- Nutrition and Cancer
early as the 1930s, experiments on laboratory animals revealed
that diet can considerably influence the process of cancer causation
and development (carcinogenesis) (Tannenbaum 1942a, 1942b; Tannenbaum
and Silverstone 1953). It was several decades later, however,
that the first epidemiological studies appeared to indicate that
diet could play a role in human cancer. A key conference held
in 1975, entitled "Nutrition in the Causation of Cancer,"
summarized the existing knowledge and hypotheses (Wynder, Peters,
and Vivona 1975). From that moment, research in experimental systems,
including animal models and epidemiological studies, increased
rapidly, providing extensive information on the impact of nutritional
traditions and specific macro- and micronutrients on several types
of cancer. Considerable progress had already been made in several
underlying sciences. For example, advances had been achieved in
understanding the mechanisms of action of nutrients, the process
of carcinogenesis, and the classification of carcinogens according
to their mode of action (Kroes 1979; Weisburger and Williams 1991).
particular, epidemiological studies on the international variations
in incidence rates for certain cancers pointed to the existence
of one or more exogenous factors that could be controlled. Observational
studies had been conducted with migrants from countries with lower
incidence rates to countries with higher incidence rates. A rapid
increase from the lower to the higher incidence in those migrants
supported the suggestion that environmental causes, and especially
prevailing dietary habits, may influence the development of a
number of neoplasms.
example, in the Western world, high incidences of cancers in the
lung, colon and rectum, breast, prostate, pancreas, endometrium,
and ovary were observed. But these diseases were, until recently,
quite rare in Japan and other Asian countries, where cancers of
the stomach, esophagus, and liver were the major diseases. Yet,
in migrant populations the risk of cancer shifted from the risk
prevalent in their native country to that seen in the new host
country, sometimes within the same generation (colon), sometimes
in the next generation (breast) (Parkin 1993).
results of experimental and epidemiological studies have led to
hypotheses concerning factors involved in cancer causation. In
fact, E. L. Wynder and G. B. Gori (1977) and R. Doll and R. Peto
(1981) estimated that 35 percent of cancer mortality may be attributable
to diet, thereby placing diet at the same "risk factor"
level as smoking, which was calculated to cause about 30 percent
of cancer mortality. In fact, current views suggest that dietary
habits may account for 55 to 60 percent of cancer mortality. The
interpretation of such multidisciplinary investigations has shed
light on underlying mechanisms of cancer causation and has provided
an understanding of the role of specific dietary risk factors.
this chapter, the focus is the role of diet in cancer causation.
First, attention is drawn to aspects of mechanisms in carcinogenesis.
The major strengths and weaknesses of experiments in animal models
and epidemiological studies are discussed, and then the major
diet-related causes are examined and their suggested mechanisms
and possible preventive measures described. The safest (but in
the publics perception the most dangerous) intentional additives
in food are evaluated for their cancer risk, as are nonintentional
contaminants, along with substances that occur naturally in food.
Finally, the key role that diet may play in an integrated approach
to (chronic) disease prevention is presented. Health promotion
through research-based nutrition not only is important for the
individual but, on a global level, may also appreciably lower
the cost of medical care. A research-based healthy lifestyle is
designed to allow people to "die young, as late in life as
possible," as Dr. Ernst L. Wynder, president of the American
Health Foundation, has said.
Strengths and Weaknesses
tumor models are often used in experimental designs to study the
mechanisms of cancer causation, to examine the effects of modulating
factors on the genesis and development of cancer, to assess therapeutic
modalities, and to explore possible adverse effects.
models are specifically used to investigate etiologic and physiopathological
properties or processes, especially those which, for obvious practical
and ethical reasons, cannot be studied in humans. The ideal animal
tumor is histologically similar to the human neoplasm of concern,
and latency period, growth, and tendency to metastasize should
both be predictable and resemble those of the human neoplasm.
The animals should be cost effective, be easily available, and
have a genetic uniformity. Variables should be controllable, thereby
making it possible to investigate the influence of isolated factors
(Davidson, Davis, and Lindsey 1987; Galloway 1989; Weisburger
and Kroes 1994).
research into matters of nutrition and cancer, chemically induced
tumors in animals, predominantly those in rats and mice, are the
most important models because they usually best mimic existing
types of human cancer (Kroes et al. 1986). For most, if not all,
nutrition-related human cancers, tumor model systems are available.
They provide an ideal research tool for investigating the influence
of individual factors, either in the initiation phase or in the
progression phase of tumor development, or in the overall process.
leads from epidemiological studies can be further investigated
in models, thus providing more detailed information, especially
regarding risk factors and mechanisms that can be the basis for
new epidemiological studies to test a presumed hypothesis. However,
animal tumors are only approximations that are rarely identical
to human disease. For example, relatively high dosages of genotoxic
carcinogens are used to induce the tumor, which tends to distort
circumstances when modulating factors are investigated.
metabolism, growth, potential for and pattern of metastasis, and
clinical features can also differ from the human disease. Multiple
tumors often occur in models, but seldom in humans. Moreover,
the nutrition patterns of experimental animals can be quite distinct
from those of humans. Nonetheless, diets can be designed in terms
of macro- and micronutrient intake that mimic specific human nutritional
studies are best understood as providing support for epidemiological
studies. It is the integration of results from epidemiological
and animal studies that provides the best insight into the etiology
and growth of cancer, as well as its treatment, and brings us
nearer to the ultimate goal of such research, cancer prevention.
Studies Concerning Nutrition and Cancer
research on cancer and diet seeks to associate exposure to certain
dietary factors with the occurrence of cancer in selected population
groups. Studies can be descriptive, reporting the occurrence of
cancers in populations, in subgroups of a given population, or
in a certain population over time. Observed patterns may be related
to particular variables, such as diet, but although the results
of such investigations are suggestive, they are certainly not
definitive. Their use is especially valuable, however, in identifying
populations at risk.
studies investigate the possible relationships between more-or-less
crude exposure data and cancer incidence data in different populations
or nations in order to generate new hypotheses. But they are generally
of limited value, because national per-capita food intake and
cancer incidence data are only approximations and differ from
place to place in terminological definition and accuracy. Results
should be used mainly as an indication of trends or relationships.
type of investigation is the case control study, in which the
investigator is able to collect data from individuals instead
of groups, and confounding variables can be controlled to a certain
extent. In studies of a specific type of cancer, food intake data
are collected and are compared to data similarly obtained in matched
controls. When known biases and chance can be excluded, associations
can be made between exposure and disease. Case control studies
are relatively cheap and are of short duration but never prove
more expensive, time consuming, and elaborate are prospective
cohort studies that focus on individuals in a given (large) population
and establish exposure or nutrition data before the occurrence
of the disease. Thus, at the time of disease occurrence, exposure
data of the patients are compared to data from people not having
the disease, thereby providing evidence for a possible causal
relationship. Drawbacks in such studies are that the exposure
assessment at any given time may not be representative of the
individuals whole life, and this is especially likely in
the case of diet.
intervention studies provide the investigator with the possibility
of a random assignment of subjects of a given (often high-risk)
population into groups that are treated or fed differently under
controlled conditions. In this type of trial, causal relationships
can be established.
investigations focused on the relationship between nutritional
factors and cancer, the methods used for determining dietary intake
are crucial and difficult. All dietary intake measures share certain
limitations, because people vary in their abilities to estimate
the amount of something they have eaten. Indeed, sometimes they
may even fail to notice or report consumption of certain foods,
and they usually possess insufficient knowledge about the ingredients
in the foods they consume. A further handicap is that accuracy
in dietary recall deteriorates over time. Finally, in the case
of cancer, it is very difficult to relate varying diets to the
disease because the latter has a long course of development before
becoming clinically manifest (10 to 40 years).
major strength of epidemiological studies, however, is their focus
on human populations, thus avoiding the need to extrapolate from
other species. They tend to afford an opportunity to examine different
effects at different exposure levels, and they are always realistic,
in contrast to the high exposure levels usually employed with
animals (National Research Council 1982; International Agency
for Research on Cancer 1990; Weisburger and Kroes 1994). In this
connection, however, it should be noted that in specific investigations
into the role of nutrients such as fat, the experimental design
in laboratory animals usually faithfully mimics the situation
of human populations at high or low risk, thus providing relatively
reliable comparative data. But at the same time, as noted, it
should also be recognized that the normal food patterns of laboratory
animals differ from those of humans.
concept that chemicals can induce cancer through a variety of
modes of action is derived from a greater understanding of the
complex processes of carcinogenesis (Williams and Weisburger 1991).
Cancer causation and development involves a series of essential
steps (Figure IV.F.7.1). In the first step, a reactive form of
carcinogen (often produced metabolically from a procarcinogen)
binds to DNA, or DNA is altered by the effective generation of
hydroxy radicals. This reaction, in turn, leads to translocation
and amplification of specific genes, proto-oncogenes, or a mutation
in tumor suppressor genes, that translate to a distinct expression
of the properties of the cells bearing such altered genes (Williams
and Weisburger 1991; Ronai 1992; Miller 1994).
property to bind to DNA is the basis for the development of specific
rapid, efficient, and economical in vitro bioassays, such as a
mutation assay in prokaryotic or eukaryotic cell systems. Advantage
can also be taken of the presence of enzyme systems performing
DNA repair; these can provide effective complementary test systems
to outline the possible DNA-reactivity of chemicals (Weisburger
and Williams 1991; Weisburger 1994). Moreover, the 32P-postlabeling
procedure of K. Randerath and colleagues (1989) yields information
about the presence of reactive carcinogenDNA adducts.
a chemical displays properties of reacting with DNA and inducing
mutations and DNA repair in a number of cell systems, it can be
considered DNA-reactive or genotoxic. Most human carcinogens are
genotoxic. Other agents, such as the hormonoïd diethylstilbestrol
(DES) or the hormone estradiol, may give rise to genotoxic products
(Liehr 1990). The fact that a given product is genotoxic may signal
that, with sufficient dosage and chronicity of exposure, it poses
a cancer risk to humans.
oxygen, hydroxy radicals, or hydrogen peroxide can be generated
in metabolic processes. On the other hand, there are endogenous
defense mechanisms, such as catalase-destroying hydrogen peroxide
or superoxide dismutase or glutathione peroxidase (in turn, involving
glutathione [GSH] or sulfhydryl amino acids), that neutralize
reactive oxygen. Exogenous antioxidants (such as those in vegetables,
tomatoes, and tea), carotene, vitamins C and E, selenium, and
sources of GSH aid in the disposition of reactive species (Harris
1991; Olson and Kobayashi 1992; Packer 1992; Sai et al. 1992).
consequences of DNAcarcinogen interactions are beginning
to be explored in terms of proto-oncogene oncogene codon
translation and amplification that can be measured by highly specific
and sensitive polymerase chain reaction techniques (Brugge et
al. 1991). Errors may be introduced into DNA during biosynthesis
(Echols and Goodman 1991). Mutational events in tumor-suppressor
genes also yield abnormal DNA, which is of growing interest (Brugge
et al. 1991). The rate of cell duplication is important in generating
abnormal DNA. A rapid rate decreases the chances of successful
repair and is a reason that growing organisms or proliferating
tissues are often more sensitive to carcinogens (Cohen and Ellwein
1992). For example, radiation exposure during the Hiroshima atom-bomb
explosion caused a fourfold higher breast-cancer incidence in
the 10- to 15-year-old age group (with mammary gland cells in
rapid DNA synthesis and mitosis) than in younger or older groups
(Land et al. 1980).
carcinogens modify not only DNA but also proteins. Both types
of interactions can serve as sensitive markers for qualitative
and quantitative analysis, especially the readily measured hemoglobin
adducts (Brugge et al. 1991).
carcinogens and promoters cannot cause cancer without an antecedent
mutational event and cell change. For example, mice with mammary
tumor virus (MTV) develop mammary tumors proportional to the level
of estrogen administered, but those without MTV do not, no matter
what dose of estrogen is used (Highman, Norvell, and Shellenberg
1977). The action of promoters requires their presence at relatively
high levels for a long time, and that action is often tissue specific.
For example, bile acids are promoters of colon cancer, and very
high dosages of sodium saccharin act as a promoter for cancer
of the urinary bladder. The interruption of gap junctions and
intercellular communication plays a key role in promotion, and
promoters can be detected through this characteristic (Yamasaki
1990; Trosko and Goodman 1994).
promoters are nongenotoxic substances, linear extrapolation for
health-risk assessment seems unrealistic and, actually, scientifically
improper (Kroes 1987; Williams and Weisburger 1991; Weisburger
1994). In order to better assess risk using appropriate epidemiological
and biostatistical approaches, new procedures to define the mode
of action of epigenetic (nongenotoxic) agents are being developed.
Most likely, dose-response studies will yield a typical pharmacological
S-shape response, with a definite no-effect level. This is especially
important when fundamental insights into the properties of carcinogens
and promoters are applied to the area of nutritional mechanisms
in cancer causation.
chemical carcinogens can be classified into two main groups: (1)
DNA-reactive substances that are genotoxic in appropriate test
systems and (2) epigenetic (nongenotoxic) agents operating by
producing some other specific biological effect as the basis for
their carcinogenicity. Genotoxic carcinogens alter DNA, are mutagenic,
and lead to transformed cells with neoplastic attributes. Nongenotoxic
carcinogens involve other mechanisms, such as cytotoxicity, chronic
tissue injury, hormonal imbalances, immunologic effects, or promotional
extensive reviews addressing diet-related neoplasms have been
published in the past decades. In the Western world, cancers associated
with nutrition account for a substantial percentage about
35 to 45 percent of premature deaths. In this section,
characteristics of the different types of cancer, their established
or suggested relationships with dietary factors, and their presumed
mechanisms of action are described. In addition, possible measures
to prevent or decrease the risk of developing the disease are
Pharynx, and Esophagus
of the oral cavity and pharynx account for approximately 400,000
new cancer cases each year in the world. High incidences are noted
in France, Switzerland, northern Italy, Central and South America,
parts of Pakistan, and India. These cancers occur much more frequently
in males than females, and differences between high- and low-incidence
areas may be as much as 20-fold.
rates of cancer of the esophagus are found in the so-called Asian
esophageal cancer belt, which extends from eastern Iran, along
the Caspian Sea, through Turkmenistan, Tajikistan, Uzbekistan,
and Kyrgyzstan, and into parts of China. Except for the high-incidence
areas, where the sex ratio almost equals 1:1, males show predominantly
higher incidences. World incidence rates differ more than 100-fold,
and globally more than 300,000 new cases occur each year.
of the esophagus is especially common among individuals who chew
or smoke tobacco and drink alcoholic beverages. Consumption of
alcohol alone especially hard liquor seems to be
a risk factor as well (Seitz and Simanowski 1991; Castelleto et
al. 1994). Smoking and alcohol consumption have a synergistic
effect on carcinogenesis in the upper alimentary tract. In Asian
and African populations, dietary deficiencies of zinc, riboflavin,
vitamins A and C, manganese, and molybdenum may play a role, as
well as mycotoxins, bracken fern, opium pyrolysates, and betel
quids. The consumption of salted fish is an established risk factor
in southern Chinese populations, probably because of the formation
of specific nitrosamines (Craddock 1992; Zeng et al. 1993). Consumption
of very hot beverages, along with the use of substances that irritate
the oral cavity, pharynx, and esophagus, all of which lead to
increased cell proliferation, may enhance the incidence of neoplasia.
substantial differences in incidence between high- and low-risk
areas indicate that there exists considerable potential for prevention.
Frequent consumption of fresh fruits and vegetables, as well as
tea, appears to be associated with a lower risk for these types
of cancer. The potential reduction has been estimated to be around
75 percent (Negri et al. 1993). Preventive measures involve the
avoidance of tobacco and very hot beverages, along with moderate
alcohol use and a well-balanced diet that includes a sizable increase
in the regular consumption of vegetables and fruits (Block, Patterson,
and Subar 1992).
the 1980s, gastric cancer was still considered to be the most
common cancer in the world. Indeed, with almost 700,000 new cases
per year, it represented approximately 10 percent of all cancers.
Differences between high- and low-incidence areas vary by 40-fold.
However, a large decrease in rates has occurred in most populations
during the last four to five decades, indicating a reduction in
exposure to tissue-specific carcinogens and/or the introduction
of a protective agent.
suffer approximately twice the incidence and mortality of females,
although the sex ratio is not constant by age group. The sex ratio
equals 1:1 in people under the age of 30, but the disease is rare
in this group. High-risk populations usually consume considerable
quantities of pickled vegetables, dried salted fish, smoked fish,
and other smoked, salted, and dried foods. Consumption of certain
salted and pickled fish has yielded high levels of mutagenicity
and evidence of carcinogenicity. One of the mutagens present has
been identified as 2-chloro-4-methylthiobutanoic acid. This finding
was totally unexpected, because in the past, nitroso compounds
were associated with stomach cancer (Chen et al. 1995).
contrast, a negative association has been established between
mutagenicity and the regular intake of green leafy vegetables
and citrus fruits. Laboratory experiments show that vitamins C
and E block the formation of mutagens when fish is treated with
nitrite, mimicking pickling (Weisburger 1991).
with Helicobacter pylori and associated conditions, such
as atrophic gastritis, ulceration, partial gastrectomy, bile acid
reflux, and pernicious anemia, are additional risk factors. Several
of these increase cell-duplication rates, rendering the gastric
cells more sensitive to genotoxic carcinogens.
high level of consumption of salted, pickled, or smoked food was
once customary in the Western world. However, better access to
home refrigeration, improved and cheaper transport and,
therefore, increased availability of fresh fruit and vegetables
seems to correlate well with the decline of this type of cancer
(Howson, Hiyama, and Wynder 1986; Weisburger 1991). The relevant
mechanism begins with the development of atrophic gastritis due
to the cytotoxic activity of salt and vitamin deficiencies. The
consequent decrease in gastric acidity permits uninhibited bacterial
growth. Bacterial growth then converts dietary nitrates to nitrites,
which are further metabolized into carcinogenic nitroso derivatives
or reactive carcinogens (Correa 1992; Chen et al. 1995). Because
vitamins C and E are known to be effective inhibitors of nitrosation,
it is plausible that an increased intake of these vitamins, or
foods containing them, should reduce the risk of gastric cancer
by inhibiting nitrosation.
measures are the introduction of food refrigeration, the reduction
of salt and pickled food intake, and an increased consumption
of fruits and vegetables. Especially in areas with high prevailing
environmental nitrate levels, vitamin C and vitamin E supplementation
may be useful for preventing formation of nitrite-derived reactive
carcinogens and reducing nitrite produced by conversion of nitrate
in the mouth. The preventive potential has been estimated to be
about 50 percent but may well be much higher.
600,000 new cases of colorectal cancer are diagnosed worldwide
each year. It is particularly a disease of the developed countries,
which to some extent reflects increasing life expectancy. Differences
in incidence may be 60-fold. The lowest incidence rates are found
in Africa and Asia, although incidences are rising, especially
in areas where the risk was formerly low, as in Japan. Colon cancer
affects the sexes equally. The distribution for rectal cancer
is similar to that for colon cancer. Incidences are usually lower,
and there is a malefemale ratio of 1.5:2.0, especially in
evidence suggests that (Western) lifestyle is an important determinant
of risk for colorectal cancer: Migrants to Western countries acquire
a higher risk for the disease in the first generation, and Mormons
and Seventh Day Adventists enjoy a low risk. Familial polyposis,
ulcerative colitis, and Crohns disease are identified risk
factors for colon cancer, but these are uncommon conditions.
high in fats and low in fiber and vegetables are associated with
increased risk for colon cancer. A fatfiber interaction
has been suggested, and the type of fiber is important as well
(Kroes, Beems, and Bosland 1986; Weisburger 1992). It is interesting
to note that some polyunsaturated fats found in fish and some
vegetable seeds inhibit colon cancer formation. Moreover, olive
oil intake, as in the Mediterranean countries, does not increase
the risk of the nutritionally linked cancers or heart disease,
a fact also documented in animal models (Reddy 1992). An inverse
relationship has also been found for the consumption of fruits
and vegetables, as well as for calcium intake and regular exercise;
the same is true of coffee and tea for colon and rectal cancer,
respectively (Baron, Gerhardson de Verdier, and Ekbom 1994).
and epidemiological research has revealed that bile acids promote
cancer formation (Reddy 1992). The case is similar with alcohol,
especially for rectal cancer, perhaps accounting for the higher
male-to-female ratio (Seitz and Simanowski 1991). Recent surveys
also indicate that intake of heavily fried or grilled meat and
gravies is positively related to colorectal cancer, suggesting
that chemicals produced during the frying or grilling of meats
(heterocyclic aromatic amines) may be the initiating carcinogens,
particularly for breast, colon, and, perhaps, prostate and pancreatic
cancer (Adamson et al. 1995).
mechanisms in colon cancer development are the increased bile
acid concentrations in individuals consuming high levels of many
types of dietary fat. The higher concentrations of bile acids
may lead to increased turnover of the epithelial cells of the
intestines, reflecting increased risk of carcinogenDNA adducts
to cause translocation and amplification of abnormal genes or
mutated tumor-suppressor genes. This phenomenon is inhibited by
increased dietary calcium. The toxicity of bile acids is also
reduced at a lower luminal pH. Alcohol may act as a promoter at
the level of the rectum, and its metabolite acetaldehyde, which
occurs at higher concentration in the rectum, may induce cytotoxicity,
thus leading to increased cell proliferation and turnover.
fibers at adequate concentrations are thought to dilute and particularly
bind the genotoxic agents present in the gut, decreasing fecal
mutagenic activity. Fibers also modify the metabolic activity
of the gut flora and lower luminal pH. Wheat bran increases the
bulk of the gut contents, thus diluting bile acids and decreasing
their adverse effect on the mucosal lining of the bowel (Reddy
1992). Regular physical exercise also lowers transit time of the
luminal contents and appears to decrease risk of colorectal cancer.
Fruits and vegetables generally reduce cancer risk through several
mechanisms (Block et al. 1992). They provide fibers and antioxidants
that can detoxify active genotoxins and also contain a number
of chemopreventive agents, such as indole derivatives, that are
anticarcinogenic. Tea antagonizes the effect of heterocyclic amines
present in fried or broiled meats, which are thought to be carcinogens
for the colon.
reduction of colorectal cancers through prevention has been estimated
at 35 percent, mainly of distal colon cancer and rectal cancer.
The risk factors for proximal colon cancer are not well known,
although general recommendations for lower risk may apply to colorectal
cancer overall. This would involve a low fat intake (20 to 25
percent of calories), use of monounsaturated fats such as olive
oil, an adequate fiber intake (25 to 30 g/day), moderate alcohol
consumption (an average of 2 drinks/day), fish 2 to 3 times a
week, an increased calcium (lowfat milk or yoghurt) intake (1,200
to 1,500 mg), increased consumption of vegetables and fruits (ideally
5 to 9 servings/day), tea (4 to 5 cups per day), and regular exercise.
cancer is the third most common cancer in the world; every year
about 600,000 new cases are detected, which is about 9 percent
of the global cancer burden. It is important to distinguish between
premenopausal breast cancer, in which diet plays a minor role
(except for some protection afforded by consumption of vegetables
and fruits, including soy products), and peri- and postmenopausal
disease, in which diet may exert important controlling effects.
Breast cancer occurs almost exclusively in women, and in high-risk
areas (North America and western Europe), the incidence is about
4 to 30 times higher than in low-risk areas like China, Japan,
and Sri Lanka, although there has been an appreciable increase
in Japan during the last decade the result of a westernization
of dietary customs.
risk factors for breast cancer are a family history of the disease,
a low number of offspring, avoidance of breast feeding of infants,
a late age at first pregnancy, an early menarche, a late age at
menopause, and high consumption of fats (about 30 to 40 percent
of calories) and, possibly, alcohol. During the last decade, increasing
evidence has been adduced indicating that there is an inverse
relationship between breast cancer and increased intake of vegetables
and fruits. Food antioxidants (such as selenium, retinoids, and
polyphenols), as well as bran cereal fibers, have been suggested
as inhibiting factors. Obviously, endocrine factors are important
in breast cancer development. Fat may increase breast cancer risk
by its control of hormonal regulation. In addition, high fat and
high energy intakes, coupled with lack of exercise, lead to obesity,
a possible contributory factor in breast cancer in postmenopausal
however, seems inversely related to the risk of breast cancer
in premenopausal women. F. De Waard has developed a unifying concept
on the etiology of breast cancer, which focuses on the events
that occur during adolescence and early reproductive ages (see
Weisburger and Kroes 1994). He has suggested that preneoplastic
lesions develop at early ages, from 15 years onward. Several factors,
such as nutritional status, high fat intake, low consumption of
protective vegetables, fruit, and fibers, along with reproductive
life, interact in inducing a long period of cell proliferation
without sufficient differentiation in the breast.
the other hand, early pregnancy and long-term lactation will raise
the differentiation of cells, thus limiting the proliferation
of less differentiated cells, the latter being more vulnerable
to genotoxic attack. Fat may also influence the immune system,
increase prostaglandin synthesis, and increase membrane fluidity,
all phenomena bearing on the promotion and growth of neoplastic
cells. Therefore, the appropriate dietary preventive measures
are avoidance of heavily fried or broiled meats, a limited fat
intake (possibly as low as 20 to 25 percent of total calories),
preference for monounsaturated fats such as olive oil, an increased
intake of vegetables, fruits, tea, and insoluble bran cereal fiber,
and an energy intake that balances energy need with the avoidance
In this latter connection, an increase of exercise
has been shown to lower risk and assist in weight control.
cancer strikes approximately 150,000 women in the world each year,
with tenfold differences in incidence, depending on location.
High incidences are found in Argentina, the United States, Canada,
and western Europe, whereas a low incidence has been noted in
Asian populations. Identified risk factors are, in particular,
endogenous estrogen and higher amounts of exogenous hormones employed
for the management of menopausal and postmenopausal symptoms.
Obesity and fat consumption are also associated with increased
risk. Estrogen therapy, as practiced for postmenopausal symptoms
between 1960 and 1975, has been documented as a causal element
for endometrial cancer, most probably because it was given in
relatively large dosages and was not balanced by progesterone.
If the action of limited amounts of estrogens is balanced by progesterone,
cancer risk is decreased.
role of obesity or high fat consumption in endometrial cancer
may be explained by the fact that fat cells produce estrogen,
which itself is a key effector in neoplastic development through
its specific effect on endometrial tissue and on overall endocrine
balances. As dietary factors may be responsible for an appreciable
percentage of cases, limited fat intake and avoidance of excessive
energy intake are suggested preventive measures. Regular exercise,
likewise, constitutes a protective element.
cancer is common in western Europe and North America, whereas
it has a low frequency in Indian, Japanese, and other Asian populations.
Unlike that of many other types of cancer, the incidence of ovarian
cancer in the Western world has remained rather constant over
time. The risk factors for ovarian cancer are the same as those
for breast and uterine cancer, meaning a positive association
with endocrine factors and dietary fat intake and a negative association
with parity and elements that suppress ovulation. Thus, oral contraceptives
may substantially reduce the risk of ovarian cancer. Limited fat
intake (perhaps 20 to 25 percent of calories or less) and consumption
of vegetables and fruits are suggested as preventive measures.
cancer occurs more frequently in developed countries, comprising
approximately 3 percent of the worldwide cancer burden. The disease,
however, is increasing in incidence over time and has a very high
mortality rate because of late diagnosis and, thus, has low success
in therapy. Every year, approximately 140,000 new cases are diagnosed.
In the last 40 years, pancreatic cancer incidence has doubled
in western Europe and quadrupled in Japan (Hirayama 1989).
smoking has been implicated as a major risk factor, which can
explain the increasing incidence, especially in those countries
where the pancreatic cancer incidence is still relatively low.
Convincing evidence also exists from experimental animal research
that carcinogens from tobacco and a high fat intake are positively
related, whereas caloric restriction, selenium, and retinoids
are inversely related. Of interest is the role shown by trypsin
inhibitors in pancreatic carcinogenesis in experimental animals.
These trypsin inhibitors do reduce trypsin levels in the gut,
stimulating the secretion of cholecystokinin (CCK) as a feedback
phenomenon. CCK stimulates pancreatic growth, thus promoting pancreatic
carcinogenesis. Trypsin inhibitors, present in soy proteins, are
heat labile. Soy proteins are high-quality foods, but they should
be incorporated in foods and cooked (Watanapa and Williamson 1993).
research reveals a positive relationship for dietary fat, fried
or grilled meats, and, possibly, alcohol or cholesterol, whereas
an inverse relationship has been observed for caloric restriction,
omega-3 fatty acids (fish and some seeds like flax seed), and
fresh fruits and vegetables (Bueno de Mesquita 1992). Preventive
potential has been estimated to be 70 percent. Cessation of tobacco
smoking, moderate alcohol use, low fat consumption, and increased
intake of vegetables and fruits are the main measures for prevention.
This is particularly important because of its grim prognosis.
Thus, control is optimal through prevention by lifestyle adjustment.
cancer is the fifth most common cancer among males, and especially
predominant in older males. Approximately 240,000 new cases of
clinical invasive prostate cancer occur each year, and high-incidence
areas are northwestern Europe and North America; in the latter,
African-Americans have a particularly high incidence. Low rates
are found in India, China, and Japan. There exists a 50-fold difference
between populations with the highest rates of prostate cancer
(blacks in Detroit, Michigan) and populations with the lowest
incidence (Asians in Shanghai, China) (Nomura and Kolonel 1991).
Endocrine factors may play a role in prostate carcinogenesis,
but geographic pathology indicates that dietary factors are probably
also important. Populations with a tradition of high fat and high
protein intake have a high risk. The diet controls the endocrine
associations have been suggested for vitamin A, beta-carotene,
vegetables, fruits, selenium, fish, and fiber. Sugar and egg consumption
are weakly positive (Bosland 1986). Genetic, sexual, and dietary
factors seem to play a role in prostate carcinogenesis, indicating
a multifactorial process. As is true for other endocrine-controlled
neoplasms, a dietary regime low in fat and rich in vegetables
and fruits, coupled with regular exercise, may contribute to lower
risk irrespective of sexual and genetic elements (Wynder, Rose,
and Cohen 1994).
is surprising to note that more and more data have become available
to indicate that lung cancer is influenced by dietary factors.
Clearly, the disease is associated with cigarette smoking, but
since E. Bjelke (1975) and G. Kvale, Bjelke, and J. J. Gart (1983)
found in metabolic epidemiological studies that smokers with a
higher level of vitamin A in plasma had a lower risk of lung cancer,
more attention has been given to dietary factors (Ziegler et al.
1992; Le Marchand et al. 1993). Also, for humans, an inverse relationship
between lung cancer development and fruit and vegetable intake
has been observed, whereas other data suggest a positive relationship
between dietary fat intake and lung cancer (Wynder, Taioli, and
Fujita 1992). In addition, the antioxidants in tea may provide
a protective effect. Currently, there are more smokers in Japan
than in the United States or the United Kingdom, but the incidence
of lung cancer is lower in Japan. It has been suggested that the
Japanese have a lower risk because of a lower total fat intake
and more frequent intake of fish, soy foods, and tea.
although the first recommendation should be to quit smoking
or, in fact, never to start an increased intake of fruits
and vegetables (especially those containing retinoids) and also
of fish, soy-derived foods, and tea, coupled with a lowered fat
consumption, may serve as preventive measures and could be particularly
appropriate for ex-smokers.
Contaminants, and Natural Toxins
decades, the possibility of cancer risks from food additives and
contaminants has been widely publicized, especially in the developed
countries, where there has been an increase in the addition of
various substances to food for preservative and commercial purposes.
Thus, food additives and contaminants are viewed by many as a
major threat to human health and one that may cause cancer.
Scientific information, however, shows exactly the opposite: Food
additives are safer than everyday traditional nutrients, and the
same is true for most contaminants (Miller 1992; Weisburger 1994;
Weisburger and Kroes 1994).
opposite perceptions may be explained by the misinterpretation
of epidemiological reports in the late sixties, when the term
"environmental" (as in "environmental factors")
was used to account for major causes of cancer. In fact, what
was meant was as lifestyle factors, but the general public (and
especially the news media) misinterpreted this to mean synthetic
chemicals, including food additives and contaminants.
addition, several episodes have enhanced this misconception, as,
for example, when certain food additives (that is, some food dyes
in Western countries and the preservative AF-2 in Japan) were
first permitted and later correctly withdrawn because of their
demonstrated carcinogenicity in animals (Sugimura 1992). Regulatory
action, especially in the United States, aimed at such chemicals
as sodium saccharin and cyclamate, further deepened public suspicion.
Yet the latter substances are now considered safe, at least at
the normal intake levels that humans experience. In fact, certain
substances with antioxidant properties, which are used as food
additives, are even believed to reduce cancer risk. Thus, Wynder
and Gori (1977), as well as Doll and Peto (1981), have estimated
that cancer mortality from food additives ranges from 5
to +2 percent, the negative score specifically addressing the
beneficial aspects of antioxidants used in foods.
are used to improve the stability and storability of foods, as
well as their flavor, consistency, appearance, texture, and nutritional
quality. In certain cases, they are a necessity, such as in the
case of preservatives that prevent food-borne microbial infections.
And in any event, the risk of disease from food additives today
is minimal, because efficient and effective control practices
are available and applied to ensure safety.
of human-made origin are, like food additives, extensively tested
in animals before use, and the levels permissible in crops are
well controlled internationally. Thus, the margin of safety for
pesticide residues in food runs usually between 1,000 and several
millions, whereas for several macro- and micronutrients, the margin
of safety is as small as 2 to 10 (Kroes in press). In fact, B.
N. Ames and colleagues (1990, 1992) have listed a number of naturally
occurring substances in food that, because of uncontrolled exposure,
provide much more concern for cancer risk than synthetic chemicals.
About half of such natural chemicals that have undergone standard
high-dose animal cancer tests proved to be animal carcinogens,
such as the mold-generated hepatic carcinogen, aflatoxin (International
Agency for Research on Cancer 1993b). In addition, as noted, powerful
carcinogens are formed during the cooking of meats and during
the salting and pickling of some fish and meats.
natural defenses of humans, however, may make them capable of
detoxifying low doses of most toxins, whether synthetic or natural.
For example, despite a continuing low-level presence of aflatoxin
B1 in some foods, the incidence of primary liver cancer in the
United States and Europe is not significant. Yet it is quite high
in parts of Africa and China, where the dietary contamination
is appreciable and where more people carry the hepatitis B antigen,
potentiating the action.
in light of the foregoing, it seems relevant to invest more research
capacity in the identification of possible risks and benefits
of naturally occurring substances. This is especially true because
many are also known to possess anticarcinogenic properties
properties that are believed to be the reason for the inverse
relationship between several cancers (and heart diseases) and
the regular intake of vegetables, fruits, and tea.
preparation has entailed cancer risk in the past and will continue
to do so in the future. Preservation methods, for example, such
as the use of salt or pickling solutions, are associated with
a high risk of stomach cancer and in some areas, such as China,
with cancer of the esophagus. Salted fish causes nasopharyngeal
cancer, and salt and high nitrate (saltpeter) concentrations in
several meat products can lead to the formation of carcinogenic
nitroso compounds, or of the chloro analog of methionine, either
in the food itself or in the stomach. Salt is cytotoxic to the
gastric mucosa, translated by increased cell duplication rates
and, in turn, to more efficient carcinogenesis. Some salted, pickled
foods contain direct-acting mutagens thought to be gastric carcinogens
(Weisburger 1992; Chen et al. 1995). Salt, not balanced by potassium
from vegetables, and calcium from dairy products is also a cause
of hypertension and stroke. In Japan (Sugimura 1992) and in Belgium
(Joossens, Hill, and Geboers 1985), formal plans were introduced
to lower salt intake by people.
meats or fish have at their surface polycyclic aromatic hydrocarbons
that are established animal carcinogens. But it is important to
note that the ordinary cooking (broiling, frying) of meats or
fish can produce powerful mutagens, consisting of about 19 heterocyclic
amines (also established animal carcinogens) for specific target
organs. They are believed to be the key carcinogens causing increased
incidence of several human cancers, such as those in the breast,
prostate, colon, and pancreas. Certainly it has been shown that
those who generally eat well-done meat increase their risk of
colon cancer. The formation of heterocyclic amines during the
heating of meats can be reduced by preliminary brief microwave
cooking (removing essential creatinine) or by the addition of
antioxidants, soy protein, or the indole amino acids tryptophan
and proline, which all compete with creatinine in the so-called
Maillard reaction, forming heterocyclic amines (Weisburger and
An Integrated Approach
substantial amount of solid epidemiological and experimental evidence
indicates that the majority of human cancers, and indeed many
other chronic diseases, such as heart disease, hypertension, and
adult-onset diabetes, are largely preventable. Complex causes
have been, or are being, identified, and the underlying mechanisms
elucidated. Control of many major diseases of humankind in the
past, such as scurvy, pellagra, rickets, polio, smallpox, rabies,
and tuberculosis, has been achieved by prevention strategies.
Therefore, a clear and balanced prevention approach to the effective
control of human cancers (and other chronic illnesses, such as
cardiovascular diseases) is likely to be successful as well.
in the past two decades with other chronic ailments, such as cardiovascular
diseases, indicates that the application of sometimes even simple
measures can have a considerable impact on their outcome (Meyskens
1992). In fact, cancer prevention runs a decade behind the scientific
understanding of the disease, as a number of lifestyle-associated
factors contributing significantly to cancer risk are well known.
Tobacco and nutritional traditions, in particular, and
to a lesser extent radiation, some chemicals, and certain
viruses, are documented, avoidable risk factors.
and Gori (1977), Doll and Peto (1981), and J. H. Weisburger (1992)
have contributed substantially to the evidence of preventive potential
for many types of cancer through their listing and documentation
of avoidable risks of cancer. Unfortunately, not only are such
concrete factors as tobacco, diet, lifestyle, and radiation contributing
to the cancer burden, but poverty does as well, because the need
for essential lifestyle changes has been difficult to communicate
effectively to the lower socioeconomic groups (Tomatis 1992).
prevention programs should be based on reliable epidemiological
and laboratory evidence, and on ethical and moral responsibility,
and ought to specify clearly achievable outcomes in mortality
and morbidity reduction. Moreover, they should be integrated with
other chronic-disease-prevention programs. The multifactorial
elements, such as nutritional traditions, sedentary habits, and
tobacco use, which represent a risk for diseases like coronary
heart disease, hypertension, stroke, obesity, and many neoplastic
diseases, have to do with lifestyle. In fact, these factors are
the major causes and modulators of these diseases.
IV.F.2.1 depicts several realistic actions to take in order to
lower the risk for certain common diseases. In the Western world,
nutritional traditions with a relatively high fat intake (38 to
46 percent of energy intake), low cereal fiber, and low vegetable
and fruit consumption, along with a lack of regular physical exercise,
are associated with high incidence and high cost of the management
of chronic diseases, such as cardiovascular diseases, diabetes,
obesity, and specific types of cancer. In the Far East and in
Central and South America, prevailing illnesses seem to stem from
other nutritional traditions, such as the use of highly salted
and pickled foods and a limited variety in diet. Currently, the
changing nutritional habits in Japan to a Western style parallel
an increase in heart disease and the kind of cancers common in
the Western world. This provides strong additional support for
the thesis that dietary customs and specific chronic diseases
knowledge enables us to recommend a healthy dietary regime in
which fats should be replaced by complex carbohydrates (starches)
that should provide around 70 to 75 percent of the calories needed
for energy. Furthermore, a protein intake of between 10 to 15
percent from animal and vegetable sources (more in growing young
children, less in older individuals) is recommended. Fats should
consist of a fair proportion of monounsaturated oils, such as
olive oil or canola oil, and omega-3 fatty acids as found in fish
and some seeds, like flaxseed.
salting, pickling, and smoking of food as a mode of preservation
should, ideally, be abandoned, and foods should be preserved by
refrigeration or freezing, or eaten fresh. Caloric intake should
be equal to energy need as an effective means to avoid obesity.
The intake of fruits and vegetables should be increased considerably
ideally to more than 5 servings per day. Bran cereal fibers,
or breads baked with high-fiber flour, increase stool bulk, avoid
constipation, and lower the risk of colon and breast cancer and
perhaps other diseases. A low intake of total salt, 3g/day or
less, and adequate calcium (1,000 to 1,500 mg) and magnesium (300
mg) are beneficial; less is needed on a low-protein diet. Moderate,
but regular, physical exercise is also part of a healthy lifestyle.
Alcohol consumption ought to be moderate, but adequate fluid intake
(2 to 2.5 liters daily for adults) is essential for maintenance
of physiologic functions. Tea, an extract of the plant Camellia
sinensis, is, after water, the second-most-used beverage in
the world. Because it is made with boiling water, it is sterile
even if the water source is not pure. Tea is rich in fluoride,
potassium, and especially in antioxidants that lower the risk
of coronary heart disease and many types of cancer (Weisburger
1996; Weisburger and Comer this volume).
recommendations will contribute to better health by lowering the
risk for major chronic diseases. In education and in medical practice,
emphasis must be placed on the importance and the efficacy of
available methods for chronic disease prevention. One task of
practicing nutritionists and home economists ought to be that
of devising practical recipes for cooks to incorporate the essence
of a new, health-promoting lifestyle that the public will find
attractive. Indeed, it is essential to devise appealing dishes
and drinks for the public that are also designed for chronic disease
prevention, and when such preventive approaches are successful,
health-care costs should decrease. Good health into old age is
not only a desirable goal for the individual but may have major
economic savings for the population at large. To repeat our earlier
quotation, the ultimate goal, as expressed by Ernst Wynder, should
be "to die young, as late in life as possible" (Wynder
et al. 1994).
J. H. Weisburger
in Weisburgers laboratory is supported by USPHS-NIH grants
and contracts from the National Cancer Institute, grants from
the Tea Trade Health Research Association and the American Cancer
Society, and gifts from Texaco, Inc., and the Friends Against
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