SAFETY OF GENETICALLY ENGINEERED FOODS

APPROACHES TO ASSESSING UNINTENDED HEALTH EFFECTS

Committee on Identifying and Assessing Unintended Effects of Genetically Engineered Foods on Human Health

Board on Life Sciences

Food and Nutrition Board

Board on Agriculture and Natural Resources

INSTITUTE OF MEDICINE AND NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects SAFETY OF GENETICALLY ENGINEERED FOODS APPROACHES TO ASSESSING UNINTENDED HEALTH EFFECTS Committee on Identifying and Assessing Unintended Effects of Genetically Engineered Foods on Human Health Board on Life Sciences Food and Nutrition Board Board on Agriculture and Natural Resources INSTITUTE OF MEDICINE AND NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, D.C. 20001 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. Support for this project was provided by the U.S. Department of Health and Human Services Food and Drug Administration under contract number 223-93-1025, the U.S. Department of Agriculture under contract number 59-0790-1-183, and the U.S. Environmental Protection Agency under contract number X-82956001. The views presented in this report are those of the Committee on Identifying and Assessing Unintended Effects of Genetically Engineered Foods on Human Health and are not necessarily those of the funding agencies. International Standard Book Number 0-309-09209-4 (Book) International Standard Book Number 0-309-53194-2 (PDF) Library of Congress Control Number: 2004107570 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2004 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and 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 M. 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. Wm. A. Wulf 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. Harvey V. Fineberg 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 M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects COMMITTEE ON IDENTIFYING AND ASSESSING UNINTENDED EFFECTS OF GENETICALLY ENGINEERED FOODS ON HUMAN HEALTH BETTIE SUE MASTERS (chair), Department of Biochemistry, University of Texas Health Science Center, San Antonio FULLER W. BAZER, Department of Animal Sciences, Texas A&M University, College Station SHIRLEY A. A. BERESFORD, Department of Epidemiology, University of Washington, Seattle DEAN DELLAPENNA, Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing TERRY D. ETHERTON, Department of Dairy and Animal Science, The Pennsylvania State University, University Park CUTBERTO GARZA, Division of Nutritional Sciences, Cornell University, Ithaca, New York LYNN GOLDMAN, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland SIDNEY GREEN, Department of Pharmacology, Howard University College of Medicine, Washington, DC (until April, 2003) JESSE F. GREGORY, III, Department of Food Science and Human Nutrition, University of Florida, Gainesville JENNIFER HILLARD, Past Vice President (Policy & Issues), Consumer’s Association of Canada, Winnipeg, Manitoba ALAN G. MCHUGHEN, Department of Botany and Plant Sciences, University of California, Riverside SANFORD A. MILLER, Center for Food and Nutrition Policy, Virginia Polytechnic and State University, Alexandria STEVE L. TAYLOR, Department of Food Science and Technology, University of Nebraska, Lincoln TIMOTHY ZACHAREWSKI, Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing Staff ANN YAKTINE, Senior Program Officer MICHAEL KISIELEWSKI, Research Assistant SYBIL BOGGIS, Senior Project Assistant ANGELA ARMENDARIZ, Intern (June to August 2003)

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects COMMITTEE ON AGRICULTURAL BIOTECHNOLOGY, HEALTH, AND THE ENVIRONMENT BARBARA A. SCHAAL (chair), Washington University, St. Louis DAVID A. ANDOW, University of Minnesota NEAL L. FIRST, University of Wisconsin, Madison LYNN J. FREWER, University of Wageningen HENRY L. GHOLZ, National Science Foundation, Arlington, Virginia EDWARD GROTH, III, Groth Consulting Services, Yonkers, New York ERIC M. HALLERMAN, Virginia Polytechnic and State University RICHARD R. HARWOOD, Michigan State University CALESTOUS JUMA, Harvard University SAMUEL B. LEHRER, Tulane University SANFORD A. MILLER, Center for Food and Nutrition Policy, Virginia Polytechnic and State University, Alexandria PHILIP G. PARDEY, University of Minnesota ELLEN K. SILBERGELD, University of Maryland Medical School ROBERT E. SMITH, R.E. Smith Consulting, Inc. ALLISON A. SNOW, The Ohio State University PAUL B. THOMPSON, Michigan State University DIANA H. WALL, Colorado State University

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects BOARD ON LIFE SCIENCES COREY S. GOODMAN (chair), Renovis, Inc., South San Francisco, California R. ALTA CHARO, University of Wisconsin, Madison JOANNE CHORY, The Salk Institute for Biological Studies, La Jolla, California ELAINE FUCHS, The University of Chicago DAVID J. GALAS, Keck Graduate Institute of Applied Life Sciences, Claremont, California BARBARA GASTEL, Texas A&M University JAMES M. GENTILE, Hope College, Holland, Michigan LINDA GREER, Natural Resources Defense Council, New York, New York ED HARLOW, Harvard Medical School, Boston, Massachusetts GREGORY A. PETSKO, Brandeis University, Waltham, Massachusetts STUART L. PIMM, Columbia University, New York, New York JOAN B. ROSE, Michigan State University GERALD M. RUBIN, Howard Hughes Medical Institute, Chevy Chase, Maryland BARBARA A. SCHAAL, Washington University, St. Louis RAYMOND L. WHITE, DNA Sciences, Inc., Fremont, California Staff FRANCES SHARPLES, Director

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects FOOD AND NUTRITION BOARD CATHERINE E. WOTEKI (chair), Iowa State University, Ames ROBERT M. RUSSELL (vice chair), Tufts University, Boston, Massachusetts LARRY R. BEUCHAT, University of Georgia, Griffin SUSAN FERENC, SAF Risk, LC, Madison, Wisconsin NANCY F. KREBS, University of Colorado Health Sciences Center, Denver SHIRIKI KUMANYIKA, University of Pennsylvania School of Medicine, Philadelphia REYNALDO MARTORELL, Emory University, Atlanta, Georgia LYNN PARKER, Food Research and Action Center, Washington, DC NICHOLAS J. SCHORK, University of California, San Diego JOHN W. SUTTIE, University of Wisconsin, Madison STEVE L. TAYLOR, University of Nebraska, Lincoln BARRY L. ZOUMAS, Pennsylvania State University, University Park Staff LINDA D. MEYERS, Director GAIL SPEARS, Staff Editor GERALDINE KENNEDO, Administrative Assistant ELISABETH RIMAUD, Financial Associate

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects BOARD ON AGRICULTURE AND NATURAL RESOURCES MAY BERENBAUM, (chair), University of Illinois, Urbana-Champaign SANDRA BARTHOLMEY, Univesity of Illinois, Chicago DEBORAH BLUM, University of Wisconsin, Madison H. H. CHENG, University of Minnesota, St. Paul BARBARA P. GLENN, Biotechnology Industry Organization, Washington, DC LINDA F. GOLODNER, National Consumers League, Washington, DC W. R. (REG) GOMES, University of California, Oakland PERRY R. HAGENSTEIN, Institute for Forest Analysis, Planning, and Policy, Wayland, Massachusetts JANET C. KING, Children’s Hospital Oakland Research Center, California DANIEL P. LOUCKS, Cornell University, Ithaca, New York WHITNEY MACMILLAN, Cargill, Inc., Minneapolis, Minnesota TERRY L. MEDLEY, DuPont Agriculture and Nutrition, Wilmington, Delaware OLE NIELSEN, Ontario Veterinary College, Canada ALICE N. PELL, Cornell University, Ithaca, New York BOBBY PHILLS, Florida A&M University, Tallahassee SHARRON S. QUISENBERRY, Virgnia Polytechnic Institute and State University SONYA B. SALAMON, University of Illinois, Urbana-Champaign G. EDWARD SCHUH, Humphrey Institute of Public Affairs, Minneapolis, Minnesota BRIAN J. STASKAWICZ, University of California, Berkeley JACK WARD THOMAS, University of Montana, Missoula JAMES H. TUMLINSON, Pennsylvania State University, University Park B. L. TURNER, Clark University, Worcester, Massachusetts Staff CHARLOTTE KIRK BAER, Director KAREN L. IMHOF, Administrative Assistant DONNA LEE JAMEISON, Administrative Assistant (through October 2003)

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects Preface Genetically modified foods and food products derived from genetically engineered organisms are among a number of biotechnological developments intended to improve shelf life, nutritional content, flavor, color, and texture, as well as agronomic and processing characteristics. Although in popular parlance the term genetically modified often is used interchangeably with genetically engineered, in this report genetic modification refers to a range of methods used to alter the genetic composition of a plant or animal, including traditional hybridization and breeding. Genetic engineering is one type of genetic modification that involves the intention to introduce a targeted change in a plant, animal or microbial gene sequence to effect a specific result. While there are a variety of methods for identifying and measuring specific changes that result from genetic engineering, as well as from conventional breeding techniques, such changes are not always easily discernible—particularly when they are unexpected outcomes of the process or when they result from latent expression of the genetic change or accumulated changes in functional effects in the modified organism. The addition of genetic engineering to the repertoire of methods to genetically modify organisms has increased the number and type of substances that can be intentionally introduced into the food supply, as well as the magnitude of these changes. While these intended changes can be readily evaluated for their safety in food, unintentionally introduced changes in the composition of foods may be more difficult to identify and assess. Whether genetic engineering per se affects the likelihood of unintentionally introducing undesired compositional changes in food is not fully understood. In contrast to adverse health effects that have been associated with some traditional food production methods, similar serious health

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects effects have not been identified as a result of genetic engineering techniques used in food production. This may be because developers of bioengineered organisms perform extensive compositional analyses to determine that each phenotype is desirable and to ensure that unintended changes have not occurred in key components of food. Improvement in currently available methods for identifying and assessing unintended compositional changes in food could further enhance the ability of product developers and regulators to perform appropriate testing to assure the safety of food. Whether all such analyses are warranted and are the most appropriate methods for discovering unintended changes in food composition that may have human health consequences remains to be determined. Scientific advances in agricultural biotechnology continue to improve our understanding of plant crops, microorganisms, and food-animal genetics. Nevertheless, the public health system continues to face many questions about the impact of agricultural biotechnology on human health. As a result of these new scientific advances and public concern about the potential for unintended compositional changes in genetically engineered food that might in turn result in unintended health effects, the National Academies convened this committee to explore the similarities and differences between genetic engineering and other genetic modifications, including conventional breeding practices, with respect to the frequency and nature of unintended effects associated with them—in particular with regard to potential changes in the biochemical composition of plant- and animal-derived foods and methods that would be most useful in assessing the occurrences of unintended changes that might affect consumer health. ACKNOWLEDGMENTS The Committee on Identifying and Assessing Unintended Effects of Genetically Engineered Foods on Human Health was aided in its challenging tasks by the invaluable contributions of a number of individuals. First and foremost, many thanks are due to the committee members who volunteered countless hours to the research, deliberations, and preparation of the report. Their dedication to this project and to a stringent time-line was commendable and was the foundation of our success. Many individuals volunteered significant time and effort to address and educate our committee members during the workshops. Additionally, the committee wishes to acknowledge the invaluable contributions of the study staff: Ann Yaktine, senior program officer and study director; Michael Kisielewski, research assistant; and Sybil Boggis, senior project assistant. The committee also acknowledges other staff members who contributed to the development and initial conduct of this study: Jennifer Kuzma, study director until September 2002; Abigail Stack, study director until February 2003; and Tamara Dawes, project assistant until February 2003. This collaborative project benefited from the general guid-

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects ance of Allison Yates, director emeritus of the Food and Nutrition Board; and Linda Meyers, the Board’s current director; Charlotte Kirk Baer, director of the Board on Agriculture and Natural Resources; and Frances Sharples, director of the Board on Life Sciences. The committee also thanks Geraldine Kennedo for logistical arrangements and Craig Hicks for writing assistance and technical editing. Bettie Sue Masters, Chair Committee on Identifying and Assessing Unintended Effects of Genetically Engineered Foods on Human Health

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Arthur J. L. Cooper, Burke Medical Research Institute Neal First, University of Wisconsin Michael Grusak, Baylor College of Medicine Harry A. Kuiper, RIKILT-Wageningen University Research Center Terry Medley, DuPont Agriculture and Nutrition Ian Munro, CanTox, Inc. James Murray, University of California, Davis Marion Nestle, New York University Nicholas J. Schork, University of California, San Diego Margaret E. Smith, Cornell University Mark Westhusin, Texas A&M University Walter Willett, Harvard University Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recom-

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects mendations nor did they see the final draft of the report before its release. The review of this report was overseen by Mary Jane Osborn, University of Connecticut Health Center and Michael P. Doyle, University of Maryland, College Park. Appointed by the National Research Council and Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects Contents     EXECUTIVE SUMMARY   1      Background for the Study,   1      Committee Charge and Approach,   2      Mechanisms by Which Unintended Compositional Changes in Food Occur as a Result of Breeding or Propagation Method,   3      Methods to Detect Unintended Changes in Food Composition,   3      Methods to Assess the Potential Human Consequences of Unintended Compositional Changes in Food,   5      Framework for Identifying and Assessing Unintended Adverse Effects from Genetically Modified Foods,   6      Conclusion,   15 1   INTRODUCTION   17      Historical Background,   17      Genetic Modification of Food,   18      The Charge to the Committee,   20      References,   22 2   METHODS AND MECHANISMS FOR GENETIC MANIPULATION OF PLANTS, ANIMALS, AND MICROORGANISMS   23      Background,   23      Plant Genetic Modification,   24      Animal Genetic Modification,   30      Genetic Modification of Microbes,   35      References,   36

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects 3   UNINTENDED EFFECTS FROM BREEDING   39      Background,   39      Plant Breeding,   40      Animal Breeding,   49      Mechanisms by Which Unintended Effects in Genetically Engineered Organisms Arise,   55      The Genetic Manipulation Continuum,   62      Discussion,   66      References,   67 4   NEW APPROACHES FOR IDENTIFYING UNINTENDED CHANGES IN FOOD COMPOSITION   73      Background,   73      Targeted Quantitative Analysis versus Profiling Methods,   75      Nontargeted Analytical Methods for Metabolites,   83      Bioinformatic Issues in Profiling Analysis,   88      Profiling Methods for Analysis of Inorganic Elements of Nutritional and Toxicological Importance,   92      Genomics,   93      Proteomics,   94      Information Obtained from New Analytical Techniques,   98      Discussion,   99      References,   99 5   ADVERSE IMPACTS OF FOOD ON HUMAN HEALTH   103      Introduction,   103      Food Safety Hazards in Food Products,   104      Safety Hazards in Food Products Associated with Genetic Modification,   118      References,   121 6   METHODS FOR PREDICTING AND ASSESSING UNINTENDED EFFECTS ON HUMAN HEALTH   127      Background,   127      Stages in the Development of Genetically Engineered Foods,   128      Substantial Equivalence and its Role in Safety Assessment,   129      Current Safety Standards for Genetically Engineered Foods,   131      Safety Assessment Prior to Commercialization,   132      Application, Validation, and Limitations of Tools for Identifying and Predicting Unintended Effects,   141      Evaluation of Possible Unintended Consequences of Inserted Genes,   145      Tools for Predicting and Assessing Unintended Effects,   148      Need for Clinical and Epidemiological Studies,   152

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects      Safety Assessment after Commercialization,   153      Discussion,   166      References,   167 7   FRAMEWORK, FINDINGS, AND RECOMMENDATIONS   175      Background,   175      Framework for Assessing Potential Unintended Effects,   175      Findings and Recommendations,   179      Concluding Remarks,   186     APPENDIXES         A Glossary   191     B Open Session and Workshop Agendas   207     C Committee Member Biographical Sketches   211     SUBREPORT: METHODS AND MECHANISMS OF GENETIC MANIPULATION AND CLONING OF ANIMALS   217      Introduction,   217      Animal Biotechnology,   218      Cloning,   219      Evaluating Methods to Detect Potential Unintended Compositional Changes and Adverse Health Effects of Foods Derived from Cloned Animals,   223      Conclusions,   232      Recommendations,   233      References,   233

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