Functions and Actions of Retinoids and Carotenoids:
Building on the Vision of James Allen Olson
Vitamin A Deficiency Disorders: International Efforts to Control A
Preventable “Pox”1
Barbara A. Underwood2
Institute of Medicine, National Academies, 2101 Constitution Ave., NW, Washington, D.C. 20418
ABSTRACT Visual symptoms (night blindness) of vitamin A deficiency (VAD) were among the earliest diet-related
deficiencies documented. Knowledge of vitamin A chemistry, metabolism and deficiency consequences accrued
rapidly during the first eight decades of the 20th century. A series of disorders were described in animals, including
impaired growth, reproduction, epithelial integrity, and disease resistance that were relieved by consumption of
both animal and plant sources of the vitamin. Identification of the intestinal beta-carotene cleavage enzyme in the
laboratory of James Allen Olson was seminal to understanding the mechanism for formation of vitamin A from
ingested carotenoids. WHO’s 1990 estimate of about 40 million children annually with clinical eye signs of VAD was
revised upward to 140 –250 million at risk of vitamin A deficiency disorders (VADD) when epidemiological and
clinical trials demonstrated morbidity and mortality risk even in the absence of ocular signs. Alternative methods
for VAD status assessment and more reliable analytical techniques were developed, several in Dr. Olson’s
laboratory. The last decade has seen global progress in VADD control by expanding distribution of medicinal
supplements, fortification of foods and dietary diversification through horticulture and education programs.
Experience shows that achievements gained through narrowly focused interventions are fragile and vulnerable to
national political and economic instability. Contextually relevant, community-centered strategies that improve
household food and nutrition security and self-reliance are critical to sustaining international efforts to control the
VADD “pox.” J. Nutr. 134: 231S–236S, 2004.
KEY WORDS: ● history vitamin A deficiency
● intervention programs ● IVACG
●
vitamin A
●
vitamin A deficiency disorders
Written evidence for micronutrient deficiencies appear in
ancient writings, including those that describe night blindness
symptoms relieved by certain animal foods. For example, physician-followers of Hypocrites and others through the centuries
associate cure with animal liver ingested or its juice placed on
the eye. Wolf (1,2) provides an insightful historical record
from early times to the present of anecdotal accountings of this
association. Early in the 19th century, Sepoys in India ascribed
night blindness to a bad diet and insufficient food (3). Not
until the latter half of the 19th century, however, did investigations become more systematic. Credit is given to Eduard
Schwarz for conducting an early experiment in nutrition during an around the world scientific exploration from 1857 to
1859 (2). Night blindness (often in conjunction with scurvy)
frequently was reported during long sea voyages. Physician
colleagues of Schwarz were said to have requested him to test
the administration of boiled ox liver against night blindness
symptoms. Schwartz records a miraculous permanent cure occurred and this confirmation of old folk medicine firmly established night blindness as a nutritional disease. By the turn
of the 19th century, reports from dissimilar parts of the world
had clearly linked diet and eye health in both man and large
animals. These findings set the stage for the exciting early
years of the 20th century and the birth of the scientific
Pre20th century efforts
Micronutrient deficiencies were unlikely features of humankind’s early existence. As a hunter-gatherer the primary food
sources were flesh foods, wild fruits and vegetables that provided a quality-rich diet. Most likely deficiency problems
emerged as lifestyles gradually changed toward more stationary
living and dependence on subsistence agricultural. Cultivated
cereals, fruits and vegetables significantly replaced flesh foods,
which almost certainly introduced bioavailability problems for
several micronutrients, including provitamin A carotenoids
from plant sources.
1
Presented as part of the James Allen Olson Memorial Symposium, “Functions and Actions of Retinoids and Carotenoids” held at Iowa State University,
June 21–24, 2001 to honor the memory of James Allen Olson. This conference
was supported by the U.S. Department of Agriculture; National Institutes of
Health; Department of Biochemistry, Biophysics and Molecular Biology, Iowa
State University (ISU); Department of Food Science and Human Nutrition, ISU;
College of Liberal Arts and Sciences, ISU; F. Hoffmann-La Roche; Kemin Foods,
L.C., Procter & Gamble Company; Lipton; Best Foods; BASF; SmithKline
Beecham; Cognis Corporation; Allergen and INEXA. Guest editor for this symposium was Norman I. Krinsky, Department of Biochemistry, School of Medicine,
and the Jean Mayer Human Nutrition Research Center on Aging, Tufts University,
Boston, MA 02111-1837.
2
To whom correspondence should be addressed.
E-mail: e-mail: bunderwo@adnc.com.
0022-3166/04 $8.00 © 2004 American Society for Nutritional Sciences.
231S
232S
SUPPLEMENT
underpinning of knowledge about vitamin A and its public
health consequences.
many proteins has invigorated retinoid studies by basic scientists in the last decade.
20th century efforts
Human studies
Animal studies. There are many historical accountings of
the exciting first three to four decades of the 20th century
when scientists systematically disassembled animal and plant
foods to isolate, characterize and synthesize their chemical
constituents with curative activity. Rapid progress, led by
McCollum (4) and Osborne and Mendel (5), was made possible after McCollum first convinced peers of the validity of
using rats, rather than large animal models for nutritional
investigations (6). Early pioneers were then able to feed purified diets and systematically add back individual foods or
isolates from them to evaluate impact and to begin exploring
biochemical functioning of vitamin A. By mid-century, vitamin A and pro-vitamin A carotenoids had been chemically
characterized and synthesized (7). Additions to animal diets
were evaluated for effectiveness in preventing elevated cerebral spinal fluid pressure, eye signs and growth faltering, and in
maintaining epithelial tissue integrity, supporting reproduction and extending survival. Comparisons were made to human conditions and links established to dietary improvements
and outcomes, mainly ocular and epithelial tissue health (8).
From 1930 to about 1975 vitamin A-related research focused on clarifying the pathology of deficiency both in ocular
and nonocular tissues, interactions with other nutrients and
disease conditions, and the teratogenic effects resulting from
too little or too much vitamin A. Although others had worked
extensively on defining components related to vision, the
superb work of Wald, his colleague Dowling and their students
first documented the specific biochemical pathway linking
retinol to opsin and the formation and breakdown of rhodopsin in the visual cycle (9). That seminal work, the first
to tie a biochemical function to a fat-soluble nutrient, has
stood the test of time, although refined in detail in subsequent years (10).
This remarkable achievement provided the scientific explanation for the age-old symptom of night blindness and its
association with nutrition, but it did not explain the nonocular molecular functioning of vitamin A. It was clear from
Dowling and Wald’s subsequent work (11), as well as many
others (12) that nearly all of the nonocular roles, including
survival— excepting those associated with reproduction—
were carried out by retinoic acid. Dr. Olson and colleagues in
Thailand during the 1970s provided a methodology for clarifying the sequence of appearance of deficiency signs and symptoms using dietary retinoic acid for draining body stores of
retinyl esters and retinol while maintaining survival even into
adulthood. Vitamin A-deprived rats were maintained until
their growth stopped or began to decline. Nonstorable dietary
retinoic acid was provided for 18 d to stimulate stalled growth
followed by withdrawal for 10 d to drain residual vitamin A
stores (13). The rats after repeated cycling became blind and
could not reproduce but otherwise appeared healthy. Synchronized deficiency permitted study of mature deficient animals,
as well as those still growing, and thereby to clarify the
sequential pathology of vitamin A deficiency in rats (14).
Notwithstanding the work of Dr. Olson and many others
that elucidated mechanisms of absorption and metabolism of
retinol and showed the efficacy of retinoic acid in fulfilling
most nonocular functions, a molecular explanation awaited
the seminal reports of Chambon and colleagues (15) and
Evans and colleagues (16). Their revelation of a pivotal nuclear role for retinoic acid that modulates genetic expression of
The synthesis of vitamin A around 1930 permitted fortification of foods and availability of medicinal supplements in
the US and other developed countries that virtually eliminated ocular forms of vitamin A deficiency (VAD) as a public
health problem six decades into the 20th century. However,
there are some populations of children in the US whose
vitamin A status is not optimal even today as shown using a
modified dose-response methodology developed by Dr. Olson
and colleagues (17). Cross-sectional serum distribution of vitamin A from the National Health and Nutrition Examination
Survey (NHANES) III survey (18) also suggests suboptimal
status among some children 4 – 8 y (younger children were not
studied) and some minority groups, but few (around 1%) had
values to suggest clinical risk, i.e., ⬍0.7 ␮mol /L. Indeed,
today, there is little evidence that VAD is of public health
significance in most developed countries although status could
be improved for some by increased intake to Recommended
Dietary Allowance (RDA) levels of vitamin A from food
sources or supplements. Regrettably, the early programmatic
success with food fortification (19) and medicinal supplements
in the developed world were not transferred even today to
many developing countries where the “pox” of VAD continues
to take a toll on the sight and life of children.
How large is the problem in the developing world?
WHO-sponsored the first systematic attempt to quantify
the magnitude and public health dimensions of VAD in the
early 1960s. Based on clinic records, anecdotal observations
and personal interviews, 20,000 to 100,000 children were
projected to be affected (20). This “guestimate” was shown to
underestimate the problem upon completion of the first carefully conducted national representative survey in Indonesia.
From this survey about 60,000 corneal and 1.3 million noncorneal cases of xerophthalmia were calculated to occur annually in this one country (21), and 500,000 corneal and 4 – 8
million noncorneal xerophthalmia cases annually in four
South and East Asia countries (India, Bangladesh, Philippines
and Indonesia). Further, globally 13 million children were
estimated to be overtly deficient (xerophthalmic) with another 40 – 80 million at risk of subclinical deficiency (22).
Recognizing that health consequences occurred before clinical eye signs, WHO in 1995 redefined VAD to include tissue
depletion below which functional impairment was likely. The
prevalence of low serum levels (⬍0.7 ␮mol/L) of vitamin A
was used as a population-based indicator of health risks (23).
By the end of the decade, 140 –250 million preschool age
children were estimated to be at risk of vitamin A deficiency
disorders (VADD, clinically deficient and subclinically at
risk), including 3 million who annually have clinical signs
(24). Progress in implementing broad coverage interventions—primarily high-dose vitamin A supplements—in the
last two decades undoubtedly has reduced the magnitude of
VADD, but documentation awaits postintervention surveys of
serum distribution levels that show impact.
3
Abbreviations used: IVACG, International Vitamin A Consultative Group;
NHANES, National Health and Nutrition Examination Survey; RDA, Recommended Dietary Allowance; RDR, relative dose response; USAID, United States
Agency for International Development; VAD, vitamin A deficiency; VADD, vitamin
A deficiency disorders.
VADD INTERNATIONAL CONTROL EFFORTS
What accounted for accelerated efforts to purge the “pox”?
Committed scientists. Before 1974, there was little coordinated global commitment toward elimination of the vitamin
A “pox” that had plagued society since ancient times. A few
committed clinicians, nutritional biochemists and public
health workers, even several WHO World Health Assembly
Resolutions, were unsuccessful in attracting substantial attention and resources for actions to rid societies of VAD. In
1974 a joint WHO/United States Agency for International
Development (USAID) meeting to consider priorities for research and action programs to combat vitamin A deficiency
and xerophthalmia brought together concerned nutritionists,
pediatricians, ophthalmologists, UN agencies, nongovernmental organizations and private industry (25). Dr. Olson at this
time had completed his time at Mahidol University in Thailand with the Rockefeller Foundations and was in Brazil continuing work for the Foundation. He was among the small
number of nutritional biochemists invited to the Jakarta meeting in recognition of his biochemical expertise in vitamin A
nutrition, experiences with assessment methodology in rats
and humans, and exposure to human deficiency problems in
Southeast Asia. The Jakarta gathering was a stormy meeting
with strongly expressed opposing views between biochemists,
ophthalmologists and clinicians. Program implementers sat in
shock that there were such dissimilar points of view among
scientists. At issue were criteria for classifying xerophthalmia
(e.g., was night blindness a primary or secondary indicator
under field-survey conditions); prevalence of cut-off values for
each ocular sign as indicative of a public health problem;
validity of ocular and biochemical assessment indicators; nonocular health consequences of inadequate vitamin A status;
and effectiveness/efficacy of different interventions strategies.
WHO did produce a meeting report (25) that included a
summary of current knowledge on chemistry and metabolism,
available assessment methodologies, epidemiology of the problem and available intervention programs. Research priorities
were also set forth to resolve outstanding controversies prominent in the meeting that were limiting progress in eliminating
the VADD “pox.”
The following year (1975) USAID formally established the
International Vitamin A Consultative Group (IVACG) to
provide a forum for information exchange across professions
and programs and to produce task force reports on issues
relevant to moving forward in controlling VADD. Dr. Olson
was a charter member and very active in preparing many of the
early reports (26). He continued his contributions to IVACG
publications, including the 1999 review entitled “The Bioavailability of Dietary Carotenoids: Current Concepts.” In
addition, Dr. Olson missed few IVACG meetings and was
called upon frequently for an update on biochemical advances
relative to the continuing global public health problem. He
was preparing a background paper for the 25th anniversary
meeting of IVACG celebrated in Hanoi, February 2001 when
his untimely death occurred.
Following the 1974 seminal meeting in Jakarta and the
formation of IVACG, researchers from 1975 to the early 1990s
went to their bench and field laboratories to implement carefully designed studies aimed at resolving controversial issues.
The 1975 national survey in Indonesia improved knowledge of
the regional magnitude of the problem, and epidemiological
studies that followed over the next several years showed associations with morbidity and mortality (21). However, Sommer
(an ophthalmologist/epidemiologist) and colleagues shocked
the scientific world with their public announcement published
in 1986 of a 34% reduction in child mortality in Aceh,
233S
Indonesia by giving 200,000 IU vitamin A concentrate at 6 mo
intervals (27). (In the 1974 meeting the ophthalmologists
generally viewed vitamin A deficiency as an ocular problem
with little or no nonocular health consequences!) Some biochemists (myself among them), based on VAD animal studies,
firmly believed in nonocular health consequences of VAD, but
disbelieved that a single nutrient “magic bullet” could have
such a profound effect in the midst of unrelenting chronic
undernutrition, poverty and social deprivation. The Aceh
report stimulated vitamin A researchers to design replication
trials in other settings. Many of us were certain we would
validate our skepticism, but later had to reevaluate positions as
earlier anecdotal observations in human populations were
replaced by findings from well-designed randomized controlled
community intervention trials.
Mortality reduction. Early in 1990, randomized intervention studies using vitamin A supplements and evaluating morbidity and/or mortality impacts had been completed. Variable
results were reported. Beaton et al. (28) summarized sixteen
studies and determined that seven, in addition to the Aceh
study, were appropriate for a meta-analysis to determine if
reduced childhood mortality could be expected by restoring
adequate vitamin A status to deficient children. The analysis
concluded that on average a 23% reduction could be expected,
but that variation based on program area context could be
considerable. Further, the analysis related the positive effect to
restoring vitamin A status in amounts approaching the RDA
either by daily or weekly low doses or by periodic medicinal
high doses. This finding opened doors to a variety of intervention strategies that could be adapted to the community setting
according to the context and available resources, e.g., foodbased approaches through fortification and/or increasing intake of natural food sources. Similar meta-analyses corroborated the conclusions (29,30). Mortality reduction was real
though variable in magnitude!
Assessment indicators. An early IVACG task force, on
which Dr. Olson participated, clearly advocated use of serum
retinol distribution curves for evaluation of program effectiveness, while recognizing the inadequacy of serum levels for
individual assessment of vitamin A status (31). Other assessment tools clearly were needed. Liver reserves of vitamin A
were recognized as the best indicator of status but of course,
not ethical or feasible to obtain for living population assessment. Postmortem liver analyses were suggested as a surrogate
for identifying areas and population groups at risk. Dr. Olson
provided assessments of this type from Thailand (32,33), Brazil
(34) and the US (35) but there were problems in acceptance
and routine use of this assessment approach.
To overcome deterrents to direct liver analyses, a more
feasible indirect indicator of liver reserves was proposed based
on animal studies from DeWitt Goodman’s laboratory and my
laboratory (36). The procedure, which we called the relative
dose response (RDR) test, was developed in rats from a series
of observations of factors influencing homeostatic control over
blood levels of vitamin A (37–39). The RDR as an indirect
measure of critically depleted liver stores was evaluated among
Brazilian preschool age children suspected to be subclinically
deficient before receiving a vitamin A supplement and periodically for six months after supplementation (40); to evaluate
the affect of an unexpected infection on depletion of vitamin
A stores (41); and in repeated surveys to determine how many
rounds of six monthly distributions of high-dose capsules were
needed to restore population distribution curves to that of
apparently nondeficient populations (42). Dr. Olson, with
colleagues at Iowa, validated the RDR test in human surgical
patients from whom liver biopsies also were analyzed (43,44).
234S
SUPPLEMENT
Although the RDR test proved valid, logistical limitations
were encountered in field studies because it required two blood
samplings with an intervening five-hour wait. It is challenging
to keep young children and their mothers under surveillance
and entertained for five hours. The group in Iowa modified the
RDR procedure to provide a fasting tracer dose of a naturally
occurring vitamin A derivative, i.e., didehydroretinol (Vitamin A2), in the home, thus eliminating a baseline blood
drawing and limiting to sampling only once after five hours
(45). This modification was more field-friendly for use with
children, although technically more laborious and costly for
obtaining the tracer, and it required sophisticated analytical
instrumentation (HPLC). Other assessment procedures also
emanated from Dr. Olson’s laboratory, including isotope dilution and glucuronide metabolite excretion, both of which hold
promise as reliable indicators for evaluating vitamin A status
and biological impact and are discussed by others.
From the studies cited and many more not reviewed, it is
obvious that from 1974 to 1990 a committed scientific community had removed many gaps in knowledge on researchable
issues hindering progress in eliminating the “pox” through
public health interventions. More advocacy was needed, however, to mobilize the global community’s resources toward
large-scale public health actions.
Committed politicians
Political clout was needed to mobilize international and
national resolve and resources. James Grant, Director of
UNICEF in 1990 and a strong advocate for child health, was
briefed on micronutrient control issues and the exciting data
available from the vitamin A mortality and morbidity field
trials. Micronutrients were placed on the agenda for the politically high level (ministerial and heads of state) Summit for
Children hosted by UNICEF in NY, September 1990. At last
the attention of politicians was captured and commitments
were made at the Summit for virtual elimination of VADD by
the end of the decade. Important to successfully recruiting
Mr. Grant as advocate for political commitment to reducing
vitamin A deficiency was the convincing scientific-based evidence for magnitude, public health consequences and available cost-effective interventions to support his call for action.
Subsequent international policy-setting meetings in 1991,
1992 and 1996 reinforced the micronutrient deficiency reduction goals, and resources began to flow into global intervention
strategies (46).
Committed program implementers
High-level international and national commitments and
policies must become relevant actions at country level for
impact on child health and survival to occur. Affordable
efficacious interventions were known in 1990 and awaited
implementation for short and longer term curative and control
programs (47).
Periodic supplementation. To rapidly respond, many
countries accepted external donor pressures to distribute highdose vitamin A capsules periodically. Donors were willing to
subsidize purchase of capsules and national governments were
agreeable to their health workers providing support for distribution. Coverage rates, low and inconsistent in the early days,
reached levels up to 90% when a link was made to the
campaign approach of the WHO expanded program of immunization (48). Fortunately for the successful polio eradication
campaign, these annual immunization days are scheduled to
stop in the near future. However, this leaves countries to find
alternative affordable approaches for twice-yearly delivery of
capsules sustaining the coverage levels reached earlier. Some
countries already have met the challenge by establishing
twice-yearly micronutrient days or finding ways to integrate
the activity into routine health programs.
Progress dependent primarily on supplement distribution,
however, can be fragile. For example, Indonesia had made
significant progress declaring itself xerophthalmia free and
assumed full financial responsibility for integration into the
national health program (49). The recent economic decline
and even more recent civil unrest, however, interrupted programs and led to a reappearance of xerophthalmia. This country experience illustrates that consistent periodic capsule distribution can control VADD, but sustained control is fragile
when not underpinned by other measures that concurrently
address underlying constraints to achieving adequate diets,
reducing frequent infections and combating socio-economic
underdevelopment (47).
Food fortification. Attention of external agencies and
donors recently has turned toward expanding access to fortified
foods. As noted earlier, this has been a successful sustainable
strategy in industrialized countries (19) and some countries in
mid-level development status. An often-cited model for
VADD control is progress in control of iodine deficiency by
iodized salt universally mandated. Iodized salt has reached
even remote areas in less developed countries (24). Comparable condiments or single foods with the characteristics necessary for mandatory fortification are more difficult to identify for
vitamin A. Guatemala is exemplary as a country with over
three decades of experience with a mandated vitamin A sugar
fortification program documented to be effective in raising
vitamin A status of the population (50). The mandated program in Guatemala, however, has experienced a rocky political
road. It was disrupted for a few years for economic and political
reasons, reinstated around 1990 and even today continues to
struggle to remain a government-mandated program. Stoppage
of the program was soon followed by a decline in vitamin A
status throughout the country that was reversed when the
program was reinstated. It is too early to predict the sustainability and impact of newly created fortification programs in
less developed countries that lack an established infrastructure
for monitoring, quality control and enforcement.
Dietary quality and diversity. Most give lip service to
food-based programs linked to production and consumption of
vitamin A-dense foods in a varied diet as the most sustainable
intervention with wide-ranging benefits for health. Food-based
interventions, however, have received inadequate attention
and resources, in part because of the widely held view that
they require difficult to change eating behaviors too labor
intensive and too costly for mass scale application. The strategy also involves linking agriculture to nutrition and health
education, and with gender considerations, which are particularly important in developing countries (51). There have
been successful experiences that claim biological impact and
have been sustained for at least ten years of follow-up (52), but
most food-centered programs are criticized for not being rigorously evaluated. Evaluation of a community food-based approach is costly and difficult due to multiple potential cofounders in free-living communities that defy rigorous control.
Among communities deriving most vitamin A activity from
plants, some question whether VAD can be controlled due to
limited bioavailability from green leafy vegetables (53). Notwithstanding such variability, recent studies demonstrate that
body stores of vitamin A are retained, though not substantially
increased, in children consuming predominately mixed vegetable diets, including green leafy vegetables (54,55).
VADD INTERNATIONAL CONTROL EFFORTS
At IVACG meetings, as well as at Experimental Biology,
Dr. Olson strongly supported the benefits associated with
carotenoid-rich diets. He lamented the fact that the IVACG
meetings in recent years downplayed food-based interventions
and he organized breakout groups to provide a forum for
information exchange among those with similar interests.
These sessions were well attended, participants always feeling
they had learned from Dr. Olson’s excellent leadership of
sessions. Unfortunately, his absence from the most recent
IVACG meeting was evident by the absence of such a forum,
in part due to a change in meeting format that only allowed
breakout groups to meet over dinner at a local restaurant—
hardly a milieu conducive to substantive information exchange. Interestingly, the participants’ call from the meeting
floor was for future IVACG meetings to give greater emphasis
to food-based interventions.
Scientific evidence is accumulating to substantiate earlier
anecdotal and experiential reports that food-based approaches
are effective, sustainable and worthy of their share of donoragency support. The UN General Assembly Special Session on
Children was held in New York City May 2002. The session
report is titled “A World Fit for Children.” Paragraph 22 of the
draft action plan provided a timely opportunity to reaffirm the
call for the virtual elimination of VADD using a combined
approach of dietary diversification, food fortification and supplement distribution, while recognizing also the importance of
disease control and poverty reduction to sustained elimination
of the “pox” by 2010.
CONCLUSION
Slow progress in overcoming the VADD “pox” that plagued
humankind through millenniums to the 1990s has yielded to
accelerated progress in the last decade. Renewed international
political commitment occurred at the UN General Assembly
Special Session on Children May 2002. With continued commitment by all the players, scientists, politicians and program
implementers, and with allocation of necessary resources, “A
World Fit for Children” free of the VADD “pox” is possible.
James Allen Olson’s contributions toward this goal will long
be remembered through his scientific work and that of the
students and colleagues, including me, for whom he served as
role model and mentor.
LITERATURE CITED
1. Wolf, G. (1979) An historical note on the mode of administration of
vitamin A for the cure of night blindness. Am. J. Clin. Nutr. 31: 290 –292.
2. Wolf, G. (1996) A history of vitamin A and retinoids. FASEB J. 10:
1102–1107.
3. Aykroyd, W. R. (1944) An early reference to night-blindness in India,
and its relation to diet deficiency. Current Science, No. 6. pp. 149 –150.
4. McCollum, E. V. & Davis, M. (1913) The necessity of certain lipins in
the diet during growth. J. Biol. Chem. 15: 167–175.
5. Osborne, T. B. & Mendel, L. B. (1913) The relation of growth to the
chemical constituents of the diet. J. Biol. Chem. 15: 311–326.
6. McCollum, E. V. (1953) My early experiences in the study of foods and
nutrition. Ann. Rev. Biochem. 22: 1–16.
7. Moore, T. (1957) Vitamin A. Elsevier Publishing Co., N. Y. 1957. p. 645.
8. Underwood, B. A. (1984) Vitamin A in animal and human nutrition. In: The
Retinoids (Sporn, M. B., Roberts, A. B. & Goodman, D. S., eds.), pp. 281–392,
Academic Press, Inc., New York, NY.
9. Wolf, G. (2001) The discovery of the visual function of vitamin A. J.
Nutr. 131: 1647–1650.
10. Saari, J. C. (1994) Retinoids in photosensitive systems. In: The Retinoids: Biology, Chemistry and Medicine (Sporn, M. B., Roberts, A. B. & Goodman,
D. S., eds.), pp. 351–385, Raven Press, NY.
11. Dowling, J. E. & Wald, G. (1960) The biological function of vitamin A
acid. Proc. Natl. Acad. Sci. U.S.A. 46: 587– 608.
12. Rogers, A. E., Anderson, G. H., Lenhardt, G. M., Wolf, G. & Newberne,
P. M. (1974) A semi-synthetic diet for long-term maintenance of hamsters to
study effects of dietary vitamin A. Lab. Animal. Sci. 24: 495– 499.
235S
13. Lamb, A. J., Apiwatanaporn, P. & Olson, J. A. (1974) Induction of
rapid, synchronous vitamin A deficiency in the rat. J. Nutr. 104: 11401148.
14. Anzono, M. A., Lamb, A. J. & Olson, J. A. (1979) Growth, appetite,
sequence of pathological signs and survival following the induction of rapid,
synchronous vitamin A deficiency in the rat. J. Nutr. 109: 1419 –1431.
15. Chambone, P. A. (1996) A decade of molecular biology of retinoic acid
receptors. FASEB J. 10: 940 –954.
16. Giguère, V., Ong, E. S., Segui, P. & Evans, R. M. (1987) Identification
of a receptor for the morphogen retinoic acid. Nature 330: 624 – 629.
17. Tanumihardjo, S. A., Furr, H. C., Erdman, J. W., Jr. & Olson, J. A. (1990)
Use of the modified relative dose response (MRDR) assay in rats and its application to humans for the measurement of vitamin A status. Eur. J. Clin. Nutr. 44:
219 –224.
18. Ballew, C., Bowman, B. A., Sowell, A. L. & Gillespie, C. (2001) Serum
retinol distributions in residents of the United States: third National Health and
Nutrition Examination Survey, 1988 –1994. Am. J. Clin. Nutr. 73: 586 –593.
19. Mertz, W. (1997) Food fortification in the United States. Nutr. Rev. 55:
44 – 49.
20. Oomen, H.A.P.C., McLaren, D. S. &, Escopini, H. (1964) Epidemiology
and public health aspects of hypovitaminosis A. A global survey on xerophthalmia. Trop. Geogr. Med. 16: 271–315.
21. Sommer, A. (1982) Magnitude and distribution. In: Nutritional Blindness (Sommer A., ed.), pp. 162–175. Oxford University Press, NY.
22. Sommer, A., Tarwotjo, I., Hussaini, G., Susanto, D. & Soegiharto, T.
(1981) Incidence, prevalence, and scale of blinding malnutrition. Lancet 1:
1407–1408.
23. WHO (1995) Global prevalence of vitamin A deficiency. Micronutrient
Deficiency Information System, MDIS Working Paper #2, WHO/NUT/95.3. World
Health Organization, Geneva.
24. ACC/SCN (2000) Fourth Report on the World Nutrition Situation.
ACC/SCN in collaboration with IFPRI, Geneva.
25. WHO/USAID (1976) Vitamin A deficiency and xerophthalmia. Report
of a Joint WHO/USAID Meeting. Tech. Rept. Ser. 590. World Health Organization,
Geneva.
26. McLaren, D. S. (1987) A decade of achievement: The International
Vitamin A Consultative Group (IVACG). International Life Science Institute, Washington, D.C.
27. Sommer, A., Tarwotjo, I., Djunadi, E., West, K. P., Loeden, A. A., Tilden,
R. Mele, L. & the Aceh study group. (1986) Impact of vitamin A supplementation on childhood mortality. A randomized controlled community trial. Lancet i:
1169 –1173.
28. Beaton, G. H., Martorell, R., Aronson, K. J., Edmonston, B., McCabe, G.,
Ross, A. C. & Harvey, B. (1993) Effectiveness of vitamin A supplementation in
the control of young child morbidity and mortality in developing countries. ACC/
SCN State-of-the-art series, Nutrition Policy Discussion Paper No. 13. ACC/SCN,
Geneva.
29. Fawzi, W. W., Chalmers, T. C., Herrera, G. & Mosheller, F. (1993)
Vitamin A supplementation and child mortality. A meta-analysis. J. Amer. Med.
Assoc. 269: 896 –903.
30. Glasziou, P. P. & Mackerras, D.W.M. (1993) Vitamin A supplementation in infectious diseases: a meta-analysis. Brit. Med. J. 306: 366 –370.
31. IVACG (1977) Guidelines for the eradication of vitmain A deficiency
and xerophthalmia. International Vitamin A Consultative Group, Nutrition Foundation, Washington, D.C.
32. Suthutvoravoot, S. & Olson, J. A. (1974) Plasma and liver concentration of vitamin A in a normal population of urban Thai. Am. J. Clin. Nutr. 27:
883– 891.
33. Montreewasuwat, N. & Olson, J. A. (1979) Serum and liver concentrations of vitamin A in Thai fetuses as a function of gestational age. Am. J. Clin.
Nutr. 32: 601– 606.
34. Olson, J. A. (1979) Liver vitamin A reserves of neonates, preschool
children and adults dying of various causes in Salvador, Brazil. Arch. Latinoam.
Nutr. 29: 521–545.
35. Olson, J. A., Gunning, D. B. & Tilton, R. A. (1984) Liver concentrations
of vitamin A and carotenoids as a function of age and other parameters of
American children who died of various causes. Am. J. Clin. Nutr. 39: 903–910.
36. Underwood, B. A. (1990) Dose-response tests in field surveys. J. Nutr.
120: 1455–1458.
37. Loerch, J., Underwood, B. A. & Lewis, K. (1979) Response of plasma
levels of vitamin A to a dose of vitamin A as an indicator of hepatic vitamin A
reserves in rats, J. Nutr. 109: 778 –786.
38. Keilson, B., Underwood, B. A. & Loerch, J. D. (1979) Effects of retinoic
acid on the mobilization of vitamin A from the liver in rats. J. Nutr. 109: 787–795.
39. Underwood, B. A. (1980) Effect of protein quantity and quality on
plasma response to an oral dose of vitamin A as an indicator of hepatic vitamin A
reserves in rats. J. Nutr. 110: 1635–1640.
40. Flores, H., Campos, F., Araujo, C.R.C. & Underwood, B. A. (1984)
Assessment of marginal vitamin A deficiency in Brazilian children using the
relative dose response procedure. Am. J. Clin. Nutr. 40: 1281–1289.
41. Campos, F.A.C.S, Flores, H. & Underwood, B. A. (1987) Effect of an
infection on vitamin A status of children as measured by the relative dose
response (RDR). Am. J. Clin. Nutr. 46: 91– 4.
42. Flores, H., Azevedo, M.N.A., Campos, F.A.C.S., Barreto-Lins, M. C.,
Cavalcanti, A. A., Salzano, A. C., Varela, R. M. & Underwood, B. A. (1991)
Serum vitamin A distribution curve for children aged 2– 6 y known to have
adequate vitamin A status: a reference population. Am. J. Clin. Nutr. 54: 707–11.
236S
SUPPLEMENT
43. Amedee-Manesme, O., Anderson, D. & Olson, J. A. (1984) Relation of
the relative dose response to liver concentrations of vitamin A in generally
well-nourished surgical patients. Am. J. Clin. Nutr. 39: 898 –902.
44. Amedee-Manesme, O., Furr, H. C. & Olson, J. A. (1984) The correlation between liver vitamin A concentrations in micro- (needle biopsy) and macro
samples of human liver specimens obtained at autopsy. Am. J. Clin. Nutr. 39:
315–319.
45. Tanumihardjo, S. A., Koeliner, P. G. & Olson, J. A. (1990) The modified
relative-dose-response assay as an indicator of vitamin A status in a population
of well nourished American children. Am. J. Clin. Nutr. 52: 1064 –1067.
46. Underwood, B. A. (1998) From research to global reality: The micronutrient story. J. Nutr. 128: 145–151.
47. Underwood, B. A. Smitasiri, S. (1999) Micronutrient malnutrition: Policies and programs for control and their implications. Ann. Rev. Nutr. 19: 303–324.
48. Goodman, T., Dalmiya, N., de Benoist, B. & Schultink, W. (2000) Polio
as a platform: using national immunization days to deliver vitamin A supplements.
Bull. WHO 78: 305–314.
49. Underwood, B. A. Prevention of Vitamin A Deficiency. (1998) In: Prevention of Micronutrient Deficiencies. Tools for Policymakers and Public Health
Workers (Howson, C. P., Kennedy, E. T. & Horwitz, A., eds.), Board on Interna-
tional Health and Food and Nutrition Board, Institute of Medicine, National Academy Press, Washington, D.C.
50. Arroyave, G., Aguilar, J. R., Flores, M. & Guzmán, M. A. (1979) Evaluation of sugar fortification with vitamin A at the national level. Sci. Publ. No. 384.
Pan American Health Organization, Washington, D.C.
51. Johnson-Welch, C. (1999) Focusing on women works: Research on
improving micronutrient status, through food-based interventions. International
Center for Research on Women, Washington, D.C. Pg. 31.
52. Smitasiri, S. (2000) Engaging communities in a sustainable dietary
approach: A Thai perspective. Food and Nutr. Bull. 21: 149 –156.
53. West, C. E. (2001) Meeting requirements for vitamin A. Nutr. Rev. 58:
341–345.
54. Tang, G., Gu, X., Hu, S., Xu, Q., Qin, J., Dalnikowski, G. G., Fjeld, C. R.,
Gao, X., Russell, R. M. & Yin, S. (1999) Green and yellow vegetables can
maintain body stores of vitamin A in Chinese children. Am. J. Clin. Nutr. 70:
1069 –1076.
55. Ribayo-Mercado, J. D., Solon, F. S., Solon, M. A., Cabal-Barza, M. S.,
Perfecto, C. S., Tang, G., Solon, J.A.A., Fjeld, C. R. & Russel, R. M. (2000)
Bioconversion of plant carotenoids to vitamin A in Filipino school-aged children
varies inversely with vitamin A status. Am. J. Clin. Nutr. 72: 455– 465.