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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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