5
CAROTENOIDS
Beta-carotene,
carotenoids,
and disease
prevention
in
humans
SUSAN TAYLOR MAYNE1
Department of Epidemiology and Public Health, Yale University School of Medicine and Yale Cancer Center, New
Haven, Connecticut 06520, USA
In this, the final article in the series on carotenoids,
Susan Taylor Mayne has presented
a balanced
review
of the potential role of beta-carotene
and other carotenoids in human health and disease. Much of the data
indicating
a beneficial
effect of dietary carotenoids
is
derived from epidemiological
studies in which a lower
risk of a variety of chronic diseases
including
various
cancers,
cardiovascular
disease,
age-related
macular
degeneration,
and cataracts
is correlated
with the dietary conSUm[)tiOn of fruits and vegetables
rich in carotenoids.
However,
to determine
whether a specific
compound
(or compounds)
of fruits and vegetables
is
beneficial,
human
intervention
studies,
using either
single components
or mixtures,
must be conducted.
These intervention
studies have focused on beta-carotene as the potential
protective
carotenoid.
Somewhat
surprisingly,
the results
of the intervention
studies
through 1995 did not indicate any protective
action of
supplementary
beta-carotene
with respect
to cancer
prevention.
In fact, the ATBC study from Finland reported a negative effect of beta-carotene
supplementation with respect
to the incidence
of lung cancer in
smokers.
Since then, two other major studies in the
United States have shown either no effect or a negative
effect on chronic diseases.
In concluding,
the author
supports an increased
consumption
of fruits and vegetables and the avoidance
of supplementary
beta-carotene for smokers. Her recommendations
are timely.
-Norman
I Krinsky,
Coordinating
supplements
are of little or no value in preventing
cardiovascular
disease and the major cancers
occurring in well-nourished
populations,
and may actually
increase,
rather than reduce,
lung cancer incidence
in smokers.
As a consequence
of these findings,
some
of the ongoing
trials of beta-carotene
and disease
prevention
have been terminated
or have dropped
beta-carotene
from their interventions.
Researchers
should
now seek explanations
for the apparently
discordant
findings of observational
studies vs. intervention
trials. The most pressing
research
issues
include
studies
of interactions
of carotenoids
with
themselves
and with other
phytochemicals
and
mechanistic
studies
of the actions
of beta-carotene
in lung carcinogenesis
and cardiovascular
disease.
Paradoxically,
the finding
that lung carcinogenesis
and cardiovascular
disease can be enhanced
by supplemental
beta-carotene
may ultimately
lead to a
clearer
understanding
of the role of diet in the
etiology
and prevention
of these diseases.
The conclusion
that major public health benefits
could be
achieved
by increasing
consumption
of carotenoidrich fruits
and vegetables
still appears
to stand;
however,
the pharmacological
use of supplemental
beta-carotene
for the prevention
of cardiovascular
disease and lung cancer,
particularly
in smokers,
can
no longer
be recommended.-Mayne,
S. T. Betacarotene,
carotenoids,
and disease
prevention
in
humans.
FASEBJ.
10, 690-701
(1996)
Editor
Key Words: cancer prevention
ABSTRACT
A growing
body of literature
regarding
the effects
of beta-carotene
and
exists
other
carotenoids
on chronic diseases
in humans. This
article reviews and critically
evaluates
this literature
and identifies
areas for further research.
This review
is restricted
to studies in humans,
with a major
emphasis
on the most recent literature
in the area of
carotenoids
and selected
cancers.
Effects of carotenoids
on cardiovascular
diseases,
photosensitivity
diseases,
cataracts,
and age-related
macular
degeneration are also discussed
briefly.
Numerous
observational
studies
have found that people
who ingest
more carotenoids
in their diets have a reduced
risk
of several chronic diseases. However,
trials of supplemental
beta-carotene
690
intervention
indicate that
‘cardiovascular
disease
Beta-carotene
is one of a number of naturally
occurring
compounds
called carotenoids.
More than 600 naturally
occurring carotenoids
have been identified,
approximately
50 of which have vitamin A activity (1). Carotenoids
are
widespread
in plants
and in photosynthetic
bacteria,
where they serve two essential
functions:
as accessory
pigments in photosynthesis
and in photoprotection.
These
two functions
are a consequence
of the conjugated
polyene structure
of carotenoids,
which allows the mole-
tAddress
partment
208034,
correspondence
of Epidemiology
New Haven,
and reprint
and
Public
CT 06520-8034,
requests
Health,
to Dr.
60 College
Mayne,
St.,
at: DeP.O.
Box
USA.
0892-6638/96/001
0-0690/$01
.50. © FASEB
cule to absorb light and to quench, or inactivate,
singlet
oxygen and free radicals.
Humans
routinely
ingest a variety of different carotenoids, including
those occurring
naturally
in foods (primarily fruits and vegetables)
and those added as food
colorants.
Functions
of carotenoids
in humans are not entirely clear. Provitamin
A carotenoids
can be converted
enzymatically
in the intestinal
mucosa to yield retinal
and ultimately
retinol; retinol (vitamin A) is required for
vision, maintenance
of differentiated
epithelia,
mucus secretion, and reproduction.
Not all dietary carotenoids
are
metabolized
in the intestinal
mucosa following ingestion;
rather, significant
quantities
of provitamin
as well as nonprovitamin
A carotenoids
accumulate
in human blood and
tissues. A pressing research question is whether these carotenoids serve any function in human tissues or whether
they simply reflect passive accumulation
from the diet.
A voluminous
body of literature
including in vitro studies, animal
studies,
human observational
studies,
and
clinical
trials has suggested
a multiplicity
of health effects of carotenoids
in humans (Fig. 1). An exhaustive
review of this literature
is beyond the scope of this article. Instead, this paper will focus on epidemiologic
studies in humans,
with a primary
emphasis
on the most
recent literature
in the area of carotenoids
and selected
cancers.
Effects
of carotenoids
on cardiovascular
diseases, photosensitivity
diseases,
cataracts,
and age-related macular degeneration
are also briefly discussed.
OVERVIEW OF EPIDEMIOLOGIC
CAROTENOIDS
Observational
studies
STUDIES
of carotenoids
OF
and disease
Epidemiologic
studies of carotenoids
and disease can be
divided broadly into two categories:
observational
studies
and intervention
trials. Observational
studies examine the
association
between
carotenoid
intake and disease incidence, or between
blood or tissue levels of carotenoids
and disease incidence.
Although these studies have contributed enormously
to the literature
regarding
effects of
carotenoids
on disease, the interpretation
of these studies
is difficult for many reasons. First, fruits and vegetables
Ischemlc
Heart Disease
Stroke
/
Cancer
Aging
Photo-
(‘‘NOD’”)’”
,.____
Cataract
Immunomodulation
Macular
Degeneration
Figure
1. Reported
CARflTfNflIflS
ANn
prOtective
DISFASI
effects
IN
of carotenoids
HI IMANS
in
humans.
are complex mixtures
of vitamins,
minerals,
fibers, and
numerous
other phytochemicals.
Thus, people who consume more carotenoids
in their diet also consume more of
these other substances,
many of which may have diseasepreventive
properties
(2). Also, individuals
who consume
more fruits and vegetables
may also consume less dietary
fat or may be more health-conscious
in other ways than
individuals
who consume relatively few fruits and vegetables. Observational
epidemiologic
studies of carotenoids
and human health
must therefore
be interpreted
cautiously, as it is entirely possible that effects observed may
result from dietary or other factors correlated
with carotenoid intake rather than from carotenoids
themselves.
Another
complexity
in the interpretation
of observational epidemiologic
studies
of carotenoids
and disease
arises from the lack of a standard,
reproducible
approach
for quantifying
carotenoid
intake. The older literature
is
replete with terms such as “vitamin A from plants,” “carotene index,” and “yellow-green
vegetables.”
Exactly what
constitutes
these indices is far from clear. This problem
is a consequence
of the lack of availability
of adequate
carotenoid
food composition
tables, which until recently
have not contained
information
regarding
the amounts of
various carotenoids
in foods commonly
consumed.
The
U.S. Department
of Agriculture
released
a carotenoid
food composition
database
in 1993 (3); the availability
of
this database now allows researchers
to estimate intake of
several major dietary carotenoids
including
alpha-carotene, beta-carotene,
beta-cryptoxanthin,
the combination
of lutein plus zeaxanthin,
and lycopene.
These advances
are enhancing
observational
epidemiologic
studies of carotenoids and disease.
Advances
in analytical
technology
allow for the relatively rapid measurement
of a number of carotenoids
in
human blood and/or tissues, facilitating
the conduct
of
biochemical
epidemiologic
studies of carotenoids
and disease. However,
carotenoid
levels in blood have been
shown to reflect fruit and vegetable
intake (4), and thus
biochemical
assessment
of carotenoid
status in observational studies does not overcome the problem of carotetioids potentially
acting as a marker for other correlated
etiologic factors.
Interveiition
trials
of carotenoids
and disease
For these reasons,
effects of carotenoids
on disease
can
be implied from observational
studies; however, supporting
data from intervention
studies
are important
for
causal inference.
Intervention
trials of carotenoids
and
health primarily consist of beta-carotene
supplementation
trials. Large-scale
supplement
trials have been restricted
to beta-carotene,
as this is the only carotenoid
that has
been readily available
in large quantities
in pill form and
for which data existed supporting
the lack of toxicity of
pharmacological
doses in humans
(safety concerns
existed for canthaxanthin,
as discussed
below). Some fruit
and vegetable interventions
are ongoing (5), but none has
been completed.
i,q 1
Randomized,
placebo-controlled
intervention
trials, unlike the observational
studies, generally are not subject to
bias and confounding.
However, the interpretation
of intervention
trials of carotenoids
and disease is also somewhat complex, as detailed further below.
CAROTENOIDS
AND
CANCER
Lung
Numerous
epidemiologic
studies
have shown that individuals who consume a relatively large quantity of carotenoid-rich
fruits and vegetables
have a decreased
risk of
cancer at several tumor sites, as reviewed elsewhere
(6).
The consistency
of the results from observational
studies
is particularly
striking for lung cancer, where carotenoid
and/or fruit and vegetable
intake has been associated
with reduced lung cancer risk in 8 of 8 prospective
studies and in 18 of 20 retrospective
studies reviewed
(7).
The majority of these studies examined
protective
effects
of carotenoids
against lung cancer in smokers;
more recent studies have attempted
to determine
whether these
effects extend to nonsmokers.
Alavanja and colleagues
(8)
reported
that beta-carotene,
total vegetable
intake, and
intake of yellow and green leafy vegetables
were not significantly
protective
against lung cancer in nonsmoking
women. In contrast,
we (9) reported
that dietary betacarotene and fruit and vegetable
intake were significantly
associated
with a reduction
in lung cancer risk in nonsmoking men and women. Our data showed that risk reduction was greater from fruits and vegetables
typically
consumed
in a raw form vs. those typically
cooked or
processed
in some manner. Cooking apparently
increases
the bioavailability
of some carotenoids
such as alphaand beta-carotene
(10), but even moderate
cooking has
been shown to destroy substantial
quantities
of some of
the xanthophyllic
carotenoids
in foods (11, 12). Thus,
cooking has complex effects on carotenoid
bioavailability,
and some of the xanthophyllic
carotenoids
or other heatlabile phytochemicals
could be important
in lung cancer
prevention.
Epidemiologic
studies
that specifically
address the effects of cooking/processing
of fruits and vegetables on cancer risk are needed,
along with laboratory
studies of effects of food. preparation
on levels of other
phytochemicals
in foods.
Studies of carotenoids
other than beta-carotene
and lung
cancer risk are now becoming available. Le Marchand and
colleagues
(13) found that dietary intake of alpha-carotene,
beta-carotene,
and lutein was associated
with reduced lung
cancer risk in both men and women. Ziegler and colleagues
(14) also found significant
inverse trends for dietary alphaand beta-carotene,
and a marginally
significant
effect for
lutein. In both studies, high intake of a variety of vegetables
was more strongly associated
with reduced risk than high
intake of the individual carotenoids.
The consistency
of the literature
from observational
studies regarding carotenoids
and lung cancer prevention
served as the impetus for a number of large-scale
inter.Q)
‘./,-,l
10
kA,,,
1QO.
Tk.,
CACCO
vention trials of beta-carotene
in the prevention
of lung
premalignant
endpoints
or lung cancer. The Tyler (Texas)
Chemoprevention
Trial randomized
755 asbestos workers
to receive beta-carotene
(50 mg/day) and retinol (25,000
IU every other day) vs. placebo to see whether the nutrient combination
could reduce the prevalence
of atypical
cells in sputum. After a mean intervention
period of 58
months, the prevalence
of sputum atypia was nonsignificantly increased,
not reduced,
in the subjects
receiving
supplements
(15). Supplemental
beta-carotene
(20
mg/day),
however,
reduced
micronuclei
counts significantly in sputum from heavy smokers
in a 14 wk, randomized
intervention
trial
(16). The relevance
of
micronuclei
to lung carcinogenesis
is unknown.
Two trials using lung cancer
as a primary
endpoint
have now been completed
(Table 1). The Alpha-Tocopherol Beta-Carotene
(ATBC)2 Trial involved
29,133
males age 50-69 years old from Finland (17) who were
heavy cigarette
smokers at entry (average one pack/day
for 36 years). The study design was a two-by-two factorial
with participants
randomized
to receive either supplemental alpha-tocopherol
(50 mg/day), beta-carotene
(20
mg/day),
the combination,
or placebo
for 5 to 8 years.
Unexpectedly,
participants
receiving beta-carotene
(alone
or in combination with vitamin E) had a significantly
higher
incidence
of lung cancer
(RR1.18;
95%
C11.03-1.36)
and total mortality
(RR1.08,
95%
C1 1.01-1.16)
than participants
receiving
the placebo.
Supplemental
beta-carotene
did not affect the incidence
of other major cancers occurring
in this population
(prostate, bladder, colon/rectum,
stomach). Tumor site-specific
data were not presented
regarding
the effects of supplemental beta-carotene
on less common cancers. Within the
placebo
group, higher beta-carotene
intake and serum
beta-carotene
concentrations
at baseline
were associated
with a lower subsequent
lung cancer incidence,
consistent with other literature.
The finding of an increased
incidence
of lung cancer in
beta-carotene-supplemented
smokers has now been replicated in another major trial. Investigators
of CARET (Camtene and Retinol Efficacy Trial) held a press conference
on
January 18, 1996, to announce that the intervention
component of CARET was being terminated
nearly 2 years early.
CARET is a multicenter lung cancer prevention trial of supplemental
beta-carotene
(30 mg/day) plus retinol (25,000
lU/day) vs. placebo in asbestos workers and smokers. According
to Dr. Gilbert Omenn,
the lead investigator
of
CARET, the intervention
was stopped early because interim
analyses
of the data indicated
that should the trial have
continued for its planned duration, it is highly unlikely that
the intervention
would have been found to be beneficial,
given the results as of late 1995. Furthermore,
the interim
results indicated that the supplemented
group was develop-
2Abbreviations:
ATBC Trial, Alpha-Tocopherol
Beta-Carotene
CARET, Carotene and Retinol Efficacy Trial; EPP, erythropoietic
phorphyria;
IHD, ischemic heart disease.
Trial;
proto-
TABLE
1. Complet ed beta-carotene
cancer prevention
clinical
trials:
cancer incidence or mortality as primary endpoints
Tumor site
Total n
n-Carotene dose
Relative risk (95% Cl)”
Reference
Lung
Esophagus/stomach
29,133
18,314
29,584
20 mg/day
30 mg/day
15 mg/day
+ 25,000 LU retinol/day
+ 30 mg vitamin E + 50 .tg Selenium
17
CARETb
26
Esophagus/stomach
3,318
15 mg/day
+ multivitamin/multimineral
Skin (nonmelanoma)
Total cancer
1805
22,071
50 mg/day
50 mg/every
1.18 (1.03-1.36)
1.28 (1.04-1.57)
0.79 (0.64-0.99)
0.96 (0.78-1.18)
1.18 (0.76-1.85)
0.84 (0.54-1.29)
1.05 (0.91-1.22)
Not significantL
Lung
other day
“Risk for site-specific cancer incidence (ATBC, CARET, Greenberg)
or mortality (Blot, Li).
ing more lung cancer, not less, consistent with the results of
the Finnish trial. Overall, lung cancer incidence
was increased by 28% in the supplemented
subjects (RR = 1.28;
95% CI=1.04-1.57)
and total mortality was also increased
(RR 1.17, 95% CI 1.03-1.33).
Although the P value for
the lung cancer increase (P0.032)
is less than the conventional P value of 0.05, it cannot be concluded
that this trial
provided statistically
significant
evidence of harm. This is
because trials with interim analyses must have more stringent nominal significance
levels for each repeated look at the
data, such that the overall significance
level is kept at
P0.05
(18). In other words, if investigators
analyzed the
data often enough in a large trial one would expect to get P <
0.05 eventually,
regardless
of whether there is a genuine
treatment difference (18).
Major findings of one additional
trial, the Physicians’
Health Study of supplemental
beta-carotene
vs. placebo in
22,071 male U.S. physicians,
were also released at the same
press conference.
Dr. Charles Hennekens,
lead investigator
of the Physicians’ Health Study, announced that there was no
significant effect-positive
or negative-of
12 years of supplementation
of beta-carotene
(50 mg every other day) on
cancer or cardiovascular
disease. The apparent lack of an
effect of long-term supplementation
of beta-carotene
on lung
cancer incidence in this cohort is noteworthy.
Nonetheless,
these negative results should not be overinterpreted
as only
11% of the cohort were current smokers at entry.
In contrast to these findings are results of an esophageal
and gastric cancer prevention
trial in China (discussed
below). This trial had limited statistical power for lung cancer
with only 31 total lung cancer deaths (19). However, the
relative risk of death from lung cancer was 0.55 (95%
CIO.26-1.14)
among those receiving the combination
of
beta-carotene,
alpha-tocopherol,
and selenium. The smoking prevalence,
including individuals
who had ever smoked
cigarettes for6 or more months, was 30% in this study population. Possible reasons for the discrepant
results of the
CARET, ATBC, Physicians’
and Chinese
trials are discussed below (see “Carotenoids
and Cancer: Overall Assessment”).
Oral, pharynx,
and larynx
As reviewed elsewhere,
epidemiologic
studies of diet and
serum, studies using the hamster buccal pouch model, and
CAflTFN1flIflc
ANfl
flISFASF
IN
HI
MANS
Stomach
Esophagus
Stomach
Esophagus
27
28
Physicians’
Health Studyh
tResults fmm NIH press release 1/18/96.
human intervention
trials using intermediate
markers of oral
carcinogenesis
strongly suggest that beta-carotene
plays a
protective role in the prevention of cancers of the oral cavity,
pharynx, and larynx (20). The etiology of these cancers, also
known as head and neck cancers, is thought to be multifactorial. Well-characterized
risk factors include tobacco and alcohol exposures. A recent case-control
study of oral cancer
from northern Italy attempted to estimate the relative contribution of beta-carotene
intake, alcohol, and tobacco exposures to this cancer (21). In this study, smoking accounted
for 81-87% of oral cancer in males and 42-47%
in females;
alcohol explained
about 60% of male cases vs. 15% of female cases, and low beta-carotene
intake accounted for 25%
of cases in males vs. 17% in females. Even though this study
provides new information regarding the relative importance
of diet in the etiology of these cancers, the calculated
attributable risk for low beta-carotene
intake should be interpreted cautiously,
as the beta-carotene
index was derived
from a few selected indicator foods rather than from an analysis of the whole diet. Thus, some misclassification
of intake is
likely.
Another recent study of relevance
to the issue of carotenoids
and head and neck cancer
risk is a nested
case-control
study of serum micronutrients
and subsequent
risk of oral and pharyngeal
cancer (22). Blood
samples were collected and stored in 1974 from a cohort
of 25,802 adults in Maryland.
During the next 15 years,
28 individuals
developed
oral or pharyngeal
cancer. Serum analyses indicated
that prediagnostic
serum levels of
all the major individual
carotenoids,
and particularly
beta-carotene,
were lower among the case group than
among controls
selected
from the same cohort. Adjustment for smoking, which is known to be associated
with
decreased
serum carotenoid
levels, attenuated
the protective association
slightly.
The unadjusted
and adjusted
relative odds of oral/pharyngeal
cancer comparing
the upper tertile of serum beta-carotene
concentrations
vs. the
lower tertile were 0.50 and 0.69, respectively.
These and other observational
studies strongly suggest
that fruits and vegetables
have cancer inhibitory
properties for mouth and throat cancers.
Human intervention
trials using beta-carotene
in the prevention
and/or reversal of oral micronuclei
and oral leukoplakia
(precancerous changes) lend further credence
to the hypothesis
that
beta-carotene
is at least one of the agents responsible
for
protective
effects of fruits and vegetables.
Intervention
trials of oral leukoplakia
are summarized
in Table 2. Although many of these trials were not placebo-controlled,
and were thus subject to bias, the consistency
of the results strongly suggests a role for supplemental
beta-carotene in the prevention
of oral cancers.
Based on these results, three trials involving beta-carotene and head and neck cancer prevention
were initiated:
one in the U.S. (23), one in Italy (24), and one in Canada
(25). All are designed to determine
whether supplemental
beta-carotene,
alone (23, 24) or in combination
with vitansin E (25), reduces
the incidence
of second malignant
cancers
of the oral cavity, pharynx,
larynx, esophagus,
and lung in patients who have been “cured” of an earlystage head or neck cancer. More than 260 patients have
been randomized
in the U.S. trial, approximately
200 in
the Italian trial (24), and 145 in the Canadian
trial (Dr.
Francois Meyer, personal communication).
The results of
these studies will be followed with interest.
beta-carotene
(15 mg) reduced
esophageal
and gastric
cardia cancers in 3318 Linxian residents
with esophageal
dysplasia
(27). Cumulative
esophageal/gastric
cardia
death rates after an intervention
period of 6 years were
8% lower (RRO.92,
95% C10.67-1.28),
esophageal
cancer
mortality
was 16% lower (RRO.84,
95%
CIO.54-1.29),
total mortality was 7% lower (RRO.93,
95% C10.75-1.16),
and total cancer mortality was 4%
lower (RRO.96,
95% C10.71-1.29)
in the supplemented group. Stomach cancer
mortality,
however,
was
18% higher (RR1.18,
95% CIO.76-1.85)
in the supplemented
group. None of these results were statistically
significant,
as is evident
from the confidence
intervals,
which all include 1.0. Therefore,
this trial failed to demonstrate
a significant
reduction
in cancer incidence
or
mortality during a 6-year vitamin/mineral
intervention
in
relatively high-risk participants.
Esophagus/stomach
Many observational
studies
have suggested
that dietary
intake of fruits and vegetables
is inversely
associated
with colorectal
cancer risk, as reviewed
elsewhere
(6).
Prevention
trials of beta-carotene
for this tumor site typically use colorectal adenomas,
thought to be precursors
of
invasive
cancer,
as the primary
endpoint.
The largest
such completed
trial studied 864 patients
who had had
an adenoma diagnosed
and removed within the previous
3 months (28). Participants
were randomized
using a twoby-two factorial design, with the active treatments
being
beta-carotene
(25 mg/day) and the combination
of 1 g of
vitamin C plus 400 mg vitamin E (equivalent
to 400 IU).
There was no evidence
that either beta-carotene
and/or
vitamins
C and E reduced
the incidence
of adenomas.
The relative
risk for beta-carotene
was 1.01 (95%
C10.85-1.20);
for vitamins C and E it was 1.08 (95%
C10.91-1.29).
The lack of efficacy
for supplemental
beta-carotene
persisted when the analyses were restricted
to those patients with the lowest quartile of serum betacarotene
levels or to those with the lowest quartile
of
beta-carotene
intake as reported at enrollment.
The finding that beta-carotene
did not reduce the recurrence
of
colorectal
adenomas
is consistent
with the results of a
smaller trial (n291)
using a lower dose of 15 mg betacarotene/day
(29).
The National Cancer Institute is coordinating
an ongoing
adenoma
prevention
trial involving
dietary intervention
rather than a nutrient supplement
(5). The study is designed
to determine
whether a low-fat, high-fiber,
vegetableand
fruit-enriched
diet will decrease the recurrence
rate of large
bowel adenomatous
polyps. The trial is a multicenter,
randomized, controlled trial involving approximately
2000 men
and women with a 4-year follow-up period. This trial will test
the assumption
that fruit and vegetable intake can be modulated successfully
for a substantial
period of time. Although
the trial will not be able to test chemopreventive
effects of
carotenoids
per Se, its outcome is nonetheless
relevant to
investigations
of carotenoids and cancer prevention.
Certain
regions of the world have strikingly
high incidence rates of esophageal
and gastric cancers;
Linxian,
China is one such region. Blood levels of various micronutrients including
retinol, beta-carotene,
riboflavin, vitamin C, and vitamin E have been shown to be consistently
low in the Linxian population
(26). Numerous
investigations indicate that intake of fresh fruits and vegetables
is
inversely correlated
with risk for esophageal
and gastric
cancers (6). These observations
led to two related chemoprevention
trials of esophageal
and gastric
cancer
in
Linxian County, China.
The first trial was conducted
in residents from the general population
of Linxian
County (26). Nearly 30,000
men and women aged 40-69
took part in the study,
which tested the efficacy of four different nutrient combinations at inhibiting
the development
of esophageal
and
gastric cancers. The nutrient combinations
included
retinol plus zinc, riboflavin
plus niacin, ascorbic
acid plus
molybdenum,
and the combination
of beta-carotene,
selenium, and alpha-tocopherol.
After an intervention
period
of 5 years, those given the combination
of beta-carotene,
vitamin E, and selenium
had a 13% reduction
in cancer
deaths (RRO.87;
95% CIO.75-1.00),
a 9% reduction
in total deaths (RRO.91;
95% C10.84-O.99),
a 4%
reduction
in esophageal
cancer deaths (RRO.96;
95%
C10.78-1.18),
and a 21% reduction
in gastric cancer
deaths
(RRO.79;
95% C10.64-0.99).
None of the
other nutrient combinations
reduced gastric or esophageal
cancer deaths significantly
in this trial. These encouraging results suggest that the concept of cancer prevention
via nutrient
supplementation
is still valid; however, the
agents used, population
studied, and endpoint may all be
critical in determining
efficacy.
Along with the general population
trial, a second and
smaller trial was done to determine
whether supplementation with a multivitamin/multimineral
preparation
plus
F.c14 Vol
10 Mw
The
FASFR
Colon/rectum
Ir,,,rnI
kAAVkW
TABLE 2. completed
beta-carotene
trials: oral leukoplakia,
oral dysplasia
Tumor site
Total n
fl-Carotene dose
Outcome
Reference
Oral
Oral
Oral
Oral
24
50
18
111
30 mg/day
60 mg/day
90 mg/day
180 mg/wk
180 mg/wk + 100,000 IU vitamin AJwk
40 mg/day + 100,000 IU vitamin AJwk
+ 80 mg vitamin E/wk
40 mg/day + 100,000 LU vitamin AJwk
+ 80 mg vitamin E/wk
120 mg/day
30 mg/day + 1000 mg vitamin C/day
+ 800 IU vitamin E/day
71% Overall response#{176}
52% Overall response
44% Overall response
15% Complete response
28% Complete response
38% Decrease in leukoplakia
(prevalence odds ratio)
35% Decrease in risk of
progression (esophagitis)
44% Overall response
49% Overall responsec
64
65
66
67”
leukoplakia
leukoplakia
leukoplakia
leukoplakia
Oral leukoplakia/esophagitis
384
291
18
79
Oral dysplasia
Oral leukoplakia
“Complete response plus partial response.
bplaceba_contmlled studies.
Clinical response in
intervention (clinical response 90% in those who took supplements and reduced tobacco use).
Breast
Even though most epidemiological
studies of carotenoids
and human cancer have investigated
a possible preventive role of these compounds,
a relatively
new research
area concerns
prognostic
and potentially
therapeutic
effects of carotenoid-rich
diets. Ingram (30) interviewed
women with breast cancer 3 months after surgery, and
found that women with breast cancer who reported
consuming more beta-carotene
in their diets up until the
time of breast cancer diagnosis had a significant
improvement in survival.
More specifically,
in the tertile
of
women who consumed
the highest beta-carotene
levels,
only one woman died from breast cancer. In contrast, 8
women in the intermediate
consumption
group and 12
women in the lowest consumption
group died from their
disease over a 6-year follow-up period. Dietary data were
not reassessed
during the follow-up period; therefore, it is
unclear if diet at the time of diagnosis
was important
or
whether dietary changes made postdiagnosis
affected survival in women with breast cancer. Also, although these
results
are intriguing,
estimates
were not adjusted
for
other known prognostic
factors such as the stage of the
disease at diagnosis.
It is possible that women who consumed relatively
low levels of dietary carotenoids
were
less health-conscious,
and thus more likely to be diagnosed with late-stage
disease with a correspondingly
reduced survival.
Using a different
study design,
Jam and colleagues
(31) studied a cohort of 678 women with breast cancer
from the National Breast Screening
Study in Canada who
had completed
a diet history questionnaire
before cancer
diagnosis.
Higher intake of saturated
fats and lower intake of beta-carotene
and vitamin C before diagnosis
increased
the risk of dying of breast cancer. The hazard
ratio for the highest quartile of dietary beta-carotene
was
0.48 (95% CI=0.23-0.99),
with evidence
of a significant
dose-response
relationship.
Information
was available
on
axillary lymph node status for a subset of cases; the inclusion of the number of positive lymph nodes (an indicator of stage of disease)
in multivariate
analyses
did not
substantially
alter the risk estimates.
As with Ingram’s
rAROTFNOInS
AND
DISFASF
IN HI IMANS
those
686
69
70
patients who did not reduce tobacco use dunng 9 month
study (30), dietary change after diagnosis
was not measured, and further research
is needed to better understand
whether increasing
consumption
of carotenoid-rich
fruits
and vegetables
after cancer diagnosis affects survival.
Prostate
Although
several human studies have observed
a direct
association
between
retinol intake and risk of prostate
cancer (32), studies of dietary beta-carotene
and prostate
cancer have shown mixed results. Data regarding carotenoids other than beta-carotene
and prostate
cancer risk
are limited; however, one recent study evaluated
associations between
dietary
beta-carotene,
alpha-carotene,
lutein,
lycopene,
and beta-cryptoxanthin
and prostate
cancer
risk (33). The study was a prospective
cohort
study of participants
in the Health Professionals
Followup Study, 812 of whom were diagnosed with prostate cancer during the 6-year follow-up.
Intake of tomato-based
foods (tomato sauce, tomatoes,
and pizza, but not tomato
juice) and the carotenoid
lycopene,
which is found predominantly
in tomato products,
was associated
with significantly lower prostate cancer risk.
Cervical
Two additional
reports can be added to the body of literature suggesting
a role for beta-carotene
and carotenoids
in the prevention
of cervical
cancer.
Batieha
and colleagues (34) conducted
a nested case-control
study, analyzing a variety of carotenoids
in sera stored from 50
women who had developed
either invasive cervical cancer
or carcinoma
in situ during a 15-year follow-up,
and in
99 controls pair-matched
to the cases. The risk of cervical cancer was significantly
higher among women with
the lowest prediagnostic
serum levels of total carotenoids
(0R2.7;
95% CI, 1.1-6.4),
alpha-carotene
(0R3.1,
95% CI, 1.3-7.6),
and beta-carotene
(0R3.1;
95%
CI,1.2-8.1)
as compared
to women in the upper tertiles. Trends were also statistically
significant.
Mean serum levels of cryptoxanthin
were also lower among cases
relative to controls (P0.03).
69S
Promising results regarding supplemental
beta-carotene
and cervical cancer prevention
have been reported
in a
recently completed
phase II intervention
trial (35). Thirty
women with cervical
dysplasia
received
oral beta-carotene supplements
(30 mg/day) for 6 months. Women were
considered
“responders”
if they had negative Pap smears
and either negative colposcopic
findings or a negative biopsy. After 6 months, 21 women (70%) responded,
and at
1 year (6 months off therapy) 30% continued
to respond.
These results are in contrast to those of an earlier negative clinical trial that randomized
women to a much lower
dose of 10 mg beta-carotene/day
vs. placebo (36).
Skin
Greenberg
and colleagues
(37) demonstrated
that supplementation
with 50 mg beta-carotene/day
for 5 years did
not reduce the occurrence
of new skin cancers (relative
ratel.05;
95% C10.91-1.22)
in 1805 persons with a
previous nonmelanoma
skin cancer.
CAROTENOIDS
AND CANCER:
OVERALL
ASSESSMENT
Taking
the epidemiological
evidence
regarding
carotenoids and cancer as a whole, the consistent
protective
effects found in the observational
studies are strikingly
at
odds with the findings of the large supplement
intervention trials, only one of which showed a decrease in cancer
incidence
with supplementation
(26), three of which
showed essentially
no effect (28, 37, Physicians’
Health
Study), and two of which showed an increase
in cancer
incidence
(17, CARET). The discrepant
results in these
trials may be a consequence
of the use of different populations with varying baseline nutritional
status and smoking habits,
different
tumor
sites,
combination
supplements
vs. single agent supplements,
and perhaps
even different formulations.
The failure to see a protective
effect of supplemental
beta-carotene
in the null studies could be due to many
factors: 1) dietary, blood, or tissue carotenoids
might primarily serve as a marker for other protective
factors; 2)
beta-carotene
may interact synergistically
with other carotenoids and phytochemicals
found in a natural food matrix to inhibit carcinogenesis,
but not when given as a
high-dose
supplement;
3) beta-carotene
may have been
administered
too late in the carcinogenic
process; and 4)
the duration
of supplementation
may have been inadequate. Explanations
for the apparent enhancement
of lung
carcinogenesis
are more difficult. The publication
of the
CARET results, anticipated
by Spring of 1996, will undoubtedly
be accompanied
by a plethora
of possible
mechanisms.
Some that have been proposed include inhibition of the intestinal
absorption
of other nutrients
by
daily large doses of beta-carotene
and a possible prooxidant effect of beta-carotene
in the damaged lungs of longterm heavy smokers (38).
f.Q(.
Vol
10 Mv
qq
The FAcFR
Regarding
the first possibility,
a few reports in the literature
have suggested
that pharmacological
doses of
beta-carotene
may adversely
affect vitamin E levels in
blood (39, 40) or tissues (40). Both studies (39, 40) were
fairly small, consisting
of 45 and 58 total subjects,
respectively.
The report of an adverse effect of supplemental beta-carotene
on plasma vitamin E levels in 1992 (39)
prompted
further investigations
of interactions
between
beta-carotene
and vitamin E in data available
from other
ongoing trials. Nierenberg
and colleagues
(41) analyzed
data from more than 500 patients enrolled in a polyp prevention trial. Blood vitamin E levels did not change after
9 months
of supplementation
with 25 mg beta-carotene/day (2% increase relative to baseline measurement).
Similarly,
Goodman and colleagues
(42) analyzed
serum
alpha-tocopherol
levels in 2319 participants
enrolled
in
CARET, who had taken daily supplements
of 30 mg betacarotene and 25,000 IU retinol for up to 6 years. A small
but statistically
significant
increase in serum aipha-tocopherol levels was observed
in the supplemented
subjects
in this very robust study. There was no evidence of a decrease in vitamin E levels in any of the subgroups
examined. These and other reports do not support an adverse
effect of long-term supplemental
beta-carotene
on vitamin
E levels in blood, although data are lacking regarding effects on tissue stores of vitamin E.
Adverse
effects
of supplemental
beta-carotene
on
plasma levels of other carotenoids
also have been considered. Micozzi and colleagues
(43) showed that supplementation with either 12 or 30 mg beta-carotene/day
for 6
wk reduced plasma lutein levels relative to placebo (five
subjects/group).
Kostic and colleagues
(44) gave single
oral doses of lutein with and without beta-carotene
(both
0.5 p.mollkg body weight) and showed that when both carotenoids
were administered
together, the mean area under-the-curve
for plasma lutein was reduced significantly.
In contrast
to these relatively
small, short-term
studies,
Wahlqvist
and colleagues
(45) reported
that supplementation of 20 mg beta-carotene/day
for 24 months not only
elevated plasma alpha-carotene
levels (211% in men and
166% in women),
but also lycopene
levels (176% in
men; lycopene
levels were elevated
nonsignificantly
in
women; total n224).
Lutein/zeaxanthin
levels were unaffected
by beta-carotene
supplementation.
Omenn and
colleagues
(46) reported that supplemental
beta-carotene
plus retinol increased
blood levels of alpha-carotene
in
participants
in the Asbestos
Workers
Pilot Study for
CARET (n721).
Although
the results of the latter two
studies appear reassuring,
an increase
in plasma alphacarotene
could reflect subdetectable
alpha-carotene
or
other substances
that coelute with alpha-carotene
in betacarotene
capsules.
The observed
increase
in lycopene
(45) also must be interpreted
cautiously,
as this study
was done within a polyp prevention
trial with a 2 X 2 X 2
factorial design, the other factors being fat reduction
and
wheat bran supplementation.
Changes in lycopene
could
have resulted from dietary change over the 2-year period,
although
the authors attempted
to adjust their estimates
ln,,rn,I
kA AMC
for changes
in carotenoid
intake. Additional
investigations of carotenoid
interactions
clearly are needed.
Regarding
the possibility
that beta-carotene
might have
acted as a prooxidant, two in vitro studies-one
in a solventbased system (47) and one in rat liver microsomes (48)-reported
that beta-carotene
acted
as a prooxidant
at
supraphysiological
oxygen concentrations
and as an antioxidant at physiological
oxygen concentrations.
Handelman
and colleagues (49) demonstrated
that the gas phase of cigarette smoke led to the depletion of carotenoids
and alpha-tocopherol
in freshly
obtained
human
plasma.
They
commented
that “it would be especially
interesting
if cigarette smoke-induced
biotransformations
in antioxidant
molecules themselves
could influence respiratory
tract epithelial cell function(s).”
Additional
studies of oxidation,
simulating the environment
found in lung tissue exposed to
tobacco smoke, could help to clarify the likelihood of prooxidant activity in contributing
to lung carcinogenesis.
Mechanistic
considerations
should also take into account
dose-response
effects. This analysis is not straightforward,
however, in that the bioavailability
of a given oral dose of
beta-carotene
could be affected by coadministration
of other
agents such as retinol, may differ with different formulations,
and is affected by dietary variables such as fat intake. These
and other factors may account for the fact that populations
appear to differ in their plasma responses
to supplemental
beta-carotene.
For example,
median serum beta-carotene
levels in the participants
receiving 20 mg beta-carotene/day
(Hoffmann-LaRoche
product) in the Finnish trial rose from
0.18 mg/i at baseline to 3.0 mg/l at 3 years (17). In contrast,
median plasma beta-carotene
levels in the participants
receiving 50 mg beta-carotene/day
in the skin cancer prevention trial (BASF product) rose from 0.18 mg/i at baseline to
only 1.7 mg/l at 3 years (37). In our experience,
median
plasma beta-carotene
levels of patients with a prior head or
neck malignancy,
who received the same 50 mg beta-carotene/day supplement
used by Greenberg and colleagues, rose
from 0.18 mg/l at baseline to approximately
1.2 mg/lat 3 and
12 months (unpublished
data). Thus, an analysis of dose-response effects should consider blood and tissue levels of
beta-carotene,
as well as oral dose levels, due to wide discrepancies in physiologic responses to a given oral dose.
The currently available data indicate that supplemental
beta-carotene
is unlikely to be beneficial
in reducing the
major cancers occurring in westernized
populations.
These
findings, however, may not extend to less common malignancies. In this regard, supplemental
beta-carotene
has been
shown to reduce precancerous
lesions of the oral cavity (Table
2) and cervix (35), but not of the lung (15). Thus, the possible
efficacy of beta-carotene
and othercarotenoids
in the prevention of oral and cervical neoplasia should be explored further.
OTHER HEALTH EFFECTS
Photosensitivity
OF CAROTENOIDS
disorders
Carotenoids,
including
beta-carotene
tent canthaxanthin,
have been used
CAPC1TrMC1IDc
AND
nicicr
IN
HI
MANS
and to a lesser exsuccessfully
to treat
certain photosensitivity
diseases
for more than 25 years.
This clinical application
derived from the recognition
that
carotenoids
protect
photosynthetic
bacteria,
algae, and
green plants against photosensitization
(50). As reviewed
elsewhere
(50), many studies have demonstrated
that the
majority of patients with the genetic disease erythropoietic protoporphyria
(EPP) benefit from high-dose
supplementation
of beta-carotene
and/or
canthaxanthin.
Recommended
beta-carotene
doses for adults with EPP
are approximately
180 mg/day, substantially
higher than
the doses investigated
for cancer
prevention
purposes
(15-50
mg/day).
Despite
these relatively
high doses,
some patients
with EPP do not respond
to carotenoid
therapy, due either to poor absorption
of the carotenoids
or to markedly elevated blood porphyrin levels.
No serious side effects from high-dose
beta-carotene
supplements
have been reported in EPP patients, and no
long-term
toxicity
has been observed
(50). High-dose
supplementation
with canthaxanthin,
however,
has been
shown to produce deposition
of pigmented
granules in the
retinas of some patients, with occasional
effects on night
vision (51). Because
many patients with EPP have been
maintained
on high doses of beta-carotene
for a relatively
long time, a retrospective
cohort analysis of these patients
to assess the incidence
of chronic disease would be instructive.
The problem with this approach
is difficulty in
assembling
a suitable control group (EPP patients without
carotenoid
therapy).
Cardiovascular
diseases
Epidemiologic
studies, including
descriptive,
cohort, and
case control studies, suggest that carotenoidand/or betacarotene-rich
diets may prevent cardiovascular
disease,
as reviewed elsewhere
(52). For example,
Gey and colleagues (53) reported data from the Vitamin Substudy
of
the WHO/MONICA
Project,
in which plasma
was obtained from approximately
100 healthy males from each
of 16 study sites within Europe for antioxidant
nutrient
analyses.
Median antioxidant
nutrient
levels were then
compared
with concurrent
age-specific
ischemic
heart
disease (IHD) mortality in the 16 study populations.
Results showed a striking inverse correlation
of IHD mortality with plasma
vitamin
E levels (r20.63).
A similar
comparison
between median plasma beta-carotene
levels
and IHD mortality revealed no association
when considering all 16 study sites (r20.04).
However, a reasonably
strong inverse association
was evident (r20.50)
when
three study sites, all apparent
outliers
(and all Finnish
sites), were excluded from the analysis.
Gey and colleagues
(53) also presented
data from the
Basel Prospective
study, which revealed
that men who
had low concentrations
of beta-carotene
and vitamin C in
their blood had a significantly
increased
risk of subsequent
ischemic
heart disease
(RR1.96;
PO.022)
and stroke (RR4.17;
PO.002).
The Health Professionals Follow-up
Study (54) reported
protective
effects of
dietary carotene,
with a relative risk for coronary
heart
(,07
disease of 0.71 (95% C10.55-0.92)
for those at the top
quintile
of total carotene
intake (>19,034
lU/day) relative to the lowest quintile
of intake. Effect modification
by smoking
was evident:
among current
smokers,
the
relative risk was 0.30 (95% C10.11-0.82);
among former smokers,
the risk was 0.60 (95% C10.38-O.94),
and among
nonsmokers,
the risk was 1.09 (95%
C10.66-1.79).
Total serum carotenoids,
measured
at
baseline in the placebo group of the Lipid Research
Clinics Coronary Primary Prevention
Trial, were inversely related to subsequent
coronary
heart disease events (55).
Men in the highest quartile
of total serum carotenoids
had
an adjusted
relative
risk
of 0.64
(95%
C10.44-0.92);
among those who had never smoked, the
relative risk was 0.28 (95% CIO.11-0.73).
Using a different
approach
for quantifying
beta-carotene status,
Kardinaal
and colleagues
(56) measured
beta-carotene
concentrations
in adipose
tissue samples
collected
by needle aspiration
from the buttocks of 683
people with myocardial
infarction
and 727 age-matched
controls. Risk of myocardial
infarction in the lowest quintile of adipose beta-carotene
compared
with the highest
was 2.62 (95% C11.79-3.83),
and was primarily
confined to current smokers (0R2.39;
95% C11.35-4.25
vs. 0R1.07
for nonsmokers).
These observational
studies
suggest that carotenoidcontaining
diets are protective
against cardiovascular
disease; evidence that beta-carotene
per se is protective
can
best be obtained
by randomized
trials. Some of the first
such data to become available
were early analyses of 333
men enrolled
in the Physicians’
Health Study who were
known to have stable angina or a previous coronary revascularization
procedure.
Among subjects
who received
supplemental
beta-carotene
for 5 years, there was a 51%
reduction
in risk of major coronary events and a 54% reduction
in risk of major vascular
events
(57). In the
esophageal/gastric
cancer prevention
trial in the general
population
in Linxian,
China, the combination
of betacarotene,
vitamin E, and selenium
resulted in a 10% reduction
in mortality
due to cerebrovascular
disease
(RRO.90;
95% CIO.76-1.O7),
with this disease
accounting
for approximately
25% of all deaths
in this
population
(26). In individuals
with esophageal
dysplasia
(27), supplementation
of a multivitamin/multimineral
preparation
plus 15 mg beta-carotene
reduced
cerebrovascular
mortality
by 38%
(RRO.62,
95%
CI=O.37-1.06).
In contrast, the recently completed
Finnish lung cancer
prevention
trial found no reduction
in cardiovascular
deaths in the men supplemented
with beta-carotene
(17).
Rather, the men taking beta-carotene
had 11% more total
cardiovascular
deaths including
deaths from ischemic
heart disease, all types of stroke, and other cardiovascular disease. An even more pronounced
increase in cardiovascular
mortality
was noted in the CARET
trial of
supplemental
beta-carotene
pius retinol: the relative risk
was 1.26 (95% CIO.99-1.61).
These results are tempered by the announcement
from the Physicians’
Health
698
Vol. lOMav
1996
study
that
12 years
of supplementation
of beta-carotene
effect, positive
or cancer.
(50 mg every other day) had no significant
or negative,
on cardiovascular
In conclusion,
disease
the consumption
of beta-carotene-rich
foods has been associated
consistently
with a decreased
risk of cardiovascular
disease.
In contrast,
supplementation with beta-carotene
in major intervention
trials generally has failed to reduce the incidence
of cardiovascular
disease. The lack of benefit seen for both cardiovascular
disease and lung cancer simplifies
public health recommendations
for individuals
who smoke. An appropriate
public
health
recommendation
for smokers
is 1) quit
smoking; 2) ingest more carotenoid-containing
fruits and
vegetables;
and 3) do not rely on beta-carotene
supplements for protection from chronic disease.
Age-related
macular
degeneration/cataract
Dietary carotenoids
may be important in the prevention
of
two ocular conditions:
age-related
macular
degeneration
and senile cataract. The macula is a small, yellow region
in the center of the retina. Degeneration
of the macula is
the most common cause of irreversible
blindness
in people over the age of 65 (58). Cataracts
are also problematic, with cataract
extraction
being the most frequently
performed
surgical
procedure
in the elderly
(59). Although the etiologies of these conditions
are not known,
oxidative processes may play a role. Cataracts are thought
to result from photooxidation
of lens proteins resulting in
protein damage,
accumulation,
aggregation,
and precipitation in the lens (59). The cornea and lens filter out ultraviolet
light, but visible blue light reaches
the retina
and may contribute
to photic damage or other oxidative
insults (58). Carotenoids
could potentially
interfere
with
both processes.
Seddon and colleagues
(58) analyzed
the association
between
carotenoid
intake
and advanced
age-related
macular degeneration
in a multicenter
case-control
study
involving 356 cases and 520 control subjects
with other
ocular conditions.
Those in the highest quintile of carotenoid intake had a 43% lower risk for macular degeneration compared
with those
in the lowest
quintile
(0R0.57,
95% C10.35-0.92).
Among the specific carotenoids,
intake of lutein and zeaxanthin
(grouped in the
carotenoid
food composition
database)
was most strongly
associated
with reduced
risk. Increased
consumption
of
spinach
and collard
greens,
rich dietary
sources
of
lutein/zeaxanthin,
was also associated
with a significant
risk reduction.
Protective
effects of lutein/zeaxanthin
against macular
degeneration
are biologically
plausible,
as these carotenoids
selectively
accumulate
in the macula
(60, 61) and account for the yellow color observed in this
region of the retina.
Dietary intake of carotenoids
also has been found to be
protective
against various forms of cataract,
as reviewed
by Taylor (59). Regarding
intervention
trials, the cancer
prevention
trials in Linxian, China, included special endof-trial ocular examinations
of participants
in the dys-
The FASEB Iournal
MAVNF
plasia trial and a subset of participants
in the general
population
trial. The combination
of beta-carotene,
alphatocopheroi,
and selenium
did not reduce the prevalence
of cataract in the population
trial. In contrast, in the dysplasia trial there was a statistically
significant
36% reduction in the prevalence
of nuclear cataract for persons
aged 65 to 74 years who were supplemented
with multiple vitamins and minerals plus beta-carotene
(15 mg/day)
for 6 years (62).
POUCY
IMPLICATIONS
Observational
studies suggest that increased
consumption
of various carotenoids
in the diet is associated
with a
lower risk of several common chronic diseases.
No specific recommendation
for carotenoid
intake exists; however, recommendations
to increase
consumption
of fruits
and vegetables
are likely to increase
intake of at least
some carotenoids.
In 1993, before the release
of the
ATBC or CARET Trial results,
Gey suggested
establishment of thresholds
of “optimum” plasma levels of antioxidant vitamins,
including
a threshold
for alpha- plus
beta-carotene
in the plasma of >0.4-0.5
j.tmol/l (63). Although the concept of such a threshold
is appealing,
the
setting of an optimum threshold level for alpha- and betacarotene
might be interpreted
as scientific
endorsement
of their “known” disease-preventive
properties.
In fact,
these relationships
are solely associative.
Thus, an inordinate emphasis
might mistakenly
be placed on the ingestion of these two carotenoids
rather than on the intake of
fruits and vegetables.
RECOMMENDATIONS
FOR
FURTHER
CONCLUSIONS
Numerous
observational
studies
who ingest more carotenoids
have
found
that
people
or more fruits and vegeta-
bles-the
primary dietary sources of carotenoids-have
a
reduced
risk of several chronic diseases
including,
but
not limited to, cancer, cardiovascular
disease, age-related
macular degeneration
and cataract. However, with the notable exception
of certain photosensitivity
diseases,
protective effects of individual
carotenoids
have yet to be
established
for most chronic
diseases.
Recent
studies
even suggest that supplemental
beta-carotene
may increase risk of cardiovascular
disease
and lung cancer,
particularly
in smokrs.
These recent results emphasize
the value of well-designed,
randomized
clinical trials for
demonstrations
of efficacy.
Clinical
intervention
trials,
however,
also have limitations:
1) only a single dosage
level is usually tested; 2) thus far, only beta-carotene
has
been used; and 3) the results may not apply to populations other than those studied. Due to the inherent limitations of both observational
studies and intervention
trials,
public health recommendations
must consider
the full
weight of the evidence regarding carotenoids
and disease
prevention.
At present, such an assessment
indicates
that
major public health benefits could be achieved
by generally increasing
consumption
of fruits and vegetables,
including
those
rich
in carotenoids.
However,
supplementation
of pharmacological
doses of beta-carotene for the prevention
of common chronic diseases is not
recommended,
at least in well-nourished
populations,
and
particularly
not in current smokers.
The author wishes to thank the following individuals
for comments on
this manuscript:
Drs. James Olson and Norman Krinsky. This work was
supported in part by NIH grants CA42101 and CA64567.
RESEARCH
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