BIOLOGIC MARKERS IN URINARY TOXICOLOGY

Subcommittee on Biologic Markers in Urinary Toxicology

Committee on Biologic Markers

Board on Environmental Studies and Toxicology

Commission on Life Sciences

National Research Council

NATIONAL ACADEMY PRESS
WASHINGTON, D.C.
1995



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Biologic Markers in Urinary Toxicology BIOLOGIC MARKERS IN URINARY TOXICOLOGY Subcommittee on Biologic Markers in Urinary Toxicology Committee on Biologic Markers Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS WASHINGTON, D.C. 1995

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Biologic Markers in Urinary Toxicology NATIONAL ACADEMY PRESS 2101 Constitution Ave., N.W. Washington, D.C. 20418 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 report has been reviewed by a group other than the authors according to procedures approved by a report review committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of 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. Bruce Alberts 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. Harold Liebowitz 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. Kenneth I. Shine 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. Bruce Alberts and Dr. Harold Liebowitz are chairman and vice chairman, respectively, of the National Research Council. The project was supported by the Agency for Toxic Substances and Disease Registry under grant nos. U50/ATU30009-05 and U50/ATU300009-04 and the National Institute for Environmental Health Sciences under contract nos. NOI-ES-35366 and 273-MH-107389. Library of Congress Catalog Card No. 94-69722 International Standard Book No 0-309-05228-9 Additional copies of this report are available from: National Academy Press 2101 Constitution Ave., NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington Metropolitan Area) B-509 Copyright 1995 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Biologic Markers in Urinary Toxicology SUBCOMMITTEE ON BIOLOGIC MARKERS IN URINARY TOXICOLOGY WILLIAM F. FINN (Chair), School of Medicine, University of North Carolina, Chapel Hill, N.C. GEORGE P. HEMSTREET III (Vice-Chair), University of Oklahoma Health Sciences Center, Oklahoma City, Okla. BRUCE C. ALLEN, ICF Kaiser, Morrisville, N.C. ROBERT L. ANDERSON, Menlo Park, Calif. WILLIAM O. BERNDT, University of Nebraska Medical Center, Omaha, Neb. FRANKLIN H. EPSTEIN, Beth Israel Hospital, Boston, Mass. ERNEST C. FOULKES, University of Cincinnati, College of Medicine, Cincinnati, Ohio BRUCE FOWLER, University of Maryland, Baltimore, Md. CARL W. GOTTSCHALK, School of Medicine, University of North Carolina, Chapel Hill, N.C. ERNEST E. MCCONNELL, Raleigh, N.C. BERNICE NOBLE, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, N.Y. JEAN C. PARKER, U.S. Environmental Protection Agency, Washington, D.C. GEORGE A. PORTER, Oregon Health Sciences Center, Portland, Ore. Technical Advisers LAWRENCE LASH, Wayne State University, Detroit, Mich. ROBERT SAFIRSTEIN, University of Texas Medical Branch-Galveston, Galveston, Tex. Staff CAROL A. MACZKA, Program Director J. DAVID SANDLER, Project Director ROBERT BELILES, Project Director (until 1992) NORMAN GROSSBLATT, Editor LINDA V. LEONARD, Senior Project Assistant Sponsors Agency for Toxic Substances and Disease Registry National Institute of Environmental Health Sciences

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Biologic Markers in Urinary Toxicology COMMITTEE ON BIOLOGIC MARKERS BERNARD GOLDSTEIN (Chair), UMDNJ-Robert Wood Johnson Medical School, Piscataway, N.J. JAMES GIBSON, Dow-Elanco, Indianapolis, Ind. ROGENE F. HENDERSON, Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.M. JOHN E. HOBBIE, Marine Biological Laboratory, Woods Hole, Mass. PHILIP J. LANDRIGAN, Mount Sinai Medical Center, New York, N.Y. DONALD R. MATTISON, University of Arkansas for Medical Sciences and National Center for Toxicological Research, Little Rock, Ark. FREDERICA PERERA, Columbia University, New York, N.Y. EMIL A. PFITZER, Hoffmann-La Roche, Inc., Nutley, N.J. ELLEN K. SILBERGELD, Environmental Defense Fund, Washington, D.C.

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Biologic Markers in Urinary Toxicology BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY PAUL G. RISSER (Chair), Miami University, Oxford, Ohio MICHAEL J. BEAN, Environmental Defense Fund, Washington, D.C. EULA BINGHAM, University of Cincinnati, Cincinnati, Ohio EDWIN H. CLARK II, Clean Sites, Inc., Alexandria, Va. ALLAN H. CONNEY, Rutgers University, Piscataway, N.J. ELLIS COWLING, North Carolina State University, Raleigh, N.C. JOHN L. EMMERSON, Eli Lilly & Company, Greenfield, Ind. ROBERT C. FORNEY, Unionville, Penn. ROBERT A. FROSCH, Harvard University, Cambridge, Mass. KAI LEE, Williams College, Williamstown, Mass. JANE LUBCHENCO, Oregon State University, Corvallis, Ore. GORDON ORIANS, University of Washington, Seattle, Wash. FRANK L. PARKER, Vanderbilt University, Nashville, Tenn. GEOFFREY PLACE, Hilton Head, S.C. DAVID P. RALL, Washington, D.C. LESLIE A. REAL, Indiana University, Bloomington, Ind. KRISTIN SHRADER-FRECHETTE, University of South Florida, Tampa, Fla. BURTON H. SINGER, Princeton University, Princeton, N.J. MARGARET STRAND, Bayh, Connaughton and Malone, Washington, D.C. GERALD VAN BELLE, University of Washington, Seattle, Wash. BAILUS WALKER, JR., Howard University, Washington, D.C. Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Program Director for Natural Resources and Applied Ecology CAROL A. MACZKA, Program Director for Toxicology and Risk Assessment LEE R. PAULSON, Program Director for Information Systems and Statistics RAYMOND A. WASSEL, Program Director for Environmental Sciences and Engineering

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Biologic Markers in Urinary Toxicology COMMISSION ON LIFE SCIENCES THOMAS D. POLLARD (Chair), Johns Hopkins Medical School, Baltimore, Md. BRUCE N. AMES, University of California, Berkeley, Calif. JOHN C. BAILAR III, McGill University, Montreal, Quebec MICHAEL BISHOP, Hooper Research Foundation, University of California Medical Center, San Francisco, Calif. JOHN E. BURRIS, Marine Biological Laboratory, Woods Hole, Mass. MICHAEL T. CLEGG, University of California, Riverside, Calif. GLENN A. CROSBY, Washington State University, Pullman, Wash. MARIAN E. KOSHLAND, University of California, Berkeley, Calif. RICHARD E. LENSKI, Michigan State University, East Lansing, Mich. EMIL A. PFITZER, Hoffmann-La Roche Inc., Nutley, N.J. MALCOLM C. PIKE, University of Southern California School of Medicine, Los Angeles, Calif. HENRY C. PITOT III, University of Wisconsin, Madison, Wisc. JONATHAN M. SAMET, The Johns Hopkins University School of Medicine, Baltimore, Md. HAROLD M. SCHMECK, JR., Armonk, N.Y. CARLA J. SHATZ, University of California, Berkeley, Calif. SUSAN S. TAYLOR, University of California at San Diego, La Jolla, Calif. P. ROY VAGELOS, Merck & Company, Whitehouse Station, N.J. JOHN L. VANDEBERG, Southwestern Foundation for Biomedical Research, San Antonio, Tex. PAUL GILMAN, Executive Director

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Biologic Markers in Urinary Toxicology OTHER RECENT REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Science and the Endangered Species Act (1995) Wetlands: Characteristics and Boundaries (1995) Biologic Markers in Urinary Toxicology (1995) Review of EPAs' Environmental Monitoring and Assessment Program (three reports, 1994–1995) Science and Judgment in Risk Assessment (1994) Ranking Hazardous Sites for Remedial Action (1994) Review of EPA's Environmental Monitoring and Assessment Program: Forests and Estuaries (1994) Review of EPA's Environmental Monitoring and Assessment Program: Surface Waters (1994) Pesticides in the Diets of Infants and Children (1993) Issues in Risk Assessment (1993) Setting Priorities for Land Conservation (1993) Protecting Visibility in National Parks and Wilderness Areas (1993) Biologic Markers in Immunotoxicology (1992) Dolphins and the Tuna Industry (1992) Environmental Neurotoxicology (1992) Hazardous Materials on the Public Lands (1992) Science and the National Parks (1992) Animals as Sentinels of Environmental Health Hazards (1991) Assessment of the U.S. Outer Continental Shelf Environmental Studies Program, Volumes I–IV (1991–1993) Human Exposure Assessment for Airborne Pollutants (1991) Monitoring Human Tissues for Toxic Substances (1991) Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991) Decline of the Sea Turtles (1990) Tracking Toxic Substances at Industrial Facilities (1990) Biologic Markers in Pulmonary Toxicology (1989) Biologic Markers in Reproductive Toxicology (1989) Copies of these reports may be ordered from the National Academy Press: (800) 624-6242; (202) 334-3313

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Biologic Markers in Urinary Toxicology PREFACE There is an increasing need for accurate information on the health effects of pollutants. In keeping with that need, the Agency for Toxic Substances and Disease Registry of the U.S. Public Health Service and the National Institute of Environmental Health Sciences asked the National Research Council to examine the potential for use of biologic markers in environmental health research. The term biologic markers has been used by the National Research Council's Committee on Biological Markers to refer to indicators of toxicologic events in biologic systems or samples. The Committee on Biological Markers was organized to consider which uses of biologic markers offered the greatest potential for major contributions. Four biologic systems were chosen: the reproductive system, the respiratory system, the immune system, and the urinary system. This report is the product of the Subcommittee on Biologic Markers in Urinary Toxicology, which comprised scientists with backgrounds in and knowledge of nephrology, urology, pathology, renal toxicology and metabolism, pharmacokinetics, immunology, risk assessment, pharmacology, renal physiology, and other disciplines. The subcommittee reviewed research on known biologic markers and identified and evaluated promising new technologies to find markers, important research opportunities in the field, and subjects in which interdisciplinary research is needed. During the subcommittee's deliberations, several scientists were asked to provide information. The subcommittee especially wishes to recognize the contributions of Lawrence Lash, Wayne State University, and Robert Safirstein, University of Texas-Galveston. This report could not have been produced without the efforts of the National Research Council staff, especially J. David Sandler, project director, and Linda V. Leonard, senior project assistant; Norman Grossblatt, editor, Carol Maczka, program director; Gail Charnley, acting program director (through September 1994); Robert P. Beliles and Joyce Walz (the project director and assistant during the early months of the project); and James J. Reisa, director of BEST. WILLIAM F. FINN, M.D., CHAIRMAN SUBCOMMITTEE ON BIOLOGIC MARKERS IN URINARY TOXICOLOGY

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Biologic Markers in Urinary Toxicology CONTENTS     EXECUTIVE SUMMARY   1 1   INTRODUCTION   15     Biologic Markers   16     Validity of Biologic Markers   18     Ethical Issues   21     Structure of the Report   22 2   TOXIC EXPOSURE OF THE URINARY TRACT   23     The Urinary Tract   25     Mechanisms of Renal Toxicity   27     Host Factors in Renal Toxicity   30     Clinical Effects of Chemical Exposure on the Kidney   35     Cancer of the Bladder, Kidney, and Prostate   40     Animal Models of Interstitial Cystitis   51     Summary   52 3   BIOLOGIC MARKERS OF SUSCEPTIBILITY AND EXPOSURE   53     Populations at Risk   53     Markers of Susceptibility   58     Markers of Exposure   76     Summary   78

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Biologic Markers in Urinary Toxicology 4   BIOLOGIC MARKERS OF EFFECT   81     External Visualization   82     Urinary Clearance Measurements   82     Urinalysis   85     Markers of Cytotoxicity and Cellular Response   95     Markers of Neoplasia   103     Markers of Interstitial Cystitis   114     Summary   116 5   BIOLOGIC MARKERS IN EXTRAPOLATION   153     Basis of Extrapolation   156     Techniques Used in Risk Assessment   166     Improved Risk-Assessment Extrapolation   180     Summary   187 6   NEW TECHNOLOGIES   191     Markers of Cell Injury, Regeneration, and Hypertrophy   191     Cancer of the Bladder   199     Differential-Display Polymerase Chain Reaction   202     Cancer of the Prostate   203     Cancer of the Kidney   207 7   CONCLUSIONS AND RECOMMENDATIONS   217     Toxic Exposure of the Urinary Tract   217     Biologic Markers of Exposure and Susceptibility   220     Biologic Markers of Effect   221     Use of Biologic Makers in Extrapolation   223     New Technologies   224     REFERENCES   227