The National Academies Press

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
174 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 ...
HARMONIZATION
HARMONIZATION
OF
APPROACHES
OF
APPROACHES
TO
NUTRIENT
TO
NUTRIENT
REFERENCE VALUES
REFERENCE VALUES
APPLICATIONS TO YOUNG CHILDREN AND
APPLICATIONS YOUNG CHILDREN
WOMEN OFTOREPRODUCTIVE AGE 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
Copyright National Academy of Sciences. All rights reserved.

THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001
This activity was supported by a contract between the National Academy of Sci-
ences and the Bill & Melinda Gates Foundation (Grant OPP1150751) and by the
Kellogg Endowment Fund of the National Academy of Sciences’ Health and Medi-
cine 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: 978-0-309-47769-7

International Standard Book Number-10: 0-309-47769-7
Digital Object Identifier: https://doi.org/10.17226/25148
Additional copies of this publication are available for sale from the National Acad-
emies 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.

The National Academy of Sciences was established in 1863 by an Act of

Congress, signed by President Lincoln, as a private, nongovernmental institu-
tion 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 char-
ter 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 ad-
vice 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.

Consensus Study Reports published by the National Academies of

Sciences, Engineering, and Medicine document the evidence-based con-
sensus on the study’s statement of task by an authoring committee of
experts. Reports typically include findings, conclusions, and recommen-
dations based on information gathered by the committee and the com-
mittee’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.

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, Agricultural Research Center, 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


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 manu-
script 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 com-

ments and suggestions, they were not asked to endorse the conclusions or
recommendations of this report nor did they see the final draft before its re-
lease. The review of this report was overseen by M. R. C. GREENWOOD,
vii

viii REVIEWERS
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 accor-
dance 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.

Preface
The establishment of reference values for nutrient intakes of popula-

tions is essential for making recommendations for appropriate, safe dietary
intakes and for designing nutritional interventions, such as nutrient fortifi-
cation of foods. Traditionally these efforts have been directed at preventing
nutrient deficiencies. Additionally, with the increasing globalization of in-
formation 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 nu-
tritional 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
ix

x PREFACE
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 updat-
ing 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 rec-
ommendations remain current and relevant to those population subgroups.
With these activities as a backdrop, the Bill & Melinda Gates Foun-
dation recognized the need for action toward developing a uniform and
consistent basis for setting nutrient intake recommendations across coun-
tries. The foundation therefore asked the National Academies of Sciences,
Engineering, and 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 coun-
tries in setting nutrient intake recommendations. The workshop provided a
backdrop and a resource for the consensus study committee’s task. Specifi-
cally, the Bill & Melinda Gates Foundation asked the committee to focus on
young children and women of reproductive age and to apply its findings to

PREFACE xi
these target population subgroups using case scenarios informed by work-

shop 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 to-
gether 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 stan-
dardizing 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
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 commend-
able. 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
Young Children and Women of Reproductive Age


Contents
ACRONYMS AND ABBREVIATIONS xv
SUMMARY 1
1 INTRODUCTION AND PROBLEM STATEMENT 15

Background for the Study, 15
The Committee’s Task, 17
The Study Process, 18
Organization of the Report, 19
References, 19
CONCEPTUAL FOUNDATIONS OF NUTRIENT REFERENCE

2
VALUE DEVELOPMENT 21
Background, 21
Nutrient Reference Values, 23
Guiding Principles in Setting Nutrient Reference Values, 28
Conclusion and Recommendation, 36
References, 37
3 A HARMONIZED PROCESS FOR NUTRIENT REFERENCE

VALUE DEVELOPMENT 41
Key Steps in the Process for Deriving Nutrient Reference
Values, 42
Other Uncertainties to Consider When Estimating a UL, 62
A Framework for Deriving Nutrient Reference Values, 65
xiii

xiv CONTENTS
Findings, Conclusion, and Recommendation, 66

Chapter Summary, 69
References, 69
4 APPLYING METHODOLOGICAL APPROACHES TO

NUTRIENT REFERENCE VALUES FOR YOUNG CHILDREN
AND WOMEN OF REPRODUCTIVE AGE:
AN ASSESSMENT OF EXEMPLAR NUTRIENTS 73
Harmonizing the Process for Nutrient Reference Values
Using Exemplar Nutrients, 74
Zinc Case Analysis, 76
Findings and Conclusions for Zinc, 90
Proposed Solutions for Zinc, 92
Iron Case Analysis, 92
Findings and Conclusions for Iron, 101
Proposed Solutions for Iron, 103
Folate Case Analysis, 103
Findings and Conclusions for Folate, 111
Proposed Solutions for Folate, 113
Overall Conclusion, 114
Applications of Nutrient Reference Values in Low- and
Middle-Income Countries, 114
References, 115
5 FUTURE DIRECTIONS AND DATA GAPS 121

Advantages of Harmonizing Methodologies to Derive
Nutrient Reference Values, 122
Steps Required to Encourage Commitment to the Guidelines, 122
Moving Forward Toward Harmonization, 124
References, 126
APPENDIXES
A Glossary 127
B Workshop Agenda 131
C AGREE II Instrument 137
D Tools and Methods to Evaluate the Risk of Bias in
Individual Studies 141
E Scaling Methods to Extrapolate from Reference Values of
One Age Group to Another 143
F European Food Safety Authority’s Scientific Opinion on Dietary
Reference Values for Protein: Growth Factors for Children
Age 6 Months to 17 Years 147
G Committee Member Biographies 151

Acronyms and Abbreviations
AHRQ Agency for Healthcare Research and Quality

AI adequate intake
AMDR acceptable macronutrient distribution range
ANR average nutrient requirement
AR average requirement
ASEAN Association of Southeast Asian Nations
COMA United Kingdom Committee on Medical Aspects of Food

and Nutrition Policy
CV coefficient of variation
D-A-CH Nutrition Societies of Germany, Austria, Switzerland

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

FZA fractional zinc absorption
xv

xvi ACRONYMS AND ABBREVIATIONS
GRADE Grading of Recommendations, Assessment, Development

and Evaluation
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
LTI lowest threshold intake
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/PECO population, intervention/exposure, comparator, and

outcome of interest
PRI population reference intake
RCT randomized controlled trial

RDA recommended dietary allowance
RI recommended intake
RNI reference nutrient intake
SADC Southern African Development Community

SRDR Systematic Review Data Repository
SUL safe upper level
TAZ total absorbed zinc
UK United Kingdom
UL tolerable upper intake level
UNICEF United Nations Children’s Fund
UNL upper nutrient level
WHO World Health Organization

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 in-
take 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 meth-
odological 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
1 In this report, “young children” includes birth up to 5 years of age.

2 HARMONIZATION OF APPROACHES TO NRVs
international experts in Italy, in 2005, to review the methodological ap-

proaches in use at that time. Attendees at the Italy meeting identified four
basic reasons why global harmonization of the methodologies is important.
A harmonization of the process will:
1. Improve the objectivity and transparency of values derived by di-

verse national, regional, and international groups.
2. Provide a common basis or background for groups of experts to
consider throughout processes leading to NRVs.
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 reference values to meet their
populations’ specific requirements, objectives, and national policies.
4. 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 fortifica-
tion programs, and for addressing regulatory and trade issues.
Here, the committee defines the harmonization of approaches as reach-

ing global agreement on the most appropriate methods or procedures for
deriving NRVs. The concept of methodological harmonization is particu-
larly important for low- and middle-income countries whose access to es-
sential 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 chil-
dren 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, convene a consensus committee to examine
these issues, and make recommendations for a unified approach to develop-
ing 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 Agricul-
ture 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.

SUMMARY 3
BOX S-1
Statement of Task
An ad hoc committee will be convened to review and assess methodologi-

cal approaches to developing nutrient intake recommendations using evidence
presented and discussions that took place in the workshop Global Harmoniza-
tion 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 de-
riving 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 pre-
pared 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.
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.
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 de-
velopment 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
2 Other terms include reference nutrient intake (RNI), recommended nutrient intake (RNI),
recommended dietary allowance (RDA), and recommended dietary intake (RDI).

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 require-
ment (AR) and safe upper levels of intake (ULs). Their reports should
estimate the interindividual 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:
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 coop-
eration. 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 in-
ternational organizations responsible for facilitating cooperation in
global health, nutrition, and agriculture. Setting and promoting in-
ternational 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.
Given the interface between their missions, WHO and FAO have
a history of collaboration, they share funding for the Codex Ali-
mentarius, 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 Interna-
tional Union of Nutritional Sciences (IUNS), might have equally
good convening authority among scientific experts needed for an
international harmonization effort. Another possibility is that in-
ternational collaboration could be carried out at the regional level.
Recommendation 2. To set a nutrient reference value, ideally, a global

body, such as the World Health Organization (WHO), the United Na-
tions’ Food and Agriculture Organization (FAO), or the International
Union of Nutritional Sciences (IUNS), or secondarily, a regional con-
sortium, should convene an expert panel to identify relevant outcome
measures and request a systematic review for the nutrient of interest,

SUMMARY 5
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, up-
dated, 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, bio-
availability of the nutrient, and the presence of infection and other
local factors that influence the requirement for the population un-
der 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 re-

view process is essential to maintaining the credibility of the nutri-
ent 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 (NRVs), to achieve transparency the nutrient review
expert panel should clearly report the reference population, adjust-
ment factors, and the methodology used. Expert panels should also
document the uncertainty in the evidence and in the methods used
to develop the NRVs 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.

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 as-
sessment, (3) assessment of the prevalence of intakes outside the reference values, and (4)
characterization of risks association with excess intake.
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 pat-
terns, 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 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 (see Figure S-1). The framework provides a plat-
form for establishing NRVs that can be applied across countries and vari-
ous 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 NUTRIENTS

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

SUMMARY 7
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 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 neces-
sarily 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 in-
creases in plasma zinc concentrations irrespective of dietary intake.
Although linear growth has been recommended as a functional
indicator of zinc status, because 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 require-
ments influence the effect of phytate on zinc absorption. Because
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 supplementa-
tion 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 vul-
nerable to developing zinc deficiency and are more prone to de-
velop 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 re-
serves or enhancing immune function.
• Because the physiological requirements and ARs for young chil-
dren 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 RIs based on the dietary
zinc source (i.e., bioavailability) and the average body size of the
population.
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 recommenda-
tions. However, quantitative data are lacking for growing children. In ad-
dition 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 dietary zinc than plasma/serum zinc concentrations,
studies are needed to help identify the potential influence of genetic poly-
morphisms (i.e., genetic variations) on individual dietary zinc requirements.
Furthermore, the development of comprehensive models of inhibitors of

SUMMARY 9
zinc absorption across diverse populations would improve estimates of

dietary requirements.
Iron Case Analysis

Iron deficiency is a 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 lim-
ited 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 hor-
mone hepcidin, a key 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 bio-
availability 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 physiologi-
cal 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 addi-
tion, several biomarkers of iron status (e.g., ferritin) are modified
by infection, chronic disease, and deficiencies of other nutrients.
• 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 ane-
mic 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 physiolog-
ical 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 es-
sential 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 dif-
ferent 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 m etabolism 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.

SUMMARY 11
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 widespread 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 underes-
timation can explain discrepancies between intakes calculated from
older food composition data versus more recent estimates based on
measures of folate status.
• 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. There-
fore, 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 popula-
tions 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 es-
pecially 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 re-
quirements 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 the 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 vari-
ability 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 deriv-
ing 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 deriving an RI, as
was done in recommendations from the Germany, Austria, and
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 mi-
cronutrients affect folate requirements.
Proposed Solutions
Generally, dose–response modeling is used when there is a clear rela-
tionship 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 a safe upper level of intake. The
dose–response method is the preferred approach to derive ARs for folate.
Folate recommendations for women and children are remarkably simi-
lar 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 authorita-
tive bodies or to modifying them to the local context. However, the com-
mittee 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;

SUMMARY 13
• Knowledge gaps around the local contribution of other micronu-

trient 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 appli-
cation 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 support-
ing 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 na-
tional 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 set-
ting 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 har-

monization 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 har-
monizing 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 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 method-
ological 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.

Introduction and Problem Statement
BACKGROUND FOR THE STUDY

Traditionally, recommended intake levels for nutrients and other di-
etary components were designed primarily to prevent nutrient deficiency
diseases in a population. Furthermore, although used for individual coun-
seling, 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 identifica-
tion 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 and published 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 ad-
dressed in order to move the RDA process forward. The discussion included
the question of whether there was sufficient evidence to change the exist-
ing single value—the RDA—to include other values or intake ranges. The
15

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).
These activities galvanized action in the United States and Canada to
move toward a more uniform and comprehensive approach to setting nutri-
ent intake recommendations. The result was the Dietary Reference Intakes
(DRIs) produced jointly by the United States and Canada. Other authorita-
tive 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).
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:
• S upport 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 poli-
cies; and
• Enhance the transparency of national standards to trade and other regu-
latory actions with economic, health, and safety implications.
SOURCE: King and Garza, 2007.

INTRODUCTION AND PROBLEM STATEMENT 17
THE COMMITTEE’S TASK

While there is general consistency between many developed countries,
including the United States, Canada, and European countries, in the meth-
odological 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 popu-
lation 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 popu-
lation subgroups varies widely across countries and in some cases may not
exist, resulting in gaps and inconsistencies in nutrition policy goals, guide-
lines, and recommendations. The experiences and the lessons learned from
those countries that have worked toward harmonization of methodologies
for deriving NRVs provide a rich backdrop for dialogue about the possibili-
ties 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 ap-
proaches 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 young chil-
dren 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 recom-
mendations 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 ex-
pertise relevant to the international harmonization of methodological ap-
proaches to setting intake standards. The workshop, Global Harmonization
of Methodological Approaches to Nutrient Intake Recommendations, held
at the Food and Agriculture Organization (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 recom-
mendations (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 com-
mittee 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

BOX 1-2
Statement of Task
An ad hoc committee will be convened to review and assess methodologi-

cal approaches to developing nutrient intake recommendations using evidence
presented and discussions that took place in the workshop Global Harmoniza-
tion 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 de-
riving 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 pre-
pared 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.
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 har-
monization and standardization of methodological approaches for setting
nutrient-based intake recommendations on a global scale (see Box 1-2). The
committee was not asked to address the actual harmonization of NRVs,
only the approaches used to derive them. Nor was the committee asked
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) include con-
sideration of other age categories in some instances, depending on data
availability or age ranges used to set NRVs (e.g., see Chapter 4, 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, DRIs, dietary patterns, epidemiology, study design

INTRODUCTION AND PROBLEM STATEMENT 19
and methodology, statistics or biostatistics, and international nutrition

standards. The committee attended the international workshop Global
Harmonization of Methodological Approaches to Nutrient Intake Recom-
mendations held in Rome, Italy, at the headquarters of FAO 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.
ORGANIZATION OF THE REPORT

This report reviews and evaluates the evidence for global harmoniza-
tion 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 fu-
ture 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 Appraisal
of Guidelines for Research and Evaluation II (AGREE II) instrument. Ap-
pendix 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 the European Food Safety Authority’s Scien-
tific 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. https://doi.org/10.17226/9194.
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.

NASEM (National Academies of Sciences, Engineering, and Medicine). 2018. Global har-
monization of methodological approaches to nutrient intake recommendations: Pro-
ceedings of a workshop. Washington, DC: The National Academies Press. https://doi.
org/10.17226/25023.
UK (United Kingdom) Department of Health. 1991. Dietary reference values for food en-
ergy 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%20Oct%202016.pdf (accessed March
4, 2018).

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 val-
ues, 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
21

United Nations University’s Food and Nutrition Programme, in collabora-

tion with the Food and Agriculture Organization (FAO), the World Health
Organization (WHO), and the United Nations Children’s Fund (UNICEF)
(King and Garza, 2007).
The 2007 international panel’s next task was to identify the core rea-
sons 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 through-
out 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 popula-
tions’ 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 require-
ments (ANRs) for a population and (2) defining an upper nutrient level
(UNL). The ANR was to be derived from a normal distribution of nutri-
ent 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 in-
dividuals in the population.
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 de-
scribed in a consistent way (i.e., according to their application). Table 2-1

CONCEPTUAL FOUNDATIONS OF NRV DEVELOPMENT 23
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 physi-
ological 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.
compares terminology used to describe nutrient reference values currently

in use around the world.
NUTRIENT REFERENCE VALUES

In this report, the committee describes the four core reference values:
average requirement (AR), recommended intake (RI), adequate intake (AI),

TABLE 2-1 Comparison of Terms for Nutrient Reference Values (NRVs)

Currently in Use Around the World
United States United European
Recommendation and Canada Kingdom Union/EFSA WHO/FAO
Umbrella term for DRI DRV DRV
NRVs
Average requirement EAR EAR AR
Recommended intake RDA RNI PRI RNI
level
Lower reference intake LRNI LTI
Adequate intake AI AI
Safe upper level of UL SUL UL UL

intake
Appropriate AMDR AMDR RI Population mean
macronutrient intake goals
distribution range
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.
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.
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

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 popula-
tion 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) (Institute of Medicine),
recommended nutrient intakes (RNIs) (World Health Organization/United Nations’
Food and Agriculture Organization), and population reference intakes (PRIs)
(European Food Safety Authority).
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.

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 statisti-
cally 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 cal-
culate 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 fortifica-
tion 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 plan-
ning was not recognized. The exceptions in the WHO/FAO recommenda-
tions are vitamin B12 and folate, because these recommendations were
established later than the AR values already established by the Institute of
Medicine (IOM, 1998).
An additional problem is that the evidence for deriving an AR is lim-
ited 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 de-
rive 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 (interindividual variability) is not known
precisely, in most cases it is assumed to be 10 to 15 percent of the AR. Be-
cause RIs meet the needs of almost all individuals, estimating the prevalence
of inadequacy as the percent of intakes below these 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, how-
ever, 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 provid-
ing 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

New tools and methods either previously unavailable or not used in the
past have enabled global opportunities for harmonizing methodological ap-
proaches to deriving NRVs. Since the 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 transpar-
ency 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 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 carbohy-
drates, protein, and fat that reduce chronic disease risks associated
with the intake of these macronutrients;
4. Consider nutrient–nutrient interactions and quantify them, if pos-
sible; and
5. Consider subpopulations with special needs, keeping in mind, how-
ever, 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 obe-
sity 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 Acad-
emies’ report Guiding Principles for Developing Dietary Reference Intakes
Based on Chronic Disease, which recommends that future DRI committees
“characterize the health status of the population in terms of who is included
and excluded for each DRI” (NASEM, 2017, p. 30). The committee recog-
nizes the importance of chronic disease, however, most NRVs for pregnancy
and children are aimed at meeting specific nutrient needs for the most rel-
evant 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) and EFSA1 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;
1 See https://www.efsa.europa.eu/en/topics/topic/dietary-reference-values-and-dietary-
guidelines (accessed August 7, 2018).

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 pop-
ulation 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 accessi-
bility 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 harmoniza-
tion of methodologies for NRVs (NASEM, 2018), Joseph Lau argued that
because human physiology is essentially the same across the same subpopu-
lations around the world, the same evidence base can be used to inform nu-
trient 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, collabora-
tive, Web-based repository of systematic review data established by the U.S.

Agency for Healthcare Research and Quality (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 ongo-
ing basis (NASEM, 2017).
Also at the Global Harmonization workshop (NASEM, 2018), Lau em-
phasized 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 key
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 se-
lected according to their results, such as if only studies with statistically
significant results were included. Eligibility criteria include study design
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: associa-
tion 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 ex-
posure. 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 the Health and Medicine workshop, September 21,
2017. From Russell et al., 2009.

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 effect being considered?
(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 indica-
tor being set (e.g., AR or UL), an outcome can be a clinical condition asso-
ciated 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
process, immune status, or other functional metrics of nutrient status.
Select an indicator The nutrient review process begins by selecting an indi-

cator 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 are
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 valid-
ity 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 sam-
ples 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 nutri-
ent. 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 in-
terest 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, 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; Med-
scape, 2017). The EFSA 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).
As discussed below, biomarkers can also be used to establish an associa-
tion between a nutrient intake and risk of chronic disease. 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 ba-

sis for establishing NRVs. In the United States, the first RDAs (1941) were
used to inform food relief programs following the Great Depression; pro-
vide 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 ad-
vances, 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 dis-
eases can take decades to develop, and many factors influence their etiology,
including diet, with each factor playing only a small part in the causal path-
way. Additionally, intake of a given nutrient or nonessential 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 dis-
ease in question, or a valid surrogate for these outcomes (NASEM, 2017).
The analytical strategy for incorporating chronic disease into consideration
for deriving an 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 is addressed.
Determining a safe upper 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 up-
per bound is both conceptually 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
(also see 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 one-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 one-quarter to one-half
of adults take dietary supplements regularly (Bailey et al., 2013; Office of
Dietary Supplements, 2015). Research from Europe suggests wider varia-
tion 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 indi-

cators 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 consider-
ation 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 appro-
priate 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 in-
takes 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 preva-
lence of deficiency or excess. Correction for intraindividual variability (day-
to-day) is important and can be achieved by quantifying intake on one day
for the full sample, or two or more nonconsecutive days on a representa-
tive 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. Addition-
ally, 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 for-
tification 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, infor-

mation 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 interindividual variability of requirements and use it to derive the
AR. The expert panel should also acknowledge the basis and uncer-
tainty 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., and M. Haskell. 2002. Estimating the potential for vitamin A toxicity in women
and young children. The Journal of Nutrition 132:2907S-2919S.
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 Agri-
culture Organization.
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 nutrimen-
tos 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. Sum-
mary report. EFSA supporting publication 2017:e15121.
EFSA. 2017b. Overview on tolerable upper intake levels as derived by the Scientific Com-
mittee 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 (ac-
cessed January 11, 2018).
EFSA Dietetic Products, Nutrition, and Allergies (NDA) Panel. 2006. Tolerable upper intake
levels for vitamins and minerals. EFSA Journal 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. https://doi.org/10.2903/j.etsa.2013.3418.
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:
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. Washing-
ton, DC: The National Academies Press. https://doi.org/10.17226/13059.
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. Brit-
ish 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 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 prin-
ciples 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 rec-
ommendations: Proceedings of a workshop. Washington, DC: The National Academies
Press. 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:
NRC. 1986. Nutrient adequacy: Assessment using food consumption surveys. Washington,
DC: National Academy 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 No-
vember 30, 2017).

Paik, H. Y. 2008. Dietary reference intakes for Koreans (KDRIS). Asia Pacific Journal of Clini-
cal Nutrition 17(Suppl. 2):416-419.
Russell, R., M. Chung, E. M. Balk, S. Atkinson, E. L. Giovanucci, S. Ip, A. H. Lichtenstein,
S. T. Mayne, G. Raman, A. C. Ross, T. A. Trikalinos, K. P. West, Jr., and J. Lau. 2009.
Opportunities and challenges in conducting systematic reviews to support the develop-
ment of nutrient reference values: Vitamin A as an example. The American Journal of
Clinical Nutrition 89(3):728-733.
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. Euro-
pean 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. 2006. Critique of the considerations for establishing the tolerable upper intake
level for vitamin D: Critical need for revision upwards. The Journal of Nutrition
136:1117-1122.
WHO (World Health Organization). 2018. Vitamin A supplementation in infants and chil-
dren 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-285S.


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 com-
mittee examines and assesses in greater detail key steps in the nutrient re-
view 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 frame-
work 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.
41

KEY STEPS IN THE PROCESS FOR DERIVING

For methodological approaches to establishing NRVs to be adapted
globally, there are certain key steps in the process that should be consis-
tent 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.
Importantly, and as discussed throughout this chapter, the process to re-
view 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 develop-
ers, 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 re-
view, as well as the age and sex groups in the relevant population. In some
situations, the reference values may be reexamined only for select popula-
tion 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’s
(EFSA’s) scientific opinions on nutrient references (Atkinson, 2011; EFSA,
2017).
Reexamining existing NRVs requires justification, including new evi-
dence for the nutrient, or policy changes, such as fortification, that make

A HARMONIZED PROCESS FOR NRV DEVELOPMENT 43
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.

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 ac-
cepted for consideration based on (1) a rationale and description of why a
nutrient 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 organiz-
ing 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, nu-
trition, 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 infor-
mation 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 pro-
cess (FAO/WHO, 2018d). Codex delegates set standards for, among other
things, nutrition and labeling information, a topic inextricably related to
NRVs (FAO/WHO, 2018c). This body is in a position to negotiate the lo-
gistics 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 Interna-
tional 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 more than
80 countries, and one of the main objectives of IUNS is to encourage inter-
national 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 net-
works could be a particularly promising strategy in developing countries.
Where regional economic communities such as the South African Develop-
ment Community (SADC) and the Association of Southeast Asian Nations
(ASEAN) are already committed to advancing regional development there is
precedent for such networks working on common problems related to nu-
trition 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:
Two international organizations, WHO and FAO, both with mis-

sions to facilitate global cooperation in nutrition and health mat-
ters, present an opportunity for enabling harmonization of the
process for deriving NRVs on a global scale by serving as a con-
vener 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 tech-
nical 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.
The committee recognizes that political issues as well as country-

specific conventions and traditions may present a barrier to coun-
tries to fully committing to a shared process for deriving NRVs. For
the near future, national 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 re-

views 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 an 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 know-
ing 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 outcome of interest
(PICO/PECO) elements; assessing uncertainty in the evidence (i.e., apprais-
ing 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 infec-
tion, or when the population has unique physiological characteristics such
as obesity, advanced age, or pregnancy, reference values must be adjusted
accordingly. Studies on individuals suffering from chronic infections may
be included, but separated later by a subgroup analysis.
The I/E or intervention/exposure component of PICO/PECO refers to
exposure to the nutrient. To identify I/E 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 biologi-
cally 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 popula-
tion 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 still-
birth in a population. When conducting this last step of the PICO/PECO
process, separating reviews of observational studies from RCTs is gener-
ally 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 so-
dium 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 consid-
ered 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 as-
sessment 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 de-
pendent and have to be assessed with this principle in mind; they are evalu-
ated by a multidisciplinary team of experts, including both methodologists
and domain experts.
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 ap-
proach, 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 per-
forming sensitivity scenario analysis, which involves rerunning the evidence
synthesis under various conditions (e.g., including or excluding studies af-
fected 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 regard-
ing 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 rea-
son, 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 heteroge-
neity 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 uncer-
tainty (Hill, 1965), pooling studies should be done only if they meet the
criteria for a meta-analysis protocol. Additionally, when using the system-
atic 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, al-
lowing 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 pro-
cess, 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 cal-
cium and vitamin D. This evidence map shows that in human nutrition the

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 √ √ √ √b √b
Cancer
Colorectal √ √ √ √ —
Adenoma
Prostate — √ √ — —
Cancer
Vitamin D
All Cancers √ √ √ — √b
Breast — — √ — √b
Cancer
Colorectal √ √ √ — √b
Cancer
Colorectal √ √ √ — √b
Adenoma
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, p. 1020.
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, As-
sessment, Development and Evaluation (GRADE) can also be used to sum-

marize 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 ac-
count for the direction or magnitude of bias in the evidence (i.e., the biases
in individual studies). Assessors using GRADE must evaluate whether evi-
dence 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.
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 re-
view 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 signifi-
cant trade ties tend to share the work and expense of convening nutrient
reference panels (NASEM, 2018). 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.
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 organiza-
tion, 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 average requirements (ARs) and upper limits (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.
BOX 3-2
Steps That Guide Decision Making by a Nutrient Review Panel
When Updating or Adapting Existing NRVs
• Describe the basis for each nutrition reference value 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., average require-
ment, tolerable upper intake level, recommended intake, adequate intake)
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 fac-
tors 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 Harmo-
nization of Methodological Approaches to Nutrient Intake Recommendations, held in Rome,
Italy, September 21–22, 2017.

BOX 3-3
General Steps That Guide the Actions Undertaken by a
Nutrient Review Panel to Establish a New Nutrient Reference
Value (NRV)
• S et up an organizing or analytic framework to help formulate the ques-

tions for deriving a reference value, and define the protocol for a system-
atic review.
• Identify population, intervention/exposure, comparator, and outcome of
interest elements that are relevant for the indicator for the average re-
quirement or tolerable upper level intake. 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 crite-
ria, 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 evi-
dence 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 fac-
tors that could limit generalizability of the reference value or would
require consideration for adaptation (e.g., reference body weight,
genetics, environmental conditions).
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.
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 a safe upper 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 rela-
tionship 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. Typi-
cally, 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 there-
fore 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 param-
eters 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 re-
sponse 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 un-

certainties 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.
The Factorial Approach

As explained in Chapter 2, the factorial approach is useful with bio-
chemical indicators that are insensitive to nutrient levels. This approach is
generally used to set ARs for minerals because minerals cannot be metabo-
lized 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 physi-
ological 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 nutri-
ent kinetics, and to measure true absorption and retention rates.
As also stated in Chapter 2, the efficiency of mineral absorption (bio-
availability) 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, pp. 69–70) 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 lev-
els 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 ab-
sorption, the chemical form of the nutrient, supplements, nutrition and
health of the individual, excretory losses, and nutrient–nutrient interac-
tions. In addition, pathophysiologic changes can affect bioavailability; for
example, vitamin B12 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 nutri-
ent 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 nutri-
ents, 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 increas-
ingly 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 dis-
ease, and can also be useful for deriving a folate level that reduces the risk
of neural 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 re-
ducing chronic disease endpoints was recognized when the DRI framework

was first developed (IOM, 1994), because of insufficient data needed to set
an AR, only AIs have been derived at this point 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) limita-
tions in the data used as evidence, including data scarcity, and (2) shortcom-
ings 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 “Assess Uncertainty in the Evidence: Appraisal of 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 vari-
ability 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 expo-
sure) 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 (haz-
ard 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 vari-
ability 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 proba-
bilistic approach aimed at expressing the uncertainty factor as probability

distributions based on physiological considerations provides a more realis-

tic and less conservative approach.
Interindividual Variability
Generally, interindividual variability has a greater magnitude than in-
traindividual variability and consequently a greater influence on the deri-
vation 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.
Considerations around interindividual variability with important impli-
cations for deriving NRVs include the fact that the distribution of biologi-
cal 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 interindividual variability, is un-
known, because experimental trials with different doses in humans to iden-
tify potential thresholds for the occurrence of adverse effects are unethical.
In a systematic review, a way to estimate the interindividual variability is
to compute a weighted average of the sampling standard deviations of each
study in the review. Alternatively, a value for the interindividual variability
(e.g., expressed as a standard deviation) of between 10 and 15 percent of
the AR could be used (Cashman and Kiely, 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 two
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, 2010a); however, it remains a
challenge.
Expressing Uncertainty
Uncertainty affecting the estimate of an NRV can be expressed in sev-
eral ways. It can be expressed as an uncertainty factor that incorporates all
identified limitations in the data and possible shortcomings in the method-
ology. 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 val-
ues. Finally, one could provide a qualitative description of the plausibility
of a set of values for the parameter. However, more challenging quantita-
tive 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 recommended method of adjusting for this problem is
to measure at least 2 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., intraindividual to interindividual 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 1 day of intake data per person has been col-
lected, 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 et al., 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, lifestyle, 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 characteris-
tics, in some populations, genetic factors can influence dose–response rela-
tionships 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 con-
centration 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 extrapola-
tion of reference values.
Interpopulation 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 re-
quirements 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, inappropri-
ate 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 require-
ment or the upper intake level is proportional to body mass; for example,
adult requirements are often adjusted downward for children. When ex-
trapolating downward, 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 be-
tween 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 dif-
ferent 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, allome-
tric 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 ac-
tive 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 downward 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 previ-
ous 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 re-
quirement 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 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, coun-

tries or regions should look at existing values derived by expert pan-
els 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 out-
comes. The discussion below summarizes the differences between these
competing risk–benefit analyses and methods for managing this type of
uncertainty.

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

SOURCE: EFSA, 2010.
Competing Risk–Benefit Analyses

In contrast to nonessential food components, for which the process of
risk assessment1 was originally developed, essential nutrients satisfy a phys-
iological function. An evaluation of the effects of exposure to a nutrient in-
cludes 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, 2010b), 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).
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
1 Risk assessment is a process of (1) identification of risk of toxicity, (2) dose–response as-
sessment, (3) assessment of intakes outside the reference values, and (4) characterization of
risks associated with excess intake.

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).
NOTE: UL = safe upper intake level.
SOURCES: Presented by Amanda MacFarlane at the Health and Medicine Division workshop,
September 21, 2017. From Yetley et al., 2017.
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 in-
takes 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
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

Tools/Resources Data Approach/Methods Key Reference

Values
Dose−response
Nutrient status modeling
Systematic reviews
Health outcomes
Average
Physiological
requirement
requirement
Bioavailability Factorial approach
Databases Health factors (e.g., Recommended
infection) intake
Body size
Dietary patterns
Risk assessment* Upper limit
Nutrient intakes
Local and regional
Biomarkers
factors
Risk of chronic
disease
FIGURE 3-4 Framework for harmonizing the process for deriving nutrient reference values
(NRVs).
NOTES: There are four major steps to setting key NRVs: (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 average requirement and tolerable upper intake level. Components are shown
below each step.
* Risk assessment is a process of (1) identification of risk of toxicity, (2) dose–response as-
sessment, (3) assessment of the prevalence of intakes outside the reference values, and (4)
characterization of risks association with excess intake.
prevention of chronic diseases is taken into consideration concurrently with

the avoidance of adverse effects.
A FRAMEWORK FOR DERIVING NUTRIENT REFERENCE VALUES

Based on its review of the strengths and weaknesses in available method-
ologies, 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, three primary tools are needed to
develop NRVs: systematic reviews, comprehensive databases, and
information about relevant local and regional factors (local con-
text) that can influence NRVs.
2. Collect data from those tools—Data that are essential for under-
standing and selecting biomarkers of status, including pregnant and
lactating women and young children; health outcomes; the influ-

ence 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 deter-
mine 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 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.
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
conclusion 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.
Findings on the Process of Setting Nutrient Reference Values

General principles for setting NRVs are summarized in Box 3-4. In-
cluded 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.
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., interindividual variability in a study population);

• flaws in study design;
• risk of bias;
• extrapolation from one population subgroup to a different, unre-
lated 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.
Identifying a strategy for managing uncertainties is critical to main-

taining the accuracy and relevance of all NRVs as well as assuring
BOX 3-4
General Principles for Setting
Nutrient Reference Values (NRVs)
• T ransparency: 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. Inter-
est 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 consideration and what
outcomes are being evaluated. The population, intervention/exposure,
comparator, and outcome of interest method is invaluable in formulating
questions regarding the population, intervention/exposure, c omparator 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 determi-
nation 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.

the credibility of the evidence analysis. A thorough understanding

of the uncertainties that affect the nutrient review process under-
pins 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 ap-
proaches 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 refer-
ence 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 re-
quired to undertake the development or revision of existing refer-
ence 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 (NRVs), to achieve transparency the nutrient review
expert panel should clearly report the reference population, adjust-
ment factors, and the methodology used. Expert panels should also
document the uncertainty in the evidence and in the methods used
to develop the NRVs 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.
CHAPTER SUMMARY
In summary, the committee’s examination of the steps used to develop
NRVs identified several new tools in the process that enhance the trans-
parency, 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. Medi-
cal Decision Making 33(5):618-640.
EFSA (European Food Safety Authority). 2010a. Scientific opinion on principles for deriving
and applying dietary reference values. EFSA Panel of Dietetic Products, Nutrition, and
Allergies (NDA). EFSA Journal 8(3):1458.
EFSA. 2010b. 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. En-
ergy and protein requirements. Report of a joint FAO/WHO/UNU expert consultation.
World Health Organization Technical Reports Series 724:1-206.
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-codex
alimentarius/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 statisti-
cal 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). 1994. How should the recommended dietary allowances be
revised? Washington, DC: National Academy Press.

IOM. 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:
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 Sciences). 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).
NASEM (National Academies of Sciences, Engineering, and Medicine). 2017. Guiding prin-
ciples 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 rec-
ommendations: Proceedings of a Workshop. Washington, DC: The National Academies
Press. https://doi.org/10.17226/25023.
National Toxicology Program. 2015. Handbook for conducting a literature-based health as-
sessment using OHAT approach for systematic review and evidence integration. Washing-
ton, 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.
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 refer-
ence intake development. Critical Reviews in Food Science and Nutrition 50(Suppl.
1):33-34.
SADC (Southern African Development Community). 2014. Food and nutrition security strat-
egy 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 cal-
cium 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)
Suppl. 1:S101-S115.

Tooze, J. A., D. Midthune, K. W. Dodd, L. S. Freedman S. M. Krebs-Smith, A. F. Subar, P. M.

Guenther, R. J. Carroll, and V. Kipnis. 2006. A new statistical method for estimating
the usual intake of episodically consumed foods with application to their distribution.
Journal of the American Dietetic Association 106(10):1575-1587.
Turner, R. M., D. J. Spiegelhalter, G. C. Smith, and S. G. Thompson. 2009. Bias modelling in
evidence synthesis. Journal of the Royal Statistical Society, Series A Statistics in Society
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 bas-
ing 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-285S.

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 method-

ological 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, zinc, iron, and folate. This chapter summarizes the
committee’s application of its proposed framework for deriving NRVs
for these exemplar nutrients. The committee did not carry out an analysis
for the two population subgroups for each nutrient. Rather, the three nutri-
ents were s elected 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 d escribes 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 method-
ologies for deriving NRVs on a global scale and a discussion of the applica-
tion of NRVs in low- and middle-income countries.
The committee was not tasked with actually setting NRVs for the ex-
emplar nutrients. Additionally, because the nutrient review process applies
to nutrients derived from the diet, not from supplements, although supple-
ments 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.
73

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 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., infec-
tion, 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 de-
tailed 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 fea-
sibility of its recommendations for harmonizing methodologies for deriv-
ing 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,

APPLYING METHODOLOGICAL APPROACHES TO NRVs 75
FIGURE 4-1 Flow diagram for using the factorial approach or dose–response assessment in
deriving nutrient reference values (NRVs) for zinc and iron, or the dose–response modeling
for folate.
NOTES: This figure represents a detailed subset of the flow diagram for deriving NRVs shown
in Figure 3-1. No actual derivation of NRVs was carried out by the committee.
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 method-
ologies used to derive them is discussed; finally, the derivation of ARs and
ULs is 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 pro-
posed solutions for future recommendations regarding each nutrient. In

Chapter 5, the committee discusses consideration of data gaps and options

for moving toward harmonization.
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 par-
ticularly 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, 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 diar-
rheal infections (King et al., 2016).
Factors Influencing Zinc Requirements

A number of contextual factors affect the zinc requirement of a popu-
lation. 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 in-
creases, 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, endog-
enous 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 diar-
rheal 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 mani-
festations 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 re-
current 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 reproduc-
tive performance problems, and impair work capacity (Bernhardt et al.,
2012; 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 cere-

als 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 irriga-
tion 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, al-
though the availability of zinc from diets with phytate: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 ab-
sorption 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 ad-
equate, regardless of whether phytate concentration was either low or high
(Hunt and Beiseigel, 2009).
Generally, zinc absorption is enhanced by dietary protein (both quan-
tity 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). Diar-
rheal 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 supplemen-
tal 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).
Assessment of Strengths and Weaknesses in

Methodologies to Determine Zinc Requirements
The committee assessed the strengths and weaknesses of all three meth-
ods 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 di-
etary 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 et al., 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. 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

TABLE 4-1 Health Outcomes Associated with Inadequate Zinc Intakes

for Various Population Subgroups
Pregnant and
Infants Children and Adolescents Lactating Women
Growth Growth Fetus:
Immune response to vaccination Immune function Growth
Neurodevelopment Cognitive function Malformation
Dermatitis Mother:
Preeclampsia
Preterm delivery
SOURCE: Adapted from Lowe et al., 2013.
associated with inadequate zinc intakes in the population subgroups ad-

dressed in this report are identified in Table 4-1.
Factorial Approach
Given the aforementioned limitation of the balance method, and be-
cause 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 re-
quirement. This approach requires estimating the amount of absorbed zinc
needed to replace endogenous zinc losses, as well as estimating the endog-
enous zinc losses, including both endogenous fecal zinc (EFZ) losses and
nonintestinal losses via the urine, integument (skin, hair, nails, and sweat),
menstrual flow in women, and semen in men. As stated previously, total
nonintestinal losses are constant over a wide range of zinc intake (4–25
mg/d) (IOM, 2001). 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 rec-
ommended 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.

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 nonintestinal endogenous losses (mg) 0.60 1.27 1.15 1.14
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 nonintestinal endogenous losses (mg) 0.50 1.00 0.80 0.63
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: EFSA = European Food Safety Authority; IOM = Institute of Medicine; IZiNCG =
International Zinc Nutrition Consultative Group; WHO = World Health Organization.
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 require-
ments 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 needs 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, the International Zinc Nutrition Consultative
Group (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

FIGURE 4-2 The relationship among total absorbed zinc (TAZ), dietary phytate, and total
dietary zinc.
SOURCE: EFSA NDA Panel, 2014a.
itself is based on 650 individual measurements from 18 publications, the

European Food Safety Authority (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, 2014a). 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/
Food and Agriculture Organization (FAO), IZiNCG, and EFSA are listed
in Table 4-3.
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 gen-
der 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. Because 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 body mass index 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).
Determination of zinc ARs and RIs for infants and children Among infants
and children, the physiological zinc requirement equals the total endog-
enous 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 tis-
sue 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

84
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
Physiol Physiol
Wt requirements AR RI Wt requirements AR RI
Age, Sex (kg) (mg/d) (mg/d)a (mg/d)a Age, Sex (kg) (mg/d) (mg/d) (mg/d)
7–12 mo 9 0.84 ––b 2.5 7–12 mo 9 0.84 2.2 3.0
1–3 yrs 12 0.83 1.66 2.4 1–3 13 0.74 2.2 3.0
3–6 yrs 17 0.97 1.94 2.9 4–8 22 1.20 4.0 5.0
6–10 yrs 25 1.12 2.25 3.3
10–12 M 35 1.40 2.80 5.1c 9–13 40 2.12 7 8
10–12 F 37 1.26 2.38 4.3c
12–15 M 48 1.82 3.65
12–15 F 48 1.55 3.07

15–18 M 64 1.97 3.90 14–18 M 64 3.37 8.5 11
15–18 F 55 1.54 3.08 14–18 F 57 3.02 7.5 9

IZiNCG EFSA
Physiol Physiol
Wt requirements AR RI Wt Req AR RI
Age, Sex (kg) (mg/d) (mg/d) (mg/d) Age, Sex (kg) (mg/d) (mg/d) (mg/d)
6–11 mo 9 0.84 3 4 7–11 mo 2.4 2.9
1–3 12 0.53 2 3 1–3 11.9 1.074 3.6 4.3
4–8 21 0.83 3 4 4–6 19.0 1.390 4.6 5.5
7–10 28.7 1.869 6.2 7.4
9–13 38 1.53 5 6 11–14 M 44 2.635 8.9 9.4
11–14 F 45 2.663 8.9 9.4
14–18 M 64 2.52 8 10d 15–17 M 64 3.544 11.8 12.5

14–18 F 56 1.98 7 9d 15–17 F 56 2.969 9.9 10.4
NOTE: AR = average requirement; EFSA = European Food Safety Authority; IOM = Institute of Medicine; IZiNCG = International Zinc Nutrition
Consultative Group; Physiol = physiological; RI = recommended intake; WHO = World Health Organization; wt = weight.
a WHO AR and RI values included here were estimated for high bioavailability (50 percent).
b 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.
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.

85
(see Table 4-3). Estimates of total endogenous losses were determined by

extrapolation from adult values, based on metabolic weight (WHO) or ref-
erence body weights (the IOM, IZiNCG, EFSA) (extrapolation is explained
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 di-
etary 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 to 5.5 mg/day. Among school-age children
from 7–13 years of age, AR estimates range from 7 to 9 mg/d, which trans-
lates to an RI of 6 to 9.4 mg/day. For adolescents aged 14–18 years, AR
estimates range from 8 to 11 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 high zinc bio-
availability (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 subsist-
ing 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 bioforti-
fied 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 (Ariff,
2014; Chomba, 2015).
Also of relevance, previous studies have shown that supplemental iron

reduces zinc absorption (Chung et al., 2002; O’Brien et al., 2000). How-
ever, a recent study of 6-month-old, nonanemic infants showed that the
addition of iron to micronutrient powders did not reduce zinc absorption
(Esamai et al., 2014). This is an encouraging finding as iron and zinc defi-
ciencies 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
et al., 2015), which raises questions about using the dietary phytate:zinc
molar ratios to predict dietary zinc absorption and, therefore, the zinc AR.
Determination of the 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 physi-
ological 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/FAO, 2004). No adapta-
tions 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, 2001; 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 quar-
ters 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 (the 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 concen-
trations, 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 assump-

88
TABLE 4-4 Zinc Average Requirement (AR) and Recommended Intake (RI) During Pregnancy and Lactation by
WHO, the IOM, IZiNCG, and EFSA
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
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.

tion 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, 2014a).
EFSA NDA Panel (2014a) also estimated RIs for nonpregnant and non-
lactating 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 addi-
tional 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-old children. EFSA did not derive a
UL for any life stage group.
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 recom-
mended 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 as-
sessing 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) causes a marked, rapid decline in plasma zinc,
it can take weeks for levels to return to baseline upon zinc reple-
tion. 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 concentra-
tions 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 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 deter-
minant 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, 2014a). 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 recom-
mendations need to be matched to the amount and type of protein
in the diet (i.e., animal or vegetable). When developing zinc supple-
mentation 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 vul-
nerable to developing zinc deficiency and are more prone to de-
velop 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:
Additional data are needed to determine if age or physiological zinc

need influence the effect of phytate on zinc absorption.
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 enhanc-
ing 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.
Since the zinc physiological requirements and ARs for young chil-
dren 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 con-
solidate these estimates globally. However, there may still be a need
to set national RIs based on the dietary zinc source (i.e., bioavail-
ability) and the average body size of the population.
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 chil-
dren, 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 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.
PROPOSED SOLUTIONS FOR ZINC1

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 recom-
mendations. 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 dietary zinc than plasma/serum zinc concentra-
tions, studies are needed to help identify the potential influence of genetic
polymorphisms (i.e., genetic variations) on individual dietary zinc require-
ments. Furthermore, the development of comprehensive models of inhibi-
tors of zinc a bsorption across diverse populations would improve estimates
of dietary requirements.
IRON CASE ANALYSIS

Iron deficiency is a 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
1 This text was revised after prepublication release.

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 require-
ments of a population. In addition to the dietary intake pattern described
above, these include the physiological state of an individual or group, envi-
ronmental 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 require-
ments 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 deter-
mined in the absence of disease by the size of body iron stores. The iron sta-
tus 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 ki-
logram 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 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 prepara-
tion 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 Harmoni-
zation 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 regula-
tion (Nemeth and Ganz, 2009).

Infection
Seth Adu-Afarwuah, in his presentation at the Global Harmonization
workshop (NASEM, 2018), 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).
Assessment of Strengths and Weaknesses in

Methodologies to Derive Iron ARs
Although attempts have been made to define a dose–response relation-
ship 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 ap-
proach for deriving NRVs. In a series of systematic reviews undertaken
by the European Micronutrient Recommendations Aligned (EURRECA),
a large degree of heterogeneity among the study populations, iron doses,
and outcome measures was found (Harvey et al., 2013). This heterogene-
ity 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 system-
atic review (NNR, 2004), the Nordic Council of Ministers attempted to
determine the relationship between iron intake and adequate growth, de-
velopment, and health maintenance (Domellof et al., 2013). A total of 55
articles were identified as relevant, and the evidence was assessed using the
Grading of Recommendations, Assessment, Development and Evaluation
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 varia-
tions 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 rela-
tive 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 ap-
proach 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 propor-
tion 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 calculating total loss, if the dis-
tributions 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

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
EFSA
NDA
WHO/ IOM D-A-CH NNR Aus/NZ NL UK COMA Panel
FAO (2004) (2001) (2015) (2012) (2017) (1992) (1991) (2015)
Premenopausal
Median basal iron losses (mg/d) 0.87 1.4 1.54 1.35 1.6 1.56 1.34
Bioavailability factor (percent) 12–15: 18 10–15 15 18 12 15 18
meat-based
5–10:
cereal-based
AR (mg/d) — 8.1 — 9 8 14 11.4 7
Pregnancy
Total cost of pregnancy (mg) 840 700–800 800 1,040 680 835
AR (mg/d) — 23 (14–18 y) — 9 23 (14–18 y) 9: 1st tri 14.8 7
22 (> 18 y) 22 (≥ 19 y) 14: 2nd tri
18: 3rd tri
Lactation
Milk secretion (mg/d) 0.3 0.27 0.25–0.34
Bioavailability factor (percent) — 18 18
AR (mg/d) — 6.5 — 9 7 (14–18 y) 19 11.4 7
6.5 (≥ 19 y)
NOTE: AR = average requirement; 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; NDA = nutrition, novel foods, and allergens; NL

= Netherlands Food and Nutrition Council; NNR = Nordic Nutrition Recommendations; tri = trimester; UK COMA = United Kingdom Committee
on Medical Aspects of Food and Nutrition Policy; WHO/FAO = World Health Organization/Food and Agriculture Organization.
97
Number of Subjects
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.
data from Hallberg et al. (1966a,b) 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 interindividual 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 h emoglobin
of 3.39 mg/g;2 assuming a 28-day cycle, this equates to 0.51 mg/d of men-
strual loss.
The EFSA Dietetic Products, Nutrition, and Allergies (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 distribu-
tion 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.
2 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.

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 percentiles, the values are 1.34 (50th percentile),
2.8–2.94 (95th percentile), and 3.13–3.15 (97.5th percentile).
Estimating ARs for pregnancy Different authoritative bodies’ estimates

of the total iron cost of pregnancy and ARs for pregnancy are also sum-
marized 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 preg-
nancy. There are two main reasons for this disparity in iron recommenda-
tions 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 (Barrett et al.,
1994; Whittaker et al., 1991). 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 preg-
nancy 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). Al-
though 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 suf-
ficient iron stores, WHO/FAO’s estimated net pregnancy iron requirement
is 840 mg. Similarly, the United Kingdom Committee on Medical Aspects
of Food and Nutrition Policy 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.
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 gastroin-
testinal side effects caused by high iron intakes. A lowest observed adverse
effect level (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 approxi-
mates to a UL of 45 mg/day.
Similarly, the Australia/New Zealand report based its ULs for iron on
gastrointestinal symptoms. For adults, an 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 extrapolate from the LOAEL, resulting in a UL of 45 mg/d after round-
ing. Because of the limited data available, the same figure was applied to
pregnant and lactating women.

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 NDA Panel, Assuming the total requirement for absorbed iron during the
2015 first months of lactation to be 1.3 mg/d, no increase in AR was
recommended.
NOTE: AR = average requirement; D-A-CH = Nutrition Societies of Germany, Austria,
and Switzerland; EFSA = European Food Safety Authority; IOM = Institute of Medicine;
NDA = nutrition, novel foods, and allergens; NL = Netherlands Food and Nutrition Council;
NNR = Nordic Nutrition Recommendations; RI = recommended intake; UK COMA = United
Kingdom Committee on Medical Aspects of Food and Nutrition Policy; WHO/FAO = World
Health Organization/Food and Agriculture Organization.
The Nordic Council of Ministers (2012) was unable to set a quantita-

tive 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 premeno-
pausal 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 bio-
availability 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 us-
ing 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 physiologi-
cal 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 diffi-
cult because of limited information on heme iron in food composi-
tion 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 physiolog-
ical 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:
At present, the factorial approach is the only feasible option for

deriving iron NRVs, and values for iron availability need to take

into account the usual dietary composition of the population,

which may result in differences in NRVs, as illustrated by WHO’s
approach in which it provides values for four different global
scenarios.
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.
There are challenges for setting an iron UL, but the value is es-
sential 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 glob-
ally, there remains wide variation in NRVs determined for women of repro-
ductive 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 bur-
dens of infection or other widespread health concerns, such as hemoglo-
binopathies 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

The global prevalence of folate deficiency and depletion is not well
documented, but data are in the process of being added to WHO’s Vita-
min and Mineral Nutrition Information System (VMNIS).3 Populations
in low- and middle-income countries are not necessarily at greater risk of
3 Available at http://www.who.int/vmnis/en (accessed May 16, 2018).

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.
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.
Factors Influencing Folate Requirements

Two key factors affect the folate requirements of a population: bio-
availability and several specific genetic polymorphisms. Both of these are
reviewed below.
Bioavailability
The primary dietary sources of folate are legumes, green leafy veg-
etables, 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 underesti-
mate actual folate content owing to incomplete release of the folate prior
to analysis and incomplete hydrolysis of the polyglutamyl folates. Diges-
tion 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 bioavailabil-
ity 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 per-
cent 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.
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 par-
ticular authoritative bodies were selected because their recommendations
were made within the last 20 years.
Several other potential markers of folate adequacy have been consid-
ered by various authoritative bodies, but they have not been used in deriv-
ing 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 psy-
chiatric 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, eryth-
rocyte folate, and plasma homocysteine) (IOM, 1998). Cut-point values
for “normal” were defined based on associations with biochemical abnor-
malities. 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 show-
ing 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 val-
ues 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 concentra-
tions. 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

TABLE 4-7 Comparison of Factors Used in Dose–Response Modeling for Folate in Women of Reproductive Age
NNR (Herbert
et al., 1962; Australia/ EFSA
WHO/FAO IOM Milne et al., 1983; New Zealand (Milne et al., 1983;
(O’Keefe et al., (O’Keefe et al., Sauberlich et al., (O’Keefe et al., Sauberlich et al.,
1995) 1995) D-A-CH 1987) 1995) 1987)
Biomarkers:
RBC folate (nmol/L) > 305 > 305 > 317 — > 340
Serum folate (nmol/L) > 10 >7 > 10 > 6.8 — > 10
Erythrocyte folate > 340

(nmol/L)
Homocysteine < 16 < 16 9.3–16.3 —

(µmol/L)
AR DFE (µg/d) 400 400 220 300 400 220
NOTE: AR = average requirement; D-A-CH = Nutrition Societies of Germany, Austria, and Switzerland; DFE = dietary folate equivalents; EFSA =
European Food Safety Authority; IOM = Institute of Medicine; NNR = Nordic Nutrition Recommendations; RBC = red blood cell; WHO/FAO =
World Health Organization/Food and Agriculture Organization.

107
108
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 biomarkers 320 320 220 320 250
(DFEa µg/d)
Bioavailability factor (%)b 50 50 50 50 50
AR (DFE µg/d) 320 320 220 320 250
Pregnancy
Total basal requirement (DFE µg/d) 320 320 220 320 320
AR (DFE µg/d) 520 520 420 520 —
Lactation
Milk secretion (DFE µg/d) 130 130 120 133 130
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 factor — — 700 kcal/d required × 12 Weight0.75 Weight0.75
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 factor Weight0.75 Weight0.75 Weight0.75 Weight0.75 Weight0.75
Growth factor 0.3 v0.3 0.3 0.3 0.3
AR (DFE µg/d) 120 120 79.8 (males) 120 80
92 (females)
Children 4–8 years
Extrapolation factor Weight0.75 Weight0.75 Weight0.75 Weight0.75 Weight0.75
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
NOTE: AI = adequate intake; AR = average requirement; Aus/NZ = Australia/New Zealand; D-A-CH = Nutrition Societies of Germany, Austria,
Switzerland; EFSA = European Food Safety Authority; IOM = Institute of Medicine; WHO/FAO = World Health Organization/Food and Agriculture
Organization.
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.

109
(O’Keefe et al., 1995) used by the IOM. Germany, Austria, and 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 vita-
mins 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 differ-
ent authoritative bodies (the IOM, WHO/FAO, D-A-CH, Australia/New
Zealand, 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 sum-
marized 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 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 downward 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 fac-
tors 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 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 appli-
cable 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 downward 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 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 re-
quirements that depend on breast milk folate concentration. Folate
requirements are not affected by maternal status or intake, or bio-
availability from different foods (except for the higher bioavailabil-
ity 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 percentage of Africans. There appears to
be large variability in prevalence across Asian populations. Com-
pared 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:
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 be-
tween intakes calculated from older food composition data versus
more recent estimates based on measures of folate status.
While the cooking technique affects the amount of folate required

from food sources, it does not affect physiological requirements.

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 popula-
tions 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 monitor-
ing folate status may be especially important in populations with a
high prevalence of vitamin B12 deficiency since there is some evi-
dence that a high folic acid intake may exacerbate B12 deficiency.
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.
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.
There is no evidence that deficiencies or high intakes of other mi-

cronutrients affect folate requirements.
PROPOSED SOLUTIONS FOR FOLATE

Folate recommendations for women and children are remarkably simi-
lar 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 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 develop-
ment of targeted intervention programs, such as food assistance or forti-
fication 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; aca-
demic 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.
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. As-
sessment 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 IZiNCG Steering Committee. 2009a. Galvanizing action: Con-
clusions 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 supplementa-
tion among infants, preschoolers, and older prepubertal children. Food and Nutrition
Butterworth, C. E., and T. Tamura. 1989. Folic acid safety and toxicity: A brief review. Ameri-
can 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 require-
ments 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. Estima-
tion 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.
Department of Health. 1991. Dietary reference values for food energy and nutrients. Report of
the panel on dietary reference values of the committee on medical aspects of food policy.
Report on health and social subjects 41. London HMSO.
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). https://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.
EFSA NDA Panel (European Food Safety Authority Panel on Dietetic Products, Nutrition, and
Allergies). 2004. Scientific opinion on dietary reference values for iron. EFSA Journal
80(1-22).
EFSA NDA Panel. 2014a. Scientific opinion on dietary reference values for zinc. EFSA Journal
12(10):3844 (revised May 20, 2015).
EFSA NDA Panel. 2014b. Scientific opinion on dietary reference values for folate. EFSA
Journal 12(11):3893. https://doi.org.10.2903/j.efsa.2014.
EFSA NDA Panel. 2015. Scientific opinion on dietary reference values for iron. EFSA Journal
13(10):4254. https://doi.org.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 af-
fected 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. Ameri-
can 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 diversifica-
tion or modification strategies with the potential to enhance intakes of total and absorb-
able 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-Hultén. 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 popu-
lation 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.
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.
Harvey, L. J., C. Berti, A. Casgrain, I. Cetin, R. Collings, M. Gurinovic, M. Hermoso, L.
Hooper, R. Hurst, B. Koletzko, J. Ngo, B. R. Vinas, C. Volhardt, V. Vucic, and S. J.
Fairweather-Tait. 2013. EURRECA-estimating iron requirements for deriving dietary
reference values. Critical Reviews in Food Science and Nutrition 53(10):1064-1076.
Herbert, V., N. Cunneen, L. Jaskiel, and C. Kapff. 1962. Minimal daily adult folate require-
ment. 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.
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 inhibi-
tion 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.

International Zinc Nutrition Consultative Group (IZiNCG), K. H. Brown, J. A. Rivers, Z.

Bhutta, R. S. Gibson, J. C. King, B. Lönnerdal, M. T. Ruel, B. Sandström, E. Wasantwisut,
and C. Hotz. 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.
IOM (Institute of Medicine). 1998. Dietary Reference Intakes for thiamin, riboflavin, niacin,
vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC:
IOM. 2001. Dietary Reference Intakes for vitamin A, vitamin K, arsenic, boron, chromium,
copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Wash-
ington, 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., 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 recom-
mendations 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.
Lynch, S. 2011. Case studies: Iron. American Journal of Clinical Nutrition 94(2):6735-6785.
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.
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 ha-
bitual diets of Indians studied by the extrinsic tag technique. Indian Journal of Medical
Research 77:648-657.

org/10.17226/25023.
National Health and Medical Research Council, Australian Government Department of
Health and Aging, New Zealand Ministry of Health. 2006. Nutrient reference values
for Australia and New Zealand. Canberra, Australia: National Health and Medical
Research Council.
Nemeth, E., and T. Ganz. 2009. The role of hepcidin in iron metabolism. Acta Haematologica
122:78-86.
NNR (Nordic Nutrition Recommendations). 2004. Nordic Nutrition Recommendations, 4th
ed. Nord 2004:13.
Nordic Council of Ministers. 2012. Nordic Nutrition Recommendations 2012: Integrat-
ing nutrition and physical activity, 5th ed. Copenhagen, Sweden: Nordic Council of
Ministers. https://doi.org/10.6027/Nord2014-002 (accessed June 3, 2018).
NRC (National Research Council). 1989. Recommended dietary allowances, 10th ed. Wash-
ington, DC: National Academy Press. 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.
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 liq-
uid 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. Exchange-
able zinc pool masses and turnover are maintained in healthy men on low zinc intakes.
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 hu-
man 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 Nutri-
tion 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 Nu-
trition 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. https://doi.
org/10.3390/nu5103920.

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.
Voedingsraad, Nederlandseroedingsnorman. 1989, 1992. Voorlichtingsbureau voor de Voed-
ing: Den Haag. Pp. 1-293.
Wapnir, R. A. 2000. Zinc deficiency, malnutrition and the gastrointestinal tract. Journal of
Nutrition 130(Suppl. 5):1388S-1392S.
Wapnir, R. A., and L. Stiel. 1986. Zinc intestinal absorption in rats: Specificity of amino acids
as ligands. Journal 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 diar-
rhoeal disease in the next 15 years. PLoS Medicine 10(5):e1001446.
Wessels, K. R., G. M Singh., and K. H. Brown. 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: World
Health Organization.
WHO/UNICEF (United Nation’s Children Fund). 2004. Clinical management of acute diar-
rhea. Geneva, Switzerland: World Health Organization/United Nation’s Children Fund.

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 back-
ground, the committee examined the strengths and weaknesses of current
approaches, evaluated their application to two high-risk population sub-
groups, young children (birth through 5 years of age) and women of repro-
ductive age, and assessed the feasibility of harmonizing methodologies to
derive NRVs on a global scale. While it was beyond the committee’s scope
approach to deriving NRVs, it did consider possible next steps toward
implementation. This final chapter reiterates the advantages of the harmoni-
zation of approaches used to derive NRVs; considers options and strategies
to facilitate harmonization; and identifies data gaps that need to be filled.
121

ADVANTAGES OF HARMONIZING METHODOLOGIES

TO DERIVE NUTRIENT REFERENCE VALUES
Building on the work of King and Garza (2007), the committee iden-
tified several additional reasons to harmonize the approach to deriving
NRVs. First, a harmonized approach will prioritize the derivation of the
average requirements (ARs) and tolerable upper intake level (UL). Currently
many countries and/or organizations do not appreciate that deriving values
for ARs and 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, 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 United Nations’ 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 frame-
work for harmonizing NRVs proposed in the King and Garza (2007)
report. Moving forward will require overcoming the barriers to implemen-
tation that clearly exist and that were discussed at the Global Harmoni-
zation 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.

FUTURE DIRECTIONS AND DATA GAPS 123
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 composi-
tion 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 in-
formation 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 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 Nutritional Sciences
(IUNS). Such a manual could become an important mechanism for com-
municating information with a majority of nutrition societies internation-
ally, as well as to academic institutions that teach nutrition. Such a manual
could also be used for explaining the importance of harmonization, includ-
ing 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;
1 Available at http://www.who.int/vmnis/en (accessed May 16, 2018).

• 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 inad-
equate 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 support-
ing 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 (see 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 har-
monizing the approach to deriving NRVs globally, future dialogue will be
needed across countries to garner support for a harmonization effort and
to identify a pathway for implementing the recommendations of this re-
port. It is the committee’s view that achieving global harmonization of the

FUTURE DIRECTIONS AND DATA GAPS 125
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 har-
monization 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 har-
monization 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 com-
mittee 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 communica-
tion) 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 popula-
tions. 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
org/10.17226/25023.

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 as-
sociated 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 nutri-
ent. 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 ad-
equacy. It is used by the European Food Safety Authority.
Dietary Reference Intake (DRI) – In this report, this term refers to the val-
ues produced jointly by the United States and Canada. The values under
this umbrella term are the estimated average requirement (EAR), recom-
127

mended 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 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 (SULs), 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.
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.
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.
lowest 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.
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).

APPENDIX A 129
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 nutri-

ent 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 unde-
sirable 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.
REFERENCES
King, J. C., H. H. Vorster, and D. G. Tome. 2007. Nutrient intake values (NRVs): A recom-
mended terminology and framework for the derivation of values. Food and Nutrition


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 dif-
ferent 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 meth-
odologies for nutrient intake recommendations.
• Identify the advantages, barriers, and challenges to global har-
monization of methodologies to establish nutrient intake
recommendations.
131

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
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, Emerita, 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

APPENDIX B 133
10:50 Discussion with Session Speakers
11:10 Break
11:30 Panel Discussion: Current Models for Establishing Intake

Recommendations
Canada: 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
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
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, Emerita, 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

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?
• 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

APPENDIX B 135
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, tool kits, technical
briefs
• Potential for acceptance of methodological approaches
across countries
• Potential ways forward
1:00 pm Chair’s Summary and Discussion of Next Steps

Committee Chair
1:30 Adjourn Meeting


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 lon-
gevity 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 Con-
sortium 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).
137

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.

APPENDIX C 139
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 devel-
opment, reporting and evaluation in healthcare. Canadian Medical Association Journal
182:E839-E842.


Appendix D
Tools and Methods to Evaluate the

Risk of Bias in Individual Studies
Below are examples of tools and methods that were developed to mea-
sure the strength of various studies as well as the risk of bias in random-
ized 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
Tool Applicable Setting Institution Reference
Office of Health Experimental National Toxicology https://ntp.niehs.nih.
Assessment and animal studies, Programme (NTP) gov/ntp/ohat/pubs/
Translation Risk of human randomized riskofbiastool_508.
Bias (RoB) Tool controlled trial pdf (accessed
(RCT), human August 6, 2018)
observational
RoB 2.0 Risk of bias in Cochrane https://sites.
randomized trials collaboration google.com/site/
riskofbiastool/
welcome/rob-2-
0-tool (accessed
August 6, 2018)
continued
141

Study Design or
Tool Applicable Setting Institution Reference
Robins-I Risk of bias in Cochrane https://sites.
nonrandomized collaboration google.com/site/
studies of riskofbiastool/
interventions welcome/home
(accessed August 6,
2018)
RoB Diagnostic Risk of bias in Cochrane Canada http://training.
Test Accuracy diagnostic test cochrane.
accuracy org/resource/
primer-cochrane-
diagnostic-test-
accuracy-reviews
(accessed August 6,
2018)
Tool to assess risk Risk of bias in CLARITY Group https://www.
of bias in cohort cohort studies evidencepartners.
studies com/resources/
methodological-
resources (accessed
August 6, 2018)
Tool to assess Risk of bias in RCT CLARITY Group https://www.
risk of bias in evidencepartners.
randomized com/resources/
controlled trials methodological-
resources (accessed
August 6, 2018)
Tool to assess risk Risk of bias in case CLARITY Group https://www.
of bias in case control studies evidencepartners.
control studies com/resources/
methodological-
resources (accessed
August 6, 2018)
SOURCE: Adapted with permission from EFSA et al., 2018.
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 be-
hind EFSA’s Guidance on Uncertainty Analysis in Scientific Assessment. EFSA Journal
16(1):5122-5235.

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).
REFERENCE
IOM (Institute of Medicine). 2002/2005. Dietary Reference Intakes for energy, carbohydrate,
fiber, fat, fatty acids, cholesterol, protein, and amino acids. Washington, DC: The Na-
tional Academies Press. https://doi.org/10.17226/10490.
143

TABLE E-1 Extrapolation by Scaling
144
Allometric, E
Nutrient Extrapolation xponent; 0.75 Isometric Growth Factor Other
Choline AI adult →AI child yes yes
AI 0–6m→AI 7–12m yes no
Biotin AI 0–6m→AI 7–12m, 1–18y, yes no
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 1–3 and 4–8y yes no

5mg/kg/d
Potassium AI adult→AI 1–18y AI child = AI adult × F
F = energy intakechild/
energy intake adult
UL child = UL adult × F
F= energy intake adult/
UL adult →UL child energy intake child
Sodium Same as potassium
Vitamin A, chromium, EAR/AI adult→EAR/AI child yes yes
copper, molybdenum, (no extrapolation for iodine
iodine for 1–3 y and 4–8 y old) yes
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

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
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
EAR adult→AI 7–12m yes no
UL adult →UL child yes yes
yes no
Folate AI 0–6m →AI 7–12m yes no
EAR adult→EARchild yes yes
UL adult →UL child yes no
Vitamin B12 EAR adult→EARchild 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

Selenium AI 0–6m →AI 7–12m yes no

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.
145

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
147

EFSA GROWTH FACTORS

Maintenance Growth Average
Requirement Requirement Requirement Calculated
(g protein/ (g protein/ for Protein Growth
Age kg per day) kg per day) (g/kg per day) Factor Growth Factor
(years) (A) (B) (A+B) (B/A) per Age Group
Boys
0.5 0.66 0.46 1.12 0.70 7–11 mo: 0.57
1 0.66 0.29 0.95 0.44
1 0.66 0.29 0.95 0.44 1–3 yrs: 0.25
2 0.66 0.13 0.79 0.20
3 0.66 0.07 0.73 0.11
4 0.66 0.03 0.69 0.05 4–6 yrs: 0.06
5 0.66 0.03 0.69 0.05
6 0.66 0.06 0.72 0.09
7 0.66 0.08 0.74 0.12 7–10 yrs: 0.13
8 0.66 0.09 0.75 0.14
9 0.66 0.09 0.75 0.14
10 0.66 0.09 0.75 0.14
11 0.66 0.09 0.75 0.14 11–14 yrs:
12 0.66 0.08 0.74 0.12 0.11
13 0.66 0.07 0.73 0.11
14 0.66 0.06 0.72 0.09
15 0.66 0.06 0.72 0.09 15–17 yrs:
16 0.66 0.05 0.71 0.08 0.08
17 0.66 0.04 0.70 0.06

APPENDIX F 149
Maintenance Growth Average

Requirement Requirement Requirement Calculated
(g protein/ (g protein/ for Protein Growth
Age kg per day) kg per day) (g/kg per day) Factor Growth Factor
(years) (A) (B) (A+B) (B/A) per Age Group
Girls
0.5 0.66 0.46 1.12 0.70 7–11 mo: 0.57

1 0.66 0.29 0.95 0.44
1 0.66 0.29 0.95 0.44 1–3 yrs: 0.25
2 0.66 0.13 0.79 0.20
3 0.66 0.07 0.73 0.11
4 0.66 0.03 0.69 0.05 4–6 yrs: 0.06
5 0.66 0.03 0.69 0.05
6 0.66 0.06 0.72 0.09
7 0.66 0.08 0.74 0.12 7–10 yrs: 0.13
8 0.66 0.09 0.75 0.14
9 0.66 0.09 0.75 0.14
10 0.66 0.09 0.75 0.14
11 0.66 0.07 0.73 0.11 11–14 yrs:
12 0.66 0.06 0.72 0.09 0.08
13 0.66 0.05 0.71 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.


Appendix G
Committee Member Biographies
Robert E. Black, M.D., M.P.H. (Chair), is Professor and Director of the In-
stitute 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 epidemi-
ologist at the Centers for Disease Control and Prevention and worked at
institutions in Bangladesh and Peru on research related to childhood infec-
tious 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, micronutri-
ents, 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 past 20 years he led work that demon-
strated 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 organiza-
tions, 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
151

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 Nutri-
tion 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 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 col-
laborating 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 high performance liquid chromatography
methods for the measurement of multiple vitamins simultaneously in hu-
man 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), the United Nations Children’s Fund, the Asian Development Bank,
the World Bank, the 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 Interven-

APPENDIX G 153
tions, 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 McCol-
lum International Lectureship. Dr. Allen is currently a member of the steer-
ing committee of the Micronutrient Forum and the International Nutrition
Foundation, and Chair of the National Institutes of Health’s Biomarkers in
Nutrition and Development Expert Panel on Vitamin B12.
Zulfiqar A. Bhutta, M.B.B.S., 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 Univer-
sity (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 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 Immuniza-
tions 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 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 com-
mittee 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 (M.B.B.S.)
and obtained his Ph.D. from the Karolinska Institute, Sweden. He is a Fel-
low 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 re-

search 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 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 Gas-
troenterology and Nutrition and the Federation of Asia-Oceania Perinatal
Societies. As the current President of the International Pediatric Associa-
tion, 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 later as Head of the Nutrition Division,
and Programme Leader for Micronutrients. In 2007, she was offered a
personal chair at 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 Bio-
technology and Biological Sciences Research Council 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
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 more
than 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 com-
pleted his medical training at the University of Khartoum, Sudan, and his
Doctorate of Public Health in 1992 in the Departments of Epidemiology

APPENDIX G 155
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 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
HIV/AIDS Care and Treatment Program in Tanzania, which provides for
scaling up quality care and treatment services and building operational re-
search 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 Nutri-
tion 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 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 Noncommuni-
cable Diseases; the former having 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’Abbé 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 (EFSA) in Parma (Italy). Before joining 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
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 ex-
perimental studies as well as in the methodology for food and feed risk as-
sessment. 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 meth-
ods 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 statistics for scientific
research, having completed postgraduate training at the University of Bo-
logna and 6-month scholarship at the 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 require-
ment 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 De-
partment of Cell Biology and Clinical Genetics of the Erasmus-University,
Rotterdam, as head of the Unit for Metabolic Disorders and of the Meta-
bolic 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 d ietetic
therapy, both on national and international panels. Since the founda-
tion of the Federal Institute for Risk Assessment in November 2002,
Dr. Przyrembel’s tasks have been predominanty on the assessment of both

APPENDIX G 157
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 chil-
dren). In 2000, Dr. Przyrembel started as an expert in the working groups
on Upper Levels of Vitamins and Minerals, on Infant Formula Composi-
tion, and on Food Additives (Nutrient Compounds) of the Scientific Com-
mittee 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 Johns 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 me-
tabolism; efficacy of food-based interventions to address micronutrient defi-
ciencies; maternal and child nutrition policy; and program implementation.


The National Academies Press

Enviado por

Dados do documento

Título original

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

The National Academies Press

Enviado por

Direitos autorais:

Formatos disponíveis

THE NATIONAL ACADEMIES PRESS

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

Harmonization of Approaches to Nutrient Reference Values:

174 pages | 6 x 9 | PAPERBACK

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

– Access to free PDF downloads of thousands of scientiﬁc reports

Copyright © National Academy of Sciences. All rights reserved.

Committee on the Application of Global Harmonization of

Food and Nutrition Board

Health and Medicine Division

A Consensus Study Report of

Copyright National Academy of Sciences. All rights reserved.

International Standard Book Number-13: 978-0-309-47769-7

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.

Copyright National Academy of Sciences. All rights reserved.

The National Academy of Sciences was established in 1863 by an Act of

The National Academy of Medicine (formerly the Institute of Medicine) was

The three Academies work together as the National Academies of Sciences,

Copyright National Academy of Sciences. All rights reserved.

Consensus Study Reports published by the National Academies of

Proceedings published by the National Academies of Sciences,

For information about other products and activities of the National

Copyright National Academy of Sciences. All rights reserved.

COMMITTEE ON THE APPLICATION OF GLOBAL

ROBERT E. BLACK (Chair), Edgar Berman Professor, Director, Institute

Copyright National Academy of Sciences. All rights reserved.

Copyright National Academy of Sciences. All rights reserved.

This Consensus Study Report was reviewed in draft form by individuals

STEPHANIE A. ATKINSON, McMaster University

Although the reviewers listed above provided many constructive com-

Copyright National Academy of Sciences. All rights reserved.

University of California, Davis, and Santa Cruz, and SUSAN C.

Copyright National Academy of Sciences. All rights reserved.

The establishment of reference values for nutrient intakes of popula-

Copyright National Academy of Sciences. All rights reserved.

Copyright National Academy of Sciences. All rights reserved.

these target population subgroups using case scenarios informed by work-

Robert E. Black, Chair

Copyright National Academy of Sciences. All rights reserved.

Copyright National Academy of Sciences. All rights reserved.

ACRONYMS AND ABBREVIATIONS xv

1 INTRODUCTION AND PROBLEM STATEMENT 15

CONCEPTUAL FOUNDATIONS OF NUTRIENT REFERENCE

3 A HARMONIZED PROCESS FOR NUTRIENT REFERENCE

Copyright National Academy of Sciences. All rights reserved.

Findings, Conclusion, and Recommendation, 66

4 APPLYING METHODOLOGICAL APPROACHES TO

5 FUTURE DIRECTIONS AND DATA GAPS 121

Copyright National Academy of Sciences. All rights reserved.

Acronyms and Abbreviations

AHRQ Agency for Healthcare Research and Quality

COMA United Kingdom Committee on Medical Aspects of Food

D-A-CH Nutrition Societies of Germany, Austria, Switzerland

EAR estimated average requirement

FAO Food and Agriculture Organization

Copyright National Academy of Sciences. All rights reserved.

xvi ACRONYMS AND ABBREVIATIONS

GRADE Grading of Recommendations, Assessment, Development

INL individual nutrient level

LOAEL lowest observed adverse effect level

NIV nutrient intake value

3 A HARMONIZED PROCESS FOR NUTRIENT REFERENCE

4 APPLYING METHODOLOGICAL APPROACHES TO