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OCR for page 36
7 vitamins, Minerals, and Nonnutritive
Inhibitors of Carc~nogenesis
Many microconstituents of the diet have been found to have an
impact on carcinogenesis. Only three groups of these substances are
discussed in this chapter: vitamins A, C, and E and the carotenes;
selenium and selected trace elements; and some nonnutritive compounds
(i.e., indoles, phenols, aromatic isothiocyanates, methylated flavones,
protease inhibitors, and plant sterols) that inhibit carcinogenesis in
experimental systems. The ubiquity of these compounds is such that it
is impossible for humans not to consume some of them. Evidence relat-
ing these and other microconstituents to carcinogenesis was discussed
in Chapters 9, 10, and 15 of the committee's first report (National
Research Council, 1982~. Data relating other microconstituents (e.g.,
the B vitamins) to carcinogenesis are extremely limited, as explained
in the first report.
A striking feature of many of the compounds in the three groups
mentioned above is their capacity to prevent or retard the occurrence
of neoplasia. However, there is a paucity of data concerning the
conditions under which inhibition occurs, the mechanisms of inhibition,
and the precise impact of these microconstituents on humans. Better
data on these compounds will assist in the formulation of more defini-
tive conclusions and recommendations to reduce the risk of cancer.
VITAMINS, CAROTENES, AND RETINOIDS
. . .
The dosages of vitamins used in experimental work and in human
studies may range from levels recommended for optimal nutrition to
megadoses. If research on vitamins and carcinogenesis suggests that
large doses of specific vitamins or their analogs are needed to achieve
effects, it should be noted that such doses are pharmacological in
nature and may have deleterious consequences.
Vitamin A, Carotenes, and Retinoids
As explained In the first report, several epidemiological investi-
gations indicate that there is an inverse relationship between esti-
mated "vitamin A" intake and the occurrence of a variety of cancers.
With few exceptions, the estimates of vitamin A intake in such studies
were based on the frequency of ingestion of certain food groups,
especially green and yellow vegetables that contain carotene (a pro-
vitamin that is enzymatically converted to vitamin A in vivo) and a
OCR for page 37
Vitamins, Minerals, and Nonnutritive Inhibitors of Carcinogenesis 37
few foods, such as whole milk and liver, containing preformed retinal
(vitamin A). Thus, these studies do not clearly distinguish between
the effect of vitamin A Jeer _ and that of carotene.
Experimental studies of the effects of vitamin A on carcinogenesis
were also reviewed in the committee's first report (National Research
Council, 1982, Chapter 9~. Animal experiments indicate that increased
intake of this vitamin has a protective effect against the induction of
cancer by chemical carcinogens in most but not in all instances. Only a
few experiments have been published on the capacity of carotenes to
inhibit chemically induced carcinogenesis. In contrast, their inhibi-
tory effect on ultraviolet light-induced neoplasia of the skin has been
well documented. There is a need to gain a detailed understanding of
the effects of carotenes on carcinogenesis and the conditions under
which vitamin A alters responses to neoplastic agents.
In other animal experiments, certain nonnutritive compounds (i.e.,
indoles, phenols, aromatic isothiocyanates, methylated flavones, and
plant sterols) present in fruits and vegetables were found to inhibit
carcinogenesis. The specific agents responsible for the lower cancer
incidence observed in populations that frequently consumed fruits and
carotene-containing vegetables have not been identified (National
Research Council, 1982, Chapter 9~. Although it is entirely appro-
priate to propose interim dietary guidelines on the basis of current
knowledge, identification of the responsible compounds is extremely
important to assist in designing better epidemiological studies and in
planning more precisely focused intervention studies concerning the
consumption of green and yellow vegetables and certain fruits and the
occurrence of cancer.
Early studies indicating that vitamin A inhibits the occurrence
of neoplasia in animals but that it can be toxic in high doses led to
the synthesis of analogs of vitamin A--the retinoids. Certain retinoids
are less toxic than vitamin A and can be targeted to specific organs
where they exhibit inhibitory effects on carcinogenesis. Because of
these properties, retinoids are an especially useful group of compounds
for further investigation.
Vitamin C (Ascorbic Acid)
.
Epidemiological studies have suggested that frequent consumption of
foods containing vitamin C may be associated with a lower risk of
cancer in humans, especially in the esophagus and stomach. However,
there have been no systematic studies of populations consuming pharma-
cological doses of vitamin C. Vitamin C has also been studied under a
variety of experimental conditions for its effects on carcinogenesis.
It has been well established that this vitamin can inhibit the forma-
tion of nitroso carcinogens from precursor substances. Investigations
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38 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
of its effects on already-for~ed carcinogens have yielded less impres-
sive results, with the possible exception of chemically induced neo-
plasia of the large bowel. It should be pointed out, however, that
almost all studies of the inhibitory properties of vitamin C have been
conducted in species that synthesize their own vitamin C, unlike humans,
who require a dietary source of this vitamin. There is some indication
that vitamin C has mutagenic activity. However, ~n-vitro studies have
generally indicated that vitamin C can prevent or, under some circum-
stances, retard the manifestations of malignancy in cultured cells.
Vi tamin E
There are no epidemiological data concerning vitamin E and the risk
of cancer in human populations. Such data may prove difficult to obtain
because of the widespread occurrence of the vitamin in foods and the
lack of a clear-cut deficiency syndrome in humans. For many years,
efforts have been made to inhibit neoplasia by administering large
amounts of vitamin E to laboratory animals, but the results of such
studies have been inconclusive. However, because some of these report s
indicate that vitamin E may inhibit carcinogenesi s and the mounting
evidence that antioxidants may play a role in inhibiting neoplasia
(Wattenberg, 1981), further investigations of the effects of vitamin E
a re warranted .
SELENIUM AND OTHER TRACE MINERALS
Although humans require very low levels of dietary trace minerals,
these micronutrients are as essential to good health as protein and
energy sources. Several diseases of previously unknown etiology have
been identified as trace mineral deficiencies. The prevention of
goiter in the United States by supplementation of food supplies with
the missing micronutrient iodine ranks among the most successful public
health measures undertaken. Because minerals function in very funda-
rnental biochemical processe s, including immune reactions, detoxif i-
cation, and free-radical trapping, it is reasonable to postulate that
they may influence mechanisms that affect the development of cancer.
On the other hand, although there is an adequate understanding of the
mechanisms and sites of the physiological action of the trace elements
iron, iodine, zinc, copper, chromium, and selenium, there is no precise
knowledge of the mechanisms that might be involved in their effects on
carcinogenesis. It is also unknown whether mechanisms for the action
of pharmacological doses of trace minerals are the same as or different
from those of phy Biological levels that are needed f or normal nutri-
tion. Furthermore, although the requirements for trace elements that
are accepted as being essential for humans are well defined when
protection against deficiency is used as a criterion, there is great
controversy about whether higher intakes provide additional health
benef it s or pose the risk of adverse effect s. The safety of trace
OCR for page 39
Vitamins, Minerals, arid, Nonnutritive Inhibitors of Carcinogenesis 39
element intake s substantially exceeding the Recommended Dietary Allow-
ances (National Research Council, 1980a) has not been established.
There i s very little reliable information on the trace element
composition of foods, except for their iron content. But even the
reported and widely used data on this element have been recognized as
erroneous and are being revised by the U.S. Department of Agriculture.
Data on other important trace element s, such as selenium, are sparse .
Moreover, their reliability i s questionable because most have not been
validated by the use of standard reference materials. In addition,
since most of the analytical studies were not designed to detect
regional differences, their results cannot be regarded as a reliable
basis for epidemiological correlations. Finally, the rapid sequence in
which trace element s with essential nutritional functions have been
discovered during recent decades suggests that our pre sent knowl-
edge of essential trace minerals may still not be complete (National
Re search Council, 1982, Chapter 10) .
The bioevailability of different chemical forms of trace elements
can vary widely. For example, some selenium compounds have no bio-
logical activity, wherea s others have pronounced physiological
effects. The bioavailability of dietary iron compounds can differ by
at least a factor of 10 (Bowering _ al., 1976~. For most micronu-
trients, the scientific basis for these differences has not been deter-
mined and the degree of bioavailability has not been quantif led. Food
processing is known to have a strong influence on the concentration and
bioavailability of most trace elements, but this influence has not been
adequately quantif fed .
Hundreds of nutrient-nutrient interactions have been described
qualitatively, and many more may yet be discovered. These interactions
are strong determinants of bioavailability and are involved in mecha-
nisms that lead to the early signs of chronic toxicity. For example,
large amounts of vitamin C greatly increase the bioavailability of iron
compound s, while simultaneously reducing selenite to the biologically
unavailable elemental selenium (Monsen et al., 1978; Newberry and
Christian, 1965~.
High but not excessive supplements of certain trace elements,
although not necessarily toxic by themselves, can interfere with the
metabolism of other elements to create secondary deficiencies
Levander and Cheng, 1980) . Such ef f ect s have been clearly demon-
strated for only one trace element, zinc, but they can be expected
for others whenever high intakes of trace element s are maintained over
prolonged period s.
Selenium
Selenium has two known biochemical modes of action: as a constit-
uent of glutathione peroxide se, it prevents free-radical damage to
OCR for page 40
40 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
cell constituents, and it acts as a potent antagonist of chronic and
acute toxicity resulting from exposure to cadmium and mercury. Although
both these modes of action may be related to reduction in the risk of
cancer, it is not known whether these are the mechanisms by which selen-
ium affects carcinogenesis, nor is it known at which stage of carcino-
genesis selenium might be effective.
There is only limited knowledge about the effect of different doses
of selenium on the reduction of cancer incidence in animals. Much of
the information on the element's inhibitory effects has been obtained
with doses that are close to toxic levels. One study suggests that
selenium-deficient diets increase the risk of cancer, compared to diets
containing nutritionally adequate but not excessive levels (Ip and
Sinha, 1981~. Because of the relatively narrow range between toxic and
optimum levels of selenium (National Research Council, 1980a), it is
essential to define a range of selenium intake that does not result in
chronic toxicity but is effective in reducing cancer risk. Experiments
to establish nutrient requirements have demonstrated that the amount of
selenium required for optimum nutrition is dependent on dietary levels
of fat, vitamin E, and certain heavy metals. There is also evidence
that at least the interaction between selenium and fat is an important
determinant of the element's effect on cancer. However, these inter-
actions have not been quantified (Levander and Cheng, 1980~.
The results of a few epide~iological studies suggest a correlation
between exposure to high levels of selenium and a reduction in the risk
of certain cancers (National Research Council, 1982, Chapter 10~. But
these data are not conclusive, partly because the data base on the
selenium content of foods is poor. Because selenium concentrations in
food are dependent on the geochemical environment, dietary selenium
levels vary widely from one region to another and cannot be calculated
accurately on the basis of universal food composition data. Other
reservations apply to blood concentrations of selenium as indicators of
nutritional status, since there are no standard reference materials to
safeguard analytical accuracy and comparability of results obtained by
different laboratories. Populations in certain geographical areas of
the world have substantially different levels of selenium intake, al-
though other nutrient intakes are virtually identical. Epidemiological
and/or intervention studies in such areas appear to be more promising
than those in populations either with adequate selenium intakes or with
relatively small differences in intake.
The metabolisms of selenium depends on the chemical fore of the
element. These metabolic differences may affect the impact of selenium
on carcinogenesis. Very little is known about the long-ter~ conse-
quences of elevated intakes of different forms of selenium, and there
are no adequate means for diagnosing subclinical pathogenesis resulting
from the accumulation of selenium in tissues.
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Vitamins, Minerals, arid, Nonnutritive Inhibitors of Carcinogenesis 41
Molybdenum, Zinc, Iron, Iodine, and Arsenic
As indicated in the committee's first report, evidence that molyb-
denum, zinc, iron, iodine, and arsenic play a role in carcinogenesis is
limited and, in some cases, contradictory (National Research Council,
1982, Chapter 10~. Molybdenum is essential for the function of certain
enzymes. The next three elements are essential for human nutrition.
For example, iron, zinc, and iodine have a profound influence on immune
function or on hormonal status, or both, and deficiencies in these ele-
ments reported worldwide have presented major health hazards. Arsenic
is considered to be essential for growth in animals. Because of their
frequent occurrence in the diet of humans, basic research is necessary
to formulate definitive conclusions about the role of these trace
elements in carcinogenesis.
Epidemiological associations of diet with cancer rely on the
adequacy with which food intake data are collected and evaluated or on
the adequacy with which nutritional status is assessed by direct mea-
surements in individuals. The data base for essential trace elements
(exclusive of iron) is inadequate and, in part, erroneous. Expanded
efforts to analyze trace elements in foods are essential in order to
create a reliable and complete data base. Similarly, there are only a
few reliable methods for the direct assessment of nutritional status
for essential trace elements other than iron and iodine. Any progress
in the development of such methods will significantly increase the
reliability of epidemiological studies of diet and cancer.
NONNUTRITIVE INHIBITORS OF CARCINOGENESIS
An increasing number of nonnutritive substances in food have been
found to inhibit carcinogenesis in laboratory animals. Included among
these substances are phenols, indoles, aromatic isothiocyanates,
methylated flavones, protease inhibitors, and plant sterols (National
Research Council, 1982, Chapter 15~. The chemical diversity of these
inhibitors suggests that other compounds with inhibitory activity are
likely to exist in food, but, for the most part, efforts at identifying
such substances have been haphazard (Wattenberg, 1983~. It is impor-
tant to develop the technology to identify inhibitors of carcinogenesis
in food and then to apply it systematically.
The occurrence of cancer can be inhibited at three specific stages
during the succession of events leading to development of neoplasia.
These stages, in sequence, are (1) inhibition of the formation of
carcinogens from precursor compounds, (2) prevention of carcinogens
from reaching or reacting with critical target sites, (3) inhibition of
the postinitiation stages. Some procedures have been developed for
identifying inhibitors that are effective at one or more of these
stages, but the scope of the procedures is limited. Those that do
exist have not been extensively exploited (Wattenberg, 1983~.
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42 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
Investigations of the inhibition of carcinogen formation have been
limited largely to studies of nitroso compounds in laboratory animals.
Extension of such work to investigations in humans, especially in
population subgroups that appear to be at high ri sk f ram exposure to
nitroso carcinogens, should be explored. Techniques of this nature
are discussed in Chapter 5.
Food contains many compound s that prevent carcinogens f rom reach-
ing or reacting with critical target site s. These so-called "blocking
agents" have been identified by virtue of their ability to enhance the
activities of enzyme systems that can detoxify chemical carcinogens.
One such system i s the glutathione S-transferase enzyme system
(Sparnins and Wattenberg, 1981; Sparnins et al., 1982~. Only limited
efforts have been made to use this enzyme system to detect blocking
agents in foods. Other marker systems exist as well. Research should
be conducted to determine which of these systems would be effective in
detecting inhibitors. Those systems should then be used for the system-
atic identification of inhibitors in food.
Current technology makes it feasible to identify dietary compounds
that can inhibit neoplasia during the promotion phase. For example,
there are three biochemical events that are associated with some facets
of tumor promotion in laboratory animals. The induction of ornithine
decarboxylase activity occurs in some tumor promotion systems (Boutwell,
1977), and inhibition of the induction of this enzyme's activity could
be used as a parameter for identifying putative inhibitors of tumor
promotion. The inhibition of free radicals that are formed during tumor
promotion could be used as another method for identifying such inhibi-
tors (Troll _ al., 1982~. Finally, inhibition of the stages in the
arachidonic acid metabolism cascade has also been used to study inhibi-
tion of promotion (Verne et al., 1980~. Accordingly, the development
of appropriate methodology offers promise that putative dietary inhibi-
tors of promotion can be identified.
The identification of compounds that can inhibit carcinogenesis
after exposure to neoplastic agents would be very important. The pro-
totype compound in this category is vitamin A. The mechanism by which
vitamin A and its synthetic analogs, the retinoids, bring about inhibi-
tion has not been established. Pending the emergence of definitive
data on the mechanism of action, it may be possible to apply some of
the existing technology to detect other dietary constituents that
inhibit by the same means. Inhibitors of arachidonic acid metabolism
have been found to inhibit carcinogenesis when administered during the
postinitiation stages. Detection of dietary constituents that inhibit
components of this cascade might aid in the identification of compounds
that can inhibit carcinogenesis after exposure to carcinogenic agents.
GENERAL RESEARCH RE CO!IMENDAT IONS
Because the data accumulated thus far suggest that further study of
dietary inhibitors may be fruitful, the recommendations in this chapter
are more detailed than in some other chapters.
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Vitamins, Minerals, and Nonnutritive Inhibitors of Carcinogenesis 43
· Research should be conducted to de ter~i ne the labora t ory con-
ditions under which the occurrence of neoplasia can be prevented by
the microconstituents discussed in this chapter, i.e., vitamins A, C,
and E and the carotenes; selenium and possibly some other trace min-
erals; and nonnutritive inhibitors of carcinogenesis.
· The mechanisms by which these microconstituents prevent car-
cinogenesis should be determined.
· Efforts should be made to establish dose-response curves for
microconstituents (e.g., vitamin A, carotenes, and selenium) that
inhibit carcinogenesis.
0 The metabolism of vitamins A, C, E, carotenes, and possibly some
trace elements should be fully elucidated.
· Studies should be undertaken to determine if there are biochemi-
cal markers that are indicative of long-term nutritional status of
humans with regard to these microconstituents.
Investigations should be expanded to include a determination of
the amounts of these microconstituents in various foods. These should
be followed by analytical epidemiological studies (case-control or
cohort studies) to determine the effects exerted by various levels of
microconstituent intake on the occurrence of cancers in humans.
· Consideration should be given to studying the incidence of
specific cancers in populations consuming large doses of vitamin
supplements.
· When justified by sufficiently definitive data from experimental
and/or epidemiological investigations, intervention studies with these
microconstituents or with foods rich in these substances should be
considered (see Chapter 4~.
O Techniques should be developed for detecting dietary compounds
that have the capacity to inhibit carcinogenesis. These should be
applied systematically to identify such inhibitors, and when new ones
are discovered, they should be subjected to each of the recommendations
mentioned above.
· Experiments should be conducted in animals to evaluate the
effects of dietary microconstituents on later stages of carcinogenesis.
SPECIFIC RESEARCH RECOMMENDATIONS
Chapters 4 and 5 contain general suggestions for improving both epi-
demiological and laboratory methods. Recommendations pertaining spe-
cifically to microconstituents and inhibitors are presented below.
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44 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
Vitami n A and Carotene s
· Case-control or cohort studies are needed to distinguish between
the effects of retinal and those of ,8-carotene as they pertain to
cancer ri sk, since the dietary sources of these two nutrients are dif-
f Brent .
· Studies to examine the potential risk-reducing effect of ''vita-
min A" and the retinoids would be worthwhile. For example, studies
could be conducted on certain high-risk groups, such as asbestos
workers who smoke. Intervention trials on this subject may be produc-
t ive.
· Experiments in several different animal models should be con-
ducted to determine the inhibitory effect of different doses of vita-
min A.
· Studies to determine the mechanists) of inhibition for vitamin
A and the retinoids should be pursued.
· Additional experiments should be conducted in animals to deter-
mine if ~ -carotene and other carotene s have the capacity to inhibit
carcinogenesis and, if so, to identify the conditions under which such
inhibition occurs and the mechanism by which it occurs.
· Improved techniques for evaluating vitamin A and carotene levels
in human tissues would be helpful, as would be studies of the metabo-
lism of vitamin A and carotenes.
Vitamin C ~ Ascorbic Acid)
· The effects of vitamin C on chemically induced neoplasia of the
large bowel should be studied further in laboratory animals, especially
in the guinea pig.
· Further studies should be pursued to determine if vitamin C has
broadly applicable inhibitory effects on neoplastic manifestations of
cells in culture.
o Epidemiological studies should be conducted to assess more
directly the possible inhibitory effect s of vitamin C on the induction
of gastric cancer and possibly cancer of other sites in the gastrointes-
tinal tract, e.g., the colorectum.
Vi tamin E
o S tudies should be conducted in laboratory animals to determine
the effects of vitamin E on chemically induced neoplasia of the large
bowel and the breast.
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Vitamins, Minerals, and Nonnutritive Inhibitors of Carcinogenesis 45
o Epidemiological studies should be conducted to examine the
relationship of vitamin E to cancer risk in humans.
Selenium and Other Trace Elements
Selenium
· Basic studies should be conducted to determine the effect of
selenium on immune reactions, its interactions with DNA, its interac-
tions with heavy metals, and the mechanisms by which it protects tissues
against attack by free radicals.
· The stage of carcinogenesis at which selenium is most effective
should be determined.
· A complete dose-response curve for the protective effect of
selenium against chemical and viral carcinogens should be established,
and the influence of dietary fats, heavy metals, and vitamin E on such
curves should be quantified.
· Better methods to analyze the selenium content of foods should
be developed, and the results of the subsequent analyses should be con-
solidated into a data bank and validated. This effort must be under-
taken for each different geochemical region.
O Valid methods should be developed to assess the nutritional
status of humans with regard to selenium. This would require that
standard reference materials (e.g., foods, blood, and urine) be
developed for selenium.
· Cohort studies based on biochemical assays of selenium are needed
to corroborate observations from correlation studies. Epidemiological
studies of selenium and cancer will need to take into account the
interactions of selenium with other dietary constituents (e.g., vitamin
C, copper, and zinc), since these interactions can affect the bioavaila-
bility of selenium.
· Studies in humans should be conducted under close medical super-
vision to monitor the metabolic effects of different forms of selenium
supplements used in moderate amounts.
· Ultimately, consideration should be given to intervention
studies in countries known to have inadequate selenium intakes, e.g.,
China, New Zealand, and Finland.
Molybdenum, Zinc, Iron, Iodine, and Arsenic
o Initially, research on molybdenum, zinc' iron> and iodine should
be directed toward confirming or disproving their carcinogenicity when
administered orally.
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46 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
· If justified by findings from the initial research, basic
research should be pursued to elucidate the mechanisms by which molyb-
denuqn, iron, iodine, and zinc might affect carcinogenesis.
· Analytical methods should be developed to determine snore accu-
rately the molybdenum, iron, iodine, and zinc content of foods.
· Valid 'methods should be developed to assess the nutritional
status of individuals in regard to molybdenum, zinc, iron, iodine, and
arsenic.
Analytical epide~iological studies should be conducted to
examine the possible carcinogenic effects of exposure to the low levels
of zinc, iodine, and arsenic that are present in the average diet. The
relationship between exposure to iodine and thyroid cancer should be
examined in case-control studies that clearly separate the follicular
and papillary histological types of tumors.
Nonnutritive Inhibitors of Carcinogenesis
· Studies should be conducted to detect dietary constituents that
have the capacity to prevent the occurrence of neoplasia.
· Studies should be conducted in animals to determine the condi-
tions under which these compounds will inhibit carcinogenesis and to
identify characteristics that are related to their potential for pre-
venting neoplasia. Their mechani sms of inhibition and their adverse
effects, if any, also need to be identified.
1
· Short-term studies should be conducted in humans to identify the
protective responses elicited by these compounds.
Epidemiologica1 studie s, including intervention trial s when
appropriate, should be conducted to determine if consumption of foods
containing high concentrations of these compounds results in a lower
incidence of cancer ~ see also Chapter 4) .
Representative terms from entire chapter:
inhibit carcinogenesis
