.0dose-effect relationship between cumulativneuropsychological performance at a time association with current blood Pb. 
 AX6-37 Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposur

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpreCanada (cont’d) Bleecker et al. (2002) Canada 256 smelter workers from the above population were currently employed and took the test battery in English. Their mean age was 41 (7.9) yrs, and education 10 (2.8) yrs. The goal was to determine if educational achievement as measured by WRAT-R Reading modified performance on MMSE. Linear regression assessed the contribution of age, WRAT-R, education, alcohol intake, cigarette use, IBL and IBL

ΗWRAT-R on MMSE performance. 

Mean (SD) blood Pb 28 (8.8) μg/dL Mean (SD) IBL 725 (434) μg·yr/dL 

MMSE had a median (range) score of 29 (errors were recall of 3 items (38%), spell wrepetition of “no ifs ands or buts” (21%) anintersecting pentagons (16%). WRAT-R rmeasure of educational achievement becauof MMSE performance than yrs of educatiinteraction (

♠

R2 = 2%, p = 0.01) explained 

IBL and MMSE only in the 78 workers wilevel less than 6. The workers with higher same cumulative Pb exposure were able to of Pb on the MMSE because of increased 

Bleecker et al. (2005a) Canada 

256 smelter workers currently employed and took the test battery in English. Their mean age was 41 (7.9) yrs, and education 10 (2.8) yrs. The purpose was to determine whether components of verbal memory as measured on the Rey Auditory Verbal Learning Test (RAVLT) were differentially affected by Pb exposure. Linear regression and ANCOVA assessed the relationship of Pb and components of verbal learning and memory. 

Mean (SD) blood Pb 28 (8.8) μg/dL Mean (SD) TWA 39 (12.3) μg/dL Mean (SD) IBL 725 (434) μg·yr/dL 

Outcome variables RAVLT a word list tesimmediate memory span and attention (Trincremental learning across the five trials ((Recognition) and retrieval (Delayed Reca

significantly contributed to the explanation (♠

R2 = 1.4%, p < 0.03) and Delayed Reca

after adjusting for age and WRAT-R while Recognition (

♠

R2 = 2.0%, p = <0.02) and 

(♠

R2 = 1.1%, p = 0.06). Workers stratifie

clinical memory difficulties-Group1 had nretrieval; Group2 could encode and store vdifficulty with retrieval and Group 3 had aand retrieval but was still able to learn new ANCOVA adjusting for age and WRAT-R across the memory groups. Blood Pb showand IBL were significantly higher in Grou(p < 0.05 for both). Internal strategies usefive trials found that Groups 1 and 2 remembeginning of the list while group 3 rememAt a time when blood Pb was not associatecumulative Pb exposure resulted in poorer previously learned material. Alterations in materials in long term memory interferes w
 AX6-38 Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposu

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpCanada (cont’d) Bleecker et al. (1997a) New Brunswick 1992-1993 The performance of the 467 current and retired smelter workers as described in Lindgren et al. (1996) administered a screening neuropsychological battery by testers blinded to the degree of Pb exposure of the worker had their performance compared to age matched norms. If performance on two or more tests in any functional domain was below 1.5 standard deviations the worker was invited for a complete clinical evaluation. Eighty current workers were identified by this criterion. Mean yrs - age 44 (8.4) yrs, education 8 (2.8) yrs and duration employed 20 (5.3) yrs. Five neuropsychological tests commonly associated with Pb exposure were examined for a differential association with blood Pb, IBL,TWA and bone Pb. Mean (SD) blood Pb 26 (7.07) μg/dL Mean (SD) TWA 42 (8.4) μg/dL Mean (SD) IBL 903 (305.9) μg·yr/dL, Mean (SD) tibial bone Pb 41 μg/g bone mineral Relationship of 5 neuropsychological tests 

after adjusting for age age2 and education, 

V and Verbal Paired Associates were asso(♠

R2 = 6.2%, p = 0.02; 

♠

R2 = 5.5%, p = 0

p = 0.09; 

♠

R2 = 13.9%; P = 0.00) while D

Pegboard were associated with TWA (

♠

R

p = 0.02) and IBL (

♠

R2 = 4.8%, p = 0.01; 

grooved pegboard was associated with bon

Block design was not associated with any an effect modifier with grooved pegboard. older workers when compared to younger 

Bleecker et al. (1997b) New Brunswick 1992-1993 

Of the 80 current smelter workers described above 78 completed a simple visual reaction time (SRT) and had mean yrs age 44 (8.2) yrs, education 8 (7.2) yrs and duration employed 20 (5.6) yrs. 

Mean (SD) blood Pb, 26 (7.2) μg/dL Mean (SD) blood Pb from bone 7 (4.2) μg/dL Mean (SD) blood Pb from environment 19 (7.0) μg/dL Mean (SD) bone Pb 40 (25.2) μg/g bone mineral 

SRT consisted of 44 responses to a visual 

intervals (ISI) varying between 1 through (median) of 262 (179 to 387) ms. Blood Pcurvilinear relationship R2 = Pb + Pb2, 13.7

age and education with slowing of SRT be~30 μg/dL. No relationship existed betwea stronger association between Pb and Pb2 

to 10 seconds (R2 = 13.9%, p < 0.01), as a

the shorter ISI = s but not the longer ones. contribution of bone Pb to blood Pb had bewhere for a bone Pb level of 100 μg Pb/g bblood Pb was derived from internal bone sthe environment. Blood Pb was fractionatbn) vs. blood Pb from the environment (blto examine the relationship of blood Pb-bn adjusting for the covariates found significaof SRT only for blood Pb-en (R2 for blood 

p < 0.01). The absence of a contribution bwith ISIs of 6 to 10 sec supports using this 
 AX6-39 Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretCanada (cont’d) Lindgren et al. (2003) New Brunswick 1992-1993 In an attempt to separate the effects of past high Pb exposure from a lower proximate exposure, examination of the pattern of Pb levels of the 467 Canadian Pb smelter workers found 40 workers who had high past exposure followed by yrs where 90% of blood Pb were above 40 μg/dL (High- High = H-H) while another group of 40 workers had similar past high Pb exposure followed by yrs where 90% of blood Pb were below 40 μg/dL (High-Low = H-L). The groups did not differ on age, education, yrs of employment or CES-D. Five outcomes examined-Purdue Pegboard assembly, Block Design, Digit Symbol, Rey Auditory Verbal Learning Test-total score, delayed 

Logical Memory. 

Mean (SD) IBL for past exposure H-H 633 (202.2) μg·yr/dL H-L 557 (144.8) μg·yr/dL Mean (SD) IBL for the proximate exposure H-H 647 (58.7) μg·yr/dL H-L 409 (46.4) μg·yr/dL Mean (SD) blood Pb H-H 37 (5.1) μg/dL H-L 24 (5.2) μg/dL 

Of the five neuropsychological measures e(total score) and Logical Memory (delayeddifferent after adjusting for the covariates Use of regression analyses found pattern gsignificantly (R2 = 4%, p < 0.05) to the exp

RAVLT after accounting for current blood 

IBL measures (R2 = 7%, p < 0.01). For pacorrelated more strongly with RAVLT (r = had no relationship with past exposure (r = the difference was maintained between H-pattern (r = 0.00). The authors suggested tassociation between past high Pb exposure H-L pattern group may reflect reversibility is maintained below 40 μg/dL. 

Braun and Daigneault (1991) Quebec 

41 workers from a secondary Pb smelter, mean age 35 (9.6) yrs and yrs of education 10 (2.1) were compared to a control group mean age 37 (10.1) yrs and yrs of education 11 (1.3) on tests of cognitive and motor function. MANCOVA and dose-effect relationships after adjusting for potential confounders were performed. 

Mean (SD) TWA 53 (7.5) μg/dL Mean (SD) maximum blood Pb 87 (22.4) μg/dL 

None of the measures of cognitive executidifferences. Partial correlation adjusting fdose related variables found no statistical sfunction the exposed workers had significatime (p = 0.05). However partial correlatiofound dose-effect correlation in both negatGroup of exposed workers was mixed for currently working and the remainder with Also two of the exposed workers had been 
 AX6-40 Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretEurope H

≅nninen et al. (1998) 

Finland 

Fifty-four Pb battery workers were stratified by those whose blood Pb never exceeded 50 μg/dL (n = 26) (group 1) and those who had higher exposure in the past (n = 28) (group 2) to examine the neuropsychological effects of current low level blood Pb from higher blood Pb in the past. Mean age group 1was 42 (9.3) yrs, education 8 (1.7) yrs and yrs of exposure 12 (6.7). Mean age group 2 was 47 (6.2) yrs, education 8 (1.0) yrs and yrs of exposure 21 (6.9). Analysis included partial correlations within the groups and ANCOVA within group 1 divided at the median TWA3 of 29 μg/dL. 

Group 1 Mean IBL 330 μg·yr/dL Maximum blood Pb 40 μg/dL TWA 29 μg/dL Tibial Pb 20 μg/g Calcaneal Pb 79 μg/g Group 2 Mean IBL 823 μg·yr/dL Maximum blood Pb 69 μg/dL TWA 40 μg/dL Tibial Pb 35 μg/g Calcaneal Pb 100 μg/g IBL, TWA and maximum blood Pb were also calculated for the previous 3 yrs with a median TWA3 of 29 μg/dL 

Partial correlations controlling for age, sex found block design, digit symbol, digit spaand memory for design significantly assocof exposure and embedded figures with m2 embedded figures, digit symbol, block dlearning were associated with IBL and /or Calcaneal Pb was weakly associated with retention, and synonyms. There was no aseither group. Group 1 divided at the medifound the high group had lower scores for visuoperceptive tasks (digit symbol, embefor design). Overall past high exposure, bgreatest effect on tests requiring the encodpresented stimuli. The authors conclude thfunction is better reflected by history of blin bone. 

Lucchini et al. (2000) Italy 

66 workers in Pb manufacturing, mean age 40 (8.6) yrs, mean education 8 ( 2.4) yrs and mean exposure time 11 (9) yrs and a control group of 86 with mean age 43 (8.8) yrs, mean yrs of education 9 (2.7) yrs. Group differences examined and dose-effect relationship with correlation and ANOVA. 

Pb workers Mean (SD) blood Pb 28 (11) μg/dL Mean (SD) IBL 410 (360.8) μg·yr/dL Mean (SD) TWA 32 (14.1) μg/dL Mean (SD) yrs exposed 11(8.1) Control Mean (SD) blood Pb 8 4.5) μg/dL 

No association with neuropsychological tefinger tapping symbol digit and motor test TWA or IBL were found. Blood Pb and vthe high frequencies were significantly assBlood Pb and serum prolactin in the whole associated. Increased prolactin secretion oneurotoxins and reflects impaired dopaminThe estimated threshold for a significant inlevels was at a blood Pb of 10 μg/dL. 
 AX6-41 Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretaEurope (cont’d)_sterberg et al. (1997) Sweden 

38 workers, median age 42 (no range) yrs at a secondary smelter stratified by finger bone Pb concentration and along with 19 controls matched triplets for age, education and job 

level. Median yrs employed 10 (2-35). 

High bone Pb Median (range) bone 32 (17-101) μg/g Median (range) blood Pb 38 (19-50) μg/dL Median (range) peak blood Pb 63 (46-90) μg/dL Median (range) IBL 408 (129-1659) μg·yr/dL Low bone Pb Median (range) bone 16 (!7 to 49) μg/g Median (range) blood Pb 34 (17-55) μg/dL Median (range) peak blood Pb 57 (34-78) μg/dL Median (range) IBL 250 (47-835) μg·yr/dL Controls Median (range) bone 4 (!19 to 18) μg/g Median (range) blood Pb 4 (1-7) μg/dL 

A cognitive test battery (36 tests) covering visuomotor function, visuospatial functionsustained attention found no impairment orelationships with any of the markers of Pb scores (belong to 10% lowest reference nobone Pb (1 vs. 4 vs. 4). None of the deviatsignificantly correlated with any of the Pb was taken into account the significant asso

and Pb exposure metrics did not exceed chnumerous analyses performed. These werexposed workers in Sweden. It was unusutasks significantly different had better perfexposed workers compared to the controls
 AX6-42 Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretEurope (cont’d) Stollery et al. (1991) England Seventy Pb-exposed workers, mean age 41(no SD) yrs, grouped by blood Pb (<20 μg/dL, 21-40 μg/dL and 41-80 μg/dL) examined on three occasions each separated by four mos. Tested on a computer for syntactic reasoning, delayed five choice reaction time, visual spatial memory, and category search task. Low blood Pb Mean blood Pb 14 μg/dL Mean ZPP 13 mg/dL Mean urinary ALA 2 mg/L Mean yrs exposed 7 Medium blood Pb Mean blood Pb 31 μg/dL Mean ZPP 33 mg/dL Mean urinary ALA 3 mg/L Mean yrs exposed 10 High blood Pb Mean blood Pb 52 μg/dL Mean ZPP 77 mg/dL Mean urinary ALA 6 mg/L Mean yrs exposed 11 Pb exposure was stable over the 8 mos of t

drank significantly less alcohol and rated tdemanding. Performance and exposure stagroup where decision time was slowed moalong with concentration difficulties that rtesting sessions. Movement and decision tcorrelated for each duration of waiting. Orecalled nouns, the memory deficit associa

p = 0.003) was restricted to recall of nouns (distracters) (p = 0.04) that did not improvof difficulties with incidental learning. W>40 μg/dL had impairments that correlated over the preceding 8 mos. Workers with b40 μg/dL had essentially no impairment. 

Stollery (1996) England 

Same as above except this was a further analysis of the five choice reaction time. 

Same as above Movement and decision slowing was corre

Slowed movement time was constant acrointervals in contrast to decision time that wPb especially at the shortest response-stimThis supported the finding that decision gaopposed to movement gaps are selectively this population. 

Barth et al. (2002) Austria 

47 Pb storage-battery workers, mean age 40 (9.7) yrs and 53 nonexposed controls, mean age 39 (8.4) yrs were matched for age and verbal intelligence. Group differences and dose-response relationship were explored. 

Pb workers Mean (SD) blood Pb 31 (11.2) μg/dL Mean (SD) IBL 384 (349.0) μg·yr/dL Mean (SD) yrs employed 12 (9.0) Controls Mean (SD) blood Pb 4 (2.0) μg/dL 

Significant differences were found for blocrecognition (p # 0.01) and Wisconsin card 

p = 0.0005, total errors p = 0.0025, persevsorting principle p = 0.003) but not SRT oexposed group partial correlation adjusting significant associations with IBL (n = 53). correlation was significant for blood Pb anblock design and visual recognition (n = 1and executive function were better predictcumulative Pb exposure. It is unusual that associated with blood Pb when SRT and daffects of Pb are not. 
 AX6-43 Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretEurope (cont’d) Winker et al. (2005) Austria 48 workers formerly Pb-exposed, mean duration since last exposure 5 (3.5) yrs, and mean age 40 (8.8) yrs were matched with 48 controls for age, verbal intelligence, yrs of education and number of alcoholic drinks. Group differences and dose-response relationship were explored. Formerly Pb-exposed Mean (SD, range) blood Pb 5.4 (2.7, 1.6-14.5) μg/dL Mean (SD) IBL 4153.3 (36930.3) μg·yr/dL Controls Mean (SD, range) blood Pb 4.7 (2.5, 1.6-12.6) μg/dL No significant differences on neurobehavio

when groups compared by t-tests for pairegroups were combined, partial correlation significant negative correlation between bl(r = 

−0.28, p < 0.01) Visual Recognition (r 

Digit Symbol Substitution (r = 

−0.26, p < 

conclude that the cognitive deficits associaexposure are reversible. However there apprimarily from those with the highest past 

Winker et al. (2006) Austria 

The same 48 workers formerly Pb-exposed described above were compared to the 47 exposed workers described by Barth et al. (2002). Both groups were comparable for age and verbal intelligence. Group differences and differences by duration of exposure and exposure absence were evaluated. 

Exposed workers Mean (SD, range) blood Pb 31 (11.2, 10.6-62.1) μg/dL Mean (SD) IBL 4613 (4187.6) μg·yr/dL Formerly Pb-exposed Mean (SD, range) blood Pb 5.4 (2.7, 1.6-14.5) μg/dL Mean (SD) IBL 4153.3 (36930.3) μg·yr/dL 

Mann-Whitney test found significantly betformerly Pb-exposed workers for Block DWisconsin Card Sorting Test (categories p p = 0.005, perseverations p = 0.0095 and lp = 0.02). To further examine the reductiowith absence of exposure, workers were stexposure and exposure absence – short explong exposure and long absence; short expand long exposure and short/no absence. L

Design (p = 0.003) and Wisconsin Card Sop < 0.001, total errors p = 0.001, perseverasorting principle p = 0.030) were highly sihypothesized direction. Results were belieof cognitive deficits related to occupationa
 AX6-44 Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretLatin America Maizlish et al. (1995) Venezuela 43 workers from a Pb smelter, mean age 34 (9) yrs and 47 nonexposed workers, mean age 35 (11) yrs completed the WHO neurobehavioral core test battery. ANCOVA and linear regression adjusting for potential confounders examined relationship of Pb exposure and NCTB. Pb workers Mean (SD) blood Pb 43 (12.1) μg/dL Mean (SD) peak blood Pb 60 (20.3) μg/dL Mean (SD) TWA 48 (12.1) μg/dL Controls Mean (SD) blood Pb 15 (6) μg/dL Mean (SD) peak blood Pb 15 (6) μg/dL Mean TWA 15 (6) μg/dL Group comparison was significant for SRT 

exposed workers performed faster. Linear poorer performance with blood Pb and TWWith peak blood Pb SRT improved with inIn this study only symptoms were significa

the groups. Asia Schwartz et al. 

(2001a) South Korea 

803 Korean Pb-exposed workers, 80% men and 20% women, mean age 40 (10.1) yrs from a variety of industries, and 135 controls, 92% men and 8% women, mean age 35 (9.1) yrs. Educational levels Pbexposed workers/controls #6 yrs = 23% / 7%, 7-9 yrs 23% / 11%, 10-12 yrs = 46% / 70%, and >12 yrs 8% / 12%. Group differences on neurobehavioral testing after controlling for covariates and linear regression controlling for covariates examined the presence of a dose-effect relationship. 

Pb workers Mean (SD) blood Pb 32 (15) μg/dL Mean (SD) tibia bone Pb 37 (40.3) μg/g Mean (SD) DMSAchelatable Pb level 186 (208.1) μg Controls Mean (SD) blood Pb 5 (1.8) μg/dL Mean (SD) Tibia bone Pb 6 (7) μg/g 

Nineteen outcomes examined. Compared workers performed significantly worse on Visual Retention, Colored Progressive MaPurdue Pegboard after controlling for age, association of DMSA with test performancof blood Pb. Bone Pb was not associated wperformance. Blood Pb was the best predidecrements in neurobehavioral performanc

[SE 0.0009], p < 0.01), Purdue Pegboard (0.0042], p < 0.01; non-dominant ∃ = 0.016both ∃ = !0.0142 [SE 0.0038], p < 0.01; as

0.0151], p < 0.01), and Pursuit Aiming (# 0.0473], p < 0.01; # incorrect ∃ = !0.0046 

magnitude of the effect for these eight testwith blood Pb was an increase in blood Pb to an increase of 1.05 yrs in age. Use of LPegboard (assembly) and Trails B suggest18 μg/dL after which there is a decline of p
 AX6-45 Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretAsia (cont’d) Schwartz et al. (2005) South Korea 1997-2001 Longitudinal decline in neurobehavioral performance examined in 576 of the above group of Pb exposed workers who completed 3 visits at one yr intervals. Mean age at baseline was 41 (9.5) yrs and job duration 9 (6.3) yrs and 76% were men. Compared to non-completers Pb workers who completed 3 visits were 3.3 yrs older, baseline mean blood Pb was 2.0μg/dL lower, on the job 1.6 yrs longer, 24% women vs. 10% of noncompleters, and usually had less than high school education. Models examined short-term vs. long-term effects. Final model had current blood Pb, tibia bone Pb and longitudinal blood Pb and covariates. Baseline mean (SD) blood Pb 31 (14.2) μg/dL Mean (SD) tibia Pb 38 (43) μg/g Blood Pb from baseline correlated with tho

baseline tibial Pb correlated with that measectional associations of blood Pb or shortTrails A (∃ = !0.0020 [95% CI: !0.0040, !(∃ = !0.0037 [95% CI: !0.0057, !0.0017]), 

[95% CI: !0.1375, !0.0019]) , Purdue Peg(dominant ∃ = !0.0131 [95% CI: !0.0231, 

∃ = !0.0161 (95% CI: !0.0267, !0.0055); b

!0.0259, !0.0067]; assembly (∃ = !0.0536 !0.0175]), and Pursuit Aiming (# correct ∃ 

!0.2631, !0.0421]) after covariates. Howewas only associated with poorer performan(non-dominant ∃ = !0.0086 [95% CI: !0.0

(∃ = !0.0063 [95% CI: !0.0122, 0.0004]; aCI: !0.0532, !0.0046]). Historical tibial bodigit symbol (∃ = !0.0067 [95% CI: !0.01Pegboard (dominant ∃ = !0.0012, [95% CIMagnitude of Pb associations was expressincreased age at baseline that was equivalethe 25th to 75th percentile. At baseline, thequivalent to 3.8 yrs of age for cross-sectioage for historical tibial Pb and 4.8 yrs of agPb. Analyses showed decline in performantibia Pb. 
 AX6-46 Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretAsia (cont’d) Hwang et al. (2002) South Korea From the above cohort of 803 Korean Pb workers, 212 consecutively enrolled workers, were examined for protein kinase C (PKC) activity and the relations between blood Pb and neurobehavioral performance. PKC activity assessed by measuring levels of phosphorylation of three erythrocyte membrane proteins. Seventy-four percent of workers were men, mean age 36(0.8)yrs, duration of exposure 9 (0.6) and education 93% had high school or less. For the female workers, mean age 47 (0.9) yrs, duration of exposure 6 (0.5), and education 95% had high school or less. Male workers Mean (SD) blood Pb 32 (13.0) μg/dL Mean (SD) tibia Pb 38 (39.6) μg/g Mean (SD) ZPP 69 (47.8) μg/dL Female workers Mean (SD) blood Pb 20 (9.2) μg/dL Mean (SD) tibia Pb 26 (14.7) μg/g Mean (SD) ZPP 72 (29.7) μg/dL Blood Pb was associated significantly with 

(∃ = !0.003 [SE 0.002], p < 0.10), SRT (∃ p < 0.10) and Purdue Pegboard (dominant 

p < 0.05); non-dominant (∃ = !0.021 [SE 0(∃ = !0.021 [SE 0.009], p < 0.05). PKC acphosphorylation of erythrocyte membrane with neurobehavioral test scores. Addition blood Pb by back-phosphorylation dichotosignificant effect modification with the assand poorer neurobehavioral performance oworkers with lower back-phosphorylation higher in vivo PKC activity. Association o52 kDa subunit with high in vivo PKC acti

p < 0.01) and for low in vivo PKC (adjuste

The authors suggest that PKC activity may increase risk of neurobehavioral effects of 

Chuang et al. (2005) Taiwan 

27 workers from a glazing factory were administered a computerized neurobehavioral battery 3 times over 4 yrs. At yr 1, the mean age was 40 (9.6) yrs. In the first yr workers were compared to a referent group matched for age and education. Neurobehavioral performance compared in first yr to referent group with adjustment for age and Vocabulary. Generalized mixed linear mixed models 

analyzed relationship between blood Pb level and neurobehavioral test performance after adjusting for age and Vocabulary. 

Pb workers Yr 1 Mean (SD) blood Pb 26 (12) Yr 3 Mean (SD) blood Pb 11 (6.4) Yr 4 Mean (SD) blood Pb 8 (6.9) Referent Mean (SD) blood Pb 7 (4.2) 

Referents scored significantly lower on qusymptoms in yr 1. In the mixed model anadominant (p = 0.008) and non-dominant (p significantly inversely associated with blo(p < 0.001) and Pattern memory (p = 0.06) blood Pb levels improved. Chronic symptperformance appear to reverse when Pb exHowever since the referent group was not was not possible to control for practice effrepeat neurobehavioral testing even at two 
 AX6-47 Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretAsia (cont’d) Tsai et al. (2000) Taiwan 19 Pb workers and 19 referents included in the above publication, mean age 39 yrs in both groups and mean education 10 (2.9) and 9 (3.2) yrs, respectively, were tested with a computerized neurobehavioral battery. Alcohol use was similar. Mean duration of Pb exposure 6 (2.5) yrs. Student’s t compared neurobehavioral performance between the two groups. Mean (SD) blood Pb 32 (12.2) μg/dL Referent Mean (SD) blood Pb 7 (2.7) μg/dL Poorer performance in Pb workers for fing

non-dominant, and continuous performanctapping was significant. Pb workers perfoon Associate Learning, Pattern ComparisoTest, Visual Delay and Associate Learning attributed to higher mean education. Chia et al. (2004) Singapore 120 workers from Pb stabilizer factories, mean age 40 (10.7) yrs, duration of exposure 10.2 (7.9) were given a neurobehavioral battery. Genotyping of ALAD polymorphisms was performed. ANCOVA used to test for differences in neurobehavioral performance among ALAD 

polymorphism types adjusting for age, exposure duration and blood Pb. 

Mean (SD) blood Pb 22 (9.4) μg/dL Mean (SD) ALAD0.6 (0.25) μm of porphobilinogen/h/ml of RBC Mean (SD) ALAU0.9 (0.56) mg/g creatinine 

Frequency of ALAD11, 87%, ALAD12, 1Mean blood Pb adjusting for age and expofor ALAD11 (n = 107) and 20.4 μg/dL for However ALAU was significantly higher iAfter adjusting for the covariates significapegboard dominant hand (p = 0.01), non-dand grooved pegboard mean time (p = 0.00ALAD11 and ALAD12 and 22. Consideriof battery it is surprising education was ignauthors the study only had 13 in the group and the ALAD12 or 22 genotypes limiting 

Chia et al. (1997) Singapore 

50 Pb battery manufacturing workers, mean age 36 (10.6) yrs, education 8.6 (2.1) yrs duration of employment 9 (7.4) yrs and 97 controls, mean age 34 (3.7) yrs, and education 12 (1.8) yrs were administered a neurobehavioral battery. ANCOVA and 

linear regression used to assess relationship of Pb dose and performance. 

Pb workers Median (range) blood Pb of 38 (13.2-64.6) μg/dL Median (range) IBL 264 (10.0-1146.2) μg·yr/dL Controls Median (range) blood Pb 6 (2.4-12.4) μg/dL 

Significant group differences for Santa Ansymbol, pursuit aiming and Trails A and B education, smoking, ethnic group and alcogroup was stratified by age, in the group >performance on digit symbol and Trails A associated with cumulative Pb and not blofor age and education. 
 AX6-48 Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretAsia (cont’d) Niu et al. (2000) China 44 Pb-exposed workers (17 men, 27 women) from Pb printing houses, mean age 35 (4.9) and education 9.3 (no SD) yrs and 34 controls (19 men and 15 women), mean age 33 (7.4) yrs and education 9.5 (no SD) yrs completed the NCTB. ANCOVA controlling for age, sex and education examined group differences and linear regression for dose- response relationship. Pb workers Mean (SD) blood Pb 29 (26.5) μg/dL (8 workers blood Pb exceeded 50 μg/dL) Controls Mean (SD) blood Pb 13 (9.9) μg/dL (1 control blood Pb exceeded 50 μg/dL) SRT (F = 2.30, p < 0.05), digit symbol (F 

aiming # correct (F = 7.186, p < 0.01) and (F = 6.576, p < 0.01) had significantly pooto controls. No repression analyses provid

Boey and Jeyaratnam (1988) Singapore 49 Pb-exposed workers, mean age 26 (7.6) yrs and 36 controls, mean age 30 (6.4) yrs completed SRT and 8 psychological tests covering attention, vigilance, visual-motor speed, short-term memory, visuomotor 

tracking, visual scanning, and manual dexterity. Control group was matched for education level. Discriminate analysis of neurobehavioral tests performed to determine which best discriminate the groups. 

Pb workers Mean (SD) blood Pb 49 (15) μg/dL Controls Mean (SD) blood Pb 15 (3) μg/dL 

Six tests were significantly different betweSymbol, Bourdon-Wiersma, Trails A, SanFusion and SRT. The group of tests that bexposed workers from nonexposed workerTime, Digit Symbol (WAIS) and Trail Malong latency in reaction time contributing tderived function than Digit Symbol (WAIS
 AX6-49 Table AX6-3.4. Meta-analyses of Neurobehavioral Effects with Occupational Lead Exposure 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpreBalbus-Kornfeld et al. (1995) Reviewed 21 studies from 28 publications; number of subjects ranged from 9-708. Mean blood Pb in most exposed group 28-68 μg/dL. Only 5 studies used a measure of cumulative exposure or absorption of Pb, 2 studies used duration of exposure. Dexterity (17/21 studies) and executive o

studies were the functional domains most Pb. Age not adequately controlled in mosmeans or medians. Intellectual abilities padjusted for with education; however, Vooverall intellectual ability still different beThe conclusion reached that evidence of eexposure or absorption of Pb was inadequ

Davis and Svendsgaard (1990) Meta-analysis of 32 studies of nerve conduction studies and Pb exposure. Presented 41 effect sizes with the overall 

D = !0.369 (p # 0.001). All median nerve(p # 0.001) and for all ulnar nerves D = !0

median motor was most sensitive with an (p # 0.001). Overall blood Pb was a weak the peripheral nervous system. Paradoxicsize smaller with increasing blood Pb but exposure. Meyer-Baron and 

Seeber (2000) 

Meta-analysis of studies with blood Pb <70 μg/dL found 12 studies with comparable test procedure and sufficient documentation of results. Thirteen tests from the 12 studies examined. 

Exposed group Range of mean blood Pb 31 to 49 μg/dL Controls Range of mean blood Pb 6 to 18 μg/dL 

Block Design, Logical Memory, and Santdeficits with small effect size. For Block comparable to changes observed with 20 Trials A and B, Digit Span and Digit Symperformance but the large variance for efffactors besides Pb exposure influenced peconclude, “that the evidence of neurobehaof ~40 μg/dL is obvious.” 

Goodman et al. (2002) Meta-analysis of 22 studies with median 

blood Pb <70 μg/dL, numbers of exposed and unexposed workers given with scores and dispersion on neurobehavioral tests. 

Exposed group Range blood Pb 24 to 63 μg/dL Unexposed group Range blood Pb 0 to 28 μg/dL 

Digit symbol and D-2 errors significant eweighted random effects and unweighted reaction time, grooved pegboard, Trails A visual reproduction, eye-hand coordinatiosignificant effects for the fixed effects moconclude none of the individual studies wof subclinical neurobehavioral effects of ebiological effects of blood Pb <70 μg/dL Schwartz et al. (2002) for comments). 
 AX6-50 Table AX6-3.4 (cont’d). Meta-analyses of Neurobehavioral Effects with Occupational Lead Expos

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpreSchwartz et al. (2002) Letter to the Editor commenting on shortcomings in the Goodman et al. (2002) meta-analysis on studies of neurobehavioral testing in workers occupationally exposed to Pb. The six points regarding problems with th

(1) no evaluation of quality of study desig(2) data from poorly done and well done (3) included 6 studies with no age adjustmadjustment for education, (4) confounding when addressed the variation across studieffect only examined exposed vs. nonexpknown to have the lowest power, cannot erelationships and have a tendency for selethe 22 studies included contributed to effe

Seeber et al. (2002) A comparison of the two meta-analyses Meyer-Baron and Goodman) performed to evaluate recommendations of a German BEI of 40 μg/dL. Effect size calculated for 12 tests in two m

from one meta-analyses found subtle impblood Pb between37 μg/dL and 52 μg/dL Visual Reproduction, Simple Reaction TiBlock Design, and Picture Completion, SPegboard and Eye-hand Coordination. Efnorms between ~40 to 50 yrs. For exampDesign = 10 to 15 yrs; !3.5 score on Digit on Cancellation d2 = 10 yrs; and +5 to +6 This analyses concluded that both meta-arecommendation for German BEI of 40 μ

Graves et al. (1991) A meta-analysis on 11 case-control studies of 

Alzheimer’s disease for occupational exposure to solvents and Pb. 

 Four studies had data for Pb exposure wit

relative risks for occupational Pb of 0.71 The exposure frequencies were 16/261 fothe controls. 
 AX6-51 Table AX6-3.5. Neurophysiological Function and Occupational Lead Exposure in Adu

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretCanada Bleecker et al. (2005b) New Brunswick 1992-1993 74 current smelter workers, mean age 44 (8.4) yrs, education 8 (2.8) yrs and employment duration 20 (5.3) yr had current perception threshold (CPT) measured for large and small myelinated and unmyelinated nerve fibers in the finger. Linear regression modeled CPT on metrics of Pb dose after adjusting for covariates. Interaction of Pb dose and ergonomic stressor on peripheral nerve function was assessed. Mean (SD) blood Pb 26 (7.1) μg/dL Mean (SD) IBL 891 (298.8) μg·yr/dL Mean (SD) TWA 42 (8.4)μg/dL Mean (SD) tibia bone 40 (23.8) μg/g 5 metrics relating to IBL cumulated only exposure above increasing blood Pb ranging from 20 to 60 μg/dL Blood Pb and tibial bone Pb were not asso

nerve fiber populations. IBL and TWA acpercentage of the variance only for the larg(♠

R2 = 3.9%, 

♠

R2 = 8.7% respectively). T

TWA was curvilinear with a minimum at a Unique variance of CPT for large myelinadifferent thresholds of IBL were IBL – 3.9p < 0.03, IBL30 – 7.8%, p < 0.02; IBL40, p < 0.005; and IBL60, p < 0.005. IBL60 avariance of CPT for small myelinated nervincreased impairment in peripheral nerve fmyelinated sensory nerve fibers was enhanergonomic stress was added to the model f

Europe Kovala et al. (1997) Finland 

60 workers in a Pb battery factory with a mean age of 43 (9) yrs and mean exposure duration of 16 (8) yrs. Nerve conduction studies, vibration thresholds, and quantitative EEG were performed. Relationship of Pb exposure with peripheral nerve function and quantitative EEG were examined by partial correlation and regression analyses adjusting for age. 

Mean (SD) tibial Pb 26 (17) mg/kg Mean (SD) calcaneal Pb 88 (54) mg/kg Mean (SD) IBL 546 (399) μg·yr/dL Mean (SD) TWA 34 (8.4) μg/dL Mean (SD) maximum blood Pb 53 (19) μg/dL, Mean (SD) blood Pb 27 (8.4) μg/dL 

The sensory amplitude of the median and correlation with IBL and duration of exposage. Vibration threshold at the ankle relatduration of exposure after adjusting for agthe finger was associated with blood Pb anpast three yrs. The alpha and beta frequenworkers with higher long term Pb exposurcalcaneal, IBL and TWA. Overall historicmore closely associated with peripheral neconcentrations. The study had no compariaccount for the effect of smoking and alcoin this population. 
 AX6-52 Table AX6-3.5 (cont’d). Neurophysiological Function and Occupational Lead Exposure in A

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpretAsia Schwartz et al. (2001a) South Korea 1997-1999 804 workers from 26 different Pb using facilities and 135 controls with a mean age of 40 ( 10.1) and 35 (9.1) yrs respectively, job duration of 8 (6.5) and 9 (5.3) yrs respectively, and education level 42 % and 69% completed high school respectively had comparable alcohol and smoking use. Linear regression used to compare vibration threshold in Pb exposed and controls controlling for potential confounders. Pb-exposed workers Mean (SD) blood Pb 32 (15) μg/dL Mean (SD) tibia bone Pb 37 (40.3) μg/g Mean (SD) DMSA- chelatable Pb 186 (208.1) μg (4 h collection) After adjustment for age, gender, educatio

not blood Pb was significantly associated wthreshold in the dominant great toe but not 

[SE 0.0007], p < 0.01). These results contneurobehavioral measures (see above) perfwhere tibial Pb was not a predictor of perf

Schwartz et al. (2005) South Korea 1997-2001 Longitudinal decline in neurobehavioral performance examined in 576 of the above group of Pb exposed workers who completed 3 visits at one yr intervals. Mean age at baseline was 41 (9.5) yrs and job duration 9 (6.3) yrs and 76% were men. 

Compared to non-completers Pb workers who completed 3 visits were 3.3 yrs older, baseline mean blood Pb was 2.0 μg/dL lower, on the job 1.6 yrs longer, 24% women vs. 10% of noncompleters, and usually had less than high school education. Models examined short-term vs. long-term effects. Final model had current blood Pb, tibia bone Pb and longitudinal blood Pb and covariates. 

Baseline mean (SD) blood Pb 31 (14.2) μg/dL Mean (SD) tibia Pb 38 (43) μg/g 

After adjustment for age, visit number, edu(for vibration) and BMI (for grip strength threshold in the dominant great toe and nowith tibia Pb (∃ = !0.0006 [95% CI: !0.00

longitudinal blood Pb (∃ = !0.0051 [95% Cin one model and blood Pb (∃ = !0.0019 [9in another model. 
 AX6-53 Table AX6-3.5 (cont’d). Neurophysiological Function and Occupational Lead Exposure in A

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpreAsia (cont’d) Chuang et al. (2000) Taiwan 206 Pb battery workers, mean age 41 yrs, with annual blood Pb for the previous five yrs had vibration perception measured in hand and foot. Relationship of Pb exposure term and vibration perception threshold assessed with multiple regressions, hockey stick regression analysis after adjusting for potential confounders. Mean blood Pb 28 μg/dL Mean blood Pb over past 5 yrs 32 μg/dL Mean maximum blood Pb 39 μg/dL Mean index of cumulative exposure 425 μg·yr/dL Mean TWA 32 μg/dL Mean working duration 13 yrs and life span in work 31% After adjustment for age, sex, body heigh

consumption, and use of vibrating hand tobetween mean blood Pb and mean TWA athe foot were found. After adjustment for stick regression analysis of foot vibration Pb concentration for 5 yrs found an inflecwith a positive linear relation above this pthreshold. Chia et al. (1996a) Singapore 72 workers in a Pb battery manufacturing factory with a mean age of 30 yrs and reference group of 82 workers had nerve conduction studies and blood Pb performed every 6 mos over the course of three yrs. Only 28 Pb battery workers completed the 

program. At the end of the first yr of the 82 workers in the comparison group only 26 remained and by yr 3 this had decreased to 4. Mean nerve conduction values examined by ANCOVA between the exposed and reference after adjustment for age, ethnic group, smoking and drinking habits. Analysis of serial nerve conduction values and blood Pb treated as a clustered sample had the within-cluster regression coefficient examined. The 28 exposed workers were stratified by blood Pb level and the relationship between nerve conduction values and blood tested within the cluster. 

Geometric mean blood Pb concentrations for the 6 testing periods: 37, 41, 42, 40, 41, and 37 μg/dL Overall range for blood Pb 16-73 μg/dL 

The relationship between blood Pb levels values for the 28 exposed workers was sigexcept median motor conduction velocity conduction velocity and ulnar sensory amcorrelation coefficients for blood Pb >40 all parameters except the median sensory for blood Pb <40 μg/dL there was no assoconduction values. Therefore the blood Pno change in nerve conduction studies wa
 AX6-54 Table AX6-3.5 (cont’d). Neurophysiological Function and Occupational Lead Exposure in A

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpreAsia (cont’d) Chia et al. (1996b) Singapore Extension of above study - 72 workers in Pb battery manufacturing and 82 controls. Mean duration of exposure 5.3 yrs. Mean blood Pb 37 μg/dL Mean cumulative blood Pb 137 μg·yr/dL ANCOVA found significant differences f

parameters except three for the ulnar nervethnic groups, smoking and drinking habisignificant correlation between blood Pb awith nerve conduction values after linear for confounders. When cumulative blood workers <40 μg·yr/dL, 28 workers 40-300 >300 μg·yr/dL ANCOVA found significa5 nerve conduction parameters. The stronrelationship was for sensory nerve conduc

Chuang et al. (2004) Taiwan 181 Pb battery manufacture workers were stratified by milk drinkers, n = 158 and non- or rare mild drinkers n = 23. Mean age in the two groups was 40 and 36 yrs and working duration 10/8 yrs respectively. Peripheral nerve evaluation was with current perception 

threshold at 3 frequencies 5Hz = C fibers, 250 Hz = A-delta fibers and 2000 Hz = Abeta fibers. Linear regression estimated the association of CPT and Pb exposure variable and adjustment of milk intake and potential confounders. 

Blood Pb Milk drinkers 25 μg/dL Non or rare milk drinkers 30 μg/dL TWA Milk drinkers 28 μg/dL Non or rare milk drinkers 32 μg/dL IBL Milk drinkers 316 μg·yr/dLNon or rare mild drinkers 245 μg·yr/dL 

Age was significantly different but distribalcohol use, use of hand vibration tool, wowere not different. Linear regressions fouand 250 Hz CPT in hand and foot with bloIBL. However the protective effects of drall fiber populations only in the hands. Thunusual finding of subclinical Pb neuropaunmyelinated and small myelinated fibersclassically involve the large nerve fibers. may be related to other nutritional deficiemalabsorption syndrome that lead to the n

Yokoyama et al. (1998) Japan 

17 gun-metal workers, mean age 48 yrs and a 20 controls with a mean age of 45 yrs had distribution of conduction velocities (DCV) measured and the maximum median sensory conduction velocity (SVC) performed twice at a yr interval. Group differences controlling for confounders and dose-effect relationships were examined. 

Mean blood Pb 40 μg/dL Mean mobilized Pb (CaEDTA) in urine 1 mg/24 h 

ANCOVA controlling for age and alcohoassociated with significant slowing in the blood Pb was not. Workers with increaseover 1 yr interval (mean 0.44 mg/24hr) halarge fiber (V95) conduction velocity whichange in mobilized Pb (0.08 mg/24hr) dichange in DCV or SVC. It appears that lanerve fibers are susceptible to Pb and a m(readily mobilized Pb from soft tissue) is change than blood Pb. 
 AX6-55 Table AX6-3.5 (cont’d). Neurophysiological Function and Occupational Lead Exposure in A

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpreAsia (cont’d) He et al. (1988) China 40 workers in a Pb smelter with age range 20 to 45 yrs (no mean provided) and duration of exposure 5.4 yrs. Fifty controls age 20 to 55 yrs. Nerve conduction studies examined 11 parameters. Student = s t-test examined for differences between exposed and controls. Mean blood Pb 40 μg/dL Mean urinary Pb 71 μg/dL Mean ALAU5 μg/dL There were no symptoms or signs of perip

Both motor and sensory conduction velocexposed groups. 10 nerve conduction parthe group with blood Pb >40 μg/dL and 6 significant in the group with blood Pb <40 finding in this study was the lack of age aconduction values and therefore it was noanalyses. Niu et al. (2000) China 44 Pb-exposed workers (17 men, 27 women) from Pb printing houses, mean age 35 (4.9) and education 9.3 (no SD)yrs and 34 controls (19 men and 15 women), mean age 33 (7.4) yrs and education 9.5 (no SD) yrs had nerve conduction studies for maximal motor nerve conduction velocity. ANCOVA controlling for age, sex and education examined group 

differences and linear regression for doseresponse relationship. 

Pb workers Mean blood Pb 29 (26.5) μg/dL (8 workers blood Pb exceeded 50 μg/dL) Controls Mean blood Pb 13 (9.9) μg/dL (1 control blood Pb exceeded 50 μg/dL) 

Only 12 Pb exposed workers and 24 contrLeft ulnar nerve was significantly slower right ulnar were faster in the Pb exposed aslightly slower. This appears to be a findismall n. For the Pb exposed group mean the mean right ulnar CV was 59 while for was 58 while the mean right ulnar CV wa
 AX6-56 Table AX6-3.6. Evoked Potentials and Occupational Lead Exposure in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

Canada Bleecker et al. (2003) New Brunswick 1992-1993 359 currently employed smelter workers, mean age 41 yrs, had brainstem auditory evoked potentials (BAEP) measured. Relationship between absolute latencies and interpeak latencies assessed using linear regression after adjusting for potential confounders. Exposure was assessed in cases with clinical abnormalities in Wave I and I-V interpeak latency compared to those workers with normal BAEP using post-hoc analysis. Mean blood Pb 28 μg/dL Mean TWA 39 μg/dL Mean IBL 719 μg·yr/dL Linear regression after the contr

Pb and TWA were significantly while IBL was significantly assoIII interpeak interval. Four grouabnormalities based upon clinicand I-V interpeak interval had sand IBL were all significantly hprolonged Wave I and I-V interpto the group with normal BAEP support involvement of the brainwith Pb exposure. Europe Abbate et al. (1995) Italy 300 Pb exposed men ages 30 to 40 yrs in good health with no other neurotoxic exposure had P100 latency measured for visual evoked potentials (VEP) for 15 

and 30 minute of arc. Groups created based upon blood Pb had VEPS examined followed by linear regression for each group. 

Blood Pb 17 to 60 μg/dL range Mean blood Pb for 4 groups n = 39 23 μg/dL n = 113 30 μg/dL n = 89 47 μg/dL n = 59 56 μg/dL 

ANOVA of the blood Pb and P1significantly prolonged for 15 anLinear regression found the assoP100 were significant in each grwas not proportional (angular coPb on VEP began at 17-20 μg/ddecade, contribution from age wthough no comparison group, caother medical and eye conditionexposures. 

Discalzi et al. (1992) Italy 

49 Pb exposed workers and 49 age and sex matched controls had BAEPs measured. Relationship of 6 BAEP outcome variables and Pb exposure examined with analysis of variance and linear regression. 

Mean blood Pb 55 μg/dL Mean TWA for previous 3 yrs 54 μg/dL 

Latencies for waves I, III, V and III, and III-V were all significanexposed workers (p < 0.04). No found with linear regression betexposure variables. In those wo>50 μg/dL, I-V latency was signcompared to workers with TWA 
 AX6-57 Table AX6-3.6 (cont’d). Evoked Potentials and Occupational Lead Exposure in Adu

Reference, Study Location, and Period Study Description Pb Measurement Findings, Europe (cont’d) Discalzi et al. (1993) Italy 22 battery storage workers, mean age 35 yrs and 22 control group, age and sex matched, with normal hearing had BAEPs recorded. Latencies I and V and Pb exposure examined by ANOVA after stratifying blood Pb. Mean blood Pb 48μg/dL Interpeak latency I-V was sig

exposed workers (p = 0.001)linear regression between I-V Pb exposed workers by bloointerpeak latency significantlsubgroup with higher blood 

Latin America Counter and Buchanan (2002) Ecuador 30 Pb-glazing workers, median age 35 yrs, had pure- tone thresholds and BAEPs performed. Regression analyses examined relations between auditory outcomes and blood Pb. Mean blood Pb 45 μg/dL (range 11 to 80 μg/dL) Sixty percent of the men and 

abnormal high-frequency thrsignificant relationship with at all frequencies. Analysis between latencies for Waves hearing status. Interpeak latebut no analysis provided with a Pb contaminated environmstorage batteries. Therefore exposure may have been mo

Asia Holdstein et al. (1986) Israel 

20 adults and 8 children (mean age 27 yrs, range 8 - 56 yrs) accidentally exposed to Pb through food until one yr prior to measurement of BAEP. 

Mean blood Pb Adult 31 μg/dL Children 22 μg/dL 10 mo avg blood Pb Adults 43 μg/dL Children 36 μg/dL 

In adults, latencies I, III and were significantly longer thaWhen group stratified by 10 interval was longer in the higwere not studied due to few interval reflects transmission VIIIth nerve. 
 AX6-58 Table AX6-3.6 (cont’d). Evoked Potentials and Occupational Lead Exposure in Adu

Reference, Study Location, and Period Study Description Pb Measurement FindinAsia (cont’d) Hirata and Kosaka (1993) Japan 41 Pb-exposed men from Pb-glass-based colors manufacturing (n = 20), production of Pb electrode plates (n = 8), casting of Pb- bronze (n = 4) and casting of Pb pipes and plates (n = 9) had mean age 41 yrs, mean duration of exposure 13 yrs. A battery of tests administered including radial nerve conduction study, electroretinogram (ERG), visual evoked potential (VEP), brainstem auditory evoked potential (BAER), and short-latency somatosensory evoked potential (SSEP). Comparison group of 39 unexposed used only for BAER analysis by Student’s t test. Correlation and linear regression controlling for age examined the relationship of Pb and the other variables. Mean (range) blood Pb 43 μg/dL (13-70) Mean (range) TWA (based upon previous 5 yrs) 43 μg/dL (13-70) Mean (range) duration of exposure 13 (0.6-29) yrs Significant partial co

included TWA and rblood Pb and sensorduration and VEP, bComparison of BAEcontrols found interpprolonged significancomparison group onConsidering the largwith three exposure be by chance alone. Murata et al. (1993) Japan 22 gunmetal foundry workers with age range of 32 to 59 yrs and work duration of 1 to 19 yrs and control group matched for age, no chronic disease and no Pb exposure participated. No significant difference between groups for age, height, skin temperature, alcohol consumption, and yrs of schooling. The test 

battery consisted of visual evoked potential (VEP), brainstem auditory evoked potential (BAEP), short latency somatosensoryevoked potential (SSEP), event related potential (P300) and EKG R-R interval variability. Paired-sample t test examined for differences between the matched groups. Dose-effect relationships examined with partial correlation adjusting for age and stepwise linear regression. 

Blood Pb 12 to 64 μg/dL (no mean provided) 

For VEPs, N75 and prolonged in the Pb interpeak latency of prolonged. BAEP ladifferences. P300 bfunction was proloncorrelated with bloonervous system effefor CVR-R and for a m

activity C-CVRSA. F

variables showed sigthere is limited dose the exposed group. conclusions with 20 biomarkers of Pb ex
 AX6-59 Table AX6-3.7. Postural Stability, Autonomic Testing, Electroencephalogram, Hearing Thresh

Occupational Lead Exposure in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

United States Dick et al. (1999) U.S. 145 workers from a secondary Pb smelter, mean age 33 (8.7) and duration of employment 5 (4.8) yrs and 84 comparison workers mean age 30 (9.3) and duration of employment 4 (4.3) yrs had postural sway testing performed. The analysis of exposure with test conditions and covariates used mixed models. Pb workers Mean (SD) blood Pb 39 (8.5) μg/dL Mean (SD) ZPP 55 (42.2) μg/dL Mean (SD) CBL 230 (217.9) μg·yr/dL Mean (SD) TWA 35 9 (8.5) μg/dL Comparison workers Mean (SD) blood Pb 2 (1.7) μg/dL The postural sway test had 6 con

challenge to the vestibular and pvisual system. Only blood Pb hprimarily on the one leg conditiocovariates age, height, mass, and exposure slope estimate for area p = 0.0001) and length (b = 0.00were significant. For the right lestimate for length (b = 0.0033, significant. Dose effect was onlworkers were combined with cocomparison workers with blood removed no significant exposure 

Europe Kovala et al. (1997) Finland 

60 workers in a Pb battery factory with a mean age of 43 (9) yrs and mean exposure duration of 16 (8) yrs. Quantitative EEG were performed. Relationship of Pb exposure with quantitative EEG were examined by partial correlation and regression analyses adjusting for age. 

Mean (SD) tibial Pb 26 (17) mg/kg Mean (SD) calcaneal Pb 88 (54) mg/kg Mean (SD) IBL 546 (399) μg·yr/dL, Mean (SD) TWA 34 (8.4) μg/dL, Mean (SD) maximum blood Pb 53 (19) μg/dL Mean (SD) blood Pb 27 (8.4) μg/dL 

The alpha and/or beta frequenciworkers with higher long term P(p < 0.05) and calcaneal (p < 0.0TWA (p < 0.05). Slow alpha in correlate with increased episodeThe study had no comparison grthe effect of smoking and alcohothis population. 
 AX6-60 Table AX6-3.7 (cont’d). Postural Stability, Autonomic Testing, Electroencephalogram, Hearing Th

Occupational Lead Exposure in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia Iwata et al. (2005) Japan 121 workers from a battery recycling plant and 60 age matched comparison group, mean age 46 (11) yrs. Height, body weight, body mass index, and alcohol use was similar in both groups. Pb group had significantly more smokers. ANCOVA used to evaluate postural sway after controlling for age, height, and smoking and drinking status. Benchmark dose level was calculated as the 95% lower confidence limit of the benchmark dose. Mean (SD) blood Pb 40 (15) μg/dL Referent Not done Except for sagittal sway, all postural sway 

were significantly larger in Pb workers. Bwas significantly associated with to sagittHz with eyes open, and sagittal and transv2-4 Hz with eyes closed. The mean benchblood Pb level for postural sway was 14.3 and 14.6 μg/dL for the K power model. Yokoyama et al. (1997) Japan 49 chemical workers exposed to Pb stearate, mean age 48 (1.3) yrs and 23 controls, mean age 47 (2.5) had postural sway evaluated. ANCOVA examined group differences after 

adjusting for covariates. 

Mean (SD) blood Pb 18 (1.0) μg/dL Mean (SD) maximum blood Pb 48 (3.8) μg/dL Mean (SD) TWA 24 (1.3) μg/dL Mean (SD) Cumulative blood Pb 391 (48.2) μg·yr/dL 

There were significant increases in sway 

low frequencies with eyes open and eyes Regression analysis found blood Pb assocanterior-posterior direction, 0.5-1Hz (0.32p = 0.04) and TWA associated with right p = 0.02) after adjustment for the covariatalcohol consumption. The authors concluvestibulo-cerebellum is affected by blood cerebellar lobe is affected by past Pb expo

Chia et al. (1994a) Singapore 

60 Pb storage workers, mean age 32 (7.7) yrs and 60 controls, mean age 35 (7.4) had postural sway parameters measured. ANCOVA used to examine group differences after adjusting for covariates. Linear regression examined relationship between Pb exposure and postural sway. 

Pb workers Mean (SD) blood Pb 36 (11.7) μg/dL Controls Mean (SD) blood Pb 6 (2.4) μg/dL 

Computerized postural sway measuremenhave poorer postural stability that increas(p < 0.01). Regression analysis adjusting weight found no significant association w

Chia et al. (1996c) Singapore 

The same 60 Pb storage workers as above and 60 control had postural sway data examined for contribution of cumulative blood Pb fractionated over 10 yrs of exposure. 

Pb workers Mean (SD) blood Pb 36 (11.7) μg/dL Controls Mean (SD) blood Pb 6 (2.4) μg/dL 

The Pb exposed group had significantly ppostural sway parameters with eyes closeadjusting for height, weight, age and drinAll postural sway parameters with eyes classociated with IBL for the 2 yrs prior to 
 AX6-61 Table AX6-3.7 (cont’d). Postural Stability, Autonomic Testing, Electroencephalogram, Hearing Th

Occupational Lead Exposure in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia (cont’d) Ratzon et al. (2000) Israel 63 Pb battery workers, mean age 39 (8.7) yrs and 48 controls mean age 36 (11.8) yrs, matched for age with similar sex and education, had postural control measured. Group differences examined with t test. Dose-effect relations assessed with Pearson = s correlation coefficients. Linear regression done with exposure category as major predictor. Mean past blood Pb 38 μg/dL Mean yrs employed 11 Cumulative Pb determined by avg blood Pb 

Η yrs 

employed 

Using a computerized sway measurement workers had significantly increased mean closed (p < 0.01) and head tilted forward correlation adjusting for education, coffee and estimate of health was significant onlincreased body oscillations with head tilte

p = 0.0089). In order to maintain balance required increased oscillations when visuwere altered. 

Teruya et al. (1991) Japan 

172 Pb exposed workers, mean age 34 (18.4-57.4) yrs had cardiac autonomic nervous system evaluated by R-R intervals variation with respiration measured. 

Mean (range) blood Pb 36 (5-76) μg/dL 

Age adjustment controlled for by use of robserved values. A significant dose relatevariation during deep breathing was presestable blood Pb over the past yr (p < 0.01prominent in younger workers with blood decrease present at blood Pb ∃20 μg/dL. variation indicates decreased cardiac para

Ishida et al. (1996) Japan 

128 workers in the ceramic painting industry, 58 men, mean age 55 (11.7) yrs and 70 women, mean age 52 (9.2) yrs had measures of sympathetic function by variations in R-R interval on EKG and changes in finger blood flow with postural changes using Doppler flowmetry. Correlation analyses and linear regression examined relationship of finger blood flow and Pb exposure after adjusting for covariates. 

Men Mean (SD) blood Pb 17 (2.1) μg/dL Mean (SD) ALAD% 61.6 (28.3)% Women Mean (SD) blood Pb 11 (1.7) μg/dL Mean (SD) ALAD% 72.6 (20.8)% 

22% had blood Pb >20 μg/dL, and 43% h46 workers in the lowest group with blooALAD% >80% equivalent to nonoccupattherefore served as the control group. Blop = 0.02), smoking (∃ = 

−0.464, p < 0.01)

p = 0.01) were significant predictors of chwith postural change. Decrease in change compatible with a peripheral sympathetic 
 AX6-62 Table AX6-3.7 (cont’d). Postural Stability, Autonomic Testing, Electroencephalogram, Hearing Th

Occupational Lead Exposure in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia (cont’d) Niu et al. (2000) China 44 Pb-exposed workers (17 men, 27 women) from Pb printing houses, mean age 35 (4.9) and education 9.3 (no SD) yrs and 34 controls (19 men and 15 women), mean age 33 (7.4) yrs and education 9.5 (no SD) yrs had autonomic nervous system examined. ANCOVA controlling for age, sex and education examined group differences and linear regression for dose-response relationship. Pb workers Mean (SD) blood Pb 29 (26.5) μg/dL (8 workers blood Pb exceeded 50 μg/dL) Controls Mean (SD) blood Pb 13 (9.9) μg/dL (1 control blood Pb exceeded 50 μg/dL) Niu et al. (2000) examined autonomic ner

exposed workers, mean blood Pb 29 μg/dblood Pb, 13 μg/dL. Linear regression foblood Pb and decreased R-R interval with p < 0.05) and duration of Pb exposure and with deep breathing (F/T 3.263, p < 0.01) education, smoking and drinking. In the EEG found significant abnormalities in thdominant low amplitude in 59%, dominanand abnormalities in 81%. 
 AX6-63 Table AX6-3.8. Occupational Exposure to Organolead and Inorganic Lead in Adult

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterprUnited States Schwartz et al. (1993) U.S. Two hundred and twenty-two current employees that manufactured tetraethyl Pb participated in a study to determine if there was impairment on a neurobehavioral battery associated with a measure of cumulative exposure to organic and inorganic Pb derived from 12 yrs of air sampling. Mean age was 44 (8.7) yrs, education 13 (1.7) yrs. Mean (SD) cumulative Pb exposure (inorganic and organic) 869 (769) μg·yr/m3 Mean (SD) yrs of exposure 13 (9.5) Exposure was divided into 4 groups wit

exposure and cumulative Pb exposure seAfter adjustments for premorbid intellecalcohol consumption, cumulative Pb exp

association poorer performance in many often in manual dexterity and verbal me

on tests associated with exposure was 5 groups when compared with the low exp

Stewart et al. (1999) U.S. 543 former organolead workers, mean yrs since last exposure18, examined for ongoing neurobehavioral impairment related to past Pb exposure. Thirty-eight % were age 60 or older, predominantly white, 93% had at least a high school degree. Linear regression assessed the relationship between Pb dose and neurobehavioral function adjusting for 

the covariates. 

Mean (SD) tibial Pb 14 (9.3) μg/g Mean (SD) peak tibial bone Pb (extrapolated back using a clearance half-time of Pb in tibia of 27 yrs) 24 (17.4) μg/g Mean (SD) DMSA chelatable Pb 19 (17.2) μg (urine collected for 4 hrs) 

Peak tibial Pb was a significant predictoVocabulary (∃ = !0.063, p = 0.02), seria

p = 0.04), RAVLT trial 1 (∃ = !0.054, p (∃ = !0.019, p = 0.03), Trails B (∃ = !0.0

nondominant (∃ = !0.042, p = 0.02), Pur

(∃ = !0.043, p = 0.00), nondominant (∃ 

(∃ = !0.038, p = 0.00), assembly (∃ = !0(∃ = !0.014, p = 0.00). Current tibial Pb had similar associationp = 0.04), Digit Symbol (∃ = !0.095, p = dominant (∃ = !0.87, p = 0.02), finger ta

(∃ = 0.102, p = 0.00), Purdue Pegboard p = 0.01), nondominant (∃ = !0.091, p = 

p = 0.00), assembly (∃ = !0.197, p = 0.0

p = 0.01). DMSA-chelatable Pb was only significareaction time (∃ = !0.001, p = 0.01). 
 AX6-64 Table AX6-3.8 (cont’d). Occupational Exposure to Organolead and Inorganic Lead in Ad

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterprUnited States (cont’d) Stewart et al. (2002) U.S. From the above group of former organolead workers 535 were re-examined twice or four times over a four yr period. Also a nonexposed control group of 118 had repeat examinations. Mean age at first visit exposed/controls 56 (7.4)/59 (7.0), percentage with at least a high school education 66/71.2. 1st examination Mean (SD) blood Pb 5 (2.7) μg/dL Mean (SD) tibia Pb 14 (9.3) μg/g Mean (SD) peak tibia Pb 23 (16.5) μg/g Mean (SD) exposure duration 8 (9.7) yrs Mean (SD) duration since last exposure 16 (11.7) yrs On 17 of 19 neurobehavioral tests, form

demonstrated greater annual decline in compared to controls with significant dFigure copy, RAVLT Trial 1 and RAVdeclines in performance showed greateworkers compared to controls for block serial digit learning, finger tapping and predict annual change scores but peak digit, Rey Complex Figure delayed recRAVLT delayed recall, Purdue pegboaStroop. For these 6 tests it was determ15.7 μg/g bone mineral of peak tibia Peffect on annual test decline to 5 more Authors conclude that data supports onassociated with past occupational expo

Balbus et al. (1997) U.S. 

222 organolead manufacturing workers, mean age 44 (8.7) yrs and 62 nonexposed referents, mean age 43 (10) yrs performed simple visual reaction time (SVRT). Linear regression examined relationship between Pb exposure and mean RT, median RT and standard deviation of RT after controlling for covariates. 

Mean (SD) blood Pb 20 (9.5) μg/dL Mean (SD) peak urine Pb level 143 (130) μg/L 

Balbus et al. (1998) U.S. 

A second publication further examined the above data for relationship of interstimulus interval (ISI) and Pb exposure. 

Same as above Short ISIs of 1-3 seconds had no relati

while ISIs of 4-6 seconds were significPb (∃ = 0.06 [SE 0.02], p = 0.02 along (∃ = 0.05 [SE 0.02], p = 0.03). ISIs 7-Pb levels (∃ = 64.29 [SE 21.86], p < 0.
 AX6-65 Table AX6-3.8 (cont’d). Occupational Exposure to Organolead and Inorganic Lead in A

Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation United States (cont’d) Stewart et al. (2002) U.S. Population as described in Stewart et al. (1999) and Schwartz et al. (2000b). Data on 20 neurobehavioral tests from 529 former organolead workers were evaluated to determine if the previously described relationship with bone Pb levels is influenced by the apolipoprotein E (ApoE) genotype. In 20 linear regression models, coefficie

interaction term were negative in 19 with symbol (∃ = !0.109 [SE 0.054], p # 0.05(∃ = 0.068 [SE 0.028], p # 0.05) and com

[SE 0.001], p#0.05) and borderline signi(∃ = !0.046 [SE 0.026], p # 0.10), Trails 

p # 0.10) and Stroop (∃ = !0.013 [SE 0.0

relation between tibia Pb and neurobehanegative in those individuals with at leas

without this allele. It is suggested that th

increases the risk of persistent central ne

Tassler et al. (2001) U.S. 

490 former organolead workers, mean age 58 (7.5) yrs. The peripheral nervous system was examined with sensory pressure thresholds, and pinch and grip strength. 

Mean (SD) blood Pb 5 (2.6) μg/dL Mean (SD) DMSA-chelatable Pb 19 (16.3) μg Mean (SD) current tibia Pb 15 (9.4) μg/g Mean (SD) peak tibia Pb 24 (17.6) μg/g 

No strong association was found betweeof sensory and motor function after adjuattributed the findings to decreased sensthis dose range of inorganic Pb or the pothe peripheral nervous system compared 

Bolla et al. (1995) U.S. 

190 current workers in organolead manufacturing (from the 222 described in Schwartz et al., 1993) mean age 45 (8) yrs compared to 52 referents, mean age 45 (8) yrs and 144 solvent exposed workers, mean age 42 (8) yrs. 

IH found organic Pb was 65 to 70% of exposure in production area. Mean (SD) weighted avg blood Pb 24 (9.4) μg/dL 

Pb and solvent exposure associated with manual dexterity. When compared to thgreater impairment on memory and learntests. An elevated neuropsychiatric scorgroup, 15% of the solvent and 7% of the 

Mitchell et al. (1996) U.S. 

58 organolead workers, self-selected for a clinical evaluation. Mean age 45 (7.1) yrs. 

Mean (SD) blood Pb 19 (6.5) μg/dL Mean (SD) lifetime blood Pb 26 (9.1) μg/dL Mean (SD) lifetime urine Pb 51 (18.8) μg/L 

The most common symptoms were memtrouble sleeping 54%, irritability 51%, pnightmares 35%, moodiness 28%, headaOf the 31 workers receiving nerve conducarpal tunnel syndrome 36%, cubital tunneuropathy 3%, ulnar neuropathy 23%, mextremity 5%, tarsal tunnel syndrome 7% polyneuropathy 36%. 39 workers had n64% had abnormal tests of which 46% wwith a toxic exposure. 
 AX6-66 Table AX6-3.9. Other Neurological Outcomes Associated with Lead Exposure in Ad

Reference, Study Location, and Period Study Description Pb Measurement Findings, IntUnited States Louis et al. (2005) New York 63 cases of essential tremor (ET) and 101 controls, similar for age, 67 (16.6) and 65 (11.1) yrs, education, gender and ethnicity were examined for interaction of blood Pb and ALAD gene polymorphisms and increased odds of ET. ET Mean (SD) blood Pb 4 (2.2) μg/dL Controls Mean (SD) blood Pb 3 (1.5) μg/dL 2 ET cases but no controls had blood Pb >10 μg/dL Of the 63 ET cases 18 (29%) vs. 17 

ALAD2 allele (OR = 1.98 [95% CIlog blood Pb was examined by presblood Pb was highest in ET cases wintermediate in ET cases without an controls (test for trend, ∃ = 0.10; p was present, blood Pb was significa(OR = 80.29 [95% CI: 3.08, 2.096]odds of ET with an ALAD2 allele windividual with only an ALAD1 alltertile, ALAD2 allele was present in controls. It was proposed that increALAD2 allele could affect the cererisk of tremor. Louis et al. (2003) New York 100 cases of ET and 143 controls matched for age, sex, 

and ethnicity. The relationship between blood Pb and ET was examined. 

ET Mean blood Pb 3 μg/dL Controls Mean blood Pb 2 μg/dL 

Ten cases and 7 controls had bone Psignificantly correlated with blood Pb may have occurred in the past. correlated with blood Pb (r = 0.14, adjusting for age and current cigare

for ET was 1.19 (95% CI: 1.03, 1.3Blood Pb was higher in those 39 ET Both current and lifetime prevalencwas the same in ET cases and controccupational exposure did have a hwithout this history (median, 3.1 μg

Kamel et al. (2002) Massachusetts 

109 cases of ALS and 256 controls matched for age, sex and region of residence examined the relation of Pb and ALS. 

Cases/controls Mean (SD) blood Pb 5 (0.4) / 3 (0.4) μg/dL 3 cases and no controls had blood Pb >10 μg/dL Mean (SD) patella Pb 21 (2.1) / 17 (2.0) μg/g 5 cases and 1 control had patella Pb levels 

>50 μg/g Mean (SD) tibia Pb 15 (1.6) / 11 (1.6) μg/g 2 cases and no controls had tibia Pb >50 μg/g. 

Increased risk of ALS was found foexposure (adjusted OR = 1.9 [95% days of exposure (adjusted OR = 2.Association of blood Pb and ALS (2.6]). Elevation in both blood Pb afound in ALS cases though the precwas questioned (Patella Pb adjusted and tibia Pb adjusted OR = 2.3 [95% this study found Pb exposure from biological markers associated with 
 AX6-67 Table AX6-3.9 (cont’d). Other Neurological Outcomes Associated with Lead Exposure in 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpUnited States (cont’d) Kamel et al. (2003) Massachusetts As above, the same data was used to determine the associations of ALS with polymorphism in ALAD and the vitamin D receptor (VDR) and the influence of genotype. Same as above The ALAD2 allele was associated with 

after adjustment for the covariates, agephysical activity adjusted (OR = 1.9 [9Additionally adjusting for blood Pb strALAD2 and ALS risk adjusted (OR = was not found for bone Pb or occupatio(patella-adjusted OR = 2.1 [95% CI: 02.2 [95% CI: 0.66, 7.3]; occupational (OR = 2.4 [95% CI: 0.67, 8.7]). VDR ALS risk. Armon et al. (1991) Minnesota A case-control design with 47 ALS patients, mean age 61 with involvement of upper and lower motor neurons and 201 controls, mean age 62. For the Pb exposure analysis 45 male matched pairs were examined. Lifetime exposure to Pb of 200 hrs or more (yrs on job x hrs spent per wk) Of 13 discordant pairs for Pb exposurerelative risk was 5.5 (95% CI: 1.44, 2weakened by 3 controls with highest liALS worked more often at blue collar time welding (p < 0.01). These results that found a higher incidence of heavy 

Europe Chancellor et al. (1993) Scotland 1990-1991 

A case-control design 103 ALS patients from the Scottish Motor Neuron Disease Register and matched community controls. Differences in potential occupational exposures were determined between cases and controls. 

Exposure to Pb obtained by lifetime employment history from Office of Population and Censuses and Surveys. Physician’s record review and direct interview questionnaire. 

Odds ratio for manual labor in ALS pa6.3). Occupational exposure to Pb was patients (OR = 5.7 [95% CI: 1.6, 30]). 

Gunnarsson et al. (1992) Sweden 1990 

A case-control study of 92 cases of MND and 372 controls. MND included ALS, progressive bulbar paresis (PBP), and progressive muscular atrophy (PMA). Relation of MND to risk factors including occupational exposure examined. 

Exposure information obtained by self-administered questionnaire. 

Exposure to heavy metals primarily froMantel-Haenszel OR = 3.7 [95% CI: 1
 AX6-68 Table AX6-3.9 (cont’d). Other Neurological Outcomes Associated with Lead Exposure in A

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpreEurope (cont’d) Guidetti et al. (1996) Italy A retrospective incidence, prevalence, and mortality survey of ALS in northern Italy was performed. Mean air Pb 3 μg/m3 in 1975 to 1 μg/m3 in 1985; blood Pb in monitored children decreased 18, 14, and 11 μg/dL in same time period. The area studied had documented Pb poll

79 cases incidence and prevalence rate wesurrounding area. Vinceti et al. (1997) Italy 19 ALS cases, mean age 66 (14) yrs and 39 controls, mean age 64 (12.9) yrs. Sporadic ALS Mean (SD) blood Pb 13 (6.8) μg/dL Controls Mean (SD) blood Pb 11 (4.4) μg/dL There were no cases familial ALS. Blood 

and controls was not significantly differenwith disability due to ALS but no support of Pb in the etiology of sporadic ALS. 
 AX6-69 

ANNEX TABLES AX6-4 
 AX6-70

Table AX6-4.1. Renal Effects of Lead in the General Population 

Reference, Study Location, and Period Study Description Pb Measurement Findings, InteUnited States Kim et al. (1996) Boston, MA 1979-1994 

459 men in the Normative Aging Study; periodic exams every 3-5 yrs. Mean serum creatinine at baseline1.2 mg/dL Random effects modeling, adjusting for baseline age, time since initial visit, body mass index, smoking status, alcohol ingestion, education level, hypertension (defined as blood pressure ≥160 or 95 

mm Hg or anti-hypertensive medication use), and, in longitudinal analysis, baseline serum creatinine and time between visits. 

Mean (SD) blood Pb at 

baseline9.9 (6.1) μg/dL Blood Pb levels from stored red blood cells were adjusted for hematocrit; the assay and adjustment procedure were validated against freshly collected samples. Storage tubes were shown to be Pb free. 

Cross-sectional

Positive association between loand concurrent serum creatininlevel associated with 0.08 mg/d(95% CI: 0.02, 0.13). Association stronger in participPb levels. ∃ coefficient (95% Cwhose peak blood Pb #10 μg/d0.097). LongitudinalPositive association between loand change in serum creatinine period in participants whose pe∃ coefficient 0.027 (95% CI: 0Slope of age-related increase in group with highest quartile of texposure compared to the lowe
 AX6-71 Table AX6-4.1 (cont’d). Renal Effects of Lead in the General Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

United States (cont’d) Muntner et al. (2003) U.S. 1988-1994 Blood Pb levels measured in 15,211 adult subjects enrolled in the NHANES III study. Study cohort representative of U.S. population; non-Hispanic African Americans, Mexican Americans, the elderly and children over-sampled to allow stable estimates in these groups. Hypertension defined as blood pressure ∃140 and/or 90 mm Hg and/or current antihypertensive medication use. Based on evidence of interaction between blood Pb and hypertension, the population was stratified by hypertension for further analysis. 4,813 hypertensives; 10,398 normotensives. Elevated serum creatinine (%)

Defined as ∃99th percentile of each race-gender specific distribution for healthy young adults [age 20-39 without hypertension or diabetes]. 11.5 % (hypertensives) 1.8 % (normotensives) Chronic kidney disease (%)Chronic kidney disease defined as GFR <60 mL/min/1.73 m2; 

estimated by MDRD equation (Levey et al. [1999]). 10 % (hypertensives) 1.1% (normotensives) Multiple logistic regression. Age, race, gender, diabetes, systolic blood pressure, smoking status, history of cardiovascular disease, body mass index, alcohol consumption, household income, marital status, and health insurance. 

Mean (SD) blood Pb

4.21 (0.14) μg/dL (hypertensives) 3.30 (0.10) μg/dL (normotensives) 

Higher odds ratios of both inand chronic kidney disease bhypertensives but not in normHypertensives

Odds ratios for elevated seruadjustment: Blood Pb (range, 

μg/dL) 

Quartile 1 (0.7 to 2.4) Quartile 2 (2.5 to 3.8) 1Quartile 3 (3.9 to 5.9) 1Quartile 4 (6.0 to 56.0) 1p < 0.001 for chi-squared tesOdds ratios for chronic kidneadjustment: Blood Pb % Odds rat

Quartile 1 6.1 1.00 Quartile 2 10.4 1.44 (Quartile 3 10.8 1.85 (Quartile 4 14.1 2.60 (p < 0.001 for chi-squared tesAssociations were similar whtransformed continuous variaIn non-hypertensives, higher with a higher prevalence of cnot elevated serum creatinine
 AX6-72 Table AX6-4.1 (cont’d). Renal Effects of Lead in the General Population Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

United States (cont’d) Payton et al. (1994) Boston, MA 1988-1991 Blood Pb levels measured in 744 men enrolled in the Normative Aging Study. Serum creatinine 1.3 mg/dL Measured creatinine clearance 88.2 mL/min Calculated creatinine clearance 71 mL/min Multiple linear regression adjusting for age, body mass index, analgesic and diuretic use, alcohol consumption, smoking status, systolic/ diastolic blood 

pressure. 

Mean blood Pb

8.1 μg/dL Blood Pb levels below the limit of detection of 5 μg/dL were recoded as 4 μg/dL (n not stated). 

In blood Pb negatively associatcreatinine clearance (∃ = !0.04 

10 μg/dL higher blood Pb assolower creatinine clearance. Borderline significant associatiblood Pb and both serum creati

nor CI provided) and estimated (∃ = !0.022; neither SE nor CI 

Shadick et al. (2000) Boston, MA 1991-1996 

777 participants in all male Normative Aging Study. Mean blood Pb

5.9 μg/dL Mean tibia Pb20.8 μg/g bone mineral Mean patella Pb

30.2 μg/g bone mineral 

A significant association betwe

(∃ = 0.0007 [95% CI: 0.001, 0after adjustment for age, BMI, alcohol ingestion, and serum crsignificant associations betweePb (p = 0.1) and uric acid were these associations were significfor blood pressure and renal fuevidence that low level Pb incrparticipants had gout; Pb dose for gout. 
 AX6-73 Table AX6-4.1 (cont’d). Renal Effects of Lead in the General Population Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

United States (cont’d) Tsaih et al. (2004) Boston, MA 1991-~2001 448 men enrolled in the Normative Aging Study. Baseline Serum Creatinine 1.3 mg/dL Longitudinal analysis of data from 2 evaluations a mean of 6 yrs apart. Annual change in serum creatinine = (follow-up serum creatinine – baseline serum creatinine) / yrs of follow-up. Covariates assessed = age, age squared, body mass index, hypertension (defined as blood pressure ∃160 or 95 mm Hg or physician diagnosis with use of 

antihypertensive medication), diabetes (defined as use of oral hypoglycemic drugs or insulin or reported physician diagnosis), smoking status, alcohol consumption, analgesic use, and, in longitudinal models, baseline serum creatinine and its square. Six percent and 26% of subjects had diabetes and hypertension, at baseline, respectively. 

Mean (SD) baseline blood Pb

6.5 (4.2) μg/dL Mean (SD) baseline tibia Pb21.5 (13.5) μg/g bone mineral Mean (SD) baseline patella Pb

32.4 (20.5) μg/g 

Mean blood Pb levels and serusignificantly over the follow-up dose not associated with changSignificant interaction of blood in predicting annual change in ∃ (95% CI) for natural ln basel0.121) compared to 0.006 (!0.0diabetics. ∃ (95% CI) for natural ln basel0.135) compared to 0.005 (!0.0diabetics. Significant interaction of tibia in predicting annual change in ∃ (95% CI) for natural ln basel0.019) compared to 0.0004 (!0hypertensives. Follow-up serum creatinine wain longitudinal analyses; diabetbetween baseline tibia Pb and f
 AX6-74 Table AX6-4.1 (cont’d). Renal Effects of Lead in the General Population Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

United States (cont’d) Wu et al. (2003a) Boston, MA 1991-1995 709 men enrolled in the Normative Aging Study. Serum creatinine 1.2 mg/dL Calculated creatinine clearance 71.3 mL/min Serum uric acid 6.5 mg/dL Multiple linear regression, adjusting for age, body mass index, blood pressure or HTN (depending on model), and alcohol ingestion. Uric acid models also adjusted for serum creatinine, other outcome models 

adjusted for smoking status and analgesic medication use. 

Mean (SD) blood Pb

6.2 (4.2) μg/dL Mean (SD) tibia Pb

22 (13.4) μg/g bone mineral Mean (SD) patella Pb

32.1 (19.5) μg/g bone mineral 

Significant inverse association creatinine clearance. ∃ = !0.069, SE not provided Borderline significant (p = 0.08between tibia Pb and creatinine significant (p = 0.08) positive aand patella Pb and uric acid. Nassociated with serum creatininALAD gene polymorphism alsparticipants had the ALAD2 vahomozygous). None of the thrby genotype. Effect modificatiassociation between tibia Pb anobserved; the beta coefficient (the group with the variant allel

provided]; p = 0.03). Effect modification of borderli

relations between of patella anobserved; this was significant i

Pb levels were above 15 

μg/g b

not provided]; p = 0.04 ). Simimodel, patella Pb was associatethose with the variant allele. G

associations in models of estim
 AX6-75 Table AX6-4.1 (cont’d). Renal Effects of Lead in the General Population Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

Europe Alfven et al. (2002) Sweden OSCAR Study Date not provided N = 479 men, 542 women. All resided near two battery plants, 117 participants were current or former workers from plants. Renal outcome = urinary 

α1 microglobulin. 

Multiple linear regression. Age, smoking status, gender (by stratification), blood cadmium. 

Mean blood Pb

0.16 μmolg/L men 0.11 μmolg/L women 

Blood Pb not associated with u

(regression performed separate

Akesson et al. (2005) Women’s Health in the Lund Area Study, 1999-2000 

N = 820 women Renal outcomes = GFR (estimated with cystatin C), estimated creatinine clearance, urinary NAG and 

α1

microglobulin. Multiple linear regression. Age, body mass index, diabetes, hypertension, and regular use of nephrotoxic drug, blood and urinary cadmium (in separate models), smoking status (by stratification). 

Mean blood Pb

2.2 μg/dL 

Blood Pb negatively associatecreatinine clearance. No assoc

microglobulin. ∃ (95% CI) for association betestimated creatinine clearance (!3.0, !0.7). 
 AX6-76 Table AX6-4.1 (cont’d). Renal Effects of Lead in the General Population Reference, Study Location, and Period Study Description Pb Measurement Findi

Europe (cont’d) De Burbure et al. (2003) France Study date not provided 600 adults (399 exposed, 201 age and gender matched controls). 400 children (200 exposed, 200 age and gender matched controls). Age ranged from 8.5 to 12.3 yrs. Exposure from residence near smelters. Exclusion criteria for children included obesity, diabetes, and puberty; for adults included pregnancy, cancer, diabetes, and kidney disease. Serum creatinine 1.43 mg/dL (adult male controls) 1.38 mg/dL (exposed adult males) 1.33 mg/dL (adult female controls) 1.26 mg/dL (exposed adult females) Urinary ∃2-microglobulin 68.16 μg/g creatinine (adult male controls) 76.29 μg/g creatinine (exposed adult males) 63.79 μg/g creatinine (adult female controls) 71.98 μg/g creatinine (exposed adult females) 

87.8 μg/g creatinine (boy controls) 97.3 μg/g creatinine (exposed boys) 88.2 μg/g creatinine (girl controls) 94.8 μg/g creatinine (exposed girls) Urinary NAG

1.12 IU/g creatinine (adult male controls) 1.24 IU/g creatinine (exposed adult males) 0.98 IU/g creatinine (adult female controls) 1.28 IU/g creatinine (exposed adult females) 2.29 IU/g creatinine (boy controls) 1.70 IU/g creatinine (exposed boys) 2.21 IU/g creatinine (girl controls) 1.07 IU/g creatinine (exposed girls) Urinary RBP

82.8 μg/g creatinine (adult male controls) 85.8 μg/g creatinine (exposed adult males) 83.42 μg/g creatinine (adult female controls) 95.81 μg/g creatinine (exposed adult females) 94 μg/g creatinine (boy controls) 99 μg/g creatinine (exposed boys) 110 μg/g creatinine (girl controls) 109 μg/g creatinine (exposed girls) Renal outcome measures also included urinary total protein, albumin, transferrin, and brush border antigens. Multiple linear regression adjusting for age, sex, body mass index, area of residence, smoking, alcohol ingestion, mercury, cadmium and urinary creatinine level. 

Geometric mean blood 

Pb

7.13 μg/dL (adult male controls) 6.78 μg/dL (exposed adult males) 4.17 μg/dL (adult female controls) 5.25 μg/dL (exposed adult females) 3.42 μg/dL (boy controls) 4.22 μg/dL (exposed boys) 2.74 μg/dL (girl controls) 3.69 μg/dL (exposed girls) 

Adults

Mean blood Pb levemen. None of the renany significant diffeunexposed groups. Ablood Pb was not asChildren

Mean blood Pb levegeometric mean blooof the renal outcomeexposed. After adjuwas not associated wblood cadmium was This association was exposed areas. Participants with extexcluded from data asubjects in data table
 AX6-77 Table AX6-4.1 (cont’d). Renal Effects of Lead in the General Population Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

Europe (cont’d) Factor-Litvak et al. (1993) Kosovo, Yugoslavia 1985-1986 1447 Yugoslavian women in prospective study of environmental Pb exposure and pregnancy. Exposure from Kosovska Mitrovica with a Pb smelter, refinery, and battery plant. Controls from Pristina, 25 miles away. Renal outcome = Proteinuria assessed with a dipstick. Exclusionary criteria included HTN (n = 37 excluded, similar blood Pb levels to remaining participants). Multiple logistic regression adjusting for age (linear and quadratic), height (linear and quadratic), cigarette smoking, gestational age (linear and quadratic), daily 

milk consumption, number of previous live births, avg weekly meat consumption, hemoglobin level and ethnic group. 

Mean blood Pb

17.1 μg/dL (582 exposed) 5.1 μg/dL (865 controls) 

Proteinuria (negative, trace, or 

Exposed = 16.2% negative, 74∃1+ proteinuria. Controls = 32and 7.1% with ∃1+ proteinuriahigh proportion of proteinuria tHigher blood Pb associated witrace and ∃1+ proteinuria. Comparing women in upper 10lower 10th percentile of exposu(95% CI) for trace and ∃1+ pro

and 4.5 (1.5, 13.6), respectivelyLimitations = limited renal out

Staessen et al. (1990) London, England Study date not provided 

531 London civil servants (398 male, 133 female). Exclusionary criteria = occupational exposure to heavy metals. Serum creatinine

1.10 mg/dL (men) 0.88 mg/dL (women) 

Mean blood Pb

12.4 μg/dL (men) 10.2 μg/dL (women) 

After removal of 2 outliers, the correlation between serum creamen. No correlation between serum in women. Limitations = lack of adjustmePb dose and renal outcome assanalyzing gender in separate m
 AX6-78 Table AX6-4.1 (cont’d). Renal Effects of Lead in the General Population Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

Europe (cont’d) Staessen et al. (1992) Belgium 1985-1989 Blood Pb levels were measured in 1981 adult subjects (965 males, 1016 females) enrolled in the Cadmibel study of general Belgian population in four cadmium polluted and unpolluted areas. Inclusion criteria included age ∃20 yrs and residence in one of four study areas for ∃8 yrs. Participants were randomly selected from the study areas; participation rates were 78% in the two rural areas but only 39% in the urban areas (one area from each category was known to be cadmium polluted). Measured creatinine clearance 99 mL/min (males) 80 mL/min (females) 

Calculated creatinine clearance

80 mL/min (males) 69 mL/min (females) Multiple linear regression. Covariates assessed included age, age squared, gender (by stratifying), body mass index, blood pressure, ferritin level, smoking status, alcohol ingestion, rural vs. urban residence, analgesic and diuretic use, blood and urinary cadmium, diabetes, occupational exposure to heavy metals, and gamma glutamyl transpeptidase. 

Blood Pb

11.4 μg/dL (males) 7.5 μg/dL (females) Zinc protoporphyrin also assessed. 

After adjustment, log transformassociated with measured creat∃ coefficient (95% CI)

!9.5 (!0.9, !18.1) males !12.6 (!5.0, !20.3) females A 10 fold increase in blood Pb in creatinine clearance of 10 anwomen, respectively. Log transformed blood Pb also calculated creatinine clearance∃ coefficient (95% CI)!13.1 (!5.3, !20.9) males !30.1 (!23.4, !36.8) females Log transformed zinc protoporassociated with measured and cclearances and positively assoc

microglobulin in both sexes anmen. Blood Pb positively associated 

microglobulin in men. 
 AX6-79 Table AX6-4.1 (cont’d). Renal Effects of Lead in the General Population Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

Asia Lin et al. (1993) Taiwan Study date not provided 123 adults living near a Pb battery factory for more than 10 yrs. Divided into 3 groups by proximity to the factory. Group 1 ≤500 m (n = 49) Group 2 1000-1500 m (n = 47) Group 3 farther away (n = 27) Exclusionary criteria included history of exposure to nephrotoxicants and nephrotoxicant medications, such as NSAIDs. 24 h urinary NAG excretion 3.3 U/day (Group 1) 2.4 U/day (Group 3) 

Multiple linear regression with adjustment for age. 

Mean blood Pb

16.6 μg/dL (Group 1) 13.5 μg/dL (Group 2) 7.9 μg/dL (Group 3) EDTA diagnostic chelation (done in Group 1)126.1 μg/24 hrs 

Significantly higher prevalence found in the exposed group 1 c(55.6% compared to 11.1%; p NAG not significantly higher iIn all 45 participants in whom EDTA chelatable Pb was not cexcretion. However, a significchelatable Pb #200 μg/24 hrs a

observed in the 39 participants evaluation with multiple linear revealed a ∃ = 0.034 (95% CI: No correlation noted between bNAG. Limitations = small sample sizinfluential outliers. 

Satarug et al. (2004) Bangkok, Thailand Study date not provided 

118 Thai adults (53 men, 65 women). Renal outcome measures noted below, also include BUN and total urinary protein. Serum creatinine

0.94 mg/dL (males) 0.66 mg/dL (females) Urinary NAG

4.4 U/g creatinine (males) 4.6 U/g creatinine (females) Urinary ∃2-microglobulin51 μg/g creatinine (males) 29 μg/g creatinine (females) 

Mean “serum” Pb

0.42 μg/dL (males) 0.3 μg/dL (females) Note – cannot determine from article if actually serum Pb (much less commonly used) or blood Pb. Mean urinary Pb

1.3 μg/g creatinine (males) 2.4 μg/g creatinine (females) Urinary cadmium also assessed. 

In men, urinary Pb excretion coprotein at borderline significanIn women, urinary Pb excretion (r = 0.5, p < 0.001), protein (r = ∃2-microglobulin (r = 0.36, p = 

After adjustment for urinary cabetween urinary Pb and NAG rThree urinary renal biomarkers cadmium, although only at borfor ∃2-microglobulin. 

Limitations = small sample sizonly urine Pb used in renal ana
 AX6-80 Table AX6-4.1 (cont’d). Renal Effects of Lead in the General Population Reference, Study Location, and Period Study Description Pb Measurement Findings, Inte

Asia (cont’d) Satarug et al. (2004) Bangkok, Thailand Study date not provided 96 Thai men. Subjects subdivided into nonsmokers (n = 53), current smokers (n = 27), and ex-smokers (n = 16). Renal outcome measures noted below, also include BUN and total urinary protein. Serum creatinine 0.94 mg/dL (nonsmokers) 0.93 mg/dL (smokers) 0.96 mg/dL (ex-smokers) Urinary NAG 4.4 U/g creatinine (nonsmokers) 

4.2 U/g creatinine (smokers) 3.8 U/g creatinine (ex-smokers) Urinary ∃2-microglobulin51 μg/g creatinine (nonsmokers) 95 μg/g creatinine (smokers) 98 μg/g creatinine (ex-smokers) 

Mean “serum” Pb

0.42 μg/dL (nonsmokers) 0.9 μg/dL (smokers) 0.61 μg/dL (ex-smokers) Mean urinary Pb

1.3 μg/g creatinine (nonsmokers) 1.4 μg/g creatinine (smokers) 1.4 μg/g creatinine (exsmokers) Urinary cadmium also assessed. 

Urinary Pb correlated with urinp < 0.01) in smokers and at bor(r = 0.22; p = 0.06) in never smwith ∃2-microglobulin in ex-sm

significance (r = 0.39; p = 0.06Urinary cadmium correlated wand never smokers and at bord(p = 0.07) in ex-smokers. Also protein and ∃2-microglobulin in 

borderline significance, in neveLimitations = small sample sizonly urine Pb used in renal ana

Middle East 

Mortada et al. (2004) Egypt Study date not provided 

68 Egyptian men (35 smokers, 33). Renal outcomes included serum creatinine, BUN, and ∃2- microglobulin and urinary albumin, NAG, ∃2-

microglobulin, alkaline phosphatase, and γ-glutamyl transferase. 

Mean blood Pb

14.4 μg/dL (smokers) 10.2 μg/dL (nonsmokers) Pb also measured in urine, hair, and nails. Also measured cadmium, and mercury. 

Blood and hair Pb levels signifcompared to nonsmokers. No significant differences in resmoking status. No correlation and renal outcome measures. Limitations: small sample sizeadjustment. 
 AX6-81 Table AX6-4.2. Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings

United States Smith et al. (1995) U.S. Study date not provided 691 construction workers. 96 participants with the ALAD2 allele. Mean blood Pb 7.8 μg/dL (ALAD11) 7.7 μg/dL (ALAD12 or 22) Higher mean BUN (p = 0

ALAD2 allele compared genotype. However, afteingestion, and blood Pb, tsignificant. Effect modif

Europe Bergdahl et al. (1997) Sweden Study date not provided 89 Pb workers; 7 had the ALAD2 allele. 34 controls; 10 had the ALAD2 allele. Median blood Pb 31.1 μg/dL in Pb workers with ALAD11 28.8 μg/dL in Pb workers with ALAD12 or 22 3.7 μg/dL in control workers with ALAD11 3.7 μg/dL in control workers 

with ALAD12 or 22 

Higher crude mean serum participants with the ALAwith the ALAD11 genoty
 AX6-82 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings

Europe (cont’d)C<rdenas et al. (1993) Belgium Study date not provided 

N = 41 Pb smelter workers, 41 controls (all males). Study started with 50 Pb smelter workers and 50 controls. Blood Pb level >35 

μg/dL and exposure >1 yr were required 

in exposed workers. Participants with renal disease, renal risk factors, such as diabetes or regular analgesic medication use, or urinary cadmium >2 

μg/g creatinine, were excluded. 

Multiple linear regression; adjusted for urinary creatinine and, in some cases, BMI. Serum creatinine1.02 mg/dL (workers) 1.03 mg/dL (controls) Battery of more than 20 renal biomarkers obtained including: RBP

68 μg/L (workers) 64 μg/L (controls) NAG

1.56 U/L (workers) 1.21 U/L (controls) 

Mean blood Pb

48.0 μg/dL (workers) 16.7 μg/dL (controls) Mean duration of Pb exposure = 14 yrs Urinary cadmium also measured as potential confounder. 

Serum creatinine was not compared to controls; assserum creatinine, if assesreported. In all 82, blood Pb: -associated with thrombo

-negatively associated wi

(∃ = !0.179, p < 0.01). Zinc protoporphyrin posiexcretion. NAG increased in Pb worcadmium. Limitations = sample sizebias, limited statistical an
 AX6-83 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, I

Europe (cont’d) Coratelli et al. (1988) Study location and date not provided; authors from Italy 20 Pb battery factory workers. 20 controls. 12 mo longitudinal study. Renal outcomes = urinary alanine aminopeptidase, NAG and lysozyme. Initial mean blood Pb 47.9 μg/dL (workers) 23.6 μg/dL (controls) NAG and lysozyme higher 

controls throughout study. decline in urinary NAG wa

one mo period of decreased Pb workers. NAG correlate(nonlinear) but not blood Pbmeasures were not studied. Fels et al. (1994) Study location and date not provided 81 male Pb workers; 45 age matched controls. Extensive exclusionary criteria. Renal outcomes Serum creatinine 

Glomerular markers = 6-keto-prostaglandin F1 alpha, 

thromboxane B2, and fibronectin. 

Proximal tubular markers = brush border antigens (BBA, BB50, HF5) and intestinal alkaline phosphatase. Distal nephron markers = prostaglandin E2, prostaglandin 

F2 alpha. 

Median blood Pb

42.1 μg/dL (workers) 7.0 μg/dL (controls) 

Serum creatinine similar in Medians of several markers compared to controls. Afteerythrocyte protoporphyrinshowed “some relation” to bdata shows r and r2 but not 

actual statistical method useStudy limitations include laanalysis, potential for health

Garçon et al. (2004) France Study date not provided 

35 male nonferrous metal smelter workers. Renal outcomes = α1-microprotein, ∃2-microglobulin, 

retinol binding protein, α and π glutathione S transferases 

(GST). Oxidative stress markers also measured. All variables log transformed. 

Mean blood Pb

39.6 μg/dL Mean blood cadmium

5.8 μg/L Mean urine cadmium

4.7 μg/g creatinine 

Correlations between urine outcomes assessed (not blooSignificant positive correlaturine Pb and α GST (p < 0.0

urine cadmium and RBP (p Also, urine cadmium and 8-Limitations = use of urine Pcovariates, sample size. Significant correlations betwmarkers of oxidative stress correlation between blood coxidative stress. 
 AX6-84 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Find

Europe (cont’d) Gennart et al. (1992) Study location and dates not provided; authors from Belgium 98 Pb workers and 85 controls from initial group of 221. Renal outcomes = urinary retinol-binding protein, ∃-2 microglobulin, albumin, NAG, and serum creatinine and 

∃-2 microglobulin and estimated creatinine clearance. 

Exclusionary criteria included lack of exposure to other metals or solvents, urinary cadmium <2 μg/g creatinine, neurologic or renal disease, certain medications, blood Pb level >40 μg/dL (workers) and <40 μg/dL for controls. 

Mean blood Pb

51 μg/dL (workers) 20.9 μg/dL (controls) Mean duration of employment10.6 yrs 

Mean renal outcocompared to contvalues was not grcontrols. An anaparticipants, by cemployment, ZPPacid showed no r

(data were not shLimitations incluadjustment only fpotential healthy 
 AX6-85 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Find

Europe (cont’d) Gerhardsson et al. (1992) Sweden Study date not provided 70 current Pb smelter workers. 30 retired Pb smelter workers. 31 active and 10 retired truck assembly workers (controls). Renal outcomes = serum creatinine, urinary ∃-2 microglobulin, NAG, and albumin, clearances of creatinine, albumin, relative albumin, ∃-2 microglobulin and relative ∃-2 microglobulin. Blood Pb measured annually since 1950; time integrated blood Pb index = summation of annual blood Pb measurements. Median blood Pb 31.9 μg/dL (current Pb workers) 9.9 μg/dL (retired Pb workers) 4.1 μg/dL (current control workers) 3.5 μg/dL (retired control workers) Median time integrated blood Pb index 369.9 μg/dL (current Pb workers) 1496.1 μg/dL (retired Pb workers) Median calcaneus Pb 48.6 μg/g bone mineral (current Pb workers) 

100.2 μg/g bone mineral (retired Pb workers) Median tibia Pb

13.0 μg/g bone mineral (current Pb workers) 39.3 μg/g bone mineral (retired Pb workers) 3.4 μg/g bone mineral (current control workers) 12.0 μg/g bone mineral (retired control workers) 

Creatinine clearap-values not repovalues between PIn current Pb wocorrelated with uintegrated blood NAG (data not shStrengths include inclusion of formLimitations = staby stratifying. 
 AX6-86 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Europe (cont’d) Pergande et al. (1994) Study location and date not provided; research team is German 82 male Pb workers. 44 age-matched healthy male volunteers without known exposure to Pb and living “in areas distant from the exposed people.” Renal outcomes = serum creatinine and ∃2 microglobulin, urinary albumin and 14 other early biological effect markers. Exclusion criteria included prescription medication use and many diseases; 11 workers and 3 controls excluded. Mean blood Pb 42.1 μg/dL (workers) 7.0 μg/dL (controls) Erythrocyte protoporphyrin also measured. Serum creatinine and ∃2 mi

exposed compared to controwith these outcomes not reperythrocyte protoporphyrin urinary renal outcomes. Study limitations include lastatistical analysis, potentiapotential for differences betgroups. Restek-Samaržija et al. (1996) 

Croatia Study date not provided 

74 patients treated between 1951 and 1989 for at least one episode of Pb poisoning (53 occupational, 23 environmental). Renal outcomes = measured creatinine clearance (collection time not specified), GFR assessed with 

99mTc-diethylenetriaminepenta-acetic acid (DTPA) 

clearance. 

Number of past Pb poisoninwith creatinine and DTPA c

Restek-Samaržija et al. (1997) Croatia Study date not provided 

38 patients with occupational Pb poisoning, 23 occupationally exposed workers. Renal outcomes = serum creatinine, measured creatinine clearance (collection time not specified), hippuran renal flow. 

Mean blood Pb

1.5 μmol/L (poisoned workers) 1.6 μmol/L (workers) 

Creatinine clearance signifigroup. 
 AX6-87 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Europe (cont’d) Roels et al. (1994) Belgium Study date not provided 76 Pb smelter workers (including 21 participants from Cardenas et al. [1993] [Dr. Roels, email communication]) 68 controls. All males. Matched for age, sex, socioeconomic status, residence, and workshift characteristics. Extensive exclusionary criteria included renal disease, analgesic abuse, chronic medication for gout, diabetes, occupational exposure to other nephrotoxicants, and prior EDTA chelation. Renal outcomes included serum creatinine and urea nitrogen, measured creatinine clearance, NAG, RBP, 

serum and urinary ∃2-microglobulin, as well as other renal 

early biological effect markers. Measured creatinine clearance

121.3 mL/min/1.73 m2 (workers) 

115.5 mL/min/1.73 m2 (controls) Multiple linear regression, adjusted for age, urinary cadmium, hypertension, serum gamma-glutamyl transpeptidase, smoking, exposure status (exposed vs. control), and interaction between exposure variables and hypertension. 

Mean blood Pb

43.0 μg/dL (workers) 14.1 μg/dL (controls) Mean tibia Pb66 μg/g bone mineral (workers) 21 μg/g bone mineral (controls) Urinary cadmium also measured. 

Creatinine clearance measuprotein load to determine if Cardenas et al. (1993) had c

protein ingestion causes inctransient hyperfiltration thochanges in vasodilator proshypothesized that, if the chaet al. (1993) were clinically hyperfiltration response woworkers.). All participants had normal clearances (>80 mL/min/1.7Pb-exposed workers showecreatinine clearance after prHowever, mean creatinine chigher in Pb workers compaPb was positively correlated creatinine clearance in the c(∃ = 0.0319, SE not provideThis was unexpected as the found in the initial study wovasodilatation with increasewas not possible to measure follow-up study. No other between Pb measures and robserved. Urinary cadmium 
 AX6-88 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Europe (cont’d) Verschoor et al. (1987) Study location and date not provided; authors from The Netherlands 155 Pb workers (Pb battery and plastic stabilizer). 126 control industrial workers. Workers with renal disease, HTN, prescription medications excluded. Renal outcomes = BUN, serum creatinine, uric acid, 

∃2-microglobulin, and RBP, and urinary RBP, NAG, 

albumin, uric acid, ∃2-microglobulin, IgG, and total 

protein. Urine protein electrophoresis performed on subset (n = 25). Cadmium in blood and, in a subset of exposed workers, in urine was also assessed due to this exposure in one plant each from which Pb exposed and control workers were drawn. 

Mean blood Pb

47.5 μg/dL (workers) 8.3 μg/dL (controls) Zinc protoporphyrin also used as Pb dose measure. 

Mean renal outcomes in all categorical Pb levels. NAG Pb levels >21 μg/dL compalevel (statistical significanc

microglobulin and urinary tPb levels >21 μg/dL compalevel (again, statistical signiIn simple linear regression urinary total protein, urinary 

microglobulin, higher log trsignificantly associated with 

microglobulin and higher RA matched pair analysis of within 5 yrs, smoking, socioduration of employment fououtcomes between exposed Limitations = lack of adjustworker bias, occupational c(including in controls) not a

Latin and South America 

Cardozo dos Santos et al. (1994) Study location and date not provided; authors from Brazil 

166 Pb battery workers. 60 control workers. Renal outcomes = serum creatinine, NAG, urine albumin, 

and total urinary protein, γ-glutamyl-transpeptidase, 

alanine-aminopeptidase. 

Median blood Pb

36.8 μg/dL (workers) 11.6 μg/dL (controls) 

Significant results. Median NAG higher in expBlood Pb level and duration with NAG in combined grocoefficients = 0.32 and 0.22

both). No results mentioned for seLimitations = statistical anarenal outcomes). 
 AX6-89 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Latin and South America (cont’d) Pinto de Almeida et al. (1987) Northeast Brazil Study date not provided 52 primary Pb smelter workers (had to have worked ≥ 5 yrs on production line). 44 control paper mill workers in same city. All males. Renal outcomes = BUN, serum creatinine, uric acid, proteinuria, creatinine clearance. Only 2 participants excluded for medical reasons. Mean blood Pb 64.1 μg/dL (workers) 25.5 μg/dL (controls) Also measured zinc protoporphyrin and delta- aminolevulinic acid Mean serum creatinine and 

than controls (1.23 vs. 1.1 m4.7 mg/dL; p < 0.001, respeSerum creatinine ∃1.5 mg/dworkers compared to only 2Serum creatinine correlated employment. Limitations = data analysis adjustment, several outcom

Australia Pollock and Ibels 

(1988) Harbor Bridge workers in Sydney, Australia Study date not provided 

38 bridge workers. Twenty-four h urine Pb excretion following 1 g of EDTA. Renal outcomes = serum creatinine, creatinine clearance, and 24 h urine protein excretion. 

Mean (range) blood Pb

34.8 (21.8 to 56.2) μg/dL (Pb intoxication) 19.9 (9.5 to 26.1) μg/dL (nontoxic) EDTA chelatable Pb range

443 to 2366 μg/24 hrs (Pb intoxication) 131 to 402 μg/24 hrs (nontoxic) 

No significant differences iexposure group. Two workhad evidence of Pb nephrop
 AX6-90 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Chia et al. (1994b) Study location not provided; authors from Singapore 1982-1992 (blood Pb measurements obtained every 6 mos over this time) 128 Pb workers. 152 control workers without Pb or cadmium exposure. Renal outcomes = total NAG, NAG-B isoenzyme (released with lysosomal breakdown assoc with cell membranes, thought to indicate proximal tubular cell toxicity), NAG-A (released by exocytosis). Cross-sectional outcomes but longitudinal exposure data. Median blood Pb 33.8 μg/dL (workers) 8.7 μg/dL (controls) Median cumulative blood Pb (mean of 3.6 blood Pb levels per worker) 208.3 μg·yr/dL Mean change in blood Pb (in 6 mos preceding NAG measurement) 5.8% NAG not different in expos

workers. After adjustment for race, rwas significantly associated (standardized partial regresfrom 0.31 for NAG-A to 0.6SE nor CI provided). In contrast, current blood Pwith NAG-A and NAG-B swith total NAG. Authors dinconsistencies. NAG not associated with cuStrengths = longitudinal expLimitations = data analysis 

Chia et al. (1994c) Singapore Study location not provided; authors from Singapore 1982-1992 (blood Pb measurements obtained every 6 mos over this time) 

63 Pb workers of >6 mos work duration (median = 3 yrs). 91 Pb workers of <6 mos work duration were considered controls. Renal outcomes = urinary BB-50 (brush border antigen in proximal tubule), total NAG, NAG-B isoenzyme, RBP, 

α1-microgobulin, albumin and urine and serum ∃2-

microglobulin. Cross-sectional outcomes but longitudinal exposure data. 

Pb dose measures 

(means or medians not stated) Most recent blood Pb, time integrated blood Pb index, relative % change in blood Pb, absolute change in blood Pb, number of times blood Pb level >40, 50, and 60 μg/dL. 

Urinary BB-50 higher in exhire “control” workers. Timnumber of times blood Pb >change in recent blood Pb wurinary BB-50. Strengths = longitudinal expLimitations = data analysis reported), clarity and adjust
 AX6-91 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings

Asia (cont’d) Chia et al. (1995a) Study location not provided; authors from Singapore 1982-1993 (blood Pb measurements obtained every 6 mos over this time) 137 Pb stabilizer workers. Control group of 153 postal workers (older than Pb workers). Renal outcomes = serum creatinine, four h creatinine clearance, serum ∃-2 microglobulin, serum α-1 microglobulin, urine albumin. Longitudinal blood Pb data (mean of 4.5 measurements per Pb worker). Pb dose measures (means or medians not stated) Most recent blood Pb, time integrated blood Pb index, relative % change in recent blood Pb, absolute change in recent blood Pb, number of times blood Pb level >40, 50, and 60 μg/dL. In analysis of covariance m

mean serum α-1 microglobusignificantly higher in contrSerum ∃-2 microglobulin wworkers ≥30 yrs of age. After adjustment for age, rafor abnormal values of serumicroglobulin were higher integrated blood Pb index in (PRR = 3.8 [95% CI: 1.1, 126.9], respectively). Strengths = longitudinal expLimitations = data analysis reported), clarity and adjust

Chia et al. (1995b) Study location not provided; authors from Singapore 1982-1993 (blood Pb measurements obtained every 6 mos over this time) 

128 Pb stabilizer factory workers. 93 unexposed control subjects (evaluated at preemployment examination; all quit within 1 mo of hire). Blood and urinary cadmium also measured on random subset (40 controls and 31 Pb workers). Renal outcomes = serum ∃-2 microglobulin and urinary α1 microglobulin, ∃-2 microglobulin, albumin, RBP. 

Mean recent blood Pb

32.6 μg/dL (workers) 9.0 μg/dL (controls) Mean time integrated blood 

Pb index

119.9 μg/dL 

Η yr (workers) 

0.05 μg/dL 

Η yr (controls) 

Mean relative change in 

recent blood Pb28.2 % (workers) Mean absolute change in recent blood Pb6.4 μg/dL/yr (workers) Number of times blood Pb level >40, 50 and 60 μg/dL 

Only urinary α-1 microglobworkers compared to controIn multiple linear regression ethnicity and smoking, at lesignificantly associated with Outcome Pb measU 

α-1 MG cum. blo

U 

α-1 MG # blood P

U ∃-2 MG cum. bloU RBP # blood S ∃-2 MG # blood PU Alb # blood Cadmium dose measures remodels (although power wocadmium measured only in Strengths = longitudinal expLimitations = data analysis in populations between this 
 AX6-92 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings

Asia (cont’d) Endo et al. (1990) Study location not provided; authors from Japan 1987 39 male workers. 7 female workers (none directly exposed to Pb). Secondary Pb refinery, mean job duration = 10.5 yrs Renal outcomes = BUN, serum creatinine and uric acid, urinary NAG, and tubular reabsorption of phosphate. Mean blood Pb Ranged from 24.1 to 67.6 μg/dL (males) 19.6 μg/dL (females) Other Pb measures included urinary Pb, delta- aminolevulinic acid, and coproporphyrin. Significant correlations of b

acid with BUN and NAG wbetween blood Pb and NAG number of workers whose b80 μg/dL. Limitations include absence analysis, small sample size. Endo et al. (1993) Study location and date not provided; authors from Japan 99 male Pb workers. Renal outcomes = serum creatinine and serum and urine alpha-1-microglobulin. Median blood Pb Ranged from 7.9 μg/dL in category I consisting of 16 office workers who did not work directly with Pb to 

76.2 μg/dL in 16 workers in the highest exposure group (category V). 

Median urinary alpha-1-miccategories III–V compared office workers. This was alsignificantly correlated with correlation). After alpha-1-microglobulin (by stratifying); few significanalysis approach resulted i
 AX6-93 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Hsiao et al. (2001) Taiwan, PR China 1991-1998 30 Pb battery workers. Mean serum creatinine at baseline ~ 1.0 mg/dL (based on figure; exact values not provided) Longitudinal Analysis, 8 annual evaluations. Generalized estimating equations used to adjust for autocorrelation in multiple datapoints from each participant. Adjusted for age, gender, and, in models of change in serum creatinine, creatinine at beginning of interval. Mean blood Pb at baseline ~35 μg/dL (based on figure; exact values not provided) Mean duration of exposure at baseline 13.1 yrs Cross-sectional higher blood Pb associated 

serum creatinine. Longitudinal Change in blood Pb negativ

concurrent change in serum Blood Pb at the beginning owith change in serum creatiAssociations may represent However, as noted by the aumay also be a factor. Mean just before renal data collecinverse longitudinal associapersistently elevated cumulunmeasured but, as evidencbone Pb, likely did not declHowever, authors did not mor analyze effect modificatiexposure duration to determchanged in a pattern consistThe small sample size also be drawn from these results individuals may be overly iStrengths = longitudinal datLimitations = data analysis reported), clarity and adjust
 AX6-94 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Huang et al. (1988) Beijing, China Study date not provided 40 Pb workers (4 women). Control group not described. Renal outcomes = serum beta-2-microglobulin and urinary beta-2-microglobulin, total protein, IgG. Geometric mean blood Pb 40 μg/dL Increased urinary ∃2 microg

compared to controls. Multiple limitations includicontrol group, data analysis

Jung et al. (1998) Korea Study date not provided 75 randomly selected male Pb workers. 64 male office workers (controls). Renal outcomes = BUN, serum creatinine, uric acid and urinary NAG, albumin, 

α1 microglobulin and ∃2 

microglobulin. 

Mean blood Pb

Means ranged from 24.3 to 74.6 μg/dL (workers) 7.9 μg/dL (controls) Other Pb measures included zinc protoporphyrin, δ-aminolevulinic acid activity and urinary Pb, coproporphyrin, and δ-aminolevulinic acid. 

Blood Pb, zinc protoporphy

aminolevulinic acid significNAG, and 

α1 microglobulin 

group analysis). Limitation = statistical anal

Konishi, et al. (1994) Study location not provided; research team from Japan 1991 

99 male Pb workers, including 16 office workers to serve at controls. renal outcomes = fractional clearances of 

α1 microglobulin 

and ∃2 microglobulin (utilizing serum and urinary levels of 

both biomarkers), BUN, serum creatinine, uric acid and 

urinary NAG. 

Median blood Pb

Range from 7.9 μg/dL in controls to 76.2 μg/dL in Category V 

Urinary NAG, 

α1 microglob

clearance of 

α1 microglobul

blood Pb category. Spearmafractional clearance of 

α1 m

was significant. This relatiolinear regression with adjusindependent variables were with the fractional clearanc

Limitation = statistical anal
 AX6-95 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Kumar and Krishnaswamy (1995) India Study date not provided 22 auto mechanics volunteers. 27 male control workers (from Institute performing study). Renal outcomes = serum creatinine, 4 h creatinine clearance and urinary NAG and ∃-2 microglobulin. Renal disease, diabetes, HTN and occupational exposures excluded in controls, possibly excluded in workers. Blood Pb range 24.3-62.4 μg/dL (exposed) 19.4-30.6 μg/dL (controls) Urinary NAG and ∃2 micro

significantly higher in expoHowever, only NAG was siblood Pb (r = 0.58, p < 0.01Limitations = study size and analysis, values for 4 h creaabnormal low range in both 

Lim et al. (2001) Singapore 1999 Blood Pb levels every 6 mos from 1982 to 1999 

55 male Pb workers. Workers followed since 1982, many of same workers as in Chia et al. (1995b). Renal outcomes = 4 h creatinine clearance and urinary albumin, RBP, 

α1 microglobulin, ∃2 microglobulin, NAG, 

NAG-A, and NAG-B. Exclusionary criteria included diabetes, HTN, recent ingestion of analgesics, antipyretics, or antibiotics, and thalassemia; 24 participants of the original 80 were excluded as a result. One female also excluded. 

Mean current blood Pb

24.1 μg/dL Cumulative blood index880.6 μg 

Η yrs/dL (geometric 

mean) Number of times blood Pb

exceeded 40 μg/dL

1.9 (geometric mean) 

In separate models, after adsmoking, higher categorical and number of times blood associated with lower creatiAfter adjustment, higher nuexceeded 40 μg/dL was assalbumin, 

α1 microglobulin, 

Similarly, cumulative blood higher urinary albumin, 

α1 m

microglobulin. No associations between rethe renal outcomes was obsAnalysis of covariance was and age. Limitation = statistical analsmall sample size, potential 
 AX6-96 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Ong et al. (1987) Singapore and Japan Study date not provided 209 Pb workers (51 females). 30 control workers from research staff. Renal outcomes = BUN, serum creatinine, calculated creatinine clearance, and urinary NAG. Mean blood Pb 42.1 μg/dL (males) 31.9 μg/dL (females) Urine Pb also measured. Blood Pb correlated with B

serum creatinine (r = 0.26; p clearance (r = 

−0.16; p < 0.

with NAG after adjustment specified). Higher NAG in exposed costratified by categorical ageStrengths = sample size. Limitations = statistical anaurinary NAG not adjusted f

Wang et al. (2002b) Taiwan Study date not provided 

229 Pb battery workers, including 109 females. Renal outcomes = BUN, serum creatinine, serum uric acid. Multiple linear & logistic regression. Adjustment for age, gender, smoking, alcohol ingestion, milk ingestion. 

Mean blood Pb67.7 μg/dL (males) 48.6 μg/dL (females) 

∃ (95% CI) for blood Pb in adjustment for Pb job durat(0.042, 0.082). ∃ (95% CI) for blood Pb in adjustment for gender and w(0.001, 0.016). Blood Pb not associated ser
 AX6-97 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Weaver et al. (2003a) South Korea 1997-1999 803 Pb workers including 164 females and 94 former Pb workers. Serum creatinine 0.90 mg/dL Calculated creatinine clearance 94.7 mL/min 4-hr measured creatinine clearance 114.7 mL/min RBP 63.6 μg/g creatinine NAG

215.3 

μmol/h/g creatinine 

Multiple linear regression, adjusting for age, gender, BMI, work status (current vs. former worker), HTN or blood pressure (depending on model), and, for the EBE markers, alcohol ingestion and diabetes. 42 associations modeled (7 Pb measures with 6 renal outcomes). Interaction models that assessed effect modification by age in tertiles in 24 associations (4 Pb exposure/dose measures with 6 renal outcomes). 

Mean blood Pb

32.0 μg/dL Mean tibia Pb37.2 

μg/g bone mineral 

Mean DMSA-chelatable Pb767.8 

μg/g creatinine 

Pb exposure also assessed with job duration and three hematologic measures as surrogates for Pb dose (aminolevulinic acid in plasma, zinc protoporphyrin, and hemoglobin). Mean urinary cadmium

measured in 

subset (n = 191)

1.1 μg/g creatinine 

After adjustment, higher Pb worse renal function in 9 of Associations in the opposite measures associated with lohigher creatinine clearancesOpposite direction (inversein models of the clinical ouassociations between higher function were predominantlmodels. In three of 16 clinical renal associations between higher renal function in participantwere significantly different in the youngest age tertile wdirection. - This pattern was observed (p < 0.1) in 3 other models. - Pattern was not observed iUrinary cadmium associateAuthors concluded that occthe moderate dose range ha

function. Inverse associatiohyperfiltration. Environmen

adverse impact, at least on N
 AX6-98 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Weaver et al. (2003b) Korea Pb workers 1997-1999 798 Pb workers with genotype information in same population as in Weaver et al. (2003a). 79 (9.9%) participants were heterozygous for the ALAD2 allele (none was homozygous). 89 (11.2%) had VDR genotype Bb or BB. Mean blood Pb 31.7 μg/dL (ALAD11) 34.2 μg/dL (ALAD12) 31.6 μg/dL (VDR bb) 34.8 μg/dL (VDR Bb or BB) Mean tibia Pb 37.5 

μg/g (ALAD11) 

31.4 μg/g (ALAD12) 37.1 μg/g (VDR bb) 38.1 μg/g (VDR Bb or BB) 

Data were analyzed to deter

polymorphisms in the geneacid dehydratase (ALAD), synthase (eNOS), and the vwere associated with renal orelations of Pb exposure anoutcomes. After adjustment, participanhad lower mean serum creacreatinine clearance. Effect associations between blood chelatable Pb and three of sobserved. Among those wihigher Pb measures were asand serum creatinine and hiclearance. No significant differences wby VDR genotype nor was modification observed. 
 AX6-99 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, I

Asia (cont’d) Weaver et al. (2005a) Korea 1997-1999 803 current and former Pb workers; 164 females. Serum Uric acid 4.8 mg/dL Other renal outcomes as listed in Weaver et al., 2003a. Multiple linear regression. Interaction models that assessed effect modification by age in tertiles. Mean blood Pb 32.0 μg/dL Mean tibia Pb 37.2 (40.4) μg/g bone mineral Mean DMSA- chelatable Pb 767.8 μg/g creatinine Work to address whether one mec

nephrotoxicity, even at current lowincreasing serum uric acid. Assesassociated with uric acid and 2) wassociations between Pb dose and 2003) were altered after adjustmeAfter adjustment for age, gender, Pb biomarkers not associated with However, in interaction models, bsignificantly associated in particip(∃ = 0.0111 [95% CI: 0.003, 0.01blood and tibia Pb, respectively). for blood pressure and renal functdysfunction are known to increase risks associated with Pb exposurevariables in models of associationlikely results in over-control. On 

factors contribute to both renal dypressure, lack of adjustment likely Therefore, as expected, associatiodecreased after adjustment for syscreatinine, although blood Pb remassociated (∃ = 0.0071 [95% CI: population was restricted to the olcreatinine greater than the median risk segment of the population, blassociated with uric acid even aftepressure and serum creatinine (∃ = Next, in models of renal function significantly (p < 0.05) associated NAG. In models in the oldest tertile of w51.1 yrs, range 46.0 to 64.8 yrs), aassociations between Pb dose and of the previously significant (p # 0dose and the clinical renal outcomremained significant. 
 AX6-100 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Weaver et al. (2005b) South Korea 1999-2001 652 Pb workers including 149 females and 200 former workers. Patella Pb measured in the third evaluation of the same study reported in Weaver et al. (2003a). Data collection performed a mean of 2.2 yrs after collection of the data presented in Weaver et al. (2003a). Same renal outcomes as Weaver et al. (2003a). Serum creatinine 0.87 mg/dL Calculated creatinine clearance 97.0 mL/min Multiple linear regression, adjusting for age, gender, BMI, 

work status (current vs. former worker), HTN or blood pressure (depending on model), diabetes, smoking status, and, for the clinical measures, use of analgesics Interaction models assessed effect modification by age, dichotomized at the 67th percentile. 

Mean blood Pb

30.9 μg/dL Mean tibia Pb33.6 μg/g bone mineral Mean patella Pb

75.1 μg/g bone mineral Mean DMSA-chelatable Pb

0.63 

μg Pb/mg creatinine 

All 4 Pb measures were cor0.76). Patella, blood and DMSA-cassociated with NAG. Higher DMSA-chelatable Pcreatinine and higher calculInteraction models All four Pb measures assocparticipants in oldest age teHigher blood, tibia, and patserum creatinine among old-Beta coefficients less in ththe younger two-thirds of thslopes in the two age groupfor association of blood Pb Inverse DMSA associations associated with lower serum creatinine clearance) signifiPatella Pb associations were tibia Pb; DMSA-chelatable Authors hypothesized that sand tibia Pb associations cocorrelations among the Pb bDespite similar high correlaassociations with serum creclearance were unique. Thifunction and the collection amount of Pb that is excreteafter chelation may be influburden, but also by high-noglomerular filtration which workers. 
 AX6-101 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Weaver et al. (2005c) Korea 1997-1999 798 current and former Pb workers. Same population as in Weaver et al. (2003a,b). Data were analyzed to deter

polymorphisms in the geneacid dehydratase (ALAD), synthase (eNOS), and the vwere associated with uric acPb exposure and dose measUric acid not different by AAmong older workers (age ALAD genotype modified adose and uric acid levels. Hsignificantly associated with workers with the ALAD11 in the opposite direction in ALAD12 genotype. 

Ye et al. (2003) Chinese Pb workers Study date not provided 

216 Pb workers. Renal outcomes = urinary NAG and albumin. 

Geometric mean blood Pb 37.8 

μg/dL (n = 14 workers 

with the ALAD12 genotype) 

32.4 

μg/dL (n = 212 workers 

with the ALAD11 genotype) 31.9 μg/dL (VDR bb) 41.7 μg/dL (in 20 participants with VDR Bb or BB) 

After adjustment for age, Nin those with the ALAD varlevels were ≥40 

μg/dL (p = 

after adjustment for age, geingestion, a statistically signbetween blood Pb and creatobserved in the workers witbut not in Pb workers with tgroups were analyzed separinteraction model). No effect modification by Vassociations between blood and NAG observed (separat
 AX6-102 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Middle East Al-Neamy et al. (2001) United Arab Emirates Feb-June, 1999 100 “industrial” workers exposed in a range of industries 100 working controls. Matched for age, sex, and nationality. Renal outcomes = BUN, serum creatinine. Mean blood Pb 77.5 μg/dL (workers) 19.8 μg/dL (controls) Mean BUN and serum cre

different between exposed Limitations = data analysi

Ehrlich et al. (1998) South Africa Study date not provided 382 Pb battery factory workers. Mean age = 41.2 yrs. All males. 

Multiple linear regression adjusted for age, weight, and height (Covariates assessed for inclusion also included smoking, alcohol ingestion, and diabetes). Clinical renal outcomes included serum creatinine, uric acid, and BUN. Mean serum creatinine

1.13 mg/dL Renal early biological effect markers (NAG, RBP, intestinal alkaline phosphatase, tissue nonspecific alkaline phosphatase, Tamm-Horsfall glycoprotein, epidermal growth factor, and microalbuminuria) were measured in 199 participants randomly selected by tertiles of current blood Pb. 

Mean blood Pb

53.5 μg/dL Mean exposure duration

11.6 yrs Mean cumulative blood Pb(defined as sum of the avg blood Pb in each yr over all yrs of employment; done in subset of 246 with past blood Pb data)579.0 (μg 

Η yr)/dL 

Mean historical blood Pb

(defined as cumulative blood Pb divided by yrs of exposure) 57.3 μg/dL Mean tibia Pb

69.7 

μg/g bone mineral 

(measured 2 yrs after initial study on random sample of 40) 

After adjustment for age, wcategorical current and hisprotoporphyrin were assocand uric acid, in separate mbetween cumulative blood and the renal outcomes weAmong the EBE markers, borderline associated with Associations with renal dyblood Pb levels <40 

μg/dL

effect on blood pressure siassociated with blood presmeasured in 56 participanstudy. All low (#1.2 

μg/L

occupational level cadmiucontributing factor. The abody burden, which was stibia Pb. However, cumulassociated in this study anet al. (1994) was similar (iassociation with creatinine 
 AX6-103 Table AX6-4.2 (cont’d). Renal Effects of Lead in the Occupational Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Middle East (cont’d) El-Safty et al. (2004) Egypt Study date not provided 45 Pb workers with Pb job duration <20 yrs. 36 Pb workers with Pb job duration ≥20 yrs. 75 control workers. Renal outcomes = urinary 

α1-microglobulin, NAG, and 

glutathione S-transferase. 

Median urine Pb

Ranged from 15.4 μg/g creatinine in nonsmoking control workers to 250.4 μg/g creatinine in smoking Pb workers with ∃20 yrs Pb job 

duration. 

Medians of all 3 renal outcin Pb workers regardless ostratified by smoking statuUrine Pb significantly cor

microglobulin and glutathnonsmoking Pb workers asmoking Pb workers. Limitations include using measure and data analysis

Mortada et al. (2001) Egypt Study date not provided 

43 traffic policemen. 52 matched control office workers (similar in terms of age, gender, smoking, and “social life”). Renal outcomes = serum creatinine, beta-2 microglobulin, BUN and urinary ∃-2- microglobulin, NAG, alkaline phosphatase, γ-glutamyl transferase, and albumin. Exclusionary criteria included diabetes, HTN, hepatic, renal or urologic diseases. 

Mean blood Pb

32.1 μg/dL (exposed) 12.4 μg/dL (controls) Pb also measured in hair, urine and nails. 

NAG and albumin significcompared to controls. NA(Pearson’s) with job duratUrinary albumin positively duration and blood and haLimitations: data analysis parametric correlation techbe nonparametric; study si
 AX6-104 Table AX6-4.3. Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, 

United States Osterloh et al. (1989) Northern CA Study date not provided 40 male subjects with hypertensive nephropathy (hypertension preceded renal insufficiency; serum creatinine 1.8-4 mg/dL). 24 controls with renal dysfunction from other causes. Patients recruited from the Kaiser Permanente Regional Laboratory database (large health maintenance organization) in northern California. Mean blood Pb 7.3 μg/dL (in both hypertensive nephropathy and controls CRI from other causes) Mean EDTA chelatable Pb levels 153.3 μg/72 hrs (hypertensive nephropathy) 126.4 μg/72 hrs (control CRI) No significant difference i

levels; highest chelatable P609.2 μg/72 hrs. Pb dose and serum creatinBlood and chelatable Pb lereported by Wedeen et al. Sanchez-Fructuoso et al. (Only 17% of their study papossible Pb exposure basemuch lower than the two o

Steenland et al. (1990) Michigan Diagnosis from 1976-1984 

325 men with ESRD (diabetes, congenital and obstructive nephropathies excluded). Controls by random digit dialing, matched by age, race, and place of residence. 

Risk of ESRD significantlalcohol consumption (OR analgesic consumption, famdisease, and occupational esolvents. 

Europe 

Behringer et al. (1986) Germany Study date not provided 

16 patients with CRI (median serum creatinine = 2.2 mg/dL) and gout. 19 patients with CRI (median serum creatinine = 5.1 mg/dL) without gout. 21 healthy controls. Pb excretion in the 96 hrs after administration of 1 g EDTA iv. 

Median blood Pb

7.2 μg/dL (controls) 11.5 μg/dL (CRI, no gout) 15.3 μg/dL (CRI & gout) Median EDTA chelatable Pb(μg/4 days/1.73 m2

)

63.4 (controls) 175.9 (CRI, no gout) 261.3 (CRI & gout) 

EDTA chelatable Pb highedeveloped gout after CRI tpreceded CRI (statistical teshown). Authors conclude with gout occurring in settcontributes to renal functiorenal disease from other caLimitations = small group
 AX6-105 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, I

Europe (cont’d) Colleoni and D’Amico (1986) Italy (~1982-1985) 12 consecutive patients with CRI (mean serum creatinine = 3.3 mg/dL) and gout, renal diagnosis consistent with chronic interstitial nephritis in all; 7 had history of occupational Pb exposure. 12 controls with chronic glomerulonephritis and no history of Pb exposure or gout. Pb excretion in the 48 hrs after administration of 1.5 g EDTA im. Mean EDTA chelatable Pb (μg/48 hrs) 180 (CRI, no gout) 505 (CRI & gout) Significantly higher EDT

group with CRI and gout EDTA chelatable Pb signserum creatinine in patiennot CRI alone. Authors cCRI with gout but renal iresponsible for increased of evidence for reverse caLimitations = small sampanalysis. Colleoni et al. (1993) Italy Study date not 

provided 

All 115 patients on hemodialysis at the time of the study; 41 women. Blood Pb data from prior study of 383 healthy controls in same geographical area served as comparison. 

Mean blood Pb

(corrected for hemoglobin)

19.9 μg/dL (patients) 14.7 μg/dL (controls) 

Significantly higher mean patients compared to healblood Pb levels >30 μg/dassociated with duration olevels higher in smokers ingestion. Pb not detectaLimited data analysis. 

Craswell et al. (1987) Germany and Australia Study date not provided 

See discussion below under Australia. 
 AX6-106 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, I

Europe (cont’d) Fontanellas et al. (2002) Spain Study date not provided ALAD/restored ALAD as a possible index of Pb poisoning in chronic renal failure patients. Restored ALAD was mea

zinc and dithiothreitol (Dmedia. The ALAD/restored ALAcorrelate with the results mobilization test. Patient3860 μg Pb per 72 hrs hachronic renal failure patie322 μg Pb (range 195 to 3In comparison, normal co

Jones et al. (1990) Study location and date not provided; authors from UK 

27 dialysis patients. 59 healthy controls. 

Mean blood Pb

8.1 μg/dL (patients) 10.0 μg/dL (controls) 

Tibia Pb levels not correlcorrelated with Pb in bon(r = 0.42). Limitations = data analys

Koster et al. (1989) Study location and date not provided; authors from Germany 

91 patients with CRI (median serum creatinine = 2.5 mg/dL). 46 age-matched normal controls. Pb excretion in the 4 days after 1 g EDTA iv. 

Mean blood Pb

(corrected for hemoglobin)

11.2 μg/dL (patients) 7.6 μg/dL (controls) Mean EDTA chelatable Pb

164.7 μg/4 days /1.73 m2 (patients) 63.6 μg/4 days /1.73 m2 (controls) 

CRI patients had significaEDTA chelatable Pb levethe CRI patients, EDTA chighest value in controls chelatable Pb levels were creatinine in patients (r = Limitations = data analys
 AX6-107 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, 

Europe (cont’d) Miranda-Carús et al. (1997) Spain 1990-1994 27 patients with gout and CRI. 50 patients with gout only. 26 controls with normal renal function and no gout. Multiple purine metabolism measures including serum urate, hypoxanthine, and xanthine, as well as their excretion, clearance and fractional excretion measures. Mean blood Pb 17.8 μg/dL (gout and CRI) 14.9 μg/dL (gout only) 12.4 μg/dL (controls) Mean EDTA chelatable Pb 845 μg/120 hrs (gout and CRI) 342 μg/120 hrs (gout only) 215 μg/120 hrs (controls) Pb dose measures significa

gout and CRI compared to EDTA chelatable Pb invercreatinine clearance. Each were dichotomized by ED600 

μg/120 hrs, resulting i

from 6 to 14) and one grougout and EDTA chelatable significant differences in mmeasures were observed. correlations between EDTpurine measures were assesmall groups were combinlack of power may be one with Lin’s work. Differenfactor as well. Uric acid parameters were chelation in 6 participants above 600 μg/120 hrs. Agmay be a factor but the smdetails on the group make 

Nuyts et al. (1995) Belgium Study date not provided 

Case-control study. 272 cases with chronic renal failure (all types) matched to 272 controls by age, sex and residence. Exposure assessed by 3 industrial hygienists blinded to 

case or control status. 

Significantly increased odfailure with Pb exposure (O4.36]) as well as several otwith diabetic nephropathy
 AX6-108 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Europe (cont’d) Sánchez-Fructuoso et al. (1996) Spain Study date not provided 296 patients: Group I = 30 normal control subjects Group II = 104 patients with essential HTN & normal renal function Group III-A = 68 patients with HTN and CRI of uncertain etiology but presumed nephroangiosclerosis Group III-B = 64 patients with HTN, CRI, and gout Group IV = 30 patients with CRI of known etiology Mean blood and EDTA- chelatable Pb levels Group I 16.7 μg/dL 324 μg/72 hrs Group II 16.8 μg/dL 487 μg/72 hrs Group III-A 18.5 μg/dL 678 μg/72 hrs Group III-B

21.1 μg/dL 1290 μg/72 hrs Group IV

16.5 μg/dL 321 μg/72 hrs 

EDTA chelatable Pb >600 group II, 30 patients in grogroup III-B, but no patientMean blood and EDTA chpatients with CRI of knowstatistically different from 

function. However, baselilower in group IV. This pregarding the “reverse cauincreased Pb burden due to CRI. Significant correlations no(assessed by biopsy) and E12 patients whose chelatabμg/72 hrs; provides supporPb levels in CRI. A positive correlation was creatinine levels and EDTA>600 μg/72 hrs but not belIn group III, mean measursignificantly lower in thoslevels >600 

μg/72 hrs com

chelatable Pb <600 

μg/72 
 AX6-109 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Europe (cont’d) Van de Vyver et al. (1988) Belgium, France and Germany Study date not provided Transiliac bone biopsies obtained from: 11 cadavers without known Pb exposure and with normal renal function 13 patients with CRI, gout and/or HTN 22 Pb workers 153 dialysis patients Mean transiliac Pb levels 5.5 μg/g (153 dialysis pts) 20.6 μg/g (in highest 5% dialysis pts) 3.7 μg/g (in 10 pts on dialysis due to analgesic nephropathy) 6.3 μg/g (11 cadavers) 30.1 μg/g (22 Pb workers) In 5% of the hemodialysis 

concentrations approximatactive Pb workers, suggestof their renal failure. Leveanalgesic nephropathy werevidence against reverse cIn the combined group of and/or HTN and 22 Pb wocorrelated with Pb in bone 

Winterberg et al. (1991) Study location and date not provided; authors from Germany 

Iliac crest bone Pb measured by biopsy in: 8 controls 8 patients with CRI 14 dialysis patients 

Mean iliac crest bone Pb levels

1.63 μg/g (8 controls) 2.18 μg/g (8 patients with CRI) 3.59 μg/g (in 14 dialysis pts) 

Noted that the bone Pb levanalgesic nephropathy and Vyver et al. (1988) were mgroups of other researcherconcern that Pb did accumexcretion. 

Latin and South America

Navarro et al. (1992) Venezuela Study date not provided 

18 dialysis patients. 14 controls. Bone (biopsy) and blood levels of Pb and several other metals. 

Mean blood Pb

5.2 μg/dL (patients) 11.5 μg/dL (controls) Mean Pb in bone

9.7 μg/g (patients) 7.0 μg/g (controls) 

Blood but not bone Pb signcompared to controls. Autaccumulation of aluminumnot Pb, occurred in dialysiLimitations = sample size, lack of adjustment. 
 AX6-110 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Australia Craswell et al. (1987) Germany and Australia Study date not provided German participants from industrialized area where chronic Pb nephropathy not previously observed. Gp 1 = 8 healthy controls (from hospital staff) Gp 2a = 12 CRI patients, no gout or Pb exposure Gp 2b = 7 CRI patients, no gout but + Pb exposure Gp 3a = 7 CRI patients with gout but no Pb exposure Gp 3b = 6 CRI patients with gout and Pb exposure Australian participants from Queensland site of known chronic Pb nephropathy. Gp 1 = 9 healthy controls (from hospital staff) Gp 2a = 14 CRI patients, no gout or Pb exposure Gp 2b = 11 CRI patients, no gout but + Pb exposure Gp 3a = 25 CRI patients with gout but no Pb exposure Gp 3b = 11 CRI patients with gout and Pb exposure CRI defined as serum creatinine ≥ 1.5 mg/dL 

“Excess” EDTA chelatable Pb defined as Pb excreted over 4 days after EDTA minus twice baseline Pb excreted preEDTA. 

Median blood Pb (hemoglobin 

corrected)

Gp 1

German = 6.8 μg/dL Australian = 11.0 μg/dL Gp 2a

German = 6.2 μg/dL Australian = 9.1 μg/dL Gp 2b

German = 8.5 μg/dL Australian = 16.2 μg/dL Gp 3a

German = 10.6 μg/dL Australian = 12.8 μg/dL Gp 3b

German = 12.0 μg/dL Australian = 27.1 μg/dL Median “excess” EDTA 

chelatable PbGp 1

German = 68.4 μg Australian =82.9 μg Gp 2a

German = 126.4 μg Australian = 393.7 μg Gp 2b

German = 489.0 μg Australian = 1181.1 μg Gp 3a

German = 227.9 μg Australian = 808.1 μg Gp 3b

German = 422.7 μg Australian = 1077.5 μg 

Using nonparametric statisskewed data, German partistatistically less Pb than thMean EDTA chelatable Pb higher in German patients without gout; the observed patients was of borderline Limitations = small group
 AX6-111 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Australia (cont’d) Price et al. (1992) Queensland, Australia 1981-1986 8 renal patients compared with age-matched controls. X-ray fluorescence of finger bone Pb conducted twice 5 yrs apart. Authors conclude that Pb i

renal patients compared to Study limitations substantiLimitations = small numbemeasured in more patientsof detection, inclusion of o

statistical analysis. Asia Lin and Lim (1992) Chinese population (likely in Taiwan) Study date not 

provided 

10 healthy controls. 10 patients with CRI but no gout. 8 patients with gout and subsequent CRI. 6 patients with CRI and subsequent gout. Exclusionary criteria included + history of occupational or environmental Pb exposure. 

Mean EDTA chelatable Pb in 

μg/72 hrs/1.73 m2

90.2 (controls) 98 (CRI, no gout) 171.6 (gout, then CRI) 359.8 (CRI, then gout) 

Pb body burden higher in pespecially when CRI preceLimitations = small sampl

Lin and Huang (1994) Taiwan Study date not provided 

Group 1 = 10 patients with normal renal function and no gout; Group 2 = 10 patients with CRI (serum creatinine >1.4 mg/dL) and subsequent gout; Group 3 = 20 patients with CRI but no gout. All males. Pb body burden assessed with 1 g EDTA iv followed by 72 hr urine collection. 

Mean EDTA chelatable Pb

Gp 1 = 60.55 μg/ 72 hrs Gp 2 = 252.24 μg/ 72 hrs Gp 3 = 84.86 μg/ 72 hrs 

Mean EDTA chelatable Pb significantly higher in the adjustment for creatinine cEDTA chelatable Pb was sserum urate levels (∃ = 0.7p < 0.05), daily urate excre

!118.1, !2.16]; p < 0.05), u

[95% CI: !1.34, !0.282]; p urate excretion (∃ = !1.535 p < 0.05). EDTA chelatabcreatinine clearance. Limitations = small samplin regression analyses. 
 AX6-112 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Lin and Lim (1994) Taiwan Study date not provided Gp 1 = 12 healthy controls. Gp 2 = 10 patients with HTN. Gp 3 = 12 patients with HTN, then CRI (hypertensive nephropathy). Gp 4 = 12 patients with CRI only. Gp 5 = 12 patients with CRI not due to HTN, but subsequent HTN. Mean EDTA chelatable Pb Gp 1 = 76.6 μg/72 hrs Gp 2 = 67.96 μg/72 hrs Gp 3 = 182.9 μg/72 hrs Gp 3 = 84.46 μg/72 hrs Gp 3 = 92.86 μg/72 hrs Higher mean EDTA chela

5 of 12 had history of gout Limitations = small sampl

Lin et al. (1999) Taiwan Study date not provided 32 patients selected from 102 patients with serum creatinine from 1.5–4.0 mg/dL who were followed in the Institution’s outpatient clinics. Eligibility criteria included serum creatinine from 1.5 – 4.0 mg/dL, stable renal function over 6 mos before study entry; controlled blood pressure and cholesterol; daily 

protein intake <1 g/kg body wt; no known history of exposure to Pb or other heavy metals and EDTA chelatable Pb >150 but <600 

μg/72 h. 

Exclusionary criteria included potentially reversible or unstable renal disease (i.e., due to systemic diseases such as lupus and diabetes), and nephrotoxicant medications. Patients divided into 16 patients receiving 1 g EDTA i.v. weekly for two mos and a control group of 16 patients who received no therapy. 

Mean EDTA chelatable Pb

levels pre-chelation

254.9 

μg/72 hrs in group 

receiving subsequent chelation279.7 

μg/72 hrs in control 

group Blood Pb levels not mentioned. 

Rates of progression of renfollowed by reciprocal of s12 mos prior to therapy antherapy. Rates of progresswere similar in the treatmegroup during the baseline improvement in renal funcEDTA chelation. Followinstabilized in the treated groin the control group. At 12 mean difference in the chaserum creatinine between t0.000042 L/

μmol per mo (

0.00007). Results using a patients lost to follow-up (gave similar results. 
 AX6-113 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Lin et al. (2001a) Taiwan Study date not provided 24 mo prospective observational study 110 patients with CRI dichotomized by EDTA chelatable Pb level of 80 μg/72 hrs into two groups of 55 each. Eligibility criteria included serum creatinine from 1.5 – 4.0 mg/dL, stable renal function (decrease in GFR <5 mL/min over 6 mos); blood pressure <140/90 mm Hg; cholesterol level <240 mg/dL; daily protein intake <1 g/kg body wt; no known history of exposure to Pb or other heavy metals and EDTA chelatable Pb <600 

μg/72 h. 

Exclusionary criteria included potentially reversible or unstable renal disease (i.e., due to systemic diseases such as lupus and diabetes), nephrotoxicant medications, and drug allergies. 196 patients initially screened for study; details on reasons for non-eligibility not provided. Primary outcome = 1.5 times increase in the initial creatinine level or need for dialysis; secondary outcome = change in creatinine clearance. Cox proportional-hazards model analysis for primary outcome. Mean differences in creatinine clearance compared at sequential time points with t or MannWhitney U tests. Adjustment for age, gender, baseline BMI, smoking, proteinuria, hypertension, hyperlipidemia, daily protein intake, and underlying renal disease. Intention-to-Treat and sensitivity analyses compared creatinine clearance a by time period in high and low Pb groups. 

Mean blood Pb levels 

6.6 μg/dL in high normal Pb body burden group (n = 55) 3.9 μg/dL in low normal Pb body burden group (n = 55) Mean EDTA chelatable Pb

levels pre-chelation

182.9 μg/72 hrs in high normal Pb body burden group (n = 55)37.9 μg/72 hrs in low normal Pb body burden group (n = 55) 

24 mo prospective observaPb dose measures were onbetween high and low normOf the 96 participants who study, 14 patients in the higroup reached the primary patient in the low body Pb log-rank test). From mo 12 to mo 24, crenormal body Pb burden paborderline statistically lowburden patients; from 18-295% CI for the difference 

difference in creatinine cle0.15 mL/s at that point. In a Cox multivariate regrePb was significantly assocthe primary endpoint (RR 440.8]; p = 0.002). In this basal daily proteinuria werincreased risk. 
 AX6-114 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Lin et al. (2001a) (cont’d) 3 mo clinical trial of chelation with 1 yr follow-up At 24 mos, 36 patients whose EDTA chelatable Pb levels were 80 - 600 

μg/72 hrs and serum creatinine levels of 

<4.2 mg/dL were randomized; 24 to a 3-mo treatment period consisting of weekly chelation with 1 g EDTA iv until their excreted Pb levels fell below 80 

μg/72 hrs and 

12 to placebo infusion. Intention-to-Treat and sensitivity analyses compared creatinine clearance by time period in treated and control groups. 

3 mo clinical trial of chela

The two groups were similfactors (although numbers possible). Mean EDTA dose during tAfter three mos of Pb chelburden of the patients in thdecreased from 198 to 39.2 chelation and 3 mos of folincreased by 0.08 mL/s in declined by 0.04 mL/s in tAt the end of the study perclearance was 0.68 mL/s in compared to 0.48 mL/s in (p < 0.05; 95% CI for the dgroups = –25.0 to –0.2). 
 AX6-115 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Lin et al. (2001b) Study location and date not provided; authors from Taiwan 101 patients with CRI (defined as serum creatinine between 1.5 and 3.0 mg/dL). 67 with CRI and gout. 34 with CRI only. Eligibility criteria included no known history of Pb exposure, certain diagnoses, and medications. CRI must have preceded gout diagnosis. Randomized chelation trial 30 participants with CRI, gout, and EDTA-chelatable Pb levels between 80.2 and 361 

μg/72 hrs randomized to 

either a treatment group receiving 1 gram EDTA iv per wk for 4 wks (N = 20) or to a control group who received glucose in normal saline iv. 

Mean blood Pb

5.4 μg/dL (CRI and gout) 4.4 μg/dL (CRI only) Mean EDTA-chelatable Pb

138.1 μg/72 hrs (CRI and gout) 64.2 μg/72 hrs (CRI only) (p < 0.01) 

In 101, EDTA-chelatable PCRI and gout compared to EDTA-chelatable Pb, but nassociated positively with with daily urate excretion, fractional urate excretion. Randomized chelation tria

The two groups had similaand Pb measures pre-chelamean EDTA-chelatable Pb 41 

μg/72 hrs; mean serum 

to 8.6 mg/dL (% change cogroup = !22.4 [95% CI: !4mean urate clearance incre4.2 mL/min (% change com= 67.9 [95% CI: 12.2, 121fractional urate excretion wdifferent between the two creatinine clearance increa54.2 mL/min (% change cogroup = 8.0 [95% CI: !0.4
 AX6-116 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Lin et al. (2002) Study location and date not provided; authors from Taiwan 84 healthy participants. 27 participants with gout. All with normal renal function (defined as serum creatinine ≤1.4 mg/dL). Participants with a history of occupational heavy metal exposure, EDTA-chelatable Pb levels >600 

μg/72 hrs, or 

systemic diseases were excluded. Randomized chelation trial

24 participants with EDTA-chelatable Pb levels between 75 and 600 

μg/72 hrs randomized to either a treatment 

group receiving 1 gram EDTA iv per wk for 4 wks (N = 12) or to a control group who received glucose in normal saline i.v. Multiple linear regression, adjustment for age, sex, BMI, daily protein intake, and creatinine clearance. 

Mean blood Pb

3.9 μg/dL (controls) 4.2 μg/dL (gout) Mean EDTA-chelatable Pb

45 μg/72 hrs (controls) 84 μg/72 hrs (gout) (p < 0.0001) 

Significantly higher mean lower urate clearance were gout compared to those wi

/1.73 m2; p < 0.001 for ura

After adjustment, EDTA-cwith all four uric acid meaurate excretion, urate clearexcretion). Blood Pb assoAll associations in same d(2001). Randomized chelation triaThe two groups had similaPb measures pre-chelationblood and EDTA-chelatab5.0 to 3.7 

μg/dL and 110 t

respectively). Statistically observed in all four urate mgroup compared to the con
 AX6-117 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Lin et al. (2003) Study location and date not provided; authors from Taiwan 24 mo prospective observational study 202 patients with CRI Eligibility criteria included serum creatinine from 1.5 - 3.9 mg/dL, stable renal function (decrease in GFR <5 mL/min over 6 mos); blood pressure <140/90 mm Hg; cholesterol level <240 mg/dL; daily protein intake <1 g/kg body wt; no known history of exposure to Pb or other heavy metals and EDTA chelatable Pb <600 

μg/72 h. 

Exclusionary criteria included potentially reversible or unstable renal disease (i.e., due to systemic diseases such as lupus and diabetes), nephrotoxicant medications, and drug allergies. 250 patients initially observed, loss due to noncompliance or unstable renal function, baseline data on the 48 who left or were removed from the study not provided. Cox proportional-hazards model analysis for primary outcome. Generalized estimating equations (GEE) for associations between baseline chelatable Pb or blood Pb level and longitudinal change in GFR (estimated by an MDRD equation [Levey et al., 1999]) and by measurement of creatinine clearance. Adjustment for age, gender, baseline BMI, smoking, baseline serum creatinine, proteinuria, hypertension, hyperlipidemia, daily protein intake, and underlying renal diseases. 

Mean blood Pb levels

5.3 μg/dL in total group (n = 202) 6.1 μg/dL pre-chelation in chelated group (n = 32) 5.9 μg/dL pre-chelation in control group Mean EDTA chelatable Pb

levels pre-chelation

104.5 μg/72 hrs in total group (n = 202) 150.9 μg/72 hrs pre-chelation in chelated group 144.5 μg/72 hrs pre-chelation in control group 

24 mo prospective observaPrimary endpoint = increatimes baseline or need for 24 participants. Secondary estimated glomerular filtraIn a Cox multivariate regrePb was significantly assocthe primary endpoint (haza

chelatable Pb was 1.00 [95p = 0.03). In this model, bwas also associated (hazarwas 2.75 [95% CI: 1.46, 5borderline significance (p protein excretion and smokThe association between bchange in GFR was model!0.003 (p = <0.001) (neiththis model, gender and daiassociated with increased Gcreatinine level, daily urinthe presence of polycystic significant predictors of a glomerular filtration rate. Based on this model, a 10 chelatable Pb level was asdecrease of 0.03 mL per m

surface area during the 2 yAlthough statistically signclinically small. Furthermthat reported in Yu et al. (2period that is only two-fol
 AX6-118 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Asia (cont’d) Lin et al. (2003) (cont’d) Study location and date not provided; authors from Taiwan 27 mo clinical trial of chelation At 24 mos, 64 patients whose EDTA chelatable Pb levels were 80 - 600 

μg/72 hrs and serum creatinine levels of 

<4.2 mg/dL were randomized; half to a 3-mo treatment period consisting of weekly chelation with 1 g EDTA iv until their excreted Pb levels fell below 60 

μg/72 hrs and 

half to five wks of placebo infusion. Intention-to-Treat analysis compared creatinine clearance and GFR by time period in treated and control groups. 

27 mo clinical trial of chel

The two groups were similfactors (although numbers possible). After three mos of Pb chelburden of the patients in thdecreased from 150.9 to 43Pb levels decreased from 6increased by 3.4 mL/min/1

in contrast, it decreased by 

control group. Mean EDTperiod was 5.2 μg. In the subsequent 24 mos, participants was repeated dcreatinine in association wEDTA chelatable Pb leveladditional chelation series of 13.7 mos after the first cpatients receiving placebo six mos. At the end of the study perglomerular filtration rate inmL/min/1.73 m2 of body-s

group compared to a declin(p < 0.01; 95% CI for the d–11.0 to –5.1). 
 AX6-119 Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient Population Reference, Study Location, and Period Study Description Pb Measurement Findings

Asia (cont’d) Yu et al. (2004) Study location and date not provided; authors from Taiwan 121 patients followed over a four yr observational period. Eligibility criteria included serum creatinine from 1.5 -3.9 mg/dL, stable renal function (decrease in GFR <5 mL/min over 6 mos); blood pressure <140/90 mm Hg; cholesterol level <240 mg/dL; daily protein intake <1 g/kg body wt; no known history of exposure to Pb or other heavy metals and EDTA chelatable Pb <600 

μg/72 h. Exclusionary criteria included potentially reversible or unstable renal disease (i.e., due to systemic diseases such as lupus and diabetes), medical noncompliance (patients were followed for 6 mos to assess compliance before enrollment in the study), nephrotoxicant medications, and drug allergies. Cox proportional hazards model analysis for primary outcomes and generalized estimating equations (GEE) 

for associations between baseline chelatable Pb or blood Pb level and longitudinal change in GFR (estimated by an MDRD equation [Levey et al., 1999]). Adjustment for age, gender, baseline BMI, smoking, baseline serum creatinine, proteinuria, hypertension, hyperlipidemia, daily protein intake, use of ACE inhibitor or angiotensin-receptor antagonists (since not all patients were on these), and chronic glomerulonephritis (other underlying renal diseases included in GEE as well). 

Mean (SD) blood Pb at baseline

3.4 (1.3) 

μg/dL in 58 patients 

with “low-normal” EDTA chelatable Pb levels (<80 

μg 

Pb/72 hrs) 4.9 (2.6) 

μg/dL in 63 patients 

with “high-normal” EDTA chelatable Pb levels (∃80 but <600 

μg/72 hrs) 

The two groups (dichotomizPb of 80 

μg Pb/72 hrs ) were 

other than Pb body burden. (p < 0.1) differences includechelatable Pb group and certglomerulosclerosis, chronic inephropathy; surprisingly boless common in the lower Pb Fifteen patients in the “high-reached the primary endpointhe 4 yr study period or need two in the “low-normal” groanalysis). In a Cox multivariate regresssignificantly associated with endpoint (hazard ratio for ea[95% CI: 1.00, 1.01]; p = 0.variable reaching at least borbaseline serum creatinine. The associations between balevel and change in GFR we

∃ = !0.1295 (p = 0.002) for P∃ = !4.0123 (p = 0.02) for blBased on these models, a 10 level or 1

μg/dL higher blood 

mL/min declines in GFR, resperiod. Similar to the primartraditional renal risk factors diagnosis of chronic interstitassociated, in this case with chronic interstitial nephritis win the group with the low-noThe authors stated that these publications (which are descTherapeutic EDTA Chelatio
 AX6-120 Table AX6-4.4. Renal Effects of Lead on Mortality Reference, Study Location, and Period Study Description Pb Measurement Findings, In

United States Cooper (1988); Cooper et al. (1985) 16 U.S. plants Employment between 1946 and 1970; mortality from 1947 to 1980 4519 male battery plant workers. 2300 male Pb production workers. Employed for at least one yr between 1946 and 1970. Cause of death per death certificate (extrapolated when missing). Standardized mortality ratios (SMRs) compared with national age-specific rates. PMR also assessed. Analyzed separately by battery and Pb production, by hire date before and after 1/1/1946, and by cumulative yrs of employment (1-9, 10-19, 20+). Mean blood Pb 63 μg/dL in n = 1326 battery workers 80 μg/dL in n = 537 production workers Past Pb exposures poorly documented prior to 1960 Follow-up >90% in both g

observed. “Chronic or unspecified ne222 (95% CI: 135, 343) in 265 (95% CI: 114, 522) in “Other hypertensive diseasand related renal disease wdisease)”: 320 (95% CI: 197, 489) in 475 (95% CI: 218, 902) in Race adjusted proportionasimilar. Nephritis deaths observed before 1946. Limitations = due to mortaof death certificates, exposlimited). 

Steenland et al. (1992) Idaho Employed between 1940 and 1965; mortality up to 1988 

1990 male Pb smelter workers. Employed in a Pb-exposed department for at least one yr between 1940 and 1965. Vital status was determined using records from the Social Security Administration and the National Death Index. 

Mean blood Pb56.3 μg/dL (n = 173, measured in 1976) High Pb exposure defined as workers from departments with an avg >0.2 mg/m3

airborne Pb or ∃50% of jobs had avg levels more than twice that level (1975 survey). In this category, n = 1,436. 

Compared to the U.S. whitstandardized mortality ratidisease, based on only 8 deCI = 0.54, 2.49). SMR = 1group, also not significantkidney disease increased wfrom 0.79 in workers expoworkers exposed >20 yrs; significant. 
 AX6-121 Table AX6-4.4 (cont’d). Renal Effects of Lead on Mortality Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Europe Fanning (1988) UK Deaths from 1926-1985 Deceased males identified through pension records of Pb battery and other factory workers. 867 deaths of mean with high Pb exposure compared to 1206 men with low or no Pb exposure. Range of blood Pb 40-80 μg/dL since ~1968 in high Pb exposure group; thought not to have had clinical Pb poisoning due to medical surveillance. <40 μg/dL since ~1968 in little or no exposure group. Odds ratio for renal diseas

based on only 11 deaths. nephritis. Possible decreadeaths with mention of nebut not significant and numLimitations = standard moalthough deaths compared general population which study. 
 AX6-122 Table AX6-4.5. Renal Effects of Lead in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, In

United States Hu (1991) U.S. Study date not provided 21 of 192 adults who were hospitalized at Boston Children’s Hospital between 1932 to 1942 for childhood Pb poisoning were traced to a Boston area address. Matched on age, sex, race, and neighborhood to 21controls. Mean (SD) blood Pb 6.0 μg/dL (Pb poisoned) 7.5 μg/dL (controls) No significant differences 

creatinine, or BUN. Mean clearance higher in the precompared to controls (112

[p < 0.01]). Mean in the Phigher than the predicted vm2 from the nomogram of 

Suggests Pb-related hyperfsection 6.4, one survivor, iin the study, had disease cnephropathy. Limitations = small study survivor bias in the study g

Loghman-Adham (1998) Chicago, IL Study date not provided 

134 children and young adults, 8 to 13 yrs after chelation therapy for severe Pb poisoning. Mean age at poisoning = 2.3 yrs Mean age at follow-up = 13.4 yrs 

Mean peak blood Pb level

121 μg/dL Mean blood Pb level at time 

of study

18.6 μg/dL 

Mean serum creatinine waCalculated creatinine clearchildren. No correlation bcurrent blood Pb and serum creatinine clearance. Urinary α-amino nitrogen significantly increased commatched controls and were blood Pb levels. Thirty-twglycosuria. Fractional exchowever, was normal in alconcluded that a partial Fapersist for up to 13 yrs afteThe author notes that the pthis is unknown at present
 AX6-123 Table AX6-4.5 (cont’d). Renal Effects of Lead in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Europe McDonald and Potter (1996) Boston, MA 1991 454 pediatric hospital patients who were diagnosed with Pb poisoning between 1923 and 1966 were traced through 1991. Mortality study, comparison with U.S. population. Chronic nephritis was not 

Mortality from all cardiovelevated (observed/expect3.2]) and cerebral vascular common among women (o[95% CI: 1.1, 15.9]). Moel and Sachs (1992) Chicago, IL 1974-1989 62 participants with blood Pb >100 μg/dL, diagnosed and chelated between 1966 and 1972, together with 19 age- matched control siblings with initial blood Pbs less than 40 μg/dL. Mean age at follow-up = 22 yrs. Renal outcomes = serum creatinine, uric acid, and ∃2- microglobulin, fractional excretion of ∃2-microglobulin, urinary protein:creatinine ratio, and tubular reabsorption of phosphate. Mean initial blood Pb 150.3 μg/dL (highly poisoned as children) Data for siblings not available as levels <40 μg/dL not quantified. There were no statistical d

function or blood pressure control siblings. Initial blassociated with serum creaage, gender, and body masin serum creatinine values yr period in four of the 62 1.6 mg/dL). 

Bernard et al. (1995b) Czech Republic Study date not provided 

144 children living close to a Pb smelter (exposed groups 1 and 2). 51 controls living in a rural area presumed to be relatively unpolluted with Pb. Mean age = 13.5 yrs. Renal outcome measures included urinary albumin, RBP, NAG, Clara cell protein, and ∃2-microglobulin. 

Retinol binding protein

73.8 μg/g creatinine (controls) 109.4 μg/g creatinine (exposed group 1) 117.8 μg/g creatinine (exposed group 2) ∃2-microglobulin

60.3 μg/g creatinine (controls) 89.1 μg/g creatinine (exposed group 1) 66.4 μg/g creatinine (exposed group 2) NAG

1.56 IU/g creatinine (controls) 2.32 IU/g creatinine (exposed group 1) 1.46 IU/g creatinine (exposed group 2) Multiple linear adjusting for age and gender. 

Blood Pb

8.7 μg/dL (control boys) 8.39 μg/dL (control girls) 10.9 μg/dL (exposed boys 1) 9.4 μg/dL (exposed girls 1) 14.9 μg/dL (exposed boys 2) 12.9 μg/dL (exposed girls 2) 

Mean blood Pb levels signexposed groups compared contrast, blood cadmium lall groups. After adjustmecadmium, and zinc protopblood Pb was associated w(∃ = 0.302, p = 0.005). 
 AX6-124 Table AX6-4.5 (cont’d). Renal Effects of Lead in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Europe (cont’d) De Burbure et al. (2006) France, the Czech Republic, and Poland Study date not provided 804 exposed and control children. Exposed children recruited from residents near historical nonferrous smelters, must have lived ∃8 yrs near smelters. Mean age = 10 yrs; range = 8.5-12.3 yrs. Renal outcome measures included serum creatinine, cystatin C and ß2-microglobulin as well as urinary RBP, NAG, Clara cell protein. Mean blood Pb Ranged from 2.8 to 4.2 mg/dL in various control and exposed groups. Urinary cadmium, arsenic and mercury as well as blood cadmium also assessed. Serum concentrations of c

ß2-microglobulin negative

levels. Authors state suggestive ohyperfiltration that avgd 7PbB levels (>5.5 μg/dL; m

Factor-Litvak et al. (1999) Kosovo, Yugoslavia 1985-1993 

577 children followed at 6 mo intervals through 7.5 yrs of age. Divided into a high exposure and a low exposure group, based on residence in Kosovska Mitrovica with a Pb smelter, refinery, and battery plant or in Pristina, 25 miles away. Renal outcome = Proteinuria assessed with a dipstick. Multiple logistic regression modeling of proteinuria dichotomized as either any or none, adjusting for socioeconomic status, maternal education/ intelligence, and quality of childrearing environment. 

Mead blood Pb from graph peaked at ~38 μg/dL between ages 3-5 in Kosovska Mitrovica and at ~10 μg/dL in controls. Blood Pb level ranged from 1 to 70 μg/dL. 

In higher exposed group, awas 3.5 (95% CI: 1.7, 7.2proteinuria increased by 1unit increase in blood Pb iProteinuria unrelated to blcontrol group. Limitations = limited renadropout rate in the study. 
 AX6-125 Table AX6-4.5 (cont’d). Renal Effects of Lead in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Europe (cont’d) Fels et al. (1998) Poland 1995 112 children (50 controls, 62 exposed). Mean age = 9.9 yrs and 10.6 yrs in controls and exposed group, respectively. Numerous (29) renal outcome measures were examined including serum creatinine and ∃2-microglobulin, and urinary NAG, RBP, Clara cell protein, ∃2-microglobulin, 6-keto-prostaglandin F1α (6-keto-PGF1α), prostaglandin 

E2 (PGE2) and thromboxane B2 (TXB2). 

Urinary RBP46 μg/g creatinine (exposed) 42 μg/g creatinine (controls) Urinary ∃2-microglobulin

89 μg/g creatinine (exposed) 37 μg/g creatinine (controls) Serum creatinine

0.63 mg/dL (exposed) 0.63 mg/dL (controls) 

Mean blood Pb13.3 μg/dL (exposed) 3.9 μg/dL (controls) 

Significantly higher mean 

and urinary transferrin, 6-k

B2, epidermal growth facto

and Clara cell protein in thcontrast, NAG-B was lowCategorical blood Pb assovalues above the upper refbiomarkers. Urinary 6-ke

microglobulin, Clara cell pfactor and PGE2 positively 

(r = 0.441, 0.225, 0.203, 0respectively; all with signiLimitations = data analysi

_ktem et al. (2004) Turkey Study date not provided 

79 adolescent auto repair workers (mean age 17.3 yrs). 71 rural adolescents as negative controls (mean age 17.0 yrs). Renal outcomes = urinary NAG, ∃2-microglobulin, uric 

acid, and calcium; blood urea nitrogen (BUN), serum creatinine and uric acid. 

Mean blood Pb

7.79 μg/dL (exposed workers) 1.6 μg/dL (controls) 

No difference in mean BUacid, or GFR (apparently eand controls. Urinary NAG and calcium workers compared to contpositively correlated blood Limitations = data analysi
 AX6-126 Table AX6-4.5 (cont’d). Renal Effects of Lead in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, In

Europe (cont’d) Price et al. (1999) Belgium, Poland, Germany and Italy Study date not provided Urinary Pb measured in 481 European children (236 controls, 245 exposed) aged 6 – 14 yrs. Several renal outcome measures assessed including urinary NAG and ∃2-microglobulin; values not reported. Mean urinary Pb Range from 3.9 to 7.2 μg/g creatinine (controls) Range from 5.2 to 24.6 μg/g creatinine (exposed) Urinary Pb generally high

compared to controls. Ausubstantial differences in rsite. Authors note several between exposed and contquestioned the use of “conexposures. Sch

≅rer et al. (1991) 

Germany 1988-1989 

22 children, age 5-14 yrs, with CRI. 20 siblings or neighbors as lower exposed group. 16 control children without known Pb exposure. 

Mean blood Pb

2.9 μg/dL in children with CRI, not tested in other groups Mean dental Pb content

2.8 μg/g in children with CRI 1.7 μg/g in sibs/neighbors 1.4 μg/g in controls 

Pb levels in teeth significapatient and sibling/neighbto the unexposed control g

S⎯nmez et al. (2002) 

Turkey Study date not provided 

39 adolescent auto repair workers (mean age 16.2 yrs). 13 adult battery workers as positive controls (mean age 32 yrs). 29 rural adolescents as negative controls (mean age 14.8 yrs). Serum creatinine

0.99 mg/dL (exposed group) 0.99 mg/dL (positive/ adult controls) 0.89 mg/dL (negative/ adolescent controls) Urinary NAG

4.7 IU/g creatinine (exposed group) 7.4 IU/g creatinine (positive/ adult controls) 3.1 IU/g creatinine (negative/ adolescent controls) 

Mean blood Pb

8.13 μg/dL (exposed group) 25.3 μg/dL (positive/adult controls) 3.49 μg/dL (negative/ adolescent controls) 

All participants had normaand uric acid levels as welurinalysis. Blood Pb level and urinary in adolescent auto repair wnegative control group. Limitations = data analysi
 AX6-127 Table AX6-4.5 (cont’d). Renal Effects of Lead in Children Reference, Study Location, and Period Study Description Pb Measurement Findin

Europe (cont’d) Staessen et al. (2001) Belgium 1999 100 exposed and 100 control children. Mean age = 17 yrs. Two exposed groups were recruited from industrialized suburbs while the control group was recruited from a rural area. 

∃2-microglobulin

5.22 μg/mmol creatinine (controls) 5.3 μg/mmol creatinine (exposed group 1) 9.09 μg/mmol creatinine (exposed group 2) Cystatin-C0.65 mg/L (controls) 0.63 mg/L (exposed group 1) 0.71 mg/L (exposed group 2) Multiple linear regression adjusting for sex and smoking status. 

Mean blood Pb1.5 μg/dL (controls) 1.8 μg/dL (exposed group 1) 2.7 μg/dL (exposed group 2) 

Blood Pb, ∃2-microglohigher in exposed groexposed group 1. After adjustment for swas associated with b

cystatin-C. A two-folassociated with a 3.6% Cystatin-C and a 16% ∃2-microglobulin. Blo

with either outcome. 

Verberk et al. (1996) Romania 1991-1992 

151 children who resided at different distances from a Pb smelter. Mean age = 4.6 yrs. Renal outcomes = urinary RBP, NAG, α1-microglobulin, 

albumin and alanine aminopeptidase. Geometric means

Urinary RBP

49.4 μg/g creatinine Urinary NAG

6.9 U/g creatinine Urinary α1-microglobulin

2.4 mg/g creatinine Urinary alanine aminopeptidase

19.8 U/g creatinine Multiple regression analysis adjusting for age and gender. 

Mean (SD) blood Pb

34.2 (22.4) μg/dL 

After adjustment for aincrease in blood Pb wincrease in NAG excrNo threshold was obseassociations noted. 
 AX6-128 Table AX6-4.5 (cont’d). Renal Effects of Lead in Children Reference, Study Location, and Period Study Description Pb Measurement Findin

Africa Diouf et al. (2003) Senegal 1998 38 Senegalese children (19 exposed, 19 controls). Age range = 8 – 12 yrs old. Renal function assessed by measuring urinary alpha- glutathione S-transferase (αGST). Mean (SD) blood Pb 10.7 (1.7) μg/dL (exposed) 6.1 (1.8) μg/dL (controls) Blood Pb significantly 

dwellers) as compared Unclear as to whether controls as compared higher in controls in thhigher in the exposed Regardless, the differesignificant. Limitations = small sa
 AX6-129 

ANNEX TABLES AX6-5 
 AX6-130 Table AX6-5.1. Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretatio

Meta-analysis Nawrot et al. (2002) 31 U.S. and European studies, community and occupationally exposed, published between 1981 and 2001. 48 different groups, 32 of which were only of men, 15 of which were only of women, and one studying both sexes. Total meta-analysis N > 58,490. Age ranged from 15 to 93 yrs, depending on the study. Two methods of meta-analysis were used, subject-weighted and non- weighted, using study-reported effect sizes and standard errors, transformed from the original study specification of blood Pb (linear, logarithmic, or blood Pb group) to a single effect size for doubling of blood Pb. Also did analyses 

stratified by race and sex. 

Mean blood Pb concentration across studies ranged from 2.3 to 63.8 μg/dL. Total range of blood Pb across studies was 0 to 97.9 μg/dL. 

Each doubling of blood Pb was associated with a (95% CI: 0.5, 1.4) increase in systolic blood presmm Hg (95% CI: 0.4, 0.8) increase in diastolic bldifferences in Pb effect were not statistically diffenot describe test nor give statistics other than p-vawhite differences as a trend for blacks to be “more but presented no tests. Statistically examined assumptions of homogeneisignificant heterogeneity. Tested for publication bresults tend to be published more than non-signifievidence. Found no significant effects of removinsensitivity analysis. It appears that the presented rconfidence intervals were calculated by the subjec

was not made explicit. Included some studies thacoefficients or standard errors, assuming effect sizreported effect sizes without these studies did not overall effect sizes. For studies using a linear Pb calculated by doubling the arithmetic mean blood response curve for the Pb-blood pressure relationscharacterized by a log-linear function, the authorsblood Pb term with high avg blood Pb led to overthe relationship and those studies with low blood estimation of the slope of the relationship. 
 AX6-131 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretatio

United States Cheng et al. (2001) U.S.-Boston, Normative Aging Study (VA) 1991-1997 833 males (~97% white), avg age (SD): 65.5 (7.2) Normotensive subjects, N = 337 68.3 (7.8) Borderline hypertensive subjects, N = 181 67.9 (6.8) Definite hypertensive subjects, N = 314 474 males with no history of hypertension at first measurement, returning up to 6 yrs later for 

hypertension study. Linear multiple regression models of blood pressure and Cox proportional hazard models of new cases of hypertension after up to 7 yrs, with one group of covariates forced into models based on biological plausibility and another group forced based on significant univariate or bivariate results or >20% effect modification of Pb variable coefficient in multiple models. Linear blood Pb, tibia Pb, and patella Pb forced in separate models. 

Arithmetic mean (SD) blood Pb: 5.9-6.4 μg/dL (3.7-4.2), depending on hypertension group (only data shown). 

Multiple regression models of blood pressure alwsquared, BMI, family history of hypertension, dai

and daily calcium consumption. Increasing tibia Passociated with increased systolic blood pressure baseline measurements in subjects (n = 519) free f

(systolic >160 mm Hg, diastolic >95 mm Hg, or tmedication). Each increase of 10 μg/g tibia Pb cowith an increase in systolic blood pressure of 1.0 m1.99). Patella and linear blood Pb were not signifCox proportional hazard models always included family history of hypertension. In follow up (n = patella Pb predicted increasing risk of definite hypclassified as normotensive at baseline. For every Pb risk ratio increased 1.14 (95% CI: 1.02, 1.28). hypertension (systolic 141-160 mm Hg or diastolidefinite hypertension (n = 306), the relative risk rcombined hypertensive associated with a 10 μg/g 1.23 (95% CI: 1.03, 1.48). Linear blood Pb and tsignificant. Linear blood Pb is not indicated for blood pressurlikelihood of significant residual heteroscedasticitRelatively small sample size may have prevented in the Cox proportional hazard models. 
 AX6-132 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretat

United States (cont’d) Den Hond et al. (2002) U.S.-NHANES III 1988-1994 4,685 white males, 5,138 white females, 1,761 black males, 2,197 black females, from 20 yrs up. Log- transformed blood Pb, systolic and diastolic blood pressure measured at survey time and analyzed with forward, stepwise multiple regression with covariates. Avg age: White Male: 44.3 yrs Female: 46.2 yrs Black Male: 40.5 yrs 

 Female: 41.5 yrs 

Geometric mean (25th-75th percentile) blood Pb: White male mean 3.6 μg/dL (2.3-5.3) White female mean 2.1 μg/dL(1.3-3.4) Black male mean 4.2 μg/dL (2.7-6.5) Black female mean 2.3 μg/dL(1.4-3.9) 

After adjusting for age, age-squared, BMI, hematoindicator variable for use of antihypertensive medfurther modified by a unique mix of other covariaconsumption, dietary calcium, dietary sodium/calcprotein, total serum calcium, diabetes, and poverty last. In stratified analyses, only blacks had significant passociations with log blood Pb. Each doubling of increase of black male systolic blood pressure of 01.8), black female systolic blood pressure of 1.2 mfemale diastolic blood pressure of 0.5 mm Hg (95males only, each doubling of blood Pb was signifidecrease in diastolic blood pressure of -0.6 mm H

Stepwise models can rely on chance associations usually lead to a different pattern of covariate adjuInclusion of likely confounding variables such as affected estimated Pb effects. No testing for signidifferences between each stratum. No model diagexplanation offered for inverse relationship betwepressure in white males. No adjustment for surve

Gerr et al. (2002) U.S.-Spokane WA and area around Silver Valley ID 1994 

502 young people, age 19-29 yrs, 53% female, nearly evenly divided into the Spokane group (no unusual childhood exposure) and the Silver Valley group, where a Pb smelter operated during their childhood. Multiple regression models of systolic blood pressure and diastolic blood pressure. All covariates forced into model as block with both linear blood Pb and tibia bone Pb in each model. 

Mean (SD) blood Pb only given stratified on tibia Pb category: Tibia <1 μg/g: 1.9 μg/dL (1.6) Tibia 1-5 μg/g: 2.3 μg/dL (2.1) Tibia 6-10 μg/g: 2.4 μg/dL (2.4) Tibia <10 μg/g: 3.2 μg/dL (2.3) No other descriptive tibia Pb data given. 

Adjusting for sex, age, height, BMI, education, inalcohol use, childhood residence (the two recruitm

control pills, hemoglobin, and serum albumin, onlPb, was significantly related to systolic and diastoto the <1 μg/g tibia Pb category, subjects in the >4.3 mm Hg (95% CI: 1.4, 6.7) higher systolic blo(95% CI: 0.4, 5.2) higher diastolic blood pressureLinear blood Pb is not indicated for blood Pb-blooNo diagnostic testing reported. Insufficient descri
 AX6-133 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretatio

United States (cont’d) Glenn et al. (2003) U.S.-New Jersey 1994-1998 496 males, mean (SD, range) age 55.8 (7.4, 40-71) yrs, working or formerly working at a plant producing tetraethyl or tetramethyl Pb until 1991, were followed from 10 mos to 3.5 yrs during which blood pressure was repeatedly tested. Blood Pb was tested only at baseline. Tibia Pb was tested in 1991 (at the end of organic Pb production at the plant) and called “peak tibia Pb” and again during 1997 (yr 3). Generalized estimating equations with an exchangeable correlation structure for repeated 

measurements were used for systolic and diastolic blood pressure. One group of covariates was forced into the model as a block (age at baseline, race, BMI, indicator variable for technician, Pb variable (linear blood Pb, peak tibia Pb, and tibia Pb each tested separately), duration of follow up, and the interaction between the Pb variable and the duration term. Potential confounding variables were entered stepwise and retained in the model if significant. Alternate models not using linear time were constructed, using quartile of follow up time to avoid assuming a linear relationship of change in blood pressure with time. 

Arithmetic mean (SD, range) blood Pb at baseline: 4.6 μg/dL (2.6, !1 to 20) 

Tibia Pb at yr 3: 14.7 μg/g (9.4, !1.6 to 52) Peak tibia Pb: 24.3 μg/g (18.1, !2.2 to 118.8) 

Controlling for baseline age, BMI, antihypertensiveducation, technician and number of yrs to each beach 1 μg/dL increase in linear baseline blood Pb systolic blood pressure increase of 0.64 mm Hg/yeach 10 μg/g increase in yr 3 tibia Pb with an avg (95% CI: 0.23, 1.23), and each increase of 10 μg/avg increase of 0.61 mm Hg/yr (95% CI: 0.09, 1.obtained using the follow up time quartile designapressure with all subjects and with subjects not takmedications. This was one of the few studies using a prospectivstatistical technique accounting for repeated measfor using an exchangeable correlation structure inOnly examined cortical bone Pb (tibia) and not tracalcaneus). Linear blood Pb may not be indicated pressure models. Stepwise modeling involves mudata set with no control for altered probabilities. Npresented. 
 AX6-134 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretatio

United States (cont’d) Glenn et al. (2001) U.S.-New Jersey 1996-1997 213 males (92% white), mean (SD) age 58.0 (7.4) yrs, working or formerly working at a plant producing tetraethyl or tetramethyl Pb until 1991, were genotyped for ATP1A2(5’) and ATP1A2(3’) polymorphism. ATPase is thought to play a role in regulating blood pressure and Pb inhibits its activity. Blood pressure, blood Pb, and tibia Pb were measured. Multiple linear regression models were used for systolic and diastolic blood pressure. Logistic regression model was reported for hypertension (systolic >160 mm Hg, 

diastolic > 96 mm Hg, or taking 

antihypertensive medications). Covariate entry methods not specified, but were likely stepwise. Covariates for the blood pressure model were age, use of antihypertensive medications, alcohol, smoking, season of yr, linear blood Pb, tibia Pb (the two Pb measures apparently tested separately), ATP1A2(5’) and ATP1A2(3’) polymorphism (each tested separately), and an interaction term between polymorphism and Pb. Covariates for the hypertension models were age, BMI, lifetime alcoholic drinks, linear blood Pb and tibia Pb, and polymorphism, each Pb measure and polymorphism tested separately. 

Arithmetic mean (SD, range) blood Pb: 5.2 μg/dL (3.1, 1-20) Mean (SD) tibia Pb: 16.3 μg/g (9.3) 

None of the relationships between the ATP1A2(5’) poor bone Pb or blood pressure were significant. The ATP1A2(3’) polymorphism was homogenous for (10.5/10.5) in 11 subjects, heterogeneous for the 10.5 (10.5/4.3) in 82 subjects, and heterogeneous (10.5/4.3

of the 10.5 allele was significantly higher in blacks th

Regression coefficients of 4.3/4.3 and 10.5/4.3 genotydifferent and all subsequent analyses compared the 10combined 4.3/4.3-10.5/4.3) genotype. The significanblood Pb and the 10.5/10.5 genotype showed that for systolic blood pressure increased 5.6 mm Hg (95% CIpressure of the combined genotype group. Blood Pb rgenotype group was twice that of the 10.5/10.5 groupmake blood Pb of both groups cover the same range, clinear blood Pb interaction term did not change apprec

Pb interacted with genotype on blood pressure but shotype or size of effect. Diastolic blood pressure was noto the interaction between Pb and genotype. Prevalence of hypertension (30% in total sample) was 

the 10.5/10.5 group (63.4 %) than among the combinefor age, BMI, and lifetime alcohol, the odds of hypertwere OR = 7.7 (95% CI: 1.9, 31.4) compared to the 4heterogeneous group was not significantly different frLinear blood Pb specification not indicated for blood Examination of partial residual plot for systolic blood shows typical heterogeneity of residuals as a function 

presented coefficients may be inefficient and biased. homogenous for 10.5/10.5 in the multiple regression mwas tested, not trabecular bone Pb. Cortical bone Pb quantitatively described. Blood Pb rounded to neares

inorganic Pb exposure. Relatively small sample size 

of other significant effects. No model diagnostics des
 AX6-135 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpreta

United States (cont’d) Hu et al. (1996) U.S.-Boston- Normative Aging Study- VA 1991-1994 590 males (over 98% white), mean age around 67 yrs, divided into 146 hypertensives (systolic >160 mm Hg, diastolic >95 mm Hg, or daily antihypertensive medication) and 444 non- hypertensives. Linear blood Pb, tibia and patella bone Pb added separately to logistic regression model containing forced covariates of age, race, BMI, family history of hypertension, pack-yrs smoking, alcohol ingestion dietary sodium and calcium. Then, a backward elimination procedure starting with all covariates, including all Pb variables, resulted in a model in which only significant covariates were retained. Hypertensives: Arithmetic mean (SD) blood Pb: 6.9 μg/dL (4.3) Mean tibia Pb: 23.7 μg/g (14.0) Mean patella Pb: 35.1 μg/g (19.5) Non-hypertensives: Arithmetic mean (SD) blood Pb: 6.1 μg/dL (4.0) 

Mean tibia Pb: 20.9 μg/g (11.4) Mean patella Pb: 31.1 μg/g (18.3) 

Logistic regression model with all forced covariateffects when the three Pb variables were forced inbackward elimination, the only significant covariahistory of hypertension. Of all the Pb variables, omodel. With each increase of 10 μg/g of tibia Pb, hypertensive rose (OR = 1.21; 95% CI: 1.04, 1.43Stepwise regression, backward or forward, involv

data set, capitalizes on chance occurrence in the dprobability values. No model diagnostic testing re
 AX6-136 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretati

United States (cont’d) Korrick et al. (1999) U.S.-Boston-Nurse Health Study 1993-1995 284 women, from 47-74 yrs, mean age (SD) 58.7 (7.2), were divided into 97 cases (systolic ∃140 mm Hg, diastolic ∃90 mm Hg, or physician- diagnosed hypertension) and 195 controls. Controls were further classified as low normal (<121/75 mm Hg) and high normal >121/75 mm Hg). Three ordinal regression models were constructed, each containing either blood Pb, tibia Pb or patella Pb with forced entry of all other covariates. A final backwards elimination ordinal regression model started with all covariates, including all 

Pb variables, excluding each until only significant variables were left. Interactions were tested in the final model between patella Pb and alcohol use, age, and menopausal status. 

Mean blood Pb (SD, range): 3.1 μg/dL (2.3, <1 to 14) Mean tibia Pb (SD, range): 13.3 μg/g (9.0, !5 to 69) Mean patella Pb (SD, range): 17.3 μg/g (11.1, !5 to 87) 

Only patella Pb was significantly related to increin the preliminary models, adjusted for age, BMIand sodium, ever smoke, and family hypertensiopatella Pb was associated with increased odds of (95% CI: 1.03, 1.60). In the backward eliminatiBMI dietary sodium and family hypertension, onpatella Pb remained in the model. Identical odds obtained in both models. None of the interaction Small study size may have limited power to deteThe proportional odds assumption of the ordinal verified. Note that the odds ratios above are for two lower categories, low normal and high normcategory as patella Pb increased. No other mode

Morris et al. (1990) U.S.-sampled from general population around Portland, OR responding to ads to participate in clinical trials of nonpharmacological management of blood pressure. 1984-1989? 

145 males and 106 females, 73% with arterial pressures >105 mm Hg, provided blood pressure measurements once a wk over four consecutive wks. Blood for Pb analysis was collected during this period. Stepwise multiple regression was used to construct separate models of systolic and diastolic 

blood pressure stratified by sex. Covariates available to be entered were age, BMI, dietary calcium and “other nutrient intakes,” ionized serum calcium, erythrocyte protoporphyrin and natural log transformed blood Pb. 

Arithmetic mean (SD) blood Pb: Males: 8.0 μg/dL (4.4) Females: 6.9 μg/dL (3.6) 

Natural log blood Pb was only a significant predmales. Adjusting for age and ionized serum calcincrease in blood Pb was significantly associated 

(neither SE nor CI stated) in systolic blood presshemoglobin, age, and current smoking, a 1.90 mstated) in diastolic blood pressure. The usual precautions regarding multiple testing patterns in stratified models constructed with steReporting of effects not complete. Small sample about non-significant effects. High prevalence odue to study recruitment design. Blood Pb technpresented graph, had a detection limit of 5 μg/dL
 AX6-137 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation United States (cont’d) Nash et al. (2003) U.S.-NHANES III 1988-1994 1084 premenopausal and 633 postmenopausal women, from 40 to 59 yrs. Multiple linear regression models with covariates, including linear blood Pb, entered as a block for systolic and diastolic blood pressure. Logistic regression models with same covariates and Pb quartile added last for hypertension. Mean (range) blood Pb by Pb quartile: 1st quartile 1.0 μg/dL (0.5-1.6) 2nd quartile 2.1 μg/dL (1.7-2.5) 3rd quartile 3.2 μg/dL (2.6-3.9) 4th quartile 6.4 μg/dL (4.0-31.1) Linear blood Pb was entered last after forcing in age, race/

cigarette smoking, BMI, and kidney function (serum creatimodels for all women and women stratified by menopause diastolic blood pressure. Pb quartile was added to logistic hypertension (systolic ∃140 mm Hg, diastolic ∃90 mm Hg 

medication with the same covariates as the blood pressure stratified by menopausal status. Tested additional models hypertension were excluded from models. All models werdesign and weighting. Each increase of 1 μg/dL of blood Pb was significantly ass(95% CI: 0.01, 0.63) increase of systolic blood pressure an0.07, 0.43) increase of diastolic blood pressure in all womemenopausal status. In analyses stratified by menopausal st

women showed a significant blood Pb effect. For each 1 μwas associated with significantly increased diastolic blood −0.11, 0.39 sic.) only in postmenopausal women. Referenced to the 1st blood Pb quartile, no other quartile sincreased odds for hypertension in all subjects or in subjecstatus. With further analyses stratified by systolic and diaswomen taking antihypertensive medications, in the combinpostmenopausal women the odds of diastolic hypertension 4th Pb quartile was compared to the 1st quartile (OR = 3.4 model of only postmenopausal women untreated for hyperhypertension were significantly increased in the higher thre(OR = 4.6 [95% CI: 1.1, 19.2], OR = 5.9 [95% CI: 1.5, 232.6, 24.7], respectively) and odds of systolic hypertension two middle Pb quartiles (OR = 3.0 [95% CI: 1.3, 6.9], OR respectively). Linear blood Pb is suspect in linear regression models of busually associated with biased and inefficient estimation of probable heteroscedasticity and non-normal distribution of diagnostics were reported. No statistical testing for differeaccording to strata. Nine stratified models overall. Not all and standard errors in the blood pressure model table correvariables. 
 AX6-138 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation United States (cont’d) Proctor et al. (1996) U.S.-Boston- Normative Aging Study (VA) 1992-1993 798 men from 17 to 44 yrs. Multiple linear regression models of natural log blood Pb on systolic and diastolic blood pressure. All covariates forced into model. Arithmetic mean (SD, range) blood Pb: 6.5 μg/dL (4.0, 0.5-35) Natural log blood Pb, age, age-squared, BMI, adjusted diet

indicator variables for current and former smoker, daily alc

heart rate, and hematocrit were entered into multiple regresfor significance. Increased diastolic, but not systolic, blood pressure was sigincreased blood Pb. Each natural log increase in blood Pb 1.2 mm Hg (95% CI: 0.1, 2.2) increase in diastolic blood pInteractions between dietary calcium and blood Pb on bloosignificant. Further analyses stratified on use of antihypertthose older than or equal to 74 yrs still revealed significant pressure relationships. Blood Pb in over half the study group (n = 410) was determpreviously frozen erythrocytes collected several yrs prior tmeasurements used in the study and corrected by using hemmeasured when blood was originally collected. Combining nearly half the group was tested for the effects of blood Pb measured at the same time, the other half measured severacorrection in models for this potential effect. The effect of medication could have been assessed in a single model by No statistical testing for the effects of stratification on the brelationship. No model diagnostics. 
 AX6-139 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretati

United States (cont’d) Rothenberg et al. (1999) U.S.-Los Angeles 1995-1998 1188 immigrants and 439 nonimmigrants, from 15 to 43 yrs, all women in 3rd trimester of pregnancy. Multiple regression models of natural log blood Pb on systolic and diastolic blood pressure with all covariates forced into models. Covariates selected from larger set based on significant univariate or bivariate tests. Geometric mean (SD) blood Pb: Immigrants: 2.3 μg/dL (1.4) Non-immigrants: 1.9 μg/dL (1.3) Natural log blood Pb, age, BMI, coffee drinking, iron 

were entered as a block without regard to significance models of systolic and diastolic blood pressure stratifiIncreased blood Pb was significantly associated with immigrants. Each natural log unit increase in blood P1.7 mm Hg (95% CI: 0.7, 2.8) increase in systolic blo(95% CI: 0.5, 1.9) increase in diastolic blood pressurUsed and reported model diagnostic tests, as evidencecalculations robust to residual heteroscedasticity. Staimmigrant status were significant differences between blood pressure, age, BMI, and education. Did not stacoefficients between the immigration strata. Did not cin age effects on blood pressure. 

Rothenberg et al. (2002a) U.S.-Los Angeles 1995-2001 

668 women, 15 to 44 yrs, studied in 3rd trimester pregnancy and again a mean of 10 wks postpartum. Exclusion criteria were diabetes, renal or cardiovascular disease, extreme postnatal obesity (BMI >40), and subjects using stimulant drugs. Multiple linear regression models of natural log blood Pb, tibia and calcaneus Pb on systolic and diastolic blood pressure with all covariates and all Pb variables forced into model. Separate models for 3rd trimester and postpartum, excluding all women with hypertension (see below) during each specific period. Logistic regression for hypertension (systolic ∃140 mm Hg or diastolic ∃90), 

specific to 3rd trimester and postpartum periods with the same covariates and Pb variables. 

Geometric mean blood Pb (SD): 3rd trimester: 1.9 μg/dL (1.7) Postpartum: 2.3 μg/dL (2.0) Tibia mean Pb (SD): 8.0 μg/g (11.4) Calcaneus mean Pb (SD): 10.7 μg/g (11.9) 

Multiple linear regression models for normotensives ahypertension (3rd trimester model only), BMI, age, paimmigrant status, and educational level plus all three was associated with blood pressure in 3rd trimester mcalcaneus Pb was associated with 0.70 mm Hg (95% systolic blood pressure and a 0.54 mm Hg (95% CI: 0blood pressure. In postpartum models, natural log blostatistically associated with blood pressure. Every naPb was associated with !1.52 mm Hg (95% CI: !2.83

blood pressure and a 

−1.67 mm Hg (95% CI: !2.85, !

pressure. In logistic models, only calcaneus Pb was significantlfor hypertension. Each 10 μg/g increase in calcaneus 1.86 (95% CI: 1.04, 3.32) of 3rd trimester hypertensiwas associated with postpartum hypertension. Models did not use age-squared covariate. Models distatistics. No statistical comparisons between 3rd trim

Model diagnostic tests reported. 
 AX6-140 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation United States (cont’d) Schwartz et al. (2000c) U.S.-Eastern 1996-1997 543 mostly former organolead workers, predominantly white (92.8%), at a tetraethyl/tetramethyl plant, mean (SD) [range] age 7.6 (7.6) [41.7-73.7] yrs had blood Pb, DMSA- chelatable Pb (4-hr. urinary Pb excretion after a single 10 mg/kg dose of DMSA) measured for modeling systolic and diastolic blood pressure and hypertension (systolic >160 mm Hg or diastolic ∃96 mm Hg or taking antihypertensive medications. Tibia Pb ~2 yrs later was also used as a Pb index. For blood pressure, linear multiple regression with backward 

elimination of non-significant covariates or covariates that “had important influence on the coefficients for the Pb-dose terms.” Each Pb variable was tested in a separate model. Potential covariates for these models were age, BMI, current tobacco use, and current use of antihypertensive medications. Other models were constructed taking out those subjects using antihypertensive medications. Both linear and linear + quadratic blood and tibia Pb terms were tested. Logistic regression analyses were used to test the effect of the Pb variables on hypertension, controlling for age, diabetes, lifetime alcohol consumption, and BMI. Logistic models also tested each Pb measure in interaction with age. 

Blood Pb arithmetic mean (SD, range): 4.6 μg/dL (2.6, 1 to 20) DMSA-chelatable Pb mean (SD, range): 19.0 μg (16.6, 1.2 to 136) Tibia Pb mean (SD, range): 14.4 μg/g (9.3, !1.6 to 52) 

Adjusting for age, BMI, current smoking, and current use oeach 1 μg/dL increase in blood Pb-squared was significant(95% CI: 0.087, 0.330) increase in systolic blood pressure With the same covariates, each 1 μg/dL increase in linear bassociated with 0.310 mm Hg (95% CI: 0.028, 0.592) in dover a 2-yr period (n = 525). No other Pb variables were sFor the hypertension models, only the interaction of linear with subjects showing significant decrease in odds ratio of increase of 1 μg/dL blood Pb and 1 yr increase in age (line[95% CI: 0.97, 0.99]). The interaction suggested a concenbetween linear blood Pb and hypertension only up to ~58 yAuthors note that blood pressure findings “were not affectesubjects using antihypertensive medications,” but do not prstatistical tests to evaluate that conclusion. No other modeAlthough blood Pb was also modeled as a quadratic Pb term analysis was shown for non-linear blood Pb terms for diastTrabecular bone Pb was not tested, though other studies inthan cortical Pb for cross-sectional blood pressure and hypAlthough the backward procedures described could have reconsidered covariates entering the models, all model presethe Pb coefficients and all models indicated in a footnote thadjusted for each possible covariate for that model. While list of covariates, given the 14 models presented one might where one of the covariates did not remain. 
 AX6-141 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation United States (cont’d) Schwartz (1995) 15 prior U.S. and European studies published between 1985 and 1993 Total subjects not specified, men and women ages 18 to 74 yrs. Random effects meta-analysis with inverse variance weighting of Pb-blood pressure coefficients from each study. Sensitivity analysis performed by dropping study with largest or smallest effect. Blood Pb levels not stated. Each doubling of natural log blood Pb level was associated 

mm Hg (95% CI: 0.87, 1.63) systolic blood pressure. Sennegligible change in meta-analysis coefficient. Concluded would not change calculated coefficient. Noted Pb-blood plower Pb levels than at higher Pb levels. The study only analyzed systolic, not diastolic, blood pressNawrot et al. (2002). Schwartz (1991) NHANES II U.S. 1976-1980 Under 10,000 subjects (exact number not reported), males and females, aged 25 to 74 yrs for left ventricular hypertrophy results with logistic regression. Linear blood Pb used for LVH. For blood pressure results, 

multiple linear regressions stratified by sex, with one block of variables forced, another block of variables entered with stepwise regression, aged 6 mos to 74 yrs, exact number not given. Natural log blood Pb used for linear regression. Both logistic and linear regressions adjusted for survey design. 

No blood Pb descriptive data given. 

Used logistic regression to study Pb effect on left ventriculdetermined by a combination of electrocardiogram paramecontrolling for age, race, and sex. Every 10 μg/dL blood Pwith increased odds of LVH of 1.33 (95% CI: 1.20, 1.47). by blood Pb and sex by blood Pb were not significant. Blood pressure models stratified by sex always included Brace, and natural log blood Pb. Male blood pressure modehistory of hypertension, cholesterol, height, cigarette use, sfold. Female model also included serum zinc, family histoskin fold, and cholesterol. Every 1 natural log unit of blooassociated with an increase in diastolic blood pressure of 24.98) in males and 1.64 mm Hg (95% CI: 0.27, 3.01). Userace-blood Pb and sex-blood Pb in a non-stratified model aeffect of race or sex on the blood Pb-blood pressure coefficIncomplete reporting of subject size for models and for desvariables in models. Tested both linear and log transformeFound log Pb had lower probability values than linear Pb flinear Pb had lower probability values than log Pb for LVHdifference between the two blood Pb specifications. No mOnly reported diastolic blood pressure results. 
 AX6-142 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation United States (cont’d) Sokas et al. (1997) U.S.-Maryland 1989-1990 264 active or retired construction workers, over 99% men, who were not involved in Pb work at time of testing, mean age (range) 43 yrs (18-79). Multiple regression modeling of systolic and diastolic blood pressure adjusted for covariates of BMI, age, hematocrit, erythrocyte protoporphyrin, race, linear blood Pb and a race-linear blood Pb interaction. Method of covariate entry not made explicit, though it appeared to be forced. Mean blood Pb (range): 8.0 μg/dL (1-30) Linear blood Pb was not significantly related to either syst

pressure, though the race by linear blood Pb interaction wa(p = 0.09). Each 1 μg/dL increase in blood Pb increased b0.86 mm Hg (no SE or 95% CI reported) more than white Linear blood Pb term may not be appropriate. Small sampinterpretation of non-significant results. By using erythrocblood Pb in the same model, these two measures of Pb expconfounded. Incomplete reporting of procedures and resultests reported. Sorel et al. (1991) 

U.S.-NHANES II 1976-1980 

2056 females, 2044 males, 473 blacks and 3627 whites, from 18-74 yrs, were used in survey design and weight adjusted multiple linear regressions stratified by sex, with separate models for systolic and diastolic blood pressure. Covariates included age, BMI, race, and poverty income ratio and linear blood Pb. Method of covariate entry not specified but may have been forced. Different covariate groups were used for different models. Primary test for the effect of race on the Pb-blood pressure relationship was to note the change in the race coefficient in models with and without 

the linear blood Pb variable. 

Age-adjusted arithmetic mean blood Pb: Black female: 13.2 μg/dL (no variance information for any blood Pb) White female: 12.1 μg/dL Black male: 20.1 μg/dL White male: 16.8 μg/dL 

Linear blood Pb was significantly related only to diastolic 

adjusting for age and BMI. For every 1 μg/dL blood Pb inpressure increased 0.13 mm Hg (95% CI: 0.04, 0.21). Adand without linear blood Pb terms did not appear to change Adding poverty index to the models with and without bloosmall change in poverty index coefficient. Linear blood Pb may not be appropriate. Only confidence assess the significance of changes in race and poverty indemodels with and without Pb, instead of using interaction te

with Pb. Incomplete reporting of procedures and results. Nreported. 
 AX6-143 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

United States (cont’d) Sharp et al. (1990) U.S.-San Francisco, CA 1986 After exclusion of subjects under treatment for hypertension, 249 male bus drivers, 132 of whom were black, age from 31 to 65 yrs, were used in race stratified multiple regression models of systolic and diastolic blood pressure with covariate forced entry of age, age-squared, BMI, caffeine use, tobacco use, and natural log blood Pb. Alcohol use was added in other models. Other models stratified by caffeine use. Geometric mean (range) blood Pb: Black males: 6.5 μg/dL (3-21) Non-black males: 6.2 μg/dL (2-15) Significant log blood Pb effects were noted in bl

use, for every one natural log unit increase of blo7.53 mm Hg (95% CI: 0.86, 14.2) and diastolic (95% CI: 0.15, 9.29). Stratified by infrequent/frinfrequent caffeine users showed a significant renatural log unit increase of blood Pb, systolic bloCI: 3.83, 29.5) and diastolic blood pressure rose Non-black blood pressure was decreased with inmarginally significant. In all non-black subjectsblood Pb, systolic blood pressure decreased 

−5.7

Addition of alcohol to the models decreased all cProgressive addition of age, BMI, caffeine, and tincreased the coefficient of natural log blood Pb blood pressure in blacks. Removal of two black results for blacks. No statistical tests for comparing stratified modeuse, effect of progressive addition of covariates, diagnostics reported for detecting the two outlyinreported. Small differences in text and table reposample size limits interpretation of non-significa
 AX6-144 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

United States (cont’d) Tepper et al. (2001) U.S.-Cincinnati, OH After 1991 to before 2001 43 females and 57 males, current or former workers at a Pb-acid battery factory, between 36 and 73 yrs of age, with at least 10 yrs working in battery production, participated. Multivariate regression models and logistic regression models were constructed to assess Pb exposure effect on outcome (hypertension: >140/90 mm Hg and >160/95 mm Hg or taking antihypertensive meds; diastolic and systolic blood pressure, and left ventricular mass/body surface area (g/m2). Echocardiograms were used to determine left ventricular mass. Variables used to adjust all models 

were age, BMI, sex, and family history of hypertension. 

Plant blood Pb records were used to calculate cumulative blood Pb index (CBLI) used as a tertile measure, a linear continuous measure, and a log transformed measure. CBLI μg/dL-yr 1st tertile: 138-504 2nd tertile: 505-746 3rd tertile: 747-1447 Time-avgd blood Pb TABL) was treated the same way: TABL μg/dL 1st tertile: 12-25 2nd tertile: 26-33 3rd tertile: 34-50 

No odds ratios were given for hypertension and adefined as >140/90 mm Hg but ORs were claime2.71 and 1.44 for the 3rd tertile CBLI and TABL 

apparently significant, but no probabilities, SEs oWith the 81 subjects not taking anti-hypertensive TABL tertile were significantly associated with e

pressure (coefficients, SEs or 95% CIs not givenprobability of a positive association with diastolitransformed TABL, probability of a positive asso

was 0.10. No coefficients, SEs, or CIs given. Left ventricular mass adjusted for body surface aany Pb measure. No coefficients, SEs or CIs givDespite the certainty of the authors that “we founassociation...”, the very low power of this study 

findings. Very poor reporting of results further rNo model diagnostic testing was reported. 
 AX6-145 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

United States (cont’d) Vupputuri et al. (2003) U.S.-NHANES III 1988-1994 5188 white women, 2300 black women, 5360 white men, and 2104 black men, aged 18 yrs and older. Survey adjusted multiple linear and logistic regression were used to assess linear blood Pb effect on systolic and diastolic blood pressure and hypertension in race and sex stratified models. Arithmetic mean (SD) blood Pb: White women 3.0 μg/dL (7.2) Black women 3.4 μg/dL (4.8) White men 4.4 μg/dL (7.3) Black men 5.4 μg/dL (9.3) Multiple linear regression models were all adjust

consumption, leisure time physical activity, dieta

calories. Only black women and men showed si1 μg/dL increase in blood Pb was associated with CI: 0.14, 0.80) in systolic and 0.32 mm Hg (95% pressure in black women, and 0.25 mm Hg (95% mm Hg (95% CI: 0.02, 0.36) diastolic blood preOdds of hypertension (systolic ∃140 mm Hg, dia

antihypertensive medication) significantly increablood Pb level in black women (OR = 1.39 [95% (OR = 1.32 [95% CI: 1.14, 1.52]), in black men but not in white men. Linear blood Pb terms are usually not appropriatof blood pressure. Furthermore, they reported thunit of Pb. Linear SD of Pb is incorrect for log-nmodel diagnostic tests reported. Discrepancy besex-Pb interactions in simple, not multiple, analyinteractions for race-Pb and sex-Pb in multiple reregression and logistic regression models, withouinteraction analyses. The probability of the stateextremely low, given the degree of 95% CI overlstratified models. No model diagnostics reported
 AX6-146 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpreta

Europe Bost et al. (1999) Europe-England- Health Survey for England 1995 2763 women and 2563 men from a multi- stage stratified probability survey representative of the English population living in private residences, mean (SE) age for men 47.5 yrs (0.34) and for women 47.7 yrs (0.33) (all subjects 16 yrs and older) were used in an analysis of blood Pb association with systolic and diastolic blood pressure. Stepwise multiple regression analysis were used testing natural log blood Pb against common log systolic blood pressure and non-transformed diastolic blood pressure, with the following potential covariates: age, BMI, smoking status, region of residence, social class, and alcohol consumption. Models were 

stratified by sex, with and without adjustment for alcohol, including or excluding those taking antihypertensive medications. 

Geometric mean blood Pb: Men: 3.7 μg/dL (no stated measure of variance) Women: 2.6 μg/dL (no stated measure of variance 

Model tables presented only standardized variaconsistent results were reported on common lodiastolic blood pressure. Every doubling of bloassociated with an increase of 0.78 mm Hg (95blood pressure, adjusted for age, log BMI, and on antihypertensive medication. Every doublinsignificantly associated with an increase of 0.81.63) in the same model with men on antihyperdoubling of blood Pb was significantly associatmm Hg (95% CI: 0.23, 1.70) in the same modeantihypertensive medication and not adjusting of blood Pb was significantly associated with a(95% CI: 0.37, 1.78) including men taking antnot accounting for alcohol. None of the multipsignificant Pb terms for women. This report was not sufficiently detailed. Stepwprone to the usual pitfalls. Survey design adjuswas not entered in models in which criterion pr(p > 0.05). No rationale given for stratifying. among Pb coefficients for the different models been especially valuable to compare models adalcohol use. No explanation for using log systodependent variable. No model diagnostics repo
 AX6-147 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretati

Europe (cont’d) Fewtrell et al. (2004) Global 1988-2002 Using available global figures on categorized blood Pb ranges by age group, authors calculated relative risk ratios relating increased blood pressure to ischemic heart disease, cerebrovascular disease, hypertensive disease, and other cardiac diseases. They used a calculation of “impact fraction,” based on the proportion of the population within the particular Pb exposure category and the relative risk at that exposure category compared to the risk at the reference level. They used the meta- analysis of Schwartz (1995) to derive an accumulating 1.25 mm Hg increase in blood pressure in men for 5-10, 10-15, and 15-20 μg/dL, and an increase of 

3.75 mm Hg for blood Pb levels above 20 μg/dL. Comparable blood pressure increases in women for each Pb category was 0.8 mm Hg for each of the first three categories and 2.4 mm Hg for blood Pb >20 μg/dL. 

See left for blood Pb categories used. 

The largest risk ratios were for hypertensive diseascalculated at 1.12, 1.41, 1.78, and 2.00 for each of men, and 1.08, 1.25, 1.45, and 1.56 for women. Rcategories increased with increasing Pb category aolder than 44 yrs. The authors assumed a linear relationship between Pb, whereas available evidence suggests it may be blood pressure concentration-response function is accepted by over half the reviewed studies, the calall cardiovascular disease will be overestimated at underestimated at lower blood Pb levels. 
 AX6-148 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation Europe (cont’d) Maheswaran, et al. (1993) Europe-England- Birmingham 1981 809 out of 870 workers, mean (SD) age 43.3 (10.4) yrs, at an Pb acid battery plant were used in the study. Women and workers taking antihypertensive medications were excluded. Used multiple linear regression analyses of systolic and diastolic blood pressure, forcing age, BMI, alcohol use, linear blood Pb, zinc protoporphyrin, yrs of work exposure, cigarette smoking as covariates. Geometric mean (SD) blood Pb: 31.6 μg/dL (5.5) Linear blood Pb was not significant for either systolic or di

Authors used two indices of Pb exposure in the same modeblood Pb range, zinc protoporphyrin was likely collinear wmay not be the appropriate metric to use in blood pressure to adjust for non-linear relationship of blood pressure with diagnostics. Menditto et al. (1994) Europe-RomeNew Risk Factors 

Survey 1989-1990

1319 males, mean (range) age 63 (55-75) yrs, not treated for hypertension, were used in forward stepwise multiple linear regression models of systolic and diastolic blood pressure with available covariates of age, BMI, heart rate, serum high density lipoprotein, non-high density lipoprotein, triglycerides, glucose, cigarette use, alcohol use, sum of five skinfold thicknesses (triceps, biceps, subscapular, suprascapular, and suprailiac), and natural log transformed blood Pb. 

Median (2.5th-97.5th percentiles, range) blood Pb: 11.3 μg/dL (6.2-24.7, 4-44.2) 

Only BMI, heart rate, and serum glucose were not simultancorrelated with both natural log blood Pb and blood pressumodel adjusted for BMI, age, heart rate, high and non-high glucose, and cigarettes, each unit increase in natural log blassociated with a 5.6 mm Hg (95% CI: neither SE nor CI In a diastolic blood pressure model adjusted for BMI, hearand high density lipoprotein, each unit increase in natural lassociated with a 1.7 mm Hg (95% CI: neither SE nor CI In stratified models for alcohol drinkers (n = 1068) and nodrinkers showed significant natural log blood Pb associated coefficients similar to those of the entire group. Authors observed change in natural log blood Pb coefficienof covariates to models. In no case did the coefficients chaaddition of a covariate. Authors noted that wine was the pand that the correlation between alcohol consumption and highest among all correlations reported (p < 0.001; correlaNo statistical tests were made to determine if the change in covariates was significant, nor were statistical tests made tin the alcohol use stratified models were significantly diffealcohol drinking group in stratified analysis precludes intereffects. Incomplete reporting of results. Paper published imeeting papers may indicate that it received less that the npublished research articles. No model diagnostic tests wer
 AX6-149 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpret

Europe (cont’d) Møller and Kristensen (1992) Europe-Denmark- Copenhagen County-Glostrup Population Studies 1976-1990 A cohort born in 1936 was followed at age 40 (women n = 546, men n = 504), age 45 (women n = 430, men n = 463) and again at age 51 (men only n = 439). Reported no difference in results if subjects taking antihypertensive medications were excluded. Reported results included these subjects. Linear multiple regression models of systolic and diastolic blood pressure of follow up, stratified by sex and by yr, used a sequence of forced entry of covariates: natural log blood Pb was tested alone (unadjusted), then adjusted for tobacco, cholesterol, physical activity, and sex (Model 1), then adjusted for the above 

covariates plus systolic blood pressure (Model 2), and then adjusted for the above covariates plus alcohol (Model 3). Another group of linear multiple regression models of change of systolic and diastolic blood pressure from age 40 to 51 yrs in men only, following the same covariate entry scheme as above, but used change in covariates instead of the original covariates. All subjects were followed until 54 yrs of age (from 1976 to 1990) to assess Pb association with total mortality and with coronary heart disease (CHD; ICD-8 410-414) and cardiovascular disease (CVD; ICD-8 430-435) combined morbidity and mortality using Cox proportional hazards models (n = 1050). Cox models were adjusted as above. 

Arithmetic mean (SD, range) blood Pb by age and sex: Women 40 yrs: 9.6 μg/dL (3.8, 4-39) Women 45 yrs: 6.8 μg/dL (3.5, 2-41) Men 40 yrs: 13.6 μg/dL (5.7, 5-60) Men 45 yrs: 9.6 μg/dL (4.3, 3-39) Men 51 yrs: 8.3 μg/dL (4.1, 2-62) 

In women, each one unit increase in natural log bloosignificant increase in systolic blood pressure of 4.9CI stated) at age 40 and an increase of 2.64 mm Hg at age 45, in models adjusted for tobacco, BMI, and alcohol (Model 2) or alcohol plus hemoglobin (Modblood pressure relationships were not significant at echange in natural log blood Pb, diastolic pressure inneither SE nor CI stated) at 40 yrs and 3.26 mm Hg stated) at 45 yrs in Model 1. In Model 2, the increas3.21 mm Hg (p = 0.02; neither SE nor CI stated) at 4neither SE nor CI stated) at 45 yrs. In Model 3, the 

was 2.65 mm Hg (p = 0.07; neither SE nor CI stated(p = 0.01; neither SE nor CI stated) at 45 yrs. In men, the only significant association between natpressure was at 45 yrs. For every increase of one unincrease in systolic blood pressure was 2.73 mm Hg stated). The change in blood Pb between 40 and 51 yrs was change in systolic or diastolic blood over the same pNone of the relative hazard ratios for CHD and DVD 

between 40 and 54 yrs were significantly related to mortality, however, was significantly increased with every increase of one natural log unit of blood Pb wrelative hazard of mortality of 1.96 (p = 0.009; neithevery increase of one natural log unit of blood Pb wrelative hazard of mortality of 1.82 (p = 0.03; neithecases of CHD recorded, of which 13 were fatal. Thof which 19 were fatal. Of the total of 46 subjects w(70%) died of cardiovascular problems. It was not cor a mean blood Pb across ages was used in the Cox 
 AX6-150 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretatio

Europe (cont’d) Møller and Kristensen (1992) (cont’d) Though this study was one of the few to use a long

take advantage of that design feature in blood presssectional multiple regression modeling at each age available in repeated measures modeling. Power to much higher in repeated measurement modeling thmodeling. Analyzing only change in blood pressurregarding starting and ending blood pressure. Incluproblematical due to the unknown history of Pb expthe study, the resultant bone Pb load as a result of pPb contribution of bone to blood, and the unknown past exposure and present exposure to alteration in other covariates as change is also questionable. BMknown and strong effects on blood pressure, may bconstant over the study period or low and relatively both cases, the change in BMI will be small, but thassociated with higher blood pressure than will the modeled as change in BMI should have the same efwhen the high BMI subject has expected higher bloBMI subject. Using difference scores for the depenvariables also risks confounding secular trends in evariables, for whatever reasons, with independent ddependent difference variable effect. The Cox proportional hazards model, however, is lFailure to detect significant associations between Pmorbidity/mortality could have been due to the smatype of analysis. The blood pressure part of the stuinto account during the study, which could have proincreasing “healthy subject” effect. Since subjects medications were included in analyses, an indicator used to account for them, whether or not their excluproduced no apparent change in results. This paper discussion of confounding variables. Incomplete reprocedures. No model diagnostic tests were report
 AX6-151 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation Europe (cont’d) Staessen et al. (1996a) Europe-Belgium- PheeCad study. 1985-1995 359 men and 369 women participated at baseline (between 1985 and 1989) and again about 5 yrs later (median 5.2 yrs) at follow up (between 1991 and 1995), mean age (range) at baseline 46 yrs (20-82), about half of whom were recruited from towns surrounding a non-ferrous smelter (targeted to produce high cadmium exposure) and half from towns without heavy metal production. Over half the men had occupational exposure (59.0% from the near smelter towns, 17.4% from the other 

towns). Four different outcomes were explored: time-integrated conventional blood pressure (avg of 10 baseline and 5 follow up blood pressure measurements), 24-h ambulatory blood pressure only during the follow up period (avg of readings every 20 minutes from 8 AM to 10 PM and every 45 minutes from 10 PM to 8 AM, weighted by interval between measurements), difference in conventional blood pressure over the five yr follow up period, and incidence of developing hypertension during follow up. 

Geometric mean (5th95th percentile) by sex and time period: Baseline women: 6.6 μg/dL (3.3-14.5) Follow up women: 4.8 μg/dL (1.7-11.8) Baseline men: 11.4 μg/dL (5.6-28.8) Follow up men: 7.7 μg/dL (3.7-20.1) 

The study was one of the few prospective longitudinal studieuse of 24-h ambulatory blood pressure as one of its outcome Time-integrated conventional blood pressure models: In 187 peri- and post-menopausal women, after adjusting for glutamyltransferase activity, and hematocrit, each increase of was associated with an increase in diastolic blood pressure of 13.50). No other time-integrated conventional blood pressure 

associated with time-integrated natural log blood Pb in either groups within sex. Ambulatory 24-h blood pressure models: In all 345 women, after adjusting for age, hematocrit, gammaoral contraceptive use, each one unit increase in natural log bincrease of diastolic blood pressure of 3.49 mm Hg (95% CI: limited to the 174 premenopausal women each unit increase iassociated with an increase of diastolic blood pressure of 5.48 Difference in blood pressure between baseline and follow upAfter adjustment for change in BMI, beginning use of antihypcontraceptive medication during the follow up period, and stasignificant relationship between difference in either systolic oPb in women. After adjustment for change in BMI, change in smoking, beginning use of antihypertensive medication in merelationship between difference in either systolic or diastolic 

men. Incidence of hypertension: 

At baseline 107 (14.7%) and 120 (16.5%) subjects had borderespectively. At follow up 98 (13.5%) and 186 (25.5%) had bhypertension, respectively. 51 of 501 initially normotensive hypertensive and 47 of the 501 became border line hypertensAfter adjusting for sex, age, and BMI, natural log baseline blrisk ratios of becoming hypertensive (not stated, but presumaborderline hypertension) or becoming a definite hypertensive
 AX6-152 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretati

Europe (cont’d) Staessen et al. (1996a) (cont’d) Multiple regression models were used to test the association between natural log transformed blood Pb (mean of baseline and follow up Pb) and blood pressure (systolic and diastolic), stratified by sex, then further stratified by use of antihypertensive medications in men and menopausal status in women. Age and age- squared (calculated in quintiles) were forced into the models, then remaining covariates were stepwise added to the model. Though not explicitly stated, natural log blood Pb (mean of baseline and follow up) was likely forced in last. Other candidate covariates were BMI, hemoglobin or hematocrit, serum gamma- glutamyltransferase activity (an index of alcohol 

use) and serum calcium, 24 h urinary sodium and potassium excretion, energy expenditure, exposure to heavy metals (at the workplace), social class, smoking and drinking habits, menstrual status in women, and use of antihypertensive medications, oral contraceptives, and hormone replacement therapy. In ambulatory blood pressure models, differences between baseline and follow up blood pressure models were constructed in the same way. For the difference models “concurrent variations in blood Pb concentrations” were used, presumably difference in baseline and blood Pb. 

The study does not use the full power of repeated analyses. For problems encountered when collapmeasurements to difference measures, see Mølleregressions are prone to capitalizing on chance retesting of the same data and almost always producovariates when they are stratified. Thus, it was information on the effects of stepwise covariate aavailable in this article, that the same covariates based on the stratification variable. There is excfractionation of the data set due to multiple stratireducing the number of subjects in a model to as models using the most subjects had only 359 subsignificant effects cautions against any interpretaresults. The time-integrated model used 10 basemeasurements and 5 follow up blood pressure mweighting the avg toward baseline blood pressurbiochemical correlate of alcohol use in most of theffects and Pb-containing alcohol effects on blooespecially given the European setting and the timstudy was conducted. Control for use of hyperteentered models and partial control for this variabstratified analyses, further reducing power to detremaining subgroup. No justification was given Incomplete information in statistical methods an

interpretation. It was uncertain if stepwise regremodels. No comparisons were performed to assesubject attrition over the course of the study. 
 AX6-153 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretati

Europe (cont’d) Staessen et al. (1996a) (cont’d) For the hypertension incidence model two definitions of hypertension were used: definite hypertension (systolic >160 mm Hg, diastolic >95 mm Hg or taking antihypertensive medications) and borderline hypertension (systolic between 141 to 159 mm Hg and diastolic between 91 to 94 mm Hg). Method of covariate entry into hypertension incidence models not stated. Baseline natural log blood Pb was used as the exposure index. The over six decades of age represented in the samp

quadratic terms based on age quintiles rather than cothat adequate control for age effects on blood pressuthe “healthy subject” effect seen in older groups waaddition of significant covariates was used in the blowere covariates in those models that were marked in non-significant not included in the models, and if th

where the probability values that substitute for the cwere derived. There were no model diagnostic tests 

Staessen et al. (1993) Belgium-Cadmibel Study 1985-1989 

827 males and 821 females recruited from two areas in Belgium, one of them surrounding a non-ferrous smelter, mean age (SD) 46 (15) and 44 (15) yrs, in men and women respectively. Subjects taking antihypertensive medication were excluded from the analyses. Stepwise multiple regression models of systolic and diastolic blood pressure were stratified by sex. Covariates available for entry were age and age-squared, BMI, pulse rate, log protoporphyrin, log gammaglutamyltranspeptidase, serum calcium, log serum ferritin, log serum creatinine, log serum zinc, urinary calcium, urinary sodium, and urinary potassium. Natural log blood Pb was the only variable forced into the models. Additional models tested the interaction of serum calcium and blood Pb on blood pressure. 

Geometric mean blood Pb (range), stratified by sex: Male blood Pb: 10.4 μg/dL (2.7, 84.9) Female blood Pb: 6.2 μg/dL (1.3, 42.4) 

In men, adjusting for age and age-squared, BMI, puglutamyltranspeptidase, serum calcium, and log serunatural log blood Pb increase was significantly assoCI: !0.5, !9.9) decrease in systolic blood pressure. Nsignificant in the model for diastolic blood pressure diastolic blood pressure for women. Adjusting for age and age-squared, BMI, pulse rate, glutamyltranspeptidase, the interaction term betweeserum calcium was only significant for systolic bloodoubling of blood Pb was associated with a 1.0 mm pressure at serum calcium concentration of 2.31 mmincrease in systolic blood pressure of 1.5 mm Hg at 

of 2.42 mmol/L (75th percentile). Stepwise multiple regression analyses run risks of adue to multiple analyses of the same data set. The ruse markers in confounding Pb effect on blood presbeen noted. The unexplained interaction between sehighlights the potential confounding role of serum cpressure studies. The study shows graphs indicating serum calcium and age-blood Pb relationships for myrs of age serum calcium is higher than from 

≤ 29-4
 AX6-154 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation Europe (cont’d) Staessen et al. (1993) (cont’d) exceeds serum calcium of men at those older ages. 

women’s blood Pb with age occurs between the 40-4The timing of these changes in women suggests that factor, which was accounted for only in the model fIt also suggests that serum calcium level and age weblood pressure models. As serum creatinine clearaninversely related, and serum creatinine is a significablood pressure model for men with a significant negit is possible that serum creatinine and blood Pb are pressure in the men’s systolic blood pressure modelassessments of subject selection bias due to exclusioexamining quintile blood pressure relationships with the acceptability of the linear relationship implied btechnique. No other model diagnostic tests were rep

Telišman et al. (2004) Europe-CroatiaZagreb Date of data collection not given. 

100 workers from factories producing Pbbased products, mean (range) age 30 (20-43) yrs. Exclusion criteria were absence of psychological stress (e.g., death in family) over last 4 mos, absence of verified diabetes, coronary heart disease, cerebrovascular and peripheral vascular disease, renal disease, hyperthyroidism, androgenital syndrome, primary aldosteronism, and “other diseases that could influence blood pressure or metal metabolism.” Linear or natural log blood Pb were considered for stepwise entry in models of systolic and diastolic blood pressure, forcing in all other covariates: blood cadmium, BMI, age, serum zinc, serum copper, hematocrit, smoking, and alcohol. 

Arithmetic mean (range) blood Pb: 36.7 μg/dL (9.9-65.9) 

Neither linear nor natural log blood Pb entered as siregression models of systolic and diastolic blood preVery small sample size limited power to detect signsignificant effects should not be interpreted as lack ocovariates for a small study. Almost no subjects belhypertensive medications not controlled, likely a prodiastolic blood pressure in the group 170 mm Hg anNo model diagnostic testing reported. 
 AX6-155 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretatio

Asia Lee et al. (2001) Korea-Chonan 1997-1999 798 workers from various Pb-using or producing factories, mean (SD, range) age 40.5 yrs (10.1) [17.8-64.8], 79.4% male, were classified as to Vitamin D receptor genotype (VDR bb or Bb/BB) and delta-aminolevulinic acid dehydratase (ALAD11 or 12) genotype, as VDR polymorphism has been implicated in modifications of Pb absorption and Pb uptake and release from bone as well as risk for elevated blood pressure and hypertension, and ALAD polymorphism affects Pb binding to it in the erythrocyte, the major storage depot of Pb in blood. The hypothesis was that polymorphism type could influence the effect of Pb on blood pressure and hypertension. 

Multiple linear regression models of linear blood Pb, DMSA-chelatable Pb, and tibia Pb effect on systolic and diastolic blood pressure with potential covariates of age and agesquared, sex, creatinine clearance, hemoglobin, weight, height, BMI, job duration, tobacco and alcohol consumption, pack-yrs of tobacco, and cumulative life time alcoholic drinks. Stepwise procedure allowed retention of covariates only if they were significant or “there were substantive changes in the coefficients of predictor variables after” their inclusion. In the models shown, Appearance of multiple Pb variables and the interaction between Pb variables and genotype for each gene depended upon the specific model. Both ALAD and VDR receptor polymorphism were sometimes tested simultaneously in each model containing polymorphism terms and sometimes VDR appeared without ALAD. 

Arithmetic mean (SD, range) blood Pb: 32.0 μg/dL (15.0, 4-86) Mean (SD, range) DMSA-chelatable Pb: 186 μg (208.4, 4.8-2103) Mean (SD, range) tibia Pb: 37.2 μg/g (40.4, !7 to 338) 

With simple t-tests, subjects with VDR Bb/BB allehad more DMSA-chelatable Pb, and had higher sypressure than subjects with VDR bb allele. In multiple regression models of systolic blood preand age-squared, sex, BMI, antihypertensive medilife-time alcoholic drinks, adding tibia Pb, VDR tyincrease of 10 μg/g of tibia Pb was associated with (95% CI: 

−0.01, 0.49) and VDR BB/Bb type was 

of 3.24 mm Hg (95% CI: 0.18, 6.30) blood pressutype. ALAD genotype was not significant. In the substituting linear blood Pb for tibia Pb, each increblood Pb was associated with an increase of 0.07 m0.14) and VDR BB/Bb type was associated with a(95% CI: !0.22, 5.94) blood pressure compared to genotype had no significant effects on blood pressWhen both tibia and linear blood Pb were entered VDR genotype, adjusting for the same covariates, significant; compared to VDR bb, blood pressure w2.41, 8.61) higher. ALAD genotype had no signifpressure. In a model without any Pb terms, VDR genotype wand the age-squared terms. The VDR Bb/BB genolinear age term was significant for systolic blood pthe bb genotype the VDR Bb/BB genotypes’ blood 0.36 mm Hg (95% CI: 0.06, 0.66) per yr faster wi

There were no significant effects of any Pb variablpressure, though the VDR Bb/BB genotype had sigpressure (1.9 mm Hg; not enough information givebb genotypes. There were no significant interactions of the Pb mfor either ALAD or VDR. 
 AX6-156 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretati

Asia (cont’d) Lee et al. (2001) (cont’d) Logistic regression analysis was used to test the effect of the Pb indices on hypertension (systolic >160 mm Hg or diastolic >96 mm Hg or taking antihypertensive medications) using the same group of potential covariates, testing the Pb terms and the Pb-genotype interaction terms separately. The hypertension models tested both gene polymorphisms separately. Subjects with the Bb/BB genotypes had a significantl

prevalence (OR = 2.1 [95% CI: 1.0, 4.4]) than subjecadjusting for age, sex, BMI, tibia Pb, and current alcosignificant effects of any Pb variable nor of ALAD on Linear blood Pb may not give efficient and unbiased eblood pressure. The descriptive data shows highly skDMSA-chelatable Pb, and tibia Pb in this group, suggeffect on blood pressure may not have been efficient ausually produce different covariate patterns for differe

indicate that the covariates used for all the models dismodel diagnostic tests were reported. Lustberg et al. (2004) 

Korea-Chonan 1997-1999 (period of enrollment; no statement on dates of data collection) 

793 (number given for genotype analysis; numbers in models not given) current and former Pb workers, mean (SD) age 40 (10) yrs and 80% male, were genotyped for the three polymorphisms of endothelial nitric oxide synthase (eNOS) (GG, GT, TT), an enzyme that is a modulator of vascular resistance. The effect of genotype and the interaction of genotype with blood Pb and tibia Pb on systolic and diastolic blood pressure were evaluated by multiple linear regression analyses, forcing covariates of age (modeled as a 2 degree of freedom spline with knot at 45 yrs), sex, natural log BMI, smoking and alcohol consumption, high school education, and job duration. Both blood Pb and tibia Pb were entered as percentiles and entered together. Logistic models of hypertension (systolic ∃140 mm Hg or diastolic ∃90 mm Hg or 

reported use of antihypertensive medication) used the same covariates. Interaction terms between each of the Pb measures (plus a Pb-squared term) and genotype was used to determine differential effect of Pb according to genotype. 

Pb according to genotype: Arithmetic mean (SD) blood Pb, GG: 32 (15) μg/dL Arithmetic mean (SD) blood Pb, TG/TT: 32 (15) μg/dL Mean (SD) tibia Pb, GG: 37 (42) μg/g Mean (SD) tibia Pb, TC/TT: 36 (34) μg/g 

85% (673/793) of the group were typed GG, 14% (11were TT. TG and TT groups were combined for analMean systolic and diastolic blood pressures, adjusted significantly different between GG and TG/TT groupIn multiple regression models for systolic and diastoli

percentile blood Pb nor percentile tibia Pb, entered topredictors. Interaction terms between the Pb variablesignificant. In the logistic regression model for hypertension, neitpercentile tibia Pb, entered together, were significant Reporting was incomplete: number of subjects entericomparisons between recruited subjects and subjects nreporting non-significant interactions, the paper showanalyses stratified by genotype, reporting significant aand blood Pb in the GG genotype, insignificant in the plots revealed striking non-linearity for both adjusted and adjusted tibia Pb-systolic blood pressure relationsTG/TT genotypes and highly unbalanced terms of the contributed to the non-significant interactions. Althoualso probed as a quadratic function, the tibia Pb interapoor concentration-response specification in the mode

the lack of significant main effects and interactions. 
 AX6-157 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretatio

Asia (cont’d) Nomiyama et al. (2002) China, Beijing No statement on dates of data collection 123 female Pb-exposed leaded crystal toy workers, mean age (range) 27.3 (17-44) yrs, and 70 female sewing workers (reference group), mean age (range) 24.2 (16-58) yrs were tested. Forward stepwise multiple regression models of systolic and diastolic blood pressure of the combined groups were used with linear blood Pb and a set of covariates. Variables with p < 0.2 were allowed to enter. The covariate set was selected from a larger set of potential covariates by factor analysis, and a representative variable from each factor was selected for possible entry in the regressions. 

Alternate models were constructed using four ordered categories of blood Pb, instead of the linear continuous blood Pb variable. Logistic regressions were used to determine the odds of elevated systolic (∃125 mm Hg) and elevated diastolic (∃80 mm Hg) blood 

pressure as a function of blood Pb category. 

Blood Pb mean (SD, range) in Pb workers: 55.4 (13.5, 22.5- 99.4 μg/dL Blood Pb mean (SD, range) in nonPb workers: 6.4 (1.6, 3.8- 11.4) μg/dL 

Adjusted for age, urine protein, and plasma triglyceridlinear blood Pb significantly associated with a 0.13 mblood pressure (no SE or CI given; p = 0.0003). Adjuage, urine protein, plasma low density lipoprotein, and 1 μg/dL increase in linear blood Pb was associated widiastolic blood pressure (no SE or CI given; p = 0.000Using the ordered categories of blood Pb and the samdiastolic blood pressure, the 40-60 μg/dL group had 4higher systolic blood pressure and 4.1 mm Hg (95% Cblood pressure than the reference group (blood Pb (<1∃60 μg/dL blood Pb had 7.5 mm Hg (95% CI: 3.0, 126.3 mm Hg (95% CI: 3.4, 9.1) diastolic blood pressurgroup. Logistic regression models for “elevated” blood presscovariates were similar. In the 40-60 μg/dL group od∃125 mm Hg and diastolic blood pressure ∃80 mm H

17.04) and 2.43 (95% CI: 0.97, 6.04), respectively, hThe odds of “elevated” systolic and diastolic blood prPb ∃60 μg/dL were 7.48 (95% CI: 1.86, 30.12) and 3

respectively. Incomplete reporting in paper: no model N, no SEs fono description of type of factor analysis used or dates use of factor analysis to select covariates that, depend

was run, could have produced a set of orthogonal variHowever, BMI was not included in the original set of Small sample size limits conclusions based on nonsigregression produced a different covariate pattern for e

pressure. The linear blood Pb variable may be inapprskewness of blood Pb in descriptive analysis. The 11 between Pb workers and non-Pb workers could have ianalyses with continuous blood Pb. Larger age spread exposed group could have caused misspecification of antihypertensive medication use. No model diagnosti
 AX6-158 Table AX6-5.1 (cont’d). Effects of Lead on Blood Pressure and Hypertension Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretatio

Asia (cont’d) Wu et al. (1996) Central Taiwan No statement on dates of data collection 222 workers in two Pb battery plants, 112 men, mean (range) age 36.2 (18-67) yrs, and 110 women, mean (range) age 36.2 (18-71) yrs were tested for blood Pb relationships with systolic and diastolic blood pressure in multiple regression models, using a fixed, forced set of covariates: age, sex, BMI, working history, yrs of work, noise exposure, natural log ambient air Pb concentration, and ordered categorical blood Pb concentration. Arithmetic mean (SD, range) blood Pb: Women: 44.6 (18.4, 8.3-103.1) μg/dL Men: 60.2 (26.8, 17.0-150.4) μg/dL Using four ordered blood Pb categories (<25 μg/dL 

40 μg/dL [58/222; 26.1%], 41-60 μg/dL [63/222; 2[85/222; 38.3%]) adjusted systolic and diastolic bl

significantly related to the top three blood Pb categlowest, natural log ambient Pb. Yrs in work envirpredictor of both systolic and diastolic blood pressmarginally significant for systolic blood pressure adiastolic blood pressure. Small study size limits any conclusions drawn from Three measures, all related to Pb exposure, were smodels. While blood Pb may only be weakly corrambient air Pb would be expected to be much bettThere is a clear possibility of collinearity among thwould inflate standard errors and reduce coefficienordered categories of Pb to “avoid unnecessary assuse of natural log air Pb concentration suggests tharun, but no model diagnostic tests were reported. antihypertensive medication use. 
 AX6-159 Table AX6-5.2. Effects of Lead on Cardiovascular Morbidity Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation United States Cheng et al. (1998) U.S.-Boston, Normative Aging Study (VA) 1991-1995 775 males (97% white), mean age (SD, range) 67.8 yrs (7.3, 48-93). Multiple linear regression models of heart rate-corrected QT and QRS electrocardiogram intervals were adjusted by stepwise entry of covariates, retaining only those that remained significant at p < 0.10. Linear blood Pb, tibia, and patella bone Pb were apparently (not described in text) entered separately. Logistic regression models for Minnesota ECG Coding Center diagnoses of intraventricular conduction deficit 

(IVCD), atrioventricular conduction deficit (AVCD), and arrhythmia were adjusted by covariates the same way. Only analyses stratified by age (<65 yrs, n = 277; ∃65 yrs, n = 498) were presented 

Arithmetic mean (SD) blood Pb: 5.8 μg/dL (3.4)Mean (SD) tibia Pb: 22.2 μg/g (13.4) Mean (SD) patella Pb: 30.8 μg/g (19.2) 

Multiple regression models of QT intervals, adjusted BMI, and diastolic blood pressure, found that only tibsignificantly related to outcome in the under 65 grouptibia and patella Pb was associated with a 5.0 ms (95% (95% CI: 0.2, 5.8) increase in QT interval, respectivemodels of QRS intervals, adjusted for age, fasting glublood pressure, also found that only tibia and patella Pto outcome in the under 65 group. Every 10 μg/g incrwas associated with a 4.8 ms (95% CI: 1.8, 7.8) and 2increase in QRS interval, respectively. There were no the 65 and over group. Logistic regression models of IVCD, adjusted for age found that only tibia Pb was significantly related to ou65 group. Every 10 μg/g increase of tibia Pb was assoof IVCD, OR = 2.23 (95% CI: 1.28, 3.90). There wein the 65 and over group for IVCD. Logistic regressioadjusted for age and serum HDL level, found that botsignificantly related to outcome in the 65 and over groincrease of tibia Pb and patella Pb was associated with OR = 1.22 (95% CI: 1.02, 1.47) and OR = 1.14 (95% respectively. Pb was not significantly related to AVCThere were no significant effects of Pb on arrhythmia Stepwise models may capitalize on chance association

specification may not be appropriate in some or all of three models were constructed for each stratified analbased on a different Pb index. No statistical comparismodel diagnostics were presented. 

Gump et al. (2005) U.S.-Oswego, NY Dates of study not given 

See Gump et al. (2005) entry in Blood Pressure and Hypertension section for heart rate, stroke volume, cardiac output, total peripheral resistance, and cardiac interbeat interval data. 
 AX6-160 Table AX6-5.2 (cont’d). Effects of Lead on Cardiovascular Morbidity Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation United States (cont’d) Navas-Acien (2004) U.S.-NHANES IV-Phase 1 1999-2000 2125 subjects (1070 males, 1055 females), age 40->70 yrs were tested for peripheral arterial disease (PAD; n = 139) by taking the ratio of the ankle mean systolic blood pressure to the arm mean systolic blood pressure. Any subject with the ratio <0.90 was classified as PAD. Logistic regression analysis was weighted and adjusted by sample design. Covariates forced into the models were age, sex, race, education, and Pb quartile (Model 1); Model 1 covariates plus BMI, alcohol intake, hypertension, diabetes, hypercholesterolemia, glomerular 

filtration rate, and C-reactive protein (Model 2); Model 2 covariates plus self-reported smoking status and serum 

cotinine (Model 3); and Model 3 covariates plus cadmium quartile (Model 4). Tested interactions between Pb and cadmium on PAD, and between Pb and sex, race, smoking status, renal function, and c-reactive 

protein on PAD. Tested for trend of OR as a function of Pb quartile. 

Geometric mean blood Pb (25th-75th percentile): 2.1 μg/dL (1.4, 2.9) Pb quartile 1: <1.4 μg/dLPb quartile 2: 1.4-2.1 μg/dL Pb quartile 3: 2.1-2.9 μg/dL Pb quartile 4: >2.9 μg/dL 

Odds for PAD significantly increased with Pb quartile comparison) for all four models. Only models 1 and 2

significant increase in odds of PAD for the 4th Pb quaquartile, OR = 3.78 (95% CI: 1.08, 13.19) and OR = None of the tested interactions with blood Pb quartile Well-designed study with sound statistical analysis. Ismoking in Models 3 and 4 (smoking status and cotincontrolled for smoking). There was a trend toward inincreased smoking status and with increased cotinine tests of trend were reported. Thus the two smoking vbeen confounded with PAD. No model diagnostic tes

Schwartz (1991) NHANES II U.S. 1976-1980 

See Schwartz (1991) entry in Blood Pressure and Hypertension for left ventricular hypertrophy results. 
 AX6-161 Table AX6-5.2 (cont’d). Effects of Lead on Cardiovascular Morbidity Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation United States (cont’d) Tepper et al. (2001) U.S.-Cincinnati, OH After 1991 to before 2001 See Tepper et al. (2001) entry in Blood Pressure and Hypertension for left ventricular mass results. Europe Gustavsson et al. (2001) Europe- Stockholm, Sweden 1992-1994 Study base was all Swedish citizens 45-70 yrs old from Stockholm County free of previous myocardial infarction. Cases who survived at least 28 days after infarct (1,105 males and 538 females) of which 937 men (85%) and 

398 women (74%) had sufficient information on occupational exposures and “main confounders”, were compared against referents (1,120 men and 538 women) matched to cases by sex, age, yr, and hospital catchment area. Risk ratios for the case group compared to referent group were adjusted on the basis of the matching variables and smoking, alcohol drinking, hypertension, overweight, diabetes mellitus, leisure physical “inactivity”, and were calculated for a number of exposure factors separately, including Pb. 

Pb exposure was classified as none, low or high corresponding to airborne dust levels of 0, >0 to 0.03, and ∃0.04 mg/m3, 

respectively, for the highest intensity of exposure during at least one yr of work. The same three classifications were used for 0, >0 to 0.04, and ∃0.05 mg/m3 for cumulative exposure. 

All risk ratios were calculated relative to the “no exporisk ratios for surviving a myocardial infarction were and 1.03 (95% CI: 0.64, 1.65) for low and high exposexposure, and were 0.81 (95% CI: 0.60, 1.11) and 1.0and high cumulative exposure groups. This study of myocardial morbidity was compromised characterization (occupational air dust Pb concentratiocovariate collinear with Pb exposure and confounded hypertension, in the adjusted models. No model diagnostics were reported. 
 AX6-162 Table AX6-5.3. Effects of Lead on Cardiovascular Mortality Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation United States Lustberg and Silbergeld (2002) U.S.-NHANES II 1976-1980, follow up to 1992 4190 persons, 30 to 74 yrs, 929 of whom died during follow up, had baseline blood Pb measurements during the NHANES II period. Proportional hazard models for circulatory disease-related death (ICD-9 codes 390-459) were based on the complex survey design, but not weighted. Presented models were unadjusted, adjusted for age and sex, and adjusted for age, sex, location, education, race, income, smoking, BMI, and exercise. Blood Pb was entered as an ordinal three-category variable. Blood Pb <10 μg/dL, n = 818 Blood Pb 10-19 μg/dL, n = 2735 Blood Pb 20-29 μg/dL, n = 637 Blood Pb ∃30 μg/dL, n = 102, excluded from analysis Crude, sex and age adjusted, and multivariate adju

mortality were all significantly increased in the 20to the <10 μg/dL reference group. Risk ratio for thcrude circulatory mortality was 1.74 (95% CI: 1.2adjusted circulatory mortality was 1.48 (95% CI: multivariate circulatory mortality was 1.39 (95% CStratified analyses were performed by race, sex, agbut only for all-cause mortality. No model diagno

Schober et al. (2006) U.S.-NHANES III 1988-1994, follow up to 2000 

9757 persons, age 40 yrs, 2515 of whom died during follow-up (median length of follow-up 8.55 yrs), had baseline blood Pb measurements during the NHANES III period. Analyses were performed using proportional hazard models for all cause deaths, major cardiovascular disease-related deaths (I00-I78), and malignant neoplasms (C00-C97). Multivariate models were adjusted for sex, race/ethnicity, education, and smoking status and stratified by age. Blood Pb was entered as an ordinal threecategory variable. 

Blood Pb <5 μg/dL (median 2.6 μg/dL), n = 6608 Blood Pb 5-9 μg/dL (median 6.3 μg/dL), n = 2532 Blood Pb 10 μg/dL (median 11.8 μg/dL), n = 617 

Multivariate-adjusted cardiovascular disease mortaincreased in the 10 μg/dL group compared to the <All cause and cancer mortalities were significantly and 10 μg/dL groups. Relative risk for cardiovascular disease mortality, 5-9 μg/dL: 1.20 (95% CI: 0.93, 1.55) 10 μg/dL: 1.55 (95% CI: 1.16, 2.07) Relative risk for all cause mortality, compared to <5-9 μg/dL: 1.24 (95% CI: 1.05, 1.48) 10 μg/dL: 1.59 (95% CI: 1.28, 1.98) Relative risk for cancer mortality, compared to <5 5-9 μg/dL: 1.44 (95% CI: 1.12, 1.86) 10 μg/dL: 1.69 (95% CI: 1.14, 2.52) Tests for trends were statistically significant for al
 AX6-163 Table AX6-5.3 (cont’d). Effects of Lead on Cardiovascular Mortality Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation United States (cont’d) Michaels et al. (1991) U.S.-New York City 1961-1984 1261 males, avg age (range) at the beginning of study 49.6 yrs (19-83), representing 24,473 person-yrs were followed. 498 died in the interval. Subjects belonged to the International Typographical Union and worked at two large city newspapers. Hot Pb linotyping was discontinued at the newspapers during 1974-1978, providing the primary source of occupational exposure. Last exposure for all subjects still employed was at the end of 1976. Standardized mortality ratios (SMR) were calculated using the LTAS program developed by NIOSH, calculating the 

expected number of deaths of the cohort referenced to a comparison population, in this case disease-specific mortality rates from New York City. Cohort was stratified based on yrs of employment. Causes of death were based on ICD-8 codes. 

Exposure was estimated based on yrs of linotype employment before the end of 1976. Authors note that, based on measurements at other print shops using hot Pb linotype, air Pb levels probably did not exceed 20 μg/m3. 

Standardized mortality ratio was significant (SMR = only for cerebrovascular disease in those working, and or more. Neither arteriosclerotic heart disease (ICD-8 lesions of the central nervous system (ICD-8 430-438the total cohort not stratified by yrs of exposure. No direct measurement of Pb exposure. Many groupiexplored in stratified and unstratified analyses, with thelevated SMR found for cerebrovascular disease. No General weakness of all studies relying on a compariscohort belongs to the comparison population and can mortality rates in direct proportion to the ratio betweepopulation size. 
 AX6-164 Table AX6-5.3 (cont’d). Effects of Lead on Cardiovascular Mortality Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation United States (cont’d) Steenland et al. (1992) U.S.-Idaho >1941 to 1988 The death certificates of 1028 males of the 1990 who worked at a smelter plant at least one yr between 1940 and 1965 were examined to construct standardized mortality ratios (SMR) for various ICD-9 disease classifications using the U.S. population as a referent group. In 1976 blood Pb of 173 workers avgd (SD) 56.3 μg/dL (12.9). Air Pb was measured in 1975 at 3.1 mg/m3 in 208 personal 8-h samples. High Pb departments in the plant were defined as those exceeding 0.2 mg/m3 in the 1975 survey. Non-malignant respiratory disease and accidents acco

significantly elevated SMR in the group. SMRs were for ischemic heart disease (410-414), SMR = 0.94 (95hypertension with heart disease (402, 404), SMR = 0.hypertension with no heart disease (401, 403, 405), SM3.77); or cerebrovascular diseases (430-436), SMR = Similar results were found for the people working in tThough there is no doubt that this group was highly echaracterization over the working lifetime was not wedata were available, and poor demographic data for th

allowed a comparison with total U.S. population. As exposed groups, selection bias may influence results. available for the group. In industrial conditions smokwith other Pb exposure (constant hand to mouth behavexposure smokers to more Pb via the oral route than i
 AX6-165 Table AX6-5.3 (cont’d). Effects of Lead on Cardiovascular Mortality Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpretation Europe Gerhardsson et al. (1995) Europe-southern Sweden 1969-1989 664 male workers at a secondary Pb smelter had blood Pb tested every 2-3 mos since 1969. The past blood Pb level of 201 workers who had been working at the plant from before 1969 was estimated from their 1969 results. Median (10th percentile, 90th percentile) yr of birth was 1943 (1918, 1960). Median (10th percentile, 90th percentile) duration of employment was 2.8 yrs (0.3, 25.7) and median (10th percentile, 90th percentile) duration of follow up was 13.8 yrs (2.8, 20.9). A total of 8706 person-yrs were represented in the study. Standardized mortality ratios based on county 

mortality tables by calendar yr, cause, sex and five-yr age group were calculated. Cardiovascular diseases were coded by ICD-8 from death certificates. 

Arithmetic mean blood Pb levels dropped from ~62 μg/dL in 1969 to ~33 μg/dL in 1985. 95% CI were difficult to extract from the presented graph, but appeared to be no more than 5-6 μg/dL about the mean. 

All cardiovascular disease mortality (ICD-8 390-458) above that expected from the county mortality tables 1.05, 2.02]), with 39 of the 85 deaths observed in the heart disease (ICD-8 410-414), SMR = 1.72 (95% CIworkers with 34 of the 85 deaths observed in the cohorecorded for cerebrovascular diseases (ICD-9 430-438concentration-response relationship, using peak blood blood Pb. Problems inherent in using standardized mortality ratihave been discussed above. The sample size was too among 664 workers) to interpret non-significant resul

Møller and Kristensen (1992) Europe-DenmarkCopenhagen County-Glostrup Population Studies 1976-1990 

See Møller et al. (1992) entry in Blood Pressure and Hypertension for results of cardiovascular disease and coronary heart disease mortality. 
 AX6-166 Table AX6-5.4. Cardiovascular Effects of Lead on Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

United States Chen et al. (2006) U.S.-Baltimore, MD; Cincinnati, OH; Newark, NJ; Philadelphia, PA ~1998-2004 780 children from 12-33 mos participated in a randomized clinical trial of oral succimer chelation in four clinical centers. Half the children had up to three 26-day treatments, the other half were given placebo. 75% got two treatment sessions and 81% of those with two treatments received a third. Blood pressure was measured pre- treatment, at 7, 28, and 42 days after each treatment, then every 3 to 4 mos for five yrs of follow up. Cross-sectional multiple regression models adjusting for clinic location, baseline linear Pb, race, sex, parents’ education, single parent, age 

at test, height at test, and BMI at test for each period of the study tested the difference of diastolic and systolic blood pressure between placebo and succimer groups. Cross-sectional multiple regression models for the effect of linear blood Pb at each period on blood pressure adjusted for clinic location, treatment group, race, sex, parents’ education, single parent, age at test, height and BMI. Two mixed models, one from start of treatment to 9-mo follow up, the other from 12 to 60 mos follow up, adjusted for the same variables, and tested the effect of treatment group over time. 

Blood Pb ranged from 20-44 μg/dL at pre-treatment and from 1-27 μg/dL at 5 yr follow up. Succimer-treated group had significantly lower blood Pb than placebo group only for 9-10 mos following the end of treatment. Blood Pb did not differ significantly beyond that period. 

Adjusted systolic blood pressure was signifgroup than the placebo group at 36 mos (1.22.48]) and at 60 mos follow up (1.69 mm HSystolic blood pressure was not significantlperiod; diastolic blood pressure was never sgroups. Concurrent linear blood Pb was not associatcross-sectional models at any time point in coefficients for linear blood Pb and systolic 1.36 mm Hg (95% CI: !0.58, 3.30) at pre-trCI: !1.91, 0.48) at 36 mos of follow up. Di

were generally lower but followed the same Mixed model analysis for start of treatment showed succimer treatment effect of 0.24 mfor systolic and 0.46 mm Hg (95% CI: !0.4pressure. The treatment effect from 12 thro1.09 mm Hg (95% CI: 0.27, 1.90) systolic !0.45, 0.75) for diastolic blood pressure. The only reliable effect of succimer treatmeblood pressure, especially notable between treatment. The authors could not account foblood pressure in the succimer-treated grouIt is notable that the two groups had differena yr after succimer treatment ended, a perioany beneficial effect of treatment. Failure tblood Pb on blood pressure, especially pre-t

exposure for a period of less than three yrs aaffect blood pressure or that blood pressure yrs of life are highly variable, as could be sepressure vs. blood Pb at pre-treatment compuse of linear Pb term may have reduced sen

blood Pb effect on blood pressure. No mod
 AX6-167 Table AX6-5.4 (cont’d). Cardiovascular Effects of Lead on Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpret

United States (cont’d) Gump et al. (2005) U.S.-Oswego, NY Dates of study not given 122 9.5-yr old children participated. Multiple regression models of percent changes in systolic and diastolic blood pressure, heart rate, stroke volume, cardiac output, and total peripheral resistance due to acute stress were adjusted by stepwise entry of up to 50 possible control variables with quartile blood Pb forced in last. A linear contrast was used to test dose-response effects of quartile Pb. Linear Pb terms were also used. Contemporary blood Pb quartile: 1st quartile: 1.5-2.8 μg/dL 2nd quartile: 2.9-4.1 μg/dL 3rd quartile: 4.2-5.4 μg/dL 4th quartile: 5.5-13.1 μg/dL All ∃ represent percent change in outcome f

condition for each change in 1 μg/dL blood Systolic blood pressure: ∃ = !0.009 (95% CDiastolic blood pressure: ∃ = 0.069 (95% CHeart rate: ∃ = 0.013 (95% CI: !0.046, 0.0Stroke volume: ∃ = !0.069 (95% CI: !0.12

Cardiac output: ∃ = !0.056 (95% CI: !0.11

Total peripheral resistance: ∃ = 0.088 (95% 

Mean successive difference of cardiac inter∃ = !0.028 (95% CI: (!0.098, 0.042) Despite low power to detect significant effeoutput, and total peripheral resistance changwith contemporary blood Pb. Stepwise modmodels for each outcome. Some models haplus Pb, an excessive number for only 122 sregression with linear Pb and bar charts of rshowed obvious non-linearity, though all Pb linear effects. Probability of contemporary PCB’s was very high. No model diagnostic 

Europe 

Factor-Litvak et al. (1996) Europe-Kosovska Mitrovica and Pristina, Kosovo ~1992-1993 

281 5.5-yr old children studied since pregnancy participated. Multiple linear regression models of systolic blood pressure, adjusted for height, BMI, gender, ethnic group, and birth order, and diastolic blood pressure, adjusted for waist circumference, ethnic group, and birth order were constructed by stepwise elimination from a larger pool of potential confounding variables and retained if they modified the linear blood Pb coefficient by more the 10%. 

Blood Pb arithmetic mean (range): 22.7 μg/dL (5-55) 

For each increase of 1 μg/dL of blood Pb: Systolic blood pressure: ∃ = 0.054 (95% CIDiastolic blood pressure: ∃ = 0.042 (95% CDespite low power to detect significant effesignificant tendency for blood pressure to bblood Pb. Stepwise multiple regression machance results. The linear Pb term may havdetect significant effects of Pb if the modelenonlinear. Log Pb was tested but not reportwas reported nonsignificant. No model diag
 AX6-168

ANNEX TABLES AX6-6 
 AX6-169 Table AX6-6.1. Placental Transfer of Lead from Mother to Fetus Reference and Study Location Study Description Pb Measurement Findings

United States Harville et al. (2005) Pittsburgh, PA 159 mother-infant pairs. Maternal blood Pb at delivery: Mean 1.93 μg/dL (range 0.55-4.70) Cord blood Pb: Mean 1.64 μg/dL (range 0.05-3.95) Correlation coefficien

On avg, cord blood Pblood Pb by 0.03 μg/

Angell and Lavery (1982) Louisville, KY 635 cord blood specimens. 154 maternal and infant blood samples collected 24 h postpartum from these deliveries. Maternal blood Pb: Mean 9.85 μg/dL (SD 4.4) Infant blood Pb: Mean 9.82 μg/dL (SD 4.8) Cord blood Pb: Mean 9.78 μg/dL (SD 4.1) Maternal-infant blood 

Correlation coefficienMaternal-cord blood Correlation coefficienCord-infant blood PbCorrelation coefficien

Bogden et al. (1978) Newark, NJ 25 deliveries of infants with birth weights between 1,500-2,500g and 50 matched controls with birth weights above 2,500g. Low birth weight infants: Maternal blood Pb: 

Mean 16.2 μg/dL (SD 4.5) Cord blood Pb: Mean 13.8 μg/dL (SD 4.4) Normal birth weight infants: Maternal blood Pb: Mean 15.3 μg/dL (SD 5.2) Cord blood Pb: Mean 13.1 μg/dL (SD 4.3) 

No significant differecord blood ratios in lobirth weight infants. Correlation coefficien
 AX6-170 Table AX6-6.1 (cont’d). Placental Transfer of Lead from Mother to Fetus Reference and Study Location Study Description Pb Measurement Findings

United States (cont’d) Fahim et al. (1976) Missouri 249 mother-infant pairs from Columbia. Samples also collected from 253 mothers from Rolla who delivered near Pb mining areas. Term pregnancies: Columbia (n = 240): Maternal blood Pb: Mean 13.1 μg/100 g (SE 0.31) Fetal blood Pb: Mean 4.3 μg/100 g (SE 0.10) Placenta blood Pb: Mean 7.0 μg/100 g (SE 0.01) Cord blood Pb: Mean 11.0 μg/100 g (SE 0.31) Rolla (n = 177): 

Maternal blood Pb: Mean 14.3 μg/100 g (SE 0.16) Fetal blood Pb: Mean 4.6 μg/100 g (SE 0.08) Placenta blood Pb: Mean 8.0 μg/100 g (SE 0.06) Cord blood Pb: Mean 11.0 μg/100 g (SE 0.14) 

Maternal-fetal blood Correlation coefficien
 AX6-171 Table AX6-6.1 (cont’d). Placental Transfer of Lead from Mother to Fetus Reference and Study Location Study Description Pb Measurement Findings

United States (cont’d) Gershanik et al. (1974) Shreveport, LA 98 mother-infant pairs. Maternal blood Pb during labor: Mean 10.3 μg/dL Cord blood Pb: Mean 10.1 μg/dL Correlation coefficienEurope Graziano et al. (1990) Kosovo, Yugoslavia 902 births in Titova Mitrovica, site of a large Pb smelter, refinery, and battery factory, and Pristina, a non-Pb-exposed control town. Maternal blood Pb at mid-pregnancy: Geometric means: Titova Mitrovica 17.1 μg/dL (95% CI: 16.9, 42.6) Pristina 5.1 μg/dL (95% CI: 2.5, 10.6) Maternal blood Pb at 

blood Pb: Correlation coefficien

Huel et al. (1981) France Hair sample pairs (n = 100) from mothers and newborns at time of delivery. Maternal hair Pb: Geometric mean 8.5 μg/dL Fetal hair Pb: 

Geometric mean 7.3 μg/dL 

Correlation coefficien

Lauwerys et al. (1978); Roels et al. (1978) Belgium 

474 mother-infant pairs from Antwerp, Brussels, Leuven, Tournai, and Vilvoorde. 

Maternal blood Pb: Mean 10.1 μg/dL (range 3.1-31) Infant blood Pb: Mean 8.3 μg/dL (range 2.7-27.3) Placenta blood Pb: Median 7.5 μg/100 g wet weight (range 1.1-39.5) 

Maternal-infant blood Correlation coefficienln placenta-maternal Correlation coefficienln placenta-infant bloCorrelation coefficien

Barltrop (1969) England 

29 paired maternal and fetal samples. Maternal blood Pb: 

Mean 13.9 μg/100 g Cord blood Pb: Mean 10.8 μg/100 g 

Correlation coefficien
 AX172 Table AX6-6.1 (cont’d). Placental Transfer of Lead from Mother to Fetus Reference and Study Location Study Description Pb Measurement Findings

Europe (cont’d) Barltrop (1969) England 34 fetuses at gestational age 10 to 40 wks obtained from termination of pregnancy and neonatal deaths. Blood Pb levels in femur, liver, blood, brain, heart, and kidney measured. Pb became detectable 

wks. For skeletal (fehigh affinity (liver), Pprogressively until tetissue with low affiniincrease in Pb levels wks and term. Latin America Chuang et al. (2001) Mexico City, Mexico 615 women recruited in 1994-1995. Investigators used structural equation modeling to estimate plasma Pb as the unmeasured variable and to quantify the interrelations of cord blood Pb with plasma Pb, whole blood Pb, and bone Pb (cortical and trabecular). Maternal whole blood Pb: Mean 8.45 μg/dL (SD 3.94) Maternal patella bone Pb: Mean 14.24 μg/g bone mineral (SD 14.19) Maternal tibia bone Pb: Mean 9.67 μg/g bone mineral (SD 9.21) 

Cord blood Pb: Mean 6.55 μg/dL (SD 3.45) 

ln cord-ln maternal wCorrelation coefficienln cord-ln maternal pCorrelation coefficienln cord-maternal pateCorrelation coefficienln cord-maternal tibia Correlation coefficienThe structural equatiomaternal plasma Pb hwith fetal cord blood whole blood Pb. In asuggested a significanthe skeletal system to a contribution that is influence of maternal 
 AX6-173 Table AX6-6.1 (cont’d). Placental Transfer of Lead from Mother to Fetus Reference and Study Location Study Description Pb Measurement Findings

Other Locations Clark (1977) Zambia 122 mother-infant pairs residing near the Broken Hill Pb Mine and Smelter. Control group of 31 mother-infant pairs. Mine group: Maternal blood Pb: Mean 41.2 μg/dL (SD 14.4) Infant cord blood Pb: Mean 37.0 μg/dL (SD 15.3) Control group: Maternal blood Pb: Mean 14.7 μg/dL (SD 7.5) Infant cord blood Pb: Mean 11.8 μg/dL (SD 5.6) Mine group: Correlation coefficien

Control group: Correlation coefficien

Casey and Robinson (1978) New Zealand 

40 fetuses (23 stillborn and 17 died within 24 hrs), 22 to 43 wks gestation. 

Pb detected in 73% of liver, 23% of kidneys, 40% of brain, 25% of heart, 33% skeletal muscle, and 70% of bone samples. Pb also detected in 11 of 14 lung samples (79%). Overall Pb concentration in soft tissue: 0.1-2.4 μg/g dry matter Pb concentration in bone samples: 0.4-4.3 μg/g dry matter 

Pb concentrations in the other tissues. Levels in brain, heartvalues reported for chin liver, kidney, lungthan adult values, sugenters the body after tissues. 

Chaube et al. (1972) 50 embryos and fetuses 31 to 261 days 

gestational age that were aborted. 

Among the 1st trimester specimens: Pb detected in 77% of liver, 15% of brain, and 30% of kidney samples. 

Placental transfer occtrimester of pregnanc
 AX6-174 Table AX6-6.2. Lead Exposure and Male Reproduction: Semen Quality Reference and Study Location Study Description Pb Measurement Findings

United States Benoff et al. (2003a) New York 74 male partners of women undergoing their first in vitro fertilization cycle. Seminal plasma Pb: Mean 39.50 μg/dL (SD 35.97) Significant negative c

plasma Pb and fertilizStatistically significavalues of <!0.3) were plasma Pb levels and morphology. Strongewere observed betwevalues and mannose r!0.383), and mannose(r = !0.423). 

Benoff et al. (2003b) New York 

15 semen donors in an artificial insemination program. None were occupationally exposed to Pb. 

Seminal plasma Pb: Range <10 to >150 μg/dL 

Correlation coefficienand artificial fecundit

Cullen et al. (1984) U.S. 

Seven men with symptomatic occupational Pb intoxication. 

Maximum whole blood Pb levels: 66-139 μg/dL 

Although serum testonormal in six patientsspermatogenesis, incloligospermia and two examinations after chonly partial improvemHeavy occupational eassociated with diffuand reproductive funrapidly reversible wit
 AX6-175 Table AX6-6.2 (cont’d). Lead Exposure and Male Reproduction: Semen Quality Reference and Study Location Study Description Pb Measurement Findings

Canada Alexander et al. (1996a) British Columbia 119 workers employed at a Pb smelter. Current blood Pb: Mean 22.4 μg/dL (range 5-58) Sperm concentration 

inversely related to cconcentration, with thamong men with blooμg/dL or more. Blood Pb (μg/dL)  <15 

15-24 25-39 

∃40 

Blood Pb levels were with abnormal morphthe sperm. When classified by loPb, calculated from thconcentrations of the trends were observed
 AX6-176 Table AX6-6.2 (cont’d). Lead Exposure and Male Reproduction: Semen Quality Reference and Study Location Study Description Pb Measurement Findings

Europe Bonde et al. (2002) UK, Belgium, Italy European study of 503 men (362 exposed to Pb, 141 unexposed controls) employed in Pb industry. Blood Pb: Exposed workers: Mean 31.0 μg/dL (range 4.6-64.5) Unexposed workers: Mean 4.4 μg/dL Median sperm concen

men with blood Pb leOdds ratio for sperm men with blood Pb leto <10 μg/dL was 4.4 Regression analyses iof 44 μg/dL below wassociations were fou

Assennato et al. (1986) Italy 18 battery workers (exposed group) and 18 cement workers (control group). Blood Pb: Battery workers: Mean 61 μg/dL (SD 20) Cement workers: Mean 18 μg/dL (SD 5) 

Semen Pb: Battery workers: Mean 79 μg/dL (SD 36) Cement workers: Mean 22 μg/dL (SD 9) 

Sperm count and bloor

2

 = !0.385 

Sperm count and sperr

2

 = !0.026 

38% lower median spgreater prevalence of 5.5%) in battery workworkers. 

Lancranjan et al. (1975) Europe 

150 men occupationally exposed to Pb divided into four groups: Pb-poisoned workmen (n = 23) and those showing a moderate (n = 42), slight (n = 35), or physiologic absorption (n = 50). 

Blood Pb: Pb poisoned workers: Mean 74.5 μg/dL Moderately exposed workers: Mean 52.8 μg/dL 

Decreased sperm couprevalence of morphoamongst workers witexposure to Pb. 
 AX6-177 Table AX6-6.2 (cont’d). Lead Exposure and Male Reproduction: Semen Quality Reference and Study Location Study Description Pb Measurement Findings

Latin America Hernandez-Ochoa et al. (2005) Region Lagunera, Mexico 68 environmentally-exposed men residing in Torreón, Gómez Palacio, and Lerdo for at least 3 yrs. Blood Pb: Geometric mean 9.3 μg/dL (range 2-24) Seminal fluid Pb: Geometric mean 2.02 μg/L (range 1.14-12.4) Pb in spermatozoa: Geometric mean 0.047 ng/106 cells (range 0.032- 0.245) Decreased sperm con

morphology and viabspermatozoa. Reducwith seminal fluid PbMultiple linear regrespercentages of progremorphology were the to Pb toxicity, which percentages of abnormquality parameters evaluated. No associations were 

Lerda (1992) Argentina 38 male workers exposed to Pb in a battery factory and 30 controls. Blood Pb: A (n = 12): mean 86.6 μg/dL (SD 0.6) 

B (n = 11): mean 65.9 μg/dL (SD 1.6) C (n = 15): mean 48.6 μg/dL (SD 4.2) Controls (n = 30): mean 23.5 μg/dL (SD 1.4) 

Decreased sperm coumotility, and increasemorphology observed groups compared to c

Asia 

Chowdhury et al. (1986) India 

Ten men occupationally exposed to Pb in a printing press. 

Blood Pb: Exposed group: Mean 42.5 μg/dL Unexposed group: Mean 14.8 μg/dL 

Decrease in sperm coincrease in number omorphology observed 
 AX6-178 Table AX6-6.3. Lead Exposure and Male Reproduction: Time to Pregnancy Reference and Study Location Study Description Pb Measurement Findings

Europe Joffe et al. (2003) Belgium, England, Finland, Italy Asclepios Project, large European collaborative cross-sectional study. 1,108 men (638 occupationally exposed to Pb at the time of pregnancy) who have fathered a child. Blood Pb: Belgium: mean 31.7 μg/dL England: mean 37.2 μg/dL Finland: mean 29.3 μg/dL Italy: mean 29.2 μg/dL 

Blood Pb (μg/dL)  control 

<20 

20-29 30-39 

∃40 

Results indicate that between blood Pb anpregnancy. Similar rduration of exposure used as the exposure 

Apostoli et al. (2000) Italy 

Italian men included in the Asclepios project. 251 exposed men and 45 unexposed men with at least one completed pregnancy. 

Blood Pb distribution among exposed men:  Percentage Blood Pb (μg/dL) of population 0-19 14%  20-29 40%  30-39 32% 

∃40 14% 

Time to pregnancy shmale partner exposed Among the exposed mpregnancy observed w∃40 μg/dL, though no
 AX6-179 Table AX6-6.3 (cont’d). Lead Exposure and Male Reproduction: Time to Pregnancy Reference and Study Location Study Description Pb Measurement Findings

Europe (cont’d) Sallm

θn et al. 

(2000a) Finland 

502 occupationally exposed males monitored by the Finnish Institute of Occupational Health. 

Blood Pb distribution (available close to time of conception in 62% of men; in 38% estimated based on blood Pb levels obtained at other times or based on job histories):  Percentage Blood Pb (μg/dL) of population

 <10 35%  10-20 40%  21-30 16%  31-39 4% 

∃40 5% 

Results suggest that pbe associated with in Blood Pb (μg/dL)  <10  10-20  21-30  31-39 

∃40 

Asia 

Shiau, et al. (2004) Taiwan 

280 pregnancies in 133 couples in which male partner employed in battery plant. 127 conceived during exposure; remainder conceived prior to exposure. 

Blood Pb: Annual means from 1987 to 1999 ranged from 32 to 41 μg/dL. 

 Blood Pb (μg/dL)  unexposed  <20  20-29  30-39 

∃40 

Using blood Pb as a crestricting the analysibetween 10 and 40 μincreased by 0.15 moin blood Pb level. 
 AX6-180 Table AX6-6.4. Lead Exposure and Male Reproduction: Reproductive History Reference and Study Location Study Description Pb Measurement Findings

United States Lin et al. (1996) New York 4,256 male workers reported to the New York State Heavy Metals Registry (exposed) and 5,148 male bus drivers from the New York State Department of Motor Vehicles file (control), frequency-matched for age and residence. Fertility during the period of 1981 to 1992. Records linked to birth certificates from the New York State Office of Vital Statistics. Blood Pb in Pb-exposed men: Mean 37.2 μg/dL (SD 11.1) Standardized fertility 

comparison with non(95% CI: 0.81, 0.95)Exposed group had feAmong those employ5 yrs, a relative risk o0.61) was observed aeducation, and reside

Europe Gennart et al. (1992) Belgium 74 men occupationally exposed to Pb for more than 1 yr and 138 men in reference group with no occupational exposure. Blood Pb in Pb-exposed men: Mean 40.3 μg/dL Duration of Pb exposure: Mean 10.7 yrs Compared to referenc

one live birth reduced the period of Pb expo[95% CI: 0.43, 0.98]Fertility decreased w(although number of levels small). 

Bonde and Kolstad (1997) Denmark 

1,349 male employees ages 20-49 yrs from three battery plants and control group of 9,656 men not employed in Pb industry. Cohorts identified by records in a national pension fund. Information on births obtained from Danish Population Register. 

Blood Pb in subset of battery worker cohort (4,639 blood samples from 400 workers): Mean 35.9 μg/dL (SD 13.0) 

No associations founmeasure and birth ratRelative risk compariPb exposure with yrs was 0.88 (95% CI: 0
 AX6-181 Table AX6-6.4 (cont’d). Lead Exposure and Male Reproduction: Reproductive Histor

Reference and Study Location Study Description Pb Measurement FindingsEurope (cont’d) Sallm

θn et al. 

(2000b) Finland 

Occupationally exposed males monitored by the Finnish Institute of Occupational Health. 2,111 individuals with probable exposure (a blood Pb level ∃10 μg/dL within a 5-yr time period including a calendar yr preceding the yr of marriage and 4 consecutive yrs) and 681 controls (with mean blood Pb levels <10 μg/dL). 

Blood Pb distribution among individuals probably exposed:  Percentage Blood Pb (μg/dL) of population

 10-20 51%  21-30 30%  31-40 11%  41-50 5% 

∃51 3% 

Risk ratios among megroup: Blood Pb (μg/dL) In

 controls 

 10-20  21-30  31-40  41-50 

∃51 

Results suggest that pincreases the risk of ioccupational exposur
 AX6-182 

ANNEX TABLES AX6-7
 AX6-183 Table AX6-7.1. Recent Studies of Lead Exposure and Genotoxicity Reference, Study Location, and Period Study Description Pb Measurement Findings and Inter

Europe Fracasso et al. (2002) Italy Case-control design. 37 workers employed at a battery plant. 29 student and office worker volunteers with no known occupational exposure to genotoxins. Peripheral lymphocytes isolated from whole blood. Reactive Oxygen Species (ROS) production, cellular GSH level, PKC isoforms, and DNA breaks (via comet) assayed. ANOVA and logistic regression used to compare workers vs. healthy volunteers. Adjusted for age, alcohol use, and smoking. Battery plant workers. Blood Pb categories used for some comparisons, with <25, 25-35, and >35 μg/100mL as cutpoints. Mean blood Pb 39.6 μg/100mL for workers, 4.4 μg/100mL for volunteers. OR (95% CI) Workers vs. Volunteers: ROS: 1.43 (0.79, 2.60) DNA breaks (tail moment): 1.07 (1.0

GSH: 0.64 (0.49, 0.82) PKC α reduced in workers, atypical Pvolunteers (no statistics provided). Means (SE) via blood Pb category for 

<25 μg/100 mL 4.9 (0.425-35 μg/100 mL 5.4 (0.7>35 μg/100 mL 5.4 (0.5

Major analyses controlled for age, smAnalyses by blood Pb category not coor alcohol intake but these factors saiand/or results “significantly.” No concoexposures. 
 AX6-184 Table AX6-7.1 (cont’d). Recent Studies of Lead Exposure and Genotoxicity Reference, Study Location, and Period Study Description Pb Measurement Findings and Inter

Europe Palus et al. (2003) Poland Cross-sectional design. Battery plant workers: 34 acid battery, 22 alkaline battery, and 52 plant personnel from departments with no known exposure to Pb or cadmium. Lymphocytes isolated from whole blood. SCE, MN, DNA damage (via comet) assayed. Means compared via ANOVA. Workers considered Pb-exposed if from acid battery department, cadmium-exposed if from alkaline, unexposed if from other department. Mean blood Pb 504 μg/L for Pb-exposed workers, 57 μg/L for cadmium-exposed, and 56 μg/L for other workers. Mean (SD) Pb exposed workers (all combined): SCEs 7.48 (0.88) MN 18.63 (5.01) NDI 1.89 (no SD given) Cadmium exposed workers (all comb

SCEs 6.95 (0.79) MN 15.86 (4.92) NDI 1.96 (no SD given) Other workers (all combined): SCEs 6.28 (1.04) MN 6.55 (3.88) NDI 1.86 (no SD given) Elevation of SCEs and MN vs. con

p < 0.01, respectively. 

Both SCEs and MN elevated among Pas cadmium-exposed workers compargreatest for Pb-exposed workers. Higher SCE and MN also occurred amafter stratification by smoking status. No direct control for potential coexpocadmium no higher in Pb-exposed tha
 AX6-185 Table AX6-7.1 (cont’d). Recent Studies of Lead Exposure and Genotoxicity Reference, Study Location, and Period Study Description Pb Measurement Findings and Inter

Europe (cont’d) Van Larebeke et al. (2004) Belgium Cross-sectional design. 99 female nonsmokers, ages 50-65, drawn from rural and industrial areas. Peripheral lymphocytes isolated from blood. HPRT variant frequency determined. Pb concentration measured in blood (serum). Women also classified as above vs. below median for blood Pb. HPRT variant frequency Above median serum Pb: 9.45 

Η 10-6 

Below median serum Pb: 5.21 

Η 10-6 

P-value for difference = 0.08 adjusted smoking, BMI, and serum selenium. (association noted between variant freselenium.) Uncontrolled for potential genotoxins. 

Latin America

Minozzo et al. (2004) Brazil 

Cross-sectional design. 26 workers employed at a battery recyclery for 0.5 to 30 yrs. 29 healthy volunteers of similar age range and SES. Peripheral lymphocytes isolated from whole blood. Fixed blood slides stained with Giemsa visually evaluated to determine micronuclear frequency (MN) and cellualr proliferation as nuclear division index (NDI). ANOVA and logistic regression used to compare workers vs. healthy volunteers. Adjusted for age, alcohol use, and smoking. 

Battery recyclery workers were considered exposed. Blood Pb also determined. Mean blood Pb 35.4 μg/dL for workers, 2.0 μg/dL for volunteers. 

Means (SD) for workers and volunteeMN: 3.85 (2.36) and 1.45 (1.43) NDI: 1.77 (0.22) and 1.89 (0.18) Kendal correlation coefficient: All workers {assuming recyclery worpopulation, but no population number Blood Pb 

Η MN: 0.061 (p = 0.33) 

Blood Pb 

Η NDI: 0.385 (p = 0.003) 

Not controlled for age or SES, althoupopulations said to be of similar age a

potential coexposures. Correlations asmoking, age, or other factors. Differminor for smokers vs. nonsmoker, ho“similar” for workers and controls, alsimilarity provided. 
 AX6-186 Table AX6-7.2. Key Occupational Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and In

United States Steenland et al. (1992) (follow-up of Selevan et al. (1985) U.S. 1940-1988 Cohort design. 1,990 male workers employed for at least 1 yr in a Pb-exposed department at a U.S. Pb smelter in Idaho during 1940-1965. Mortality traced through 1988 to determine cause of death. SMR computed for workers vs. national rates for age-comparable counterparts. Exposure categorizations based on airborne Pb measurements from 1975 survey. High-Pb-exposure subgroup consisted of 1,436 workers from departments with an avg of least 0.2 mg/m3 airborne Pb or ≥50% of jobs showing 0.40 mg/m3 or greater. Mean blood Pb 56 μg/dL in 1976. SMR (95% CI); number of deaths Total cohort: Nonsignificantly elevated RRs: kidne

cancer. High-Pb-exposure subgroup: Kidney 2.39 (1.0

Bladder 1.33 (0.4Stomach 1.28 (0.6Lung 1.11 (0.8

No control for smoking or exposure t

Wong and Harris (2000) (follow-up of Cooper et al. (1985) U.S. 1947-1995 Cohort design. Pb battery plant (4,518) and smelter (2,300) workers. Worker mortality was followed up through 1995. Cause of death was identified from 

death certificates. Mortality was compared with U.S. national age-, calendar-yr-, and genderspecific rates to compute the SMR. (See additional entry for nested study of stomach cancer.) 

Workers were evaluated as a whole, and also as separate battery plant and smelter worker populations. Job histories were also used to stratify workers by cumulative yrs of employment (1-9, 10-19, 20+), date of hire (pre-1946 vs. 1946 on), and lag between exposure and cancer (<20, 20-34, >34 yrs). Mean blood Pb 80 μg/dL during 1947-72 among smelter workers, 63 μg/dL among battery workers. 

SMR (95% CI) Battery plant workers: 

All cancer 1.05 (0.9All respiratory 1.13 (0.9Stomach 1.53 (1.Lung, trachea, bronchus 1.14 ( 0Thyroid, Hodgkin’s: nonsignBladder 0.49 (0.

Smelter workers: 

Digestive, respiratory, thyroid: noLung 1.22 (1.0

Battery plant and smelter workers com

All cancer 1.04 (0.9All respiratory 1.15 (1.0Stomach 1.47 (1.Lung, trachea, bronchus 1.16 ( 1Thyroid/endocrine 3.08 (1.

Lung and stomach risks lower pre-19employed 10-19 yrs than <10, but lowwith 20- to 34-yr latency for lung, buNo control for smoking or exposure tof employment history after 1981. 
 AX6-187 Table AX6-7.2 (cont’d). Key Occupational Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Interp

United States (cont’d) Wong and Harris (2000) U.S. 1947-1995. (Nested in Wong and Harris 200 cohort.) Case-control design. Cases: the 30 stomach cancer cases occurring in a Philadelphia Pb battery plant. Controls: 120 age-matched cohort members. Mean exposure was compared for cases vs. controls. Odds of exposure were also computed for increasing quartiles of cumulative exposure. Job titles were used to classify Pb exposure as low, intermediate, or high; total mos of any exposure, of intermediate or high exposure only, and of cumulative exposure, with mos weighted by 1, 2, or 3 if spent in low-, intermediate-, or high-exposure job. Mean mos of employment, of intermed

weighted exposure to Pb were all nonsicases. OR for cumulative weighted exposure i1st quartile 1.00 2nd quartile 0.62 3rd quartile 0.82 4th quartile 0.61 p for trend = 0.47; ORs showed no posany index of exposure. Analyses appear uncontrolled for smokexposures, or other risk factors. Europe 

Fanning (1988) (Cases overlap those occurring in Dingwall-Fordyce and Lane, 1963; and Malcolm and Barnett, 1982). U.K. 1926-1985 

Proportional mortality/cohort design.

Subjects: 2,073 deceased males identified through pension records of Pb battery and other factory workers in the U.K. Workers dying from a specific cancer were compared with workers dying from all other causes 

Workers were classified as High or moderate Pb exposure vs. little or no exposure based on job titles. 

OR (95% CI); number of deaths Lung cancer: 0.93 (0.8, 1.1); 76 Stomach cancer: 1.34; 31 No associations for other cancer types; total digestive cancers limited to the pe
 AX6-188 Table AX6-7.2 (cont’d). Key Occupational Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Inter

Europe (cont’d) Anttila et al. (1995) Finland 1973-1988 Cohort plus case-referent design. 20,700 workers with at least one blood Pb measurement between 1973 and 1983. Workers were linked to the Finnish Cancer Registry for follow-up through 1988. For deceased workers, cause of death was identified from death certificate. Mortality and incidence were compared with gender-, 5-yr age, and 4-yr calendar-yr matched national rates. Exposure was categorized according to the highest peak blood level measured: Low: 0-0.9 μmol/L (0-18.6 μg/dL) Moderate: 1-1.9 μmol/L (20.7-39.4 μg/dL) High: 2-7.8 μmol/L (41.4-161.6 μg/dL) Mean blood Pb 26 μg/dL. Total cohort: No elevation in total or site-specif

Moderately exposed: Total respiratory and lung cancer: SIR = 1.4 (95% CI: 1.0, 1.9) for b

Total digestive, stomach, bladder, 

nonsignificant elevations. Highly exposed: No increase in risks. All cancer: RR = 1.4 (95% CI: 1.1, 1.8) Lung or tracheal: RR = 2.0 (95% CI: 1.2, 3.2) No increase in high-exposure grouNo RRs reported for other cancers

Case-referent substudies: 

Lung cancer ORs increased with in

exposure to Pb. 

Highly exposed: squamous-cell lu

(95% CI: 1.1, 15) after adjustment 

Short follow-up period limits statis

large degree by the substantial sam

exposure to other potential carcino
 AX6-189 Table AX6-7.2 (cont’d). Key Occupational Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and In

Europe (cont’d) Anttila et al. (1996) Finland 1973-1988 (Nested analysis based on Antilla et al., 1995 cohort) Case-control design. (See Anttila et al., 1995 for basic information on the source population.) Cases: 26 Finnish men with CNS cancer. Controls: 200 Finnish men without CNS cancer. Nested case-control analysis. Peak blood Pb levels used to categorize exposure as 0.1-0.7, 0.8-1.3, and 1.4-4.3 μg/L. Cumulative exposure estimated by using mean annual blood Pb level to categorize exposure as 0, 1-6, 7-14, or 15-49 μg/L. Interviews were used to obtain occupational history and other risk- factor data from patients or next of kin. Number of cases or deaths CNS cancer incidence (26 cases): Ro

blood Pb measurements; not significaGlioma mortality (16 deaths): Rose cwith peak and mean blood Pb level, dcumulative exposure. Mortality by cumulative exposure, co

and yr monitoring began: Low (13 subjects) 2.0 (

Medium (14 subjects) 6.2 (High (16 subjects) 12.0 (

One death among 26 subjects with no significant at p = 0.02. Controlled for smoking as well as exp

Complete follow-up with minimal dis

Gerhardsson et al. (1995) Sweden 1969-1989 

Cohort design. 684 male Swedish secondary Pb smelter workers with Pb exposure. Cancer incidence among workers was traced through 1989. Incidence was compared with county rates. 

Blood Pb level: any worker with a detectable blood Pb level was classified as exposed. 

SIR (95% CI); number of cases All malignancies: 

1.27 (0.91, 1.74); 40 

Respiratory: 

1.32 (0.49, 2.88); 6 

All gastrointestinal: 

Cohort 1.84 (0.92, 3.29); 11 Highest quartile 2.34 (1.07, 4.45); 9 

Stomach: 

1.88 (0.39, 5.50); 3 

Colon: 

1.46 (0.30, 4.28); 3 

SIRs for all other sites except brain w

too few cases. No control for smoking. Small numbresponse analyses not possible for mo
 AX6-190 Table AX6-7.2 (cont’d). Key Occupational Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Inter

Europe (cont’d) Lundström et al. (1997) (follow-up of Gerhardsson et al. (1986) (see also subcohort analyses of Englyst et al., 2001). Sweden 1928-1987 Cohort design. 3,979 copper and Pb smelter workers. Standardized mortality and incidence ratios were computed for workers compared with age-, yr-, gender-, and county-specific rates for the general population. For some analyses, the entire cohort was treated as exposed. For others, job histories were used to single out 1,992 workers belonging to departments thought to be exposed to “Pb only.” Mean blood Pb monitoring test results across time were used to single out a “highly exposed” group of 1,026 workers with blood Pb levels ≥10 μmol/L 

[≥207 μg/dL]. Mean blood Pb 60 μg/dL in 1959. 

SMR (95% CI); number of deaths Lung: 

Total cohort 2.8 (2Highly exposed 2.8 (

SIR (95% CI); number of cases Lung with 15-yr lag: 

Total cohort 2.9 (2Highly exposed 3.4 (Pb-only 3.1 (1.7Pb-only highly exposed 5.1 (2.0

Other highly exposed (total cohort), w

Brain 1.6 (Renal pelvis, ureter, bladder 1.8 (Kidney 0.9 (All cancer 1.1 (No control for smoking. 

Englyst et al. (2001) (follow-up and subanalysis of Lundström et al., 1997). Sweden 1928-1987 

Nested cohort analysis. Limited to 1,093 workers in the smelter’s Pb department, followed through 1997. Incidence was compared with county rates; age-specific SIRs with 15-yr lag. 

Workers were divided into Subcohorts I and II for ever and never worked in areas generally associated with exposure to arsenic or other known carcinogens (701 and 383 workers, respectively). Detailed individual assessment of arsenic exposure was made for all lung-cancer cases. 

SIR (95% CI); number of cases Subcohort I (coexposed): Lung 2.4 (1.2, 4.5); 10 Subcohort II (not coexposed): Lung 3.6 (1.2, 8.3); 5 Subjects with lung cancer found to havexposure to arsenic: 9/10 among SubcSubcohort II. No control for smoking. 
 AX6-191 Table AX6-7.2 (cont’d). Key Occupational Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Inter

Europe (cont’d) Carta et al. (2003) Sardinia 1972-2001 Cohort design. 918 Pb smelter workers. Mortality traced from 1972 through 2001. Standardized mortality ratios computed. Smelter workers considered exposed. Job histories also used to categorize degree of exposure based on environmental and blood Pb measurements for specific departments and tasks during 1985-2001. SMR; number of cases Smelter workers as a whole All cancer 1.01; 108 Gastric cancer 1.22; 4 Lymphoma/leukemia 1.82; 6 Lung cancer 1.21; 18 Highly exposed workers Lung cancer 1.96 (95% CI: 1.02, 3.6

group, with statistically significant upAnalyses for worker population as a wpresence of dose-response pattern for estimated exposure. Modest populatidose-response for cancers of interest for smoking or other occupational exp
 AX6-192 Table AX6-7.3. Key Studies of Lead Exposure and Cancer in the General Populatio

Reference, Study Location, and Period Study Description Pb Measurement Findings and InterUnited States Jemal et al. (2002) (same cohort as in Lustberg and Silbergeld, 2002 except for inclusion criteria) U.S. 1976-1992. Cohort design. 3,592 white participants from the 1976-1980 NHANES II survey who had blood Pb measured at entry. Mortality was followed through 1992 via NDI and SSADMF. RRs were calculated for the various exposure groups compared to survey participants with the lowest exposure, adjusted for age and smoking. Blood Pb (μg/dL) was measured by atomic absorption and used to classify subjects into exposure quartiles or groups above vs. below median exposure. Median blood Pb 12 μg/dL. RR (95% CI); number of deaths Lung (above vs. below median): Total cohort 1.5 (0.7, 2.9); 71 Male 1.2 (0.6, 2.5); 52 Female 2.5 (0.7, 8.4); 19 Stomach (above vs. below median): Total cohort 2.4 (0.3, 19.1); 5 Male 3.1 (0.3, 37.4); 4 Female no deaths in referent group All cancer: total cohort by quartile (age-a

(p = 0.16 for trend). Smoking was controlled for. Pb levels ocwere examined, not just those in workers wpotential. Exposure to other carcinogens wresidual confounding by degree and duraticontrolled for never, former, current <1, ccase numbers yield low statistical power f
 AX6-193 Table AX6-7.3 (cont’d). Key Studies of Lead Exposure and Cancer in the General Popu

Reference, Study Location, and Period Study Description Pb Measurement Findings and InterUnited States Lustberg and Silbergeld (2002) (same cohort as Jemal et al., 2002 except for inclusion criteria) U.S. 1976-1992. Cohort design. 4,190 U.S. participants from the 1976- 1980 NHANES II health and nutrition survey who had blood Pb measured at entry and whose levels fell below 30 μg/dL. Mortality was followed through 1992 via NDI and SSADMF. RRs were calculated for the various exposure groups compared to survey participants with the lowest exposure, adjusted for age, smoking and other factors. Blood Pb (μg/dL) measured by atomic absorption was used to classify subjects into exposure groups: Low: <10 Medium: 10-19 High: 20-19 Mean blood Pb 14 μg/dL. RR (95% CI) All cancer, vs. low exposure: Medium 1.5 (0.9, 2.5) High 1.7 (1.0, 2.8) Lung, vs. low exposure: Medium 1.7 (0.6, 4.8) High 2.2 (0.8, 6.1) Non-lung, vs. low exposure: Medium 1.5 (0.8, 2.8) High 1.5 (0.8, 2.8). Significant upward trends noted for all-ca

mortality with increasing Pb category. Smoking was controlled for in the analysigeneral population were examined, with in

consistent with intense occupational expoexploration of potential effects outside of occupational exposure. Exposure to other Potential for residual confounding by degrexists (only controlled for never, former, cLimited case numbers yield low statistical cancers. 
 AX6-194 Table AX6-7.4. Other Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Interpr

United States Mallin et al. (1989) Illinois 1979-1984 Case-control design. Cases: random sample of 10,013 deaths from 7 specific cancers, identified from death certificates for Illinois males between 1979 and 1984. Controls: 3,198 randomly selected deaths from other causes. Odds of exposure computed for glass workers vs. other occupations. Exposure was based on occupations abstracted from death certificates. No specific measure of Pb exposure; glass workers can be considered potentially exposed. Brain cancer, white male glass workers: OR = 3.0, p < 0.05 No significant associations for other cance

No control for smoking or other risk factoexposure. Cocco et al. (1998a) U.S. 1984-1992 Case-control design. Cases: all 27,060 brain cancer deaths occurring among persons aged 35 or older during 1984-1992, from U.S. 24-state death certificate registry. Controls: 4 gender-, race-, age-, and region-matched controls per case 

selected from deaths due to nonmalignant causes. Subjects were subdivided into 4 groups by gender and race (white or AfricanAmerican) for all analyses. 

A job-exposure matrix was applied to death certificate-listed occupations to categorize persons as having low, medium, or high probability and intensity of exposure. 

Risk of brain cancer mortality increased cexposure among African-American malesgroups. Probability of exposure alone was not conrisk. In the high-probability group, risk increas

for all groups except African-American whigh-probability group). Exposure estimate was based solely on oc

certificate, hence there was substantial oppmisclassification. 
 AX6-195 Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Interpr

United States (cont’d) Cocco et al. (1998b) U.S. 1984-1992 Case-control design. Cases: all 28,416 CNS cancer deaths occurring among persons aged 35 or older during 1984-1992, from U.S. 4-state death certificate registry. Controls: 4 gender-, race-, age-, and region-matched controls per case selected from deaths due to nonmalignant causes. Subjects were subdivided into 4 groups by gender and race (white or African- American) for all analyses. Death certificate listed industry and occupation was used to categorize decedents. No estimates of Pb exposure specifically. OR (95% CI) All occupations or industries with ORs ab

least one race-gender group were reported Newspaper printing and publishing industWhite male 1.4 (1.1, 1.8) Black male 3.1 (0.9, 10.9) Typesetting and compositing: White male 2.0 (1.1, 3.8) White female 1.3 (0.4, 3.8) Black female 4.2 (0.6, 30.7) No deaths among black males. Only two Pb exposure associated occupatistatistically significant elevation of mortalof Pb exposure. Occupation based solely there was substantial opportunity for misc
 AX6-196 Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Interpr

United States (cont’d) Cocco et al. (1999) U.S. 1984-1996 Case-control design. Cases: all 41,957 stomach cancer deaths occurring among persons aged 35 or older during 1984-1996, from U.S. 24-state death certificate registry. Controls: 2 gender-, race-, age-, and region-matched controls per case selected from deaths due to nonmalignant causes. Subjects were subdivided into 4 groups by gender and race (white or African- American) for all analyses. A job-exposure matrix was applied to death certificate- listed occupations to categorize persons as having low, medium, or high probability and intensity of exposure. OR (95% CI) Adjusted for age, ethnicity, marital status, 

socioeconomic status. Elevated ORs: White female, high probability of exposurBlack male, high probability of exposure Black female, high probability of exposurHighly exposed group included 1,503 whi65 white and 10 black women; no pattern levels. Intensity of exposure showed no associatiexcept for black women: Low 1.82 (1.04, 3.18) Moderate 1.39 High 1.25 No control for other occupational exposurbased on occupation listed on death certifimisclassification due to missing longest-h
 AX6-197 Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Interpr

Canada Risch et al. (1988) Canada 1979-1982 Case-control design. Cases: 826 Canadian men with histologically confirmed bladder cancer during 1979-1982. Controls: 792 controls from Canadian population, matched on age, gender, and area. Odds of exposure to Pb for cases vs. controls were computed, adjusted for smoking and other risk factors. Subjects were interviewed regarding length of occupational exposure to Pb compounds, as well as 17 other substances. OR (95% CI) 61 men ever exposed to Pb (smoking-adju

2.0 (1.2, 3.5) Trend per 10 yrs duration of exposure: 1.45 (1.09, 2.02) No other substances showed significant as

cancer. Controlled for smoking, marital status, soceducation, ethnicity, and urban vs. rural re

No control for other occupational exposurrate (53%), which could result in biased c

Siemiatycki et al. (1991) Canada Case-control design. Cases: 3,730 various histologically confirmed cancers. 

Controls: specific cancer types were compared with other cancers as a control group, excluding lung cancer. Separate subgroup analysis was restricted to French Canadians. 

Occupational exposure to 293 substances, including Pb, was estimated from interviews. Exposure was classified as “any”; a subgroup with “substantial” exposure also was identified. 

OR (90% CI); number of cases Any exposure to Pb: 

Lung 1.1 (0.9, 1.4); 326 (French Canadians only) Stomach 1.2 (1.0, 1.6); 126 Bladder 1.3 (1.0, 1.6); 155 (French Canadians only) Kidney 1.2 (1.0, 1.6); 88 

ORs rose in the “substantial” exposure sublung, but not for bladder or kidney cancerControlled for smoking but not for other o
 AX6-198 Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Interpr

Europe Sankila et al. (1990) Finland 1941-1977 Cohort design. 1,803 male and 1,946 female glass workers employed for at least 3 mos at one of 2 Finnish glass factories in 1953- 1971 or 1941-1977. Cancer incidence was compared with age-, gender-, and calendar-yr-specific national rates. Stomach, lung, and skin cancer rates also were compared separately for 201 male and 34 female glassblowers and non- glassblowers. No specific Pb exposure indices were computed. Analyses did examine glass workers as a whole and then glassblowers specifically, which comprised the group at highest risk for Pb exposure. SIR (95% CI); number of cases Lung cancer, all glass workers: Male 1.3 (1.0, 1.7); 62 Female 1.1 (0.5, 2.3); 7 Lung cancer risk showed no specificity fo

Skin cancer, males and females combined

All workers 1.5 (0.8, 2.7); 11 (little Glassblowers 6.2 (1.3, 18.3); 3 Stomach cancer, males and females combGlassblowers 2.3 (0.9, 5.0); 6 No increase in other glass workers No increase in cancers of other sites. No c

or occupational coexposures. 

Kauppinen et al. (1992) Finland 1976-1981 

Case-control design. 

Cases: 344 primary liver cancer deaths reported to the Finnish Cancer Registry in 1976-1978 or 1981. Controls: registry-reported stomach cancer (476) or myocardial infarction (385) deaths in the same hospitals, frequency matched by age and gender. 

Questionnaires regarding job history and personal habits were sent to the closest available relative. U.K. based job-exposure matrix was used to rate potential exposure to 50 substances, including Pb compounds Industrial hygienists also inspected histories to identify those with highly probable exposure and rate it as high, low, or moderate (<10 yrs high or 10+ yrs low exposure). 

OR (95% CI) 52 workers with potential Pb exposure: 

0.91 (0.65, 1.29) 

11 women with potential Pb exposure: 

1.84 (0.83, 4.06) 

5 men with probable moderate exposure: 

2.28 (0.68, 7.67) 

None had high exposure and only 1 had lo4 controls had high exposure. Female controls appeared to underreport tMost controls had stomach cancer, which results toward the null. Few subjects were probability of exposure. 
 AX6-199 Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Inte

Europe (cont’d) Wesseling et al. (2002) Finland 1971-1995 Cohort design, but at ecologic level. 413,877 Finnish women with occupation reported in 1970 linked to Finnish Cancer Registry to identify new cases of brain or nervous system cancer arising form 1971 to 1995. Poisson regression was used to calculate SIRs for exposed vs. unexposed groups. Reported occupation in 1970 was used to classify women into job titles. Potential exposure for each job title was estimated using a job matrix after excluding women in the highest social classes or in farming. Pb and 23 other workplace agents examined. Rates for each job title were calculated, and SIRs for low and medium/high exposure calculated (avg estimated blood Pb of 0.3 μmol/L served as cut point between low and medium/high exposure). SIR (95% CI), unadjusted for other m

Low exposure: 1.25 (0.68, 1.81) Medium/high exposure: 1.33 (0.90, 1SIR (95% CI), adjusted for cadmium Low exposure: 1.18 (0.88, 1.59) Medium/high exposure: 1.24 (0.77, 1All results were adjusted for birth cohjob turnover rate. Incidence, exposure to Pb, and potencalculated at the level of job title rathlevel. Exposure and other estimates workers pooled, not for women speciwas based on a single yr, not lifetime 

Pesch et al. (2000) Germany 1991-1995 

Case-control design. Cases: 935 renal-cell cancer patients in five German areas. Controls: 4,298 region, age, and gendermatched controls from the surrounding population. ORs were adjusted for age, center, and smoking. 

Job histories were used to categorize exposure to cadmium, Pb, and other potential as low vs. medium, high, or substantial. Separate exposure estimates were obtained from British and from German-derived jobexposure matrices. 

OR (95% CI); number of cases Substantial Pb exposure based on BrMale 1.5 (1.0, 2.3); 29 Female 2.6 (1.2, 5.5); 11 Substantial Pb exposure based on BrMale 1.3 (0.9, 2.0); 30 Female not reported Analyses controlled for smoking. No other occupational agents. 
 AX6-200 Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and In

Europe (cont’d) Kandiloris et al. (1997) Greece Case-control design. Cases: 26 patients with histologically confirmed laryngeal carcinoma and no history of Pb exposure or toxicity. Controls: 53 patients with similar demographic profiles and no history of cancer from the same hospital. Blood Pb levels and ALAD activity were measured. Blood Pb levels were similar, bu

significantly lower in cases than vs. 59.76 U/L, p < 0.01). No coPotential distortion by effects of ALAD parameters.) Cordioli et al. (1987) Italy 1953-1967 Cohort design. 468 Italian glass workers employed for at least one yr between 1953 and 1967. Mortality among workers was tracked and cause of death was determined for deceased workers. Standardized mortality ratios were computed for workers vs. national population counterparts. Workers producing low-quality glass containers were classified as Pb-exposed. SMR (95% CI); number of deat

All cancer 1.3 (0.8, 1.8Lung 2.1 (1.1, 3.6Laryngeal 4.5 (1.2, 11

Cocco et al. (1994a) (expansion of Carta et al., 1994). Sardinia 1931-1992 

Cohort design. 

1,741 male Sardinian Pb and zinc miners from two mines employed at least one yr between 1931 and 1971. Mortality traced through 1992 to determine cause of death. Mortality among miners was compared with age- and calendar-yr-specific regional rates to compute an SMR. 

All miners were considered to be exposed to Pb. 

SMR (95% CI); number of deat

All cancer 0.94 (0Prostate 1.21; 1

Bladder 1.15; 1Kidney 1.28; 7 Nervous system 1.17; 8 Oral 0.61; 8 Lymphohemopoietic 0.91; 2Digestive 0.83; 8Peritoneum 3.67 (1

No other p < 0.05. No control for smoking or expoother exposures. 
 AX6-201 Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Interpr

Europe (cont’d) Cocco et al. (1994b) Sardinia 1951-1988 Cohort design. 526 female Sardinian Pb and zinc miners from the same mines as in Cocco et al. (1994a). Mortality traced through 1992 to determine cause of death. Mortality among miners was compared with age- and calendar-yr-specific regional rates to compute an SMR. All miners were considered to be exposed to Pb. SMR (95% CI) Liver 5.02 (1.62, 11.70) Lung 2.32 (0.85, 5.05) Other cancers showed nonsignificantly reduc

No control for smoking or exposure to silica, Low statistical power due to small population during follow-up. Cocco et al. (1996) Sardinia 1973-1992 Cohort design. 1,222 male Sardinian Pb and zinc smelter workers whose G6PD phenotypes had been determined, employed any 

time from 1973-1990. Mortality traced through 1992 to determine cause of death. Mortality was compared with regional rates. 

All workers were considered to be exposed to Pb. Workers were subdivided into 6PD-normal and -deficient groups. 

All cancer and lung cancer: mortality lower Stomach cancer: mortality higher than expecG6PD deficiency had little apparent effect on cause mortality was slightly lower among G6among G6PD-normal workers. No control for smoking or exposure to other Healthy worker bias-evident (all-cause mortaexpected), brief follow-up, low proportion of entry 30, avg follow-up less than 11 yrs), no 
 AX6-202 Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Interpr

Europe (cont’d) Cocco et al. (1997) Sardinia 1931-1992 Cohort design. 1,388 male production and maintenance workers employed for at least 1 yr at a Sardinian Pb and zinc smelter between June of 1932 and July of 1971. Mortality was followed up through 1992. Mortality was compared with age- and calendar-yr-specific regional rates. Since regional rates were only available for 1965 and later, analyses were limited to this period. All workers were considered to be exposed to Pb. SMRs vs. regional rates (95% CI); numbe

Lung 0.82 (0.56, 1.16); 31 Stomach 0.97 (0.53, 1.62); 14 All cancers 0.93 (0.78, 1.10); 132 Kidney 1.75 (0.48, 4.49); 4 Bladder 1.45 (0.75, 2.53); 12 Brain 2.17 (0.57, 5.57); 4 Kidney cancer showed a significant trend increasing duration of exposure No significant trends were noted for lung Brain cancer excess was limited to workerless. No control for smoking or exposure to arsrelated exposures. No data on intensity of 

Strong association of smelter work with prespiratory disease (SMR = 4.47, 95% CI: outcome includes silicosis, which is thougto lung cancer, some lung cancer deaths mmisclassification of cause of death based o

Wingren and Axelson (1987, 1993) (update of Wingren and Axelson, 1985, same basic cohort as in Wingren and Englander (1990) Sweden 1950-1982 

Case-control design. 

Source population: 5,498 men aged 

45 or older in 11 Swedish parishes, including 887 glass workers. Cancer-specific nested case-control analysis: Cases: deaths due to stomach, colon, and lung cancer from 1950-1982 Controls: deaths due to causes other than cancer or cardiovascular disease 

Glass workers were considered exposed. Glassblowers also singled out as workers with higher exposure potential. Job history applied to job matrix to categorize occupations as low, moderate, or high Pb exposure. 

OR (90% CI); number of deaths All glass workers: 

Lung 1.7 (1.1, 2.5); 86 Stomach 1.5 (1.1, 2.0); 206 Colon 1.6 (1.0, 2.5); 79 

Glassblowers: 

Lung 2.3 Stomach 2.6 Colon 3.1 

Glassblowers singled out from glass workhigher estimated risk. ORs for high or moshowed no consistent increase for lung or although they did show mild upward trend No control for smoking or other occupatio
 AX6-203 Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Interpr

Europe (cont’d) Wingren and Englander (1990) Sweden 1964-1985 (same population as in case-control analyses of Wingren and Axelson 1985, 1987, 1993) Cohort design. 625 Swedish glass workers employed for at least 1 mo between 1964 and 1985. Mortality was compared with national rates. Workers from areas with airborne Pb levels up to 0.110 mg/m3 were classified as exposed. SMR (95% CI) Pharyngeal: 9.9 (1.2, 36.1) Lung: 1.4 (0.5, 3.1) Colon: nonsignificant Dingwall-Fordyce and Lane (1963) U.K. 1925-1962 Cohort design. 425 male employees drawing pensions from U.K. battery plants. Standardized mortality for employees vs. national population counterparts. Battery plant workers were assumed to be exposed, and their mortality compared to that of like age and gender in the U.K. population as a whole. Urinary Pb excretion was also used to categorize workers by 

estimated exposure (none, light, or heavy): 80 lightly and 187 heavily (at least 100 μg/L) exposed. 

SMR (95% CI); number observed deaths All cancer: 1.2 (0.8, 1.7); 267 No consistent increase in SMRs across catexposure. Limitations: No cancer site-specific analypotential confounders including smoking other metals. 

Malcolm and Barnett (1982) (follow-up of Dingwall-Fordyce and Lane, 1963) U.K. 1925-1976 

Cohort design. 1,898 Pb-acid battery workers. Mortality was traced for the Pb-acid battery workers to determine cause of death. The proportion of deaths due to cancer (all types and major subcategories) among the worker population was compared to that seen in corresponding members of the general population, yielding a PMR. 

Job histories were reviewed to classify workers’ Pb exposure as high, medium, or none. 

Proportionate mortality ratio (PMR) All cancers: 

1.15 (136 deaths), p > 0.05 

By exposure: 

None 1.02 Medium 1.06 High 1.30 

No significant excesses for individual candigestive cancer PMR of 1.67, p < 0.01, amThe difference in exposure for the high annarrowed greatly over the follow-up, thus 

of dose-response patterns. No control for exposure to other carcinogens. 
 AX6-204 Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and In

Europe (cont’d) Ades and Kazantzis (1988) U.K. 1943-1982 Cohort design. 4,393 male zinc, Pb, and cadmium smelter workers. (Workers born after 1939 or who had worked less than one yr at the facility were excluded.) Workers followed up for mortality. Nested case-control analysis also conducted to quantitatively assessed cadmium and, secondarily, arsenic, Pb, and other metal exposures among 174 cases. Job histories were used to quantify cadmium exposure and assign ordinal ranks for exposure to Pb and other metals. Standardized lung cancer mortality ratio computed for workers vs. national rates. SMR (95% CI); number of deat

Cohort: Lung 1.25 (1.07, 1.44); 174 Increased significantly with dNested case-control analyses did department or process, nor did cor dust exposure account for the Cumulative exposure to Pb and positive associations with lung cimportance of these two exposuCadmium exposure did not accobut analyses could not control foadjusted for smoking. Asia

Hu et al. (1998) China 1989-1996 

Case-control design. Cases: 218 patients with histologicallyconfirmed primary gliomas occurring during 1989-1996 at 6 Chinese hospitals. Controls: 436 patients with non-neurological, nonmalignant disease, matched by age, gender, 

and residence from the same hospitals (excluding one cancer-only center). 

Patients were interviewed, and those with factory or farm occupations were further interviewed to identify exposure to Pb (or other potentially toxic substances). 

Occupational exposure to Pb: Not reported for any glioma pat4 controls. No control for exposure to other environmental agents. 
 AX6-205 Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and Cancer Reference, Study Location, and Period Study Description Pb Measurement Findings and Interpr

Asia (cont’d) Hu et al. (1999) China 1989-1996 Case-control design. Cases: 383 patients with histologically confirmed primary meningiomas occurring during 1989-1996 at 6 Chinese hospitals. Controls: 366 patients with non- neurological, nonmalignant disease matched by age, gender, and residence from the same hospitals (excluding one cancer-only center). Patients were interviewed, and those with factory or farm occupations were further interviewed to identify exposure to Pb (or other potentially toxic substances). OR (95% CI); number of cases Occupational exposure to Pb: Male: 7.20 (1.00, 51.72); 6 Female: 5.69 (1.39, 23.39); 10 Results were adjusted for income, educati

intake, plus cigarette pack-yrs for the womexposure to additional metals or other occ

Shukla et al. (1998) India 1995-1996 Case-control design. Cases: 38 patients with newly diagnosed, histologically confirmed gall bladder cancer cases assembled from a surgical unit. Controls: 58 patients with gall stones 

diagnosed at the same surgical unit, matched on geographic area. Mean bile Pb content was compared between cases and controls. 

Heavy metal content was measured in bile drawn from the gall bladder at time of surgery. 

Bile Pb content: mean (SE) Gall bladder cancer: 58.38 mg/L (1.76) Gallstones: 3.99 mg/L (0.43) Cadmium and chromium levels also were but less than Pb. No control for smoking 
 AX6-206

ANNEX TABLES AX6-8 
 AX6-207 Table AX6-8.1. Effects of Lead on Immune Function in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

United States Joseph et al. (2005) SE Michigan (1994-1998) Design: prospective (1 yr following 3-yr baseline recruitment) Subjects: children (n = 4634), age range 0.4–3.0 yr Outcome measures: asthma prevalence and incidence. Analysis: multivariate proportional hazard model (Cox) Blood Pb (μg/dL) mean (SD, median, % >10): 5.5 (4.0, 4.0, 8.6%) Covariate-adjusted hazards ratio (HR, ast

compared to ∃5 or ∃10 μg /dL): Caucasian: ∃5 μg/dL, 1.4 (95% CI: 0.7

∃10 μg/dL, 1.1 (95% CI: 0.

African American: ∃5 μg/dL, 1.0 (95% C

∃10 μg/dL, 0.9 (95% 

HR for asthma incidence in African AmeCaucasians (<5 μg/dL): <5 μg/dL: 1.6 (95% CI: 1.4, 2.0) ∃5 μg/dL: 1.4 (95% CI: 1.2, 1.6) ∃10 μg/dL: 2.1 (95% CI: 1.2, 3.6) Covariates included: avg annual income, 

Sarasua et al. (2000) ATSDR Multi-site Study: Granite City, IL, Galena, KA; Joplin, MO; Palmerton, PA 1991 

Design: cross-sectional Subjects: children and adults (n = 2036) Outcome measures: total lymphocyte count, lymphocyte phenotype abundance, serum IgA, IgG, and IgM. Analysis: multivariate linear regression 

Blood Pb (μg/dL) mean (SD, 5th–95th %): 6–35 mo: 7.0 (16, 1.1–16.1) 36–71 mo: 6.0 (4.3, 1.6–14.1) 6–15 yr: 4.0 (2.8,1.1–9.2) 16–75 yr: 4.3 (2.9, 1.0–9.9) 

Significant association (p < 0.05) betweeincreasing serum IgA, IgG, IgM, and B-cand decreasing T-cell abundance (%) in 6adjusted for age, sex, and study site. Comacross blood Pb quartiles (1st quartile as lower): [+] lymphocyte count (4th quarti(4th quartile, p = 0.09), B-cell count (4th % (4th quartile, p = 0.09). 

Rabinowtiz et al. (1990) Boston, MA 1979–1987 

Design: cross-sectional Subjects: infants/children (n = 1768) Outcome measures: incidence of illness in children was solicited from parents by questionnaire. Analysis: relative risk of illness estimated from incidence ratios, highest: combined lower blood Pb deciles, without adjustment for covariates or confounders. 

Cord blood Pb (μg/dL) ~90th %: 10 Shed tooth Pb (μg/g) ~90th %: 5 

Relative risk (unadjusted) was elevated focategories: severe incidence of ear infectother respiratory illness, 1.5 (95% CI: 1.illness other than cold or flu, 1.3 (95% C
 AX6-208 Table AX6-8.1 (cont’d). Effects of Lead on Immune Function in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

United States (cont’d) Lutz et al. (1999) Springfield-Green Co, MO NR Design: cross-sectional Subjects: children (n = 279; age range 9 mo–6 yr) Outcome measures: differential blood cell counts; lymphocyte phenotype abundance (%); and serum IL-4, soluble CD25, CD27, IgE and IgG (Rubella). Analysis: nonparametric comparison of outcome measures (adjusted for age) for blood Pb categories, correlation Blood Pb (μg/dL) range: 1–45 Blood Pb categories: <10 μg/dL, 10–14 μg/dL, 15–19 μg/dL, 20–45 μg/dL Significant association (p < 0.05) betwee

(categorical) and increasing serum IgE le

Europe Annesi-Maesano et al. (2003) France 1985, 1992 

Design: cross-sectional Subjects: mother/newborn pairs (n = 374), mean age 30 yr Outcome measures: maternal venous and newborn cord serum IgE levels Analysis: multivariate linear regression, ANOVA 

Blood Pb (μg/dL) mean (SD): Infant cord: 67.3 (47.8) Maternal: 96.4 (57.7) Hair Pb (ppm) mean (SD): Infant: 1.38 (1.26) Maternal: 5.16 (6.08) 

Significant (p < 0.0001) association betwPb and infant cord serum IgE levels. Although medical histories were taken to factors (asthma, allergies) and “confounddo not appear to have been quantitatively regression models. Allergy status and blounrelated to load biomarkers or serum IgE reported). 

Karmaus et al. (2005) Germany 1994–1997 

Design: cross-sectional Subjects: children (n = 331, 57% male), age 7–8 yrs (96%), 9–10 yrs (4%)

Outcome measures: differential blood cell count; lymphocyte phenotype abundance; and serum IgA, IgE, IgG, IgM Analysis: multivariate linear regression 

Blood Pb (μg/dL) mean (95% CI): Males: 2.5 (1.1, 4.4) Females (2.8 (1.5, 4.8) Blood Pb quartile ranges: <2.2 (n = 82) 2.2–2.8 (n = 81) 2.8–3.4 (n = 86) >3.4 (n = 82) 

Significant association between blood Pb (not monotonic with quartile range). Comoutcomes (p#0.05) across blood Pb quartreference, [+], higher, [

−] lower): [

−] CD

[−] C3+CD8+ T-cells (2nd quartile), [+] C

quartile). Covariates retained: age, sex, environmesmoke, infections (in last 12 mo), serum triglycerides. 
 AX6-209 Table AX6-8.1 (cont’d). Effects of Lead on Immune Function in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Europe (cont’d) Reigart and Graber (1976) NR NR Design: clinical Subjects: children (n = 19), ages 4–6 yrs Outcome measures: serum IgA, IgG, IgM, total complement and C-3, before and after immunization with tetanus toxoid Analysis: none; presentation of prevalence of clinically low, normal, and high values of outcome measures Blood Pb (μg/dL) mean (range): High: >40 (n = 12): 45.3 (41–51) Low: #30 (n = 7): 22.6 (14–30) No apparent difference in prevalence of a

immunoglobulin or complement (no stati

Wagnerova et al. (1986) Czech NR Design: longitudinal cohort (repeated measures for 2-yrs) Subjects: children (n = 92, 38 females) ages 11–13 yrs residing near a smelter; reference group (n = 67, 36 females), ages 11–13 yrs Outcome measures: serum IgA, IgE, IgG, IgM 

Analysis: comparison of outcome measures and between exposed and reference groups, stratified sex and season of sampling 

Blood Pb (μg/dL) mean: Pb: ~23–42 Reference: ~5–22 

Significant (p NR, statistic NR) lower serexposed group compared to reference gro

Latin America Pineda-Zavaleta et al. (2004) Mexico NR 

Design: cross-sectional Subjects: children (n = 30 female, 35 male) ages 6–11 yrs, residing near smelter Outcome measures: mitogen- (PHA) and cytokine- (IFN-() induced nitric oxide and 

superoxide production in lymphocytes Analysis: multivariate linear regression 

Blood Pb (μg/dL) mean (range) for 3 schools: 1 (n = 21): 7.0 (3.5–25.3) 2 (n = 21): 20.6 (10.8–49.2) 3 (n = 23): 30.4 (10.3–47.5) 

Significant (p = 0.036) association betweconcentration and covariate adjusted decrproduction in PHA-activated lymphocyte

−0.0017, 

−0.00005]). 

Significant (p = 0.034) association betweconcentration and covariate adjusted incrproduction in IFN-(-activated lymphocyt

0.00031, 0.00748]). Covariates considerallergies, and blood arsenic (age, sex, and 

retained). Significant effect of sex on associations, interaction. Covariates considered included age, sex, (age, sex, and urinary arsenic were retain
 AX6-210 Table AX6-8.1 (cont’d). Effects of Lead on Immune Function in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia Sun et al. (2003); Zhao et al. (2004) China NR Design: cross-sectional Subjects: children (n = 73) age 3–6 yrs Outcome measures: serum IgE, IgG, IgM; lymphocyte phenotype abundance Analysis: Nonparametric comparisons of outcome measures stratified by blood Pb Blood Pb (μg/dL) mean (SD, range) (n = 217): 9.5 (5.6, 2.6–43.7) Females: significantly higher (p < 0.05) 

category (∃10 μg/dL, n = 16) compared tn = 17), and significantly lower IgG and analysis of association between blood Pb described in sufficient detail to evaluate. All children: significantly lower (p < 0.0

CD3+CD8+ (%), CD4+CD8+ (%) in high 

n = 38) compared to low blood Pb (10 μg
 AX6-211 Table AX6-8.2. Effects of Lead on Immune Function in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

United States Pinkerton et al. (1998) U.S. NR Design: cross-sectional cohort Subjects: adult male smelter workers (n = 145, mean age 32.9

∀8.6); reference 

group, male hardware workers (n = 84, mean age 30.1

∀9.3) 

Outcome measures: differential blood cell counts; lymphocyte phenotype abundance; serum IgA, IgG, IgM; salivary IgA; lymphocyte proliferation (tetanus toxoid) Analysis: multivariate logistic regression with comparison of adjusted outcome measures between exposed and nonexposed groups 

Blood Pb (μg/dL) median (range) Pb: 39 (15–55) Reference: <2 (<2–12) 

Covariate-adjusted outcomes in Pb worke(p < 0.05) different from nonexposed ([+

monocytes, [

−] % CD4+CD8+ cells, [

−] % 

Significant (p < 0.05) adjusted regression group for independent variable: blood Pb: [+] CD19+ B-cells (%, no) 

time-integrated blood Pb: [

−] serum IgG

(%, number) Covariates considered in the analysis inclhabits, alcohol consumption, marijuana ufactors that might stimulate or suppress thexposure to direct sunlight, sleep hrs, alleCovariates retained in the final model wesmoking habits. 

Sarasua et al. (2000) ATSDR Multi-site Study: Granite City, IL, Galena, KA; Joplin, MO; Palmerton, PA 1991 

Design: cross-sectional cohort Subjects: children and adults (n = 2036) Outcome measures: total lymphocyte count, lymphocyte phenotype abundance, serum IgA, IgG, and IgM Analysis: multivariate linear regression 

Blood Pb (μg/dL) mean (SD, 5th–95th %): 6–35 mo: 7.0 (16, 1.1–16.1) 36–71 mo: 6.0 (4.3, 1.6–14.1) 6–15 yr: 4.0 (2.8,1.1–9.2) 16–75 yr: 4.3 (2.9, 1.0–9.9) 

No significant association (p < 0.05) betwoutcomes in adults (age ∃16 yr). 

Covariates retained: age, sex, cigarette sm
 AX6-212 Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

United States (cont’d) Fischbein et al. (1993) New York NR Design: cross-sectional cohort Subjects: adult firearms instructors (n = 51), mean age 48 yr; age-matched reference subjects (n = 36). Outcome measures: lymphocyte phenotype abundance, lymphocyte proliferation (PHA, PWM, Staph. aureus) Analysis: comparison of outcome measures between reference and blood Pb categories; multivariate linear regression Blood Pb (μg/dL) mean (SD) Pb high (∃25): 31.4 (4.3) Pb low (<25): 14.6 (4.6) Reference: <10 Outcomes in Pb workers that were signif

from reference group ([+], higher, [

−] low

[−] CD+

3 cells (%, number), [

−] CD4+ ce

CD4+CD8+ cells (number), [

−] HLA-DR 

cells (%, number), [

−] mitogen (PHA)-in

proliferation, [

−] mitogen (PWM)-induce

[−] lymphocyte response in mixed-lymphantigen (Staph. aureus)-induced lymphoc

Significant (p < 0.05) association betweedecreasing abundance of CD4+ phenotyp

lymphocyte proliferative response in mixCovariates retained: age, sex, smoking hexposure. 

Europe 

Bergeret et al. (1990) France NR 

Design: cross-sectional cohort Subjects: adult battery smelting workers (n = 34), mean age 40 yr; reference subjects (n = 34), matched for age, sex, ethnic origin, smoking and alcohol consumption habits, 

intake of antibiotics, and NSAIDs Outcome measures: PMN chemotaxis (FMLP); PMN phagocytosis (opsonized zymosan) Analysis: comparison of outcome measures between worker and reference groups 

Blood Pb (μg/dL) mean (SD): Pb: 70.6 (18) Reference: 9.0 (4.3) 

Significantly (p < 0.05) lower PMN chemand phagocytic response in Pb workers. 
 AX6-213 Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Europe (cont’d) Ewers et al. (1982) Germany NR Design: cross-sectional cohort Subjects: adult male battery manufacture or smelter workers (n = 72), mean age 36.4 yr (16–58); reference workers (n = 53), mean age 34.8 yr (21–54) Outcome measures: serum IgA, IgG, IgM, C3; saliva IgA Analysis: parametric and nonparametric comparison of outcome measures between Pb workers and reference subjects; linear regression Blood Pb (μg/dL) mean (range): Pb: 55.4.0 (18.6–85.2) Reference: 12.0 (6.6–20.8) Significantly (p < 0.05) lower serum IgM

workers compared to reference group. Coscia et al. (1987) Italy NR Design: cross-sectional cohort Subjects: adult Pb workers (n = 32, 2 female), mean age 42.8 yr (SD 11.5); reference subjects (n = 25), mean age 38.6 yr 

(SD 13.3) Outcome measures: serum IgA, IgG, IgM, C3-C4; lymphocyte phenotype abundance Analysis: parametric comparison of outcome measures between worker and reference groups 

Blood Pb (μg/dL) mean (SD): Pb: 62.3 (21.6) Reference: NR 

Outcomes in Pb workers that were signiffrom reference group ([+], higher, [

−] low

serum C4, [+] lymphocyte abundance (%number, E-rosette forming cells), [+] B-cimmunoglobulin-bearing cells), [+] CD8+ 

Governa et al. (1987) Italy NR 

Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 9), mean age 38.4 yr (SD 13.7); age-matched reference subjects (n = 18) Outcome measures: PMN chemotaxis (zymosan-activated serum) Analysis: parametric comparison of outcome measures between worker and reference groups, correlation 

Blood Pb (μg/dL) mean (SD): Pb: 63.2 (8.2) Reference: 19.2 (6.4) 

Significantly (p < 0.05) lower PMN chemzymosan activated serum. Effect magnitublood Pb. 
 AX6-214 Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Europe (cont’d) Valentino et al. (1991) Italy NR Design: cross-sectional cohort Subjects: adult male Pb scrap refining workers (n = 10), mean age 41.1 yr (SD 7.3, range 28–54); age-matched reference subjects (n = 10) Outcome measures: PMN chemotaxis (C5 or FMLP) and phagocytosis (FMLP) Analysis: comparison of outcome measures between worker and reference groups, correlation Blood Pb (μg/dL) mean (SD, range): Pb: 33.2 (5.6, 25–42) Reference: 12.6 (2.5, 8.9– 18) Significantly (p < 0.002) lower PMN che

FMLP and higher stimulated production workers compared to reference group. Ewith blood Pb. No effect on phagocytic a

Kimber et al. (1986) UK NR Design: cross-sectional cohort Subjects: adult male TEL manufacture workers (n = 39) mean age: 45.1 yr; and age-matched reference subjects (n = 21); mean age 32.2 yr Outcome measures: serum IgA, IgG, IgM; 

mitogen (PHA)-induced lymphoblastogenesis; and NK cell cytotoxicity Analysis: comparison of outcome measures for exposed and reference groups 

Blood Pb (μg/dL) mean (SD, range): Pb: 38.4 (5.6, 25–53) Reference: 11.8 (2.2, 8–17) 

No significant (p < 0.05) differences in oand reference groups. 

Latin America Queiroz et al. (1993) Brazil NR 

Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 39), mean age 33.9 yr (SD 12.1, range 18–56); reference subjects (n = 39) matched by age and race Outcome measures: PMN chemotaxis (endotoxin LPS); phagocytic (endotoxin LPS) respiratory burst activity (NBT reduction) Analysis: nonparametric comparison of outcome measures between worker and reference groups 

Blood Pb (μg/dL) range: Pb: 14.8–91.4 (>30, n = 52) Reference: <10 

Significantly (p < 0.001) lower chemotaclower phagocytic respiratory burst, in Pb reference group. 
 AX6-215 Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Latin America (cont’d) Queiroz et al. (1994a) Brazil NR Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 60), mean age 33.9 yr (range 18–56); reference subjects (n = 49) matched by age and race Outcome measures: PMN phagocytic/lytic activity (opsonized yeast) Analysis: nonparametric comparison of outcome measures between worker and reference groups Blood Pb (μg/dL) range: Pb: 14.8–91.4 (>30, n = 27) Reference: <10 Significantly (p < 0.001) lower lytic activ

relative to reference group. Queiroz et al. (1994b) Brazil NR Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 33), mean age 32.4 yr (range 18–56); reference subjects (n = 20) matched by age and race Outcome measures: serum IgA, IgG, IgM; 

mitogen (PHA)-induced lymphocyte proliferation Analysis: parametric comparison of outcome measures between worker and reference groups 

Blood Pb (μg/dL) range: Pb: 12.0–80.0 (>30, n = 27) Reference: <10 

No significant difference in outcomes (p reference groups overlap) between Pb wo

Asia Kuo et al. (2001) China NR 

Design: cross-sectional cohort Subjects: adult battery manufacture workers (n = 64, 21 female) 14 subject aged <40 yr and 14 subjects aged >50 yr; nonexposed reference subjects (n = 34, 17 female). 

Outcome measures: differential blood cell counts, lymphocyte phenotype abundance Analysis: comparison of outcome measures in exposed and reference groups, multivariate linear regression 

Blood Pb (μg/dL) mean: Pb: 30 

Significantly (p < 0.05) adjusted mean hinumber), lower B cells (%), lower lymphgranulocytes (number) in Pb workers comCovariates retained: age, gender, and disreported). 
 AX6-216 Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia (cont’d) Mishra et al. (2003) India NR Design: cross-sectional cohort Subjects: adult males occupationally exposed to Pb (n = 84), mean age 30 yr; reference subjects (n = 30), mean age 29 yr Outcome measures: serum IFN-( level, mitogen (PHA)-induced lymphocyte proliferation, NK cell cytotoxicity Analysis: comparison of outcome measures between Pb-exposed and reference groups, correlation Blood Pb (μg/dL) mean (SD, range): 3-wheel drivers (n = 30): 6.5 (4.7, 0.0–17.5) Battery workers (n = 34): 128.1 (13.2–400.8) Jewelry makers: 17.8 (18.5, 3.1–76.8) Reference: 4.5 (NR, 1.6– 9.8) Significantly (p < 0.001) lower lymphocy

PHA in Pb-exposed groups compared to IFN-( production by blood monocytes. Alomran and Shleamoon (1988) Iraq NR Design: cross-sectional cohort Subjects: adult Pb (oxide) workers (n = 39), mean age 35.6 yr (9,2, SD); age-matched reference subjects (n = 19) Outcome measures: serum IgA, IgG; 

mitogen (PHA, Con-A)-induced lymphocyte proliferation Analysis: comparison of outcome measures between Pb workers and reference group 

Blood Pb (μg/dL) mean: Pb: 54–64 Reference: NR 

Significantly (p < 0.05) lower lymphocyt

PHA or Con A in Pb workers, compared 

Cohen et al. (1989) Israel NR 

Design: cross-sectional cohort Subjects: adult male occupationally Pb exposed (n = 10), age range 22–70; agematched reference subjects (n = 10) Outcome measures: mitogen (Con A, PHA)-induced-lymphocyte proliferation and Tsuppressor cell proliferation; lymphocyte phenotype abundance Analysis: parametric comparison of outcome means between Pb-exposed and reference groups 

Blood Pb (μg/dL) range: Exposed: 40–51 Reference: <19 

Significantly (p < 0.02) higher mitogen (Ccell activity. No significant (p not reportT-cells (E-rosette-forming cells), OKT+

4, 

ratio; mitogen (Con A or PHA)-induced l
 AX6-217 Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia (cont’d) Sata et al. (1998) Japan NR Design: cross-sectional cohort Subjects: adult male Pb stearate manufacture workers (n = 71), mean age 48 yr (range 24– 74); reference subjects (n = 28), mean age 55 yr (range 33–67). Outcome measures: lymphocyte phenotype abundance Analysis: comparison of outcome measures in exposed and reference groups (ANCOVA), multivariate linear regression Blood Pb (μg/dL) mean (range): Pb: 19 (7–50) Reference: NR Pb workers vs. reference: significantly (p 

lower CD3+CD45RO+ (number) and high

Significant (p < 0.05) association betweeyes/no) and lower CD3+CD45RO+cells (n

Covariates retained: age and cigarette sm

Sata et al. (1997) Japan NR Design: clinical Subjects: adult male Pb smelter workers (n = 2) who underwent CaEDTA therapy Outcome measures: serum IgA, IgG, IgD, IgM; lymphocyte phenotype abundance 

Analysis: Parametric comparison of outcome measures before and after treatment, correlation of outcome means with blood Pb 

Blood Pb (μg/dL): Subject 1: 81 μg/dL at referral; mean before EDTA: 45.1 (SD 16.0); after chelation: 31.0 (9.8) Subject 2: 68 μg/dL at referral; mean before EDTA: 43.3 (SD 14.1); after chelation: 33.7 (7.2) 

Blood Pb and outcome measures were saafter 3 CaEDTA treatments (on consecutwks. Comparison of mean outcome meaafter treatments showed significantly (p < IgM; and significantly higher CD8+ T-ce

after treatment in subject 1. Serum IgG lsignificantly correlated (r = 

−0.72) with b

Heo et al. (2004) Korea NR

Design: cross-sectional cohort Subjects: adults, battery manufacture workers (n = 606; 52 females); ages: <30 yr, n = 184; >40 yr, n = 123. Outcome measures: serum IgE, IL-4, IFN(Analysis: comparison of outcomes measures (ANOVA), stratified by age and blood Pb 

Blood Pb (μg/dL) mean (SD): <30 yr: 22.0 (10.4) 30–39 yr: 23.0 (11.3) ∃40 yr: 24.1 (9.3) 

Significantly higher (p < 0.05) serum IgE category (∃30 μg/dL) compared to low ca29 μg/dL). 
 AX6-218 Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia (cont’d) Ünde er et al. (1996); Ba

∏aran and Ünde er 

(2000) Turkey NR 

Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 25), mean age, 33 yr (22–55); reference subjects (n = 25) mean age 33 yr (22–56). Outcome measures: differential blood cell counts; lymphocyte phenotype abundance; serum IgA, IgG, IgM, C3, and C4; neutrophil chemotaxis (zymosan-activated serum); latex particle-induced neutrophil phagocytic (latex 

particles) respiratory burst (NBT reduction) Analysis: nonparametric and parametric comparisons of outcome measures for exposed and reference groups 

Blood Pb (μg/dL) mean (SD): Pb: 74.8 (17.8) Reference: 16.7 (5.0) 

Workers relative to reference: significanIgG, IgM, C3, and C4 levels; lower CD4+ 

lower neutrophil chemotactic response; nCD20+ (B-cell) , CD8+ (“T-suppressor”) 

abundance, or particle-induced NK cell r

Yücesoy et al. (1997a) Turkey NR 

Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 20), ages 39–48 yr; agematched reference subjects (n = 12) Outcome measures: serum cytokines IL-1∃, IL-2, TNF

∀, IFN-(

Analysis: parametric and nonparametric comparison of outcome measures in exposed and reference groups 

Blood Pb (μg/dL) mean (SE, range): Pb: 59.4 (3.2, 42–94) Reference: 4.8 (1.0, 2–15) 

Significantly (p < 0.05) lower serum IL-1

workers compared to controls. 

Yücesoy et al. (1997b) Turkey NR 

Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 50), ages 39–48 yr; agematched reference subjects (n = 10) Outcome measures: lymphocyte phenotype abundance, NK cell cytotoxicity Analysis: comparison of outcome measures in exposed and reference groups 

Blood Pb (μg/dL) mean (SE, range): Pb 1 (n = 20): 59.4 (3.2, 42–94) Pb 2 (n = 30): 58.4 (2.5, 26–81) Reference: 4.0 (0.4, 2–6) 

Significantly (p < 0.05) lower CD20+ B-c

workers compared to controls, no differen

abundance. 
 AX6-219 Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Africa Anetor and Adeniyi (1998) Nigeria NR Design: cross-sectional cohort Subjects: adult male “Pb workers” (n = 80), mean age, 36 yr (21–66) and reference subjects (n = 50), mean age 37 yr (22–58). Outcome measures: serum IgA, IgG, and IgM; lymphocyte count Analysis: comparison of outcomes measures in workers and reference group, linear regression, principal component analysis Blood Pb (μg/dL) mean (SE): Pb: 53.6 (0.95) Reference: 30.4 (1.4) Significantly lower (p < 0.05) serum IgA

lymphocyte levels; significant associationblood Pb and serum total globulins (note reference). 
 AX6-220

ANNEX TABLES AX6-9 
 AX6-221 Table AX6-9.1. Effects of Lead on Biochemical Effects in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

United States Marcus and Schwartz (1987) U.S. 1976–1980 Design: cross-sectional national survey (NHANES II) Subjects: ages 2-6 yr (n = 1677) Outcome measures: EP, red blood cell count, mean corpuscular volume, iron status variables Analysis: nonlinear least squares regression Blood Pb (μg/dL) range: 6-65 Non-linear regression used to fit kineti

to EP, in strata having low (<14%), me(>31%) percent transferrin saturation (included: parameters for total red cell cell Pb concentration, equilibrium concand whole blood. Blood Pb increase (fdouble EP: 22 (PST < 14%), 24 (PST (PST > 31%). Piomelli et al. (1982) New York 1976 Design: cross-sectional Subjects: children (n = 2002), ages 2–12 yr Outcome measures: EP Analysis: linear regression Blood Pb (μg/dL) range: 2–98 Regression equation relating blood Pb 

(log-transformed): ∀ = 1.099, ∃ = 0.016, r = 0.509, p < 0.Threshold for increase in EP estimated CI: 12.9, 18.2) 

Soldin et al. (2003) Washington DC 2001–2002 

Design: cross-sectional Subjects: children (n = 4908, 1812 females), age range 0–17 yr Outcome measures: EP Analysis: locally weighted scatter plot smoother (LOWESS) 

Blood Pb (μg/dL): Mean (range 1–17 yr): 2.2–3.3 Median (1–17 yr): 3 Range: <1–103 

EP increases as blood Pb concentration 15 mg/dL. A doubling of EP occurred Pb concentration of ~20 μg/dL (a polya function of blood Pb (PbB) is: EP = 

−0.0015(blood Pb)3 + 0.1854(blo

+ 30.911 (r2 = 0.9986) 

(derived from data in Table 2 of Soldin 

Europe

Roels and Lauwerys (1987) Belgium 1974–1980 

Design: cross-sectional Subjects: children (n = 143), age range 10–13 yr Outcome measures: ALAD, urinary ALA, EP Analysis: linear regression, correlation 

Blood Pb (μg/dL) range: 15–41 

Linear regression for EP (log-transformconcentration: ∀ = 1.321, ∃ = 0.025, r = 0.73 (n = 51) Linear regression for ALA (log-transfoconcentration: ∀ = 0.94, ∃ = 0.11, r = 0.54 (n = 37) Linear regression for ALAD (log-transconcentration: ∀ = 1.864, ∃ = 

−0.015, r = 

−0.87 (n = 
 AX6-222 Table AX6-9.1 (cont’d). Effects of Lead on Biochemical Effects in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

Latin America Perez-Bravo et al. (2004) Chile NR Design: cross-sectional; Subjects: children (n = 93, 43 males), aged 5- 12 yrs who attended school near a powdered Pb storage facility Outcome measures: blood Hgb and Hct, ALAD genotype Analysis: comparison of outcome measures between ALAD genotype strata Blood Pb (μg/dL) mean (SE): ALAD1 (n = 84): 13.5 (8.7) ALAD2 (n = 9): 19.2 (9.5) Mean blood Pb, blood Hgb, and Hct no

genotypes (p = 0.13). 
 AX6-223 Table AX6-9.2. Effects of Lead on Biochemical Effects in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

Europe Gennart et al. (1992) Belgium NR Design: cross-sectional cohort Subjects: adult battery manufacture workers (n = 98), mean age, 37.7 yr (range 22–55); reference group (n = 85), mean age 38.8 yr (24–55) Outcome measures: blood Hct, blood EP, urine ALA Analysis: linear regression Blood Pb (μg/dL) mean (SD, range): Pb: 51.0 (8.0, 40–70) Reference: 20.9 (11.1, 4.4–30.0) Significant association between increas

and increasing (log) blood EP (

∀ = 0.06

p = 0.0001) or (log) urine ALA (

∀ = 0.

p < 0.0001) (No apparent analysis of covariables) 

Mohammed-Brahim et al. (1985) Belgium NR

Design: cross-sectional cohort Subjects: adult smelter and ceramics manufacture workers (n = 38, 13 females); reference subjects (n = 100) matched with worker group by age, sex, and socioeconomic status. Outcome measures: blood P5N, EP, ALAD, R/ALAD (ratio of ALAD before and after 

reactivation). Analysis: comparison of outcome measures (ANOVA) between Pb workers and reference 

group; correlation 

Blood Pb (μg/dL) mean (SD, range): Pb: 48.5 (9.1, 27.8–66.6) Reference: 14.3 (6.7, 5.6–33.6) Urine Pb (μg/g creatinine) mean (SD, range): Pb: 84.0 (95.9, 21.8–587) Reference: 10.5 (8.2, 1.7–36.9) 

Significantly lower (p = NR) P5N in Pb or combined) compared to correspondinCorrelations with blood Pb: log P5N r = 

−0.79 (p < 0.001) 

log ALAD r = 

−0.97 (p = NR) 

R/ALAD r = 

−0.94 (p < 0.001) 

log EP r = 0.86 (p = NR) Correlations with urine Pb: log P5N r = 

−0.74 (p = NR) 

log ALAD r = 

−0.79 (p = NR) 

R/ALAD r = 

−0.84 (p < 0.001) 

log EP r = 0.80 (p = NR) 

Roels and Lauwerys (1987) Belgium 1974–1980

Design: cross-sectional Subjects: adults (n = 75, 36 females) Outcome measures: ALAD, urinary ALA, EP Analysis: linear regression, correlation 

Blood Pb (μg/dL) range: adult males: 10–60 adult females: 7–53 

Linear regression for EP (log-transformconcentration: adult male (n = 39): 

∀ = 1.41, ∃ = 0.01

adult female (n = 36): 

∀ = 1.23, ∃ = 0.0

Linear regression for ALA (log-transfoconcentration: adult male (n = 39): 

∀ = 0.37, ∃ = 0.00

adult female (n = 36): 

∀ = 0.15, ∃ = 0.0
 AX6-224 Table 6-9.2 (cont’d). Effects of Lead on Biochemical Effects in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

Europe (cont’d) Grandjean (1979) Denmark NR Design: longitudinal Subjects: male battery manufacture workers (n = 19), mean age 32 yr (range 22–49) Outcome measures: EP Analysis: EP and blood Pb for serial measurements displayed graphically Blood Pb (μg/dL) median (range): Group 1 (n = 5): 47.7 (22.8–53.9) Group 2 (n = 5): 37.3 (35.2–53.9) Five subjects (group 1) showed decline

blood Pb (33–58 μg/dL) over a 10-mo pshowed no change in EP with a change (25–54 μg/dL) over the same period. Alessio et al. (1976) Italy NR Design: cross-sectional Subjects: adult male Pb worker (n = 316), age range NR Outcome measures: blood ALAD, EP, urine ALA, CP Analysis: linear regression, correlation Blood Pb (μg/dL) range: 10–150 Regression relating outcomes to blood ALAD (ln-transformed) (n = 169): 

∀ = 

ALAU (ln-transformed) (n = 316): 

∀ = 

UCP (ln-transformed) (n = 252): 

∀ = 2

EP (log-transformed (males, n = 95): 

∀ 

EP (log-transformed (females, n = 93): 

Cocco et al. (1995) Italy 1990 

Design: longitudinal Subjects: adult male foundry workers (n = 40), mean age 25.1 yr (SD 2.1, range 21–28) Outcome measures: serum total-, HDL- and LDL-cholesterol, blood Hgb, urine ALA, erythrocyte G6PD Analysis: comparison of outcomes between pre-exposure (at start of employment, sample 1) and after 172 (range 138–217, sample 2) days 

Blood Pb (μg/dL) mean (range): Sample 1: 10.0 (7–15) Sample 2: 32.7 (20–51) 

G6PD levels were unrelated to starting increased in subjects whose blood Pb co<30 μg/dL to >30 μg/dL or decreased f<30 μg/dL. Increasing exposure duratiassociated with decreasing magnitude oSample 1 <30 μg/dL: ∃ = 

−0.3980 (SE 

Sample 1 >30 μg/dL: ∃ = 

−1.3148 (SE 

In the >30 μg/dL subgroup, increasing with decreasing magnitude of change o

0.7173], p < 0.05). Serum cholesterol levels were unrelated 
 AX6-225 Table 6-9.2 (cont’d). Effects of Lead on Biochemical Effects in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

Europe (cont’d) Fracasso et al. (2002) Italy NR Design: cross-sectional cohort Subjects: adult battery manufacture workers (n = 37, 6 females), mean age 41 yr (SD 7); reference office workers (n = 29, 8 females), mean age 38 yr (SD 21) Outcome measures: lymphocyte DNA strand breaks, ROS, GSH Analysis: comparison of outcome measures between Pb workers and reference group (ANOVA), logistic regression Blood Pb (μg/dL) mean (SD): Pb: 39.6 (7.6) Reference: 4.4 (8.6) Covariate-adjusted DNA strand breaks 

Pb workers compared to the reference g

associated with increased blood Pb (p = Covariate-adjusted lymphocyte ROS wGSH significantly lower in the Pb workreference group. Lower GSH levels wewith increasing blood Pb concentration Odds ratios (OR) for DNA strand break

were significant (Pb workers vs. referenDNA strand breaks: OR = 1.069 (95% p = 0.005 GSH: OR = 0.634 (95% CI: 0.488, 0.8ROS: OR = 1.430 (95% CI: 0.787, 2.5Covariates retained: age, alcohol consusmoking. Hernberg et al. (1970) Poland NR Design: cross-sectional Subjects: adult Pb workers (n = 166); reference group (n = 16) Outcome measures: blood ALAD Analysis: regression, correlation Blood Pb (μg/dL) range: 5–95 Linear regression for blood ALAD (logconcentration (n = 158): ∀ = 2.274, ∃ = 

−0.018, r = 

−0.90, p < 0

Bergdahl et al. (1997) Sweden NR 

Design: cross-sectional Subjects: adult smelter worker (n = 89); reference groups (n = 24) Outcome measures: blood Pb, erythrocyte ALAD-bound Pb, ALAD genotype Analysis: comparison of outcome measures 

Blood Pb (μg/dL) range: 0.8–93 Urine Pb (mg/L) range: 1–112 Bone Pb (μg/g) range: −19–101 

No association between ALAD genotyp

Selander and Cram

θr 

(1970) Sweden NR 

Design: cross-sectional Subjects: adult battery manufacture workers (n = 177) Outcome measures: urine ALA Analysis: regression, correlation 

Blood Pb (μg/dL) range: 6–90 

Linear regression for urine ALA (log-trconcentration (n = 150): ∀ = 

−1.0985, ∃ = 0.0157, r = 0.74 
 AX6-226 Table 6-9.2 (cont’d). Effects of Lead on Biochemical Effects in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

Europe (cont’d) Wildt et al. (1987) Sweden NR Design: longitudinal Subjects: adult battery manufacture workers (n = 234, 37 females) mean age 35 y (range 17–70); reference group (n = 951, 471 females), mean age 39 yr (range 19–67) Outcome measures: EP Analysis: analysis of variability over time, linear regression, correlation Blood Pb (μg/dL) mean (range): Pb: 10–80 Reference: Male: 11.3 (8–27) Female: 8.5 (5–21) Linear regression for EP (log-transform

concentration: Males (n = 851): 

∀ = 1.21, ∃ = 0.0148, 

Females (n = 139): 

∀ = 1.48, ∃ = 0.011

Asia

Hsieh et al. (2000) China NR 

Design: cross-sectional Subjects: Adults in general population (n = 630, 255 females) Outcome measures: blood Hgb, Hct, RBC count, ALAD genotype Analysis: comparison of outcome measures between ALAD genotype strata 

Blood Pb (μg/dL) mean (SD): ALAD1,1 (n = 630): 6.5 (5.0) ALAD1,1/2,2 (n = 30): 7.8 (6.0) 

Mean blood Pb not different between A(p = 0.17). RBC count, Hgb, Hct not dgenotype strata (p = 0.7) 

Jiun and Hsien (1994) China 1992 

Design: longitudinal Subjects: adult male Pb workers (n = 62), ages NR; reference group (n = 62, 40 females), ages NR Outcome measures: plasma MDA Analysis: comparison of outcome measures between Pb workers and reference group, linear regression 

Blood Pb (μg/dL) mean (SD, range): Pb: 37.2 (12.5, 18.2–76.0) Reference: 13.4 (7.5, 4.8–43.9) 

Plasma MDA levels significantly (p < 0workers whose blood Pb concentration #30 μg/dL. In subjects with blood Pb >plasma MDA were significantly correlablood Pb = 9.584(MDA) + 24.412 (r = 

Froom et al. (1999) Israel 1980–1993 

Design: longitudinal survey Subjects: adult male battery manufacturing workers (n = 94), mean age, 38 yr (SD 9, range 26–60) Outcome measures: blood Hgb, blood EP Analysis: multivariate linear regression 

Blood Pb (μg/dL) range of 13-yr individual subject means: 20–61 μg/dL 

Weak (and probably not significant) cobetween blood Hgb and individual sam

[SE 0.0002]), subject avg blood Pb (∃ = 

blood EP (∃ = 

−0.001 [SE 0.0007]) 

Covariates retained in model were age a
 AX6-227 Table 6-9.2 (cont’d). Effects of Lead on Biochemical Effects in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

Asia (cont’d) Kristal-Boneh et al. (1999) Israel 1994–1995 Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 56), mean age 43.1 yr (SD 10.6); reference group (n = 87), mean age 43.2 yr (SD 8.3) Outcome measures: serum total-, HDL-, LDL- cholesterol, HDL: total ratio, triglycerides Analysis: comparison of outcome measures between Pb workers and reference group (ANOVA), multivariate linear regression Blood Pb (μg/dL) mean (SD): Pb: 42.3 (14.9) Reference: 2.7 (3.6) Covariate-adjusted serum total-choleste

cholesterol (p = 0.001) levels were signworkers compared to reference group. ANOVA: age, body mass index, seasovariables (dietary fat, cholesterol, calciualcohol consumption, cigarette smokingIncreasing blood Pb concentration was with covariate-adjusted total cholestero

p = 0.017) and HDL-cholesterol (∃ = 0.

Covariates retained: age, body mass inother potential confounders had no effe

Solliway et al. (1996) Israel NR Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 34), mean age: 44 yr (SD 13); reference subjects (n = 56), mean age 43 yr (SD 12); cohorts constructed to have similar age, ethnic characteristics, socioeconomic status, education level, and occupation Outcome measures: urinary ALA, erythrocyte GSH-peroxidase Analysis: parametric comparison of outcome measures between Pb and reference groups, correlation Blood Pb (μg/dL) mean (SD, range): Pb: 40.7 (9.8, 23–63) Reference: 6.7 (2.4, 1–13) Significantly lower mean erythrocyte G

(p < 0.005) in and higher urinary ALA compared to reference group. Ito et al. (1985) Japan NR Design: cross-sectional cohort Subjects: adult male steel (smelting, casting) workers (n = 712), age range 18–59 yr; reference (office workers) group (n = 155, total), age range 40–59 yr Outcome measures: serum LPO and SOD, total and HDL-cholesterol, phospholipid Analysis: comparison of outcome measures between Pb workers and reference group, 

correlation 

Blood Pb (μg/dL) range: Pb: 5–62 Reference: NR 

When stratified by age, significantly (p cholesterol and LPO in Pb workers, age to corresponding strata of reference grolevels increased as blood Pb increased aSOD appeared to decrease with increas(p = NR) 
 AX6-228 Table 6-9.2 (cont’d). Effects of Lead on Biochemical Effects in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

Asia (cont’d) Makino et al. (1997) Japan 1990–1994 Design: longitudinal survey Subjects: adult male pigment or vinyl chloride stabilizer manufacture workers (n = 1573) mean age 45 yr Outcome measures: blood Hgb, Hct, RBC count Analysis: parametric comparison of outcome measures, stratified by blood Pb, linear regression Blood Pb (μg/dL) mean (SD, range): 12.6 (2.0, 1–39) Urine Pb (μg/L) mean (SD, range): 10.2 (2.7, 1–239) Significantly higher (p < 0.001) Hct, bl

blood Pb category 16–39 μg/dL, compacategory. Significant positive correlation between and Hct: 

∀ = 42.95, ∃ = 0.0586 (r = 0.1

Hgb: 

∀ = 14.65, ∃ = 0.0265 (r = 0.1835

count 

∀ = 457, ∃ = 0.7120 (r = 0.1408, 

Morita et al. (1997) Japan NR 

Design: cross-sectional cohort Subjects: male Pb workers (n = 76), mean age 42 yr (range 21–62); reference subjects (n = 13, 6 females), mean age, males 41 yr (range 26–52), females 45 yr (range 16–61) Outcome measures: blood NADS, ALAD Analysis: comparison of outcome measures (ANOVA) between blood Pb categories, linear regression 

Blood Pb (μg/dL) mean (SD, range) Pb: 34.6 (20.7, 2.2–81.6) 

Significantly lower (p < 0.01) blood NAcategories >20 μg/dL compared to <20 magnitude of difference. Significant associations between increadecreasing blood NADS and ALAD in NADS: 

∀ = 0.843, ∃ = 

−0.00971, r = 

−

log ALAD: 

∀ = 1.8535, ∃ = 

−0.015, r 

Oishi et al. (1996) Japan NR 

Design: cross-sectional Subjects: adult glass and pigment manufacture workers (n = 418, 165 females), mean age 33 yr (range 18–58); reference workers (n = 227, 89 females), mean age 30 yr (range 17–59) Outcome measures: plasma ALA, urinary ALA Analysis: linear regression, correlation 

Blood Pb (μg/dL) mean (SD, range): Pb: 48.5 (17.0, 10.3–99.4 Reference: 9.6 (3.3, 3.8–20.4) 

Significant correlation between blood Pand urinary ALA (both log-transformedPlasma ALA: 

∀ = 0.327, ∃ = 0.022, r = 

Urinary ALA: 

∀ = 

−0.387, ∃ = 0.022, r 

Significant correlation between plasma ∀ = 6.038, ∃ = 4.962, r = 0.897 
 AX6-229 Table 6-9.2 (cont’d). Effects of Lead on Biochemical Effects in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

Asia (cont’d) Sugawara et al. (1991) Japan NR Design: cross-sectional cohort Subjects: adult Pb workers and reference group (n = 32, total), ages NR Outcome measures: plasma and erythrocyte lipoperoxide and SOD; erythrocyte CAT, GSH, and methemoglobin Analysis: comparisons of outcome measures between Pb workers and reference group, linear regression and correlation Blood Pb (μg/dL) mean (SD, range): Pb: 57.1 (17.6, 20–96) Reference: NR Significantly (p < 0.01) higher erythroc

CAT and GSH levels in workers compaErythrocyte lipoperoxide (r = 0.656) ansignificantly correlated with blood Pb. 

Kim et al. (2002) Korea 1996 

Design: cross-sectional cohort Subjects: adult male secondary Pb smelter workers (n = 83), mean age: 38.7 yr (SD 10.8); reference subjects (n = 24), mean age: 32.0 (SD 10.8) Outcome measures: blood Hgb, blood ALAD, blood EP, blood P5N Analysis: parametric comparison (ANOVA) of outcome measures between Pb workers and reference group, correlation, multivariate linear regression 

Blood Pb (μg/dL) mean (SD) Pb: 52.4 (17.7) Reference: 6.2 (2.8) 

Significantly (p < 0.05) lower blood P5higher blood EP in Pb workers compareSignificant (p < 0.001) correlations (in blood Pb: P5N (r = 

−0.704), log EP (r = 

(r = 

−0.622). 

Significant association between increasblood Hgb: blood Pb ∃60 μg/dL: ∃ = 

−1.546 (95% 

r

2 = 0.513, p = 0.001 

blood Pb <60 μg/dL: ∃ = 

−1.036 (95% 

r

2 = 0.177, p = 0.003 

Significant association between increasblood Hgb (high blood Pb group only): blood Pb ∃60 μg/dL: ∃ = 0.222 (95% Cr

2 = 0.513, p = 0.036 

Covariates included in model: P5N, log 

Lee et al. (2000) Korea NR 

Design: cross-sectional cohort Subjects: adult male Pb workers (n = 95; secondary smelter, PVC-stabilizer manufacture, battery manufacture); mean age 42.8 yr (SD 9.3, range 19–64); reference group (n = 13), mean age 35.1 yr (SD 9.9, range 22–54) Outcome measures: urinary ALA, EP Analysis: correlation 

Blood Pb (μg/dL) mean (SD, range): Pb: 44.6 (12.6, 21.4–78.4) Reference: 5.9 (1.2, 4.0–7.2) 

Significant correlation between increasiurinary Pb and urinary ALA (r = 0.31, p p < 0.001). 
 AX6-230 Table 6-9.2 (cont’d). Effects of Lead on Biochemical Effects in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpr

Asia (cont’d) Schwartz et al. (1997) Korea 1994-1995 Design: cross-sectional Subjects: adult male battery manufacture workers (n = 57), mean age 32 yrs (SD 6). Outcome measures: blood Hgb, HgbA1, and HgbA2, ALAD genotype Analysis: comparison of outcome measures between ALAD genotype strata Blood Pb (μg/dL) mean (SD): ALAD1,1 (n = 38): 26.1 (9.8) ALAD1,2 (n = 19): 24.0 (11.3) Mean blood Pb (p = 0.48) and blood Hg

not different between ALAD genotype 

Gurer-Orhan et al. (2004) Turkey NR Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 20), mean age 35 yr (SD 8); reference workers (n = 16), mean age 32 yr (SD 9) Outcome measures: blood ALAD, EP, erythrocyte MDA, CAT, G6PD, blood GSH:GSSG Analysis: comparison of outcome measures between Pb workers and reference group, correlation Blood Pb (μg/dL) mean (SD): Pb: 54.6 (17) Reference: 11.8 (3.2) Significant correlation between blood P

ALAD (r = -0.85, p < 0.0001) and EP (Significant correlation between blood P

erythrocyte MDA (r = 0.80, p = <0.000(r = 0.70, p < 0.0001, erythrocyte CAT GSH (r = 0.64, p < 0.0005), blood GSSGSH: GSSG ratio lower (p = NR) in Pto controls (8.0). Süzen et al. (2003) Turkey NR Design: cross-sectional Subjects: Male Pb battery manufacture workers (n = 72), age range 24-45 yrs. Outcome measures: blood ALAD, urine ALA, ALAD genotype Analysis: comparison of outcome measures between ALAD genotype strata Blood Pb (μg/dL) mean (SD, range): All: 34.5 (12.8, 13.4–71.8) ALAD1,1 (n = 51) 34.4 (13.1, 13.4–71.8) ALAD2 (n = 21) 34.9 (12.6, 19.2–69.6) Mean blood Pb concentration (p = 0.88(p = 0.33) were not different between AMean urinary ALA was significantly hiALAD1,1 stratum. 
 AX6-231 Table AX6-9.3. Effects of Lead on Hematopoietic System in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

United States Liebelt et al. (1999) Connecticut NR Design: cross-sectional Subjects: children (n = 86, 31 female), ages 1–6 yr Outcome measures: serum EPO, blood Hgb Analysis: ANOVA of outcome measures stratified by blood Pb, linear regression Blood Pb (μg/dL) median (range): 18 (2–84) 84% <35 Significant association between increasin

and decreasing serum EPO concentration 

Covariates included in model were blood 

(age was not included), r2 = 0.224. Predi

per 10 μg/dL was 0.03 mIU/mL. No signblood Pb and blood Hgb. 

Schwartz et al. (1990) Idaho 1974 

Design: cross-sectional Subjects: children (n = 579), ages 1–5 yr, residing near an active smelter (with uncontrolled emissions) Outcome measures: Hct Analysis: logistic regression 

Blood Pb (μg/dL) range: 11–164 

Significant association between increasinand probability of anemia (Hct < 35%) (∃

and age (∃2 = 

−0.3831 [SE 0.1134]). A 1

was predicted to be associated with blood ~20 μg/dL at age 1 yr, 50 μg/dL at age 3 yrs (from Fig. 2 Schwartz et al. (1990). Regression model relating Hct to blood P(AGE, yr): Hct = A/[1 + exp(∃0 + ∃1BL 

A = 39.42 (SE 0.79), p = 0.0001 ∃0 = 

−3.112 (SE 0.446), p = 0.0001 

∃1 = 0.0133 (SE 0.0041), p = 0.0005 

∃2 = 

−0.2016 (SE 0.0905), p = 0.0129 

Based on above model, a 10% decrease in 35.5%) is predicted in association with bl85, 115, and 145 μg/dL, at ages 1, 3, and 
 AX6-232 Table AX6-9.3 (cont’d.). Effects of Lead on Hematopoietic System in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Europe Graziano et al. (2004) (Factor Litvak et al. (1999, 1998) Yugoslavia 1985–1998 Design: prospective Subjects: children (n = 311; age range 4.5–12 yr) from high-Pb (smelter/refinery) and low-Pb areas Outcome measures: blood Hgb, serum EPO. Analysis: multivariate linear regression (GEE for repeated measures) Blood Pb (μg/dL) range: 4.5 yr: 4.6–73.1 6.5 yr: 3.1–71.7 9.0 yr: 2.3–58.1 Blood Pb (μg/dL) means for ages 4.5–12 yrs: High Pb: 30.6–39.3 Low Pb: 6.1–9.0 Significant association between increasin

and increasing serum EPO concentration and 6.5 yr (p < 0.0007), with decreasing r4.5 yr: ∃ = 0.21 (SE 0.043), p = 0.0001; 6

p = 0.0103; 9.5 yr: ∃ = 0.029 (SE 0.033), 

(SE 0.031), p = 0.60. Covariates retained in regression model w

and blood Hgb ((). GEE for repeated meLitvak et al., 1998, updated from personaGraziano 07/2005): (: 0.6097 (95% CI: 

−0.0915, 

−0.0479), p 

4.5 yr: 

∀ = 1.3421 (95% CI: 1.0348, 1.6

∃ = 0.2142 (95% CI: 0.1282, 0.3

6.5 yr: 

∀ = 1.6620 (95% CI: 1.3737, 1.9

∃ = 0.1167 (95% CI: 0.0326, 0.2

9.5 yr: 

∀ = 1.7639 (95% CI: 1.4586, 2.0

∃ = 0.0326 (95% CI: 

−0.0346, 0

12 yr: 

∀ = 1.8223 (95% CI: 1.524, 2.11

∃ = 0.0112 (95% CI: 

−0.0359, 0

Based on the GEE, the predicted increase μg/dL increase in blood Pb concentration 1.25 mIU/mL (36%) at age 4.5 yr and 1.1Blood Hgb levels were not significantly dhigh-Pb area (mean 25–38 μg/dL) compa5–9 μg/dL). 
 AX6-233 Table AX6-9.3 (cont’d). Effects of Lead on Hematopoietic System in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Latin America Perez-Bravo et al. (2004) Chile NR Design: cross-sectional; Subjects: children (n = 93, 43 males), aged 5-12 yrs who attended school near a powdered Pb storage facility Outcome measures: blood Hgb and Hct, ALAD genotype Analysis: comparison of outcome measures between ALAD genotype strata Blood Pb (μg/dL) mean (SE): ALAD1 (n = 84): 13.5 (8.7) ALAD2 (n = 9): 19.2 (9.5) Mean blood Pb, blood Hgb, and Hct not d

genotypes 
 AX6-234 Table AX6-9.4. Effects of Lead on Hematopoietic System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

United States Hu et al. (1994) U.S. 1991 Design: survey Subjects: adult male carpentry workers (n = 119), mean age: 48.6 yr (range 23–67) Outcome measures: blood Hct, blood Hgb Analysis: multivariate linear regression Blood Pb (μg/dL) mean (SD, range): 8.3 (4.0, 2–25) Bone Pb (μg/g) mean (SD, range) Tibia: 9.8 (9.5, 

−15 to 39) 

Patella: 13.9 (16.6, 

−11 to 

78) 

Significant association between increasindecreasing covariate adjusted blood Hgb p = 0.008, r2 = 0.078) and blood Hct (∃ = 

p = 0.009, r2 = 0.061). After adjustment 

error, a 37 μg/dL increase in patella bone to highest quintile) was associated with a Hct of 11 g/L (95% CI: 2.7, 19.3) and 0.respectively. Covariates considered: age, body mass inblood Pb, current smoking status, alcohol Covariates retained: patella bone Pb, alcmass index. 

Europe

Osterode et al. (1999) Austria NR 

Design: cross-sectional cohort Subjects: adult male Pb workers (n = 20), ages 46 yr (SD, 7); age-matched reference group (n = 20) Outcome measures: blood PCV, blood Hgb, serum EPO, blood erythroid progenitor (BFU-E) cell count, blood pluripotent progenitor (CFU-GEMM) cell count, blood granulocyte/macrophage progenitor (CFUGM) cell count. Analysis: parametric and nonparametric comparison of outcomes between Pb workers and reference group; correlation 

Blood Pb (μg/dL) mean (range): Pb: 45.5 (16–91) Reference: 4.1 (3–14) Urine Pb (μg/L) mean (range): Pb: 46.6 (7–108) Reference: 3.7 (2–16) 

Significantly lower (p < 0.001) BFU-E cohad blood Pb concentrations ∃60 μg/dL, group. Significant negative correlation bPb and CFU-GM and CFU-E. Serum EPHct in Pb workers, however, serum EPO with decrease in Hct in reference group. 
 AX6-235 Table AX6-9.4 (cont’d). Effects of Lead on Hematopoietic System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Europe (cont’d) Gennart et al. (1992) Belgium NR Design: cross-sectional cohort Subjects: adult battery manufacture workers (n = 98), mean age, 37.7 yr (range 22–55); reference group (n = 85), mean age 38.8 yr (24–55) Outcome measures: blood Hgb, RBC count, Hct, blood EP Analysis: linear regression Blood Pb (μg/dL) mean (SD, range): Pb: 51.0 (8.0, 40–70) Reference: 20.9 (11.1, 4.4– 30.0) Significant association between increasin

and decreasing blood Hgb (∃ = 

−0.011, r 

(∃ = -0.035, r = 0.24, p < 0.01). Significant association between increasinand increasing blood EP (∃ = 0.0191, r = (No apparent analysis of covariables). 

Mohammed-Brahim et al. (1985) Belgium NR 

Design: cross-sectional cohort Subjects: adult smelter and ceramics manufacture workers (n = 38, 13 females); reference subjects (n = 100) matched with 

worker group by age, sex, and socioeconomic status Outcome measures: blood P5N, EP, ALAD, R/ALAD (ratio of ALAD before and after 

reactivation). Analysis: comparison of outcome measures (ANOVA) between Pb workers and reference group; correlation 

Blood Pb (μg/dL) mean (SD, range): Pb: 48.5 (9.1, 27.8–66.6) Reference: 14.3 (6.7, 5.6–33.6) Urine Pb (μg/g creatinine) mean (SD, range): Pb: 84.0 (95.9, 21.8–587) Reference: 10.5 (8.2, 1.7–36.9) 

Significantly lower (p = NR) P5N in Pb wor combined) compared to corresponding Correlations with blood Pb: log P5N r = 

−0.79 (p < 0.001) 

log ALAD r = 

−0.97 (p = NR) 

R/ALAD r = 

−0.94 (p < 0.001) 

log EP r = 0.86 (p = NR) Correlations with urine Pb: log P5N r = 

−0.74 (p = NR) 

log ALAD r = 

−0.79 (p = NR) 

R/ALAD r = 

−0.84 (p < 0.001) 

log EP r = 0.80 (p = NR) 

Hajem et al. (1990) France NR 

Design: cross-sectional Subjects: adult males (n = 129), mean age 36 yr (SD 7.8, range 24–55), with no environmental exposure to Pb Outcome measures: erythrocyte membrane activities of Na+-K+-ATPase, Na+-K+-cotransport, Na+-Li+-antiport, and passive Na+ and K+ permeability Analysis: linear regression, correlation 

Blood Pb (μg/dL) geometric mean (95% CI, range): 16.0 (15.2–16.8, 8.0–33.0) Hair Pb (μg/g) geometric 

mean (95% CI, range): 5.3 (4.44–6.23, 0.9–60) 

Na+-K+-co-transport activity negatively concentration (r = 

−0.23, p = 0.02); linea

∀ = 583.19, ∃ = 

−170.70 

Na+-K+-ATPase activity negatively corr(r = 

−0.18, p = 0.04); simple linear regres

∀ = 3.34, ∃ = 

−0.02 
 AX6-236 Table AX6-9.4 (cont’d). Effects of Lead on Hematopoietic System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Europe (cont’d) Poulos et al. (1986) Greece NR Design: cross-sectional cohort Subjects: adult male cable production workers who were exposed to Pb (worker 1; n = 50, mean age 37 yr); male cable workers who had not direct contact with Pb (worker 2, n = 75, mean age 36.5 yr); reference group (n = 35, mean age 39 yr) Outcome measures: blood Hgb, Hct Analysis: simple linear regression in the form: mean Hct = a + ∃(individual Hct – group mean Hct) Blood Pb (μg/dL) mean (SE): Worker 1: 27.0 (0.7) Worker 2: 18.3 (0.6) Reference: 21.5 (1.5) Significant association between increasin

Hct: Worker 1: 

∀ = 46.50, ∃ = 

−0.170 (SE 0.0

Worker 2: 

∀ = 44.57, ∃ = 

−0.180 (SE 0.0

Reference: 

∀ = 44.69, ∃ = 

−0.255 (SE 0.

Significant association between increasinblood Hgb: Worker 1: 

∀ = 15.23, ∃ = 

−0.058 (SE 0.0

Worker 2: 

∀ = 14.58, ∃ = 

−0.071 (SE 0.0

Reference: 

∀ = 14.64, ∃ = 

−0.087 (SE 0.

Romeo et al. (1996) Italy NR 

Design: cross-sectional cohort Subjects: adult male Pb workers (n = 28), age range, 17–73; reference group (n = 113), age range, 21–75 yr Outcome measures: serum EPO, blood Hgb Analysis: nonparametric comparison of outcome measures between Pb workers and reference group; correlation 

Blood Pb (μg/dL) mean (SD, range): Pb 1: 32.3 (5.6, 30–49) Pb 2: 65.1 (16, 50–92) Reference: 10.4 (4.3, 3–20) 

Significantly (p = 0.021) lower serum EPto reference group. No significant (p < 0Hgb. 

Graziano et al. (1990) Yugoslavia 1986 

Design: prospective Subjects: pregnant women (n = 1502) from high-Pb (smelter/refinery) and low-Pb areas Outcome measures: Hgb Analysis: comparison of outcome measures between high-and low-Pb groups 

Blood Pb (μg/dL) mean (95% CI): High Pb: 17.1 (6.9, 42.6) Low Pb: 5.1 (2.5, 10.6) 

Mean blood Hgb levels (g/dL) in high-Pb 10.3, 14.5) not different from low-Pb gro14.7). 
 AX6-237 Table AX6-9.4 (cont’d). Effects of Lead on Hematopoietic System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Europe (cont’d) Graziano et al. (1990) Yugoslavia 1986 Design: prospective Subjects: pregnant women (n = 48) from high-Pb (smelter/refinery) and low-Pb areas (6 highest and lowest mid-pregnancy blood Pb concentrations), within each of 4 Hgb strata (g/dL): 9.0–9.9, 10.0–10.9, 11.0–11.9, 12.0–12.9 Outcome measures: Hgb, EPO Analysis: ANOVA of outcome measures in subjects stratified by blood Pb and blood Hgb Blood Pb (μg/dL) mean range for Hgb strata High Pb: 16.9–38.6 Low Pb: 2.4–3.6 Significant effect of blood Pb (p = 0.049) 

on mid-term and term serum EPO (blood p = 0.009), with significantly lower serum higher blood Pb. Asia Hsiao et al. (2001) China 1989–1999 Design: longitudinal Subjects: adult battery manufacture workers (n = 30, 13 females), mean age 38.3 yr Outcome measures: blood Hgb, Hct, RBC count Analysis: GEE for repeated measures (models: linear correlation, threshold change, synchronous change, lag change); logistic regression Blood Pb (μg/dL) mean: 1989: 60 1999: 30 Significant association between increasinRBC count and Hct: Odds ratios (95% CI): Synchronous change model: Blood Hgb: 0.95 (0.52, 1.78) RBC count: 3.33 (1.78, 6.19) Hct: 2.19 (1.31, 3.66) Lag change: Blood Hgb: 1.70 (0.99, 2.92) RBC count: 2.26 (1.16, 4.41) Hct: 2.08 (1.16, 4.41) Hsieh et al. (2000) China NR Design: cross-sectional Subjects: Adults in general population (n = 630, 255 females) Outcome measures: blood Hgb, Hct, RBC count, ALAD genotype Analysis: comparison of outcome measures between ALAD genotype strata Blood Pb ( μg/dL) mean (SD): ALAD1,1 (n = 630): 6.5 (5.0) ALAD1,1/2,2 (n = 30): 7.8 (6.0) Mean blood Pb not different between AL(p = 0.17). RBC count, Hgb, Hct not diffgenotype strata (p = 0.7). 
 AX6-238 Table AX6-9.4 (cont’d). Effects of Lead on Hematopoietic System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia (cont’d) Froom et al. (1999) Israel 1980–1993 Design: longitudinal survey Subjects: adult male battery manufacturing workers (n = 94), mean age, 38 yr (SD 9, range 26–60) Outcome measures: blood Hgb, blood EP Analysis: multivariate linear regression Blood Pb (μg/dL) range of 13-yr individual subject means: 20–61 μg/dL Weak (and probably not significant) cova

between blood Hgb and individual sampl[SE 0.0002]), subject avg blood Pb (∃ = 

−

blood EP (∃ = 

−0.001 [SE 0.0007]). 

Covariates retained in model were age an

Solliway et al. (1996) Israel NR 

Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 34), mean age: 44 yr (SD 13); reference subjects (n = 56), mean age 43 yr (SD 12); cohorts constructed to have similar age, ethnic characteristics, socioeconomic status, education level, and occupation Outcome measures: blood Hgb, RBC count Analysis: parametric comparison of outcome measures between Pb and reference groups, correlation 

Blood Pb (μg/dL) mean (SD, range): Pb: 40.7 (9.8, 23–63) Reference: 6.7 (2.4, 1–13) 

Significantly lower (p < 0.05) mean RBC compared to reference group. Significanbetween blood Pb concentration and RBC 

p < 0.05). Mean comparison for blood Hwith blood Pb concentration (r = 

−0.05, p 

Horiguchi et al. (1991) Japan NR 

Design: cross-sectional cohort Subjects: adult male secondary Pb refinery workers (n = 17), mean age: 44.9 yr (range 24–58); reference male subjects (n = 13), mean age: 33.5 yr (range 22–44) Outcome measures: RBC deformability (microfiltration at 

−20 cm H2O pressure), 

RBC count, Hct, blood Hgb Analysis: comparisons of outcome measures between Pb workers and reference group 

Blood Pb (μg/dL) mean (SD): Pb: 53.5 (16.1) Reference: NR Urine Pb (μg/L) mean (SD): Pb: 141.4 (38.1) Reference: NR 

Significantly lower RBC deformability (p (p < 0.01) Hct (p < 0.01), and blood Hgb compared to reference group. 
 AX6-239 Table AX6-9.4 (cont’d). Effects of Lead on Hematopoietic System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia (cont’d) Makino et al. (1997) Japan 1990–1994 Design: longitudinal survey Subjects: adult male pigment or vinyl chloride stabilizer manufacture workers (n = 1573) mean age 45 yr Outcome measures: blood Hgb, Hct, RBC count Analysis: parametric comparison of outcome measures, stratified by blood Pb, linear regression Blood Pb (μg/dL) mean (SD, range): 12.6 (2.0, 1–39) Urine Pb (μg/L) mean (SD, range): 10.2 (2.7, 1–239) Significantly higher (p < 0.001) Hct, bloo

blood Pb category 16–39 μg/dL, compareSignificant positive correlation between bHct: 

∀ = 42.95, ∃ = 0.0586 (r = 0.1553, p 

∀ = 14.65, ∃ = 0.0265 (r = 0.1835, p < 0.∀ = 457, ∃ = 0.7120 (r = 0.1408, p < 0.00

Morita et al. (1997) Japan NR 

Design: cross-sectional cohort Subjects: male Pb workers (n = 76), mean age 42 yr (range 21–62); reference subjects (n = 13, 6 females), mean age, males 41 yr (range 26–52), females 45 yr (range 16–61) Outcome measures: blood NADS, ALAD Analysis: comparison of outcome measures (ANOVA) between blood Pb categories, linear regression 

Blood Pb (μg/dL) mean (SD, range) Pb: 34.6 (20.7, 2.2–81.6) 

Significantly lower (p < 0.01) blood NADcategories >20 μg/dL compared to <20 μmagnitude of difference. Significant associations between increasiblood NADS and ALAD in Pb workers: NADS: 

∀ = 0.843, ∃ = 

−0.00971, r = 

−0

logALAD: 

∀ = 1.8535, ∃ = 

−0.015, r = 

−

Kim et al. (2002) Korea 1996 

Design: cross-sectional cohort Subjects: adult male secondary Pb smelter workers (n = 83), mean age: 38.7 yr (SD 10.8); reference subjects (n = 24), mean age: 32.0 (SD 10.8) Outcome measures: blood Hgb, blood ALAD, blood EP, blood P5N Analysis: parametric comparison (ANOVA) of outcome measures between Pb workers and reference group, correlation, multivariate linear regression 

Blood Pb (μg/dL) mean (SD) Pb: 52.4 (17.7) Reference: 6.2 (2.8) 

Significantly (p < 0.05) lower blood P5Nhigher blood EP in Pb workers compared Significant (p < 0.001) correlations (in Pb Pb: P5N (r = 

−0.704), log EP (r = 0.678)

(r = -0.622). 

Significant association between increasinHgb: blood Pb ∃60 μg/dL: ∃ = 

−1.546 (96% C

r

2 = 0.513, p = 0.001 

blood Pb <60 μg/dL: ∃ = 

−1.036 (96% C

r

2 = 0.177, p = 0.003 

Significant association between increasinHgb (high blood Pb group only): blood Pb ∃60 μg/dL: ∃ = 0.222 (96% CI

p = 0.036 Covariates included in model: P5N, log 
 AX6-240 Table AX6-9.4 (cont’d). Effects of Lead on Hematopoietic System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia (cont’d) Schwartz et al. (1997) Korea 1994-1995 Design: cross-sectional Subjects: adult male battery manufacture workers (n = 57), mean age 32 yrs (SD 6). Outcome measures: blood Hgb, HgbA1, and HgbA2, ALAD genotype Analysis: comparison of outcome measures between ALAD genotype strata Blood Pb (μg/dL) mean (SD): ALAD1,1 (n = 38): 26.1 (9.8) ALAD1,2 (n = 19): 24.0 (11.3) Mean blood Pb (p = 0.48) and blood Hgb 

different between ALAD genotype strata
 AX6-241 Table AX6-9.5. Effects of Lead on the Endocrine System in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

United States Mahaffey et al. (1982) Wisconsin, New York NR Design: cross-sectional Subjects: children/adolescents (n = 177), ages 1–16 yr Outcome measures: serum 1,25-OH-D Analysis: comparison of outcome measures between age, location and blood Pb strata, linear regression Blood Pb (μg/dL) range: 12–120 Serum 1,25-OH-D levels were significan

age group 11–16 yr compared to age grouIncreasing blood Pb (log-transformed) sig

decreasing serum 1,25-OH-D levels in ch(∀ = 74.5, ∃ = 

−34.5, r = 

−0.884, n = 50) 

Dietary calcium: NR 

Rosen et al. (1980) New York NR 

Design: cross-sectional Subjects: children (n = 45), ages 1–5 yr Outcome measures: serum calcium, PTH, 25-OH-D, 1,25-OH-D Analysis: comparison of outcome measures between blood Pb strata, and before and after chelation, correlation 

Blood Pb (μg/dL) mean (SE, range): #29 (n = 15): 18 (1, 10–26) 30–59 (n = 18): 47 (2, 33–55) ∃60 (n = 12): 74 (98, 62–120) 

Significantly higher serum PTH levels anPb group compared to low-Pb group; signlevels in moderate- and high-Pb group coSerum levels of 1,25-OH-D were negativPb (high Pb: r = 

−0.71, moderate: r = 

−0

chelation therapy, blood Pb decreased anincreased to levels not significantly differgroup, 25-OH-D levels were unchanged. Dietary calcium intake (mg/day) mean (SLow Pb: 800 (30) Moderate Pb: 780 (25) High Pb: 580 (15) 

Sorrell et al. (1977) New York 1971–1975 

Design: cross-sectional Subjects: children (124), ages 1–6 yr Outcome measures: serum calcium, phosphate, 25-OH-D Analysis: comparison of outcome measures between blood Pb strata, correlation 

Blood Pb (μg/dL) mean (SE): #29 (n = 40): 23 (1) 30–59 (n = 35): 48 (1) ∃60 (n = 49): 84 (5.0) 

Serum calcium and 25-OH-D were signifgroup (p < 0.001). Significant negative cPb and serum calcium (high Pb, r = 

−0.78

intake high Pb, (r = 

−0.82, p < 0.001) in a

25-OH-D was significantly positively corintake, but not with blood Pb. Dietary calcium intake (mg/day) mean (SLow Pb: 770 (20) Moderate Pb: 760 (28) High Pb: 610 (20) 
 AX6-242 Table AX6-9.5 (cont’d). Effects of Lead on the Endocrine System in Children Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

United States (cont’d) Siegel et al. (1989) Connecticut 1987 Design: cross-sectional Subjects: children (n = 68, 32 female), ages 11 mo to 7 yr Outcome measures: serum FT4, TT4 Analysis: linear regression Blood Pb (μg/dL) mean (range): 25 (2–77) No significant association between blood 

thyroid hormone outcomes. Linear regreFT4: 

∀ = 1.55 (SE 0.05), ∃ = 0.0024 (SE 

p = 0.13 TT4: 

∀ = 8.960 (SE 0.39), ∃ = 0.0210 (S

p = 0.10 

Koo et al. (1991) Ohio NR 

Design: longitudinal (subset of prospective) Subjects: children (n = 105, 56 females), age 21, 27, 33 mo Outcome measures: serum calcium magnesium, phosphorus, PTH, CAL, 25-OHD, 1,25-OH-D, and bone mineral content 

Analysis: structural equation modeling 

Blood Pb (μg/dL) geometric mean (GSD, range): Lifetime mean, based on quarterly measurements: 9.74 (1.44, 4.8–23.6) Concurrent: 15.01 (1.52, 6–44) Maximum observed: 18.53 (1.53, 6–63) 

Significant association between increasinand covariate-adjusted decreasing serum (∀ = 1.83, ∃ = 

−0.091). No other covaria

significantly associated with blood Pb. Covariates retained: age, sex, race, and sDietary calcium intake (mg/day) #600: n = 4 (4%) 600–1200: n = 58 (55%) >1200: n = 43 (41%) 
 AX6-243 Table AX6-9.6. Effects of Lead on the Endocrine System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, In

United States Cullen et al. (1984) Connecticut 1979 NR Design: clinical case study Subjects: adult males with neurological symptoms of Pb poisoning Outcome measures: serum, FSH, LH, PRL, TES Analysis: clinical outcomes in terms of abnormal values Blood Pb (μg/dL) range: 66–139 Five subjects with defects in 

azospermia), with no change PRL, and TES. Robins et al. (1983 Connecticut NR Design: cross-sectional Subjects: adult male brass foundry workers (n = 47), age range 20–64 yr Outcome measures: FT4 Analysis: simple linear regression with stratification by age and race. Blood Pb (μg/dL) range: 16–127 Significant association betweconcentration and decreasing ∃ = 

−0.0042 [95% CI: 

−0.00

p = 0.048). Significant interwhite) and blood Pb. When stratified by race: Black: 

∀ = 1.13, ∃ = 

−0.005

−0.0095), r2 = 0.21, p = 0.03 White: r2 = 0.05, p = 0.27 Strength of association not cthe regression model. 

Braunstein et al. (1978) California NR 

Design: clinical Subjects: adult male secondary Pb smelter (n = 12), mean age 38 yr, reference group, (n = 9), mean age 29 yr Outcome measures: serum EST, FSH, LH, TES, HCG-stimulated EST and TES, GnRHstimulated serum FSH and LH Analysis: comparisons of outcome measures between patients symptomatic for Pb poisoning, Pb-exposed patients not symptomatic, reference group 

Blood Pb (μg/dL) mean (SD): Symptomatic (n = 9): Time of test: 38.7 (3.0) Highest: 88.2 (4.0) Asymptomatic (n = 4): Time of test: 29.0 (5.0) Highest: 80.0 (0.0) Reference: 16.1 (1.7) 

Statistically significant (p < TES, higher TES response to reduced LH response to GnRfor Pb poisoning (including E>500 μg/24 hr). 

Refowitz (1984) NR 

Design: cross-sectional survey Subjects: secondary copper smelter workers (n = 58) Outcome measures: FT4, TT4 Analysis: linear regression 

Blood Pb (μg/dL) range: 5–60 

No significant association behormone levels: FT4: 

∀ = 2.32, ∃ = 

−0.0067 

TT4: 

∀ = NR, ∃ = 

−0.28 (95

No significant association wwhite) 
 AX6-244 Table AX6-9.6 (cont’d). Effects of Lead on the Endocrine System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Canada Alexander et al. (1998, 1996a) British Columbia 1993 Design: cross-sectional Subjects: adult male primary smelter workers (n = 152), mean age 40 yr Outcome measures: serum FSH, LH, TES Analysis: multivariate linear regression Blood Pb (μg/dL) range (n = 81): 22.8 (5–58) Semen Pb (μg/dL) range: 1.9 (0.1–17.6) No significant association between cova

hormone levels (p ∃ 0.5) or prevalence oSignificant association between covariatsemen Pb concentration and decreasing 

p = 0.004). Covariates considered: age, smoking, al(arsenic, cadmium, copper, zinc), abstinecollection, and sperm count. 

Schumacher et al. (1998) British Columbia 1993 

Design: cross-sectional Subjects: adult male smelter workers (n = 151) mean age 40 yr (SD 7.2) Outcome measures: serum FT4, TT4, TSH Analysis: linear regression, ANOVA 

Blood Pb (μg/dL) mean: 24.1 (n = 151) <15 (n = 36) 15–24 (n = 52) 25–39 (n = 41) ∃40 (n = 22) 

No significant effect of blood Pb (categoor unadjusted FT4 (p = 0.68), TT4 (p = 0significant association of blood Pb with values of hormones. No significant assoblood Pb and hormone levels or prevalenCovariates considered: age and alcohol 

EuropeGennart et al. (1992) Belgium NR 

Design: cross sectional cohort Subjects: adult battery manufacture workers (n = 98), mean age 37.7 yr (SD 8.3, range 22–55); reference worker group (n = 85), mean age 38.8 yr (SD 8.7, range 22–55) Outcome measures: serum TT3, FT4, TT4, TSH, FSH, LH Analysis: comparison of outcome measures between Pb workers and reference group 

Blood Pb (μg/dL) mean (SD, range): Pb: 51.0 (8.0, 40.0–75.0) Reference: 20.9 (11.1, 4.4–39.0) Urine Pb (μg/g creatinine) mean (range): Pb: 57.8 (1.95, 4.3–399) Reference: 9.75 (2.73, 1.45–77.7) 

Mean hormone levels in Pb workers and different (p = NR); no association betweblood Pb or exposure duration quartile. 
 AX6-245 Table AX6-9.6 (cont’d). Effects of Lead on the Endocrine System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Europe (cont’d) Assennato et al. (1987) Italy NR Design: cross-sectional Subjects: adult male battery manufacture workers (n = 39), mean age 41 yr (SD 10); reference cement plant workers (n = 18), mean age 40 yr (SD 10) Outcome measures: serum FSH, LH, PRL, TES; urinary 17-ketosteroids Analysis: parametric comparison of outcome measures between Pb and reference groups Blood Pb (μg/dL) mean (SD): Pb: 61 (20) Reference: 18 (5) Urinary Pb (μg/L) mean (SD): Pb: 79 (37) Reference: 18 (8) No significant association (p > 0.05) bet

hormone levels. Govoni et al. (1987) Italy NR Design: cross-sectional Subjects: adult male pewter manufacture workers (n = 78), mean age 35 yr (SD 19, range 19–52) Outcome measures: serum PRL Analysis: parametric comparison of outcome measures between blood Pb and ZPP strata Blood Pb (μg/dL) mean (SD)/blood ZPP (μg/dL) mean (SD): A (n = 22): 28.2 (7.1)/24.4 (8.7) B (n = 33): 60/3 (19.3)/131 (107) C (n = 13): 33.1 (6.7)/77.0 (42.2) D (n = 8): 49.1 (4.2)/34.0 (4.8) Significantly (p < 0.02) higher serum PR

C, compared to low ZPP strata A). Rodamilans et al. (1988) Spain NR Design: cross-sectional cohort Subjects: adult male Pb smelter workers (n = 23), age range 21–44 yr; reference group (n = 20), age range 20–60 yr Outcome measures: serum FSH, LH, TES, FTES, SHBG Analysis: comparison of outcome measures between exposure duration strata Blood Pb (μg/dL) mean (SD) Pb <1 yr (n = 5): 66 (22) Pb 1–5 yr (n = 8): 73 (24) Pb >5 yr (n = 10): 76 (11) Reference (n = 20): 17.2 (13) Serum TES (p = 0.01) and FTES (p = 0.

SHBG significantly higher (p < 0.025) in compared to reference group; serum LH higher in all exposure groups compared 
 AX6-246 Table AX6-9.6 (cont’d). Effects of Lead on the Endocrine System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, I

Europe (cont’d) Erfurth et al. (2001) Sweden NR Design: cross-sectional cohort Subjects: adult male active secondary smelter workers (n = 62), mean age 43 yr (range 21– 78) reference worker group (n = 26), mean age 43 yr (range 23–66) Outcome measures: serum FT3, FT4, TSH, TES, SHBG; TRH-stimulated serum TSH; GnRH-stimulated serum FSH, LH, and PRL Analysis: nonparametric comparison of outcome measures between Pb workers and reference group; multivariate linear regression Blood Pb (μg/dL) median (range): Pb: 31.1 (8.3–93.2) Reference: 4.1 (0.8–6.2) Plasma Pb (μg/dL) median (range): Pb: 31.1 (8.3–93.2) Reference: 4.1 (0.8–6.2) Urine Pb (μg/g creatinine) median (range): Pb: 19.6 (3.1–80.6) Reference: 4.1 (2.4–7.3) Bone (finger) Pb (μg/g) median (range): Pb: 25 (

−13 to 99) 

Reference: 2 (

−21 to 14) 

Basal hormone levels in wreference group (p ∃ 0.05hormone levels not assocPb, urine Pb, or bone Pb. of the cohorts (n = 9 Pb wmedian GnRH-stimulated significantly (p = 0.014) l

workers than in reference No association between sPRL and Pb measures. 

Gustafson et al. (1989) Sweden NR 

Design: cross-sectional cohort Subjects: adult male secondary smelter workers (n = 21) mean age 36.0 yr (SD 10.4); individually matched for age, sex, and work shift (n = 21) Outcome measures: serum FTES, TTES; FSH, LH, PRL, COR, TSH, TT3, TT4 Analysis: nonparametric comparison of outcome measures between Pb workers and reference group, correlation 

Blood Pb (μg/dL) mean (SE): Pb: 39.4 (2.1) Reference: 5.0 (0.2) 

Significantly higher TT4 FSH (p = 0.009) in Pb woreference group. When r<40 yr, Pb workers had s(p = 0.01) and lower FSH and COR (p = 0.04), comgroup. 

Campbell et al. (1985) UK NR 

Design: cross-sectional cohort Subjects: adult male welders (n = 25); reference subjects (n = 8) (ages NR) Outcome measures: plasma ACE, AI, PRA, plasma ALD Analysis: linear regression, nonlinear least squares 

Blood Pb (μg/dL) mean (SD, range): 35.6 (15.3, 8–62) 

Significant positive correconcentration and plasma p < 0.002), PRA (r = 

−0.7

p < 0.002), and ACE (r = 
 AX6-247 Table AX6-9.6 (cont’d). Effects of Lead on the Endocrine System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Europe (cont’d) Chalkley et al. (1998) UK 1979–1984 Design: cross-sectional Subjects: adult male primary metal (cadmium, Pb, zinc) workers (n = 19), ages NR Outcome measures: blood calcium, serum 25- OH-D, 1,25-OH-D, 24,25-OH-D Analysis: comparison of outcome measures (ANOVA) in group stratified by blood Pb and urinary cadmium Blood Pb (μg/dL) mean (SD, range): 47 (21–76) After stratification by blood Pb and urin

OH-D levels in strata were significantly higher mean values in high blood Pb (>4cadmium (>0.9 μg/L)/high urine cadmiucompared to low blood Pb (<40 μg/dL)/(>0.9 μg/L)/high urine cadmium >3.1 μgOH-D levels decreased with increasing u

Mason et al. (1990) UK NR Design: cross-sectional Subjects: adult male Pb workers (n = 63), age range 21–63 yr; reference male subjects (n = 75), age range 22–64 yr Outcome measures: serum calcium phosphate, PTH, 1,25-OH-D Analysis: comparison of al outcome measures between Pb workers and reference group, multivariate regression Blood Pb (μg/dL) range: Pb (15–94) Reference: NR Tibia Pb (μg/g) Pb: 0–93 Reference: NR Significantly higher (p < 0.025) prevalen

(>2 SD of reference mean) in Pb workerreference group (1/75, 1.3%). Serum levsignificantly (p < 0.05) higher in Pb worgroup. After stratification of Pb workers into exblood Pb ∃40 μg/dL and bone Pb ∃40 μg

#40 μg/dL and bone Pb #40 μg/g), serum 

significantly (p < 0.01) higher in the higIncreasing blood Pb was significantly (p increasing 1,25-OH-D levels (r2 = 0.206

included, r2 = 0.218). After excluding 1

concentrations >60 μg/dL, r2 = 0.162 (p 

McGregor and Mason, (1990) UK NR 

Design: cross-sectional cohort Subjects: adult male Pb workers (n = 90), mean age (31.5 yr (SD 11.9); reference workers (n = 86), mean age 40.6 yr (SD 11.8) Outcome measures: serum FSH, LH, TES, SHBG Analysis: comparison of outcome means between Pb workers and reference groups, multivariate regression, correlation 

Blood Pb (μg/dL) range: Pb: 17–77 Reference: <12 

Age-adjusted serum FSH was significanworkers compared to reference group. Increasing serum FSH significantly (p = Pb and age. Increasing serum LH signifincreasing exposure duration (not blood No significant association between serum Pb or exposure duration. No significant difference in prevalence obetween groups. 
 AX6-248 Table AX6-9.6 (cont’d). Effects of Lead on the Endocrine System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Latin AmericaL

∴pez et al. (2000) 

Argentina NR 

Design: cross sectional Subjects: adult male battery manufacture workers (n = 75), age range 21–56 yr; reference group (n = 62), age NR Outcome measures: serum TT3, FT4, TT4, TSH Analysis: comparison of outcome measures between Pb workers and reference group, correlation 

Blood Pb (μg/dL) mean (range): Pb: 50.9 (23.3, 8–98) Reference: 19.1 (7.1, 4–39)

Significantly higher serum FT4 (p < 0.0workers compared to reference group. Scorrelation between blood Pb and serum (p < 0.01), TT4 (p < 0.05), and TSH (p < 8–50 μg/dL; and for TSH (p < 0.05) for 26 μg/dL. 

Roses et al. (1989) Brazil NR 

Design: adult male Pb workers (n = 70), age range 20–53 yr; reference group (n = 58), age range 25–37 yr. Outcome measures: serum PRL Analysis: comparison of outcome measure between Pb workers and reference group, linear regression 

Blood Pb (μg/dL) range: Pb: 9–86 Reference: 8–28 

Serum RL levels in Pb workers and refesignificantly different (p = NR). Correlaand blood Pb (r = 0.57, p = NR). 

AsiaDursun and Tutus (1999) Turkey NR 

Design: cross-sectional Subjects: adult metal powder manufacture workers (n = 27) mean age 41.1 yr (SD 5.45, range 25–50); reference group (n = 30), mean age 42 yr (SD 3.42, range 28–49) Outcome measures: serum FT4, TT4, FT3, TT3, TSH Analysis: parametric comparison of outcome measures between Pb and reference groups, simple and multivariate linear regression 

Blood Pb (μg/dL) mean (range): Pb: 17.1 (9.0, 6–36) Reference: 2.4 (0.1, 1–4) 

Significantly (p < 0.0001) higher mean Tworkers compared to reference group. Significant association between TT4, agexposure duration (∃ = 

−0.20, p > 0.01), 

NR) in linear regression model that incluexposure duration (

∀ = 2.76, r2 = 0.3, p 
 AX6-249 Table AX6-9.6 (cont’d). Effects of Lead on the Endocrine System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia (cont’d) Kristal-Boneh et al. (1998) Israel NR Design: cross-sectional cohort Subjects: adult male battery manufacture/recycling workers (n = 56), mean age 43.4 yr (SD 11.2); reference workers (n = 90), mean age 41.5 yr (SD 9.3) Outcome measures: serum calcium, magnesium, phosphorus, PTH, 25-OH-D, 1,25-OH-D Analysis: parametric comparison of outcome measures between Pb workers and reference group, multivariate linear regression Blood Pb (μg/dL) mean (SD, range): Pb: 42.6 (14.5, 20–77) Reference: 4.5 (2.6, 1.4– 19) Serum 1,25-OH-D (p = 0.0001) and PTH 

significantly higher in Pb workers compIncreasing blood Pb concentration (ln-trsignificantly associated with covariate-aPTH and 1,25-OH-D levels: PTH: ∃ = 4.8 (95% CI: 0.8, 8.8), r2 = 0

1,25-OH-D: ∃ = 4.8 (95% CI: 2.7, 6.9)

Occupational Pb exposure (yes) significincreasing PTH and 1,25-OH-D levels. Covariates retained: age, alcohol consummagnesium, and calorie intake: PTH: ∃ = 7.81 (95% CI: 3.7, 11.5) 1,25-OH-D: ∃ = 12.3 (95% CI: 3.84, 20

Horiguchi et al. (1987) Japan NR Design: cross-sectional Subjects: adult secondary Pb refinery (n = 60, 8 females), mean age 49 yr (range 15–69) Outcome measures: serum TT3, TT4, TSH Analysis: comparison of outcome measures (method NR), between job categories, correlation Blood Pb (μg/dL) mean (SD): Male: 31.9 (20.4) Female: 13.5 (9.5) Urine Pb (μg/L) mean (SD): Male: 59.3 (76.3) Female: 26.0 (19.7) No significant differences (p = NR) betw

Pb categories: mean blood Pb (μg/dL, S(15.4), 49.9 (18.7). No significant correhormone levels and blood or urine Pb le

Ng et al. (1991) China NR Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 122), mean age 32.6 (SD 8,2, range 17–54); reference group (n = 49), mean age 43.4 yr (SD 13.4, range 18–74) Outcome measures: serum FSH, LH, PRL, TES Analysis: multivariate linear regression ANCOVA Blood Pb (μg/dL) mean (SD, range): Pb: 35.2 (13.2, 9.6–77.4) Reference: 8.3 (2.8, 2.6– 14.8) When cohorts were stratified by age seru

significantly (p < 0.02) higher in Pb worcompared to corresponding age strata of TES was significantly (p < 0.01) lower i

Covariate-adjusted serum TES were signin Pb workers in the ∃10-yr exposure du

to the reference group. Covariate-adjustsignificantly higher (p < 0.01) in Pb worduration category, compared to the referCovariates: age and tobacco smoking. 
 AX6-250 Table AX6-9.6 (cont’d). Effects of Lead on the Endocrine System in Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia (cont’d) Zheng et al. (2001) China NR Design: retrospective cross-sectional Subjects: adult hospital patients (n = 82, 32 females) mean age 49.6 yr (SD 18.7) Outcome measures: serum and CSF TTR, TT4 Analysis: simple and multivariate linear regression Blood Pb (μg/dL) mean (SD): All: 14.9 (8.3) Female: 14.2 (8.76) Male: 15.4 (8.07) No significant association between bloo

(r = 

−0.114, p = 0.307), TT4 (r = 

−0.160

Significant association between age-adju(r = 

−030, p = 0.023). 

No significant association between CSF (r = 

−0.22, p = 0.090). 

Singh et al. (2000) India NR 

Design: cross-sectional cohort Subjects: adult male petrol pump attendants (n = 58), mean age 31.7 yr (SD 10.6); reference group (n = 35), mean age 28.9 yr (SD 4.20) Outcome measures: serum TT3, TT4, TSH Analysis: parametric comparison of outcome measures between Pb workers and reference group, stratified by blood Pb or exposure duration 

Blood Pb (μg/dL) mean (SD): Pb: 51.6 (9.3) Reference: 9.5 (8.7) 

Serum TSH significantly higher (p < 0.0to reference group, significantly higher i(#70 μg/dL, mean 54.5 μg/dL) compared #41 μg/dL, mean 31.3 μg/dL). Serum TPb workers who were exposed for #60 mexposed for >60 mo. 

Africa Tuppurainen et al. (1988) Kenya 1984 

Design: cross-sectional Subjects: adult male battery manufacture workers (n = 176), mean age 34.1 yr (SD 8.1, range 21–54) Outcome measures: serum TT3, FT4, TT4, TSH Analysis: multivariate linear regression and correlation 

Blood Pb (μg/dL) mean (SD, range): 55.9 (23.8, 14.5–133.6) 

Increasing exposure duration significantdecreasing FT4 (r2 = 0.071, p = 0.001) a

p = 0.021); regression not improved by iStrength of association greater when resan exposure duration >7.6 yrs: FT4: r2 r

2 = 0.21, p < 0.001. 

No significant association between bloo
 AX6-251 Table AX6-9.7. Effects of Lead on the Hepatic System in Children and Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Children United States Saenger et al. (1984) New York NR Design: clinical cases Subjects: children (n = 26) ages 2–9 yr; age- matched reference group (n = NR) Outcome measures: urinary cortisol and 6∃- OH-cortisol (CYP3A metabolite of cortisol) Analysis: comparison of outcome measure between children who qualified for EDTA treatment (EDTA provocation >500 μg/24 hr) Blood Pb (μg/dL) mean (SE, range): Chelated: 46 (2, 33–60) Not chelated: 42 (3, 32–60) Urinary Pb (μg/24 hr) mean (SE, range), EDTA- provocation: Chelated: 991 (132, 602– 2247) Not chelated: 298 (32, 169–476) Significantly lower (~45% lower) urinary 

cortisol (p = 0.001) and urinary 6∃-OH-c

(p < 0.001) in children who qualified for who did not qualify and significantly lowreference group. Urinary 6∃-OH-cortisol

significantly correlated with blood Pb (r = 

urinary Pb, and EDTA provocation urina

p < 0.001). 

AdultsAsiaAl-Neamy et al. (2001) United Arab Emirates 1999 

Design: cross-sectional cohort Subjects: adult male (n = 100) workers (e.g., gas pump attendants, garage workers, printing workers, construction workers), mean age 34.6 yr (SD 8.0); reference group (n = 100) matched with Pb workers for age, sex, nationality. Outcome measures: serum protein, albumin, ALT, AP, AST, BUN, (GT, LDH Analysis: comparison of outcome measures between Pb workers and reference group 

Blood Pb (μg/dL) mean (SD): Pb: 77.5 (42.8) Reference: 19.8 (12.3) 

Significantly higher serum AP (p = 0.012Pb workers compared to reference group range). 
 AX6-252 Table AX6-9.7 (cont’d). Effects of Lead on the Hepatic System in Children and Adult

Reference, Study Location, and Period Study Description Pb Measurement Findings, InterpreAsia (cont’d) Hsiao et al. (2001) China 1989–1999 Design: longitudinal Subjects: adult battery manufacture workers (n = 30, 13 females), mean age 38.3 yr Outcome measures: serum ALT Analysis: GEE for repeated measures (models: linear correlation, threshold change, synchronous change, lag change); logistic regression Blood Pb (μg/dL) mean: 1989: 60 (~25–100) 1999: 30 (~10–60) No association between blood Pb and AL

Odds ratios (95% CI): Synchronous change model: 1.25 (0.69, Lag change: 1.76 (0.76, 4.07) Satarug et al. (2004) Thailand NR Design: cross-sectional Subjects: adults from general population (n = 118, 65 female), age range, 21–57 yr Outcome measures: coumarin-induced urinary 7-OH-coumarin (marker for CYP2A6 activity) Analysis: multivariate linear regression Urinary Pb (μg/g creatinine) mean (SD, range): Males: 1.3 (1.8, 0.1–12) Females: 2.4 (1.1, 0.6–6.8) Serum Pb (μg/L) mean (SD, range): Males: 4.2 (5.4, 1–28) Females: 3.0 (2.2, 1–12) Significant association between increasincovariate-adjusted urinary 7-OH-coumarimales, but not in females. Covariates retexcretion. Significant association in oppourinary cadmium and urinary 7-OH-coum
 AX6-253 Table AX6-9.8. Effects of Lead on the Gastrointestinal System Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Canada Holness and Nethercott (1988) Ontario 1982–1984 Design: longitudinal Subjects: adult male demolition workers (n = 119), age NR Outcome measures: prevalence of symptoms Analysis: comparison of prevalence of symptoms (questionnaire) stratified by job phase or blood Pb Blood Pb (μg/dL) mean (range): Phase 1: 59 (15–99) Phase 2: 30 Phase 3: 19 Phase 4: 17 Prevalence of reporting of symptoms of a

constipation increased with increasing bl(p < 0.05): <50 μg/dL: 8%, 6% 50–70 μg/dL: 37%, 42% >70 μg/dL: 77%, 62% Caribbean Matte et al. (1989) Jamaica 1987 Design: survey Subjects: battery manufacture/repair workers (n = 63), mean age ~30 yr (range 11–47) Outcome measures: prevalence of symptoms Analysis: comparison of GI symptoms (questionnaire) between blood Pb strata Blood Pb (μg/dL) geometric mean site range: 40–64 Blood Pb distribution: >60: 60% <60: 40% When stratified by blood Pb, <60 μg/dL 

prevalence ratio (high/low) was not signi(1.5, [95% CI: 0.5, 4.6]), or for any otheweakness). Asia Bercovitz and Laufer (1991) Israel NR Design: cross-sectional Subjects: health individuals (n = 12), peptic ulcer patients (n = 11), and individuals with heart disease (n = 11) with environmental exposure Analysis: one-way ANOVA used to compare tooth Pb concentrations in the three groups Tooth Pb (:g/g dry dentine) mean (SE): Healthy: 25.62 (10.15) Peptic ulcer: 75.02 (8.15) Heart disease: 20.30 (2.70) Tooth Pb levels in patients with gastroint

significantly higher than that in healthy sthe 11 peptic ulcer patients had a higher Psubjects. In these 10 patients, increased slongevity of suffering was associated witThere was no significant difference betwthe healthy subjects and in the heart disea
 AX6-254 Table AX6-9.8 (cont’d). Effects of Lead on the Gastrointestinal System Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Asia (cont’d) Lee et al. (2000) Korea NR Design: cross-sectional cohort Subjects: adult male Pb workers (n = 95; secondary smelter, PVC-stabilizer manufacture, battery manufacture); mean age 42.8 yr (SD 9.3, range 19–64); reference group (n = 13), mean age 35.1 yr (SD 9.9, range 22–54) Outcome measures: prevalence of GI symptoms (self-administered questionnaire) Analysis: multivariate logistic regression Blood Pb (μg/dL) mean (SD, range): Pb: 44.6 (12.6, 21.4–78.4) Reference: 5.9 (1.2, 4.0–7.2) Covariate-adjusted OR for GI symptoms 

constipation or diarrhea, abdominal pain) included in model) were not significant: Blood Pb (45.7 μg/dL vs. <45.7 μg/dL): CI: 0.7, 4.5) DMSA-provoked urinary Pb (>260.5 vs. (95% CI: 0.4, 2.5) OR for neuromuscular symptoms were siDMSA-provoked Pb (OR = 7.8 [95% CIblood Pb. Covariates retained: age, tobacco smokinconsumption. Africa Awad el Karim et al. (1986) Sudan NR Design: cross-sectional cohort Subjects: adult male battery manufacture workers (n = 92), mean age 31.1 yr (SD 8.2); reference group (n = 40), mean age 33.7 yr (SD 9.7) Outcome measures: clinical evaluation Analysis: comparison of prevalence of symptoms of Pb poisoning between Pb workers and reference group Blood Pb distribution for Pb workers >80: 23% 40–80: 72% <40: 5% Blood Pb (μg/dL) mean (SD, range): Pb: 55–81 (mean range for various jobs), range 39–107 Reference: 21 (8.5, 7.4– 33.1) Prevalences of abdominal colic (pain) anand 41.4 % in Pb workers and 7.5% and reference group. 
 AX6-255 Table AX6-9.9. Effects of Lead on Bone and Teeth in Children and Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Children United States Moss et al. (1999) U.S. 1988–1994 Design: cross-sectional national survey (NHANES III) Subjects: general population (n = 24,901), ages 2–5 yr (n = 3,547), 6–11 yr (n = 2,894), 

∃12 yr (18,460) Outcome measures: number of caries (dfs, DFS, DMFS) Analysis: multivariate linear regression and logistic regression 

Blood Pb (:g/dL) geometric mean (SE): 2–5 yr: 2.90 (0.12) 6–11 yr: 2.07 (0.08) ∃12 yr: 2.49 (0.06) 

Increasing blood Pb concentration (log-trassociated with covariate adjusted increa2–5 yr: ∃ = 1.78 (SE 0.59), p = 0.004 

6–11 yr: ∃ = 1.42 (SE 0.51), p = 0.007 

Increases in DFS: 6–11 yr: ∃ = 0.48 (SE 0.22), p = 0.03 

∃12 yr: ∃ = 2.50 (SE 0.69), p < 0.001 

Increases in DMFS: ∃12 yr: ∃ = 5.48 (SE 1.44), p = 0.01 

Odds ratio (OR) for caries (∃1 DMFS, ag

attributable risk (PAR) in association wittertiles, compared to 1st tertile were: 1st tertile (#1.66 :g/dL) 2nd tertile (1.66–3.52 :g/dL): OR = 1.36 PAR = 9.6% 3rd tertile (>3.52 :g/dL): OR = 1.66 (95% PAR = 13.5% For an increase of blood Pb of 5 :g/dL, OCovariates retained were age, gender, racratio, exposure to cigarette smoke, geogralevel of head of household, carbohydrate dental visits. 
 AX6-256 Table AX6-9.9 (cont’d). Effects of Lead on Bone and Teeth in Children and Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

United States (cont’d) Schwartz et al. (1986) U.S. 1976–1980 Design: cross-sectional national survey (NHANES II) Subjects: ages <7 yr (n = 2,695) Outcome measures: variables of stature, including height, weight, and chest circumference Analysis: multivariate weighted linear regression Blood Pb (:g/dL) range: 5-35 Blood Pb levels were a statistically signif

height (p < 0.0001), weight (p < 0.001), a(p < 0.026), after controlling for age in mHeight: ∃ = 

−0.119 (SE 0.0005) 

Weight: ∃ = 

−1.0217 (SE 0.08) for log-tr

Chest circumference: ∃ = 

−0.6476 (SE 0.

blood Pb There are several explanations for the invblood Pb and growth in children. First, bcomposite factor for genetic, ethnic, nutrisociocultural factors. Second, nutritional also enhance Pb absorption. Finally, therlow level Pb on growth in children. 

Gemmel et al. (2002) Boston/Cambridge, MA NR 

Design: cross-sectional Subjects: children (n = 543), ages 6–10 yr Outcome measures: number of caries (dfs, DFS) Analysis: multivariate linear regression 

Blood Pb (:g/dL) mean (SD, max): Urban (n = 290): 2.9 (2.0, 13) Rural (n = 253): 1.7 (1.0, 7) 

Increasing blood Pb (ln-transformed) was with covariate-adjusted number of caries transformed) in the urban (∃ = 0.22 [SE 0not in the rural group (∃ = 

−0.15 [SE 0.09

numbers were stratified by permanent or Pb association in the urban group was sigteeth. (∃ = 0.28, SE 0.09, p = 0.002), but not foSE 0.07, p = 0.8). Covariates retained: age, sex, ethnicity, ffemale guardian, maternal smoking, frequfirmness of toothbrush bristles, and frequ

Campbell et al. (2000) New York 1995–1997 

Design: retrospective cohort Subjects: children (n = 154), ages 6.9–12 yr Outcome measures: prevalence of caries (dfs, DMFS) Analysis: multivariate logistic regression 

Blood Pb (:g/dL) mean (range): 10.7 (18.0–36.8) (measured at ages 18 and 37 mo) 

Covariate-adjusted odds ratios for caries Pb <10 or ∃10 :g/dL, were: permanent teeth (DMFS): OR = 0.95 (95deciduous teeth (dfs): OR = 1.77 (95% CCovariates retained: age, grade in school, at risk. Other covariates explored, that haassociation with blood Pb were: sex, ethnscore. 
 AX6-257 Table AX6-9.9 (cont’d). Effects of Lead on Bone and Teeth in Children and Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Adults United States Dye et al. (2002) U.S. 1988–1994 Design: cross-sectional national survey (NHANES III) Subjects: adults in general population (n = 10,033; 5,255 females), ages 20–69 yr Outcome measures: symptoms of periodontal bone loss (attachment loss, periodontal pocket depth) Analysis: multivariate linear regression Blood Pb (:g/dL) geometric mean (SE, range): 2.5 (0.08) (2.36% > 10) Increasing blood Pb (log-transformed) w

with increasing prevalence of covariate-a(∃ = 0.13 [SE 0.05], p = 0.005). Covariarace/ethnicity, education, smoking, and astatus interaction was significant when ininteraction term (∃ = 0.10 [SE 0.05], p = smoking status, association between dentwas significant for current smokers (∃ = 0

and former smokers (∃ = 0.17 [SE 0.07], 

nonsmokers (∃ = 

−0.02 [SE 0.07], p = 0.7

Europe Tvinnereim et al. (2000) Norway 1990–1994 

Design: cross-sectional Subjects: 1,271 teeth samples collected by dentists in all 19 counties in Norway Analysis: Student’s t-test comparing metal concentrations in teeth with caries, roots, and in different tooth groups 

Tooth Pb (:g/g tooth) 

geometric mean (SD, range): 1.16 (1.72, 0.12–18.76) 

Also examined mercury, cadmium, and zhigher Pb concentrations in carious than igeometric mean Pb concentration in cariocompared to 1.10 :g/g (p = 0.001). 
 AX6-258 Table AX6-9.10. Effects of Lead on Ocular Health in Children and Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Children Latin America Rothenberg et al. (2002b) Mexico 1987–1997 Design = longitudinal (subset of prospective) Subjects: children (n = 45, 24 female), ages 7–10 yr Outcome measures: ERG Analysis: comparison of outcome measures between blood Pb tertiles (ANOVA for repeated measures) Blood Pb (:g/dL) median (range) at 85–124 mo: 1st tertile: 4.0 (2.0–4.5) 2nd tertile: 6.0 (5.0–6.5) 3rd tertile: 7.5 (7.0–16.0) Blood Pb (:g/dL) median (range), maternal at 12 wk of gestation: 1st tertile: 4.0 (2.0–5.5) 2nd tertile: 8.5 (6.0–10.0) 3rd tertile: 14.0 (10.5– 32.5) Significant association between increasin

12 wk of gestation and increasing ERG awave amplitude (p = 0.007), with significthe 2nd blood Pb tertile (6.0–10.0 :g/dL), the 3rd blood Pb tertile (10.5–32.5 :g/dL)Pb tertile. Adults United States Schaumberg et al. (2004) Massachusetts 1991–2002 Design = longitudinal (subset of Normative Aging Study) Subjects: adult male (n = 642), mean age 69 yr (range 60–93) Outcome measures: cataract diagnosis Analysis: multivariate logistic regression, odds ratio (vs. 1st quintile) Blood Pb (:g/dL) median (range): 5 (0–35) Bone Pb (:g/g) median (range): Patella : 29 (0–165) Tibia: 20 (0–126) Significant covariate adjusted odds ratio tibia bone Pb quintile (31.0–125 :g/g), OR 

6.90), p = 0.01. OR for cataracts were no

with patella bone Pb (5th quintile: 43.0–1CI: 0.88, 4.02), or blood Pb (5th quintile0.89 (95% CI: 0.46, 1.72). Covariates retained: age, smoking, historof vitamin C, vitamin E, and carotenoids
 AX6-259 Table AX6-9.10 (cont’d). Effects of Lead on Ocular Health in Children and Adults Reference, Study Location, and Period Study Description Pb Measurement Findings, Interpre

Adults Europe Cavalleri et al. (1982) Italy NR Design = cross-sectional cohort Subjects: adult male vinyl chloride pipe manufacture workers, exposed to Pb stearate (n = 35), mean age 45 yr (SD 14, range 21– 59); reference group (n = 35) matched for age, smoking, and alcohol consumption. Outcome measures: visual field Analysis: comparison of outcome measures between Pb workers and reference group Blood Pb (:g/dL) mean (SD, range): Pb: 46 (14, 21–82) Reference: 23 (4, 21–37) Urine Pb (:g/L) mean (SD, range): Pb: 71 (18, 44–118) Reference: 30 (5, 21–42) Visual sensitivity was significantly (p = 0

compared to the reference group; howevewas not significantly associated with bloofield scotoma prevalence was 10 of 35 (2in the reference group. 
AX6-260

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October 2006

EPA/600/R-05/144bF 

Air Quality Criteria for Lead 

Volume II of II 
EPA/600/R-05/144bF 

October 2006 

Air Quality Criteria for Lead 

Volume II 

National Center for Environmental Assessment-RTP Division 

Office of Research and Development 

U.S. Environmental Protection Agency 

Research Triangle Park, NC
 II-iii

PREFACE 

National Ambient Air Quality Standards (NAAQS) are promulgated by the United States 

Environmental Protection Agency (EPA) to meet requirements set forth in Sections 108 and 109 

of the U.S. Clean Air Act. Those two Clean Air Act sections require the EPA Administrator 

(1) to list widespread air pollutants that reasonably may be expected to endanger public health or 

welfare; (2) to issue air quality criteria for them that assess the latest available scientific 

information on nature and effects of ambient exposure to them; (3) to set “primary” NAAQS to 

protect human health with adequate margin of safety and to set “secondary” NAAQS to protect 

against welfare effects (e.g., effects on vegetation, ecosystems, visibility, climate, manmade 

materials, etc); and (5) to periodically review and revise, as appropriate, the criteria and NAAQS 

for a given listed pollutant or class of pollutants. 

Lead was first listed in the mid-1970’s as a “criteria air pollutant” requiring NAAQS 

regulation. The scientific information pertinent to Pb NAAQS development available at the time 

was assessed in the EPA document Air Quality Criteria for Lead; published in 1977. Based on 

the scientific assessments contained in that 1977 lead air quality criteria document (1977 Lead 

AQCD), EPA established a 1.5 μg/m3 (maximum quarterly calendar average) Pb NAAQS in 

1978. 

To meet Clean Air Act requirements noted above for periodic review of criteria and 

NAAQS, new scientific information published since the 1977 Lead AQCD was later assessed in 

a revised Lead AQCD and Addendum published in 1986 and in a Supplement to the 1986 

AQCD/Addendum published by EPA in 1990. A 1990 Lead Staff Paper, prepared by EPA’s 

Office of Air Quality Planning and Standards (OPQPS), drew upon key findings and conclusions 

from the 1986 Lead AQCD/Addendum and 1990 Supplement (as well as other OAQPSsponsored lead exposure/risk analyses) in posing options for the EPA Administrator to consider 

with regard to possible revision of the Pb NAAQS. However, EPA chose not to revise the Pb 

NAAQS at that time. Rather, as part of implementing a broad 1991 U.S. EPA Strategy for 

Reducing Lead Exposure, the Agency focused primarily on regulatory and remedial clean-up 

efforts to reduce Pb exposure from a variety of non-air sources that posed more extensive public 

health risks, as well as other actions to reduce air emissions. 
 II-iv

The purpose of this revised Lead AQCD is to critically assess the latest scientific 

information that has become available since the literature assessed in the 1986 Lead 

AQCD/Addendum and 1990 Supplement, with the main focus being on pertinent new 

information useful in evaluating health and environmental effects of ambient air lead exposures. 

This includes discussion in this document of information regarding: the nature, sources, 

distribution, measurement, and concentrations of lead in the environment; multimedia lead 

exposure (via air, food, water, etc.) and biokinetic modeling of contributions of such exposures 

to concentrations of lead in brain, kidney, and other tissues (e.g., blood and bone concentrations, 

as key indices of lead exposure).; characterization of lead health effects and associated exposureresponse relationships; and delineation of environmental (ecological) effects of lead. This final 

version of the revised Lead AQCD mainly assesses pertinent literature published or accepted for 

publication through December 2005. 

The First External Review Draft (dated December 2005) of the revised Lead AQCD 

underwent public comment and was reviewed by the Clean Air Scientific Advisory Committee 

(CASAC) at a public meeting held in Durham, NC on February 28-March 1, 2006. The public 

comments and CASAC recommendations received were taken into account in making 

appropriate revisions and incorporating them into a Second External Review Draft (dated May, 

2006) which was released for further public comment and CASAC review at a public meeting 

held June 28-29, 2006. In addition, still further revised drafts of the Integrative Synthesis 

chapter and the Executive Summary were then issued and discussed during an August 15, 2006 

CASAC teleconference call. Public comments and CASAC advice received on these latter 

materials, as well as Second External Review Draft materials, were taken into account in making 

and incorporating further revisions into this final version of this Lead AQCD, which is being 

issued to meet an October 1, 2006 court-ordered deadline. Evaluations contained in the present 

document provide inputs to an associated Lead Staff Paper prepared by EPA’s Office of Air 

Quality Planning and Standards (OAQPS), which poses options for consideration by the EPA 

Administrator with regard to proposal and, ultimately, promulgation of decisions on potential 

retention or revision, as appropriate, of the current Pb NAAQS. 

Preparation of this document has been coordinated by staff of EPA’s National Center for 

Environmental Assessment in Research Triangle Park (NCEA-RTP). NCEA-RTP scientific 

staff, together with experts from academia, contributed to writing of document chapters. Earlier 
 II-v

drafts of document materials were reviewed by scientists from other EPA units and by non-EPA 

experts in several public peer consultation workshops held by EPA in July/August 2005. 

NCEA acknowledges the valuable contributions provided by authors, contributors, and 

reviewers and the diligence of its staff and contractors in the preparation of this document. The 

constructive comments provided by public commenters and CASAC that served as valuable 

inputs contributing to improved scientific and editorial quality of the document are also 

acknowledged by NCEA. 

DISCLAIMER 

Mention of trade names or commercial products in this document does not constitute 

endorsement or recommendation for use. 

. 
 II-vi

Air Quality Criteria for Lead 

(Second External Review Draft) 

VOLUME I 

EXECUTIVE SUMMARY .........................................................................................................E-1 

1. INTRODUCTION ........................................................................................................... 1-1 

2. CHEMISTRY, SOURCES, AND TRANSPORT OF LEAD.......................................... 2-1 

3. ROUTES OF HUMAN EXPOSURE TO LEAD AND OBSERVED 

ENVIRONMENTAL CONCENTRATIONS.................................................................. 3-1 

4. TOXICOKINETICS, BIOLOGICAL MARKERS, AND MODELS OF LEAD 

BURDEN IN HUMANS.................................................................................................. 4-1 

5. TOXICOLOGICAL EFFECTS OF LEAD IN LABORATORY ANIMALS 

AND IN VITRO TEST SYSTEMS................................................................................. 5-1 

6. EPIDEMIOLOGIC STUDIES OF HUMAN HEALTH EFFECTS 

ASSOCIATED WITH LEAD EXPOSURE.................................................................... 6-1 

7. ENVIRONMENTAL EFFECTS OF LEAD ................................................................... 7-1 

8. INTEGRATIVE SYNTHESIS OF LEAD EXPOSURE/HEALTH 

EFFECTS INFORMATION............................................................................................ 8-1 

VOLUME II 

CHAPTER 4 ANNEX (TOXICOKINETICS, BIOLOGICAL MARKERS, AND 

MODELS OF LEAD BURDEN IN HUMANS)..................................................... AX4-1 

CHAPTER 5 ANNEX (TOXICOLOGICAL EFFECTS OF LEAD IN 

LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS)................ AX5-1 

CHAPTER 6 ANNEX (EPIDEMIOLOGIC STUDIES OF HUMAN HEALTH 

EFFECTS ASSOCIATED WITH LEAD EXPOSURE)................................. AX6-1 

CHAPTER 7 ANNEX (ENVIRONMENTAL EFFECTS OF LEAD).................................. AX7-1 
II-vii

Table of Contents 

Page

PREFACE......................................................................................................................................iii 

DISCLAIMER ................................................................................................................................ v 

List of Tables ................................................................................................................................. xi 

List of Figures..............................................................................................................................xiii 

Authors, Contributors, and Reviewers.......................................................................................... xv 

U.S. Environmental Protection Agency Project Team for Development 

 of Air Quality Criteria for Lead.............................................................................................. xxi 

U.S. Environmental Protection Agency Science Advisory Board (SAB) 

 Staff Office Clean Air Scientific Advisory Committee (CASAC).......................................xxiii 

Abbreviations and Acronyms ..................................................................................................... xxv 

AX7. CHAPTER 7 ANNEX (ENVIRONMENTAL EFFECTS OF LEAD).................... AX7-1 

 AX7.1 TERRESTRIAL ECOSYSTEMS............................................................ AX7-1 

 AX7.1.1 Methodologies Used in Terrestrial Ecosystems 

Research............................................................................... AX7-1 

AX7.1.1.1 Lead Isotopes and Apportionment................. AX7-1 

AX7.1.1.2 Speciation in Assessing Lead 

Bioavailability in the Terrestrial 

Environment................................................... AX7-3 

AX7.1.1.3 Tools for Bulk Lead Quantification 

and Speciation................................................ AX7-9 

AX7.1.1.4 Biotic Ligand Model.................................... AX7-18 

AX7.1.1.5 Soil Amendments......................................... AX7-19 

 AX7.1.2 Distribution of Atmospherically Delivered Lead in 

Terrestrial Ecosystems....................................................... AX7-22 

AX7.1.2.1 Speciation of Atmospherically-Delivered 

Lead in Terrestrial Ecosystems.................... AX7-24 

AX7.1.2.2 Tracing the Fate of AtmosphericallyDelivered Lead in Terrestrial 

Ecosystems................................................... AX7-31 

AX7.1.2.3 Inputs/Outputs of AtmosphericallyDelivered Lead in Terrestrial 

Ecosystems................................................... AX7-34 

AX7.1.2.4 Resistance Mechanisms ............................... AX7-44 

AX7.1.2.5 Physiological Effects of Lead ...................... AX7-46 

AX7.1.2.6 Factors that Modify Organism Response..... AX7-48 

AX7.1.2.7 Summary...................................................... AX7-55 

 AX7.1.3 Exposure-Response of Terrestrial Species......................... AX7-57 

AX7.1.3.1 Summary of Conclusions from the 

1986 Lead Criteria Document...................... AX7-59 

AX7.1.3.2 Recent Studies on the Effects of Lead 

on Primary Producers................................... AX7-61 
II-viii

Table of Contents 

(cont’d) 

Page

AX7.1.3.3 Recent Studies on the Effects of Lead 

on Consumers............................................... AX7-64 

AX7.1.3.4 Recent Studies on the Effects of Lead 

on Decomposers........................................... AX7-81 

AX7.1.3.5 Summary...................................................... AX7-86 

 AX7.1.4 Effects of Lead on Natural Terrestrial Ecosystems ........... AX7-88 

AX7.1.4.1 Effects of Terrestrial Ecosystem Stresses 

on Lead Cycling........................................... AX7-89 

AX7.1.4.2 Effects of Lead Exposure on Natural 

Ecosystem Structure and Function............... AX7-95 

AX7.1.4.3 Effects of Lead on Energy Flows and 

Biogeochemical Cycling.............................. AX7-99 

AX7.1.4.4 Summary.................................................... AX7-105 

 AX7.2 AQUATIC ECOSYSTEMS................................................................. AX7-106 

 AX7.2.1 Methodologies Used in Aquatic Ecosystem Research..... AX7-106 

AX7.2.1.1 Analytical Methods.................................... AX7-107 

AX7.2.1.2 Ambient Water Quality Criteria: 

Development.............................................. AX7-108 

AX7.2.1.3 Ambient Water Quality Criteria: 

Bioavailability Issues................................. AX7-111 

AX7.2.1.4 Sediment Quality Criteria: 

Development and Bioavailability Issues.... AX7-113 

AX7.2.1.5 Metal Mixtures........................................... AX7-116 

AX7.2.1.6 Background Lead....................................... AX7-117 

 AX7.2.2 Distribution of Lead in Aquatic Ecosystems ................... AX7-117 

AX7.2.2.1 Speciation of Lead in Aquatic 

Ecosystems................................................. AX7-118 

AX7.2.2.2 Spatial Distribution of Lead in 

 Aquatic Ecosystems................................... AX7-122 

AX7.2.2.3 Tracing the Fate and Transport of 

Lead in Aquatic Ecosystems...................... AX7-142 

AX7.2.2.4 Summary.................................................... AX7-145 

 AX7.2.3 Aquatic Species Response/Mode of Action..................... AX7-146 

AX7.2.3.1 Lead Uptake............................................... AX7-146 

AX7.2.3.2 Resistance Mechanisms ............................. AX7-152 

AX7.2.3.3 Physiological Effects of Lead .................... AX7-159 

AX7.2.3.4 Factors That Modify Organism 

Response to Lead ....................................... AX7-162 

AX7.2.3.5 Factors Associated with Global 

Climate Change.......................................... AX7-174 

AX7.2.3.6 Summary.................................................... AX7-174 
II-ix

Table of Contents 

(cont’d) 

Page

 AX7.2.4 Exposure/Response of Aquatic Species........................... AX7-175 

AX7.2.4.1 Summary of Conclusions From the 

Previous Criteria Document....................... AX7-175 

AX7.2.4.2 Recent Studies on Effects of Lead on 

Primary Producers...................................... AX7-177 

AX7.2.4.3 Recent Studies on Effects of Lead 

on Consumers............................................. AX7-183 

AX7.2.4.4 Recent Studies on Effects of Lead 

on Decomposers......................................... AX7-193 

AX7.2.4.5 Summary.................................................... AX7-193 

 AX7.2.5 Effects of Lead on Natural Aquatic Ecosystems ............. AX7-194 

AX7.2.5.1 Case Study: Coeur d’Alene River 

Watershed .................................................. AX7-196 

AX7.2.5.2 Biotic Condition......................................... AX7-198 

AX7.2.5.3 Summary.................................................... AX7-209 

 REFERENCES .................................................................................................... AX7-211 
II-x

List of Tables 

Page

AX7-1.1.1 Relative Standard Deviation (RSD) for Lead Isotope Ratios on 

Selected Mass Spectrometers................................................................... AX7-2 

AX7-1.1.2 National Institute of Standards and Technology Lead SRMs................ AX7-10 

AX7-1.1.3 Characteristics for Direct Speciation Techniques.................................. AX7-17 

AX7-1.2.1 Tissue Lead Levels in Birds Causing Effects ........................................ AX7-43 

AX7-1.3.1 Plant Toxicity Data Used to Develop the Eco-SSL............................... AX7-62 

AX7-1.3.2 Plant Toxicity Data Not Used to Develop the Eco-SSL........................ AX7-63 

AX7-1.3.3 Avian Toxicity Data Used to Develop the Eco-SSL ............................. AX7-66 

AX7-1.3.4 Mammalian Toxicity Data Used to Develop the Eco-SSL.................... AX7-72 

AX7-1.3.5 Invertebrate Toxicity Data Used to Develop the Eco-SSL.................... AX7-82 

AX7-1.3.6 Invertebrate Toxicity Data Not Used to Develop the Eco-SSL............. AX7-84 

AX7-2.1.1 Common Analytical Methods for Measuring Lead in Water, 

Sediment, and Tissue .......................................................................... AX7-107 

AX7-2.1.2 Development of Current Acute Freshwater Criteria for Lead ............. AX7-109 

AX7-2.1.3 Recommended Sediment Quality Guidelines for Lead ....................... AX7-115 

AX7-2.2.1 NAWQA Land Use Categories and Natural/Ambient 

Classification........................................................................................ AX7-125 

AX7-2.2.2 Summary Statistics of Ambient and Natural Levels of Dissolved 

Lead in Surface Water ......................................................................... AX7-126 

AX7-2.2.3 Summary Statistics of Ambient and Natural Levels of Total 

Lead in <63 μm Bulk Sediment........................................................... AX7-127 

AX7-2.2.4 Summary Statistics of Ambient and Natural Levels of Lead in 

Whole Organism and Liver Tissues..................................................... AX7-136 

AX7-2.2.5 Comparison of NCBP and NAWQA Ambient Lead Levels in 

Whole Organism Tissues ..................................................................... AX7-138 
II-xi

List of Tables 

(cont’d) 

Page

AX7-2.3.1 Bioconcentration Factors for Aquatic Plants ....................................... AX7-151 

AX7-2.3.2 Bioconcentration Factors for Aquatic Invertebrates............................ AX7-151 

AX7-2.4.1 Effects of Lead to Freshwater and Marine Invertebrates..................... AX7-185 

AX7-2.4.2 Effects of Pb to Freshwater and Marine Fish....................................... AX7-190 

AX7-2.4.3 Nonlethal Effects in Amphibians......................................................... AX7-192 

AX7-2.5.1 Ecological Attributed Studies by Maret et al. (2003) in the 

Coeur d’Alene Watershed.................................................................... AX7-197 

AX7-2.5.2 Essential Ecological Attributes for Natural Aquatic Ecosystems 

Affected by Lead.................................................................................. AX7-200 
II-xii

List of Figures 

Number Page

AX7-1.1.1 Relationship of bioaccessibility (low, medium, high) versus 

speciation as shown with scanning electron micrographs of 

various Pb-bearing materials........................................................................ AX7-5 

AX7-1.1.2 Variation of bioavailability with particle size.............................................. AX7-7 

AX7-1.1.3 Illustration of particle lability and bioavailability at two different 

sites with similar total Pb concentrations and Pb forms .............................. AX7-8 

AX7-1.1.4 Scanning electron micrograph of a large native Pb particle showing 

outer ring of highly bioavailable Pb-chloride and Pb-oxide........................ AX7-8 

AX7-1.1.5 Bulk lead versus single species modality................................................... AX7-12 

AX7-1.2.1 Long-term (1982-1989) annual trends in lead concentrations (μg/L) 

in Lewes, Delaware precipitation .............................................................. AX7-35 

AX7-1.3.1 Avian reproduction and growth toxicity data considered in 

development of the Eco-SSL ..................................................................... AX7-69 

AX7-1.3.2 Mammalian reproduction and growth toxicity data considered in 

development of the Eco-SSL ..................................................................... AX7-81 

AX7-2.2.1 Distribution of aqueous lead species as a function of pH based on 

a concentration of 1 μg Pb/L.................................................................... AX7-119 

AX7-2.2.2 Lead speciation versus chloride content .................................................. AX7-121 

AX7-2.2.3 Spatial distribution of natural and ambient surface water/sediment 

sites .......................................................................................................... AX7-128 

AX7-2.2.4 Spatial distribution of natural and ambient liver tissue sample sites....... AX7-129 

AX7-2.2.5 Spatial distribution of natural and ambient whole organism tissue 

sample sites .............................................................................................. AX7-130 

AX7-2.2.6 Frequency distribution of ambient and natural levels of surface 

water dissolved lead (μg/L). .................................................................... AX7-131 

AX7-2.2.7 Spatial distribution of dissolved lead in surface water (N = 3445). ........ AX7-132 
II-xiii

List of Figures 

(cont’d) 

Number Page

AX7-2.2.8 Frequency distribution of ambient and natural levels of bulk 

sediment <63 μm total Pb (μg/g)............................................................. AX7-134 

AX7-2.2.9 Spatial distribution of total lead in bulk sediment <63 um 

(N = 1466)................................................................................................ AX7-135 

AX7-2.2.10 Frequency distribution of ambient and natural levels of lead in 

liver tissue (μg/g dry weight)................................................................... AX7-137 

AX7-2.2.11 Frequency distribution of ambient and natural levels of lead in 

whole organism tissue (μg/g dry weight). ............................................... AX7-137 

AX7-2.2.12 Spatial distribution of lead in liver tissues (N = 559). ............................. AX7-139 

AX7-2.2.13 Spatial distribution of lead in whole organism tissues (N = 332)............ AX7-140 

AX7-2.2.14 Lead cycle in an aquatic ecosystem......................................................... AX7-143 
II-xiv

Authors, Contributors, and Reviewers 

CHAPTER 4 ANNEX (TOXICOKINETICS, BIOLOGICAL MARKERS, AND 

MODELS OF LEAD BURDEN IN HUMANS) 

Chapter Managers/Editors

Dr. James Brown—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Principal Authors

Dr. Brian Gulson—Graduate School of the Environment, Macquarie University 

Sydney, NSW 2109, Australia 

Contributors and Reviewers

Dr. Lester D. Grant—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

CHAPTER 5 ANNEX (TOXICOLOGICAL EFFECTS OF LEAD IN HUMANS 

AND LABORATORY ANIMALS) 

Chapter Managers/Editors

Dr. Anuradha Mudipalli—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Srikanth Nadadur—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Lori White—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

 
II-xv

Authors, Contributors, and Reviewers 

(cont’d) 

Principal Authors

Dr. Anuradha Mudipalli—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Stephen Lasley—Dept. of Biomedical and Therapeutic Sciences, Univ. of Illinois College of 

Medicine, PO Box 1649, Peoria, IL 61656 

Dr. Lori White—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Gary Diamond— Syracuse Research Corporation, 8191 Cedar Street, Akron, NY 14001 

Dr. N.D. Vaziri—Division of Nephrology and Hypertension, University of California – Irvine 

Medical Center, 101, The City Drive, Bldg 53, Room #125. Orange, CA 92868 

Dr. John Pierce Wise, Sr.—Maine Center for Toxicology and Environmental Health, 

Department of Applied Medical Sciences, 96 Falmouth Street, PO Box 9300, Portland, ME 

04104-9300 

Dr. Harvey C. Gonick—David Geffen School of Medicine, University of California at 

Los Angeles, 201 Tavistock Ave, Los Angeles, CA 90049 

Dr. Gene E. Watson—University of Rochester Medical Center, Box 705, Rochester, NY 14642 

Dr. Rodney Dietert—Institute for Comparative and Environmental Toxicology, College of 

Veterinary Medicine, Cornell University, Ithaca, NY 14853 

Contributors and Reviewers

Dr. Lester D. Grant—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Paul Reinhart—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Michael Davis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. David A. Lawrence—Dept of Environmental and Clinical Immunology, Empire State Plaza 

P.O. Box 509, Albany, NY 12201 
II-xvi

Authors, Contributors, and Reviewers 

(cont’d) 

Contributors and Reviewers

(cont’d) 

Dr. Michael J. McCabe, Jr.—Dept of Environmental Medicine, University of Rochester, 

575 Elmwood Avenue, Rochester, NY 14642 

Dr. Theodore I. Lidsky—New York State Institute for Basic Research, 1050 Forest RD, 

Staten Island, NY 10314 

Dr. Mark H. Follansbee—Syracuse Research Corporation, 8191 Cedar St. Akron, NY 14001 

Dr. William K. Boyes—National Health and Environmental Effects Research Laboratory, 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Philip J. Bushnell—National Health and Environmental Effects Research Laboratory, 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Ms. Beth Hassett-Sipple—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Zachary Pekar—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

CHAPTER 6 ANNEX (EPIDEMIOLOGICAL STUDIES OF AMBIENT LEAD 

EXPOSURE EFFECTS) 

Chapter Managers/Editors

Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 
II-xvii

Authors, Contributors, and Reviewers 

(cont’d) 

Principal Authors

Dr. David Bellinger—Children’s Hospital, Farley Basement, Box 127, 300 Longwood Avenue, 

Boston, MA 02115 

Dr. Margit Bleecker—Center for Occupational and Environmental Neurology, 2 Hamill Road, 

Suite 225, Baltimore, MD 21210 

Dr. Gary Diamond— Syracuse Research Corporation, 8191 Cedar Street. 

Akron, NY 14001 

Dr. Kim Dietrich—University of Cincinnati College of Medicine, 3223 Eden Avenue, 

Kettering Laboratory, Room G31, Cincinnati, OH 45267 

Dr. Pam Factor-Litvak—Columbia University Mailman School of Public Health, 

722 West 168th Street, Room 1614, New York, NY 10032 

Dr. Vic Hasselblad—Duke University Medical Center, Durham, NC 27713 

Dr. Stephen J. Rothenberg—CINVESTAV-IPN, Mérida, Yucatán, México & National Institute 

of Public Health, Cuernavaca, Morelos, Mexico 

Dr. Neal Simonsen—Louisiana State University Health Sciences Center, School of Public Health 

& Stanley S Scott Cancer Center, 1600 Canal Street, Suite 800, New Orleans, LA 70112 

Dr. Kyle Steenland—Rollins School of Public Health, Emory University, 1518 Clifton Road, 

Room 268, Atlanta, GA 30322 

Dr. Virginia Weaver—Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe 

Street, Room 7041, Baltimore, MD 21205 

Contributors and Reviewers

Dr. J. Michael Davis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Lester D. Grant—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Kazuhiko Ito—Nelson Institute of Environmental Medicine, New York University School of 

Medicine, Tuxedo, NY 10987 
II-xviii

Authors, Contributors, and Reviewers 

(cont’d) 

Contributors and Reviewers

(cont’d) 

Dr. Kathryn Mahaffey—Office of Prevention, Pesticides and Toxic Substances, 

U.S. Environmental Protection Agency, Washington, DC 20460 

Dr. Karen Martin—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Zachary Pekar—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Ms. Beth Hassett-Sipple—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

CHAPTER 7 ANNEX (ENVIRONMENTAL EFFECTS OF LEAD) 

Chapter Manager/Editor

Dr. Timothy Lewis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Principle Authors

Dr. Ruth Hull—Cantox Environmental Inc., 1900 Minnesota Court, Suite 130, Mississauga, 

Ontario, L5N 3C9 Canada 

Dr. James Kaste—Department of Earth Sciences, Dartmouth College, 352 Main Street, 

Hanover, NH 03755 

Dr. John Drexler—Department of Geological Sciences, University of Colorado, 

1216 Gillespie Drive, Boulder, CO 80305 

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

365 Link Hall, Syracuse, NY 13244 

Dr. William Stubblefield—Parametrix, Inc. 33972 Texas St. SW, Albany, OR 97321 
II-xix

Authors, Contributors, and Reviewers 

(cont’d) 

Principle Authors

(cont’d) 

Dr. Dwayne Moore—Cantox Environmental, Inc., 1550A Laperriere Avenue, Suite 103, 

Ottawa, Ontario, K1Z 7T2 Canada 

Dr. David Mayfield—Parametrix, Inc., 411 108th Ave NE, Suite 1800, Bellevue, WA 98004 

Dr. Barbara Southworth—Menzie-Cura & Associates, Inc., 8 Winchester Place, Suite 202, 

Winchester, MA 01890 

Dr. Katherine Von Stackleberg—Menzie-Cura & Associates, Inc., 8 Winchester Place, 

Suite 202, Winchester, MA 01890 

Contributors and Reviewers

Dr. Jerome Nriagu—Department of Environmental Health Sciences, 109 South Observatory, 

University of Michigan, Ann Arbor, MI 48109 

Dr. Judith Weis—Department of Biology, Rutgers University, Newark, NJ 07102 

Dr. Sharon Harper—National Exposure Research Laboratory (D205-05), U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Karen Bradham—National Research Exposure Laboratory (D205-05), U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Dr. Ginger Tennant—Office of Air Quality Planning and Standards, U.S. Environmental 

Protection Agency, Research Triangle Park, NC 27711 

Ms. Gail Lacey—Office of Air Quality Planning and Standards, U.S. Environmental Protection 

Agency, Research Triangle Park, NC 27711 

Dr. John Vandenberg—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 
II-xx

U.S. Environmental Protection Agency Project Team 

for Development of Air Quality Criteria for Lead 

Executive Direction

Dr. Lester D. Grant (Director)—National Center for Environmental Assessment-RTP Division, 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Scientific Staff

Dr. Lori White (Lead Team Leader)—National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. James S. Brown—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Robert Elias—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Retired) 

Dr. Brooke Hemming—National Center for Environmental Assessment (B243-01), U.S. 

Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Timothy Lewis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Anuradha Muldipalli—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Srikanth Nadadur—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Paul Reinhart—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. Mary Ross— National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 
II-xxi

U.S. Environmental Protection Agency Project Team 

for Development of Air Quality Criteria for Lead 

(cont’d) 

Technical Support Staff

Mr. Douglas B. Fennell—Technical Information Specialist, National Center for Environmental 

Assessment (B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 

27711 (Retired) 

Ms. Emily R. Lee—Management Analyst, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Ms. Diane H. Ray—Program Specialist, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Ms. Donna Wicker—Administrative Officer, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Retired) 

Mr. Richard Wilson—Clerk, National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Document Production Staff

Ms. Carolyn T. Perry—Task Order Manager, Computer Sciences Corporation, 2803 Slater Road, 

Suite 220, Morrisville, NC 27560 

Mr. John A. Bennett—Technical Information Specialist, Library Associates of Maryland, 

11820 Parklawn Drive, Suite 400, Rockville, MD 20852 

Mr. William Ellis—Records Management Technician, InfoPro, Inc., 8200 Greensboro Drive, 

Suite 1450, McLean, VA 22102 

Ms. Sandra L. Hughey—Technical Information Specialist, Library Associates of Maryland, 

11820 Parklawn Drive, Suite 400, Rockville, MD 20852 

Dr. Barbara Liljequist—Technical Editor, Computer Sciences Corporation, 2803 Slater Road, 

Suite 220, Morrisville, NC 27560 

Ms. Michelle Partridge-Doerr—Publications/Graphics Specialist, TEK Systems, 1201 Edwards 

Mill Road, Suite 201, Raleigh, NC 27607 

Mr. Carlton Witherspoon—Graphic Artist, Computer Sciences Corporation, 2803 Slater Road, 

Suite 220, Morrisville, NC 27560 
II-xxii

U.S. Environmental Protection Agency 

Science Advisory Board (SAB) Staff Office 

Clean Air Scientific Advisory Committee (CASAC) 

Chair

Dr. Rogene Henderson*—Scientist Emeritus, Lovelace Respiratory Research Institute, 

Albuquerque, NM 

Members

Dr. Joshua Cohen—Faculty, Center for the Evaluation of Value and Risk, Institute for Clinical 

Research and Health Policy Studies, Tufts New England Medical Center, Boston, MA 

Dr. Deborah Cory-Slechta—Director, University of Medicine and Dentistry of New Jersey and 

Rutgers State University, Piscataway, NJ 

Dr. Ellis Cowling*—University Distinguished Professor-at-Large, North Carolina State 

University, Colleges of Natural Resources and Agriculture and Life Sciences, North Carolina 

State University, Raleigh, NC 

Dr. James D. Crapo [M.D.]*—Professor, Department of Medicine, National Jewish Medical and 

Research Center, Denver, CO 

Dr. Bruce Fowler—Assistant Director for Science, Division of Toxicology and Environmental 

Medicine, Office of the Director, Agency for Toxic Substances and Disease Registry, U.S. 

Centers for Disease Control and Prevention (ATSDR/CDC), Chamblee, GA 

Dr. Andrew Friedland—Professor and Chair, Environmental Studies Program, Dartmouth 

College, Hanover, NH 

Dr. Robert Goyer [M.D.]—Emeritus Professor of Pathology, Faculty of Medicine, University of 

Western Ontario (Canada), Chapel Hill, NC 

Mr. Sean Hays—President, Summit Toxicology, Allenspark, CO 

Dr. Bruce Lanphear [M.D.]—Sloan Professor of Children’s Environmental Health, and the 

Director of the Cincinnati Children’s Environmental Health Center at Cincinnati Children’s 

Hospital Medical Center and the University of Cincinnati, Cincinnati, OH 

Dr. Samuel Luoma—Senior Research Hydrologist, U.S. Geological Survey (USGS), 

Menlo Park, CA 
II-xxiii

U.S. Environmental Protection Agency 

Science Advisory Board (SAB) Staff Office 

Clean Air Scientific Advisory Committee (CASAC) 

(cont’d) 

Members

(cont’d) 

Dr. Frederick J. Miller*—Consultant, Cary, NC 

Dr. Paul Mushak—Principal, PB Associates, and Visiting Professor, Albert Einstein College of 

Medicine (New York, NY), Durham, NC 

Dr. Michael Newman—Professor of Marine Science, School of Marine Sciences, Virginia 

Institute of Marine Science, College of William & Mary, Gloucester Point, VA 

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

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

Dr. Michael Rabinowitz—Geochemist, Marine Biological Laboratory, Woods Hole, MA 

Dr. Joel Schwartz—Professor, Environmental Health, Harvard University School of Public 

Health, Boston, MA 

Dr. Frank Speizer [M.D.]*—Edward Kass Professor of Medicine, Channing Laboratory, 

Harvard Medical School, Boston, MA 

Dr. Ian von Lindern—Senior Scientist, TerraGraphics Environmental Engineering, Inc., 

Moscow, ID 

Dr. Barbara Zielinska*—Research Professor, Division of Atmospheric Science, Desert Research 

Institute, Reno, NV 

SCIENCE ADVISORY BOARD STAFF 

Mr. Fred Butterfield—CASAC Designated Federal Officer, 1200 Pennsylvania Avenue, N.W., 

Washington, DC, 20460, Phone: 202-343-9994, Fax: 202-233-0643 (butterfield.fred@epa.gov) 

(Physical/Courier/FedEx Address: Fred A. Butterfield, III, EPA Science Advisory Board Staff 

Office (Mail Code 1400F), Woodies Building, 1025 F Street, N.W., Room 3604, Washington, 

DC 20004, Telephone: 202-343-9994) 

*Members of the statutory Clean Air Scientific Advisory Committee (CASAC) appointed by the 

 U.S. EPA Administrator 
II-xxiv

Abbreviations and Acronyms 

αFGF α-fibroblast growth factor

AA arachidonic acid 

AAL active avoidance learning 

AAS atomic absorption spectroscopy 

ABA β-aminoisobutyric acid 

ACBP Achenbach Child Behavior Profile 

ACE angiotensin converting enzyme 

ACh acetylcholine 

AChE acetylcholinesterase 

ACR acute-chronic ratio 

AD adult 

ADC analog digital converter 

ADP adenosine diphosphate 

AE anion exchange 

AEA N-arachidonylethanolamine 

AFC antibody forming cells 

2-AG 2-arachidonylglycerol 

A horizon uppermost layer of soil (litter and humus) 

AHR aryl hydrocarbon receptor 

AI angiotensin I 

ALA ∗-aminolevulinic acid 

ALAD ∗-aminolevulinic acid dehydratase 

ALAS aminolevulinic acid synthetase 

ALAU urinary δ-aminolevulinic acid 

ALD aldosterone 

ALS amyotrophic lateral sclerosis 

ALT alanine aminotransferase 

ALWT albumin weight 

AMEM Alpha Minimal Essential Medium 

AMP adenosine monophosphate 

ANCOVA analysis of covariance 

ANF atrial natriuretic factor 

Ang II angiotensin II 
II-xxv

ANOVA analysis of variance 

ANP atrial natriuretic peptide 

AP alkaline phosphatase 

AP-1 activated protein-1 

ApoE apolipoprotein E 

AQCD Air Quality Criteria Document 

Arg arginine 

AS52 cells derived from the CHO cell line 

ASGP-R aceyl glycoprotein receptor 

AST aspartate aminotransferase 

ASV anode stripping voltammetry 

3-AT 3-aminotriazole; 3-amino triazide 

ATP adenosine triphosphate 

ATP1A2 sodium-potassium adenosine triphosphase α2 

ATPase adenosine triphosphatase 

ATSDR Agency for Toxic Substances and Disease Research 

AVCD atrioventricular conduction deficit 

AVS acid volatile sulfide 

AWQC ambient water quality criteria 

∃ beta-coefficient; slope of an equation 

∃FGF ∃-fibroblast growth factor

17∃–HS 17∃-hydroxysteriod 

3∃-HSD 3∃-hydroxysteriod dehydrogenase 

17∃-HSDH 17∃-hydroxysteriod dehydrogenase 

6∃-OH-cortisol 6-∃-hydroxycortisol 

B both 

BAEP brainstem auditory-evoked potentials 

BAER brainstem auditory-evoked responses 

BAF bioaccumulation factor 

B cell B lymphocyte 

BCFs bioconcentration factors 

BCS bovine calf serum 

BDNF brain derived neurotrophic factor 

BDWT body weight changes 

BEI biological exposure index 
II-xxvi

BFU-E blood erythroid progenitor 

BLL blood lead level 

BLM biotic ligand model 

BM basement membrane 

BMI body mass index 

BDNF brain-derived neurotrophic factor 

BOTMP Bruinicks-Oseretsky Test of Motor Proficiency 

BP blood pressure 

BPb blood lead concentration 

BSA bovine serum albumin 

BSI Brief Symptom Inventory 

BTQ Boston Teacher Questionnaire 

BUN blood urea nitrogen 

bw, b. wt., BW body weight 

C3H10T/12 mouse embryo cell line 

C3, C4 complement proteins 

CA chromosome aberration 

CA3 cornu ammonis 3 region of hippocampus 

45Ca calcium-45 radionuclide 

Ca-ATP calcium-dependent adenosine triphosphate 

Ca-ATPase calcium-dependent adenosine triphosphatase 

CaCO3 calcium carbonate 

CaEDTA calcium disodium ethylenediaminetetraacetic acid 

CAL calcitonin 

CaM calmodulin 

Ca-Mg-ATPase calcium-magnesium-dependent adenosine triphosphatase 

cAMP cyclic adenosinemonophosphate 

CaNa2 EDTA calcium disodium ethylenediaminetetraacetic acid 

CANTAB Cambridge Neuropsychological Testing Automated Battery 

CAT catalase; Cognitive Abilities Test 

CBCL Achenbach Child Behavior Checklist 

CBCL-T Total Behavior Problem Score 

CBL cumulative blood lead 

CBLI cumulative blood lead index 

CCB cytochalasin B 
II-xxvii

CCD charge-coupled device 

CCE Coordination Center for Effects 

CCL carbon tetrachloride 

CCS cosmic calf serum 

C-CVRSA coefficient of component variance of respiratory sinus arrhythmia 

Cd cadmium 

109Cd cadmium-109 radionuclide 

CdU urinary cadmium 

CEC cation exchange capacity 

CESD, CES-D Center for Epidemiologic Studies Depression (scale) 

GFAP glial fibrillary acidic protein 

CFU-E colony forming unit blood-erythroid progenitor (cell count) 

CFU-GEMM colony forming unit blood-pluripotent progenitor (cell count) 

CFU-GM blood granulocyte/macrophage progenitor (cell count) 

cGMP cyclic guanosine-3',5'-monophosphate 

ChAT choline acetyltransferase 

CHD coronary heart disease 

CHO Chinese hamster ovary cell line 

CI confidence interval 

CLE-SV competitive ligand-exchange/stripping voltammetry 

CLRTAP Convention on Long-Range Transboundary of Air Pollution 

CLS Cincinnati Lead Study 

CMC criterion maximum concentration 

CMI cell-mediated immunity 

CNS central nervous system 

COH cation-osmotic hemolysis 

ConA concanavalin A 

COR cortisol 

CoTx cotreatment 

COX-2 cyclooxygenase-2 

CP coproporphryn 

CPT current perception threshold 

cr creatinine 

CRAC calcium release activated calcium reflux 

CREB cyclic AMP-response element binding protein 
II-xxviii

CRF chronic renal failure 

CRI chronic renal insufficiency 

CSF cerebrospinal fluid 

CuZn-SOD copper and zinc-dependent superoxide dismutase 

CV conduction velocity 

CVLT California Verbal Learning Test 

CVR-R coefficient of variation of the R-R interval 

CYP cytochrome (e.g., CYP1A, CYP-2A6, CYP3A4, CYP450) 

CYP3a11 cytochrome P450 3a11 

D D-statistic 

DA dopamine; dopaminergic 

dbcAMP dibutyryl cyclic adenosine-3',5'-monophosphate 

DCV distribution of conduction velocities 

DEAE diethylaminoethyl (chromatography) 

DET diffusive equilibrium thin films 

DEYO death of young 

DFS decayed or filled surfaces, permanent teeth 

dfs covariate-adjusted number of caries 

DG dentate gyrus 

DGT diffusive gradient thin films 

DL DL-statistic 

DMEM Dulbecco’s Minimal Essential Medium 

DMEM/F12 Dulbecco’s Minimal Essential Medium/Ham’s F12 

DMFS decayed, missing, or filled surfaces, permanent teeth 

DMPS 2,3-dimercaptopropane 1-sulfonate 

DMSA 2,3-dimercaptosuccinic acid 

DMT Donnan membrane technique 

DMTU dimethylthiourea 

DNA deoxyribonucleic acid 

DO distraction osteogenesis 

DOC dissolved organic carbon 

DOM dissolved organic carbon 

DOPAc 3,4-dihydroxyphenylacetic acid 

DPASV differential pulse anodic stripping voltammetry 

dp/dt rate of left ventricular isovolumetric pressure 
II-xxix

DPPD N-N-diphenyl-p-phynylene-diamine 

DR drinking water 

DSA delayed spatial alternation 

DTC diethyl dithiocarbomate complex 

DTH delayed type hypersensitivity 

DTPA diethylenetriaminepentaacetic acid 

DTT dithiothreitol 

dw dry weight 

E embryonic day 

E2 estradiol 

EBE early biological effect 

EBV Epstein-Barr virus 

EC European Community 

EC50 effect concentration for 50% of test population 

eCB endocannabinoid 

ECG electrocardiogram 

Eco-SSL ecological soil screening level 

EDS energy dispersive spectrometers 

EDTA ethylenediaminetetraacetic acid 

EEDQ N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinone 

EEG electroencephalogram 

EG egg 

EGF epidermal growth factor 

EGG effects on eggs 

EGPN egg production 

EKG electrocardiogram 

electro electrophysiological stimulation 

EM/CM experimental medium-to-control medium (ratio) 

EMEM Eagle’s Minimal Essential Medium 

eNOS endothelial nitric oxide synthase 

EP erythrocyte protoporphyrin 

EPA U.S. Environmental Protection Agency 

Epi epinephrine 

EPMA electron probe microanalysis 

EPO erythropoietin 
II-xxx

EPSC excitatory postsynaptic currents 

EPT macroinvertebrates from the Ephemeroptera (mayflies), 

Plecoptera (stoneflies), and Trichoptera (caddisflies) group 

ERG electroretinogram; electroretinographic 

ERL effects range – low 

ERM effects range – median 

EROD ethoxyresorufin-O-deethylase 

ESCA electron spectroscopy for chemical analysis 

ESRD end-stage renal disease 

EST estradiol 

ESTH eggshell thinning 

ET endothelein; essential tremor 

ETOH ethyl alcohol 

EXAFS extended X-ray absorption fine structure 

EXANES extended X-ray absorption near edge spectroscopy 

F F-statistic 

F344 Fischer 344 (rat) 

FAV final acute value 

FBS fetal bovine serum 

FCS fetal calf serum 

FCV final chronic value 

FD food 

FEF forced expiratory flow 

FEP free erythrocyte protoporphyrin 

FERT fertility 

FEV1 forced expiratory volume in one second 

FGF fibroblast growth factor (e.g., βFGF, αFGF) 

FI fixed interval (operant conditioning) 

FIAM free ion activity model

FMLP N-formyl-L-methionyl-L-leucyl-L-phenylalanine 

fMRI functional magnetic resonance imaging 

FR fixed-ratio operant conditioning 

FSH follicle stimulating hormone 

FT3 free triiodothyronine 

FT4 free thyroxine 
II-xxxi

FTES free testosterone 

FTII Fagan Test of Infant Intelligence 

FTPLM flow-through permeation liquid membranes 

FURA-2 1-[6-amino-2-(5-carboxy-2-oxazolyl)-5-benzofuranyloxy]-2-(2-

amino-5-methylphenoxy) ethane-N,N,N',N'-tetraacetic acid 

FVC forced vital capacity 

(-GT (-glutamyl transferase 

G gestational day 

GABA gamma aminobutyric acid 

GAG glycosaminoglycan 

G12 CHV79 cells derived from the V79 cell line 

GCI General Cognitive Index 

GD gestational day 

GDP guanosine diphosphate

GEE generalized estimating equations 

GFAAS graphite furnace atomic absorption spectroscopy 

GFR glomerular filtration rate 

GGT (-glutamyl transferase 

GH growth hormone 

GI gastrointestinal 

GIME-VIP gel integrated microelectrodes combined with voltammetric 

in situ profiling 

GIS geographic information system 

GLU glutamate 

GMAV genus mean acute value 

GMCV genus mean chronic value 

GMP guanosine monophosphate 

GMPH general morphology 

GnRH gonadotropin releasing hormone 

GOT aspartate aminotransferase 

GP gross productivity 

G6PD, G6PDH glucose-6-phosphate dehydrogenase 

GPEI glutathione S-transferase P enhancer element 

gp91phox NAD(P)H oxidase 

GPT glutamic-pyruvic transaminase 

GPx glutathione peroxidase 
II-xxxii

GRO growth 

GRP78 glucose-regulated protein 78 

GSD geometric standard deviation 

GSH reduced glutathione 

GSIM gill surface interaction model 

GSSG glutathione disulfide 

GST glutathione-S-transferase 

GSTP placental glutathione transferase 

GTP guanosine triphosphate 

GV gavage 

H+

 acidity 

3

H hydrogen-3 radionuclide (tritium) 

HA humic acid; hydroxyapatite 

Hb hemoglobin 

HBEF Hubbard Brook Experimenatl Forest 

HBSS Hank’s Balanced Salt Solution 

HCG; hCG human chorionic gonadotropin 

Hct hematocrit 

HDL high-density lipoprotein (cholesterol) 

HEP habitat evaluation procedure 

HET Binghamton heterogeneous stock 

HFPLM hollow fiber permeation liquid membranes 

Hgb hemoglobin 

HGF hepatocyte growth factor 

HH hydroxylamine hydrochloride 

H-H high-high 

HHANES Hispanic Health and Nutrition Examination Survey 

H-L high-low 

HLA human leukocyte antigen 

H-MEM minimum essential medium/nutrient mixture–F12-Ham 

HMP hexose monophosphate shunt pathway 

HNO3 nitric acid 

H2O2 hydrogen peroxide 

HOME Home Observation for Measurement of Environment 

HOS TE human osteosarcoma cells 
II-xxxiii

HPLC high-pressure liquid chromatography 

H3PO4 phosphoric acid 

HPRT hypoxanthine phosphoribosyltransferase (gene) 

HR heart rate 

HSI habitat suitability indices 

H2SO4 sulfuric acid 

HSPG heparan sulfate proteoglycan 

Ht hematocrit 

HTC hepatoma cells 

hTERT catalytic subunit of human telomerase 

HTN hypertension 

IBL integrated blood lead index 

IBL Η WRAT-R integrated blood lead index Η Wide Range Achievement 

Test-Revised (interaction) 

ICD International Classification of Diseases 

ICP inductively coupled plasma 

ICP-AES inductively coupled plasma atomic emission spectroscopy 

ICP-MS, ICPMS inductively coupled plasma mass spectrometry 

ID-MS isotope dilution mass spectrometry 

IFN interferon (e.g., IFN-() 

Ig immunoglobulin (e.g., IgA, IgE, IgG, IgM) 

IGF-1 insulin-like growth factor 1 

IL interleukin (e.g., IL-1, IL-1∃, IL-4, IL-6, IL-12) 

ILL incipient lethal level 

immuno immunohistochemical staining 

IMP inosine monophosphate 

iNOS inducible nitric oxide synthase 

i.p., IP intraperitoneal 

IPSC inhibitory postsynaptic currents 

IQ intelligence quotient 

IRT interresponse time 

ISEL in situ end labeling 

ISI interstimulus interval 

i.v., IV intravenous 

IVCD intraventricular conduction deficit 
II-xxxiv

JV juvenile 

KABC Kaufman Assessment Battery for Children 

KTEA Kaufman Test of Educational Achievement 

KXRF, K-XRF K-shell X-ray fluorescence 

LA lipoic acid 

LB laying bird 

LC lactation 

LC50 lethal concentration at which 50% of exposed animals die 

LC74 lethal concentration at which 74% of exposed animals die 

LD50 lethal dose at which 50% of exposed animals die 

LDH lactate dehydrogenase 

LDL low-density lipoprotein (cholesterol) 

L-dopa 3,4-dihydroxyphenylalanine (precursor of dopamine) 

LE Long Evans (rat) 

LET linear energy transfer (radiation) 

LH luteinizing hormone 

LHRH luteinizing hormone releasing hormone 

LN lead nitrate 

L-NAME L-NG-nitroarginine methyl ester 

LOAEL lowest-observed adverse effect level 

LOEC lowest-observed-effect concentration 

LOWESS locally weighted scatter plot smoother 

LPO lipoperoxide 

LPP lipid peroxidation potential 

LPS lipopolysaccharide 

LT leukotriene 

LT50 time to kill 50% 

LTER Long-Term Ecological Research (sites) 

LTP long term potentiation 

LVH left ventricular hypertrophy 

μPIXE microfocused particle induced X-ray emission 

μSXRF microfocused synchrotron-based X-ray fluorescence 

MA mature 

MA-10 mouse Leydig tumor cell line 

MANCOVA multivariate analysis of covariance 
II-xxxv

MAO monoamine oxidase 

MATC maximum acceptable threshold concentration 

MDA malondialdehyde 

MDA-TBA malondialdehyde-thiobarbituric acid 

MDCK kidney epithelial cell line 

MDI Mental Development Index (score) 

MDRD Modification of Diet in Renal Disease (study) 

MEM Minimal Essential Medium 

MG microglobulin 

Mg-ATPase magnesium-dependent adenosine triphosphatase 

MiADMSA monoisamyl dimercaptosuccinic acid 

Mi-DMSA mi monoisoamyl dimercaptosuccinic acid 

MK-801 NMDA receptor antagonist 

MLR mixed lymphocyte response 

MMSE Mini-Mental State Examination 

MMTV murine mammary tumor virus 

MN micronuclei formation 

MND motor neuron disease 

MNNG N-methyl-N'-nitro-N-nitrosoguanidine 

MPH morphology 

MRI magnetic resonance imaging 

mRNA messenger ribonucleic acid 

MROD methoxyresorufin-O-demethylase 

MRS magnetic resonance spectroscopy 

MS mass spectrometry 

MSCA McCarthy Scales of Children’s Abiltities 

mSQGQs mean sediment quality guideline quotients 

MT metallothionein 

MVV maximum voluntary ventilation 

MW molecular weight (e.g., high-MW, low-MW) 

N, n number of observations 

N/A not available 

NAAQS National Ambient Air Quality Standards 

NAC N-acetyl cysteine 

NAD nicotinamide adenine dinucleotide 
II-xxxvi

NADH reduced nicotinamide adenine dinucleotide 

NADP nicotinamide adenine dinucleotide phosphate 

NAD(P)H, NADPH reduced nicotinamide adenine dinucleotide phosphate 

NADS nicotinamide adenine dinucleotide synthase 

NAF nafenopin 

NAG N-acetyl-∃-D-glucosaminidase 

Na-K-ATPase sodium-potassium-dependent adenosine triphosphatase 

NAWQA National Water-Quality Assessment 

NBT nitro blue tetrazolium 

NCBP National Contaminant Biomonitoring Program 

NCD nuclear chromatin decondensation (rate) 

NCS newborn calf serum 

NCTB Neurobehavioral Core Test Battery 

NCV nerve conduction velocity 

ND non-detectable; not detected 

NDI nuclear divison index 

NE norepinephrine 

NES Neurobehavioral Evaluation System 

NF-κB nuclear transcription factor-κB 

NGF nerve growth factor 

NHANES National Health and Nutrition Examination Survey 

NIOSH National Institute for Occupational Safety and Health 

NIST National Institute for Standards and Technology 

NK natural killer 

NMDA N-methyl-D-aspartate 

NMDAR N-methyl-D-aspartate receptor 

NMR nuclear magnetic resonance 

NO nitric oxide 

NO2 nitrogen dioxide 

NO3 nitrate 

NOAEC no-observed-adverse-effect concentration 

NOAEL no-observed-adverse-effect level 

NOEC no-observed-effect concentration 

NOEL no-observed-effect level 

NOM natural organic matter 
II-xxxvii

NORs nucleolar organizing regions 

NOS nitric oxide synthase; not otherwise specified 

NOx nitrogen oxides 

NP net productivity 

NPSH nonprotein sulfhydryl 

NR not reported 

NRC National Research Council 

NRK normal rat kidney 

NS nonsignificant 

NSAID non-steroidal anti-inflammatory agent 

NT neurotrophin 

NTA nitrilotriacetic acid 

O2 oxygen 

ODVP offspring development 

OH hydroxyl 

7-OH-coumarin 7-hydroxy-coumarin 

1,25-OH-D, 1,25-OH D3 1,25-dihydroxyvitamin D 

24,25-OH-D3 24,25-dihydroxyvitamin D

25-OH-D3 25-hydroxyvitamin D

8-OHdG 8-hydroxy-2'-deoxyguanosine 

O horizon forest floor 

OR odds ratio; other oral 

OSWER Office of Solid Waste and Emergency Response 

P, p probability value 

P300 event-related potential 

P450 1A1 cytochrome P450 1A1 

P450 1A2 cytochrome P450 1A2 

P450 CYP3a11 cytochrome P450 3a11 

PAD peripheral arterial disease 

PAH polycyclic aromatic hydrocarbon 

PAI-1 plasminogen activator inhibitor-1 

PAR population attributable risk 

Pb lead 

203Pb lead-203 radionuclide 

204Pb, 206Pb, 207Pb, 208Pb stable isotopes of lead-204, -206, -207, -208, respectively 
II-xxxviii

210Pb lead-210 radionuclide 

Pb(Ac)2 lead acetate 

PbB blood lead concentration 

PbCl2 lead chloride 

Pb(ClO4)2 lead chlorate 

PBG-S porphobilinogen synthase 

PBMC peripheral blood mononuclear cells 

Pb(NO3)2 lead nitrate 

PbO lead oxides (or litharge) 

PBP progressive bulbar paresis 

PbS galena 

PbU urinary lead 

PC12 pheochromocytoma cell 

PCR polymerase chain reaction 

PCV packed cell volume 

PDE phosphodiesterase 

PDGF platelet-derived growth factor 

PDI Psychomotor Development Index 

PEC probable effect concentration 

PEF expiratory peak flow 

PG prostaglandin (e.g., PGE2, PGF2); prostate gland 

PHA phytohemagglutinin A 

Pi inorganic phosphate 

PIXE particle induced X-ray emission 

PKC protein kinase C 

pl NEpi plasma norepinephrine 

PMA progressive muscular atrophy 

PMN polymorphonuclear leucocyte 

PMR proportionate mortality ratio 

PN postnatal (day) 

P5N pyrimidine 5'-nucleotidase 

PND postnatal day 

p.o., PO per os (oral administration) 

POMS Profile of Mood States 

ppb parts per billion 
II-xxxix

ppm parts per million 

PPVT-R Peabody Picture Vocabulary Test-Revised 

PRA plasma renin activity 

PRL prolactin 

PROG progeny counts or numbers 

PRR prevalence rate ratio 

PRWT progeny weight 

PST percent transferrin saturation 

PTH parathyroid hormone 

PTHrP parathyroid hormone-related protein 

PVC polyvinyl chloride 

PWM pokeweed mitogen 

PRWT progeny weight 

QA/QC quality assurance/quality control 

Q/V flux of air (Q) divided by volume of culture (V) 

r Pearson correlation coefficient 

R2 multiple correlation coefficient 

r

2 correlation coefficient 

226Ra most stable isotope of radium 

R/ALAD ratio of ALAD activity before and after reactivation 

RAVLT Rey Auditory Verbal Learning Test 

86Rb rubidium-86 radionuclide 

RBA relative bioavailablity 

RBC red blood cell; erythrocyte 

RBF renal blood flow 

RBP retinol binding protein 

RBPH reproductive behavior 

RCPM Ravens Colored Progressive Matrices 

REL rat epithelial (cells) 

REP reproduction 

RHIS reproductive organ histology 

222Rn most stable isotope of radon 

RNA ribonucleic acid 

ROS reactive oxygen species 

ROS 17.2.8 rat osteosarcoma cell line 
II-xl

RPMI 1640 Roswell Park Memorial Institute basic cell culture medium 

RR relative risk; rate ratio 

RT reaction time 

RSEM resorbed embryos 

RSUC reproductive success (general) 

RT reproductive tissue 

∑SEM sum of the molar concentrations of simultaneously extracted metal 

SA7 simian adenovirus 

SAB Science Advisory Board 

SAM S-adenosyl-L-methionine 

SBIS-4 Stanford-Binet Intelligence Scale-4th edition 

s.c., SC subcutaneous 

SCAN Test for Auditory Processing Disorders 

SCE selective chemical extraction; sister chromatid exchange 

SCP stripping chronopotentiometry 

SD Spraque-Dawley (rat); standard deviation 

SDH succinic acid dehydrogenase 

SDS sodium dodecyl sulfate; Symbol Digit Substitution 

SE standard error; standard estimation 

SEM standard error of the mean 

SES socioeconomic status 

sGC soluble guanylate cyclase 

SH sulfhydryl 

SHBG sex hormone binding globulin 

SHE Syrian hamster embryo cell line 

SIMS secondary ion mass spectrometry 

SIR standardized incidence ratio 

SLP synthetic leaching procedure 

SM sexually mature 

SMAV species mean acute value 

SMR standardized mortality ratio 

SNAP Schneider Neonatal Assessment for Primates 

SNP sodium nitroprusside 

SO2 sulfur dioxide 

SOD superoxide dismutase 
II-xli

SOPR sperm-oocyte penetration rate 

SPCL sperm cell counts 

SPCV sperm cell viability 

SQGs sediment quality guidelines 

SRA Self Reported Antisocial Behavior scale 

SRD Self Report of Delinquent Behavior 

SRIF somatostatin 

SRM Standard Reference Material 

SRT simple reaction time 

SSADMF Social Security Administration Death Master File 

SSB single-strand breaks 

SSEP somatosensory-evoked potential 

StAR steroidogenic acute regulatory protein 

STORET STOrage and RETrieval 

SVC sensory conduction velocity 

SVRT simple visual reaction time 

T testosterone 

TA tail 

TABL time-averaged blood lead 

T&E threatened and endangered (species) 

TAT tyrosine aminotransferase 

TB tibia 

TBARS thiobarbituric acid-reactive species 

TBPS Total Behavior Problem Score 

TCDD methionine-choline-deficient diet 

T cell T lymphocyte 

TCLP toxic characteristic leaching procedure 

TE testes 

TEC threshold effect concentration 

TEDG testes degeneration 

TEL tetraethyl lead 

TES testosterone 

TEWT testes weight 

TF transferrin, translocation factor 

TG 6-thioguanine 
II-xlii

TGF transforming growth factor 

TH tyrosine hydroxylase 

232Th stable isotope of thorium-232 

TLC Treatment of Lead-exposed Children (study) 

TNF tumor necrosis factor (e.g., TNF-α) 

TOF time-of-flight 

tPA plasminogen activator 

TPRD total production 

TRH thyroid releasing hormone 

TRV toxicity reference value 

TSH thyroid stimulating hormone 

TSP triple-super phosphate 

TT3 total triiodothyronine 

TT4 serum total thyroxine 

TTES total testosterone 

TTR transthyretin 

TU toxic unit 

TWA time-weighted average 

TX tromboxane (e.g., TXB2) 

U uriniary 

235U, 238U uranium-234 and -238 radionuclides 

UCP urinary coproporphyrin 

UDP uridine diphosphate 

UNECE United Nations Economic Commission for Europe 

Ur urinary 

USFWS U.S. Fish and Wildlife Service 

USGS United States Geological Survey 

UV ultraviolet 

V79 Chinese hamster lung cell line 

VA Veterans Administration 

VC vital capacity; vitamin C 

VDR vitamin D receptor 

VE vitamin E 

VEP visual-evoked potential 

VI variable-interval 
II-xliii

vit C vitamin C 

vit E vitamin E 

VMA vanilmandelic acid 

VMI Visual-Motor Integration 

VSM vascular smooth muscle (cells) 

VSMC vascular smooth muscle cells 

WAIS Wechsler Adult Intelligence Scale 

WDS wavelength dispersive spectrometers 

WHO World Health Organization 

WISC Wechsler Intelligence Scale for Children 

WISC-R Wechsler Intelligence Scale for Children-Revised 

WO whole organism 

WRAT-R Wide Range Achievement Test-Revised 

WT wild type 

WTHBF-6 human liver cell line 

ww wet weight 

XAFS X-ray absorption fine structure 

XANES X-ray absorption near edge spectroscopy 

XAS X-ray absorption spectroscopy 

XPS X-ray photoelectron spectroscopy 

X-rays synchrotron radiation 

XRD X-ray diffraction 

XRF X-ray fluorescence 

ZAF correction in reference to three components of matrix effects: 

atomic number (Z), absorption (A), and fluorescence (F) 

ZnNa2 DTPA zinc disodium diethylenetriaminepentaacetic acid 

ZnNa2 EDTA zinc disodium ethylenediaminetetraacetic acid 

ZPP zinc protoporphyrin 
 AX7-1 

AX7. CHAPTER 7 ANNEX - ENVIRONMENTAL 

EFFECTS OF LEAD 

AX7.1 TERRESTRIAL ECOSYSTEMS 

AX7.1.1 Methodologies Used in Terrestrial Ecosystems Research 

The distribution of Pb throughout the terrestrial ecosystem, via aerial deposition, has been 

discussed throughout this document. Its further impacts on soil, sediment, and water provide 

numerous pathways that may promote unacceptable risk to all levels of biota. Stable isotopes of 

Pb have been found useful in identifying sources and apportionment to various sources. One of 

the key factors affecting assessment of risk is an understanding, and perhaps quantification, of 

bioavailability. Therefore, the bioavailability of Pb is a key issue to the development of 

NAAQS. However, the discussion of all methods used in characterizing bioavailability is 

beyond the scope of this chapter. The following topics are discussed in this chapter. 

• Lead Isotopes and Apportionment 

• Methodologies to determine Pb speciation 

• Lead and the Biotic Ligand Model (BLM) 

• In situ methods to reduce Pb bioavailability 

AX7.1.1.1 Lead Isotopes and Apportionment 

Determination of the extent of Pb contamination from an individual source(s) and its 

impact are of primary importance in risk assessment. The identification of exposure pathway(s) 

is fundamental to the risk analysis and critical in the planning of remediation scenarios. 

Although societies have been consuming Pb for nearly 9,000 years, production of Pb in 

the United States peaked in 1910 and 1972, at approximately 750 and 620 kt/year, respectively 

(Rabinowitz, 2005). The diversity of potential Pb sources (fossil fuel burning, paint pigments, 

gasoline additives, solders, ceramics, batteries) and associated production facilities (mining, 

milling, smelting-refining) make fingerprinting of sources difficult. (See Chapter 2 and its 

Annex for additional information on sources.) Therefore, dealing with multiple sources (point 

and nonpoint), a reliable and specific fingerprinting technique is required. It has been well 

established (Sturges and Barrie, 1987; Rabinowitz, 1995) that the stable isotope composition of 
 AX7-2 

Pb is ideally suited for this task. Lead isotopic ratio differences often allow multiple sources to 

be distinguished, with an apportionment of the bulk Pb concentration made to those sources. 

Lead has four stable isotopes: 204Pb, 206Pb, 207Pb, and 208Pb in natural abundances of 1.4, 

24.1, 22.1, and 52.4%, respectively. The radiogenic 206Pb, 207Pb, and 208Pb are produced by 

radioactive decay of 238U, 235U, and 232Th, respectively. Thus, the isotopic composition of Pb 

varies based on the U:Pb and Th:Pb ratios of the original ore’s source and age (Faure, 1977). 

Because of the small fractional mass differences of the Pb isotopes, ordinary chemical and 

pyrometallurgical reactions will not alter their original composition. Therefore, anthropogenic 

sources reflect the isotopic composition of the ores from which the Pb originated. 

To acquire the Pb isotopes, a sample, generally in aqueous form, is analyzed on an 

ICP/MS (quadrapole, magnetic sector, or time-of-flight). Studies reviewing the most common 

analytical and sample preparation procedures include Ghazi and Millette (2004), Townsend et al. 

(1998), and Encinar et al. (2001a,b). The correction factor for mass discrimination biases is 

generally made by analyzing the National Institute for Standards and Technology (NIST), 

Standard Reference Material (SRM) 981 and/or spiked 203Tl and 205Tl isotopes (Ketterer et al., 

1991; Begley and Sharp, 1997). The overall success of Pb isotope fingerprinting is generally 

dependent on analysis precision, which in turn depends on the type of mass analyzer used 

(Table AX7-1.1.1). 

Table AX7-1.1.1. Relative Standard Deviation (RSD) for Lead Isotope 

Ratios on Selected Mass Spectrometers 

RSD Quadrapole Double-Focusing 

Single-Focusing 

Magnetic Sector 

High-Resolution 

Magnetic Sector 

ICP/MS 

204Pb:206Pb 0.0031 0.0032 0.00053 0.0011 

207Pb:206Pb 0.0032 0.0027 0.00053 0.00048 

208Pb:206Pb 0.0026 0.0024 0.00053 0.00046 

An extensive database comprising primarily North American Pb sources can be assembled 

from Doe and Rohrbough (1977), Doe and Stacey (1974), Doe et al. (1968), Heyl et al. (1974), 
 AX7-3 

Leach et al. (1998), Stacey et al. (1968), Zartman (1974), Cannon and Pierce (1963), Graney 

et al. (1996), Unruh et al. (2000), James and Henry (1993), Rabinowitz (2005), and 

Small (1973). 

The use of Pb isotopes to quantitatively apportion source contributions follows the simple 

mixing rule when only two sources are possible (Faure, 1977). Once multiple sources need to be 

considered, a unique solution can no longer be calculated (Fry and Sherr, 1984). Phillips and 

Gregg (2003) have designed a model to give feasible source contributions when multiple sources 

are likely. Many studies have demonstrated the usefulness of this apportionment technique. 

Media of all types have been studied: water (Flegal et al., 1989a,b; Erel et al., 1991; Monna 

et al., 1995), ice (Planchon et al., 2002), dust (Adgate et al., 1998; Sturges et al., 1993), and 

soil/sediments (Hamelin et al., 1990; Farmer et al., 1996; Bindler et al., 1999; Haack et al., 2004; 

Rabinowitz and Wetherill, 1972; Rabinowitz, 2005; Ketterer et al., 2001). 

AX7.1.1.2 Speciation in Assessing Lead Bioavailability in the Terrestrial Environment 

One of the three processes defined by the National Research Council in its review on 

bioavailability (NRC, 2002) is “contaminant interactions between phases”, more commonly 

referred to as “speciation.” 

A wide variety of analytical (XRD, EPMA, EXAFS, PIXE, XPS, XAS, SIMS) and 

chemical speciation modeling (SOILCHEM, MINTEQL, REDEQL2, ECOSAT, MINTEQA2, 

HYDRAQL, PHREEQE, WATEQ4F) tools have been used to characterize a metal’s speciation 

as it is found in various media. Currently, for risk assessment purposes (not considering 

phytotoxicity), where large sites with numerous media, pathways, and metals must often be 

characterized in a reasonable time frame, electron microprobe analysis (EMPA) techniques 

provide the greatest information on metal speciation. Other techniques such as extended X-ray 

absorption fine structure (EXAFS) and extended X-ray absorption near edge spectroscopy 

(EXANES) show great promise and will be important in solving key mechanistic questions. 

In the case of phytotoxicity, the speciation of metals by direct measurement or chemical models 

of pore-water chemistry is most valuable. Further work needs to be done in developing 

analytical tools for the speciation of the methyl-forming metals (Hg, As, Sb, Se, and Sn) in soils 

and sediments. 
 AX7-4 

Concept 

For a given metal or metalloid (hereafter referred to as metal), the term speciation refers 

to its chemical form or species, including its physicochemical characteristics that are relevant to 

bioavailability. As a result of the direct impact these factors often have on a metal’s 

bioavailability, the term “bioaccessibility” has been adopted to define those factors. 

Speciation Role 

The accumulation of metals in the lithosphere is of great concern. Unlike organic 

compounds, metals do not degrade and, thus, have a greater tendency to bioaccumulate. It is 

now well accepted that knowledge of the bulk, toxic characteristic leaching procedure (TCLP), 

or synthetic leaching procedure (SLP) concentrations for any metal is not a controlling factor in 

understanding a metal’s environmental behavior or in developing remedies for its safe 

management. Although these tests are essential to site characterization and management, they 

offer no insight into risk assessment. Rather, it is the metal’s bioavailability (the proportion of a 

toxin that passes a physiological membrane [the plasma membrane in plants or the gut wall in 

animals] and reaches a target receptor [cytosol or blood]), which plays a significant role in the 

risk assessment of contaminated media. 

The NRC review (NRC, 2002) on bioavailability defined bioavailability processes in 

terms of three key processes: 

• contaminant interactions between phases (association-dissociation/bound-released), 

• transport of contaminants to organism, and 

• passage across a physiological membrane. 

As mentioned previously, the first process is more commonly referred to as speciation. 

The speciation of a toxic metal in the environment is a critical component of any ecosystem 

health risk assessment. Four important toxicologic and toxicokinetic determinants relating 

speciation to bioavailability are the (1) chemical form or species, (2) particle size of the metal 

form, (3) lability of the chemical form, and (4) source. 
 AX7-5 

Chemical Form of Species 

The solid phase in a medium controls the activity of a metal in solution, whether the 

solution is surface, ground, or pore water or GI fluids, and plays a profound role in metal 

bioavailability. This is perhaps best illustrated by in vivo and in vitro results for many of the 

common Pb-bearing minerals (Drexler, 1997) (Figure AX7-1.1.1). The metal species found in 

media are often diverse, and data suggest that their bioavailability may be significantly 

influenced by site-specific variations within these identified metal species (Davis et al., 1993; 

Ruby et al., 1992; Drexler and Mushak, 1995). 

Figure AX7-1.1.1. Relationship of bioaccessibility (low, medium, high) versus speciation 

as shown with scanning electron micrographs of various Pb-bearing 

materials. 

Particle Size of Metal Species 

Particle size of a metal form is an important factor in the mobilization of the metal, 

primarily because as size decreases, the surface area of the particle increases, thereby increasing 

solubility. Thus, although solubility is not the only control for bioavailability, an increase in 

bioavailability has been directly attributed to a decrease in particle size: Barltrop and Meek 
 AX7-6 

(1979) observed that “the smaller the lead particle, the higher blood lead level.” Similar 

observations were made by Healy et al. (1992) using and an in vitro dissolution technique. 

Drexler (1997) presented in vitro results on numerous Pb-bearing phases ranging in particle size 

from 35 to 250 μm. While all phases studied showed increased bioavailability with decreasing 

particle size, more significantly, not all forms showed the same degree or magnitude of change 

(Figure AX7-1.1.2). Atmospheric particles are generally found to occur in bimodal populations: 

fine; 0.1 to 2.5 μm and coarse; 2.5 to 15 μm. This distribution is both a function of there 

transport mechanism and emission source. Although the upper size limit for particles that can be 

suspended in air is about 75 μm (Cowherd et al., 1974), other means of mechanical entrainment 

(saltation, and creep) can transport particles as large as 1000 μm, supporting the importance of 

fugative emissions on media contamination. In addition, particle size can change post 

depositional, as soluble forms re-precipitate or sorb onto other surfaces. Limited data are 

available on the particle-size of discrete Pb phases from multimedia environments. One example 

is the study by Drexler, 2004 at Herculaneum, Missouri. At this site, galena (PbS) was the 

dominant Pb species with mean particle-size distributions of 4, 6, and 14 μm in PM10 filters, 

house dust, and soils, respectively. These findings support the conclusion that aerial transport 

was the primary mechanism for Pb deposition in residential yards. Finally, such laboratory data 

have been supported by extensive epidemiologic evidence, enforcing the importance of particle 

size (Bornschein et al., 1987; Brunekreef et al., 1983; Angle et al., 1984). 

Particle Lability 

The impact on bioavailability of a metal particle’s lability (its associations within the 

medium matrix) is not well documented, but it follows the premise put forth by many of the 

developing treatment technologies regarding its being bound or isolated from its environment. 

Data from several EPA Superfund sites and the Region VIII swine study (U.S. Environmental 

Protection Agency, 2004a) suggest that matrix associations, such as liberated versus enclosed, 

can play an important part in bioavailability. As illustrated in Figure AX7-1.1.3, two different 

media with similar total Pb concentrations and Pb forms (slag, Pb-oxide, and Pb-arsenate) 

exhibit significantly different bioavailabilities. In the Murray, UT sample (bioaccumulation 

factor [BAF] = 53%), a greater fraction of the more bioavailable Pb-oxides are liberated and 

not enclosed in the less-soluble glass-like slag as observed in the Leadville, CO sample 
 AX7-7 

Figure AX7-1.1.2. Variation of bioavailability with particle size. 

(BAF = 17%). Other evidence is more empirical, as illustrated in Figure AX7-1.1.4, where a 

large particle of native Pb is shown to have developed a weathering ring of highly bioavailable 

Pb-chloride and Pb-oxide. Such observations can be useful in understanding the mechanistic 

phenomena controlling bioavailability. In addition, they will aid in developing and validating 

models to predict metal-environment interactions. 
 AX7-8 

Figure AX7-1.1.3. Illustration of particle lability and bioavailability at two different sites 

with similar total Pb concentrations and Pb forms. 

Figure AX7-1.1.4. Scanning electron micrograph of a large native Pb particle showing 

outer ring of highly bioavailable Pb-chloride and Pb-oxide. 
 AX7-9 

Source 

Although the source of a metal is not directly related to bioavailability, it plays an 

important role in risk assessment with the evaluation of metal (1) pathways, (2) background, 

and (3) apportionment. It is important to understand a metal’s pathway before any remedial 

action can be taken; otherwise, recontamination of the primary pathway and reexposure can 

occur. Knowledge of background is important, as an action level cannot be established below 

natural background levels. 

Plants 

When considering the bioavailability of a metal to plants from soils and sediments, it is 

generally assumed that both the kinetic rate of supply and the speciation of the metal to either the 

root or shoot are highly important. In soils and sediments generally, only a small volume of 

water is in contact with the chemical form, and although the proportion of a metal’s 

concentration in this pore water to the bulk soil/sediment concentration is small, it is this phase 

that is directly available to plants. Therefore, pore water chemistry (i.e., metal concentration as 

simple inorganic species, organic complexes, or colloid complexes) is most important. 

Tools currently used for metal speciation for plants include (1) in-situ measurements 

using selective electrodes (Gundersen et al., 1992; Archer et al., 1989; Wehrli et al., 1994); 

(2) in-situ collection techniques using diffusive equilibrium thin films (DET) and diffusive 

gradient thin films (DGT) followed by laboratory analyses (Davison et al., 1991, 1994; Davison 

and Zhang, 1994; Zhang et al., 1995); and (3) equilibrium models ( SOILCHEM) (Sposito and 

Coves, 1988). 

AX7.1.1.3 Tools for Bulk Lead Quantification and Speciation 

Bulk Quantification 

The major analytical methods most commonly used for bulk analyses outlined in the 1986 

Lead ACQD included: 

• Atomic Absorption Spectrometry (AAS) 

• Emission Spectrometry (Inductively coupled plasma/atomic emission spectrometry) 

• X-ray Fluorescence (XRF) 

• Isotope Dilution Mass Spectrometry (ID/MS) 
 AX7-10 

• Colorimetric 

• Electrochemical (anodic stripping voltametry and differential pulse polarography). 

The choice of analytical method today for bulk quantification is generally ICP/AES or 

ICP/MS (U.S. Environmental Protection Agency, 2001). Since 1986, numerous SRMs have 

been developed for Pb (Table AX7-1.1.2), and several significant technological improvements 

have been developed. 

Table AX7-1.1.2. National Institute of Standards and Technology Lead SRMs 

 NIST SRM Medium 

Mean Pb 

mg/kg 

 2710 Soil 5532 

 2711 Soil 1162 

 2709 Soil 18.9 

 2587 Soil (paint) 3242 

 2586 Soil (paint) 432 

 2783 Filter (PM2.5) 317 

 1648 Urban particulate 6550 

 1649a Urban dust 12,400 

 2584 Indoor dust 9761 

 2583 Indoor dust 85.9 

 1515 Apple leaves 0.47 

 1575 Pine needles 0.167 

Modern spectrometry systems have replaced photomultiplier tubes with a charge-coupled 

device (CCD). The CCD is a camera that can detect the entire light spectrum (>70,000 lines) 

from 160 to 785 nm. This allows for the simultaneous measurement of all elements, as well as 

any interfering lines (a productivity increase), and increases precision. The detection limit for Pb 

in clean samples can now be as low as 40 ppb. 
 AX7-11 

Modern ICP/AES systems offer a choice of either axial viewed plasma (horizontal), 

which provides greater sensitivity (DL= 0.8 μg Pb/L), or radial (vertical) viewed plasma, which 

performs best with high total dissolved samples (DL = 5.0 μg Pb/L). 

The development of reaction or collision cells have expanded the capabilities of ICP/MS 

and lowered detection limits for many elements that were difficult to analyze because of 

interferences such as Se, As, Ti, Zn, Ca, Fe, and Cr. The cells provide efficient interference 

(isobaric, polyatomic, and argide) removal independent of the analyte and sample matrix by 

using various reaction gases (H2, He, NH3), eliminating the need for interference correction 

equations. 

Speciation Tools 

A wide variety of analytical and chemical techniques have been used to characterize a 

metal’s speciation (as defined above) in various media (Hunt et al., 1992; Manceau et al., 1996, 

2000a; Welter et al., 1999; Szulczewski et al., 1997; Isaure et. al., 2002; Lumsdon and Evans, 

1995; Gupta and Chen, 1975; Ma and Uren, 1995; Charlatchka et al., 1997). Perhaps the most 

important factor that one must keep in mind in selecting a technique is that, when dealing with 

metal-contaminated media, one is most often looking for the proverbial “needle in a haystack.” 

Therefore, the speciation technique must not only provide the information outlined above, but it 

must also determine that information from a medium that contains very little of the metal. 

As illustrated in Figure AX7-1.1.5, for a Pb-contaminated soil, less than 1% (modally) of a 

single species can be responsible for a bulk metal’s concentration above an action level. This 

factor is even more significant for other metals (i.e., As, Cd, or Hg) were action levels are often 

below 100 mg/kg. 

Of the techniques tested (physicochemical, extractive, and theoretical), the tools that have 

been used most often to evaluate speciation for particle-bound metal include X-ray absorption 

spectroscopy (XAS), X-ray diffraction (XRD), particle induced X-ray emission (PIXE and 

μPIXE), electron probe microanalysis (EPMA), secondary ion mass spectrometry (SIMS), 

X-ray photoelectron spectroscopy (XPS), sequential extractions, and single chemical extractions. 

The tools that have been used most often to evaluate speciation for metal particles in solution 

include the following computer-based models: MINTEQL, REDEQL2, ECOSAT, MINTEQA2, 

HYDRAQL, PHREEQE, and WATEQ4F. These tools are briefly described below. 
 AX7-12 

Figure AX7-1.1.5. Bulk lead versus single species modality. Shaded area represents 

typical soil-lead concentrations found at remediation sites in the 

western United States. 

Particle-Bound Metal 

Direct Approaches

Over the past decade, numerous advances in materials science have led to the 

development of a wide range in analytical tools for the determination of metal concentration, 

bonding, and valance of individual particles on a scale that can be considered useful for the 

speciation of environmentally important materials (i.e., soils, wastes, sediments, and dust). 

This review will provide the reader with a brief description of these techniques, including their 

benefits, limitations (cost, availability, sample preparation, resolution), and usability as well as 

references to current applications. Although most of these tools are scientifically sound and 

offer important information on the mechanistic understanding of metal occurrence and behavior, 

only a few currently provide useful information on metal bioavailability at a “site” level. 

However, one may still find other techniques essential to a detailed characterization of a selected 
 AX7-13 

material to describe the chemical or kinetic factors controlling a metal’s release, transport, 

and/or exposure. 

X-Ray absorption Spectroscopy (XAS). X-ray absorption spectroscopy (XAS) is a 

powerful technique using the tunable, monochromatic (white light) X-rays produced by a 

synchrotron (2-4 GeV) to record oscillations in atomic absorption within a few 100 GeV of an 

element’s absorption edge. Spectra provide information on both chemical state and atomic 

structure. Measurements are theoretically available for all elements and are not surface-sensitive 

nor sample-sensitive (i.e., gases, liquids, solids, and amorphous materials are testable). 

High-energy spectra within 30 eV of the edge, termed XANES (X-ray absorption near 

edge structure spectroscopy (Fendorf et al., 1994; Maginn, 1998), are particularly suited for 

determination and quantification (10 to 100 ppm) of metal in a particular oxidation state 

(Szulczewski et al., 1997; Shaffer et al., 2001; Dupont et al., 2002). The lower-energy spectra 

persist some 100 eV above the edge. These oscillations are termed EXAFS (extended X-ray 

absorption fine structure) and are more commonly used for speciation analyses (Welter et al., 

1999; Manceau et al., 1996, 2000a; Isaure et al., 2002). 

The main limitations to XAS techniques are (1) the lack of spatial resolution; (2) XAS 

techniques provide only a weighted average signal of structural configurations, providing 

information on the predominant form of the metal, while minor species, which may be more 

bioavailable, can be overlooked; (3) access to synchrotrons is limited and the beam time required 

to conduct a site investigation would be prohibitive; (4) a large spectral library must be 

developed; (5) generally, poor fits to solution models are achieved when the compound list is 

large; and (6) high atomic number elements have masking problems based on compound density. 

X-Ray Diffraction (XRD). In X-ray diffraction, a monochromatic Fe, Mo, Cr, Co, W, or 

Cu X-ray beam rotates about a finely powdered sample and is reflected off the interplanar 

spacings of all crystalline compounds in the sample, fulfilling Bragg’s law (nλ = 2dsinθ). The 

identification of a species from this pattern is based upon the position of the lines (in terms of 

θ or 2θ) and their intensities as recorded by an X-ray detector. The diffraction angle (2θ) is 

determined by the spacing between a particular set of atomic planes. Identification of the species 

is empirical, and current available databases contain more than 53,000 compounds. 

If a sample contains multiple compounds, interpretation becomes more difficult and 

computer-matching programs are essential. In some instances, by measuring the intensity of the 
 AX7-14 

diffraction lines and comparing them to standards, it is possible to quantitatively analyze 

crystalline mixtures; however, if the species is a hydrated form or has a preferred orientation, 

this method is only semiquantitative at best. Since this technique represents a bulk analysis, 

no particle size or lability information can be extracted from the patterns. 

Particle Induced X-Ray Emission (PIXE and μPIXE). Particle induced X-ray emission 

(PIXE) uses a beam, ~4 μm in diameter, of heavy charged particles (generally He) to irradiate 

the sample. The resulting characteristic X-rays are emitted and detected in a similar manner as 

XRF, using Si-Li detectors. Particles generated from a small accelerator or cyclotron, with a 

potential of 2 to 4 MeV, are commonly used. Detection limits on the order of 1 mg/kg are 

achieved on thin-film samples. Disadvantages to its use for speciation include (1) only a small 

volume of material can be analyzed (1 to 2 mg/cm2

); (2) no particle size information is provided; 

(3) peak overlaps associated with Si-Li detectors limit identification of species; (4) limited 

availability; and (5) high cost. For a further review of PIXE analysis and applications, see 

Maenhaut (1987). 

Electron Probe Microanalysis (EPMA). Electron probe microanalysis uses a finely 

focused (1 μm) electron beam (generated by an electron gun operating at a 2 to 30 kV 

accelerating voltage and pico/nanoamp currents) to produce a combination of characteristic 

X-rays for elemental quantification along with secondary electrons and/or backscatter electrons 

for visual inspection of a sample. Elements from beryllium to uranium can be nondestructively 

analyzed at the 50-ppm level with limited sample preparation. X-ray spectra can be rapidly 

acquired using either wavelength dispersive spectrometers (WDS) or energy dispersive 

spectrometers (EDS). 

With WDS, a set of diffracting crystals, of known d-spacing, revolve in tandem with a 

gas-filled proportional counter inside the spectrometer housing so that Bragg’s law is satisfied 

and a particular wavelength can be focused. Photon energy pulses reflecting off the crystal are 

collected for an individual elemental line by the counter as a first approximation to 

concentration. For quantitative analysis, these intensities are compared to those of known 

standards and must be corrected for background, dead time, and elemental interactions (ZAF) 

(Goldstein et al., 1992). ZAF correction is in reference to the three components of matrix 

effects: atomic number (Z), absorption (A), and fluorescence (F). 
 AX7-15 

With EDS, a single Si-Li crystal detector is used in conjunction with a multichannel 

analog-digital converter (ADC) to sort electrical pulses (with heights approximately proportional 

to the quantum energy of the photon that generated them), producing a spectrum of energy 

(wavelength) versus counts. The net area under a particular peak (elemental line) is proportional 

to its concentration in the sample. For quantitative analyses, corrections similar to WDS analysis 

must be performed. Although EDS detectors are more efficient than WDS, detection limits are 

significantly greater (~1000 ppm), because of elevated backgrounds and peak overlaps. 

For speciation analysis, the EDS system must NEVER be used as the primary detector, as 

numerous errors in species identification are often made. These are generally the result of 

higher-order X-ray line overlaps. 

This technique has been routinely used for site characterizations (Linton et al., 1980; 

Hunt et al., 1992; Camp, Dresser, and McKee (CDM), 1994; U.S. Environmental Protection 

Agency, 2002). Currently this technique offers the most complete data package on metal 

speciation than any of the other tools. The method is relatively fast and inexpensive, available, 

and provides all of the required information for bioavailability assessments (i.e., particle size, 

species, lability, and sourcing). A number of limitations still need to be addressed including: 

(1) its inability to quickly isolate a statistically significant population of particles in soils with 

low bulk metal concentrations (<50 mg/kg), meaning that for some metals with low 

concentrations of concern (i.e., Cd, Mo, Sb, Se), this method may be less useful; (2) the more 

volatile metals (i.e., Hg, Tl) are often volatilized under the electron beam or lost during sample 

preparation. 

Secondary Ion Mass Spectrometry (SIMS). Secondary ion mass spectrometry (also known 

as ion microprobes or ion probes) is a well-known technique, primarily surface focused, that uses 

a 0.5 to 20 kV O, Ar, Ga, In, or Cs ion beam in bombarding (sputtering) the surface of a sample 

while emitting secondary ions that are detected by either quadrapole, time-of-flight (TOF), or 

magnetic sector mass spectrometers. Sensitivity is very high, in the ppb range for elements 

hydrogen to uranium, providing quantitative results on elemental or isotopic metals and organic 

compounds. With the advent of liquid metal (In and Ga) ion beams, beam sizes of less than 

1 μm are possible, although 20 μm is more commonly used. 
 AX7-16 

The major disadvantage of SIMS to species identification is that each element or isotope 

must be tuned and analyzed sequentially. This makes the identification of a metal form highly 

time-consuming and, thus, the characterization of a multiphase medium impractical. 

X-Ray Photoelectron Spectroscopy (XPS). X-ray photoelectron spectroscopy or ESCA 

(electron spectroscopy for chemical analysis, as it was previously known) is a classical surface, 

10 to 50 Å in depth, analytical technique for determining qualitative elemental concentrations of 

elements greater than He in atomic number and provides limited structural and oxidation state 

information. In XPS, the high-energy (15 kV) electrons are typically produced from a dualanode (Al-Mg) X-ray tube. The excitation or photoionization of atoms within the near surface of 

the specimen emit a spectrum of photoelectrons. The measured binding energy is characteristic 

of the individual atom to which it was bound. Monochromatic sources are often employed to 

improve energy resolution, allowing one to infer oxidation states of elements or structure of 

compounds (organic and inorganic) by means of small chemical shifts in binding energies 

(Hercules, 1970). The major disadvantages of XPS for environmental speciation studies is its 

poor sensitivity, especially in complex matrices and its large, 100-200 μm, spatial resolution. 

The direct speciation techniques discussed above are summarized in Table AX7-1.1.3. 

Indirect Approaches

A more indirect approach to speciation than the methods previously described include the 

functional or operational extraction techniques that have been used extensively over the years 

(Tessier et al., 1979; Tessier and Campbell, 1988; Gupta and Chen, 1975). These methods use 

either a single or sequential extraction procedure to release species associated with a particular 

metal within the media. Single chemical extractions are generally used to determine the 

bioavailable amount of metal in a functional class: water-soluble, exchangeable, organically 

bound, Fe-Mn bound, or insoluble. 

In a similar approach, sequential extractions treat a sample with a succession of reagents 

intended to specifically dissolve different, less available phases. Many of these techniques have 

been proposed, most of which are a variation on the classical method of Tessier et al. (1979), 

in which metal associated with exchangeable, carbonate-bound, Fe-Mn bound, organically 

bound, and residual species can be determined. Beckett (1989), Kheboian and Bauer (1987), 

and Foerstner (1987) provide excellent reviews on the use and abuse of extractions. These 
 AX7-17 Table AX7-1.1.3. Characteristics for Direct Speciation Techniques Tools 

Species Lability 

Species Particle 

Size 

Species Valance 

State 

Species Bonding 

Species 

Composition 

Species 

Abundance 

Element 

Specificity 

Isotopic 

Character 

Element 

Sensitivity 

Resolution 

XRD No No No No No# No No No 3-4 vol% Bulk EMPA Yes Yes Yes+ No Yes Yes? B-U No*** 50 ppm 0.5-1 μm SIMS No Yes No No Yes* Yes** Li-U Yes 1 ppb 10 μm XPS No No Yes Yes Yes* Yes** H-U No wt.% 100 μm XAS No No Yes Yes Yes* Yes** He-U No ppb 2 μm PIXIE No No No No Yes Yes** B-U No 10 ppm 4 μm * Technique requires each element be tuned and standardized, requiring unreasonable time limits. ** Techniques designed and tested only on simple systems. Multiple species require lengthy analytical times and data reduction. *** Limited when combined with ICP/MS/LA. # Identifies crystalline compounds and stoichiometric compositions only. ? Technique has limitations based on particle counting statistics. + Valance determined by charge balance of complete analyses. 
 AX7-18 

techniques can be useful in a study of metal uptake in plants, where transfer takes place 

predominately via a solution phase. However, one must keep in mind that they are not 

“selective” in metal species, give no particle size information and, above all, these leachable 

fractions have never been correlated to bioavailability. 

Solution Speciation Using Computer-Based Models. Computer-based models are either 

based upon equilibrium constants or upon Gibb’s free energy values in determining metal 

speciation from solution chemistry conditions (concentration, pH, Eh, organic complexes, 

adsorption/desorption sites, and temperature). Both approaches are subject to mass balance and 

equilibrium conditions. These models have undergone a great deal of development in recent 

years, as reliable thermodynamic data has become available and can provide some predictive 

estimates of metal behavior. A good review of these models and their applications is provided 

by Lumsdon and Evans (1995). 

Speciation can be controlled by simple reactions; however, in many cases, particularly in 

contaminated media, their state of equilibrium and reversibility are unknown. In addition, these 

models suffer from other limitations such as a lack of reliable thermodynamic data on relevant 

species, inadequacies in models to correct for high ionic strength, reaction kinetics are poorly 

known, and complex reactions with co-precipitation/adsorption are not modeled. 

The first limitation is perhaps the most significant for contaminated media. For example, 

none of the models would predict the common, anthropogenic, Pb phases, i.e., paint, solder, 

and slag. 

AX7.1.1.4 Biotic Ligand Model 

The biotic ligand model (BLM) is an equilibrium-based conceptual model that has been 

incorporated into regulatory agencies guidelines (including the EPA) to predict effects of metals 

primarily on aquatic biota and to aid in the understanding of their interactions with biological 

surfaces (see Annex Section AX7.2.1.3). 

Because of assumed similarities in mechanisms of toxicity between aquatic and terrestrial 

organisms, it is likely that the BLM approach as developed for the aquatic compartment may also 

be applicable to the terrestrial environment. Recent research has been directed toward extending 

the BLM to predict metal toxicity in soils (Steenbergen et al., 2005). Steenbergen et al. (2005) 

pointed out that, until recently, the BLM concept has not been applied to predict toxicity to soil 
 AX7-19 

organisms. The authors believe there may be two reasons for this. First, metal uptake routes in 

soils are generally more complex than those in water, because exposure via pore water and 

exposure via ingestion of soil particles may, in principle, both be important. Second, it remains 

very difficult to univariately control the composition of the soil pore water and the metal 

concentrations in the pore water, due to re-equilibration of the system following modification of 

any of the soil properties (including addition of metal salts). 

Steenbergen et al. (2005) assessed acute copper toxicity to the earthworm Aporrectodea 

caliginosa using the BLM. To overcome the aforementioned problems inherent in soil toxicity 

tests they developed an artificial flow-through exposure system consisting of an inert quartz sand 

matrix and a nutrient solution, of which the composition was univariately modified. Thus, the 

obstacles in employing the BLM to terrestrial ecosystems seem to be surmountable, and future 

research may provide useful information on Pb bioavailability and toxicity to terrestrial 

organisms. 

AX7.1.1.5 Soil Amendments 

The removal of contaminated soil to mitigate exposure of terrestrial ecosystem 

components to Pb can often present both economic and logistic problems. Because of this, 

recent studies have focused on in situ methodologies to lower soil-Pb RBA (Brown et al., 

2003a,b). To date, the most common methods studied include the addition of soil amendments 

in an effort either to lower the solubility of the Pb form or to provide sorbtion sites for fixation of 

pore-water Pb. These amendments typically fall within the categories of phosphate, biosolid, 

and Al/Fe/Mn-oxide amendments. 

Phosphate Amendments 

Phosphate amendments have been studied extensively and, in some cases, offer the most 

promising results (Brown et al., 1999; Ryan et al., 2001; Cotter-Howells and Caporn, 1996; 

Hettiarachchi et al., 2001, 2003; Rabinowitz, 1993; Yang et al., 2001; Ma et al., 1995). Research 

in this area stems from early work by Nriagu (1973) and Cotter-Howells and Caporn (1996), who 

pointed out the very low solubilities for many Pb-phosphates (Ksp !27 to !66), particularly 

chloropyromorphite [Pb5(PO4)3Cl]. The quest to transform soluble Pb mineralogical forms into 

chloropyromorthite continues to be the primary focus of most studies. Sources of phosphorous 
 AX7-20 

have included phosphoric acid (H3PO4), triple-super phosphate (TSP), phosphate rock, and/or 

hydroxyapatite (HA). Various studies have combined one or more of these phosphorous sources 

with or without lime, iron, and/or manganese in an attempt to enhance amendment qualities. 

Most amendments are formulated to contain between 0.5 and 1.0% phosphorous by weight. 

They are then either applied wet or dry and then mixed or left unmixed with the contaminated 

soil. Success of phosphate amendments has been variable, and the degree of success appears to 

depend on available phosphorous and the dissolution rate of the original Pb species. 

A number of potentially significant problems associated with phosphate amendments have 

been recognized, including both phyto- and earthworm toxicity (Ownby et al., 2005; Cao et al., 

2002; and Rusek and Marshall, 2000). Both of these toxicities are primarily associated with very 

high applications of phosphorous and/or decreased soil pH. Indications of phytotoxicity are 

often balanced by studies such as Zhu et al. (2004) that illustrate a 50 to 70% reduction in shootroot uptake of Pb in phosphate-amended soils. Additionally, the added phosphate poses the 

potential risk of eutrophication of nearby waterways from soil runoff. Finally, Pb-contaminated 

soils from the extractive metals industry or agricultural sites often have elevated concentrations 

of arsenic. It has been shown (Impellitteri, 2005; Smith et al., 2002; Chaney and Ryan, 1994; 

and Ruby et al., 1994) that the addition of phosphate to such soils would enhance arsenic 

mobility (potentially moving arsenic down into the groundwater) through competitive anion 

exchange. Some data (Lenoble et al., 2005) indicate that if one could amend arsenic and Pb 

contaminated soils with iron(III) phosphate this problem can be mitigated, however the increased 

concentrations of both phosphate and iron still exclude the application when drinking water is an 

issue. 

Biosolid Amendments 

Historically, biosolids have been used in the restoration of coal mines (Haering et al., 

2000; Sopper, 1993). More recently, workers have demonstrated the feasibility of their use in 

the restoration of mine tailings (Brown et al., 2003a), and urban soils (Brown et al., 2003b; 

Farfel et al., 2005). Mine tailings are inherently difficult to remediate in that they pose numerous 

obstacles to plant growth. They are most often (1) acidic; (2) high in metal content, thus prone to 

phytotoxicity; (3) very low in organic content; and (4) deficient in macro- and micronutrients. 
 AX7-21 

Stabilization (i.e., the establishment of a vegetative cover) of these environments is essential to 

the control of metal exposure or migration from soil/dust and groundwater pathways. 

At Bunker Hill, ID, Brown et al. (2003b) demonstrated that a mixture of high nitrogen 

biosolids and wood pulp or ash, when surface applied at a rate of approximately 50 and 

220 tons/ha, respectively, increased soil pH from 6.8 to approximately 8.0, increased plant 

biomass from 0.01 mg/ha to more than 3.4 tons/ha, and resulted in a healthy plant cover within 

2 years. Metal mobility was more difficult to evaluate. Plant concentrations of Zn and Cd were 

generally normal for the first 2 years of the study; however, Pb concentrations in vegetation 

dramatically increased two to three times in the first year. Additionally, macronutrients (Ca, K, 

and Mg) decreased in plant tissue. 

Urban soils, whether contaminated from smelting, paint, auto emissions, or industrial 

activity, are often contaminated with Pb (Agency for Toxic Substances and Disease Registry 

[ATSDR], 1988) and can be a significant pathway to elevated child blood Pb levels (Angle et al., 

1974). Typically, contaminated residential soils are replaced under Superfund rules. However, 

urban soils are less likely to be remediated unless a particular facility is identified as the 

contaminate source. Application of biosolids to such soils may be a cost-effective means for 

individuals or communities to lower Pb RBAs. 

A field study by Farfel et al. (2005) using the commercial biosolid ORGO found that, 

over a 1-year period, Pb in the dripline soils of one residence had reduced RBAs by ~60%. 

However, soils throughout the remainder of the yard showed either no reduction in RBA or a 

slight increase. A more complex study was conducted by Brown et al. (2003a) on an urban 

dripline soil in the lab. The study used an assortment of locally derived biosolids (raw, ashed, 

high-Fe compost, and compost) with and without lime. All amendments were incubated with 

approximately 10% biosolids for a little more than 30 days. In vitro and in vivo data both 

indicated a 3 to 54% reduction in Pb RBA, with the high-Fe compost providing the greatest 

reduction. 

As with phosphate amendments, problems with biosolid application have also been 

documented. Studies have shown that metal transport is significantly accelerated in soils 

amended with biosolids (Al-Wabel et al., 2002; McBride et al., 1997, 1999; Lamy et al., 1993; 

Richards et al., 1998, 2000). Some of these studies indicate that metal concentrations in soil 

solutions up to 80 cm below the amended surface increased by 3- to 20-fold in concentration up 
 AX7-22 

to 15 years after biosolid application. The increase in metal transport is likely the result of 

elevated dissolved organic carbon (DOC) in the amended soil. Anodic stripping voltammetry 

has indicated that very low percentages (2 to 18%) of the soluble metals are present as ionic or 

inorganic complexes (McBride, 1999; Al-Wabel et al., 2002). 

AX7.1.2 Distribution of Atmospherically Delivered Lead in 

Terrestrial Ecosystems 

The 1986 Lead AQCD (U.S. Environmental Protection Agency, 1986a) contains only a 

few minor sections that detail the speciation, distribution, and behavior of atmospherically 

delivered Pb in terrestrial ecosystems. The document concluded that the majority of Pb in the 

atmosphere at that time was from gasoline consumption: of the 34,881 tons of Pb emitted to the 

atmosphere in 1984, 89% was from gasoline use and minor amounts were from waste oil 

combustion, iron and steel production, and smelting. Lead in the atmosphere today, however, is 

not primarily from leaded-gasoline consumption, but results largely from iron and steel 

foundaries, boilers and process heaters, the combustion of fossil fuels in automobiles, trucks, 

airplanes, and ships, and other industrial processes (Table 2-8, Polissar et al., 2001; Newhook 

et al., 2003). The emission source can determine the species of Pb that are delivered to terrestrial 

ecosystems. For example, Pb species emitted from automobile exhaust is dominated by 

particulate Pb halides and double salts with ammonium halides (e.g., PbBrCl, PbBrCl2NH4Cl), 

while Pb emitted from smelters is dominated by Pb-sulfur species (Habibi, 1973). The halides 

from automobile exhaust break down rapidly in the atmosphere, possibly via reactions with 

atmospheric acids (Biggins and Harrison, 1979). Lead phases in the atmosphere, and 

presumably the compounds delivered to the surface of the earth (i.e., to vegetation and soils), 

are suspected to be in the form of PbSO4, PbS, and PbO (Olson and Skogerboe, 1975; Clevenger 

et al., 1991; Utsunomiya et al., 2004). 

There are conflicting reports of how atmospherically derived Pb specifically behaves in 

surface soils. This disagreement may represent the natural variability of the biogeochemical 

behavior of Pb in different terrestrial systems, the different Pb sources, or it may be a function of 

the different analytical methods employed. The importance of humic and fulvic acids (Zimdahl 

and Skogerboe, 1977; Gamble et al., 1983) and hydrous Mn- and Fe-oxides (Miller and McFee, 

1983) for scavenging Pb in soils are discussed in some detail in the 1986 Lead AQCD. Nriagu 
 AX7-23 

(1974) used thermodynamics to argue that Pb-orthophosphates (e.g., pyromorphite) represented 

the most stable Pb phase in many soils and sediments. He further suggested that, because of the 

extremely low solubility of Pb-phosphate minerals, Pb deposition could potentially reduce 

phosphorous availability. Olson and Skogerboe (1975) reported that solid-phase PbSO4

dominated gasoline-derived Pb speciation in surface soils from Colorado, Missouri, and Chicago, 

while Santillan-Medrano and Jurinak (1975) suggested that Pb(OH)2, Pb(PO4)2, and PbCO3

could regulate Pb speciation in soils. However, insoluble organic material can bind strongly to 

Pb and prevent many inorganic phases from ever forming in soils (Zimdahl and Skogerboe, 

1977). 

The vertical distribution and mobility of atmospheric Pb in soils was poorly documented 

prior to 1986. Chapter 6 of the 1986 AQCD cited a few references suggesting that atmospheric 

Pb is retained in the upper 5 cm of soil (Reaves and Berrow, 1984). Techniques using radiogenic 

Pb isotopes had been developed to discern between gasoline-derived Pb and natural, geogenic 

(native) Pb, but these techniques were mostly applied to sediments (Shirahata et al., 1980) prior 

to the 1986 Lead AQCD. Without using these techniques, accurate determinations of the depthdistribution and potential migration velocities for atmospherically delivered Pb in soils were 

largely unavailable. 

Several technological advances, combined with the expansion of existing technologies 

after 1986 resulted in the publication of a large body of literature detailing the speciation, 

distribution, and geochemical behavior of gasoline-derived Pb in the terrestrial environment. 

Most notably, the development of selective chemical extraction (SCE) procedures as a rapid and 

inexpensive means for partitioning Pb into different soil and sediment phases (e.g., Pb-oxides, 

Pb-humate, etc.) has been exploited by a number of researchers (Tessier et al., 1979; Johnson 

and Petras, 1998; Ho and Evans, 2000; Scheckel et al., 2003). Also, since 1986, several workers 

have exploited synchrotron-based XAS in order to probe the electron coordination environment 

of Pb in soils, organic matter, organisms, and sediments (Manceau et al., 1996; Xia et al., 1997; 

Trivedi et al., 2003). X-ray absorption studies can be used for the in-situ determination of the 

valence state of Pb and can be used to quantify Pb speciation in a variety of untreated samples. 

Biosensors, which are a relatively new technology coupling biological material, such as an 

enzyme, with a transducer, offer a new, simple, and inexpensive means for quantifying available 

Pb in ecosystems (Verma and Singh, 2005). Advances in voltammetric, diffusive gradients in 
 AX7-24 

thin films (DGT), and ICP techniques have also increased the abilities of researchers to quantify 

Pb phases in solutions (Berbel et al., 2001; Scally et al., 2003). In addition to the development of 

techniques for describing and quantifying Pb species in the soils and solutions, researchers have 

used radiogenic Pb isotopes (206Pb, 207Pb, 208Pb) to quantify the distribution, speciation, and 

transport of anthropogenic Pb in soil profiles and in vegetation (Bindler et al., 1999; Erel et al., 

2001; Kaste et al., 2003; Klaminder et al., 2005). 

Over the past several decades, workers have also developed time-series data for Pb in 

precipitation, vegetation, organic horizons, mineral soils, and surface waters. Since 

atmospherically delivered Pb often comprises a significant fraction of the “labile” Pb (i.e., Pb not 

associated with primary minerals), these data have been useful for developing transport and 

residence time models of Pb in different terrestrial reservoirs (Friedland et al., 1992; Miller and 

Friedland, 1994; Johnson et al., 1995a; Wang and Benoit, 1997). Overall, a significant amount 

of research has been published on the distribution, speciation, and behavior of anthropogenic Pb 

in the terrestrial environment since 1986. However, certain specific details on the behavior of Pb 

in the terrestrial environment and its potential effects on soil microorganisms remain elusive. 

AX7.1.2.1 Speciation of Atmospherically-delivered Lead in Terrestrial Ecosystems 

Lead in the Solid Phases 

Lead can enter terrestrial ecosystems through natural rock weathering and by a variety of 

anthropogenic pathways. These different source terms control the species of Pb that is 

introduced into the terrestrial environment. While Pb is highly concentrated (percent level) in 

certain hydrothermal sulfide deposits (e.g., PbS) that are disseminated throughout parts of the 

upper crust, these occurrences are relatively rare. Therefore, the occurrence of Pb as a minor 

constituent of rocks (ppm level), particularly granites, rhyolites, and argillaceous sedimentary 

rocks is the more pertinent source term for the vast majority of terrestrial ecosystems. During 

the hydrolysis and oxidation of Pb-containing minerals, divalent Pb is released to the soil 

solution where it is rapidly fixed by organic matter and secondary mineral phases (KabataPendias and Pendias, 1992). The geochemical form of natural Pb in terrestrial ecosystems will 

be strongly controlled by soil type (Emmanuel and Erel, 2002). In contrast, anthropogenically 

introduced Pb has a variety of different geochemical forms, depending on the specific source. 

While Pb in soils from battery reclamation areas can be in the form of PbSO4 or PbSiO3, Pb in 
 AX7-25 

soils from shooting ranges and paint spills is commonly found as PbO and a variety of Pb 

carbonates (Vantelon et al., 2005; Laperche et al., 1996; Manceau et al., 1996). Atmospherically 

delivered Pb resulting from fossil fuel combustion is typically introduced into terrestrial 

ecosystems as Pb-sulfur compounds and Pb oxides (Olson and Skogerboe, 1975; Clevenger 

et al., 1991; Utsunomiya et al., 2004). After deposition, Pb species are likely transformed. 

Although the specific factors that control the speciation of anthropogenic Pb speciation in soils 

are not well understood, there are many studies that have partitioned Pb into its different 

geochemical phases. A thorough understanding of Pb speciation is critical in order to predict 

potential mobility and bioavailability (see Section AX7.1.1). 

Selective chemical extractions have been employed extensively over the past 20 years for 

quantifying amounts of a particular metal phase (e.g., PbS, Pb-humate, Pb-Fe/Mn-oxide) present 

in soil or sediment rather than total metal concentration. Sometimes selective chemical 

extractions are applied sequentially to a particular sample. For example, the exchangeable metal 

fraction is removed from the soil using a weak acid or salt solution (e.g., BaCl2), followed 

immediately by an extraction targeting organic matter (e.g., H2O2 or NaOCl), further followed by 

an extraction targeting secondary iron oxides (e.g., NH2OH·HCl), and finally, a strong reagent 

cocktail (e.g., HNO3-HCl-HF) targets primary minerals. Tessier et al. (1979) developed this 

technique. More recently, this technique has been modified and developed specifically for 

different metals and different types of materials (Keon et al., 2001). Alternatively, batch-style 

selective chemical extractions have been used on soils and sediments to avoid the problems 

associated with nonselective reagents (Johnson and Petras, 1998). Selective extractions can be a 

relatively rapid, simple, and inexpensive means for determining metal phases in soils and 

sediments, and the generated data can be linked to potential mobility and bioavailability of the 

metal (Tessier and Campbell, 1987). However, some problems persist with the selective 

extraction technique. First, extractions are rarely specific to a single phase. For example, while 

H2O2 is often used to remove metals bound to organic matter in soils, others have demonstrated 

that this reagent destroys clay minerals and sulfides (Ryan et al., 2002). Peroxide solutions may 

also be inefficient in removing metals bound to humic acids, and in fact could potentially result 

in the precipitation of metal-humate substances. In addition to the nonselectivity of reagents, 

significant metal redistribution has been documented to occur during sequential chemical 

extractions (Ho and Evans, 2000; Sulkowski and Hirner, 2006), and many reagents may not 
 AX7-26 

completely extract targeted phases. While chemical extractions provide some useful information 

on metal phases in soil or sediment, the results should be treated as “operationally defined,” e.g., 

“H2O2-liberated Pb” rather than “organic Pb.” 

Lead forms strong coordination complexes with oxygen on mineral surfaces and organic 

matter functional groups (Abd-Elfattah and Wada, 1981), because of its high electronegativity 

and hydrolysis constant. Therefore, Pb is generally not readily exchangeable, i.e., the amount of 

Pb removed from soils by dilute acid or salts is usually less that 10% (Karamanos et al., 1976; 

Sposito et al., 1982; Miller and McFee, 1983; Johnson and Petras, 1998; Bacon and Hewitt, 

2005). Lead is typically adsorbed to organic and inorganic soil particles strongly via innersphere adsorption (Xia et al., 1997; Bargar et al., 1997a,b, 1998). Kaste et al. (2005) found that a 

single extract of 0.02 M HCl removed 15% or less Pb in organic horizons from a montane forest 

in New Hampshire. The fact that relatively concentrated acids, reducing agents, oxidizing 

agents, or chelating agents are required to liberate the majority of Pb from soils is used as one 

line of evidence that Pb migration and uptake by plants in soils is expected to be low. 

Lead that is “organically bound” in soils is typically quantified by extractions that 

dissolve/disperse or destroy organic matter. The former approach often employs an alkaline 

solution (NaOH), which deprotonates organic matter functional groups, or a phosphate solution, 

which chelates structural cations. Extractions used to destroy organic matter often rely on H2O2

or NaOCl. Both organic and mineral horizons typically have significant Pb in this soil phase. 

Miller and McFee (1983) used Na4P2O7 to extract organically bound Pb from the upper 2.5 cm of 

soils sampled from northwestern Indiana. They found that organically bound Pb accounted for 

between 25 and 50% of the total Pb present in the sampled topsoils. Jersak et al. (1997), Johnson 

and Petras (1998), and Kaste et al. (2005) selectively extracted Pb from spodosols from the 

northeastern United States. Using acidified H2O2, Jersak et al. (1997) found that very little 

(<10 %) of the Pb in mineral soils (E, B, C) sampled from New York and Vermont was organic. 

Johnson and Petras (1998) used K4P2O7 to quantify organically bound Pb in the Oa horizon and 

in mineral soils from the Hubbard Brook Experimental Forest in New Hampshire. They reported 

that 60% of the total Pb in the Oa horizon was organic and that between 8 and 17% of the total 

Pb in the mineral soil was organic. However, in the E, Bh, and Bs1 horizons, organically bound 

Pb dominated the total “labile” (non-mineral lattice) Pb. Kaste et al. (2005) used selective 

chemical extractions on organic horizons from montane forests in Vermont and New Hampshire. 
 AX7-27 

They found that repeated extractions with Na4P2O7 removed between 60 and 100% of the Pb 

from their samples. Caution should be used when interpreting the results of pyrophosphate 

extractions. Although they are often used to quantify organically bound metals, this reagent can 

both disperse and dissolve Fe phases (Jeanroy and Guillet, 1981; Shuman, 1982). Acidified 

H2O2 has also been reported to destroy and release elements associated with secondary soil 

minerals (Papp et al., 1991; Ryan et al., 2002). 

Aside from organic forms, Pb is often found to be associated with secondary oxide 

minerals in soils. Pb can be partitioned with secondary oxides by a variety of mechanisms, 

including (1) simple ion exchange, (2) inner-sphere or outer-sphere adsorption, and (3) coprecipitation and/or occlusion (Bargar et al., 1997a,b, 1998, 1999). As discussed above, very 

little Pb is removed from soil via dilute acid or salt solutions, so adsorption and co-precipitation 

are likely the dominant Pb interactions with secondary mineral phases. Reagents used to 

quantify this phase are often solutions of EDTA, oxalate, or hydroxylamine hydrochloride (HH). 

Miller and McFee (1983) used an EDTA solution followed by an HH solution to quantify Pb 

occluded by Fe and Mn minerals, respectively, in their surface-soil samples from Indiana. They 

reported that approximately 30% of the total soil Pb was occluded in Fe minerals, and 5 to 15% 

was occluded in Mn phases. In soils from the northeastern United States, Jersak et al. (1997) 

used various strengths of HH solutions and concluded that negligible Pb was associated with 

Mn-oxides and that 1 to 30% of the Pb was associated with Fe phases in the mineral soils in their 

study. Johnson and Petras (1998) reported that no Pb was removed from the Oa horizon at the 

Hubbard Brook Experimental Forest (HBEF) by oxalate, but that 5 to 15% of the total Pb in 

mineral soils was removed by this extraction, presumably because it was bound to amorphous 

oxide minerals. Kaste et al. (2005), however, reported that HH removed 30 to 40% of the Pb 

from organic horizons in their study. They concluded that Fe phases were important in 

scavenging Pb, even in soil horizons dominated by organic matter. 

Synchrotron radiation (X-rays) allows researchers to probe the electron configuration of 

metals in untreated soil and sediment samples. This type of analysis has been extremely valuable 

for directly determining the coordination environment of Pb in a variety of soils and sediments. 

Since different elements have different electron binding energies (Eb), X-rays can be focused in 

an energy window specific to a metal of interest. In experiments involving XAS, X-ray energy is 

increased until a rapid increase in the amount of absorption occurs; this absorption edge 
 AX7-28 

represents Eb. The precise energy required to dislodge a core electron from a metal (i.e., Eb) will 

be a function of the oxidation state and covalency of the metal. X-ray absorption studies that 

focus on the location of the absorption edge are referred to as XANES (X-ray absorption near 

edge structure). In the energy region immediately after the absorption edge, X-ray absorption 

increases and decreases with a periodicity that represents the wave functions of the ejected 

electrons and the constructive and destructive interference with the wave functions of the nearby 

atoms. X-ray absorption studies used to investigate the periodicity of the absorption after Eb are 

referred to as EXAFS (extended X-ray absorption fine structure). Since the electron 

configuration of a Pb atom will be directly governed by its speciation (e.g., Pb bound to organics, 

Pb adsorbed to oxide surfaces, PbS, etc.) X-ray absorption studies provide a powerful in-situ 

technique for determining speciation without some of the problems associated with chemical 

extractions (Bargar et al., 1997a,b, 1998). 

Manceau et al. (1996) used EXAFS to study soil contaminated by gasoline-derived Pb in 

France and found that the Pb was divalent and complexed to salicylate and catechol-type 

functional groups of humic substances. He concluded that the alkyl-tetravalent Pb compounds 

that were added to gasoline were relatively unstable and will not dominate the speciation of Pb 

fallout from the combustion of leaded gasoline. The binding mechanism of Pb to organics is 

primarily inner-sphere adsorption (Xia et al., 1997). DeVolder et al. (2003) used EXAFS to 

demonstrate that Pb phases were shifting to the relatively insoluble PbS when contaminated 

wetland soils were treated with sulfate. Strawn and Sparks (2000) gave evidence that added Pb 

was adsorbed directly onto organic matter in an untreated silt loam, but in the absence of organic 

matter (treated with sodium hypochlorite) the added Pb appeared to adsorb instead to some form 

of SiO2. More recent XAS studies have demonstrated the importance of biomineralization of Pb 

in soils by bacteria and nematodes (Xia et al., 1997; Templeton et al., 2003a,b; Jackson et al., 

2005). Templeton et al. (2003a,b) demonstrated that biogenic precipitation of pyromorphite was 

the dominant source of Pb uptake by Burkholderia cepacia biofilms below pH 4.5. Above pH 

4.5, adsorption complexes began to form in addition to Pb mineral precipitation. 

In addition to XAS studies of Pb in environmental samples, numerous experimental-based 

XAS studies have documented in detail the coordination environment of Pb adsorbed to Feoxides, Mn-oxides, Al-oxides, and clay minerals (Manceau et al., 1996, 2000a,b, 2002; Bargar 

et al., 1997a,b, 1998, 1999; Strawn and Sparks, 1999; Trivedi et al., 2003; Chen et al., 2006). 
 AX7-29 

Bargar et al. (1997a) showed that Pb can adsorb to FeO6 octahedra on three different types of 

sites: on corners, edges, or faces. Ostergren et al. (2000a,b) showed that the presence of 

dissolved carbonate and sulfate increased Pb adsorbtion on goethite. The relative fraction of 

corner-sharing complexes can be greatly increased by the presence of these ligands, as bridging 

complexes between the metal and the corners are formed (Ostergren et al., 2000a,b). 

Furthermore, Elzinga and Sparks showed that the mechanism of Pb sorption to SiO2 surfaces is 

pH-dependent. In acid environments (pH < 4) Pb adsorbs largely as an inner-sphere mononulear 

complex, but as pH increases, Pb sorption increasingly occurs via the formation of surfaceattached covalent polynuclear Pb species. 

Recently, Jackson et al. (2005) used microfocused synchrotron-based X-ray fluorescence 

(ΦSXRF) to detail the distribution of Pb and Cu in the nematode Caenorhabditis elegans. They 

found that, while Cu was evenly distributed throughout the bodies of exposed C. elegans, Pb was 

concentrated in the anterior pharynx region. Microfocused X-ray diffraction indicated that the 

highly concentrated Pb region in the pharynx was actually comprised of the crystalline Pb 

mineral, pyromorphite. The authors concluded that C. elegans precipitated pyromorphite in the 

pharynx as a defense mechanism to prevent spreading the toxic metal to the rest of the 

organism’s body. They further suggested that, because of the high turnover rate of nematodes, 

biomineralization could play an important role in the speciation of Pb in certain soils. 

Lead Solid-solution Partitioning 

The concentration of Pb species dissolved in soil solution is probably controlled by some 

combination of (a) Pb-mineral solubility equilibria, (b) adsorption reactions of dissolved Pb 

phases on inorganic surfaces (e.g., crystalline or amorphous oxides of Al, Fe, Si, Mn, etc.; clay 

minerals), and (c) adsorption reactions of dissolved Pb phases on soil organic matter. Dissolved 

Pb phases in soil solution can be some combination of Pb2+ and its hydrolysis species, Pb bound 

to dissolved organic matter, and Pb complexes with inorganic ligands such as Cl!

 and SO4

2!

. 

Alkaline soils typically have solutions supersaturated with respect to PbCO3, Pb3(CO3)2(OH)2, 

Pb(OH)2, Pb3(PO4)2, Pb5(PO4)3(OH), and Pb4O(PO4)2 (Badawy et al., 2002). Pb-phosphate 

minerals in particular are very insoluble, and calculations based on thermodynamic data predict 

that these phases will control dissolved Pb in soil solution under a variety of conditions (Nriagu, 
 AX7-30 

1974; Ruby et al., 1994). However, certain chelating agents, such as dissolved organic matter, 

can prevent the precipitation of Pb minerals (Lang and Kaupenjohann, 2003). 

Using a combination of desorption experiments and XAS, EXAFS, and XANES, Rouff 

et al. (2006) found that aging of Pb-calcite suspensions resulted in changes in the solid-phase 

distribution of Pb. Increased sorption time can reduce trace metal desorption by enhancing the 

stability of surface complexes (Rouff et al., 2005) or by mechanisms involving microporous 

diffusion (Backes et al., 1995), recrystallization-induced incorporation into the solid phase 

(Ainsworth et al., 1994), and formation and stabilization of surface precipitates (Ford et al., 

1999). For adsorption of Pb to hydrous Fe oxides, goethite, and Pb-contaminated soils, aged 

samples show Pb to be reversibly bound, suggesting Pb adsorption primarily to the substrates’ 

surfaces (Rouff et al., 2006). However, for Pb adsorption to calcite aging played a significant 

role due to detection of multiple sorption mechanisms, even for short sorption times (Rouff et al., 

2006). pH also played a role in Pb sorption. Over long sorption periods (60 to 270 days), slow 

continuous uptake of Pb occurred at pH 7.3 and 8.2. At pH 9.4, no further uptake occurred with 

aging and very little desorption occurred. These results show the importance of contact time and 

pH on Pb solid-phase partitioning, particularly in geochemical systems in which calcite may be 

the predominant mineralogical constituent. 

Soil solution dissolved organic matter content and pH typically have very strong positive 

and negative correlations, respectively, with the concentration of dissolved Pb species (Sauvé 

et al., 1998, 2000a, 2003; Weng et al., 2002; Badawy et al., 2002; Tipping et al., 2003). In the 

case of adsorption phenomena, the partitioning of Pb2+ to the solid phase is also controlled by 

total metal loading, i.e., high Pb loadings will result in a lower fraction being partitioned to the 

solid phase. Sauvé et al. (1997, 1998) demonstrated that only a fraction of the total Pb in 

solution was actually Pb2+ in soils treated with leaf compost. The fraction of Pb2+ to total 

dissolved Pb ranged from <1 to 60%, depending on pH and the availability of Pb-binding 

ligands. Nolan et al. (2003) used Donnan dialysis to show that 2.9 to 48.8% of the dissolved Pb 

was Pb2+ in pore waters of agricultural and contaminated soils from Australia and the United 

States. In acidic soils, Al species can compete for sites on natural organic matter and inhibit Pb 

binding to surfaces (Gustafsson et al., 2003). 

Differential pulse anodic stripping voltammetry (DPASV) is a technique that is useful for 

identifying relatively low concentrations of Pb2+ and has found many applications in adsorption 
 AX7-31 

and partitioning experiments. This technique has been particularly useful for quantifying the Kd, 

or partitioning ratio of Pb in the solid-to-liquid phase (Kd = [total solid-phase metal in mg kgΓ1

] / 

[dissolved metal in mg L!1

]). While the exact Kd value is a function of pH, organic matter 

content, substrate type, total metal burden, and concentrations of competing ligands, such studies 

typically show that Pb has very strong solid-phase partitioning. Partitioning ratios determined by 

DPASV generally range from 103 to 106 in soils in the typical pH range (Sauvé et al., 2000b). 

Aualiitia and Pickering (1987) used thin film ASV to compare the relative affinity of Pb for 

different inorganic particulates. They reported that Mn(IV) oxides completely adsorbed the Pb, 

regardless of pH in the range of 3 to 9, and had the highest affinity for Pb in their study. The 

adsorption of Pb to pedogenic Fe-oxides, Al-hydroxides, clay minerals, and Fe ores was reported 

to be pH-dependent. Sauvé et al. (1998) used DPASV to study the effects of organic matter and 

pH on Pb adsorption in an orchard soil. They demonstrated that Pb complexation to dissolved 

organic matter (DOM) increased Pb solubility, and that 30 to 50% of the dissolved Pb was bound 

to DOM at pH 3 to 4, while >80% of the dissolved Pb was bound to DOM at neutral pH. They 

concluded that in most soils, Pb in solution would not be found as Pb2+ but as bound to DOM. 

Sauvé et al. (2000a) compared the relative affinity of Pb2+ for synthetic ferrihydrite, leaf 

compost, and secondary oxide minerals collected from soils. They reported that the inorganic 

mineral phases were more efficient at lowering the amount of Pb2+ that was available in solution 

than the leaf compost. Glover et al. (2002) used DPASV in studying the effects of time and 

organic acids on Pb adsorption to goethite. They found that Pb adsorption to geothite was very 

rapid, and remained unchanged after a period of about 4 h. Lead desorption was found to be 

much slower. The presence of salicylate appeared to increase the amount of Pb that desorbed 

from goethite more so than oxalate. 

AX7.1.2.2 Tracing the Fate of Atmospherically-delivered Lead in Terrestrial Ecosystems 

Radiogenic Pb isotopes offer a powerful tool for separating anthropogenic Pb from natural 

Pb derived from mineral weathering (Erel and Patterson, 1994; Erel et al., 1997; Semlali et al., 

2001). This has been particularly useful for studying Pb in mineral soil, where geogenic Pb 

often dominates. The three radiogenic stable Pb isotopes (206Pb, 207Pb, and 208Pb) have a 

heterogeneous distribution in the earth’s crust primarily because of the differences in the halflives of their respective parents (238U, T1/2 = 4.7 × 109

 year; 235U, T1/2 = 0.7 × 109 year; 232Th, 
 AX7-32 

T1/2 = 14 × 109

 year). The result is that the ore bodies from which anthropogenic Pb are typically 

derived are usually enriched in 207Pb relative to 206Pb and 208Pb when compared with Pb found in 

granitic rocks. Graney et al. (1995) analyzed a dated core from Lake Erie, and found that the 

206Pb/207Pb value in sediment deposited in the late 1700s was 1.224, but in 20th-century 

sediment, the ratio ranged from 1.223 to 1.197. This shift in the Pb isotopic composition 

represents the introduction of a significant amount of anthropogenic Pb into the environment. 

Bindler et al. (1999) and Emmanuel and Erel (2002) analyzed the isotopic composition of Pb in 

soil profiles in Sweden and the Czech Republic, respectively, and determined that mineral soils 

immediately below the organic horizon had a mixture of both anthropogenic and geogenic Pb. 

Anthropogenic Pb has been detected relatively deep into the soil profile (>25 cm) in Europe, 

presumably this represents very “old”( i.e., pre-1900) Pb (Steinnes and Friedland, 2005). 

Erel and Patterson (1994) used radiogenic Pb isotopes to trace the movement of industrial 

Pb from topsoils to groundwaters to streams in a remote mountainous region of Yosemite 

National Park in California. They calculated that total 20th-century industrial Pb input to their 

study site was approximately 0.4 g Pb mΓ2

. Lead concentrations in organic material were highest 

in the upper soil horizons, and decreased with depth. During snowmelt, Pb in the snowpack was 

mixed with the anthropogenic and geogenic Pb already in the topsoil, and spring melts contained 

a mixture of anthropogenic and geogenic particulate Pb. During base flows, however, 80% of 

the Pb export from groundwater and streams was from natural granite weathering (Erel and 

Patterson, 1994). 

Uranium-238 series 210Pb also provides a tool for tracing atmospherically delivered Pb in 

soils. After 222Rn (T1/2 = 3.8 days) is produced from the decay of 226Ra (T1/2 = 1600 years), some 

fraction of the 222Rn escapes from rocks and soils to the atmosphere. It then decays relatively 

rapidly to 210Pb (T1/2 = 22.3 years), which has a tropospheric residence time of a few weeks 

(Koch et al., 1996). Fallout 210Pb is deposited onto forests via wet and dry deposition, similar to 

anthropogenic Pb deposition in forests, and is thus useful as a tracer for non-native Pb in soils. 

Lead-210 is convenient to use for calculating the residence time of Pb in soil layers, because its 

atmospheric and soil fluxes can be assumed to be in steady state at undisturbed sites (Dörr and 

Münnich, 1989; Dörr, 1995; Kaste et al., 2003). Atmospheric 210Pb (210Pbex hereafter,210Pb in 

“excess” of that supported by 222Rn in the soil) must be calculated by subtracting the amount of 
 AX7-33 

210Pb formed in soils by the in-situ decay of 222Rn from the total 210Pb (Moore and Poet, 1976; 

Nozaki et al., 1978). 

Benninger et al. (1975) measured fallout 210Pb in soils and streamwater at Hubbard Brook 

and at an undisturbed forest in Pennsylvania. They estimated atmospheric 210Pb export in 

streamwaters to be <0.02% of the standing 210Pb crop in the organic horizons. They used a 

simple steady-state model to calculate the residence time of Pb in the organic horizons to be 

5,000 years. This overestimate of the Pb residence time in the organic horizons was likely a 

result of the low resolution of their sampling. Since they only sampled the upper 6 cm of soil 

and the drainage waters, they did not accurately evaluate the distribution of 210Pb in the soil 

column in between. Dörr and Münnich (1989, 1991) used 210Pb profiles in soils of southern 

Germany to evaluate the behavior of atmospherically delivered Pb. They calculated the vertical 

velocity of Pb by dividing the relaxation depth (i.e., the depth at which 210Pb activity decreases to 

1/e, or approximately 37% of its surface value) by the 210Pb mean life of 32 years. They reported 

downward transit velocities of atmospherically deposited Pb at 0.89 ± 0.33 mm yearΓ1. The 

downward transport of atmospheric Pb was not affected by pH or soil type. However, since Pb 

velocities in the soil profile where identical to carbon velocities calculated with 14C, they 

concluded that Pb movement in forest soils is probably controlled by carbon transport. Kaste 

et al. (2003) used 210Pb to model the response time of atmospherically delivered Pb in the O 

horizon at Camel’s Hump Mountain in Vermont. They concluded that the forest floor response 

time was between 60 and 150 years, depending on vegetation zone and elevation. Using 

206Pb:207Pb, they also demonstrated that some gasoline-derived Pb migrated out of the O horizon 

and into the mineral soil in the deciduous vegetation zone on the mountain, while all of the 

atmospheric Pb was retained in the upper 20 cm of the soil profile. Klaminder et al. (2006) used 

210Pb distributions to calculate the residence time of Pb in soils of Northern Sweeden. They 

concluded that atmospheric Pb had a residence time of ~200 years in the mor layer of mature 

forests. They also provided evidence suggesting that forests in an earlier stage of ecological 

succession have a much shorter Pb residence time in the mor horizon (<50 years). 

Researchers assessing the fate of atmospheric Pb in soils have also relied on repeated 

sampling of soils and vegetation for total Pb (e.g., Zhang, 2003). This technique works best 

when anthropogenic Pb accounts for the vast majority of total Pb in a particular reservoir. 

Johnson et al. (1995a), Yanai et al. (2004), and Friedland et al. (1992) used O horizon (forest 
 AX7-34 

floor) time-series data to evaluate the movement of gasoline-derived Pb in the soil profile. These 

studies have concluded that the distribution of Pb in the upper soil horizons has changed over the 

past few decades. Yanai et al. (2004) documented a decline in Pb from the Oie horizon between 

the late 1970s to the early 1990s in remote forest soils in New Hampshire. Johnson et al. (1995a) 

and Friedland et al. (1992) demonstrated that some fraction of Pb had moved from the O horizon 

to the mineral soil during the 1980s at Hubbard Brook and at selected remote sites in the 

northeastern United States, respectively. Evans et al. (2005) demonstrated that Pb concentrations 

in the litter layer (fresh litter + Oi horizon) sampled in a transect from Vermont to Quebec 

decreased significantly between 1979 and 1996, reflecting a decrease in Pb deposition to forests 

and upper soil horizons during that time period. Miller et al. (1993) and Wang and Benoit 

(1997) used forest floor time-series data to model the response time (e folding time, the time it 

takes a reservoir to decrease to the 1/e, (ca. 37%) of its original amount) of Pb in the forest floor. 

Miller et al. (1993) calculated O horizon response times of 17 years for the northern hardwood 

forest and 77 years in the spruce-fir zone on Camel’s Hump Mountain in Vermont. Wang and 

Benoit (1997) determined that the O horizon would reach steady state with respect to Pb 

(1.3 μg gΓ1 Pb) by 2100. Both suggested that the vertical movement of organic particles 

dominated Pb transport in the soil profile. 

AX7.1.2.3 Inputs/Outputs of Atmospherically-delivered Lead in Terrestrial Ecosystems 

The concentration of Pb in contemporary rainfall in the mid-Atlantic and northeastern 

United States is on the order of 0.5 to 1 μg/L (Wang et al., 1995; Kim et al., 2000; Scudlark 

et al., 2005). Long-term trends in nine elemental concentrations (including Pb) in wet deposition 

were measured on the Delmarva Peninsula near Lewes, Delaware, over the period from 1982 to 

1989 (Figure AX7-1.2.1) (Scudlark et al., 1994). Of the nine elements measured, only Pb (and 

possibly Al and Cd), indicated a decreasing trend over time (3 μg/L in 1982 to <1.0 μg/L in 

1989). The authors attributed the dramatic decrease in Pb to the phasing out of Pb-alkyl 

additives from gasoline as mandated in the 1972 Clean Air Act. For comparison, rainfall 

measured in Los Angeles (CA) during 2003-2004 averaged 0.15 μg/L, but showed nearly an 

order-of-magnitude variation, presumably because of the arid environmental (Sabin et al., 2005). 

See also Table 2-22 for additional rainfall information. 
 AX7-35 

Figure AX7-1.2.1. Long-term (1982-1989) annual trends in lead concentrations (μg/L) in 

Lewes, Delaware precipitation. 

Source: Scudlark et al. (1994) 

The role of dry deposition in the total deposition of Pb to terrestrial ecosystems is not 

constrained well. Researchers have estimated that dry deposition accounts for anywhere 

between 10 to >90% of total Pb deposition (Galloway et al., 1982; Wu et al., 1994; Sabin et al., 

2005). Migon et al. (1997) found total, wet, and dry Pb deposition to be 8.6, 1.6 and 

7.0 μg/m2/d, respectively, over the Ligurian Sea, France. Dry deposition velocities were 

estimated at approximately 0.2 cm/sec, similar to anthropogenic element deposition velocities 

measured at remote lakes around Lake Michigan (Yi et al., 2001). Yi et al. (2001) found that dry 

deposition velocities for elements were correlated with particle concentrations in the following 

order: coarse > total particle > fine particle. Refer to Table 2-21 for additional information on 

dry, wet, and total Pb deposition velocities and fluxes. 

Arid environments appear to have a much higher fraction of dry deposition: total 

deposition (Sabin et al., 2005). Furthermore, it is possible that Clean Air Act Legislation enacted 

in the late 1970s preferentially reduced Pb associated with fine particles, so the relative 
 AX7-36 

contributions of dry deposition may have changed in the last few decades. If the major source of 

Pb to a terrestrial ecosystem is resuspended particulates from transportation corridors, then the 

particle size fraction that dominates deposition may be relatively coarse (>50 μm) relative to 

other atmospheric sources (Pirrone et al., 1995; Sansalone et al., 2003). 

Total contemporary loadings to terrestrial ecosystems are approximately 1 to 2 mg mΓ2

year

Γ1

 (Wu et al., 1994; Wang et al., 1995; Simonetti et al., 2000; Sabin et al., 2005). This is a 

relatively small annual flux of Pb if compared to the reservoir of approximately 0.5 to 4 g mΓ2 of 

gasoline-derived Pb that is already in surface soils over much of the United States (Friedland 

et al., 1992; Miller and Friedland, 1994; Erel and Patterson, 1994; Marsh and Siccama, 1997; 

Yanai et al., 2004; Johnson et al., 2004; Evans et al., 2005). While vegetation can play an 

important role in sequestering Pb from rain and dry deposition (Russell et al., 1981), direct 

uptake of Pb from soils by plants appears to be low (Klaminder et al., 2005). High elevation 

areas, particularly those near the base level of clouds often have higher burdens of atmospheric 

contaminants (Siccama, 1974). A Pb deposition model by Miller and Friedland (1994) predicted 

2.2 and 3.5 g Pb mΓ2

 deposition for the 20th century in the deciduous zone (600 m) and the 

coniferous zone (1000 m), respectively. More recently, Kaste et al. (2003) used radiogenic 

isotope measurements on the same mountain to confirm higher loadings at higher elevation. 

They measured 1.3 and 3.4 g gasoline-derived Pb mΓ2 in the deciduous zone and coniferous 

zones, respectively. Higher atmospheric Pb loadings to higher elevations are attributed to 

(1) the higher leaf area of coniferous species, which are generally more prevalent at high 

elevation; (2) higher rainfall at higher elevation; and (3) increased cloudwater impaction at high 

elevation (Miller et al., 1993). 

Although inputs of Pb to ecosystems are currently low, Pb export from watersheds via 

groundwater and streams is substantially lower than inputs. Therefore, even at current input 

levels, watersheds are accumulating industrial Pb. However, burial/movement of lead over time 

down into lower soil/sediment layers also tends to sequester it away from more biologically 

active parts of the watershed (unless later disturbed or redistributed, e.g., by flooding, dredging, 

etc.). Seeps and streams at the HBEF have Pb concentrations on the order of 10 to 30 pg Pb gΓ1

(Wang et al., 1995). At a remote valley in the Sierra Nevada, Pb concentrations in streamwaters 

were on the order of 15 pg Pb gΓ1 (Erel and Patterson, 1994). Losses of Pb from soil horizons are 

assumed to be via particulates (Dörr and Münnich, 1989; Wang and Benoit, 1996, 1997). Tyler 
 AX7-37 

(1981) noted that Pb losses from a spruce forest A-horizon soil in Sweden were influenced by 

season; with highest Pb fluxes being observed during warm, wet months. He suggested that 

DOC production and Pb movement were tightly linked. 

Surface soils across the United States are enriched in Pb relative to levels expected from 

solely natural geogenic inputs (Friedland et al., 1984; Herrick and Friedland, 1990; Francek, 

1992; Erel and Patterson, 1994; Marsh and Siccama, 1997; Yanai et al., 2004; Murray et al., 

2004). While some of this contaminant Pb is attributed to paint, salvage yards, shooting ranges, 

and the use of Pb arsenate as a pesticide in localized areas (Francek, 1997), Pb contamination of 

surface soils is essentially ubiquitous because of atmospheric pollution associated with metal 

smelting and production, the combustion of fossil fuels, and waste incineration (Newhook et al., 

2003; Polissar et al., 2001). Surface soils in Michigan, for example, typically range from 8 to 

several hundred ppm Pb (Francek, 1992; Murray et al., 2004). Soils collected and analyzed 

beneath 50 cm in Michigan, however, range only from 4 to 60 ppm Pb (Murray et al., 2004). 

In remote surface soils from the Sierra Nevada Mountains, litter and upper soil horizons are 20 to 

40 ppm Pb, and approximately 75% of this Pb has been attributed to atmospheric deposition 

during the 20th century (Erel and Patterson, 1994). Repeated sampling of the forest floor 

(O horizon) in the northeastern United States demonstrates that the organic layer has retained 

much of the Pb load deposited on ecosytems during the 20th century. Total Pb deposition during 

the 20th century has been estimated at 1 to 3 g Pb mΓ2

, depending on elevation and proximity to 

urban areas (Miller and Friedland, 1994; Johnson et al., 1995a). Forest floors sampled during the 

1980s and 1990s, and in early 2000 had between 0.7 and 2 g Pb mΓ2

 (Friedland et al., 1992; 

Miller and Friedland, 1994; Johnson et al., 1995a; Kaste et al., 2003; Yanai et al., 2004; Evans 

et al., 2005). The pool of Pb in above- and below-ground biomass at the HBEF is on the order of 

0.13 g Pb mΓ2 (Johnson et al., 1995a). 

The amount of Pb that has leached into mineral soil appears to be on the order of 20 to 

50% of the total anthropogenic Pb deposition. Kaste et al. (2003) and Miller and Friedland 

(1994) demonstrated that Pb loss from the forest floor at Camel’s Hump Mountain in Vermont 

depended on elevation. While the mineral soil in the deciduous forest had between 0.4 and 0.5 g 

Pb mΓ2

 (out of 1 to 2 g Pb mΓ2 in the total soil profile), at higher elevations the thicker coniferous 

forest floor retained more than 90% of the total Pb deposition (Kaste et al., 2003). Johnson et al. 

(1995a) determined that the forest floor at HBEF in the mid-1980s had about 0.75 g Pb mΓ2

. 
 AX7-38 

Compared to their estimated 20th-century atmospheric Pb deposition of 0.9 g Pb mΓ2

, the forest 

floor has retained 83% of the atmospheric Pb loadings (Johnson et al., 1995a). Johnson et al. 

(2004) noted that gasoline-derived Pb was a significant component of the labile Pb at the HBEF. 

They calculated that Pb fluxes to the HBEF by atmospheric pollution were essentially equivalent 

to the Pb released by mineral weathering over the past 12,000 years. Marsh and Siccama (1997) 

used the relatively homogenous mineral soils underneath formerly plowed land in Rhode Island, 

New Hampshire and Connecticut to assess the depth-distribution of atmospheric Pb. They 

reported that 65% of the atmospheric Pb deposited during the 20th century is in the mineral soil 

and 35% is in the forest floor. At their remote study site in the Sierra Nevada Mountains, Erel 

and Patterson (1994) reported that most of the anthropogenic Pb was associated with the humus 

fraction of the litter layer and soils sampled in the upper few cm. 

Atmospherically delivered Pb is probably present in ecosystems in a variety of different 

biogeochemical phases. A combination of Pb adsorbtion processes and the precipitation of Pb 

minerals will typically keep dissolved Pb species low in soil solution, surface waters, and 

streams (Sauvé et al., 2000a; Jackson et al., 2005). While experimental and theoretical evidence 

suggest that the precipitation of inorganic Pb phases and the adsorption of Pb on inorganic 

phases can control the biogeochemistry of contaminant Pb (Nriagu, 1974; Ruby et al., 1994; 

Jackson et al., 2005), the influence of organic matter on the biogeochemistry of Pb in terrestrial 

ecosystems cannot be ignored in many systems. Organic matter can bind to Pb, preventing Pb 

migration and the precipitation of inorganic phases (Manceau et al., 1996; Xia et al., 1997; Lang 

and Kaupenjohann, 2003). As the abundance of organic matter declines in soil, Pb adsorption to 

inorganic soil minerals and the direct precipitation of Pb phases may dominate the 

biogeochemistry of Pb in terrestrial ecosystems (Ostergren et al., 2000a,b; Sauvé et al., 2000a). 

Conclusions 

Advances in technology since the 1986 Lead AQCD have allowed for a quantitative 

determination of the mobility, distribution, uptake, and fluxes of atmospherically delivered Pb in 

ecosystems. Among other things, these studies have shown that industrial Pb represents a 

significant fraction of total labile Pb in watersheds. Selective chemical extractions and 

synchrotron-based X-ray studies have shown that industrial Pb can be strongly sequestered by 

organic matter and by secondary minerals such as clays and oxides of Al, Fe, and Mn. Some of 
 AX7-39 

these studies have provided compelling evidence that the biomineralization of Pb phosphates by 

soil organisms can play an important role in the biogeochemistry of Pb. Surface soils sampled 

relatively recently demonstrate that the upper soil horizons (O + A horizons) are retaining most 

of the industrial Pb burden introduced to the systems during the 20th century. The migration and 

biological uptake of Pb in ecosystems is relatively low. The different biogeochemical behaviors 

of Pb reported by various studies may be a result of the many different analytical techniques 

employed, or they may be a result of natural variability in the behavior of Pb in different 

systems. 

Lead Uptake into Plants 

Plants take up Pb via their foliage and through their root systems (U.S. Environmental 

Protection Agency, 1986a; Påhlsson, 1989). Surface deposition of Pb onto plants may represent 

a significant contribution to the total Pb in and on the plant, as has been observed for plants near 

smelters and along roadsides (U.S. Environmental Protection Agency, 1986a). The importance 

of atmospheric deposition on above-ground plant Pb uptake is well-documented (Dalenberg and 

Van Driel, 1990; Jones and Johnston, 1991; Angelova et al., 2004). Data examined from 

experimental grassland plots in southeast England demonstrated that atmospheric Pb is a greater 

contributor than soil-derived Pb in crop plants and grasses (Jones and Johnston, 1991). A study 

by Dalenberg and Van Driel (1990) showed that 75 to 95% of the Pb found in field-grown test 

plants (i.e., the leafy material of grass, spinach, and carrot; wheat grain; and straw) was from 

atmospheric deposition. Angelova et al. (2004) found that tobacco grown in an industrial area 

accumulated significant amounts of Pb from the atmosphere, although uptake from soil was also 

observed. The concentration of Pb in tobacco seeds was linearly related to the concentration of 

Pb in the exchangeable and carbonate-bound fractions of soil, as measured using sequential 

extraction (Angelova et al., 2004). Lead in soil is more significant when considering uptake into 

root vegetables (e.g., carrot, potato), since, as was noted in the 1986 Lead AQCD (U.S. 

Environmental Protection Agency, 1986a), most Pb remains in the roots of plants. 

There are two possible mechanisms (symplastic or apoplastic) by which Pb may enter the 

root of a plant. The symplastic route is through the cell membranes of root hairs; this is the 

mechanism of uptake for water and nutrients. The apoplastic route is an extracellular route 

between epidermal cells into the intercellular spaces of the root cortex. Previously, Pb was 
 AX7-40 

thought to enter the plant via the symplastic route, probably by transport mechanisms similar to 

those involved in the uptake of calcium or other divalent cations (i.e., transpirational mass flow, 

diffusion, or active transport). However, it also had been speculated that Pb may enter the plant 

via the apoplastic route (U.S. Environmental Protection Agency, 1986a). Sieghardt (1990) 

determined that the mechanism of Pb uptake was via the symplastic route only and that the 

apoplastic pathway of transport was stopped in the primary roots by the endodermis. He studied 

the uptake of Pb into two plants, Minuartia verna (moss sandwort) and Silene vulgaris (bladder 

campion) that colonize metal-contaminated sites. In the roots of both plants, Pb was found 

mainly in the root cortex. Active ion uptake was required to transport the Pb into the stele and 

then into the shoots of the plant (Sieghardt, 1990). 

Although some plants translocate more Pb to the shoots than others, most Pb remains in 

the roots of plants. Two mechanisms have been proposed to account for this relative lack of 

translocation to the shoots: (1) Pb may be deposited within root cell wall material, or (2) Pb may 

be sequestered within root cell organelles (U.S. Environmental Protection Agency, 1986a). 

Påhlsson (1989) noted that plants can accumulate large quantities of Pb from the soil but that 

translocation to shoots and leaves is limited by the binding of Pb ions at root surfaces and cell 

walls. In a study by Wierzbicka (1999), 21 different plant species were exposed to Pb2+ in the 

form of Pb-chloride. The plant species included cucumber (Cucumis sativus), soy bean (Soja 

hispida), bean (Phaseolus vulgaris), rapeseed (Brassica napus), rye (Secale cereale), barley 

(Hordeum vulgare), wheat (Triticum vulgare), radish (Raphanus sativus), pea (Pisum sativum), 

maize (Zea mays), onion (Allium cepa), lupine (Lupinus luteus), bladder campion (Silene 

vulgaris), Buckler mustard (Biscutella laevigata), and rough hawkbit (Leontodon hispidus). 

Although, the amount of Pb taken up by the plant varied with species, over 90% of absorbed Pb 

was retained in the roots. Only a small amount of Pb was translocated (~2 to 4%) to the shoots 

of the plants. Lead in roots was present in the deeper layers of root tissues (in particular, the root 

cortex) and not only on the root surface. There was no correlation between Pb tolerance 

(measured as root mass increase expressed as a percentage of controls) and either root or shoot 

tissue concentrations (Wierzbicka, 1999). The study by Wierzbicka (1999) was the first to report 

that plants developing from bulbs, in this case the onion, were more tolerant to Pb than plants 

developing from seeds. This tolerance was assumed to be related to the large amounts of Pb that 

were transported from the roots and stored in the bulb of the plant (Wierzbicka, 1999). 
 AX7-41 

(AX7-1) 

Uptake of Pb from soil into plants was modeled as part of Eco-SSL development (U.S. 

Environmental Protection Agency, 2005a). The relationship derived between Pb in the soil and 

Pb in a plant was taken from Bechtel Jacobs Company (BJC) (1998) and is as follows: 

Ln(Cp) = 0.561 * Ln(Csoil) − 1.328 

where Cp is the concentration of Pb in the plant (dry weight) and Csoil is the concentration of Pb 

in the soil. This equation recognizes that the ratio of Pb concentration in plant to Pb 

concentration in soil is not constant. 

Invertebrates 

There was no clear evidence suggesting a differential uptake of Pb into different species 

of earthworm (Lumbricus terrestris, Aporrectodea rosea, and A. caliginosa) collected around a 

smelter site near Avonmouth, England (Spurgeon and Hopkin, 1996a). This is in contrast to Pižl 

and Josens (1995) and Terhivuo et al. (1994) who found Aporrectodea spp. accumulated more 

Pb than Lumbricus. The authors suggested that these differences could be due to different 

feeding behaviors, as Lumbricus feeds on organic material and Apporectodea species are 

geophagus, ingesting large amounts of soil during feeding. The differences between species also 

may be related to differing efficiencies in excretory mechanisms (Pižl and Josens, 1995). 

However, the interpretation of species difference is complicated by a number of potentially 

confounding variables, such as soil characteristics (e.g., calcium or other nutrient levels) 

(Pižl and Josens, 1995). 

The bioaccumulation of Pb from contaminated soil was tested using the earthworm 

Eisenia fetida, and the amount of Pb accumulated did not change significantly until the 

concentration within soil reached 5000 mg/kg (Davies et al., 2003). This coincided with the 

lowest soil concentrations at which earthworm mortality was observed. The ratio of the 

concentration of Pb in worms to the concentration in soil decreased from 0.03 at 100 mg/kg to 

0.001 at 3000 mg/kg, but then increased quickly to 0.02 at 5000 mg/kg. The authors concluded 

that earthworms exhibit regulated uptake of Pb at levels of low contamination (<3000 mg/kg) 

until a critical concentration is reached, at which point this mechanism breaks down, resulting in 

unregulated accumulation and mortality. This study was conducted using test methods where 
 AX7-42 

(AX7-2) 

soil was not allowed to equilibrate following the addition of Pb and prior to the addition of the 

test organisms. This may have resulted in an increased bioavailability and overestimated Pb 

toxicity relative to actual environmental conditions (Davies et al., 2003). See the discussion in 

Section AX7.1.2 on the effects of aging on Pb sorption processes. 

Lock and Janssen (2002) and Bongers et al. (2004) found that Pb-nitrate was more toxic 

than Pb-chloride to survival and reproduction of the springtail Folsomia candida. However, 

percolation (removal of the chloride or nitrate counterion) caused a significant decrease in Pbnitrate toxicity such that there was no difference in toxicity once the counterion was removed 

(Bongers et al., 2004). No change in toxicity was observed for Pb-chloride once the chloride 

was removed from the soil. Bongers et al. (2004) suggested that the nitrate ion was more toxic 

than the chloride ion to springtails. 

Uptake of Pb from soil into earthworms was also modeled as part of Eco-SSL 

development (U.S. Environmental Protection Agency, 2005a). The relationship derived between 

Pb in the soil and Pb in an earthworm was taken from Sample et al. (1999) and is as follows: 

Ln(Cworm) = 0.807 * Ln(Csoil) – 0.218 

where Cworm is the concentration of Pb in the earthworm (dry weight) and Csoil is the 

concentration of Pb in the soil. This equation recognizes that the ratio of Pb concentration in 

worm to Pb concentration in soil is not constant. 

Wildlife 

Research has been conducted to determine what Pb concentrations in various organs 

would be indicative of various levels of effects. For example, Franson (1996) compiled data to 

determine what residue levels were consistent with three levels of effects in Falconiformes (e.g., 

falcons, hawks, eagles, kestrels, ospreys), Columbiformes (e.g., doves, pigeons), and Galliformes 

(e.g., turkey, pheasant, partridge, quail, chickens). The three levels of effect were (1) subclinical, 

which are physiological effects only, such as the inhibition of δ-aminolevulinic acid dehydratase 

(ALAD; see Section AX7.1.3.3); (2) toxic, a threshold level marking the initiation of clinical 

signs, such as anemia, lesions in tissues, weight loss, muscular incoordination, green diarrhea, 

and anorexia; and (3) compatible with death, an approximate threshold value associated with 
 AX7-43 

death in field, captive, and/or experimental cases of Pb poisoning. The tissue Pb levels 

associated with these levels of effects are presented in Table AX7-1.2.1. 

Table AX7-1.2.1. Tissue Lead Levels in Birds Causing Effects 

(taken from Franson, 1996) 

Order 

Blood 

(μg/dL) 

Liver 

(ppm wet wt.) 

Kidney 

(ppm wet wt.) 

Falconiformes 

 Subclinical 0.2 – 1.5 2 – 4 2 – 5 

 Toxic >1 >3 >3 

 Compatible with death >5 >5 >5 

Columbiformes 

 Subclinical 0.2 – 2.5 2 – 6 2 – 20 

 Toxic >2 >6 >15 

 Compatible with death >10 >20 >40 

Galliformes 

 Subclinical 0.2 – 3 2 – 6 2 – 20 

 Toxic >5 >6 >15 

 Compatible with death >10 >15 >50 

Tissue residue levels below the subclinical levels in Table AX7-1.2.1 should be 

considered “background” (Franson, 1996). Levels in the subclinical range are indicative of 

potential injury from which the bird would probably recover if Pb exposure was terminated. 

Toxic residues could lead to death. Residues above the compatible-with-death threshold are 

consistent with Pb-poisoning mortality (Franson, 1996). Additional information on residue 

levels for Passeriformes (e.g., sparrows, starlings, robins, cowbirds), Charadriiformes (e.g., gulls, 

terns), Gruiformes (e.g., cranes), Ciconiformes (e.g., egrets), Gaviformes (e.g., loons), and 

Strigiformes (e.g., owls) is available in Franson (1996). Scheuhammer (1989) found blood Pb 

concentrations of between 0.18 and 0.65 μg/mL in mallards corresponded to conditions 

associated with greater than normal exposure to Pb but that should not be considered Pb 

poisoning. 
 AX7-44 

(AX7-3) 

Lead concentrations in various tissues of mammals also have been correlated with toxicity 

(Ma, 1996). The tissues commonly analysed for Pb are blood, liver, and kidney. Typical 

baseline levels of blood Pb are approximately 4 to 8 μg/dL for small mammals, and 2 to 6 μg/dL 

for mature cattle. Typical baseline levels of Pb in liver are 1 to 2 mg/kg dw for small mammals. 

Typical baseline levels of Pb in kidney are 0.2 to 1.5 mg/kg dw for mice and voles, but shrews 

typically have higher baseline levels of 3 to 19 mg/kg dw. Ma (1996) concluded that Pb levels 

less than 5 mg/kg dw in liver and 10 mg/kg dw in kidney were not associated with toxicity, but 

that levels greater than 5 mg/kg dw in liver and greater than 15 mg/kg dw in kidney could be 

taken as a chemical biomarker of toxic exposure to Pb in mammals. Humphreys (1991) noted 

that the concentrations of Pb in liver and kidney can be elevated in animals with normal blood Pb 

concentrations (and without exhibiting clinical signs of Pb toxicity), because Pb persists in these 

organs longer than in blood. 

Uptake of Pb from soil into small mammals was also modeled as part of Eco-SSL 

development (U.S. Environmental Protection Agency, 2005a). The relationship derived between 

Pb in the soil and Pb in the whole-body of a small mammal was taken from Sample et al. (1998) 

and is as follows: 

Ln(Cmammal) = 0.4422 * Ln(Csoil) + 0.0761 

Where Cmammal is the concentration of Pb in small mammals (dry weight) and Csoil is the 

concentration of Pb in the soil. Similar to the uptake equations for plants (Eq. 8-1) and 

earthworms (Eq 8-2), the equation for mammalian uptake recognizes that the ratio of Pb 

concentration in small mammals to Pb concentration in soil is not constant. 

AX7.1.2.4 Resistance Mechanisms 

Many mechanisms related to heavy metal tolerance in plants and invertebrates have been 

described, including avoidance (i.e., root redistribution, food rejection), exclusion (i.e., selective 

uptake and translocation), immobilization at the plant cell wall, and excretion (i.e., foliar 

leakage, moulting) (Tyler et al., 1989; Patra et al., 2004). The following section reviews the 

recent literature on the resistance mechanisms of plants and invertebrates through mitigation of 

Pb (1) toxicity or (2) exposure. 
 AX7-45 

Detoxification Mechanisms 

Lead sequestration in cell walls may be the most important detoxification mechanism in 

plants. Calcium may play a role in this detoxification by regulating internal Pb concentrations 

through the formation of Pb-containing precipitates in the cell wall (Antosiewicz, 2005). Yang 

et al. (2000) screened 229 varieties of rice (Oryza sativa) for tolerance or sensitivity to Pb and 

found that the oxalate content in the root and root exudates was increased in Pb-tolerant varieties. 

The authors suggested that the oxalate reduced Pb bioavailability, and that this was an important 

tolerance mechanism (Yang et al., 2000). Sharma et al. (2004) found Pb-sulfur and Pb-sulfate in 

the leaves, and Pb-sulfur in the roots of Sesbania drummondii (Rattlebox Drummond), a Pb 

hyperaccumulator plant grown in Pb-nitrate solution. They hypothesized that these sulfur 

ligands were indicative of glutathione and phytochelatins, which play a role in heavy metal 

homeostasis and detoxification (Sharma et al., 2004). 

Sea pinks (Armeria maritima) grown on a metal-contaminated site (calamine spoils more 

than 100 years old) accumulated 6Η the concentrations of Pb in brown (dead and withering) 

leaves than green leaves (Szarek-Lukaszewska et al., 2004). The concentration of Pb in brown 

leaves was similar to that in roots. This greater accumulation of Pb into older leaves was not 

observed in plants grown hydroponically in the laboratory. The authors hypothesized that this 

sequestering of Pb into the oldest leaves was a detoxification mechanism (Szarek-Lukaszewska 

et al., 2004). 

Terrestrial invertebrates also mitigate Pb toxicity. Wilczek et al. (2004) studied two 

species of spider, the web-building Agelena labyrinthica, and the active hunter wolf spider 

Pardosa lugubris. The activity of metal detoxifying enzymes (via the glutathione metabolism 

pathways) was greater in A. labyrinthica and in females of both species (Wilczek et al., 2004). 

Marinussen et al. (1997) found that earthworms can excrete 60% of accumulated Pb very 

quickly once exposure to Pb-contaminated soils has ended. However, the remainder of the body 

burden is not excreted, possibly due to the storage of Pb in waste nodules that are too large to be 

excreted (Hopkin, 1989). Gintenreiter et al. (1993) found that Lepidoptera larvae (in this case, 

the gypsy moth Lymantria dispar) eliminated Pb, to some extent, in the meconium (the fluid 

excreted shortly after emergence from the chrysalis). 

Lead, in the form of pyromorphite (Pb5(PO4)3Cl), was localized in the anterior pharynx 

region of the nematode Ceanorhabditis elegans (Jackson et al., 2005). The authors hypothesized 
 AX7-46 

that the nematode may detoxify Pb via its precipitation into pyromorphite, which is relatively 

insoluble (Jackson et al., 2005). 

Avoidance Response 

Studies with soil invertebrates hypothesize that these organisms may avoid soil with high 

Pb concentrations. For example, Bengtsson et al. (1986) suggested that the lower Pb 

concentrations in earthworm tissues may be a result of lowered feeding activity of worms at 

higher Pb concentrations in soil. 

AX7.1.2.5 Physiological Effects of Lead 

Several studies have measured decreased blood ALAD activity in birds and mammals 

exposed to Pb (U.S. Environmental Protection Agency, 1986a). Recent studies on the 

physiological effects of Pb to consumers have focused on heme synthesis (as measured by 

ALAD activity and protoporphyrin concentration), lipid peroxidation, and production of fatty 

acids. Effects on growth are covered in Section AX7.1.4. 

Biochemically, Pb adversely affects hemoglobin synthesis in birds and mammals. Early 

indicators of Pb exposure in birds and mammals include decreased blood ALAD concentrations 

and increased protoporphyrin IX activity. The effects of Pb on blood parameters and the use of 

these parameters as sensitive biomarkers of exposure has been well documented (Eisler, 1988; 

U.S. Environmental Protection Agency, 2005b). However, the linkage between these 

biochemical indicators and ecologically relevant effects is less well understood. Low-level 

inhibition of ALAD is not generally considered a toxic response, because this enzyme is thought 

to be present in excess concentrations; rather, it may simply indicate that the organism has 

recently been exposed to Pb (Henny et al., 1991). 

Schlick et al. (1983) studied ALAD inhibition in mouse bone marrow and erythrocytes. 

They estimated that an absorbed dose of between 50 and 100 μg Pb-acetate/kg body weight per 

day would result in long-term inhibition of ALAD. 

Beyer et al. (2000) related blood Pb to sublethal effects in waterfowl along the 

Coeur d=Alene River near a mining site in Idaho. The sublethal effects measured included, 

among others, red blood cell ALAD activity and protoporphyrin levels in the blood. As found in 

other studies, ALAD activity was the most sensitive indicator of Pb exposure, decreasing to 3% 
 AX7-47 

of the reference value at a blood Pb concentration of 0.68 mg/kg ww (wet weight). 

Protoporphyrin concentrations showed a 4.2-fold increase at this same concentration. 

Henny et al. (1991) studied osprey along the Coeur d=Alene River. There were no 

observations of death, behavioral abnormalities, or reduced productivity related to Pb exposure, 

although inhibition of blood ALAD and increased protoporphyrin concentrations were measured 

in ospreys. Henny et al. (1991) hypothesized that no impacts to osprey were observed, even 

though swan mortality was documented in the area because swans feed at a lower trophic level 

(i.e., Pb does not biomagnify, and thus is found at higher concentrations in lower trophic level 

organisms). 

Hoffman et al. (2000a) also studied the effects of Coeur d’Alene River sediment on 

waterfowl, focusing on mallard ducklings for 6 weeks after hatching. The study revealed that a 

90% reduction in ALAD activity and a greater than 3-fold increase in protoporphyrin 

concentration occurred when blood Pb reached a concentration of 1.41 mg/kg ww as a result of 

the ducklings being fed a diet composed of 12% sediment (3449 mg/kg Pb). Those ducklings 

fed a diet composed of 24% sediment were found to have a mean blood Pb concentration of 

2.56 mg/kg ww and a greater than 6-fold increase in protoporphyrin concentration. Hoffman 

et al. (2000b) also studied Canada Geese (Branta canadensis) goslings in a similar fashion. 

The results revealed that, while blood Pb concentrations in goslings were approximately half 

(0.68 mg/kg ww) of those found in ducklings under the same conditions (12% diet of 

3449 mg/kg sediment Pb), goslings showed an increased sensitivity to Pb exposure. Goslings 

experienced a 90% reduction in ALAD activity and a 4-fold increase in protoporphyrin 

concentration, similar to conditions found in the ducklings, although blood Pb concentrations 

were half those found in the ducklings. More serious effects were seen in the goslings when 

blood Pb reached 2.52 mg/kg, including decreased growth and mortality. 

Redig et al. (1991) reported a hawk LOAEL (lowest observed adverse effect level) of 

0.82 mg/kg-day for effects on heme biosynthetic pathways. Lead dosages as high as 1.64 to 

6.55 mg/kg-day caused neither mortality nor clinical signs of toxicity. A dose of 6.55 mg/kg-day 

resulted in blood Pb levels of 1.58 μg/mL. There were minimal changes in immune function 

(Redig et al., 1991). 

Repeated oral administration of Pb resulted in biochemical alterations in broiler chickens 

(Brar et al., 1997a,b). At a dose of 200 mg/kg-day Pb-acetate, there were significant increases in 
 AX7-48 

plasma levels of uric acid and creatinine and significant declines in the levels of total proteins, 

albumin, glucose, and cholesterol. Brar et al. (1997a) suggested that increased uric acid and 

creatinine levels could be due to an accelerated rate of protein catabolism and/or kidney damage. 

They also suggested that the decline in plasma proteins and albumin levels may be caused by 

diarrhea and liver dysfunction due to the Pb exposure. Brar et al. (1997b) also found that 

significant changes in plasma enzymes may be causing damage to other organs. 

Lead can cause an increase in tissue lipid peroxides and changes in glutathione 

concentrations, which may be related to peroxidative damage of cell membranes (Mateo and 

Hoffman, 2001). There are species-specific differences in resistance to oxidative stress (lipid 

peroxidation), which may explain why Canada geese are more sensitive to Pb poisoning than 

mallards (Mateo and Hoffman, 2001). Lead also caused an increase in the production of the fatty 

acid arachidonic acid, which has been associated with changes in bone formation and immune 

response (Mateo et al., 2003a). The effects observed by Mateo et al. (2003a,b) were associated 

with very high concentrations of Pb in the diet (1840 mg Pb/kg diet), much higher than would be 

found generally in the environment, and high enough that birds decreased their food intake. 

Lead also induces lipid peroxidation in plants. Rice plants exposed to a highly toxic level 

of Pb (1000 μM in nutrient solution) showed elevated levels of lipid peroxides, increased activity 

of superoxide dismutase, guaiacol peroxidase, ascorbate peroxidase, and glutatione reductase 

(Verma and Dubey, 2003). The elevated levels of these enzymes suggest the plants may have an 

antioxidative defense mechanism against oxidative injury caused by Pb (Verma and Dubey, 

2003). 

AX7.1.2.6 Factors that Modify Organism Response 

Research has demonstrated that Pb may affect survival, reproduction, growth, 

metabolism, and development in a wide range of species. These effects may be modified by 

chemical, biological, and physical factors. The factors that modify responses of organisms to Pb 

are described in the following sections. 

Genetics 

Uptake and toxicity of Pb to plants are influenced strongly by the type of plant. Liu et al. 

(2003) found that Pb uptake and translocation by rice plants differed by cultivar (a cultivated 
 AX7-49 

variety of plant produced by selective breeding) but was not related to genotype. Twenty 

cultivars were tested from three genotypes. The differences in Pb concentrations among 

cultivars were smallest when comparing concentrations in the grains at the ripening stage. 

This study also found that toxicity varied by cultivar; at 800 mg Pb/kg soil, some cultivars 

were greatly inhibited, some were significantly improved, and others showed no change. 

Dearth et al. (2004) compared the response of Fisher 344 (F344) rats and Sprague-Dawley 

(SD) rats to exposure via gavage to 12 mg Pb/mL as Pb-acetate. Blood Pb levels in the F344 

dams were higher than those of the SD dams. Lead delayed the timing of puberty and 

suppressed hormone levels in F344 offspring. These effects were not observed in the offspring 

of SD rats, even when the dose was doubled. The authors conclude that F344 rats are more 

sensitive to Pb (Dearth et al., 2004). 

Biological Factors 

Several biological factors may influence Pb uptake and organism response, including 

organism age, sex, species, feeding guild, and, for plants, the presence of mycorrhizal fungi. 

Monogastric animals are more sensitive to Pb than ruminants (Humphreys, 1991). 

Younger organisms may be more susceptible to Pb toxicity (Eisler, 1988; Humphreys, 

1991). Nestlings are more sensitive to the effects of Pb than older birds, and young altricial birds 

(species unable to self-regulate body heat at birth, such as songbirds), are considered more 

sensitive than precocial birds (species that have a high degree of independence at birth, such as 

quail, ducks, and poultry) (Scheuhammer, 1991). 

Gender can also have an effect on the accumulation of Pb by wildlife (Eisler, 1988). 

Female birds accumulate more Pb than males (Scheuhammer, 1987; Tejedor and Gonzalez, 

1992). These and other authors have related this to the increased requirement for calcium in 

laying females. 

Different types of invertebrates accumulate different amounts of Pb from the environment 

(U.S. Environmental Protection Agency, 1986a). There may be species- and sex-specific 

differences in accumulation of Pb into invertebrates, specifically arthropods. This has been 

shown by Wilczek et al. (2004) who studied two species of spider, the web-building 

A. labyrinthica and the active hunter wolf spider P. lugubris. The body burdens of Pb in the 

wolf spider were higher than in the web-building spider, and this may be due to the more 
 AX7-50 

effective use of glutathione metabolism pathways in A. labyrinthica. Body burdens of females 

were lower than those of males in both species. This was also observed in spiders by Rabitsch 

(1995a). Females are thought to be able to detoxify and excrete excess metals more effectively 

than males (Wilczek et al., 2004). Lead accumulation has been measured in numerous species of 

arthropods with different feeding strategies. Differences were observed between species 

(Janssen and Hogervorst, 1993; Rabitsch, 1995a) and depending upon sex (Rabitsch, 1995a), 

developmental stage (Gintenreiter et al., 1993; Rabitsch, 1995a), and season (Rabitsch, 1995a). 

Uptake of Pb may be enhanced by symbiotic associations between plant roots and 

mycorrhizal fungi. Similar to the mechanism associated with increased uptake of nutrients, 

mycorrhizal fungi also may cause an increase in the uptake of Pb by increasing the surface area 

of the roots, the ability of the root to absorb particular ions, and the transfer of ions through the 

soil (U.S. Environmental Protection Agency, 1986a). There have been contradictory results 

published in the literature regarding the influence of mycorrhizal organisms on the uptake and 

toxicity of Pb to plants (see review in Påhlsson, 1989). Lin et al. (2004) found that the 

bioavailability of Pb increased in the rhizosphere of rice plants, although the availability varied 

with Pb concentration in soil. Bioavailability was measured as the soluble plus exchangeable Pb 

fraction from sequential extraction analysis. The authors hypothesized that the enhanced 

solubility of Pb may be due to a reduced pH in the rhizosphere or, more likely, the greater 

availability of organic ligands, which further stimulates microbial growth (Lin et al., 2004). 

Increased bioavailability of Pb in soil may increase the uptake of Pb into plants, although 

this was not assessed by Lin et al. (2004). However, Dixon (1988) found that red oak 

(Quercus rubra) seedlings with abundant ectomycorrhizae had lower Pb concentrations in their 

roots than those seedlings without this fungus, although only at the 100 mg Pb/kg sandy loam 

soil concentration (no differences were found at lower Pb concentrations). Lead in soil also was 

found to be toxic to the ectomycorrhizal fungi after 16 weeks of exposure to 50 mg Pb/kg or 

more (Dixon, 1988). Malcova and Gryndler (2003) showed that maize root exudates from 

mycorrhizal fungi can ameliorate heavy metal toxicity until a threshold metal concentration was 

surpassed. This may explain the conflicting results in the past regarding the uptake and toxicity 

of Pb to plants with mycorrhizal fungi. 

The type of food eaten is a major determinant of Pb body burdens in small mammals, with 

insectivorous animals accumulating more Pb than herbivores or granivores (U.S. Environmental 
 AX7-51 

Protection Agency, 1986a). In fact, the main issue identified by the EPA (U.S. Environmental 

Protection Agency, 1986a) related to invertebrate uptake of Pb was not toxicity to the 

invertebrates, but accumulation of Pb to levels that may be toxic to their consumers. Several 

authors suggest that shrews are a good indicator of metal contamination, because they tend to 

accumulate higher levels of metals than herbivorous small mammals (see data summary in 

Sample et al. (1998)). Shrews accumulate higher levels of metals in contaminated habitats, 

because their diet mainly consists of detritivores (i.e., earthworms) and other soil invertebrates in 

direct contact with the soil (Beyer et al., 1985). 

Physical/Environmental Factors 

Plants 

The uptake and distribution of Pb into higher plants from the soil is affected by various 

chemical and physical factors including the chemical form of Pb, the presence of other metal 

ions, soil type, soil pH, cation exchange capacity (CEC), the amount of Fe/Mn-oxide films 

present, organic matter content, temperature, light, and nutrient availability. A small fraction of 

Pb in soil may be released into the soil water, which is then available to be taken up by plants 

(U.S. Environmental Protection Agency, 1986a). 

The form of Pb has an influence on its toxicity to plants. For example, Pb-oxide is less 

toxic than more bioavailable forms such as Pb-chloride or Pb-acetate. In a study by Khan and 

Frankland (1983), radish plants were exposed to Pb-oxide and Pb-chloride in a loamy sand at pH 

5.4, in a 42-day study. In a tested concentration range of 0 to 5000 mg/kg, root growth was 

inhibited by 24% at 500 mg/kg for Pb-chloride and an EC50 of 2400 mg/kg was calculated from a 

dose-response curve. Plant growth ceased at 5000 mg/kg and shoots exhibited an EC50 of 

2800 mg/kg. For Pb-oxide exposure (concentration range of 0 to 10,000 mg/kg), reported results 

indicate an EC50 of 12,000 mg/kg for shoot growth and an EC50 of 10,000 mg/kg for root growth. 

There was no effect on root growth at 500 mg/kg and a 26% reduction at 1000 mg/kg Pb oxide. 

Soil pH is the most influential soil property with respect to uptake and accumulation of Pb 

into plant species. This is most likely due to increased bioavailability of Pb created by low soil 

pH. At low soil pH conditions, markedly elevated Pb toxicity was reported for red spruce 

(P. rubens) (Seiler and Paganelli, 1987). At a soil pH of 4.5, ryegrass (Lolium hybridum) 
 AX7-52 

and oats (Avena sativa) had significantly higher Pb concentrations after 3 months of growth 

compared to plants grown at pH 6.4 (Allinson and Dzialo, 1981). 

Invertebrates 

The uptake of Pb into invertebrates depends on the physical environment and parameters 

such as pH, calcium concentration, organic matter content, and CEC. Greater accumulation is 

found generally when the soil pH or organic content is lower (U.S. Environmental Protection 

Agency, 1986a). 

Soil pH has a significant influence on uptake of Pb into invertebrates. Perämäki et al. 

(1992) studied the influence of soil pH on uptake into the earthworm Aporrectodea caliginosa. 

Lead accumulation was lowest at the highest pH values, but there was no statistical difference 

due to variability in the data. Variability in the response also was found by Bengtsson et al. 

(1986), who reared earthworms (Dendrobaena rubida) in acidified soils at pH 4.5, 5.5, or 6.5. 

Lead uptake into worms was pH-dependent, although the highest concentrations were not always 

found at the lowest pH. There was no clear relationship between Pb concentration in cocoons 

and soil pH, and Pb concentrations were higher in the hatchlings than in the cocoons. As has 

been reported in many other studies (Neuhauser et al., 1995), concentration factors (ratio of Pb in 

worm to Pb in soil) were lower at higher Pb concentrations in soil. The authors attribute some of 

this to a lowered feeding activity in worms at higher Pb concentrations (Bengtsson et al., 1986). 

Beyer et al. (1987) and Morgan and Morgan (1988) recognized that other factors beyond 

soil pH could influence the uptake of Pb into earthworms, which may be the cause of the 

inconsistencies reported by several authors. Both studies evaluated worm uptake of Pb relative 

to pH, soil calcium concentration, and organic matter content. Morgan and Morgan (1988) also 

considered CEC, and Beyer et al. (1987) considered concentrations of phosphorus, potassium, or 

magnesium in soil. Both studies found that calcium concentrations in soil were correlated with 

soil pH. Morgan and Morgan (1988) also found that CEC was correlated with percentage 

organic matter. Soil pH (coupled with CEC) and soil calcium were found to play significant 

roles in the uptake of Pb into worms (Beyer et al., 1987; Morgan and Morgan, 1988). Beyer 

et al. (1987) noted that concentrations of phosphorus in soil had no effect. 
 AX7-53 

Nutritional Factors 

Diet is a significant modifier of Pb absorption and of toxic effects in many species of 

birds and mammals (Eisler, 1988). Dietary deficiencies in calcium, zinc, iron, vitamin E, copper, 

thiamin, phosphorus, magnesium, fat, protein, minerals, and ascorbic acid increased Pb 

absorption and its toxic effects (Eisler, 1988). 

Mateo et al. (2003b) studied intraspecies sensitivity to Pb-induced oxidative stress, by 

varying the vitamin E content of mallard diets. Vitamin E can protect against peroxidative 

damage and was found to decrease the lipid peroxidation in nerves of birds; however, it did not 

alleviate any sign of the Pb poisoning. The authors hypothesize that inhibition of antioxidant 

enzymes and interaction with sulfhydryl groups of proteins may have a greater influence on Pb 

toxicity than lipid peroxidation (Mateo et al., 2003b). The effects observed by Mateo et al. 

(2003b) were associated with very high concentrations of Pb in diet (1840 mg Pb/kg diet), much 

higher than would be found generally in the environment, and high enough that the birds 

decreased their food intake. 

Mallard ducklings were exposed to Pb-contaminated sediment and either a low nutrition 

or optimal nutrition diet (Douglas-Stroebel et al., 2005). Lead exposure combined with a 

nutritionally inferior diet caused more changes in behavior (as measured by time bathing, resting, 

and feeding) than Pb exposure or low-nutrition diet alone. These effects may be due to the lownutrition diet being deficient in levels of protein, amino acids, calcium, zinc, and other nutrients. 

Zebra finches (Taeniopygia guttata) were exposed to Pb-acetate via drinking water at 

20 mg/L for 38 days, along with either a low- or high-calcium diet (Snoeijs et al., 2005). Lead 

uptake into tissues was enhanced by a low-calcium diet. Lead did not affect body weight, 

hematocrit, or adrenal stress response. Lead suppressed the humoral immune response only in 

females on a low-calcium diet, suggesting increased susceptibility of females to Pb (Snoeijs 

et al., 2005). 

Interactions with Other Pollutants 

Lead can interact with other pollutants to exert toxicity in an antagonistic (less than 

additive), independent, additive, or synergistic (more than additive) manner. Concurrent 

exposure to Pb and additional pollutant(s) can affect the ability of plants to uptake Pb or the 

other pollutant. However, the uptake and toxic response of plants exposed to Pb combined with 
 AX7-54 

other metals is inconsistent (Påhlsson, 1989). Therefore, no generalizations can be made about 

the relative toxicity of metal mixtures. For example, An et al. (2004) conducted acute, 5-day 

bioassays on cucumber exposed to Pb, Pb + copper, Pb + cadmium, or Pb + copper + cadmium 

in a sandy loam soil of pH 4.3. Shoot and root growth were measured. Depending on the tissue 

and metal combination, additivity, synergism, or antagonism was observed in the responses to 

these metals. In fact, the response in roots was not consistent with the response in shoots for the 

binary mixtures. However, the combined effects were greater in the roots than the shoots, which 

may be explained by the tendency for Pb and other heavy metals to be retained in the roots of 

plants. In addition, the pattern of metal bioaccumulation into plant tissue did not always 

correlate with the toxic response. However, antagonism was observed in the response of roots 

and shoots exposed to all three metals, and this was reflected in the decreased accumulation of 

metals into plant tissues. The authors hypothesized that this may be due to the formation of less 

bioavailable metal complexes (An et al., 2004). 

He et al. (2004) found that selenium and zinc both inhibited the uptake of Pb into Chinese 

cabbage (Brassica rapa) and lettuce (Lactuca sativa). Zinc applied at 100 mg/kg or selenium 

applied at 1 mg/kg decreased the uptake of Pb (present in soil at 10 mg/kg as Pb-nitrate) into 

lettuce by 15% and 20%, respectively, and into Chinese cabbage by 23 and 20%, respectively. 

Selenium compounds were evaluated to determine whether they could change the 

inhibition of ALAD in liver, kidney, or brain of mice exposed to Pb-acetate (Perottoni et al., 

2005). Selenium did not affect the inhibition of ALAD in the kidney or liver, but it did reverse 

the ALAD inhibition in mouse brain. 

Co-occurrence of cadmium with Pb resulted in reduced blood Pb concentrations in rats 

(Garcia and Corredor, 2004). The authors hypothesized that cadmium may block or antagonize 

the intestinal absorption of Pb, or the metallothionein induced by cadmium may sequester Pb. 

However, this was not observed in pigs, where blood Pb concentrations were greater when 

cadmium was also administered (Phillips et al., 2003). The effect on growth rate also was 

additive when both metals were given to young pigs (Phillips et al., 2003). 
 AX7-55 

AX7.1.2.7 Summary 

The current document expands upon and updates knowledge related to the uptake, 

detoxification, physiological effects, and modifying factors of Pb toxicity to terrestrial 

organisms. 

Surface Deposition onto Plants 

Recent work (Dalenberg and Van Driel, 1990; Jones and Johnston, 1991; Angelova et al., 

2004) has supported previous results and conclusions that surface deposition of Pb onto aboveground vegetation from airborne sources may be significant (U.S. Environmental Protection 

Agency, 1986a). Similarly, it has been well documented previously that Pb in soil also is taken 

up by plants, although most remains in the roots, there is little translocation to shoots, leaves, or 

other plant parts (U.S. Environmental Protection Agency, 1986a). More recent work continues 

to support this finding (Sieghardt, 1990), and one study found increased tolerance in species with 

bulbs, possibly due to the storage of Pb in the bulb (Wierzbicka, 1999). 

Uptake Mechanism into Plants 

Lead was thought previously to be taken up by plants via the symplastic route (through 

cell membranes), although it was unknown whether some Pb also may be taken up via the 

apoplastic route (between cells) (U.S. Environmental Protection Agency, 1986a). Recent work 

has shown that the apoplastic route of transport is stopped in the primary roots by the endodermis 

(Sieghardt, 1990), supporting the previous conclusion that the symplastic route is the most 

significant route of transport into plant cells. 

Species Differences in Uptake into Earthworms 

Different species of earthworm accumulated different amounts of Pb, and this was not 

related to feeding strategy (U.S. Environmental Protection Agency, 1986a). This is supported by 

recent work, which has shown Aporrectodea accumulated more than Lumbricus (Terhivuo et al., 

1994; Pižl and Josens, 1995), although this is not consistently observed (Spurgeon and Hopkin, 

1996a). 
 AX7-56 

Speciation and Form of Lead 

Recent work supports previous conclusions that the form of metal tested, and its 

speciation in soil, influence uptake and toxicity to plants and invertebrates (U.S. Environmental 

Protection Agency, 1986a). The oxide form is less toxic that the chloride or acetate forms, 

which are less toxic than the nitrate form of Pb (Khan and Frankland, 1983; Lock and Janssen, 

2002; Bongers et al., 2004). However, these results must be interpreted with caution, as the 

counterion (e.g., the nitrate ion) may be contributing to the observed toxicity (Bongers et al., 

2004). 

Detoxification in Plants 

Lead may be deposited in root cell walls as a detoxification mechanism (U.S. 

Environmental Protection Agency, 1986a), and this may be influenced by calcium concentrations 

(Antosiewicz, 2005). Yang et al. (2000) suggested that the oxalate content in root and root 

exudates reduced the bioavailability of Pb in soil, and that this was an important tolerance 

mechanism. Other hypotheses put forward recently include the presence of sulfur ligands 

(Sharma et al., 2004) and the sequestration of Pb in old leaves (Szarek-Lukaszewska et al., 2004) 

as detoxification mechanisms. 

Detoxification in Invertebrates 

Lead detoxification has not been studied extensively in invertebrates. Glutathione 

detoxification enzymes were measured in two species of spider (Wilczek et al., 2004). Lead may 

be stored in waste nodules in earthworms (Hopkin, 1989) or as pyromorphite in the nematode 

(Jackson et al., 2005). 

Physiological Effects 

The effects on heme synthesis (as measured by ALAD activity and protoporphyrin 

concentration, primarily) have been well-documented (U.S. Environmental Protection Agency, 

1986a) and continue to be studied (Schlick et al., 1983; Scheuhammer, 1989; Henny et al., 1991; 

Redig et al., 1991; Beyer et al., 2000; Hoffman et al., 2000a,b). However, Henny et al. (1991) 

caution that changes in ALAD and other enzyme parameters are not always related to adverse 

effects, but simply indicate exposure. Other effects on plasma enzymes, which may damage 
 AX7-57 

other organs, have been reported (Brar et al., 1997a,b). Lead also may cause lipid peroxidation 

(Mateo and Hoffman, 2001), which may be alleviated by vitamin E, although Pb poisoning may 

still result (Mateo et al., 2003b). Changes in fatty acid production have been reported, which 

may influence immune response and bone formation (Mateo et al., 2003a). 

Response Modification 

Genetics, biological factors, physical/environmental factors, nutritional factors, and other 

pollutants can modify terrestrial organism response to Pb. Fisher 344 rats were found to be more 

sensitive to Pb than Sprague-Dawley rats (Dearth et al., 2004). Younger animals are more 

sensitive than older animals (Eisler, 1988; Scheuhammer, 1991), and females generally are more 

sensitive than males (Scheuhammer, 1987; Tejedor and Gonzalez, 1992; Snoeijs et al., 2005). 

Monogastric animals are more sensitive than ruminants (Humphreys, 1991). Insectivorous 

mammals may be more exposed to Pb than herbivores (Beyer et al., 1985; Sample et al., 1998), 

and higher tropic-level consumers may be less exposed than lower trophic-level organisms 

(Henny et al., 1991). Diets deficient in nutrients (including calcium) result in increased uptake 

of Pb (Snoeijs et al., 2005) and greater toxicity (Douglas-Stroebel et al., 2005) in birds, relative 

to diets containing adequate nutrient levels. 

Mycorrhizal fungi may ameliorate Pb toxicity until a threshold is surpassed (Malcova and 

Gryndler, 2003), which may explain why some studies show increased uptake into plants (Lin 

et al., 2004) while others show no difference or less uptake (Dixon, 1988). Uptake of Pb into 

plants and soil invertebrates increases with a decrease in soil pH. However, calcium content, 

organic matter content, and cation exchange capacity of soils also have had a significant 

influence on uptake of Pb into plants and invertebrates (Beyer et al., 1987; Morgan and Morgan, 

1988). 

Interactions of Pb with other metals are inconsistent, depending on the endpoint 

measured, the tissue analyzed, the animal species, and the metal combination (Phillips et al., 

2003; An et al., 2004; He et al., 2004; Garcia and Corredor, 2004; Perottoni et al., 2005). 

AX7.1.3 Exposure-Response of Terrestrial Species 

Section AX7.1.3 summarized the most important factors related to uptake of Pb by 

terrestrial organisms, the physiological effects of Pb, and the factors that modify terrestrial 
 AX7-58 

organism responses to Pb. Section AX7.1.4 outlines and highlights the critical recent 

advancements in the understanding of the toxicity of Pb to terrestrial organisms. This section 

begins with a summary of the conclusions from the 1986 Lead AQCD (U.S. Environmental 

Protection Agency, 1986a) and then summarizes the more recent critical research conducted on 

effects of Pb on primary producers, consumers, and decomposers. All concentrations are 

expressed as mg Pb/kg soil dw, unless otherwise indicated. 

Lead exposure may adversely affect organisms at different levels of organization, i.e., 

individual organisms, populations, communities, or ecosystems. Generally, however, there is 

insufficient information available for single materials in controlled studies to permit evaluation 

of specific impacts on higher levels of organization (beyond the individual organism). Potential 

effects at the population level or higher are, of necessity, extrapolated from individual level 

studies. Available 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). Therefore, the best documented links 

between lead and effects on the environment are with effects on individual organisms. Impacts 

on terrestrial ecosystems are discussed in Section 7.1.5 and Annex AX7.1.5. 

The summary of recent critical advancements in understanding toxicity relies heavily on 

the work completed by a multi-stakeholder group, consisting of federal, state, consulting, 

industry, and academic participants, led by the EPA to develop Ecological Soil Screening Levels 

(Eco-SSLs). Eco-SSLs describe the concentrations of contaminants in soils that would result in 

little or no measurable effect on ecological receptors (U.S. Environmental Protection Agency, 

2005a). They were developed by the U.S. EPA for use in screening-level assessments at 

Superfund sites to identify contaminants requiring further evaluation in an ecological risk 

assessment and were not designed to be used as cleanup target levels. The Eco-SSLs are 

intentionally conservative in order to provide confidence that contaminants, which could present 

an unacceptable risk, are not screened out early in the evaluation process. That is, at or below 

these levels, adverse effects are considered unlikely. Eco-SSLs were derived for terrestrial 

plants, soil invertebrates, birds, and mammals. Detailed procedures using an extensive list of 

acceptability and exclusion criteria (U.S. Environmental Protection Agency, 2005a) were used in 

screening the toxicity studies to ensure that only those that met minimum quality standards were 

used to develop the Eco-SSLs. In addition, two peer reviews were completed during the 
 AX7-59 

Eco-SSL development process. The first was a consultation with the EPA Science Advisory 

Board (SAB) in April 1999, and the second was a peer review workshop in July 2000, which was 

open to the public. 

Several conservative factors were incorporated into the development of the Eco-SSLs. 

For the plant and invertebrate Eco-SSLs, studies were scored to favor relatively high 

bioavailability. For wildlife Eco-SSLs, only species with a clear exposure link to soil were 

considered (generalist species, species with a link to the aquatic environment, or species which 

consume aerial insects were excluded), simple diet classifications were used (100% plants, 100% 

earthworms or 100% animal prey) when in reality wildlife consume a varied diet, species were 

assumed to forage exclusively at the contaminated site, relative bioavailability or Pb in soil and 

diet was assumed to be 1, and the TRV was selected as the geometric mean of NOAELs unless 

this value was higher than the lowest bounded LOAEL for mortality, growth or reproduction 

(U.S. Environmental Protection Agency, 2005a,b). 

Areas of research that were not addressed are effects from irrelevant exposure conditions 

relative to airborne emissions of Pb (e.g., Pb shot, Pb paint, injection studies, studies conducted 

on mine tailings, and studies conducted with hydroponic solutions); mixture toxicity (addressed 

in Section AX7.1.3); issues related to indirect effects (e.g., effects on predator/prey interactions, 

habitat alteration, etc.); and human health-related research (e.g., hypertension), which is 

addressed in other sections of this document. 

The toxicity data presented herein should be reviewed with a note of caution regarding 

their relevance to field conditions. Laboratory studies, particularly those using Pb-spiked soil, 

generally do not allow the soil to equilibrate following the addition of Pb and prior to the 

addition of test organisms. This may result in increased bioavailability and overestimation of Pb 

toxicity relative to actual environmental conditions (Davies et al., 2003). 

AX7.1.3.1 Summary of Conclusions from the 1986 Lead Criteria Document 

The 1996 Lead AQCD, Volume II (U.S. Environmental Protection Agency, 1986a) 

reviewed the literature on the toxicity of Pb to plants, soil organisms, birds, and mammals. 

The main conclusions from that document are provided below. 
 AX7-60 

Primary Producers 

Commonly reported effects of Pb on vascular plants include the inhibition of 

photosynthesis, respiration, and/or cell elongation, all of which reduce plant growth. However, it 

was noted that studies of other effects on plant processes such as maintenance, flowering, and 

hormone development had not been conducted; therefore, no conclusion could be reached 

concerning effects of Pb on these processes. 

The EPA (U.S. Environmental Protection Agency, 1986a) concluded that most plants 

experience reduced growth when Pb concentrations in soil moisture (the film of moisture 

surrounding soil particles in the root zone of soil) exceed 2 to 10 mg/kg. It also was concluded 

that most plants would experience reduced growth (inhibition of photosynthesis, respiration, or 

cell elongation) in soils of ∃10,000 mg/kg when soil composition and pH are such that 

bioavailability of Pb in the soil is low (see Section AX7.1.3 for details on factors affecting 

bioavailability of Pb in soil). Acid soils or soils with low organic matter tend to increase Pb 

bioavailability and would inhibit plants at much lower Pb concentrations (e.g., as low as 

<100 mg/kg). 

Many effect levels have been reported at Pb concentrations much lower than 

10,000 mg/kg soil. For example, effects on rye grass (Lolium rigidum) exposed to Pb in soil 

included inhibition of germinating root elongation (at <2.5 mg/kg), absence of root growth 

(at 5 mg/kg), or 55% inhibition of seed germination (at 20 to 40 mg/kg). Stunted growth in 

radish (Raphanus sativus) was observed at 1000 mg/kg soil, with complete growth inhibition at 

5000 mg/kg, when Pb was added as Pb-chloride; effects were less severe when the Pb was added 

as Pb-oxide. 

Consumers 

The EPA (U.S. Environmental Protection Agency, 1986a) concluded that food is the 

largest contributor of Pb to animals, with inhalation rarely accounting for more than 10 to 15% 

of daily intake of Pb and drinking water exposures being quite low. It also was concluded that a 

regular dose of 2 to 8 mg/kg-day causes death in most animals. Grazing animals may consume 

more than 1 mg/kg-day in habitats near smelters and roadsides, but no toxic effects were 

documented in these animals. 
 AX7-61 

Decomposers 

Lack of decomposition has been observed as a particular problem around smelter sites. 

Lead concentrations between 10,000 and 40,000 mg/kg soil can eliminate populations of 

decomposer bacteria and fungi (U.S. Environmental Protection Agency, 1986a). Lead may 

affect decomposition processes by direct toxicity to specific groups of decomposers, by 

deactivating enzymes excreted by decomposers to break down organic matter, or by binding with 

the organic matter and rendering it resistant to the action of decomposers. 

Microorganisms are more sensitive than plants to Pb in soil. Delayed decomposition may 

occur at between 750 and 7500 mg/kg soil (depending on soil type and other conditions). 

Nitrification is inhibited by 14% at 1000 mg/kg soil. 

U.S. Environmental Protection Agency Staff Review of 1986 Criteria Document 

The EPA reviewed the 1986 Lead AQCD and presented an overall summary of 

conclusions and recommendations (U.S. Environmental Protection Agency, 1990). The major 

conclusion was that available laboratory and field data indicated that high concentrations of Pb 

can affect certain plants and alter the composition of soil microbial communities. It was noted 

that few field studies were available in which Pb exposures and associated effects in wildlife 

were reported. 

AX7.1.3.2 Recent Studies on the Effects of Lead on Primary Producers 

Several studies published since 1986 have reported terrestrial plant exposure to Pb in soil, 

many of which were reviewed during the development of the Eco-SSLs (U.S. Environmental 

Protection Agency, 2005b). The relevant information from the Eco-SSL document (U.S. 

Environmental Protection Agency, 2005b) is summarized below. A literature search and review 

also was conducted to identify critical papers published since 2002, which is when the literature 

search was completed for Eco-SSL development, and no new papers were identified as critical to 

the understanding of Pb toxicity to terrestrial primary producers. 

Effects observed in studies conducted since the 1986 Lead AQCD are similar to those 

reported previously and include decreased photosynthetic and transpiration rates and decreased 

growth and yield (U.S. Environmental Protection Agency, 2005b). The phytotoxicity of Pb is 

considered relatively low, due to the limited availability and uptake of Pb from soil and soil 
 AX7-62 

solution and minimal translocation of Pb from roots to shoots (Påhlsson, 1989). Although many 

laboratory toxicity studies have reported effects on plants, there are few reports of phytotoxicity 

from Pb exposure under field conditions. For example, Leita et al. (1989) and Sieghardt (1990) 

reported high concentrations of Pb and other metals in soil and vegetation collected around 

mining areas in Europe, with no toxicity symptoms observed in plants or fruit. 

The literature search completed for the terrestrial plant Eco-SSL development identified 

439 papers for detailed review, of which 28 met the minimum criteria (U.S. Environmental 

Protection Agency, 2005a). Thirty ecotoxicological endpoints were gleaned from these 28 

papers and were further evaluated; most of those evaluated growth (biomass), which was 

considered the most sensitive and ecologically relevant endpoint (U.S. Environmental Protection 

Agency, 2005b). Five of the endpoints, representing four species tested under three different 

combinations of pH and organic matter content, were used to develop the Eco-SSL of 120 mg/kg 

(115 mg/kg rounded to two significant digits) (Table AX7-1.3.1). 

Table AX7-1.3.1. Plant Toxicity Data Used to Develop the Eco-SSL

Plant Species Soil pH 

% Organic 

Matter 

Toxicity 

Parameter 

Pb in Soil 

(mg/kg dw) 

Loblolly pine (Pinus taeda) 4 2.5 MATC* (growth) 144 

Red maple (Acer rubrum) 4 2.5 MATC (growth) 144 

Berseem clover 

(Trifolium alexandrium) 

6.3 0.94 MATC (growth) 316 

Berseem clover 6.7 3.11 MATC (growth) 141 

Rye grass (Lolium rigidum) 5.6 0.1 MATC (growth) 22 

 Geometric Mean 115 

*MATC = Maximum Acceptable Threshold Concentration, or the geometric mean of the NOAEC 

 (no-observed-adverse-effect concentration) and LOAEC (lowest-observed-adverse-effect concentration). 

Source: U.S. Environmental Protection Agency (2005b). 

The 25 ecotoxicological endpoints that were not used to develop the Eco-SSL for plants 

are presented in Table AX7-1.3.2. The first six endpoints were considered eligible for Eco-SSL 

derivation but were not used; the remainder did not meet all of the requirements to be considered 

for inclusion in the Eco-SSL derivation process. 
 AX7-63 

Table AX7-1.3.2. Plant Toxicity Data Not Used to Develop the Eco-SSL 

Plant Species Soil pH 

% Organic 

Matter Toxicity Parameter 

Pb in Soil 

(mg/kg dw) 

Studies eligible for Eco-SSL derivation, but not used 

Berseem clover 

(Trifolium alexandrium) 

6.7 3.11 MATC 141 

Tomato 

(Lycopericon esculentum) 7.73 1.70 MATC 71 

Tomato 8.20 0.86 MATC 71 

Fenugreek 

(Trigonella foenum-graecum) 8.3 0.5 MATC 283 

Spinach (Spinacea oleracea) 6.7 3.0 MATC 424 

Corn (Zea mays) 6.5 2.1 MATC 158 

Sow thistle (Sonchus oleraceus) 7.23 1.6 MATC 2,263 

Studies not eligible for Eco-SSL derivation 

Loblolly pine (Pinus taeda) 5.5 3.4 NOAEC 480 

Red oak (Quercus rubra) 6 1.5 LOAEC 100 

Spinach 6.7 0.0 NOAEC 600 

Alfalfa (Medicago sativa) 6.4 1.0 NOAEC 250 

Alfalfa 6.9 1.7 NOAEC 250 

Alfalfa 6.9 1.7 NOAEC 250 

Radish (Raphanus sativus) 6.9 1.0 LOAEC 500 

Radish 6.9 1.0 LOAEC 100 

Radish 6.9 1.0 LOAEC 100 

Onion (Allium cepa) 8.3 0.5 LOAEC 50 

Radish 5.1 8.0 NOAEC 600 

Carrot (Daucus carota) 7.0 0.6 NOAEC 85 

Peas (Pisum sativum) 7.0 0.6 NOAEC 85 

Barley (Hordeum vulgare) 6.0 2.5 NOAEC 1,000 

Alfalfa 6.9 4.8 NOAEC 250 

Tomato 7.45 2.06 MATC 35 

Spinach 6.7 8.0 NOAEC 600 

Radish 6.2 8.0 NOAEC 600 

Radish 7.1 8.0 NOAEC 600 

*MATC = Maximum Acceptable Threshold Concentration, or the geometric mean of the NOAEC 

 (no-observed-adverse-effect concentration) and LOAEC (lowest-observed-adverse-effect concentration). 

Source: U.S. Environmental Protection Agency (2005b). 
 AX7-64 

AX7.1.3.3 Recent Studies on the Effects of Lead on Consumers 

Since the 1986 Lead AQCD (U.S. Environmental Protection Agency, 1986a), there have 

been several studies in which birds and mammals were exposed to Pb via ingestion (primarily 

through dietary Pb). Many of these were reviewed during development of the Eco-SSLs (U.S. 

Environmental Protection Agency, 2005b). The relevant information from the Eco-SSL 

document (U.S. Environmental Protection Agency, 2005b) is described below. A literature 

search and review was conducted to identify critical papers published since 2002. These recent 

critical papers are described briefly below. No studies were found that used inhalation exposures 

to evaluate endpoints such as survival, growth, and reproduction in birds or mammals. All 

studies described below exposed organisms via ingestion (drinking water or diet) or gavage. 

The Eco-SSLs for avian and mammalian consumers are presented as Pb concentrations in 

soil. These concentrations were calculated by assuming exposure to Pb via incidental soil 

ingestion and ingestion of Pb-contaminated food, and using a NOAEL as the TRV (U.S. 

Environmental Protection Agency, 2005a). A simplified version of the equation used to 

calculate the Eco-SSL is: 

[( ) ( )]

TRV

IRCIRC BW

HQ soil soil food food ÷×+× =

where: 

HQ = hazard quotient (1 mg Pb/kg bw/day) 

Csoil = concentration of Pb in soil (mg Pb/kg soil) 

IRsoil = incidental soil ingestion rate (kg soil/day) 

Cfood = concentration of Pb in food (mg Pb/kg food) 

IRfood = food ingestion rate (kg food/day) 

BW = body weight (kg) 

TRV = toxicity reference value (mg Pb/kg bw/day) 

Food ingestion was estimated by modeling the uptake of Pb from soil into each diet 

component (e.g., vegetation, invertebrates, etc.). Bioavailability of Pb in soil and food was 

assumed to be 100%. The Eco-SSL is equivalent to the concentration of Pb in soil that results in 

an HQ = 1. The two factors that may have the most significant influence on the resulting EcoSSL are the assumption of 100% bioavailability of Pb in soil and diet and the selection of the 

(AX7-4) 
 AX7-65 

TRV. The toxicity data that were reviewed to develop the TRV are presented in the following 

subsections. 

Representative avian and mammalian wildlife species were selected for modeling Pb 

exposures to wildlife with different diets and calculating the Eco-SSL. The avian species 

selected were dove (herbivore), woodcock (insectivore), and hawk (carnivore). The mammalian 

species selected were vole (herbivore), shrew (insectivore), and weasel (carnivore). The lowest 

of the three back-calculated soil concentrations, which resulted in an HQ = 1, was selected as the 

Eco-SSL. For Pb, the lowest values were for the insectivorous species of bird and mammal. 

Avian Consumers 

Effects on birds observed in studies conducted since the 1986 Lead AQCD (U.S. 

Environmental Protection Agency, 1986a) are similar to those reported previously: mortality, 

changes in juvenile growth rate and weight gain, effects on various reproductive measures, and 

changes in behavior (U.S. Environmental Protection Agency, 2005b). Reproductive effects 

following Pb exposure included declines in clutch size, number of young hatched, and number of 

young fledged as well as decreased fertility or eggshell thickness. Few significant reproductive 

effects have been reported in birds at Pb concentrations below 100 mg/kg in the diet 

(Scheuhammer, 1987). 

The literature search completed for Eco-SSL development identified 2,429 papers for 

detailed review for either avian or mammalian species, of which 54 met the minimum criteria for 

further consideration for avian Eco-SSL development (U.S. Environmental Protection Agency, 

2005b). The 106 toxicological data points for birds that were further evaluated included 

biochemical, behavioral, physiological, pathological, reproductive, growth, and survival effects. 

Growth and reproduction data were used to derive the Eco-SSL (Table AX7-1.3.3; 

Figure AX7-1.3.1). The geometric mean of the NOAELs was calculated as 10.9 mg/kg-day, 

which was higher than the lowest bounded LOAEL (the term “bounded” means that both a 

NOAEL and LOAEL were obtained from the same study). Therefore, the highest bounded 

NOAEL that was lower than the lowest bounded LOAEL for survival, growth, or reproduction 

(1.63 mg Pb/kg bw-day) was used as the TRV (U.S. Environmental Protection Agency, 2005b). 

The TRV was used to back-calculate the Eco-SSL of 11 mg/kg soil for avian species (U.S. 

 
 AX7-66 Table AX7-1.3.3. Avian Toxicity Data Used to Develop the Eco-SSL Avian Species No. of Doses Route of Exposure Exposure Duration Duration Units Age Age Units Lifestage Sex Effect Type Effect Measure Response Site 

Reproduction Japanese quail 4 FD 5 w 6 w LB F REP PROG WO 

Chicken 3 FD 4 w NR NR LB F REP PROG WO Chicken 4 FD 30 d 22 w LB F EGG ALWT EG Mallard 2 FD 76 d NR NR SM F EGG ESTH EG American kestrel 3 FD 6 mo 1-6 yr AD F REP RSUC WO Japanese quail 5 FD 5 w 6 d JV M REP TEWT TE Japanese quail 5 FD 5 w 1 d JV M REP TEWT TE Japanese quail 3 FD 32 d NR NR AD F REP PROG WO Japanese quail 5 FD 12 w 0 d LB B REP EGPN EG Japanese quail 4 FD 12 w NR NR LB F REP PROG WO Chicken 5 FD 10 w NR NR LB F REP PROG WO Ringed turtle dove 2 DR 11 w NR NR AD M REP TEWT TE Japanese quail 2 FD 1 w 14 w JV F REP TPRD WO Japanese quail 

2 FD 27 d NR NR AD F REP PROG WO 
 AX7-67 Table AX7-1.3.3 (cont’d). Avian Toxicity Data Used to Develop the Eco-SSL Avian Species No. of Doses Route of Exposure Exposure Duration Duration Units Age Age Units Lifestage Sex Effect Type Effect Measure Response Site 

Growth Japanese quail 3 FD 5 w 1 d JV F GRO BDWT WO Japanese quail 3 FD 2 w 1 d JV B GRO BDWT WO Japanese quail 2 FD 2 w 1 d JV NR GRO BDWT WO Japanese quail 3 FD 4 w 0 d JV F GRO BDWT WO Chicken 4 FD 4 w 4 w JV NR GRO BDWT WO Chicken 4 FD 4 w 4 w JV NR GRO BDWT WO Japanese quail 5 FD 12 w 0 d JV F GRO BDWT WO Japanese quail 5 FD 12 w 1 w JV F GRO BDWT WO Japanese quail 5 FD 2 w 6 d JV NR GRO BDWT WO Japanese quail 5 FD 1 w 1 d JV NR GRO BDWT WO Chicken 2 FD 21 d 1 d JV B GRO BDWT WO Duck 3 GV 3 mo 24 w MA F GRO BDWT WO American kestrel 4 GV 10 d 1 d JV NR GRO BDWT WO Chicken 2 FD 20 d 1 d JV B GRO BDWT WO Japanese quail 

5 FD 14 d 1 d JV B GRO BDWT WO 
 AX7-68 Table AX7-1.3.3 (cont’d). Avian Toxicity Data Used to Develop the Eco-SSL Avian Species No. of Doses Route of Exposure Exposure Duration Duration Units Age Age Units Lifestage Sex Effect Type Effect Measure Response Site 

American kestrel 4 FD 60 d 1-2 yr AD B GRO BDWT WO Chicken 5 FD 2 w 1 d JV M GRO BDWT WO Mallard 4 FD 8 d 9 d JV NR GRO BDWT WO Chicken 5 FD 20 d 1 d JV M GRO BDWT WO Chicken 2 FD 3 w 1 d JV M GRO BDWT WO Japanese quail 3 FD 32 d NR NR AD F GRO BDWT WO Chicken 2 FD 19 d 1 d JV M GRO BDWT WO Chicken 3 FD 2 w 1 d JV M GRO BDWT WO Chicken 4 FD 14 d 8 d JV M GRO BDWT WO Chicken 2 FD 20 d 1 d JV M GRO BDWT WO Chicken 2 OR 4 w NR NR JV B GRO BDWT WO Chicken 2 FD 7 d 1 d JV M GRO BDWT WO Chicken 2 FD 2 w 1 d JV M GRO BDWT WO Chicken 2 FD 7 d 1 d IM NR GRO BDWT WO Chicken 2 FD 14 d 8 d JV M GRO BDWT WO AD = adult; ALWT = albumin weight; B = both; BDWT = body weight changes; d = days; DR = drinking water; EG = egg; EGG = effects on eggs; EGPN = egg produthinning; F = female; FD = food; GRO = growth; GV = gavage; JV = juvenile; LB = laying bird; MA = mature; M = male; mo = months; NR = not reported; OR = otheor numbers; REP = reproduction; RSUC = reproductive success; SM = sexually mature; TE = testes; TEWT = testes weight; TPRD = total production; w = weeks; WO 

Source: U.S. Environmental Protection Agency (2005b) 
 AX7-69 

Figure AX7-1.3.1. Avian reproduction and growth toxicity data considered in 

development of the Eco-SSL. 

Source: U.S. Environmental Protection Agency (2005b). 

Environmental Protection Agency, 2005b). For more information on the rationale for selecting 

TRVs, please refer to U.S. Environmental Protection Agency (2003). 

Many of the toxicity data presented in the Eco-SSL document (U.S. Environmental 

Protection Agency, 2005b) are lower than those discussed in the 1986 Lead AQCD. The TRV 

and resulting Eco-SSL were derived using many conservative assumptions. For example, the 

EPA (U.S. Environmental Protection Agency, 2005b) recognizes that toxicity is observed over a 

wide range of doses (<1 to >100 mg Pb/kg bw/day), even when considering only reproductive 

effects in the same species. In addition, the TRV of 1.63 mg/kg-day is lower than most of the 

reported doses that have been associated with measured effects. This is true for not only 

survival, growth, and reproductive effects but also biochemical, behavioral, physiological, and 

pathological effects, which generally are observed at lower concentrations than effects on growth 

or reproduction. In addition, the Eco-SSL was back-calculated using conservative modeling 

assumptions. Therefore, the Eco-SSL of 11 mg/kg may be considered a conservative value. 
 AX7-70 

Very little research has been done to expand the knowledge of the toxicity of Pb to birds 

since the Eco-SSL work was done. However, several studies have been conducted on waterfowl. 

Toxicity data for waterfowl (in particular, mallards) were included in the soil Eco-SSL 

development process (Table AX7-1.3.3), although mallards may be more exposed to 

contaminants in sediment than soil. Effects on waterfowl may vary depending on the form of Pb, 

characteristics of the sediment, the foraging strategy of the species (which may vary during 

reproduction), and the nutritional status of the animal. Sediment is recognized as an important 

route of exposure for waterfowl, particularly those species that dabble (i.e., forage on 

invertebrates in the sediment) (Beyer et al., 2000; Douglas-Stroebel et al., 2005). DouglasStroebel et al. (2005) found that mallard ducklings exposed to Pb-contaminated sediment and a 

low nutrition diet exhibited more changes in behavior (as measured by time bathing, resting, and 

feeding) than Pb exposure or low nutrition exposure alone. These effects may be due to the low 

nutrition diet being deficient in levels of protein, amino acids, calcium, zinc, and other nutrients. 

Beyer et al. (2000) related blood Pb to sublethal effects in waterfowl along the Coeur 

d=Alene River near a mining site in Idaho. The authors suggested that 0.20 mg/kg ww blood Pb 

represents the no-effect level. This no-effect blood concentration corresponds to a sediment Pb 

concentration of 24 mg/kg. A sediment concentration of 530 mg/kg, associated with a blood Pb 

concentration of 0.68 mg/kg ww, is suggested to be the lowest-effect concentration. These 

results are consistent with those of Scheuhammer (1989) who found blood Pb concentrations of 

0.18 μg/mL to 0.65 μg/mL in mallards corresponded to conditions associated with greater than 

normal exposure to Pb, but that that should not be considered Pb poisoning. The study by Beyer 

et al. (2000) related blood Pb to waterfowl mortality and concluded that some swan mortality 

may occur at blood Pb levels of 1.9 mg/kg ww, corresponding to a sediment Pb concentration of 

1800 mg/kg. Using the mean blood level of 3.6 mg/kg ww from all moribund swans in the 

study, it was predicted that half of the swans consuming sediment at the 90th percentile rate 

would die with chronic exposure to sediment concentrations of 3600 mg/kg. 

Mammalian Consumers 

Effects on mammals observed in studies conducted since the 1986 Lead AQCD (U.S. 

Environmental Protection Agency, 1986a) are similar to those reported previously: mortality, 

effects on reproduction, developmental effects, and changes in growth (U.S. Environmental 
 AX7-71 

Protection Agency, 2005b). Very little research has been done to expand the knowledge of the 

toxicity of Pb to mammalian wildlife, since the Eco-SSL work was done. Most studies 

conducted on mammals use laboratory animals to study potential adverse effects of concern for 

humans, and such studies are summarized in other sections of this document. 

Of the 2,429 papers identified in the literature search for Eco-SSL development, 219 met 

the minimum criteria for further consideration for mammalian Eco-SSL development (U.S. 

Environmental Protection Agency, 2005b). The 343 ecotoxicological endpoints for mammals 

that were further evaluated included biochemical, behavioral, physiological, pathological, 

reproductive, growth, and survival effects. Growth and reproduction data were used to derive 

the Eco-SSL (Table AX7-1.3.4, Figure AX7-1.3.2). The geometric mean of the NOAELs was 

calculated as 40.7 mg/kg-day, which was higher than the lowest bounded LOAEL for survival, 

growth, or reproduction. Therefore, the highest bounded NOAEL that was lower than the lowest 

bounded LOAEL for survival, growth, or reproduction (4.7 mg Pb/kg bw-day) was used as the 

TRV (U.S. Environmental Protection Agency, 2005b). The TRV was used to back-calculate the 

Eco-SSL of 56 mg/kg soil (U.S. Environmental Protection Agency, 2005b). For more 

information on the rationale for selecting TRVs, please refer to U.S. Environmental Protection 

Agency (2003). 

A review of the data presented in the Eco-SSL document (U.S. Environmental Protection 

Agency, 2005b) reveals that effects on survival generally are observed at Pb doses much greater 

than those reported in the 1986 Lead AQCD, where it was concluded that most animals would 

die when consuming a regular dose of 2 to 8 mg Pb/kg bw-day (U.S. Environmental Protection 

Agency, 1986a). However, the data presented in the Eco-SSL document (U.S. Environmental 

Protection Agency, 2005b) generally do not support this. While five studies reported decreased 

survival at these levels, 34 other studies reported no mortality or a LOAEL for mortality at 

significantly higher doses (U.S. Environmental Protection Agency, 2005b). The five studies that 

supported this low toxic level were conducted on three species (mouse, rat, and cow) and used 

either gavage or drinking water as the exposure method. The 34 other studies included data on 

these three species as well as five other species (rabbit, dog, pig, hamster, and shrew) and 

included gavage and drinking water as well as food ingestion exposure methods. The NOAELs 

for survival ranged from 3.5 to 3200 mg/kg-day (U.S. Environmental Protection Agency, 

2005b). Therefore, the review of data in the Eco-SSL document suggests effects on survival of 
 AX7-72 Table AX7-1.3.4. Mammalian Toxicity Data Used to Develop the Eco-SSL Mammalian Species No. of Doses Route of Exposure Exposure Duration Duration Units Age Age Units Lifestage Sex Effect Type Effect Measure Respon

Site 

Reproduction Rat 5 DR 62 d 21 d GE F REP PRWT WO Rat 6 DR 21 d NR NR GE F REP PRWT WO Rat 3 DR 35 d NR NR AD M REP RSUC WO 

Rat 4 DR 62 d 21 d GE B REP PRWT WO 

Sheep 3 FD 27 w NR NR GE F REP RSUC WO Rat 6 DR 21 d NR NR GE F REP PRWT WO 

Guinea pig 3 DR 40 d NR NR GE F REP PRWT WO Rat 5 FD 92 w 21 d JV M REP TEWT TE 

Rat 4 DR 23.8 d 21 d LC F REP Other WO Rat 5 DR 23.8 d 21 d GE F REP Other WO Cotton rat 3 DR 7 w NR NR AD M REP RHIS RT Rat 4 GV 9 w 10 w JV M REP SPCV TE Rat 3 DR 100 d 21 d GE F REP PRWT WO Rat 2 FD 35 d 70 d LC F REP PRWT WO Rat 4 DR 60 d NR NR SM M REP TEWT TE 

Rat 4 DR 56 d 70 d LC F REP PROG WO 

Rat 3 DR 31 d NR NR LC F REP PRWT WO 

Rat 4 GV 41 d NR NR GE F REP PRWT WO 

Rat 5 DR 1 w 94 d JV M REP SPCL SM 

Rat 4 DR 30 d NR NR SM M REP Other SV 
 AX7-73 Table AX7-1.3.4 (cont’d). Mammalian Toxicity Data Used to Develop the Eco-SSL Mammalian Species No. of Doses Route of Exposure Exposure Duration Duration Units Age Age Units Lifestage Sex Effect Type Effect Measure Respon

Site 

Hamster 2 DR 51 d 15 w GE F REP PROG WO Hamster 2 DR 14 d 11 w GE F REP PROG WO Rat 4 DR 37 d NR NR GE F REP PRWT WO Rat 5 GV 12 d NR NR GE F REP RSEM EM Rat 3 DR 68 d 25 d GE F REP PRWT WO Rat 4 DR 77 d 25 d GE F REP PRWT WO Rat 2 DR 21 d NR NR LC F REP PRWT WO Mouse 3 FD 8 w 2 mo GE M REP SPCV TE Mouse 7 FD 30 d NR NR LC F REP PRWT WO Mouse 7 FD 30 d NR NR LC F REP PRWT WO Rat 4 DR 21 d NR NR GE F REP DEYO WO Rat 5 DR 10 w NR NR AD M REP TEWT MT Rat 2 GV 102 d 30 d GE F REP PRWT WO Rat 2 DR 9 mo NR NR SM M REP RHIS TE Rat 4 FD 4 d NR NR LC F REP PRWT WO Rat 4 DR 13 w NR NR JV M REP FERT WO Mouse 4 GV 60 d NR NR AD F REP RPRD OV Rat 3 FD 339 d 26-27 d JV B REP PRWT WO Rat 2 DR 9 mo 21 d JV F REP DEYO WO Mouse 2 DR 6 mo 21 d JV F REP DEYO WO Mouse 4 GV 52 d 2 mo GE F REP PROG EM Rat 2 DR 120 d 1 d GE M REP SPCL TE 
 AX7-74 Table AX7-1.3.4 (cont’d). Mammalian Toxicity Data Used to Develop the Eco-SSL Mammalian Species No. of Doses Route of Exposure Exposure Duration Duration Units Age Age Units Lifestage Sex Effect Type Effect Measure Respon

Site 

Mouse 2 DR 5 w NR NR AD M REP TEDG TE Mouse 2 GV 2 w NR NR JV M REP SPCL SM Rat 2 FD 102 d NR NR GE F REP PROG WO Rat 2 GV 3 mo 8 w SM M REP TEDG TE Rat 2 DR 18 d NR NR GE F REP PRWT WO Rat 3 DR 90 d NR NR AD M REP SPCL SM Mouse 2 DR 23 d NR NR GE F REP PRWT WO Mouse 2 DR 62 d NR NR GE F REP PRWT WO Mouse 2 DR 18 w 6-8 w LC F REP PRWT WO Mouse 2 DR 12 w 9 w SM M REP PRFM WO Mouse 4 FD 18 d NR NR GE F REP PRWT WO Rat 2 DR 4 w 99 d JV M REP SPCL SM Rat 5 DR 6 w 4 mo GE F REP RHIS WO 

Rat 2 DR 22 d NR NR GE F REP PRWT WO Rat 3 DR 30 d 52 d JV M REP GREP PG Rat 2 DR 13 w NR NR GE F REP PRWT WO Rat 2 DR 21 d 80 d JV F REP PRWT WO Rat 4 FD 3 w NR NR LC F REP PRWT WO Rat 2 FD 1 w 19 w LC F REP PRWT WO Rat 4 FD 3 w NR NR LC F REP PRWT WO Rat 3 FD 25 d NR NR LC F REP PRWT WO Rat 2 DR 21 d NR NR LC F REP PRWT WO 
 AX7-75 Table AX7-1.3.4 (cont’d). Mammalian Toxicity Data Used to Develop the Eco-SSL Mammalian Species No. of Doses Route of Exposure Exposure Duration Duration Units Age Age Units Lifestage Sex Effect Type Effect Measure Respon

Site 

Rat 2 DR 30 d 52 d JV M REP SPCL SM Rat 2 DR 17 d NR NR GE F REP PRWT WO Rat 2 DR 24 d NR NR LC F REP PRWT WO Rat 2 DR 12 d NR NR GE F REP PRWT WO Rat 2 DR 30 d 27 d JV M REP SPCL SM Mouse 2 DR 44 d NR NR GE F REP PRWT WO Mouse 2 DR 14 d NR NR LC F REP PRWT WO Rat 2 DR 50 d 24 d JV F REP RBEH WO Mouse 2 DR 45 d 50-100 d GE F REP ODVP WO Rat 2 DR 22 d NR NR GE F REP PRWT WO Mouse 2 DR 48 d NR NR GE F REP PRWT WO Rat 2 DR 9 mo 3 mo SM M REP SPCL TE Rat 2 DR 9 mo NR NR SM M REP TEDG TE Rat 2 DR 3 w 14 w LC F REP PRWT WO Mouse 2 FD 7 d NR NR GE F REP RSUC EM Rat 2 DR 126 d 1 d GE F REP PROG WO Rat 2 DR 20 w 10 w GE F REP PRWT WO Mouse 2 DR 4 d NR NR LC F REP PRWT WO Rat 2 FD 2 w NR NR LC F REP PRWT WO Rat 2 FD 7 d NR NR LC F REP PRWT WO Rat 2 FD 21 d NR NR LC F REP PRWT WO Mouse 4 DR 18 w 11 w JV F REP TEWT WO 
 AX7-76 Table AX7-1.3.4 (cont’d). Mammalian Toxicity Data Used to Develop the Eco-SSL Mammalian Species No. of Doses Route of Exposure Exposure Duration Duration Units Age Age Units Lifestage Sex Effect Type Effect Measure Respon

Site 

Rat 2 FD 30 d NR NR LC F REP PRWT WO Mouse 2 DR 14 w NR NR GE B REP PROG WO Rat 2 FD 16 d NR NR LC F REP PROG WO Rat 2 FD 7 d NR NR LC F REP PRWT WO Rat 2 FD 25 d NR NR LC F REP PRWT WO Rat M FD 27 d NR NR LC C REP PROG WO Mouse 2 DR 14 w 21 d JV B REP PROG WO Rat 2 FD 17 d NR NR LC F REP PRWT WO Growth Horse 2 FD 15 w 20-21 w JV M GRO BDWT WO Rat 2 FD 21 d 0 d JV F GRO BDWT WO Rat 6 DR 21 d NR NR GE F GRO BDWT WO 

Rat 5 DR 7 d 50 d AD F GRO BDWT WO Cattle 4 OR 7 w 1 w JV M GRO BDWT WO Rat 3 DR 14 d 21 d JV F GRO BDWT WO Rat 2 DR 332 d 28 d JV B GRO BDWT WO Rat 4 DR 7 w 21 d GE F GRO BDWT WO Dog 3 FD 7 mo NR NR JV NR GRO BDWT WO Rat 3 DR 30 d 22-24 d JV M GRO BDWT WO Rat 4 DR 23 d 22 d JV F GRO BDWT WO Cattle 3 OR 84 d NR NR JV M GRO BDWT WO Rat 2 OR 6 w NR NR AD M GRO BDWT WO 
 AX7-77 Table AX7-1.3.4 (cont’d). Mammalian Toxicity Data Used to Develop the Eco-SSL Mammalian Species No. of Doses Route of Exposure Exposure Duration Duration Units Age Age Units Lifestage Sex Effect Type Effect Measure Respon

Site 

Rat 2 GV 8 w NR NR JV F GRO BDWT WO Rat 3 DR 6 mo NR NR AD M GRO BDWT WO Rabbit 3 GV 10 d 1 d JV F GRO BDWT WO Rat 2 DR 140 d 21 d JV M GRO BDWT WO Rat 2 DR 6 w NR NR JV M GRO BDWT WO 

Rat 2 FD 10 w NR NR JV M GRO BDWT WO 

Rat 2 OR 6 w NR NR AD M GRO BDWT WO 

Rat 2 DR 7 w NR NR JV M GRO BDWT WO 

Mouse 3 DR 14 d 0 d JV NR GRO BDWT WO Rat 4 GV 9 w 10 w JV M GRO BDWT WO 

Rat 3 FD 339 d 26-27 d JV B GRO BDWT WO Rat 4 GV 29 d NR NR SM F GRO BDWT WO 

Rat 7 DR 10 w NR NR JV M GRO BDWT WO Rat 4 DR 56 d 70 d LC F GRO BDWT WO Sheep 5 FD 84 d NR NR JV M GRO BDWT WO Rat 2 DR 10 w NR NR JV M GRO BDWT WO Cattle 4 FD 7 w 16 w JV M GRO BDWT WO Rat 2 GV 28 d 2 d JV B GRO BDWT WO Rat 5 DR 4 w 94 d JV M GRO BDWT WO Rat 4 GV 12 d 2 d JV B GRO BDWT WO 

Rat 2 FD 4 w NR NR JV M GRO BDWT WO 

Rat 6 DR 10 w NR NR JV M GRO BDWT WO 
 AX7-78 Table AX7-1.3.4 (cont’d). Mammalian Toxicity Data Used to Develop the Eco-SSL Mammalian Species No. of Doses Route of Exposure Exposure Duration Duration Units Age Age Units Lifestage Sex Effect Type Effect Measure Respon

Site 

Mouse 3 FD 4 w 3 mo JV B GRO BDWT WO Mouse 2 DR 18 w 6-8 w LC F GRO BDWT WO Mouse 2 DR 12 w NR NR GE M GRO BDWT WO Rat 3 DR 30 d 52 d JV M GRO BDWT WO Rat 2 DR 4 w 99 d JV B GRO BDWT WO Rat 4 GV 18 d 3 d JV M GRO BDWT WO Mouse 3 DR 6 w 7 w SM M GRO BDWT WO Rat 4 GV 18 d 2 d JV B GRO BDWT WO Rat 2 GV 91 d NR NR JV M GRO BDWT WO Rat 2 DR 21 d 80 d JV F GRO BDWT WO Rat 4 FD 1 w NR NR LC F GRO BDWT WO 

Rat 4 DR 30 d NR NR JV M GRO BDWT WO Mouse 5 DR 10 w NR NR JV M GRO BDWT WO Rat 2 DR 30 d 52 d JV M GRO BDWT WO Rat 4 GV 14 d 14 d JV NR GRO BDWT WO Rat 5 GV 14 d 20 d JV NR GRO BDWT WO Rat 2 FD 14 mo 0 d JV NR GRO BDWT WO Rat 2 GV 102 d 30 d LC F GRO BDWT WO 

Mouse 4 GV 12 d 6 d JV M GRO BDWT WO Mouse 7 FD 30 d NR NR LC F GRO BDWT WO Rat 2 DR 126 d 1 d GE F GRO BDWT WO Rat 2 DR 20 w 10 w GE F GRO BDWT WO 
 AX7-79 Table AX7-1.3.4 (cont’d). Mammalian Toxicity Data Used to Develop the Eco-SSL Mammalian Species No. of Doses Route of Exposure Exposure Duration Duration Units Age Age Units Lifestage Sex Effect Type Effect Measure Respon

Site 

Mouse 7 FD 28 d NR NR LC F GRO BDWT WO Rat 4 FD 18 d NR NR LC F GRO BDWT WO Rat 2 DR 9 d 21 d JV M GRO BDWT WO Cattle 2 FD 283 d 7 mo JV M GRO BDWT WO Rat 3 DR 92 d 25 d GE F MPH GMPH TB 

Rat 4 DR 7 d 25 d GE F GRO BDWT WO 

Rat 2 DR 5 d 26 d JV F GRO BDWT WO Rat 2 DR 26 d 22 d JV F GRO BDWT WO Rat 2 DR 14 d 26 d JV F MPH Other TA Rat 2 DR 10 d 26 d JV F GRO BDWT WO Mouse 2 GV 3 w NR NR JV M GRO BDWT WO Dog 2 OR 5 w <1 yr JV NR GRO BDWT WO Shrew 4 FD 31 d NR NR JV B GRO BDWT WO Rat 3 GV 58 d 2 d JV B GRO BDWT WO Pig 2 FD 13 w 4 w JV NR GRO BDWT WO Rat 2 GV 29 d 2 d JV F GRO BDWT WO Rat 2 FD 5 w NR NR MA NR GRO BDWT WO 

Rat 2 GV 6 d 1 d JV B GRO BDWT WO Rat 2 DR 30 d 27 d JV M GRO BDWT WO Rat 2 DR 50 d 24 d JV M GRO BDWT WO Rat 2 GV 28 d 2 d JV M GRO BDWT WO Rat 4 GV 14 d 18 d JV NR GRO BDWT WO 
 AX7-80 Table AX7-1.3.4 (cont’d). Mammalian Toxicity Data Used to Develop the Eco-SSL Mammalia n Species No. of Doses Route of Exposure Exposure Duration Duration Units Age Age Units Lifestage Sex Effec t Type Effect Measur e Respon

Site 

Mouse 2 DR 45 d 50-100 d GE F GRO BDWT WO Rat 4 FD 1 w NR NR LC F GRO BDWT WO Rat 2 DR 6 w 14 w LC F GRO BDWT WO Mouse 4 DR 10 w 11 w JV F GRO BDWT WO Rat 2 FD 21 d NR NR LC F GRO BDWT WO Rat 2 GV 18 d 2 d JV B GRO BDWT WO Rat 2 FD 2 w 0 d JV NR GRO BDWT WO Rat 4 GV 14 d 24 d JV NR GRO BDWT WO Rat 2 FD 2 w 60-80 d JV M GRO BDWT WO Rat 3 GV 14 d 16 d JV NR GRO BDWT WO Rat 2 FD 14 d 60 d JV M GRO BDWT WO AD = adult; B = both; BDWT = body weight changes; d = days; DEYO = death of young; DR = drinking water; F = female; FD = food; FERT = fertility; GMPH = gen

GRO = growth; GV = gavage; JV = juvenile; LC = lactation; M = male; MA = mature; mo = months; MPH = morphology; NR = not reported; ODVP = offspring devel

PG = prostate gland; PROG = progeny counts or numbers; PRWT = progeny weight; RBPH = reproductive behavior; REP = reproduction; RHIS = reproductive organ embryos; RSUC = reproductive success (general); RT = reproductive tissue; SM = sexually mature; SPCL = sperm cell counts; SPCV = sperm cell viability; TA = tail; 

TEDG = testes degeneration; TEWT = testes weight; w = weeks; WO = whole organism; yr = years. Source: U.S. Environmental Protection Agency (2005b). 
 AX7-81 

Figure AX7-1.3.2. Mammalian reproduction and growth toxicity data considered in 

development of the Eco-SSL. 

Source: U.S. Environmental Protection Agency (2005b). 

wildlife generally would occur at doses greater than the 2 to 8 mg/kg-day reported to be toxic to 

most animals in the 1986 Lead AQCD (U.S. Environmental Protection Agency, 1986a). 

AX7.1.3.4 Recent Studies on the Effects of Lead on Decomposers 

Recent studies on effects of Pb to two groups of decomposers are summarized in this 

subsection. Effects on terrestrial invertebrates, such as earthworms and springtails, are described 

first, followed by effects on microorganisms. 

Effects on Invertebrates 

Since the 1986 Lead AQCD, there have been several studies in which terrestrial 

invertebrates were exposed to Pb in soil. Many of these were reviewed during the development 

of the Eco-SSLs (U.S. Environmental Protection Agency, 2005b). The relevant information 

from the Eco-SSL document is described below. 
 AX7-82 

A literature search and review was conducted to identify critical papers published since 

2002. Effects on earthworms and other invertebrates observed in studies conducted since the 

1986 Lead AQCD are similar to those reported previously: mortality and decreased growth and 

reproduction (Lock and Janssen, 2002; Davies et al., 2002; Rao et al., 2003; Bongers et al., 2004; 

Nursita et al., 2005; U.S. Environmental Protection Agency, 2005b). 

The literature search completed for terrestrial invertebrate Eco-SSL development 

identified 179 papers for detailed review, of which 13 met the minimum criteria for further 

consideration (U.S. Environmental Protection Agency, 2005b). Most of the 18 ecotoxicological 

endpoints that were further evaluated measured reproduction or survival as the ecologically 

relevant endpoint. Four of these, representing one species under three different pH test 

conditions were used to develop the Eco-SSL of 1700 mg/kg soil (Table AX7-1.3.5). 

Table AX7-1.3.5. Invertebrate Toxicity Data Used to Develop the Eco-SSL 

Invertebrate Species Soil pH 

% Organic 

Matter Toxicity Parameter 

Pb in Soil 

(mg/kg dw) 

Collembola 

 (Folsomia candida) 

6.0 10 MATC1 (reproduction) 3162 

Collembola 4.5 10 MATC (reproduction) 3162 

Collembola 5.0 10 MATC (reproduction) 894 

Collembola 6.0 10 MATC (reproduction) 894 

 Geometric Mean 1682 

* MATC = Maximum Acceptable Threshold Concentration, or the geometric mean of the NOEC (no-observedeffect concentration) and LOEC (lowest-observed-effect concentration). 

Source: U.S. Environmental Protection Agency (2005b). 

In a study designed to test the toxicity of Pb to the earthworm Eisenia fetida, Davies 

et al. (2002) found that the 28-day LC50 (± 95% confidence intervals) for Pb in soils 

contaminated with Pb(NO3)2 was 4379 ∀ 356 mg/kg. Twenty-eight day EC50 values 

(±95% confidence intervals) for weight change and cocoon production were 1408 ∀ 198 and 
 AX7-83 

971 ∀ 633 mg/kg, respectively. Significant mortalities were noted at concentrations of 2000 

mg/kg. These data are consistent with those reported in the Eco-SSL document (U.S. 

Environmental Protection Agency, 2005b) for the same species of earthworm. 

Nursita et al. (2005) found no mortality and no adverse effects on reproduction (i.e., 

number of juveniles) of the collembolan Proisotoma minuta exposed for 42 days to 300, 750, 

1500, or 3000 mg Pb/kg as Pb-nitrate in an acidic (pH = 4.88) sandy loam soil. It was noted that 

the soils were allowed to equilibrate for 4 weeks after adding the Pb-nitrate before the organisms 

were added. The observation of no effect at 3000 mg/kg is consistent with that of Sandifer and 

Hopkin (1996). Sandifer and Hopkin (1996) determined a NOEC (no-observed-effect 

concentration) and LOEC (lowest-observed-effect concentration) for collembolan reproduction 

of 2000 and 5000 mg/kg, respectively. (A MATC [maximum-acceptable-threshold 

concentration] of 3162 mg/kg was used to develop the Eco-SSL). 

The remaining 14 toxicity endpoints that were not used to develop the Eco-SSL for 

invertebrates are presented in Table AX7-1.3.6. None of these endpoints was considered eligible 

for Eco-SSL derivation. 

Lock and Janssen (2002) exposed the potworm Enchytraeus albidus to Pb, as Pb-nitrate. 

The 21-day LC50 was 4530 mg/kg, and the 42-day EC50 for juvenile reproduction was 

320 mg/kg. The F1 generation was then grown to maturity in the same concentration soil and 

subsequently used in a reproduction test. The EC50 for the F1 generation (394 mg/kg) was 

similar to that of the P generation. The authors concluded that the two-generation assay did not 

increase the sensitivity of the test (Lock and Janssen, 2002). None of the 18 toxicity endpoints 

evaluated in detail during development of the Eco-SSLs used this species. The LC50 reported for 

the potworm was higher than reported for nematodes and similar to that reported for the 

earthworm. The EC50 for reproduction was lower than reported for the earthworm or collembola. 

Recent work by Bongers et al. (2004) cautioned against attributing all toxicity observed in 

a spiked-soil toxicity test to Pb. They found that the counterion may also contribute to the 

toxicity of Pb in the springtail Folsomia candida. This may have implications on the 

interpretation of the Eco-SSL data, because the toxicity of the counterion (nitrate) was not taken 

into account during Eco-SSL development. Percolation (removal of the counterion) had no 

statistically significant effect on Pb-chloride toxicity (LC50 = 2900 mg/kg for both nonpercolated and percolated soil; EC50 for reproduction = 1900 mg/kg or 2400 mg/kg for 
 AX7-84 

Table AX7-1.3.6. Invertebrate Toxicity Data Not Used to Develop the Eco-SSL 

Invertebrate Species Soil pH 

% Organic 

Matter 

Toxicity 

Parameter 

Pb in Soil 

(mg/kg dw) 

Nematode 4 1.14 LC50 285 

Nematode 4 1.14 LC50 297 

Nematode 4 4.2 LC50 847 

Nematode 4 4.2 LC50 1341 

Nematode 6.2 1.7 LC50 1554 

Nematode 5.1 3.0 LC50 891 

Earthworm 6.3 10.0 EC50 1940 

Earthworm 6.1 10.0 EC50 1629 

Earthworm 6.0 10.0 LC50 3716 

Earthworm 6.5 10.0 ILL 1.16 

Nematode 4 10 LC50 1434 

Nematode 4 10 NOAEC 2235 

Nematode 6.1 3.4 LC50 13.9 

Nematode 6.2 2.2 LC50 11.6 

*NOAEC (no-observed-adverse-effect concentration); LC50 (concentration lethal to 50% of test population); 

 EC50 (effect concentration for 50% of test population); ILL (incipient lethal level). 

Source: U.S. Environmental Protection Agency (2005b). 

non-percolated or percolated soil, respectively). However, percolation did have a significant 

effect on Pb-nitrate toxicity (LC50 = 980 mg/kg or 2200 mg/kg for non-percolated or percolated 

soil, respectively; EC50 for reproduction = 580 mg/kg or 1700 mg/kg for non-percolated or 

percolated soil, respectively). Lead nitrate was more toxic than Pb-chloride for survival and 

reproduction. However, the toxicity of Pb, from chloride or nitrate, was not significantly 

different after the counterion was percolated out of the test soil. It is noted that the soil was left 

for 3 weeks to equilibrate before testing. Lock and Janssen (2002) also found that Pb-nitrate was 

more toxic than Pb-chloride, and they used Pb-nitrate in their experiments because 1000 mg/kg 

Pb-chloride did not produce any mortality in their range-finding tests. This difference in 
 AX7-85 

chloride and nitrate toxicity has not been found for earthworms (Neuhauser et al., 1985; Bongers 

et al., 2004). 

Rao et al. (2003) exposed the earthworm Eisenia fetida to Pb-oxide in an artificial soil 

with a pH of 6 at the LC50 concentration of 11 mg/kg. Exposure for 14 days resulted in a number 

of effects including body fragmentation, protrusions, rupture of the cuticle, etc. Many of these 

effects may trigger defensive mechanisms. For example, fragmentation of the affected posterior 

region was followed by regeneration and a new ectoderm layer was formed to cover affected 

areas, both of which processes may serve to prevent soil bacteria from further affecting the 

earthworm (Rao et al., 2003). 

Effects on Microorganisms and Microbial Processes 

Microorganisms and microbial processes were not included in the Eco-SSL development 

process (see Attachment 1-2 of OSWER Directive 92857-55 dated November 2003 in U.S. 

Environmental Protection Agency [2005a]). Many reasons were given, including that it is 

unlikely that site conditions would only pose unacceptable risk to microbes and not be reflected 

as unacceptable risks to higher organisms; that the significance of laboratory-derived effects data 

to the ecosystem is uncertain; and that the spatial (across millimeter distances) and temporal 

(within minutes to hours) variation makes understanding ecological consequences challenging. 

Microbial endpoints often vary dramatically based on moisture, temperature, oxygen, and many 

non-contaminant factors. Therefore, the recommendation arising from the Eco-SSL 

development process was that risks to microbes or microbial processes not be addressed through 

the chemical screening process but that they should be addressed within a site-specific risk 

assessment (U.S. Environmental Protection Agency, 2005b). 

Few studies on the effects of Pb to microbial processes have been published since 1986. 

As the direct toxicity to fungi and bacterial populations are difficult to determine and interpret, 

indicators for soil communities are often measured as proxies for toxicity (e.g., urease activity in 

soil). Recent studies of this nature (Doelman and Haanstra, 1986; Wilke, 1989; Haanstra and 

Doelman, 1991) are summarized in this subsection. The Pb concentrations in these recent 

studies (1000 to 5000 mg/kg) are consistent with those reported in the 1986 Lead AQCD (U.S. 

Environmental Protection Agency, 1986a) as associated with effects on microbial processes 

(750 to 7500 mg/kg). 
 AX7-86 

The effects of Pb-chloride on the processes of nitrification and nitrogen mineralization 

were studied in a 28-day experiment by Wilke (1989). The authors reported that nitrification 

was increased by 12 and 16% at levels of 1000 and 4000 mg/kg, respectively, and that nitrogen 

mineralization was reduced by 32 and 44% at concentrations of 1000 and 4000 mg/kg, 

respectively. 

The effects of Pb on arylsulfatase (Haanstra and Doelman, 1991) and urease activity 

(Doelman and Haanstra, 1986) in soil were investigated. LC50s for decreases in arylsulfatase 

activity were reported at Pb concentrations of 3004 and 4538 mg/kg in a silty loam soil, at pH 6 

and 8, respectively. The LC50 for a decrease in urease activity was 5060 mg Pb/kg in a sandy 

loam soil. 

In laboratory microcosm studies Cotrufo et al. (1995) found that decomposition of oak 

(Quercus ilex) leaf litter was reduced at elevated Pb (~20 mg Pb g!1 C) levels after 8 months 

compared to controls (~2 mg Pb g!1 C). The researchers found soil respiration and amount of 

soil mycelia correlated negatively with soil Pb, Zn and Cr concentration. 

AX7.1.3.5 Summary 

The current document expands upon and updates knowledge related to the effects of Pb 

on terrestrial primary producers, consumers, and decomposers. 

Primary Producers 

The effects of Pb on terrestrial plants include decreased photosynthetic and transpiration 

rates in addition to decreased growth and yield. The phytotoxicity of Pb is considered to be 

relatively low, and there are few reports of phytotoxicity from Pb exposure under field 

conditions. Recently, phytotoxicity data were reviewed for the development of the Eco-SSL 

(U.S. Environmental Protection Agency, 2005b). Many of the toxicity data presented in the EcoSSL document (U.S. Environmental Protection Agency, 2005b) are lower than those discussed in 

the 1986 Lead AQCD, although both documents acknowledged that toxicity is observed over a 

wide range of concentrations of Pb in soil (tens to thousands of mg/kg soil). This may be due to 

many factors, such as soil conditions (e.g., pH, organic matter) and differences in bioavailability 

of the Pb in spiked soils perhaps due to lack of equilibration of the Pb solution with the soil after 

spiking. Most phytotoxicity data continue to be developed for agricultural plant species (i.e., 
 AX7-87 

vegetable and grain crops). Few data are available for trees or native herbaceous plants, 

although two of the five toxicity endpoints used to develop the Eco-SSL were for trees and two 

were for clover. 

Consumers 

Effects of Pb on avian and mammalian consumers include decreased survival, 

reproduction, and growth as well as effects on development and behavior. There remain few 

field effects data for consumers, except from sites with multiple contaminants, for which it is 

difficult to attribute toxicity specifically to Pb. Avian and mammalian toxicity data recently 

were reviewed for the development of Eco-SSLs (U.S. Environmental Protection Agency, 

2005b). Many of the toxicity data presented in the Eco-SSL document (U.S. Environmental 

Protection Agency, 2005b) are lower than those discussed in the 1986 Lead AQCD, although the 

EPA (U.S. Environmental Protection Agency, 2005b) recognizes that toxicity is observed over a 

wide range of doses (<1 to >1000 mg Pb/kg bw-day). Most toxicity data for birds have been 

derived from chicken and quail studies, and most data for mammals have been derived from 

laboratory rat and mouse studies. Data derived for other species would contribute to the 

understanding of Pb toxicity, particularly for wildlife species with different gut physiologies. 

In addition, data derived using environmentally realistic exposures, such as from Pbcontaminated soil and food, may be recommended. Finally, data derived from inhalation 

exposures, which evaluate endpoints such as survival, growth, and reproduction, would 

contribute to understanding the implications of airborne releases of Pb. 

Decomposers 

Effects of Pb on soil invertebrates include decreased survival, growth, and reproduction. 

Effects on microorganisms include changes in nitrogen mineralization and enzyme activities. 

Recent data on 1986 Lead toxicity to soil invertebrates and microorganisms are consistent with 

those reported in the 1986 Lead AQCD (U.S. Environmental Protection Agency, 1986a), with 

toxicity generally observed at concentrations of hundreds to thousands of mg/kg soil. Studies on 

microbial processes may be influenced significantly by soil parameters, and the significance of 

the test results is not clear. 
 AX7-88 

Ecological Soil Screening Levels (Eco-SSLs) 

Eco-SSLs are concentrations of contaminants in soils that would result in little or no 

measurable effect on ecological receptors (U.S. Environmental Protection Agency, 2005a). They 

were developed following rigorous scientific protocols and were subjected to two rounds of peer 

review. Due to conservative modeling assumptions (e.g., metal exists in most toxic form or 

highly bioavailable form, high food ingestion rate, high soil ingestion rate) which are common to 

screening processes, several Eco-SSLs are derived below the average background soil 

concentration for a particular contaminant. 

The Eco-SSLs for terrestrial plants, birds, mammals, and soil invertebrates are 120, 11, 

56, and 1700 mg Pb/kg soil, respectively. 

AX7.1.4 Effects of Lead on Natural Terrestrial Ecosystems 

The concept that organisms are part of larger systems that include both biotic and abiotic 

components of the environment dates back to the naturalists of the Victorian era. However, the 

breakthrough in what we now consider the ecosystem approach to ecology occurred in the 1950s 

and 1960s when E.P. and H.T. Odum pioneered the quantitative analysis of ecosystems 

(Odum, 1971). This approach encouraged the calculation of energy flows into, out of, and 

within explicitly defined ecosystems. The rapid development of computer technology aided in 

the growth of ecosystem ecology by allowing the development and use of increasingly complex 

models for estimating fluxes that could not be directly measured. 

It was not long before the quantitative analysis of ecosystems was extended to examine 

the flows of nutrients and other chemical compounds. In temperate terrestrial systems, the 

watershed was identified as a convenient and informative experimental unit (Bormann and 

Likens, 1967). A major conceptual breakthrough in the watershed approach was that drainage 

water chemistry could be used as an indicator of the “health” of the ecosystem. In a system 

limited by nitrogen, for example, elevated concentrations of NO3

!

 in drainage waters indicate that 

the ecosystem is no longer making optimal use of available nutrients. 

The ecosystem approach can also be used effectively in the study of trace element 

biogeochemistry. Input-output budgets can be used to determine whether an ecosystem is a net 

source or sink of a trace element. Changes to the input-output balance over time can be used to 

assess the effects of natural or experimental changes in deposition, land use, climate, or other 
 AX7-89 

factors. In addition, examination of fluxes within the ecosystem (in plant uptake, soil solutions, 

etc.) can be used to understand the processes that are most influential in determining the fate and 

transport of the trace element. 

Many published ecosystem studies include data for 1 to 3 years, the typical duration of 

research grant funding or doctoral dissertation research. While these studies enrich our 

understanding of terrestrial ecosystems, the most valuable studies are those that are maintained 

over many years. Natural variations in climate, pests, animal migrations, and other factors can 

make inferences from short-term studies misleading (Likens, 1989). To nurture long-term 

research, the National Science Foundation supports a network of Long-Term Ecological 

Research (LTER) sites that represent various biomes. 

This section describes terrestrial ecosystem research on Pb, focusing on work done since 

the 1986 Lead AQCD (U.S. Environmental Protection Agency, 1986a) and highlighting key 

long-term studies. Unfortunately, there are few studies that feature long-term data on trace metal 

behavior at multiple levels of organization. Therefore, this examination of the effects of Pb on 

terrestrial ecosystems combines insights from long- and short-term investigations as well as 

studies at scales including whole ecosystems, communities, populations, and individual species. 

AX7.1.4.1 Effects of Terrestrial Ecosystem Stresses on Lead Cycling 

Terrestrial ecosystems may respond to stressors in a variety of ways, including reductions 

in the vigor and/or growth of vegetation, reductions in biodiversity, and effects on microbial 

processes. Each of these effects may lead to the “leakage” of nutrients, especially nitrogen, in 

drainage waters. The reduced vigor or growth of vegetation results in a lower uptake of nitrogen 

and other nutrients from soils. Reduced biodiversity accompanied by lower total net primary 

productivity for the ecosystem would also result in a lower nutrient uptake. Effects of stress in 

microbial populations are less obvious. If the stress reduces microbial activity rates, then 

nutrients bound in soil organic matter (e.g., organic nitrogen compounds) will likely be 

mineralized at a lower rate and retained in the system. On the other hand, disturbances such as 

clear-cutting, ice-storm damage, and soil freezing can result in substantial nutrient losses from 

soils (Bormann et al., 1968; Likens et al., 1969; Mitchell et al., 1996; Groffman et al., 2001; 

Houlton et al., 2003). 
 AX7-90 

Since the movement and fate of Pb in terrestrial ecosystems is strongly related to the 

organic matter cycle (Section AX7.1.2), stressors that could lead to disruption or alteration of the 

soil organic matter pool are of particular concern in assessing effects of ecosystem stress on Pb 

cycling. By binding soluble Pb, soil organic matter acts as a barrier to the release of Pb to 

drainage waters (Wang et al., 1995; Kaste et al., 2003; Watmough and Hutchinson, 2004). As a 

result, concentrations of Pb in soil solutions and drainage waters tend to be low (Driscoll et al., 

1988; Wang et al., 1995; Bacon and Bain, 1995; Johnson et al., 1995a). Through decomposition 

and leaching, soluble organic matter is released to solution, and with it, some Pb is also 

mobilized. Wang and Benoit (1996) found that essentially all of the Pb in soil solutions in a 

hardwood forest in New Hampshire was bound to dissolve organic matter (DOM). This release 

of soluble Pb does not typically result in elevated surface water Pb concentrations, because 

(1) organic matter has a relatively long residence time in most temperate soils (Gosz et al., 1976; 

Schlesinger, 1997), so only a small fraction of the organic matter pool is dissolved at any time; 

(2) DOM-Pb complexes solubilized in upper soil horizons may be precipitated or adsorbed lower 

in the soil profile; (3) the DOM to which Pb is bound may be utilized by microbes, allowing the 

associated Pb to bind anew to soil organic matter. Together, these factors tend to moderate the 

release of Pb to surface waters in temperate terrestrial ecosystems. However, stressors or 

disturbances that result in increased release of DOM from soils could result in the unanticipated 

release of Pb to groundwater and/or surface waters. 

Acidification 

The effect of acidification on ecosystem cycling of Pb is difficult to predict. Like most 

metals, the solubility of Pb increases as pH decreases (Stumm and Morgan, 1995), suggesting 

that enhanced mobility of Pb should be found in ecosystems under acidification stress. However, 

Pb is also strongly bound to organic matter in soils and sediments. Reductions in pH may cause 

a decrease in the solubility of DOM, due to the protonation of carboxylic functional groups 

(Tipping and Woof, 1990). Because of the importance of Pb complexation with organic matter, 

lower DOM concentrations in soil solution resulting from acidification may offset the increased 

solubility of Pb and hence decrease the mobility of the organically bound metal. 

In a study of grassland and forest soils at the Rothamsted Experiment Station in England, 

long-term (i.e., >100 years) soil acidification significantly increased the mobility of Pb in the soil 
 AX7-91 

(Blake and Goulding, 2002). However, the increased mobility was only observed in very acid 

soils, those with pH of <4.5. The fraction of exchangeable Pb (extracted with 0.1 M CaCl2) 

increased from about 3% to 15% of the total Pb in the most acidified soils. Similarly, the 

fraction of organically bound Pb increased from about 2% of total Pb in neutral soils to 12% of 

total Pb in the most acidified soils. Similarly, Nouri and Reddy (1995) observed higher levels of 

diethylenetriaminepentaacetic-acid-[DTPA]-extractable Pb in soils in a loblolly pine forest 

treated with simulated acid rain, but only in the most acidic treatment, with simulated rain with a 

pH of 3.5. 

Although acidification may increase the mobility of Pb in some soils, it is not clear that 

this Pb is actually moving through or out of the soil profile. In an examination of running waters 

in Sweden, Johansson et al. (1995) found no relationship between acidification and Pb 

concentrations in drainage waters and concluded that Pb concentrations were governed by the 

DOM concentration, which masked any association with acidification. In an in situ lysimeter 

study, Bergkvist (1986) measured lower concentrations of Pb in soil solutions draining 

experimentally acidified plots than in unacidified plots. In a laboratory study using large soil 

columns, Merino and García-Rodeja (1997) observed no effect of experimental acidification on 

the release of Pb to soil solution. Thus, while acidification may increase the potential mobility of 

Pb in soils, as indicated by increases in labile soil fractions such as exchangeable and DTPAextractable Pb, the actual movement of Pb in the soil is limited by DOM solubilization and 

transport. It is worth noting that in all of these studies, significant effects of acidification were 

observed for other trace metals (Bergkvist, 1986; Johansson et al., 1995; Merino and GarcíaRodeja, 1997). 

Acidification may enhance Pb export to drainage water in very sandy soils, soils with 

limited ability to retain organic matter. Studies in the McDonald’s Branch watershed in the 

New Jersey pine barrens, where soil texture is similar to beach sands, suggested little Pb 

retention in the mineral soil (Swanson and Johnson, 1980; Turner et al., 1985). If acidification 

results in the mobilization of Pb and organic matter into these mineral soils, then increased 

streamwater Pb concentrations would likely follow. 
 AX7-92 

Land Use and Industry 

Changes in land use also represent potentially significant changes in the cycling of 

organic matter in terrestrial ecosystems. Conversion of pasture and croplands to woodlands 

changes the nature and quantity of organic matter inputs to the soil. In temperate climates, forest 

ecosystems tend to accumulate organic matter in an O horizon on the forest floor, whereas 

organic matter in grasslands and agricultural fields is concentrated in an A horizon at the soil 

surface. Andersen et al. (2002) compared the trace metal concentrations in arable fields in 

Denmark to nearby sites that had been converted to forest land. After 34 years of afforestation, 

the soils showed no significant difference in Pb concentration or fractionation, despite significant 

acidification of the soils. Afforestation had no effect on the soil carbon concentration, 

suggesting that land use change may have little effect on Pb cycling unless soil carbon pools are 

affected. 

Similarly, the introduction of industrial activity may have consequences for organic 

matter cycling, and subsequently, Pb mobilization. In a rare long-term study of polluted soils, 

Egli et al. (1999) studied the changes in trace metal concentrations in forest soils at a site in 

western Switzerland between 1969 and 1993. The site is 3 to 6 km downwind from an aluminum 

industrial plant that operated between the 1950s and 1991. In the 24-year period of study, the 

site experienced significant declines in organic carbon in surface (0 to 5 cm depth) and 

subsurface (30 to 35 cm) soils. In the 30 to 35 cm layer, the organic carbon concentration 

declined by more than 75%. Extractable Pb (using an ammonium acetate and EDTA mixture) 

declined by 35% in the same layer. The authors suggested that the Pb lost from the soil had been 

organically bound. While this study indicates that loss of soil carbon can induce the mobilization 

and loss of Pb from terrestrial ecosystems, it is also worth noting that the decline in soil Pb was 

considerably smaller than the decline in organic carbon. This suggests that Pb mobilized during 

organic matter decomposition can resorb to remaining organic matter or perhaps to alternate 

binding sites (e.g., Fe and Mn oxides). 

The effects of industries that emit Pb to the atmosphere are discussed in Sections 

AX7.1.5.2 and AX7.1.5.3 below. 

Forest harvesting represents a severe disruption of the organic matter cycle in forest 

ecosystems. Litter inputs are severely reduced for several years after cutting (e.g., Hughes and 

Fahey, 1994). The removal of the forest canopy results in reduced interception of precipitation, 
 AX7-93 

and, therefore, increased water flux to the soil surface. Also, until a new canopy closes, the soil 

surface is exposed to increased solar radiation and higher temperatures. Together, the higher 

moisture and temperature in surface soils tend to increase the rate of organic matter 

decomposition. Several studies have estimated decreases of up to 40% in the organic matter 

content of forest floor soils after clear-cutting (Covington, 1981; Federer, 1984; Johnson et al., 

1995b). This loss of organic matter from the forest floor could result in the mobilization of 

organically complexed Pb. However, observations from clear-cut sites in the United States and 

Europe indicate that forest harvesting causes little or no mobilization of Pb from forest soils. 

At the Hubbard Brook Experimental Forest in New Hampshire, whole-tree harvesting, the 

most intensive form of clear-cutting, resulted in very small increases in Pb concentrations in soil 

solutions draining the Oa soil horizon despite substantial reductions in the organic matter mass of 

that horizon (Fuller et al., 1988; Johnson et al., 1995b). These increases were associated with 

similarly small increases in dissolved organic carbon (DOC) concentrations in the Oa horizon 

soil water. Output of Pb from the watershed stream was unaffected by clear-cutting. Similarly, 

Berthelsen and Steinnes (1995) observed small decreases in the Pb content of the Oa horizon 

(“H” in the European system of soil classification) in clear-cut sites in Norway, compared to 

uncut reference sites. This mobilization of Pb from the Oa horizon was accompanied by an 

increase in the Pb content of the upper mineral soil horizons. The Pb decline in the Oa horizon 

was accompanied by a decrease in the organic matter content, leading the authors to attribute the 

Pb dynamics to leaching with DOM. In a study conducted in Wales, Durand et al. (1994) 

observed lower Pb outputs from a stream draining a clear-cut watershed than from where the 

stream drained the upper reaches of the watershed, which were uncut. The DOC and H+

 outputs 

were also lower in the clear-cut area. These patterns persisted in all 5 years of the study. 

Forest harvesting is a severe form of ecosystem disturbance, and, thus, it is somewhat 

surprising that studies of clear-cutting have shown little or no effect on Pb mobility or loss from 

forest ecosystems. Perhaps the strong complexation behavior of Pb with natural organic matter 

results in the retention of Pb in forest soils. Even in cases where Pb is mobilized in forest floor 

soils (Fuller et al., 1988; Berthelsen and Steinnes, 1995), there is no evidence of loss of Pb from 

the ecosystem, indicating that mineral soils are efficient in capturing and retaining any Pb that is 

mobilized in the forest floor. Therefore, the principal risk associated with forest harvesting is the 

loss of Pb in particulate form to drainage waters through erosion. In some relatively remote 
 AX7-94 

lakes in the United Kingdom the distribution of sediment-bound trace elements (including Pb) 

have been affected by forestry activities and catchment erosion (Yang and Rose, 2005). Yang 

and Rose (2005) believe that more contaminated soil in-wash could increase sediment heavy 

metal concentrations while less contaminated soil in-wash could dilute sediment heavy metal 

levels. 

Climate Change 

Atmospheric Pb is not likely to contribute significantly to global climate change. Lead 

compounds have relatively short residence times in the atmosphere, making it unlikely that they 

will reach the stratosphere. Also, Pb compounds are not known to absorb infrared radiation and, 

therefore, are unlikely to contribute to stratospheric ozone depletion or global warming. 

Climate change does, however, represent a disturbance to terrestrial ecosystems. 

Unfortunately, the potential linkages between climate-related stress and Pb cycling are poorly 

understood. As in the previous examples, effects related to alterations in organic matter cycling 

may influence Pb migration. For example, an increase in temperature leading to increased rates 

of organic matter decomposition could lead to temporary increases in DOM concentrations and 

smaller steady-state pools of soil organic matter. Either of these factors could result in increased 

concentrations of Pb in waters draining terrestrial ecosystems. 

Climate change may also affect the fluctuations of temperature and/or precipitation in 

terrestrial ecosystems. For example, there is some evidence for recent increases in the frequency 

of soil freezing events in the northeastern United States (Mitchell et al., 1996). Soil freezing 

occurs when soils have little or no snow cover to insulate them from cold temperatures and 

results in an increased release of nitrate and DOC from the O horizons of forest soils (Mitchell 

et al., 1996; Fitzhugh et al., 2001). Increased DOC losses from O horizons subjected to freezing 

may also increase Pb mobilization. 

Increased fluctuations in precipitation may induce more frequent flooding, with 

potentially significant consequences for Pb contamination of floodplain ecosystems. Soils 

collected from the floodplain of the Elbe River, in Germany, contained elevated concentrations 

of Pb and other trace metals (Krηger and Grongroft, 2003). Tissues of plants from floodplain 

sites did not, however, contain higher Pb concentrations than control sites. More frequent 
 AX7-95 

or more severe flooding would likely result in increased inputs of Pb and other metals to 

floodplain soils. 

AX7.1.4.2 Effects of Lead Exposure on Natural Ecosystem Structure and Function 

The effects of Pb exposure on natural ecosystems are confounded by the fact that Pb 

exposure cannot be decoupled from other factors that may also affect the ecosystem under 

consideration. Principal among these factors are other trace metals and acidic deposition. 

Emissions of Pb from smelting and other industrial activities are accompanied by other trace 

metals (e.g., Zn, Cu, and Cd) and sulfur dioxide (SO2) that may cause toxic effects independently 

or in concert with Pb. Reductions in the use of alkyl-Pb additives in gasoline have resulted in 

significant decreases in Pb deposition to natural ecosystems in the northeastern United States 

(Johnson et al., 1995a). However, the period in which Pb deposition has declined (ca. 1975 to 

the present) has also seen significant reductions in the acidity (i.e., increased pH) of precipitation 

in the region (Likens et al., 1996; Driscoll et al., 1998). Therefore, changes in ecosystem Pb 

fluxes may be the result of reduced Pb inputs and/or reduced acidity. 

Experimental manipulation studies do not suffer from these confounding effects, because 

Pb can be added in specific amounts, with or without other compounds. Unfortunately, 

ecosystem-level manipulations involving Pb additions have not been undertaken. Therefore, we 

must use observations from field studies of Pb behavior in sites exposed to various forms of Pb 

pollution to assess the effects of Pb on terrestrial ecosystems. This section includes a discussion 

of effects of Pb in the structure and function of terrestrial ecosystems. Effects on energy flows 

(food chain effects) and biogeochemical cycling are discussed in Section AX7.1.5.3. 

Sites Affected by Nearby Point Sources of Lead 

Natural terrestrial ecosystems near smelters, mines, and other industrial plants have 

exhibited a variety of effects related to ecosystem structure and function. These effects include 

decreases in species diversity, changes in floral and faunal community composition, and 

decreasing vigor of terrestrial vegetation. 

All of these effects were observed in ecosystems surrounding the Anaconda smelter in 

southwestern Montana, which operated between 1884 and 1980 (Galbraith et al., 1995). Soils in 

affected areas around the Anaconda smelter were enriched in Pb, arsenic, copper, cadmium, and 
 AX7-96 

zinc; had very low pH; and were determined to be phytotoxic to native vegetation (Kapustka 

et al., 1995). The elevated soil arsenic and metal concentrations occurred despite significantly 

lower organic matter concentrations in affected soils relative to reference sites (Galbraith et al., 

1995). Line-transect measurements indicated that affected sites had an average of 6.9 species per 

10-m of transect, compared to 20.3 species per 10-m in the reference areas. More than 60% of 

the reference sites supported coniferous (58%) or deciduous (3%) forest communities, whereas 

less than 1% of the affected sites retained functioning forest stands. Abundant dead timber and 

stumps confirmed that the affected sites were once as forested as the reference sites. Affected 

grassland sites were also less diverse and had higher abundances of invasive species than 

reference grasslands. More than 50% of the affected sites were classified as bare ground. The 

occurrence of bare ground was significantly correlated with the phytotoxicity scores derived by 

Kapustka et al. (1995), indicating a link between phytotoxicity and the loss of vegetation in the 

affected area. 

Because of the plant community changes near the Anaconda smelter, the vertical diversity 

of habitats in the affected ecosystems decreased, with only shrubs and soil remaining as viable 

habitats. Galbraith et al. (1995) also used the Bureau of Land Management’s habitat evaluation 

procedure (HEP) to estimate habitat suitability indices (HSI) for two indicator species, marten 

(Martes americana) and elk (Cervus elaphus). The HSI value ranges from 0 (poor habitat) to 

1 (ideal habitat). In sites affected by the Anaconda smelter, HSI values for marten averaged 0.0, 

compared to 0.5 to 0.8 for the reference sites. For elk, affected sites had an average HSI of 0.10, 

compared to 0.31 at reference sites. 

Similar observations were made in the area surrounding Palmerton, Pennsylvania, where 

two zinc smelters operated between 1898 and 1980. Soils in the area were enriched in Cd, Zn, 

Pb, and Cu, with concentrations decreasing with distance from the smelter sites (Beyer et al., 

1985; Storm et al., 1994). Smelting was determined to be the principal source of Pb in soils in 

residential and undeveloped areas around Palmerton (Ketterer et al., 2001), which lies on the 

north side of a gap in Blue Mountain, a ridge running roughly east-west in east-central 

Pennsylvania. Much of the north-facing side of Blue Mountain within 3 km of the town is bare 

ground or sparsely vegetated, whereas the surrounding natural landscape is predominantly oak 

forest (Sopper, 1989; Storm et al., 1994). Biodiversity in affected areas is considerably lower 

than at reference sites, a pattern attributed to emissions from the smelters (Beyer et al., 1985; 
 AX7-97 

Sopper, 1989). The history is complicated, however, by the land use history of the area. 

Logging and fire in the early 20th century may also have played a role in the changes in the 

terrestrial ecosystems (Jordan, 1975). Extensive logging occurred after the smelters began 

operation, suggesting that some of the logging may have been salvage logging in affected areas. 

Regardless, the smelter emissions appear to have inhibited the regrowth of ecosystems compared 

to those in nearby unaffected areas. As in Anaconda, MT, the changes in the structure and 

function of the Palmerton ecosystem changed its suitability as a habitat for fauna that would 

normally inhabit the area. Storm et al. (1994) did not find amphibians or common invertebrates 

in two study sites nearest to the smelters. In the larger study area, they documented elevated 

concentrations of Pb, Cd, Cu, and Zn in tissues of species ranging in size from red-backed 

salamanders (Pletheron cenereus) to white-tailed deer (Odocoilius virginianus). 

Metal pollution around a Pb-Zn smelter near Bristol, England has not resulted in the loss 

of oak woodlands within 3 km of the smelter, despite significant accumulation of Pb, Cd, Cu, 

and Zn in soils and vegetation (Martin and Bullock, 1994). However, the high metal 

concentrations have favored the growth of metal-tolerant species in the woodland. 

The effects of Pb and other chemical emissions on terrestrial ecosystems near smelters 

and other industrial sites decrease downwind from the source. Several studies using the soil 

burden as an indicator have shown that much of the contamination occurs within a radius of 

20 to 50 km around the emission source (Miller and McFee, 1983; Martin and Bullock, 1994; 

Galbraith et al., 1995; Spurgeon and Hopkin, 1996a; see also Section AX7.1.2). For example, 

the concentration of Pb in forest litter declined downwind from a Pb-Zn smelter near Bristol, 

UK, from 2330 to 3050 ppm in a stand 2.9 km from the smelter to 45 to 110 ppm in a stand 

23 km from the smelter (Martin and Bullock, 1994). Thus, while sites near point sources of Pb 

may experience profound effects on ecosystem structure and function, the extent of those effects 

is limited spatially. Elevated metal concentrations around smelters have been found to persist 

despite significant reductions in emissions (Hrsak et al., 2000). Most terrestrial ecosystems are 

far enough from point sources that long-range Pb transport is the primary mechanism for Pb 

inputs. 
 AX7-98 

Sites Affected by Long-Range Lead Transport 

Because the effects of anthropogenic Pb emissions tend to be restricted in geographic 

extent, most natural terrestrial ecosystems in the U.S. sites have Pb burdens derived primarily 

from long-range atmospheric transport. Pollutant Pb represents a large fraction of the Pb in 

many of these ecosystems. In particular, many of these sites have accumulated large amounts of 

Pb in soils. For example, at the Hubbard Brook Experimental Forest in New Hampshire, the 

amount of Pb in the forest floor was estimated to have increased from about 1.35 kg ha!1 in 1926 

(before the introduction of alkyl-Pb additives in gasoline) to 10.5 kg ha!1 in 1977 (Johnson et al., 

1995a). They also estimated the atmospheric Pb deposition from 1926 to 1987 to be 8.7 kg ha!1

, 

an amount that could account for nearly all of the increase in Pb in the forest floor during the 

period. The input of precipitation Pb to the Hubbard Brook ecosystem in the six decades 

spanning 1926 to 1987 was more than half of the total Pb estimated to have been released by 

mineral weathering in the entire 12,000- to 14,000-year post-glacial period (14.1 kg ha!1

: 

[Johnson et al., 2004]). Other studies employing Pb budgets (Miller and Friedland, 1994; 

Watmough et al., 2004), and Pb isotopes (Bacon et al., 1995, 1996; Watmough et al., 1998; 

Bindler et al., 1999; Hansmann and Köppel, 2000; Kaste et al., 2003), have also shown that 

pollutant Pb, primarily from gasoline combustion, represents a quantitatively significant fraction 

of labile Pb in temperate soils, especially in the upper, organic-rich horizons. 

Despite years of elevated atmospheric Pb inputs and elevated concentrations in soils, there 

is little evidence that sites affected primarily by long-range Pb transport have experienced 

significant effects on ecosystem structure or function. Low concentrations of Pb in soil 

solutions, the result of strong complexation of Pb by soil organic matter, may explain why few 

ecological effects have been observed. At Hubbard Brook, for example, the concentration of Pb 

in soil solutions draining the Oa horizon is <0.1 μM and is even lower in solutions draining 

mineral-soil horizons (Driscoll et al., 1988; Wang et al., 1995). Friedland and Johnson (1985) 

measured similar concentrations in soil solutions collected from deciduous and spruce-fir stands 

on Camel’s Hump Mountain in Vermont. In an undeveloped, forested watershed in Maryland, 

Scudlark et al. (2005) found that atmospheric input of some elements (Al, Cd, Ni, Zn) is 

effectively transmitted through the watershed, whereas other elements (Pb, As, Se, Fe, Cr, Cu) 

are strongly sequestered, in the respective order noted. 
 AX7-99 

In ecosystems where Pb concentrations in soil solutions are low, toxicity levels for 

vegetation are not likely to be reached regardless of the soil Pb concentration. Furthermore, 

mycorrhizal infection of tree roots appears to reduce the translocation of Pb from roots to shoots 

(Marschner et al., 1996; Jentschke et al., 1998). In a study of mycorrhizal and non-mycorrhizal 

Norway spruce (Picea abies (L.) Karst.), mycorrhizal infection of roots was not affected by Pb 

dose. Some, but not all, species of mycorrhizae showed reductions in the amount of 

extrametrical mycelium with Pb exposure but only at solution concentrations of 5 μM, a level at 

least 50 times greater than typical concentrations in forest soils. In a related study, the growth 

rate of mycorrhizal fungi was unaffected at solution Pb concentrations of 1 and 10 μM, but 

decreased at 500 μM (Marschner et al., 1999). 

Low soil solution Pb concentrations and the influence of mycorrhizal symbionts also 

result in low uptake of Pb by terrestrial vegetation. The net flux of Pb into vegetation in the 

northern hardwood forest at Hubbard Brook in the 1980s was estimated as only 1 g ha!1 year!1

(Johnson et al., 1995a), representing 3% of the precipitation input. Klaminder et al. (2005) also 

measured a Pb uptake of 1 g ha!1 year!1 in a spruce-pine forest in northern Sweden. Despite plant 

uptake fluxes being very low, they are sensitive to differences and changes in Pb deposition. 

Berthelsen et al. (1995) observed decreases in the Pb content of stem, twig, leaf, and needle 

tissues of a variety of tree species in Norway between 1982 and 1992, when atmospheric Pb 

deposition declined by approximately 70%. They also observed significantly lower Pb 

concentrations in tree tissues collected in northern Norway versus southern Norway, where 

atmospheric Pb deposition is greater. 

Even at subtoxic concentrations, Pb and other metals may influence species diversity in 

terrestrial ecosystems. However, little work has been done on the effect of low-level metal 

concentrations on species diversity. In one study, plant species diversity was positively 

correlated to the concentration of available Pb in natural and artificial urban meadows in Britain 

(McCrea et al., 2004). The authors hypothesized that Pb may inhibit phosphorous uptake by 

dominant species, allowing less abundant (but more Pb-tolerant) ones to succeed. 

AX7.1.4.3 Effects of Lead on Energy Flows and Biogeochemical Cycling 

In terrestrial ecosystems, energy flow is closely linked to the carbon cycle. The principal 

input of energy to terrestrial ecosystems is through photosynthesis, in which CO2 is converted to 
 AX7-100 

biomass carbon. Because of this link between photosynthesis and energy flow, any effect that Pb 

has on the structure and function of terrestrial ecosystems (as discussed in Section AX7.1.5.3.) 

influences the flow of energy into the ecosystem. This section focuses on how Pb influences 

energy transfer within terrestrial ecosystems, which begin with the decomposition of litter and 

other detrital material by soil bacteria and fungi, and cascade through the various components of 

the detrital food web. Because the mobility of Pb in soils is closely tied to organic matter 

cycling, decomposition processes are central to the biogeochemical cycle of Pb. This section 

concludes with a discussion of how biogeochemical cycling of Pb has changed in response to the 

changing Pb inputs to terrestrial ecosystems. 

Effects of Lead on Detrital Energy Flows 

Lead can have a significant effect on energy flows in terrestrial ecosystems. At some sites 

severely affected by metal pollution, death of vegetation can occur, dramatically reducing the 

input of carbon to the ecosystem (Jordan, 1975; Galbraith et al., 1995). Subsequently, wind and 

erosion may remove litter and humus, leaving bare mineral soil, a nearly sterile environment in 

which very little energy transfer can take place (Little and Martin, 1972; Galbraith et al., 1995). 

At Pb-affected sites that can retain a functioning forest stand, the rate of decomposition of 

litter may be reduced, resulting in greater accumulation of litter on the forest floor than in 

unpolluted stands. Numerous investigators have documented significant declines in litter 

decomposition rates (Cotrufo et al., 1995; Johnson and Hale, 2004) and/or the rate of carbon 

respiration (Laskowski et al., 1994; Cotrufo et al., 1995; Saviozzi et al., 1997; Niklínska et al., 

1998; Palmborg et al., 1998; Aka and Darici, 2004) in acid- and metal-contaminated soils or soils 

treated with Pb. The resulting accumulation of organic matter on the soil surface can be 

dramatic. For example, an oak woodland 3 km from a smelter in Bristol, England had a litter 

layer mass 10 times greater than the mass in a similar stand 23 km from the smelter (Martin and 

Bullock, 1994). 

Reduced decomposition rates in polluted ecosystems are the result of the inhibition of soil 

bacteria and fungi and its effects on microbial community structure (Bååth, 1989). Kuperman 

and Carreiro (1997) observed 60% lower substrate-induced respiration in heavily polluted 

grassland soils near the U.S. Army’s Aberdeen Proving Ground in Maryland. This decline in 

carbon respiration was associated with 81% lower bacterial biomass and 93% lower fungal 
 AX7-101 

biomass. Similar declines in the activities of carbon-, nitrogen-, and phosphorus-acquiring 

enzymes were also observed. Such dramatic effects have only been observed in highly 

contaminated ecosystems. In a less contaminated grassland site near a Pb factory in Germany, 

Chander et al. (2001) observed a lower ratio of microbial biomass carbon to soil organic carbon 

in polluted soils. The ratio of basal respiration to microbial biomass (the “metabolic quotient,” 

qCO2) declined with increasing metal concentration, though this observation depended on the 

procedure for measuring microbial biomass (substrate-induced respiration versus fumigationextraction). The combined effect of lower microbial biomass per unit soil carbon and similar or 

lower qCO2 on polluted sites indicates that the ability of soil microorganisms to process carbon 

inputs is compromised by metal pollution. 

The type of ecosystem also plays a role in determining the effects of Pb and other metals 

on the microbial processing of litter. Forest soils in temperate zones accumulate organic matter 

at the soil surface to a greater degree than in grasslands. This organic-rich O horizon can support 

a large microbial biomass; but it is also an effective trap for Pb inputs, because of the association 

between Pb and soil organic matter. At highly contaminated forest sites, microbial biomass and 

enzyme activities may be depressed (Fritze et al., 1989; Bååth et al., 1991), causing slower 

decomposition of the litter. 

In addition to effects on decomposition and carbon transformations, Pb and other trace 

metals can also influence key nitrogen cycling processes. Studies in the 1970s demonstrated that 

Pb and other metals inhibit the mineralization of nitrogen from soil organic matter and 

nitrification (Liang and Tabatabai, 1977, 1978), resulting in lower nitrogen availability to plants. 

More recent research has documented significant inhibitory effects of Pb and other metals on the 

activities of several enzymes believed to be crucial to nitrogen mineralization in soils (Senwo 

and Tabatabai, 1999; Acosta-Martinez and Tabatabai, 2000; Ekenler and Tabatabai, 2002). This 

suggests that the inhibitory effect of Pb and other metals is broad-based, and not specific to any 

particular metabolic pathway. In reducing environments, the rate of denitrification is also 

depressed by trace metals. Fu and Tabatabai (1989) found that 2.5 μmol g!1

 of Pb (ca. 

500 mg/kg!1) was sufficient to cause 0, 27, and 52% decreases in nitrogen reductase activity in 

three different soils. 

Metal pollution can also affect soil invertebrate populations. Martin and Bullock (1994) 

observed lower abundances of a variety of woodlice, millipedes, spiders, insects, and earthworms 
 AX7-102 

in an oak woodland site 3 km from a Pb-Zn smelter in Bristol, England, compared to a reference 

site 23 km from the smelter. The differences were most dramatic when expressed per unit mass 

of litter. Several species that were abundant in the reference site were not found in the 

contaminated woodland. For example, the abundance of the woodlice Trichoniscus pusillus

was 151 individuals per m2

 in the reference woodland, but none were found in the contaminated 

soils. This was also true of 2 of the 3 millipede species, and 4 of the 5 earthworm species 

studied. At six sites within 1 km from the smelters, no earthworms were present at all (Spurgeon 

and Hopkin, 1996a). Contamination at this site has apparently reduced both the population and 

biodiversity of the soil invertebrate community. 

The effect of metal pollution on soil invertebrates may be a threshold-type response. In a 

study conducted in woodlands near two zinc smelters in Noyelles-Godault, in northern France, 

soils at the most polluted site were devoid of mites and millipedes, while the remaining sites had 

diversity measures similar to control sites (Grelle et al., 2000). 

While Pb pollution affects the population and diversity of soil fauna, there is little 

evidence of significant bioaccumulation of Pb in the soil food web (see also Section AX7.1.3). 

In the Bristol, England study, Pb concentrations in earthworms were lower than soil Pb 

concentrations and much lower than litter Pb concentrations (Martin and Bullock, 1994). Litterdwelling mites had Pb concentrations that were 10% of the average litter concentration. The 

predator centipedes Lithobius forficatus and L. variegatus had mean Pb concentrations of 

18.6 and 44.0 mg kg!1

, respectively, two orders of magnitude lower than the Pb concentration of 

litter (2193 mg kg!1

) and lower than the concentrations of their known prey species. In a study 

conducted in a Norway spruce forest affected primarily by automobile exhaust from a nearby 

highway, earthworms had Pb concentrations similar to the soil (Roth, 1993). Almost all of the 

litter decomposers, however, had Pb concentrations that were less than 20% of the litter. All but 

3 of the zoophagous arthropods had Pb concentrations that were less than 40% of their prey; the 

remaining 3 had Pb concentrations similar to their prey. Because of the absence of significant 

bioaccumulation in the soil food web, predator species will be affected by Pb pollution primarily 

through effects on the abundance of their prey (Spurgeon and Hopkin, 1996b). 

Taken as a whole, ecosystem-level studies of the soil food web indicate that Pb can affect 

energy flows in terrestrial ecosystems through two principal mechanisms. In the most severely 

polluted sites, the death of primary producers directly decreases the flow of energy into the 
 AX7-103 

ecosystems. More commonly, the accumulation of toxic levels of Pb or other metals in litter and 

soil decreases the rate of litter decomposition through decreases in microbial biomass and/or 

respiration. These reductions can subsequently affect higher trophic levels that depend on these 

organisms. It is important to note that sites that have exhibited significant disruption to energy 

flows and the terrestrial food web are sites that have experienced severe metal contamination and 

adverse effects from SO2 from smelters or other metals-related activities. 

Lead Dynamics in Terrestrial Ecosystems 

Lead inputs to terrestrial ecosystems in the United States have declined dramatically in the 

past 30 years, primarily because of the almost complete elimination of alkyl-Pb additives in 

gasoline in North America. Also, Pb emissions from smelters have declined as older plants have 

been shut down or fitted with improved emissions controls. Unfortunately, there are few longterm data sets of precipitation inputs to terrestrial ecosystems. At the Hubbard Brook 

Experimental Forest, in New Hampshire, Pb input in bulk deposition declined by more than 97% 

between 1976 and 1989 (Johnson et al., 1995a). Studies of freshwater sediments also indicate a 

dramatic decline in Pb inputs since the mid-1970s (Graney et al., 1995; Johnson et al., 1995a; 

Farmer et al., 1997; Brännvall et al., 2001a,b). 

Reported concentrations of Pb in waters draining natural terrestrial ecosystems have 

always been low (Wang et al., 1995; Bacon and Bain, 1995; Johnson et al., 1995a; Vinogradoff 

et al., 2005), generally less than 1 ng L!1, even at moderately polluted sites (Laskowski et al., 

1995). Consequently, most terrestrial ecosystems in North America and Europe remain sinks for 

Pb despite reductions in atmospheric Pb deposition of more than 95%. At Hubbard Brook, for 

example, the input of Pb in bulk precipitation declined from 325 g ha!1

 year!1 between 1975 and 

1977 compared to 29 g ha!1

 year!1 between 1985 and 1987 (Johnson et al., 1995a). During the 

same period, the output of Pb in stream water declined from 6 g ha!1

 year!1 to 4 g ha!1 year!1. 

Thus, despite the decline in Pb input, 85% of the incoming Pb was still retained in the terrestrial 

ecosystem in the later time period. Similar observations have been made in Europe, where the 

use of leaded gasoline has also declined in the last few decades. At the Glensaugh Research 

Station in Scotland, the input of Pb to the forest ecosystem was estimated as 42.6 g ha!1

 year!1

between 2001 and 2003, about six times the stream export of 7.2 g ha!1

 year!1 (Vinogradoff et al., 

2005). Similarly, Huang and Matzner (2004) reported a throughfall flux of 16.5 g ha!1

 year!1 at 
 AX7-104 

the forested Lehstenbach catchment in Bavaria, about six times the efflux in runoff of 2.82 g ha!1

year!1

. 

Lead pollution has resulted in the accumulation of large Pb burdens in terrestrial 

ecosystems (see also Section AX7.1.2). Despite reductions in emissions, this accumulation of Pb 

continues, though at markedly lower rates. The large pool of Pb bound in soils may potentially 

be a threat to aquatic ecosystems (see Section AX7.2), depending on its rate of release from the 

soil. Early estimates of the residence time of Pb in the forest floor ranged from 220 to 5,000 

years (Benninger et al., 1975; Friedland and Johnson, 1985; Turner et al., 1985). However, more 

recent literature suggests that Pb is transported more rapidly within soil profiles than previously 

believed. The pool of Pb in forest floor soils of the northeastern United States declined 

significantly in the late 20th century. Friedland et al. (1992) reported a 12% decline in the 

amount of Pb in forest floor soils at 30 sites in the region between 1980 and 1990, a much greater 

decline than would be expected for a pool with a residence time of 220 to 5,000 years. 

At Hubbard Brook, the pool of Pb in the forest floor declined by 29% between 1977 and 1987, 

an even more rapid rate of loss than reported by Friedland et al. (1992). More recently, Evans 

et al. (2005) reported significant declines in the Pb content of forest floor soils in the 

northeastern United States and eastern Canada between 1979 and 1996. The magnitude of the 

decrease in Pb content was greatest at their sites in southern Vermont, and smallest at sites on the 

Gaspe Peninsula in Quebec, reflecting the historic gradient in Pb deposition in the region. At the 

Vermont site, the Pb concentration in the litter layer (Oi horizon) was 85% lower in 1996 than in 

1979. In the Gaspe peninsula of Quebec, the decrease was only 50%. 

Since drainage water Pb concentrations remain low, the Pb released from forest floor soils 

in the past has been largely immobilized in mineral soils (Miller and Friedland, 1994; Johnson 

et al., 1995a; Johnson and Petras, 1998; Watmough and Hutchinson, 2004; Johnson et al., 2004). 

This is supported by evidence from Pb-isotope analyses. Gasoline-derived Pb has a 206Pb:207Pb 

ratio that can be easily discriminated from Pb in the rocks from which soils are derived. Using 

isotopic mixing models with gasoline-Pb and Pb in soil parent materials as end members, 

a number of researchers have documented the accumulation of pollutant Pb in mineral soils 

(Bindler et al., 1999; Kaste et al., 2003; Watmough and Hutchinson, 2004; Bacon and Hewitt, 

2005; Steinnes and Friedland, 2005). In a hardwood stand on Camel’s Hump Mountain in 

Vermont, as much as 65% of the pollutant Pb deposited to the stand had moved into mineral 
 AX7-105 

horizons by 2001 (Kaste et al., 2003). In a spruce-fir stand, containing a thicker organic forest 

floor layer, penetration of pollutant Pb into the mineral soil was much lower. 

This recent research has resulted in a reevaluation of the turnover time of Pb in forest 

floor soils. The Camel’s Hump data suggest that Pb resides in the forest floor of deciduous 

stands for about 60 years and about 150 years in coniferous stands (Kaste et al., 2003). These 

values are somewhat greater than those published previously by Miller and Friedland (1994), 

who used a Pb budget approach. Extremely rapid turnover of Pb was observed in some 

hardwood forest floor soils in south-central Ontario (Watmough et al., 2004). Their estimated 

turnover times of 1.8 to 3.1 years are much lower than any other published values, which they 

attribute to the mull-type forest floor at their sites. Mull-type forest floors are normally underlain 

by organic-rich A horizons, capable of immobilizing Pb released from the forest floor. Indeed, 

at the same site in Ontario, Watmough and Hutchinson (2004) found that 90% of the pollutant Pb 

could be found in this A horizon. 

The time period over which the accumulated Pb in soils may be released to drainage 

waters remains unclear. If Pb moves as a pulse through the soil, there may be a point in the 

future at which problematic Pb concentrations occur. However, several authors have argued 

against this hypothesis (Wang and Benoit, 1997; Kaste et al., 2003; Watmough et al., 2004), 

contending that the strong linkage between Pb and DOM will result in a temporally dispersed 

release of Pb in the form of Pb-DOM complexes. Thus, the greatest threat is likely to be in the 

most highly contaminated areas surrounding point sources of Pb, where the amount of Pb 

accumulated in the soil is high, and the death of vegetation has resulted in reduced soil organic 

matter levels. 

AX7.1.4.4 Summary 

Atmospheric Pb pollution has resulted in the accumulation of Pb in terrestrial ecosystems 

throughout the world. In the United States, pollutant Pb represents a significant fraction of the 

total Pb burden in soils, even in sites remote from smelters and other industrial plants. However, 

few significant effects of Pb pollution have been observed at sites that are not near point sources 

of Pb. Evidence from precipitation collection and sediment analyses indicates that atmospheric 

deposition of Pb has declined dramatically (>95%) at sites unaffected by point sources of Pb, and 
 AX7-106 

there is little evidence that Pb accumulated in soils at these sites represents a threat to 

groundwaters or surface water supplies. 

The highest environmental risk for Pb in terrestrial ecosystems exists at sites within about 

50 km of smelters and other Pb-emitting industrial sites. Assessing the risks specifically 

associated with Pb is difficult, because these sites also experience elevated concentrations of 

other metals and because of effects related to SO2 emissions. The concentrations of Pb in soils, 

vegetation, and fauna at these sites can be two to three orders of magnitude higher than in 

reference areas (see Sections AX7.1.2 and AX7.1.4.2). In the most extreme cases, near smelter 

sites, the death of vegetation causes a near-complete collapse of the detrital food web, creating a 

terrestrial ecosystem in which energy and nutrient flows are minimal. More commonly, stress in 

soil microorganisms and detritivores can cause reductions in the rate of decomposition of detrital 

organic matter. Although there is little evidence of significant bioaccumulation of Pb in natural 

terrestrial ecosystems, reductions in microbial and detritivorous populations can affect the 

success of their predators. Thus, at present, industrial point sources represent the greatest Pbrelated threat to the maintenance of sustainable, healthy, diverse, and high-functioning terrestrial 

ecosystems in the United States. 

AX7.2 AQUATIC ECOSYSTEMS 

AX7.2.1 Methodologies Used in Aquatic Ecosystem Research 

As discussed in previous sections, aerial deposition is one source of Pb deposition to 

aquatic systems. Consequently, to develop air quality criteria for Pb, consideration must be 

given to not only the environmental fate of Pb, but also to the environmental effects of Pb in the 

aquatic environment through consideration of laboratory toxicity studies and field evaluations. 

Perhaps the most straightforward approach for evaluating the effects of Pb is to consider extant 

criteria for Pb in aquatic ecosystems, i.e., water and sediment quality criteria. A key issue in 

developing Pb water and sediment criteria that are broadly applicable to a range of water bodies 

is properly accounting for Pb bioavailability and the range in species sensitivities. This section 

summarizes how these criteria are derived, the types of toxicity studies considered, and key 

factors that influence the bioavailability of Pb in surface water and sediment to aquatic life. 

Because Pb in the aquatic environment is often associated with other metals (e.g., cadmium, 
 AX7-107 

copper, zinc), the importance of considering the toxicity of metal mixtures is also discussed. 

Finally, some issues related to background Pb concentrations are briefly addressed. It is beyond 

the scope of this section to review all methodologies in aquatic system research, but good 

reviews can be found in summary books, such as Rand et al. (1995). 

AX7.2.1.1 Analytical Methods 

Common analytical methods for measuring Pb in the aquatic environment are summarized 

in Table AX7-2.1.1. For relevance to the ambient water quality criteria (AWQC) and sediment 

quality criteria for Pb discussed below, minimum detection limits should be in the low parts per 

billion (ppb) range for surface water and the low parts per million (ppm) range for sediment. 

Table AX7-2.1.1. Common Analytical Methods for Measuring Lead in Water, 

Sediment, and Tissue 

Analysis Type Analytical Method 

Direct-Aspiration (Flame) Atomic Absorption Spectroscopy 

(AAS) 

EPA SW-846 Method 7420 a, 

EPA Method 239.1b

, 

Standard Method 3111c

Graphite Furnace Atomic Absorption Spectroscopy 

(GFAAS) 

EPA SW-846 Method 7421 a, 

EPA Method 239.2b

, 

Standard Method 3113c

Inductively Coupled Plasma 

(ICP) 

EPA SW-846 Method 6010B a, 

EPA Method 200.7b

, 

Standard Method 3120c

Inductively Coupled Plasma-Mass Spectrometry 

(ICP-MS) 

EPA SW-846 Method 6020 a, 

EPA Method 200.8b

a

 U.S. Environmental Protection Agency (1986c) Test Methods for Evaluating Solid Waste, Physical/Chemical 

Methods (SW-846). Third Edition, September 1986; Final Updates I (7/92), IIA (8/93), II (9/94), IIB (1/95), 

III (12/96), IIIA (4/98), IIIB (11/04). 

b

 U.S. Environmental Protection Agency (1991) Methods for the Determination of Metals in Environmental 

Samples. EPA/600/4-91-010. June 1991 (Supplement I, EPA/600/R-94-111, May 1994). 

c

 American Public Health Association (1995) Standard Methods for the Examination of Water and Wastewater, 

19th Edition. American Public Health Association, American Water Works Association, Water Pollution 

Control Federation. 

In addition to the methods presented in Table AX7-2.1.1, many of the methods discussed 

in Section AX7.1.1 can be applied to suspended solids and sediments collected from aquatic 
 AX7-108 

ecosystems. Just as in the terrestrial environment, the speciation of Pb and other trace metals in 

natural freshwaters and seawater plays a crucial role in determining their reactivity, mobility, 

bioavailability, and toxicity. Many of the same speciation techniques employed for the 

speciation of Pb in terrestrial ecosystems (see Section AX7.1.1 and AX7.1.2) are applicable in 

aquatic ecosystems. 

There is now a better understanding of the potential effects of sampling, sample handling, 

and sample preparation on aqueous-phase metal speciation. Thus, a need has arisen for dynamic 

analytical techniques that are able to capture a metal’s speciation, in-situ and in real time. Some 

of these recently developed dynamic trace metal speciation techniques include: 

• Diffusion gradients in thin-film gels (DGT) 

• Gel integrated microelectrodes combined with voltammetric in situ profiling 

(GIME-VIP) 

• Stripping chronopotentiometry (SCP) 

• Flow-through and hollow fiber permeation liquid membranes (FTPLM and HFPLM) 

• Donnan membrane technique (DMT) 

• Competitive ligand-exchange/stripping voltammetry (CLE-SV) 

Various dynamic speciation techniques were compared in a study by Sigg et al. (2006) using 

freshwaters collected in Switzerland. They found that techniques involving in-situ measurement 

(GIME-VIP) or in-situ exposure (DGT, DMT, and HFPLM) appeared to the most appropriate for 

avoiding Pb and other trace metal speciation artifacts associated sampling and sample handling. 

AX7.2.1.2 Ambient Water Quality Criteria: Development 

The EPA’s procedures for deriving AWQC are described in Stephan et al. (1985) and are 

summarized here. With few exceptions, AWQC are derived based on data from aquatic toxicity 

studies conducted in the laboratory. In general, both acute (short term) and chronic (long term) 

AWQC are developed. Depending on the species, the toxicity studies considered for developing 

acute criteria range in length from 48 to 96 hours. Acceptable endpoints for acute AWQC 

development are mortality and/or immobilization, expressed as the median lethal concentration 

(LC50) or median effect concentration (EC50). For each species, the geometric mean of the 

acceptable LC50/EC50 data is calculated to determine the species mean acute value (SMAV). 
 AX7-109 

For each genera, the geometric mean of the relevant SMAVs is then calculated to determine the 

genus mean acute value (GMAV). The GMAVs are then ranked from high to low, and the final 

acute value (FAV; the 5th percentile of the GMAVs, based on the four GMAVs surrounding the 

5th percentile) is determined. Because the FAV is based on LC50/EC50 values (which represent 

unacceptably high levels of effect), the FAV is divided by two to estimate a low-effect level. 

This value is then termed the acute criterion, or criterion maximum concentration (CMC). Based 

on the most recent AWQC document for Pb (U.S. Environmental Protection Agency, 1985), 

Table AX7-2.1.2 shows the freshwater SMAVs and GMAVs for Pb, and the resulting freshwater 

CMC. Note that the freshwater AWQC are normalized for the hardness of the site water, as 

discussed further below in Section AX7.2.1.3. 

Table AX7-2.1.2. Development of Current Acute Freshwater Criteria for Lead 

(U.S. Environmental Protection Agency, 1985)1

Rank Species 

GMAV 

(μg/L) 

SMAV 

(μg/L) 

 10 Midge (Tanytarsus dissimilis) 235,900 235,900 

 9 Goldfish (Carassius auratus) 101,100 101,100 

 8 Guppy (Poecilia reticulata) 66,140 66,140 

 7 Bluegill (Lepomis macrochirus) 52,310 52,310 

 6 Fathead minnow (Pimephales promelas) 25,440 25,440 

 5 Brook trout (Salvelinus fontinalis) 4,820 4,820 

 4 Rainbow trout (Oncorhynchus mykiss) 2,448 2,448 

 3 Snail (Aplexa hypnorum) 1,040 1,040 

 2 Cladoceran (Daphnia magna) 447.8 447.8 

 1 Amphipod (Gammarus pseudolimnaeus) 142.6 142.6 

 FAV = 67.54 μg/L 

 CMC = 33.77 μg/L 

1 All values are normalized to a hardness of 50 mg/L (see Section AX7.2.1.3).
 AX7-110 

To develop chronic AWQC, acceptable chronic toxicity studies should encompass the full 

life cycle of the test organism, although for fish, early life stage or partial life cycle toxicity 

studies are considered acceptable. Acceptable endpoints include reproduction, growth and 

development, and survival, with the effect levels expressed as the chronic value, which is the 

geometric mean of the no-observed-effect concentration (NOEC)1

 and the lowest-observedeffect concentration (LOEC)2

. Although a chronic criterion could be calculated as the 5th 

percentile of genus mean chronic values (GMCVs), sufficient chronic toxicity data are generally 

lacking, as is the case for Pb. Consequently, an acute-chronic ratio (ACR) is typically applied to 

the FAV to derive the chronic criterion. As the name implies, the ACR is the ratio of the acute 

LC50 to the chronic value, based on studies with the same species and in the same dilution water. 

For Pb, the final ACR is 51.29, which results in a final chronic value (FCV) of 1.317 μg/L (at a 

hardness of 50 mg/L). The U.S. EPA guidelines for developing AWQC (Stephan et al., 1985) are 

now more than 20 years old and thus are not reflective of scientific advances in aquatic 

toxicology and risk assessment that have developed since the 1980s. For example, the 

toxicological importance of dietary metals has been increasingly recognized and approaches for 

incorporating dietary metals into regulatory criteria are being evaluated (Meyer et al., 2005). 

Other issues include consideration of certain sublethal endpoints that are currently not directly 

incorporated into AWQC development (e.g., endocrine toxicity, behavioral responses) and 

protection of threatened and endangered (T&E) species (U.S. Environmental Protection Agency, 

2003). In deriving appropriate and scientifically defensible air quality criteria for Pb, it will be 

important that the state-of-the-science for metals toxicity in aquatic systems be incorporated into 

the development process. 

Subsequent sections summarize some of the toxicity studies that meet the AWQC 

development guidelines, with an emphasis on key studies published since the last Pb AWQC 

were derived in 1984. 

 1

 The NOEC is the highest concentration tested that did not result in statistically significant effects relative 

to the control. 

2

 The LOEC is the lowest concentration tested that resulted in statistically significant effects relative to 

the control. 
 AX7-111 

AX7.2.1.3 Ambient Water Quality Criteria: Bioavailability Issues 

In surface waters, the environmental fate of metal contaminants is mitigated through 

adsorption, complexation, chelation, and other processes that affect bioavailability. The toxicity 

of divalent cations tends to be highest in soft waters with low concentrations of dissolved organic 

matter and suspended particles. In an acidic environment (pH <4), the ionic form of most metals 

generally predominates and is considered to be the more toxic form. As the pH increases, 

carbonate, oxide, hydroxide, and sulfide complexes of the metals tend to predominate, and tend 

to be less toxic (Florence, 1977; Miller and Mackay, 1980). The portion of dissolved metal 

available for uptake or bioaccumulation is influenced by modifying factors that “sequester” the 

metal in an environmental matrix, thereby reducing the bioavailability of the metal at the sites of 

action. Metals can become complexed (bound) to a ligand that can make metals either more 

toxic (via transport mechanisms) or less toxic (by changing the metal’s biological activity). 

Metals that complex tightly to ligands generally are not readily bioavailable and, thus, are less 

toxic to aquatic biota than their free-metal ion counterparts (Carlson et al., 1986; McCarthy, 

1989). There are many kinds of ligands, organic and inorganic, as well as natural and manmade. Ligands found in natural surface waters and municipal and industrial effluent discharges 

include glycine, ammonia, oxalate, humic or fulvic acids, hydroxide, carbonate, bicarbonate, 

chloride, and hydrogen sulfide (Stumm and Morgan, 1970; Martin, 1986; Pagenkopf, 1986). 

Recognizing the importance of calcium and magnesium ions (hardness) in modifying Pb 

toxicity, the current freshwater AWQC for Pb are normalized based on the hardness of the site 

water. The acute freshwater criteria, for example, are 30, 65, and 136 μg/L at hardness levels of 

50, 100, and 200 mg/L (as CaCO3). Although it has been known for some time that other water 

quality parameters such as pH, dissolved organic carbon (DOC), and alkalinity affect the 

bioavailability of metals to aquatic biota, it was the relatively recent development of the biotic 

ligand model (BLM) that allows for AWQC to potentially consider all of these factors. Paquin 

et al. (2002) provided a thorough review of the factors influencing metal bioavailability and how 

research over the last few decades has culminated in the development of the BLM. 

By understanding the binding affinities of various natural ligands in surface waters and 

how the freshwater fish gill interacts with free cations in the water, one can predict how metals 

exert their toxic effects (Schwartz et al., 2004). Models developed prior to the BLM are the freeion activity model (FIAM) and the gill surface interaction model (GSIM). The FIAM accounts 
 AX7-112 

for the binding of free-metal ion and other metal complexes to the site of toxic action in an 

organism; and it also considers competition between metal species and other cations (Paquin 

et al., 2002). The GSIM is fundamentally similar to the FIAM in that it accounts for competition 

between metal ions and hardness cations at the physiological active gill sites, but whereas the 

FIAM is largely conceptual, the GSIM was used in interpreting toxicity test results for individual 

metals and metal mixtures (Pagenkopf, 1983). The BLM was adapted from the GSIM and uses 

the biotic ligand, rather than the fish gill as the site of toxic action (Di Toro et al., 2001; Paquin 

et al., 2002). This approach, therefore, considers that the external fish gill surface contains 

receptor sites for metal binding (Schwartz et al., 2004) and that acute toxicity is associated with 

the binding of metals to defined sites (biotic ligands) on or within the organism (Paquin et al., 

2002). The model is predicated on the theory that mortality (or other toxic effects) occurs when 

the concentration of metal bound to biotic ligand exceeds a threshold concentration (Di Toro 

et al., 2001; Paquin et al., 2002). Free metal cations “out compete” other cations and bind to the 

limited number of active receptor sites on the gill surface, which may ultimately result in 

suffocation and/or disruption of ionoregulatory mechanisms in the fish, leading to death (Di Toro 

et al., 2001; Paquin et al., 2002). Because the BLM uses the biotic ligand (not the fish gill) as 

the site of action, the model can be applied to other aquatic organisms, such as crustaceans, 

where the site of action is directly exposed to the aqueous environment (Di Toro et al., 2001). 

Although the BLM is currently being considered as a tool for regulating metals on a sitespecific basis, there are potential limitations in using the BLM to regulate metals in surface 

waters that should be understood in developing air quality criteria for lead. For example, BLMs 

developed to-date have focused on acute mortality/immobilization endpoints for fish and 

invertebrates. Chronic exposures are typically of greatest regulatory concern, but chronic BLMs 

to date have received limited attention (De Schamphelaere and Janssen, 2004). In addition, 

BLMs account for uptake of dissolved metal, but dietary metals have also been shown to 

contribute to uptake by aquatic biota and, in some cases, increased toxicity. Besser et al. (2005) 

observed that chronic (42-day) Pb toxicity to the amphipod Hyalella azteca was greater from a 

combined aqueous and dietary exposure than from a water-only exposure and the authors 

conclude that estimates of chronic toxicity thresholds for Pb should consider both aqueous and 

dietary exposure routes. The feasibility of incorporating dietary metals into BLMs is under 

investigation. Another important issue that must be addressed in developing and applying a 
 AX7-113 

BLM in AWQC development is the type of dissolved organic matter used in model development 

relative to the types of dissolved organic matter at the site of interest. Richards et al. (2001) 

demonstrated that natural organic matter (NOM) of different types differentially influenced Pb 

and Cu accumulation by gills of rainbow trout. There are also other ligands not accounted for in 

the BLM that require more research. Bianchini and Bowles (2002) emphasized the importance 

of reduced sulfur as a metal ligand, limitations in scientific knowledge on reduced sulfur, and 

provided recommendations for studies necessary to incorporate sulfide ligands into the BLM. 

The U.S. EPA is currently revising the aquatic life AWQC for lead, which will include 

toxicity data published after the 1985 AWQC were released and incorporation of the BLM is 

being evaluated. If an acute BLM is incorporated into the revised AWQC for lead, the chronic 

criteria would likely be estimated using an ACR (the same approach used when the acute 

criterion is based on empirical toxicity data; see above). 

AX7.2.1.4 Sediment Quality Criteria: Development and Bioavailability Issues 

As with metals in surface waters, the environmental fate of metal contaminants in 

sediments is moderated through various binding processes that reduce the concentration of free, 

bioavailable metal. Sediments function as a sink for Pb, as with most metals. Lead compounds 

such as Pb-carbonates, Pb-sulfates, and Pb-sulfides predominate in sediments (Prosi, 1989). 

Total Pb has a higher retention time and a higher percentage is retained in sediments compared to 

copper and zinc (Prosi, 1989). Lead is primarily accumulated in sediments as insoluble Pb 

complexes adsorbed to suspended particulate matter. Naturally occurring Pb is bound in 

sediments and has a low geochemical mobility (Prosi, 1989). Organic-sulfide and moderately 

reducible fractions are less mobile, whereas cation-exchangeable fractions and easily-reducible 

fractions are more mobile and more readily bioavailable to biota (Prosi, 1989). Most Pb 

transported in surface waters is in a particulate form, originating from the erosion of sediments in 

rivers or produced in the water column (Prosi, 1989). 

Sediment quality criteria have yet to be adopted by the EPA, but an equilibrium 

partitioning procedure has recently been published (U.S. Environmental Protection Agency, 

2005c). The EPA has selected an equilibrium partitioning approach because it explicitly 

accounts for the bioavailability of metals. This approach is based on mixtures of cadmium, 

copper, Pb, nickel, silver, and zinc. Equilibrium partitioning (EqP) theory predicts that metals 
 AX7-114 

partition in sediment between acid-volatile sulfide, pore water, benthic organisms, and other 

sediment phases such as organic carbon. When the sum of the molar concentrations of 

simultaneously extracted metal (∑SEM) minus the molar concentration of AVS is less than zero, 

it can accurately be predicted that sediments are not toxic because of these metals. Note that this 

approach can be used to predict the lack of toxicity, but not the presence of toxicity. It is 

important to emphasize that metals must be evaluated as a mixture using this approach. 

If individual metals, or just two or three metals, are measured in sediment, ∑SEM would be 

misleadingly small and it may inaccurately appear that ∑SEM / AVS is less than 1.0. 

If ∑SEM / AVS is normalized to the organic carbon fraction (i.e., (∑SEM / AVS)/fOC), 

mortality can be more reliably predicted by accounting for both the site-specific organic carbon 

and AVS concentrations. When evaluating a metal mixture containing cadmium, copper, Pb, 

nickel, silver, and zinc, the following predictions can be made (U.S. Environmental Protection 

Agency, 2005c): 

• A sediment with (SEM / AVS)/fOC < 130 μmol/gOC should pose low risk of adverse 

biological effects due to these metals. 

• A sediment with 130 μmol/gOC < (SEM / AVS)/fOC < 3000 μmol/gOC may have adverse 

biological effects due to these metals. 

• In a sediment with (SEM / AVS)/fOC > 3000 μmol/gOC, adverse biological effects may 

be expected. 

A third approach is to measure pore water concentrations of cadmium, copper, Pb, nickel, 

and zinc and then divide the concentrations by their respective FCVs. If the sum of these 

quotients is <1.0, these metals are not expected to be toxic to benthic organisms. 

It should be noted that although EPA has endorsed the AVS-SEM approach for 

developing sediment guidelines, other investigators do not necessarily agree, as the AVS-SEM 

approach may not be relevant to benthic organisms that ingest sediment particles. For example, 

Griscom et al. (2002) found that metals associated with either reduced or oxidized sediment 

particles can be assimilated by deposit and suspension feeding bivalve species due to the low pH 

and moderate reducing conditions in bivalve guts. Although Lee et al. (2000) agreed that the 

AVS-based approach may be appropriate for protecting some benthic organisms from acute 

toxicity associated with exposure to very high pore water concentrations of metals, they 

questioned whether the AVS-based approach is relevant to less contaminated sediments under 
 AX7-115 

more natural conditions with vertical stratification of oxygen concentrations and, hence, varying 

levels of AVS. The authors concluded that important uncertainties remain in the application of 

the AVS-SEM approach as a regulatory tool. Similarly, some studies suggest that AVS-SEM 

measurements in the natural environment must be interpreted cautiously as AVS can be quite 

variable with sediment depth and season (Van den Berg et al., 1998). Finally, Long et al. (1998) 

critically compared the ability of AVS-SEM and dry weight-normalized concentrations to predict 

toxicity of sediment-associated trace metals. Based on an analysis of 77 field-collected sediment 

samples, Long et al. (1998) found that dry weight-normalized concentrations were equally or 

slightly more accurate than AVS-SEM in predicting non-toxic and toxic results in laboratory 

bioassays. Long et al. suggests that a limitation of the AVS-SEM approach is that the criteria 

were not derived from field studies with mixture of toxic chemicals and thus may be less relevant 

to sites comprising complex chemical mixtures. Thus, although the AVS-SEM approach for 

developing sediment quality criteria is being pursued by the U.S. EPA, there is clearly not 

scientific consensus on this approach, at least not for all circumstances. 

Many alternative approaches for developing sediment quality guidelines are based on 

empirical correlations between metal concentrations in sediment to associated biological effects, 

based on sediment toxicity tests (Long et al., 1995; Ingersoll et al., 1996; MacDonald et al., 

2000). However, these guidelines are based on total metal concentrations in sediment and do not 

account for the bioavailability of metals between sediments. Sediment quality guidelines 

proposed for Pb from these other sources are shown in Table AX7-2.1.3. 

Table AX7-2.1.3. Recommended Sediment Quality Guidelines for Lead 

Source Water Type Guideline Type Conc. (mg/kg dw) 

MacDonald et al. (2000) Freshwater TEC 

PEC 

35.8 

128 

Ingersoll et al. (1996) Freshwater ERL 

ERM 

55 

99 

Long et al. (1995) Saltwater ERL 

ERM 

46.7 

218 

TEC = Threshold effect concentration; PEC = Probable effect concentration; ERL = Effects range – low; 

ERM = Effects range – median 
 AX7-116 

AX7.2.1.5 Metal Mixtures 

As discussed above, the EPA’s current approach for developing sediment criteria for Pb 

and other metals is to consider the molar sum of the metal concentrations (∑SEM). Although a 

similar approach has not been applied to AWQC, metal mixtures have been shown to be more 

toxic than individual metals (Spehar and Fiandt, 1986; Enserink et al., 1991). Spehar and Fiandt 

(1986) evaluated the acute and chronic toxicity of a metal mixture (arsenic, cadmium, chromium, 

copper, mercury, and Pb) to fathead minnows (Pimephales promelas) and a daphnid 

(Ceriodaphnia dubia). In acute tests, the joint toxicity of these metals was observed to be more 

than additive for fathead minnows and nearly strictly additive for daphnids. In chronic tests, the 

joint toxicity of the metals was less than additive for fathead minnows and nearly strictly 

additive for daphnids. One approach for considering the additive toxicity of Pb with other metals 

is to use the concept of toxic units (TUs). Toxic units for each component of a metal mixture are 

derived by dividing metal concentrations by their respective acute or chronic criterion. The TUs 

for all the metals in the mixture are then summed. A ∑TU > 1.0 suggests the metal mixture is 

toxic (note that this is the same approach as discussed above for developing metal sediment 

criteria based on pore water concentrations). According to Norwood et al. (2003), the TU 

approach is presently the most appropriate model for predicting effects of metal mixtures based 

on the currently available toxicity data. However, it should also be emphasized that the TU 

approach is most appropriate at a screening level, because the true toxicity of the mixture is 

dependent on the relative amounts of each metal. The TU approach is also recommended with 

mixtures containing less than six metals. 

Lead and other metals often co-occur in sediments with other toxicants, such as organic 

contaminants. Effects-based sediment quality guidelines (SQGs) have been developed over the 

past 20 years to aid in the interpretation of the relationships between complex chemical 

contamination and adverse biological effects (Long et al., 2006). Mean sediment quality 

guideline quotients (mSQGQs) can be calculated by dividing the concentrations of chemicals in 

sediments by their respective SQGs and then calculating the mean of the quotients for the 

individual chemicals. Long et al. (2006) performed a critical review of this approach and found 

that it reasonably predicts the incidence and magnitude of toxicity in laboratory tests and the 

incidence of impairment to benthic communities increases incrementally with increasing 

mSQGQs. However, the authors pointed out some of the limitations of this approach, such as a 
 AX7-117 

lack of agreement on the level of mSQGQs, masking of an individual chemical’s effect due to 

data aggregation, lack of SQGs for all chemicals of concern, and mSQGQs were not initially 

derived as a regulatory standard or criterion, thus there is a reluctance to use them in 

enforcement or remediation (Long et al., 2006). 

For assessing Pb effects on aquatic ecosystems, it is not truly feasible to account for metal 

mixtures, because these will obviously vary highly from site to site. However, the toxicity of 

metal mixtures in surface water should be considered on a site-specific basis. 

AX7.2.1.6 Background Lead 

Because Pb is naturally occurring, it is found in all environmental compartments 

including surface water, sediment, and aquatic biota. Background Pb concentrations are spatially 

variable depending on geological features and local characteristics that influence Pb speciation 

and mobility. In the European Union risk assessments for metals, an “added risk” approach has 

been considered that assumes only the amount of metal added above background is relevant in a 

toxicological evaluation. However, this approach ignores the possible contribution of 

background metal levels to toxic effects, and background metal levels are regionally variable, 

precluding the approach from being easily transferable between sites. In terms of deriving 

environmental criteria for Pb, background levels should be considered on a site-specific basis if 

there is sufficient information that Pb concentrations are naturally elevated. As discussed 

previously, the use of radiogenic Pb isotopes is useful for source apportionment. 

AX7.2.2 Distribution of Lead in Aquatic Ecosystems 

Atmospheric Pb is delivered to aquatic ecosystems primarily through deposition (wet 

and/or dry) or through erosional transport of soil particles (Baier and Healy, 1977; Dolske and 

Sievering, 1979; and Yang and Rose, 2005). A number of physical and chemical factors govern 

the fate and behavior of Pb in aquatic systems. The EPA summarized some of these controlling 

factors in the 1986 Lead AQCD (U.S. Environmental Protection Agency, 1986a). For example, 

the predominant form of Pb in the environment is in the divalent (Pb2+) form and complexation 

with inorganic and organic ligands is dependent on pH (Lovering, 1976; Rickard and Nriagu, 

1978). A significant portion of Pb in the aquatic environment exists in the undissolved form 

(i.e., bound to suspended particulate matter). The ratio of Pb in suspended solids to Pb in filtrate 
 AX7-118 

varies from 4:1 in rural streams to 27:1 in urban streams (Getz et al., 1977). In still waters, Pb is 

removed through sedimentation at a rate determined by temperature, pH, oxidation-reduction 

(redox) potential, organic content, grain size, and chemical form of Pb in the water and 

biological activities (Jenne and Luoma, 1977). Since the publication of the 1986 Lead AQCD 

(U.S. Environmental Protection Agency, 1986a), knowledge of the properties of Pb in aquatic 

ecosystems has expanded. This section will provide further detail on the chemical species and 

the environmental factors affecting speciation of Pb in the aquatic environment. In addition, 

quantitative distributions of Pb in water, sediment, and biological tissues will be presented for 

aquatic ecosystems throughout the United States. Finally, recent studies discussing the tracing of 

Pb in aquatic systems will be summarized. 

AX7.2.2.1 Speciation of Lead in Aquatic Ecosystems 

The speciation of Pb in the aquatic environment is controlled by many factors. The 

primary form of Pb in aquatic environments is divalent (Pb2+), while Pb4+ exists only under 

extreme oxidizing conditions (Rickard and Nriagu, 1978). Labile forms of Pb (e.g., Pb2+, 

PbOH+, PbCO3) are a significant portion of the Pb inputs to aquatic systems from atmospheric 

washout. Lead is typically present in acidic aquatic environments as PbSO4, PbCl4, ionic Pb, 

cationic forms of Pb-hydroxide, and ordinary Pb-hydroxide (Pb(OH)2). In alkaline waters, 

common species of Pb include anionic forms of Pb-carbonate (Pb(CO3)) and Pb(OH)2. 

Speciation models have been developed based on the chemical equilibrium model developed by 

Tipping (1994) to assist in examining metal speciation. The EPA MINTEQA2 computer model 

(http://www.epa.gov/ceampubl/mmedia/minteq/) is one such equilibrium speciation model that 

can be used to calculate the equilibrium composition of dilute aqueous solutions in the laboratory 

or in natural aqueous systems. The model is useful for calculating the equilibrium mass 

distribution among dissolved species, adsorbed species, and multiple solid phases under a variety 

of conditions, including a gas phase with constant partial pressures. In addition to chemical 

equilibrium models, the speciation of metals is important from a toxicological perspective. 

The BLM was developed to study the toxicity of metal ions in aquatic biota and was previously 

described in Section AX7.2.1.3. Further detail on speciation models is not provided herein, 

rather a general overview of major speciation principles are characterized in the following 

sections. 
 AX7-119 

Acidity (pH) 

Freshwater

Most of the Pb in aquatic environments is in the inorganic form (Sadiq, 1992). The 

speciation of inorganic Pb in freshwater aquatic ecosystems is dependent upon pH and the 

available complexing ligands. Solubility varies according to pH, temperature, and water 

hardness (Weber, 1993). Lead rapidly loses solubility above pH 6.5 (Rickard and Nriagu, 1978) 

and as water hardness increases. In freshwaters, Pb typically forms strong complexes with 

inorganic OH!and CO3

2!

 and weak complexes with Cl! (Long and Angino, 1977; Bodek et al., 

1988). The primary form of Pb at low pH (#6.5) is predominantly Pb2+ and less abundant 

inorganic forms include Pb(HCO)3, Pb(SO4)2

2!

, PbCl, PbCO3, and Pb2(OH)2CO3

(Figure AX7-2.2.1). At higher pH (∃7.5), Pb forms hydroxide complexes (PbOH+, Pb(OH)2, 

Pb(OH)3

!

, Pb(OH)4

2!

). 

Figure AX7-2.2.1. Distribution of aqueous lead species as a function of pH based on 

a concentration of 1 μg Pb/L (U.S. Environmental Protection 

Agency, 1999). 
 AX7-120 

Organic compounds in surface waters may originate from natural (e.g., humic or fulvic 

acids) or anthropogenic sources (e.g., nitrilotriacetonitrile and ethylenediaminetetraacetic acid 

[EDTA]) (U.S. Environmental Protection Agency, 1986b). The presence of organic complexes 

has been shown to increase the rate of solution of Pb bound as Pb-sulfide (Lovering, 1976). 

Soluble organic Pb compounds are present at pH values near 7 and may remain bound at pH 

values as low as 3 (Lovering, 1976; Guy and Chakrabarti, 1976). At higher pH (7.4 to 9), 

Pb-organic complexes are partially decomposed. Water hardness and pH were found to be 

important in Pb-humic acid interactions (O’Shea and Mancy, 1978). An increase in pH 

increased the concentration of exchangeable Pb complexes, while an increase in hardness tended 

to decrease the humic acid-Pb interactions. Thus, the metals involved in water hardness 

apparently inhibit the exchangeable interactions between metals and humic acids. 

Marine Water

In marine systems, an increase in salinity increases complexing with chloride and 

carbonate ions and reduces the amount of free Pb2+. In seawaters and estuaries at low pH, Pb is 

primarily bound to chlorides (PbCl, PbCl2, PbCl3

!

, PbCl4

2!

) and may also form inorganic 

Pb(HCO)3, Pb(SO4)2

2!

, or PbCO3. Elevated pH in saltwater environments results in the 

formation of Pb hydroxides (PbOH+, Pb(OH)2, Pb(OH)3

!

, Pb(OH)4

2!

) (Figure AX7-2.2.2). 

A recent examination of Pb species in seawater as a function of chloride concentration suggested 

that the primary species were PbCl3

!

 > PbCO3 > PbCl2 > PbCl+ > and Pb(OH)+ (Fernando, 1995). 

Lead in freshwater and seawater systems is highly complexed with carbonate ligands suggesting 

that Pb is likely to be highly available for sorption to suspended materials (Long and Angino, 

1977). 

Current information suggests that inorganic Pb is the dominant form in seawater; 

however, it has been shown that organically bound Pb complexes make up a large portion of the 

total Pb (Capodaglio et al., 1990). 

Sorption 

Sorption processes (i.e., partitioning of dissolved Pb to suspended particulate matter or 

sediments) appear to exert a dominant effect on the distribution of Pb in the environment 

(U.S. Environmental Protection Agency, 1979). Sorption of Pb results in the enrichment of 
 AX7-121 

Figure AX7-2.2.2. Lead speciation versus chloride content (Fernando, 1995). 

bed sediments, particularly in environments with elevated organic matter content from 

anthropogenic sources. Lead adsorption to aquatic sediments is correlated with pollution in sites 

containing high levels of anthropogenic organic content, even under acidic conditions (Tada and 

Suzuki, 1982; Brook and Moore, 1988; Davis and Galloway, 1993; Botelho et al., 1994; Davis 

et al., 1996). Particulate-bound forms are more often linked to urban runoff and mining effluents 

(Eisler, 2000). 

Solid Pb complexes form when Pb precipitates or adsorbs to suspended particulate matter 

and sediments. Inorganic Pb adsorption to suspended organic matter or sediments is dependent 

on parameters such as, pH, salinity, water hardness, and the composition of the organic matter 

(U.S. Environmental Protection Agency, 1979). In addition to suspended organic matter, Pb can 

adsorb to biofilms (i.e., bacteria) (Nelson et al., 1995; Wilson et al., 2001). Adsorption typically 

increases with increasing pH, increasing amounts of iron or manganese; and with a higher degree 

of polarity of the particulate matter (e.g., clays). Adsorption decreases with water hardness 

(Syracuse Research Corporation, 1999). At higher pH, Pb precipitates as Pb(OH)+

 and PbHCO3

+

into bed sediments (Weber, 1993). Conversely, at low pH, Pb is negatively sorbed (repelled 

from the adsorbent surface) (U.S. Environmental Protection Agency, 1979; Gao et al., 2003). 

In addition, Pb may be remobilized from sediment with a decrease in metal concentration in the 
 AX7-122 

solution phase, complexation with chelating agents (e.g., EDTA), and changing redox conditions 

(Gao et al., 2003). Changes in water chemistry (e.g., reduced pH or ionic composition) can 

cause sediment Pb to become remobilized and potentially bioavailable to aquatic organisms 

(Weber, 1993). 

Biotransformation 

Methylation may result in Pb remobilization and reintroduction into the aqueous 

environment compartment and its subsequent release into the atmosphere (Syracuse Research 

Corporation., 1999). However, methylation is not a significant environmental pathway 

controlling the fate of Pb in the aquatic environment. The microbial methylation of Pb in aquatic 

systems has been demonstrated experimentally, but evidence for natural occurrence is limited 

(Beijer and Jernelov, 1984; DeJonghe and Adams, 1986). Reisinger et al. (1981) examined the 

methylation of Pb in the presence of numerous bacteria known to alkylate metals and did not find 

evidence of Pb methylation under any test condition. Tetramethyl-Pb may be formed by the 

methylation of Pb-nitrate or Pb-chloride in sediments (Bodek et al., 1988). However, 

tetramethyl-Pb is unstable and may degrade in aerobic environments after being released from 

sediments (U.S. Environmental Protection Agency, 1986b). Methylated species of Pb may also 

be formed by the decomposition of tetralkyl-Pb compounds (Radojevic and Harrison, 1987; 

Rhue et al., 1992). Sadiq (1992) reviewed the methylation of Pb compounds and suggested that 

chemical methylation of Pb is the dominant process and that biomethylation is of secondary 

importance. 

AX7.2.2.2 Spatial Distribution of Lead in Aquatic Ecosystems 

National Water Quality Assessment (NAWQA)

The 1986 Lead AQCD (U.S. Environmental Protection Agency, 1986b) did not describe 

the distribution and concentration of Pb throughout aquatic ecosystems of the United States. 

Consequently, an analysis of readily available data on Pb concentrations was conducted to 

determine the distribution of Pb in the aquatic environment. Data from the United States 

Geological Survey (USGS) National Water-Quality Assessment (NAWQA) program were 

queried and retrieved. NAWQA contains data on Pb concentrations in surface water, bed 

sediment, and animal tissue for more than 50 river basins and aquifers throughout the country, 
 AX7-123 

and it has been used by the EPA for describing national environmental concentrations for use in 

developing AWQC. The authors recognize that the NAWQA program encountered analytical 

challenges with the chemical analysis of Pb in surface waters. The analytical methods available 

during the NAWQA program were not as sensitive as methods currently applied today. 

Therefore, analytical detection limits are elevated and a large portion of the data set contains 

non-detected values. Nevertheless, this data provides a comprehensive overview of Pb 

concentrations in U.S. surface waters that is supplemented with data from other relevant studies. 

The following sections describe the estimated concentrations of Pb from NAWQA and other 

research programs. 

NAWQA data are collected during long-term, cyclical investigations wherein study units 

undergo intensive sampling for 3 to 4 years, followed by low-intensity monitoring and 

assessment of trends every 10 years. The NAWQA program’s first cycle was initiated in 1991; 

therefore, all available data are less than 15 years old. The second cycle began in 2001 and is 

ongoing; data are currently available through 30 September 2003. The NAWQA program study 

units were selected to represent a wide variety of environmental conditions and contaminant 

sources; therefore, agricultural, urban, and natural areas were all included. Attention was also 

given to selecting sites covering a wide variety of hydrologic and ecological resources. 

NAWQA sampling protocols are designed to promote data consistency within and among 

study units while minimizing local-scale spatial variability. Water-column sampling is 

conducted via continuous monitoring, fixed-interval sampling, extreme-flow sampling, as well as 

seasonal, high-frequency sampling in order to characterize spatial, temporal, and seasonal 

variability as a function of hydrologic conditions and contaminant sources. Sediment and tissue 

samples are collected during low-flow periods during the summer or fall to reduce seasonal 

variability. Where possible, sediment grab samples are collected along a 100-m stream reach, 

upstream of the location of the water-column sampling. Five to ten depositional zones at various 

depths, covering left bank, right bank, and center channel, are sampled to ensure a robust 

representation of each site. Fine-grained samples from the surficial 2 to 3 cm of bed sediment at 

each depositional zone are sampled and composited. Tissue samples are collected following a 

National Target Taxa list and decision trees that help guide selection from that list to 

accommodate local variability. 
 AX7-124 

The NAWQA dataset was chosen over other readily available national databases (i.e. the 

USEPA-maintained database for the STOrage and RETrieval [STORET] of chemical, physical, 

and biological data), because the study design and methods used to assess the water quality of 

each study unit are rigorous and consistent, and, as such, these data may be presented with a high 

level of confidence. This is in stark contrast to the STORET database, which essentially serves 

as a depot for any organization wishing to share data they have generated. This lack of a 

consistent methodology or QA/QC protocol has lead to the STORET data being highly qualified 

and offered with only a mild level of confidence. Furthermore, because there is no standard for 

site selection within STORET, the database may be biased toward contaminated sites. Finally, 

and, perhaps most importantly, the majority of the available Pb data in STORET predate the use 

of clean techniques for Pb quantification. 

The authors recognize the existence of several local and regional datasets that may be of 

quality equal to NAWQA; however, due to the national scope of this assessment, these datasets 

were not included in the following statistical analyses. However, because the NAWQA database 

does not cover lakes and the marine/estuarine environment, and we were unable to identify any 

monitoring data of similar quality, local and regional datasets were used in these cases to provide 

general information on environmental Pb concentrations. 

Data Acquisition and Analysis

The following data were downloaded for the entire United States (all states) from the 

NAWQA website (http://water.usgs.gov/nawqa/index.html): site information, dissolved Pb 

concentration in surface water (μg/L), total Pb concentration (μg/g) in bed sediment (<63 μm)3

, 

and Pb concentration in animal tissue (μg/g dw). Using the land use classification given for each 

site, the data were divided into two groups: “natural” and “ambient” (Table AX7-2.2.1). 

All samples were considered to fall within the ambient group (the combined contribution of 

natural and anthropogenic sources), whereas the natural group comprised “forest,” “rangeland,” 

or “reference” samples only4

. These groups follow those defined and recommended for use by 

the EPA’s Framework for Inorganic Metals Risk Assessment (U.S. Environmental Protection 

 3

 NAWQA sediment samples are sieved to <63 μm to promote the collection of fine-grained surficial 

sediments, which are natural accumulators of trace elements. 

4

 The authors acknowledge that while Pb samples collected from sites classified under these three land use 

categories will most closely reflect natural background concentrations, atmospheric input of lead may be present. 
 AX7-125 

Table AX7-2.2.1. NAWQA Land Use Categories and 

Natural/Ambient Classification 

NAWQA Land Use Categories Classification 

 Agricultural Ambient 

 Commercial/Industrial Ambient 

 Cropland Ambient 

 Forest Ambient/Natural 

 Mining Ambient 

 Mixed Ambient 

 NA Ambient 

 Orchard/Vineyard Ambient 

 Other/Mixed Ambient 

 Pasture Ambient 

 Rangeland Ambient/Natural 

 Reference Ambient/Natural 

 Residential Ambient 

 Urban Ambient 

Agency, 2004b). Finally, in addition to the natural/ambient classification, tissue samples were 

further divided into “whole organism” and “liver” groups. 

All data were compiled in spreadsheets wherein non-detect values were converted to onehalf the detection limit and the total number of samples, percentage of non-detect values (percent 

censorship), minimum, maximum, median, mean, standard deviation, and cumulative density 

functions were calculated for each endpoint for both the natural and ambient groups. 

As discussed below, some datasets were highly censored; however, deletion of non-detect data 

has been shown to increase the relative error in the mean to a greater extent than inclusion of 

non-detects as 1⁄2 of the detection limit (Newman et al., 1989); therefore means and other 

statistics were calculated using the latter method for this analysis. Finally, since all data were 

geo-referenced, a geographic information system (GIS; ArcGIS) was used to generate maps, 

conduct spatial queries and analyses, and calculate statistics. 
 AX7-126 

Lead Distributions Generated from the NAWQA Database 

Natural versus Ambient Groups

There were four to eight times more ambient surface water (Table AX7-2.2.2) and bulk 

sediment (Table AX7-2.2.3) samples in the compiled dataset than natural samples. This is most 

likely a function of both the NAWQA program site selection process and the fact that sites 

unaffected by human activities are extremely limited. The spatial distributions of natural and 

ambient surface water/sediment sites were fairly comparable, with natural samples located in 

almost all of the same areas as ambient samples except in the Midwest (Ohio, Illinois, Iowa, and 

Michigan), where natural sites were not present (Figure AX7-2.2.3). This exception may be 

because these areas are dominated by agricultural and urban areas. The same spatial 

distributions were observed for the natural and ambient liver and whole organism tissue 

samples (Figure AX7-2.2.4 and Figure AX7-2.2.5). 

 

Table AX7-2.2.2. Summary Statistics of Ambient and Natural Levels of 

Dissolved Lead in Surface Water 

Surface Water Dissolved Pb (μg/L) 

Statistic Natural Ambient 

 % Censorship 87.91 85.66 

 N 430 3445 

 Minimum 0.04 0.04 

 Maximum 8.40 29.78 

 Mean 0.52 0.66 

 Standard Deviation 0.59 1.20 

 Median 0.50 0.50 

 90th Percentile 0.50 0.50 

 95th Percentile 0.50 1.10 

 96th Percentile 0.67 2.00 

 97th Percentile 1.00 2.34 

 98th Percentile 1.79 3.58 

 99th Percentile 2.48 5.44 
 AX7-127 

Table AX7-2.2.3. Summary Statistics of Ambient and Natural Levels of Total Lead in 

<63 μm Bulk Sediment 

Bulk Sediment <63 um Total Lead (μg/g) 

Statistic Natural Ambient 

 % Censorship 1.16 0.48 

 N 258 1466 

 Minimum 0.50 0.50 

 Maximum 12000 12000 

 Mean 109.07 120.11 

 Standard Deviation 786.74 672.41 

 Median 22.00 28.00 

 90th percentile 66.30 120.00 

 95th percentile 161.50 200.00 

Surface Water

The total number of surface water Pb samples was 3,445; however these data were highly 

censored with 85.66% of the ambient samples (2951/3445) and 87.91% of the natural samples 

(378/430) below the detection limit5 (Table AX7-2.2.2). Consequently, the majority of the 

variability between these two datasets fell between the 95th and 100th (maximum) percentiles, 

as was shown by the frequency distributions of the two groups deviating only at the upper and 

lower tails with most of the overlapping data falling at 0.50 μg/L (one-half of the most common 

detection limit, 1.0 μg/L; Figure AX7-2.2.6). As expected, due to the definitions of the natural 

and ambient groups, the 95th and 100th percentiles were consistently higher for the ambient 

samples than the natural samples. Similarly, the mean ambient Pb concentration (0.66 μg/L) 

was higher than the mean natural Pb concentration (0.52 μg/L).6

 5

 The NAWQA dataset contains multiple detection limits for Pb in surface water that have decreased over 

time. While the majority of data were analyzed with a detection limit of 1.0 μg/L (before 2000/2001), the most 

recent samples were analyzed with either a 0.5, 0.2, 0.16, or 0.08 μg/L detection limit (after 2000/2001), and some 

older samples (N = 20) were analyzed with a detection limit of 2.0 μg/L. 

6 The same pattern was observed upon calculating the mean Pb concentrations based on detect data only 

(ambient mean = 1.66 μg/L, natural mean = 0.87 μg/L); however, as previously discussed, calculations included 

non-detect data as 1⁄2 of the detection limit to reduce the relative error in the mean. 
 AX7-128 

Figure AX7-2.2.3. Spatial distribution of natural and ambient surface water/sediment sites (Surface wate

ambient N = 3445; Sediment: natural N = 258, ambient N = 1466). 
 AX7-129 

Figure AX7-2.2.4. Spatial distribution of natural and ambient liver tissue sample sites (Natural N = 83, 
 AX7-130 

Figure AX7-2.2.5. Spatial distribution of natural and ambient whole organism tissue sample sites (Natu

Ambient N = 332). 
 AX7-131 

Figure AX7-2.2.6. Frequency distribution of ambient and natural levels of surface water 

dissolved lead (μg/L). 

 Due to the preponderance of non-detectable (ND) measurements, assessing national trends 

in surface water-dissolved Pb concentrations was not possible. However, areas with elevated Pb 

concentrations were identified by classifying the data with detectable Pb concentrations above 

and below the 99th percentile. The 99th percentile (versus the 95th percentile) was chosen in 

this instance to represent extreme conditions given the small window of variability in the dataset. 

By convention, the 95th percentile was used in subsequent analyses of this type. Areas with high 

surface water Pb concentrations were observed in Washington, Idaho, Utah, Colorado, Arkansas, 

and Missouri (Figure AX7-2.2.7). The maximum measured Pb concentration was located in 

Canyon Creek at Woodland Park, ID, a site classified as mining land use. 

Sediment

There were approximately one-half of the number of surface water data available for 

sediments (N = 1466). In contrast to the surface water data, however, very few sediment data 

were below the detection limit (7/1466 ambient ND, 3/258 natural ND; Table AX7-2.2.3). 

As expected, the mean ambient Pb concentration was higher than the mean natural Pb 
 AX7-132 Figure AX7-2.2.7. Spatial distribution of dissolved lead in surface water (N = 3445). 

`
 AX7-133

concentration (120.11 and 109.07 μg/g, respectively). Similarly, the median ambient Pb 

concentration was higher than the median natural Pb concentration (28.00 and 22.00 μg/g, 

respectively) and the ambient 95th percentile was higher than the natural 95th percentile 

(200.00 and 161.50 μg/g, respectively). While the natural and ambient surface water Pb 

distributions differed only at the extremes, the natural sediment Pb percentiles were consistently 

lower than the ambient percentiles throughout the distributions (Figure AX7-2.2.8). Unlike the 

surface water dataset, because the sediment dataset was not heavily censored, assessing national 

trends in sediment Pb concentrations was possible. The data were mapped and categorized into 

the four quartiles of the frequency distribution (Figure AX7-2.2.9). The following observations 

were made: 

• Sediment Pb concentrations generally increased from west to east (the majority of 

sites along East Coast had Pb concentrations in the fourth quartile of the sediment Pb 

concentration frequency distribution). 

• Several “hot spots” of concentrated sites with elevated sediment Pb concentrations 

were apparent in various western states. 

• Sediment Pb concentrations were generally lowest in the midwestern states 

(the majority of sites in North Dakota, Nebraska, Minnesota, and Iowa had Pb 

concentrations in the first or second quartile of sediment Pb concentration 

frequency distribution). 

As was seen with surface water Pb concentrations, the highest measured sediment Pb 

concentrations were found in Idaho, Utah, and Colorado. Not surprisingly, of the top 10 

sediment Pb concentrations recorded, 7 were measured at sites classified as mining land use. 

Tissue 

As was true for the surface water data, there were a high number of tissue samples below 

the detection limit (47/93 natural whole organism ND, 130/332 ambient whole organism ND, 

74/83 natural liver ND, 398/559 ambient liver ND; Table AX7-2.2.4). In general, more 

non-censored data were available for whole organism samples than liver samples, and for 

ambient sites than natural sites. As expected, for whole organism samples, the 95th percentile Pb 

concentration measured at ambient sites was higher than that measured at natural sites (3.24 and 

2.50 μg/g, respectively); however, Pb liver concentration 95th percentiles for ambient and 

natural samples were very similar, with the natural 95th percentile actually higher than the 
 AX7-134

Figure AX7-2.2.8. Frequency distribution of ambient and natural levels of bulk sediment 

<63 μm total Pb (μg/g). 

ambient 95th percentile (1.26 and 1.06 μg/g, respectively). In addition, as expected, the median 

and mean Pb liver concentrations of ambient samples (0.15 and 0.36 μg/g, respectively) were 

higher than the median and mean Pb liver concentrations of natural samples (0.11 and 0.28 μg/g, 

respectively). The same pattern was observed in the whole organism median and mean Pb 

concentrations (ambient: median = 0.59, mean = 1.03; natural: median = 0.35, mean = 

0.95 μg/g). In addition, the frequency distributions of the liver and whole organism Pb 

concentrations followed the same trends, with the natural percentiles consistently lower than the 

ambient percentiles throughout the distributions (Figure AX7-2.2.10 and Figure AX7-2.2.11). 

These whole organism results were compared with findings from the 1984 U.S. Fish and 

Wildlife Service (USFWS) National Contaminant Biomonitoring Program (NCBP) (Schmitt and 

Brumbaugh, 1990). As part of this program, 321 composite samples of 3 to 5 whole, adult fish 

of a single species were collected from 109 river and Great Lake stations throughout the country. 

Samples were analyzed for Pb concentrations (μg/g ww) and the geometric mean, maximum, and 

85th percentile were calculated. Upon comparing these summary statistics with the equivalent 

NAWQA ambient group value (NCBP stations were representative of both natural and 

anthropogenically influenced conditions), a very strong agreement between the two analyses was 
 AX7-135 Figure AX7-2.2.9. Spatial distribution of total lead in bulk sediment <63 μm (N = 1466). 
 AX7-136 

Table AX7-2.2.4. Summary Statistics of Ambient and Natural Levels of Lead 

in Whole Organism and Liver Tissues 

Tissue Pb (μg/g dry weight) 

Whole Organism Liver 

Statistic Natural Ambient Natural Ambient 

% Censorship 50.54 39.16 89.16 71.20 

N 93 332 83 559 

Minimum 0.08 0.08 0.01 0.01 

Maximum 22.60 22.60 3.37 12.69 

Mean 0.95 1.03 0.28 0.36 

Standard Deviation 2.53 1.74 0.54 0.96 

Median 0.35 0.59 0.11 0.15 

90th percentile 1.40 2.27 0.37 0.59 

95th percentile 2.50 3.24 1.26 1.06 

observed for each endpoint (Table AX7-2.2.5). For example, NCBP and NAWQA geometric 

mean Pb concentrations were nearly identical(0.55 and 0.54 μg/g dw, respectively) and the 

85th percentiles only differed by 0.5 μg Pb/g dw (NCBP, 1.10 and NAWQA, 1.60). The authors 

acknowledge that a high degree of censorship is present in both of these datasets and no firm 

conclusions can be drawn by comparing these means. The objective of this exercise was limited 

to showing how the NAWQA data compare to other national datasets. 

As was the case with surface water data, the high amount of non-detectable measurements 

did not allow for a national assessment of spatial trends in Pb tissue concentrations. Instead, 

areas with high Pb tissue concentrations were identified by classifying the data above and below 

the 95th percentile. Similar to surface water and sediments, tissue concentrations were found to 

be elevated in Washington, Idaho, Utah, Colorado, Arkansas, and Missouri; however, several of 

the highest measured Pb concentrations were also found in study units in the southwestern and 
 AX7-137 

Figure AX7-2.2.10. Frequency distribution of ambient and natural levels of lead in liver 

tissue (μg/g dry weight). 

Figure AX7-2.2.11. Frequency distribution of ambient and natural levels of lead in whole 

organism tissue (μg/g dry weight). 
 AX7-138 

Table AX7-2.2.5. Comparison of NCBP and NAWQA Ambient Lead Levels 

in Whole Organism Tissues 

Whole Organism Lead Concentration (μg/g dry weight) 

Statistic NCBP1 NAWQA 

Geometric Mean 0.55 0.54 

Maximum 24.40 22.60 

85th Percentile 1.10 1.60 

1

 To convert between wet and dry weight, wet weight values were multiplied by a factor of five. 

southeastern states (Figure AX7-2.2.12 and Figure AX7-2.2.13). As expected, the majority of 

the samples with elevated Pb concentrations were taken from sites classified as urban, 

commercial/industrial, or mining. 

Input and Distribution of Lead in Other Aquatic Systems 

Because the NAWQA database does not cover lakes or the sea where atmospheric 

deposition of Pb is highly likely, the primary literature was searched for studies using ultra-clean 

sampling/analytical techniques to characterize Pb concentrations in these environments. Lead 

concentrations in lakes and oceans were generally found to be much lower than those measured 

in the lotic waters assessed by NAWQA. Surface water concentrations of dissolved Pb measured 

in Hall Lake, Washington in 1990 ranged from 2.1 – 1015.3 ng/L (Balistrieri et al., 1994). 

Nriagu et al. (1996) found that the average surface water dissolved Pb concentrations measured 

in the Great Lakes (Superior, Erie, and Ontario) between 1991 and 1993 were 3.2, 6.0, and 

9.9 ng/L, respectively. Lead concentrations ranged from 3.2 – 11 ng/L across all three lakes. 

Similarly, 101 surface water total Pb concentrations measured at the HOT station ALOHA 

between 1998 and 2002 ranged from 25 – 57 pmol/kg (5 – 11 ng/kg; (Boyle et al., 2005). Based 

on the fact that Pb is predominately found in the dissolved form in the open ocean (<90%; 

Schaule and Patterson, 1981), dissolved Pb concentrations measured at these locations would 

likely have been even lower than the total Pb concentrations reported. 
 AX7-139 Figure AX7-2.2.12. Spatial distribution of lead in liver tissues (N = 559). 
 AX7-140 Figure AX7-2.2.13. Spatial distribution of lead in whole organism tissues (N = 332). 
 AX7-141 

In open waters of the North Atlantic the decline of Pb concentrations has been associated 

with the phasing out of leaded gasoline in North America and western Europe (Véron et al., 

1998). Likewise, Pb restrictions in gasoline appear to have been effective in reducing 

atmospheric Pb loading to the Okefenokee Swamp in southern Georgia/northern Florida 

(Jackson et al., 2004). Based on sediment cores from the Okefenokee Swamp, Pb concentrations 

were approximately 0.5 mg/kg prior to industrial development, reached a maximum of 

approximately 31 mg/kg from about 1935 to 1965, and following passage of the Clean Air Act in 

1970 concentrations have declined to about 18 mg/kg in 1990 (Jackson et al., 2004). Trends in 

metals concentrations (roughly 1970-2001) in sediment cores from 35 reservoirs and lakes in 

urban and reference settings were analyzed by Mahler et al. (2006) to determine the effects of 

three decades of legislation, regulation, and changing demographics and industrial practices in 

the United States on concentrations of metals in the environment. The researchers found that 

decreasing trends outnumbered increasing trends for all seven metals analyzed (Cd, Cr, Cu, Pb, 

Hg, Ni, and Zn). The most consistent trends were for Pb and Cr: For Pb, 83% of the lakes had 

decreasing trends and 6% had increasing trends; for Cr, 54% of the lakes had decreasing trends 

and none had increasing trends. Mass accumulation rates of metals in cores, adjusted for 

background concentrations, decreased from the 1970s to the 1990s, where median changes 

ranged from 246% (Pb) to 23% (Hg and Zn). The largest decreases were found in lakes located 

in dense urban watersheds where the overall metals contamination in recently deposited 

sediments decreased to on-half its 1970s median value. However, Mahler et al. (2006) found 

that anthropogenic mass accumulation rates in dense urban lakes remained elevated over those in 

lakes in undeveloped watersheds, in some cases by as much as two orders of magnitude (Cr, Cu, 

and Zn), indicating that urban fluvial source signals can overwhelm those from regional 

atmospheric sources. In estuarine systems, however, it appears that similar declines following 

the phase-out of leaded gasoline are not necessarily as rapid. Steding et al. (2000) used isotopic 

evidence to demonstrate the continued cycling of Pb in the San Francisco Bay estuary. In the 

southern arm of San Francisco Bay, which has an average depth of <2 m, Steding et al. (2000) 

found that isotopic compositions were essentially invariant, with 90% of the Pb derived from 

1960s-1970s leaded gasoline. The authors attributed this to the limited hydraulic flushing and 

remobilization of Pb from bottom sediments. In the northern arm of San Francisco Bay, 

although seasonal and decadal variations in Pb isotope composition were observed, mass balance 
 AX7-142 

calculations indicate that only a small fraction of leaded gasoline fallout from the late 1980s has 

been washed out of the San Joaquin and Sacramento rivers’ drainage basin by 1995 and 

consequently freshwater inputs remain a Pb source to the bay (Steding et al., 2000). The authors 

suggest that the continuous source of Pb from the river systems draining into the bay, coupled 

with benthic remobilization of Pb, indicates that historic gasoline deposits may remain in the 

combined riparian/estuarine system for decades. 

AX7.2.2.3 Tracing the Fate and Transport of Lead in Aquatic Ecosystems 

The following section presents a generalized framework for the fate and transport of Pb in 

aquatic systems (Figure AX7-2.2.14). The primary source of Pb in natural systems is 

atmospheric deposition (Rickard and Nriagu, 1978; U.S. Environmental Protection Agency, 

1986a). Estimated median global atmospheric emission for anthropogenic and natural sources 

are 332 Η 106

 kg/year and 12 Η 106 kg/year, respectively (summarized by Giusti et al., 1993). 

Inorganic and metallic Pb compounds are nonvolatile and will partition to airborne particulates 

or water vapors (Syracuse Research Corporation., 1999). Dispersion and deposition of Pb is 

dependent on the particle size (U.S. Environmental Protection Agency, 1986a; Syracuse 

Research Corporation., 1999). More soluble forms of Pb will be removed from the atmosphere 

by washout in rain. 

In addition to atmospheric deposition, Pb may enter aquatic ecosystems through industrial 

or municipal wastewater effluents, storm water runoff, erosion, or direct point source inputs 

(e.g., Pb shot or accidental spills). Once in the aquatic environment, Pb will partition between 

the various compartments of the system (e.g., dissolved phase, solid phase, biota). The 

movement of Pb between dissolved and particulate forms is governed by factors such as pH, 

sorption, and biotransformation (see Section AX7.2.2.1). Lead bound to organic matter will 

settle to the bottom sediment layer, be assimilated by aquatic organisms, or be resuspended in the 

water column. The uptake, accumulation, and toxicity of Pb in aquatic organisms from water 

and sediments are influenced by various environmental factors (e.g., pH, organic matter, 

temperature, hardness, bioavailability). These factors are further described in Section 

AX7.2.3.4). The remainder of this section discusses some methods for describing the 

distribution of atmospheric Pb in the aquatic environment. 
 AX7-143 

Figure AX7-2.2.14. Lead cycle in an aquatic ecosystem. 

Sediment Core Dating and Source Tracing

In addition to directly measuring Pb concentrations in various aquatic compartments (see 

Section AX7.2.3.3), it is useful to study the vertical distribution of Pb. Sediment profiling and 

core dating is a method used to determine the extent of accumulation of atmospheric Pb and 

provide information on potential anthropogenic sources. Sediment concentration profiles are 

typically coupled with Pb isotopic analysis. The isotope fingerprinting method utilizes 

measurements of the abundance of common Pb isotopes (i.e., 204Pb, 206Pb, 207Pb, 208Pb) to 

distinguish between natural Pb over geologic time and potential anthropogenic sources. Details 

of this method were described in Section AX7.1.2. The concentration of isotope 204Pb has 

remained constant throughout time, while the other isotope species can be linked to various 

anthropogenic Pb sources. Typically, the ratios or signatures of isotopes (e.g., 207Pb:206Pb) are 

compared between environmental samples to indicate similarities or differences in the site being 

investigated and the potential known sources. 

Generally, Pb concentrations in sediment vary with depth. For example, Chow et al. 

(1973) examined sediment Pb profiles in southern California. Lead concentrations were 

increased in the shallower sediment depths and comparatively decreased at greater depths. These 

changes in sediment vertical concentration were attributed to higher anthropogenic Pb fluxes 
 AX7-144 

from municipal sewage, storm runoff, and atmospheric deposition. Similar experiments 

conducted throughout the United States have also suggested an increase in Pb concentrations in 

the upper sediment layer concomitant with increases in anthropogenic inputs (Bloom and 

Crecelius, 1987; Case et al., 1989; Ritson et al., 1999; Chillrud et al., 2003). 

Sediment Pb concentration profiles and isotope analysis have also been used to identify 

specific anthropogenic sources. For example, Flegal et al. (1987) used isotopic ratios to trace 

sources of Pb in mussels from Monterey Bay, CA to a specific slag deposit. Several 

investigators have examined isotopic tracers to determine potential regional sources of Pb in 

eastern North America and the Great Lakes (Flegal et al., 1989b; Graney et al., 1995; Blais, 

1996). Water samples from Lake Erie and Lake Ontario were collected and analyzed. Lead 

isotope ratios (206Pb:207Pb) from the lakes were compared to known ratios for Pb aerosols derived 

from industrial sources in Canada and the United States and found to correlate positively. This 

indicated that a majority of Pb in the lakes was derived from those industrial sources (Flegal 

et al., 1989b). Similarly, Gallon et al. (2006) used 206Pb:207Pb ratios in sediment cores collected 

from a 300 km transect in Canadian Shield headwater lakes to differentiate Pb contributions from 

smelter emissions relative to Pb contributions from other anthropogenic inputs. The authors 

were able to estimate the amounts of smelter-derived Pb in sediment collected along the 300 km 

transect. Lead isotopes in sediment cores from Quebec and Ontario, Canada were also used to 

distinguish between the amount of Pb deposited from local Canadian sources (28.4 to 61.7%) 

and U.S. sources (38.3 to 71.6%) (Blais, 1996). Examination of Pb isotopes in sediment and 

suspended sediment in the St. Lawrence River were used to identify potential anthropogenic Pb 

sources from Canada (Gobeil et al., 1995, 2005). Graney et al. (1995) used Pb isotope 

measurements to describe the differing historic sources of Pb in Lake Erie, Ontario and in 

Michigan. Temporal changes in Pb isotopic ratios were found to correspond to sources such as 

regional deforestation from 1860 through1890, coal combustion and or smelting through 1930, 

and the influence of leaded gasoline consumption from 1930 to 1980. 

The historic record of atmospheric Pb pollution has been studied to understand the natural 

background Pb concentration and the effects of Pb accumulation on ecosystems (Bindler et al., 

1999; Renberg et al., 2000, 2002; Brännvall et al., 2001a,b). The most extensive work in this 

area has been conducted at pristine locations in Sweden (Bindler et al., 1999). In this study, soil, 

sediment, and tree rings were sampled for Pb concentrations and isotopic analyses were 
 AX7-145 

conducted on the soil samples. From this record, historic Pb concentrations and Pb accumulation 

rates were estimated. Present day concentrations in the forest soils ranged from 40 to 100 mg/kg, 

while a natural background concentration was estimated at <1 mg/kg. The authors were able to 

model Pb concentrations for the past 6,000 years and also to project Pb concentrations for the 

next 400 years, given an assumed atmospheric deposition rate of 1 mg Pb m!2/year. Models such 

as this are useful tools in determining the critical limits of metals in soils or sediments (Bindler et 

al., 1999; Renberg et al., 2002). 

Lead source association may also be assessed through retrospective measurements. 

Squire et al. (2002) used a time-series approach to evaluate the change in Pb in San Francisco 

Bay, CA from 1989 to 1999. This approach involved the use of detailed linear regression models 

and long-term monitoring data to determine changes in Pb concentrations and to identify events 

corresponding to those changes. Sediment and water samples were collected throughout the bay 

and combined with data on effluent discharges, urban runoff, atmospheric deposition, and river 

discharges. The authors identified a 40% decline of Pb in the southern portion of the bay but 

found no change in the northern reach. The decline was attributed to a reduction in wastewater 

source loadings over the previous decade. 

AX7.2.2.4 Summary

Lead is widely distributed in aquatic ecosystems, predominantly originating from 

atmospheric deposition or point source contribution. The fate and behavior of Pb in aquatic 

systems is regulated by physical and chemical factors such as pH, salinity, sediment sorption, 

transformation, and uptake by aquatic biota. In the United States, Pb concentrations in surface 

waters, sediments, and fish tissues range from 0.04 to 30 μg/L, 0.5 to 12,000 mg/kg, and 0.08 to 

23 mg/kg, respectively. Atmospheric sources are generally decreasing, as the United States has 

removed Pb from gasoline and other products. However, elevated Pb concentrations remain at 

sites associated with mining wastes or wastewater effluents. Since the 1986 Lead AQCD, much 

has been learned about the processes affecting Pb fate and transport. Detailed analyses are 

currently available (i.e., Pb isotope dating) to allow for constructing the history of Pb 

accumulation and identifying specific Pb contaminant sources. Continued source control along 

with examination of the physical and chemical properties will further allow for the reduction of 

Pb concentrations throughout the United States. 
 AX7-146 

AX7.2.3 Aquatic Species Response/Mode of Action 

Recent advancements in understanding the responses of aquatic biota to Pb exposure are 

highlighted in this section. A summary of the conclusions on the review of aquatic responses to 

Pb from the appropriate sections of the 1986 Lead AQCD, Volume II (U.S. Environmental 

Protection Agency, 1986a) and the subsequent conclusions and recommendations contained in 

the EPA staff review of that document (U.S. Environmental Protection Agency, 1990) are also 

provided. In addition, this section summarizes research subsequent to the 1986 Lead AQCD on 

Pb uptake into aquatic biota, effects of Pb speciation on uptake, resistance mechanisms to Pb 

toxicity, physiological effects of Pb, factors that affect responses to Pb, and factors associated 

with global climate change. Areas of research that are not addressed here include literature 

related to exposure to Pb shot or pellets and studies that examine human health-related endpoints 

(e.g., hypertension), which are described in other sections of this document. 

AX7.2.3.1 Lead Uptake 

Lead is nutritionally nonessential and non-beneficial and is toxic to living organisms in all 

of its forms (Eisler, 2000). Lead can bioaccumulate in the tissues of aquatic organisms through 

ingestion of food and water and adsorption from water (Vázquez et al., 1999; Vink, 2002) and 

subsequently lead to adverse effects if tissue levels are sufficiently high (see Section AX7.2.5). 

Recent research has suggested that due to the low solubility of Pb in water, dietary Pb (i.e., lead 

adsorbed to sediment, particulate matter, and food) may contribute substantially to exposure and 

toxicity in aquatic biota (Besser et al., 2005). Besser et al. (2004) exposed the amphipod 

Hyalella azteca to concentrations of Pb to evaluate the influence of waterborne and dietary Pb 

exposure on acute and chronic toxicity. The authors found that acute toxicity was unaffected by 

dietary exposure but that dietary Pb exposure did contribute to chronic toxic effects (i.e., 

survival, growth, reproduction) in H. azteca. Field studies in areas affected by metal 

contamination (i.e., Clark Fork River, MO; Coeur d’Alene, ID) (Woodward et al., 1994, 1995; 

Farag et al., 1994) have also demonstrated the effects of dietary metals on rainbow trout. 

However, there has been a debate on the importance of dietary exposure, as few controlled 

laboratory studies have been able to replicate the effects observed in the field studies (Hodson 

et al., 1978; Mount, 1994; Erikson, 2001). This may be due to differences in the availability of 

Pb from the dietary sources used in laboratory studies, differences in speciation, and/or 
 AX7-147 

nutritional characteristics of the Pb dosed diets. In many field and laboratory studies, dietary 

exposure is rarily considered, but food provided to biota in these studies adsorb metals from 

water. Therefore, both dietary and waterborne exposure are occurring and both may be 

considered to play roles in eliciting the measured effects. 

Lead concentrations in the tissues of aquatic organisms are generally higher in algae and 

benthic organisms and lower in higher trophic-level consumers (Eisler, 2000). Thus, trophic 

transfer of Pb through food chains is not expected (Eisler, 2000). Metals are not metabolized; 

therefore, they are good integrative indicators of exposure in aquatic biota (Luoma and Rainbow, 

2005). Metal uptake is complex, being influenced by geochemistry, route of exposure (diet and 

adsorption), depuration, and growth (Luoma and Rainbow, 2005). This section discusses the 

factors affecting uptake of Pb by aquatic biota and the state of current research in this area. 

As described in Section AX7.2.2.1, the solubility of Pb in water varies with pH, 

temperature, and ion concentration (water hardness) (Weber, 1993). Lead becomes soluble and 

bioavailable under conditions of low pH, organic carbon content, suspended sediment 

concentrations, and ionic concentrations (i.e., low Cd, Ca, Fe, Mn, Zn) (Eisler, 2000). Lead 

rapidly loses solubility above pH 6.5 (Rickard and Nriagu, 1978) and precipitates out as Pb(OH)+

and PbHCO3

+

 into bed sediments. However, at reduced pH levels or ionic concentrations, 

sediment Pb can remobilize and potentially become bioavailable to aquatic organisms (Weber, 

1993). 

The most bioavailable inorganic form of Pb is divalent Pb (Pb2+), which tends to be more 

readily assimilated by organisms than complexed forms (Erten-Unal et al., 1998). On the other 

hand, the low solubility of Pb salts restricts movement across cell membranes, resulting in less 

accumulation of Pb in fish in comparison to other metals (e.g., Hg, Cu) (Baatrup, 1991). 

The accumulation of Pb in aquatic organisms is, therefore, influenced by water pH, with 

lower pHs favoring bioavailability and accumulation. For example, fish accumulated Pb at a 

greater rate in acidic lakes (pH = 4.9 to 5.4) than in more neutral lakes (pH = 5.8 to 6.8) (Stripp 

et al., 1990). Merlini and Pozzi (1977) found that pumpkinseed sunfish exposed to Pb at pH 6.0 

accumulated three-times as much Pb as fish kept at pH 7.5. However, Albers and Camardese 

(1993a,b) examined the effects of pH on Pb uptake in aquatic plants and invertebrates in acidic 

(pH ~5.0) and nonacidic (pH ~6.5) constructed wetlands, ponds, and small lakes in Maine and 

Maryland. Their results suggested that low pH had little effect on the accumulation of metals by 
 AX7-148 

aquatic plants and insects and on the concentration of metals in the waters of these aquatic 

systems (Albers and Camardese, 1993a,b). 

Three geochemical factors that influence metal bioaccumulation in aquatic organisms 

include speciation, particulate metal form, and metal form in the tissues of prey items (Luoma 

and Rainbow, 2005). Lead is typically present in acidic aquatic environments as PbSO4, PbCl4, 

ionic Pb, cationic forms of Pb-hydroxide, and ordinary hydroxide Pb(OH)2. In alkaline waters, 

common species of Pb include anionic forms of Pb-carbonate (Pb(CO3)) and Pb(OH)2. Labile 

forms of Pb (e.g., Pb2+, PbOH+

, PbCO3) are a significant portion of the Pb inputs to aquatic 

systems from atmospheric washout. Particulate-bound forms are more often linked to urban 

runoff and mining effluents (Eisler, 2000). Little research has been done to link the complex 

concepts of chemical speciation and bioavailability in natural systems (Vink, 2002). The 

relationship between the geochemistry of the underlying sediment and the impact of temporal 

changes (e.g., seasonal temperatures) to metal speciation are particularly not well studied (Vink, 

2002; Hassler et al., 2004). 

Generally speaking, aquatic organisms exhibit three Pb accumulation strategies: 

(1) accumulation of significant Pb concentrations with a low rate of loss, (2) excretion of Pb 

roughly in balance with availability of metal in the environment, and (3) weak net accumulation 

due to very low metal uptake rate and no significant excretion (Rainbow, 1996). Species that 

accumulate nonessential metals such as Pb and that have low rates of loss must partition it 

internally in such a way that it is sparingly available metabolically. Otherwise, it may cause 

adverse toxicological effects (Rainbow, 1996). Aquatic organisms that exhibit this type of 

physiological response have been recommended for use both as environmental indicators of 

heavy metal pollution (Borgmann et al., 1993; Castro et al., 1996; Carter and Porter, 1997) and, 

in the case of macrophytes, as phytoremediators, because they accumulate heavy metals rapidly 

from surface water and sediment (Gavrilenko and Zolotukhina, 1989; Simòes Gonçalves et al., 

1991; Carter and Porter, 1997). 

Uptake experiments with aquatic plants and invertebrates (e.g., macrophytes, 

chironomids, crayfish) have shown steady increases in Pb uptake with increasing Pb 

concentration in solution (Knowlton et al., 1983; Timmermans et al., 1992). In crayfish, the 

process of molting can cause a reduction in body Pb concentrations, as Pb incorporated into the 

crayfish shell is eliminated (Knowlton et al., 1983). Vázquez et al. (1999) reported on the uptake 
 AX7-149 

of Pb from solution to the extracellular and intracellular compartments of 3 species of aquatic 

bryophytes. Relative to the 6 metals tested, Pb was found to accumulate to the largest degree in 

the extracellular compartments of all 3 bryophytes. The extracellular metals were defined as 

those that are incorporated into the cell wall or are found on the outer surface of the plasma 

membrane (i.e., adsorbed) (Vázquez et al., 1999). Intracellular metals were defined as metals 

introduced into the cell through a metabolically controlled process. 

Arai et al. (2002) examined the effect of growth on the uptake and elimination of trace 

metals in the abalone Haliotos. They reported that older abalones had generally lower whole 

body concentrations of heavy metals than did younger, rapidly growing individuals. During the 

rapid growth of juveniles, the organism is less able to distinguish between essential (e.g., Zn), 

and nonessential metals (e.g., Pb). Once they reach maturity, they develop the ability to 

differentiate these metals. Li et al. (2004) reported a similar response in zebra fish embryolarvae. Li et al. (2004) suggested that mature physiological systems are not developed in the 

embryo-larvae to handle elevated concentrations of metals. Therefore, metals are transported 

into the body by facilitated diffusion. Both the zebra fish and juvenile abalone demonstrate a 

rapid accumulation strategy followed by a low rate of loss as described above. There are 

insufficient data available to determine whether this phenomenon is true for other aquatic 

organisms. 

Growth rates are generally thought to be an important consideration in the comparison of 

Pb levels in individuals of the same species. The larger the individual the more the metal content 

is diluted by body tissue (Rainbow, 1996). 

Once Pb is absorbed, it may sequester into varying parts of the organism. Calcium 

appears to have an important influence on Pb transfer. For example, Pb uptake and retention in 

the skin and skeleton of coho salmon was reduced when dietary Ca was increased (Varanasi and 

Gmur, 1978). Organic Pb compounds tend to accumulate in lipids, and are taken up and 

accumulated in fish more readily than inorganic Pb compounds (Pattee and Pain, 2003). 

Given the complexities of metal uptake in natural systems, a model incorporating some of 

the factors mentioned above is desirable. The EPA’s Environmental Research Laboratory in 

Duluth, Minnesota developed a thermodynamic equilibrium model, MINTEQ that predicts 

aqueous speciation, adsorption, precipitation, and/or dissolution of solids for a defined set of 

environmental conditions (MacDonald et al., 2002; Playle, 2004). Although not specifically 
 AX7-150 

designed to model uptake, MINTEQ provides an indication of what forms of the metal are likely 

to be encountered by aquatic organisms by estimating the formation of metal ions, complexation 

of metals, and the general bioavailability of metals from environmental parameters. More 

recently, a mechanistic model centered on biodynamics has been proposed by Luoma and 

Rainbow (2005) as a method of tying together geochemical influences, biological differences, 

and differences among metals to model metal bioaccumulation. The biodynamic model would 

be useful in determining the potential adverse effects on aquatic biota, which species are most 

useful as indicators of metal effects, and how ecosystems may change when contaminated by 

metals. Two prominent models examine trace metal bioavailability and its link to effects 

(Hassler et al., 2004). These include the free ion activity model (FIAM) and the biotic ligand 

model (BLM). Specific information on these models, including their limitations, is provided in 

Section AX7.2.1.3. These models are useful for advancing our understanding of how metal 

uptake occurs in aquatic organisms and how uptake and toxic effects are linked. 

Bioconcentration Factors (BCF)

BCFs for Pb are reported for various aquatic plants in Table AX7-2.3.1. The green alga 

Cladophora glomerata is reported as having the highest BCF (Keeney et al., 1976). Duckweed 

(Lemna minor) exhibited high BCF values ranging from 840 to 3560 depending on the method of 

measurement (Rahmani and Sternberg, 1999). Duckweed that was either previously exposed or 

not exposed to Pb was exposed to a single dose of Pb-nitrate at 5000 μg/L for 21 days. 

Duckweed that was previously exposed to Pb removed 70 to 80% of the Pb from the water, while 

the previously unexposed duckweed removed 85 to 90%. Both plant groups were effective at 

removing Pb from the water at sublethal levels. 

BCFs for Pb are reported for various invertebrates in Table AX7-2.3.2. BCFs for 

freshwater snails were 738 for a 28-day exposure (Spehar et al., 1978) and 1,700 for a 120-day 

exposure (Borgmann et al., 1978). Other reported values for invertebrates included a BCF of 

1930 for the scud during a 4-day exposure (MacLean et al., 1996), and BCFs of 499 and 1120 for 

the caddis fly and stonefly, respectively, in 28-day exposures (Spehar et al., 1978). In a 28-day 

exposure, midge larvae were reported with a BCF of 3670 (Timmermans et al., 1992). 
 AX7-151 

Table AX7-2.3.1. Bioconcentration Factors for Aquatic Plants 

BCF Species Test Conditions Reference 

840 to 2700 

(measured digestion) 

Duckweed 

(Lemna minor) 

21 days, Pb-nitrate Rahmani and Sternberg 

(1999) 

1150 to 3560 

(measured solution) 

Duckweed 21 days, Pb-nitrate Rahmani and Sternberg 

(1999) 

16,000 to 20,000 Alga (Cladophora 

glomerata) 

not specified Keeney et al. (1976) 

Table AX7-2.3.2. Bioconcentration Factors for Aquatic Invertebrates 

BCF Species Test Conditions Reference 

738 Snail (Physa integra) 28 days, Pb-nitrate Spehar et al. (1978) 

1700 Snail (Lymnaea palustris) 120 days, Pb-nitrate Borgmann et al. (1978) 

499 Caddis fly (Brachycentrus sp.) 28 days, Pb-nitrate Spehar et al. (1978) 

1120 Stonefly (Pteronarcys dorsata) 28 days, Pb-nitrate Spehar et al. (1978) 

1930 Scud (Hyalella azteca) 4 days, Pb-chloride MacLean et al. (1996) 

3670 Midge larvae (Chironomus riparius) 28 days Timmermans et al. (1992) 

BCFs for freshwater fish were 42 and 45 for brook trout and bluegill, respectively 

(Holcombe et al., 1976; Atchison et al., 1977). Although no BCFs have been reported for 

amphibians, Pb-nitrate was reported to accumulate mainly in the ventral skin and in the kidneys 

of frogs (Vogiatzis and Loumbourdis, 1999). 

Bioconcentration factors and bioaccumulation factors (BAFs) are not necessarily the best 

predictors of tissue concentration levels given exposure concentration levels (Kapustka et al., 

2004). The role of homeostatic mechanisms is a major consideration in tissue concentrations 

found in exposed biota. Similarly, measuring BCFs and BAFs in organisms may not accurately 

reflect how metals are treated within the organisms (e.g., partitioning to specific organelles, 
 AX7-152 

sequestering to organ tissues). Therefore, they are not recommended for use in conducting metal 

risk assessments (Kapustka et al., 2004). 

AX7.2.3.2 Resistance Mechanisms 

Detoxification Mechanisms 

Detoxification includes the biological processes by which the toxic qualities, or the 

probability and/or severity of harmful effects, of a poison or toxin are reduced by the organism. 

In the case of heavy metals, this process frequently involves the sequestration of the metal, 

rendering it metabolically inactive. Recent research into heavy metal detoxification in aquatic 

biota has focused on several physiological and biochemical mechanisms for detoxifying Pb. 

This section examines these mechanisms and the ability of plants, protists, invertebrates, and fish 

to mitigate Pb toxicity. 

Plants and Protists 

Deng et al. (2004) studied the uptake and translocation of Pb in wetland plant species 

surviving in contaminated sites. They found that all plants tended to sequester significantly 

larger amounts of Pb in their roots than in their shoots. Deng et al. (2004) calculated a 

translocation factor (TF), the amount of Pb found in the shoots divided by the amount of Pb 

found in the root system, and found that TFs ranged from 0.02 to 0.80. Concentrations of Pb in 

shoots were maintained at low levels and varied within a narrow range. Deng et al. (2004) 

observed that plants grown in Pb-contaminated sites usually contained higher concentrations 

than the 27 mg/kg toxicity threshold established for plants by Beckett and Davis (1977). Some 

of the wetland plants examined by Deng et al. (2004) also accumulated high concentrations of 

metals in shoot tissues; however, these metals were assumed to be detoxified (metabolically 

unavailable), as no toxic response to these elevated concentrations was observed. Deng et al. 

(2004) suggested that this ability is likely related to discrete internal metal detoxification 

tolerance mechanisms. 

Phytochelatins are thiol-containing intracellular metal-binding polypeptides that are 

produced by plants and protists in response to excessive uptake of heavy metals (Zenk, 1996). 

Phytochelatins are synthesized by the enzyme phytochelatin synthase that is activated by the 

presence of metal ions and uses glutathione as a substrate. When phytochelatins are synthesized 
 AX7-153 

in sufficient amounts to chelate the metal ion, the enzyme is deactivated (Morelli and Scarano, 

2001). 

Morelli and Scarano (2001) studied phytochelatin synthesis and stability in the marine 

diatom Phaeodactylum tricornutum in the presence of Pb. They found that when metal exposure 

was alleviated, significant cellular Pb-phytochelatin complex content was lost. Their findings 

support a hypothesis of vacuolarization proposed for higher plants (Zenk, 1996), in which metalphytochelatin complexes are actively transported from the cytosol to the vacuole, where they 

undergo rapid turnover. Zenk (1996) suggested that the complex dissociates, and the metal-free 

peptide is subsequently degraded. Morelli and Scarano (2001) proposed concomitant occurrence 

of phytochelatin synthesis and release during metal exposure, as a coincident detoxification 

mechanism in P. tricornutum. 

Aquatic Invertebrates 

Like plants and protists, aquatic animals detoxify Pb by preventing it from being 

metabolically available, though their mechanisms for doing so vary. Invertebrates use 

lysosomal-vacuolar systems to sequester and process Pb within glandular cells (Giamberini and 

Pihan, 1996). They also accumulate Pb as deposits on and within skeletal tissue (Knowlton 

et al., 1983; Anderson et al., 1997; Boisson et al., 2002), and some can efficiently excrete Pb 

(Vogt and Quinitio, 1994; Prasuna et al., 1996). 

Boisson et al. (2002) used radiotracers to evaluate the transfer of Pb into the food pathway 

of the starfish Asterias rubens as well as its distribution and retention in various body 

compartments. Boisson et al. (2002) monitored Pb elimination after a single feeding of Pbcontaminated molluscs and found that Pb was sequestered and retained in the skeleton of the 

starfish, preventing it from being metabolically available in other tissues. Elimination (as 

percent retention in the skeleton) was found to follow an exponential time course. Elimination 

was rapid at first, but slowed after 1 week, and eventually stabilized, implying an infinite 

biological half-life for firmly bound Pb. Results of radiotracer tracking suggest that Pb migrates 

within the body wall from the organic matrix to the calcified skeleton. From there, the metal is 

either absorbed directly or adsorbed on newly produced ossicles (small calcareous skeletal 

structures), where it is efficiently retained as mineral deposition and is not metabolically active 

(Boisson et al., 2002). 
 AX7-154 

AbdAllah and Moustafa (2002) studied the Pb storage capability of organs in the marine 

snail Nerita saxtilis. Enlarged electron-dense vesicles and many granules were observed in 

digestive cells of these snails and are suggested to be the site of storage of detoxified metals. 

N. saxtilis were found to be capable of concentrating Pb up to 50 times that of surrounding 

marine water without exhibiting signs of histopathologic changes. This ability has been 

attributed to chelation with various biochemical compounds, such as thionine (forming 

metallothionine) (Rainbow, 1996), or complexation with carbonate, forming lipofuchsin 

(AbdAllah and Moustafa, 2002). Granules observed in lysosomal residual bodies were presumed 

to be the result of Pb accumulation. The presence of large vacuoles and residual bodies were 

indicative of the fragmentation phase of digestion, suggesting that Pb was also processed 

chemically in the digestive cells. 

The podocyte cells of the pericardial gland of bivalves are involved in the ultrafiltration of 

the hemolymph (Giamberini and Pihan, 1996). A microanalytical study of the podocytes in 

Dreissena polymorpha exposed to Pb revealed lysosomal-vacuolar storage/processing similar to 

that in the digestive cells of Nerita saxtilis. The lysosome is thought to be the target organelle 

for trace metal accumulation in various organs of bivalves (Giamberini and Pihan, 1996). 

Epithelial secretion is the principal detoxification mechanism of the tiger prawn Penaeus 

monodon. Vogt and Quinitio (1994) found that Pb granules tended to accumulate in the 

epithelial cells of the antennal gland (the organ of excretion) of juveniles exposed for 5 and 

10 days to waterborne Pb. The metal is deposited in vacuoles belonging to the lysosomal 

system. Continued deposition leads to the formation of electron-dense granules. Mature 

granules are released from the cells by apocrine secretion into the lumen of the gland, and 

presumably excreted through the nephridopore (i.e., the opening of the antennal gland). 

Apocrine secretion is predominant, so that as granules form, they are kept at low levels. 

Excretion was also found to be a primary and efficient detoxification mechanism in the shrimp 

Chrissia halyi (Prasuna et al., 1996). 

Crayfish exposed to Pb have been shown to concentrate the metal in their exoskeleton and 

exuvia through adsorption processes. More than 80% of Pb found in exposed crayfish has been 

found in exoskeletons (Knowlton et al., 1983; Anderson et al., 1997). Following exposure, 

clearance is most dramatic from the exoskeleton. The result of a 3-week Pb-clearance study with 

red swamp crayfish Procambarus clarkia, following a 7-week exposure to 150 μg Pb/L, showed 
 AX7-155 

an 87% clearance from the exoskeleton due, in part, to molting. Other organs or tissues that take 

up significant amounts of Pb include the gills, hepatopancreas, muscle, and hemolymph, in 

decreasing order. These parts cleared >50% of accumulated Pb over the 3-week clearance 

period, with the exception of the hepatopancreas. The hepatopancreas is the organ of metal 

storage and detoxification, although the molecular mechanisms of metal balance in crayfish have 

yet to be extensively investigated (Anderson et al., 1997). 

Fish

Most fish use mucus as a first line of defense against heavy metals (Coello and Khan, 

1996). In fish, some epithelia are covered with extracellular mucus secreted from specialized 

cells. Mucus contains glycoproteins, and composition varies among species. Mucosal 

glycoproteins chelate Pb, and settle, removing the metal from the water column. Fish may 

secrete large amounts of mucus when they come into contact with potential chemical and 

biochemical threats. Coello and Khan (1996) investigated the role of externally added fish 

mucus and scales in accumulating Pb from water, and the relationship of these with the toxicity 

of Pb in fingerlings of green sunfish, goldfish and largemouth bass. The authors compared trials 

in which fish scales from black sea bass (Centropristis striata) and flounder (Pseudopleuronectes 

americanus) and mucus from largemouth bass were added to green sunfish, goldfish, and 

largemouth bass test systems and to reference test systems. On exposure to Pb, fish immediately 

started secreting mucus from epidermal cells in various parts of the body. Metallic Pb stimulated 

filamentous secretion, mostly from the ventrolateral areas of the gills, while Pb-nitrate stimulated 

diffuse molecular mucus secretion from all over the body. The addition of largemouth bass 

mucus significantly increased the LT50 (the time to kill 50%) for green sunfish and goldfish 

exposed to 250 mg/L of Pb-nitrate. In contrast, Tao et al. (2000) found that mucus reduced the 

overall bioavailability of Pb to fish but that the reduction was insignificant. Coello and Khan 

(1996) found that scales were more significant in reducing LT50 than mucous. Fish scales can 

accumulate high concentrations of metals, including Pb, through chelation with keratin. Scales 

were shown to buffer the pH of Pb-nitrate in solution and remove Pb from water after which they 

settled out of the water column. Addition of scales to test water made all species (green sunfish, 

goldfish, and largemouth bass) more tolerant of Pb. 
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Summary of Detoxifiction Processes

Mechanisms of detoxification vary among aquatic biota and include processes such as 

translocation, excretion, chelation, adsorption, vacuolar storage, and deposition. Lead 

detoxification has not been studied extensively in aquatic organisms, but existing results indicate 

the following: 

• Protists and plants produce intracellular polypeptides that form complexes with Pb (Zenk, 

1996; Morelli and Scarano, 2001). 

• Macrophytes and wetland plants that thrive in Pb-contaminated regions have developed 

translocation strategies for tolerance and detoxification (Knowlton et al., 1983; Deng et al., 

2004). 

• Some starfish (asteroids) sequester the metal via mineral deposition into the exoskeleton 

(Boisson et al., 2002). 

• Species of mollusc employ lysosomal-vacuolar systems that store and chemically process Pb 

in the cells of their digestive and pericardial glands (Giamberini and Pihan, 1996; AbdAllah 

and Moustafa, 2002). 

• Decapods can efficiently excrete Pb (Vogt and Quinitio, 1994; Giamberini and Pihan, 1996) 

and sequester metal through adsorption to the exoskeleton (Knowlton et al., 1983). 

• Fish scales and mucous chelate Pb in the water column, and potentially reduce visceral 

exposure. 

Avoidance Response 

Avoidance is the evasion of a perceived threat. Recent research into heavy metal 

avoidance in aquatic organisms has looked at dose-response relationships as well as the effects of 

coincident environmental factors. Preference/avoidance response to Pb has not been extensively 

studied in aquatic organisms. In particular, data for aquatic invertebrates is lacking. 

Using recent literature, this section examines preference-avoidance responses of 

invertebrates and fish to Pb and some other environmental gradients. 

Aquatic Invertebrates

Only one study was identified on avoidance response in aquatic invertebrates. Lefcort 

et al. (2004) studied the avoidance behavior of the aquatic pulmonate snail Physella columbiana

from a pond that had been polluted with heavy metals for over 120 years. In a Y-maze test, first 

generation P. columbiana from the contaminated site avoided Pb at 9283 μg/L (p < 0.05) and 
 AX7-157 

moved toward Pb at 6255 μg/L (p < 0.05). It is thought that attraction to Pb at certain elevated 

concentrations is related to Pb neuron-stimulating properties (Lefcort et al., 2004). These results 

are consistent with those from similar studies. Control snails from reference sites, and first and 

second-generation snails from contaminated sites were capable of detecting and avoiding heavy 

metals, although the first generation was better than the second generation, and the second was 

better than the controls at doing so. This suggests that detection and avoidance of Pb is both 

genetic and environmentally based for P. columbiana. Lefcort et al. (2004) observed heightened 

sensitivity to, and avoidance of, heavy metals by the snails when metals where present in 

combination. 

Aquatic Vertebrates

Steele et al. (1989) studied the preference-avoidance response of bullfrog (Rana 

catesbeiana) to plumes of Pb-contaminated water following 144-h exposure to 0 to 1000 μg 

Pb/L. In this laboratory experiment, tadpoles were exposed to an influx of 1000 μg Pb/L at five 

different infusion rates (i.e., volumes per unit time into the test system). Experiments were 

videotaped and location data from the tank were used to assess response. No significant 

differences were seen in preference-avoidance responses to Pb in either nonexposed or 

previously exposed animals. In a similar subsequent study, Steele et al. (1991) studied 

preference-avoidance response to Pb in American toad (Bufo americanus) using the same 

exposure range (0 to 1000 μg Pb/L). B. americanus did not significantly avoid Pb, and 

behavioral stress responses were not observed. The results do not indicate whether the tadpoles 

were capable of perceiving the contaminant. Lack of avoidance may indicate insufficient 

perception or the lack of physiological stress (Steele et al., 1991). 

The olfactory system in fish is involved in their forming avoidance response to heavy 

metals (Brown et al., 1982; Svecevičius, 1991). It is generally thought that behavioral avoidance 

of contaminants may be a cause of reduced fish populations in some water bodies, because of 

disturbances in migration and distribution patterns (Svecevičius, 2001). Unfortunately, 

avoidance of Pb by fish has not been studied as extensively as for other heavy metals 

(Woodward et al., 1995). 

Woodward et al. (1995) studied metal mixture avoidance response in brown trout 

(Salmo trutta), as well as the added effects of acidification. A 1-fold (1Η) mixture contained 
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1.1 μg/L Cd, 12 μg/L Cu, 55 μg/L Zn, and 3.2 μg/L Pb (all metals were in the form of chlorides). 

Avoidance was quantified as time spent in test water, trip time to test water, and number of trips. 

Brown trout avoided the 1Η mixture as well as the 0.5Η, 2Η, 4Η, and 10Η mixtures, but not the 

0.1Η mixture. Reduced avoidance was observed at higher concentrations (4Η and 10Η). The 

authors proposed that the reduced avoidance response was due to impaired perception due to 

injury. These responses are typical of other fish species to individual metals of similar 

concentrations (Woodward et al., 1995). This study does not conclusively indicate which of the 

metals in the mixture may be causing the avoidance response. However, given the neurotoxic 

effects of Pb, impaired perception is a likely response of Pb-exposed fish. 

When test water was reduced in pH from 8 to 7, 6 to 5, brown trout avoidance increased, 

but with no significant difference between metal treatments and controls. However, in the 1Η

metal mixture treatment, brown trout made fewer trips into the test water chamber at the lower 

pHs (Woodward et al., 1995). This response may be related to an increased abundance of Pb 

cations at lower pH values in the test system. 

Scherer and McNicol (1998) investigated the preference-avoidance responses of lake 

whitefish (Coregonus clupeaformis) to overlapping gradients of light and Pb. Whitefish were 

found to prefer shade in untreated water. Lead concentrations under illumination ranged from 

0 to 1000 μg/L, and from 0 to 54,000 μg/L in the shade. Under uniform illumination, Pb was 

avoided at concentrations above 10 μg/L, but avoidance behavior lacked a dose-dependent 

increase over concentrations ranging from 10 to 1000 μg Pb/L. Avoidance in shaded areas was 

strongly suppressed, and whitefish only avoided Pb at concentrations at or above 32,000 μg/L. 

Summary of Avoidance Response

In summary, of those aquatic organisms studied, some are quite adept at avoiding Pb in 

aquatic systems, while others seem incapable of detecting its presence. Snails have been shown 

to be sensitive to Pb and to avoid it at high concentrations. Conversely, anuran (frog and toad) 

species lack an avoidance response to the metal. Fish avoidance of many chemical toxicants has 

been well established, and it is a dominant sublethal response in polluted waters (Svecevičius, 

2001). However, no studies have been located specifically examining avoidance behavior for Pb 

in fish. Environmental gradients, such as light and pH, can alter preference-avoidance responses. 
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AX7.2.3.3 Physiological Effects of Lead 

This section presents a review of the physiological effects and functional growth 

responses associated with the exposure of aquatic biota to Pb. Physiological effects of Pb on 

aquatic biota can occur at the biochemical, cellular, and tissue levels of organization and include 

inhibition of heme formation, adverse effects to blood chemistry, and decreases in enzyme 

levels. Functional growth responses resulting from Pb exposure include changes in growth 

patterns, gill binding affinities, and absorption rates. 

Biochemical Effects

Lead was observed to have a gender-selective effect on brain endocannabinoid (eCB) 

(e.g., 2-arachidonylglycerol [2-AG] and N-arachidonylethanolamine [AEA]) levels in fathead 

minnow Pimephales promelas (Rademacher et al., 2005). Cannabinoids, such as eCB, influence 

locomotor activity in organisms. Increased levels of cannabinoids have been shown to stimulate 

locomotor activity and decreased levels slow locomotor activity (Sañudo-Peña et al., 2000). 

Male and female fathead minnows were exposed to 0 and 1000 μg/L of Pb. Female minnows in 

the control group contained significantly higher levels of AEA and 2-AG compared to males. 

At a concentration of 1000 μg Pb/L, this pattern reversed, with males showing significantly 

higher levels of AEA in the brain than females (Rademacher et al., 2005). After 14-days 

exposure to the 1000 μg Pb/L treatment, significantly higher levels of 2-AG were found in male 

fathead minnows, but no effect on 2-AG levels in females was observed (Rademacher et al., 

2005). 

Lead acetate slightly inhibited 7-ethoxyresorufin-o-deethylase (7-EROD) activity in 

Gammarus pulex exposed for up to 96 h to a single toxicant concentration (EC50) (Kutlu and 

Susuz, 2004). The exact concentration used in the study was not reported. The EROD enzyme 

is required to catalyze the conjugation and detoxification of toxic molecules and has been 

proposed as a biomarker for contaminant exposure. The authors believe more detailed studies 

are required to confirm EROD as a biomarker for Pb exposure. The enzyme group alanine 

transferases (ALT) has been suggested as a bioindicator/biomarker of Pb stress (Blasco and 

Puppo, 1999). A negative correlation was observed between Pb accumulation and ALT 

concentrations in the gills and soft body of Ruditapes philippinarum exposed to 350 to 700 μg/L 

of Pb for 7 days (Blasco and Puppo, 1999). 
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Studies have identified ALAD in fish and amphibians as a useful indicator of Pb exposure 

(Gill et al., 1991; Nakagawa et al., 1995a,b). ALAD catalyzes the formation of hemoglobin and 

early steps in the synthesis of protoporphyrin (Gill et al., 1991; Nakagawa et al., 1995b). The 

absence of an inhibitory effect on this enzyme following exposure to cadmium, copper, zinc, and 

mercury suggests that this enzyme reacts specifically to Pb (Johansson-Sjöbeck and Larsson, 

1979; Gill et al., 1991). A 0% decrease in ALAD activity was reported in common carp 

(Cyprinus carpio) exposed to a Pb concentration of 10 μg/L for 20 days (Nakagawa et al., 

1995b). The recovery of ALAD activity after exposure to Pb has also been examined in carp 

(Nakagawa et al., 1995a). After 2-week exposure to 200 μg Pb/L, ALAD activity decreased to 

approximately 25% of value reported for controls (Nakagawa et al., 1995a). Fish removed from 

the test concentration after 2 weeks and placed in a Pb-free environment recovered slightly, but 

ALAD activity was only 50% of the controls even after 4 weeks (Nakagawa et al., 1995a). 

Vogiatzis and Loumbourdis (1999) exposed the frog (Rana ridibunda) to a Pb concentration of 

14,000 μg/L over 30 days and a 90% decrease in ALAD activity was observed in the frogs. 

Blood Chemistry

Numerous studies have examined the effects of Pb exposure on blood chemistry in aquatic 

biota. These studies have primarily used fish in acute and chronic exposures to Pb 

concentrations ranging from 100 to 10,000 μg/L. Decreased erythrocyte, hemoglobin, and 

hemocrit levels were observed in rosy barb (Barbus puntius) during an 8-week exposure to 

126 μg/L of Pb-nitrate (Gill et al., 1991). 

No difference was found in red blood cell counts and blood hemoglobin in yellow eels 

(Anguilla anguilla) exposed to 0 and 300 μg/L of Pb for 30 days (Santos and Hall, 1990). The 

number of white blood cells, in the form of lymphocytes, increased in the exposed eels. The 

authors concluded this demonstrates the lasting action of Pb as a toxicant on the immune system 

(Santos and Hall, 1990). Significant decreases in red blood cell counts and volume was reported 

in blue tilapia (Oreochromis aureus) exposed to Pb-chloride at a concentration of 10,000 μg/L 

for 1 week (Allen, 1993). 

Blood components, such as plasma glucose, total plasma protein, and total plasma 

cholesterol, were unaffected in yellow eels exposed to 300 μg/L of Pb for 30 days (Santos and 

Hall, 1990). Effects on plasma chemistry were observed in Oreochromis mossambicus exposed 
 AX7-161 

to 0, 18,000, 24,000, and 33,000 μg/L of Pb (Ruparelia et al., 1989). Significant decreases in 

plasma glucose (hypoglycemic levels) were reported at concentrations of 24,000 and 33,000 Φg 

Pb/L after 14 and 21 days of exposure, and at 18,000 μg Pb/L after 21 days of exposure 

(Ruparelia et al., 1989). Plasma cholesterol levels dropped significantly in comparison to 

controls after 14 days of exposure to 33,000 μg Pb/L and in all test concentrations after 21 days 

of exposure (Ruparelia et al., 1989). Similarly, concentrations of blood serum protein, albumin, 

and globulin were identified as bioindicators of Pb stress in carp (Cyprinus carpio) exposed to 

Pb-nitrates at concentrations of 800 and 8000 μg Pb/L (Gopal et al., 1997). 

Tissues

In fish, the gills serve as an active site for ion uptake. Recent studies have examined the 

competition between cations for binding sites at the fish gill (e.g., Ca2+, Mg2+, Na+

, H+, Pb2+) 

(MacDonald et al., 2002; Rogers and Wood, 2003, 2004). Studies suggest that Pb2+ is an 

antagonist of Ca2+ uptake (Rogers and Wood, 2003, 2004). MacDonald et al. (2002) proposed a 

gill-Pb binding model that assumes Pb2+ has a ∃100 times greater affinity for binding sites at the 

fish gill than other cations. More toxicity studies are required to quantify critical Pb burdens that 

could be used as indicators of Pb toxicity (Niyogi and Wood, 2003). 

Growth Responses

A negative linear relationship was observed in the marine gastropod abalone (Haliotis) 

between shell length and muscle Pb concentrations (Arai et al., 2002). Abalones were collected 

from two sites along the Japanese coast. Haliotis discus hannai were collected from along the 

coast at Onagawa; Haliotis discus were collected from along the coast at Amatsu Kominato. The 

authors did not report significant differences between the two sampling sites. From samples 

collected at Onagawa, Pb concentrations of 0.03 and 0.01 μg/g were associated with abalone 

shell lengths of 7.7 cm (3 years old) and 12.3 cm (6 years old), respectively. From samples 

collected at Amatsu Kominato, Pb concentrations of 0.09 and 0.01 μg/g were associated with 

abalone shell lengths of 3.9 cm (0 years old) and 15.3 cm (8 years old), respectively (Arai et al., 

2002). The authors theorized that young abalones, experiencing rapid growth, do not 

discriminate between the uptake of essential and nonessential metals. However, as abalones 

grow larger and their rate of growth decreases, they increasingly favor the uptake of essential 
 AX7-162 

metals over nonessential metals. This is demonstrated by the relatively consistent concentrations 

of Cu, Mn, and Zn that were reported for the abalone samples (Arai et al., 2002). 

Other Physiological Effects

Increased levels of Pb in water were found to increase fish production of mucus: excess 

mucus coagulates were observed over the entire body of fishes. Buildup was particularly high 

around the gills, and in the worst cases, interfered with respiration and resulted in death by 

anoxia (Aronson, 1971; National Research Council of Canada., 1973). 

AX7.2.3.4 Factors That Modify Organism Response to Lead 

A great deal of research has been undertaken recently to better understand the factors that 

modify aquatic organism response to metals including lead. A discussion of research on the 

many factors that can modify aquatic organism response to Pb is provided in this section. 

Influence of Organism Age and Size on Lead Uptake and Response 

It is generally accepted that Pb accumulation in living organisms is controlled, in part, by 

metabolic rates (Farkas et al., 2003). Metabolic rates are, in-turn, controlled by the physiological 

conditions of an organism, including such factors as size, age, point in reproductive cycle, 

nutrition, and overall health. Of these physiological conditions, size and age are the most 

commonly investigated in relation to heavy metal uptake. This section reviews recent research 

focusing on relationships between body size, age, and Pb accumulation in aquatic invertebrates 

and fish. 

Invertebrates

MacLean et al. (1996) investigated bioaccumulation kinetics and toxicity of Pb in the 

amphipod Hyalella azteca. Their results indicated that body size did not greatly influence Pb 

accumulation in H. azteca exposed to 50 or 100 μg/L of PbCl2 for 4 days. Canli and Furness 

(1993) found similar results in the Norway lobster Nephrops norvegicus exposed to 100 μg/L of 

Pb(NO3)2 for 30 days. No significant sex- or size-related differences were found in 

concentrations of Pb in the tissue. The highest tissue burden was found in the carapaces (42%). 

Several studies have determined that Pb can bind to the exoskeleton of invertebrates and 
 AX7-163 

sometimes dominate the total Pb accumulated (Knowlton et al., 1983). This adsorption of Pb to 

the outer surface of invertebrates can result in strong negative relationships for whole-body Pb 

concentration as a function of body mass (i.e., concentrations decrease rapidly with increased 

body size and then stabilize) (MacLean et al., 1996). 

Drava et al. (2004) investigated Pb concentrations in the muscle of red shrimp Aristeus 

antennatus from the northwest Mediterranean. Lead concentrations ranged from 0.04 to 

0.31 μg/g dw. No significant relationships between size and Pb concentration in A. antennatus 

were found, and concentrations were not related to reproductive status. 

Arai et al. (2002) analyzed abalones (Haliotis) at various life stages from coastal regions 

of Japan. They investigated growth effects on the uptake and elimination of Pb. Results 

indicated a significant negative linear relationship between age, shell length and Pb 

concentrations in muscle tissue. The relationship was consistent despite habitat variations in 

Pb concentrations between the study sites, suggesting that Pb concentrations changed with 

growth in the muscle tissue of test specimens and implying that abalone can mitigate Pb 

exposure as they age. 

Fish

Douben (1989) investigated the effects of body size and age on Pb body burden in the 

stone loach (Noemacheilus barbatulus L.). Fish were caught during two consecutive springs 

from three Derbyshire rivers. Results indicated that Pb burden increased slightly with age. 

Similarly, Köck et al. (1996) found that concentrations of Pb in the liver and kidneys of Arctic 

char (Salvelinus alpinus) taken from oligotrophic alpine lakes were positively correlated with 

age. It has been suggested that fish are not able to eliminate Pb completely, and that this leads to 

a stepwise accumulation from year to year (Köck et al., 1996). In contrast, Farkas et al. (2003) 

found a negative relationship between Pb concentrations and muscle and gill Pb concentrations 

in the freshwater fish Abramis brama. Fish were taken from a low-contaminated site and 

contained between 0.44 and 3.24 μg/g Pb dw. Negative correlations between metal 

concentration and fish size in low-contaminated waters likely results from variations in feeding 

rates associated with developmental stages. This hypothesis is consistent with the fact that in 

low-contaminated waters, feeding is the main route of uptake and feeding rates decrease with 

development in fish (Farkas et al., 2003). 
 AX7-164 

In summary, relationships between age, size, and Pb body burden in aquatic invertebrates 

and fish are interspecifically variable and depend on many environment-related variables (e.g., 

exposure) (Farkas et al., 2003). 

Genetics 

There are few studies documenting the effects of Pb on organismal and population 

genetics, although rapid advances in biotechnology have prompted recent research in this area 

(Beaty et al., 1998). There are two principal effects that sublethal exposure to a contaminant can 

have on the genetics of an organism and/or population: (1) a contaminant may influence 

selection by selecting for certain phenotypes that enable populations to better cope with the 

chemical; or (2) a contaminant can be genotoxic, meaning it can produce alterations in nucleic 

acids at sublethal exposure concentrations, resulting in changes in hereditary characteristics or 

DNA inactivation (Shugart, 1995). Laboratory studies have shown that exposure to Pb2+ at 

10 mg/mL in blood produces chromosomal aberrations (i.e., deviations in the normal structure or 

number of chromosomes) in some organisms (Cestari et al., 2004). Effects of genotoxicity and 

toxin-induced selection do not preclude one another, and may act together on exposed 

populations. This section reviews Pb genotoxicity and the effects of Pb-induced selection in 

aquatic populations.

Selection

Evidence for genetic selection in the natural environment has been observed in some 

aquatic populations exposed to metals (Rand et al., 1995; Beaty et al., 1998; Duan et al., 2000; 

Kim et al., 2003). Because tolerant individuals have a selective advantage over vulnerable 

individuals in polluted environments, the frequency of tolerance genes will increase in exposed 

populations over time (Beaty et al., 1998). Several studies have shown that heavy metals can 

alter population gene pools in aquatic invertebrates. These changes have resulted in decreased 

genetic diversity and are thought to be a potential source of population instability (Duan et al., 

2000; Kim et al., 2003). 

Kim et al. (2003) investigated genetic differences and population structuring in the 

gastropod Littorina brevicula from heavy-metal polluted and unpolluted environments. 

Organisms from polluted sites contained a mean of 1.76 μg Pb/g, while organisms from 
 AX7-165 

unpolluted sites contained 0.33 μg Pb/g. They found significant differences in haplotypes 

between the test groups and allelic diversity was significantly lower among L. brevicula from 

polluted regions. In contrast, Yap et al. (2004) performed a similar experiment with the greenlipped mussel Perna viridis; they found that mussels from contaminated sites containing between 

4 and 10 μg Pb/g, as well as other heavy metals, exhibited a higher percentage of polymorphic 

loci and excess heterozygosity compared to those from uncontaminated sites. The higher level 

of genetic diversity was attributed to greater environmental heterogeneity (i.e., variation due to 

pollution gradients) in contaminated sites (Yap et al., 2004). 

Duan et al. (2000) investigated amphipod (Hyalella azteca) selective mortality and 

genetic structure following acute exposure to Pb (5.47 mg/L Pb(NO2)2) as well as exposure to 

other heavy metals. They found that genetic differentiation consistently increased among 

survivors from the original population, supporting the hypothesis that heavy metals, including 

Pb, have the potential to alter the gene pools of aquatic organisms. 

Genotoxicity

Lead exposure in water (50 μg/L) over 4 weeks resulted in DNA strand breakage in the 

freshwater mussel Anodonta grandis (Black et al., 1996), although higher concentrations (up to 

5000 μg/L) did not result in significant breakage by the end of the study period. These results 

suggest that a threshold effect for DNA damage and repair exists, where DNA repair only occurs 

once a certain body exposure level has been reached. More recently, Cestari et al. (2004) 

observed similar results in neotropical fish (Hoplias malabaricus) that were fed Pb-contaminated 

food over 18, 41, and 64 days. Lead body burdens in H. malabaricus were approximately 21 μg 

Pb 2+/g. Results indicated that exposure to Pb significantly increased the frequency of 

chromosomal aberrations and DNA damage in kidney cell cultures, although when assessed at 

the end of the longer exposure periods, aberrations were less common. 

Environmental Biological Factors 

Environmental factors that are biological in origin can alter the availability, uptake and 

toxicity of Pb to aquatic organisms. These factors can be grouped into living and non-living 

constituents. For example, living organisms may sequester Pb from the water column, reducing 

the availability and toxicity of the metal in the water column to other biota, thus reducing 
 AX7-166 

potential toxic effects in other organisms. Non-living organic material (e.g., components of 

sloughed-off scales, mucus, carcasses, and other decomposing, humic material) can similarly 

combine with Pb from the water column, rendering it unavailable. This section will review the 

literature on biological environmental factors and their influence on the bioavailability, uptake, 

and toxicity of Pb. 

Van Hattum et al. (1996) studied the influence of abiotic variables, including DOC on Pb 

concentrations in freshwater isopods (Proasellus meridianus and Asellus aquaticus). They found 

that BCFs were significantly negatively correlated with DOC concentrations. Thus, as DOC 

concentrations increased, BCFs decreased in P. meridianus and A. aquaticus, indicating that 

DOC acts to inhibit the availability of Pb to these isopods. 

Kruatrachue et al. (2002) investigated the combined effects of Pb and humic acid on total 

chlorophyll content, growth rate, multiplication rate, and Pb uptake of common duckweed. 

When humic acid was added to the Pb-nitrate test solutions (50, 100, and 200 mg Pb(NO3)2/ L), 

toxicity of Pb to duckweed was decreased. The addition of humic acid to the Pb-nitrate solution 

increased the pH. The authors suggested that there was a proton dissociation from the carboxyl 

group in the humic acid that complexed with Pb, resulting in a decrease in free Pb ions available 

to the plant. 

Schwartz et al. (2004) collected natural organic matter (NOM) from several aquatic sites 

across Canada and investigated the effects of NOM on Pb toxicity in rainbow trout 

(Oncorhynchus mykiss). They also looked at toxicity effects as they related to the optical 

properties of the various NOM samples. The results showed that NOM in test water almost 

always increased LT50 and that optically dark NOM tended to decrease Pb toxicity more than did 

optically light NOM in rainbow trout. 

In summary, non-living constituents of biological origin in the environment have been 

shown to reduce Pb availability and, therefore, toxicity in some aquatic organisms. It is 

generally thought that this occurs through complexation or chelation processes that take place in 

the water column. 
 AX7-167 

Physicochemical Environmental Factors 

This section reviews the literature on physicochemical environmental factors and their 

influence on the bioavailability, uptake, and toxicity of Pb in aquatic organisms. These factors 

are discussed with regard to their influence individually and in combination. 

Studies generally agree that as pH increases, the toxicity of Pb decreases (Horne and 

Dunson, 1995b; MacDonald et al., 2002). As pH decreases, Pb becomes more soluble and more 

readily bioavailable to aquatic organisms (Weber, 1993). Significantly lower survival, decreased 

hatching success, slower development, and increased egg mass and larval mortality were 

observed in Jefferson salamanders (Ambystoma jeffersonianum) and wood frogs (Rana sylvatica) 

exposed to Pb at a pH of 4.5 versus a pH of 5.5 (Horne and Dunson, 1995b). Contradictory 

results have been reported for invertebrates. Over a 96-h exposure period, mortality increased 

with decreasing pH for the bivalve Pisidium casertanum, while pH-independent mortality was 

reported for gastropods and crustacea under similar exposure conditions (Mackie, 1989). 

Cladocerans (C. dubia) and amphipods (H. azteca) were also more sensitive to Pb toxicity at pH 

6 to 6.5 than at higher pH levels (Schubauer-Berigan et al., 1993). Lead was 100 times more 

toxic to the amphipod Hyalella azteca at a pH range of 5.0 to 6.0 (Mackie, 1989) than at a pH 

range of 7.0 to 8.5 (Schubauer-Berigan et al., 1993). Lead was also more toxic to fathead 

minnows at lower pH levels (Schubauer-Berigan et al., 1993). 

The influence of pH on Pb accumulation has also been observed in sediments. 

Accumulation of Pb by the isopod Asellus communis was enhanced at low pH, after a 20-day 

exposure to Pb-contaminated sediments (Lewis and McIntosh, 1986). In A. aquaticus, 

temperature increases were found to be more important than increased pH in influencing Pb 

accumulation (Van Hattum et al., 1996). Increased water temperature was also found to reduce 

Pb uptake fluxes in green microalga (Chlorella kesslerii) (Hassler et al., 2004). Lead and zinc 

body concentrations in Asellus sp. were found to vary markedly with seasonal temperature 

changes, with greater concentrations present in spring and summer (Van Hattum et al., 1996). 

Acute and chronic toxicity of Pb increases with decreasing water hardness, as Pb becomes 

more soluble and bioavailable to aquatic organisms (Horne and Dunson, 1995a; Borgmann et al., 

2005). There is some evidence that water hardness and pH work together to increase or decrease 

the toxicity of Pb. Jefferson salamanders exposed to Pb for 28 days at low pH and low water 

hardness experienced 50% mortality, while exposure to Pb at high pH and high water hardness 
 AX7-168 

resulted in 91.7% survival (Horne and Dunson, 1995a). Exposure to Pb at high pH and low 

water hardness or low pH and high water hardness resulted in 75 and 41.7% survival, 

respectively (Horne and Dunson, 1995a). Similar results were reported for Jefferson 

salamanders during a 7-day exposure and wood frogs during 7- and 28-day exposures (Horne 

and Dunson, 1995c). In some cases, water hardness and pH in the absence of Pb have been 

shown to affect survival adversely. Mean acute survival of wood frogs and Jefferson 

salamanders exposed to low pH and low water hardness, in the absence of Pb, was 83.3 and 

91.7%, respectively. Mean chronic survival of wood frogs and Jefferson salamanders exposed to 

low pH and low water hardness, in the absence of Pb, was 79.2 and 41.7%, respectively (Horne 

and Dunson, 1995c). 

High Ca2+ concentrations have been shown to protect against the toxic effects of Pb 

(Sayer et al., 1989; MacDonald et al., 2002; Hassler et al., 2004; Rogers and Wood, 2004). 

Calcium affects the permeability and integrity of cell membranes and intracellular contents 

(Sayer et al., 1989). As Ca2+ concentrations decrease, the passive flux of ions (e.g., Pb) and 

water increases. At the lowest waterborne Ca2+ concentration (150 μmol/L), Pb accumulation in 

juvenile rainbow trout (Oncorhynchus mykiss) branchials significantly increased as Pb 

concentration in water increased (Rogers and Wood, 2004). At higher Ca2+ concentrations, Pb 

accumulation did not significantly increase with Pb concentration in water. This result 

demonstrates the protective effects of waterborne Ca2+ and supports the suggestion that the Ca2+

component of water hardness determines the toxicity of Pb to fish (Rogers and Wood, 2004). 

Rogers and Wood (2004) reported that the uptake of Ca2+ and Pb2+ involves competitive 

inhibition of apical entry at lanthanum-sensitive Ca2+ channels and interference with the function 

of the ATP-driven baso-lateral Ca2+ pump. High mortality was reported in brown trout (Salmo 

trutta) fry exposed to Pb at a waterborne Ca2+ concentration of 20 μmol/L, while negligible 

mortality was reported at the same Pb concentration but at a waterborne Ca2+ concentration of 

200 μmol/L (Sayer et al., 1989). Adverse effects to mineral uptake and skeletal development 

were observed in the latter test group (Sayer et al., 1989). 

The bioavailability of Pb and other metals that can be simultaneously extracted in 

sediments may be modified through the role of acid volatile sulfide (AVS) under anoxic 

conditions (Tessier and Campbell, 1987; Di Toro et al., 1992; Casas and Crecelius, 1994). The 

term AVS (iron sulfide is an example) refers to the fraction of the sediment that consists of a 
 AX7-169 

reactive pool of solid-phase sulfide. This phase is available to bind divalent metals that then 

become unavailable for uptake by aquatic biota. The models proposed by Di Toro et al. (1992) 

and Casas and Crecelius (1994) predict that when the molar ratio of simultaneously extractable 

metals (SEM) to AVS in sediments is less than one, the metals will not be bioavailable due to 

complexation with available sulfide. 

Salinity is an important modifying factor to metal toxicity. Verslycke et al. (2003) 

exposed the estuarine mysid Neomysis integer to individual metals, including Pb, and metal 

mixtures under changing salinity. At a salinity of 5%, the reported LC50 for Pb was 1140 μg/L 

(95% CL = 840, 1440 μg/L). At an increased salinity of 25l, the toxicity of Pb was substantially 

reduced (LC50 = 4274 μg/L [95% CL = 3540, 5710 μg/L]) (Verslycke et al., 2003). The 

reduction in toxicity was attributed to increased complexation of Pb2+ with Cl!

 ions. 

Nutritional Factors 

The relationship between nutrition and Pb toxicity has not been thoroughly investigated in 

aquatic organisms. In fact, algae species are the only aquatic organisms to have been studied 

fairly frequently. Although nutrients have been found to have an impact on Pb toxicity, the 

mechanisms involved are poorly understood. It is unclear whether the relationship between 

nutrients and toxicity comprises organismal nutrition (the process by which a living organism 

assimilates food and uses it for growth and for replacement of tissues), or whether nutrients have 

interacted directly with Pb, inhibiting its metabolic interaction in the organism. This section 

reviews the little information that has been gathered from studies documenting apparent Pbnutrition associations in aquatic organisms. 

Jampani (1988) looked at the impact of various nutrients (i.e., sodium acetate, citric acid, 

sodium carbonate, nitrogen, and phosphates) on reducing growth inhibition in blue-green algae 

(Synechococcus aeruginosus) exposed to 200 mg Pb/L. Exposure to this Pb treatment 

concentration caused 100% mortality in algae. Results indicated that additional nitrogen, 

phosphates, and some carbon sources, including sodium acetate, citric acid and sodium 

carbonate, all protected the algae from Pb toxicity. Algae that had been starved prior to the 

experiment were found to be significantly more sensitive to Pb exposure. Glucose was the only 

nutrient tested that did not have a significant impact on Pb toxicity in S. aeruginosus. In a 

similar study by Rao and Reddy (1985) on Scenedesmus incrassatulus, nitrogen, phosphate and 
 AX7-170 

carbon sources (including glucose), all had protective effects, and reduced Pb toxicity at 300 and 

400 mg Pb/L. Both studies proposed similar hypotheses regarding nutrient-Pb mechanisms that 

led to reduced toxicity. One hypothesis was that the nutrients were able to reverse toxic effects. 

The second hypothesis was that the nutrients interacted directly with Pb, in some way 

sequestering the metal so as to inhibit its metabolic interaction with the organism (Rao and 

Reddy, 1985; Jampani, 1988). 

Rai and Raizada (1989) investigated the effects of Pb on nitrate and ammonium uptake as 

well as carbon dioxide and nitrogen fixation in Nostoc muscorum over a 96-h period. Test 

specimens were exposed to 10, 20, and 30 mg Pb/L. At 20 mg Pb/L, nitrate uptake was inhibited 

by 64% after 24 h and by 39% after 96 h. Ammonium uptake was inhibited, and similarly, 

inhibition decreased from 72% inhibition after 24 h to 26% inhibition after 96 h of exposure. 

Carbon dioxide fixation and nitrogenase activity followed similar patterns, and results indicated 

that Pb exposure can affect the uptake of some nutrients in N. muscorum. 

Adam and Abdel-Basset (1990) studied the effect of Pb on metabolic processes of 

Scenedesmus obliquus. They found that nitrogenase activity was inhibited by Pb nitrate, but 

enhanced by Pb-acetate. As photosynthetic products and respiratory substrates, carbohydrate 

and lipid levels were altered by Pb. Above 30 mg/L of Pb-nitrate, both macronutrients were 

reduced. However, Pb-acetate was found to increase carbohydrate levels. Results suggest that 

Pb can have an effect on macronutrients in S. obliquus and that effects may vary depending on 

the chemical species. 

Simòes Gonçalves et al. (1991) studied the impact of light, nutrients, air flux, and Pb, in 

various combinations, on growth inhibition in the green algae Selenastrum capricornutum. 

Results indicated that at lower Pb concentrations (<0.207 mg/L) and increased nutrient 

concentrations, algae release more exudates that form inert complexes with Pb anions in the 

water. This suggests that S. capricornutum can use exudates as a protection and that this 

protective mechanism depends on nutrient supply. These results are consistent with those of 

Capelo et al. (1993), who investigated uptake of nitrogen and phosphorus in the algae 

Selenastrum capricornutum over time in the absence and presence of 0.207 mg Pb/L. They 

found that the presence of Pb had no significant influence on the assimilation of nitrogen and 

phosphorus. However, they did find that in the presence of Pb, algae released higher 

concentrations of organics with Pb-chelating groups. 
 AX7-171 

Amiard et al. (1994) investigated the impact on soft tissue Pb concentrations of various 

feeding regimes on oysters (Crassostrea gigas) during their spat rearing. They fed test groups of 

C. gigas different amounts of Skeletonema costatum and additional natural phytoplankton grown 

in test solutions. Results showed that size and food intake both negatively correlated with metal 

concentrations in soft tissue. The authors hypothesized that this relationship was due in part to a 

diluting effect of the food. 

In summary, nutrients affect Pb toxicity in those aquatic organisms that have been studied. 

Some nutrients seem to be capable of reducing toxicity, though the mechanisms have not been 

well established. Exposure to Pb has not been shown to reduce nutrient uptake ability, though it 

has been demonstrated that Pb exposure may lead to increased production and loss of organic 

material (e.g., mucus and other complex organic ligands) (Capelo et al., 1993).

Interactions with Other Pollutants 

Most of the scientific literature reviewed in this section considered how Pb and other 

elements combine to affect uptake and exert toxicity. Research on the interactions of Pb with 

complexing ligands and other physical and biological factors was more thoroughly discussed in 

Section AX7.2.3.4. Predicting the response of organisms to mixtures of chemicals is difficult 

(Norwood et al., 2003). There are two schools of thought on addressing chemical mixtures in 

toxicology. The first focuses on the combined mode of action of the individual mixture 

substances while the other focuses on the organism response to the mixture as being additive, or 

some deviation from additive (synergistic or antagonistic). The mode of action model assumes 

that each of the individual substances has similar pharmacokinetics as well as mode of action. 

Approaches to modeling combined mode of action include: 1) joint independent action for 

toxicants with different modes of action; and 2) joint similar mode of action. Within the 

scientific literature the deviations from additivity approach can be confusing as some authors 

report concentration additivity, while others report effect additivity. The concentration additivity 

model assumes that the sum of the concentrations will result in a level of effect similar to the 

simple sum of the effects observed if each chemical were applied separately (e.g., Herkovits and 

Perez-Coll, 1991). Toxic units (TU) may be used to describe the concentration additivity results 

for mixtures (e.g., Hagopian-Schlekat et al., 2001). Effects additivity suggests that the level of 

effect of a mixture will be the sum of the effects of each chemical used separately. Thus, the 
 AX7-172 

separate concentration-effects models for each chemical are used to predict individual effects and 

the sum of these predictions is then compared to the actual effect of the mixture. Deviations 

from the mixture effect are then classified as less than additive (antagonistic) or more than 

additive (synergistic) (see Piegorsch et al., 1988; Finney 1947 for further information). 

The complexity of metal mixture interactions as different metal concentrations, 

environmental conditions (e.g., temperature, pH), and other factors can cause marked changes in 

the effects observed (Norwood et al., 2003). In describing Pb interactions with other elements, 

the different approaches to modeling mixture toxicity are considered. Specific reference to 

known Pb-metal interactions and implications on Pb uptake and toxicity will also be made in 

each of the studies below. 

Less than additive or antagonistic interactions can reduce metal bioavailability when 

metals are present in combination, and may lead to reduced potential for toxicity (Hassler et al., 

2004). A number of elements act in an antagonistic fashion with Pb. For example, Pb is a wellknown antagonist to Ca2+ (Niyogi and Wood, 2004; Hassler et al., 2004), which is an essential 

element, required for a number of physiological processes in most organisms. Lead ions have an 

atomic structure similar to Ca2+ and can be transported either actively or passively across cell 

membranes in place of Ca2+. An example of this interaction was reported by Behra (1993a,b) 

where Pb was shown to activate calmodulin reactions in rainbow trout (O. mykiss) and sea 

mussel (Mytilus sp.) tissues in the absence of calcium. Calmodulin (CaM) is a major 

intracellular calcium receptor and regulates the activities of numerous enzymes and cellular 

processes. Allen (1994) reported that Pb can replace calcium in body structures (e.g., bones, 

shells); replace zinc in ALAD, which is required for heme biosynthesis; and react with 

sulfhydryl groups, causing conformation protein distortion and scission of nucleic acids 

(Herkovits and Perez-Coll, 1991). Lead is also a known antagonist to Mg2+, Na+

, and Cl!

regulation in fish (Ahern and Morris, 1998; Rogers and Wood, 2003, 2004; Niyogi and Wood, 

2004). Li et al. (2004) reported on the interaction of Pb2+ with Cd2+ in the context of adsorption 

from solution by Phanerochaete chrysosporium, a filamentous fungus. The authors found that 

cadmium uptake decreased with increasing concentration of Pb ions with Pb2+ outcompeting 

Cd2+ for binding sites. 

Hassler et al. (2004) reported that in the presence of copper (Cu2+), there was a 

significantly higher rate of internalization of Pb in the green algae Chlorella kesserii. It was 
 AX7-173 

suggested that Cu2+ may have affected organism physiology through the disruption of cell 

membrane integrity. This would allow increased cation (i.e., Pb2+) permeability and, therefore, 

substantially increase internalization of Pb and result in effects that were more than additive 

(synergistic). Hagopian-Schlekat et al. (2001) examined the impact of individual metals and 

complex metal mixtures containing Cd, Cu, Ni, Zn, and Pb to the estuarine copepod Amphiascus 

tenuiremis. The copepods were exposed to metal-spiked sediment and pore water. The mixed 

metal sediment toxicity tests demonstrated greater than additive toxicity to A. tenuiremis. It was 

postulated that the synergism observed was due to two or more metals affecting the same 

biological function. Herkovits and Perez-Coll (1991) exposed Bufo arenarum larvae to various 

Pb and zinc concentrations in solution. At low zinc concentrations, (2:1 Pb:Zn ratio), 

a synergistic toxic effect was observed in the frog larvae relative to the effects observed from 

exposure to the individual metals and at higher zinc concentrations. Enhanced Pb toxicity was 

attributed to the interference of Pb with cellular activities due to binding with sulfhydryl 

polypeptides and nucleic acid phosphates (Herkovits and Perez-Coll, 1991). Allen (1994) 

reported on the accumulation of numerous metals and ions into specific tissues of the tilapia 

Oreochromis aureus. Tilapia exposed to low concentrations of Pb and mercury (both at 

0.05 mg/L) had significantly higher concentrations of Pb in internal organs than those fish 

exposed to Pb alone. Similarly, low concentrations of cadmium with low concentrations of Pb 

caused increased uptake of Pb in certain organs (e.g., liver, brain, and caudal muscle). 

Lead has been shown to complex with Cl! in aquatic systems. For example, Verslycke 

et al. (2003) exposed the estuarine mysid Neomysis integer to six different metals, including Pb, 

and a combined metal mixture under changing salinity conditions. At a salinity of 5%, the 

reported LC50 for Pb was 1140 μg/L (840, 1440 μg/L). At an increased salinity of 25l, the 

toxicity of Pb was substantially reduced (LC50 = 4274 μg/L [3540, 5710 Φg/L]) (Verslycke 

et al., 2003). This reduction in toxicity was attributed to the increased concentration of Cl!

 ion 

due to increased salinity, in that it complexed with divalent Pb in the test system. Exposure of N. 

integer to Pb in combination with the other five metals (Hg, Cd, Cu, Zn, Ni) resulted in roughly 

strictly additive toxicity (Verslycke et al., 2003). 

Long et al. (2006) performed a critical review of the uses of mean sediment quality 

guideline quotients (mSQGQs) in assessing the toxic effects of contaminant mixtures (metals and 

organics) in sediments. This approach has been used in numerous surveys and studies since 
 AX7-174 

1994. mSQGQs are useful to risk assessors but their inherent limitations and underlying 

assumptions must be fully understood (see Section AX7.2.1.5). 

Summary of Interactions With Other Pollutants 

Norwood et al. (2003) reported that in a review and reinterpretation of published data on 

the interactions of metals in binary mixtures (n = 15 studies), antagonistic (6) and additive 

interactions (6) were the most common for Pb. The complexity of the interactions and possible 

modifying factors makes determining the impact of even binary metal mixtures to aquatic biota 

difficult (Norwood et al., 2003; Playle, 2004). The two most commonly reported Pb-element 

interactions are between Pb and calcium and between Pb and zinc. Both calcium and zinc are 

essential elements in organisms and the interaction of Pb with these ions can lead to adverse 

effects both by increased Pb uptake and by a decrease in Ca and Zn required for normal 

metabolic functions. 

AX7.2.3.5 Factors Associated with Global Climate Change 

It is highly unlikely that Pb has any influence on generation of ground-level ozone, 

depletion of stratospheric ozone, global warming, or other indicators of global climate change. 

Lead compounds have relatively short residence times in the atmosphere, making it unlikely that 

they will reach the stratosphere, and they do not absorb infrared radiation, making them unlikely 

to contribute to stratospheric ozone depletion or global warming. Also, these compounds are 

unlikely to have a significant interaction with ground-level nitrogen oxides or volatile organic 

compounds, thus precluding generation of ground-level ozone. 

Approached from another viewpoint, climate change can have a major impact on the 

fate/behavior of Pb in the environment and, therefore, can subsequently alter organism or 

ecosystem responses. For example, changes in temperature regime (Q10 rule), changes in 

precipitation quantity and quality (e.g., acidic deposition) may influence fate, transport, uptake, 

and bioavailability of Pb (Syracuse Research Corporation., 1999). 

AX7.2.3.6 Summary 

There have been a number of advancements in the understanding of Pb behavior in the 

environment and its impact on aquatic organisms since 1986. In particular, greater knowledge of 
 AX7-175 

factors that influence Pb accumulation in aquatic organisms, mechanisms of detoxification and 

avoidance of Pb, and greater understanding of the interactions of Pb in aquatic systems. All of 

these factors require some consideration when attempting to determine the potential for exposure 

and subsequent response of aquatic species to lead. The following section provides a review on 

the current understanding of lead and its impacts on aquatic biota. 

AX7.2.4 Exposure/Response of Aquatic Species 

This section outlines and highlights the critical recent advancements in the understanding 

of the toxicity of Pb to aquatic biota. The section begins with a review of the major findings and 

conclusions from the 1986 Lead AQCD (U.S. Environmental Protection Agency, 1986a). The 

following sections summarize the research conducted since 1986 on determining the 

concentrations of Pb that cause the effects discussed in Section 7.2.3. 

Lead exposure may adversely affect organisms at different levels of organization, i.e., 

individual organisms, populations, communities, or ecosystems. Generally, however, there is 

insufficient information available for single materials in controlled studies to permit evaluation 

of specific impacts on higher levels of organization (beyond the individual organism). Potential 

effects at the population level or higher are, of necessity, extrapolated from individual level 

studies. Available 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). Therefore, the best documented links 

between lead and effects on the environment are with effects on individual organisms. Impacts 

on aquatic ecosystems are discussed in Section 7.2.5 and Annex AX7.2.5. 

AX7.2.4.1 Summary of Conclusions From the Previous Criteria Document 

The 1986 Lead AQCD (U.S. Environmental Protection Agency, 1986a) reviewed data in 

the context of the sublethal effects of lead exposure. The document focused on describing the 

types and ranges of lead exposures in ecosystems likely to adversely impact domestic animals. 

As such, the criteria document did not provide a comprehensive analysis of the effects of lead to 

most aquatic primary producers, consumers, and decomposers. For the aquatic environment, 

general reviews of the effects of lead to algae, aquatic vertebrates, and invertebrates were 

undertaken. A summary of these reviews is provided below. 
 AX7-176 

Algae 

The 1986 Lead AQCD (U.S. Environmental Protection Agency, 1986a) reported that 

some algal species (e.g., Scenedesmus sp.) were found to exhibit physiological changes when 

exposed to high lead or organolead concentrations in situ. The observed changes included 

increased numbers of vacuoles, deformations in cell organelles, and increased autolytic activity. 

Increased vacuolization was assumed to be a tolerance mechanism by which lead was 

immobilized within cell vacuoles. 

Aquatic Vertebrates 

The 1986 Lead AQCD (U.S. Environmental Protection Agency, 1986a) reported that 

hematological and neurological responses were the most commonly reported effects in aquatic 

vertebrates. These effects include red blood cell destruction and inhibition of the enzyme 

ALAD, required for hemoglobin synthesis. At high lead concentrations, neurological responses 

included neuromuscular distortion, anorexia, muscle tremor, and spinal curvature (e.g., lordosis). 

The lowest reported exposure concentration causing either hematological or neurological effects 

was 8 μg/L (U.S. Environmental Protection Agency, 1986a). 

Aquatic Invertebrates 

Numerous studies were cited on the effects of lead to aquatic invertebrates in the 1986 

Lead AQCD (U.S. Environmental Protection Agency, 1986a). In general, lead concentrations in 

aquatic invertebrates were found to be correlated closely with concentrations in water rather than 

food. Freshwater snails were found to accumulate lead in soft tissue, often in granular bodies of 

precipitated lead. Mortality and reproductive effects were reported to begin at 19 μg Pb/L for the 

freshwater snail Lymnea palutris and 27 μg Pb/L for Daphnia sp. 

The review of the NAAQS for Pb (U.S. Environmental Protection Agency, 1990) made 

only one recommendation reported in the sections of the 1986 Lead AQCD dealing with effects 

to aquatic biota. This was the need to consider the impact of water hardness on Pb 

bioavailability and toxicity, to be consistent with the recommendations of the AWQC for the 

protection of aquatic life (U.S. Environmental Protection Agency, 1985). 
 AX7-177 

AX7.2.4.2 Recent Studies on Effects of Lead on Primary Producers 

Using literature published since the 1986 Lead AQCD (U.S. Environmental Protection 

Agency, 1986a), this section examines the toxicity of Pb (individually and in metal mixtures) to 

algal and aquatic plant growth, its effects on metabolic processes (e.g., nutrient uptake), and its 

impact on primary productivity in natural systems. 

Toxicity of Lead to Algae 

The toxicity of Pb to algal growth has been investigated for a number of species including 

Chlorella vulgaris, Closterium acerosum, Pediastrum simplex, Scenedesmus quadricauda, 

Scenedesmu obliquus, Syneschoccus aeruginosus, and Nostoc muscorum (Jampani, 1988; Rai 

and Raizada, 1989; Adam and Abdel-Basset, 1990; Fargašová, 1993; Bilgrami and Kumar, 

1997). Study durations ranged from 7 to 20 days and Pb-nitrate was the most commonly used 

form of Pb. Effects to algal growth (Chlorella vulgaris, Closterium acerosum, Pediastrum 

simplex, Scenedesmus quadricauda), ranging from minimal to complete inhibition, have been 

reported at Pb concentrations between 100 and 200,000 μg/L (Jampani, 1988; Bilgrami and 

Kumar, 1997). Most studies report the percent inhibition in test groups compared to controls 

rather than calculating the LOEC, NOEC, or EC50 values. Clinical signs of Pb toxicity include 

the deformation and disintegration of algae cells and a shortened exponential growth phase 

(Jampani, 1988; Fargašová, 1993). Other effects of Pb block the pathways that lead to pigment 

synthesis, thus affecting photosynthesis, the cell cycle and division, and ultimately result in cell 

death (Jampani, 1988). 

From the studies reviewed, Closterium acerosum is the most sensitive alga species tested 

(Bilgrami and Kumar, 1997). Exposure of these algae to 1000 and 10,000 μg/L as lead nitrate 

for 6 days resulted in cell growth that was 52.6 and 17.4%, respectively, of controls (Bilgrami 

and Kumar, 1997). Chlorella vulgaris, Pediastrum simplex, and Scenedesmus quadricauda were 

also exposed to Pb-nitrate in this study. Compared to controls, cell growth at 1000 and 

10,000 μg Pb-nitrate/L was 65.3 and 48.7%, 64.5 and 42.7%, and 77.6 and 63.2%, respectively 

(Bilgrami and Kumar, 1997). Scenedesmus quadricauda exhibited a similar magnitude of effects 

when exposed to lead (Pb2+) for 20 days at 0, 5500, 11,000, 16,500, 22,000, 27,500, and 

33,000 μg/L (Fargašová, 1993). This study reported an EC50 for growth inhibition at 

13,180 μg/L (95% CI: 10,190, 14,620). Decreased cell number, but increased cell size, was 
 AX7-178 

observed in Selenastrum capricornutum7 exposed to lead (Pb2+) at 207.2 μg/L and a Q/V (flux of 

air [Q] divided by volume of the culture [V]) of 4.7 Η 10!3

 sec!1 for 9 days (Simòes Gonçalves 

et al., 1991). The Q/V is a measure of culture growth where an increase in the Q/V ratio 

indicates growth. The pigment concentration per cell decreased with exposure to Pb, so while 

the algae cells were larger, they were less healthy (Simòes Gonçalves et al., 1991). Growth rates 

were not reported, making comparison with other studies difficult. 

High Pb concentrations were required to elicit effects in Nostoc muscorum and 

Scenedesmus aeruginosus (Jampani, 1988; Rai and Raizada, 1989). Following 15-day 

exposures, test groups exposed to 10,000, 20,000, and 30,000 μg Pb/L experienced growth rates 

that were 90.5, 76.9, and 66.7% of the controls (Rai and Raizada, 1989). Synechococcus 

aeruginosus experienced little inhibition of growth from exposure to Pb-nitrate up to a 

concentration of 82,000 μg/L (Jampani, 1988). At a test concentration of 100,000 μg/L, 

complete inhibition of growth was observed, and at a concentration of 200,000 μg/L, algae failed 

to establish a single colony (Jampani, 1988). Scenedesmus obliquus are quite tolerant to the 

effects of Pb-nitrate and Pb-acetate on growth. Algae exposed to Pb-nitrate or Pb-acetate up to 

180,000 μg/L had higher cell numbers than controls (Adam and Abdel-Basset, 1990). Exposure 

to the highest concentration of 300,000 μg/L Pb-nitrate or Pb-acetate resulted in cell numbers 

that were 81 and 90% of the controls, respectively (Adam and Abdel-Basset, 1990). 

Lead in combination with other metals (e.g., Pb and Cd, Pb and Ni, etc.) is generally less 

toxic than exposure to Pb alone (Rai and Raizada, 1989). Nostoc muscorum exposed to 

chromium and Pb in combination demonstrated better growth than when exposed to either of the 

metals alone (Rai and Raizada, 1989). Antagonistic interaction was observed in the exposure of 

Nostoc muscorum to Pb and nickel in combination (Rai and Raizada, 1989). When applied 

separately, these metals demonstrated different levels of toxicity; however, in combination, they 

exerted similar effects (Rai and Raizada, 1989). More information on toxic interactions of Pb 

with other metals is provided in Section AX7.2.3.5. 

 7

The species name Selenastrum capricornutum has been changed to Pseudokirchneriella subcapitata. The 

former species name is used in this report.
 AX7-179 

Aquatic Plants 

The toxicity of Pb to aquatic plant growth has been studied using Spirodela polyrhiza, 

Azolla pinnata, and Lemna gibba (Gaur et al., 1994; Gupta and Chandra, 1994; Miranda and 

Ilangovan, 1996). Test durations ranged from 4 to 25 days and test concentrations ranged 

between 49.7 and 500,000 μg Pb/L (Gaur et al., 1994; Miranda and Ilangovan, 1996). Research 

on aquatic plants has focused on the effects of Pb on aquatic plant growth and chlorophyll and 

protein content. 

Of the species reviewed here, the effects of Pb on aquatic plant growth are most 

pronounced in Azolla pinnata (Gaur et al., 1994). An EC50 of 1100 μg/L was reported for 

A. pinnata exposed to Pb-nitrate for 4 days. S. polyrhiza exposed to Pb-nitrate under the same 

test conditions had a reported EC50 for growth of 3730 μg/L (Gaur et al., 1994). Lemna gibba

was shown to be the least sensitive plant species to Pb: significant growth inhibition was 

reported at concentrations of 200,000 μg/L or greater after 25 days of exposure to concentrations 

of 30,000, 50,000, 100,000, 200,000, 300,000, or 500,000 μg/L (Miranda and Ilangovan, 1996). 

The maximum growth rate for L. gibba was observed at 10 days of exposure. After this point, 

the growth rate declined in controls and test concentrations (Miranda and Ilangovan, 1996). 

Clinical signs of Pb toxicity include yellowing and disintegration of fronds, reduced frond size, 

and chlorosis (Gaur et al., 1994; Miranda and Ilangovan, 1996). Toxicity results suggest that 

effects to growth from Pb exposure occur in a dose-dependent manner (Gaur et al., 1994). 

Effects of Lead on Metabolic Processes 

Algal and aquatic plant metabolic processes are variously affected by exposure to Pb, both 

singularly and in combination with other metals. Lead adversely affects the metabolic processes 

of nitrate uptake, nitrogen fixation, ammonium uptake, and carbon fixation at concentrations of 

20,000 μg Pb/L or greater (Rai and Raizada, 1989). Lead in combination with nickel has an 

antagonistic effect on nitrogen fixation and ammonium uptake, but a synergistic effect on nitrate 

uptake and carbon fixation (Rai and Raizada, 1989). Lead in combination with chromium has an 

antagonistic effect on nitrate uptake, but it has a synergistic effect on nitrogen fixation, 

ammonium uptake, and carbon fixation (Rai and Raizada, 1989). 

Lead effects on nitrate uptake in Nostoc muscorum (μg NO3/μg Chl a) were greatest after 

24 h, when exposure to 20,000 μg/L reduced nitrate uptake by 64.3% compared to controls. 
 AX7-180 

Nitrate uptake reported after 48, 72, and 96 h was reduced by 30.0, 37.5, and 38.9%, 

respectively, compared to controls (Rai and Raizada, 1989). Lead in combination with 

chromium, both at a test concentration of 20,000 μg/L, demonstrated antagonistic effects on 

nitrate uptake. Compared to controls, nitrate uptake was reduced by 52.4, 30, 25, and 22.2% at 

24, 48, 72 and 96 h, respectively (Rai and Raizada, 1989). The greatest effect on uptake 

occurred at 24 h when, compared to controls, a 52.4% reduction was reported in the test 

concentration. Lead and nickel in combination at test concentrations of 20,000 and 1000 μg/L, 

respectively, resulted in a greater reduction of nitrate uptake than Pb alone at 48, 72, and 96 h 

(Rai and Raizada, 1989). 

After 24, 48, and 72 h of Pb exposure at 20,000 μg/L, nitrogenase activity (nmol C2H4/ μg 

protein/hr) in Nostoc muscorum was reduced by 39.3, 61.8, and 14.1%, respectively, compared 

to controls (Rai and Raizada, 1989). A concentration of 207.2 μg Pb/L had little effect on 

nitrogen or phosphorus assimilation in Selenastrum capricornutum over 7 days (Capelo et al., 

1993). An antagonistic effect on nitrogenase activity was generally reported for Nostoc 

muscorum exposed to Pb in combination with nickel at 20,000 and 1,000 μg/L, respectively 

(Rai and Raizada, 1989). Compared to controls, nitrogenase activity was reduced by 42.9, 32.7, 

and 13.6% at 24, 48, and 72 h, respectively (Rai and Raizada, 1989). Lead and chromium, both 

administered at a concentration of 20,000 μg/L, had a synergistic impact on nitrogenase activity 

in Nostoc muscorum. Nitrogenase activity in the test group was reduced by 60.7, 60, and 50% 

compared to the controls at 24, 48, and 72 h, respectively (Rai and Raizada, 1989). 

Lead-induced inhibition of ammonium uptake (μg NH4 uptake/μg Chl a) was greatest in

Nostoc muscorum after 48 h of exposure to 20,000 μg/L of lead. Compared to controls, the Pb 

test concentration 20,000 μg/L reduced ammonium uptake by 72, 82, 61, and 26 % at 24, 48, 72, 

and 96 h, respectively (Rai and Raizada, 1989). Lead in combination with nickel at 

concentrations of 20,000 and 1,000 μg/L, respectively, demonstrated an antagonistic effect on 

ammonium uptake. Compared to controls, ammonium uptake in the test group was reduced by 

44.9, 54.1, 23.3, and 4% at 24, 48, 72, and 96 h, respectively (Rai and Raizada, 1989). Lead in 

combination with chromium, both at concentrations of 20,000 μg/L, demonstrated a synergistic 

interaction with 24, 48, 72, and 96 h uptake rates reduced by 87.2, 88.5, 72.5, and 50 %, 

respectively, compared to controls (Rai and Raizada, 1989). 
 AX7-181 

Nostoc muscorum exposed to 20,000 μg Pb/L experienced the greatest reduction in carbon 

fixation at 0.5 h of exposure: 62% compared to controls. Inhibition of carbon fixation in the test 

group was less pronounced after 1 and 2 h of exposure: 29 and 13% of controls (Rai and 

Raizada, 1989). Lead in combination with nickel or chromium had synergistic effects to carbon 

fixation. Lead and nickel concentrations of 20,000 and 1000 μg/L, respectively, resulted in 0.5, 

1, and 2 h carbon fixation rates reduced by 93, 92, and 91%, respectively, compared to controls 

(Rai and Raizada, 1989). Lead with chromium at concentrations of 20,000 μg/L resulted in 0.5, 

1, and 2 h carbon fixation rates reduced by 65, 58, and 50%, respectively, compared to controls. 

Nutrients such as nitrogen, phosphate, sodium acetate, sodium carbonate, and citric acid 

have been shown to protect against the toxic effects of Pb to algae (Jampani, 1988). Nitrogen 

compounds (ammonium chloride, potassium nitrate, sodium nitrate, sodium nitrite) protected 

Synechococcus aeruginosus from a lethal Pb-nitrate dose of 200,000 μg/L (Jampani, 1988). Two 

phosphates (K2HPO4 and Na2HPO4) were found to improve Synechococcus aeruginosus survival 

from 0 to 72% at 200,000 μg/L of Pb-nitrate (Jampani, 1988). 

Compared to controls, protein content was reduced by 54.2 and 51.9% in aquatic plants 

Vallisneria spiralis and Hydrilla verticillata, respectively, exposed to Pb for 7 days at 

20,720 μg/L (Gupta and Chandra, 1994). Decreased soluble protein content has been observed 

in Scenedesmus obliquus exposed to Pb-nitrate or Pb-acetate at concentrations greater than 

30,000 μg/L, and in L. gibba at concentrations greater than 200,000 μg/L (Adam and 

Abdel-Basset, 1990; Miranda and Ilangovan, 1996). Lemna gibba also showed increased loss of 

soluble starch at concentrations >200,000 μg/L (Miranda and Ilangovan, 1996). Under the 

conditions described previously (Gupta and Chandra, 1994), EC50 values for chlorophyll content 

were 14,504 and 18,648 μg/L for Vallisneria spiralis and Hydrilla verticillata, respectively 

(Gupta and Chandra, 1994). Effects to chlorophyll a content have been observed in 

Scenedesmus obliquus at Pb-nitrate and Pb-acetate concentrations >30,000 μg/L (Adam and 

Abdel-Basset, 1990). 

Summary of Toxic Effects Observed in Single-Species Bioassays 

Algae and aquatic plants have a wide range in sensitivity to the effects of Pb in water. 

Both groups of primary producers experience EC50 values for growth inhibition between 

approximately 1000 and >100,000 μg/L (Jampani, 1988; Gaur et al., 1994; Bilgrami and Kumar, 
 AX7-182 

1997). The most sensitive primary producers reported in the literature for effects to growth were 

Closterium acersoum and Azolla pinnata (Gaur et al., 1994; Bilgrami and Kumar, 1997). The 

least sensitive primary producers reported in the literature for effects to growth were 

Synechococcus aeruginosus and Lemna gibba (Jampani, 1988; Miranda and Ilangovan, 1996). 

Exposure to Pb in combination with other metals is generally less toxic to growth than exposure 

to lead alone. Studies have shown that lead adversely affects the metabolic processes of nitrate 

uptake, nitrogen fixation, ammonium uptake, and carbon fixation (Rai and Raizada, 1989). Lead 

in combination with nickel or chromium produced synergistic effects for nitrate uptake, 

nitrogenase activities, ammonium uptake, and carbon fixation (Rai and Raizada, 1989). 

Leads Effects on Primary Productivity 

Lead nitrate and Pb-acetate have been shown to have adverse effects on the primary 

productivity of aquatic plants in two water bodies in India (Jayaraj et al., 1992). One of the two 

water bodies was a freshwater tank that receives wastewater and supports a rich population of 

hyacinths, and the other was a wastewater stabilization pond. Water quality characteristics in the 

freshwater tank were pH = 7.5, dissolved oxygen = 6 mg/L, and water hardness (CaCO3) = 

100 mg/L. Water quality characteristics in the wastewater pond were pH = 8.1, dissolved 

oxygen = 6.2 mg/L, and water hardness (CaCO3) = 160 mg/L (Jayaraj et al., 1992). Lead nitrate 

concentrations of 500, 5000, 10,000, 25,000, and 50,000 μg/L were combined with appropriate 

water samples in light and dark bottles and suspended in each of the water bodies for 4 h. The 

concentrations of Pb-acetate (5000, 10,000, 25,000, 50,000, and 100,000 μg/L) were applied in 

the same manner. The EC50 values were determined based on the concentration required to 

inhibit gross productivity (GP) and net productivity (NP) by 50% (Jayaraj et al., 1992). The 

results demonstrated that Pb-nitrate was more toxic to primary production than Pb-acetate. 

In the freshwater tank, Pb-nitrate EC50 values for GP and NP were 25,100 and 6310 μg/L, 

respectively, compared to Pb-acetate EC50 values of 50,100 and 28,200 μg/L for GP and NP, 

respectively (Jayaraj et al., 1992). In the stabilization pond, Pb-nitrate EC50 values for GP and 

NP were 31,600 and 28,200 μg/L, respectively, compared to Pb-acetate EC50 values of 79,400 

and 316 μg/L for GP and NP, respectively (Jayaraj et al., 1992). The higher toxicity reported in 

the freshwater tank was attributed to differences in species composition and diversity. The 

freshwater tank was dominated by water hyacinths that decreased the photic zone available for 
 AX7-183 

photosynthesis and consumed a great deal of available nutrients. The stabilization pond had 

a rich nutrient budget, resulting in improved alga growth and species diversity (Jayaraj 

et al., 1992). 

AX7.2.4.3 Recent Studies on Effects of Lead on Consumers 

This section focuses on the effects of Pb to aquatic biota including invertebrates, fish, and 

other biota with an aquatic life stage (e.g., amphibians). It is not intended to be a comprehensive 

review of all research conducted. Rather, the intent is to illustrate the concentrations and effects 

of Pb on freshwater and marine aquatic species. Eisler (2000) provides an overview of much of 

the recent available literature on the toxicity of Pb to fish and aquatic invertebrates. An 

extensive literature search was conducted using numerous electronic bibliographic and database 

services (e.g., DIALOG, EPA ECOTOX) and limited temporally from 1986 to present. This 

temporal limit was due to the availability of the EPA water quality criteria report for the 

protection of aquatic life, released in 1986 (U.S. Environmental Protection Agency, 1986b). 

Based on the results of the literature search and recent reviews of the toxicity of Pb (Eisler, 

2000), numerous studies have been published on the toxicity of Pb to aquatic consumers. 

Hardness, pH, temperature, and other factors are important considerations when characterizing 

the acute and chronic toxicity of lead (Besser et al., 2005) (Section AX7.2.3.5). However, many 

of the studies reviewed did not report critical information on control mortality, water quality 

parameters, or statistical methods, making comparing effects between studies difficult. Studies 

reporting only physiological responses to Pb exposure (e.g., reduction of ALAD) are not 

discussed here, as this topic was covered more completely in Section AX7.2.3.4. This section 

provides a review of toxicity studies conducted with invertebrates, fish, and other aquatic 

organisms. 

Invertebrates 

Exposure of invertebrates to Pb can lead to adverse effects on reproduction, growth, 

survival, and metabolism (Eisler, 2000). The following presents information on the toxicity of 

Pb to invertebrates in fresh and marine waters. 
 AX7-184 

Freshwater Invertebrates 

Acute and chronic Pb toxicity data for freshwater invertebrates are summarized in Table 

AX7-2.4.1. As described in Section AX7.2.3.5, water hardness is a critical factor governing the 

solubility, bioavailability, and ultimately the toxicity of Pb. The acute and chronic toxicity of Pb 

increases with decreasing water hardness as Pb becomes more soluble and bioavailable to 

aquatic organisms. For example, Borgmann et al. (2005) examined the toxicity of 63 metals, 

including Pb, to Hyalella azteca at two levels of water hardness (soft water hardness, 18 mg 

CaCO3/L; hard water, 124 mg CaCO3/L). Lead was 23 times more acutely toxic to H. azteca in 

soft water than hard water. Besser et al. (2005) found that acute toxicity to H. azteca was also 

modified by water hardness. 

At a mean pH of 7.97 in soft water (hardness (CaCO3) = 71 mg/L) mortality was >50% 

for H. azteca at a dissolved Pb concentration of 151 μg/L. The LOEC for survival in hard water 

(hardness (CaCO3) = 275 mg/L) at pH 8.27 was 192 μg/L as dissolved Pb and 466 μg/L as total 

Pb. Both waterborne and dietary Pb were found to contribute to reduced survival of H. azteca

(Besser et al., 2005). 

Exposure duration may also play an important role in Pb toxicity in some species. 

For example, Kraak et al. (1994) reported that filtration in the freshwater mussel Dreissena 

polymorpha was adversely affected at significantly lower Pb concentrations over 10 weeks of 

exposure than was the case after 48 h of exposure. 

The influence of pH on lead toxicity in freshwater invertebrates varies between 

invertebrate species. Over a 96-h exposure period, mortality increased with decreasing pH in the 

bivalve Pisidium casertanum, while pH-independent mortality was reported for gastropod and 

crustacean species under similar exposure conditions (Mackie, 1989). Cladocerans 

(Ceriodaphnia dubia), amphipods (H. azteca), and mayflies (Leptophlebia marginata) were also 

more sensitive to Pb toxicity at lower pH levels (Schubauer-Berigan et al., 1993; Gerhardt, 

1994). Lead was 100 times more toxic to the amphipod, Hyalella azteca, at a pH range of 5.0 to 

6.0 (Mackie, 1989) than at a pH range of 7.0 to 8.5 (Schubauer-Berigan et al., 1993). 

The physiology of an aquatic organism at certain life stages may be important when 

determining the toxicity of metals to test organisms. For example, Bodar et al. (1989) exposed 

early life stages of Daphnia magna to concentrations of Pb(NO3)2. The test medium had a pH 

of 8.3 ∀ 0.2, water hardness (CaCO3) of 150 mg/L, and temperature of 20 ∀ 1 ΕC. Lead 
 AX7-185 Table AX7-2.4.1. Effects of Lead to Freshwater and Marine Invertebrates Species Chemical Endpoint: Conc. (μg/L)* Duration of Exposure Water Chemistry Test Type - Effe

Freshwater Cladoceran (Ceriodaphnia dubia) lead chloride LC50: 280 >2,700 >2,700 48 h pH: 6–6.5 7–7.5 8–8.5 Hardness: 280-300 mg/L CaCO3 static-survival 

Worm (Lumbriculus variegatus) 

lead chloride 

LC50: 

>8,000 >8,000 >8,000 

96 h pH: 

6–6.5 7–7.5 8–8.5 Hardness: 280-300 mg/L CaCO3

static-survival 

Amphipod (Hyalella azteca)

lead chloride 

LC50: 

<90 >5,400 >5,400 

96 h pH: 

6–6.5 7–7.5 8–8.5 Hardness: 280-300 mg/L CaCO3

static-survival 

Amphipod (Hyalella azteca) 

lead chloride 

LC50: 

27 (20.1-36.4) 

8 days Hardness 

130 mg/L pH 7.8-8.6 

renewal, 1-weekold amphipods 

Amphipod (Hyalella azteca) 

lead chloride 

LC50: 

60 (53.6-67.3) 

8 days Hardness 

130 mg/L pH 7.8–8.6 

renewal, 10- to 1week old amphipods 

Mayfly (Leptophlebia marginata)

lead chloride 

LC50: 

1090 (400-133200) 

96 h pH: 

4.5 

acute - survival 

Mayfly (Leptophlebia marginata) 

lead chloride 

LC50: 

5000 

96 h pH 

7.0 

acute - survival 
 AX7-186 Table AX7-2.4.1 (cont’d). Effects of Lead to Freshwater and Marine Invertebrates Species Chemical Endpoint: Conc. (μg/L)* Duration of Exposure Water Chemistry Test Type - Effe

Amphipod (Hyalella azteca) 

lead nitrate 

LC50: 

10 21 18 

96 h pH: 

5.0 5.5 6.0 

acute-survival 

Bivalve (Pisidium compressum) 

lead nitrate 

LC50: 

38,000 21,300 11,400 

96 h pH: 

3.5 4.0 4.5 

acute- survival 

Bivalve (Pisidium casertanum) 

lead nitrate 

LC50: 

23,600 23,500 56,000 

96 h pH: 

3.5 4.0 4.5 

acute- survival 

Gastropod (Amnicola limosa)

lead nitrate 

LC50: 

10,300 20,600 9,500 

96 h pH: 

3.5 4.0 4.5 

acute- survival 

Mussel (Dreissena polymorpha) 

lead nitrate 

EC50: 

370 91 

48 h 

10 wks 

pH = 7.9; Hardness = 150 mg CaCO3/L; Temp = 15 ΕC 

renewal - filtratio

Mussel (Dreissena polymorpha) 

lead nitrate 

LT50: 

358 

72 days pH = 7.9; Hardness = 150 mg 

CaCO3/L; Temp = 15 ΕC 

renewal - filtratio

Amphipod (Hyalella azteca) 

lead nitrate 

LC50: 

4.8 (3.3 - 7.1) 

7 days pH = 7.37 - 8.27 

Hardness = 18 mg CaCO3/L 

DOC = 0.28 mg/L 

renewal - surviva

Amphipod (Hyalella azteca) 

lead nitrate 

LC50: 

113 (101 -126) 

7 days pH = 8.21 - 8.46 

Hardness = 124 mg CaCO3/L; 

DOC = 1.1 mg/L 

renewal - surviva
 AX7-187 Table AX7-2.4.1 (cont’d). Effects of Lead to Freshwater and Marine Invertebrates Species Chemical Endpoint: Conc. (

Φg/L)* 

Duration of 

Exposure Water Chemistry Test Type - Effe

Mayfly (Leptophlebia marginata) 

lead chloride 

LC50: 

1090 (95% C.I. = 133.2) >5000 

96 h pH = 4.5 - 6.5; 

DOC - 21.6 mg Cl!1; 

Cond = 7.0 

ΦS cm!1

renewal - surviva

Cladoceran (D. magna) 

lead nitrate 

LC50: 

0.45 

48 h pH = 8.3

∀ 0.2 

Hardness (CaCO3) = 150 mg/L 

Temp= 20 ΕC 

static - embryogenesis 

Cladoceran (D. magna) 

lead chloride 

NOEC: 260 

12 to 21 d Not specified renewal - 

reproduction 

Cladoceran (D.magna) 

lead chloride 

NOEC: 270 

10 d Not specified renewal - growth 

Amphipod (Hyalella azteca) 

lead LOEC: 

(Dissolved Pb) 192 (Total Pb) 466 

96 h pH = 8.27 

Hardness (CaCO3) = 275 mg/L 

Temp = 21.1 ΕC 

flow through - survival 

Tubificid worm (Tubifex tubifex) 

lead nitrate 

EC50: 

237 (183–316) 142 (107–184) 

24 h 48 h 

pH = 7.5–7.7 Hardness = 245 mg/L Temp = 29.5–31 ΕC 

static - immobilization 

MarineCopepod (Amphiascus tenuiremis) 

lead LC50: sediment 

2462 μg metal/dry sediment 

96 h pH = 7.7 

∀ 0.1 

Dissolved O2 -6.3 

∀ 0.3 mg/L 

Salinity – 32 ppt 

 

Bivalve (Mytilus galloprovincialis) 

lead nitrate 

EC50 : 221 

(58.9–346.3) LOEC : 50 

 artificial seawater embryogenesis 

* - Brackets after effect concentration are 95% confidence intervals. 
AX7-188

concentrations of <100 mg/L had no impact on Daphnia egg development. The authors 

suggested that this might due to the Daphnia egg structure, which consists of two layers: the 

inner vitelline layer and outer chlorion layer. The chlorion layer in other species (e.g., rainbow 

trout) is known to adsorb metals, thereby, preventing ionic injury to the developing embryo. 

Exposures to sediment-associated Pb can be toxic to sediment-dwelling organisms. 

In freshwater sediments, 48-h exposure of water fleas (Daphnia magna) to 7000 mg Pb/kg dw 

significantly reduced mobility, while exposure to 13,400 mg Pb/kg dw for 24 h produced the 

same effect (Dave, 1992a,b). Longer-term (i.e., 14-day) exposure of midges (Chironomus 

tentans) to sediments containing 31,900 mg Pb/kg dw resulted in 100% mortality. 

Marine Invertebrates 

In estuarine environments, salinity is an important modifying factor to Pb toxicity. 

Verslycke et al. (2003) exposed the estuarine mysid Neomysis integer to individual metals, 

including Pb, and metal mixtures under changing salinity. Water temperature (20 ∀ 1o

C) and 

salinity were reported, although no other water quality parameters were available (e.g., pH, water 

hardness). At a salinity of 5l, the reported LC50 for Pb was 1140 μg/L (95% CI: 840, 

1440 μg/L). At an increased salinity of 25l, the toxicity of lead was substantially reduced (LC50

= 4274 μg/L [3540, 5710 μg/L]) (Verslycke et al., 2003). 

Sensitivity to Pb can also vary between genders in some aquatic organisms. For example, 

Hagopian-Schlekat et al. (2001) examined the toxicity of Pb-chloride in sediment and sediment 

pore water to female and male estuarine copepods Amphiascus tenuiremis. The reported LC50

for total lead was 2462 mg Pb/kg dw (95% CI: 2097, 2891 mg Pb/kg dw). Gender effects were 

observed in that male copepods were more sensitive (p = 0.038) to Pb than females as 

determined by generalized linear model analysis. 

Beiras and Albentosa (2003) examined the inhibition of embryo development in 

commercial bivalves Ruditapes decussatus and Mytilus galloprovincialis after exposure to 

concentrations of Pb(NO3)2 in seawater. No water chemistry parameters other than temperature 

were reported (test conducted at 20 oC). An EC50 range for R. decussatus was reported as 156 to 

312 μg/L, as insufficient data were available to calculate the actual EC50. The lowest observable 

effect concentration (LOEC) was 156 μg/L. For M. galloprovincialis, the EC50 was 221 μg/L 

(95% CI: 58.9, 346.3) while the LOEC was reported as 50 μg/L. 
AX7-189

Fish 

The general symptoms of Pb toxicity in fish include production of excess mucus, lordosis, 

anemia, darkening of the dorsal tail region, degeneration of the caudal fin, destruction of spinal 

neurons, ALAD inhibition, growth inhibition, renal pathology, reproductive effects, growth 

inhibition, and mortality (Eisler, 2000). Toxicity in fish has been closely correlated with 

duration of Pb exposure and uptake (Eisler, 2000). The following presents information on the 

toxicity of Pb to fish in fresh and marine waters. Table AX7-2.4.2 summarizes the effects of Pb 

on freshwater and marine fish. 

Freshwater Fish 

Many of the toxicity modifying factors described above and in Section AX7.2.3.5 (e.g., 

pH, DOC) for invertebrates are also important modifying factors for Pb toxicity to fish species. 

The effects of pH on Pb bioavailability and subsequent toxicity have been well-studied (Sayer 

et al., 1989; Spry and Wiener, 1991; Schubauer-Berigan et al., 1993; Stouthart et al., 1994; 

MacDonald et al., 2002; Rogers and Wood, 2003). Schubauer-Berigan et al. (1993) exposed 

fathead minnow to Pb-chloride over 96 hours. The reported LC50 ranged from 810 to 

>5400 μg/L at pH 6 to 6.5 and pH 7 to 8.5, respectively. 

Water hardness also has a strong influence on the effects of lead to fish. Chronic 

exposure of rainbow trout fry to Pb in soft water resulted in spinal deformities at 71 to 146 μg/L 

after 2 months of exposure (Sauter et al., 1976) or 13.2 to 27 μg/L (Davies and Everhart, 1973; 

Davies et al., 1976), after 19 months of exposure. When exposed to Pb in hard water, only 0 and 

10% of the trout (Oncorhynchus mykiss) developed spinal deformities at measured Pb 

concentrations of 190 and 380 μg/L, respectively. In soft water, 44 and 97% of the trout 

developed spinal deformities at concentrations of 31 and 62 μg/L, respectively (Davies et al., 

1976). The maximum acceptable toxicant concentration (MATC) for rainbow trout fry in soft 

water was 4.1 to 7.6 μg/L (Davies et al., 1976), while the MATC for brook trout was 58 to 

119 μg/L (Holcombe et al., 1976). Histological reproductive abnormalities were noted in mature 

male rainbow trout at 10 μg/L Pb-nitrate (Ruby et al., 1993). 

Schwartz et al. (2004) examined the influence of NOM on Pb toxicity to rainbow trout 

exposed for 96 h in a static system. The pH of the exposure system ranged between 6.5 and 7.0, 

temperature was maintained between 9 and 11 ΕC, and Pb was added as PbCl2. NOM from a 
 AX7-190 Table AX7-2.4.2. Effects of Pb to Freshwater and Marine Fish Species Chemical Endpoint: Conc. (

Φg/L) 

Duration of 

Exposure Water Chemistry Comments 

Freshwater 

Fathead minnow (Pimephales promelas) 

lead chloride 

LC50: 

810 >5,400 >5,400 

96 h pH: 

6–6.5 7–7.5 8–8.5 Hardness: 280-300 mg/L CaCO3

static, measured 

Rainbow trout - mature males (Oncorhynchus mykiss) 

lead nitrate 

Reproductive effects: 10 

12 days Hardness 128 mg/L 

CaCO3

Decreased spermatocyte development 

Fathead minnow (Pimephales promelas) 

lead acetate 

Reproductive Effects: 500 

29 days pH: 

7.5–8.5; Hardness 130 mg/L CaCO3; 

22–25 ΕC 

(Pb 95% soluble) 

Fewer viable eggs produced, testicular damage 

Rainbow trout – Juvenile (Oncorhynchus mykiss) 

lead nitrate 

LC50: 1000 

(800 - 1400) 

96 h pH: 

7.9–8.0 DOC = 3 mg/L Hardness (CaCO3) = 

140 mg/L 

Flow through - Surviv

Common carp (Cyprinus carpio) 

not reported 

LC50: 

6.5 cm fish – 1030 3.5 cm fish – 300 

96 h pH: 

7.1 Temperature–15 ΕC 

Oxygen sat. 6.4 mg/L 

static-renewal - Survival 
 AX7-191

number of U.S. rivers and lakes was then added to the test system, and the LT50 was reported. 

NOM was found to reduce the toxic effects of Pb to rainbow trout. 

Fish size is an important variable in determining the adverse effects of Pb. Alam and 

Maughan (1995) exposed two different sizes of common carp (Cyprinus carpio) to Pb 

concentrations to observed effects on carp mortality. Water chemistry parameters were reported 

(pH = 7.1; temperature = 20 ΕC). Smaller fish (3.5 cm) were found to be more sensitive to Pb 

than were larger fish (6.5 cm). The reported LC50s were 0.44 mg/L and 1.03 mg/L, respectively. 

Marine Fish 

There were no studies available that examined the toxicity of Pb to marine fish species for 

the time period examined (1986 to present). However, Eisler (2000) reviewed available research 

on Pb toxicity to marine species and reported studies done prior to 1986. Acute toxicity values 

ranged from 50 μg/L to 300,000 μg/L in plaice (Pleuronectes platessa) exposed to organic and 

inorganic forms of Pb (Eisler, 2000). Organolead compounds (e.g., tetramethyl Pb, tetraethyl Pb, 

triethyl Pb, diethyl Pb) were generally more toxic to plaice than inorganic Pb (Maddock and 

Taylor, 1980). 

Other Aquatic Biota 

A paucity of data exist on the effects of Pb to growth, reproduction, and survival of 

aquatic stages of frogs and turtles. Rice et al. (1999) exposed frog larvae (Rana catesbeiana) to 

780 μg Pb/L and two oxygen concentrations (3.5 or 7.85 mg/L) for 7 days (Table AX7-2.4.3). 

Exposure conditions included water hardness of 233 to 244 mg CaCO3/L, pH from 7.85 to 7.9, 

and temperature at 23 ΕC. Frog larvae were found to display little to no activity in the low 

oxygen and high Pb treatment. Hypoxia-like behavior was exhibited in larvae exposed to both 

low and high oxygen concentrations and high Pb. Therefore, larvae of R. catesbeiana showed 

sensitivity to Pb and responded with hypoxia-like behavior. Additionally, the larvae in the Pb 

treatment were found to have lost body mass relative to controls and the other treatments. Rice 

et al. (1999) suggested that the decrease in mass likely indicated the beginning of a period of 

reduced growth rate. Larvae exposed for longer periods (>4 weeks) were smaller and 

metamorphosed later compared to unexposed individuals. 
 AX7-192 Table AX7-2.4.3. Nonlethal Effects in Amphibians Species Chemical Endpoint: Concentration Duration of Exposure Water Chemistry Comments 

Frogs (Rana ridibunda) 

lead nitrate Biochemical effects: 

14,000 μg/L 

30 days Not specified Hepatic ALAD decreased by 

90% 

Frogs (Bufo arenarum) 

 Mortality: 

16 mg Pb2+/L 

5 days Not specified Effects reported include erratic 

swimming, loss of equilibrium 

Frogs (Rana catesbeiana) 

 Hypoxia-like behavior:

780 μg/L 

7 days O2 = 3.5-7.85 mg/L 

pH = 7.85-7.9 Temp = 23

ΕC 

CaCO3 = 233-244 

mg/L 

Larvae used 

Turtle Hatchlings (Trachemys scripta) 

lead acetate NOEL: 100 μg/g 

(Survival and behavior) 

4 weeks N/A Exposure via single injection 
 AX7-193

Herkovits and Pérez-Coll (1991) examined Pb toxicity to amphibian larvae (Bufo 

arenarum). Larvae (n = 50) were exposed for up to 120 h at two Pb concentrations, 8 mg Pb2+/L 

and 16 mg Pb2+/L. Relative to controls, the 8 mg Pb2+/L treatment group exhibited 40% 

mortality and the 16 mg Pb2+/L group 60% mortality after 120 h (p < 0.05). The authors reported 

behavioral effects, erratic swimming, and loss of equilibrium during the tests, symptoms that are 

consistent with the action of Pb on the central and peripheral nervous systems (Rice et al., 1999). 

Behavior (i.e., righting, body turnover, seeking cover), growth, and survival of hatchling 

slider turtles (Trachemys scripta) exposed to Pb-acetate were investigated in one study (Burger 

et al., 1998). In the first part of the study, 6-month-old hatchlings received single Pb-acetate 

injections at 50 or 100 μg/g body weight (bw). In the second part of the study, 3-week-old 

turtles were injected once with doses of 250, 1000 or 2500 μg/g bw. There were no differences 

in survival, growth, or behavior for hatchlings in the first study, however, several effects were 

reported from the second part of the study at doses in the range of 250 to 2,500 μg/g bw. As the 

dose increased, so did the plastron length (i.e., ventral section of the shell), carapace length, and 

weight. The highest dose group had the lowest survival rate with an LD50 of 500 μg/g bw. 

Behavioral effects included slower times of righting behavior and seeking cover. The authors 

suggested a NOEL of 100 μg/g bw for slider turtles for survival and behavior. 

AX7.2.4.4 Recent Studies on Effects of Lead on Decomposers 

In this section, decomposers are defined as being bacteria and other microorganisms. 

Many invertebrates are also potentially considered decomposers, but the effects of Pb to 

invertebrates have been described in previous sections. There were no toxicity studies located on 

the effects of Pb to aquatic decomposers in the time period of interest. 

AX7.2.4.5 Summary 

Lead in all its forms is known to cause adverse effects in aquatic organisms (Eisler, 2000). 

Effects to algal growth have been observed at b concentrations ranging from 100 to 

200,000 μg/L. Clinical signs of Pb toxicity in plants include the deformation and disintegration 

of algae cells and a shortened exponential growth phase. Other effects of Pb include a blocking 

of the pathways that lead to pigment synthesis, thus affecting photosynthesis, cell cycle and 

division, and ultimately resulting in death. The toxicity of Pb to macrophyte growth has been 
 AX7-194

studied using Spirodela polyrhiza, Azolla pinnata, and Lemna gibba. Test durations ranged from 

4 to 25 days and test concentrations ranged between 49.7 and 500,000 μg/L. 

Waterborne Pb is highly toxic to aquatic organisms, with toxicity varying with the species 

and life stage tested, duration of exposure, form of Pb tested, and water quality characteristics. 

Among the species tested, aquatic invertebrates, such as amphipods and water fleas, were the 

most sensitive to the effects of Pb, with adverse effects being reported as low as 0.45 μg/L. 

Effects concentrations for aquatic invertebrates were found to range from 0.45 to 8000 μg/L. 

Freshwater fish demonstrated adverse effects at concentrations ranging from 10 to >5400 μg/L, 

depending generally upon water quality parameters. Amphibians tend to be relatively Pb tolerant 

(Eisler, 2000); however, they may exhibit decreased enzyme activity (e.g., ALAD reduction) and 

changes in behavior (e.g., hypoxia response behavior). Lead tends to be more toxic with longerterm exposures. 

The primary focus of this section was on effects at the individual level of organization. 

This narrow focus is primarily due to a lack of information on the effects of lead on higher levels 

of organization (e.g., populations, communities, and ecosystems). The impact of lead at higher 

levels of biological organization should be considered in future reviews of lead toxicity. 

In considering these higher levels of organization, cause-effect models and relationships that 

examine the roles of life history strategy and optimal foraging theory, community processes and 

associated theory, and ecosystem processes and the influences of redundancy/interactions should 

be taken into account. 

AX7.2.5 Effects of Lead on Natural Aquatic Ecosystems 

Introduction 

As discussed previously, lead exposure may adversely affect organisms at different levels 

of organization, i.e., individual organisms, populations, communities, or ecosystems. Generally, 

however, there is insufficient information available for single materials in controlled studies to 

permit evaluation of specific impacts on higher levels of organization (beyond the individual 

organism). Potential effects at the population level or higher are, of necessity, extrapolated from 

individual level studies. Available 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). Therefore, 
 AX7-195

the best documented links between lead and effects on the environment are with effects on 

individual organisms. 

This section discusses the effects of Pb on natural aquatic ecosystems. Such effects 

include changes in species composition and richness, ecosystem function, and energy flow due to 

Pb stress. The format of this section generally follows a conceptual framework for discussing 

the effects of a stressor such as Pb on an ecosystem. This conceptual framework was developed 

by the EPA Science Advisory Board (Young and Sanzone, 2002). The essential attributes used 

to describe ecological condition include landscape condition, biotic condition, chemical and 

physical characteristics, ecological processes, hydrology and geomorphology and natural 

disturbance regimes. The majority of the published literature pertaining to Pb and aquatic 

ecosystems focuses on the biotic condition, one of several essential attributes of an ecosystem as 

described in Young and Sanzone (2002). For the biotic condition, the SAB framework identifies 

community extent, community composition, trophic structure, community dynamics, and 

physical structure as factors for assessing ecosystem health. Other factors for assessing the 

biotic condition such as effects of Pb on organs, species, populations, and organism conditions 

(e.g., physiological status) were discussed in Sections AX7.2.3 and AX7.2.4. 

For natural aquatic ecosystems, the focus of study in the general literature has been on 

evaluating ecological stress where the sources of Pb were from urban and mining effluents rather 

than atmospheric deposition (Poulton et al., 1995; Deacon et al., 2001; Mucha et al., 2003). The 

atmospheric deposition of Pb in remote lakes has been evaluated; however, the direct effects of 

Pb on aquatic ecosystems was not evaluated in many cases (Larsen, 1983; Köck et al., 1996; 

Allen-Gil et al., 1997; Outridge, 1999; Lotter et al., 2002). In other studies, although Pb 

deposition was studied, the effects of acid deposition on aquatic life were the focus of the study 

and perceived to be more relevant (Mannio, 2001; Nyberg et al., 2001). Finally, the effects of 

Pb, other metals, and acidification on phytoplankton have only been inferred based on the 

paleolimnolical record (Tolonen and Jaakkola, 1983; Rybak et al., 1989). The statistical 

methods used when evaluating the effects of Pb on aquatic ecosystems are important, as more 

than one variable may be related to the observed effect. Studied variables include water 

hardness, pH, temperature, and physical factors such as embeddedness, dominant substrate, and 

velocity. In most cases, single variable statistical techniques were used to evaluate the data. 
 AX7-196

However, in other cases multivariate techniques were used. Therefore, where appropriate, some 

detail on the statistical methods used is presented. 

Although most of the available studies discussed in this section focus on the biotic 

condition, one case study examining multiple components of the EPA conceptual framework is 

also included. The remainder of this section describes the effects of Pb on the biotic condition. 

AX7.2.5.1 Case Study: Coeur d’Alene River Watershed 

The Coeur d’Alene River watershed is an area of Idaho impacted by Pb and other metals 

from historic mining waste releases. Maret et al. (2003) examined several ecological 

components to determine any negative associations with metals and the watershed communities. 

The variables examined and associated ecological conditions are presented in Table AX7-2.5.1. 

In addition to measurements of non-metal variables (e.g., dissolved oxygen levels, water 

temperature and pH, embeddedness), Cd, Pb, and Zn levels were also compared in affected sites 

versus reference sites. 

Some of the above non-metal variables are important to macroinvertebrate communities. 

For example, a stream with highly embedded substrate can have a lower number of individuals 

within a species or a different species composition compared to a stream with less embeddedness 

(Waters, 1995). Macroinvertebrates from the Ephemeroptera (mayflies), Plecoptera (stoneflies), 

and Trichoptera (caddisflies) (EPT) group inhabit the surface of cobble and the interstitial spaces 

between and underneath cobble. When substrate is embedded, these interstitial spaces are filled, 

leaving less habitat space for EPT taxa. In another example, water temperature is important; 

some macroinvertebrates (e.g., stoneflies) are usually only found in cooler water (Harper and 

Stewart, 1984). 

Of the variables examined only metal concentrations, mine density, site elevation, and 

water temperature were significantly different between reference and mine-affected sites. 

A Mann-Whitney t-test was used to evaluate statistical differences between reference and 

test sites for physical and water quality parameters, while Spearman’s rank correlation matrices 

were used to compare all possible response and explanatory variables. Lead concentrations were 

significantly correlated with the number of mines in proximity to the watershed. Lead 

concentrations in sediment and water were strongly correlated to Pb levels in whole caddisflies, 

r

2

 = 0.90 and 0.63, respectively. Furthermore, mine density was significantly correlated to Pb in 
 AX7-197

Table AX7-2.5.1. Ecological Attributed Studies by Maret et al. (2003) 

in the Coeur d’Alene Watershed 

Ecological Attribute Subcategory Measure 

Landscape condition Areal extent 

landscape pattern 

Basin area (km2) 

Production mine density/km2

Biotic Condition Organism condition 

population structure/ 

dynamics 

Caddisfly tissue concentrations (mg/kg) 

Number of EPT taxa 

Density of EPT individuals (no./m2

) 

Chemical/physical 

characteristics 

Chemical/physical 

parameters 

Dissolved oxygen (mg/L) 

Specific conductance (μS/cm) 

Water temperature (E ΕC) 

pH 

Water hardness (mg/L) 

Total NO3 (mg/L) 

Total P (mg/L) 

Dissolved NH3

 (mg/L) 

Sediment Cd, Pb, Zn (mg/kg) 

Dissolved Cd, Pb, Zn in water (mg/L) 

Ecological processes — None measured 

Hydrology/geomorphology Channel morphology 

and distribution 

Site elevation (m) 

Stream gradient (%) 

Stream discharge (m3

/s) 

Stream width (m) 

Stream depth (m) 

Open canopy (%) 

Stream velocity (m/s) 

Embeddedness (%) 

Dominant substrate (mm) 

Natural disturbance regimes — None measured 

tissue, r2

 = 0.64. Although temperature was significantly different between reference and 

mine-affected sites, temperature conditions were concluded to be non-limiting to aquatic life. 

For example, reference and mine-affected sites had at least 15 and 13 obligate cold-water taxa, 

respectively. 

A significant negative correlation between Pb in the water column (0.5 to 30 μg/L 

dissolved) and total taxa richness, EPT taxa richness, and the number of metal-sensitive mayfly 
 AX7-198

species was observed. Similar, significant negative correlations were found between sediment 

Pb levels (132 to 6252 μg/g) and the same macroinvertebrate community metrics and caddisfly 

tissue levels. Negative correlations were also found between Cd and Zn in the water and 

sediment and the macroinvertebrate community metrics. In an analysis of cumulative toxicity, 

Pb was judged to be the most significant metal in sediment related to the cumulative toxicity 

measured. This study provided multiple lines of evidence (i.e., mine density, metal 

concentrations, bioaccumulation in caddisfly tissue and benthic invertebrate assemblage 

structure) of the negative impacts of mining in the Coeur d’Alene River, suggesting that Pb (and 

other metals) were primary contributors to the effects observed in the Coeur d’Alene River 

watershed (Maret et al., 2003). 

AX7.2.5.2 Biotic Condition 

In an evaluation of the biotic condition, the SAB framework described by Young and 

Sanzone (2002) identifies community extent, community composition, trophic structure, 

community dynamics, and physical structure as essential ecological attributes for assessing 

ecosystem health. The following two sections describe the effects of Pb on community 

composition, community dynamics, and trophic structure. To date, no available studies were 

located on the effects of Pb on physical structure (e.g., change in riparian tree canopy height, 

ecosystem succession). 

Ecosystems and Communities, Community Composition 

To measure community composition, an inventory of the species/taxa found in the 

ecological system must be conducted. According the SAB framework, useful measures of 

composition include the total number of species or taxonomic units, their relative abundance, 

presence and abundance of native and non-native species, and information on the presence and 

abundance of focal or special interest species (Young and Sanzone, 2002). Focal or special 

species of interest can be those that play a critical role in ecosystem processes such as flows of 

materials or energy within complex food-webs (Young and Sanzone, 2002). Community 

composition as assessed in Pb studies has included the following measures. 
 AX7-199

• Changes in energy flow or nutrient cycling: 

o Increased or decreased respiration or biomass 

o Increased or decreased turnover/cycling of nutrients 

• Changes in community structure: 

o Reduced species abundance (i.e., the total number of individuals of a species within 

a given area or community) 

o Reduced species richness (i.e., the number of different species present in 

a community) 

o Reduced species diversity (i.e., a measure of both species abundance and species 

richness) 

Investigators have evaluated the effects of Pb on aquatic communities through microcosm 

and mesocosm studies in natural aquatic systems. Field studies in the general literature have 

focused on natural systems that were affected by metal stress from various anthropogenic 

sources. In most of those natural systems, the sources evaluated were from direct mining waste 

inputs, rather than atmospheric deposition, of Pb. Studies published since the 1986 Lead AQCD 

(U.S. Environmental Protection Agency, 1986a) that describe the effects of Pb on natural aquatic 

ecosystems are presented below and summarized in Table AX7-2.5.2. Studies included here 

evaluated the effects of Pb on watersheds, landscapes, aquatic ecosystems, aquatic communities, 

biodiversity, lakes, rivers, streams, estuaries, wetlands, and species interaction. 

Aquatic Microcosm Studies 

The examination of simulated aquatic ecosystems (i.e., microcosms) provides limited 

information on the effects of pollutants on natural systems. Microcosm studies typically focus 

on only a few aspects of the natural system and do not incorporate all of the ecological, 

chemical, or biological interactions. Nevertheless, a few microcosm studies have been 

conducted that indicate potential effects of Pb on the community structure of aquatic ecosystems. 

Fernandez-Leborans and Antonio-García (1988) evaluated the effect of Pb on a natural 

community of freshwater protozoans in simulated aquatic ecosystems and found a reduction in 

the abundance and composition of protozoan species with increasing Pb concentrations (0.05 to 

1.0 mg/L) compared to controls. Studies with marine protozoan communities in laboratory 

microcosms indicated that waterborne Pb exposure reduced protozoan abundance, biomass, and 
 AX7-200 Table AX7-2.5.2. Essential Ecological Attributes for Natural Aquatic Ecosystems Affected b

Category Species Condition Measures Exposure Medium Location Exposure Concentrations Oth

Met

Pres

Biotic Condition Ecosystems and Communities- Community Composition Protozoan community Reduced species abundance and diversity Marine water Laboratory microcosm 0.02– 0.05 mg/L N 

Protozoan community Reduced species abundance Freshwater water Laboratory microcosm 0.05–1 mg/L N 

Protist community Reduced species abundance and diversity Marine water Laboratory microcosm 1 mg/L N 

Meiofauna community Reduced abundance Marine sediment Laboratory microcosm 177 mg/kg dw Y Algal community Increased respiration Freshwater Domestic water stabilization pond 25–80 mg/L ? 

Algal community Decreased primary productivity Freshwater Sharana Basaveshwara Tank, India 6–32 mg/L ? 

Meiobenthic community (primarily nematodes) Reduced species abundance No effect on abundance Marine sediment Laboratory microcosm 1343 mg/kg dw 1580 mg/kg dw N 
 AX7-201 Table AX7-2.5.2 (cont’d). Essential Ecological Attributes for Natural Aquatic Ecosystems Affect

Category Species Condition Measures Exposure Medium Location Exposure Concentrations Oth

Met

Pres

Macroinvertebrate community Lower total abundance, decreased taxa, and EPT richness, larger percentage of tolerant species of benthic macroinvertebrates. Freshwater and sediment Mining sites in the Upper Colorado Basin <0.001–0.02 mg/L 145-850 mg/kg dw (<63 μM fraction) Y Macroinvertebrate community Negatively correlated with species richness and diversity indices Estuary sediment Douro Estuary, Portugal 0.25–192 mg/kg dw Y 

Macroinvertebrate community Reduced species abundance Freshwater sediment River Ill and tributaries, France 1–16 mg/kg dw Y 

Fish, crustacean and macroinvertebrate community Correlation with changes in species abundance and distribution Marine Sediment Spencer Gulf, South Australia 156–5270 mg/kg dw Y 

Chironomid community Reduced chironomid richness Whole organism residue New Brunswick, Canada 40.3–1,387 mg/kg dw (periphyton) 1.6–131 mg/kg dw (chironomid tissue) Y 

Macroinvertebrate community Lead in tissues negatively correlated with taxa richness, EPT richness, chironomid richness, and species density. Whole organism residue Clark Fork River, MT 32.2–67.1 mg/kg dw Y 

Macroinvertebrate community Lead in tissues negatively correlated with EPT richness and abundance. Biofilm residues Boulder River, MT 32–1540 mg/kg dw Y 
 AX7-202 Table AX7-2.5.2 (cont’d). Essential Ecological Attributes for Natural Aquatic Ecosystems Affect

Category Species Condition Measures Exposure Medium Location Exposure Concentrations Oth

Meta

Prese

 Macroinvertebrate Community Lead in tissues and sediment not correlated to diversity and richness Sediment and whole organism residue Aquashicola Creek tributaries, Palmerton, PA 7.5–59.5 mg/kg dw (sediment) 0.25-6.03 mg/kg dw (macroinvertebrates) Y 

Fish Community Lead in tissues and sediment not correlated to diversity and richness Sediment and whole organism residue Aquashicola Creek tributaries, Palmerton, PA 7.5–59.5 mg/kg dw (sediment) 0.1-0.86 mg/kg dw (fish) Y 

Ecosystems and Communities- Community Dynamics and Trophic Structure Snails and tadpoles Lead affected predator- prey interactions Sediment Outdoor mini- ecosystems Not cited Y 

Snails and caddisflies No avoidance of predator by snail. Caddisfly did respond to predator Water Field microcosm for snail; in-stream disturbance for caddisfly 27.7–277.6 mg/kg dw (snail tissue) 223–13,507 mg/kg dw (caddisfly tissue) Y Fathead minnow Feeding behavior altered Water Laboratory microcosm 0.5–1.0 mg/L N 

American toad No avoidance of lead Water Laboratory microcosm 0.5–1.0 mg/L N 

Mummichog Feeding behavior altered and predator avoidance affected Water Laboratory 0.3–1.0 mg/L N 
 AX7-203

diversity at concentrations of 0.02 to 1.0 mg/L Pb (Fernandez-Leborans and Novillo, 

1992, 1994). 

Austen and McEvoy (1997) studied the effects of Pb on an estuarine meiobenthic 

community (mainly nematodes) in a microcosm setting using sediment samples collected 

offshore from England. A multivariate analysis of similarities (ANOSIM) test with square roottransformed data was used to evaluate differences between treatments and controls. Lead was 

found to significantly affect species abundance at 1343 mg/kg dw relative to a control at 

56 mg/kg dw, but no significant adverse effects were observed at the highest dose tested, 

1580 mg/kg dw. The authors did not attempt to explain why the 1580 mg/kg dw dose was not 

significant while the 1343 mg/kg dw dose was. None of the Pb exposures were significantly 

different than the controls based on separate univariate tests of abundance, richness, and 

diversity. There were no other confounding metals in the Pb tests, as the experiments were with 

a single metal dose. In one other mesocosm study, the effects of a mixture of metals (Cu, Cd, 

Pb, Hg, and Zn) on a salt marsh meiofaunal community were evaluated (Millward et al., 2001). 

After 30-days exposure, significant reductions in copepod, gastropod, and bivalve 

abundances were observed at the highest Pb exposure concentration, 177 mg/kg dw. Ostracods 

and nematodes were not affected. The authors believed that the response of the meiofauna taxa 

to metals was in part due to the various feeding strategies in that deposit feeders were most 

affected. 

Natural Aquatic Ecosystem Studies 

Lead stress in aquatic ecosystems has also been evaluated in natural communities. 

Studies examining community-scale endpoints, however, are complex, and interpretation can be 

confounded by the variability found in natural systems and the presence of multiple stressors. 

Natural systems frequently contain multiple metals, making it difficult to attribute observed 

adverse effects to single metals. For example, macroinvertebrate communities have been widely 

studied with respect to metals contamination and community composition and species richness 

(Winner et al., 1980; Chadwick et al., 1986; Clements, 1994). In these studies, multiple metals 

are evaluated and correlations between observed community level effects are ascertained. The 

results often indicate a correlation between the presence of one or more metals (or total metals) 

and the negative effects observed. While, correlation may imply a relationship between two 
 AX7-204

variables, it does not imply causation of effects. The following studies suggest an association 

between Pb concentration and an alteration of community structure and function (see summary 

in Table AX7-2.6.2): 

Reduced Primary Productivity and Respiration 

Jayaraj et al. (1992) examined the effects of Pb on primary productivity and respiration in 

an algal community of two water bodies. Concentrations of Pb in water (6 to 80 mg/L) were 

found to significantly reduce primary productivity and increase respiration. The authors 

suggested that increased respiration indicated a greater tolerance to or adaptive mechanisms of 

the resident heterotrophs to cope with lead stress. 

Alterations of Community Structure 

Deacon et al. (2001) studied a macroinvertebrate community in mine-affected waters of 

Colorado. Initially, transplanted bryophytes were used to assess whether metals could 

bioaccumulate at various mine-affected and unaffected sites (Deacon et al., 2001; Mize and 

Deacon, 2002). Lead was bioaccumulated by the bryophytes, and median tissue concentrations 

at mine-affected sites (34 to 299 μg/g dw) were higher than at reference sites (2.5 to 14.7 μg/g 

dw). Lead concentrations in surface water and sediment ranged from <0.001 to 0.02 mg/L and 

145 to 850 mg/kg dw (<63 μm fraction), respectively. The same sites were also evaluated for the 

effects of various metals on macroinvertebrate communities. Values of total abundance, taxa 

richness, mayfly, and stonefly abundance were reduced at mining sites. Lead levels along with 

Cd, Cu, and Zn were correlated with reduced abundance and diversity indices. 

Macrobenthic communities studied in a Portuguese estuary were affected by Pb at a range 

from 0.25 to 192 mg/kg dw (Mucha et al., 2003). Species richness was decreased in areas with 

increased Pb concentrations in the sediment. Interpretation of Pb effects was complicated by 

other non-metal stressors, namely sediment particle size and organic matter content. 

Furthermore, other metals were present (e.g., Al, Cu, Cr, Mn, Zn) and may have affected the 

community (Mucha et al., 2003). 

The effects of Pb on oligochaetes in the Ill River and its tributaries in France were 

evaluated by Rosso et al. (1994). Lead in sediment (5 to 16 μg/g dw at affected sites) was 

positively correlated to the abundance of the oligochaete, Nais sp., and negatively correlated to 
 AX7-205

Tubificidae abundance. Lead was the only metal that was positively correlated to Nais species, 

while other metals were negatively correlated to Tubificidae (Rosso et al., 1994). 

The effects of metals and particle size on structuring epibenthic sea grass fauna (fish, 

mollusks, crustaceans, and polychaetes) was evaluated near a Pb smelter in South Australia 

(Ward and Young, 1982; Ward and Hutchings, 1996). Effluent from the smelter was the primary 

source of Pb and other metal contamination. Species richness and composition were evaluated 

near the Pb smelter along with metal concentrations in sediment. Lead levels in sediment (up to 

5270 mg/kg dw) correlated with negative effects on species richness and composition, while the 

other metals evaluated had similar correlations. Therefore, Pb alone could not be identified as 

the sole metal causing stress. 

Tissue Bioaccumulation Associated with Alterations of Community Structure 

Several studies have examined the bioaccumulation of lead in aquatic systems with 

indices of community structure and function. A focused study on changes in Chironomidae 

community composition in relation to metal mines (New Brunswick, Canada) identified changes 

in Chironomidae richness (Swansburg et al., 2002). Lead was not detected (detection limit not 

given for any matrix) in the water column at any site. However, Pb levels in periphyton were 

significantly higher at mining sites (40.3 to 1387 mg/kg dw) compared to reference sites (not 

detected [ND], 33.3 mg/kg dw). Furthermore, Pb in chironomids was significantly higher at 

mine-affected sites (1.6 to 131 mg/kg dw) compared to reference sites (ND, 10.2 mg/kg dw). 

The concentrations in biota indicate that Pb is mobile and available to the aquatic community 

even though water concentrations were undetectable. Chironomidae richness was reduced at the 

sites receiving mining effluent containing Pb, Cd, Cu, and Zn. 

In another study, macroinvertebrate lead tissue concentrations (32.2 to 67.1 mg/kg dw at 

affected sites) collected from the Clark Fork River, Montana correlated negatively with total 

richness, EPT richness, and density (Poulton et al., 1995). Mean Pb levels were as high as 

67.1 mg/kg dw at sites most affected by lead. However, other metals, including Cd, Cu, and Zn, 

also were negatively correlated with total richness and EPT richness. Therefore, attribution of 

the observed effects to Pb is difficult, as other metals may be contributing factors. 

In Montana, the potential effects of metals on macroinvertebrate communities in the 

Boulder River watershed were evaluated (Rhea et al., 2004). Similar to the approach taken by 
 AX7-206

Poulton et al. (1995), the effects on richness and abundance of EPT taxa were compared to metal 

concentrations in tissue (i.e., biofilm and macroinvertebrates). Lead levels in biofilm (32 to 

1540 mg/kg dw) were significantly correlated with habitat scores and macroinvertebrate indices 

(e.g., EPT taxa). However, macroinvertebrate tissue Pb levels were not significantly correlated 

with macroinvertebrate community level metrics. As with most natural systems with potential 

mine impacts, other metals also correlated with community level effects. However, the authors 

indicated that Pb concentrations in biofilm appeared to have the most significant impact on 

macroinvertebrate metrics. 

A detailed investigation of sediment, macroinvertebrates, and fish was conducted for 

tributaries in the Aquashicola Creek watershed near a former zinc smelter in Palmerton, PA 

(Carline and Jobsis, 1993). The smelter deposited large amounts of Cd, Cu, Pb, and Zn on the 

surrounding landscape during its operation from 1898 to 1980. The goal of the study was to 

evaluate if there was a trend in the metal levels in sediment, macroinvertebrate and fish tissue, 

and community indices going away from the smelter. Sites were chosen, from 7.8 to 24.6 km 

from the smelter. There were no clear associations between proximity to the smelter and Pb 

levels in sediment, macroinvertebrate tissue, and fish tissue. Furthermore, there were no 

associations between proximity to the smelter and macroinvertebrate and fish diversity and 

richness. The authors suggested that the transport of metals in the watershed has decreased since 

the smelter ceased operation, and thereby no effects were observed. 

Ecosystems and Communities, Community Dynamics, and Trophic Structure 

As described in the SAB framework, community dynamics include interspecies 

interactions such as competition, predation, and succession (Young and Sanzone, 2002). 

Measures of biotic interactions (e.g., levels of seed dispersal, prevalence of disease in 

populations of focal species) provide important information about community condition. If the 

community dynamics are disrupted, then the trophic structure may also be disrupted. According 

to the SAB framework, trophic structure refers to the distribution of species/taxa and functional 

groups across trophic levels. Measures of trophic structure include food web complexity and the 

presence/absence of top predators or dominant herbivores. Therefore, this section discusses how 

aquatic species interactions can be affected by Pb. Examples of species interactions can include: 
 AX7-207

• Predator-prey interactions (e.g., reduced avoidance of predators) 

• Prey consumption rate (e.g., increase or decrease in feeding) 

• Species competition (e.g., interference with another species, increased aggressive 

behavior) 

• Species tolerance/sensitivity (e.g., the emergence of a dominant species due to 

contaminant tolerance or sensitivity) 

Species interactions are highly relevant to a discussion about the effects of Pb on natural 

aquatic ecosystems, because effects on species interactions could potentially affect ecosystem 

function and diversity. Some examples of Pb induced changes in species interactions are 

presented below (see summary in Table AX7-2.5.2). 

Predator-prey Interactions 

Lefcort et al. (1999) examined the competitive and predator avoidance behaviors of snails 

and tadpoles in outdoor mini-ecosystems with sediment from a metals-contaminated Superfund 

site (i.e., Pb, Zn, Cd). Previous investigations of aquatic invertebrates and vertebrates yielded Pb 

tissue concentrations of 9 to 3800 mg/kg dw and 0.3 to 55 mg/kg dw, respectively. Several 

species interactions were studied in the presence of metal-contaminated sediment: 

Snails and tadpoles have similar dietary behaviors. Thus, when placed in the same habitat 

they will compete for the same food items and negatively affect one another. However, when 

tadpoles exposed to a predator (i.e., through biweekly additions of 20 mL of water from tanks 

housing sunfish—10 mL from sunfish-fed snails, 10 mL from sunfish-fed tadpoles) were placed 

with snails, the tadpoles reduced sediment ingestion, while snails increased ingestion. Thus, 

snails were exposed to greater quantities of metals in sediment. 

In an uncontaminated environment, snail recruitment (i.e., reproduction) was reduced in 

the presence of tadpoles. The addition of tadpoles increased the competition for food in the form 

of floating algae and the snails switched to feeding on algae that grew on the sediment. This 

decrease was due to competition alone. The effects on snail recruitment were even higher when 

tadpoles, the influence of a predator (i.e., sunfish extract), and metals in the sediment were all 

present. However, the predator effect was indirect in that the tadpoles hid in the algal mats 

forcing the snails to feed primarily on the benthic algae that grew on the sediment with high 
 AX7-208

metal levels. Furthermore, although not significant, Pb levels in snails were higher when 

tadpoles and sunfish extract were present than when only metals in the sediment were present. 

Finally, snail predator avoidance was assessed. Snails (control and lead-exposed) were 

stimulated with a predator indicator (i.e., crushed snails and an extract of crushed snail). Control 

snails changed behaviors in the presence of the predator indicator, while exposed snails did not 

alter their behavior. The authors suggested that metal exposure caused behavioral changes that 

alter competitive interactions and the perception of predators by the snails. Thus, Pb may affect 

the predator avoidance response of snails. 

In further study, Lefcort et al. (2000) examined the predator avoidance behaviors of snails 

and caddisflies. In separate experiments, the avoidance behavior of the snail, Physella 

columbiana, and four caddisfly genera (Agrypnia, Hydropsyche, Arctopsyche, Neothremma) 

were evaluated. The snails were collected from reference lakes and lakes downstream of the 

Bunker Hill Superfund site. The snails from the affected lakes generally had higher cadmium, 

Pb, and zinc tissue levels implying previous exposure to these metals. Snail predator avoidance 

behavior was tested by exposure to crushed snail extract. Snails from the affected lakes did not 

reduce their activity when exposed to the snail extract, implying a reduced predator avoidance. 

The lack of response may make the snails at the affected lakes more prone to predation. 

The caddisflies were evaluated at 36 sites from six different streams. As with the snails, 

the caddisflies from the affected streams had higher cadmium, Pb and zinc tissue levels. The 

time for caddisfly larvae to respond (i.e., how long immobile) to disturbance (i.e., lifted from 

water for 3 seconds and moved to a new location) was evaluated. There was no correlation 

between tissue metal level and any response variable (Lefcort et al., 2000). Therefore, the 

authors concluded that preexposure to metals did not reduce predator avoidance for caddisflies. 

Weber (1996) examined juvenile fathead minnows exposed to 0, 0.5, or 1.0 ppm Pb in 

water during a 2-week preexposure and 2-week testing period (4 weeks total exposure). Feeding 

behavior was evaluated by presenting two prey sizes (2-day-old and 7-day-old Daphnia magna). 

Control fish began switching from larger, more difficult-to-capture 7-day-old daphnids to 

smaller, easier-to-catch 2-day-old prey by day 3. Lead-exposed fish displayed significant 

switching at day 3 (at 0.5 ppm) or day 10 (at 1.0 ppm). Thus, exposure to Pb delayed the altering 

of prey size choices to less energetically costly prey. 
 AX7-209

Lefcort et al. (1998) exposed spotted frogs (Rana luteiventris) to 0.05 to 50 ppm Pb in 

water for 3 weeks. High levels of Pb reduced the fright response of tadpoles; suggesting a 

reduced avoidance of predators. 

Bullfrog larvae exposed to Pb in water (0.78 mg/L) and high or low dissolved oxygen 

were monitored for respiratory surfacing behavior (Rice et al., 1999). Larvae had a significantly 

increased number of trips to the water surface regardless of oxygen content. Thus, the authors 

suggest that Pb may affect oxygen uptake such that larvae are under greater predation pressure 

due to increased time spent at the surface. 

Weis and Weis (1998) evaluated the effect of Pb exposure on mummichog (Fundulus 

heteroclitus) larvae prey capture rate, swimming behavior, and predator avoidance. Prey capture 

rates were affected after 4 weeks exposure at 1.0 mg Pb/L. The larvae were also more 

vulnerable to predation by grass shrimp (Palaemonetes pugio) at 1.0 mg Pb/L. Finally, the 

swimming behavior of mummichog larvae was affected at 0.3 and 1.0 mg Pb/L. Once the larvae 

were no longer exposed to Pb, they recovered their ability to capture prey and avoid predators. 

Clearly, exposure to Pb does affect the predator-prey interactions and the ability of prey to 

avoid predators. The effect of Pb on these ecological functions may alter community dynamics. 

AX7.2.5.3 Summary 

The effects of Pb have primarily been studied in instances of point source pollution rather 

than area-wide atmospheric deposition; thus, the effects of atmospheric Pb on ecological 

condition remains to be defined. The evaluation of point source Pb within the EPA Ecological 

Condition Framework has been examined primarily in relation to biotic conditions. The 

available literature focuses on studies describing the effects of Pb in natural aquatic ecosystems 

with regard to community composition and species interactions. The effects of Pb on the biotic 

condition of natural aquatic systems can be summarized as follows: there is a paucity of data in 

the general literature that explores the effects of Pb in conjunction with all or several of the 

various components of ecological condition as defined by the EPA. However, numerous studies 

are available associating the presence of Pb with effects on biotic conditions. 

In simulated microcosms or natural systems, environmental exposure to Pb in water and 

sediment has been shown to affect energy flow and nutrient cycling and benthic community 

structure. In field studies, Pb contamination has been shown to significantly alter the aquatic 
 AX7-210

environment through bioaccumulation and alterations of community structure and function. 

Exposure to Pb in laboratory studies and simulated ecosystems may alter species competitive 

behaviors, predator-prey interactions, and contaminant avoidance behaviors. Alteration of these 

interactions may have negative effects on species abundance and community structure. In 

natural aquatic ecosystems, Pb is often found coexisting with other metals and other stressors. 

Thus, understanding the effects of Pb in natural systems is challenging given that observed 

effects may be due to cumulative toxicity from multiple stressors. 
 AX7-211

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