Cover Image

HARDBACK
$59.95



View/Hide Left Panel

DIETARY SUPPLEMENTS

A FRAMEWORK FOR EVALUATING SAFETY

Committee on the Framework for Evaluating the Safety of Dietary Supplements

Food and Nutrition Board

Board on Life Sciences

INSTITUTE OF MEDICINE AND NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES
Washington, D.C.
www.nap.edu



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety DIETARY SUPPLEMENTS A FRAMEWORK FOR EVALUATING SAFETY Committee on the Framework for Evaluating the Safety of Dietary Supplements Food and Nutrition Board Board on Life Sciences INSTITUTE OF MEDICINE AND NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES Washington, D.C. www.nap.edu

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety 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 study was supported by Contract Number 223-00-2458 between the National Academy of Sciences and the Food and Drug Administration. Additional support came from Institute of Medicine internal funds. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project. Library of Congress Cataloging-in-Publication Data Dietary supplements : a framework for evaluating safety / Committee on the Framework for Evaluating the Safety of Dietary Supplements, Food and Nutrition Board [and] Board on Life Sciences. p. ; cm. Includes bibliographical references and index. ISBN 0-309-09110-1 (hardcover) 1. Dietary supplements—Evaluation. 2. Dietary supplements—Toxicology. [DNLM: 1. United States. Food and Drug Administration. 2. Dietary Supplements—standards—United States. 3. Safety—United States. 4. Government Regulation—United States. 5. Product Surveillance, Postmarketing—methods—United States. QU 145.5 D5639 2004] I. Committee on the Framework for Evaluating the Safety of Dietary Supplements. RM258.5.D543 2004 613.2′8—dc22 2004022339 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2005 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. Cover photo of red ginger taken by Dr. Aniko Solyom, University of Arizona.

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety 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. 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. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety COMMITTEE ON THE FRAMEWORK FOR EVALUATING THE SAFETY OF DIETARY SUPPLEMENTS BARBARA O. SCHNEEMAN (Chair), Departments of Nutrition and Food Science, Division of Clinical Nutrition and Metabolism, and Office of University Outreach, University of California, Davis DANIEL L. AZARNOFF, D.L. Azarnoff Associates and Clinical/ Regulatory Affairs, Cellegy Pharmaceuticals, South San Francisco, California CINDY LYNN CHRISTIANSEN, Center for Health Quality, Outcomes, and Economic Research, Bedford V.A. Hospital, and Boston University School of Public Health, Massachusetts ALICE M. CLARK, Office of Research and Sponsored Programs, University of Mississippi, Oxford NORMAN R. FARNSWORTH, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago TED GANSLER, Medical Information Strategy, American Cancer Society, Atlanta, Georgia JAMES E. GIBSON, Department of Pharmacology and Toxicology, The Brody School of Medicine at East Carolina University, North Carolina STEPHEN A. GOLDMAN, Stephen A. Goldman Consulting Services, LLC, Morris Plains, New Jersey PHILIP S. GUZELIAN, Department of Medicine, University of Colorado Health Sciences Center, Denver ELIZABETH JEFFERY, Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign LOREN D. KOLLER, Loren Koller and Associates, LLC, Corvallis, Oregon JOSEPH LAU, Institute for Clinical Research and Health Policy Studies, Tufts New England Medical Center, Boston, Massachusetts RUSSELL J. MOLYNEUX, USDA Western Regional Research Center, Albany, California SUSAN S. PERCIVAL, Department of Food Science and Human Nutrition, University of Florida, Gainesville CHERYL L. ROCK, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla JERROLD M. WARD, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety Consultants LEWIS A. GROSSMAN, Washington College of Law, American University, Washington, D.C. JOSEPH RODRICKS, ENVIRON International, Arlington, Virginia Staff ALLISON A. YATES, Study Director MARILEE SHELTON-DAVENPORT, Program Officer JANICE OKITA, Program Officer CRYSTAL RASNAKE, Research Assistant SANAIT TESFAGIORGIS, Senior Project Assistant

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety PROTOTYPE MONOGRAPHS Chaparral Consultants CYNTHIA K. ARON, University of Massachusetts Memorial Medical Center, Worcester MARILYN BARRET, Pharmacognosy Consulting Services, San Carlos, California CARL K. WINTER, Department of Food Science and Technology, University of California, Davis Chromium Picolinate Consultants AARON BARCHOWSKY, Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire MAX COSTA, Department of Environmental Medicine, New York University Medical School, New York City JIM K. LIU, College of Pharmacy, University of New Mexico, Albuquerque STEVEN R. PATIERNO, Department of Pharmacology, George Washington University School of Medicine, Washington, D.C. STEVEN R. SMITH, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge BARBARA STOECKER, Department of Nutritional Sciences, Oklahoma State University, Stillwater Glucosamine Consultants H.B. “SKIP” MATTHEWS, Consultant, Hertford, North Carolina TIMOTHY EDWARD McALINDON, Boston University School of Medicine, Massachusetts DONALD ALLAN McCLAIN, Division of Endocrinology and Metabolism, University of Utah School of Medicine, Salt Lake City Melatonin Consultants ANITA CAVALLO, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio STANLEY T. OMAYE, Department of Nutrition, University of Nevada, Reno PHYLLIS C. ZEE, Neurobiology and Physiology, Northwestern University Institute for Neuroscience, Chicago, Illinois

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety Saw Palmetto Consultants SHUTSUNG LIAO, Ben May Institute, University of Chicago, Chicago, Illinois LEONARD S. MARKS, Urological Sciences Research Foundation, Culver City, California STEPHEN H. SAFE, Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station Shark Cartilage Consultants SAMUEL M. COHEN, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha SUSAN E. CRAWFORD, Department of Pathology, Northwestern University Medical School, Chicago, Illinois JOSEPH A. SCIMECA, General Mills, Inc., St. Louis Park, Minnesota KIN-PING WONG, College of Science and Mathematics, California State University, Fresno

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety FOOD AND NUTRITION BOARD CATHERINE E. WOTEKI (Chair), College of Agriculture, Iowa State University, Ames ROBERT M. RUSSELL (Vice Chair), Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts LARRY R. BEUCHAT, Center for Food Safety, University of Georgia, Griffin SUSAN FERENC, SAF*Risk, LC, Madison, Wisconsin NANCY F. KREBS, Department of Pediatrics, University of Colorado Health Sciences Center, Denver SHIRIKI KUMANYIKA, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia REYNALDO MARTORELL, Rollins School of Public Health, Emory University, Atlanta, Georgia LYNN PARKER, Child Nutrition Programs and Nutrition Policy, Food Research and Action Center, Washington, D.C. BARBARA O. SCHNEEMAN, Department of Nutrition, University of California, Davis NICHOLAS J. SCHORK, Polymorphism Research Laboratory, University of California, San Diego JOHN W. SUTTIE, Department of Biochemistry, University of Wisconsin, Madison STEVE L. TAYLOR, Department of Food Science and Technology and Food Processing Center, University of Nebraska, Lincoln BARRY L. ZOUMAS, Department of Agricultural Economics and Rural Sociology, Pennsylvania State University, University Park Staff LINDA D. MEYERS, Director starting October 2003 ALLISON A. YATES, Director through September 2003 GERALDINE KENNEDO, Administrative Assistant GAIL SPEARS, Staff Editor ELISABETH RIMAUD, Financial Associate

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety BOARD ON LIFE SCIENCES COREY S. GOODMAN (Chair), Department of Molecular and Cell Biology, University of California, Berkeley RUTH BERKELMAN, Rollins School of Public Health, Emory University, Atlanta, Georgia R. ALTA CHARO, Law and Medical Ethics, University of Wisconsin, Madison JOANNE CHORY, The Salk Institute for Biological Studies, La Jolla, California JEFFREY L. DANGL, Department of Biology, University of North Carolina, Chapel Hill PAUL EHRLICH, Department of Biological Sciences, Stanford University, Palo Alto, California JAMES M. GENTILE, Natural Science Division, Hope College, Holland, Michigan LINDA E. GREER, Natural Resources Defense Council, Washington, D.C. ED HARLOW, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts DAVID HILLIS, Institute for Cellular and Molecular Biology, University of Texas, Austin KENNETH F. KELLER, Humphrey Institute of Public Affairs, University of Minnesota, Minneapolis RANDALL MURCH, Institute for Defense Analyses, Alexandria, Virginia ROBERT T. PAINE, Department of Zoology, University of Washington, Seattle GREGORY A. PETSKO, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts STUART L. PIMM, Nicholas School of Environmental and Earth Sciences, Duke University, Durham, North Carolina BARBARA A. SCHAAL, Department of Biology, Washington University, St. Louis, Missouri JAMES TIEDJE, Center for Microbial Ecology, Michigan State University, East Lansing KEITH YAMAMOTO, Department of Cellular and Molecular Pharmacology, University of California, San Francisco Staff FRANCES SHARPLES, Director MARILEE SHELTON-DAVENPORT, Program Officer

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety This page intentionally left blank.

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety Preface The Committee on the Framework for Evaluating the Safety of Dietary Supplements was asked to develop a framework for use by the Food and Drug Administration (FDA) to evaluate the safety of dietary supplement ingredients (see Appendix B for scope of work). It was to include, from a science-based perspective, a system for prioritizing review of dietary supplement ingredients that could be extended to new ingredients as notifications regarding intent to market are submitted by manufacturers. Although evaluation of data regarding the efficacy of such ingredients to maintain health is of interest to many, a review of these data was specifically not included in the charge to the committee. Once a proposed framework was constructed, FDA requested that it be made available to the dietary supplement industry and other stakeholders for review and comment. In addition, it requested that six prototype safety monographs be developed using the proposed framework. In July 2002, the proposed framework was released for comment, along with the list and a brief rationale for which six dietary supplement ingredients were to undergo a safety review and development of a prototype safety monograph. The committee valued the input received regarding the workability and utility of the proposed framework (see summary in Appendix B). Subsequently, new members with expertise in toxicology, natural product chemistry, pharmacokinetics, and pharmacoepidemiology were added to the committee and several aspects of the proposed framework were revised. Included in the proposed framework released in July 2002 was a requirement that, prior to the completion of a monograph, there would be a sharing of information obtained to date on the dietary supplement ingredi-

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety ent under review and a request for additional information regarding its safety. Thus during the fall and early spring of 2002–2003, comments were received on the six prototype monographs as well as on the framework itself. What follows in this report is a framework for prioritizing and evaluating the safety of dietary supplements based on existing information available to FDA and others. This framework, the primary work of the committee, was developed in the context of the current law regulating dietary supplements, the Dietary Supplement Health and Education Act of 1994 (DSHEA). It has been nearly 10 years since Congress passed DSHEA, and considerable experience has been gained in attempting to protect public health under its provisions. Consequently, in the process of completing our task, the committee identified several ways that the law could be more effective in meeting the goal of protecting public health, and these findings and recommendations are included in this report. Although some might consider such recommendations to be outside the scope of the task, the committee felt it had gained valuable insight into this challenging task through its work on the framework and felt it was important to convey this information to policy-makers. Although this study is under the primary management of the staff of the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM), it has been conducted as a collaborative project within the National Academies by the FNB and the Board on Life Sciences (BLS) of the Division of Earth and Life Studies of the National Research Council (NRC). The committee was assisted in its task by the invaluable contributions of a number of individuals. Christine Lewis Taylor, Ph.D., Director of FDA’s Office of Nutritional Products, Dietary Supplements, and Labeling and the FDA’s Project Officer for this project; Susan Walker, M.D., Director of the Division of Dietary Supplement Programs; and Elizabeth Yetley, Ph.D., Lead Scientist for Nutrition, all from the Center for Food Safety and Applied Nutrition of FDA, met with the committee in open session at almost every meeting to respond to questions and provide insight into what would be useful to the agency in developing the framework. We appreciated their clear presentations about the committee’s task. The committee also recognizes the significant contributions made by two former members of the committee, Lars Noah of the University of Florida and Adriane Fugh-Berman of George Washington University, who resigned during the development of the initial report released for comment in 2002; their insights were very valuable to the initial thinking of the proposed process. We also gratefully acknowledge the significant assistance of the four consultants: Dr. Kenneth Fisher, now with the Office of Dietary Supplements at the National Institutes of Health, who assisted in the early development of the proposed framework report; Dr. Edward Bortnichak,

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety Sanofi-Synthelabo, who was also involved in the early phases; Mr. Lewis Grossman, American University, who came into the project to assist after Mr. Noah resigned and guided us through the areas of food and drug law; and Dr. Joseph Rodricks of Environ International, who provided significant assistance in how risk assessment and toxicology are applied to chemicals and other substances. We also gratefully appreciate the assistance of Stephen F. McNamara of Hyman, Phelps, and McNamara, for his early technical review of Chapter 1. During the development of the prototype monographs, we were fortunate to have outstanding experts as consultants who participated in the working groups on the ingredients reviewed. Their input was invaluable for the monograph development which also helped the committee rethink aspects of the framework. These experts are listed in the front of this report, and we do appreciate their assistance. The committee was greatly assisted by the very able work of Dr. Marilee Shelton-Davenport, program officer for BLS, who has provided major and critical assistance in the management and conceptual development of the framework; her efforts to move the project forward have been key to the process. Dr. Janice Rice Okita, who served as the monographer for the project, provided the resources, knowledge, and organizational skills to help the working groups complete their tasks in a timely manner. Throughout all aspects of the project Dr. Allison A. Yates, Study Director, has provided valuable insight and input for accomplishing the task of the committee. We also greatly appreciate the able and dedicated assistance of FNB research associates Alice Vorosmarti and Vivica Kraak, as well as senior project assistant Sybil Boggis, who assisted in the early phases with the proposed framework, and most recently the significant dedication and assistance of Crystal Rasnake, research assistant for the second phase of the study and for the monograph documentation. Thanks also go to Sanait Tesfagiorgis, senior project assistant, who assisted with the completion of this final report; Gail Spears for her editorial assistance; Gary Walker and Elisabeth Rimaud for financial management; and members of IOM’s Office of Reports and Communication for assistance in the production and dissemination of the report. 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 delibera-

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety tive process. We wish to thank the following individuals for their review of this report: Neal L. Benowitz, University of California, San Francisco; Joseph M. Betz, National Institutes of Health; Steven Dentali, Dentali Associates; John Edgar, Honorary Fellow, CSIRO Livestock Industries; Kenneth D. Fisher, KD Consultants; Freddie Ann Hoffman, HeteroGeneity, LLC; Marvin M. Lipman, Consumers Union of U.S., Inc.; Richard A. Merrill, The University of Virginia and Covington & Burling; Robert M. Russell, Tufts University; Meir Stampfer, Harvard University; Brian L. Strom, University of Pennsylvania; and Roy Upton, American Herbal Pharmacopoeia. 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 Sanford A. Miller, Virginia Polytechnic Institute and State University, coordinator, appointed by the IOM, and Ronald Estabrook, The University of Texas Southwestern Medical Center at Dallas, monitor, appointed by the NRC’s Report Review Committee. The coordinator and monitor 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. As a final note, I extend the appreciation and respect of the committee to our Study Director, Dr. Allison Yates, as she completes her position of director of the Food and Nutrition Board and wish her the best in future endeavors. I personally am grateful to my fellow committee members for their commitment to the work of the committee under a rather demanding time schedule. Their quick and constructive responses to the many drafts of the report, their respect for each other’s opinion and willingness to find common ground, has made the task possible. It has been a pleasure to work with this entire group. Barbara O. Schneeman Committee Chair

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety Contents     EXECUTIVE SUMMARY   1 1   INTRODUCTION AND BACKGROUND   19      Committee Charge,   21      General Background Information About Dietary Supplements,   22      References,   39 2   APPROACHES USED BY OTHERS AND EXISTING SAFETY FRAMEWORKS   43      Resources on Dietary Supplements,   44      Consideration of Frameworks for Evaluating the Safety of Other Substances,   79      Summary,   81      References,   81 3   THE FRAMEWORK   85      Considerations in Designing the Framework,   85     I.   The Process,   86     II.   Applying Science-Based Principles to Establish Risk,   100      General Principles and Concepts When Considering Data,   114      Utilizing the Framework,   117      Summary,   117     Annex 3-1.   Applying the Safety Framework to Required Nutrients,   118     Annex 3-2.   Monograph Preparation and Public Access,   121     Annex 3-3.   The Use of an External Advisory Committee,   123     References,    124

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety 4   CATEGORIES OF SCIENTIFIC EVIDENCE—HUMAN INFORMATION AND DATA   126      Spontaneously Reported Adverse Events,   127      Historical Use,   136      Clinical Studies,   141      Epidemiological Studies,   146      Summary,   151      References,   153 5   CATEGORIES OF SCIENTIFIC EVIDENCE—ANIMAL DATA   156      Power and Relevance of Animal Data,   157      General Types of Animal Data,   158      Considerations for Assessing Animal Data,   161      When Do Animal Data Warrant Consideration as an Indicator of Serious Risk to Human Health?,   165      Risk Assessment Strategy for Considering Animal Data,   167      Summary,   172      References,   173 6   CATEGORIES OF SCIENTIFIC EVIDENCE—INFORMATION ABOUT RELATED SUBSTANCES   175      Considering Information About Chemical Components and Related Botanicals as Signals of Potential Risk of Botanical Dietary Supplement Ingredients,   176      Other Approaches for Considering Structural Similarity to Known Classes of Toxic Compounds,   205      Consideration of Substances Related to Endogenous Substances,   208      Constituents Functionally Related to Known Classes of Toxic Compounds,   210      Summary,   212      References,   215 7   CATEGORIES OF SCIENTIFIC EVIDENCE—IN VITRO DATA   217      Considerations and Relevance to Humans,   218      General Types of In Vitro Assays,   219      Validated In Vitro Assays,   222      Seriousness of Harm Predicted by the Assay,   224      Summary,   224     Annex 7-1.   Use of Genetic Toxicology Information,   225     Annex 7-2.   In Vitro Tests Validated for Use in Regulatory Toxicology Contexts,   229

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety     Annex 7-3.   Use of New Technologies in Predicting Risks,   231      References,   232 8   INTERACTIONS   235      Types of Interactions,   236      Predicting the Potential of Ingredients to Cause Pharmacokinetic Interactions,   240      Summary,   243      References,   244 9   VULNERABLE GROUPS AND PREVALENCE OF USE   247      Use by Vulnerable Subpopulations,   247      Prevalence of Use in the Population,   250      References,   251 10   SCIENTIFIC PRINCIPLES FOR INTEGRATING AND EVALUATING THE AVAILABLE DATA   253      A Formulaic Approach for Integrating Data Is Not Practical,   254      Amount of Information Needed to Draw a Conclusion,   255      Integrating Information,   255      Weighing Evidence That May Appear Inconsistent,   262      Proof of Harm,   267      References,   268 11   APPLYING THE FRAMEWORK: CASE STUDIES USING THE PROTOTYPE SAFETY MONOGRAPHS   269      Prototype Monograph Development,   269      Use of the Framework in Evaluating Prototype Ingredients,   272      Principles Identified from the Prototypes,   283      References,   291 12   FACTORS INFLUENCING USE OF THE SAFETY FRAMEWORK   292      Features of the Framework,   292      Constraints in Using the Safety Framework,   293      Summary,   296 13   FINDINGS AND RECOMMENDATIONS   297      Ability to Determine Unreasonable Risk,   297      Legal and Regulatory Barriers to Evaluation of the Safety of Dietary Supplements,   299      Specific Findings and Recommendations,   300      References,   305

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety     APPENDIXES     A   Existing Frameworks or Systems for Evaluating the Safety of Other Substances   307 B   Scope of Work and Comments to Initial July 2002 Framework   316 C   Plant Family Information   322 D   Chaparral: Prototype Monograph Summary   356 E   Glucosamine: Prototype Monograph Summary   363 F   Melatonin: Prototype Monograph Summary   367 G   Chromium Picolinate: Prototype Monograph Summary   372 H   Saw Palmetto: Prototype Monograph Summary   376 I   Shark Cartilage: Prototype Monograph Summary   380 J   Prototype Focused Monograph: Review of Liver-Related Risks for Chaparral   385 K   Prototype Focused Monograph: Review of Antiandrogenic Risks of Saw Palmetto Ingestion by Women   450 L   Acknowledgments   478 M   Biographical Sketches of Committee Members   481     INDEX   489

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety DIETARY SUPPLEMENTS A FRAMEWORK FOR EVALUATING SAFETY

OCR for page R1
Dietary Supplements: A Framework for Evaluating Safety This page intentionally left blank.