Carcinogens and Anticarcinogens in the Human Diet

A Comparison of Naturally Occurring and Synthetic Substances

Committee on Comparative Toxicity of Naturally Occurring Carcinogens

Board on Environmental Studies and Toxicology

Commission on Life Sciences

National Research Council

NATIONAL ACADEMY PRESS
Washington, D.C.
1996



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--> Carcinogens and Anticarcinogens in the Human Diet A Comparison of Naturally Occurring and Synthetic Substances Committee on Comparative Toxicity of Naturally Occurring Carcinogens Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1996

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--> NATIONAL ACADEMY PRESS 2101 Constitution Ave., N.W. Washington, D.C. 20418 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 consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Harold Liebowitz is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. The National Research Council was organized 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 advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce Alberts and Dr. Harold Liebowitz are chairman and vice chairman, respectively, of the National Research Council. The project was supported by the National Institute for Environmental Health Sciences, U.S. Environmental Protection Agency, the National Cancer Institute, and the U.S. Food and Drug Administration under contract no. NO1-ES-25355, and by the American Industrial Health Council and Nabisco Foods. Library of Congress Catalog Card No. 95-73149 International Standard Book No. 0-309-05391-9 Additional copies of this report are available from the National Academy Press, Box 285, Washington, DC 20055. Copyright 1996 by the National Academy of Sciences. All rights reserved. Printed in the United States of America First Printing, February 1996 Second Printing, October 1996

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--> COMMITTEE ON COMPARATIVE TOXICITY OF NATURALLY OCCURRING CARCINOGENS RONALD ESTABROOK (Chair), Southwestern Medical Center, University of Texas, Dallas, Tex. DIANE BIRT , University of Nebraska Medical Center, Omaha, Neb. GARY P. CARLSON , Purdue University, West Lafayette, Ind. SAMUEL M. COHEN , University of Nebraska Medical Center, Omaha, Neb. ERIC E. CONN , University of California, Davis, Calif. NORMAN R. FARNSWORTH , College of Pharmacy, University of Illinois at Chicago, Chicago, Ill. DAVID W. GAYLOR , U.S. Food and Drug Administration, Jefferson, Ark. RICHARD L. HALL , Baltimore, Md. JOHN HIGGINSON , Bethesda, Md. ERNEST HODGSON , North Carolina State University, Raleigh, N.C. LAURENCE N. KOLONEL , Cancer Research Center, University of Hawaii, Honolulu, Hawaii DANIEL K REWSKI , Health Canada, Ottawa, Ontario, Canada CHARLENE A. MCQUEEN , University of Arizona, College of Pharmacy, Tucson, Ariz. MICHAEL W. PARIZA , University of Wisconsin - Madison, Madison, Wisc. JANARDAN K. REDDY , Northwestern University Medical School, Chicago, Ill. I. GLENN SIPES , University of Arizona, College of Pharmacy, Tucson, Ariz.

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--> BERNARD WAGNER, Wagner Associates, Inc., Millburn, N.J. PAUL B. WATKINS, Clinical Research Center, University of Michigan, Ann Arbor, Mich. I. BERNARD WEINSTEIN, Columbia-Presbyterian Cancer Center and Columbia University, College of Physicians, New York, N.Y. LAUREN ZEISE, California Environmental Protection Agency, Berkeley, Calif. BEST Liaisons ALLAN H. CONNEY, Rutgers, The State University of New Jersey, Piscataway, N.J. DAVID P. RALL, Washington, D.C. Staff CAROL A. MACZKA, Program Director J. DAVID SANDLER, Project Director LINDA V. LEONARD, Senior Project Assistant KATHRINE IVERSON, Library Assistant Sponsors National Institute for Environmental Health Sciences U.S. Environmental Protection Agency National Cancer Institute U.S. Food and Drug Administration American Industrial Health Council Nabisco Foods Group

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--> BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY PAUL G. RISSER (Chair), Oregon State University, Corvallis, Ore. MICHAEL J. BEAN, Environmental Defense Fund, Washington, D.C. EULA BINGHAM, University of Cincinnati, Cincinnati, Ohio PAUL BUSCH, Malcom Pirnie, Inc., White Plains, N.Y. EDWIN H. CLARK II, Clean Sites, Inc., Alexandria, Va. ALLAN H. CONNEY, Rutgers University, Piscataway, N.J. ELLIS COWLING, North Carolina State University, Raleigh, N.C. GEORGE P. DASTON, The Procter & Gamble Co., Cincinnati, Ohio DIANA FRECKMAN, Colorado State University, Ft. Collins, Colo. ROBERT A. FROSCH, Harvard University, Cambridge, Mass. RAYMOND C. LOEHR, The University of Texas, Austin, Tex. GORDON ORIANS, University of Washington, Seattle, Wash. GEOFFREY PLACE, Hilton Head, S.C. DAVID P. RALL, Washington, D.C. LESLIE A. REAL, Indiana University, Bloomington, Ind. KRISTIN SHRADER-FRECHETTE, University of South Florida, Tampa, Fla. BURTON H. SINGER, Princeton University, Princeton, N.J. MARGARET STRAND, Bayh, Connaughton and Malone, Washington, D.C. GERALD VAN BELLE, University of Washington, Seattle, Wash. BAILUS WALKER, JR., Howard University, Washington, D.C. TERRY F. YOSIE, E. Bruce Harrison Co. Washington, D.C.

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--> Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Program Director for Natural Resources and Applied Ecology CAROL A. MACZKA, Program Director for Toxicology and Risk Assessment LEE R. PAULSON, Program Director for Information Systems and Statistics RAYMOND A. WASSEL, Program Director for Environmental Sciences and Engineering

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--> COMMISSION ON LIFE SCIENCES THOMAS D. POLLARD, (Chair), The Johns Hopkins University, Baltimore, Md. FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, D.C. JOHN C. BAILAR III, University of Chicago, Chicago, Ill. JOHN E. BURRIS, Marine Biological Laboratory, Woods Hole, Mass. MICHAEL T. CLEGG, University of California, Riverside, Calif. GLENN A. CROSBY, Washington State University, Pullman, Wash. URSULA W. GOODENOUGH, Washington University, St. Louis, Mo. SUSAN E. LEEMAN, Boston University School of Medicine, Boston, Mass. RICHARD E. LENSKI, Michigan State University, East Lansing, Mich. THOMAS E. LOVEJOY, Smithsonian Institution, Washington, D.C. DONALD R. MATTISON, University of Pittsburgh, Pittsburgh, Penn. JOSEPH E. MURRAY, Wellesley Hills, Mass. EDWARD E. PENHOET, Chiron Corporation, Emeryville, Calif. EMIL A. PFITZER, Research Institute for Fragrance Materials, Hackensack, N.J. MALCOLM C. PIKE, University of Southern California, Los Angeles, Calif. HENRY C. PITOT III, University of Wisconsin, Madison, Wisc. JONATHAN M. SAMET, The Johns Hopkins University, Baltimore, Md. HAROLD M. SCHMECK, JR., North Chatham, Mass. CARLA J. SHATZ, University of California, Berkeley, Calif. JOHN L. VANDEBERG, Southwest Foundation for Biomedical Research, San Antonio, Texas PAUL GILMAN, Executive Director

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OTHER RECENT REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Upstream: Salmon and Society in the Pacific Northwest (1996) Science and the Endangered Species Act (1995) Wetlands: Characteristics and Boundaries (1995) Biologic Markers (Urinary Toxicology (1995), Immunotoxicology (1992), Environmental Neurotoxicology (1992), Pulmonary Toxicology (1989), Reproductive Toxicology (1989)) Review of EPA's Environmental Monitoring and Assessment Program (three reports, 1994-1995) Science and Judgment in Risk Assessment (1994) Ranking Hazardous Sites for Remedial Action (1994) Pesticides in the Diets of Infants and Children (1993) Issues in Risk Assessment (1993) Setting Priorities for Land Conservation (1993) Protecting Visibility in National Parks and Wilderness Areas (1993) Dolphins and the Tuna Industry (1992) Hazardous Materials on the Public Lands (1992) Science and the National Parks (1992) Animals as Sentinels of Environmental Health Hazards (1991) Assessment of the U.S. Outer Continental Shelf Environmental Studies Program, Volumes I-IV (1991-1993) Human Exposure Assessment for Airborne Pollutants (1991) Monitoring Human Tissues for Toxic Substances (1991) Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991) Decline of the Sea Turtles (1990) Tracking Toxic Substances at Industrial Facilities (1990) Copies of these reports may be ordered from the National Academy Press: (800) 624-6242 or (202) 334-3313

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--> Preface Numerous reports, including some from the National Research Council, have examined the relationship of diet to cancer. It is generally accepted that diet is a contributing factor to the onset or progression of some types of cancer and that a prudent selection of foods, including fruits and vegetables, and avoidance or decreased consumption of other foods might influence the risk to an individual of contracting cancer. But can specific chemicals in our diet be identified as causative agents (carcinogens) or protective agents (anticarcinogens) for cancer? Some naturally occurring chemicals that are part of our diet have been shown in animal models to cause cancer—and therefore might also serve as potential cancer-causative agents in humans. Almost daily, the news media report on the presence of one chemical or another that is claimed to be carcinogenic. Many of these are naturally occurring chemicals. The public is bombarded with reports that raise fear and apprehension. To make a rational estimate of the risk associated with the diet one must know the level of exposure as well as the carcinogenic potency of a suspected chemical. That basic principle of toxicology is sometimes offset by the belief (often associated with the Delany amendment) that the presence of a potentially hazardous chemical at even minuscule concentrations is dangerous. In addition, the credibility of such a conclusion often depends on the validity of the test used to identify a specific chemical as a carcinogen. Many of

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--> the data used in this report are based on studies using the rodent bioassay, where tests are carried out at high exposure levels. The ability to relate results obtained using rodent bioassays to the risk for humans—who are exposed to low levels of a chemical in a complex mixture, such as the diet—is a weakness that puts into question how the results of such evaluations are applied. This committee has labored diligently and long as it studied, debated, reargued, and wrote the different facets of what some might consider a complex problem that is unsolvable. As we submit this report we recognize that some readers will look for the identification of a single causative agent to remove from the diet. Others will seek evidence of a panacea—a chemical that will shield them against the causative agents of cancer. Both groups will be disappointed. As the report indicates, we need to know much more than we know today before we can speak with greater certainty about the role of chemicals in the diet as contributors to the burden of cancer in the human population. Such information will come only by continued research, new hypotheses, and a clearer understanding of human biology. The ability to complete a report of this complexity requires a dedicated staff. We are indebted to efforts and technical expertise of J. David Sandler, project director; Linda V. Leonard, senior project assistant; Carol A. Maczka, program director; Gail Charnley and Richard Thomas (program directors during the early stages of the project); and James J. Reisa, director of the Board on Environmental Studies and Toxicology. Many distinguished scientists met with the committee and shared their ideas, findings, and interpretations, including: Richard Adamson (National Cancer Institute), Bruce Ames (University of California), Victor Feron (Toxicology and Nutrition Institute, the Netherlands), Adam Finkel (Resources for the Future), Ronald Hart (National Center for Toxicological Research), Donald Hughes (American Industrial Health Council), Richard Jackson (California Department of Health Services), David

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--> Longfellow (National Cancer Institute), Richard Merrill (University of Virginia), Hugh McKinnon (Environmental Protection Agency), Gerard Mulder (Center for Bio-Pharmaceutical Sciences, Sylvius Laboratories, the Netherlands), David Rall, Robert Scheuplein (Food and Drug Administration), Sidney Siegel (National Library of Medicine), and Lee Wattenberg (University of Minnesota). Some of these individuals' affiliations have changed since they provided input to the committee. Our sincere thanks to them for providing guideposts that served to mark the path of progress as the committee deliberated specific issues. Each member of this committee deserves praise and congratulations for his or her wisdom, dedication, perception, and friendship. Although many sessions were exhausting, the high level of interest of each member made this exercise a rewarding and productive experience. Thanks to each and everyone of you for all your good work. Ronald W. Estabrook Chairman

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--> Contents     EXECUTIVE SUMMARY   1 1   INTRODUCTION   19     Statement of Task and Deliberations of the Committee   26     Definitions   28     Structure of the Report   31     References   32 2   NATURALLY OCCURRING CARCINOGENS AND ANTICARCINOGENS IN THE DIET   35     Exposure to Naturally Occurring Chemicals   35     The Composition of Foods   36     Naturally Occurring Carcinogens Formed During Processing or Contamination of Food   59     Current State of Knowledge of Human Dietary Carcinogens   65     Current State of Knowledge of Human Dietary Anticarcinogens   76     Effect of Dietary Macronutrients on Carcinogenesis   80     Effect of Dietary Micronutrients on Carcinogenesis   87     Engineering an Optimal Diet   100     Summary and Conclusions   103     References   104

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--> 3   SYNTHETIC CARCINOGENS IN THE DIET   127     Synthetic Food Additives   129     Occurrence and Exposure   132     Mechanisms of Carcinogenesis   141     Metabolism   144     Toxicological Comparisons   148     Summary and Conclusions   163     References   164 4   METHODS FOR EVALUATING POTENTIAL CARCINOGENS AND ANTICARCINOGENS   181     Methods for Evaluating Chemical Carcinogens   185     Comparison of Methods for Evaluating Natural and Synthetic Carcinogens   204     Criteria for Selecting and Testing   205     Summary and Conclusions   208     References   209 5   RISK COMPARISONS   219     Monitoring Food Consumption   223     Dietary Exposure to Potential Carcinogens and Anticarcinogens   229     Measures of Carcinogenic Potency   252     Dietary Cancer Risks   278     Estimating Human Cancer Risks   266     Summary and Conclusions   303     Overall Conclusions   311     References   312

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--> 6   CONCLUSIONS, RECOMMENDATIONS, AND FUTURE DIRECTIONS   335     Conclusions   336     Recommendations   341     Future Directions   346     Closing Remarks   355     References   356 APPENDIX A:   SELECTED SUBSTANCES IN FOOD SUBJECTED TO SOME DEGREE OF CARCINOGENICITY TESTING IN ANIMALS AND FOR WHICH SOME POSITIVE RESULTS HAVE BEEN REPORTED   359 APPENDIX B:   AGENTS WITH POTENTIAL CARCINOGENIC ACTIVITY AND THEIR OCCURRENCE IN THE DIET   377 APPENDIX C:   CHEMICAL COMPOUNDS OCCURRING IN DIETARY PLANTS THAT HAVE BEEN REPORTED TO INHIBIT CARCINOGENESIS IN VIVO   407

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