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OCR for page 25
6 Macro cons tit u ents
The literature concerning dietary macroconstituents (i.e., fats,
protein, carbohydrates, dietary fiber, alcohol, and total caloric
intake) and their associations with carcinogenesis was reviewed
extensively in Chapters 4 through 11 of the committee's first report
(National Research Council, 1982~. The paragraphs below describe the
major gaps in knowledge, which are discussed in more detail in the
first report, and provide recommendations for future research in those
areas.
Food is a complex mixture of chemicals, and the effects of individ-
ual dietary components are dependent on many factors, including inter-
actions among dietary constituents. However, for the sake of conve-
nience, each macroconstituent is discussed separately.
FATS
After assessing the literature, the committee concluded that there
is significant epidemiological evidence for an association between
dietary fat and cancer at a number of sites, especially the breast and
the large bowel. The evidence associating high fat intake with a high
incidence of or mortality from these cancers was derived from both
correlation and case-control studies in various populations. In most
of the studies, it was not possible to identify clearly which compo-
nents of fat were responsible for the observed effects. Where such a
distinction was possible, however, total fat and saturated fat were
implicated most frequently (National Research Council, 1982, Chapter 5~.
The committee also noted that the epidemiological data are not
entirely consistent, even though they point in the same direction.
For example, the magnitude of the association between fat intake and
breast cancer appears greater in the correlation data than in the
case-control data, and some studies of large bowel cancer do not
demonstrate an association with dietary fat. Possible explanations
for these discrepancies were discussed in the first report.
The committee was unable to reach a definitive conclusion about the
relationship between serum cholesterol and cancer in humans, because the
evidence is inconsistent and not sufficiently convincing to establish
a causal relationship. Data on dietary cholesterol and cancer ri sk
are also too limited to permit any inferences to be drawn (National
Re search Council, 1982) .
Numerous experiments on animals also indicate that dietary lipid
influences tumorigenesis, especially in the breast and the colon. An
25
OCR for page 26
26 DIET, NUTRITION, AND CANCER: DIRECTIONS [OR RESEARCH
increase in total dietary fat from 5% to 20% of the weight of the diet
(i.e., from approximately 10% to 40% of total calories) appears to
increase tumor incidence in each of these tissues. At low intakes of
total fat, polyunsaturated fat appears to be more effective than satu-
rated fat in enhancing tumorigenesis; however, the effect of polyun-
saturated fat becomes less prominent as total dietary fat is increased
to 20% of the diet, suggesting that total fat intake is the more
significant factor. In general, the epidemiological data and the
laboratory evidence are consistent (National Research Council, 1982~.
The limited data on the possible mechanisms of action by which fat
exerts its effects indicate that ingested fat affects tumor promotion
rather than tumor initiation; however, an effect on initiation cannot
yet be ruled out. The specific mechanism involved in tumor promotion
is not known, although some evidence suggests that colon cancer i s
associated with increased concentrations of bile acids in the feces
(National Research Council, 1982~.
The committee noted that of all the dietary factors that have been
associated with cancers of various sites, fat has probably been studied
most thoroughly and has produced the greatest frequency of direct
associations (National Research Council, 1982~. Nevertheless, it is
clear that there is a need for more accurate data on fat intake in
specific populations and on its precise effect on tumorigenesis. For
example, fat intake varies widely among individuals in the United
States. We are not certain that there are differences in cancer
incidence between individuals at the high and low ends of the intake
spectrum.
Unsaturated fat appears to exert a promoting effect on some experi-
mentally induced tumors. Diets containing unsaturated fat may be hypo-
cholesterolemic, and the results of some population studies suggest
that individuals with low levels of serums cholesterol exhibit a greater
incidence of tumors. These studies suggest that more data are needed
to clarify the effects of unsaturated fat. For example, if unsatu-
rated fat acts as a tumor promoter, what is its mechanism of action?
Does it involve epoxidation, products of oxidation and degradation such
as short-chain aldehydes, or effects on prostaglandin formation? There
are many such unanswered questions. Therefore, the mechanists) by
which different types of dietary fat exert their effects roust be clari-
fied. For example, effects on the immune system require further study.
lIeiniger (1981) demonstrated that some inhibitors of cholesterol biosyn-
thesis suppress immune response. These finds ngs suggest that the
effects of lipids and lipoproteins (dietary fat, lipoprotein, and
apolipoprotei n) on the immune system require extensive investigation.
Evidence implying that males with blood cholesterol levels less
than 200 rng/100 ml are at increased risk of cancer, especially
colorectal cancer, was derived largely from follow-up examinations of
individual s in studies directed primarily toward cardiovascular dis-
ease. Most of these were observational studies in which blood
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Macroconstituents 27
cholesterol level s were measured and the subsequent mortality from
cardiac and other diseases assessed. However, a few studies included
deliberate attempts to lower blood cholesterol in subjects whose levels
were high. The results from this latter type of study do not clearly
indicate whether those with an increased risk of cancer were derived
from the groups with initially low blood cholesterol or from groups in
which blood cholesterol was lowered as a result of intervention to
levels less than 200 mg/100 ml. Several investigators have suggested
that the observed increase in mortality from cancer may be due to the
presence of undetected cancer at the start of the study rather than to
its development after blood cholesterol was measured. Thus, it is not
clear whether low blood cholesterol is a consequence or possible cause
of cancer (National Research Council, 1982~. If causal, the responsi-
ble mechanism could be the excretion of high levels of cholesterol
breakdown products in the intestine of persons with low blood choles-
terol. This could occur despite the consumption of the standard North
American high fat diet, which usually results in blood cholesterol
levels that are higher than those in populations consuming diets with
lower levels of fat. Metabolic studies are required to determine
whether the excretion of cholesterol breakdown products is more active
in individuals with low blood cholesterol levels.
The effect of a high cholesterol diet on the risk of colon cancer
is also unclear. ~ Canadian case-control study of diet and colorectal
cancer showed that a much weaker effect resulted from high cholesterol
intake than from high saturated fat intake (Jain et al., 1980~. It
has been known for some time that a major dietary contributor to in-
creased blood cholesterol is not cholesterol but, rather, high levels
of fat (National Research Council, 1980b).
Thus, further epidemiological and biochemical studies are required
to explain the relationship of dietary fat and cholesterol intake to
serum or plasma cholesterol levels and to the excretion of cholesterol
and its metabolites (i.e., neutral and acidic steroids and their micro-
bial by-products). We need to define the level to which the current
high fat intake can be lowered to achieve a maximum reduction in the
risk of cancer without concomitantly increasing the risk of other
disease states. In this regard, the optimum proportions of saturated,
monounsaturated, and polyunsaturated fats should be delineated.
PROTEIN
Epidemiological studies reviewed by the committee indicate possi-
ble associations between high levels of dietary protein and increased
risk of cancers at a number of different sites, including the breast,
colon, pancreas, prostate, and endometrium. However, the litera-
ture on protein is much more limited than that on fats. In addition,
the high correlation between fat and protein intake in Western diets
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28 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
and the more consistent and often stronger association of these cancers
with fat intake make it seem likely that dietary fat is the more active
component. Nevertheless, the committee concluded that the evidence
does not completely preclude an independent effect of protein
(National Research Council, 1982, Chapter 6~.
In laboratory experiments, the relationship between dietary protein
and carcinogenesis appears to depend upon the level of protein intake.
In most studies, carcinogenesis was found to be suppressed by diets
containing levels of protein at or below the minimum required for opti-
~num growth. Chemically induced carcinogenesis is generally enhanced as
protein intake is increased up to 2 or 3 times the normal requirement;
however, higher levels of protein begin to inhibit carcinogenesis.
A review of the preliminary data on possible mechanisms of action
suggested that protein may affect both the initiation and the subse-
quent growth and development of tumors (National Research Council,
1982).
Thus, the association between dietary protein, especially different
types of protein, and cancers of the breast, endometrium, prostate,
colorectum, pancreas, and kidney needs further clarification. Studies
should be specifically designed to determine whether the apparent
effect of major dietary sources of protein, which contain a variety of
other nutrients and nonnutritive components, is due to a direct asso-
ciation of protein with cancer at these sites or reflects the action
of another constituent of protein-rich foods.
CARBOHYDRATES
The committee found only extremely limited and inconclusive epidem-
iological evidence concerning the role of carbohydrates (exclusive of
dietary fiber) in the development of cancer in humans. The data from
the few laboratory experiments on this subject could not be interpreted
because of generally poor experimental designs and uncertainty about
the actual carbohydrate content of the test diets (National Research
Council, 1982, Chapter 7~.
Thus, in contrast to lipids and protein, very little work has been
d irected toward the study of carbohydrate intake, e specially the level s
of dif ferent types of carbohydrate, and the occurrence of cancer. How-
ever, one study has suggested that rats fed sucrose are more suscepti-
ble to chemically induced tumors than are rats fed starch (Hoehn and
Carroll, 197 9) . Thi s area requires further investigation. A complete
understanding of the effects of carbohydrates on carcinogenesis may
depend on a thorough knowledge of the effect s and interactions of each
dietary component.
DIETARY F IBER
The association between dietary f iber and carcinogenesis, espe-
cially in the colon, has been investigated at length in epidemiological
OCR for page 29
Macroconstituents 29
studies. However, both correlation and case-control studies have
yielded inconsistent results. Many of these studies were based on
total fiber consumption estimated by grouping foods (such as fruits,
vegetable s, and cereals) according to their f iber content . However, in
the only case-control study and the only correlation study in which the
total fiber consumption was quantified rather than estimated from the
fiber-rich foods in the diet, no association was found between total
fiber intake and the risk of colon cancer. Thus, the committee
concluded that the epidemiological evidence suggesting an inverse
relationship between total fiber intake and the occurrence of colon
-
cancer is not compelling (National Research Council, 1982~.
In the only study in which the effects of individual components of
fiber were assessed, there was an inverse correlation between the in-
cidence of colon cancer and the consumption of the pentose-containing
fraction of fiber. Thus, it seems likely that further epidemiological
study of fiber will be productive only if the relationship of cancer to
specific components of fiber can be analyzed (National Resea rch
Council, 1982, Chapter 8) .
A few laboratory studies have also shown that some types of fiber
(e.g., cellulose and bran) inhibit chemically induced tumorigenesis in
the bowel. However, the data are somewhat inconsistent with respect
to the type of fiber or specific chemical carcinogen. Moreover, the
results of epidemiological and laboratory studies are difficult to
equate, because most laboratory experiments have examined fiber-rich
materials or their individual components, whereas most epide~iological
studies have focused on fiber-containing foods whose exact composition
has not been determined. Therefore, to obtain meaningful results,
further information is needed on the basic chemistry and biological
effects of fiber and its components (National Research Council, 1982~.
Recently, more attention has been directed toward the physiological
significance of dietary fiber, which generally includes indigestible
carbohydrates and carbohydrate-like components of food such as cellu-
lose, lignin, hemicelluloses, pentosans, gums, and pectins. Neverthe-
less, because of the complex composition of dietary fiber, the physio-
logical functions and metabolic activity of its individual components
have not yet been studied sufficiently.
Although epidemiological data concerning the role of total dietary
fiber in the development of colon cancer are somewhat inconsistent,
studies in animals have demonstrated that individual components of
fiber, e.g., bran and cellulose, exert protective effects against the
induction of cancer by chemicals, but that another type, agar, does not
(Barbolt and Abraham, 1978; Freeman et al., 1978; Glauert et al.,
1981~. The effects of fiber should be correlated with its structural
properties. It would be useful to compare the effects of adding fiber-
containing foods to the diet with the effects resulting from the addi-
tion of specific dietary fibers, since current hypotheses concerning the
OCR for page 30
DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
effects of fiber are based on dietary patterns--not on the addition of
specific fibers or fiber-containing foods.
Studies are also required to separate the beneficial effects of
high intakes of certain cruciferous vegetables on colon cancer from the
effects, if any, of dietary fiber per se. There is little information
concerning pathophysiological changes In the bowel that are associated
with different types of high-fiber diets. The relationship of various
types of fiber to the enterohepatic circulation of sterols, including
sterol-derived hormone s, i s al so not understood .
ALCOHOL
There have been many studies concerning the effects of alcohol
consumption on cancer incidence in human populations. In some
countries, including the United States, excessive beer drinking has
been associated with an increased risk of colorectal cancer, espe-
c tally rectal cancer. Although it i s recognized that excessive
alcohol consumption contributes to hepatic injury and cirrhosis, there
is only limited evidence that this in turn leads to hepatocellular car-
cinoma. Furthermore, excessive consumption of alcoholic beverages and
cigarette smoking appear to act synergistically to increase the risk
for cancer of the mouth, larynx, esophagus, and the respiratory tract
(National Research Council, 1982, Chapter 11~.
Although some reports have suggested that alcohol consumption per
se is related to cancer, others have implicated specific alcoholic
beverages as risk factors for cancers at certain sites, such as the
esophagus and gastrointestinal tract. This suggests that nonalcoholic
components of alcoholic beverages may be the responsible agents.
Furthermore, it is not yet clear what role nutrient inadequacies,
imposed by excessive alcohol consumption, play in the process of car-
cinogenesis.
TOTAL CALORIC INTAKE
The committee found it especially difficult to separate the effect
of caloric intake per se on carcinogenesis from the effects due to
changes in the levels of the three macronutrients: fat, protein, and
carbohydrates. It concluded that the epidemiological evidence support-
ing total caloric intake as a risk factor for cancer is slight and
largely indirect, because much of it is based on associations between
body weight or obesity and cancer rather than on direct measurements of
caloric intake. Studies that have evaluated both the caloric content
of the diet and the intake of fat suggest that dietary fat is the more
relevant variable (National Research Council, 1982, Chapter 4~.
Similarly, studies in animals to examine the effect of caloric
intake on carcinogenesis have been few and are difficult to interpret.
OCR for page 31
Macroconstituents 31
In these experiments, animals on calorie-restricted diets developed
fewer tumors and their lifespan far exceeded that of animals fed ad
libitum, thereby indicating a decrease in the age-specific incidence
of tumors. For example, McCay et al. (1943) and Ross and Bras (1973)
showed that underfed rats lived longer and developed fewer tumors than
their littermates, which were fed ad libitum. In another experiment,
Lavik and Baumann (1943) found that methylcholanthrene-treated rats on
restricted caloric intake developed fewer tumors than did treated rats
fed ad libitum. However, because the intake of all nutrients was
simultaneously depressed in these studies, the observed reduction in
tumor incidence or delayed onset of tumors might have been due to the
reduction of other nutrients such as fat. It is also difficult to
interpret experiments in which caloric intake has been modified by
varying dietary fat or fiber, both of which may by themselves exert
effects on tumorigenesis (National Research Council, 1982~.
Neither the epidemiological nor the experimental studies permit a
clear interpretation of the specific effect of caloric intake. How-
ever, the effects of over- and underfeeding as such warrant further
study, even though it may be difficult to separate caloric effects fray
the effects of the specific nutrients that contribute to total caloric
intake.
RESEARCH RECOMMENDATIONS
A better understanding of the relationship between certain macro-
constituents (e.g., fat) and cancer has enabled the committee to make
some more specific recommendations in this chapter than in other chap-
ters.
General Recommendations for Epidemiological Research
~ There is probably considerable interaction among the many compo-
nents of the diet. Therefore, some potentially harmful substances may
be "neutralized" by other dietary ingredients. For this reason, there
is a need to evaluate the interrelationships among calories, protein,
and fat (and its various components) and their effect on, for example,
breast and colorectal cancer.
0 Simultaneously, the opportunity should be taken to evaluate the
interrelationships between these nutrients and (1) the effects of
hormonal status on breast cancer and (2) the effects of fiber, its
components, and various micronutrients, especially vitamins and
possible inhibitors in vegetables of the genus Brassica, on the eti-
ology of colorectal cancer.
o Research on interrelationships among macroconstituents should be
designed so that it is possible to determine the overall effect of
different groups of foods and not just individual foods or nutrients,
as discussed in Chapter 4.
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32 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
· The completed dietary studies on breast and colon cancer should
be extended to examine other possibly diet-associated cancers that have
been correlated with breast and colon cancer. In addition to the on-
going investigations of prostate cancer, studies should be conducted on
endometrial, ovarian, pancreatic, and renal cancers.
· More frequent monitoring of food intake, especially changes
in intake of macronutrients in the average diet, is essential (see
Chapter 4~.
· Reliable data bases for food composition should be developed for
the analysis of macronutrients (see Chapter 4~. It is especially
important that such data bases contain more information on the fiber
content of each food and on the chemical composition of each type of
fiber.
· It is now essential to give high priority to some long-term
cohort studies that will test hypotheses about macronutrients and
cancer (see Chapter 4~.
· Carefully planned intervention studies, involving changes in the
macronutrient content of the diet, should be conducted in humans (see
discussion of intervention studies in Chapter 4~. Such studies may be
the only way to gain an understanding of the relative effects and the
interrelationships among,Luacronutrients. In such studies, it may be
conceptually easier to plan for the addition of constituents, e.g.,
specific types of fiber, to the diet. However, we should not overlook
the need to evaluate the effect of reducing dietary fat by consumption
of foods low in fat.
· The effects of dietary macroconstituents on the later stages of
carcinogenesis need to be examined in laboratory studies.
General Recommendations for Laboratory Research
.
o For animal experiments, the first priority is standardization of
methodology. This is discussed in Chapter 5.
· The epidemiological data linking specific dietary components to
cancers of the prostate, pancreas, and endometrium are limited. An
expansion of the experimental data base, i.e., development of suitable
animal models, is required in order to put these data into proper
perspective.
Specific Recommendations
Fat: Epidemiological Studies
.
o More discriminating data are needed on the effect of the level
and type of fat intake by humans. For example, we need to answer the
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Macroconstituents 33
question, "What level of fat intake is associated with the maximum
reduction in cancer incidence?" Is it 307 of calories, as recently
recommended by this committee? Is it 25%, 20X, or lower levels?
O More discriminating data are also needed on the effects of
different types of fat. Studies should be conducted to answer the
following questions: Is the finding that polyunsaturated fat increases
tumor incidence in laboratory animals relevant to humans? Is this
finding also relevant to the results emerging from intervention trials
for cardiovascular disease? What should be the relative proportion of
polyunsaturated, monounsaturated, and saturated fats in the optimal
diet?
· Metabolic studies are required to evaluate the role of the break-
down products of cholesterol in individuals with low blood cholesterol
levels.
o The mechanism underlying the reported association between low
blood cholesterol and neoplasia should be determined. For example, it
would be helpful to know whether hypocholesterolemic individuals are at
high risk only if they consume a high fat diet and whether lowering fat
intake in such individuals will reduce their risk. Further analysis
of existing data on humans may help to answer these questions.
Fat: Laboratory Studies
~ The relative roles of the level and type of fat (e.g., essential
fatty acids ~ in al 1 phases of tumor formation should be studied. The
stage at which dietary fat exerts its effects on the induction of
tumorigenesis and its effects in the prepromotional, promotional, tumor
development, and metastatic stages should be systematically investi-
gated. Other aspects of lipid nutriture and carcinogenesis also need
resolution. For example, further investigation is needed to determine
the effects of bans unsaturated fats, lipid pyrolysis products, and
lipid peroxides and to study the effects of lipids on membrane phe-
nomena, on prostaglandin synthesis, and on immune phenomena.
o The interplay among dietary lipids (including cholesterol), hypo-
cholesterolemic agents, neutral and acidic fecal steroids, and gut
microflora should be clarified with respect to their effects on tumori-
genesis.
o Studies should be conducted in animals to determine the
threshold level (percent of calories) at which dietary fat begins to
exert measurable effects on carcinogenesis.
O The cholesterol vehicle (lipoprotein) should be examined for its
ability to carry other substances that may affect tumor growth.
Protein: Epidemiological Studies
~ The independent effects of the amount and type of protein and of
their interaction with other macronutrients on the incidence of tumors
in humans should be investigated.
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34 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
Protein: Laboratory Studies
.
· The inf luence of the biological value of protein and the level
and type of protein should be studied in different experimental systems.
The effects of animal protein and vegetable protein should be compared.
· The effect of protein on different stages of carcinogenesis and
the mechanism underlying this effect need further investigation.
Carbohydrates: Laboratory Studies
· Simple sugars (mono- and disaccharides) should be compared with
starches from various sources for their effects on tumor formation.
Calorie s: Epiderniological S tudie s
o The relationship between total caloric intake and cancer in
humans should be studied further, together with the modifying inf lu-
ence of energy expenditure through occupation or exerci se .
Calo rie s: La boratory S tudie s
· The mechanism for the putative effect of caloric intake on car-
cinogene si s need s to be determined . For example, to what extent are
the calories provided by fat, protein, and carbohydrate responsible
for the effect on carcinogenesi s? And i s the effect of the caloric
contribution by each of the three macronutrients equivalent?
· Effects of age at which caloric restriction is instituted should
be assessed.
· Carbohydrate i s usually used to replace fat or protein in the
diet without considering how this may influence the outcome. However,
the effect of replacing dietary fat with protein or carbohydrate in iso-
caloric diet s has not been examined . Although thi s may be difficult to
accomplish, it is important to attempt to study the individual effects
of protein, carbohydrate, and fat in animals fed ad libitum.
Fiber: Epidemiological Studies
· The content of f iber components in foods should be determined
In order to assess dietary intake more accurately.
O The inf luence of f iber on cancers other than colorectal
cancer should be studied.
Fi her: Laboratory S tudies
· The structure-function relationships of fiber (e.g., its pentose
content and it s bile-acid binding capacity) in tumor formation should
be studied.
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Macroconstituents 35
· The physiological properties of different components of fiber and
their effects on the absorption and availability of nutrients should be
systematically evaluated in metabolic studies.
~ The influence of fiber on tumors at sites other than the colon
should be investigated.
Alcohol: Epidemiological Studies
· Reliable methods are needed to quantitate alcohol intake. This
should be followed by investigation of the effects of different intake
levels on cancer risk.
· The influence of different alcoholic beverages (e.g., wine,
beer, whisky, or liqueurs) on esophageal, gastric, and other cancers
should be studied.
Alcohol: Laboratory Studies
· Studies should be conducted to determine the influence of
nonalcoholic components of alcoholic beverages on experimentally in-
duced carcinogenesis.
· The association between carcinogenesis and nutrient deficiencies
imposed by excessive alcohol intake should be evaluated.
Representative terms from entire chapter:
caloric intake
