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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.
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Copyright 1998 by the National Academy of Sciences. All rights reserved.
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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