Golden Rice: To Combat Vitamin A Deficiency for Public Health

Abstract

Vitamin A deficiency (VAD) has been recognised as a significant public health problem continuously for more than 30 years, despite current interventions. The problem is particularly severe in populations where rice is the staple food and diversity of diet is limited, as white rice contains no micronutrients. Golden Rice is a public-sector product designed as an additional intervention for VAD. There will be no charge for the nutritional trait, which has been donated by its inventors for use in public-sector rice varieties to assist the resource poor, and no limitations on what small farmers can do with the crop-saving and replanting seed, selling seed and selling grain are all possible. Because Golden Rice had to be created by introducing two new genes-one from maize and the other from a very commonly ingested soil bacterium-it has taken a long time to get from the laboratory to the field. Now it has been formally registered as safe as food, feed, or in processed form by four industrialised counties, and applications are pending in developing countries. The data are summarised here, and criticisms addressed, for a public health professional audience: is it needed, will it work, is it safe and is it economic? Adoption of Golden Rice, the next step after in-country registration, requires strategic and tactical cooperation across professions, non-governmental organisations (NGOs) and government departments often not used to working together. Public health professionals need to play a prominent role.

Full text


Chapter
Golden Rice: To Combat Vitamin A
Deficiency for Public Health
AdrianDubock
Abstract
Vitamin A deficiency (VAD) has been recognised as a significant public health
problem continuously for more than 30years, despite current interventions. The
problem is particularly severe in populations where rice is the staple food and
diversity of diet is limited, as white rice contains no micronutrients. Golden Rice is a
public-sector product designed as an additional intervention for VAD.There will be
no charge for the nutritional trait, which has been donated by its inventors for use
in public-sector rice varieties to assist the resource poor, and no limitations on what
small farmers can do with the crop—saving and replanting seed, selling seed and
selling grain are all possible. Because Golden Rice had to be created by introducing
two new genes—one from maize and the other from a very commonly ingested soil
bacterium—it has taken a long time to get from the laboratory to the field. Now
it has been formally registered as safe as food, feed, or in processed form by four
industrialised counties, and applications are pending in developing countries. The
data are summarised here, and criticisms addressed, for a public health professional
audience: is it needed, will it work, is it safe and is it economic? Adoption of Golden
Rice, the next step after in-country registration, requires strategic and tactical
cooperation across professions, non-governmental organisations (NGOs) and
government departments often not used to working together. Public health profes-
sionals need to play a prominent role.
Keywords: Golden Rice, VAD, biofortification, β-carotene, micronutrients, estimated
average requirement (EAR), recommended daily allowance (RDA), novel proteins,
allergenicity, substantial equivalence, hidden hunger
. Introduction
Research was initiated in the early 1990s which led in 2000 to the publication
of the technology behind what came to be known as Golden Rice [1, 2]. From the
outset, the intention was to create a source of vitamin A in the endosperm of rice,
as an additional intervention for vitamin A deficiency. Philanthropy and the public
sector funded the research [1]. In 2001, the inventors, Professor Ingo Potrykus
and Dr. (now Professor) Peter Beyer, assigned their patents to Syngenta for com-
mercial exploitation as part of a transaction which obliged the company to assist
the inventors’ humanitarian and altruistic objectives [1, 3, 4]. At the same time, the
nutritional technology was donated by its inventors for use in developing countries
[3, 4]. The inventors licenced a network of Asian government-owned rice research
institutes to deliver their objectives. Product development was initiated through the
International Rice Research Institute (IRRI) and the network. The whole network,

Vitamin A

including IRRI, worked to a common set of goals defined in licences each institution
signed with the inventors. The terms included that there would be no charge for
the nutritional technology and it would only be introduced to publicly owned rice
varieties. Improvements were made to the technology by Syngenta scientists [5]. In
2005 and 2006, pursuant to Syngenta’s legal obligations entered into with the inven-
tors in 2001, Syngenta provided selected transformation events of the improvements
to the Golden Rice Humanitarian Board. The Humanitarian Board, via Syngenta
and IRRI, made these new versions available to the Golden Rice licensee network
[4, 6]. In 2004 Syngenta ceased its commercial interest in Golden Rice [7]. From
2004 development was again only funded by philanthropy and the public sector; the
national budgets of Bangladesh, China, India, Indonesia, Philippines and Vietnam;
as well as the US National Institutes of Health together with the Rockefeller and Bill
& Melinda Gates Foundations and USAID.Golden Rice is a not-for-profit project:
no individual, nor organisation involved with its development, has any financial
interest in the outcome.
To date the Golden Rice project has principally engaged plant scientists. Activist
opposition to Golden Rice has been led principally by non-scientists, who have
been very successful in developing a narrative about Golden Rice and gmo crops
which serves the activist’s purpose1 but is fundamentally inaccurate [8]. Further
background to the development of Golden Rice, including the political dimensions,
is detailed elsewhere [6, 9, 10].
A few years ago, at Tufts University, USA, I gave a presentation about Golden
Rice. The symposium was organised by the Friedman School of Nutrition Science
and Policy whose strategic aims today include ‘Reduce nutrition-related health
inequities’ and ‘Promote food systems that increase agricultural sustainability
while improving human health’ [11]. I was dismayed to learn that the anti-gmo and
anti-Golden Rice activists’ narrative was widely accepted by the participants—all of
whom were studying or working in nutrition and well aware of nutritional inequi-
ties in public health.
Without adoption, that is, regular growth and consumption of Golden Rice by
populations in countries where rice is the staple and VAD is problematic, Golden
Rice cannot deliver any public health and welfare benefits. Adoption requires
cooperative working by different specialists, including medical, nutritional and
public health specialists [12]. This chapter is designed to answer anticipated ques-
tions from such specialists, to facilitate adoption of Golden Rice as an additional
intervention for vitamin A deficiency.
. Rice, diet and deficiency
Rice is the most important staple crop [6]: more than half of the global popula-
tion eats it every day. In some countries, 70–80% of an individual’s calorie intake is
from consumption of rice [13, 14].
For storage without becoming rancid, the husk and the aleurone layer of rice
have to be removed. What remains after polishing-white rice, the endosperm-
contains small amounts of fat and is an excellent source of carbohydrate for energy
but contains no micronutrients. Yet humans require both macronutrients (carbohy-
drates, proteins, fats) and micronutrients (minerals and vitamins) for a healthy life.
Like all plants, rice obtains its minerals from the soil. Vitamins are synthesised by
plants and/or animals, including humans.
1 For example: https://www.heartland.org/_template-assets/documents/12-3-18%20Analysis%20of%20
Greenpeace%20Business%20Model.pdf

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Golden Rice: To Combat Vitamin A Deficiency for Public Health
DOI: http://dx.doi.org/10.5772/intechopen.84445
Human health is best served by a ‘balanced diet’ that is varied, containing both
macronutrients and micronutrients, including animal products and, as sources
of provitamin A, coloured fruits and vegetables. Micronutrient sources are insuf-
ficiently represented in the diets of many people in countries where rice is the
staple. The reasons often include poverty: such dietary components are expensive
compared to the cost of rice [15]. In countries where rice is the staple, the aver-
age consumption is 75.20kg/capita/year. Of those countries where micronutrient
deficiencies are common, consumption increases to 150kg/capita/year [16]. In such
populations micronutrient deficiencies, like poverty itself, often occur as part of an
intergenerational cycle [17].
For the past 15years, 800 million people—more than 10% of the global popula-
tion—are hungry every day. These chronically hungry individuals lack sufficient
calories in their daily diet [18–20]; indeed over the past 3 years, the trend is upward
[20]. Even more alarming is that 2 billion people—almost 25% of global popula-
tion—are micronutrient deficient; they suffer from ‘hidden hunger’, with important
associated morbidity and mortality [17] and related economic impact [6, 17].
Figure  shows that over the 20-year period 1990–2010, the rate of reduction of
chronic hunger (that is, macronutrient—carbohydrate, proteins and fats—dietary
insufficiency) has been faster than the rate of reduction for hidden hunger (that
is, dietary insufficiency of minerals and vitamins) [21] Dr. Matin Qaim, member
of the Golden Rice Humanitarian Board and one of the authors of the paper from
which Figure  is extracted, has commented: ‘In the future the hidden hunger [e.g.
micronutrient deficiency] burden will be larger, [than chronic hunger – principally
carbohydrate deficiency] unless targeted efforts to reduce micronutrient malnutri-
tion are implemented at larger scale’ (pers comm: Dr. M Qaim).
Interventions for micronutrient deficiencies include supplementation (with pills,
syrups or capsules containing micronutrients [22]) and fortification (adding micro-
nutrients to processed food). Both interventions require some level of manufactur-
ing and/or distribution infrastructure.
With the creation of Golden Rice in 1999 [2]—the first purposefully created
biofortified crop—a new term was required: ‘biofortification’. The word was first
used in 2002 [23] and first defined in 2004 [24]: “biofortification” is a word coined
Figure 1.
Disability-adjusted life years (DALYs) lost due to chronic hunger and hidden hunger between 1990 and 2010.
Please refer to text for further explanation (Figure 1 here is part of Figure 2 from Ref. [21]).

Vitamin A

to refer to increasing the bioavailable micronutrient content of food crops through
genetic selection via plant breeding.’ In 2003 ‘Harvest Plus’ a not-for-profit public-
sector programme started to biofortify staple crops by conventional plant breeding,
to benefit the poor, and progress with biofortification through conventional plant
breeding was rewarded by the World Food Prize in 2016 [25].
The intention of biofortification is to deliver public health benefits to popula-
tions which are micronutrient deficient, through consumption of the staple
crop including the extra nutrition within the edible part of the crop. In this
way minimal cultural change is required to food—production, processing or
consumption—systems. For the most marginal members of the population,
this biofortification approach overcomes the inherent access, cost and non-
sustainability difficulties of supplementation and fortification. In 2017 the World
Bank recommended that biofortified staple crops should be the norm rather than
the exception: ‘conventionally’ bred biofortified crops and also genetically engi-
neered crops—gmo crops—were both recommended with Golden Rice specifically
mentioned [26].
For Golden Rice to deliver benefits, it has to be grown and consumed within
target countries where VAD remains problematic despite significant progress with
other interventions, notably vitamin A capsules, which have undoubtedly saved
millions of lives and will save more, since they were introduced (accompanied by
controversy) in the 1990s [15, 22]. And success or failure with Golden Rice will
directly affect future adoption also of high zinc, high iron and high folate rice and
their impact on public health for hundreds of millions of people. All these traits,
introduced to the endosperm of rice, necessitated using gmo techniques [16, 27],
and all cost no more than white rice to the grower or consumer. Eventually, as the
end point of product development, it is planned to include all these nutritional
traits together in multi-micronutrient-Golden Rice.
Adoption of Golden Rice requires public health professionals as well as agricultural
and other professionals, to work together in each country [12]. Any scepticism created
by the past 18years of negative activist influence will prevent success, if not positively
addressed by all involved. For billions of people, the stakes could not be higher.
. The questions and answers
. Is Golden Rice needed?
For more than a quarter of a century, vitamin A deficiency (VAD) has been
recognised by the United Nations as a significant public health problem. Key
milestones included the:
 United Nations (UN) World Summit for Children, where 50 heads of
government and senior government officials committed their governments to the
virtual elimination of VAD by the year 2000 [28].
 UN International Conference on Nutrition, which concluded that
• VAD control is the most cost-effective child health/survival strategy govern-
ments can pursue.
• All sectors of society should support the virtual elimination of VAD.
• Strategies should include promoting breast-feeding, dietary diversification,
vitamin A supplementation and food fortification.
• Locally available food-based strategies are the first priority. Vitamin A capsule
supplementation is only an interim measure [29].

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Golden Rice: To Combat Vitamin A Deficiency for Public Health
DOI: http://dx.doi.org/10.5772/intechopen.84445
 United Nations International Children’s Emergency Fund (UNICEF)
and the Micronutrient Initiative Report ‘Vitamin and Mineral Deficiency’,
which concluded that ‘controlling vitamin and mineral deficiency is an affordable
opportunity to improve the lives of two billion people and strengthen the pulse of
economic development’ and that ‘probably no other technology available today
offers as large an opportunity to improve lives and accelerate development at such
low cost’ [30].
Nevertheless, vitamin A deficiency (VAD) remains a major public health
problem, in more than half of all countries, especially in Africa and south-east Asia
(Figure ), hitting hardest young children and pregnant women [31] especially in
countries where rice is the staple food. Food sources that are most valuable in terms
of micronutrients—for vitamin A, animal products including milk, eggs, butter,
liver and fish—are usually more expensive and ‘beyond the reach of poor families’
[15]. Food security staple crops such as rice are cheaper and therefore make up most
of the diet.
The problem of VAD is exacerbated by the limited bioavailability of vitamin A
from fruit and vegetables [33]. It has been estimated that young children between ages
1 and 3 years would need to eat eight servings of dark green leafy vegetables per day
in order to meet the recommended dietary allowance (‘RDA’) for vitamin A.These
facts have resulted in the conclusion of ‘the virtual impossibility for most poor, young
children to meet their vitamin A requirements through vegetable and fruit intake
alone’ [15].
VAD is the principal cause of irreversible blindness in children [34]. Another
morbidity of VAD is related to impairment of the immune system [15]: most
children and mothers who die as a result of VAD do not become blind first but die
of common childhood diseases. VAD is a nutritionally acquired immune deficiency
syndrome [15]. Increased susceptibility to disease as a result of VAD results in the
majority of the millions of preventable deaths annually, mainly of children less
than 5years old (<5 years) [22]. Meta-analyses have shown that 23–34% of global
mortality of children <5 years can be prevented by a universally available source of
vitamin A [22, 35, 36] and up to 50% for measles sufferers [31]. As the UN regularly
Clinical
Severe: subclinical
Moderate: subclinical
Mild: sporadic or
high risk
No data: problem likely
Figure 2.
Public health importance for vitamin A deficiency, by country. Source [32] (the original WHO map has been
redrawn and is provided here by courtesy of Banson, a publisher).

Vitamin A

measures and publishes global all-cause child mortality, the importance of VAD
mortality can be stated compared with other public health mortality causes, also
reported regularly by the UN (Tabl e ).
In 2016, 26years after the first UN commitment to virtually eliminate VAD by the
year  [28], and despite existing knowledge and interventions, 1.3–1.9 million,
mostly children less than 5years old, and many mothers, died from this preventable
vitamin deficiency (Tab le  ).
. Will Golden Rice work?
There is not one type of Golden Rice. The ‘genetic modification’ part of the pro-
cess used to create Golden Rice occurred only once, in about 2004 [5]. The preferred
‘transformation event GR2E’ was selected in late 2013 [6, 9] and subsequently intro-
duced by ‘conventional plant breeding’ into more than a dozen cultivars of the Oryza
sativa indica rice variety agronomically adapted to and preferred by the farming and
rice-consuming populations of India and Asia. These cultivars can be grown directly
and harvested and the polished Golden Rice sold and consumed, or the Golden Rice
seed can be used by rice breeders as ‘parents’ to introduce the trait into any locally
adapted and preferred rice variety, of which there are over 20,000.
The agronomy of Golden Rice—how it grows, its resistance to pests and dis-
eases, its water requirements and days to maturity and plant and grain morpholo-
gies—and yield are the same as the variety into which the nutritional trait has been
introduced. An avoidable human error was made in an earlier selection of ‘a lead
transformation event: GR2R’, which led to plants in open fields falling over when
subject to wind and rain, and a small yield loss of about 2% was the result [9, 38].
GR2R was dropped from development in late 2013. The current lead transformation
event, GR2E, was selected in the same year. GR2E has been, and will be, registered
for use and has no problems associated with it [6].
In his wonderful book The Vitamin A Story: Lifting the Shadow of Death [15], the
author Dr. Semba wrote (p.159): ‘From a public health standpoint, for food fortifi-
cation to be effective in reducing a population’s micronutrient deficiency, the food to
be fortified must be a dietary staple eaten daily with little or no variation. Further,
the fortified food should reach the entire population. Of course, the fortification
process must be economically feasible and have minimal effect on the cost of the
food treated. The micronutrient with which the staple is treated must be chemically
stable and undetectable by persons consuming it. Finally, to enable observation and
measurement of results, location or processing and distribution must be finite and
constant’. The book was published in 2012, when biofortification was known, but
Global mortality (millions) aa/
Vitamin A deficiency 1.9–2.8 1.4–2.1 1.3–1.9 (2016)b
HIV/AIDS 1.8 1.2 0.94 (2017)c
Tuberculosis (TB) 1.4 1.1 1.6 (2017)d
Malaria 0.7 0.6 0.45 (2016)e
aSource: []
bSource: –—see text—of .months < years children in  []
cSource: http://www.unaids.org/en/resources/fact-sheet [Accessed: January , ]
dSource: https://www.who.int/news-room/fact-sheets/detail/tuberculosis [Accessed: January , ]
eSource: https://reliefweb.int/report/world/world-malaria-report- [Accessed: January , ]
Tab le 1 .
Annual mortality from different public health diseases (VAD deaths exclude significant maternal mortality).

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Golden Rice: To Combat Vitamin A Deficiency for Public Health
DOI: http://dx.doi.org/10.5772/intechopen.84445
not sufficiently established to have any practical history. For whatever reason, Dr.
Semba does not mention biofortification, nor Golden Rice, in his book.
Nevertheless, for Golden Rice ‘from a public health standpoint, for food fortifi-
cation to be effective’, all the characteristics listed by Dr. Semba are satisfied, except
when it comes to ‘undetectable by persons consuming it’. The Golden Rice colour
is caused by the β-carotene content, a source of vitamin A for humans, which in
Golden Rice is about 80–90% of all carotenoids [5]. It is the same β-carotene which
colours mangos, papaya, squash and carrots, all of which consumers readily accept,
and there is no taste associated with the β-carotene content. In Golden Rice, the
intensity of the colour is proportional to the β-carotene content. The colour is obvi-
ous and cannot be ignored (Figure ).
In 2009 MBA students at the Asian Institute of Management conducted qualita-
tive attitudinal surveys of small farmers and consumers in four different repre-
sentative island locations in the Philippines. Neither the colour nor the way it was
created was considered a block to trying Golden Rice, so long as it was expected to
assist their family’s health and was affordable. The solid colour of Golden Rice was
recognisably distinct from the rather blotchy yellow colour of poorly stored white
rice, which is sometimes offered cheaply by governments to assist poor people.
From several perspectives the colour of Golden Rice is positive. Consumers have
a choice about whether to select it for cooking and whether to consume it or not.
Such consumer choice is denied and therefore only made by governments or plant
breeders, when the biofortified trait is ‘undetectable by persons consuming it’ [15],
as in the case of invisible biofortificants such as iron or zinc introduced into biofor-
tified grain crops or used in fortification of processed food. The colour of Golden
Rice makes the consumers’ choice clear, even in populations with a variety of
languages and dialects or where individuals are illiterate: each grain of Golden Rice
is individually labelled, by its colour. No labelling is required on any packaging, and
preference can be beneficially affected by communication of its lack of any adverse
associations, and anticipated health benefits, from consumption.
Eighty percent—about 380 million tonnes—of global rice production is pro-
duced on small farms for family consumption, usually unprocessed except for
polishing [38]. It is probably not stored for long, as rice is produced, usually, in two
or three growth cycles annually, and storage facilities are limited. Data have shown
that degradation of the β-carotene is minimal 2 months after harvest and samples of
Golden Rice stored in ambient temperatures for 4.5years remain noticeably yellow,
indicating continued presence of β-carotene [39].
In early 2001, a year after the seminal paper describing the ‘proof of concept’
technology [2], Greenpeace made a press release: ‘Genetically modified “Golden
Rice” containing provitamin A will not solve the problem of malnutrition in devel-
oping countries,… Greenpeace calculations show… , that an adult would have to eat
Figure 3.
Polished white and Golden Rice and (a different cultivar, after 2months of postharvest storage) after cooking.

Vitamin A

at least 3.7 kilos of dry weight rice, i.e. around 9 kilos of cooked rice, to satisfy their
daily need of vitamin A from “Golden Rice” …’ [40].
It is unclear how Greenpeace came to their conclusion. At the time, it was known
that the bioavailability of carotenoids is influenced by nine different factors [41]. But
no one knew how efficiently the β-carotene in Golden Rice was converted to circulat-
ing vitamin A, retinol, by human adults or children. And nutritionists agreed that
animal models would not be helpful because animals metabolise carotenoids differ-
ently than humans. Research was needed to determine how efficiently the β-carotene
in Golden Rice is converted to circulating retinol, in children in developing countries
where rice is the staple, the population segment which suffers most from VAD.
A February 2002 grant application to the US governments National Institutes
of Health (NIH) for a project, which is entitled ‘Retinol Equivalents of Plant
Carotenoids in Chinese Children’, states ‘This project is to determine the vitamin A
value (equivalence) of dietary provitamin A carotenes from spinach, Golden Rice,
and pure β-carotene (β-c) in oil. These experiments will be conducted in children
(ages 6–8) with/without adequate vitamin A nutrition’.
On February 10, 2004, Tufts University Institutional Review Board (IRB)
approved the research Protocol for ‘Retinol Equivalents of Plant carotenoids in
Chinese Children’ and noted that ‘The Zhejiang Academy of Medical Sciences
[China] approval is on file’.
On March 11, 2008, the Tufts IRB reviewed and on May 10, 2008, approved
the study ‘Vitamin A Value of Plant Carotenoids (Spinach and Golden Rice in
Children)’ based on the Protocol ‘Retinol equivalents of plant carotenoids in
Chinese children’. Both Protocols referenced ‘NIH grant proposal 1R01 DK060021’.
On March 30, 2008, with respect to ‘Retinol Equivalents of Plant carotenoids
in Chinese Children’ and ‘NIH Grant 1R01 DK060021-01’: The Ethical Review
Committee of Zhejiang Academy of Medical Sciences confirmed that they had
‘reviewed the proposed use of human subject identified on June 27, 2003’ and certi-
fied that ‘the approval notice is still valid’.
Although the Chinese children research was planned in 2003, various practical
setbacks in the production2 of the deuterium-labelled Golden Rice [9] meant that the
field work in China was not completed until mid-June 2008 and, due to the complex-
ity of analysis combined with limited analytical resources, publication not until 2012.
In the meantime, similar research was approved and conducted with adult
volunteers in the USA.Data confirmed that 3.8 molecules of β-carotene derived by
consumption of a single meal of Golden Rice converted to one molecule of circulat-
ing retinol [42]; this 3.8:1 bioconversion compared very favourably with conver-
sion ratios established using other plant sources [33]. When the Chinese children
research were published online on August 8, 2012, the authors reported a bioconver-
sion ratio of 2.3:1.0, later adjusted to 2.1:1.0, and neither ratio significantly different,
statistically, from the 2.0:1.0 of β-carotene in oil, another treatment in the same
research. A third treatment, spinach, showed a 7.5:1.0 conversion. In each case the
sophisticated research design measured the efficiency of conversion of β-carotene
to circulating retinol following a single meal containing the β-carotene source. The
publication noted that ‘In summary, the high bioconversion efficiency of Golden
Rice β-carotene to vitamin A shows that this rice can be used as a source of vitamin
A.Golden Rice may be as useful as a source of preformed vitamin A from vitamin A
capsules, eggs or milk to overcome VAD in rice-consuming populations’ [4, 6].
These results were clearly very different from Greenpeace’s 2001 prediction.
Instead of welcoming the excellent news of a potentially useful additional VAD
intervention, Greenpeace, on August 29, 2012, issued a further press release in
2 At Baylor College of Medicine, Children’s Nutrition Research Center, Houston, USA

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Golden Rice: To Combat Vitamin A Deficiency for Public Health
DOI: http://dx.doi.org/10.5772/intechopen.84445
China from their Netherlands HQ: ‘Greenpeace alarmed at US-backed GE food trial
on Chinese children’…‘It is incredibly disturbing to think that an American research
body used Chinese children as guinea pigs for genetically engineered food,…
The relevance of this study is questionable,…Nor does high conversion rate solve
all the technical, environmental and ethical issues around Golden Rice’ [6, 10].
Greenpeace claimed that the Chinese authorities agreed to halt the research before
it started3 but were unable to substantiate their claim to an independent journalist.
The press release created hysteria in China and, 4years after the field research had
been completed, caused the parents of the subject children consternation.
Tufts University IRB carried out an investigation and concluded that there were
‘no concerns related to the integrity of the study data, the accuracy of the research
results or the safety of the research subjects. In fact, the study indicated that a single
serving of the test product, Golden Rice, could provide greater than 50 percent of
the recommended daily intake of vitamin A in these children, which could signifi-
cantly improve health outcomes if adopted as a dietary regimen’. Tufts also noted
that ‘the research itself was found not to have been conducted in full compliance
with IRB policy or federal regulations’ [43].
Eventually following this Greenpeace Press release, Tang etal. (2012) was
retracted by the American Society of Clinical Nutrition in 2015 for procedural rea-
sons. The full details of this and other impediments to Golden Rice’s development
are given elsewhere [6, 9, 10, 43].
Separately, the Chair of the Tufts IRB, a computer scientist, in complaint to the
publisher of one critical review of the case [10], wrote: ‘There was no research ethics
committee or IRB review and approval in effect for the study when it was conducted
in 2008’. This gross error of fact, with reference to the NIH grant and related
IRB authorisations quoted above, itself calls into question the professionalism or
objectivity of the 2012 Tufts IRB review which led to the retraction. (The research
sophistication and quality of the retracted paper can be reviewed online [44]).
Henry Miller, a physician, molecular biologist and the founding director of the
US Food and Drug Administration (FDA), commented in 2015 on the retracted
paper: ‘A 2012 article in the nutrition literature might have been the most momen-
tous contribution to public health worldwide since Dr. Jonas Salk’s announcement
of the polio vaccine. The operative phrase is might have been, because intimidation,
politics and the dishonest, anti-science efforts of NGOs to impugn the research have
delayed the translation of its findings to life-saving interventions for millions of
children. Why do anti-genetic engineering activists want to save the whales but let
children go blind and die?’ [45].
The data generated by the above-mentioned research allow determination of the
proportion of the estimated average requirement (EAR) the β-carotene content of
Golden Rice can provide to children and adults (Table ). If Golden Rice was the
sole source of β-carotene in the diet, 50% of the EAR is sufficient to combat VAD
[46]. Many nutritionists consider that supply of 30–40% of the EAR will be suf-
ficient to combat VAD because the biofortified staple crop is seldom the only source
of β-carotene. (The recommended daily allowance—RDA—which implies mainte-
nance of 3-months liver stores of vitamin A, is not required to combat VAD.) The
calculations (Tabl e ) use the β-carotene levels observed in different Golden Rice
cultivars (e.g. RC82, BR29, IR36, IR64) of Golden Rice GR2E 2months after har-
vest, when degradation has stabilised. A 6% loss of β-carotene in cooking Golden
Rice, or 25% loss of β-carotene when a Golden Rice meal is parboiled first, and then
reheated, has not been taken into account.
3 http://www.greenpeace.org/eastasia/news/blog/24-children-used-as-guinea-pigs-in-geneticall/
blog/41956/

Vitamin A

. Is Golden Rice safe?
Golden Rice differs from white rice only in that it contains β-carotene, that is,
provitamin A, which the human body converts to vitamin A.Golden Rice contains
no vitamin A itself. So the question about safety relates principally to β-carotene,
which is anyway ubiquitous in a balanced human diet and the environment.
At the levels found in food, β-carotene is a safe source of vitamin A, and classed
as ‘generally recognised as safe’ (GRAS), by the United States Food and Drug
Administration (US FDA) [47, 48]. At these physiological doses, consumption of
β-carotene over several years has no adverse health effects [49–52]. The human
body only converts to vitamin A, in the form of circulating retinol, the amount of
β-carotene necessary, with the rest being excreted or stored unchanged in body tis-
sues (e.g. fat, liver, etc.). It is impossible to induce vitamin A toxicity by consuming
β-carotene (pers. comm. Dr. R Russell).
In all β-carotene-containing crops, immediately after harvest the level of
β-carotene reduces. For Golden Rice carotenoid degradation mechanisms have been
thoroughly investigated4 and the products of degradation quantitated. Additionally,
102 plant food items from Philippine markets, together with orange- or yellow-
coloured soft drinks, as well as non-gmo field grown, in all cases, orange maize cobs
and yellow cassava storage roots from Zambia, and orange-fleshed sweet potato
tubers from Uganda, were analysed for the cleavage products of β-carotene, apoca-
rotenoids [53]. The potential risks arising from ‘aberrant plant carotenoid synthesis’
[54] in genetically modified plants, including Golden Rice, or from non-gmo crops
biofortified with pro-vitamin A, have been thoroughly investigated, the authors
4 Golden Rice cv. Kaybonnet was investigated because it was available [5] and has high degradation poten-
tial. Kaybonnet is not a cultivar that will be used anywhere.
Amount of β-carotene in Golden Rice
μg/g
Rice consumption per day (g of
dry rice before cooking)
Percentage of EAR
provided
β-carotene to circulating retinol bioconversion rate: .: (e.g. children) To a childa
4.0 40 36%
4.0 100 91%
6.0 40 54%
6.0 100 136%
11.2 40 102%
11.2 100 254%
β-carotene to circulating retinol bioconversion rate: .: (e.g. adults) To an adult
4.0 40 20%
4.0 100 50%
6.0 40 30%
6.0 100 75%
11.2 40 56%
11.2 100 140%
aFor - to -year-old child,  of EAR is μg RAE/day. An EAR that does not ensure adequate stores but is
enough for normal dark adaptation is set at  g ~ EAR []
Tab le 2 .
The potential for Golden Rice to deliver the estimate average requirement of β-carotene, as a source of vitamin A,
to 1–3-year-old children and adults.

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Golden Rice: To Combat Vitamin A Deficiency for Public Health
DOI: http://dx.doi.org/10.5772/intechopen.84445
reporting that ‘Our analysis and quantification of β-carotene derived cleavage
products across biofortified and non-biofortified crop plant tissues combined with
the calculation of potential exposure document no reason for concern’ [53].
For the formal regulatory approvals for the use of a gmo crop in food, as animal
feed or in food or feed processing, on a country by country basis, detailed data sets
have to be submitted. For permission to grow a gmo crop in a country, additional
data have to be generated5 and submitted showing environmental safety.6 The ‘food,
feed and processing’ data package developed for Golden Rice GR2E is extensive (42
megabytes of data). It is available without cost to all Golden Rice licensee countries
consistent with long-standing Golden Rice Humanitarian Board policy. Here are the
key summaries of the regulatory data submission made in the Philippines:
“PROPOSAL FOR DIRECT USE AS FOOD AND FEED, OR FOR PROCESSING
Provitamin A Biofortified GRE Rice
Description of the Regulated Article for Direct Use
Rice event GRE (IR-ØØGRE-) was developed using recombinant-DNA techniques
to express elevated levels of provitamin A (mainly β-carotene) in the rice endosperm,
which is converted in the body to vitamin A.GRE rice was produced by Agrobacterium
tumefaciens-mediated transformation of embryogenic rice calli with plasmid pSYN
resulting in the introduction of the phytoene synthase (psy) gene from Zea mays
(Zmpsy), the carotene desaturase I (crtI) gene from Pantoea ananatis,7 and the phospho-
mannose isomerase (pmi) gene from Escherichia coli as a selectable marker.
GRE rice is intended to complement existing efforts to mitigate vitamin A deficiency
by supplying consumers in societies whose diet is primarily rice-based with a portion of
the estimated average requirement for vitamin A.
Summary of Potential Effects on Human and Animal Health
The safety assessment of GRE rice evaluated information on the history of safe use
of rice as a crop, the source of donor genes introduced into GRE rice, the molecular
characterisation of the modified plant, the stability of the inserted genetic elements,
characterisation of new proteins produced in the modified plant and their expression
levels, the potential allergenicity and potential toxicity of the newly expressed proteins,
and the nutrient composition of GRE rice compared to conventional rice.
Molecular characterisation of the introduced DNA within event GRE confirmed
the presence at a single insertion site of one copy of the inserted DNA that was stably
inherited over multiple generations as a single genetic locus per Mendelian rules of
inheritance. Expression of the ZmPSY and CRTI proteins was limited to the rice
endosperm with maximum concentrations in mature grain of approximately . and
.ppm, respectively. The PMI protein was expressed in all rice tissues measured
and accumulated to maximum concentrations of . and .ppm in mature
grain and straw, respectively.
A tiered “weight-of-evidence” approach was followed in assessing the safety of the
ZmPSY, CRTI, and PMI proteins expressed in GRE rice. The ZmPSY and CRTI
proteins did not display significant amino acid sequence similarity with known aller-
gens nor were there any primary sequence structural alerts for potential toxicity based
on similarity searches against a database of known and putative protein toxins. Both
ZmPSY and CRTI were rapidly and completely digested in the presence of simulated
gastric fluid containing pepsin, and the enzymatic activity of both proteins was destroyed
following treatment at temperatures well below those used during cooking.
5 Agronomic/phenotypic data and related studies for GR2E Golden Rice can be found at: http://www.
agbios.org/?page_id=767
6 The regulations exist and have to be complied with. Nevertheless, many disagree that they are justified
[6, 10, 59, 73–76].
7 This is the same organism as Erwinia uredovora [2, 5]. The name was changed.

Vitamin A

Due to the non-food source of the crtI gene, acute oral toxicity testing of CRTI protein
in mice was conducted as a further assurance of safety and demonstrated a lack of any
observable adverse effects at a dose of mg/kg body weight, which represents at least a
,-fold margin of exposure relative to any realistically conceivable human dietary
intake from GRE rice.
Based on its presence in a wide range of food and feedstuffs derived from genetically
engineered maize lines, and on the extensive history of prior regulatory reviews in the
Philippines, additional characterisation of the PMI protein was unnecessary. Previously
submitted safety studies reviewed in the context of other genetically engineered plant events
are directly applicable to the safety assessment of PMI protein expressed in GRE rice.
The genetic modification resulting in GRE rice was only intended to increase levels
of provitamin A (primarily β-carotene) in the rice endosperm. To confirm the intended
effect and the lack of any meaningful unintended consequences of the genetic modification,
compositional parameters were compared between GRE rice and control, unmodified,
rice. Compositional analyses were performed on samples of rice grain and straw obtained
from PSB Rc rice containing event GRE and near-isogenic control PSB Rc rice that
was grown at four separate sites in the Philippines during  and again in . The
compositional assessment included analyses for proximates, fibre, and minerals in samples
of straw, and analyses for proximates, minerals, vitamins, amino acids, fatty acids,
vitamins, and key anti-nutrients in grain samples. Samples of processed bran derived from
GRE and control rice were also analysed for proximates, fibre, and minerals.
Among the  compositional components that were tested for in samples of GRE
and control PSB Rc rice grain, and  components that were assessed in derived
bran and straw samples, the only statistically significant difference observed from
the multi-year combined-site analysis was for stearic (C:) acid, a minor fatty
acid component, measured in grain samples (not including the intended difference in
provitamin A levels). Except for β-carotene and related carotenoids, the compositional
parameters measured in samples of GRE rice, including stearic acid, were within or
similar to the range of natural variability of those components in conventional rice
varieties with a history of safe consumption. Overall, no consistent patterns emerged
to suggest that biologically meaningful changes in composition or nutritive value of the
grain or straw had occurred as an unexpected, unintended consequence of the genetic
modification.
Collectively, the studies performed for GRE rice have not identified potential health
and safety concerns, and support the conclusion that food and/or livestock animal feed
derived from provitamin A biofortified GRE rice is as safe and nutritious as food or feed
derived from conventional rice varieties.”
Although it is hard to imagine that such golden grains of polished Golden Rice
could be included in commercial shipments of white rice by accident, in the modern
world, any such inclusion could be damaging to international trade. To prevent even
such an unlikely situation, the Golden Rice regulatory data have been submitted
to regulatory authorities in countries which import rice, where VAD is not a public
health issue. As a result of these data submissions, Golden Rice GR2E has been
confirmed as safe for use as food, in feed, and for processing by the government’s
regulatory authorities in Australia, Canada, New Zealand and USA.The regulatory
deliberations and decisions are publicly available: Australia and New Zealand,8
Canada9 and the USA.10
8 http://www.foodstandards.gov.au/code/applications/Pages/A1138GMriceGR2E.aspx
9 https://www.canada.ca/en/health-canada/services/food-nutrition/genetically-modified-foods-other-
novel-foods/approved-products/golden-rice-gr2e.html
10 https://www.accessdata.fda.gov/scripts/fdcc/?set=Biocon&id=IR-00GR2E-5

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Golden Rice: To Combat Vitamin A Deficiency for Public Health
DOI: http://dx.doi.org/10.5772/intechopen.84445
Because in these industrialised countries rice forms only a tiny proportion of
standard diets which already contain ample sources of vitamin A, the amounts of
β-carotene in Golden Rice would have no significant additional nutritional benefit
there. Comments to this effect by the US regulatory authorities were implied by
anti-gmo crop opponents to be applicable also in developing countries where the
dietary situation is completely different. Such implication has been rebutted by
the US FDA [55]. The regulators in these industrialised countries concurred with
Tufts University’s statement issued after their investigation of the ‘Chinese children’
research: ‘… Golden Rice, …could significantly improve health outcomes if adopted
as a dietary regimen’ [43].
Further regulatory submissions have been made, and registrations are expected,
in countries where VAD is a public health problem [56]. In the Philippines the pro-
cess is not yet complete; nevertheless various government departments have already
expressed their support.11
Gmo crops have been vilified by activist groups since the 1990s. ‘Frankenstein
foods’ were used in a letter in the New York Times on June 16, 1992. The Daily Mail, a
UK newspaper, headlined the same phrase in February 1998 and subsequently and
extensively used ‘Frankenfoods’ [57]. The ‘anti-gmo groups’, in various guises, have
been critical of Golden Rice, a gmo crop, since 2001 [6, 10, 40].
Notwithstanding this opposition, all independent scientific institutions globally
have determined, for many years, that there is no inherent danger to crop plants, or
the human use of crops plants, or the environment from transferring genes from
one organism to another, to create gmo crops, also known as genetically engineered
(GE) crops, including transfer of genes between species which cannot sexually
reproduce to transfer the genes ‘naturally’ [6, 58, 59].
Norero [60] provides a list of more than 240 independent science institutions
from all over the globe which have commented on the safety of the techniques of
genetic modification. A particularly clear reference comes from the heart of the
geography politically most opposed to gmo technology, the European Commission
of the European Union:
‘The main conclusion to be drawn from the efforts of more than 130 research
projects, covering a period of more than 25 years of research and involving more
than 500 independent research groups, is that biotechnology, and in particular
GMOs, are not per se more risky than, for example, conventional plant breeding
technologies’ [61].
At the time of writing, 141 Nobel Laureates, of about 290 living, have signed an
open letter dated June 29, 2016, addressed to the leaders of Greenpeace, the United
Nations and governments around the world calling for the campaign against Golden
Rice specifically, and crops and foods improved through biotechnology in general,
to cease ‘Opposition based on emotion and dogma contradicted by data must be
stopped’ [8]. The letter also has the support of more than 13,000 other scientists
and citizens.
. Is Golden Rice economic?
Golden Rice seed and regulatory data packages are available—without cost—to
public-sector rice-breeding institutions in less developed countries where rice is
the staple and vitamin A deficiency endemic. Supply is subject only to national
and international regulations and simple and free agreements [4]. The licences
11 http://www.agbios.org:8085/wp-content/uploads/2018/07/Consolidated-Report-gr2e-rice_revised-1.
pdf

Vitamin A

ensure that the inventor’s, Professors Potrykus and Beyer, objectives for their
donated technology cannot be frustrated: only publicly owned rice varieties can
be used, and the nutritional trait cannot be ‘stacked’ with any other gmo trait,
unless the latter is also under the control of the public sector. There will be no
charge to growers or consumers for the nutritional trait: Golden Rice will cost the
same as white rice. Golden Rice homozygous seed, which breeds true generation
to generation, will be provided by public-sector rice breeders. All small-holder
family farmers—responsible for 80% of global rice production [38]—will eventu-
ally have access to it, with (except for commercial export—not a resource-poor
farmer activity) no limitations on planting or replanting, harvest or sale of seed
or grain.
Addressing micronutrient malnutrition, including VAD, is consistently ranked
by the Copenhagen Consensus process, as the first, or at least within the top5,
most cost-effective investments with the potential to address the world’s 30 most
intractable problems [62–64]. Investing in alleviating malnutrition would repay
$45 for each dollar invested compared with $36 from fighting malaria and $10 from
combatting HIV [65].
Compared with the World Bank standard, or the full cost of provision of vitamin
A capsules, a common dietary supplement intervention for VAD since the early
1990s [15, 22], the cost of Golden Rice to save each disability-adjusted life year
(DALY) is expected to be very low, perhaps US$0.5 [9, 66, 67].
Economists have calculated that conservative adoption of Golden Rice would
benefit the gross domestic product (GDP) of Asian countries by US$6.4 bil-
lion (value in US$ of 2005) annually through increased productivity enabled
by reduced vitamin A deficiency-induced sickness, and improved eyesight, and
~US$17.4 billion (value in US$ of 2005) if Golden Rice adoption encouraged
adoption of other nutritional traits in rice [68]. Recently, HarvestPlus has exceeded
target levels of iron and zinc in rice, which they were unable to achieve by conven-
tional breeding, using gmo techniques [16]. Genetic modification has also been
used to introduce folate into rice endosperm [27, 69]. The delay to the introduc-
tion of Golden Rice in India has been calculated to have cost Indian GDP US$199
million perannum for the decade from 2002 [70, 71], in total about US$1.7 billion
(value in US$ of 2014).
Costs (US of ) Highest efficiency Lowest efficiency
World Bank cost-effective standarda$200 $200
Providing vitamin A capsulesa$134 $599
Vitamin A fortification of fooda$84 $98
Golden Rice, India @ 12:1a$3.10 $19.4
Golden Rice, Bangladesh 6:1b & 12:1c$4.0b$54.0c
Golden Rice, abovea,b,c adjusted 2.1:1d$0.5 $1.4 $3.4 $9.5
The earlier studies occurred before these bioconversion ratios had been elucidated
aSource: []
bSource: []
cSource: []
dSource: From the bioconversion efficiency .: Ta ble 
Table 3.
Relative costs of saving one disability-adjusted life year using different sources of vitamin A and, for Golden
Rice, different bioconversion ratios of β-carotene to circulating vitamin A.


Golden Rice: To Combat Vitamin A Deficiency for Public Health
DOI: http://dx.doi.org/10.5772/intechopen.84445
Adoption of biofortified crops, including Golden Rice, will facilitate attainment of
six of the most important Sustainable Development Goals 2015–2030 (Tabl e ). The
standard costs used by the economists referenced in Tables  and  [62–64, 66, 67]
refer to the costs of supplementation with vitamin A capsules. As when using Golden
Rice, the vitamin A source has zero cost to the grower or consumer; the cost benefit of
Golden Rice will be very significantly better than using vitamin A capsules.
. Conclusions
Vitamin A deficiency remains a huge public health problem despite existing
interventions. Biofortification of staple foods is a new policy priority internation-
ally. Golden Rice is safe. There is excellent human evidence that it will work. It is
expected to be extremely cost-effective.
For successful adoption of Golden Rice as an additional intervention for vitamin
A deficiency, the support of public health professionals is critical.
Acknowledgements
Dr. Robert Russell chaired the ‘panel on micronutrients’ the output of which,
published in 2001 [72], created the US Governments’ dietary reference intakes for
14 micronutrients, including vitamin A.Also, in 2001, he joined the Golden Rice
Humanitarian Board. I am grateful for his nutritional advice and instruction over
the intervening years and for checking my calculations in connection with Table
 and the surrounding text. I have known Dr. Guangwen Tang almost as long and
thank her for providing, years ago, copies of the original documents which allowed
me to construct with confidence the chronology of the IRB permissions 2003 and
2008in the USA and China, all referring to the same NIH grant. Since 2015, the
project has benefited from another specialist professional, Dr. Donald MacKenzie,
who, aside from managing the GR2E regulatory data package generation, com-
pilation and submissions, has also provided the web-links, which I have listed as
footnotes in the ‘Safety’ section of this chapter. Thank you, Don, for your critically
important work.
Conflict of interest
The author declares no conflict of interest.
Goal  Goal Potential impact of biofortification
1No poverty Micronutrients in staple crops reduce effects
2Zero hunger Whole populations will be micronutrient sufficient
3Good health Provitamin A, Fe, Zn, Folate: less morbidity and mortality
4Quality education Pupils learn when adequately fed: Fe important
5Gender equality Biofortified staples available to whole population
7Decent work and
economic growth
Increased productivity from biofortified rice alone will add
US$17.4 (in US$ of 2005) to Asian GDP
Tab le 4 .
Biofortification and some Sustainable Development Goals 2015–2030.

Vitamin A

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Author details
AdrianDubock
Golden Rice Humanitarian Board, Switzerland
*Address all correspondence to: contact@goldenrice.org


Golden Rice: To Combat Vitamin A Deficiency for Public Health
DOI: http://dx.doi.org/10.5772/intechopen.84445
References
[1] Potrykus I.From the concept
of totipotency to biofortified
cereals. Annual Review of
Plant Biology. 2014;(1):1-22.
Available from: http://www.
annualreviews.org/doi/abs/10.1146/
annurev-arplant-043014-114734
[2] Ye X, Al-Babili S, Klöti A, etal.
Engineering the provitamin A
(β-carotene ) biosynthetic
pathway into (carotenoid-free)
rice endosperm. Annual Review of
Plant Biology. 2000;(5451):303-
305. Available from: http://www.
annualreviews.org/doi/abs/10.1146/
annurev-arplant-043014-114734
[3] Potrykus I.The private sectors role
for public sector genetically engineered
crop projects. Pontifical Academy of
Sciences. 2010;(43660):578-571.
Available from: http://www.pas.va/
content/dam/accademia/pdf/sv113/
sv113-potrykus3.pdf
[4] Dubock A.Golden Rice: A Long-
Running Story at the Watershed of
the GM Debate. 2013. Available from:
www.goldenrice.org; http://b4fa.
org/wp-content/uploads/2013/10/
Viewpoints-Dubock.pdf. pp.1-12
[5] Paine J, Shipton C, Chaggar S, etal.
Improving the nutritional value
of Golden Rice through increased
pro-vitamin A content. Nature
Biotechnology. 2005;(4):482-487.
Available from: http://www.ncbi.nlm.
nih.gov/pubmed/15793573
[6] Dubock A.An overview of
agriculture, nutrition and fortification,
supplementation and biofortification:
Golden Rice as an example for enhancing
micronutrient intake. Agriculture &
Food Security. 2017;(1):1-20. DOI:
10.1186/s40066-017-0135-3
[7] Maeder C, Michaelis D.Syngenta to
Donate Golden Rice to Humanitarian
Board. Form 6-K, Securities and
Exchange Commission, Washington,
DC. 2004. Available from: http://
www.sec.gov/Archives/edgar/
data/1123661/000095010304001433/
oct1504_6k.htm
[8] Richard R etal. 2016. Available from:
http://supportprecisionagriculture.org/
nobel-laureate-gmo-letter_rjr.html
[9] Dubock A.The present status of
Golden Rice. Journal of Huazhong
Agricultural University. 2014;(6):69-
84. Available from: http://www.
goldenrice.org/PDFs/DubockThe_
present_status_of_Golden_Rice-2014.pdf
[10] Dubock AC.The politics of Golden
Rice. GM Crops & Food. 2014;(3):
210-222. Available from: https://
www.landesbioscience.com/journals/
gmcrops/
[11] Tufts University, The Gerald J.
and Dorothy R.Friedman School of
Nutrition Science and Policy. Strategic
Plan Summary. Available from: https://
nutrition.tufts.edu/sites/default/
files/strategic-plan/strategic-plan-
summary.pdf
[12] Dubock A.Golden Rice:
Instructions for use. Agriculture & Food
Security. 2017;(1):1-6. DOI: 10.1186/
s40066-017-0136-2
[13] Bouis H, Islam Y.Chapter 10:
Biofortification: Leveraging agriculture
to reduce hidden hunger. In: Fan S,
Pandya-Lorch R, editors. Reshaping
Agriculture for Nutrition and Health.
Washington, DC: International Food
Policy Research Institute; 2012.
https://www.ifpri.org/publication/
reshapingagriculture-nutrition-and-
health
[14] Zhu etal. Carbon dioxide levels
this century will alter the protein,
micronutrients, and vitamin content

Vitamin A

of rice grains with potential health
consequences for the poorest rice-
dependent countries. Science Advances.
2018;(eaaq1012):8
[15] Semba RD.The vitamin A story:
Lifting the shadow of death. World
Review of Nutrition and Dietetics.
2012;:1-207
[16] Trijatmiko KR etal. Biofortified
indica rice attains iron and zinc
nutrition dietary targets in the field.
Scientific Reports. 2016;(19792):1-13.
Available from: http://www.nature.com/
articles/srep19792
[17] Bailey R, West K, Black R.The
epidemiology of global micronutrient
deficiencies. Annals of Nutrition &
Metabolism. 2015;(Suppl. 2):22-33
[18] FAO of UN.The Scourge of
“Hidden Hunger”: Global Dimensions
of Micronutrient Deficiencies. 2003.
Available from: ftp://ftp.fao.org/
docrep/fao/005/y8346m/y8346m01.
pdf
[19] Ministers GA.G20 Agriculture
Ministers Meeting Communiqué. 2016.
Available from: http://www.g20.org/
English/Documents/Current/201606/
t20160608_2301.html
[20] FAO, IFAD, UNICEF, WFP and
WHO.The State of Food Security and
Nutrition in the World 2018. Building
Climate Resilience for Food Security
and Nutrition. Rome: FAO; 2018
[21] Gödecke T, Stein A, Qaim M.The
global burden of chronic and hidden
hunger: Trends and determinants.
Global Food Security. 2018;:21-29
[22] West K, Klemm R, Sommer A.
Sound science, sound policy. Journal
of World Public Health Nutrition
Association. 2010;(5):211-229
[23] Welch R.Breeding strategies
for biofortified staple plant foods to
reduce micronutrient malnutrition
globally. The Journal of Nutrition.
2002;:495S-499S
[24] Welch R, Graham R.Breeding for
micronutrients in staple food crops
from a human nutrition perspective.
Journal of Experimental Botany.
2004;(396):353-364
[25] WFP.World Food Prize. 2016.
Available from: https://www.
worldfoodprizeorg/en/laureates/2016__
andrade_mwanga_low_and_bouis/
[26] World Bank Group. An Overview
of Links Between Obesity and Food
Systems. 2017. Available from: http://
www.gainhealth.org/wp-content/
uploads/2017/07/Final-Overweight-
Obesity-Report.pdf
[27] Storozhenko S, De Brouwer V,
Volckaert M, etal. Folate fortification of
rice by metabolic engineering. Nature
Biotechnology. 2007;:1277-1279
[28] United Nations. UN World Summit
for Children. NewYork. 1990. Available
from: http://www.unicef.org/wsc/
[29] FAO of UN.The International
Conference on Nutrition. 1992.
Available from: http://www.fao.org/
docrep/v7700t/v7700t02.htm
[30] UNICEF and The Micronutrient
Initiative. Vitamin & Mineral
Deficiency. A Global Damage
Assessment Report. 2004. Available
from: http://www.micronutrient.
org/CMFiles/PubLib/Report-67-
VMD-A-Global-Damage-Assessment-
Report1KSB-3242008-9634.pdf
[31] WHO.Nutrition, Micronutrient
Deficiencies, Vitamin A Deficiency.
2018. Available from: http://www.who.
int/nutrition/topics/vad/en/
[32] WHO. Global prevalence of vitamin
A deficiency in populations at risk 1995-
2005. WHO Global Database on Vitamin


Golden Rice: To Combat Vitamin A Deficiency for Public Health
DOI: http://dx.doi.org/10.5772/intechopen.84445
A Deficiency. Geneva: World Health
Organization; 2009
[33] Tang G.Using plant foods rich
in β-carotene to combat vitamin A
deficiency. Sight and Life. 2013;(1).
Available from: http://www.
sightandlife.org/fileadmin/data/
Magazine/2013/27_1_2013/using_plant_
foods_rich_in_beta_carotene_to_
combat_VAD.pdf
[34] Whitcher J, Srinivasan M,
Upadhyay M.Corneal blindness: A
global perspective. Bulletin of the World
Health Organization. 2001;(3):214-
221. http://www.who.int/bulletin/
archives/79(3)214.pdf
[35] Mayo-Wilson E, Imdad A, Herzer K,
etal. Vitamin A supplements for
preventing mortality, illness, and
blindness in children aged under 5:
Systematic review and meta-analysis.
BMJ. 2011;:d5094. Available from:
http://www.bmj.com/cgi/doi/10.1136/
bmj.d5094
[36] Fawzi W, Chalmers T, Herrera M,
etal. Vitamin A supplementation and
child mortality. A meta-analysis. Journal
of the American Medical Association.
1993;:898-903
[37] UN Inter-Agency Group for Child
Mortality Estimation. Levels and
Trends in Child Mortality—Report
2017. NewYork. 2017. Available from:
https://www.unicef.org/publications/
index_101071.html
[38] Bollinedi H, Krishnan G, Prabhu K,
etal. Molecular and functional
characterization of GR2-R1 event based
backcross derived lines of Golden Rice
in the genetic background of a mega rice
variety Swarna. PLoS One. 2017. journal.
pone.0169600
[39] Dubock A.Greenpeace, GMO
Critics Misrepresent Humanitarian
Project 2016. Available from: https://
geneticliteracyproject.org/2016/06/30/
adrian-dubock-golden-rice-scientist-
greenpeace-gmo-critics-misrepresent-
humanitarian-project/. 8pp
[40] Greenpeace. Genetically Engineered
“Golden Rice” is Fools Gold Press
Release. 2001. Available from: http://
www.greenpeace.org/new-zealand/en/
press/genetically-engineered-golden/
[41] Castenmiller J, West C.
Bioavailability of carotenoids.
Pure and Applied Chemistry.
1997;(10):2145-2150
[42] Tang G, Qin J, Dolnikowski GD,
Russell R, Grusak M.Golden Rice is
an effective source of vitamin A.The
American Journal of Clinical Nutrition.
2009;:1-8. Available from: http://ajcn.
nutrition.org/content/89/6/1776.short
[43] Tufts University. Tufts University
Statement on Golden Rice Research. 2013.
Available from: http://academicsreview.
org/2013/09/tufts-university-statement-
on-golden-rice-research/
[44] Tang G, Hu Y, Yin S, Wang Y,
Dallal G, Grusak MRR. Β-carotene in
Golden Rice is as good as β-carotene in
oil at providing vitamin A to children
(retraction of vol 96, p. 658-684, 2012).
The American Journal of Clinical
Nutrition. 2015;(3):715
[45] Miller H.Blood on their hands’?
Withdrawal of Golden Rice Study
for Non Science Reasons Feeds
Anti-GMO Fervor. Genetic Literacy
Project. 2015. Available from:
geneticliteracyproject.org/2015/08/11/
blood-on-their-hands-withdrawal-of-
golden-rice-study-for-non-science-
reasonsfeeds-anti-gmo-fervor/
[46] Institute of Medicine. Dietary
Reference Intakes for Vitamin A.
Washington, DC: National Academy
Press; 2001. pp.82-161. Available from:
https://www.nap.edu/catalog/10026/
dietary-reference-intakes-for-vitamin-
a-vitamin-k-arsenic-boron-chromium-

Vitamin A

copper-iodine-iron-manganese-
molybdenum-nickel-silicon-vanadium-
and-zinc
[47] Grune T, Lietz G, Palou A, etal.
Betacarotene is an important vitamin
A source. American Society for
Nutrition. The Journal of Nutrition.
2010;:2268S-2285S
[48] U.S.Food and Drug
Administration, Grune T, Lietz G,
Palou A, etal. Select Committee
on GRAS Substances (SCOGS)
Opinion: Carotene (β-carotene).
The Journal of Nutrition.
1979;:2268S-2285S.Available from:
http://www.pubmedcentral.nih.gov/
articlerender.fcgi?artid=3139236&tool=
pmcentrez&rendertype=abstract
[49] Shekelle R, Lepper M, Liu S, etal.
Dietary vitamin A and risk of cancer
in the Western Electric study. Lancet.
1981:1185-1190
[50] Grodstein F, Kang J, Glynn R, etal.
A randomized trial of beta carotene
supplementation and cognitive function
in men: The Physicians’ Health Study
II.Archives of Internal Medicine.
2007;:2184-2190
[51] Kang J, Cook N, Manson J, etal.
Vitamin E, vitamin C, Beta carotene,
and cognitive function among women
with or at risk of cardiovascular
disease: The women’s antioxidant and
cardiovascular study. Circulation.
2009;(21):2772-2780
[52] Kang J, Grodstein F.Plasma
carotenoids and tocopherols and
cognitive function: A prospective
study. Neurobiology of Aging.
2008;(29):1394-1403
[53] Schaub P, Wüst F, Koschmieder J,
etal. Nonenzymatic β-carotene
degradation in provitamin
A-biofortified crop plants. Journal
of Agricultural and Food Chemistry.
2017;:6588-6598
[54] David S.The problem with
nutritionally enhanced plants. Journal
of Medicinal Food. 2008;(4):5
[55] Porterfield A.Anti-GMO
Groups Draw FDA Rebuke Over
Misrepresentation of Golden Rice
Nutrition. Genetic Literacy Project
2018. Available from: https://
geneticliteracyproject.org/2018/06/29/
golden-rice-misinformation-fda-
debunks-michael-pollan-independent-
science-news/. 4pp
[56] Owens B.Golden Rice is safe to
eat, says FDA.Nature Biotechnology.
2018;(7):559-560
[57] Parliamentary Office of Science and
Technology. THE ‘GREAT GM FOOD
DEBATE’—A Survey of Media Coverage
in the First Half of 1999. Available from:
http://www.parliament.uk/documents/
post/report138.pdf
[58] Robert P.Starved for Science,
How Biotechnology is Being Kept out
of Africa. Cambridge, MA: Harvard
University Press; 2008. 235p
[59] Dubock A.Crop conundrum.
Nutrition Reviews. 2009;(1):17-20.
Available from: http://www.ncbi.nlm.
nih.gov/pubmed/19146502
[60] Norero D.More-Than-240-
Organizations-and-Scientific-
Institutions-Support-the-Safety-of-
gm-crops. Available from: http://www.
siquierotransgenicos.cl/2015/06/13/
more-than-240-organizations-and-
scientific-institutions-support-the-
safety-of-gm-crops/
[61] European Commission. A Decade of
EU-Funded GMO Research (2001-2010).
2010. Available from: https://ec.europa.
eu/research/biosociety/pdf/a_decade_
of_eu-funded_gmo_research.pdf
[62] Copenhagen Consensus.
Copenhagen Consensus 2004.
Available from: https://www.


Golden Rice: To Combat Vitamin A Deficiency for Public Health
DOI: http://dx.doi.org/10.5772/intechopen.84445
copenhagenconsensus.com/publication/
copenhagen-consensus-final-results
[63] Copenhagen Consensus.
Copenhagen Consensus 2008.
Available from: https://www.
copenhagenconsensus.com/sites/
default/files/cc08_results_final_0.pdf
[64] Copenhagen Consensus.
Copenhagen Consensus
2012. Available from: https://
www.copenhagenconsensus.
com/sites/default/files/
cc12resultspressreleasefinal_0.pdf
[65] Copenhagen Consensus.
Copenhagen Consensus—Post 2015.
2016. Available from: http://www.
copenhagenconsensus.com/post-2015-
consensus/nobel-laureates-guide-
smarter-global-targets-2030
[66] Stein A, Sachdev H, Qaim M.
Potential impact and cost-effectiveness
of Golden Rice. Nature Biotechnology.
2006;(10):200-201
[67] Zimmermann R, Ahmed F.Rice
biotechnology and its potential to
combat vitamin A deficiency: A case
study of golden rice in Bangladesh.
Bonn. Discussion papers on development
policy; 2006. Report No: 104. Available
from: http://hdl.handle.net/10419/32303
[68] Anderson K, Jackson L, Nielsen C.
Genetically modified rice adoption:
Implications for welfare and poverty
alleviation. Journal of Economic
Integration. 2005;(4):1-25
[69] Blancquaert D, Van Daele J, Strobbe
S, etal. Improving folate (vitamin B9)
stability in biofortified rice through
metabolic engineering. Nature
Biotechnology. 2015;(10):1076-1078.
Available from: http://www.nature.
com/nbt/journal/v33/n10/full/nbt.3358.
html?WT.ec_id=NBT-
[70] Wesseler J, Zilberman D.The
economic power of the Golden
Rice opposition. Environment
and Development Economics.
2014;(6):724-742
[71] Wesseler J, Zilberman D.Golden
Rice: No progress to be seen. Do we still
need it? Environment and Development
Economics. 2016;:1-3
[72] Institute of Medicine (US) Panel
on Micronutrients. Dietary Reference
Intakes for Vitamin A, Vitamin K,
Arsenic, Boron, Chromium, Copper,
Iodine, Iron, Manganese, Molybdenum,
Nickel, Silicon, Vanadium, and Zinc.
2001. Available from: https://www.ncbi.
nlm.nih.gov/books/NBK222310/
[73] Potrykus I, Ammann K.Transgenic
plants for food security in the context
of development. Statement of the
Pontifical Academy of Sciences.
2010;:445-717. Available from: http://
www.ask-force.org/web/Vatican-PAS-
Statement-FPT-PDF/PAS-Statement-
English-FPT.pdf
[74] Potrykus I.Unjustified regulation
prevents use of GMO technology for
public good. Trends in Biotechnology.
2013;(3):131-133. Available from:
http://www.ncbi.nlm.nih.gov/
pubmed/23273413
[75] Giddings LV, Potrykus I, Ammann
K, Fedoroff NV.Confronting the
Gordian knot. Nature Biotechnology.
2012;:208-209. Available from:
http://www.ncbi.nlm.nih.gov/
pubmed/22398608
[76] Potrykus I. “Golden Rice”, a
GMO-product for public good, and
the consequences of GE-regulation.
Journal of Plant Biochemistry and
Biotechnology. 2012;(S1):68-75.
Available from: http://link.springer.
com/10.1007/s13562-012-0130-5