DIETARY REFERENCE INTAKES FOR Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc

NATIONAL ACADEMY PRESSWashington, D.C.A Report of thePanel on Micronutrients,Subcommittees on Upper Reference Levels of Nutrients and ofInterpretation and Uses of Dietary Reference Intak

NATIONAL ACADEMY PRESSWashington, D.C.

A Report of thePanel on Micronutrients,Subcommittees on Upper Reference Levels of Nutrients and ofInterpretation and Uses of Dietary Reference Intakes, and theStanding Committee on the Scientific Evaluation of

Dietary Reference IntakesFood and Nutrition BoardInstitute of Medicine

FOR

Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc

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.

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, T03; the National Institutes of Health Office of Dietary Supplements; the Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Division

of Nutrition and Physical Activity; Health Canada; the Institute of Medicine; the Dietary Reference Intakes Private Foundation Fund, including the Dannon Institute and the Inter- national Life Sciences Institute; and the Dietary Reference Intakes Corporate Donors’ Fund.

Contributors to the Fund to date include Daiichi Fine Chemicals, Inc., Kemin Foods, L.C., M&M/Mars, Mead Johnson Nutritionals, Nabisco Foods Group, Natural Source Vitamin E Association, Roche Vitamins Inc., U.S Borax, and Weider Nutritional Group The opinions

or conclusions expressed herein do not necessarily reflect those of the funders.

Library of Congress Cataloging-in-Publication Data

Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc : a report of the Panel on Micronutrients [et al.], Standing Committee on the Scientific Evaluation

of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine.

p cm.

Includes bibliographical references and index.

ISBN 0-309-07279-4 (pbk.)—ISBN 0-309-07290-5 (hc.)

1 Trace elements in nutrition 2 Vitamin A in human nutrition 3 Vitamin K 4.

Reference Values (Medicine) I Institute of Medicine (U.S.) Panel on Micronutrients.

QP534 D54 2002

This report 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.

For more information about the Institute of Medicine or the Food and Nutrition Board, visit

the IOM home page at http://www.iom.edu.

Copyright 2001 by the National Academy of Sciences All rights reserved.

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National Academy of SciencesNational Academy of EngineeringInstitute of Medicine

National Research Council

PANEL ON MICRONUTRIENTS

ROBERT RUSSELL (Chair), Jean Mayer U.S Department of Agriculture

Human Nutrition Research Center on Aging, Tufts University,Boston, Massachusetts

JOHN L BEARD, Department of Nutrition, The Pennsylvania StateUniversity, University Park

ROBERT J COUSINS, Center for Nutritional Sciences, University ofFlorida, Gainesville

JOHN T DUNN, University of Virginia Health System, Charlottesville

GUYLAINE FERLAND, Department of Nutrition, University of Montreal,Quebec, Canada

K MICHAEL HAMBIDGE, Department of Pediatrics, University ofColorado Health Sciences Center, Denver

SEAN LYNCH, Veterans Administration Medical Center, Hampton,Virginia

JAMES G PENLAND, U.S Department of Agriculture Human NutritionResearch Center, Grand Forks, North Dakota

A CATHARINE ROSS, Department of Nutrition, The Pennsylvania StateUniversity, University Park

BARBARA J STOEKER, Department of Nutritional Sciences, OklahomaState University, Stillwater

JOHN W SUTTIE, Department of Biochemistry, University of Wisconsin,Madison

JUDITH R TURNLUND, U.S Department of Agriculture WesternHuman Nutrition Research Center, Davis, California

KEITH P WEST, Center for Human Nutrition, Johns Hopkins School ofHygiene and Public Health, Baltimore, Maryland

STANLEY H ZLOTKIN, Departments of Pediatrics and NutritionalSciences, The Hospital for Sick Children and The University ofToronto, Ontario, Canada

PAULA R TRUMBO, Study Director

ALICE L VOROSMARTI, Research Associate

MICHELE RAMSEY, Senior Project Assistant

SUBCOMMITTEE ON UPPER REFERENCE

LEVELS OF NUTRIENTS

IAN C MUNRO (Chair), CanTox, Inc., Mississauga, Ontario, Canada

GEORGE C BECKING, Phoenix OHC, Kingston, Ontario, Canada

RENATE D KIMBROUGH, Institute for Evaluating Health Risks,Washington, D.C

RITA B MESSING, Division of Environmental Health, MinnesotaDepartment of Health, St Paul

SANFORD A MILLER, Graduate School of Biomedical Sciences,University of Texas Health Sciences Center, San Antonio

HARRIS PASTIDES, School of Public Health, University of SouthCarolina, Columbia

JOSEPH V RODRICKS , The Life Sciences Consultancy LLC,

SANDRA SCHLICKER, Study Director

ELISABETH A REESE, Research Associate

MICHELE RAMSEY, Senior Project Assistant

SUBCOMMITTEE ON INTERPRETATION AND USES OF

DIETARY REFERENCE INTAKES

SUZANNE MURPHY (Chair), Cancer Research Center of Hawaii,

University of Hawaii, Honolulu

LENORE ARAB, University of North Carolina School of Public Health,Chapel Hill

SUSAN I BARR, University of British Columbia, Vancouver

SUSAN T BORRA, International Food Information Council,Washington, D.C

ALICIA CARRIQUIRY, Iowa State University, Ames

BARBARA L DEVANEY, Mathematica Policy Research, Princeton,New Jersey

JOHANNA T DWYER, Frances Stern Nutrition Center, New EnglandMedical Center and Tufts University, Boston, Massachusetts

JEAN-PIERRE HABICHT, Cornell University, Ithaca, New York

HARRIET V KUHNLEIN, Centre for Indigenous Peoples’ Nutrition andEnvironment, McGill University, Ste Anne de Bellevue, Quebec,Canada

Staff

MARY POOS, Study Director

ALICE L VOROSMARTI, Research Associate

SHELLEY GOLDBERG, Senior Project Assistant

STANDING COMMITTEE ON THE SCIENTIFICEVALUATION 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 at Urbana-Champaign

LINDSAY H ALLEN, Department of Nutrition, University of California,Davis

STEPHANIE A ATKINSON, Department of Pediatrics, Faculty of HealthSciences, McMaster University, Hamilton, Ontario, Canada

ROBERT J COUSINS, Center for Nutritional Sciences, University ofFlorida, Gainesville

JOHANNA T DWYER, Frances Stern Nutrition Center, New EnglandMedical Center and Tufts University, Boston, Massachusetts

JOHN D FERNSTROM, University of Pittsburgh School of Medicine,Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania

SCOTT M GRUNDY, Center for Human Nutrition, University of TexasSouthwestern Medical Center, Dallas

SANFORD A MILLER, Graduate School of Biomedical Sciences,University of Texas Health Science Center, San Antonio

WILLIAM M RAND, Department of Family Medicine and CommunityHealth, Tufts University School of Medicine, Boston, Massachusetts

U.S Government Liaison

ELIZABETH CASTRO, Office of Disease Prevention and HealthPromotion, U.S Department of Health and Human Services,Washington, D.C

Canadian Government Liaison

PETER W.F FISCHER, Nutrition Research Division, Health ProtectionBranch, Health Canada, Ottawa

Consultant

GEORGE BEATON, GHB Consulting, Willowdale, Ontario, Canada

Staff

ALLISON A YATES, Study Director

SANDRA SCHLICKER, Senior Program Officer

MARY POOS, Senior Program Officer

PAULA TRUMBO, Senior Program Officer

ALICE L VOROSMARTI, Research Associate

KIMBERLY FREITAG, Research Assistant

MICHELE RAMSEY, Senior Project Assistant

GAIL E SPEARS, Administrative Assistant

FOOD AND NUTRITION BOARD

CUTBERTO GARZA (Chair), Division of Nutrition, Cornell University,

Ithaca, New York

ALFRED H MERRILL, JR. (Vice Chair), Department of Biochemistry,

Emory Center for Nutrition and Health Sciences, Emory University,Atlanta, Georgia

ROBERT M RUSSELL (Vice Chair), Jean Mayer U.S Department of

Agriculture Human Nutrition Research Center on Aging, TuftsUniversity, Boston, Massachusetts

VIRGINIA A STALLINGS (Vice Chair), Division of Gastroenterology and

Nutrition, The Children’s Hospital of Philadelphia, Pennsylvania

LARRY R BEUCHAT, Center for Food Safety and QualityEnhancement, University of Georgia, Griffin

BENJAMIN CABALLERO, Center for Human Nutrition, Johns HopkinsSchool of Hygiene and Public Health, Baltimore, Maryland

FERGUS M CLYDESDALE, Department of Food Science, University ofMassachusetts, Amherst

ROBERT J COUSINS, Center for Nutritional Sciences, University ofFlorida, Gainesville

JOHANNA T DWYER, Frances Stern Nutrition Center, New EnglandMedical Center and Tufts University, Boston, Massachusetts

SCOTT M GRUNDY, Center for Human Nutrition, University of TexasSouthwestern Medical Center, Dallas

SHIRIKI KUMANYIKA, University of Pennsylvania School of Medicine,Philadelphia

LYNN PARKER, Child Nutrition Programs and Nutrition Policy, FoodResearch and Action Center, Washington, D.C

ROSS L PRENTICE, Division of Public Health Sciences, FredHutchinson Cancer Research Center, Seattle, Washington

A CATHARINE ROSS, Department of Nutrition, The Pennsylvania StateUniversity, University Park

ROBERT E SMITH, R.E Smith Consulting, Inc., Newport, Vermont

STEVE L TAYLOR, Department of Food Science and Technology andFood Processing Center, University of Nebraska, Lincoln

Staff

ALLISON A YATES, Director

GAIL E SPEARS, Administrative Assistant

GARY WALKER, Financial Associate

This report is one in a series that presents a comprehensive set ofreference values for nutrient intakes for healthy U.S and Canadianpopulations It is a product of the Food and Nutrition Board of theInstitute of Medicine (IOM) working in cooperation with Canadianscientists

The report establishes a set of reference values for vitamin A,vitamin K, chromium, copper, iodine, iron, manganese, molybdenum,and zinc to replace previously published Recommended DietaryAllowances (RDAs) and Recommended Nutrient Intakes (RNIs) forthe United States and Canada The report also examines data aboutarsenic, boron, nickel, silicon, and vanadium Although all refer-ence values are based on data, available data often were scanty ordrawn from studies that had limitations in addressing the variousquestions that confronted the Panel Thus, although governed byreasoning, informed judgments often were required in setting ref-erence values The reasoning used is described for each nutrient inChapters 4 through 13

Close attention was given to the evidence relating intake of nutrients to reduction of the risk of chronic disease, and the dailyamounts needed to maintain normal status based on biochemicalindicators and daily body losses In addition, a major task of thePanel on Micronutrients, Subcommittee on Upper Reference Levels

micro-of Nutrients (UL Subcommittee), and the Standing Committee onthe Scientific Evaluation of Dietary Reference Intakes (DRI Com-mittee) was to analyze the evidence on beneficial and adverse effects

of arsenic, boron, nickel, silicon, and vanadium—in the context ofsetting Dietary Reference Intakes (DRIs).

Another major task of the report was to outline a research agenda

to provide a basis for future public policy decisions related to ommended intakes of these micronutrients and ways to achievethose intakes Many of the questions that were raised about require-ments for and recommended intakes of micronutrients were notanswered fully because of inadequacies in the published database

rec-Apart from studies of overt deficiency diseases, there is a dearth ofstudies that address specific effects of inadequate micronutrientintakes on health status For most of the micronutrients, there is nodirect information that permits estimating the amounts required bychildren, adolescents, the elderly, and pregnant and lactating women

For four of the micronutrients, data were sparse for setting TolerableUpper Intake Levels (ULs), precluding reliable estimates of howmuch can be ingested safely For some of these micronutrients,there are questions about how much is contained in the foods NorthAmericans eat

Readers are urged to recognize that the establishment of DRIs is

an iterative process that is expected to evolve as its conceptualframework is applied to new nutrients and food components Withmore experience, the proposed models for establishing referenceintakes of nutrients and food components that play a role in healthwill be refined Also, as new information or new methods of analysisare adopted, these reference values undoubtedly will be reassessed

Thus, because the project is ongoing, many comments were solicitedand have been received on the reports that have been previouslypublished Refinements that have resulted from this iterative pro-cess have been included in the general information regarding ap-proaches used (Chapters 1 through 3) and in the discussion of uses

of DRIs (Chapter 14 in this report)

The Subcommittee on the Interpretation and Uses of Dietary erence Intakes (Uses Subcommittee), formed subsequent to therelease of the first two reports, has been primarily responsible forchapter 14, which addresses major issues conceptually includedsince the beginning of the DRI process that relate to the anticipateduses and applications of reference values as developed further bythe Uses Subcommittee

Ref-This report reflects the work of the Food and Nutrition Board’sDRI Committee, its expert Panel on Micronutrients, and the ULand Uses Subcommittees We gratefully acknowledge the support ofthe government of Canada and Canadian scientists in this initiative

that represents a pioneering first step in the standardization ofnutrient reference intakes at least within a major part of one conti-nent A brief description of the overall project of the DRI Com-mittee and of the panel’s task is given in Appendix A We hope thatthe critical, comprehensive analyses of available information andknowledge gaps contained in this initial series of reports will assistthe private sector, foundations, universities, government laboratories,and other institutions with the development of a productive re-search agenda for the next decade.

The DRI Committee, the Panel on Micronutrients, the UL andUses Subcommittees, and the Food and Nutrition Board wish toextend sincere thanks to the many experts who assisted with thisreport by giving presentations, providing written materials, partici-pating in discussions, analyzing data, and other means Many, butfar from all, of these individuals are named in Appendix B Specialthanks go to George Beaton and the staff at the National Center forHealth Statistics, the Food Surveys Research Group of the Agricul-tural Research Service, ENVIRON Corporation, Health Technomics,and the Department of Statistics at Iowa State University for exten-sive analyses of survey data

The respective chairs and members of the Panel on Micronutrientsand subcommittees have performed their work under great timepressure Their dedication made the completion of this report pos-sible All gave of their time willingly and without financial reward;

the public and the science and practice of nutrition are among themajor beneficiaries

The DRI Committee and the Food and Nutrition Board wish toacknowledge, in particular, the commitment shown by RobertRussell, Chair of the Panel on Micronutrients, who guided this diffi-cult project through challenging and innovative paths His ability tokeep the effort and various biases moving in a positive direction isvery much appreciated Thanks are also due to the DRI Committeemembers, Lindsay Allen and William Rand, who served as in-depthinternal reviewers for this report

Special thanks also are expressed to the staff of the Food andNutrition Board and foremost to Paula Trumbo, who was the studydirector for the panel and without whose assistance, both intellectualand managerial, this report would neither have been as polishednor as timely in its release It is, of course the Food and NutritionBoard staff who get much of the work completed and so the panel,committees, and the Food and Nutrition Board wish to thank AllisonYates, Director of the Food and Nutrition Board, for her and her

staff’s constant assistance Thus, we also recognize and appreciatethe contributions of Sandra Schlicker, Mary Poos, Elisabeth Reese,Alice Vorosmarti, Gail Spears, and Michele Ramsey and thank PatStephens for editing the manuscript, Jacqueline Dupont for tech-nical review, and Claudia Carl for assistance with publication.

Vernon Young

Chair, Standing Committee on the Scientific

Evaluation of Dietary Reference IntakesCutberto Garza

Chair, Food and Nutrition Board

This report has been reviewed in draft form by individuals chosenfor their diverse perspectives and technical expertise, in accordancewith 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

pub-lished report as sound as possible and to ensure that the reportmeets institutional standards for objectivity, evidence, and respon-siveness to the study charge The review comments and draft manu-script remain confidential to protect the integrity of the delibera-tive process We wish to thank the following individuals for theirreview of this report:

Sarah L Booth, Tufts UniversityJames D Cook, Kansas University Medical CenterMark L Failla, University of North CarolinaJeanne Freeland-Graves, University of TexasJames K Friel, Memorial University of NewfoundlandWalter Mertz, Rockville, Maryland

Phylis B Moser-Veillon, University of MarylandRobert S Parker, Cornell University

John B Stanbury, Massachusetts General HospitalClive E West, Wageningen Agricultural UniversityAlthough the reviewers listed above have provided many construc-tive comments and suggestions, they were not asked to endorse the

conclusions or recommendations nor did they see the final draft ofthe report before its release The review of this report was overseen

by Kurt J Isselbacher, Massachusetts General Hospital and Ronald

W Estabrook, University of Texas Southwestern Medical Center atDallas Appointed by the National Research Council and Institute

of Medicine, they were responsible for making certain that an pendent examination of this report was carried out in accordancewith institutional procedures and that all review comments werecarefully considered Responsibility for the final content of thisreport rests entirely with the authoring committees and the institution

inde-SUMMARY 1

What Are Dietary Reference Intakes?, 2Approach for Setting Dietary Reference Intakes, 7Nutrient Functions and the Indicators Used to EstimateRequirements, 10

Criteria and Proposed Values for Tolerable Upper IntakeLevels, 16

Using Dietary Reference Intakes to Assess Nutrient Intakes ofGroups, 19

Consideration of the Risk of Chronic Degenerative Disease, 22Research Recommendations, 26

1 INTRODUCTION TO DIETARY REFERENCE INTAKES 29

What Are Dietary Reference Intakes?, 29Categories of Dietary Reference Intakes, 30Parameters for Dietary Reference Intakes, 36Summary, 42

References, 42

Methodological Considerations, 45Estimates of Nutrient Intake, 54Dietary Intakes in the United States and Canada, 55Summary, 58

References, 58

Contents

3 A MODEL FOR THE DEVELOPMENT OF TOLERABLE

Intake Assessment, 79Risk Characterization, 79References, 80

Summary, 82Background Information, 83Selection of Indicators for Estimating the Requirement forVitamin A, 97

Factors Affecting the Vitamin A Requirement, 106Findings by Life Stage and Gender Group, 110Intake of Vitamin A, 122

Tolerable Upper Intake Levels, 125Research Recommendations for Vitamin A, 146References, 146

Summary, 162Background Information, 162Selection of Indicators for Estimating the Requirement forVitamin K, 165

Factors Affecting the Vitamin K Requirement, 173Findings by Life Stage and Gender Group, 176Intake of Vitamin K, 184

Tolerable Upper Intake Levels, 187Research Recommendations for Vitamin K, 189References, 189

Summary, 197Background Information, 197Selection of Indicators for Estimating the Requirement forChromium, 202

Factors Affecting the Chromium Requirement, 204Findings by Life Stage and Gender Group, 205Intake of Chromium, 211

Tolerable Upper Intake Levels, 213Research Recommendations for Chromium, 216References, 217

Summary, 224Background Information, 224Selection of Indicators for Estimating the Requirement forCopper, 229

Factors Affecting the Copper Requirement, 233Findings by Life Stage and Gender Group, 235Intake of Copper, 245

Tolerable Upper Intake Levels, 246Research Recommendations for Copper, 252References, 252

Summary, 258Background Information, 258Selection of Indicators for Estimating the Requirement forIodine, 262

Factors Affecting the Iodine Requirement, 267Findings by Life Stage and Gender Group, 268Intake of Iodine, 277

Tolerable Upper Intake Levels, 278Research Recommendations for Iodine, 284References, 284

Summary, 290Background Information, 290Selection of Indicators for Estimating the Requirement forIron, 300

Factors Affecting the Iron Requirement, 311Findings by Life Stage and Gender Group, 316Intake of Iron, 355

Tolerable Upper Intake Levels, 356Research Recommendations for Iron, 378References, 378

10 MANGANESE 394

Summary, 394Background Information, 394Selection of Indicators for Estimating the Requirement forManganese, 397

Factors Affecting the Manganese Requirement, 401Findings by Life Stage and Gender Group, 402Intake of Manganese, 407

Tolerable Upper Intake Levels, 408Research Recommendations for Manganese, 414References, 415

Summary, 420Background Information, 420Selection of Indicators for Estimating the Requirement forMolybdenum, 422

Factors Affecting the Molybdenum Requirement, 424Findings by Life Stage and Gender Group, 425Intake of Molybdenum, 432

Tolerable Upper Intake Levels, 433Research Recommendations for Molybdenum, 439References, 439

Summary, 442Background Information, 442Selection of Indicators for Estimating the Requirement forZinc, 447

Factors Affecting the Zinc Requirement, 454Findings by Life Stage and Gender Group, 458Intake of Zinc, 480

Tolerable Upper Intake Levels, 481Research Recommendations for Zinc, 488References, 489

13 ARSENIC, BORON, NICKEL, SILICON, AND

Summary, 502Arsenic, 503Boron, 510Nickel, 521Silicon, 529

Vanadium, 532References, 543

14 USES OF DIETARY REFERENCE INTAKES 554

Overview, 554Assessing Nutrient Intakes of Individuals, 555Assessing Nutrient Intakes of Groups, 558Planning Nutrient Intakes of Individuals, 562Planning Nutrient Intakes of Groups, 563Nutrient-Specific Considerations, 564Summary, 576

References, 578

Approach, 580Major Knowledge Gaps, 581The Research Agenda, 584

APPENDIXES

A Origin and Framework of the Development of Dietary

Reference Intakes, 587

B Acknowledgments, 591

C Dietary Intake Data from the Third National Health and Nutrition

Examination Survey (NHANES III), 1988–1994, 594

D Dietary Intake Data from the Continuing Survey of Food

Intakes By Individuals (CSFII), 1994–1996, 644

E Dietary Intake Data from the U.S Food and Drug

Administration Total Diet Study, 1991–1997, 654

F Canadian Dietary Intake Data, 1990, 674

G Biochemical Indicators for Iron, Vitamin A, and Iodinefrom

the Third National Health and Nutrition ExaminationSurvey (NHANES III), 1988–1994, 680

H Comparison of Vitamin A and Iron Intake and Biochemical

Indicators from the Third National Health and NutritionExamination Survey (NHANES III), 1988–1994, 692

I Iron Intakes and Estimated Percentiles of the Distribution of

Iron Requirements from the Continuing Survey of FoodIntakes by Individuals (CSFII), 1994–1996, 697

J Glossary and Acronyms, 704

K Conversion of Units, 709

L Options for Dealing with Uncertainties, 710

M Biographical Sketches of Panel and Subcommittee Members, 715

INDEX 729 SUMMARY TABLE, Dietary Reference Intakes:

Recommended Intakes for Individuals, Vitamins 770

SUMMARY TABLE, Dietary Reference Intakes:

Recommended Intakes for Individuals, Elements 772

DRIDIETARY REFERENCE INTAKES

FORVitamin A,Vitamin K,Arsenic, Boron,Chromium,Copper, Iodine, Iron,Manganese,Molybdenum,Nickel, Silicon,Vanadium, and Zinc

This report provides quantitative references intakes for vitamin A,vitamin K, boron, chromium, copper, iodine, iron, manganese, mo-lybdenum, nickel, vanadium, and zinc No recommendations areprovided for arsenic and silicon This is one volume in a series ofreports that presents dietary reference values for the intake of nutri-ents by Americans and Canadians The development of DietaryReference Intakes (DRIs) expands and replaces the series of Rec-ommended Dietary Allowances (RDAs) in the United States andRecommended Nutrient Intakes (RNIs) in Canada A major impetusfor the expansion of this review is the growing recognition of themany uses to which RDAs and RNIs have been applied and thegrowing awareness that many of these uses require the application

of statistically valid methods that depend on reference values otherthan RDAs and RNIs This report includes a review of the roles thatmicronutrients are known to play in traditional deficiency diseasesand evaluates possible roles in chronic diseases

The overall project is a comprehensive effort undertaken by theStanding Committee on the Scientific Evaluation of Dietary Refer-ence Intakes (the DRI Committee) of the Food and NutritionBoard, Institute of Medicine, The National Academies, with activeinvolvement of Health Canada (See Appendix A for a description

of the overall process and its origins.) This study was requested bythe U.S Federal Advisory Steering Committee for Dietary Refer-ence Intakes in collaboration with Health Canada

Major new approaches and findings in this report include thefollowing:

• The establishment of new estimates for the conversion of vitamin A carotenoids to vitamin A: 1 µg retinol activity equivalent(µg RAE) is equal to 1 µg all-trans-retinol, 12 µg β-carotene, and 24

pro-µg α-carotene or β-cryptoxanthin This recognizes that 50 percentless bioconversion of carotenoids to vitamin A occurs than was pre-viously thought, a change that means twice as much provitamin A-rich carotenoids contained in green leafy vegetables and certainfruits are required to provide a given amount of vitamin A activity

Given possible future changes in equivalency, weight of carotenoidsshould be given in food tables

• The establishment of RDAs for copper and molybdenum

• The establishment of Tolerable Upper Intake Levels (ULs) forvitamin A, boron, copper, iodine, iron, manganese, molybdenum,nickel, vanadium, and zinc

• Research recommendations for information needed to advanceunderstanding of human micronutrient requirements and the ad-verse effects associated with intake of higher amounts

WHAT ARE DIETARY REFERENCE INTAKES?

Dietary Reference Intakes (DRIs) are reference values that are

quanti-tative estimates of nutrient intakes to be used for planning andassessing diets for apparently healthy people They include not onlyRecommended Dietary Allowances (RDAs) but also three othertypes of reference values (see Box S-1) Although the referencevalues are based on data, the data were often scanty or drawn fromstudies that had limitations in addressing the question Thus, scien-tific judgment was required for evaluating the evidence and in set-ting the reference values, and that process is delineated for eachnutrient in Chapters 4 through 13

Recommended Dietary Allowances

The process for setting the RDA depends on being able to set an

Estimated Average Requirement (EAR) Before the EAR is set, a specific

criterion of adequacy is selected on the basis of a careful review ofthe literature In the selection of the criterion, reduction of diseaserisk is considered along with many other health parameters

If the standard deviation (SD) of the EAR is available and therequirement for the nutrient is symmetrically distributed, the RDA

is set at two SDs above the EAR:

RDA = EAR + 2 SDEAR

If data about variability in requirements are insufficient to late an SD, a coefficient of variation (CV) for the EAR of 10 percent

calcu-is assumed, unless available data indicate a greater variation in quirements

re-If 10 percent is assumed to be the CV, then twice that amountwhen added to the EAR is defined as equal to the RDA The result-ing equation for the RDA is then

RDA = 1.2 × EAR

This level of intake statistically represents 97.5 percent of the quirements of the population If the distribution of the nutrientrequirement is known to be skewed for a population, as with iron,

re-Box S-1 Dietary Reference Intakes

Recommended Dietary Allowance (RDA): the average daily dietary nutrient

intake level sufficient to meet the nutrient requirement of nearly all (97 to 98 percent) healthy individuals in a particular life stage and gender group.

Adequate Intake (AI): the recommended average daily intake level based on observed

or experimentally determined approximations or estimates of nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate—used when

an RDA cannot be determined.

Tolerable Upper Intake Level (UL): the highest average daily nutrient intake

level that is likely to pose no risk of adverse health effects to almost all individuals in the general population As intake increases above the UL, the potential risk of adverse effects may increase.

Estimated Average Requirement (EAR): the average daily nutrient intake level

estimated to meet the requirement of half the healthy individuals in a particular life stage and gender group.

other approaches are used to find the seventh to eighth percentile to set the RDA.

ninety-The RDA for a nutrient is a value to be used as a goal for dietaryintake for the healthy individual As discussed in Chapter 14, theRDA is not intended to be used to assess the diets of either individ-uals or groups or to plan diets for groups Only if intakes have beenobserved for a large number of days (i.e., usual intake) and are at

or above the RDA, or if observed intakes for fewer days are wellabove the RDA, should one have a high level of confidence that theintake is adequate (see Box S-2) The EAR is also used as the basis

to address diets of groups

Adequate Intakes

The Adequate Intake (AI) is set instead of an RDA if sufficient

scientific evidence is not available to calculate an EAR The mainintended use of the AI is as a goal for the nutrient intake of individ-uals For example, the AI for young infants, for whom human milk

is the recommended sole source of food for most nutrients upthrough the first 4 to 6 months of age, is based on the daily meannutrient intake supplied by human milk for apparently healthy, full-term infants receiving human milk The goal may be different forinfants consuming infant formula for which the bioavailability of anutrient may be different from that in human milk, such as iron,which is high in infant formula due to its lower bioavailability thanthat found in human milk

Comparison of Recommended Dietary Allowances

and Adequate Intakes

Although both the RDA and AI are to be used as a goal for intake

by individuals, the RDA differs from the AI Intake of the RDA for anutrient is expected to meet the needs of 97 to 98 percent of theapparently healthy individuals in a life stage and gender group (seeFigure S-1) However, because no distribution of requirements isknown for nutrients with an AI, it is not possible to know whatpercentage of individuals are covered by the AI The AI for a nutri-ent is expected to exceed the RDA for that nutrient, and thus itshould cover the needs of more than 97 to 98 percent of the indi-

viduals The degree to which an AI exceeds the RDA is likely to

differ among nutrients and population groups

For people who have diseases that increase specific nutrient quirements or who have other special health needs, the RDA and

re-Box S-2 Uses of Dietary Reference Intakes for Healthy Individuals and Groups

Type of Use For the Individual a For a Group b

Assessment EAR: use to examine the

probability that usual intake is inadequate.

RDA: usual intake at or above this level has a low probability of inadequacy.

AIc: usual intake at or above this level has a low probability of inadequacy.

UL: usual intake above this level may place an individual at risk of adverse effects from excessive nutrient intake.

EAR: use to estimate the lence of inadequate intakes within a group.

preva-RDA: do not use to assess intakes of groups.

AIc: mean usual intake at or above this level implies a low prevalence of inadequate intakes.

UL: use to estimate the age of the population at poten- tial risk of adverse effects from excess nutrient intake.

percent-Planning RDA: aim for this intake.

AIc: aim for this intake.

UL: use as a guide to limit intake; chronic intake of higher amounts may increase the poten- tial risk of adverse effects.

EAR: use to plan an intake distribution with a low preva- lence of inadequate intakes.

AIc: use to plan mean intakes.

UL: use to plan intake tions with a low prevalence of intakes potentially at risk of adverse effects.

distribu-RDA = Recommended Dietary Allowance EAR = Estimated Average Requirement

AI = Adequate Intake

UL = Tolerable Upper Level

a Evaluation of true status requires clinical, biochemical, and anthropometric data.

b Requires statistically valid approximation of distribution of usual intakes.

c For the nutrients in this report, AIs are set for infants for all nutrients, and for other age groups for vitamin K, chromium, and manganese The AI may be used as a guide for infants as it reflects the average intake from human milk.

O b se rve d Lev e l of Intake

Aver-AI each may serve as the basis for adjusting individual dations Qualified health professionals should adapt the recom-mended intake to cover higher or lower needs

recommen-Tables S-1 through S-9 provide the recommended intake levels,whether RDAs or AIs, for vitamin A, vitamin K, chromium, copper,iodine, iron, manganese, molybdenum, and zinc by life stage andgender group For most of these micronutrients, AIs rather thanRDAs are proposed for infants to age 1 year EARs and RDAs, how-ever, are proposed for iron and zinc for infants 7 to 12 months ofage because the level of iron and zinc in human milk does not meetthe needs of the older infants and because factorial data are avail-able to estimate the average requirement Neither AIs nor RDAswere proposed for arsenic, boron, nickel, silicon, or vanadium

Tolerable Upper Intake Levels

The Tolerable Upper Intake Level (UL) is the highest level of daily

nutrient intake that is likely to pose no risk of adverse health effectsfor almost all individuals in the general population (see Table S-10)

As intake increases above the UL, the potential risk of adverse effectsmay increase The term “tolerable intake” was chosen to avoid imply-ing a possible beneficial effect Instead, the term is intended toconnote a level of intake that can, with high probability, be toleratedbiologically The UL is not intended to be a recommended level ofintake There is no established benefit for apparently healthy indi-viduals if they consume nutrient intakes above the RDA or AI

ULs are useful because of the increased interest in and availability

of fortified foods and the increased use of dietary supplements ULsare based on total intake of a nutrient from food, water, and supple-ments if adverse effects have been associated with total intake How-ever, if adverse effects have been associated with intake from sup-plements or food fortificants only, the UL is based on nutrientintake from one or both of those sources only, rather than on totalintake The UL applies to chronic daily use

For vitamin K, arsenic, chromium, and silicon, there are cient data for developing a UL This does not mean that there is nopotential for adverse effects resulting from high intake; for exam-ple, arsenic is a human poison at high intakes However, at levelsbelow what is known to be toxic, little data are available Wheredata about adverse effects are extremely limited, extra caution may

insuffi-be warranted

APPROACH FOR SETTING DIETARY REFERENCE INTAKES

The scientific data used to develop Dietary Reference Intakes(DRIs) have come from observational and experimental studies

Studies published in peer-reviewed journals were the principalsource of data Life stage and gender were considered to the extentpossible, but the data did not provide a basis for proposing differ-ent requirements for men and for nonpregnant and nonlactating

women in different age groups for many of the micronutrients Two

of the categories of reference values—the Estimated Average quirement (EAR) and Recommended Dietary Allowance (RDA)—

Re-are defined by specific criteria of nutrient adequacy; the third, theTolerable Upper Intake Level (UL), is defined by a specific end-point of adverse effect, when one is available In all cases, data wereexamined closely to determine whether a functional endpoint could

TABLE S-1 Criteria and Dietary Reference Intake Values forVitamin A by Life Stage Group

EAR ( µg

> 0 through 6 mo Average vitamin A intake from human milk

> 7 through 12 mo Extrapolation from 0 through 6 mo AI

> 14 through 18 y Adolescent female EAR plus average amount of vitamin A

secreted in human milk

> 19 through 50 y Adult female EAR plus average amount of vitamin A

secreted in human milk

a EAR = Estimated Average Requirement The intake that meets the estimated nutrient needs of half of the individuals in a group.

b RDA = Recommended Dietary Allowance The intake that meets the nutrient need of almost all (97–98 percent) of individuals in a group.

c AI = Adequate Intake The observed average or experimentally determined intake by a

be used as a criterion of adequacy The quality of studies was ined by considering study design; methods used for measuring intakeand indicators of adequacy; and biases, interactions, and confound-ing factors

exam-Although the reference values are based on data, the data wereoften scanty or drawn from studies that had limitations in address-ing the various questions that confronted the panel Therefore,many of the questions raised about the requirements for and recom-mended intakes of these micronutrients cannot be answered fullybecause of inadequacies in the present database Apart from studies

of overt deficiency diseases, there is a dearth of studies that addressspecific effects of inadequate intakes on specific indicators of healthstatus, and a research agenda is proposed (see Chapter 15) The

s for

400 500

of health The AI is used if sufficient scientific evidence is not available to derive an

EAR For healthy infants receiving human milk, the AI is the mean intake The AI is not

equivalent to an RDA.

reasoning used to establish the values is described for each nutrient

in Chapters 4 through 13 While the various recommendations areprovided as single rounded numbers for practical considerations, it

is acknowledged these values imply a precision not fully justified bythe underlying data in the case of currently available human studies

The scientific evidence related to the prevention of chronic generative disease was judged to be too nonspecific to be used asthe basis for setting any of the recommended levels of intake for allthese nutrients For all of the micronutrients, the EAR is higherthan the amount needed to prevent overt deficiency diseases inessentially all individuals in the life stage group and is based on limiteddata indicating laboratory evidence of sufficiency The indicatorsused in deriving the EARs, and thus the RDAs, are described below

de-TABLE S-2 Criteria and Dietary Reference Intake Values forVitamin K by Life Stage Group

AI ( µg/d

> 1 through 3 y Median intake of vitamin K from the Third National

Pregnancy

> 14 through 18 y Adolescent female median intake

> 19 through 50 y Adult female median intake Lactation

> 14 through 18 y Adolescent female median intake

> 19 through 50 y Adult female median intake

a AI = Adequate Intake The observed average or experimentally determined intake by

a defined population or subgroup that appears to sustain a defined nutritional status, such as growth rate, normal circulating nutrient values, or other functional indicators

of health The AI is used if sufficient scientific evidence is not available to derive an

NUTRIENT FUNCTIONS AND THE INDICATORS USED TO

ESTIMATE REQUIREMENTS

Vitamin A functions to maintain normal reproduction, vision, and

immune function A deficiency of vitamin A, although uncommon

in North America, can result initially in abnormal dark adaptation(night blindness) followed by xerophthalmia The method used toset an Estimated Average Requirement (EAR) for vitamin A is based

on a computational analysis to assure adequate body stores of min A The Recommended Dietary Allowance (RDA) for adultsfor vitamin A is set at 900 µg RAE/day for men and 700 µg RAE/dayfor women One µg retinol activity equivalent (µg RAE) is equal

vita-to 1 µg all-trans-retinol, 12 µg β-carotene, and 24 µg α-carotene orβ-cryptoxanthin

Vitamin K functions as a coenzyme in the synthesis of the

biologi-cally active form of a number of proteins involved in blood tion and bone metabolism Because of the lack of data to set an

75 90 Estimated Average Requirement (EAR) For healthy infants receiving human milk, the

AI is the mean intake The AI is not equivalent to a Recommended Dietary Allowance

(RDA).

EAR, an Adequate Intake (AI) is set based on representative dietaryintake data from healthy individuals from the Third Nutrition andHealth Examination Survey (NHANES III) The AI for adults is 120and 90 µg/day, for men and women, respectively

Chromium potentiates the action of insulin in vivo and in vitro.

There was not sufficient evidence to set an EAR for chromium

Therefore, an AI was set based on estimated intakes of chromiumderived from the average amount of chromium/1,000 kcal of bal-anced diets and average energy intake from NHANES III The AI is

35 µg/day for young men and 25 µg/day for young women

Copper functions to catalyze the activity of many copper

metalloen-zymes that act as oxidases to achieve the reduction of molecularoxygen Frank copper deficiency in humans is rare; the deficiencysymptoms include normocytic and hypochromic anemia, leukope-nia, and neutropenia The method used to set an EAR for copper isbased on the changes in a combination of biochemical indicators

TABLE S-3 Criteria and Dietary Reference Intake Values forChromium by Life Stage Group

AI ( µg/d

≥ 7 through 12 mo Average chromium intake from human milk and

≥ 19 through 50 y Average chromium intake based on the chromium content

≥ 51 y Average chromium intake based on the chromium content

Pregnancy

≥ 14 through 18 y Extrapolation from adolescent AI based on body weight

≥ 19 through 50 y Extrapolation from adult woman AI based on body weight Lactation

≥ 14 through 18 y Adolescent female intake plus average amount of

chromium secreted in human milk

≥ 19 through 50 y Adult female intake plus average amount of chromium

secreted in human milk

a AI = Adequate Intake The observed average or experimentally determined intake by

a defined population or subgroup that appears to sustain a defined nutritional status, such as growth rate, normal circulating nutrient values, or other functional indicators

of health AI is used if sufficient scientific evidence is not available to derive an mated Average Requirement (EAR) For healthy infants receiving human milk, AI is the

Esti-resulting from varied levels of copper intake The RDA for copper

is 900 µg/day for men and women There were insufficient data toset a different EAR and RDA for each gender

Iodine is an important component of the thyroid hormones that

are involved with the regulation of metabolism Severe iodine ciency can result in impaired cognitive development in childrenand goiter in adults The method used to set an EAR for iodine isiodine accumulation and turnover The adult RDA for iodine is 150

defi-µg/day There were insufficient data to set a different EAR andRDA for each gender

Iron functions as a component of hemoglobin, myoglobin,

cyto-chromes, and enzymes Iron deficiency anemia is the most common

mean intake The AI is not equivalent to a Recommended Dietary Allowance (RDA).

b The average chromium content in well balanced diets was determined to be 13.4 µg/

1,000 kcal and the average energy intake for adults was obtained from the Third National Health and Nutrition Examination Survey.

nutritional deficiency in the world, resulting in fatigue and impairedcognitive development and productivity The required amount ofabsorbed iron is estimated based on factorial modeling The EAR isdetermined by dividing the required amount of absorbed iron bythe fractional absorption of dietary iron, estimated to be 18 percentfor adults for the typical North American diet The RDA for menand premenopausal women is 8 and 18 mg/day, respectively TheRDA for pregnant women is 27 mg/day

Manganese is involved in the formation of bone and in amino acid,

lipid, and carbohydrate metabolism There were insufficient data toset an EAR for manganese An AI was set based on median intakesreported from the U.S Food and Drug Administration Total Diet

TABLE S-4 Criteria and Dietary Reference Intake Values forCopper by Life Stage Group

EAR ( µg/

≥ 0 through 6 mo Average copper intake from human milk

≥ 7 through 12 mo Average copper intake from human milk and

complementary foods

≥ 19 through 50 y Plasma copper, serum ceruloplasmin, and platelet

copper concentrations and erythrocyte superoxide

Pregnancy

≥ 14 through 18 y Adolescent female EAR plus fetal accumulation of copper

≥ 19 through 50 y Adult female EAR plus fetal accumulation of copper Lactation

≥ 14 through 18 y Adolescent female EAR plus average amount of copper

secreted in human milk

≥ 19 through 50 y Adult female EAR plus average amount of copper

secreted in human milk

a EAR = Estimated Average Requirement The intake that meets the estimated nutrient needs of half of the individuals in a group.

b RDA = Recommended Dietary Allowance The intake that meets the nutrient need of almost all (97–98 percent) of individuals in a group.

c AI = Adequate Intake The observed average or experimentally determined intake by a

Study The AI for adult men and women is 2.3 and 1.8 mg/day,respectively

Molybdenum functions as a cofactor for several enzymes in a form

called molybdopterin An inborn error of metabolism that leads to

a deficiency of sulfite oxidase is due to the lack of molybdopterin,which results in neurological dysfunction and mental retardation

Molybdenum balance data were used to set an EAR The RDA foradults for molybdenum is 45 µg/day for men and women Therewere insufficient data to set a different EAR and RDA for each gender

s for

200 220

Zinc functions through the catalysis of various enzymes, the

main-tenance of the structural integrity of proteins, and the regulation ofgene expression Overt human zinc deficiency is rare, and the symp-toms of a mild deficiency are diverse due to zinc’s ubiquitous in-volvement in metabolic processes Factorial analysis of zinc lossesand requirements for growth, as well as fractional absorption, wereused to set an EAR The RDA for zinc is set at 11 mg/day for menand 8 mg/day for women

defined population or subgroup that appears to sustain a defined nutritional status, such as growth rate, normal circulating nutrient values, or other functional indicators

of health The AI is used if sufficient scientific evidence is not available to derive an

EAR For healthy infants receiving human milk, the AI is the mean intake The AI is not

equivalent to an RDA.

TABLE S-5 Criteria and Dietary Reference Intake Values forIodine by Life Stage Group

EAR ( µg/

≥ 0 through 6 mo Average iodine intake from human milk

≥ 7 through 12 mo Extrapolation from 0 through 6 mo AI

≥ 51 y Extrapolation of iodine turnover studies from 19

Pregnancy

≥ 14 through 18 y Balance data during pregnancy

≥ 19 through 50 y Balance data during pregnancy Lactation

≥ 14 through 18 y Adolescent female average requirement plus average

amount of iodine secreted in human milk

≥ 19 through 50 y Adult female average requirement plus average amount

of iodine secreted in human milk

a EAR = Estimated Average Requirement The intake that meets the estimated nutrient needs of half of the individuals in a group.

b RDA = Recommended Dietary Allowance The intake that meets the nutrient need of almost all (97–98 percent) of individuals in a group.

c AI = Adequate Intake The observed average or experimentally determined intake by a

CRITERIA AND PROPOSED VALUES FOR TOLERABLE

UPPER INTAKE LEVELS

A risk assessment model is used to derive Tolerable Upper IntakeLevels (ULs) The model consists of a systematic series of scientificconsiderations and judgments The hallmark of the risk assessmentmodel is the requirement to be explicit in all of the evaluations andjudgments made

The adult ULs for vitamin A (3,000 µg/day), boron (20 mg/day),copper (10,000 µg/day), iodine (1,100 µg/day), iron (45 mg/day),manganese (11 mg/day), molybdenum (2,000 µg/day), nickel (1.0