INTENTIONAL HUMAN DOSING STUDIES FOR EPA REGULATORY PURPOSES
SCIENTIFIC AND ETHICAL ISSUES
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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 study was supported by Contract No. 68-W-02-071, between the National Academies and the U.S. Environmental Protection Agency. The views presented in this report are those of the National Research Council Committee on the Use of Third Party Toxicity Research with Human Research Participants and are not necessarily those of the funding agencies.
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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. Bruce M. Alberts is president of the National Academy of Sciences.
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COMMITTEE ON THE USE OF THIRD PARTY TOXICITY RESEARCH WITH HUMAN RESEARCH PARTICIPANTS
JAMES F. CHILDRESS, Cochair (IOM), John Allen Hollingsworth Professor of Ethics, Professor of Medical Education, and Director,
Institute of Practical Ethics and Public Life, University of Virginia, Charlottesville, Virginia
MICHAEL R. TAYLOR, Cochair, Senior Fellow and Director,
Risk, Resource, and Environmental Management Division, Resources for the Future, Washington, D.C.
JAMES V. BRUCKNER, Professor of Pharmacology and Toxicology,
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia
ALICIA L. CARRIQUIRY, Associate Provost and Professor of Statistics,
Office of the Provost, Iowa State University, Ames, Iowa
ELLEN WRIGHT CLAYTON, Rosalind E. Franklin Professor of Genetics and Health Policy; Director of Genetics and Health Policy Center; Senior Fellow,
Institute for Public Policy Studies;
Professor of Pediatrics; Professor of Law,
Vanderbilt University, Nashville, Tennessee
JOHN DOULL, Professor Emeritus,
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
HENRY T. GREELY, C. Wendell and Edith M. Carlsmith Professor of Law; Professor, by courtesy, of Genetics; Co-director,
Program in Genomics, Ethics, and Society and Program in Law, Science, and Technology, Stanford University Law School, Stanford, California
SIOBAN D. HARLOW, Associate Professor; Associate Director,
International Institute; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan
LESTER B. LAVE (IOM), University Professor, the Harry B. and James H. Higgins Professor of Economics; Professor,
Engineering and Public Policy;
Green Design Initiative;
University Electricity Industry Center, Graduate School of Industrial Administration, Carnegie Mellon University, Pittsburgh, Pennsylvania
BERNARD LO (IOM), Professor of Medicine and Director,
Program in Medical Ethics, University of California, San Francisco, California
THOMAS A. LOUIS, Professor,
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
JOSEPH V. RODRICKS, Founding Principal,
ENVIRON International Corporation, Arlington, Virginia
CHRISTOPHER H. SCHROEDER, Charles S. Murphy Professor of Law and Public Policy Studies and Director,
Program in Public Law, Duke University Law School, Durham, North Carolina
ROBERT TEMPLE, Director,
Office of Medical Policy, Center for Drug Evaluation and Research;
Office of Drug Evaluation, U.S. Food and Drug Administration, Rockville, Maryland
Liaison to Science, Technology, and Law Program
DAVID KORN (IOM), Senior Vice President for Biomedical and Health Sciences Research,
Association of American Medical Colleges, Washington, D.C.
ANNE-MARIE MAZZA, Study Director
MICHELLE C. CATLIN, Senior Program Officer
KATHI E. HANNA, Consultant
STACEY E. SPEER, Senior Project Assistant
SARA DAVIDSON MADDOX, Editor
CAMILLE M. COLLETT, Research Associate (through March 2003)
SUSIE BACHTEL, Administrative Assistant (through August 2003)
The committee gratefully acknowledges the contributions of many individuals who provided invaluable information and data for the study:
Stanley H. Abramson, Arent Fox Kinter Plotkin & Kahn, PLLC; John Adgate, University of Minnesota; Stephen W. Brimijoin, Mayo Clinic; Angus Cameron, Roslin BioCentre; Arthur L. Caplan, University of Pennsylvania; Neil Carmichael, Bayer CropScience; Gail Charnley, HealthRisk Strategies; Ian Chart, AMVAC Chemical Corporation; Shelley Davis, Farm Worker Justice Fund; Michael L. Dourson, Technology Excellence for Risk Assessment; Monty Eberhart, Bayer CropScience; William H. Farland, U.S. Environmental Protection Agency; Daniel D. Federman, Harvard Medical School; Penelope A. Fenner-Crisp, International Life Sciences Institute; Lynn R. Goldman, Johns Hopkins Bloomberg School of Public Health; Suzanne T. Ildstad, University of Louisville; Stephen L. Johnson, U.S. Environmental Protection Agency; William Jordan, U.S. Environmental Protection Agency; Jeffrey P. Kahn, University of Minnesota; Nancy E. Kass, Johns Hopkins University Bloomberg School of Public Health; William Kelly, Center for Regulatory Effectiveness; Steven Lamm, Consultants in Epidemiology and Occupational Health, Inc.; Philip J. Landrigan, Mt. Sinai School of Medicine; Alan H. Lockwood, State University of New York; Judith A. MacGregor, Toxicology Consulting Services; Susan Makris, U.S. Environmental Protection Agency; Karen M. Martin, U.S. Environmental Protection Agency; Ray S. McAllister, CropLife America; Ernest E. McConnell, ToxPath, Inc.; Deidre L. Murphy, U.S. Environmental Protection Agency; Herbert L. Needleman, University of Pittsburgh Medical School; Erik D. Olson, Natural Resources Defense Council;
Jacqueline Patterson, Technology Excellence for Risk Assessment; Christopher J. Portier, National Institute of Environmental Health Sciences; Peter W. Preuss, U.S. Environmental Protection Agency; Jennifer Sass, Natural Resources Defense Council; Rita S. Schoeny, U.S. Environmental Protection Agency; Vera Hassner Sharav, Alliance for Human Research Protection; Bob Sielken, Sielken & Associates Consulting, Inc.; Christina B. Swartz, U.S. Environmental Protection Agency; Abraham J. Tobia, Bayer CropScience; Richard Wiles, Environmental Working Group; and Chris F. Wilkinson, C. Wilkinson, LLC.
This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process.
We wish to thank the following individuals for their review of this report: William Cain, University of California, San Diego; Daniel Farber, University of Minnesota; Penelope Fenner-Crisp, International Life Sciences Institute; Lynn Goldman, Johns Hopkins University; Bernard Goldstein, University of Pittsburgh; Fernando Guerra, San Antonio Metropolitan Health District; Carol Henry, American Chemistry Council; David Hoel, Medical University of South Carolina; Jeffrey Kahn, University of Minnesota; Mary Faith Marshall, Kansas University Medical Center; Thomas McGarity, University of Texas; Gary Rischitelli, Oregon Health and Science University; and Jonathan Samet, Johns Hopkins University.
Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by R. Alta Charo, University of Wisconsin, and Donald Mattison, National Institutes of Health. Appointed by the National Research Council, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
One of the Environmental Protection Agency’s (EPA’s) most important and difficult tasks is regulation of the use of chemicals in order to protect human health and the environment. For several years it has struggled to determine whether in discharging this responsibility it should consider, accept, and rely on data from third-party studies that deliberately expose humans to toxicants. In accepting EPA’s request for assistance in resolving this question, the National Academy of Sciences established an interdisciplinary committee under the auspices of the Science, Technology, and Law Program to prepare a report and make recommendations.
EPA’s difficulty—and the committee’s difficulty—in resolving this question arises from several conflicting interests and social values. For many the idea of research that intentionally exposes humans to toxicants is repugnant. Yet for others the potential of such studies to define more accurately human risk makes them worthwhile and acceptable. Recognizing the range of views, the committee proceeded to analyze and assess the arguments for and against intentional human dosing studies. Supporters of these studies see them as similar to Phase 1 drug trials, which expose participants to chemicals without the prospect of direct benefit to them and which can be ethically justified if they assiduously follow certain standards and procedures, such as those embedded in the Common Rule. However, critics contend that third-party studies conducted for EPA regulatory purposes, but not conducted or sponsored by EPA, usually fail to follow those standards and procedures. Defenders of human dosing studies hold that they can provide scientific data that are more relevant for
regulatory purposes than data from animal studies, while critics charge that most of these studies lack scientific validity and, in any event, see little benefit in raising acceptable limits for toxicants, the usual purpose of such studies. These conflicting views represent a sample of the concerns, found among members of the committee as well as in society at large, that have animated the debate.
Like other groups that have addressed this subject, we note that such testing should be approached with the utmost caution and care. This committee consisted of members with expertise in ethics, law, pharmacology, toxicology, genetics, pediatrics, statistics/biostatistics, economics, epidemiology, risk assessment, and clinical trials. We met 6 times over 12 months in open and closed sessions and invited testimony from a number of individuals. In addition, we convened one public forum on January 8, 2003, to receive public input on the topics under consideration. During the course of the study, we received and reviewed voluminous studies voluntarily provided by a number of pesticide companies that had previously conducted intentional dosing studies and submitted their results to EPA for consideration. Some of these submissions were complete files on a particular chemical, while others were partial files. All of these materials were placed in the National Academies’ public access file for this project.
In addition, committee staff filed a Freedom of Information request with EPA for all information relevant to the intentional dosing studies that had been submitted to the Office of Pesticide Programs. Committee staff reviewed these studies and briefed the full committee on their findings. In addressing EPA’s questions, members of the committee read and listened carefully and thought rigorously and imaginatively about the recommendations that could be made and the rationale for those recommendations. As a result, every member of the committee changed his or her mind on some important topic in this report in the course of the extended and intense discussions and deliberations. As cochairs of this committee, we express our deep gratitude to committee members and staff, all of whom devoted enormous time and intellectual energy to the development of this report.
James F. Childress and Michael R. Taylor
List of Tables and Boxes
Relevant Pesticide Studies Received by EPA Since April 1991,
Federal Agencies Subject to the Common Rule,
Legal Statutes for EPA Regulation of Chemicals,
Four-Step Process for Human Health Risk Assessment,
Common Rule Requirements for IRB Review,
Specific Statement of Task,
Committee’s Use of Risk Terminology for Data Derived from Intentional Human Dosing Studies,
Criteria for Judging the Adequacy of the Scientific Justification for Intentional Human Dosing Studies,
Examples of Study Designs That Identify a NOELHU,
Committee’s Use of Risk Terminology for Data Derived from Intentional Human Dosing Studies,
U.S. Department of Health, Education, and Welfare
U.S. Department of Health and Human Services
Data Monitoring Committee
Data and Safety Monitoring Board
U.S. Environmental Protection Agency
U.S. Food and Drug Administration
Federal Food, Drug, and Cosmetic Act
Federal Insecticide, Fungicide, and Rodenticide Act
Food Quality and Protection Act
Good Clinical Practice
Human Equivalent Dose
Investigational New Drug
Institute of Medicine
Institutional Review Board
Integrated Risk Information System
Lowest Observed Adverse Effect Level
Lowest Observed Effect Level
Maximally Tolerated Doses
National Academy of Sciences
National Bioethics Advisory Commission
National Committee on Quality Assurance
National Institutes of Health
No Observed Adverse Effect Level
No Observed Effect Level
National Research Council
Office for Human Research Protections
Office of Inspector General
Office for Protection from Research Risks
U.S. Public Health Service
Recombinant DNA Advisory Committee
Science Advisory Board
Science Advisory Panel
Toxic Substance Control Act
Volatile Organic Chemicals