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Diet, Nutrition, and Cancer Committee on Diet, Nutrition, and Cancer Assembly of Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1982

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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the Councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consist- ing of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Research Council was established by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and of advising the federal government. The Council operates in accordance with general policies determined by the Academy under the authority of its Congressional charter of 1863, which establishes the Academy as a private, nonprofit, self-governing membership corporation. The Council has become the principal operating agency for both the National Academy of Sciences and the National Academy of Engineering in the conduct of their services to the government, the public, and the scientific and engineering communi- ties. It is administered jointly by both Academies and the Institute of Medicine. The National Academy of Engineering and the Institute of Medicine were established in 1964 and 1970, respectively, under the charter of the National Academy of Sciences. The work on which this publication is based was performed pursuant to Contract No. NO1-CP-05603 with the National Cancer Institute. Library of Congress Catalog Card Number 82-81777 International Standard Book Number 0-309-03280-6 Available from NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, D.C. 20418 Printed in the United States of America First Printing, June 1982 Second Printing, September 1982 Third Printing, November 1982 Fourth Printing, May 1983 Fifth Printing, October 1984

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Committee on Diet, Num~aon, and Cancer1 CLIFFORD GROBSTEIN, Chairman JOHN CAIRNS, Vice Chairman ROBERT BERLINER SELWYN A. BROITMAN T. COLIN CAMPBELL JOAN D. GUSSOW LAURENCE N. KOLONEL DAVID KRITCHEVSKY WALTER MERTZ ANTHONY B. MILLER MICHAEL J. PRIVAL THOMAS SLAGA LEE WATTENBERG TAKASHI SUGIMURA, Advisor National Research Council Staff SUSHMA PALMER, Project Director KULBIR BAKSHI, Staff Officer LESLIE J. GRAYBILL, Research Associate ROBERT HILTON, Research Associate FRANCES M. PETER, Editor See Appendix A for further information on committee members and staff - ~ .

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Preface Heightened interest in reducing the risk of three of the most dreaded diseases--heart disease, cancer, and stroke--has resulted in periodic efforts to "improve" food habits. These efforts attracted national attention during the last decade when a White House confer- ence and congressional hearings explored the state of our knowledge concerning the status and health effects of nutrition in the United States. During the hearings there were inquiries about the relative emphasis placed on nutritional factors in the research strategy of the National Cancer Institute (NCI). The study described in this report is an outgrowth of theme inquiries. In June 1980, the NCI commissioned the National Research Council (NRC) to conduct a comprehensive study of the Scientific information pertaining to the relationship of diet and nutrition to cancer. The NCI requested that the study committee (1) "review ... the state of knowledge and information pertinent to diet/nutrition and the incidence of cancer"; (2) "develop a series of recommendations related to dietary components (nutrients and toxic contaminants) and nutritional factors which can be communicated to the public"; and (3) "based on the above state-of-the-art appraisals and the identification of gap areas, de- velop a series of research recommendations related to dietary compo- nents and nutritional factors and the incidence of cancer." The agency also asked that two reports be prepared: the first to advise the NCI and the public whether evidence indicates that certain dietary habits may affect the risk of developing cancer and the second to inform NCI and the scientific community about useful directions research might take to increase our knowledge in this area. The first report is con- tained in this volume. It summarizes the most relevant scientific information on diet and cancer and recommends several interim dietary guidelines for dissemination to the public. In the second report, which is expected to be completed in approximately 1 year, the com- mittee will consider potentially profitable areas for future research. The NRC Governing Board assigned administrative responsibility for this project to the Executive Office of the Assembly of Life Sciences (ALS). Subsequently, a 13-member committee and one advisor were appointed to conduct the study. The diverse expertise repre- sented on the committee includes such disciplines as biochemistry, microbiology, embryology, epidemiology, experimental oncology, in- ternal medicine, microbial genetics, molecular biology, molecular genetics, nutrition, nutrition education, public health, and toxi- cology. Institutional affiliations and major research interests of the committee members and the staff are presented in Appendix A at the end of this report. This multidisciplinary composition has served to ensure comprehensive coverage of the scientific literature and to provide a broad perspective to the committee's conclusions. The work of the committee has been aided by extensive consultation with sci- entific colleagues, by specially arranged technical conferences on v

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vi Preface specific subjects, and by a public meeting to receive such additional information and advice as scientists and others wished to provide. Food, nutrition, diet, and cancer are teems that encompass a very broad subject area, and the already vast accumulation of literature on the interrelationship of these factors is growing rapidly. Thus, the committee began its work by developing a preliminary map of its territory. Having initially interpreted its charge to mean that no part should be arbitrarily excluded, the committee came to recognize that it would be wasteful to duplicate effort, especially when certain subjects have recently been evaluated in detailed reviews. After careful consideration, the decision was made to refer the reader to these comprehensive reviews and to concentrate in this report on the relationship between diet and its nutritional components and cancer in a narrower sense. Subjects not covered in detail include the health effects of nitrate, nitrite, and N-nitroso compounds, which have recent- ly been studied by another ALS committee, and drinking water--a carrier of nutrients and potential toxic substances--also examined by an ALS committee. The Committee on Diet, Nutrition, and Cancer evaluated the evidence for selected contaminants and food additives, but did not dis- cuss them in detail because the emphasis in this report is placed on the selection of particular foods or dietary regimens made by individ- uals or population groups, and the significance of these choices for cancer incidence. During its preliminary mapping of territory, the committee recog- nized that its charge does not include the evaluation of diet and nu- trition in relation to cancer therapy, but rather it stipulated that the committee's effort be directed toward the assessment of these factors in the etiology and prevention of cancer. The committee is aware that several aspects of its charge are matters of controversy, either within the scientific and medical com- munity or among the general population. Controversies are inevitable when data are neither clear-cut nor complete. Interpretations then depend on the criteria selected for evaluation and are influenced by individual or collective judgment. The committee has attempted to present the evidence as objectively as possible and to indicate the range of scientifically acceptable interpretation. It hopes that the results will be useful to all interested parties. The charge to the committee also included a request for dietary recommendations that could be used in the formulation of public policy. Although the com- mittee decided that the data base is not yet adequate for firm recom- mendations to be made, it did conclude that there was sufficient justi- fication for certain interim guidelines, which are presented in the Executive Summary (Chapter 1) of this report. Scientifically valid data on diet and nutrition in relation to cancer are provided by three major sources: epidemiological studies on human populations; experimental studies on animals; and in vitro tests

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Preface vii for genetic toxicity. All three types of studies provide useful in- formation, especially when data derived from all sources point in the same direction. Accordingly, after a general introduction, this report presents the epidemiological and laboratory evidence for indi- vidual components of the diet, giving special attention to the degree of concordance between the epidemiological and experimental evidence. Nutrients are reviewed in Section A, and nonnutritive components are reviewed in Section B. Because of the great interest in the possible etiological and preventive roles of the dietary factors reviewed in Section B. a separate chapter is devoted to constituents that may act as inhibitors of carcinogenesis. The trends in cancer incidence have been the subject of intense public interest and constant debate among scientists. Although this report does not purport to examine this issue in detail, Section C (Chapters 16 and 17) summarizes the current state of knowledge while focusing on the role that diet plays in the incidence of cancer at specific sites. Chapter 18 describes a framework for risk assessment with particular attention to the nuances that must be taken into account when quantifying the effects of so complex a mixture as diet. In the Executive Summary (Chapter 1), the committee has assembled a general picture of the role of dietary and nutritional factors in the development and prevention of cancer from the detailed information presented in other chapters. The report concludes with a glossary of technical terms. The committee particularly wishes to commend the able and devoted assistance of an NRC staff headed by Dr. Sushma Palmer, and consisting of Dr. Kulbir Bakshi, Mrs. Frances Peter, Mrs. Leslie Graybill, Mr. Robert Hilton, Mrs. Susan Barron, Mrs. Dena Banks, and Mrs. Eileen Brown. The committee is also greatly indebted to Drs. Kenneth D. Fisher and Richard G. Allison from the Federation of American Societies for Experimental Biology; Dr. Michael Kazarinoff from Cornell University; Dr. Dietrich Knorr from the University of Delaware; Dr. Angela Little from the University of California at Berkeley; and Dr. Leonard Stoloff of the Food and Drug Administration, who served as consultants and in this capacity wrote manuscripts for the consideration and use of the committee, and extends thanks to those who gave testimony at the public meeting or, upon request, presented data and engaged in discussions during committee meetings, conferences, or workshops. Many others, especially Drn. Willard Visek, Kenneth Carroll, Morris Ross, Juanell Boyd, Joseph Rodricks, and Elizabeth Weisburger, also provided valua- ble advice to the committee from time to time. Furthermore, the committee is grateful to Drs. Andrew Chiarodo and Diane Fink, the current and former project officers for this study at NCI, for their continuous interest and support; to Drs. Alvin G. Lazen and Robert Tardiff of the NRC staff; to members of the Board

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viii preface on Toxicology and Environmental Health Hazards for their advice in the planning of this study; to Ms. Barbara Jaffe, Miss Virginia White, and the staff of the Toxicology Information Center for their assistance and cooperation in supplying bibliographic material; to Ms. Estelle Miller and her coworkers at the NRC Manuscript Processing Unit; and to Mrs. Cecil Read, Mrs. Barbara Wensus, Mrs. Barbara Smith, and Mrs. Ute Hayman for their constant support in the preparation of the report. ~'~ CLIFFORD GROBSTEIN Chairman Committee on Diet, Nutrition, and Cancer

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Contents 1 EXECUTIVE SUMMARY Summary and Conclusions, 2 Interim Dietary Guidelines, 14 2 CANCER: ITS NATURE AND RELATIONSHIP TO DIET The Nature of dancer, 17 The Causes of Cancer, 23 The Influence of Diet on Experimentally Induced Cancers, 26 References, 29 3 METHODOLOGY Epidemiological Methods, 31 Laboratory Methods, 38 Committee Approach to Evaluation of the Literature, 43 Summary and Conclusions, 44 References, 47 SECTION A - THE RELATIONSHIP BETWEEN NUTRIENTS AND CANCER Changes in the Food Supply, S1 Summary and Conclusions, 62 References, 64 TOTAL CALORIC INTAKE Epidemiological Evidence, 66 Experiments in Animals, 68 Summary and Conclusions, 69 References, 71 5 LIPIDS (FATS AND CHOLESTEROL) Epidemiological Evidence, 73 Relationship of Fecal Steroid Excretion to Bowel Carcinogenesis, 81 Experimental Evidence, 83 Summary, 89 Conclusions, 92 References, 94 PROTEIN Epidemiological Evidence, 106 Experimental Evidence, 109 Summary, 116 Conclusion, 116 References, 117 IX 1 17 30 51 66 73 106

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x 8 9 Contents CARBOHYDRATES Epidemiological Evidence, 123 Experimental Evidence, 124 Summary, 126 Conclusion, 127 References, 128 DIETARY FIBER Epidemiological Evidence, 130 Experimental Evidence, 132 Summary, 134, Conclusion, 134 References, 135 VITAMINS Vitamin A, 138 Vitamin C (Ascorbic Acid), 144 Vitamin E ta-Tocopherol), 147 Choline and Selected B Vitamins, 149 References, 154 10 MINERALS Selenium, 163 Zinc, 169 Iron, 172 Copper, 173 Iodine, 175 Molybdenum, 178 Cadmium, 179 Arsenic, 181 Lead, 184 References, 187 11 ALCOHOL Epidemiological Evidence, 202 Experimental Evidence, 206 Summary and Conclusions, 208 References, 209 SECTION B - THE ROLE OF NONNUTRITIVE DIETARY CONSTITUENTS Food Additives, 217 Contaminants, 218 The Delaney Clause and Other Regulatory Actions, 219 Exposure of Humans, 222 The Carcinogenicity of Food Additives and Contaminants, 224 Assessment of Effects on Human Health, 228 References, 229 123 130 138 162 202 217

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Contents xi NATURALLY OCCURRING CARCINOGENS Mycotoxins, 234 Hydrazines in Mushrooms, 240 Plant Constituents and Metabolites, 242 Metabolites of Animal Origin, 250 Fermentation Product, 251 Nitrate, Nitrite, and N-Nitroso Compounds, 252 Sununary and Conclusions, 257 References, 259 13 MUTAGENS IN FOOD Mutagens Resulting from Cooking of Foods, 278 Plant Flavonoids, 286 Mutagenic Activity in Extracts of Foods and Beverages, 287 Modifiers of Mutagenic Activity, 288 Summary and Conclusions, 292 References, 293 14 ADDITIVES AND CONTAMINANTS Additives, 304 Environmental Contaminants, 317 Overall Summary and Conclusions, 33 2 References, 333 15 INHIBITORS OF CARCINOGENESIS Epidemiological Studies, 358 Experimental Studies, 359 SunuTlary, 366 Conclusion, 366 References, 367 S ECTION C PATTERNS OF DIET AND CANCER 16 CANCER INCIDENCE AND MORTALITY Geographical Differences Related to Ethnicity, 372 Changes Subsequent to Migration, 374 Changing Time Trends in Incidence and Mortality, 376 Intersite Correlations of Incidence, 378 Associations with Socioeconomic Status, 379 Religious Practices and Cancer Incidence an d Mortality, 381 Correlations of Incidence and Mortality with Dietary and Other Variables, 382 Associations with Other Diseases, 384 Summary, 384 References, 385 234 277 304 358 371 372

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xii Contents 17 THE RELATIONSHIP OF DIET TO CANCER AT SPECIFIC SITES Esophageal Cancer, 391 Stomach Cancer, 393 Colon and Rectal Cancer, 396 Liver Cancer, 401 Pancreatic Cancer, 402 Gallbladder Cancer, 404 Lung Cancer, 404 Bladder Cancer, 405 Renal Cancer, 406 Breast Cancer, 407 Endometrial Cancer, 409 Ovarian Cancer, 409 Prostate Cancer, 410 References, 412 18 ASSESSMENT OF RISK TO HUMAN HEALTH Initiators of Carcinogenesis, 431 Modifiers of Carcinogenesis, 434 Use of Mutagenicity Tests, 435 Use of Epidemiological Studies, 436 Diet-Related Carcinogenesis, 437 Contribution of Diet to Overall Risk of Cancer, 439 References, 441 GLOSSARY APPENDIX A - COMMITTEE ON DIET, NUTRITION, AND CANCER-- AFFILIATIONS AND MAJOR RESEARCH INTERESTS INDEX 391 430 447 453 457

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Diet, Nutrition, and Cancel

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