HUMAN BIOMONITORING FOR ENVIRONMENTAL CHEMICALS

Committee on Human Biomonitoring for Environmental Toxicants

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, DC
www.nap.edu



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Human Biomonitoring for Environmental Chemicals HUMAN BIOMONITORING FOR ENVIRONMENTAL CHEMICALS Committee on Human Biomonitoring for Environmental Toxicants Board on Environmental Studies and Toxicology Division on Earth and Life Studies NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, DC www.nap.edu

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Human Biomonitoring for Environmental Chemicals THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This project was supported by Contract No. 68-C-03-081 between the National Academy of Sciences and the U.S. Environmental Protection Agency with the cosponsorship of the Centers for Disease Control and Prevention. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the organizations or agencies that provided support for this project. International Standard Book Number-10: 0-309-10272-3 (Book) International Standard Book Number-13: 978-0-309-10272-8 (Book) International Standard Book Number-10: 0-309-66315-6 (PDF) International Standard Book Number-13: 978-0-309-66315-1 (PDF) Library of Congress Control Number 2006933400 Additional copies of this report are available from The National Academies Press 500 Fifth Street, NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2006 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Human Biomonitoring for Environmental Chemicals THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Human Biomonitoring for Environmental Chemicals COMMITTEE ON HUMAN BIOMONITORING FOR ENVIRONMENTAL TOXICANTS Members THOMAS BURKE (Chair), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD MARK CULLEN, Yale Occupational and Environmental Medicine Program, New Haven, CT GEORGE EADON, New York State Department of Health, Albany, NY PETER B. FARMER, University of Leicester, Leicester, United Kingdom GARY GINSBERG, Connecticut Department of Public health, Hartford, CT CAROL J. HENRY, American Chemistry Council, Arlington, VA NINA T. HOLLAND, University of California, Berkeley, Berkeley, CA GUNNAR JOHANSON, Karolinska Institutet, Stockholm, Sweden BRANDEN B. JOHNSON, New Jersey Department of Environmental Protection, Trenton, NJ DOROTHY E. PATTON, International Life Sciences Institute, Washington, DC GERALD VAN BELLE, University of Washington, Seattle, WA CLAUDE VIAU, University of Montreal, Montreal, Quebec ROBIN WHYATT, Columbia University, New York, NY RAYMOND S.H. YANG, Colorado State University, Fort Collins, CO Staff EILEEN N. ABT, Project Director JENNIFER SAUNDERS, Associate Program Officer NORMAN GROSSBLATT, Senior Editor RUTH CROSSGROVE, Senior Editor MIRSADA KARALIC-LONCAREVIC, Research Associate LUCY FUSCO, Program Associate MORGAN MOTTO, Senior Project Assistant RADIAH A. ROSE, Senior Project Assistant TAMARA DAWSON, Senior Project Assistant KEMI YAI, Project Assistant SAMMY BARDLEY, Librarian Sponsors U.S. Environmental Protection Agency Centers for Disease Control and Prevention

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Human Biomonitoring for Environmental Chemicals BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1 Members JONATHAN M. SAMET (Chair), Johns Hopkins University, Baltimore, MD RAMÓN ALVAREZ, Environmental Defense, Austin, TX JOHN M. BALBUS, Environmental Defense, Washington, DC THOMAS BURKE, Johns Hopkins University, Baltimore, MD DALLAS BURTRAW, Resources for the Future, Washington, DC JAMES S. BUS, Dow Chemical Company, Midland, MI COSTEL D. DENSON, University of Delaware, Newark E. DONALD ELLIOTT, Willkie Farr & Gallagher LLP, Washington, DC J. PAUL GILMAN, Oak Ridge National Laboratory, Oak Ridge, TN SHERRI W. GOODMAN, Center for Naval Analyses, Alexandria, VA JUDITH A. GRAHAM, American Chemistry Council, Arlington, VA DANIEL S. GREENBAUM, Health Effects Institute, Cambridge, MA WILLIAM P. HORN, Birch, Horton, Bittner and Cherot, Washington, DC ROBERT HUGGETT, Michigan State University (emeritus), East Lansing JAMES H. JOHNSON JR., Howard University, Washington, DC JUDITH L. MEYER, University of Georgia, Athens PATRICK Y. O’BRIEN, ChevronTexaco Energy Technology Company, Richmond, CA DOROTHY E. PATTON, International Life Sciences Institute, Washington, DC STEWARD T.A. PICKETT, Institute of Ecosystem Studies, Millbrook, NY DANNY D. REIBLE, University of Texas, Austin JOSEPH V. RODRICKS, ENVIRON International Corporation, Arlington, VA ARMISTEAD G. RUSSELL, Georgia Institute of Technology, Atlanta ROBERT F. SAWYER, University of California, Berkeley LISA SPEER, Natural Resources Defense Council, New York, NY KIMBERLY M. THOMPSON, Massachusetts Institute of Technology, Cambridge MONICA G. TURNER, University of Wisconsin, Madison MARK J. UTELL, University of Rochester Medical Center, Rochester, NY CHRIS G. WHIPPLE, ENVIRON International Corporation, Emeryville, CA LAUREN ZEISE, California Environmental Protection Agency, Oakland Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Scholar RAYMOND A. WASSEL, Senior Program Officer for Environmental Sciences and Engineering 1 This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology.

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Human Biomonitoring for Environmental Chemicals KULBIR BAKSHI, Senior Program Officer for Toxicology EILEEN N. ABT, Senior Program Officer for Risk Analysis KARL E. GUSTAVSON, Senior Program Officer K. JOHN HOLMES, Senior Program Officer ELLEN K. MANTUS, Senior Program Officer SUSAN N.J. MARTEL, Senior Program Officer SUZANNE VAN DRUNICK, Senior Program Officer RUTH E. CROSSGROVE, Senior Editor

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Human Biomonitoring for Environmental Chemicals OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues (2006) New Source Review for Stationary Sources of Air Pollution (2006) Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment (2006) Fluoride in Drinking Water: A Scientific Review of EPA’s Standards (2006) State and Federal Standards for Mobile-Source Emissions (2006) Superfund and Mining Megasites—Lessons from the Coeur d’Alene River Basin (2005) Health Implications of Perchlorate Ingestion (2005) Air Quality Management in the United States (2004) Endangered and Threatened Species of the Platte River (2004) Atlantic Salmon in Maine (2004) Endangered and Threatened Fishes in the Klamath River Basin (2004) Cumulative Environmental Effects of Alaska North Slope Oil and Gas Development (2003) Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002) Biosolids Applied to Land: Advancing Standards and Practices (2002) The Airliner Cabin Environment and Health of Passengers and Crew (2002) Arsenic in Drinking Water: 2001 Update (2001) Evaluating Vehicle Emissions Inspection and Maintenance Programs (2001) Compensating for Wetland Losses Under the Clean Water Act (2001) A Risk-Management Strategy for PCB-Contaminated Sediments (2001) Acute Exposure Guideline Levels for Selected Airborne Chemicals (4 volumes, 2000-2004) Toxicological Effects of Methylmercury (2000) Strengthening Science at the U.S. Environmental Protection Agency (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) Ecological Indicators for the Nation (2000) Waste Incineration and Public Health (1999) Hormonally Active Agents in the Environment (1999) Research Priorities for Airborne Particulate Matter (4 volumes, 1998-2004) The National Research Council’s Committee on Toxicology: The First 50 Years (1997) Carcinogens and Anticarcinogens in the Human Diet (1996)

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Human Biomonitoring for Environmental Chemicals Upstream: Salmon and Society in the Pacific Northwest (1996) Science and the Endangered Species Act (1995) Wetlands: Characteristics and Boundaries (1995) Biologic Markers (5 volumes, 1989-1995) Review of EPA’s Environmental Monitoring and Assessment Program (3 volumes, 1994-1995) Science and Judgment in Risk Assessment (1994) Pesticides in the Diets of Infants and Children (1993) Dolphins and the Tuna Industry (1992) Science and the National Parks (1992) Human Exposure Assessment for Airborne Pollutants (1991) Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991) Decline of the Sea Turtles (1990) Copies of these reports may be ordered from the National Academies Press (800) 624-6242 or (202) 334-3313 www.nap.edu

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Human Biomonitoring for Environmental Chemicals Preface Biomonitoring has various applications; the focus in this report is on the role of biomonitoring as an exposure-assessment tool, which is central to public-health efforts. Repeatedly throughout recent history, biomonitoring data have helped to confirm health effects of environmental exposures and have validated public-health policies. Population-based biomonitoring studies have identified new chemicals found in the environment and in human tissues, monitored changes in exposures, and established the distribution of exposures among the general population. Biomonitoring data— when used in conjunction with available epidemiology, toxicology, and pharmacokinetic modeling data—can estimate how much of a chemical has been absorbed into the body and provide a measure of potential health risk. The ultimate objective of biomonitoring is to link information on exposures, susceptibility, and effects to understand the public health implications of exposure to environmental chemicals. In spite of its potential, tremendous challenges surround the use of biomonitoring, and our ability to generate biomonitoring data has exceeded our ability to interpret what the data mean to public health. The challenges include improving the design of biomonitoring studies, interpreting what biomonitoring data mean, and understanding ethical and communication issues that are essential to the continued advancement of this field. To address the challenges, Congress asked the National Academies to assess key uncertainties related to the use and interpretation of biomonitoring data. In this report, the Committee on Human Biomonitoring for Environmental Toxicants reviews current practices and makes recommendations for

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Human Biomonitoring for Environmental Chemicals Contents     SUMMARY   1 1   INTRODUCTION   15      Background,   16      Current Biomonitoring Activities,   17      Challenges,   17      Biomarkers and Biomonitoring,   21      The National Research Council Committee,   23      Organization of the Report,   24      References,   24 2   U.S. AND INTERNATIONAL BIOMONITORING EFFORTS   27      Human Biomonitoring in the United States,   28      International Biomonitoring Efforts,   58      Human-Specimen Banking,   60      General Observations,   62      Conclusions,   64      Recommendations,   64      References,   64 3   FRAMEWORK TO CHARACTERIZE BIOMARKERS AND USES OF BIOMONITORING   71      Rationale for a Framework to Characterize Biomarkers,   71      Types of Biomarkers,   72      Key Uses of Biomonitoring Data,   73

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Human Biomonitoring for Environmental Chemicals      Properties of and Grouping Framework for Biomarkers of Exposure,   75      Conclusions,   82      Recommendations,   82      References,   82 4   CONSIDERATIONS IN THE DESIGN OF BIOMONITORING STUDIES   84      Study Design,   86      Study Conduct,   110      Statistical Analysis,   121      Summary and Conclusions,   124      Recommendations,   125      References,   127 5   INTERPRETATION OF BIOMONITORING RESULTS   132      Introduction,   132      Initial Review of Biomonitoring Data,   133      Overview of Interpretive Options for Biomonitoring Data,   134      Reference Ranges,   139      Adapting Workplace Biologic Reference Values for Interpreting Biomonitoring Results,   151      Using Biomonitoring Results to Estimate Risk,   158      Biomonitoring-Based Risk Assessment,   159      Using Existing Risk Assessments for Interpreting Biomonitoring Data,   163      Biomonitoring-Led Risk-Assessment Approaches,   164      Summary,   185      Conclusions,   190      Recommendations,   192      References,   193 6   COMMUNICATING RESULTS, INTERPRETATIONS, AND USES OF BIOMONITORING DATA TO NONSCIENTISTS   201      Limits of This Chapter’s Discussion,   202      Principles of Risk Communication,   205      Trading Off Avoidance of False Positives and False Negatives in Communication,   211      Discussing Results Below the Limit of Detection for Biomarkers,   213      Communicating Health Interpretations of Detected Biomarkers,   214      Recommendations,   227      References,   233

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Human Biomonitoring for Environmental Chemicals 7   RESEARCH AGENDA   238      Introduction,   238      Research Recommendations,   239      Infrastructure Needs to Implement Research Agenda,   247      Summary,   251      References,   253     APPENDIXES     A   Biographic Information on the Committee on Human Biomonitoring for Environmental Toxicants   257 B   Additional Case Studies Used to Exemplify Interpretative Approaches Described in Chapter 5   263 C   PBPK Modeling   278     GLOSSARY   287

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Human Biomonitoring for Environmental Chemicals Boxes, Figures, and Tables BOXES 3-1   Continuum of Risk-Assessment and -Management Activities Related to Exposure Biomonitoring,   74 5-1   Case Example: Organophosphorus Metabolites in Pregnant Farm Workers,   145 5-2   Reference Ranges Encourage Public-Health Action,   150 5-3   Potential Utility of Pilot Data from “Other” Populations,   150 5-4   Brief Overview of Pharmacokinetic Models,   165 FIGURES 1-1   Simplified flow chart of classes of biomarkers,   22 2-1   Timeline of major U.S. biomonitoring efforts,   29 3-1   Operational relationships between internal dose, external dose, and biologic effects,   76 4-1   Stages of a biomonitoring study,   86 4-2   Contribution of exposures to biomarker concentrations and effect of limit of detection on its potential uses,   88 4-3   Effect of half-life on contributions of exposures during the last presampling hour, day, week, month, and half-year to biologic levels of determinants,   92 4-4   Influence of biologic half-life relationship between exposure level and biomarker level,   93

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Human Biomonitoring for Environmental Chemicals 4-5   Pharmacokinetics of environmental chemicals in body and what matrices are available for analyses,   111 5-1   Overview of interpretive options for biomonitoring data,   133 5-2   Illustration of the interpretive risk-based options,   136 5-3   Distribution of biomarker concentrations in generic reference population,   143 5-4   Cumulative frequency distribution of the urinary excretion of 1-hydroxypyrene in people living in two rural districts of Burundi, in Bujumbura and in a reference group at the University of Montreal,   146 5-5   Daily average workplace xylene air and urinary methylhippuric acid in exposed workers,   155 5-6   Evolution of risk assessment and risk management,   160 5-7   Conversion of biomonitoring data to daily dose on the basis of one- compartment (body-burden) model,   166 5-8   Blood concentrations of rapidly cleared chemical to which there is frequent and nearly uniform exposure,   167 5-9   Conversion of biomonitoring data to daily dose on basis of one-compartment model for non-lipid-soluble chemicals at steady state,   168 5-10   Predictiveness of PFOA rat model,   177 5-11   Median concentrations of BDE-47, BDE-99, and BDE-153 in human milk from different countries,   184 TABLES 1-1   Numbers of Chemicals in Third National Report on Human Exposures to Environmental Chemicals for Which Health-Based Values Are Available,   20 1-2   Challenges to Interpreting and Using Biomonitoring Data,   21 2-1   Examples of Current U.S. and International Biomonitoring Efforts,   32 3-1   Framework for Grouping Biomarkers of Exposure,   77 4-1   Goal-Based and Process-Based Criteria for Evaluating Communication,   108 4-2   Matrices for Biomonitoring Studies,   112 5-1   Overview of Major Biomarker Case Examples Used to Illustrate Interpretive Options,   138 5-2   Blood Concentrations for Cadmium in the U.S. Population Aged 1 Year and Older,   140 5-3   Urine Concentrations for Cadmium in the U.S. Population Aged 6 Years and Older,   142

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Human Biomonitoring for Environmental Chemicals 5-4   Comparison of Biomarker Reference Values Proposed by ACGIH and Observed Concentrations in Adults for Same Determinants from NHANES 1999-2002,   152 5-5   Estimated Exposures (µg/kg/day) to the General Population Based on Extrapolated Intake from Urinary Metabolites in 289 Individuals Measured by Blount et al. (2000),   170 5-6   Properties of Biomarkers Used as Examples in Chapter 5,   188 7-1   Summary of Major Points in Research Agenda,   252

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Human Biomonitoring for Environmental Chemicals HUMAN BIOMONITORING FOR ENVIRONMENTAL CHEMICALS

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