Vous êtes sur la page 1sur 139

THE NATIONAL ACADEMIES PRESS

This PDF is available at http://nap.edu/25148 SHARE


   

Harmonization of Approaches to Nutrient Reference Values


Applications to Young Children and Women of Reproductive
Age

DETAILS

170 pages | 6 x 9 | PAPERBACK


ISBN 978-0-309-47769-7 | DOI 10.17226/25148

CONTRIBUTORS

GET THIS BOOK Committee on the Application of Global Harmonization of Methodological


Approaches to Nutrient Intake Recommendations for Young Children and Women of
Reproductive Age; Food and Nutrition Board; Health and Medicine Division;
FIND RELATED TITLES National Academies of Sciences, Engineering, and Medicine


Visit the National Academies Press at NAP.edu and login or register to get:

– Access to free PDF downloads of thousands of scientific reports


– 10% off the price of print titles
– Email or social media notifications of new titles related to your interests
– Special offers and discounts

Distribution, posting, or copying of this PDF is strictly prohibited without written permission of the National Academies Press.
(Request Permission) Unless otherwise indicated, all materials in this PDF are copyrighted by the National Academy of Sciences.

Copyright © National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Harmonization of Approaches to Nutrient


Reference Values: Applications to Young
Children and Women of Reproductive Age

Committee on the Application of Global Harmonization of Methodological


Approaches to Nutrient Intake Recommendations for Young Children and Women
of Reproductive Age

Food and Nutrition Board

Health and Medicine Division

A Consensus Study Report of

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


H a r m o n i z a t i o n o f A p p r o a c h e s t o N u t r i e n t

THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001

This activity was supported by a contract between the National Academy of Sciences and the Bill
& Melinda Gates Foundation (Grant OPP1150751) and by the Kellogg Endowment Fund of the
National Academy of Sciences’ Health and Medicine Division. Any opinions, findings,
conclusions, or recommendations expressed in this publication do not necessarily reflect the views
of any organization or agency that provided support for the project.

International Standard Book Number-13: 978-0-309-XXXXX-X


International Standard Book Number-10: 0-309-XXXXX-X
Digital Object Identifier: https://doi.org/10.17226/25148

Additional copies of this publication are available for sale from the National Academies Press, 500
Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313;
http://www.nap.edu.

Copyright 2018 by the National Academy of Sciences. All rights reserved.

Printed in the United States of America

Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2018.


Harmonization of approaches to nutrient reference values: Applications to young children and
women of reproductive age. Washington, DC: The National Academies Press. doi:
https://doi.org/10.17226/25148.

PREPUBLICATION COPY: UNCORRECTED PROOFS

C o p y r i g h t N a t i o n a l A c a d e m y
Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by
President Lincoln, as a private, nongovernmental institution to advise the nation on issues
related to science and technology. Members are elected by their peers for outstanding
contributions to research. Dr. Marcia McNutt is president.

The National Academy of Engineering was established in 1964 under the charter of the
National Academy of Sciences to bring the practices of engineering to advising the nation.
Members are elected by their peers for extraordinary contributions to engineering. Dr. C. D.
Mote, Jr., is president.

The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970
under the charter of the National Academy of Sciences to advise the nation on medical and
health issues. Members are elected by their peers for distinguished contributions to medicine
and health. Dr. Victor J. Dzau is president.

The three Academies work together as the National Academies of Sciences, Engineering, and
Medicine to provide independent, objective analysis and advice to the nation and conduct other
activities to solve complex problems and inform public policy decisions. The National Academies
also encourage education and research, recognize outstanding contributions to knowledge, and
increase public understanding in matters of science, engineering, and medicine.

Learn more about the National Academies of Sciences, Engineering, and Medicine at
www.nationalacademies.org.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Consensus Study Reports published by the National Academies of Sciences, Engineering, and
Medicine document the evidence-based consensus on the study’s statement of task by an
authoring committee of experts. Reports typically include findings, conclusions, and
recommendations based on information gathered by the committee and the committee’s
deliberations. Each report has been subjected to a rigorous and independent peer-review
process and it represents the position of the National Academies on the statement of task.

Proceedings published by the National Academies of Sciences, Engineering, and


Medicine chronicle the presentations and discussions at a workshop, symposium, or
other event convened by the National Academies. The statements and opinions contained in
proceedings are those of the participants and are not endorsed by other participants, the
planning committee, or the National Academies.

For information about other products and activities of the National Academies, please
visit www.nationalacademies.org/about/whatwedo.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


H a r m o n i z a t i o n o f A p p r o a c h e s t o N u t

COMMITTEE ON THE APPLICATION OF GLOBAL HARMONIZATION OF


METHODOLOGICAL APPROACHES TO NUTRIENT INTAKE
RECOMMENDATIONS FOR YOUNG CHILDREN AND WOMEN OF
REPRODUCTIVE AGE

ROBERT E. BLACK (Chair), Edgar Berman Professor, Director, Institute for International Programs,
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore,
Maryland
LINDSAY ALLEN, Center Director, ARS Western Human Nutrition Research Center, U.S. Department of
Agriculture, Davis, California
ZULFIQAR A. BHUTTA, Noordin Noormahomed Sheriif Endowed Professor and Founding Chair,
Division of Women and Child Health, Aga Khan University, Toronto, Ontario
SUSAN FAIRWEATHER-TAIT, Professor, Human Nutrition, Norwich Medical School, University of
East Anglia, Norwich, United Kingdom
WAFAIE FAWZI, Richard Saltonstall Professor of Population Sciences, Professor of Nutrition,
Epidemiology, and Global Health, Chair, Department of Global Health and Population, Harvard T.H.
Chan School of Public Health, Boston, Massachusetts
MARY L’ABBÉ, Earle W. McHenry Professor, Chair, Department of Nutritional Sciences, University of
Toronto, Ontario, Canada
LAURA MARTINO, Senior Statistician, Systematic Review and Experimental Design Team, Assessment
and Methodological Support Unit, European Food Safety Authority, Parma, Italy
HILDEGARD PRZYREMBEL, Professor, Director, Federal Institute for Risk Assessment, Berlin,
Germany
EMORN UDOMKESMALEE, Senior Advisor, Institute of Nutrition, Mahidol University, Nakhon
Pathom Province, Thailand

Study Staff
GILLIAN BUCKLEY, Study Director
AMANDA NGUYEN, Associate Program Officer
MEREDITH YOUNG, Senior Program Assistant
ANN L. YAKTINE, Director, Food and Nutrition Board

Consultants
JANET KING, Professor Emeritus, University of California, Berkeley, and Davis; Senior Scientist,
Children’s Hospital Oakland Research Institute, Oakland, California
LESLIE PRAY, Science Writer

PREPUBLICATION COPY: UNCORRECTED PROOFS


v

C o p y r i g h t N a t i o n a l A c a d e
Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Copyright National Academy of Sciences. All rights reserved.


H a r m o n i z a t i o n o f A p p r o a c h e s t o N u t r i e

Reviewers

This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse
perspectives and technical expertise. The purpose of this independent review is to provide candid and
critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in
making each published report as sound as possible and to ensure that it meets the institutional standards
for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft
manuscript remain confidential to protect the integrity of the deliberative process.
We thank the following individuals for their review of this report:

Stephanie A. Atkinson, McMaster University


Patsy M. Brannon, Cornell University
Kathryn G. Dewey, University of California, Davis
Susan Krebs-Smith, National Cancer Institute, National Institutes of Health
Joseph Lau, Brown University School of Public Health
Amanda MacFarlane, Health Canada
Suzanne P. Murphy, Emerita, University of Hawaii at Manoa
Patrick J. Stover, Texas A&M University System

Although the reviewers listed above provided many constructive comments and suggestions, they
were not asked to endorse the conclusions or recommendations of this report nor did they see the final
draft before its release. The review of this report was overseen by M. R. C. Greenwood, University of
California, Davis, and Santa Cruz, and Susan C. Scrimshaw, Tufts University. They were responsible for
making certain that an independent examination of this report was carried out in accordance with the
standards of the National Academies and that all review comments were carefully considered.
Responsibility for the final content rests entirely with the authoring committee and the National
Academies.

PREPUBLICATION COPY: UNCORRECTED PROOFS


vii

C o p y r i g h t N a t i o n a l A c a d e m
Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Preface

The establishment of reference values for nutrient intakes of populations is essential for making
recommendations for appropriate, safe dietary intakes and for designing nutritional interventions, such as
nutrient fortification of foods. Traditionally these efforts have been directed at preventing nutrient
deficiencies. Additionally, with the increasing globalization of information and identification of factors
that influence the specific nutritional needs of different population groups (e.g., young children and
women of reproductive age), there has been a growing appreciation for the need to develop nutrient
reference values that are applicable across countries and that take into account the varying needs of
different population subgroups.
In recognition of this expanding range of concerns regarding the nutritional needs of populations, the
United Kingdom and the United States, in the 1990s, convened a group of experts who proposed a new
approach to setting nutrient intake recommendations to address these concerns. The outcome of those
efforts was the development of new methodologies for setting nutrient intake values that were adopted
initially in the United States in collaboration with Canada, and in the United Kingdom. Similar
approaches were developed and adopted by many European and other middle- and high-income countries.
In spite of these advances, the methods are challenging for countries to apply, and there has been limited
guidance on when and how to adapt the values from high-income countries for use in more resource-
constrained countries. While the World Health Organization (WHO) and the Food and Agriculture
Organization (FAO) have published nutrient reference values with some consideration of diverse dietary
and environmental conditions, these recommendations have not been updated regularly and have not
employed recent advances in methods for synthesis and analysis of evidence.
In 2009, the Department of Nutrition for Health and Development of WHO established a new process
and approach for developing and updating nutrition guidelines, and in 2010 a WHO Nutrition Guidance
Expert Advisory Group (NUGAG) was formed to strengthen the role of WHO in providing science-based
advice, evidence-informed policy, and program guidance in support of the WHO Nutrition Program.
Simultaneously, the Global Network of Institutions for Scientific Advice on Nutrition was formed to
provide scientific advice on nutrition and to establish nutrition recommendations and guidelines. The
Global Network met in Geneva, Switzerland, in 2010 to share information about nutrition guidance and
explore opportunities for collaboration as a step toward harmonization of diet- and nutrition-related
recommendations and guidelines. An important outcome of the meeting was recognition of the need to
synergize efforts and examine approaches for developing nutrition guidance, including the harmonization
of methods for (1) assessing the evidence underpinning nutrition science and (2) developing nutrient
intake recommendations and guidance to steer national policy development.
Today there is greater consistency across high-income countries in the methodological approach used
to derive an average nutrient requirement (AR) and safe upper intake level (UL), the two fundamental
values needed for establishing nutrient intake recommendations. However, there remains considerable
inconsistency across other national and international bodies, particularly in low- and middle-income
countries, in the approaches used to derive nutrient intake recommendations for their populations.
Moreover, there are no consistent processes in place to ensure that any such intake recommendations
remain current and relevant to those population subgroups.
With these activities as a backdrop, the Bill & Melinda Gates Foundation recognized the need for
action toward developing a uniform and consistent basis for setting nutrient intake recommendations
across countries. The foundation therefore asked the National Academies of Sciences, Engineering, and

PREPUBLICATION COPY: UNCORRECTED PROOFS


ix

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Medicine to do two things: first, to convene a workshop to explore questions about the uses of nutrient
intake recommendations, the frameworks used for their development, the status of nutrient intake
recommendations globally, and experiences and expertise in methodological approaches; and, second, to
convene a consensus study committee to assess methodological approaches that could be applied
uniformly across countries in setting nutrient intake recommendations. The workshop provided a
backdrop and a resource for the consensus study committee’s task. Specifically, the Bill & Melinda Gates
Foundation asked the committee to focus on young children and women of reproductive age and to apply
its findings to these target population subgroups using case scenarios informed by workshop presentations
and further review of global evidence and opportunities.
This committee’s work builds on the previous work of WHO, FAO, and other relevant authoritative
bodies to bring international stakeholders together to exchange data, experience, and ideas in an open
setting, and then to examine the current evidence, conceptualize candidate methodologies, and develop
recommendations for ways to move toward the goal of standardizing methodologies for establishing
nutrient intake recommendations.
The committee’s analyses, findings, and recommendations are presented in this report. The report
provides a framework for how stakeholders can, within the context of a country or a region’s needs and
abilities, generate a uniform approach for establishing nutrient intake recommendations that take into
account culturally and context-specific food choices and dietary patterns.
The Committee on the Application of Global Harmonization of Methodological Approaches to
Nutrient Intake Recommendations for Young Children and Women of Reproductive Age was supported
in its task by the invaluable contributions of a number of individuals. First, many thanks are owed to the
members of the committee who volunteered their time and expertise to a complex and challenging task
and to the preparation of this report. Their dedication to the project was commendable. Special thanks go
to the contributions of Janet King, who served as a consultant to the committee. Additional thanks go to
WHO and FAO for facilitating the workshop, as well as the many individuals who gave presentations at
the workshop hosted at FAO headquarters in Rome, Italy. Finally, the committee wishes to acknowledge
the contributions of the study staff: Gillian Buckley, study director; Amanda Nguyen, associate program
officer; and Meredith Young, senior program assistant. Finally, this project benefited from the general
guidance and assistance of Ann Yaktine, director of the Food and Nutrition Board.

Robert E. Black, Chair


Committee on the Application of Global Harmonization of Methodological
Approaches to Nutrient Intake Recommendations for Young Children and Women of
Reproductive Age

PREPUBLICATION COPY: UNCORRECTED PROOFS


x

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Contents

ACRONYMS AND ABBREVIATIONS xiii

SUMMARY S-1

1 Introduction Statement of the Problem 1-1


Background for the Study, 1-1
The Committee’s Task, 1-2
The Study Process, 1-3
Organization of the Report, 1-4
References, 1-4

2 Conceptual Foundations of Nutrient Reference Value Development 2-1


Background, 2-1
Nutrient Reference Values, 2-4
Guiding Principles in Setting Nutrient Reference Values, 2-6
Conclusions and Recommendations, 2-13
References, 2-13

3 A Harmonized Process for Nutrient Reference Value Development 3-1


Key Steps in the Process for Deriving Nutrient Reference Values, 3-1
Other Uncertainties to Consider When Estimating a UL, 3-17
A Framework for Deriving Nutrient Reference Values, 3-19
Findings and Conclusions, 3-20
Chapter Summary, 3-23
References, 3-23

4 Applying Methodological Approaches to Nutrient Intake Recommendations


for Young Children and Women of Reproductive Age: An Assessment of
Exemplar Nutrients 4-1
Harmonizing the Process for Nutrient Reference Values Using Exemplar
Nutrients, 4-1
Zinc Case Analysis, 4-3
Findings and Conclusions for Zinc, 4-13
Iron Case Analysis, 4-15
Findings and Conclusions for Iron, 4-22
Proposed Solutions for Iron, 4-23
Folate Case Analysis, 4-23
Findings and Conclusions for Folate, 4-29
Proposed Solutions for Folate, 4-30
Conclusions, 4-30
Applications of Nutrient Reference Values in Low- and Middle-Income
Countries, 4-31
References, 4-31

PREPUBLICATION COPY: UNCORRECTED PROOFS


xi

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

5 Future Directions and Data Gaps 5-1


Advantages of Harmonizing Methodologies to Derive Nutrient Reference
Values, 5-1
Steps Required to Encourage Commitment to the Guidelines, 5-2
Moving Forward Toward Harmonization, 5-3
References, 5-4

APPENDIXES

A Glossary A-1
B Workshop Agenda B-1
C Agree II Instrument C-1
D Tools and Methods to Evaluate the Risk of Bias in Individual Studies D-1
E Scaling Methods to Extrapolate from Reference Values of One Age Group
to Another E-1
F European Food Safety Authority’s Scientific Opinion on Dietary Reference
Values for Protein: Growth Factors for Children 6 Months to 17 Years F-1
G Committee Member Biographies G-1

PREPUBLICATION COPY: UNCORRECTED PROOFS


xii

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Acronyms and Abbreviations

AFSSA Agence Française de Sécurité Sanitaire des Aliments


AGP acid glycoprotein
AHRQ Agency for Healthcare Research and Quality
AI adequate intake
AMDR acceptable macronutrient distribution range
ANR average nutrient requirement
ANSES Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement, et
du Travail
AR average requirement
ASEAN Association of Southeast Asian Nations

COMA United Kingdom Committee on Medical Aspects of Food Policy


CRP c-reactive protein
CV coefficient of variation
CVD cardiovascular disease

D-A-CH Germany, Austria, Switzerland


DH United Kingdom Department of Health
DRI Dietary Reference Intake
DRV dietary reference value

EAR estimated average requirement


EDTA ethylenediaminetetra-acetic acid
EFSA European Food Safety Authority
EFZ endogenous fecal zinc
EURRECA European Micronutrient Recommendations Aligned

FAO Food and Agriculture Organization


FNB Food and Nutrition Board
FZA fractional zinc absorption

GRADE Grading of Recommendations, Assessment, Development, and Evaluation

HMD Health and Medicine Division

IDR ingestión diaria recomendada

PREPUBLICATION COPY: UNCORRECTED PROOFS


xiii

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

IDS ingestion diaria sugerida


INL individual nutrient level
IOM Institute of Medicine
IUNS International Union of Nutritional Sciences
IZiNCG International Zinc Nutrition Consultative Group

LOAEL lowest observed adverse effect level


LRNI lower reference nutrient intake
LSC límite superior de consume
LTI lowest threshold intake

NHANES National Health and Nutrition Examination Survey


NIV nutrient intake value
NL Netherlands Food and Nutrition Council
NNR Nordic Nutrition Recommendations
NOAEL no observed adverse effect level
NRV nutrient reference value

OHAT Office of Health Assessment and Translation

PICO population, interventions/exposures, comparators, and outcomes of interest


PRI population reference intake
PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analysis

RCT randomized controlled trial


RDA recommended dietary allowance
RI recommended intake
RN promedio de los requerimientos nutrimentales
RNI reference nutrient intake

SAARC South Asian Association for Regional Cooperation


SADC Southern African Development Community
SRDR Systematic Review Data Repository
SUL safe upper level

TAZ total absorbed zinc

UF uncertainty factor
UK United Kingdom
UL tolerable upper intake level
UN United Nations
UNICEF United Nations Children’s Fund
UNL upper nutrient level

VNR valores nutrimentales de referencia

PREPUBLICATION COPY: UNCORRECTED PROOFS


xiv

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

WHO World Health Organization

PREPUBLICATION COPY: UNCORRECTED PROOFS


xv

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Summary

STATEMENT OF THE PROBLEM

Recommended intake levels for nutrients and other dietary components were designed
initially to prevent nutrient deficiency diseases in a given population, and the original
methodological approach used to derive intake values did not include consideration for other
applications. However, with the increasing globalization of information and the identification of
a variety of factors specific to different population subgroups (e.g., young children1 and women
of reproductive age) that influence their nutritional needs, there has been increasing recognition
of the need to consider methodological approaches to deriving nutrient reference values (NRVs)
that are applicable across countries and that take into account the varying needs of different
population subgroups.
In response to the recognized need for a more comprehensive approach to developing
nutrient intake recommendations, the United Kingdom, the European Union, and the United
States jointly with Canada, developed dietary reference values (DRVs) and Dietary Reference
Intakes (DRIs) for their respective populations. Other authoritative bodies around the globe
developed similar approaches, including in China; Korea and Southeast Asia; Germany, Austria,
and Switzerland; Australia and New Zealand; and Mexico. This set the stage for discussions
about harmonizing the different methodologies being used to establish NRVs.
One outcome of these discussions was the convening of a group of international experts in
Italy, in 2005, to review the methodological approaches in use at that time. Attendees at the Italy
meeting identified four basic reasons why global harmonization of the methodologies is
important:
1. Harmonization of the process will improve the objectivity and transparency of values
derived by diverse national, regional, and international groups.
2. A harmonized process will provide a common basis or background for groups of experts
to consider throughout processes leading to NRVs.
3. A harmonized process will permit developing countries, which often have limited access
to scientific and economic resources, to convene groups of experts to identify how to
modify existing reference values to meet their populations’ specific requirements,
objectives, and national policies.
4. A harmonized process will supply a common basis for the use of reference values across
countries, regions, and the globe for establishing public and clinical health objectives and
food and nutrition policies, such as fortification programs, and for addressing regulatory
and trade issues.

1
In this report, “young children” includes birth up to 5 years of age.

PREPUBLICATION COPY: UNCORRECTED PROOF


S-1

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

S-2 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Here, the committee defines the harmonization of approaches as reaching global agreement
on the most appropriate methods or procedures for deriving NRVs. The concept of
methodological harmonization is particularly important for low- and middle-income countries
whose access to essential resources is limited or absent.

THE COMMITTEE’S TASK

The need for guidance and recommendations about methodological approaches, as well as
their potential for application to an international process for the development of NRVs, and
particularly for young children and women of reproductive age, prompted the Bill & Melinda
Gates Foundation to ask the National Academies of Sciences, Engineering, and Medicine to hold
a workshop and to convene a consensus committee to examine these issues, and to make
recommendations for a unified approach to developing NRVs that would be acceptable globally.
To set the stage for the consensus committee’s work, a workshop, Global Harmonization of
Methodological Approaches to Nutrient Intake Recommendations, was convened at the United
Nations’ Food and Agriculture Organization (FAO) headquarters in Rome. The workshop
provided a venue for dialogue and discussion about the experiences, both positive and negative,
of current approaches to deriving NRVs (see Appendix B for the workshop agenda), and it
served as a foundation for discussion of evidence by the consensus committee in carrying out its
task.
The Gates Foundation asked the committee to consider the implications of harmonizing
methodological approaches to deriving NRVs for a specific population subset—young children
(birth up to 5 years of age) and women of reproductive age. The committee was not asked,
however, to address the derivation of any actual values for NRVs. Nor was the committee asked
to determine how to implement its recommendations for a harmonized approach to deriving
NRVs, although it did consider possible next steps toward implementation (see Chapter 5). The
committee’s task is shown in Box S-1.

BOX S-1
Statement of Task
An ad hoc committee will be convened to review and assess methodological
approaches to developing nutrient intake recommendations using evidence presented
and discussions that took place in the workshop, Global Harmonization of
Methodological Approaches to Nutrient Intake Recommendations. The committee will
use cases derived from the workshop presentations to develop a framework that
demonstrates the application of a methodological approach for deriving nutrient intake
recommendations using a selected nutrient. The framework will take into account
impacts and trade-offs in consideration of methodological approaches for developing
intake recommendations globally. A report will be prepared that includes
recommendations for methodological approaches to achieve a uniform and consistent
basis for setting nutrient intake recommendations for young children and women of
child-bearing age across countries, and that will be reviewed and published in
accordance with institutional guidelines.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

SUMMARY S-3

KEY FINDINGS, CONCLUSIONS AND RECOMMENDATIONS

The purpose of developing NRVs, is to assure that, if met, the majority of a generally healthy
population will have sufficient intake levels to prevent nutrient deficiency disease and avoid
adverse effects of excessive intake. When applicable, reference values may also be determined to
reduce risk of chronic disease.
The traditional risk assessment model for deriving NRVs led to the development of a range
of reference values. These include the average nutrient requirement (AR), the recommended
intake (RI)2 (derived from the average requirement), and the safe upper intake level (UL). The
AR and the UL are core reference values. To reach global agreement on the most appropriate
methods and procedures for the derivation of standards used to establish NRVs, the focus must
be on these two values.

Recommendation 1. Nutrient reference expert panels should make two values their
priority: specifically, the population average requirement (AR) and safe upper levels of
intake (UL). Their reports should estimate the inter-individual variability of requirements
and use it to derive the AR. The expert panel should also acknowledge the basis and
uncertainty in estimation of both values.

The committee came to the following conclusions:


1. The need for nutritional benchmarks is critical all over the world. This shared
need, combined with the substantial effort and expense of deriving NRVs, is a
strong justification for international cooperation. Indeed, convening a global
expert panel would be ideal for promoting a harmonized process and making
efficient use of the funding to support these efforts. The committee deliberated
on the potential role of a central organizing body, such as the World Health
Organization (WHO) or FAO. WHO and FAO are both international
organizations responsible for facilitating cooperation in global health,
nutrition, and agriculture. Setting and promoting international norms and
standards is one of WHO’s responsibilities. FAO, similarly, is responsible for
supporting international policies that make up-to-date nutrition information
available.
2. Given the interface between their missions, WHO and FAO have a history of
collaboration, they share funding for the Codex Alimentarius, and have over
time established a trust fund to support the capacity of participants in low- and
middle-income countries to participate in the nutrient reference setting process.
Alternatively, it is possible that a technical organization, such as the
International Union of Nutrition Sciences (IUNS), might have equally good
convening authority among scientific experts needed for an international
harmonization effort. Another possibility is that international collaboration
could be carried out at the regional level.

2
Other terms include reference nutrient intake (RNI), recommended nutrient intake (RNI), recommended
dietary allowance (RDA), and recommended dietary intake (RDI).

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

S-4 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Recommendation 2. To set a nutrient reference value, ideally, a global body, such as the
World Health Organization (WHO), the United Nations’ Food and Agriculture
Organization (FAO), or the International Union of Nutritional Sciences (IUNS), or
secondarily, a regional consortium, should convene an expert panel to identify relevant
outcome measures and request a systematic review for the nutrient of interest, and appoint
a panel to advise on how to adapt the values to different population subgroups and settings.

Regardless of the convening organization, there are certain key steps in the process
of deriving NRVs that should be consistent across countries. Inherent in the
decision-making process is the determination of whether an existing NRV can be
accepted, updated, or a new value should be derived. Either way, selecting a
methodological approach for a nutrient review depends on the role of the nutrient
in meeting physiological needs, intake patterns, bioavailability of the nutrient, and
the presence of infection and other local factors that influence the requirement for
the population under consideration. The option to accept, update, or adapt existing
NRVs means that it is not necessary to go into a full review; rather, adjust existing
reference values and document how it was done. For new values, a full review is
required.

Recommendation 3. Expert groups should assess relevant evidence and, as needed, analyze
existing or new data to assess the characteristics of various diets that can affect the
bioavailability of specific nutrients.

Recommendation 4. When deriving nutrient reference values, countries or regions should


look at existing values derived by expert panels and determine whether to accept, update,
or adapt them to their context, if possible. If values are not relevant locally, an expert panel
should adapt values to the local context or modify existing values from other experts.

A thorough understanding of the uncertainties that affect the review process is


essential to maintaining the credibility of the nutrient review process, as well as the
accuracy and relevance of NRVs; enabling decision makers to use NRVs in
nutrition policy; and developing quantitative evidence assessment models.

Recommendation 5. After having adapted or created new nutrient reference values, to


achieve transparency the nutrient review expert panel should clearly report the reference
population, adjustment factors, and the methodology used. Expert panels should also
document the uncertainty in the evidence and in the methods used to develop the nutrient
reference values quantitatively. If this is not possible, then they should provide a qualitative
evaluation of the confidence in the body of evidence and in the methods used.

Since the first NRVs were developed, the process for deriving them has been made more
scientifically rigorous and transparent through the use of new tools that were either unavailable
or not used in the past. These include systematic reviews, larger and more accessible databases,
information of factors affecting culture- and context-specific food choices and dietary patterns,
new modeling techniques (e.g., new tools for assessing risk of bias), and new metabolic markers
of nutritional status. Based on its assessment of the strengths and weaknesses in methods

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

SUMMARY S-5

Key reference
Tools/Resources Data Approach/Methods
values

Nutrient status Dose−response


Systematic reviews Health outcomes modeling
Average
Physiological
requirement
requirement
Factorial approach
Bioavailability
Databases Recommended
Health factors (e.g., intake
infection)

Body size
Dietary patterns
Risk assessment* Upper limit
Nutrient intakes
Local and regional
factors Biomarkers
Risk of chronic
disease

FIGURE S-1 Framework for harmonizing the process to derive NRVs.


*Risk assessment is a process of (1) identification of risk of toxicity, (2) dose–response assessment, (3)
assessment of the prevalence of intakes outside the reference values, and (4) characterization of risks
association with excess intake.

currently being used to derive NRVs, as well as the rigor and transparency made possible by the
use of these tools, the committee developed a framework for harmonizing the process of deriving
NRVs (Figure S-1). The framework provides a platform for establishing NRVs that can be
applied across countries and various population subgroups. The framework involves four major
steps: (1) choose the appropriate tools, (2) collect relevant data from these tools, (3) identify the
best approach, or method of derivation, for the nutrient under consideration, and (4) derive the
two key reference values, the AR and UL.

ASSESSMENT OF EXEMPLAR NUTRIENT

The committee applied the framework to two population groups, young children and women
of reproductive age, and used case analyses of three exemplar nutrients—zinc, iron, and folate—
to examine the feasibility of its recommendations for harmonizing the methodological
approaches to deriving NRVs on a global scale. The committee did not actually derive any
NRVs. Rather, its focus was on the derivation process and mostly on which of the two
recommended approaches to deriving an AR, dose–response modeling or the factorial approach,
could apply to these three nutrients. Also, the committee did not carry out analyses for both
population groups for all three nutrients; rather, the case studies were selected to illustrate the
methodological applications across age groups.

Zinc Case Analysis

Certain population groups, especially those living in low- and middle-income countries, are
known to be potentially deficient and particularly vulnerable to the constellation of problems that

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

S-6 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

present with zinc deficiency. A number of factors contribute to the risk of zinc deficiency in
populations, including poor dietary quality. In other instances, while diets may not necessarily be
low in zinc, bioavailability caused by dietary factors such as high phytate concentration in foods
may be important. Other causes of zinc deficiency include an increase in the zinc physiological
requirement to meet the needs for pregnancy and growth in young children and an increased zinc
loss caused by diarrheal infections. From its review of evidence, the committee made the
following findings:
• A sensitive, specific biomarker of zinc nutrition is not available.
• Although severe dietary zinc restriction (i.e., diets providing less than 1 mg zinc per day)
causes a marked, rapid decline in plasma zinc, it can take weeks for levels to return to
baseline upon zinc repletion. Surveys show that plasma zinc concentrations remain
relatively stable over a wide range of less restricted zinc intakes. In contrast, supplements
have been shown to cause prompt increases in plasma zinc concentrations irrespective of
dietary intake. Although linear growth has been recommended as a functional indicator of
zinc status, since low height- or length-for-age has been shown to be responsive to
supplemental zinc, as with plasma zinc concentrations, the response to additional dietary
zinc is not as strong as the response to similar doses of supplemental zinc.
• Among adults, dietary phytate is a major determinant of zinc absorption. Thus, the
phytate/zinc molar ratio is often used to calculate a population’s dietary zinc
requirements. However, a recent study failed to find an effect of phytate on zinc
absorption in young children and in pregnant or lactating women. Additional data are
needed to determine if age or physiological zinc requirements influence the effect of
phytate on zinc absorption. Since zinc is generally associated with proteins in body cells
and tissues, it is important to determine whether dietary zinc recommendations need to be
matched to the amount and type of protein in the diet (i.e., animal or vegetable). When
developing zinc supplementation or fortification programs, it is generally assumed that all
zinc organic and inorganic salts are equally absorbed. However, the bioavailability of
zinc–amino acid complexes may be used more effectively if certain amino acids are
functioning as ligands.
• Survey data suggest that growing children are particularly vulnerable to developing zinc
deficiency and are more prone to develop gastrointestinal or pulmonary zinc infection as
a result. The physiology underlying this increased vulnerability in children is unknown.
Possibly, children lack tissue or cellular reserves to draw on when diet is marginal.
Alternatively, their immune systems are less well developed than adults. Research is
needed to determine if a modest, consistent increase in dietary zinc could reduce a child’s
susceptibility to zinc deficiency by increasing the level of zinc reserves or enhancing
immune function.
• Since the physiological requirements and ARs for young children and women of
reproductive age that have been made by the authoritative bodies reviewed in this report
are very similar, efforts should be made to consolidate these estimates globally. However,
there may still be a need to set national RKs based on the dietary zinc source (i.e.,
bioavailability) and the average body size of the population.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

SUMMARY S-7

Proposed Solutions
Because a sensitive biomarker of zinc inadequacy is not available, the factorial method is the
only feasible approach for estimating dietary zinc requirements at this time. The factorial
approach involves estimating the amount of a nutrient needed to replace that lost through fecal,
urine, and skin routes, either unchanged, or as a metabolite, then estimating the additional
amount required to support growth, pregnancy, or lactation. Currently, all international and
national groups reviewed in this report use the factorial approach for establishing zinc nutrient
intake recommendations. However, quantitative data are lacking for growing children. In
addition to data gaps identified and listed in the findings, including the need to continue to search
for a reliable biomarker of zinc status that is more sensitive to changes in diet zinc than
plasma/serum zinc concentrations, studies are needed to help identify the potential influence of
genetic polymorphisms (i.e., genetic variations) on individual dietary zinc requirements. Further,
the development of comprehensive models of inhibitors of zinc absorption across diverse
populations would improve estimates of dietary requirements.

Iron Case Analysis

Iron deficiency is the most common nutritional deficiency worldwide and a major cause of
infant mortality. Young children and women of reproductive age, especially during pregnancy,
are at increased risk because of the high iron requirements for growth or the replacement of iron
lost in menses. Iron deficiency is particularly common in low-income countries because of
limited intakes of animal products (which contain the more highly bioavailable heme iron) and
the regular consumption of cereal grain and legume-based diets (which are low in bioavailable
iron owing to the presence of phytate and other compounds that inhibit iron absorption). Iron
requirements can also be affected by the effects of infection and inflammation on the hormone
hepcidin, a principle regulator of iron. From its review of evidence, relevant to iron NRVs, the
committee made the following findings:
• The derivation of most values used for bioavailability is neither transparent nor evidence
based. This is because data on iron bioavailability from the whole diet is limited. The one
exception is the approach used by the European Food Safety Authority (EFSA), which is
based on a model in which the iron absorption from the whole (Western) diet is predicted
using good quality individual data on dietary intake, serum ferritin concentration, and
calculated physiological iron requirements. The model has since been refined and
updated and an interactive modeling tool published.
• The lack of agreement for reference values is attributable largely to the choice of
bioavailability factor used to convert physiological requirements into dietary intakes,
which results from limited information on iron absorption from complete diets, as well as
assumptions about iron storage at conception.
• When assessing the iron status of a population in relation to public health policies such as
food fortification, it is crucial to have good quality representative data for iron intake. If
the mean iron intake is below the AR, then evidence of iron deficiency must be supported
by measures of iron status. However, because dietary iron exists in two forms, measuring
dietary intake is difficult owing to limited information on heme iron in food composition
databases. In addition, several biomarkers of iron status (e.g., ferritin) are modified by
infection, chronic disease, and deficiencies of other nutrients.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

S-8 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

• Pregnancy is a normal physiologic condition, which should not require a major change in
food intake, provided the habitual diet contains all nutrients at levels that are consistent
for optimal health. However, many women become increasingly iron deficient or anemic
during pregnancy because they do not have adequate iron stores at conception or dietary
iron bioavailability is insufficient to meet their needs, despite the well-known adaptive
mechanisms that are designed to maintain iron homeostasis.
• NRVs are derived for healthy populations, and although physiological requirements for
iron should be the same for each population subgroup in every country or region, dietary
iron bioavailability will depend on the local diet composition, the risk of anemia in the
population, and infection or inflammation, which may change the AR.
• There are several factors related to diet, lifestyle, infection, and disease that confound the
association between iron intake and health outcomes, obscuring the dose–response
relationship needed to accurately estimate reference values.
• There are challenges to setting an iron UL, but such a value is essential for evaluating the
safety of food iron fortification and other public health programs.

Proposed Solutions
Although the factorial method has been universally adopted by authoritative bodies globally,
there remains wide variation in NRVs determined for women of reproductive age, mainly
because of different calculations used to transform physiological requirements into dietary
intakes. Although the bioavailability model used by EFSA is the preferred approach to determine
iron bioavailability from the whole diet, it is applicable in low- and middle-income countries
only if it is appropriately adapted. In low- and middle-income countries, intakes of iron
absorption inhibitors may be higher and heme iron intakes lower than in Western diets.
Additionally, many low- and middle-income countries have high burdens of infection and other
widespread health concerns, including hemoglobinopathies and thalassemia, which affect iron
metabolism and biomarkers of iron status. Thus, there is also a need to take into consideration
the effect of infection and inflammation on serum ferritin concentration, which is one of the most
widely used biomarkers of iron status. Serum ferritin is also an important tool for identifying
poor iron status among populations in low- and middle-income countries.

Folate Case Analysis

The global prevalence of folate deficiency and depletion is not well documented. However,
populations in low- and middle-income countries are not necessarily at greater risk of deficiency
than those in high-income countries, especially if the usual diet is high in legumes and
green leafy vegetables. Inadequate intakes are less prevalent in populations where folic acid has
been added to staple foods as a result of wide spread fortification policies. From its review of
evidence, the committee derived the following findings:
• Measurement of food folate levels for use in the derivation of NRVs may require
adjustment. For example, validation of folate values in food composition tables is an area
of concern. In the 1980s and 1990s it was recognized that folate content in foods can be
substantially underestimated unless the tri-enzyme procedure for releasing the vitamin
from food is used. This likelihood of underestimation can explain discrepancies between
intakes calculated from older food composition data versus more recent estimates based
on measures of folate status.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

SUMMARY S-9

• Some food preparation procedures can cause substantial losses of folate, which is
relatively unstable to heat and oxidation. From 50 to 80 percent of the folate in green
vegetables, and 50 percent of the folate in legumes, is lost during boiling. When
estimating the prevalence of inadequate intakes, folate values based on local cooked
recipes should be used whenever possible. While cooking techniques affect the amount of
folate required from food sources, it does not affect physiological requirements.
• As with food preparation, while folic acid fortification of staple and other foods does not
affect the physiological requirement for folate, it does affect the amount required from
food sources. Therefore, data on folate intake in food intake surveys must include the
amounts of fortified food consumed and the levels of folic acid in that food. High folate
status has emerged in a number of populations after initiating folic acid fortification
programs. Although folic acid is generally regarded as not toxic, it may be a factor in
neurological injury when pernicious anemia is present. Thus, avoiding excessive intakes
and monitoring folate status may be especially important in populations with a high
prevalence of vitamin B12 deficiency since there is some evidence that a high folic acid
intake may exacerbate B12 deficiency.
• It is unlikely that local adjustments will need to be made in requirements that depend on
breast milk folate concentration. Folate requirements are not affected by maternal status
or intake of foods with different bioavailabilities (except for the higher bioavailability of
folic acid in fortified foods). Thus, adjustments are probably not necessary.
• The prevalence of MTHFR genotype varies substantially across populations. In
Caucasians, this genotype occurs in from 2 to 16 percent of the population, compared to
25 percent of Hispanics, and a very low percent of Africans. There appears to be large
variability in prevalence across Asian populations. Compared to CC or CT genotypes,
homozygosity for the T allele results in lower plasma and erythrocyte folate, and higher
plasma homocysteine in those with plasma folate below about 15 nmol/L. Because
deriving a recommended intake (RI) to cover 97.5 percent of the population depends on
the variation around the AR and because populations with a higher variance will have a
higher RI, a high prevalence in a population may justify a higher coefficient of variation
for deriving an RI, as was done in recommendations from the Germany-Austria-
Switzerland group.
• Folate is synthesized by malarial parasites, so assessment of red blood cell count folate
should not be conducted immediately after an episode of malaria with fever, to avoid
spuriously high values.
• There is no evidence that deficiencies or high intakes of other micronutrients affect folate
requirements.
• Proposed Solutions
• Generally, dose–response modeling is used when there is a clear relationship between the
intake of a nutrient and a metabolic or functional outcome, such as preventing deficiency
disease, assessing biomarkers for health or risk of disease, or determining an upper safe
level of intake. The dose–response method is the preferred approach to derive ARs for
folate. Below, the methodology of dose–response assessment is described, including
options for managing uncertainty.
Folate recommendations for women and children are remarkably similar across countries,
owing to general agreement on biomarker cut points and the relatively few factors that can affect
requirements. There are no major deterrents to using existing reference values published by

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

S-10 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

authoritative bodies or to modifying them to the local context. However, the committee
identified a number of data gaps for deriving new, country-specific folate NRVs:
• The lack of validated data on the folate content of foods in low- and middle-income
countries, especially cooked foods;
• Increasing, but still insufficient evidence for population prevalence of polymorphisms
and their effect on folate requirements;
• Knowledge gaps around the local contribution of other micronutrient deficiencies
(vitamins B12, riboflavin, and B6) to plasma homocysteine levels; and
• The need to consider local consequences of poor B12 status on the prevalence of neural
tube defects and its interaction with high folate intake.

CONCLUSION AND NEXT STEPS

From its assessment of the current process for deriving NRVs, the application of new tools to
this process, and its three nutrient case analyses, the committee concluded that it is feasible to
harmonize the process to derive reference values globally.
Recommendation 6. Researchers and funding organizations should advance the knowledge of
nutrient requirement research by supporting research that uses modern technology, techniques, or
methods for assessing requirements.
In addition to the four major steps of the framework illustrated in Figure S-1, the committee
identified six core values as being critical to this effort:
1. NRVs are regularly updated.
2. The process is clear and transparent.
3. The methods are rigorous and relevant.
4. Factors influencing the NRV are documented.
5. The strength of the evidence is determined.
6. The review is complete and efficient.
The many potential users of NRVs include international organizations such as WHO and
FAO; nonprofit organizations; local, regional, and national governments; academic researchers;
health care providers; the food industry; and the general public. Because of the many ways that
NRVs are used and applied, from formulating food and nutrition policies to planning and
assessing diets for individuals and groups, it is important that users of NRVs understand their
derivation, particularly the AR and UL, as well as their application to public health.
Among the issues raised at the Global Harmonization workshop was that stakeholders need
to be convinced that a harmonized approach to setting NRVs is advantageous and necessary.
Influential organizations such as WHO and FAO, policy makers, nonprofit organizations, and
researchers, are needed to help launch an initiative that will explain the proposed harmonization
approach and advocate for its implementation, including its advantages as well as the reasons for
using a shared paradigm.
While this report describes the data gaps and offers a model for harmonizing the approach to
deriving NRVs globally, future dialogue will be needed across countries to garner support for a
harmonizing effort and to identify a pathway for implementing the recommendations of this
report. This means that it is crucial to have active participation and buy-in from the organizations
and groups to whom global harmonization will be entrusted. The collective effort of these groups

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

SUMMARY S-11

is needed to launch an initiative that will explain the proposed harmonization approach and
advocate for its implementation, including its advantages and the reasons for a shared paradigm.
An important next step is for the key enablers of harmonizing NRVs to develop a tool kit that
participants, particularly those from low- and middle-income countries, can use to guide the
development of methodological approaches to deriving NRVs for their populations. This report’s
intent is to provide the guidance needed as global stakeholders consider moving toward the
subsequent steps of implementation, dissemination, and evaluation.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Introduction and Problem Statement

BACKGROUND FOR THE STUDY

Traditionally, recommended intake levels for nutrients and other dietary components were
designed primarily to prevent nutrient deficiency diseases in a population. Furthermore, although
used for individual counseling, the recommended dietary allowances (RDAs) were not designed
for dietary planning and assessment of the dietary needs of individuals and they did not take into
consideration chronic disease endpoints (NASEM, 2018). However, with increasing
globalization of information and the identification of a variety of factors specific to different
population subgroups that influence their nutritional needs, there was recognition of the need for
a more encompassing approach to setting nutrient reference values (NRVs). To address these
issues, the United Kingdom (UK) Committee on Medical Aspects of Food and Nutrition Policy
began the process by defining a lower reference intake and an average requirement (see Chapter
2, Table 2-1). A reference nutrient intake that meets the needs of practically all healthy
individuals was retained (UK Department of Health, 1991).
Subsequently, the Food and Nutrition Board organized a symposium under the auspices of
the Institute of Medicine of the National Academies and published a report of the proceedings:
How Should the Recommended Dietary Allowances Be Revised? (IOM, 1994). The symposium
brought together stakeholders from government, academia, industry, and clinical dietetic practice
to discuss issues that should be addressed in order to move the RDA process forward. The
discussion included the question of whether there was sufficient evidence to change the existing
single value—the RDA—to include other values or intake ranges. The symposium participants
recognized the need to use a statistical approach to define the average requirement and
recommended intakes. The need for safe upper intake levels for nutrients was identified.
Subsequently, when NRVs were developed, there was recognition of the need to understand the
application of the values to facilitate planning and assessment of diets for individuals and
populations (IOM, 2003). NRVs and intake ranges are discussed in more detail in Chapter 2 (see
Box 2-1).

PREPUBLICATION COPY: UNCORRECTED PROOFS


1-1

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

1-2 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

BOX 1-1
Harmonization of Methodological Approaches to Nutrient Reference Values

Harmonization of approaches used to derive nutrient reference values (NRVs)


means reaching global agreement on the most appropriate concepts and approaches to
establish NRVs. Global agreement on NRV methodologies are needed to:

• Support the resolution of differences across countries in setting national and


international nutrition standards;
• Promote consistency in public and clinical health objectives;
• Provide a mechanism for designing national and international food policies, and
• Enhance the transparency of national standards to trade and other regulatory
actions with economic, health, and safety implications.

SOURCE: King and Garza, 2007.

These activities galvanized action in the United States and Canada to move toward a more
uniform and comprehensive approach to setting nutrient intake recommendations. The result was
the Dietary Reference Intakes (DRIs) produced jointly by the United States and Canada. Other
authoritative bodies in the following countries then developed similar approaches: the European
Union; China; Korea and Southeast Asia; Germany, Austria, and Switzerland; Australia and New
Zealand; and Mexico.
With adoption of a methodological structure for developing NRVs, there was recognition of
an opportunity for global harmonization of the methods and approaches used (see Box 1-1). In an
international meeting held in Florence, Italy, the importance of methodological harmonization
was recognized and guidelines for its implementation were proposed (King and Garza, 2007).

THE COMMITTEE’S TASK

While there is general consistency between many developed countries, including the United
States, Canada, and European countries, in the methodological approach to derive NRVs,
particularly the average requirement (AR) and upper level (UL), there remains considerable
inconsistency across other national and international bodies. This is particularly true in the
developing world in the approaches used to derive NRVs for specific population subgroups. Few
review processes are in place to ensure that NRVs remain current and relevant to those
population subgroups. Furthermore, the scientific resources needed to review and revise NRVs
for specific population subgroups varies widely across countries and in some cases may not
exist, resulting in gaps and inconsistencies in nutrition policy goals, guidelines, and
recommendations. The experiences and the lessons learned from those countries that have
worked toward harmonization of methodologies for deriving NRVs provides a rich backdrop for
dialogue about the possibilities and limitations of standardizing approaches to setting such
reference values across countries and globally, particularly among low- and middle-income
countries.
The need for guidance and recommendations on methodological approaches and their
potential for application to an international process for the development of NRVs, as well as the
methodological approaches to recommended intakes across population subgroups (particularly

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

INTRODUCTION AND PROBLEM STATEMENT 1-3

young children and women of reproductive age), prompted the Bill & Melinda Gates Foundation
to ask the National Academies of Sciences, Engineering, and Medicine (the National Academies)
to examine this issue and make recommendations for a more unified approach that would be
acceptable globally.
A two-part process was undertaken. First, a planning committee was convened to plan an
international workshop to explore questions about frameworks used in the development of
nutrient intake recommendations, the status of intake recommendations globally, and experiences
and expertise relevant to the international harmonization of methodological approaches to setting
intake standards. The workshop, Global Harmonization of Methodological Approaches to
Nutrient Intake Recommendations, held at the FAO headquarters in Rome, Italy, provided a
venue for dialogue and discussion about the experiences, both positive and negative, of current
approaches to nutrient intake recommendations (NASEM, 2018).
The workshop (see Appendix B for the workshop agenda) served as a foundation for a
discussion of the evidence by an ad hoc consensus committee to explore the experiences of
different countries or authoritative bodies’ current approaches to developing nutrient intake
recommendations; examine the current evidence, including the strengths and weaknesses in
current and proposed methodological approaches to setting nutrient intake recommendations
across developed and developing countries; assess the feasibility of harmonizing identified
methodologies using a selected nutrient test case; and offer recommendations and action steps to
facilitate the harmonization and standardization of methodological approaches for setting
nutrient-based intake recommendations on a global scale. The committee was not asked to
address the actual harmonization of NRVs, only the approaches used to derive them. Nor was the
committee asked to determine how to implement its recommendations for a harmonized
approach to deriving NRVs, although it did consider possible next steps toward implementation
(see Chapter 5).
In its task, the committee was asked to consider the implications of harmonizing
methodological approaches to deriving NRVs for a specific population subset, young children
and women of reproductive age. While “young children” is defined in this report as birth to 5
years of age, the committee’s analyses of exemplar nutrients (see Chapter 4) includes
consideration of other age categories in some instances, depending on data availability or age
ranges used to set NRVs (e.g., see Table 4-3).

THE STUDY PROCESS

In response to the Gates Foundation request, the Health and Medicine Division of the
National Academies established a committee with expertise in nutrition science, Dietary
Reference Intakes, dietary patterns, epidemiology, study design and methodology, statistics or
biostatistics, and international nutrition standards. The committee attended the international
workshop, Global Harmonization of Methodological Approaches to Nutrient Intake
Recommendations, held in Rome, Italy, at the headquarters of the Food and Agriculture
Organization of the United Nations on September 21–22, 2017 (see Appendix B). The committee
then met in closed session and by conference calls to deliberate on its task. The committee’s
findings, conclusions, and recommendations are derived from its assessment of relevant
evidence.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

1-4 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

BOX 1-2
Statement of Task

An ad hoc committee will be convened to review and assess methodological


approaches to developing nutrient intake recommendations using evidence presented
and discussions that took place in the workshop, Global Harmonization of
Methodological Approaches to Nutrient Intake Recommendations. The committee will
use cases derived from the workshop presentations to develop a framework that
demonstrates the application of a methodological approach for deriving nutrient intake
recommendations using a selected nutrient. The framework will take into account
impacts and trade-offs in consideration of methodological approaches for developing
intake recommendations globally. A report will be prepared that includes
recommendations for methodological approaches to achieve a uniform and consistent
basis for setting nutrient intake recommendations for young children and women of
child-bearing age across countries, and that will be reviewed and published in
accordance with institutional guidelines.

ORGANIZATION OF THE REPORT

This report reviews and evaluates the evidence for global harmonization of methodological
approaches to deriving NRVs with a specific focus on young children and women of
reproductive age. The report is organized into five chapters. Chapter 1 describes the background
for the study and the statement of task. Chapter 2 describes the concepts underpinning the
development of NRVs. Chapter 3 examines the key steps in the process for deriving reference
values. Chapter 4 applies a framework to three nutrient case analyses to examine the feasibility
of harmonizing the methodological approach. Although Chapter 4 focuses on three specific
nutrients (zinc, iron, folate), the committee uses relevant examples of other nutrients in other
sections of the report. Chapter 5 proposes a way forward with future directions to achieve
harmonization and examines current data and research gaps.
Appendix A presents a glossary of terms used in the report. Appendix B presents the agenda
for the workshop held in Rome and an additional open session held by the committee. Appendix
C describes the AGREE II instrument. Appendix D presents a table of tools and methods to
evaluate the risk of bias in an individual study. Appendix E shows a compilation of the scaling
methods used to extrapolate from the reference values of one age group to another. Appendix F
contains EFSA’s Scientific Opinion on Dietary Reference Values for Protein: Growth Factors for
Children Age 6 Months to 17 Years. Appendix G contains the committee members’ biographical
sketches.

REFERENCES

IOM (Institute of Medicine). 1994. How should the recommended dietary allowances be revised?
Washington, DC: National Academy Press.
IOM. 2003. Dietary Reference Intakes: Applications in dietary planning. Washington, DC: The National
Academies Press. https://doi.org/10.17226/10609.
King J. C., and C. Garza. 2007. Harmonization of nutrient intake values. Food and Nutrition Bulletin
28(Suppl. 1):S3-S12.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

INTRODUCTION AND PROBLEM STATEMENT 1-5

NASEM (National Academies of Sciences, Engineering, and Medicine). 2018. Global harmonization of
methodological approaches to nutrient intake recommendations: Proceedings of a workshop.
Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25023.
UK (United Kingdom) Department of Health. 1991. Dietary reference values for food energy and
nutrients in the United Kingdom (Report on health and social subjects; 41). London, UK: Her
Majesty’s Stationery Office.
https://www.nutrition.org.uk/attachments/article/234/Nutrition%20Requirements_Revised%20Oc
t%202016.pdf (accessed March 4, 2018).

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Conceptual Foundations of Nutrient Reference Value


Development

The following discussion provides background and supporting evidence for the committee’s
assessment of methodological approaches to achieve a uniform and consistent basis for deriving
nutrient reference values (NRVs) for young children (birth up to 5 years of age) and women of
reproductive age across countries. The committee drew on evidence from the published literature
as well as evidence presented and discussions that took place in the workshop, Global
Harmonization of Methodological Approaches to Nutrient Intake Recommendations (NASEM,
2018). Specifically, this chapter provides historical perspective on efforts to harmonize
approaches to deriving NRVs; it describes the NRVs identified in this report; it reviews the
components of the framework being used to derive NRVs; and it offers a recommendation for
which NRVs to prioritize.

BACKGROUND

As described in Chapter 1, the United Kingdom (1991), the European Union (1992), and the
United States jointly with Canada (1994), initiated the new approach to setting nutrient intake
recommendations based on a set of NRVs rather than a single recommended intake. This new
approach allowed for greater flexibility and broader application of the reference values,
including the ability to plan and assess diets for individuals as well as groups. As more countries
began to adopt the concept of a set of NRVs, the need for a more unified and consistent approach
to deriving the values became apparent. In response, a core organizing framework for deriving
NRVs was developed by an expert international panel convened by the United Nations
University’s Food and Nutrition Programme, in collaboration with the Food and Agriculture
Organization (FAO), the World Health Organization (WHO), and the United Nations
International Children’s Fund (UNICEF) (King and Garza, 2007).

PREPUBLICATION COPY: UNCORRECTED PROOFS


2-1

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

2-2 HARMONIZATION OF NUTRIENT REFERENCE VALUES

TABLE 2-1 Comparison of Terms for Nutrient Reference Values (NRVs) Currently in Use Around the
World
Recommendation United States United European Union/ WHO/FAO
and Canada Kingdom EFSA
Umbrella term for NRVs: DRI DRV DRV

Average requirement EAR EAR AR


Recommended intake level RDA RNI PRI RNI
Lower reference intake LRNI LTI
Adequate intake AI AI
Safe upper level of intake UL SUL UL UL
Appropriate macronutrient AMDR AMDR RI Population
distribution range mean intake
goals
NOTE: AR = average requirement; DRI = Dietary Reference Intake; DRV = dietary reference value;
EAR = estimated average requirement; EFSA = European Food Safety Authority; FAO = Food and
Agriculture Organization; LRNI = lower reference nutrient intake; LTI = lower threshold intake; PRI =
population reference intake; RDA = recommended dietary allowance; RI = reference intake range for
macronutrients; RNI = reference nutrient intake; SUL = safe upper intake level; UK = United Kingdom;
UL = tolerable upper intake level; WHO = World Health Organization.
SOURCE: Adapted from King and Garza, 2007.

The 2007 international panel’s next task was to identify the core reasons justifying the need
for a conceptual framework to harmonize the process used to derive NRVs (King and Garza,
2007). They identified four core reasons:
1. Improve the objectivity and transparency of values that are derived by diverse national,
regional, and international groups.
2. Provide a common basis for groups of experts to consider throughout processes that lead
to nutrient reference values.
3. Permit developing countries, which often have limited access to scientific and economic
resources, to convene groups of experts to identify how to modify existing intake values
to meet their populations’ specific requirements, objectives, and national policies.
4. Provide a common basis for the use of NRVs across countries, regions, and the globe for
establishing public and clinical health objectives and food and nutrition policies, such as
fortification programs, and for addressing regulatory and trade issues.
The organizing framework developed by the 2007 international panel focused on two key
concepts: (1) estimating the average nutrient requirements (ANR) for a population and (2)
defining an upper nutrient level (UNL). The ANR was to be derived from a normal distribution
of nutrient intakes needed to achieve a specified health outcome for the reference population.
The UNL was determined as the highest level of usual intake of a nutrient that would pose no
risk of adverse health effects in most individuals in the population.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

CONCEPTUAL FOUNDATIONS 2-3

FIGURE 2-1 Proposed organizing framework for deriving nutrient reference values (NRVs) with
applications.
NOTES: NRVs are the average nutrient requirement (ANR) and the upper nutrient level (UNL). Other
NRVs can be derived from these two values, (e.g., the individual nutrient levelx [INLx], which is used for
guiding individual intakes is the ANR plus some percentile of the mean). The ANR and UNL are derived
from estimates of amounts needed for a specific physiological criterion, such as tissue stores, metabolic
balance, or a biochemical function. The NRVs are modified for population differences in the food supply,
host factors (e.g., infection and genetic variations), and needs for sustaining long-term health. The
methods of using NRVs to assess or evaluate intakes of individuals and populations differ from those
used for planning diets for individuals and populations. NRVs are the basis for a number of policy
applications. LOAEL = lowest observed adverse effect level; NIV = nutrient intake value; NOAEL = no
observed adverse effect level.
SOURCE: King and Garza, 2007.

The 2007 organizing framework, shown in Figure 2-1, is grounded in a risk assessment
model and is based on expert review of primary data (King and Garza, 2007). That framework
set the stage for developing future NRVs and became a baseline for this committee’s
development of a separate framework for harmonizing methodological approaches for deriving
NRVs globally.
Collectively, NRVs are described in this report as reference values rather than intake values
because actual intakes of any nutrient vary widely across a population (Bourges et al., 2005;
EFSA NDA Panel, 2010; Paik, 2008; Sasaki, 2008). The NRVs identified in the King and Garza
(2007) organizing framework, while not standardized across countries, can be described in a
consistent way (i.e., according to their application).

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

2-4 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

BOX 2-1
Nutrient Reference Values

Average requirement (AR) is the level of daily intake for a nutrient that is estimated to
meet the requirements of 50 percent of individuals in a given population subgroup. The AR
can be used to assess the probability of adequate intake.
Recommended intake (RI), derived from the AR, is the level of daily intake for a nutrient
that is sufficient to meet the requirements of 97–98 percent of a given population subgroup.
The RI can be used to plan the diets of individuals, but not those of population subgroups.
Terms that have been used for recommended intakes include recommended dietary
allowances (RDAs) (IOM), recommended nutrient intakes (RNIs) (FAO/WHO), and
population reference intakes (PRIs) (EFSA).
Adequate intake (AI) is the recommended average intake of a nutrient based on
observed or experimentally determined estimates for an apparently healthy population. This
reference value is determined when there is insufficient evidence to set an average
requirement.
Upper level (UL) values represent the highest intake of a nutrient that is likely to pose no
risk of adverse effects to most individuals in a population. The UL does not refer to the acute
effects of an episodic high intake that might be consumed in a supplement, for example.

The graph illustrates the relationship between the nutrient reference values.

NUTRIENT REFERENCE VALUES

In this report, the committee describes the four core reference values: average requirement
(AR), recommended intake (RI), adequate intake (AI), and safe upper intake level (UL). Of
these, ARs and ULs are critical for evaluating and planning nutrient intakes at the population
level. RIs are used as the basis of dietary planning for individuals, and AIs are useful only as a
benchmark that enables the risk of inadequate intake to be judged as low. Box 2-1 shows the four
reference values and their definitions.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

CONCEPTUAL FOUNDATIONS 2-5

Average Requirement

The AR is defined as the intake needed by 50 percent of a population subgroup (defined


based on age, gender, and physiological status) to meet a specific criterion of nutrient adequacy.
Examples of adequacy criteria include liver stores of vitamin A, normal hematological status and
serum concentrations in the case of vitamin B12, and normal hematology and plasma
homocysteine in the case of folate.
Two commonly used methods to derive the AR are dose–response (or intake–response) and
the factorial approach. Dose–response, the most frequently used, provides a direct determination
of a nutrient requirement (e.g., the level of intake that maintains the plasma level of a vitamin
and its metabolites). The factorial approach involves estimating the amount of a nutrient needed
to replace the amount lost through fecal, urine, and skin routes, either unchanged, or as a
metabolite; then estimating the additional amount required to support growth, pregnancy, or
lactation. Another, less commonly used method to derive an AR is the nitrogen balance study for
use in estimating protein requirements.
The prevalence of intakes below the AR has been shown to be a statistically valid estimate of
the prevalence of inadequate intakes in a population subgroup (Carriquiry, 1999; IOM, 2000). In
what is known as the “EAR cut-point” method, both the AR and nutrient intake data are used to
calculate the prevalence (percent of persons in each population subgroup) of inadequate intakes,
(i.e., intakes below the AR) (Barr et al., 2002). This cut-point method is valid for almost all
nutrients except energy; protein; and in premenopausal menstruating women, iron (Carriquiry,
1999).
In countries or regions where risk of deficiency is high, food fortification or other programs
can be used to plan fortification levels in foods such that intakes of only 2.5–5 percent of a group
will fall below the AR (Allen, 2006; Allen et al., 2006).
Unfortunately, WHO/FAO and many other authoritative bodies do not provide ARs in their
recommendations, in part because when ARs were developed, their importance for population
dietary assessment and planning was not recognized. The exceptions in the WHO/FAO
recommendations are vitamin B12 and folate, because these recommendations were established
later than the AR values already established by the IOM (1998).
An additional problem is that the evidence for deriving an AR is limited for some nutrients.
Indeed, in the recently completed set of nutrient intake recommendations by the European Food
Safety Authority (EFSA), ARs were determined for only seven vitamins and three minerals
owing to the fact that there were insufficient data to derive an AR with adequate certainty
(EFSA, 2017a). In the absence of an AR, it is not possible to derive recommended intake (RI)
levels (i.e., the RDA, RNI, or PRI). In which case, the AI is closest in value as it represents the
daily intake that appears to be adequate for a population.

Recommended Intake

RIs are calculated to meet the needs of 97.5 percent of individuals in a population, most
commonly by adding two standard deviations to the AR of that group. RIs can be used to plan
the diets of individuals, but not those of population subgroups. Individuals with intakes above the
recommended levels will have a very low risk of inadequacy. If the variability of nutrient
requirements among individuals (inter-individual variability) is not known precisely, in most
cases it is assumed to be 10 to 15 percent of the AR. Because RIs meet the needs of almost all
individuals, estimating the prevalence of inadequacy as the percent of intakes below these

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

2-6 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

recommendations will substantially overestimate the true prevalence of inadequate intakes in a


population subgroup; thus ARs are the only useful value for estimating the prevalence of
inadequacy.

Adequate Intake

AIs should be established as a last resort if adequate data to derive an AR are lacking. An AI
is the observed median intake of a nutrient by a group of healthy people with apparently
adequate status of that nutrient. Because the AI of a population subgroup is likely to be even
higher than the RI for that group, it should not be used as the basis for estimating the prevalence
of inadequate intakes either. The only assumption that can be made is that, if the mean intake of
a group is greater than the AI, then the prevalence of inadequacy is likely to be low. If the mean
intake is less than the AI, then assessment of adequacy will have to depend on clinical and/or
biochemical measures of nutrient status. It is clearly important that future efforts to develop
nutrient intake recommendations should aim to develop ARs rather than AIs, given their limited
usefulness.

Tolerable Upper Levels

ULs represent daily intakes that, if consumed chronically over time, will have a very low risk
of causing adverse effects. They do not however, refer to the acute effects of a high dose that
might be consumed in a supplement. Criteria for deriving ULs have been described most recently
by EFSA (EFSA, 2017b) and have been established for most nutrients by the IOM (1998b).
Given the higher risks attached to excessive intake during different life stages, such as
pregnancy, ULs can vary substantially across population subgroups. A general goal is to have
less than 5 percent of a population subgroup with an intake greater than the UL, including
intakes from supplements and fortified foods (IOM, 2000). This is sometimes a challenge when
planning nutrient levels for fortification, and the goal is to have a low proportion of a population
with intakes less than the AR; yet, the ULs of some population subgroups, such as children
consuming fortified cereals, are easily exceeded. This problem is sometimes resolved by
providing different types of fortified foods to meet the varying needs for specific nutrients
among different population subgroups. There is no UL for some nutrients owing to insufficient
data.

GUIDING PRINCIPLES IN SETTING NUTRIENT REFERENCE VALUES

New tools and methods either previously unavailable or not used in the past have enabled
global opportunities for harmonizing methodological approaches to deriving NRVs. Since
publication of the original organizing framework by King and Garza (2007), NRVs developed,
for example by the United States and Canada for calcium and vitamin D have incorporated
components into the original framework that introduced greater transparency and scientific rigor
into the process and enhanced the accuracy and replicability of the values derived (IOM, 2011a).
More recently, guidelines for the inclusion of chronic disease endpoints have been proposed by
the U.S. National Academies (NASEM, 2017; Yetley et al., 2017). Before examining in depth
how these changes have created an opportunity for the committee to propose a way toward
harmonizing the nutrient review process, core components and guiding principles of the current

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

CONCEPTUAL FOUNDATIONS 2-7

process for setting NRVs are described in brief below. Relevant components are further
described and analyzed relative to the committee’s task in Chapter 3.

The Average Requirement and Upper Level:


Core Components of the Organizing Framework

The two core reference values used to derive all other reference values in the King and Garza
(2007) organizing framework are the AR and the UL. As described by Janet King at the Global
Harmonization Workshop (NASEM, 2018), the process for setting an AR should:
1. Be based on the mean nutrient intake of a specific population;
2. Be established for all essential nutrients and food components that have public health
relevance;
3. Include acceptable macronutrient distribution ranges for carbohydrates, protein, and fat
that reduce chronic disease risks associated with the intake of these macronutrients;
4. Consider nutrient–nutrient interactions and quantify them, if possible; and
5. Consider subpopulations with special needs, keeping in mind, however, that reference
values are intended for apparently healthy individuals.
As described by King and Garza (2007), the UL is not a recommended intake, rather it is the
highest level of usual daily nutrient intake that poses no risk of adverse health effects in most
individuals in the population. Although the magnitude of uncertainty in risk of adverse effects
needs to be considered when setting the UL, it cannot be assumed that a selected uncertainty
factor will be the same for all nutrients (NASEM, 2018).
Defining the population to be covered by an NRV has been an evolving concept over the past
several decades. Previously, NRVs were derived to meet the needs of an “apparently healthy”
population. This definition did not include individuals with disease states requiring medical
management; frank malnutrition; malabsorption syndromes; or energy requirements linked to
medical or physical disability. At the present time, while there is some correlation between
obesity prevalence and a country’s wealth, recent data supports that about one-third of the global
population is overweight or obese (Ng et al., 2014).
The implication of a rising global prevalence of overweight and obesity is a corresponding
increase in risk of chronic disease. Thus, across most developed countries, and increasingly
among low- and middle-income countries, a healthy population has become difficult to
characterize; and the definition of an “apparently healthy” population has come into question.
Concerns about the applicability of future DRIs to the variability in the health status of the
general U.S. population informed the National Academies’ report Guiding Principles for
Developing Dietary Reference Intakes Based on Chronic Disease, which recommend that future
DRI committees “characterize the health status of the population in terms of who is included and
excluded for each DRI” (NASEM, 2017). The committee recognizes the importance of chronic
disease, however, most NRVs for pregnancy and children are aimed at meeting specific nutrient
needs for the most relevant health outcomes (e.g., growth, cognitive development). For the target
age groups in this report, chronic disease is not a priority outcome.

Overview of the Process for Setting Nutrient Reference Values

After an authoritative body is convened to identify a nutrient for review, the overarching
steps described by most authoritative bodies, including the National Academies (NASEM, 2018)

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

2-8 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

and EFSA (https://www.efsa.europa.eu/en/topics/topic/dietary-reference-values-and-dietary-


guidelines), for deriving NRVs are:
1. An existing systematic review is updated or a new review is initiated;
a. An indicator is selected for the systematic review;
2. The appropriate method is selected:
a. Dose/intake–response assessment,
b. Factorial approach, or
c. Balance study;
3. The usual intake characteristics and dietary patterns of the target population subgroup are
assessed; and
4. Implications or special concerns for the population are considered.
Each of these steps is described in turn below. Relevant components are further described
and analyzed relative to the committee’s task in Chapter 3.

Revise or Initiate and Carry Out a Systematic Review


Systematic reviews are conducted using evidence from a range of population subgroups;
however, they generally comprise adult populations. Evidence from adults is frequently used as a
basis for extrapolating values to children.
In the past, nutrient reviews were carried out using narrative evidence reviews. Now NRVs
are derived from evidence gathered through systematic evidence-based reviews. The systematic
review is a core tool for evaluating the strength and quality of evidence for associations between
a nutrient under review and relevant health outcomes, as well as relevant endpoints. Generally,
the systematic review is initiated once the nutrient for review has been identified by an
authoritative body and before an expert nutrient review panel begins its work.
The process of systematically reviewing the literature in order to draw a conclusion about a
scientific question hinges on the concept of evidence-based research. This concept promotes the
systematic and transparent use of existing studies in order to increase validity, transparency, and
accessibility of research results. It is based on the assertion that “to avoid waste of research, no
new studies should be done without a systematic review of existing evidence” (Lund et al.,
2016). Although originally developed to address intervention questions (Higgins and Green,
2011), over time, the systematic review approach has been adapted to broader questions and is
now seen by various organizations as a way to strengthen the scientific value of their
assessments (EFSA NDA Panel, 2010; IOM, 2011b; Slutsky et al., 2008).
In making his case (at the Global Harmonization workshop) that the systematic review
should be a core component of the global harmonization of methodologies for NRVs (NASEM,
2018), Joseph Lau argued that because human physiology is essentially the same across the same
subpopulations around the world, the same evidence base can be used to inform nutrient intake
recommendations. Plus, the cost in expertise, time, and money to conduct a systematic review
can be minimized through collaboration and sharing of resources. In addition, review panels now
have at their disposal the Systematic Review Data Repository (SRDR), an open access,
collaborative, Web-based repository of systematic review data established by the U.S. Agency
for Healthcare Research and Quality (AHRQ) (AHRQ, 2013). The SRDR serves as an archive
and a data extraction tool that is available to users worldwide to assist with the development of a
systematic review. An advantage of this database is that it can be reviewed, revised, and
supplemented on an ongoing basis (NASEM, 2017).

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

CONCEPTUAL FOUNDATIONS 2-9

Also at the Global Harmonization workshop (NASEM, 2018), Lau emphasized that
constructing a predefined analytic framework for a systematic review is a key step in the
systematic review process (see Figure 2-2). The framework defines the scope of the evidence
review, influences the selection of specific outcomes to assess, helps to establish a common set
of research questions and review criteria for the systematic review, and can be used to construct
an evidence map of the issues and questions to be addressed. Other key steps of the systematic
review process are described below. The EFSA Guidance Document (EFSA NDA Panel, 2010)
also describes keys steps in the systematic review process.
Eligibility criteria The evidence to be included in a systematic review is selected according to
eligibility criteria defined a priori. This reduces the risk of bias that could be introduced into the
process if studies were selected according to their results, such as if only studies with statistically
significant results were included. Eligibility criteria include study design (e.g., randomized trials,
observational studies, mechanistic studies, animal studies), age and sex of the study populations,
and outcomes of interest as specified in the PICO/PECO tables (see Box 2-2). Depending on the
indicator being set (e.g., AR or UL), an outcome can be a clinical condition associated with
nutrient deficiency or excess; a measureable, reliable, and valid biomarker (e.g., plasma
concentration) of the intake/status of the nutrient concerned; or a biomarker associated with a
metabolic or inflammatory processes, immune status, or other functional metrics of nutrient
status.

FIGURE 2-2 A generic analytic framework for use indicators of health in a systematic review.
NOTES: Arrow 1: association of exposure with clinical outcomes of interest. Arrow 2: association of
exposure with surrogate or intermediate outcomes. Arrow 3: association of indicators of exposure to
clinical outcomes Arrow 4: Association between exposure and indicators of exposure. Arrow 5:
Association of indicators of exposure to surrogate or intermediate outcomes. Arrow 6: Association
between surrogate outcomes and clinical outcomes.
SOURCES: Presented by Joseph Lau at HMD Workshop, September 21, 2017. From Russell et al., 2009.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

2-10 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

BOX 2-2
The PICO/PECO Model
The PICO/PECO model is a tool for organizing and focusing questions into a
searchable query. The PICO/PECO elements help identify search terms and concepts to
use in searching the literature. The elements of the model are:
P = Population: How would you describe the population subgroup? What are the most
important characteristics of the population?
I/E = Intervention/Exposure: What primary intervention or exposure are you
considering?
C = Comparison: What is the main alternative to compare with the intervention?
O= Outcome: What is the outcome or affect being considered?

Select an indicator The nutrient review process begins by selecting an indicator for the AR or
UL (see Figure 2-2). This indicator is a health outcome or surrogate marker that serves as a
measure of exposure to the nutrient of interest and becomes the foundation for estimating the
reference values. In most cases, there is a single outcome measure for each nutrient’s AR or UL,
and age/sex group. Indicator selection is generally based on expert judgment, and selection
includes a thorough review of all relevant evidence, particularly when associations between a
nutrient and health outcome is controversial.
Appraisal of internal and external validity (risk of bias) Evaluation of risk of bias is an
inherent step in the systematic review process that requires assessment of limitations to the
internal and external validity of each study included in a systematic review (Higgins and Green,
2011). Internal validity represents the extent to which a given study is able to provide accurate
estimates of its outcomes of interest: external validity indicates the extent to which the results of
a study can be extrapolated to a population that differs from the study population in some
respect. Limitations to internal and external validity can also be expressed as risk of internal and
external bias. Limitations to internal validity can arise, for example, by using samples from a
limited number of countries to provide estimates of the entire population, or by considering a
limited number of food items as a proxy for the entire diet of an individual. The concept of risk
of bias is different from that of study quality since even a well-designed study can be affected by
some type of risk of bias (e.g., sometimes, for ethical reasons it is not possible to randomize the
treatment to the individual). Risk of bias and ways to evaluate and manage it are discussed in
more detail in Chapter 3.

Select an Appropriate Method: Intake–Response Assessment, Factorial Approach, or Balance


Studies
Intake–response assessment The intake–response assessment describes how a known
physiological outcome changes according to the intake of a nutrient. The physiological outcome
may be a biomarker of function, disease, or other health outcome. Biomarkers are indicators on
the causal pathway that link the intake of a nutrient to an endpoint or health outcome of interest
and, as such, can be used to establish a causal relationship between nutrient intake and a
deficiency disease. To illustrate, vitamin C is required to prevent scurvy, a disease characterized
by fatigue, inflamed and bleeding gums, easy bruising, and poor wound healing (Medscape,

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

CONCEPTUAL FOUNDATIONS 2-11

2017). Research in men recovering from scurvy has shown that vitamin C intakes (60 to 100
mg/day) elevate plasma ascorbate concentrations to about 50 μmol/L and body stores to between
1 and 1.5 grams (EFSA NDA Panel, 2013; Medscape, 2017). The European Food Safety
Authority Committee on Dietary Reference Values chose an average vitamin C requirement of
80 mg/d for women and 90 mg/d for men to maintain fasting plasma ascorbate concentrations of
50 μmol/L (EFSA NDA Panel, 2013).
Biomarkers can also be used to establish an association between a nutrient intake and risk of
chronic disease (see below). Also described below, in addition to being used for the goals of
preventing deficiency and preventing risk of chronic disease, intake–response assessments are
also used to determine safe upper intake levels.
Preventing deficiency Avoiding nutrient deficiency was the original basis for establishing NRVs.
In the United States, the first RDAs (1941) were used to inform food relief programs following
the Great Depression; provide nutritionally adequate food provisions for the military in the
Second World War; and serve as a basis for food fortification and other federal food guidance
policies (Murphy et al., 2016; NRC, 1941). Establishing intake recommendations to prevent
deficiency requires a thorough understanding of a population’s dietary patterns, adequacy of
intake, and a sensitive and specific biomarker of nutritional status with an established cutoff
value that defines deficiency. Even when the relationship between nutrient intake and clinical
manifestations of deficiency are clear, deriving NRVs is often complicated by related questions,
such as how to maintain reserves of the nutrient or ensure optimal biological activity.
Preventing risk of chronic disease Avoiding nutritional deficiency is still a more pressing
public health concern than reducing risk of chronic disease in much of the world. However,
although scarcity of data remains a problem, as scientific understanding of the relationship
between diet and disease advances, it has become apparent that it is necessary to evaluate the
influence of different nutrients and nonessential food substances on the long-term probability of
developing chronic diseases such as cancer, cardiovascular disease, or diabetes (NASEM, 2017;
Yetley et al., 2017). Yet, chronic diseases can take decades to develop, and many factors
influence their etiology, including diet, with each factor playing only a small part in the causal
pathway. Additionally, intake of a given nutrient or non-essential food substance varies widely
over the latency period for a chronic disease; much of the uncertainty in assessing relationships
between intake and chronic disease lies in accurately measuring dietary patterns (NASEM,
2017).
Although biomarkers of intake can be objective measures of diet, they are prone to random
error. As such, using biomarkers of intake for chronic disease endpoints introduces uncertainty.
Thus, a biomarker of intake must be validated (NASEM, 2017; Yetley et al., 2017). Another
challenge lies in choosing meaningful and suitable outcome indicators for the chronic disease in
question, or a valid surrogate for these outcomes (NASEM, 2017). The analytical strategy for
incorporating chronic disease into consideration for deriving a NRV has to account for such
challenges, and the experts responsible for such analysis, as with all such studies, must be clear
about how uncertainty in the data are addressed.
Determining an upper safe level of intake NRVs usually include a safe upper intake level. As
stated previously, ULs are not recommended intakes, rather they are estimates of the highest
level of daily intake that convey no appreciable risk of adverse health effects (EFSA NDA Panel,
2006; King and Garza, 2007). While setting the lower bound of a reference value is often a
matter of estimating an intake that would avoid deficiency, the upper bound is both conceptually

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

2-12 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

and analytically more complicated to derive. For this reason, the concept has been called
ambiguous, “based more on what it is not, than on what it is” (Vieth, 2007). Either the no
observable adverse effect level (NOAEL) or the lowest observable adverse effect level (LOAEL)
is used to identify a UL, with adjustments made for uncertainty (discussed below and in Chapter
3).
An additional challenge with the UL is that when the usual dietary intake pattern results in a
percentage of the population exceeding the UL, questions arise about the observable toxicity
level. Vitamin A intake in young children illustrates the problem. In 2002, roughly a quarter of
preschool-aged children in the United States exceeded the UL for vitamin A intake from dietary
sources alone; among those who took multivitamins, three-quarters exceeded the UL (Allen and
Haskell, 2002). In contrast, dietary vitamin A deficiency is common among children in South
Asia and sub-Saharan Africa. In low-income countries, twice-yearly supplementation programs
for young children are a common strategy to combat this problem (Kraemer et al., 2008; WHO,
2018), and there is growing interest in home and commercial fortification programs to improve
intake of vitamin A and other micronutrients on a more regular basis (Kraemer et al., 2008).
When faced with such variation in dietary intake patterns, policy makers all over the world need
to know just how narrow the safe intake range is.
Even consumption at or near the upper bound of a nutrient intake is not necessarily desirable,
especially if sustained over a long period of time. Yet, consumption of many nutrients at higher
levels is not uncommon in affluent countries, partly because of supplement use. U.S. national
survey data suggest that about 30 percent of children and a quarter to one-half of adults take
dietary supplements regularly (Bailey et al., 2013; Office of Dietary Supplements, 2015).
Research from Europe suggests wider variation in supplement use, ranging from low prevalence
in Greece to half of men and almost two-thirds of women in Denmark (Skeie et al., 2009).
Factorial approach The factorial approach is used when biochemical indicators are not
representative of actual nutrient levels. Instead, this method uses quantification of nutrient losses
as an estimate of the physiological requirement. Use of the factorial approach requires taking
into consideration the efficiency of absorption, and accounting for phytates and other mineral-
binding compounds in food that can affect absorption.
Balance study Similar to the factorial approach that can be used when a nutrient under review
does not have a biomarker representative of actual nutrient level is the balance study. Balance
studies measure input and excretion—when they are equal it is assumed that the body is
saturated. Also assumed is that the size of the body pool of the nutrient is appropriate and that
increasing the levels of intake do not provide additional benefit. This approach is most often used
to determine protein and mineral requirements. For protein, nitrogen balance studies are used to
determine the amount of protein needed to replace losses without increasing the total body
nitrogen level. As an example of the use of balance studies to estimate a mineral NRV, EFSA
found that adults older than 25 years need only replace the calcium lost in urine, feces, sweat,
and skin cells (EFSA NDA Panel, 2015).

Conduct a Dietary Intake Assessment of the Population


The dietary intake assessment is used to assess the prevalence of intakes that fall outside a
reference value or range in a specific population subgroup. Population-based intake data,
generally available from national surveys or other large population databases, is used to estimate
the prevalence of deficiency or excess. Correction for intra-individual variability (day-to-day) is

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

CONCEPTUAL FOUNDATIONS 2-13

important and can be achieved by quantifying intake on one day for the full sample, or two or
more nonconsecutive days on a representative subsample (NRC, 1986). Biomarkers may be
useful for estimating and validating the adequacy of reported intakes relative to the reference
value (Carriquiry, 1999).

Consider Implications or Special Concerns for the Population of Interest


Of particular concern is consideration for adjustments in the reference values for
populations, especially for those consuming a plant-based diet. In the case of zinc, for example,
NRVs are adjusted to account for reduced absorption where phytates are present in food sources
(Gibson et al., 2010). Deriving reference values for vulnerable population subgroups also
includes consideration of uncertainties when making these adjustments. Additionally, the public
health policy implications of the reference values need to be considered. In Chapter 4, the
committee examines how these adjustments, uncertainties, and implications are managed for
young children (birth up to 5 years of age) and women of reproductive age.

CONCLUSION AND RECOMMENDATION

The committee came to the following conclusion:


The purpose of deriving NRVs is to ensure that the majority of a generally healthy
population will have sufficient nutrient intake levels to prevent deficiency disease
and avoid adverse effects of excessive intake. Additionally, when applicable,
reference values may be determined to reduce risk of chronic disease. The AR and
UL are the two key values needed to carry out the necessary risk assessment and to
develop public health policies, such as food fortification strategies. Statistical tools
can be employed to calculate other values that represent the needs of a specific
proportion of the population, for example, the intake value that meets the needs of
97.5 percent of the population (i.e., the RI). Additionally, information on the degree
of uncertainty is an important consideration when estimating these values.

Recommendation 1. Nutrient reference expert panels should make two values their
priority: specifically, the population average requirement (AR) and safe upper levels of
intake (UL). Their reports should estimate the inter-individual variability of requirements
and use it to derive the AR. The expert panel should also acknowledge the basis and
uncertainty in estimation of both values.

REFERENCES

AHRQ (Agency for Healthcare Research and Quality). 2013. SRDR: Systematic review data repository.
Rockville, MD: Agency for Healthcare Research and Quality.
http://www.ahrq.gov/cpi/about/otherwebsites/srdr.ahrq.gov/index.html (accessed May 31, 2018).
Allen, L. H. 2006. New approaches for designing and evaluating food fortification programs. Journal of
Nutrition 136:1055-1058.
Allen, L. H., B. de Benoist, O. Dary, and R. Hurrell. 2006. Guidelines on food fortification with
micronutrients. Geneva, Switzerland: World Health Organization, Food and Agriculture
Organization.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

2-14 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Bailey, R. L., J. J. Gahche, P. R. Thomas, and J. T. Dwyer. 2013. Why US children use dietary
supplements. Pediatric Research 74:737
Barr, S. I., S. P. Murphy, and M. I. Poos. 2002. Interpreting and using the dietary references intakes in
dietary assessment of individuals and groups. Journal of the American Dietetic Association
102:780-788.
Bourges, H., E. Casaneuva, and J. Rozado. 2005. Recomendaciones de ingestion de nutrimentos para la
poblacion mexicana. Mexico: Instituto Danone.
Carriquiry, A. L. 1999. Assessing the prevalence of nutrient inadequacy. Public Health and Nutrition
2:23-33.
EFSA (European Food Safety Authority). 2017a. Dietary reference values for nutrients. Summary report.
EFSA supporting publication 2017:e15121.
EFSA. 2017b. Overview on tolerable upper intake levels as derived by the Scientific Committee on Food
(SCF) and the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA).
https://www.efsa.europa.eu/sites/default/files/assets/UL_Summary_tables.pdf (accessed January
11, 2018).
EFSA NDA Panel. 2006. Tolerable upper intake levels for vitamins and minerals. EFSA Journal 2006:1-
480.
EFSA NDA Panel. 2010. Scientific opinion on principles for deriving and applying dietary reference
values. EFSA Journal 8(3):1458-1488.
EFSA NDA Panel. 2013. Scientific opinion on dietary reference values for vitamin C. EFSA Journal
11(11):3418:68. http://www.efsa.europa.eu/efsajournal (accessed January 11, 2018).
EFSA NDA Panel. 2015. Scientific opinion on dietary reference values for calcium. EFSA Journal
13(5):4101.
Gibson, R. S., K. B. Bailey, M. Gibbs, and E. L. Ferguson. 2010. A review of phytate, iron, zinc, and
calcium concentrations in plant-based complementary foods used in low-income countries and
implications for bioavailability. Food and Nutrition Bulletin 31(2 Suppl):S134-S146.
Higgins, J. P. T., and S. Green (editors). 2011. Cochrane handbook for systematic reviews of
interventions version 5.1.0. The Cochrane Collaboration. http://handbook.cochrane.org (accessed
February 10, 2018).
IOM (Institute of Medicine). 1998a. Dietary Reference Intakes for thiamin, riboflavin, niacin, vitamin b6,
folate, vitamin b12, pantothenic acid, biotin, and choline. Washington, DC: National Academy
Press. https://doi.org/10.17226/6015
IOM. 1998b. Dietary Reference Intakes: A risk assessment model for establishing upper intake levels for
nutrients. Washington, DC: National Academy Press. https://doi.org/10.17226/6432
IOM. 2000. Dietary Reference Intakes: Applications in dietary assessment. Washington, DC: National
Academy Press. https://doi.org/10.17226/9956
IOM. 2011a. Dietary Reference Intakes for calcium and vitamin D. Washington, DC: The National
Academies Press. https://doi.org/10.17226/13050.
IOM. 2011b. Finding what works in health care: Standards for systematic reviews. Washington, DC: The
National Academies Press. https://doi.org/10.17226/13059
King, J. C., and C. Garza. 2007. Harmonization of nutrient intake values. Food and Nutrition Bulletin
28(1):S3-S12.
Kraemer, K., M. Waelti, S. de Pee, R. Moench-Pfanner, J. N. Hathcock, M. W. Bloem, and R. D. Semba.
2008. Are low tolerable upper intake levels for vitamin A undermining effective food fortification
efforts? Nutrition Reviews 66(9):517-525.
Lund, H., K. Brunnhuber, C. Juhl, K. Robinson, M. Leenaars, B. F. Dorch, G. Jamtvedt, M. W. Nortvedt,
R. Christensen, and I. Chalmers. 2016. Towards evidence based research. British Medical Journal
355:i5440
Medscape. 2017. Scurvy: Practice essentials. https://emedicine.medscape.com/article/125350-overview
(accessed November 9, 2017).
Murphy, S. P., A. A. Yates, S. A. Atkinson, S. I. Barr, and J. Dwyer. 2016. History of nutrition: The long

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

CONCEPTUAL FOUNDATIONS 2-15

road leading to the dietary reference intakes for the United States and Canada. Advances in
Nutrition 7(1):157-168.
NASEM (National Academies of Sciences, Engineering, and Medicine). 2017. Guiding principles for
developing Dietary Reference Intakes based on chronic disease. Washington, DC: The National
Academies Press. https://doi.org/10.17226/24828
NASEM. 2018. Global harmonization of methodological approaches to nutrient intake
recommendations: Proceedings of a workshop. Washington, DC: The National Academies Press.
doi: https://doi.org/10.17226/25023.
Ng, M., T. Fleming, M. Robinson, T. Blake, N. Graetz, C. Margono, E. C. Mullany, S. Biryukov, C.
Abbafati, S. F. Abera, J. P. Abraham, et al. 2014. Global, regional, and national prevalence of
overweight and obesity in children and adults during 1980–2013: A systematic analysis for the
Global Burden of Disease Study 2013. Lancet 384(9945):766-781.
NRC (National Research Council). 1941. Recommended dietary allowances. Washington, DC: National
Academy Press. https://doi.org/10.17226/13286
NRC. 1986. Nutrient adequacy: Assessment using food consumption surveys. Washington, DC: The
National Academies Press. https://doi.org/10.17226/618.
Office of Dietary Supplements. 2015. Multivitamin/mineral supplements fact sheet for health
professionals. https://ods.od.nih.gov/factsheets/MVMS-HealthProfessional (accessed November
30, 2017).
Paik, H. Y. 2008. Dietary reference intakes for Koreans (KDRIS). Asia Pacific Journal of Clinical
Nutrition 17(Suppl 2):416-419.
Russell, R. M. 2010. Integration of epidemiologic and other types of data into Dietary Reference Intake
development. Critical Reviews in Food Science and Nutrition 50(S1):33-34. doi:
10.1080/10408398.2010.526879.
Sasaki, S. 2008. Dietary reference intakes (DRIs) in Japan. Asia Pacific Journal of Clinical Nutrition
17:420-444.
Skeie, G., T. Braaten, A. Hjartåker, M. Lentjes, P. Amiano, P. Jakszyn, V. Pala, A. Palanca, E. M.
Niekerk, H. Verhagen, K. Avloniti, et al. 2009. Use of dietary supplements in the European
Prospective Investigation into Cancer and Nutrition Calibration Study. European Journal of
Clinical Nutrition 63:S226-S238.
Slutsky, J., D. Atkins, S. Chang, and B. A. Sharp. 2010. Comparing medical interventions: AHRQ and the
effective health care program. Journal of Clinical Epidemiology 63(5):481-483.
Vieth R. 2007. Vitamin D toxicity, policy, and science. Journal of Bone and Mineral Research
22(2):V64-V68.
WHO (World Health Organization). 2018. Vitamin A supplementation in infants and children 6-59
months of age. http://www.who.int/elena/titles/guidance_summaries/vitamina_children/en
(accessed January 11, 2018).
Yetley, E. A., A. J. MacFarlane, L. S. Greene-Firestone, C. Garza, J. D. Ard, S. A. Atkinson, D. M. Bier,
A. L. Carriquiry, W. R. Harlan, D. Hattis, J. C. King, D. Krewski, D. L. O’Connor, R. L.
Prentice, J. V. Rodricks, and G. A. Wells. 2017. Options for basing dietary reference intakes
(DRIs) on chronic disease endpoints: Report from a joint US/Canadian-sponsored working group.
American Journal of Clinical Nutrition 105(Suppl):249S-855S.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A Harmonized Process for Nutrient Reference Value


Development

In the previous chapter, the committee reviewed the current process being used by most
authoritative bodies to derive nutrient reference values (NRVs) and offered a recommendation
regarding which NRVs should be prioritized. The current process for deriving NRVs, while
based on the King and Garza (2007) conceptual framework, has also been made more rigorous
and transparent through the use of new tools and methods that were either unavailable or not
used in the past. In this chapter, the committee examines and assesses in greater detail key steps
in the nutrient review process, with a focus on how to assess relevant data from systematic
reviews and other data resources and how to account for local context (e.g., culturally specific
food choices and dietary patterns). Based on this assessment, the chapter concludes with the
committee’s proposed framework for harmonizing approaches used to derive NRVs on a global
scale. Throughout the chapter, the committee emphasizes the need for nutrient review panels to
recognize and manage any uncertainties that may exist in either the data or methods used to
derive NRVs. Also throughout the chapter, the committee offers three separate recommendations
to support a harmonized process for NRV development. It was beyond the committee’s task (see
Box 1-2) and, thus, beyond the scope of this report to address specific ways to implement these
recommendations, although some possible next steps are discussed in Chapter 5.

KEY STEPS IN THE PROCESS FOR DERIVING NUTRIENT REFERENCE VALUES

For methodological approaches to establishing NRVs to be adapted globally, there are certain
key steps in the process that should be consistent across countries. These key steps are illustrated
as a flow diagram in Figure 3-1. Each step is discussed in detail in this chapter. The four steps of
the King and Garza (2007) approach to deriving NRVs (see Chapter 2) are embedded in the flow
diagram. In the figure, the option to update or adapt existing NRVs means that it is not necessary
to go into a full review, rather, adjust existing reference values and document how it was done.
For new values, a full review is required.

PREPUBLICATION COPY: UNCORRECTED PROOFS


3-1

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-2 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Authoritative body or
expert panel identifies
nutrient for review

Accept, revise existing Convene expert


or conduct new nutrient review panel
systematic review

Evaluate existing
NRVs

Option to keep Option to establish


and update or new NRVs
adapt NRV

Describe the nutrient Define approach


and outcomes selected
and approach used

Dose-response Factorial
assessment approach
Describe the
evidence base

Appraise the
evidence
Evaluate usual
intakes and dietary
patterns
Evaluate usual intakes
and dietary patterns

Document
adjustments to
Assess local
local context
context

Accept, revise or derive

FIGURE 3-1 Flow diagram for deriving nutrient reference values.


Note: NRV = nutrient reference value

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A HARMONIZED PROCESS 3-3

Importantly, and as discussed throughout this chapter, the process to review any NRV must
be transparent and include the following components:
• Document each stage of the process.
• Assess and document limitations in the data and methods.
• Consider uncertainties,
• Conduct a rigorous peer review of the nutrient review report.
The AGREE II Instrument (see Appendix C) serves as an example of a generic tool that has
been used by health care providers, guidelines developers, and policy makers to evaluate the
quality of clinical practice guidelines and it may serve as a useful template for similar
applications in nutrition (Brouwers et al., 2010).

An Authoritative Body or Expert Panel Identifies a Nutrient for Review

The first step in deriving an NRV is identifying the nutrient(s) for review, as well as the age
and sex groups in the relevant population. In some situations, the reference values may be
reexamined only for select population subgroups, such as children or pregnant women.
Reexamining existing NRVs requires justification, including either new evidence for the nutrient
or policy changes, such as fortification, that make it necessary to reassess the values (NASEM,
2018). In most cases, an authoritative body, such as a sponsoring governmental agency,
identifies the nutrient(s) to be reviewed from among those under consideration. The United
States and Canada, for example, collaborate on the Dietary Reference Intakes (DRIs), and the
European Commission sponsors the European Food Safety Authority (EFSA) scientific opinions
on nutrient references (Atkinson, 2011; EFSA, 2017).
Reexamining existing NRVs requires justification, including new evidence for the nutrient,
or policy changes, such as fortification, that make it necessary to reassess the values (NASEM,
2018). In the case of the joint U.S. and Canadian nutrient DRI review process, nutrient
nominations were requested through formal notification. Candidate nutrients were accepted for
consideration based on (1) a rationale and description of why a nutrient a review was warranted,
and how it would address a current public health concern, and (2) a documented literature search
demonstrating new, relevant literature since the last nutrient DRI review. Another process that
has been used is that the governmental agency or other authoritative body requests public input
on candidate nutrients (as discussed by Peter Clifton at the Global Harmonization workshop)
(NASEM, 2018).
The committee deliberated on the potential role of a central organizing body such as the
World Health Organization (WHO) and the United Nations’ Food and Agriculture Organization
(FAO), two international organizations responsible for facilitating cooperation in global health,
nutrition, and agriculture. Setting and promoting international norms and standards is one of
WHO’s responsibilities. FAO, similarly, is responsible for supporting international policies that
make up-to-date nutrition information available (FAO, 2018). Given the overlap in their
missions, WHO and FAO have a history of collaboration, most notably on the international food
standards contained in the Codex Alimentarius (FAO/WHO, 2018a). The Codex Alimentarius
Commission (Codex) is a vast and well-established international body. Its first formal meetings
were in 1961, although regional Codex meetings started in the 1940s (FAO/WHO, 2018b).
WHO and FAO share funding for the Codex and have, over time, established a trust fund to
support the capacity of participants in low- and middle-income countries to participate in the
standard setting process (FAO/WHO, 2018d). Codex delegates set standards for, among other

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-4 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

things, nutrition and labeling information, a topic inextricably related to NRVs (FAO/WHO,
2018c). This body is in a position to negotiate the logistics and funding of a similar effort for
deriving NRVs. To illustrate, the Joint FAO/WHO Expert Committee on Food Additives is an
international expert scientific committee that evaluates the safety of food additives. The
committee conducts risk assessments and safety evaluations on a number of food additives and
food contaminants. It is also concerned with developing principles for safety assessment of
chemicals in foods that are aligned with current risk assessment approaches and methodologies.
Or, it is possible that a technical organization, such as the International Union of Nutritional
Sciences (IUNS) might also have equally good convening authority among the scientific experts
needed for such a project. Its adhering bodies include scientific and nutrition societies in over 80
countries, and one of the main objectives of IUNS is to encourage international scientific
collaboration (IUNS, 2018a). IUNS is formally affiliated with various international and regional
nutrition organizations, including the African Nutrition Society, the Asia Pacific Clinical
Nutrition Society, the International Zinc Consultative Group, and the Iodine Global Network
(IUNS, 2018b).
Another possibility is that international collaboration may be more efficiently carried out at
the regional level. Working through regional networks could be a particularly promising strategy
in developing countries. Where regional economic communities such as the South African
Development Community (SADC) and the Association of Southeast Asia Nations (ASEAN) are
already committed to advancing regional development there is precedent for such networks
working on common problems related to nutrition and food security. The SADC Food and
Nutrition Security Strategy 2015–2025 is meant to promote food fortification and good nutrition,
goals that cannot be realized without suitable NRVs (SADC, 2014). The ASEAN nutrition
program puts similar emphasis on tracking malnutrition in the region, something entirely
dependent on accurate reference values ([ASEAN], 2016, 2017). Elsewhere, the Mercosur trade
partnership has harmonized nutrition labeling regulations and food labeling laws across South
America.

Conclusions and Recommendation to Support the Process for Convening a Review of


Nutrient Reference Values

The committee came to the following conclusions:


1. Two international organizations, WHO and FAO, both with missions to
facilitate global cooperation in nutrition and health matters, present an
opportunity for enabling harmonization of the process for deriving NRVs on a
global scale by serving as a convener of an expert review panel. Convening a
global expert panel would be ideal for promoting a harmonized process and
making efficient use of the available resources. Or, it is possible that a technical
organization, such as the IUNS might also have equally good convening
authority among the scientific experts needed for such a project. Another
possibility, one that is particularly promising in developing countries, is that
international collaboration may be more efficiently carried out at the regional
level.
2. The committee recognizes that political issues as well as country-specific
conventions and traditions may present a barrier to countries to fully
committing to a shared process for deriving NRVs. For the near future, national

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A HARMONIZED PROCESS 3-5

governments may still convene their own expert panels for this process. In such
cases, those national panels would make better use of their resources by
adapting international values to their context and making use of existing
systematic reviews when available.

Recommendation 2. To set a nutrient reference value, ideally a global body, such as the
World Health Organization (WHO), the United Nations’ Food and Agriculture
Organization (FAO), or the International Union of Nutritional Sciences (IUNS), or
secondarily, a regional consortium, should convene an expert panel to identify relevant
outcome measures and request a systematic review for the nutrient of interest, and appoint
a panel to advise on how to adapt the values to different population subgroups and settings.

Revise and Existing or Conduct a New Systematic Review

Key steps in the systematic review process are described in Chapter 2, beginning with the
necessity of understanding the status of the evidence for the nutrient under review prior to
initiating a review. This includes knowing whether there is an existing systematic review that can
be updated or if a new review is needed. Evaluating the relevance of the evidence in an existing
review involves careful selection of the eligibility requirements prior to implementing the review
and consideration of clinical measures of deficiency or excess, measureable and validated
biomarkers for the nutrient of interest, and other factors. If it is decided that a new systematic
review is needed, there are several elements that can increase the strength, rigor, and
transparency of the process to derive NRVs. These include identifying Population,
Intervention/Exposure, Comparator, and Outcomes (PICO/PECO) elements; assessing
uncertainty in the evidence (i.e. appraising risk of bias in individual studies); assessing bias in
the systematic review process; and grading the strength of the body of evidence. Each of these is
discussed below.

Identify PICO/PECO Elements


As stated in Chapter 2, the evidence to be included in a systematic review is selected
according to eligibility criteria defined a priori, including criteria specified for PICO/PECO
tables. Indeed, the PICO/PECO process serves as a core organizing framework for a systematic
review. PICO/PECO elements are used to build conceptual relationships among the research
questions being addressed, guide the identification of a database to search (such as PubMed or
Embasse), and define the search strategy. If there is a previous systematic review on a nutrient,
the PICO/PECO process may serve as the basis for an updated review.
In identifying the P component, that is, the population of interest, relevant demographic
factors, including age, sex, and ethnicity, need to be considered as well as the public health
significance. As an example of the latter, women of reproductive age are a vulnerable group, and
as such, they require special consideration because of the complexity of determining the
nutritional needs of a population subgroup with limited access for clinical research.
Deriving NRVs is usually based on data from a healthy reference population (see discussion
in Chapter 2). When the population of interest is not healthy, such as when a population has a
high prevalence of infection, or when the population has unique physiological characteristics
such as obesity, advanced age, or pregnancy, reference values must be adjusted accordingly.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-6 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Studies on individuals suffering from chronic infections may be included, but separated later by
a subgroup analysis.
The I or intervention/exposure component of PICO/PECO refers to exposure to the nutrient.
To identify I elements, expert review panels judge the quality of intake data from foods and other
substances, such as supplements or water (e.g., water can be a dietary route for iodine and
magnesium). In reviewing the literature, it may be necessary to exclude research when the dose
of the nutrient in question is not within a biologically relevant range.
The C or comparator or control component facilitates assessment of the effect of an
alternative to the intervention. For data from randomized controlled trials (RCTs), for example,
comparisons can be made relative to a placebo group, to a nonintervention group, or an existing
standard of care group. In observational cohort studies, the comparison could be performed
between groups stratified by differences in usual intake.
The last step of the PICO/PECO process, the O component, involves the listing and ranking
of outcomes of interest. Prioritizing the many health outcomes that can be influenced by
exposure to a nutrient often compels difficult decision-making and may require an iterative
review of the population data available for different outcomes. Yet, it is a necessary process for
managing the scope, time, and expense of a systematic review.
As stated in Chapter 2 (see Figure 2-2), proximal biomarkers of the outcome of interest may
be useful in assessing and prioritizing health outcomes. Red blood cell folate levels, for example,
can be an important biomarker of folic acid status, as can rates of neural tube defects and
stillbirth in a population. When conducting this last step of the PICO/PECO process, separating
reviews of observational studies from RCTs is generally necessary because RCTs tend to have
shorter exposure windows and follow-up times, which may be more relevant to proximal
outcomes than to some clinical outcomes. Clinical outcomes can require longer exposure times
to see an effect. Additionally, RCTs may have more stringent criteria for assessing intake.
Additionally and importantly, a given outcome may not be relevant to all members of a
population. In considering the relationship between sodium intake and chronic disease, for
example, blood pressure is a surrogate marker of interest for both adults and children.
PICO/PECO tables should be created separately for different age groups and sexes, in the
population or subgroup of interest. PICO/PECO elements should be carefully considered and
assessed when adapting existing NRVs to a different context or population subgroup.

Assess Uncertainty in the Evidence—Appraisal of Risk of Bias in Individual Studies


Evaluation of risk of bias is an inherent step in the systematic review process. As stated in
Chapter 2, an evaluation of risk of bias requires assessment of both the internal and external
validity of each individual study (Higgins et al., 2011). Bias occurs when systematic flaws or
limitations in the design, conduct, or analysis of a review distort the review results or
conclusions (Whitinga et al., 2016). Bias can be introduced into a study at multiple levels: when
estimating nutrient intakes (referred to as exposure assessment), when identifying outcomes
(hazard identification), or when measuring outcomes (hazard characterization of biomarkers of
nutrient status or adverse or beneficial health effects). Regardless of where it is introduced, bias
can affect the conclusions drawn about the relationship between a nutrient and an outcome, as
well as affect the interpretation of the study results. Many sources of bias are study design and
outcome dependent and have to be assessed with this principle in mind; they are evaluated by a
multidisciplinary team of experts, including both methodologists and domain experts.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A HARMONIZED PROCESS 3-7

Several tools have been developed in recent years to evaluate different types of risk of bias
that can affect an individual study. These tools were originally developed for clinical
interventions and subsequently adapted to other research areas. The tools comprise checklists of
a series of items that have to be evaluated. Exemplar tools are shown in Appendix D.
Traditionally, risk of bias has been addressed using a qualitative approach, that is, by
classifying studies into tiers that reflect the level of confidence or certainty in the evidence (e.g.,
low, medium, or high), and performing sensitivity scenario analysis, which involves rerunning
the evidence synthesis under various conditions (e.g., including or excluding studies affected by
high risk of bias) and assessing how much the conclusions change accordingly. When these
analyses suggest serious bias, then bias-adjusted meta-analysis may be necessary (Dias et al.,
2013; Turner et al., 2009).
Bias-adjusted meta-analyses are methods that allow for adjustments of the estimates of the
response based on an assessment of the direction of the bias and a quantitative expression of its
magnitude. They rely on the use of expert judgment elicitation and modeling (Dias et al., 2013;
Turner et al., 2009) and consist of probability distributions expressing the expected magnitude of
the bias. The National Toxicology Program and the National Institute of Environmental Health
Sciences’ Office of Health Assessment and Translation encourages this approach but warns that
judgment regarding the effect of the bias on the estimate of the response must be based on sound
data (National Toxicology Program, 2015).
In many fields, including nutrition, such data are still extremely scarce and thus, bias-
adjusted meta-analyses might not be feasible. Although not ideal, in these cases a possible
alternative approach is the exclusion of the studies with a high risk of bias from the risk-of-bias
analysis. For this reason, researchers in nutrition are encouraged to engage in collecting such
information and make it publicly available.

Assessing Uncertainties in the Systematic Review Process


One of the main shortcomings of systematic reviews is the heterogeneity that results from
pooling studies carried out with different types of evidence, such as animal versus human data or
study designs, different population subgroups, exposure doses, administration routes, or levels of
compliance. Because such heterogeneity ultimately translates into uncertainty (Hill, 1965),
pooling studies should be done only if they meet the criteria for a meta-analysis protocol.
Additionally, when using the systematic review approach, consideration also must be given to
the language used to search the literature, as well as the search strings, defined eligibility criteria,
and the potential for a selective tendency from editors to publish papers with positive, versus
negative, results. Any of these elements could introduce a bias in the results of the systematic
review.
One approach to mitigating such biases is evidence mapping. Evidence mapping allows for
investigation before starting a systematic review, allowing reviewers, for instance, to identify
evidence that could be excluded based on language (i.e., considering only a single language) or
eligibility criteria, such as restricting the systematic review to a specific study design or
analytical method. Evidence mapping also allows, via an iterative process, a means to identify
the best search string, language, eligibility criteria, and other factors to consider when selecting
studies to include. The results of the evidence map can be presented in a graphical or tabular
format showing, for instance, how many citations would be retrieved using other languages in
addition to English. Box 3-1 shows an example of an evidence map from the Institute of
Medicine (IOM) (2011) report on DRIs for calcium and vitamin D. This evidence map shows

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-8 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

that in human nutrition the evidence for adverse health effects of a nutrient that forms the basis
for deriving a UL relies to a high degree on observational studies on humans.

Grading the Strength of the Body of Evidence


While still an exploratory approach, grading of recommendations, assessment, development,
and evaluation (GRADE) can also be used to summarize uncertainties that arise when evidence
from heterogeneous sources is integrated to draw conclusions about causal relationships between
a nutrient intake and a health outcome (Guyatt et al., 2008; WHO, 2014). GRADE provides a
transparent means for evaluating a range of factors that can affect study quality, such as the
limitations of each study considered, consistency of findings across studies, elements of
directness and external validity, and the likelihood of publication bias. GRADE ranks the
strength of the evidence into four categories: high, moderate, low, and very low.
Because of its qualitative nature, GRADE-based judgments do not account for the direction
or magnitude of bias in the evidence (i.e., the biases in individual studies). Assessors using
GRADE must evaluate whether evidence exists that allows for a probabilistic judgment of the
direction and magnitude of bias that could affect the results of the assessment. In such cases, the
methods discussed previously for quantitatively adjusting for bias could be applied.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A HARMONIZED PROCESS 3-9

BOX 3-1
Example Evidence Map: Cancer and Neoplasms as an Indicator for Calcium and
Vitamin D
Randomized Trials
Secondary or
Non-
Mechanistic Animal Observational Primary Prespecified
Indicator Data Data Studies Outcome Outcomesa
Calcium
All Cancers √ √ √ √b √b
Breast --- ---
Cancer --- --- √
Colorectal
Cancer √ √ √ √b √b
Colorectal
Adenoma √ √ √ √ ---
Prostate
Cancer --- √ √ --- ---
Vitamin D
All Cancers √ √ √ --- √b
Breast
Cancer --- --- √ --- √b
Colorectal
Cancer √ √ √ --- √b
Colorectal
Adenoma √ √ √ --- √b
Prostate
Cancer --- --- √ --- ---
NOTE: √ = evidence is published; --- = no available evidence.
a Secondary outcomes often were not prespecified by the investigators.
b Limited data.

SOURCE: IOM, 2011.

Convene an Expert Panel to Evaluate the Evidence

After selecting a nutrient for review and initiating a systematic review, an expert nutrient
review panel is convened and given its charge. The review panel may, in some cases, be
convened to assist with structuring the systematic review (NASEM, 2018). In Figure 3-1, the
relationship between the review panel and the systematic review is indicated by dotted arrows.
Conducting nutrient reviews is challenged by constraints in policy priority, availability of
funding, and expertise, but the need for nutritional benchmarks is critical all over the world. This
shared need, combined with the substantial effort and expense of deriving NRVs, is a strong
justification for international cooperation. Already, neighboring countries with significant trade
ties tend to share the work and expense of convening nutrient reference panels (Przyrembel
2017). For example, as mentioned above, the United States and Canada collaborate on a single
process for deriving a set of NRVs that is used by both countries.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-10 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

BOX 3-2
Steps That Guide Decision Making by a Nutrient Review Panel When Updating
or Adapting Existing NRVs

• Describe the basis for each NRV set.


o Consider the nutrient and outcomes used/selected in each review, and
the approach used.
• Describe the evidence base.
o For studies included in the review, consider when the study was
conducted.
• Describe which reference values have been set (e.g., AR, UL, RI, AI) and the
age/sex/physiological states for which these values have been set:
o Consider reference body weights.
o Consider reference energy intakes.
o Consider whether a standard deviation was used or uncertainty factors
applied and what statistical approaches were used.
o Consider how any new data will be incorporated into the review.
• Document any adjustments made. If applicable, adjustment factors can
include:
o Bioavailability
o Genetics (polymorphisms)
o Interactions
o Assumed status, or adjustments made based on status of population
o Levels of infection
o Extrapolations (e.g. weight/weight gain; changes in blood volume, milk
volume)
• Provide tables that can be used for adjustments (e.g., bioavailability tables).
SOURCE: Adapted from data presented by Rosalind Gibson at the workshop, Global
Harmonization of Methodological Approaches to Nutrient Intake Recommendations,
held in Rome, Italy, September 21–22, 2017.

Evaluating Existing Reference Values

The next step, as illustrated by the flow diagram in Figure 3-1, is to decide whether an
existing NRV will be updated or adapted, or if a new NRV will be established. Either way,
regardless of the convening organization, there are certain key steps in the process that should be
implemented using a consistent process across countries.

Option: Keep and Update or Adapt an Existing Nutrient Reference Value


Box 3-2 outlines the tasks that must be completed when updating or adapting existing ARs
and ULs to a local context where unique physiological and environmental issues, such as a high
prevalence of infection, may be contributing to population-wide nutritional problems. The
challenge of extrapolation is discussed later in this chapter.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A HARMONIZED PROCESS 3-11

Option: Establish a New Nutrient Reference Value


Precision and clarity are extremely important in the early stages of the process of deriving
NRVs because the parameters of the question dictate the breadth and depth of the work. A
transparent, rigorous, and consistent process will facilitate the task of establishing a new
reference value. Box 3-3 summarizes the general steps in the process for deriving new NRVs.

BOX 3-3
General Steps That Guide the Actions Undertaken by a Nutrient Review Panel to
Establish a New NRV

• Set up an organizing or analytic framework to help formulate the questions for


deriving a reference value, and define the protocol for a systematic review.
• Identify PICO/PECO elements that are relevant for the indicator for the AR or UL.
Some of these elements may not be necessary, such as in cases when a
factorial approach is used.
• Collect the evidence using a systematic review:
o Retrieve the evidence according to previously defined eligibility criteria,
search strings, and other factors.
o Appraise the risk of bias at the level of the individual study.
o Grade the strength of the body of evidence.
• Define the approach to take:
o Determine whether to use a factorial approach, an intake–response
relationship, or other approach to derive the new NRV.
• Analyze the evidence:
o Based on the defined approach, synthesize and integrate the evidence
accounting for uncertainties beyond risk of bias (which should already
have been accounted before for in previous steps) and assess the
confidence in the overall body of evidence.
o Appraise the evidence from the systematic review:
 Draw conclusions about the NRV.
 Document the process, including methods, assumptions, and
factors that could limit generalizability of the reference value or
would require consideration for adaptation (e.g., reference body
weight, genetics, environmental conditions).

Establishing a New NRV: Define the Approach to Take

If it is decided the new NRVs will be established, for the AR the next step is to define the
approach to take: dose–response modeling, the factorial approach, or balance studies. Each of
these approaches is discussed below. ULs, which are determined through risk assessment, are
addressed later in the chapter.

Dose–Response Modeling
The different purposes of a dose–response assessment were described in Chapter 2:
preventing deficiency disease, assessing biomarkers for health or risk of disease, and determining

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-12 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

an upper safe level of intake. Below, the methodology of dose–response assessment is described,
including options for managing uncertainty.
Generally, dose–response modeling is used when there is a clear relationship between the
intake of a nutrient and a metabolic or functional outcome. However, since functional tests tend
to be less responsive than biochemical tests to small changes in nutrient status they are rarely
used, except for folate, to determine the AR for a population.
Relationships between nutrient intake and health outcomes are complex and difficult to
estimate accurately and precisely, even when an advanced model or suite of models, rather than a
single model, is used to estimate the quantitative relationship between nutrient intake and a
response. Typically, several confounders or modifiers have the capacity to influence a given
relationship between a nutrient and a health outcome. For example, sun exposure is known to
influence the level of serum 25(OH)D, and can therefore modify the effect of measured vitamin
D levels at the different intake levels. One way to address this challenge is to incorporate the
potentially confounding factors into the model, adjusting the estimate of the parameters and the
expected intake–response using a multivariate metaregressive approach (van Houwelingen et al.,
2002). Yetley et al. (2017) described this challenge to using dose–response modeling to set
NRVs, especially when dealing with chronic disease endpoints.
When multiple intake–response studies have been identified from a systematic review,
several different modeling approaches are possible. One of these is the multivariate dose–
response meta-analysis (Crippa and Orsini, 2016), which is not only a valid methodological
solution for integrating data from different sources in intake–response modeling, but it also
adjusts for confounding factors that are assumed to have an influence on the response and/or
exposure. Orsini et al. (2012) illustrates several examples of the application of this method on
observational and experimental data for linear and nonlinear models, and for either continuous or
quantal response variables.
Uncertainty in the dose/intake response relationship As emphasized throughout this chapter,
expressing uncertainty is a key step in the process of deriving NRVs. In assessing dose–response
relationships, statistical uncertainties may stem from any number of different sources:
• The type of model used, such as linear versus nonlinear or Hill versus exponential to fit a
continuous outcome;
• Normality assumptions of the model for either raw or transformed data;
• Sampling uncertainty, which is traditionally expressed using confidence/credible
intervals for the parameter estimates;
• Identification of the response level associated with a risk/benefit outcome, such as the
level of total calcium intake that leads to hypercalcemia or body weight development in
infants and children corresponding to retarded growth; and
• Correlation among arms from the same study or among related outcomes, such as the
same organ/physiological function.
A number of methods are available to address uncertainties in the intake–response approach
and are further described in NASEM (2017) and Yetley et al. (2017). These include assessing the
effect of heterogeneity using sensitivity scenario analysis, considering use of moderator variables
to adjust intake–response relationships, average models, and estimating confidence intervals for
reference values.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A HARMONIZED PROCESS 3-13

The Factorial Approach


As explained in Chapter 2, the factorial approach is useful with biochemical indicators that
are insensitive to nutrient levels. This approach is generally used to set ARs for minerals because
minerals cannot be metabolized and, therefore, losses of minerals via the urine, feces, skin,
menstrual blood, or semen are in the same inorganic form as in the diet. With the factorial
approach, quantification of losses is used to estimate the physiological requirement of a nutrient
to ensure that basic physiological needs are met and that the level of intake will support growth
and development from pregnancy through infancy and childhood. The process of quantifying
nutrient losses is facilitated by the use of stable isotopes to calculate nutrient kinetics, and to
measure true absorption and retention rates.
As also stated in Chapter 2, the efficiency of mineral absorption (bioavailability) is one of
several factors that needs to be considered when quantifying nutrient losses from a typical diet.
For example, if total body losses of a given mineral total 5 mg per day, but only 20 percent of the
dietary intake of that mineral is typically absorbed, then 25 mg would need to be consumed daily
to replace total endogenous losses. The IOM (2001) defined bioavailability as a nutrient’s
“accessibility to normal metabolic and physiologic processes.” As described in that report,
“Bioavailability influences a nutrient’s beneficial effects at physiologic levels of intake and also
may affect the nature and severity of toxicity due to excessive intakes.”
A number of factors can affect nutrient bioavailability. These include nutrient concentration,
dietary substances that can enhance or impair absorption, the chemical form of the nutrient,
supplements, nutrition and health of the individual, excretory losses, and nutrient–nutrient
interactions. In addition, pathophysiologic changes can affect bioavailability; for example,
vitamin B-12 absorption is reduced when secretion of gastric intrinsic factor is reduced or
impaired.
As discussed in detail in Chapter 4, a dietary factor that affects nutrient bioavailability that is
of particular concern for low- and middle-income countries is phytate, which progressively
decreases the bioavailability of zinc and other minerals such as iron and calcium. Bioavailability
of nutrients, particularly zinc and iron, is a concern globally because of its potential effect on
nutritional status across populations.

Balance Studies
Another approach useful for estimating mineral requirements and the one generally used to
estimate protein requirements is the balance study. When the amount of a dietary mineral or
dietary nitrogen balances (or equals) the amount lost in the feces, urine, and integument, it is
assumed that the body is saturated, that all needs have been met, and that a higher intake of the
nutrient would not have a beneficial effect. Protein ARs are estimated from nitrogen balance
studies by examining the effects of increasingly concentrated intakes that just replaces the
amount lost; this level is considered to be the nitrogen and, therefore, protein requirement
because the average nitrogen content of protein is 16 percent.

Combining Approaches with Other Data to Reduce Chronic Disease Risk


Observational epidemiological studies can be used to determine whether usual intakes are in
agreement with values obtained through any of these three approaches. This is useful when
setting intake recommendations that support nutritional functions while also reducing the risk of
chronic disease, and can also be useful for deriving a folate level that reduces the risk of neural

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-14 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

tube defects. Usually, prospective cohort studies and, to a lesser degree, other observational
studies, are combined with dose–response or factorial data.
While the importance of considering the role of nutrient intakes in reducing chronic disease
endpoints was recognized when the DRI framework was first developed (IOM, 1004), at this
point because of insufficient data needed to set an AR, only AIs have been derived and only for a
few nutrients (and disease endpoints): calcium (fracture rates), vitamin D (fracture rates),
fluoride (dental carries), potassium (hypertension, kidney stones), and fiber (coronary heart
disease) (Russell, 2010).

Establishing a New Nutrient Reference Value: Appraise the Evidence

The next step to deriving a new NRV, as illustrated in the flow diagram in Figure 3-1, is to
synthesize and integrate the evidence while accounting for sources of uncertainty. Identifying the
various sources of uncertainty and developing and applying methods to manage uncertainties
increases the credibility of assessment results and facilitates decision making for public health
managers. Identification of uncertainties can also stimulate research that will fill knowledge gaps
and help in the development of models for the quantitative assessment of evidence.
Uncertainty in any assessment arises from two main sources: (1) limitations in the data used
as evidence, including data scarcity, and (2) shortcomings in the methodology and processes
applied to derive NRVs. Uncertainty caused by limitations in data was discussed earlier in this
chapter in the section titled “Uncertainty in the Evidence: Appraising Risk of Bias in Individual
Studies.” Uncertainties caused by shortcomings in the methodology and processes to derive
NRVs are described throughout this chapter. In addition to these two main sources of
uncertainty, although variability between individuals, as well as within individuals, is different
from uncertainty, variability can be a major contributor to overall uncertainty when its magnitude
and distribution is unknown. It is important to address variability in individual susceptibility to a
nutrient’s effect due to age, sex, developmental stage, environment, disease, or genetic
heterogeneity (i.e., the distribution in individual susceptibility around a median value of
exposure) separately from uncertainty caused by limitations in data.
The possible strategies to address uncertainty can vary depending on the steps of the
assessment process and whether the objective of the analysis is establishing a causal relationship
between a nutrient and outcomes (hazard identification) or rather characterizing this same
relationship (hazard characterization). Traditionally, in the assessment of risk related to nutrient
intakes, uncertainty owing to a lack of data or lack of knowledge of variability is addressed with
uncertainty factors used to derive the UL from a no observed adverse effect level (NOAEL) or
lowest observed adverse effect level (LOAEL). These uncertainty factors are discrete values
derived in a toxicological context and frequently use very limited evidence. A probabilistic
approach, aimed at expressing the uncertainty factor as probability distributions based on
physiological considerations provides a more realistic and less conservative approach.

Inter-Individual Variability
Generally, inter-individual variability has a greater magnitude than intra-individual
variability and consequently a greater influence on the derivation of nutrient reference values,
and must be taken into account by mathematical modeling using, among others, justified expert
assumptions on the likely shape of the distribution.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A HARMONIZED PROCESS 3-15

Considerations around inter-individual variability with important implications for deriving


NRVs include the fact that the distribution of biological endpoints is rarely normal; therefore,
using the traditional approach of adding two standard deviations to the mean value of
requirement is not always the most appropriate. In addition, the magnitude of the variability is
frequently unknown, which is the case when NRVs are derived using a systematic review and the
data are available only in an aggregated form. In particular, most of the variability in
susceptibility to adverse health effects, which is one of the main components of inter-individual
variability, is unknown, because experimental trials with different doses in humans to identify
potential thresholds for the occurrence of adverse effects are unethical. In a systematic review, a
way to estimate the inter-individual variability is to compute a weighted average of the sampling
standard deviations of each study in the review. Alternatively, a value for the inter-individual
variability (e.g., expressed as a standard deviation) of between 10 and 15 percent of the AR
could be used (Cashman et al., 2013).
When establishing a recommended intake (RI), the distribution of a nutrient requirement
among individuals within a population serves as the reference. The 50th percentile of the
population distribution (AR), plus 2 standard deviations (or a percentage of the average
requirement judged to be appropriate) assures, under a normal distribution, that the
recommended intake is adequate for 97.5 percent of the population. If requirements are not
normally distributed, then adding two standard deviations to the AR will not cover 97.5 percent
of the population. Other methodologies have been used to address the problem (EFSA, 2016);
however, it remains a challenge.

Expressing Uncertainty
Uncertainty affecting the estimate of an NRV can be expressed in several ways. It can be
expressed as an uncertainty factor that incorporates all identified limitations in the data and
possible shortcomings in the methodology. This is typically how it is expressed for the UL in
order to maintain a “margin of safety” and especially when extrapolation is used from one
species to another or from certain experimental/observational conditions to others. Or,
uncertainty can be expressed as the range of possible values for a parameter, either with or
without explicit expression of the coverage of the true value. For instance, in the case of sodium
and blood pressure, a UL might be expressed as the range of intake least likely to lead to blood
pressure elevation in subjects with normal blood pressure. Another way to express uncertainty is
as a full probability distribution of the parameter values. Finally, one could provide a qualitative
description of the plausibility of a set of values for the parameter. However, more challenging
quantitative methods to characterize and express uncertainty are considered to be better
approaches as they allow the use of mathematical tools to combine diverse sources of uncertainty
and avoid ambiguity in the interpretation of the conclusions (EFSA Scientific Committee et al.,
2018).

Evaluating Usual Intake Levels

After describing the existing evidence base, when updating or adapting an existing NRV, or
appraising the evidence (when establishing a new NRV), the next step in developing an NRV is
to evaluate usual intakes. From one day to the next, individuals eat different foods in different
amounts and consequently their intakes vary over time. Intakes on a single day usually greatly
overestimate the usual intake of some nutrients and underestimate that of others. The

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-16 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

recommended method of adjusting for this problem is to measure at least two nonconsecutive
days of intake on a representative subset of each population (at least 35 people) (Tooze et al.,
2006). The ratio of the within-person day-to-day variance to the variance between persons (i.e.,
intra-individual to inter-individual variance) is then used to adjust the distribution of intakes
statistically such that the lower and upper tails of the distribution move toward the median.
Methods for making this adjustment have been described (Carriquiry, 1999; Nusser et al., 1996),
and software is available for this purpose.
In the event that only one day of intake data per person has been collected, intraindividual
variance estimates can be calculated from other data sets in the region, or taken from the
software that enables the adjustment of the intake distributions (Iowa State University, 2001). An
example of this approach has been used to assess adequacy of nutrient intakes from a Mexican
national survey (Sanchez-Pimienta, 2016).

Assess Needs of Populations in Consideration of Local Context

A final step in the process of deriving an NRV is to assess the local context. When reference
values that are set in one country or region, based on data from a well-characterized population
(e.g., with respect to body size, life style, and environment), are adopted by another country or
region, comparability of the characteristics of the two populations must be taken into
consideration. If the two populations differ significantly, adjustments must be made to account
for differences.
In addition to body size, lifestyle, and other environmental characteristics, in some
populations, genetic factors can influence dose–response relationships and, therefore the
magnitude of the reference values. For example, being homozygous for methylene
tetrahydrofolate reductase (MTHFR) deficiency changes the relationship between folate and
homocysteine concentration in plasma and, presumably, the probability of any associated health
outcome as well, such as cardiovascular disease (Stover, 2007). Thus, if the percentage of
homozygous individuals differs significantly between populations, the estimated requirement for
folate within these populations will be different. The greater challenge in this particular situation,
however, is the correct characterization of a reference population, not the extrapolation of
reference values.

Inter-Population Extrapolation
When data are insufficient, the AR or adequate intake (AI) for infants or children must be
extrapolated or interpolated from experimental data that came from adults. Nutrient
recommendations for infants and children may be extrapolated from adult standards by either
scaling down the requirements based on body weight or by using a metabolic factor (i.e., body
weight to the 0.75 power). These estimates are then adjusted for growth or tissue deposition
needs. As a final step, the estimated ARs should be reviewed across age groups to ensure that
there are no abrupt, inappropriate increases or decreases between age groups. Extrapolation of
data from outside an observed range may be useful for forming new reference values when dose–
response data, intake data, biomarkers of function, or health outcomes are missing for a
population subgroup. A composite of scaling methods to extrapolate from reference values of
one age group to another is provided in Appendix E.
One method for extrapolation assumes that the physiologic requirement or the upper intake
level is proportional to body mass; for example, adult requirements are often adjusted

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A HARMONIZED PROCESS 3-17

downwards for children. When extrapolating downwards, not only from adults to children, but
from any other group with a higher absolute requirement (group 1 in the formula below) to one
with a lower absolute requirement (group 2 in the formula), the general formula is:

Average Value2 = Average Value1 × (scaling factor).

When the need for a nutrient is proportional to body mass, the scaling factor is isometric,
meaning that it is calculated simply as the quotient between the reference body weights, and
therefore the extrapolation is made on the basis of actual body weight. Isometric scaling is
appropriate when the nutrient in question is distributed homogenously across the whole body or
when a nutrient is distributed in one specific tissue or organ or in different tissues and organs, but
only if the proportional relationship to body mass is preserved as body size changes.
For some nutrients, the proportional relationship between a nutrient and body mass is not
preserved as body size changes. In such cases, allometric scaling is necessary. With allometric
scaling, adjustments for body size are based on body mass modified by an exponent, typically
0.75 (Rucker, 2007). The 0.75 exponent is thought to account better for metabolically active
tissue, the percentage of which is higher in infants (and possibly around puberty) than in adults.
An example of allometric extrapolation is that a child weighing 22 kg would require 42 percent
of what an adult weighing 70 kg would require; this is a higher percentage than what an
isometric calculation would yield (32 percent) (IOM, 1998).
When extrapolating downwards for children, in addition to the scaling factor, a growth factor
can also be included to account for the additional nutritional demands needed to support growth.
The growth is calculated as the proportional increase in estimated additional protein
requirements for growth relative to the maintenance requirement at the different ages
(FAO/WHO, 1985). Growth factors used in EFSA’s extrapolations are shown in Appendix F;
these were calculated based on the assumption that nutrient requirements increase in proportion
to the protein growth increment (West et al., 1997). When a growth factor is included in the
extrapolation, the general formula is:

Average Valuechild = Average Valueadult × (scaling factor) × (1 + growth factor).

The average value for each age group corresponds to the mean of values for the included
years (EFSA, 2014).

Findings, Conclusions and Recommendations

The flow diagram in Figure 3-1 is based on availability of several new tools and
methodologies that were either not available or not used in previous nutrient reviews. These
include the process of systematic review, which provides new data on nutrient requirements that
facilitate decision making about whether a requirement should be updated or adapted or a new
requirement is needed; application of the factorial approach, which takes into account
bioavailability when determining an NRV from a typical diet; and new data sources that can be
useful for assessing local factors that affect the requirement for the population under
consideration, such as infection.
The committee came to the following conclusion:

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-18 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

The discrepancies between nutrient needs to support growth and development in


infants and young children and the derivation of an AR or AI from extrapolation
have posed major challenges to determining the composition of nutrient
supplements and fortified products for this age group.

Recommendation 3. Expert groups should assess relevant evidence and, as needed, analyze
existing or new data to assess the characteristics of various diets that can affect the
bioavailability of specific nutrients. For example, iron bioavailability models should be
validated using European data for factorial estimates, using iron intake and serum ferritin
(adjusted where necessary) data from low- and middle-income countries.

Recommendation 4. When deriving nutrient reference values, countries or regions should


look at existing values derived by expert panels and determine whether to accept, update,
or adapt them to their context, if possible. If values are not relevant locally, an expert panel
should adapt values to the local context or modify existing values from other experts.

OTHER UNCERTAINTIES TO CONSIDER WHEN ESTIMATING A UL

In addition to the different types of uncertainty discussed earlier in this chapter, another type
of uncertainty in estimating NRVs arises from the use of competing risk–benefit analyses when
evaluating ULs based on chronic disease risk-related outcomes versus toxicity-related outcomes.
The discussion below summarizes the differences between these competing risk-benefit analyses
and methods for managing this type of uncertainty.

Competing Risk–Benefit Analyses

In contrast to nonessential food components, for which the process of risk assessment1 was
originally developed, essential nutrients satisfy a physiological function. An evaluation of the
effects of exposure to a nutrient includes beneficial or physiological effects in addition to
toxicological effects. In the risk assessment process used to establish DRIs, for example, DRIs
are set to avoid both the risk of deficiency (the AR) and risk of adverse effects from excess
intake (the UL) (IOM, 2000). The assessment of a nutrient can, therefore, be done as a risk–
benefit analysis (EFSA, 2010), which means that similar hazard and benefit assessment steps are
performed in parallel with the totality of evidence being assessed at the end (see Figure 3-2).

1
Risk assessment is a process of (1) identification of risk of toxicity, (2) dose–response assessment, (3) assessment
of intakes outside the reference values, and (4) characterization of risks associated with excess intake.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A HARMONIZED PROCESS 3-19

FIGURE 3-2 Decision tree for a combined risk/benefit assessment of an NRV.


SOURCE: EFSA, 2010.
Modeling the prevention of deficiency as part of the derivation of an AR is a relatively more
direct process than modeling the prevention of chronic disease or avoidance of long-term
toxicity. Figure 3-3 shows that with increasing intake of a nutrient, the risk of chronic disease
can either decrease abruptly (disease A; blue line), decrease continuously (disease C, green line)
or increase (disease B; black line).
In the case of an abrupt increase in intake, the increase in risk can be considered an adverse
health effect and may be used, with a high degree of uncertainty, to define a UL related to
chronic disease risk despite the inherent individual variability in susceptibility (NASEM, 2018).
Notably, any change in risk of a chronic disease with increasing intake is relative to a baseline
risk. In contrast, toxicity from intake of a nutrient arises when intake surpasses a threshold value
or range of values and results from intakes that are outside homeostatic mechanisms.

Methods for Managing Uncertainty

It is important that NRV estimates that clearly reflect any uncertainty encountered in the
process be considered in their derivation. While, for the practical purposes, point estimates of
NRVs are preferred, interval estimates are preferable for expressing limitations in knowledge
and the shortcomings of the derivation methods. This conflict becomes even more evident when
prevention of chronic diseases is taken into consideration concurrently with the avoidance of
adverse effects.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-20 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

FIGURE 3-3 Differences in the risks of chronic diseases (left y-axis) versus toxicity (right y-axis) with
increasing nutrient intake levels (x-axis).
SOURCES: Amanda MacFarlane presentation, Rome, Italy, September 21, 2017; modified from Yetley
et al., 2017.

A FRAMEWORK FOR DERIVING NUTRIENT REFERENCE VALUES

Based on its review of the strengths and weaknesses in available methodologies, as detailed
throughout this chapter, the committee developed a new framework for harmonizing the process
for deriving NRVs. The framework is shown in Figure 3-4. A harmonized process involves four
major steps:
1. Choose the appropriate tools and data resources—As shown on the left side of the
framework, the three primary tools are needed to develop NRVs: systematic reviews,
comprehensive databases, and information about relevant local and regional factors (local
context) that can influence NRVs.
2. Collect data from those tools—Data that are essential for understanding and selecting
biomarkers of status including pregnant and lactating women and young children; health
outcomes; the influence of dietary factors on absorption; and the effects of factors such as
infection and diarrhea that can affect nutrient requirements.
3. Identify the best approach for the nutrient under consideration—There are several
options for approaches that can be used to determine key reference values. Dose–
response modeling is used to set an AR or UL when there is a clear relationship between
the intake of a nutrient and a metabolic or functional outcome. The factorial approach is

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A HARMONIZED PROCESS 3-21

generally used for minerals because losses of minerals via the urine, feces, skin,
menstrual blood, or semen are in the same organic form as in the diet.
4. Derive the two key reference values, the AR and the UL—These are the core values from
which other NRVs are derived. RIs for various populations within a region, country, or
globally may also be developed, but they are derived from the AR.
These major steps represent key components of the flow diagram in Figure 3-1. Applications
and uses of NRVs, which were included in the King and Garza (2007) framework, are not
included in this framework. However, they are discussed at the end of Chapter 4.

Key reference
Tools/Resources Data Approach/Methods
values

Nutrient status Dose-response


Systematic reviews Health Outcomes modeling
Average
Physiological
requirement
requirement
Factorial approach
Bioavailability
Databases Recommended
Health factors (e.g.
intake
infection)

Body size
Dietary patterns
Risk assessment* Upper limit
Nutrient intakes
Local and regional
factors Biomarkers
Risk of chronic
disease

FIGURE 3-4 Framework for harmonizing the process for deriving NRVs.
NOTES: There are four major steps to setting key nutrient reference values: (1) choosing the appropriate
tools and resources, (2) collecting relevant data from the tools and other resources, (3) identifying the best
approach for the nutrient under consideration, and (4) deriving the two key reference values, the AR and
UL. Components are shown below each step.
* Risk assessment is a process of (1) identification of risk of toxicity, (2) dose–response assessment, (3)
assessment of the prevalence of intakes outside the reference values, and (4) characterization of risks
association with excess intake.
Notably, the balance method, while mentioned at various places in this report, is not included
in the committee’s framework because the focus of this report is on zinc, iron, and folate,
nutrients of concern for young children and women of reproductive age, and the balance method
is not appropriate for those nutrients (see Chapter 4).

FINDINGS, CONCLUSION AND RECOMMENDATION

The following discussion summarizes the committee’s findings and conclusions related to the
overall process of deriving NRVs, including how to manage uncertainties that can arise at
various points during the process, and provides a recommendation based on these findings and
conclusions.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-22 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Findings on the Process of Setting Nutrient Reference Values

General principles for setting NRVs are summarized in Box 3-4. Included in Box 3-4, and as
emphasized earlier in this chapter, it is critical that all steps in the decision-making process are
documented and transparent.

BOX 3-4
General Principles for Setting Nutrient Reference Values

• Transparency: Beginning with the formation of an expert nutrient review panel, be


clear about selection criteria, and use an a priori process for declaration and
management of biases and conflicts of interest. Interest in transparency should
extend to justification of all panel decisions, including what evidence to draw on and
how to handle uncertainty, such as reasoning behind any extrapolation and the
methods used for it, as well any statistical adjustments applied.
• Clarity: Be precise as to what questions are under considerations and what
outcomes are being evaluated. The PICO/PECO method is invaluable in formulating
questions regarding the population, intervention/exposure, comparator or control
group, and outcomes of interest.
• Evidence review: Use a thorough, systematic, and open process when reviewing the
quality and generalizability of studies used in the determination of reference values.
• Documentation: Record all other considerations or adjustments used to set NRVs,
such as modifications for infection, malnutrition, bioavailability, body size, or lean
mass.
• Assessment of confidence: Evaluate the strength of the body of evidence reviewed,
and summarize its confidence in the report’s recommendations.
• Peer review: Submit the final report and reference values to external review by
experts prior to publication.

Findings for Uncertainties in the Nutrient Review Process

To maintain the credibility of the nutrient review process, it is essential that the numerous
sources of uncertainty be taken into consideration. As discussed throughout this chapter, the
range of uncertainty factors includes
• data limitations (e.g., inter-individual variability in a study population);
• flaws in study design;
• risk of bias;
• extrapolation from one population subgroup to a different, unrelated population
subgroup;
• heterogeneity in the evidence (e.g. biological and methodological heterogeneity across
pooled studies);
• parameters of the search strategy for a systematic review;
• confounders or modifiers affecting intake–response in determining a causal relationship;
and
• competing analyses of different outcomes, such as deficiency versus chronic disease.
The committee came to the following conclusion:

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A HARMONIZED PROCESS 3-23

Identifying a strategy for managing uncertainties is critical to maintaining the


accuracy and relevance of all NRVs as well as assuring the credibility of the
evidence analysis. A thorough understanding of the uncertainties that affect the
nutrient review process underpins the process used by decision makers and public
health officials in determining nutrition policy. Additionally, understanding the
type of uncertainties that can influence a nutrient review is key to identifying
research gaps and developing quantitative evidence assessment models.

Core Values of the Nutrient Reference Value Review Process to Support Harmonization

The committee identified the following characteristics of the NRV review process as being
critical to supporting harmonization of the approaches to setting NRVs globally. NRVs must be:
1. Regularly updated—Given the rapid pace of the generation of knowledge and data upon
which NRVs are based, it is important to maintain the currency of information on nutrient
outcomes as well as the nutritional profile of populations, particularly as supplement use
increases and fortification programs are established.
2. Clear and transparent—Confidence in the systematic reviews that lead to the
establishment of reference values is necessary to ensure their use by policy makers and
researchers alike. Such credibility requires the establishment of a transparent process
including how members of the review panels are selected and the training and expertise
of each; public availability of all material reviewed by the committee during its
deliberations; and written protocols for systematic reviews, quality assessment of each
study, assumptions made, and evidence synthesis leading up to the established reference
values.
3. Rigorous and relevant—Consistent methods need to be established and applied across
nutrients, for various values (AR, RI, AI, and UL), and for various categories of age, sex
and life stage (e.g., pregnancy). A uniform approach for conducting systematic reviews
and establishing values for nutrients where there is limited evidence is also needed. Given
the changing epidemiologic and nutritional status across populations, values need to be
relevant to contexts where chronic disease is rising, in addition to being relevant to the
prevention of deficiency.
4. Documented—At each stage in the process, all considerations or adjustments that
influence the potential NRV must be documented, as well as the methodologies used and
the assumptions behind them.
5. Based on a determination of the strength of the evidence—Limitations in the data and
methods are assessed and documented, and uncertainties are taken into account.
6. Complete and efficient—Given the cost, time, and expertise required to undertake the
development or revision of existing reference values even in high-income countries, low-
and middle-income countries should consider using existing NRVs already developed by
another international partner if they are deemed adequate.
Recommendation 5. After having adapted or created new nutrient reference values, to
achieve transparency the nutrient review expert panel should clearly report the reference
population, adjustment factors, and the methodology used. Expert panels should also
document the uncertainty in the evidence and in the methods used to develop the nutrient
reference values quantitatively. If this is not possible, then they should provide a qualitative
evaluation of the confidence in the body of evidence and in the methods used.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-24 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

CHAPTER SUMMARY

In summary, the committee’s examination of the process of steps used to develop NRVs
identified several new tools in the process that enhance the transparency, efficiency, and
scientific rigor of the approach. These tools have either not been available or not used in past
nutrient reviews. They are (1) systematic review, (2) larger and more accessible databases, and
(3) information on factors affecting the culturally and context-specific food choices and dietary
patterns among diverse populations. Finally, based on the availability of these new tools, the
committee proposes a framework for a process to harmonize the approach used to derive NRVs.
Chapter 4 examines the feasibility of a harmonized approach, based on this proposed framework,
applying it to three exemplar nutrients.

REFERENCES

ASEAN (Association of Southeast Asian Nations). 2016. ASEAN works towards ensuring good nutrition
for all children in the region. ASEAN Secretariat News, March 28.
ASEAN. 2017. Asean to address malnutrition and all its forms. ASEAN Secretariat News, February 22.
Atkinson, S. A. 2011. Defining the process of dietary reference intakes: Framework for the United States
and Canada. American Journal of Clinical Nutrition 94(2):655S-657S.
Brouwers, M. C., M. E. Kho, G. P. Browman, J. S. Burgers, F. Cluzeau, G. Feder, B. Fervers, I. D.
Graham, J. Grimshaw, S. E. Hanna, P. Littlejohns, J. Makarski, L. Zitzelsberger, and the ANS
Consortium. 2010. AGREE II Advancing guideline development, reporting and evaluation in
health care. Canadian Medical Association Journal 182(18):E839-E842.
Carriquiry, A. L. 1999. Assessing the prevalence of nutrient inadequacy. Public Health and Nutrition
2(1):23-33.
Cashman, K. D., and M. Kiely. 2013 EURRECA-estimating vitamin D requirements for deriving dietary
reference values. Critical Review of Food Sciemce and Nutrition 53:1097-1109.
Crippa, A., and N. Orsini. 2016. Multivariate dose-response meta-analysis: The dosresmeta R package.
Journal of Statistical Software 72(Code Snippet 1):15.
Dias, S., A. J. Sutton, N. J. Welton, and A. E. Ades. 2013. Evidence synthesis for decision making 3:
Heterogeneity--subgroups, meta-regression, bias, and bias-adjustment. Medical Decision Making
33(5):618-640.
EFSA (European Food Safety Authority). 2010. Guidance on human health risk-benefit assessment of
foods. EFSA Journal 8(7):1673.
EFSA. 2014. Essential composition of infant and follow-on formulae. EFSA Journal 12(7):3760.
EFSA. 2017. EFSA Journal: Special Edition on dietary reference values.
http://www.efsa.europa.eu/en/press/news/171211 (accessed February 2, 2018).
EFSA Scientific Committee, D. Benford, T. Halldorsson, M. J. Jeger, H. K. Knutsen, S. More, H.
Naegeli, H. Noteborn, C. Ockleford, A. Ricci, G. Rychen, J. R. Schlatter, V. Silano, R. Solecki,
D. Turck, M. Younes, P. Craig, A. Hart, N. Von Goetz, K. Koutsoumanis, A. Mortensen, B.
Ossendorp, L. Martino, C. Merten, O. Mosbach-Schulz, and A. Hardy. 2018. Guidance on
uncertainty analysis in scientific assessments. EFSA Journal 16(1):5123-5162.
FAO (Food and Agriculture Organization). 2018. What we do. http://www.fao.org/about/what-we-do/en
(accessed February 2, 2018).
FAO/WHO (Food and Agriculture Organization and World Health Organization). 1985. Energy and
protein requirements. Report of a joint FAO/WHO/UNU expert consultation. World Health
Organization Technical Reports Series 724:1-206.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A HARMONIZED PROCESS 3-25

FAO/WHO. 2018a. Codex alimentarius international food standards. http://www.fao.org/fao-who-


codexalimentarius/en (accessed February 2, 2018).
FAO/WHO. 2018b. Codex alimentarius timeline. http://www.fao.org/fao-who-codexalimentarius/about-
codex/history/en (accessed February 2, 2018).
FAO/WHO. 2018c. Codex committee on food labeling (CCFL). http://www.fao.org/fao-who-
codexalimentarius/committees/committee/en/?committee=CCFL (accessed June 1, 2018).
FAO/WHO. 2018d. FAO/WHO codex trust fund. http://www.fao.org/fao-who-codexalimentarius/about-
codex/faowho-codex-trust-fund/en (accessed June 1, 2018).
Guyatt, G. H., A. D. Oxman, R. Kunz, Y. Falck-Ytter, G. E. Vist, A. Liberati, H. J. Schunemann, and the
GRADE Working Group. 2008. GRADE: An emerging consensus on rating quality of evidence
and strength of recommendations. British Medical Journal 336(7652):1170-1173.
Higgins, J. P., D. G. Altman, P. C. Gotzsche, P. Juni, D. Moher, A. D. Oxman, K. F. Savovic, L. Schulz,
J. A. Weeks, and G. Stern. 2011. Cochrane bias methods, and Cochrane statistical methods. The
Cochrane collaboration's tool for assessing risk of bias in randomised trials. British Medical
Journal 343:d5928.
Hill, A. B. 1965. The environment and disease: Association or causation? Proceedings of the Royal
Society of Medicine 58:295-300.
IOM (Institute of Medicine). 1998. Dietary Reference Intakes: A risk assessment model for establishing
upper intake levels for nutrients. Washington, DC: National Academy Press.
https://doi.org/10.17226/6432
IOM. 2000. Dietary Reference Intakes. Applications in dietary assessment. Washington, DC: National
Academy Press. doi.org/10.17226/9956
IOM. 2001. Dietary Reference Intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron,
manganese, molybdenum, nickel, silicon, vanadium and zinc. Washington, DC: National
Academy Press. https://doi.org/10.17226/10026
IOM. 2011. Dietary Reference Intakes for calcium and vitamin D. Washington, DC: The National
Academies Press. https://doi.org/10.17226/13050.
Iowa State University. 2001.Software for intake distribution estimation. http://www.side.stat.iastate.edu
(accessed March 20, 2018).
IUNS (International Union of Nutritional Scientists). 2018a. Adhering bodies.
http://www.iuns.org/adhering-bodies (accessed February 2, 2018).
IUNS. 2018b. Affiliated bodies. http://www.iuns.org/affiliated-bodies (accessed February 2, 2018).
King J. C., and C. Garza. 2007. Harmonization of nutrient intake values. Food and Nutrition Bulletin
28(Suppl 1):S3-S12.
MacFarlane, E. A. 2017. Endpoints - Deficiency vs. chronic disease. In Global harmonization of
methodological approaches to nutrient intake recommendations: Proceedings of a workshop.
Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25023.
NASEM (National Academies of Sciences, Engineering, and Medicine). 2018. Global harmonization of
methodological approaches to nutrient intake recommendations: Proceedings of a Workshop.
Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25023.
National Toxicology Program. 2015. Handbook for conducting a literature-based health assessment using
OHAT approach for systematic review and evidence integration. Washington, DC, Office of
Health Assessment and Translation (OHAT), Division of the National Toxicology Program,
National Institute of Environmental Health Sciences.
Nusser, S. M., A. L. Carriquiry, K. W. Dodd, and W. A. Fuller. 1996. A semiparametric transformation
approach to estimating usual daily intake distributions. Journal of the American Statistical
Association 91:1440-1449.
Orsini, N., R. Li, A. Wolk, P. Khudyakov, and D. Spiegelman. 2012. Meta-analysis for linear and
nonlinear dose-response relations: Examples, an evaluation of approximations, and software.
American Journal of Epidemiology 175(1):66-73.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

3-26 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Przyrembel, H. 2017. Experiences from countries that have collaborated: EFSA reporting. In Global
Harmonization of Methodological Approaches to Nutrient Intake Recommendations: Proceedings
of a workshop. Washington, DC: The National Academies Press. doi:
https://doi.org/10.17226/25023.
Rucker, R. B. 2007. Allometric scaling, metabolic body size and interspecies comparisons of basal
nutritional requirements. Journal of Animal Physiology and Animal Nutrition (Berlin) 91(3-
4):148-156.
Russell, R. M. 2010. Integration of epidemiologic and other types of data into dietary reference intake
development. Critical Reviews in Food Science and Nutrition 50(Suppl 1):33-34.
SADC (Southern African Development Community). 2014. Food and nutrition security strategy 2015-
2025. Paper read at SADC Food and Nutrition Security Strategy 2015-2025. Lilongwe, Malawi.
Sanchez-Pimienta, T. G., N. Lopez-Olmedo, S. Rodriguez-Ramirez, A. Garcia-Guerra, J. A. Rivera, A. L.
Carriquiry, and S. Villalpando. 2016. High prevalence of inadequate calcium and iron intakes by
Mexican population groups as assessed by 24-hour recalls. Journal of Nutrition 146(9):1874S-
1880S.
Stover, P.J. 2007. Human nutrition and genetic variation. Food and Nutrition Bulletin 28(1 4040 Suppl
International):S101-S115.
Turner, R. M., D. J. Spiegelhalter, G. C. Smith, and S. G. Thompson. 2009. Bias modelling in evidence
synthesis. Journal of the Royal Statistical Soc, Series A Stat Soc 172(1):21-47.
van Houwelingen, H, C., L. R. Arends, and T. Stijnen. 2002. Advanced methods in meta-analysis:
Multivariate approach and meta-regression. Statistics in Medicine 21:589-624.
West, G. B., J. H. Brown, and B. J. Enquist. 1997. A general model for the origin of allometric scaling
laws in biology. Science (276):122-126.
Whitinga, P., J. Savovi, J. Higgins, D. Caldwella, B. C. Reevese, B. Sheaf, P. Daviesa, J. Kleijnenc, R.
Churchilla, and the ROBIS group. 2016. ROBIS: A new tool to assess risk of bias in systematic
reviews was developed. Journal of Clinical Epidemiology 69:225-234.
WHO (World Health Organization). 2014. WHO handbook for guideline development, 2nd ed.
http://www.who.int/publications/guidelines/guidelines_review_committee/en (accessed February
14, 2018).
Yetley, E. A., A. J. MacFarlane, L. S. Greene-Firestone, C. Garza, J. D. Ard, S. A. Atkinson, D. M. Bier,
A. L. Carriquiry, W. R. Harlan, D. Hattis, J. C. King, D. Krewski, D. L. O’Connor, R. L.
Prentice, J. V. Rodricks, and G. A. Wells. 2017. Options for basing dietary reference intakes
(DRIs) on chronic disease endpoints: Report from a joint US/Canadian-sponsored working group.
American Journal of Clinical Nutrition 105(Suppl):249S-855S.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Applying Methodological Approaches to Nutrient Reference


Values for Young Children and Women of Reproductive Age:
An Assessment of Exemplar Nutrients

In response to its task to demonstrate the application of a methodological approach for


deriving nutrient reference values (NRVs) using an analysis of an exemplar nutrient, the
committee determined there was a need to address three nutrients of concern for young children
and women of reproductive age. This chapter summarizes the committee’s application of its
proposed framework for deriving NRVs for three exemplar nutrients. The committee did not
carry out an analysis for the two population subgroups for each nutrient. Rather, the three
nutrients were selected to illustrate the methodological applications, applicable to the target
population subgroups. The chapter begins with an overview of the key steps and core principles
underlying the committee’s framework; then describes in detail its three exemplar nutrient
analyses, with a focus on defining the specific method to be used to derive an NRV; and
concludes with the committee’s assessment of the feasibility of harmonizing methodologies for
deriving NRVs on a global scale and a discussion of the application of NRVs in low- and
middle-income countries.
The committee was not tasked with actually setting NRVs for the exemplar nutrients.
Additionally, because the nutrient review process applies to nutrients derived from the diet, not
from supplements, although supplements are mentioned briefly in certain contexts when
relevant, a review or discussion of supplements was outside the committee’s task. Finally, while
the committee evaluated the strengths and weaknesses of methods currently being used to derive
NRVs as they apply to the three exemplar nutrients, it was not within the committee’s scope to
compare these methods or to identify which methods would be most suitable for other nutrients.

HARMONIZING THE PROCESS FOR NUTRIENT REFERENCE VALUES USING


EXEMPLAR NUTRIENTS

In the previous chapter, the committee reviewed the key steps in the process of deriving
NRVs as outlined in Chapter 3, Figure 3-1; then, based on its assessment of strengths and
weaknesses in the methodologies for each of these steps, the committee developed a framework

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-2 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

for establishing key NRVs. The framework, illustrated in Figure 3-4, includes four major steps to
deriving key NRVs:
1. Choose the appropriate tools and resources.
2. Collect relevant data from the tools and other resources.
3. Identify the best approach or method for the nutrient under consideration
4. Derive two key reference values, the average requirement (AR) and the tolerable upper
intake level (UL).
Also in Chapter 3, the committee identified six core values as being critical to global
harmonization of methodologies for setting NRVs:
1. Regularly update existing NRVs.
2. Manage the process with clarity and transparency.
3. Assess the quality of evidence with rigor.
4. Document all factors that influence the potential NRV (e.g., infection, body size)
5. Determine the strength of the evidence reviewed
6. Assure that the review is complete and efficient.
As a part of this process, any uncertainties in the data need to be considered and fully
described. The specific methodology applied in this chapter for deriving NRVs is based on these
key steps and core values, along with consideration for the specific characteristics of the nutrient
under review.
More specifically, the flow diagram illustrated in Figure 4-1 is a detailed subset of the
committee’s proposed framework for deriving NRVs. This chapter describes how the committee
used this subset of the proposed framework in its analyses of zinc, iron, and folate to demonstrate
the feasibility of its recommendations for harmonizing methodologies for deriving NRVs on a
global scale. As discussed below, zinc NRVs can only be estimated using the factorial approach;
iron NRVs can be estimated using either the factorial approach or dose–response modeling, but
the values derived by the factorial approach are recommended; and dose–response assessment is
the preferred approach for folate. As explained in Chapter 3, the balance method is used to
estimate protein and mineral requirements and is therefore not relevant to these case analyses.
For each nutrient, the case analysis begins with a statement of the problem relative to the
nutrient under consideration; next, factors that influence derivation of NRVs and the strengths
and weaknesses of methodologies used to derive them is discussed; finally, the derivation of ARs
and ULs are discussed. The committee did not carry out analyses for both young children and
women of reproductive age for all three nutrients. Rather, the three nutrients were selected to
illustrate the application of the framework across age groups. In addition, the committee did not
actually derive any NRVs. Lastly the committee presents its findings, conclusions, and proposed
solutions for future recommendations regarding each nutrient. In Chapter 5, the committee
discusses consideration of data gaps and options for moving toward harmonization.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-3

Evaluate existing NRVs


Zinc
Iron
Decision to keep and Folate
adapt or derive a new
value

Option to keep and Option to establish new


update or adapt NRV NRV
Factors to consider when interpreting data For the nutrient of interest:
from systematic reviews: • identify population groups
• reference weights • collect data from systematic review
• country-specific issues (e.g. infection and Define approach • consider population distribution
inflammation)
• presence of deficiency
• other factors (e.g. iron menstrual blood
loss modifiers)
Dose-response Factorial
assessment approach

Appraise the
evidence

Evaluate usual
intakes and
dietary patterns

Assess local context

Derive NRV

FIGURE 4-1 Flow diagram for using the factorial approach or dose–response assessment in deriving
nutrient reference values for zinc and iron, or the dose–response modeling for folate.
NOTEs: This figure represents a detailed subset of the flow diagram for deriving nutrient reference values
(NRVs) shown in Figure 3-1. No actual derivation of NRVs was carried out by the committee.

ZINC CASE ANALYSIS

Introduction and Statement of the Problem

Certain population subgroups, especially those living in low- and middle-income countries,
are known to be potentially deficient and particularly vulnerable to the constellation of problems
that present with zinc deficiency. These include infants and young children and pregnant and
lactating women with increased zinc requirements who are also consuming diets that are low in
zinc and/or high in phytate (i.e., cereal-based diets) (Shah et al., 2016). A number of factors
contribute to risk of zinc deficiency in populations, including poor dietary quality, especially in
populations with widespread zinc depletion in top soils (Roohani et al., 2013). In other instances,

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-4 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

while diets may not be necessarily low in zinc, low bioavailability caused by dietary factors such
as high phytate concentration in staple foods may be important. Indeed, many populations living
in the African nations, the Eastern Mediterranean, and South and Southeast Asia frequently are at
risk of zinc deficiency because of inadequate intake (Hess et al., 2009; Wessells et al., 2012).
Other causes include increased zinc loss due to diarrheal infections (King et al., 2016).

Factors Influencing Zinc Requirements

A number of contextual factors affect the zinc requirement of a population. These include
intake patterns of foods rich in zinc or fortified with zinc, dietary components that inhibit zinc
absorption (e.g., phytates), increased dietary requirements to support the gain of new tissue
during pregnancy or growth, and the presence of infections that cause impaired zinc absorption
and/or increased gastrointestinal losses. Key factors are reviewed below.

Whole Body Zinc Utilization and Status


The total amount of zinc absorbed is directly related to the amount of dietary zinc; as dietary
zinc increases, the total amount absorbed also increases, although the percent or fractional zinc
absorption declines. Shifts in endogenous fecal losses are the primary mechanism for
maintaining whole body zinc homeostasis. When the amount of dietary zinc declines,
endogenous fecal losses also decline to reestablish zinc balance, at least initially. A reduction in
dietary zinc causes a decline in endogenous fecal losses within 2 days. Urinary and integumental
zinc losses, in contrast, vary little with shifts in dietary zinc (Hotz and Brown, 2004). If
insufficient intakes persist, tissue zinc catabolism may occur to mobilize zinc from a small,
vulnerable pool for the body’s needs. Plasma zinc is thought to be a component of this pool.
However, a moderate reduction in dietary zinc of 3–5 mg per day reduces plasma zinc
concentrations only if the limited intake is continued for several months or if endogenous losses
are increased because of diarrheal disease. Even though circulating levels remain relatively
stable over a wide range of zinc intakes, serum/plasma zinc concentrations are the most widely
used biochemical indicator of zinc status (King et al., 2016). A more sensitive biomarker to
changes in zinc intake has not been identified.

Physiological Requirements
The physiological zinc requirement is the amount of absorbed zinc required to offset all
obligatory zinc losses, plus any additional amounts needed for growth, pregnancy, or lactation
(Gibson et al., 2016). Certain populations, including children, adolescents, and pregnant and
lactating women, are at increased risk of zinc deficiency because of their higher physiologic
requirements (Roohani et al., 2013). This is true even though zinc absorption increases during
pregnancy and lactation, especially if the dietary intake is low.
Because zinc is involved in many core metabolic pathways, the manifestations of its
deficiency are nonspecific (King et al., 2016). In childhood, zinc deficiency retards growth
(stunting), impairs cognitive function (Gogia and Sachdev, 2012; Levenson and Morris, 2011),
increases the risk of recurrent infections and diarrhea (Lazzerini and Ronfani, 2012), causes hair
loss, and may trigger conjunctival and eyelid inflammation. Stunting in growing children
because of inadequate zinc intakes has led to its wide use in nutritional assessment (Brown et al.,
2004; de Benoist et al., 2007). In adolescents and adults, zinc deficiency can reduce fertility,
cause reproductive performance problems, and impair work capacity (Bernhardt et al., 2012;

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-5

Kawade, 2012). In the elderly, recurrent infections may occur when zinc levels are low (Pae et
al., 2012). Zinc deficiency can lead to death from complications caused by diarrhea, pneumonia,
and malaria (Wazny et al., 2013).

Dietary Zinc Sources


Zinc is present in many types of food but is often associated with proteins in lean tissue.
Animal source foods (i.e., the organs and flesh of mammals, fowl, fish, and crustaceans) are the
richest source of absorbable zinc (King et al., 2016). Other good zinc sources include ready-to-
eat cereals that are fortified with zinc, and certain nuts, seeds, and legumes (Shah et al., 2016).
Amounts of zinc in grains and legumes are influenced by the soil zinc concentration. For
example, increasing the soil zinc content via irrigation has doubled the concentration of zinc in
wheat (Rosado et al., 2009).

Zinc Bioavailability
As mentioned previously, zinc absorption varies with the amount of phytate in the food;
animal foods do not contain phytate, but unrefined cereals and legumes contain high amounts
(Gibson, 2012). However, although the availability of zinc from diets with phytate-to-zinc molar
ratios greater than 15 is generally low, fermentation or germination of these plant foods causes
phytate to be hydrolyzed by phytase enzymes to lower levels of inositol phosphates (i.e., from
IP6 to IP4 or lower) that do not inhibit zinc absorption (Gibson and Anderson, 2009). In
addition, recent research has shown that dietary phytate does not have a detectable effect on zinc
absorption in infants and young children; rather, the total amount of dietary zinc was found to be
the primary determinant of zinc absorption (Miller et al., 2015). Further research is needed,
however, to determine if the effect of phytate on zinc absorption differs in growing children
compared to adults.
Animal studies conducted in the 1980s suggested that calcium could inhibit zinc absorption
because of the formation of an insoluble calcium-zinc-phytate complex. However, later studies in
humans confirmed that calcium did not impede zinc absorption when dietary zinc intake was
adequate, regardless of whether phytate concentration was either low or high (Hunt and
Beiseigel, 2009).
Generally, zinc absorption is enhanced by dietary protein (both quantity and quality).
However, some individual proteins, such as casein, have a modest inhibitory effect on zinc
absorption. Organic acids, such as citrate, enhance zinc absorption (Lonnerdal, 2000). Also
ethylenediaminetetra-acetic acid (EDTA) has been shown to modestly enhance zinc absorption
from ZnSO4-fortified cereals, but not ZnO-fortified cereals (Brnic et al., 2014).

Infection
Zinc is required for the synthesis and function of immune regulatory proteins and for
maintaining immune function (King et al., 2014). Diarrheal infections reduce zinc absorption,
which further impairs immune function and the defense against infections (Wapnir, 2000).
Currently, the World Health Organization (WHO) recommends that 20 mg supplemental zinc be
given in conjunction with oral rehydration therapy to children being treated for diarrheal disease
(WHO/UNICEF, 2004). Importantly, supplemental zinc reduces child mortality from diarrheal
disease by about 6 percent; in children over 12 months of age the effect is higher—about an 18
percent reduction in mortality (Brown et al., 2009a). Zinc insufficiency also increases the risk of
acute, lower respiratory tract infections (Brown et al., 2009b).

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-6 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Assessment of Strengths and Weaknesses in Methodologies to Determine Zinc


Requirements

The committee assessed the strengths and weaknesses of all three methods for deriving
NRVs (balance studies, dose–response modeling, and the factorial approach) in relation to zinc.
As discussed below, the factorial approach is the preferred method for determining zinc NRVs.

Zinc Balance Studies


The Institute of Medicine (IOM) first established a recommended dietary allowance (RDA)
for zinc in 1989 (NRC, 1989). The authoring committee of that first zinc RDA considered
balance data, as well as the factorial approach, and found that what it considered to be the “most
reliable balance studies” indicated that 12.7 mg zinc per day (mg/d) was needed from a typical
U.S. mixed diet to maintain zinc status. From other data (human studies), daily endogenous zinc
losses were estimated to be about 2.5 mg/d; assuming an absorption efficiency of 20 percent, the
dietary requirement to replace these endogenous losses was estimated to be 12.5 mg/d, which
agreed with the 12.7 mg/d estimated from balance studies. Based on these estimates, the 1989
RDA for zinc was set at 15 mg/d for men and 12 mg/d for women. However, after zinc metabolic
studies showed that zinc balance could be achieved from diets as low as 4.6 mg zinc/d to over 20
mg/d (Pinna, 2001), subsequent NRVs for zinc have been derived using the factorial approach,
not the balance method. Such a wide range makes it impossible to identify the lowest intake that
replaces zinc losses while maintaining zinc functions and health.

Dose–Response Estimates
The dose–response estimate is not used to estimate zinc NRVs because the primary indicator
of zinc status, plasma zinc concentrations, remains constant over a wide range of zinc intakes
(see above). Consistent with the evidence cited above, a review of studies of zinc status at the
population level showed that serum zinc concentrations remained unchanged from diets
providing between 3 and 60 mg zinc/d (Gibson et al., 2008). Several health outcomes associated
with inadequate zinc intakes in the population subgroups addressed in this report are identified in
Table 4-1.

TABLE 4-1 Health Outcomes Associated with Inadequate Zinc Intakes for Various Population
Subgroups
Pregnant and Lactating
Infants Children and Adolescents Women
Growth Growth Fetus:
Immune response to Immune function Growth
vaccination Cognitive function Malformation
Neurodevelopment Dermatitis Mother:
Preeclampsia
Preterm delivery
SOURCE: Adapted from Lowe et al., 2013.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-7

Factorial Approach
Given the aforementioned limitation of the balance method, and because there is no known
biomarker of dietary zinc or a selected health outcome that is sensitive to variations in dietary
zinc, the factorial approach is the only method that can be used to estimate the physiological zinc
requirement. This approach requires estimating the amount of absorbed zinc needed to replace
endogenous zinc losses, as well as estimating the endogenous zinc losses, including both
endogenous fecal zinc (EFZ) losses and non-intestinal losses via the urine, integument (skin,
hair, nails, and sweat), menstrual flow in women, and semen in men. As stated previously, total
non-intestinal losses are constant over a wide range of zinc intake (4–25 mg/d) (IOM, 2002). In
contrast, EFZ losses vary with the amount of zinc absorbed and are a major component of zinc
homeostasis. Table 4-2 shows the estimated EFZ losses in adult men and women as determined
by four different authoritative bodies.

Derivation of Zinc Nutrient Reference Values

Here, different authoritative bodies’ derivations of zinc ARs and recommended intakes (RIs)
are explained for adult men and women because this group includes women of reproductive age
and also to illustrate certain details of the methodology for deriving ARs and RIs that can be
applied across population subgroups (i.e., infants and children, and pregnant and lactating
women). Additionally, the derivation of ULs are discussed.

Conversion of Physiological Zinc Requirements as Determined by the Factorial Approach to


ARs and RIs for Adult Men and Women
The estimated AR is the amount of dietary zinc that will replace total endogenous losses. In
other words, it is the amount of dietary zinc needed to meet the physiological requirement. To
convert the physiological requirements into ARs, it is necessary to determine the fractional zinc
absorption (FZA) from different diets. Radioactive and stable isotopes of zinc are used to
estimate the FZA. In addition, as discussed in Chapters 2 and 3, the efficiency of mineral
absorption (bioavailability) is one of several factors that need to be considered when using the
factorial approach to derive an AR. Although recent research suggests phytate may not be a
primary determinant of zinc absorption (Miller et al., 2015), the dietary phytate content remains
a primary factor considered when determining the AR. In the case of zinc, often the phytate:zinc
molar ratio is used to estimate bioavailability. For example, IZiNCG estimated that the
phytate:zinc molar ratio is 11 for a mixed/refined vegetarian diet, compared to 24 for an
unrefined cereal-based diet (Hotz and Brown, 2004). Experimental studies cited in IZiNCG
(2004) have shown that for phytate:zinc molar ratios between 4 and 18, zinc absorption is about
26 percent in males and 34 percent in females; for phytate:zinc ratios greater than 18, zinc
absorption declines to 18 in males and 25 percent in females.
Using a trivariate model that examined the relationship between total absorbed zinc, total
dietary zinc, and dietary phytate (see Figure 4-2), which itself is based on 650 individual
measurements from 18 publications, EFSA estimated that a man consuming a diet with about
1,200 mg phytate/day would need to consume 12.1 mg zinc/day to meet a physiological
requirement of 3.4 mg/d (EFSA NDA Panel, 2014). However, if the phytate intake is cut in half
to 600 mg/d (a phytate:zinc ratio of about 9.8), only about 10 mg of dietary zinc would need to
be consumed to meet the physiological requirement. The different AR estimates for zinc for
adult men and women, as determined by WHO/FAO, IZiNCG, and EFSA are listed in Table 4-3.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-8 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

TABLE 4-2 Comparison of Estimates of Endogenous Losses Used in Factorial Modeling for Zinc in
Adult Men and Women
WHO IOM IZiNCG EFSA
Adult Men

Body weight, kg 65 75 65 72.7


Total non-intestinal endogenous losses
0.60 1.27 1.15 1.14
(mg)
Endogenous fecal losses (mg) 0.80 2.57 1.54 2.40
Total endogenous losses (mg) 1.40 3.84 2.69 3.54

Adult Women

Body weight (kg) 55 65 55 59.1


Total non-intestinal endogenous losses
0.50 1.00 0.80 0.63
(mg)
Endogenous fecal losses (mg) 0.50 2.30 1.06 2.30
Total endogenous losses (mg) 1.00 3.30 1.86 2.93
NOTE: IOM = Institute of Medicine; IZiNCG = International Zinc Nutrition Consultative Group;
WHO = World Health Organization.
After an AR is determined, an RI that is sufficient to meet the needs of almost all (97–98
percent) healthy people in a particular life stage and gender group is established. The RI is the
AR plus 2 standard deviations above the AR. Knowledge of the coefficient of variation (CV) in
zinc requirements within a healthy population is required to determine the RI. WHO, the IOM,
and IZiNCG all used different estimates to determine the RI for zinc. WHO estimated that an
additional 25 percent is needed to establish an RI, based on an assumed variation in protein
requirements (i.e., 12.5 percent) plus an additional 12.5 percent variation for zinc.
The IOM and IZiNCG both used an estimate of the CV of the zinc requirement. However,
the IOM assumed that the coefficient of variation was 10 percent, whereas IZiNCG used 12.5
percent. EFSA took a different approach. Since multiple regression analysis showed that body
weight was a strong determinant of the zinc requirement, it estimated the RI as the requirement
for individuals with a body weight at the 97.5th percentile using the reference body weights of
men and women. EFSA assumed a median body weight of 58.5 kg for women and 68.1 kg for
men. This is equivalent to a BMI of 22 kg/m2. The zinc RIs for adult men and women that have
been established by these four authoritative bodies, as well as other national or international
groups, vary widely depending on dietary phytate or bioavailability estimates. Individuals
consuming diets with high zinc availability may only require about 5 mg/d, whereas those with
low availability may need as much as 19 mg/d (Wessells et al., 2012).

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-9

FIGURE 4-2 The relationship between total absorbed zinc (TAZ), dietary phytate, and total dietary zinc.
SOURCE: EFSA NDA Panel, 2014.
Determination of zinc ARs and RIs for infants and children Among infants and children, the
physiological zinc requirement equals the total endogenous losses plus the additional zinc
required for growth. Because the need for zinc to support growth has not been measured in
infants between 0 and 6 months, it can be estimated in one of two ways: (1) from the usual
amount of tissue gained during this time period and assuming that the tissue contains 20 μg
zinc/g tissue gained, or (2) from the amount of zinc provided in breast milk, assuming that breast
milk supplies an adequate amount of zinc for growth during the first 6 months. When using the
latter method, an average breast milk zinc concentration over the entire time period is used, even
though it is known that the breast milk zinc concentration declines between 0 to 6 months.
WHO, the IOM, IZiNCG, and EFSA all used different assumptions for estimating the zinc
needs of infants between 0 to 6 months of age. WHO based its estimate on the amount of lean
tissue gained and concluded that the zinc need ranged from 0.7 to 1.3 mg/d depending on the
amount of tissue gained. The IOM assumed that the zinc supplied in breast milk was an
“adequate intake” over the first 5 months and, that the need for zinc was 2.0 mg/d. IZiNCG also
concluded that breast milk was a sufficient source of zinc for exclusively breastfed infants;
however, in addition, if food is also consumed, the infant needs to absorb about 1.3 and 0.7 mg
zinc/day from the food during 0 to 3 months and 3 to 5 months, respectively, to support growth.
EFSA also based its estimate on the amount of breast milk consumed as well; it concluded that
2.0 mg zinc is required daily based on an average breast milk volume of 0.80 L/d and with a zinc
concentration of 2.5 mg/L.
All four authoritative bodies used the factorial approach to estimate the AR for absorbed zinc
for infants 6 to 12 months and children 1 to 18 years (see Table 4-3). Estimates of total
endogenous losses were determined by extrapolation from adult values, based on metabolic
weight (WHO) or reference body weights (the IOM, IZiNCG, EFSA) (extrapolation is explained

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-10 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

in Chapter 3). To estimate the amount of zinc needed to synthesize new tissue, the IOM,
IZiNCG, and EFSA assumed that new tissue, irrespective of whether it was lean or adipose
tissue, had a zinc concentration of 20 μg/g tissue.
WHO assumed a zinc concentration of 30 μg/g wet tissue weight in infants and children up to
10 years of age, and 23 μg/g thereafter. The estimated amount of new tissue gained varied
slightly among the four authoritative bodies, which accounts for the differences in the estimated
physiological requirements. As shown in Table 4-3, in general, the estimated physiological
requirement ranged from less than 1 to 1.9 mg/d up to 10 years of age. Between 10 and 18 years
of age, the physiological requirement ranges from about 1.5 to 3.5mg/d. The values for males
tend to be higher than the values for females.
Also shown in Table 4-3, after adjusting for the bioavailability of dietary zinc, among 7–12
month-old infants, the AR estimates by the IOM, IZiNCG, and EFSA range from 2.2 to 3 mg/d,
which translates to an RI of 3 to 4 mg/d.
AR estimates range from 2.2 to 3.6 mg/d, and the RI estimates range from 3 to 4.3 mg/d for
1–3 years of age. After 3 years of age, AR estimates increase to about 2 to 4 mg/d during the
preschool years (4–8 years of age), and the RI range increases to 4–5.5 mg/day. Among school-
age children from 7–13 years of age, AR estimates range from 7 to 9 mg/d, which translates to an
RI of 6 to 9.4 mg/day. For adolescents aged 14–18 years, AR estimates range from 8 to11 mg/d,
with RI estimates ranging from about 10 to 14 mg/d.
WHO estimates of RI shown in Table 4-3 are based on f high zinc bioavailability (50
percent). Not shown in the table, WHO estimated the RIs from diets with moderate (30 percent)
and low (15 percent) bioavailability as well; for 7–12 month old infants, the RIs are 2.5, 4.1, and
8.4 mg zinc/d (WHO/FAO, 2004).
Recently, zinc absorption and retention was studied in young children between 1 and 3 years
of age from low-income countries who are subsisting on cereal-based diets that have been
fortified with zinc. Normally, FZA declines with increased amounts of zinc in the diet. That was
not observed, however, when zinc intakes were increased in toddlers by feeding biofortified
cereals or micronutrient powders. Thus, increasing dietary zinc intakes from zinc supplements or
fortified foods may improve tissue zinc levels and growth in vulnerable populations subsisting
on cereal-based diets (Chomba, 2015; Ariff, 2014).
Also of relevance, previous studies have shown that supplemental iron reduces zinc
absorption (Chung, 2002; O’Brien, 2000). However, a recent study of 6-month old, nonanemic
infants showed that the addition of iron to micronutrient powders did not reduce zinc absorption
(Esamai, 2014). This is an encouraging finding as iron and zinc deficiencies tend to coexist in
infants and toddlers. As previously mentioned, another important recent finding is the absence of
a negative effect of dietary phytate on zinc absorption in infants and young children (Miller,
2015), which raises questions about using the dietary phytate:zinc molar ratios to predict dietary
zinc absorption and, therefore, the zinc AR.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age
5-12 HARMONIZATION OF NUTRIENT REFERENCE VALUES

TABLE 4-3 Estimated Physiological Requirements for Absorbed Zinc, ARs, (mg/d) and for the RIs During Childhood by Age Group and Gender
WHO IOM IZiNCG EFSA
Age, Wt Physiol AR RI, Age, Wt Physiol AR RI Age, Wt Physiol AR RI Age, Wt Physiol AR RI
Sex (kg) require (mg/ (mg/ Sex (kg) require (mg/d) (mg/d) Sex (kg) require (mg/d) (mg/d) Sex (kg) Req (mg/d) (mg/
ments d)b d)b ments ments (mg/d) d)
(mg/d) (mg/d) (mg/d)
Copyright National Academy of Sciences. All rights reserved.

7–12 9 0.84 ––a 2.5 7–12 9 0.84 2.2 3.0 6–11 9 0.84 3 4 7–11 2.4 2.9
mo mo mo mo
1–3 12 0.83 1.66 2.4 1–3 13 0.74 2.2 3.0 1–3 12 0.53 2 3 1–3 11.9 1.074 3.6 4.3
3–6 17 0.97 1.94 2.9 4–8 22 1.20 4.0 5.0 4–8 21 0.83 3 4 4–6 19.0 1.390 4.6 5.5
6–10 25 1.12 2.25 3.3 7–10 28.7 1.869 6.2 7.4
c
10–12 M 35 1.40 2.80 5.1 9–13 40 2.12 7 8 9–13 38 1.53 5 6 11–14 44 2.635 8.9 9.4
c
10–12 F 37 1.26 2.38 4.3 M 45 2.663 8.9 9.4
12–15 M 48 1.82 3.65 11–14
12–15 F 48 1.55 3.07 F
15–18 M 64 1.97 3.90 14–18 64 3.37 8.5 11 14–18 64 2.52 8 10d 64 3.544 11.8 12.5
15–18 F 55 1.54 3.08 M 57 3.02 7.5 9 M 56 1.98 7 9d 56 2.969 9.9 10.4
14–18 F 14–18 15–17
F M
15–17
F
a
In its estimate of an AR for 7- to 12-month-old infants, WHO adjusted adult values based on metabolic rate. The resulting value, 0.6 mg/d, was less than
the physiological requirement. Adjustments made by the IOM, IZiNCG, and EFSA were based on reference body weights.
b
WHO AR and RI values included here were estimated for high bioavailability (50 percent).
c
For children between 10 and 18 years of age, WHO established only two RIs, one for each sex that cover the entire age group.
d
The IZiNCG RIs included here are for a mixed diet. RIs were also established by an unrefined diet.
SOURCE: Brown et al., 2004.

PREPUBLICATION COPY: UNCORRECTED PROOFS


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 5-13

Determination of Zinc AR and RI for Pregnant and Lactating Women


Table 4-4 summarizes WHO, the IOM, IZiNCG, and EFSA estimates of ARs and RIs for
zinc for pregnant and lactating women. The physiological zinc requirement for pregnant women
can be estimated from the amount of zinc retained throughout pregnancy. WHO estimated that
100 mg of zinc is retained during pregnancy (WHO, 2004). No adaptations in zinc absorption or
excretion were considered. Both WHO and the IOM determined the amount of zinc needed per
trimester according to differences in the rates of fetal growth (IOM, 2002; WHO/FAO, 2004).
Alternatively, IZiNCG used a single value of 0.7 mg/d as the amount of zinc retained throughout
pregnancy based on the recognition that this rate of zinc retention overestimates the needs in the
first and second trimester. EFSA used 0.4 mg/d as a lower average rate of retention over the four
quarters of pregnancy. To meet these additional needs, the IOM and IZiNCG estimated that the
zinc AR is 9.5 or 8 mg/d for women over 19 years of age, with an RI of 11 or 10 mg/d. Not
shown in Table 4-4, but of note, the ARs are higher for pregnant adolescents, 10.5 (IOM) or 12
(IZiNCG) mg/d, based on evidence that these young women may have additional needs to
support any continued growth. The IOM and IZiNCG estimates of RI for pregnant adolescents
are 13 and 15 mg zinc/day, respectively.
Estimating the additional zinc needed for lactation requires taking into consideration breast
milk zinc concentration. Breast milk zinc appears to be relatively similar among women with
different zinc intakes, owing to the redistribution of tissue zinc from uterus involution, and the
release of zinc to maternal tissues resulting from the decline in blood volume during early
lactation. However, breast milk volume, and thus breast milk zinc concentrations, do change
over time. WHO recommended an additional 1.4 mg/d of zinc from 0 to 3 months and 0.5 mg/d
from 6 to 12 months. The IOM, IZiNCG, and EFSA made one recommendation to be applied
throughout lactation, recognizing that the actual need varies with time. For example, EFSA
recommended an additional 1.1 mg/d of zinc, based on the assumption that the mean increases in
physiological requirement are 1.5 mg/d for the first trimester, 1.37 mg/d for the second trimester,
and 0.86 mg/d for the third trimester (EFSA NDA Panel, 2014).
EFSA (2014) also estimated RIs for nonpregnant and nonlactating women consuming
different levels of phytate. The additional zinc needed for pregnancy or lactation is added to the
RI based on the amount of phytate normally consumed. For example, 9.3 mg of zinc per day is
the RI for women of reproductive age who are consuming 600 mg of phytate per day. To meet
the needs for pregnancy, 1.6 mg of additional zinc should be added (i.e., 9.3 + 1.6 = 10.9 mg
zinc/d; for lactation, 2.9 mg of additional zinc is added (i.e., 9.3 + 2.9 = 12.2 mg zinc/d).

Safe Upper Levels of Intake


As described in Chapter 3, the UL is defined as the highest daily intake level of a nutrient
that is likely to pose no risk of adverse health effects for almost all individuals. The
physiological basis for the zinc UL is the effect of high doses of supplemental zinc (50 mg
zinc/d) on the activity of erythrocyte copper-zinc superoxide dismutase. The IOM set a UL of 40
mg zinc/d as an intake with no observed adverse effect level (NOAEL) for adult men and
women. A value of 4.0 mg/d was set for infants 0–6 months of age; 7 mg/d for 1- to 3-year-old
children and 12 mg/d for 4- to 8-year-old children. IZiNCG adopted the IOM UL for adults.
Given that U.S. children frequently have zinc intakes above the IOM’s UL without any evidence
of adverse effects, IZiNCG set a NOAEL of 6 mg zinc/d for 6- to 11-year-old children and 8
mg/d for 1- to 3-year-olds. EFSA did not derive a UL for any life stage group.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-13

WHOa IOMb IZiNCGb EFSAb


Pregnancy Lactation Pregnancy Lactation Pregnancy Lactation Pregnancy Lactation
AR RI AR RI AR RI AR RI AR RI AR RI AR RI AR RI
— 3.4 — 5.8 9.5 11 10.4 12 8.0 10 7.0 9 +1.3 +1.6 +2.4 +2.9
4.2 5.3
6.0 4.3
TABLE 4-4 Zinc Average Requirement (AR) and Recommended Intake (RI) During Pregnancy and
Lactation by WHO, IOM, IZiNCG, and EFSA
NOTE: EFSA = European Food Safety Authority; IOM = Institute of Medicine; IZiNCG = International
Zinc Nutrition Consultative Group; WHO = World Health Organization.
a
WHO made RI recommendations for each trimester and for 0–3, 3–6, and 6–12 months lactation.
b
The IOM, IZiNCG, and EFSA made a single recommendation for pregnancy and lactation.

Alternative Approaches to Determining Zinc Requirements


Another approach for assessing the adequacy of dietary zinc intake could be the effect of
changes in zinc intakes on selected biochemical and/or functional markers of zinc adequacy.
However, as discussed previously, at present, there are no quantitative zinc biomarkers available
that reflect changes in the zinc status of an individual with changes in intake. IZiNCG and the
Biomarkers of Nutrition for Development (BOND) both recommended serum/plasma zinc levels
as one of the best biomarkers of zinc status currently available (Brown et al., 2004; King et al.,
2016). But, as stated previously, plasma zinc concentrations remain constant over a range of
dietary zinc intakes from 4 to 60 mg/d (Gibson et al., 2008). Thus, they cannot be used to derive
ARs or RIs.
Other biomarkers that have been used to assess zinc status include, but are not limited to,
erythrocyte zinc levels, urinary zinc excretion, hair zinc levels, and alkaline phosphatase activity
(Lowe et al., 2009). Unfortunately, these biomarkers are also limited in their sensitivity and/or
specificity for assessing whole body zinc status, and thus, would not be useful for estimating
dietary zinc requirements. In population studies, the prevalence of stunting is among the most
widely used biomarkers for assessing zinc status, along with dietary intake and serum zinc levels
(King et al., 2016; Roohani et al., 2013). Stunting is the preferred functional marker by
physicians, and it is generally responsive to the administration of supplemental zinc (Hotz and
Brown, 2001; Roohani et al., 2013). Other nutrients can also affect stunting.

FINDINGS AND CONCLUSIONS FOR ZINC

• There is no available sensitive, specific biomarker of zinc nutrition. Although severe


dietary zinc restriction (i.e., diets providing less than 1 mg zinc/day) cause a marked,
rapid decline in plasma zinc, it can take weeks for levels to returns to baseline upon zinc
repletion. Plasma zinc concentrations seem to be more responsive to zinc
supplementation than to added zinc from food; supplements have been shown to cause
prompt increases in plasma zinc concentrations irrespective of dietary zinc intake (King
et al., 2016). Surveys show that plasma zinc concentrations remain relatively stable over
a wide range of less restricted zinc intakes (i.e., from about 4 to 60 mg of zinc per day)
(Gibson et al., 2008). Although linear growth has been recommended as a functional
indicator of zinc status, since low height- or length-for-age has been shown to be

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-14 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

responsive to supplemental zinc (Hotz and Brown, 2001), as with plasma zinc
concentrations, the response to additional dietary zinc is not as strong as the response to
supplemental zinc.
• Among adults, dietary phytate is thought to be a major determinant of zinc absorption.
Thus, the phytate:zinc molar ratio is used to calculate a population’s dietary zinc
requirements. EFSA initiated this approach in its 2014 recommendations (EFSA NDA
Panel, 2014). However, a recent study failed to find an effect of phytate on zinc
absorption in young children and in pregnant or lactating women (Miller et al., 2015).
• Since zinc is generally associated with proteins in body cells and tissues, it is important to
determine whether dietary zinc recommendations need to be matched to the amount and
type of protein in the diet (i.e., animal or vegetable). When developing zinc
supplementation or fortification programs, it is generally assumed that all zinc organic
and inorganic salts are equally absorbed (Hotz et al., 2005). However, the bioavailability
of zinc-amino acid complexes may be used more effectively if certain amino acids are
functioning as ligands (Wapnir and Stiel, 1986).
• Survey data suggest that growing children are particularly vulnerable to developing zinc
deficiency and are more prone to develop gastrointestinal or pulmonary zinc infections as
a result. The physiology underlying this increased vulnerability in children is unknown.
Possibly, children lack tissue or cellular reserves to draw on when diet is marginal.
Alternatively, their immune systems are less well developed than adults.
Based on its findings for zinc, the committee came to the following conclusions:
1. Additional data are needed to determine if age or physiological zinc need
influence the effect of phytate on zinc absorption.
2. Further research will be needed to determine if a modest, consistent increase
in dietary zinc could reduce a child’s susceptibility to zinc deficiency by
increasing the level of tissue zinc reserves or enhancing immune function. As
part of this research, careful thought should be directed toward recommending
a zinc intake that would achieve an increased resistance to disease.
3. Since the zinc physiological requirements and ARs for young children and
women of reproductive age that have been made by the authoritative bodies
reviewed in this report are very similar (as shown in Tables 4-2, 4-3, and 4-4),
efforts should be made to consolidate these estimates globally. However, there
may still be a need to set national RIs based on the dietary zinc source (i.e.,
bioavailability) and the average body size of the population.
4. Reviews addressing dietary factors influencing zinc absorption and
physiological losses among various population subgroups are needed.
In reference to the four steps for setting NRVs outlined in Figure 3-4, these are the issues
regarding zinc recommendations:
• Currently, systematic reviews of dietary zinc requirements are lacking.
• Limited experimental data are available for infants, young children, and pregnant and
lactating women from different regions. Comprehensive studies of these populations are
especially needed in low- and middle-income countries.
• The factorial approach is the preferred method for estimating zinc reference values, but
those data should be supplemented with dose–response modeling, which shows the effect

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-15

of various zinc intakes on the growth rate of toddlers or the association between zinc
intake and immune function biomarkers in children or pregnant/lactating women.

IRON CASE ANALYSIS

Introduction and Statement of the Problem

Iron deficiency is the most common nutritional deficiency worldwide and a major cause of
infant mortality (Rahman et al., 2016). Young children and women of reproductive age,
especially during pregnancy, are at increased risk because of the high iron requirements for
growth or the replacement of iron lost in menses. Women with high menstrual losses have a
greater risk of iron deficiency, compared to women with lower menstrual losses (Harvey et al.,
2005). Iron deficiency is particularly common in low-income countries because of limited
intakes of animal products (which contain the more highly bioavailable heme iron, which can
promote nonheme iron absorption) and the consumption of repetitive diets based on cereal grains
and legumes. Cereal grain and legume-based diets are low in bioavailable iron owing to the
presence of phytate and certain polyphenols that inhibit iron absorption (Hurrell and Egli, 2010).
This dietary pattern leads to iron deficiency and anemia, which results in pathophysiological
conditions such as low birth weight, stunted growth, delayed mental development, and impaired
motor function.

Factors Influencing Requirements

As with zinc, a number of contextual factors affect the iron requirements of a population. In
addition to the dietary intake pattern described above, these include the physiological state of an
individual or group, environmental influences on nutrient intake, and a population’s health
status. In the future, it may be important to consider the genetic background of a population as
well (Stover, 2007). The key factors influencing iron requirements are whole body iron
metabolism, physiological requirements dietary sources, iron bioavailability, and infection.

Whole Body Iron Utilization and Status


Iron absorption is a tightly regulated function; its efficiency is determined in the absence of
disease by the size of body iron stores. The iron status of healthy populations is usually measured
using serum ferritin level as a biomarker. However, infections and inflammatory disorders can
increase serum ferritin concentrations even when body iron stores are depleted. Similarly, other
iron biomarkers, such as soluble transferrin receptors, can be modified by chronic disease or
deficiencies of other nutrients (Lynch, 2011). Thus, accurately estimating iron status can be
challenging, especially in populations where infection is common.

Physiological Requirements
Physiological iron requirements are based on the amount needed to replace losses. Using data
from radioisotope studies, Green et al. (1968) estimated total iron losses from skin, intestine, and
the urinary tract to be, on average (among men from three different countries), 0.014 mg per
kilogram of body weight per day. A more recent study used radioisotopes to measure total iron
losses in women as well as men (Hunt et al., 2009). The values for men are similar to the earlier

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-16 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

study, but in women of reproductive age the values are higher than for men because of menstrual
losses, with a mean value of 0.025 mg per kilogram of body weight per day.

Dietary Patterns
The requirement for a given nutrient in a population depends on the amount of the nutrient
ingested through usual dietary patterns, as well as the iron bioavailability from the diet and the
presence of infections in the population (King and Garza, 2007). As stated above, habitual
consumption of foods that contain such iron-binding components, that is, phytate and
polyphenols, increases dietary requirements for iron. Using food preparation techniques that
enhance iron absorption, such as cooking in iron pots, may increase iron intake.

Iron Bioavailability
Iron is absorbed either as heme iron, which is found in meat and fish, or as nonheme iron, as
found in plant foods. Heme iron has greater bioavailability than nonheme forms. Typically, 15 to
35 percent of heme iron is absorbed, while nonheme iron absorption can range from 2 to 20
percent, depending on the type of grain or legume; the presence of other dietary components,
such as phytate, which inhibits iron absorption; or iron status (Abbaspour et al., 2014). For
example, at the Global Harmonization of Methodological Approaches to Nutrient Intake
Recommendations workshop (NASEM, 2018), Umi Fahmida described work from Narasinga
Rao et al. (1983) reporting iron absorption rates of 1.7–1.8 percent for a millet-based diet, 3.5–
4.0 percent for a wheat-based diet, and 8.3–10.3 percent for a rice-based diet.
Not only do meat, fish, and poultry have high iron bioavailability because of their heme iron,
but also heme iron from animal sources can enhance nonheme iron absorption from vegetable
and grain sources. Also at the Global Harmonization workshop, Fahmida described data showing
that iron absorption rates of 1.7 percent for a rice-based diet increased to 5.5 percent with the
addition of 15 grams of fish, and to 10.1 percent with the addition of 40 grams of fish (Aung-
Than-Batu et al., 1976). Grain- and vegetable-based food sources are more prevalent in low- and
middle-income countries where diet, poverty, or cultural norms limit consumption of meat and
fish, thus contributing to the higher prevalence of iron deficiency in those populations.
Additionally, because iron absorption depends on levels of hepcidin (a hormone that
regulates iron absorption), iron bioavailability is also affected by the effects of infection and
inflammatory disorders on hepcidin regulation (Nemeth and Ganz, 2009).

Infection
Seth Adu-Afarwuah (2018), in his presentation at the Global Harmonization workshop
explained that infections can affect nutrient requirements by decreasing food intake, impairing
nutrient absorption or reabsorption, increasing absolute or direct losses of body nutrients, and
altering uptake, diversion, or sequestration of body nutrients (Bresnahan and Tanumihardjo,
2014). In the case of iron, not only does poor iron status impair host defenses against infection,
but the presence of infection worsens the deficiency state by triggering a physiologic down-
regulation of iron absorption (Drakesmith and Prentice, 2012).

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 5-13

Assessment of Strengths and Weaknesses in Methodologies to Derive Iron ARs

Although attempts have been made to define a dose–response relationship between iron
intake and an iron status biomarker or selected health outcome, too many uncertainties remain.
The strengths and weaknesses of both approaches are discussed below.

Dose–Response Assessment
As summarized in Chapters 2 and 3, standardized systematic review methodologies are an
important component of the methodological approach for deriving NRVs. In a series of
systematic reviews undertaken by the European Micronutrients Recommendations Aligned
(EURRECA), a large degree of heterogeneity among the study populations, iron doses, and
outcome measures was found (Harvey et al., 2013). This heterogeneity precluded using meta-
analyses for determining the relationship between iron intake and several selected outcomes:
tiredness, physical performance, immune function, thermoregulation, restless leg syndrome, and
cognitive function). Thus, it was not possible to draw conclusions about associations between
iron intake and those selected outcomes. In a separate systematic review (NNR, 2004), the
Nordic Council of Ministers attempted to determine the relationship between iron intake and
adequate growth, development, and health maintenance (Domellof et al., 2013). A total of 55
articles were identified as relevant, and the evidence was assessed using the GRADE system.
Most of the studies focused on vulnerable groups, namely young children and women of
reproductive age. There was some evidence that treatment of iron deficiency anemia improved
attention and concentration in adult women.
Based on these findings on selected health outcomes, as well as other studies cited previously
in this chapter on iron intake and status biomarkers (e.g., serum ferritin levels), the committee
identified a number of problems in attempting to establish reference values for iron using dose–
response assessment:
• Inaccurate estimates of iron intake and quantities of heme and nonheme iron in the diet
• Poor correlation between iron intake (bioavailability) and status
• Difficulty in measuring adaptive and functional responses to variations in iron intake
• Lack of sensitive and specific markers to determine iron status
• Confounding by other dietary and lifestyle factors and by responses to infection and
inflammation
• Inadequate characterization of iron deficiency anemia and the relative role of iron
deficiency and other causes of anemia

The Factorial Approach


In the absence of a sensitive biomarker or health outcome for defining a dose–response
relationship for iron intake, the factorial approach is the preferred method for estimating
physiological iron requirements. This approach involves estimating the quantity of absorbed iron
needed to replace iron losses. Table 4-5 summarizes different authoritative bodies’ estimates of
iron losses, bioavailability factors (used to determine the usual proportion of dietary iron
absorbed), and AR for women of reproductive age.
Estimating iron losses Iron losses or needs are divided into three categories: (1) basal losses, (2)
menstrual losses in women, and (3) iron accretion for pregnancy and growth in children. When

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-18 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

calculating total loss, if the distributions of a component are not normally distributed, data from a
large theoretical population with characteristics similar to the population of interest are collected
and the median percentile of the distribution is used instead (e.g., see discussion of menstrual
blood loss below).
Basal losses refer to the obligatory iron losses in feces, urine, sweat, and skin cell exfoliation.
As mentioned previously, Green et al. (1968) measured basal iron losses using long-lived radio-
labeled iron (55Fe) and calculated an average loss of about 14 mg/kg body weight per day, which
is about 0.9 to 1.0 mg of iron per day. This value is corroborated by the IOM measures of whole
body iron excretion (IOM, 2001). Variation in whole body iron excretion among different
population subgroups is explained primarily by body weight and the magnitude of iron stores.
When menstrual iron losses are added to these basal iron losses, using data from Hallberg et
al. (1966a,b), Hallberg (1991), and Hallberg and Rossander-Hultén (1991) , the estimated total
iron loss increased to ~1.5 mg/d. As shown in Figure 4-3, there is wide inter-individual
variability in menstrual losses and a skewed distribution (Harvey et al., 2005). Thus, to obtain
this estimated total of ~1.5 mg/d, menstrual blood loss was predicted from a log-normal
distribution, with a predicted median of 30.9 mL/cycle, with a hemoglobin of 3.39 mg/g1;
assuming a 28-day cycle, this equates to 0.51 mg/d of menstrual loss.
The EFSA NDA Panel (2015) took a unique approach to estimating iron requirements by
using the whole-body iron loss data derived from isotope studies (Hunt et al., 2009). In
premenopausal women, the 50th percentile of the model-based distribution of obligatory iron
losses was 1.34 mg/day (see Table 4-5). Thus there appears to be good agreement between this
newer data from Hunt et al. (2009) and the older data generated by Green et al. (1968). The 90th,
95th, and 97.5th percentiles of iron loss were, respectively, 2.44, 2.80, and 3.13 mg iron/day.

35
30
No. subjects

25
20
15
10
5
0
0

0
10

00

11

13
-2

-3

-4

-5

-6

-7

-8

-9

-1
0-

10

20

30

40

50

60

70

80

0-

0-
90

10

12

Blood loss (ml) per cycle

FIGURE 4-3 Frequency distribution of menstrual blood loss (ml/cycle) in women aged 18–45 years.
NOTE: N = 90.
SOURCE: Harvey et al., 2005.

1
Iron lost blood was calculated from the total menstrual blood loss using the equation: MIL (mg = d) = MBL (ml) ×
Hb (mg = ml) × 0·00334 /cycle length. MIL is menstrual Fe loss, MBL is menstrual blood loss, Hb is hemoglobin,
and 0·00334 is equivalent to the fraction of iron in hemoglobin at a concentration of 1 mg/ml.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-19

As summarized in Table 4-5, there is good agreement between the values derived by
different organizations for absorbed iron to replace obligatory losses of iron from women of
reproductive age. Median values range from 1.4 to 1.54 mg/d, with average physiological
requirement of 1.6 (for women aged 18–22 years) to 1.7 (women aged greater than 22 years)
mg/d. When expressed in centiles, the values are 1.34 (50th centile), 2.8–2.94 (95th centile), and
3.13–3.15 (97.5th centile).
Estimating ARs for pregnancy Different authoritative bodies’ estimates of the total iron cost of
pregnancy and ARs for pregnancy are also summarized in Table 4-5. EFSA’s estimate of an AR
for pregnancy is the same estimate for premenopausal women, and WHO/FAO did not establish
an AR for pregnancy. In contrast, the IOM, Australia and New Zealand, and the Netherlands all
increased their estimated ARs for women during pregnancy. There are two main reasons for this
disparity in iron recommendations among authoritative bodies. One is the assumption about the
level of iron stores at conception. As explained below, both EFSA and WHO/FAO assumed
there was a storage of iron in the liver at the beginning of pregnancy that could then be mobilized
for pregnancy needs. In contrast, other authorities assumed that many women, particularly
teenage girls who became pregnant, do not have sufficient iron stores, and therefore all of the
additional iron has to be obtained from the diet (or supplements).
The second reason for the different recommendations is uncertainty about the degree to which
the efficiency of absorption increases during pregnancy. Also explained below, both EFSA and
WHO/FAO assumed an increased efficiency of absorption.
The total iron cost of pregnancy represents the iron deposited in the fetus, placenta, and
umbilicus, plus the amount needed for hemoglobin mass expansion. Estimates of the iron content
of the fetus and placental tissue range from 320 mg (IOM, 2001) to 450 mg (375 for the fetus
and 75 for the placenta) (Hytten and Leitch, 1971). The amount of iron needed for expansion of
the hemoglobin mass is thought to be about 450 to 500 mg with most of the gain occurring in the
second and third trimesters. EFSA, however, in its determination of an iron intake for pregnancy,
did not include an iron allocation for expanding the hemoglobin mass based on evidence that the
efficiency of iron absorption increases exponentially up to about 10 mg/d during the last 6 weeks
of pregnancy (Whittaker et al., 1991; Barrett et al., 1994). This increased efficiency can
compensate for the higher needs, it argued, provided that adequate iron stores are present at
conception. If the serum ferritin concentration is 30 μg/L at conception, then around 120 mg of
stored iron can be mobilized to support the pregnancy needs.
WHO/FAO (2004) did not derive a separate iron intake requirement for pregnancy, arguing
that iron balance in pregnant women depends on the properties of the diet and on iron stores and
that the requirements could be met by the increased efficiency of iron absorption (Milman,
2006). Although its estimated total iron requirements are 1,040 mg (300 mg for the fetus, 50 mg
for the placenta, 450 mg for the expansion of maternal red cell mass, and 240 mg for basal iron
losses), because of the assumption of sufficient iron stores, WHO/FAO’s estimated net
pregnancy iron requirement is 840 mg. Similarly, the UK COMA did not give a pregnancy
recommendation, nor did Nordic Nutrition Recommendations, although it did state that the
physiological requirements for some women may not be satisfied during the last two trimesters
of pregnancy.
Determining AR and RI for lactating women As with pregnancy, there is also inconsistency
among authoritative bodies for recommendations during lactation (see Table 4-6). When using
the factorial approach to calculate additional iron needed to support lactation, some agencies do
not account for increased iron losses in breast milk.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age
APPLYING METHODOLOGICAL APPROACHES 5-13

TABLE 4-5 Comparison of Factors Used in Factorial Modeling to Determine an AR for Iron in Women of Reproductive Age

Values used by authoritative bodies to derive iron ARs for women of reproductive age
WHO/ D-A-CH UK COMA EFSA
IOM (2001) NNR (2012) Aus/NZ (2017) NL (1992)
FAO (2004) (2015) (1991) (2015)
Premenopausal
Median basal
Copyright National Academy of Sciences. All rights reserved.

iron losses 0.87 1.4 1.54 1.35 1.6 1.56 1.34


(mg/d)
Bioavailability 12–15: meat-
factor (percent) based
18 10-15 15 18 12 15 18
5–10: cereal-
based
AR (mg/d) — 8.1 — 9 8 14 11.4 7
Pregnancy
Total cost of
840 700–800 0800 1,040 680 835
pregnancy (mg)
9: 1st tri
23 (14–18 y) 23 (14–18 y)
AR (mg/d) — — 9 14: 2nd tri 14.8 7
22 (> 18 y) 22 (≥ 19 y)
18: 3rd tri
Lactation
Milk secretion
0.3 0.27 0.25–0.34
(mg/d)
Bioavailability
— 18 18
factor (percent)
7 (14–18 y)
AR (mg/d) — 6.5 — 9 19 11.4 7
6.5 (≥ 19 y)
NOTE: Aus/NZ = nutrient reference values for Australia and New Zealand; D-A-CH = Nutrition Societies of Germany, Austria, and Switzerland;
EFSA = European Food Safety Authority; IOM = Institute of Medicine; NNR = Nordic Nutrition Recommendations; NL = Netherlands Food and
Nutrition Council; NNR = Nordic Nutrition Recommendations; UK COMA = United Kingdom Committee on Medical Aspects of Food and
Nutrition Policy; tri = trimester; WHO/FAO = World Health Organization/Food and Agriculture Organization.

PREPUBLICATION COPY: UNCORRECTED PROOFS


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 5-13

TABLE 4-6 Comparison of Recommendations During Lactation from Different Authoritative Bodies
Recommending Body NRVs for lactation
WHO/FAO, 2004 The usual practice in WHO/FAO reports is to report
only an RI, not an AR. Based on a median daily
milk iron loss of 1.15 mg/d, the RI is estimated to
be 10 mg/d for a dietary bioavailability of 15
percent and 30 mg/d for a bioavailability of 5
percent.
IOM, 2001 Based on an average milk iron loss of 0.27 ± 0.09
mg/d and assuming a bioavailability of 18 percent,
the AR was estimated at 6.5 mg/d.
D-A-CH, 2015 An RI of 20 mg/d was recommended to replace
losses caused by pregnancy and to meet lactation
needs. No AR was reported.
NNR, 2012 An AR of 9 mg/d and an RI of 15 mg/d were
recommended; these are the same as those for
nonpregnant and nonlactating women.
NL, 1992 The AR increased to 19 mg/d to replace iron lost
during birth and in milk.
UK COMA, 1991 Based on an estimated milk iron loss of 0.25–0.34
mg/d. No increase in AR was recommended.
EFSA Assuming the total requirement for absorbed iron
during the first months of lactation to be 1.3 mg/d,
no increase in AR was recommended.
NOTE: Aus/NZ = nutrient reference values for Australia and New Zealand; D-A-CH = Nutrition
Societies of Germany, Austria, and Switzerland; EFSA = European Food Safety Authority; IOM =
Institute of Medicine; NNR = Nordic Nutrition Recommendations; NL = Netherlands Food and Nutrition
Council; UK COMA = United Kingdom Committee on Medical Aspects of Food and Nutrition Policy;
WHO/FAO = World Health Organization/Food and Agriculture Organization.

Derivation of Safe Upper Levels of Intake

Here, several different authoritative bodies’ recommendations for a UL for iron, or reasons
for not setting a UL, are described. First, because of the absence of more serious adverse effects
(including vascular disease and cancer), the IOM (2001) based its recommendations for a UL on
gastrointestinal side effects caused by high iron intakes. An LOAEL was set based on a study in
Sweden where 97 men and women were give iron supplements (60 mg/day as ferrous fumarate)
in addition to an estimated dietary intake of 11 mg iron/day (Frykman et al., 1994). Most
participants reported minor side effects although five withdrew because they considered the side
effects (e.g., constipation) severe enough to stop taking the medication. An uncertainty factor of
1.5 was selected to account for extrapolation from an LOAEL to an NOAEL, which
approximates to a UL of 45 mg/day.
Similarly, the Australia/New Zealand report based its ULs for iron on gastrointestinal
symptoms. For adults, a LOAEL of 70 mg/d was set based on the same supplementation study by
Frykman et al. (1994), together with median population dietary intakes (IOM, 2001). Because of
the self-limiting nature of the adverse outcomes, a relatively low uncertainty factor was used to

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-22 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

extrapolate from the LOAEL, resulting in a UL of 45 mg/d after rounding. Because of the limited
data available, the same figure was applied to pregnant and lactating women.
The Nordic Council of Ministers (NNR, 2012) was unable to set a quantitative iron UL based on
risk of chronic disease. Instead, it set a UL of 60 mg/d, based on knowledge that a regular intake
of 60 mg/d in premenopausal women may lead to iron overload. It provided further support for
this value by noting that the local intestinal toxicity seen with therapeutic iron occurs in the range
of 50 to 60 mg/day. Finally, EFSA reported that data were insufficient to derive a UL (EFSA
NDA Panel, 2004).

FINDINGS AND CONCLUSIONS FOR IRON

Based on its review of the evidence, the committee made the following findings:
• The derivation of most values used for bioavailability is neither transparent nor evidence
based. This is because data on iron bioavailability from the whole diet is limited. The one
exception is the approach used by EFSA, which is based on a model in which the iron
absorption from the whole (Western) diet is predicted using good quality individual data
on dietary intake, serum ferritin concentrations, and calculated physiological iron
requirements. The model has since been refined and updated and an interactive modeling
tool published.
• The lack of agreement for reference values is caused largely by the choice of
bioavailability factor used to convert physiological requirements into dietary intakes,
which results from limited information on iron absorption from complete diets, as well as
assumptions about storage iron at conception.
• When assessing the iron status of a population in relation to public health policies such as
food fortification, it is crucial to have good quality representative data for iron intake. If
the mean iron intake is below the average requirement, then evidence of iron deficiency
must be supported by measures of iron status. However, because dietary iron exists in
two forms, measuring dietary intake is difficult because of limited information on heme
iron in food composition databases. In addition, several biomarkers of iron status (e.g.,
ferritin) are modified by infection, chronic disease, and deficiencies of other nutrients.
• Pregnancy is a normal physiological condition, which should not require a major change
in food intake, provided the habitual diet contains all nutrients at levels that are consistent
for optimal health. Many women become increasingly iron deficient or anemic during
pregnancy because they do not have adequate iron stores at conception and/or their
dietary iron bioavailability is insufficient to meet their needs despite the well-accepted
adaptive mechanisms designed to maintain iron homeostasis.
• NRVs are derived for healthy populations, and although physiological requirements for
iron should be the same for each population subgroup in every country or region, dietary
iron bioavailability will depend on the local diet composition, which may change the AR.
Based on its findings, the committee came to the following conclusions for iron:
1. At present, the factorial approach is the only feasible option for deriving iron
NRVs, and that values for iron availability need to take into account the usual
dietary composition of the population, which may result in differences in NRVs,

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-23

as illustrated by WHO’s approach in which it provides values for four different


global scenarios.
2. There are several factors related to diet and lifestyle, infection, and disease that
confound the association between iron intake and health outcomes, obscuring
the dose–response relationship that are needed to accurately estimate reference
values.
3. There are challenges for setting an iron UL, but the value is essential for
evaluating the safety of food iron fortification and other public health
programs.

PROPOSED SOLUTIONS FOR IRON

Although authoritative bodies have adopted the factorial method globally, there remains wide
variation in NRVs determined for women of reproductive age, mainly attributable to different
calculations used to transform physiological requirements into dietary intakes. The
bioavailability model used by EFSA (Dainty et al., 2014) and subsequently updated
(Fairweather-Tait et al., 2017) is the best approach to determine iron bioavailability from the
whole diet. However, the approach is only applicable in low- and middle-income countries if it is
appropriately adapted; in low- and middle-income countries, intakes of iron absorption inhibitors
may be higher and heme iron intakes lower than in Western diets.
Additionally, many low- and middle-income countries have high burdens of infection or
other widespread health concerns, such as hemoglobinopathies and thalassemia, that have an
effect on iron metabolism and biomarkers of iron status. In these countries, assessing the
prevalence of iron deficiency may require measuring serum ferritin and then correcting for
inflammation using the most appropriate method (e.g., regression analysis).

FOLATE CASE ANALYSIS

Introduction and Statement of the Problem

The global prevalence of folate deficiency and depletion is not well documented, but data are
in the process of being added to WHO’s Vitamin and Mineral Nutrition Information System
(VMNIS)2. Populations in low- and middle-income countries are not necessarily at greater risk of
deficiency compared to populations in high-income countries, especially if the usual diet in the
lower-income population is high in legumes and green leafy vegetables (see discussion below).
The classical signs of severe folate deficiency include megaloblastic anemia with
hypersegmented neutrophils, and an elevated mean red cell volume. However, the greatest global
concern is that low folate intakes in the periconceptional period is a risk factor for infant neural
tube defects (NTDs), especially in women with genetic predisposition. Supplementation and
food fortification with folic acid reduce the prevalence of NTDs in women of reproductive age,
especially in regions where folate status is poor and there is a high baseline prevalence of NTDs.
Recognition of this issue has mobilized the global community around recommendations for folic
acid requirements, supplementation, and fortification.

2
Available at http://www.who.int/vmnis/en (accessed May 16, 2018).

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-24 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Factors Influencing Folate Requirements

Two key factors affect the folate requirements of a population: bioavailability and several
specific genetic polymorphisms. Both of these are reviewed below.

Bioavailability
The primary dietary sources of folate are legumes, green leafy vegetables, liver (but not meat
in general), and some fruits, including oranges, mangoes, and papayas (Allen, 2008). This is why
poor folate status is often more common in wealthier populations than in lower income
populations with higher intake of legumes and greens. Inadequate intakes of folate are less
prevalent in populations where folic acid has been added to staple foods through fortification.
In foods, folates are present as polyglutamate derivatives, which are hydrolyzed by intestinal
enzymes to monoglutamates prior to absorption. Most of the traditional methods for food folate
analysis tend to underestimate actual folate content owing to incomplete release of the folate
prior to analysis and incomplete hydrolysis of the polyglutamyl folates. Digestion with three
enzymes (amylase, protease, and folate conjugase) has been shown to increase quantitative
estimates of folate values in both folic acid-fortified and nonfortified cereals (Pfeiffer et al.,
1997). The method should be optimized for different foods; however, it usually is not (Tamura et
al., 1997). Most values are obtained from the U.S. Department of Agriculture food composition
tables, but even these may be underestimates.
The bioavailability of folate from food sources is estimated to be about 50 percent, a value
that is generally accepted as appropriate for all foods. However, a substantial source of folate in
many populations is folic acid, which is used in supplements and as a fortificant in cereals in at
least 80 countries (Food Fortification Initiative, 2017). The estimated bioavailability of folic acid
is 85 percent. Because of this difference in bioavailability between folate and folic acid, the
amount of folate present in the diet is calculated as µg food folate + 1.7 × µg folic acid; the sum
is expressed as dietary folate equivalents (DFEs).

Genetic Factors
As discussed by Patrick Stover at the Global Harmonization workshop (NASEM, 2018),
several polymorphisms, or genetic variations, in folate metabolism can affect folate
requirements. The most common is a C667T polymorphism in the gene that codes for 5, 10-
methylenetetrahydrofolate reductase (MTHFR). Women with the MTHFR TT genotype have a
50 percent greater risk of an NTD birth than those with CC or CT genotypes. In some European
countries up to 24 percent of the population is homozygous for this allele; thus, although EFSA
did not increase the AR for folate, it did increase the coefficient of variation used to set the AI to
15 percent to reflect the genetic variability in requirements.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 5-13

TABLE 4-7 Comparison of Factors Used in Dose–Response Modeling for Folate in Women of
Reproductive Age

NNR (Herbert et
Australia/ EFSA (Milne
WHO/FAO IOM al., 1962; Milne
New Zealand et al., 1983;
(O’Keefe et (O’Keefe et D-A-CH et al., 1983;
(O’Keefe et Sauberlich et
al., 1995) al., 1995) Sauberlich et al.,
al., 1995) al., 1987)
1987)
Biomarkers:
RBC folate > 305 > 305 > 317 — > 340
(nmol/L)
Serum folate > 10 >7 > 10 > 6.8 — > 10
(nmol/L)
Erythrocyte folate > 340
(nmol/L)
Homocysteine < 16 < 16 9.3–16.3 —
(µmol/L)

AR DFE 400 400 220 300 400 220


(µg/d)
NOTE: Aus/NZ = nutrient reference values for Australia and New Zealand; D-A-CH = Nutrition
Societies of Germany, Austria, and Switzerland; EFSA = European Food Safety Authority; IOM =
Institute of Medicine; NNR = Nordic Nutrition Recommendations; WHO/FAO = World Health
Organization/Food and Agriculture Organization.

Methodologies to Determine Folate Requirements

A factorial method cannot be used to derive the AR because there are insufficient data on
folate pool size and turnover, and because folate is metabolized into so many end products. The
adequacy of folate intake can be determined, however, by its relationship to biomarkers of folate
status, in other words, through dose–response assessment.

Biomarkers for Use in Folate Dose–Response Assessment


Serum or plasma folate is the most commonly used status measure in population surveys, but
it reflects recent intake of the vitamin. Erythrocyte folate, also known as red blood cell (RBC)
folate, serves as a more reliable indicator of longer-term status because red blood cells survive
for 120 days and are not affected by short-term folate intakes (i.e., within weeks). It is also more
stable in pregnancy. WHO recently recommended that RBC folate concentration be used as the
sole indicator for NTD risk (Bailey and Hausman, 2018). A third folate status biomarker, plasma
homocysteine level, increases with lower folate intakes and poor folate status and can be an
indicator of response to folate interventions. However, homocysteine is also increased by
inadequate intakes of vitamins B12, riboflavin, and B6, making it a nonspecific indicator of
folate status. Because laboratory assessment can be problematic for all three biomarkers,
regardless of the biomarker used, recent sample handling and analytical guidelines should be
followed, and the folate values in older population subgroups checked for their validity (Pfeiffer
et al., 1997). The biomarkers used by different authoritative bodies to derive ARs for folate for
women of reproductive age, and the AR value themselves, are summarized in Table 4-7. These

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-26 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

particular authoritative bodies were selected because their recommendations were made within
the last 20 years.
Several other potential markers of folate adequacy have been considered by various
authoritative bodies, but they have not been used in deriving the AR. These include
• Anemia and hematological abnormalities, which have not been used because they occur
only in relatively severe folate deficiency;
• Reduced risks of vascular disease, certain types of cancer, and psychiatric and mental
disorders, for which the evidence was found insufficient to guide setting ARs;
• Kinetic studies of body pool size and turnover;
• Folate catabolites in urine; and
• Repletion of severe folate deficiency.
The IOM’s estimated folate requirements are based on the level of intake required to
maintain normal blood levels of all three previously described biomarkers of folate status (i.e.,
plasma or serum folate, erythrocyte folate, and plasma homocysteine (IOM, 1998). Cut-point
values for “normal” were defined based on associations with biochemical abnormalities. The
main source of data was four controlled metabolic studies in which folate was given as folate in
food or as both folate in food plus folic acid supplement. In these studies the amount of intake
required to maintain or restore status (after depletion) was determined (Herbert, 1962; Milne et
al., 1983; O’Keefe et al., 1995; Sauberlich et al., 1987). Based on the dose–response data, 320 µg
DFEs was accepted as the AR for premenopausal women (see Table 4-7). This was supported by
epidemiological data showing that elevated homocysteine concentrations were more prevalent in
the United States when intake was less than 280 µg/day (i.e., in the lowest four deciles).
Requirements for older adults were determined to be the same as those of younger adults.
WHO/FAO accepted the IOM methods and values for folate recommendations (and thus, reports
an AR for this nutrient, rather than only an RI, which is the usual practice in WHO/FAO reports).
EFSA’s dose–response approach to deriving folate NRVs is based on the folate intake
required to maintain serum and erythrocyte folate concentrations. As shown in Tables 4-7 and 4-
8, its recommendations are lower than those of the IOM and WHO/FAO. This is because it used
older studies, which showed that lower intakes were sufficient and rejected the main study
(O’Keefe et al., 1995) used by the IOM. Germany-Austria-Switzerland (D-A-CH) reduced their
folate ARs for adults in 2014, from 400 µg to 300 µg DFE/day, based on lack of evidence from
recent randomized controlled trials that lowering homocysteine with supplements of folate and
other B vitamins would reduce risk of cardiovascular disease (Krawinkel, et al., 2014). The
Australia/New Zealand recommendations use erythrocyte folate as the primary indicator because
it reflects folate stores although serum folate and plasma homocysteine are used to support
decisions on adult values.

Determination of a Folate Requirement for Infants and Children


Intake levels, bioavailability factors, and other factors used by different authoritative bodies
(IOM, WHO/FAO, D-A-CH, Aus/NZ, and EFSA) to derive folate ARs for young children (or
AIs for infants aged 0 to 6 months) and women of reproductive age are also summarized in Table
4-8.
For infants aged 0 to 6 months, as is the case for many other nutrients, the folate
recommendation is an AI, not an AR, because of the lack of data on dose–response relationships

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-27

at this age. As shown in Table 4-8, AIs in most reports are around 65 µg/day, calculated as the
folate concentration in milk (~85 µg/L) × milk volume (780 ml/d).
The IOM and WHO/FAO folate recommendations for infants aged 6 to 12 months are based
on data derived from studies that measured intake from breast milk and/or formula, leading to an
estimated intake of 80 µg/day to maintain normal levels of serum and erythrocyte folate.
Australia/New Zealand and EFSA obtained the same value but by extrapolating up or down from
younger infants and adults respectively, and scaling for body weight. D-A-CH also used an
extrapolation method to obtain a slightly different value of 85 µg/day. The process of
extrapolating NRVs from one age group to another is described in Chapter 3; methods used are
listed in Appendix E.
All of the ARs for older children listed in Table 4-8 were derived by extrapolating
downwards from adult AR values, scaling by body weight to the 0.75 power, and assuming that
maintenance requirements for folate are the same per unit body weight for children as they are
for adults. A growth factor of 0.30 was added to the formula for extrapolation (see Chapter 3 and
Appendix E) for children from 7 months to 3 years and growth factors of 0.15 and 0.40 for male
and female children aged 4 to 18 years, respectively. The ARs are remarkably similar across
NRVs from different authoritative bodies except for the lower ARs set by D-A-CH for children
aged 4 to 8 years (Krawinkel et al., 2014). The D-A-CH values are based on the IOM (1998) AR
and the usual growth factor of 0.15 for this age. The reason for the lower values is unclear. The
D-A-CH also gave differing AR values for male and female children.

Determination of Folate Requirements for Pregnant and Lactating Women


For pregnancy, the outcome status biomarker used by the IOM was maintenance of
erythrocyte folate (IOM, 1998). Not only is this a better indicator of tissue stores than serum or
plasma levels, but in pregnancy plasma folate levels are more affected by hemodilution. In
addition, plasma homocysteine is generally lower during pregnancy. Using this biomarker, dose–
response studies have shown that an additional 200 µg/day DFEs need to be added to the AR for
nonpregnant women, for a total of 520 µg/day (Stamm and Houghton, 2013). The
recommendations for pregnancy are identical across countries except for D-A-CH, which is
attributable to its lower estimate for nonpregnant values.
For lactating women, a total of 450 µg/day DFE is generally accepted as adequate to replace
130 µg/day secreted in milk. As shown in Table 4-8, all of the listed authoritative bodies
assumed that 120–130 µg/day DFE are secreted in milk daily. Concentrations of folate in milk
are relatively unaffected by maternal folate status or intake so the value of 80–85 µg/L is likely
applicable worldwide. However, care must be taken to release the folate from its conjugates in
human milk.

Derivation of Safe Upper Levels of Intake

The UL set by the IOM at 1 mg/day, using an uncertainty factor of 5, has been adopted by
other authoritative bodies. The UL for young children is adjusted downwards to 300–400 µg/day
of folic acid. There is no evidence that high intakes of folate from food have adverse effects;
rather, these folate ULs are based on intake of folic acid from supplements and fortified foods.
The main concern about high levels of folic acid intake centers on its possible exacerbation of
the adverse effects of vitamin B12 deficiency, such as neurological impairment (Butterworth and

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-28 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

TABLE 4-8 Values used by authoritative bodies to derive ARs for young children and women of
reproductive age.
IOM WHO/FAO D-A-CH AUS/NZ EFSA
Premenopausal
women
Intake to maintain 320 320 220 320 250
biomarkers
(DFEa µg/d)
Bioavailability 50 50 50 50 50
factor (%)b
AR (DFE µg/d) 320 320 220 320 250
Pregnancy
Total basal 320 320 220 320 320
requirement (DFE
µg/d)
AR (DFE µg/d) 520 520 420 520 --
Lactation
Milk secretion 130 130 120 133 130
(DFE µg/d)
AR (DFE µg/d) 450 450 450 450 380
Infants 0–6
months
AI (DFE µg/d)c 65 65 60 65 64
Infants 6–12
months
Extrapolation -- -- 700 kcal/d Weight0.75 Weight0.75
factor required x 12 µg
folate/100 kcal
milk
Growth factor -- -- -- 0.3 0.3
AR or AI 80 80 85 80 80
(DFE µg/d)
Children 1–3
years
Extrapolation Weight0.75 Weight0.75 Weight0.75 Weight0.75 Weight0.75
factor
Growth factor 0.3 0.3 0.3 0.3 0.3
AR (DFE µg/d) 120 120 79.8 (males) 120 80
92 (females)
Children 4–8
years
Extrapolation Weight0.75 Weight0.75 Weight0.75 Weight0.75 Weight0.75
factor
Growth factor 0.15 0.15 0.15 -- 0.38
AR (DFE µg/d) 160 160 106 F, 94 M 160 110 F, 160 M

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-29

a
DFE – Dietary folate equivalent.
b
Calculated as 50 percent for food folates and 85 percent for folic acid.
c
For infants aged 0 to 6 months, the folate recommendation is an AI, because of the lack of data on dose-
response relationships at this age.
Tamura, 1989). There is also evidence from vitamin B12 deficient patients that doses of folic
acid greater than 5 mg/day can cause progression of neurological disorders (Dickinson, 1995).

FINDINGS AND CONCLUSIONS FOR FOLATE

Folate values in foods can vary depending on the local context. From its review of the
evidence, the committee derived the following findings regarding local and contextual factors
that can affect estimations of folate levels for intake and thus the derivation of NRVs from
locally available data sources.
• Measurement of food folate levels for use in the derivation of NRVs may require
adjustment, and the validity of folate values available in food composition tables is of
concern.
• Some food preparation procedures can cause substantial losses of folate, which is
relatively unstable to heat and oxidation. From 50 to 80 percent of the folate in green
vegetables, and 50 percent of the folate in legumes, is lost during boiling. When
estimating the prevalence of inadequate intakes, folate values based on local recipes
should be used whenever possible.
• As with food preparation, while folic acid fortification of staple and other foods does not
affect the physiological requirement for folate, it will affect the amount of folate required
from food sources.
• It is unlikely that local adjustments will need to be made for requirements that depend on
breast milk folate concentration. Folate requirements are not affected by maternal status
or intake, of for bioavailability from different foods (except for the higher bioavailability
of folic acid in fortified foods). Thus adjustments are probably not necessary.
• The prevalence of the MTHFR TT genotype varies substantially across populations. In
Caucasians, this genotype occurs in from 2 to 16 percent of the population, compared to
25 percent of Hispanics and a very low percent of Africans. There appears to be large
variability in prevalence across Asian populations. Compared to CC or CT genotypes,
homozygosity for the T allele results in lower plasma and erythrocyte folate levels and
higher plasma homocysteine levels in individuals with plasma folate levels below about
15 nmol/L.
Based on its findings, the committee came to the following conclusions about folate:
1. In the 1980s and 1990s, it was recognized that folate content in foods can be
substantially underestimated unless the trienzyme laboratory procedure for
releasing the vitamin from food was used. This likelihood of underestimation
can explain discrepancies between intakes calculated from older food
composition data versus more recent estimates based on measures of folate
status.
2. While the cooking technique affects the amount of folate required from food
sources, it does not affect physiological requirements.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-30 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

3. Data on folate intake in food intake surveys must include the amounts of
fortified food consumed and the levels of folic acid in that food. High folate
status has emerged in a number of populations after initiating folic acid
fortification programs. Although folic acid is generally regarded as not toxic,
it may be a factor in neurological injury when pernicious anemia is present
(Butterworth and Tamura, 1989). Thus, avoiding excessive intakes and
monitoring folate status may be especially important in populations with a high
prevalence of vitamin B12 deficiency since there is some evidence that a high
folic acid intake may exacerbate B12 deficiency.
4. Because deriving an RI to cover 97.5 percent of the population depends on the
variation around the AR and because populations with a higher variance will
have a higher RI, a high prevalence in a population may justify a higher
coefficient of variation for setting an RI, as was done in the D-A-CH
recommendations.
5. Folate is synthesized by malarial parasites, so to avoid spuriously high values,
assessment of RBC folate should not be conducted immediately after an episode
of malaria with fever.
6. There is no evidence that deficiencies or high intakes of other micronutrients
affect folate requirements.

PROPOSED SOLUTIONS FOR FOLATE

Folate recommendations for women and children are remarkably similar across countries,
owing to general agreement on biomarker cut points and the relatively few factors that can affect
requirements. There are no major deterrents to using existing NRVs published by authoritative
bodies or modifying them for local factors.
However, the committee identified a number of data gaps for deriving new country-specific
folate NRVs.
• There is a lack of validated data on the folate content of foods in low- and middle-income
countries, especially cooked foods.
• The evidence for population prevalence of polymorphisms and their effect on folate
requirements is increasing; however, it is not yet sufficient to use in deriving NRVs.
• The local contribution of other micronutrient deficiencies (vitamin B12, riboflavin,
vitamin B6) to plasma homocysteine levels is not well understood.
• There is a need to consider local consequences of poor B12 status on NTD prevalence
and its interaction with high folate intake.

OVERALL CONCLUSION

The committee came to the following overall conclusion:


From its assessment of the three nutrient case analyses described in this chapter,
combined with its assessment of the process for deriving NRVs and the application
of new tools to this process (discussed in Chapters 2 and 3 and throughout this

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-31

chapter), the committee concludes that it is feasible to harmonize the process for
deriving reference values globally.
The framework for harmonization being proposed in this report is based on four key
steps (see Figure 3-4):
1. Choose the appropriate tools.
2. Collect the needed data.
3. Identify the best approach.
4. Derive the key reference values, the AR and the UL.
This framework is based on six core values:
1. NRVs are regularly updated.
2. The process is clear and transparent.
3. The methods are rigorous and relevant.
4. Factors influencing the NRV are documented.
5. The strength of the evidence is determined.
6. The review is complete and efficient.

APPLICATIONS OF NUTRIENT REFERENCE VALUES IN LOW- AND MIDDLE-


INCOME COUNTRIES

Applications of NRVs for populations living in low- and middle-income countries include
formulation of food and nutrition policies; the development of targeted intervention programs,
such as food assistance or fortification programs; nutrition education; and the evaluation or
monitoring of population health (NASEM, 2018). An important use of NRVs across applications
is planning and assessing diets for both individuals and groups. Users of NRVs include
international organizations such as WHO or FAO; nonprofit organizations; local, regional, and
national governments; academic researchers; health care providers; the food industry; and the
general public. It is important that these potential users understand their derivation, particularly
the AR and UL, as well as their application to public health. In the case of zinc, iron, and folate,
all nutrients of particular concern for young children and women of reproductive age,
bioavailability is one of a number of factors related to local context that needs to be considered
when prioritizing nutrients for developing country-specific NRVs. For example, as discussed
throughout this report, typical foods consumed in low- and middle-income countries may be high
in phytate, which has been shown to reduce nutrient absorption. Additionally, the prevalence of
micronutrient deficiencies as well as risk of chronic disease will be strong determinants for
establishing country-specific NRVs.
Options and strategies to facilitate harmonization of the approaches used to derive NRVs as
well as data gaps that need to be filled are discussed in the following chapter.

REFERENCES

Abbaspour, N., R. Hurrell, and R. Kelishadi. 2014. Review on iron and its importance to public health.
Journal of Research in Medical Sciences 19(2):164-174.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-32 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Adu-Afarwuah, S. 2017. The role of health status. In Global Harmonization of Methodological


Approaches to Nutrient Intake Recommendations: Proceedings of a workshop. Washington, DC:
The National Academies Press. doi: https://doi.org/10.17226/25023.
Allen, L. H. 2008. Causes of vitamin B12 and folate deficiency. Food and Nutrition Bulletin 29:S20-S34.
Ariff, S., N. Krebs, S, Soofi, J. Westcott, A. Bhatti, F. Tabassum, and Z. A. Bhutta. 2014. Absorbed zinc
and exchangeable zinc pool size are greater in Pakistani infants receiving traditional
complementary foods with zinc-fortified micronutrient powder. Journal of Nutrition 144(1):20-
26.
Aung-Than-Batu, Thein-Than, and Thane-Toe. 1976. Iron absorption from Southeast Asian rice-based
meals. American Journal of Clinical Nutrition 29(2):219-225.
Bailey, L. B., and D. B. Hausman. 2018. Folate status in women of reproductive age as basis of neural
tube defect risk assessment. Annals of the New York Academy of Sciences 1414(2018):82-95.
Barrett, J. F., P. G. Whittaker, J. G. Williams, and T. Lind. 1994. Absorption of non-haem iron from food
during normal pregnancy. British Medical Journal 309:79-82.
Bernhardt, M. L., B. Y. Kong, A. M. Kim, T. V, O'Halloran, and T. K. Woodruff. 2012. A zinc-dependent
mechanism regulates meiotic progression in mammalian oocytes. Biology and Reproduction
86(4):114.
Bresnahan, K. A., and S. A. Tanumihardjo. 2014. Undernutrition, the acute phase response to infection,
and its effects on micronutrient status indicators. Advances in Nutrition 5(6):702-711.
Brnic, M., R. Wegmuller, C. Zeder, G. Senti, and R. F. Hurell. 2014. Influence of phytase, EDTA, and
polyphenols on zinc absorption in adults from porridges fortified with zinc sulfate or zinc oxide.
Journal of Nutrition 144(9):1467-1473.
Brown, K. H., J. A. Rivera, Z. Bhutta, R. S. Gibson, J. C. King, B. Lonnerdal, M. T. Ruel, B. Sandtrom,
E. Wasantwisut, C. Hotz, D. Lopez de Romana, and J. M. Peerson. 2004. International Zinc
Nutrition Consultative Group (IZiNCG) technical document 1. Assessment of the risk of zinc
deficiency in populations and options for its control. Food and Nutrition Bulletin 25(1 Suppl
2):S99-S203.
Brown, K. H., S. K. Baker, and I.S. Committee. 2009a. Galvanizing action: Conclusions and next steps
for mainstreaming zinc interventions in public health programs. Food and Nutrition Bulletin
30(1):S179-S184.
Brown, K. H., J. M. Peerson, S. K. Baker, and S. Y. Hess. 2009b. Preventive zinc supplementation among
infants, preschoolers, and older prepubertal children. Food and Nutrition Bulletin 30(1):S12-S40.
Butterworth, C. E., and T. Tamura. 1989. Folic acid safety and toxicity: A brief review. American Journal
of Clinical Nutrition 50(2):353-358.
Chomba, E., C. M. Westcott, J. E. Westcott, E. M. Mpabalwani, N. F. Krebs, Z. W. Patinkin, and K. M.
Hambidge. 2015. Zinc absorption from biofortified maize meets the requirements of young rural
Zambian children. Journal of Nutrition 145(3):514-519.
Chung, C. S., D. A. Nagey, C. Veillon, K. Y. Patterson, R. T. Jackson, and P. B. Moser-Veillon. 2002. A
single 60-mg iron dose decreases zinc absorption in lactating Women. Journal of Nutrition
132(7):1903-1905.
Dainty, J. R., R. Berry, S. R. Lynch, L. J. Harvey, and S. J. Fairweather-Tait. 2014. Estimation of dietary
iron bioavailability from food iron intake and iron status. PLoS ONE 9:e111824.
de Benoist, B., I. Darnton-Hill, L. Davidsson, O. Fontain, and C. Hotz. 2007. Conclusions of the Joint
WHO/UNICEF/IAEA/IZiNCG interagency meeting on zinc status indicators. Food Nutrition
Bulletin 28(Suppl 3):S480-S484.
Dickinson, C.J. 1995. Does folic acid harm people with vitamin B12 deficiency? QJM 88(5):357-364.
Domellof, M., I. Thorsdottir, and K. Thorstensen. 2013. Health effects of different dietary iron intakes: A
systematic literature review for the 5th Nordic nutrition recommendations. Food and Nutrition
Research 57(1). doi: org/10.3402/fnr.v57i0.21667.
Drakesmith, H., and A. M. Prentice. 2012. Hepcidin and the iron-infection axis. Science 338(6108):768-
772.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-33

EFSA NDA Panel (European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies).
2014. Scientific opinion on dietary reference values for zinc. EFSA Journal 12(10):3844 (revised
May 20, 2015).
EFSA NDA Panel. 2014. Scientific opinion on dietary reference values for folate. EFSA Journal
12(11):3893. doi: 10.2903/j.efsa.2014.
EFSA NDA Panel. 2015. Scientific opinion on dietary reference values for iron. EFSA Journal
13(10):4254. doi: 10.2903/j.efsa.2015.4254.
Esamai, F., E. Liechty, J. Ikemeri, J. Westcott, J. Kemp, D. Culbertson, L. Miller, M. Hambidge, and N.
Krebs. 2014. Zinc absorption from micronutrient powder is low but is not affected by iron in
Kenyan infants. Nutrients 6:5636-5651.
Fairweather-Tait, S. J., A. Jennings, L. J. Harvey, R. Berry, J. Walton, and J. R. Dainty. 2017. Modeling
tool for calculating dietary iron bioavailability in iron-sufficient adults. American Journal of
Clinical Nutrition 105(6):1408-1414.
Food Fortification Initiative. 2017. NTD summary.
http://www.ffinetwork.org/why_fortify/documents/NTD_Summary_July_2017.pdf (accessed
March 2, 2018).
Frykman, E., M. Bystrom, U. Jansson, A. Edberg, and T. Hansen. 1994. Side effects of iron supplements
in blood donors: Superior tolerance of heme iron. Journal of Laboratory and Clinical Medicine
123:561-564.
Gibson, R. S. 2012. A historical review of progress in the assessment of dietary zinc intake as an indicator
of population zinc status. Advances in Nutrition 3(6):772-782.
Gibson, R., and V. P. Anderson. 2009. A review of interventions based on dietary diversification or
modification strategies with the potential to enhance intakes of total and absorbable zinc. Food
and Nutrition Bulletin 30(1):S108-S143.
Gibson, R. S., S. Y. Hess, C. Hotz, and K. H. Brown. 2008. Indicators of zinc status at the population
level: A review of the evidence. British Journal of Nutrition 99(S3):S14-S23.
Gibson, R. S., J. C. King, and N. Lowe. 2016. A review of dietary zinc recommendations. Food and
Nutrition Bulletin 37(4):443-460.
Gogia, S., and H. S. Sachdev. 2012. Zinc supplementation for mental and motor development in children.
Cochrane Database Systematic Reviews 12:CD007991.
Green, R., R. Charlton, H. Seftel, T. Bothwell, F. Mayet, B. Adams, C. Finch, and M. Layrisse. 1968.
Body iron excretion in man: A collaborative study. American Journal of Medicine 45(3):336-353.
Hallberg, L., and L. Rossander-Hulten. 1991. Iron requirements in menstruating women. American
Journal of Clinical Nutrition 54(6):1047-1058.
Hallberg, L., A. M. Hogdahl, L. Nilsson, and G. Rybo. 1966a. Menstrual blood loss—A population study.
Variation at different ages and attempts to define normality. Acta Obstetricia et Gynecologica
Scandinavia 45(3):320-351.
Hallberg, L., A. M. Hogdahl, L. Nilsson, and G. Rybo. 1966b. Menstrual blood loss and iron deficiency.
Acta Medica Scandinavia 180(5):639-650.
Hallberg, L., L. Hultén, and E. Gramatkovski. 1997. Iron absorption from the whole diet in men: How
effective is the regulation of iron absorption? American Journal of Clinical Nutrition 66(2):347-
356.
Harvey, L. J., C. N. Armah, J. R. Dainty, R. J. Foxall, D. John Lewis, N. J. Langford, and S. J.
Fairweather-Tait. 2005. Impact of menstrual blood loss and diet on iron deficiency among women
in the UK. British Journal of Nutrition 94(4):557-564.
Herbert, V. 1962. Minimal daily adult folate requirement. Archives of Internal Medicine 110:649-652.
Hess, S., B. Lonnerdal, C. Hotz, J. A. Rivera, and K. H. Brown. 2009. Recent advances in knowledge of
zinc nutrition and human health. Food and Nutrition Bulletin 31(1):S5-S11.
Hotz, C., and K. H. Brown. 2001. Identifying populations at risk of zinc deficiency: The use of
supplementation trials. Nutrition Reviews 59(3):80-88.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-34 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Hotz, C., and K. H. Brown. 2004. Assessment of the risk of zinc deficiency in populations and options for
its control. Food and Nutrition Bulletin 25(1):S94-S203.
Hotz, C., J. DeHaene, L. R. Woodhouse, S. Villalpando, J. A. Rivera, and J. C. King. 2005. Zinc
absorption from zinc oxide, zinc sulfate, zinc oxide + EDTA, or sodium-zinc EDTA does not
differ when added as fortificants to maize tortillas. Journal of Nutrition 135(5):1102-1105.
Hunt, J. R., and J. M. Beiseigel. 2009. Dietary calcium does not exacerbate phytate inhibition of zinc
absorption by women from conventional diets. American Journal of Clinical Nutrition 89(3):839-
843.
Hunt, J. R., C. A. Zito, and L. K. Johnson. 2009. Body iron excretion by healthy men and women.
American Journal of Clinical Nutrition 89(6):1792-1798.
Hurrell, R., and I. Egli. 2010. Iron bioavailability and dietary reference values. American Journal of
Clinical Nutrition 91(5):1461S-1467S.
Hytten, F. E., and I. Leitch. 1971. The physiology of human pregnancy. 2nd ed. Oxford, UK: Blackwell
Scientific Publications.
IOM (Institute of Medicine). 1998. Dietary Reference Intakes for thiamin, riboflavin, niacin, vitamin B6,
folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy
Press. https://doi.org/10.17226/6015
IOM. 2001. Dietary Reference Intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper,
iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC:
National Academy Press. https://doi.org/10.17226/10026
Kawade, R. 2012. Zinc status and its association with the health of adolescents: a review of studies in
India. Global Health Action 5(1):7353.
King, J. C., and C. Garza. 2007. Harmonization of nutrient intake values. Food and Nutrition Bulletin
28(Suppl 1):S3-S12.
King, J. C., R. J. Cousins, M. E. Shils, M. Shike, A. C. Ross, and B. Caballero. 2014. Zinc. In Modern
nutrition in health and disease.11th ed. Philadelphia, PA: Lippincott Williams & Wilkins, Pp.
189-205.
King, J. C., K. H. Brown, R. S. Gibson, N. F. Krebs, N. M. Lowe, J. H. Siekmann, and D. J. Raiten. 2016.
Biomarkers of nutrition for development (BOND)-zinc review. Journal of Nutrition 146(4):858S-
885S.
Krawinkel, M. B., D. Strohm, A. Weissenborn, B. Watzl, M. Eichholzer, K. Bärlocher, I. Elmadfa, E.
Leschik-Bonnet, and H. Heseker. 2014. Revised D-A-CH intake recommendations for folate:
How much is needed? European Journal of Clinical Nutrition 68:719-723.
Lazzerini, M., and L. Ronfani. 2008. Oral zinc for treating diarrhoea in children. Cochrane Database of
Systematic Reviews. 3:CD005436.
Levenson, C. W., and D. Morris. 2011. Zinc and neurogenesis: Making new neurons from development to
adulthood. Advances in Nutrition 2(2):96-100.
Lonnerdal, B. 2000. Dietary factors influencing zinc absorption. Journal of Nutrition 130(5):1378S-
1383S.
Lowe, N. M., K. Fekete, and T. Decsi. 2009. Methods of assessment of zinc status in humans: A
systematic review. American Journal of Clinical Nutrition 89(6):2040S-2051S.
Lowe, N. M., F. C. Dykes, A. L. Skinner, S. Patel, M. Warthon-Medina, T. Decsi, K. Fekete, O. W.
Souverein, C. Dullemeijer, A. E. Cavelaars, L. Serra-Majem, M. Nissensohn, S. Bel, L. A.
Moreno, M. Hermoso, C. Vollhardt, C. Berti, I. Cetin, M. Gurinovic, R. Novakovic, L. J. Harvey,
R. Collings, S. Hall, and V. Moran. 2013. EURRECA-Estimating zinc requirements for deriving
dietary reference values. Critical Reviews in Food Science and Nutrition 53(10):1110-1123.
Miller, L. V., K. Hambidge, and N. F. Krebs. 2015. Zinc absorption is not related to dietary phytate intake
in infants and young children based on modeling combined data from multiple studies. Journal of
Nutrition 145(8):1763-1769.
Milman, N. 2006. Iron and pregnancy—a delicate balance. Annals of Hematology 85:559-565.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPLYING METHODOLOGICAL APPROACHES 4-35

Milne, D. B., W. K. Canfield, J. R. Mahalko, and H. H. Sandstead. 1983. Effect of dietary zinc on whole
body surface loss of zinc: Impact on estimation of zinc retention by balance method. American
Journal of Clinical Nutrition 38(2):181-186.
Narasinga Rao, B. S., C. Vijayasarathy, and T. Prabhavathi. 1983. Iron absorption from habitual diets of
Indians studied by the extrinsic tag technique. Indian Journal of Medical Research 77:648-657.
NASEM (National Academies of Sciences, Engineering, and Medicine). 2018. Global harmonization of
methodological approaches to nutrient intake recommendations: Proceedings of a workshop.
Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25023.
Nemeth, E., and T. Ganz. 2009. The role of hepcidin in iron metabolism. Acta Haematologica 122:78-86.
Nordic Council of Ministers (NNR). 2012. Nordic nutrition recommendations 2012: Integrating nutrition
and physical activity. 5th ed. Copenhagen, Sweden: Nordic Council of Ministers.
http://dx.doi.org/10.6027/Nord2014-002 (accessed June 3, 2018).
NRC (National Research Council). 1989. Recommended dietary allowances. 10th ed. Washington, DC:
National Academy Press. doi: https://doi.org/10.17226/1349.
O’Brien, K. O., N. Zavaleta, L. E. Caulfield, J. Wen, and S. A. Abrams. 2000. Prenatal iron supplements
impair zinc absorption in pregnant Peruvian Women. Journal of Nutrition 130(9):2251-2255.
O’Keefe, C. A., L. B. Bailey, E. A. Thomas, S. A. Hofler, B. A. Davis, J. J. Cerda, and J. F. Gregory.
1995. Controlled dietary folate affects folate status in nonpregnant women. Journal of Nutrition
125:2717-2725.
Pae, M., S. N. Meydani, and D. Wu. 2012. The role of nutrition in enhancing immunity in aging. Aging
Diseases 3(1):91-129.
Pfeiffer, C. M., L. M. Rogers, and J. F. Gregory. 1997. Determination of folate in cereal-grain food
products using trienzyme extraction and combined affinity and reversed-phase liquid
chromatography. Journal of Agriculture and Food Chemistry. 45:407-413.
Pinna, K., L. R. Woodhouse, B. Sutherland, D. M. Shames, and J. C. King. 2001. Exchangeable zinc pool
masses and turnover are maintained in healthy men on low zinc intakes. Journal of Nutrition
131:2288-2294.
Rahman, S., T. Ahmed, A. S. Rahman, N. Alam, A. S. Ahmed, S. Ireen, I. A. Chowdhury, P. S.
Chowdhury, and S. M. Rahman. 2016. Determinants of iron status and hb in the Bangladesh
population: The role of groundwater iron. Public Health Nutrition 19(10):1862-1874.
Roohani, N., R. Hurrell, R. Kelishadi, and R. Shulin. 2013. Zinc and its importance for human health: An
integrative review. Journal of Research in Medical Science 18(2):144-157.
Rosado, J. L., K. M. Hambidge, L. V. Miller, O. P. Garcia, J. Westcott, K. Gonzalez, J. Conde, C. Hotz,
W. Pfeiffer, I. Ortiz-Monasterio, and N. F. Krebs. 2009. The quantity of zinc absorbed from
wheat in adult women is enhanced by biofortification. Journal of Nutrition 139(10):1920-1925.
Sauberlich, H. E., M. J. Kretsch, J. H. Skala, H. L. Johnson, and P. C. Taylor. 1987. Folate requirement
and metabolism in nonpregnant women. American Journal of Clinical Nutrition 46:1016-1028.
Shah, D., H. S. Sachdev, T. Gera, L. M. De-Regil, and J. P. Pena-Rosas. 2016. Fortification of staple
foods with zinc for improving zinc status and other health outcomes in the general population.
Cochrane Database Systematic Reviews 6:CD010697.
Stamm, R. A., and L. A. Houghton. 2013. Nutrient intake values for folate during pregnancy and lactation
vary widely around the world. Nutrients 5(10):3920–3947. http://doi.org/10.3390/nu5103920
(accessed June 3, 2018).
Stover, P. J. 2007. Human nutrition and genetic variation. Food and Nutrition Bulletin 28(Suppl 1):S101-
S115.
Tamura, T., Y. Mizuno, K. E. Johnston, and R. A. Jacob. 1997. Food folate assay with protease, α-
amylase, and folate conjugase treatments. Journal of Agriculture and Food Chemistry 45:135-
139.
Wapnir, R. A. 2000. Zinc deficiency, malnutrition and the gastrointestinal tract. Journal of Nutrition
130(Suppl 5):1388S-1392S.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

4-36 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Wapnir, R. A., and L. Stiel. 1986. Zinc intestinal absorption in rats: Specificity of amino acids as ligands.
Joural of Nutrition 116(11):2171-2179.
Wazny, K., A. Zipursky, R. Black, S. Curtis, C. Duggan, R. Guerrant, M. Levine, W. A. Petri, Jr., M.
Santosham, R. Scharf, P. M. Sherman, E. Simpson, M. Young, and Z. A. Bhutta. 2013. Setting
research priorities to reduce mortality and morbidity of childhood diarrhoeal disease in the next
15 years. PLoS Medicine 10(5):e1001446.
Wessels, K.R., Singh G.M., Brown, K.H. 2012. Estimating the global prevalence of zinc deficiency:
Results based on zinc availability in national food supplies and the prevalence of stunting. PLoS
One 7(11):e50568.
Whittaker, P., T. Lind, and J. Williams. 1991. Iron absorption during normal human pregnancy: A study
using stable isotopes. British Journal of Nutrition 65(3):457-463.
WHO/FAO (World Health Organization and Food and Agriculture Organization). 2004. Vitamin and
mineral requirements in human nutrition. Geneva, Switzerland: WHO.
WHO/UNICEF (United Nation’s Children Fund). 2004. Clinical management of acute diarrhea. Geneva,
Switzerland: WHO/UNICEF.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Future Directions and Data Gaps

As elaborated in the earlier chapters in this report, the concept for a structure to harmonize
the methodologies for establishing nutrient reference values (NRVs) began in the 1990s, with
discussions among experts from the United States, Canada, and the United Kingdom. This led to
convening an international stakeholder group to lay out the components of a universally
applicable organizing framework (King and Garza, 2007). In the interim, new tools have been
developed that were not available or used previously. These include systematic reviews, larger
and more accessible databases, information on factors affecting culture- and context-specific
food choices and dietary patterns, new modeling techniques (e.g., new tools for assessing risk of
bias), and new metabolic biomarkers of nutritional status.
These tools have enabled more transparent, scientifically rigorous, and efficient approaches
that enhance the feasibility of developing NRVs across broader, more diverse population
subgroups. Building on this background, the committee examined the strengths and weaknesses
of current approaches, evaluated their application to two high-risk population subgroups, young
children (birth through 5 years of age) and women of reproductive age, and assessed the
feasibility of harmonizing methodologies to derive NRVs on a global scale. While it was beyond
the committee’s scope to determine how to implement its recommendations for a harmonized
approach to deriving NRVs, it did consider possible next steps toward implementation. This final
chapter reiterates the advantages of the harmonization of approaches used to derive NRVs;
considers options and strategies to facilitate harmonization; and identifies data gaps that need to
be filled.

ADVANTAGES OF HARMONIZING METHODOLOGIES TO DERIVE NUTRIENT


REFERENCE VALUES

Building on the work of King and Garza (2007), the committee identified several additional
reasons to harmonize the approach to deriving NRVs. First, a harmonized approach will
prioritize the derivation of the AR and UL. Currently many countries and/or organizations do not
appreciate that deriving values for average requirements (ARs) and upper levels (ULs) is a
greater priority than recommended intakes (RIs). It is not possible to derive valid estimates of the
prevalence of inadequate nutrient intakes without first deriving the AR and UL. Furthermore, the
AR and UL are necessary values for estimating nutrient intake gaps that require agricultural,

PREPUBLICATION COPY: UNCORRECTED PROOFS


5-1

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

5-2 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

fortification, or supplementation programs, as well as being necessary for evaluating the


effectiveness and safety of policies to fill these gaps.
In addition, the high cost of the process of deriving NRVs means that nutrient intake
recommendations are updated infrequently. It will be much more cost-effective to use a
harmonized approach than to have different countries or organizations developing their own. The
cost of conducting systematic reviews alone is prohibitive even for global organizations, such as
the World Health Organization (WHO) and the Food and Agriculture Organization (FAO) and
wealthier countries. For example, it was suggested at the Global Harmonization workshop that a
central repository for systematic reviews and other data sources be established that is accessible
to all countries. Another advantage of harmonization is that it will enable comparison of the
adequacy of nutrient intakes around the world. Finally, the increasing globalization of trade in
processed and fortified foods means that labeling and nutrient content information on foods must
be as consistent and understandable as possible; a harmonized approach will help to achieve
consistency.

STEPS REQUIRED TO ENCOURAGE COMMITMENT TO THE GUIDELINES

There has been relatively little implementation of the organizing framework for harmonizing
NRVs proposed in the King and Garza (2007) report. Moving forward will require overcoming
the barriers to implementation that clearly exist and that were discussed at the Global
Harmonization workshop (NASEM, 2018). The committee identified two sets of options for
overcoming these barriers: (1) increasing access to systematic reviews and other data sources for
low- and middle-income countries; and (2) sharing scientific expertise and improving
consistency between trade partners on nutrient content information.

Increasing Access to Data

One option for increasing access to data is to create data repositories and make them publicly
and globally available. Such repositories could include systematic reviews of existing literature
on nutrients; food composition data; or nutrient bioavailability data and algorithms. Some
databases may need to include locally- or regionally specific data. While making the repositories
available online would increase access for low- and middle-income countries, finding a host
institution to accrue and update the information may be a challenge. An exemplar model might
be the Vitamin and Mineral Nutrition Information System hosted by WHO.1 In addition, by
coupling repositories with software packages that include algorithms or models that make
bioavailability corrections that use AR and UL data, low- and middle-income countries would be
able to use this data to estimate the prevalence of inadequate and excessive intakes in specific
population subgroups.

Sharing Scientific Expertise

Scientific expertise is not always available to cover reviews for all nutrients or population
subgroups (e.g., infants) in a country. A manual with training modules and other supportive
information could be of great value in training new scientists and for guiding agencies who are

1
Available at http://www.who.int/vmnis/en (accessed May 16, 2018).

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

FUTURE DIRECTIONS AND DATA GAPS 5-3

interested in working on nutrient requirement recommendations. The modules could be made


available online and implemented with the support of national nutrition societies, such as the
International Union of Nutrition Sciences (IUNS). Such a manual could become an important
mechanism for communicating information with a majority of nutrition societies internationally,
as well as to academic institutions that teach nutrition. Such a manual could also be used for
explaining the importance of harmonization, including justification for making resources
available globally. The manual could contain such information as:
• A clear explanation of terminology;
• A description of available resources, such as existing systematic reviews and databases;
• Guidance on when to include or exclude data from systematic reviews, and how to
establish endpoints;
• Methods used to assess status and requirements for each nutrient;
• Information on bioavailability adjustments, with case studies to explain the process for
some specific nutrients;
• Guidance on how to manage factors such as dietary patterns, life stage concerns, genetic
variability, morbidity and infections, and physiological requirements;
• How to use the AR and UL to estimate the prevalence of inadequate and excessive
intakes, respectively, in population subgroups; and
• For each nutrient, a description of symptoms and problems caused by exceeding the UL
of intake.
Global consensus on gaps in scientific information could help to drive a new agenda for
obtaining this information and funding the necessary research.

Recommendation 6. Researchers and funding organizations should advance the knowledge


of nutrient requirement research by supporting research that uses modern technology,
techniques, or methods for assessing requirements.

Additional Considerations

To facilitate local and regional implementation of a harmonized process to derive NRVs,


there is a need for additional guidance (i.e., beyond what is here) on how to use the tools and
apply the steps identified in the proposed framework in this report (Chapter 3, Figure 3-4). Such
guidance could include information on:
• Managing missing ARs;
• Increasing the availability of local and regional data;
• Encouraging regional working groups and partnerships;
• Clarifying data uncertainties, such as food intake and composition data limitations; and
• Facilitating access to harmonization tools, for example, through a “Secretariat” or other
international organization

MOVING FORWARD TOWARD HARMONIZATION

While this report describes the data gaps and offers a model for harmonizing the approach to
deriving NRVs globally, future dialogue will be needed across countries to garner support for a

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

5-4 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

harmonization effort and to identify a pathway for implementing the recommendations of this
report. It is the committee’s view that achieving global harmonization of the methodological
approaches to deriving NRVs requires that the following overlapping steps be taken:
1. Design a process by which harmonization can be achieved.
2. Test the proposed process.
3. Implement the process.
4. Communicate and support the incorporation of the results of harmonization at all levels
(i.e., country, regional, global).
5. Perform process and outcome evaluations throughout
Each of these steps entails specific activities that are key to the harmonization of
methodologies to derive NRVs. The first two steps are encompassed in the activities that resulted
in the convening of the Global Harmonization workshop and the subsequent work of this
consensus committee and its report. This report’s intent is to provide the guidance needed as
global stakeholders consider moving toward the subsequent steps of implementation,
communication, and evaluation.
An important next step (as part of implementation and communication) is for the key
enablers of harmonizing NRVs to develop a tool kit that participants from low- and middle-
income countries can use to guide the development of harmonized approaches to deriving NRVs
for their populations. To be effective and useful, the NRVs for a specific country or region need
to address specific economic, social, and cultural influences on the food supply and the
population’s nutritional status. Systematic reviews of NRVs from other countries will identify
the key factors that need to address specific economic, social, and cultural influences on the food
supply and the population’s nutritional status. Systematic reviews from other countries can be
used to identify the key factors that need to be addressed when deriving NRVs, and possibly, to
adjust estimated NRVs based on variations in the food supply, physical activity, and usual body
size.
The path forward requires active participation and investment from groups and organizations
to whom global harmonization will be entrusted. This may include WHO and FAO at the global
level; nongovernmental stakeholder organizations and foundations at the regional level; and the
joint U.S. and Canadian Dietary Reference Intake steering committee, the European Food Safety
Authority, and other federal-level agencies at the national level. The collective effort of these
groups is needed to launch an initiative that will explain the proposed harmonization approach
and advocate for its implementation, including its advantages and the reasons for using a shared
paradigm.

REFERENCES

King, J. C., and C. Garza. 2007. Harmonization of nutrient intake values. Food and Nutrition Bulletin
28(1):S3-S12.
NASEM (National Academies of Sciences, Engineering, and Medicine). 2018. Global harmonization of
methodological approaches to nutrient intake recommendations: Proceedings of a workshop.
Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25023.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Appendix A

Glossary

acceptable macronutrient distribution range (AMDR) – In this report, this term refers to the
range of intake for a particular energy source that is associated with reduced risk of chronic
disease while providing intakes of essential nutrients.
adequate intake (AI) – In this report, this term is used to describe the value estimated when
neither an average requirement or recommended dietary allowance are able to be set. It is the
observed median intake of a nutrient by a group of healthy people with apparently adequate
status of that nutrient. This term is used by the United States and Canada and the European Food
Safety Authority.
average nutrient requirement (ANR) – In this report, this refers to a term that was proposed by
King and Garza (2007). It is a median value that is estimated from a distribution of requirements
based on a specific criterion in healthy individuals.
average requirement (AR) – This term can be defined as the intake needed by 50 percent of a
population subgroup to meet a specific criterion of adequacy. It is used by the European Food
Safety Authority.
Dietary Reference Intake DRI) – In this report, this term refers to the values produced jointly
by the United States and Canada. The values under this umbrella term are the estimated average
requirement (EAR), recommended dietary allowance (RDA), adequate intake (AI), and tolerable
upper intake level (UL).
dietary reference value (DRV) – In this report, this term refers to a series of estimates of energy
and nutritional requirements of different groups of healthy people. These were set by the United
Kingdom’s Committee on Medical Aspects of Food and Nutrition Policy (COMA) in 1991, and
they include the estimated average requirement (EAR), reference nutrient intake (RNI), lower
reference nutrient intake (LRNI), safe upper levels (SUL), and the adequate macronutrient
distribution range (AMDR).
estimated average requirement (EAR) – This term, used by the United States, Canada, and the
United Kingdom, estimates the average requirement of energy or of a nutrient needed to meet the
needs of 50 percent of the population. It is similar in meaning to the European Food Safety
Authority’s average requirement.

PREPUBLICATION COPY: UNCORRECTED PROOFS


A-1

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

A-2 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

individual nutrient level (INL) – This harmonized term was proposed by King et al. (2007). It
represents a value that is derived from the average nutrient requirement plus an identified
percentile of a calculated mean. It is used for guiding individual intake.
low observed adverse effect level (LOAEL) – In this report, this term refers to a factor that is
used in conjunction with an uncertainty factor to derive an upper level. It is derived in a
toxicological context, and it is the lowest level at which an adverse effect is recorded.
lower reference nutrient intake (LRNI) – The amount of a nutrient that is enough for only a
small number of individuals in a group who have low requirements for that specific nutrient. A
majority of the population will require more than this amount. This term is used by the United
Kingdom.
no observed adverse effect level (NOAEL) – In this report, this term refers to a factor that is
used in conjunction with an uncertainty factor to derive an upper level. It is derived in a
toxicological context, and it is the level at which no adverse effect is recorded.
nutrient intake value (NIV) – This harmonized term was proposed by King et al. (2007), and in
this report it refers to the set of values composed of the average nutrient requirement (ANR),
individual nutrient level (INLx), and upper nutrient level (UNL).
nutrient reference value (NRV) – In this report, this is used as a broad term to describe a
specific nutrient value that is calculated for a generally healthy population. Examples of nutrient
reference values are average requirements and upper intake levels.
population reference intake (PRI) – In this report, this term refers to the amount of an
individual nutrient that a majority of people in a population need for good health depending on
their age and sex. This term is used by the European Food Safety Authority, and it is considered
to be similar to the United States and Canada’s recommended dietary allowance (RDA) and the
United Kingdom’s reference nutrient intake (RNI).
recommended dietary allowance (RDA) – This is the average daily level of intake sufficient to
meet the nutrient requirements of nearly all (97–98 percent) healthy people. This term is used by
the United States and Canada.
reference nutrient intake (RNI) – This is defined as the amount of a nutrient that is enough to
ensure that the needs of nearly all of a group (97.5 percent) are being met. This term is used by
the United Kingdom.
safe intake – This is an amount of a nutrient deemed sufficient for everyone in a population
subgroup, but it is below a level that would produce undesirable effects. This term is used by the
United Kingdom.
tolerable upper intake level (UL) – In this report, this term refers to the highest level of nutrient
intake that is likely to pose no risk of adverse health effects for almost all individuals in the
general population. This term is used by the European Food Safety Authority, the United States,
and Canada.
upper nutrient level (UNL) – This harmonized term was proposed by King et al. (2007). These
values represent intakes that, if chronically consumed, will have a very low risk of causing
adverse effect.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPENDIX A A-3

REFERENCE

King J. C., H. H. Vorster, and D. G. Tome. 2007. Nutrient intake values (NRVs): A recommended
terminology and framework for the derivation of values. Food and Nutrition Bulletin 28(1):S16-
S26.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Appendix B

Workshop Agenda

September 21–22, 2017


Headquarters of the Food and Agriculture Organization of the United Nations
Viale delle Terme di Caracalla
Rome, Italy

Workshop Objectives

• Describe potential frameworks to enable global harmonization of methodologies to establish


nutrient intake recommendations.
• Explore approaches for evaluating the evidence to facilitate global harmonization of
methodologies to establish nutrient intake recommendations.
• Examine the potential for addressing contextual factors from different population subgroups,
regions, and countries that may or may not be conducive to harmonization.
• Consider approaches to facilitate global sharing of resources to maintain quality and support
cost-effectiveness to develop methodologies for nutrient intake recommendations.
• Identify the advantages, barriers, and challenges to global harmonization of methodologies to
establish nutrient intake recommendations.

Day 1
8:30 am Registration

INTRODUCTION AND OPENING REMARKS

9:00 Welcome
Kostas Stamoulis, Food and Agriculture Organization Assistant Director-General,
Economic and Social Development Department
Stephanie Atkinson, McMaster University, Planning Committee Chair

9:15 Defining the Problem: Partner Panel


Chizuru Nishida, Coordinator, Nutrition Policy and Scientific Advice, Department
of Nutrition for Health and Development, World Health Organization
Anna Lartey, Director of Nutrition, United Nations Food and Agriculture
Organization
B-1
PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

B-2 HARMONIZATION OF APPRACHES TO NUTRIENT REFERENCE VALUES

9:30 Background for the Workshop


Moderated by: Stephanie Atkinson, McMaster University, Planning Committee
Chair

Harmonizing the Nutrient Intake Values: Phase 1


Janet King, Children’s Hospital Oakland Research Institute

Applications and Uses of Nutrient Intake Recommendations


Suzanne Murphy, Emeritus, University of Hawaii

SESSION 1: HARMONIZATION FRAMEWORKS


Moderated by: Peter Clifton, University of South Australia

10:00 Terminology and Models


Peter Clifton, University of South Australia

10:20 Endpoints—Deficiency Versus Chronic Disease


Amanda MacFarlane, Health Canada

10:40 Guiding Principles for Developing Dietary Reference Intakes Based on


Chronic Disease
Janet King, Children’s Hospital Oakland Research Institute

10:50 Discussion with Session Speakers

11:10 Break

11:30 Panel Discussion: Current Models for Establishing Intake Recommendations


Hasan Hutchinson, Health Canada, Panel Chair and Moderator
United Kingdom: Ann Prentice, University of Cambridge
Australia and New Zealand: Peter Clifton, University of South Australia
South Korea: Hee Young Paik, Seoul National University
India: Thingnganing Longvah, National Institute of Nutrition, India

SESSION 2: APPROACHES TO EVALUATING THE EVIDENCE


Moderated by Ann Prentice, University of Cambridge

12:10 pm Tools for Evaluating Strength and Quality of Evidence


George Wells, Ottawa Heart Institute

12:30 Global Systematic Reviews: How Can It Be Done?


Joseph Lau, Brown University

12:50 Risk–Benefit Analysis


Hans Verhagen, European Food Safety Authority

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPENDIX B B-3

1:10 Discussion with Session Speakers

1:35 Break for Lunch

SESSION 3: CONTEXTUAL FACTORS: HOST, DIET/ENVIRONMENT, AND HEALTH


STATUS
Moderated by Suzanne Murphy, Emeritus, University of Hawaii, and John Muyonga, Makerere
University

2:25 The Role of Host: Genetic Variation


Patrick Stover, Cornell University

2:45 The Role of Host: Physiology


Anura Kurpad, St. John’s Medical College

3:05 The Role of Health Status


Seth Adu-Afarwuah, University of Ghana
Caryl Nowson, Deakin University

3:45 The Role of Diet and Environment: Bioavailability, Processing,


Environmental Exposure, and Nutrient Interactions
Rosalind Gibson, University of Otago
Umi Fahmida, University of Indonesia

4:20 Panel Discussion with Session Speakers

4:50 Closing Remarks


Stephanie Atkinson, McMaster University, Planning Committee Chair

5:00 Adjourn for the Day

Day 2

SESSION 4: APPLICATIONS, FACILITATING QUALITY, AND COST-


EFFECTIVENESS
Moderated by: Lindsay Allen, University of California, Davis

8:30 am Setting the Stage for Participant Discussion


Catherine Leclercq, United Nations Food and Agriculture Organization

8:45 Breakout Group Topics for Participant Discussion:


• What are the advantages of global harmonization of methodologies for
developing nutrient intake recommendations from your standpoint?

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

B-4 HARMONIZATION OF APPRACHES TO NUTRIENT REFERENCE VALUES

• What additional resources and expertise would facilitate adoption of a


harmonized approach in your region or country?
• What are the likely barriers and challenges to achieving global harmonization
from your standpoint?

10:00 Rapporteurs Report on Breakout Discussion

10:30 Break

11:00 Synthesis of Breakout Discussion


Lindsay Allen, University of California, Davis

SESSION 5: ADVANTAGES, BARRIERS, AND CHALLENGES TO GLOBAL


HARMONIZATION OF METHODOLOGIES FOR NUTRIENT INTAKE
RECOMMENDATIONS
Moderated by: Susan Fairweather-Tait, University of East Anglia, and Amanda MacFarlane,
Health Canada

11:30 Panel Discussion—Experiences from Countries that Have Collaborated


Southeast Asia—Emorn Udomkesmalee, Mahidol University
European Micronutrient Recommendations Aligned—Christophe Matthys,
University of Leuven
European Food Safety Authority—Hildegard Przyrembel, Federal Institute for
Risk Assessment
Africa—James Ntambi, University of Wisconsin–Madison
Norway—Helle Margrete Meltzer, Norwegian Institute of Public Health

Topics for Discussion:


• Similarities and differences
• Challenges and advantages
• Mechanisms that could be considered for setting priorities for activities, such
as systematic reviews, toolkits, technical briefs
• Potential for acceptance of methodological approaches across countries
• Potential ways forward

1:00 pm Chair’s Summary and Discussion of Next Steps


Stephanie Atkinson, McMaster University, Planning Committee Chair

1:30 Adjourn Meeting

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Appendix C

AGREE II Instrument
APPRAISAL OF GUIDELINES FOR RESEARCH AND EVALUATION II

The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument is a
generic tool designed to assess the quality of clinical practice guidelines. It outlines a
methodological approach to evaluate guideline longevity and subsequent implementation by
assessing the transparency of the guidelines and the rigor of their development. A quality score
is derived by independently calculating a domain score for each of the tool’s six domains. The
interpretation of this score is left to the user, and the AGREE II Consortium did not set values for
minimum domain scores as they relate to the quality of a guideline. End users of this tool include
health care providers, guideline developers, and policy makers (Brouwers et al., 2010).
Domain 1. Scope and Purpose
1. The overall objective(s) of the guideline is (are) specifically described.
2. The health question(s) covered by the guideline is (are) specifically described.
3. The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described.
Domain 2. Stakeholder Involvement
4. The guideline development group includes individuals from all the relevant professional groups.
5. The views and preferences of the target population (patients, public, etc.) have been sought.
6. The target users of the guideline are clearly defined.
Domain 3. Rigor of Development
7. Systematic methods were used to search for evidence.
8. The criteria for selecting the evidence are clearly described.
9. The strengths and limitations of the body of evidence are clearly described.
10. The methods for formulating the recommendations are clearly described.
11. The health benefits, side effects, and risks have been considered in formulating the recommendations.
12. There is an explicit link between the recommendations and the supporting evidence.
13. The guideline has been externally reviewed by experts prior to its publication.
14. A procedure for updating the guideline is provided.
Domain 4. Clarity of Presentation
15. The recommendations are specific and unambiguous.
16. The different options for management of the condition or health issue are clearly presented.
17. Key recommendations are easily identifiable.
Domain 5. Applicability
18. The guideline describes facilitators and barriers to its application.

C-1
PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

C-2 HARMONIZATION OF APPRACHES TO NUTRIENT REFERENCE VALUES

19. The guideline provides advice or tools on how the recommendations can be put into practice.
20. The potential resource implications of applying the recommendations have been considered.
21. The guideline presents monitoring or auditing criteria.
Domain 6. Editorial Independence
22. The views of the funding body have not influenced the content of the guideline.
23. Competing interests of guideline development group members have been recorded and addressed.

REFERENCE

Brouwers, M. C., M. E. Kho, G. P. Browman, J. S. Burgers, F. Cluzeau, G. Feder, B. Fervers, I. D.


Graham, J. Grimshaw, S. E. Hanna, P. Littlejohns, J. Makarski, and L. Zitzelsberger. 2010. For the
AGREE Next Steps Consortium. AGREE II: Advancing guideline development, reporting and
evaluation in healthcare. Canadian Medical Association Journal 182:E839-E842.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Appendix D

Tools and Methods to Evaluate Risk of Bias in Individual


Studies

Below are examples of tools and methods that were developed to measure the strength of
various studies as well as the risk of bias in randomized trials, nonrandomized studies, diagnostic
test accuracy, cohort studies, randomized controlled trials, and case control studies. The table
below has been adapted from the European Food Safety Authority’s 2017 report The Principles
and Methods Behind EFSA’s Guidance on Uncertainty Analysis in Scientific Assessment.
Study Design or Applicable
Tool Setting Institution Reference
Office of Health Experimental animal studies, National Toxicology https://ntp.niehs.nih.gov/ntp/oh
Assessment and human randomized controlled Programme (NTP) at/pubs/riskofbiastool_508.pdf
Translation Risk of trial (RCT), human
Bias (RoB) Tool observational
Rob 2.0 Risk of bias in randomized Cochrane collaboration https://sites.google.com/site/ris
trials kofbiastool/welcome/rob-2-0-
tool
Robins-I Risk of bias in nonrandomized Cochrane collaboration https://sites.google.com/site/ris
studies of interventions kofbiastool/welcome/home
RoB Diagnostic Test Risk of bias in diagnostic test Cochrane Canada http://training.cochrane.org/res
Accuracy accuracy ource/primer-cochrane-
diagnostic-test-accuracy-
reviews

Tool to assess risk of Risk of bias in cohort studies CLARITY Group https://www.evidencepartners.
bias in cohort studies com/resources/methodological
-resources
Tool to assess risk of Risk of bias in RCT CLARITY Group https://www.evidencepartners.
bias in randomized com/resources/methodological
controlled trials -resources
Tool to assess risk of Risk of bias in case control CLARITY Group https://www.evidencepartners.
bias in case control studies com/resources/methodological
studies -resources
SOURCE: Adapted with permission from EFSA et al., 2018.

D-1
PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

D-2 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

REFERENCE

EFSA Scientific Committee, D. Benford, T. Halldorsson, M. J. Jeger, H. K. Knutsen, S. More, H. Naegeli,


H. Noteborn, C. Ockleford, A. Ricci, G. Rychen, J. R. Schlatter, V. Silano, R. Solecki, D. Turck,
M. Younes, P. Craig, A. Hart, N. Von Goetz, K. Koutsoumanis, A. Mortensen, B. Ossendorp, A.
Germini, L. Martino, C. Merten, O. Mosbach-Schulz, A. Smith, and A. Hardy. 2018. Scientific
opinion on the principles and methods behind EFSA’s Guidance on Uncertainty Analysis in
Scientific Assessment. EFSA Journal 16(1):5122-5235.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Appendix E

Scaling Methods to Extrapolate from Reference Values of One


Age Group to Another

Table E-1 shows a compilation of the scaling methods to extrapolate from the reference
values of one age group to another age group (IOM, 2002/2005).
TABLE E-1 Extrapolation by Scaling
Allometric,
Exponent; Growth
Nutrient Extrapolation 0.75 Isometric Factor Other
Choline AI adult → AI child yes yes
AI 0–6m→AI 7–12m yes no
Biotin AI 0–6m→AI 7–12m, yes no
1–18y, adult
Pantothenic acid adult→children yes yes
AI 0–6m→AI 7–12m yes no
Fluoride 0.05 mg/kg/d no yes no
Vitamin D adult→1–9y yes no

Magnesium EAR 10–15y→EAR yes no


5mg/kg/d
1–3 and 4–8y
Potassium AI adult→AI 1–18y AI child =AI adult × F
F = energy
intakechild/energy
intake adult
UL child = UL adult × F
UL adult →UL child F= energy intake
adult/energy intake
child
Sodium Same as potassium
Vitamin A, chromium, EAR/AI yes yes
copper, molybdenum, adult→EAR/AI child
iodine (no extrapolation for iodine yes
for 1–3 y and 4–8 y old)
AI 0–6m →AI 7–12m no
Vitamin K AI 7–12m→ AI 0–6m yes no
Iron No extrapolation
for 7–12 m, 1–8y;
9–18 y
Manganese EAR adult→EARchild yes yes
AI 0–6m → AI 7–12m no no

E-1
PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

E-2 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Zinc Factorial similar to


allometric
extrapolation from
adult plus GF
Thiamin EAR adult→EARchild yes yes
EAR adult→ AI 7–12m yes yes
Riboflavin EAR adult→EARchild yes yes
AI 0–6m → AI 7–12m yes no
Niacin EAR adult→EARchild yes yes
EAR adult→ AI 7–12m yes yes
UL adult →UL child yes no
Vitamin B6 EAR adult→EARchild yes yes
AI 7–12m from mean of
extrapolations:
AI 0–6m → AI 7–12m yes no
EAR adult→ AI 7–12m yes yes
UL adult →UL child yes no
Folate AI 0–6m → AI 7–12m yes no
EAR adult→ AI 7–12m yes yes
EAR adult→EARchild yes yes
UL adult →UL child yes no
Vitamin B12 EAR adult→EARchild yes yes
EAR adult→ AI 7–12m yes yes
Vitamin C AI 0–6m → AI 7–12m yes no
EAR adult→EARchild no no

Vitamin E AI 0–6m → AI 7–12m yes no


EAR adult→EARchild yes yes

Selenium AI 0–6m → AI 7–12m yes no


EAR adult→EARchild yes yes
NOTE: When data are insufficient, the estimated average requirement (EAR) or adequate intake (AI) for
infants or children can be extrapolated down by scaling the requirements for adults to the 0.75 power of
body mass.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Appendix F

European Food Safety Authority’s Scientific Opinion on Dietary


Reference Values for Protein: Growth Factors for Children Age
6 Months to 17 Years
EFSA GROWTH FACTORS

Age Maintenance Requirement Growth Requirement Average Requirement for Calculated Growth
(years) (g protein/kg per day) (g protein/kg per day) Protein (g/kg per day) Growth Factor Factor per
(A) (B) (A+B) (B/A) Age Group
Boys

0.5 0.66 0.46 1.12 0.70 7–11 mo:


1 0.66 0.29 0.95 0.44 0.57

1 0.66 0.29 0.95 0.44


1–3 yrs:
2 0.66 0.13 0.79 0.20
0.25
3 0.66 0.07 0.73 0.11

4 0.66 0.03 0.69 0.05


4–6 yrs:
5 0.66 0.03 0.69 0.05
0.06
6 0.66 0.06 0.72 0.09

7 0.66 0.08 0.74 0.12


8 0.66 0.09 0.75 0.14 7–10 yrs:
9 0.66 0.09 0.75 0.14 0.13
10 0.66 0.09 0.75 0.14

11 0.66 0.09 0.75 0.14


12 0.66 0.08 0.74 0.12 11–14 yrs:
13 0.66 0.07 0.73 0.11 0.11
14 0.66 0.06 0.72 0.09

0.72
15 0.66 0.06 0.09
0.71 15–17 yrs:
16 0.66 0.05 0.08
0.70 0.08
17 0.66 0.04 0.06

F-1
PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

F-2 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

Girls

0.5 0.66 0.46 1.12 0.70 7–11 mo:


1 0.66 0.29 0.95 0.44 0.57

1 0.66 0.29 0.95 0.44


1–3 yrs:
2 0.66 0.13 0.79 0.20
0.25
3 0.66 0.07 0.73 0.11

4 0.66 0.03 0.69 0.05


4–6 yrs:
5 0.66 0.03 0.69 0.05
0.06
6 0.66 0.06 0.72 0.09

7 0.66 0.08 0.74 0.12


8 0.66 0.09 0.75 0.14 7–10 yrs:
9 0.66 0.09 0.75 0.14 0.13
10 0.66 0.09 0.75 0.14

11 0.66 0.07 0.73 0.11


12 0.66 0.06 0.72 0.09 11–14 yrs:
13 0.66 0.05 0.71 0.08 0.08
14 0.66 0.04 0.70 0.06

15 0.66 0.03 0.69 0.05


15–17 yrs:
16 0.66 0.02 0.68 0.03
0.03
17 0.66 0.01 0.67 0.02

REFERENCE

EFSA NDA Panel (European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies).
2012. Scientific Opinion on Dietary Reference Values for protein. EFSA Journal 10(2):2557. doi:
10.2903/j.efsa.2012.2557.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Appendix G

Committee Member Biographies

Robert E. Black, M.D., M.P.H. (Chair), is Professor and Director of the Institute for
International Programs of the Johns Hopkins Bloomberg School of Public Health in Baltimore,
Maryland. Dr. Black is trained in medicine, infectious diseases, and epidemiology. He served as a
medical epidemiologist at the Centers for Disease Control and Prevention and worked at
institutions in Bangladesh and Peru on research related to childhood infectious diseases and
nutritional problems. He was Chair of the Department of International Health of the Bloomberg
School of Public Health from 1985 to 2013.
Dr. Black’s current research includes field trials of vaccines, micronutrients, and other
interventions; effectiveness studies of health programs; and evaluation of preventive and curative
health service programs in low- and middle-income countries. In the last 20 years he led work
that demonstrated the benefits of zinc supplements in prevention and treatment of childhood
diarrhea and pneumonia. His other interests are related to the use of evidence in policy and
programs, including estimates of the causes of child mortality, the development of research
capacity, and the strengthening of public health training.
As a member of the U.S. National Academy of Medicine and advisory bodies of the World
Health Organization, the International Centre for Diarrhoeal Disease Research, Bangladesh, and
other international organizations, he assists with the development of research and policies
intended to improve child health. He chaired the Child Health and Nutrition Research Initiative
and serves on the governing boards of Nutrition International and Vitamin Angels. He has more
than 700 scientific journal publications and is co-editor of the textbook Global Health. Dr. Black
is the recipient of the Programme for Global Paediatric Research Award for Outstanding
Contributions to Global Child Health in 2010, the Prince Mahidol Award for Public Health in
2010, the Canada Gairdner Global Health Award in 2011, the Nutrition Leadership Award from
Sight and Life in 2013, and the Jimmy and Rosalynn Carter Humanitarian Award in 2016.

Lindsay Allen, Ph.D., has been the Center Director of the U.S. Department of Agriculture’s
Agricultural Research Services Western Human Nutrition Research Center, since 2004. She was
formerly a Professor in the Department of Nutrition at the University of California, Davis, where
she is now an adjunct Research Professor. Dr. Allen’s research focuses on the prevalence, causes,
and consequences of micronutrient deficiencies, primarily in developing countries. She has
evaluated interventions with micronutrient supplements, food fortification, and food-based
approaches to improve nutritional status, pregnancy outcome, and child development, resulting in

G-1
PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

G-2 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

more than 200 publications from many countries. One of her most important achievements has
been to document the widespread high prevalence of vitamin B12 deficiency. Her research
investigates the adverse functional consequences of this deficiency on infants, children, and
women in developing countries and elderly in the United States, and the effects of different
interventions to alleviate this deficiency. These interventions have included supplements for
lactating women, infants and children, animal source foods (meat and milk), and intramuscular
injection of high doses.
She is part of a team testing the use of 14C-vitamin B12, measured by accelerator mass
spectrometry, for measuring vitamin B12 absorption and bioavailability in various conditions.
Her laboratory is currently collaborating in the development and evaluation of a new combined
indicator of vitamin B12 status, cB12. Dr. Allen’s laboratory has recently developed efficient
mass spectrometry and HPLC methods for the measurement of multiple vitamins simultaneously
in human milk. Application of these methods is revealing poor breast milk micronutrient content
in some populations consuming poor-quality diets, and enabling assessment of the impact of
maternal supplementation on breast milk quality. Dr. Allen has served on 10 committees of the
Food and Nutrition Board of the National Academies of Sciences, Engineering, and Medicine,
including the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. She
has advised many national, bilateral, and international organizations including the World Health
Organization (WHO), United Nations Children’s Fund, the Asian Development Bank, the World
Bank, Pan American Health Organization, and the Food and Agriculture Organization. She is the
principal author of the book What Works? A Review of the Efficacy and Effectiveness of Nutrition
Interventions, and of WHO’s Guidelines on Food Fortification with Micronutrients. She served
as President of the American Society of Nutritional Sciences and the Society for International
Nutrition Research, and Vice President of the International Union of Nutritional Sciences. From
the American Society for Nutrition she received the Kellogg Prize for International Nutrition, the
Conrad A. Elvehjem Award for Public Service in Nutrition, and the McCollum International
Lectureship. Dr. Allen is currently a member of the steering committee of the Micronutrient
Forum and the International Nutrition Foundation, and Chair of the National Institutes Health’s
Biomarkers in Nutrition and Development Expert Panel on Vitamin B12.

Zulfiqar A. Bhutta, Ph.D., is the Robert Harding Inaugural Chair in Global Child Health at the
Hospital for Sick Children, Toronto; Co-Director of the SickKids Centre for Global Child Health;
and the Founding Director of the Centre of Excellence in Women and Child Health at the Aga
Khan University, unique joint appointments. He also holds adjunct professorships at several
leading universities globally, including the Schools of Public Health at Johns Hopkins University
(Baltimore), Tufts University (Boston), Boston University, University of Alberta, and the London
School of Hygiene & Tropical Medicine. He is a designated Distinguished National Professor of
the Government of Pakistan and was the Founding Chair of the National Research Ethics
Committee of the Government of Pakistan from 2003 to 2014. Dr. Bhutta was a member of the
Independent Expert Review Group (iERG) appointed by the United Nations Secretary-General
for monitoring global progress in maternal and child health Millennium Development Goals
(2011–2015). He represented the global academic and research organizations on the Global
Alliance for Vaccines and Immunizations (Gavi) Board and serves on its Evaluation Advisory
Committee. Dr. Bhutta is the Co-Chair of the Global Countdown for 2015 and 2030 Initiatives
from 2006 to 2017, the Co-Chair of the Maternal and Child Health oversight committee of World
Health Organization (WHO) Eastern Mediterranean Region (EMRO), and the Chairman of the

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPENDIX G G-3

Coalition of Centres in Global Child Health with its secretariat based at the Hospital for Sick
Children, Toronto. He is a technical member of the recently appointed high-level United Nations
Health and Human Rights committee, an executive committee member of Partnership for
Maternal, Newborn & Child Health (PMNCH) and a member of the Independent Expert Group
producing the Global Nutrition Reports since 2014.
Professor Bhutta was educated at the University of Peshawar (MBBS) and obtained his Ph.D.
from the Karolinska Institute, Sweden. He is a Fellow of the Royal College of Physicians
(Edinburgh & London), the Royal College of Paediatrics and Child Health (London), American
Academy of Pediatrics, and the Pakistan Academy of Sciences. He heads a large research team in
Pakistan working on issues of maternal, newborn, and child survival and nutrition globally and
regionally. Dr. Bhutta has served as a member of the Global Advisory Committee for Health
Research for WHO, the Board of Child & Health and Nutrition Initiative of Global Forum for
Health Research, and the steering committees of the International Zinc and Vitamin A Nutrition
Consultative Groups. He was a founding board member of the PMNCH and a board member of
the International Center for Diarrheal Diseases Research (2011–2017). Dr. Bhutta was a member
of the WHO Strategic Advisory Committee for Vaccines (SAGE) from 2010 to 2015 and the
Advisory Committee for Health Research of the WHO EMRO. He is the past President of the
Commonwealth Association of Paediatric Gastroenterology and Nutrition (CAPGAN) and the
Federation of Asia-Oceania Perinatal Societies (FAOPS). As the current President of the
International Pediatric Association (IPA 2016–2019), he is a leading voice for health
professionals supporting integrated maternal, newborn, and child health globally.

Susan Fairweather-Tait, Ph.D., D.Sc., is Professor of Human Nutrition in the Norwich Medical
School at the University of East Anglia (UEA), United Kingdom. She has a B.Sc. (Food
Sciences), an M.Sc. (Nutrition), a Ph.D. from King’s College London (formerly Queen Elizabeth
College), and a D.Sc. from the University of London. After her Ph.D. she worked for the food
industry and then moved to the Institute of Food Research, Norwich, to undertake research on
mineral bioavailbility, initially as a Senior Research Scientist and latterly as Head of the
Nutrition Division, and Programme Leader for Micronutrients. In 2007, she was offered a
personal chair at University of East Anglia (UEA). Professional activities include membership of
the Editorial Board of the American Journal of Clinical Nutrition (2006–2012), Academy of
Finland Expert Group (2010–2012), International Reference Group for Nordic Nutrition
Recommendations 5 (2010–2012), and Biotechnology and Biological Sciences Research Council
(BBSRC) Agri-Food Committee (2006–2009). In 2009 she was appointed as an expert for the
European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies (NDA)
Panel and the Working Groups on Dietary Reference Values and Health Claims. In 2017 she was
elected as a member of the American Society for Nutrition Class of Fellows. Her research
interests are mineral requirements for optimal health and the prevention of chronic disease, and
she has over 220 peer-reviewed publications.

Wafaie Fawzi, M.B.B.S., Dr.P.H., is Professor of Nutrition, Epidemiology and Global Health
and Chair of the Department of Global Health and Population at the Harvard T.H. Chan School
of Public Health. He completed his medical training at the University of Khartoum, Sudan, and
his Doctorate of Public Health in 1992 in the Departments of Epidemiology and Nutrition at the
Harvard T.H. Chan School of Public Health. He has experience in the design and implementation
of randomized controlled trials and observational epidemiologic studies of perinatal health and

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

G-4 HARMONIZATION OF APPROACHES TO NUTRIENT REFERENCE VALUES

infectious diseases, with emphasis on nutritional factors. These include examining the
epidemiology of adverse pregnancy outcomes, childhood infections, and HIV/AIDS,
tuberculosis, and malaria among populations in Ethiopia, India, Tanzania, Uganda, and other
developing countries. Dr. Fawzi has been a Principal Investigator of the Management and
Development for Health (MDH) HIV/AIDS Care and Treatment Program in Tanzania, which
provides for scaling up quality care and treatment services and building operational research
capacity. He is a founding member of the Africa Academy of Public Health, a Harvard-affiliated
organization that aims to train future public health leaders and build strong research
collaborations with partners in Africa.

Mary L’Abbé, Ph.D., M.Sc., is the Earle W. McHenry Professor and Chair of the Department of
Nutritional Sciences, Faculty of Medicine, at the University of Toronto, where she leads a
research group on Food and Nutrition Policy for Population Health. Dr. L’Abbé is an expert in
public health nutrition, nutrition policy, and food and nutrition regulations, with a long career in
in mineral nutrition research. Her research examines the nutritional quality of the Canadian food
supply, food intake patterns, and consumer research on food choices related to obesity and
chronic disease. Dr. L’Abbé is a member of several committees of the World Health
Organization (WHO), including the Nutrition Guidance Expert Advisory Group on Diet and
Health and the Global Coordinating Mechanism for Noncommunicable Diseases; the former
which recently released the WHO Guidelines on Sugars. Dr. L’Abbé was Co-Chair of the
Canadian Trans Fat Task Force, led the Trans Fat Monitoring Program, and served as Chair and
Vice Chair of the Canadian Sodium Working Group. Before joining the University of Toronto,
Dr. L’Abbe was Director, Bureau of Nutritional Sciences, at Health Canada. Dr. L’Abbé holds a
Ph.D. in nutrition from McGill University and has authored more than 180 peer-reviewed
scientific publications, book chapters, and government reports.

Laura Martino, Ph.D., has been a senior statistician since January 2014 and Team Leader of the
Systematic Review and Experimental Design Team of the Assistance and Methodological
Support Unit at the European Food Safety Authority in Parma (Italy). Before joining the
European Food Safety Authority (EFSA) in 2011 she was a detached national expert at the
European Statistical Institute (Eurostat) in Luxembourg in the Unit Agricultural Statistics Farms,
Agri-Environment and Rural Development land use/cover area frame survey (LUCAS) team.
Previously Dr. Martino served as a researcher in methodological statistics at the National
Statistical Institute in Rome (Italy) leading the Unit Crop, forestry and hunting statistic in the
Department for Statistical production.
She has extensive experience in the design of observational and experimental studies as well
as in the methodology for food and feed risk assessment. Dr. Martino’s research focuses on
modeling association between dietary intake and health outcomes with a specific center on
establishing dietary reference values, methods for equivalence testing, and uncertainty analysis.
Her methodological expertise has led to contributions to several methodological guidance
documents. She gave lectures on statistical methods in various master training programmes
including the BIOSAFE summer school jointly organized by Università Cattolica del Sacro
Cuore, Università degli Studi di Milano, and EFSA.
Dr. Martino holds a Ph.D. in methodological statistic for scientific research, having
completed postgraduate training at the University of Bologna and 6-month scholarship at the

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

APPENDIX G G-5

Texas A&M University at College Station (United States). She is a member of the Italian
Statistical Society, the International Biometric Society, and the Statistical Modeling Society.

Hildegard Przyrembel, M.D., Ph.D., is retired Director and Professor at the Federal Institute for
Risk Assessment in Berlin, Germany (since 2007). She started her career at the University
Children’s Hospital Ulm working on a project from the German Society for Research on the
amino acid requirement of premature infants, combining analytical laboratory work with a
clinical education in paediatrics, with special emphasis on inborn errors of metabolism.
Thereafter she worked at the University Children’s Hospital Düsseldorf and the University
Children’s Hospital Rotterdam and the Department of Cell Biology and Clinical Genetics of the
Erasmus-University, Rotterdam, as head of the Unit for Metabolic Disorders and of the
Metabolic Laboratory. In cooperation the with the Department of Biochemistry in Rotterdam, the
metabolic laboratories of the Hammersmith Hospital, London, the University Children’s Hospital
in Utrecht, and the John F. Kennedy Institute for Basic Research in Mental Retardation in
Denver, Colorado, she detected two new inborn errors of lysine metabolism and shifted the
emphasis of her work to defects in fatty acid oxidation and of the mitochondrial respiratory chain
and their accessability to therapeutic measures. In 1990, Dr. Przyrembel accepted a position in
the Unit Nutrition in Medicine at the Federal Institute of Health at Berlin and became lecturer in
pediatrics at the Humboldt University Berlin.
She worked as a consultant in infant and child nutrition and dietetic therapy, both on national
and international panels. Since the foundation of the Federal Institute for Risk Assessment in
November 2002, Dr. Przyrembel’s tasks have been predominanty on the assessment of both
benefits and risks in connection with dietary habits, including breastfeeding, and connected with
the use of ingredients, nutrients, whole foods, and with residues (if the latter occur in human milk
or foods for infants and children). In 2000, Dr. Przyrembel started as an expert in the working
groups on Upper Levels of Vitamins and Minerals, on Infant Formula Composition, and on Food
Additives (Nutrient Compounds) of the Scientific Committee on Food of the European
Commission. In 2003 Dr. Przyrembel was appointed a member of the Scientific Panel on
Nutrition, Dietetic Foods and Allergy of the European Food Safety Authority (EFSA) until 2012.
She is an expert in several working groups of EFSA and has contributed to more than 400 EFSA
Opinions.

Emorn Udomkesmalee, Ph.D., is Senior Advisor and Former Director of the Institute of
Nutrition of the Mahidol University in Thailand. Currently, she is Adjunct Associate Professor in
the Department of International Health at John Hopkins University in the United States. She
received her Ph.D. in nutritional biochemistry and metabolism from the Massachusetts Institute
of Technology in 1985. Her postdoctoral training was at the Vitamin and Mineral Nutrition
Laboratory in the U.S. Department of Agriculture. She is currently a member of several
international committees related to nutrition advocacy, food policy, micronutrients, and
implementation science. Her research interests include micronutrient assessment, bioavailability,
and metabolism; efficacy of food-based interventions to address micronutrient deficiencies;
maternal and child nutrition policy; and program implementation.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Copyright National Academy of Sciences. All rights reserved.


Harmonization of Approaches to Nutrient Reference Values Applications to Young Children and Women of Reproductive Age

Copyright National Academy of Sciences. All rights reserved.