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Extending the prudent diet to cancer prevention
PREVENTIVE
9, 297-304
MEDICINE
Extending JOHN
(1980)
the Prudent
H. WEISBURGER,$*~ AND
Diet to Cancer D. MARK HEGSTED,? BARRY LEWIS*
Prevention’ GIO B. GORI,$
*Department of Chemicul Pathology and Metabolic Disorders, St. Thomas’s Hospital Medicul School, London, Englund, tHuman Nutrition Center. U.S. Department of Agriculture, ZDivision of Comer Cuuse and Prevention. National Cuncer Institute, and fjNuy10r Dana Institute. American Health Foundation, Valhalla, New York 10595 The basis for the formulation of a “prudent diet” is briefly reviewed. Epidemiologic, clinical, and experimental studies related to cancer, coronary heart disease, obesity, diabetes, and hypertension support the position that it is prudent to limit consumption of fats, cholesterol, sugar, and salt, and increase the consumption of fruit, vegetables, and cereals. It is also prudent to limit consumption of products suspected to cause or promote cancer.
Many experts in the field of atherosclerosis have recommended a modification of the typical Western diet so as to reduce the prevalence of hyperlipidemia. A measure of public acceptance of this recommendation may have contributed to the recent reduction in the death rate from myocardial infarction (5). In many countries there is a parallel between the mortality from coronary heart disease and several types of cancer, mainly those in the colon, pancreas, and the endocrine-sensitive organs such as breast, ovary, endometrium, and prostate (18, 23, 49). Thus, the question arises whether diet modification could also contribute to a reduction of the incidence of these numerically important cancers in man. THE PRUDENT DIET AND PREVENTION OF ATHEROSCLEROSIS The design of a diet for reduction of CHD risk has evolved considerably in the two decades since the term “prudent diet” was coined (6). Few of the underlying principles have been altered, but quantitative recommendations have been modified. When it was observed that substitution of saturated fatty acids (SFA) by polyunsaturated fatty acids (PUFA) led to a fall in plasma cholesterol concentration, recommendations were made for a diet little changed in total fat intake but with a marked increase in PUFA:SFA ratio (P:S ratio). Over the years a few trends have been evident (1, 11): (a) Increasing emphasis on reducing dietary cholesterol. Though the mean effect of cholesterol intake on plasma cholesterol level is modest, some persons are remarkably sensitive to this effect because their homeostatic response is apparently relatively inefficient. (b) A reemphasis on reduction of fat intake with moderate increase in P:S ratio to achieve the desired fall in plasma cholesterol level. This was based on a general view that a diet for widespread use should resemble the habitual diets of I Presented at the American Health FoundatiomDeutsche Krebshilfe Conference on the Primary Prevention of Cancer: Assessment of Risk Factors and Future Directions, N.Y., N.Y., June 7-8, 1979. 2 To whom requests for reprints should be sent. 297 0091-7435/80/020297-08$0200/0 Copyright 0 19l?Jl by Academic Press. Inc. AU rights of reproduction in any form reserved.
298
WEISBURGER
ET AL.
healthy populations rather than being novel and seemingly artificial. In addition, the notion that low fat intakes would be unpalatable to Western taste was progressively discounted. The possibility that diets lower in total fat, but with high P:S ratio, might increase the risk of malignant disease was not borne out by an extensive study of pooled data (13a). Increased biliary lithogenicity has only been observed experimentally as P:S ratios far beyond those recommended for population use. (c) The recognition that correction of obesity or moderate weight reduction leads to moderate but variable reduction in plasma lipid levels, an effect additive with that of qualitative dietary change. (d) Acceptance by many of the role of reduced sodium intake in lowering mildly elevated blood pressure levels. (e) The evidence that low-density and high-density lipoproteins of plasma (LDL and HDL) differ in their physiological roles and in their relationship to coronary heart disease risk (12, 15, 16, 21, 27, 37, 40, 41, 44). A prudent diet should, therefore, lead to an optimal lipoprotein distribution as well as reducing total plasma cholesterol concentration. Two newer areas of research show the importance of other dietary constituents in altering plasma lipid and lipoprotein levels. Changes in the fiber intake have a potentially desirable influence on lipoprotein metabolism, colonic function, carbohydrate tolerance, and biliary lithogenesis (24, 26). Also, altered patterns of protein intake (substitution of vegetable protein for proteins of animal sources) reduce plasma cholesterol levels-a small effect has been well documented (8). These lead to the possibility that a prudent diet design incorporating these additional features might have far more substantial effects on lipoprotein levels and on CHD risk than the traditionally recommended diet. Such a combined approach would be necessary if the present mean plasma cholesterol level in U.S. adults, about 220 mgidl, were to be reduced to a recently recommended optimum of 160 -+ 30 mgidl (1). The effects of changing the nature and amount of dietary fat may be predicted from the formulas of McGandy and Hegsted (28) and Keys et al. (25). Reduction of fat intake from 40 to 30% of food energy, with a change of P:S ratio from 0.4 to 1, would decrease plasma cholesterol by 20 mgidl. Reduction of dietary cholesterol from 500 to 200 mgiday would decrease it by a further 8 mgidl. An increase of fiber intake from 6 to 26 g/day (adding largely mucilaginous fiber, e.g., pectins, gums, and cereal bran) would reduce it by some 8 mg/dl (1). In obese persons some fall of plasma cholesterol usually follows moderate weight reduction (Table 1.) It is urgently necessary to assess the effects of such dietary proposals as part of a new multifactorial prudent diet. At present it is unknown to what extent these changes are additive, though Keys’ feeding studies and observations on vegetarians (35) indicate that the effects may be additive or even to some extent synergistic. Hence, there is some reason to anticipate that a striking reduction in lipoprotein-mediated CHD risk might be attainable by a dietary pattern which appears feasible in terms of nutritional soundness, acceptable on aesthetic grounds, and compatible with agricultural capacity.
CONFERENCE:
PRIMARY
PREVENTION
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OF CANCER
TABLE 1 COMPARISONS OF KEY DIETARY ELEMENTS IN RELATION TO SERUM CHOLESTEROL Diet
U.S.
Japan
U.S.
Japan
Prudent
Estimated decrease in cholesterol
40 500 mg
7 200 mg
40 500 mg 6g
12 200 mg
30 200 mg 26g
20 mgidl 8 mgidl 10 mgidl
1954
Food energy 0% of fat) Dietary cholesterol Fiber” Vegetable protein (% of total protein) Total reduction
30
Current
60
30
50
50
8 mgidl 46 mg/dl
if effects are additive
” Fresh fruit and vegetables.
THE PRUDENT
DIET AND CANCER
PREVENTION
Epidemiological evidence supported by metabolic studies on man as well as animal experimentation suggests that the Western type of high fat diet may play a role, by various mechanisms, in the pathogenesis of several types of human cancer (34, 48, 49, 58) (Table 2). Two distinct differences in the diet as it relates to carcinogenesis or to atherosclerosis are that: (a) Serum cholesterol levels do not appear to relate to carcinogenesis, and (b) in this instance, total dietary fat, rather than a specific intake of saturated or unsaturated fats, appears to be a factor of etiological importance, on the limited available evidence. Briefly stated (the evidence is described in more detail elsewhere), a modificaTABLE 2 PUTATIVE CAUSES OF HUMAN CANCERS
Type 1. Occupational cancers: various organs 11. Cryptogenic cancers: lymphomas, leukemias. sarcomas, cervix(?) (virus?) III. Lifestyle cancers A. Tobacco-related: lung, pancreas, bladder, kidneys B. Diet-related 1. Nitrate-nitrite, low vitamin C, mycotoxin: stomach, liver 2. High fat, low fiber, broiled or fried foods: large bowel, pancreas breast, prostate, ovary, endometrium C. Multifactorial I. Tobacco and alcohol: oral cavity, esophagus 2. Tobacco and asbestos; tobacco-mining; tobaccouranium-radium: lung, respiratory tract IV. Iatrogenic-radiation, drugs: varied organs Note. Calculated Ref. (48).
Percentage of total 1-5 10-15
23 5 44
5 l-5 1
from the 1978 incidence figures published by the American Cancer Society.
From
300
WEISBURGER
ET AL.
tion of the Western diet along some modified principles of the prudent diet is as follows: (a) lower the total fat intake, (b) increase natural fiber intake, (c) increase and balance intake of micronutrients-vitamins and minerals, (d) moderate intake of highly fried foods, and (e) lower NA’ intake or balance K+/NA+ ratio (48-50). Carcinomu
of the Breast
Population comparisons reveal a positive correlation between total fat intake and mortality rates from mammary cancer (34, 60). Studies of migrants support the view that environmental factors play a significant role in its etiology, for within two generations mortality rates in migrants approximate those in the host country (13, 18). A growing body of information exists as to plausible mechanisms for this association. The high fat intake acts as a tumor promoter in rats pretreated with a mammary carcinogen through indirect mechanisms involving endocrine balance. That such a link may be mediated by an effect of fat intake on peak prolactin secretion has been put forward as a result of studies on normal women (19). Hence, a case can be made for studying the effect of low fat versions of the prudent diet on the biochemical and endocrine parameters related to the disease, and subsequently perhaps, on breast cancer mortality. Carcinoma
of the Prostate,
Ovary, und Endometrium
Epidemiological data comparable with those pertaining to breast cancer suggest the possibility that a modification of the Western diet might also benefit a reduction in incidence of these cancers (34). One difference is that endometrial cancer is significantly related to body weight so that a reduction of total calories would attain a higher priority (3, 4). Environmental determinants are equally evident, and the possible roles of two groups of nutrients, fat and fiber, are supported by an increasing weight of evidence (7, 33). One hypothesis is that fiber such as that in cereal bran, by increasing fecal bulk, and, possibly by adsorption of bile acids and yet to be identified carcinogens, may reduce fecal concentrations of substances which may act as promoters or cocarcinogens (33). Conversely, high fat diets, whether rich in SFA or PUFA, increase fecal bile acid excretion. Hence, there are grounds for exploring the effects of low fat, high fiber versions of the prudent diet in experimental carcinogenesis, on human bile acid metabolism, and perhaps, in due course, on colon cancer mortality. As such nutrients are more likely to be related to promoter activity than carcinogenicity, it is possible that changes in mortality would be detectable in a relatively short period. Curcinomcr of the Stomrrch
The reduction of stomach cancer during the past 50 years has been attributed to increased consumption of fresh fruit and vegetables and a lower intake of salted foods (22, 53). There are other reasons, in addition to these views relating to gastric cancer, for advocating a generous intake of vegetables and fruit and for reduced sodium intake’.
CONFERENCE:
ALLOWABLE
PRIMARY
PREVENTION
301
OF CANCER
CONCENTRATIONS OF FOOD ADDITIVES CONTAMINANTS
AND FOOD
In addition to essential macronutrients and micronutrients, food also contains unintentional and intentional additives and contaminants. They occur often in trace amounts and in many instances their biological effect may be unmeasurably low, even though their concentrations are now readily measured (20). Current research programs suggest that there may be adverse effects of substances arising in the course of cooking (31, 38, 39, 54). Certain plant constituents have toxic effects in animals (30, 46, 56). Their relevance to man is not known and requires consideration. These include carcinogens such as cycasin, bracken fern, and toxins including hydrazine derivatives in some types of mushroom. In particular, the false morel, Gyromitru esculentrr, includes a derivative of N-methyl-N-formyl-hydrazine with appreciable carcinogenicity in animal models. Microbial toxins in food may be produced by Clostridium botulinurn and Staphylococcus aureus. Nitrate or nitrite is used to inhibit their formation (see below). There is a series of toxins produced by fungi, as for example, Aspergitlus. Peniciliium, and Fusarium organisms, which have led to cancer in animal models, mainly in the liver. In particular, the class of aflatoxins is a powerful carcinogen in animals and is strongly suspected to be responsible for liver cancer in man in parts of Africa and, possibly, other tropical countries (56). The mode of cooking of food has recently drawn renewed interest. It has been thought for many years that smoked food containing among other carcinogens, polycyclic aromatic hydrocarbons, may be involved in human cancer. Following the finding of powerful mutagenic activity in charcoal-broiled meats or fish by the group of Sugimura, which far exceeded the mutagenic activity due to the presence of polycyclic aromatic hydrocarbons, a number of heterocyclic compounds which are highly mutagenic were found in the pyrolysis products of amino acids (31). It may be, as Spingarn and Weisburger (38) have noted, that frying or broiling may produce the carcinogens responsible for several important human cancers like those in the large bowel, breast, or prostate (38, 39, 54). Intentional food additives include antioxidants which in the amounts used exert no obvious adverse effects. In larger amounts, as described by Wattenberg (45), they actually inhibit the effect of carcinogens in experimental situations. Nitrate and nitrite consumption is influenced by geochemical factors and by the intake of vegetables such as spinach, carrots, or lettuce which provide large amounts of nitrate. Nitrate is also reduced to nitrite by the action of microorganisms in the oral cavity of man (42). In addition, there is conversion of nitrate to nitrite in foods not stored at low temperatures (52). Preservation of vegetables, meats, or fish by pickling has been used since antiquity. This involved the addition of saltpeter and salt. Weisburger et rrl. have postulated and subsequently demonstrated that fish, so preserved, contain mutagenic activity. The possibility exists that this is a causal factor in gastric cancer (52, 53). If so, the fall in gastric cancer incidence in the U.S. may stem from the lesser need for high levels of such preservatives since the advent of refrigeration. In addition, there is more widespread use of vegetables and salads, as sources of
302
WEISBURGER ET AL.
vitamin C which inhibits the formation of nitrosamines from nitrate and nitrite. The custom of adding low levels (100 ppm) of nitrite to meat products appears safe although pickling of other protein foods, such as fish, may not be entirely safe. There is much controversy surrounding the use of sweeteners such as cyclamate and saccharin. Despite the extensive use of saccharin for decades, there are no recorded adverse effects in man (10,61). Current evidence suggests that cyclamate, and probably saccharin, are not genotoxic carcinogens but at high dose levels may exert a promoting effect (9, 10). Dose-response studies will establish whether current intakes are safe. Certain food dyes, e.g., butter yellow were used many years ago until it was found that they could be carcinogenic in rats. It appears that current food dyes, consisting mainly of highly sulfonated molecules, are safe (32, 47). With the advent of rapid methods of assessing carcinogenic risks of chemicals, we have at hand the means to forestall the introduction into the human environment of materials which are potentially harmful (2, 51, 55). ACKNOWLEDGMENTS The authors wish to thank Mrs. Clara Horn for editorial assistance and final preparation of the manuscript.
REFERENCES 1. American Health Foundation. Conference on the health effects of blood lipids: Optimal distribution for populations. Prev. Med. 8, 580-607 (1979). 2. Ames, B. N. Identifying environmental chemicals causing mutations and cancer. Science 204, 587-593 (1979). 3. Armstrong, B. K. The role of diet in human carcinogenesis with special reference to endometrial cancer, in “Origins of Human Cancer” (H. H. Hiatt, J. D. Watson, and J. A. Winsten, Eds.), pp. 557-565. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1977. 4. Armstrong, B. K. Diet and hormone in the epidemiology of breast and endometrial cancers. N&r. Cancer 1,90-95 (1979). 5. Beaglehole, R., La Rosa, J., Heiss, G., Davis, C. E., Williams, 0. D., Tyroler, H. A., and Rifkind, B. M. Serum cholesterol, diet, and the decline in coronary heart disease mortality. Prrv. Med. 8, 538-547 (1979). 6. Bennett, I., and Simon, I. “Prudent Diet.” David White, Port Washington, N.Y., 1972. 7. Burkitt, D. Large bowel cancer: An epidemiologic jigsaw puzzle. J. Nut. Cuncer Inst. 54,3 (1975). 8. Carroll, K. K., and Hamilton, R. Effects of dietary protein and carbohydrate on plasma cholesterol levels in relation to atherosclerosis. J. Food Sci. 40, 18-23 (1975). 9. Chowaniec, J., and Hicks, R. M. Response of the rat to saccharin with particular reference to the urinary bladder. &it. J. Cuncer 39, 355-375 (1979). 10. Cohen, S. M., Masayuki, A., Jacobs, J. B., and Friedell, G. H. Promoting effect of saccharin and or-tryptophan in urinary bladder carcinogenesis. Cuncer Res. 39, 1207- 1217(1979). 11. Connor, W. E. Too little or too much: The case for preventive nutrition. Amer. J. C/in. Nutr. 32, 1975- 1978 (1979). 12. Dawber, T. Annual discourse-unproved hypothesis. New Engl. J. Med. 299, 452-458 (1978). 13. de Waard, F. Premenopausal and postmenopausal breast cancer: One disease or two? J. Ntrf. Cancer Inst. 63, 549-552 (1979). 13a. Ederer, F., Leren, P., Turpemen, O., and Frantz, I. D. Cancer among men in cholesterol-lowering diets. Lancet 2, 203-206 (1971). 14. Freis, E. D. Salt in hypertension and the effect of diuretics. Annu. Rev. Pharmrrcol. Toxicol. 19, 13-23 (1979).
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15. Glueck. C. J., and Conner, W. E. Diet-coronary heart disease relationships reconnoitered. Amer. J. Clin. Ntrtr. 31, 721-737 (1978). 16. Glueck, C. J., Mattson, F., and Bierman, E. L. Diet and coronary heart disease: Another view. New Engi. J. Med. 298, 1471-1473 (1978). 17. Goodman, D. S. Vitamin A and retinoids: Recent advances. Fed. Proc. 38, 2501-2543 (1979). 18. Haenszel, W. Migrant studies, in “Persons at High Risk of Cancer” (J. F. Fraumeni, Jr., Ed.), pp. 361-372. Academic Press, New York, 1975. 19. Hill, P., and Wynder, E. L. Diet and prolactin release. Ltrncet 2, 806-807 (1976). 20. International Symposium. Threshold doses in chemical carcinogenesis. Oncol. 33, 50- 100 (1976). 21. Jacobs, D. R., Jr., Anderson, J. T., and Blackburn, H. Diet and serum cholesterol. Amer. J. Epitletnid. 110, 77-87 (1979). 22. Joossens, J. V., Kesteloot, H., and Amery, A. Salt intake and mortality from stroke. Ne113Engl. J. Med. 300, 1396 (1979).
23. Kato, H., Tillotson, J., Nichaman, M. L., Rhoads, G. G., and Hamilton, H. B. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii, and California. Amer. J. Epidetnid. 97, 372-385 (1973). 24. Kay, R. M., and Strasberg, S. M. Origin, chemistry, physiological effects and clinical importance of dietary fibre. Clin. Invest. Med. 1, 9-24 (1978). 25. Keys, A., Grande, F., and Anderson, J. T. Bias and misrepresentation revisited: Perspective on saturated fat. Amer. J. C/in. Ntrrr. 27, 188 (1974). 26. Kritchevsky, D. Fiber, lipids, and atherosclerosis. Amer. J. C/in. Nutr. 31, S65-S74 (1978). 27. Lewis, B. Hypothesis into theory-the development of aetiological concepts of ischaemic heart disease: A review. J. R. Sm. Mc,d. 71, 809-818 (1978). 28. McGandy, R. B., and Hegsted, D. M. Quantitative effects of dietary fat and cholesterol on serum cholesterol in man, in “The Role of Fats in Human Nutrition” (A. J. Vergroesen, Ed.). pp. 21 l-230. Academic Press, London, 1975. 29. Meneely, G. R., and Battarbee, H. D. High sodium-low potassium environment and hypertension. Amer. J. Curdid. 38, 768-781, (1976). 30. Miller, J. A. Naturally occurring substances that can induce tumors, in “Toxicants Occurring Naturally in Foods,” 2nd ed., pp. 508-549. National Academy of Sciences, Washington. D.C., 1973. 31. Nagao, M., Sugimura, T., and Matsushima, T. Environmental mutagens and carcinogens. Ann/t. Ku\,. Getter. 12, I177 I59 (1978). 32. Noonan, J. Color additives in food, in “Handbook of Food Additives” (T. E. Furia, Ed.). Chem. Rubber Co., Cleveland, 1968. 33. Reddy, B. S., Hedges, A. R., Laakso, K., and Wynder, E. L. Metabolic epidemiology of large bowel cancer. Crrlrcef 42, 2832-2838 (1978). 34. Reddy, B. S., Cohen, L. A., McCoy, D., Hill, P., Weisburger, J. H., and Wynder, E. L. Nutrition and its relationship to cancer. Adlwtt. Ctrncer RPS., in press. 35. Sacks, F. M., Castelli, W. P., Donner, A., and Kass, E. H. Plasma lipids and lipoproteins in vegetarians and controls. Ncn, Engl. J. Mecl. 292, I I48 (1975). 36. Sandstead, H. H., MUAOZ, J. M., Jacob, R. A., Klevay, L., Reck, S. J., Logan, Jr., G. M., Dintzis. F. R.. Inglett. G. E., and Shuey, W. C. Influence of dietary fiber on trace element balance. Amer. J. C/in. N/r/r. 31, Sl80-Sl84 (1978). 37. Schaefer, E. J., Eisenberg, S.. and Levy, R. I. Lipoprotein apoprotein metabolism. J. Lipid Re.,. 19, 667-687 (1978). 38. Spingarn, N. E., and Weisburger, J. H. Formation of mutagens in cooked foods. I. Beef. Ctrtwet Lett. 7, 259-264
(1979).
39. Spingarn. N. E., and Garvie, C. T. Formation of mutagens in sugar ammonia systems. J. Agr. Fmx/ Chrtn. 27, 1319%1321(1979). 40. Stamler, J. Lifestyles, major risk factors, proof and public policy. Circrrlrrtiott 58, 3- 19 (1978). 41. Tall, A. R., and Small. D. M. Plasma high density lipoproteins. Neu, Envy/..I. Med. 299, 1232-1236 (1978). 42. Tannenbaum. S. R., Moran, D., Rand, W.. Cuello, C., and Correa, P. Gastric cancer in Columbia.
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43. 44. 45. 46. 47. 48. 49.
50. 51. 52. 53. 54.
55. 56. 57. 58. 59. 60. 61.
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AL.
IV. Nitrite and other ions in gastric contents of residents from a high-risk region. J. Nat. Conrer Inst. 62, 9- 12 (1979). Tobian, L. Salt and hypertension. Ann. N. Y. Acud. SC;. 304, 178 (1978). Truswell, A. S. Diet and plasma lipids-a reappraisal. Amer. J. C/in. Nufr. 31, 977-989 (1978). Wattenberg, L. W. Inhibition of chemical carcinogenesis. J. Nrrr. Ctrncer Inst. 60, 11 (1978). Weisburger, E. K. Carcinogenic natural products, in “Structural Correlates of Carcinogenesis and Mutagenesis” (1. M. Asher and C. Zervos, Eds.), pp. 184-194. Office of Science, FDA, Rockville, Md., 1977. Weisburger, J. H. Warning: False cancer claims may be hazardous to your health. Ctr. 28, 124-126 (1978). Weisburger, J. H. Mechanism of action of diet as a carcinogen. Ctrncer 43, 1987- 1995 (1979). Weisburger, J. H., Wynder, E. L., and Cohen, L. A. On the etiology and metabolic epidemiology of the main human cancers, in “Origins of Human Cancer” (H. H. Hiatt, J. D. Watson, and J. A. Winsten, Eds.), pp. 567-602. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1977. Weisburger, J. H., and Arnold, C. Dietary risk factors in cardiovascular disease and cancer, in “American Health Foundation Food and Nutrition Committee Activities Report No. 2” (G. Livingston and P. Ashwanden, Eds.), pp. 6-25. Amer. Health Foundation, New York, 1979. Weisburger, J. H., and Williams, G. M. Chemical carcinogenesis, in “Toxicology, The Basic Science of Poisons” (J. Doull, C. Klaasen, and M. Amdur, Eds.)., Macmillan, New York, in press. Weisburger, J. H., Marquardt, H., Mower, H., Hirota, N., Mori, H., and Williams, G. M. Inhibition of carcinogenesis: Vitamin C and the prevention of gastric cancer. Prev. Med., in press. Weisburger, J. H., Marquardt, H., Hirota, N., Mori, H., and Williams, G. M. Induction of cancer of the glandular stomach in rats by an extract of nitrite-treated fish. J. Nrrr. Crrncer Inst., in press. Weisburger, J. H., Reddy, B. S., Spingarn, N. E., and Wynder, E. L. Current views on the mechanisms involved in the etiology of colorectral cancer, in “Progress in Cancer Research” (S. J. Winawer et rtl., Eds.). Raven Press, New York, in press. Williams, G. M., and Laspia, M. F. The detection of various nitrosamines in the hepatocyte primary cultureiDNA repair test. Cancer Letr. 6, 1999206 (1979). Wogan, G. M. Naturally occurring carcinogens, in “The Physiopathology of Cancer” (F. Homburger, Ed.), Vol. II, pp. 64-110. Karger, Switzerland, 1976. Wynder, E. L. An epidemiological evaluation of the causes of cancer of the pancreas. Ctrncer Res. 3.5, 2228-2232 (1975). Wynder, E. L. Dietary habits and cancer epidemiology. Ctrnc,er 43, 1955-1961 (1979). Wynder, E. L., and Goldsmith, R. The epidemiology of bladder cancer: A second look. Ctrncer 40, 1246-1268 (1977). Wynder, E. L., MacCornack, F. A., and Stellman, S. D. The epidemiology ofbreast cancer in 785 United States Caucasian women. Cancer 41, 2341-2354 (1978). Wynder, E. L., and Stellman, S. Artificial sweetener use and bladder cancer: A case control study. Science. in press.
9, 297-304
MEDICINE
Extending JOHN
(1980)
the Prudent
H. WEISBURGER,$*~ AND
Diet to Cancer D. MARK HEGSTED,? BARRY LEWIS*
Prevention’ GIO B. GORI,$
*Department of Chemicul Pathology and Metabolic Disorders, St. Thomas’s Hospital Medicul School, London, Englund, tHuman Nutrition Center. U.S. Department of Agriculture, ZDivision of Comer Cuuse and Prevention. National Cuncer Institute, and fjNuy10r Dana Institute. American Health Foundation, Valhalla, New York 10595 The basis for the formulation of a “prudent diet” is briefly reviewed. Epidemiologic, clinical, and experimental studies related to cancer, coronary heart disease, obesity, diabetes, and hypertension support the position that it is prudent to limit consumption of fats, cholesterol, sugar, and salt, and increase the consumption of fruit, vegetables, and cereals. It is also prudent to limit consumption of products suspected to cause or promote cancer.
Many experts in the field of atherosclerosis have recommended a modification of the typical Western diet so as to reduce the prevalence of hyperlipidemia. A measure of public acceptance of this recommendation may have contributed to the recent reduction in the death rate from myocardial infarction (5). In many countries there is a parallel between the mortality from coronary heart disease and several types of cancer, mainly those in the colon, pancreas, and the endocrine-sensitive organs such as breast, ovary, endometrium, and prostate (18, 23, 49). Thus, the question arises whether diet modification could also contribute to a reduction of the incidence of these numerically important cancers in man. THE PRUDENT DIET AND PREVENTION OF ATHEROSCLEROSIS The design of a diet for reduction of CHD risk has evolved considerably in the two decades since the term “prudent diet” was coined (6). Few of the underlying principles have been altered, but quantitative recommendations have been modified. When it was observed that substitution of saturated fatty acids (SFA) by polyunsaturated fatty acids (PUFA) led to a fall in plasma cholesterol concentration, recommendations were made for a diet little changed in total fat intake but with a marked increase in PUFA:SFA ratio (P:S ratio). Over the years a few trends have been evident (1, 11): (a) Increasing emphasis on reducing dietary cholesterol. Though the mean effect of cholesterol intake on plasma cholesterol level is modest, some persons are remarkably sensitive to this effect because their homeostatic response is apparently relatively inefficient. (b) A reemphasis on reduction of fat intake with moderate increase in P:S ratio to achieve the desired fall in plasma cholesterol level. This was based on a general view that a diet for widespread use should resemble the habitual diets of I Presented at the American Health FoundatiomDeutsche Krebshilfe Conference on the Primary Prevention of Cancer: Assessment of Risk Factors and Future Directions, N.Y., N.Y., June 7-8, 1979. 2 To whom requests for reprints should be sent. 297 0091-7435/80/020297-08$0200/0 Copyright 0 19l?Jl by Academic Press. Inc. AU rights of reproduction in any form reserved.
298
WEISBURGER
ET AL.
healthy populations rather than being novel and seemingly artificial. In addition, the notion that low fat intakes would be unpalatable to Western taste was progressively discounted. The possibility that diets lower in total fat, but with high P:S ratio, might increase the risk of malignant disease was not borne out by an extensive study of pooled data (13a). Increased biliary lithogenicity has only been observed experimentally as P:S ratios far beyond those recommended for population use. (c) The recognition that correction of obesity or moderate weight reduction leads to moderate but variable reduction in plasma lipid levels, an effect additive with that of qualitative dietary change. (d) Acceptance by many of the role of reduced sodium intake in lowering mildly elevated blood pressure levels. (e) The evidence that low-density and high-density lipoproteins of plasma (LDL and HDL) differ in their physiological roles and in their relationship to coronary heart disease risk (12, 15, 16, 21, 27, 37, 40, 41, 44). A prudent diet should, therefore, lead to an optimal lipoprotein distribution as well as reducing total plasma cholesterol concentration. Two newer areas of research show the importance of other dietary constituents in altering plasma lipid and lipoprotein levels. Changes in the fiber intake have a potentially desirable influence on lipoprotein metabolism, colonic function, carbohydrate tolerance, and biliary lithogenesis (24, 26). Also, altered patterns of protein intake (substitution of vegetable protein for proteins of animal sources) reduce plasma cholesterol levels-a small effect has been well documented (8). These lead to the possibility that a prudent diet design incorporating these additional features might have far more substantial effects on lipoprotein levels and on CHD risk than the traditionally recommended diet. Such a combined approach would be necessary if the present mean plasma cholesterol level in U.S. adults, about 220 mgidl, were to be reduced to a recently recommended optimum of 160 -+ 30 mgidl (1). The effects of changing the nature and amount of dietary fat may be predicted from the formulas of McGandy and Hegsted (28) and Keys et al. (25). Reduction of fat intake from 40 to 30% of food energy, with a change of P:S ratio from 0.4 to 1, would decrease plasma cholesterol by 20 mgidl. Reduction of dietary cholesterol from 500 to 200 mgiday would decrease it by a further 8 mgidl. An increase of fiber intake from 6 to 26 g/day (adding largely mucilaginous fiber, e.g., pectins, gums, and cereal bran) would reduce it by some 8 mg/dl (1). In obese persons some fall of plasma cholesterol usually follows moderate weight reduction (Table 1.) It is urgently necessary to assess the effects of such dietary proposals as part of a new multifactorial prudent diet. At present it is unknown to what extent these changes are additive, though Keys’ feeding studies and observations on vegetarians (35) indicate that the effects may be additive or even to some extent synergistic. Hence, there is some reason to anticipate that a striking reduction in lipoprotein-mediated CHD risk might be attainable by a dietary pattern which appears feasible in terms of nutritional soundness, acceptable on aesthetic grounds, and compatible with agricultural capacity.
CONFERENCE:
PRIMARY
PREVENTION
299
OF CANCER
TABLE 1 COMPARISONS OF KEY DIETARY ELEMENTS IN RELATION TO SERUM CHOLESTEROL Diet
U.S.
Japan
U.S.
Japan
Prudent
Estimated decrease in cholesterol
40 500 mg
7 200 mg
40 500 mg 6g
12 200 mg
30 200 mg 26g
20 mgidl 8 mgidl 10 mgidl
1954
Food energy 0% of fat) Dietary cholesterol Fiber” Vegetable protein (% of total protein) Total reduction
30
Current
60
30
50
50
8 mgidl 46 mg/dl
if effects are additive
” Fresh fruit and vegetables.
THE PRUDENT
DIET AND CANCER
PREVENTION
Epidemiological evidence supported by metabolic studies on man as well as animal experimentation suggests that the Western type of high fat diet may play a role, by various mechanisms, in the pathogenesis of several types of human cancer (34, 48, 49, 58) (Table 2). Two distinct differences in the diet as it relates to carcinogenesis or to atherosclerosis are that: (a) Serum cholesterol levels do not appear to relate to carcinogenesis, and (b) in this instance, total dietary fat, rather than a specific intake of saturated or unsaturated fats, appears to be a factor of etiological importance, on the limited available evidence. Briefly stated (the evidence is described in more detail elsewhere), a modificaTABLE 2 PUTATIVE CAUSES OF HUMAN CANCERS
Type 1. Occupational cancers: various organs 11. Cryptogenic cancers: lymphomas, leukemias. sarcomas, cervix(?) (virus?) III. Lifestyle cancers A. Tobacco-related: lung, pancreas, bladder, kidneys B. Diet-related 1. Nitrate-nitrite, low vitamin C, mycotoxin: stomach, liver 2. High fat, low fiber, broiled or fried foods: large bowel, pancreas breast, prostate, ovary, endometrium C. Multifactorial I. Tobacco and alcohol: oral cavity, esophagus 2. Tobacco and asbestos; tobacco-mining; tobaccouranium-radium: lung, respiratory tract IV. Iatrogenic-radiation, drugs: varied organs Note. Calculated Ref. (48).
Percentage of total 1-5 10-15
23 5 44
5 l-5 1
from the 1978 incidence figures published by the American Cancer Society.
From
300
WEISBURGER
ET AL.
tion of the Western diet along some modified principles of the prudent diet is as follows: (a) lower the total fat intake, (b) increase natural fiber intake, (c) increase and balance intake of micronutrients-vitamins and minerals, (d) moderate intake of highly fried foods, and (e) lower NA’ intake or balance K+/NA+ ratio (48-50). Carcinomu
of the Breast
Population comparisons reveal a positive correlation between total fat intake and mortality rates from mammary cancer (34, 60). Studies of migrants support the view that environmental factors play a significant role in its etiology, for within two generations mortality rates in migrants approximate those in the host country (13, 18). A growing body of information exists as to plausible mechanisms for this association. The high fat intake acts as a tumor promoter in rats pretreated with a mammary carcinogen through indirect mechanisms involving endocrine balance. That such a link may be mediated by an effect of fat intake on peak prolactin secretion has been put forward as a result of studies on normal women (19). Hence, a case can be made for studying the effect of low fat versions of the prudent diet on the biochemical and endocrine parameters related to the disease, and subsequently perhaps, on breast cancer mortality. Carcinoma
of the Prostate,
Ovary, und Endometrium
Epidemiological data comparable with those pertaining to breast cancer suggest the possibility that a modification of the Western diet might also benefit a reduction in incidence of these cancers (34). One difference is that endometrial cancer is significantly related to body weight so that a reduction of total calories would attain a higher priority (3, 4). Environmental determinants are equally evident, and the possible roles of two groups of nutrients, fat and fiber, are supported by an increasing weight of evidence (7, 33). One hypothesis is that fiber such as that in cereal bran, by increasing fecal bulk, and, possibly by adsorption of bile acids and yet to be identified carcinogens, may reduce fecal concentrations of substances which may act as promoters or cocarcinogens (33). Conversely, high fat diets, whether rich in SFA or PUFA, increase fecal bile acid excretion. Hence, there are grounds for exploring the effects of low fat, high fiber versions of the prudent diet in experimental carcinogenesis, on human bile acid metabolism, and perhaps, in due course, on colon cancer mortality. As such nutrients are more likely to be related to promoter activity than carcinogenicity, it is possible that changes in mortality would be detectable in a relatively short period. Curcinomcr of the Stomrrch
The reduction of stomach cancer during the past 50 years has been attributed to increased consumption of fresh fruit and vegetables and a lower intake of salted foods (22, 53). There are other reasons, in addition to these views relating to gastric cancer, for advocating a generous intake of vegetables and fruit and for reduced sodium intake’.
CONFERENCE:
ALLOWABLE
PRIMARY
PREVENTION
301
OF CANCER
CONCENTRATIONS OF FOOD ADDITIVES CONTAMINANTS
AND FOOD
In addition to essential macronutrients and micronutrients, food also contains unintentional and intentional additives and contaminants. They occur often in trace amounts and in many instances their biological effect may be unmeasurably low, even though their concentrations are now readily measured (20). Current research programs suggest that there may be adverse effects of substances arising in the course of cooking (31, 38, 39, 54). Certain plant constituents have toxic effects in animals (30, 46, 56). Their relevance to man is not known and requires consideration. These include carcinogens such as cycasin, bracken fern, and toxins including hydrazine derivatives in some types of mushroom. In particular, the false morel, Gyromitru esculentrr, includes a derivative of N-methyl-N-formyl-hydrazine with appreciable carcinogenicity in animal models. Microbial toxins in food may be produced by Clostridium botulinurn and Staphylococcus aureus. Nitrate or nitrite is used to inhibit their formation (see below). There is a series of toxins produced by fungi, as for example, Aspergitlus. Peniciliium, and Fusarium organisms, which have led to cancer in animal models, mainly in the liver. In particular, the class of aflatoxins is a powerful carcinogen in animals and is strongly suspected to be responsible for liver cancer in man in parts of Africa and, possibly, other tropical countries (56). The mode of cooking of food has recently drawn renewed interest. It has been thought for many years that smoked food containing among other carcinogens, polycyclic aromatic hydrocarbons, may be involved in human cancer. Following the finding of powerful mutagenic activity in charcoal-broiled meats or fish by the group of Sugimura, which far exceeded the mutagenic activity due to the presence of polycyclic aromatic hydrocarbons, a number of heterocyclic compounds which are highly mutagenic were found in the pyrolysis products of amino acids (31). It may be, as Spingarn and Weisburger (38) have noted, that frying or broiling may produce the carcinogens responsible for several important human cancers like those in the large bowel, breast, or prostate (38, 39, 54). Intentional food additives include antioxidants which in the amounts used exert no obvious adverse effects. In larger amounts, as described by Wattenberg (45), they actually inhibit the effect of carcinogens in experimental situations. Nitrate and nitrite consumption is influenced by geochemical factors and by the intake of vegetables such as spinach, carrots, or lettuce which provide large amounts of nitrate. Nitrate is also reduced to nitrite by the action of microorganisms in the oral cavity of man (42). In addition, there is conversion of nitrate to nitrite in foods not stored at low temperatures (52). Preservation of vegetables, meats, or fish by pickling has been used since antiquity. This involved the addition of saltpeter and salt. Weisburger et rrl. have postulated and subsequently demonstrated that fish, so preserved, contain mutagenic activity. The possibility exists that this is a causal factor in gastric cancer (52, 53). If so, the fall in gastric cancer incidence in the U.S. may stem from the lesser need for high levels of such preservatives since the advent of refrigeration. In addition, there is more widespread use of vegetables and salads, as sources of
302
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vitamin C which inhibits the formation of nitrosamines from nitrate and nitrite. The custom of adding low levels (100 ppm) of nitrite to meat products appears safe although pickling of other protein foods, such as fish, may not be entirely safe. There is much controversy surrounding the use of sweeteners such as cyclamate and saccharin. Despite the extensive use of saccharin for decades, there are no recorded adverse effects in man (10,61). Current evidence suggests that cyclamate, and probably saccharin, are not genotoxic carcinogens but at high dose levels may exert a promoting effect (9, 10). Dose-response studies will establish whether current intakes are safe. Certain food dyes, e.g., butter yellow were used many years ago until it was found that they could be carcinogenic in rats. It appears that current food dyes, consisting mainly of highly sulfonated molecules, are safe (32, 47). With the advent of rapid methods of assessing carcinogenic risks of chemicals, we have at hand the means to forestall the introduction into the human environment of materials which are potentially harmful (2, 51, 55). ACKNOWLEDGMENTS The authors wish to thank Mrs. Clara Horn for editorial assistance and final preparation of the manuscript.
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