Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients

Food and Nutrition Board

Institute of Medicine

NATIONAL ACADEMY PRESS
Washington, D.C.
1998



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--> Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients Food and Nutrition Board Institute of Medicine NATIONAL ACADEMY PRESS Washington, D.C. 1998

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--> NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. 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. The Institute of Medicine was established in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under both the Academy's 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. This project was funded by the U.S. Department of Health and Human Services Office of Disease Prevention and Health Promotion, Contract No. 282-96-0033; the National Institutes of Health Office of Nutrition Supplements, Contract No. N01-OD-4-2139, T024; the Food and Drug Administration, Contract No. 223-90-2223; Health Canada; the Institute of Medicine; and the Dietary Reference Intakes Corporate Donors' Fund. Contributors to the Fund include Roche Vitamins Inc, Mead Johnson Nutrition Group, Daiichi Fine Chemicals, Inc, Kemin Foods, Inc, M&M Mars, Weider Nutrition Group, and Natural Source Vitamin E Association. The opinions or conclusions expressed herein do not necessarily reflect those of the funders. This publication is available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055; call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP's on-line bookstore at http:/www.nap.edu. International Standard Book No. 0-309-06348-5 For more information about the Institute of Medicine or the Food and Nutrition Board, visit the IOM home page at http://www2.nas.edu/iom. Copyright 1998 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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--> SUBCOMMITTEE ON UPPER REFERENCE LEVELS OF NUTRIENTS IAN C. MUNRO (Chair), CanTox, Incorporated, Mississauga, Ontario, Canada WALTER MERTZ, Retired, Human Nutrition Research Center, Rockville, Maryland RITA B. MESSING, Division of Environmental Health, Minnesota Department of Health, St. Paul SANFORD A. MILLER, Graduate School of Biomedical Sciences, University of Texas Health Sciences Center, San Antonio SUZANNE P. MURPHY, Department of Nutritional Sciences, University of California, Berkeley JOSEPH V. RODRICKS, ENVIRON Corporation, Arlington, Virginia IRWIN H. ROSENBERG, Clinical Nutrition Division, USDA Human Nutrition Research Center on Aging, Tufts University and New England Medical Center, Boston, Massachusetts STEVE L. TAYLOR, Department of Food Science and Technology, University of Nebraska, Lincoln ROBERT H. WASSERMAN, Department of Physiology, College of Veterinary Medicine, Cornell University, Ithaca, New York Consultant HERBERT BLUMENTHAL, Retired, Food and Drug Administration, Washington, DC Staff SANDRA A. SCHLICKER, Study Director ELISABETH A. REESE, Research Associate GERALDINE KENNEDO, Project Assistant

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--> PANEL ON CALCIUM AND RELATED NUTRIENTS STEPHANIE A. ATKINSON (Chair), Department of Pediatrics, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada STEVEN A. ABRAMS, Department of Pediatrics, USDA Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas BESS DAWSON-HUGHES, Calcium and Bone Metabolism Laboratory, USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts ROBERT P. HEANEY, Creighton University, Omaha, Nebraska MICHAEL F. HOLICK, Endocrinology, Nutrition and Diabetes Section and Vitamin D, Skin, and Bone Research Laboratory, Boston University School of Medicine and Boston Medical Center, Massachusetts SUZANNE P. MURPHY, Department of Nutritional Sciences, University of California, Berkeley ROBERT K. RUDE, Department of Medicine, University of Southern California, Los Angeles BONNY L. SPECKER, Department of Pediatrics, University of Cincinnati and Children's Hospital Medical Center, Ohio CONNIE M. WEAVER, Department of Food and Nutrition, Purdue University, West Lafayette, Indiana GARY M. WHITFORD, Department of Oral Biology and Physiology, School of Dentistry, Medical College of Georgia, Augusta Staff SANDRA A. SCHLICKER, Study Director ELISABETH A. REESE, Research Associate ALICE L. KULIK, Research Associate GERALDINE KENNEDO, Project Assistant GAIL E. SPEARS, Administrative Assistant

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--> PANEL ON FOLATE, OTHER B VITAMINS, AND CHOLINE ROY M. PITKIN (Chair), Obstetrics & Gynecology, Los Angeles, California LINDSAY H. ALLEN, Department of Nutrition, University of California, Davis LYNN B. BAILEY, Food Science and Human Nutrition Department, University of Florida, Gainesville MERTON BERNFIELD, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts PHILLIPE De WALS, Department of Community Health Sciences, University of Sherbrooke, Quebec, Canada RALPH GREEN, Department of Pathology, University of California at Davis Medical Center, Sacramento DONALD B. McCORMICK, Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia ROBERT M. RUSSELL, Department of Medicine and Nutrition, USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts BARRY SHANE, Department of Nutritional Sciences, University of California, Berkeley STEVEN ZEISEL, Department of Nutrition, University of North Carolina School of Public Health and School of Medicine, Chapel Hill IRWIN H. ROSENBERG, (Liaison from the Subcommittee on Upper Reference Levels of Nutrients), Clinical Nutrition Division, USDA Human Nutrition Research Center on Aging, Tufts University and New England Medical Center, Boston, Massachusetts Staff CAROL W. SUITOR, Study Director ELISABETH A. REESE, Research Associate ALICE L. KULIK, Research Associate MICHELE RAMSEY, Project Assistant

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--> STANDING COMMITTEE ON THE SCIENTIFIC EVALUATION OF DIETARY REFERENCE INTAKES VERNON R. YOUNG (Chair), Laboratory of Human Nutrition, School of Science, Massachusetts Institute of Technology, Cambridge JOHN W. ERDMAN, JR. (Vice Chair), Division of Nutritional Sciences, College of Agricultural, Consumer and Environmental Sciences, University of Illinois, Urbana-Champaign JANET C. KING (Vice Chair), USDA Western Human Nutrition Research Center, Presidio of San Francisco, California LINDSAY H. ALLEN, Department of Nutrition, University of California at Davis STEPHANIE A. ATKINSON, Department of Pediatrics, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada JOHANNA T. DWYER, Frances Stern Nutrition Center, New England Medical Center and Tufts University, Boston, Massachusetts JOHN D. FERNSTROM, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pennsylvania SCOTT M. GRUNDY, Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas CHARLES H. HENNEKENS, Department of Medicine, Harvard Medical School, Boston, Massachusetts SANFORD A. MILLER, Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio U.S. Government Liaison LINDA MEYERS, Office of Disease Prevention and Health Promotion, US Department of Health and Human Services, Washington, DC Canadian Government Liaison PETER W.F. FISCHER, Nutrition Research Division, Health Protection Branch, Health Canada, Ottawa Staff ALLISON A. YATES, Study Director GERALDINE KENNEDO, Project Assistant GAIL E. SPEARS, Administrative Assistant

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--> FOOD AND NUTRITION BOARD CUTBERTO GARZA (Chair), Cornell University, Ithaca, New York JOHN W. ERDMAN, JR. (Vice Chair), Division of Nutritional Sciences, College of Agricultural, Consumer and Environmental Sciences, University of Illinois, Urbana-Champaign LINDSAY H. ALLEN, Department of Nutrition, University of California at Davis BENJAMIN CABALLERO, Center for Human Nutrition, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland FERGUS M. CLYDESDALE, Department of Food Science, University of Massachusetts at Amherst ROBERT J. COUSINS, Center for Nutritional Sciences, University of Florida, Gainesville JOHANNA T. DWYER, Frances Stern Nutrition Center, New England Medical Center and Tufts University, Boston, Massachusetts SCOTT M. GRUNDY, Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas CHARLES H. HENNEKENS, Department of Medicine, Harvard Medical School, Boston, Massachusetts SANFORD A. MILLER, Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio ROSS L. PRENTICE, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington A. CATHARINE ROSS, Department of Veterinary Science, The Pennsylvania State University, University Park ROBERT E. SMITH, R.E. Smith Consulting, Newport, Vermont VIRGINIA A. STALLINGS, Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Pennsylvania VERNON R. YOUNG, Laboratory of Human Nutrition, School of Science, Massachusetts Institute of Technology, Cambridge Staff ALLISON A. YATES, Study Director GAIL E. SPEARS, Administrative Assistant

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--> Contents     Introduction   1     What are Dietary Reference Intakes?   2     Recommended Dietary Allowance   3     Adequate Intake   4     Tolerable Upper Intake Level   4     Approach for Setting Dietary Reference Intakes, Including Tolerable Upper Intake Levels   5     Terminology   5     Concept   6     Model for the Derivation of Tolerable Upper Intake Levels   6     Risk Assessment and Food Safety   7     Basic Concepts   7     Steps in the Risk Assessment Process   8     Thresholds   9     Application of the Risk Assessment Model to Nutrients   10     Special Problems Associated with Substances Required for Human Nutrition   11     Consideration of Variability in Sensitivity   12     Bioavailability   13     Nutrient-Nutrient Interactions   13     Other Relevant Factors Affecting Bioavailability of Nutrients   14     Steps in the Development of the Tolerable Upper Intake Level   14     Step 1.Hazard Identification   14     Step 2.Dose-Response Assessment   17

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-->     Derivation of ULs: Summary of Progress to Date   20     Derivation of UFs   20     Derivation of a UL   21     Derivation of a UL for Other Groups   21     References   24     Appendixes     A   Recommended Dietary Intakes for Individuals   27 B   Options for Dealing with Uncertainties   31 C   Reference Heights and Weights for Children and Adults   35 D   Case Studies of Application of Risk Assessment Model for Nutrients   37     A.Calcium   37     B.Folate   51     C.Riboflavin   64 E   Biographical Sketches of Subcommittee on Upper Reference Levels of Nutrients   67