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Issues in Risk Assessment
ISSUES IN RISK ASSESSMENT
Committee on Risk Assessment Methodology
Board on Environmental Studies and Toxicology
Commission on Life Sciences
National Research Council
NATIONAL ACADEMY PRESS
Washington, DC
1993
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Issues in Risk Assessment
NATIONAL ACADEMY PRESS
2101 Constitution Ave., NW Washington, DC 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 competencies 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, non-profit, 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. Frank Press 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. Robert M. White 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 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. Frank Press and Dr. Robert M. White are chairman and vice chairman, respectively, of the National Research Council.
The project was supported by the U.S. Environmental Protection Agency under Cooperative Agreement #CR-815682, the American Petroleum Institute, and the American Industrial Health Council. Funds were also contributed by the National Institute for Occupational Safety and Health and the U.S. Army Biomedical Research and Development Laboratory.
Library of Congress Catalog Card No. 92-61838
International Standard Book Number 0-309-04786-2
Additional copies of this report are available from the
National Academy Press,
2101 Constitution Avenue, NW, Washington, DC 20418.
B-023
Copyright 1993 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America
First Printing,January 1993
Second Printing,March 1993
Third Printing,March 1995
Fourth Printing,September 1997
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Issues in Risk Assessment
Committee on Risk Assessment Methodology
BERNARD D. GOLDSTEIN (Chairman),
Environmental and Occupational Health Sciences Institute, Robert Wood Johnson Medical School, and Rutgers University, Piscataway, NJ
DONALD R. MATTISON (Vice-Chairman),
University of Pittsburgh, Graduate School of Public Health, Pittsburgh
JOHN C. BAILAR, III,
McGill University School of Medicine, Montreal
PAUL T. BAILEY,
Mobil Oil Corporation, Princeton
LAWRENCE W. BARNTHOUSE,
Oak Ridge National Laboratory, Oak Ridge, TN
KENNY S. CRUMP,
Clement Associates, Inc., Ruston, LA
JOHN DOULL,
University of Kansas Medical Center, Kansas City
MICHAEL A. GALLO,
Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway
RICHARD A. GRIESEMER,
National Institute of Environmental Health Sciences, National Toxicology Program, Research Triangle Park, NC
WILLIAM E. HALPERIN,
National Institute for Occupational Safety and Health, Cincinnati
ROGENE HENDERSON,
Lovelace Biomedical and Environmental Research Institute, Albuquerque
BRIAN P. LEADERER,
John B. Pierce Foundation, Yale University School of Medicine, New Haven, CT
ALAN W. MAKI,
Exxon Corporation, Houston
FRANKLIN E. MIRER,
United Auto Workers, Detroit
DANIEL W. NEBERT,
Institute of Environmental Health, University of Cincinnati Medical Center, The Kettering Laboratory, Cincinnati
D. WARNER NORTH,
Decision Focus, Inc., Mountain View, CA
RICHARD H. REITZ,
The Dow Chemical Company, Midland, MI
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Issues in Risk Assessment
Staff
RICHARD D. THOMAS, Principal Staff Scientist
GAIL CHARNLEY, Project Director
KATHLEEN R. STRATTON, Project Director (until March 1992)
MARVIN A. SCHNEIDERMAN, Senior Staff Scientist
ANNE M. SPRAGUE, Information Specialist
IAN C.T. NISBET, Technical Adviser
DANIEL KREWSKI, Technical Adviser
LINDA V. LEONARD, Senior Project Assistant
RUTH DANOFF, Project Assistant
JOYCE WALZ, Project Assistant
Sponsors
U.S. Environmental Protection Agency
American Petroleum Institute
American Industrial Health Council
National Institute for Occupational Safety and Health
U.S. Army Biomedical Research and Development Laboratory
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Issues in Risk Assessment
Committee on Risk Assessment Methodology
Federal Liaison Group
WILLIAM H. FARLAND (Co-chair),
U.S. Environmental Protection Agency, Washington, DC
ROBERT SCHEUPLEIN (Co-chair),
U.S. Food and Drug Administration, Washington, DC
DEBORAH BARSOTTI,
Agency for Toxic Substances and Disease Registry, Atlanta, GA
JAMES BEALL,
U.S. Department of Energy, Washington, DC
JAMES BILSTAD,
U.S. Food and Drug Administration, Rockville, MD
WILLIAM CIBULAS,
Agency for Toxic Substances and Disease Registry, Atlanta, GA
MURRAY S. COHN,
Consumer Product Safety Commission, Bethesda, MD
JOSEPH COTRUVO,
U.S. Environmental Protection Agency, Washington, DC
GERALD A. FAICH,
U.S. Food and Drug Administration, Rockville, MD
HENRY S. GARDNER,
U.S. Army Biomedical Research Development Laboratory, Frederick, MD
HERMAN GIBB,
U.S. Environmental Protection Agency, Washington, DC
WALTER H. GLINSMANN,
U.S. Food and Drug Administration, Washington, DC
BRYAN D. HARDIN,
National Institute for Occupational Safety and Health, Cincinnati
RONALD W. HART,
National Center for Toxicological Research, Jefferson, AR
RICHARD N. HILL,
U.S. Environmental Protection Agency, Washington, DC
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KAREN HOGAN,
U.S. Environmental Protection Agency, Washington, DC
PETER INFANTE,
U.S. Department of Labor, Washington, DC
MICHAEL A. LIDSKY,
U.S. Department of Agriculture, Hyattsville, MD
RONALD J. LORENTZEN,
U.S. Food and Drug Administration, Rockville, MD
JOHN MARTONIK,
U.S. Department of Agriculture, Washington, DC
GERALD F. MEYER,
U.S. Food and Drug Administration, Rockville, MD
EDWARD OHANIAN,
U.S. Environmental Protection Agency, Washington, DC
RICHARD ORR,
U.S. Department of Agriculture, Hyattsville, MD
RICHARD PARRY, JR.,
U.S. Department of Agriculture, Beltsville, MD
DOROTHY PATTON,
U.S. Environmental Protection Agency, Washington, DC
PETER PREUSS,
U.S. Environmental Protection Agency, Washington, DC
LORENZ R. RHOMBERG,
U.S. Environmental Protection Agency, Washington, DC
MATTHEW H. ROYER,
U.S. Department of Agriculture, Hyattsville, MD
LILLY SANATHAN,
U.S. Food and Drug Administration, Rockville, MD
LINDA SCHIEROW,
U.S. Library of Congress, Washington, DC
JENNIFER SEED,
U.S. Environmental Protection Agency, Washington, DC
MICHAEL SLIMAK,
U.S. Environmental Protection Agency, Washington, DC
JANET A. SPRINGER,
U.S. Environmental Protection Agency, Washington, DC
BRUCE V. STADEL,
U.S. Food and Drug Administration, Rockville, MD
LESLIE T. STAYNER,
National Institute for Occupational Safety and Health, Cincinnati
ROBERT J. TEMPLE,
U.S. Food and Drug Administration, Rockville, MD
ANGELO TURTURRO,
National Center for Toxicological Research, Jefferson, AR
MICHAEL T. WERNER,
U.S. Department of Agriculture, Hyattsville, MD
MAURICE ZEEMAN,
U.S. Environmental Protection Agency, Washington, DC
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Issues in Risk Assessment
Board on Environmental Studies and Toxicology
PAUL G. RISSER (Chair),
University of New Mexico, Albuquerque
FREDERICK R. ANDERSON,
Cadwalader, Wickersham & Taft, Washington, DC
JOHN C. BAILAR, III,
McGill University School of Medicine, Montreal
GARRY D. BREWER,
University of Michigan, Ann Arbor
JOHN CAIRNS, JR.,
Virginia Polytechnic Institute and State University, Blacksburg
EDWIN H. CLARK,
Department of Natural Resources and Environmental Control, State of Delaware, Dover
JOHN L. EMMERSON,
Lilly Research Laboratories, Greenfield, IN
ROBERT C. FORNEY,
Unionville, PA
ALFRED G. KNUDSON,
Fox Chase Cancer Center, Philadelphia
KAI LEE,
Williams College, Williamstown, MA
GENE E. LIKENS,
The New York Botanical Garden, Millbrook
JANE LUBCHENCO,
Oregon State University, Corvallis
DONALD MATTISON,
University of Pittsburgh, Pittsburgh
HAROLD A. MOONEY.
Stanford University, Stanford, CA
GORDON ORIANS,
University of Washington, Seattle
FRANK PARKER,
Vanderbilt University, Nashville
GEOFFREY PLACE,
Hilton Head, SC
MARGARET M. SEMINARIO,
AFL/CIO, Washington, DC
I. GLENN SIPES,
University of Arizona, Tucson
BAILUS WALKER, JR.,
University of Oklahoma, Oklahoma City
WALTER J. WEBER, JR.,
University of Michigan, Ann Arbor
Staff
JAMES J. REISA, Director
DAVID J. POLICANSKY, Associate Director and Program Director for Natural Resources and Applied Ecology
RICHARD D. THOMAS, Associate Director and Program Director for Human 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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Issues in Risk Assessment
Commission on Life Sciences
BRUCE M. ALBERTS (Chairman),
University of California, San Francisco
BRUCE N. AMES,
University of California, Berkeley
J. MICHAEL BISHOP,
Hooper Research Foundation, University of California Medical Center, San Francisco
DAVID BOTSTEIN,
Stanford University School of Medicine, Stanford
MICHAEL T. CLEGG,
University of California, Riverside
GLENN A. CROSBY,
Washington State University, Pullman
LEROY E. HOOD,
University of Washington, Seattle
MARIAN E. KOSHLAND,
University of California, Berkeley
RICHARD E. LENSKI,
University of Oxford
STEVEN P. PAKES,
Southwestern Medical School at Dallas
EMIL A. PFITZER,
Hoffmann-La Roche Inc., Nutley, NJ
MALCOLM C. PIKE,
University of Southern California School of Medicine, Los Angeles
THOMAS D. POLLARD,
Johns Hopkins Medical School, Baltimore
PAUL G. RISSER,
University of New Mexico, Albuquerque
JOHNATHAN M. SAMET,
University of New Mexico School of Medicine, Albuquerque
HAROLD M. SCHMECK, JR.,
Armonk, NY
CARLA J. SHATZ,
University of California, Berkeley
SUSAN S. TAYLOR,
University of California at San Diego, La Jolla
P. ROY VAGELOS,
Merck and Company, Inc., Rahway, NJ
TORSTEN N. WIESEL,
Rockefeller University, New York
Staff
ALVIN G. LAZEN, Acting Executive Director
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Issues in Risk Assessment
Preface
This volume is the first in a series to be prepared by the Committee on Risk Assessment Methodology (CRAM) in the National Research Council's Board on Environmental Studies and Toxicology. The committee was charged with identifying and investigating important scientific issues in risk assessment. Three issues related to risk assessment are addressed here: use of the maximum tolerated dose (MTD) in animal bioassays for carcinogenicity, the two-state model of carcinogenesis, and a paradigm for ecologic risk assessment.
The use of the MTD in animal bioassays has been standard practice in the United States for more than 15 years, and controversy surrounding its use is not new. However, questions continue to be raised about the utility of the data derived from such tests and about the validity of inferences drawn from the data. Stimulated by the information presented in a workshop held on September 6, 1990, and discussions held at later meetings, CRAM has examined the issues related to the MTD. The first report in this volume contains its findings and recommendations on the issues. The workshop included presentations by Eugene McConnell on "Definition and Application of MTD," by Daniel Krewski on "Correction Between the MTD and Measures of Carcinogenic Potency: Implications for Risk Assessment," and by Bruce Ames on ''What Are Bioassays Conducted at the MTD Telling Us?" The program, a workshop summary, and a list of attendees appear as appendixes to the first report in this volume. Dr. Krewski's presentation summarized findings from a review paper with the same title, which was developed specifically for the work-
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Issues in Risk Assessment
shop. Invited to discuss the presentations were Edmund Crouch, Kenny Crump, John Emmerson, Reto Engler, Michael Gallo, David Gaylor, Ian Munro, Thomas Starr, James Wilson, and Lauren Zeise.
In the second report in this volume, CRAM examines the use of the two-stage model of carcinogenesis, which is based on a paradigm that is thought to reflect the biologic mechanisms underlying carcinogenesis, for human risk assessment. Like the use of the MTD, the use of empirically based mathematical models for evaluating the relationship between dose and response in rodent bioassays and extrapolating from high to low doses is standard. However, questions have been raised about the biologic relevance of such procedures and about the validity of human risk assessments based on the models. This report was based on information presented in a workshop held on November 8, 1990, and discussions held at later meetings. The workshop included presentations by Alfred Knudson on "Biological Factors in Two-Stage Models," by Suresh Moolgavkar on "Two-Stage Clonal Expansion Model of Carcinogenesis," and by Samuel Cohen on "Application of the Two-Stage Model to Animal Data." Invited to discuss those presentations were Carl Barrett, William Farland, Robert Maronpot, Robert Sielken, Todd Thorslund, and James Wilson.
The third report in this volume examines the overall process of ecological risk assessment and was stimulated by information presented at a workshop held on February 26-March 1, 1991, and discussions held at later meetings. The workshop included numerous speakers and discussants, whose goals were to survey existing approaches to ecological risk assessment, consider developing a consistent framework for ecological risk assessment, and identify major uncertainties and research needs. The keynote speakers were Terry Yosie, of the American Petroleum Institute; Michael Slimak, deputy director of the Office of Ecological Processes and Effects Research, U.S. Environmental Protection Agency; and Warner North, of Decision Focus, Inc., a member of the committee.
Some of the other reports being prepared by CRAM will re-evaluate established practices or principles in light of potential alternatives, and some will address new concepts to advance the science of risk assessment. It is hoped that the series of reports that result from the committee's deliberations will help scientists in regulatory agencies, academe, and industry to find common ground for defining, understanding, and discussing important ideas in the field.
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Issues in Risk Assessment
The conclusions and recommendations presented herein were arrived at by the committee in executive session. Thus, the scientific interpretations are those of committee members and not necessarily those of other participants in the workshops. The committee's reports were reviewed according to standard NRC practices, and the committee thanks the reviewers for their close attention and useful comments. The workshop summaries in the appendixes were prepared as working papers for the committee by the workshop organizers and participants; they are not NRC reports and have not been subjected to NRC review procedures.
The committee thanks the persons who participated in the workshops, especially the speakers, whose presentations provided important information for the consideration of the committee. Special thanks also are given to the members of the federal liaison group, whose names and affiliations are listed in the front of this report.
Two task groups of the committee took special responsibility for the workshops and reports. Although the entire committee shares the responsibility for the contents of the reports, the task-group members listed below must be credited for having done the key work of organizing the workshops and preparing their findings and recommendations for review and endorsement by the full committee.
No effort of this kind can be accomplished without the hard work and dedication of a talented staff. The committee joins me in thanking the following staff of the Board on Environmental Studies and Toxicology: James Reisa, Richard Thomas, Gail Charnley, Kathleen Stratton, Mary Paxton, Marvin Schneiderman, Anne Sprague, Ruth Danoff, and Linda Leonard.
Bernard Goldstein
Chairman, CRAM
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MTD and Two-Stage Model Task Group Members
Kenny S. Crump, Chairman, MTD
Richard A. Griesemer, Chairman, Two-Stage
Paul T. Bailey
Michael A. Gallo
Rogene Henderson
Donald R. Mattison
Richard H. Reitz
Ecological Risk Assessment Task Group Members
Lawrence W. Barnthouse, Chairman
Alan W. Maki
D. Warner North
Technical Advisers
Daniel Krewski
Lois Gold
Ian C.T. Nisbet
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Issues in Risk Assessment
Contents
PREFACE
ix
EXECUTIVE SUMMARY
1
USE OF THE MAXIMUM TOLERATED DOSE IN ANIMAL BIOASSAYS FOR CARCINOGENICITY
1
INTRODUCTION
15
Background,
15
Scope of Report,
18
2
CORRELATIONS BETWEEN CARCINOGENIC POTENCY AND OTHER MEASURES OF TOXICITY
21
Definitions and Background,
21
Correlations,
24
Relationship Between Toxicity and Carcinogenicity Observed at MTD,
33
3
ADVANTAGES AND DISADVANTAGES OF BIOASSAYS THAT USE THE MTD
43
Qualitative Information,
43
Quantitative Information,
49
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4
OPTIONS CONSIDERED
53
Option 1,
53
Option 2,
54
Option 3,
55
Option 4,
57
5
CONCLUSIONS AND RECOMMENDATIONS
61
REFERENCES
67
APPENDIXES
79
A Workshop Summary—Maximum Tolerated Dose: Implications for Risk Assessment,
79
B Workshop Organizing Subcommittee,
91
C Workshop Federal Liaison Group,
93
D Workshop Program,
95
E Workshop Attendees,
97
F Correlation Between Carcinogenic Potency and the Maximum Tolerated Dose: Implications for Risk Assessment,
111
G Informal Search for "Supercarcinogens,"
173
THE TWO-STAGE MODEL OF CARCINOGENESIS
ISSUES IN RISK ASSESSMENT
187
Introduction,
187
Biologic Considerations,
188
The Two-Stage Model,
190
Applications of the Two-Stage Model to Animal Data,
196
Discussion,
212
Conclusions and Recommendations,
215
REFERENCES
217
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APPENDIXES
A
Workshop Summary—Two-Stage Models of Carcinogenesis,
223
B
Workshop Program,
233
C
Workshop Federal Liaison Group,
235
D
Workshop Attendees,
237
E
Workshop Organizing Task Group,
239
A PARADIGM FOR ECOLOGICAL RISK ASSESSMENT
1
INTRODUCTION
243
2
SCOPE OF ECOLOGICAL RISK ASSESSMENT
247
3
REVISION OF 1983 FRAMEWORK TO INCORPORATE ECOLOGICAL RISK ASSESSMENT
249
Components of the 1983 Framework,
249
Consistency of Case Studies with the 1983 Framework,
251
Integration of Ecological Risk into the 1983 Framework,
254
Definition of Framework Components,
255
4
KEY SCIENTIFIC PROBLEMS LIMITING APPLICATION OF ECOLOGICAL RISK ASSESSMENT
259
Extrapolation Across Scales,
259
Quantification of Uncertainty,
261
Validation of Predictive Tools,
262
Valuation,
263
5
CONCLUSIONS
265
6
RECOMMENDATIONS
267
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REFERENCES
269
APPENDIXES
273
A
Workshop Participants,
273
B
Workshop Organizing Subcommittee and Federal Liaison Group,
279
C
Workshop Introduction,
281
D
Opening Plenary Presentations,
283
E
Case Studies and Commentaries,
293
F
Breakout Sessions,
309
G
Contemplations on Ecological Risk Assessment,
337
H
Workshop Summary,
343
I
References for Appendixes,
347
J
Workshop Program,
351
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