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OCR for page R1
Toxicity Testing
Strategies to Determine
Needs and Priorities
Steering Committee on identification of Toxic and Potentially Toxic
Chemicals for Consicleration by the National Toxicology Program
Board on Toxicology and Environmental Health Hazarcis
Commission on Life Sciences
National Research Council
NATIONAL ACADEMY PRESS
Washington, D. C. 1984
/
OCR for page R2
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 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 Research Council was established 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 of advising the
federal government. The Council operates in accordance with general policies
determined by the Academy under the authority of its congressional charter of
1863, which establishes the Academy as a private, nonprofit, self-governing
membership corporation. The Council has become the principal operating agency
of both the National Academy of Sciences and the National Academy of
Engineering in the conduct of their services to the government, the public,
and the scientific and engineering communities. It is administered jointly by
both Academies and the Institute of Medicine. The National Academy of
Engineering and the Institute of Medicine were established in 1964 and 1970,
respectively, under the charter of the National Academy of Sciences.
The work on which this publication is based was performed pursuant to
Contract NO1-ES-0-0008 with the National Toxicology Program.
Library of Congress Catalog Card Number 84-60095
International Standard Book Number 0-309-03433-7
Printed in the United States of America
OCR for page R3
STEERING COMMITTEE ON IDENTIFICATION OF TOXIC AND POTENTIALLY TOXIC
CHEMICALS FOR CONSIDERATION BY THE NATIONAL TOXICOLOGY PROGRAM
James L. Whittenberger, Chairman
Southern Occupational Health Center
University of California
Irvine, California
John C. Bailar
School of Public Health
Harvard University
Boston, Massachusetts
John Doull
Department of Pharmacology
University of Kansas Medical Center
Kansas City, Kansas
Emil A. Pfitzer
Department of Toxicology and
Experimental Pathology
Hoffman-LaRoche, Inc.
Nutley, New Jersey
Arthur C. Upton
Institute of Environmental Medicine
New York University Medical Center
New York, New York
Staff
Robert G. Tardiff
Project Director (until July 1983)
Alvin G. Lazen
Project Director (from July 1983)
Norman Grossblatt
Editor
Jacqueline K. Prince
Staff Assistant
· · ~
111
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COMMITTEE ON STATISTICAL SAMPLING METHODS
(Conunittee on Sampling Strategies)
John C. Bailar, Chairman
Department of Biostatistics
Harvard School of Public Health
Boston, Massachusetts
William W. Carlton
Department of Veterinary Microbiology
Purdue University
Lafayette, Indiana
Bernard D. Goldstein
Department of Environmental and
Community Medicine
University of Medicine and Dentistry
of New Jersey/Rutgers Medical School
Piscataway, New Jersey
William D. Kalsbeek
Population Laboratories
University of North Carolina
Chapel Hill, North Carolina
Richard D. Remington
Office of the Vice President
for Academic Affairs
University of Iowa
Iowa City, Iowa
Benjamin Tepping
Silver Spring, Maryland
William L. Wagner
Rocky Mountain Center for Occupational
and Environmental Health
University of Utah
Salt Lake City, Utah
Joseph Waksberg
Westat, Inc.
Rockville, Maryland
Staff
Scott R. Baker
Project Director
Resha M. Putzrath
Staff Officer (until September 1983)
iv
Michele W. Zinn
Administrative Assistant
Shirley A. Perry
Secretary
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COMMITTEE ON CHARACTERI ZATION OF STATUS OF TOXICITY
DATA ELEMENTS E OR A SELECT UNIVERSE OF COMPOUNDS
(Committee on Toxicity Data Elements)
John Doull, Co-Chairman
Department of Pharmacology
University of Kansas Medical Center
Kansas City, Kansas
Emil A. Pfitzer, Co-Chairman
Department of Toxicology and Pathology
Hoffmann-LaRoche, Inc.
Nutley, New Jersey
Eula gingham
Kettering Laboratory
University of Cincinnati Medical Center
Cincinnati, Ohio
David J. Brusick
Department of Genetics
Litton Bionetics Research Laboratory
Kensington, Maryland
George T. Bryan
Department of Human Oncology
Clinical Science Center
Madison, Wisconsin
Robert T. Drew
Medical Department
Brookhaven National Laboratory
Upton, New York
E. Marshall Johnson
College of Medicine
Comas Jefferson University
Philadelphia, Pennsylvania
Morton Lippmann
Aerosol and Inhalation Research Laboratory.
New York University
New York, New York
Stat f
Scott R. Baker
Project Director
Gordon W. Newell
Project Director ( until October 1981)
Barbara B. Jaf fe
Senior Staff Officer (until July 1983)
Resha M. Putzzath
Staff Officer (until September 1983)
Comas Mack
Cancer Surveillance Program
University of Southern California
School of Medicine
Los Angeles, California
Gilbert J. Mannering
Department of Pharmacology
University of Minnesota
Minneapolis, Minnesota
Donald E. McHillan
Department of Pharmacology
University of Arkansas
Little Rock, Arkansas
Robert A. Neal
Chemical Industry Institute
of Toxicology
Research Triangle Park, North Carolina
Edward O. Oswald
Department of Environmental
Health Sciences
University of South Carolina
Columbia, South Carolina
Marvin A. Schneiderman
Clement Associates
Washington, D.C.
Carrol S. Well
Carnegie-Mellon Institute
of Research
Carnegie-Mellon University
Pittsburgh, Pennsylvania
Hanspeter R. Witschi
Biology Division
Oak Ridge National Laboratory
Oak Ridge, Tennessee
Leslye B. Giese
Research Assistant
Ronnie M. Good
Bibliographic Assistant
Michele W. Zinn
Administrative Assistant
Shirley A. Perry
Secretary
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COMMITTEE ON RESEARCH OF AGENTS
POTENTIALLY HAZARDOUS TO HUMAN HEALTH
(Committee on Priority Mechanisms)
Arthur C. Upton, Chairman
Institute of Environmental Medicine
New York University Medical Center
New York, New York
Bernard D. Astill
Health, Safety and Human Factors
Laboratory
Eastman Kodak Company
Rochester, New York
Stephen L. Brown
Center for Health and
Environmental Research
SRI International
Menlo Park, California
Patricia A. Buffler
School of Public Health
University of Texas
Houston, Texas
Richard M. Cooper
Williams and Connolly
Washington, D.C.
Baruch Fischhoff
Decision Research, Inc.
Eugene, Oregon
Corwin H. Hansch
Department of Chemistry
Pomona College
Claremont, California
Sheldon D. Murphy
Department of Pharmacology
University of Texas Medical School
Houston, Texas
Michael R. Overcash
Department of Chemical Engineering
North Carolina State University
Raleigh, North Carolina
Talbot R. Page
Environmental Quality Laboratory
California Institute of Technology
Pasadena, California
V1
Verne A. Ray
Medical Research Laboratory
Pfizer, Inc.
Groton, Connecticut
Harold R. Ward
Center for Environmental
Studies
Brown University
Providence, Rhode Island
Staff
Samuel B. McKee
Project Director
Walter G. Rosen
Project Director (until July 1983)
Azora L. Irby
Secretary
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BOARD ON TOXICOLOGY AND ENVIRONMENTAL HEALTH HAZARDS
Gerald N. Wogan, Chairman
Department of Nutrition and Food
Science
Massachusetts Institute of Technology
Cambridge, Massachusetts
Philip J. Landrigan, Co-Vice-Chairman
National Institute for Occupational
Safety and Health
Cincinnati, Ohio
Donald F. Hornig, Co-Vice-Chairman
School of Public Health
Harvard University
Boston, Massachusetts
Edward Bresnick
Eppley Institute for Cancer Research
University of Nebraska Medical Center
Omaha, Nebraska
Herman N. Eisen
Department of Biology
Massachusetts Institute of Technology
Cambridge, Massachusetts
Ronald W. Estabrook
Department of Biochemistry
University of Texas Medical School
Dallas, Texas
Emmanuel Farber
Department of Pathology
University of Toronto
Toronto, Ontario
David G. Hoel
Biometry and Risk Assessment Program
National Institute of Environmental
Health Sciences
Research Triangle Park, North Carolina
Michael W. Lieberman
Deparment of Pathology
Washington University
St. Louis, Missouri
vii
Abraham M. Lilienfeld
School of Hygiene and Public Health
The Johns Hopkins University
Baltimore, Maryland
Richard Merrill
School of Law
University of Virginia
Charlottesville, Virginia
Vaun A. Newill
Medicine and Environmental
Health Department
Exxon Corporation
New York, New York
John Peters
Department of Preventive Medicine
University of Southern California
Los Angeles, California
Joseph V. Rodricks
Environ Corporation
Washington, D.C.
Liane B. Russell
Biology Division
Oak Ridge National Laboratory
Oak Ridge, Tennessee
Ellen Silbergeld
Environmental Defense Fund
Washington, D.C.
Ex Officio
Gary P. Carlson
Department of Pharmacology
and Toxicology
Purdue University
Lafayette, Indiana
Maureen M. Henderson
Department of Epidemiology
University of Washington
Seattle, Washington
OCR for page R8
Roger 0. McClellan
Lovelace Inhalation Toxicology
Research Institute
Albuquerque, New Mexico
Daniel Menzel
Departments of Pharmacology and Medicine
Duke University Medical Center
Durham, North Carolina
Norton Nelson
Institute of Environmental Medicine
New York University Medical Center
New York, New York
Staff
Devra Lee Davis, Executive Director
Jacqueline K. Prince, Staff Assistant
Shirley A. Ash, Administrative Secretary
mini
OCR for page R9
PREFACE
In September 1980, the National Toxicology Program (NTP), through the
National Institute of Environmental Health Sciences, contracted with the
National Research Council (NRC) and the National Academy of Sciences for
study with two principal charges:
(1) To characterize the toxicity-testing needs for substances to
which there is known or anticipated human exposure' so that federal
agencies responsible for the protection of public health will have the
appropriate information needed to assess the toxicity of such substances.
(2) To develop and validate uniformly applicable and w~de-ranging
criteria by which to set priorities for research on substances with
potentially adverse public-heath impact.
me study, titled "Identification of Toxic and Potentially Toxic
Chemicals for Consideration by the National Toxicology Program," was
established in the Board on Toxicology and Environmental Health Hazards
of the NRC's Commission on Life Sciences.
A Steering Committee was formed to address the charges and coordinate
the efforts of three operating committees. The Committee on Statistical
Sampling Methods ("Committee on Sampling Strategies") and the Committee
on Characterization of the Status of Toxicity Data Elements ("Committee
on Toxicity Data Elements") addressed the first charge. The Committee on
Research of Agents Potentially Hazardous to Human Health ("Committee on
Priority Mechanisms") addressed the second charge.
m e two charges of the study involved concepts with many
similarities, but they also required different approaches. The first
charge--to characterize the status of toxicity-testing information on
substances--required a detailed examination of existing toxicity data
based on available criteria for qualitative and quantitative
characteristics of adequacy. The approach required judgments on the
adequacy of testing of specific substances, independently of whether the
substances were potent agents or relatively inert substances with low
toxicity. The second charge--to develop criteria for setting research
priorities--required a detailed examination of methods of selecting
potentially toxic substances from a large universe of substances on which
there was little or no toxicity information. The approach required
judgments on the predictability of testing procedures, the nature and
severity of potential toxic effects, and the systemic modeling of steps
in decision-making.
This is the final report of the four committees. It represents the
work of their members, NRC staff, a large number of consultants, ano
others who provided invaluable assistance to the committees. This report
is designed to be a stand-alone document, summarizing and synthesizing
1X
OCR for page R10
the full scope of work first described at two interim stages of evolution
in documents entitled Strategies to Determine Needs and Priorities for
Toxicity Testing--Volume 1: Design and Volume 2: Development. These
earlier reports were published at the end of the first and second years
of the study.
The activities to address the two charges were conducted with
substantial interchange of concepts and practices, but they were
recognized to be sufficiently different in approach to warrant
presentation as two distinct parts. The specific differences are
presented in a final appendix to Part 2. The reader should be aware of
this intent when reading Parts 1 and 2 of this report.
We of the Steering Committee thank all the participants, who have
contributed so much to this study. The amount of work performed
indicates the magnitude of the task that faces NTP. In particular, we
wish to recognize the enormous effort dedicated to this study by the
three operating committees and the NRC staff. The dossiers containing
the analyses of all toxicity data that were available on a subsample of
100 substances constitute approximately 2 cubic meters of decision-making
information. me collection, analysis, and interpretation of information
on just this small number of substances in general use required thousands
of hours of the time of volunteer committee members, the staff, and other
participants over a 3-year period. The thoughtfulness and computer work
needed to select the study samples and model the criteria for
priority-setting required no less intensive an effort.
The large scope of work addressed by the committees could not have
been accomplished without the assistance of the skilled and dedicated
staff of the Board on Toxicology and Environmental Health Hazards. We
wish to thank Robert G. Tardiff, who was project director for this study
during his tenure with the Board, and Alvin G. Lazen, who was associated
with the study in its last stages. We also thank Scott R. Baker for his
important contributions to the "needs" section of this report and Samuel
B. McKee and Walter G. Rosen for their work on the "priorities" section;
Lamar B. Dale, Leslye R. Giese, Ronnie M. Good, Norman Grossblatt, Cheryl
J. Haily, Veronica C. Harris, Azora L. Irby, Barbara B. Jaffe, Paula H.
Morris, Gordon W. Newell, Shirley A. Perry, Frances M. Peter, Jacqueline
K. Prince, Resha M. Putzrath, Joyce A. Russell, Patricia A. Sterling,
Robert J. Comas, and Michele W. Zinn for their professional and
administrative contributions; and Andrew M. Pope, Gerald M. Rosen, and
Jeannee K. Yermakoff for their contributions while they were serving as
National Research Council Fellows.
We are particularly grateful for the assistance provided by Raymond
E. Shapiro, who served as the study's project officer for NTP.
1
James L. Whittenberyer' Chairman
John C. Bailar
John Doul1
Emil A. Pfitzer
Arthur C. Upton
x
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ACKNOWLEDGMENTS
Valuable contributions to this study were made by Steven Wilhelm
and Yvonne Hales, who served as technical consultants, and by Lynn
Jones, Nora Riley, and Janice Miller, who assisted in the acquisition
of documents.
The following colleagues in both the public and private sectors
generously shared information, resource material, and expertise:
Wellman Bachtel, Susan Bloodworth, Miles Bogle, Keith Booman, Edward
Brooks, Dorothy Canter, Michael Conners, Paul Craig, Sonia Crisp,
Denny Daniels, Karen Dickerson, David Disbennett, Ronald Dunn, Donald
Dunnom, Robert Elder, Curt Enslein, Norman Estrin, Theodore Farber,
Kenneth Fisher, Gary Flamm, Richard Ford, Vasilios Frankos, John
Froines, Vera Glocklin, John Gordon, Martin Greif, Allen Heim, Joseph
Highland, Louis Hades, David Hoel, Maurice Hubert, Vera Hudson, Julius
Johnson, Judy Jones, Henry Kissman, Mary Rose Kornreich, Raymona
Kukol, Ann McCann, Arthur McCreesch, Jerald McEwan, Carolyn McHale,
Joseph Merenda, Mary Lou Miller, William Milne, Victor Morgenroth,
Therese Murtaugh, Ian Nisbet, William Olson, Donald Opdyke, Norbert
Page, William Payne, Alan Rulis, Andrew Sage, Virginia Salzman,
Phillip Sartwell, Takashi Sugimura, John Tinker, Justine Welch, and
Karen Wetterhahn.
xi
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CONTENTS
EXECUTIVE SUMMARY
INTRODUCTION
PART 1: TOXICITY-TESTING NEEDS IN THE SELECT UNIVERSE
Contents to Part 1
PART 2: SETTING PRIORITIES FOR TOXICITY TESTING
Contents to Part 2
xiii
Page
1
19
23
199
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