# 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 reasonabl y may be expected to endanger public health or

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

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

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

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

materials, etc); and (5) to peri odically 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 inform ation pertinent to Pb NAAQS de velopment 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/m 3 

# (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 si nce 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 L ead 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 sin ce the literature asse ssed in the 1986 Lead

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

information useful in evaluating health and enviro nmental effects of ambien t air lead exposures.

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

distribution, measurement, and c oncentrations of lead in the environment; multimedia lead

exposure (via air, food, water, et c.) and biokinetic modeling of c ontributions of such exposures

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

as key indices of lead exposure).; characterization of l ead health effects and associated exposureresponse relationships; and delineation of environmen tal (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 receiv ed were taken into account in making

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

2006) which was released for further public co mment 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 commen ts and CASAC advice received on these latter

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

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

issued to meet an October 1, 2006 court-ordered d eadline. Evaluations c ontained 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, ul timately, promulgation of decisions on potential

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

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

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

staff, together with experts from academia, contri buted to writing of docum ent 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 valuab le contributions provided by authors, contributors, and

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

constructive comments provided by public comment ers 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 produc ts 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, AN D 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 (ENVIRONMENTA L 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 Scient ific Advisory Committee (CASAC)......................................... xix

Abbreviations and Acronyms ..................................................................................................... . xxi

AX6. CHAPTER 6 ANNEX (EPIDEMI OLOGIC 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 St udies of Neurocognitive Ability in

Children............................................................................................................ AX6-3

AX6-2.2 Meta- and Pooled-Analyses of Neur ocognitive Ability in Children ............... AX6-9

AX6-2.3 Cross-Sectional Studies of Neur ocognitive 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, Learni ng, and Visual-spatial Skills............. AX6-17

AX6-2.6 Effects of Lead on Disturban ces in Behavior, Mood, and Social

Conduct in Children....................................................................................... AX6-19

AX6-2.7 Effects of Lead on Sensor y Acuities in Children........................................... AX6-23

AX6-2.8 Effects of Lead on Neuromot or 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-relate d Deficits in Children......................................... AX6-27

AX6-3.1 Neurobehavioral Effects A ssociated with Environmental

Lead Exposure in Adults................................................................................ AX6-30

AX6-3.2 Symptoms Associated with Occupa tional Lead Exposure in Adults............. AX6-33

AX6-3.3 Neurobehavioral Effects Asso ciated with Occupational Lead

Exposure in Adults......................................................................................... AX6-36

AX6-3.4 Meta-analyses of Neurobehavi oral 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, Autonomi c 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 Associat ed 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 Pr essure and Hypertension ................................. AX6-130

AX6-5.2 Effects of Lead on Card iovascular Morbidity ............................................. AX6-159

AX6-5.3 Effects of Lead on Card iovascular 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 Reproduc tion: Time to Pregnancy ..................... AX6-178

AX6-6.4 Lead Exposure and Male Reproduc tion: 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 Ca ncer 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 Biochemi cal Effects in Children ................................... AX6-221

AX6-9.2 Effects of Lead on Bioche mical 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 Hematopoi etic 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 Endoc rine 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 Ga strointestinal 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 H ealth in Children and Adults........................... AX6-258

# II-xi Authors, Contributors, and Reviewers

CHAPTER 4 ANNEX (TOXICOKINETIC S, 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 Ther apeutic 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 Cor poration, 8191 Cedar Street, Akron, NY 14001

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

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

Dr. John Pierce Wise, Sr.—Maine Center fo r 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 Comparativ e and Environmental Toxicology, College of

Veterinary Medicine, Cornel l 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—Nationa l Center for Environmental Assessment (B243-01),

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

Dr. Michael Davis—Nationa l 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 Environm ental Medicine, University of Rochester,

575 Elmwood Avenue, Rochester, NY 14642

Dr. Theodore I. Lidsky—New York State Inst itute 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 En vironmental 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 Pla nning 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 (EPIDEMIOLOGICA L 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, Fa rley 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 Resear ch 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, Ro om 1614, New York, NY 10032

Dr. Vic Hasselblad—Duke University Medical Center, Durham, NC 27713

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

of Public Health, Cuernavaca, Morelos, Mexico

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

& Stanley S Scott Cancer Center, 1600 Cana l 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, Ne w 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 Preventi on, Pesticides and Toxic Substances,

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

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

Protection Agency, Research Triangle Park, NC 27711

Dr. Zachary Pekar—Office of Air Quality Pla nning 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 (ENVIRONME NTAL 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., 190 0 Minnesota Court, Suite 130, Mississauga,

Ontario, L5N 3C9 Canada

Dr. James Kaste—Department of Earth Scienc es, Dartmouth College, 352 Main Street,

Hanover, NH 03755

Dr. John Drexler—Department of Geologica l Sciences, University of Colorado,

1216 Gillespie Drive, Boulder, CO 80305

Dr. Chris Johnson—Department of Civil and Envir onmental 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 & Associ ates, 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 Environmenta l Health Sciences, 109 South Observatory,

University of Michigan, Ann Arbor, MI 48109

Dr. Judith Weis—Department of Biol ogy, 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 Exposur e Laboratory (D205-05), U.S. Environmental

Protection Agency, Research Triangle Park, NC 27711

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

Protection Agency, Research Triangle Park, NC 27711

Ms. Gail Lacey—Office of Air Quality Planning a nd 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 Cent er 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)—Nati onal Center for Environmental Assessment

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

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

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

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

U.S. Environmental Protection Agency, Re search 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—Nationa l 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 Sp ecialist, National Center for Environmental

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

27711 (Retired)

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

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

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

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

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

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

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

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

Document Production Staff

Ms. Carolyn T. Perry—Task Order Manager, Com puter Sciences Corpor ation, 2803 Slater Road,

Suite 220, Morrisville, NC 27560

Mr. John A. Bennett—Technical Information Sp ecialist, Library Asso ciates of Maryland,

11820 Parklawn Drive, Suite 400, Rockville, MD 20852

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

Suite 1450, McLean, VA 22102

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

11820 Parklawn Drive, Suite 400, Rockville, MD 20852

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

Suite 220, Morrisville, NC 27560

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

Mill Road, Suite 201, Raleigh, NC 27607

Mr. Carlton Witherspoon—Graphic Artist, Comput er 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 Advi sory Committee (CASAC)

Chair

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

Albuquerque, NM

Members

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

Research and Health Policy Studies, Tuft s 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, Departme nt of Medicine, National Jewish Medical and

Research Center, Denver, CO

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

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

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

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

College, Hanover, NH

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

Western Ontario (Canada), Chapel Hill, NC

Mr. Sean Hays—President, Summ it Toxicology, Allenspark, CO

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

Director of the Cincinnati Ch ildren’s Environmental Health Ce nter at Cincinnati Children’s

Hospital Medical Center and the Univer sity of Cincinnati, Cincinnati, OH

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

Menlo Park, CA

# II-xx U.S. Environmental Protection Agency

Science Advisory Board (SAB) Staff Office

Clean Air Scientific Advi sory Committee (CASAC)

(cont’d)

Members

(cont’d)

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

Dr. Paul Mushak—Principal, PB A ssociates, 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 Di vision, 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 H ealth, Harvard University School of Public

Health, Boston, MA

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

Harvard Medical School, Boston, MA

Dr. Ian von Lindern—Senior Scientist, TerraG raphics Environmenta l Engineering, Inc.,

Moscow, ID

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

Institute, Reno, NV

SCIENCE ADVISORY BOARD STAFF

Mr. Fred Butterfield—CASAC Designated Fede ral Officer, 1200 Pennsyl vania Avenue, N.W.,

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

(Physical/Courier/FedEx Address: Fred A. Butterf ield, 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

α FGF 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 α 2

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 audito ry-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 ne urotrophic 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

45 

# Ca calcium-45 radionuclide

Ca-ATP calcium-dependent adenosine triphosphate

Ca-ATPase calcium-dependent adenosine triphosphatase

CaCO 3 

# calcium carbonate

CaEDTA calcium disodium ethyl enediaminetetraacetic acid

CAL calcitonin

CaM calmodulin

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

cAMP cyclic adenosinemonophosphate

CaNa 2 

# EDTA calcium disodium ethyl enediaminetetraacetic acid

CANTAB Cambridge Neuropsychologi cal 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-CV RSA 

# coefficient of component variance of respiratory sinus arrhythmia

Cd cadmium

109 

# Cd cadmium-109 radionuclide

CdU urinary cadmium

CEC cation exchange capacity

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

GFAP glial fibrillary acidic protein

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

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

CFU-GM blood granulocyte/macro phage 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

CV R-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 ad enosine-3',5'-monophosphate

DCV distribution of conduction velocities

DEAE diethylaminoet hyl (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 anod ic stripping voltammetry

dp/dt rate of left ventri cular 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

E 2 

# estradiol

EBE early biological effect

EBV Epstein-Barr virus

EC European Community

EC 50 

# effect concentration fo r 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-eth oxy-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 nitr ic 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

FEV 1 

# forced expiratory volume in one second

FGF fibroblast growth factor (e.g., β FGF, α FGF)

FI fixed interval (operant conditioning)

FIAM free ion activity model

FMLP N -formyl-L-methionyl-L-l eucyl-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 microelect rodes 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

gp91 phox 

# 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 lipopr otein (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

HNO 3 

# nitric acid

H 2 

# O 2 

# hydrogen peroxide

HOME Home Observation for Measurement of Environment

HOS TE human osteosarcoma cells

# II-xxx HPLC high-pressure liquid chromatography

H 3 

# PO 4 

# phosphoric acid

HPRT hypoxanthine phosphoribosyltransferase (gene)

HR heart rate

HSI habitat suitability indices

H 2 

# SO 4 

# 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 plas ma atomic emission spectroscopy

ICP-MS, ICPMS inductively coupl ed 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

LC 50 

# lethal concentration at which 50% of exposed animals die

LC 74 

# lethal concentration at which 74% of exposed animals die

LD 50 

# 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- N G 

# -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

LT 50 

# 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-dep endent 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- κ B nuclear transcription factor- κ B

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

NO 2 

# nitrogen dioxide

NO 3 

# 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

NO

x 

# 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

O 2 

# oxygen

ODVP offspring development

OH hydroxyl

7-OH-coumarin 7-hydroxy-coumarin

1,25-OH-D, 1,25-OH D 3 

# 1,25-dihydroxyvitamin D

24,25-OH-D 3 

# 24,25-dihydroxyvitamin D

25-OH-D 3 

# 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

203 

# Pb lead-203 radionuclide

204 

# Pb, 206 

# Pb, 207 

# Pb, 208 

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

# II-xxxv 210 

# Pb lead-210 radionuclide

Pb(Ac) 2 

# lead acetate

PbB blood lead concentration

PbCl 2 

# lead chloride

Pb(ClO 4 

# ) 2 

# lead chlorate

PBG-S porphobilinogen synthase

PBMC peripheral bl ood mononuclear cells

Pb(NO 3 

# ) 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., PGE 2 

# , PGF 2 

# ); 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 hor mone-related protein

PVC polyvinyl chloride

PWM pokeweed mitogen

PRWT progeny weight

QA/QC quality assura nce/quality control

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

r Pearson correlation coefficient

R 2 

# multiple correlation coefficient

r 2 

# correlation coefficient

226 

# Ra most stable isotope of radium

R/ALAD ratio of ALAD activity be fore and after reactivation

RAVLT Rey Auditory Verbal Learning Test

86 

# Rb 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

222 

# Rn 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 In stitute 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

SO 2 

# 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 Admini stration 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

232 

# Th 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., TXB 2 

# )

U uriniary

235 

# U, 238 

# U 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 thr ee components of matrix effects:

atomic number (Z), absorpti on (A), and fluorescence (F)

ZnNa 2 

# DTPA zinc disodium diet hylenetriaminepentaacetic acid

ZnNa 2 

# EDTA zinc disodium ethyl enediaminetetraacetic acid

ZPP zinc protoporphyrin

# AX6-1 

# AX6. CHAPTER 6 ANNEX

# AX6-2 

# ANNEX TABLES AX6-2

# AX6-3Table AX6-2.1. Prospective Longitudinal CohortStudies of Neurocognitive Ability in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesBellinger et al. (1992)U.S.148 subjects from the Boston Prospective Studywere re-evaluated at 10 yrs of age. The WISCRwas used to index intellectual status. Extensiveassessment of medicaland sociodemographiccovariates.Cord and serial postnatalblood Pb assessmentsCord blood Pb grouping <3,6-7, >10 μg/dLBlood Pb at 2 yrs 6.5(SD 4.9) μg/dLIncrease of 10 μg/dL in blood Pb level at age two wasassociated with a decrement of ~6 IQ points. Relationshipwas stronger for verbal compared to performance IQ.Prenatal exposure to Pb as indexed by cord blood Pb levelswas unrelated to psychometric intelligence.Dietrich et al.(1991, 1992, 1993a);Ris et al. (2004)U.S.253-260 children followed since birth in theCincinnati Pb Study were re-evaluated at 4, 5, and6.5 yrs of age. At 4 and 5 yrs, the KABC was usedto index intellectual status. At 6.5 yrs, the WISCRwas administered. At 15-17 yrs of age, 195Cincinnati Pb Study subjects were re-evaluated byuse of a comprehensive neuropsychological batterythat yielded a “Learning/IQ” factor in a principalcomponents analysis. Extensive assessment ofmedical and sociodemographic covariates.Prenatal (maternal) and serialpostnatal blood PbassessmentsPrenatal blood Pb 8.3(SD 3.7) μg/dLBlood Pb at 2 yrs 17.4(SD 8.8) μg/dLFew statistically significant relationships between blood Pbindices and covariate-adjusted KABC scales at 4 and 5 yrsof age. One KABC subscale that assesses visual-spatialskills was associated with late postnatal blood Pb levelsfollowing covariate adjustment. After covariateadjustment, avg postnatal blood Pb level was significantlyassociated with WISCR performance IQ at 6.5 yrs. BloodPb concentrations >20 μg/dL were associated with deficitsin performance IQ on the order of 7 points compared withchildren with mean blood Pb concentrations <10 μg/dL.At 15-17 yrs, late childhood blood Pb levels weresignificantly associated with lower covariate-adjustedLearning/IQ factor scores.Canfield et al. (2003a)U.S.172 predominantly African-American, lowersocioeconomic status children in Rochester, NYfollowed since they were 5 to 7 mos were evaluatedat 3 and 5 yrs. An abbreviated form of theStanford-Binet Intelligence Scale-4 (SBIS-4) wasused to index intellectual status. Extensiveassessment of medicaland sociodemographiccovariates.Serial postnatal blood PbBlood Pb at 2 yrs9.7 μg/dLFollowing covariate adjustment, there was a significantinverse relationship between blood Pb indices and IQ at allages. Overall estimate indicated that an increase in avglifetime blood Pb concentration of 1 μg/dL was associatedwith a loss of 1⁄2 IQ point. Effects were stronger forsubjects whose blood Pb levels never exceeded 10 μg/dL.Semiparametric analysis indicated a decline in IQ of 7.4points for a lifetime avg blood Pb concentration up to10 μg/dL, while for levels between 10 and 30 μg/dL amore gradual decrease in IQ was estimated. Authorsconcluded that the most important aspect of their findingswas that effects below 10 μg/dL observed in previouscross-sectional studies havenow been confirmed by thisrigorous prospective study.

# AX6-4Table AX6-2.1 (cont’d). Prospective Longitudinal Cohort Studies of Neurocognitive Ability in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited States(cont’d)Bellinger andNeedleman (2003)U.S.Reanalysis of data from the Boston ProspectiveStudy focusing on 48 subjects at 10 yrs of agewhose blood Pb levels never exceeded 10 μg/dL.WISCR was used to index intellectual status. Seealso Bellinger et al. (1992)Serial postnatal blood PbBlood Pb at 2 yrs 6.5(SD 4.9) μg/dLIQ was inversely related to two-yr blood Pb levelsfollowing covariate adjustment. Blood Pb coefficient(!1.56) was greater than that derived from analysesincluding children with concentrations above 10 μg/dL(!0.58). Authors conclude that children’s IQ scores arereduced at Pb levels still prevalent in U.S.Chen et al. (2005)U.S.Repeat measure psychometric data on 780 childrenenrolled in Treatment of Pb-Exposed Children(TLC) clinical trial were analyzed to determine ifblood Pb concentrations at2 yrs of age constitute acritical period of exposure for expression of laterneurodevelopmental deficits. Data for placebo andactive drug groups were combined in theseanalyses, which spanned ~2 to 7 yrs of age.Measures of intellectual status included the BayleyMental Development Index (MDI) and full scale IQderived from age-appropriate Wechsler scales.Blood PbRange 20-44 μg/dLBaseline blood Pb 26(SD 26.5) μg/dL in both drugand placebo groupsBlood Pb at 7 yrs 8.0(SD 4.0) μg/dLAssociation between blood Pb and psychometricintelligence increased in strength as children became older,whereas the relation between baseline (2 yr) blood Pb andIQ attenuated. Peak blood Pb concentration thus does notfully account for the observed association in older childrenbetween their lower blood Pb concentrations and IQ. Theeffect of concurrent blood Pb on IQ may thusly be greaterthan currently believed. Authors conclude that these data(a) support the idea that Pb exposure continues to be toxicto children as they reach school age and (b) do not lendsupport to the interpretation that majority of the damage isdone by the time the child reaches 2 to 3 yrs of age.

# AX6-5Table AX6-2.1 (cont’d). Prospective Longitudinal Cohort Studies of Neurocognitive Ability in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEuropeWasserman et al. (1992,1994, 2003); Factor-Litvak et al. (1999)YugoslaviaBirth cohort of ~300-400 infants followed sincebirth residing in two towns in Kosovo, Yugoslavia,one group near a longstanding Pb smelter andbattery manufacturing facility and another in arelatively unexposed location 25 miles away.Intellectual status was monitored from 2 to10-12 yrs of age with the Bayley Scales of InfantDevelopment, McCarthy Scales of Children’sAbilities, and WISCIII. Extensive assessment ofmedical and sociodemographic covariates.Maternal prenatal, umbilicalcord, and serial postnatalblood PbMaternal blood Pb in exposedarea 19.9 (SD 7.7) μg/dL,unexposed area 5.6 (SD 2.0)μg/dLUmbilical cord blood Pb inexposed area 22.2 (SD 8.1)μg/dL, unexposed area 5.5(SD 3.3) μg/dLBlood Pb at 2 yrs inexposed area 35.4 μg/dL,unexposed area 8.5 μg/dLPostnatal blood Pb increment from 10 to 30 μg/dL at 2 yrsof age associated with covariate-adjusted decline of 2.5points in Bayley MDI. Maternal and cord blood Pb notconsistently associated withBayley outcomes. Higherprenatal and cord blood Pb concentrations associated withlower McCarthy General Cognitive Index (GCI) scores at4 yrs. Scores on the Perceptual-Performance subscaleparticularly affected. After covariate-adjustment, childrenof mothers with prenatal blood Pb levels >20 μg/dL scoreda full standard deviation below children in the lowestexposure group (<5 μg/dL prenatal blood Pb). Postnatalblood Pb also associated with poorer performance.Increase in blood Pb level from 10 to 25 μg/dL associatedwith a reduction of 3.8 points in GCI after covariateadjustment. Effects even more pronounced on thePerceptual-Performance subscale. At 7 yrs, significantinverse associations betweenlifetime avg blood Pb andWISCIII IQ were observed, including consistently strongerassociations with Performance IQ and later blood Pbmeasures. Adjusted intellectual loss associated with anincrease in lifetime avg blood Pb from 10 to 30 μg/dL wasover 4 points in WISCIII Full-Scale and Performance IQ.At 10-12 yrs, subjects wereagain assessed with theWISCIII. Following covariate-adjustment, avg lifetimeblood Pb was associated with all components of theWISCIII, with effect sizes similar to those observed at7 yrs. In most instances, bone Pb-IQ relationships werestronger than those for blood Pb among subjects residingnear the Pb smelter.

# AX6-6Table AX6-2.1 (cont’d). Prospective Longitudinal Cohort Studies of Neurocognitive Ability in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationLatin AmericaSchnaas et al. (2000)Mexico112 children followed since birth with completepsychometric data from the Mexico CityProspective Study were examined. Intellectualstatus indexed by General Cognitive Index (GCI)from McCarthy Scales of Children’s Abilities(MSCA). Purpose of the study was to determine ifmagnitude of the effect ofpostnatal blood Pb levelson cognition varies with time between blood Pband cognitive assessments.Serial postnatal blood PbAvg blood Pb24-36 mos 9.7(range 3-48) μg/dLA number of significant interactions observed betweenblood Pb levels and age of assessment. Greatest effectobserved at 48 mos, when a 5.8 deficit in adjusted GCIscores was observed for each natural log increment inblood Pb. Authors concluded that four to five yrs of ageappears to be a critical period for manifestation of earlierpostnatal blood Pb level effects on cognition.Schnaas et al. (2006)MexicoFrom the Mexico City Prospective Study, 150children followed since birth with complete datafor all covariates were examined. Intelligence fromage 6 to 10 yrs was assessed using the WISC-R.Blood Pb measurements from various time points,starting from maternal blood Pb levels during the2nd trimester to postnatal Pblevels at age 10 yrs.Serial prenatal (maternal) andpostnatal blood PbGeometric mean blood PbDuring pregnancy 8.0(range 1-33) μg/dLAge 1-5 yrs 9.8(range 2.8-36.4) μg/dLAge 6-10 yrs 6.2(range 2.2-18.6) μg/dLAmong all the Pb variables atthe various time points, onlylog-transformed blood Pb levels during the 3rd trimesterwere significantly associated with full scale IQ at ages 6 to10 yrs, after adjusting forpotential confounders. A 3.44point deficit in full scale IQwas observed for each naturallog increment in blood Pb.The authors note that, given the modest sample size andrelatively low power of this study, they do not claim thatPb exposure from other developmental period has no effecton child IQ.Gomaa et al. (2002)Mexico197 two yr-old children residing in Mexico Cityfollowed since birth. Bayley Scales of InfantDevelopment Mental Development Index (MDI)used to index intellectual status. Extensiveassessment of medicaland sociodemographiccovariates.Umbilical cord and serialpostnatal blood PbUmbilical cord bloodPb 6.7 (SD 3.4) μg/dLBlood Pb at 2 yrs 8.4(SD 4.6) μg/dLMaternal tibial and patellarbone PbPatellar (trabecular)bone Pb 17.9 (SD 15.2) μg/gUmbilical cord blood Pb and patellar (trabecular) bone Pbsignificantly associated withlower Bayley MDI scores.Maternal trabecular bone Pb levels predicted poorersensorimotor functioning at two yrs independent ofconcentration Pb measured in cord blood. Increase in cordblood Pb level from 5 to 10 μg/dL was associated with a3.1 point decrement in adjusted MDI scores. In relation tolowest quartile of trabecular bone Pb, the 2nd, 3rd, and 4thquartiles were associated with 5.4, 7.2, and 6.5 decrementin MDI following covariate adjustment. Authorsconcluded that higher maternal trabecular bone Pb levelsconstitute an independent risk factor for impaired mentaldevelopment in infancy, likelydue to the mobilization ofmaternal bone Pb stores over gestation.

# AX6-7Table AX6-2.1 (cont’d). Prospective Longitudinal Cohort Studies of Neurocognitive Ability in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationLatin America (cont’d)Téllez-Rojo et al.(2006)Mexico294 one and two yr-olds residing in Mexico Cityfollowed since birth. The Bayley Scales of InfantDevelopment-II (MDI and PDI) were used to indexdevelopmental status. There was extensiveassessment of medicaland sociodemographiccovariates.Umbilical cord blood Pb andpostnatal blood Pb at 12 and24 mosUmbilical cord blood Pb 4.8(SD 3.0) μg/dLBlood Pb at 1 yr 4.27 (SD2.1) μg/dLBlood Pb at 2 yrs 4.3 (SD2.2) μg/dLBlood Pb at 12 mos was not associated with MDI at eitherage. Blood Pb at 24 mos was significantly associated with24 mo MDI. An increase of one logarithmic unit in 24 moblood Pb level was associatedwith a reduction of ~5 pointsin MDI. Findings for PDI were similar. In comparison toa supplemental subsample of 90subjects with blood Pblevels >10 μg/dL, the coefficient for blood Pb wassignificantly larger for infants never exceeding that levelof internal dose. A steeper inverse slope was observedover the blood Pb range up to 5 μg/dL (!1.71 points per1 μg/dL increase in blood Pb, p = 0.01) compared to therange between 5 and 10 μg/dL (!0.94 points, p = 0.12);however, these slopes were not significantly different(p = 0.34). In conclusion, a major finding of thisprospective study was that a significant inverserelationship between blood Pb concentration andneurodevelopment was observed among children whoseblood Pb levels did not exceed 10 μg/dL at any age.AustraliaBaghurst et al. (1992);McMichael et al.(1994); Tong et al.(1996)Australia400-500 subjects residing inand near Port Pirie,Australia and followed since birth were re-evaluatedat 7 to 8 and 11-13 yrs of age. WISCR was used toindex intellectual statusat both ages. Extensiveassessment of medicaland sociodemographiccovariates.Maternal prenatal, umbilicalcord and serial postnatal bloodPbAntenatal avg blood Pb10.1 (SD 3.9) μg/dLUmbilical cord blood Pb9.4 (SD 3.9) μg/dLBlood Pb at 2 yrsgeometric mean 21.3(SD 1.2) μg/dLDeciduous central incisorwhole tooth PbTooth Pb geometric 8.8(SD 1.9) μg/gSignificant decrements in covariate-adjusted full scale IQwere observed in relationship topostnatal blood Pb levelsat both ages. At 7 to 8 yrs of age a loss of 5.3 points wasassociated with an increase in blood Pb from 10 to30 μg/dL. At 11-13 yrs, mean full scale IQ declined by 3.0points for an increase in lifetime avg blood Pbconcentrations from 10 to 20 μg/dL. Pb levels in centralupper incisors were also associated with lower 7-8 yr IQfollowing covariate adjustment. Adjusted estimateddecline in IQ across the range of tooth Pb from 3 to22 ppm was 5.1 points.

# AX6-8Table AX6-2.1 (cont’d). Prospective Longitudinal Cohort Studies of Neurocognitive Ability in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationAustralia(cont’d)Cooney et al. (1991)Australia175 subjects from the Sydney,Australia ProspectiveStudy were assessed at 7 yrs of age. The WISCRwas used to index intellectual status. Extensiveassessment of medicaland sociodemographiccharacteristics.Maternal and cord blood PbCord 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 were not associated with anymeasure of psychometric intelligence. Authors concludethat the evidence from their study indicates that ifdevelopmental deficits do occur at blood Pb levels<25 μg/dL, the effect size is likely to be small (<5%).Sydney results are difficult to interpret from the statisticalpresentation in their report. Itis not clear which covariateswere entered into regression analyses nor is the empiricalor substantive basis for their conclusion.AsiaShen et al. (1998)ChinaPregnant women and newborns in Shanghai, Chinarecruited from health care facilities in the communityon the basis of cord blood Pb concentrationpercentiles (30th and 70th) yielding a total N of 173subjects. The Bayley Scales of Infant DevelopmentMental Development Index (MDI) and PsychomotorDevelopment Index (PDI) were used to indexsensorimotor/intellectual statusat 3, 6, and 12 mos.Extensive assessment of medical andsociodemographic characteristics.Cord blood Pb“High group” 13.4 (SD 2.0)μg/dL“Low group” 5.3 (SD 1.4)μg/dLBlood Pb at 1 yr“High group” 14.9 (SD 8.7)μg/dL“Low group” 14.4 (SD 7.7)μg/dLAt all ages the Bayley MDI was associated with cordblood Pb groupings following adjustment for covariates.Postnatal blood Pb unrelated to any Bayley measures.Differences in MDI betweenprenatal blood Pb exposuregroupings generally in accordwith similar investigationsin Boston, Cincinnati, and Cleveland. Authors concludethat the adverse effects of prenatal Pb exposure are readilydiscernible and stable over the first yr of life.

# AX6-9Table AX6-2.2. Meta- and Pooled-Analysesof Neurocognitive Ability in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationLanphear et al. (2005) Pooled analysisof seven international prospectivestudies involving 1,333 school-age children.Primary outcome measure was full-scale IQ asassessed by age-appropriate Wechsler scale.Measures of exposure were concurrent, peak, avglifetime and “early” blood Pb(i.e. mean blood Pbfrom 6-24 mos). Cord blood Pb was alsoinvestigated for those studies that collected thesesamples at birth. Multivariate regression modelswere developed adjusting for site as well as 10common covariates. BloodPb measure with thelargest adjusted R2was nominated a priori as thepreferred index for relating Pb exposure to IQ insubsequent analyses. Results evaluated by applyinga random-effects model.Umbilical cord blood PbSerial postnatal blood PbLifetime avg blood Pb 12.4(range 4.1-34.8) μg/dLConcurrent blood Pb level exhibited the strongestrelationship with IQ, although results of regression analysesfor all blood Pb variables were similar. Steepest declines inIQ were at blood Pb concentrations below 10 μg/dL. Forthe entire pooled data set, a decline of 6.2 IQ points (95%CI: 3.8, 8.6) was estimatedfor an increment in blood Pbfrom 1 to 10 μg/dL.Needleman andGatsonis (1990)Meta analysis of 12 studies chosen on the basis ofquality—covariate assessment and application ofmultiple regression techniques. Studies weighted onbasis of sample size. Studies divided according totissue analyzed (blood or teeth). Joint p-values andavg effect sizes calculated using two differentmethods.Blood PbTooth PbJoint p-values for blood Pb studies were <0.0001 for bothmethods, whereas joint p-values of <0.0006 and <0.004were obtained for teeth. Partial correlations ranged from–0.27 to –0.0003. No single study was responsible for thesignificance of the final findings. Authors concluded thatthe hypothesis that Pb lowers children’s IQ at relatively lowdose is strongly supported by results of this quantitativereview.Schwartz (1994) Meta analysis of7 recent studies relating blood Pb toIQ were reviewed, three longitudinal and four crosssectional. Measure of effect was estimated decreasein IQ for an increase in blood Pb from 10 to 20μg/dL. Studies were weighted by the inverse of thevariances using randomBlood Pb Estimated decrease in IQper blood Pb increment from 10 to20 μg/dL was –2.6 points (SE 0.41). Results were notdetermined by any individual study. Effect estimates weresimilar for longitudinal and cross-sectional studies.For studies with mean blood Pblevels <15 μg/dL, estimatedeffect sizes were larger. When the study with the lowestexposures was examined alone using nonparametricsmoothing (Boston), no evidence of a threshold wasobserved down to a blood Pb level of 1 μg/dL. Authorconcludes that these data provide further evidence of Pbeffects on cognition at levels below 10 μg/dL.

# AX6-10Table AX6-2.2 (cont’d). Meta- and Pooled-Analyses of Neurocognitive Ability in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationPocock et al. (1994) Meta-analysis offive prospective and fourteen cross-sectional studies (including tooth and blood tissues)were included. The fixed effect method ofThompson and Pocock (1992) was employed.Only blood Pb at or near two yrs of age wasconsidered for the prospective studies.Blood PbTooth PbOverall conclusion was that a doubling of blood Pb levelsfrom 10 to 20 μg/dL, or tooth Pb from 5 to 10 μg/g wasassociated with an avg estimated deficit in IQ of ~1-2points. Authors caution interpretation of these results andPb literature in general, citing questions aboutrepresentativeness of the samples, residual confounding,selection bias, and reverse causality.

# AX6-11Table AX6-2.3. Cross-Sectional Studiesof Neurocognitive Ability in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited StatesLanphear et al. (2000)U.S.4,853 U.S. children ages six to 16 yrs enrolled inNHANES-III. Two subtests of the WISC-R (BlockDesign and Digit Span) used to assess intellectualstatus. Medical and sociodemographic covariates wereassessedBlood Pb at time of testingGeometric blood Pb 1.9(SE 0.1) μg/dL2.1% with blood Pb∃10 μg/dLMultivariate analyses revealed a significant associationbetween blood Pb levels and both WISC-R subtests.Associations remained statistically significant whenanalyses were restricted to children with blood Pb levelsbelow 10 μg/dL. Authors caution that lack of control forparental intelligence and variables like the HOME scaleshould temper any conclusions regarding observed effects.Emory et al. (2003)U.S.77 healthy, lower-risk African-American infants age 7mos. The Fagan Test of Infant Intelligence (FTII) wasadministered to assess intellectual status. Birth weightand gestational age examined as potentialcovariates/confounders.Maternal blood PbBlood Pb 0.72 (SD 0.86)μg/dLInfants scoring in the upper 5th to 15th percentiles for theFTII had mother with significantly lower maternal bloodPb levels when compared to those scoring in the lower5th or 15th percentile. Findings of this study should beconsidered preliminary due tosmall sample size and lackof covariate assessment or control.Chiodo et al. (2004)U.S.237 African-American inner-city children assessed at7.5 yrs of age. Cohort was derived from a larger studyof the effects of prenatal alcohol exposure on childdevelopment. 83% of children in Pb study had little orno gestational exposure to alcohol. WISC-III wasadministered to assess intellectual status. Medical andsociodemographic covariates were assessed.Blood Pb at time of testingBlood Pb 5.4 (SD 3.3)μg/dLFollowing covariate adjustment statistically significantrelationships between blood Pband full-scale, verbal andperformance IQ were observed.Significant effects of Pbon full-scale and performance IQ was evident at blood Pbconcentrations below 7.5 μg/dL.EuropeWalkowiak et al.(1998)Germany384 six-yr-old children in three German cities. Twosubtests of the WISC (Vocabulary and Block Design)used to estimate IQ. Both subscales were combined toform a “WISC Index.” Medical and sociodemographiccovariate covariates were assessed.Blood Pb at time of testingBlood Pb 4.2 μg/dL95th percentile 8.9 μg/dLFollowing covariate-adjustment, WISC Vocabulary wassignificantly associated withblood Pb but combined WISCindex was borderline. Authors conclude that findingsroughly correspond with those of other studies that findeffects below 10 μg/dL but caution that potentiallyimportant covariates such as HOME scores were notcontrolled.Prpic-Majic et al.(2000)Croatia275 3rd and 4th grade students in Zagreb, Croatia.WISC-R was administered to assess intellectual status.Covariate factors limited to parents’ educational statusand gender of child.Blood Pb at time of testingBlood Pb 7.1 (SD 1.8)μg/dLFollowing covariate adjustment,no statistically significantassociations were observed for Pb or other indicators oftoxicity (ALAD, EP) on WISC-R. Authors argue thatstudy had sufficient power and that the “no-effect”threshold for Pb must be in the upper part or above thestudy’s range of exposures.

# AX6-12Table AX6-2.3 (cont’d). Cross-Sectional Studies of Neurocognitive Ability in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationLatin AmericaKordas et al. (2004,2006)Mexico602 1st grade children in public schools in a highlyindustrialized area of northern Mexico. Premise ofstudy was that effects of Pb could be explained bycorrelated nutritional factors such as iron status,anemia, and growth. Peabody Picture VocabularyTest-Revised (PPVT-R),Cognitive Abilities Test(CAT), and an abbreviated form of the WISC-R wereadministered to assess intellectual status. Medical andsociodemographic covariates were assessed.Blood Pb at time of testingBlood Pb 11.5(SD 6.1) μg/dLFollowing covariate adjustment blood Pb levels weresignificantly associated with poorer performance on thePPVT-R, WISC-R Coding, and Number and LetterSequencing, a Math Achievement Test, and the SternbergMemory Test. Authors concluded that Pb’s associationwith iron deficiency anemiaor growth retardation couldnot explain relationship between Pb and cognitiveperformance. Non-linear analyses of selectedneurocognitive outcomes revealed that dose-responsecurves were steeper at lower than at higher blood Pblevels. Moreover, the slopesappeared negative at bloodPb levels below 10 μg/dL, above which they tend toplateau. Effects of Pb on neurocognitive attainmentappeared to be greatestamong the least advantagedmembers of the cohort.Counter et al. (1998)Ecuador77 chronically Pb-exposed children living inEcuadorian villages where Pb is used extensively incommercial ceramics production. Ravens ColoredProgressive Matrices (RCPM) used to indexintellectual status. Only half of the sample wasassessed. No assessment of medical orsociodemographic covariates.Blood Pb at time of testingBlood Pb 47.4 (SD 22)μg/dLSimple regression analysis revealed a correlation betweenblood Pb and RCPM of only borderline significance.Results difficult to interpret because there was no attemptto age-adjust. When analysis restricted to children 9 to11 yrs of age, a highly significant negative correlation wasobtained. Study has little relevance to the question of Pbhazards in the U.S. because of unusually high levels ofexposure.AsiaRabinowitz et al.(1991)Taiwan443 children in grades one to three in Taipei City andthree schools near Pb smelters. Ravens ColoredProgressive Matrices (RCPM) used to indexintellectual status. Medical and sociodemographiccovariate factorswere assessed.Dentin tooth PbTaipei City 4.3 (SD 3.7)μg/gSmelter areas 6.3 (SD 3.3)μg/gScores on the RCPM were negatively correlated with toothPb concentrations. In multivariate analyses, parentaleducation was the most important predictor of RCPMscores, but tooth Pb concentrations still significantlypredicted lower scores in females residing in low-incomefamilies.Bellinger et al. (2005)India74 four to fourteen yr-old children residing in Chennai,India were enrolled in the study, 31 of which wereassessed with the Binet-Kamath Intelligence test. Datawere collected on sociodemographic features ofsubjects’ families.Blood Pb at time of testingBlood Pb 11.1 (SD 5.6)μg/dLCovariate-adjusted blood Pbcoefficient was negative butnonsignificant, perhaps due tosmall sample size andhighly variable performance of subjects with the leastelevated blood Pb concentrations.

# AX6-13Table AX6-2.3 (cont’d). Cross-Sectional Studies of Neurocognitive Ability in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationMiddle EastAl-Saleh et al. (2001)Saudi Arabia533 Riyadh, Saudi Arabian girls (6-12 yrs of age) wereadministered a variety of standardized tests includingthe TONI, and the Beery VMI. Extensive data werecollected on potentially confounding variablesincluding sociodemographic variables, earlydevelopmental milestones and child health status.Blood Pb at time of testingBlood Pb 8.1 (SD 3.5)μg/dLBlood Pb levels had no impact onTONI scores but this testhas limited evidence of validity in this population.Significant negative associations were noted betweenblood Pb levels and the Beery VMI suggesting anassociation between impairment in visual-spatial skills inSaudi children with blood Pb levels in the range of 2.3 to27.4 μg/dL.

# AX6-14Table AX6-2.4. Effects of Lead onAcademic Achievement in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited StatesLanphear et al. (2000)U.S.Design: Cross-sectional.4,853 U.S. children agessix to 16 yrs enrolled in NHANES-III. Subjectswere administered the Arithmetic and Readingsubtests of the WideRange Achievement Test-Revised (WRATR). Anumber of medical andsociodemographic covariates were assessed andentered into multivariable models.Blood Pb at time of testingGeometric blood Pb 1.9(SE 0.1) μg/dL2.1% with blood Pb∃10 μg/dLFollowing covariate adjustment, a statistically significantrelationship between blood Pb and WRATR performancewas found. A 0.70 point decrement in Arithmetic scoresand a 1 point decrement in Reading scores for each1 μg/dL increase in blood Pb concentration was observed.Statistically significant inverse relationships between bloodPb levels and performance for both Reading andArithmetic subtests were found for children with blood Pbconcentrations <5 μg/dL. Authors concluded that resultsof these analyses suggest thatdeficits in academic skillsare associated with blood Pb concentrations lower than5 μg/dL. They cautioned,however, that two covariatesthat have been shown to be important in other Pb studies(i.e., parental IQ and HOME scores) were notavailable.This may have over or under estimated deficits inacademic skills related to Pb. They further caution that, aswith all cross-sectional studies utilizing blood Pb as theindex of dose it is not clearwhether deficits in academicskills were due to Pb exposure that occurred sometimeduring early childhood or due to concurrent exposure.Nevertheless, concurrent bloodPb levels reflect bothongoing exposure and preexisting body burden.Needleman et al. (1990)U.S.Design: Prospective cohort.Re-examination of theChelsea and Somerville cohort recruited in the1970’s (Needleman et al.,1979). 132 adolescentswere recalled. Large battery of tests wasadministered to examine neurobehavioral deficitsand academic achievement inhigh school and shortlyfollowing graduation. Extensive assessment ofmedical and sociodemographic covariates.Tooth (dentin) PbTooth Pb median 8.2 μg/gSubjects with dentin Pb levels>20 ppm were at higher riskof dropping out of high school (adjusted OR = 5.8 [95%CI: 1.4, 40.7]) and of having a reading disability (adjustedOR = 5.8 [95% CI: 1.7, 19.7]). Higher dentin Pb levelswere also significantly associated with lower classstanding, increased absenteeism, and lower vocabulary andgrammatical reasoning scores on the NeurobehavioralEvaluation System (NES). Authors conclude that undueexposure to Pb has enduring and important effects onobjective parameters of success in life.

# AX6-15Table AX6-2.4 (cont’d). Effects of Leadon Academic Achievement in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited States(cont’d)Bellinger et al. (1992)U.S.Design: Prospective longitudinal. 148 children inthe Boston Pb Study cohort were examined at 10 yrsof age. The short-form of the Kaufman Test ofEducational Achievement (KTEA) was used to assessacademic achievement. Primary outcome was theBattery Composite Score. Extensive assessment ofmedical and sociodemographic covariates.Cord and serial postnatalblood Pb assessments.Cord blood Pb grouping <3,6-7, >10 μg/dLBlood Pb at 2 yrs 6.5(SD 4.9) μg/dLAfter covariate-adjustment, blood Pb levels at 24 mos weresignificantly predictive of lower academic achievement(∃=!0.51, SE 0.20). Battery Composite Scores declined by8.9 points for each 10 μg/dL increase in blood Pb. Thisassociation was significant after adjustment for IQ. Authorsconclude that Pb-sensitive neuropsychological processing andlearning factors not reflected in measures of global intelligencemay contribute to deficits in academic achievement.Leviton et al. (1993)U.S.Design: Prospective cohort.Teachers of ~2000 eightyr-old children born in 1 hospital in Boston between1979 and 1980 filled out the Boston TeachersQuestionnaire (BTQ) to assess academicperformance and behavior. Limited information isprovided on the assessment of covariate factors but anumber were considered and controlled for inmultivariable analyses.Cord blood PbCord blood Pb 6.8 μg/dLTooth (dentin) PbTooth Pb 2.8 μg/gFollowing adjustment for potential confounding variables,elevated dentin Pb concentrations were associated withstatistically significant reading and spelling difficulties asassessed by the BTQ among girls in the sample. Authorsconclude that their findings support the case for Pb-associatedlearning problems at levels that were prevalent at that time inthe general population. However, authors add that the inabilityto assess child-rearing quality inthis study conducted by maillimits the inferences that can be drawn.AustraliaFergusson et al. (1993,1997); Fergusson andHorwood (1993)New ZealandDesign: Prospective cohort.Academic performancewas examined in a birth cohort of 1200 New Zealandchildren enrolled in the Christchurch Health andDevelopment Study. Measures of academicperformance at 12-13 yrsincluded the Brut ReadingTest, Progressive Achievement Test, Test ofScholastic Abilities, and teacher ratings of classroomperformance in the areas of reading, writing, andmathematics. The growth of word recognition skillsfrom 8 to 12 yrs was also examined using growthcurve modeling methods. Academic achievement inrelationship to Pb was re-examined in this cohort at18 yrs. Measures of academic achievement includedthe Burt Reading Test, number of yrs of secondaryeducation, number of certificates passed (based onnational examinations), and leaving school withoutformal qualifications(failing to graduate). Extensiveassessment of medical and social covariates.Tooth (dentin) PbTooth Pb 6.2 (SD 6.2) μg/gFollowing covariate adjustment, dentin Pb levels weresignificantly associated with virtually every formal index ofacademic skills and teacher ratings of classroom performancein 12-13 yr-olds. After adjustment for covariates, tooth Pblevels greater than 8 μg/g were associated with significantlyslow growth in word recognitionabilities with no evidence ofcatch up. At 18 yrs, tooth Pb levels were significantlyassociated with lower reading test scores, having a readinglevel of less than 12 yrs, failing to complete three yrs of highschool, leaving school withoutqualifications, and meannumber of School Certificates passed. Authors conclude thatearly exposure to Pb is independently associated withdetectable and enduring deficits in children’s academicabilities. They further conclude that their findings areparticularly significant in that they confirm the findings ofNeedleman (1990), albeit in a cohort with lower levels ofexposure to environmental Pb.

# AX6-16Table AX6-2.4 (cont’d). Effects of Leadon Academic Achievement in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationAsiaWang et al. (2002a)TaiwanDesign: Cross-sectional. 934 3rd graders living inan urban industrial area of Taiwan. Outcomevariables were grades for Chinese (reading, writing),mathematics, history, and natural science. Gradeswere converted into individual class rankings toavoid teacher bias. Limited data on medical andsociodemographic covariates.Blood Pb at time ofevaluationBlood Pb 5.5 (SD 1.9)μg/dLFollowing covariate adjustment, blood Pb was significantlyassociated with lower class ranking in all academicsubjects. Major shortcomingof this study is lack ofcontrol for potentially important covariates such asparental IQ. However, the relatively low levels ofexposure in this sample and strength and consistency of thereported relationships suggest that Pb may be playing somerole in lowering academic performance.Rabinowitz et al. (1992)TaiwanDesign: Cross-sectional. Teachers of 493 childrenin grades 1-3 filled out the Boston TeachersQuestionnaire (BTQ) to assess academicperformance and behavior. Sociodemographic andmedical covariate factors were assessed.Tooth (dentin) PbTooth Pb 4.6 (SD 3.5) μg/gPrior to adjustment for covariates, girls with higherexposures to Pb evinced a borderline significant trend forreading difficulties while byes displayed significantlyincreased difficulties with respect to activity levels andtask attentiveness. In logistic regression models thatinclude significant covariatefactors, the tooth Pb termsfailed to achieve statistical significance. Authors concludethat Pb levels found in the teeth of children in thisTaiwanese sample are not associated with learningproblems as assessed by the BTQ.Middle EastAl Saleh et al. (2001)Saudi ArabiaClass rank, as assessed by the teacher, was examinedin conjunction with blood Pb levels in 533 Riyadh,Saudi Arabian girls (6-12 yrs of age). Extensive datawere collected on potentially confounding variablesincluding sociodemographic variables, earlydevelopmental milestones and child health status.Blood Pb at time of testingBlood Pb 8.1 (SD 3.5)μg/dLA significant inverse relationship between blood Pb levelsand rank percentile scores was observed after adjusting fora number of demographic and socioeconomic variables.When multiple regression models were fitted to a subset ofstudents with blood Pb levels below 10 μg/dL, class rankpercentile continued to show a statistically significantassociation with blood Pb levels.

# AX6-17Table AX6-2.5. Effects of Lead on Specific Cognitive Abilitiesin Children — Attention/Executive Functions, Learning, andVisual-spatial SkillsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesBellinger et al. (1994a)U.S.Design: Prospective cohort. 79 subjects from theoriginal Chelsea and Somerville, MA Pb study werere-evaluated at 19-20 yrs of age with the Mirskybattery of attentional measures. Extensive measuresof medical and sociodemographic covariates.Tooth (dentin) PbTooth Pb 13.7 (SD 11.2)μg/gKXRF Bone PbTibial bone Pb(range <1 - >10) μg/gPatellar bone Pb(range <1 - >15) μg/gHigher tooth Pb concentrations were significantlyassociated with poorer scores on the Focus-Execute andShift factors of the Mirsky battery. Few significantassociations were observedbetween bone Pb levels andperformance. Authors conclude that early Pb exposuremay be associated with poorer performance onexecutive/regulatory functions, which are thought todepend on the frontal or prefrontal regions of the brain.Stiles and Bellinger(1993)U.S.Design: Prospective longitudinal. 148 subjects fromthe Boston Pb Study were re-evaluated at 10 yrs ofage with an extensive neuropsychological battery.Tests included the California Verbal Learning Test,Wisconsin Card Sorting Test, Test of Visual-MotorIntegration, Rey-Osterieth Complex Figure, StoryRecall, Finger Tapping, and Grooved Pegboard.Extensive measures of medical andsociodemographic covariates.Cord and serial postnatalblood Pb assessmentsCord blood Pb grouping <3,6-7, >10 μg/dLBlood Pb at 2 yrs 6.5(SD 4.9) μg/dLAuthors point out that the number of significantassociations was about equal to those that would beexpected by chance. However, tasks that assess attentionalbehaviors and executive functions tended to among thosefor which Pb was a significant predictor of performance.Following covariate adjustment, higher blood Pbconcentrations at two yr were significantly associated withlower scores on Freedom from Distractibility factor of theWechsler scales, increase in percentage of perseverativeerrors on the Wisconsin Card Sorting Test and theCalifornia Verbal Learning Test.Canfield et al. (2003b,2004)U.S.Design: Prospective longitudinal. 170-174 childrenfrom the Rochester Pb Study were administered anumber of learning and neuropsychologicalfunctioning at 48, 54, and 66 mos of age. At 48 and54 mos the Espy Shape School Task wasadministered while at 66 mos the Working Memoryand Planning assessment protocols of the CambridgeNeuropsychological Test Automated Battery(CANTAB) was given. Extensive measures onmedical and sociodemographic covariates.Serial postnatal blood PbBlood Pb at 2 yrs 9.7 μg/dLLifetime avg blood Pb 7.2(range 0-20) μg/dLFollowing covariate adjustment, blood Pb level at 48 moswas negatively associated withchildren’s focused attentionwhile performing the Shape School Tasks, efficiency atnaming colors, and inhibition of automatic responding.Children with higher blood Pb concentrations alsocompleted fewer phases of the Espy tasks and knew fewercolor and shape names. On the CANTAB battery, childrenwith higher lifetime avg blood Pb levels showed impairedperformance on spatial working memory, spatial memoryspan, and cognitive flexibility and planning. Authorsconclude that the effects ofpediatric Pb exposure are notrestricted to global measures of intellectual functioning andexecutive processes may be at particular risk.

# AX6-18Table AX6-2.5 (cont’d). Effects of Leadon Specific Cognitive Abilities in Children — Attention/Executive Functions,Learning, and Visual-spatial SkillsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited States(cont’d)Ris et al. (2004)U.S.Design: Prospective longitudinal. 195 subjects fromthe Cincinnati Pb Study were administered anextensive and comprehensive neuropsychologicalbattery at 16-17 yrs of age. Domains assessedincluded Executive Functions, Attention, Memory,Achievement, Verbal Skills, Visuoconstructional,and Fine Motor. Factor scores transformed to ranksderived from a principal components factor analysisof the neuropsychological test scores were theprimary outcome variables.Extensive measures onmedical and sociodemographic covariates.Prenatal (maternal) andserial postnatal blood PbassessmentsPrenatal blood Pb 8.3(SD 3.7) μg/dLBlood Pb at 2 yrs 17.4(SD 8.8) μg/dLFollowing covariate adjustment, strongest associationsbetween Pb exposure and performance were observed forfactor scores derived from the Attention component, whichincluded high loadings on variables from the ConnersContinuous Performance Test. This relationship wasstrongest in males. Authors speculate that since theincidence of Attention Deficit/Hyperactivity Disorder isgreater in males in general, early exposure to Pb mayexacerbate a latent potential for such problems.

# AX6-19Table AX6-2.6. Effects of Lead on Disturbancesin Behavior, Mood, and Social Conduct in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesSciarillo et al. (1992)U.S.Design: Cross-sectional. 150 2-5 yr-old children inBaltimore separated into “high” (2 consecutive bloodPb levels >15 μg/dL) and “low” groups. Mothersfilled out the Achenbach Child Behavior Checklist(CBCL). The Center for Epidemiologic StudiesDepression Scale (CESD) was administered tomothers as a control measure.Screening blood Pbs atvarious times beforeassessmentHigh group 28.6(SD 9.3) μg/dLLow group 11.3(SD 4.3) μg/dLWhen compared to lower exposed group, children in thehigh group had a significantly higher CBCL TotalBehavior Problems Score (TBPS) and Internalizing andExternalizing scores. After adjustment for maternaldepression, blood Pb concentrations were still significantlyassociated with an increase in the TBPS. Children in highgroup were nearly 3 times morelikely to have a TBPS inthe clinical range. A significantly higher percentage ofchildren in the high group scored in the clinical range forCBCL subscales measuring aggressive and destructivebehavioral tendencies.Bellinger et al. (1994b)U.S.Design: Prospective cohort: 1782 children bornwithin a 1-yr period at a single Boston hospital wereexamined at 8 yrs of age. Teachers filled out theAchenbach Child Behavior Profile (ACBP). Medicaland sociodemographic characteristics assessed byquestionnaire and chart review.Umbilical cord blood PbCord blood Pb 6.8(SD 3.1) μg/dLTooth (dentin) PbTooth Pb 3.4(SD 2.4) μg/gCord blood Pb levels were not associated with theprevalence or nature of behavioral problems reported byteachers. Tooth Pb levels were significantly associatedwith ACBP Total Problem Behavior Scores (TPBS).Statistically significant tooth Pb-associated increases inboth Externalizing and Internalizing scores were observed.Each log unit increase in tooth Pb was associated with a1.5-point increase in T scores for these scales. Authorscaution that residual confounding cannot be ruled outbecause of the lack of information on parentalpsychopathology or observations of the familyenvironment. However, these results are in accord withother studies that social andemotional dysfunction may bean important expression of elevated Pb levels during earlychildhood.Denno (1990)U.S.Design: Prospective cohort. Survey of 987Philadelphia African-American youths enrolled inthe Collaborative Perinatal Project. Data availablefrom birth through 22 yrs of age. Analysisconsidered 100 predictorsof violent and chronicdelinquent behavior.Blood PbValues not providedRepeat offenders presented consistent features such as lowmaternal education, prolonged male-providerunemployment, frequent moves, and higher Pbintoxication. In male subjects, a history of Pb poisoningwas among the most significant predictors of delinquencyand adult criminality.

# AX6-20Table AX6-2.6 (cont’d). Effects of Lead on Disturbances in Behavior, Mood, and Social Conduct in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited States(cont’d)Needleman et al.(1996)U.S.Design: Prospective cohort. 850 boys enrolled in thePittsburgh Youth Study were prescreened to assessdelinquent behavioral tendencies. Subjects whoscored in the 30th percentile on the risk score and anequal number randomly selected from the remainderform the sample of 530 subjects. Measures ofantisocial behavior were administered at 7 and 11 yrsof age including the Self Reported Antisocial Behaviorscale (SRA), Self Reportof Delinquent Behavior(SRD), and parents’ and teachers’ versions of theAchenbach Child Behavior Profile (CBCL). Extensiveassessment of medicaland sociodemographiccovariates.Bone Pb by K-XRFBone Pb (exactconcentrations not reported)Negative values treatedcategorically as 1 andpositive values grouped intoquintiles.Following covariate-adjustment, parents of subjects withhigher Pb levels in bone reported significantly moresomatic complaints, more delinquent and aggressivebehavior, and higher Internalizing and Externalizingscores. Teachers reported significant increase in scores onsomatic complaints, anxious/depressed, social problems,attention problems, delinquent behavior, aggressivebehavior, internalizing and externalizing problems in thehigher bone Pb subjects. At 11 yrs, subject’s SRD scoreswere also significantly related to bone Pb levels. Morehigh Pb subjects had CBCL T scores in the clinical rangefor attention, aggression,and delinquency. Authorsconclude that Pb exposure is associated with increased riskfor antisocial and delinquent behavior.Dietrich et al. (2001)U.S.Design: Prospective longitudinal. 195 subjects fromthe Cincinnati Pb Study were examined at 16-17 yrs ofage. Parents were administered a questionnairedeveloped specifically for the study while CLSsubjects were given the Self Report of DelinquentBehavior. Extensive assessment of medical andsociodemographic covariates.Prenatal (maternal) andserial postnatal blood Pbassessments.Prenatal blood Pb 8.3(SD 3.7) μg/dLBlood Pb at 2 yrs 17.4(SD 8.8) μg/dLPrenatal (maternal) blood Pb was significantly associatedwith a covariate-adjusted increase in the frequency ofparent-reported delinquent and antisocial acts. Prenataland measures of postnatal Pb exposure were significantlyassociated with self-reported delinquent and antisocialbehaviors. Authors concluded that Pb might play ameasurable role in the development of behavioral problemsin inner-city children independent of other important socialand biomedical cofactors.Needleman et al.(2002)U.S.Design: Case-control. 194 adjudicated delinquentsand 146 non-delinquent controls recruited from highschools in the City ofPittsburgh and AlleghenyCounty, PA. Covariate assessments were notextensive but did include race, parentalsociodemographic factors, and neighborhood crimerates.Bone Pb by KXRFCases 11.0 (SD 32.7) μg/gControls 1.5 (SD 32.1) μg/gCases had significantly higher avg concentrations of Pb intibia than controls. Following covariate adjustment,adjudicated delinquents were 4times more likely to havebone Pb concentration >25 μg/g then controls. Bone Pblevel was the second strongest factor in the logisticregression models, exceededonly by race. In modelsstratified by race, bone Pb was exceeded as a risk factoronly by single parent status. Authors conclude thatelevated body Pb burdens are associated with increasedrisk for adjudicated delinquency.

# AX6-21Table AX6-2.6 (cont’d). Effects of Lead on Disturbances in Behavior, Mood, and Social Conduct in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEuropeWasserman et al.(1994)YugoslaviaDesign: Prospective longitudinal. Birth cohortof ~300-400 infants followed since birthresiding in two towns in Kosovo, Yugoslavia,one group near a longstanding Pb smelter andbattery manufacturing facility and another in arelatively unexposed location 25 miles away.379 children at 3 yrs of age were examined.Parents were interviewed with the AchenbachChild Behavior Checklist (CBCL). Extensiveassessment of medicaland sociodemographiccovariates.Maternal prenatal, umbilical cordand serial postnatal blood PbMaternal blood Pb in exposedarea 19.9(SD 7.7) μg/dL,unexposed area 5.6(SD 2.0) μg/dLUmbilical cord blood Pb inexposed area 22.2(SD 8.1) μg/dL,unexposed area 5.5(SD 3.3) μg/dLBlood Pb at 2 yrs in exposed area35.4 μg/dL, unexposed area8.5 μg/dLFollowing covariate adjustment, concurrent blood Pb levelswere associated with increased Destructive Behaviors on theCBCL subscale, although the variance accounted for by Pbwas small compared to sociodemographic factors. As bloodPb increased from 10 to 20 μg/dL, subscale scores increasedby 0.5 points. The authors conclude that while statisticallysignificant, the contribution of Pb to social behavioralproblems in this cohort was small compared to the effects ofcorrelated social factors.AustraliaBurns et al. (1999)AustraliaDesign: Prospective longitudinal. 322 subjectsresiding in and near Port Pirie, Australia andfollowed since birth were re-evaluated at 11-13yrs of age. Parents completed the AchenbachChild Behavior Checklist. Extensiveassessment of medicaland sociodemographiccharacteristics.Maternal prenatal, umbilical cordand serial postnatal blood PbAntenatal avg bloodPb 10.1 (SD 3.9) μg/dLUmbilical cord blood Pb9.4 (SD 3.9) μg/dLBlood Pb at 2 yrsgeometric mean 21.3(SD 1.2) μg/dLAfter adjustment for covariates, regression models revealedthat for an increase in avg lifetime blood Pb concentrationsfrom 10 to 30 μg/dL, the Externalizing behavior problem Tscore increased by 3.5 points in boys (95% CI: 1.6, 5.4), butonly 1.8 points (95% CI:!0.1, 11.1) in girls. Internalizingbehavior problems were predicted to rise by 2.1 points (95%CI: 0.0, 4.2) in girls by only 0.8 (95% CI:!0.9, 2.4) in boys.Authors concluded that Pb exposure is associated with anincrease in externalizing (undercontrolled) behaviors in boys.Fergusson et al. (1993)New ZealandDesign: Prospective cohort. 690-891 childrenages 12 and 13 yrs from the Christchurch Childand Health Study, New Zealand were examined.Mothers and teachers were asked to respond toa series of items derived from the Rutter andConners parental and teacher questionnaires.Extensive assessment of sociodemographic andmedical covariates.Tooth (dentine) PbTooth Pb range 3–12 μg/gStatistically significant dose-effect relationships wereobserved between tooth Pb levels and theinattention/restlessness variable at each age. Authorsconclude that this evidence isconsistent with the view thatmildly elevated Pb levels are associated with small but longterm deficits in attentional behaviors.

# AX6-22Table AX6-2.6 (cont’d). Effects of Lead on Disturbances in Behavior, Mood, and Social Conduct in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAustraliaSilva et al. (1988)New ZealandAs part of the 11-yr follow-up of the DunedinMultidisciplinary Health and Development Study, alongitudinal study of a birth cohort of children bornin Dunedin’s only obstetric hospital, blood Pb levelswere measured in 579 children at age 11 yrs old.The study sample was over-representative of higherSES, but was found to be representative of Dunedinchildren in educational attainment. Blood Pb levelswere examined in association with intelligenceassessed using the WISC-Rand behavioral problemsas assessed by both parents and teachers.Blood Pb at time of testingBlood Pb at age 11 yrs 11.1(SD 4.91, range 4-50) μg/dLLog blood Pb levels were significantly correlated with mostmeasures of behavioral problems, including the Parents’ andTeachers’ Rutter BehavioralScale, the Parents’ andTeachers’ Hyperactivity Scale, and the Teachers’ InattentionScale, after adjustment for various potential confounders. Noassociations were observed between log blood Pb levels andIQ. Authors concluded that exposure to Pb is associated withincreases in children’s’ general behavioral problems,especially in inattention and hyperactivity.

# AX6-23Table AX6-2.7. Effects of Lead onSensory Acuities in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesSchwartz and Otto(1991)U.S.Design: Cross-sectional. 3545 subjects 6-19 yrs oldwho participated in the Hispanic Health andNutrition Examination Survey. Pure toneaudiometric evaluations were performed at 500 Hz,2000 Hz, and 4000 Hz. Extensive measures onmedical and sociodemographic covariates.Blood Pb at the time oftestingBlood Pb 50th percentile8 μg/dLFollowing covariate adjustment, higher blood Pbconcentrations were associated with an increased risk ofhearing thresholds that were elevated above the standardreference level at all four frequencies. Blood Pb was alsoassociated higher hearing threshold when treated as acontinuous outcome. These relationships extended to bloodPb levels below 10 μg/dL. An increase in blood Pb from 6 to18 μg/dL was associated with a 2-dB loss at all frequencies.Authors conclude that HHANES results those reportedearlier for NHANES-II.Dietrich et al. (1992)U.S.Design: Prospective/longitudinal. 215 subjectsdrawn from the Cincinnati PbStudy at the age of 5yrs. Children were administered the SCAN-astandardized test of central auditory processing.Extensive measurement of medical andsociodemographic covariatesPrenatal (maternal) and serialpostnatal blood PbassessmentsPrenatal blood Pb 8.3(SD 3.7) μg/dLBlood Pb at 2 yrs 17.4 (SD8.8) μg/dLHigher prenatal (maternal), neonatal and postnatal blood Pbconcentrations were associated with more incorrectidentification of common monosyllabic words presentedunder conditions of muffling. Following covariateadjustment, avg childhood blood Pb level remainedsignificantly associated with impaired performance on theSCAN subtest. Authors conclude that Pb-related deficits inhearing and auditory processing may be one plausiblemechanism by which an increased Pb burden might impede achild’s learning.EuropeOsman et al. (1999)PolandDesign: Cross-sectional. 155 children 4-14 yr-oldliving in an industrial region of Poland. Pure toneaudiometric evaluations were performed at 500 Hz,1000 Hz, 2000 Hz, 4000 Hz, 6000Hz, and 8000 Hz.Basic data on medical history, limited information onsociodemographic covariates such as familystructure and income.Blood Pb at the timeof testingBlood Pb median 7.2(range 1.9-28) μg/dLHigher blood Pb concentrationswere significantly associatedwith increased hearing thresholds at all frequencies studied.This relationship remained significant when analyses werelimited to subjects with blood Pb levels below 10 μg/dL.Authors conclude that auditory function in children isimpaired at blood Pb concentrations below 10 μg/dL.

# AX6-24Table AX6-2.8. Effects of Lead onNeuromotor Function in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesDietrich et al. (1993b);Bhattacharya et al.(1995); Ris et al.(2004)U.S.Design: Prospective longitudinal. Relationshipbetween Pb exposure and neuromotor function hasbeen examined in several studies on the Cincinnati PbStudy Cohort from 6 to 17 yrs of age. At 6 yrs of age245 subjects were administered the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP); at 6-10 yrs of age subjects were assessed for posturalinstability using a microprocessor-based strain gaugeplatform system and at 16-17 yrs of age the fine-motor skills of study subjects were assessed with thegrooved pegboard and finger tapping tasks (part of acomprehensive neuropsychological battery).Extensive measurement of medical andsociodemographic factors.Prenatal (maternal) andserial postnatal blood PbassessmentsPrenatal blood Pb 8.3(SD 3.7) μg/dLBlood Pb at 2 yrs 17.4 (SD8.8) μg/dLFollowing covariate adjustment, postnatal Pb exposure wassignificantly associated with poorer scores on BOTMPmeasures of bilateral coordination, visual-motor control,upper-limb speed and dexterity and the Fine MotorComposite score. Low-level neonatal blood Pbconcentrations were also significantly associated with poorerscores on the aforementioned subtests, as well as measuresof visual-motor control.Postnatal Pb exposure wassignificantly associated with greater postural instability in 6-10 yr-old subjects and poorer fine-motor coordination whenexamined at 16-17 yrs.Authors conclude that effects of early Pb exposure extendinto a number of dimensions ofneuromotor development.EuropeWasserman et al.(2000a)YugoslaviaDesign: Prospective longitudinal. Birth cohort of~300-400 infants followed since birth residing in twotowns in Kosovo, Yugoslavia, one group near alongstanding Pb smelterand battery manufacturingfacility and another in a relatively unexposed location25 miles away. 283 children at age 54 mos wereadministered the Beery Developmental Test ofVisual-Motor Integration (VMI) and the BruininksOseretsky Test of Motor Proficiency (BOTMP).Extensive measurement of medical andsociodemographic factors.Maternal prenatal, umbilicalcord and serial postnatalblood PbMaternal blood Pb inexposed area 19.9(SD 7.7) μg/dL,unexposed area 5.6(SD 2.0) μg/dLUmbilical cord blood Pb inexposed area 22.2(SD 8.1) μg/dL,unexposed area 5.5(SD 3.3) μg/dLBlood Pb at 2 yrs in exposedarea 35.4 μg/dL, unexposedarea 8.5 μg/dLFollowing covariate-adjustment,the log avg of serial bloodPb assessments to 54 mos was associated with lower FineMotor Composite and VMI scores. Pb exposure wasunrelated to gross motor performance. With covariateadjustment, an increase in avg blood Pb from 10 to 20 μg/dLwas associated with a loss of 0.62 and 0.42 pointsrespectively, in Fine Motor Composite and VMI. Authorsnoted that other factors such as indicators of greaterstimulation in the home make a larger contribution to motordevelopment than Pb.

# AX6-25Table AX6-2.9. Effects of Lead on Direct Measures of Brain AnatomicalDevelopment and Activity in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesTrope et al. (1998)U.S.Design: Case-control. One 10 yr-old subject withhistory of Pb poisoning and unexposed 9 yr-oldcousin. Magnetic Resonance Imaging (MRI) andMagnetic Resonance Spectroscopy (MRS) wereused to assess differences in cortical structures andevidence of neuronal loss. This was the first studyto attempt to determine in vivo structural and/ormetabolic differences in the brain of a childexposed to Pb compared with a healthy control.Blood PbPb poisoned case 51 μg/dLat 38 moUnexposed control notreported.Both children presented with normal volumetric MRI. MRSrevealed a significant alterationin brain metabolites, with areduction in N-acetylaspartate:creatine ratio for both grayand white matter compared to the subject’s cousin. Authorsconclude that results suggestneuronal loss related to earlierPb exposure.Trope et al. (2001)U.S.Design: Case-control. 16 subjects with a history ofelevated blood Pb levels before 5 yrs of age and5 age-matched siblings orcousins were evaluated.Avg age at time of evaluation was 8 yrs. MagneticResonance Imaging (MRI) and MagneticResonance Spectroscopy (MRS) were used toassess differences in cortical structures andevidence of neuronal loss.Blood PbRange in Pb-exposed 23 to65 μg/dLControls <10 μg/dLAll children had normal MRI examinations, but Pb-exposedsubjects exhibited a significant reduction inN-acetylaspartate:creatine and pohosphocreatine ratios infrontal gray matter compared tocontrols. Authors concludethat Pb has an effect on brain metabolites in cortical graymatter suggestive of neuronal loss.Cecil et al. (2005)U.S.Design: Prospective/longitudinal. 48 young adultsages 20 to 23 yrs werere-examined. FunctionalMRI (fMRI) was used to examine the influence ofchildhood Pb exposure on language function.Subjects performed a verb generation/fingertapping paradigm. Extensive measurement ofmedical and sociodemographic covariatesBlood PbAvg childhood blood Pb13.9 (SD 6.6, range4.8-31.1) μg/dLHigher avg childhood blood Pb levels was significantlyassociated with reduced activation in Broca’s area in the lefthemisphere and increased activation in the right temporallobe, the homologue of Wernicke’a area in the lefthemisphere. Authors concludethat elevated childhood Pbexposure strongly influences neural substrates of semanticlanguage function on normal language areas withconcomitant recruitment of contra-lateral regions resulting ina striking dose-dependent atypical organization of languagefunction.

# AX6-26Table AX6-2.9 (cont’d). Effects of Lead on Direct Measuresof Brain Anatomical Development and Activity in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationLatin AmericaRothenberg et al. (2000)MexicoDesign: Prospective/longitudinal. 113 5-7 yr-oldchildren from the Mexico City Prospective Studywere re-examined. Brain stem auditory evokedpotentials were recorded to assess the impact ofprenatal and postnatal Pbexposure on developmentof auditory pathways. Results adjusted for genderand head circumference.Blood PbPrenatal (20 wks) 8.1(SD 4.1) μg/dLCord 8.7 (SD 4.3) μg/dLPostnatal 18 mo 10.8(SD 5.2) μg/dLPrenatal blood Pb at 20 wks was associated with decreasedinterpeak intervals. After fitting a nonlinearmodel to thesedata, I-V and III-V interpeak intervals decreased as blood Pbrose from 1 to 8 μg/dL and increased as blood Pb rose from8 to 30 μg/dL. Increased blood Pb at 12 and 48 mos wasrelated to decreased conduction intervals for I-V and II-Vacross the entire blood Pb range suggesting pathway lengtheffects.AsiaMeng et al. (2005)ChinaDesign: Case-control. 6 subjects with blood Pbconcentrations∃27 μg/dL and 6 controls withblood Pb concentrations <10 μg/dL were evaluatedwith Magnetic Resonance Imaging (MRI) andMagnetic Resonance Spectroscopy to evaluatestructural abnormalities and differences in Nacetylaspartate, creatine, and choline in frontallobes and hippocampus ofcases and controls.Blood PbCases 37.7 (SD 5.7) μg/dLControls 5.4 (SD 1.5)μg/dLAll children presented with normal MRI. Peak values of Nacetylaspartate, choline, and creatine in all four brain regionswere reduced in Pb exposed children relativeto controls.Authors conclude that reducedbrain N-acetylaspartate incases may be related to decreased neuronal density or loss.Reduced choline signal may indicate decreased cellmembrane turnover or myelin alterations while lowercreatine may indicate reduced neuronal cell viability.

# AX6-27Table AX6-2.10. Reversibility of Lead-related Deficits in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesRuff et al. (1993)U.S.Design: Intervention study, non-randomized.126 children with complete data age 13 to 87 mosand with blood Pb levels between 25 and 55 μg/dLwere given chelation with ETDA and/or therapeuticiron where indicated. At baseline and follow-up,patients were evaluated with the Bayley Scales ofInfant Development, Mental Development Index,or Stanford Binet Scales of Intelligence dependingupon age.Blood Pb at time oftreatmentBlood Pb 31.2 (SD 6.5)μg/dLWithout respect to treatment regimen, changes inperformance on cognitive measures after 6 mos weresignificantly related to changes in blood Pb levels aftercontrol for confounding factors.Standardized scores on testsincreased 1 point for every 3 μg/dL decrement in blood Pb.Rogan et al. (2001);Dietrich et al. (2004)U.S.Design: Double blind,placebo-controlledrandomized clinical trial.The Treatment of Pb-Exposed Children (TLC) clinical trial of 780children in 4 centers was designed to determine ifchildren with moderately elevated blood Pbconcentrations given succimer would have betterneuropsychological outcomes than children givenplacebo. Children between 12 and 33 mos of agewere evaluated 3 yrs following treatments andagain at 7 and 7.5 yrs of age. A wide range ofneurological, neuropsychological, and behavioraltests was administered. Assessment of potentiallyconfounding factors included sociodemographicsand parental IQ.Blood PbBaseline blood Pb 26(SD 26.5) μg/dL in bothdrug and placebo groupsSuccimer was effective in lowering blood Pb levels insubjects on active drug during the first 6 mos of the trial.However, after 1 yr differences in the blood Pb levels ofsuccimer and placebo groups had virtually disappears.3 yrs following treatment, nostatistically significantdifferences between active drug and placebo groups wereobserved for IQ or other more focused neuropsychologicaland behavioral measures. Whenevaluated at 7 and 7.5 yrs ofage, TLC could demonstrate nobenefits of earlier treatmenton an extensive battery of cognitive, neurological, behavioraland neuromotor endpoints. Authors conclude that the TLCregimen of chelation therapy is not associated withneurodevelopmental benefits in children with blood Pb levelsbetween 20 and 44 μg/dL and that these results emphasizethe importance of taking environmental measures to preventexposure to Pb in light of the apparent irreversibility of Pbassociated neurodevelopmental deficits.

# AX6-28Table AX6-2.10 (cont’d). Reversibility ofLead-related Deficits in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited 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 relationshipsbetween falling blood Pb levels and changes incognitive functioning. 741 children recruitedbetween 13 and 33 mos of age were assessed atbaseline and 6 mos later with the Bayley MentalDevelopment Index (MDI) and 36 mos post-randomization with the Wechsler Preschool andPrimary Scales of Intelligence-Revised toobtain IQ.Blood PbBaseline blood Pb 26.2(SD 5.1) μg/dL36 mos post-randomizationblood Pb 12.2 (SD 5.2)μg/dLTLC found no overall effect of changing blood Pb level onchange in cognitive test scores from baseline to 6 mos.Slope estimated to be 0.0 points per 10 μg/dL change inblood Pb. From baseline to 36 mos and 6 mos to 36 mos,falling blood Pb levels were significantly associated withincreased cognitive test scores, but only because of anassociation in the placebo group. Authors conclude thatbecause improvements were not observed in all children, thedata do not provide supportthat Pb-induced cognitiveimpairments are reversible. Although the possibleneurotoxicity of succimer cannot be ruled out.LatinAmericaKordas et al. (2005);Rico et al. (2006)MexicoDesign: Double-blind, placebo-controllednutritional supplementation clinical trial conductedamong 602 1st grade children ages 6-8 yrs inTorreón, Mexico. Subjects received iron, zinc,both or placebo for 6 mos.Parents and teachersfilled out the Conners Rating Scales at baseline andfollow-up six mos following the end ofsupplementation to index behavioral changesfollowing therapy. In addition, 11 cognitive testsof memory, attention, visual-spatial abilities, andlearning were administered, including WISCR-M atbaseline and follow-up 6 mos later.Blood PbBaseline blood Pb 11.5(SD 6.1) μg/dLNo significant effects of treatment on behavior or cognitioncould be detected with any consistency. Authors concludethat this regimen of supplementation does not result inimprovements in ratings of behavior or cognitiveperformance.AustraliaTong et al. (1998)AustraliaDesign: Prospective longitudinal. 375 childrenfrom the Port Pirie Prospective Study werefollowed from birth to the age of 11-13 yrs. BayleyMental Development Index (MDI) at 2 yrs, theMcCarthy Scales General Cognitive Index (GCI)and IQs from the Wechsler Intelligence Scaleserved as the primary indicators of intellectualstatus. The purpose of the study was to assess thereversibility of Pb effects on cognition inrelationship to declines in blood Pb over time.Postnatal blood PbMean blood Pb at 2 yrs21.2 μg/dL declining to7.9 μg/dL at 11-13 yrsAlthough blood Pb levels declined substantially, covariateadjusted scores on standardized measures of intellectualattainment administered at 2, 4,7, and 11-13 yrs of age wereunrelated to declining body burden. Authors conclude thateffects of early exposure to Pb during childhood are notreversed by a subsequent decline in blood Pb concentration.

# AX6-29 

# ANNEX TABLES AX6-3

# AX6-30Table AX6-3.1. Neurobehavioral Effects Associated with Environmental Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited StatesKrieg et al. (2005)1988-1994U.S.4,937 adults aged 20-59 yrs fromNHANES III completed threeneurobehavioral tests.Regression analysesof neurobehaqvioral test and log of bloodPb concentration adjusted for sex, ageeducation, family income, race/ethnicity,computer or videogame familiarity,alcohol use, test language, and surveyphase.Mean blood Pb 3.3 μg/dLRange 0.7 to 41.7 μg/dLNo statistically significant relationship between blood Pb concentrationand mean simple reaction time, symbol-digit substitution latency anderrors and serial digit learning trials to criterion and total score afteradjustments for covariates.Muldoon et al. (1996)U.S.325 women from rural location (mean age71) and 205 women from a city location(mean age 69) participants in the Study forOsteoporotic Fractures had the associationof nonoccupational Pb exposure andcognitive function examined. Logisticregression determined effect of blood Pbon neuropsychological performance.Rural groupBlood Pb 5 μg/dLUrban groupBlood Pb 5 μg/dLGroups were significantly differentwith the urban group more educatedand smoked and drank more. Performance in each group stratified byexposure into three groups (low <4μg/dL, medium 4-7 μg/dL, high>7 μg/dL rural and >8 μg/dL) — no significant associations werepresent in the urban group but the rural group had significantly poorerperformance with increasing blood Pbfor Trails B (OR = 2.6 [95% CI:1.04, 6.49]), Digit Symbol (OR =3.73 [95% CI: 1.57, 8.84]),andReaction Time in the lower (OR = 2.84 [95% CI: 1.19, 6.74]) andupper extremities (OR = 2.43 [95% CI:1.01, 5.83]). The fact thatmarked differences exist between the low Pb groups for rural and urban(the lowest 15th percentile) suggests the differences between the twogroups are unrelated to Pb. Response time for reaction time across Pbgroups increased for the rural group and decreased or remained thesame for the urban group. As response time is sensitive to Pb effect,this raises question whether factors not measured accounted fordifference. Namely MMSE for the whole population was 25 (15-26)with poorer performance in the rural group. The clinical cutoff scorefor MMSE is 24 suggesting the presence of clinical cognitive disorders.Even though this is a simple neuropsychological battery up to 9 wereunable to perform some of the tests including 3 on the MMSE.

# AX6-31Table AX6-3.1 (cont’d). Neurobehavioral Effects Associated with EnvironmentalLead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited States(cont’d)Payton et al. (1998)U.S.141 healthy men in VA normal aging studyevaluated every 3 to 5 yrs with cognitivebattery and blood Pb and once ameasurement of patellaand tibia bone Pb.Statistics are confusing as it is not clearwhen ANCOVA is used and how thegroups are created.Mean blood Pb 6 μg/dLMean patella bone Pb 32μg/gMean tibia bone Pb 23 μg/gbone mineralRegressions adjusted for age and education found significantrelationship of blood Pb with Pattern Comparison (perceptual speed),Vocabulary, Word List Memory, Constructional Praxis, BostonNaming Test, and Verbal Fluency Test. Only for Constructional Praxiswere bone Pb and blood Pb significantly associated. Mechanism mostsensitive to low levels Pb exposure believed to be response speed.Vocabulary is significantly associated with blood Pb. Education isnegatively correlated to bone and blood Pb. It is not clear how multiplecomparisons were handledRhodes et al. (2003)U.S.526 participants with mean age 67 yrs,47% had education level of high school orless. Mood symptoms evaluated with BriefSymptom Inventory (BSI). Use of logisticregression adjusting for covariatesexamined association of BSI scales andblood Pb and bone Pb levels.Mean blood Pb 6 μg/dLMean tibia Pb 22 μg/gMean patella Pb 32 μg/gBSI found mood symptoms for anxietyand depression were potentiallyassociated with bone Pb levels.Education was inversely related tobone Pb and high school graduates had significantly higher odds ofGlobal Severity Index andPositive Symptom Total.Wright et al. (2003)U.S.736 healthy men (mean age 68) inNormative Aging Study examined every 3to 5 yrs were administered the MiniMental State Exam (MMSE). Linearregression examined relationship ofMMSE and blood Pb, patella and tibiabone Pb measurements after adjusting forcovariates.Mean blood Pb 5 μg/dL,Mean patella bone Pb 30μg/gMean tibia bone Pb 22 μg/gMean MMSE score 27. Relation ofMMSE scores <24 (n = 41) andblood Pb by logistic regression found OR = 1.21 (95% CI: 1.07, 1.36)and for patella Pb OR = 1.21 (95% CI: 1.00, 1.03) and tibia Pb OR =1.02 (95% CI: 1.00, 1.04). Risk of MMSE <24 when comparing thelowest and highest quartiles of patella Pb was 2.1 (95% CI: 1.1, 4.1),for tibia Pb was 2.2 (95% CI: 1.1, 3.8) and blood Pb was 3.4 (95% CI:1.6, 7.2). Interaction between patella Pb and age, and blood Pb and agein predicting MMSE found steeper decrease in MMSE score relative toage in the higher quartiles ofpatella Pb and blood Pb.MMSE very sensitive to yrs of education below 8 yrs. In this study 213subjects had less than high school education. If the communitydwelling population had older individuals with less education living inareas with higher past pollution the confounding may be impossible tosort out. Initially at beginning ofNAS subjects were eliminated withchronic medical problems or bloodpressure >140/90. It is notaddressed how the development ofmedical conditions during theduration of the study are handled.

# AX6-32Table AX6-3.1 (cont’d). Neurobehavioral Effects Associated with EnvironmentalLead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited States(cont’d)Weisskopf et al.(2004b)U.S.466 men, mean age 70 yrs, in the VANormative Aging Study had 2 MMSE tests3.5 yrs apart.Mean blood Pb 4 μg/dLMean patella bone Pb 23μg/gMean tibia bone Pb 19 μg/gBaseline mean MMSE score was 27 and mean change in MMSEscore over 3.5 yrs was 0.3. Change in MMSE associated with oneinterquartile range increment for bone Pb and blood Pb foundrelationship between patella Pb and change in MMSE was unstablewhen patella Pb is∃90 μg/g bone mineral. Examination of patella Pbbelow this level found a greater inverse association with MMSE atlower Pb concentrations (∃=!0.25 [95% CI:!0.45,!0.05]). A similarbut weaker association existed for tibia Pb when values∃67 μg/gbone mineral were removed (∃=!0.19 [95% CI:!0.39, 0.02]). Therewas no association of MMSE change and blood Pb (∃=!0.01 [95%CI:!0.13, 0.11]). There was no interaction of age and bone Pb.These are very high bone Pb levels for environmental exposure. Thebiological plausibility of change in the MMSE over 3.5 yrs wouldhave been reinforced if the change by functional domain in theMMSE was provided.EuropeNordberg et al. (2000)Sweden762 participants, mean age 88 yrs, in a studyof aging and dementia examined MMSE.Used blood Pb as dependent and examinedcontribution of covariates and MMSE.Mean blood Pb 3.7 μg/dL Mean MMSE 25 found norelation of blood Pb and MMSE. In thispopulation was fairly homogenous, all elderly Swedes, and thelikelihood of prior exposure to elevated Pb levels was low.

# AX6-33Table AX6-3.2. Symptoms Associated withOccupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationCanadaLindgren et al. (1999)CanadaSmelter workers (n = 467) with a mean ageof 40 yrs completed the Profile of MoodScale. Factor structure of POMS validated inthis occupational population. Regressionanalysis determined association with Pbexposure.Mean (SD, range) blood Pb28 (8.5, 4-62) μg/dLMean (SD, range) IBL 711(415.5, 1-1537) μg·yr/dLFactor analysis found one factor labeled “general distress” composedof POMS subscales anger, confusion, depression, fatigue and tensionand a second factor labeled ‘psychological adjustment.’ IBL wassignificantly associated with ‘general distress’ after adjustment for thecovariates (∃= 0.28 [SE 1.51Η10!4], p = 0.01) while there was norelation with blood Pb. The factorstructure of POMS originallyvalidated in a clinical populationhad six mood subscales however thefactor structure in this occupational population was found to haveonly two subscales.Holness et al. (1988)Canada47 demolition workers with acute Pbintoxication - Phase 1 - were followed withblood Pb and symptoms during engineeringmodifications to control exposure –Phases 2-4. Workers stratified by blood Pband symptom frequency was analyzed.Phase I - Mean blood Pb59 μg/dLPhase 2 - Mean blood Pb30 μg/dLPhase 3 - Mean blood Pb19 μg/dLPhase 4 - Mean blood Pb17 μg/dLBelow blood Pb <50 μg/dL, workers reported symptoms of fatigue(25%), headache (14%), dizzy (9%), sleep (8%), abdominal cramps(8%), muscle ache (8%), paresthesiae (8%), appetite (7%),constipation (6%), and weakness (6%). All symptoms weresignificantly lower except for paresthesiae when compared to groupwith blood Pb >70 μg/dL. Of interest, at beginning of Phase 4 whenmean blood Pb was 13 μg/dL, no symptoms were reported. At theend of Phase 4, mean blood Pb was 17 μg/dL and one workercomplained of fatigue.EuropeLucchini et al. (2000)Italy66 workers in Pb manufacturing, mean age40 (8.7) yrs and 86 controls mean age 43(8.8) yrs were administered a questionnairewith neuropsychological (14 items), sensorymotor (3 items), memory (4 items) andextrapyramidal (8 items), 10 Parkinsonsymptoms and the Mood Scale. Groupcomparisons and linear regression examinedrelationship of symptoms and Pb exposure.Pb workersMean (SD, range) blood Pb27 (11.0, 6-61) μg/dLMean (SD, range) TWA 32(14.1, 6-61) μg/dLMean (SD, range) IBL 410(360.8, 8-1315) μg·yr/dLControlsMean (SD, range) blood Pb8 (4.5, 2-21) μg/dLPb exposed worker reported confusion, somnolence, abnormalfatigue, irritability, and muscular pain more frequently (p < 0.04).There were no group differences for the parkinsonism symptoms orMood Scale. Linear regression combing exposed and control groupfound neurological symptoms significantly associated with blood Pbr = 0.22, p = 0.006). Neuropsychological symptoms weresignificantly higher in the High-IBL compared to the Low-IBL group.The estimated threshold for a significant increase (prevalence of 5%)of a high score for neurological symptoms was at a blood Pb of12 μg/dL.

# AX6-34Table AX6-3.2 (cont’d). Symptoms Associatedwith Occupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationLatin AmericaMaizlish et al. (1995)Venezuela43 workers from a Pb smelter, mean age 34(9) yrs and 47 nonexposed workers, meanage 35 (11) yrs completed the profile ofmood states (POMS) questionnaire and aquestionnaire of symptoms of the central andperipheral nervous system, andgastrointestinal. Prevalence ratios used toexamine symptoms and Pb. ANCOVA andlinear regression adjusting for potentialconfounders examined relationship of Pbexposure and POMS.Pb workersMean (SD) blood Pb 43(12.1) μg/dLMean (SD) peak blood Pb60 (20.3) μg/dLMean (SD) TWA 48 (12.1)μg/dLControlsMean (SD) blood Pb 15 (6)μg/dLMean (SD) peak blood Pb15 (6) μg/dLMean (SD) TWA 15 (SD 6)μg/dLSignificantly increased relative risks found for difficultyconcentrating (RR = 1.8 [95% CI: 1.0, 3.1]), often being angry orupset without reason (RR = 2.2 [95% CI: 1.2, 4.1]), feelingabnormally tired (RR = 2.2 [95% CI: 0.9, 5.3]) and joint pain(RR = 1.8 [95% CI: 1.0, 3.3]).The six subscales of the POMS werenot significantly different betweenthe exposed and control groups.However dose-related analysis found significantly poorer scores fortension-anxiety and blood Pb (p = 0.009), hostility and blood Pb(p = 0.01) and TWA (p = 0.04), and depression and blood Pb(p = 0.003) and peak Pb (p = 0.003) and TWA (p = 0.004).AsiaSchwartz et al.(2001a)Korea803 Pb-exposed Korean workers, mean age40 yrs completed the Center forEpidemiologic Studies Depression Scale.Linear regression examined for associationof CES-D and Pb biomarkers after adjustingfor the covariates.Mean (SD) blood Pb 32(15.0) μg/dLMean (SD) tibia Pb 37(40.3) μg/g bone mineralAfter adjustment for age, gender and education significantassociations found for CES-D and tibia Pb (∃= 0.0021 [SE 0.0008];p < 0.01) but not with blood Pb. This occupational Pb-exposedpopulations had higher past Pb exposure compared to the currentmean blood Pb of 32 μg/dL.Lee et al. (2000)Korea95 Korean Pb exposed workers, mean age 43yrs, completed questionnaire of Pb-relatedsymptoms present over last three mos.Relationship between symptom score andmeasures of Pb exposure assessed by linearregression. Logistic regression use to modelpresence or absence of symptoms forgastrointestinal, neuromuscular, and general.DMSA-chelatable Pb Mean(SD) 289 (167.7) μgMean (SD) ZPP 108 (60.6)μg/dLMean (SD) ALAU3 (2.8)mg/LMean(SD) blood Pb 45(SD 9.3) μg/dLWorkers with DMSA-chelatable Pbabove the median of 261 μg were6.2 (95% CI: 2.4, 17.8) times more likely to have tingling ornumbness in their extremities, 3.3 (95% CI: 1.2, 10.5) times morelikely to experience muscle pain and 3.2 (95% CI: 1.3, 7.9) timesmore likely to feel irritable. The workers with higher chelatable Pbwere 7.8 (95% CI: 2.8, 24.5) times more likely to experienceneuromuscular symptoms compared to workers with lower chelatablePb. In this study ZPP predicted weakness of ankle and wrist(OR = 2.9 [95% CI: 1.1, 8.1]) and fatigue (OR = 2.9 [95% CI:1.1, 8.7]) while ALAU predicted inability to sleep (OR = 5.4 [95%CI: 1.2, 33.2]) and blood Pb was not significantly associated with anysymptoms. A measure of Pb in bioavailable storage pools was thestrongest predictor of symptomsparticularly neuromuscular.

# AX6-35Table AX6-3.2 (cont’d). Symptoms Associatedwith Occupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationAsia(cont’d)Niu et al. (2000)China44 Pb-exposed workers (17 men, 27 women)from Pb printing houses, mean age 35 (4.9)and education 9.3 (no SD) yrs and 34controls (19 men and 15 women), mean age33 (7.4) yrs and education 9.5 (no SD) yrscompleted the profile of mood state as part ofthe NCTB. ANCOVA controlling for age,sex and education examined groupdifferences and linear regression for dose-response relationship.Mean blood Pb 29(SD 26.5) μg/dL(8 workers blood Pbexceeded 50 μg/dL)ControlsMean blood Pb 13(SD 9.9) μg/dL(1 control blood Pbexceeded 50 μg/dL)POMS subscales for confusion (F = 3.02, p < 0.01), fatigue (F = 3.61,p < 0.01), and tension (F = 2.82, p <0.01) were significantly elevatedin the Pb exposed group. Regression analyses found a dose response(data not shown).

# AX6-36Table AX6-3.3. Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesFiedler et al. (2003)New Jersey40 workers with Pb exposure, mean age48 (9.5) yrs completed a neurobehavioralbattery and was compared to 45 Pb/solventworkers, mean age 47 (10.2), 39 solventexposed workers, mean age 43 (9.4), and33 controls, mean age 44 (10.2). Groupdifferences and dose-effect relationshipswere assessed after adjusting for potentialconfounding.Mean (SD) blood Pbμg/dL; mean (SD) bone Pbppm (dry weight)Pb workers14 (11.7); 2.7 (0.7)Pb/Solvent workers12 (11.6); 2.8 (0.6)Solvent workers5 (4.1);!1.8 (1.8)Controls4 (1.4);!1.1 (1.6)Of nineteen outcomes, significant differences found on the Californiaverbal learning test (CVLT) (p= 0.05) and positive symptom distressindex on the Symptom checklist-90-R. On the CVLT the controlsperformed significantly better ontrials 2 and 3 demonstratingefficiency of verbal learning.Symbol digit substitution (SDS)approached significance (p = 0.09) with Pb and Pb/solvent groupslower on latency of response but not accuracy. Bone Pb was asignificant predictor of latency ofresponse on SDS, total errors onpaced auditory serial addition task and simple reaction time non-preferred hand. Bone Pb and SRT, preferred hand approachedsignificance. This is a confusing study design as bone Pb is used as apredictor in workers both with andwithout occupational Pb exposure.CanadaLindgren et al. (1996)Canada467 Canadian former and current, Frenchand English speaking Pb smelter workers,mean age 43 (11.0) yrs and education10 (3.2) yrs were administered aneuropsychological battery in English orFrench. Data analyses used MANCOVAadjusting for age, education, measure ofdepressive symptoms and self reportedalcohol use.Mean (SD) yrs employment18 (7.4)Mean (SD) blood Pb 28(8.4) μg/dLMean (SD) TWA 40(4-66) μg/dLMean (SD) IBL 765(1-1626) μg·yr/dLFourteen neuropsychological variables examined by MANCOVAwith the grouping variable exposure (high, medium and low) and thecovariates, age, education, CES-D,and alcohol use found no exposureterm significant until yrs of employment, a suppressor term, wasadded as a covariate. IBL exposure groups differed significantly (df2,417) on digit symbol (F = 3.03, p= 0.05), logical memory (F = 3.29,P = 0.04), Purdue dominant hand (F = 4.89, p = 0.01), and trails A(F = 3.89, p = 0.02) and B (F = 3.2,p = 0.04). This study showed adose-effect relationship betweencumulative Pb exposure (IBL) andneuropsychological performanceat a time when there was noassociation with current blood Pb.

# AX6-37Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationCanada(cont’d)Bleecker et al. (2002)Canada256 smelter workers from the abovepopulation were currently employed andtook the test battery in English. Their meanage was 41 (7.9) yrs, and education 10 (2.8)yrs. The goal was to determine ifeducational achievement as measured byWRAT-R Reading modified performance onMMSE. Linear regression assessed thecontribution of age, WRAT-R, education,alcohol intake, cigarette use, IBL andIBLΗWRAT-R on MMSE performance.Mean (SD) blood Pb 28(8.8) μg/dLMean (SD) IBL 725 (434)μg·yr/dLMMSE had a median (range) score of 29 (19-30). The most commonerrors were recall of 3 items (38%), spell world backwards (31%),repetition of “no ifs ands or buts” (21%) and copy a design to twointersecting pentagons (16%). WRAT-R reading used as an additionalmeasure of educational achievement because it was a stronger predictorof MMSE performance than yrs of education. The significantinteraction (♠R2= 2%, p = 0.01)explained by a dose-effect betweenIBL and MMSE only in the 78 workers with a WRAT-R reading gradelevel less than 6. The workers with higher reading grade levels and thesame cumulative Pb exposure were able to compensate for the effectsof Pb on the MMSE because of increased cognitive reserve.Bleecker et al. (2005a)Canada256 smelter workers currently employed andtook the test battery in English. Their meanage was 41 (7.9) yrs, and education 10 (2.8)yrs. The purpose was to determine whethercomponents of verbal memory as measuredon the Rey Auditory Verbal Learning Test(RAVLT) were differentially affected by Pbexposure. Linear regression and ANCOVAassessed the relationship of Pb andcomponents of verbal learning and memory.Mean (SD) blood Pb 28(8.8) μg/dLMean (SD) TWA 39 (12.3)μg/dLMean (SD) IBL 725 (434)μg·yr/dLOutcome variables RAVLT a word list test included measures ofimmediate memory span and attention (Trial 1), best learning (Trial V),incremental learning across the five trials (Total Score), and storage(Recognition) and retrieval (DelayedRecall) of verbalmaterial. TWAsignificantly contributed to the explanation of variance for Trial V(♠R2= 1.4%, p < 0.03) and Delayed Recall (♠R2= 1.4%, p = 0.03)after adjusting for age and WRAT-R while IBL did the same withRecognition (♠R2= 2.0%, p = <0.02) and Delayed Recall(♠R2= 1.1%, p = 0.06). Workers stratified into 3 group by increasingclinical memory difficulties-Group1had normal encoding, storage andretrieval; Group2 could encode andstore verbal information but haddifficulty with retrieval and Group 3 had abnormal encoding, storageand retrieval but was still able to learn new verbal information.ANCOVA adjusting for age and WRAT-R compared Pb exposureacross the memory groups. Blood Pb showed no difference but TWAand IBL were significantly higher in Group 3 compared to Group 1(p < 0.05 for both). Internal strategies used on the RAVLT over thefive trials found that Groups 1 and 2 remembered more words from thebeginning of the list while group 3 remembered more from the end.At a time when blood Pb was notassociated with performance,cumulative Pb exposure resulted inpoorer storage and retrieval ofpreviously learned material. Alterations in the ability to organizematerials in long term memory interferes with retrieval efficiency.

# AX6-38Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationCanada(cont’d)Bleecker et al. (1997a)New Brunswick1992-1993The performance of the 467 current and retiredsmelter workers as described in Lindgren et al.(1996) administered a screeningneuropsychological battery by testers blindedto the degree of Pb exposure of the worker hadtheir performance compared to age matchednorms. If performance on two or more tests inany functional domain was below 1.5 standarddeviations the worker was invited for acomplete clinical evaluation. Eighty currentworkers were identified by this criterion.Mean yrs - age 44 (8.4) yrs, education 8 (2.8)yrs and duration employed 20 (5.3) yrs. Fiveneuropsychological testscommonly associatedwith Pb exposure were examined for adifferential association with blood Pb,IBL,TWA and bone Pb.Mean (SD) blood Pb 26(7.07) μg/dLMean (SD) TWA 42(8.4) μg/dLMean (SD) IBL 903(305.9) μg·yr/dL,Mean (SD) tibial bone Pb41 μg/g bone mineralRelationship of 5 neuropsychologicaltests with 4 measures of Pb doseafter adjusting for age age2and education,education2found RAVLT trialV and Verbal Paired Associates were associated with blood Pb(♠R2= 6.2%, p = 0.02;♠R2= 5.5%, p = 0.07) and TWA (♠R2= 3.2%,p = 0.09;♠R2= 13.9%; P = 0.00) while Digit Symbol and GroovedPegboard were associated with TWA (♠R2= 6.1%, p = 0.00;♠R2= 5.5%,p = 0.02) and IBL (♠R2= 4.8%, p = 0.01;♠R2= 5.7%, p = 0.02). Onlygrooved pegboard was associated with bone Pb (♠R2= 4.2%, p = 0.05).Block design was not associated withany measures of Pb dose. Age wasan effect modifier with grooved pegboard. There was enhanced slowing inolder workers when compared to younger workers with the identical IBL.Bleecker et al. (1997b)New Brunswick1992-1993Of the 80 current smelter workers describedabove 78 completed a simple visual reactiontime (SRT) and had mean yrs age 44 (8.2) yrs,education 8 (7.2) yrs and duration employed20 (5.6) yrs.Mean (SD) blood Pb, 26(7.2) μg/dLMean (SD) blood Pb frombone 7 (4.2) μg/dLMean (SD) blood Pb fromenvironment 19(7.0) μg/dLMean (SD) bone Pb 40(25.2) μg/g bone mineralSRT consisted of 44 responses to avisual stimulusat interstimulusintervals (ISI) varying between 1 through 10 seconds with a mean SRT(median) of 262 (179 to 387) ms. Blood Pb and median SRT had acurvilinear relationship R2= Pb+ Pb2, 13.7%, p < 0.01) after adjusting forage and education with slowing of SRT beginning at a blood Pb of~30 μg/dL. No relationship existedbetween bone Pb and SRT. There wasa stronger association between Pb and Pb2and SRT for the longer ISIs of 6to 10 seconds (R2= 13.9%, p < 0.01), as age was significantly related tothe shorter ISI = s but not the longer ones. In this population thecontribution of bone Pb to blood Pb had been previously where estimatedwhere for a bone Pb level of 100 μg Pb/g bone mineral, 17 μg Pb/dL of theblood Pb was derived from internal bone stores with the remainder fromthe environment. Blood Pb was fractionated to that from bone (blood Pbbn) vs. blood Pb from the environment (blood Pb-en). Regression analysisto examine the relationship of blood Pb-bn and blood Pb-en and SRT afteradjusting for the covariates found significant contribution to the varianceof SRT only for blood Pb-en (R2for blood Pb-en + blood Pb-en2= 14.4%,p < 0.01). The absence of a contribution by age and more stable responseswith ISIs of 6 to 10 sec supportsusing this component of SRT.

# AX6-39Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationCanada(cont’d)Lindgren et al. (2003)New Brunswick1992-1993In an attempt to separate the effects of pasthigh Pb exposure from a lower proximateexposure, examination of the pattern of Pblevels of the 467 Canadian Pb smelterworkers found 40 workers who had high pastexposure followed by yrs where 90% ofblood Pb were above 40 μg/dL (High-High = H-H) while another group of 40workers had similar past high Pb exposurefollowed by yrs where 90% of blood Pb werebelow 40 μg/dL (High-Low = H-L). Thegroups did not differ on age, education, yrsof employment or CES-D. Five outcomesexamined-Purdue Pegboard assembly,Block Design, Digit Symbol, Rey AuditoryVerbal Learning Test-total score, delayedLogical Memory.Mean (SD) IBL for pastexposureH-H 633 (202.2) μg·yr/dLH-L 557 (144.8) μg·yr/dLMean (SD) IBL for theproximate exposureH-H 647 (58.7) μg·yr/dLH-L 409 (46.4) μg·yr/dLMean (SD) blood PbH-H 37 (5.1) μg/dLH-L 24 (5.2) μg/dLOf the five neuropsychologicalmeasures examined only RAVLT(total score) and Logical Memory(delayed) were significantlydifferent after adjusting for the covariates in the two pattern groups.Use of regression analyses found pattern group contributedsignificantly (R2= 4%, p < 0.05) to the explanation of variance inRAVLT after accounting for current blood Pb (R2= 3%, p < 0.10) andIBL measures (R2= 7%, p < 0.01). For past IBL, H-H patterncorrelated more strongly with RAVLT (r =!0.21) while H-L patternhad no relationship with past exposure (r = 0.08). For proximate IBLthe difference was maintained between H-H (r =!0.11) and H-Lpattern (r = 0.00). The authors suggested that the absence of anassociation between past high Pb exposure and verbal memory in theH-L pattern group may reflect reversibility of function when blood Pbis maintained below 40 μg/dL.Braun and Daigneault(1991)Quebec41 workers from a secondary Pb smelter,mean age 35 (9.6) yrs and yrs of education10 (2.1) were compared to a control groupmean age 37 (10.1) yrs and yrs of education11 (1.3) on tests of cognitive and motorfunction. MANCOVA and dose-effectrelationships after adjusting for potentialconfounders were performed.Mean (SD) TWA 53(7.5) μg/dLMean (SD) maximumblood Pb 87 (22.4) μg/dLNone of the measures of cognitive executive function showed groupdifferences. Partial correlation adjusting for age and education withdose related variables found no statistical significance. On motorfunction the exposed workers had significantly slower simple reactiontime (p = 0.05). However partial correlations with measures of dosefound dose-effect correlation in bothnegative and positive directions.Group of exposed workers was mixed for Pb exposure with 11currently working and the remainderwith no exposure up to 84 mos.Also two of the exposed workers had been treated with chelation.

# AX6-40Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEuropeH≅nninen et al. (1998)FinlandFifty-four Pb battery workers werestratified by those whose blood Pb neverexceeded 50 μg/dL (n = 26) (group 1)and those who had higher exposure in thepast (n = 28) (group 2) to examine theneuropsychological effects of current lowlevel blood Pb from higher blood Pb inthe past. Mean age group 1was 42 (9.3)yrs, education 8 (1.7) yrs and yrs ofexposure 12 (6.7). Mean age group 2 was47 (6.2) yrs, education 8 (1.0) yrs and yrsof exposure 21 (6.9). Analysis includedpartial correlations within the groups andANCOVA within group 1 divided at themedian TWA3 of 29 μg/dL.Group 1Mean IBL 330 μg·yr/dLMaximum blood Pb 40 μg/dLTWA 29 μg/dLTibial Pb 20 μg/gCalcaneal Pb 79 μg/gGroup 2Mean IBL 823 μg·yr/dLMaximum blood Pb 69 μg/dLTWA 40 μg/dLTibial Pb 35 μg/gCalcaneal Pb 100 μg/gIBL, TWA and maximumblood Pb were also calculatedfor the previous 3 yrs with amedian TWA3 of 29 μg/dLPartial correlations controlling for age, sex and education in group 1found block design, digit symbol, digit span, similarities, Santa Ana 1and memory for design significantly associated with recent measuresof exposure and embedded figureswith maximum blood Pb. In group2 embedded figures, digit symbol, block design, and associativelearning were associated with IBL and /or maximum blood Pb.Calcaneal Pb was weakly associated with digit symbol, digit symbolretention, and synonyms. There was no association with tibial Pb ineither group. Group 1 divided at the median TWA3 of 29 μg/dLfound the high group had lower scores for visuospatial andvisuoperceptive tasks (digit symbol, embedded figures and memoryfor design). Overall past high exposure, blood Pb >50 μg/dL, had thegreatest effect on tests requiring the encoding of complex visuallypresented stimuli. Theauthors conclude that the effect of Pb on brainfunction is better reflected by history of blood Pb than content of Pbin bone.Lucchini et al. (2000)Italy66 workers in Pb manufacturing, meanage 40 (8.6) yrs, mean education 8 ( 2.4)yrs and mean exposure time 11 (9) yrsand a control group of 86 with mean age43 (8.8) yrs, mean yrs of education 9(2.7) yrs. Group differences examinedand dose-effect relationship withcorrelation and ANOVA.Pb workersMean (SD) blood Pb 28(11) μg/dLMean (SD) IBL 410(360.8) μg·yr/dLMean (SD) TWA 32(14.1) μg/dLMean (SD) yrs exposed11(8.1)ControlMean (SD) blood Pb 84.5) μg/dLNo association with neuropsychological tests (addition, digit span,finger tapping symbol digit and motor test from Luria) and blood Pb,TWA or IBL were found. Blood Pb andvisual contrast sensitivities atthe high frequencies were significantly associated for the entire group.Blood Pb and serum prolactin in the whole group was significantlyassociated. Increased prolactin secretion occurs with a variety ofneurotoxins and reflects impaireddopamine function in the pituitary.The estimated threshold for a significant increase of high prolactinlevels was at a blood Pb of 10 μg/dL.

# AX6-41Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEurope(cont’d)_sterberg et al. (1997)Sweden38 workers, median age 42 (no range) yrs ata secondary smelter stratified by finger bonePb concentration and along with 19 controlsmatched triplets for age, education and joblevel. Median yrs employed 10 (2-35).High bone PbMedian (range) bone 32(17-101) μg/gMedian (range) blood Pb38 (19-50) μg/dLMedian (range) peak bloodPb 63 (46-90) μg/dLMedian (range) IBL 408(129-1659) μg·yr/dLLow bone PbMedian (range) bone 16(!7 to 49) μg/gMedian (range) blood Pb34 (17-55) μg/dLMedian (range) peak bloodPb 57 (34-78) μg/dLMedian (range) IBL 250(47-835) μg·yr/dLControlsMedian (range) bone 4(!19 to 18) μg/gMedian (range) blood Pb 4(1-7) μg/dLA cognitive test battery (36 tests) covering learning and memory,visuomotor function,visuospatial function, concentration andsustained attention found no impairment or dose-responserelationships with any of the markers of Pb exposure. Deviating testscores (belong to 10% lowest reference norms) were less in highbone Pb (1 vs. 4 vs. 4). None ofthe deviating parameters weresignificantly correlated with any of the Pb indices. Even when agewas taken into account the significant associationsbetween outcomeand Pb exposure metrics did not exceed chance in light of thenumerous analyses performed. These were the most heavily Pbexposed workers in Sweden. Itwas unusual that the 2 visuomotortasks significantly different hadbetter performance in the Pbexposed workers compared to the controls.

# AX6-42Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEurope(cont’d)Stollery et al. (1991)EnglandSeventy Pb-exposed workers, mean age41(no SD) yrs, grouped by blood Pb(<20 μg/dL, 21-40 μg/dL and 41-80 μg/dL)examined on three occasions each separatedby four mos. Tested on a computer forsyntactic reasoning, delayed five choicereaction time, visual spatial memory, andcategory search task.Low blood PbMean blood Pb 14 μg/dLMean ZPP 13 mg/dLMean urinary ALA 2 mg/LMean yrs exposed 7Medium blood PbMean blood Pb 31 μg/dLMean ZPP 33 mg/dLMean urinary ALA 3 mg/LMean yrs exposed 10High blood PbMean blood Pb 52 μg/dLMean ZPP 77 mg/dLMean urinary ALA 6 mg/LMean yrs exposed 11Pb exposure was stable over the 8 mos of testing. The low Pb groupdrank significantly less alcohol and rated their work as lessdemanding. Performance and exposure stable except in the high Pbgroup where decision time was slowed more than movement timealong with concentration difficulties that remained stable acrosstesting sessions. Movement and decision times were significantlycorrelated for each duration of waiting. On the memory test ofrecalled nouns, the memory deficit associated with Pb (r =!0.35,p = 0.003) was restricted to recall of nouns unrelated to task(distracters) (p = 0.04) that did not improve with repetition suggestiveof difficulties with incidental learning. Workers with blood Pb>40 μg/dL had impairments that correlated best with avg blood Pbover the preceding 8 mos. Workers with blood Pb between 21 to40 μg/dL had essentially no impairment.Stollery (1996)EnglandSame as above except this was a furtheranalysis of the five choice reaction time.Same as above Movement and decisionslowing was correlated with blood Pb.Slowed movement time was constant across response-stimulusintervals in contrast to decision time that was increasingly affected byPb especially at the shortest response-stimulus intervals.This supported the finding that decision gaps, central in origin, asopposed to movement gaps are selectively affected by Pb exposure inthis population.Barth et al. (2002)Austria47 Pb storage-battery workers, mean age40 (9.7) yrs and 53 nonexposed controls,mean age 39 (8.4) yrs were matched for ageand verbal intelligence. Group differencesand dose-response relationship wereexplored.Pb workersMean (SD) blood Pb 31(11.2) μg/dLMean (SD) IBL 384(349.0) μg·yr/dLMean (SD) yrs employed12 (9.0)ControlsMean (SD) blood Pb 4(2.0) μg/dLSignificant differences were found for block design (p#0.01), visualrecognition (p#0.01) and Wisconsin card sorting (categoriesp = 0.0005, total errors p = 0.0025, perseverations p = 0.001, loss ofsorting principle p = 0.003) but not SRT or digit symbol. In theexposed group partial correlation adjusting for age found nosignificant associations with IBL (n = 53). In the entire group the fullcorrelation was significant for blood Pb and Wisconsin card sorting,block design and visual recognition(n = 100). Visuospatial abilitiesand executive function were better predicted by blood Pb thancumulative Pb exposure. It is unusual that a frontal lobe task isassociated with blood Pb when SRT and digit symbol sensitive to theaffects of Pb are not.

# AX6-43Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEurope(cont’d)Winker et al. (2005)Austria48 workers formerly Pb-exposed, meanduration since last exposure 5 (3.5) yrs, andmean age 40 (8.8) yrs were matched with 48controls for age, verbal intelligence, yrs ofeducation and number of alcoholic drinks.Group differences and dose-responserelationship were explored.Formerly Pb-exposedMean (SD, range) blood Pb5.4 (2.7, 1.6-14.5) μg/dLMean (SD) IBL 4153.3(36930.3) μg·yr/dLControlsMean (SD, range) blood Pb4.7 (2.5, 1.6-12.6) μg/dLNo significant differences on neurobehavioral battery were presentwhen groups compared by t-tests for paired samples. When thegroups were combined, partial correlation adjusting for age foundsignificant negative correlation between blood Pb and Block Design,(r =−0.28, p < 0.01) Visual Recognition (r =−0.21, p < 0.05) andDigit Symbol Substitution (r =−0.26, p < 0.01). The authorsconclude that the cognitive deficits associated with low-level Pbexposure are reversible. However there appears to be a residual effectprimarily from those with thehighest past Pb exposure.Winker et al. (2006)AustriaThe same 48 workers formerly Pb-exposeddescribed above were compared to the47 exposed workers described by Barth et al.(2002). Both groups were comparable forage and verbal intelligence. Groupdifferences and differences by duration ofexposure and exposure absence wereevaluated.Exposed workersMean (SD, range) blood Pb31 (11.2, 10.6-62.1) μg/dLMean (SD) IBL 4613(4187.6) μg·yr/dLFormerly Pb-exposedMean (SD, range) blood Pb5.4 (2.7, 1.6-14.5) μg/dLMean (SD) IBL 4153.3(36930.3) μg·yr/dLMann-Whitney test found significantly better performance in theformerly Pb-exposed workers for Block Design (p = 0.005) andWisconsin Card Sorting Test (categories p = 0.0005, total errorsp = 0.005, perseverations p = 0.0095 and loss of sorting principlep = 0.02). To further examine the reduction of cognitive impairmentwith absence of exposure, workers were stratified by duration ofexposure and exposure absence – short exposure and long absence;long exposure and long absence; short exposure and short/no absenceand long exposure and short/no absence. Linear contrasts for BlockDesign (p = 0.003) and WisconsinCard Sorting Test (categoriesp < 0.001, total errors p = 0.001, perseverations p = 0.019 and loss ofsorting principle p = 0.030) were highly significant in thehypothesized direction. Results were believed to support reversibilityof cognitive deficits relatedto occupational Pb exposure.

# AX6-44Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationLatin AmericaMaizlish et al. (1995)Venezuela43 workers from a Pb smelter, mean age 34(9) yrs and 47 nonexposed workers, meanage 35 (11) yrs completed the WHOneurobehavioral coretest battery. ANCOVAand linear regression adjusting for potentialconfounders examined relationship of Pbexposure and NCTB.Pb workersMean (SD) blood Pb 43(12.1) μg/dLMean (SD) peak blood Pb60 (20.3) μg/dLMean (SD) TWA 48(12.1) μg/dLControlsMean (SD) blood Pb 15(6) μg/dLMean (SD) peak blood Pb15 (6) μg/dLMean TWA 15 (6) μg/dLGroup comparison was significant for SRT (p = 0.06) but the Pbexposed workers performed faster. Linear regression found SRTpoorer performance with blood Pband TWA but not significant.With peak blood Pb SRT improvedwith increasing Pb exposure.In this study only symptoms weresignificantly different betweenthe groups.AsiaSchwartz et al.(2001a)South Korea803 Korean Pb-exposed workers, 80% menand 20% women, mean age 40 (10.1) yrsfrom a variety of industries, and 135controls, 92% men and 8% women, meanage 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 testingafter controlling for covariates and linearregression controlling for covariatesexamined the presence of a dose-effectrelationship.Pb workersMean (SD) blood Pb 32(15) μg/dLMean (SD) tibia bone Pb37 (40.3) μg/gMean (SD) DMSAchelatable Pb level 186(208.1) μgControlsMean (SD) blood Pb 5(1.8) μg/dLMean (SD) Tibia bone Pb 6(7) μg/gNineteen outcomes examined. Compared to controls Pb exposedworkers performed significantly worse on SRT, Digit Span, BentonVisual Retention, Colored Progressive Matrices, Digit Symbol, andPurdue Pegboard after controlling forage, gender and education. Theassociation of DMSA with test performance was lost by the additionof blood Pb. Bone Pb was not associated with neurobehavioralperformance. Blood Pb was thebest predictor for significantdecrements in neurobehavioralperformance on trails B (∃=!0.0025[SE 0.0009], p < 0.01), Purdue Pegboard (dominant∃=!0.0159 [SE0.0042], p < 0.01; non-dominant∃= 0.0169 [SE 0.0042], p < 0.01;both∃=!0.0142 [SE 0.0038], p < 0.01; assembly∃=!0.0493 [SE0.0151], p < 0.01), and Pursuit Aiming (# correct∃=!0.1629 [SE0.0473], p < 0.01; # incorrect∃=!0.0046 [SE 0.0023], p < 0.05). Themagnitude of the effect for these eight tests significantly associatedwith blood Pb was an increase in blood Pb of 5 μg/dL was equivalentto an increase of 1.05 yrs in age. Use of Lowess lines for PurduePegboard (assembly) and Trails B suggested a threshold at blood Pb18 μg/dL after which there is a decline of performance.

# AX6-45Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Schwartz et al. (2005)South Korea1997-2001Longitudinal decline in neurobehavioralperformance examinedin 576 of the abovegroup of Pb exposed workers who completed3 visits at one yr intervals.Mean age at baseline was 41 (9.5) yrs andjob duration 9 (6.3) yrs and 76% were men.Compared to non-completers Pb workerswho 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 lessthan high school education. Modelsexamined short-term vs. long-term effects.Final model had current blood Pb, tibia bonePb and longitudinal blood Pb and covariates.Baseline mean (SD) bloodPb 31 (14.2) μg/dLMean (SD) tibiaPb 38 (43) μg/gBlood Pb from baseline correlated with those from visit 2 and 3 andbaseline tibial Pb correlated with that measured at visit 2. Cross-sectional associations of blood Pb orshort-term change occurred withTrails A (∃=!0.0020 [95% CI:!0.0040,!0.0001]) and B(∃=!0.0037 [95% CI:!0.0057,!0.0017]), Digit Symbol (∃=!0.0697[95% CI:!0.1375,!0.0019]) , Purdue Pegboard(dominant∃=!0.0131 [95% CI:!0.0231,!0.0031]; non-dominant∃=!0.0161 (95% CI:!0.0267,!0.0055); both (∃=!0.0163, [95% CI:!0.0259,!0.0067]; assembly (∃=!0.0536 [95% CI:!0.0897,!0.0175]), and Pursuit Aiming (# correct∃= 0.1526, [95% CI:!0.2631,!0.0421]) after covariates. However, longitudinal blood Pbwas only associated with poorerperformance on Purdue Pegboard(non-dominant∃=!0.0086 [95% CI:!0.0157,!0.0015]; both(∃=!0.0063 [95% CI:!0.0122, 0.0004]; assembly (∃=!0.0289 [95%CI:!0.0532,!0.0046]). Historical tibial bone Pb was associated withdigit symbol (∃=!0.0067 [95% CI:!0.0120, 0.0014]) and PurduePegboard (dominant∃=!0.0012, [95% CI:!0.0024,!0.0001]).Magnitude of Pb associations wasexpressed as the number of yrs ofincreased age at baseline that was equivalent to an increase of Pb fromthe 25th to 75th percentile. At baseline, these Pb associations wereequivalent to 3.8 yrs of age for cross-sectional blood Pb, 0.9 yrs ofage for historical tibial Pb and 4.8 yrs of age for longitudinal bloodPb. Analyses showed decline in performance over time related totibia Pb.

# AX6-46Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Hwang et al. (2002)South KoreaFrom the above cohort of 803 Korean Pbworkers, 212 consecutively enrolled workers,were examined for protein kinase C (PKC)activity and the relations between blood Pband neurobehavioral performance. PKCactivity assessed by measuring levels ofphosphorylation of three erythrocytemembrane proteins. Seventy-four percent ofworkers were men, mean age 36(0.8)yrs,duration of exposure 9 (0.6) and education93% had high school or less. For the femaleworkers, mean age 47 (0.9) yrs, duration ofexposure 6 (0.5), and education 95% hadhigh school or less.Male workersMean (SD) blood Pb 32(13.0) μg/dLMean (SD) tibia Pb 38(39.6) μg/gMean (SD) ZPP 69(47.8) μg/dLFemale workersMean (SD) blood Pb 20(9.2) μg/dLMean (SD) tibia Pb 26(14.7) μg/gMean (SD) ZPP 72(29.7) μg/dLBlood Pb was associated significantlywith decrements in Trails B(∃=!0.003 [SE 0.002], p < 0.10), SRT (∃=!0.0005 [SE 0.0003],p < 0.10) and Purdue Pegboard (dominant∃=!0.21 [SE 0.010],p < 0.05); non-dominant (∃=!0.021 [SE 0.010], p < 0.05); both(∃=!0.021 [SE 0.009], p < 0.05). PKCactivity as measured by backphosphorylation of erythrocyte membrane proteins was not associatedwith neurobehavioral test scores. Addition of the interaction term ofblood Pb by back-phosphorylation dichotomized at the median foundsignificant effect modification with the association of higher blood Pband poorer neurobehavioral performance occurring only amongworkers with lower back-phosphorylation levels that corresponds tohigher in vivo PKC activity. Association of blood Pb and SRT for the52 kDa subunit with high invivo PKC activity (adjusted∃=!0.001,p < 0.01) and for low in vivo PKC (adjusted∃=!0.0001, p = 0.92).The authors suggest that PKC activity may identifya subpopulation atincrease risk of neurobehavioral effects of Pb.Chuang et al. (2005)Taiwan27 workers from a glazing factory wereadministered a computerizedneurobehavioral battery 3 times over 4 yrs.At yr 1, the mean age was 40 (9.6) yrs. Inthe first yr workers were compared to areferent group matched for age andeducation. Neurobehavioral performancecompared in first yr to referent group withadjustment for age and Vocabulary.Generalized mixed linear mixed modelsanalyzed relationship between blood Pb leveland neurobehavioral test performance afteradjusting for age and Vocabulary.Pb workersYr 1Mean (SD) blood Pb 26(12)Yr 3Mean (SD) blood Pb 11(6.4)Yr 4Mean (SD) blood Pb 8 (6.9)ReferentMean (SD) blood Pb 7 (4.2)Referents scored significantly lower on questionnaire for chronicsymptoms in yr 1. In the mixed model analyses finger tappingdominant (p = 0.008) and non-dominant (p = 0.025) weresignificantly inversely associatedwith blood Pb. Pattern comparison(p < 0.001) and Pattern memory (p = 0.06) improved significantly asblood Pb levels improved. Chronic symptoms and neurobehavioralperformance appear to reverse when Pb exposure is decreased.However since the referent group was not tested in yr 3 and yr 4 itwas not possible to control for practice effect known to occur withrepeat neurobehavioral testingeven at two yr intervals.

# AX6-47Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Tsai et al. (2000)Taiwan19 Pb workers and 19 referents included inthe above publication, mean age 39 yrs inboth groups and mean education 10 (2.9) and9 (3.2) yrs, respectively, were tested with acomputerized neurobehavioral battery.Alcohol use was similar. Mean duration ofPb exposure 6 (2.5) yrs. Student’s tcompared neurobehavioral performancebetween the two groups.Mean (SD) blood Pb 32(12.2) μg/dLReferentMean (SD) blood Pb 7(2.7) μg/dLPoorer performance in Pb workersfor finger tapping, dominant andnon-dominant, and continuous performance task but only fingertapping was significant. Pb workers performed better than referentson Associate Learning, Pattern Comparison Test, Pattern MemoryTest, Visual Delay and Associate Learning Delayed that wasattributed to higher mean education.Chia et al. (2004)Singapore120 workers from Pb stabilizer factories,mean age 40 (10.7) yrs, duration of exposure10.2 (7.9) were given a neurobehavioralbattery. Genotyping of ALADpolymorphisms was performed. ANCOVAused to test for differences inneurobehavioral performance among ALADpolymorphism types adjusting for age,exposure duration and blood Pb.Mean (SD) blood Pb 22(9.4) μg/dLMean (SD) ALAD0.6(0.25) μm ofporphobilinogen/h/ml ofRBCMean (SD) ALAU0.9(0.56) mg/g creatinineFrequency of ALAD11, 87%, ALAD12, 12%, and ALAD22, 1%.Mean blood Pb adjusting for age and exposure duration was 20 μg/dLfor ALAD11 (n = 107) and 20.4 μg/dL for ALAD12 and 22 (n = 13).However ALAU was significantly higher in ALAD11 (p = 0.023).After adjusting for the covariates significant differences for groovedpegboard dominant hand (p = 0.01), non-dominant hand (p = 0.04),and grooved pegboard mean time (p = 0.006) were found betweenALAD11 and ALAD12 and 22. Considering cognitive tests were partof battery it is surprising education was ignored. As noted by theauthors the study only had 13 in the group with better performanceand the ALAD12 or 22 genotypes limiting the power.Chia et al. (1997)Singapore50 Pb battery manufacturing workers, meanage 36 (10.6) yrs, education 8.6 (2.1) yrsduration of employment 9 (7.4) yrs and97 controls, mean age 34 (3.7) yrs, andeducation 12 (1.8) yrs were administered aneurobehavioral battery. ANCOVA andlinear regression used to assess relationshipof Pb dose and performance.Pb workersMedian (range) blood Pb of38 (13.2-64.6) μg/dLMedian (range) IBL 264(10.0-1146.2) μg·yr/dLControlsMedian (range) blood Pb 6(2.4-12.4) μg/dLSignificant group differences for Santa Ana, grooved pegboard, digitsymbol, pursuit aiming and Trails A and B after adjusting for age,education, smoking, ethnic group andalcohol use. When the exposedgroup was stratified by age, in the group >35 yrs the poorerperformance on digit symbol and Trails A was significantlyassociated with cumulative Pb and not blood Pb after adjustingfor age and education.

# AX6-48Table AX6-3.3 (cont’d). Neurobehavioral Effects Associated with Occupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Niu et al. (2000)China44 Pb-exposed workers (17 men, 27 women)from Pb printing houses, mean age 35 (4.9)and education 9.3 (no SD) yrs and 34controls (19 men and 15 women), mean age33 (7.4) yrs and education 9.5 (no SD) yrscompleted the NCTB. ANCOVA controllingfor age, sex and education examined groupdifferences and linear regression for dose-response relationship.Pb workersMean (SD) blood Pb 29(26.5) μg/dL(8 workers blood Pbexceeded 50 μg/dL)ControlsMean (SD) blood Pb 13(9.9) μg/dL(1 control blood Pbexceeded 50 μg/dL)SRT (F = 2.30, p < 0.05), digit symbol (F = 4.81, p < 0.01) pursuitaiming # correct (F = 7.186, p < 0.01) and pursuit aiming total(F = 6.576, p < 0.01) had significantly poorer performance comparedto controls. No repression analyses provided.Boey and Jeyaratnam(1988)Singapore49 Pb-exposed workers, mean age 26 (7.6)yrs and 36 controls, mean age 30 (6.4) yrscompleted SRT and 8 psychological testscovering attention, vigilance, visual-motorspeed, short-term memory, visuomotortracking, visual scanning, and manualdexterity. Control group was matched foreducation level. Discriminate analysis ofneurobehavioral tests performed to determinewhich best discriminate the groups.Pb workersMean (SD) blood Pb 49(15) μg/dLControlsMean (SD) blood Pb 15(3) μg/dLSix tests were significantly different between the two groups-DigitSymbol, Bourdon-Wiersma, TrailsA, Santa Ana dominant, FlickerFusion and SRT. The group of tests that best differentiates Pbexposed workers from nonexposed workers were Simple ReactionTime, Digit Symbol (WAIS) and Trail Making Test (Part A) withlong latency in reaction time contributing three times more to thederived function than Digit Symbol (WAIS) or Trails A.

# AX6-49Table AX6-3.4. Meta-analyses of Neurobehavioral Effects with Occupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationBalbus-Kornfeld et al.(1995)Reviewed 21 studies from 28 publications;number of subjects ranged from 9-708.Mean blood Pb in mostexposed group28-68 μg/dL. Only 5studies used a measure ofcumulative exposure orabsorption of Pb, 2 studiesused duration of exposure.Dexterity (17/21 studies) and executive or psychomotor 11/21studies were the functional domains most commonly associated withPb. Age not adequately controlledin most studies, usually matchingmeans or medians. Intellectualabilities prior to exposure usuallyadjusted for with education; however, Vocabulary, a measure ofoverall intellectual ability stilldifferent between the groups.The conclusion reached that evidence of effects from cumulativeexposure or absorption of Pb was inadequate.Davis and Svendsgaard(1990)Meta-analysis of 32 studies of nerveconduction studies and Pb exposure.Presented 41 effect sizes with the overall effect size for all studiesD =!0.369 (p#0.001). All median nerves combined was D =!0.481(p#0.001) and for all ulnar nerves D =!0.211 (p#0.001). Themedian motor was most sensitive with an effect size of D =!0.553(p#0.001). Overall blood Pb was a weak measure of exposure forthe peripheral nervous system. Paradoxical association found effectsize smaller with increasing blood Pbbut increased with duration ofexposure.Meyer-Baron andSeeber (2000)Meta-analysis of studies with blood Pb<70 μg/dL found 12 studies with comparabletest procedure and sufficient documentationof results. Thirteen tests from the 12 studiesexamined.Exposed groupRange of mean blood Pb 31to 49 μg/dLControlsRange of mean blood Pb 6to 18 μg/dLBlock Design, Logical Memory,and Santa Ana had performancedeficits with small effect size. For Block Design the effect size wascomparable to changes observed with 20 yrs of aging. Aiming, SRT,Trials A and B, Digit Span and Digit Symbol also had poorerperformance but the large variance for effect sizes suggest otherfactors besides Pb exposure influenced performance. The authorsconclude, “that the evidence of neurobehavioral deficits at a blood Pbof ~40 μg/dL is obvious.”Goodman et al. (2002) Meta-analysis of 22 studies with medianblood Pb <70 μg/dL, numbers of exposedand unexposed workers given with scoresand dispersion on neurobehavioral tests.Exposed groupRange blood Pb 24 to63 μg/dLUnexposed groupRange blood Pb 0 to28 μg/dLDigit symbol and D-2 errors significant effect forfixed effects,weighted random effects and unweighted random effects. Simplereaction time, grooved pegboard, Trails A and B, picture completionvisual reproduction, eye-hand coordination and vocabulary hadsignificant effects for the fixedeffects model only. The authorsconclude none of the individual studies were adequate or conclusiveof subclinical neurobehavioral effects of exposure to Pb as thebiological effects of blood Pb <70 μg/dL are inconsistent. (SeeSchwartz et al. (2002) for comments).

# AX6-50Table AX6-3.4 (cont’d). Meta-analyses of NeurobehavioralEffects with Occupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationSchwartz et al. (2002)Letter to the Editor commenting onshortcomings in the Goodman et al. (2002)meta-analysis on studies of neurobehavioraltesting in workers occupationally exposed toPb.The six points regarding problems with the methodology included:(1) no evaluation of quality of study design or statistical methods,(2) data from poorly done and well done studies are combined,(3) included 6 studies with no age adjustment and 3 with noadjustment for education, (4) confounding of age and educationwhen addressed the variation acrossstudies not discussed, (5) maineffect only examined exposed vs. nonexposed comparisons that areknown to have the lowest power, cannot evaluated dose-effectrelationships and have a tendency for selection bias, and (6) few ofthe 22 studies included contributed to effect size.Seeber et al. (2002) A comparison of the two meta-analysesMeyer-Baron and Goodman) performed toevaluate recommendations of a German BEIof 40 μg/dL.Effect size calculated for 12 testsin two meta-analyses and 10 testsfrom one meta-analyses found subtleimpairments associated withblood Pb between37 μg/dL and 52 μg/dL for Logical Memory,Visual Reproduction, Simple Reaction Time, Attention Test d2,Block Design, and Picture Completion, Santa Ana, GroovedPegboard and Eye-hand Coordination. Effect sizes related to agenorms between ~40 to 50 yrs. For example,!3 score on BlockDesign = 10 to 15 yrs;!3.5 score on Digit Symbol = 10 yrs;!21 scoreon Cancellation d2 = 10 yrs; and +5 to +6 on Trails A = 10 to 20 yrs.This analyses concluded thatboth meta-analyses supportedrecommendation for German BEI of 40 μg/dL.Graves et al. (1991) A meta-analysis on 11 case-control studies ofAlzheimer’s disease for occupationalexposure to solvents and Pb.Four studies had data for Pb exposure with a pooled analysis ofrelative risks for occupational Pb of 0.71 (95% CI: 0.36, 1.41).The exposure frequencies were 16/261 for the cases and 28/337 forthe controls.

# AX6-51Table AX6-3.5. Neurophysiological Function and OccupationalLead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationCanadaBleecker et al. (2005b)New Brunswick1992-199374 current smelter workers, mean age44 (8.4) yrs, education 8 (2.8) yrs andemployment duration 20 (5.3) yr had currentperception threshold (CPT) measured forlarge and small myelinated and unmyelinatednerve fibers in the finger. Linear regressionmodeled CPT on metrics of Pb dose afteradjusting for covariates. Interaction of Pbdose and ergonomic stressor on peripheralnerve function was assessed.Mean (SD) blood Pb 26(7.1) μg/dLMean (SD) IBL 891(298.8)μg·yr/dLMean (SD) TWA 42(8.4)μg/dLMean (SD) tibia bone 40(23.8) μg/g5 metrics relating to IBLcumulated only exposureabove increasing blood Pbranging from 20 to60 μg/dLBlood Pb and tibial bone Pb were not associated with any of the threenerve fiber populations. IBL and TWA accounted for a significantpercentage of the variance only for the large myelinated nerve fibers(♠R2= 3.9%,♠R2= 8.7% respectively). The relationship of CPT andTWA was curvilinear with a minimum at a TWA of 28 μg/dL.Unique variance of CPT for large myelinated fibers explained bydifferent thresholds of IBL were IBL – 3.9%, p = 0.08; IBL20 – 5.8%,p < 0.03, IBL30 – 7.8%, p < 0.02; IBL40, p < 0.005; IBL50,p < 0.005; and IBL60, p < 0.005. IBL60 also explained significantvariance of CPT for small myelinated nerve fibers demonstrating anincreased impairment in peripheralnerve function. This effect onmyelinated sensory nerve fibers was enhanced when a measure ofergonomic stress was added to the model for IBL60.EuropeKovala et al. (1997)Finland60 workers in a Pb battery factory with amean age of 43 (9) yrs and mean exposureduration of 16 (8) yrs. Nerve conductionstudies, vibration thresholds, and quantitativeEEG were performed. Relationship of Pbexposure with peripheral nerve function andquantitative EEG were examined by partialcorrelation and regression analyses adjustingfor age.Mean (SD) tibial Pb 26(17) mg/kgMean (SD) calcaneal Pb88 (54) mg/kgMean (SD) IBL 546(399)μg·yr/dLMean (SD) TWA 34(8.4) μg/dLMean (SD) maximumblood Pb 53 (19) μg/dL,Mean (SD) blood Pb 27(8.4) μg/dLThe sensory amplitude of the medianand sural nerves had a negativecorrelation with IBL and duration of exposure that was not related toage. Vibration threshold at the ankle related significantly to IBL andduration of exposure after adjusting for age. Vibration threshold inthe finger was associated with bloodPb and blood Pb avgs over thepast three yrs. The alpha and beta frequencies were more present inworkers with higher long term Pb exposure such as tibial andcalcaneal, IBL and TWA. Overall historical blood Pb measures weremore closely associated with peripheral nerve function than bone Pbconcentrations. The study had no comparison group and did notaccount for the effect of smoking and alcohol use or give their usagein this population.

# AX6-52Table AX6-3.5 (cont’d). Neurophysiological Functionand Occupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsiaSchwartz et al.(2001a)South Korea1997-1999804 workers from 26 different Pb usingfacilities and 135 controls with a mean age of40 ( 10.1) and 35 (9.1) yrs respectively, jobduration of 8 (6.5) and 9 (5.3) yrsrespectively, and education level 42 % and69% completed high school respectively hadcomparable alcohol and smoking use. Linearregression used to compare vibrationthreshold in Pb exposed and controlscontrolling for potential confounders.Pb-exposed workersMean (SD) blood Pb32 (15) μg/dLMean (SD) tibia bone Pb37 (40.3) μg/gMean (SD) DMSA-chelatable Pb186 (208.1) μg (4 hcollection)After adjustment for age, gender,education and height, tibia Pb butnot blood Pb was significantly associated with poorer vibrationthreshold in the dominant great toe but not the finger (∃=!0.0020[SE 0.0007], p < 0.01). These results contrast with those forneurobehavioral measures (see above) performed in the same studywhere tibial Pb was not a predictor of performance.Schwartz et al. (2005)South Korea1997-2001Longitudinal decline in neurobehavioralperformance examinedin 576 of the abovegroup of Pb exposed workers who completed3 visits at one yr intervals.Mean age at baseline was 41 (9.5) yrs andjob duration 9 (6.3) yrs and 76% were men.Compared to non-completers Pb workerswho completed 3 visits were 3.3 yrs older,baseline mean blood Pb was 2.0 μg/dLlower, on the job 1.6 yrs longer, 24% womenvs. 10% of noncompleters, and usually hadless than high school education. Modelsexamined short-term vs. long-term effects.Final model had current blood Pb, tibia bonePb and longitudinal blood Pb and covariates.Baseline mean (SD) bloodPb 31 (14.2) μg/dLMean (SD) tibia Pb 38(43) μg/gAfter adjustment for age, visit number, education, gender, height(for vibration) and BMI (for grip strength and pinch) vibrationthreshold in the dominant great toe and not the finger was associatedwith tibia Pb (∃=!0.0006 [95% CI:!0.0010,!0.0002]) andlongitudinal blood Pb (∃=!0.0051 [95% CI:!0.0078,!0.0024])in one model and blood Pb (∃=!0.0019 [95% CI:!0.0039, 0.0001])in another model.

# AX6-53Table AX6-3.5 (cont’d). Neurophysiological Functionand Occupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationAsia(cont’d)Chuang et al. (2000)Taiwan206 Pb battery workers, mean age 41 yrs,with annual blood Pb for the previous fiveyrs had vibration perception measured inhand and foot. Relationship of Pb exposureterm and vibration perception thresholdassessed with multiple regressions, hockeystick regression analysis after adjusting forpotential confounders.Mean blood Pb 28 μg/dLMean blood Pb over past5 yrs 32 μg/dLMean maximum blood Pb39 μg/dLMean index of cumulativeexposure 425 μg·yr/dLMean TWA 32 μg/dLMean working duration13 yrs and life span inwork 31%After adjustment for age, sex, body height, smoking, alcoholconsumption, and use of vibratinghand tools, significant associationbetween mean blood Pb and mean TWA and vibration perception inthe foot were found. After adjustment for the covariates, a hockeystick regression analysis of footvibration threshold vs. mean bloodPb concentration for 5 yrs found an inflection point around 30 μg/dLwith a positive linear relation above this point suggesting a potentialthreshold.Chia et al. (1996a)Singapore72 workers in a Pb battery manufacturingfactory with a mean age of 30 yrs andreference group of 82 workers had nerveconduction studies and blood Pb performedevery 6 mos over the course of three yrs.Only 28 Pb battery workers completed theprogram. At the end of the first yr of the 82workers in the comparison group only 26remained and by yr 3 this had decreased to 4.Mean nerve conduction values examined byANCOVA between the exposed andreference after adjustment for age, ethnicgroup, smoking and drinking habits.Analysis of serial nerve conduction valuesand blood Pb treated as a clustered samplehad the within-cluster regression coefficientexamined. The 28 exposed workers werestratified by blood Pb level and therelationship between nerve conduction valuesand blood tested within the cluster.Geometric mean blood Pbconcentrations for the 6testing periods: 37, 41, 42,40, 41, and 37 μg/dLOverall range for blood Pb16-73 μg/dLThe relationship between blood Pb levels and nerve conductionvalues for the 28 exposed workers was significantfor all outcomesexcept median motor conduction velocity and ulnar sensory nerveconduction velocity and ulnar sensory amplitude. The regressioncorrelation coefficients for blood Pb >40 μg/dL was significant forall parameters exceptthe median sensory conduction velocity andfor blood Pb <40 μg/dL there was no association with nerveconduction values. Therefore the blood Pb level associated withno change in nerve conduction studies was <40 μg/dL.

# AX6-54Table AX6-3.5 (cont’d). Neurophysiological Function and Occupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationAsia(cont’d)Chia et al. (1996b)SingaporeExtension of above study - 72 workers in Pbbattery manufacturing and 82 controls. Meanduration of exposure 5.3 yrs.Mean blood Pb 37 μg/dLMean cumulative blood Pb137 μg·yr/dLANCOVA found significant differences for all nerve conductionparameters except three for the ulnar nerve, after adjusting for age,ethnic groups, smoking and drinking habits. There was nosignificant correlation between blood Pb and cumulative blood Pbwith nerve conduction values afterlinear regression with adjustmentfor confounders. When cumulative blood Pb was stratified- 12workers <40 μg·yr/dL, 28 workers 40-300 μg·yr/dL, 21 workers>300 μg·yr/dL ANCOVA found significant differences for5 nerve conduction parameters. The strongest dose effectrelationship was for sensorynerve conduction velocity.Chuang et al. (2004)Taiwan181 Pb battery manufacture workers werestratified by milk drinkers, n = 158 and non-or rare mild drinkers n = 23. Mean age in thetwo groups was 40 and 36 yrs and workingduration 10/8 yrs respectively. Peripheralnerve evaluation was with current perceptionthreshold at 3 frequencies 5Hz = C fibers,250 Hz = A-delta fibers and 2000 Hz = Abeta fibers. Linear regression estimated theassociation of CPT and Pb exposure variableand adjustment of milk intake and potentialconfounders.Blood PbMilk drinkers 25 μg/dLNon or rare milk drinkers30 μg/dLTWAMilk drinkers 28 μg/dLNon or rare milk drinkers32 μg/dLIBLMilk drinkers 316 μg·yr/dLNon or rare mild drinkers245 μg·yr/dLAge was significantly different butdistributions of gender, smoking,alcohol use, use of hand vibrationtool, working history and heightwere not different. Linear regressions found association of 5 Hz CPTand 250 Hz CPT in hand and foot with blood Pb and TWA but notIBL. However the protective effects of drinking milk was present forall fiber populations only in the hands. This paper presents anunusual finding of subclinical Pb neuropathy involving theunmyelinated and small myelinated fibers. Toxic axonopathiesclassically involve the large nervefibers. The main group differencemay be related to other nutritional deficiencies associated with themalabsorption syndrome that lead to the non-milk drinking status.Yokoyama et al.(1998)Japan17 gun-metal workers, mean age 48 yrs and a20 controls with a mean age of 45 yrs haddistribution of conduction velocities (DCV)measured and the maximum median sensoryconduction velocity (SVC) performed twiceat a yr interval. Group differencescontrolling for confounders and dose-effectrelationships were examined.Mean blood Pb 40 μg/dLMean mobilized Pb(CaEDTA) in urine1 mg/24 hANCOVA controlling for age and alcohol found mobilized Pb wasassociated with significant slowing in the large nerve fibers whileblood Pb was not. Workers with increased change in mobilized Pbover 1 yr interval (mean 0.44 mg/24hr) had significant reduction inlarge fiber (V95) conduction velocity while those workers with lesschange in mobilized Pb (0.08mg/24hr) did not have significantchange in DCV or SVC. It appears that larger faster conductingnerve fibers are susceptible to Pb and a measure of body burden(readily mobilized Pb from soft tissue) is a stronger predictor of thischange than blood Pb.

# AX6-55Table AX6-3.5 (cont’d). Neurophysiological Function and Occupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)He et al. (1988)China40 workers in a Pb smelter with age range 20to 45 yrs (no mean provided) and duration ofexposure 5.4 yrs. Fifty controls age 20 to55 yrs. Nerve conduction studies examined11 parameters.Student = s t-test examinedfor differences between exposed andcontrols.Mean blood Pb 40 μg/dLMean urinary Pb 71 μg/dLMean ALAU5 μg/dLThere were no symptoms or signs of peripheral nerve disorder.Both motor and sensory conduction velocities were slowed in the Pbexposed groups. 10 nerve conductionparameters were significant inthe group with blood Pb >40 μg/dL and 6 parameters weresignificant in the group with blood Pb <40 μg/dL. An unusualfinding in this study was the lackof age association with nerveconduction values and therefore it was not controlled for in theanalyses.Niu et al. (2000)China44 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 nerveconduction studies formaximal motor nerveconduction velocity.ANCOVA controllingfor age, sex and education examined groupdifferences and linear regression for doseresponse relationship.Pb workersMean blood Pb 29(26.5) μg/dL(8 workers blood Pbexceeded 50 μg/dL)ControlsMean blood Pb 13(9.9) μg/dL(1 control blood Pbexceeded 50 μg/dL)Only 12 Pb exposed workers and 24 controls examined for NCV.Left ulnar nerve was significantlyslower but the left median andright ulnar were faster in the Pbexposed and the right median wasslightly slower. This appears to be a finding of chance due to thesmall n. For the Pb exposed group mean left ulnar CV was 52 whilethe mean right ulnar CV was 59 while for the controls left ulnar CVwas 58 while the mean right ulnar CV was 55.

# AX6-56Table AX6-3.6. Evoked Potentials and Occupational Lead Exposure in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationCanadaBleecker et al. (2003)New Brunswick1992-1993359 currently employed smelter workers, mean age 41yrs, had brainstem auditory evoked potentials (BAEP)measured. Relationship between absolute latenciesand interpeak latencies assessed using linear regressionafter adjusting for potential confounders. Exposurewas assessed in cases withclinical abnormalities inWave I and I-V interpeak latency compared to thoseworkers with normal BAEPusing post-hoc analysis.Mean blood Pb 28 μg/dLMean TWA 39 μg/dLMean IBL 719 μg·yr/dLLinear regression after the contribution of age found bloodPb and TWA were significantly associated with Wave Iwhile IBL was significantly associated with Wave III and I-III interpeak interval. Fourgroups created with increasingabnormalities based upon clinical cut-off scores for Wave Iand I-V interpeak interval hadsimilar age. blood Pb, TWAand IBL were all significantly higher in the group withprolonged Wave I and I-V interpeak interval comparedto the group with normal BAEP = s. These findingssupport involvement of the brainstem and auditory nervewith Pb exposure.EuropeAbbate et al. (1995)Italy300 Pb exposed men ages 30 to 40 yrs in good healthwith no other neurotoxic exposure had P100 latencymeasured for visual evoked potentials (VEP) for 15and 30 minute of arc. Groups created based uponblood Pb had VEPS examined followed by linearregression for each group.Blood Pb 17 to 60 μg/dLrangeMean blood Pb for 4 groupsn = 39 23 μg/dLn = 113 30 μg/dLn = 89 47 μg/dLn = 59 56 μg/dLANOVA of the blood Pb and P100 latencies weresignificantly prolonged for 15 and 30 minutes of arc.Linear regression found the association of blood Pb andP100 were significant in each group but the relationshipwas not proportional (angular coefficient). Effect of bloodPb on VEP began at 17-20 μg/dL.With age limited to onedecade, contribution from age was not a concern. Eventhough no comparison group, careful screening ruled outother medical and eye conditions and other potentialexposures.Discalzi et al. (1992)Italy49 Pb exposed workers and 49 age and sex matchedcontrols had BAEPs measured. Relationship of 6BAEP outcome variables and Pb exposure examinedwith analysis of variance and linear regression.Mean blood Pb 55 μg/dLMean TWA for previous3 yrs 54 μg/dLLatencies for waves I, III, V and interpeak latencies, I-V, IIII, and III-V were all significantly prolonged in the Pbexposed workers (p < 0.04).No significant associationfound with linear regression between BAEP outcomes andexposure variables. In those workers with TWA>50 μg/dL, I-V latency was significantly prolongedcompared to workers with TWA <50 μg/dL.

# AX6-57Table AX6-3.6 (cont’d). Evoked Potentialsand Occupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Discalzi et al. (1993)Italy22 battery storage workers, mean age 35 yrs and 22control group, age and sex matched, with normalhearing had BAEPs recorded. Latencies I and V and Pbexposure examined by ANOVA after stratifying bloodPb.Mean blood Pb 48μg/dL Interpeak latency I-V was significantly prolonged in Pbexposed workers (p = 0.001). No significant associations bylinear regression between I-V and Pb exposure. StratifyingPb exposed workers by blood Pb 50 μg/dL found I-Vinterpeak latency significantly prolonged (p = 0.03) insubgroup with higher blood Pb.Latin AmericaCounter and Buchanan(2002)Ecuador30 Pb-glazing workers, median age 35 yrs, had pure-tone thresholds and BAEPs performed. Regressionanalyses examined relations between auditory outcomesand blood Pb.Mean blood Pb 45 μg/dL(range 11 to 80 μg/dL)Sixty percent of the men and 20 percent of the women hadabnormal high-frequency thresholds, however there was nosignificant relationship with blood Pb and pure tone thresholdat all frequencies. Analysis of BAEPs found agreementbetween latencies for WavesI, III and V and peripheralhearing status. Interpeak latencies were within normal limitsbut no analysis provided with Pb exposure. Workers lived ina Pb contaminated environment from discarded Pb-acidstorage batteries. Therefore a measure of chronic Pbexposure may have been more appropriate.AsiaHoldstein et al. (1986)Israel20 adults and 8 children (mean age 27 yrs, range 8 - 56yrs) accidentally exposed to Pb through food until one yrprior to measurement of BAEP.Mean blood PbAdult 31 μg/dLChildren 22 μg/dL10 mo avg blood Pb Adults43 μg/dLChildren 36 μg/dLIn adults, latencies I, III andI-III and I-V interpeak intervalswere significantly longer than the control group (p < 0.05).When group stratified by 10 mo avg blood Pb I-III interpeakinterval was longer in the high group. Age and blood Pbwere not studied due to fewsubjects. The I-III interpeakinterval reflects transmission in the lower brainstem andVIIIth nerve.

# AX6-58Table AX6-3.6 (cont’d). Evoked Potentialsand Occupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Hirata and Kosaka(1993)Japan41 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 meanage 41 yrs, mean duration of exposure 13 yrs. A battery of testsadministered including radial nerve conduction study,electroretinogram (ERG), visual evoked potential (VEP),brainstem auditory evoked potential (BAER), and short-latencysomatosensory evoked potential (SSEP). Comparison group of 39unexposed used only for BAER analysis by Student’s t test.Correlation and linear regression controlling for age examined therelationship of Pb and the other variables.Mean (range) blood Pb43 μg/dL (13-70)Mean (range) TWA (basedupon previous 5 yrs)43 μg/dL (13-70)Mean (range) duration ofexposure 13 (0.6-29) yrsSignificant partial correlation after adjusting for ageincluded TWA and radial motor conduction velocity,blood Pb and sensory conduction velocity, exposureduration and VEP, blood Pb and SSEP-N20.Comparison of BAERs of 15 Pb exposed and 39controls found interpeak interval III-V wasprolonged significantly. It is not clear whycomparison group only used for BAERs.Considering the large number of variables examinedwith three exposure terms some of the findings couldbe by chance alone.Murata et al. (1993)Japan22 gunmetal foundry workers with age range of 32 to 59 yrs andwork duration of 1 to 19 yrs and control group matched for age,no chronic disease and no Pbexposure participated. Nosignificant difference betweengroups for age, height, skintemperature, alcohol consumption,and yrs of schooling. The testbattery consisted of visual evoked potential (VEP), brainstemauditory evoked potential (BAEP), short latency somatosensoryevoked potential (SSEP), event related potential (P300) and EKGR-R interval variability. Paired-sample t test examined fordifferences between the matched groups. Dose-effectrelationships examined with partial correlation adjusting for ageand stepwise linear regression.Blood Pb 12 to 64 μg/dL(no mean provided)For VEPs, N75 and N145 were significantlyprolonged in the Pb exposed workers. N9-N13interpeak latency of the SSEP was significantlyprolonged. BAEP latencies showed no significantdifferences. P300 believed to reflect cognitivefunction was prolonged in the Pb workers andcorrelated with blood Pb, and PbU. Autonomicnervous system effects weresignificantly diminishedfor CVR-Rand for a measure of parasympatheticactivity C-CVRSA. Fifty percent of the outcomevariables showed significant group differences butthere is limited dose effect for any outcome withinthe exposed group. Small sample size limitedconclusions with 20 outcome variables and 8biomarkers of Pb exposure.

# AX6-59Table AX6-3.7. Postural Stability, Autonomic Testing, Electroencephalogram, Hearing Thresholds, andOccupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesDick et al. (1999)U.S.145 workers from a secondary Pb smelter, meanage 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 hadpostural sway testing performed. The analysis ofexposure with test conditions and covariates usedmixed models.Pb workersMean (SD) blood Pb 39(8.5) μg/dLMean (SD) ZPP 55 (42.2) μg/dLMean (SD) CBL 230(217.9) μg·yr/dLMean (SD) TWA 35 9(8.5) μg/dLComparison workersMean (SD) blood Pb 2(1.7) μg/dLThe postural sway test had 6 conditions that varied thechallenge to the vestibular and proprioceptive afferents andvisual system. Only blood Pb had a significant effectprimarily on the one leg condition after the effects of thecovariates age, height, mass, and race. For the left leg,exposure slope estimate for area (b = 0.0067, t = 3.88,p = 0.0001) and length (b = 0.0046, t = 4.11, p = 0.0001)were significant. For the right leg only the exposure slopeestimate for length (b = 0.0033, t = 3.02, p = 0.0029) wassignificant. Dose effect was only significant when Pbworkers were combined with comparison workers. Ifcomparison workers with blood Pb level below 12 μg/dLremoved no significant exposure effect was found.EuropeKovala et al. (1997)Finland60 workers in a Pb battery factory with a meanage of 43 (9) yrs and mean exposure duration of16 (8) yrs. Quantitative EEG were performed.Relationship of Pb exposure with quantitativeEEG were examined by partial correlation andregression analyses adjusting for age.Mean (SD) tibial Pb 26(17) mg/kgMean (SD) calcaneal Pb88 (54) mg/kgMean (SD) IBL 546(399)μg·yr/dL,Mean (SD) TWA 34 (8.4) μg/dL,Mean (SD) maximum blood Pb53 (19) μg/dLMean (SD) blood Pb 27(8.4) μg/dLThe alpha and/or beta frequencies were more present inworkers with higher long term Pb exposure such as tibial(p < 0.05) and calcaneal (p < 0.05), IBL (p < 0.01) andTWA (p < 0.05). Slow alpha in workers was believed tocorrelate with increased episodes of ‘microdrowsiness’.The study had no comparison group and did not account forthe effect of smoking and alcoholuse or give their usage inthis population.

# AX6-60Table AX6-3.7 (cont’d). Postural Stability, Autonomic Testing, Electroencephalogram, Hearing Thresholds, andOccupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsiaIwata et al. (2005)Japan121 workers from a battery recycling plantand 60 age matched comparison group, meanage 46 (11) yrs. Height, body weight, bodymass index, and alcohol use was similar inboth groups. Pb group had significantlymore smokers. ANCOVA used to evaluatepostural sway after controlling for age,height, and smoking and drinking status.Benchmark dose level was calculated as the95% lower confidence limit of thebenchmark dose.Mean (SD) blood Pb 40(15) μg/dLReferentNot doneExcept for sagittal sway, all postural sway parameters with eyes openwere significantly larger in Pb workers. Blood Pb level in workerswas significantly associated with tosagittal sway at 1-2 Hz and 2-4Hz with eyes open, and sagittal and transversal sways at 1-2 Hz and2-4 Hz with eyes closed. The mean benchmark dose level of currentblood Pb level for postural sway was 14.3 μg/dL for the linear modeland 14.6 μg/dL for the K power model.Yokoyama et al.(1997)Japan49 chemical workers exposed to Pb stearate,mean age 48 (1.3) yrs and 23 controls, meanage 47 (2.5) had postural sway evaluated.ANCOVA examined group differences afteradjusting for covariates.Mean (SD) blood Pb 18(1.0) μg/dLMean (SD) maximumblood Pb 48 (3.8) μg/dLMean (SD) TWA 24(1.3) μg/dLMean (SD) Cumulativeblood Pb 391(48.2) μg·yr/dLThere were significant increases in sway in all directions at high andlow frequencies with eyes open and eyes closed (p < 0.05).Regression analysis found blood Pb associated with sway in theanterior-posterior direction, 0.5-1Hz (0.321, p = 0.03), 1-2Hz (0.313,p = 0.04) and TWA associated with right to left sway (0.326,p = 0.02) after adjustment for the covariates age, height, weight andalcohol consumption. The authors conclude that change in thevestibulo-cerebellum is affected by blood Pb while in the anteriorcerebellar lobe is affected by past Pb exposure.Chia et al. (1994a)Singapore60 Pb storage workers, mean age 32 (7.7) yrsand 60 controls, mean age 35 (7.4) hadpostural sway parameters measured.ANCOVA used to examine group differencesafter adjusting for covariates. Linearregression examined relationship between Pbexposure and postural sway.Pb workersMean (SD) blood Pb 36(11.7) μg/dLControlsMean (SD) blood Pb 6(2.4) μg/dLComputerized postural sway measurements found Pb workershave poorer postural stability thatincreased with eyes closed(p < 0.01). Regression analysisadjusting for age, height, andweight found no significantassociation with blood Pb.Chia et al. (1996c)SingaporeThe same 60 Pb storage workers as aboveand 60 control had postural sway dataexamined for contribution of cumulativeblood Pb fractionated over 10 yrs ofexposure.Pb workersMean (SD) blood Pb 36(11.7) μg/dLControlsMean (SD) blood Pb 6(2.4) μg/dLThe Pb exposed group had significantly poorer performance on allpostural sway parameters with eyesclosed compared to controls afteradjusting for height, weight, age and drinking habits (p < 0.01).All postural sway parameters witheyes closed were significantlyassociated with IBL for the 2 yrs prior to testing (n = 23, p < 0.05).

# AX6-61Table AX6-3.7 (cont’d). Postural Stability, Autonomic Testing, Electroencephalogram, Hearing Thresholds, andOccupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Ratzon et al. (2000)Israel63 Pb battery workers, mean age 39 (8.7) yrsand 48 controls mean age 36 (11.8) yrs,matched for age with similar sex andeducation, had postural control measured.Group differences examined with t test.Dose-effect relations assessed withPearson = s correlation coefficients. Linearregression done with exposure category asmajor predictor.Mean past blood Pb38 μg/dLMean yrs employed 11Cumulative Pb determinedby avg blood PbΗyrsemployedUsing a computerized sway measurement system the exposedworkers had significantly increased mean body oscillations with eyesclosed (p < 0.01) and head tilted forward (p < 0.001). Partialcorrelation adjusting for education, coffee consumption, hrs of sleepand estimate of health was significant only for total Pb exposure andincreased body oscillations with head tilted forward (∃= 2.25,p = 0.0089). In order to maintain balance Pb exposed workersrequired increased oscillations whenvisual and vestibular inputswere altered.Teruya et al. (1991)Japan172 Pb exposed workers, mean age 34(18.4-57.4) yrs had cardiac autonomicnervous system evaluated by R-R intervalsvariation with respiration measured.Mean (range) blood Pb 36(5-76) μg/dLAge adjustment controlled for byuse of ratios of predicted toobserved values. A significant doserelated decrease of R-R intervalvariation during deep breathing was present in 132 workers withstable blood Pb over the past yr (p < 0.01). This finding was moreprominent in younger workers with blood Pb∃30 μg/dL but a milddecrease present at blood Pb∃20 μg/dL. A decrease in R-R intervalvariation indicates decreased cardiac parasympathetic function.Ishida et al. (1996)Japan128 workers in the ceramic painting industry,58 men, mean age 55 (11.7) yrs and70 women, mean age 52 (9.2) yrs hadmeasures of sympathetic function byvariations in R-R interval on EKG andchanges in finger blood flow with posturalchanges using Doppler flowmetry.Correlation analyses and linear regressionexamined relationship of finger blood flowand Pb exposure after adjusting forcovariates.MenMean (SD) blood Pb 17(2.1) μg/dLMean (SD) ALAD% 61.6(28.3)%WomenMean (SD) blood Pb 11(1.7) μg/dLMean (SD) ALAD% 72.6(20.8)%22% had blood Pb >20 μg/dL, and 43% had ALAD% <60%. The46 workers in the lowest group with blood Pb <10 μg/dL hadALAD% >80% equivalent tononoccupational exposure andtherefore served as the control group. Blood Pb (∃= 0.205,p = 0.02), smoking (∃=−0.464, p < 0.01), and BMI (∃= 0.213,p = 0.01) were significant predictors of change in finger blood flowwith postural change. Decrease inchange of finger blood flow iscompatible with a peripheral sympathetic nerve impairment.

# AX6-62Table AX6-3.7 (cont’d). Postural Stability, Autonomic Testing, Electroencephalogram, Hearing Thresholds, andOccupational Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Niu et al. (2000)China44 Pb-exposed workers (17 men, 27 women)from Pb printing houses, mean age 35 (4.9)and education 9.3 (no SD) yrs and 34controls (19 men and 15 women), mean age33 (7.4) yrs and education 9.5 (no SD) yrshad autonomic nervoussystem examined.ANCOVA controlling for age, sex andeducation examined group differences andlinear regression for dose-responserelationship.Pb workersMean (SD) blood Pb 29(26.5) μg/dL(8 workers blood Pbexceeded 50 μg/dL)ControlsMean (SD) blood Pb 13(9.9) μg/dL(1 control blood Pbexceeded 50 μg/dL)Niu et al. (2000) examined autonomic nervous system in 44 Pbexposed workers, mean blood Pb29 μg/dL, and 34 controls, meanblood Pb, 13 μg/dL. Linear regression found association betweenblood Pb and decreased R-R interval with valsalva (F/T 2.349,p < 0.05) and duration of Pb exposure and decreased R-R intervalwith deep breathing (F/T 3.263, p < 0.01) after adjusting for age, sex,education, smoking and drinking.In the same study, quantitativeEEG found significant abnormalities in the Pb-exposed workers,dominant low amplitude in 59%, dominant beta frequency in 42%and abnormalities in 81%.

# AX6-63Table AX6-3.8. Occupational Exposure to Organolead and Inorganic Lead in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited StatesSchwartz et al. (1993)U.S.Two hundred and twenty-two currentemployees that manufactured tetraethyl Pbparticipated in a study to determine if therewas impairment on a neurobehavioral batteryassociated with a measure of cumulativeexposure to organic and inorganic Pb derivedfrom 12 yrs of air sampling. Mean age was44 (8.7) yrs, education 13 (1.7) yrs.Mean (SD) cumulative Pbexposure (inorganic andorganic) 869 (769) μg·yr/m3Mean (SD) yrs of exposure13 (9.5)Exposure was divided into 4 groups with the lowest for yrs ofexposure and cumulative Pb exposure serving as the reference group.After adjustments for premorbid intellectual ability, age, race, andalcohol consumption, cumulative Pb exposure had differentialassociation poorer performance in many cognitive domains but mostoften in manual dexterity and verbal memory/learning. Performanceon tests associated with exposure was 5 to 22% lower in the highestgroups when compared with the low exposure reference group.Stewart et al. (1999)U.S.543 former organolead workers, mean yrssince last exposure18, examined for ongoingneurobehavioral impairment related to pastPb exposure. Thirty-eight % were age 60 orolder, predominantly white, 93% had at leasta high school degree. Linear regressionassessed the relationship between Pb doseand neurobehavioral function adjusting forthe covariates.Mean (SD) tibial Pb 14(9.3) μg/gMean (SD) peak tibial bonePb (extrapolated back using aclearance half-time of Pb intibia of 27 yrs) 24(17.4) μg/gMean (SD) DMSA chelatablePb 19 (17.2) μg (urinecollected for 4 hrs)Peak tibial Pb was a significant predictor of poorer performance onVocabulary (∃=!0.063, p = 0.02), serial digit learning (∃=!0.043,p = 0.04), RAVLT trial 1 (∃=!0.054, p = 0.03), RAVLT recognition(∃=!0.019, p = 0.03), Trails B (∃=!0.002, p = 0.03), finger tappingnondominant (∃=!0.042, p = 0.02), Purdue pegboard dominant(∃=!0.043, p = 0.00), nondominant (∃=!0.49, p = 0.00), both(∃=!0.038, p = 0.00), assembly (∃=!0.133, p = 0.00), and Stroop(∃=!0.014, p = 0.00).Current tibial Pb had similarassociations – Vocabulary (∃= 0.103,p = 0.04), Digit Symbol (∃=!0.095, p = 0.05), finger tappingdominant (∃=!0.87, p = 0.02), finger tapping nondominant(∃= 0.102, p = 0.00), Purdue Pegboard dominant (∃=!0.065,p = 0.01), nondominant (∃=!0.091, p = 0.00), both (∃=!0.068,p = 0.00), assembly (∃=!0.197, p = 0.03 ), and Stroop (∃= 0.017,p = 0.01).DMSA-chelatable Pb was only significantly associated with choicereaction time (∃=!0.001, p = 0.01).

# AX6-64Table AX6-3.8 (cont’d). Occupational Exposure to Organolead and Inorganic Lead in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited States(cont’d)Stewart et al. (2002)U.S.From the above group of former organoleadworkers 535 were re-examined twice or fourtimes over a four yr period. Also anonexposed control group of 118 had repeatexaminations. Mean age at first visitexposed/controls 56 (7.4)/59 (7.0),percentage with at least a high schooleducation 66/71.2.1st examinationMean (SD) blood Pb 5(2.7) μg/dLMean (SD) tibia Pb 14(9.3) μg/gMean (SD) peak tibia Pb23 (16.5) μg/gMean (SD) exposure duration8 (9.7) yrsMean (SD) duration since lastexposure 16 (11.7) yrsOn 17 of 19 neurobehavioral tests, former organolead workersdemonstrated greater annual decline in adjusted test scorescompared to controls with significant differences for Rey complexFigure copy, RAVLT Trial 1 and RAVLT recognition. Annualdeclines in performance showed greater age-related change in Pbworkers compared to controls for block design, digit symbol,serial digit learning, finger tappingand Trails A. Blood Pb did notpredict annual change scores butpeak tibial Pb did for symboldigit, Rey Complex Figure delayed recall, RAVLT trial 1,RAVLT delayed recall, Purduepegboard (1 measure) and theStroop. For these 6 tests it was determined that an increase of15.7 μg/g bone mineral of peak tibia Pb was equivalent in itseffect on annual test decline to 5 more yrs of age at baseline.Authors conclude that data supports ongoing cognitive declineassociated with past occupational exposure to Pb.Balbus et al. (1997)U.S.222 organolead manufacturing workers,mean age 44 (8.7) yrs and 62 nonexposedreferents, mean age 43 (10) yrs performedsimple visual reaction time (SVRT). Linearregression examined relationship between Pbexposure and mean RT, median RT andstandard deviation of RT after controlling forcovariates.Mean (SD) blood Pb 20(9.5) μg/dLMean (SD) peak urine Pb level143 (130) μg/LBalbus et al. (1998)U.S.A second publication further examined theabove data for relationship of interstimulusinterval (ISI) and Pb exposure.Same as above Short ISIs of 1-3 secondshad no relationship with Pb exposurewhile ISIs of 4-6 seconds were significantly associated with bloodPb (∃= 0.06 [SE 0.02], p = 0.02 along with ISIs of 7-10 seconds(∃= 0.05 [SE 0.02], p = 0.03). ISIs7-10 seconds with peak urinePb levels (∃= 64.29 [SE 21.86], p < 0.01).

# AX6-65Table AX6-3.8 (cont’d). Occupational Exposure to Organolead and Inorganic Lead in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited States(cont’d)Stewart et al. (2002)U.S.Population as described in Stewart et al.(1999) and Schwartz et al. (2000b). Dataon 20 neurobehavioral tests from 529former organolead workers wereevaluated to determine if the previouslydescribed relationship with bone Pblevels is influenced by the apolipoproteinE (ApoE) genotype.In 20 linear regression models, coefficients for the ApoE and tibia Pbinteraction term were negative in19 with significance reached for digitsymbol (∃=!0.109 [SE 0.054], p#0.05), Purdue pegboard dominant(∃= 0.068 [SE 0.028], p#0.05) and complex reaction time (∃=!0.003[SE 0.001], p#0.05) and borderline significance existed for symbol digit(∃=!0.046 [SE 0.026], p#0.10), Trails A (∃=!0.303, [SE 0.164]p#0.10) and Stroop (∃=!0.013 [SE 0.008], p#0.10). The slope of therelation between tibia Pb and neurobehavioral outcome was morenegative in those individuals with at least oneε4 allele than individualswithout this allele.It is suggested thatthe presence of one Apo-ε-4 alleleincreases the risk of persistent central nervous system effects of Pb.Tassler et al. (2001)U.S.490 former organolead workers, meanage 58 (7.5) yrs. The peripheral nervoussystem was examined with sensorypressure thresholds, and pinch and gripstrength.Mean (SD) blood Pb 5(2.6) μg/dLMean (SD) DMSA-chelatable Pb19 (16.3) μgMean (SD) current tibia Pb15 (9.4) μg/gMean (SD) peak tibia Pb 24(17.6) μg/gNo strong association was found between Pb biomarkers and measuresof sensory and motor function after adjusting for age. The authorsattributed the findings to decreased sensitivity of the peripheral nerves inthis dose range of inorganic Pb or thepossibility of differential repair inthe peripheral nervous system compared to the central nervous system.Bolla et al. (1995)U.S.190 current workers in organoleadmanufacturing (from the 222 described inSchwartz et al., 1993) mean age 45 (8)yrs compared to 52 referents, mean age45 (8) yrs and 144 solvent exposedworkers, mean age 42 (8) yrs.IH found organic Pb was 65 to70% of exposure in productionarea.Mean (SD) weighted avg bloodPb 24 (9.4) μg/dLPb and solvent exposure associated with adverse effects on tests ofmanual dexterity. When compared to the solvent group Pb exposure hadgreater impairment on memory andlearning and less on executive/motortests. An elevated neuropsychiatric score was present in 43% of the Pbgroup, 15% of the solvent and 7% of the referent group.Mitchell et al. (1996)U.S.58 organolead workers, self-selected fora clinical evaluation. Mean age 45 (7.1)yrs.Mean (SD) blood Pb 19(6.5) μg/dLMean (SD) lifetime blood Pb 26(9.1) μg/dLMean (SD) lifetime urine Pb 51(18.8) μg/LThe most common symptoms were memory loss 74%, joint pain 56%,trouble sleeping 54%, irritability 51%, paresthesia 49%, fatigue 49%,nightmares 35%, moodiness 28%, headaches 21% and depression 21%.Of the 31 workers receiving nerve conduction studies, 29% were normal,carpal tunnel syndrome 36%, cubital tunnel syndrome 3%, medianneuropathy 3%, ulnar neuropathy 23%, mononeuropathy in lowerextremity 5%, tarsal tunnelsyndrome 7% and sensorimotorpolyneuropathy 36%. 39 workers hadneurobehavioral evaluation with64% had abnormal tests of which 46% were considered to be consistentwith a toxic exposure.

# AX6-66Table AX6-3.9. Other Neurological Outcomes Associated with Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesLouis et al. (2005)New York63 cases of essential tremor(ET) and 101 controls,similar for age, 67 (16.6) and65 (11.1) yrs, education,gender and ethnicity wereexamined for interaction ofblood Pb and ALAD genepolymorphisms and increasedodds of ET.ETMean (SD) blood Pb 4 (2.2) μg/dLControlsMean (SD) blood Pb 3 (1.5) μg/dL2 ET cases but no controls had blood Pb>10 μg/dLOf the 63 ET cases 18 (29%) vs. 17 (17%) of 101 controls had anALAD2 allele (OR = 1.98 [95% CI: 0.93, 4.21]; p = 0.077). Whenlog blood Pb was examined by presence of ALAD2 allele in ET, logblood Pb was highest in ET cases with and ALAD2 allele,intermediate in ET cases without an ALAD2 allele and lowest incontrols (test for trend,∃= 0.10; p = 0.001). When ALAD2 allelewas present, blood Pb was significantly associated with odds of ET(OR = 80.29 [95% CI: 3.08, 2.096]; p = 0.008). This increasedodds of ET with an ALAD2 allelewas 30 times greater than in anindividual with only an ALAD1 alleles. In the highest log blood Pbtertile, ALAD2 allelewas present in 22% of ET cases and 5% ofcontrols. It was proposed that increased blood Pb along with theALAD2 allele could affect the cerebellum and thereby increase therisk of tremor.Louis et al. (2003)New York100 cases of ET and 143controls matched for age, sex,and ethnicity.The relationship betweenblood Pb and ET wasexamined.ETMean blood Pb 3 μg/dLControlsMean blood Pb 2 μg/dLTen cases and 7 controls had bonePb levels measured that weresignificantly correlated with blood Pb suggesting that higher bloodPb may have occurred in the past. Total tremor score wascorrelated with blood Pb (r = 0.14, p = 0.03). Logistic regressionadjusting for age and current cigarette smoking found the odds ratiofor ET was 1.19 (95% CI: 1.03, 1.37) per unit increase in blood Pb.Blood Pb was higher in those 39 ET cases with no family history.Both current and lifetime prevalence of occupational Pb exposurewas the same in ET cases and controls but those with history ofoccupational exposure did have a higher blood Pb than thosewithout this history (median, 3.1 μg/dL vs. 2.4 μg/dL, p = 0.004).Kamel et al. (2002)Massachusetts109 cases of ALS and 256controls matched for age, sexand region of residenceexamined the relation of Pband ALS.Cases/controlsMean (SD) blood Pb 5 (0.4) / 3 (0.4) μg/dL3 cases and no controls had blood Pb >10 μg/dLMean (SD) patella Pb 21 (2.1) / 17 (2.0) μg/g5 cases and 1 control had patella Pb levels>50 μg/gMean (SD) tibia Pb 15 (1.6) / 11 (1.6) μg/g2 cases and no controls had tibia Pb >50 μg/g.Increased risk of ALS was foundfor history of occupational Pbexposure (adjusted OR = 1.9 [95% CI: 1.1, 3.3]) increased lifetimedays of exposure (adjusted OR = 2.3 [95% CI: 1.1, 4.9]).Association of blood Pb and ALS (adjusted OR = 1.9 [95% CI: 1.4,2.6]). Elevation in both blood Pband patella and tibia bone Pb wasfound in ALS cases though the precision of these measurementswas questioned (Patella Pb adjusted OR = 3.6 [95% CI: 0.6, 20.6]and tibia Pb adjusted OR = 2.3 [95% CI: 0.4, 14.5]). Therefore,this study found Pb exposure fromhistorical questionnaire data andbiological markers associated with ALS.

# AX6-67Table AX6-3.9 (cont’d). Other Neurological OutcomesAssociated with Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited States(cont’d)Kamel et al. (2003)MassachusettsAs above, the same data was used todetermine the associations of ALS withpolymorphism in ALADand the vitamin Dreceptor (VDR) and the influence ofgenotype.Same as above The ALAD2 allele was associated with a 2-fold increase risk of ALSafter adjustment for the covariates, age, sex, region, education andphysical activity adjusted (OR =1.9 [95% CI: 0.60, 6.3]).Additionally adjusting for blood Pbstrengthened the association ofALAD2 and ALS risk adjusted (OR = 3.6 [95% CI: 0.9, 15]). Thiswas not found for bone Pb or occupational history of Pb exposure(patella-adjusted OR = 2.1 [95% CI:0.61, 6.9]; tibial-adjusted (OR =2.2 [95% CI: 0.66, 7.3]; occupational history-adjusted(OR = 2.4 [95% CI: 0.67, 8.7]). VDR was not associated with Pb orALS risk.Armon et al. (1991)MinnesotaA case-control design with 47 ALS patients,mean age 61 with involvement of upper andlower motor neurons and 201 controls, meanage 62. For the Pb exposure analysis 45 malematched pairs were examined.Lifetime exposure to Pb of200 hrs or more (yrs on job xhrs spent per wk)Of 13 discordant pairs for Pb exposure, 11 were in ALS patient. Therelative risk was 5.5 (95% CI: 1.44, 21.0). A dose-response wasweakened by 3 controls with highest lifetime exposure. Men withALS worked more often at blue collar jobs and significantly moretime welding (p < 0.01). These results expanded a prior pilot studythat found a higher incidence of heavy metal exposure in ALS cases.EuropeChancellor et al.(1993)Scotland1990-1991A case-control design 103 ALS patients fromthe Scottish Motor Neuron Disease Registerand matched community controls.Differences in potential occupationalexposures were determined between casesand controls.Exposure to Pb obtained bylifetime employment historyfrom Office of Population andCensuses and Surveys.Physician’s record review anddirect interview questionnaire.Odds ratio for manual labor in ALS patients was 2.6 (95% CI: 1.1,6.3). Occupational exposure toPb was more common in ALSpatients (OR = 5.7 [95% CI: 1.6, 30]).Gunnarsson et al.(1992)Sweden1990A case-control study of 92 cases of MNDand 372 controls. MND included ALS,progressive bulbar paresis (PBP), andprogressive muscular atrophy (PMA).Relation of MND to risk factors includingoccupational exposure examined.Exposure informationobtained by self-administeredquestionnaire.Exposure to heavy metals primarily from welding had an increasedMantel-Haenszel OR = 3.7 [95% CI: 1.1, 13.0].

# AX6-68Table AX6-3.9 (cont’d). Other Neurological OutcomesAssociated with Lead Exposure in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Guidetti et al. (1996)ItalyA retrospective incidence, prevalence, andmortality survey of ALS in northern Italywas performed.Mean air Pb 3 μg/m3in1975 to 1 μg/m3in 1985;blood Pb in monitoredchildren decreased 18, 14,and 11 μg/dL in same timeperiod.The area studied had documented Pb pollution for yrs. Based upon79 cases incidence and prevalence rate were comparable to thesurrounding area.Vinceti et al. (1997)Italy19 ALS cases, mean age 66 (14) yrs and39 controls, mean age 64 (12.9) yrs.Sporadic ALSMean (SD) blood Pb 13(6.8) μg/dLControlsMean (SD) blood Pb11 (4.4) μg/dLThere were no cases familial ALS. Blood Pb between ALS casesand controls was not significantly different. Blood Pb was associatedwith disability due to ALS but no support was found for involvementof Pb in the etiology of sporadic ALS.

# AX6-69 

# ANNEX TABLES AX6-4

# AX6-70Table AX6-4.1. Renal Effects of Lead in the General PopulationReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited StatesKim et al. (1996)Boston, MA1979-1994459 men in the Normative Aging Study; periodicexams every 3-5 yrs.Mean serum creatinine at baseline1.2 mg/dLRandom effects modeling, adjusting for baseline age,time since initial visit,body mass index, smokingstatus, alcohol ingestion, education level,hypertension (defined as blood pressure≥160 or 95mm Hg or anti-hypertensive medication use), and, inlongitudinal analysis, baseline serum creatinine andtime between visits.Mean (SD) blood Pb atbaseline9.9 (6.1) μg/dLBlood Pb levels from storedred blood cells were adjustedfor hematocrit; the assay andadjustment procedure werevalidated against freshlycollected samples. Storagetubes were shown to be Pbfree.Cross-sectionalPositive association between log transformed blood Pband concurrent serum creatinine. 10-fold higher blood Pblevel associated with 0.08 mg/dL higher serum creatinine(95% CI: 0.02, 0.13).Association stronger in participants with lower peak bloodPb levels.∃coefficient (95% CI) in the 141 participantswhose peak blood Pb#10 μg/dL: 0.06 (95% CI: 0.023,0.097).LongitudinalPositive association between log transformed blood Pband change in serum creatinine over subsequent follow-upperiod in participants whose peak blood Pb was#25 μg/dL∃coefficient 0.027 (95% CI: 0.0, 0.054)Slope of age-related increase in serum creatinine steeper ingroup with highest quartile of time weighted avg Pbexposure compared to the lowest quartile.

# AX6-71Table AX6-4.1 (cont’d). Renal Effects of Lead in the General PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Muntner et al. (2003)U.S.1988-1994Blood Pb levels measured in 15,211 adult subjects enrolled inthe NHANES III study.Study cohort representative of U.S. population; non-HispanicAfrican Americans, Mexican Americans, the elderly andchildren over-sampled to allow stable estimates in these groups.Hypertension defined as blood pressure∃140 and/or 90 mm Hgand/or current antihypertensive medication use. Based onevidence of interaction between blood Pb and hypertension, thepopulation was stratified by hypertension for further analysis.4,813 hypertensives; 10,398 normotensives.Elevated serum creatinine (%)Defined as∃99th percentile of each race-gender specificdistribution for healthy young adults [age 20-39 withouthypertension 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, smokingstatus, history of cardiovascular disease, body mass index,alcohol consumption, householdincome, marital status, andhealth insurance.Mean (SD) blood Pb4.21 (0.14) μg/dL(hypertensives)3.30 (0.10) μg/dL(normotensives)Higher odds ratios of both increased serum creatinineand chronic kidney disease by quartile of blood Pb inhypertensives but not in normotensives.HypertensivesOdds ratios for elevated serum creatinine after fulladjustment:Blood Pb (range,μg/dL)%Odds ratio (95% CI)Quartile 1 (0.7 to 2.4) 7.2 1.00Quartile 2 (2.5 to 3.8) 12.1 1.47 (1.03, 2.10)Quartile 3 (3.9 to 5.9) 12.4 1.80 (1.34, 2.42)Quartile 4 (6.0 to 56.0) 16.3 2.41 (1.46, 3.97)p < 0.001 for chi-squared test for trend.Odds ratios for chronic kidney disease after fulladjustment:Blood Pb%Odds ratio (95% CI)Quartile 1 6.1 1.00Quartile 2 10.4 1.44 (1.00, 2.09)Quartile 3 10.8 1.85 (1.32, 2.59)Quartile 4 14.1 2.60 (1.52, 4.45)p < 0.001 for chi-squared test for trend.Associations were similar when Pb was entered as a logtransformed continuous variable.In non-hypertensives, higherblood Pb was associatedwith a higher prevalence of chronic kidney disease, butnot elevated serum creatinine, in diabetics.

# AX6-72Table AX6-4.1 (cont’d). Renal Effects of Lead in the General PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Payton et al. (1994)Boston, MA1988-1991Blood Pb levels measured in 744 men enrolled in theNormative Aging Study.Serum creatinine1.3 mg/dLMeasured creatinine clearance88.2 mL/minCalculated creatinine clearance71 mL/minMultiple linear regression adjusting for age, bodymass index, analgesic anddiuretic use, alcoholconsumption, smoking status, systolic/ diastolic bloodpressure.Mean blood Pb8.1 μg/dLBlood Pb levels below thelimit of detection of 5 μg/dLwere recoded as 4 μg/dL (nnot stated).In blood Pb negatively associated with ln measuredcreatinine clearance (∃=!0.04 [95% CI:!0.079,!0.001]).10 μg/dL higher blood Pb associated with a 10.4 mL/minlower creatinine clearance.Borderline significant associations (p < 0.1) betweenblood Pb and both serum creatinine (∃= 0.027; neither SEnor CI provided) and estimated creatinine clearance(∃=!0.022; neither SE nor CI provided).Shadick et al. (2000)Boston, MA1991-1996777 participants in all male Normative Aging Study.Mean blood Pb5.9 μg/dLMean tibia Pb20.8 μg/g bone mineralMean patella Pb30.2 μg/g bone mineralA significant association between patella Pb and uric acid(∃= 0.0007 [95% CI: 0.001, 0.013]; p = 0.02) was found,after adjustment for age, BMI, diastolic blood pressure,alcohol ingestion, and serum creatinine. Borderlinesignificant associations between tibia (p = 0.06) and bloodPb (p = 0.1) and uric acid were also observed. Notablythese associations were significant even after adjustmentfor blood pressure and renal function, providing furtherevidence that low level Pb increases uric acid. Fifty-twoparticipants had gout; Pb dose was not associated with riskfor gout.

# AX6-73Table AX6-4.1 (cont’d). Renal Effects of Lead in the General PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Tsaih et al. (2004)Boston, MA1991-~2001448 men enrolled in the Normative Aging Study.Baseline Serum Creatinine1.3 mg/dLLongitudinal analysis of data from 2 evaluations amean of 6 yrs apart.Annual change in serum creatinine = (follow-upserum creatinine – baseline serum creatinine) / yrs offollow-up.Covariates assessed = age,age squared, body massindex, hypertension (defined as blood pressure∃160or 95 mm Hg or physician diagnosis with use ofantihypertensive medication), diabetes (defined as useof oral hypoglycemic drugsor insulin or reportedphysician diagnosis), smoking status, alcoholconsumption, analgesic use, and, in longitudinalmodels, baseline serum creatinine and its square.Six percent and 26% of subjects had diabetes andhypertension, at baseline, respectively.Mean (SD) baseline blood Pb6.5 (4.2) μg/dLMean (SD) baseline tibia Pb21.5 (13.5) μg/g bone mineralMean (SD) baseline patella Pb32.4 (20.5) μg/gMean blood Pb levels and serum creatinine decreasedsignificantly over the follow-up period in the group. Pbdose not associated with change in creatinine overall.Significant interaction of blood and tibia Pb with diabetesin predicting annual change in serum creatinine.∃(95% CI) for natural ln baseline blood Pb 0.076 (0.031,0.121) compared to 0.006 (!0.004, 0.016) for nondiabetics.∃(95% CI) for natural ln baseline tibia Pb 0.082 (0.029,0.135) compared to 0.005 (!0.005, 0.015) for nondiabetics.Significant interaction of tibia Pb with hypertensive statusin predicting annual change in serum creatinine.∃(95% CI) for natural ln baseline tibia Pb 0.023 (0.003,0.019) compared to 0.0004 (!0.001, 0.002) for nonhypertensives.Follow-up serum creatinine wasalso modeled separatelyin longitudinal analyses; diabetes modified the associationbetween baseline tibia Pb and follow-up serum creatinine.

# AX6-74Table AX6-4.1 (cont’d). Renal Effects of Lead in the General PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Wu et al. (2003a)Boston, MA1991-1995709 men enrolled in the Normative Aging Study.Serum creatinine1.2 mg/dLCalculated creatinine clearance71.3 mL/minSerum uric acid6.5 mg/dLMultiple linear regression, adjusting for age, bodymass index, blood pressureor HTN (depending onmodel), and alcohol ingestion.Uric acid models alsoadjusted for serum creatinine, other outcome modelsadjusted for smoking statusand analgesic medicationuse.Mean (SD) blood Pb6.2 (4.2) μg/dLMean (SD) tibia Pb22 (13.4) μg/g bone mineralMean (SD) patella Pb32.1 (19.5) μg/g bone mineralSignificant inverse association between patella Pb andcreatinine clearance.∃=!0.069, SE not providedBorderline significant (p = 0.08) inverse associationbetween tibia Pb and creatinine clearance. Borderlinesignificant (p = 0.08) positive associations between tibiaand patella Pb and uric acid.No Pb measure significantlyassociated with serum creatinine.ALAD gene polymorphismalso assessed. 114participants had the ALAD2 variant allele (7 werehomozygous). None of the three renal outcomes differedby genotype. Effect modification by genotype on theassociation between tibia Pb and serum creatinine wasobserved; the beta coefficient (and slope) was greater inthe group with the variant allele (∃= 0.002 [SE notprovided]; p = 0.03).Effect modification of borderline significance (p < 0.1) onrelations between of patella and tibia Pb with uric acid wasobserved; this was significant inparticipants whose patellaPb levels were above 15μg/g bone mineral (∃= 0.016 [SEnot provided]; p = 0.04 ). Similar to the serum creatininemodel, patella Pb was associated with higher uric acid inthose with the variant allele.Genotype did not modify Pbassociations in models of estimated creatinine clearance.

# AX6-75Table AX6-4.1 (cont’d). Renal Effects of Lead in the General PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEuropeAlfven et al. (2002)SwedenOSCAR StudyDate not providedN = 479 men, 542 women. All resided near twobattery plants, 117 participants were current or formerworkers from plants.Renal outcome = urinaryα1microglobulin.Multiple linear regression.Age, smoking status, gender (by stratification),blood cadmium.Mean blood Pb0.16 μmolg/L men0.11 μmolg/L womenBlood Pb not associated with urinaryα1microglobulin(regression performed separately in men and women).Akesson et al. (2005)Women’s Health inthe Lund Area Study,1999-2000N = 820 womenRenal outcomes = GFR (estimated with cystatin C),estimated creatinine clearance,urinary NAG andα1microglobulin.Multiple linear regression.Age, body mass index, diabetes, hypertension, andregular use of nephrotoxic drug, blood and urinarycadmium (in separate models), smoking status(by stratification).Mean blood Pb2.2 μg/dLBlood Pb negatively associated with estimated GFR andcreatinine clearance. No associations with NAG orα1microglobulin.∃(95% CI) for association between blood Pb (μg/dL) andestimated creatinine clearance (mL/min) is!1.8(!3.0,!0.7).

# AX6-76Table AX6-4.1 (cont’d). Renal Effects of Lead in the General PopulationReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEurope(cont’d)De Burbure et al.(2003)FranceStudy date not provided600 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 creatinine1.43 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-microglobulin68.16 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 NAG1.12 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 RBP82.8 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 andurinary creatinine level.Geometric mean bloodPb7.13 μg/dL (adult malecontrols)6.78 μg/dL (exposedadult males)4.17 μg/dL(adult female controls)5.25 μg/dL(exposed adult females)3.42 μg/dL (boycontrols)4.22 μg/dL (exposedboys)2.74 μg/dL (girlcontrols)3.69 μg/dL (exposedgirls)AdultsMean blood Pb level higher in exposed women but notmen. None of the renal outcomes analyzed showedany significant difference between exposed andunexposed groups. After adjustment for covariates,blood Pb was not associated with any renal outcomes.ChildrenMean blood Pb levels higher in exposed. The highestgeometric mean blood cadmium was 0.52 μg/L. Noneof the renal outcomes weresignificantly higher inexposed. After adjustment for covariates, blood Pbwas not associated with any renal outcomes, however,blood cadmium was positively associated with NAG.This association was present in both control andexposed areas.Participants with extremes of urinary creatinineexcluded from data analyses. As a result, number ofsubjects in data tables substantially less than in study.

# AX6-77Table AX6-4.1 (cont’d). Renal Effects of Lead in the General PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Factor-Litvak et al.(1993)Kosovo, Yugoslavia1985-19861447 Yugoslavian women in prospective study ofenvironmental Pb exposure and pregnancy.Exposure from Kosovska Mitrovica with a Pb smelter,refinery, and battery plant. Controls from Pristina, 25miles 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 (linearand quadratic), height (linearand quadratic), cigarettesmoking, gestational age (linear and quadratic), dailymilk consumption, number ofprevious live births, avgweekly meat consumption, hemoglobin level andethnic group.Mean blood Pb17.1 μg/dL (582 exposed)5.1 μg/dL (865 controls)Proteinuria (negative, trace, or∃1+)Exposed = 16.2% negative, 74.1% trace and 9.7% with∃1+ proteinuria. Controls = 32.4% negative, 60.6% traceand 7.1% with∃1+ proteinuria. Authors attributed overallhigh proportion of proteinuria to pregnancy.Higher blood Pb associated with increased odds ratio fortrace and∃1+ proteinuria.Comparing women in upper 10th percentile of exposure tolower 10th percentile of exposure, adjusted odds ratios(95% CI) for trace and∃1+ proteinuria was 2.3 (1.3, 4.1)and 4.5 (1.5, 13.6), respectively.Limitations = limited renal outcomes assessed.Staessen et al. (1990)London, EnglandStudy date notprovided531 London civil servants (398 male, 133 female).Exclusionary criteria = occupational exposure toheavy metals.Serum creatinine1.10 mg/dL (men)0.88 mg/dL (women)Mean blood Pb12.4 μg/dL (men)10.2 μg/dL (women)After removal of 2 outliers, the study found no significantcorrelation between serum creatinine and log blood Pb inmen.No correlation between serum creatinine and log blood Pbin women.Limitations = lack of adjustment in data analysis, limitedPb dose and renal outcome assessment, loss of power byanalyzing gender inseparate models.

# AX6-78Table AX6-4.1 (cont’d). Renal Effects of Lead in the General PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Staessen et al. (1992)Belgium1985-1989Blood Pb levels were measured in 1981 adult subjects(965 males, 1016 females) enrolled in the Cadmibelstudy of general Belgian population in four cadmiumpolluted and unpolluted areas.Inclusion criteria included age∃20 yrs and residencein one of four study areas for∃8 yrs. Participantswere randomly selected from the study areas;participation rates were 78% in the two rural areas butonly 39% in the urban areas (one area from eachcategory was known to be cadmium polluted).Measured creatinine clearance99 mL/min (males)80 mL/min (females)Calculated creatinine clearance80 mL/min (males)69 mL/min (females)Multiple linear regression.Covariates assessed included age, age squared, gender(by stratifying), body massindex, blood pressure,ferritin level, smoking status, alcohol ingestion, ruralvs. urban residence, analgesic and diuretic use, bloodand urinary cadmium, diabetes, occupational exposureto heavy metals, and gamma glutamyl transpeptidase.Blood Pb11.4 μg/dL (males)7.5 μg/dL (females)Zinc protoporphyrin alsoassessed.After adjustment, log transformed blood Pb negativelyassociated with measured creatinine clearance.∃coefficient (95% CI)!9.5 (!0.9,!18.1) males!12.6 (!5.0,!20.3) femalesA 10 fold increase in blood Pb associated with a decreasein creatinine clearance of 10 and 13 mL/min in men andwomen, respectively.Log transformed blood Pb alsonegatively associated withcalculated creatinine clearance.∃coefficient (95% CI)!13.1 (!5.3,!20.9) males!30.1 (!23.4,!36.8) femalesLog transformed zinc protoporphyrin negativelyassociated with measured and calculated creatinineclearances and positively associated with serum∃2-microglobulin in both sexes and with serum creatinine inmen.Blood Pb positively associated with serum∃2-microglobulin in men.

# AX6-79Table AX6-4.1 (cont’d). Renal Effects of Lead in the General PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsiaLin et al. (1993)TaiwanStudy date notprovided123 adults living near a Pb battery factory for morethan 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 tonephrotoxicants and nephrotoxicant medications, suchas NSAIDs.24 h urinary NAG excretion3.3 U/day (Group 1)2.4 U/day (Group 3)Multiple linear regression with adjustment for age.Mean blood Pb16.6 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 hrsSignificantly higher prevalence of abnormal urinary NAGfound in the exposed group 1 compared to the control group 3(55.6% compared to 11.1%; p < 0.001). However, meanNAG not significantly higher in Group 1.In all 45 participants in whomboth measures were obtained,EDTA chelatable Pb was notcorrelated with urinary NAGexcretion. However, a significant correlation between EDTAchelatable Pb#200 μg/24 hrs and urinary NAG excretion wasobserved in the 39 participants in this group. Furtherevaluation with multiple linear regression, adjusting for age,revealed a∃= 0.034 (95% CI: 0.009, 0.059); p = 0.01.No correlation noted between blood Pb level and urinaryNAG.Limitations = small sample size, plots indicate potential forinfluential outliers.Satarug et al. (2004)Bangkok, ThailandStudy date notprovided118 Thai adults (53 men, 65 women).Renal outcome measures noted below, also includeBUN and total urinary protein.Serum creatinine0.94 mg/dL (males)0.66 mg/dL (females)Urinary NAG4.4 U/g creatinine (males)4.6 U/g creatinine (females)Urinary∃2-microglobulin51 μg/g creatinine (males)29 μg/g creatinine (females)Mean “serum” Pb0.42 μg/dL (males) 0.3 μg/dL(females)Note – cannot determine fromarticle if actually serum Pb(much less commonly used) orblood Pb.Mean urinary Pb1.3 μg/g creatinine (males)2.4 μg/g creatinine(females)Urinary cadmium alsoassessed.In men, urinary Pb excretion correlated only with urinaryprotein at borderline significance (r = 0.22, p < 0.06).In women, urinary Pb excretion correlated with urinary NAG(r = 0.5, p < 0.001), protein (r = 0.31, p = 0.01) and∃2-microglobulin (r = 0.36, p = 0.002) excretion.After adjustment for urinary cadmium, only associationbetween urinaryPb and NAG remained significant.Three urinary renal biomarkers correlated with urinarycadmium, although onlyat borderline significance (p = 0.06)for∃2-microglobulin.Limitations = small sample size, Pb dose assessment sinceonly urine Pb used in renal analyses, limiteddata analysis.

# AX6-80Table AX6-4.1 (cont’d). Renal Effects of Lead in the General PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Satarug et al. (2004)Bangkok, ThailandStudy date notprovided96 Thai men.Subjects subdivided into nonsmokers (n = 53), currentsmokers (n = 27), andex-smokers (n = 16).Renal outcome measures noted below, also includeBUN and total urinary protein.Serum creatinine0.94 mg/dL (nonsmokers)0.93 mg/dL (smokers)0.96 mg/dL (ex-smokers)Urinary NAG4.4 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” Pb0.42 μg/dL (nonsmokers)0.9 μg/dL (smokers)0.61 μg/dL (ex-smokers)Mean urinary Pb1.3 μg/g creatinine(nonsmokers)1.4 μg/g creatinine (smokers)1.4 μg/g creatinine (exsmokers)Urinary cadmiumalso assessed.Urinary Pb correlated with urinary protein (r = 0.49,p < 0.01) in smokers and at borderline significance(r = 0.22; p = 0.06) in neversmokers. Also correlatedwith∃2-microglobulin in ex-smokers at borderlinesignificance (r =0.39; p = 0.06).Urinary cadmium correlated with urinary NAG in currentand never smokers and at borderline significance(p = 0.07) in ex-smokers. Also correlated with urinaryprotein and∃2-microglobulin in current smokers and, atborderline significance, in never smokers.Limitations = small sample size, Pb dose assessment sinceonly urine Pb used in renal analyses, limiteddata analysis.Middle EastMortada et al. (2004)EgyptStudy date notprovided68 Egyptian men (35 smokers, 33).Renal outcomes included serum creatinine, BUN, and∃2- microglobulin and urinary albumin, NAG,∃2-microglobulin, alkaline phosphatase, andγ-glutamyltransferase.Mean blood Pb14.4 μg/dL (smokers)10.2 μg/dL (nonsmokers)Pb also measured in urine,hair, and nails.Also measured cadmium, andmercury.Blood and hair Pb levels significantly higher in smokers ascompared to nonsmokers.No significant differences inrenal outcome measures bysmoking status. No correlation between exposure indicesand renal outcome measures.Limitations: small sample size, data analysis – noadjustment.

# AX6-81Table AX6-4.2. Renal Effects of Leadin the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited StatesSmith et al. (1995)U.S.Study date notprovided691 construction workers.96 participants with the ALAD2allele.Mean blood Pb7.8 μg/dL (ALAD11)7.7 μg/dL (ALAD12 or 22)Higher mean BUN (p = 0.03) in participants with theALAD2 allele compared to those with the ALAD11genotype. However, after adjustment for age, alcoholingestion, and blood Pb, the association was no longersignificant. Effect modification was not evaluated.EuropeBergdahl et al. (1997)SwedenStudy date notprovided89 Pb workers; 7 had the ALAD2 allele.34 controls; 10 had the ALAD2 allele.Median blood Pb31.1 μg/dL in Pb workerswith ALAD1128.8 μg/dL in Pb workerswith ALAD12 or 223.7 μg/dL in control workerswith ALAD113.7 μg/dL in control workerswith ALAD12 or 22Higher crude mean serum creatinine (p = 0.11) inparticipants with the ALAD2 allele compared to thosewith the ALAD11 genotype. Adjusted data not presented.

# AX6-82Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEurope(cont’d)C<rdenas et al. (1993)BelgiumStudy date notprovidedN = 41 Pb smelter workers,41 controls (all males).Study started with 50 Pb smelter workers and 50 controls.Blood Pb level >35μg/dL and exposure >1 yr were requiredin exposed workers. Participants with renal disease, renalrisk factors, such as diabetes or regular analgesic medicationuse, or urinary cadmium >2μg/g creatinine, were excluded.Multiple linear regression; adjusted for urinary creatinineand, in some cases, BMI.Serum creatinine1.02 mg/dL (workers)1.03 mg/dL (controls)Battery of more than 20 renal biomarkers obtainedincluding:RBP68 μg/L (workers)64 μg/L (controls)NAG1.56 U/L (workers)1.21 U/L (controls)Mean blood Pb48.0 μg/dL (workers)16.7 μg/dL (controls)Mean duration of Pbexposure = 14 yrsUrinary cadmium alsomeasured as potentialconfounder.Serum creatinine was not increased in Pb workerscompared to controls; associations between Pb dose andserum creatinine, if assessed, were not specificallyreported.In all 82, blood Pb:-associated with thromboxane B2(∃= 0.36, p < 0.01).-negatively associated with 6-keto-prostaglandin F1 alpha(∃=!0.179, p < 0.01).Zinc protoporphyrin positively associated with sialic acidexcretion.NAG increased in Pb workers butassociated with urinarycadmium.Limitations = sample size, potential for healthy workerbias, limited statistical analysis.

# AX6-83Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Coratelli et al. (1988)Study location anddate not provided;authors from Italy20 Pb battery factory workers.20 controls.12 mo longitudinal study.Renal outcomes = urinary alanine aminopeptidase, NAGand lysozyme.Initial mean blood Pb47.9 μg/dL (workers)23.6 μg/dL (controls)NAG and lysozyme higher inexposed compared tocontrols throughout study.A statistically significantdecline in urinary NAG was noted in association with aone mo period of decreased occupational exposure in thePb workers. NAG correlated with time of exposure(nonlinear) but not blood Pb. Clinical renal functionmeasures were not studied.Fels et al. (1994)Study location anddate not provided81 male Pb workers; 45 age matched controls.Extensive exclusionary criteria.Renal outcomesSerum creatinineGlomerular 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, prostaglandinF2 alpha.Median blood Pb42.1 μg/dL (workers)7.0 μg/dL (controls)Serum creatinine similar in exposed compared to controls.Medians of several markers statistically greater in workerscompared to controls. After adjustment for age anderythrocyte protoporphyrin, several renal marker outcomesshowed “some relation” to blood Pb. The table of thesedata shows r and r2but not beta coefficients making theactual statistical method used unclear.Study limitations include lack of adjustment in statisticalanalysis, potential for healthy worker bias.Garçon et al. (2004)FranceStudy date notprovided35 male nonferrous metal smelter workers.Renal outcomes =α1-microprotein,∃2-microglobulin,retinol binding protein,αandπglutathione S transferases(GST).Oxidative stress markers also measured.All variables log transformed.Mean blood Pb39.6 μg/dLMean blood cadmium5.8 μg/LMean urine cadmium4.7 μg/g creatinineCorrelations between urine Pband cadmium and the renaloutcomes assessed (not blood Pb or cadmium).Significant positive correlations included:urine Pb andαGST (p < 0.01)urine cadmium and RBP (p < 0.05)Also, urine cadmium and 8-OHdG negatively correlated.Limitations = use of urine Pb, lack of adjustment for othercovariates, sample size.Significant correlations between blood Pb and twomarkers of oxidative stresswere observed along with acorrelation between blood cadmium and one marker ofoxidative stress.

# AX6-84Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Gennart et al. (1992)Study location anddates not provided;authors from Belgium98 Pb workers and 85 controls from initial group of 221.Renal outcomes = urinary retinol-binding protein,∃-2microglobulin, albumin, NAG,and serum creatinine and∃-2 microglobulin and estimated creatinine clearance.Exclusionary criteria included lack of exposure to othermetals or solvents, urinarycadmium <2 μg/g creatinine,neurologic or renal disease,certain medications, blood Pblevel >40 μg/dL (workers) and <40 μg/dL for controls.Mean blood Pb51 μg/dL (workers)20.9 μg/dL (controls)Mean duration of employment10.6 yrsMean renal outcomes were not different in workerscompared to controls. Prevalence of abnormalvalues was not greater in workers compared tocontrols. An analysis of variance, in allparticipants, by categorical blood Pb, duration ofemployment, ZPP, and delta-aminolevulinicacid showed no relations with any of the outcomes(data were not shown).Limitations include highPb levels in controls,adjustment only for age in statistical analysis,potential healthy worker bias.

# AX6-85Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Gerhardsson et al.(1992)SwedenStudy date notprovided70 current Pb smelter workers.30 retired Pb smelter workers.31 active and 10 retired truck assembly workers (controls).Renal outcomes = serum creatinine, urinary∃-2microglobulin, NAG, and albumin, clearances ofcreatinine, albumin, relative albumin,∃-2 microglobulinand relative∃-2 microglobulin.Blood Pb measured annually since 1950; time integratedblood Pb index = summation of annual blood Pbmeasurements.Median blood Pb31.9 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 index369.9 μg/dL (current Pb workers)1496.1 μg/dL (retired Pb workers)Median calcaneus Pb48.6 μg/g bone mineral(current Pb workers)100.2 μg/g bone mineral(retired Pb workers)Median tibia Pb13.0 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 clearance was higher in Pb workers;p-values not reported for this or other medianvalues between Pb workers and controls.In current Pb workers, blood Pb was positivelycorrelated with urinary∃-2 microglobulin and timeintegrated blood Pb index was correlated withNAG (data not shown).Strengths include assessment of cumulative Pb,inclusion of former workers.Limitations = statistical analysis, lack of powerby stratifying.

# AX6-86Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Pergande et al. (1994)Study location anddate not provided;research team isGerman82 male Pb workers.44 age-matched healthy male volunteers without knownexposure to Pb and living “in areas distant from theexposed people.”Renal outcomes = serum creatinine and∃2microglobulin,urinary albumin and 14 other early biological effectmarkers.Exclusion criteria includedprescription medication useand many diseases; 11 workers and 3 controls excluded.Mean blood Pb42.1 μg/dL (workers)7.0 μg/dL (controls)Erythrocyte protoporphyrinalso measured.Serum creatinine and∃2microglobulin not increased inexposed compared to controlparticipants; correlationswith these outcomes not reported. Blood Pb and/orerythrocyte protoporphyrin correlated with 9 of theurinary renal outcomes.Study limitations include lack of adjustment instatistical analysis, potential for healthy worker bias,potential for differences between exposed and controlgroups.Restek-Samaržijaet al. (1996)CroatiaStudy date notprovided74 patients treated between 1951and 1989 for at least oneepisode of Pb poisoning (53 occupational, 23environmental).Renal outcomes = measured creatinine clearance(collection time not specified), GFR assessed with99mTc-diethylenetriaminepenta-acetic acid (DTPA)clearance.Number of past Pb poisonings negatively correlatedwith creatinine and DTPA clearances.Restek-Samaržijaet al. (1997)CroatiaStudy date notprovided38 patients with occupational Pb poisoning, 23occupationally exposed workers.Renal outcomes = serum creatinine, measured creatinineclearance (collection time notspecified), hippuran renalflow.Mean blood Pb1.5 μmol/L (poisonedworkers)1.6 μmol/L (workers)Creatinine clearance significantly lower in poisonedgroup.

# AX6-87Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Roels et al. (1994)BelgiumStudy date notprovided76 Pb smelter workers (including 21 participants fromCardenas et al. [1993] [Dr.Roels, email communication])68 controls.All males.Matched for age, sex, socioeconomic status, residence, andworkshift characteristics.Extensive exclusionary criteria included renal disease,analgesic abuse, chronic medication for gout, diabetes,occupational exposure to other nephrotoxicants, and priorEDTA chelation.Renal outcomes included serum creatinine and ureanitrogen, measuredcreatinine clearance, NAG, RBP,serum and urinary∃2-microglobulin, as well as other renalearly biological effect markers.Measured creatinine clearance121.3 mL/min/1.73 m2(workers)115.5 mL/min/1.73 m2(controls)Multiple linear regression, adjusted for age, urinarycadmium, hypertension, serum gamma-glutamyltranspeptidase, smoking, exposure status (exposed vs.control), and interaction between exposure variables andhypertension.Mean blood Pb43.0 μg/dL (workers)14.1 μg/dL (controls)Mean tibia Pb66 μg/g bone mineral(workers)21 μg/g bone mineral(controls)Urinary cadmium alsomeasured.Creatinine clearance measured before and after an oralprotein load to determine if eicosanoid changes inCardenas et al. (1993) had clinical implications (Acuteprotein ingestion causes increased renal perfusion andtransient hyperfiltration thought to be mediated bychanges in vasodilator prostanoids. Therefore, it washypothesized that, if the changes noted in Cardenaset al. (1993) were clinically significant, thehyperfiltration response wouldbe diminished in the Pbworkers.).All participants had normal baseline creatinineclearances (>80 mL/min/1.73m2). Both control andPb-exposed workers showed a similar increment increatinine clearance after protein load.However, mean creatinine clearance was statisticallyhigher in Pb workers compared to controls. Log tibiaPb was positively correlated with log measuredcreatinine clearance in the combined group(∃= 0.0319, SE not provided).This was unexpected as the change in eicosanoidsfound in the initial study would not seem to result invasodilatation with increased GFR. Unfortunately, itwas not possible to measure eicosanoid levels in thefollow-up study. No other significant associationsbetween Pb measures and renal outcomes wereobserved. Urinary cadmium associated with NAG.

# AX6-88Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Verschoor et al.(1987)Study location anddate not provided;authors from TheNetherlands155 Pb workers (Pb batteryand plastic stabilizer).126 control industrial workers.Workers with renal disease, HTN, prescriptionmedications excluded.Renal outcomes = BUN, serum creatinine, uric acid,∃2-microglobulin, and RBP, and urinary RBP, NAG,albumin, uric acid,∃2-microglobulin, IgG, and totalprotein. Urine protein electrophoresis performed on subset(n = 25).Cadmium in blood and, in a subset of exposed workers, inurine was also assessed due to this exposure in one planteach from which Pb exposed and control workers weredrawn.Mean blood Pb47.5 μg/dL (workers)8.3 μg/dL (controls)Zinc protoporphyrinalso used as Pb dose measure.Mean renal outcomes in all participants shown bycategorical Pb levels. NAG and RBP higher at bloodPb levels >21 μg/dL compared to those below thislevel (statistical significance not reported). Serum∃2-microglobulin and urinary total protein lower at bloodPb levels >21 μg/dL compared to those below thislevel (again, statistical significance not reported).In simple linear regression models of log transformedurinary total protein,urinary RBP, NAG and serum∃2-microglobulin, higher log transformed blood Pb wassignificantly associated with lower serum∃2-microglobulin and higher RBP and NAG.A matched pair analysis of 55 pairs matched for agewithin 5 yrs, smoking, socioeconomic status, andduration of employment found no differences in renaloutcomes between exposed and controls.Limitations = lack of adjustment, potential for healthyworker bias, occupational cadmium exposure(including in controls) not adequately adjusted.Latin and South AmericaCardozo dos Santoset al. (1994)Study location anddate not provided;authors from Brazil166 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 exposed group (p < 0.001).Blood Pb level and duration of exposure correlatedwith NAG in combined group (Spearman’s correlationcoefficients = 0.32 and 0.22,respectively, p < 0.001 forboth).No results mentioned for serum creatinine.Limitations = statistical analysis (no regression forrenal outcomes).

# AX6-89Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationLatin and South America(cont’d)Pinto de Almeidaet al. (1987)Northeast BrazilStudy date notprovided52 primary Pb smelter workers (had to have worked≥5yrs 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 Pb64.1 μg/dL (workers)25.5 μg/dL (controls)Also measured zincprotoporphyrin and delta-aminolevulinic acidMean serum creatinine and uric acid higher in exposedthan controls (1.23 vs. 1.1 mg/dL; p < 0.05 and 6.6 vs.4.7 mg/dL; p < 0.001, respectively).Serum creatinine∃1.5 mg/dL present in 32.7% Pbworkers compared to only 2.3% controls.Serum creatinine correlated with duration ofemployment.Limitations = data analysis including lack ofadjustment, several outcomes not analyzed.AustraliaPollock and Ibels(1988)Harbor Bridgeworkers in Sydney,AustraliaStudy date notprovided38 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 (Pbintoxication)19.9 (9.5 to 26.1) μg/dL(nontoxic)EDTA chelatable Pb range443 to 2366 μg/24 hrs (Pbintoxication)131 to 402 μg/24 hrs(nontoxic)No significant differencesin renal outcomes by Pbexposure group. Two workers in high exposure grouphad evidence of Pb nephropathy.

# AX6-90Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Chia et al. (1994b)Study location notprovided; authorsfrom Singapore1982-1992 (blood Pbmeasurementsobtained every 6 mosover 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 cellmembranes, thought to indicate proximal tubular celltoxicity), NAG-A (released by exocytosis).Cross-sectional outcomes butlongitudinal exposure data.Median blood Pb33.8 μg/dL (workers)8.7 μg/dL (controls)Median cumulative blood Pb(mean of 3.6 blood Pb levelsper worker)208.3 μg·yr/dLMean change in blood Pb(in 6 mos preceding NAGmeasurement)5.8%NAG not different in exposed compared to controlworkers.After adjustment for race, recent change in blood Pbwas significantlyassociated with all NAG outcomes(standardized partial regression coefficients rangedfrom 0.31 for NAG-A to 0.64 for total NAG; neitherSE nor CI provided).In contrast, current blood Pbwas inversely associatedwith NAG-A and NAG-B separately but, oddly, notwith total NAG. Authors do not comment on theseinconsistencies.NAG not associated withcumulative Pb dose.Strengths = longitudinal exposure data.Limitations = data analysis clarity and adjustment.Chia et al. (1994c)SingaporeStudy location notprovided; authorsfrom Singapore1982-1992 (blood Pbmeasurementsobtained every 6 mosover this time)63 Pb workers of >6 mos work duration (median = 3 yrs).91 Pb workers of <6 mos work duration were consideredcontrols.Renal outcomes = urinary BB-50 (brush border antigen inproximal tubule), totalNAG, NAG-B isoenzyme, RBP,α1-microgobulin, albumin and urine and serum∃2-microglobulin.Cross-sectional outcomes butlongitudinal exposure data.Pb dose measures(means or medians not stated)Most recent blood Pb, timeintegrated blood Pb index,relative % change in bloodPb, absolute change in bloodPb, number of times blood Pblevel >40, 50, and 60 μg/dL.Urinary BB-50 higher in exposed compared to recenthire “control” workers.Time integrated blood Pb,number of times blood Pb >40 μg/dL, and relativechange in recent blood Pb were associated withurinary BB-50.Strengths = longitudinal exposure data.Limitations = data analysiscontent (Pb dose means notreported), clarity and adjustment.

# AX6-91Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Chia et al. (1995a)Study location notprovided; authorsfrom Singapore1982-1993 (blood Pbmeasurementsobtained every 6 mosover this time)137 Pb stabilizer workers.Control group of 153 postal workers (older than Pbworkers).Renal outcomes = serum creatinine, four h creatinineclearance, serum∃-2 microglobulin, serumα-1microglobulin, urine albumin.Longitudinal blood Pb data (mean of 4.5 measurementsper Pb worker).Pb dose measures(means or medians not stated)Most recent blood Pb, timeintegrated blood Pb index,relative % change in recentblood Pb, absolute change inrecent blood Pb, number oftimes blood Pb level >40, 50,and 60 μg/dL.In analysis of covariance modeling, adjusted for age and race,mean serumα-1 microglobulin and urine albumin weresignificantly higher in control compared to Pb workers.Serum∃-2 microglobulin was significantly higher in Pbworkers≥30 yrs of age.After adjustment for age, race, and smoking, prevalence ratesfor abnormal values of serum creatinine and∃-2microglobulin were higher in the highest category of timeintegrated blood Pb index in workers∃30 yrs of age(PRR = 3.8 [95% CI: 1.1, 13.3] and 10.3 [95% CI: 3.9,26.9], respectively).Strengths = longitudinal exposure data.Limitations = data analysiscontent (Pb dose means notreported), clarity and adjustment.Chia et al. (1995b)Study location notprovided; authorsfrom Singapore1982-1993 (blood Pbmeasurementsobtained every 6 mosover 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 randomsubset (40 controls and 31 Pb workers).Renal outcomes = serum∃-2 microglobulin and urinaryα1 microglobulin,∃-2 microglobulin, albumin, RBP.Mean recent blood Pb32.6 μg/dL (workers)9.0 μg/dL (controls)Mean time integrated bloodPb index119.9 μg/dLΗyr (workers)0.05 μg/dLΗyr (controls)Mean relative change inrecent blood Pb28.2 % (workers)Mean absolute change inrecent blood Pb6.4 μg/dL/yr (workers)Number of times blood Pblevel >40, 50 and 60 μg/dLOnly urinaryα-1 microglobulin was significantly higher in Pbworkers compared to controls.In multiple linear regression analysis, adjusted only forethnicity and smoking, at least one Pb measure wassignificantly associated with eachof the five renal outcomes.OutcomePb measure∃(95% CI)Uα-1 MG cum. blood Pb 0.10 (0.06, 0.14)Uα-1 MG # blood Pb >50 0.43 (0.04, 0.82)U∃-2 MG cum. blood Pb 0.05 (0.01, 0.09)U RBP # blood Pb >50 0.35 (0.12, 0.59)S∃-2 MG # blood Pb >60 0.47 (0.29, 0.65)U Alb # blood Pb >60 0.66 (0.13, 1.19)Cadmium dose measures reportedly not significant in thesemodels (although power would have been reduced ascadmium measured only in a subset).Strengths = longitudinal exposure data.Limitations = data analysis clarity and adjustment. Overlapin populations between this study and earlier ones possible.

# AX6-92Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Endo et al. (1990)Study location notprovided; authorsfrom Japan198739 male workers.7 female workers (none directly exposed to Pb).Secondary Pb refinery, mean job duration = 10.5 yrsRenal outcomes = BUN, serum creatinine and uric acid,urinary NAG, and tubular reabsorption of phosphate.Mean blood PbRanged from 24.1 to67.6 μg/dL (males)19.6 μg/dL (females)Other Pb measures includedurinary Pb, delta-aminolevulinic acid, andcoproporphyrin.Significant correlations of bloodPb and delta-amino-levulinicacid with BUN and NAG wereobserved. The correlationbetween blood Pb and NAG was dependent on a smallnumber of workers whose bloodPb levels were above80 μg/dL.Limitations include absence of adjustment in statisticalanalysis, small sample size.Endo et al. (1993)Study location anddate not provided;authors from Japan99 male Pb workers.Renal outcomes = serum creatinine and serum and urinealpha-1-microglobulin.Median blood PbRanged from 7.9 μg/dL incategory I consisting of 16office workers who did notwork directly with Pb to76.2 μg/dL in 16 workers inthe highest exposure group(category V).Median urinary alpha-1-microglobulin significantly higher incategories III–V compared to the low exposure group ofoffice workers. This was also the only renal outcome to besignificantly correlated with blood Pb (Spearman rankcorrelation).After alpha-1-microglobulin adjusted for age and blood Pb(by stratifying); few significantdifferences noted. However,analysis approach resulted in substantial loss of power.

# AX6-93Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Hsiao et al. (2001)Taiwan, PR China1991-199830 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 forautocorrelation in multiple datapoints from eachparticipant.Adjusted for age, gender, and, in models of change inserum creatinine, creatinine at beginning of interval.Mean blood Pb at baseline~35 μg/dL (based on figure;exact values not provided)Mean duration of exposureat baseline13.1 yrsCross-sectionalhigher blood Pb associated with lower concurrentserum creatinine.LongitudinalChange in blood Pb negatively associated withconcurrent change in serum creatinine (p = 0.07).Blood Pb at the beginning of the interval not associatedwith change in serum creatinine in the following yr.Associations may represent Pb-related hyperfiltration.However, as noted by the authors, cumulative Pb dosemay also be a factor. Mean blood Pb declined greatlyjust before renal data collection started. Therefore, theinverse longitudinal associations could be due topersistently elevated cumulative dose (which wasunmeasured but, as evidenced by the long half-life ofbone Pb, likely did not declineas much as blood Pb).However, authors did not model cumulative blood Pbor analyze effect modification by time period, age, orexposure duration to determine if these associationschanged in a pattern consistent with hyperfiltration.The small sample size also limits conclusions that maybe drawn from these results since a small number ofindividuals may be overly influential.Strengths = longitudinal data.Limitations = data analysiscontent (Pb dose means notreported), clarity and adjustment.

# AX6-94Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Huang et al. (1988)Beijing, ChinaStudy date notprovided40 Pb workers (4 women).Control group not described.Renal outcomes = serum beta-2-microglobulin and urinarybeta-2-microglobulin, total protein, IgG.Geometric mean blood Pb40 μg/dLIncreased urinary∃2microglobulin in workerscompared to controls.Multiple limitations including lack of information oncontrol group, data analysis.Jung et al. (1998)KoreaStudy date notprovided75 randomly selected male Pb workers.64 male office workers (controls).Renal outcomes = BUN, serum creatinine, uric acid andurinary NAG, albumin,α1microglobulin and∃2microglobulin.Mean blood PbMeans ranged from 24.3 to74.6 μg/dL (workers)7.9 μg/dL (controls)Other Pb measures includedzinc protoporphyrin,δ-aminolevulinic acid activityand urinary Pb,coproporphyrin, andδ-aminolevulinic acid.Blood Pb, zinc protoporphyrin, and urinaryδaminolevulinic acid significantly correlated with BUN,NAG, andα1microglobulin (appears to be combinedgroup analysis).Limitation = statistical analysis - lack of adjustment.Konishi, et al. (1994)Study locationnot provided;research team fromJapan199199 male Pb workers, including 16 office workers to serveat controls.renal outcomes = fractional clearances ofα1microglobulinand∃2microglobulin (utilizing serum and urinary levels ofboth biomarkers), BUN, serumcreatinine, uric acid andurinary NAG.Median blood PbRange from 7.9 μg/dL incontrols to 76.2 μg/dL inCategory VUrinary NAG,α1microglobulin and fractionalclearance ofα1microglobulin increased with higherblood Pb category. Spearman rank correlation betweenfractional clearance ofα1microglobulin and blood Pbwas significant. This relation also assessed by multiplelinear regression with adjustment for age; bothindependent variables were significantly associatedwith the fractional clearance ofα1microglobulin.Limitation = statistical analysis - lack of adjustment.

# AX6-95Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Kumar andKrishnaswamy(1995)IndiaStudy date notprovided22 auto mechanics volunteers.27 male control workers (from Institute performing study).Renal outcomes = serum creatinine, 4 h creatinineclearance and urinary NAG and∃-2 microglobulin.Renal disease, diabetes, HTN and occupational exposuresexcluded in controls, possibly excluded in workers.Blood Pb range24.3-62.4 μg/dL (exposed)19.4-30.6 μg/dL (controls)Urinary NAG and∃2microglobulin levels weresignificantly higher in exposed compared to controls.However, only NAG was significantly correlated withblood Pb (r = 0.58, p < 0.01).Limitations = study size and lack of adjustment inanalysis, values for 4 h creatinine clearance inabnormal low range in both exposed and controls.Lim et al. (2001)Singapore1999Blood Pb levels every6 mos from 1982 to199955 male Pb workers.Workers followed since 1982, many of same workers as inChia et al. (1995b).Renal outcomes = 4 h creatinine clearance and urinaryalbumin, RBP,α1microglobulin,∃2microglobulin, NAG,NAG-A, and NAG-B.Exclusionary criteria included diabetes, HTN, recentingestion of analgesics, antipyretics, or antibiotics, andthalassemia; 24 participants of the original 80 wereexcluded as a result. One female also excluded.Mean current blood Pb24.1 μg/dLCumulative blood index880.6 μgΗyrs/dL (geometricmean)Number of times blood Pbexceeded 40 μg/dL1.9 (geometric mean)In separate models, after adjustment for age andsmoking, higher categoricalcumulative blood indexand number of times blood Pb exceeded 40 μg/dL wereassociated with lower creatinine clearance (P < 0.001).After adjustment, highernumber of times blood Pbexceeded 40 μg/dL was associated with higher urinaryalbumin,α1microglobulin, RBP, NAG, and NAG-B.Similarly, cumulative blood index was associated withhigher urinary albumin,α1microglobulin, RBP, and∃2microglobulin.No associations between recent blood Pb and any ofthe renal outcomes was observed.Analysis of covariance was used to adjust for smokingand age.Limitation = statistical analysis - lack of adjustment,small sample size, potential for healthy worker bias.

# AX6-96Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Ong et al. (1987)Singapore and JapanStudy date notprovided209 Pb workers (51 females).30 control workers from research staff.Renal outcomes = BUN, serum creatinine, calculatedcreatinine clearance,and urinary NAG.Mean blood Pb42.1 μg/dL (males)31.9 μg/dL (females)Urine Pb also measured.Blood Pb correlated with BUN(r = 0.16; p < 0.01),serum creatinine (r = 0.26; p < 0.001) and creatinineclearance (r =−0.16; p < 0.01). Blood Pb associatedwith NAG after adjustment for age (method notspecified).Higher NAG in exposed compared to controls whenstratified by categorical age.Strengths = sample size.Limitations = statistical analysis - lack of adjustment,urinary NAG not adjustedfor urine dilution.Wang et al. (2002b)TaiwanStudy date notprovided229 Pb battery workers, including 109 females.Renal outcomes = BUN, serum creatinine, serumuric acid.Multiple linear & logistic regression.Adjustment for age, gender,smoking, alcohol ingestion,milk ingestion.Mean blood Pb67.7 μg/dL (males)48.6 μg/dL (females)∃(95% CI) for blood Pb in model of BUN, afteradjustment for Pb job duration/age = 0.062(0.042, 0.082).∃(95% CI) for blood Pb in model of uric acid, afteradjustment for gender and weight = 0.009(0.001, 0.016).Blood Pb not associated serum creatinine.

# AX6-97Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Weaver et al. (2003a)South Korea1997-1999803 Pb workers including 164 females and 94 former Pbworkers.Serum creatinine0.90 mg/dLCalculated creatinine clearance94.7 mL/min4-hr measured creatinine clearance114.7 mL/minRBP63.6 μg/g creatinineNAG215.3μmol/h/g creatinineMultiple linear regression, adjusting for age, gender, BMI,work status (current vs. former worker), HTN or bloodpressure (depending on model), and, for the EBE markers,alcohol ingestion and diabetes.42 associations modeled (7Pb measures with 6 renaloutcomes).Interaction models that assessed effect modification byage in tertiles in 24 associations (4 Pb exposure/dosemeasures with 6 renal outcomes).Mean blood Pb32.0 μg/dLMean tibia Pb37.2μg/g bone mineralMean DMSA-chelatable Pb767.8μg/g creatininePb exposure also assessedwith job duration and threehematologic measures assurrogates for Pb dose(aminolevulinic acid inplasma, zinc protoporphyrin,and hemoglobin).Mean urinary cadmiummeasured insubset (n = 191)1.1 μg/g creatinineAfter adjustment, higher Pb measures associated withworse renal function in 9 of 42 models.Associations in the opposite direction (higher Pbmeasures associated with lower serum creatinine andhigher creatinine clearances) in five models.Opposite direction (inverse)associations observed onlyin models of the clinical outcomes whereas theassociations between higher Pb dose and worse renalfunction were predominantly among the biomarkermodels.In three of 16 clinical renal interaction models, positiveassociations between higher Pb measures and worserenal function in participants in the oldest age tertilewere significantly differentfrom associations in thosein the youngest age tertile which were in the oppositedirection.- This pattern was observed at borderline significance(p < 0.1) in 3 other models.- Pattern was not observed in the EBE marker models.Urinary cadmium associated with NAG.Authors concluded that occupational Pb exposure inthe moderate dose range hasan adverse effect on renalfunction. Inverse associations may representhyperfiltration. Environmental cadmium may have anadverse impact, at least on NAG.

# AX6-98Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Weaver et al. (2003b)Korea Pb workers1997-1999798 Pb workers with genotype information in samepopulation as in Weaver et al. (2003a).79 (9.9%) participants were heterozygous for the ALAD2allele (none was homozygous).89 (11.2%) had VDR genotype Bb or BB.Mean blood Pb31.7 μg/dL (ALAD11)34.2 μg/dL (ALAD12)31.6 μg/dL (VDR bb)34.8 μg/dL (VDR Bb or BB)Mean tibia Pb37.5μg/g (ALAD11)31.4 μg/g (ALAD12)37.1 μg/g (VDR bb)38.1 μg/g (VDR Bb or BB)Data were analyzed todetermine whetherpolymorphisms in the genes encodingδ-aminolevulinicacid dehydratase (ALAD), endothelial nitric oxidesynthase (eNOS), and the vitamin D receptor (VDR)were associated with renal outcomes or modifiedrelations of Pb exposure and dose measures with renaloutcomes.After adjustment, participants with the ALAD2 allelehad lower mean serum creatinine and higher calculatedcreatinine clearance. Effect modification by ALAD onassociations between blood Pb and/or DMSAchelatable Pb and three of six renal outcomes wasobserved. Among those with the ALAD12 genotype,higher Pb measures were associated with lower BUNand serum creatinine and higher calculated creatinineclearance.No significant differences were seen in renal outcomesby VDR genotype nor was consistent effectmodification observed.

# AX6-99Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Weaver et al. (2005a)Korea1997-1999803 current and former Pb workers; 164 females.Serum Uric acid4.8 mg/dLOther renal outcomes as listedin Weaver et al., 2003a.Multiple linear regression.Interaction models that assessed effect modification by agein tertiles.Mean blood Pb32.0 μg/dLMean tibia Pb37.2 (40.4) μg/g bonemineralMean DMSA-chelatable Pb767.8 μg/g creatinineWork to address whether one mechanism for Pb-relatednephrotoxicity, even at current lower levels of Pb exposure, is viaincreasing serum uric acid. Assessed 1) whether Pb dose wasassociated with uric acid and 2) whether previously reportedassociations between Pb dose and renal outcomes (Weaver et al.,2003) were altered after adjustment for uric acid.After adjustment for age, gender,body mass index, and alcohol use,Pb biomarkers not associated with uric acid in all participants.However, in interaction models, both blood and tibia Pb weresignificantly associated in participants in the oldest age tertile(∃= 0.0111 [95% CI: 0.003, 0.019] and 0.0036 [0.0001, 0.007] forblood and tibia Pb, respectively). These models were further adjustedfor blood pressure and renal function. Hypertension and renaldysfunction are known to increase uric acid. However, they are alsorisks associated with Pb exposure.Therefore, adjustment for thesevariables in models of associations between Pb dose and uric acidlikely results in over-control. Onthe other hand, since nonPb relatedfactors contribute to both renal dysfunction and elevated bloodpressure, lack of adjustment likely results in residual confounding.Therefore, as expected, associations between Pb dose and uric aciddecreased after adjustment for systolic blood pressure and serumcreatinine, although blood Pb remained borderline significantlyassociated (∃= 0.0071 [95% CI:!0.001, 0.015]). However, when thepopulation was restricted to the oldest tertile of workers with serumcreatinine greater than the median (0.86 mg/dL), likely the highestrisk segment of the population, blood Pb remained significantlyassociated with uric acid even after adjustment for systolic bloodpressure and serum creatinine (∃= 0.0156).Next, in models of renal function in all workers, uric acid wassignificantly (p < 0.05)associated with all renal outcomes exceptNAG.In models in the oldest tertile ofworkers (266 workers, median age51.1 yrs, range 46.0 to 64.8 yrs), after adjustment for uric acid,associations between Pb dose and NAG were unchanged, but fewerof the previously significant (p#0.05) associations noted between Pbdose and the clinical renal outcomes in Weaver et al. (2003a)remained significant.

# AX6-100Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Weaver et al. (2005b)South Korea1999-2001652 Pb workers including 149 females and 200 formerworkers.Patella Pb measured in the third evaluation of the samestudy reported in Weaver etal. (2003a). Data collectionperformed a mean of 2.2 yrs after collection of the datapresented in Weaveret al. (2003a).Same renal outcomes as Weaver et al. (2003a).Serum creatinine0.87 mg/dLCalculated creatinine clearance97.0 mL/minMultiple linear regression, adjusting for age, gender, BMI,work status (current vs. former worker), HTN or bloodpressure (depending on model), diabetes, smoking status,and, for the clinical measures, use of analgesicsInteraction models assessed effect modification by age,dichotomized at the 67th percentile.Mean blood Pb30.9 μg/dLMean tibia Pb33.6 μg/g bone mineralMean patella Pb75.1 μg/g bone mineralMean DMSA-chelatable Pb0.63μg Pb/mg creatinineAll 4 Pb measures were correlated (Spearman’s r = 0.51 –0.76).Patella, blood and DMSA-chelatable Pb levels positivelyassociated with NAG.Higher DMSA-chelatable Pb associated with lower serumcreatinine and higher calculated creatinine clearance.Interaction modelsAll four Pb measures associated with higher NAG amongparticipants in oldest age tertile.Higher blood, tibia, and patellaPb associated with higherserum creatinine among older participants.-Beta coefficients less in the Pb workers whose ages were inthe younger two-thirds of the age range; difference betweenslopes in the two age groups wasstatistically significant onlyfor association of blood Pb and serum creatinine.Inverse DMSA associations(higher DMSA-chelatable Pbassociated with lower serum creatinine and higher calculatedcreatinine clearance) significant in younger workers.Patella Pb associations were consistent with those of blood andtibia Pb; DMSA-chelatable Pb associations unique.Authors hypothesized that similarities between patella, blood,and tibia Pb associations could be due, in part, to highcorrelations among the Pb biomarkers in this population.Despite similar high correlations, DMSA-chelatable Pbassociations with serum creatinine and calculated creatinineclearance were unique. This biomarker is dependent on renalfunction and the collection timewas only 4 h. Therefore, theamount of Pb that is excreted in this relatively short time periodafter chelation may be influencednot only by bioavailable Pbburden, but also by high-normal aswell as actual supranormalglomerular filtration which are more common in the youngerworkers.

# AX6-101Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Weaver et al. (2005c)Korea1997-1999798 current and former Pb workers.Same population as in Weaver et al. (2003a,b).Data were analyzed todetermine whetherpolymorphisms in the genes encodingδ-aminolevulinicacid dehydratase (ALAD), endothelial nitric oxidesynthase (eNOS), and the vitamin D receptor (VDR)were associated with uric acid or modified relations ofPb exposure and dose measures with uric acid.Uric acid not different by ALAD or VDR genotype.Among older workers (age≥median of 40.6 yrs),ALAD genotype modified associations between Pbdose and uric acid levels. Higher Pb dose wassignificantly associated with higher uric acid inworkers with the ALAD11 genotype; associations werein the opposite direction in participants with the variantALAD12 genotype.Ye et al. (2003)Chinese Pb workersStudy date notprovided216 Pb workers.Renal outcomes = urinary NAG and albumin.Geometric mean blood Pb37.8μg/dL (n = 14 workerswith the ALAD12genotype)32.4μg/dL (n = 212 workerswith the ALAD11 genotype)31.9 μg/dL (VDR bb)41.7 μg/dL (in 20 participantswith VDR Bb or BB)After adjustment for age,NAG was borderline higherin those with the ALAD variant allele whose blood Pblevels were≥40μg/dL (p = 0.06). In all Pb workers,after adjustment for age,gender, smoking, and alcoholingestion, a statistically significant positive associationbetween blood Pb and creatinine adjusted NAG wasobserved in the workers with the ALAD12 genotypebut not in Pb workers with the ALAD11 genotype (thegroups were analyzed separately rather than in aninteraction model).No effect modification by VDR genotype onassociations between blood Pb and urinary albuminand NAG observed (separate analysis reduced power).

# AX6-102Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationMiddle EastAl-Neamy et al.(2001)United Arab EmiratesFeb-June, 1999100 “industrial” workers exposed in a range of industries100 working controls.Matched for age, sex, and nationality.Renal outcomes = BUN, serum creatinine.Mean blood Pb77.5 μg/dL (workers)19.8 μg/dL (controls)Mean BUN and serum creatinine not statisticallydifferent between exposed workers and controls.Limitations = data analysis.Ehrlich et al. (1998)South AfricaStudy date notprovided382 Pb battery factory workers.Mean age = 41.2 yrs.All males.Multiple linear regression adjusted for age, weight, andheight (Covariates assessedfor inclusion also includedsmoking, alcohol ingestion, and diabetes).Clinical renal outcomes included serum creatinine, uricacid, and BUN.Mean serum creatinine1.13 mg/dLRenal early biological effect markers (NAG, RBP,intestinal alkaline phosphatase, tissue nonspecific alkalinephosphatase, Tamm-Horsfall glycoprotein, epidermalgrowth factor, and microalbuminuria) were measured in199 participants randomly selected by tertiles of currentblood Pb.Mean blood Pb53.5 μg/dLMean exposure duration11.6 yrsMean cumulative blood Pb(defined as sum of the avgblood Pb in each yr over all yrsof employment; done in subsetof 246 with past blood Pb data)579.0 (μgΗyr)/dLMean historical blood Pb(defined as cumulative bloodPb divided by yrs of exposure)57.3 μg/dLMean tibia Pb69.7μg/g bone mineral(measured 2 yrs after initialstudy on random sample of 40)After adjustment for age, weight, and height,categorical current and historical blood Pb and zincprotoporphyrin were associated with serum creatinineand uric acid, in separatemodels. Associationsbetween cumulative blood Pb or exposure durationand the renal outcomes were not observed.Among the EBE markers, only current blood Pb wasborderline associatedwith NAG (p = 0.09).Associations with renal dysfunction wereobserved atblood Pb levels <40μg/dL. Not explained by aneffect on blood pressure since Pb measures notassociated with blood pressure. Blood cadmiummeasured in 56 participants 2 yrs after the initialstudy. All low (#1.2μg/L) suggesting thatoccupational level cadmium exposure was not acontributing factor. Theauthors did implicate Pbbody burden, which was substantial based on meantibia Pb. However, cumulative blood Pb was notassociated in this study and mean tibia Pb in Roelset al. (1994) was similar (in that study a positiveassociation with creatinine clearance was observed).

# AX6-103Table AX6-4.2 (cont’d). Renal Effects ofLead in the Occupational PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationMiddle East(cont’d)El-Safty et al. (2004)EgyptStudy date notprovided45 Pb workers with Pb job duration <20 yrs.36 Pb workers with Pb job duration≥20 yrs.75 control workers.Renal outcomes = urinaryα1-microglobulin, NAG, andglutathione S-transferase.Median urine PbRanged from 15.4 μg/gcreatinine in nonsmokingcontrol workers to 250.4 μg/gcreatinine in smoking Pbworkers with∃20 yrs Pb jobduration.Medians of all 3 renal outcomes significantly higherin Pb workers regardless ofsmoking status (analysisstratified by smoking status).Urine Pb significantly correlated with urinaryα1-microglobulin and glutathione S-transferase innonsmoking Pb workers and with NAG as well insmoking Pb workers.Limitations include using urine Pb as sole Pb dosemeasure and data analysis.Mortada et al. (2001)EgyptStudy date notprovided43 traffic policemen.52 matched control office workers (similar in terms ofage, gender, smoking, and “social life”).Renal outcomes = serum creatinine, beta-2 microglobulin,BUN and urinary∃-2- microglobulin, NAG, alkalinephosphatase,γ-glutamyl transferase, and albumin.Exclusionary criteria included diabetes, HTN, hepatic,renal or urologic diseases.Mean blood Pb32.1 μg/dL (exposed)12.4 μg/dL (controls)Pb also measured in hair, urineand nails.NAG and albumin significantly higher in policemencompared to controls.NAG positively correlated(Pearson’s) with job duration and blood and nail Pb.Urinary albumin positively correlated with jobduration and blood and hair Pb.Limitations: data analysis– no adjustment, use ofparametric correlation techniques with data likely tobe nonparametric; study size.

# AX6-104Table AX6-4.3. Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited StatesOsterloh et al. (1989)Northern CAStudy date notprovided40 male subjects with hypertensive nephropathy(hypertension preceded renal insufficiency; serumcreatinine 1.8-4 mg/dL).24 controls with renal dysfunction from other causes.Patients recruited from the Kaiser Permanente RegionalLaboratory database (large health maintenanceorganization) in northern California.Mean blood Pb7.3 μg/dL (in bothhypertensive nephropathy andcontrols CRI from othercauses)Mean EDTA chelatable Pblevels153.3 μg/72 hrs (hypertensivenephropathy)126.4 μg/72 hrs (control CRI)No significant difference in EDTA chelatable Pblevels; highest chelatable Pb level was609.2 μg/72 hrs.Pb dose and serum creatinine were not correlated.Blood and chelatable Pb levels much lower than thosereported by Wedeen et al. (1983) andSanchez-Fructuoso et al. (1996).Only 17% of their study participants had a history ofpossible Pb exposure based on questionnaire, againmuch lower than the two other studies.Steenland et al. (1990)MichiganDiagnosis from1976-1984325 men with ESRD (diabetes,congenital and obstructivenephropathies excluded).Controls by random digit dialing, matched by age, race,and place of residence.Risk of ESRD significantly related to moonshinealcohol consumption (OR= 2.43), as well asanalgesic consumption, family history of renaldisease, and occupational exposure to silica orsolvents.EuropeBehringer et al.(1986)GermanyStudy date notprovided16 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 gEDTA 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 higher in gout patients whodeveloped gout after CRI than those in which goutpreceded CRI (statistical test results not mentioned orshown). Authors conclude arole for Pb in patientswith gout occurring in setting of CRI and that Pb maycontributes to renal function decline in establishedrenal disease from other causes.Limitations = small groups, limited data analysis.

# AX6-105Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Colleoni andD’Amico (1986)Italy(~1982-1985)12 consecutive patients with CRI (mean serumcreatinine = 3.3 mg/dL) and gout, renal diagnosisconsistent with chronic interstitial nephritis in all; 7 hadhistory of occupational Pb exposure.12 controls with chronic glomerulonephritis and nohistory of Pb exposure or gout.Pb excretion in the 48 hrs after administration of 1.5 gEDTA im.Mean EDTA chelatable Pb(μg/48 hrs)180 (CRI, no gout)505 (CRI & gout)Significantly higher EDTA chelatable Pb in thegroup with CRI and gout compared to CRI alone.EDTA chelatable Pb significantly correlated withserum creatinine in patients with CRI and gout butnot CRI alone. Authors conclude that Pb is cause ofCRI with gout but renal insufficiency alone notresponsible for increased Pb body burden (absenceof evidence for reverse causation).Limitations = small sample size, limited dataanalysis.Colleoni et al. (1993)ItalyStudy date notprovidedAll 115 patients on hemodialysisat the time of the study;41 women.Blood Pb data from prior study of 383 healthy controls insame geographical area served as comparison.Mean blood Pb(corrected for hemoglobin)19.9 μg/dL (patients)14.7 μg/dL (controls)Significantly higher mean blood Pb in hemodialysispatients compared to healthy controls. 13% hadblood Pb levels >30 μg/dL.Blood Pb level was notassociated with duration of hemodialysis. Mean Pblevels higher in smokers and in relation to alcoholingestion. Pb not detectable in dialysis fluids.Limited data analysis.Craswell et al. (1987)Germany andAustraliaStudy date notprovidedSee discussion below under Australia.

# AX6-106Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Fontanellas et al.(2002)SpainStudy date notprovidedALAD/restored ALAD as a possible index of Pb poisoningin chronic renal failure patients.Restored ALAD was measured after the addition ofzinc and dithiothreitol (DTT) to the incubationmedia.The ALAD/restored ALAD ratio was found tocorrelate with the results of the EDTA Pbmobilization test. Patients excreting I,115 to3860 μg Pb per 72 hrs had a ratio of 0.19 whilechronic renal failure patients excreting an avg of322 μg Pb (range 195 to 393) had a ratio of 0.47.In comparison, normal controls had a ratio of 0.5.Jones et al. (1990)Study location anddate not provided;authors from UK27 dialysis patients.59 healthy controls.Mean blood Pb8.1 μg/dL (patients)10.0 μg/dL (controls)Tibia Pb levels not correlated with blood Pb but werecorrelated with Pb inbone biopsy measurements(r = 0.42).Limitations = data analysis.Koster et al. (1989)Study location anddate not provided;authors fromGermany91 patients with CRI (median serum creatinine =2.5 mg/dL).46 age-matched normal controls.Pb excretion in the 4 days after1 g EDTA iv.Mean blood Pb(corrected for hemoglobin)11.2 μg/dL (patients)7.6 μg/dL (controls)Mean EDTA chelatable Pb164.7 μg/4 days /1.73 m2(patients)63.6 μg/4 days /1.73 m2(controls)CRI patients had significantly higher blood andEDTA chelatable Pb levels than controls. In 13% ofthe CRI patients, EDTA chelatable Pb exceeded thehighest value in controls (328.8 μg). EDTAchelatable Pb levels were correlated with serumcreatinine in patients (r = 0.37; p < 0.007).Limitations = data analysis.

# AX6-107Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Miranda-Carús et al.(1997)Spain1990-199427 patients with gout and CRI.50 patients with gout only.26 controls with normal renal function and no gout.Multiple purine metabolism measures including serumurate, hypoxanthine, and xanthine, as well as theirexcretion, clearance and fractional excretion measures.Mean blood Pb17.8 μg/dL (gout and CRI)14.9 μg/dL (gout only)12.4 μg/dL (controls)Mean EDTA chelatable Pb845 μg/120 hrs (gout and CRI)342 μg/120 hrs (gout only)215 μg/120 hrs (controls)Pb dose measures significantly higher in patients withgout and CRI compared to the other two groups.EDTA chelatable Pb inversely correlated withcreatinine clearance. Each of the 2 patient groupswere dichotomized by EDTA-chelatable Pb level of600μg/120 hrs, resulting in 3 small groups (n rangingfrom 6 to 14) and one group of 44 participants withgout and EDTA chelatable Pbbelow the cut-off. Nosignificant differences in mean purine metabolismmeasures were observed. It is not clear whethercorrelations between EDTA-chelatable Pb and thepurine measures were assessed and if so whether thesmall groups were combinedfor this analysis. Thuslack of power may be onereason for the inconsistencywith Lin’s work. Different Pb body burdens may be afactor as well.Uric acid parameters were unchanged followingchelation in 6 participants with EDTA-chelatableabove 600 μg/120 hrs. Again higher Pb body burdensmay be a factor but the small number and limiteddetails on the group make firmconclusions difficult.Nuyts et al. (1995)BelgiumStudy date notprovidedCase-control study.272 cases with chronic renal failure (all types) matched to272 controls by age, sex and residence.Exposure assessed by 3 industrial hygienistsblinded tocase or control status.Significantly increased odds ratio for chronic renalfailure with Pb exposure (OR = 2.11 [95% CI: 1.23,4.36]) as well as several other metals. Increased riskwith diabeticnephropathy.

# AX6-108Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Sánchez-Fructuosoet al. (1996)SpainStudy date notprovided296 patients:Group I = 30 normal control subjectsGroup II = 104 patients with essential HTN & normalrenal functionGroup III-A = 68 patients with HTN and CRI of uncertainetiology but presumed nephroangiosclerosisGroup III-B = 64 patients with HTN, CRI, and goutGroup IV = 30 patients with CRI of known etiologyMean blood and EDTA-chelatable Pb levelsGroup I16.7 μg/dL324 μg/72 hrsGroup II16.8 μg/dL487 μg/72 hrsGroup III-A18.5 μg/dL678 μg/72 hrsGroup III-B21.1 μg/dL1290 μg/72 hrsGroup IV16.5 μg/dL321 μg/72 hrsEDTA chelatable Pb >600 μg/72 hrs in 16 patients ingroup II, 30 patients in group III-A, 44 patients ingroup III-B, but no patients in either group I and IV.Mean blood and EDTA chelatable Pb levels in thepatients with CRI ofknown cause were notstatistically different fromcontrols with normal renalfunction. However, baseline urinary Pb excretion waslower in group IV. This provides conflicting evidenceregarding the “reverse causality” hypothesis ofincreased Pb burden due to decreased excretion inCRI.Significant correlations notedbetween bone Pb levels(assessed by biopsy) and EDTA chelatable Pb level in12 patients whose chelatable Pb levels were >600μg/72 hrs; provides support for validity of chelatablePb levels in CRI.A positive correlation was observed between serumcreatinine levels and EDTA-chelatable Pb levels>600 μg/72 hrs but not below this level.In group III, mean measuredcreatinine clearance wassignificantly lower in thosewith EDTA chelatable Pblevels >600μg/72 hrs compared to participants withchelatable Pb <600μg/72 hrs.

# AX6-109Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Van de Vyver et al.(1988)Belgium, Franceand GermanyStudy date notprovidedTransiliac bone biopsies obtained from:11 cadavers without known Pb exposure and with normalrenal function13 patients with CRI, gout and/or HTN 22 Pb workers153 dialysis patientsMean transiliac Pb levels5.5 μg/g (153 dialysis pts)20.6 μg/g (in highest 5%dialysis pts)3.7 μg/g (in 10 pts on dialysisdue to analgesic nephropathy)6.3 μg/g (11 cadavers)30.1 μg/g (22 Pb workers)In 5% of the hemodialysis patients studied, bone Pbconcentrations approximated the levels found inactive Pb workers, suggesting Pb as a primary causeof their renal failure. Levels in the 10 patients withanalgesic nephropathy were the lowest (all <7 μg/g),evidence against reverse causality.In the combined group of 13 patients with CRI, goutand/or HTN and 22 Pb workers, EDTA chelatable Pbcorrelated with Pb in bone biopsies (r = 0.87).Winterberg et al.(1991)Study location anddate not provided;authors fromGermanyIliac crest bone Pb measured by biopsy in:8 controls8 patients with CRI14 dialysis patientsMean iliac crest bone Pb levels1.63 μg/g (8 controls)2.18 μg/g (8 patients withCRI)3.59 μg/g (in 14 dialysis pts)Noted that the bone Pb levels in patients withanalgesic nephropathy and cadaver controls in Van deVyver et al. (1988) were much higher than in controlgroups of other researchers. They reiterated theconcern that Pb did accumulate due to decreased renalexcretion.Latin and South AmericaNavarro et al. (1992)VenezuelaStudy date notprovided18 dialysis patients.14 controls.Bone (biopsy) and blood levels of Pb and several othermetals.Mean blood Pb5.2 μg/dL (patients)11.5 μg/dL (controls)Mean Pb in bone9.7 μg/g (patients)7.0 μg/g (controls)Blood but not bone Pb significantly higher in patientscompared to controls. Authors concluded that boneaccumulation of aluminum, iron and vanadium, butnot Pb, occurred in dialysis patients.Limitations = sample size, data analysis includinglack of adjustment.

# AX6-110Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAustraliaCraswell et al. (1987)Germany andAustraliaStudy date notprovidedGerman participants fromindustrialized area wherechronic Pb nephropathy not previously observed.Gp 1 = 8 healthy controls (from hospital staff)Gp 2a = 12 CRI patients, no gout or Pb exposureGp 2b = 7 CRI patients, no gout but + Pb exposureGp 3a = 7 CRI patients with gout but no Pb exposureGp 3b = 6 CRI patients with gout and Pb exposureAustralian participants from Queensland site of knownchronic Pb nephropathy.Gp 1 = 9 healthy controls (from hospital staff)Gp 2a = 14 CRI patients, no gout or Pb exposureGp 2b = 11 CRI patients, no gout but + Pb exposureGp 3a = 25 CRI patients with gout but no Pb exposureGp 3b = 11 CRI patients with gout and Pb exposureCRI defined as serum creatinine≥1.5 mg/dL“Excess” EDTA chelatable Pb defined as Pb excreted over4 days after EDTA minus twice baseline Pb excreted preEDTA.Median blood Pb (hemoglobincorrected)Gp 1German = 6.8 μg/dLAustralian = 11.0 μg/dLGp 2aGerman = 6.2 μg/dLAustralian = 9.1 μg/dLGp 2bGerman = 8.5 μg/dLAustralian = 16.2 μg/dLGp 3aGerman = 10.6 μg/dLAustralian = 12.8 μg/dLGp 3bGerman = 12.0 μg/dLAustralian = 27.1 μg/dLMedian “excess” EDTAchelatable PbGp 1German = 68.4 μgAustralian =82.9 μgGp 2aGerman = 126.4 μgAustralian = 393.7 μgGp 2bGerman = 489.0 μgAustralian = 1181.1 μgGp 3aGerman = 227.9 μgAustralian = 808.1 μgGp 3bGerman = 422.7 μgAustralian = 1077.5 μgUsing nonparametric statistical techniques due toskewed data, German participants excretedstatistically less Pb than their Australian counterparts.Mean EDTA chelatable Pb levels were significantlyhigher in German patients with gout than in thosewithout gout; the observed increase in the Australianpatients was of borderline significance (p < 0.1).Limitations = small groups, limited data analysis.

# AX6-111Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAustralia(cont’d)Price et al. (1992)Queensland,Australia1981-19868 renal patients compared with age-matched controls.X-ray fluorescence of finger bone Pb conducted twice 5yrs apart.Authors conclude that Pb in bone half-life is similar inrenal patients compared to age-matched controls.Study limitations substantial, however.Limitations = small numbers (although bone Pbmeasured in more patients, many were below the limitof detection, inclusion of outlierswithout formalstatistical analysis.AsiaLin and Lim (1992)Chinese population(likely in Taiwan)Study date notprovided10 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 orenvironmental Pb exposure.Mean EDTA chelatable Pb inμg/72 hrs/1.73 m290.2 (controls)98 (CRI, no gout)171.6 (gout, then CRI)359.8 (CRI, then gout)Pb body burden higher in patients with CRI and gout,especially when CRI precedes gout.Limitations = small sample sizes, statistical analysis.Lin and Huang(1994)TaiwanStudy date notprovidedGroup 1 = 10 patients with normal renal function and nogout; Group 2 = 10 patients with CRI (serum creatinine>1.4 mg/dL) and subsequent gout; Group 3 = 20 patientswith CRI but no gout.All males.Pb body burden assessed with 1 g EDTA iv followed by72 hr urine collection.Mean EDTA chelatable PbGp 1 = 60.55 μg/ 72 hrsGp 2 = 252.24 μg/ 72 hrsGp 3 = 84.86 μg/ 72 hrsMean EDTA chelatable Pb and serum uratesignificantly higher in thepatients with gout. Afteradjustment for creatinine clearance, log transformedEDTA chelatable Pb was significantly associated withserum urate levels (∃= 0.757 [95% CI: 0.142, 1.372];p < 0.05), daily urate excretion (∃=!60.15 [95% CI:!118.1,!2.16]; p < 0.05), urate clearance (∃=!0.811[95% CI:!1.34,!0.282]; p < 0.05), and fractionalurate excretion (∃=!1.535 [95% CI:!2.723,!0.347];p < 0.05). EDTA chelatable Pb not associated withcreatinine clearance.Limitations = small sample sizes, limited adjustmentin regression analyses.

# AX6-112Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Lin and Lim (1994)TaiwanStudy date notprovidedGp 1 = 12 healthy controls.Gp 2 = 10 patients with HTN.Gp 3 = 12 patients with HTN, then CRI (hypertensivenephropathy).Gp 4 = 12 patients with CRI only.Gp 5 = 12 patients with CRI not due to HTN, butsubsequent HTN.Mean EDTA chelatable PbGp 1 = 76.6 μg/72 hrsGp 2 = 67.96 μg/72 hrsGp 3 = 182.9 μg/72 hrsGp 3 = 84.46 μg/72 hrsGp 3 = 92.86 μg/72 hrsHigher mean EDTA chelatable Pb level in Gp 3;5 of 12 had history of gout developing after CRI.Limitations = small sample sizes, limited analyses.Lin et al. (1999)TaiwanStudy date notprovided32 patients selected from 102 patients with serumcreatinine from 1.5–4.0 mg/dL who were followed in theInstitution’s outpatient clinics.Eligibility criteria included serum creatinine from 1.5 –4.0 mg/dL, stable renal function over 6 mos before studyentry; controlled blood pressure and cholesterol; dailyprotein intake <1 g/kg body wt; no known history ofexposure to Pb or otherheavy metals and EDTAchelatable Pb >150 but <600μg/72 h.Exclusionary criteria included potentially reversible orunstable renal disease (i.e., due to systemic diseases suchas lupus and diabetes), andnephrotoxicant medications.Patients divided into 16 patients receiving 1 g EDTA i.v.weekly for two mos and a control group of 16 patientswho received no therapy.Mean EDTA chelatable Pblevels pre-chelation254.9μg/72 hrs in groupreceiving subsequent chelation279.7μg/72 hrs in controlgroupBlood Pb levels notmentioned.Rates of progression of renal insufficiency werefollowed by reciprocal of serum creatinine during the12 mos prior to therapy and for 12 mos followingtherapy. Rates of progression of renal insufficiencywere similar in the treatment group and the controlgroup during the baseline observation. However,improvement in renal function was observed duringEDTA chelation. Following chelation, renal functionstabilized in the treated group but continued to declinein the control group. At 12 mos after treatment, themean difference in the change in the reciprocal ofserum creatinine between the two groups was0.000042 L/μmol per mo (95% CI: 0.00001,0.00007). Results using a sensitivity analysis forpatients lost to follow-up (only one in each group)gave similar results.

# AX6-113Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Lin et al. (2001a)TaiwanStudy date notprovided24 mo prospective observational study110 patients with CRI dichotomized by EDTA chelatablePb level of 80 μg/72 hrs into two groups of 55 each.Eligibility criteria included serum creatinine from 1.5 – 4.0mg/dL, stable renal function (decrease in GFR <5 mL/minover 6 mos); blood pressure <140/90 mm Hg; cholesterollevel <240 mg/dL; daily protein intake <1 g/kg body wt;no known history of exposure to Pb or other heavy metalsand EDTA chelatable Pb <600μg/72 h.Exclusionary criteria included potentially reversible orunstable renal disease (i.e., due to systemic diseases suchas lupus and diabetes), nephrotoxicant medications, anddrug allergies.196 patients initially screenedfor study; details on reasonsfor non-eligibility not provided.Primary outcome = 1.5 times increase in the initialcreatinine level or need fordialysis; secondary outcome =change in creatinine clearance.Cox proportional-hazards model analysis for primaryoutcome. Mean differences in creatinine clearancecompared at sequential time points with t or MannWhitney U tests.Adjustment for age, gender,baseline BMI, smoking,proteinuria, hypertension, hyperlipidemia, daily proteinintake, and underlying renal disease.Intention-to-Treat and sensitivity analyses comparedcreatinine clearance a by time period in high and low Pbgroups.Mean blood Pb levels6.6 μg/dL in high normal Pbbody burden group (n = 55)3.9 μg/dL in low normal Pbbody burden group (n = 55)Mean EDTA chelatable Pblevels pre-chelation182.9 μg/72 hrs in high normalPb body burden group (n = 55)37.9 μg/72 hrs in low normalPb body burden group(n = 55)24 mo prospective observational studyPb dose measures were only significant differencesbetween high and low normal Pb body burden groups.Of the 96 participants who completed the observationstudy, 14 patients in the high normal body Pb burdengroup reached the primary endpoint compared to 1patient in the low body Pb burden group (p < 0.001 bylog-rank test).From mo 12 to mo 24, creatinine clearance in highnormal body Pb burden patients was at leastborderline statistically lower than in low body Pbburden patients; from 18-24 mos, 95% CI excluded 0.95% CI for the difference at 24 mos was (–15.0,!3.8);difference in creatinine clearance between groups was0.15 mL/s at that point.In a Cox multivariate regression analysis, chelatablePb was significantly associated with overall risk forthe primary endpoint (RR = 41.5 [95% CI: 3.9,440.8]; p = 0.002). In this model, age, basal BMI, andbasal daily proteinuria werealso associated withincreased risk.

# AX6-114Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Lin et al. (2001a)(cont’d)3 mo clinical trial of chelation with 1 yr follow-upAt 24 mos, 36 patients whose EDTA chelatable Pb levelswere 80 - 600μg/72 hrs and serum creatinine levels of<4.2 mg/dL were randomized; 24 to a 3-mo treatmentperiod consisting of weekly chelation with 1 g EDTA ivuntil their excreted Pb levels fell below 80μg/72 hrs and12 to placebo infusion.Intention-to-Treat and sensitivity analyses comparedcreatinine clearance by time period in treated and controlgroups.3 mo clinical trial of chelation with 1 yr follow-upThe two groups were similar in baseline renal riskfactors (although numbers small so beta errorpossible).Mean EDTA dose during the 3 mo period was 5 μg.After three mos of Pb chelation therapy, the body Pbburden of the patients in the chelation groupdecreased from 198 to 39.2 μg. After 3 mos ofchelation and 3 mos of follow-up, creatinine clearanceincreased by 0.08 mL/s in the treated group butdeclined by 0.04 mL/s in the controls.At the end of the study period, mean creatinineclearance was 0.68 mL/s in the chelated groupcompared to 0.48 mL/s in the control group(p < 0.05; 95% CI for the difference betweengroups = –25.0 to –0.2).

# AX6-115Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Lin et al. (2001b)Study location anddate not provided;authors from Taiwan101 patients with CRI (defined as serum creatininebetween 1.5 and 3.0 mg/dL).67 with CRI and gout.34 with CRI only.Eligibility criteria included no known history of Pbexposure, certain diagnoses,and medications. CRI musthave preceded gout diagnosis.Randomized chelation trial30 participants with CRI, gout, and EDTA-chelatable Pblevels between 80.2 and 361μg/72 hrs randomized toeither a treatment group receiving 1 gram EDTA iv per wkfor 4 wks (N = 20) or to a control group who receivedglucose in normal saline iv.Mean blood Pb5.4 μg/dL (CRI and gout)4.4 μg/dL (CRI only)Mean EDTA-chelatable Pb138.1 μg/72 hrs (CRI andgout)64.2 μg/72 hrs (CRI only)(p < 0.01)In 101, EDTA-chelatable Pb higher in patients withCRI and gout compared to those with CRI only.EDTA-chelatable Pb, but not blood Pb, wasassociated positively with serum urate and negativelywith daily urate excretion, urate clearance, andfractional urate excretion.Randomized chelation trialThe two groups had similar uric acid, renal function,and Pb measures pre-chelation. In the treated group,mean EDTA-chelatable Pb declined from 159.2 to41μg/72 hrs; mean serum urate decreased from 10.2to 8.6 mg/dL (% change compared to the controlgroup =!22.4 [95% CI:!46.0,!1.5]; p = 0.02), andmean urate clearance increased from 2.7 to4.2 mL/min (% change compared to the control group= 67.9 [95% CI: 12.2, 121.2]; p < 0.01). Daily andfractional urate excretionwere also significantlydifferent between the two groups. Mean measuredcreatinine clearance increased from 50.8 to54.2 mL/min (% change compared to the controlgroup = 8.0 [95% CI:!0.4, 20.1]; p = 0.06).

# AX6-116Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Lin et al. (2002)Study location anddate not provided;authors from Taiwan84 healthy participants.27 participants with gout.All with normal renal function (defined as serumcreatinine≤1.4 mg/dL).Participants with a history of occupational heavy metalexposure, EDTA-chelatable Pb levels >600μg/72 hrs, orsystemic diseases were excluded.Randomized chelation trial24 participants with EDTA-chelatable Pb levels between75 and 600μg/72 hrs randomized to either a treatmentgroup receiving 1 gram EDTA iv per wk for 4 wks(N = 12) or to a control group who received glucose innormal saline i.v.Multiple linear regression, adjustment for age, sex, BMI,daily protein intake, and creatinine clearance.Mean blood Pb3.9 μg/dL (controls)4.2 μg/dL (gout)Mean EDTA-chelatable Pb45 μg/72 hrs (controls)84 μg/72 hrs (gout)(p < 0.0001)Significantly higher mean EDTA-chelatable Pb andlower urate clearance were present in patients withgout compared to those without (3.7vs. 6.0 mL/min/1.73 m2; p < 0.001 for urate clearance).After adjustment, EDTA-chelatable Pb associatedwith all four uric acid measures (serum urate, dailyurate excretion, urate clearance, and fractional urateexcretion). Blood Pb associated with serum urate.All associations in same direction as in Lin et al.(2001).Randomized chelation trial.The two groups had similar urate, renal function, andPb measures pre-chelation. In the treated group, meanblood and EDTA-chelatable Pblevels declined (from5.0 to 3.7μg/dL and 110 to 46μg/72 hrs,respectively). Statistically significant improvementobserved in all four uratemeasures in the treatedgroup compared to the control group.

# AX6-117Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Lin et al. (2003)Study location anddate not provided;authors from Taiwan24 mo prospective observational study202 patients with CRIEligibility criteria included serum creatinine from 1.5 - 3.9mg/dL, stable renal function (decrease in GFR <5 mL/minover 6 mos); blood pressure <140/90 mm Hg; cholesterollevel <240 mg/dL; daily protein intake <1 g/kg body wt;no known history of exposure to Pb or other heavy metalsand EDTA chelatable Pb <600μg/72 h.Exclusionary criteria included potentially reversible orunstable renal disease (i.e., due to systemic diseases suchas lupus and diabetes), nephrotoxicant medications, anddrug allergies.250 patients initially observed, loss due to noncomplianceor unstable renal function, baseline data on the 48 who leftor were removed from the study not provided.Cox proportional-hazards model analysis for primaryoutcome. Generalized estimating equations (GEE) forassociations between baseline chelatable Pb or blood Pblevel and longitudinal change in GFR (estimated by anMDRD equation [Levey et al.,1999]) and by measurementof creatinine clearance.Adjustment for age, gender,baseline BMI, smoking,baseline serum creatinine, proteinuria, hypertension,hyperlipidemia, daily protein intake, and underlying renaldiseases.Mean blood Pb levels5.3 μg/dL in total group(n = 202)6.1 μg/dL pre-chelation inchelated group (n = 32)5.9 μg/dL pre-chelation incontrol groupMean EDTA chelatable Pblevels pre-chelation104.5 μg/72 hrs in total group(n = 202)150.9 μg/72 hrs pre-chelationin chelated group144.5 μg/72 hrs pre-chelationin control group24 mo prospective observational studyPrimary endpoint = increase in serum creatinine to 1.5times baseline or need for hemodialysis; occurred in24 participants. Secondary endpoint = change inestimated glomerular filtration rate (GFR).In a Cox multivariate regression analysis, chelatablePb was significantly associated with overall risk forthe primary endpoint (hazard ratio for each 1μgchelatable Pb was 1.00 [95% CI: 1.00, 1.01];p = 0.03). In this model, baseline serum creatininewas also associated (hazard ratio for each 1 mg/dLwas 2.75 [95% CI: 1.46, 5.18]; p = 0.002) and, atborderline significance (p < 0.1), baseline dailyprotein excretion and smoking were as well.The association between baseline chelatable Pb andchange in GFR was modeled using GEE.Estimate =!0.003 (p = <0.001) (neither SE nor CI provided). Inthis model, gender and daily protein intake wereassociated with increased GFR; baseline serumcreatinine level, daily urinary protein excretion, andthe presence of polycystic kidney disease weresignificant predictors of a progressive decline inglomerular filtration rate.Based on this model, a 10μg higher baselinechelatable Pb level was associated with a GFRdecrease of 0.03 mL per minute per 1.73 m2of bodysurface area during the 2 yr observation period.Although statistically significant, this effect isclinically small. Furthermore, it is 40 fold lower thanthat reported in Yu et al. (2004) over a follow-upperiod that is only two-fold shorter.

# AX6-118Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Lin et al. (2003)(cont’d)Study location anddate not provided;authors from Taiwan27 mo clinical trial of chelationAt 24 mos, 64 patients whose EDTA chelatable Pb levelswere 80 - 600μg/72 hrs and serum creatinine levels of<4.2 mg/dL were randomized; half to a 3-mo treatmentperiod consisting of weekly chelation with 1 g EDTA ivuntil their excreted Pb levels fell below 60μg/72 hrs andhalf to five wks of placebo infusion.Intention-to-Treat analysiscompared creatinine clearanceand GFR by time period in treated and control groups.27 mo clinical trial of chelationThe two groups were similar in baseline renal riskfactors (although numbers small so beta errorpossible).After three mos of Pb chelation therapy, the body Pbburden of the patients in the chelation groupdecreased from 150.9 to 43.2 μg and their mean bloodPb levels decreased from 6.1 to 3.9 μg/dL. GFRincreased by 3.4 mL/min/1.73 m2in the treated group;in contrast, it decreased by 1.1 mL/min/1.73 m2in thecontrol group. Mean EDTA dose during the 3 moperiod was 5.2 μg.In the subsequent 24 mos, chelation in 19 (59%)participants was repeated due to increases in serumcreatinine in associationwith rebound increases inEDTA chelatable Pb levels. Each received oneadditional chelation series (mean 4.1 g EDTA) a meanof 13.7 mos after the first chelation period. Controlpatients receiving placebo weekly for five wks everysix mos.At the end of the study period, mean estimatedglomerular filtration rate increased by 2.1mL/min/1.73 m2of body-surface area in the chelatedgroup compared to a decline of 6.0 in the controls(p < 0.01; 95% CI for the difference between groups =–11.0 to –5.1).

# AX6-119Table AX6-4.3 (cont’d). Renal Effects of Lead in the Patient PopulationReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationAsia(cont’d)Yu et al. (2004)Study location anddate not provided;authors from Taiwan121 patients followed over a four yr observationalperiod.Eligibility criteria included serum creatinine from 1.5-3.9 mg/dL, stable renal function (decrease in GFR <5mL/min over 6 mos); blood pressure <140/90 mm Hg;cholesterol level <240 mg/dL; daily protein intake <1g/kg body wt; no known history of exposure to Pb orother heavy metals and EDTA chelatable Pb <600μg/72 h.Exclusionary criteria included potentially reversible orunstable renal disease (i.e., due to systemic diseasessuch as lupus and diabetes), medical noncompliance(patients were followed for 6 mos to assesscompliance before enrollment in the study),nephrotoxicant medications, and drug allergies.Cox proportional hazards model analysis for primaryoutcomes and generalized estimating equations (GEE)for associations between baseline chelatable Pb orblood 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 ACEinhibitor or angiotensin-receptor antagonists (sincenot all patients wereon these), and chronicglomerulonephritis (other underlying renal diseasesincluded in GEE as well).Mean (SD) blood Pb at baseline3.4 (1.3)μg/dL in 58 patientswith “low-normal” EDTAchelatable Pb levels (<80μgPb/72 hrs)4.9 (2.6)μg/dL in 63 patientswith “high-normal” EDTAchelatable Pb levels (∃80 but<600μg/72 hrs)The two groups (dichotomized bydiagnostic EDTA chelatablePb of 80μg Pb/72 hrs ) were similar inmost baseline risk factorsother than Pb body burden. Borderline statistically significant(p < 0.1) differences included mean older age in the highchelatable Pb group and certain renal diagnoses (chronicglomerulosclerosis, chronic interstitial nephritis, hypertensivenephropathy; surprisingly both ofthe latter two diagnoses wereless common in the lower Pb body burden group).Fifteen patients in the “high-normal” chelatable Pb groupreached the primary endpoint (doubling of serum creatinine overthe 4 yr study period or need for hemodialysis) compared to onlytwo in the “low-normal” group (p = 0.001 by Kaplan-Meieranalysis).In a Cox multivariate regression analysis, chelatable Pb wassignificantly associated with overall risk for the primaryendpoint (hazard ratio for each 1μg chelatable Pb was 1.01[95% CI: 1.00, 1.01]; p = 0.002).In this model, the only othervariable reaching at least borderline significance (p < 0.1) wasbaseline serum creatinine.The associations between baseline chelatable Pb or blood Pblevel and change in GFR weremodeled separately using GEE.∃=!0.1295 (p = 0.002) for Pb body burden∃=!4.0123 (p = 0.02) for blood PbBased on these models, a 10μg higher baseline chelatable Pblevel or 1μg/dL higher blood Pb level predicted 1.3 and 4.0mL/min declines in GFR, respectively, during the four yr studyperiod. Similar to the primary outcome analysis, of the manytraditional renal risk factors adjusted for in these models, onlydiagnosis of chronic interstitial nephritis was significantlyassociated, in this case with an increase in GFR. Of note,chronic interstitial nephritis wasalso a more frequent diagnosisin the group with the low-normal chelatable Pb levels (p = 0.09).The authors stated that these patients were not included in earlierpublications (which are described below in Section 6.4.4.3.3Therapeutic EDTA Chelation in Patients).

# AX6-120Table AX6-4.4. Renal Effects of Lead on MortalityReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited StatesCooper (1988);Cooper et al. (1985)16 U.S. plantsEmployment between1946 and 1970;mortality from 1947to 19804519 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 whenmissing).Standardized mortality ratios (SMRs) compared withnational age-specific rates. PMR also assessed.Analyzed separately by battery and Pb production, by hiredate before and after 1/1/1946, and by cumulative yrs ofemployment (1-9, 10-19, 20+).Mean blood Pb63 μg/dL in n = 1326 batteryworkers80 μg/dL in n = 537production workersPast Pb exposures poorlydocumented prior to 1960Follow-up >90% in both groups; 2339 deathsobserved.“Chronic or unspecified nephritis” SMR:222 (95% CI: 135, 343) in battery workers265 (95% CI: 114, 522) in Pb production workers“Other hypertensive disease” SMR (“includes HTNand related renal disease without mention of heartdisease)”:320 (95% CI: 197, 489) in battery workers475 (95% CI: 218, 902) in Pb production workersRace adjusted proportionatemortality ratios analysessimilar.Nephritis deaths observed primarily in workers hiredbefore 1946.Limitations = due to mortality analysis (inaccuraciesof death certificates, exposure assessment generallylimited).Steenland et al. (1992)IdahoEmployed between1940 and 1965;mortality up to 19881990 male Pb smelter workers.Employed in a Pb-exposed department for at least one yrbetween 1940 and 1965.Vital status was determined using records from the SocialSecurity Administration andthe National Death Index.Mean blood Pb56.3 μg/dL (n = 173, measuredin 1976)High Pb exposure defined asworkers from departmentswith an avg >0.2 mg/m3airborne Pb or∃50% of jobshad avg levels more than twicethat level (1975 survey). Inthis category, n = 1,436.Compared to the U.S. white male population, thestandardized mortality ratio (SMR) for chronic kidneydisease, based on only 8 deaths, was 1.26 (95%CI = 0.54, 2.49). SMR = 1.55 in high Pb exposuregroup, also not significant. The SMR for chronickidney disease increased with duration of exposurefrom 0.79 in workers exposed 1-5 yrs to 2.79 inworkers exposed >20 yrs; however SMR was notsignificant.

# AX6-121Table AX6-4.4 (cont’d). Renal Effects of Lead on MortalityReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEuropeFanning (1988)UKDeaths from1926-1985Deceased males identified through pension records of Pbbattery and other factory workers.867 deaths of mean with high Pb exposure compared to1206 men with low or no Pb exposure.Range of blood Pb40-80 μg/dL since ~1968 inhigh Pb exposure group;thought not to have hadclinical Pb poisoning due tomedical surveillance.<40 μg/dL since ~1968 in littleor no exposure group.Odds ratio for renal disease = 0.62, not significant,based on only 11 deaths. Similar for diagnosis ofnephritis. Possible decreasing odds ratio over time ofdeaths with mention of nephritis on death certificatebut not significant and numbers still quite small.Limitations = standardmortality study issuesalthough deaths compared with other workers and notgeneral population which is a strength in this type ofstudy.

# AX6-122Table AX6-4.5. Renal Effects of Lead in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited StatesHu (1991)U.S.Study date notprovided21 of 192 adults who werehospitalized at BostonChildren’s Hospital between 1932 to 1942 for childhoodPb poisoning were traced to a Boston area address.Matched on age, sex, race, and neighborhood to21controls.Mean (SD) blood Pb6.0 μg/dL (Pb poisoned)7.5 μg/dL (controls)No significant differencesin blood Pb level, serumcreatinine, or BUN. Mean measured creatinineclearance higher in the previously Pb poisoned groupcompared to controls (112.8 vs. 88.8 mL/min/1.73 m2[p < 0.01]). Mean in the Pb exposed group was alsohigher than the predicted value of 94.2 mL/min/1.73m2from the nomogram of Rowe et al. (1976).Suggests Pb-related hyperfiltration. As noted insection 6.4, one survivor, identified but not includedin the study, had disease consistent with Pbnephropathy.Limitations = small study size and concern forsurvivor bias in the study group.Loghman-Adham(1998)Chicago, ILStudy date notprovided134 children and young adults, 8 to 13 yrs after chelationtherapy for severe Pb poisoning.Mean age at poisoning = 2.3 yrsMean age at follow-up = 13.4 yrsMean peak blood Pb level121 μg/dLMean blood Pb level at timeof study18.6 μg/dLMean serum creatinine was normal (0.8 mg/dL).Calculated creatinine clearance normal in all but 3children. No correlation between either initial orcurrent blood Pb and serumcreatinine or calculatedcreatinine clearance.Urinaryα-amino nitrogen concentrations weresignificantly increased compared with 19 healthy agematched controls and were correlated with currentblood Pb levels. Thirty-two children (24%) hadglycosuria. Fractionalexcretion of phosphate,however, was normal in all children. The authorconcluded that a partial Fanconi syndrome couldpersist for up to 13 yrs after childhood Pb poisoning.The author notes that the prognostic significance ofthis is unknown at present.

# AX6-123Table AX6-4.5 (cont’d). Renal Effects of Lead in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEuropeMcDonald and Potter(1996)Boston, MA1991454 pediatric hospital patientswho were diagnosed withPb poisoning between 1923 and 1966 were tracedthrough 1991.Mortality study, comparison with U.S. population.Chronic nephritis was not a significant cause of death.Mortality from all cardiovascular disease waselevated (observed/expected = 2.1 [95% CI: 1.3,3.2]) and cerebral vasculardeaths were particularlycommon among women (observed/expected = 5.5[95% CI: 1.1, 15.9]).Moel and Sachs (1992)Chicago, IL1974-198962 participants with blood Pb>100 μg/dL, diagnosed andchelated between 1966 and 1972, together with 19 age-matched control siblings with initial blood Pbs less than40 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 reabsorptionof phosphate.Mean initial blood Pb150.3 μg/dL (highly poisonedas children)Data for siblings not availableas levels <40 μg/dL notquantified.There were no statistical differences in either renalfunction or blood pressure between study subjects andcontrol siblings. Initial blood Pb level was notassociated with serum creatinine, after adjustment forage, gender, and body mass index. A modest increasein serum creatinine values was observed over a nine-yr period in four of the 62 study subjects (up to1.6 mg/dL).Bernard et al. (1995b)Czech RepublicStudy date notprovided144 children living close to a Pb smelter (exposed groups1 and 2).51 controls living in a rural area presumed to berelatively unpolluted with Pb.Mean age = 13.5 yrs.Renal outcome measures included urinary albumin, RBP,NAG, Clara cell protein, and∃2-microglobulin.Retinol binding protein73.8 μg/g creatinine (controls)109.4 μg/g creatinine (exposed group 1)117.8 μg/g creatinine (exposed group 2)∃2-microglobulin60.3 μg/g creatinine (controls)89.1 μg/g creatinine (exposed group 1)66.4 μg/g creatinine (exposed group 2)NAG1.56 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 significantly higher in bothexposed groups compared to the control group. Incontrast, blood cadmium levels were similar amongall groups. After adjustment for age, sex, bloodcadmium, and zinc protoporphyrin, log transformedblood Pb was associated with log transformed RBP(∃= 0.302, p = 0.005).

# AX6-124Table AX6-4.5 (cont’d). Renal Effects of Lead in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)De Burbure et al.(2006)France, the CzechRepublic, and PolandStudy date notprovided804 exposed and control children.Exposed children recruited from residents near historicalnonferrous smelters, must have lived∃8 yrs nearsmelters.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 PbRanged from 2.8 to 4.2 mg/dLin various control and exposedgroups.Urinary cadmium, arsenic andmercury as well as bloodcadmium also assessed.Serum concentrations of creatinine, cystatin C, andß2-microglobulin negatively correlated with blood Pblevels.Authors state suggestive of an early renalhyperfiltration that avgd 7% in the upper quartile ofPbB levels (>5.5 μg/dL; mean 7.84 μg/dL).Factor-Litvak et al.(1999)Kosovo, Yugoslavia1985-1993577 children followed at 6 mo intervals through 7.5 yrsof age.Divided into a high exposure and a low exposure group,based on residence in Kosovska Mitrovica with a Pbsmelter, refinery, and battery plant or in Pristina, 25 milesaway.Renal outcome = Proteinuria assessed with a dipstick.Multiple logistic regression modeling of proteinuriadichotomized as either any or none, adjusting forsocioeconomic status, maternal education/ intelligence,and quality of childrearing environment.Mead blood Pb from graphpeaked at ~38 μg/dL betweenages 3-5 in KosovskaMitrovica and at ~10 μg/dL incontrols.Blood Pb level ranged from1 to 70 μg/dL.In higher exposed group, adjusted OR for proteinuriawas 3.5 (95% CI: 1.7, 7.2); adjusted odds ofproteinuria increased by 1.15 (95% CI: 1.1, 1.2) perunit increase in blood Pb in the higher exposed group.Proteinuria unrelated to blood Pb in lower exposedcontrol group.Limitations = limited renal outcomes assessed, highdropout rate in the study.

# AX6-125Table AX6-4.5 (cont’d). Renal Effects of Lead in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Fels et al. (1998)Poland1995112 children (50 controls, 62 exposed).Mean age = 9.9 yrs and 10.6 yrs in controls and exposedgroup, respectively.Numerous (29) renal outcome measures were examinedincluding serum creatinine and∃2-microglobulin, andurinary NAG, RBP, Clara cell protein,∃2-microglobulin,6-keto-prostaglandin F1α(6-keto-PGF1α), prostaglandinE2(PGE2) and thromboxane B2(TXB2).Urinary RBP46 μg/g creatinine (exposed)42 μg/g creatinine (controls)Urinary∃2-microglobulin89 μg/g creatinine (exposed)37 μg/g creatinine (controls)Serum creatinine0.63 mg/dL (exposed)0.63 mg/dL (controls)Mean blood Pb13.3 μg/dL (exposed)3.9 μg/dL (controls)Significantly higher mean serum∃2-microglobulin,and urinary transferrin, 6-keto-PGF1α, thromboxaneB2, epidermal growth factor,∃2-microglobulin, PGE2,and Clara cell protein in the exposed children. Incontrast, NAG-B was lower in the exposed group.Categorical blood Pb associated with prevalence ofvalues above the upper reference limits for severalbiomarkers. Urinary 6-keto-PGF1α, TXB2,∃2-microglobulin, Clara cell protein, epidermal growthfactor and PGE2positively correlated with blood Pb(r = 0.441, 0.225, 0.203, 0.261, 0.356, and 0.23,respectively; all with significant p-values).Limitations = data analysis, limited adjustment._ktem et al. (2004)TurkeyStudy date notprovided79 adolescent auto repair workers (mean age 17.3 yrs).71 rural adolescents as negative controls (mean age 17.0yrs).Renal outcomes = urinary NAG,∃2-microglobulin, uricacid, and calcium; blood urea nitrogen (BUN), serumcreatinine and uric acid.Mean blood Pb7.79 μg/dL (exposed workers)1.6 μg/dL (controls)No difference in mean BUN, serum creatinine, uricacid, or GFR (apparently estimated) between workersand controls.Urinary NAG and calcium significantly higher inworkers compared to controls. Urinary NAGpositively correlated blood Pb (r = 0.427).Limitations = data analysis, lack of adjustment.

# AX6-126Table AX6-4.5 (cont’d). Renal Effects of Lead in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEurope(cont’d)Price et al. (1999)Belgium, Poland,Germany and ItalyStudy date notprovidedUrinary Pb measured in 481 European children (236controls, 245 exposed) aged 6 – 14 yrs.Several renal outcome measures assessed includingurinary NAG and∃2-microglobulin; values not reported.Mean urinary PbRange from 3.9 to 7.2 μg/gcreatinine (controls)Range from 5.2 to 24.6 μg/gcreatinine (exposed)Urinary Pb generally higherin exposed children ascompared to controls. Authors unexpectedly foundsubstantial differences inrenal biomarkers by studysite. Authors note several renal biomarkers differedbetween exposed and control groups. Alsoquestioned the use of “control” groups in ubiquitousexposures.Sch≅rer et al. (1991)Germany1988-198922 children, age 5-14 yrs, with CRI.20 siblings or neighbors as lower exposed group.16 control children without known Pb exposure.Mean blood Pb2.9 μg/dL in children withCRI, not tested in other groupsMean dental Pb content2.8 μg/g in children with CRI1.7 μg/g in sibs/neighbors1.4 μg/g in controlsPb levels in teeth significantly higher in both thepatient and sibling/neighbor control groups comparedto the unexposed control group.S⎯nmez et al. (2002)TurkeyStudy date notprovided39 adolescent auto repair workers (mean age 16.2 yrs).13 adult battery workers as positive controls (mean age32 yrs).29 rural adolescents as negative controls (mean age14.8 yrs).Serum creatinine0.99 mg/dL (exposed group)0.99 mg/dL (positive/ adult controls)0.89 mg/dL (negative/ adolescent controls)Urinary NAG4.7 IU/g creatinine (exposed group)7.4 IU/g creatinine (positive/ adult controls)3.1 IU/g creatinine (negative/ adolescent controls)Mean blood Pb8.13 μg/dL (exposed group)25.3 μg/dL(positive/adult controls)3.49 μg/dL(negative/ adolescent controls)All participants had normal blood urea, creatinine,and uric acid levels as well as normal routineurinalysis.Blood Pb level and urinaryNAG significantly higherin adolescent auto repair workers compared to thenegative control group.Limitations = data analysis, lack of adjustment.

# AX6-127Table AX6-4.5 (cont’d). Renal Effects of Lead in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEurope(cont’d)Staessen et al. (2001)Belgium1999100 exposed and 100 control children.Mean age = 17 yrs.Two exposed groups were recruited from industrializedsuburbs while the control group was recruited from a ruralarea.∃2-microglobulin5.22 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 smokingstatus.Mean blood Pb1.5 μg/dL (controls)1.8 μg/dL (exposed group 1)2.7 μg/dL (exposed group 2)Blood Pb,∃2-microglobulin, and Cystatin-C levelshigher in exposed group 2 as compared to controls andexposed group 1.After adjustment for sex and smoking status, blood Pbwas associated with both∃2-microglobulin andcystatin-C. A two-fold increase in blood Pb wasassociated with a 3.6% (95%CI: 1.5, 5.7) increase inCystatin-C and a 16% (95% CI: 2.7, 31) increase in∃2-microglobulin. Blood cadmium was not associatedwith either outcome.Verberk et al. (1996)Romania1991-1992151 children who resided at different distances from a Pbsmelter.Mean age = 4.6 yrs.Renal outcomes = urinary RBP, NAG,α1-microglobulin,albumin and alanine aminopeptidase.Geometric meansUrinary RBP49.4 μg/g creatinineUrinary NAG6.9 U/g creatinineUrinaryα1-microglobulin2.4 mg/g creatinineUrinary alanine aminopeptidase19.8 U/g creatinineMultiple regression analysis adjusting for age and gender.Mean (SD) blood Pb34.2 (22.4) μg/dLAfter adjustment for age and gender, a 10 μg/dLincrease in blood Pb was associated with a 13.5%increase in NAG excretion (90% CI: 10.2, 17).No threshold was observed. No other significantassociations noted.

# AX6-128Table AX6-4.5 (cont’d). Renal Effects of Lead in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAfricaDiouf et al. (2003)Senegal199838 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 Pb10.7 (1.7) μg/dL (exposed)6.1 (1.8) μg/dL (controls)Blood Pb significantly higher in exposed group (urbandwellers) as compared tocontrols (rural dwellers).Unclear as to whetherαGST was higher or lower incontrols as compared to exposed group (stated to behigher in controls in the results section BUT stated to behigher in the exposed group in the discussion).Regardless, the difference was not statisticallysignificant.Limitations = small sample size, data analysis.

# AX6-129 

# ANNEX TABLES AX6-5

# AX6-130Table AX6-5.1. Effects of Lead onBlood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationMeta-analysisNawrot et al. (2002)31 U.S. and Europeanstudies, communityand occupationallyexposed, publishedbetween 1981 and2001.48 different groups, 32 of whichwere only of men, 15 of which wereonly of women, and one studyingboth sexes. Total meta-analysisN > 58,490. Age ranged from 15 to93 yrs, depending on the study.Two methods of meta-analysis wereused, subject-weighted and non-weighted, using study-reportedeffect sizes and standard errors,transformed from the original studyspecification of blood Pb (linear,logarithmic, or blood Pb group) to asingle effect size for doubling ofblood Pb. Also did analysesstratified by race and sex.Mean blood Pb concentrationacross studies ranged from2.3 to 63.8 μg/dL. Totalrange of blood Pb acrossstudies was 0 to 97.9 μg/dL.Each doubling of blood Pb was associated with a significant 1.0 mm Hg(95% CI: 0.5, 1.4) increase in systolic blood pressure and a significant 0.6mm Hg (95% CI: 0.4, 0.8) increase in diastolic blood pressure. Stated thatdifferences in Pb effect were not statistically different between sexes, but didnot describe test nor givestatistics other than p-values. Presented black andwhite differences as a trend for blacks to be “more susceptible than whites,”but presented no tests.Statistically examined assumptionsof homogeneity of effect and found nosignificant heterogeneity. Tested for publication bias (statistically significantresults tend to be published more than non-significant results) and found noevidence. Found no significant effectsof removing one study at a time insensitivity analysis. It appears that the presented results of effect sizes andconfidence intervals were calculated bythe subject-weightedmethod, but thiswas not made explicit. Included some studies that presented no Pbcoefficients or standard errors, assuming effect size of zero, though thereported effect sizes without these studies did not appear to be different fromoverall effect sizes. For studies using a linear Pb measure, effect sizes werecalculated by doubling the arithmetic mean blood Pb. If the concentrationresponse curve for the Pb-blood pressurerelationship was really bettercharacterized by a log-linear function, the authors’ use of studies with a linearblood Pb term with high avg blood Pb led to over-estimation of the slope ofthe relationship and those studies withlow blood Pb avgs produced an underestimation of the slope of the relationship.

# AX6-131Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited StatesCheng et al. (2001)U.S.-Boston,Normative AgingStudy (VA)1991-1997833 males (~97% white), avg age(SD):65.5 (7.2) Normotensive subjects,N = 33768.3 (7.8) Borderline hypertensivesubjects, N = 18167.9 (6.8) Definite hypertensivesubjects, N = 314474 males with no history ofhypertension at first measurement,returning up to 6 yrs later forhypertension study.Linear multiple regression models ofblood pressure and Cox proportionalhazard models of new cases ofhypertension after up to 7 yrs, withone group of covariates forced intomodels based on biologicalplausibility and another groupforced based on significantunivariate or bivariate results or>20% effect modification of Pbvariable coefficient in multiplemodels. Linear blood Pb, tibia Pb,and patella Pb forced in separatemodels.Arithmetic mean (SD) bloodPb:5.9-6.4 μg/dL (3.7-4.2),depending on hypertensiongroup (only data shown).Multiple regression models of blood pressure always included age, agesquared, BMI, family history of hypertension, daily alcohol consumption,and daily calcium consumption. Increasing tibia Pb concentration wasassociated with increased systolic bloodpressure (diastolic not addressed) inbaseline measurements insubjects (n = 519) free from definite hypertension(systolic >160 mm Hg, diastolic >95 mmHg, or taking daily antihypertensivemedication). Each increase of 10 μg/g tibia Pb concentration was associatedwith an increase in systolic blood pressure of 1.0 mm Hg (95% CI: 0.01,1.99). Patella and linear blood Pb were not significant.Cox proportional hazard models always included age, age-squared, BMI, andfamily history of hypertension. In follow up (n = 474), only increasingpatella Pb predicted increasing riskof definite hypertension in thoseclassified as normotensive at baseline. For every 10 μg/g increase in patellaPb risk ratio increased 1.14 (95% CI: 1.02, 1.28). Combining borderlinehypertension (systolic 141-160 mm Hg or diastolic 91-95 mm Hg) withdefinite hypertension (n = 306), the relative risk ratio of becoming acombined hypertensive associated with a 10 μg/g increase in patella Pb was1.23 (95% CI: 1.03, 1.48). Linear blood Pb and tibia Pb were notsignificant.Linear blood Pb is not indicated for blood pressure models due to stronglikelihood of significant residual heteroscedasticity and non-normality.Relatively small sample size may haveprevented tibia blood Pb significancein the Cox proportional hazard models.

# AX6-132Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Den Hond et al.(2002)U.S.-NHANES III1988-19944,685 white males, 5,138 whitefemales, 1,761 black males, 2,197black females, from 20 yrs up. Log-transformed blood Pb, systolic anddiastolic blood pressure measured atsurvey time and analyzed withforward, stepwise multipleregression with covariates.Avg age:WhiteMale: 44.3 yrsFemale: 46.2 yrsBlackMale: 40.5 yrsFemale: 41.5 yrsGeometric 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, hematocrit, smoking, alcohol, and anindicator variable for use of antihypertensive medications, each model wasfurther modified by a unique mix ofother covariates, including: coffeeconsumption, dietary calcium, dietary sodium/calcium ration, total serumprotein, total serum calcium, diabetes, and poverty index. Log Pb was forced inlast.In stratified analyses, only blacks had significant positive blood pressureassociations with log blood Pb. Each doubling of blood Pb was associated withincrease of black male systolic blood pressure of 0.9 mm Hg (95% CI: 0.04,1.8), black female systolicblood pressure of 1.2 mm Hg (95% CI: 0.4, 2.0), andfemale diastolic blood pressure of 0.5 mmHg (95% CI: 0.01, 1.1). In whitemales only, each doubling of blood Pb was significantly associated with adecrease in diastolic blood pressure of -0.6 mm Hg (95% CI:−0.9,−0.3).Stepwise models can rely on chance associations due to multiple testing andusually lead to a different pattern of covariate adjustment in different models.Inclusion of likely confounding variables such as serum calcium could haveaffected estimated Pb effects. No testing for significant Pb coefficientdifferences between each stratum. Nomodel diagnostic tests reported. Noexplanation offered for inverse relationship between Pb and diastolic bloodpressure in white males. No adjustment for survey design.Gerr et al. (2002)U.S.-Spokane WAand area aroundSilver Valley ID1994502 young people, age 19-29 yrs,53% female, nearly evenly dividedinto the Spokane group (no unusualchildhood exposure) and the SilverValley group, where a Pb smelteroperated during their childhood.Multiple regression models ofsystolic blood pressure and diastolicblood pressure. All covariatesforced into model as block with bothlinear blood Pb and tibia bone Pb ineach model.Mean (SD) blood Pb onlygiven stratified on tibia Pbcategory: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 Pbdata given.Adjusting for sex, age, height, BMI, education, income, current smoker, currentalcohol use, childhood residence (the two recruitment areas), current birthcontrol pills, hemoglobin,and serum albumin, only tibia Pb, and not linear bloodPb, was significantly related to systolicand diastolic blood pressure. Comparedto the <1 μg/g tibia Pb category,subjects in the >10 μg/g category had4.3 mm Hg (95% CI: 1.4, 6.7) highersystolic blood pressure and 2.8 mm Hg(95% CI: 0.4, 5.2) higher diastolic blood pressure.Linear blood Pb is not indicated for blood Pb-blood pressure models.No diagnostic testing reported. Insufficient descriptive data given for tibia Pb.

# AX6-133Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Glenn et al. (2003)U.S.-New Jersey1994-1998496 males, mean (SD, range) age55.8 (7.4, 40-71) yrs, working orformerly working at a plantproducing tetraethyl or tetramethylPb until 1991, were followed from10 mos to 3.5 yrs during whichblood pressure was repeatedlytested. Blood Pb was tested only atbaseline. Tibia Pb was tested in1991 (at the end of organic Pbproduction at the plant) and called“peak tibia Pb” and again during1997 (yr 3). Generalized estimatingequations with an exchangeablecorrelation structure for repeatedmeasurements were used for systolicand diastolic blood pressure. Onegroup of covariates was forced intothe model as a block (age atbaseline, race, BMI, indicatorvariable for technician, Pb variable(linear blood Pb, peak tibia Pb, andtibia Pb each tested separately),duration of follow up, and theinteraction between the Pb variableand the duration term. Potentialconfounding variables were enteredstepwise and retained in the model ifsignificant. Alternate models notusing linear time were constructed,using quartile of follow up time toavoid assuming a linear relationshipof change in blood pressure withtime.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 to118.8)Controlling for baseline age, BMI, antihypertensive medication use, smoking,education, technician and number of yrs to each blood pressure measurement,each 1 μg/dL increase in linear baseline blood Pb was associated with avgsystolic blood pressure increase of 0.64 mm Hg/yr (95% CI: 0.14, 1.14),each 10 μg/g increase in yr 3 tibia Pb with an avg increase of 0.73 mm Hg/yr(95% CI: 0.23, 1.23), and each increase of10 μg/g of peak tibia Pb with anavg increase of 0.61 mm Hg/yr (95% CI: 0.09, 1.13). Similar results wereobtained using the follow up time quartile designation for systolic bloodpressure with all subjects and withsubjects not taking antihypertensivemedications.This was one of the few studies usinga prospective design and that used astatistical technique accounting for repeated measures. No justification givenfor using an exchangeable correlation structure instead of an alternate one.Only examined cortical bonePb (tibia) and not trabecular bone Pb (patella orcalcaneus). Linear blood Pb may not be indicated for use in blood Pb-bloodpressure models. Stepwise modeling involves multiple testing of the samedata set with no control for alteredprobabilities. Nomodel diagnosticspresented.

# AX6-134Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Glenn et al.(2001)U.S.-New Jersey1996-1997213 males (92% white), mean (SD)age 58.0 (7.4) yrs, working orformerly working at a plantproducing tetraethyl or tetramethylPb until 1991, were genotyped forATP1A2(5’) and ATP1A2(3’)polymorphism. ATPase is thought toplay a role in regulating bloodpressure and Pb inhibits its activity.Blood pressure, blood Pb, and tibiaPb were measured. Multiple linearregression models were used forsystolic and diastolic blood pressure.Logistic regression model wasreported for hypertension(systolic >160 mm Hg,diastolic >96 mm Hg, or takingantihypertensive medications).Covariate entry methods notspecified, but were likely stepwise.Covariates for the blood pressuremodel were age, use ofantihypertensive medications,alcohol, smoking, season of yr, linearblood Pb, tibia Pb (the two Pbmeasures apparently testedseparately), ATP1A2(5’) andATP1A2(3’) polymorphism (eachtested separately), and an interactionterm between polymorphism and Pb.Covariates for the hypertensionmodels were age, BMI, lifetimealcoholic drinks, linear blood Pb andtibia Pb, and polymorphism, each Pbmeasure and polymorphism testedseparately.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 theATP1A2(5’) polymorphism and either bloodor bone Pb or blood pressure were significant.The ATP1A2(3’) polymorphism was homogenous for the 10.5 kilobase allele(10.5/10.5) in 11 subjects, heterogeneousfor the 10.5 and 4.3 kilobase allele(10.5/4.3) in 82 subjects, and heterogeneous(10.5/4.3) in 116 subjects. Prevalenceof the 10.5 allele was significantlyhigher in blacks than in whites.Regression coefficients of 4.3/4.3 and 10.5/4.3 genotypes were not significantlydifferent and all subsequent analyses compared the 10.5/10.5 genotype with thecombined 4.3/4.3-10.5/4.3) genotype. The significant interaction between linearblood Pb and the 10.5/10.5 genotype showed that for every 1 μg/dL of blood Pbsystolic blood pressure increased 5.6 mm Hg (95% CI: 1.2, 9.9) more than the bloodpressure of the combined genotype group. Blood Pb range of the combinedgenotype group was twice that of the 10.5/10.5 group. When data were truncated tomake blood Pb of both groups cover the samerange, coefficients of the genotypelinear blood Pb interaction term did not change appreciably. Authors state that tibiaPb interacted with genotype on blood pressurebut showed no data to estimate eithertype or size of effect. Diastolic blood pressure was not related to genotype, to Pb orto the interaction between Pb and genotype.Prevalence of hypertension (30% in total sample) was significantly higher amongthe 10.5/10.5 group (63.4 %) than among the combined group (28.3 %). Adjustingfor age, BMI, and lifetime alcohol, the oddsof hypertension in the 10.5/10.5 groupwere OR = 7.7 (95% CI: 1.9, 31.4) compared to the 4.3/4.3 group. Theheterogeneous group was not significantly different from the 4.3/4.3 group.Linear blood Pb specification not indicated for blood Pb-blood pressure modeling.Examination of partial residual plot forsystolic blood pressure and linear blood Pbshows typical heterogeneity ofresiduals as a function of predicted values. Thus,presented coefficients may be inefficient and biased. Only 9 subjects werehomogenous for 10.5/10.5 in the multiple regression model. Only cortical bone Pbwas tested, not trabecular bone Pb. Cortical bone Pb models not shown orquantitatively described. Blood Pb roundedto nearest unit μg/dL. Mixed organicinorganic Pb exposure. Relatively small sample size may have prevented detectionof other significant effects.No model diagnostics described.

# AX6-135Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference,StudyLocation, andPeriodStudy Description Pb Measurement Findings, InterpretationUnited States(cont’d)Hu et al. (1996)U.S.-Boston-NormativeAging Study-VA1991-1994590 males (over 98% white), mean agearound 67 yrs, divided into 146hypertensives (systolic >160 mm Hg,diastolic >95 mm Hg, or dailyantihypertensive medication) and 444 non-hypertensives. Linear blood Pb, tibia andpatella bone Pb added separately to logisticregression model containing forcedcovariates of age, race, BMI, family historyof hypertension, pack-yrs smoking, alcoholingestion dietary sodiumand calcium. Then,a backward elimination procedure startingwith all covariates, including all Pbvariables, resulted in a model in which onlysignificant 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 withall forced covariates revealed no significant Pbeffects when the three Pb variables were forced into the model separately. Afterbackward elimination, the only significantcovariates left were BMI and familyhistory of hypertension. Of all the Pb variables, only tibia Pb remained in themodel. With each increase of 10 μg/gof tibia Pb, odds of being classifiedhypertensive rose (OR = 1.21; 95% CI: 1.04, 1.43).Stepwise regression, backward or forward,involves multiple testing with the samedata set, capitalizes on chance occurrencein the data set, and gives over-optimisticprobability values. No model diagnostic testing reported.

# AX6-136Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Korrick et al.(1999)U.S.-Boston-NurseHealth Study1993-1995284 women, from 47-74 yrs, mean age(SD) 58.7 (7.2), were divided into 97cases (systolic∃140 mm Hg,diastolic∃90 mm Hg, or physician-diagnosed hypertension) and195 controls. Controls were furtherclassified as low normal(<121/75 mm Hg) and high normal>121/75 mm Hg). Three ordinalregression models were constructed,each containing either blood Pb, tibia Pbor patella Pb with forced entry of allother covariates. A final backwardselimination ordinal regression modelstarted with all covariates, including allPb variables, excluding each until onlysignificant variables were left.Interactions were tested in the finalmodel between patellaPb and alcoholuse, 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 increased odds of hypertensionin the preliminary models, adjusted for age, BMI,alcohol, dietary calciumand sodium, ever smoke, and family hypertension. Each 10 μg/g increase inpatella Pb was associated with increased odds of hypertension OR = 1.28(95% CI: 1.03, 1.60). In the backwardelimination model adjusted for age,BMI dietary sodium and family hypertension, only natural log transformedpatella Pb remained in the model. Identical odds ratios from patella Pb wereobtained in both models. None of the interaction tests were significant.Small study size may have limited power to detect significant interactions.The proportional odds assumption ofthe ordinal regression model wasverified. Note that the odds ratios above are for movement from one of thetwo lower categories, low normal andhigh normal, to the next highercategory as patella Pb increased. No other model diagnostic tests reported.Morris et al. (1990)U.S.-sampled fromgeneral populationaround Portland,OR responding toads to participate inclinical trials ofnonpharmacologicalmanagement ofblood pressure.1984-1989?145 males and 106 females, 73% witharterial pressures >105 mm Hg,provided blood pressure measurementsonce a wk over four consecutive wks.Blood for Pb analysis was collectedduring this period. Stepwise multipleregression was used to constructseparate models of systolic and diastolicblood pressure stratified by sex.Covariates availableto be entered wereage, BMI, dietary calcium and “othernutrient intakes,” ionized serumcalcium, erythrocyte protoporphyrin andnatural log transformed blood Pb.Arithmetic mean (SD) bloodPb:Males: 8.0 μg/dL (4.4)Females: 6.9 μg/dL (3.6)Natural log blood Pb wasonly a significant predictor of blood pressure inmales. Adjusting for age and ionized serum calcium, every one natural unitincrease in blood Pb was significantly associated with a 4.58 mm Hg(neither SE nor CI stated) in systolic blood pressure and, adjusting forhemoglobin, age, and current smoking, a 1.90 mm Hg (neither SE nor CIstated) in diastolic blood pressure.The usual precautions regarding multiple testing and different covariatepatterns in stratified models constructed with stepwise regression apply.Reporting of effects not complete. Small sample size limits conclusionsabout non-significant effects. High prevalence of hypertensives in sampledue to study recruitment design. Blood Pb technique, as represented bypresented graph, had a detection limitof 5 μg/dL. No model diagnostics.

# AX6-137Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Nash et al. (2003)U.S.-NHANES III1988-19941084 premenopausal and 633postmenopausal women, from 40to 59 yrs. Multiple linearregression models withcovariates, including linear bloodPb, entered as a block for systolicand diastolic blood pressure.Logistic regression models withsame covariates and Pb quartileadded last for hypertension.Mean (range) blood Pb byPb 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/ethnicity, alcohol use,cigarette smoking, BMI, and kidney function (serum creatinine) in multiple regressionmodels for all women and women stratifiedby menopause status for systolic anddiastolic blood pressure. Pb quartile wasadded to logistic regression models ofhypertension (systolic∃140 mm Hg, diastolic∃90 mm Hg or taking antihypertensivemedication with the same covariates as the blood pressure models, in all women andstratified by menopausal status. Tested additional models in which women treated forhypertension were excluded from models.All models were adjusted for sampledesign and weighting.Each increase of 1 μg/dL of blood Pb was significantly associated with a 0.32 mm Hg(95% CI: 0.01, 0.63) increase of systolicblood pressure and a 0.25 mm Hg (95% CI:0.07, 0.43) increase of diastolic blood pressure in all women without respect tomenopausal status. In analyses stratified by menopausalstatus, only postmenopausalwomen showed a significant blood Pb effect. For each 1 μg/dL increase of blood Pbwas associated with significantly increased diastolic blood pressure of 0.14 (95% CI:−0.11, 0.39sic.) only in postmenopausal women.Referenced to the 1st blood Pb quartile,no other quartile showed significantlyincreased odds for hypertension in all subjectsor in subjects stratified by menopausalstatus. With further analyses stratified bysystolic and diastolic hypertension withoutwomen taking antihypertensive medications, in the combined group of pre andpostmenopausal women the oddsof diastolic hypertension were significant when the4th Pb quartile was compared to the 1st quartile (OR = 3.4 [95% CI: 1.3, 8.7]). In amodel of only postmenopausalwomen untreated for hypertension, odds of diastolichypertension were significantly increasedin the higher three quartiles of blood Pb(OR = 4.6 [95% CI: 1.1, 19.2], OR = 5.9 [95% CI: 1.5, 23.1], OR = 8.1 [95% CI:2.6, 24.7], respectively) and odds of systolichypertension were significant only for thetwo middle Pb quartiles (OR = 3.0 [95% CI: 1.3, 6.9], OR = 2.7 [95% CI: 1.2, 6.2],respectively).Linear blood Pb is suspect in linear regression models of bloodpressure as it isusually associated with biased and inefficient estimation of Pb coefficients due toprobable heteroscedasticityand non-normal distribution ofresiduals. No modeldiagnostics were reported. Nostatistical testing for differences in Pb coefficientsaccording to strata. Nine stratified models overall. Not all stated significance levelsand standard errors in the blood pressure model table corresponded for certainvariables.

# AX6-138Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Proctor et al.(1996)U.S.-Boston-Normative AgingStudy (VA)1992-1993798 men from 17 to 44 yrs.Multiple linear regression modelsof natural log blood Pb onsystolic and diastolic bloodpressure. All covariates forcedinto 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 dietary calcium, exercise,indicator variables for current and formersmoker, daily alcohol consumption, sittingheart rate, and hematocrit were entered into multiple regression models without regardfor significance.Increased diastolic, but not systolic, blood pressure was significantly associated withincreased blood Pb. Each natural log increase in blood Pb was associated with a1.2 mm Hg (95% CI: 0.1, 2.2) increase in diastolic blood pressure.Interactions between dietary calcium and blood Pb onblood pressure were notsignificant. Further analyses stratifiedon use of antihypertensive medication andthose older than or equal to 74 yrs stillrevealed significant blood Pb-diastolic bloodpressure relationships.Blood Pb in over half the study group (n = 410) was determined by analyzingpreviously frozen erythrocytes collected several yrs prior to the blood pressuremeasurements used in the study and corrected by using hematocrit values alsomeasured when blood was originally collected. Combining both groups means thatnearly half the group was tested for the effects of blood Pb on blood pressuremeasured at the same time, the other half measured several yrs apart. There was nocorrection in models for this potential effect. The effect of taking antihypertensivemedication could have been assessed in a single model by using an indicator variable.No statistical testing for the effects ofstratification on the blood Pb-blood pressurerelationship. No model diagnostics.

# AX6-139Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Rothenberg et al.(1999)U.S.-Los Angeles1995-19981188 immigrants and 439 nonimmigrants,from 15 to 43 yrs, all women in 3rdtrimester of pregnancy. Multipleregression models of natural log blood Pbon systolic and diastolic blood pressurewith all covariates forced into models.Covariates selectedfrom larger set basedon 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 supplementation, and job stresswere entered as a block without regard to significance in linear multiple regressionmodels of systolic and diastolic blood pressure stratified by immigration status.Increased blood Pb was significantly associated with increased blood pressure only inimmigrants. Each natural log unit increase in blood Pb was associated with a1.7 mm Hg (95% CI: 0.7, 2.8) increase insystolic blood pressure and a 1.5 mm Hg(95% CI: 0.5, 1.9) increase in diastolic blood pressure in immigrants.Used and reported model diagnostic tests, asevidenced by the use of standard errorcalculations robust to residual heteroscedasticity. Stated reasons for stratification onimmigrant status were significant differences between the two groups in blood Pb,blood pressure, age, BMI, and education. Did not statistically test difference in Pbcoefficients between the immigration strata. Did not correct for potential non-linearityin age effects on blood pressure.Rothenberg et al.(2002a)U.S.-Los Angeles1995-2001668 women, 15 to 44 yrs, studied in 3rdtrimester pregnancy and again a mean of10 wks postpartum. Exclusion criteriawere diabetes, renal or cardiovasculardisease, extreme postnatal obesity(BMI >40), and subjects using stimulantdrugs. Multiple linear regression modelsof natural log blood Pb, tibia andcalcaneus Pb on systolic and diastolicblood pressure with all covariates and allPb variables forced into model. Separatemodels 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 postpartumperiods with the same covariates and Pbvariables.Geometric mean bloodPb (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 adjusted for postnatalhypertension (3rd trimester model only), BMI,age, parity, smoking, alcohol,immigrant status, and educational level plus all three Pb indices. Only calcaneus Pbwas associated with blood pressure in 3rd trimester models. Every 10 μg/g increase incalcaneus Pb was associated with 0.70 mm Hg (95% CI: 0.04, 1.36) increase insystolic blood pressure and a 0.54 mm Hg (95% CI: 0.01, 1.08) increase in diastolicblood pressure. In postpartum models, natural log blood Pb was the only variablestatistically associated with blood pressure. Every natural log unit increase in bloodPb was associated with!1.52 mm Hg (95% CI:!2.83,!0.20) decrease in systolicblood pressure and a−1.67 mm Hg (95% CI:!2.85,!0.50) decrease in diastolic bloodpressure.In logistic models, only calcaneus Pb was significantly associated with increased oddsfor hypertension. Each 10 μg/g increase in calcaneus Pb was associated with an OR =1.86 (95% CI: 1.04, 3.32) of 3rd trimesterhypertension. None of the Pb variableswas associated with postpartum hypertension.Models did not use age-squared covariate.Models did not use repeated measuresstatistics. No statistical comparisons between 3rd trimester andpostpartum models.Model diagnostic tests reported.

# AX6-140Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Schwartz et al.(2000c)U.S.-Eastern1996-1997543 mostly former organoleadworkers, predominantly white(92.8%), at a tetraethyl/tetramethylplant, mean (SD) [range] age 7.6 (7.6)[41.7-73.7] yrs had blood Pb, DMSA-chelatable Pb (4-hr. urinary Pbexcretion after a single 10 mg/kg doseof DMSA) measured for modelingsystolic and diastolic blood pressureand hypertension (systolic >160mm Hg or diastolic∃96 mm Hg ortaking antihypertensive medications.Tibia Pb ~2 yrs later was also used asa Pb index. For blood pressure, linearmultiple regression with backwardelimination of non-significantcovariates or covariates that “hadimportant influence on the coefficientsfor the Pb-dose terms.” Each Pbvariable was tested in a separatemodel. Potential covariates for thesemodels were age, BMI, currenttobacco use, and current use ofantihypertensive medications. Othermodels were constructed taking outthose subjects using antihypertensivemedications. Both linear and linear +quadratic blood and tibia Pb termswere tested. Logistic regressionanalyses were used to test the effect ofthe Pb variables on hypertension,controlling for age, diabetes, lifetimealcohol consumption, and BMI.Logistic models also tested each Pbmeasure in interaction with age.Blood Pb arithmeticmean (SD, range):4.6 μg/dL (2.6, 1to 20)DMSA-chelatable Pbmean (SD, range):19.0 μg (16.6, 1.2to 136)Tibia Pb mean (SD,range): 14.4 μg/g(9.3,!1.6 to 52)Adjusting for age, BMI, current smoking, andcurrent use of antihypertensive medications,each 1 μg/dL increase in blood Pb-squared was significantly associated with 0.189 mm Hg(95% CI: 0.087, 0.330) increase in systolic blood pressure with three outliers removed.With the same covariates, each 1 μg/dLincrease in linear blood Pb was significantlyassociated with 0.310 mm Hg (95% CI: 0.028, 0.592) in diastolic blood pressure takenover a 2-yr period (n = 525). No other Pb variables were significant.For the hypertension models, only the interaction of linear blood Pb by age was significant,with subjects showing significant decrease in odds ratio of hypertension with every jointincrease of 1 μg/dL blood Pb and 1 yr increase in age (linear blood Pb X age OR = 0.98;[95% CI: 0.97, 0.99]). The interaction suggested a concentration-response relationshipbetween linear blood Pb and hypertension only up to ~58 yrs of age.Authors note that blood pressure findings “werenot affected by exclusion or inclusion ofsubjects using antihypertensive medications,”but do not present either the data or thestatistical tests to evaluate that conclusion.No other model diagnostics were reported.Although blood Pb was also modeled as a quadratic Pb term for systolic blood pressure, noanalysis was shown for non-linear blood Pbterms for diastolic blood pressure.Trabecular bone Pb was not tested, though otherstudies indicate that it is a better Pb indexthan cortical Pb for cross-sectional blood pressure and hypertension study.Although the backward procedures described could have resulted in less than the full set ofconsidered covariates entering the models, all model presentations were limited to showingthe Pb coefficients and all models indicated in a footnote that the Pb coefficients wereadjusted for each possible covariate for that model. While this is possible with the shortlist of covariates, given the 14 models presented one might expect to see at least one modelwhere one of the covariates did not remain.

# AX6-141Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Schwartz (1995)15 prior U.S. andEuropean studiespublished between1985 and 1993Total subjects not specified, men andwomen ages 18 to 74 yrs. Randomeffects meta-analysis with inversevariance weighting of Pb-bloodpressure coefficients from each study.Sensitivity analysis performed bydropping study with largest or smallesteffect.Blood Pb levels notstated.Each doubling of natural log blood Pb level was associated with an increase of 1.25mm Hg (95% CI: 0.87, 1.63) systolic bloodpressure. Sensitivity analysis showednegligible change in meta-analysis coefficient. Concluded that adding newer studieswould not change calculated coefficient.Noted Pb-blood pressure slope was larger atlower Pb levels than at higher Pb levels.The study only analyzed systolic, not diastolic, blood pressure. Superseded byNawrot et al. (2002).Schwartz (1991)NHANES IIU.S.1976-1980Under 10,000 subjects (exact numbernot reported), males and females, aged25 to 74 yrs for left ventricularhypertrophy results with logisticregression. Linear blood Pb used forLVH. For blood pressure results,multiple linear regressions stratified bysex, with one block of variablesforced, another block of variablesentered with stepwise regression, aged6 mos to 74 yrs, exact number notgiven. Natural log blood Pb used forlinear regression. Both logistic andlinear regressions adjusted for surveydesign.No blood Pbdescriptive datagiven.Used logistic regression to study Pb effect on left ventricular hypertrophy (LVH)determined by a combination of electrocardiogram parameters and body habitus,controlling for age, race, and sex. Every 10 μg/dL blood Pb increase was associatedwith increased odds of LVH of 1.33 (95% CI: 1.20, 1.47). Interaction terms for raceby blood Pb and sex by bloodPb were not significant.Blood pressure models stratified by sex always included BMI, age and age-squared,race, and natural log blood Pb. Male blood pressure model also included familyhistory of hypertension, cholesterol, height,cigarette use, serum zinc, and tricep skinfold. Female model also included serum zinc, family history of hypertension, tricepskin fold, and cholesterol. Every 1 natural log unit of blood Pb increase wasassociated with an increase in diastolic blood pressure of 2.93 mm Hg (95% CI: 0.93,4.98) in males and 1.64 mm Hg (95% CI:0.27, 3.01). Used interaction terms forrace-blood Pb and sex-blood Pb in a non-stratified model and found no significanteffect of race or sex on the blood Pb-blood pressure coefficient.Incomplete reporting of subject size for models and for descriptive statistics for allvariables in models. Tested both linear and log transformed Pb in preliminary testing.Found log Pb had lower probability values than linear Pb for blood pressure, andlinear Pb had lower probability values than log Pb for LVH. No testing of significantdifference between the two blood Pb specifications. No model diagnostics reported.Only reported diastolic blood pressure results.

# AX6-142Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Sokas et al. (1997)U.S.-Maryland1989-1990264 active or retired constructionworkers, over 99% men, who were notinvolved in Pb work at time of testing,mean age (range) 43 yrs (18-79).Multiple regression modeling ofsystolic and diastolic blood pressureadjusted for covariates of BMI, age,hematocrit, erythrocyteprotoporphyrin, race, linear blood Pband a race-linear blood Pb interaction.Method of covariate entry not madeexplicit, though it appeared to beforced.Mean blood Pb(range): 8.0 μg/dL(1-30)Linear blood Pb was not significantly related to either systolic or diastolic bloodpressure, though the race by linear bloodPb interaction was marginally significant(p = 0.09). Each 1 μg/dL increase in bloodPb increased black systolic blood pressure0.86 mm Hg (no SE or 95% CI reported) more than white systolic blood pressure.Linear blood Pb term may not be appropriate. Small sample compromisesinterpretation of non-significant results.By using erythrocyte protoporphyrin andblood Pb in the same model, these two measures of Pb exposure may have beenconfounded. Incomplete reporting of procedures and results.No model diagnostictests reported.Sorel et al. (1991)U.S.-NHANES II1976-19802056 females, 2044 males, 473 blacksand 3627 whites, from 18-74 yrs, wereused in survey design and weightadjusted multiple linear regressionsstratified by sex, with separate modelsfor systolic and diastolic bloodpressure. Covariates included age,BMI, race, and poverty income ratioand linear blood Pb. Method ofcovariate entry not specified but mayhave been forced. Different covariategroups were used for different models.Primary test for the effect of race onthe Pb-blood pressure relationship wasto note the change in the racecoefficient in modelswith and withoutthe linear blood Pb variable.Age-adjustedarithmetic meanblood Pb:Black female:13.2 μg/dL (novariance informationfor any blood Pb)White female:12.1 μg/dLBlack male:20.1 μg/dLWhite male:16.8 μg/dLLinear blood Pb was significantly related only to diastolic blood pressure in males,adjusting for age and BMI. For every 1 μg/dL blood Pb increase diastolic bloodpressure increased 0.13 mm Hg (95% CI: 0.04, 0.21). Adding race to the model withand without linear blood Pb terms did not appear to change the race coefficient.Adding poverty index to the models withand without blood Pb produced the samesmall change in poverty index coefficient.Linear blood Pb may not be appropriate. Only confidence intervals were used toassess the significance of changes in race and poverty index coefficients acrossmodels with and withoutPb, instead of using interaction terms of these two variableswith Pb. Incomplete reporting of procedures and results. Nomodel diagnostic testsreported.

# AX6-143Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Sharp et al. (1990)U.S.-SanFrancisco, CA1986After exclusion of subjects undertreatment for hypertension, 249 malebus drivers, 132 of whom were black,age from 31 to 65 yrs, were used inrace stratified multiple regressionmodels of systolic and diastolic bloodpressure with covariate forced entry ofage, age-squared, BMI, caffeine use,tobacco use, and natural log blood Pb.Alcohol use was added in othermodels. Other models stratified bycaffeine 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 inblacks. In models excluding alcoholuse, for every one natural log unit increase of blood Pb, systolic blood pressure rose7.53 mm Hg (95% CI: 0.86, 14.2) and diastolic blood pressure rose 4.72 mm Hg(95% CI: 0.15, 9.29). Stratified by infrequent/frequent caffeine users, only blackinfrequent caffeine users showed a significant response to blood Pb. For every onenatural log unit increase of blood Pb, systolic blood pressure rose 16.69 mm Hg (95%CI: 3.83, 29.5) and diastolic blood pressurerose 10.43 mm Hg (95% CI: 1.26, 19.6).Non-black blood pressure was decreasedwith increasing natural log Pb but wasmarginally significant. In all non-black subjects, for every unit increase in natural logblood Pb, systolic blood pressure decreased−5.71 mm Hg (95% CI:−12.0, 0.6).Addition of alcohol to the models decreased all coefficients a small amount.Progressive addition of age, BMI, caffeine, and tobacco, in that order, progressivelyincreased the coefficient of natural log bloodPb in models of systolic and diastolicblood pressure in blacks. Removal of two black outliers did not materially change theresults for blacks.No statistical tests for comparing stratifiedmodels, models withand without caffeineuse, effect of progressive addition of covariates, or addition of alcohol. Influencediagnostics reported for detecting the two outlying subjects. No other diagnostic testsreported. Small differences in text and table reports of the same coefficients. Smallsample size limits interpretation of non-significant results.

# AX6-144Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Tepper et al.(2001)U.S.-Cincinnati,OHAfter 1991 tobefore 200143 females and 57 males, current orformer workers at a Pb-acid batteryfactory, between 36 and 73 yrs of age,with at least 10 yrs working in batteryproduction, participated. Multivariateregression models and logisticregression models were constructed toassess Pb exposure effect on outcome(hypertension: >140/90 mm Hg and>160/95 mm Hg or takingantihypertensive meds; diastolic andsystolic blood pressure, and leftventricular mass/body surface area(g/m2). Echocardiograms were used todetermine left ventricular mass.Variables used to adjust all modelswere age, BMI, sex, and family historyof hypertension.Plant blood Pb records wereused to calculate cumulativeblood Pb index (CBLI) used asa tertile measure, a linearcontinuous measure, and a logtransformed measure.CBLI μg/dL-yr1st tertile: 138-5042nd tertile: 505-7463rd tertile: 747-1447Time-avgd blood Pb TABL)was treated the same way:TABL μg/dL1st tertile: 12-252nd tertile: 26-333rd tertile: 34-50No odds ratios were given for hypertensionand any Pb variable for hypertensiondefined as >140/90 mm Hg butORs were claimed not significant. Odds ratios were2.71 and 1.44 for the 3rd tertile CBLI and TABLPb measures compared to 1st tertile,apparently significant, but no probabilities, SEs or CIs given.With the 81 subjects not taking anti-hypertensive meds, neither CBLI tertile norTABL tertile were significantly associatedwith either diastolic or systolic bloodpressure (coefficients, SEs or 95% CIsnot given). Using log transformed CBLIprobability of a positive association with diastolic blood pressure was 0.06. Using logtransformed TABL, probabilityof a positive association with diastolic blood pressurewas 0.10. No coefficients, SEs, or CIs given.Left ventricular mass adjusted for body surface area was not significantly related toany Pb measure. No coefficients, SEs or CIs given.Despite the certainty of the authors that “we found no convincing evidence of anassociation...”, the very low power of thisstudy gives certainty to none of thefindings. Very poor reporting of results further reduces the possibility of evaluation.No model diagnostic testing was reported.

# AX6-145Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Vupputuri et al.(2003)U.S.-NHANES III1988-19945188 white women, 2300 blackwomen, 5360 white men, and 2104black men, aged 18 yrs and older.Survey adjusted multiple linear andlogistic regression were used to assesslinear blood Pb effect on systolic anddiastolic blood pressure andhypertension in race and sex stratifiedmodels.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 adjusted for age, education, BMI, alcoholconsumption, leisure time physical activity, dietary sodium and potassium, and totalcalories. Only black women and men showed significant linear Pb effects. Every1 μg/dL increase in blood Pb was associated with an increase of 0.47 mm Hg (95%CI: 0.14, 0.80) in systolic and 0.32 mmHg (95% CI: 0.11, 0.54) diastolic bloodpressure in black women, and 0.25 mm Hg(95% CI: 0.06, 0.44) systolic and 0.19mm Hg (95% CI: 0.02, 0.36) diastolic blood pressure in black men.Odds of hypertension (systolic∃140 mm Hg, diastolic∃90 mm Hg, or takingantihypertensive medication) significantlyincreased for every SD (3.3 μg/dL) ofblood Pb level in black women (OR = 1.39 [95% CI: 1.21, 1.61]), in white women(OR = 1.32 [95% CI: 1.14, 1.52]), in black men (OR = 1.26 [95% CI: 0.99, 1.19]),but not in white men.Linear blood Pb terms are usually not appropriate in multiple linear regression modelsof blood pressure. Furthermore, they reportedtheir results in terms of change in 1 SDunit of Pb. Linear SD of Pb is incorrect for log-normal distributions of blood Pb. Nomodel diagnostic tests reported. Discrepancy between Methods report of race-Pb andsex-Pb interactions in simple, not multiple, analyses, but Results reports significantinteractions for race-Pb and sex-Pb in multiple regression models for both linearregression and logistic regression models, without showing the results of theinteraction analyses. The probability of the stated interactions (p < 0.001) appearsextremely low, given the degree of 95%CI overlap in Pb coefficients among thestratified models. No model diagnostics reported.

# AX6-146Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEuropeBost et al. (1999)Europe-England-Health Survey forEngland19952763 women and 2563 men from a multi-stage stratified probability surveyrepresentative of the English populationliving in private residences, mean (SE) agefor men 47.5 yrs (0.34) and for women 47.7yrs (0.33) (all subjects 16 yrs and older)were used in an analysis of blood Pbassociation with systolic and diastolic bloodpressure. Stepwise multiple regressionanalysis were used testing natural log bloodPb against common log systolic bloodpressure and non-transformed diastolicblood pressure, with the following potentialcovariates: age,BMI, smoking status,region of residence, social class, andalcohol consumption.Models werestratified by sex, with and withoutadjustment for alcohol, including orexcluding those taking antihypertensivemedications.Geometric mean blood Pb:Men: 3.7 μg/dL (no statedmeasure of variance)Women: 2.6 μg/dL(no stated measure ofvarianceModel tables presented only standardized variable coefficients. The mostconsistent results were reported on common log Pb association with men’sdiastolic blood pressure. Every doubling of blood Pb was significantlyassociated with an increase of 0.78mm Hg (95% CI: 0.01, 1.55) diastolicblood pressure, adjusted for age, logBMI, and alcohol, but excluding menon antihypertensive medication. Every doubling of blood Pb wassignificantly associated with an increase of 0.88 mm Hg (95% CI: 0.13,1.63) in the same model with men onantihypertensive medication. Everydoubling of blood Pb was significantly associated with an increase of 0.96mm Hg (95% CI: 0.23, 1.70) in the same model excluding men onantihypertensive medication and not adjusting for alcohol. Every doublingof blood Pb was significantly associated with an increase of 1.07 mm Hg(95% CI: 0.37, 1.78) including men taking antihypertensive medication andnot accounting for alcohol. None of the multiple regression models hadsignificant Pb terms for women.This report was not sufficiently detailed. Stepwise regression modeling isprone to the usual pitfalls. Survey design adjusted analysis not used. Pbwas not entered in models in which criterion probability was exceeded(p > 0.05). No rationale given for stratifying. No testing of differencesamong Pb coefficients for the different models was made, which would havebeen especially valuable to compare models adjusted and not adjusted foralcohol use. No explanation for using log systolic blood pressure asdependent variable. Nomodel diagnostics reported.

# AX6-147Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Fewtrell et al.(2004)Global1988-2002Using available global figures oncategorized blood Pb ranges by age group,authors calculated relative risk ratiosrelating increased blood pressure toischemic heart disease, cerebrovasculardisease, hypertensivedisease, and othercardiac diseases. Theyused a calculation of“impact fraction,” based on the proportionof the population within the particular Pbexposure category and the relative risk atthat exposure category compared to the riskat the reference level. They used the meta-analysis of Schwartz (1995) to derive anaccumulating 1.25 mm Hg increase inblood pressure in men for 5-10, 10-15, and15-20 μg/dL, and an increase of3.75 mm Hg for blood Pb levels above20 μg/dL. Comparable blood pressureincreases in women for each Pb categorywas 0.8 mm Hg for each of the first threecategories and 2.4 mm Hg for blood Pb>20 μg/dL.See left for blood Pbcategories used.The largest risk ratios were for hypertensive disease populations at ages 15-44,calculated at 1.12, 1.41, 1.78, and 2.00 for each of the four Pb categories formen, and 1.08, 1.25, 1.45, and 1.56 forwomen. Risk ratios for all diseasecategories increased withincreasing Pb category anddecreased for populationsolder than 44 yrs.The authors assumed a linear relationship between blood pressure and bloodPb, whereas available evidence suggests it may be non-linear. If blood Pbblood pressure concentration-responsefunction is log-linear, as implicitlyaccepted by over half the reviewed studies, the calculated global risk ratios forall cardiovascular disease will be overestimated at higher blood Pb levels andunderestimated at lower blood Pb levels.

# AX6-148Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Maheswaran, et al.(1993)Europe-England-Birmingham1981809 out of 870 workers, mean (SD)age 43.3 (10.4) yrs, at an Pb acidbattery plant were used in the study.Women and workers takingantihypertensive medications wereexcluded. Used multiple linearregression analyses of systolic anddiastolic blood pressure, forcing age,BMI, alcohol use,linear blood Pb, zincprotoporphyrin, 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 diastolic blood pressure.Authors used two indices of Pb exposure in the same models. Over much of the studiedblood Pb range, zinc protoporphyrin was likely collinear with blood Pb. Linear blood Pbmay not be the appropriate metric to use in blood pressure models. Did not use age-squaredto adjust for non-linear relationship of bloodpressure with age. Did not report modeldiagnostics.Menditto et al.(1994)Europe-RomeNew Risk FactorsSurvey1989-19901319 males, mean (range) age 63 (55-75) yrs, not treated for hypertension,were used in forward stepwisemultiple linear regression models ofsystolic and diastolic blood pressurewith available covariates of age, BMI,heart rate, serum high densitylipoprotein, non-high densitylipoprotein, triglycerides, glucose,cigarette use, alcoholuse, sum of fiveskinfold thicknesses (triceps, biceps,subscapular, suprascapular, andsuprailiac), and natural logtransformed blood Pb.Median (2.5th-97.5thpercentiles, range)blood Pb: 11.3 μg/dL(6.2-24.7, 4-44.2)Only BMI, heart rate, and serum glucosewere not simultaneously and significantlycorrelated with both natural log blood Pb and blood pressure. In a systolic blood pressuremodel adjusted for BMI, age,heart rate, high and non-high density lipoprotein, triglycerides,glucose, and cigarettes, each unit increasein natural log blood Pb was significantlyassociated with a 5.6 mm Hg (95% CI: neither SEnor CI stated) increase in blood pressure.In a diastolic blood pressure model adjusted for BMI, heart rate, age, cigarettes, triglycerides,and high density lipoprotein, each unit increase in natural log blood Pb was significantlyassociated with a 1.7 mm Hg (95% CI: neither SEnor CI stated) increase in blood pressure.In stratified models for alcohol drinkers (n = 1068) and non-drinkers (n = 251) only alcoholdrinkers showed significant natural log blood Pbassociated blood pressure increase, with Pbcoefficients similar to those of the entire group.Authors observed change in natural log blood Pb coefficient produced by successive additionof covariates to models. In no case did the coefficients change by more than 30% afteraddition of a covariate. Authors noted that wine was the predominant drink in alcohol usersand that the correlation between alcohol consumption and natural log blood Pb level was thehighest among all correlations reported (p < 0.001; correlation coefficient not stated).No statistical tests were made to determine ifthe change in Pb coefficients with addition ofcovariates was significant, nor were statistical tests made to determine if the Pb coefficientsin the alcohol use stratified models were significantly different. Small size of the nonalcohol drinking group in stratified analysis precludes interpretation of non-significanteffects. Incomplete reporting of results. Paper published in a supplement issue reportingmeeting papers may indicate that it received less that thenormal peer-review scrutiny forpublished research articles. No model diagnostic tests were reported.

# AX6-149Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Møller andKristensen (1992)Europe-Denmark-CopenhagenCounty-GlostrupPopulation Studies1976-1990A cohort born in 1936 was followed atage 40 (women n = 546, men n = 504),age 45 (women n = 430, men n = 463) andagain at age 51 (men only n = 439).Reported no difference in results ifsubjects taking antihypertensivemedications were excluded. Reportedresults included these subjects. Linearmultiple regression models of systolic anddiastolic blood pressure of follow up,stratified by sex and by yr, used asequence of forced entry of covariates:natural log blood Pb was tested alone(unadjusted), then adjusted for tobacco,cholesterol, physicalactivity, and sex(Model 1), then adjusted for the abovecovariates plus systolic blood pressure(Model 2), and then adjusted for the abovecovariates plus alcohol (Model 3).Another group of linear multipleregression models ofchange of systolicand diastolic blood pressure from age 40to 51 yrs in men only, following the samecovariate entry scheme as above, but usedchange in covariates instead of theoriginal covariates. All subjects werefollowed until 54 yrs of age (from 1976 to1990) to assess Pb association with totalmortality and with coronary heart disease(CHD; ICD-8 410-414) andcardiovascular disease (CVD; ICD-8 430-435) combined morbidity and mortalityusing Cox proportional hazards models(n = 1050). Cox modelswere adjusted asabove.Arithmetic mean (SD,range) blood Pb by ageand 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 blood Pb was associated with asignificant increase in systolic blood pressure of 4.93 mm Hg (p = 0.002; neither SE norCI stated) at age 40 and an increase of 2.64mm Hg (p = 0.06; neither SE nor CI stated)at age 45, in models adjusted for tobacco,BMI, and physical activity (Model 1). Whenalcohol (Model 2) or alcohol plus hemoglobin (Model 3) were added to the models Pbblood pressure relationships were not significant at either age. With each one unitchange in natural log blood Pb, diastolicpressure increased 4.26 mm Hg (p = 0.002;neither SE nor CI stated) at 40 yrs and 3.26 mm Hg (p = 0.002; neither SE nor CIstated) at 45 yrs in Model 1. In Model 2,the increase in diastolic blood pressure was3.21 mm Hg (p = 0.02; neither SE nor CI stated) at 40 yrs and 2.86 mm Hg (p = 0.01;neither SE nor CI stated) at 45 yrs. In Model 3, the increase in diastolic blood pressurewas 2.65 mm Hg (p = 0.07; neither SE norCI stated) at 40 yrs and 2.78 mm Hg(p = 0.01; neither SE nor CI stated) at 45 yrs.In men, the only significantassociation between natural log blood Pb and bloodpressure was at 45 yrs. For every increase of one unit of natural log blood Pb theincrease in systolic blood pressure was2.73 mm Hg (p = 0.05; neither SE nor CIstated).The change in blood Pb between 40 and 51 yrs was not significantly associated withchange in systolic or diastolic blood over the same period in any of the models.None of the relative hazard ratios for CHD and DVD combined morbidity and mortalitybetween 40 and 54 yrs were significantly related to blood Pb concentration. Totalmortality, however, was significantly increased with increased blood Pb. In Model 1,every increase of one natural log unit of blood Pb was associated with an increasedrelative hazard of mortality of 1.96 (p = 0.009; neither SE nor CI stated). For Model 2,every increase of one natural log unit of blood Pb was associated with an increasedrelative hazard of mortality of 1.82 (p = 0.03;neither SE nor CI stated). There were 40cases of CHD recorded, of which 13 were fatal. There were 54 cases of CVD recorded,of which 19 were fatal. Of the total of46 subjects who died during the period, 32(70%) died of cardiovascular problems. It was not clear if blood Pb at a particular ageor a mean blood Pb across ages was usedin the Cox proportional hazards models.

# AX6-150Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Møller andKristensen (1992)(cont’d)Though this study was one of the few touse a longitudinal design, it did nottake advantage of that design feature in blood pressure modeling. Cross-sectional multiple regression modeling at each age loses valuable informationavailable in repeated measures modeling. Power to detect significant effects ismuch higher in repeated measurement modeling than in cross-sectionalmodeling. Analyzing only change inblood pressure loses informationregarding starting and ending blood pressure. Including change in blood Pb isproblematical due to the unknown history ofPb exposure prior to the start ofthe study, the resultant bone Pb load asa result of past exposure, the unknownPb contribution of bone to blood, and the unknown relative contributions ofpast exposure and present exposure toalteration in blood pressure. Modelingother covariates as change is also questionable. BMI, to pick a covariate withknown and strong effects on blood pressure, may be high and relativelyconstant over the study period or low and relatively constant over the study. Inboth cases, the change in BMI will besmall, but the high BMI will beassociated with higher blood pressure thanwill the low BMI. Thus, both casesmodeled as change in BMI should have the same effect on blood pressurewhen the high BMI subject has expectedhigher blood pressure than the lowBMI subject. Using difference scoresfor the dependent and the exposurevariables also risks confounding secular trends in either or both of thesevariables, for whatever reasons, with independent difference variable effect ondependent difference variable effect.The Cox proportional hazards model, however, is longitudinal in nature.Failure to detect significant associations between Pb and cardiovascularmorbidity/mortality could have been due tothe small sample size used for thistype of analysis. The blood pressure part of the study did not take mortalityinto account during the study, which could have produced a progressivelyincreasing “healthy subject” effect. Since subjects taking antihypertensivemedications were included in analyses, anindicator variableshould have beenused to account for them, whether or nottheir exclusion in preliminary testingproduced no apparent change in results. This paper contained a gooddiscussion of confounding variables.Incomplete reporting of results andprocedures. No model diagnostic tests were reported.

# AX6-151Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Staessen et al.(1996a)Europe-Belgium-PheeCad study.1985-1995359 men and 369 womenparticipated at baseline (between1985 and 1989) and again about 5yrs later (median 5.2 yrs) atfollow up (between 1991 and1995), mean age (range) atbaseline 46 yrs (20-82), abouthalf of whom were recruited fromtowns surrounding a non-ferroussmelter (targeted to produce highcadmium exposure) and half fromtowns without heavy metalproduction. Over half the menhad occupational exposure(59.0% from the near smeltertowns, 17.4% from the othertowns).Four different outcomes wereexplored: time-integratedconventional blood pressure (avgof 10 baseline and 5 follow upblood pressure measurements),24-h ambulatory blood pressureonly during the follow up period(avg of readings every 20 minutesfrom 8 AM to 10 PM and every45 minutes from 10 PM to 8 AM,weighted by interval betweenmeasurements), difference inconventional blood pressure overthe five yr follow up period, andincidence of developinghypertension during follow up.Geometric mean (5th95th percentile) by sexand 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 studies reported and was innovative in itsuse of 24-h ambulatory blood pressureas one of its outcome variables.Time-integrated conventional blood pressure models:In 187 peri- and post-menopausal women,after adjusting for age, BMI, gammaglutamyltransferase activity, and hematocrit, each increase of one unit of natural log blood Pbwas associated with an increase in diastolic blood pressure of 7.49 mm Hg (95% CI: 1.48,13.50). No other time-integrated conventionalblood pressure measurements were significantlyassociated with time-integrated natural log blood Pb in either men or women, nor in stratifiedgroups within sex.Ambulatory 24-h blood pressure models:In all 345 women, after adjusting for age, hematocrit, gamma-glutamyltransferase activity, andoral contraceptive use, each one unit increase in natural log blood Pb was associated with anincrease of diastolic blood pressure of 3.49 mmHg (95% CI: 0.02, 6.96). When the group waslimited to the 174 premenopausal women eachunit increase in natural log blood Pb wasassociated with an increase of diastolic bloodpressure of 5.48 mm Hg (95% CI: 0.56, 10.40).Difference in blood pressure between baseline and follow up:After adjustment for change in BMI, beginning use of antihypertensive medication andcontraceptive medication during the follow upperiod, and starting smoking there was nosignificant relationship between difference in either systolicor diastolic bloodpressure and bloodPb in women. After adjustment for change in BMI, change in exposure at work, change insmoking, beginning use of antihypertensive medication in men there was no significantrelationship between difference ineither systolic ordiastolic blood pressure and blood Pb inmen.Incidence of hypertension:At baseline 107 (14.7%) and 120 (16.5%) subjects had borderline and definite hypertension,respectively. At follow up 98 (13.5%) and 186 (25.5%) had borderline and definitehypertension, respectively. 51 of 501 initially normotensive subjects became borderlinehypertensive and 47 of the 501 became border linehypertensive during the follow up period.After adjusting for sex, age, and BMI, natural log baseline blood Pb was not related to significantrisk ratios of becoming hypertensive (not stated, but presumably combined definite andborderline hypertension) or becoming a definite hypertensive.

# AX6-152Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Staessen et al.(1996a) (cont’d)Multiple regression models were used to test theassociation between natural log transformedblood Pb (mean of baseline and follow up Pb)and blood pressure (systolic and diastolic),stratified by sex, then further stratified by use ofantihypertensive medications in men andmenopausal status in women. Age and age-squared (calculated in quintiles) were forced intothe models, then remaining covariates werestepwise added to the model. Though notexplicitly stated, natural log blood Pb (mean ofbaseline and follow up) was likely forced in last.Other candidate covariates were BMI,hemoglobin or hematocrit, serum gamma-glutamyltransferase activity (an index of alcoholuse) and serum calcium, 24 h urinary sodium andpotassium excretion, energy expenditure,exposure to heavy metals (at the workplace),social class, smokingand drinking habits,menstrual status in women, and use ofantihypertensive medications, oral contraceptives,and hormone replacement therapy. In ambulatoryblood pressure models,differences betweenbaseline and follow up blood pressure modelswere constructed in the same way. For thedifference models “concurrent variations in bloodPb concentrations” were used, presumablydifference in baseline and blood Pb.The study does not use the full power of repeated measurements in theanalyses. For problems encountered when collapsing repeatedmeasurements to difference measures, see Møller(1992) above. Stepwiseregressions are prone to capitalizing on chance results due to multipletesting of the same data and almostalways produce a different mix ofcovariates when they are stratified. Thus, it was puzzling to find that whereinformation on the effects of stepwise covariate addition to models wasavailable in this article, that the same covariates were listed for both modelsbased on the stratification variable.There is excessive reliance onfractionation of the data set due to multiple stratification, sometimesreducing the number of subjects in a model to as few as 171. Even themodels using the most subjects had only 359 subjects. Lowpower to detectsignificant effects cautions againstany interpretation of non-significantresults. The time-integrated modelused 10 baseline blood pressuremeasurements and 5 follow up blood pressure measurements, thusweighting the avg toward baseline blood pressure. The entry of thebiochemical correlate of alcohol use inmost of the models suggests that Pbeffects and Pb-containing alcohol effects on blood pressure were confused,especially given the European setting and the time period during which thestudy was conducted. Control for useof hypertensive medication rarelyentered models and partial control forthis variable was achieved only bystratified analyses, further reducing powerto detect significant effects in theremaining subgroup. No justificationwas given for stratified analyses.Incomplete information in statistical methods and results complicatesinterpretation. It was uncertain if stepwise regression was used for logisticmodels. No comparisons were performed to assess possible bias due tosubject attrition over the course of the study.

# AX6-153Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Staessen et al.(1996a) (cont’d)For the hypertension incidence model twodefinitions of hypertension were used:definite hypertension (systolic >160 mm Hg,diastolic >95 mm Hg or takingantihypertensive medications) and borderlinehypertension (systolic between 141 to159 mm Hg and diastolic between 91 to94 mm Hg). Method of covariate entry intohypertension incidence models not stated.Baseline natural log blood Pb was used as theexposure index.The over six decades of age representedin the sample was modeled by linear andquadratic terms based on age quintiles rather than continuous age, making it likelythat adequate control for age effects on blood pressure was not achieved and thatthe “healthy subject” effect seen in older groups was not controlled. If stepwiseaddition of significant covariates was used in the blood pressure difference models,were covariates in those models that were marked in the coefficient column asnon-significant not included in the models,and if that were so, it is unclear fromwhere the probability values that substitutefor the coefficients of those variableswere derived. There were no model diagnostic tests reported.Staessen et al.(1993)Belgium-CadmibelStudy1985-1989827 males and 821 females recruited from twoareas in Belgium, one of them surrounding anon-ferrous smelter, mean age (SD) 46 (15)and 44 (15) yrs, in men and womenrespectively. Subjects taking antihypertensivemedication were excluded from the analyses.Stepwise multiple regression models ofsystolic and diastolic blood pressure werestratified by sex. Covariates available forentry were age and age-squared, BMI, pulserate, log protoporphyrin, log gammaglutamyltranspeptidase, serum calcium, logserum ferritin, log serum creatinine, log serumzinc, urinary calcium, urinary sodium, andurinary potassium. Natural log blood Pb wasthe only variable forced into the models.Additional models tested the interaction ofserum calcium and blood Pb on bloodpressure.Geometric meanblood 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, pulse rate, log gammaglutamyltranspeptidase, serum calcium,and log serum creatinine, every unitnatural log blood Pb increase was significantly associated with a -5.2 mm Hg (95%CI:!0.5,!9.9) decrease in systolic blood pressure. Natural log blood Pb was notsignificant in the model for diastolic blood pressure for men nor the systolic ordiastolic blood pressure for women.Adjusting for age and age-squared,BMI, pulse rate, and log gammaglutamyltranspeptidase, the interactionterm between natural log blood Pb andserum calcium was only significant for systolic blood pressure in women. Everydoubling of blood Pb was associated with a 1.0 mm Hg decreasein systolic bloodpressure at serum calcium concentrationof 2.31 mmol/L (25th percentile) and anincreasein systolic blood pressure of 1.5 mm Hg at serum calcium concentrationof 2.42 mmol/L (75th percentile).Stepwise multiple regression analyses run risks of accepting chance associationsdue to multiple analyses of the same dataset. The role of alcohol use or alcoholuse markers in confounding Pb effect on bloodpressure in this setting has alreadybeen noted. The unexplained interaction between serum calcium and blood Pbhighlights the potential confounding roleof serum calcium with Pb in bloodpressure studies. The study shows graphsindicating distinct differences in the ageserum calcium and age-blood Pb relationships for men and women. From 50-70yrs of age serum calcium is higher than from≤29-49 yrs in women and

# AX6-154Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEurope(cont’d)Staessen et al.(1993) (cont’d)exceeds serum calcium of men at those older ages. The steepest rise inwomen’s blood Pb with age occurs between the 40-49 and 50-59 yr decades.The timing of these changes in women suggests that menopause may be afactor, which was accounted for only in the model for diastolic blood pressure.It also suggests that serum calcium level and age were also confounded in theblood pressure models. As serum creatinine clearance and blood Pb areinversely related, and serum creatinine is a significant covariate in the systolicblood pressure model for men with a significant negative bloodPb coefficient,it is possible that serum creatinine and blood Pb are confounded with bloodpressure in the men’s systolic blood pressure model. There were noassessments of subject selection bias due to exclusions. The authors noteexamining quintile blood pressure relationships with all covariates to determinethe acceptability of the linear relationship implied by the linear modelingtechnique. No other model diagnostic tests were reported.Telišman et al.(2004)Europe-CroatiaZagrebDate of datacollection notgiven.100 workers from factories producing Pbbased products, mean (range) age 30 (20-43)yrs. Exclusion criteria were absence ofpsychological stress (e.g., death in family)over last 4 mos, absence of verified diabetes,coronary heart disease, cerebrovascular andperipheral vascular disease, renal disease,hyperthyroidism, androgenital syndrome,primary aldosteronism, and “other diseasesthat could influence blood pressure or metalmetabolism.” Linear or natural log blood Pbwere considered for stepwise entry in modelsof systolic and diastolic blood pressure,forcing in all other covariates: bloodcadmium, BMI, age, serum zinc, serumcopper, 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 significant in multipleregression models of systolicand diastolic blood pressure.Very small sample sizelimited power todetect significant effects; nonsignificant effects should notbe interpreted as lackof effect. Too manycovariates for a small study. Almost no subjects below 10 μg/dL. Takinghypertensive medications not controlled,likely a problem with top systolic anddiastolic blood pressure in the group 170 mm Hg and 110 mm Hg, respectively.No model diagnostic testing reported.

# AX6-155Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsiaLee et al. (2001)Korea-Chonan1997-1999798 workers from various Pb-using orproducing factories, mean (SD, range) age 40.5yrs (10.1) [17.8-64.8], 79.4% male, wereclassified as to Vitamin D receptor genotype(VDR bb or Bb/BB) and delta-aminolevulinicacid dehydratase (ALAD11 or 12) genotype, asVDR polymorphism has been implicated inmodifications of Pb absorption and Pb uptakeand release from bone as well as risk forelevated blood pressure and hypertension, andALAD polymorphism affects Pb binding to it inthe erythrocyte, the major storage depot of Pb inblood. The hypothesis was that polymorphismtype could influence the effect of Pb on bloodpressure and hypertension.Multiple linear regression models of linearblood Pb, DMSA-chelatable Pb, and tibia Pbeffect on systolic and diastolic blood pressurewith potential covariates of age and agesquared, sex, creatinine clearance, hemoglobin,weight, height, BMI, job duration, tobacco andalcohol consumption, pack-yrs of tobacco, andcumulative life time alcoholic drinks. Stepwiseprocedure allowed retention of covariates onlyif they were significant or “there weresubstantive changes in the coefficients ofpredictor variables after” their inclusion. In themodels shown, Appearance of multiple Pbvariables and the interaction between Pbvariables and genotype for each gene dependedupon the specific model. Both ALAD and VDRreceptor polymorphism were sometimes testedsimultaneously in each model containingpolymorphism termsand sometimes VDRappeared without ALAD.Arithmetic mean(SD, range) bloodPb: 32.0 μg/dL(15.0, 4-86)Mean (SD, range)DMSA-chelatablePb: 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 allele were significantly older,had more DMSA-chelatable Pb, and hadhigher systolic and diastolic bloodpressure than subjects with VDR bb allele.In multiple regression models of systolic blood pressure, controlling for ageand age-squared, sex, BMI, antihypertensive medication use, and cumulativelife-time alcoholic drinks, adding tibiaPb, VDR type, and ALAD type, eachincrease of 10 μg/g of tibia Pb was associated with an increase of 0.24 mm Hg(95% CI:−0.01, 0.49) and VDR BB/Bb type was associated with an increaseof 3.24 mm Hg (95% CI: 0.18, 6.30) blood pressure compared to the VDR bbtype. ALAD genotype was not significant. In the same model, butsubstituting linear blood Pb for tibia Pb, each increase in 1 μg/dL of linearblood Pb was associated with an increase of 0.07 mm Hg (95% CI: 0.00,0.14) and VDR BB/Bb type was associated with an increase of 2.86 mm Hg(95% CI:!0.22, 5.94) blood pressure compared to the VDR bb type. ALADgenotype had no significant effects on blood pressure.When both tibia and linear blood Pbwere entered simultaneously along withVDR genotype, adjusting for the same covariates, only VDR Bb/BB wassignificant; compared to VDR bb, bloodpressure was 3.51 mm Hg (95% CI:2.41, 8.61) higher. ALAD genotypehad no significant effects on bloodpressure.In a model without any Pb terms, VDR genotype was interacted with the ageand the age-squared terms. The VDRBb/BB genotype interaction with thelinear age term was significant for systolic blood pressure. Compared withthe bb genotype the VDR Bb/BB genotypes’ blood pressure increased0.36 mm Hg (95% CI: 0.06, 0.66) per yr faster with increasing age.There were no significant effects ofany Pb variable with diastolic bloodpressure, though the VDR Bb/BB genotype had significantly higher bloodpressure (1.9 mm Hg; not enough information given to calculate CI) than thebb genotypes.There were no significant interactions ofthe Pb measures with the genotypesfor either ALAD or VDR.

# AX6-156Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Lee et al. (2001)(cont’d)Logistic regression analysis was used to testthe effect of the Pb indices on hypertension(systolic >160 mm Hg or diastolic>96 mm Hg or taking antihypertensivemedications) using the same group ofpotential covariates, testing the Pb termsand the Pb-genotype interaction termsseparately. The hypertension models testedboth gene polymorphisms separately.Subjects with the Bb/BB genotypes had a significantly higher odds hypertensionprevalence (OR = 2.1 [95% CI: 1.0, 4.4]) than subjects with the bb genotype,adjusting for age, sex, BMI, tibia Pb, and current alcohol use. There were nosignificant effects of any Pb variablenor of ALAD on hypertension status.Linear blood Pb may not give efficient and unbiased estimates of blood Pb effect onblood pressure. The descriptive data shows highly skewed distributions for blood Pb,DMSA-chelatable Pb, and tibia Pb in this group, suggesting that coefficients of all Pbeffect on blood pressure may not have beenefficient and unbiased. Stepwise modelsusually produce different covariate patterns for different models, though the tablesindicate that the covariatesused for all the models discussed above were the same. Nomodel diagnostic tests were reported.Lustberg et al.(2004)Korea-Chonan1997-1999 (periodof enrollment; nostatement on datesof data collection)793 (number given for genotype analysis;numbers in models notgiven) current andformer Pb workers, mean (SD) age 40 (10)yrs and 80% male, were genotyped for thethree polymorphisms of endothelial nitricoxide synthase (eNOS)(GG, GT, TT), anenzyme that is a modulator of vascularresistance. The effect of genotype and theinteraction of genotype with blood Pb andtibia Pb on systolic and diastolic bloodpressure were evaluated by multiple linearregression analyses, forcing covariates ofage (modeled as a 2 degree of freedomspline with knot at 45 yrs), sex, natural logBMI, smoking and alcohol consumption,high school education, and job duration.Both blood Pb and tibia Pb were entered aspercentiles and entered together. Logisticmodels of hypertension (systolic∃140 mm Hg or diastolic∃90 mm Hg orreported use of antihypertensivemedication) used the same covariates.Interaction terms between each of the Pbmeasures (plus a Pb-squared term) andgenotype was used to determine differentialeffect of Pb according to genotype.Pb according togenotype:Arithmetic mean(SD) blood Pb, GG:32 (15) μg/dLArithmetic mean(SD) blood Pb,TG/TT: 32(15) μg/dLMean (SD) tibia Pb,GG: 37 (42) μg/gMean (SD) tibia Pb,TC/TT: 36 (34) μg/g85% (673/793) of the group were typed GG, 14% (114/793) were TG, and 1% (6/793)were TT. TG and TT groups werecombined for analysis (TG/TT).Mean systolic and diastolic blood pressures, adjusted for all covariates, were notsignificantly different between GG and TG/TT groups.In multiple regression models for systolic and diastolic blood pressure, neitherpercentile blood Pb nor percentile tibiaPb, entered together, were significantpredictors. Interaction terms betweenthe Pb variables and genotype were notsignificant.In the logistic regression model for hypertension, neither percentile blood Pb norpercentile tibia Pb, entered together, were significant predictors.Reporting was incomplete: number of subjectsentering the models was not stated; nocomparisons between recruited subjects and subjects not used in models. Despitereporting non-significant interactions, the paper showed both loess plots and tables ofanalyses stratified by genotype, reportingsignificant associations between both tibiaand blood Pb in the GG genotype, insignificant in the other. Inspection of the loessplots revealed striking non-linearity for bothadjusted blood Pb-systolic blood pressureand adjusted tibia Pb-systolic blood pressure relationships. Small group size of theTG/TT genotypes and highly unbalancedterms of the interaction may havecontributed to the non-significant interactions. Although the interaction Pb term wasalso probed as a quadratic function, the tibiaPb interaction was not, suggesting thatpoor concentration-response specification in the model mayalso have contributed tothe lack of significant main effects and interactions.

# AX6-157Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Nomiyama et al.(2002)China, BeijingNo statement ondates of datacollection123 female Pb-exposedleaded crystal toyworkers, mean age (range) 27.3 (17-44) yrs,and 70 female sewing workers (referencegroup), mean age (range) 24.2 (16-58) yrswere tested. Forward stepwise multipleregression models of systolic and diastolicblood pressure of the combined groupswere used with linear blood Pb and a set ofcovariates. Variables with p < 0.2 wereallowed to enter. The covariate set wasselected from a larger set of potentialcovariates by factor analysis, and arepresentative variable from each factorwas selected for possible entry in theregressions.Alternate models wereconstructed usingfour ordered categories of blood Pb, insteadof the linear continuous blood Pb variable.Logistic regressions were used to determinethe odds of elevated systolic (∃125 mm Hg)and elevated diastolic (∃80 mm Hg) bloodpressure as a function of blood Pb category.Blood Pb mean(SD, range) in Pbworkers: 55.4(13.5, 22.5-99.4 μg/dLBlood Pb mean(SD, range) in nonPb workers:6.4 (1.6, 3.8-11.4) μg/dLAdjusted for age, urine protein, and plasmatriglyceride, each 1 μg/dL increase inlinear blood Pb significantly associated with a 0.13 mm Hg increase in systolicblood pressure (no SE or CI given; p = 0.0003). Adjusted for plasma triglyceride,age, urine protein, plasma low density lipoprotein, and hypertension heredity, each1 μg/dL increase in linear blood Pb was associated with a 0.10 mm Hg increase indiastolic blood pressure (no SEor CI given; p = 0.0001).Using the ordered categories of blood Pb and the same covariates for systolic anddiastolic blood pressure, the 40-60 μg/dL group had 4.2 mm Hg (95% CI: 0.0, 8.5)higher systolic blood pressure and 4.1 mm Hg(95% CI: 1.3, 6.8) higher diastolicblood pressure than the reference group (blood Pb (<11.4 μg/dL). The group with∃60 μg/dL blood Pb had 7.5 mm Hg (95% CI:3.0, 12.0) systolic blood pressure and6.3 mm Hg (95% CI: 3.4, 9.1) diastolic blood pressure higher than the referencegroup.Logistic regression modelsfor “elevated” blood pressure, modeled using the samecovariates were similar. In the 40-60 μg/dL group odds of systolic blood pressure∃125 mm Hg and diastolic blood pressure∃80 mm Hg were 4.26 (95% CI: 1.07,17.04) and 2.43 (95% CI: 0.97, 6.04), respectively, higher than the reference group.The odds of “elevated” systolic and diastolic blood pressure in the group with bloodPb∃60 μg/dL were 7.48 (95% CI: 1.86, 30.12) and 3.31 (95% CI: 1.29, 8.50),respectively.Incomplete reporting in paper: no modelN, no SEs for linear blood Pb regressions,no description of type of factor analysis used or dates of data collection. Innovativeuse of factor analysis to select covariatesthat, depending on howthe factor analysiswas run, could have produced a set oforthogonal variables for model entry.However, BMI was not included in the original set of covariates or in the models.Small sample size limits conclusions based on nonsignificant results. Stepwiseregression produced a different covariatepattern for each component of bloodpressure. The linear blood Pb variable may be inappropriate given the markedskewness of blood Pb in descriptive analysis. The 11 μg/dL gap in blood Pbbetween Pb workers and non-Pb workers could have introduced problems inanalyses with continuous blood Pb. Larger age spread in non-exposed group than inexposed group could have caused misspecification of age variable. No control forantihypertensive medication use. No model diagnostics reported.

# AX6-158Table AX6-5.1 (cont’d). Effects of Leadon Blood Pressure and HypertensionReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationAsia(cont’d)Wu et al. (1996)Central TaiwanNo statement ondates of datacollection222 workers in two Pb battery plants, 112men, mean (range) age 36.2 (18-67) yrs, and110 women, mean (range) age 36.2 (18-71)yrs were tested for blood Pb relationshipswith systolic and diastolic blood pressure inmultiple 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, andordered categorical bloodPb concentration.Arithmetic mean (SD,range) blood Pb:Women: 44.6 (18.4,8.3-103.1) μg/dLMen: 60.2 (26.8,17.0-150.4) μg/dLUsing four ordered blood Pb categories (<25 μg/dL [n = 16/222; 6.8%], 25-40 μg/dL [58/222; 26.1%], 41-60 μg/dL [63/222; 27.9%], and >60 μg/dL[85/222; 38.3%]) adjusted systolic and diastolic blood pressure were notsignificantly related to the top three blood Pb categories compared to thelowest, natural log ambient Pb. Yrs in work environment was a significantpredictor of both systolic and diastolic blood pressure, but age was onlymarginally significant for systolic blood pressure and not significant fordiastolic blood pressure.Small study size limits any conclusionsdrawn from non-significant results.Three measures, all related to Pb exposure, were simultaneously tested in themodels. While blood Pb may only be weakly correlated with yrs of work,ambient air Pb would be expected to be much better correlated with blood Pb.There is a clear possibility of collinearity among those three variables, whichwould inflate standard errors and reduce coefficients. Authors selectedordered categories of Pb to “avoid unnecessary assumption of linearity.” Theuse of natural log air Pb concentration suggests that some diagnostics wererun, but no model diagnostic tests were reported. No control forantihypertensive medication use.

# AX6-159Table AX6-5.2. Effects of Lead on Cardiovascular MorbidityReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited StatesCheng et al.(1998)U.S.-Boston,Normative AgingStudy (VA)1991-1995775 males (97% white), mean age (SD,range) 67.8 yrs (7.3, 48-93).Multiple linear regression models ofheart rate-corrected QT and QRSelectrocardiogram intervals wereadjusted by stepwise entry ofcovariates, retaining only those thatremained significant at p < 0.10.Linear blood Pb, tibia, and patella bonePb were apparently (not described intext) entered separately. Logisticregression models for Minnesota ECGCoding Center diagnoses ofintraventricular conduction deficit(IVCD), atrioventricular conductiondeficit (AVCD), and arrhythmia wereadjusted by covariates the same way.Only analyses stratified by age (<65yrs, n = 277;∃65 yrs, n = 498) werepresentedArithmetic 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 for age, alcohol intake,BMI, and diastolic blood pressure, foundthat only tibia and patella Pb weresignificantly related to outcome in the under 65 group. Every 10 μg/g increase oftibia and patella Pb was associated with a 5.0 ms (95% CI: 0.8, 9.2) and 3.0 ms(95% CI: 0.2, 5.8) increase in QT interval, respectively. Multiple regressionmodels of QRS intervals, adjusted for age, fasting glucose level, and diastolicblood pressure, also found that only tibia and patella Pb were significantly relatedto outcome in the under 65 group. Every 10 μg/g increase of tibia and patella Pbwas associated with a 4.8 ms (95% CI: 1.8, 7.8) and 2.2 ms (95% CI: 0.1, 4.4)increase in QRS interval, respectively. There were no significant effects of Pb inthe 65 and over group.Logistic regression models of IVCD, adjusted for age and serum HDL level,found that only tibia Pb was significantly related to outcome in the under65 group. Every 10 μg/g increase of tibia Pb was associated with increased oddsof IVCD, OR = 2.23 (95% CI: 1.28, 3.90). There were no significant Pb effectsin the 65 and over group for IVCD. Logistic regression models of AVCD,adjusted for age and serum HDL level, found that both tibia and patella Pb weresignificantly related to outcome in the 65 and over group. Every 10 μg/gincrease of tibia Pb and patella Pb was associated with increased odds of AVCD,OR = 1.22 (95% CI: 1.02, 1.47) and OR = 1.14 (95% CI: 1.00, 1.29),respectively. Pb was not significantlyrelated to AVCD in the under 65 group.There were no significant effects of Pbon arrhythmia in either age group.Stepwise models may capitalize on chance associations.Linear blood Pbspecification may not be appropriate in someor all of these models. Not clear ifthree models were constructed for each stratified analysis for each outcome, eachbased on a different Pb index. No statistical comparisons across strata. Nomodel diagnostics were presented.Gump et al. (2005)U.S.-Oswego, NYDates of study notgivenSee Gump et al. (2005) entry in BloodPressure and Hypertension section forheart rate, stroke volume, cardiacoutput, total peripheral resistance, andcardiac interbeat interval data.

# AX6-160Table AX6-5.2 (cont’d). Effects ofLead on Cardiovascular MorbidityReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Navas-Acien(2004)U.S.-NHANESIV-Phase 11999-20002125 subjects (1070 males, 1055females), age 40->70 yrs were testedfor peripheral arterial disease (PAD;n = 139) by taking the ratio of theankle mean systolic blood pressure tothe arm mean systolic blood pressure.Any subject with the ratio <0.90 wasclassified as PAD. Logistic regressionanalysis was weighted and adjusted bysample design. Covariates forced intothe models were age, sex, race,education, and Pbquartile (Model 1);Model 1 covariates plus BMI, alcoholintake, hypertension, diabetes,hypercholesterolemia, glomerularfiltration rate, and C-reactive protein(Model 2); Model 2 covariates plusself-reported smokingstatus and serumcotinine (Model 3); and Model 3covariates plus cadmium quartile(Model 4). Tested interactionsbetween Pb and cadmium on PAD,and between Pb and sex, race, smokingstatus, renal function, and c-reactiveprotein on PAD. Tested for trend ofOR 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/dLPb quartile 3:2.1-2.9 μg/dLPb quartile 4: >2.9 μg/dLOdds for PAD significantly increased with Pb quartile (1st quartile used ascomparison) for all four models. Onlymodels 1 and 2,however, showed asignificant increase in odds of PAD for the 4th Pb quartile compared to the 1st Pbquartile, OR = 3.78 (95% CI: 1.08, 13.19) and OR = 4.07 (95% CI: 1.21, 13.73).None of the tested interactions with blood Pb quartile were significant.Well-designed study with sound statisticalanalysis. Including two variables forsmoking in Models 3 and 4 (smoking status and cotinine) may have overcontrolled for smoking). There was a trend toward increased blood Pb level withincreased smoking status and with increasedcotinine levels,though no statisticaltests of trend were reported. Thus the two smoking variables and Pb may havebeen confounded with PAD. Nomodel diagnostic tests reported.Schwartz (1991)NHANES IIU.S.1976-1980See Schwartz (1991) entry in BloodPressure and Hypertension for leftventricular hypertrophy results.

# AX6-161Table AX6-5.2 (cont’d). Effects ofLead on Cardiovascular MorbidityReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Tepper et al.(2001)U.S.-Cincinnati,OHAfter 1991 tobefore 2001See Tepper et al. (2001) entry in BloodPressure and Hypertension for leftventricular mass results.EuropeGustavsson et al.(2001)Europe-Stockholm,Sweden1992-1994Study base was all Swedish citizens45-70 yrs old from Stockholm Countyfree of previous myocardial infarction.Cases who survived at least 28 daysafter infarct (1,105 males and 538females) of which 937 men (85%) and398 women (74%) had sufficientinformation on occupational exposuresand “main confounders”, werecompared against referents (1,120 menand 538 women) matched to cases bysex, age, yr, and hospital catchmentarea. Risk ratios for the case groupcompared to referent group wereadjusted on the basis of the matchingvariables and smoking, alcoholdrinking, hypertension, overweight,diabetes mellitus, leisure physical“inactivity”, and were calculated for anumber of exposure factors separately,including Pb.Pb exposure wasclassified as none, low orhigh corresponding toairborne dust levels of 0,>0 to 0.03, and∃0.04 mg/m3,respectively, for thehighest intensity ofexposure during at leastone yr of work. The samethree classifications wereused for 0, >0 to 0.04, and∃0.05 mg/m3forcumulative exposure.All risk ratios were calculated relative to the “no exposure” groups. Adjustedrisk ratios for surviving a myocardialinfarction were 0.88 (95% CI: 0.69, 1.12)and 1.03 (95% CI: 0.64, 1.65) for low and high exposure groups for peak Pbexposure, and were 0.81 (95% CI: 0.60, 1.11) and 1.00 (0.74, 1.34) for the lowand high cumulative exposure groups.This study of myocardial morbidity was compromised by poor Pb exposurecharacterization (occupational air dust Pb concentration) and by including acovariate collinear with Pb exposure and confounded with the outcome,hypertension, in the adjusted models.No model diagnostics were reported.

# AX6-162Table AX6-5.3. Effects of Lead on Cardiovascular MortalityReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited StatesLustberg andSilbergeld (2002)U.S.-NHANES II1976-1980,follow up to 19924190 persons, 30 to 74 yrs, 929 of whomdied during follow up, had baseline blood Pbmeasurements during the NHANES IIperiod. Proportional hazard models forcirculatory disease-related death (ICD-9codes 390-459) were based on the complexsurvey design, but not weighted. Presentedmodels were unadjusted, adjusted for ageand sex, and adjusted for age, sex, location,education, race, income, smoking, BMI, andexercise. Blood Pb was entered as anordinal three-category variable.Blood Pb <10 μg/dL,n = 818Blood Pb 10-19 μg/dL,n = 2735Blood Pb 20-29 μg/dL,n = 637Blood Pb∃30 μg/dL,n = 102, excluded fromanalysisCrude, sex and age adjusted, and multivariate adjusted circulatory diseasemortality were all significantly increased in the 20-29 μg/dL group comparedto the <10 μg/dL reference group. Risk ratio for the highest Pb group forcrude circulatory mortality was 1.74 (95% CI: 1.25, 2.40), for age and sexadjusted circulatory mortality was 1.48 (95% CI: 1.10, 2.01), and formultivariate circulatory mortality was 1.39 (95% CI: 1.01, 1.91).Stratified analyses were performed by race, sex, age, smoking, education, etc.,but only for all-cause mortality.No model diagnostics reported.Schober et al.(2006)U.S.-NHANESIII1988-1994,follow up to 20009757 persons, age 40 yrs, 2515 of whomdied during follow-up (median length offollow-up 8.55 yrs), had baseline blood Pbmeasurements during the NHANES IIIperiod. Analyses were performed usingproportional hazard models for all causedeaths, major cardiovascular disease-relateddeaths (I00-I78), and malignant neoplasms(C00-C97). Multivariate models wereadjusted 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 = 6608Blood Pb 5-9 μg/dL(median 6.3 μg/dL),n = 2532Blood Pb 10 μg/dL(median 11.8 μg/dL),n = 617Multivariate-adjusted cardiovascular disease mortality was significantlyincreased in the 10 μg/dL group compared to the <5 μg/dL reference group.All cause and cancer mortalities were significantly increased in the 5-9 μg/dLand 10 μg/dL groups.Relative risk for cardiovascular disease mortality, compared to <5 μg/dL: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 μg/dL: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 μg/dL: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 all three mortality groups.

# AX6-163Table AX6-5.3 (cont’d). Effects ofLead on Cardiovascular MortalityReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Michaels et al.(1991)U.S.-New YorkCity1961-19841261 males, avg age (range) at thebeginning of study 49.6 yrs (19-83),representing 24,473 person-yrs werefollowed. 498 died in the interval.Subjects belonged to the InternationalTypographical Union and worked at twolarge city newspapers. Hot Pb linotypingwas discontinued at the newspapersduring 1974-1978, providing the primarysource of occupational exposure. Lastexposure for all subjects still employedwas at the end of 1976.Standardized mortality ratios (SMR)were calculated using the LTAS programdeveloped by NIOSH, calculating theexpected number of deaths of the cohortreferenced to a comparison population, inthis case disease-specific mortality ratesfrom New York City. Cohort wasstratified based on yrs of employment.Causes of death were based on ICD-8codes.Exposure was estimatedbased on yrs of linotypeemployment before theend of 1976. Authorsnote that, based onmeasurements at otherprint shops using hot Pblinotype, air Pb levelsprobably did not exceed20 μg/m3.Standardized mortality ratio was significant (SMR = 1.68 [95% CI: 1.18, 2.31])only for cerebrovascular disease in thoseworking, and thus exposed, for 30 yrsor more. Neither arteriosclerotic heart disease (ICD-8 410-414) nor vascularlesions of the central nervous system(ICD-8 430-438) had significant SMR inthe total cohort not stratified by yrs of exposure.No direct measurement of Pb exposure.Many groupings of ICD codes wereexplored in stratified and unstratified analyses, with the only significantlyelevated SMR found for cerebrovascular disease. No a priori hypotheses.General weakness of all studies relying on a comparison population is that thecohort belongs to the comparison population and can influence the comparisonmortality rates in direct proportion tothe ratio between cohort and comparisonpopulation size.

# AX6-164Table AX6-5.3 (cont’d). Effects ofLead on Cardiovascular MortalityReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationUnited States(cont’d)Steenland et al.(1992)U.S.-Idaho>1941 to 1988The death certificatesof 1028 males ofthe 1990 who worked at a smelter plantat least one yr between 1940 and 1965were examined to construct standardizedmortality ratios (SMR) for various ICD-9disease classifications using the U.S.population as a referent group.In 1976 blood Pb of173 workers avgd (SD)56.3 μg/dL (12.9). AirPb was measured in1975 at 3.1 mg/m3in208 personal 8-hsamples. High Pbdepartments in the plantwere defined as thoseexceeding 0.2 mg/m3inthe 1975 survey.Non-malignant respiratory disease andaccidents accounted for most of thesignificantly elevated SMR in the group.SMRs were not significantly elevatedfor ischemic heart disease (410-414), SMR = 0.94 (95% CI: 0.84, 1.05);hypertension with heart disease (402, 404), SMR = 0.97 (95% CI: 0.53, 1.63);hypertension with no heart disease (401,403, 405), SMR = 1.73 (95% CI: 0.63,3.77); or cerebrovascular diseases (430-436), SMR = 1.05 (95% CI: 0.82, 1.32).Similar results were found for the peopleworking in the “high Pb departments.”Though there is no doubt that this group was highly exposed to Pb, exposurecharacterization over the working lifetime was not well defined, few blood Pbdata were available, and poor demographic datafor the exposed group onlyallowed a comparison with total U.S. population. As is usual with occupationallyexposed groups, selection bias may influence results. No smoking data wereavailable for the group. In industrial conditions smoking will be confoundedwith other Pb exposure (constant hand tomouth behavior on the plant floor willexposure smokers to more Pb via theoral route than in non-smokers).

# AX6-165Table AX6-5.3 (cont’d). Effects ofLead on Cardiovascular MortalityReference, StudyLocation, andPeriod Study Description Pb Measurement Findings, InterpretationEuropeGerhardsson et al.(1995)Europe-southernSweden1969-1989664 male workers at a secondary Pbsmelter had blood Pb tested every 2-3mos since 1969. The past blood Pb levelof 201 workers who had been working atthe plant from before 1969 was estimatedfrom their 1969 results. Median (10thpercentile, 90th percentile) yr of birthwas 1943 (1918, 1960). Median (10thpercentile, 90th percentile) duration ofemployment was 2.8 yrs (0.3, 25.7) andmedian (10th percentile, 90th percentile)duration of follow up was 13.8 yrs (2.8,20.9). A total of 8706 person-yrs wererepresented in the study. Standardizedmortality ratios based on countymortality tables by calendar yr, cause,sex and five-yr age group werecalculated. Cardiovascular diseases werecoded by ICD-8 from death certificates.Arithmetic mean bloodPb levels dropped from~62 μg/dL in 1969 to~33 μg/dL in 1985.95% CI were difficultto extract from thepresented graph, butappeared to be no morethan 5-6 μg/dL aboutthe mean.All cardiovascular diseasemortality (ICD-8 390-458) was significantly elevatedabove that expected from the county mortality tables (SMR = 1.46 [95% CI:1.05, 2.02]), with 39 of the 85 deaths observed in the cohort. For just ischemicheart disease (ICD-8 410-414), SMR = 1.72 (95% CI: 1.20, 2.42) in the plantworkers with 34 of the 85 deaths observed in the cohort. There were no deathsrecorded for cerebrovascular diseases (ICD-9 430-438). There was no apparentconcentration-response relationship, using peak blood Pb and time-integratedblood Pb.Problems inherent in using standardized mortality ratios in such mortality studieshave been discussed above. The samplesize was too small (85 all cause deathsamong 664 workers) to interpret non-significant results.Møller andKristensen (1992)Europe-DenmarkCopenhagenCounty-GlostrupPopulation Studies1976-1990See Møller et al. (1992) entry in BloodPressure and Hypertension for results ofcardiovascular disease and coronary heartdisease mortality.

# AX6-166Table AX6-5.4. Cardiovascular Effects of Lead on ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited StatesChen et al. (2006)U.S.-Baltimore, MD;Cincinnati, OH;Newark, NJ;Philadelphia, PA~1998-2004780 children from 12-33 mos participatedin a randomized clinical trial of oralsuccimer chelation in four clinicalcenters. Half the children had up to three26-day treatments, the other half weregiven placebo. 75% got two treatmentsessions and 81% of those with twotreatments received a third.Blood pressure was measured pre-treatment, at 7, 28, and 42 days after eachtreatment, then every 3 to 4 mos for fiveyrs of follow up. Cross-sectionalmultiple regression models adjusting forclinic location, baseline linear Pb, race,sex, parents’ education, single parent, ageat test, height at test, and BMI at test foreach period of the study tested thedifference of diastolic and systolic bloodpressure between placebo and succimergroups. Cross-sectional multipleregression models forthe effect of linearblood Pb at each period on bloodpressure 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-mofollow up, the other from 12 to 60 mosfollow up, adjusted for the samevariables, and tested the effect oftreatment group over time.Blood Pb ranged from20-44 μg/dL at pre-treatmentand from 1-27 μg/dL at 5 yrfollow up. Succimer-treatedgroup had significantlylower blood Pb than placebogroup only for 9-10 mosfollowing the end oftreatment. Blood Pb did notdiffer significantly beyondthat period.Adjusted systolic blood pressure was significantly higher in the succimergroup than the placebo group at 36 mos (1.27 mm Hg [95% CI: 0.06,2.48]) and at 60 mos follow up (1.69 mm Hg [95% CI: 0.34, 3.04]).Systolic blood pressure was not significantly different at any other timeperiod; diastolic blood pressure wasnever significantly different betweengroups.Concurrent linear blood Pb was not associated with blood pressure incross-sectional models at any timepoint in the study. Adjustedcoefficients for linear blood Pb and systolic blood pressure ranged from1.36 mm Hg (95% CI:!0.58, 3.30) at pre-treatment to!0.72 mm Hg (95%CI:!1.91, 0.48) at 36 mos of follow up.Diastolic pressure coefficientswere generally lower but followed the same pattern.Mixed model analysis for start of treatment through 9 mos follow upshowed succimer treatment effect of 0.24 mm Hg (95% CI:!0.79, 1.28)for systolic and 0.46 mm Hg (95% CI:!0.44, 1.36) for diastolic bloodpressure. The treatment effect from 12 through 60 mos follow up was1.09 mm Hg (95% CI: 0.27, 1.90) systolic and 0.15 mm Hg (95% CI:!0.45, 0.75) for diastolic blood pressure.The only reliable effect of succimer treatment was an elevation of systolicblood pressure, especially notablebetween three and five yrs posttreatment. The authors could notaccount for the apparent increase inblood pressure in the succimer-treatedgroup 3-5 yrs after treatment ended.It is notable that thetwo groups had different mean blood Pb for less thana yr after succimer treatment ended, a period perhaps too short to observeany beneficial effect of treatment. Failure to find cross-sectional effects ofblood Pb on blood pressure, especiallypre-treatment, may indicate that Pbexposure for a period of less than threeyrs after birth is not sufficient toaffect blood pressure or that blood pressure measurements in the first threeyrs of life are highly variable, as could be seen from scatter plots of bloodpressure vs. blood Pb at pre-treatment compared 60 mo follow up. Theuse of linear Pb term may have reduced sensitivityto finding a significantblood Pb effect on blood pressure.No model diagnostics mentioned.

# AX6-167Table AX6-5.4 (cont’d). Cardiovascular Effects of Lead on ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited States(cont’d)Gump et al. (2005)U.S.-Oswego, NYDates of study notgiven122 9.5-yr old children participated.Multiple regression models of percentchanges in systolic and diastolic bloodpressure, heart rate, stroke volume,cardiac output, andtotal peripheralresistance due to acute stress wereadjusted by stepwise entry of up to50 possible control variables withquartile blood Pb forced in last. A linearcontrast was used to test dose-responseeffects of quartile Pb. Linear Pb termswere also used.Contemporary blood Pbquartile:1st quartile: 1.5-2.8 μg/dL2nd quartile: 2.9-4.1 μg/dL3rd quartile: 4.2-5.4 μg/dL4th quartile: 5.5-13.1 μg/dLAll∃represent percent change in outcome from nonstress to stresscondition for each change in 1 μg/dL blood Pb.Systolic blood pressure:∃=!0.009 (95% CI:!0.74, 0.055)Diastolic blood pressure:∃= 0.069 (95% CI:!0.001, 0.138)Heart rate:∃= 0.013 (95% CI:!0.046, 0.072)Stroke volume:∃=!0.069 (95% CI:!0.124,!0.015)Cardiac output:∃=!0.056 (95% CI:!0.113, 0.001)Total peripheral resistance:∃= 0.088 (95% CI: 0.024, 0.152)Mean successive difference ofcardiac interbeat interval:∃=!0.028 (95% CI: (!0.098, 0.042)Despite low power to detect significant effects, blood pressure, cardiacoutput, and total peripheral resistance change to stress were associatedwith contemporary blood Pb. Stepwise modeling creates uniquemodels for each outcome. Some models had up to 12 control variablesplus Pb, an excessive number for only 122 subjects. Scatter plots ofregression with linear Pb and barcharts of response to quartile Pbshowed obvious non-linearity, though all Pb effects were modeled aslinear effects. Probability of contemporary exposure to mercury andPCB’s was very high. No model diagnostic testing reported.EuropeFactor-Litvak et al.(1996)Europe-KosovskaMitrovica and Pristina,Kosovo~1992-1993281 5.5-yr old children studied sincepregnancy participated. Multiple linearregression models of systolic bloodpressure, adjusted for height, BMI,gender, ethnic group, and birth order, anddiastolic blood pressure, adjusted forwaist circumference, ethnic group, andbirth order were constructed by stepwiseelimination from a larger pool ofpotential confounding variables andretained if they modified the linear bloodPb 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% CI:!0.024, 0.13)Diastolic blood pressure:∃= 0.042 (95% CI:!0.01, 0.090)Despite low power to detect significant effects, there was a marginallysignificant tendency for blood pressureto be positivelyassociated withblood Pb. Stepwise multiple regression may have capitalized onchance results. The linear Pb term may have reduced the ability todetect significant effects of Pbif the modeled relationship werenonlinear. Log Pb was tested but notreported. A quadratic Pb termwas reported nonsignificant. No model diagnostics reported.

# AX6-168 

# ANNEX TABLES AX6-6

# AX6-169Table AX6-6.1. Placental Transfer of Lead from Mother to FetusReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationUnited StatesHarville et al. (2005)Pittsburgh, PA159 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 coefficient = 0.79On avg, cord blood Pb was lower than maternalblood Pb by 0.03 μg/dL (95% CI: 0.21, 0.38).Angell and Lavery(1982)Louisville, KY635 cord blood specimens. 154 maternaland infant blood samples collected 24 hpostpartum 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 Pb:Correlation coefficient = 0.73,∃= 0.73Maternal-cord blood Pb:Correlation coefficient = 0.60,∃= 0.55Cord-infant blood Pb:Correlation coefficient = 0.77,∃= 0.90Bogden et al. (1978)Newark, NJ25 deliveries of infants with birth weightsbetween 1,500-2,500g and 50 matchedcontrols 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 differencesin maternal blood tocord blood ratios in low birth weight and normalbirth weight infants.Correlation coefficient = 0.55

# AX6-170Table AX6-6.1 (cont’d). Placental Transfer of Lead from Mother to FetusReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationUnited States(cont’d)Fahim et al. (1976)Missouri249 mother-infant pairs from Columbia.Samples also collected from 253 mothersfrom Rolla who delivered near Pb miningareas.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 Pb:Correlation coefficient = 0.29

# AX6-171Table AX6-6.1 (cont’d). Placental Transfer of Lead from Mother to FetusReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationUnited States(cont’d)Gershanik et al.(1974)Shreveport, LA98 mother-infant pairs. Maternal blood Pb during labor:Mean 10.3 μg/dLCord blood Pb:Mean 10.1 μg/dLCorrelation coefficient = 0.64EuropeGraziano et al.(1990)Kosovo, Yugoslavia902 births in Titova Mitrovica, site of alarge Pb smelter, refinery, and batteryfactory, and Pristina, a non-Pb-exposedcontrol 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 delivery and cordblood Pb:Correlation coefficient = 0.920,∃= 0.928Huel et al. (1981)FranceHair sample pairs (n = 100) from mothersand newborns at time of delivery.Maternal hair Pb:Geometric mean 8.5 μg/dLFetal hair Pb:Geometric mean 7.3 μg/dLCorrelation coefficient = 0.24Lauwerys et al.(1978); Roels et al.(1978) Belgium474 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 Pb:Correlation coefficient = 0.81,∃= 0.73ln placenta-maternal blood Pb:Correlation coefficient = 0.22ln placenta-infant blood Pb:Correlation coefficient = 0.28Barltrop (1969)England29 paired maternal and fetalsamples. Maternal blood Pb:Mean 13.9 μg/100 gCord blood Pb:Mean 10.8 μg/100 gCorrelation coefficient = 0.86

# AX172Table AX6-6.1 (cont’d). Placental Transfer of Lead from Mother to FetusReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Barltrop (1969)England34 fetuses at gestational age 10 to 40 wksobtained from termination of pregnancy andneonatal deaths.Blood Pb levels in femur, liver, blood, brain, heart,and kidney measured.Pb became detectable at gestational age 12 -14wks. For skeletal (femur) and soft tissue withhigh affinity (liver), Pb levels increasedprogressively until term. In contrast, in softtissue with low affinity (heart), only a modestincrease in Pb levels was observed between 14wks and term.Latin AmericaChuang et al. (2001)Mexico City, Mexico615 women recruited in 1994-1995.Investigators used structural equationmodeling to estimate plasma Pb as theunmeasured variable and to quantify theinterrelations of cord blood Pb with plasmaPb, whole blood Pb, and bone Pb (corticaland 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 whole blood Pb:Correlation coefficient = 0.82ln cord-ln maternal plasma Pb:Correlation coefficient = 0.89ln cord-maternal patella Pb:Correlation coefficient = 0.23ln cord-maternal tibia Pb:Correlation coefficient 0.18The structural equation models indicated thatmaternal plasma Pb had a stronger associationwith fetal cord blood Pb compared to that ofwhole blood Pb. In addition, the modelssuggested a significant contribution of Pb fromthe skeletal system toplasma during pregnancy,a contribution that is independent of theinfluence of maternal whole blood Pb.

# AX6-173Table AX6-6.1 (cont’d). Placental Transfer of Lead from Mother to FetusReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationOther LocationsClark (1977)Zambia122 mother-infant pairs residing near theBroken Hill Pb Mine and Smelter. Controlgroup 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 coefficient = 0.77Control group:Correlation coefficient = 0.56Casey and Robinson(1978)New Zealand40 fetuses (23 stillborn and 17 died within24 hrs), 22 to 43 wks gestation.Pb detected in 73% of liver, 23% of kidneys, 40%of brain, 25% of heart, 33% skeletal muscle, and70% of bone samples. Pb also detected in 11 of 14lung samples (79%).Overall Pb concentration in soft tissue:0.1-2.4 μg/g dry matterPb concentration in bone samples:0.4-4.3 μg/g dry matterPb concentrations in bonewere higher than inthe other tissues.Levels in brain, heart, and muscle similar tovalues reported for children and adults. Levelsin liver, kidney, lung, and bone were much lessthan adult values, suggesting much of the Pb thatenters the body after birth accumulates in thesetissues.Chaube et al. (1972) 50 embryos and fetuses 31 to 261 daysgestational 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 occurs as early as the 1sttrimester of pregnancy.

# AX6-174Table AX6-6.2. Lead Exposure and Male Reproduction: Semen QualityReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationUnited StatesBenoff et al. (2003a)New York74 male partners of women undergoingtheir first in vitro fertilization cycle.Seminal plasma Pb:Mean 39.50 μg/dL (SD 35.97)Significant negative correlation between seminalplasma Pb and fertilization rate (r =!0.447).Statistically significant inverse correlations (rvalues of <!0.3) were found between seminalplasma Pb levels and sperm count, motility, andmorphology. Stronger negative relationshipswere observed between seminal plasma Pbvalues and mannose receptor expression (r =!0.383), and mannose-stimulated acrosome loss(r =!0.423).Benoff et al. (2003b)New York15 semen donors in an artificialinsemination program. None wereoccupationally exposed to Pb.Seminal plasma Pb:Range <10 to >150 μg/dLCorrelation coefficient for seminal plasma Pband artificial fecundity rate is!0.641.Cullen et al. (1984)U.S.Seven men with symptomatic occupationalPb intoxication.Maximum whole blood Pb levels:66-139 μg/dLAlthough serum testosterone concentration wasnormal in six patients, five had defects inspermatogenesis, including two witholigospermia and two withazoospermia. Repeatexaminations after chelation therapy showedonly partial improvement.Heavy occupational exposure to Pb may beassociated with diffuse disturbances of endocrineand reproductive functions in men that are notrapidly reversible with standard treatment.

# AX6-175Table AX6-6.2 (cont’d). Lead Exposure and Male Reproduction: Semen QualityReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationCanadaAlexander et al.(1996a)British Columbia119 workers employed at a Pb smelter. Current blood Pb:Mean 22.4 μg/dL (range 5-58)Sperm concentration and total sperm count wereinversely related to current blood Pbconcentration, with the largest effects detectedamong men with blood Pb concentrations of 40μg/dL or more.Geometric meanBlood Pb (μg/dL)sperm count×106<15 186.015-24 153.025-39 137.0∃40 89.1Blood Pb levels were notconsistently associatedwith abnormal morphology and poor motility ofthe sperm.When classified by long term exposure toPb, calculated from the mean blood Pbconcentrations of the preceding 10 yrs, similartrends were observed.

# AX6-176Table AX6-6.2 (cont’d). Lead Exposure and Male Reproduction: Semen QualityReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationEuropeBonde et al. (2002)UK, Belgium, ItalyEuropean study of 503 men (362 exposed toPb, 141 unexposed controls) employed inPb industry.Blood Pb:Exposed workers:Mean 31.0 μg/dL (range 4.6-64.5)Unexposed workers:Mean 4.4 μg/dLMedian sperm concentration reduced by 49% inmen with blood Pb levels >50 μg/dL.Odds ratio for sperm count#50 million/ml inmen with blood Pb levels >50 μg/dL comparedto <10 μg/dL was 4.4 (95% CI: 1.6, 11.6).Regression analyses indicated a threshold valueof 44 μg/dL below which no adverseassociations were found.Assennato et al.(1986)Italy18 battery workers (exposed group) and 18cement 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 blood Pb:r2=!0.385Sperm count and sperm Pb:r2=!0.02638% lower median sperm count and threefoldgreater prevalence of oligospermia (16.7% vs.5.5%) in battery workers compared to cementworkers.Lancranjan et al.(1975)Europe150 men occupationally exposed to Pbdivided into four groups: Pb-poisonedworkmen (n = 23) and those showing amoderate (n = 42), slight (n = 35), orphysiologic absorption (n = 50).Blood Pb:Pb poisoned workers:Mean 74.5 μg/dLModerately exposed workers:Mean 52.8 μg/dLDecreased sperm counts and increasedprevalence of morphologically abnormal spermamongst workers withheavy and moderateexposure to Pb.

# AX6-177Table AX6-6.2 (cont’d). Lead Exposure and Male Reproduction: Semen QualityReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationLatin AmericaHernandez-Ochoaet al. (2005)Region Lagunera,Mexico68 environmentally-exposed men residingin Torreón, Gómez Palacio, and Lerdo forat 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/106cells (range 0.032-0.245)Decreased sperm concentration, motility, normalmorphology and viability correlated with Pb inspermatozoa. Reduced semen volume associatedwith seminal fluid Pb.Multiple linear regression indicated thatpercentages of progressive motility andmorphology were the most sensitive parametersto Pb toxicity, which showed the highestpercentages of abnormality among the semenquality parametersevaluated.No associations were found with blood Pb.Lerda (1992)Argentina38 male workers exposed to Pb in a batteryfactory 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 count, decreased percentmotility, and increased percent with abnormalmorphology observed in all three exposuregroups compared to control group.AsiaChowdhury et al.(1986)IndiaTen men occupationally exposed to Pb in aprinting press.Blood Pb:Exposed group:Mean 42.5 μg/dLUnexposed group:Mean 14.8 μg/dLDecrease in sperm count, percent motility andincrease in number of sperm with abnormalmorphology observed in these semen samples.

# AX6-178Table AX6-6.3. Lead Exposure and MaleReproduction: Time to PregnancyReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationEuropeJoffe et al. (2003)Belgium, England,Finland, ItalyAsclepios Project, large Europeancollaborative cross-sectional study.1,108 men (638 occupationally exposed toPb at the time of pregnancy) who havefathered a child.Blood Pb:Belgium: mean 31.7 μg/dLEngland: mean 37.2 μg/dLFinland: mean 29.3 μg/dLItaly: mean 29.2 μg/dLFecundity densityBlood Pb (μg/dL)ratios (95% CI)control 1.00<20 1.12 (0.84, 1.49)20-29 0.96 (0.77, 1.19)30-39 0.88 (0.70, 1.10)∃40 0.93 (0.76, 1.15)Results indicate thatno association was foundbetween blood Pb and delayed time topregnancy. Similar results were found whenduration of exposure or cumulative exposure wasused as the exposure metric.Apostoli et al. (2000)ItalyItalian men included in the Asclepiosproject. 251 exposed men and 45unexposed men with at least one completedpregnancy.Blood Pb distribution among exposed men:PercentageBlood Pb (μg/dL)of population0-19 14%20-29 40%30-39 32%∃40 14%Time to pregnancy shorter in couples in whichmale partner exposed compared to unexposed.Among the exposed men, a longer time topregnancy observed with blood Pb levels∃40 μg/dL, though not statistically significant.

# AX6-179Table AX6-6.3 (cont’d). Lead Exposure and Male Reproduction: Time to PregnancyReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Sallmθn et al.(2000a)Finland502 occupationally exposed malesmonitored by the Finnish Institute ofOccupational Health.Blood Pb distribution (available close to time ofconception in 62% of men;in 38% estimated basedon blood Pb levels obtainedat other times or basedon job histories):PercentageBlood Pb (μg/dL)of population<10 35%10-20 40%21-30 16%31-39 4%∃40 5%Results suggest that paternal exposure to Pb maybe associated with increased time to pregnancy.Fecundity densityBlood Pb (μg/dL)ratios (95% CI)<10 1.0010-20 0.92 (0.73, 1.16)21-30 0.89 (0.66, 1.20)31-39 0.58 (0.33, 0.96)∃40 0.83 (0.50, 1.32)AsiaShiau, et al. (2004)Taiwan280 pregnancies in 133 couples in whichmale partner employed in battery plant.127 conceived during exposure; remainderconceived prior to exposure.Blood Pb:Annual means from 1987 to 1999 ranged from 32to 41 μg/dL.Fecundity densityBlood Pb (μg/dL)ratios (95% CI)unexposed 1.00<20 0.91 (0.61, 1.35)20-29 0.71 (0.46, 1.09)30-39 0.50 (0.34, 0.74)∃40 0.38 (0.26, 0.56)Using blood Pb as a continuous variable andrestricting the analysis to blood Pb levelsbetween 10 and 40 μg/dL, time to pregnancyincreased by 0.15 mos for each 1 μg/dL increasein blood Pb level.

# AX6-180Table AX6-6.4. Lead Exposure and MaleReproduction: Reproductive HistoryReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationUnited StatesLin et al. (1996)New York4,256 male workers reported to the NewYork State Heavy Metals Registry(exposed) and 5,148 male bus drivers fromthe New York State Department of MotorVehicles file (control), frequency-matchedfor age and residence. Fertility during theperiod of 1981 to 1992. Records linked tobirth certificates from the New York StateOffice of Vital Statistics.Blood Pb in Pb-exposed men:Mean 37.2 μg/dL (SD 11.1)Standardized fertility ratio of Pb-exposed men incomparison with non-exposed men was 0.88(95% CI: 0.81, 0.95).Exposed group had fewer births than expected.Among those employed in Pb industry over5 yrs, a relative risk of 0.38 (95% CI: 0.23,0.61) was observed after adjusting for age, race,education, and residence.EuropeGennart et al. (1992)Belgium74 men occupationally exposed to Pb formore than 1 yr and 138 men in referencegroup with no occupational exposure.Blood Pb in Pb-exposed men:Mean 40.3 μg/dLDuration of Pb exposure:Mean 10.7 yrsCompared to reference group, odds of at leastone live birth reduced in exposed group duringthe period of Pb exposure (odds ratio of 0.65[95% CI: 0.43, 0.98]).Fertility decreased with increasing exposure(although number of men at higher exposurelevels small).Bonde and Kolstad(1997)Denmark1,349 male employees ages 20-49 yrs fromthree battery plants and control group of9,656 men not employed in Pb industry.Cohorts identified by records in a nationalpension fund. Information on birthsobtained from Danish Population Register.Blood Pb in subset of battery worker cohort (4,639blood samples from 400 workers):Mean 35.9 μg/dL (SD 13.0)No associations found between exposuremeasure and birth rate.Relative risk comparing person yrs at risk fromPb exposure with yrs at risk in reference groupwas 0.88 (95% CI: 0.81, 0.95).

# AX6-181Table AX6-6.4 (cont’d). Lead Exposure and Male Reproduction: Reproductive HistoryReference andStudy LocationStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Sallmθn et al.(2000b)FinlandOccupationally exposed males monitoredby the Finnish Institute of OccupationalHealth. 2,111 individuals with probableexposure (a blood Pb level∃10 μg/dLwithin a 5-yr time period including acalendar yr preceding the yr of marriageand 4 consecutive yrs) and 681 controls(with mean blood Pb levels <10 μg/dL).Blood Pb distribution among individuals probablyexposed:PercentageBlood Pb (μg/dL)of population10-20 51%21-30 30%31-40 11%41-50 5%∃51 3%Risk ratios among men in the probably exposedgroup:Blood Pb (μg/dL)Infertility ratios (95% CI)controls 1.0010-20 1.27 (1.08, 1.51)21-30 1.35 (1.12, 1.63)31-40 1.37 (1.08, 1.72)41-50 1.50 (1.08, 2.02)∃51 1.90 (1.30, 2.59)Results suggest that paternal exposure to Pbincreases the risk of infertility at lowoccupational exposure levels.

# AX6-182 

# ANNEX TABLES AX6-7

# AX6-183Table AX6-7.1. Recent Studies of Lead Exposure and GenotoxicityReference, StudyLocation, andPeriod Study Description Pb Measurement Findings and InterpretationEuropeFracasso et al. (2002)ItalyCase-control design.37 workers employed at a battery plant.29 student and office worker volunteerswith no known occupational exposure togenotoxins.Peripheral lymphocytes isolated fromwhole blood.Reactive Oxygen Species (ROS)production, cellular GSH level, PKCisoforms, and DNA breaks (via comet)assayed.ANOVA and logistic regression used tocompare workers vs. healthy volunteers.Adjusted for age, alcohol use, andsmoking.Battery plant workers. Blood Pbcategories used for somecomparisons, with <25, 25-35, and>35 μg/100mL as cutpoints.Mean blood Pb 39.6 μg/100mL forworkers, 4.4 μg/100mL forvolunteers.OR (95% CI)Workers vs. Volunteers:ROS: 1.43 (0.79, 2.60)DNA breaks (tail moment):1.07 (1.02, 1.12)GSH: 0.64 (0.49, 0.82)PKCαreduced in workers, atypical PKC unchanged vs.volunteers (no statistics provided).Means (SE) via blood Pb category for ROS and GSH:<25 μg/100 mL 4.9 (0.4) and 12.8 (0.8)25-35 μg/100 mL 5.4 (0.7) and 7.7 (1.7)>35 μg/100 mL 5.4 (0.5) and 9.2 (1.2)Major analyses controlled for age,smoking, and alcohol intake.Analyses by blood Pb category not controlled for age, smoking,or alcohol intake but these factors said not to influence endpointand/or results “significantly.” No control for potentialcoexposures.

# AX6-184Table AX6-7.1 (cont’d). Recent Studies of Lead Exposure and GenotoxicityReference, StudyLocation, andPeriod Study Description Pb Measurement Findings and InterpretationEuropePalus et al. (2003)PolandCross-sectional design.Battery plant workers: 34 acid battery,22 alkaline battery, and 52 plantpersonnel from departments with noknown 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 iffrom acid battery department,cadmium-exposed if from alkaline,unexposed if from other department.Mean blood Pb 504 μg/L forPb-exposed workers, 57 μg/L forcadmium-exposed, and 56 μg/L forother 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 combined):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. controls at p < 0.05 andp < 0.01, respectively.Both SCEs and MN elevated among Pb-exposed workers as wellas cadmium-exposed workers compared to controls. Differencesgreatest for Pb-exposed workers.Higher SCE and MN also occurred among Pb-exposed workersafter stratificationby smoking status.No direct control for potential coexposures, but mean bloodcadmium no higher in Pb-exposed than in other worker group.

# AX6-185Table AX6-7.1 (cont’d). Recent Studies of Lead Exposure and GenotoxicityReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings and InterpretationEurope(cont’d)Van Larebeke et al.(2004)BelgiumCross-sectional design.99 female nonsmokers, ages 50-65,drawn from rural and industrial areas.Peripheral lymphocytes isolated fromblood. HPRT variant frequencydetermined.Pb concentration measured in blood(serum).Women also classified as above vs.below median for blood Pb.HPRT variant frequencyAbove median serum Pb: 9.45Η10-6Below median serum Pb: 5.21Η10-6P-value for difference = 0.08 adjusted for age, education,smoking, BMI, and serum selenium. (Significant inverseassociation noted between variant frequency and serumselenium.) Uncontrolled forpotential exposure to othergenotoxins.Latin AmericaMinozzo et al. (2004)BrazilCross-sectional design.26 workers employed at a batteryrecyclery for 0.5 to 30 yrs.29 healthy volunteers of similar agerange and SES.Peripheral lymphocytes isolated fromwhole blood.Fixed blood slides stained with Giemsavisually evaluated to determinemicronuclear frequency (MN) andcellualr proliferation as nucleardivision index (NDI).ANOVA and logistic regression usedto compare workers vs. healthyvolunteers. Adjusted for age, alcoholuse, and smoking.Battery recyclery workers wereconsidered exposed.Blood Pb also determined.Mean blood Pb 35.4 μg/dL forworkers, 2.0 μg/dL for volunteers.Means (SD) for workers and volunteersMN: 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 workers only, not totalpopulation, but no population number given in table.}Blood PbΗMN: 0.061 (p = 0.33)Blood PbΗNDI: 0.385 (p = 0.003)Not controlled for age or SES, although worker and volunteerpopulations said to be of similarage and SES. Uncontrolled forpotential coexposures. Correlations appear uncontrolled forsmoking, age, or other factors. Differences in MN and NDIminor for smokers vs. nonsmoker, however. Diet “type”“similar” for workers and controls, although no definition ofsimilarity provided.

# AX6-186Table AX6-7.2. Key Occupational Studies of Lead Exposure and CancerReference, StudyLocation, and Period Study DescriptionPb Measurement Findings and InterpretationUnited StatesSteenland et al. (1992)(follow-up of Selevanet al. (1985)U.S.1940-1988Cohort design.1,990 male workers employed forat least 1 yr in a Pb-exposeddepartment at aU.S. Pb smelterin Idaho during 1940-1965.Mortality traced through 1988 todetermine cause of death.SMR computed for workers vs.national rates for age-comparablecounterparts.Exposure categorizations based onairborne Pb measurements from1975 survey. High-Pb-exposuresubgroup consisted of 1,436 workersfrom departments with an avg of least0.2 mg/m3airborne Pb or≥50% ofjobs showing 0.40 mg/m3or greater.Mean blood Pb 56 μg/dL in 1976.SMR (95% CI); number of deathsTotal cohort:Nonsignificantly elevated RRs: kidney, bladder, stomach, and lungcancer.High-Pb-exposure subgroup:Kidney 2.39 (1.03, 4.71); 8Bladder 1.33 (0.48, 2.90); 6Stomach 1.28 (0.61, 2.34); 10Lung 1.11 (0.82, 1.47); 49No control for smoking or exposure to other metals.Wong and Harris(2000)(follow-up of Cooperet al. (1985)U.S.1947-1995Cohort design.Pb battery plant (4,518) and smelter(2,300) workers.Worker mortality was followed upthrough 1995.Cause of death was identified fromdeath certificates.Mortality was compared with U.S.national age-, calendar-yr-, and genderspecific rates to compute the SMR.(See additional entry for nested studyof stomach cancer.)Workers were evaluated as a whole,and also as separate battery plant andsmelter worker populations.Job histories were also used tostratify workers by cumulative yrs ofemployment (1-9,10-19, 20+), dateof hire (pre-1946 vs. 1946 on), andlag between exposure and cancer(<20, 20-34, >34 yrs). Mean bloodPb 80 μg/dL during 1947-72 amongsmelter workers, 63 μg/dL amongbattery workers.SMR (95% CI)Battery plant workers:All cancer 1.05 (0.97, 1.13)All respiratory 1.13 (0.98, 1.29)Stomach 1.53 (1.12, 2.05)Lung, trachea, bronchus 1.14 ( 0.99, 1.30)Thyroid, Hodgkin’s: nonsignificantBladder 0.49 (0.23, 0.90)Smelter workers:Digestive, respiratory, thyroid: nonsignificantLung 1.22 (1.00, 1.47)Battery plant and smelter workers combined:All cancer 1.04 (0.97, 1.11)All respiratory 1.15 (1.03, 1.28)Stomach 1.47 (1.13, 1.90)Lung, trachea, bronchus 1.16 ( 1.04, 1.30)Thyroid/endocrine 3.08 (1.33, 6.07)Lung and stomach risks lower pre-1946 hires; higher for workersemployed 10-19 yrs than <10, but lower for >19 yrs; SMRs peakedwith 20- to 34-yr latency forlung, but <20 yrs for stomach.No control for smoking or exposure to other agents. No assessmentof employment history after 1981.

# AX6-187Table AX6-7.2 (cont’d). Key OccupationalStudies of Lead Exposure and CancerReference, StudyLocation, and Period Study DescriptionPb Measurement Findings and InterpretationUnited States(cont’d)Wong and Harris(2000)U.S.1947-1995.(Nested in Wong andHarris 200 cohort.)Case-control design.Cases: the 30 stomach cancer casesoccurring in a Philadelphia Pb batteryplant.Controls: 120 age-matched cohortmembers.Mean exposure was compared forcases vs. controls. Odds of exposurewere also computed for increasingquartiles of cumulative exposure.Job titles were used to classify Pbexposure as low, intermediate, orhigh; total mos of any exposure, ofintermediate or high exposure only,and of cumulative exposure, withmos weighted by 1, 2, or 3 if spent inlow-, intermediate-, or high-exposurejob.Mean mos of employment, of intermediate or high exposure, or ofweighted exposure to Pb wereall nonsignificantly lower amongcases.OR for cumulative weighted exposure in the 10 yrs prior to death:1st quartile 1.002nd quartile 0.623rd quartile 0.824th quartile 0.61p for trend = 0.47; ORs showed no positive association withany index of exposure.Analyses appear uncontrolled for smoking, other occupationalexposures, or other risk factors.EuropeFanning (1988)(Cases overlap thoseoccurring inDingwall-Fordyce andLane, 1963; andMalcolm and Barnett,1982).U.K.1926-1985Proportional mortality/cohort design.Subjects:2,073 deceased malesidentified through pension records ofPb battery and other factory workers inthe U.K.Workers dying from a specific cancerwere compared with workers dyingfrom all other causesWorkers were classified as High ormoderate Pb exposure vs. little or noexposure based on job titles.OR (95% CI); number of deathsLung cancer: 0.93 (0.8, 1.1); 76Stomach cancer: 1.34; 31No associations for other cancer types; elevations in stomach andtotal digestive cancers limited to the period before 1966.

# AX6-188Table AX6-7.2 (cont’d). Key OccupationalStudies of Lead Exposure and CancerReference, StudyLocation, and Period Study DescriptionPb Measurement Findings and InterpretationEurope(cont’d)Anttila et al. (1995)Finland1973-1988Cohort plus case-referent design.20,700 workers with at least one bloodPb measurement between 1973 and1983.Workers were linked to the FinnishCancer Registry for follow-up through1988. For deceased workers, cause ofdeath was identified from deathcertificate.Mortality and incidence were comparedwith gender-, 5-yr age, and 4-yrcalendar-yr matched national rates.Exposure was categorized accordingto the highest peak blood levelmeasured: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-specific cancer mortality.Moderately exposed:Total respiratory and lung cancer:SIR = 1.4 (95% CI: 1.0, 1.9) for bothTotal digestive, stomach, bladder, and nervous system: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 group.No RRs reported for other cancers.Case-referent substudies:Lung cancer ORs increased with increasing cumulativeexposure to Pb.Highly exposed: squamous-cell lung cancer OR of 4.1(95% CI: 1.1, 15) after adjustment for smoking.Short follow-up period limits statistical power, offset to alarge degree by the substantialsample size. No control forexposure to other potential carcinogens.

# AX6-189Table AX6-7.2 (cont’d). Key Occupational Studies of Lead Exposure and CancerReference, StudyLocation, and Period Study DescriptionPb Measurement Findings and InterpretationEurope(cont’d)Anttila et al. (1996)Finland1973-1988(Nested analysis basedon Antilla et al., 1995cohort)Case-control design.(See Anttila et al., 1995 for basicinformation on thesource population.)Cases: 26 Finnish men with CNScancer.Controls:200 Finnish men withoutCNS cancer.Nested case-control analysis.Peak blood Pb levels used tocategorize exposure as 0.1-0.7,0.8-1.3, and 1.4-4.3 μg/L.Cumulative exposure estimated byusing mean annual blood Pb level tocategorize exposure as0, 1-6, 7-14,or 15-49 μg/L.Interviews were used to obtainoccupational history and other risk-factor data from patients or nextof kin.Number of cases or deathsCNS cancer incidence(26 cases):Rose with increasing peak lifetimeblood Pb measurements; not significant.Glioma mortality(16 deaths):Rose consistently and significantlywith peak and mean blood Pb level, duration of exposure, andcumulative exposure.Mortality by cumulative exposure,controlled for cadmium, gasoline,and yr monitoring began:Low (13 subjects) 2.0 (2)Medium (14 subjects) 6.2 (2)High (16 subjects) 12.0 (5)One death among 26 subjects with no exposure: test for trendsignificant at p= 0.02.Controlled for smoking as well as exposure to cadmium and gasoline.Complete follow-up with minimal disease misclassification.Gerhardsson et al.(1995)Sweden1969-1989Cohort design.684 male Swedish secondary Pb smelterworkers with Pb exposure.Cancer incidence among workers wastraced through 1989.Incidence was compared with countyrates.Blood Pb level: any worker with adetectable blood Pb level wasclassified as exposed.SIR (95% CI); number of casesAll malignancies:1.27 (0.91, 1.74); 40Respiratory:1.32 (0.49, 2.88); 6All gastrointestinal:Cohort 1.84 (0.92, 3.29); 11Highest quartile 2.34 (1.07, 4.45); 9Stomach:1.88 (0.39, 5.50); 3Colon:1.46 (0.30, 4.28); 3SIRs for all other sites except brain were nonsignificantly elevated;too few cases.No control for smoking. Small numbers, so meaningful doseresponse analyses not possible for most cancer sites.

# AX6-190Table AX6-7.2 (cont’d). Key OccupationalStudies of Lead Exposure and CancerReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings and InterpretationEurope(cont’d)Lundström et al.(1997)(follow-up ofGerhardsson et al.(1986)(see also subcohortanalyses of Englystet al., 2001).Sweden1928-1987Cohort design.3,979 copper and Pb smelter workers.Standardized mortality and incidenceratios were computed for workerscompared with age-, yr-, gender-, andcounty-specific rates for the generalpopulation.For some analyses, the entire cohortwas treated as exposed. For others,job histories were used to single out1,992 workers belonging todepartments thought to be exposed to“Pb only.” Mean blood Pbmonitoring test results across timewere used to single out a “highlyexposed” group of 1,026 workerswith blood Pb levels≥10 μmol/L[≥207 μg/dL].Mean blood Pb 60 μg/dL in 1959.SMR (95% CI); number of deathsLung:Total cohort 2.8 (2.0, 3.8); 39Highly exposed 2.8 (1.8, 4.5); 19SIR (95% CI); number of casesLung with 15-yr lag:Total cohort 2.9 (2.1, 4.0); 42Highly exposed 3.4 (2.2, 5.2); 23Pb-only 3.1 (1.7, 5.2); 14Pb-only highly exposed 5.1 (2.0, 10.5); 7Other highly exposed (total cohort), with 15-yr lag:Brain 1.6 (0.4, 4.2); 4Renal pelvis, ureter, bladder 1.8 (0.8, 3.4); 9Kidney 0.9 (0.2, 2.5); 3All cancer 1.1 (0.9, 1.4); 83No control for smoking.Englyst et al. (2001)(follow-up and subanalysis of Lundströmet al., 1997).Sweden1928-1987Nested cohort analysis.Limited to 1,093 workers in thesmelter’s Pb department, followedthrough 1997.Incidence was compared with countyrates; age-specific SIRs with 15-yr lag.Workers were divided intoSubcohorts I and II for ever andnever worked in areas generallyassociated with exposure to arsenicor other known carcinogens (701 and383 workers, respectively).Detailed individual assessment ofarsenic exposure was made for alllung-cancer cases.SIR (95% CI); number of casesSubcohort I (coexposed):Lung 2.4 (1.2, 4.5); 10Subcohort II (not coexposed):Lung 3.6 (1.2, 8.3); 5Subjects with lung cancer found to have history of “considerable”exposure to arsenic: 9/10among Subcohort I, 4/5 amongSubcohort II.No control for smoking.

# AX6-191Table AX6-7.2 (cont’d). Key OccupationalStudies of Lead Exposure and CancerReference, StudyLocation, and Period Study DescriptionPb Measurement Findings and InterpretationEurope(cont’d)Carta et al. (2003)Sardinia1972-2001Cohort design.918 Pb smelter workers.Mortality traced from 1972 through2001.Standardized mortality ratios computed.Smelter workers considered exposed.Job histories also used to categorizedegree of exposure based onenvironmental and blood Pbmeasurements for specificdepartments and tasks during1985-2001.SMR; number of casesSmelter workers as a wholeAll cancer 1.01; 108Gastric cancer 1.22; 4Lymphoma/leukemia 1.82; 6Lung cancer 1.21; 18Highly exposed workersLung cancer 1.96 (95% CI: 1.02, 3.68) for highest exposuregroup, with statistically significant upward trend.Analyses for worker population as a whole supported bypresence of dose-response pattern for lung cancer based onestimated exposure. Modest population size, inability to assessdose-response for cancers of interest other than lung. No controlfor smoking or other occupational exposures.

# AX6-192Table AX6-7.3. Key Studies of Lead Exposureand Cancer in the General PopulationReference, StudyLocation, and Period Study DescriptionPb Measurement Findings and InterpretationUnited StatesJemal et al. (2002)(same cohort as inLustberg andSilbergeld, 2002except for inclusioncriteria)U.S.1976-1992.Cohort design.3,592 white participants from the1976-1980 NHANES II survey whohad blood Pb measured at entry.Mortality was followed through 1992via NDI and SSADMF.RRs were calculated for the variousexposure groups compared to surveyparticipants with the lowest exposure,adjusted for age and smoking.Blood Pb (μg/dL) was measuredby atomic absorption and used toclassify subjects into exposurequartiles or groups above vs.below median exposure.Median blood Pb 12 μg/dL.RR (95% CI); number of deathsLung (above vs. below median):Total cohort 1.5 (0.7, 2.9); 71Male 1.2 (0.6, 2.5); 52Female 2.5 (0.7, 8.4); 19Stomach (above vs. below median):Total cohort 2.4 (0.3, 19.1); 5Male 3.1 (0.3, 37.4); 4Female no deaths in referent groupAll cancer: total cohort by quartile(age-adjusted) 1.0, 1.2, 1.3, 1.5(p = 0.16 for trend).Smoking was controlled for. Pb levelsoccurring in the general populationwere examined, not just those in workers with high occupational exposurepotential. Exposure to other carcinogenswere not examined. Potential forresidual confounding by degree andduration of smoking exists (onlycontrolled for never, former, current<1, current 1+ pack/day). Limitedcase numbers yield low statistical power for stomach or other cancers.

# AX6-193Table AX6-7.3 (cont’d). Key Studies of Lead Exposure and Cancer in the General PopulationReference, StudyLocation, and Period Study DescriptionPb Measurement Findings and InterpretationUnited StatesLustberg andSilbergeld (2002)(same cohort as Jemalet al., 2002 except forinclusion criteria)U.S.1976-1992.Cohort design.4,190 U.S. participants from the 1976-1980 NHANES II health and nutritionsurvey who had blood Pb measured atentry and whose levels fell below30 μg/dL.Mortality was followed through 1992via NDI and SSADMF.RRs were calculated for the variousexposure groups compared to surveyparticipants with the lowest exposure,adjusted for age, smoking and otherfactors.Blood Pb (μg/dL) measured byatomic absorption was used toclassify subjects into exposuregroups:Low: <10Medium: 10-19High: 20-19Mean 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 forall-cause and for cardiovascularmortality with increasing Pb category.Smoking was controlled for in the analysis. Pb levels occurring in thegeneral population wereexamined, with individuals showing levelsconsistent with intense occupational exposure excluded, thus allowingexploration of potential effects outside of groups experiencing intenseoccupational exposure. Exposure to other carcinogens were not examined.Potential for residual confounding bydegree and duration of smokingexists (only controlled fornever, former, current <1, current 1+ pack/day).Limited case numbers yield low statistical power for stomach or othercancers.

# AX6-194Table AX6-7.4. Other Studies ofLead Exposure and CancerReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings and InterpretationUnited StatesMallin et al. (1989)Illinois1979-1984Case-control design.Cases: random sample of 10,013 deathsfrom 7 specific cancers, identified fromdeath certificates for Illinois malesbetween 1979 and 1984.Controls: 3,198 randomly selecteddeaths from other causes.Odds of exposure computed for glassworkers vs. other occupations.Exposure was based onoccupations abstracted fromdeath certificates.No specific measure of Pbexposure; glass workers can beconsidered potentially exposed.Brain cancer, white male glass workers:OR = 3.0, p < 0.05No significant associationsfor other cancer sites.No control for smoking or other riskfactors. Poor specificity for Pbexposure.Cocco et al. (1998a)U.S.1984-1992Case-control design.Cases: all 27,060 brain cancer deathsoccurring among persons aged 35 orolder during 1984-1992, from U.S.24-state death certificate registry.Controls: 4 gender-, race-, age-, andregion-matched controls per caseselected from deaths due tononmalignant causes.Subjects were subdivided into 4 groupsby gender and race (white or AfricanAmerican) for all analyses.A job-exposure matrix wasapplied to death certificate-listedoccupations to categorizepersons as having low, medium,or high probability and intensityof exposure.Risk of brain cancer mortality increased consistently with intensity ofexposure among African-American males, but not other race-gendergroups.Probability of exposure alone was not consistently associated withrisk.In the high-probability group, riskincreased with exposure intensityfor all groups except African-American women (only 1 death in thehigh-probability group).Exposure estimate was based solely on occupation listed on deathcertificate, hence there wassubstantial opportunity formisclassification.

# AX6-195Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and CancerReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings and InterpretationUnited States(cont’d)Cocco et al. (1998b)U.S.1984-1992Case-control design.Cases: all 28,416 CNS cancer deathsoccurring among persons aged 35 orolder during 1984-1992, from U.S.4-state death certificate registry.Controls: 4 gender-, race-, age-, andregion-matched controls per caseselected from deaths due tononmalignant causes.Subjects were subdivided into 4 groupsby gender and race (white or African-American) for all analyses.Death certificate listed industryand occupation was used tocategorize decedents. Noestimates of Pb exposurespecifically.OR (95% CI)All occupations or industries withORs above 1.0 and p < 0.05 in atleast one race-gender group were reportedNewspaper printing and publishing industry:White 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 associatedoccupations or industries showed astatistically significant elevation of mortality. No specific measuresof Pb exposure. Occupation basedsolely on death certificate, hencethere was substantial opportunity for misclassification.

# AX6-196Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and CancerReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings and InterpretationUnited States(cont’d)Cocco et al. (1999)U.S.1984-1996Case-control design.Cases: all 41,957 stomach cancer deathsoccurring among persons aged 35 orolder during 1984-1996, from U.S.24-state death certificate registry.Controls: 2 gender-, race-, age-, andregion-matched controls per caseselected from deaths due tononmalignant causes.Subjects were subdivided into 4 groupsby gender and race (white or African-American) for all analyses.A job-exposure matrix wasapplied to death certificate-listed occupations to categorizepersons as having low, medium,or high probability and intensityof exposure.OR (95% CI)Adjusted for age, ethnicity, marital status, urban residence, andsocioeconomic status.Elevated ORs:White female, high probability ofexposure 1.53 (1.10, 2.12)Black male, high probability ofexposure 1.15 (1.01, 1.32)Black female, high probability ofexposure 1.76 (0.74, 4.16)Highly exposed group included 1,503 white and 453 black men and65 white and 10 black women; no pattern of increase across exposurelevels.Intensity of exposure showed noassociation with stomach cancerexcept for black women:Low 1.82 (1.04, 3.18)Moderate 1.39High 1.25No control for other occupational exposures. Exposure estimatebased on occupation listed on deathcertificate and hence subject tomisclassification due tomissing longest-held job.

# AX6-197Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and CancerReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings and InterpretationCanadaRisch et al. (1988)Canada1979-1982Case-control design.Cases:826 Canadian men withhistologically confirmed bladder cancerduring 1979-1982.Controls:792 controls fromCanadian population, matched on age,gender, and area.Odds of exposure toPb for cases vs.controls were computed, adjusted forsmoking and other risk factors.Subjects were interviewedregarding length ofoccupational exposure to Pbcompounds, as well as 17 othersubstances.OR (95% CI)61 men ever exposed to Pb (smoking-adjusted):2.0 (1.2, 3.5)Trend per 10 yrs duration of exposure:1.45 (1.09, 2.02)No other substances showed significant associations with bladdercancer.Controlled for smoking, maritalstatus, socioeconomic status,education, ethnicity, and urban vs. rural residence.No control for other occupationalexposures. Low control interviewrate (53%), which could resultin biased control sample.Siemiatycki et al.(1991)CanadaCase-control design.Cases:3,730 various histologicallyconfirmed cancers.Controls:specific cancer types werecompared with other cancers as a controlgroup, excluding lung cancer.Separate subgroup analysis wasrestricted to French Canadians.Occupational exposure to293 substances, including Pb,was estimated from interviews.Exposure was classified as“any”; a subgroup with“substantial” exposure also wasidentified.OR (90% CI); number of casesAny exposure to Pb:Lung 1.1 (0.9, 1.4); 326(French Canadians only)Stomach 1.2 (1.0, 1.6); 126Bladder 1.3 (1.0, 1.6); 155(French Canadians only)Kidney 1.2 (1.0, 1.6); 88ORs rose in the “substantial”exposure subgroup for stomach andlung, but not for bladder or kidney cancer.Controlled for smoking but not for other occupational exposures.

# AX6-198Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and CancerReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings and InterpretationEuropeSankila et al. (1990)Finland1941-1977Cohort design.1,803 male and 1,946 female glassworkers employed for at least 3 mos atone of 2 Finnish glass factories in 1953-1971 or 1941-1977.Cancer incidence was compared withage-, gender-, and calendar-yr-specificnational rates.Stomach, lung, and skin cancer rates alsowere compared separately for 201 maleand 34 female glassblowers and non-glassblowers.No specific Pb exposure indiceswere computed. Analyses didexamine glass workers as awhole and then glassblowersspecifically, which comprisedthe group at highest risk for Pbexposure.SIR (95% CI); number of casesLung cancer, all glass workers:Male 1.3 (1.0, 1.7); 62Female 1.1 (0.5, 2.3); 7Lung cancer risk showed no specificity for glassblowers.Skin cancer, males and females combined:All workers 1.5 (0.8, 2.7); 11 (little difference between genders)Glassblowers 6.2 (1.3, 18.3); 3Stomach cancer, males and females combined:Glassblowers 2.3 (0.9, 5.0); 6No increase in other glass workersNo increase in cancers of other sites. No control for smokingor occupational coexposures.Kauppinen et al.(1992)Finland1976-1981Case-control design.Cases:344 primary liver cancer deathsreported to the Finnish Cancer Registryin 1976-1978 or 1981.Controls:registry-reported stomachcancer (476) or myocardial infarction(385) deaths in the same hospitals,frequency matched by age and gender.Questionnaires regarding jobhistory and personal habits weresent to the closest availablerelative.U.K. based job-exposure matrixwas used to rate potentialexposure to 50 substances,including Pb compoundsIndustrial hygienists alsoinspected histories to identifythose with highly probableexposure and rate it as high,low, or moderate (<10 yrs highor 10+ yrs low exposure).OR (95% CI)52 workers with potential Pb exposure:0.91 (0.65, 1.29)11 womenwith 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 only1 had low exposure, whereas4 controls had high exposure.Female controls appeared to underreport their job history.Most controls had stomach cancer, which if caused by Pb would biasresults toward the null. Few subjects were rated as having a highprobability of exposure.

# AX6-199Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and CancerReference, StudyLocation, andPeriod Study Description Pb Measurement Findings and InterpretationEurope(cont’d)Wesseling et al.(2002)Finland1971-1995Cohort design, but at ecologic level.413,877 Finnish women with occupationreported in 1970 linked to Finnish CancerRegistry to identify new cases of brain ornervous system cancer arising form1971 to 1995.Poisson regression was used to calculate SIRsfor exposed vs. unexposed groups.Reported occupation in 1970 wasused to classify women into jobtitles. Potential exposure foreach job title was estimatedusing a job matrix afterexcluding women in the highestsocial classes or in farming. Pband 23 other workplace agentsexamined. Rates for each jobtitle were calculated, and SIRsfor low and medium/highexposure calculated (avgestimated blood Pb of0.3 μmol/L served as cut pointbetween low and medium/highexposure).SIR (95% CI), unadjusted for other metalsLow exposure: 1.25 (0.68, 1.81)Medium/high exposure: 1.33 (0.90, 1.96)SIR (95% CI), adjusted for cadmium and nickel exposureLow exposure: 1.18 (0.88, 1.59)Medium/high exposure: 1.24 (0.77, 1.98)All results were adjusted for birth cohort, period of diagnosis, andjob turnover rate.Incidence, exposure to Pb, andpotential confounding factors werecalculated at the level of job title rather than at the individuallevel. Exposure and other estimates were based on data for allworkers pooled, not for women specifically. Job classificationwas based on a single yr,not lifetime job history.Pesch et al. (2000)Germany1991-1995Case-control design.Cases:935 renal-cell cancer patients in fiveGerman areas.Controls:4,298 region, age, and gendermatched controls from the surroundingpopulation.ORs were adjusted for age, center,and smoking.Job histories were used tocategorize exposure to cadmium,Pb, and other potential as low vs.medium, high, or substantial.Separate exposure estimateswere obtained from British andfrom German-derived jobexposure matrices.OR (95% CI); number of casesSubstantial Pb exposure based on British matrix:Male 1.5 (1.0, 2.3); 29Female 2.6 (1.2, 5.5); 11Substantial Pb exposure based on British matrix:Male 1.3 (0.9, 2.0); 30Female not reportedAnalyses controlled for smoking. No control for exposure toother occupational agents.

# AX6-200Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and CancerReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings and InterpretationEurope(cont’d)Kandiloris et al. (1997)GreeceCase-control design.Cases:26 patients with histologicallyconfirmed laryngeal carcinoma and nohistory of Pb exposure or toxicity.Controls:53 patients with similardemographic profiles and no history ofcancer from the same hospital.Blood Pb levels and ALAD activity weremeasured.Blood Pb levels were similar, but ALAD activity wassignificantly lower in casesthan controls (Mean 50.79 U/Lvs. 59.76 U/L, p < 0.01). No control for other risk factors.Potential distortion by effects of disease on Pb and/orALAD parameters.)Cordioli et al. (1987)Italy1953-1967Cohort design.468 Italian glass workers employed forat least one yr between 1953 and 1967.Mortality among workers was trackedand cause of death was determined fordeceased workers. Standardizedmortality ratios were computed forworkers vs. national populationcounterparts.Workers producing low-quality glasscontainers were classified as Pb-exposed.SMR (95% CI); number of deathsAll cancer 1.3 (0.8, 1.8); 28Lung 2.1 (1.1, 3.6); 13Laryngeal 4.5 (1.2, 11.4); 4Cocco et al. (1994a)(expansion of Cartaet al., 1994).Sardinia1931-1992Cohort design.1,741 male Sardinian Pband zinc minersfrom two mines employed at least one yrbetween 1931 and 1971.Mortality traced through 1992 todetermine cause of death.Mortality among miners was comparedwith age- and calendar-yr-specificregional rates to compute an SMR.All miners were considered to be exposedto Pb.SMR (95% CI); number of deathsAll cancer 0.94 (0.83, 1.05); 293Prostate 1.21; 16Bladder 1.15; 17Kidney 1.28; 7Nervous system 1.17; 8Oral 0.61; 8Lymphohemopoietic 0.91; 21Digestive 0.83; 86Peritoneum 3.67 (1.35, 7.98); 6No other p < 0.05.No control for smoking or exposure to silica, radon, orother exposures.

# AX6-201Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and CancerReference, StudyLocation, and Period Study DescriptionPb Measurement Findings and InterpretationEurope(cont’d)Cocco et al. (1994b)Sardinia1951-1988Cohort design.526 female Sardinian Pb andzinc miners from the samemines as in Cocco et al.(1994a).Mortality traced through 1992to determine cause of death.Mortality among miners wascompared with age- andcalendar-yr-specific regionalrates to compute an SMR.All miners were considered to beexposed to Pb.SMR (95% CI)Liver 5.02 (1.62, 11.70)Lung 2.32 (0.85, 5.05)Other cancers showed nonsignificantly reduced rates.No control for smoking or exposure to silica, radon, or other exposures.Low statistical power dueto small population and paucity of cancersduring follow-up.Cocco et al. (1996)Sardinia1973-1992Cohort design.1,222 male Sardinian Pb andzinc smelter workers whoseG6PD phenotypes had beendetermined, employed anytime from 1973-1990.Mortality traced through 1992to determine cause of death.Mortality was compared withregional rates.All workers were considered to beexposed to Pb.Workers were subdivided into6PD-normal and -deficient groups.All cancer and lung cancer: mortality lower than expectedStomach cancer: mortality higher than expectedG6PD deficiency had little apparent effect on mortality: cancer and allcause mortality was slightly loweramong G6PD-deficient workers thanamong G6PD-normal workers.No control for smoking or exposure to other agents in the smelter.Healthy worker bias-evident (all-cause mortality 31 observed vs. 44expected), brief follow-up, low proportion of older ages (mean age atentry 30, avg follow-up less than 11 yrs), no cumulative exposure data.

# AX6-202Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and CancerReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings and InterpretationEurope(cont’d)Cocco et al. (1997)Sardinia1931-1992Cohort design.1,388 male production and maintenanceworkers employed for at least 1 yr at aSardinian Pb and zinc smelter betweenJune of 1932 and July of 1971.Mortality was followed up through 1992.Mortality was compared with age- andcalendar-yr-specificregional rates.Since regional rates were only availablefor 1965 and later, analyses were limitedto this period.All workers were considered tobe exposed to Pb.SMRs vs. regional rates (95% CI); number of deathsLung 0.82 (0.56, 1.16); 31Stomach 0.97 (0.53, 1.62); 14All cancers 0.93 (0.78, 1.10); 132Kidney 1.75 (0.48, 4.49); 4Bladder 1.45 (0.75, 2.53); 12Brain 2.17 (0.57, 5.57); 4Kidney cancer showed a significanttrend toward increasing risk withincreasing duration of exposureNo significant trends were noted for lung or other cancersBrain cancer excess was limited to workers employed for 10 yrs orless.No control for smoking or exposure to arsenic or other smelter-related exposures. No dataon intensity of exposure.Strong association of smelter workwith pneumoconiosis and otherrespiratory disease (SMR = 4.47, 95% CI: 3.37, 5.80); since thisoutcome includes silicosis, which isthought to predispose individualsto lung cancer, some lung cancer deaths may have been missed due tomisclassification of cause of death based on death certificates.Wingren and Axelson(1987, 1993)(update of Wingrenand Axelson, 1985,same basic cohort as inWingren andEnglander (1990)Sweden1950-1982Case-control design.Source population:5,498 men aged45 or older in 11 Swedish parishes,including 887 glass workers.Cancer-specific nested case-controlanalysis:Cases:deaths due to stomach, colon,and lung cancer from 1950-1982Controls:deaths due to causes otherthan cancer or cardiovascular diseaseGlass workers were consideredexposed.Glassblowers also singled outas workers with higherexposure potential.Job history applied to jobmatrix to categorizeoccupations as low, moderate,or high Pb exposure.OR (90% CI); number of deathsAll glass workers:Lung 1.7 (1.1, 2.5); 86Stomach 1.5 (1.1, 2.0); 206Colon 1.6 (1.0, 2.5); 79Glassblowers:Lung 2.3Stomach 2.6Colon 3.1Glassblowers singled out from glass workers as a whole thus showedhigher estimated risk. ORs for high or moderate vs. low exposureshowed no consistent increase for lung or stomach cancer, however,although they did show mild upward trend for colon cancer.No control for smoking or other occupational exposures.

# AX6-203Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and CancerReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings and InterpretationEurope(cont’d)Wingren andEnglander (1990)Sweden1964-1985(same population as incase-control analysesof Wingren andAxelson 1985, 1987,1993)Cohort design.625 Swedish glass workers employedfor at least 1 mo between 1964and 1985.Mortality was compared with nationalrates.Workers from areas withairborne Pb levels up to 0.110mg/m3were classified asexposed.SMR (95% CI)Pharyngeal:9.9 (1.2, 36.1)Lung:1.4 (0.5, 3.1)Colon: nonsignificantDingwall-Fordyceand Lane (1963)U.K.1925-1962Cohort design.425 male employees drawing pensionsfrom U.K. battery plants.Standardized mortality for employeesvs. national population counterparts.Battery plant workers wereassumed to be exposed, andtheir mortality compared to thatof like age and gender in theU.K. population as a whole.Urinary Pb excretion was alsoused to categorize workers byestimated exposure (none, light,or heavy): 80 lightly and 187heavily (at least 100 μg/L)exposed.SMR (95% CI); number observed deathsAll cancer: 1.2 (0.8, 1.7); 267No consistent increase in SMRsacross categories of increasing Pbexposure.Limitations: No cancer site-specific analyses. No control forpotential confounders including smoking and exposure to arsenic orother metals.Malcolm and Barnett(1982) (follow-up ofDingwall-Fordyce andLane, 1963)U.K.1925-1976Cohort design.1,898 Pb-acid battery workers.Mortality was traced for the Pb-acidbattery workers to determine cause ofdeath. The proportion of deaths due tocancer (all types and majorsubcategories) among the workerpopulation was compared to that seen incorresponding members of the generalpopulation, yielding a PMR.Job histories were reviewed toclassify workers’ Pb exposureas high, medium, or none.Proportionate mortality ratio (PMR)All cancers:1.15 (136 deaths), p > 0.05By exposure:None 1.02Medium 1.06High 1.30No significant excesses for individual cancer sites except fordigestive cancer PMR of 1.67, p< 0.01, among nonexposed workers.The difference in exposure for the high and medium exposure groupsnarrowed greatly over the follow-up,thus complicating interpretationof dose-response patterns. No control for smoking or occupationalexposure to other carcinogens.

# AX6-204Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and CancerReference, StudyLocation, and Period Study DescriptionPb Measurement Findings and InterpretationEurope(cont’d)Ades and Kazantzis(1988)U.K.1943-1982Cohort design.4,393 male zinc, Pb,and cadmium smelterworkers.(Workers born after 1939 or who had workedless than one yr at the facility were excluded.)Workers followed up for mortality.Nested case-control analysis also conducted toquantitatively assessed cadmium and,secondarily, arsenic,Pb, and other metalexposures among 174 cases.Job histories were used to quantifycadmium exposure and assignordinal ranks for exposure to Pb andother metals.Standardized lung cancer mortalityratio computed for workers vs.national rates.SMR (95% CI); number of deathsCohort:Lung 1.25 (1.07, 1.44); 174Increased significantly with duration of employment.Nested case-control analyses did not implicate anydepartment or process, nor didcadmium, zinc, sulfur dioxide,or dust exposure account for the observed increase.Cumulative exposure to Pb and to arsenic both showedpositive associations with lung cancer, but the relativeimportance of these two exposures could not be determined.Cadmium exposure did not account for the elevated SMR,but analyses could not control for exposure, and were notadjusted for smoking.AsiaHu et al. (1998)China1989-1996Case-control design.Cases:218 patients with histologicallyconfirmed primary gliomas occurring during1989-1996 at 6 Chinese hospitals.Controls:436 patients withnon-neurological,nonmalignant disease, matched by age, gender,and residence from the same hospitals(excluding one cancer-only center).Patients were interviewed, and thosewith factory or farm occupationswere further interviewed to identifyexposure to Pb (or other potentiallytoxic substances).Occupational exposure to Pb:Not reported for any glioma patients, but was reported for4 controls.No control for exposure to other occupational orenvironmental agents.

# AX6-205Table AX6-7.4 (cont’d). Other Studies of Lead Exposure and CancerReference, StudyLocation, and Period Study DescriptionPb Measurement Findings and InterpretationAsia(cont’d)Hu et al. (1999)China1989-1996Case-control design.Cases:383 patients with histologicallyconfirmed primary meningiomasoccurring during 1989-1996 at 6 Chinesehospitals.Controls:366 patients with non-neurological, nonmalignant diseasematched by age, gender, and residencefrom the same hospitals (excluding onecancer-only center).Patients were interviewed, andthose with factory or farmoccupations were furtherinterviewed to identifyexposure to Pb (or otherpotentially toxic substances).OR (95% CI); number of casesOccupational exposure to Pb:Male: 7.20 (1.00, 51.72); 6Female: 5.69 (1.39, 23.39); 10Results were adjusted for income, education, and fruit and vegetableintake, plus cigarette pack-yrs for the women. No control forexposure to additional metals orother occupational exposures.Shukla et al. (1998)India1995-1996Case-control design.Cases:38 patients with newlydiagnosed, histologically confirmed gallbladder cancer cases assembled from asurgical unit.Controls:58 patients with gall stonesdiagnosed at the same surgical unit,matched on geographic area.Mean bile Pb content was comparedbetween cases and controls.Heavy metal content wasmeasured in bile drawn fromthe gall bladder at time ofsurgery.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 elevated in cancer patients,but less than Pb. No control for smoking or any other risk factors.

# AX6-206 

# ANNEX TABLES AX6-8

# AX6-207Table AX6-8.1. Effects of Lead on Immune Function in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesJoseph et al. (2005)SE Michigan(1994-1998)Design: prospective (1 yr following 3-yrbaseline recruitment)Subjects: children (n = 4634), age range0.4–3.0 yrOutcome measures: asthma prevalence andincidence.Analysis: multivariate proportional hazardmodel (Cox)Blood Pb (μg/dL) mean(SD, median, % >10):5.5 (4.0, 4.0, 8.6%)Covariate-adjusted hazards ratio (HR, asthma incidence <5 μg/dLcompared to∃5 or∃10 μg /dL):Caucasian:∃5 μg/dL, 1.4 (95% CI: 0.7, 2.9)∃10 μg/dL, 1.1 (95% CI: 0.2, 8.4)African American:∃5 μg/dL, 1.0 (95% CI: 0.8, 1.3)∃10 μg/dL, 0.9 (95% CI: 0.5, 1.4)HR for asthma incidence in African Americans, compared toCaucasians (<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, birth weight, and gender.Sarasua et al. (2000)ATSDR Multi-siteStudy: Granite City,IL, Galena, KA; Joplin,MO; Palmerton, PA1991Design: cross-sectionalSubjects: children and adults (n = 2036)Outcome measures: total lymphocyte count,lymphocyte phenotype abundance, serumIgA, IgG, and IgM.Analysis: multivariate linear regressionBlood 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) between increasing blood Pb andincreasing serum IgA, IgG, IgM,and B-cell abundance (%, number),and decreasing T-cell abundance (%) in 6–35 mo age category;adjusted for age, sex, and studysite. Comparison of outcome meansacross blood Pb quartiles (1st quartile as reference, [+], higher, [−]lower): [+] lymphocyte count (4thquartile, p = 0.02), T-cell count(4th quartile, p = 0.09), B-cell count(4th quartile, p < 0.01), B-cell% (4th quartile, p = 0.09).Rabinowtiz et al. (1990)Boston, MA1979–1987Design: cross-sectionalSubjects: infants/children (n = 1768)Outcome measures: incidence of illness inchildren was solicited from parents byquestionnaire.Analysis: relative risk of illness estimatedfrom incidence ratios, highest: combinedlower blood Pb deciles, without adjustmentfor covariates or confounders.Cord blood Pb (μg/dL)~90th %: 10Shed tooth Pb (μg/g) ~90th%: 5Relative risk (unadjusted) was elevated for the following illnesscategories: severe incidence of earinfection, 1.2 (95% CI: 1.0, 1.4),other respiratory illness, 1.5 (95% CI: 1.0, 2.3), school absence forillness other than cold or flu, 1.3 (95% CI: 1.0, 1.5).

# AX6-208Table AX6-8.1 (cont’d). Effects of Lead on Immune Function in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited States(cont’d)Lutz et al. (1999)Springfield-Green Co,MONRDesign: cross-sectionalSubjects: children (n = 279; age range 9mo–6 yr)Outcome measures: differential blood cellcounts; lymphocyte phenotype abundance(%); and serum IL-4, soluble CD25, CD27,IgE and IgG (Rubella).Analysis: nonparametric comparison ofoutcome measures (adjusted for age) forblood Pb categories, correlationBlood Pb (μg/dL) range:1–45Blood Pb categories:<10 μg/dL, 10–14 μg/dL,15–19 μg/dL, 20–45 μg/dLSignificant association (p < 0.05) between increasing blood Pb(categorical) and increasing serum IgE levels, after adjusting for age.EuropeAnnesi-Maesano et al.(2003)France1985, 1992Design: cross-sectionalSubjects: mother/newborn pairs (n = 374),mean age 30 yrOutcome measures: maternal venous andnewborn cord serum IgE levelsAnalysis: multivariate linear regression,ANOVABlood 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) associationbetween increasing infant hairPb and infant cord serum IgE levels.Although medical histories were taken to identify potential IgE riskfactors (asthma, allergies) and“confounders” (e.g.,smoking), thesedo not appear to have been quantitatively integrated into theregression models. Allergy statusand blood levels were reportedlyunrelated to load biomarkers or serum IgE (basis for conclusion notreported).Karmaus et al. (2005)Germany1994–1997Design: cross-sectionalSubjects: children (n = 331, 57% male), age7–8 yrs (96%), 9–10 yrs (4%)Outcome measures: differential blood cellcount; lymphocyte phenotype abundance;and serum IgA, IgE, IgG, IgMAnalysis: multivariate linear regressionBlood 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 (p < 0.05) and serum IgE(not monotonic with quartile range).Comparison of adjusted meanoutcomes (p#0.05) across blood Pb quartiles (1st quartile asreference, [+], higher, [−] lower): [−] CD3+T-cells (2nd quartile),[−] C3+CD8+T-cells (2nd quartile), [+] C3+CD5+CD19+B-cells (2ndquartile).Covariates retained: age, sex, environmental exposure to tobaccosmoke, infections (in last 12mo), serum cholesterol, andtriglycerides.

# AX6-209Table AX6-8.1 (cont’d). Effects of Lead on Immune Function in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Reigart and Graber(1976)NRNRDesign: clinicalSubjects: children (n = 19), ages 4–6 yrsOutcome measures: serum IgA, IgG, IgM,total complement and C-3, before and afterimmunization with tetanus toxoidAnalysis: none; presentation of prevalenceof clinically low, normal, and high values ofoutcome measuresBlood 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 abnormal values for serumimmunoglobulin or complement (nostatistical analysis applied).Wagnerova et al. (1986)CzechNRDesign: longitudinal cohort (repeatedmeasures for 2-yrs)Subjects: children (n = 92, 38 females) ages11–13 yrs residing near a smelter; referencegroup (n = 67, 36 females), ages 11–13 yrsOutcome measures: serum IgA, IgE, IgG,IgMAnalysis: comparison of outcome measuresand between exposed and reference groups,stratified sex and season of samplingBlood Pb (μg/dL) mean:Pb: ~23–42Reference: ~5–22Significant (p NR, statistic NR) lower serum IgE and IgM levels inexposed group compared to reference group.Latin AmericaPineda-Zavaleta et al.(2004)MexicoNRDesign: cross-sectionalSubjects: children (n = 30 female, 35 male)ages 6–11 yrs, residing near smelterOutcome measures:mitogen- (PHA) andcytokine- (IFN-() induced nitric oxide andsuperoxide production in lymphocytesAnalysis: multivariate linear regressionBlood 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 between increasing blood Pbconcentration and covariate adjusted decreasing nitric oxideproduction in PHA-activated lymphocytes (∃=−0.00089 [95% CI:−0.0017,−0.00005]).Significant (p = 0.034) association between increasing blood Pbconcentration and covariate adjusted increasing super oxideproduction in IFN-(-activated lymphocytes (∃=−0.00389 [95% CI:0.00031, 0.00748]). Covariates considered included age, sex,allergies, and blood arsenic (age, sex, and blood arsenic wereretained).Significant effect of sex on associations, significant blood Pb-arsenicinteraction.Covariates considered included age, sex, allergies, urinary arsenic(age, sex, and urinary arsenic were retained).

# AX6-210Table AX6-8.1 (cont’d). Effects of Lead on Immune Function in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsiaSun et al. (2003); Zhaoet al. (2004)ChinaNRDesign: cross-sectionalSubjects: children (n = 73) age 3–6 yrsOutcome measures: serum IgE, IgG, IgM;lymphocyte phenotype abundanceAnalysis: Nonparametric comparisons ofoutcome measures stratified by blood PbBlood Pb (μg/dL) mean(SD, range) (n = 217):9.5 (5.6, 2.6–43.7)Females: significantly higher (p <0.05) IgE levels in high blood Pbcategory (∃10 μg/dL, n = 16) compared to low category (<10 μg/dL,n = 17), and significantly lower IgG and IgM levels. A multivariateanalysis of association between blood Pb and IgE was noted but notdescribed in sufficient detail to evaluate.All children: significantly lower (p < 0.05) CD3+CD4+(%),CD3+CD8+(%), CD4+CD8+(%) in high blood Pb (∃10 μg/dL,n = 38) compared to low blood Pb (10 μg/dL, n = 35) group.

# AX6-211Table AX6-8.2. Effects of Lead on Immune Function in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesPinkerton et al. (1998)U.S.NRDesign: cross-sectional cohortSubjects: adult male smelter workers(n = 145, mean age 32.9∀8.6); referencegroup, male hardware workers (n = 84, meanage 30.1∀9.3)Outcome measures: differential blood cellcounts; lymphocyte phenotype abundance;serum IgA, IgG, IgM; salivary IgA;lymphocyte proliferation (tetanus toxoid)Analysis: multivariate logistic regressionwith comparison of adjusted outcomemeasures between exposed and nonexposedgroupsBlood Pb (μg/dL) median(range)Pb: 39 (15–55)Reference: <2 (<2–12)Covariate-adjusted outcomes in Pbworkers that were significantly(p < 0.05) different from nonexposed ([+], higher, [−] lower): [−] %monocytes, [−] % CD4+CD8+cells, [−] % CD8+CD56+cells.Significant (p < 0.05) adjusted regression coefficients in exposedgroup for independent variable:blood Pb: [+] CD19+B-cells (%, no)time-integrated blood Pb: [−] serum IgG, [+] CD4+CD45RA+cells(%, number)Covariates considered in the analysis included age, race, smokinghabits, alcohol consumption, marijuana use, work shift, and variousfactors that might stimulate or suppress the immune system (e.g.,exposure to direct sunlight, sleep hrs,allergy, flu or cold symptoms).Covariates retained in the final model were age, race, work shift,smoking habits.Sarasua et al. (2000)ATSDR Multi-siteStudy: Granite City,IL, Galena, KA; Joplin,MO; Palmerton, PA1991Design: cross-sectional cohortSubjects: children and adults (n = 2036)Outcome measures: total lymphocyte count,lymphocyte phenotype abundance, serumIgA, IgG, and IgMAnalysis: multivariate linear regressionBlood 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) between blood Pb andoutcomes in adults (age∃16 yr).Covariates retained: age, sex,cigarette smoking, and study site.

# AX6-212Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited States(cont’d)Fischbein et al. (1993)New YorkNRDesign: cross-sectional cohortSubjects: adult firearms instructors (n = 51),mean age 48 yr; age-matched referencesubjects (n = 36).Outcome measures:lymphocyte phenotypeabundance, lymphocyte proliferation (PHA,PWM,Staph. aureus)Analysis: comparison of outcome measuresbetween reference and blood Pb categories;multivariate linear regressionBlood Pb (μg/dL) mean(SD)Pb high (∃25): 31.4 (4.3)Pb low (<25): 14.6 (4.6)Reference: <10Outcomes in Pb workers that were significantly (p < 0.05) differentfrom reference group ([+], higher, [−] lower):[−] CD+3cells (%, number), [−] CD4+cells (%, number), [−]CD4+CD8+cells (number), [−] HLA-DR cells (number), [+] CD20+cells (%, number), [−] mitogen (PHA)-induced lymphocyteproliferation, [−] mitogen (PWM)-induced lymphocyte proliferation;[−] lymphocyte response in mixed-lymphocyte culture. No effect onantigen (Staph. aureus)-induced lymphocyte proliferation.Significant (p < 0.05) association between increasing blood Pb anddecreasing abundance of CD4+phenotypes (%), and decreasinglymphocyte proliferative response in mixed lymphocyte cultures.Covariates retained: age, sex,smoking habits, and duration ofexposure.EuropeBergeret et al. (1990)FranceNRDesign: cross-sectional cohortSubjects: 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 NSAIDsOutcome measures: PMN chemotaxis(FMLP); PMN phagocytosis (opsonizedzymosan)Analysis: comparison of outcome measuresbetween worker and reference groupsBlood Pb (μg/dL) mean(SD):Pb: 70.6 (18)Reference: 9.0 (4.3)Significantly (p < 0.05) lower PMN chemotactic response (index)and phagocytic response in Pb workers.

# AX6-213Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Ewers et al. (1982)GermanyNRDesign: cross-sectional cohortSubjects: adult malebattery manufacture orsmelter workers (n = 72), mean age 36.4 yr(16–58); reference workers (n = 53), meanage 34.8 yr (21–54)Outcome measures: serum IgA, IgG, IgM,C3; saliva IgAAnalysis: parametric and nonparametriccomparison of outcome measures betweenPb workers and reference subjects; linearregressionBlood 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, lower salivary IgA in Pbworkers compared to reference group.Coscia et al. (1987)ItalyNRDesign: cross-sectional cohortSubjects: adult Pb workers (n = 32, 2female), 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 abundanceAnalysis: parametric comparison ofoutcome measures between worker andreference groupsBlood Pb (μg/dL) mean(SD):Pb: 62.3 (21.6)Reference: NROutcomes in Pb workers that were significantly (p < 0.05) differentfrom reference group ([+], higher, [−] lower): [−] serum IgM, [+]serum C4, [+] lymphocyte abundance (%), [−] T-cell abundance (%,number, E-rosette forming cells), [+] B-cellabundance (%,number,immunoglobulin-bearing cells), [+] CD8+cell abundance (number).Governa et al. (1987)ItalyNRDesign: cross-sectional cohortSubjects: adult male battery manufactureworkers (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 ofoutcome measures between worker andreference groups, correlationBlood Pb (μg/dL) mean(SD):Pb: 63.2 (8.2)Reference: 19.2 (6.4)Significantly (p < 0.05) lowerPMN chemotactic response tozymosan activated serum. Effect magnitude was not correlated withblood Pb.

# AX6-214Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEurope(cont’d)Valentino et al. (1991)ItalyNRDesign: cross-sectional cohortSubjects: adult male Pb scrap refiningworkers (n = 10), mean age 41.1 yr (SD 7.3,range 28–54); age-matched referencesubjects (n = 10)Outcome measures: PMN chemotaxis (C5 orFMLP) and phagocytosis (FMLP)Analysis: comparison of outcome measuresbetween worker and reference groups,correlationBlood 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 PMNchemotactic response to C5 orFMLP and higher stimulated production of LT (leukotriene)B4 in Pbworkers compared to reference group. Effect magnitude correlatedwith blood Pb. No effect on phagocytic activity.Kimber et al. (1986)UKNRDesign: cross-sectional cohortSubjects: adult male TEL manufactureworkers (n = 39) mean age: 45.1 yr; andage-matched reference subjects (n = 21);mean age 32.2 yrOutcome measures: serum IgA, IgG, IgM;mitogen (PHA)-inducedlymphoblastogenesis; and NK cellcytotoxicityAnalysis: comparison of outcome measuresfor exposed and reference groupsBlood 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 outcomes between exposedand reference groups.Latin AmericaQueiroz et al. (1993)BrazilNRDesign: cross-sectional cohortSubjects: adult male battery manufactureworkers (n = 39), mean age 33.9 yr (SD 12.1,range 18–56); reference subjects (n = 39)matched by age and raceOutcome measures: PMN chemotaxis(endotoxin LPS); phagocytic (endotoxinLPS) respiratory burst activity (NBTreduction)Analysis: nonparametric comparison ofoutcome measures between worker andreference groupsBlood Pb (μg/dL) range:Pb: 14.8–91.4 (>30,n = 52)Reference: <10Significantly (p < 0.001) lower chemotactic activity of PMNs, andlower phagocytic respiratory burst, in Pb workers relative toreference group.

# AX6-215Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationLatin America(cont’d)Queiroz et al. (1994a)BrazilNRDesign: cross-sectional cohortSubjects: adult male battery manufactureworkers (n = 60), mean age 33.9 yr (range18–56); reference subjects (n = 49) matchedby age and raceOutcome measures: PMN phagocytic/lyticactivity (opsonized yeast)Analysis: nonparametric comparison ofoutcome measures between worker andreference groupsBlood Pb (μg/dL) range:Pb: 14.8–91.4 (>30,n = 27)Reference: <10Significantly (p < 0.001) lower lytic activity of PMNs in Pb workersrelative to reference group.Queiroz et al. (1994b)BrazilNRDesign: cross-sectional cohortSubjects: adult male battery manufactureworkers (n = 33), mean age 32.4 yr (range18–56); reference subjects (n = 20) matchedby age and raceOutcome measures: serum IgA, IgG, IgM;mitogen (PHA)-induced lymphocyteproliferationAnalysis: parametric comparison ofoutcome measures between worker andreference groupsBlood Pb (μg/dL) range:Pb: 12.0–80.0 (>30,n = 27)Reference: <10No significant difference in outcomes(p < NR; SD of Pb worker andreference groups overlap) between Pbworkers and reference group.AsiaKuo et al. (2001)ChinaNRDesign: cross-sectional cohortSubjects: adult battery manufacture workers(n = 64, 21 female) 14 subject aged <40 yrand 14 subjects aged >50 yr; nonexposedreference subjects (n= 34, 17 female).Outcome measures: differential blood cellcounts, lymphocyte phenotype abundanceAnalysis: comparison of outcome measuresin exposed and reference groups,multivariate linear regressionBlood Pb (μg/dL) mean:Pb: 30Significantly (p < 0.05) adjusted mean higher monocytes (%,number), lower B cells (%), lowerlymphocytes (number), and lowergranulocytes (number) in Pb workers compared to controls.Covariates retained: age, gender,and disease status (definition notreported).

# AX6-216Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Mishra et al. (2003)IndiaNRDesign: cross-sectional cohortSubjects: adult males occupationallyexposed to Pb (n = 84), mean age 30 yr;reference subjects (n = 30), mean age 29 yrOutcome measures: serum IFN-(level,mitogen (PHA)-induced lymphocyteproliferation, NK cell cytotoxicityAnalysis: comparison of outcome measuresbetween Pb-exposed and reference groups,correlationBlood 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 lymphocyte proliferative response toPHA in Pb-exposed groups compared to reference groups, higherIFN-(production by blood monocytes.Alomran andShleamoon (1988)IraqNRDesign: cross-sectional cohortSubjects: adult Pb (oxide) workers (n = 39),mean age 35.6 yr (9,2, SD); age-matchedreference subjects (n = 19)Outcome measures: serum IgA, IgG;mitogen (PHA, Con-A)-induced lymphocyteproliferationAnalysis: comparison of outcome measuresbetween Pb workers and reference groupBlood Pb (μg/dL) mean:Pb: 54–64Reference: NRSignificantly (p < 0.05) lower lymphocyte proliferative response toPHA or Con A in Pb workers, compared to reference group.Cohen et al. (1989)IsraelNRDesign: cross-sectional cohortSubjects: adult male occupationally Pbexposed (n = 10), age range 22–70; agematched reference subjects (n = 10)Outcome measures: mitogen (Con A, PHA)-induced-lymphocyte proliferation and Tsuppressor cell proliferation; lymphocytephenotype abundanceAnalysis: parametric comparison ofoutcome means between Pb-exposed andreference groupsBlood Pb (μg/dL) range:Exposed: 40–51Reference: <19Significantly (p < 0.02) highermitogen (Con-A)-induced suppressorcell activity. No significant (p not reported) effects on abundance ofT-cells (E-rosette-forming cells), OKT+4, OKT+8, or OKT4+/T8+ratio; mitogen (Con A or PHA)-induced lymphocyte proliferation.

# AX6-217Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Sata et al. (1998)JapanNRDesign: cross-sectional cohortSubjects: adult male Pb stearate manufactureworkers (n = 71), mean age 48 yr (range 24–74); reference subjects (n = 28), mean age 55yr (range 33–67).Outcome measures:lymphocyte phenotypeabundanceAnalysis: comparison of outcome measuresin exposed and reference groups(ANCOVA), multivariate linear regressionBlood Pb (μg/dL) mean(range):Pb: 19 (7–50)Reference: NRPb workers vs. reference: significantly (p < 0.05) covariate-adjustedlower CD3+CD45RO+(number) and higher CD8+cells (%).Significant (p < 0.05) associationbetween exposure(categorical:yes/no) and lower CD3+CD45RO+cells (number).Covariates retained: ageand cigarette smoking habits.Sata et al. (1997)JapanNRDesign: clinicalSubjects: adult male Pb smelter workers(n = 2) who underwent CaEDTA therapyOutcome measures: serum IgA, IgG, IgD,IgM; lymphocyte phenotype abundanceAnalysis: Parametric comparison ofoutcome measures before and aftertreatment, correlation of outcome means withblood PbBlood Pb (μg/dL):Subject 1: 81 μg/dL atreferral; mean beforeEDTA: 45.1 (SD 16.0);after chelation: 31.0 (9.8)Subject 2: 68 μg/dL atreferral; mean beforeEDTA: 43.3 (SD 14.1);after chelation: 33.7 (7.2)Blood Pb and outcome measures were sampled prior to and 24 hrsafter 3 CaEDTA treatments (onconsecutive days) per wk for 10wks. Comparison of mean outcome measures assessed before andafter treatments showed significantly(p < 0.05) higher IgA, IgG, andIgM; and significantly higher CD8+T-cells and CD57+NK cellsafter treatment in subject 1. Serum IgG levels in subject 1 weresignificantly correlated (r =−0.72) with blood Pb concentration.Heo et al. (2004)KoreaNRDesign: cross-sectional cohortSubjects: adults, battery manufactureworkers (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 PbBlood 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 levels in blood Pbcategory (∃30 μg/dL) compared to low categories (<10 or 10–29 μg/dL).

# AX6-218Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Ünde er et al. (1996);Ba∏aran and Ünde er(2000)TurkeyNRDesign: cross-sectional cohortSubjects: adult male battery manufactureworkers (n = 25), mean age, 33 yr (22–55);reference subjects (n = 25) mean age 33 yr(22–56).Outcome measures: differential blood cellcounts; lymphocyte phenotype abundance;serum IgA, IgG, IgM, C3, and C4; neutrophilchemotaxis (zymosan-activated serum); latexparticle-induced neutrophil phagocytic (latexparticles) respiratoryburst (NBT reduction)Analysis: nonparametric and parametriccomparisons of outcome measures forexposed and reference groupsBlood Pb (μg/dL) mean(SD):Pb: 74.8 (17.8)Reference: 16.7 (5.0)Workers relative to reference: significantly (p < 0.05) lower serumIgG, IgM, C3, and C4 levels; lower CD4+(“T-helper”) abundance,lower neutrophil chemotactic response; no significant difference inCD20+(B-cell) , CD8+(“T-suppressor”) cell, CD56+(NK) cellabundance, or particle-induced NK cell respiratory burst.Yücesoy et al. (1997a)TurkeyNRDesign: cross-sectional cohortSubjects: adult male battery manufactureworkers (n = 20), ages 39–48 yr; agematched reference subjects (n = 12)Outcome measures: serum cytokines IL-1∃,IL-2, TNF∀, IFN-(Analysis: parametric and nonparametriccomparison of outcomemeasures in exposedand reference groupsBlood 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∃and IFN-(levels in Pbworkers compared to controls.Yücesoy et al. (1997b)TurkeyNRDesign: cross-sectional cohortSubjects: adult male battery manufactureworkers (n = 50), ages 39–48 yr; agematched reference subjects (n = 10)Outcome measures:lymphocyte phenotypeabundance, NK cell cytotoxicityAnalysis: comparison of outcome measuresin exposed and reference groupsBlood 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-cell (%) abundance in Pbworkers compared to controls, no difference in % CD4+T-cellabundance.

# AX6-219Table AX6-8.2 (cont’d). Effects of Lead on Immune Function in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAfricaAnetor and Adeniyi(1998)NigeriaNRDesign: cross-sectional cohortSubjects: adult male “Pb workers” (n = 80),mean age, 36 yr (21–66) and referencesubjects (n = 50), mean age 37 yr (22–58).Outcome measures: serum IgA, IgG, andIgM; lymphocyte countAnalysis: comparison of outcomes measuresin workers and reference group, linearregression, principal component analysisBlood Pb (μg/dL) mean(SE):Pb: 53.6 (0.95)Reference: 30.4 (1.4)Significantly lower (p < 0.05) serum IgA, IgG, and total bloodlymphocyte levels; significant associations and interactions betweenblood Pb and serum total globulins (note high blood Pb levels inreference).

# AX6-220 

# ANNEX TABLES AX6-9

# AX6-221Table AX6-9.1. Effects of Lead onBiochemical Effects in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesMarcus and Schwartz(1987)U.S.1976–1980Design: 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 variablesAnalysis: nonlinear least squares regressionBlood Pb (μg/dL) range:6-65Non-linear regression used to fit kinetic model relating blood Pbto EP, in strata having low (<14%), medium (14-31%), or high(>31%) percent transferrin saturation (PST). Parameters in modelincluded: parameters for total red cell surface area, maximum redcell Pb concentration, equilibrium concentration ratio for plasmaand whole blood. Blood Pb increase (from 10 μg/dL) predicted todouble EP: 22 (PST < 14%), 24 (PST = 14-31%), 37(PST > 31%).Piomelli et al. (1982)New York1976Design: cross-sectionalSubjects: children (n = 2002), ages 2–12 yrOutcome measures: EPAnalysis: linear regressionBlood Pb (μg/dL) range:2–98Regression equation relating blood Pb concentration to EP(log-transformed):∀= 1.099,∃= 0.016, r = 0.509, p < 0.001Threshold for increase in EP estimated to be: 15.4 μg/dL (95%CI: 12.9, 18.2)Soldin et al. (2003)Washington DC2001–2002Design: cross-sectionalSubjects: children (n = 4908, 1812 females),age range 0–17 yrOutcome measures: EPAnalysis: locally weighted scatter plotsmoother (LOWESS)Blood Pb (μg/dL):Mean (range 1–17 yr):2.2–3.3Median (1–17 yr): 3Range: <1–103EP increases as blood Pb concentration increased above15 mg/dL. A doubling of EP occurred with an increase in bloodPb concentration of ~20 μg/dL (apolynomial expression for EP asa function of blood Pb (PbB) is:EP =−0.0015(blood Pb)3+ 0.1854(blood Pb)2−2.7554(blood Pb)+ 30.911 (r2= 0.9986)(derived from data in Table 2 of Soldin et al. (2003)EuropeRoels and Lauwerys(1987)Belgium1974–1980Design: cross-sectionalSubjects: children (n = 143), age range10–13 yrOutcome measures: ALAD, urinary ALA, EPAnalysis: linear regression, correlationBlood Pb (μg/dL) range:15–41Linear regression for EP (log-transformed) and blood Pbconcentration:∀= 1.321,∃= 0.025, r = 0.73 (n = 51)Linear regression for ALA (log-transformed) and blood Pbconcentration:∀= 0.94,∃= 0.11, r = 0.54 (n = 37)Linear regression for ALAD (log-transformed) and blood Pbconcentration:∀= 1.864,∃=−0.015, r =−0.87 (n = 143)

# AX6-222Table AX6-9.1 (cont’d). Effects of Lead on BiochemicalEffects in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationLatin AmericaPerez-Bravo et al.(2004)ChileNRDesign: cross-sectional;Subjects: children (n = 93, 43 males), aged 5-12 yrs who attended school near a powdered Pbstorage facilityOutcome measures: blood Hgb and Hct, ALADgenotypeAnalysis: comparison of outcome measuresbetween ALAD genotype strataBlood 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 different between ALADgenotypes (p = 0.13).

# AX6-223Table AX6-9.2. Effects of Lead onBiochemical Effects in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEuropeGennart et al. (1992)BelgiumNRDesign: cross-sectional cohortSubjects: 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 ALAAnalysis: linear regressionBlood 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 increasing blood Pb concentrationand increasing (log) blood EP (∀= 0.06,∃= 0.019, r = 0.87,p = 0.0001) or (log) urine ALA (∀= 0.37,∃= 0.008, r = 0.64,p < 0.0001)(No apparent analysis of covariables)Mohammed-Brahimet al. (1985)BelgiumNRDesign: cross-sectional cohortSubjects: adult smelter and ceramicsmanufacture workers (n = 38, 13 females);reference subjects (n= 100) matched withworker group by age, sex, and socioeconomicstatus.Outcome measures: blood P5N, EP, ALAD,R/ALAD (ratio of ALADbefore and afterreactivation).Analysis: comparison of outcome measures(ANOVA) between Pb workers and referencegroup; correlationBlood 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 workers (males or females,or combined) compared to corresponding reference groups.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)Roels and Lauwerys(1987)Belgium1974–1980Design: cross-sectionalSubjects: adults (n = 75, 36 females)Outcome measures: ALAD, urinary ALA, EPAnalysis: linear regression, correlationBlood Pb (μg/dL) range:adult males: 10–60adult females: 7–53Linear regression for EP (log-transformed) and blood Pbconcentration:adult male (n = 39):∀= 1.41,∃= 0.014, r = 0.74, p < 0.001adult female (n = 36):∀= 1.23,∃= 0.027, r = 0.81, p < 0.001Linear regression for ALA (log-transformed) and blood Pbconcentration:adult male (n = 39):∀= 0.37,∃= 0.006, r = 0.41, p < 0.01adult female (n = 36):∀= 0.15,∃= 0.015, r = 0.72, p < 0.001

# AX6-224Table 6-9.2 (cont’d). Effects of Leadon Biochemical Effects in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Grandjean (1979)DenmarkNRDesign: longitudinalSubjects: male battery manufacture workers(n = 19), mean age 32 yr (range 22–49)Outcome measures: EPAnalysis: EP and blood Pb for serialmeasurements displayed graphicallyBlood 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) showeddeclines in EPwith decliningblood Pb (33–58 μg/dL) over a 10-mo period; 5 subjects (group 2)showed no change in EP with achange in blood Pb concentration(25–54 μg/dL) over the same period.Alessio et al. (1976)ItalyNRDesign: cross-sectionalSubjects: adult male Pb worker (n = 316), agerange NROutcome measures: blood ALAD, EP, urineALA, CPAnalysis: linear regression, correlationBlood Pb (μg/dL) range:10–150Regression relating outcomes to blood Pb concentration:ALAD (ln-transformed) (n = 169):∀= 3.73,∃=−0.031, r = 0.871ALAU (ln-transformed) (n = 316):∀= 1.25,∃= 0.014, r = 0.622UCP (ln-transformed) (n = 252):∀= 2.18,∃= 0.34, r = 0.670EP (log-transformed (males, n = 95):∀= 0.94,∃= 0.0117EP (log-transformed (females, n = 93):∀= 1.60,∃= 0.0143Cocco et al. (1995)Italy1990Design: longitudinalSubjects: adult male foundry workers(n = 40), mean age 25.1 yr (SD 2.1, range21–28)Outcome measures: serum total-, HDL- andLDL-cholesterol, blood Hgb, urine ALA,erythrocyte G6PDAnalysis: comparison of outcomes betweenpre-exposure (at start of employment,sample 1) and after 172 (range 138–217,sample 2) daysBlood Pb (μg/dL) mean(range):Sample 1: 10.0 (7–15)Sample 2: 32.7 (20–51)G6PD levels were unrelated to starting blood Pb; however, theyincreased in subjects whose bloodPb concentration increased from<30 μg/dL to >30 μg/dL or decreased from >30 μg/dL to<30 μg/dL. Increasing exposure duration was significantlyassociated with decreasing magnitude of change in G6PD.Sample 1 <30 μg/dL:∃=−0.3980 (SE 0.1761), p < 0.05Sample 1 >30 μg/dL:∃=−1.3148 (SE 0.3472), p < 0.05In the >30 μg/dL subgroup, increasing blood Pb was associatedwith decreasing magnitude of change of G6PD (∃=−2.0797 [SE0.7173], p < 0.05).Serum cholesterol levels were unrelated to blood Pb concentration.

# AX6-225Table 6-9.2 (cont’d). Effects of Leadon Biochemical Effects in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Fracasso et al. (2002)ItalyNRDesign: cross-sectional cohortSubjects: 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 strandbreaks, ROS, GSHAnalysis: comparison of outcome measuresbetween Pb workers and reference group(ANOVA), logistic regressionBlood Pb (μg/dL) mean(SD):Pb: 39.6 (7.6)Reference: 4.4 (8.6)Covariate-adjusted DNA strand breaks were significantly higher inPb workers compared to the reference group andsignificantlyassociated with increased blood Pb (p = 0.011).Covariate-adjusted lymphocyte ROS was significantly higher andGSH significantly lower in the Pb workers compared to thereference group. Lower GSH levelswere significantly associatedwith increasing blood Pb concentration (p = 0.006).Odds ratios (OR) for DNA strandbreaks and lower GSH levelswere significant (Pb workers vs. reference):DNA strand breaks: OR = 1.069 (95% CI: 1.020, 1.120),p = 0.005GSH: OR = 0.634 (95% CI: 0.488, 0.824), p = 0.001ROS: OR = 1.430 (95% CI: 0.787, 2.596), p = 0.855Covariates retained: age, alcohol consumption and tobaccosmoking.Hernberg et al. (1970)PolandNRDesign: cross-sectionalSubjects: adult Pb workers (n = 166);reference group (n = 16)Outcome measures: blood ALADAnalysis: regression, correlationBlood Pb (μg/dL) range:5–95Linear regression for blood ALAD (log-transformed) and blood Pbconcentration (n = 158):∀= 2.274,∃=−0.018, r =−0.90, p < 0.001Bergdahl et al. (1997)SwedenNRDesign: cross-sectionalSubjects: adult smelter worker (n = 89);reference groups (n = 24)Outcome measures: blood Pb, erythrocyteALAD-bound Pb, ALAD genotypeAnalysis: comparison of outcome measuresBlood Pb (μg/dL) range:0.8–93Urine Pb (mg/L) range:1–112Bone Pb (μg/g) range:−19–101No association between ALAD genotype and Pb measures.Selander and Cramθr(1970)SwedenNRDesign: cross-sectionalSubjects: adult battery manufacture workers(n = 177)Outcome measures: urine ALAAnalysis: regression, correlationBlood Pb (μg/dL) range:6–90Linear regression for urine ALA (log-transformed) and blood Pbconcentration (n = 150):∀=−1.0985,∃= 0.0157, r = 0.74

# AX6-226Table 6-9.2 (cont’d). Effects of Leadon Biochemical Effects in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Wildt et al. (1987)SwedenNRDesign: longitudinalSubjects: adult battery manufacture workers(n = 234, 37 females) mean age 35 y (range17–70); reference group (n = 951, 471females), mean age 39 yr (range 19–67)Outcome measures: EPAnalysis: analysis ofvariability over time,linear regression, correlationBlood Pb (μg/dL) mean(range):Pb: 10–80Reference:Male: 11.3 (8–27)Female: 8.5 (5–21)Linear regression for EP (log-transformed) and blood Pbconcentration:Males (n = 851):∀= 1.21,∃= 0.0148, r = 0.72Females (n = 139):∀= 1.48,∃= 0.0113, r = 0.56AsiaHsieh et al. (2000)ChinaNRDesign: cross-sectionalSubjects: Adults in general population(n = 630, 255 females)Outcome measures:blood Hgb, Hct, RBCcount, ALAD genotypeAnalysis: comparison of outcome measuresbetween ALAD genotype strataBlood 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 ALAD genotype strata(p = 0.17). RBC count, Hgb, Hct not different between ALADgenotype strata (p = 0.7)Jiun and Hsien (1994)China1992Design: longitudinalSubjects: adult male Pb workers (n = 62),ages NR; reference group (n = 62, 40 females),ages NROutcome measures: plasma MDAAnalysis: comparison of outcome measuresbetween Pb workers and reference group,linear regressionBlood 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 < 0.0001) higher (~2x) in Pbworkers whose blood Pb concentration 35 μg/dL compared to#30 μg/dL. In subjects with blood Pb >35 μg/dL, blood Pb andplasma MDA were significantly correlated:blood Pb = 9.584(MDA) + 24.412 (r = 0.85)Froom et al. (1999)Israel1980–1993Design: longitudinal surveySubjects: adult malebattery manufacturingworkers (n = 94), mean age, 38 yr (SD 9,range 26–60)Outcome measures:blood Hgb, blood EPAnalysis: multivariate linear regressionBlood Pb (μg/dL) range of13-yr individual subjectmeans:20–61 μg/dLWeak (and probably not significant) covariate-adjusted associationbetween blood Hgb and individual sample blood Pb (∃=−0.0039[SE 0.0002]), subject avg blood Pb (∃=−0.0027 [SE 0.0036]), orblood EP (∃=−0.001 [SE 0.0007])Covariates retained in model were age andsmoking habits.

# AX6-227Table 6-9.2 (cont’d). Effects of Leadon Biochemical Effects in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Kristal-Boneh et al.(1999)Israel1994–1995Design: cross-sectional cohortSubjects: adult male battery manufactureworkers (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, triglyceridesAnalysis: comparison of outcome measuresbetween Pb workers and reference group(ANOVA), multivariate linear regressionBlood Pb (μg/dL) mean(SD):Pb: 42.3 (14.9)Reference: 2.7 (3.6)Covariate-adjusted serum total-cholesterol (p = 0.016) and HDL-cholesterol (p = 0.001) levelswere significantly higher in Pbworkers compared to reference group. Covariates retained inANOVA: age, body mass index,season of sampling, nutritionalvariables (dietary fat, cholesterol, calcium intakes), sport activities,alcohol consumption, cigarette smoking, education, job seniority.Increasing blood Pb concentration was significantly associatedwith covariate-adjusted total cholesterol (∃= 0.130 [SE 0.054],p = 0.017) and HDL-cholesterol (∃= 0.543 [SE 0.173], p = 0.002).Covariates retained: age, body mass index. Stepwise inclusion ofother potential confounders had no effect.Solliway et al. (1996)IsraelNRDesign: cross-sectional cohortSubjects: adult male battery manufactureworkers (n = 34), mean age: 44 yr (SD 13);reference subjects (n = 56), mean age 43 yr(SD 12); cohorts constructed to have similarage, ethnic characteristics, socioeconomicstatus, education level, and occupationOutcome measures: urinary ALA, erythrocyteGSH-peroxidaseAnalysis: parametric comparison of outcomemeasures between Pband reference groups,correlationBlood Pb (μg/dL) mean(SD, range):Pb: 40.7 (9.8, 23–63)Reference: 6.7 (2.4, 1–13)Significantly lower mean erythrocyte GSH-peroxidase activity(p < 0.005) in and higher urinary ALA (p < 0.001) in Pb workerscompared to reference group.Ito et al. (1985)JapanNRDesign: cross-sectional cohortSubjects: adult male steel (smelting, casting)workers (n = 712), age range 18–59 yr;reference (office workers) group (n = 155,total), age range 40–59 yrOutcome measures: serum LPO and SOD,total and HDL-cholesterol, phospholipidAnalysis: comparison of outcome measuresbetween Pb workers and reference group,correlationBlood Pb (μg/dL) range:Pb: 5–62Reference: NRWhen stratified by age, significantly (p < 0.05) higher serum HDLcholesterol and LPO in Pb workers, age range 40–49 yr, comparedto corresponding strata of reference group. Serum lipoperoxidelevels increased as blood Pb increased above 30 μg/dL (p = NR),SOD appeared to decrease with increasing blood Pb concentration(p = NR)

# AX6-228Table 6-9.2 (cont’d). Effects of Leadon Biochemical Effects in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Makino et al. (1997)Japan1990–1994Design: longitudinal surveySubjects: adult male pigment or vinyl chloridestabilizer manufacture workers (n = 1573)mean age 45 yrOutcome measures:blood Hgb, Hct,RBC countAnalysis: parametric comparison of outcomemeasures, stratified by blood Pb, linearregressionBlood 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, blood Hgb and RBC count inblood Pb category 16–39 μg/dL, compared to 1–15 μg/dLcategory.Significant positive correlation between blood Pb concentrationand Hct:∀= 42.95,∃= 0.0586 (r = 0.1553, p < 0.001), bloodHgb:∀= 14.65,∃= 0.0265 (r = 0.1835, p < 0.001) and RBCcount∀= 457,∃= 0.7120 (r = 0.1408, p < 0.001).Morita et al. (1997)JapanNRDesign: cross-sectional cohortSubjects: male Pb workers (n = 76), mean age42 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, ALADAnalysis: comparison of outcome measures(ANOVA) between blood Pb categories, linearregressionBlood Pb (μg/dL) mean(SD, range)Pb: 34.6 (20.7, 2.2–81.6)Significantly lower (p < 0.01) blood NADS and ALAD in blood Pbcategories >20 μg/dL compared to <20 μg/dL, with dose trend inmagnitude of difference.Significant associations between increasing blood Pb anddecreasing blood NADS andALAD in Pb workers:NADS:∀= 0.843,∃=−0.00971, r =−0.867, p < 0.001, n = 76log ALAD:∀= 1.8535,∃=−0.015, r =−0.916, p < 0.001, n = 58Oishi et al. (1996)JapanNRDesign: cross-sectionalSubjects: adult glass and pigment manufactureworkers (n = 418, 165 females), mean age 33yr (range 18–58); reference workers (n = 227,89 females), mean age 30 yr (range 17–59)Outcome measures: plasma ALA, urinaryALAAnalysis: linear regression, correlationBlood Pb (μg/dL) mean(SD, range):Pb: 48.5 (17.0, 10.3–99.4Reference: 9.6 (3.3, 3.8–20.4)Significant correlation between bloodPb concentration and plasmaand urinary ALA (both log-transformed):Plasma ALA:∀= 0.327,∃= 0.022, r = 0.742Urinary ALA:∀=−0.387,∃= 0.022, r = 0.711Significant correlation between plasma and urinary ALA:∀= 6.038,∃= 4.962, r = 0.897

# AX6-229Table 6-9.2 (cont’d). Effects of Leadon Biochemical Effects in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationAsia(cont’d)Sugawara et al. (1991)JapanNRDesign: cross-sectional cohortSubjects: adult Pb workers and referencegroup (n = 32, total), ages NROutcome measures: plasma and erythrocytelipoperoxide and SOD; erythrocyte CAT,GSH, and methemoglobinAnalysis: comparisons of outcome measuresbetween Pb workers and reference group,linear regression and correlationBlood Pb (μg/dL) mean(SD, range):Pb: 57.1 (17.6, 20–96)Reference: NRSignificantly (p < 0.01) higher erythrocyte LPO and lower SOD,CAT and GSH levels in workers compared to reference group.Erythrocyte lipoperoxide (r = 0.656) and GSH (r =−0.631) weresignificantly correlated with blood Pb.Kim et al. (2002)Korea1996Design: cross-sectional cohortSubjects: adult male secondary Pb smelterworkers (n = 83), mean age: 38.7 yr (SD10.8); reference subjects (n = 24), mean age:32.0 (SD 10.8)Outcome measures:blood Hgb, blood ALAD,blood EP, blood P5NAnalysis: parametric comparison (ANOVA)of outcome measures between Pb workers andreference group, correlation, multivariatelinear regressionBlood Pb (μg/dL) mean(SD)Pb: 52.4 (17.7)Reference: 6.2 (2.8)Significantly (p < 0.05) lowerblood P5N, ALAD, and Hgb; andhigher blood EP in Pb workers compared to controls.Significant (p < 0.001) correlations (in Pb worker group) withblood Pb: P5N (r =−0.704), log EP (r = 0.678), log ALAD(r =−0.622).Significant association between increasing EP and decreasingblood Hgb:blood Pb∃60 μg/dL:∃=−1.546 (95% CI:−2.387,−0.704),r2= 0.513, p = 0.001blood Pb <60 μg/dL:∃=−1.036 (95% CI:−1.712,−0.361),r2= 0.177, p = 0.003Significant association between increasing P5N and increasingblood Hgb (high blood Pb group only):blood Pb∃60 μg/dL:∃= 0.222 (95% CI: 0.015, 0.419),r2= 0.513, p = 0.036Covariates included in model: P5N, log serum ferritin, log EPLee et al. (2000)KoreaNRDesign: cross-sectional cohortSubjects: adult male Pb workers (n = 95;secondary smelter,PVC-stabilizermanufacture, battery manufacture); mean age42.8 yr (SD 9.3, range 19–64); reference group(n = 13), mean age 35.1 yr (SD 9.9, range22–54)Outcome measures: urinary ALA, EPAnalysis: correlationBlood 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 betweenincreasing DMSA-provokedurinary Pb and urinary ALA (r = 0.31, p < 0.002) and EP (r = 0.35,p < 0.001).

# AX6-230Table 6-9.2 (cont’d). Effects of Leadon Biochemical Effects in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationAsia(cont’d)Schwartz et al. (1997)Korea1994-1995Design: cross-sectionalSubjects: adult male battery manufactureworkers (n = 57), mean age 32 yrs (SD 6).Outcome measures: blood Hgb, HgbA1, andHgbA2, ALAD genotypeAnalysis: comparison of outcome measuresbetween ALAD genotype strataBlood 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 levels (p = 0.34) werenot different between ALAD genotype strata.Gurer-Orhan et al.(2004)TurkeyNRDesign: cross-sectional cohortSubjects: adult male battery manufactureworkers (n = 20), mean age 35 yr (SD 8);reference workers (n = 16), mean age32 yr (SD 9)Outcome measures: blood ALAD, EP,erythrocyte MDA, CAT, G6PD, bloodGSH:GSSGAnalysis: comparison of outcome measuresbetween Pb workers and reference group,correlationBlood Pb (μg/dL) mean(SD):Pb: 54.6 (17)Reference: 11.8 (3.2)Significant correlation between blood Pb concentration and bloodALAD (r = -0.85, p < 0.0001) and EP (r = 0.83, p < 0.001).Significant correlation betweenblood Pb concentration anderythrocyte MDA (r = 0.80, p = <0.0001), erythrocyte G6PD(r = 0.70, p < 0.0001, erythrocyte CAT (r = 0.62, p < 0.001), bloodGSH (r = 0.64, p < 0.0005), blood GSSG (r = 0.67, p < 0.0001).GSH: GSSG ratio lower (p = NR) in Pb workers (3.2), comparedto controls (8.0).Süzen et al. (2003)TurkeyNRDesign: cross-sectionalSubjects: Male Pb battery manufactureworkers (n = 72), age range 24-45 yrs.Outcome measures: blood ALAD, urine ALA,ALAD genotypeAnalysis: comparison of outcome measuresbetween ALAD genotype strataBlood 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) and blood ALAD activity(p = 0.33) were not differentbetween ALAD genotype strata.Mean urinary ALA was significantly higher (p < 0.05) in theALAD1,1 stratum.

# AX6-231Table AX6-9.3. Effects of Lead onHematopoietic System in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesLiebelt et al. (1999)ConnecticutNRDesign: cross-sectionalSubjects: children (n =86, 31 female), ages1–6 yrOutcome measures: serum EPO, blood HgbAnalysis: ANOVA of outcome measuresstratified by blood Pb, linear regressionBlood Pb (μg/dL) median(range):18 (2–84)84% <35Significant association between increasing blood Pb concentrationand decreasing serum EPO concentration (∃=−0.03, p = 0.02).Covariates included in model were blood Hgb (∃=−1.36, p < 0.01)(age was not included), r2= 0.224. Predicted decrease in serum EPOper 10 μg/dL was 0.03 mIU/mL. Nosignificant association betweenblood Pb and blood Hgb.Schwartz et al. (1990)Idaho1974Design: cross-sectionalSubjects: children (n = 579), ages 1–5 yr,residing near an active smelter (withuncontrolled emissions)Outcome measures: HctAnalysis: logistic regressionBlood Pb (μg/dL) range:11–164Significant association between increasing blood Pb concentrationand probability of anemia (Hct < 35%) (∃1= 0.3083 [SE 0.0061])and age (∃2=−0.3831 [SE 0.1134]). A 10% probability of anemiawas predicted to be associatedwith blood Pb concentration of~20 μg/dL at age 1 yr, 50 μg/dL at age 3 yr, and 75 μg/dL at age 5yrs (from Fig. 2 Schwartz et al. (1990).Regression model relating Hct to blood Pb (BL μg/dL) and age(AGE, yr): Hct = A/[1 + exp(∃0+∃1BL +∃2AGE)]: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 = 0.0129Based on above model, a 10% decrease in hematocrit (from 39.5 to35.5%) is predicted in associationwith blood Pb concentrations of85, 115, and 145 μg/dL, at ages 1, 3, and 5 yrs, respectively.

# AX6-232Table AX6-9.3 (cont’d.). Effects of Leadon Hematopoietic System in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEuropeGraziano et al. (2004)(Factor Litvak et al.(1999, 1998)Yugoslavia1985–1998Design: prospectiveSubjects: children (n = 311; age range4.5–12 yr) from high-Pb (smelter/refinery)and low-Pb areasOutcome measures:blood Hgb, serum EPO.Analysis: multivariate linear regression(GEE for repeated measures)Blood Pb (μg/dL) range:4.5 yr: 4.6–73.16.5 yr: 3.1–71.79.0 yr: 2.3–58.1Blood Pb (μg/dL) meansfor ages 4.5–12 yrs:High Pb: 30.6–39.3Low Pb: 6.1–9.0Significant association between increasing blood Pb concentrationand increasing serum EPO concentration at ages 4.5 (p < 0.0001)and 6.5 yr (p < 0.0007), with decreasing regression slope with age:4.5 yr:∃= 0.21 (SE 0.043), p = 0.0001; 6.5 yr:∃= 0.11 (SE 0.41),p = 0.0103; 9.5 yr:∃= 0.029 (SE 0.033), p = 0.39; 12 yr:∃= 0.016(SE 0.031), p = 0.60.Covariates retained in regression model were age (∀), blood Pb (∃),and blood Hgb ((). GEE for repeated measures yielded (FactorLitvak et al., 1998, updatedfrom personal communication fromGraziano 07/2005):(: 0.6097 (95% CI:−0.0915,−0.0479), p < 0.00014.5 yr:∀= 1.3421 (95% CI: 1.0348, 1.6194), p < 0.0001∃= 0.2142 (95% CI: 0.1282, 0.3003), p < 0.00016.5 yr:∀= 1.6620 (95% CI: 1.3737, 1.9503), p < 0.0001∃= 0.1167 (95% CI: 0.0326, 0.2008), p < 0.0019.5 yr:∀= 1.7639 (95% CI: 1.4586, 2.0691), p < 0.0001∃= 0.0326 (95% CI:−0.0346, 0.0998), p = 0.164512 yr:∀= 1.8223 (95% CI: 1.524, 2.1121), p < 0.0001∃= 0.0112 (95% CI:−0.0359, 0.0584), p = 0.1645Based on the GEE, the predictedincrease in serum EPO per 10μg/dL increase in blood Pb concentration (at Hgb = 13 g/dL) \ was:1.25 mIU/mL (36%) at age 4.5 yr and 1.18 (18%) at age 6.5 yr.Blood Hgb levels were not significantly different in children fromhigh-Pb area (mean 25–38 μg/dL) compared to low-Pb area (mean5–9 μg/dL).

# AX6-233Table AX6-9.3 (cont’d). Effects of Leadon Hematopoietic System in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationLatin AmericaPerez-Bravo et al.(2004)ChileNRDesign: cross-sectional;Subjects: children (n = 93, 43 males), aged5-12 yrs who attended school near apowdered Pb storage facilityOutcome measures:blood Hgb and Hct,ALAD genotypeAnalysis: comparison of outcome measuresbetween ALAD genotype strataBlood 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 different between ALADgenotypes

# AX6-234Table AX6-9.4. Effects of Lead onHematopoietic System in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited StatesHu et al. (1994)U.S.1991Design: surveySubjects: adult male carpentry workers(n = 119), mean age:48.6 yr (range 23–67)Outcome measures:blood Hct, blood HgbAnalysis: multivariate linear regressionBlood 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 to78)Significant association between increasing patella bone Pb anddecreasing covariate adjusted blood Hgb (∃=−0.019 [SE 0.0069],p = 0.008, r2= 0.078) and blood Hct (∃=−0.052 [SE 0.019],p = 0.009, r2= 0.061). After adjustment for bone Pb measurementerror, a 37 μg/dL increase in patella bone Pb level (from the lowestto highest quintile) was associated with a decrease in blood Hgb andHct of 11 g/L (95% CI: 2.7, 19.3) and 0.03 (95% CI: 0.01, 0.05),respectively.Covariates considered: age, bodymass index, tibia Pb, patella Pb,blood Pb, current smoking status, alcohol consumptionCovariates retained: patella bonePb, alcohol consumption, bodymass index.EuropeOsterode et al. (1999)AustriaNRDesign: cross-sectional cohortSubjects: adult male Pb workers (n = 20),ages 46 yr (SD, 7); age-matched referencegroup (n = 20)Outcome measures:blood PCV, blood Hgb,serum EPO, blood erythroid progenitor(BFU-E) cell count, blood pluripotentprogenitor (CFU-GEMM) cell count, bloodgranulocyte/macrophage progenitor (CFUGM) cell count.Analysis: parametric and nonparametriccomparison of outcomes between Pb workersand reference group; correlationBlood 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 counts in Pb workers whohad blood Pb concentrations∃60 μg/dL, compared to referencegroup. Significant negative correlation between blood Pb or urinePb and CFU-GM and CFU-E. Serum EPO was not correlated withHct in Pb workers, however, serum EPO increased exponentiallywith decrease in Hct in reference group.

# AX6-235Table AX6-9.4 (cont’d). Effects of Leadon Hematopoietic System in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationEurope(cont’d)Gennart et al. (1992)BelgiumNRDesign: cross-sectional cohortSubjects: 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 EPAnalysis: linear regressionBlood 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 increasing blood Pb concentrationand decreasing blood Hgb (∃=−0.011, r = 0.22, p = 0.003) or Hct(∃= -0.035, r = 0.24, p < 0.01).Significant association between increasing blood Pb concentrationand increasing blood EP (∃= 0.0191, r = 0.87, p = 0.0001)(No apparent analysis of covariables).Mohammed-Brahimet al. (1985)BelgiumNRDesign: cross-sectional cohortSubjects: adult smelter and ceramicsmanufacture workers (n = 38, 13 females);reference subjects (n= 100) matched withworker group by age, sex, andsocioeconomic statusOutcome measures: blood P5N, EP, ALAD,R/ALAD (ratio of ALADbefore and afterreactivation).Analysis: comparison of outcome measures(ANOVA) between Pb workers andreference group; correlationBlood 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 workers (males or females,or combined) compared to corresponding reference groups.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)FranceNRDesign: cross-sectionalSubjects: adult males (n = 129), mean age36 yr (SD 7.8, range 24–55), with noenvironmental exposure to PbOutcome measures: erythrocyte membraneactivities of Na+-K+-ATPase, Na+-K+-cotransport, Na+-Li+-antiport, and passive Na+and K+ permeabilityAnalysis: linear regression, correlationBlood Pb (μg/dL)geometric mean (95% CI,range):16.0 (15.2–16.8, 8.0–33.0)Hair Pb (μg/g) geometricmean (95% CI, range):5.3 (4.44–6.23, 0.9–60)Na+-K+-co-transport activity negatively correlated with blood Pbconcentration (r =−0.23, p = 0.02); linear regression:∀= 583.19,∃=−170.70Na+-K+-ATPase activity negatively correlated with hair Pb(r =−0.18, p = 0.04); simple linear regression:∀= 3.34,∃=−0.02

# AX6-236Table AX6-9.4 (cont’d). Effects of Leadon Hematopoietic System in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Poulos et al. (1986)GreeceNRDesign: cross-sectional cohortSubjects: adult male cable productionworkers who were exposed to Pb (worker 1;n = 50, mean age 37 yr); male cable workerswho had not direct contact with Pb (worker2, n = 75, mean age 36.5 yr); reference group(n = 35, mean age 39 yr)Outcome measures:blood Hgb, HctAnalysis: simple linear regression in theform: 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 increasing blood Pb and decreasingHct:Worker 1:∀= 46.50,∃=−0.170 (SE 0.079), p < 0.05Worker 2:∀= 44.57,∃=−0.180 (SE 0.083), p < 0.05Reference:∀= 44.69,∃=−0.255 (SE 0.044), p < 0.001Significant association between increasing blood Pb and decreasingblood Hgb:Worker 1:∀= 15.23,∃=−0.058 (SE 0.028), p < 0.05Worker 2:∀= 14.58,∃=−0.071 (SE 0.034), p < 0.05Reference:∀= 14.64,∃=−0.087 (SE 0.015), p < 0.001Romeo et al. (1996)ItalyNRDesign: cross-sectional cohortSubjects: adult male Pb workers (n = 28),age range, 17–73; reference group (n = 113),age range, 21–75 yrOutcome measures: serum EPO, blood HgbAnalysis: nonparametric comparison ofoutcome measures between Pb workers andreference group; correlationBlood 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 EPO in Pb workers comparedto reference group. No significant(p < 0.05) Pb effect on bloodHgb.Graziano et al. (1990)Yugoslavia1986Design: prospectiveSubjects: pregnant women (n = 1502) fromhigh-Pb (smelter/refinery) and low-Pb areasOutcome measures: HgbAnalysis: comparison of outcome measuresbetween high-and low-Pb groupsBlood 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 group (12.4; 95% CI:10.3, 14.5) not different from low-Pb group (12.3; 95% CI: 10.0,14.7).

# AX6-237Table AX6-9.4 (cont’d). Effects of Leadon Hematopoietic System in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Graziano et al. (1990)Yugoslavia1986Design: prospectiveSubjects: pregnant women (n = 48) fromhigh-Pb (smelter/refinery) and low-Pb areas(6 highest and lowest mid-pregnancy bloodPb concentrations), within each of 4 Hgbstrata (g/dL): 9.0–9.9, 10.0–10.9, 11.0–11.9,12.0–12.9Outcome measures: Hgb, EPOAnalysis: ANOVA of outcome measures insubjects stratified by blood Pb and bloodHgbBlood Pb (μg/dL) meanrange for Hgb strataHigh Pb: 16.9–38.6Low Pb: 2.4–3.6Significant effect of blood Pb (p = 0.049) and blood Hgb (p = 0.001)on mid-term and term serum EPO (blood Pb p = 0.055, Hgbp = 0.009), with significantly lower serum EPO associated withhigher blood Pb.AsiaHsiao et al. (2001)China1989–1999Design: longitudinalSubjects: adult battery manufacture workers(n = 30, 13 females), mean age 38.3 yrOutcome measures:blood Hgb, Hct,RBC countAnalysis: GEE for repeated measures(models: linear correlation, thresholdchange, synchronous change, lag change);logistic regressionBlood Pb (μg/dL) mean:1989: 601999: 30Significant association between increasing blood Pb and increasingRBC 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)ChinaNRDesign: cross-sectionalSubjects: Adults in general population(n = 630, 255 females)Outcome measures:blood Hgb, Hct, RBCcount, ALAD genotypeAnalysis: comparison of outcome measuresbetween ALAD genotype strataBlood 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 differentbetween ALAD genotype strata(p = 0.17). RBC count, Hgb, Hct not different between ALADgenotype strata (p = 0.7).

# AX6-238Table AX6-9.4 (cont’d). Effects of Leadon Hematopoietic System in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationAsia(cont’d)Froom et al. (1999)Israel1980–1993Design: longitudinal surveySubjects: adult malebattery manufacturingworkers (n = 94), mean age, 38 yr (SD 9,range 26–60)Outcome measures:blood Hgb, blood EPAnalysis: multivariate linear regressionBlood Pb (μg/dL) range of13-yr individual subjectmeans: 20–61 μg/dLWeak (and probably not significant) covariate-adjusted associationbetween blood Hgb and individual sample blood Pb (∃=−0.0039[SE 0.0002]), subject avg blood Pb (∃=−0.0027 [SE 0.0036]) orblood EP (∃=−0.001 [SE 0.0007]).Covariates retained in model were age andsmoking habits.Solliway et al. (1996)IsraelNRDesign: cross-sectional cohortSubjects: adult male battery manufactureworkers (n = 34), mean age: 44 yr (SD 13);reference subjects (n = 56), mean age 43 yr(SD 12); cohorts constructed to have similarage, ethnic characteristics, socioeconomicstatus, education level, and occupationOutcome measures:blood Hgb, RBC countAnalysis: parametric comparison ofoutcome measures between Pb and referencegroups, correlationBlood 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 count in Pb workerscompared to reference group.Significant negative correlationbetween blood Pb concentration and RBC count (r =−0.29,p < 0.05). Mean comparison for blood Hgb (p = 0.4); correlationwith blood Pb concentration (r =−0.05, p = 0.7).Horiguchi et al. (1991)JapanNRDesign: cross-sectional cohortSubjects: adult male secondary Pb refineryworkers (n = 17), mean age: 44.9 yr (range24–58); 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 HgbAnalysis: comparisons of outcome measuresbetween Pb workers and reference groupBlood Pb (μg/dL) mean(SD):Pb: 53.5 (16.1)Reference: NRUrine Pb (μg/L) mean(SD):Pb: 141.4 (38.1)Reference: NRSignificantly lower RBC deformability (p < 0.01), RBC count(p < 0.01) Hct (p < 0.01), and blood Hgb (p > 0.001) in Pb workerscompared to reference group.

# AX6-239Table AX6-9.4 (cont’d). Effects of Leadon Hematopoietic System in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationAsia(cont’d)Makino et al. (1997)Japan1990–1994Design: longitudinal surveySubjects: adult male pigment or vinylchloride stabilizer manufacture workers(n = 1573) mean age 45 yrOutcome measures:blood Hgb, Hct, RBCcountAnalysis: parametric comparison ofoutcome measures, stratified by blood Pb,linear regressionBlood 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, blood Hgb, and RBC count inblood Pb category 16–39 μg/dL, compared to 1–15 μg/dL category.Significant positive correlation between blood Pb concentration andHct:∀= 42.95,∃= 0.0586 (r = 0.1553, p < 0.001), blood Hgb:∀= 14.65,∃= 0.0265 (r = 0.1835, p < 0.001), and RBC count∀= 457,∃= 0.7120 (r = 0.1408, p < 0.001).Morita et al. (1997)JapanNRDesign: cross-sectional cohortSubjects: male Pb workers (n = 76), meanage 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, ALADAnalysis: comparison of outcome measures(ANOVA) between blood Pb categories,linear regressionBlood Pb (μg/dL) mean(SD, range)Pb: 34.6 (20.7, 2.2–81.6)Significantly lower (p < 0.01) blood NADS and ALAD in blood Pbcategories >20 μg/dL compared to <20 μg/dL, with dose trend inmagnitude of difference.Significant associations between increasing blood Pb and decreasingblood NADS and ALAD in Pb workers:NADS:∀= 0.843,∃=−0.00971, r =−0.867, p < 0.001, n = 76logALAD:∀= 1.8535,∃=−0.015, r =−0.916, p < 0.001, n = 58Kim et al. (2002)Korea1996Design: cross-sectional cohortSubjects: adult male secondary Pb smelterworkers (n = 83), mean age: 38.7 yr (SD10.8); reference subjects (n = 24), mean age:32.0 (SD 10.8)Outcome measures:blood Hgb, bloodALAD, blood EP, blood P5NAnalysis: parametric comparison (ANOVA)of outcome measures between Pb workersand reference group, correlation, multivariatelinear regressionBlood Pb (μg/dL) mean(SD)Pb: 52.4 (17.7)Reference: 6.2 (2.8)Significantly (p < 0.05) lowerblood P5N, ALAD, and Hgb; andhigher blood EP in Pb workers compared to controls.Significant (p < 0.001) correlations (in Pb worker group) with bloodPb: P5N (r =−0.704), log EP (r = 0.678), log ALAD(r = -0.622).Significant association between increasing EP and decreasing bloodHgb:blood Pb∃60 μg/dL:∃=−1.546 (96% CI:−2.387,−0.704),r2= 0.513, p = 0.001blood Pb <60 μg/dL:∃=−1.036 (96% CI:−1.712,−0.361),r2= 0.177, p = 0.003Significant association between increasing P5N and increasing bloodHgb (high blood Pb group only):blood Pb∃60 μg/dL:∃= 0.222 (96% CI: 0.015, 0.419), r2= 0.513,p = 0.036Covariates included in model: P5N, log serum ferritin, log EP

# AX6-240Table AX6-9.4 (cont’d). Effects of Leadon Hematopoietic System in AdultsReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationAsia(cont’d)Schwartz et al. (1997)Korea1994-1995Design: cross-sectionalSubjects: adult male battery manufactureworkers (n = 57), mean age 32 yrs (SD 6).Outcome measures: blood Hgb, HgbA1, andHgbA2, ALAD genotypeAnalysis: comparison of outcome measuresbetween ALAD genotype strataBlood 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 levels (p = 0.34) were notdifferent between ALADgenotype strata.

# AX6-241Table AX6-9.5. Effects of Lead on the Endocrine System in ChildrenReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesMahaffey et al. (1982)Wisconsin, New YorkNRDesign: cross-sectionalSubjects: children/adolescents (n = 177),ages 1–16 yrOutcome measures: serum 1,25-OH-DAnalysis: comparison of outcome measuresbetween age, location and blood Pb strata,linear regressionBlood Pb (μg/dL) range:12–120Serum 1,25-OH-D levels were significantly (p = 0.05) higher in theage group 11–16 yr compared to age groups 1–5 or 6–10 yr.Increasing blood Pb (log-transformed)significantly associated withdecreasing serum 1,25-OH-D levels in children 1–5 yr of age(∀= 74.5,∃=−34.5, r =−0.884, n = 50)Dietary calcium: NRRosen et al. (1980)New YorkNRDesign: cross-sectionalSubjects: children (n = 45), ages 1–5 yrOutcome measures: serum calcium, PTH,25-OH-D, 1,25-OH-DAnalysis: comparison of outcome measuresbetween blood Pb strata, and before and afterchelation, correlationBlood 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 and lower 25-OH-D in highPb group compared to low-Pb group; significantly lower 1,25-OH-Dlevels in moderate- and high-Pb group compared to low-Pb group.Serum levels of 1,25-OH-D werenegatively correlated with bloodPb (high Pb: r =−0.71, moderate: r =−0.63, p < 0.01). Afterchelation therapy, blood Pb decreased and serum 1,25-OH-D levelsincreased to levels not significantly different (p > 0.1) from low-Pbgroup, 25-OH-D levels were unchanged.Dietary calcium intake (mg/day) mean (SE):Low Pb: 800 (30)Moderate Pb: 780 (25)High Pb: 580 (15)Sorrell et al. (1977)New York1971–1975Design: cross-sectionalSubjects: children (124), ages 1–6 yrOutcome measures: serum calcium,phosphate, 25-OH-DAnalysis: comparison of outcome measuresbetween blood Pb strata, correlationBlood 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 weresignificantly lower in high Pbgroup (p < 0.001). Significant negative correlation between bloodPb and serum calcium (high Pb, r =−0.78, p < 0.001) or calciumintake high Pb, (r =−0.82, p < 0.001) in all three Pb strata. Serum25-OH-D was significantly positively correlated with vitamin Dintake, but not with blood Pb.Dietary calcium intake (mg/day) mean (SE):Low Pb: 770 (20)Moderate Pb: 760 (28)High Pb: 610 (20)

# AX6-242Table AX6-9.5 (cont’d). Effects of Leadon the Endocrine System in ChildrenReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationUnited States(cont’d)Siegel et al. (1989)Connecticut1987Design: cross-sectionalSubjects: children (n =68, 32 female), ages11 mo to 7 yrOutcome measures: serum FT4, TT4Analysis: linear regressionBlood Pb (μg/dL) mean(range):25 (2–77)No significant association between blood Pb concentration andthyroid hormone outcomes. Linear regression parameters:FT4:∀= 1.55 (SE 0.05),∃= 0.0024 (SE 0.0016), r2= 0.03,p = 0.13TT4:∀= 8.960 (SE 0.39),∃= 0.0210 (SE 0.0127), r2= 0.04,p = 0.10Koo et al. (1991)OhioNRDesign: longitudinal (subset of prospective)Subjects: children (n = 105, 56 females), age21, 27, 33 moOutcome measures: serum calciummagnesium, phosphorus, PTH, CAL, 25-OHD, 1,25-OH-D, and bonemineral contentAnalysis: structural equation modelingBlood Pb (μg/dL)geometric mean(GSD, range):Lifetime mean, based onquarterly 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 increasing blood Pb (ln-transformed)and covariate-adjusted decreasing serum phosphorus(∀= 1.83,∃=−0.091). No other covariate-adjusted outcomes weresignificantly associated with blood Pb.Covariates retained: age, sex, race, and sampling season.Dietary calcium intake (mg/day)#600: n = 4 (4%)600–1200: n = 58 (55%)>1200: n = 43 (41%)

# AX6-243Table AX6-9.6. Effects of Lead onthe Endocrine System in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited StatesCullen et al. (1984)Connecticut1979NRDesign: clinical case studySubjects: adult males with neurologicalsymptoms of Pb poisoningOutcome measures: serum, FSH, LH, PRL,TESAnalysis: clinical outcomes in terms ofabnormal valuesBlood Pb (μg/dL) range:66–139Five subjects with defectsin spermatogenesis (includingazospermia), with no change in basal serum FSH, LH,PRL, and TES.Robins et al. (1983ConnecticutNRDesign: cross-sectionalSubjects: adult male brass foundry workers(n = 47), age range 20–64 yrOutcome measures: FT4Analysis: simple linear regression withstratification by age and race.Blood Pb (μg/dL) range:16–127Significant association between increasing blood Pbconcentration and decreasing FT4 (∀= 1.22,∃=−0.0042 [95% CI:−0.0002,−0.0082], r2= 0.085,p = 0.048). Significant interaction between race (black,white) and blood Pb.When stratified by race:Black:∀= 1.13,∃=−0.0051 (95% CI: 0.0007,−0.0095), r2= 0.21, p = 0.03White: r2= 0.05, p = 0.27Strength of association not changed by including age inthe regression model.Braunstein et al.(1978)CaliforniaNRDesign: clinicalSubjects: adult male secondary Pb smelter(n = 12), mean age 38 yr, reference group,(n = 9), mean age 29 yrOutcome measures: serum EST, FSH, LH,TES, HCG-stimulated EST and TES, GnRHstimulated serum FSH and LHAnalysis: comparisons of outcome measuresbetween patients symptomatic for Pbpoisoning, Pb-exposed patients notsymptomatic, reference groupBlood 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 < 0.05) lower basal serumTES, higher TES response to HCG, and significantlyreduced LH response to GnRH in workers symptomaticfor Pb poisoning (including EDTA-provoked urinary Pb>500 μg/24 hr).Refowitz (1984)NRDesign: cross-sectional surveySubjects: secondary copper smelter workers(n = 58)Outcome measures: FT4, TT4Analysis: linear regressionBlood Pb (μg/dL) range:5–60No significant association between blood Pb andhormone levels:FT4:∀= 2.32,∃=−0.0067 (95% CI:−0.18, 0.0043)TT4:∀= NR,∃=−0.28 (95% CI:−0.059, 0.0002)No significant association when ratified by race (black,white)

# AX6-244Table AX6-9.6 (cont’d). Effects of Leadon the Endocrine System in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationCanadaAlexander et al. (1998,1996a)British Columbia1993Design: cross-sectionalSubjects: adult male primary smelter workers(n = 152), mean age 40 yrOutcome measures: serum FSH, LH, TESAnalysis: multivariate linear regressionBlood Pb (μg/dL) range(n = 81): 22.8 (5–58)Semen Pb (μg/dL) range:1.9 (0.1–17.6)No significant association betweencovariate-adjusted blood Pb andhormone levels (p∃0.5) or prevalence of abnormal levels.Significant association between covariate-adjusted increasingsemen Pb concentration and decreasing serum TES (∃=−1.57,p = 0.004).Covariates considered: age, smoking, alcohol, other metals in blood(arsenic, cadmium, copper, zinc), abstinence days prior to samplecollection, and sperm count.Schumacher et al.(1998)British Columbia1993Design: cross-sectionalSubjects: adult male smelter workers(n = 151) mean age 40 yr (SD 7.2)Outcome measures: serum FT4, TT4, TSHAnalysis: linear regression, ANOVABlood 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(categorical) on covariate-adjustedor unadjusted FT4 (p = 0.68), TT4 (p = 0.13), TSH (p = 0.54). Nosignificant association of blood Pbwith prevalence of abnormalvalues of hormones. No significant association between 10-yr avgblood Pb and hormone levels orprevalence of abnormal values.Covariates considered: age and alcohol consumption.EuropeGennart et al. (1992)BelgiumNRDesign: cross sectional cohortSubjects: adult battery manufacture workers(n = 98), mean age 37.7 yr (SD 8.3, range 22–55); reference worker group (n = 85), meanage 38.8 yr (SD 8.7, range 22–55)Outcome measures: serum TT3, FT4, TT4,TSH, FSH, LHAnalysis: comparison of outcome measuresbetween Pb workers and reference groupBlood 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 reference group notdifferent (p = NR); no association between hormone levels andblood Pb or exposure duration quartile.

# AX6-245Table AX6-9.6 (cont’d). Effects of Leadon the Endocrine System in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Assennato et al. (1987)ItalyNRDesign: cross-sectionalSubjects: adult male battery manufactureworkers (n = 39), mean age 41 yr (SD 10);reference cement plant workers (n = 18), meanage 40 yr (SD 10)Outcome measures: serum FSH, LH, PRL,TES; urinary 17-ketosteroidsAnalysis: parametric comparison of outcomemeasures between Pb and reference groupsBlood 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) between blood Pb andhormone levels.Govoni et al. (1987)ItalyNRDesign: cross-sectionalSubjects: adult male pewter manufactureworkers (n = 78), mean age 35 yr (SD 19,range 19–52)Outcome measures: serum PRLAnalysis: parametric comparison of outcomemeasures between blood Pb and ZPP strataBlood 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 PRL in high ZPP strata (B andC, compared to low ZPP strata A).Rodamilans et al.(1988)SpainNRDesign: cross-sectional cohortSubjects: adult male Pb smelter workers(n = 23), age range 21–44 yr; reference group(n = 20), age range 20–60 yrOutcome measures: serum FSH, LH, TES,FTES, SHBGAnalysis: comparison of outcome measuresbetween exposure duration strataBlood 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= 0.001) significantly lower andSHBG significantly higher (p < 0.025) in >5-yr exposure groupcompared to reference group; serumLH was significantly (p < 0.01)higher in all exposure groups compared to reference group.

# AX6-246Table AX6-9.6 (cont’d). Effects of Leadon the Endocrine System in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Erfurth et al. (2001)SwedenNRDesign: cross-sectional cohortSubjects: adult male active secondary smelterworkers (n = 62), mean age 43 yr (range 21–78) reference worker group (n = 26), meanage 43 yr (range 23–66)Outcome measures: serum FT3, FT4, TSH,TES, SHBG; TRH-stimulated serum TSH;GnRH-stimulated serum FSH, LH, and PRLAnalysis: nonparametric comparison ofoutcome measures between Pb workers andreference group; multivariate linear regressionBlood 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 workers not different fromreference group (p∃0.05); age-adjusted basalhormone levels not associated with plasma Pb, bloodPb, urine Pb, or bone Pb. In an age-matched subsetof the cohorts (n = 9 Pb workers, n = 11 reference),median GnRH-stimulated serum FSH wassignificantly (p = 0.014) lower (77 IU/LΗhr) in Pbworkers than in reference group (162 IU/LΗhr).No association between stimulated TSH, LH, FSH orPRL and Pb measures.Gustafson et al. (1989)SwedenNRDesign: cross-sectional cohortSubjects: adult male secondary smelterworkers (n = 21) mean age 36.0 yr (SD 10.4);individually matched for age, sex, and workshift (n = 21)Outcome measures: serum FTES, TTES;FSH, LH, PRL, COR, TSH, TT3, TT4Analysis: nonparametric comparison ofoutcome measures between Pb workers andreference group, correlationBlood Pb (μg/dL) mean (SE):Pb: 39.4 (2.1)Reference: 5.0 (0.2)Significantly higher TT4 (p < 0.02) and lower serumFSH (p = 0.009) in Pb workers compared toreference group. When restricted to the age range<40 yr, Pb workers had significantly higher TT4(p = 0.01) and lower FSH (p = 0.03), LH (p = 0.04),and COR (p = 0.04), compared to the referencegroup.Campbell et al. (1985)UKNRDesign: cross-sectional cohortSubjects: adult male welders (n = 25);reference subjects (n = 8) (ages NR)Outcome measures: plasma ACE, AI, PRA,plasma ALDAnalysis: linear regression, nonlinear leastsquaresBlood Pb (μg/dL) mean(SD, range): 35.6(15.3, 8–62)Significant positive correlation between blood Pbconcentration and plasma ALD level (r = 0.53,p < 0.002), PRA (r =−0.76, p < 0.001), AI (r = 0.68,p < 0.002), and ACE (r = 0.74, p < 0.001).

# AX6-247Table AX6-9.6 (cont’d). Effects of Leadon the Endocrine System in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationEurope(cont’d)Chalkley et al. (1998)UK1979–1984Design: cross-sectionalSubjects: adult male primary metal(cadmium, Pb, zinc) workers (n = 19), agesNROutcome measures:blood calcium, serum 25-OH-D, 1,25-OH-D, 24,25-OH-DAnalysis: comparison of outcome measures(ANOVA) in group stratified by blood Pb andurinary cadmiumBlood Pb (μg/dL) mean(SD, range): 47 (21–76)After stratification by blood Pband urinary cadmium, serum 1,25-OH-D levels in strata were significantly different (p = 0.006), withhigher mean values in high blood Pb (>40 μg/dL)/high bloodcadmium (>0.9 μg/L)/high urinecadmium >3.1 μg/L) stratumcompared to low blood Pb (<40 μg/dL)/high blood cadmium(>0.9 μg/L)/high urine cadmium >3.1 μg/L) stratum. Serum 24,25-OH-D levels decreased with increasing urinary cadmium (p = NR)Mason et al. (1990)UKNRDesign: cross-sectionalSubjects: adult male Pb workers (n = 63), agerange 21–63 yr; reference male subjects(n = 75), age range 22–64 yrOutcome measures: serum calciumphosphate, PTH, 1,25-OH-DAnalysis: comparison of al outcome measuresbetween Pb workers and reference group,multivariate regressionBlood Pb (μg/dL) range:Pb (15–94)Reference: NRTibia Pb (μg/g)Pb: 0–93Reference: NRSignificantly higher (p < 0.025) prevalence of elevated 1,25-OH-D(>2 SD of reference mean) in Pb workers (8/63, 13%) compared toreference group (1/75, 1.3%). Serum levels of 1,25-OH-Dsignificantly (p < 0.05) higher in Pb workers compared to referencegroup.After stratification of Pb workersinto exposure categories (high:blood Pb∃40 μg/dL and bone Pb∃40 μg/g, low: blood Pb#40 μg/dL and bone Pb#40 μg/g), serum 1,25-OH-D levels weresignificantly (p < 0.01) higher in the high Pb group.Increasing blood Pb was significantly (p = NR) associated withincreasing 1,25-OH-D levels (r2= 0.206; with age and bone Pbincluded, r2= 0.218). After excluding12 subjects whose blood Pbconcentrations >60 μg/dL, r2= 0.162 (p = 0.26).McGregor and Mason,(1990)UKNRDesign: cross-sectional cohortSubjects: adult male Pb workers (n = 90),mean age (31.5 yr (SD 11.9); referenceworkers (n = 86), mean age 40.6 yr (SD 11.8)Outcome measures: serum FSH, LH, TES,SHBGAnalysis: comparison of outcome meansbetween Pb workers and reference groups,multivariate regression, correlationBlood Pb (μg/dL) range:Pb: 17–77Reference: <12Age-adjusted serum FSH was significantly (p = 0.004) higher in Pbworkers compared to reference group.Increasing serum FSH significantly(p = NR) associated with bloodPb and age. Increasing serum LH significantly associated withincreasing exposure duration (not blood Pb or age).No significant association between serum TES or SHBG and bloodPb or exposure duration.No significant difference in prevalence of abnormal hormone levelsbetween groups.

# AX6-248Table AX6-9.6 (cont’d). Effects of Leadon the Endocrine System in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationLatin AmericaL∴pez et al. (2000)ArgentinaNRDesign: cross sectionalSubjects: adult male battery manufactureworkers (n = 75), age range 21–56 yr;reference group (n = 62), age NROutcome measures: serum TT3, FT4, TT4,TSHAnalysis: comparison of outcome measuresbetween Pb workers and reference group,correlationBlood Pb (μg/dL) mean(range):Pb: 50.9 (23.3, 8–98)Reference: 19.1 (7.1, 4–39)Significantly higher serum FT4 (p < 0.01) and TT4 (p < 0.05) in Pbworkers compared to reference group. Significant positivecorrelation between blood Pb and serum TT3 (p < 0.05), FT4(p < 0.01), TT4 (p < 0.05), and TSH (p < 0.05), for blood Pb range8–50 μg/dL; and for TSH (p < 0.05) for blood Pb range 8–26 μg/dL.Roses et al. (1989)BrazilNRDesign: adult male Pb workers (n = 70), agerange 20–53 yr; reference group (n = 58), agerange 25–37 yr.Outcome measures: serum PRLAnalysis: comparison of outcome measurebetween Pb workers and reference group,linear regressionBlood Pb (μg/dL) range:Pb: 9–86Reference: 8–28Serum RL levels in Pb workers and reference group notsignificantly different (p = NR).Correlation between serum PRLand blood Pb (r = 0.57, p = NR).AsiaDursun and Tutus(1999)TurkeyNRDesign: cross-sectionalSubjects: adult metal powder manufactureworkers (n = 27) mean age 41.1 yr (SD 5.45,range 25–50); reference group (n = 30), meanage 42 yr (SD 3.42, range 28–49)Outcome measures: serum FT4, TT4, FT3,TT3, TSHAnalysis: parametric comparison of outcomemeasures between Pband reference groups,simple and multivariate linear regressionBlood 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 TT4, FT4, and FT3 in Pbworkers compared to reference group.Significant association between TT4, age (∃= 0.23, p < 0.006), andexposure duration (∃=−0.20, p > 0.01), but not blood Pb (∃= 0.00,NR) in linear regression model that included age, blood Pb, andexposure duration (∀= 2.76, r2= 0.3, p = 0.03).

# AX6-249Table AX6-9.6 (cont’d). Effects of Leadon the Endocrine System in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Kristal-Boneh et al.(1998)IsraelNRDesign: cross-sectional cohortSubjects: adult male batterymanufacture/recycling workers (n = 56), meanage 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-DAnalysis: parametric comparison of outcomemeasures between Pb workers and referencegroup, multivariate linear regressionBlood 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 (p = 0.042) weresignificantly higher in Pb workers compared to reference groupIncreasing blood Pb concentration (ln-transformed) wassignificantly associated with covariate-adjusted increasing serumPTH and 1,25-OH-D levels:PTH:∃= 4.8 (95% CI: 0.8, 8.8), r2= 0.121,25-OH-D:∃= 4.8 (95% CI: 2.7, 6.9), r2= 0.10Occupational Pb exposure (yes) significantly associated withincreasing PTH and 1,25-OH-D levels.Covariates retained: age, alcoholconsumption, smoking; calcium,magnesium, and calorie intake:PTH:∃= 7.81 (95% CI: 3.7, 11.5)1,25-OH-D:∃= 12.3 (95% CI: 3.84, 20.8)Horiguchi et al. (1987)JapanNRDesign: cross-sectionalSubjects: adult secondary Pb refinery (n = 60,8 females), mean age 49 yr (range 15–69)Outcome measures: serum TT3, TT4, TSHAnalysis: comparison of outcome measures(method NR), between job categories,correlationBlood 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) between hormone levels in jobPb categories: mean blood Pb(μg/dL, SD): 17.9 (10.7), 25.6(15.4), 49.9 (18.7). No significantcorrelations (p = NR) betweenhormone levels and blood or urine Pb levels.Ng et al. (1991)ChinaNRDesign: cross-sectional cohortSubjects: adult male battery manufactureworkers (n = 122), mean age 32.6 (SD 8,2,range 17–54); reference group (n = 49), meanage 43.4 yr (SD 13.4, range 18–74)Outcome measures: serum FSH, LH, PRL,TESAnalysis: multivariate linear regressionANCOVABlood 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 serum FSH and LH weresignificantly (p < 0.02) higher in Pb workers <40 yrs of agecompared to corresponding age strata of the reference group; serumTES was significantly (p < 0.01) lower in Pb workers∃40 yr of age.Covariate-adjusted serum TES weresignificantly lower (p < 0.01)in Pb workers in the∃10-yr exposure duration category, comparedto the reference group. Covariate-adjusted serum FSH and LH weresignificantly higher (p < 0.01) in Pb workers in the <10-yr exposureduration category, compared to the reference group.Covariates: age and tobacco smoking.

# AX6-250Table AX6-9.6 (cont’d). Effects of Leadon the Endocrine System in AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Zheng et al. (2001)ChinaNRDesign: retrospective cross-sectionalSubjects: adult hospital patients (n = 82, 32females) mean age 49.6 yr (SD 18.7)Outcome measures: serum and CSF TTR,TT4Analysis: simple and multivariate linearregressionBlood Pb (μg/dL) mean(SD):All: 14.9 (8.3)Female: 14.2 (8.76)Male: 15.4 (8.07)No significant association between blood Pb and serum TTR(r =−0.114, p = 0.307), TT4 (r =−0.160, p = 0.152).Significant association between age-adjusted CSF Pb and CSF TTR(r =−030, p = 0.023).No significant association between CSF Pb and CSF TT4(r =−0.22, p = 0.090).Singh et al. (2000)IndiaNRDesign: cross-sectional cohortSubjects: adult malepetrol 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, TSHAnalysis: parametric comparison of outcomemeasures between Pb workers and referencegroup, stratified by blood Pb or exposuredurationBlood Pb (μg/dL) mean(SD):Pb: 51.6 (9.3)Reference: 9.5 (8.7)Serum TSH significantlyhigher (p < 0.01) in Pb workers comparedto reference group, significantlyhigher in high blood Pb category(#70 μg/dL, mean 54.5 μg/dL) compared to low worker group#41 μg/dL, mean 31.3 μg/dL). Serum TSH significantly higher inPb workers who were exposed for#60 mo, compared to workersexposed for >60 mo.AfricaTuppurainen et al.(1988)Kenya1984Design: cross-sectionalSubjects: adult male battery manufactureworkers (n = 176), mean age 34.1 yr(SD 8.1, range 21–54)Outcome measures: serum TT3, FT4,TT4, TSHAnalysis: multivariate linear regressionand correlationBlood Pb (μg/dL) mean(SD, range):55.9 (23.8, 14.5–133.6)Increasing exposure duration significantly associated withdecreasing FT4 (r2= 0.071, p = 0.001) and TT4 (r2= 0.059,p = 0.021); regression not improved by including age or blood Pb.Strength of association greater whenrestricted to workers who hadan exposure duration >7.6 yrs: FT4: r2= 0.33, p < 0.002; TT4:r2= 0.21, p < 0.001.No significant association between blood Pb and hormone levels.

# AX6-251Table AX6-9.7. Effects of Lead on theHepatic System in Children and AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationChildrenUnited StatesSaenger et al. (1984)New YorkNRDesign: clinical casesSubjects: 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 measurebetween children whoqualified for EDTAtreatment (EDTA provocation >500 μg/24hr)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 excretion of 6∃-OH-cortisol (p = 0.001) and urinary 6∃-OH-cortisol: cortisol ratio(p < 0.001) in children who qualifiedfor chelation than in childrenwho did not qualify and significantly lower than age-matchedreference group. Urinary 6∃-OH-cortisol: cortisol ratio wassignificantly correlated with blood Pb (r =−0.514, p < 0.001),urinary Pb, and EDTA provocation urinary Pb (r =−0.593,p < 0.001).AdultsAsiaAl-Neamy et al. (2001)United Arab Emirates1999Design: cross-sectional cohortSubjects: 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, LDHAnalysis: comparison of outcome measuresbetween Pb workers and reference groupBlood Pb (μg/dL) mean(SD): Pb: 77.5 (42.8)Reference: 19.8 (12.3)Significantly higher serum AP (p = 0.012) and LDH (p = 0.029) inPb workers compared to reference group (values within normalrange).

# AX6-252Table AX6-9.7 (cont’d). Effects of Lead onthe Hepatic System in Children and AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAsia(cont’d)Hsiao et al. (2001)China1989–1999Design: longitudinalSubjects: adult battery manufacture workers(n = 30, 13 females), mean age 38.3 yrOutcome measures: serum ALTAnalysis: GEE for repeated measures(models: linear correlation, thresholdchange, synchronous change, lag change);logistic regressionBlood Pb (μg/dL) mean:1989: 60 (~25–100)1999: 30 (~10–60)No association between blood Pb and ALT.Odds ratios (95% CI):Synchronous change model: 1.25 (0.69, 2.25)Lag change: 1.76 (0.76, 4.07)Satarug et al. (2004)ThailandNRDesign: cross-sectionalSubjects: adults from general population(n = 118, 65 female), age range, 21–57 yrOutcome measures: coumarin-inducedurinary 7-OH-coumarin (marker forCYP2A6 activity)Analysis: multivariate linear regressionUrinary Pb (μg/gcreatinine) 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 increasing urinary Pb and decreasingcovariate-adjusted urinary 7-OH-coumarin (∃=−0.29, p = 0.003) inmales, but not in females. Covariates retained: age and zincexcretion. Significant association in opposite direction betweenurinary cadmium and urinary 7-OH-coumarin (∃= 0.38, p = 0.006).

# AX6-253Table AX6-9.8. Effects of Lead on the Gastrointestinal SystemReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationCanadaHolness and Nethercott(1988)Ontario1982–1984Design: longitudinalSubjects: adult male demolition workers(n = 119), age NROutcome measures: prevalence of symptomsAnalysis: comparison of prevalence ofsymptoms (questionnaire) stratified by jobphase or blood PbBlood Pb (μg/dL) mean(range):Phase 1: 59 (15–99)Phase 2: 30Phase 3: 19Phase 4: 17Prevalence of reporting of symptoms of abdominal cramps orconstipation increased with increasing blood Pb concentration(p < 0.05):<50 μg/dL: 8%, 6%50–70 μg/dL: 37%, 42%>70 μg/dL: 77%, 62%CaribbeanMatte et al. (1989)Jamaica1987Design: surveySubjects: battery manufacture/repairworkers (n = 63), mean age ~30 yr(range 11–47)Outcome measures: prevalence of symptomsAnalysis: comparison of GI symptoms(questionnaire) between blood Pb strataBlood Pb (μg/dL)geometric mean site range:40–64Blood Pb distribution:>60: 60%<60: 40%When stratified by blood Pb, <60 μg/dL (low) or∃60 μg/dL (high),prevalence ratio (high/low) wasnot significant forabdominal pain(1.5, [95% CI: 0.5, 4.6]), or for any other Pb symptom (e.g. muscleweakness).AsiaBercovitz and Laufer(1991)IsraelNRDesign: cross-sectionalSubjects: health individuals (n = 12), pepticulcer patients (n = 11), and individuals withheart disease (n = 11) with environmentalexposureAnalysis: one-way ANOVA used tocompare tooth Pb concentrations in the threegroupsTooth 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 gastrointestinal ulcers (n = 11), weresignificantly higher than that in healthy subjects (p = 0.001)). Ten ofthe 11 peptic ulcer patients had a higher Pb level than the healthsubjects. In these 10 patients, increased severity of the ulcer andlongevity of suffering was associated with increased tooth Pb levels.There was no significant differencebetween the tooth Pb levels inthe healthy subjects and inthe heart disease patients.

# AX6-254Table AX6-9.8 (cont’d). Effects of Lead on the Gastrointestinal SystemReference, StudyLocation, and Period Study DescriptionPb Measurement Findings, InterpretationAsia(cont’d)Lee et al. (2000)KoreaNRDesign: cross-sectional cohortSubjects: adult male Pb workers (n = 95;secondary smelter,PVC-stabilizermanufacture, battery manufacture); mean age42.8 yr (SD 9.3, range 19–64); referencegroup (n = 13), mean age 35.1 yr (SD 9.9,range 22–54)Outcome measures: prevalence of GIsymptoms (self-administered questionnaire)Analysis: multivariate logistic regressionBlood 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 (loss of appetite,constipation or diarrhea, abdominalpain) in workers (referents notincluded in model) were not significant:Blood Pb (45.7 μg/dL vs. <45.7 μg/dL): OR = 1.8 (95%CI: 0.7, 4.5)DMSA-provoked urinary Pb (>260.5 vs. <260.5 μg): OR = 1.1(95% CI: 0.4, 2.5)OR for neuromuscular symptoms were significantly associated withDMSA-provoked Pb (OR = 7.8 [95% CI: 2.8, 24.5]), but not withblood Pb.Covariates retained: age,tobacco smoking, and alcoholconsumption.AfricaAwad el Karim et al.(1986)SudanNRDesign: cross-sectional cohortSubjects: adult male battery manufactureworkers (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 evaluationAnalysis: comparison of prevalence ofsymptoms of Pb poisoning between Pbworkers and reference groupBlood Pb distribution forPb workers>80: 23%40–80: 72%<40: 5%Blood Pb (μg/dL) mean(SD, range):Pb: 55–81 (mean range forvarious jobs), range 39–107Reference: 21 (8.5, 7.4–33.1)Prevalences of abdominalcolic (pain) and constipation were 41.3%and 41.4 % in Pb workers and 7.5%and 10%, respectively, in thereference group.

# AX6-255Table AX6-9.9. Effects of Lead on Bone and Teeth in Children and AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationChildrenUnited StatesMoss et al. (1999)U.S.1988–1994Design: 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 andlogistic regressionBlood Pb (:g/dL) geometricmean (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-transformed) significantlyassociated with covariate adjusted increases in dfs:2–5 yr:∃= 1.78 (SE 0.59), p = 0.0046–11 yr:∃= 1.42 (SE 0.51), p = 0.007Increases in DFS:6–11 yr:∃= 0.48 (SE 0.22), p = 0.03∃12 yr:∃= 2.50 (SE 0.69), p < 0.001Increases in DMFS:∃12 yr:∃= 5.48 (SE 1.44), p = 0.01Odds ratio (OR) for caries (∃1 DMFS, ages 5–17 yr) and populationattributable risk (PAR) in association with 2nd or 3rd blood Pbtertiles, compared to 1st tertile were:1st tertile (#1.66:g/dL)2nd tertile (1.66–3.52:g/dL): OR = 1.36 (95% CI: 1.01, 2.83);PAR = 9.6%3rd tertile (>3.52:g/dL): OR = 1.66 (95% CI: 1.12, 2.48);PAR = 13.5%For an increase of blood Pb of 5:g/dL, OR = 1.8 (95% CI: 1.3, 2.5)Covariates retained were age, gender, race/ethnicity, poverty incomeratio, exposure to cigarette smoke, geographic region, educationallevel of head of household, carbohydrate and calcium intakes, anddental visits.

# AX6-256Table AX6-9.9 (cont’d). Effects of Leadon Bone and Teeth in Children and AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationUnited States(cont’d)Schwartz et al. (1986)U.S.1976–1980Design: cross-sectional national survey(NHANES II)Subjects: ages <7 yr (n = 2,695)Outcome measures: variables of stature,including height, weight, and chestcircumferenceAnalysis: multivariate weighted linearregressionBlood Pb (:g/dL) range:5-35Blood Pb levels were a statisticallysignificant predictor of children’sheight (p < 0.0001), weight (p< 0.001), and chest circumference(p < 0.026), after controlling for age in mos, race, sex, and nutrition.Height:∃=−0.119 (SE 0.0005)Weight:∃=−1.0217 (SE 0.08) for log-transformed blood PbChest circumference:∃=−0.6476 (SE 0.077) for log-transformedblood PbThere are several explanations for the inverse correlation betweenblood Pb and growth in children.First, blood Pb level may be acomposite factor for genetic, ethnic, nutritional, environmental, andsociocultural factors. Second, nutritional deficits that retard growthalso enhance Pb absorption. Finally, there may be a direct effect oflow level Pb on growth in children.Gemmel et al. (2002)Boston/Cambridge, MANRDesign: cross-sectionalSubjects: children (n = 543), ages 6–10 yrOutcome measures: number of caries (dfs,DFS)Analysis: multivariate linear regressionBlood 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 significantly associatedwith covariate-adjusted number of caries (dfs + DFS) (lntransformed) in the urban (∃= 0.22 [SE 0.08], p = 0.005) group, butnot in the rural group (∃=−0.15 [SE 0.09], p = 0.09). When dfsnumbers were stratified by permanent or deciduous teeth, the bloodPb association in the urban group was significant for deciduousteeth.(∃= 0.28, SE 0.09, p = 0.002), but not for permanent teeth (∃= 0.02,SE 0.07, p = 0.8).Covariates retained: age, sex, ethnicity, family income, education offemale guardian, maternal smoking,frequency of tooth brushing,firmness of toothbrush bristles,and frequency of chewing gum.Campbell et al. (2000)New York1995–1997Design: retrospective cohortSubjects: children (n = 154), ages 6.9–12 yrOutcome measures: prevalence of caries(dfs, DMFS)Analysis: multivariate logistic regressionBlood Pb (:g/dL) mean(range): 10.7 (18.0–36.8)(measured at ages 18 and37 mo)Covariate-adjusted odds ratios forcaries in association with bloodPb <10 or∃10:g/dL, were:permanent teeth (DMFS): OR =0.95 (95% CI: 0.43, 2.09)deciduous teeth (dfs): OR = 1.77 (95% CI: 0.97, 3.24)Covariates retained: age, gradein school, number of tooth surfacesat risk. Other covariates explored, that had no effect on strength ofassociation with blood Pb were: sex, ethnicity, and oral hygienescore.

# AX6-257Table AX6-9.9 (cont’d). Effects of Leadon Bone and Teeth in Children and AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAdultsUnited StatesDye et al. (2002)U.S.1988–1994Design: cross-sectional national survey(NHANES III)Subjects: adults in general population(n = 10,033; 5,255 females), ages 20–69 yrOutcome measures: symptoms ofperiodontal bone loss(attachment loss,periodontal pocket depth)Analysis: multivariate linear regressionBlood Pb (:g/dL) geometricmean (SE, range):2.5 (0.08) (2.36% > 10)Increasing blood Pb (log-transformed) was significantly associatedwith increasing prevalence of covariate-adjusted dental furcation(∃= 0.13 [SE 0.05], p = 0.005). Covariates retained: age, sex,race/ethnicity, education, smoking, and age of home. Smokingstatus interaction was significant when included in the model as aninteraction term (∃= 0.10 [SE 0.05], p = 0.034). When stratified bysmoking status, association betweendental furcation and blood Pbwas significant for current smokers (∃= 0.21 [SE 0.07], p = 0.004)and former smokers (∃= 0.17 [SE 0.07], p = 0.015), but not fornonsmokers (∃=−0.02 [SE 0.07], p = 0.747).EuropeTvinnereim et al.(2000)Norway1990–1994Design: cross-sectionalSubjects: 1,271 teeth samples collected bydentists in all 19 counties in NorwayAnalysis: Student’s t-test comparing metalconcentrations in teeth with caries, roots, andin different tooth groupsTooth Pb (:g/g tooth)geometric mean (SD,range):1.16 (1.72, 0.12–18.76)Also examined mercury, cadmium, and zinc. All tooth groups hadhigher Pb concentrations in cariousthan in non-carious teeth. Thegeometric mean Pb concentration in carious teeth was 1.36:g/gcompared to 1.10:g/g (p = 0.001).

# AX6-258Table AX6-9.10. Effects of Lead on Ocular Health in Children and AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationChildrenLatin AmericaRothenberg et al.(2002b)Mexico1987–1997Design = longitudinal (subset of prospective)Subjects: children (n = 45, 24 female), ages7–10 yrOutcome measures: ERGAnalysis: comparison of outcome measuresbetween blood Pbtertiles (ANOVA forrepeated 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 wkof 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 increasing maternal blood Pb at12 wk of gestation and increasing ERG a-wave (p = 0.025) and b-wave amplitude (p = 0.007), with significant increases in a-wave inthe 2nd blood Pb tertile (6.0–10.0:g/dL), and a-wave and b-wave inthe 3rd blood Pb tertile (10.5–32.5:g/dL), compared to the 1st bloodPb tertile.AdultsUnited StatesSchaumberg et al.(2004)Massachusetts1991–2002Design = longitudinal (subset of NormativeAging Study)Subjects: adult male (n = 642), mean age69 yr (range 60–93)Outcome measures: cataract diagnosisAnalysis: 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 (OR) for cataracts in 5thtibia bone Pb quintile (31.0–125:g/g), OR = 3.19 (95% CI: 1.48,6.90), p = 0.01. OR for cataractswere not significantly associatedwith patella bone Pb (5th quintile: 43.0–165:g/g), OR = 1.88 (95%CI: 0.88, 4.02), or blood Pb (5th quintile: 8.17–35.0:g/dL), OR =0.89 (95% CI: 0.46, 1.72).Covariates retained: age, smoking,history of diabetes, daily intakeof vitamin C, vitamin E, and carotenoids.

# AX6-259Table AX6-9.10 (cont’d). Effects of Lead on Ocular Health in Children and AdultsReference, StudyLocation, and PeriodStudy Description Pb Measurement Findings, InterpretationAdultsEuropeCavalleri et al. (1982)ItalyNRDesign = cross-sectional cohortSubjects: adult male vinyl chloride pipemanufacture workers, exposed to Pb stearate(n = 35), mean age 45 yr (SD 14, range 21–59); reference group (n = 35) matched forage, smoking, and alcohol consumption.Outcome measures: visual fieldAnalysis: comparison of outcome measuresbetween Pb workers and reference groupBlood 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 = 0.003) lower in Pb workerscompared to the reference group; however, visual sensitivity indexwas not significantly associated with blood or urine Pb. Mesopicfield scotoma prevalence was 10 of 35 (28%) in Pb workers and 0%in the reference group.

# AX6-260 

# REFERENCES

Abbate, C.; Buceti, R.; Munaò, F.; Giorgianni, C.; Ferrer i, G. (1995) Neurotoxicity induced by Pb levels: an

electrophysiological study. Int. Arch. Occup. Environ. Health 66: 389-392.

Adachi, J. D.; Arlen, D.; We bber, C. E.; Chettle, D. R.; Beaumont, L. F.; Gordon, C. L. (1998) Is there any

association between the presence of bone disease and cumulative exposur e to Pb? Calcif. Tissue Int.

63: 429-432.

Ades, A. E.; Kazantzis, G. (1988) Lung cancer in a non-ferrous smelter: the role of cadmium. Br. J. Ind. Med.

45: 435-442.

Agency for Toxic Substances and Diseas e Registry. (1993) Toxicological profile for cadmium. Atlanta, GA: U.S.

Department of Health & Human Services, Public Health Service; report no. ATSDR/TP-92/06. Available

from: NTIS, Springfield, VA; PB93-182418.

Agency for Toxic Substances and Disease Registry. (199 9) Toxicological profile for Pb. Atlanta, GA: U.S.

Department of Health and Human Services, Public Health Service.

Agency for Toxic Substances and Diseas e Registry. (2005) Toxicological profile for Pb [draft]. Atlanta, GA: U.S.

Department of Health and Human Services , Public Health Service. Available:

http://www.atsdr.cdc.gov/toxprofile s/tp13.pdf [5 May, 2006]. Ǻ kesson, A.; Lundh, T.; Vahter, M.; Bjelle rup, P.; Lidfeldt, J.; Nerbrand, C.; Go ran, S.; Strömberg, U.; Skerfving,

S. (2005) Tubular and glomerular kidney effects in Swedish women with low environmental cadmium

exposure. Environ. Health Perspect. 113: 1627-1631. Ǻ kesson, A. (2006) Personal communication [from Agneta Ǻ kesson to Virginia Weaver with attached

GFR plots]. April 12.

Al-Ashban, R. M.; Aslam, M.; Shah, A. H. (2004) Kohl (surma): a toxic traditional eye cosmetic study in Saudi

Arabia. Public Health 118: 292-298.

Al-Hakkak, Z. S.; Hamamy, H. A.; Murad, A. M.; Hussain, A. F. (1986) Chromosome ab errations in workers at a

storage battery plant in Iraq. Mutat. Res. 171: 53-60.

Al-Neamy, F. R.; Almehdi, A. M.; Alwash, R.; Pasha, M. A. H.; Ibrahim, A.; Bener, A. (2001) Occupational Pb

exposure and amino acid profiles and liver function te sts in industrial worker s. Int. J. Environ.

Health Res. 11: 181-188.

Al-Saleh, I.; Nester, M.; DeVol, E.; Shinwari, N.; Munchari, L.; Al-Shahria, S. (2001) Relationships between blood

Pb concentrations, intelligence, and academic achieveme nt of Saudi Arabian schoolgirls. Int. J. Hyg.

Environ. Health 204: 165-174.

Alessio, L.; Bertazzi, P. A.; Monelli, O.; Toffoletto, F. (1976) Free erythrocyte protoporphyr in as an indicator of the

biological effect of Pb in adult males. III. Behavior of free erythrocyte protoporphyrin in workers with past

Pb exposure. Int. Arch. Occup. Environ. Health 38: 77-86.

Alessio, L.; Castoldi, M. R.; Buratti, M.; Maroni, M.; Bertazzi, P. A. (1977) Behaviour of some indicators of

biological effect in female Pb workers. Int. Arch. Occup. Environ. Health 40: 283-292.

Alexander, B. H.; Checkoway, H.; Van Netten, C.; Muller, C. H.; Ewers, T. G.; Kaufman, J. D.; Mueller, B. A.;

Vaughan, T. L.; Faustman, E. M. (1996a) Semen quality of men employed at a Pb smelter. Occup. Environ.

Med. 53: 411-416.

Alexander, B. H.; Checkoway, H.; Van Netten, C.; Kaufman, J. D.; Vaughan, T. L.; Mueller, B. A.; Faustman, E. M.

(1996b) Paternal occupational Pb exposure and pregnancy outcome. Int. J. Occup. Environ. Health 2: 280-

285.

Alexander, B. H.; Checkoway, H.; Faustman, E. M.; Van Ne tten C.; Muller, C. H.; Ewers, T. G. (1998) Contrasting

associations of blood and semen Pb concentrations with semen quality among Pb smelter workers. Am. J.

Ind. Med. 34: 464-469.

Alfvén, T.; Järup, L.; Elinder, C.-G. (2002) Cadmium and Pb in blood in relation to low bone mineral density and

tubular proteinuria. Environ. Health Perspect. 110: 699-702.

Alomran, A. H.; Shleamoon, M. N. (1988) The influence of chronic Pb exposure on lymphocyte proliferative

response and immunoglobulin levels in storage battery workers. J. BioI. Sci. Res. 19: 575-585.

American Educational Research Association, Ameri can Psychological Association, National Council on

Measurement in Education. (1999) Standards for educational and psychological testing. Washington, DC:

American Psychological Association.

American Thoracic Society. (2000) What constitutes an advers e health effect of air pollu tion? Am. J. Respir. Crit.

Care Med. 161: 665-673.

# AX6-261 Anetor, J. I.; Adeniyi, F. A. A. (1998) Decreased immune status in Nigerian workers occupationally exposed to Pb.

Afr. J. Med. Med. Sci. 28: 169-172.

Angell, N. F.; Lavery, J. P. (1982) The relationship of blood levels to obstetric outcome. Am. J. Obstet. Gynecol.

142: 40-46.

Angle, C. B.; Kuntzelman, D. R. (1989) Increased erythrocyte protoporphyrins and blood Pb; a pilot study of

childhood growth patterns. J. Toxicol. Environ. Health 26: 149-156.

Angle, C. R.; McIntire, M. S. (1978) Low level Pb and in hibition of erythrocyte pyrimidine nucleotidase. Environ.

Res. 17: 296-302.

Angle, C. R.; McIntire, M. S.; Swanson, M. S.; Stohs, S. J. (1982) Erythrocyte nucleotides in children - increased

blood Pb and cytidine triphosphate. Pediatr. Res. 16: 331-334.

Annesi-Maesano, I.; Pollitt, R.; King, G.; Bousquet , J.; Hellier, G.; Sahuquillo, J.; Huel, G. (2003) In utero exposure

to Pb and cord blood total IgE. Is there a connection? Allergy 58: 589-594.

Annest, J. L.; Pirkle, J. L.; Makuc, D.; Neese, J. W.; Bayse, D. D.; Kovar, M. G. (1983) Chronological trend in

blood Pb levels between 1976 and 1980. N. Engl. J. Med. 308: 1373-1377.

Anttila, A.; Heikkila, P.; Pukkala, E.; Nykyri, E.; Kauppin en, T.; Hernberg, S; Hemminki, K. (1995) Excess lung

cancer among workers exposed to Pb. Scand. J. Work Environ. Health. 21: 460-469.

Anttila, A.; Heikkila, P.; Nykyri, E.; Kauppinen, T.; Pukk ala, E.; Hernberg, S.; Hemminki, K. (1996) Risk of

nervous system cancer among workers exposed to Pb. J. Occup. Environ. Med. 38: 131-136.

Apostoli, P.; Maranelli, G.; Dei Cas, L.; Micciolo, R. (1990) Blood Pb and blood pressure: a cross sectional study in

a general population group. Cardiologia 35: 597-603.

Apostoli, P.; Kiss, P.; Porru, S.; Bonde, J. P.; Va nhoorne, M.; the ASCLEPIOS study group. (1998) Male

reproductive toxicity of Pb in animals and humans. Occup. Environ. Med. 55: 364-374.

Apostoli, P.; Bellini, A.; Porru, S.; Bisa nti, L. (2000) The effect of Pb on male fertility: a time to pregnancy (TTP)

study. Am. J. Ind. Med. 38: 310-315.

Armon, C.; Kurland, L. T.; Daube, J. R.; Obrien, P. C. (1991) Epidemiologic correlates of sporadic amyotrophic

lateral sclerosis. Neurology 41: 1077-1084.

Arnvig, E.; Grandjean, P.; Beckmann, J. (1980) Neurotoxic effects of heavy Pb exposure determined with

psychological tests. Toxicol. Lett. 5: 399-404.

Aro, A. C. A.; Todd, A. C.; Amarasiriwardena, C.; Hu, H. (1994) Improvemen ts in the calibration of 109 

# Cd K x-ray

fluorescence systems for measuring bone Pb in vivo . Phys. Med. Biol. 39: 2263-2271.

Assennato, G.; Paci, C.; Baser, M. E.; Molinini, R.; Cand ela, R. G.; Altamura, B. M.; Giorgino, R. (1986) Sperm

count suppression without endocrine dysfunction in Pb-exposed men. Arch. Environ. Health 41: 387-390.

Assennato, G.; Baser, M.; Molinini, R.; Candela, R. G.; Altamura, B. M.; Gi orgino, R.; Abbaticchio, G.; Paci, C.

(1987) Sperm count suppression without endocrine dysfunction in Pb-exposed men. Arch. Environ. Health

42: 124-127.

Astrin, K. H.; Bishop, D. F.; Wetmur, J. G.; Kaul, B.; Davidow, B.; Desnick, R. J. (1987) δ -aminolevulinic acid

dehydratase isozymes and Pb toxicity. In: Silbergeld, E. K.; Fowler, B. A., eds. Mechanisms of chemicalinduced porphyrinopathies. New York, NY: New York Academy of Sciences; pp. 23-29. (Annals of the

New Yord Academy of Sciences: v. 514).

Auger, J.; Kunstmann, J. M.; Czyglik, F.; Jouannet, P. (1995) Decline in semen quality among fertile men in Paris

during the past 20 yrs. N. Engl. J. Med. 332: 281-285.

Awad El Karim, M. A.; Hamed, A. S.; Elhaimi, Y. A.; Osma n, Y. (1986) Effects of exposure to Pb among Pb-acid

battery factory workers in Sudan. Arch. Environ. Health 41: 261-265.

Axelson, O.; Steenland, K. (1988) Indir ect methods of assessing the effects of tobacco use in occupational studies.

Am. J. Ind. Med. 13: 105-118.

Ayatollahi, M. (2002) Study of the impact of blood Pb level on humoral immunity in humans. Toxicol. Ind.

Health 18: 39-44.

Azcona-Cruz, M. I.; Rothenberg, S. J.; Schnaas-Arrieta, L.; Romero-Placeres, M.; Perroni-Hernández, E. (2000)

Niveles de plomo en sangre en niños de 8 a 10 años y su relación con la alteración en el sistema visomotor

y del equilibrio [Relationship of blood Pb levels with visual-motor and equilibrium disturbances in children

aged 8 to 10 yrs]. Salud Publica Mex. 42: 279-287.

Baghurst, P. A.; McMichael, A. J.; Wigg, N. R.; Vimpani, G. V.; Robertson, E. F.; Roberts, R. J.; Tong, S.-L.

(1992) Environmental exposure to Pb and children's intelligence at the age of seven yrs: the Port Pirie

cohort study. N. Engl. J. Med. 327: 1279-1284.

# AX6-262 Baghurst, P. A.; McMichael, A. J.; Tong, S.; Wigg, N. R.; Vimpani, G. V.; Robertson, E. F. (1995) Exposure to

environmental Pb and visual-motor integration at age 7 yrs: the Port Pirie cohort study. Epidemiology 6:

104-109.

Bairati, C.; Goi, G.; Bollini, D.; Ro ggi, C.; Luca, M.; Apostoli, P.; Lomb ardo, A. (1997) Effects of Pb and

manganese on the release of lysosomal enzymes in vitro and in vivo. Clin. Chim. Acta 261: 91-101.

Baird, D. D.; Wilcox, A. J.; Weinberg, C. R. (1986) Use of time to pregnancy to study environmental exposures.

Am. J. Epidemiol. 124: 470-480.

Baker, E. L., Jr.; Landrigan, P. J.; Barbour, A. G.; Cox, D. H.; Folland, D. S.; Ligo, R. N.; Throckmorton, J. (1979)

Occupational Pb poisoning in the United States: clinical and biochemical findings related to blood Pb

levels. Br. J. Ind. Med. 36: 314-322.

Balbus, J. M.; Stewart, W.; Bolla, K. I.; Schwartz, B. S. (1 997) Simple visual react ion time in organolead

manufacturing workers: comparison of different methods of modeling Pb exposure and reaction time. Am.

J. Ind. Med. 32: 544-549.

Balbus, J. M.; Stewart, W.; Bolla, K. I.; Schwartz, B. S. (1 998) Simple visual react ion time in organolead

manufacturing workers: influence of the interstimulus interval. Arch. Environ. Health 53: 264-270.

Balbus-Kornfeld, J. M.; Stewart, W.; Bolla, K. I.; Schwartz, B. S. (1995) Cumulative exposure to inorganic Pb and

neurobehavioural test performance in adults: an epidemiological review. Occup. Environ. Med. 52: 2-12.

Ball, G. V.; Sorensen, L. B. (1969) Pathogenesis of hyperuricemia in saturnine gout. N. Engl. J. Med.

280: 1199-1202.

Ballard, J. L.; Novak, K. K.; Driver, M. (1979) A simplif ied score for assessment of fetal maturation of newly born

infants. J. Pediatr. 95: 769-774.

Baloh, R. W.; Spivey, G. H.; Brown, C. P.; Morgan, D.; Campion, D. S.; Browdy, B. L.; Valen tine, J. L. (1979)

Subclinical effects of chronic increased Pb absorption - a prospective study. II. Results of baseline

neurologic testing. J. Occup. Med. 21: 490-496.

Barltrop, D. (1969) Transfer of Pb to the human foetus. In: Barltrop, D.; Burl and, W. L., eds. Mineral metabolism in

pediatrics. Philadelphia, PA: F. A. Davis Co.; pp. 135-151.

Barth, A.; Schaffer, A. W.; Osterode, W.; Winker, R.; Konnaris, C.; Valic, E.; Wolf, C.; Rüdiger, H. W. (2002)

Reduced cognitive abilities in Pb-exposed men. Int. Arch. Occup. Environ. Health 75: 394-398. Basaran, N.; Ündeger, U. (2000) Effects of Pb on immune parameters in occupationally exposed workers. Am. J.

Ind. Med. 38: 349-354.

Battistuzzi, G.; Petrucci, R.; Silvagni, L. ; Urbani, F. R.; Caiola, S. (1981) δ -aminolevulinate dehydrase: a new

genetic polymorphism in man. Ann. Hum. Genet. 45: 233-229.

Batuman, V. (1993) Pb nephropathy, gout, and hypertension. Am. J. Med. Sci. 305: 241-247.

Bauchinger, M.; Dresp, J.; Schmid, E.; Englert, N.; Krause, Chr. (1977) Chromosome analyses of children after

ecological Pb exposure. Mutat. Res. 56: 75-80.

Behringer, D.; Craswell, P.; Mohl, C.; Stoeppler, M.; Ritz, E. (1986) Urinar y Pb excretion in uremic patients.

Nephron 42: 323-329.

Bellinger, D. C. (1995) Interpreting the literature on Pb and child development: the neglected role of the

"experimental system." Neurotoxicol. Teratol. 17: 201-212.

Bellinger, D. C. (2000) Effect modification in epidemiologic studies of low-level neurotoxicant exposures and

health outcomes. Neurotoxicol. Teratol. 22: 133-140.

Bellinger, D. (2002) Perspectives on incorporating human neurobehavioral end points in risk assessments. Risk

Anal. 22: 487-498.

Bellinger, D. C. (2003) Perspectives on incorporating human neurobehavioral end points in risk assessments. Risk

Anal. 23: 163-174.

Bellinger, D. C. (2004) Assessing environmental neurotoxicant exposures and child neurobehavior: confounded by

confounding? Epidemiology 15: 383-384.

Bellinger, D. C. (2005) Teratogen update: Pb and pregnancy. Birth Defects Res. Part A 73: 409-420.

Bellinger, D. C.; Needleman, H. L. (2003) Intellectual impairment and blood Pb levels [letter]. N. Engl. J. Med. 349:

500.

Bellinger, D.; Rappaport, L. (2002) Developmental assessment and interventions. In: Managing elevated blood Pb

levels among young children: recommendations from the Advisory Committee on Childhood Pb Poisoning

Prevention. Atlanta, GA: Centers for Disease Control; pp. 79-95.

Bellinger, D.; Needleman, H. L.; Bromfield, R.; Mintz, M. (1984) A followup study of the academic attainment and

classroom behavior of children with elevated dentine Pb levels. Biol. Trace Elem. Res. 6: 207-223.

# AX6-263 Bellinger, D.; Leviton, A.; Waternaux, C.; Needleman, H.; Rabinowitz, M. (1987) Longitudinal analyses of prenatal

and postnatal Pb exposure and early cognitive de velopment. N. Engl. J. Med. 316: 1037-1043.

Bellinger, D.; Leviton, A.; Waternaux, C.; Needleman, H. ; Rabinowitz, M. (1988) Low-level Pb exposure, social

class, and infant development. Neurotoxicol. Teratol. 10: 497-503.

Bellinger, D.; Leviton, A.; Waternaux, C. (1989) Pb, IQ and social cla ss. Int. J. Epidemiol. 18: 180-185.

Bellinger, D.; Leviton, A.; Rabinowitz, M.; Allred, E.; Needleman, H.; Schoenbaum, S. (1991) Weight gain and

maturity in fetuses exposed to low levels of Pb. Environ. Res. 54: 151-158.

Bellinger, D. C.; Stiles, K. M.; Needleman, H. L. (1992) Low-level Pb exposure, intelligence and academic

achievement: a long-term follow-up study. Pediatrics 90: 855-861.

Bellinger, D.; Hu, H.; Titlebaum, L.; Needleman, H. L. (19 94a) Attentional correlates of dentin and bone Pb levels

in adolescents. Arch. Environ. Health 49: 98-105.

Bellinger, D.; Leviton, A.; Allred, E.; Rabinowitz, M. (1994b) Pre- and postnatal Pb exposure and behavior

problems in school-aged children. Environ. Res. 66: 12-30.

Bellinger, D. C.; Hu, H.; Kalaniti, K.; Thomas, N.; Rajan, P.; Sambandam, S.; Ramaswamy, P.; Balakrishnan, K.

(2005) A pilot study of blood Pb levels and neurobehavioral function in children living in Chennai, India.

Int. J. Occup. Environ. Health 11: 138-143.

Benetou-Marantidou, A.; Nakou, S.; Micheloyannis, J. (1988) Neurobehavioral estimation of children with life-long

increased Pb exposure. Arch. Environ. Health 43: 392-395.

Benoff, S.; Centola, G. M.; Millan, C.; Napolitano, B.; Ma rmar, J. L.; Hurley, I. R. (2003a) Increased seminal

plasma Pb levels adversely affect the fertility pot ential of sperm in IVF. Hum. Reprod. 18: 374-383.

Benoff, S.; Hurley, I. R.; Millan, C.; Napolitano, B.; Cent ola, G. M. (2003b) Seminal Pb concentrations negatively

affect outcomes of artificial insemi nation. Fertil. Steril. 80: 517-525.

Bercovitz, K.; Laufer, D. (1991) Age and gender influence on Pb accumulation in root dentine of human permanent

teeth. Arch. Oral Biol. 36: 671-673.

Bergdahl, I. A.; Gerhardsson, L.; Schütz, A.; Desnick, R. J.; Wetmur, J. G.; Skerfving, S. (1997) Deltaaminolevulinic acid dehydratase polymorphism: influence on Pb levels and kidney function in humans.

Arch. Environ. Health 52: 91-96.

Bergeret, A.; Pouget, E.; Tedone, R.; Meygert, T.; Cadot, R.; Descotes, J. (1990) Neutrophil functions in Pbexposed workers. Hum. Exp. Toxicol. 9: 231-233.

Bernard, A. (2004) Renal dysfunction induced by cadmium: biomarkers of critical effects. Biometals 17: 519-523.

Bernard, A.; Thielemans, N.; Roels, H.; Lauwerys, R. (1995a) Association between NAG-B and cadmium in urine

with no evidence of a threshold. Occup. Environ. Med. 52: 177-180.

Bernard, A. M.; Vyskocil, A.; Roels, H. ; Kriz, J.; Kodl, M.; Lauwer ys, R. (1995b) Renal effects in children living in

the vicinity of a Pb smelter. Environ. Res. 68: 91-95.

Bhattacharya, A.; Shukla, R.; Dietrich, K.; Bornschein, R.; Berger, O. (1995) Effect of early Pb exposure on

children's postural balance. Dev. Med. Child Neurol. 37: 861-878.

Bleecker, M.; Bolla-Wilson, K.; Kawas, C. ; Agnew, J. (1988) Age-specific no rms for the mini-mental state exam.

Neurology 38: 1565-1568.

Bleecker, M. L.; Lindgren, K. N.; Ford, D. P. (1997a) Differential contribution of current and cumulative indices of

Pb dose to neuropsychological performance by age. Neurology 48: 639-645.

Bleecker, M. L.; Lindgren, K. N.; Tibu rzi, M. J.; Ford, D. P. (1997b) Cu rvilinear relationship between blood Pb

level and reaction time. Differential association with blood Pb fractions derived from exogenous and

endogenous sources. J. Occup. Environ. Med. 39: 426-431.

Bleecker, M. L.; Lindgren, K. N.; Ford, D. P.; Tiburzi, M. J. (2002) The inte raction of education and cumulative Pb

exposure on the mini-mental state examinatio n. J. Occup. Environ. Med. 44: 574-578.

Bleecker, M. L.; Ford, D. P.; Lindgren, K. N.; Scheetz, K.; Tiburzi, M. J. (2 003) Association of chronic and current

measures of Pb exposure with different components of brainstem auditory evoked potentials.

Neurotoxicology 24: 625-631.

Bleecker, M. L.; Ford, D. P.; Lindgren, K. N.; Hoese, V. M.; Wa lsh, K. S.; Vaughan, C. G. (2005a) Differential

effects of Pb exposure on components of verbal memory. Occup. Environ. Med. 62: 181-187.

Bleecker, M. L.; Ford, D. P.; Baughan, C. G.; Lindgren, K. N.; Tiburzi, M. J.; Walsh, K. S. (20 05b) Effect of Pb

exposure and ergonomic stressors on peripheral nerve function. Environ. Health Perspect. 113: 1730-1734.

Boey, K. W.; Jeyaratnam, J. (1988) A discriminant analysis of neuropsychological effect of low Pb exposure.

Toxicology 49: 309-314.

Bogden, J. D.; Thind, I. S.; Louria, D. B.; Caterini, H. (1978) Maternal and cord blood metal concentrations and low

birth weight—a case-control study. Am. J. Clin. Nutr. 31: 1181-1187.

# AX6-264 Bolla, K. I.; Schwartz, B. S.; Stewart, W.; Rignani, J.; Agnew, J.; Ford, D. P. (1995) Comparison of neurobehavioral

function in workers exposed to a mixture of organic and inorganic Pb and in workers exposed to solvents.

Am. J. Ind. Med. 27: 231-246.

Bonde, J. P. E.; Kolstad, H. (1997) Fertility of Danish battery workers ex posed to Pb. Int. J. Epidemiol.

26: 1281-1288.

Bonde, J. P.; Joffe, M.; Apostoli, P.; Dale, A. Kiss, P.; Spano, M.; Caruso, F. ; Giwercman, A.; Bisanti, L.; Porru, S.;

Vanhoorne, M.; Comhaire, F.; Zschiesche, W. (2002) Sperm count and chromatin structure in men exposed

to inorganic Pb: lowest adverse effect levels. Occup. Environ. Med. 59: 243-242.

Borja-Aburto, V. H.; Hertz-Picciotto, I. ; Lopez, M. R.; Farias, P.; Rios, C.; Blanco, J. (1999) Blood Pb levels

measured prospectively and risk of spontaneous abortion. Am. J. Epidemiol. 150: 590-597.

Bornschein, R. L.; Rabinowitz, M. B. (1985) The second international conference on prospective studies of Pb -

foreword. Environ. Res. 38: 1-2.

Bornschein, R. L.; Grote, J.; Mitchell, T., Succop. P. A.; Dietrich, K. N.; Krafft, K. M.; Hammond, P. B. (1989)

Effects of prenatal Pb exposure on in fant size at birth. In: Smith, M. A.; Grant, L. D.; Sors, A. I., eds. Pb

exposure and child development: an international assessment [workshop organized by the Commission of

the European Communities and the U.S. Environmental Protection Agency]; September 1986; Edinburgh,

United Kingdom. Dordrecht, The Netherlands: Kluwer Academic Publishers BV; pp. 307-319.

Bost, L.; Primatesta, P.; Dong, W.; Poulter, N. (1999) Blood Pb and blood pressure: evidence from the Health

Survey for England 1995. J. Hum. Hypertens. 13: 123-128.

Bound, J. P.; Harvey, P. W.; Francis, B. J.; Awwad, F.; Gatrell, A. C. (1997) Involvement of deprivation and

environmental Pb in neural tube defects: a matched case-control study. Arch. Dis. Child. 76: 107-112.

Bratton, G. R.; Hiney, J. K.; Dees, W. L. (1994) Pb (Pb) alters the norepinephrine-indu ced secretion of luteinizing

hormone releasing hormone from the medium eminence of adult male rats in vitro . Life Sci. 55: 563-571.

Braun, C. M. J.; Daigneault, S. (1991) Sparing of cognitive executive functions and impairment of motor functions

after industrial exposure to Pb: a field study with control group. Neuropsychology 5: 179-193.

Braunstein, G. D.; Dahlgren, J.; Loriau x, D. L. (1978) Hypogonadism in chronically Pb-poisoned men. Infertility 1:

33-51.

Brody, D. J.; Pirkle, J. L.; Kramer, R. A.; Flegal, K. M.; Matte, T. D.; Gu nter, E. W.; Paschal, D. C. (1994) Blood

Pb levels in the US population: phase 1 of the third National Health and Nutrition Examination Survey

(NHANES III, 1988 to 1991). JAMA J. Am. Med. Assoc. 272: 277-283.

Buchet, J. P.; Lauwer ys, R.; Roels, H.; Bernard, A.; Bruaux, P.; Claey s, F.; Ducoffre, G.; De Plaen, P.; Staesen, J.;

Amery, A.; Linjen, P.; Thijs, L.; Rondia, D.; Sartor, F.; Saint Remy, A.; Nick, L. (1990) Renal effects of

cadmium body burden of the general population. Lancet 336: 699-702.

Burns, J. M.; Baghurst, P. A.; Sawyer, M. G.; McMichael, A. J.; Tong, S.-L. (1999) Lifetime low-level exposure to

environmental Pb and children's emotional and behavioral development at ages 11-13 yrs. The Port Pirie

cohort study. Am. J. Epidemiol. 149: 740-749.

Campara, P.; D'Andrea, F.; Micciolo, R.; Savonitto , C.; Tansella, M.; Zimmermann-Tansella, C. (1984)

Psychological performance of workers with blood-Pb concentration below the current threshold limit value.

Int. Arch. Occup. Environ. Health 53: 233-246.

Campbell, B. C.; Meredith, P. A.; Sc ott, J. J. C. (1985) Pb exposure and changes in the renin-angiotensinaldosterone system in man. Toxicol. Lett. 25: 25-32.

Campbell, J. R.; Moss, M. E.; Rauberta s, R. F. (2000) The association be tween caries and childhood Pb exposure.

Environ. Health Perspect. 108: 1099-1102.

Canfield, R. L.; Henderson, C. R., Jr.; Cory-Slechta, D. A.; Cox, C.; Jusko, T. A.; Lanphear, B. P. (2003a)

Intellectual impairment in children with blood Pb concentrations below 10 μ g per deciliter. N. Engl. J.

Med. 348: 1517-1526.

Canfield, R. L.; Kreher, D. A.; Cornwell, C.; Henderson , C. R., Jr. (2003b) Low-level Pb exposure, executive

functioning, and learning in early childhood. Child Neuropsychol. 9: 35-53.

Canfield, R. L.; Gendle, M. H.; Cory-Sl echta, D. A. (2004) Impaired neuropsychological functioning in Pb-exposed

children. Dev. Neuropsychol. 26: 513-540.

Cantarow, A.; Trumper, M. (1944) Pb poisoning. Baltimore, MD: Williams & Wilkins Co.

Cárdenas, A.; Roels, H.; Bernard, A. M.; Barbon, R.; Buchet, J. P.; Lauwerys, R. R.; Rose lló, J.; Ramis, I.; Mutti,

A.; Franchini, I.; Fels, L. M.; Stolte, H.; De Broe, M. E.; Nuyts, G. D.; Taylor, S. A.; Price, R. G. (1993)

Markers of early renal changes induced by industrial pollutants. II. Application to workers exposed to Pb.

Br. J. Ind. Med. 50: 28-36.

# AX6-265 Cardozo dos Santos, A.; Colacciopo, S.; Bó, C. M. R. dal; Santos, N. A. G. dos. (1994) Occupational exposure to

Pb, kidney function tests, and blood pressure. Am. J. Ind. Med. 26: 635-643.

Carta, P.; Cocco, P.; Picchiri, G. ( 1994) Lung cancer mortality and airway s obstruction among metal miners exposed

to silica and low levels of radon daughters. Am. J. Ind. Med. 25: 489-506.

Carta, P.; Aru, G.; Cadeddu, C.; Nieddu , V.; Polizzi, M.; Nurchis, P.; Flore, C.; Salis, S.; Randaccio, F. S. (2003)

Mortalità per cancro polmonare in lavoratori di una fonderia di piombo della Sardegna [Follow-up: 1972-

2001] [Lung cancer mortality among workers of a Sardinian Pb smelte r]. G. Ital. Med. Lav. Ergon.

25(suppl. 3): 17-18.

Carta, P.; Aru, G.; Nurchis, P.; Cade ddu, C.; Polizzi, M.; Nieddu , V.; Salis, G.; Gaviano, L.; Flore, C.; Randaccio,

F. S. (2005) Studio di mortalità per cause specifiche in lavoratori di una fonderia di piombo e zinco della

Sardegna. G. Ital. Med. Lav. Ergon. 27(suppl. 1): 43-45.

Casey, C. E.; Robinson, M. F. (1978) Copper, manganese, zinc, nickel, cadmium and Pb in human foetal tissue. Br.

J. Nutr. 39: 639-646.

Cavalleri, A.; Trimarchi, F.; Gelmi, C.; Baruffini, A.; Minoia, C.; Biscaldi, G.; Gallo, G. (1982) Effects of Pb on the

visual system of occupationally exposed subjects. Scan d. J. Work Environ. Health 8(suppl. 1): 148-151.

Cecil, K. M.; Yuan, W.; Holland, S.; Wessel, S.; Dietri ch, K.; Ris, D.; Lanphear, B. (2005) The influence of

childhood Pb exposure on language function in young adults: an fMRI study. Presented at: International

Society for Magnetic Resonance Imaging: 12th scientif ic meeting and exhibition; May; Miami, FL; A1443.

Centers for Disease Control and Prevention. (1991) Preventing Pb poisoning in young children: a statement by the

Centers for Disease Control. Atlanta, GA: U.S. De partment of Health and Human Services; October.

Centers for Disease Control and Preventio n. (1993) Pb poisoning associated with use of traditional ethnic remedies.

Morb. Mortal. Wkly. Rep. 42: 521-524.

Centers for Disease Control and Preven tion. (1997) Update: blood Pb levels - United States, 1991-1994. Morb.

Mortal. Wkly. Rep. 46: 141-146.

Centers for Disease Control and Prevention. (2000) Blood Pb levels in young children

― United States and selected

states, 1996-1999. Morb. Mortal. Wkly. Rep. 49: 1133-1137.

Centers for Disease Control and Prevention. (2005) Preventing Pb poisoning in young children: a statement by

the Centers for Disease Control - August 2005. Atlanta, GA: U.S. Department of Health & Human

Services, Public Health Service. Washington, DC: U.S. Environmental Protection Agency; document

ID EPA-HQ-ORD-2004-0018-0105.1. Available: http://www.regulations.gov/fdmspublic/component/main

[5 July, 2006].

Chalkley, S. R.; Richmond, J.; Barltrop, D. (1998) Measurement of vitamin D 3 

# metabolites in smelter workers

exposed to Pb and cadmium. Occup. Environ. Med. 55: 446-452.

Chancellor, A. M.; Slattery, J. M.; Fraser, H.; Warlow, C. P. (1993) Risk factors for motor neuron disease: a casecontrol study based on patients from the Scottish Moto r Neuron Disease Register . J. Neurol. Neurosurg.

Psychiatry 56: 1200-1206.

Chaube, S.; Swinyard, C. A.; Nishimura, H. (1972) A quantitative study of human embryonic and fetal Pb

with considerations of maternal fetal Pb gradients and the effect of Pb on human reproduction. Teratology

5: 253.

Chen, A.; Dietrich, K. N.; Ware, J. H.; Radcliffe, J.; Rogan, W. J. (2005) IQ and blood Pb from 2 to 7 yrs of age: are

the effects in older children the residual of high blood Pb concentrations in 2-yr-olds? Environ. Health

Perspect. 113: 597-601.

Chen, A.; Rhoads, G. G.; Cai, B.; Salganik, M.; Rogan, W. J. (2006) The effect of chelation on blood pressure in Pbexposed children: a randomized study. Environ. Health Perspect. 114: 579-583.

Cheng, Y.; Schwartz, J.; Vokonas, P. S.; Weiss, S. T.; Aro, A.; Hu, H. (1998) Electrocardiographic conduction

disturbances in association with low-level Pb exposu re (the Normative Aging Study). Am. J. Cardiol.

82: 594-599.

Cheng, Y.; Schwartz, J.; Sparrow, D.; Aro, A.; Weiss, S. T.; Hu, H. (2001) Bone Pb and blood Pb levels in relation

to baseline blood pressure and the prospective development of hypertension: the Normative Aging Study.

Am. J. Epidemiol. 153: 164-171.

Chia, S. E.; Chua, L. H.; Ng, T. P.; Fo o, S. C.; Jeyaratnam, J. (1994a) Postur al stability of workers exposed to Pb.

Occup. Environ. Med. 51: 768-771.

Chia, K. S.; Mutti, A.; Tan, C.; Ong, H. Y.; Jeyaratnam, J.; Ong, C. N. ; Lee, E. (1994b) Urinary N-acetyl- β

- D



# glucosaminidase activity in workers exposed to inorganic Pb. Occup. Environ. Med. 51: 125-129.

Chia, K. S.; Mutti, A.; Alinovi, R.; Jeya ratnam, J.; Tan, C.; Ong, C. N.; Lee, E. (1994c) Urinary excretion of tubular

brush-border antigens among Pb exposed workers. Ann. Acad. Med. Singapore 23: 655-659.

# AX6-266 Chia, K. S.; Jeyaratnam, J.; Tan, C.; Ong, H. Y.; Ong, C. N.; Lee, E. (1995a) Glomerular function of Pb-exposed

workers. Toxicol. Lett. 77: 319-328.

Chia, K. S.; Jeyaratnam, J.; Lee, J.; Tan, C.; Ong, H. Y. ; Ong, C. N.; Lee, E. (1995b) Pb-induced nephropathy:

relationship between various biological exposure indices and early markers of nephrotoxicity. Am. J. Ind.

Med. 27: 883-895.

Chia, S.-E.; Chia, K.-S; Chia, H.-P.; Ong, C.-N.; Jeya ratnam, J. (1996a) Three-yr follow-up of serial nerve

conduction among Pb-exposed workers. Scand. J. Work Environ. Health 22: 374-380.

Chia, S. E.; Chia, H. P.; Ong, C. N.; Jeyaratnam, J. (1996b) Cumulative blood Pb levels and nerve conduction

parameters. Occup. Med. 46: 59-64.

Chia, S. E.; Chia, H. P.; Ong, C. N.; Jeyaratnam, J. (1 996c) Cumulative concentrations of blood Pb and postural

stability. Occup. Environ. Med. 53: 264-268.

Chia, S.-E.; Chia, H.-P.; Ong, C.-N.; Jeyaratnam, J. (1997) Cumulative blood Pb levels and neurobehavioral test

performance. Neurotoxicology 18: 793-803.

Chia, S. E.; Yap, E.; Chia, K. S. (2004) δ -aminolevulinic acid dehydratase (A LAD) polymorphism and susceptibility

of workers exposed to inorganic Pb and its effects on neurobehavioral functions. Neurotoxicology 25:

1041-1047.

Chiodo, L. M.; Jacobson, S. W.; Jacobson, J. L. (2004) Neurodevelopmental effects of postnatal Pb exposure at very

low levels. Neurotoxicol. Teratol. 26: 359-371.

Chowdhury, A. R.; Chinoy, N. J.; Gautam, A. K.; Rao, R. V.; Parikh, D. J.; Shah , G. M.; Highland, H. N.; Patel, K.

G.; Chatterjee, B. B. (1986) Effect of Pb on human semen. Adv. Contracept. Delivery Syst. 2: 208-210.

Chu, N.-F.; Liou, S.-H.; Wu, T.-N.; Chang, P.-Y. (1999) Reappraisal of the relation be tween blood Pb concentration

and blood pressure among the general population in Taiwan. Occup. Environ. Med.

56: 30-33.

Chuang, H.-Y.; Schwartz, J.; Tsai, S.-Y.; Lee, M.-L. T.; Wa ng, J.-D.; Hu, H. (2000) Vibration perception thresholds

in workers with long term exposure to Pb. Occup. Environ. Med. 57: 588-594.

Chuang, H. Y.; Schwartz, J.; Gonzales-Cossio, T.; Lugo, M. C.; Palazuelos, E.; Aro, A.; Hu, H.; Hernandez-Avila,

M. (2001) Interrelations of Pb levels in bone, venous blood, and umbilical cord blood with exogenous Pb

exposure through maternal plasma Pb in peripartum women. Environ. Health Perspect. 109: 527-532.

Chuang, H.-Y.; Yu, K.-T.; Ho, C.-K.; Wu , M.-T.; Lin, G.-T.; Wu, T.-N. (2004) Investigations of vitamin D receptor

polymorphism affecting workers' susceptibility to Pb. J. Occup. Health 46: 316-322.

Chuang, H.-Y.; Chao, K.-Y.; Tsai, S.-Y. (2005) Reversible neurobehavioral performance with reductions in blood

Pb levels–a prospective study on Pb workers. Neurotoxicol. Teratol. 27: 497-504.

Clark, A. R. L. (1977) Placen tal transfer of Pb and its effects on the newborn. Post grad. Med. J. 53: 674-678.

Clark, C. S.; Bornschein, R. L.; Succo p, P.; Que Hee, S. S.; Hammond, P. B.; Peace, B. (1985) Condition and type

of housing as an indicator of potential environmental Pb exposure and pediatric blood Pb levels. Environ.

Res. 38: 46-53.

Cocco, P. L.; Carta, P.; Belli, S.; Picchir i, G. F.; Flore, M. V. (1994a) Mortality of Sardinian Pb and zinc miners:

1960-88. Occup. Environ. Med. 51: 674-682.

Cocco, P. L.; Carta, P.; Flore, V.; Picchiri, G. F.; Zucca, C. (1994b) Lung cancer mortality among female mine

workers exposed to silica. J. Occup. Med. 36: 894-898.

Cocco, P.; Salis, S.; Anni, M.; Cocco, M. E.; Flore, C.; Ib ba, A. (1995) Effects of short-term occupational exposure

to Pb on erythrocyte glucose-6-phosphate dehydrogenase activity and serum cholesterol. J. Appl. Toxicol.

15: 375-378.

Cocco, P.; Carta, P.; Flore, C.; Congia, P.; Manca, M. B.; Saba, G.; Salis, S. (1996) Mortality of Pb smelter workers

with the glucose-6-phosphate dehydrogenase-deficient phenotype. Cancer Epidemiol. Biomarkers Prev. 5:

223-225.

Cocco, P.; Hua, F.; Boffetta, P.; Carta, P. ; Flore, C.; Flore, V.; Onnis, A.; Picch iri, G. F.; Colin, D. (1997) Mortality

of Italian Pb smelter workers. Scand. J. Work Environ. Health 23: 15-23.

Cocco, P.; Dosemeci, M.; Heineman, E. F. (1998a) Brain cancer and occupa tional exposure to Pb. J. Occup.

Environ. Med. 40: 937-942.

Cocco, P.; Dosemeci, M.; Heineman, E. F. (1998b) Occupational risk factor s for cancer of the central nervous

system: A case-control study of death certificates fr om 24 U.S. States. Am. J. Ind. Med. 33: 247-255.

Cocco, P.; Ward, M. H.; Dosemeci, M. (1999) Risk of stomach cancer associated with 12 workplace hazards:

Analysis of death certificates from 24 states of the United States with the aid of job exposure matrices.

Occup. Environ. Med. 56: 781-787.

Cockcroft, D. W.; Gault, M. H. (1976) Prediction of crea tinine clearance from serum cr eatinine. Nephron 6: 31-41.

# AX6-267 Cohen, N.; Modai, D.; Golik, A.; Weissgarten, J.; Peller, S.; Katz, A.; Averbukh, Z.; Sh aked, U. (1989) Increased

concanavalin A-induced suppressor cell activity in hu mans with occupational Pb exposure. Environ. Res.

48: 1-6.

Colleoni, N.; D'Amico, G. (1986) Chronic Pb accumulation as a possible cause of renal failure in gouty patients.

Nephron 44: 32-35.

Colleoni, N.; Arrigo, G.; Gandini, E.; Cori gliano, C.; D'Amico, G. (1993) Blood Pb in hemodialysis patients. Am. J.

Nephrol. 13: 198-202.

Constantine, N. A.; Kraemer, H. C.; Kendall-Tackett, K. A.; Bennett, F. C.; Tyson, J. E.; Gross, R. T. (1987) Use of

physical and neurologic observations in assessment of gestational age in low birth weight infants. J.

Pediatr. (St. Louis, MO, U.S.) 110: 921-928.

Cooney, G. H.; Bell, A.; McBride, W.; Carter, C. (1989a ) Neurobehavioural consequenc es of prenatal low level

exposures to Pb. Neurotoxicol. Teratol. 11: 95-104.

Cooney, G. H.; Bell, A.; McBride, W.; Carter, C. (1989b ) Low-level exposures to Pb: the Sydney Pb study. Dev.

Med. Child Neurol. 31: 640-649.

Cooney, G.; Bell, A.; Stavrou, C. (199 1) Low level exposures to Pb and neurobehavioural development: the Sydney

study at seven yrs. In: Farmer, J. G., ed. Internationa l conference: heavy metals in the environment, v. 1;

September; Edinburgh, United Kingdom. Edinburgh, United Kingdom: CEP Consultants, Ltd.; pp. 16-19.

Cooper, W. C. (1988) Deaths from chronic renal disease in U. S. battery and Pb production workers. In: Victery, W.,

ed. Symposium on Pb-blood pressure relationships; Apr il 1987; Chapel Hill, NC. Environ. Health Perspect.

78: 61-63.

Cooper, W. C.; Gaffey, W. R. (1975) Mortality of Pb workers. In: Cole, J. F., ed. Proceedings of the 1974

conference on standards of occupational Pb exposure; February 1974; Washington, DC. J. Occup. Med. 17:

100-107.

Cooper, W. C.; Tabershaw, I. R.; Nelson, K. W. (1973) La boratory studies of workers in Pb smelting and refining.

In: Barth, D.; Berlin, A.; Engel, R.; Recht, P.; Sm eets, J., eds. Environmental health aspects of Pb:

proceedings [of an] international symposium; October 1972; Amsterdam, The Netherlands. Luxembourg:

Commission of the European Communities; pp. 517-530; report no. EUR 5004 d-e-f.

Cooper, W. C.; Wong, O.; Kheifets, L. (1985) Mortality among employees of Pb battery plants and Pb-producing

plants, 1947-1980. Scand. J. Work Environ. Health 11: 331-345.

Coratelli, P.; Giannattasio, M.; Lomonte, C.; Marzolla, R.; Rana, F.; L'Abbate, N. (1988) Enzymuria to detect

tubular injury in workers exposed to Pb: a 12-mo follow-up. In: Bianchi, C.; Bocci, V.; Carone, F. A.;

Rabkin, R., eds. Kidney and proteins in health and disease: fifth international symposium in health and

disease; July 1987; Montecatini Terme, Italy. Basel, Switzerland: S. Karger; pp. 207-211.

Cordioli, G.; Cuoghi, L.; Solari, P. L. ; Berrino, F.; Crosignani, P.; Riboli, E. (1987) Mortalità per tumore in una

coorte di lavoratori della industria del vetro [Tumor mortality in a cohort of glass industry workers].

Epidemiol. Prev. (Italy) 9(30): 16-18.

Cory-Slechta, D. A. (1995) Bridging human and experimental animal studies of Pb neurotoxicity: moving beyond

IQ. Neurotoxicol. Teratol. 17: 219-221.

Coscia, G. C.; Discalzi, G.; Ponzetti, C. (1987) Immunolog ical aspects of occupational Pb exposure. Med. Lav.

78: 360-364.

Coste, J.; Mandereau, L.; Pessione, F.; Bregu, M.; Faye, C.; Hemon, D.; Spira, A. (1991) Pb-exposed workmen and

fertility: a cohort study on 354 subjects. Eur. J. Epidemiol. 7: 154-158.

Counter, S. A.; Buchanan, L. H.; Rosas, H. D.; Ortega, F. (1998) Neurocognitive effects of chronic Pb intoxication

in Andean children. J. Neurol. Sci. 160: 47-53.

Counter, S. A.; Buchanan, L. H. (2002) Neuro-ototoxicity in Andean adults with chronic Pb and noise exposure. J.

Occup. Environ. Med. 44: 30-38.

Craswell, P. W.; Price, J.; B oyle, P. D.; Behringer, D.; Stoeppler, M.; Ritz, E. (1987) Patterns of Pb excretion in

patients with gout and chronic renal failure

― a comparative German and Australian study. Sci. Total

Environ. 66: 17-28.

Cullen, M. R.; Kayne, R. D.; Robins, J. M. (1984) Endocrine and reproductive dysfunction in men associated with

occupational inorganic Pb intoxication. Arch. Environ. Health 39: 431-440.

Dalpra, L.; Tibiletti, M. G.; Nocera, G.; Giulotto, P.; Aur iti, L.; Carnelli, V.; Simoni, G. (1983) SCE analysis in

children exposed to Pb emission from a smelting plant. Mutat. Res. 120: 249-256.

David, O. J.; Clark, J.; Voeller, K. (1972) Pb and hyperactivity. Lancet (7783): 900-903.

David, O. J.; Hoffman, S. P.; Sverd, J.; Clark, J.; Voeller, K. (1976) Pb and hyperactivity. Behavorial response to

chelation: a pilot study. Am. J. Psychiatry 133: 1155-1158.

# AX6-268 David, O. J.; Clark, J.; Hoffman, S. (1979) Childhood Pb poisoning: a re-evaluation. Arch. Environ. Health

34: 106-111.

Davies, J. M. (1984) Lung cancer mortality among worker s making Pb chromate and zinc chromate pigments at

three English factories. Br. J. Ind. Med. 41: 158-169.

Davis, J. M.; Svendsgaard, D. J. (1987) Pb and child development. Nature (London) 329: 297-300.

Davis, J. M.; Svendsgaard, D. J. (1990) Nerve conductio n velocity and Pb: a critical review and meta-analysis.

In: Johnson, B. L.; Anger, W. K.; Durao, A.; Xintaras, C., eds. Advances in neurobehavioral toxicology:

applications in environmental and occupational health: [selected papers presented at the third international

symposium on neurobehavioral and occupational health]; December 1988; Washington, DC. Chelsea, MI:

Lewis Publishers, Inc.; pp. 353-376.

Davis, J. M.; Otto, D. A.; Weil, D. E. ; Grant, L. D. (1990) The comparative developmental neurotoxicity of Pb in

humans and animals. Neurotoxicol. Teratol. 12: 215-229.

De Burbure, C.; Buchet, J. P.; Bernard, A.; Leroyer, A.; Nisse, C.; Haguenoe r, J.-M.; Bergamaschi, E.; Mutti, A.

(2003) Biomarkers of renal effects in children and adu lts with low environmental exposure to heavy metals.

J. Toxicol. Environ. Health Part A 66: 783-798.

De Burbure, C.; Buchet, J.-P.; Lero yer, A.; Nisse, C.; Haguenoer, J.-M.; Mutti, A.; Smerhovský, Z.; Cikrt, M.;

Trczinka-Ochocka, M.; Razniewska, G.; Jakubowski, M.; Bernard, A. (2006) Renal and neurologic effects

of cadmium, Pb, mercury, and arsenic in children: evid ence of early effects and multiple interactions at

environmental exposure levels. Environ. Health Perspect. 114: 584-590.

De Kort, W. L. A. M.; Verschoor, M. A.; Wibowo, A. A. E.; van Hemmen, J. J. (1987) Occupational exposure to Pb

and blood pressure: a study in 105 workers. Am. J. Ind. Med. 11: 145-156.

Den Hond, E.; Nawrot, T.; Staessen, J. A. (2002) The relationship between blood pressure and blood Pb in

NHANES III. J. Hum. Hypertens. 16: 563-568.

Denno, D. (1990) Biology and violence. From birth to adulthood. New York, NY: Cambridge University Press.

Després, C.; Beuter, A.; Richer, F.; Poitras, K.; Veilleux, A.; Ayotte, P.; De wailly, É.; Saint-Amour, D.; Muckle, G.

(2005) Neuromotor functions in Inuit preschool children exposed to Pb, PCBs, and Hg. Neurotoxicol.

Teratol. 27: 245-257.

Dick, R. B.; Pinkerton, L. E.; Krieg, E. F., Jr.; Biagini, R. E.; Deddens, J. A.; Bri ghtwell, W. S.; Grubb, P. L.;

Taylor, B. T.; Russo, J. M. (1999) Evaluation of postur al stability in workers exposed to Pb at a secondary

Pb smelter. Neurotoxicology 20: 595-608.

Dietrich, K. N.; Krafft, K. M.; Bier, M. ; Succop, P. A.; Berger, O.; Bornschein, R. L. (1986) Early effects of fetal Pb

exposure: neurobehavioral findings at 6 mos. Int. J. Biosoc. Res. 8: 151-168.

Dietrich, K. N.; Krafft, K. M.; Shukla, R.; Bornschein, R. L.; Succ op, P. A. (1987a) The neurobehavioral effects of

early Pb exposure. In: Schroeder, S. R., ed. Toxic substances and mental retardation: neurobehavioral

toxicology and teratology. Washington, DC: American Association on Mental Deficiency; pp. 71-95.

(Begab, M. J., ed. Monographs of the American Association on Mental Deficiency: no. 8).

Dietrich, K. N.; Krafft, K. M.; Bornschein, R. L.; Hamm ond, P. B.; Berger, O.; Succop, P. A.; Bier, M. (1987b)

Low-level fetal Pb exposure effect on neurobehavioral development in early infancy. Pediatrics

80: 721-730.

Dietrich, K. N.; Succop, P. A.; Bornschein, R. L.; Krafft, K. M.; Berger, O.; Hammond, P. B.; Buncher, C. R. (1990)

Pb exposure and neurobehavioral development in later infancy. In: Conference on advances in Pb research:

implications for environmental health; January 1989 ; Research Triangle Park, NC. Environ. Health

Perspect. 89: 13-19.

Dietrich, K. N.; Succop, P. A.; Berger, O. G.; Hammond, P. B.; Bornschein, R. L. (1991) Pb exposure and the

cognitive development of urban preschool children: the Cincinnati Pb study cohort at age 4 yrs.

Neurotoxicol. Teratol. 13: 203-211.

Dietrich, K. N.; Succop, P. A.; Berger, O. G.; Keith, R. W. (1992) Pb exposure and the central auditory processing

abilities and cognitive development of urban children: the Cincinnati Pb study cohort at age 5 yrs.

Neurotoxicol. Teratol. 14: 51-56.

Dietrich, K. N.; Berger, O. G.; Succop, P. A.; Hammond, P. B.; Bornschein, R. L. (1993a) The developmental

consequences of low to moderate prenatal and postnatal Pb exposure: intellectual attainment in the

Cincinnati Pb Study Cohort following school entry. Neurotoxicol. Teratol. 15: 37-44.

Dietrich, K. N.; Berger, O. G.; Succop, P. A. (1993b) Pb exposure and the motor developmental status of urban sixyr-old children in the Cincinnati prospective study. Pediatrics 91: 301-307.

Dietrich, K. N.; Ris, M. D.; Succop, P. A.; Berger, O. G.; Bornschein, R. L. (2001) Early exposure to Pb and

juvenile delinquency. Neurotoxicol. Teratol. 23: 511-518.

# AX6-269 Dietrich, K. N.; Ware, J. H.; Salganik, M.; Radcliffe, J.; Ro gan, W. J.; Rhoads, G. G.; Fay, M. E.; Davoli, C. T.;

Denckla, M. B.; Bornschein, R. L. ; Schwarz, D.; Dockery, D. W.; Adubato, S.; Jones, R. L.; for the

Treatment of Pb-Exposed Children Clinical Trial Group. (2004) Eff ect of chelation therapy on the

neuropsychological and behavioral development of Pb-exposed children after school entry. Pediatrics 114:

19-26.

Dietrich, K. N.; Eskenazi, B.; Schantz, S.; Yolton, K.; Ra uh, V. A.; Johnson, C. B.; Alkon, A.; Canfield, R. L.;

Pessah, I. N.; Berman, R. F. (2005) Principles and practices of neurodevelopmental assessment in children:

lessons learned from the Centers for Children's Envi ronmental Health and Disease Prevention Research.

Environ. Health Perspect. 113: 1437-1446.

Dingwall-Fordyce, I.; Lane, R. E. (1963) A follow-up study of Pb workers. Br. J. Ind. Med. 20: 313-315.

Diouf, A.; Garcon, G.; Thiaw, C.; Diop , Y.; Fall, M.; Ndiaye B.; Siby, T.; Ha nnothiaux, M. H.; Zerimech, F.; Ba,

D.; Haguenoer, J. M.; Shirali, P. (2003) Environmenta l Pb exposure and its relationship to traffic density

among Senegalese children: a pilot study. Hum. Exp. Toxicol. 22: 559-564.

Discalzi, G. L.; Capellaro, F.; Bottalo, L.; Fabbro, D.; Mocellini, A. (1992) Auditory brainstem evoked potentials

(BAEPS) in Pb-exposed workers. Neurotoxicology 13: 207-209.

Discalzi, G.; Fabbro, D.; Meliga, F.; Mocellini, A.; Capellaro, F. (1993) Effects of occupational exposure to mercury

and Pb on brainstem auditory evoked potentials. Int. J. Psychophysiol. 14: 21-25.

Dowd, T. L.; Rosen, J. F.; Gundberg, C. M.; Gupta, R. K. (1994) The displacement of calcium from osteocalcin at

submicromolar concentrations of free Pb. Biochim. Biophys. Acta 1226: 131-137.

Driscoll, R. J. (1998) Epidemiologic study of adverse reproductive outcomes among women in the U.S. Forest

Service. In: Driscoll, R. J.; Reh, B. D.; Esswein, E. J. ; Mattorano, D. A. Health hazard evaluation report no.

93-1035-2686, section 2. Washington, DC: U.S. Department of Agriculture, Forest Service; pp. 33-71.

Available from: NTIS, Springfield, VA; PB99-152241.

Dursun, N.; Tutus, A. (1999) Chronic oc cupational Pb exposure and thyroid f unction. J. Trace Elem. Exp. Med. 12:

45-49.

Duydu, Y.; Süzen, H. S.; Aydin, A.; Cander, O.; Uysal, H. ; Isimer, A.; Vural, N. (2001) Correlation between Pb

exposure indicators and sister chromatid exchange (SCE) frequencies in lymphocytes from inorganic Pb

exposed workers. Arch. Environ. Contam. Toxicol. 41: 241-246.

Duydu, Y.; Dur, A.; Süzen, H. S. (2005) Evaluation of increased proportion of cells with unusually high sister

chromatid exchange counts as a cytogenetic biomarker for Pb exposure. Biol. Trace Elem. Res.

104: 121-129.

Dye, B. A.; Hirsch, R.; Brody, D. J. (2002) The relationship between blood Pb levels and periodontal bone loss in

the United States, 1988-1994. Environ. Health Perspect. 110: 997-1002.

EL-Safty, I. A.; Afifi, A. M.; Shouman, A. E.; EL-Sady, A. K. R. (2004) Effects of smoking and Pb exposure on

proximal tubular integrity among Egyptian industrial workers. Arch. Med. Res. 35: 59-65.

Elwood, P. C.; Davey-Smith, G.; Oldham, P. D.; Toothill, C. (1988a) Two Welsh surveys of blood Pb and blood

pressure. In: Victery, W., ed. Symposium on Pb-blood pressure relationships; April 1987; Chapel Hill, NC.

Environ. Health Perspect. 78: 119-121.

Elwood, P. C.; Yarnell, J. W. G.; Oldh am, P. D.; Catford, J. C.; Nutbeam, D.; Davey-Smith, G.; Toothill, C. (1988b)

Blood pressure and blood Pb in surveys in Wales. Am. J. Epidemiol. 127: 942-945.

Ehrlich, R.; Robins, T.; Jordaan, E.; Miller, S.; Mbuli, S.; Selby, P.; Wync hank, S.; Cantrell, A.; De Broe, M.;

D'Haese, P.; Todd, A.; Landrigan, P. (1998) Pb absorption and renal dysfunction in a South African battery

factory. Occup. Environ. Med. 55: 453-460.

Elmarsafawy, S. F.; Tsaih, S.-W.; Korrick, S.; Dickey, J. H.; Sparrow, D.; Aro, A. ; Hu, H. (2002) Occupational

determinants of bone and blood Pb levels in middle aged and elderly men from the general community: the

Normative Aging Study. Am. J. Ind. Med. 42: 38-49.

Emmerson, B. T. (1965) The renal excretion of urate in chronic Pb nephropathy. Australas. Ann. Med.

14: 295-303.

Emmerson, B. T.; Ravenscroft, P. J. (1975) Abnormal renal urate homeostasis in systemic disorders. Nephron

14: 62-80.

Emory, E.; Ansari, Z.; Pattillo, R.; Archibold, E.; Cheva lier, J. (2003) Maternal blood Pb effects on infant

intelligence at age 7 mos. Am. J. Obstet. Gynecol. S26-S32.

Endo, G.; Horiguchi, S.; Kiyota, I. (1990) Urinary N -acetyl- β -D-glucosaminidase activity in Pb-exposed workers. J.

Appl. Toxicol. 10: 235-238.

Endo, G.; Konishi, Y.; Kiyota, A.; Horiguchi, S. (1993) Urinary ά 1 

# microglobulin in Pb workers. Bull. Environ.

Contam. Toxicol. 50: 744-749.

# AX6-270 Englyst, V.; Lundstrom, N. G.; Gerhardsson, L.; Rylander, L.; Nordberg, G. (2001) Lung cancer risks among Pb

smelter workers also exposed to arsenic. Sci. Total Environ. 273: 77-82.

Erfurth, E. M.; Gerhardsson, L.; Nilsso n, A.; Rylander, L.; Schütz, A.; Skerfvin g, S.; Börjesson, J. (2001) Effects of

Pb on the endocrine system in Pb smelter workers. Arch. Environ. Health 56: 449-455.

Ernhart, C. B. (1995) In consistencies in the Pb-effects literature exist and cannot be explained by "effect

modification." Neurotoxicol. Teratol. 17: 227-233.

Ernhart, C. B. (2006) Effects of Pb on IQ in children [letter]. Environ. Health Perspect. 114: A85-A86.

Ernhart, C. B.; Greene, T. (1990) Low-level Pb exposure in the prenatal and early preschool periods: language

development. Arch. Environ. Health 45: 342-354.

Ernhart, C. B.; Landa, B.; Wolf, A. W. (1985) Subclinical Pb level and developm ental deficit; reanalyses of data. J.

Learning Disabilities 18: 475-479.

Ernhart, C. B.; Wolf, A. W.; Kennard, M. J.; Erhard, P.; Filipovich, H. F.; Sokol, R. J. (1986) Intrauterine exposure

to low levels of Pb: the status of the ne onate. Arch. Environ. Health 41: 287-291.

Ernhart, C. B.; Morrow-Tlucak, M.; Marler, M. R.; Wolf, A. W. (1987) Low level Pb exposure in the prenatal and

early preschool periods: early preschool development. Neurotoxicol. Teratol. 9: 259-270.

Ernhart, C. B.; Morrow-Tlucak, M.; Wolf, A. W. (1988) Low level Pb exposure and intelligence in the preschool

yrs. Sci. Total Environ. 71: 453-459.

Espy, K. A. (1997) The Shape School: assessing executive function in presch ool children. Dev. Neuropsychol.

13: 495-499.

Ewers, U.; Stiller-Winkler, R.; Idel, H. (1982) Serum im munoglobulin, complement C3, and salivary IgA levels in

Pb workers. Environ. Res. 29: 351-357.

Factor-Litvak, P.; Graziano, J. H.; Klin e, J. K.; Popovac, D.; Mehmeti, A.; Ahmedi, G.; Shrout, P.; Murphy, M. J.;

Gashi, E.; Haxhiu, R.; Rajovic, L.; Nenezic, D. U.; Stein, Z. A. (1991) A prospective study of birthweight

and length of gestation in a population surrounding a Pb smelter in Kosovo, Yugoslavia. Int. J. Epidemiol.

20: 722-728.

Factor-Litvak, P.; Stein, Z.; Graziano, J. (1993) Increased risk of proteinuria among a cohort of Pb-exposed pregnant

women. Environ. Health Perspect. 101: 418-421.

Factor-Litvak, P.; Kline, J. K.; Popovac, D.; Hadzialjevic, S.; Lekic, V.; Preteni-Rexh epi, E.; Capuni-Paracka, S.;

Slavkovich, V.; Graziano, J. (1996) Blood Pb and blood pressure in young children. Epidemiology

7: 633-637.

Factor-Litvak, P.; Slavkovich, V.; Liu, X.; Popovac, D.; Preteni, E.; Capuni-Par acka, S.; Hadzialjevic, S.; Lekic, V.;

LoIacono, N.; Kline, J.; Graziano, J. (1998) Hyperproduction of erythropoietin in nonanemic Pb-exposed

children. Environ. Health Perspect. 106: 361-364.

Factor-Litvak, P.; Wasserman, G.; Klin e, J. K.; Graziano, J. (1999) The Yugoslavia prospective study of

environmental Pb exposure. Environ. Health Perspect. 107: 9-15.

Fahim, M. S.; Fahim, Z.; Hall, D. G. (1976) Effects of subtoxic Pb levels on pregnant women in the state of

Missouri. Res. Commun. Chem. Pathol. Pharmacol. 13: 309-331.

Fanning, D. (1988) A mortality study of Pb workers, 1926-1985. Arch. Environ. Health 43: 247-251.

Farrow, S. (1994) Falling sp erm quality: fact of fiction? Br. Med. J. 309: 1-2.

Fels, L. M.; Herbort, C. ; Pergande, M.; Jung, K.; Hotter, G.; Roselló, J.; Gelpi, E.; Mutti, A.; De Broe, M.; Stolte, H.

(1994) Nephron target sites in chronic exposure to Pb. Nephrol. Dial. Transplant. 9: 1740-1746.

Fels, L. M.; Wünsch, M.; Baranowski, J.; Norska-Borówka, I. ; Price, R. G.; Taylor, S. A.; Patel, S.; De Broe, M.;

Elsevier, M. M.; Lauwerys, R.; Roels, H.; Bernard, A.; Mutti, A.; Gelpi, E.; Roselló, J.; Stolte, H. (1998)

Adverse effects of chronic low level Pb exposure on kidney function

― a risk group study in children.

Nephrol. Dial. Transplant 13: 2248-2256.

Fergusson, D. M.; Horwood, L. J. (1993) The effects of Pb levels on the growth of word recognition in middle

childhood. Int. J. Epidemiol. 22: 891-897.

Fergusson, D. M.; Fergusson, J. E.; Horwood, L. J.; Kinzett, N. G. (1988a) A longitudinal study of dentine Pb

levels, intelligence, school performance and behaviour. Part II. Dentine Pb and cognitive ability. J. Child

Psychol. Psychiatry Allied Discip. 29: 793-809.

Fergusson, D. M.; Fergusson, J. E.; Horwood, L. J.; Kinzett, N. G. (1988b) A longitudinal study of dentine Pb

levels, intelligence, school performance and behaviour. Part III. Dentine Pb levels and attention/activity. J.

Child Psychol. Psychiatry Allied Discip. 29: 811-824.

Fergusson, D. M.; Fergusson, J. E.; Horwood, L. J.; Kinzett, N. G. (1988c) A longitudinal study of dentine Pb

levels, intelligence, school performance and behaviour . Part I. Dentine Pb levels and exposure to

environmental risk factors. J. Child Psyc hol. Psychiatry Allied Discip. 29: 781-792.

# AX6-271 Fergusson, D. M.; Horwood, L. J.; Lynskey, M. T. (199 3) Early dentine Pb levels and subsequent cognitive and

behavioural development. J. Child Psychol . Psych. Allied Disciplines 34: 215-227.

Fergusson, D. M.; Horwood, L. J.; Lynskey, M. T. (1997) Early dentine Pb levels and educational outcomes at 18

yrs. J. Child Psychol. Psychiatry 38: 471-478.

Fewtrell, L. J.; Prüss-Üstün, A.; Landri gan, P.; Ayuso-Mateos, J. L. (2004) Estimating the global burden of disease

of mild mental retardation and cardiovascular diseases from environmental Pb exposure. Environ. Res. 94:

120-133.

Fiedler, N.; Weisel, C.; Lynch, R.; Kelly-McNeil, K.; We deen, R.; Jones, K.; Udasin, I.; Ohman-Strickland, P.;

Gochfeld, M. (2003) Cognitive effects of chronic expo sure to Pb and solvents. Am. J. Ind. Med.

44: 413-423.

Fisch, H.; Andrews, H.; Hendricks, J.; Goluboff, E. T.; Olso n, J. H.; Olsson, C. A. (1997) The relationship of sperm

counts to birth rates: a population based study. J. Urol. (Hagerstown, MD, U.S.) 157: 840-843.

Fischbein, A.; Alvares, A. P.; Anderson, K. E.; Sassa, S.; Kappas, A. (1977) Pb intoxication among demolition

workers: the effect of Pb on the he patic cytochrome P-450 systems in hum ans. J. Toxicol. Environ. Health

3: 431-437.

Fischbein, A.; Tsang, P.; Luo, J.-C. J.; Roboz, J. P.; Jiang, J. D.; Bekesi, J. G. (1993) Phenotypic aberrations of the

CD3 + 

# and CD4 + 

# cells and functional impairments of lymphocytes at low-level occupational exposure to Pb.

Clin. Immunol. Immunopathol. 66: 163-168.

Fleming, D. E. B.; Chettle, D. R.; Wetmur, J. G.; Desnick, R. J.; Robin, J.-P.; Boulay, D.; Richard, N. S.; Gordon,

C. L.; Webber, C. E. (1998) Effect of the delta-aminolevulinate dehydratase polymorphism on the

accumulation of Pb in bone and blood in Pb smelter workers. Environ. Res. 77: 49-61.

Flood, P. R.; Schmidt, P. F.; Wesenberg, G. R.; Gadeholt, H. (1988) The distribution of Pb in human hemopoietic

tissue and spongy bone after Pb poisoning and Ca-EDTA chelation therapy: observations made by atomic

absorption spectroscopy, laser micr obeam mass analysis and electron microbeam X-ray analysis. Arch.

Toxicol. 62: 295-300.

Folstein, M. F.; Folstein, S. E.; McHugh , P. R. (1975) Mini-Mental State: a practical method of grading the state of

patients for the clinician. J. Psychiatr. Res. 12: 189-198.

Fontanellas, A.; Navarro, S.; Morán-Jiménez, M.-J.; Sánchez-Fructuoso, A. I.; Vegh, I.; Barrientos, A.; De

Salamanca, R. E. (2002) Erythrocyte aminolevulinate dehydratase activity as a Pb marker in patients with

chronic renal failure. Am. J. Kidney Dis. 40: 43-50.

Forni, A.; Cambiaghi, G.; Secchi, G. C. (1976) Initial occupational exposure to Pb: chromosome and biochemical

findings. Arch. Environ. Health 31: 73-78.

Forni, A.; Sciame’, A.; Bertazzi, P. A.; Alessio, L. (1980) Chromosome and biochemical studies in women

occupationally exposed to Pb. Arch. Environ. Health 35: 139-146.

Foster, W. G. (1992) Reproductive toxi city of chronic Pb exposure in th e female cynomolgus monkey. Reprod.

Toxicol. 6: 123-131.

Fracasso, M. E.; Perbellin i, L.; Solda, S.; Talamini, G. ; Franceschetti, P. (2 002) Pb induced DNA strand breaks

in lymphocytes of exposed workers: role of reactive oxygen species and protein kinase C. Mutat. Res.

515: 159-169.

Franks, P. A.; Laughlin, N. K.; Dierschk e, D. J.; Bowman, R. E.; Meller, P. A. (1989) Effects of Pb on luteal

function in rhesus monkeys. Biol. Reprod. 41: 1055-1062.

Froom, P.; Kristal-Boneh, E.; Benbassat, J., Ashkanazi, R.; Ribak, J. (1999) Pb exposure in battery-factory workers

is not associated with anemia. J. Occup. Environ. Med. 41: 120-123.

Fu, H.; Boffetta, P. (1995) Cancer and occupational exposure to inorganic Pb compounds: a meta-analysis of

published data. Occup. Environ. Med. 52: 73-81.

Fulton, M.; Raab, G.; Thomson, G.; Laxen, D.; Hunter, R.; Hepburn, W. (1987) Influence of blood Pb on the ability

and attainment of children in Edinburgh. Lancet (8544): 1221-1226.

Garçon, G.; Leleu, B.; Zerimech, F.; Mare z, T.; Haguenoer, J.-M.; Furon, D.; Sh irali, P. (2004) Biologic markers of

oxidative stress and nephrotoxicity as studied in biomonitoring and adverse effects of occupational

exposure to Pb and cadmium. J. Occup. Environ. Med. 46: 1180-1186.

Gartside, P. S. (1988) The relationship of blood Pb levels and blood pressure in NHAN ES II: additional calculations.

In: Victery, W., ed. Symposium on Pb-blood pressure relationships; April 1987; Chapel Hill, NC. Environ.

Health Perspect. 78: 31-34.

Gemmel, A.; Tavares, M.; Alperin, S.; Soncini, J.; Dani el, D.; Dunn, J.; Crawford, S.; Braveman, N.; Clarkson,

T. W.; McKinlay, S.; Bellinger, D. C. (2002) Blood Pb level and dental caries in school-age children.

Environ. Health Perspect. 110: A625-A630.

# AX6-272 Gennart, J. P.; Bernard, A.; Lauwerys, R. (1992) Assessment of thyroid, testes, kidney and autonomic nervous

system function in Pb-exposed workers. Int. Arch. Occup. Environ. Health 64: 49-57.

Gerhardsson, L.; Brune, D.; Nordberg, G. F.; Wester, P. O. (1986) Distribution of cadmium, Pb and zinc in lung,

liver and kidney in long-term exposed smelter workers. Sci. Total Environ. 50: 65-85.

Gerhardsson, L.; Chettle, D. R.; Englyst, V.; Nordberg, G. F.; Nyhlin, H.; Scott, M. C.; Todd, A. C.; Vesterberg, O.

(1992) Kidney effects in long term exposed Pb smelter workers. Br. J. Ind. Med. 49: 186-192.

Gerhardsson, L.; Attewell, R.; Chettle, D. R.; Englyst, V. ; Lundström, N.-G.; Nordberg, G. F.; Nyhlin, H.; Scott,

M. C.; Todd, A. C. (1993) In vivo measurements of Pb in bone in long-term exposed Pb smelter workers.

Arch. Environ. Health 48: 147-156.

Gerhardsson, L.; Hagmar, L.; Rylander, L.; Skerfving, S. (1995) Mortality and cancer incidence among secondary

Pb smelter workers. Occup. Environ. Med. 52: 667-672.

Gerr, F.; Letz, R.; Stokes, L.; Chettle, D.; McNeill, F.; Ka ye, W. (2002) Association between bone Pb concentration

and blood pressure among young adults. Am. J. Ind. Med. 42: 98-106.

Gershanik, J. J.; Brooks, G. G.; Little, J. A. (1974) Blood Pb values in pregnant women and their offspring. Am. J.

Obstet. Gynecol. 119: 508-511.

Gil, F.; Pérez, M. L.; Facio, A.; Villanueva, E.; Tojo, R.; Gil, A. (1994) Dental Pb levels in the Galacian population,

Spain. Sci. Total Environ. 156: 145-150.

Glenn, B. S.; Stewart, W. F.; Schwar tz, B. S.; Bressler, J. (2001) Relation of alleles of the sodium-potassium

adenosine triphosphatase ά 2 gene with blood pressure and Pb exposure. Am. J. Epidemiol. 153: 537-545.

Glenn, B. S.; Stewart, W. F.; Links, J. M.; Todd, A. C.; Schwartz, B. S. (2 003) The longitudinal association of Pb

with blood pressure. Epidemiology 14: 30-36.

Glickman, L.; Valciukas, J. A.; Lilis, R.; Weisman, I. (1984) Occupational Pb exposu re: effects on saccadic eye

movements. Int. Arch. Occup. Environ. Health 54: 115-125.

Gomaa, A.; Hu, H.; Bellinger, D.; Schwar tz, J.; Tsaih, S.-W.; Gonzalez-Cossio, T.; Schnaas, L.; Peterson, K.; Aro,

A.; Hernandez-Avila, M. (2002) Maternal bone Pb as an independent risk factor for fetal neurotoxicity: a

prospective study. Pediatrics 110: 110-118.

Gonick, H. C.; Behari, J. R. (2002) Is Pb exposure the principal cause of essential hypertension? Med. Hypotheses

59: 239-246.

Gonick, H. C.; Cohen, A. H.; Ren, Q.; Saldanha, L. F.; Kha lil-Manesh, F.; Anzalone, J.; Sun, Y. Y. (1996) Effect of

2,3-dimercaptosuccinic acid on nephrosclerosis in the Da hl rat. I. Role of reac tive oxygen species. Kidney

Int. 50: 1572-1581.

González-Cossío, T.; Peterson, K. E.; Sa nín, L.-H.; Fishbein, E.; Palazuelos, E.; Aro, A.; Herná ndez-Avila, M.; Hu,

H. (1997) Decrease in birth weight in relation to maternal bone-Pb burden. Pediatrics 100: 856-862.

Goodman, M.; LaVerda, N.; Clarke, C.; Foster, E. D.; Iannuzzi, J.; Mandel, J. (2002) Neurobehavioural testing in

workers occupationally exposed to Pb: systematic review and meta-analysis of publications. Occup.

Environ. Med. 59: 217-223.

Governa, M.; Valentino, M.; Visonà, I. (1987) In vitro impairment of human granulocyte functions by Pb. Arch.

Toxicol. 59: 421-425.

Govoni, S.; Battaini, F.; Fernicola, C.; Castelletti, L.; Trabucchi, M. (1987) Pl asma prolactin concentrations in Pb

exposed workers. J. Environ. Path oI. Toxicol. Oncol. 7: 13-15.

Goyer, R. A.; Epstein, S.; Bhattachar yya, M.; Korach, K. S.; Pounds, J. (1994) Environmental risk factors for

osteoporosis. Environ. Health Perspect. 102: 390-394.

Grandjean, P. (1979) Occupational Pb exposure in Denmark: screening with the haematofluorometer. Br. J. Ind.

Med. 36: 52-58.

Grandjean, P.; Arnvig, E.; Beckmann, J. (1978) Psychological dysfunctions in Pb-exposed workers: relation to

biological parameters of exposure. Scand. J. Work Environ. Health 4: 295-303.

Grandjean, P.; Wulf, H. C.; Niebuhr, E. (1983) Sister chromatid exchange in response to variations in occupational

Pb exposure. Environ. Res. 32: 199-204.

Grandjean, P.; Hollnagel, H.; Hedegaard, L.; Christensen, J. M.; Larsen, S. (1989) Blood Pb-blood pressure

relations: alcohol intake and hemoglobin as co nfounders. Am. J. Epidemiol. 129: 732-739.

Graves, A. B.; Van Duijn, C. M.; Chandra, V.; Fratiglioni , L.; Heyman, A.; Jorm, A. F.; Kokmen, E.; Kondo, K.;

Mortimer, J. A.; Rocca, W. A.; Shalat, S. L.; Soininen, H.; Hofman , A. (1991) Occupational exposures to

solvents and Pb as risk factors for Alzheimer's diseas e: a collaborative re-analysis of case-control studies.

Int. J. Epidemiol. 20(suppl. 2): S58-S61.

Graziano, J. H.; Popovac, D. ; Factor-Litvak, P.; Shrout, P.; Kline, J.; Murphy, M. J.; Zhao, Y.-H.; Mehmeti, A.;

Ahmedi, X.; Rajovic, B.; Zvicer, Z.; Nenezic, D. U.; Lolacono, N. J.; Stein, Z. (1990) Determinants of

# AX6-273 elevated blood Pb during pregnancy in a population surrounding a Pb smelter in Kosovo, Yugoslavia. In:

Conference on advances in Pb rese arch: implications for environmental health; January 1989; Research

Triangle Park, NC. Environ. Health Perspect. 89: 95-100.

Graziano, J. H.; Slavkovic, V.; Factorlitvak, P.; Popovac, D.; Ahmedi, X.; Mehmeti, A. (1991) Depressed serum

erythropoietin in pregnant women with elevated blood Pb. Arch. Environ. Health 46: 347-350.

Graziano, J.; Slavkovich, V.; Liu X., Factor-Litvak, P.; Todd, A. (2004) A prospective study of prenatal and

childhood Pb exposure and erythropoietin production. J. Occup. Environ. Med. 46: 924-929.

Greene, T.; Ernhart, C. B. (1993) Dentine Pb and intelligence prior to school entry: a statistical sensitivity analysis.

J. Clin. Epidemiol. 46: 323-339.

Greene, T.; Ernhart, C. B.; Boyd, T. A. (1992) Contributions of risk factors to elevated blood and dentine Pb levels

in preschool children. Sci. Total Environ. 115: 239-260.

Groth-Marnat, G. (2003) Handbook of psychological assessment. 4th ed. Hoboken, NJ: John Wiley & Sons.

Guidetti, D.; Bondavalli, M.; Sabadini, R.; Marcello, N.; Vinceti, M.; Cavalletti, S.; Marbini, A.; Gemignani, F.;

Colombo, A.; Ferriari, A.; Vivoli, G.; Solime, F. (1 996) Epidemiological survey of amyotrophic lateral

sclerosis in the province of Reggio Emilia, Italy: influence of environmental exposure to Pb.

Neuroepidemiology 15: 301-312.

Gulson, B. L.; Mizon, K. J.; Palmer, J. M.; Korsch, M. J.; Taylor, A. J.; Mahaffey, K. R. (2004) Blood Pb

changes during pregnancy and postpartum with calcium supplementation. Environ. Health Perspect.

112: 1499-1507.

Gump, B. B.; Stewart, P.; Reihman, J.; Lonky, E.; Darvill, T.; Matthews, K. A.; Parsons, P. J. (2005) Prenatal and

early childhood blood Pb levels and cardiovascular functioning in 91⁄2 yr old children. Neurotoxicol.

Teratol. 27: 655-665.

Gunnarsson, L. G.; Bodin, L.; Söderfeldt, B.; Axelson, O. (1992) A case-control study of motor neurone disease: its

relation to heritability, and occupational exposures, par ticularly to solvents. Br. J. Ind. Med. 49: 791-798.

Guo, T. L.; Mudzinski, S. P.; Lawrence, D. A. (1996a) The heavy metal Pb modulates the expression of both TNF- ά

and TNF- ά receptors in lipopolysaccharide- activated human peripheral blood mononuclear cells. J. Leukoc.

Biol. 59: 932-939.

Guo, T. L.; Mudzinski, S. P.; Lawren ce, D. A. (1996b) Regulation of HLA-DR and invariant chain expression

by human peripheral blood mononuclear cells with Pb, interferon- γ , or interleukin-4. Cell. Immunol.

171: 1-9.

Gurer-Orhan, H.; Sabir, H.D.; Ozgunes, H. (2004) Correlation between clinical indicators of Pb poisoning and

oxidative stress parameters in controls and Pb-exposed workers. Toxicology 195: 147-154.

Gustafson, Å.; Hedner, P.; Schütz, A.; Skerfving, S. (1989) Occupational Pb exposure and pituitary function. Int.

Arch. Occup. Environ. Health 61: 277-281.

Gustavsson, P.; Plato, N.; Hallqvist, J.; Hogstedt, C.; Le wne, M.; Reuterwall, C.; Sch eele, P. (2001) A populationbased case-referent study of myocardial infarction and occupational exposure to motor exhaust, other

combustion products, organic solvents, Pb, and dynamite. stockholm heart epidemiology program (SHEEP)

study group. Epidemiology 12: 222-228.

Gyllenborg, J.; Skakkebaek, N. E.; Nielsen, N. C.; Keiding, N.; Giwercman, A. (1999) Secular and seasonal changes

in semen quality among young Danish men: a statistical analysis of semen samples from 1927 donor

candidates during 1977-1995. Int. J. Androl. 22: 28-36.

Hagmar, L.; Strömberg, U.; Bonassi, S.; Hansteen, I.-L.; Knudsen, L. E.; Lindholm, C.; Norppa, H. (2004) Impact of

types of lymphocyte chromosomal aberrations on human cancer risk: results from Nordic and Italian

cohorts. Cancer Res. 64: 2258-2263.

Hajem, S.; Moreau, T.; Hannaert, P.; Lellouch, J.; Huel, G.; Hellier, G.; Orssaud, G.; Claude, J. R.; Juguet, B.;

Festy, B.; Garay, R. P. (1990) Influence of environmental Pb on membrane ion transport in a French urban

male population. Environ. Res. 53: 105-118.

Hammond, P. B.; Lerner, S. I.; Gartside, P. S.; Hanenson, I. B.; Roda, S. B.; Foulkes, E. C.; Johnson, D. R.; Pesce,

A. J. (1980) The relationship of biological indices of Pb exposure to the health status of workers in a

secondary Pb smelter. J. Occup. Med. 22: 475-484.

Haenninen, H.; Hernberg, S.; Mantere, P.; Vesanto, R.; Jalkanen, M. (1978) Psychological performance of subjects

with low exposure to Pb. J. Occup. Med. 20: 683-689.

Haenninen, H.; Mantere, P.; Hernberg, S.; Seppalainen, A. M.; Kock, B. (1979) Subjective symptoms in low-level

exposure to Pb. Neurotoxicology 1: 333-347.

Hänninen, H.; Aitio, A.; Kovala, T.; Lu ukkonen, R.; Matikainen, E.; Mannelin, T.; Erkkilä, J.; Riihimäki, V. (1998)

Occupational exposure to Pb and neuropsychological dysfunction. Occup. Environ. Med. 55: 202-209.

# AX6-274 Haraguchi, T.; Ishizu, H.; Takehisa, Y.; Kawai, K.; Yoko ta, O.; Terada, S.; Tsuchiya, K.; Ikeda, K.; Morita, K.;

Horike, T.; Kira, S.; Kuroda, S. (2001) Pb content of brain tissue in diffuse neurofibrillary tangles with

calcification (DNTC): the possibility of Pb neurotoxicity. Neuroreport 12: 3887-3890.

Harville, E. W.; Hertz-Picciotto, I.; Schramm, M.; Watt-Morse, M.; Chantala, K.; Osterloh, J.; Parsons, P. J.; Rogan,

W. (2005) Factors influencing the difference between maternal and cord blood Pb. Occup. Environ. Med.

62: 263-290.

Hatzakis, A.; Salaminios, F.; Kokevi, A.; Katsouyanni, K.; Maravelias, K.; Kalandidi, A.; Koutselinis, A.; Stefanis,

K.; Trichopoulos, D. (1985) Blood Pb and classr oom behaviour of children in two communities with

different degree of Pb exposure: evidence of a dose -related effect? In: Lekkas, T. D., ed. International

conference: heavy metals in the environment, v. 1; September; Athens, Greece. Edinburgh, United

Kingdom: CEP Consultants, Ltd.; p. 47.

Hatzakis, A.; Kokkevi, A.; Maravelias, C.; Katsouyanni, K.; Salaminios, F.; Kala ndidi, A.; Koutselinis, A.; Stefanis,

C.; Trichopoulos, D. (1989) Psychometric intelligence de ficits in Pb-exposed children. In: Smith, M. A.;

Grant, L. D.; Sors, A. I., eds. Pb exposure and child development: an international assessment [workshop

organized by the Commission of the European Communities and the U.S. Environmental Protection

Agency]; September 1986; Edinburgh, United Kingdom. Dordrecht, The Netherlands: Kluwer Academic

Publishers BV; pp. 211-223.

Haynes, E. N.; Kalkwarf, H. J.; Hornung , R.; Wenstrup, R.; Dietrich, K.; Lanphe ar, B. P. (2003) Vitamin D receptor

Fok1 polymorphism and blood Pb concentration in children. Environ. Health Perspect. 111: 1665-1669.

He, F. S.; Zhang, S. L.; Li, G.; Zhang, S. C.; Huang, J. X.; Wu, Y. Q. (1988) An electroneurographic assessment of

subclinical Pb neurotoxicity. Int. Arch. Occup. Environ. Health 61: 141-146.

Hellström, L.; Elinder, C.-G.; Dahlberg, B.; Lundberg, M. ; Järup, L.; Persson, B.; Axelson, O. (2001) Cadmium

exposure and end-stage renal disease. Am. J. Kidney Dis. 38: 1001-1008.

Hemdan, N. Y. A.; Emmrich, F.; Adham, K.; Wichmann, G.; Lehmann, I.; El-Massry, A.; Ghoneim, H.; Lehmann,

J.; Sack, U. (2005) Dose-dependent modulation of the in vitro cytokine production of human immune

competent cells by Pb salts. Toxicol. Sci. 86: 75-83.

Henderson, D. A. (1955) Chroni c nephritis in Queensland. Australas. Ann. Med. 4: 163-177.

Hense, H. W.; Filipiak, B.; Keil, U. (1993) The associatio n of blood Pb and blood pressure in population surveys.

Epidemiology 4: 173-179.

Hense, H. W.; Filipiak, B.; Keil, U. (1994) Alcohol consum ption as a modifier of the relation between blood Pb and

blood pressure. Epidemiology 5: 120-123.

Heo, Y.; Lee, B.-K.; Ahn, K.-D.; Lawrence, D. A. (2004) Serum IgE elevation correlates with blood Pb levels in

battery manufacturing workers. Hum. Exp. Toxicol. 23: 209-213.

Hernandez-Avila, M.; Peterson, K. E.; G onzalez-Cossio, T.; Sanin, L. H.; Aro, A.; Schnaas, L.; Hu, H. (2002) Effect

of maternal bone Pb on length and head circumference of newborns and 1-mo-old infants. Arch. Environ.

Health 57: 482-488.

Hernandez-Avila, M.; Gonzalez-Cossio, T.; Hernandez-Av ila, J. E.; Romieu, I.; Peterson, K. E.; Aro, A.;

Palazuelos, E.; Hu, H. (2003) Dietary calcium supplements to lower blood Pb levels in lactating women: a

randomized placebo-controlled tria l. Epidemiology 14: 206-212.

Hernández-Ochoa, I.; García-Vargas, G.; López-Carrillo, L.; Ru bio-Andrade, M.; Morán- Martínez, J.; Cebrián,

M. E.; Quintanilla-Vega, B. (2005) Low Pb enviro nmental exposure alters semen quality and sperm

chromatin condensation in northern Mexico. Reprod. Toxicol. 20: 221-228.

Hernberg, S.; Nikkanen, J.; Mellin, G.; Lilius, H. (1970) δ -aminolevulinic acid dehydrase as a measure of Pb

exposure. Arch. Environ. Health 21: 140-145.

Hertz-Picciotto, I. (2000) The evidence that Pb increases the ri sk for spontaneous abortion. Am. J. Ind. Med.

38: 300-309.

Hertz-Picciotto, I.; Schramm, M.; Watt- Morse, M.; Chantala, K.; Anderson, J. ; Osterloh, J. (2000) Patterns and

determinants of blood Pb during pregnancy. Am. J. Epidemiol. 152: 829-837.

Hill, A. B. (1965) The environment and disease: asso ciation or causation? Proc. R. Soc. Med. 58: 295-300.

Hirata, M.; Kosaka, H. (1993) Effects of Pb exposure on neurophysiological parameters. Environ. Res. 63: 60-69.

Hogstedt, C.; Hane, M.; Agrell, A; Bodin, L. (1983) Neuropsychological test results and symptoms among workers

with well-defined long-term exposure to Pb. Br. J. Ind. Med. 40: 99-105.

Holness, D. L.; Nethercott, J. R. (1 988) Acute Pb intoxication in a group of demolition workers. Appl. Ind.

Hyg. 3: 338-341.

Holdstein, Y.; Pratt, H.; Goldsher, M.; Rosen, G.; Shenha v, R.; Linn, S.; Mor, A.; Barkai, A. (1986) Auditory

brainstem evoked potentials in asymptomatic Pb-exposed subjects. J. Laryngol. Otol. 100: 1031-1036.

# AX6-275 Horiguchi, S.; Endo, G.; Kiyota, I. (1987 ) Measurement of total triiodothyronine (T 3 

# ), total thyroxine (T 4 

# ) and

thyroid-stimulating hormone (TSH) levels in Pb-exposed workers. Osaka City Med J. 33: 51-56.

Horiguchi, S.; Matsumura, S.; Fukumo to, K.; Karai, I.; Endo, G.; Teramo to, K.; Shinagawa, K.; Kiyota, I.;

Wakitani, F.; Takise, S.; Kawaraya, T. (1991) Erythr ocyte deformability in workers exposed to Pb. Osaka

City Med. J. 37: 149-155.

Hotz, P.; Buchet, J. P.; Bernard, A. ; Lison, D.; Lauwerys, R. (1999) Rena l effects of low-level environmental

cadmium exposure: 5-yr follow-up of a subcohort from the Cadmibel study. Lancet 354: 1508-1513.

Hsiao, C. Y.; Wu, H. D.; Lai, J. S.; Kuo, H. W. (2001) A longitudinal study of the effects of long-term exposure to

Pb among Pb battery factory workers in Taiwan (1989-1999). Sci. Total Environ. 279: 151-158.

Hsieh, L. L.; Liou, S. H.; Chen, Y. H.; Tsai, L. C.; Yang , T.; Wu, T. N. (2000) Association between aminolevulinate

dehydrogenase genotype and blood Pb levels in Taiwan. J. Occup. Environ. Med. 42(2): 151-155.

Hu, H. (1991) A 50-yr follow-up of childhood plumbism: hypertension, renal function, and hemoglobin levels

among survivors. Am. J. Dis. Child. 145: 681-687.

Hu, H.; Milder, F. L.; Burger, D. E. (1991) The use of K X-ray fluores cence for measuring Pb burden in

epidemiological studies: high and low Pb burdens and measurement uncertainty. Environ. Health Perspect.

94: 107-110.

Hu, H.; Watanabe, H.; Payton, M.; Korrick, S.; Rotnitz ky, A. (1994) The relationship between bone Pb and

hemoglobin. JAMA J. Am. Med. Assoc. 272: 1512-1517.

Hu, H.; Aro, A.; Payton, M.; Korrick, S.; Sparrow, D.; Weiss, S. T.; Rotnitzky, A. (1996) The relationship of bone

and blood Pb to hypertension. The Normative Aging Study. JAMA J. Am. Med. Assoc. 275: 1171-1176.

Hu, H.; Rabinowitz, M.; Smith, D. (1998) Bone Pb as a biological marker in epidem iologic studies of chronic

toxicity: conceptual paradigms. Environ. Health Perspect. 106: 1-8.

Hu, J.; La Vecchia, C.; Negri, E.; Chatenoud, L.; Bosetti, C.; Jia, X.; Liu, R.; Huang, G.; Bi, D.; Wang, C. (1999)

Diet and brain cancer in adults: a case-control study in no rtheast China. Int. J. Cancer 81: 20-23.

Hu, H.; Wu, M.-T.; Cheng, Y.; Sparrow, D.; Weiss, S.; Kelsey, K. (2001) The δ -aminolevulinic acid dehydratase

(ALAD) polymorphism and bone and blood Pb levels in community-exposed men: the Normative Aging

Study. Environ. Health Perspect. 109: 827-832.

Huang, J.; He, F.; Wu, Y.; Zhang, S. (1988) Observations on renal function in workers exposed to Pb. Sci. Total

Environ. 71: 535-537.

Huel, G.; Boudene, C.; Ibrahim, M. A. (1981) Cadmium and Pb content of maternal and newborn hair: relationship

to parity, birth weight, and hypertension. Arch. Environ. health 36: 221-227.

Hunter, J.; Urbanowicz, M. A.; Yule, W.; Lansdown, R. (1985) Automated testing of reaction time and its

association with Pb in children. Int. Ar ch. Occup. Environ. Health 57: 27-34.

Hwang, K.-Y.; Lee, B.-K.; Bressler, J. P.; Bolla, K. I.; Stewart, W. F.; Schwartz, B. S. (2002) Protein kinase C

activity and the relations between blood Pb and neurobehavioral function in Pb workers. Environ. Health

Perspect. 110: 133-138.

International Agency for Research on Cancer (IARC). (1980) Some metals and metallic compounds. Lyon, France:

International Agency for Research on Cancer. (IARC monographs on the evaluation of the carcinogenic

risk of chemicals to humans: volume 23).

International Agency for Research on Cancer (IARC). (2005) Inorganic and organic Pb compounds. Lyon, France:

International Agency for Research on Cancer. (IARC monographs on the evaluation of the carcinogenic

risk of chemicals to humans: volume 87: in preparation). Irgens, Å.; Krüger, K.; Skorve, A. H.; Irgens, L. M. (1998) Reproductive outcome in offspring of parents

occupationally exposed to Pb in Norway. Am. J. Ind. Med. 34: 431-437.

Ishida, M.; Ishizaki, M.; Yamada, Y. (1996) Decreases in postural change of finger blood flow in ceramic painters

chronically exposed to low level Pb. Am. J. Ind. Med. 29: 547-553.

Ito, Y.; Niiya, Y.; Kurita, H.; Shima, S.; Sarai, S. (1985) Serum lipid peroxide level and blood superoxide dismutase

activity in workers with occupational exposure to Pb. Int. Arch. Occup. Environ. Health 56: 119-127.

Iwata, T.; Yano, E.; Karita, K.; Dakeishi, M.; Murata, K. (2 005) Critical dose of Pb affecting postural balance in

workers. Am. J. Ind. Med. 48: 319-325.

Jackson, L. W.; Correa-Villaseñor, A.; L ees, P. S. J.; Dominici, F.; Stewart, P. A.; Breysse, P. N.; Matanoski,

G. (2004) Parental Pb exposure and total anomalous pulmonary venous return. Birth Defects Res.

Part A 70: 185-193.

Järup, L.; Hellström, L.; Alfvèn, T.; Carlsson, M. D.; Grubb, A.; Persson, B.; Pettersson, C.; Spång, G.; Schutz, A.;

Elinder, C.-G. (2000) Low level exposure to cadmium and early kidney damage: the OSCAR study. Occup.

Environ. Med. 57: 668-672.

# AX6-276 Jemal, A.; Graubard, B. I.; Devesa, S. S.; Flegal, K. M. (2002) The association of blood Pb level and cancer

mortality among whites in the United States. Environ. Health Perspect. 110: 325-329.

Jiun, Y. S.; Hsien, L. T. (1994) Lipid peroxidation in workers exposed to Pb. Arch. Environ. Health 49: 256-259.

Joffe, M.; Bisanti, L.; Apostoli, P.; Kiss, P.; Dale, A.; Roeleveld, N.; Lindbohm, M.-L.; Sallmén, M.; Vanhoorne,

M.; Bonde, J. P.; Asclepios. (2003) Time to pregnancy and occupational Pb exposure. Occup. Environ.

Med. 60: 752-758.

Johnson, R. J.; Kang, D.-H.; Feig, D.; Kivlighn, S.; Kane llis, J.; Watanabe, S.; Tuttle, K. R.; Rodriguez-Iturbe, B.;

Herrera-Acosta, J.; Mazzali, M. (2003) Is there a pat hogenetic role for uric acid in hypertension and

cardiovascular and renal disease? Hypertension 41: 1183-1190.

Jones, S. J.; Williams, A. J.; Kudlac, H.; Hainsworth, I. R.; Morgan, W. D. (1990) The measurement of bone Pb

content in patients with end stage failure. In: Yasumura , S.; Harrison, J. E., eds. In vivo body composition

studies: recent advances. New York, NY: Plenum Pre ss; pp. 259-262. (Basic life sciences: v. 55).

Joseph, C. L. M.; Havstad, S.; Ownby, D. R.; Peterson, E. L.; Maliarik, M. ; McCabe, M. J.; Barone, C.; Johnson,

C. C. (2005) Blood Pb levels and risk of asthma. Environ. Health Perspect. 113: 900-904.

Jung, K.-Y.; Lee, S.-J.; Kim, J.-Y.; Hong, Y.-S.; Kim, S.-R.; Kim, D.-I.; Song, J.-B. (1998) Renal dysfunction

indicators in Pb exposed workers. J. Occup. Health 40: 103-109.

Kamel, F.; Umbach, D.; Munsat, T.; Shefner, J.; Hu, H. ; Sandler, D. (2002) Pb exposure and amyotrophic later

sclerosis. Epidemiology 13: 311-319.

Kamel, F.; Umbach, D. M.; Lehman, T. A.; Park, L. P.; M unsat, T. L.; Shefner, J. M.; Sandler, D. P.; Hu, H.;

Taylor, J. A. (2003) Amyotrophic lateral sclerosis, Pb, and genetic susceptibility: polymorphisms in the δ

aminolevulinic acid dehydrat ase and vitamin D receptor genes. Enviro n. Health Perspect. 111: 1335-1339.

Kandiloros, D. C.; Goletsos, G. A.; Nikolopoulos, T. P.; Fe rekidis, E. A.; Tsomis, A. S.; Adamopoulos, G. K. (1997)

Effect of subclinical Pb intoxication on la ryngeal cancer. Br. J. C lin. Practice 51: 69-70.

Kannel, W. B. (2000a) Elevated systolic blood pressure as a cardiovascular risk factor. Am. J. Cardiol. 85: 251-255.

Kannel, W. B. (2000b) Risk stratification in hypertension: new insights from the Framingham Study. Am. J.

Hypertens. 13: 3S-10S.

Karakaya, A. E.; Ozcagli, E.; Ertas, N.; Sardas, S. (2005) Assessment of abnormal DNA repair responses and

genotoxic effects in Pb exposed workers. Am. J. Ind. Med. 47: 358-363.

Karmaus, W.; Brooks, K. R.; Nebe, T.; Witten, J.; Obi-Osiu s, N.; Kruse, H. (2005) Immune function biomarkers in

children exposed to Pb and organochlorine compounds: a cross-sectional study. Environ. Health Glob.

Access Sci. 4: 1-10.

Kaufman, A. S.; Kaufman, N. L. (1983) Kaufman assessm ent battery for children. Circle Pines, MN: American

Guidance Service.

Kauppinen, T.; Riala, R.; Seitsamo, J.; Hernberg, S. (1992 ) Primary liver cancer and occupational exposure. Scand.

J. Work Environ. Health. 18: 18-25.

Kavlock, R. J.; Daston, G. P.; DeRosa, C.; Fenner-Crisp. P. ; Gray, L. E.; Kaattari, S.; Lucier, G.; Luster, M.; Mac,

M. J.; Maczka, C.; Miller, R.; Moore, J.; Rolland, R.; Scott, G.; Sheeha n, D. M.; Sinks, T.; Tilson, H. A.

(1996) Research needs for the risk assessment of health and environmental effects of endocrine disruptors:

a report of the U.S. EPA-sponsored workshop. Environ. Health Perspect. Suppl. 104(4): 715-740.

Kelada, S. N.; Shelton, E.; Kaufma nn, R. B.; Khoury, M. J. (2001) δ -aminolevulinic acid dehydratase genotype and

Pb toxicity: a HuGE review. Am. J. Epidemiol. 154: 1-13.

Khalil-Manesh, F.; Gonick, H. C.; Cohen, A.; Bergamas chi, E.; Mutti, A. (1992) Experimental model of Pb

nephropathy. II. Effect of removal from Pb exposure and chelation treatment w ith dimercaptosuccinic acid

(DMSA). Environ. Res 58: 35-54.

Keiding, N.; Skakkebaek, N. E. (1996) Sperm dec line--real or artifact? Fer til. Steril. 65: 450-453.

Keiding, N.; Giwercman, A.; Carlsen, E.; Skakkebaek, N. E. (1994) Comment on "Farrow, S. (1994) Falling sperm

quality: fact of fiction? Br. Med. J. 309: 1-2." Br. Med. J. 309: 131.

Kim, R.; Rotnitsky, A.; Sparrow, D.; Weiss, S. T.; Wager, C.; Hu, H. (1996) A longitudinal study of low-level

Pb exposure and impairment of renal function. The Normative Aging Study. JAMA J. Am. Med.

Assoc. 275: 1177-1181.

Kim, Y.; Lee, H.; Lee, C. R.; Park, D. U.; Yang, J. S.; Park, I. J.; Lee, K. Y.; Lee, M.; King, T. K.; Sohn, N. S.; Cho,

Y. S.; Lee, N.; Chung, H. K. (2002) Evaluation of Pb exposure in workers at s econdary Pb smelters in

South Korea: with focus on activity of erythrocyte pyrimidine 5'-nucleotidase (P5N). Sci. Total Environ.

286: 181-189.

# AX6-277 Kimber, I.; Stonard, M. D.; Gidlow, D. A.; Niewola, Z. (1986) Influence of chronic low-level exposure to Pb on

plasma immunoglobulin concentration and cellular immune function in man. Int. Arch. Occup. Environ.

Health 57: 117-125.

Klein, D.; Wan, Y.-J. Y.; Kamyab, S.; Okuda, H.; Sokol, R. Z. (1994) Effects of toxic levels of Pb on gene

regulation in the male axis: increase in messenger ribo nucleic acids and intracellula r stores of gonadotrophs

within the central nervous system. Biol. Reprod. 50: 802-811.

Kline, J.; Stein, Z.; Hutzler, M. (1987) Cigarettes, alcohol and marijuana: varyin g associations with birthweight. Int.

J. Epidemiol. 16: 44-51.

Klitzman, S.; Sharma, A.; Nicaj, L.; V itkevich, R.; Leighton, J. (2002) Pb poisoning among pregnant women in New

York City: risk factors and screening practices. Bull. N. Y. Acad. Med. 79: 225-237.

Koller, K.; Brown, T.; Spurgeon, A.; Le vy, L. (2004) Recent developments in low-level Pb exposure and intellectual

impairment in children. Environ. Health Perspect. 112: 987-994.

Konishi, Y.; Endo, G.; Kiyota, A.; Horiguchi, S. (1994) Fractional clearances of low mo lecular weight proteins in

Pb workers. Ind. Health 32: 119-127.

Koo, W. W. K.; Succop, P. A.; Bornschein, R. L.; Krugwispe, S. K.; Steinchen, J. J.; Tsang, R. C.; Berger, O.G.

(1991) Serum vitamin D metabolites and bone mineralization in young children with chronic low to

moderate Pb exposure. Pediatrics 87: 680-687.

Kordas, K.; Lopez, P.; Rosado, J. L.; Vargas, G. G.; Rico, J. A.; Ronquillo, D.; Cebrian, M. E.; Stoltzfus, R. J.

(2004) Blood Pb, anemia, and short stature are inde pendently associated with cognitive performance in

Mexican school children. J. Nutr. 134: 363-371.

Kordas, K.; Stoltzfus, R. J.; López, P.; Rico, J. A.; Rosado, J. L. (2005) Iron and zinc supplementation does not

improve parent orteacher ratings of be havior in first grade Mexican childre n exposed to Pb. J. Pediatr. 147:

632-639.

Kordas, K.; Canfield, R. L.; López, P. ; Rosado, J. L.; Vargas, G. G.; Cébrian, M. E.; Rico, J. A.; Ronquillo, D.;

Stoltzfus, R. J. (2006) Deficits in cognitive functio n and achievement in Mexican first-graders with low

blood Pb concentrations. Environ. Res. 100: 371-386.

Korrick, S. A.; Hunter, D. J.; Rotnitzky, A.; Hu, H.; Speize r, F. E. (1999) Pb and hypertension in a sample of

middle-aged women. Am. J. Public Health 89: 330-335.

Koster, J.; Erhardt, A.; Stoeppler, M.; Mohl, C.; Ritz, E. (1989) Mobilizable Pb in patients with chronic renal failure.

Eur. J. Clin. Invest. 19: 228-233.

Kovala, T.; Matikainen, E.; Mannelin, T.; Erkkilä, J.; Riihim äki, V.; Hänninen, H.; Aitio, A. (1997) Effects of low

level exposure to Pb on neurophysiological functions among Pb battery workers. Occup. Environ. Med. 54:

487-493.

Kramer, M. S. (1987) Intrauterine growth and gestational duration determinants. Pediatrics 80: 502-511.

Kramer, M. S.; McLean, F. H. ; Boyd, M. E.; Usher, R. H. (1988) The validity of gestational age estimation by

menstrual dating in term, preterm, and postterm gestations. JAMA J. Am. Med. Assoc. 260: 3306-3308.

Krieg, E. F., Jr.; Chrislip, D. W.; Crespo, C. J.; Bri ghtwell, W. S.; Ehrenberg, R. L.; Otto, D. A. (2005) The

relationship between blood Pb levels and neurobehav ioral test performance in NHANES III and related

occupational studies. Public Health Rep. 120: 240-251.

Kristal-Boneh, E.; Froom, P.; Yerushalmi, N.; Harari, G.; Ribak, J. (1998) Calcitropic hormones and occupational

Pb exposure. Am. J. Epidemiol. 147: 458-463.

Kristal-Boneh, E.; Coller, D.; Froom, P.; Harari, G.; Ribak, J. (1999) The association between occupational Pb

exposure and serum cholesterol and lipoprotein levels. Am. J. Public Health 89: 1083-1087.

Kristensen, P.; Irgens, L. M.; Daltveit, A. K.; Anders en, A. (1993) Perinatal outcome among children of men

exposed to Pb and organic solvents in the pr inting industry. Am. J. Epidemiol. 137: 134-144.

Kromhout, D.; Wibowo, A. A. E.; Herber, R. F. M.; Dalderup, L. M.; Heerdink, H.; de Lezenne Coulander, C.;

Zielhuis, R. L. (1985) Trace metals and coronary hear t disease risk indicators in 152 elderly men (the

Zutphen study). Am. J. Epidemiol. 122: 378-385.

Kumar, B. D.; Krishnaswamy, K. (1995) Detection of oc cupational Pb nephropathy using early renal markers. J.

Toxicol. Clin. Toxicol. 33: 331-335.

Kuo, H.-W.; Hsiao, T.-Y.; Lai, J.-S. (2001) Immunological effects of long-term Pb exposure among Taiwanese

workers. Arch. Toxicol. 75: 569-573.

Lancranjan, I.; Popescu, H. I.; G ă v ă nescu, O.; Klepsch, I.; Serb ă nescu, M. (1975) Reproductive ability of workmen

occupationally exposed to Pb. Arch. Environ. Health 30: 396-401.

# AX6-278 Lanphear, B. P.; Howard, C.; Eberly, S.; Auinger, P.; Ko lassa, J.; Weitzman, M.; Schaff er, S. J.; Alexander, K.

(1999) Primary prevention of childhood Pb exposure: a randomized trial of dust control. Pediatrics

103: 772-777.

Lanphear, B. P.; Dietrich, K.; Auinger, P.; Cox, C. (2000) Cognitive deficits associated with blood Pb

concentrations < 10 μ g/dL in U.S. children and adolescents. Public Health Rep. 115: 521-529.

Lanphear, B. P.; Hornung, R.; Khoury, J.; Yolton, K.; Baghurst, P.; Bellinger, D. C.; Canfield, R. L.; Dietrich,

K. N.; Bornschein, R.; Greene, T.; Rothenberg, S. J.; Needleman, H. L.; Sc hnaas, L.; Wasserman, G.;

Graziano, J.; Roberts, R. (2005) Low-level environmen tal Pb exposure and children's intellectual function:

an international pooled analysis. Environ. Health Perspect. 113: 894-899.

Lanphear, B. P.; Hornung, R.; Khoury, J.; Yolton, K.; Dietrich, K. N. (2006) Pb and IQ in children: Lanphear et al.

respond [letter]. Environ. Health Perspect. 114: A86-A87.

Last, J. M. (2001) A dictionary of epidemiology. New York, NY: Oxford University Press.

Laudanski, T.; Sipowicz, M.; Modzelewsk i, P.; Bolinski, J.; Szamatowicz, J.; Razniewska, G.; Akerlund, M. (1991)

Influence of high Pb and cadmium soil content on human reproductive outcome. Int. J. Gynecol. Obstet.

36: 309-315.

Laughlin, N. K.; Bowman, R. E.; Franks, P. A.; Dierschke, D. J. (1987) Altered menstura l cycles in rhesus monkeys

induced by Pb. Fundam. Appl. Toxicol. 9: 722-729.

Lauwers, M. C.; Hauspie, R. C.; Susanne, C.; Verheyden, J. (1986) Comparison of biometric data of children with

high and low levels of Pb in the blood. Am. J. Phys. Anthropol. 69: 107-116.

Lauwerys, R.; Buchet, J. P.; Roels, H.; Hubermont, G. (1978) Placental transfer of Pb, mercury, cadmium, and

carbon monoxide in women: I. comparison of the frequency distributions of the biological indices in

maternal and umbilical cord blood. Environ. Res. 15: 278-289.

Lazutka, J. R.; Lekevi č ius, R.; Dedonyt ė , V.; Maciulevi č i ū t ė -Gervers, L.; Mierauskien ė , J.; Rudaitien ė , S.; Slapšyt ė

, G. (1999) Chromosomal aberrations and sister-chromatid exchanges in Lithuanian populations: effects of

occupational and environmental exposures. Mutat. Res. 445: 225-239.

Leal-Garza, C.; Moates, D. O. R.; Cerd a-Flores, R. M.; et al. (1986) Frequenc y of sister-chromatid exchanges (SCE)

in Pb exposed workers. Arch. Invest. Med. 17: 267-276.

Lee, B.-K.; Ahn, K.-D.; Lee, S.-S.; Lee, G.-S.; Kim, Y.-B.; Schwartz, B. S. (2000) A comparison of different

Pb biomarkers in their associati ons with Pb-related symptoms. Int. Arch. Occup. Environ. Health

73: 298-304.

Lee, B.-K.; Lee, G.-S.; Stewart, W. F.; Ahn, K.-D.; Sim on, D.; Kelsey, K. T.; Todd, A. C.; Schwartz, B. S. (2001)

Associations of blood pressure and hypertension with Pb dose measures and polymorphisms in the vitamin

D receptor and δ -aminolevulinic acid dehydratase genes. Environ. Health Perspect. 109: 383-389.

Lerchl, A. (1995) Evidence for decreasing quality of sperm. Presenta tion of data on sperm concentration was

flawed. Br. Med. J. 311: 569-570.

Lerda, D. (1992) Study of sperm char acteristics in persons occupationally ex posed to Pb. Am. J. Ind. Med.

22: 567-571.

Levey, A. S.; Bosc, J. P.; Lewis, J. B.; Greene, T.; Rogers, N.; Roth, D. (1999) A more accurate method to

estimate glomerular filtration rate from serum creatin ine: a new prediction equation. Ann. Intern. Med.

130: 461-470.

Levey, A. S.; Coresh, J.; Balk, E.; Kaus z, A. T.; Levin, A.; Steffes, M. W.; Hogg, R. J.; Perrone, R. D.; Lau, J.;

Eknoyan, G. (2003) National kidney foundation practice guidelines for chronic kidney disease: evaluation,

classification, and stratification. Ann. Intern. Med. 139: 137-147.

Leviton, A.; Bellinger, D.; Allred, E. N.; Rabinowitz, M.; Needleman, H.; Schoenbaum, S. (1993) Pre- and postnatal

low-level Pb exposure and children's dysfunction in school. Environ. Res. 60: 30-43.

Lezak, M. D.; Howieson, D. B. ; Loring, D. W.; Hannay, H. J.; Fischer, J. S. (2004) Neuropsychological assessment.

4th ed. New York, NY: Oxford University Press.

Lidsky, T. I.; Schneider, J. S. (2003) Pb neurotoxicity in children: basic mechanisms an d clinical correlates. Brain

126: 5-19.

Liebelt, E. L.; Schonfeld, D. J.; Gallagher, P. (1999) Elev ated blood Pb levels in child ren are associated with lower

erythropoietin concentrations. J. Pediatr. 134: 107-109.

Lilis, R.; Eisinger, J.; Blumberg, W.; Fischbein, A.; Seli koff, I. J. (1978) Hemogl obin, serum iron, and zinc

protoporphyrin in Pb-exposed workers. Environ. Health Perspect. 25: 97-102.

Lim, Y. C.; Chia, K. S.; Ong, H. Y.; Ng, V.; Chew, Y. L. (2001) Renal dysfunction in workers exposed to inorganic

Pb. Ann. Acad. Med. Singapore 30: 112-117.

# AX6-279 Lin, J. L.; Huang, P. T. (1994) Body Pb stores and urate excretion in men with chronic renal disease. J. Rheumatol.

21: 705-709.

Lin, J.-L.; Lim, P.-S. (1992) Elevated Pb burden in Chinese patients without occupational Pb exposure. Miner.

Electrolyte Metab. 18: 1-5.

Lin, J.-L.; Lim, P.-S. (1994) Does Pb play a role in the development of renal insufficiency in some patients with

essential hypertension? J. Hu m. Hypertens. 8: 495-500.

Lin, J.-L.; Yeh, K.-H.; Tseng, H.-C.; Chen, W- Y.; Lai, H.-H.; Lin, Y.-C.; Green Cross Health Service Association

Study Group. (1993) Urinary N-acetyl-glucosaminidase excretion and environmental Pb exposure. Am. J.

Nephrol. 13: 442-447.

Lin, S.; Hwang, S. A.; Marshall, E. G.; Stone, R.; Chen, J. (1996) Fertility rates among Pb workers and professional

bus drivers: a comparative study. Ann. Epidemiol. 6: 201-208.

Lin, S.; Hwang, S.-A.; Marshall, E. G.; Marion, D. (1998) Do es paternal occupational Pb exposure increase the risks

of low birth weight or prematurity? Am. J. Epidemiol. 148: 173-181.

Lin, J.-L.; Ho, H.-H.; Yu, C.-C. (1999) Chelation therapy for patients with elevated body Pb burden and progressive

renal insufficiency. A randomized, controlled trial. Ann. Intern. Med. 130: 7-13.

Lin, J.-L.; Tan, D.-T.; Hsu, K.-H.; Yu, C.-C. (2001a) Environmental Pb exposure and progressive renal

insufficiency. Arch. Intern. Med. 161: 264-271.

Lin, J.-L.; Yu, C.-C.; Lin-Tan, D.-T.; Ho, H.-H. (2001b) Pb chelation therapy and urat e excretion in patients with

chronic renal diseases and gout. Kidney Int. 60: 266-271.

Lin, J.-L.; Tan, D.-T.; Ho, H.-H.; Yu, C.-C. (2002) Environmental Pb exposure and urate excretion in the general

population. Am. J. Med. 113: 563-568.

Lin, J.-L.; Lin-Tan, D.-T.; Hsu, K.-H.; Yu, C.-C. (2003) Environmental Pb exposure and progression of chronic

renal diseases in patients without diabetes. N. Engl. J. Med. 348: 277-286.

Lindbohm, M.-L.; Hemminki, K.; Bonhomme, M. G.; Anttila , A.; Rantala, K.; Heikkila , P.; Rosenberg, M. J.

(1991a) Effects of paternal occupational exposure on spontaneous abortions. Am. J. Public Health

81: 1029-1033.

Lindbohm, M. L.; Sallmen, M.; Anttila, A.; Taskinen, H.; He mminki, K. (1991b) Paternal occupational Pb exposure

and spontaneous abortion. Scand. J. Work Environ. Health 17: 95-103.

Lindeman, R. D.; Tobin, J.; Shock, N. W. (1985) Longitudinal studies on the rate of decline in renal function with

age. J. Am. Geriatr. Soc. 33: 278-285.

Lindgren, K.; Masten, V.; Ford, D.; Bleecker, M. (1996) Relation of cumula tive exposure to inorganic Pb and

neuropsychological test performance. Occup. Environ. Med. 53: 472-477.

Lindgren, K. N.; Masten, V. L.; Tiburzi, M. J.; Ford, D. P.; Bleecker, M. L. (1999) The factor structure of the

profile of mood states (POMS) and its relationship to occupational Pb exposure. J. Occup. Environ. Med.

41: 3-10.

Lindgren, K. N.; Ford, D. P.; Bleecker , M. L. (2003) Pattern of blood Pb levels over working lifetime and

neuropsychological performance. Arch. Environ. Health 58: 373-379.

Liu, X.; Dietrich, K. N.; Radcliffe, J.; Ragan, N. B.; Rhoads, G. G.; Rogan, W. J. (2002) Do children with falling

blood Pb levels have improved cognition? Pediatrics 110: 787-791.

Lockett, C. J.; Arbuckle, D. (1987) Pb, ferritin, zinc, and hypertension. Bull. Environ. Contam. Toxicol.

38: 975-980.

Loeber, R.; Stouthamer-Loeber, M.; Van Kammen, W.; Farr ington, D. P. (1991) Initiation, escalation and desistance

in juvenile offending and their correlates. J. Criminal Law Criminol. 82: 36-82.

Loghman-Adham, M. (1998) Aminoaciduria and glycosuria following severe childhood Pb poisoning. Pediatr.

Nephrol. 12: 218-221.

López, C. M.; Piñeiro, A. E.; Núñez, N.; Avagnina, A. M.; Villaamil, E. C.; Roses, O. E. (2000) Thyroid hormone

changes in males exposed to Pb in the Buenos Ai res area (Argentina). Pharm acol. Res. 42: 599-602.

Louis, E. D.; Jurewicz, E. C.; Applegate, L.; Factor-Litvak , P.; Parides, M.; Andrews, L.; Slavkovich, V.; Graziano,

J. H.; Carroll, S.; Todd, A. (2003) Association between essentia l tremor and blood Pb concentration.

Environ. Health Perspect. 111: 1707-1711.

Louis, E. D.; Applegate, L.; Graziano, J. H.; Parides, M. ; Slavkovich, V.; Bhat, H. K. (2005) Interaction between

blood Pb concentration and δ -amino-levulinic acid dehydratase gene polymorphisms increases the odds of

essential tremor. Mov. Disord. 20: 1170-1177.

Lucchini, R.; Albini, E.; Cortesi, I.; Placidi, D.; Bergamas chi, E.; Traversa, F.; Alessi o, L. (2000) Assessment of

neurobehavioral performance as a function of current and cumulative occupational Pb exposure.

Neurotoxicology 21: 805-811.

# AX6-280 Lundström, N.-G.; Nordberg, G.; Englyst, V.; Gerhardsson, L.; Hagmar, L.; Jin, T.; Ryla nder, L.; Wall, S. (1997)

Cumulative Pb exposure in relation to mortality and lung cancer morbidity in a cohort of primary smelter

workers. Scand. J. Work Environ. Health 23: 24-30.

Lustberg, M.; Silbergeld, E. (2002) Blood Pb levels and mortality. Arch. Intern. Med. 162: 2443-2449.

Lustberg, M. E.; Schwartz, B. S.; Lee, B. K.; Todd, A. C.; Silbergeld, E. K. (2004) The g(894)-t(894)polymorphism

in the gene for endothelial nitric oxide synthase and blood pressure in Pb-exposed workers from Korea. J.

Occup. Environ. Med. 46: 584-590.

Lutz, P. M.; Wilson, T. J.; Ireland, A. L.; Gorman, J. S.; Gale, N. L.; Johnson, J. C.; Hewett, J. E. (1999) Elevated

immunoglobulin E (IgE) levels in children with exposure to environmental Pb. Toxicology 134: 63-78.

Mahaffey, K. R.; Annest, J. L.; Roberts, J.; Murphy, R. S. (1982) National estimates of blood Pb levels: United

States, 1976-1980. Association with selected demographic and socioeconomic factors. N. Engl. J. Med.

307: 573-579.

Maheswaran, R.; Gill, J. S.; Beevers, D. G. (1993) Blood pressure an d industrial Pb exposure. Am. J. Epidemiol.

137: 645-653.

Maizlish, N. A.; Parra, G.; Feo, O. (1995) Neurobehavioural evaluation of Venezuelan workers exposed to inorganic

Pb. Occup. Environ. Med. 52: 408-414.

Makino, S.; Shimizu, Y.; Takata, T. (1997) A study on the relationship between blood Pb levels and anemia

indicators in workers exposed to low levels of Pb. Ind. Health 35: 537-541.

Mäki-Paakkanen, J.; Sorsa, M.; Vainio, H. (1981) Chromo some aberrations and sister chromatid exchanges in Pbexposed workers. Hereditas 94: 269-275.

Malcolm, D.; Barnett, H. A. (1982) A mortality study of Pb workers 1925-76. Br. J. Ind. Med. 39: 404-410.

Mallin, K.; Rubin, M.; Joo, E. (1989) Occupational cancer mortality in Illinois white and black males, 1979-1984,

for seven cancer sites. Am. J. Ind. Med. 15: 699-717.

Mantere, P.; Hänninen, H.; Hernberg, S. (1982) Subclinical neurotoxic Pb effects: two-yr follow-up studies with

psychological test methods. Neurobehav. Toxicol. Teratol. 4: 725-727.

Marcus, A. H.; Schwartz, J. (1987) Dose-response curves for erythrocyte protoporphyrin vs blood Pb: effects of iron

status. Environ. Res. 44: 221-227.

Markowitz, M. E.; Gundberg, C. M.; Rosen, J. F. (1988) Sequential osteocalcin campling as a biochemical marker

of the success of treatment of mode rately Pb poisoned children [abs tract]. Pediatr. Res. 23: 393A.

Mason, H. J.; Somervaille, L. J.; Wright, A. L.; Chettle, D. R.; Scott, M. C. (1990) Effect of occupational Pb

exposure on serum 1,25-dihydroxyvitamin D levels. Hum. Exp. Toxicol. 9: 29-34.

Matte, T. D.; Figueroa, J. P.; Burr, G.; Flesch, J. P.; Keenlyside, R. A.; Baker, E. L. (1989) Pb exposure among Pbacid battery workers in Jamaica. Am. J. Ind. Med. 16: 167-177.

McBride, W. G.; Carter, C. J.; Bratel, J. R.; Cooney, G.; Bell, A. (1989) The Sydn ey study of health effects of Pb in

urban children. In: Smith, M. A.; Gran t, L. D.; Sors, A. I., eds. Pb exposure and child development: an

international assessment [workshop organized by the Commission of the European Communities and the

U.S. Environmental Protection Agency]; September 1986; Edinburgh, United Kingdom. Dordrecht, The

Netherlands: Kluwer Academic Publishers BV; pp. 255-259.

McCabe, M. J.; Lawrence, D. A. (1991) Pb, a major environmental pollutant, is immunomodulatory by its

differential effects on CD4+ T cell subsets. Toxicol. Appl. Pharmacol. 111: 13-23.

McCall, R. B. (1979) The development of intellectual f unctioning in infancy and the prediction of later IQ. In:

Osofsky, J. D., ed. Handbook of infant development. New York, NY: John Wiley; pp. 707-741.

McDonald, J. A.; Potter, N. U. (1996) Pb's legacy? Earl y and late mortality of 454 Pb-poisoned children. Arch.

Environ. Health. 51: 116-121.

McGregor, A. J.; Mason, H. J. (1990) Chronic occupational Pb exposure and testicular endocrine function. Hum.

Exp. Toxicol. 9: 371-376.

McMichael, A. J.; Johnson, H. M. (198 2) Long-term mortality profile of heav ily-exposed Pb smelter workers. J.

Occup. Med. 24: 375-378.

McMichael, A. J.; Vimpani, G. V.; Robe rtson, E. F.; Baghurst, P. A.; Clark, P. D. (1986) The Port Pirie cohort

study: maternal blood Pb and pregnancy outcome. J. Epidemiol. Commun. Health 40: 18-25.

McMichael, A. J.; Baghurst, P. A.; Wigg, N. R.; Vimpani, G. V.; Robertson, E. F.; Roberts, R. J. (1988) Port Pirie

cohort study: environmental exposure to Pb and children' s abilities at the age of four yrs. N. Engl. J. Med.

319: 468-475.

McMichael, A. J.; Baghurst, P. A.; Vimpani, G. V.; Robertson, E. F.; Wigg, N. R.; Tong, S.-L. (1992)

Sociodemographic factors modifying the effect of environmental Pb on neuropsychological development in

early childhood. Neurotoxicol. Teratol. 14: 321-327.

# AX6-281 McMichael, A. J.; Baghurst, P. A.; Vimpani, G. V.; Wigg, N. R.; Robertson, E. F.; Tong, S. (1994) Tooth Pb levels

and IQ in school-age children: the Port Pirie cohort study. Am. J. Epidemiol. 140: 489-499.

McNeill, F. E.; Stokes, L.; Brito, J. A.; Chettle, D. R.; Kaye, W. E. (2000) 109 

# Cd K x -ray fluorescence

measurements of tibial Pb content in young adults exposed to Pb in early childhood. Occup. Environ. Med.

57: 465-471.

Menditto, A.; Morisi, G.; Spagnolo, A.; Menotti, A.; NFR Study Group. (1994) Association of blood Pb to blood

pressure in men aged 55 to 75 yrs: effect of select ed social and biochemical co nfounders. NFR study group.

Environ. Health Perspect. 102(suppl. 9): 107-111.

Meng, X.-M.; Zhu, D.-M.; Ruan , D.-Y.; She, J.-Q.; Luo, L. (2005) Eff ects of chronic Pb exposure on H MRS of

hippocampus and frontal lobes in children. Neurology 64: 1644-1647.

Meredith, P. A.; Campbell, B. C.; Moor e, M. R.; Goldberg, A. (1977) The e ffects of industrial Pb poisoning on

cytochrome P450 mediated phenazone (antipyrine) hydroxylation. Eur. J. Clin. Pharmacol. 12: 235-239.

Meyer-Baron, M.; Seeber, A. (2000) A meta-analysis for ne urobehavioural results due to occupational Pb exposure

with blood Pb concentrations < 70 μ g/100 ml. Arch. Toxicol. 73: 510-518.

Michaels, D.; Zoloth, S. R.; St ern, F. B. (1991) Does lo w-level Pb exposure increase risk of death? A mortality

study of newspaper printers. Int. J. Epidemiol. 20: 978-983.

Min, Y.-I.; Correa-Villaseñor, A.; Stew art, P. A. (1996) Parental occupational Pb exposure and low birth weight.

Am. J. Ind. Med. 30: 569-578.

Mink, P. J.; Goodman, M.; Barraj, L. M.; Imrey, H.; Kelsh, M. A.; Yager, J. (2004) Evaluation of uncontrolled

confounding in studies of environmental exposures an d neurobehavioral testing in children. Epidemiology

15: 385-393.

Minozzo, R.; Deimling, L. I.; Gigante, L. P.; Santos-Mello, R. (2004) Micronuclei in peripheral blood lymphocytes

of workers exposed to Pb. Mutat. Res. 565: 53-60.

Miranda-Carús, E.; Mateos, F. A.; Sanz, A. G.; Herrero, E. ; Ramos, T.; Puig, J. G. (1997) Purine metabolism in

patients with gout: the role of Pb. Nephron 75: 327-335.

Mirsky, A. F. (1987) Behavioral and psychophysiological makers of disordered attention. Environ. Health Perspect.

74: 191-199.

Mishra, K. P.; Singh, V. K.; Rani, R.; Yadav, V. S.; Chan dran, V.; Srivastava, S. P.; Seth, P. K. (2003) Effect

of Pb exposure on the immune response of some occupationally exposed individuals. Toxicology

188: 251-259.

Mitchell, C. S.; Shear, M. S.; Bolla , K. I.; Schwartz, B. S. (1996) Clinical evaluation of 58 organolead

manufacturing workers. J. Occup. Environ. Med. 38: 372-378.

Moel, D. I.; Sachs, H. K. (1992) Renal function 17 to 23 yrs after chelation therapy for childhood plumbism. Kidney

Int. 42: 1226-1231.

Mohammed-Brahim, B.; Buchet, J. P.; Lauwerys, R. (1985 ) Erythrocyte pyrimidine 5'-nucleotidase activity in

workers exposed to Pb, mercury or cadmium. Int. Arch. Occup. Environ. Health 55: 247-252.

Moline, J.; Carrillo, L. L.; Sanchez, L. T.; Godbold, J.; Todd, A. (2000) Lactation and Pb body burden turnover: a

pilot study in Mexico. J. Occup. Environ. Med. 42: 1070-1075.

Møller, L.; Kristensen, T. S. (1992) Bl ood Pb as a cardiovascular risk factor. Am. J. Epidemiol. 136: 1091-1100.

Moore, M. R.; Goldberg, A.; Bushnell, I. W. R.; Day, R.; Fyfe, W. M. (1982) A prospective study of the

neurological effects of Pb in children. Neurobehav. Toxicol. Teratol. 4: 739-743.

Morgan, J. M. (1975) Chelation therapy in Pb nephropathy. South. Med. J. 68: 1001-1006.

Morita, Y.; Sakai, T.; Araki, S.; Ar aki, T.; Masuyama, Y. (1997) Nicotin amide adenine dinucleotide synthetase

activity in erythrocytes as a tool for the biological monitoring of Pb exposure. Int. Arch. Occup. Environ.

Health 70: 195-198.

Morris, C.; McCarron, D. A.; Bennett, W. M. (1990) Low-level Pb exposure, blood pressure, and calcium

metabolism. Am. J. Kidney Dis. 15: 568-574.

Mortada, W. I.; Sobh, M. A.; El-Defrawy, M. M.; Farahat, S. E. (2001) Study of Pb exposure from automobile

exhaust as a risk for nephrotoxicity among traffic policemen. Am. J. Nephrol. 21: 274-279.

Mortada, W. I.; Sobh, M. A.; El-Defrawy, M. M. (2004) The exposure to cadmium, Pb and mercury from smoking

and its impact on renal integrity. Med. Sci. Monit. 10: CR112-CR116.

Moss, M. E.; Lanphear, B. P.; Auinger, P. (1999) Association of dental caries and blood Pb levels. JAMA J. Am.

Med. Assoc. 281: 2294-2298.

Muldoon, S. B.; Cauley, J. A.; Kuller, L. H. ; Morrow, L.; Needleman, H. L. ; Sc ott, J.; Hooper, F. J. (1996) Effects

of blood Pb levels on cognitive function of older women. Neuroepidemiology 15: 62-72.

# AX6-282 Muntner, P.; He, J.; Vupputuri, S.; Coresh, J.; Batuman, V. (2003) Blood Pb and chronic kidney disease in the

general United States population: results fr om NHANES III. Kidney Int. 63: 1044-1050.

Murata, K.; Araki, S.; Yokoyama, K.; Uchida, E.; Fujimu ra, Y. (1993) Assessment of central, peripheral, and

autonomic nervous system functions in Pb workers: neuroelectrophysiological studies. Environ.

Res. 61: 323-336.

Murphy, M. J.; Graziano, J. H.; Popovac, D.; Kline, J. K.; Mehmeti, A.; Factor-Litvak, P.; Ahmedi, G.; Shrout, P.;

Rajovic, B.; Nenezic, D. U.; Stein, Z. A. (1990) Past pregnancy outcomes among women living in the

vicinity of a Pb smelter in Kosovo, Yugoslavia. Am. J. Public Health 80: 33-35.

Nash, D.; Magder, L.; Lustberg, M.; Sherwin, R. W.; Rubin, R. J.; Kaufmann, R. B.; Silbergeld, E. K. (2003) Blood

Pb, blood pressure, and hypertension in perimenopausal and postmenopausal women. JAMA J. Am. Med.

Assoc. 289: 1523-1532.

National Toxicology Program. (2003) Report on carcinogens background document for Pb and Pb compounds.

Research Triangle Park, NC: U.S. Department of Health and Human Services. Available:

http://ntp.niehs.nih.gov/ntp/newhomeroc/roc11/Pb-Public.pdf [5 May, 2006].

National Toxicology Program. (2004) Pb (CAS no. 7439-92-1) and Pb compounds. In: Report on carcinogens,

eleventh edition. Research Triangle Park, NC: U.S. De partment of Health and Human Services. Available:

http://ntp.niehs.nih.gov/ntp/roc/eleventh/pr ofiles/s101Pb.pdf [28 November, 2005].

Navarro, J. A.; Granadillo, V. A.; Salgado, O.; Rodríguez- Iturbe, B.; García, R.; Delling, G.; Romero, R. A. (1992)

Bone metal content in patients with chronic re nal failure. Clin. Chim. Acta 211: 133-142.

Navas-Acien, A.; Selvin, E.; Sharrett, A. R.; Calderon-Ara nda, E.; Silbergeld, E.; Gualla r, E. (2004) Pb, cadmium,

smoking, and increased risk of peripheral ar terial disease. Circulation 109: 3196-3201.

Nawrot, T. S.; Thijs, L.; Den Hond, E. M.; Roels, H. A.; Staessen, J. A. (2002) An epidemiological re-appraisal of

the association between blood pressure and blood Pb: a meta-analysis. J. Hum. Hypertens. 16: 123-131.

Needleman, H. L. (1995) Environmental Pb and children's intelligence: studies included in the meta-analysis are not

representative [letter]. Br. Med. J. 310: 1408.

Needleman, H. L.; Bellinger, D. (1988) Recent developments. Environ. Res. 46: 190-191.

Needleman, H. L.; Gatsonis, C. A. (1990) Low-level Pb ex posure and the IQ of children: a meta-analysis of modern

studies. JAMA J. Am. Med. Assoc. 263: 673-678.

Needleman, H. L.; Gunnoe, C.; Leviton, A.; Reed, R.; Pe resie, H.; Maher, C.; Barrett, P. (1979) Deficits in

psychologic and classroom performance of children with elevated dentine Pb levels. N. Engl. J.

Med. 300: 689-695.

Needleman, H. L.; Rabinowitz, M.; Leviton, A.; Linn, S.; Schoenbaum, S. (1984) The relationship between prenatal

exposure to Pb and congenital anomalies. JAMA J. Am. Med. Assoc. 251: 2956-2959.

Needleman, H. L.; Schell, A.; Bellinger, D.; Leviton, A.; Al lred, E. N. (1990) The long-term effects of exposure to

low doses of Pb in childhood; an 11-yr follow-up report. N. Engl. J. Med. 322: 83-88.

Needleman, H. L.; Riess, J. A.; Tobi n, M. J.; Biesecker, G. E. ; Greenhouse, J. B. (1996) Bone Pb levels and

delinquent behavior. JAMA J. Am. Med. Assoc. 275: 363-369.

Needleman, H. L.; McFarland, C.; Ness, R. B.; Fienberg, S. E.; Tobin, M. J. (2002) Bone Pb levels in adjudcated

delinquents. A case control study. Neurotoxicol. Teratol. 24: 711-717.

Neisser, U.; Boodoo, G.; Bouchard, T. J.; Boykin, A. W.; Brody, N.; Ceci, S. J.; Halpern, D. F.; Loehlin, J. C.;

Perloff, R.; Sternberg, R. J.; Ur bina, S. (1996) Intelligence: knowns and unknowns. Am. Psychol.

51: 77-101.

Nenov, V. D.; Taal, M. W.; Sakharova, O. V.; Brenner, B. M. (2000) Multi-hit nature of chronic renal disease. Curr.

Opin. Nephrol. Hypertens. 9: 85-97.

Neri, L. C.; Hewitt, D.; Orser, B. (19 88) Blood Pb and blood pressure: analys is of cross-sectional and longitudinal

data from Canada. In: Victery, W., ed. Symposium on Pb-blood pressure relationships; April 1987; Chapel

Hill, NC. Environ. Health Perspect. 78: 123-126.

Ng, T. P.; Goh, H. H.; Ng, Y. L.; Ong, H. Y.; Ong, C. N.; Chia, K. S.; Chia, S. E.; Jeyaratnam, J. (1991) Male

endocrine functions in workers with moderate exposure to Pb. Br. J. Ind. Med. 48: 485-491.

Niu, Q.; He, S. C.; Li, H. Y.; Wang, J. Y.; Dai, F. Y.; Chen, Y. L. (2000) A comprehensive neurobehavioral and

neurophysiological study for low level Pb-exposed workers. G. Ital. Med. Lav. Ergon. 22: 299-304.

Nolte, J. (1993) The human brain: an introduction to its functional anatomy. St. Louis, MO: Mosby Yr Book

Publishers.

Nomiyama, K.; Nomiyama, H.; Liu, S. J.; Tao, Y. X.; Nomiyama, T.; Omae, K. (2002) Pb induced increase of blood

pressure in female Pb workers. Occup. Environ. Med. 59: 734-738.

# AX6-283 Noonan, C. W.; Sarasua, S. M.; Campagna, D.; Kathman, S. J.; Lybarger, J. A.; Mueller, P. W. (2002) Effects

of exposure to low levels of environmental cadmium on renal biomarkers. Environ. Health Perspect.

110: 151-155.

Nordberg, M.; Winblad, B.; Fratiglioni, L.; Basun, H. (2000) Pb concentrations in elderly urban people related

to blood pressure and mental performance: results from a population-based study. Am. J. Ind. Med.

38: 290-294.

Nordenson, I.; Beckman, G.; Beckman, L.; Nordström, S. (1978) Occupational and environmental risks in and

around a smelter in northern Sweden. IV. Chromosoma l aberrations in workers exposed to Pb. Hereditas

(Lund, Swed.) 88: 263-267.

Nordström, S.; Beckman, L.; Nordenson, I. (1978a) Occupa tional and environmental risks in and around a smelter in

northern Sweden: I. Variations in birth weight. Hereditas (Lund, Swed.) 88: 43-46.

Nordström, S.; Beckman, L.; Nordenson, I. (1978b) Occupational and environmental risks in and around a smelter

in northern Sweden: III. Frequencies of spontaneous abortion. Hereditas (Lund, Swed.) 88: 51-54.

Nordström, S.; Beckman, L.; Nordenson, I. (1979) Occupational and environmental risks in and around a smelter in

northern Sweden. V. Spontaneous abortion among female employees and decreased birth weight in their

offspring. Hereditas (Lund, Swed.) 90: 291-296.

Nuyts, G. D.; Van Vlem, E.; Thys, J.; De Leersnijder, D.; D'Haese, P. C.; Elseviers, M. M.; De Broe, M. E. (1995)

New occupational risk factors for chronic renal failure. Lancet 346: 7-11.

Oishi, H.; Nomiyama, H.; Nomiyama, K.; Tomokuni, K. (1996) Comparison between males and females with

respect to the porphyrin metabolic disorders found in workers occupationally exposed to Pb. Int. Arch.

Occup. Environ. Health 68: 298-304.

Öktem, F.; Arslan, M. K.; Dündar, B.; Delibas, N.; Gülte pe, M.; Ergürhan Ilhan, I. (2004) Renal effects and

erythrocyte oxidative stress in long-term low-leve l Pb-exposed adolescent workers in auto repair

workshops. Arch. Toxicol. 78: 681-687.

Oliver, T. (1911) Pb poisoning and th e race. Br. Med. J. 1(2628): 1096-1098.

Olsen, G. W.; Bodner, K. M.; Ramlow, J. M.; Ross, C. E. ; Lipshultz, L. I. (1995) Have sperm counts been reduced

50 percent in 50 yrs? A statistical mode l revisited. Fertil. Steril. 63: 887-893.

Olsson, I.-M.; Bensryd, I.; Lundh, T.; Ottosson, H.; Skerfving, S.; Oskarsson, A. (2002) Cadmium in blood and

urine

― impact of sex, age, dietary intake, iron status, and former smoking

― association of renal effects.

Environ. Health Perspect. 110: 1185-1190.

Onalaja, A. O.; Claudio, L. (2000) Genetic susceptibility to Pb poisoning. Environ. Health Perspect. Suppl.

108(1): 23-28.

Ong, C. N.; Endo, G.; Chia, K. S.; Phoon, W. O.; Ong, H. Y. (1987) Evaluation of renal function in workers with

low blood Pb levels. In: Foá, V.; Emmett, E. A. ; Maroni, M.; Colombi, A., eds. Occupational and

environmental chemical hazards: cellular and biochemi cal indices for monitoring toxicity. New York, NY:

Halstead Press; pp. 327-333.

O'Riordan, M. L.; Evans, H. J. (1974) Absence of significant chromosome damage in males occupationally exposed

to Pb. Nature (London) 247: 50-53.

Orssaud, G.; Claude, J. R.; Moreau, T.; Lellouch, J.; Juguet, B.; Festy, B. (1985) Blood Pb concentration and blood

pressure. Br. Med. J. 290: 244.

Osman, K.; Pawlas, K.; Schütz, A.; Gazdzik, M.; Sokal, J. A.; Vahter, M. (1999) Pb exposure and hearing effects in

children in Katowice, Poland. Environ. Res. 80: 1-8. Österberg, K.; Börjesson, J.; Gerhardsson, L.; Schütz, A. ; Skerfving, S. (1997) A neurobehavioural study of longterm occupational inorganic Pb exposure. Sci. Total Environ. 201: 39-51.

Osterloh, J. D.; Selby, J. V.; Bernard, B. P.; Becker, C. E.; Menke, D. J.; Te pper, E.; Ordonez, J. D.; Behrens, B.

(1989) Body burdens of Pb in hypertensive nephropathy. Arch. Environ. Health 44: 304-310.

Osterode, W.; Barnas, D.; Geissler, K. (1999) Dose dependent reduction of erythroid progenitor cells and

inappropriate erythropoietin response in exposure to Pb: new aspects of anaemia induced by Pb. Occup.

Environ. Med. 56: 106-109.

Otto, D. A.; Fox, D. A. (1993) Auditory and visual dysfunction following Pb exposure. Presented at: Ninth

international neurotoxicology conference; October 1991; Little Rock, AR. Neurotoxicology 14(2-3):

191-207.

Otto, D.; Robinson, G.; Baumann, S.; Schroeder, S.; Mushak, P.; Kleinbaum, D.; Boone, L. (1985) Five-yr followup study of children with low-to-moderate Pb absorption: electrophysiological evaluation. Environ. Res.

38: 168-186.

# AX6-284 Paksy, K.; Gáti, I.; Náray, M.; Rajczy , K. (2001) Pb accumulation in human ova rian follicular fluid, and in vitro

effect of Pb on progesterone production by cultured human ovarian granulosa cells. J. Toxicol. Environ.

Health Part A 62: 359-366.

Palus, J.; Rydzynski, K.; Dziubaltowska, E.; Wyszynska, K.; Natarajan, A. T.; Nilsson, R. (2003) Genotoxic effects

of occupational exposure to Pb and cadmium. Mutat. Res. 540: 19-28.

Parkinson, D. K.; Hodgson, M. J.; Bromet, E. J.; Dew, M. A.; Connell, M. M. (1987) Occupational Pb exposure and

blood pressure. Br. J. Ind. Med. 44: 744-748.

Paschal, D. C.; Burt, V.; Caudill, S. P.; Gunter, E. W.; Pirkle, J. L.; Sampson, E. J.; Miller, D. T.; Jackson, R. J.

(2000) Exposure of the U.S. population aged 6 yrs and older to cadmium: 1988-1994. Arch. Environ.

Contam. Toxicol. 38: 377-383.

Patterson, C.; Ericson, J.; Manea-Krichten, M.; Shirahat a, H. (1991) Natural skeletal levels of Pb in Homo-sapiens

sapiens uncontaminated by technological Pb. Sci. Total Environ. 107: 205-236.

Payton, M.; Hu, H.; Sparrow, D.; Weiss, S. T. (1994) Lo w-level Pb exposure and renal function in the normative

aging study. Am. J. Epidemiol. 140: 821-829.

Payton, M.; Riggs, K. M.; Spiro, A., III; Weiss, S. T.; Hu, H. (1998) Relations of bone and blood Pb to cognitive

function: the VA Normative Aging Study. Neurotoxicol. Teratol. 20: 19-27.

Perez-Bravo, F.; Ruz, M; Moran-Jimen ez, M. J.; Olivares, M.; Rebolledo, A.; Codoceo, J.; Sepulveda, J.; Jenkin, A.;

Santos, J. L.; Fontanellas, A. (2004) Association between aminolevulinate dehydrase genotypes and blood

Pb levels in children from a Pb-contaminated area in Antofagasta, Chile. Arch. Environ. Contam. Toxicol.

47(2): 276-280.

Pergande, M.; Jung, K.; Precht, S.; Fels, L. M.; Herbort, C.; Stolte, H. (1994) Changed excretion of urinary proteins

and enzymes by chronic exposure to Pb. Nephrol. Dial. Transplant. 9: 613-618.

Pesch, B.; Haerting, J.; Ranft, U. ; Klimpel, A.; Oelschlägel, B.; Sc hill, W.; MURC Study Group. (2000)

Occupational risk factors for renal cell carcinoma: agent-specific resu lts from a case-control study in

Germany. Int. J. Epidemiol. 29: 1014-1024.

Philion, J. J.; Schmitt, N.; Rowe, J.; Gelp ke, P. M. (1997) Effect of Pb on fetal growth in a Canadian smelter city,

1961-1990. Arch. Environ. Health 52: 472-475.

Pineda-Zavaleta, A. P.; García-Vargas, G.; Borja-Aburto, V. H.; Acosta-Saaved ea, L. C.; Vera Aguilar, E.; GómezMuñoz, A.; Cebrián, M. E. Calderón-Aranda, E. S. (2004) Nitric oxide and superoxide anion production in

monocytes from children exposed to arsenic and Pb in region Lagunera, Mexico. Toxicol. Appl.

Pharmacol. 198: 283-290.

Pinkerton, L. E.; Biagini, R. E.; Ward, E. M.; Hull, R. D.; Deddens, J. A.; Boenig er, M. F.; Schnorr, T. M.;

MacKenzie, B. A.; Luster, M. I. (1998) Immunologic findings among Pb-exposed workers. Am. J. Ind.

Med. 33: 400-408.

Pinto de Almeida, A. R.; Carvalho, F. M.; Spinola, A. G.; Rocha, H. (1987) Renal dysfunction in Brazilian Pb

workers. Am. J. Nephrol. 7: 455-458.

Piomelli, S.; Seaman, C.; Zullow, D.; Curran, A.; Davidow, B. (1982) Threshold for Pb damage to heme synthesis in

urban children. Proc. Natl. Acad. Sci. U. S. A. 79: 3335-3339.

Pirkle, J. L.; Kaufmann, R. B.; Brody, D. J.; Hickman, T.; Gunter, E. W.; Paschal, D. C. (1998) Exposure of the U.S.

population to Pb, 1991-1994. Environ. Health Perspect. 106: 745-750.

Pocock, S. J.; Shaper, A. G.; Ashby, D.; Delves, T.; Wh itehead, T. P. (1984) Blood Pb concentration, blood

pressure, and renal function. Br. Med. J. 289: 872-874.

Pocock, S. J.; Ashby, D.; Smith, M. A. (1987) Pb expo sure and children's intellectual performance. Int. J.

Epidemiol. 16: 57-67.

Pocock, S. J.; Smith, M.; Baghurst, P. (1994) Environmental Pb and children's intelligence: a systematic review of

the epidemiological evidence. Br. Med. J. 309: 1189-1197.

Pollock, C. A.; Ibels, L. S. (1988) Pb intoxication in Sydney Harbour bridge workers. Aust. N. Z. J. Med.

18: 46-52.

Poulos, L.; Qammaz, S.; Athanaselis, S.; Maravelias, C.; Koutselinis, A. (1986) Statistically significant

hematopoietic effects of low blood Pb levels. Arch. Environ. Health 41: 384-386.

Pounds, J. G.; Long, G. J.; Rosen, J. F. (1991) Cellular and molecular toxicity of Pb in bone. Environ. Health

Perspect. 91: 17-32.

Price, J.; Grudzinski, A. W.; Craswell, P. W.; Thomas, B. J. (1992) Bone Pb measurements in patients with chronic

renal disease studied over time. Arch. Environ. Health 47: 330-335.

Price, R. G.; Patel, S.; Chivers, I.; Milligan, P.; Taylor, S. A. (1999) Early markers of nephrotoxicity: detection of

children at risk from environmenta l pollution. Renal Fail. 21: 303-308.

# AX6-285 Proctor, S. P.; Rotnitzky, A.; Sparrow, D.; Weiss, S. T.; Hu, H. (1996) The relationship of blood Pb and dietary

calcium to blood pressure in the normative aging study. Int. J. Epidemiol. 25: 528-536.

Prpi ć -Maji ć , D.; Bobi ć , J.; Šimi ć , D.; House, D. E.; Otto, D. A.; Jurasovi ć , J.; Pizent, A. (2000) Pb absorption and

psychological function in Zabreb (Croatia) school children. Neurotoxicol. Teratol. 22: 347-356.

Pueschel, S. M.; Kopito, L.; Schwachman, H. (1972) Child ren with an increased Pb burden. A screening and followup study. JAMA J. Am. Med. Assoc. 222: 462-466.

Puzas, J. E. (2000) Osteotoxicology: the role of Pb in bone disease. Curr. Opin. Orthop. 11: 360-365.

Puzas, J. E.; Sickel, M. J.; Felter, M. E. (1992) Osteoblasts and chondrocytes are important target cells for the toxic

effects of Pb. Neurotoxicology 13: 783-788.

Pyatt, D. W.; Zheng, J.-H.; Stillman, W. S.; Ir ons, R. D. (1996) Inorganic Pb activates NF- κ B in primary human

CD4 + 

# T lymphocytes. Biochem. Biophys. Res. Commun. 227: 380-385.

Queiroz, M. L. S.; Almeida, M.; Gallao, M. I.; Höehr, N. F. (1993) Defective neutrophil function in workers

occupationally exposed to Pb. Pharmacol. Toxicol. 72: 73-77.

Queiroz, M. L.; Costa, F. F.; Bincoletto , C.; Perlingeiro, R. C. R.; Dantas, D. C. M.; Cardoso, M. P.; Almeida, M.

(1994a) Engulfment and killing capabilities of neutroph ils and phagocytic splenic function in persons

occupationally exposed to Pb. Int. J. Immunopharmacol. 16: 239-244.

Queiroz, M. L. S.; Perlingeiro, R. C. R.; Bincoletto, C.; Almeida, M.; Cardos o, M. P.; Dantas, D. C. M. (1994b)

Immunoglobulin levels and cellular immune function in Pb exposed workers. Immunopharmacol.

Immunotoxicol. 16: 115-128.

Raab, G. M.; Thomson, G. O. B.; Boyd , L.; Fulton, M.; Laxen, D. P. H. (1 990) Blood Pb levels, reaction time,

inspection time and ability in Edinburgh chil dren. Br. J. Dev. Ps ychol. 8: 101-118.

Rabinowitz, M. B. (1991) Toxicokinetics of bone Pb. Environ. Health Perspect. 91: 33-37.

Rabinowitz, M.; Bellinger, D.; Leviton, A.; et al. (1987) Pregnancy hypertension, blood pressure during labor, and

blood Pb levels. Hypertension 10: 447-451.

Rabinowitz, M. B.; Allred, E. N.; Be llinger, D. C.; Leviton, A.; Needleman, H. L. (1990) Pb and childhood

propensity to infectious and allergic disorders: is th ere an association? Bull. Environ. Contam. Toxicol.

44: 657-660.

Rabinowitz, M. B.; Bellinger, D.; Leviton, A.; Wang, J.-D. (1991) Pb levels among various deciduous tooth types.

Bull. Environ. Contam. Toxicol. 47: 602-608.

Rabinowitz, M. B.; Wang, J.-D.; Soong, W. T. (1992) Children's classroom behavior and Pb in Taiwan. Bull.

Environ. Contam. Toxicol. 48: 282-288.

Rabinowitz, M. B.; Leviton, A.; Bellinge r, D. (1993) Relationships between serial blood Pb levels and exfoliated

tooth dentin Pb levels: models of tooth Pb kinetics. Calcif. Tissue Int. 53: 338-341.

Rahman, A.; Hakeem, A. (2003) Blood Pb levels during pregnancy and pregnancy outcome in Karachi women. J.

Pak. Med. Assoc. 53: 529-533.

Rajah, T.; Ahuja, Y. R. (1995) In vivo genotoxic effects of smoking and occupational Pb exposure in printing press

workers. Toxicol. Lett. 76: 71-75.

Rajah, T. T.; Ahuja, Y. R. (1996) In vivo genotoxicity of alcohol consumption and Pb exposure in printing press

workers. Alcohol 13: 65-68.

Rajegowda, B. K.; Glass, L.; Evans, H. E. (1972) Pb concentrations in the newborn infant. J. Pediatr. 80: 116-117.

Ratzon, N.; Froom, P.; Leikin, E.; Kristal-B oneh, E.; Ribak, J. (2000) Effect of exposure to Pb on postural control in

workers. Occup. Environ. Med. 57: 201-203.

Refowitz, R. M. (1984) Thyroid function and Pb: no clear relationship. J. Occup. Med. 26: 579-583.

Reigart, J. R.; Graber, C. D. (1976) Evaluation of the humoral immune response of children with low level Pb

exposure. Bull. Environ. Contam. Toxicol. 16: 112-117.

Reimer, W.; Tittelbach, U. (1989) Verhalten von Herzfreque nz, Blutdruck und systolischen Zeitintervallen in Ruhe

und wahrend Einhandarbeit bei Bleiexponierten und Kontrollpersonen [Heart rate, blood pressure and

systolic time interval in rest and during single-han d exertion in persons exposed to Pb and in control

subjects]. Z. Gesamte Hyg. Ihre Grenzgeb. 35: 491-492.

Restek-Samaržija, N.; Mom č ilovi ć , B.; Troši ć , I.; Piasek, M.; Samaržija, M. (1996) Chronic Pb poisoning, renal

function and immune response. Arh. Hig. Rada Toksikol. 47: 1-8.

Restek-Samaržija, N.; Mom č ilovi ć , B.; Turk, R.; Samaržija, M. (1997) Contribution of Pb poisoning to renal

impairment. Arh. Hig. Rada Toksikol. 48: 355-364.

Rhainds, M.; Levallois, P. (1997) Effects of maternal cigarette smoking and alcohol consumption on blood Pb levels

of newborns. Am. J. Epidemiol. 145: 250-257.

# AX6-286 Rhainds, M.; Levallois, P.; Dewailly, É.; Ayotte, P. (1999) Pb, mercury, and organochlorine compound levels in

cord blood in Québec, Canada. Arch. Environ. Health 54: 40-47.

Rhodes, D.; Spiro, A., III; Aro, A.; Hu, H. (2003) Relationship of bone and blood Pb levels to psychiatric

symptoms: The Normative Aging Study. J. Occup. Environ. Med. 45: 1144-1151.

Rico, J. A.; Kordas, K.; López, P.; Rosa do, J. L.; Vargas, G. G.; Ronquillo, D.; Stoltzfus, R. J. (2006) The efficacy

of iron and/or zinc supplementation on cognitive pe rformance of Pb-exposed Mexican school children: a

randomized, placebo-contro lled trial. Pediatrics 117: e518-e527.

Ris, M. D.; Dietrich, K. N.; Succop, P. A.; Berger, O. G.; Bornschein, R. L. (2004) Early exposure to Pb and

neuropsychological outcome in adolescence. J. Int. Neuropsychol. Soc. 10: 261-270.

Risch, H. A.; Burch, J. D.; Miller, A. B.; Hill, G. B.; Steele, R.; Howe, G. R. (1988) Occupational factors and the

incidence of cancer of the bladder in Canada. Br. J. Ind. Med. 45: 361-367.

Robins, J. M.; Cullen, M. R.; Connors, B. B.; Kayne, R. D. (1983) Depressed thyroid indexes associated with

occupational exposure to inorganic Pb. Arch. Intern. Med. 143: 220-224.

Rodamilans, M.; Osaba, M. J. M.; To-F igueras, J.; Rivera Fillat, F.; Marque s, J. M.; Pérez, P.; Corbella, J.

(1988) Pb toxicity on endocrine testicular function in an occupationally exposed population. Hum. Toxicol.

7: 125-128.

Roelofs-Iverson, R. A.; Mulder, D. W.; Elveback, L. R.; Kurland, L. T.; Molgaard, C. A. (1984) ALS and heavy

metals: a pilot case study. Neurology 34: 393-395.

Roels, H.; Lauwerys, R. (1987) Evaluation of dose-effect and dose-response relationships for Pb exposure in

different Belgian population groups (fetus, child, adult men and women). Trace Elem. Med. 4: 80-87.

Roels, H.; Hubermont, G.; Buchet, J.-P .; Lauwerys, R. (1978) Pl acental transfer of Pb, mercury, cadmium, and

carbon monoxide in women. III. Factors influencing the accumulation of heavy me tals in the placenta and

the relationship between metal concentration in the placenta and in maternal and cord blood. Environ. Res.

16: 236-247.

Roels, H. A.; Balis-Jacques, M. N.; Bu chet, J.-P.; Lauwerys, R. R. (1979) The influence of sex and of chelation

therapy on erythrocyte protoporphyrin and urinary δ -aminolevulinic acid in Pb-exposed workers. J. Occup.

Med. 21: 527-539.

Roels, H. A.; Lauwerys, R. R.; Buchet, J. P.; Bernard, A. M.; Vos, A.; Overstey ns, M. (1989) Health significance of

cadmium induced renal dysfunction: a five yr follow up. Br. J. Ind. Med. 46: 755-764.

Roels, H.; Lauwerys, R. ; Konings, J.; Buchet, J.-P.; Bernard, A.; Gr een, S.; Bradley, D.; Morgan, W.; Chettle, D.

(1994) Renal function and hyperfiltration capacity in Pb smelter workers with high bone Pb. Occup.

Environ. Med. 51: 505-512.

Roels, H.; Konings, J.; Green, S.; Br adley, D.; Chettle, D.; Lauwerys, R. (1995) Time-integrated blood Pb

concentration is a valid surrogate for estimating the cu mulative Pb dose assessed by tibial Pb measurement.

Environ. Res. 69: 75-82.

Roels, H. A.; Van Assche, F. J.; Oversteyns, M.; De Groof, M.; Lauwerys, R. R.; Lison, D. (1997) Reversibility of

microproteinuria in cadmium workers with incipient tubular dysfunction after reduction of exposure. Am.

J. Ind. Med. 31: 645-652.

Rogan, W. J.; Ware, J. H. (2003) Exposure to Pb in children

― how low is low enough? N. Engl. J. Med.

348: 1515-1516.

Rogan, W. J.; Dietrich, K. N.; Ware, J. H.; et al. (2 001) The effect of chelation therapy with succimer on

neuropsychological development in children exposed to Pb. New Engl. J. Med. 344: 1421-1426.

Rom, W. N. (1976) Effects of Pb on the female and reproduction: a review. Mt. Sinai J. Med. 43: 542-552.

Romeo, R.; Aprea, C.; Boccalon, P.; Orsi . D; Porcelli, B.; Sartorelli, P. (199 6) Serum erthropoie tin and blood Pb

concentrations. Int. Arch. Occu p. Environ. Health 69: 73-75.

Ronis, M. J. J.; Badger, T. M.; Shema, S. J.; Roberson, P. K.; Shaikh, F. (1996) Reproductive toxicity and

growth effects in rats exposed to Pb at different periods during development. Toxicol. Appl. Pharmacol.

136: 361-371.

Rose, G.; Day, S. (1990) The population mean predicts the number of deviant individuals. Br. Med. J. 301:

1031-1034.

Rosen, J. F.; Chesney, R. W.; Hamstra, A.; DeLuca, H. F.; Mahaffey, K. R. (1980) Reduction in 1,25-

dihydroxyvitamin D in children with increased Pb absorption. N. Engl. J. Med. 302: 1128-1131.

Rosenthal, R. (1984) Meta-analytic procedures for so cial research. Beverly Hills , CA: Sage Publications.

Roses, O. E.; Alvarez, S.; Conti, M. I.; Nobile, R. A.; Villaamil, E. C. (19 89) Correlation between Pb and prolactin

in males exposed and unexposed to Pb in Buenos Aires (Argentina) area. Bull. Environ. Contam. Toxicol.

42: 438-442.

# AX6-287 Rossner, P.; Boffetta, P.; Ceppi, M.; Bonassi, S.; Smerhovsky, Z.; Landa, K.; Juzova, D.; Šrám, R. J. (2005)

Chromosomal aberrations in lymphocytes of healthy subjects and risk of cancer. Environ. Health Perspect.

113: 517-520.

Rothenberg, S. J.; Rothenberg, J. C. (2005) Testing the dose-response specification in epidemiology: public health

and policy consequences for Pb. Environ. Health Perspect. 113: 1190-1195.

Rothenberg, S. J.; Schnaas, L.; Cansino- Ortiz, S.; Perroni-Hernández, E.; de la Torre, P.; Neri-Méndez, C.; Ortega,

P.; Hidalgo-Loperena, H.; Svendsgaard, D. (1989) Neurobehavioral deficits after low level Pb exposure in

neonates: the Mexico City pilot study. Neurotoxicol. Teratol. 11: 85-93.

Rothenberg, S. J.; Karchmer, S.; Schnaas, L.; Perroni, E.; Zea, F.; Alba, J. F. (1994) Changes in serial blood Pb

levels during pregnancy. Environ. Health Perspect. 102: 876-880.

Rothenberg, S. J.; Manalo, M.; Jiang, J.; Cuellar, R.; Re yes, S.; Sanchez, M.; Diaz, M.; Khan, F.; Aguilar, A.;

Reynoso, B.; Juaregui, M.; Acosta, S.; Johnson, C. (1999) Blood Pb level and blood pressure during

pregnancy in south central Los Angeles. Arch. Environ. Health 54: 382-389.

Rothenberg, S. J.; Khan, F.; Manalo, M.; Jian, J.; Cuella r, R.; Reyes, S.; Acosta, S.; Jauregui, M.; Diaz, M.;

Sanchez, M.; Todd, A. C.; Johnson, C. (2000) Maternal bone Pb contribution to blood Pb during and after

pregnancy. Environ. Res. 82: 81-90.

Rothenberg, S. J.; Kondrashov, V.; Manalo , M.; Jiang, J.; Cuellar, R.; Garcia, M.; Reynoso, B.; Reyes, S.; Diaz, M.;

Todd, A. C. (2002a) Increases in hypertension and blood pressure during pregnancy with increased bone Pb

levels. Am. J. Epidemiol. 156: 1079-1087.

Rothenberg, S. J.; Schnaas, L.; Salgado- Valladares, M.; Casanueva, E.; Geller, A. M.; Hudnell, H. K.; Fox, D. A.

(2002b) Increased ERG a- and b-wave amplitudes in 7- to 10-yr-old children resulting from prenatal Pb

exposure. Invest. Ophthalmol. Vis. Sci. 43: 2036-2044.

Rowe, J. W.; Andres, R.; Tobin, J. D.; Norris, A. H.; Sh ock, N. W. (1976) Age-adju sted standards for creatinine

clearance. Ann. Intern . Med. 84: 567-569.

Rowland, A.; Wilcox, A. (1987) Maternal blood Pb [letter]. J. Epidemiol. Community Health 41: 184.

Ruff, H. A.; Bijur P. E.; Markowitz, M.; Ma, Y.-C.; Rosen, J. F. (1993) Declining blood Pb levels and cognitive

changes in moderately Pb-poisoned children. JAMA J. Am. Med. Assoc. 269: 1641-1646.

Saenger, P.; Markowitz, M. E; Rosen, J. F. (1984) Depressed excretion of 6Beta-hydroxycortisol in Pb-toxic

children. J. Clin. Endocrinol. Metab. 58: 363-367.

Sakai, T.; Morita, Y.; Araki, T.; Kano, M. ; Yoshida, T. (2000) Relationship between δ -aminolevulinic acid

dehydratase genotypes and heme precursors in Pb workers. Am. J. Ind. Med. 38: 355-360.

Salkever, D. S. (1995) Updated estimates of earnings benefits from reduced exposure of children to environmental

Pb. Environ. Res. 70: 1-6.

Sallmén, M.; Lindbohm, M.-L.; Anttila, A.; Taskinen, H.; Hemminki, K. (1992) Paternal occupational Pb exposure

and congenital malformations. J. Epidemiol. Community Health 45: 519-522.

Sallmén, M.; Anttila, A.; Lindbohm, M.-L.; Kyyrönen, P.; Taskinen, H.; Hemminki, K. (1995) Time to pregnancy

among women occupationally exposed to Pb. J. Occup. Environ. Med. 37: 931-934.

Sallmén, M.; Lindbohm, M. L.; Anttila , A.; Taskinen, H.; Hemminki, K. (2000a) Time to pregnancy among the

wives of men occupationally exposed to Pb. Epidemiology 11: 141-147.

Sallmén, M.; Lindbohm, M. L.; Nurminen, M. (2000b) Pa ternal exposure to Pb and infertility. Epidemiology

11: 148-152.

Sánchez-Fructuoso, A. I.; Torralbo, A.; Arroyo, M.; Lu que, M.; Ruilope, L. M.; Sant os, J. L.; Cruceyra, A.;

Barrientos, A. (1996) Occult Pb in toxication as a cause of hypertension and renal failure. Nephrol. Dial.

Transplant. 11: 1775-1780.

Sanín, L. H.; González-Cossío, T.; Romieu, I.; Peterson, K. E.; Ruíz, S.; Palazuelos, E.; Hernández-Avila, M.; Hu,

H. (2001) Effect of maternal Pb burden on infant weight and weight gain at one mo of age among breastfed

infants. Pediatrics 107: 1016-1023.

Sankila, R.; Karjalainen, S.; Pukkala, E.; Oksanen, H.; Ha kulinen, T.; Teppo, L.; Hakama, M. (1990) Cancer risk

among glass factory workers: an excess of lung cancer? Br. J. Ind. Med. 47: 815-818.

Sarasua, S. M.; Vogt, R. F.; Henderson, L. O.; Jones, P. A.; Lybarger, J. A. (2000) Serum immunoglobulins and

lymphocyte subset distributions in children and adu lts living in communities assessed for Pb and cadmium

exposure. J. Toxicol. Environ. Health A. 60(1): 1-15.

Sarasua, S. M.; Mueller, P.; Kathman, S.; Campagna, D.; Uddin, M. S.; White, M. C. (2003) Confirming the utility

of four kidney biomarker tests in a longitudinal follow-up study. Renal Failure 25: 797-817.

# AX6-288 Sargent, J. D.; Dalton, M. A.; O'Connor, G. T.; Olmst ead, E. M.; Klein, R. Z. (1999) Randomized trial of

calcium glycerophosphate-supplemented infant formula to prevent Pb absorption. Am. J. Clin.

Nutr. 69: 1224-1230.

Sarto, F.; Stella, M.; Acqua, A. (1978) Cytogenetic study of a group of workers with increased Pb absorption

indices. Med. Lav. 69: 172-180.

Sata, F.; Araki, S.; Sakai, T.; Nakata, A.; Yamashita, K.; Morita, Y.; Tanigawa, T.; Miki, A. (1997) Immunological

effects of CaEDTA injection: observations in two Pb workers. Am. J. Ind. Med. 32: 674-680.

Sata, F.; Araki, S.; Tanigawa, T.; Morita, Y.; Sakurai, S.; Nakata, A.; Katsuno, N. (1998) Changes in T cell

subpopulations in Pb workers. Environ. Res. 76: 61-64.

Satarug, S.; Nishijo, M.; Ujjin, P.; Vanavanitkun, Y.; Bake r, J. R.; Moore, M. R. (2004) Evidence for concurrent

effects of exposure to environmental cadmium and Pb on hepatic CYP2A6 phenotype and renal function

biomarkers in nonsmokers. Environ. Health Perspect. 112: 1512-1518.

Satz, P. (1993) Brain reserve capacity on symptom onset after brain injury: a formulation and review of evidence for

threshold theory. Neuropsychology 7: 273-295.

Savitz, D. A.; Whelan, E. A.; Rowland, A. S.; Kleckner, R. C. (1990) Maternal employment and reproductive risk

factors. Am. J. Epidemiol. 132: 933-945.

Schafer, T. E.; Adair, S. M. (2000) Prevention of dental disease. The role of the pediatrician. Pediatr. Clin. North

Am. 47: 1021-1042.

Schantz, S. L. (1996) Developmental neurotoxicity of PCBs in humans: what do we know and where do we go from

here? Neurotoxicol. Teratol. 18: 217-227.

Schärer, K.; Veits, G.; Brockhaus, A.; Ew ers, U. (1991) High Pb content of deciduous teeth in chronic renal failure.

Pediatr. Nephrol. 5: 704-707.

Schaumberg, D. A.; Mendes, F.; Balaram, M.; Dana, M. R. ; Sparrow, D.; Hu, H. (2004) Accumulated Pb exposure

and risk of age-related cataract in men. JAMA J. Am. Med. Assoc. 292: 2750-2754.

Schmid, E.; Bauchinger, M.; Pietruck, S.; Hall, G. (1972) Die cytogenetische Wirkung von Blei in menschlichen

peripheren Lymphocyten in vitro und in vivo [The cytogeneticeffect of Pb in human peripehral

lymphocytes in vitro and in vivo]. Mutat. Res. 16: 401-406.

Schnaas, L.; Rothenberg, S. J.; Perroni, E.; Martínez, S.; Hernández, C.; Hernández, R. M. (2000) Temporal pattern

in the effect of postnatal blood Pb level on intellectual development of young children. Neurotoxicol.

Teratol. 22: 805-810.

Schnaas, L.; Rothenberg, S. J.; Flores, M.-F.; Martinez, S.; Hernandez, C.; Os orio, E.; Velasco, S. R.; Perroni, E.

(2006) Reduced intellectual development in children with prenatal Pb exposure. Environ. Health Perspect.

114: 791-797.

Schober, S. E.; Mirel, L. B.; Graubard, B. I.; Brody, D. J.; Flegal, K. M. (2006) Blood Pb levels and death from all

causes, cardiovascular disease, and cancer: results from the NHANES III Mortality Study. Environ. Health

Perspect: doi:10.1289/ehp.9123 [6 July, 2006]

Schroeder, S. R.; Hawk, B. (1987) Psycho-social factors, Pb exposure, and IQ. In: Schroeder, S. R., ed. Toxic

substances and mental retardation: neurobehavioral toxicology and teratology. Washington, DC: American

Association on Mental Deficiency; pp . 97-137. (Begab, M. J., ed. Monogr aphs of the American Association

on Mental Deficiency: no. 8).

Schuhmacher, M.; Patemain, J. L.; Domingo, J. L.; Corb ella, J. (1997) An assessment of some biomonitors

indicative of occupational exposure to Pb. Trace Elem. Electrolytes 14(3): 145-149.

Schumacher, C.; Brodkin, C. A.; Alexander, B.; Cullen, M.; Rainey, P. M.; van Netten, C.; Faustman, E.;

Checkoway, H. (1998) Thyroid function in Pb smelter workers: absence of subacute or cumulative effects

with moderate Pb burdens. Int. Arch. Occup. Environ. Health 71: 453-458.

Schwanitz, G.; Lehnert, G.; Gebhart, E. (1970) Chromosomenschaden bei beruflicher Bleibelastung [Chromosome

damage after occupational exposure to Pb]. Dtsch. Med. Wochenschr. 95: 1636-1641.

Schwanitz, G.; Gebhart, E.; Rott, H.-D.; Schaller, K.-H .; Essing, H.-G.; Lauer, O.; Prestele, H. (1975)

Chromosomenuntersuchungen bei Personen mit beruflic her Bleiexposition [Chromosome investigations in

subjects with occupational Pb exposure]. Dtsch. Med. Wochenschr. 100: 1007-1011.

Schwartz, J. (1985) Evidence for a blood Pb-blood pres sure relationship [memorandum to the Clean Air Science

Advisory Committee]. Washington, DC: U.S. Environmental Protection Agency, Office of Policy Analysis.

Available for inspection at: U.S. Environmental Protection Agency, Central Docket Section, Washington,

DC; docket no. ECAO-CD-81-2 IIA.F.60.

Schwartz, J. (1991) Pb, blood pressure, and cardiovascular disease in men and women. Environ. Health Perspect. 91:

71-75.

# AX6-289 Schwartz, J. (1994) Low-leve l Pb exposure and children's IQ: a meta-analy sis and search for a threshold. Environ.

Res. 65: 42-55.

Schwartz, J. (1995) Pb, blood pressure, and cardiovascular disease in men. Arch. Environ. Health 50: 31-37.

Schwartz, J.; Otto, D. (1987) Blood Pb, hearing thresholds, and neurobehavioral development in children and youth.

Arch. Environ. Health 42: 153-160.

Schwartz, J.; Otto, D. (1991) Pb and minor hearing impairment. Arch. Environ. Health 46: 300-305.

Schwartz, J.; Angle, C.; Pitcher, H. (1986) Relationship between childhood blood Pb and stature. Pediatrics

77: 281-288.

Schwartz, J.; Landrigan, P. J.; Baker, E. L., Jr.; Orenstein, W. A.; von Lindern, I. H. (1990) Pb-induced anemia:

dose-response relationships and evidence for a threshold. Am. J. Public. Health 80: 165-168.

Schwartz, B. S.; Bolla, K. I.; Stew art, W.; Ford, D. P.; Agnew, J.; Frumkin, H. (1993 ) Decrements in

neurobehavioral performance associated with mixed exposure to organic and inorganic Pb. Am. J.

Epidemiol. 137: 1006-1021.

Schwartz, B. S.; Lee, B.-K.; Stewart, W.; Sithisar ankul, P.; Strickland, P. T.; Ahn, K.-D.; Kelsey, K. (1997) δ

Aminolevulinic acid dehydratase genotype modifies four hour urinary Pb excretion after oral

administration of dimercaptosuccinic acid. Occup. Environ. Med. 54: 241-246.

Schwartz, B. S.; Stewart, W. F.; Kelsey, K. T.; Simon, D.; Park, S.; Li nks, J. M.; Todd, A. C. (2000a) Associations

of tibial Pb levels with BsmI polym orphisms in the vitamin D receptor in former organolead manufacturing

workers. Environ. Health Perspect. 108: 199-203.

Schwartz, B. S.; Stewart, W. F.; Bolla, K. I.; Simon, M. S.; Bandeen-R oche, K.; Gordon, B.; Links, J. M.; Todd, A.

C. (2000b) Past adult Pb exposure is associated w ith longitudinal decline in cognitive function. Neurology

55: 1144-1150.

Schwartz, B. S.; Stewart, W. F.; Todd, A. C.; Simon, D.; Links, J. M. (2000c) Different associations of blood Pb,

meso 2,3-dimercaptosuccinic acid (DMS A)-chelatable Pb, and tibial Pb leve ls with blood pressure in 543

former organolead manufacturing workers. Arch. Environ. Health. 55: 85-92.

Schwartz, B. S.; Lee, B.-K.; Lee, G.-S.; Stewart, W. F.; Simon, D.; Kelsey, K.; Todd, A. C. (2000d) Associations of

blood Pb, dimercaptosuccinic acid-ch elatable Pb, and tibia Pb with polymorphisms in the vitamin D

receptor and δ -aminolevulinic acid dehydratase genes. Environ. Health Perspect. 108: 949-954.

Schwartz, B. S.; Lee, B. K.; Lee, G. S.; Stewart, W. F.; Lee, S. S.; Hwang, K. Y.; Ahn, K.-D.; Kim, Y.-B.; Bolla,

K. I.; Simon, D.; Parsons, P. J.; Todd, A. C. (2001a) Associations of blood Pb, dimercaptosuccinic acidchelatable Pb, and tibia Pb with neurobehavioral test sc ores in South Korean Pb workers. Am. J. Epidemiol.

153: 453-464.

Schwartz, B. S.; Stewart, W. F.; Bolla, K. I.; Simon, P. D.; Bandeen-Roche, K.; Gordon, P. B.; Links, J. M.; Todd,

A. C. (2001b) Past adult Pb exposure is associated with longitudinal decline in cognitive function (erratum

to Neurology 55: 1144-1150). Neurology 56: 283.

Schwartz, B. S.; Stewart, W.; Hu, H. (2002) Neurobehavi oural testing in workers occupationally exposed to Pb

[letter]. Occup. Environ. Med. 59: 648-649.

Schwartz, B. S.; Lee, B.-K.; Bandeen-Roche, K.; Stewart, W.; Bolla, K. I. ; Links, J.; et al. (2005) Occupational Pb

exposure and longitudinal decline in neurobehavioral test scores. Epidemiology 16: 106-113.

Sciarillo, W. G.; Alexander, G.; Farrell, K. P. (1992) Pb exposure and child behavior. Am. J. Public Health

82: 1356-1360.

Seeber, A.; Meyer-Baron, M.; Schäper, M. (2002) A summary of two meta-analyses on neurobehavioural effects

due to occupational Pb exposure. Arch. Toxicol. 76: 137-145.

Selander, S.; Cramér, K. (1970) Interrelationships between Pb in blood, Pb in urine, and ALA in urine during Pb

work. Br. J. Ind. Med. 27: 28-39.

Selevan, S. G.; Landrigan, P. J.; Stern, F. B.; Jones, J. H. (1985) Mortality of Pb smelter workers. Am. J. Epidemiol.

122: 673-683.

Selevan, S. G.; Rice, D. C.; Hogan, K. A.; Euling, S. Y.; Pfahles-Hutc hens, A.; Bethel, J. (2003) Blood Pb

concentration and delayed puberty in girls. N. Engl. J. Med. 348: 1527-1536.

Shadick, N. A.; Kim, R.; Weiss, S.; Liang, M. H.; Sparro w, D.; Hu, H. (2000) Effect of low level Pb exposure

on hyperuricemia and gout among middle aged and elderly men: the normative aging study. J. Rheumatol.

27: 1708-1712.

Sharp, D. S.; Benowitz, N. L.; Osterloh , J. D.; Becker, C. E.; Smith, A. H.; Sy me, S. L. (1990) Influence of race,

tobacco use, and caffeine use on the relation between blood pressure and blood Pb concentration. Am. J.

Epidemiol. 131: 845-854.

# AX6-290 Sheffet, A.; Thind, I.; Miller, A. M.; Louria, D. B. (1982) Cancer mortality in a pigment plant utilizing Pb and zinc

chromates. Arch. Environ. Health 37: 44-52.

Shen, X.-M.; Yan, C.-H.; Guo, D.; Wu, S.-M.; Li, R.-Q.; Huang, H.; Ao, L.-M.; Zhou, J.-D.; Hong, Z.-Y.; Xu, J.-D.;

Jin, X.-M.; Tang, J.-M. (1998) Low-level prenatal Pb exposure and neurobehavioral development of

children in the first yr of life: a prospective study in Shanghai. Environ. Res. 79: 1-8.

Shen, X.-M.; Wu, S.-H.; Yan, C.-H.; Zhao, W.; Ao, L.-M.; Zhang, Y.-W.; He, J.-M.; Ying, J.-M.; Li, R.-Q.; Wu,

S.-M.; Guo, D. (2001) Delta-aminolevulinate dehydratase polymorphism and blood Pb levels in Chinese

children. Environ. Res. 85: 185-190.

Sherins, R. J. (1995) Are semen quality and male fertility changing? N. Engl. J. Med. 332: 327-328.

Shiau, C.-Y.; Wang, J.-D.; Chen, P.-C. (2004) Decreased fecundity among male Pb workers. Occup. Environ. Med.

61: 915-923.

Shukla, H.; Atakent, Y. S.; Ferrara, A.; Topsis, J.; Antoine, C. (1987) Postnatal overesti mation of gestational age in

preterm infants. Am. J. Dis. Child. 141: 1106-1107.

Shukla, R.; Bornschein, R. L.; Dietrich, K. N.; Buncher, C. R.; Berger, O. G.; Hammond, P. B.; Succop, P. A.

(1989) Fetal and infant Pb exposure: effects on growth in stature. Pediatrics 84: 604-612.

Shukla, V. K.; Prakash, A.; Tripathi, B. D.; Reddy, D. C.; Singh, S. (1998) Biliary heavy metal concentrations in

carcinoma of the gall bladder: case-control study. Br. Med. J. 317: 1288-1289.

Siegel, M.; Forsyth, B.; Siegel, L.; Cullen, M. R. (1989) The effect of Pb on thyroid function in children. Environ.

Res. 49: 190-196.

Siemiatycki, J.; Gérin, M.; Stewart, P.; Nadon, L.; Dewar, R.; Richardson, L. (1988) Associations between several

sites of cancer and ten types of exhaust and combustion products: results from a case-referent study in

Montreal. Scand. J. Work Environ. Health 14: 79-90.

Siemiatycki, J.; Gérin, M.; Dewar, R.; Nadon, L.; Lakhan i, R.; Bégin, D.; Richardson, L. (1991) Associations

between occupational circumstances and cancer. In: Siem iatycki, J., ed. Risk f actors for cancer in the

workplace. Boca Raton, FL: CRC Press; pp. 141-145.

Silbergeld, E. K. (1991) Pb in bone: implications for toxicology during pregnancy and lactation. Environ. Health

Perspect. 91: 63-70.

Silbergeld, E. K.; Sauk, J.; Somerman, M.; Todd, A.; McNeill, F.; Fowler, B.; Fontaine, A. ; van Buren, J. (1993) Pb

in bone: storage site, exposure source, and target organ. Presented at: Ninth international neurotoxicology

conference; October 1991; Little Rock, AR. Neurotoxicology 14(2-3): 225-236.

Silbergeld, E. K.; Waalkes, M.; Rice, J. M. (2000) Pb as a carcinogen: experi mental evidence and mechanisms of

action. Am. J. Ind. Med. 38: 316-323.

Silva, P. A.; Hughes, P.; Williams, S.; Faed, J. M. (1988) Blood Pb, intelligence, reading attainment, and behaviour

in eleven yr old children in Dunedin, New Zealand. J. Child Psychol. Psychiatr. Allied Discipl. 29: 43-52.

Singh, B.; Chandran, V.; Bandhu, H. K.; Mittal, B. R.; Bhattacharya, A.; Jindal, S. K.; Varma, S. (2000) Impact of

Pb exposure on pituitary-thyroid axis in humans. BioMetals 13: 187-192.

Smith, F. L., 2nd; Rathmell, T. K.; Marcil, G. E. (1938) The early diagnosis of acute and latent plumbism. Am. J.

Clin. Pathol. 8: 471-508.

Smith, C. M.; Wang, X.; Hu, H.; Kelsey, K. T. (1995) A polymorphism in the δ -aminolevulinic acid dehydratase

gene may modify the pharmacokinetics and toxicity of Pb. Environ. Health Perspect. 103: 248-253.

Sokas, R. K.; Simmens, S.; Sophar, K.; Welch, L. S.; Li ziewski, T. (1997) Pb levels in Maryland construction

workers. Am. J. Ind. Med. 31: 188-194.

Sokol, R. Z. (1987) Hormonal effects of Pb acetate in the male rat: mechanism of action. Biol. Reprod.

37: 1135-1138.

Sokol, R. Z.; Berman, N.; Okuda, H.; Raum, W. (1998) Effects of Pb exposure on GnRH and LH secretion in male

rats: response to castration and ά -methyl- p -tyrosine (AMPT) challenge. Reprod. Toxicol. 12: 347-355.

Sokol, R. Z.; Wang, S.; Wan, Y.-J. Y.; Stanczyk, F. Z.; Gentzschein, E.; Chap in, R. E. (2002) Long-term, low-dose

Pb exposure alters the gonadotropin-releasing hormone system int he male rat. Environ. Health Perspect.

110: 871-874.

Soldin, O. P.; Pezzullo, J. C.; Hanak, B. ; Miller, M.; Soldin, S. J. (2003) Changing trends in the epidemiology of

pediatric Pb exposure: interrelationship of blood Pb and ZPP concentrations and a comparison to the US

population. Ther. Drug Monit. 25: 415-420.

Solliway, B. M.; Schaffer, A.; Pratt, H. ; Yannai, S. (1996) Effect s of exposure to Pb on selected biochemical and

haematological variables. PharmacoI. ToxicoI. 78: 18-22.

# AX6-291 Sönmez, F.; Dönmez, O.; Sönmez, H. M.; Keskino ĝ lu, A.; Kabasakal, C.; Mir, S. (2002) Pb exposure and urinary Nacetyl β D glucosaminidase activity in adolescent workers in auto repair workshops. J. Adolesc. Health 30:

213-216.

Sorel, J. E.; Heiss, G.; Tyroler, H. A. ; Davis, W. B.; Wing, S. B.; Ragland, D. R. (1991) Black-white differences

in blood pressure among participants in NHANES II: the contribution of blood Pb. Epidemiology 2:

348-352.

Sorrell, M.; Rosen, J. F.; Roginsky, M. (1977) Interactions of Pb, calcium, vitamin D, and nutrition in Pb-burdened

children. Arch. Environ. Health 32: 160-164.

Sowers, M.; Jannausch, M.; Scholl, T.; Li, W.; Kemp, F. W.; Bogden, J. D. (2002) Blood Pb concentrations and

pregnancy outcomes. Arch. Environ. Health 57: 489-495.

Spencer, H.; O'Sullivan, V.; Sontag, S. J. (1992) Does Pb play a role in Paget's disease of bone? A hypothesis. J.

Lab. Clin. Med. 120: 798-800.

Spencer, H.; O'Sullivan, V.; Sontag, S. J. (1994) Occupatio nal exposure to Pb: preliminary observations in Paget's

disease of bone in women and in family members of af fected patients. J. Trace El em. Exp. Med. 7: 53-58.

Spencer, H.; O'Sullivan, V.; Sontag, S. J. (1995) Exposure to Pb, a potentially hazardous toxin: Paget's disease of

bone. J. Trace Elem. Exp. Med. 8: 163-171.

Spinnato, J. A.; Sibai, B. M.; Shaver, D. C.; Anderson, G. D. (1984) Inaccuracy of Dubo witz gestational age in low

birth weight infants. Obstet. Gynecol. (Hagerstown, MD, U.S.) 63: 491-495.

Spivey, G. H.; Baloh, R. W.; Brown, C. P.; Browdy, B. L.; Campion, D. S.; Valentine, J. L.; Morgan, D. E.; Culver,

B. D. (1980) Subclinical effects of chronic increased Pb absorption--a prospective study. III. Neurologic

findings at follow-up examination. J. Occup. Med. 22: 607-612.

Spreen, O.; Risser, A. T.; Edgell, D. (1995) Developmen tal neuropsychology. New York, NY: Oxford University

Press.

Staessen, J.; Yeoman, W. B.; Fletcher, A. E.; Markowe, H. L.; Marmot, M. G.; Rose, G.; Semmence, A.; Shipley,

M. J.; Bulpitt, C. J. (1990) Blood Pb concentration, renal function, and blood pressure in London civil

servants. Br. J. Ind. Med. 47: 442-447.

Staessen, J. A.; Lauwerys, R. R.; Buch et, J.-P.; Bulpitt, C. J.; Rondia, D.; Van Renterghem, Y.; Amery, A. (1992)

Impairment of renal function with increasing blood Pb co ncentrations in the general population. N. Engl. J.

Med. 327: 151-156.

Staessen, J. A.; Dolenc, P.; Amery, A.; Buchet, J.-P.; Cl aeys, F.; Fagard, R.; Lauwerys , R.; Lijnen, P.; Roels, H.;

Rondia, D.; Sartor, F.; Thijs, L.; Vyncke, G., on behalf of the Cadmibel Study Group. (1993)

Environmental Pb exposure does not increase blood pressure in the population: evidence from the

Cadmibel study. J. Hypertens. 11(suppl. 2): S35-S41.

Staessen, J. A.; Bulpitt, C. J.; Fagard, R.; Lauwerys, R. R.; Roels, H.; Thijs, L.; Amer y, A. (1994) Hypertension

caused by low-level Pb exposure: myth or fact? J. Cardiovasc. Risk 1: 87-97.

Staessen, J. A.; Roels, H.; Fagard, R. (1996a) Pb e xposure and conventional and ambulatory blood pressure: a

prospective population study. JAMA J. Am. Med. Assoc. 275: 1563-1570.

Staessen, J. A.; Buchet, J.-P.; Ginucchio, G.; Lauwerys, R. R.; Lijnen, P.; Roels, H.; Fagard, R. (1996b) Public

health implications of environmental exposure to ca dmium and Pb: an overview of epidemiological studies

in Belgium. J. Cardiovasc. Risk 3: 26-41.

Staessen, J. A.; Nawrot, T.; Den Hond, E.; Thijs, L.; Fagard, R.; Hoppenbrouwers, K.; Koppen, G.; Nelen, V.;

Schoeters, G.; Vanderschueren, D.; Van Hecke, E.; Verschaeve, L.; Vlietinck, R.; Roels, H. A. (2001)

Renal function, cytogenetic measurements, and sexual developments in adolescents in relation to

environmental pollutants: a feasibility study of biomarkers. Lancet 357: 1660-1669.

Steenland, K.; Boffetta, P. (2000) Pb and cancer in humans: where are we now? Am. J. Ind. Med. 38: 295-299.

Steenland, K.; Thun, M. J.; Ferguson, C. W.; Port, F. K. (1990) Occupational and other exposures associated with

male end-stage renal disease: a case/contro l study. Am. J. Public Health. 80: 153-157.

Steenland, K.; Selevan, S.; Landrigan, P. (1992) The mort ality of Pb smelter workers: an update. Am. J. Public

Health 82: 1641-1644.

Steenland, K.; Loomis, D.; Shy, C.; Simonsen, N. (1996) Review of occupational lung carcinogens. Am. J. Ind.

Med. 29: 474-490.

Steenland, K.; Mannetje, A.; Boffetta, P.; Stayner, L.; A ttfield, M.; Chen, J.; Dosemeci, M.; DeKlerk, N.; Hnizdo,

E.; Koskela, R.; Checkoway, H. (2002) Pooled exposure-response analyses and risk assessmen for lung

cancer in 10 cohorts of silica-exposed workers: an IA RC multi-centric study (vol 12, pg 773, 2001). Cancer

Causes Control 13: 777.

Stevens, L. A.; Levey, A. S. (2005a) Measurement of kidney function. Med. Clin. N. Am. 89: 457-473.

# AX6-292 Stevens, L. A.; Levey, A. S. (2005b) Chronic kidney disease in the elderly

― how to assess risk. N. Engl. J. Med.

352: 2122-2124.

Stewart, W. F.; Schwartz, B. S.; Simon, D.; Bolla, K. I.; Todd, A. C.; Links, J. (1999) Neurobehavioral function and

tibial and chelatable Pb levels in 543 former organolead workers. Neurology 52: 1610-1617.

Stewart, W. F.; Schwartz, B. S.; Simon, D.; Kelsey, K.; Todd, A. C. (2002) ApoE genotype, past adult Pb exposure,

and neurobehavioral function. Environ. Health Perspect. 110: 501-505.

Stiles, K. M.; Bellinger, D. C. (1993) Neuropsychological correlates of low-level Pb exposure in school-age

children: a prospective study. Neurotoxicol. Teratol. 15: 27-35.

Stollery, B. T. (1996) Reaction time changes in worker s exposed to Pb. Neurotoxicol. Teratol. 18: 477-483.

Stollery, B. T.; Broadbent, D. E.; Ba nks, H. A.; Lee, W. R. (1991) Short term prospective study of cognitive

functioning in Pb workers. Br. J. Ind. Med. 48: 739-749.

Sugawara, E.; Nakamura, K.; Miyake, T.; Fukumura, A.; Se ki, Y. (1991) Lipid peroxidation and concentration of

glutathione in erythrocytes from workers exposed to Pb. Br. J. Ind. Med. 48: 239-242.

Sun, L.; Hu, J.; Zhao, Z.; Li, L.; Ch eng, H. (2003) Influence of exposure to environmental Pb on serum

immunoglobulin in preschool children. Environ. Res. 92: 124-128.

Süzen, H. S.; Duydu, Y.; Aydin, A.; I ş imer, A; Vural, N. (2003) Influence of the delta-aminolevulinic acid

dehydratase (ALAD) polymorphism on biomarkers of Pb exposure in Turkish storage battery

manufacturing workers. Am. J. Ind. Med. 43: 165-171.

Tabacova, S.; Balabaeva, L. (1993) Environmental pollutants in relation to complications of pregnancy. Environ.

Health Perspect. 101(suppl. 2): 27-31.

Tang, N.; Zhu, Z. Q. (2003) Adverse reproductive effects in fe male workers of Pb battery plants. Int. J. Occup. Med.

Environ. Health 16: 359-361.

Taskinen, H. (1988) Spontaneous abortions among wome n occupationally exposed to Pb. In: Hogstedt, C.;

Reuterwall, C., eds. Progress in o ccupational epidemiology. New York, NY: Elsevier Science Publishers;

pp. 197-200.

Tassler, P.; Schwartz, B. S.; Coresh, J.; Stewart, W.; Todd, A. (2001) Associations of tibia Pb, DMSA-Chelatable

Pb, and blood Pb with measures of peripheral nervous system function in former organolead manufacturing

workers. Am. J. Ind. Med. 39: 254-261.

Taupeau, C.; Poupon, J.; Treton, D.; Brosse, A.; Richard, Y.; Machelon, V. (2003) Pb reduces messenger RNA and

protein levels of cytochro me P450 aromatase and estrogen recepto r "Beta" in human ovarian granulosa

cells. Biol. Reprod. 68: 1982-1988.

Telišman, S.; Pizent, A.; Jurasovi ć , J.; Cvitkovi ć , P. (2004) Pb effect on blood pressure in moderately Pb-exposed

male workers. Am. J. Ind. Med. 45: 446-454.

Téllez-Rojo, M. M.; Bellinger, D. C.; Arroyo-Quiroz, C.; Lamadrid-Figuero a, H.; Mercado-García, A.; SchnaasArrieta, L.; Wright, R. O.; Hernández-Avila, M.; Hu, H. (2006) Longitudinal associations between blood

Pb concentrations < 10 μ g/dL and neurobehavioral development in environmentally-exposed children in

Mexico City. Pediatrics 118: e323-e330.

Tepper, A.; Mueller, C.; Singal, M.; Sa gar, K. (2001) Blood pressure, left ventricular mass, and Pb exposure in

battery manufacturing workers. Am. J. Ind. Med. 40: 63-72.

Teruya, K.; Sakurai, H.; Omae, K.; Higashi, T.; Muto , T.; Kaneko, Y. (1991) E ffect of Pb on cardiac

parasympathetic function. Int. Arch. Occup. Environ. Health 62: 549-553.

Thacker, S. B.; Hoffman, D. A.; Smith, J.; Steinberg, K.; Zack, M. (1992) Effect of low-level body burdens of Pb on

the mental development of children: limitations of meta-analysis in a review of longitudinal data. Arch.

Environ. Health 47: 336-346.

Thompson, S. G.; Pocock, S. J. (1992) Can meta-analyses be trusted? Lancet 338: 1127-1130.

Thomson, G. O. B.; Raab, G. M.; Hepburn, W. S.; Hunter, R.; Fulton, M.; Laxen, D. P. H. (1989) Blood-Pb levels

and children's behaviour - results from the Edinburgh Pb study. J. Child Psychol. Psychiatr. 30: 515-528.

Todd, A. C.; Buchanan, R.; Carroll, S.; Moshier, E. L.; Pop ovac, D.; Slavkovich, V.; Graziano, J. H. (2001) Tibia Pb

levels and methodological uncertainty in 12 -yr-old children. Environ. Res. 86: 60-65.

Tomatis, L. (1990) Cancer: causes, occurrence, and contro l. Lyon, France: International Agency for Research on

Cancer. (IARC scientific publications: v. 100).

Tong, I. S.; Lu, Y. (2001) Identification of confounders in the assessment of the relationship between Pb exposure

and child development. Ann. Epidemiol. 11: 38-45.

Tong, S.; Baghurst, P.; McMichael, A.; Sawyer, M.; Mudge, J. (1996) Lifetime exposure to environmental Pb and

children's intelligence at 11-13 yrs: the Port Pi rie cohort study. Br. Med. J. 312: 1569-1575.

# AX6-293 Tong, S.; Baghurst, P. A.; Sawyer, M. G. ; Burns, J.; McMichael, A. J. (1998) Declining blood Pb levels and changes

in cognitive function during childhood: the Port Pirie cohort study. JAMA J. Am. Med. Assoc. 280: 1915-

1919.

Tong, S.; McMichael, A. J.; Baghurst, P. A. (2000) Interactions between environmental Pb exposure and

sociodemographic factors on cognitive development. Arch. Environ. Health 55: 330-335.

Torres-Sánchez, L. E.; Berkowitz, G.; López-Carrillo, L.; Torres-Arreola, L.; Ríos, C.; López-Cervantes, M. (1999)

Intrauterine Pb exposure and preterm birth. Environ. Res. 81: 297-301.

Trope, I.; Lopez-Villegas, D.; Lenkinsk i, R. E. (1998) Magnetic resonance imaging and spectroscopy of regional

brain structure in a 10-yr-old boy with elevated blood Pb levels. Pediatrics 101(6): E7.

Trope, I.; Lopez-Villegas, D.; Cecil, K. M.; Lenkinski, R. E. (2001) Exposure to Pb appears to selectively alter

metabolism of cortical gray matter. Pediatrics 107: 1437-1443.

Tsai, S.-Y.; Chen, T.-F.; Chao, K.-Y. (2000) Subclinical neurobehavioral effect s of low-level Pb exposure in glaze

factory workers. Acta Neurol. Taiwan. 9: 122-127.

Tsaih, S.-W.; Korrick, S.; Schwartz, J. ; Amarasiriwardena, C.; Ar o, A.; Sparrow, D; Hu, H. (2004) Pb, diabetes,

hypertension, and renal function: the Normative Aging Study. Environ. Health Perspect. 112: 1178-1182.

Tuppurainen, M.; Wagar, G.; Kurppa, K.; Sakari, W.; Wambugu, A.; Froseth, B.; Alho, J.; Nykyri, E. (1988)

Thyroid function as assessed by routine laboratory tests of workers with long-term Pb exposure. Scand. J.

Work Environ. Health 14: 175-180.

Tvinnereim, H. M.; Eide, R.; Riise, T. (2000) Heavy meta ls in human primary teeth: some factors influencing the

metal concentrations. Sci. Total Environ. 255: 21-27.

U.S. Environmental Protection Agency. (1986a) Air quality criteria for Pb. Research Triangle Park, NC: Office of

Health and Environmental Assessment, Environmental Criteria and Assessment Office; EPA report no.

EPA-600/8-83/028aF-dF. 4v. Available from: NTIS, Springfield, VA; PB87-142378.

U.S. Environmental Protection Agency. (1986b) Pb effects on cardiovascular function, early development, and

stature: an addendum to U.S. EPA Air Quality Criteria for Pb (1986). In: Air quality criteria for Pb, v. 1.

Research Triangle Park, NC: Office of Health and Environmental Assessment, Environmental Criteria and

Assessment Office; pp. A1-A67; EPA report no. EPA-600/8-83/028aF. Available from: NTIS, Springfield,

VA; PB87-142378.

U.S. Environmental Protection Agency. (1990) Air qua lity criteria for Pb: supplement to the 1986 addendum.

Research Triangle Park, NC: Office of Health and Environmental Assessment, Environmental Criteria and

Assessment Office; report no. EPA/600/8-89/049F. Available from: NTIS, Springfield, VA; PB91-138420.

U.S. Environmental Protection Agency. (2003) Evalua tion of the ICRP Pb Biokinetics Model: empirical

comparisons with observations of plasma-blood Pb concentration relationships in humans. Washington,

DC: Office of Emergency and Remedial Response; FEDSIM order no. DABT; Syracuse Research

Corporation; contract no. GS-10F-0137K.

U.S. Environmental Protection Agency. (2004) Air quality criteria for particulate matter. Research Triangle Park,

NC: National Center for Environmental Assessment; re port no. EPA/600/P-99/002aF-bF. 2v. Available:

http://cfpub.epa.gov/ncea/ [9 November, 2004].

U.S. Environmental Protection Agency. (2005) Guidelines for carcinogen risk assessment. Washington, DC:

Risk Assessment Forum; report no . EPA/630/P-03/001F. Available: http://cfpub.epa.g ov/ncea/index.cfm

[30 November, 2005].

U.S. Renal Data System. (2004) Outcomes: hospitalization & mortality. In: Annual data report. Minneapolis, MN:

USRDS Coordinating Center; pp. 118-138. Available:

http://www.usrds.org/2004/pdf/06_hosp_morte_04.pdf [21 November, 2005]. Ündeger, U.; Ba ş aran, N.; Canpinar, H.; Kansu, E. (1996) Immune alterations in Pb-exposed workers. Toxicology

109: 167-172.

Valciukas, J. A.; Lilis, R.; Eisinger, J. ; Blumberg, W. E.; Fischbein, A.; Selikof f, I. J. (1978) Behavioral indicators

of Pb neurotoxicity: results of a clinical field surv ey. Int. Arch. Occup. Environ. Health 41: 217-236.

Valentine, J. L.; Baloh, R. W.; Browdy , B. L.; Gonick, H. C.; Brown, C. P.; Spivey, G. H.; Culver, B. D. (1982)

Subclinical effects of chronic increased Pb absorption--a prospective study. J. Occup. Med. 24: 120-125.

Valentino, M.; Governa, M.; Marchiseppe, I.; Visona, I. (1991) Effects of Pb on polymorphonuclear leukocyte

(PMN) functions in occupationally exposed workers. Arch. Toxicol. 65: 685-688.

Van De Vyver, F. L.; D'Haese, P. C.; Visser, W. J.; Elsevi ers, M. M.; Knippenberg, L. J.; Lamberts, L. V.; Wedeen,

R. P.; De Broe, M. E. (1988) Bone Pb in dialysis patients. Kidney Int. 33: 601-607.

Van Den Berg, B. J.; Oechsli, F. W. (1984) Prematurity. In: Bracken, M. B., ed. Perinatal epidemiology. New York,

NY: Oxford University Press; pp. 69-85.

# AX6-294 Van Larebeke, N.; Koppen, G.; Nelen, V.; Schoeters, G.; Van Loon H, Albe ring H, Riga L, Vlietinck, R.;

Kleinjans, J.; Flemish Environment and Health Study Group. (2004) Differences in HPRT mutant

frequency among middle-aged Flemish women in association with area of residence and blood Pb levels.

Biomarkers 9: 71-84.

Verberk, M. M.; Willems, T. E. P.; Verplanke, A. J. W.; De Wolff, F. A. (1996) Envir onmental Pb and renal effects

in children. Arch. Environ. Health 51: 83-87.

Verschoor, M.; Wibowo, A.; Herber, R.; van Hemmen, J.; Zielhuis, R. (1987) Influence of occupational low-level

Pb exposure on renal parameters. Am. J. Ind. Med. 12: 341-351.

Vig, E. K.; Hu, H. (2000) Pb toxicity in older adults. J. Am. Geriatr. Soc. 48: 1501-1506.

Vimpani, G. V.; Wigg, N. R.; Robertson, E. F.; McMichael, A. J.; Baghurst, P. A.; Roberts, R. J. (1985) The Port

Pirie cohort study: blood Pb concentration and childho od developmental assessment. In: Goldwater, L. J.;

Wysocki, L. M.; Volpe, R. A., eds. Edited proceedings: Pb environm ental health - the cu rrent issues; May;

Durham, NC. Durham, NC: Duke University; pp. 139-146.

Vinceti, M.; Guidetti, D.; Bergomi, M. ; Caselgrandi, E.; Vivoli, R.; Olmi, M.; Rinaldi, L.; Rovesti, S.; Solimè, F.

(1997) Pb, cadmium, and selenium in the blood of patient s with sporadic amyotrophic lateral sclerosis. Ital.

J. Neurol. Sci. 18: 87-92.

Vupputuri, S.; He, J.; Muntner, P.; Bazzan o, L. A.; Whelton, P. K.; Batuman, V. (2003) Blood Pb level is associated

with elevated blood pressure in blacks. Hypertension 41: 463-468.

Wagnerova, M.; Wagner, V.; Madlo, Z.; Zavazal, Y.; Wokounova, D.; Kriz, J.; Mohyla, O. (1986) Seasonal

variations in the level of immunoglobulins and serum proteins of children differing by exposure to

air-borne Pb. J. Hyg. Epidemiol. Microbiol. Immunol. 30(2): 127-138.

Walkowiak, J.; Altmann, L.; Krämer, U.; Sveinsson, K.; Turfeld, M.; Weishoff-Hou ben, M.; Winneke, G.

(1998) Cognitive and sensorimotor functions in 6- yr-old children in relation to Pb and mercury

levels: adjustment for intelligence and contrast sensitivity in computerized testing. Neurotoxicol. Teratol.

20: 511-521.

Wang, C.-L.; Chuang, H.-Y.; Ho, C.-K .; Yang, C.-Y.; Tsai, J.-L.; Wu, T. -S.; Wu, T.-N. (2002a) Relationship

between blood Pb concentrations and learning ac hievement among primary school children in Taiwan.

Environ. Res. 89: 12-18.

Wang, V.-S.; Lee, M.-T.; Chiou, J.-Y.; Guu, C.-F.; Wu, C.-C.; Wu, T.-N.; Lai, J.-S. (2002b) Relationship

between blood Pb levels and renal function in Pb battery workers. Int. Arch. Occup. Environ.

Health 75: 569-575.

Ward, N. I.; Watson, R.; Bryce-Smith, D. (1987) Placental element levels in relation to fetal development for

obstetrically 'normal' births: a study of 37 elements. Evidence for effects of cadmium, Pb and zinc on fetal

growth, and for smoking as a source of cadmium. Int. J. Biosoc. Res. 9: 63-81.

Wasserman, G.; Graziano, J. H.; Factor-Litvak, R.; Po povac, D.; Morina, N.; Musa begovic, A.; Vrenezi, N.;

Capuni-Paracka, S.; Lekic, V.; Preten i-Redjepi, E.; Hadzialjevic, S.; Sla vkovich, V.; Kline, J.; Shrout, P.;

Stein, Z. (1992) Independent effects of Pb exposure and iron deficiency anemia on developmental outcome

at age 2 yrs. J. Pediatr. 121: 695-703.

Wasserman, G. A.; Graziano, J. H.; Factor-Litvak, P.; Po povac, D.; Morina, N.; Musabegovic, A.; Vrenezi, N.;

Capuni-Paracka, S.; Lekic, V.; Preten i-Redjepi, E.; Hadzialjevic, S.; Sla vkovich, V.; Kline, J.; Shrout, P.;

Stein, Z. (1994) Consequences of Pb exposure and iron supplementation on childhood development at age

4 yrs. Neurotoxicol. Teratol. 16: 233-240.

Wasserman, G. A.; Liu, X.; Lolacono, N. J.; Factor-Litvak, P.; Kline, J. K.; Popovac, D.; Morina, N.; Musabegovic,

A.; Vrenezi, N.; Capuni-Paracka, S.; Lekic, V.; Pret eni-Redjepi, E.; Hadzialj evic, S.; Slavkovich, V.;

Graziano, J. H. (1997) Pb exposure and intelligence in 7-yr-old children: the Yugoslavia prospective study.

Environ. Health Perspect. 105: 956-962.

Wasserman, G. A.; Staghezza-Jaramillo, B.; Shrout, P.; Popovac, D.; Graziano, J. (1998) The effect of Pb exposure

on behavior problems in preschool children. Am. J. Pub. Health 88 (3): 481-486.

Wasserman, G. A.; Musabegovic, A.; Liu, X.; Kline, J. ; Factor-Litvak, P.; Grazian o, J. H. (2000a) Pb

exposure and motor functioning in 4 1/2-yr-old children: the Yugoslavia prospective study. J. Pediatr. 137:

555-561.

Wasserman, G. A.; Liu, X.; Popovac, D.; Factor-Litvak, P.; K line, J.; Waternaux, C.; LoIacono, N.; Graziano, J. H.

(2000b) The Yugoslavia prospective Pb industry study: contributions of prenatal and postnatal Pb exposure

to early intelligence. Neurotoxicol. Teratol. 22: 811-818.

# AX6-295 Wasserman, G. A.; Factor-Litvak, P.; Li u, X.; Todd, A. C.; Kline, J. K.; Sl avkovich, V.; Popovac, D.; Graziano,

J. H. (2003) The relationship between blood Pb, bon e Pb and child intelligence. Child Neuropsychol.

9: 22-34.

Weaver, V. M.; Lee, B.-K.; Ahn, K.-D.; Lee, G.-S.; Todd , A. C.; Stewart, W. F.; Wen, J.; Simon, D. J.; Parsons,

P. J.; Schwartz, B. S. (2003a) Associations of Pb biomarkers with renal function in Korean Pb workers.

Occup. Environ. Med. 60: 551-562.

Weaver, V. M.; Schwartz, B. S.; Ahn, K.-D.; Stewart, W. F.; Kelsey, K. T.; Todd, A. C.; Wen, J.; Simon, D. J.;

Lustberg, M. E.; Parsons, P. J.; Silbergeld, E. K.; L ee, B.-K. (2003b) Associations of renal function with

polymorphisms in the δ -aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase

genes in Korean Pb workers. Environ. Health Perspect. 111: 1613-1619.

Weaver, V. M.; Lee, B.-K.; Todd, A. C.; Jaar, B. G.; Ahn, K.-D.; Wen, J.; Shi, W.; Parsons, P. J.; Schwartz, B. S.

(2005a) Associations of patella Pb and other Pb biomarkers with renal function in Pb workers. J. Occup.

Environ. Med. 47: 235-243.

Weaver, V. M.; Jarr, B. G.; Schwartz, B. S.; Todd, A. C.; Ahn, K.-D.; Lee, S.-S.; Wen, J.; Parsons, P. J.; Lee, B.-K.

(2005b) Associations among Pb dose biomarkers, uric acid, and renal function in Korean Pb workers.

Environ. Health Perspect. 113: 36-42.

Weaver, V. M.; Schwartz, B. S.; Jaar, B. G.; Ahn, K.-D.; Todd, A. C.; Lee, S.-S.; Kelsey, K. T.; Silbergeld, E. K.;

Lustberg, M. E.; Parsons, P. J.; Wen, J.; Lee-B.-K. (2005c) Associations of uric acid with polymorphisms

in the δ -aminolevulinic acid dehydratase, v itamin D receptor, and nitric oxid e synthase genes in Korean Pb

workers. Environ. Health Perspect. 113: 1509-1515.

Wedeen, R. P.; Mallik, D. K.; Batuman, V. (1979) Detection and treatment of occupational Pb nephropathy. Arch.

Intern. Med. 139: 53-57.

Wedeen, R. P.; Batuman, V.; Landy, E. (1983) The safety of the EDTA Pb-mobilization test. Environ. Res.

30: 58-62.

Weinberg, C. R.; Baird, D. D.; Rowland, A. S. (1993) Pitfalls inherent in retrospective time-to-event studies: the

example of time to pregnancy. Stat. Med. 12: 867-879.

Weinberg, C. R.; Baird, D. D.; Wilcox, A. J. (1994) Sources of bias in studies of time to pregnancy. Stat. Med.

13: 671-681.

Weiss, S. T.; Munoz, A.; Stein, A.; Sparrow, D.; Speize r, F. E. (1986) The relationship of blood Pb to blood

pressure in a longitudinal study of working men. Am. J. Epidemiol. 123: 800-808.

Weisskopf, M. G.; Wright, R. O.; Schwartz, J.; Spiro, A. , III; Sparrow, D.; Aro, A.; Hu, H. (2004a) Cumulative Pb

exposure and prospective change in cognition among elderly men. The VA Normative Aging Study. Am. J.

Epidemiol. 160: 1184-1193.

Weisskopf, M. G.; Hu, H.; Mulkern, R. V.; White, R.; Aro, A.; Oliveira, S.; Wrigh t, R. O. (2004b) Cognitive

deficits and magnetic resonance spectroscopy in adult monozygotic twins with Pb poisoning. Environ.

Health Perspect. 112: 620-625.

Wesseling, C.; Pukkala, E.; Neuvonen, K.; Kauppinen, T.; Bo ffetta, P.; Partanen, T. (2002) Cancer of the brain and

nervous system and ocupational exposures in Finnish women. J. Occup. Environ. Med. 44: 663-668.

Wibberley, D. G.; Khera, A. K.; Edwa rds, J. H.; Rushton, D. I. (1977) Pb levels in human placentae from normal

and malformed births. J. Med. Genet. 14: 339-345.

Wigg, N. R.; Vimpani, G. V.; McMichael, A. J.; Baghurst, P. A.; Robertson, E. F.; Roberts, R. J. (1988) Port Pirie

cohort study: childhood blood Pb and neuropsychological development at age two yrs. J. Epidemiol.

Community Health 42: 213-219.

Wildt, K.; Berlin, M.; Isberg, P. E. (1987) Monitoring of zinc protoporphyrin levels in blood following occupational

Pb exposure. Am. J. Ind. Med. 12: 385-398.

Wingren, G.; Axelson, O. (1985) Mortality pattern in a glass producing area in SE Sweden. Br. J. Ind. Med.

42: 411-414.

Wingren, G.; Axelson, O. (1987) Mortality in the Swed ish glassworks industry. Scand. J. Work Environ.

Health 13: 412-416.

Wingren, G.; Axelson, O. (1993) Epidemiologic studies of occupational cancer as related to complex mixtures of

trace elements in the art glass in dustry. Scand. J. Work Environ. Health 19(supp l. 1): 95-100.

Wingren, G. Englander, V. (1990) Mo rtality and cancer morbidity in a cohort of Swedish glassworkers. Int. Arch.

Occup. Environ. Health 62: 253-257.

Winker, R.; Barth, A.; Ponocny-Seliger, E. ; Pilger, A.; Osterode, W.; Rüdiger, H. W. (2005) No cognitive deficits in

men formerly exposed to Pb. Wien. Klin. Wochenschr. 117: 755-760.

# AX6-296 Winker, R.; Ponocny-Seliger, E.; Rüdiger, H. W.; Barth, A. (2006) Pb exposure levels and duration of exposure

absence predict neurobehavioral performance. Int. Arch. Occup. Environ. Health 79: 123-127.

Winneke, G.; Kraemer, U. (1984) Neuropsy chological effects of Pb in children: interactions with social background

variables. Neuropsychobiology 11: 195-202.

Winneke, G.; Brockhaus, A.; Ewers, U.; Kramer, U.; Neuf, M. (1990) Results from the European multicenter study

on Pb neurotoxicity in children: implications for risk assessment. Neurotoxicol. Teratol. 12: 553-559.

Winterberg, B.; Korte, R.; Bertram, H. P. (1991) Response: bone Pb is elevated in renal failure [letter]. Nephron 58:

496-497.

Wittmers, L. E.; Aufderheide, A. C.; Wa llgren, J.; Rapp, G.; Alich, A. (1988) Pb in bone. IV. Distribution of Pb in

the human skeleton. Arch. Environ. Health 43: 381-391.

Wolf, A. W.; Ernhart, C. B.; White, C. S. (1985) Intrauterine Pb exposure and early development. In: Lekkas, T. D.,

ed. International conferen ce: heavy metals in the environment, v. 2; September; Athens, Greece.

Edinburgh, United Kingdom: CEP Consultants, Ltd.; pp. 153-155.

Wong, O.; Harris, F. (2000) Cancer mortality study of em ployees at Pb battery plants and Pb smelters, 1947-1955.

Am. J. Ind. Med. 38: 255-270.

Work Group of the Advisory Committee on Childlhood Pb Poisoning Prevention. (2004) A review of evidence of

health effects of blood Pb levels <10 μ g/dl in children [draft final for ACCLPP review]. Centers for

Disease Control and Prevention, National Cent er for Environmental Health. Available:

http://www.cdc.gov/nceh/Pb/ACCLPP/meetingMinutes/lessThan10MtgMAR04.pdf [6 March, 2006].

World Health Organization. (1977) Pb. Geneva, Switzerland: World Health Organization. (Environmental health

criteria: v.3). Available: http://www.inchem.org/d ocuments/ehc/ehc/ehc003.htm [11 March, 2005].

World Health Organization. (1995) Inorganic Pb. Geneva, Switzerland: World Health Organization, International

Programme on Chemical Safety. (Env ironmental health criteria 165).

Wright, R. O.; Hu, H.; Silverman, E. K.; Tsaih, S. W.; Sc hwartz, J.; Bellinger, D.; Pala zuelos, E.; Weiss, S. T.;

Hernandez-Avila, M. (2003) Apolipoprotein E genotype predicts 24-mo bayley scales infant development

score. Pediatr. Res. 54: 819-825.

Wu, T.-N.; Shen, C.-Y.; Ko, K.-N.; Guu, C.-F.; Gau, H.-J.; Lai, J.-S.; Chen, C.-J.; Chang, P.-Y. (1996) Occupational

Pb exposure and blood pressure. Int. J. Epidemiol. 25: 791-796.

Wu, M. T.; Kelsey, K.; Schwartz, J.; Spar row, D.; Weiss, S.; Hu, H. (2003a) A δ

- aminolevulinic acid dehydratase

(ALAD) polymorphism may modify the relationship of low-level Pb exposure to uricemia and renal

function: the Normative Aging Study. Environ. Health Perspect. 111: 335-341.

Wu, T.; Buck, G. M.; Mendola, P. (2003b) Blood Pb levels and sexual maturation in U.S. girls: the Third National

Health and Nutrition Examination Survey, 1988-1994. Environ. Health Perspect. 111: 737-741.

Ye, X. B.; Wu, C. E.; Fu, H.; Yang, S.-L.; Lu, Y.-W.; Ni , W.-M. (2003) Associations of blood Pb levels, kidney

function, and blood pressure with δ -aminolevulinic acid dehydratase and vitamin D receptor gene

polymorphisms. Toxicol. Mech. Methods 13: 139-146.

Yokoyama, K.; Araki, S.; Murata, K.; Morita, Y.; Katsuno, N.; Tanigawa, T.; Mori, N.; Yokota, J.; Ito, A.; Sakata,

E. (1997) Subclinical vestibulo-cerebellar, anterior cerebellar lobe and spinocerebellar effects in Pb

workers in relation to concurrent and past exposure. Neurotoxicology 18: 371-380.

Yokoyama, K.; Araki, S.; Aono , H.; Murata, K. (1998) Calcium disodium ethylenediaminetetr aacetate-chelated Pb

as a predictor for subclinical Pb neurotoxicity: follow- up study on gun-metal foundry workers. Int. Arch.

Occup. Environ. Health 71: 459-464.

Young, S. S.; Hawkins, D. M. (1998) Using recursive partitioning to analyze a large SAR data set. SAR QSAR

Environ. Res. 8: 183-193.

Young, B. A.; Boyko, E. J.; Ross, H. J.; Fihn, S.; Brys on, C. L. (2004) Association of urine cadmium with

hypertension, microalbuminuria and reduced renal function: results from the NHANES III study [abstract].

J. Am. Soc. Nephrol. 15: 146A.

Yu, C.-C.; Lin, J.-L.; Lin-Tan, D.-T. (2004) Environmental exposure to Pb and progression of chronic renal

diseases: a four-yr prospective longitudinal study. J. Am. Soc. Nephrol. 15: 1016-1022.

Yuan, W.; Holland, S. K.; Cecil, K. M.; Dietrich, K. N.; Wessel, S. D.; Altaye, M.; Hornung, R. W.; Ris, M. D.;

Egelhoff, J. C.; Lanphear, B. P. (2006) The impact of early childhood Pb exposure on brain organization: a

functional magnetic resonance imaging study of language function. Pediatrics 118: 971-977. Yücesoy, B.; Turhan, A.; Üre, M.; İ mir, T.; Karakaya, A. (1997a) Effects of occupational Pb and cadmium exposure

on some immunoregulatory cytokine levels in man. Toxicology 123: 143-147. Yücesoy, B.; Turhan, A.; Üre, M.; İ mir, T.; Karakaya, A. (1997b) Simultaneous effects of Pb and cadmium on NK

cell activity and some phenotypic parameters. Immunopharmacol. Immunotoxicol. 19: 339-348.

# AX6-297 Yule, W.; Lansdown, R.; Millar, I. B.; Urbanowicz, M.-A. (1981) The relationship between blood Pb

concentrations, intelligence and attainment in a school population: a pilot study. Dev. Med. Child Neurol.

23: 567-576.

Yule, W.; Urbanowicz, M.-A.; Lansdown , R.; Millar, I. B. (1984) Teachers' ratings of children's behaviour in

relation to blood Pb levels. Br. J. Dev. Psychol. 2: 295-305.

Zhao, Z. Y.; Li, R.; Sun, L.; Li, Z. Y.; Yang, R. L. (2 004) Effect of Pb exposure on the immune function of

lymphocytes and erythrocytes. in preschool children. J. Zhejiang Univ. Sci. 5(8): 1001-1004.

Zheng, W.; Lu, Y. M.; Lu, G. Y.; Zhao, Q.; Cheung, 0.; Bl aner, W. S. (2001) Transthyretin, thyroxine, and retinolbinding protein in human cerebrospinal fluid: effect of Pb exposure. Toxicol. Sci. 61(1): 107-114.

Zimmermann-Tansella, C.; Campara, P. ; Andrea, F. D.; Savontto, C.; Tans ella, m. (1983) Psychological and

physical complaints of subjects with low exposure to Pb. Hum. Toxicol. 2: 615-623.

Zuckerman, B.; Amaro, H.; Cabral, H. (1989) Validity of self-reporting of marijuana and cocaine use among

pregnant adolescents. J. Pediatr. ( St. Louis) 115: 812-815.