CANCER and the ENVIRONMENT

GENE-ENVIROMENT INTERACTION

Samuel Wilson, Lovell Jones, Christine Coussens, and Kathi Hanna, Editors

Roundtable on Environment Health Sciences, Research, and Medicine

Board on Health Sciences Policy

INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS
Washington, D.C.



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Cancer and the Environment: Gene-Enviroment Interaction CANCER and the ENVIRONMENT GENE-ENVIROMENT INTERACTION Samuel Wilson, Lovell Jones, Christine Coussens, and Kathi Hanna, Editors Roundtable on Environment Health Sciences, Research, and Medicine Board on Health Sciences Policy INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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Cancer and the Environment: Gene-Enviroment Interaction NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, DC 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 this report were chosen for their special competences and with regard for appropriate balance. Support for this project was provided by the National Institute of Environmental Health Sciences, National Institute of Health (Contract No. 282-99-0045, TO#5); National Center for Environmental Health and Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention (Contract No. 200-2000-00629, TO #7); National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Centers for Disease Control and Prevention (Contract No. 0000166930); National Health and Environmental Effects Research Laboratory and National Center for Environmental Research, Environmental Protection Agency (Contract No. 282-99-0045, TO#5); American Chemistry Council (unnumbered grant); and Exxon-Mobil Corporation (unnumbered grant). This support does not constitute endorsement of the views expressed in the report. International Standard Book Number 0-309-08475-X Library of Congress Control Number 2002109770 Additional copies of this report are available for sale from the National Academy Press, 2101 Constitution Avenue, NW, Box 285, Washington, DC 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP’s on-line bookstore at www.nap.edu. The full text of the report is available on-line at www.nap.edu For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. Copyright 2002 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Cancer and the Environment: Gene-Enviroment Interaction “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE Shaping the Future for Health

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Cancer and the Environment: Gene-Enviroment Interaction THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council 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 chairman and vice-chairman, respectively, of the National Research Council.

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Cancer and the Environment: Gene-Enviroment Interaction ROUNDTABLE ON ENVIRONMENTAL HEALTH SCIENCES, RESEARCH, AND MEDICINE (membership until March 31, 2002) Paul Grant Rogers (Chair), Partner, Hogan & Hartson, Washington, DC Lynn Goldman (Vice-Chair), Professor, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD Pauline Abernathy, Program Officer, The Pew Charitable Trusts, Philadelphia, PA M. Brownell Anderson, Associate Vice President for Medical Education, Association of American Medical Colleges, Washington, DC Roger Bulger, President and CEO, Association of Academic Health Centers, Washington, DC Mark Cullen, Professor of Medicine and Public Health, Yale Occupational and Environmental Medicine Program, Yale University School of Medicine, New Haven, CT Ruth Etzel, Editor of the American Academy of Pediatrics Handbook of Pediatric Environmental Health, Adjunct Professor in the Department of Environmental and Occupational Health, George Washington University School of Public Health and Health Services, Washington, DC Henry Falk, Assistant Administrator, Agency for Toxic Substance and Disease Registry, Atlanta, GA Baruch Fischhoff, Professor of Social and Decision Sciences, Professor of Engineering and Public Policy, Department of Social and Decision Sciences, Carnegie Mellon University, Pittsburgh, PA Howard Frumkin, Professor and Chair, Department of Environmental and Occupational Health, Emory University Rollins School of Public Health, Director of the Southeast Pediatric Environmental Health Specialty Unit, Atlanta, GA Bernard D. Goldstein, Dean, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA Robert Graham, Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, Bethesda, MD John T. Grupenhoff, President, Science and Health Communications Group, Inc., Bethesda, MD Carol Henry, Vice President for Science and Research, American Chemistry Council, Arlington, VA Richard J. Jackson, Director, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA Lovell Jones, Professor, Gynecologic Oncology, University of Texas, Houston, TX Patricia G. Kenworthy, Vice-President for Policy and Research and Senior Staff Attorney, National Environmental Trust, Washington, DC

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Cancer and the Environment: Gene-Enviroment Interaction Donald Mattison, Professor, Mailman School of Public Health, Columbia University, New York, NY Roger McClellan, President Emeritus, Chemical Industry Institute of Toxicology, Albuquerque, NM Sanford Miller, Senior Fellow and Adjunct Professor, Georgetown University, Washington, DC Frank Mirer, Director, Health and Safety, International Union, United Auto Workers, Detroit, MI Alan R. Nelson, Special Advisor to the CEO, American College of Physicians–American Society of Internal Medicine, Fairfax, VA Kenneth Olden, Director, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC Peter Preuss, Director, National Center for Environmental Research, U.S. Environmental Protection Agency, Washington, DC Lawrence Reiter, Director, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC Kathleen Rest, Acting Director, National Institute of Occupational Safety and Health, Washington, DC Samuel H. Wilson, Deputy Director, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC IOM Health Sciences Policy Board Liaisons Mark Cullen, Professor of Medicine and Public Health, Yale Occupational and Environmental Medicine Program, Yale University School of Medicine, New Haven, CT Bernard D. Goldstein, Dean, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA ROUNDTABLE ON ENVIRONMENTAL HEALTH SCIENCES, RESEARCH, AND MEDICINE (Membership April 1, 2002 to Present) Paul Grant Rogers (Chair), Partner, Hogan & Hartson, Washington, DC Lynn Goldman (Vice-Chair), Professor, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD Jacquelyne Agnew, Professor, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD Jack Azar, Vice President, Environment, Health and Safety, Xerox Corporation, Webster, NY

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Cancer and the Environment: Gene-Enviroment Interaction Sophie Balk, Chairperson, Committee on Environmental Health, American Academy of Pediatrics, Bronx, NY Roger Bulger, President and CEO, Association of Academic Health Centers, Washington, DC Henry Falk, Assistant Administrator, Agency for Toxic Substance and Disease Registry, Atlanta, GA Baruch Fischhoff, Professor of Social and Decision Sciences, Professor of Engineering and Public Policy, Department of Social and Decision Sciences, Carnegie Mellon University, Pittsburgh, PA John Froines, Professor and Director, Center for Occupational and Environmental Health, Southern California Particle Center and Supersite, University of California, Los Angeles, CA Howard Frumkin, Professor and Chair, Department of Environmental and Occupational Health, Emory University Rollins School of Public Health, Director of the Southeast Pediatric Environmental Health Specialty Unit, Atlanta, GA Michael Gallo, Professor of Environmental and Community Medicine, University of Medicine and Dentistry, New Jersey–Robert Wood Johnson Medical School, Piscataway, NJ Bernard D. Goldstein, Dean, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA Robert Graham, Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, Bethesda, MD Charles Groat, Director, U.S. Geological Survey, Reston, VA Myron Harrison, Senior Health Advisor, Exxon-Mobil, Inc., Irwing, TX Carol Henry, Vice President for Science and Research, American Chemistry Council, Arlington, VA Richard J. Jackson, Director, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA Lovell Jones, Professor, Gynecologic Oncology, University of Texas, Houston, TX, University of Texas, M.D. Anderson Cancer Center, Houston, TX Alexis Karolides, Senior Research Associate, Rocky Mountain Institute, Snowmass, CO Donald Mattison, Professor, Mailman School of Public Health, Columbia University, NY Michael McGinnis, Senior Vice President and Director of the Health Group, Robert Wood Johnson Foundation, Princeton, NJ James Melius, Director, Division of Occupational Health and Environmental Epidemiology, New York State Department of Health, New York, NY James Merchant, Professor and Dean, College of Public Health, Iowa University, Iowa City, IA

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Cancer and the Environment: Gene-Enviroment Interaction Sanford Miller, Senior Fellow, Center for Food and Nutrition Policy, Virginia Polytechnic Institute and State University, Alexandria, VA Alan R. Nelson, Special Advisor to the CEO, American College of Physicians–American Society of Internal Medicine, Fairfax, VA Kenneth Olden, Director, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Research Triangle Park, NC Peter Preuss, Director National Center for Environmental Research, U.S. Environmental Protection Agency, Washington, DC Lawrence Reiter, Director, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC Kathleen Rest, Acting Director, National Institute of Occupational Safety, and Health, Centers for Disease Control and Prevention, Washington, D.C. Samuel Wilson, Deputy Director, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC IOM Health Sciences Policy Board Liaisons Mark Cullen, Professor of Medicine and Public Health, Yale Occupational and Environmental Medicine Program, Yale University, School of Medicine, New Haven, CT Bernard D. Goldstein, Dean of the University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA Study Staff Christine Coussens, Study Director Dalia Gilbert, Research Assistant Jason Harris, Senior Project Assistant Division Staff Andrew Pope, Board Director Alden Chang, Administrative Assistant Carlos Gabriel, Financial Associate Kathi Hanna, Consultant

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Cancer and the Environment: Gene-Enviroment Interaction INDEPENDENT REPORT 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 National Research Council’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 contents of 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 participation in the review of this report: Dr. Roger Giese, Director, Environmental Cancer Research Program, Northeastern University, Boston, MA Dr. Theodore Krontiris, Deputy Director, Beckman Research Institute, Duarte, CA Ms. Stacey Neloms, Director, Maryland Cancer Registry, Baltimore, MD Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the final draft of the report before its release. The review of this report was overseen by Melvin Worth, Scholar-in-Residence, Institute of Medicine, who was 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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Cancer and the Environment: Gene-Enviroment Interaction Foreword Kenneth I. Shine One of the more interesting aspects of the announcement by Ian Wilmut that he and his colleagues in Scotland had successfully “cloned” a sheep born in 1996 was the enormous public interest and misunderstanding about cloning. The common misperception, which persists to this day, is that a cloned individual would be an exact duplicate of another. In the process of trying to explain to the American public and, in fact, to some members of the scientific community what is involved in “cloning,” it became critical to point out that the relationship between cloned animals is, in fact, less close than that between identical twins. In a cloned organism the nucleus comes from one animal and the cytoplasm, which contains mitochondrial genes, comes from another. Thus, identical twins are closer in biological and genetic identity than “clones” would be. Yet, none of us would expect identical twins to actually behave the same way; in fact, they are very different people. Consideration of identical twins, and of clones, emphasizes the notion that even when two individuals have identical or nearly identical genes, the social, cultural, and physical environment in which they live has a profound impact on who they are and what they become. The long tradition of studying twins emphasizes the need for us to understand the manner by which biology and the environment influence the health and development of individuals and populations. The Institute of Medicine (IOM) has issued a number of consensus studies about environmental health. Several years ago the IOM produced a report on environmental justice, that is, how risky environments tend to be found in communities of lower socioeconomic status, resulting in disparate rates of cancer and other chronic diseases. Other aspects of IOM’s recent work have focused on the unequal burden of cancer, which dramatizes that there are both increased incidence and increased prevalence of cancer in certain groups of our population. The National Cancer Policy Board has addressed a number of issues in cancer care, including its quality and accessibility, and has demonstrated that there are substantial gaps between the average care and the best care for cancer.

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Cancer and the Environment: Gene-Enviroment Interaction IOM roundtables provide a venue in which individuals representing many different perspectives can come together to discuss important issues facing health and medicine today. Roundtables provide a forum for exploring the interfaces between the various aspects of science and the diverse characteristics of health care and public health. This workshop follows on a successful meeting convened by the Roundtable of Environmental Health Sciences, Research, and Medicine last year, Rebuilding the Unity of Health and the Environment, which emphasized the multiple interrelationships that exist among the social, natural, and built environments as they relate to human health. All of these efforts have highlighted the importance of understanding the wide array of elements that might influence the health of individuals and populations—where they live, what they eat, how they live, where they work, how they raise their children, and how they do their work. One of our goals is to encourage health professionals—physicians, nurses, and others in their communities—to recognize that these are not issues limited to the public health department or to sanitary engineers. These are issues for all of us in the health professions. Enhanced communications between the professions and the community will be necessary to convey information about the interactions between who we are genetically and the environment in which we live. These concerns remain central to gaining insight into what can be done to prevent, diagnose, and treat cancer as well as numerous other diseases, and they stress the multidisciplinary nature of the challenges we have before us.

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Cancer and the Environment: Gene-Enviroment Interaction Preface In the early 1970s, Congress was at a pivotal point in shaping the future of cancer research and policy for the United States. I remember vividly the atmosphere “on the Hill” as legislation was pending before both the House and the Senate on the funding of the National Cancer Institute (NCI) and its position within the National Institutes of Health (NIH). The American people, the Congress, and President Nixon were concerned about cancer; at the time, most people diagnosed with cancer didn’t have much hope for the future. We were losing many of our best and brightest to this deadly disease and we needed to do something about it. The result in this country was to declare a “war on cancer.” During this time, I was the chair of the Subcommittee on Health and the Environment in the House. We were known as the “Disease of the Month Club” because of the volume of legislation we were passing. We wore this label as a badge of honor because we were committed to improving the health of the citizens of the United States through increasing the government’s commitment to biomedical research. In 1971, the Senate passed legislation to make an independent agency of NCI, and President Nixon appeared ready to sign the legislation. Our committee understood the importance of this legislation, and we proceeded to hold three weeks of hearings on the bill. (Three weeks of hearings were all but unheard of, but they were necessary to ensure that members of the House were educated on the topic.) Many scientists, including several Nobel laureates, testified to the value of keeping the NCI as part of NIH. They pointed out examples of how advances in one field can impact advances in other fields. A number of prominent researchers questioned whether the exchange of information would be as great if the NCI became independent of NIH. We also had to think of our research commitment to other diseases and whether this would result in separate agencies for each disease. We, on the committee and members of the House, struggled with these issues, but decided at the end of our deliberations to keep NCI a part of NIH. We passed the National Cancer Act of 1971, and our fight against cancer began in earnest.

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Cancer and the Environment: Gene-Enviroment Interaction It has been 30 years since that landmark legislation, and we have made tremendous strides in “the war.” No longer is a person diagnosed with cancer served a death sentence. Our understanding of the mechanisms underlying cancers has allowed us to start targeting treatment and separating out a group of diseases that we call “cancer.” Molecular techniques and advances in cell biology gained from cancer research have spilled over into other areas of science such as neuroscience and physiology. Thirty years of research and clinical investigations have given us hope and promise that one day most cancers will be sucessfully treated by the wide variety of new modalities being developed. The statistics speak for themselves. A report released last year by the NCI, the American Cancer Society, the North American Association of Central Cancer Registries, the Centers for Disease Control and Prevention, and the National Center for Health Statistics reported a general decrease of 0.8 percent per year in the incidence rate for all cancers combined from 1990 to 1997. The greatest decline in cancer incidence rates has been among men, who overall have higher rates of cancer than women. There is reason for hope. While breast cancer incidence rates showed little change in the 1990s, breast cancer death rates have declined about 2 percent per year since 1990 and have dropped sharply since 1995. With the growing use of electronic media, information is readily available to more and more individuals. Although these media allow for rapid distribution of information, there is no assurance that the information provided is accurate and scientifically sound. Members of the public have many questions when they have cancer, and they don’t understand why one person develops cancer and another person doesn’t. They have questions about how their environment may have contributed to the development of their disease. The scientific community doesn’t have all the answers, but we assembled a group of researchers to discuss some of these questions. As part of its task, the Roundtable convenes workshops to inform the debate on issues related to environmental health. We continue to explore the impact that the environment has on our cities, our families, and our health. It shouldn’t be surprising to anyone that the places in which we work, eat, sleep, and play can have a dramatic impact on our health. As I have said many times, “Environmental laws are more than regulations—they are health laws!” In September 2000, the Roundtable decided to convene a workshop on Cancer and the Environment: Gene–Environment Interactions on May 16–17, 2001. During the planning, it became clear that a two-day meeting would start the process but would still leave many questions unanswered. What is clear, however, is that understanding the role of cancer and the environment is one of the greatest challenges that we face in this new century. As you can read in later sections of this report, there are significant differences in populations and the development of cancer. We have a significant vulnerable population that includes children, minorities, women, and the poor. We

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Cancer and the Environment: Gene-Enviroment Interaction are making progress against breast cancer, but not for all segments of the population. We are making progress again lung cancer, but not for all ethnic minorities. Scientists and government officials struggle with questions concerning cancer clusters. Are they just a statistical aberration or are they the result of an environmental exposure? More research and multidisciplinary approaches will begin to tease apart these issues. We hope that we will be able to continue to decrease both the cancer incidence and the mortality rates for all populations. On behalf of the Roundtable, I would like to thank a number of individuals. First are the co-chairs, Drs. Franklin Mirer and Alan Nelson, for their leadership on this planning group. I would also like to thank other members of the planning group, Dr. Ruth Etzel, Dr. Michael Gallo, Dr. Lovell Jones, Ms. Patricia Kenworthy, Dr. John Minna, Dr. Samuel Wilson, and Ms. Gerri Wolfle, who worked with the co-chairs and study staff to put this program together. The Roundtable, itself, does not take a position on any issue. The comments and summary presented here were captured to promote greater discussion of environmental influences on the health of our citizens. This summary is a report to the Roundtable, and the views and opinions expressed in the summary are the views of the speakers and workshop participants, not the Roundtable. Announcements of upcoming activities and workshops can be found at the Roundtable’s Web site: www.iom.edu/ehsrt. Paul G. Rogers, J.D. Chair

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Cancer and the Environment: Gene-Enviroment Interaction Contents     FOREWORD   xi     PREFACE   xiii     SUMMARY   1 1   CHARGE TO PARTICIPANTS AND WORKSHOP OBJECTIVES   7     Remarks and Charge to Participants,   7     Statement of Workshop Objectives,   9 2   KEYNOTE ADDRESSES   11     Cancer, the Environment, and the Media,   11     Genes and the Environment in Cancer Etiology,   14 3   THE LINKS BETWEEN ENVIRONMENTAL FACTORS, GENETICS, AND THE DEVELOPMENT OF CANCER   25     Diet as a Modifier of Cancer Risk,   26     Genetic Epidemiology as a Tool for Studying Gene–Environment Interactions,   29     Molecular Carcinogenesis, Molecular Epidemiology, and Human Risk Assessment,   31     Summary,   34 4   GENE–ENVIRONMENT INTERACTION IN SPECIAL POPULATIONS   36     Health Disparities,   36     Influence of Migration,   37     Cancer Disparities in Appalachia,   38

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Cancer and the Environment: Gene-Enviroment Interaction     Migrant Farmworkers’ Children and Pesticides: A High-Risk Population,   40     Chemicals and Cancer Clusters,   41     Cancer in Children,   42     Childhood Cancer and Diet,   43     Summary,   45 5   GENE–ENVIRONMENT INTERACTION IN SITE-SPECIFIC CANCERS   46     Breast Cancer,   46     Reproductive Hormones,   47     Breast Cancer Genetics,   48     Environmental Factors,   50     Lung Cancer,   50     Molecular and Environmental Bases of Lung Cancer,   50     Molecular Pathogenesis of Lung Cancer,   52     Colorectal Cancer,   54     Risks for Colorectal Cancer,   54     Prostate Cancer,   56     Prostate Cancer: Epidemiology, Hormones, and Diet,   56     Herbal Therapies,   58     Summary,   59 6   SPECIAL ADDRESS: A NOVEL APPROACH TO CANCER TREATMENT BASED ON IMMUNE STIMULATION AND OTHER ENVIRONMENTAL APPROACHES   60 7   CANCER AND THE ENVIRONMENT: A VIEW FROM THE HILL   63 8   MOVING FORWARD   65     Disparities,   65     Cancer Prevention,   66     Future Research Areas,   67     Cancer Registries and Large Populational Studies,   67     Research Implications,   68     Policy Implications,   69     ABSTRACTS OF TALKS   70     Gene–Environment Interactions Related to Colon Cancer,   70     Diet and Risk of Childhood Cancer,   75     Similarities of Prostate and Breast Cancer: Evolution, Diet, and Estrogens,   76

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Cancer and the Environment: Gene-Enviroment Interaction     Effect of Herbal Therapies on Prostate Cancer,   77     Colorectal Cancer and Environmental Risk Factors,   78     Genes and the Environment in Cancer Etiology,   78     Cancer Disparities in Appalachia,   79     Tumor Suppressor Genes: At the Crossroads of Molecular Carcinogenesis, Molecular Epidemiology, and Human Risk Assessment,   81     Genetic Epidemiology as a Tool for Gene–Environment Interactions,   84     Epidemiology and Genetic Susceptibility to Breast Cancer,   88     Migrant Farmworker Children at High Risk for Pesticide Exposure,   91     Chemicals and Chromosomes, Children and Cancer, Clusters and Cohorts in a New Century,   92     Health Disparities: Do Gene–Environment Interactions Play a Role?,   93     Diet and Other Environmental Factors as Modifiers of Cancer Risk,   94     Molecular Pathogenesis of Lung Cancer,   97     Breast Cancer Genetics: BRCA1 and BRCA2 Genes,   103     Types and Trends of Childhood Cancer; Cancer in Childhood Cancer Survivors,   103     Cancer Treatment Based on Immune Stimulation,   104     Genetic Susceptibility to Lung Cancer,   105     Environment and Breast Cancer,   106     Priorities and Special Populations: Ties That Bind,   107     REFERENCES   108     APPENDIXES     A   Glossary   119 B   Workshop Agenda   123 C   Speakers and Panelists   128 D   Workshop Participants   131

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