Several 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 discussed.1
Oral Cavity, Pharynx, and Esophagus
Cancers 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.
High-incidence 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.
Cancer 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.
However, 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).
Stomach
In 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 40fold. 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.
Males 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).
By 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).
Infection 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.
A 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.
Preventive 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.
Colon and Rectum
Approximately 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 male-female ratio of 1.5:2.0, especially in high-incidence areas.
Epidemiological 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 Crohn’s disease are identified risk factors for colon cancer, but these are uncommon conditions.
Diets high in fats and low in fiber and vegetables are associated with increased risk for colon cancer. A fat-fiber 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).
Experimental 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).
Suggested 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 carcino-gen-DNA 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.
Dietary 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.
Potential 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.
Breast
Breast 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.
Important 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 women.
Obesity, 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.
On 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 of obesity. In this latter connection, an increase of exercise has been shown to lower risk and assist in weight control.
Endometrium and Ovary
Endometrial 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.
The 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.
Ovarian 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.
Pancreas
Pancreatic 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).
Tobacco 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 cholecys-tokinin (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).
Epidemiological 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.
Prostate
Prostate 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 balance.
Negative 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).
Lung
It 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.
Therefore, 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.
Food Additives, Contaminants, and Natural Toxins
For 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;Weis-burger 1994;Weisburger and Kroes 1994).
Such 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.
In 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.
Additives 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.
Contaminants 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, afla-toxin (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.
The 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.
Certainly, 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.
Food 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 (Weis-burger 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.
Charcoal-broiled 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 Kroes 1994).
World History
