Nunition Research, Vol. 17. No. 3, pp. 547-580.1997
1997 Elsevier Science Inc.
Printed in the USA. All rights reserved
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PII SO271-5317(97)00011-O
BETA-CAROTENE
AND HUMAN HEALTH : A REVIEW OF CURRENT RESEARCH
Betty Jane Burri, Ph.D
Western Human Nutrition Research Center, USDA/ARS/PWA
Presidio of San Francisco, CA 94129
Phone (415) X6-6285; FAX (415) 556-1432
ABSTRACT
Beta-carotene research has progressed rapidly in the past few years. New
techniques have allowed accurate measurements of beta-carotene concentrations
in plasma, tissues, and diet. New animal models, stable isotope techniques, and
human depletion and repletion experiments are leading an explosion in the
information about beta-carotene utilization in humans. These advances are
leading to a better understanding of the possibilities and limitations of the
influence of beta-carotene on human health. This review summarizes important
new developments in beta-carotene research, and provides an interpretation of
how these results reflect the impact of beta-carotene and human health.
1997 Elsevia Science Inc.
Key Words: Beta-Carotene,
Immunology.
Human, Health, Antioxidant, Gap-Junction,
INTRODUCTION
Beta-carotene is the major source of vitamin A for most of the people in the world.(l-4)
Vitamin A is an essential vitamin: necessary for normal development, growth, and eyesight.( 1-5)
Thus, dietary beta-carotene is essential for most people. But what about the millions of people who
obtain enough vitamin A from meat, milk, or other animal products? Is beta-carotene essential, or
at least very useM, for people who eat enough preformed vitamin A?
A few years ago, most scientists and physicians would have said yes. In fact, some appeared
to believe that beta-carotene was a wonder drug. Beta-carotene was described as an antioxidant that
protected against cancer,(6-8) heart disease,(9-11) macular degeneration (12,13) and ageing.( 14)
It was non-toxic.( 15) Several large, well-funded studies were set up to give more beta-carotene to
healthy well-fed adults.(l6-19)
A research project was even conducted which gave beta-carotene
547
548
B.J. BURRI
supplements to healthy male physicians living in the United States of America--a group not previously
noted to be at-risk for any nutritional deficiency--in the hope that these supplements would delay the
onset of cancer or heart disease.( 19)
The growth in carotenoid research was explosive. Useful new methods were developed to
measure serum and tissue carotenoid concentrations;(20,21)
food composition data;(22,23) and
dietary intakes(24) Essential new information was collected about usual dietary intakes (25) and
serum concentrations in healthy well-fed individuals;(26) as well as about the mechanisms of betacarotene action in the antioxidant,(27,28) cell to cell communication,(29,30) and immunology.(3 l-32)
New and better animal models,(33) and new stable isotope methods (34) provided the hope of
measuring and understanding crucial aspects of human beta-carotene metabolism for the first time.
However, ties have changed.(35,36) Unfortunately, the potential benefits of beta-carotene-or at least beta-carotene supplementation to healthy well-nourished adults--appear to have been overrated. The results of most of the beta-carotene supplementation trials have been disappointing. Two
even suggest that long-term smokers may be harmed by beta-carotene supplements.(l6-18)
Carotenoids other than beta-carotene are believed to be more relevant to macular degeneration and
eye disease.(37) Some investigators suggest that the epidemiological results that appeared to show
such strong evidence for beta-carotene are actually related to other carotenoids,(38)
other
phytochemicals, or even to differences in lifestyle. Studies even suggest that beta-carotene from
vegetables is not very useful for preventing vitamin A deficiency.(39,40)
Is beta-\ uotene a failed wonder drug whose time has come--and gone? Or are these recent
set-backs useful corrections in an overly optimistic scenario? What does beta-carotene do? How
important is beta-carotene to human health, in general? And how important is it to certain specific
populations? How much more money, time, and effort should we spend on beta-carotene studies?
And where and how should we spend them? And what has really been accomplished in the past few
years?
What has been accomplished:
new methods for beta-carotene research
Recent progress in carotenoid methodology has been exciting. New, significantly improved
methods have been developed to measure carotenoid concentrations in blood. The National Institute
of Standards (NIST, USA) led a series of studies to systematically optimize high-performance liquid
chromatography methods to measure the six most common carotenoids in human blood (betacarotene, alpha-carotene, lutein, zeaxanthin, cryptoxanthin, and lycopene.(20,21) New column
materials have been manufactured to provide greater specificity and selectivity for the less common
carotenoids and their isomers. (41) Potentially of even greater importance, NIST has sponsored a
series of round-robin analysis workshops to standardize methods and to compare results from
different 1aboratories’Reference
data for the six major carotenoids in human plasma was collected
for non-institutionalized
population of the United States.(26)
More data on carotenoid
concentrations in serum in other populations is available, though sparse. Representative data is
shown in Table 1. This data is consistent. Most studies in the US and Europe show that people have
‘MST, US Department of Commerce, Gaithesburg MD 20899, USA. Phone (301) 977-0685.
BETA-CAROTENE
AND HUMAN HEALTH
549
TABLE 1
REPRESENTATIVE
n
ESTIMATES OF SERUM OR PLASMA CONCENTRATIONS
Sex
Concentration
Characteristics
OF BETA-CAROTENE
Reference.
(l.mofi)
22949
MfF
4+yrs
(USA)
(median)
(5th %)
(95th %)
Other population studies
physicians (USA)
22071
M
40-84 yrs
M
smokers (Finland)
29133
50-69 yrs
72
M/F
nonsmoker (USA)
18-65 yrs
M
180
(USA)
IF
220
M
1196
(Jaw)
F
618
M
116
(Europe)
(France)
527
Ml
F 23-53 yrs
353
Ml
330
(USA)
F
M
166
(Italy)
F
186
MJ
55
(USA)
F
55
0.34
0.27
0.09
0.91
Centers for
Disease
Control and
Prevention*
0.56
(19)
0.39
(16)
0.41
BUrri
(Communication)
(42)
0.21
0.32
0.35
0.64
0.32
0.56
0.54
0.26
0.41
0.32
0.48
0.29
0.42
(43)
(44)
(45)
(46)
(47)
(48)
2 Source = Centers for Disease Control and Prevention/National Center for Health Statistics, 1996.
Unpublished data presented at EB’96, April 17, 1996 in Washington, DC. Stratified multistage
national probability sample for United States of America non-institutionalized population aged 4 yrs
and older, with over sampling of children under 6 years, adults over 59 years, black- and MexicanAmericans. Measured by reversed-phase HPLC.
approximately 0.2 to 0.6 @ofi.
Smokers tend to have lower concentrations than non-smokers.
Women tend to have higher concentrations than men. People known to eat recommended amounts
of fruits and vegetables have higher serum beta-carotene concentrations, of about 0.6 to 1.5 moi/L.
B.J. BURRI
550
TABLE 2
n
Sex
Race
Location
Intake
References
(Wday)
mean
14801 All
both
7322 m
7479
f
National USA
Aged 2 mos or older
All
All
2712
1038 (median)
2922
1134 (median)
2514
960 (median)
(25)*
Other populations (less representative of overall population)
All
(food frequency.)
1100 f
1950
(49)
Caucasian
29133 m
2086
(16)
1543 (SD)
(Finnish smokers)
Caucasian
1556 m
3700
(50)
1600 (SD)
(Western Electric, USA)
3424
Burt-i
San Francisco CA
72
both
1882 (SD)
unpublished
(Nonsmokers, USA)
Beaver Dam WI
400
both
1566
(42)
1069 (SD)
USA
New Caledonia
84
8181
(51)
7775
SO-65 yr
:
2559
Tahitian
102
m
3612
f
11386
Cook Islands
98
13111
:
14051
Fijian
83
14548
f”
7281
Hawaiian
37
6475
;P
6475
Hawaiian/
64
m
6952
Caucasian
f
6841
Hawaiian/
114
m
8677
Japanese
f
7073
Hawaiian/
18
m
7345
Chinese
f
ZData from 24 hr recall. Distribution of recalls by day was not uniform, but ranged from a low of 8%
of reports for Sunday to a high of 26% of reports from Friday, due to operational procedures
allowing for more data collections on Saturday to improve response rates. Reports were collected
in English and/or Spanish.
BETA-CAROTENE
AND HUMAN HEALTH
Dietary information was improved by a) measuring the carotenoid content of 120 fruits and
vegetables (and about 2500 common foods;(20,21) b) developing food frequency questionnaires for
carotenoid intake;(22) and c) collecting reference data on the dietary intake of carotenoids (for the
non-institutionalized population of the United States of America, (23) and other populations (Table
2). Mean intakes in the USA and Europe tend to be 2 to 4 mg per day, with median intakes much
lower. Some populations, who routinely eat recommended amounts of fruits and vegetables, have
intakes of 10 mg per day or more. (Table 2).
New tiormation about carotenoid metabolism is available, too. First, several new and better
animal models have been discovered, which might mimic the metabolism of beta-carotene in humans.
None of these animal models are entirely similar to humans, but they do absorb beta-carotene intact.
These animal models include the ferret,(52) and the preruminant c&.(33,53) Second, stable isotope
methods have been developed to estimate the body pool concentrations of both vitamin A and betacarotene. These isotopes allow investigation of the metabolism, conversion, and utilization of both
vitamin A (54) and beta-carotene.(34,55-58)
Finally, there is a wealth of new information on the potential mechanisms of action of betacarotene in the human body.(27-32)
We are fortunate to be in the process of a revolution in
carotenoid methodology. At the time of this writing, much of the information about the role of betacarotene in human health is fragmentary and contradictory. However, these new methods will allow
us to answer some important questions soon.
FLINCI’IONS AND ACTIONS OF BETA-CAROTENE
Proposed Cmctions and actions of beta-carotene are listed in Table 3. Some of these
functions, such as conversion of beta-carotene to vitamin A, have been established beyond a
reasonable doubt. Others, such as possible interactions between beta-carotene and skin health or
fertility are based on the interpretations of a few studies and are much more speculative.
Beta-carotene
as a source of vitamin A
Beta-carotene plays a crucial role in human health, whenever preformed vitamin A is in short
supply. It is the major, most active precursor of vitamin A. Vitamin A is essential for human health.
It is so critical that it was the tirst vitamin discovered.(59) Vitamin A deficiency is the leading cause
of childhood blindness in the world effecting approximately 250,000 children a year.(60,61) It is also
a leading cause of death. Vitamin A supplementation alone results in a decrease in infant mortality
of as much as 60%.(60,61) Meta-analysis suggests an overall decrease in death rate of about 30%
from vitamin A supplementation of at risk children alone.(61) However, it is likely that the ranges
seen for the efficacy of vitamin A are a more accurate index of the influence of vitamin A
supplementation on these populations. Some populations will respond to vitamin A supplementation
with a substantial increase in health, while other populations with different nutritional needs will be
B.J. BURRl
552
TABLE 3
BIOCHEMICAL
FUNCTIONS
OF BETA-CAROTENE
IN HUMANS
1.
Vitamin A formation (34,55-58,63-71)
Beta-carotene is a major source of vitamin A for humans. This interaction is of significant,
proven importance to human health.
2.
Lipoxygenase (72)
Co-oxygenation of fatty acids and carotenoids. Lipoxygenases are involved in
arachadonic acid metabolism, which is inhibited by beta-carotene. Unknown impact on
human health.
3.
3-Hydroxy-3-methylglutaryl
coenzyme A (I-lMG CoA) reductase (EC 1.1.1.34; 73)
Converts HMG CoA to mevalonate, the rate-limiting enzyme in biosynthesis of
cholesterol and other non-steroidal isoprenoids. Carotenoids modify by posttranscriptional regulation. Beta-carotene may exert chemopreventive effects by inhibiting
I-WIG-CoA reductase. Unknown importance to human health.
4.
Connexin 43 (29,30,74,75)
Beta-carotene stimulates connexin 43 to increase gap junction formation; thereby
increasing cell to cell communication. This reaction is well-established in vitro, but of
unknown importance to human health.
5.
Antioxidantiprooxidant
(27,28,76-79; but see 80-82)
Established health benefit to some human and animal populations; of unknown importance
to the general human population.
6.
Immunological response (3 l-32,83-88)
Established importance to animal health; good evidence for benefit to some human
populations, but of unknown importance to the general population.
7.
Hormone regulation and fertility (89-93, but see 94)
Numerous reports of beta-carotene supplementation causing fertility improvements in
herbivores, but a substantial number of studies have also found no effect. A few reports
that carotenoids influence menstrual cycle and thyroid hormones in humans. Unknown
importance for human health
less influenced. Although most supplementation programs have used vitamin A as the
supplement, the dosage of vitamin A supplied can have toxic or teratogenic effects in some
people.( l-5) Therefore, several ongoing supplementation programs are attempting to use either
BETA-CAROTENE
AND HUMAN HEALTH
553
purified beta-carotene or fruits and vegetables high in carotenoid content instead of purified
vitamin A.(39,62) Beta-carotene capsules have been able to provide the same protection as
vitamin A capsules,(2,3,39,62) with fewer toxic side effects.(l5)
The conversion of beta-carotene to vitamin A has been studied extensively,(34,55-58,6371) but much of its metabolism remains in doubt. The main difficulty has been that humans do not
have typical mechanisms of beta-carotene metabolism and conversion. Most animals metabolize
beta-carotene differently than humans do; they do not absorb beta-carotene intact, and lowdensity lipoprotein is not their main means of beta-carotene transport(71)
Although the
importance of some of these differences are unknown, it is clear that research on metabolism done
on these common laboratory animals may not be relevant to studies of human metabolism. A
second difficulty in studying carotenoid metabolism is that a crucial enzyme involved in
carotenoid cleavage (151 S-beta-carotene dioxygenase; 65,66,70,7 1) is unstable and difficult to
purify. Other enzymes thought to be involved are nonspecific (alcohol dehydrogenase; 69,70).
So, scientists are still debating whether beta-carotene is cleaved centrally, eccentrically, or by both
mechanisms.
There is no doubt, however, that under normal conditions beta-carotene is converted to
vitamin A inefficiently. One molecule of beta-carotene, cleaved centrally, should form two
molecules of vitamin A (in the form of retinal). One molecule of beta-carotene, cleaved
eccentrically, should form one molecule of retinal. This does not seem to happen in vivo.
Healthy, vitamin A depleted individuals fed beta-carotene in easily digestible capsules appear to
derive one molecule of vitamin A from approximately two molecules of beta_carotene.(67,68,9597) Beta-carotene conversion may depend to some extent on the body stores of vitamin
A,(67,68,95-99) so repleted individuals typically obtain less vitamin A than depleted individuals
do.(34,97-98)
Worse, beta-carotene conversion to vitamin A appears to be poorest under conditions
where it is most necessary. It appears to require fat in the diet.( 100, 10 1) It appears to be
influenced unfavorably by infections, fevers, and parasite infestation.(l-5,100-102)
It is less
available in vegetables, especially abundant green leafy vegetables, than oils, fruits, or
supplements.(39,40,97,102)
Thus, it is converted with poor efficiencies by the malnourished
people who need it most. In fact, recent field studies have suggested that although beta-carotene
supplements can be used to treat vitamin A deficiency effectively (39,40,62,102-104), betacarotene from green leafy vegetables is a poor source of vitamin A for malnourished
people.(39,100-102)
Thus, feeding programs meant to enhance vitamin A status through
education, farm production and consumption of green lea@ vegetables may not be successful.
Alternative strategies, such as supplementation with vitamin A or beta-carotene capsules, may
need to be continued until a better overall diet for the population is attained.
Other functions of beta-carotene
Does marginal beta-carotene status cause subtle health problems, even when vitamin A is
provided in abundant supply? Some evidence suggests that it does. First, there is an
overwhelming consistency in epidemiological studies which point to associations between beta-
B.J. BURRI
carotene consumption or serum concentrations and decreased rates of cancer and heart disease.
These epidemiological studies will only be mentioned in this review, because they have been
summarized in other recent reviews.(6-14,105111)
Suffice it to say that the evidence is
substantial. However, epidemiological studies can only show association; they do not, and cannot
show cause and effect. Several mechanisms have been proposed to account for the observed
correlations between increased carotenoid consumption or serum concentrations and decreased
risk of degenerative diseases. Beta-carotene could timction as a redox reagent, an immunological
regulator, or by increasing cell to cell communications. There is substantial evidence that betacarotene is capable of influencing all of these mechanisms, at least in vitro. There is less evidence
that beta-carotene functions in vivo by these mechanisms, or that its infhience is substantial or
significant to human health.
Beta-carotene is an uncommon type of biological redox reagent--one that reduces
oxidation products best at low partial pressures of oxygen (less than 150 torr; 27). These low
pressures are relevant to many physiological tissues. Beta-carotene is a physiological modulator
(111) with the capacity to act as a singlet oxygen quencher (1121). It also can function as an
antioxidant or as a reductant, depending on reaction conditions. In vivo, it appears to function
most often as an antioxidant and singlet oxygen quencher. As such, it decreases lipoprotein and
DNA oxidation.(27,28, 76-79) Theoretically, these oxidations are detrimental to human health.
Lipoprotein oxidation is thought to held initiate atherogenesis.(l09,110,113)
DNA and
lipoprotein oxidation are also thought to be related to cancer and other degenerative
diseases.(lOS-107)
Gap junctions link cells within an organism to form a communicating syncytium, allowing
small molecules to pass through cells. Beta-carotene and vitamin A can both stimulate gapjunction formation between cells.(29,30,74,75) This function can also be carried out by some
other carotenoids, but it is not caused by interconversion of beta-carotene to vitamin A or to these
other carotenoids. It is an intrinsic function of beta-carotene itself. The mechanism appears to be
a stimulation of connexin 43, a gene coding for a transmembrane protein. Six of these
transmembrane proteins form a hexameric array surrounding a water-filled core. Two of these
arrays form the structural unit of a gap junction. Beta-carotene, in physiological concentrations
( 10d M range), increases the gap junction, allowing for more cell-cell communication. One
mechanism by which carotenoids might prevent cancer is through these gap junctions. Betacarotene may maintain carcinogen-initiated cells in junctional communication with nontransformed
cells, thereby preventing their transformation. This is correlated to ability to inhibit neoplastic
transformations.
It is unfortunate that connexin 43 activities and gap-junction formations have
seldom been studied in humans. Thus, their relative importance to human health is unknown at
this time.
Beta-carotene acts on the immunological system.(3 1,32,83-88) The influence of betacarotene depletion on immunology was discovered decades ago.(84,85) These early studies found
that feeding beta-carotene to depleted animals decreased the number and severity of respiratory
infections, and appeared to help overcome infections.(84,85) Beta-carotene has been implicated
in T and B cell proliferation, T helper cell increases, and natural killer cell cytotoxicity, as well as
decreased mutagenesis (decreased chromosomal abnormalities and breaks, micronuclei, and
BETA-CAROTENE
AND HUMAN HEALTH
555
urinary mutagens (3 1,83,86-88). However, the details of these interactions are still sketchy.
Interestingly, optimal immunological defense may require more beta-carotene than antioxidant
defense. Many immunological changes have been induced by relatively high carotenoid intakes, of
over 15 mg per day.(86,87,114)
Many reports suggest that beta-carotene supplementation increases fertility in herbivores
fed hay (which typically contains only low concentrations of beta_carotene).(89,92,93)
The
influence of beta-carotene supplementation on litter size has been reported for cattle, swine, and
rabbits. Furthermore, the corpus luteum of these herbivores sequesters beta-carotene. (Betacarotene gives is responsible for the coloration of the corpus luteum in these animals, for which
the gland was named). These results have been contradicted by other studies finding little or no
effect, of beta-carotene on fertility.(94) However, herbivore fertility is a complex process studied
under difficult field conditions at different locations with different basal carotenoid intakes. It is
not surprising that the evidence is contradictory. Evidence for the intluence of beta-carotene on
indices of human fertility are suggestive but minimal, resting on a few small controlled human
studies(91)
Beta-carotene may intluence thyroid hormone status.(90,115) Numerous case reports have
linked anorexia nervosa, thyroid status, and unusually high serum concentrations of betacarotene.( 115) These case reports are supported by evidence from two small controlled betacarotene depletion studies.(90) The mechanism for relating beta-carotene to thyroid hormone
status is unknown.
How important are these functions to human health? If beta-carotene is not needed for
vitamin A formation, is it needed for anything? We can answer this question by examining the
influence of carotenoid depletion on human health.
DEPLETIONSTUDIES
Studies of beta-carotene depletion in humans are rare. Furthermore, they are complicated
by other nutrient depletions. In fact, a simple beta-carotene depletion study has never been done.
Depleting beta-carotene also means--at the very least--depleting alpha-carotene, cryptoxanthin,
lutein, zeaxanthin, lycopene, and a host of carotenoids and flavonoids typically present in minute
concentrations in human tissues, There are several reasons for this. First, there are very few
known foods that are good sources of carotenoids that do not contain beta-carotene. (Of course,
most foods have not been analyzed). Second, most common carotenoids and flavonoids are not
approved for use as human supplements. At the present time, only beta-carotene and
canthaxanthin, a carotenoid that does not form vitamin A, are approved for human use. Therefore
a diet deficient in a single carotenoid cannot usually be supplemented with just this carotenoid.
Thus, it is very difficult to invent a diet (at this time) that is depleted of beta-carotene, but not of
at least some other carotenoids.
There are a few older, relatively long-term studies that are of interest to carotenoid
556
B.J. BURRI
researchers. These older studies were not planned as carotenoid depletion studies; they were
intended to measure the effects of vitamin A or vitamin C depletion. However, subjects who
participated in these studies were fed low carotenoid diets for prolonged periods of time. Thus,
they provide information on the limits of the significance of carotenoid depletion to human
health. Older studies include the Scorby Research Institute (Sheffield, UK; 95,116) studies of
vitamin A and vitamin C depletion in healthy young adults; and the US Army/Iowa State
University studies of vitamin A and vitamin C deficiency in adult males.(96,117-120)
Newer
studies are the free-living study of carotenoid depletion conducted in healthy young men at the
University of Illinois at Chicago,( 121) and two metabolic unit studies of carotenoid depletion in
healthy adult young women conducted at the Western Human Nutrition Research Center in San
Francisco, Califomia.(79,88,90,91,98,114,122-125)
Both new and old depletion studies are limited because they have all been conducted in
small numbers of relatively similar people (healthy, otherwise well-nourished young or middleaged adults). They provide almost no information on the effects of beta-carotene depletion and
requirements of infants, children, adolescents, and the elderly. They provide little information
about psychological status or stress, and none on gap junctions.
Older mixed carotenoidhitamin
deDletion studies
Two studies involving beta-carotene depletion (associated with either vitamin A or vitamin
C depletion diets) were conducted in Sheffield England during World War II. The first, a vitamin
A depletion study, ran for 6 % to 25 months during 1942 to 1944.(95) The second, vitamin C
depletion study, was conducted for 8 % to 22 months in 1944 and 1945 .( 116) Both were freeliving studies, but had more control than is typical for these types of studies because of wartime
food rationing and restrictions on movement. Twenty conscientious objectors (17 men and 3
women) participated in the vitamin A depletion study, and twenty (19 men and 1 woman) in the
vitamin C depletion study. Half of the subjects participated in both studies. Four subjects were in
both the vitamin A and the vitamin C depletion groups. No major deviation from normal
developed during the vitamin A depletion study, except that 3 men developed dark adaptation
problems on the low vitamin A diet. Scurvy developed in at least 8 of the 10 depleted subjects
given the vitamin C deficient diet. All major, defined symptoms of deficiency cleared up with
either vitamin A or vitamin C. However, four subjects who participated in both studies
developed serious or life-threatening illnesses. (The illnesses were tuberculosis of the spine,
probable heart attacks, malaria, impetigo and migraine).
U.S. Army and Iowa State University scientists conducted three controlled nutrition
studies that contained minimal amounts of beta-carotene during the 1960’s. No subjects
overlapped in these studies. Two were vitamin C depletion studies,( 117,119,120) the last was a
vitamin A depletion study.(96,117,118)
All participants were healthy middle-aged male prisoners.
Nine men participated in the vitamin C deficiency studies, and eight men in the vitamin A
depletion study. They ate several diets during these studies; a controlled formula diet that was
devoid of vitamin C and carotenoids for most of the experiments; then several solid diets based on
casein; then a restricted natural foods diet. The first vitamin C deficiency study ran for 200 days;
113 days depletion and 97 days repletion. The second had 84-92 days of depletion. The details
BETA-CAROTENE
AND HUMAN HEALTH
557
of the vitamin A depletion study plan, and some of its findings, have never been published in t%ll.
(Because guidelines for human nutrition studies became more strict between the time the study
was conducted, and the time when attempts were made to get it published). All subjects on the
vitamin C depletion diets developed classic signs of scurvy. Most developed problems with dark
adaptation (an index of mild vitamin A deficiency) on the vitamin A depletion diet. Again, no
significant identifiable symptoms occurred that were not ameliorated by vitamin A or vitamin C
repletion.
The bottom line of these mixed depletion studies, and other older studies conducted for
shorter terms,(97) is that no specific deficiency symptoms could be related specifically and solely
to carotenoid depletion. Either vitamin A alone, or vitamin C alone, was sufficient to ameliorate
these severe, identifiable deficiency symptoms. However, only acute symptoms were measured.
These depletion studies could not measure increased risks of cancer and heart disease in their
small numbers of subjects. They did not measure changes in antioxidant, gap-junction, DNA
damage, hormonal status, or fertility. Immunological tests were few, and not sensitive.
Modem
carotenoid
deDletion studies
The first modem carotenoid depletion study was a free-living study of 15 healthy young
adult men, who were fed a liquid formula diet containing no carotenoids and a high P/S ratio (to
stimulate oxidative damage) for 2 weeks.( 120) They were then fed the liquid diet supplemented
with either 15 or 120 mg per day of beta-carotene for four weeks. Several indices of oxidative
damage and immunological activity were tested.(l20) A significant change occurred for
thiobarbituric acid reactive substances (TBARS), a widely used but non-specific test of oxidative
damage.
The other two carotenoid depletion experiments were carried out on a metabolic unit; with
healthy young adult women. In the first study 9 women were fed a low carotenoid diet of natural
foods for 68 days, followed by the same diet supplemented with 15 mg per day of beta-carotene
for 16 days; then the beta-carotene supplement plus a mixed carotenoid supplement (containing
beta-carotene, alpha-carotene, vitamin E, and some lutein, and lycopene) for the final 12
days.(79,88,90,122,123)
The second study was conducted for 120 days. This was a placebocontrolled double-blind study. Twelve women started the study, nine completed. Four volunteers
were in the carotenoid depletion group, while five were in a control group that were fed the same
low carotenoid diet supplemented with 0.5 mg beta-carotene per day for 60 days. Then both
groups were fed the 0.5 mg beta-carotene supplement for the next 40 days, then all were
supplemented with 15 mg per day beta-carotene plus 3 mixed carotenoid capsules per day for the
last 20 days. Thus, the second study had a control group, but at the cost of having small numbers
of subjects in each group.(91,114,124,125)
The first metabolic unit study gave the clearest results. Several indices of oxidative
damage (TBARS, oxidized LDL products (79), ratio of oxidized to reduced glutathione (122))
increased during carotenoid depletion, then reverted to baseline upon repletion. Conjugated
dienes, measured in slowly turning over red blood cells, had the same pattern, except with a time
lag.( 122) Superoxide dismutase, an enzyme involved in oxidative defense) decreased during
558
B.J. BURRI
depletion and reverted to baseline at repletion(79) Fewer test results are available at this time
from the second study, but fewer of the tests that are available reached statistical significance
during the second study (probably because of the small siie of the depleted group). However,
malondialdehyde (an improved test equivalent to TBARS; 124) and oxidized LDL products (125)
increased in the depleted group and reverted to baseline with repletion. Malondialdehyde
concentrations in the depleted group were different from the control group during depletion, but
not after supplementation with 0.5 mg per day beta-carotene.( 124) Thus, there is good, consistent
evidence that carotenoid depletion increases oxidative damage. There was no evidence that
carotenoid supplementation decreases oxidative damage below baseline levels in these subjects.
The metabolic unit studies also showed numerous indications that carotenoid depletion
influences hormone status. In the first study, several thyroid hormones (thyroid stimulating
hormone, total thyroxine, free thyroxine) increased during depletion(90)
The increase occurred
with approximately a 4 week lag after carotenoid depletion was initiated, and began to normalize
during repletion. In the second study, only total thyroxine concentrations changed significantly in
the depleted group; thyroid stimulating hormone and free thyroxine showed similar but nonsignificant trends. Menstrual cycles and luteinizing hormone peak activities were disrupted in
both studies.(91) There was no difference between the control and depleted group in the second
study, both groups were disrupted according to baseline and post-study records. Acne appeared
in seven women during carotenoid depletion in the first study, and was inversely correlated to
serum beta-carotene concentrations during depletion and to the body pool of vitamin A.( 123)
This did not happen on the second study. (However, subjects were excluded from the second
study if they had current acne, or a history of skin problems). Thus, the group was selected so
that the appearance of acne would have been strong evidence for a role of beta-carotene in skin
health, but the absence of its appearance was not good evidence for a lack of effect.
The first study did not show changes in immunology,(88) but the second did.(ll4)
The
second study used tests conducted in whole blood, instead of washed cells, and had much less
variability. Immunological changes in the second study were the only parameters measured that
indicated an effect of beta-carotene supplementation. All other tests were reverted to baseline
values after beta-carotene supplementation.
The modem carotenoid depletion studies provide consistent evidence that antioxidant
status is intluenced by carotenoid depletion and beta-carotene repletion. How important or longterm this interaction is not known. It is also not known whether this decreased antioxidant
defense, if sustained, would be sufficient to inthrence the rates of heart disease and cancer in
humans. Furthermore, although serum vitamin C and E concentrations were increased in the
carotenoid depletion studies carried out on the metabolic unit, we do not know whether higher
dietary intakes of other antioxidants could ameliorate the effects of carotenoid depletion.
Depletion studies on the metabolic unit suggest that the carotenoid intake needed to maintain
baseline antioxidant status in healthy adults is low, possibly about 600 pg per day (approximately
l/4 the median intake of adults in the United States). Thus, our metabolic unit studies suggest
that deleterious changes in antioxidant status caused by low carotenoid dietary intakes would not
be common in the US adult population.
BETA-CAROTENE
AND HUMAN HEALTH
559
The carotenoid depletion studies carried out on the metabolic unit also suggest changes in
thyroid and menstrual cycle hormone concentrations. Again, we do not know whether these
changes are really significant, or would be prolonged. In fact, many women eating poor diets low
in carotenoids do have children, so we speculate that these menstrual hormone changes caused by
carotenoid depletion would eventually normalize.
BETA-CAROTENESUPPLEMENTATION
Results of supplementation studies are relatively difficult to interpret. There is little
information at this time about the typical dose-response curve of beta-carotene to indices of
oxidative damage in healthy adult humans, and less of the usual range of response. There is
essentially no information on the dose-response curve of beta-carotene on immunological, cell to
TABLE 4
biFLWNCE
Dose of
g-carotene
OF BETA-CAROTENE SUPPLEMENTS ON PLASMA BETA-CAROTENE CONCENTRATIONS
Duration
(days)
n
sex
Baseline
End
g-carotene
Reference
(umoW
(mg/day)
Depletion studies
Base
Depleted
15
Base
Depleted
120
Base
Depleted
15
7
m
0.28
0.10
8
m
0.24
0.11
14
28
3.4
14
28
8.8
9
f
68
28
Base
Placebo (P)
60
Control (C; 0.5)
0.5 P
40
0.5 c
15
20
(121)
0.56
0.17
(79)
5.4
11
6
5
4
5
9
f
1.11
0.23
0.59
0.67
0.83
Burri,
Personal
Communication
2.7
B.J. BURRI
560
Table 4 (continued)
Dose of
p-carotene
Duration
n
Sex
(days)
Baseline
End
P-carotene
(mg/day)
Reference
@mom)
Supplementation
studies
6
6
7
7
15
45
180
300
28
28
28
28
15
15
150
1916
15
-15000
20
20
20
2226
98
98
14560
53
70
25
25
900
4380
30
30
30
40 14 days
20 84 days
m
m
0.29
0.42
0.71
0.86
(126)
m/f
0.47 (all 35)
1.2
3.0
3.8
5.8
(127)
mlf
0.30
0.11’
3.2
1.6’
(128)
(129,130)
m
m
m
0.32
0.32
0.33
5.4
3.8
4.4
(17)
(44)
(131)
378
11036
m
m
0.36
0.56’
3.3
2.2
(132)
(19)
1
42
70
900
5
8
m
F
0.34
0.42
0.49
0.75
8.8
5.8
(103)
(133)
(134)
98
46
m
0.31
5.0
(81)
? smokers
? nonsmokers
8
10
8
9
50
2993
-900
m/f
0.61
6.1
(135)
60
270
8
m/f
1.4
2S3
(82)
90
21
10
f
0.48
6.8
(136)
15+
(137)
180300
‘Representative
Life
long
samples
133
m/f
-Erythropoetic
protoporphyria
‘Placebo group
3in lipoproteins
BETA-CAROTENE
AND HUMAN HEALTH
561
cell communication, or hormonal status. There is essentially no information on dose-response,
normal, and dangerously abnormal variations in response for people with diseases, or disease
causing habits such as smoking. There is also little or no information on the appropriate duration
of beta-carotene supplementation; or when supplementation should be started for greatest effect;
or what types and what stages of heart disease and cancer might be treatable. Thus, current
supplementation trials have tried a wide variety of dosages of beta-carotene, for various lengths of
time, for a variety of peoples, with a variety of risk factors and diseases. In fact, little attention
has been paid to the baseline beta-carotene concentrations of the populations studied. However,
information on baseline beta-carotene concentrations and of the effects of beta-carotene
supplementation on these concentrations is accumulating. This information is summarized in
Table 4. Table 4 suggests that daily supplements of 6 (to lo?) mg of beta-carotene should
increase serum beta-carotene concentrations in most individuals to the concentrations that have
been associated with reduced risks of cancer and heart disease in epidemiological studies. These
serum concentrations are also attainable Corn eating a well-rounded diet. Unfortunately, very few
supplementation studies have been conducted with these relatively low levels of supplementation.
Results from beta-carotene supplementation trials have been variable. Some have
suggested a benefit for beta-carotene supplementation, others have suggested neither benefit nor
harm, and a few have suggested that beta-carotene supplementation has been harm&l (at least to
heavy smokers and alcohol consumers). This is not surprising, because few of the participants in
supplementation trials have had low serum concentrations of beta-carotene. Most have average
concentrations, while some participants have unusually high levels. Subjects with normal to high
serum concentrations of beta-carotene are not likely to have significant responses, unless the
amounts of beta-carotene needed by the body are typically much higher than the amounts
provided by typical healthy diets.
Treatment of Dutative orecancerous states
Several studies of the effects of beta-carotene supplementation have treated putative
precancerous lesions such as the recurrence of oral leukoplakia and micronucleated cells in
smokers or betel nut chewers. Oral leukoplakia and micronucleated cells are not cancer. Oral
leukoplakia is the presence of irregular white patches of cells in the oral cavity that are not
painful, nor associated with infections such as herpes. Micronucleated cells are just an increased
percentage of cells with small nuclei. Neither essential precursors to cancer, nor does their
presence invariably lead to cancer. Most of these lesions have benign outcomes--the risk of
cancer is closer to 30 than to 100%. However, they are associated with higher than normal risks
for relatively rapid progression of oral cancers.
Most of these trials have investigated the influence of short-term (less than 6 months)
supplementation with moderate pharmacological doses of beta-carotene (30 to 90 mg per day).
These amounts of beta-carotene are very difficult, or impossible, to obtain from a normal, healthy
diet (Table 2). They are not associated with toxic symptoms.( 15,138) However, large minorities
(15% or more) of participants report skin-yellowing, suggesting that much of the beta-carotene is
not being metabolized by normal metabolic pathways.(97,135,139-143)
Most of these studies
B.J. BURRI
have reported favorable outcomes.
143)
The average response rate appears to be 50 to 60%.(44,140-
Studies measuring antioxidant status, immunology or adenomas have given more mixed
results. Several have shown that beta-carotene supplementation was associated with a significant
decrease in oxidative damage;(77,78,83,86,144,145)
other equally well-designed studies showed
no effect.(80,82,132,146)
Of course, even if beta-carotene supplementation were associated with
clear and consistent decreases in putative midpoints markers of cancer and disease, that would not
be the same as showing an actual reduction in the incidence of cancer or heart disease. They are
only midpoint indicators. Furthermore, there is no information on the duration of the effects of
carotenoid supplementation or depletion. Evidence from depletion studies suggests that at least
some of the deleterious effects of carotenoid depletion are not permanent.
CANCER AND HEART DISEASEPHASE III TRIALS
Results from four Phase III trials which used beta-carotene (usually coupled with other
antioxidants) in attempts to prevent cancer and heart disease have been reported. Phase III trials
were originally designed to test the effectiveness of a drug intervention. They work best for
testing new drugs that are unavailable to the general public, because they compare outcomes in
large numbers of people without the ability to restrict intakes in the untreated groups. In
nutritional interventions it is generally not possible to find a group that has not, and will not,
consume the nutrient being studied. Furthermore, it is difficult to restrict the dosages taken by the
control group. Thus, nutritional intervention trials typically are restricted to comparing high,
pharmacological intakes of a nutrient to a variable, high and low physiological intake of that same
nutrient in the control group. They are by far the best method available for testing the outcome of
consuming high, pharmacological intakes of a nutrient. However, they are likely to be ineffective
in testing for responses that occur at low physiological intakes. (For example, a Phase III trail of
the influence of vitamins A or C in the general population of the United States would almost
certainly show no benefit of such supplementation. In fact, unless dosages were picked carefully,
a vitamin A trial would probably show an unfavorable, toxic response in the general population.
However, it is well established that these are both essential nutrients, in small doses).
These Phase III trials administered doses of beta-carotene to healthy middle-aged and
elderly adults, in an attempt to decrease the incidence of cancer or heart disease. All were doubleblind, placebo-controlled, randomized trials Unfortunately, these trials only measured cancer,
heart-disease, and death. They did not investigate or report on oxidative damage, immunological
or precancerous midpoint markers. Thus, we know the final outcomes of the trials, but do not
know the mechanisms or changes involved that resulted in these endpoints. These trials are
summarized in Table 5.
Overall, the Phase III trials suggest that beta-carotene supplementation is of little or no
value to the general population; with the possible exceptions of populations that are at risk for
low nutrient intakes of antioxidant vitamins.(l29,130)
In the case of the ATRC and CARET
BETA-CAROTENE
AND HUMAN HEALTH
TABLE 5
PHASE 111 CANCER TRIALS
Trial
(References)
Description
(n, sex, race and nationality, age,
risk factors, dosage, length of
study)
Outcome
Linxian
(129-130)
29584, m/f,Oriental, Chinese, 40-69
years, low consumption of
nutrients, region of highest
stomach cancer incidence in
China; 15 mg, plus 50 mg
selenium and 30 mg a-tocopherol;
5.25 year duration
positive: 18% decrease
in stomach and esophageal
cancers; 8% decrease in
overall mortality.
(note: mixed supplement)
Physicians’
Health USA,
(19)
22071, m, >90% Caucasian,
40-84 yrs, none, 25 mg,
average 12 year duration
no effect on cancer, heart
disease, or death rate.
no obvious positive or
negative trends.
Skin yellowing in 17% of
supplemented group
ATBC
(Finnish)
(16917)
29133, m, Caucasian, Finland
50-69 yrs, heavy smokers (and
drinkers*), 30 mg; average 5 %
negative: 17% increase in
lung cancer; 7O/oincrease
in overall mortality
increased mortality
in heavy drinkers,
(personal communication,
Albanes). Skin yellowing
in 24% of supplemented
group. No effect on
coronary heart disease
Yrs
I
CARET
(18)
18 158, m/f, >90% Caucasian
USA, 50-69 yrs, heavy smokers
and/or asbestos exposed
workers; 30 mg plus 25000 IU
vitamin A average 4 % yr
negative (not significant)
trends toward increased
cancer and death rates;
trial ended early because
of trends similar to ATBC
results. Note: mixed
supplement, dose of
vitamin A occasionally
toxic). Skin yellowing in
25%of supplemented group
563
564
B.J. BURRI
trials, the average serum concentrations of beta-carotene were identical to the average
concentration of beta-carotene in the general US population (compare Table 5 to Table 1). Initial
serum beta-carotene concentrations were higher than average in the Physicians’ Health Trial.
Further trials may be usetbl in populations where carotenoid consumption and serum
concentrations are well below average intakes of well fed populations.
However, great caution is essential. There is no evidence that suggests that even the
subset of people with low initial beta-carotene concentrations benefited from the high-dosage
supplementation provided by the ATBC, CARET, or Physician’s Health trials.(l6-19)
At this
point, the only favorable outcome was reported in the Linxian trial; and that trial used a mixed
antioxidant supplement. The favorable outcome may have resulted from a combination of
selecting a population that had low beta-carotene consumption and status combined with
administration of physiological dosages of beta-carotene. However, the benefit observed might
also have been coincidental, or caused by another of the nutrients provided. In any case, we
should obtain better understanding of the mechanisms of action of beta-carotene and its doseresponse curves before attempting further supplementation trials. Further investigations into the
toxicity of long-term supplementation with beta-carotene should also be done.
TOXICITY
It was previously believed that beta-carotene was not toxic.(lS, 137,138) In fact, acute
toxicity--with well-defined symptoms--is obviously rare. Carotodermia, a yellow discoloration of
the skin, has been sporadically reported in the medical literature for decades.(97,137,138)
It is an
easily recognized, visible physical symptom that can occur with over-consumption of carotenoidrich foods (especially carrots, but also citrus fnits), carotenoid supplements. Carotodermia
appears in some, but not all, people when they eat large amounts of beta-carotene. Typically, the
amount consumed must be at least 15 mg of beta-carotene per day; as supplements or as fruits
and vegetables. The percentage of people with carotedermia increases as the daily intake of
carotene increases. Carotedermia appears in approximately one-quarter of people taking
supplements of 30 mg per day,( 15-19) and increases to well over half of the population taking
extremely high pharmacological intakes.(82,13 7,138) Most carotedermia is caused by high
carotenoid intakes, but it can occur through other mechanisms. It appears frequently in
anoerexia.( 115) It has also been described in a case report of a brain tumor.( 147) The etiology
of these influences are unknown. This discoloration appears to be benign. Despite being a visible,
easily investigated abnormality, no serious medical complaints have been associated with
carotodermia; nor has it been associated with increased genotoxicity or birth defects.( 15,137,138)
Studies feeding very high doses to rodents have shown few abnormalities. In fact, beta-carotene
is approved for human consumption, and has been used as a food colorant and in medical
treatments of skin conditions for over 25 years without reports of major side effects. Thus, there
is substantial evidence that beta-carotene, even given in very high pharmacological doses, is not
acutely toxic.
Almost nothing is known about the effects of chronic pharmacological
supplementation
on
BETA-CAROTENE
AND HUMAN HEALTH
565
human health. These effects, if present, are ill-defined and difficult to recognize and differentiate.
The Physician’s Health study, possibly the longest nutrient supplementation trial of a large healthy
population in history, showed no evidence of chronic toxicity.( 19) However, the ATBC
trial,( 16,17) and possibly the CARET trial,( 18) suggest that prolonged pharmacological treatment
with beta-carotene might be toxic in heavy smokers (especially if they are also heavy drinkers).
Thus, few studies suggest that beta-carotene supplementation will help or hurt most wellfed, healthy populations. Does beta-carotene supplementation benefit smaller, restricted
populations of people with certain diseases? The answer to this question is yes.
BETA-CAROTENEAND DISEASESTATES
Beta-carotene supplementation has proven beneficial to people with erythropoietic
protoporphyria (EPP). In fact, it has been an effective and standard medical treatment for this
condition for decades.( 137,148,149) Beta-carotene is used to treat this disease to such an extent
that the long term effects of beta-carotene supplementation in these individuals have never been
studied, for the simple reason that there is no control group of people with EPP that is not treated
with high doses of beta-carotene. Thus, beta-carotene is used in one of the only known beneficial
nutritional treatments of well-fed individuals.
Beta-carotene supplementation has also been attempted in diseases which have a known
defect in antioxidant or immunological status. These populations, unlike the general US or
Western European population, have diseases which result in unusually low antioxidant or
immunological defense status. Thus, supplementation of these groups is not to increase
antioxidant or immunological activity to greater than average activity (which may or may not be
beneficial). Instead, supplements are given in an attempt to raise antioxidant or immunological
activities toward the average levels of activity found in healthy people. Research results have
been promising, but are very preliminary. They are based on only a few short-term experiments in
small numbers of patients. None have been able to investigate long-term effects or
supplementation on antioxidant or immunological response. Little information is available on
effects of beta-carotene supplementation on overall health status or death of people with illnesses
(except EPP).
ErythroDoetic arotoaomhvria
Beta-carotene has been used to treat EPP for over 25 years.( 137,148,149) This
represents one of the few markedly successtbl nutritional treatments of a human disease. EPP is a
fairly common genetic disease (of unknown incidence). It is thought to be inherited as an
autosomal dominant trait with partial penetrance, but might possibly be an autosomal recessive
disease.(l48) It is not especially associated with any race or ethnic origin. Symptoms usually
appear shortly after birth, but sometimes years later. The primary defect of the disease is a
mutation of ferrochelatase (protoheme ferrolyase, EC 4.99.1. l), the last enzyme in the heme
biosynthetic pathway. Ferrochelatase synthesizes the insertion of ferrous iron into
protoporphyrin IX to form protoheme. In EPP, the activity of ferrochelatase is decreased to 10 to
566
B.J. BURRI
50% of normal. This results in increased concentrations of protoporphyrin in tissues, mainly red
blood cells. The main symptom of the disease is extreme sensitivity to sunlight. Even a few
minutes of sunlight can cause erythema, puritis, pain and burning. Untreated EPP results in
scarring, ‘orange peel’ skin, and hysteria and psychotic episodes. This symptom is thought to be
caused by excess porphyrins in the skin (though measurements of porphyrin concentrations in the
skin have been equivocal). These porphyrins can be excited by sunlight to form a highly reactive
triplet state, which catalyses oxygen free radical formation.
The main treatment for EPP is high doses of beta-carotene.( 137,148,149) Treatment of
children begins with 60 mg per day, and increases to typical doses of 180 mg per day, and even to
300 mg per day or more. Protection from sunlight usually results when blood concentrations
reach at least 7.45 umole/L (400 mg/dL). Most subjects benefit from this treatment, and can in
fact lead normal, active lives. Some do not. Factors affecting the degree of response are not
understood. However, they are not related to serum beta-carotene concentrations or to the
degree of skin discoloration achieved. Most subjects have no serious side effects, and acute
toxicity has not been observed.
Unfortunately, little is known about the effect of this treatment on antioxidant,
immunological, or gap-junction activity. Little is known about the long-term toxicity or
genotoxicity of beta-carotene in patients with EPP. The difficulty lies mainly in finding an
appropriate control group that has not been treated with beta-carotene. Beta-carotene therapy has
been attempted in several other skin disorders and photosensitivity disorders (Gunther’s disease,
actinic reticuloid, solar u&aria, hydroa aestivale, porphyria varigata) but with mixed
results.( 137,150) Pharmacological doses of beta-carotene also are effective protection against
sunburn, but the effect is too mild to use it as sole protection.( 15 1)
Cvstic Fibrosis
Several studies have shown that beta-carotene concentrations are depressed severely in
cystic fibrosis, a genetic disease that produces chronic lung infection and inflammation in children
(152- 154). Beta-carotene concentrations in these children are often one-quarter normal or less
(152-l 55). Oxidative damage appears to be abnormally high in cystic fibrosis.( 154-l 56) There
are several probable reasons for this depression: first, the chronic lung inflammation may cause
increased oxidative stress. Second, the intestinal malabsorption associated with the disease may
reduce the patients’ ability to absorb antioxidants from the diet. Two small therapeutic studies of
cystic fibrosis patients have shown a marked increase in serum beta-carotene concentration and
decreases in two indices of lipid peroxidation compared to that seen in normal control subjects
(lag time of conjugated diene formation and decrease in plasma malondialdehyde formation) after
feeding either 0.5 mg beta-carotene per kg body weight per day for 3 months (155); or 13.3 mg
per day for two months.(l56)
AIIWFIIV Infection
Plasma beta-carotene concentrations are decreased during HIV infection.( 157-160)
Scientists have found that short-term supplemental beta-carotene appears to increase CD4 cells.
BETA-CAROTENE
AND HUMAN HEALTH
567
Subjects using 180 mg per day beta-carotene had increased white blood cells, lymphocytes, Blymphocytes, t-helper (CD4) cells, and CD4/CD8 (t-helper/suppressor) ratio (158). Another
study, giving 60 mg per day for 4 months to 11 HIV-infected patients, showed no changes in
these parameters, but did show an increase in natural killer cells and activated lymphocytes.( 159)
The mechanism for this benefit is unknown. It may be related to vitamin A formation, with
vitamin A in turn stimulating lymphocytes and macrophages. It might be a direct effect of betacarotene. Beta-carotene might stimulate bone marrow to produce white blood cells, or might
block destruction of CD4 or other white cells, or might atfect cytokine formation. Alternatively,
beta-carotene might be acting as an antioxidant to enhance T-lymphocyte response by decreasing
free radicals. However, all these studies are in their infancy. They are on small numbers of
people, fed high doses of beta-carotene for short lengths of time. The long-term influence of
beta-carotene, if any, is unknown.
The explosion of research and information on carotenoids has led to rapid progress in this
field, and has produced welcome--and sometimes surprising--information about a nutrient that had
been neglected in the past. This has been an interesting time for carotenoid researchers, and will
continue to be interesting as the field evolves. Thus, my conclusions about the overall importance
of beta-carotene to human health may--and in fact in some cases probably will--be wrong.
However, I believe that they may be useful because they suggest areas for further research.
First, I believe that beta-carotene--in small amounts--is useful for maintaining normal redox,
immunological, and probably cell-to-cell communication activity in the general population. However,
the amounts of beta-carotene that are necessary appear to be low, and easily attained by the
consumption of a wide variety of diets. Therefore, I believe that it is likely that beta-carotene
supplements will not be of significant value to most healthy well-fed populations.
Ontl~otherharrl,
studies of the effectiveness of beta-carotene supplements for under-nourished populations should be
continued or increased.
Second, more investigations on the factors controlling and limiting the effectiveness of betacarotene supplements and supplementation programs to increase vitamin A status should be done.
Unfortunately, these studies may not be very rewarding scientifically. There are too many variables
in feeding, many of which cannot be identified beyond a reasonable doubt. Thus, these studies may
have to be initiated as part of broad-based government programs. My hypothesis is that betacarotene supplementation (of no more than 10 mg per day, through diet or otherwise) would be
useful in populations with serum concentrations of CO.15 umol/L, or intakes of <700 ug per day of
Any such supplementation trials should include intermediate endpoints and
beta-carotene.
biomarkers, so that we may be able to understand the mechanisms that lead to the results. Such
midpoint markers could include plasma and tissue malondialdehyde, fatty acid degradation products
and conjugated dienes; premalignant lesions such as oral leukoplakia; DNA damage adducts
(oxidation products and strand breaks); and biochemical markers (autocrine growth factors,
prostaglandin concentrations, and omithine decarboxylase).
B.J. BURRI
568
Third, research should be directed into understanding the dose-response association of betacarotene and the factors affecting its variability. These dose-response curves should be derived for
vitamin A formation, antioxidant or redox reactivity, connexin 43 activity, and suitable indicies of
immunological response. However, more basic research is also needed to define optimal ranges of
antioxidant, immunological, and connexin 43 activity. In the past most researchers, including myself,
have tacitly assumed that the greater the immunological and antioxidant activity, the better. Results
from the Phase III trial results suggest that this may be a dangerous assumption.
Fourth, researchers and physicians should continue to investigate the influence of betacarotene on disease states that cause high levels of oxidative damage, suppress immunological
response, or impair cell to cell communication. Beta-carotene is obviously beneficial to people with
EPP. It might prove usefil in cystic fibrosis, AIDS, and other diseases. However, we should no
longer assume that beta-carotene supplementation--either through foods or nutritional supplements-carries no risk. Populations can, and should, be selected where the possibility of benefit most
probably outweighs the potential risk.
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Wasantwisut E, Attig GA. Empowering vitamin A foods: A food-based process for Asia
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Sommer A, West KP Jr. Vitamin A deficiency, health, survival, and vision. New York:
Oxford Press, 1996.
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Underwood BA. Hypovitaminosis
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Subcommittee on the Tenth Edition of the RDAs. Recommended Dietary Allowances,
10th ed. Washington DC: National Academy Press, 1989: 115-24.
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Gerster H. Anticarcinogenic
1993; 63:93-121.
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Peto R, Doll R, Buckley JD, Spom MB. Can dietary beta-carotene
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van Poppel G, Goldbohm RA. Epidemiological evidence for g-carotene
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Kohlmeier L, Hastings S. Epidemiological evidence of a role of carotenoids in
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BETA-CAROTENE
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Accepted
for
publication
October
26,
1996.
and other
in cystic fibrosis
in HIV infection. J Acquir