Vitamin A fortification of wheat flour: Considerations and current recommendations

Abstract

Background : Vitamin A deficiency is a major public health nutrition problem, affecting an estimated 190 million preschool-aged children and 19 million pregnant and lactating women globally, and 83 million adolescents in Southeast Asia alone. Its consequences (disorders) include xerophthalmia (the leading cause of early childhood blindness), increased severity of infection, anemia, and death. Because vitamin A deficiency is largely due to chronic dietary insufficiency of preformed vitamin A and proactive carotenoids, food fortification can offer an effective approach to prevention. Objective: To provide guidance on fortifying wheat and maize flour milled in industrial rollers for national fortification programs in countries where vitamin A deficiency is considered a public health problem. Methods: Critical review of the literature on the dietary gap in vitamin A intake and levels of wheat flour intake among risk groups as a basis for determining vitamin A fortificant levels. Additional review of efficacy evidence, safety and cost considerations, and country experiences related to wheat-flour fortification with vitamin A. Results: Mill-rolled wheat flour is a technically fortifiable, centrally processed food vehicle that, where routinely and adequately consumed by target groups, should be considered a candidate for fortification. Vitamin A can be stable in flour under typical, ambient conditions, with processing losses estimated at approximately 30%, depending on source and premix conditions. Conclusions: Factors to guide a decision to fortify flour with vitamin A include the extent of deficiency, availability of other food vehicle options, the centrality of milling, market reach and population intake distributions of the flour products, the dietary vitamin A intake required, and associated costs. Large gaps persist in knowledge of these factors, which are needed to enable evidence-based fortification in most countries, leaving most decisions to fortify guided by assumptions. Where flour can and should be fortified, guidelines are given for providing nearly 25% of the Recommended Dietary Allowance for vitamin A to vulnerable groups consuming varying ranges of flour products. The costs will vary according to the level of fortification.

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Contents
The opportunity of flour fortification: Building on the evidence to move forward ...............................................S3
Revised recommendations for iron fortification of wheat flour and an evaluation of the expected
impact of current national wheat flour fortification programs —R. Hurrell, P. Ranum,
S. de Pee, R. Biebinger, L. Hulthen, Q. Johnson, and S. Lynch .................................................................................S7
Fortification of flour with folic acid —R. J. Berry, L. Bailey, J. Mulinare, and C. Bower ...........................S22
Considering the case for vitamin B12 fortification of flour —L. H. Allen, I. H. Rosenberg,
G. P. Oakley, and G. S. Omenn ..................................................................................................................................S36
Vitamin A fortification of wheat flour: Considerations and current recommendations
—R. D. W. Klemm, K. P. West, Jr., A. C. Palmer, Q. Johnson, P. Randall, P. Ranum,
and C. Northrop-Clewes ............................................................................................................................................S47
Zinc fortification of cereal flours: Current recommendations and research needs
—K. H. Brown, K. M. Hambidge, P. Ranum, and the Zinc Fortification Working Group .................................S62
Miller’s best/enhanced practices for flour fortification at the flour mill
—Q. W. Johnson and A. S. Wesley .............................................................................................................................S75
Maximizing the impact of flour fortification to improve vitamin and mineral nutrition in populations .............S86
List of Participants ..........................................................................................................................................................S94
Flour fortification with iron, folic acid, vitamin B12, vitamin A, and zinc: Proceedings
of the Second Technical Workshop on Wheat Flour Fortification
Guest editors: Mary Serdula, J.P. Peña-Rosas, Glen F. Maberly, and Ibrahim Parvanta
Associate Editors: Nancy Jennings Aburto, Cria G. Perrine, and Zuguo Mei

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Food and Nutrition Bulletin
Food and Nutrition Bulletin, vol. 31, no. 1 (supplement)
© The United Nations University, 2010
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University, Gerald J. and Dorothy R. Friedman School of Nutrition Science
and Policy, Boston, MA USA
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Technological Research Institute (CFTRI), Mysore, India
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Dr. Ricardo Bressani, Institute de Investigaciones, Universidad del Valle
de Guatemala, Guatemala City, Guatemala
Dr. Hernán Delgado, Director, Institute of Nutrition of Central America
and Panama (INCAP), Guatemala City, Guatemala
Dr. Cutberto Garza, Academic Vice President and Dean of Faculties, Boston
College, Chestnut Hill, Mass., USA
Dr. Joseph Hautvast, Secretary General, International Union of Nutritional
Sciences (IUNS), Department of Human Nutrition, Agricultural University,
Wageningen, Netherlands
Dr. Peter Pellett, Professor, Department of Food Science and Nutrition,
University of Massachusetts, Amherst, Mass., USA
Dr. Zewdie Wolde-Gabreil, Director, Ethiopian Nutrition Institute, Addis
Ababa, Ethiopia
Dr. Aree Valyasevi, Professor and Institute Consultant, Mahidol University,
Bangkok, Thailand

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Food and Nutrition Bulletin, vol. 31, no. 1 (supplement) © 2010, The United Nations University.
S3
The opportunity of flour fortification: Building on the
evidence to move forward
Burden of vitamin and mineral deficiencies
The World Health Report 2000 [1] identified iron,
vitamin A, and zinc deficiencies among the world’s
most serious health risk factors. Micronutrient malnu-
trition contributes to a vicious cycle of poor health and
depressed productivity, trapping families in poverty
and eroding economic security in dozens of countries
worldwide. Ensuring adequate intake of these essential
nutrients by vulnerable populations will offer enhanced
protection from a range of disabilities and diseases,
help children grow and learn, and improve health and
productivity for adults.
Iron deficiency is the most prevalent nutrient defi-
ciency in the world [2]. It is responsible for approxi-
mately 20,854 deaths and a reduction of 2 million
disability-adjusted life years (DALYs) among children
under 5 years of age [3]. In addition, iron-deficiency
anemia in pregnancy is a risk factor for maternal mor-
tality; 115,000 deaths per year from maternal causes
and losses of 3.4 million DALYs among women of
childbearing age have been attributed to iron deficiency
[2, 3]. According to a World Health Organization
(WHO) review of nationally representative surveys
from 1993 to 2005, 42% of pregnant women and 47%
of preschool children worldwide have anemia [3, 4].
Iron deficiency has its greatest impact on the health
and physical and intellectual well-being of preschool
children and women of childbearing age, though it
may also affect other population groups. Although
often more severe in poor and rural communities,
iron deficiency also occurs in wealthier and urban
populations.
Adequate folic acid intake by women before preg-
nancy and in the first weeks of gestation decreases the
risk of neural tube defects (NTDs) [5–7], the world’s
leading preventable birth defect. The geographic dis-
tribution of NTD prevalence is based in part on dietary
patterns. For example, in China folate deficiency is
more severe and the prevalence of NTDs is decid-
edly higher among the predominantly wheat-eating
populations of the northeast part of the country, where
fresh vegetables are less available, than among the
populations in the southern part of the country, where
fresh vegetables are more available year-round [7]. In
the United States and Canada, where a wide range is
foods are accessible to the majority of the populations
and vitamin and mineral deficiencies are much less
common than in most developing countries, NTD rates
were also significantly reduced following mandatory
addition of folic acid to enriched flours and cereals [8,
9]. These findings suggest it is likely that other popula-
tions around the world could also substantially reduce
NTDs by eating folic acid–fortified foods.
There is mounting evidence of widespread vitamin
B12 depletion and deficiency in many population
groups that consume low amounts of animal-source
foods, the only natural source of vitamin B12. Even
in industrialized countries there is a high prevalence
of vitamin B12 deficiency among the elderly, many of
whom require synthetic sources of vitamin B12 because
of their limited ability to release and absorb the vitamin
from foods [10, 11]. Vitamin B12 deficiency has been
linked to poor pregnancy outcomes and increased risk
of NTDs, delayed child development, abnormal cog-
nitive function and depression, anemia, and elevated
plasma homocysteine concentrations.
Vitamin A deficiency is a widespread public health
problem in developing nations, where it affects more
than 130 million preschool children and is the leading
preventable cause of childhood blindness [12] and a
major underlying cause of child mortality [13]. Suf-
ficient vitamin A intake is essential to maintain an
adequate host response to infection. Vitamin A supple-
mentation during early childhood appears to have its
greatest impact in reducing case fatality from measles,
diarrhea or dysentery, and malaria and other febrile
Please address inquiries to the corresponding author: Mary
Serdula, International Micronutrient Malnutrition Prevention
and Control Program (IMMPaCt), Division of Nutrition,
Physical Activity and Obesity, Centers for Disease Control
and Prevention; 4770 Buford Hwy NE, MS: K-25, Atlanta, GA
30341 USA; e-mail: mks1@cdc.gov.

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All participants
illnesses [14]. Twenty million pregnant and lactating
women also suffer from low vitamin A status [15],
predisposing them to higher risks of night-blindness,
anemia, morbidity, and mortality. Newborn vitamin
A supplementation appears to be a promising way to
reduce early infant mortality [13].
Zinc deficiency is responsible for approximately 4%
of deaths and 16 million lost DALYs among children
under five in lower-income countries [3] and can usu-
ally be found in populations that are iron deficient.
Inadequate zinc intake in young children increases the
rates of diarrhea and acute lower respiratory infections
and reduces linear growth and physical development
[16, 17]. Adequate zinc intake is also necessary for
women of childbearing age to ensure normal preg-
nancy outcomes [18].
Worldwide, more than 450 million tons of wheat
are used for human consumption each year. Most of
the wheat is milled by commercial roller mills and
consumed as noodles, breads, pasta, and other flour
products by people in nearly every nation of the world.
During the production of refined white flour, essential
vitamins and minerals are removed by the milling proc-
ess. As well as losing nutrients during milling, many
cereal products also have elements such as phytates that
block the absorption of iron and zinc.
Building on the past to gain consensus
Micronutrient fortification of wheat flour was intro-
duced in the United States and Canada in the 1940s. In
Latin America, Chile began to fortify wheat flour in the
early 1950s [19]. During the 1960s, a number of Latin
American countries passed legislation encouraging
the addition of iron and B vitamins to flour; as a con-
sequence, some millers began to fortify on a voluntary
basis. In 1998, the United States and Canada required
that enriched cereal grain products be additionally for-
tified with folic acid to reduce the prevalence of NTDs.
In the late 1990s and early 2000s, public and private
sector organizations organized a movement to promote
mandatory wheat and maize fortification worldwide.
Among the organizations promoting fortification
were WHO (especially the Pan American Health
Organization and the Eastern Mediterranean Regional
Office), UNICEF, the World Bank, the Asian Develop-
ment Bank, the Micronutrient Initiative, the US Agency
for International Development (USAID) the Centers
for Disease Control and Prevention (CDC), SUSTAIN,
the International Association of Operative Millers, and
the Latin American Milling Association. The effort
was also backed by leading public health and nutri-
tion scientists, milling industry executives, and other
industry and nongovernmental organization (NGO)
leaders. Significant progress toward meeting fortifica-
tion goals was made in the Americas, the Middle East,
and Central Asia. The 2002 United Nations Special
Session on Children marked the establishment of
the Global Alliance for Improved Nutrition (GAIN)
with support for food fortification from the Bill and
Melinda Gates Foundation, the Canadian Interna-
tional Development Agency, and USAID. GAIN has
since supported a number of countries in efforts to
establish flour fortification programs and to further
build national fortification alliances and has provided
funds for infrastructure to help countries move toward
nationwide flour fortification.
Following the 2004 International Grains Council,
the Flour Fortification Initiative was formed to acceler-
ate wheat flour fortification in roller mills throughout
the world [20]. The Flour Fortification Initiative is
a network of public, private, and civic sector leaders
representing more than 50 organizations and draw-
ing support from public health organizations and the
wheat-growing, wheat-trading, wheat-milling, mill
manufacturing, pharmaceutical, and vitamin/min-
eral premix industries and allied trades. Today flour
fortification is increasingly being adopted as normal
industrial milling practice in the production of quality
flour. Flour Fortification Initiative network members
are working with governments around the world to
encourage and assist them to change food regulations
and food control systems to meet mandatory flour
fortification requirements. Disability sector and other
civic sector organizations are also joining the cause.
The number of countries with mandatory wheat
flour fortification programs rose from 33 in 2004 to
54 in 2007 [21]. Worldwide, 540 million more people
gained access to wheat flour fortified with iron, folic
acid, or both in 2007, an 8% increase from 3 years
before. The number of women aged 15 to 60 years with
access to fortified wheat flour increased by 167 million,
and the number of births that potentially benefited
from wheat flour fortification increased by 14 million.
Yet despite these successes, more than two-thirds of
the world’s population, including millions of women of
childbearing age, still lack access to fortified wheat flour
and its benefits. Fortification standards and practices
vary from country to country, as do the specifications
for the type and quantity of the nutrients added [22].
As flour fortification programs gained momentum
in the late 1990s and 2000s, WHO, USAID, SUSTAIN,
and the Micronutrient Initiative engaged in a number
of consultations with countries and regions to help
establish guidelines for vitamin and mineral fortifica-
tion of flour. Meanwhile, new studies suggested that the
selection of the type of iron fortificant was complicated
by significant differences in the bioavailability of vari-
ous forms of iron powders and compounds. The Flour
Fortification Initiative, in collaboration with the CDC
and the Mexican Institute of Public Health, convened
a Technical Workshop entitled “Wheat flour fortifica-
tion: current knowledge and practical applications,”

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The opportunity of flour fortification
in Cuernavaca, Mexico, in 2004 [23]. A key focus of
the 2004 Workshop was to develop consensus recom-
mendations for fortifying wheat flour with iron and
folic acid. The recommendations were unique in that
they called for fortification of low- and high-extraction
flours with only bioavailable forms of iron fortificants
(ferrous sulfate, ferrous fumarate, or electrolytic iron
in low-extraction flour, and sodium-iron ethylenedi-
aminetetraacetate [EDTA] in high-extraction flour),
as well as folic acid. Recommendations from the Cuer-
navaca meeting are largely consistent with the recently
published WHO/Food and Agriculture Organization
(FAO) “Guidelines on food fortification with micronu-
trients” [24]. This is a key reference for countries con-
sidering food fortification to address the high public
health burden of vitamin and mineral deficiencies.
Second Technical Workshop on Wheat
Flour Fortification
Despite the established WHO/FAO guidelines and the
specific call of experts convened in Cuernavaca, many
countries where flour is fortified still use elemental iron
fortificants (i.e., some forms of hydrogen-reduced iron
and atomized iron) that are poorly absorbed. Also, in
the past few years, consultants from different interna-
tional organizations have given variable guidance and
information to developers of fortification programs,
resulting in confusion and slow progress toward effec-
tive flour fortification in a number of countries.
Other challenges include recently raised concerns
by some experts about the high burden of vitamin B12
deficiency in populations around the world, as well
as the growing awareness and understanding of zinc
nutrition, which could affect fortification goals and
programs. Furthermore, although fortification of flour
with vitamin A has been initiated in a few countries,
questions remain about the cost of adding vitamin A
to flour, as well as the stability of the vitamin A fortifi-
cant in flour and flour products. Finally, because large
populations in sub-Saharan Africa and Latin America
consume maize (corn) flour products as staple foods,
the organizers of the 2008 Workshop, the proceed-
ings of which are published in this issue, considered
it important to provide relevant guidance related to
micronutrient fortification of maize flour.
Under the direction of the Flour Fortification Ini-
tiative, a Steering Committee was established for the
Workshop. The Steering Committee was composed
of internationally recognized nutrition scientists and
a cereal chemist, representatives from United Nations
agencies and NGOs active in flour fortification, and
milling experts and staff from the CDC and the Flour
Fortification Initiative (see list of participants on page
S94).
The 4-day Second Technical Workshop on Wheat
Flour Fortification in Stone Mountain, Georgia, USA,
was supported by the CDC, GAIN, and Cargill, Inc.
and brought together nutrition researchers, public
health experts, specialists from regulatory agencies,
international development, and NGOs, and representa-
tives from the premix and milling sectors to develop
consensus on “practical and feasible recommendations”
for public health authorities, food regulators, and the
milling sector to initiate flour fortification, as well as to
improve the public health benefits of existing national
flour fortification programs.
The purpose of the Workshop was to provide guid-
ance on national fortification of wheat and maize
flours, milled in industrial roller mills (i.e., with at
least 20 metric tons (MT)/day milling capacity), with
iron, zinc, folic acid, vitamin B12, and vitamin A. The
guidance was to follow reviews of the latest evidence
of the effectiveness of flour fortification as well as new
developments in premix products and costs since the
2004 Cuernavaca meeting. The primary aim of the
Workshop was to develop consensus on formulations
of premix based on the most common ranges of flour
consumption. A secondary aim was to develop con-
sensus around the best practices guidelines for premix
manufacturers and millers.
Expert working groups prepared technical back-
ground documents and draft recommendations on
fortification of low- and high-extraction wheat flour
with iron, zinc, folic acid, vitamin A, and vitamin B12,
based on broad ranges of flour consumption. In addi-
tion, working groups prepared draft fortification guide-
lines for millers and background documents on special
issues related to maize fortification and methodological
issues in estimating wheat flour consumption.
These background documents served as the sci-
entific and technical basis for discussions during the
Workshop. The Workshop included plenary presen-
tations based on the prepared technical background
documents, breakout group discussions and debates
to propose specific recommendations, followed by a
second round of plenary discussions to finalize recom-
mendations on fortification of wheat flour with iron,
zinc, folic acid, vitamin B12, and vitamin A, as well as
to establish best practices guidelines for millers and
premix manufacturers. The technical background
documents were revised based on the discussions at the
Workshop and are published in this special supplement
of the Food and Nutrition Bulletin.
Disclaimer
The selection of the type and quantity of vitamins and
minerals to add to flour, either as a voluntary standard
or a mandatory requirement, lies with national decision
makers in each country. This meeting fully recognizes
this, and any guidance or recommendations should be

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All participants
viewed in the context of each country’s situation. In
addition, the official normative-setting international
organizations that guide countries on food standards
are WHO and FAO, the Codex Alimentarius Commis-
sion, and the Joint FAO/WHO Expert Committee on
Food Additives (JECFA).
The findings and conclusions in this report are
those of the authors and do not necessarily represent
the official position of the organizations of individuals
participating in the Workshop, including Centers for
Disease Control and Prevention.
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Food and Nutrition Bulletin, vol. 31, no. 1 (supplement) © 2010, The United Nations University.
S7
Revised recommendations for iron fortification of
wheat flour and an evaluation of the expected impact
of current national wheat flour fortification programs
Abstract
Background: Iron fortification of wheat flour is widely
used as a strategy to combat iron deficiency.
Objective: To review recent efficacy studies and update
the guidelines for the iron fortification of wheat flour.
Methods: Efficacy studies with a variety of iron-
fortified foods were reviewed to determine the minimum
daily amounts of additional iron that have been shown
to meaningfully improve iron status in children, adoles-
cents, and women of reproductive age. Recommendations
were computed by determining the fortification levels
needed to provide these additional quantities of iron each
day in three different wheat flour consumption patterns.
Current wheat flour iron fortification programs in 78
countries were evaluated.
Results: When average daily consumption of low-
extraction (≤ 0.8% ash) wheat flour is 150 to 300 g, it
is recommended to add 20 ppm iron as NaFeEDTA, or
30 ppm as dried ferrous sulfate or ferrous fumarate. If
sensory changes or cost limits the use of these compounds,
electrolytic iron at 60 ppm is the second choice. Corre-
sponding fortification levels were calculated for wheat
flour intakes of < 150 g/day and > 300 g/day. Electrolytic
iron is not recommended for flour intakes of < 150 g/day.
Encapsulated ferrous sulfate or fumarate can be added
at the same concentrations as the non-encapsulated
compounds. For high-extraction wheat flour (> 0.8%
ash), NaFeEDTA is the only iron compound recom-
mended. Only nine national programs (Argentina, Chile,
Egypt, Iran, Jordan, Lebanon, Syria, Turkmenistan, and
Uruguay) were judged likely to have a significant posi-
tive impact on iron status if coverage is optimized. Most
countries use non-recommended, low-bioavailability,
atomized, reduced or hydrogen-reduced iron powders.
Conclusion: Most current iron fortification programs
are likely to be ineffective. Legislation needs updating in
many countries so that flour is fortified with adequate
levels of the recommended iron compounds.
Introduction
The World Health Organization (WHO) estimates
the global prevalence of anemia to be 47% in children
under 5 years of age, 30% in nonpregnant women of
childbearing age, and 42% in pregnant women [1].
Prevalence rates are highest in Africa and Asia. WHO
does not report prevalence rates for iron deficiency;
however, nutritional iron deficiency is the main etio-
logic factor responsible for anemia in industrialized
countries and contributes to about 50% of the anemia
in the developing countries of Africa and Asia [2]. Iron
deficiency occurs when iron requirements cannot be
met by absorption from the diet, such as during periods
of rapid growth (infancy, adolescence), in pregnancy,
and as a result of menstrual or pathological blood loss.
Although physiologic mechanisms can up-regulate
iron absorption more than 20-fold from single meals
containing readily bioavailable iron [3], the plant-based
diets that are characteristic of developing countries
limit iron absorption because they are rich in phytate
and polyphenols [4, 5]. They also contain little animal
tissue, which is a source of highly bioavailable iron.
The resultant imbalance between requirements and
absorption leads to iron deficiency that, depending on
severity, may or may not cause anemia.
The high prevalence of iron deficiency in developing
Richard Hurrell, Peter Ranum, Saskia de Pee, Ralf Biebinger, Lena Hulthen,
Quentin Johnson, and Sean Lynch
Richard Hurrell and Ralf Biebinger are affiliated with the
Swiss Federal Institute of Technology (ETH), Zurich, Switzer-
land; Peter Ranum is a consultant for the Micronutrient Ini-
tiative, Tucson, Arizona, USA; Saskia de Pee is affiliated with
the World Food Programme, Rome, Italy; Lena Hulthen is
affiliated with the University of Gothenburg, Sweden; Quen-
tin Johnson is affiliated with the Flour Fortification Initiative,
Rockwood, Ontario, Canada; Sean Lynch is affiliated with
Eastern Virginia Medical School, Norfolk, Virginia, USA.
Please address inquiries to the corresponding author:
Richard Hurrell, Swiss Federal Institute of Technology (ETH),
Institute of Food Science and Nutrition, ETH Zentrum; LFV
D20, Schmelzbergstrasse 7, 8092 Zürich, Switzerland; e-mail:
Richard.hurrell@ilw.agrl.ethz.ch.

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R. Hurrell et al.
countries has a significant adverse impact on the
well-being and productivity of their citizens. Physical
work capacity is reduced. Iron deficiency in pregnancy
contributes to the risk of severe anemia, which is asso-
ciated with higher maternal morbidity and mortality
[6]. There is an increase in the risk of preterm delivery
and low birthweight and a higher infant mortality rate
[7]. Iron deficiency is also more likely to occur after 4
months of age in babies born to mothers with subopti-
mal iron status during pregnancy [8]. Iron deficiency
in infants and young children is associated with delayed
mental and motor development [9]. These children
may experience emotional problems and fail to meet
educational goals later in life, leading to a negative
impact on earning capacity in adulthood. The median
total annual productivity loss (physical and cognitive
combined) has been estimated to be US$16.78 per
capita or 4.05% of GDP [10]. The relationship between
iron status and infectious diseases is complex and the
subject of considerable debate. However, recent obser-
vations indicate that upper respiratory infections are
more frequent and last longer and that the risk of severe
morbidity related to falciparum malaria is increased in
iron-deficient children [11, 12].
Four strategies for alleviating nutritional iron defi-
ciency have been advocated. They are dietary diversi-
fication to improve iron bioavailability, selective plant
breeding or genetic engineering to increase the iron
content or to reduce absorption inhibitors in dietary
staples, iron fortification of industrially manufactured
foods, and iron supplementation with pharmacologi-
cal doses, usually without food. Food fortification is
regarded at the present time as the safest and most cost-
effective approach for populations that consume sig-
nificant quantities of industrially manufactured foods.
Staple foods such as cereal flours and condiments are
the most appropriate food vehicles for fortification.
Mass fortification is designed to improve the bio-
available iron intake of the whole population with the
intention of eliminating iron deficiency in young chil-
dren, adolescents, and menstruating women, without
causing harm to men and postmenopausal women,
who may consume more iron than they require. The
efficiency of the physiologic mechanisms for pre-
venting the absorption of unnecessary iron has been
questioned, and mandatory wheat flour fortification
programs were discontinued in two European coun-
tries, in part because of concern about possible adverse
effects of iron fortification [13, 14].
The mechanisms controlling iron absorption and the
central role of the hepcidin/ferroportin axis have been
elucidated recently [15]. There are very few reports
of iron overload resulting from the consumption of
large quantities of iron, even large supplemental doses,
over extended time periods by individuals with an
apparently normal hepcidin/ferroportin axis. Systemic
iron overload occurs in genetic disorders, such as
hemochromatosis, that modify the function of hepcidin
or ferroportin, or in diseases, such as the thalassemia
syndromes, that reduce the efficiency with which these
regulators prevent excessive iron accumulation [16].
Patients with phenotypically expressed iron loading
conditions suffer the consequences of excessive iron
absorption even if the diet is not fortified, although
mass fortification would be expected to modestly
increase their iron loads. These disorders are best
managed by screening and treatment. Withholding
iron fortification from the much larger population that
is in need of extra iron would prolong the suffering
and the negative health and economic consequences
related to iron deficiency and have little impact on the
clinical course of the iron overload diseases [17]. Iron
overload does not occur in genetic carriers with normal
phenotypes [18].
Effective fortification of staple foods or condiments
with iron is thus expected to have significant benefits
for large segments of the population, particularly in
developing countries, with very little risk of adverse
health effects. In this respect, wheat flour is the food
vehicle most often fortified with iron. Fortification
originally began in the United States and Europe in the
1940s as a way to combat iron deficiency by restoring
the iron level of low-extraction wheat flour to that in
the whole grain. Wheat flour fortification programs are
in place or in the planning stages in 78 countries [19].
In 2004, a Centers for Disease Control and Prevention
(CDC) expert group in Cuernavaca, Mexico, made
global recommendations for the type and level of dif-
ferent iron compounds to be added to wheat flour [20].
WHO [2] recommended the same iron compounds but
suggested that each country should estimate the level
of fortification that would provide the required iron
lacking in the traditional diet.
The first objective of this review was to evaluate and
revise the guidelines for iron fortification of wheat flour
that were formulated at the Cuernavaca Workshop [20].
This was achieved by reviewing all published efficacy
trials of iron-fortified condiments and cereal staples in
women and children. For each iron fortificant currently
recommended for wheat flour fortification, the average
increase in an individual’s daily iron intake necessary
to achieve a meaningful improvement in iron status
was estimated. This information was used to calculate
recommended fortification levels based on average per
capita wheat flour consumption. The second objec-
tive was to evaluate to what extent the flour industry
is following the Cuernavaca guidelines and to judge
the potential impact of current national, regional, or
planned wheat flour fortification programs on the iron
status of the population.

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Iron fortification of wheat flour
Using iron efficacy studies to estimate
iron fortification levels that will usefully
improve iron status
The iron fortification levels recommended in the Cuer-
navaca guidelines [20] were largely derived from what
was being practiced in the flour fortification industry
and what was expected to be organoleptically accept-
able. As wheat flour fortification has historically been
based on restoration, the iron level recommended for
ferrous sulfate fortification (30 ppm iron) was that
needed to restore the iron level of low-extraction
white wheat flour to that of the whole-grain wheat
flour. This was increased to 45 ppm iron for countries
where wheat flour consumption was less than 200 g
per person per day. Isotopic iron absorption studies in
adult humans have indicated that ferrous fumarate has
a similar bioavailability to ferrous sulfate, so the Cuer-
navaca guidelines recommended that ferrous fumarate
be added at the same level as ferrous sulfate.
Ferrous fumarate would be expected to have fewer
sensory problems than ferrous sulfate. Encapsulation of
ferrous sulfate or ferrous fumarate with hydrogenated
vegetable oils may prevent lipid oxidation during wheat
flour storage, and these compounds are useful alterna-
tives; however, at the time of the Cuernavaca meeting
the particle size of the commercially encapsulated
compounds was too large, and it was concluded that,
if added to flour, the compounds would be removed
by the sieves commonly used at the end of the milling
process. The Cuernavaca guidelines recommended that
smaller particle-size encapsulated ferrous sulfate or
encapsulated ferrous fumarate be developed for addi-
tion to wheat flour. Although this has been recently
accomplished experimentally [21], the microcapsules
need more complete sensory testing and scaling up for
commercialization. Encapsulated ferrous sulfate and
encapsulated ferrous fumarate are recommended for
cereal flour fortification in the WHO guidelines [2].
Because elemental iron powders are organoleptically
inert, they are widely used for wheat flour fortification.
In 2002, a SUSTAIN task force evaluated the usefulness
of the different elemental iron powders commonly
employed in wheat flour fortification [22]. Based on
in vitro, rat, and human studies, the task force recom-
mended that electrolytic iron be the only elemental
iron powder used and that it be added at twice the
iron level of ferrous sulfate, since it is approximately
half as well absorbed. They also recommended that
carbon monoxide–reduced iron should not be used
because of an unacceptably low absorption, and that
more studies were needed of carbonyl and hydrogen-
reduced iron powders before a recommendation could
be made. It was subsequently found that another form
of reduced iron (atomized iron powder) is widely used
for wheat flour fortification because of its low cost.
However, because of its low solubility in dilute acid
under standardized conditions and its poor absorption
in rat hemoglobin repletion studies and human iron
tolerance tests [23], atomized reduced iron powder is
not recommended for wheat flour fortification [2].
It has long been known that in the presence of
phytate, the ethylenediaminetetraacetate (EDTA) com-
ponent of NaFeEDTA enhances absorption of both the
intrinsic food iron and the fortification iron. Addition-
ally, NaFeEDTA does not promote lipid oxidation in
stored wheat flour [24]. It has thus been recommended
for the fortification of high-phytate flours (whole-grain
and unleavened low-extraction). The level recom-
mended for both whole-grain and unleavened low-
extraction flours was 30 ppm iron [20], although it was
realized that this level may be somewhat higher than
that necessary for high-extraction flours which contain
higher levels of (low-bioavailability) intrinsic iron.
The procedure used to determine the recommended
iron levels at Cuernavaca was necessarily pragmatic.
The preferred procedure would be the method recom-
mended by WHO [2], in which each country must
first measure the daily iron intake in the groups at risk
for iron deficiency, estimate the iron bioavailability
from the diet, compare estimated iron intake and bio-
availability with iron requirements (based on dietary
iron bioavailability), and calculate the amount of iron
lacking in the diet. This amount of iron should then
be added to the mean daily flour consumption of the
targeted at-risk group(s) (e.g., women of childbearing
age). Unfortunately, very few countries have the capa-
bility to use this procedure.
The approach used to develop the recommendations
in the present document is a combination of the appli-
cation of experimental evidence and pragmatism. This
was made possible by the publication of a relatively
large number of human efficacy trials, mostly after
the Cuernavaca Workshop. We have reviewed these
efficacy studies, in which different iron compounds
and different food vehicles were employed. Studies
in infants were not included, because this population
group is not a primary target for mass fortification.
Studies in which ascorbic acid was given together
with the fortified food were also excluded, as this iron
absorption enhancer is usually unstable to wheat flour
storage and heat processing. We also excluded studies
where the iron compound was not identified clearly or
where the methodological details were inadequate. The
duration of the intervention was taken into account.
Hallberg et al. [25] estimated that it takes 2 to 3 years
to stabilize the new iron balance and iron stores after
changing the amount of bioavailable iron in the diet.
However, 80% of the final impact is achieved in the
first year. From this report, it can also be estimated that

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R. Hurrell et al.
efficacy studies carried out over 5 to 6 months should
reach about 40% of final impact, whereas the final
impact of studies lasting less than 5 months is too dif-
ficult to interpret. Based on this information, and based
on the results of published efficacy studies in women
and children, the daily amount of iron necessary to
achieve an improvement in iron status was estimated
for each recommended iron compound. Two efficacy
studies in infants are referred to but are not part of the
formal analysis. These studies indicate that relatively
large quantities of electrolytic iron, especially in com-
bination with ascorbic acid, can have a positive impact
on iron status [26, 27].
It is proposed that iron fortification of wheat flour
should be considered at the national or regional level
only if there is laboratory evidence of a high preva-
lence of iron deficiency and iron-deficiency anemia
in women or children in the country or region con-
cerned (iron-deficiency anemia > 5%) and that the
program should aim to decrease the prevalence of iron
deficiency in the target at-risk populations to levels
reported in industrialized countries (< 10% iron defi-
ciency and < 5% iron-deficiency anemia [28]). These
levels should be reached in 2 to 3 years after the start of
the fortification program. For simplicity, we have based
our evaluation of the published efficacy studies on the
potential for these values to be attained. Trials that met
these criteria were considered “highly efficacious.” If
one or more iron status parameters or hemoglobin
improved significantly without satisfying these criteria,
the trial was considered to be “moderately efficacious.”
When the hemoglobin or iron status parameters were
not significantly changed, the fortification study was
considered “not efficacious.” Since the duration of
most of the trials was less than 12 months, the maximal
reduction in the percentage of iron deficiency and the
percentage of iron-deficiency anemia would not have
been reached. The model developed by Hallberg et al.
[25] was thus used to modify the criteria for describ-
ing the study as efficacious based on study duration.
A reduction in the percentage of iron deficiency and
the percentage of iron-deficiency anemia to < 12.5%
and < 6%, respectively, was required for studies lasting
around 9 months to be considered highly efficacious.
The corresponding values for studies lasting around 5
months were < 25% and < 12.5%. A major drawback
of this approach is that iron status at the start of the
intervention influences the final outcome, especially
for short-term studies; however, with one exception,
subject selection did not affect the ability to categorize
study outcome.
Efficacy studies with NaFeEDTA
NaFeEDTA has been evaluated in nine efficacy studies
employing a variety of fortified foods, including wheat
and maize flour as well as condiments such as fish
sauce, soy sauce, curry powder, and sugar (table 1).
Although only two of these studies were conducted
with wheat flour, two were conducted with maize
flour and the condiments were added to maize-based
and rice-based diets, all of which are moderately high
in phytate. The studies with curry powder [29], sugar
[30], and soy sauce [31] and one study with fish sauce
TABLE 1. Efficacy studies with NaFeEDTA
Dose
(mg/day)Subjects and vehicle
7.1 Both sexes ≥ 10 yr
Curry powder
4.6Both sexes ≥ 10 yr
Sugar
8.6 Women 17–44 yr
Fish sauce
7.5 Women 16–49 yr
Fish sauce
4.9Both sexes ≥ 3 yr
Soy sauce
7 Both sexes 11–18 yr
Wheat flour
7 Children 3-8 yr
Maize porridge
3.5Children 3–8 yr
Maize porridge
1.3Children 6–11 yr
Brown bread
Length of study
and country
24 mo
South Africa
32 mo
Guatemala
6 mo
Vietnam
18 mo
Vietnam
18 mo
China
6 mo
China
5 mo
Kenya
5 mo
Kenya
8 mo
South Africa
Impact Ref
29Highly efficacious
Moderately efficacious 30
Moderately efficacious 33
Highly efficacious 32
Highly efficacious31
Highly efficacious 34
Highly efficacious35
Moderately efficacious35
No effect on iron status36

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Iron fortification of wheat flour
[32] were relatively long term, lasting from 18 to 32
months. One of the fish sauce studies [33] and the
studies with maize flour or wheat flour lasted only 5 to
8 months [34–36]. Eight of the nine studies reported
statistically improved iron status in women and chil-
dren. Five trials that provided an additional 4.9 to
7.5 mg iron/day over 5 to 24 months were judged to be
highly efficacious. Three studies [30, 33, 35] providing
3.5 to 8.6 mg additional iron per day were categorized
as moderately efficacious. This was due in part to
unavailability of data or study design in two of them.
Viteri et al. [30] did not report the percentages of iron
deficiency or of iron-deficiency anemia in the study
subjects. Thuy et al. [33] preselected only anemic sub-
jects, and there was still a 20% residual prevalence of
iron-deficiency anemia at the end of this 6-month trial.
It is possible that the intervention would have reached
the criteria for being highly efficacious if the trial had
continued for a longer time. It was assumed, therefore,
that the interventions of Viteri et al. [30] and Thuy et
al. [33] were misclassified as moderately efficacious
rather than highly efficacious because of incomplete
data in the former and unsuitable study design in the
latter. NaFeEDTA was only moderately efficacious in
children receiving 3.5 mg additional iron per day in
fortified maize meal, whereas children given brown
bread that provided 1.3 mg/day as NaFeEDTA showed
no improvement in iron status [36].
The recommendation for the fortification of low-
extraction wheat flour with NaFeEDTA is based on
the lowest dose likely to be highly efficacious (4.6 mg
in the study of Viteri et al. [30]). A daily dose of 3.5 mg
was considered moderately efficacious, whereas 1.3
mg had no effect on iron status in children (table 1).
Fortification levels supplying between 3.5 mg and 4.6
mg have not been tested, so it is possible that a daily
iron intake from NaFeEDTA of somewhat less than 4.6
mg may suffice. Based on mean consumption rates, the
required iron concentration is 13 ppm for low-extrac-
tion wheat flour consumption levels > 300 g/day and
20 ppm for levels of 150 to 300 g/day (table 2). These
values are lower than the 30 ppm iron recommended
at Cuernavaca for the same flour consumption rates.
For a lower flour consumption level of 75 to 149 g/day,
the required iron concentration should be increased to
40 ppm. When the daily flour consumption is < 75 g,
92 ppm would be necessary.
These recommendations for the fortification of
wheat flour with NaFeEDTA would be expected to
reduce national iron-deficiency anemia and iron defi-
ciency prevalence rates to the ranges encountered in
Western countries in 2 to 3 years. They are supported
by a series of well-conducted studies. Although some
studies were not conducted with iron-fortified wheat
or maize flours, all the fortified condiments were used
within cereal-based diets relatively high in phytic acid.
We concluded, therefore, that these recommendations
can be stated with greater confidence than the recom-
mendations for ferrous sulfate and ferrous fumarate
that are reported in the following sections of this
review. Furthermore, the enhancing properties of
EDTA on iron absorption in the presence of phytate
would be expected to reduce the variability in iron
status responses caused by differences in overall meal
bioavailability.
Efficacy studies with ferrous sulfate
Four efficacy studies with ferrous sulfate have been
reported. Two studies fed foods fortified with encap-
sulated sulfate (table 3). Wheat flour or wheat flour
biscuits were fortified in three trials [21, 34, 37], and
salt was fortified in the fourth [38]. The iron-fortified
salt was largely added to bread prior to baking. All trials
reported statistically improved iron status in school-
children or young women consuming an additional
7.1 to 11.8 mg iron per day over 5.5 to 9 months. The
two studies that supplied 10.3 and 11.8 mg additional
iron per day were categorized as highly efficacious,
and the two studies providing 7.1 and 11.0 mg iron
per day were categorized as moderately efficacious.
It should be noted that Biebinger et al. [21] evaluated
a newly developed small-particle-size (d50 = 40 µm)
encapsulated ferrous sulfate that is suitable for flour
fortification and will be retained in the flour after the
sifting process.
The minimum efficacious dose for ferrous sulfate
was 7.1 mg/day. It was considered to be moderately effi-
cacious. A somewhat higher dose (~ 11 mg) was highly
efficacious in two studies, but only moderately effica-
cious in the third (table 3). It is likely that the efficacy
of ferrous sulfate will depend to some extent on the
other food items consumed in the meal containing the
fortified wheat flour. When 7.1 mg iron/day is used as
TABLE 2. Required flour fortification levels based on the mini-
mum iron dose that improved iron status in efficacy studies
Flour con-
sumption
(g/day)
NaFeEDTA > 300
150–300
75–149
< 75
Ferrous sulfate> 300
150–300
75–149
< 75
Electrolytic iron> 300
150–300
75–149
< 75
Iron compound
Required
level
(ppm)
13
20
40
92
20
32
63
142
29
44
89
200
Cuernavaca
recommenda-
tion (ppm)
30
30
30
30
30
30
45
45
60
60
90
90

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R. Hurrell et al.
the required iron dose of ferrous sulfate in wheat flour,
the required fortification level for countries consuming
> 300 g/day is 20 ppm, lower than the 30 ppm recom-
mended at Cuernavaca; for countries consuming 150 to
300 g flour per day, the required level is 32 ppm (table
2). For the countries where wheat flour consumption
is between 75 and 149 g/day, the estimated required
iron fortification level for ferrous sulfate is 63 ppm,
and for a flour consumption of < 75 g/day, the level
is 142 ppm. These latter values are much higher than
those recommended at Cuernavaca. In some settings,
the recommended fortification levels may be too low
to achieve optimal benefit.
We were unable to discover any field trials employ-
ing ferrous fumarate that met our criteria. However,
isotopic studies suggest that the absorptions of ferrous
sulfate and ferrous fumarate are equivalent. Our recom-
mendations for ferrous fumarate are therefore the same
as those for ferrous sulfate.
Efficacy studies with electrolytic iron
The results of six efficacy studies in women or children
conducted with electrolytic iron are shown in table 4.
Four studies reported no improvement in iron status
or presence of anemia. Three of these studies were rela-
tively short interventions that provided only 3.2 to 7 mg
additional iron per day to children over a period of 5 to
8 months. The fourth study was that of Nestel et al. [39].
These workers provided 12.5 mg extra iron per day in
wheat flour over 2 years to women and children in Sri
Lanka and found no change in hemoglobin. Serum
ferritin was not reported. A significant improvement
in iron status was reported in two studies. Zimmer-
mann et al. [37] fed electrolytic iron-fortified biscuits
to young Thai women providing 10 mg additional iron
per day over 9 months. The study was judged as mod-
erately efficacious. The prevalence of iron deficiency
decreased from 45% to 21%, although there was no
change in hemoglobin. Sun et al. [34] provided 21 mg
additional iron per day in wheat flour to schoolchil-
dren over 6 months. The prevalence of iron-deficiency
anemia decreased from 100% to 60%.
Two additional efficacy studies have been done in
infants [26, 27]. These short-term studies also indi-
cated that relatively large amounts of electrolytic iron
can have a positive effect on iron status; however,
both studies included ascorbic acid, which would be
TABLE 3. Efficacy studies with ferrous sulfate
Iron compound
Encapsulated ferrous sulfatea
Dose
(mg/day)
11.8
Subjects and vehicle
Children 6–15 yr
Salt (bread, fava beans)
Women 18–40 yr
Wheat flour biscuits
Students 11–18 yr
Wheat flour
Women 18–35 yr
Wheat flour biscuits
Length of study
and country
9 mo
Morocco
9 mo
Thailand
6 mo
China
5.5 mo
Kuwait
Impact Ref
38Highly efficacious
Ferrous sulfate10.3Highly efficacious 37
Ferrous sulfate 11Moderately efficacious34
Encapsulated ferrous sulfateb
7.1Moderately efficacious 21
a. Encapsulated with partially hydrogenated vegetable oil (Balchem, NY, USA).
b. Encapsulated with hydrogenated palm oil; mean particle size ca. 40 µm.
TABLE 4. Efficacy studies with electrolytic iron
Iron compound
(manufacturer)(mg/day)
A131 (HÖganäs)
DoseSubjects
and vehicle
Length of study
and country
24 mo
Sri Lanka
9 mo
Thailand
7.5 mo
South Africa
6 mo
China
5 mo
Kenya
8 mo
South Africa
ImpactRef
3912.5 Women 16–50 yr
Wheat flour
Women 18–50 yr
Wheat flour biscuits
Children 6–11 yr
Brown bread
Children 11–18 yr
Wheat flour
Children 3–8 yr
Maize porridge
Children 6–11 yr
Brown bread
No change in hemoglobin
A131 (HÖganäs)10Moderately efficacious
No change in hemoglobin
No change in iron status
37
Unknown 3.257
Unknown21 Moderately efficacious 34
IMP7 No change in iron status35
Unknown4.5 No change in iron status 36

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S13
Iron fortification of wheat flour
expected to increase iron absorption and improve the
impact on iron status. Walter et al. [26] provided 12 mg
extra iron per day in rice cereal for 4 months and Lartey
et al. [27] provided an extra 18 mg iron per day in a
complementary food based on maize, soy, and ground-
nuts. Both studies demonstrated that relatively large
doses of electrolytic iron can have a positive impact
on iron status, suggesting that this form of iron can be
used if the fortification level is high enough.
The lowest dose of electrolytic iron shown to have a
significant impact on iron status is 10 mg. However, it is
important to note that electrolytic iron was less effica-
cious than ferrous sulfate in reducing iron deficiency in
the trial from which this value is derived [37] and that
in this study there was no reduction in the percentage
of subjects with anemia. Moreover, there was a 60%
residual presence of iron-deficiency anemia among
children in China after a 6-month trial using more
than twice this 10-mg dose [34]. Because of the uncer-
tainty about the lowest effective dose of electrolytic
iron, we have not used the information summarized in
tables 2 and 4 to formulate the recommendations for
electrolytic iron. It is suggested not to change the rec-
ommendation from the Cuernavaca Workshop, which
was to add electrolytic iron at twice the concentration
of ferrous sulfate.
Efficacy studies with hydrogen-reduced iron
Five efficacy studies have been reported with hydrogen-
reduced iron (table 5). Only one of these studies [37]
showed an improvement in iron status. This was the
SUSTAIN study in Thailand, which provided 10 mg
AC-325 hydrogen-reduced iron per day in wheat
flour biscuits to young Thai women over a period of
9 months. This study showed a small reduction in the
number of women with iron deficiency, but no change
in of the percentage of women with anemia. Another
study in Zambia [40] provided 14 mg iron per day as
hydrogen-reduced iron (source not specified) in maize
meal to refugees over 8 months. There were no changes
in iron deficiency in children, adolescents, or women,
although there was a small decrease in serum transfer-
rin receptor concentration in adolescents. The percent-
age of children with anemia dropped from 48% to 24%.
However, the study lacked a control group, making
it impossible to determine whether iron fortification
played any role.
Three other studies providing 3.6 to 14.3 mg hydro-
gen-reduced iron per day failed to demonstrate an
impact on iron status or hemoglobin. It is perhaps not
surprising that providing only 3.6 mg extra iron per
day (source not specified) in a seasoning powder to
Thai children over 7.5 months had no impact on iron
status [41]; however, providing 12.5 mg iron (source
not specified) per day in wheat flour to women and
children in Sri Lanka over 24 months also resulted in
no change in hemoglobin [39]. The most pertinent
observations are those recently reported by Biebin-
ger et al. [21]. In this study, young Kuwaiti women
were fed 14.3 mg iron per day in the form of a newly
developed hydrogen-reduced iron powder (Nutrafine
RS, Höganäs AB, Sweden) in wheat flour biscuits over
5.5 months. There was no improvement in their iron
status. This study is important because Nutrafine RS is
now marketed for food fortification in place of AC-325
hydrogen-reduced iron. The other commercial product
that is used widely is Atomet™ hydrogen-reduced iron
(QMP, Canada). In vitro solubility studies, rat hemo-
globin repletion tests, and human iron tolerance studies
indicate that this iron powder is likely to be the least
bioavailable of all commercial iron powders [23].
There is thus no new evidence to suggest that forti-
fication with currently available reduced iron powders
will have a significant beneficial effect on iron status. It
is not recommended, therefore, to use any reduced iron
powder for the fortification of wheat or maize flour.
TABLE 5. Efficacy studies with reduced iron powders
Iron compound
(manufacturer)
Unknown
Dose
(mg/day)
12.5
Subjects and vehicle
Women 14–50 yr
Wheat flour
Women 18–40 yr
Wheat flour biscuits
Children 5–13 yr
Seasoning powder
Both sexes 10–59 yr
Maize meal
Length of study
and country
24 mo
Sri Lanka
9 mo
Thailand
7.5 mo
Thailand
8 mo
Zambia
Impact Ref
39 No change in hemoglobin
Hydrogen-reduced iron
AC-325 (Höganäs)
Hydrogen-reduced iron
(unknown)a
Reduced (unknown)b
10 Moderate efficacy, no change in
hemoglobin
No change in iron status
37
3.641
14Small decrease in iron defi-
ciency in adolescents only, no
change in other groups
No change in iron status
40
Hydrogen-reduced iron
Nutrafine RS (Höganäs)
a. Fortificant contained multiple micronutrients.
b. Fortificant contained vitamin A.
14.3Women 18–35 yr
Wheat flour biscuits
5.5 mo
Kuwait
21

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R. Hurrell et al.
Efficacy studies with ferric pyrophosphate
The efficacy studies conducted with ground ferric
pyrophosphate (2.5 µm, Dr Lohmann, Germany) are
summarized in table 6. Although this compound has
never been used for flour fortification, it is organolepti-
cally inert and, like electrolytic iron, would appear to be
about half as well absorbed as ferrous sulfate in human
subjects [42]. All four efficacy studies reported a sig-
nificant improvement in iron status when schoolchil-
dren consumed between 10.5 and 18.6 mg additional
iron per day over 6 to 10 months. The two studies by
Zimmermann et al. [43, 44] in Morocco fed 18 and
18.6 mg iron in salt to children over 10 months. The
salt was largely added to home-cooked bread, and this
fortification strategy was judged as highly efficacious.
A third salt study [45] providing 10.5 mg iron per day
took place in Côte D’Ivoire and was judged moderately
efficacious, as was a study in India where schoolchil-
dren were provided an extra 17 mg iron per day in
extruded rice added to school meals [46].
Micronized ground ferric pyrophosphate may be a
suitable iron compound for wheat flour fortification at
concentrations similar to those suggested for electro-
lytic iron. However, because it is more expensive than
electrolytic iron and has not been tested in wheat or
maize flour, we have not made any recommendations
for its use.
Revised recommendations for iron
fortification of wheat flour
Table 7 gives the new recommendations for the iron
fortification of wheat flour which are based on our
review and discussions at this Workshop. Before
deciding on a compound, countries should first test
the recommended amounts of the specific compounds
in both flour and final products made from fortified
flour to ensure that no unacceptable sensory changes
occur. The first choices as iron fortificants for wheat
flour fortification are NaFeEDTA, ferrous sulfate, and
ferrous fumarate. We have the greatest confidence in
the recommendations for NaFeEDTA because of the
larger database and because NaFeEDTA absorption
is less likely to be affected by other components of the
meals in which it is eaten. The higher iron bioavailabil-
ity from wheat-based foods fortified with NaFeEDTA
means that lower levels of fortification iron can be
added. This in turn leads to less potential for sensory
changes. Moreover, NaFeEDTA has been reported not
to promote lipid oxidation in stored wheat flour.
These recommendations were discussed in the
plenary session at the Workshop and are consensus
recommendations. Four different daily wheat flour
consumption ranges were agreed upon at the Work-
shop (> 300, 150 to 300, 75 to 149, and < 75 g/day),
and mean daily consumption levels of 350, 225, 113,
and 50 g, respectively, were used to compute the sug-
gested flour fortification levels within each of these
consumption bands. Recommended values (table 7)
were rounded to the nearest 5 ppm interval. The reason
for using the mean consumption, rather than the lower
limit of consumption within a designated range, is that
regulations customarily stipulate a minimum require-
ment for fortification levels or flour nutrient content.
TABLE 6. Efficacy studies with micronized ground ferric pyrophosphate (2.5 µm)
Dose
(mg/day)and vehicleand country
18Children 6–15 yr
Salt Morocco
18.6Children 6–14 yr
SaltMorocco
17Children 6–13 yr
RiceIndia
10.5 Children 5–15 yr
SaltCôte d’Ivoire
Subjects Length of study
Impact Ref
4310 moHighly efficacious
10 moHighly efficacious 44
7 moModerately efficacious46
6 moModerately efficacious45
TABLE 7. Recommended iron fortification levels (ppm) for
wheat flour according to iron compound and daily flour
consumptiona
Flour
consumption
(g/day)
> 300
150–300
75–149
NaFeEDTA
15
20
40
Ferrous
sulfate or
ferrous
fumarate
20
30
60
Electrolytic
iron powder
40
60
Not
recommended
Not
recommended
< 754060
a. These recommended levels are based on the calculated required
levels presented in table 2 but in some cases have been rounded
off. For flour consumption < 75 g/day, lower levels have been
recommended in order to cause no sensory changes.

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Iron fortification of wheat flour
It is standard procedure for producers to exceed this
amount by a small margin (overage). It was therefore
considered prudent to reduce the risk of excessive iron
intake in individuals with high flour consumption by
targeting the middle of the consumption range. The
same concern applies to the risk of exceeding the
acceptable daily intake (ADI) for EDTA in flour forti-
fied with NaFeEDTA (discussed below).
It is recommended to add 15 ppm iron as NaFeEDTA
for flour intakes > 300 g/day, 20 ppm iron for flour
intakes of 150 to 300 g/day, and 40 ppm iron for flour
intakes of 75 to 149 g/day. At these levels of iron for-
tification and consumption, the additional iron intake
from the fortified flour would be expected to improve
iron status significantly in women and children and
reduce the prevalence of iron deficiency and iron-
deficiency anemia to rates encountered in Western
societies. A fortification level of 40 ppm is suggested
for flour intakes < 75 g. At these low flour intakes, the
extra iron intake from fortified flour consumption will
make a useful contribution to improving iron status,
but fortification of other food vehicles will be needed
for an adequate iron intake to be attained. Levels of
NaFeEDTA providing 15 and 20 ppm iron are con-
sidered unlikely to cause adverse sensory changes.
Such changes are more likely with 40 ppm iron as
NaFeEDTA. If they occur, encapsulated NaFeEDTA
should be considered.
NaFeEDTA is the only iron compound that is rec-
ommended for the fortification of high-extraction
(> 0.8% ash) wheat flour. The recommended fortifica-
tion levels are the same as for low-extraction (≤ 0.8%
ash) wheat flour: 15 ppm for flour consumption > 300
g/day, 20 ppm for 150 to 300 g/day, and 40 ppm for
< 150 g/day. The higher phytate content in high-extrac-
tion wheat flour is expected to reduce the percent iron
absorption, but it is anticipated that this will be offset
by an enhancement in absorption of the native flour
iron by the EDTA. NaFeEDTA is also recommended
for wheat products, such as pasta, in which there is no
fermentation process during manufacture. There are no
published human efficacy studies to support the rec-
ommendations for the fortification of high-extraction
flour or pasta.
The widespread use of NaFeEDTA will depend on
clarification of the putative, but as yet unsubstantiated,
potential risks of increasing the EDTA consumption
of the whole population. The following recommenda-
tion [47] for the use of NaFeEDTA as a food additive
was made at the 68th Meeting of the Joint FAO/WHO
Expert Committee on Food Additives:
Sodium iron EDTA is suitable as a source of iron for
food fortification to fulfil nutritional iron require-
ments, provided that the total intake of iron from all
food sources including contaminants does not exceed
the Provisional Maximum Tolerable Daily Intake of 0.8
mg/kg body weight. Total intake of EDTA should not
exceed acceptable levels, also taking into account the
intake of EDTA from the food additive use of other
EDTA compounds. An ADI of 0–2.5 mg/kg body weight
was previously established for calcium disodium and
disodium salts of EDTA, equivalent to up to 1.9 mg/kg
body weight EDTA [47].
This specification was noted without revision at the
31st Session of the Joint FAO/WHO Food Standards
Programme Codex Alimentarius Commission in
Geneva, 30 June to 4 July 2008 [48].
The fortification levels proposed in this document
would deliver approximately 4.5 mg/day of additional
iron in the form of NaFeEDTA and 23 mg EDTA. This
would amount to 0.42 mg EDTA/kg for a 55-kg woman,
well below the ADI. However, EDTA consumption
from mass fortification with NaFeEDTA may approach
or exceed the ADI for relatively short periods of time in
very young children when growth is rapid and caloric
intake is high in relation to body weight. A 1-year-old
child would be expected to weigh approximately 10 kg
and have a caloric intake approximately half that of an
adult woman. Under these circumstances, mean EDTA
intake may exceed the ADI for EDTA of 1.9 mg/kg
if wheat flour accounts for the same proportion of
caloric intake in the child as in the adult. It will also be
important for countries to evaluate EDTA intake from
other sources, although this is likely to be low. These
factors should be considered by countries planning to
implement NaFeEDTA fortification of wheat flour or
other food products. As indicated above, the desirable
impact on iron status may be achievable with modestly
lower levels of NaFeEDTA.
Ferrous sulfate has also consistently shown good effi-
cacy in a variety of iron-fortified foods. It is widely used
to fortify infant formulas and is the iron compound
chosen by WHO for food fortification. It has been
used in the highly successful wheat flour fortification
program in Chile, where it provides about 6 mg addi-
tional iron per day in about 200 g wheat flour [2]. This
amount is similar to the 7.1 mg/day minimum amount
reported to be efficacious in the studies reviewed in
this article. Ferrous fumarate is considered to be as
efficacious as ferrous sulfate on the basis of isotopic
experiments in human volunteers [49, 50]. However,
there are no efficacy studies to support this assumption.
Ferrous sulfate is preferred to ferrous fumarate but is
more likely to lead to unacceptable sensory changes in
some situations. Encapsulation of either compound will
prevent lipid oxidation in stored flours, with no impact
on bioavailability [51]. The recommended levels of for-
tification when using these compounds are 20 ppm iron
for flour consumption > 300 g/day and 30 ppm iron for
flour consumption between 150 and 300 g/day. For
flour consumption < 150 g/day, sensory changes may
result with the recommended level of 60 ppm unless