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 bl

ages. 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 de

including 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 poten

point 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 lo

Maternal 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 g
 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 sIQ were at blood Pb concentratithe entire pooled data set, a declCI: 3.8, 8.6) was estimated for afrom 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 poPPVT-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 Com

8.9 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 t

limits 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 virtu

academic 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 on Shift 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 slower 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 elevchildhood. 

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 bbehavior, 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 on

stratified by race, bone Pb was only by single parent status. Auelevated 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 freque

associated 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 coordination

upper-limb speed and dexterity anComposite 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 norm

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 inacross 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 pblood 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. On

were 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% C

but weaker association existed for tibia Pb bone mineral were removed (∃ = !0.19 [95

was no association of MMSE change and b

CI: !0.13, 0.11]). There was no interactio

These 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 Recasignificantly 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, 13.7age 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 athe 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 deviat

significantly 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 neurobehavi

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. Howe

was only associated with poorer performan(non-dominant ∃ = !0.0086 [95% CI: !0.0

(∃ = !0.0063 [95% CI: !0.0122, 0.0004]; a

CI: !0.0532, !0.0046]). Historical tibial bodigit symbol (∃ = !0.0067 [95% CI: !0.012

Pegboard (dominant ∃ = !0.0012, [95% CI

Magnitude 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 aPb. 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 ac

phosphorylation 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 act

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 (WAI
 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 bThe 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: !0.00longitudinal blood Pb (∃ = !0.0051 [95% C

in one model and blood Pb (∃ = !0.0019 [9

in 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 fou

and 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 s

and 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 mactivity 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 relatvariation 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 expassociation poorer performance in many often in manual dexterity and verbal meon 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), seriap = 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 leaswithout 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: 
 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 creatinor 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 (!0.0

diabetics. ∃ (95% CI) for natural ln basel0.135) compared to 0.005 (!0.0

diabetics. Significant interaction of tibia in predicting annual change in ∃ (95% CI) for natural ln basel0.019) compared to 0.0004 (!0

hypertensives. 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 borderlirelations between of patella anobserved; this was significant iPb levels were above 15 

μg/g b

not provided]; p = 0.04 ). Simimodel, patella Pb was associatthose with the variant allele. Gassociations 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 wittrace 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 creatinine

1.02 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 waone 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 potential 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 wo

workers.). All participants had normal clearances (>80 mL/min/1.7

Pb-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 provide

This 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 signIn simple linear regression murinary 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 Pb36.8 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 0.22both). 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, respe

Serum 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 Pb34.8 (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 Pb

67.7 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 Pb

767.8 

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 hafunction. 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 gene

acid dehydratase (ALAD), synthase (eNOS), and the vwere associated with renal orelations of Pb exposure an

outcomes. 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 # dose 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 m

between 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 PbRanged 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 significantl

alcohol consumption (OR analgesic consumption, famdisease, and occupational solvents. 

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 Pb7.2 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 partstatistically 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 numbe

measured in more patientsof detection, inclusion of ostatistical 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 observa

Pb 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 simifactors (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: !4

mean 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 observa

Primary endpoint = increatimes baseline or need for 24 participants. Secondary estimated glomerular filtraIn a Cox multivariate regrePb was significantly assocthe primary endpoint (hazachelatable 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 simifactors (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 baseline3.4 (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 Chelation 
 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 dCI = 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 hypersection 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 Pb8.7 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 RBP

46 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 Pb

13.3 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 subjecwas 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, daiand daily calcium consumption. Increasing tibia Passociated with increased systolic blood pressure baseline measurements in subjects (n = 519) free 

(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/cal

protein, 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, in

alcohol use, childhood residence (the two recruitmcontrol 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 descr
 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 (10.5/4.3of 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 significant blood 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 group

make blood Pb of both groups cover the same range, clinear blood Pb interaction term did not change apprePb interacted with genotype on blood pressure but sho

type or size of effect. Diastolic blood pressure was no

to 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 hypert

were 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 covaria

history 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, involvdata set, capitalizes on chance occurrence in the dprobability values. No model diagnostic testing r
 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 pred

males. 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 des

variables 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 tewith 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 c

Progressive 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 mode

use, effect of progressive addition of covariates, diagnostics reported for detecting the two outlyin

reported. 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 claime

2.71 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 epressure (coefficients, SEs or 95% CIs not given

probability of a positive association with diastoli

transformed 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 modantihypertensive 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. Namong 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. R

categories 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 d

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 nondrinkers 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 p

None of the relative hazard ratios for CHD and DVD between 40 and 54 yrs were significantly related to bmortality, 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 produ

covariates 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 aninterpretation. 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. N

significant 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 neg

it 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 o

covariates 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 p

the bb genotype the VDR Bb/BB genotypes’ blood 0.36 mm Hg (95% CI: 0.06, 0.66) per yr faster wiThere were no significant effects of any Pb variabpressure, 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 group

In multiple regression models for systolic and diastolipercentile 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 nonsig

regression produced a different covariate pattern for epressure. 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/d

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. Nantihypertensive 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, anor 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 comparis

cohort belongs to the comparison population and can mortality rates in direct proportion to the ratio betwee

population 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 (95

hypertension with heart disease (402, 404), SMR = 0.hypertension with no heart disease (401, 403, 405), SM

3.77); 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 thallowed 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-tr

CI: !1.91, 0.48) at 36 mos of follow up. Diwere 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: !0.4

pressure. 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 group It is notable that the two groups had differena yr after succimer treatment ended, a perioany beneficial effect of treatment. Failure t

blood Pb on blood pressure, especially pre-texposure 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% C

Diastolic blood pressure: ∃ = 0.069 (95% CHeart rate: ∃ = 0.013 (95% CI: !0.046, 0.0

Stroke 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 interb∃ = !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 lbirth 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 fertiliz

Statistically 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, incoligospermia 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 of 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 analysbetween 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 apotential 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, bu

No 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 nonsi

cases. OR for cumulative weighted exposure 1st 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 samexposure 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 reNo 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 

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 poten

calculated 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 deatAll 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; 1Bladder 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 c

or 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 lymphocyt0.00031, 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 lymphocytPHA 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 gassociated 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 breakwere 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 = 0.183

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 increasurinary 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 A

Mean urinary ALA was significantly hi

ALAD1,1 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) compa

5–9 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 gro

14.7). 
 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), abstin

collection, 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) lworkers 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-cortisolsignificantly 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-coumarmales, but not in females. Covariates retexcretion. Significant association in oppurinary 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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