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NUTRITION AND CANCER An International Journal Vol. 1 Fall 1978 - ' No. 1 EDITORIAL FillingaNeed...,GioB.G-o_ri ........................................ ............... 4 --- .,_ SPECIAL COMMUNICATIONS Diet and Nutrition in Cancer Causation, Gio B. Gori ......................................... . 5 Nutrition and the Cancer Patient, Maurice E. Shils ......................................... 9 Mycotoxins in Food and the Variations in Tumor Incidence in Laboratory Rodents, R. Schoental ...13 REPORTS Fiber-Standardized Sources, Lon Crosby ........................... .................... 15 Inhibition of In Vitro Metabolic Activation of Carcinogens by Wheat Sprout Extracts, Chiu-Nan Lai, Betty J. Dabney, and Charles R. Shaw ..................................... _ 27 . , - --- -= ~~ ~-- - REVIEW - Early Nutrition, Growth, Disease, and Human Longevity, William A. Stini ....................... _ 31 ANNOUNCEMENTS ............. ............. -------- INSTRUCTIONS FOR AUTHORS ........................................................... .43 IIITHE FRANKLIN INSTITUTE PRESSSM TIMN 222758

THE FRANKLIN INSTITUTE PRESSSM VIRAL HEPATITIS Etiology, Epidemiology, Pathogenesis and Prevention G. Vyas, S. Cohen and R. Schmid, Editors A handsome case-bound volume, this book is intended to bring the reader up-to-date with all the very latest developments in the field of viral hepatitis. It carefully details all the proceedings of the worldwide symposium sponsored in March 1978 by the University of California. Every aspect of the gathering is covered including 32 comprehensive reviews, 12 workshop summaries, 25 general discussions and four panel discussions. LC#78-008822, Oct. 1978, 740 pp. Price: $49.50 NEOPLASM IMMUNITY: SOLID TUMOR THERAPY R. Crispen, Editor With this official publication of the proceedings of the 1977 Chicago Symposium, practitioners and re- searchers can now consult 29 papers detailing the latest methods of treating lung, gastrointestinal, breast, head and neck cancer as well as sarcomas. Included are a number of important papers on new therapeutic studies using tumor cell vaccines, viral oncolysates and MER. There are also pieces on staging categories, prognostic factors and natural history of the disease. LC#77-24479, Dec. 1977, 266 pp. Price: $22.50 CANCER THERAPY ABSTRACTS Dr. C. M. Southam, Dr. G. F. Schwartz, Dr. J. J. Saukkonen, Dr. G. P. Studzinski, and Dr. G. F. Zinninger, Editors A monthly journal devoted to the experimental and applied clinical aspects of immunotherapy and chemotherapy (including steroid hormones, or other natural products) plus documents dedicated to the treatment of malignant or premalignant cancer in humans by means of surgical excision and/or radiation. Eleven issues per year with subject and author indexes; yearly cumulative index issue. Monthly. Price per volume: US $75.00; foreign $90.00 CARCINOGENESIS ABSTRACTS Dr. George P. Studzinski, Editor Dr. Jussi J. Saukkonen, Associate Editor Dr. Elizabeth Weisburger and Joan W. Chase, IYCI Staff Consultants A monthly journal dealing with the epidemiology, biometry, pathogenesis and immunology of cancer. In ad- dition, it covers investigations relating to all aspects of chemical, physical and viral carcinogenesis. Each issue contains 600 abstracts and citations of studies reported in world-wide technical journals, reports, monographs and books. Twelve issues per year plus cumulative index. Monthly. Price per volume: US $75.00; foreign $90.00 Please remit to: The Franklin Institute Press Box 2266 Philadelphia, PA 19103 TIMN 222759 -

NUTRITION AND CANCER Dr. Gio B. Gori, Editor EDITORIAL BOARD Dr. Stanley John Dudrick Professor and Chairman Department of Surgery University of Texas Medical School at Houston John Freeman Building, Room 123 6400 West Cullen Street Houston, Texas 77025 Dr. D. Mark Hegsted Professor of Nutrition Department of Nutrition Harvard School of Public Health 665 Huntington Avenue Boston, Massachusetts 02115 Dr. Charles E. Butterworth, Jr. Professor of Medicine and Director of Nutrition Program University of Alabama Birmingham School of Medicine University Station Birmingham, Alabama 35294 Dr. George Beaton Professor and Chairman Department of Nutrition and Food Science Faculty of Medicine University of Toronto Toronto, Canada Dr. Takeshi Hirayama Chief Epidemiology Division National Cancer Center Research Institute Tokyo,Japan Dr. Lionel A. Poirier Head Nutrition and Metabolism Section Division of Cancer Cause and Prevention National Cancer Institute Bethesda, Maryland 20014 Dr. Claude Solassol General Practitioner Villa Thalia Rue Louis Bertrand Montpellier-Herault, France Dr. Ernst L. Wynder President American Health Foundation ~ 1370 Avenue of the Americas New York, New York 10019 An International Journal Dr. Lon Crosby, Assistant Editor Dr. William White, Jr., Publisher ASSOCIATE EDITORS Dr. Adrianne E. Rogers Senior Research Scientist Department of Nutrition and Food Science Massachusetts Institute of Technology Cambridge. Massachusetts 02139 Dr. Roswell K. Boutwell Professor of Oncology McArdle Laboratory for Cancer Research Medical Center University of Wisconsin Madisum, Wiscontiin 53706 Dr. Doris Howes Calloway Professor of Nutrition University of California Berkeley, California 94 720 Dr. Theodore P. Labuza Profcswr of Food Science and 1 cx'hnolop. Department of Food Sc•iena• Universitv of Minnesota St. Paul, \finncsota .55108 Dr. Jean-Pierre Habicht Professor of Epidemioloj,n• Division of Nutritional Scienccs Cornell Universitv Ithaca, Ne«• York 1484() Dr. Norge W. Jerome Associate Professor Department of Human Eaolo*• and Communitv Health University of Kansas College of Health Scienc•es and Hospital Rainbo,w Boulevard at 39th Street Kansas Citt, Kansas 66103 Dr. Kenneth K. Carroll Professor, Department of Biochemistry University of «`estern Ontario London, Ontario, Canada Dr. Isidro Martinez Director Cancer Control Program Department of Health Santurce, Puerto Rico 00908 Dr. Baruch Modan Head Department of Clinical Epidemiolo*• Chaim Sheba Medical Center Tel Hashomer and Tel Aviv University Medical School Tel Hashomer, Israel Dr. Richard G. Buckles Principal Scientist and Director Alza Company 950 Page Mill Road Palo Alto, California 94304 Dr. Johanna Dwyer Director Franc•cs Stern Nutrition Center New England Medical Center Hospital 185 Harrison Avenue Boston, Massachusetts 02111 Dr. O. L. Kline Executive Officer National Nutritional Consortium 9ti.50 Rockville Pike Bethesda, Man•land 20014 Dr. Maurice Shils Director of Nutrition Memorial Hospital 1275 York Avenue : New York, New York 10021 Dr. Jan van Eys Professor of Pediatrics University of Texas System Cancer Center M.D. Anderson Hospital and Tumor Institute 6723 Bertner Avenue Houston, Texas 77030 Dr. Okura Akira Department of Surgery Osaka University 14eciical School Fukushima - KU Usaka,Japan Dr. Harry Shizgal Royaj Victoria Hospital 687 Pine Avenue Montreal, Quebec H3A181 Dr. Edwardo Souchon Aparpado #89690 LEL HATILLO 108 Caracas, Venezuela Nutrition and Cancer, An International iournal Copyright 1978 © by The Franklin Institute Press, 20th and The Parkway, Box 2266, Phila., Pa., 19103. Published quarterly. Rates: U.S., Canada and Mexico $48.00, foreign$56.00 per year. All subscriptions are for a volume year. All rights reserved. No part of this journal may be reproduced in any form, for any purpose or by any means, abstracted, or entered into any data base, electronic or otherwise, without specific permission in writing from the publisher. TIMN 222760

EDITORIAL Filling a Need . . . Nutrition and Cancer is born not to hail a new scien- tific society or some esoteric specialty, but rather to fill a need created by the mounting interest in nutrition and its relationship to health and disease. While infectious diseases are still a reality in modern societies, chronic disease, especially cardiovascular problems, cancer, diabetes, and stroke, are now the ma- jor sources of public anxiety, disability, and overall mor- tality. Epidemiologic studies in the last thirty years have shown that most chronic diseases result from the in- teraction of individual genotypes and the combined in- fluence of diet, environment, and behavior. As the suc- cessful research and prevention efforts of the last 100 years enable us to overcome most infectious diseases, we have come to appreciate health implications of the in- fluence of human interactions with the "nonliving" en- vironment. In this context, diet offers by far the greater probability of cellular-molecular encounters than either the respiratory tract or skin contact, over an individual's lifetime. Although the preponderant etiologic role of diet in health and disease has been recognized by epidemiologic studies, it has not been as well studied as other factors. This is partly because other factors are easier to define (eg, a carcinogenic molecule) and partly because there is a reluctance to believe that diet could actually represent a hazard. Throughout history, man has experienced, as a rule, famine and scarcity and has traditionally assigned special importance to food; only in the last fifty years have significant segments of mankind, and especially Americans, enjoyed continuing abundance, resulting in excessive consumption. Perhaps this "hunger" is merely an ancestral conditioned reflex that future generations may unlearn if food remains plentiful; and, of course, food abundance may become a major evolutionary force, reducing the cultural significance of food to its purely nutritional and dietary functions, while human energy and resources historically forced toward food produc- tion, could be freed for other worthy pursuits. But until present perspectives change, people will likely continue to overeat when possible. Unfortunately, it appears that evolution has not prepared us to consume this bounty, and in fact, most chronic disease risks that are associated with diet reflect excessive food intakes. For this reason and for many more, nutrition research has become a major area of interest in modern public health. Nutrition now plays a definite role in cancer therapy. Anorexia and cachexia are the common ex- perience of most cancer patients, and nutritional ap- proaches have proved effective in alleviating the often devastating effects of modern therapies. Moreover, the nutritional therapy of cancer remains in itself an alluring hope. Nutrition and Cancer was designed as an international forum for researchers in this field and is meant to stimulate interest and enthusiasm in those scientists who are not as yet committed to it. The journal will in- clude issues in etiology; , therapy, and prevention. Etiologic interests are in clinical and experimental research in nutrition, carcinogenesis, epidemiology, an- thropology, toxicology, pharmacology, biochemistry, metabolism, and food production. Therapeutic aspects center on clinical and experimental research in clinical nutrition, clinical oncology, psychosocial intervention, dietetics, bioengineering and rehabilitation. Prevention interests include education, preventive medicine, behavior modification, and food technology. In addition, the journal will consider the impact of other disciplines on other cancer and nutrition research, methods for definition and assessment of nutritional status, nutri- tional requirements of the healthy and the ill, food com- position and microbiology, interactions of diet, nutrition and cancer with other disease, and the related method- ological advances. In this field, the journal will also offer editorials and news comments on issues relevant to research and policy. Gio B. GoRi Editor Duplication of Nutrition and Cancer, in whole or in part, by any means for any purpose is illegal. 4 Nutrition and Cancer TIMN 222761

SPECIAL COMMUNICATIONS Diet and Nutrition in Cancer Causation Epidemiology Disease patterns and resulting motality have changed considerably in the US and other developed countries since the beginning of the 20th century. Infectious diseases are no longer a major threat; rather, chronic problems, such as cancer and cardiovascular disease, are the major factors in disease and mortality.25 It has been estimated that 80-90% of the cancer in- cidence rate in the US is attributable to environmental factors.° If the causative agents could be reduced or eliminated altogether, then a vast potential for disease prevention exists. It has also been estimated that the por- tion of total cancer incidence related to diet and nutrition is 60% for women and greater than 40% for men.48 Thus, diet and nutrition appear related to the largest number of human cancers, with a specificity second only to tobac- co smoking, the next largest contributing etiologic fac- tor. These data are not meant to imply that cancer is caused directly by diet, but they do reflect the observed relationships between increased cancer incidence for particular sites and certain nutritional practices. The development of cancer depends on a number of factors, those intrinsic to an individual and those originating in his environment.74 These factors operating together can produce cellular transformations leading to cancer. Ingested substances may contain initiating as well as directly carcinogenic components,3°," and the diet may modulate susceptibility and response to causative factors. Some of the best evidence of nutrition's role in the causation of cancer comes from studies of migrant populations.48 Generally, cancer incidence patterns of migrants change from that of their native country to that common to the population of their new country. These shifts take a few generations because dietary habits learned in the country of origin are slowly changed in the process of acculturation to the new country. In Japan, the incidence rates of colon and breast cancer are low, while that of stomach cancer is high.5 The reverse is true in the US. Within two or three genera- tions, Japanese migrants to the US show a shift of cancer incidence patterns from those common in Japan Vol. I, No. 1 to those prevalent in the US.12 This observation correlates with a shift of dietary habits, and particularly with in- creased caloric and fat intake. Data collected by Staszewski and Haenszel on Polish migrants in 1965 follow the same pattern of change seen in Japanese migrant data.38 The observations on cancer incidence patterns are not confined to migrants to the US. The same pattern ap- pears for migrants to Israel and Hong Kong, and for rural migrants to Cali, Colombia.3 One could argue that the environment or lifestyle of different countries could explain the observed dif- ferences. However, general pollution and food con- tamination are similar in Japan and the US; therefore, these are not likely to be responsible for observed in- cidence differences in colon and breast cancer between the two countries, nor for the shifting patterns of in- cidence rates observed in migrant populations. Also, within a given population group, smokers are ex- posed to enormous quantities of carcinogenic substances similar to and in far larger quantities than those normally found in air, water, or food pollution."2 If these substances were important etiologic factors for those cancers associated with diet, such as colon and breast, then high incidence rates could be expected among tobacco smokers. In fact, smokers do not have an excess of these cancers and it is reasonable to surmise that carcinogens present in smoke and in air are not likely causative factors for these particular diseases.10 Such evidence suggests that environmental pollutants are not significant factors in the observed relationship of nutrition and the incidence and mortality of some cancers. Al.so, breast and colon cancer are not known to be more prevalent in occupational groups where ex- posure to environmental carcinogens is much higher than in the general population. Other major studies reinforce the evidence that diet, rather than other environmental or genetic factors, is in- volved in the causation of certain types of cancer. The best evidence comes from studies of homogeneous pop- ulation groups who live and work in the same environ- ment as their cohorts and are exposed to the same en- vironmental pollutants.78,26 Comparison of the cancer incidence and mortality Duplication of Nutrition and Cancer, in whole or in part, by any means for any purpose is illegal. 5 TIMN 222762

rates in Seventh-Day Adventists living and workirig in Los Angeles shows significant differences in cancer in- cidence for almost all tumor types.19 Some of these dif- ferences, such as for lung cancer, are clearly linked to their abstinence from smoking, even though they are ex- posed to the same environmental pollutants. Their epidemiologic evidence is consistent with the hypothesis that the Adventist lifestyle can account for a major portion of the reduced risk of non-smoking-related cancers. Phillips2' contends that the most distinctive feature in this lifestyle is their unique vegetarian diet, substantially lower In protein and higher in dietary fiber and unrefined carbohydrates than that of their counter- parts. Comparison of the cancer incidences of Mormon and non-Mormon populations living in Utah show similar significant differences in cancer incidence.s Ethnic differences also provide insights into the prob- able role of diet in causing cancer. For instance, Jews in the US show a higher rate of cancer of the stomach, col- on, pancreas, and kidney than the general population.2t Many epidemiologic studies of different ethnic groups show considerable differences for stomach and breast cancer among populations with similar genetic and en- vironmental backgrounds, but with sharply different dietary habits.15 Breast, colon, esophageal, and pancreatic cancers, which have a high correlation with diet, also have great variation in incidence around the world.5 Many epidemiologic studies have found worldwide correlation between bowel and breast cancer and fat intake. The high incidence of colon cancer in the US and low in- cidence in Japan are consistent with the differences in fat intake between the two countries. The greater in- cidence of colonic cancer in Japanese migrants to the US reflects an increase in fat intake as they change from their native habits to western dietary habits." During the last 10 years, the rates of breast and colon cancers in Japan itself have increased, probably for the same reason. Leveille has correlated the occurrence of cancer of the large intestine with foods of animal origin," especially meat, though it is not clear whether the protein, fat con- tent, or an associated factor is the significant factor. Seventh-Day Adventists have a restricted fat and meat in- take when compared to other populations living in the same district and, as indicated, they suffer considerably less often from breast and colon cancer.21 Some re- searchers have postulated that a low fiber intake in western countries may be responsible for a high in- cidence in colon cancer. Indeed the Japanese diet is high in fiber content, as is the diet of African populations. Both groups may experience a lower rate of colon cancer for this reason. Despite epidemiological evidence, the specific role of diet and nutrition in cancer etiology is still unclear. One current theory about the mechanism of dietary fats in causing certain forms of cancer is that an excessive fat intake modifies the metabolism of cholesterol, bile acids, 6 and neutral Steroids in the intestine, as well°gs the metabolism and secretion of steroid hormones in circula- tion.'s The bile acids secreted in the intestine could be degraded by the bacteria growing in the intestine to form carcinogenic substances that may initiate colon cancer." This process of degradation and transformation of bile acids could be modulated by the presence of fiber in the diet, which is known to affect the composition of bacterial and chemical conditions in the intestine,2' or by other conditions, such as the absence of antioxidants."^ It is also possible that the altered metabolism of steroid hormones could impose unnatural burdens on cellular receptors of specific target tissues, such as the uterus or breast, again to initiate cancer at those sites. The relationship between diet and certain forms of cancer still does not mean an exclusive link to causation. Many contributing factors may be involved, but perhaps the modification of even one of these factors (eg, diet) would be sufficient to stop or retard the chain of causative events. For instance, if we consider alcohol an abnormal dietary component, then clearly its excessive consumption is a very significant causative factor, par- ticularly for cancers of the upper alimentary tract a,'3 Other studies that reinforce the link of nutrition and certain cancer forms have noted changes in cancer rates over time. The sharp decrease in stomach cancer in- cidence for the US in the last 20 years suggests the prob- able introduction of as yet unknown protective factors in the diet. Gortner's recent study on nutrition in the US in- dicates changes in the consumption of specific dietary components during this same period that may explain the decrease in stomach cancer incidence. Animal Studies The epidemiological evidence relating diet and nutri- tion to cancer etiology is strongly supported by numer- ous animal studies. Of all dietary modifications, caloric restriction has had the most regular influence on tumor formation40 With few exceptions, caloric restriction generally inhibits tumor formation and increases life expectancy. Furthermore, even within a group of animals being fed identical diets, the incidence of tumors tends to be consistently greater in heavier rats than in lean rats.32 Other research in- dicates that the optimum caloric intake for an animal depends upon age and stage of development.' Longevity studies" that include the evaluation of tumor development indicate that optimum protein intake is also dependent upon developmental stage. Generally, a lower protein intake inhibits growth of spontaneous or chemically induced tumors.22,33 Amino acids have also been noted to influence cancer development in animals, indicating that neoplastic tissues may have different amino acid requirements than the normal tissues of the host.'5 Both the amount of fat in the diet as well as the satura- Duplication of Nutrition and Cancer, in whole or 7n parf, by any means for any purpose Is illeyal. Nutrition and Cancer TIMN 222763

tion of the fat tend to influence tumor incidence.',z,B,30 In- creased amounts of fat in animal diets have resulted in an increased incidence of certain tumors, notably breast tumors, and the tumors have also occurred earlier in the life of the animal. Tannenbaum" has shown that an in- crease from 25% to 28% fat in the diet of mice resulted in a doubled incidence of spontaneous mammary cancers. Vitamins have varying effects on tumor formation and growth. Certain vitamin deficiencies tend to enhance tumor development while other deficiencies suppress it. Vitamin excesses can also influence tumor development in either direction. A deficiency of vitamin A appears to enhance suscep- tibility of animals to chemical carcinogens. Supplemen- tal vitamin A has been shown to reduce chemical car- cinogenesis in epithelial cells and depress gastric tumor growth.3' Studies of the relationship between vitamin A and the growth of colonic tumors have produced conflict- ing findings; in general, however, present evidence sug- gests that vitamin A and its retinoid analogs may have anticarcinogenic or antitumorigenic in effects. Riboflavin deficiency retards the growth of spon- taneous and transplanted tumors, probably by starving the tumor cells of flavin coenzymes.24 In the case of tumors induced by chemicals such as azo dyes, however, riboflavin is needed as a protective agent in order to degrade these carcinogens." Nicotinamide has been shown to reduce the incidence of pulmonary adenomas in mice.' Vitamin E is believed to have antitumor proper- ties because of its role as an antioxidant in preventing formation of epoxides and peroxides.34 Ascorbic acid has been shown to inhibit in vitro nitrosation, thus having a potentially protective effect against the carcinogenicity of nitrosamines and nitrosamides.28 Minerals appear to have a more complex role than vitamins40 in the carcinogenic process. Most minerals ap- pear to have an optimum range for dietary consumption. Intakes above or below this range may increase tumor in- cidence or susceptibility to an exogenous carcinogen. The minerals most often associated with increased cancer incidence include arsenic, beryllium, chromium, lead, cadmium, nickel, and radium. The roles of sodium, potassium, calcium, and magnesium have not yet been clarified, but selenium, zinc, copper, and iodine have been shown to be protective under certain conditions.'5,'9 Nonnutritive dietary components also seem to play a role in cancer etiology. Dietary fiber may alter intestinal microflora concentrations or microbial metabolic path- ways. Fiber has also been shown to bind to dietary car- cinogens and precarcinogens, possibly lessening their effect, and to affect intestinal transit time. Other nutritive dietary components, such as flavones, may enhance or repress carcinogenesis through effects on a cell's drug- metabolizing system. Antioxidants have been shown to Vol. I, No. 1 decrease both the incidence of tumorigenesis and the number of tumors per mouse, following DMBA induc- tion.49 Similarly, the antioxidant BHA50 has been shown to reduce the binding of benzo(a)pyrene to the DNA in the microsomes in calf thymus.3' Although the animal data relative to the specific role individual nutrients play in carcinogenesis are not yet conclusive, it is obvious that diet and nutrition are ex- tremely important in the etiology of both naturally occur- ring and experimentally induced cancers. Conclusion While the epidemiological and laboratory data sum- marized here do not allow us to make final statements on the relationship of specific dietary components to the in- cidence of certain forms of cancer, they do show that significant correlations exist. The evidence indicates that diet functions as an etiologic factor distinct from dietary contaminants and from genetic and environmental fac- tors. Correlations between cancer incidence and dietary habits have been shown in studies of migrant popula- tions, high- and low-cancer incidence populations, and special populations. Epidemiologic and metabolic studies should be con- tinued and expanded to gain a more precise picture of nutrition interactions with health and disease. Methods for rapid and objective measurements of the nutritional status of individuals are sorely needed, as a basic premise for sound nutritional research and intervention in man. Clearly the commitment and development of these research problems cannot be expected from isolated scientists, as they require resources beyond the capabil- ity or interest of the academic laboratory. Such research would most likely be organized by government agencies, assisted by advisers from the academic community. Research in nutrition and health must develop basical- ly in physiologic, biochemical, cellular, and molecular directions, but must also strive to translate these find- ings into applicable human trends. Patient work is need- ed to identify individual dietary requirements according to different genetic, somatic, behavioral, and en- vironmental situations. In view of the multiple interactions of diet and nutrition with human health and development and with diseases that are major.sources of mortality in modern society, hardly any biomedical research field seems to hold a bet- ter promise of improved health for mankind. National Cancer Institute Bethesda, MD 20014 Gio BATTA GoRi Duplication of Nutrition and Cancer, in whole or !n part, by any means for any purpose is illeyal. 7 TIMN 222764

References and Notes ' Carrol, KK: "Experimental Evidence of Dietary Factors and Hormone-Dependent Cancers." Cancer Res 35, 3374-3383, 1975. ZCarroll, KK, and Khor, HT: "Effects of Level and Type of Dietary Fat on Incidence of Mammary Tumors Induced in Female Sprague- Dawley Rats by 7,12-dimethylbenz(a)anthracene." Lipids 6, 416. 1971. 3Correa, P, Cuello, C, and Dugue, E: "Carcinoma and Intestinal Metaplasia of the Stomach in Colombian Migrants." J Natl Cancerlnst 44, 297-306, 1970. "Doll, R: "Strategy for Detection of Cancer Hazards to Man." Nature 265, 589-596, 1977. 5Doll, R, Muir, C, and Waterhouse, J (eds): Cancer Incidence in Five Continents, Vol II. New York: Springer-Verlag, 1970. 6Enstrom, JE: "Cancer Mortality among Mormons." Cancer 36, 825-841, 1974. 'French, A: "Nicotinamide Inhibition of Urethane-Induced Pulmonary Adenomas in Mice." J Int Res Commun 1(3), 33, 1973. aGammal, EA. Carroll, KK, and Plunkett, ER: "Effects of Dietary Fat on Mammary Carcinogenesis by 7,12-dimethylbenz(a)anthracene in Rats." Cancer Res 27, 1737, 1967. 9Graham, S, Lilienfeld, AM, and Tidings, JE: "Dietary and Purga- tion Factors in the Epidemiology of Gastric Cancer." Cancer 20, 2224- 2234, 1967. tOHaenszel, W: "Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases." National Cancer Institute. Monograph 19. 1966. "Haenszel, W, and Kurihara. M: "Studies of Japanese Migrants. I. Mortality from Cancer and Other Diseases among Japanese in the United States." J Natl Cancer Inst 40, 43-68, 1968. 7zHaenszei, W. Kurihara. M, Segi, M, and Lee. RKC: "Stomach Cancer Among Japanese in Hawaii." J Natl Cancer Inst 49, 969-988, 1972. "Hankin, JH. Nomura, A, and Rhoades, AG: "Dietary Patterns Among Men of Japanese Ancestry in Hawaii." Cancer Res 35, 3259- 3264, 1975. - t4Higginson, J: "Present Trends in Cancer Epidemiology." Proc c Can Cancer Conf 8, 40-75, 1969.. 15Higginson. J,and Muir, CS: "Epidemiology in Cancer." In Holland, JF and Frei, F (eds): Cancer Medicine, Philadelphia: Lea and Febiger, 1973. 16Hili, JJ: "Metabolic Epidemiology of Dietary Factors in Large Bowel Cancer." Cancer Res 35, 3398-3402, 1975. '7Kraybill, HF: "Carcinogenesis Associated with Foods, Food Ad- ditives, Food Degradation Products, and Related Dietary Factors: " Clin Pharmacol Ther 4, 73, 1963. 18Lemon, FR, and Walden, RT: "Death from Respiratory System Disease Among Seventh-Day Adventist Men." JAMA 198,117-126, 1966. 19Lemon, FR, Walden, RT, and Woods, RW: "Cancer of the Lung and Mouth in Seventh-Day Adventists." Cancer 17(4), 486-497, 1964. 20Leveilie, GA: "Issue in Human Nutrition and their Probable Impact on Foods of Animal Origin." J Animal Science 41(2), 723-731, 1975. 2tMacMahon, B: "The Ethnic Distribution of Cancer Mortaility in New York City, 1955." Acta; Union Internationalis Contra Cancer 16, 1716-1724, 1960. Z2Madhaven, TV and Gopalan, C: "The Effect of Dietary Protein on Carcinogenesis of Afiatoxin." Arch Path 85, 133-137, 1968. 23 Moore, WEC and Holdeman, LV: "Discussion of Current Bacteriological Investigations of the Relationship between Intestinal Flora, Diet, and Colon Cancer." Cancer Res 35, 3326-3331, 1975. 8 24The Nutrition Foundation: "Riboflavin Metabolism in Cancer." Nutr Rev 32. 308. 1974. Z5Perry, TM: "The New and Old Diseases. A Study of Mortality Trends in the United States. 1900-1969:' Am J Clin Pathol 63,453, 1975. 26Phillips. RL. "Cancer and Adventists." Science 183, 471, 1974. 27Philiips. RL. --Role of Lifestyle and Dietary Habits in Risk of Cancer Among Seventh-Day Adventists." Cancer Res 35, 3513-3522, 1975. Z8Raineri, R. and Weisburger, JH: "Reduction of Gastric Car- cinogens with Ascorbic Acid." Ann NY Acad Sci 258, 181, 1975. 29Reddy. BS. Mastromarino. A, and Wynder, EL: "Further Leads on Metabolic Epidemiology of Large Bowel Cancer." Cancer Res 35, 3403-3406. 1975. 'OReddy. BS. Narisawa. T, Maronpot, R, Weisburger, JH, and Wynder, EL: "Animal Models for the Study of Dietary Factors and Cancer of the Large Bowel."Cancer Res 35, 3421-3426, 1975. 31Ross, MH: "Dietary Behavior and Longevity." Nutr Rev 35, 257-265, 1977. 'ZRoss, MH and Bras, G: "Lasting Influence of Early Caloric Restric- tion on Prevalence of Neoplasms in the Rat." J Natl Cancer Inst 47, 1095, 1971. 33Ross, MH and Bras. G: "Tumor Incidence Patterns and Nutrition in the Rat." J Nutr 87, 245-250, 1965. 34Shamberger. RJ. Baughman, FF, Kalchert, SL, Willis, CE, and Hoffman. GC: "Carcinogen-induced Chromosomal Breakage De- creased by Antioxidants." Proc Natl Acad Sci 70, 1461-1463, 1973. 35Shapiro. JR: "Seleniurri and Carcinogenesis: A Review." Ann NY Acad Sci 192. 215. 1972. 3sShubik• P: "Potential Carcinogenicity of Food Additives and Con- taminants." Cancer Res 35. 3475-3480, 1975. 37Sporn. MG. Dunlop. NM. Newton, L, and Smith, JM: "Prevention of Chemical Carcinogenesis by Vitamin A and its Synthetic Analogs (Retinoids)." Fed Proc 35. 1332-1338, 1976. 38Staszewski. J and Haenszel, W: "Cancer Mortality among the Polish Born in the United States." J Natl Cancer Inst 35, 291-297, 1965. 39Stoner, GD, Shimkin, MB, Troxell, MC, Thompson, TL, and Terry, LS: "Test for Carcinogenicity of Metallic Compounds by the Pulmonary Tumor Response in Strain A Mice." Cancer Res 36, 1744-1747, 1976. 40Tannenbaum, A: "Nutrition and Cancer." In Homburger, F(ed): Physiopathology of Cancer (2nd edition) New York: Hoeber-Harper, 1959, pp 517-562. °tTannenbaum, A: "The Genesis and Growth of Tumors. 111. Effects of a High-Fat Diet." Cancer Res 2, 468-475, 1942. 42US Department of Health, Education, and Welfare: "Toward Less Hazardous Cigarettes." Publ. No. (NIH) 76-905. 43Vitale, JJ and Coffey, J: "Alcoholism and Vitamin Metabolism." In Kissin, B and Begleiter (eds): Biochemistry. New York: Plenum Press, 1971, pp 327-352. 44Wattenberg, LW: "Effects of Dietary Constituents on the Metabolism of Chemical Carcinogens." Cancer Res 35, 3326-3331, 1975. 45Wattenberg, LW, Loub, WD, Lam, LK, and Speier, JL: "Dietary Constituents Alerting the Responses to Chemical Carcinogens." Fed Proc 35, 1327-1331, 1976. 'sWeisburger, JH and Raineri, R: "Dietary Factors and the Etiology of Gastric Cancer." Cancer Res 35, 3469-3474, 1975. 47Wissler, RW and Geer, JC (eds): The Pathogenesis of Atheroschlerosis. Baltimore: Williams and Wilkins, Co. 1972, pp 41-119. 48Wynder, EL and Gori, GB: "Contribution of the Environment to Cancer Incidence: An Epidemiologic Exercise." J Natl Cancer Inst 58, 825-832, 1977. 49DMBA =9, 10-dimethyl-1, 2-benzanthracene. 50BHA = butylated hydroxyanisole. Duplication of Nutrition and Cancer, In whole or in part, by any means for any purpose is illegal. Nutrition and Cancer TIMN 222765

N utrition and the Cancer Patient Renewed interest in clinical nutrition has accom- panied major advances in the treatment of cancer and a generally more optimistic outlook for many cancer pa- tients. This has resulted in the increasing appreciation of the close interrelations between the nutritional status of the cancer patient and the effects of cancer and its various treatments. With the exception of acute leukemias, cancer has rarely been an acutely fatal disease. With the advent of more effective treatments, it has become more and more a chronic or protracted ill- ness and, consequently, a matter of concern for long periods to the patient and the physician. Remission or potential "cure" of cancer is associated with long-term chemotherapy treatment. There is a lapse of years before the patient and the physician are willing to admit that the disease is "cured." The physician and patient are there- fore faced, each in his own way, with the effects of the disease process, the psychologic impact of its presence and long-term problems of treatment modalities and their side effects. If physicians undertake the treatment modalities indicated at the present time, they should make a sincere effort to improve or maintain a quality of life which makes for a reasonably comfortable and func- tioning individual. This concern about patient status should begin with the planning for the initial treatment and continue through to the desired long-term survival. Since it is possible to prolong life by surgery, radiation and chemotherapy or their combinations, attention must be given to the quality of life of those who survive.23 The interrelations between cancer and nutrition in- volve 1) the systemic effects of cancer, 2) the local ef- fects of cancer, 3) the effects of each of the various treatments of cancer and 4) the psychological stresses of the actual or imagined presence of cancer. While each category has its specific influences, it is important to realize that they interact and that one or more may operate simultaneously. An important manifestation of the presence of cancer is anorexia. This is not unique to cancer, but its in- cidence, prolonged duration and deleterious effect make it of special concern. It occurs most commonly and noticeably in patients with involvement of one or more areas of the alimentary tract including the liver and pan- creas?2 The onset of anorexia is often insidious and may Vol. I, No. 1 be unaccompanied by symptoms other than progressive weight loss for a significant period. It is a dictum of medicine that a patient with an unexplained weight loss should undergo a thorough search for an occult neoplasm. The anorexia may range from mild to severe. Its etiology is uncertain although many conferences and publications have considered It 8,9,",ze It has been variably attributed to the development of a toxin (although none_has ever been isolated or identified) or to abnormalities of hypothalamic control (although current evidence is against this)." It may be related to any one or more of a variety of metabolic changes associated with modified energy requirements;'~2~9 however, a specific association, if any, has not been documented.29 Whatever the etiology, anorexia is a real and trouble- some problem to the patient and to the physician. It is often associated with altered taste, and patients fre- quently ascribe their loss of appetite to a changed taste of one or more foods. Efforts have been made recently to determine the prevalence and types of taste alterations in cancer patients.8 These efforts are still very preliminary and more precise studies are needed to establish what patterns (if any) occur in relation to the type and stage of various malignancies. Alterations in taste are probably not primary to anorexia, but are part of the underlying changes initiated by tumors and psychosomatic factors. Depressed cellular immunity has been known to occur in cancer patients and in the past, has frequently been attributed to the effects of cancer per se. However, as the result of studies done initially in children,25 then in adults,i3 and then in cancer patients,5 it has become ob- vious that altered immune responses can result from malnutrition per se. Malnutrition also induces altered phagocytosis, macrophage activity and depressed com- plement levels. In cancer patients the respective effects of malnutrition and of the malignancy per se are not yet known. It has been well demonstrated in surgical pa- tients that morbidity and mortality increase in the presence of depressed cellular immunity. Active interven- tion to overcome malnutrition and to treat infection im- proves the immune response and significantly decreases morbidity and mortality.7e Data from malnourished cancer patients5 and tumor-bearing animals' show that improved nutrition substantially reverses depressed im- Duplicathn of Nutrition and Cancer, in whole or in part, by any means for any purpose is illeyal. 9 TIMN 222766

munity and that the immune response has prognostic significance on the effectiveness of antitumor therapy. Data are accumulating on the effects of malnutrition and endocrine function, particularly in children." Un- doubtedly, changes in endocrine status induced by malnutrition have relevance for the cancer patient, but this area has not been sufficiently researched. Many of the most serious effects of cancer on nutri- tional status stem from localized organ problems, such as partial or total intestinal obstruction, whereby the in- take of food is partially or totally prevented.22 In addition to impaired nutrient intake, maldigestion and malabsorp- tion may occur. Diarrhea and vomiting may be severe enough to lead to problems of fluid and electrolyte and acid-base balance. The physician must be aware of not only sodium, potassium, chloride and bicarbonate requirements in such situations but of magnesium, phosphate, calcium and trace-element requirements. This is especially important when long-term replacement is indicated or when complications arise from renal tubular defects (e.g., secondary to administration of sodium carbenicillin and/or amphotericin) which may lead to serious metabolic abnormalities if uncorrected. Production of ectopic hormones with marked effects on the intestinal tract and elsewhere is a striking illustra- tion of the interrelation of localized tumor growth with systemic effects. These ectopic hormones are produced by a group of cells derived embryologically from the neural crest and characterized by the ability to form biologically active polypeptides.27 Specific tumors pro- ducing these polypeptide hormones include the medullary carcinoma of the thyroid, oat cell carcinoma of the lung, malignant epithelial thyoma, pancreatic non- beta cell tumors, and carcinoid tumors of the foregut. Insulin-secreting tumors of the pancreas also may cause severe nutritional and metabolic problems. Often the cells produce a variety of hormones in the same patient. The secretion of hormones without the normal controls may have dramatic effects on the alimentary tract and elsewhere. The Zollinger-Ellison syndrome is associated with the ectopic production of gastrin with resultant gastric hyperacidity, ulcer formation, and maldigestion. The Verner-Morrison syndrome30 is characterized by copious diarrhea, low gastric acid production and hypokalemia. It is associated with ectopic production of vasoinhibitory peptide (VIP) and other hormones.te In- creased production of ACTH, corticosteroids, anti- diuretic hormone, serotonin, calcitonin, and others pro- duce systemic effects that disturb the nutritional status of the patient. Gastrointestinal lymphomas, particularly those of the small intestine, are often associated with malabsorption. There is a positive correlation between long-standing adult celiac disease and the development of both in- testinal lymphomas and carcinomas?2 The major therapeutic modalities of cancer-surgery, radiation therapy and chemotherapy, separately and in various combinations-may induce significant changes leading to the development of nutritional problems. Surgical procedures to cure or palliate cancer may in- volve any part of the alimentary tract from the mouth to the anus including pancreas, liver, and gall bladder. It is essential that the physician and dietition involved be aware of the potentially adverse nutritional effects that the particular surgical ablation and any anatomical rear- rangement may induce,'•,21 in order to effectively prevent development of nutritional deficiencies in these patients. Our knowledge of nutrition and of gastrointestinal physiology has reached a point where rational principles can be applied in the treatment of the patient who has undergone major alimentary tract surgery. Where surgery involves multiple portions of the alimentary tract, tradi- tional nutritional therapy may be modified and com- plicated. The clinical effects of ionizing radiation to various por- tions of the alimentary tract have been described.10 Radiotherapy to the head and neck, often in conjunction with surgery, or to the abdomen may result in nutritional problems secondary to difficulties in ingestion, chewing and swallowing or absorption. The great majority of cases with high abdominal radiation have a short-lived acute episode. However, with a tendency to increasing radiation dosage or to individual hypersensitivity there may be rapid or slow changes over months or years resulting in persistent intestinal dysfunction with stenosis, fistula formation and/or malabsorption. Obstruction or fistulas often require surgical resection of affected portions of the bowel. They often recur with fur- ther need of resection. As the result of the combination of radiation damage and resection, the patient may become an intestinal cripple requiring drastic nutritional intervention which may include long-term total parenteral nutrition. Early and adequate nutritional therapy can drastically improve the quality of life of such patients. While much has been written about the dietary management of the patient undergoing radiation therapy, such dietary prescriptions are based on limited anec- dotal experience without adequate objective com- parative studies of different modalities. Pending such ob- jective data on optimum formulations of diets and liquid formulas, the physician and dietitian must adopt the policy of testing one or more diet formulations until satisfactory results are obtained. While chemotherapy is a latecomer in cancer therapy, its development has been rapid in recent years in terms of new drug development and application. Relatively high dose, multiple combination, cyclical chemotherapy is already well established in many institutions. In addition to the bone marrow depression induced by many of these drugs, there is also a high incidence of anorexia, nausea and vomiting, mucositis, and, less commonly, diarrhea. Certain agents may induce obstipation and ulceration.15 Dosages vary depending upon patient tolerance and response, and there are marked individual responses in the degree of undesirable gastrointestinal effects and willingness to ingest food. Of particular Duplication of Nutrttton and Cancer, in whole or !n part, by any means for any purpose !s illegal. Nutrition and Cancer TIMN 222767

relevance is the fact that a number of patients who are candidates for initial or further chemotherapy are often malnourished. The physician must give serious consider- ation to the further adverse impact of treatment on such patients. Maintenance of good nutritional status or rehabilitation of the depleted patient offers the on- cologist the opportunity of more successfully executing the chemotherapeutic program. The deterioration of physical and subjective status ex- perienced by the patient as malnutrition develops is ac- companied by a variety of cellular and physiologic changes.',°,z3,2e,29 These changes result in increased mor- bidity and mortality and interference with the therapeutic program. The anorexia, nausea, mucositis and vomiting which often occur in patients given high-dose abdominal radiation and chemotherapy often prevent adequate food intake. Our lack of success in ensuring adequate feeding in such patients emphasizes the need for early initiation of parenteral nutrition by either supplementary, peri- pheral, or total central infusion. The latter is particularly useful if the chemotherapy protocol is likely to be pro- longed or where there is prolonged intestinal dysfunc- tion. Insertion of the central venous catheter is less hazardous if it is done prior to the onset of serious bone marrow depression. However, our experience with many thrombocytopenic and leukopenic patients indicates catheter insertion can be done safely immediately follow- ing or during platelet infusion. Furthermore, experience with many bone-marrow-depressed patients indicates that long-term total parenteral nutrition (TPN) is safe when there is close monitoring of the patient to detect early infection and adequate antibiotic therapy when in- fection occurs. Such experience challenges the dog- matic statements that catheters must be immediately withdrawn for a period once infection occurs. Our data indicate that the central feeding can be continued in the face of infection with the original catheters being re- placed over a sterile flexible guidewire by another catheter. This approach holds for both bacterial and fungal infections. Infection is never to be taken lightly, but with close supervision of patients the central feeding technique is safe and may be continuous with antibiotic therapy. For the patient with a severe bowel dysfunction as a result of radiation and/or resection who cannot otherwise be maintained in good nutritional condition, home total parenteral nutrition (HTPN) is now a well-established and feasible procedure.z,'2,z° Various centers around the country now train patients on a fairly routine basis." The question continues to be raised as to whether im- proved nutritional status may lead to increased tumor growth. It is well established that forced feeding with tube or parenteral feeding of experimental animals with transplanted tumors results in improved weight of the host. Repletion by a complete diet of previously protein- depleted tumor-bearing rats appreciably increased the ratio of tumor weight to host tissue weight.19 Recent observations of the effects of parenteral nutrition in tumor-bearing animals indicate some variability in results: in two of three reports, total parenteral nutrition did not increase the relative tumor weight or size;',z' in one report the tumor growth was stimulated.3 Clinical ex- perience indicates that it is a very rare patient who has obvious explosive tumor growth during a period of im- proved nutrition. It would be expected, however, that there should be some increased growth of residual tumor in patients as the result of improved nutrition since tumor cells, like host cells, have a dependency on good nutri- tion. Improved nutrition may be a therapeutically useful occurrence since actively dividing tumor cells are more likely to be sensitive to radiation therapy and to chemotherapy than are slowly dividing cells. Preliminary studies in tumor-bearing experimental animals suggests that maintenance of better nutrition by intravenous^ or oral19 means improves the sensitivity of the tumor to chemotherapeutic agents. On the basis of such data and my personal observations, it is my opinion that nutri- tional therapy must be accompanied by adequate anti- tumor treatment. The role of nutrition therapy as an adjunct to chemo- therapy and radiation needs further exploration and research to assess its clinical significance. There is no question concerning the value of nutrition therapy in rehabilitation of the malnourished and in the parenteral support of individuals unable to eat for significant periods prior to other treatment, such as surgery. Nutri- tion therapy may be the definitive treatment in the patient with serious malabsorption secondary to surgery or radiation. It is also of value in maintaining or achieving good nutritional status during prolonged courses of chemotherapy and/or radiation. However, objective data are needed to ascertain whether improved nutritional status is also associated with decreased radiation or chemotherapy toxicity and/or improved clinical response and survival. Such prospective data will, hopefully, emerge as a result of the NCI Diet, Nutrition and Cancer Program. MAURICE E. SHILS Director of Nutrition Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10021 Ouplication of Nutrition and Cancer, in whole or In part, by any means for any purpose is illegal. Vol. I, No.1 11 TIMN 222768

References and Notes 'li~rennan, MF: "Uncomplicated Starvation versus Cancer Cachexia." Cancer Res 37, 2359, 1977. 2Broviac, JW and Scribner, BH: "Prolonged Parenteral Nutrition in the Home." Surg Gynecol Obstet 130, 24, 1974. 'Cameron, JL and Pavlat, WA: "Stimulation of Growth of a Transplantable Hepatoma in Rats by Parenteral Nutrition." J Natl Cancer Inst 56, 597, 1976. 'Cameron, JL and Rogers, W: "Total Intravenous Hyperalimenta- tion and Hydroxyurea Chemotherapy in Hepatoma-Bearing." J Surg Res 23, 279, 1977. SCopeland, EM, MacFayden, BV Jr, and Dudrick, SJ: "Effect of Intravenous Hyperalimentation on Established Delayed Hypersensi- tivity in the Cancer Patient." Ann Surg 186, 241, 1977. 6Costa, G: "Cachexia, the Metabolic Component of Neoplastic Diseases." Cancer Res 37, 2327, 1977. 7 Daly, JM, Copeland, EM, Quinn, E, and Dudrick, SJ: "Relationship of Protein Nutrition to Tumor Growth and Host Immunocompetence." Surg Forum 27, 113, 1976. 8DeWys, W: "Anorexia in Cancer Patients." Cancer Res 37, 2354, 1977. 9DeWys, W: "Working Conference on Anorexia and Cachexia of Neoplastic Disease." Cancer Res 30, 2816, 1970. 70Donaldson, S: "Nutritional Consequences of Radiotherapy." Cancer Res 37, 2407, 1977. "Gardner, LI and Amacher, P (eds): Endocrine Aspects of Malnutri- tion. Kroc Foundation Series, Vol 1, New York: Raven Press, 1973. t2Langer, B, Michattie, JD, Zohrab, J, and Jeejeebhoy, KN: "Pro- longed Survival after Complete Small Bowel Resection using Intra- venous Alimentation at Home." J Surg Res 15, 226, 1973. "Law, DK, Dudrick, SJ, and Abdou, NI: "The Effect of Dietary Pro- tein Depletion on Immunocompetence. The Importance of Nutrition Repletion Prior to Immunologic Induction." Ann Surg 179, 168, 1974. "Lawrence, W Jr: "Nutritional Consequences of Surgical Resection of the Gastrointestinal Tract for Cancer." ` Cancer Res 37, 2379, 1977. 15Marsh, JC and Mitchell, MS: "Chemotherapy of Cancer." Drug Therapy 1, 43, Oct 1976, and 26, Nov 1976- 16Meakins, JL, Pietsch, JB, Bubenick, 0, Kelly, R, Rode, H, Gordon, 12 J, and MacLean, LD: "Delayed Hypersensitivity: Indicator of Acquired Failure of Host Defenses in Sepsis and Trauma." Ann Surg 186, 241, 1977. "Morrison, SD: "Origins of Anorexia in Neoplastic Disease." Am J Clin Nutr 31, 1104, 1978. tBRambaud, JC, Modigliani, R, Matuchansky, C, Bloom, S, Said, S, Passayre, D, and Bernier, JJ: "Pancreatic Cholera: Studies in Tumoral Secretions and Pathophysiology of Diarrhea." Gastroenterology 69, 110, 1975. 19Reynolds, HM Jr, Daly, JM, Copeland, EM, and Dudrick, SJ: "Ef- fects of Nutritional Repletion on Host and Tumor Response to Chemo- therapy." Fed Proc 37, 261, 1978. 20Shils, ME: "A Program for Total Parenteral Nutrition at Home" Am J Clin Nutr 28, 1429, 1975. 2tShils, ME: "Effects on Nutrition of Surgery of the Liver, Pancreas and Genitourinary Tract." Cancer Res 37, 2387, 1977. 2ZShils, ME: "Nutritional Problems Associated with Gastrointestinal and Genitourinary Cancer." Cancer Res 37, 2366, 1977. Z3Shils, ME: "Principles of Nutritional Therapy." Cancer (in press). 24Steiger, E, Oram-Smith, J, Miller, E, et al: "Effects of Nutrition on Tumor Growth and Tolerance to Chemotherapy." J Surg Res 18, 455, 1975. Z5Suskind, RM (ed): Malnutrition and the Immune Response. New York: Raven Press, 1977. 26Theologides, A: "General Perturbations in Host Physiology Caused by Localized Tumors. The Anorexia-Cachexia Syndrome." Ann NY Acad Sci 230, 14, 1974. 27Thompson, JC (ed): "Gastrointestinal Hormones." (symposium), Austin, TX: University of Texas Press, 1975. 28Wilmore, DW: The Metabolic Mangement of the Criticall lll. New York: Plenum Press, 1977, pp 140-143, 173-174. 29Young, VR: "Energy Metabolism and Requirements in the Cancer Patient." Cancer Res 37, 2336, 1977. 30The Verner-Morrison syndrome is also termed pancreatic cholera or the WDHA syndrome. 31Physicians with patients who are potential candidates for HTPN and who are unaware of these centers may obtain information from the National Registry of Patients on Home Total Parenteral Nutrition. The New York Academy of Medicine, 2 East 103 Street, New York City, New York 10029. Attention: the author. Duplication of Nutrition and Cancer, in whole or In part, by any means for any purpose Is illegal. Nutrition and Cancer TIMN 222769

Table 2. Data Availability on Fiber Types PARAMETERS tn O U) w Z 0 Z ~ ~ Z Z Z Q U FIBER zO 0 g N m m U ~O ~ < oW _ ~ 0i= ~ J p J 0 W JZ Uw p t-w ~ zo ~ Q U ~ 0 tZ U z 0 W Z Q w~ z Q 00 O W2 Z ~ O fl J ~ ~ W J Q m ~ J Z tL W J cr ~? ~ - 2 m a > LL m U ~ ~ ? - ~ a ~ Celluloses Solkafloc x x x x x x x x x x x x x x Avicel x x x x x x o x o o x o o x Hemicelluloses Wheat brans x x x x x o 0 0 0 0 0 0 0 0 Corn bran x o x x x o x o 0 o x o Brewers grains x x x x x o 0 0 0 0 0 0 0 0 Soy fibers, cotyledons x x x x x x o 0 0 0 0 0 0 - o hulls x 0 x 0 x 0 0 0 0 0 0 0 0 0 Lignins Alfalfa stems x x 0 0 0 0 0 0 0 0 0 0 0 0 Pectins Citrus pulp x x x x x o 0 0 0 0 0 0 0 0 Apple pulp x 0 x X X 0 X 0 0 0 0 0 X 0 Cutins Peanut skins Gums Guar x x x o x x x o 0 0 o x o 0 Oat x o x o x x x x o x o x x o Key: x = data: o = no data descriptive knowledge. Some of the gaps exist because the required tech- niques are still lacking or are faulty. Until recently, there were few incentives to develop the techniques relevant to human or monogastric nutrition. Efforts are now under way in the US and in Europe to standardize the parameters and delineate the analyses still lacking. A series of uniform fiber sources for nutrition research is also needed. When different investigators report on a product simultaneously, an evaluator must know that the reports refer to the same product. A supply of batches of appropriate size can ensure this. Batches need not be identical as long as they are well enough described. It is only for basic research on the mechanisms of nutrition that identical experimental substances are required, and for this the researcher seeks chemical and physical puri- ty of components. If research batches of fiber other than the AACC wheat bran are prepared, analyses should be coordinated so as to be comparable among batches. This means that one central laboratory should perform reference analyses on every batch, whether or not the producers have already done their own. A complete set of findings would then be available under conditions that are as nearly alike as possible. For analytical results that are known to vary among laboratories, the central laboratory findings will not be presumed to be more valid than those from other laboratories except for purposes of comparison and standardization. Standardization would involve multiple analyses such as that conducted by AACC and should include as a minimum the determination of (1) fiber composition (crude fiber, acid detergent fiber, neutral detergent fiber, and analyses for each constituent), (2) carbohydrates; (3) lipids; (4) protein; (5) energy; (6) minerals (all nutritional- ly or toxicologically relevant); (7) vitamins; (8) steroids; (9) contaminants; (10) water (hydration capacity, solubil- ity, viscosity in solution/suspension); (11) bulk volume; (12) particle size; (13) pH; (14) digestibility (peptic fermen- tability, persorption); (15) microbiology; (16) phar- macology (bile acid binding, cation exchange, organic chemical binding). Based on the information acquired and on the discus- sion in the two workshops, the following seem to be logical research priorities at the present time: develop- ment of adequate, reproducible assay techniques, par- Duplication of Nutrition and Cancer, in whole or in part, by any means for any purpose is illegal. Vol. I, No. 1 17 TIMN 222770

Table 3. Product Descriptions and Derivatives Cellulose: polysaccharide polymer, (C,H,o05)n, in a linear 3 1-4 configuration; degree of polymerization :5 1000 for wood pulp and 3000 for cotton; molecular weight < 160.000 to 480,000. Solkafloc Delignified wood pulp is made from debarked, chipped logs by chemical digestion to a slurry, which is washed, bleached, and sheeted. The sheets of virtually pure cellulose fibers are shredded and then processed to separate and shorten the individual fibers. The duration of processing governs the degree of fineness. Birch, maple, and beech are the chief woods used, together with poplar, elm, and oak. The end-products are designated as Powdered Cellulose. Research batches available. Avicel Dissolving pulp is treated with dilute mineral acids to disrupt the fibers by hydrolysis. Particles (fibril bundles in the colloidal range) are like those obtained by enzymatic hydrolysis, e.g., by cellulases. After spray-drying, they are porous, plastic, and compressible. Grades of these particles are designated Avicel PH, and they are used as dry powders. When the particles of washed, acid-hydrolyzed cellulose are further processed mechanically before dry- ing, and sodium carboxymethyl cellulose is added to assist dispersion, the products are graded as Avicel RC, and they are used in aqueous dispersions. - These end-products are designated as Microcrystalline Cellulose. Research batches available. Hemicellulose: cellulose with a degree of polymerization <_ 150; corn hulls are source of pure hemicelluloses. Wheat brans The outer coats of wheat seeds are removed by milling. Wheat bran AACC A blend of mainly Soft White wheats prepared under defined conditions and stored at 0°F for future reference. Research batches available. Corn bran The pericarp portion of the corn kernel, after wet milling, classification by air (the light fraction is selected), washing, pasteurizing, dewatering, drying, and grinding to desired size-range. Brewers' grains Barley malt admixed with rice is dried- milled. and sieved; the end-product is granular and may contain up to 3% hops. Soy fiber: cells A by-product of protein-isolate production: cleaned to extract cell walls (checked by SEM), dried by alternative methods according to the desired end-product. which is fine but may be ground further. The end-products are cur- rently experimental, and data are being developed, hulls A by-product of soybean oil production. Lignin: polymer of incompletely known structure, thought to be noncarbohydrate. found in many plants; wood is 25-30% lignin. Alfalfa stems A by-product of alfalfa protein production; the fraction remaining after removal of leaves from plant. Pectin: a mixture of partly esterified galacturonan, galactan, and araban as polysaccharide polymers of molecular weight 20,000-400,000; 20-60% of the carboxyl groups esterified with methyl groups in natural pectins. Citrus pulp Orange peel and some pulp minus water-solubles, dried and ground by proprietary processes. Product is low in orange-oil, represents 15% of the wet peel or 7.5% of the orange; contains about 60% of the dry matter of the peel. Apple pulp Fresh Mcintosh apples are milled, pressed (dejuiced), water added 1:1, pomace passed through paddle finisher (0.40" screen), sterilized, dried on hot drum (120 °) to < 2% moisture; flakes bladed off, can be ground. Yield ca.8%, 32% insoluble solids, 50% soluble solids. Cutin: a mixture of polysaccharides and waxes that comprises cuticles of plants. Apple skins Skins are separated in wet slurry, dried and ground. Pilot-experiment scale. Peeler removes 1/16", skin is 1t64"; no purification yet. Peanut skins A by-product of peanut processing. Gum: a complex polysaccharide polymer, insoluble in alcohol and other organic solvents, or dispersible in water; hydrates rapidly to give viscous, colloidal solutions or dispersions. Guar gum Guar beans (Cyamopsis tetragonalobus, L) are mechanically dehulled and the endosperm is recovered after dif- ferential grinding and sifting; it is either dry-ground to desired mesh sizes or hydrated and flash-ground to desired particle sizes. The pure gum is a galactomannan. Oat gum The water soluble polymer with alternating cycles of twol3 1-3 and two-to-four /3 1-4 linkages is prepared from mineral-purified oat flour, cut and rolled; the process was patented on June 7, 1977 (Quaker Oats Co.). 18 Duplication of Nutrition and Cancer, in whole or in part, by any means for any purpose is illegal. Nutrition and Cancer - TIMN 222771

Table 4. Product Composition Data COMPOSITION FIBER CONTENT D mU ~ FIBERS m > ~ a n~~ 3 3 ~ ~ ~ ~ D 0 ~ O ~ D N ~ ~ m m N Z~ rn m ? n Z n ~ n m ~ ~ ~ -n 0- c C r ~ m 0 n C) C) 62 - ~ 5~ ~ 7 w O O ~ tD. ~ 10 (D (D 7 N ~ Celluloses Solkafloc - -- - - - - - 0.2-0.4% zero 100 zero zero zero Avicel PH101 zero zero 100 zero 81 97 99,7 zero 4oppm zero 100 zero zero zero PH105 zero zero 100 zero 71 95 98.9 zero 70ppm zero 100 zero zero zero RC501 zero zero 100 zero 64 - 94.1 zero 2.34% zero 100 zero zero zero RC581 zero zero 100 zero 60 - 93.5 zero 2.67% zero 100 zero ' zero zero RC591 zero zero 100 zero 63 - 94.3 zero 2.50% zero 100 zero zero zero Hemicelluloses Wheat brans - - - - - - - - - - - - - Wheat bran AACC 14.3 5.22 - starch 17.40 8.91 40.2 11.9 - 5.12% - - - 3.2% 3.0% zero sugars 7.04 cutins Corn bran 5-7.5 1-2 80 6-9 starch 18-20 90 3 - 0.1 acid-insoluble. ° 20 8 / ° 68 9 / o 0 6 / . zero . 0 . 0 . o Brewers grains 30 2 9 8.2 44.6 - 10 40 . (Nx5.9) (biol. available) 3.5% Soy fiber Cells Hulls 10 1 76 - 38 - - 0.5 4% 73% 39% 8% 7% 19% Lignins Alfalfa stems 12-13 2-3 - 12.6-16.6 17-51 - - - 3.8-5,2 - 50-59°/ 12-16% 14-17% 9-11 °Ao pecti Pectins Citrus pulp 5.92 2.15 - starch 2.1 18.2 27.7 26.62 - 3.48 - - - 0.26 32.0 pectin (orange flour) sugars 7.0 Apple pulp 1.1 0.3 9.1 7.5 - - - 3.8 1.5 - - - - 5-8% pectin Cutins Peanut skins GumsI Guar gum 5-6 0.5-0.8 - - 1.5-5 - - - 0.5-0.9 - - - - 78-82°i° gum (Jaquar A-40-F) Oat gum "as defined by the manufacturer

Table 5. Physical Characteristics PHYSICAL DATA lL ~ N W ~ Z 0 ~ (J) < } ~ FIBERS O U Q ~ ~ J cc ¢ O 0 ~ ~ < ~ cn x m a (n > "Dry" Max kg/liter Mesh =#/#m ?/g-' Cps Celluloses Solkafloc SW40 7 glg 0.15-0.17 16 x 100-140 (av.) itm - 18-30 (1 %, 25 °C) BW40 5 g/g 0.3-0.4 16 x 50-60 (av.) pm 0.061 18-30 (1 %, 25 °C) BW 100 3.6 g/g 0.45-0.55 16 x 35-45 (av.) pm 0.055 18-30 (1 %, 25 °C) (see data sheets) Avicel PH101 <5% - 0.27-0.32 50 (av.) ym 11-24 - PH102 <5% - 0.27-0.32 100 (av.) µm 10-14 - PH103 <3% - 0.27-0.32 50 (av.) µm 11-42 - PH105 <5% - 0.27-0.32 20 (av.) pm 20-42 - RC501 <6% - 0.59 30-35°% < 0.2 um - - RC581 < 6% 0.59 60-70% < 0.2 µm - - RC591 <6% - 0.59 60-70% < 0.2 pm - - Nemicelluloses Wheat brans - 65-67 0.15 1590 (av.) pm - - Wheat bran AACC 10.4% 9.5 g/g - 1°/o on #10. 33°ro on #30 - - trace thru #70 Corn bran 6-9% s3.8g/g - - - - Brewers grains 3.7% 3-7 gig 0.46 ad libitum - 20-40 (3%, 25 °C) 120-220 (5 %, 25 °C) Soy fiber cells - = 0.16-0.48 - - - hulls 9% 3.2 g/g - all thru #40. 95°~o thru #60, 75°!o thru #100 - - Lign,ins Alfalfa stems - - - - - Pectins Citrus pulp 48 10.6g/g ca 0.47 2.6°fo on #10. 52°% on #230. 75% on #400 - - Apple pulp <2.5 5gtg 0.17 powder: all thru #100 - - flakes: all thru #8. 10-25% thru #30 Cutins Peanut skins Gums Guar gum 10-15% 90% sol. - - - 3800 (1 %, 25 °C) Oat gum all soluble range 20-600 ad libitum 100-200 (1%, 25°C) Duplication of Nutrition and Cancer, in whole or in part, by any means tor any purpose is illegal. 20 Nutrition and Cancer TIMN 222773

Table 6. Elemental Data MINERALS D ~ N oo 00 tA a w 0 o c m Q ~ ~ a:1 FIBERS D c D ~ D W n w w s w ~ ~ ~ ~ m w ' y 3 pW a 3 c ~ 0 ~ o ~o r ~ ai c B 0 ~ > ~ c 3 c ~ o ~ _ c B _ c 3 _ c B w ~ ~ _ o ~ w a c. 3 ~. 3 parts per million (ppm) Celluloses Soikafioc 4 <0.1 <0.12 3 <0.1 0.5 <0.02 200 0.2 - 1 100 0.6 0.5 50 Avicel PH101 - <0.5 <0.45 - - - <0.03 1.3 - - <0.1 1.6 <0.5 - 0.7 Avicel PH105 - <0.5 <0.45 - - - <0.03 2.4 - - <0.1 2.7 <0.5 - 1.1 Avicel RC501 - <0.5 <0.45 - - - <0.03 43.8 - - <0.1 4.5 <0.5 - 3.7 Avicet RC581 - <0.5 <0.45 - - - <0.03 28.3 - - <0.1 7.7 <0.5 - 3.3 Avicel RC591 - <0.5 <0.45 - - - <0.03 39.3 - - <0.1 7.9 <0.5 - 2.9 Hemicelluloses ~ 8 Wheat brans - - - - - - - 12 - - 8-19 23 0 - - 1 1K Wheat bran, AACC 5 - <0.1 45.07 - 4.5 2.8 1200 - 39.2 15.6 122 2.3 - 4300 Corn bran - - - - - - - - - - - - - - - Brewers grains - - - - - - - 3100 - - 28 160 - - 2700 Soy fiber, cells - - 1.2 - - - 0.23 - - - 4.3 - 0.37 - - Soy fiber, hulls - - - - - - - - - - - - - - - Lignins 8K- Alfalfa stems 16-73 - - 15-72 - - - - - 5-18 30-85 - - ~ Pectins Citrus pulp <6 - <0.1 9.2 - 32.6 <0.2 7660 - 2.4 9.9 91.6 <1.2 - 1060 Apple puip - - - - - - - - - - - - - - - Cutins Peanut skins - - - - - - - - - - - - - - - Gums Guar gum - - - - - - - - - - - trace < 10 - - Oat gum - - - - - - - - - - - - - - -

N Table 6. Elemental Data (continued) MINERALS ~ 2: o Z v ~ ~ cn z c~ cn ~ ~ ? w FI BERS m w ~ ~ o o m ~ m c° ~ ~ Q a Z r n 'o w ~ (1) m v? ~ o 0 m D m ~ ~ ~ 3 ~ o ~ 3 9 ° o, 3 C 3 ~ ~ C N .n. parts per million (ppm) Celluloses Solkafloc 2 <0.1 0.3 0.2 30 - - 10 0.05 500 10.5 2 0.2 0.3 - Avicel PH101 - <0.04 - - <1.0 3.7 - - - 5.9 - - - <0.02 - Avicel PH105 - <0.04 - - <1.0 2.5 - - - 24.9 - - - <0.02 - Avicel RC501 - <0.04 - - <1.0 26.5 - - - 70K - - - <0.02 - Avicel RC581 - <0.04 - - <1.0 10.2 - - - 81K - - - <0.02 - Avicel RC591 - <0.04 - - <1.0 10.7 - - - 80K - - - <0.13 - Hemicelluloses ~ Wheat brans 2 - - - 1&47 - - 4 ,5 16K 105 Wheat bran, AACC 80 0.002 - - 10400 13800 0.1 35 - 1000 - - - 54.5 - Corn bran - - - - - - - - - - - - - - - Brewers grains 60 - - - 6300 400 - - - 150 - - - - - Soy fiber, cells - <0.5 - - - - - - - - - - - 43 - Soy fiber, hulls - - - - 890 - - - - - - - _ - 53 - Lignins 1600- 3900- Alfalfa stems 1036 - - - 5100 20000 - - - 11b4 - - - 26-69 - Pectins Citrus pulp 6 <0.5 - - 1130 11570 0.04 220 386 - - - - 19.3 - Apple pulp - - - - - - - - - - - - - - - Cutins Peanut skins - - - - - - - - - - - - - - - Gums Guar gum - - - - - - - - - - - - - - 20 Oat gum - - - - - - - - - - - - - - -

Table 7. Pharmacological Data PHYSIOLOGICAL DATA c7 z w Z N } ~ Z W Z m F- Z 0 U F- _J Z = W Z FIBERS m m U 2 0 O Z ° X w W Z ~ ~ W 0 v J ~ ~ W Q u' _ Q O W u- °0 0 cc t- ? ~ a mEq/ mEq/g Celluloses Cu4-+ 0.054, pH 5.0 < 0.003% N Solkafloc - - 0.04 0.013, pH 3.0 - Cu number 1-2 - Fe++0.018, pH 3.0 Avicel PH101 - 1.7±0.2 - - - - zero PH102 - 1.2±0.8 - - - - zero PH105 - 2.3±0.7 - - - - - zero RC501 - 1.1 ± 0.7 - - - - zero RC581 - 1.7 ± 1.0 - - - - zero RC591 - 0.5 ± 0.3 - - - - zero Hemicelluloses Wheat brans - - - - - - - Wheat bran AACC - - - - - - - - Corn bran - - - - - - - - Brewers grains - - - - - - - Soy fiber Cells - - - - - - - - Hulls - - - - - - - - Lignins Alfalfa stems - -- 22.9±0.7 - - - - - Pectins Citrus pulp - - - - - - - Apple pulp at >26% - - - - generally, - moisture zero Cutins Apple skins Peanut skins Gums Guar gum 100% - insolubilized by - biodegradable - - polyvalent cations Oat gum 100% - - - - zero - Duplication of Nutrition and Cancer, in whole or in part, by any means for any purpose Is illegal. Vol. I, No. 1 23 TIMN 222776

Table.8. Contributors to this Study SUBSTANCES SUPPLIERS CORPORATE OFFICERS SCIENTISTS Celluloses Solkafloc. e.g., Brown Company Mr. Anthony Santucci Emerson E. Morse, Ph.D. SW40 Berlm-Gorham Division Vice-President. Marketing Director, Technical Services BW40 650 Main Street Brown Company (Berlin. NH) BW100 Berlin. NH 03570 Berlin Gorham Division 603/752-4600 555 5th Avenue New York, NY 10017 212/986-8590 Avicel, e.g., Food Machinery & Chemical Corp. Mr. V. Gordon Clemens Robert O. Barfoot PH101, PH102, PH103, Chemical Group Headquarters General Manager Business Development Analyst PH105 2000 Market Street FMC Food & Pharmaceutical (Philadelphia, PA) RC501, RC581, RC591 Philadelphia. PA 19103 Products Group 215/299fi458 IPhiladelphia. PA) Corn bran A.E. Staley Manufacturing Co. Mr. Nathan Kessler Robert V. Shanefelt. Ph.D. (high xylan) 2200 Eldorado Street Group Vice President. Technicat Director. Food & Agricultural Prod. Decatur, IL 62525 (Decatur. IL) Research & Development (Decatur. IL) 217/423-0411 Hemicelluloses Wheat brans North Dakota State University Mr. T.W. Edminster William Shuey. Ph.D. Hard red spring Soring Wheat Quality Laboratory Administrator (Fargo. ND) Hard red winter Cereal Chemistry & Tech. Dept. USDA. ARC. OA 7011237-7 7 1 1 Soft red spring Fargo, ND 58102 Administration Building. Room 302A Soft red winter Washington. D.C. 20026 Soft white AACC 2021447-3656 (FTS) Durum AACC Soft White American Association of -Cereal Mr. Raymond J. Tarleton Joseph D. Mullen. Ph.D. Chemists Executive Vice President Dept. Head. Applied Research 3340 Pilot Knob Road AACC General Mills. Inc. St. Paul. MN 55121 tSt. Paul. MN) James Ford Bell Technical Center 612i454-7250 9000 Plymouth Avenue, N. Minneapolis, MN 55427 John V. Luck. Ph.D. Vice President & Technical Director General Mills. Inc. (Minneapolis. MN) 612/540-4417 Joseph D. Mullen, Ph.D. (same address) 612/5404417 Brewers grains Anheuser-Busch. Inc. Ernest A. Robbins. Ph.D. Ernest A. Robbins. Ph.D. 721 Pestalozzi Street Associate Director. Yeast (same address) St. Louis, MO 63118 Products Research (St. Louis, MO) 314/577-3321 Soy fiber concentrates Cotyledons Ralston Purina Company Mr. J.J. Anton Wayne R. Moore, Ph.D. 900 Checkerboard Square Divisional Vice President, Protein (St. Louis. MO) St. Louis, MO 63118 & Dairy Foods Systems Marketing 314/982-3477 (St. Louis, MO) Hulls Archer Daniels Midland. Inc. Mr. James R. Randall Frank Horan, Ph.D. P.O. Box 1470 President (Decatur, IL) Decatur, IL 62525 (Decatur, IL) 217/424-5200 Lignins Alfalfa stems USDA Regional Research Center Mr. T. W. Edminster George O. Kohler, Ph.D. 800 Buchanan Street Administrator (Albany, GA) Albany, GA 94710 USDA, ARC, OA 415/486-3753 Administration Building, Room 302A Washington, D.C. 20026 202/4463658 (FTS) 24 Duplication of Nutrition and Cancer, in whole or in part, by any means for any purpose Is illegal. Nutrition and Cancer TIMN 222777

Table 8. Contributors to this Study (continued) SUBSTANCES SUPPLIERS CORPORATE OFFICERS SCIENTISTS Pectins Citrus pulp Tropicana Products, Inc. Mr. Anthony T. Rossi James M. Bonnell. Ph.D. P. O. Box 338 Chairman of the Board iBradenton. FL) Bradenton, FL 33505 and Chief Executive ts13, 7474461 (Bradenton. FL) 8131747-4461 Apple pulp Valley Evaporating Company, Inc. Wallace J. Miller. M.Sc. C. Stephen Travis P. O. Box 761 President (Che)an Falls. WA) Chelan Falls, WA 98817 Valley Evaporating Company. Inc. 509/682-5912 P. O. Box 9216 Yakima. WA 98909 5091453-7169 Cutins Peanut skins Tom's Foods, Ltd. Mr. J. Wilbur Fergnner George E. Jenkins 900 8th Street Chairman of the Board (Columbus. GA) Columbus, GA 31902 (Columbus, GA) 4041323-2721 Gums Guar gum Celanese Polymer Specialties Co. Mr. John Lauer Arthur Goldstein, Ph.D. Technical Center Vice President (Jefferson Town. KY) 9800 Bluegrass Parkway Celanese Polymer Specialties Co. 5021585-80 1 1 Jefferson Town. KY 40229 Louisville Trust Building Riverfront Plaza Max Goldfrank. Ph.D. Louisville.KY 40402 Stern-Hall. Inc. 605 3rd Avenue New York, N.Y. 10016 212/764-8853 General Mills Chemicals. Inc. Mr. Donald Carlson Kenneth Rockstrom 4620 West 77th Street President (Minneapolis. MN) Minneapolrs. MN 55435 (Minneapolis. MN) 612/830-7966 612/378-3113 Oat gum (flour) The Quaker Oats Company Mr. J.F. Angeline Sean O'Mahoney. Ph.D. 617 Main Street Vice Presrdent. R&D Robert O. Neshelm. Ph.D. Barrington. IL 60010 (Barrington. IL) (Barrington. IL) 312/381-1980 ticularly for identifying and quantifying "soft" fibers in natural sources and in prepared foods and; establish- ment of research batches representative of the major fiber categories. Enviro Control, Inc. 11300 Rockvil/e Pike Rockville, MD 20852 LON CROSBY References and Notes tAnderson, JW: "High Polysaccharide Diet Studies in Patients with Diabetes and Vascular Disease." Cereal Fds Wld 22(1), 12, 1977. 2Burkitt, DP, and Trowell, HC (eds): Refined Carbohydrate Foods and Disease. London: Academic Press, 1975. Vol. I, No. 1 312/381-1980 ~ 3Burkitt, DP, Walker, ARP, and Painter, NS: "Effect of Dietary Fibre on Stools and Transit-Times, and its Role in the Causation of Disease." Lancet 2, 1408, 1972. 'Cowgill, GR, and Anderson, WE: "Laxative Effects of Wheat Bran and "Washed Bran" in Healthy Man. A Comparative Study." JAMA 98, 1866, 1932. 5Eastwood, MA, Smith, AN, Mitchell, WD, and Pritchard, JL: "Physical Characteristics of Fiber Influencing the Bowel." Cereal Fds Wld 22(1), 10-11, 1977. 6Fantus, B, Kopstein, G, and Schmidt, HR: "Roentgen Study of In- testinal Motility as Influenced by Bran." JAMA 114, 404, 1940. 7Grande, F, Anderson, JT, and Keys, A: "Effect of Carbohydrates of Leguminous Seeds, Wheat and Potatoes on Serum Cholesterol Con- centration in Man." J Nutr 86, 313, 1965. 8Heaton, KW, and Pomare, EW: "Effect of Bran on Blood Lipids and Calcium," Lancet 1, 49, 1974. 9Jeffrys, DB: "The Effect of Dietary Fibre on the Response to Orally Administered Glucose." Proc Nutr Soc 33, 11A (abstr), 1974. 10Kelsay, JL: "A Review of Research on Effects of Fiber Intake on Man." Am J Clin Nutr 31, 142-159, 1978. "Keys, A, Anderson, JT, and Grande, F: "Diet-Type (Fats Constant) and Blood Lipids in Man." J Nutr 70, 257, 1960. Duplication of Nutrition and Cancer, in whole or in part, by any means ror any purpose is illeyal. 25 TIMN 222778

1ZMaihotra, SL: "Geographical Distribution of Gastrointestinal Cancers in India with Special Reference to Causation." Gut 8, 361, 1967. t3McCance, RA, Prior, KM, and Widdowson, EM: "A Radiological Study of the Rate of Passage of Brown and White Bread Through the Digestive Tract of Man." Brit J Nutr 7, 98, 1953. 14Painter, NS: "Diverticular Disease of the Colon. A Disease of This Century." Lancet 2, 586, 1969. 15Persson, i, Raby, K, Fonns-Bech, P, and Jensen, E: "Bran and Blood-Lipids." Lancet 2, 1208, 1975. 'BPiepmeyer, JL: "Use of Unprocessed Bran in Treatment of Irritable Bowel Syndrome." Am J Cin Nutr 23, 106, 1974. 17Spiller, GS and Amen, RJ: Fiber in Human Nutrition. New York: Plenum Press, 1977. 18Trowell, H: "Dietary Fibre, Ischaemic Heart Disease and Diabetes Mellitus." Proc Nutr Soc 32,151, 1973. "Troweil, H, Godding, E, Spiller, GS, and Briggs. G: "Fiber Biblio- graphies and Terminology." Am J Clin Nutr 31, 1489-1490, 1978. 20Ulbrecht, TLV: "Cereals, the World Food Problem and UK Self- Sufficiency." Proc Nutr Soc 36, 121-126, 1977. 2tvan Soest, P: "Dietary Fibers: Their Definition and Nutritional Properties." Am J Clin Nutr (suppl) 31(10), S12-S20, Oct 1978. 22Williams, RD and Olmsted, WH: "The Effect of Cellulose, Hemi- celluiose and Lignin on the Weight of the Stool: A Contribution to the 26 Study of Laxation in Man." J Nutr 11, 433, 1936. 23The first workshop entitled "Fiber Research" was held on March 29, 1977, in conjunction w(th the symposium Role of Dietary Fiber in Health sponsored by the National Institutes of Health. (The proceedings of the symposium are now available as a supplement to Am J Clin Nutr, 31(10) S1-S291.) Participants included: Dr. Martin A. Eastwood, Edinburgh University; Dr. Gio B. Gori, NCi; Dr. D. Mark Hegsted, Harvard University, Cambridge; Dr. David Kritchevsky, Wistar Institute, Philadelphia; Dr. Joseph L. Lyon, University of Utah; Dr. Hugh Trowell, England. The second workshop entitled "Standard Fiber Sources" was held on August 24, 1977. Participants included: Dr. D. Mark Hegsted, Harvard University; Dr. Louis E. Kovacs, Vitamins, Inc.; Dr. David Kritchevsky, Wistar Institute; Dr. Joseph D. Mullen, General Mills, Inc.; Dr. Daryl Schaller, Kellogg Company; Dr. Peter J. van Soest. Cornell University. 24Further information on the Diet, Nutrition and Cancer Program can be obtained from Dr. Guy R. Newell, Deputy Director, National Cancer Institute, Bethesda, MD 20014. 25Any additions to the available data are welcomed from readers of this report. Additions should be sent to the author. 261 would like to thank the workshop participants, suppliers, Dr. Joseph D. Mullen, the Chairman of the American Association of Cereal Chemists' Food Fiber Committee, and Dr. Humphrey Sassoon. Duplication of Nutritbn and Cano.r, in wfroN or In part, by any m.ans for any PurPosa Is IlNpal. Nutrition and Cancer TIMN 222779

Inhibition of In Vitro Metabolic Activation of Carcinogens by Wheat Sprout Extracts Abstract Extracts from the roots and the leaves of wheat sprouts selectively inhibited the mutagenic ef- fect of carcinogens requiring metabolic activa- tion as demonstrated in the Ames Salmoneila/ mammalian microsome test. Formation of di- hydrodiol metabolites of benzo(a)pyrene was significantly reduced, as seen in high pressure liquid chromatographic profiles of metabolites. Introduction There is increasing evidence that diet is a major envi- ronmental modifier of the carcinogenesis process. At least five cancer sites have been related to diet: esophagus, stomach, liver, breast, and colon.15 Associa- tion has been shown between fat intake, particularly from meat, and cancer of the large bowel and breast.',5 Groups that subsist mostly on a vegetarian diet such as the Seventh-Day Adventists have a lower incidence of cancer.9 While diet may be a factor in causing cancer, it may also exert a protective role toward carcinogens. Vitamins and trace metals appear to reduce certain chemically induced tumor formations.'2 Some of the known inhibitors, such as the indole compounds and thiocyanates, occur naturally in vegetables. They modify the response to carcinogens in animals by increasing mixed function oxidase activity. Several plant extracts were initially screened, and fresh extract of wheat sprouts was chosen for studying antagonistic activities toward known carcinogens in an established short-term assay. The Ames test, which measures the production of histidine-independent rever- tants in specially constructed mutants of Salmonella typhimurium, was selected as a direct mutagenesis assay having good predictive value for carcinogenesis.14 Materials and Methods The following materials were obtained from Aldrich Chemical Co., Milwaukee, WI: 2-aminoanthracene (2-AA), 2,acetylaminofluorene (2-AAF), 2-nitrofluorene (2-NF), N-methyl-N-nitrosoguanidine (MNNG). 3-Methyl- cholanthrene (3-MC), ethyl-rnethanesulfonate (EMS), and benzo(a)pyrene (BP) were from Eastman. Aflatoxin B, (AFb) was from Calbiochem, San Diego, CA. N-hydroxy 2-acetylaminofluorene (N-OH-AAF), N-hydroxyamino- fluorine (N-0H AF) were gifts from Drs. James and Elizabeth Miller's Laboratory. j'H) BP was obtained from Amershan, Arlington Heights, IL. Salmonella typhi- murium strain TA 100 was kindly provided by Dr. Bruce Ames. Untreated wheat berries from Arrow Mill, TX were soaked overnight in water. A monoiayer of the presoaked wheat was then spread over a container with drainage and was covered for two days until the root system started to develop. The sprouts were exposed to indirect sunlight and were ready for harvest when they were four to five inches tall (approximately 7-14 days). Extracts were made from both the roots and leafy parts of the plants by first pounding the plants with mortar and pestle over ice and mechanically pressing out the juice. The un- diluted juice was centrifuged for 30 minutes at 30,000 x g at 4°C. The clear liquid was sterilized by filtration through millipore filters (0.45 N.m). Male Long Evans hooded rats, weighing 250 g each, were given an i.p. injection of Arochlor 1254 (Monsanto Chemical Co.), a potent inducer of mixed-function ox- idases.z The preparation of the liver homogenate fraction (S-9) was carried out according to Ames.z The S-9 frac- tions were stored at -70°C until used. The S-9 mixture was prepared by mixing thawed S-9 with cofactor supple- ment having the following composition per plate: NADP, 2.85 mM; glucose-6-phosphate, 3.55 mM; KCI, 23.5 mM, MgCIZ, 5.7 mM; and phosphate buffer pH 7.4, 0.14 M. Duplication o/ Nutritlon and Cancer, in whole or in part, by any means for any purpose is illegal. Vol. I, No. 1 27 TIMN 222780

2-AAF 3 r N-OH-AAF Figure 1. His+ revertants per plate for 50 gg of 2-AAF and 5 µg of N-OH-AAF in the presence of S-9 mix and varying amounts of wheat leaf extract: 0 = no extract;A = 25 µi; •= 50 µl; tI = 100 µl; = 150 µl X ~ 0 2 Q ~ Q ~ c a ~ > I U) S 0 5 20 40 S-9 Mix(ul) In testing 2-AAF and its derivatives by the Ames Salmonella/mammalian microsome mutagenicity test, the chemicals were preincubated with the cells under testing conditions at 37°C for 30 minutes before plating with top agar. The procedure for plate incorporation was the same as described by Ames.z The chemicals and plant extracts used in the test condition did not significantly alter the viable cell counts (=5 x 106 cells per plate with the liquid preincubation, =_2 x 108 cells per plate with the direct plate incorporation method). Metabolites of BP were formed by incubating labeled ['H] BP with S-9 with or without the plant extracts. The conditions for the control were the following: 200 nM PH] BP in 20 Al DMSO, 1.96 AM unlabeled BP, 0.75 mg of NADH and NADPH each, 10 µI S-9, 0.6 µM MgC12f 10 µM Tris chloride buffer, pH 7.5, and enough distilled water to make 1 ml solution. The conditions for the samples were the same as for the control with the addition of 100 µl root or leaf extract. The mixtures were incubated at 37°C for 30 minutes. Metabolite extraction procedure was described by Selkirk.19 Metabolite separation was per- formed on a Dupont High-Pressure Liquid Chromato- graph Model 830 with multiwavelength photometer, using procedures similar to Yang24 and Huberman.10 The instrument was fitted with a Dupont i.d. 8.2 x 25 cm Zor- bax ODS column. The column was eluted with an initial mixture of 60% methanol in water to a final mixture of 95% methanol for 100 minutes. Column fractions (0.1 min) were collected and counted in a Searle Isocap 300 li- quid scintillation system using Scinti Verse (Fisher Scientific Co., Fair Lawn, NJ) as the counting fluid. 28 .5 0 i i i i 0 5 20 40 S-9 Mix (gl) Results and Discussion Results of the mutagenic assay for 2-AAF and its derivative N-0H-AAF and 3-MC are summarized in Figures 1, 2. Extracts from both the leaves and roots of wheat plants selectively inhibited the mutagenic effect of compounds requiring metabolic activation. Results with other selected known carcinogens 2-AA, BP and AFb are shown in Table 1. The qualitative feature of the dose response relationships of inhibitions are similar to that of 3-MC. No inhibition was observed in conjunction with carcinogens not requiring metabolic activation (2-NF, EMS, and MNNG). The results seen with AAF and its derivatives further il- lustrate the specificity of the inhibition. The extracts were most active in altering the primary metabolic path- way of AAF, less so with its derivative N-0H-AAF, and with no effect on N-0H-AF. This is in agreement with in vitro inhibitory action of selenium in a similar mutagenic assay." Alteration of the formation of BP metabolites was observed in the HPLC profile. The inhibitors produced selective reduction of metabolites. The formation of the dihydrodiols was reduced somewhat. Root extracts sup- pressed dihydrodiol formation more effectively than did the leaves. The relative amounts of BP metabolites for the controls versus those with added root extracts were as follows: 9,10-diol, 8.3:1.4; 4,5-diol, 4.5:1.0; 7,8-diol, 5.2:1.0; 9-OH, 3.9:2.0; 3-0H, 25.3:10.5. These results are of interest for two reasons: First, the inhibition of activation of potent carcinogens is quite Duplication of Nutrition and Cancer, In whole or in part, by any means for any purpose is illegal. Nutrition and Cancer TIMN 222781

strong at a reasonably low level of extract, and second, the wheat sprout extract is nontoxic even at high levels while most known inhibitors are toxic at medium to high leveis.22 Trace elements such as arsenic, iodine, platinum, cop- per,and particularly selenium (in a certain oxidized state) have shown antineoplastic effects.",23 In the case of selenium, epidemiological as well as animal studies have demonstrated an inverse relationship between levels of selenium and cancer.18 Animal studies have shown that selenium reduces the incidence of colon tumors in rats subjected to 1,2ciimethylhydrazine and methylazoxymethanol,t2 and the incidence of liver cancer in rats after receiving the azo dye 3-methyl~-dimethylaminobenzene.' The inhibitory properties of wheat sprout extract, however, cannot be explained by the action of selenium alone or of any other metals. Our analyses for selenium, using Chan's4 improved version of Watkinson's21 fluor- metric method, yielded less than 0.5 ppm in the leaf ex- tract. This is slightly less than 0.5,ug per plate, which is equivalent to 1/300 of the selenium level in the study reported by Jacobs et al" where 20% inhibition was achieved after incubation with AAF. Synergistic interaction of metals is very probable, and Maines et al" have reported a tenfold potentiation be- tween cobalt and iron in inducing oxygenase activity. Furthermore, trace metals may also function with vita- mins. One example is selenium and vitamin E. Dietary a- tocopherol increased the selenide form of selenium in mitochondria and microsomes.6 Petering's discussed the complex interrelationships between vitamin A and zinc metabolism. Vitamin E alone reduced the carcino- genicity of methylcholanthrene in animals,8 and vitamin A demonstrated protective effects toward chemical car- cinogenesis 20 Alternatively, the plant extracts may con- tain other antioxidants or enzymes that direct the pro- mutagens to a nonmutagenic product. Figure 2. His+ revertants per plate for 25 µg of 3-MC in the presence of S-9 mix and varying amounts of wheat leaf extract: O= no extract; •= 50 ul; ..- 100 µl; = 150 fd. 3 M 0 i 3MC i i 5 20 i 1 40 S-9 Mix (uI) I I 60 Table 1. His + Revertants/Plate for 2-AA, BP, and AFb in the Presence of S-9 Mix and Varying Amounts of Wheat Sprout Extract. Chemical Extracts (ul) S-9 (µI) His + Revertants/Plate Activity (%) 2-AA - 10 3870 100 (0.34) 50 (leaves) 10 622 16 150 (leaves) 10 265 7 150 (roots) 10 31 1 BP - 10 609 100 (5 µg) 150 (leaves) 10 487 80 50 (roots) 10 439 72 100 (roots) 10 228 37 150 (roots) 10 102 17 AFb - 10 892 100 (0.1 Ag) 100 (leaves) 10 373 42 50 (roots) 10 381 43 Duplication of Nutrition and Canoer, in whole or In part, by any means for any purpose is illegal. Vol. I, No. 1 TIMN 222782

Preliminary analysis of the active components in wheat sprouts suggested it to be a protein or bound to a protein of molecular weight greater than 100,000 and sen- sitive to heat.25 The inhibitory activities were partially destroyed at 50°C for 15 minutes. Studies with mice in- duced for colon cancer are in progress to determine the correlation between the inhibitory effect of the wheat sprouts on in vitro mutagenesis and in vivo carcinogenesis. The wheat sprout was not unique in possessing in- hibitory activity in the mutagenic assay. Two other sprouts, mung bean and lentil, demonstrated similar in- hibitory activities. However, extracts from carrots and parsley exhibited inhibitory activities not as potent as those of wheat. Extracts from wheat soaked overnight and unsprouted did not demonstrate any inhibitory activities. CHIU-NAN LAI BETTY J. DABNEY CHARLES R. SHAW Department of Biology The University of Texas System Cancer Center M. D. Anderson Hospital and Tumor Institute Houston, TX 77025 References and Notes 'Alcantara, EN, and Speckmann. EW: "Diet, Nutrition and Cancer." Am J Clin Nutr 29, 1035-1047, 1976. ZAmes, BN, McCann, J, and Yamasaki, E: "Methods for Detecting Carcinogens and Mutagens with the Salmonella/mammalian- microsome Mutagenicity Test." Muf Res 31, 347364, 1975- 3Armstrong, B, and Doll, R: "Environmental Factors and Cancer In- cidence and Mortality in Different Countries, with Special Reference to Dietary Practices." Int J Cancer 15, 617-631, 1975. 'Chan, CCY: "Improvements in the Fluorometric Determination of Selenium in Plant Materials with 2,3-Diaminonapthalene." Anal Chim Acta 82, 213-215, 1976. 5Correa, P, and Haenszel, W: "The Epidemiology of Large-Bowel Cancer." Adv Cancer Res 26, 1-141, 1978. 6Diplock, AT, Baum, H, and Lucy, JA: "The Effect of Vitamin E on the Oxidation State of Selenium in Rat Liver." Biochem J 123, 721-729, 1971. 'Griffin, AC, and Jacobs, MM: "Effects of Selenium on Azo Dye Hepatocarcinogenesis." Cancer Lett 3, 177-181, 1977. 30 BHaber, SL, and Wissler, RW: "Effect of Vitamin E on Carcino- genicity of Methylcholanthrene." Proc Soc Exp Biol Med 111, 774-775, 1962. 9Higginson, J, and Muir, CS:'The Role of Epidemiology in Elucidating the Importance of Environmental Factors in Human Cancer." Cancer Det Prev 1, 79-105, 1976. 10Huberman, E, Sachs, L, Yang, SK, and Gelboin, HV: "Identification of Mutagenic Metabolites of Benzo(a)pyrene in Mammalian Cells." Proc Natl Acad Sci USA 73, 607-611, 1976. "Jacobs, MM, Matney, TS, and Griffin, AC: "Inhibitory Effect of Selenium on the Mutagenicity of 2-Acetylaminofluorene (AAF) and AAF Derivatives." Cancer Lett 2, 319-322, 1977. tZJacobs, MM, Jansson, B, and Griffin, AC: "Inhibitory Effects of Selenium on 1,2-Dimethylhydrazine and Methylazoxymethanol Acetate In- duction of Colon Tumors." Cancer Lett 2, 133-138, 1977. 13Maines, MD, and Kappas, A: "Metals as Regulators of Heme Metabolism." Science 198, 1215-1221, 1977. 14McCann, J, Choi, E, Yamasaki, E, and Ames, BN: "Detection of Car- cinogens as Mutagens in the Sa/monella/microsome Test: Assay of 300 Chemicals." Proc Nat/ Acad Sci USA 72, 5135-5139, 1975. 15Newberne, PM: "Environmental Modifiers of Susceptibility to Car- cinogenesis." Cancer Det Prev 1, 129-173, 1976. 16Petering, HG: "Diet, Nutrition and Cancer." Advan Exp Med Biol 91, 207-228, 1978. 17Pories, WJ, Mansour, EG, and Strain, WH: "Trace Elements that Act to Inhibit Neoplastic Growth." Ann NY Acad Sc! 199, 265-271, 1972. 18Schrauzer, GN: "Trace Elements, Nutrition and Cause: Perspectives of Prevention." Adv Exp Med Biol 91, 323-344, 1978. t9Selkirk, JK, Croy, RG, Wiebel, FJ, and Gelboin, HV: "Differences in Ben- zo(a)pyrene Metabolism Between Rodent Liver Microsomes and Embryonic Cells." Cancer Res 36, 4476-4479, 1976. 20Sporn, MB, Dunlop, NM, Newton, DL, and Smith, JM: "Prevention of Chemical Carcinogenesis by Vitamin A and its Synthetic Analogs (Retinoids)." Fed Proc 35, 1332-1338, 1976. 21Watkinson, JH: "Fluorometric Determination of Selenium in Biological Material with 2,3-Diaminonaphthalene." Anal Chem 38, 92-97, 1966. 22Wattenberg, LW: "Inhibitors of Chemical Carciriogenesis-" Adv Cancer Res 26, 197-226, 1978. Z3White, DA: PhD Thesis, Department of Chemistry, University of California, San Diego, 1978. 2'Yang, SK, McCourt, DW, Roller, PP, and Gelboin, HV: "Enzymatic Conversion of Benzo(a)pyrene Leading Predominantly to the Diol-epoxide r-7,t-8-Dihydroxy-t-9,10-oxy-7,8,9,10-tetra- hydrobenzo(a)pyrene through a Single Enantiomer of r-7,t-8- dihydroxy-7,8-dihyrobenzo(a)pyrene." Proc Natl Acad Sci USA 73, 2594-2598, 1976. 2$The authors have now identified the main active factor. Details will appear in a future issue of Nutrition and Cancer. 26Supported in part by grant GM-15597 from the National Institute of General Medical Sciences. Duplication of Nutrition and Cancer, in whole or in part, by any means for any purpose is llteyal. Nutrition and Cancer TIMN 222783

REVIEW Early Nutrition, Growth, Disease, and Human Longevity Abstract portion of young individuals who are potential parents, make the situation even more alarming than mere con- sideration of probable population doubling time. Many factors combine to increase the pressure the world's human population will make on its resources in the im= mediate future. Since a large proportion of those who can reproduce will do so, a first concern must be to deter- mine how to avoid the most undesirable consequences until effective population control is accomplished. Infant feeding practices are one of the many areas of im- mediate concern. Some of the dangerous trends in infant nutrition in many parts of the world will be briefly noted here. My purpose is to show that early weaning, a prac- tice that seems to be spreading in many parts of the world, has the potential of doing much damage in both affluent and impoverished populatioris: Over the last century, there has been a signifi- cant increase in human life expectancy in many parts of the world. At the same time there has been a trend toward increased body size. While nutritional factors are involved in both of these trends, there is reason to suspect that maximiza- tion of human growth has detrimental effects that have been obscured by the concurrent im- provement in the care and prevention of infec- tious disease. The nutritional patterns of an in- creasing proportion of the world's population give evidence of being maladaptive in several im- portant sectors. In addition to increasing meta- bolic requirements (while there is a food scar- city), maximization of growth may predispose the individual to certain degenerative conditions, among them cancer. The identification of the true nutritional re- quirements of the human newborn and of the proper rate of growth for prevailing conditions is essential to further improve human longevity. Clues to the proper nutritional intake and growth rate for human infants can be found in the volume and constituents of human milk and the growth of human infants exclusively breast-fed for the first 6 to 9 months of life. Introduction The last 100 years have been a time of enormous expansion in the human population of the world. The growth in numbers has become a matter of widespread concern. However, the numbers do not tell the whole story. Demographic factors such as an increasing pro- Vol. I, No. 1 Increased Human Body Size It has been widely noted that many human popula- tions around the world are increasing in average body size.58 More than that, the adult body size is reached earlier, and there is a parallel trend toward earlier sexual maturation 62 Medical records from 100 years ago show that menarche occurred in European and North American women at an average age of 17 years, but the present average in those same populations is closer to 13 years. People are getting bigger earlier and, at least in the case of females, are lengthening their potential reproduc- tive life span. All of these factors act synergistically to in- crease the demand for food and the resources to pro- duce it. Land and resources to satisfy that demand are limited. The exploitation of new areas and the new technological means to bring them under cultivation are approaching a point of diminishing return.52 Moreover, the means by which human food requirements are satis- fied have become increasingly expensive as a result of more energy-intensive methods and a taste for animal Duplication of Nutrition and Cancer, in whole or in part, by any means for any purpose is illegal. 31 TIMN 222784

protein. An increasing proportion of the human energy in- take passes through several trophic levels after its initial appearance as solar radiation.57 Human Health and Improved Nutrition It is reasonably certain that the larger body size, earlier maturation, and increasing numbers of many human populations are at least in part attributable to improved nutritional status. Technological improvements in food production have been paralleled by significant advance- ments in medical care and public health. It is, therefore, fair to say that much of the current increase in total and potential human biomass is the direct result of human technology. It would be irresponsible to minimize the contribution technological innovations have made to the reduction of human misery. But it is essential to recognize the nature of the changes in human mortality patterns that have emerged because of them. In the US, for example, life expectancy at birth has in- creased from slightly over 45 years to slightly over 70 years (sexes combined) since the tyrn of the century. This is an impressive accomplishment. But the increase is more a result of reducing early death from infectious disease than of lengthening the human life span. More people survive through the early and middle years, but the proportion of survivors older than 70 has changed little. Thus, despite obvious improvements in the health of most human populations, certain diseases associated with increasing age have become more prevalent than before. Table 1 shows the shift in causes of death be- tween 1900 and 1968.68,87 With better control of infectious disease, the death rate from cancer and heart disease combined has increased from 409 per 100,000 persons in the US in 1900 to 532 per 100,000 today. While this increase certainly reflects the presence of a higher pro- portion of older people in the population (thereby raising the number at risk), it also gives evidence that increased body size and the associated nutritional patterns have not improved longevity as much as might be hoped. In fact, there is a real possibility that longevity in- crease will not be forthcoming until there is a shift in nutritional patterns in the more affluent countries. An im- portant element of that shift is the way in which the nutri- tional needs of each individual are determined. Since these needs result from both metabolic requirements and acquired appetites, it is essential that we scrutinize closely the earliest period of human life, when they are both subject to modification.89 If it is found that maximization of growth is not synony- mous with optimization of growth, we should focus on the early postnatal period. This is the time when normal growth should yield a phenotype reflecting more than 100,000 generations of natural selection. Such pheno- types should be the baseline from which we derive esti- mates of what is normal or optimal. Human Growth in Neonatal and Infant Life While a variety of stresses affect fetal growth, we will devote our attention primarily to the first 6 months of postnatal life. The subject of maternal nutritional status Table 1. Leading Causes of Death in the United States in 1900 and 1968.66,6' Deaths per Cause of death: 1900 100,000 1. Diseases of the heart and blood vessels 345 2. Influenza and pneumonia 202 3. Tuberculosis 194 4. Diseases of the stomach and intestines 143 5. Accidents 72 6. Cancer 64 7. Diphtheria 40 8. Typhoid and paratyphoid fever 31 9. Measles 13 10. Cirrhosis of the liver 13 32 Cause of death: 1968 Deaths per 100,000 1. Diseases of the heart 373 2. Cancer 159 3. Cerebrovascular diseases (stroke) 106 4. Accidents 58 5. influenza and pneumonia 37 6. Certain diseases of early infancy (upper respiratory and gastrointestinal) 22 7. Diabetes 19 8. Atherosclerosis 17 9. Bronchitis, emphysema, and asthma 17 10. Cirrhosis of the liver 15 Duplication of Nutrition and Cancer, in whole or !n part, by any means for any purpose is llleyal. Nutrition and Cancer ®1 TIMN 222785

have acquired a predisposition for a diet peculiar for a primate, with animal protein and fat yielding more than half of daily caloric requirements. Moreover, the infant subjected to a year of ad libitum feeding of high-protein milk or formula has more lean body mass and adipose tissue, neither of which can be functionally justified. In impoverished regions of the world, breast-feeding may well produce larger one-year-olds than does bottle- feeding, because contamination during bottle feeding is often the source of respiratory and gastrointestinal infec- tions. Also, it is often impossible to supply a sufficient replacement for breast milk when babies in impoverished regions are weaned early. Use of inferior supplements such as rice water, sugar water, or crushed bananas leads to serious nutritional deficiencies and imbalances that can develop into various forms of protein-calorie malnutrition.31 However, breast-feeding is not always possible. This is especially true when the mother is so undernourished that she is unable to sustain an ade- quate milk flow. When frequent pregnancies, poor nutri- tion, and borderline health combine to make breast- feeding impractical or impossible, supplementation of some form is unavoidable. Prepared formulas are of im- mense value, but nutritional supplementation of the in- fant is far less efficient than supplementation of the mother's diet during pregnancy. Here again, we can ap- ply an evolutionary perspective. Maternal Adaptation During the period preceding menarche the human female experiences a substantial alteration in body com- position. The amount of fat, representing stored calories, increase rapidly. Frischt5"e has argued that this alteration of body composition and the lower metabolic rate associated with it trigger hormonal changes that ultimately initiate menarche. While there is disagreement concerning Frisch's hypothesis,s'there is no doubt that a fat reserve is accumulated during adolescence. The ac- cumulation of 80,000 to 90,000 calories can carry a woman through her first pregnancy even though her nutritional intake is adequate only to supply her own metabolic requirements 3,• Thus, the human female does not usually enter reproductive life without acquiring the capacity to support her fetus. It is likely that through the history of our species, there were many times when food was too scarce to provide additional food for pregnant women. Successful reproduction even during times of famine is a strong selective advantage which is en- hanced by the ability to divert amino acids and fatty acids to the fetus and to the production of milk as needed. Thus, the human female may for a time survive on a high-carbohydrate diet while producing milk supplying the newborn with amino acids, fatty acids, immuno- Vol. I, No. 1 globulins, vitamins, and minerals. This depletes the mother's stores of scarce nutrients. It is a tribute to human adaptation that with a reasonably adequate nutri- tional intake, a woman can accomplish this feat repeat- edly. It is not surprising, however, that where births occur at frequent intervals and where nutrition is inadequate, the system is overwhelmed and both the mother and child can be adversely affected.ZS,'°,",3' The significant point is that the human female can and usually does replenish her reserve sufficiently to permit successful pregnaricy and breast-feeding if given a modest amount of appropriate nutritional supplements. The amount needed varies, and many factors including the state of health and activity level of the woman in- fluence the quality and quantity of the supplementation required. But the mother's capacity to act as a buffer be- tween the infant and the environment is part of the evolu- tionary heritage of our species. In many parts of the world, the kind of supplementa- tion needed to carry a human baby through the first months of life without breast milk is simply not possible. Adequate quantities of milk or balanced formulas require resources beyond those at hand. While. carbohydrates sources are sometimes available in suitable quantities, high-protein foods are expensive everywhere, and often prohibitively so. It is much more difficult to supplement the diet of a prematurely weaned newborn than to supplement that of the mother, who could then continue breast-feeding. More than that, early supplementation of the mother's diet during her pregnancy can reduce the risk of her giv- ing birth to an undersized infant. The prognosis for under- sized newborns is especially poor and their supplementa- tion requirements particularly demanding, so there is ad- ditional reason to direct the allocation of scarce resources to the mother. Using this order of priorities, we can make better use of local resources and at the same time permit the newborn to establish nutritional patterns consistent with our species' requirements. That success can be attained through supplementing the mother during and late in pregnancy has been shown by the work of Habicht et al in Central America.20 It is im- portant to exploit carbohydrate-rich food sources to alleviate neonatal and infant malnutrition and to provide the mother with the means to exploit an adaptive strategy selected during millions of years of human evolution. Conclusions The benefits of "nourishing the mother, thereby the in- fant," go beyond the enhanced survival of newborns.56 Breast-feeding supplies nutrients for normal infant growth; milks of other species are a nutrient source evolved to support the growth of those species in which attainment of adult size and sexual maturity usually oc- Duplication of Nutrition and Cancer, in whole or in part, by any means for any purpose Is Illegal. 37 TIMN 222786 7_. .

curs much earlier than in humans. In areas where food is scarce and will probably remain so, avoidance of factors that increase lean body mass and metabolic demand is of special importance. When the potentially harmful ef- fects of such excessive growth on the individual are taken into account, the case becomes even more compelling. It is cheaper to provide sufficient nutrition for the lac- tating mother than to supplement the baby's diet with commercial foods and formulas, as has been shown by a study in Kingston, Jamaica. Cost differences ranged from 54 cents a week for a lactating mother and 76 cents a week for artificial feeding in poor populations, to $3.78 and $5.54, respectively, in more affluent circumstances.- It is important to understand the evolutionary forces that shaped our species in order to deal with environ- mental stresses in an adaptive manner. Human growth is subject to environmental modification; body size is not fixed for any genotype. Increases in metabolic demand parallel increases in body size, so bigger people need more food. Since the increase in food requirements is of f- set by little or no functional benefit, it is reasonable to ask whether factors causing it are maladaptive. Males seem especially vulnerable to alterations in early growth,",23,5a,6° and it is the male who has the poorest rate of survivorship in most types of disease. This is strik- ingly true for cancer.6 Breast-feeding maintains growth at evolutionarily determined levels. Thus, our adaptive mechanisms have permitted our species to cope with feast and famine and allow those phenotypes best suited to individuals and populations to survive. The process then is one by which growth is optimized by permitting expression of funda- mental biological processes. Optimization of growth is not its maximization, as the foregoing argument was in- tended to show. Whatever other benefits accrue from the practices of breast-feeding in human populations, this alone would be sufficient to warrant its encouragement in affluent and impoverished populations alike. It is possible that recognition of the proper rate of growth for human infants will prove instrumental in arresting the tendency toward increasing incidence of cancer and heart disease in human populations. Department of Anthropology University of Arizona Tucson, AR 85721 WILLIAM A. STINI References and Notes 'Altman, J, Copal, DD, and Sudershan, K: "The Influence of Nutri- tion on Neural and Behavioral Development. I. Critical Review of Some Data on the Growth of the Body and the Brain following Dietary Deprivation during Gestation and Lactation." Dev Psychobiol 3(4), 281-301, 1970. 38 2Berg, JW, Howell, MA, and Silverman, SJ: "Dietary Hypotheses and Diet-Related Research in the Etiology of Colon Cancer." Health Service Reports 88, 915•924, 1973. 3Blackburn, MW, and Calloway, DH: "Basal Metabolic Rate, Work, Energy Expenditure of Mature, Pregnant Women." J Am Diet Assoc 69(1), 24-28, 1976. 4Blackburn, MW and Calloway, DH: "Energy Expenditure and Con- sumption of Mature, Pregnant and Lactating Women." J Am Diet Assoc 69(1), 29-37, 1976. SBurman, D: "Nutrition in Early Childhood." In McLaren, DS and Burman, D (eds): Textbook of Paediatric Nutrition. New York: Churchill Livingstone, 1976, pp 46-75. sCorrea, P and Heanszei, W: "Comparative International Incidence and Mortality." In Schottenfeld, D (ed): Cancer Epidemiology and Prevention. Springfield, IL• Charles C. Thomas, 1975. 7 De Waard, F and Baanders van Halewyn, EA: "A Prospective Study in General Practice on Breast Cancer Risk in Postmenopausal Women." Int J Cancer 14, 153-160, 1974. 8De Waard, F: "Breast Cancer Incidence and Nutritional Status with Particular Reference to Body Weight and Height." Presented at the conference on "Nutrition in the Causation of Cancer." Key Bis- cayne, FL, May, 1975. 9Drori, D and Folman, Y: "Environmental Effects on Longevity in the Male Rat: Exercise, Mating, Castration and Restricted Feeding." Exp Gerontol 11, 2532, 1976. 10Dubos, R: Man Adapting. New Haven, CT: Yale University Press, 1965, 119-146. "EI-Nofely, AA: "Anthropometric Study of Growth of Egyptian Nubian Children." Hum Biol 50, 183-208, 1978. 'ZEnig, MG, Munn, RV, and Keeney, M: "Dietary Fat and Cancer Trends-A Critique." Fed Proc 37, 2215-2220, 1978. t3Ferro-Luzzi, A, Norgan, NG, and Durnin, JVGA: "Food Intake, Its Relation to Body Weight and Age, and Its Apparent Nutritional Ade- quacy in New Guinean Children." Am J Clin Nutr 28, 1443-1453, 1975. "Foman, SV: Infant Nutrition. Philadelphia: W. B. Saunders Com- pany, 1967. 15Frisch, RE: "Weight at Menarche: Similarity for Well-Nourished and Undernourished- Girls at Differing Ages, and Evidence for Historical Constancy." Pediatrics 50(3), 445450, 1972. 'sFrisch, RE: "A Method of Prediction of the Age of Menarche from Height and Weight at Ages 9 Through 19 Years." Pediatrics 53, 384390, 1974. "Frisch, RE: "Population, Food Intake and Fertility." Science 199, 2230, 1978. 18Frisch, RE: "Response to Trussel." Science 200, 1509-1513, 1978. 19Gyorgy, P: "Biochemical Aspects." In "The Uniqueness of Human Milk" (symposium). Am J Clin Nutr 24, 970-975, 1971. 20Habicht, JP, Yarbrough, C, Lechtig, A, and Klein, RE: "Relation of Maternal Supplementary Feeding During Pregnancy to Birth Weight and Other Sociobiological Factors." In Winick, M(ed) Nutrition and Fetal Development. New York: John Wiley and Sons, 1974, pp 127-145. 21Haenszel, W, Berg, JW, Sezi, M, Kurihara, M, and Locke, FB: "Large Bowel Cancer in Hawaiian Japanese." J Nat/ Cancer Inst 51, 1765-1779, 1973. 22Hahn, 0 and Koldovsky, 0: Utilization of Nutrients During Postnatal Development. London: Pergamon Press, 1966. 23Hall, RL: "Sexual Dimorphism for Size in Seven Nineteenth Cen- tury Northwest Coast Populations." Hum Biol 50, 159-172, 1978. 2'Hansen, RG: "Milk in Human Nutrition." In Larson, BL and Smith, VR (eds) Lactation; A Comprehensive Treatise. New York: Academic Press, 1974, pp 281308. Z5Haymond, MW, Karl, IE, and Pagliara, AS: "Increased Gluconeo- genic Substrates in the Small-for~Gestational-Age Infant." N Eng J Med 291, 322, 1974. Duplication of Nutrition and Cancer, in whole or in part, by any means for any purpose is Illegal. Nutrition and Cancer TIMN 222787

26Higgins, A: "A Preliminary Report of a Nutrition Study on Public Maternity Patients." Workshop on Nutritional Supplementation and the Outcome of Pregnancy, National Academy of Sciences, National Research Council, Washington, DC., 1972, 3rd ed, Jacobson, 1974. Z'Hill, PH, Chan, PC, Cohen, L, Wynder, E, and Kumo, K: "Diet and Endocrine-Related Cancer." Cancer 39, 1820-1826, 1977. 28Howell, MA: "Diet as an Etiological Factor in the Development of Cancers of the Colon and Rectum." J Chronic Dis 28, 67-80, 1975. 291yengar, L and Selvaraj, RJ: "Intestinal Absorption of Immuno- globulins of Newborn Infants." Arch Dis Child 47, 411-414, 1972. 30Jacobson, HN (ed): Report of a Workshop on Nutritional Supple- mentation and the Outcome of Pregnancy. National Academy of Sciences, National Research Council, Washington, DC, 1974. "Jeliiffe, DB: Infant Nutrition in the Subtropics and Tropics. Geneva: World Health Organization, 1968. 'ZJeliiffe, DB and Jelliffe, EFP: "Introduction" in "The Uniqueness of Human Milk" (symposium). Am J Clin Nutr 24, 968-969, 1971. "Jelliffe, DB and Jelliffe, EFP: "The Cost of Breast Feeding." Lancet 21 February, 1976. 3'Jenness, R: "The Composition of Milk." In Larson, BL and Smith, VR (eds) Lactation: A Comprehensive Treatise. New York: Academic Press, 1974, pp 3-107. 35Jose, DG and Good, RA: "Quantitative Effects of Nutritional Pro- tein and Caloric Deficiency upon Immune Responses to Tumors in Mice." Cancer Res 33, 807-812, 1973. 36Jose, DG, Stutman, 0, and Good, RA: "Good, Long-Term Effects on Immune Function of Early Nutritional Deprivation." Nature 241, 57-58, 1973. 37Kaminetzky, HA, Langer, A, Baker, H, Frank, 0, Thompson, AD, Munves, ED, Opper, A, Behrle, FC, and Glista, B: "The Effect of Nutri- tlon in Teen-Age Gravidas on Pregnancy and the Status of the Neonate." Am J Obstet Gynecol 115, 639, 1973. 38Kraybill, HF: "Carcinogenesis Associated with Foods, Food Ad- ditives, Food Degradation Products and Related Dietary Factors." Clin Pharmacol Ther 4, 73-87, 1963- 39Makinodan, T: "Immunobiology of Aging." J Am Geriatr Soc 24(6), 249-252, 1976. 40Mata, LJ and Urrutia, JJ: "Intestinal Colonization of Breast-Fed Children in a Rural Area of Low Socio-Economic Level." Ann NY Acad Sci 176, 93-109, 1971. •'Mata, W and Wyatt, RG: "The Uniqueness of Human Milk; Resistance to Infection." Am J Clin Nutr 24, 976-986, 1971. d2McCay, CM, Crowell, MF, and Maynard, LA: "The Effect of Retarded Growth Upon the Length of Lifespan and Upon the Ultimate Size." J Nutr 10, 63-79, 1935. 43McKigneiy, J: "Economic Aspects." In "The Uniquness of Human Milk" (symposium). Am J Clin Nutr 24, 1005-1012, 1971. `4McLaren, DS: "The Great Protein Fiasco." Lancet 11(7872), 93-96, 1974. 45Mellander, 0, Vahlquist, B, and Mellbin, T: "Breast Feeding and Artificial Feeding" (suppi) Acta Paediat 48, 16, 1959. 46Metcoff, J: "Maternal Nutrition and Fetal Growth." In McLaren, DS and Burman, D(eds) Textbook of Paediatric Nutrition. New York: Churchill Livingstone, 1976, pp 1946. "National Dairy Council: "Nutrition, Diet and Cancer." Dairy Coun- cil Digest 46(5), 2530, 1975. 48Neumann, CG, Lawlor, GJ Jr, Stiehm, ER, Svenseid, ME, Newton, C, Herbert, J, Amman, AJ, and Jacob, M: "Immunologic Responses in Malnourished Children:" Am J Clin Nutr 28, 89-104, 1975. 49Neumann, C and Alpaugh, G: "Birthweight Doubling Time: A Fresh Look." Pediatrics 57(4), 469-473, 1976. 5oParizkova, J and Merhaustova, J: "The Comparison of Somatic De- velopment, Body Composition and Functional Characteristics in Tuni- sian and Czech Boys of 11 and 12 Years." Hum Biol 42, 391-400, 1970. 51Petros-Barvazian, A: "Maternal and Child Health and Breast Feeding." In Kretch_mer, N, Rossi, E, and Sereni, F (eds) Milk and Lacta- tion: Proceedings (symposium) Modern Problems in Paediatrics Series, vol. 15, Basel: Karger, 1975, pp 155-168. 5ZPimentai, D, Terhune, EC, Dyson-Hudson, R, Rochereau, S, Samis, R, Smith, EA, Denman, D, Reifschneider, D, and Shephard, M: "Land Degradation: Effects on Food and Energy Resources." Science 194, 149-155, 1976. 53Puffer, RR, and Serrano, CV: "Breast Feeding." In Patterns of Mor- tality in Childhood. Scientific Publication #262 PAHO/WHO, Washington, DC: World Health Organization, 1973, pp 257-271. ""Ravelli, GP, Stein, ZA, and Susser, MW: "Obesity in Young Men After Famine Exposure in Utero and Early Infancy." N Eng J Med 295(7), 349-359, 1976. 55Ross, MH, and Bras, G: "Lasting Influence of Early Caloric Restric- tion on Prevalence of Neoplasms in the Rat." J Natl Cancer Inst 47, 1095-1113, 1971. 56Sosa, R, Klaus, M, and Urrutia, JJ: "Feed the Nursing Mother, Thereby the Infant." J Pediatr 88(4), 668-670, 1976. 5'Steinhart, CE, Steinhart, JS: Energy: Sources, Use and Role in Human Affairs. North Scituate, MA: Duxbury Press, 1974, pp 65-88. 58Stini, WA: "Adaptive Strategies of Human Populations under Nutritional Stress." In Watts, ES, Johnston, FE, and Lasker, GW (eds) Biosocial Interrelations in Population Adaptation. The Hague: Mouton Publishers, 1975, pp 19-41. 59Stini, WA: "Accelerated Growth and its Long-Range Conse- quences." In Eiben, OE (ed) Growth and Development: Physique Sym- posia Biologica Hungarica (special issue) vol. 20, 1977, pp 83-95. 6oStini, WA: "Reduced Growth and Protein Deficiency in South American Populations." Proc Rocky Mtn Council on Latin American Studies 25, 6-15, 1977. etTannenbaum, A: "Nutrition and Cancer." In Homberger, F(ed) Physiopathy of Cancer. 2nd ed. New York: Hoeber-Harper, 1959, pp 517-562. 62Tanner, JM: "Earlier Maturation in Man." Sci Am 218, 21-27, 1968. 63Tanner, JM: Human Growth. London: Pergamon Press, 1962. 64 Thompson, MP and Farrell, HM Jr: "Genetic Variants of the Milk Proteins." In Larson, BL and Smith, VR (eds) Lactation: A Comprehen- sive Treatise. New York: Academic Press, 1974, pp 109-134. 65Trussel, J: "Menarche and Fatness: Reexamination of the Critical Body Composition Hypothesis." Science 200, 1506-1509, 1978. 66US Bureau of the Census: "Historical Statistics of the United States, Colonial Times to 1957." Statistical Abstract (suppl). Washington, DC: Government Printing Office, 1960. 67US Bureau of the Census: Statistical Abstract of the United States. Washington, DC: Government Printing Office, 1972. 68Walford, RL, Liu, RK, and Gerbase-Delima, M: Long Term Dietary Restriction and Immune Function in Mice: Response to Sheep Red Blood Cells and to Mutagenic Agents." Mech Ageing Dev 2, 447-454, 1973. 69Widdowson, EM, McCance, RA: "A Review: New Thoughts on Growth." Pediatr Res 9, 154-156, 1975. 70Winick, M: Malnutrition and Brain Development. New York: Oxford University Press, 1976. "Woodruff, CW, Latham, LL, and McDavid, S: "Iron Nutrition In Breast-Fed Infants." J Pediatr 90(1), 36-38, 1977. 72Wynder, EL: "Current Concepts of the Aetiology of Breast Cancer." In Forrest, APM and Kunkler, PB (eds) Prognostic Factors in Breast Cancer. New York: Churchill Livingstone, 1968, pp 32-49. "Wynder, EL, Mabuchi, K: "Etiological and Preventive Aspects of Human Cancer." Prev Med 1, 300334, 1972. 7aWynder, EL and Reddy, BS: "Dietary Fat and Colon Cancer." J Natl Cancer Inst 54, 7-10, 1975. Duptkatkn ot Nutrition and Cancer, In whote or In part, by any m.ans for any purposs is tlleyal. Vol. I, No. 1 39 TIMN 222788 -

ANNOUNCEMENTS THIRD CLINICAL CONFERENCE OF THE AMERCAN SOCIETY A LITERATURE STUDY ON PRIMITIVE POPULATIONS IN RELA- FOR PARENTERAL AND ENTERAL NUTRITION. TION TO DIET. The American Society for Parenteral and Enteral Nutrition, Inc. (ASPEN), will hold its third clinical congress on "Nutrition-A Medical Specialty" from January 30 to February 3, 1979, at the Sheraton-Boston Hotel, Boston, Massachusetts. There are general interest sessions for physicians, dieticians, nurses, pharmacists, and nutritionists and postgraduate courses on a number of subjects dealing with nutrition and diet. Registration is a prerequisite for admission to courses. Ad- mission by ticket only. Registration for members: MDs, PhDs, in- dustry-$50.00 pre and $75.00 on-site; related professions-$35.00 and $45.00. Registration for nonmembers: MDs, PhDs, and in- dustry-$60.00 pre and $85.00 on-site; related professions-$40.00 and $50.00. Students, interns, and residents-$25.00. For further informa- tion, contact: Registration, ASPEN National Office, One Central Plaza, 11300 Rockville Pike, Rockville, MD 20852. SECOND CONFERENCE OF THE INTERNATIONAL ASSOCIA- TION OF BIOINORGANIC SCIENTISTS. The International Association of Bioinorganic Scientists, Inc., will hold its second conference January 3 to 5, 1979, at the La Jolla Village Inn, La Jolla, California. The topic will be inorganic and nutritional aspects of cancer. The conference is open to both I.A.B.S. members and nonmembers; however, attendance is limited and advance registration is required. The conference fee is $75.00 for members, $100.00 for early registration for nonmembers, and $120.00 for registra- tion at the desk. For information contact: G. N. Schrauzer, Cancer Con- ference, Department of Chemistry, University of California at San Diego, Revelle College, La Jolla, California 92093. FUNDS AVAILABLE FOR CANCER AND NUTRITION RESEARCH The National Cancer Institute's Diet, Nutrition and Cancer Program is interested in receiving grant applications for cancer and nutrition related research concerned with basic and applied studies in the areas of etiology, treatment, rehabilitation and training. It is not the intent of this announcement to make or imply any delimitation relative to the nature or scope of the research which might be proposed. Applications are also requested in the area of training of individuals in the broad area of diet and nutrition as these relate to cancer. Both individual and institutional support is available through the Institu- tional Training Grants (f32), Individual Postdoctoral Fellowships (F32), and the Cancer Research Career Development Program (RCDA) (K04). More detailed information can be found in the NIH Guide for Grant and Contracts Vol. 7, No. 14, September 25, 1978, and in Vol. 7, No. 16, November 1, 1978 or by contacting Neil M. Ellison, M.D., National Cancer Institute, Bethesda, Maryland 20014: telephone (301) 496-9326. The deadline for receipt of applications for FY 1979 9 funding is December 1, 1978. Volume 2. Numbers 1-4. American Institutes for Research in the Behavioral Sciences, 22 Hilliard Street, Cambridge, Massachusetts 02138. Number 1 contalns the text, background, analysis, and recommend- ations of the study. 60 pp. NTIS Accession Number: PB2 79942/AS NTIS Paper Copy Price: $5.25 Number 2 contains bibliographic listings of references identified during a comprehensive survey. 101 pp. NTIS Accession Number: PB2 79943/AS NTIS Paper Copy Price: $6.50 Number 3 contains critical analyses of selected studies on diet and cancer. 287 pp. NTIS Accession Number: P62 79944/AS NTIS Paper Copy Price: $11.00 Number 4 contains the summaries of information gathered on selected populations and current research efforts in the field of diet and cancer in primitive populations. 47 pp. NTIS Accession Number: PB2 79945/AS NTIS Paper Copy Price: $4.50 Entire set of four numbers NTIS Accession Number: P82 79941/AS NTIS Paper Copy Price: $12.50 A LITERATURE STUDY ON INDICATORS OF HEALTH AND NUTRITIONAL STATUS WITH EMPHASIS ON PRIMITIVE POPULATIONS. Volume 4. Numbers 1-4. Medical University of South Carolina, 80 Barre Street, Charleston, South Carolina 29401. Number 1 contains the methods, results and conclusions of the study on assessment of health and nutritional status of various populations. 284 pp. NTIS Accession Number: PB2 81094/AS NTIS Paper Copy Price: $11.00 Number 2 contains extensive bibliographic listings of references pertaining to health and nutritional status. 448 pp. NTIS Accession Number: PB2 81095/AS NTIS Paper Copy Price: $14.00 Number 3 contains critical reviews of studies concerned with health and nutritional status of primitive societies. 201 pp. NTIS Accession Number: PB2 81096/AS NTIS Paper Copy Price: $9.25 Number 4 contains detailed reviews of selected studies and analyses of these studies, particularly in reference to health and nutri- tion of primitive populations. 206 pp. NTIS Accession Number: P62 81097/AS NTIS Paper Copy Price: $9.25 Entire set of four numbers NTIS Accession Number: PB2 81093/AS NTIS Paper Copy Price: $40.00 Duplication of Nutrition and Cancer, in whole or in part, by any means tor any purpose is Irleyar. 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A LITERATURE STUDY TO EVALUATE HEALTH PARAMETERS IN VARIOUS HUMAN POPULATIONS IN RELATION TO DIET. Volume 3, Numbers 1-4. American Institutes for Research in the Behavioral Sciences, 22 Hilliard Street, Cambridge, Massachusetts 02138. Number 1 contains the text, background, analysis, and recommend- ations on the evaluations of health parameters in human populations. 64 pp. NTIS Accession Number: P62 81059/AS NTIS Paper Copy Price: $5.25 Number 2 contains bibliographic listings of references pertaining to health, dietary, and environmental parameters in populations selected for various incidences of cancer. 116 pp. NTIS Accession Number: PB2 81060/AS NTIS Paper Copy Price: $6.50 Number 3 contains critical reviews of studies of parameters in various human populations selected for high or low incidences of cancer that may be related to diet. 43 pp. NTIS Accession Number: PB2 81061/AS NTIS Paper Copy Price: $4.50 Number 4 contains reviews of research efforts in 15 populations selected for high or low incidences of cancer that may be related to diet. 274 pp. NTIS Accession Number: PB2 81062IAS NTIS Paper Copy Price: $10.75 Entire set of four numbers NTIS Accession Number: P82 81058/AS NTIS Paper Copy Price: $22.50 BEHAVIOR MODIFICATION OF FOOD INTAKE: AN ANNO- TATED BIBLIOGRAPHY RELEVANT TO THE TREATMENT OF ANOREXIA IN CANCER PATIENTS. Volume 1. Midwest Research Institute, 425 Volker Boulevard, Kan- sas City, Missouri 64110. Volume 1 contains a bibliography dealing with clinical applications and methods, author and topic indices, and literature relevant to behavior modification techniques which have potential application for improvement of caloric and nutrient intake of adult and pediatric cancer patients. 230 pp. NTIS Accession Number: P62 831301AS NTIS Paper Copy Price: $9.50 CONTRACTOR REPORTS. Available from the National Technical Information Service (NTS), 5285 Port Royal Road, Springfield. VA 22161. PROGRAM STATUS REPORTS. Available from the National Cancer Institute (NCI), Dr. G. R. Newell, Deputy Director, Building 31, Room 11A52, 9000 Rockville Pike, Bethesda, Maryland 20014 and from Enviro Control, Inc., 11300 Rockville Pike, Rockville, Maryland 20852, Attn: Diet, Nutrition and Cancer Program Manager. These status reports contain the scientific background of the pro- gram, the program goals, structure, and history and analysis of pro- gram funding. Ongoing and completed projects are discussed as well as the information dissemination activities. A SURVEY OF DIETETIC PRACTICES AND PROCEDURES USED IN FEEDING CANCER PATIENTS. Volume 5. Department of Nutritional Sciences and University of Wisconsin Hospitals, University of Wisconsin-Madison, Madison, Wisconsin 53706. Volume 5 contains an in-depth analysis of food preferences of adult and pediatric cancer patients, suggestions for increasing appetite, and an extensive survey of the practices and procedures used by dietitians in feeding cancer patients. The pretest instruments are included and the results discussed. 158 pp. NTIS Accession Number: PB2 83077/AS NTIS Paper Copy Price: $8.00 Dupllcaflon of Nutrition and Canc.r, in whoN or In part, by any m.ans for any paryosa Is Ilr.pal. 42 Nutrition and Cancer TIMN 22279

INSTRUCTIONS FOR AUTHORS The Franklin Institute Press welcomes manuscripts of the following types for publication In NUTRITION AND CANCER: AN INTERNATIONAL JOURNAL: 1) Original papers containing results of experimental, clinical, or statistical studies that are timely and well documented. 2) Letters to the Editor that deal with issues of importance to researchers in the field of nutrition and cancer. Ex- perimental data should be the minimal amount required for adequate understanding. 3) Reviews on subjects of importance to researchers in the field of nutrition and cancer. 4) Brief reports of meetings and proceedings of symposia related to cancer research. 5) Announcements of future meetings of interest to readers, courses in cancer-related biomedical science, or the availability of fellowships, and listing of relevant books and other publications. Announcements should be submitted at least four (4) months prior to date of issue. 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