Advisory
Committee
on
Human
Radiation
Experiments
NATIONAL IjVSTITi NIHLIBR
JAN 2 2
BLDG 10, 10 CENTER DR BETHESDA, MD 20892-1150
Advisory Committee
on Human Radiation
Experiments
Final Report
October 1995
Additional copies of the Final Report of the Advisory Committee on Human Radiation Experiments (stock number 061-000-00-848-9) as well as copies of the Executive Summary and Guide to Final Report (stock number 061-000-00849-7) and the three supplemental volumes (061-000-00850-1, 061-000-00851-9, and 061-000-00852-7) may be purchased from the Superintendent of Documents, U.S. Government Printing Office.
All telephone orders should be directed to:
Superintendent of Documents
U.S. Government Printing Office
Washington, D.C. 20402
(202) 512-1800
FAX (202) 512-2250
8 a.m. to 4 p.m., Eastern time, M-F
All mail orders should be directed to:
U.S. Government Printing Office P.O. Box 371954 Pittsburgh, PA 15250-7954
An Internet site containing ACHRE information (replicating the Advisory Committee's original gopher) will be available at George Washington University. The site contains complete records of Advisory Committee actions as approved; complete descriptions of the primary research materials discovered and analyzed; complete descriptions of the print and non-print secondary resources used by the Advisory Committee; a copy of the Interim Report of October 21, 1994, and a copy of the Final Report; and other information. The address is http://www.seas.gwu.edu/nsarchive/radiation. The site will be maintained by the National Security Archive at GWU.
Printed in the United States of America
Contents
PREFACE 1
INTRODUCTION The Atomic Century 19
PART I Ethics of Human Subjects Research: A Historical Perspective
Overview 81
1 Government Standards for Human Experiments: The 1940s and 1950s 83
2 Postwar Professional Standards and Practices for Human Experiments .... 130
3 Government Standards for Human Experiments: The 1960s and 1970s .... 171
4 Ethics Standards in Retrospect 196
PART II Case Studies
Overview 227
5 Experiments with Plutonium, Uranium, and Polonium 233
6 The AEC Program of Radioisotope Distribution 283
7 Nontherapeutic Research on Children 320
8 Total-Body Irradiation: Problems When Research and Treatment Are Intertwined 366
9 Prisoners: A Captive Research Population 42 1
10 Atomic Veterans: Human Experimentation in Connection with Bomb
Tests 454
1 1 Intentional Releases: Lifting the Veil of Secrecy 506
12 Observational Data Gathering 563
13 Secrecy, Human Radiation Experiments, and Intentional Releases 619
PART III Contemporary Projects
Overview 669
14 Current Federal Policies Governing Human Subjects Research 675
1 5 Research Proposal Review Project 694
16 Subject Interview Study 724
Discussion of Part III 758
PART IV Coming to Terms with the Past, Looking Ahead to the Future
Overview 769
1 7 Findings 777
18 Recommendations 801
Statement By Committee Member Jay Katz 847
Official Documents
Executive Order 857
Charter | 862
Appendices
Acronyms and Abbreviations 869
Glossary 878
Selected Bibliography 886
Public Comment Participants 892
A Citizen's Guide to the Nation's Archives: Where the Records Are
and How to Find Them 897
iii
advisory committee on human radiation Experiments
1726 M STREET, N.W., SUITE 600
WASHINGTON, D.C. 20036 _ . innc
October 1995
To the Members of the Human Radiation Interagency Working Group:
Secretary Hazel O'Leaiy, Department of Energy
Secretary William Perry, Department of Defense
Attorney General Janet Reno, Department of Justice
Secretary Donna Shalala, Department of Health and Human Sen-ices
Secretary Jesse Brown. Department of Veterans Affairs
Director Alice Rivlin, Office of Management and Budget
Director John Deutch, Central Intelligence Agency
Administrator Daniel Goldin, National Aeronautics and Space Administration
On behalf of the Advisory Committee on Human Radiation Experiments, it is my privilege to transmit to you our Final Report.
Since the Committee's first meeting in April 1994 we have been able to conduct an intensive inquiry into the history of government-sponsored human radiation experiments and intentional environmental releases of radiation that occurred between 1944 and 1974. We have studied the ethical standards of that time and of today and have developed a moral framework for evaluating these experiments. Finally, we have examined the extent to which current policies and practices appear to protect the rights and interests of today's human subjects. This report documents our findings and makes recommendations for your consideration.
The committee listened to the testimony of more than 200 public witnesses who appeared before us. We are deeply grateful to all these witnesses, who overcame the obstacles of geography and emotions to assist us.
Our work and this report would not have been possible without the extraordinary effort the President and you put forward to open the government's records to our inquiry and thus to the nation. We are especially pleased that, through our joint efforts, the American people now have access to the tens of thousands of documents that bear on this important history.
None of our conclusions came easily. We endeavored, both as individuals and as a committee, to live up to the responsibility with which we were entrusted. This report represents the consensus of fair-minded people who gave the best they had to offer to their fellow citizens.
We thank President Clinton for this opportunity and for his courage and leadership in appointing the Advisory Committee.
Ruth R. Faden
Chair, Advisory Committee
on Human Radiation Experiments
®
Printed with soy ink on recycled paper
Advisory Committee on Human Radiation Experiments
Ruth R. Faden. Ph.D.. M.RH.-Chair
Philip Franklin Wagley Professor of Biomedical Ethics and Director
The Bioethics Institute
Johns Hopkins University
Baltimore, Maryland
Senior Research Scholar
Kennedy Institute of Ethics
Georgetown University
Washington, D.C.
Kenneth R. Feinberg, J.D.
Kenneth R. Feinberg & Associates Washington, D.C.
Eli Glatstein, M.D.
Professor and Chair Department of Radiation Oncology The University of Texas Southwestern Medical Center at Dallas Dallas, Texas
Jay Katz, M.D.
Elizabeth K. Dollard Professor Emeritus
of Law, Medicine and Psychiatry Harvey L. Karp Professorial Lecturer in Law
and Psychoanalysis Yale Law School New Haven, Connecticut
Patricia A. King, J.D.
Professor of Law
Georgetown University Law Center
Washington, D.C.
Susan E. Lederer, Ph.D.
Associate Professor
Department of Humanities
The Pennsylvania State University College of Medicine
Hershey, Pennsylvania
Ruth Macklin, Ph.D.
Professor of Bioethics
Department of Epidemiology & Social Medicine
Albert Einstein College of Medicine
Bronx, New York
Nancy L. Oleinick, Ph.D.
Professor of Radiation Biochemistry
Division of Radiation Biology
Case Western Reserve University School of Medicine
Cleveland, Ohio
Henry D. Royal, M.D.
Professor of Radiology
Associate Director; Division of Nuclear Medicine
Mallinckrodt Institute of Radiology
Washington University Medical Center
St. Louis, Missouri
Philip K. Russell, M.D.
Professor, Department of International Health Johns Hopkins University School of Hygiene and Public Health Baltimore, Maryland
Mary Ann Stevenson, M.D., Ph.D.
Assistant Professor of Radiation Oncology Joint Center for Radiation Therapy Harvard Medical School Boston, Massachusetts
Deputy Chief
New England Deaconess Hospital Department of Radiation Oncology Boston, Massachusetts
Duncan C. Thomas, Ph.D.
Director, Biostatistics Division
Department of Preventive Medicine
University of Southern California School of Medicine
Los Angeles, California
Lois L. Norris
Second Vice President of Omaha National Bank and Omaha National Corporation (Retired) Omaha, Nebraska
Reed V. Tuckson, M.D.
President
Charles Drew University of Medicine and Science
Los Angeles, California
Advisory Committee on Human Radiation Experiments
Jeffrey Kahn
Associate Director
Dan Guttman
Executive Director
Anna Mastroianni
Associate Director
Stephen Klaidman
Director of Communications Counselor to the Committee
Sarah Flynn
Editor
Staff*
Senior Policy and Research Analysts
Barbara Berney James David John Harbert Gregg Herken Jonathan Moreno Ronald Neumann Gary Stem Jeremy Sugarman Donald Weightman Gilbert Whittemore
Research Analysts
Jonathan Engel Patrick Fitzgerald Mark Goodman Deborah Holland Denise Holmes Michael Jasny Gail Javitt Wilhelmine Miller Patricia Perentesis Kathy Taylor Sandra Thomas Faith Weiss
Research Associates
Miriam Bowling Praveen Fernandes Sara Chandros Hull Valerie Hurt John Kruger Ellen Lee
Shobita Parthasarathy Noel Theodosiou
Information Services
David Saumweber, Director Robin Cochran, Librarian Tom Wisner, Senior Technology Consultant
Communications and Outreach
Lanny Keller Kristin Crotty
Committee and Staff Affairs
Jerry Garcia Jeanne Kepper
Consultants
Jeffrey Botkin Allen Buchanan Gwen Davis Gail Geller Steve Goodman Jon Harkness Rebecca Lowen
Suzanne White Junod Nancy Kass Charles McCarthy Monica Schoch-Spana Patricia Stewart-Henney John Till E.W. Webster
*includes both full-time and part-time staff
acknowledgments
Tt
he Committee's work over the past year and a half would have been impossible without the assistance of an extraordinary number of individuals and groups from all corners of the United States, and beyond. We wish to express the depth of our gratitude to the many people who assisted, informed, and advised us.
Some of these people are identified by name elsewhere in this report and its supplemental volumes. An appendix in this volume lists the more than 200 witnesses who appeared before the Committee at our public meetings in Washington, D.C., Cincinnati, Knoxville, San Francisco, Santa Fe, and Spokane. The supplemental volumes identify the dozens of individuals who agreed to formal, taped interviews in connection with the Committee's oral history projects. We thank all these people and many more:
• The hundreds of people who contacted the Committee with information about their own experiences or the experiences of their family members. Many of these people shared not only their personal stories but also the information they had collected in the course of conducting their own research into government archives.
• The representatives of many groups whose interests coincided with the work of the Committee. These include organizations of former subjects of biomedical radiation experiments (and their families), downwinders, atomic veterans, uranium miners, and workers in and around atomic energy communities. These groups, as well, shared the accumulated information and perspective of years of experience and research.
• The numerous professionals in fields related to our research who gave of their time and expertise to provide information or comment on the myriad factual, technical, and policy questions before the Committee. These experts provided help in understanding areas ranging from military and human rights law to the laws of the atom, from the history of the government's use of secrecy to the history of radiation science.
• The dozens of universities and independent hospitals, located in all regions of the country, that willingly provided us with the documents we needed to conduct our Research Proposal Review Project.
vn
A ckn o wledgm en (s
The nearly 1,900 individuals who graciously participated in our Subject Interview Study, and the university hospitals, veterans hospitals, and community hospitals that permitted us to conduct the study.
The numerous chairs of institutional review boards and radiation safety committees who were kind enough to share with us their views about the current status of human subject protections.
Archivists at public and private libraries, universities, and research institutions, who assisted the Committee in our search for information.
The many journalists and scholars who have previously researched and written about the subjects covered in this report, for sharing the knowledge and wisdom embodied in their own many years of inquiry and reflection.
A variety of state and local agencies for sharing with the Committee the results of their own reviews of activities that we explored.
Members of Congress and congressional staff, including the staffs of the General Accounting Office and the Office of Technology Assessment, for sharing the product of their own prior inquiries into many of the areas discussed in this report.
The members of the Human Radiation Interagency Working Group, who provided invaluable assistance. We are particularly grateful to the many employees at the Department of Energy, the Department of Defense, the Department of Health and Human Services, the Department of Veterans Affairs, the National Aeronautics and Space Administration, and the Central Intelligence Agency, who aided us in the search and retrieval of the many thousands of documents that provide the backbone for the Committee's review of human radiation experiments that took place between 1944 and 1974 and the history of government requirements for the conduct of that research. We are also grateful to the staffs of the Nuclear Regulatory Commission and the National Archives and Records Administration for their invaluable assistance. Many of the same people, as well as others, also provided advice and information as we undertook our evaluation of the conduct of research involving human subjects today.
We wish to thank both the professional and administrative members of our staff who worked so hard and showed such dedication to our task. Their talent, energy, and commitment provided the foundation for our work. It is impossible to overstate our gratitude and appreciation for their extraordinary efforts.
Finally, we wish to acknowledge our indebtedness to President Clinton for the honor he bestowed upon us when he selected us to serve on the Advisory Committee.
Vlll
Documentary Note
In fulfilling its mandate, the Advisory Committee on Human Radiation Experiments (ACHRE) relied on several thousand separate sources: primary and secondary published monographs, journal articles, historical records and manuscripts, original correspondence and surveys, interviews, specially constructed databases, searches of public and commercial databases, and documentary films. Only a fraction of these, however, is represented in the final report. More extensive information may be found in the supplemental volume Sources and Documentation, which contains a full account of the ACHRE research program, a finding aid to the complete research document collection, a bibliography of published sources used, an index to significant documents and identified experiments, and other auxiliary materials. Further information both about the sources used by the Advisory Committee generally and about the particular sources cited in this volume should be sought there.
The unpublished documents referenced in this report are identified by their places in the ACHRE Research Document Collection. These identifiers, or ACHRE document numbers, have four parts: originating institution, date of receipt, order of receipt, and document number. For example, DOE-05 1094-A- 123 is the 123d document described in the first ("A") Department of Energy ("DOE") shipment (or accession) received on May 10, 1994 ("051094"). One of the appendices, A Citizen's Guide to the Nation's Archives, provides instructions for using references to the ACHRE collection to find documents there and in the collections of the National Archives and at the agencies.
IX
FINAL REPORT
Preface
Un January 15, 1994, President Clinton created the Advisory Committee on Human Radiation Experiments in response to his concern about the growing number of reports describing possibly unethical conduct of the U.S. government, and institutions funded by the government, in the use of, or exposure to, ionizing radiation in human beings at the height of the Cold War. He directed us to uncover the history of human radiation experiments and intentional environmental releases of radiation; to identify the ethical and scientific standards for evaluating these events; and to make recommendations to ensure that whatever wrongdoing may have occurred in the past cannot be repeated.
The Advisory Committee is composed of fourteen members: a citizen representative and thirteen experts in bioethics, radiation oncology and biology, epidemiology and statistics, public health, history of science and medicine, nuclear medicine, and law. We report to a Cabinet-level group convened by the President (the Human Radiation Interagency Working Group), whose members are the secretaries of defense, energy, health and human services, and veterans affairs; the attorney general; the administrator of the National Aeronautics and Space Administration; the director of the Central Intelligence Agency; and the director of the Office of Management and Budget.
On April 21, 1994, at the end of the first day of our opening meeting, President Clinton invited us to the White House to personally communicate his commitment to the process we were about to undertake. He urged us to be fair, thorough, and unafraid to shine the light of truth on this hidden and poorly understood aspect of our nation's past. Our most important task, he said, was to tell the full story to the American public. At the same time, we were also to examine the present, to determine how the conduct of human radiation research today compares with that of the past and to assess whether, in the light of this inquiry, changes need to be made in the policies of the federal government to better protect the American people. This report and the accompanying
1
Preface
supplemental volumes constitute the Committee's attempt to tell the story of the past and to report on our inquiry into the present.
WHY THE COMMITTEE WAS CREATED
Past research with human subjects, including human radiation research, has been a source of life-saving knowledge. Research involving human subjects continues to be essential to the progress of medical science, since most advances in medicine must at some point in their development be tested in human subjects. Every one of us who has been either a patient or a loved one of a patient has benefited from knowledge gained through research with human subjects. But medical science, like all science, does not proceed or progress without the taking of risks. In medical research, these risks often fall on the human subject, who sometimes does not stand to benefit personally from the knowledge gained. This is the source of the moral tension at the core of the enterprise of research involving human subjects. In order to secure important collective goods- scientific knowledge and advances in medicine-individuals are put in harm's way. The moral challenge is how to protect the rights and interests of these individuals while enabling and encouraging the advancement of science.
The Committee had its origins when public controversy developed surrounding human radiation experiments that were conducted half a century ago. In November 1993, the Albuquerque Tribune published a series of articles that, for the first time, publicly revealed the names of Americans who had been injected with plutonium, the man-made material that was a key ingredient of the atom bomb. Reporter Eileen Welsome put a human face to what had previously been anonymous data published in official reports and technical journals. As World War II was ending, she wrote, doctors in the United States injected a number of hospitalized patients with plutonium, very likely without their knowledge or consent. The injections were part of a group of experiments to determine how plutonium courses through the human body. The experiments, and the very existence of plutonium, were shrouded in secrecy. They were conducted at the direction of the U.S. government, with the assistance of university researchers in Berkeley, Chicago, and Rochester (New York), with the expectation that the information gained could be used to limit the hazards to the thousands of workers laboring to build the bomb.
On reading the articles, Secretary of Energy Hazel O'Leary expressed shock, first to her staff, and then in response to a question posed at a press conference. She was particularly concerned because the Department of Energy had its earliest origins in the agencies responsible for building the atomic bomb and sponsoring the plutonium experiments. During the Cold War, these agencies had continued to do much of their work in the twilight zone between openness and secrecy. Now, the Cold War was over. The time had come, Secretary
Preface
O'Leary determined, to make public anything that remained to be told about the plutonium experiments.
Subsequent press reports soon noted that the plutonium injections were not the only human radiation experiments that had been conducted during the war and the decades that followed. In Massachusetts, the press reported that members of the "science club" at the Fernald School for the Retarded had been fed oatmeal containing minute amounts of radioactive material. In Ohio, news articles revived an old controversy about University of Cincinnati researchers who had been funded by the Defense Department to gather data on the effects of "total-body irradiation" on cancer patients. In the Northwest, the papers retold the story of Atomic Energy Commission funding of researchers to irradiate the testicles of inmates in Oregon and Washington prisons in order to gain knowledge for use in government programs. The virtually forgotten 1986 report prepared by a subcommittee headed by U.S. Representative Edward Markey, "American Nuclear Guinea Pigs: Three Decades of Radiation Experiments on U.S. Citizens," was also recalled to public attention.1
Coincidentally, the fact that the environment had also been used as a secret laboratory became a subject of controversy. A November 1993 congressional report uncovered thirteen cases in which government agencies had intentionally released radiation into the environment without notifying the affected populations.2 At various times, tests were conducted in Tennessee, Utah, New Mexico, and Washington state. This report had been prepared at the request of Senator John Glenn in his capacity as chair of a committee that had undertaken a comprehensive oversight investigation of the nuclear weapons complex. As a young marine in 1945, the senator was in a squadron being trained for possible deployment to Japan when the atomic bomb ended the war; as an astronaut, he had been the subject of constant testing and medical monitoring by space administration flight surgeons; as a senator he was at the center of the country's efforts to understand and control nuclear weapons. Senator Glenn understood the importance of national security, but he found it "inconceivable . . . that, even at the height of the communist threat, some of our scientists and doctors and military and perhaps political leaders approved some of these experiments to be conducted on an unknowing and unwitting public."3
In the immediate aftermath of Secretary O'Leary's press conference and the further press reports, thousands of callers flooded the Department of Energy's phone lines to recount their own experiences and those of friends and family members.
Underlying the outrage and concern expressed by government officials and members of the public were many unanswered questions. How many human radiation experiments were conducted? No one knew if the number was closer to 100 or 1,000. Were all the human radiation experiments done in secret, and were any of them still secret? Are any secret or controversial studies still ongoing?
Preface
Scientists and science journalists pointed out that some of the highly publicized experiments had long ago been the subject of technical journal articles, even press accounts, and were old news; other commentators countered that, for most of the public, articles in technical journals might as well be secret.
How, why, and from what population groups were subjects selected for experiments? Some suspected that subjects were disproportionately chosen from the most vulnerable populations-children, hospitalized patients, the retarded, the poor—those too powerless to resist the government and its researchers.
Did the experiments benefit the American people through the advancement of science and the enhancement of the ability to treat disease?
How many intentional releases took place, and how many people were unknowingly put at risk? The answer here was sketchy; the releases identified in the November 1993 Glenn report had all been performed in secret, and much information about them was still secret.
How great were the risks to which people were exposed? Many pointed out that radiation is not only present in our natural environment, but that, as a result of biomedical research, most people routinely rely on radiation as a means of diagnosing and treating disease. Others noted that while this is so, radiation can be abused, and the potential dangers of low-level exposure are still not well understood.
What did our government and the medical researchers it sponsored do to ensure that the subjects were informed of what would be done to them and that they were given meaningful opportunities to consent? Today, federal government rules require the prior review of proposed experiments, to ensure that the risks and potential benefits have been considered and that subjects will be adequately informed and given the opportunity to consent. But the standards of today, many historians and scholars of medical ethics noted, are not those of yesterday. Others, however, declared that it was self-evident that no one should be experimented upon without his or her voluntary consent. Indeed, it was pointed out that this very principle was proclaimed aloud to the world in 1947, as the plutonium experiments were coming to a close. It was the American judges at the international war crimes trials in Nuremberg, Germany, who invoked the principle in finding doctors guilty of war crimes for their vile experiments on inmates of Nazi concentration camps. How could yesterday's standard have been less strict than that of today? How, moreover, could the standard not have been known by the government that sponsored the experiments and the researchers who conducted them?
Finally, there were questions about how human experiments are conducted today. Insofar as wrong things happened in the past, how confident should we be that they could not happen again? Have practices changed? Do we have the right rules, and are they implemented and enforced?
4
Preface THE PRESIDENT'S CHARGE
The Advisory Committee was created under the Federal Advisory Committee Act of 1972, which provides that committee meetings and basic decision making be conducted in the open. The Committee's charter4 defined human radiation experiments to include
(1) experiments on individuals involving intentional exposure to ionizing radiation. This category does not include common and routine clinical practices. . . .
(2) experiments involving intentional environmental releases of radiation that (A) were designed to test human health effects of ionizing radiation; or (B) were designed to test the extent of human exposure to ionizing radiation.
The Committee was mandated to review experiments conducted between 1944 and 1974, the latter being the year that the U.S. Department of Health, Education, and Welfare issued rules for the protection of human subjects of federally sponsored research. The Committee was asked to determine the ethical and scientific standards by which to evaluate the pre- 1974 experiments and the extent to which these experiments were consistent with such standards. We were also to "consider whether (A) there was a clear medical or scientific purpose for the experiments; (B) appropriate medical follow-up was conducted; and (C) the experiments' design and administration adequately met the ethical and scientific criteria, including standards of informed consent, that prevailed at the time of the experiments and that exists today." The charter also directed that, upon completing our review, the Committee may recommend that subjects (or families) be notified of potential health risks and the need for medical follow-up and also that we "may recommend further policies, as needed, to ensure compliance with recommended ethical and scientific standards for human radiation experiments."
In order to inform the public about the conduct of research involving human subjects taking place today, we were authorized to sample and consider examples of research with human subjects currently under way.
In essence, we were to answer several fundamental questions: (1) What was the federal government's role in human radiation experiments conducted from 1944 to 1974? (2) By what standards should the ethics of these experiments be evaluated? and (3) What lessons learned from studying past and present research standards and practices should be applied to the future?
In addition, while the Committee was not expressly charged with considering issues relating to remedies, including financial compensation, we have felt obliged to address the type of remedies that we believe the government,
Preface
as an ethical matter, should provide to subjects of experiments where the circumstances warranted such a response.
THE COMMITTEES APPROACH
When those of us selected by President Clinton to serve on the Committee read about human radiation experiments in our hometown newspapers during the 1993 holiday season, none of us imagined that within months we would be embarking on such an intense and challenging investigation of an important aspect of our nation's past and present, requiring new insights and difficult judgments about enduring ethical questions.
On April 2 1 and 22, 1 994, the Committee held its first meeting, and most of us met each other for the first time. As we listened to opening statements by Cabinet members and members of Congress, as well as the first witness from the general public, it became clear how daunting a task we were undertaking. We realized that our ability to reconstruct the story of past radiation experiments required both the capacity to join with the agencies in the search through thousands of boxes for documents and the intuition to recognize which documents were important. We knew that the ability to tell that story depended on our ability to understand the full range of technically complex, often emotionally charged issues related to human radiation experiments. We could not understand, much less tell, the story until we sought out all who could enhance our understanding, a difficult job because the voices to which we had to listen spoke in the varied languages of medicine, a multiplicity of scientific disciplines, the military, policymakers, philosophers, patients, healthy subjects, family members of former subjects, and individuals in a variety of other roles.
Finally, we were also convinced that an important determinant of our success in keeping faith with the American people would be to understand not only how human subject research was conducted in the past but also how it is being conducted in the present.
Reaching In and Reaching Out
As we began our work, Committee members first sought to educate one another. Early meetings included basic presentations on such topics as research ethics, radiation, the history of human experimentation, the law of remedies, and the debate over the effects of low levels of radiation.
Then we determined to search broadly for those who could contribute to our understanding. We hired a staff with the expertise and experience need for the Committee's myriad tasks. Finally, we sought to make ourselves available to those who wanted to speak to us directly, especially people who felt they or their loved ones were harmed, or might have been harmed, by human radiation-related
Preface
research or exposure. Each of the Committee's meetings reserved a period for public comment. Since April 1994, the full Committee held sixteen public meetings, each of two to three days' duration. Fifteen of those meetings were held in Washington, D.C., and one was in San Francisco. In addition,; subsets of Committee members presided over public forums in Cincinnati, Knoxville, Santa Fe and Spokane. We traveled to these different cities in order to hear from people who could not come to Washington, D.C., and lived in communities where, or near where, experiments or intentional releases of interest to the Committee had taken place. We further sought to reach out to those who could not attend our meetings. By phone, mail, and personal visit, we and our staff communicated with members of the public, researchers, attorneys, investigative reporters, authors, and representatives of dozens of groups of interested people who shared some aspect of the Committee's concern.
The Records of Our Past: The Search for Documents
One of the most difficult tasks before the Committee was determining how many federally sponsored human radiation experiments occurred between 1944 and 1974 and who conducted them. When President Clinton established the Committee, he also directed the Human Radiation Interagency Working Group to provide us with all relevant documentary information in each of the agencies files Teams were formed to identify the hundreds of government sites where relevant documents might be located. We discovered there was no easy way to identify how many experiments had been conducted, where they took place and which government agencies had sponsored them. The location and retrieval of documents thus required an extraordinary effort, and we appreciate the assistance
of all our collaborators. . , ...
We began with documents that were assembled during the 1980s and that provided the basis for the Markey report. But review of those materials confirmed that, even for this relatively well-known group of uexP^m^; basic information was lacking. We found that the Department of Health ; an Humm Services (DHHS), which is the primary government sponsor of research involving human subjects, reported that, as permitted by federal records laws it had long since discarded files on experiments performed decades ago. Furthermore, the capsule descriptions of research that remained sometimes did not make clear whether the subjects of research had been humans or animals To complicate matters further, the DHHS also pointed out that much research documentation had originated and been retained only in the files of nonfederal grantee institutions and investigators. Other agencies did provide some lists of experiments, in many cases however, there was no information on basic questions of concern (tor example, who the subjects were and what, if anything, they were told).
What rules or policies, if any, existed to govern federally sponsored
Preface
experiments in the pre- 1974 period? The prevailing assumption was that, with a few notable exceptions, it was not until the mid-1960s that federal agencies began to develop such policies in any significant way. Most scholarship focused on divisions of the (then) Department of Health, Education, and Welfare. Little was known about approaches to human experimentation at the Atomic Energy Commission and the Department of Defense. Yet it was clear from the outset of our inquiry that these agencies, as well as the DHEW, were central to the story of human radiation experiments and that many of the experiments of interest predated by decades the mid-1960s' interest in human subject protections.
As we began our search into the past, we found that it was necessary to reconstruct a vanished world. The Committee and the agencies had to collect information scattered in warehouses throughout the country. At the same time, we had to create and test the framework needed to ensure that there would be a "big picture" into which all the pieces of the puzzle would fit.
After a few months, the outlines of a world that had been almost lost began to reemerge. Working with the Defense Department, we discovered that long-forgotten government entities had played central roles in the planning of midcentury atomic warfare-related medical research and experimentation. These groups, the piecing together of long-lost or forgotten records would show, debated the ethics of human experimentation and discussed possible human radiation experimentation: Similarly, working with the Department of Energy, we pieced together the minutes, and even many transcripts, of the key medical advisory committee to the Atomic Energy Commission. We sought to mine agency histories, when th£y existed: for example, at the Committee's request, the Defense Nuclear Agency (the heir to the part of the Manhattan Project that was transferred to the Defense Department) made public portions of the more than 500 internal histories that chronicle its story, most of which had previously been available only to those with security clearances.
Despite these successes, it became evident that the records of much of our nation's recent history had been irretrievably lost or simply could not be located. The Department of Energy told the Committee that all the records of the Intelligence Division of its predecessor, the Atomic Energy Commission, had been destroyed— mainly during the 1970s, but in some cases as late as 1989. The CIA explained, as had been previously reported, that records of the program known as MK.ULTRA, in which unwitting subjects were experimented upon with a variety of substances, had been destroyed during the 1970s, when the program became a widely publicized scandal. Though documents related to the program referred to radiation, the CIA concluded that human experiments using ionizing radiation never took place under that program, based on currently available evidence.
We also turned to nongovernmental archives throughout the country. Cryptic notes and fragments of correspondence located in private and university
8
Preface
archives were fitted into our growing outline. For example, a copy of an important 1954 Army surgeon general research policy statement, referenced in Defense Department documents, was found at Yale University among the papers
of a Nobel laureate. . ,
Bv the end of our term, the Committee had received, organized, and reviewed hundreds of thousands of pages of documents from public and private archives This collection will be available to individuals and scholars who wish to pursue the great many stories that remain to be told, and we view this as one of our most significant contributions.
The Records of Our Past: The Memories of the People
The Committee listened to the testimony of more than 200 public witnesses who appeared before us. We heard from people or their family members who had been subjects in controversial radiation experiments, including the plutonium injections, total-body irradiation experimen ts and ex Penments involving the use of radioactive tracers with institutionalized children. We heard from "atomic veterans": soldiers who had been marched to ground zero at atomic bomb tests, sailors who had walked the decks of ships contaminated by radioactive mist, and pilots who had flown through radioactive mushroom clouds. We also heard from their widows. We heard from people who lived "downwind from nuclear weapons tests in Nevada and intentional releases of radioactive material in Washington state. We heard from Navajo miners who had served the Country in uranium mines filled with radioactive dust, from native Alaskans who had been experimented upon by a military cold weather research . lab, and I from Marshall Islanders, whose Pacific homeland had been contaminated by fallout after a 1954 hvdrogen bomb test.
We heard from officials and researchers responsible for human t research today and from those who were present at or near the dawn of the Cold War. We heard from individuals who, on their own time, had long been seeking to piece together the story of human radiation experiments and offered to share their findings. We heard from scholars, from members of Congress, and from people who wanted to bear witness for those who could no longer speak We heard from a woman who, as a high-school student intern decades ago, attended at the bedside while a terminally ill patient was injected with uranium and from a powerfully spoken veteran of the nuclear weapons work force who told of the "bodv snatching" of dead friends in the name of science.
Most important, we heard from many people who believed that something involving the government and radiation happened to them or their loved ones decades ago; most had been unable to find out exactly what had happened, or whv and now they wanted to know the truth. These witnesses spoke eloquent y of their pain, their frustration, and the reasons they do not trust the government.
Preface
Their very appearance before the Committee testified to a commitment to the country and to the value of the nation's effort to understand its past. We are deeply grateful to all of these witnesses, who overcame the obstacles of geography and emotions to participate in this work.
We combined our public meetings with additional efforts to interview, and record for the nation's archives, those who could shed light on Cold War human radiation experiments and on the ethics of biomedical experimentation. Dozens of interviews were conducted with former government officials responsible for programs that included radiation research, as well as with radiation researchers.
In Mississippi we talked with a retired general who served as a military assistant to secretaries of defense in the 1940s and 1950s; in Berkeley, we talked with the chemist who was one of the discoverers of plutonium; in Rhode Island we talked with the physicist who served as the link between the civilian health and safety agencies and the Cold War military research efforts; in Florida we talked with a pioneer in health physics, a discipline created to provide for the safety of nuclear weapons workers; in San Francisco and Washington, D.C., we talked to the lawyers who advised the Atomic Energy Commission at its postwar creation; in New York we talked with the Navy radiation researcher who was rousted from his Maryland laboratory to respond to the emergency created by the exposure of the Marshall Islanders; in San Diego we talked with a researcher whose own career and massive history of radiation research had covered much of the Committee's territory.
We also launched a special effort, called the Ethics Oral History Project, to learn from eminent physicians who were beginning their careers in academic medicine in the 1940s and 1950s about how research with human subjects was then conducted. The Ethics Oral History Project also included interviews with two people who had been administrators of the National Institutes of Health during the 1950s, since they were intimately involved with ethical and legal aspects of research involving human subjects at the time.
We listened to all these people and more, and through their testimony, this report is informed.
Bounds of Our Inquiry
In the course of listening to public testimony, it became clear to us that confusion exists about what an experiment is and whether it can be distinguished from other activities in which people are put at risk and information is gathered about them. The biomedical community, for example, struggles with the distinction between scientific research and related activities. In a medical setting, it is sometimes hard to distinguish a formal experiment designed to test the effectiveness of a treatment from ordinary medical care in which the same treatment is being administered outside of a research project. The patient
10
Preface
receiving the treatment may discern no difference between the two but the Sn is relevant to questions of ethics. The physician-investigator may face conflicts between the obligation to do what is best for each individual patient .and the requirements of scientific research, whereas the physician involved only in clinical care has a responsibility solely to the patient.
Similarly, in an occupational setting in which employees are put at risk, it is often difficult to distinguish formal scientific efforts to study effects on the health of employees fromroutine monitoring of employees exposure to hazards in the work place for purposes of ensuring worker safety. In the first case, the r^les of research ethics apply; in the second they do not. And yet here too, the worker may discern no difference between the two activities. A further complication for the Committee to consider was the fact that research in occupational settings rarely takes the form of a classic experiment, in which the investigator controls the variable under study and then randomly assigns subjects to be in the "treatment" or "control" group. Instead, most occupational research employs observational and statistical methods, drawing most heavily from the field of epidemiology. These distinctions were unimportant, however to Mhe representatives of atomic veterans, uranium miners, and residents of the Marshall Islands, who told us of their belief that they, or those they spoke for, were
subjects of research. j-„*:„„
The Committee struggled with how strictly to define human radiation experiments for purposes of our inquiry. There is no sin gle clear definition of an experiment that is widely subscribed to by every member of the biomedical community. Even our description above of a classic experiment is open to contest Today, as well as in the past, the scientific community has rarely employed the term experiment in discussions of biomedical research; other terms, not necessarily synonymous-such as clinical study, clinical investigation, quasi Zeriment, and case control study--** all used. We concluded that it was not possible to interpret our charge by stipulating an artificial definition of human radiation experiment. Instead, in keeping with the realities of bl0™e?ical research, we decided to interpret our charge broadly, as including both research involving human subjects in which the research design called for exposing subjects to ionizing radiation and research designed to study the effects of radiation exposure resulting from nonexpenmental activities.
This latter category includes the research involving uranium miners and Marshall Islanders. In these cases we quickly determined that it was in some respects impossible to isolate the ethical questions raised by the research from the ethics of the context in which the research was conducted. A centra issue was the exposure of people to risk, regardless of whether they were clearly understood to be subjects of research. This characterization is true, as well, of the experience of atomic veterans. As a consequence, we considered events that might be said to be on the boundary between research and some other activity. Our inquiry
11
Preface
underscored the importance for social policy of the need to keep focused on questions of risk and well-being regardless of what side of that boundary the activity producing the risk falls.
Human Experimentation Today
In tandem with the reconstruction of the past, we undertook three projects to examine the current state of human radiation experiments.
First, we studied how each agency of the federal government that currently conducts or funds research involving human subjects regulates this activity and oversees it. We surveyed what the operative rules are, how they are implemented, and how they are enforced.
Second, from among the very large number of research projects involving human subjects currently supported by the federal government, we randomly selected 125 research projects for scrutiny by the Committee. For each of these projects, we reviewed all available relevant documentation to assess how well it appeared the rights and interests of the subjects participating in these projects were being protected. The success of this review required the cooperation of private research institutions all over the country, on whom we were dependent for access to important documents. We had expected that perhaps no more than half of those asked to cooperate would agree to do so, but with little hesitation, all of the research centers that we approached agreed to cooperate.
Third, to learn from the subjects themselves, the Committee interviewed almost 1,900 patients receiving medical care in outpatient facilities of private and federal hospitals throughout the country. We asked patients about their attitudes toward medical research with human subjects and about the meaning they attach to the different terms used to explain medical research to potential subjects. We ascertained, and attempted to verify, how many of these patients were currently or ever had been subjects of research. Patient-subjects were asked about their reasons for agreeing to join research projects; patients who reported having refused offers to enter research projects were asked why they had decided against participating.
In all three of these projects, we focused not only on human radiation experiments but on human research generally. In critical (but not all) respects, the government regulations that apply to human radiation research do not differ from those that govern other kinds of research involving human subjects. Moreover, the underlying ethical principles that should guide the conduct of research are identical, whether one is considering human radiation research or all research with human subjects. Finally, the Committee hoped to learn whether, in practice, there are any differences between the conduct of radiation and nonradiation experiments.
12
Preface LESSONS FROM HISTORY: LOOKING TO THE FUTURE
What we have found is a story about the government's attempt to serve two critical purposes: safeguarding national security and advancing medical knowledge. One-half century ago, the U.S. government and its experts in the fields of radiation and medicine were seeking to learn more about radiation in order to protect workers, service personnel, and the general public against potential atomic war and individuals against the menace of disease.
Toward these laudable ends, the government used patients, workers, soldiers, and others as experimental subjects. It acted through the experts to whom we regularly entrust the well-being of our country and our selves: elected officials, civil servants, generals, physicians, and medical researchers.
Moreover, the government acted with full knowledge that the use of individuals to serve the ends of government raises basic ethical questions. If, as we look back, there could be doubt about the importance of the matter to the leaders of the time, we need only look to the appearance before the U.S. Senate of David Lilienthal, who had been nominated to serve as the first chairman of the Atomic Energy Commission, the civilian successor to the Manhattan Project and the predecessor to today's Department of Energy. In his testimony, Lilienthal forcefully stated:
... all Government and private institutions must be designed to promote and protect and defend the integrity and the dignity of the individual. . . . Any forms of government . . . which make men means rather than ends in themselves ... are contrary to this conception; and therefore I am deeply opposed to them. . . . The fundamental tenet of communism is that the state is an end in itself, and that therefore the powers which the state exercises over the individual are without any ethical standards to limit them. This I deeply disbelieve.6
What did happen when individuals were sometimes used as means to achieve national goals? How well were the national goals of preserving the peace and advancing medical science reconciled with the equally important end of respect for individual dignity and health? What rules were followed to protect people, and how well did they work? Was the public let in on the balancing of collective and individual interest? In what sense did the public, in general, and individuals, in particular, know what was happening and have the opportunity to provide their meaningful consent?
In this report we try to convey our understanding of how, when only good
13
Preface
was sought, when its pursuit was entrusted to the experts on whom we most relied, and when missions were substantially accomplished, distrust, as well as accomplishment, remains.
We focus on the ways in which the government and its experts recognized the interest of individual dignity and sought to strike a balance with the national interests being pursued. We focus equally on the extent to which the public was privy to this balancing. In particular, we try to show how individuals' understanding and participation were limited by the conjunction of government secrecy and expert knowledge.
All Americans should experience immense satisfaction in the strides that have been made toward accomplishing both our national security and our medical research goals. However, as attested to by the many thousands of letters and calls that led to the Committee's creation, and the eloquent statements of the witnesses who appeared before us, this pride is diluted by a bitter aftertaste-distrust by many Americans of the federal government and those who served it.
The government has the power to create and keep secrets of immense importance to us all. Secret keeping is a part of life. Secret keeping by the government may be in the national interest. However, if government is to be trusted, it is important to know, at the very least, the basic rules of secrecy and to know that they are reasonable and that they are being followed.
Similarly, experts, by training and experience, have knowledge that individual people must, as a practical matter, rely on. However, legitimate questions arise when experts wear multiple hats or when they are relied on in areas beyond their expertise.
Where official secrecy is coupled with expert authority, and both are focused on a public that is not privy to secrets and does not speak the languages of experts, the potential for distrust is substantial.
In telling the story, and asking the questions, we have kept our eyes open for ways in which lost trust can be restored. It might be presumed that the past we report on here is so different from the present that it will be of little use in understanding research involving human subjects today. In fact, as we shall see, basic questions posed by the story of human radiation experiments conducted during the 1944-1974 period are no less relevant today. Then, as now, there were standards; the question is how they worked to protect individuals and the public. Then, as now, the ethical impulse was complexly alloyed with concerns for legal liability and public image. Then, as now, the most difficult questions often concerned the scope and practical meaning of ethical rules, rather than their necessity. The country has come to recognize, from its experience of the past half century, that tinkering with the regulations that govern publicly supported institutions, imposing ethical codes on experts, and altering the balance between secrecy and openness are important but not always sufficient means of reform. The most important element is a citizenry that understands the limits of these
14
Preface
activities. That is why the purpose of this story is not simply to leam which changes to make in rules or policies that apply to government or professionals, but to begin to learn something more about how the Cold War world worked, as the most important means to making the world of tomorrow work better.
HOW THIS REPORT IS ORGANIZED
Though this report is addressed largely to those who can affect future policy in light of the information the Advisory Committee has gathered, specifically the Human Radiation Interagency Working Group, it has been written in such a way that it should be accessible to a wide range of interested readers.
We begin with an introduction, titled "The Atomic Century," which describes the intersection of several developments: the birth and remarkable growth of radiation science; the parallel changes in medicine and medical research; and the intersection of these changes with government programs that called on medical researchers to play important new roles beyond that involved in the traditional doctor-patient relationship. The introduction concludes with a section titled "The Basics of Radiation Science" for the lay reader.
The remainder of the text is divided into four parts. Each part is preceded by an overview.
Part I, "Ethics of Human Subjects Research: A Historical Perspective," which contains four chapters, explores how both federal government agencies and the medical profession approached human experimentation in the period 1944 through 1974. We begin with the story of the principles stated at midcentury at the highest levels of the Cold War medical research bureaucracies and what we have ascertained about whether these principles were translated into federal rules or requirements. We then turn to the norms and practices engaged in at the time by medical researchers themselves. It is in this chapter that we report the results of our Ethics Oral History Project. In chapter 3, we review the development of formal and public regulations concerning research involving human subjects in the 1960s and 1970s. In the last chapter in part I we present our framework for evaluating the ethics of human radiation experiments, grounded in both history and philosophical analysis.
Part II, "Case Studies," approaches particular experiments from several angles, each of which raises overlapping ethical questions. The chapters on the plutonium injections and total-body irradiation consider the use of sick patients to provide data needed to protect the health of workers engaged in the production of nuclear weapons; the chapter on prisoners considers the use of healthy subjects for this purpose; the chapter on children considers experimentation with particularly vulnerable people; and the chapter on the AEC program of radioisotope distribution considers the institutional safeguards that underlay the conduct of thousands of human radiation experiments. The chapters on
15
Preface
intentional releases, atomic veterans, and observational studies consider, in common, situations in which entire groups of people were exposed to risk as a consequence of government-sponsored Cold War programs. The section concludes with a review of the degree to which secrecy impaired, and may still impair, our ability to understand human radiation experiments and intentional releases conducted in the 1944-1974 period.
Part III, "Contemporary Projects," reports the findings of our three inquiries into the present. We begin by describing what we have learned about how the different federal agencies that sponsor human research regulate and oversee this activity. Next, we report the results of our Research Proposal Review Project, followed by the results of our Subject Interview Study. Part III concludes with the Committee's synthesis of the implications of the results of all three of these projects for the current state of human subject research.
Part IV, "Coming to Terms with the Past, Looking Ahead to the Future," reports the Committee's findings and recommendations.
A FINAL NOTE
The Committee's findings and recommendations represent our best efforts to distill almost eighteen months of inquiry into, debate about, and analysis of human radiation experiments. But what they cannot fully express is the appreciation we developed for how much damage was done to individuals and to the American people during the period we investigated and how this damage endures today. The damage we speak of here is not physical injury, although this too did occur in some cases. Rather, the damage is measured in the pain felt by people who believe that they or their loved ones were treated with disrespect for their dignity and disregard for their interests by a government and a profession in which they had placed their trust. It is measured in a too-often cynical citizenry, some of whom have lost faith in their government to be honest brokers of information about risks to the public and the purposes of government actions. And it is measured in the confusion among patients that remains today about the differences between medical research and medical care— differences that can impede the ability of patients to determine what is in their own best interest.
In the period that we examined, extraordinary advances in biomedicine were achieved and a foundation was laid for fifty years without a world war. At the same time, however, it was a time of arrogance and paternalism on the part of government officials and the biomedical community that we would not under any circumstances wish to see repeated.
As we listened to the heart-rending testimony of many public witnesses, we came to feel great sorrow about the suffering they described. Our most difficult task was determining what to recommend as the appropriate national response to these emotions and the events that stimulated them. What can best
16
Preface
precipitate the healing of wounds and the restoration of trust? Appropriate remedies for those who were wronged or harmed were of critical importance, but remedies alone speak only to the past, not the future. It is equally important that, the historical record having been spelled out and appropriate remedies identified, we as a nation move forward and take action to prevent similar occurrences from happening in the future. In the end, if trust in government is to be restored, those in power must always act in good faith in their dealings with the citizenry. At the same time, however, we must recognize that unless we have expectations of honesty and fairness from our government and unless we are vigilant in holding the government to those expectations, trust will never be restored.
Finally, we hope that this report conveys the sense of gratitude and honor that we experienced as citizens serving on the Advisory Committee. We were provided by the President with extraordinary access to the records of our past and given complete liberty to deliberate on what we found. Although some of what we report is a matter for national regret, our freedom of inquiry, and the cooperation we received from officials and fellow citizens of all perspectives, confirms that our nation's highest traditions are not things of the past but live very much in the present.
17
ENDNOTES
1 . U.S. House of Representatives, Committee on Energy and Commerce, Subcommittee on Energy Conservation and Power, November 1986, "American Nuclear Guinea Pigs: Three Decades of Radiation Experiments on U.S. Citizens" (ACHRE No. CON-050594-A-1).
2. U.S. Senate, Committee on Governmental Affairs, 1 1 November 1993, "Nuclear Health and Safety: Examples of Post World War II Radiation Releases at U.S. Nuclear Sites," GAO/RCED-94-51-FS (ACHRE No. CON-042894-A-4).
3. Advisory Committee on Human Radiation Experiments, proceedings of 21 April 1994, transcript, 112-113.
4. The full text of the Committee's charter appears at the end of this report. See table of contents for page number.
5. For further information on access to this collection, see "A Citizen's Guide to the Nation's Archives" at the end of this report.
6. David E. Lilienthal, The Journals of David E. Lilienthal: 1945-1950, 2 vols. (New York: Harper and Row, 1964), as quoted in David McCullough, Truman (New York: Simon and Schuster, 1992), 537-538.
18
INTRODUCTION
The Atomic Century
One hundred years ago, a half century before the atomic bombing of Hiroshima and Nagasaki, the discovery of x rays spotlighted the extraordinary promise, and peril, of the atom. From that time until 1942, atomic research was in private hands. The Second World War and the Manhattan Project, which planned and built the first atomic bombs, transformed a cottage industry of researchers into the largest and one of the most secretive research projects ever undertaken. Scientists who had once raced to publish their results learned to speak in codes accessible only to those with a "need to know." Indeed, during the war the very existence of the man-made element plutonium was a national secret.
After the war's end, the network of radiation researchers, government and military officials, and physicians mobilized for the Manhattan Project did not disband. Rather, they began working on government programs to promote both peaceful uses of atomic energy and nuclear weapons development.
Having harnessed the atom in secret for war, the federal government turned enthusiastically to providing governmental and nongovernmental researchers, corporations, and farmers with new tools for peace-radioisotopes- mass-produced with the same machinery that produced essential materials for the nation's nuclear weapons. Radioisotopes, the newly established Atomic Energy Commission (AEC) promised, would create new businesses, improve agricultural production, and through "human uses" in medical research, save lives.
From its 1947 creation to the 1974 reorganization of atomic energy activities, the AEC produced radioisotopes that were used in thousands of human radiation experiments conducted at universities, hospitals, and government facilities.' This research brought major advances in the understanding of the
19
Introduction
workings of the human body and the ability of doctors to diagnose, prevent, and treat disease.
The growth of radiation research with humans after World War II was part of the enormous expansion of the entire biomedical research enterprise following the war. Although human experiments had long been part of medicine, there had been relatively few subjects, the research had not been as systematic, and there were far fewer promising interventions than there were in the late 1940s.
With so many more human beings as research subjects, and with potentially dangerous new substances involved, certain moral questions in the relationship between the physician-researcher and the human subject—questions that were raised in the nineteenth century-assumed more prominence than ever: What was there to protect people if a researcher's zeal for data gathering conflicted with his or her commitment to the subjects' well-being? Was the age- old ethical tradition of the doctor-patient relationship, in which the patient was to defer to the doctor's expertise and wisdom, adequate when the doctor was also a researcher and the procedures were experimental?
While these questions about the role of medical researchers were fresh in the air, the Manhattan Project, and then the Cold War, presented new ethical questions of a different order.
In March 1946, former British Prime Minister Winston Churchill told an audience in Fulton, Missouri, that an "iron curtain" had descended between Eastern and Western Europe—giving a name to the hostile division of the continent that had existed since the end of World War II. By the following year. Cold War was the term used to describe this state of affairs between the United States and its allies on the one hand and the Soviet bloc on the other. A quick succession of events underscored the scope of this conflict, as well as the stakes involved: In 1948 a Soviet blockade precipitated a crisis over Berlin; in 1949, the American nuclear monopoly ended when the Soviet Union exploded its first atomic bomb; in 1950, the Korean War began.
The seeming likelihood that atomic bombs would be used again in war, and that American civilians as well as soldiers would be targets, meant that the country had to know as much as it could, as quickly as it could, about the effects of radiation and the treatment of radiation injury.
This need for knowledge put radiation researchers, including physicians, in the middle of new questions of risk and benefit, disclosure and consent. The focus of these questions was, directly and indirectly, an unprecedented public health hazard: nuclear war. In addressing these questions, medical researchers had to define the new roles that they would play.
As advisers to the government, radiation researchers were asked to assist military commanders, who called for human experimentation to determine the effects of atomic weapons on their troops. But these researchers also knew that human experimentation might not readily provide the answers the military needed.
20
The Atomic Century
As physicians, they had a commitment to prevent disease and heal. At the same time, as government advisers, they were called upon to participate in making decisions to proceed with weapons development and testing programs that they knew could put citizens, soldiers, and workers at risk. As experts they were asked to ensure that the risks would not be excessive. And as researchers they saw these programs as an opportunity for gathering data.
As researchers, they were often among the first to volunteer to take the risks that were unavoidable in such research. But the risks could not always be disclosed to members of the public who were also exposed. In keeping with the tradition of scientific inquiry, these researchers understood that their work should be the subject of vigorous discussion, at least among other scientists in their field. But, as government officials and advisers, they understood that their public statements had to be constrained by Cold War national security requirements, and they shared in official concern that public misunderstanding could compromise government programs and their own research.
Medical researchers, especially those expert in radiation, were not oblivious to the importance of the special roles they were being asked to play. "Never before in history," began the 1949 medical text Atomic Medicine, "have the interests of the weaponeers and those who practice the healing arts been so closely related."2 This volume, edited by Captain C. F. Behrens, the head of the Navy's new atomic medicine division, was evidently the first treatise on the topic. It concluded with a chapter by Dr. Shields Warren, the first chief of the AEC's Division of Biology and Medicine, who would become a major figure in setting policy for postwar biomedical radiation research. While the atomic bomb was not "of medicine's contriving," the book began, it was to physicians "more than to any other profession" that atomic energy had brought a "bewildering array of new problems, brilliant prospects, and inescapable responsibilities." The text, a prefatory chapter explained, treats "not of high policy, of ethics, of strategy or of international control [of nuclear materials], as physicians these matters are not for us."3 Yet what many readers of Atomic Medicine could not know in 1949 was that Behrens, along with Warren and other biomedical experts, was already engaged in vigorous but secret discussions of the ethics underlying human radiation experiments. At the heart of these discussions lay difficult choices at the intersection of geopolitics, science, and medicine that would have a fundamental impact on the federal government's relationship with the American people.
This chapter provides a brief survey of the development of radiation research and the changing roles of the biomedical researcher, from the discovery of x rays by a single individual to the complex world of government-sponsored human radiation experimentation. Finally, at the end of this chapter, an aid to the reader titled "The Basics of Radiation Science" provides information needed to understand technical concepts in this report.
21
Introduction
BEFORE THE ATOMIC AGE: "SHADOW PICTURES," RADIOISOTOPES, AND THE BEGINNINGS OF HUMAN RADIATION EXPERIMENTATION
Radiation has existed in nature from the origins of the universe, but was unknown to man until a century ago. Its discovery came by accident. On a Friday evening, November 8, 1895, the German physicist Wilhelm Roentgen was studying the nature of electrical currents by using a cathode ray tube, a common piece of scientific equipment. When he turned the tube on, he noticed to his surprise that a glowing spot appeared on a black paper screen coated with fluorescent material that was across the room. Intrigued, he soon determined that invisible but highly penetrating rays were being produced at one end of the cathode ray tube. The rays could expose photographic plates, leaving shadows of dense objects, such as bone.
After about six weeks of experimenting with his discovery, which he called x rays, Roentgen sent a summary and several "shadow pictures" to a local scientific society. The society published the report in its regular journal and wisely printed extra copies. News spread rapidly; Roentgen sent copies to physicists throughout Europe. One Berlin physicist "could not help thinking that I was reading a fairy tale . . . only the actual photograph proved to everyone that this was a fact."4
Physicians immediately recognized these rays as a new tool for diagnosis, a window into the interior of the body. The useless left arm of German Emperor Wilhelm II was x-rayed to reveal the cause of his disability, while Queen Amelia of Portugal used x rays of several of her court ladies to vividly display the dangers of "tightlacing."5 Physicians began to use x rays routinely for examining fractures and locating foreign objects, such as needles swallowed by children or bullets shot into adults.6 During World War I, more than 1.1 million wounded soldiers were treated with the help of diagnostic x rays.7
In 1 896, Roentgen's insight led to the discovery of natural radioactivity. Henri Becquerel, who had been studying phosphorescence, discovered that shadow pictures were also created when wrapped photographic plates were exposed to crystals partly composed of uranium. Could this radioactive property be concentrated further by extracting and purifying some as-yet-unknown component of the uranium crystals? Marie and Pierre Curie began laborious chemical analyses that led to the isolation of the element polonium, named after Marie's native Poland.8 Continuing their work, they isolated the element radium. To describe these elements' emission of energy, they coined the word radio- activity!'
As with x rays, popular hopes and fears for natural radioactivity far exceeded the actual applications. One 1905 headline captures it all: "Radium, as a Substitute for Gas, Electricity, and as a Positive Cure for Every Disease."10
22
The Atomic Century
Following initial enthusiasm that radiation could, by destroying tumors, provide a miracle cure for cancer, the reappearance of irradiated tumors led to discouragement. Despite distressing setbacks, research into the medical uses of radiation persisted. In the 1920s French researchers, performing experiments on animals, discovered that radiation treatments administered in a series of fractionated doses, instead of a single massive dose, could eliminate tumors without causing permanent damage. With the new method of treatment, doctors began to report impressive survival rates for patients with a variety of cancers.^ Fractionation became, and remains, an accepted approach to cancer treatment.
Along with better understanding of radiation's benefits came a better practical appreciation of its dangers. Radiation burns were quickly apparent, but the greater danger took longer to manifest itself. Doctors and researchers were frequently among the victims. Radiation researchers were also slow to take steps to protect themselves from the hidden danger. One journal opened its April 1914 issue by noting that "[w]e have to deplore once more the sacrifice of a radiologist, the victim of his art."12
Clear and early evidence of tragic results sharpened both expert and public concern. By 1924, a New Jersey dentist noticed an unusual rate of deterioration of the jawbone among local women. On further investigation he learned that all at one time had jobs painting a radium solution onto watch dials. Further studies revealed that as they painted, they licked their brushes to maintain a sharp point. Doing so, they absorbed radium into their bodies. The radium gradually revealed its presence in jaw deterioration, blood disease, and eventually, a painful, disfiguring deterioration of the jaw.13 There was no question that radium was the culprit. The immediate outcome was a highly publicized crusade, investigation, lawsuits, and payments to the victims. Despite the publicity surrounding the dial painters, response to the danger remained agonizingly slow. Patent medicines containing radium and radium therapies continued.14
The tragedy of the radium dial painters and similar cases of patients who took radium nostrums have provided basic data for protection standards for radioactive substances taken into the body. One prominent researcher in the new area of radiation safety was Robley Evans. Evans was drawn into the field by the highly publicized death in 1932 of Eben Byers, following routine consumption of the nostrum Radiothor. Byers's death spurred Evans, then a California Institute of Technology physics graduate student, to undertake research that led to a study of the effects on the body of ingesting radium; this study would continue for more than half a century.15
Evans's study and subsequent studies of the effects of radium treatments provided the anchor in human data for our understanding of the effects of radiation within the human body. As the dangers of the imprudent use of x rays and internal radiation became clear, private scientific advisory committees sprang up to develop voluntary guidelines to promote safety among those working with radiation. When the government did enter the atomic age, it often referred to the
23
Introduction
guidelines of these private committees as it developed radiation protection standards."'
The Miracle of Tracers
In 1913, the Hungarian chemist Georg von Hevesy began to experiment with the use of radioactive forms of elements (radioisotopes) to trace the behavior of the normal, nonradioactive forms of a variety of elements. Ten years later Hevesy extended his chemical experiments to biology, using a radioisotope of lead to trace the movement of lead from soil into bean plants. In 1943, Hevesy won the Nobel Prize for his work on the use of radioisotopes as tracers.
Previously, those seeking to understand life processes of an organism had to extract molecules and structures from dead cells or organisms, and then study those molecules by arduous chemical procedures, or use traceable chemicals that were foreign to the organism being studied but that mimicked normal body chemicals in some important way. Foreign chemicals could alter the very processes being measured and, in any case, were often as difficult to measure precisely as were normal body constituents. The radioactive tracer— as Our Friend the Atom, a book written by Dr. Heinz Haber for Walt Disney productions, explained in 1956 to readers of all ages—was an elegant alternative: "Making a sample of material mildly radioactive is like putting a bell on a sheep. The shepherd traces the whole flock around by the sound of the bell. In the same way it is possible to keep tabs on tracer-atoms with a Geiger counter or any other radiation detector."17
By the late 1920s the tracer technique was being applied to humans in Boston by researchers using an injection of dissolved radon to measure the rate of blood circulation, an early example of using radioactivity to observe life processes.18 However, research opportunities were limited by the fact that some of the elements that are most important in living creatures do not possess naturally occurring radioactive isotopes.
The answer to this problem came simultaneously at faculty clubs and seminars in Berkeley and Boston in the early 1930s. Medical researchers realized that the famed "atom smasher," the cyclotron invented by University of California physicist Ernest Lawrence, could be used as a factory to create radioisotopes for medical research and treatment. "Take an ordinary needle," Our Friend the Atom explained, "put it into an atomic reactor for a short while. Some of the ions contained in the steel will capture a neutron and be transformed into a radio- isotope of iron. . . . Now that needle could be found in the proverbial haystack without any trouble."19
In 1936, two of Lawrence's Berkeley colleagues, Drs. Joseph Hamilton and Robert Stone, administered radiosodium to treat several leukemia patients. In 1937, Ernest Lawrence's brother, physician John Lawrence, became the first to use radiophosphorus for the treatment of leukemia. This application was
24
The Atomic Century
extended the following year to the treatment of polycythemia vera, a blood disease. This method soon became a standard treatment for that disease. In 1938, Hamilton and Stone also began pioneering work in the use of cyclotron-produced neutrons for the treatment of cancer. The following year, not long before the war in Europe began, Ernest Lawrence unveiled a larger atom smasher, to be used to create additional radioisotopes and hence dubbed the "medical cyclotron."20 The discovery that some radioisotopes deposited selectively in different parts of the body—the thyroid, for example-inspired a spirited search for a radioactive "magic bullet" that might treat, or even cure, cancer and other diseases.
In Cambridge, the age of "nuclear medicine" is said to have begun in November 1936 with a lunchtime seminar at Harvard, at which MIT President Karl Compton talked on "What Physics Can Do for Biology and Medicine." Robley Evans, by that time at MIT, is reported to have helped prepare the portion of the talk from which medical researchers at the Massachusetts General Hospital's thyroid clinic came to realize that MIT's atom smasher could produce a great research tool for their work—radioisotopes. Soon, doctors at the thyroid clinic began a series of experiments, including some involving humans, that would lead to the development of radioiodine as a standard tool for diagnosing and treating thyroid disease.21
In late 1938, the discovery of atomic fission in Germany prompted concern among physicists in England and the United States that Nazi Germany might be the first to harness the power of the atom— as a propulsion method for submarines, as radioactive poison, or most worrisome of all, as a bomb capable of unimagined destruction. In the United States, a world-famous physicist, Albert Einstein, and a recent emigre from Hungary, Leo Szilard, alerted President Franklin D. Roosevelt to the military implications of the German discovery in an August 1939 letter.
Assigning his own science adviser, Vannevar Bush, to the task of determining the feasibility of an atomic bomb, Roosevelt's simple "O.K.," scrawled on a piece of paper, set in motion the chain of events that would lead to the largest and most expensive engineering project in history. Soon, Ernest Lawrence's Radiation Laboratory and its medical cyclotron were mobilized to aid in the nationwide effort to build the world's first atomic bomb. In a related effort, Drs. Stone and Hamilton, and others, would turn their talents to the medical research needed to ensure the safety of those working on the bomb.
THE MANHATTAN PROJECT: A NEW AND SECRET WORLD OF HUMAN EXPERIMENTATION
In August 1942, the Manhattan Engineer District was created by the government to meet the goal of producing an atomic weapon under the pressure of ongoing global war. Its central mission became known as the Manhattan Project. Under the direction of Brigadier General Leslie Groves of the Army
25
Introduction
Corps of Engineers, who recently had supervised the construction of the Pentagon, secret atomic energy communities were created almost overnight in Oak Ridge, Tennessee, at Los Alamos, New Mexico, and in Hanford, Washington, to house the workers and gigantic new machinery needed to produce the bomb. The weapon itself would be built at the Los Alamos laboratory, under the direction of physicist J. Robert Oppenheimer.
Plucked from campuses around the country, medical researchers came face to face with the need to understand and control the effect upon the thousands of people, doctors included, of radioactive materials being produced in previously unimaginable quantities.
In November 1942 General Groves, through the intermediation of an Eastman Kodak official, paid a call on University of Rochester radiologist Stafford Warren. Rochester, like MIT and Berkeley, was another locale where radiation research had brought together physicists and physicians. "They wanted to know what I was doing in radiation. So I discussed the cancer work and some of the other things," Warren told an interviewer in the 1960s. Then "[w]e got upstairs and they looked in the closet and they closed the transom and they looked out the window. . . . Then they closed and locked the door and said, 'Sit down.'"22
Soon thereafter, Dr. Warren was made a colonel in the U.S. Army and the medical director of the Manhattan Project. As his deputy, Warren called on Dr. Hymer Friedell, a radiologist who had worked with Dr. Stone in California. Dr. Stone himself had meanwhile moved to the University of Chicago, where he would play a key role in Manhattan Project-related medical research.
Initially, researchers knew little or nothing about the health effects of the basic bomb components, uranium, plutonium, and polonium.23 But, as a secret history written in 1946 stated, they knew the tale of the radium dial painters:
The memory of this tragedy was very vivid in the minds of people, and the thoughts of potential dangers of working in areas where radiation hazards existed were intensified because the deleterious effects of radiation could not be seen or felt and the results of over-exposure might not become apparent for long periods after such exposure.24
The need for secrecy, Stafford Warren later recalled, compounded the urgency of understanding and controlling risk. Word of death or toxic hazard could leak out to the surrounding community and blow the project's cover.25
The need to protect the Manhattan Project workers soon gave rise to a new discipline, called health physics, which sought to understand radiation effects and monitor and protect nuclear worker health and safety. The Project was soon inundated with data from radiation-detection instruments, blood and urine samples, and physical exams. The "clinical study of the personnel," Robert Stone
26
The Atomic Century
wrote in 1943, "is one vast experiment. Never before has so large a collection of individuals been exposed to so much radiation."26 Along with these data- gathering efforts came ethical issues.
Would disclosure of potential or actual harm to the workers, much less the public, impair the program? For example, a July 1945 Manhattan Project memo discussed whether to inform a worker that her case of nephritis (a kidney disease) may have been due to her work on the Project. The issue was of special import because, the memo indicated, the illness might well be a precursor of more cases. The worker, the memo explained, "is unaware of her condition which now shows up on routine physical check and urinalysis."27
As this memo showed, there was an urgent need for decisions on how to protect the workers, while at the same time safeguard the security of the project: "The employees must necessarily be rotated out, and not permitted to resume further exposure. In frequent instances no other type of employment is available. Claims and litigation will necessarily flow from the circumstances outlined." There were also, the memo concluded, "Ethical considerations":
The feelings of the medical officers are keenly appreciated. Are they in accordance with their canons of ethics to be permitted to advise the patient of his true condition, its cause, effect, and probable prognosis? If not on ethical grounds, are they to be permitted to fulfill their moral obligations to the individual employees in so advising him? If not on moral grounds, are those civilian medical doctors employed here bound to make full disclosure to patients under penalty of liability for malpractice or proceeding for revocation of license for their failure to do so?28
It is not clear what was decided in this case. However, the potential conflict between the government doctors' duty to those working on government projects and the same doctors' obligations to the government would not disappear. Following the war, as we see in chapter 12, this conflict would be sharply posed as medical researchers studied miners at work producing uranium for the nation's nuclear weapons.
Another basic question was the extent to which human beings could or should be studied to obtain the data needed to protect them. The radium dial painter data served as a baseline to determine how the effects of exposures in the body could be measured. But this left the question of whether plutonium, uranium, and polonium behaved more or less like radium. Research was needed to understand how these elements worked in the body and to establish safety levels. A large number of animal studies were conducted at laboratories in
27
Introduction
Chicago, Berkeley, Rochester, and elsewhere; but the relevance of the data to humans remained in doubt.
The Manhattan Project contracted with the University of Rochester to receive the data on physical exams and other tests from Project sites and to prepare statistical analyses. While boxes of these raw data have been retrieved, it is not clear what use was made of them.29 Accidents, while remarkably few and far between, became a key source of the data used in constructing an understanding of radiation risk. But accidents were not predictable, and their occurrence only enhanced the immediacy of the need to gain better data.
In 1944, the Manhattan Project medical team, under Stafford Warren and with the evident concurrence of Robert Oppenheimer, made plans to inject polonium, plutonium, uranium, and possibly other radioactive elements into human beings. As discussed in chapter 5, the researchers turned to patients, not workers, as the source of experimental data needed to protect workers. By the time the program was abandoned by the government, experimentation with plutonium had taken place in hospitals at the Universities of California, Chicago, and Rochester, and at the Army hospital in Oak Ridge, and further experimentation with polonium and uranium had taken place at Rochester.
The surviving documentation provides little indication that the medical officials and researchers who planned this program considered the ethical implications of using patients for a purpose that no one claimed would benefit them, under circumstances where the existence of the substances injected was a wartime secret. Following the war, however, the ethical questions raised by these experiments would be revisited in debates that themselves were long kept secret.
In addition to experimentation with internally administered radioisotopes, external radiation was administered in human experiments directed by Dr. Stone at Chicago and San Francisco and by others at Memorial Hospital in New York City. Once again, the primary subjects were patients, although some healthy subjects were also involved. In these cases, the researchers may have felt that the treatment was of therapeutic value to the patients. But, in addition to the question of whether the patients were informed of the government's interest, this research raised the question of whether the government's interest affected the patients' treatment. As discussed in chapter 8, these questions would recur when, beginning in 1 95 1 , and for two decades thereafter, the Defense Department would fund the collection of data from irradiated patients.
Ensuring safety required more, however, than simply studying how radioactive substances moved through and affected the human body. It also involved studying how these substances moved through the environment. While undetectable to the human senses, radiation in the environment is easily measurable by instruments. When General Groves chose Hanford, on the Columbia River in Washington state, as a site for the plutonium production facility, a secret research program was mounted to understand the fate of radioactive pollution in the water, the air, and wildlife.30
28
The Atomic Century
Outdoor research was at times improvisational. Years after the fact, Stafford Warren would recall how Manhattan Project researchers had deliberately "contaminated the alfalfa field" next to the University of Rochester medical school with radiosodium, to determine the shielding requirements for radiation- measuring equipment. Warren's associate Dr. Harold Hodge recalled that a shipment of radiosodium was received by plane from Robley Evans at MIT, mixed with water in a barrel, and poured into garden sprinklers:
We walked along and sprinkled the driveway. This was after dark. . . . The next thing, we went out and sprayed a considerable part of the field. ... It was sprayed and then after a while sprayed again, so there was a second and third application. We were all in rubber, so we didn't get wet with the stuff . . . then Staff [Warren] said that one of the things we needed was to see what would be the effect on the inside of a wooden building. So we took the end of the parking garage, and we sprinkled that up about as high as our shoulders, and somebody went inside and made measurements, and we sprinkled it again. Then we wanted to know about the inside of a brick building, and so we sprinkled the side of the animal house. ... I had no idea what the readings were. . . I hadn't the foggiest idea of what we were doing, except that obviously it was something radioactive.31
Outdoor releases would put at risk unsuspecting citizens, even communities, as well as workers. There were no clear policies and no history of practice to guide how these releases should be conducted. As we explore in chapter 1 1, this would be worked out by experts and officials in secret, on behalf of the workers and citizens who might be affected.
THE ATOMIC ENERGY COMMISSION AND POSTWAR BIOMEDICAL RADIATION RESEARCH
On August 6, 1945, when the atomic bomb was dropped on Hiroshima, the most sensitive of secrets became a symbol for the ages. A week later, the bomb was the subject of a government report that revealed to the public the uses of plutonium and uranium.32 Immediately, debate began over the future of atomic energy. Could it be controlled at the international level? Should it remain entirely under control of the military? What role would industry have in developing its potential? Although American policymakers failed to establish
29
Introduction
international control of the bomb, they succeeded in creating a national agency with responsibility for the domestic control of atomic energy.
The most divisive question in the creation of the new agency that would hold sway over the atom was the role of the military. Following congressional hearings, the Atomic Energy Commission was established by the 1946 McMahon Act, to be headed by five civilian commissioners. President Truman appointed David Lilienthal, former head of the Tennessee Valley Authority, as the first chairman of the AEC, which took over responsibilities of the Manhattan Engineer District in January 1947.
Also in 1947, under the National Security Act, the armed services were put under the authority of the newly created National Military Establishment (NME), to be headed by the secretary of defense. In 1949 the National Security Act was amended, and the NME was transformed into an executive department— the Department of Defense.33 The Armed Forces Special Weapons Project, which would coordinate the Defense Department's responsibilities in the area of nuclear weapons, became the military heir to the Manhattan Engineer District. The Military Liaison Committee was also established as an intermediary between the Atomic Energy Commission and the Defense Department; it was also to help set military requirements for the number and type of nuclear weapons needed by the armed services.
Even before the AEC officially assumed responsibility for the bomb from the Manhattan Project, the Interim Medical Advisory Committee, chaired by former Manhattan Project medical director Stafford Warren, began meeting to map out an ambitious postwar biomedical research program. Former Manhattan Project contractors proposed to resume the research that had been interrupted by the war and to continue wartime radiation effects studies upon human subjects.34
In May 1947, Lilienthal commissioned a blue-ribbon panel, the Medical Board of Review, that reported the following month on the agency's biomedical program. In strongly recommending a broad research and training program, the board found the need for research "both urgent and extensive." The need was "urgent because of the extraordinary danger of exposing living creatures to radioactivity. It is urgent because effective defensive measures (in the military sense) against radiant energy are not yet known." The board, pointing to the AEC's "absolute monopoly of new and important tools for research and important knowledge," noted the commensurate responsibilities-both to employees and others who could suffer from "its negligence or ignorance" and to the scientific world, with which it was obliged to "share its acquisitions . . . whenever security considerations permit."35 In the fall of 1947, as recommended by the Medical Board of Review, the AEC created a Division of Biology and Medicine (DBM) to coordinate biomedical research involving atomic energy and an Advisory Committee for Biology and Medicine (ACBM), which reported directly to the AEC's chairman.36
Not surprisingly, the DBM and ACBM became gathering places for the
30
The Atomic Century
luminaries of radiation science. The ACBM was headed by a Rockefeller Foundation official, Dr. Alan Gregg. It settled on Dr. Shields Warren, a Harvard- trained pathologist, to serve as the first chief of the DBM. Warren, as we shall see, would play a central role in developments related to radiation research and human experimentation. In the 1930s, focusing on cancer research, and influenced by the work of Hevesy and the pioneering radioisotope work being done in Berkeley and Boston, Warren turned to the question of the effects of radiation on animals and the treatment of acute leukemia, the "most hopeless . . . of tumors at that time." As the war neared, Warren enlisted in the Naval Reserve. He continued medical work for the Navy, turning down an invitation to join Stafford Warren (no relation) on "a project . . . that he couldn't tell me anything about [the Manhattan Project].""
While most of the AEC's budget would be devoted to highly secret weapons development and related activities, the biomedical research program represented the commission's proud public face. Even before the AEC opened its doors, Manhattan Project officials and experts had laid the groundwork for a bold program to encourage the use of radioisotopes for scientific research, especially in medicine. This program was first presented to the broad public in a September 1946 article in the New York Times Magazine. The article began dramatically by describing the use of "radioactive salt" to measure circulation in a crushed leg, so that a decision on whether to amputate below or above the knee could be made.
By November 1946, the isotope distribution program was well under way, with more than 200 requests approved, about half of which were designated for "human uses." From the beginning, the AEC's Isotope Division at Oak Ridge had in its program director, Paul Aebersold, a veritable Johnny Appleseed for radioelements.39 In presentations before the public and to researchers, Aebersold, dubbed "Mr. Isotope," touted the simplicity and low cost with which scientists would be provided with radioisotopes: "The materials and services are made available . . . with a minimum of red tape and under conditions which encourage their use."40 At an international cancer conference in St. Louis in 1947, the AEC announced that it would make radioisotopes available without cost for cancer research and experimental cancer treatment. This, Shields Warren later recalled, had a "tremendous effect" and "led to a revolution in the type of work done in this
field."41 c . .__,
To AEC administrators, Aebersold emphasized the benefits to the AhC s public image: "Much of the Commission's success is judged by the public and scientists ... on its willingness to carry out a wide and liberal policy on the distribution of materials, information, and services," he wrote in a memo to the AEC's general manager.42
The AEC biomedical program as a whole also provided for funding ot cancer research centers, research equipment, and numerous other research projects. Here, too, were advances that would save many lives. Before the war, radiotherapy had reached a plateau, limited by the cost of radium and the inability
31
Introduction
of the machines of the time to focus radiation precisely on tumors to the exclusion of surrounding healthy tissue. AEC facilities inherited from the Manhattan Project could produce radioactive cobalt, a cheaper substitute for radium. As well, the AEC's "teletherapy" program funded the development of new equipment capable of producing precisely focused high-energy beams.43
The AEC's highly publicized peacetime medical program was not immune to the pressures of the Cold War political climate. Even the lives of young researchers in the AEC Fellowship Program conducting nonclassified research were subject to Federal Bureau of Investigation review despite protests from commission members. Congressionally mandated Cold War requirements such as loyalty oaths and noncommunist affidavits, Chairman Lilienthal declared, would have a chilling effect on scientific discussion and could damage the AEC's ability to recruit a new generation of scientists.44 The reach of the law, the Advisory Committee for Biology and Medicine agreed, was like a "blighting hand; for thoughtful men now know how political domination can distort free inquiry into a malignant servant of expediency and authoritarian abstraction."45 Nonetheless, the AEC accepted the congressional conditions for its fellowship program and determined to seek the program's expansion.46
The AEC's direct promotional efforts were multiplied by the success of Aebersold and his colleagues in carrying the message to other government agencies, as well as to industry and private researchers. This success led, in turn, to new programs.
In August 1947, General Groves urged Major General Paul Hawley, the director of the medical programs of the Veterans Administration, to address medical problems related to the military's use of atomic energy. Soon thereafter, Hawley appointed an advisory committee, manned by Stafford Warren and other medical researchers. The advisers recommended that the VA create both a "publicized" program to promote the use of radioisotopes in research and a "confidential" program to deal with potential liability claims from veterans exposed to radiation hazards.47 The "publicized" program soon mushroomed, with Stafford Warren, Shields Warren, and Hymer Friedell among the key advisers. By 1974, according to VA reports, more than 2,000 human radiation experiments would be performed at VA facilities,48 many of which would work in tandem with neighboring medical schools, such as the relationship between the UCLA medical school, where Stafford Warren was now dean, and the Wadsworth (West Los Angeles) VA Hospital.
While the AEC's weapons-related work would continue to be cloaked in secrecy, the isotope program was used by researchers in all corners of the land to achieve new scientific understanding and help create new diagnostic and therapeutic tools. It was, however, only a small part of an enormous institution. By 1951 the AEC would employ 60,000 people, all but 5,000 through contractors. Its land would encompass 2,800 square miles, an area equal to Rhode Island and Delaware combined. In addition to research centers throughout the United States,
32
The Atomic Century
its operations "extended] from the ore fields of the Belgian Congo and the Arctic region of Canada to the weapons proving ground at Enewetak Atoll in the Pacific and the medical projects studying the after-effects of atomic bombing in . . . Japan "49 The Isotope Division, however, would employ only about fifty people and, when reactor production time was accounted for, occupy only a fraction of its budget and resources.50
THE TRANSFORMATION IN GOVERNMENT-SPONSORED RESEARCH
The AEC's decision to proceed with a biomedical research program was part of an even greater transformation, in which government continued and expanded wartime support for research in industry and at universities. Before World War II, biomedical research was a small enterprise in which the federal government played a minor role. During the war, however, large numbers of American biomedical researchers were mobilized by the armed forces. These researchers played an important role in advancing military medicine in a wide range of areas, including blood substitutes, antimalarial drugs and, as noted above in nurturing the infant science of nuclear medicine.
' As the war was drawing to a close, President Roosevelt asked for advice from his Office of Scientific Research and Development (OSRD) on how to convert the nation's military research effort to a peacetime footing, and whether the government should take an activist role in promoting research. The OSRD, under Vannevar Bush, responded in July 1945, after Roosevelt's death, with a report called "Science, the Endless Frontier." Bush and his colleagues recommended among other things the establishment of a National Science Foundation (NSF) to support basic research in all areas including the biomedical sciences. While the principle that the federal government should fund medical research came to seem self-evident, this was hardly the case at the time. In a personal reminiscence published in 1970, Bush wrote:
To persuade the Congress of these pragmatically inclined United States to establish a strong organization to support fundamental research would seem to be one of the minor miracles. We in this country have supported well those pioneers who have created new gadgetry for our use or our amusement. But we have not had during our formative years the respect for scientific endeavors, for scholarship generally, to the extent it had been present in Europe.51
Congress worked Bush's small miracle and passed relevant legislation, but
33
Introduction
President Harry Truman vetoed the bill. When the bill passed again, however, Bush persuaded Truman to sign it.52
At the new AEC, and elsewhere, a key element of the support for science was the determination to fund extramural research, that is, research outside the agency. Prior to the war, federal support for private researchers was limited. The Manhattan Project was only one of several wartime efforts that drew private researchers into government service and that provided federal funds for those who remained in private research centers. Following the war, as researchers returned to universities, laboratories, and hospitals, the continued federal support of their efforts transformed the relationship between government and science and the dimensions of the scientific effort.53
During the war, the Committee on Medical Research (CMR) of the OSRD operated entirely by funding external research. In 1 944, Congress empowered the surgeon general of the Public Health Service to make grants to universities, hospitals, laboratories, and individuals, which provided the legislative basis for the postwar National Institute of Health (NIH) extramural program.54 In 1948, Congress authorized the National Heart Institute to join the decade-old National Cancer Institute, and NIH became the National Institutes of Health.
By the late 1960s, the annual appropriations of NIH exceeded $1 billion.55 Research involving medical uses of radioisotopes and external radiation was among the newer fields benefiting from the increased funding. As discussed in more detail in chapter 6, government-supported radioisotope research has proved profoundly important in the development of techniques for medical diagnosis and treatment.
Federal research funding has also continued to be essential to the development of the use of external sources of radiation. For example, the crude images made possible by Roentgen's discovery of x rays have been replaced by higher resolution, three-dimensional pictures, such as those produced by computerized tomographic (CT) scanning and magnetic resonance imaging (MRI).
Today, the benefits of federally sponsored medical research are often taken for granted. To many of those in the midst of the postwar planning and advocacy, however, the result was not foreordained. "Fortunately," Shields Warren recalled years later, postwar "momentum" kept AEC research budgets on track until, in 1957, the Soviet launch of Sputnik (the first space satellite) jolted the American people into a renewed commitment to the support of scientific research.56
34
The Atomic Century
THE AFTERMATH OF HIROSHIMA AND NAGASAKI: THE EMERGENCE OF THE COLD WAR RADIATION RESEARCH BUREAUCRACY
While promoting the beneficial uses of radiation, the government also wished to continue and expand research on its harmful effects. Three days after the destruction of Hiroshima, Robert Stone wrote two letters to Stafford Warren's deputy, and Stone's former student, Hymer Friedell. The first expressed hope that the contribution of medical researchers could now be made public, so that people would know what they had done during the war.57 The second letter described Stone's "mixed feelings" at the success that had been achieved and his fear that the lingering effects of radiation from the bomb had been underestimated: "I could hardly believe my eyes," Stone wrote, "when I saw a series of news releases said to be quoting Oppenheimer, and giving the impression that there is no radioactive hazard. Apparently all things are relative."58
Friedell and other researchers, including Stafford Warren and Shields Warren, soon traveled to Hiroshima and Nagasaki to begin what became an extensive research program on survivors. The data from that project quickly became and still remain the essential source of information on the long-term effects of radiation on populations of human beings. It was not long, however, before there were additional real-life data on the bomb, from postwar atomic tests. In 1946, the United States undertook the first peacetime nuclear weapons tests at Bikini Atoll in the Marshall Islands. Operation Crossroads, conducted before journalists and VIPs from around the world, was intended to test the ability of a flotilla of unmanned ships to withstand the blast. Since most of the ships remained afloat, the Navy declared Crossroads a triumph.59
Behind the scenes, however, Crossroads medical director Stafford Warren expressed horror at the level of contamination on the ships due to the underwater atomic blast.60 When the ships returned to the West Coast from the Pacific, they were extensively studied to assess the damage and contamination from the atomic bombs. The government created the Naval Radiological Defense Laboratory (NRDL) to study the effects of atomic bombs on ships and to design ways to protect them. "Crossroads," according to an NRDL history, "left no doubt that man was faced with the necessity for coping with strange and unprecedented problems for which no solutions were available."6'
Hiroshima and Nagasaki, it now seemed, were only the beginning, not the end, of human exposure to bomb-produced radiation. As Crossroads confirmed with the lingering problem of contaminated ships, what the bomb did not obliterate it might still damage by radiation over the course of days or years. It was no longer enough to know about the effects of radioactive materials on American nuclear weapons workers; now there was the urgent need to understand the effects on American soldiers, sailors, and even citizens as well.
Largely invisible to the public, an ad hoc bureaucracy sprang up to
35
Introduction
address the medical and radiation research problems of atomic warfare. This bureaucracy brought together former wartime radiation researchers, who were joined by junior colleagues, to advise, and participate in, the government's growing radiation research program. Other, already established groups-such as the AEC's Division of Biology and Medicine and its advisory committee-also had important places in the new network.
Beyond considering fallout from the testing of atomic bombs, these groups also looked at how radiation itself might be used as a weapon. During the war, scientists like J. Robert Oppenheimer had speculated on the possibility that fission products (radioactive materials produced by the bomb or by reactors) could be dispersed in the air and on the ground to kill or incapacitate the enemy. In 1946, the widespread contamination of ships at Crossroads by radioactive mist gave dramatic evidence of the potential of so-called radiological warfare, or RW. In 1947, the military created a committee of experts to study the problem. The following year, a blue-ribbon panel of physicians and physicists looked at the prospects, both offensive and defensive, of what the Pentagon termed "Rad War." The work of these panels would lead to dozens of intentional releases of radiation into the environment at the Army's Dugway, Utah, testing grounds from the late 1940s to the early 1950s. The very fact that the government was engaged in RW tests was a secret. Indeed, the records of the RW program-including, as we shall see in chapter 1 1, the debate on what the public should be told about the program-would remain largely secret for almost fifty years.
In 1 949, a military program to build a nuclear-powered airplane led to a set of proposed human radiation experiments. The NEPA (Nuclear Energy for the Propulsion of Aircraft) program had its origins in 1946 as a venture that included the Manhattan Project's Oak Ridge site, the military, and private aircraft manufacturers. Robert Stone, as we shall see in chapter 8, was a leading proponent of experiments involving healthy volunteers, as a key to answering questions about the radiation hazard faced by the crew of the proposed airplane.
The NEPA and RW groups considered important, but still discrete, projects. Where did the "big picture" discussions take place? The Advisory Committee has pieced together the records of the Armed Forces Medical Policy Council, the Committee on Medical Sciences, and the Joint Panel on the Medical Aspects of Atomic Warfare." These three Defense Department groups, all chaired by civilian doctors, guided the government on both the broad subject of military-related biomedical research and the new and special problems posed by atomic warfare.
If the surviving records are an indication, from its creation in 1949 to its evident demise with the reorganization of the Defense Department in 1953, the Joint Panel quickly became the hub of atomic warfare-related biomedical research. The Joint Panel gathered information about relevant research from all corners of the government, provided guidance for Defense Department programs,
36
The Atomic Century
and reviewed and coordinated policy in the matter of human experimentation using atomic energy.
By charter, the group was to be headed by a civilian. Harvard's Dr. Joseph Aub, a long-standing member of the Boston-based medical research community who had worked with Robley Evans on the study of the radium dial painters and had also studied lead toxicity, served as chair. Those who served with Aub included Evans, Hymer Friedell, and Louis Hempelmann, Oppenheimer's Manhattan Project medical aide. Other government participants came from the AEC, the Public Health Service, the National Institutes of Health, the Veterans Administration, and the CIA. (The charter provided that the Joint Panel should collect information on relevant research conducted abroad, which the CIA evidently provided.)63
This bureaucracy provided the venue for secret discussions that linked the arts of healing and war in ways that had little precedent. At one and the same time, for example, doctors counseled the military about the radiation risk to troops at the site of atomic bomb tests, advised on the need for research on the "psychology of panic" at such bomb tests, and debated the need for rules to govern atomic warfare-related experimentation. (See chapter 10.)
The records of the Joint Panel show that, during the height of the Cold War, the resources of civilian agencies were part of the mobilization of resources to serve national security interests. For example, Dr. Howard Andrews, trained as a physicist, was the National Institutes of Health's representative to the Joint Panel, and in the 1950s he worked with the DOD and the AEC in monitoring safety measures and measuring fallout from nuclear tests.64
In 1950 President Truman ordered federal agencies, including the Public Health Service and NIH, to focus their resources on activities that would benefit national security needs. On paper, at least, PHS and NIH policymakers sought to direct resources to questions of radiation injury, civil defense, and worker health and safety.65 For example, a 1952 internal planning memo explained that NIH "will not wait for formal requests by the armed forces ... to undertake research which NIH staff knows to be of urgent military and civilian defense significance. Limited selective conversion of research to work directly related to biological warfare, shock, radiation injury and thermal burns will begin immediately. . . ."66 The fragmentary surviving documentation, however, does not show the extent to which PHS- and NIH-funded researchers actually redirected their investigations or merely recast the purpose of ongoing work.
NEW ETHICAL QUESTIONS FOR MEDICAL RESEARCHERS
As medical researchers became fixtures in the Cold War research bureaucracy, they assumed roles that, if not entirely new, raised ethical questions with which they had rarely dealt before. The surviving records of the period
37
Introduction
reveal that frank and remarkable discussions took place among military and civilian officials and researchers, all of whom had to balance the benefits of gaining knowledge needed to fight and survive an atomic war with the risks that had to be taken to gain this knowledge. They had to consider, and even debated, whether human radiation experimentation was justified, what kinds of risks entire populations could be exposed to, and what the public could and should be told.
Whether to Experiment with Humans: The Debate Is Joined
Spurred by proposals for human radiation experiments connected with the nuclear-powered airplane (NEPA) project, AEC and DOD medical experts in 1949 and 1950 engaged in debate on the need for human experimentation. The transcript of a 1950 meeting among AEC biomedical officials and advisers and military representatives provides unique insight into the mix of moral principles and practical concerns.67
The participants in the debate included many of the key medical figures in the Manhattan Project and the postwar radiation research bureaucracy. For the Navy, for example, Captain Behrens, the editor of Atomic Medicine, made the point that an atomic bomb might contaminate, but not sink, ships. The Navy would need to know the risk of sending rescue or salvage parties into the contaminated area. There were questions of "calculated risk which all of the services are interested in, and not only the services but probably the civilians as well."68 Brigadier General William H. Powell, Jr., of the Office of the Air Force Surgeon General, added further questions: How does radiation injure tissue? Can equipment protect against the bomb's effects? Is there a way to treat radiation injury? How should mass casualties be handled?69
These questions were hardly abstract. Operation Crossroads had demonstrated that postblast contamination of Navy ships was a serious hazard. The use of the atomic bomb as a tactical weapon, declared Brigadier General James Cooney of the AEC's Division of Military Applications, "has now gone beyond the realm of possibility and into the realm of probability."70 This meant that "we have a responsibility that is tremendous," Cooney added. "If this weapon is used tactically on a corps or division, and we have, say, 5,000 troops who have received 100 Roentgens] radiation, the Commander is going to want from me, 'Is it all right for me to reassemble these men and take them into combat?' I don't know the answer to that question."71 Commanders needed to know "How much radiation can a man take?"72
Cooney argued that human experimentation was necessary. He invoked the military's tradition of experimentation with healthy volunteers, dating back to Walter Reed's famous work on yellow fever at the turn of the century. Cooney urged that the military seek volunteers within its ranks--"both officer and enlisted"--to be exposed to as much as 150 R of whole-body radiation.73
The AEC's Shields Warren took the other side in this debate. Warren
38
The Atomic Century
raised two basic points in response to Cooney. First, human experimentation was not essential because animal research would be adequate to find the answers. Second, data from human experimentation would likely be scientifically useless. "We have," Warren declared, "learned enough from animals and from humans at Hiroshima and Nagasaki to be quite certain that there are extraordinary variables in this picture. There are species variables, genetics variables within species, variations in condition of the individual within that species." The danger of failing to provide data had to be weighed against the danger of providing misleading data: "It might be almost more dangerous or misleading to give an artificial accuracy to an answer that is of necessity an answer that spreads over a broad range in light of these variables."74
There were, moreover, political obstacles to the program Cooney had proposed. Satisfactory answers, Warren concluded, would require "going to tens of thousands of individuals." But America was not the Soviet Union: "If we were considering things in the Kremlin, undoubtedly it would be practicable. I doubt that it is practicable here."75
At the heart of Warren's objections to Cooney's proposal was a concern about employing "human experimentation when it isn't for the good of the individual concerned and when there is no way of solving the problem."76 To Cooney's invocation of Walter Reed, Warren responded that, in the case of yellow fever, humans were needed as subjects because there was no nonhuman host to
Cooney did not disagree with Warren "that statistically we will prove
nothing." But, he pointed out, "[G]enerals are hard people to deal with If we
had 200 cases whereby we could say that these men did or did not get sick up to 150 R, it would certainly be a great help to us."77
Even then, Warren rejoined, the data might not be of great use: "I can think in terms of times when even if everybody on a ship was sea-sick, you would still have to keep the ship operating."78
The 1950 debate over NEPA provides clear evidence that midcentury medical experts gave thought before engaging in human experimentation that involved significant risk and was not intended to benefit the subject. On paper, the debate was decided in Shields Warren's favor. Following Warren's and DBM's opposition, Cooney and the military agreed that "human experimentation" on healthy volunteers would not be approved. However, even as this policy was declared, the Defense Department, with Warren's apparent acquiescence, proceeded to contract with private hospitals to gather data on sick patients who were being treated with radiation. The government's use of sick patients for research, as we shall see in chapter 8, raised difficult ethical questions of its own.
Whether to Put Populations at Risk: The Debate Continues
As the medical experts debated the issue of whether to put individual
39
Introduction
human subjects at risk in radiation experiments on behalf of NEPA, they were also engaged in secret discussions about whether to proceed with the testing of nuclear weapons, which might put whole populations at risk.
It was also in 1950 that the decision was made to carry out atomic bomb testing at a site in the continental United States. President Truman chose the Nevada desert as the location for the test site. Shields Warren's Division of Biology and Medicine was assigned the job of considering the safety of early tests. Like the earlier transcript, an account of a May 1951 meeting at Los Alamos, convened by Warren, provides a window onto the balancing of risks and benefits by medical researchers.
The meeting focused on the radiological hazards to populations downwind from underground testing planned at the Nevada Test Site. Those in attendance realized that the testing could be risky. "I would almost say from the discussion this far," Warren summarized, "that in light of the size and activity of some of these particles, their unpredictability of fallout, the possibility of external beta burns is quite real."79 Committee members considered the testing a "calculated risk" for populations downwind, but they thought that the information they could gain made the risk worthwhile. According to the record of the meeting, Warren summarized the view of Dr. Gioacchino Failla, a Columbia University radiological physicist: "[T]he time has come when we should take some risk and get some information ... we are faced with a war in which atomic weapons will undoubtedly be used, and we have to have some information about these things ... if we look for perfect safety we will never make these tests."80 Worried about the potential consequences of miscalculation, the AEC's Carrol Tyler observed, "We have lost a continental site no matter where we put it." Still, Tyler argued, "If we are going to gamble it might as well be done where it is operationally convenient."1" A proposed deep underground test did not take place, and a test evidently considered less risky was substituted. Ultimately, in a summary prepared at the end of the 1951 test series, the Health Division leader of the AEC's Los Alamos Laboratory recorded that perhaps only good fortune had averted significant contamination: "Thanks to the kindness of the winds, no significant activity was deposited in any populated localities. It was certainly shown however," he wrote, "that significant exposures at considerable distances could be acquired by individuals who actually were in the fallout while it was in progress."82
The NEPA debate and the advent of nuclear testing confronted biomedical experts with a set of conflicting, and even contradictory, objectives. First, they were called upon to offer advice on decisions that might inevitably put people at some risk. The risk had to be balanced against the benefit, which in most instances was defined as connected with the nation's security. In many cases, the experts agreed, it was better to bear the lesser risk now, in order to avoid a greater risk later. Second, these experts were also called upon, as in the 1951 Nevada test, to provide advice on minimizing risk. Third, as in the Nevada test, these
40
The Atomic Century
same experts saw the tests as opportunities to gather data that might ultimately be used to reduce risk for all.
Whether and What the Public Should Be Told About Government-Created Radiation Risk
Scientific research had a long and celebrated tradition of open publication in the scientific literature. But several factors caused Cold War researchers to limit their public disclosures. These included, preeminently, concern with national security, which necessarily required secrecy. But they also included the concern that the release of research information would undermine needed programs because the public could not understand radiation or because the information would embarrass the government.
The tension between the publicizing of information and the limits on disclosure was a constant theme in Cold War research. When, in June 1 947, the Medical Board of Review appointed by David Lilienthal reported on the AEC's biomedical program, it declared that secrecy in scientific research is "distasteful and in the long run contrary to the best interests of scientific progress."83 As shown by its organization of the medical isotope program, the AEC acted quickly to make sure that the great preponderance of biomedical research done under its auspices would be published in the open literature.
However, recently retrieved documents show that the need for secrecy was also invoked where national security was not endangered. At the same time that biomedical officials, such as those on the Medical Board of Review, spoke openly of the need to limit national security restrictions, internally they sometimes sided with those who would restrict information from the public even where release admittedly would not directly endanger national security. Thus, as we shall see in chapter 13, Shields Warren and other AEC medical officials agreed to withhold data on human experiments from the public on the grounds that disclosure would embarrass the government or could be a source of legal liability.
A further important qualification to what the public could know related to research connected with the atomic bomb-including the creation of a worldwide network to gather data on the effects of fallout from nuclear tests. In 1949, the AEC undertook Project Gabriel, a secret effort to study the question of whether the tests could threaten the viability of life on earth. In 1953, Gabriel led to Project Sunshine, a loose confederation of fallout research projects whose human data-gathering efforts, as we see in chapter 13, operated in the twilight between openness and secrecy.
Finally, while documents show that medical experts and officials shared an acute awareness of the importance of public support to the success of Cold War programs, this awareness was coupled with concern about the American public's ability to understand the risks that had to be borne to win the Cold War. The concern that citizens could not understand radiation risk is illustrated by a
41
Introduction
recently recovered NEPA transcript. In July 1949, the nuclear airplane project gathered radiation experts and psychologists to consider psychological problems connected to radiation hazard. To the assembled experts the greatest unknown was not radiation itself, but the basis for public fear and misunderstanding of radiation.
"I believe," General Cooney proposed, "that the general public is under the opinion that we don't know very much about this condition [radiation]. . . . We know," he ventured, "just about as much about it as we do about many other diseases that people take for granted . . . even tuberculosis."84
Yet, said the Navy's Captain Behrens, "there are some peculiar ideas relative to radiation that are related to primitive concepts of hysteria and things in that category. . . . There is such a unique element in it; for some it begins to border on the mystical."85 A good deal of the public's fear of radiation, declared Berkeley's Dr. Karl M. Bowman, a NEPA medical adviser, "is essentially the fear of the unknown. The dangers have been enormously magnified." As Dr. Bowman and others noted, the public's perception was not without reason, for "we have emphasized for purposes of getting funds for research how little we know."86
The perspective expressed in the NEPA transcript would lead, as shown in chapter 10, to the use of atomic bomb tests to perform human research on the psychology of panic and, as shown in other case studies, to decisions to hold information closely out of concern that its release could create public misunderstanding that would imperil important government programs.
CONCLUSION
In the atomic age, Captain Behrens's Atomic Medicine pointed out, radiation research was both the agent and the beneficiary of dramatic developments at the intersection of government and medicine. When ethical questions were raised by these developments, radiation researchers would be on the front line in having to deal with them. The burgeoning government- funded biomedical research, including human radiation research, required a reexamination of the traditional doctor-patient relationship. At the same time, the evolving role of medical researchers as government officials and advisers also posed questions about the place of doctors, and more generally of scientists, in service to government.
42
The Atomic Century
The Basics of Radiation Science
The ethical and historical issues of human radiation experiments cannot be understood without a basic grasp of the underlying science. This requires more than a glossary defining technical terms. At least an intuitive understanding of the natural laws and scientific techniques of radiation science is necessary. Obviously, acquiring a professional level of knowledge would require far more time than most readers can afford; indeed, entire careers are devoted to studying just one aspect of the field. To serve the interests of democracy in a technological world, however, we must provide sufficient technical background for all citizens to become active participants in considering the ethical and political dimensions of scientific research.
What follows is an attempt to provide such a background for the events and issues discussed in this report, directed toward those readers less familiar with "the basics" of radiation science. This task was deemed important enough to deserve a distinct section of this Introduction.
What Is Ionizing Radiation?
What is radiation!
Radiation is a very general term, used to describe any process that transmits energy through space or a material away from a source. Light, sound, and radio waves are all examples of radiation. When most people think of radiation, however, they are thinking of ionizing ra<//arto«--radiation that can disrupt the atoms and molecules within the body. While scientists think of these emissions in highly mathematical terms, they can be visualized either as subatomic particles or as rays. Radiation's effects on humans can best be understood by first examining the effect of radiation on atoms, the basic building blocks of matter.
What is ionization!
Atoms consist of comparatively large particles (protons and neutrons) sitting in a central nucleus, orbited by smaller particles (electrons): a miniature solar system. Normally, the number of protons in the center of the atom equals the number of electrons in orbit. An ion is any atom or molecule that does not have the normal number of electrons. Ionizing radiation is any form of radiation that has enough energy to knock electrons out of atoms or molecules, creating ions.
How is ionizing radiation measured?
Measurement lies at the heart of modern science, but a number by itself conveys no information. Useful measurement requires both an instrument for measurement (such as a stick to mark off length) and an agreement on the units to
43
Introduction
be used (such as inches, meters, or miles). The units chosen will vary with the purpose of the measurement. For example, a cook will measure butter in terms of tablespoons to ensure the meal tastes good, while a nutritionist may be more concerned with measuring calories, to determine the effect on the diner's health.
The variety of units used to measure radiation and radioactivity at times confuses even scientists, if they do not use them every day. It may be helpful to keep in mind the purpose of various units. There are two basic reasons to measure radiation: the study of physics and the study of the biological effects of radiation. What creates the complexity is that our instruments measure physical effects, while what is of interest to some are biological effects. A further complication is that units, as with words in any language, may fade from use and be replaced by new units.
Radiation is not a series of distinct events, like radioactive decays, which can be counted individually. Measuring radiation in bulk is like measuring the movement of sand in an hourglass; it is more useful to think of it as a continuous flow, rather than a series of separate events. The intensity of a beam of ionizing radiation is measured by counting up how many ions (how much electrical charge) it creates in air. The roentgen (named after Wilhelm Roentgen, the discoverer of x rays) is the unit that measures the ability of x rays to ionize air; it is a unit of exposure that can be measured directly. Shortly after World War II, a common unit of measurement was the roentgen equivalent physical (rep), which denoted an ability of other forms of radiation to create as many ions in air as a roentgen of x rays. It is no longer used, but appears in many of the documents examined by the Advisory Committee.
What are the basic types of ionizing radiation?
There are many types of ionizing radiation, but the most familiar are alpha, beta, and gamma/x-ray radiation. Neutrons, when expelled from atomic nuclei and traveling as a form of radiation, can also be a significant health concern.
Alpha particles are clusters of two neutrons and two protons each. They are identical to the nuclei of atoms of helium, the second lightest and second most common element in the universe, after hydrogen. Compared with other forms of radiation, though, these are very heavy particles—about 7,300 times the mass of an electron. As they travel along, these large and heavy particles frequently interact with the electrons of atoms, rapidly losing their energy. They cannot even penetrate a piece of paper or the layer of dead cells at the surface of our skin. But if released within the body from a radioactive atom inside or near a cell, alpha particles can do great damage as they ionize atoms, disrupting living cells. Radium and plutonium are two examples of alpha emitters.
Beta particles are electrons traveling at very high energies. If alpha particles can be thought of as large and slow bowling balls, beta particles can be visualized as golf balls on the driving range. They travel farther than alpha
44
The Atomic Century
particles and, depending on their energy, may do as much damage. For example, beta particles in fallout can cause severe burns to the skin, known as beta burns. Radiosotopes that emit beta particles are present in fission products produced in nuclear reactors and nuclear explosions. Some beta-emitting radioisotopes, such as iodine 131, are administered internally to patients to diagnose and treat disease.
Gamma and x-ray radiation consists of packets of energy known as photons. Photons have no mass or charge, and they travel in straight lines. The visible light seen by our eyes is also made up of photons, but at lower energies. The energy of a gamma ray is typically greater than 100 kiloelectron volts (keV— "k" is the abbreviation for kilo, a prefix that multiplies a basic unit by 1 ,000) per photon, more than 200,000 times the energy of visible light (0.5 eV). If alpha particles are visualized as bowling balls and beta particles as golf balls, photons of gamma and x-radiation are like weightless bullets moving at the speed of light. Photons are classified according to their origin. Gamma rays originate from events within an atomic nucleus; their energy and rate of production depend on the radioactive decay process of the radionuclide that is their source. X rays are photons that usually originate from energy transitions of the electrons of an atom. These can be artificially generated by bombarding appropriate atoms with high- energy electrons, as in the classic x-ray tube. Because x rays are produced artificially by a stream of electrons, their rate of output and energy can be controlled by adjusting the energy and amount of the electrons themselves. Both x rays and gamma rays can penetrate deeply into the human body. How deeply they penetrate depends on their energy; higher energy results in deeper penetration into the body. A 1 MeV ("M" is the abbreviation for mega, a prefix that multiplies a basic unit by 1,000,000) gamma ray, with an energy 2,000,000 times that of visible light, can pass completely through the body, creating tens of thousands of ions as it does.
A final form of radiation of concern is neutron radiation. Neutrons, along with protons, are one of the components of the atomic nucleus. Like protons, they have a large mass; unlike protons, they have no electric charge, allowing them to slip more easily between atoms. Like a Stealth fighter, high-energy neutrons can travel farther into the body, past the protective outer layer of the skin, before delivering their energy and causing ionization.
Several other types of high-energy particles are also ionizing radiation. Cosmic radiation that penetrates the Earth's atmosphere from space consists mainly of protons, alpha particles, and heavier atomic nuclei. Positrons, mesons, pions, and other exotic particles can also be ionizing radiation.
What Is Radioactivity?
What causes radioactivity?
As its name implies, radioactivity is the act of emitting radiation spontaneously. This is done by an atomic nucleus that, for some reason, is
45
Introduction
unstable; it "wants" to give up some energy in order to shift to a more stable configuration. During the first half of the twentieth century, much of modern physics was devoted to exploring why this happens, with the result that nuclear decay was fairly well understood by 1 960. Too many neutrons in a nucleus lead it to emit a negative beta particle, which changes one of the neutrons into a proton. Too many protons in a nucleus lead it to emit a positron (positively charged electron), changing a proton into a neutron. Too much energy leads a nucleus to emit a gamma ray, which discards great energy without changing any of the particles in the nucleus. Too much mass leads a nucleus to emit an alpha particle, discarding four heavy particles (two protons and two neutrons).
How is radioactivity measured?
Radioactivity is a physical, not a biological, phenomenon. Simply stated, the radioactivity of a sample can be measured by counting how many atoms are spontaneously decaying each second. This can be done with instruments designed to detect the particular type of radiation emitted with each "decay" or disintegration. The actual number of disintegrations per second may be quite large. Scientists have agreed upon common units to use as a form of shorthand. Thus, a curie (abbreviated "Ci" and named after Pierre and Marie Curie, the discoverers of radium87) is simply a shorthand way of writing "37,000,000,000 disintegrations per second," the rate of disintegration occurring in 1 gram of radium. The more modern International System of Measurements (SI) unit for the same type of measurement is the becquerel ( abbreviated "Bq" and named after Henri Becquerel, the discoverer of radioactivity), which is simply a shorthand for "1 disintegration per second."
What is radioactive half-life"!
Being unstable does not lead an atomic nucleus to emit radiation immediately. Instead, the probability of an atom disintegrating is constant, as if unstable nuclei continuously participate in a sort of lottery, with random drawings to decide which atom will next emit radiation and disintegrate to a more stable state. The time it takes for half of the atoms in a given mass to "win the lottery"-- that is, emit radiation and change to a more stable state—is called the half-life. Half-lives vary greatly among types of atoms, from less than a second to billions of years. For example, it will take about 4.5 billion years for half of the atoms in a mass of uranium 238 to spontaneously disintegrate, but only 24,000 years for half of the atoms in a mass of plutonium 239 to spontaneously disintegrate. Iodine 131, commonly used in medicine, has a half-life of only eight days.
What is a radioactive decay chain?
Stability may be achieved in a single decay, or a nucleus may decay through a series of states before it reaches a truly stable configuration, a bit like a Slinky toy stepping down a set of stairs. Each state or step will have its own
46
The Atomic Century
unique characteristics of half-life and type of radiation to be emitted as the move is made to the next state. Much scientific effort has been devoted to unraveling these decay chains, not only to achieve a basic understanding of nature, but also to design nuclear weapons and nuclear reactors. The unusually complicated decay of uranium 238, for example— the primary source of natural radioactivity on earth— proceeds as follows:"8
U-238 emits an alpha
I
Thorium 234 emits a beta
I
Protactinium 234 emits a beta
I Uranium 234 emits an alpha
1 Thorium 230 emits an alpha
1 Radium 226 emits an alpha
I
Radon 222 emits an alpha
!
Polonium 2 1 8 emits an alpha
1
Lead 214 emits a beta
1
Bismuth 214 emits a beta
I
Polonium 214 emits an alpha
I
Lead 210 emits a beta
1
Bismuth 210 emits a beta
1
Polonium 210 emits an alpha
I
Lead 206, which is stable
How can radioactivity be caused artificially?
Radioactivity can occur both naturally and through human intervention. An example of artificially induced radioactivity is neutron activation. A neutron fired into a nucleus can cause nuclear fission (the splitting of atoms). This is the basic concept behind the atomic bomb. Neutron activation is also the underlying
47
Introduction
principle of boron-neutron capture therapy for certain brain cancers. A solution containing boron is injected into a patient and is absorbed more by the cancer than by other cells. Neutrons fired at the area of the brain cancer are readily absorbed (captured) by the boron nuclei. These nuclei then become unstable and emit radiation that attacks the cancer cells. Simple in its basic physics, the treatment has been complex and controversial in practice and after half a century is still regarded as highly experimental.
What Are Atomic Number and Atomic Weight?
What is an element?
Chemical behavior is what originally led scientists to classify matter into various elements. Chemical behavior is the ability of an atom to combine with other atoms. In more technical terms, chemical behavior depends upon the type and number of the chemical bonds an atom can form with other atoms. In classroom kits for building models of molecules, atoms are usually represented by colored spheres with small holes for pegs and the bonds are represented by the small pegs that can connect the spheres. The number of peg holes signifies the maximum number of bonds an atom can form; different types of bonds may be represented by different types of pegs. Atoms that have the same number of peg holes may have similar chemical behavior. Thus, atoms that have identical chemical behavior are regarded as atoms of the same element. For example, an atom is labeled a "carbon atom" if it can form the same number, types, and configurations of bonds as other carbon atoms. Although the basics are simple to explain, how atoms bind to each other becomes very complex when studied in detail; new discoveries are still being made as new types of materials are formed.
What is atomic number?
An atom may be visualized as a miniature solar system, with a large central nucleus orbited by small electrons. The bonding capacity of an atom is determined by the electrons. For example, atoms that in their normal state have one electron are hydrogen atoms and will readily (and sometimes violently) bond with oxygen. This bonding capacity of hydrogen was the cause of the explosion of the airship Hindenburg in 1937. Atoms that in their normal state have two electrons are helium atoms, which will not bond with oxygen and would have been a better choice for filling the Hindenburg.
We can pursue the question back one step further: What determines the number of electrons? The number of protons in the nucleus of the atom. Here, the analogy between an atom and the solar system breaks down. The force that holds the planets in their orbits is the gravitational attraction between the planets and the sun. However, in an atom what holds the electrons in their orbit is the electrical attraction between the electrons and the protons in the nucleus. The
48
The Atomic Century
basic rule is that like charges repel and opposite charges attract. Although a proton has more mass than an electron, they both have the samf amount of electrical charge, but opposite in kind. Scientists have designated electrons as having a negative charge and protons as having a positive charge. One positive proton can hold one negative electron in orbit. Thus, an atom with one proton in its nucleus normally will have one electron in orbit (and be labeled a hydrogen atom); an atom with ninety-four protons in its nucleus will normally have ninety- four electrons orbiting it (and be labeled a plutonium atom).
The number of protons in a nucleus is called the atomic number and always equals the number of electrons in orbit about that nucleus (in a nonionized atom). Thus, all atoms that have the same number of protons~the atomic number— are atoms of the same element.
What is atomic weight?
The nuclei of atoms also contain neutrons, which help hold the nucleus together. A neutron has no electrical charge and is slightly more massive than a proton. Because a neutron can decay into a proton plus an electron (the essence of beta decay), it is sometimes helpful to think of a neutron as an electron and a proton blended together, although this is at best an oversimplification. Because a neutron has no charge, a neutron has no effect on the number of electrons orbiting the nucleus. However, because it is even more massive than a proton, a neutron can add significantly to the weight of an atom. The total weight of an atom is called the atomic weight. It is approximately equal to the number of protons and neutrons, with a little extra added by the electrons. The stability of the nucleus, and hence the atom's radioactivity, is heavily dependent upon the number of neutrons it contains.
What notations are used to represent atomic number and weight?
Each atom, therefore, can be assigned both an atomic number (the number of protons equals the number of electrons) and an atomic weight (approximately equaling the number of protons plus the number of neutrons). A normal helium atom, for example, has two protons and two neutrons in its nucleus, with two electrons in orbit. Its chemical behavior is determined by the atomic number 2 (the number of protons), which equals the normal number of electrons; the stability of its nucleus (that is, its radioactivity) varies with its atomic weight (approximately equal to the number of protons and neutrons). The most well- known form of plutonium, for example, has an atomic number of 94, since it has 94 protons, and with the 145 neutrons in its nucleus, an atomic weight of 239 (94 protons plus 145 neutrons). In World War II, its very existence was highly classified. A code number was developed: the last digit of the atomic number (94) and the last digit of the atomic weight (239). Thus, in some of the early documents examined by the Advisory Committee, the term 49 refers to plutonium.
49
Introduction
Styles of notation vary, but usually isotopes are written as:
atcic number Chemical abbreviation at™8ht
or as atomic weight chemical abbreviation
Thus, the isotope of plutonium just discussed would be written as:
94
Pu239 or as 239Pu
Since the atomic weight is what is often the only item of interest, it might also be written simply as Pu-239, plutonium 239, or Pu239.
Radioisotopes: What Are They and How Are They Made?
What are isotopes?
The isotopes of an element are all the atoms that have in their nucleus the number of protons (atomic number) corresponding to the chemical behavior of that element. However, the isotopes of a single element vary in the number of neutrons in their nuclei. Since they still have the same number of protons, all these isotopes of an element have identical chemical behavior. But since they have different numbers of neutrons, these isotopes of the same element may have different radioactivity. An isotope that is radioactive is called a radioisotope or radionuclide. Two examples may help clarify this.
The most stable isotope of uranium, U-238, has an atomic number of 92 (protons) and an atomic weight of 238 (92 protons plus 146 neutrons). The isotope of uranium of greatest importance in atomic bombs, U-235, though, has three fewer neutrons. Thus, it also has an atomic number of 92 (since the number of protons has not changed) but an atomic weight of 235 (92 protons plus only 143 neutrons). The chemical behavior of U-235 is identical to all other forms of uranium, but its nucleus is less stable, giving it higher radioactivity and greater susceptibility to the chain reactions that power both atomic bombs and nuclear fission reactors.
Another example is iodine, an element essential for health; insufficient iodine in one's diet can lead to a goiter. Iodine also is one of the earliest elements whose radioisotopes were used in what is now called nuclear medicine. The most common, stable form of iodine has an atomic number of 53 (protons) and an atomic weight of 127 (53 protons plus 74 neutrons). Because its nucleus has the "correct" number of neutrons, it is stable and is not radioactive. A less stable form of iodine also has 53 protons (this is what makes it behave chemically as
50
The Atomic Century
iodine) but four extra neutrons, for a total atomic weight of 131 (53 protons and 78 neutrons). With "too many" neutrons in its nucleus, it is unstable and radioactive, with a half-life of eight days. Because it behaves chemically as iodine, it travels throughout the body and localizes in the thyroid gland just like the stable form of iodine. But, because it is radioactive, its presence can be detected. Iodine 131 thus became one of the earliest radioactive tracers.
How can different isotopes of an element be produced?
How can isotopes be produced-especially radioisotopes, which can serve many useful purposes? There are two basic methods: separation and synthesis.
Some isotopes occur in nature. If radioactive, these usually are radioisotopes with very long half-lives. Uranium 235, for example, makes up about 0.7 percent of the naturally occurring uranium on the earth.*9 The challenge is to separate this very small amount from the much larger bulk of other forms of uranium. The difficulty is that all these forms of uranium, because they all have the same number of electrons, will have identical chemical behavior: they will bind in identical fashion to other atoms. Chemical separation, developing a chemical reaction that will bind only uranium atoms, will separate out uranium atoms, but not distinguish among different isotopes of uranium. The only difference among the uranium isotopes is their atomic weight. A method had to be developed that would sort atoms according to weight.
One initial proposal was to use a centrifuge. The basic idea is simple: spin the uranium atoms as if they were on a very fast merry-go-round. The heavier ones will drift toward the outside faster and can be drawn off. In practice the technique was an enormous challenge: the goal was to draw off that very small portion of uranium atoms that were lighter than their brethren. The difficulties were so enormous the plan was abandoned in 1942.90 Instead, the technique of gaseous diffusion was developed. Again, the basic idea was very simple: the rate at which gas passed {diffused) through a filter depended on the weight of the gas molecules: lighter molecules diffused more quickly. Gas molecules that contained U-235 would diffuse slightly faster than gas molecules containing the more common but also heavier U-238. This method also presented formidable technical challenges, but was eventually implemented in the gigantic gas diffusion plant at Oak Ridge, Tennessee. In this process, the uranium was chemically combined with fluorine to form a hexafluoride gas prior to separation by diffusion. This is not a practical method for extracting radioisotopes for scientific and medical use. It was extremely expensive and could only supply naturally occurring isotopes.
A more efficient approach is to artificially manufacture radioisotopes. This can be done by firing high-speed particles into the nucleus of an atom. When struck, the nucleus may absorb the particle or become unstable and emit a particle. In either case, the number of particles in the nucleus would be altered, creating an isotope. One source of high-speed particles could be a cyclotron. A
51
Introduction
cyclotron accelerates particles around a circular race track with periodic pushes of an electric field. The particles gather speed with each push, just as a child swings higher with each push on a swing. When traveling fast enough, the particles are directed off the race track and into the target.
A cyclotron works only with charged particles, however. Another source of bullets are the neutrons already shooting about inside a nuclear reactor. The neutrons normally strike the nuclei of the fuel, making them unstable and causing the nuclei to split (fission) into two large fragments and two to three "free" neutrons. These free neutrons in turn make additional nuclei unstable, causing further fission. The result is a chain reaction. Too many neutrons can lead to an uncontrolled chain reaction, releasing too much heat and perhaps causing a "meltdown." Therefore, "surplus" neutrons are usually absorbed by "control rods." However, these surplus neutrons can also be absorbed by targets of carefully selected material placed in the reactor. In this way the surplus neutrons are used to create radioactive isotopes of the materials placed in the targets.
With practice, scientists using both cyclotrons and reactors have learned the proper mix of target atoms and shooting particles to "cook up" a wide variety of useful radioisotopes.
How Does Radiation Affect Humans?
Radiation may come from either an external source, such as an x-ray machine, or an internal source, such as an injected radioisotope. The impact of radiation on living tissue is complicated by the type of radiation and the variety of tissues. In addition, the effects of radiation are not always easy to separate from other factors, making it a challenge at times for scientists to isolate them. An overview may help explain not only the effects of radiation but also the motivation for studying them, which led to much of the research examined by the Advisory Committee.
What effect can ionizing radiation have on chemical bonds?
The functions of living tissue are carried out by molecules, that is, combinations of different types of atoms united by chemical bonds. Some of these molecules can be quite large. The proper functioning of these molecules depends upon their composition and also their structure (shape). Altering chemical bonds may change composition or structure. Ionizing radiation is powerful enough to do this. For example, a typical ionization releases six to seven times the energy needed to break the chemical bond between two carbon atoms.91 This ability to disrupt chemical bonds means that ionizing radiation focuses its impact in a very small but crucial area, a bit like a karate master focusing energy to break a brick. The same amount of raw energy, distributed more broadly in nonionizing form, would have much less effect. For example, the amount of energy in a lethal dose of ionizing radiation is roughly equal to the
52
The Atomic Century
amount of thermal energy in a single sip of hot coffee.92 The crucial difference is that the coffee's energy is broadly distributed in the form of nonionizing heat, while the radiation's energy is concentrated in a form that can ionize.
What is DNA?
Of all the molecules in the body, the most crucial is DNA (deoxyribose nucleic acid), the fundamental blueprint for all of the body's structures. The DNA blueprint is encoded in each cell as a long sequence of small molecules, linked together into a chain, much like the letters in a telegram. DNA molecules are enormously long chains of atoms wound around proteins and packed into structures called chromosomes within the cell nucleus. When unwound, the DNA in a single human cell would be more than 2 meters long. It normally exists as twenty-three pairs of chromosomes packed within the cell nucleus, which itself has a diameter of only 10 micrometers (0.00001 meter).93 Only a small part of this DNA needs to be read at any one time to build a specific molecule. Each cell is continually reading various parts of its own DNA as it constructs fresh molecules to perform a variety of tasks. It is worth remembering that the structure of DNA was not solved until 1953, nine years after the beginning of the period studied by the Advisory Committee. We now have a much clearer picture of what happens within a cell than did the scientists of 1944.
What effect can ionizing radiation have on DNA?
Ionizing radiation, by definition, "ionizes," that is, it pushes an electron out of its orbit around an atomic nucleus, causing the formation of electrical charges on atoms or molecules. If this electron comes from the DNA itself or from a neighboring molecule and directly strikes and disrupts the DNA molecule, the effect is called direct action. This initial ionization takes place very quickly, in about 0.000000000000001 of a second. However, today it is estimated that about two-thirds of the damage caused by x rays is due to indirect action. This occurs when the liberated electron does not directly strike the DNA, but instead strikes an ordinary water molecule. This ionizes the water molecule, eventually producing what is known as zfree radical. A free radical reacts very strongly with other molecules as it seeks to restore a stable configuration of electrons. A free radical may drift about up to 10,000,000,000 times longer than the time needed for the initial ionization (this is still a very short time, about 0.00001 of a second), increasing the chance of it disrupting the crucial DNA molecule. This also increases the possibility that other substances could be introduced that would neutralize free radicals before they do damage.94
Neutrons act quite differently. A fast neutron will bypass orbiting electrons and occasionally crash directly into an atomic nucleus, knocking out large particles such as alpha particles, protons, or larger fragments of the nucleus. The most common collisions are with carbon or oxygen nuclei. The particles created will themselves then set about ionizing nearby electrons. A slow neutron
53
Introduction
will not have the energy to knock out large particles when it strikes a nucleus. Instead, the neutron and the nucleus will bounce off each other, like billiard balls. In so doing, the neutron will slow down, and the nucleus will gain speed. The most common collision is with a hydrogen nucleus, a proton that can excite or ionize electrons in nearby atoms.95
What immediate effects can ionizing radiation have on living cells?
All of these collisions and ionizations take place very quickly, in less than a second. It takes much longer for the biological effects to become apparent. If the damage is sufficient to kill the cell, the effect may become noticeable in hours or days. Cell "death" can be of two types. First, the cell may no longer perform its function due to internal ionization; this requires a dose to the cell of about 100 gray (10,000 rad). (For a definition of gray and rad, see the section below titled "How Do We Measure the Biological Effects of Radiation?") Second, "reproductive death" (mitotic inhibition) may occur when a cell can no longer reproduce, but still performs its other functions. This requires a dose of 2 gray (200 rad), which will cause reproductive death in half the cells irradiated (hence such a quantity is called a "mean lethal dose.")96 Today we still lack enough information to choose among the various models proposed to explain cell death in terms of what happens at the level of atoms and molecules inside a cell.97 If enough crucial cells within the body totally cease to function, the effect is fatal. Death may also result if cell reproduction ceases in parts of the body where cells are continuously being replaced at a high rate (such as the blood cell-forming tissues and the lining of the intestinal tract). A very high dose of 100 gray ( 1 0,000 rad) to the entire body causes death within twenty-four to forty-eight hours; a whole-body dose of 2.5 to 5 gray (250 to 500 rad) may produce death within several weeks.98 At lower or more localized doses, the effect will not be death, but specific symptoms due to the loss of a large number of cells. These effects were once called nonstochastic; they are now called deterministic.™ A beta burn is an example of a deterministic effect.
What long-term effects can radiation have?
The effect of the radiation may not be to kill the cell, but to alter its DNA code in a way that leaves the cell alive but with an error in the DNA blueprint. The effect of this mutation will depend on the nature of the error and when it is read. Since this is a random process, such effects are now called stochastic.™0 Two important stochastic effects of radiation are cancer, which results from mutations in nongerm cells (termed somatic cells), and heritable changes, which result from mutations in germ cells (eggs and sperm).
How can ionizing radiation cause cancer?
Cancer is produced if radiation does not kill the cell but creates an error in the DNA blueprint that contributes to eventual loss of control of cell division, and
54
The Atomic Century
the cell begins dividing uncontrollably. This effect might not appear for many years. Cancers induced by radiation do not differ from cancers due to other causes, so there is no simple way to measure the rate of cancer due to radiation. During the period studied by the Advisory Committee, great effort was devoted to studies of irradiated animals and exposed groups of people to develop better estimates of the risk of cancer due to radiation. This type of research is complicated by the variety of cancers, which vary in radiosensitivity. For example, bone marrow is more sensitive than skin cells to radiation-induced cancer.101
Large doses of radiation to large numbers of people are needed in order to cause measurable increases in the number of cancers and thus determine the differences in the sensitivity of different organs to radiation. Because the cancers can occur anytime in the exposed person's lifetime, these studies can take seventy years or more to complete. For example, the largest and scientifically most valuable epidemiologic study of radiation effects has been the ongoing study of the Japanese atomic bomb survivors. Other important studies include studies of large groups exposed to radiation as a consequence of their occupation (such as uranium miners) or as a consequence of medical treatment. These types of studies are discussed in greater detail in the section titled "How Do Scientists Determine the Long-Term Risks from Radiation?"
How can ionizing radiation produce genetic mutations?
Radiation may alter the DNA within any cell. Cell damage and death that result from mutations in somatic cells occur only in the organism in which the mutation occurred and are therefore termed somatic or nonheritable effects. Cancer is the most notable long-term somatic effect. In contrast, mutations that occur in germ cells (sperm and ova) can be transmitted to future generations and are therefore called genetic or heritable effects. Genetic effects may not appear until many generations later. The genetic effects of radiation were first demonstrated in fruit flies in the 1920s. Genetic mutation due to radiation does not produce the visible monstrosities of science fiction; it simply produces a greater frequency of the same mutations that occur continuously and spontaneously in nature.
Like cancers, the genetic effects of radiation are impossible to distinguish from mutations due to other causes. Today at least 1,300 diseases are known to be caused by a mutation.102 Some mutations may be beneficial; random mutation is the driving force in evolution. During the period studied by the Advisory Committee, there was considerable debate among the scientific community over both the extent and the consequences of radiation-induced mutations. In contrast to estimates of cancer risk, which are based in part on studies of human populations, estimates of heritable risk are based for the most part upon animal studies plus studies of Japanese survivors of the atomic bombs.
The risk of genetic mutation is expressed in terms of the doubling dose:
55
Introduction
the amount of radiation that would cause additional mutations equal in number to those that already occur naturally from all causes, thereby doubling the naturally occurring rate of mutation.
It is generally believed that mutation rates depend linearly on dose and that there is no threshold below which mutation rates would not be increased. Spontaneous mutation (unrelated to radiation) occurs naturally at a rate of approximately 1/10,000 to 1/1,000,000 cell divisions per gene, with wide variation from one gene to another.
Attempts have been made to estimate the contribution of ionizing radiation to human mutation rates by studying offspring of both exposed and nonexposed Japanese atomic bomb survivors. These estimates are based on comparisons of the rate of various congenital defects and cancer between exposed and nonexposed survivors, as well as on direct counting of mutations at a small number of genes. For all these endpoints, no excess has been observed among descendants of the exposed survivors.
Given this lack of direct evidence of any increase in human heritable (genetic) effects resulting from radiation exposure, the estimates of genetic risks in humans have been compared with experimental data obtained with laboratory animals. However, estimates of human genetic risks vary greatly from animal data. For example, fruit flies have very large chromosomes that appear to be uniquely susceptible to radiation. Humans may be less vulnerable than previously thought. Statistical lower limits on the doubling dose have been calculated that are compatible with the observed human data. Based on our inability to demonstrate an effect in humans, the lower limit for the genetic doubling dose is thought to be less than 100 rem.103
How Do We Measure the Biological Effects of External Radiation?
The methods of measuring radiation and radioactivity, purely physical events, were discussed earlier. In studying the effect of radiation on living organisms, a biological event, the crucial data are the amount of energy absorbed by a specific amount and type of tissue. This requires first measuring the amount of energy left behind by the radiation in the tissue and, second, the amount and type of tissue.
What is an absorbed dose of radiation?
The risk posed to a human being by any radiation exposure depends partly upon the absorbed dose, the amount of energy absorbed per gram of tissue. Absorbed dose is expressed in rad. A rad is equal to 100 ergs of energy absorbed by 1 gram of tissue. The more modern, internationally adopted unit is the gray (named for the English medical physicist L. H. Gray); one gray equals 100 rad. Almost all the documents from the time period studied by the Advisory Committee use the term rad rather than gray. It is important to realize that
56
The Atomic Centwy
absorbed dose refers to energy per gram of absorbing tissue, not total energy. Someone absorbing 1 gray (100 rad) in a small amount of tissue, such as a thyroid gland, will absorb much less total energy than someone absorbing 1 gray (100 rad) throughout his or her entire body. Thus, when speaking of absorbed dose, it is crucial to know the amount of tissue being exposed, not simply the number of gray or rad.
What is an equivalent dose of radiation?
Even the rad or gray, though, are still units that measure a purely physical event: the amount of energy left behind in a gram of tissue. It does not directly measure the biological effect of that radiation. The biological effect of the same amount of absorbed energy may vary according to the type of radiation involved. This biological effect can be computed by multiplying the absorbed dose (in rad or gray) by a number indicating the quality factor of the particular type of radiation. For photons and electrons the quality factor is defined to be 1; for neutrons it ranges from 5 to 20 depending on the energy of the neutron; for alpha particles it is 20. m Thus, 1 gray (100 rad) of alpha particles is currently judged to have an effect on living tissue that is twenty times more than 1 gray ( 1 00 rad) of x rays. Multiplying the absorbed dose (in rad or gray) by the quality factor (also known as the radiation weighting factor) produces what is called the equivalent dose. For the period studied by the Advisory Committee, this was expressed in terms of a unit called the rem, an acronym for roentgen equivalent man.105 (The term equivalent simply meant that an absorbed dose expressed in rem would have equivalent biological effects, regardless of the type of radiation. Thus, 10 rem of x rays should have the same biological effect as 10 rem of neutrons absorbed by the same part of the body.) The modern unit is the sievert (abbreviated Sv and named for the prominent Swedish radiologist, Rolf Sievert), which is equal to 100 rem. Thus, an equivalent dose of 200 rem would today be expressed as 2 sievert.
What is an effective dose of radiation?
Finally, the biological effect of radiation depends on the type of tissue being irradiated. As with different types of radiation, a weighting or quality factor is introduced depending on the type of tissue. The more sensitive the tissue is to radiation, the higher the factor. The effective dose is the sum of the equivalent doses of the various types of irradiated tissue, each properly weighted for its sensitivity to radiation. Tissue weighting factors are determined from the relative incidence of cancers in different tissues in the Japanese survivors of the atomic bombs.
Calculating the effective dose makes it possible to readily compare different exposures, as illustrated by the accompanying graphs.
57
Experimental and Nonexperimental Doses*
Thyroid Studies with lodine-131
Effective Dose Equivalant (millirems, thyroid excluded) 350
Study 1 Study 2 Study 3 Study 4 Background
Largest Dose
Smallest Dose
Thyroid Studies with lodine-131
Dose to Thyroid Gland (rads) 600
Study 1 Study 2 Study 3 ■ Largest Thyroid Dose H
Study 4 Medical Scan Smallest Thyroid Dose
*The experiments themselves are discussed in chapter 7. These graphs are reproduced with permission from Task Force on Human Subject Research, Commonwealth of Massachusetts Department of Mental Retardation, April 1994, "A Report on the Use of Radioactive Materials in Human Subject Research that Involved Residents of State-Operated Facilities within the Commonwealth of Massachusetts from 1942- 1973" (ACHRENo. MASS-072194-A), 17, and the Working Group on Human Subject Research, Commonwealth of Massachusetts Department of Mental Retardation, June 1994, "The Thyriod Studies: A Follow-up Report on the Use of Radioactive Materials in Human Subject Research that Involved Residents of State-Operated Facilities within the Commonwealth of Massachusetts from 1942-1973" (ACHRENo. MASS-072194-A), 14.
Fernald School Nutrition Study: Ca Tracer
Effective Dose Equivalent (millirems) 500
Smallest Dose Largest Dose
|H Annual Natural Background |
Denver Resident Study
Fernald School Nutrition Study: Fe Tracer
Effective Dose Equivalent (millirems) 500
Smallest Dose Largest Dose Denver Resident
MB Annual Natural Background H] Study
Common Medical Procedures
Whole Body Effective Dose Equivalent (millirems) 1000
Chest X-Ray BackX-Ray Colon X-Ray Brain Scan H| Annual Natural Background HH Procedure
Introduction
How Do We Measure the Biological Effects of Internal Emitters?
The general principles just described require further refinement when applied to doses from internal emitters.
What information is needed to calculate absorbed dose of a radionuclide inside the body?
Calculating the absorbed dose from a radionuclide inside the body is complex since it involves both the physics of radioactive decay and the biology of the body's metabolism. Six important factors that must be considered are these:
1. The amount of the radionuclide administered.
2. The type of radiation emitted during the decay process.
3. The physical half-life of the radionuclide.
4. The chemical form of the radionuclide.
5. The fraction of the radionuclide that accumulates in each organ.
6. The length of time that the radionuclide remains in the organ (the biological half-life).
How varied are the types of radiation that different radionuclides emit?
Radionuclides can emit several types of radiation (e.g., gamma rays, beta or alpha particles). Each radionuclide emits its own unique mixture of radiations; indeed, scientists identify radioactive materials by using these unique mixtures as if they were fingerprints. The mix of radiations for a specific radionuclide is always the same, regardless of whether the radionuclide is located on a bench in a physicist's laboratory or inside the human body. This means that the type of radiation of each radionuclide can be measured outside the body with great precision by laboratory instruments. A quality factor, discussed earlier, is used to adjust for the difference in the biological effects of different types of radiation.
What determines how long a radionuclide will irradiate the body?
The combination of the physical and biological half-life (the effective half-life) determines how long a radionuclide will continue to pump out energy into surrounding tissue. If the physical and biological half-lives of a particular chemical form of a radionuclide are very long, the radionuclide will continue to expose an individual to radiation over his or her lifetime. The total lifetime radiation exposure, expressed in rem, is called the committed dose equivalent.
The physical half-life is the length of time it will take for half of the atoms in a sample to decay to a more stable form. The physical half-life of each radionuclide can be measured precisely in the laboratory. A shorter half-life means that the miniature power source will "run down" sooner. Sometimes, however, a radionuclide will not decay immediately to a stable form, but to a
60
The Atomic Century
second, still unstable, form. A full calculation, therefore, must also include the types of radiation and physical half-lives of any decay products.
The biological half-life does not depend on the radionuclide but rather on the chemical form of the radionuclide. One chemical form of the radionuclide might be rapidly eliminated from the body whereas other chemical forms may be slowly eliminated.
To measure the biological half-life of a particular chemical form of a radionuclide, that chemical form needs to be studied in animals. Since the biological processes of different animals vary considerably, an accurate determination of the biological half-life requires that each chemical form of the radionuclide be studied in each animal of interest. Prior to studying a chemical form of a radionuclide in a human being, animal studies are performed to get some idea of what to expect.
Once the results of animal studies are available, scientists are able to predict what amount of that chemical form of the radionuclide can be safely injected into humans. An accurate determination of what fraction of each chemical form of the radionuclide accumulates in each organ and how long it stays in each organ in humans can only be determined by studying humans. These type of studies are called biodistribution studies.
What is the tissue weighting factor?
Some chemical forms of radionuclides are highly concentrated in one small organ (e.g., iodine in the thyroid gland). When this happens, that organ will absorb most of the radiated energy, and little energy will be deposited in the remainder of the body. Thus, for each chemical form of a radionuclide, there is an organ that will receive the highest dose from that radionuclide. Since organs also vary greatly in their sensitivity to radiation, the biological consequences of the radiation dose differ depending on the organ. This difference in sensitivity to radiation is represented by what is called a tissue weighting factor.
What is the difference between committed equivalent dose and committed effective dose?
An estimate of the risk posed by a radionuclide in the body depends on its chemical form, its biodistribution, its physical properties (how it decays), and the sensitivity of the organs exposed. When all these factors are considered in the calculation of risk for a single radionuclide, the total lifetime exposure is called the committed equivalent dose. If more than one radioisotope is present, the sum of all the committed equivalent doses is called the committed effective dose. Both are expressed in rem or the more modern units sieverts.m These calculations provide a basis for comparing the risk posed by different isotopes.
How do radiation risks compare with chemical risks?
It should be noted that radiation is not the only possible hazard resulting
61
Introduction
from the medical use of radionuclides. Few radioisotopes, whether intentionally or accidentally introduced into the body, enter in a chemically pure form. The radioactive atoms are usually part of a larger chemical compound. The chemical form of the radioisotope may pose its own hazards of chemical toxicity. Chemical toxicity depends upon the chemical effect of the compound on the body, quite independent of any effects of radiation. Determining chemical toxicity is an entire field of science on its own.
How Do Scientists Determine the Long-Term Risks from Radiation?
Where did the risk estimates in this report come from?
Throughout this report, the reader will find numerous statements estimating the risks of cancer and other outcomes to individuals exposed to various types of radiation. These estimates were obtained from various scientific advisory committees that have considered these questions in depth.107 Their estimates in turn are based on syntheses of the scientific data on observed effects in humans and animals.
How are risk estimates expressed?
Epidemiologists usually express the risk of disease in terms of the number of new cases {incidence rate) or deaths (mortality rate) in a population in some period of time. For example, an incidence rate might be 100 new cases per 100,000 people per year; a mortality rate might be 15 deaths per 100,000 people per year. These rates vary widely by age, conditions of exposure, and various other factors. To summarize this complex set of rates, government regulatory bodies often consider the lifetime risk of a particular outcome like cancer. When relating a disease, such as cancer, to one of its several causes, a more useful concept is the excess lifetime risk expected from one particular pattern of exposure, such as continuous exposure to 1 rad per year.
It is well established that cancer rates begin to rise above the normal background rate only some time after exposure, the latent period, which varies with the type of cancer and other factors such as age. Even after the latent period has passed and radiation effects begin to appear, not all effects are due to radiation. The excess rate may still vary by age, latency, or other factors, but for many cancers it tends to be roughly proportional to the rate in the general population. This is known as the constant relative risk model, and the ratio of rates at any given age between exposed and unexposed groups is called the relative risk. Many advisory committees have based their risk estimates on models for the relative risk as a function of dose and perhaps other factors. Other committees, however, have based their estimates on the difference in rates between exposed and unexposed groups, a quantity known as the absolute risk. This quantity also varies with dose and other factors, but when this variation is appropriately accounted for, either approach can be used to estimate lifetime risk.
62
The Atomic Century
What are the types of data on which such estimates are based?
Human data are one important source, discussed below. Two other important sources of scientific data are experiments on animals and on cell cultures. Because both types of research are done in laboratories, scientists can carefully control the conditions and many of the variables. For the same reason, the experiment can be repeated to confirm the results. Such research has contributed in important ways to our understanding of basic radiobiological principles. It also has provided quantitative estimates of such parameters as the relative effectiveness of different types of radiation and the effects of dose and dose rate. In some circumstances, where human data are limited or nonexistent, such laboratory studies may provide the only basis on which risks can be estimated.
Why are human data preferable to data on animals or tissue cultures for most purposes?
Most scientists prefer to base risk estimates for humans on human data wherever possible. This is because in order to apply animal or tissue culture data to humans, scientists must extrapolate from one species to another or from simple cellular systems to the complexities of human physiology. This requires adjusting the data for differences among species in life span, body size, metabolic rates, and other characteristics. Without actual human data, extrapolation provides no guarantee that there are no unknown factors also at work. It is not surprising that there is no clear consensus as to how to extrapolate risk estimates from one species to another. This problem is not unique to radiation effects; there are countless examples of chemicals having very different effects in different species, and humans can differ quite significantly from animals in their reaction to toxic agents.
How have human data been obtained?
There are serious ethical issues with conducting experiments on humans, as discussed elsewhere in the report. However, most of the human data that are used to estimate risks, not just risk from radiation, come from epidemiologic studies on populations that already have been exposed in various ways. For radiation effects, the most important human data come from studies of the Japanese atomic bomb survivors carried out by the Radiation Effects Research Foundation (formerly the Atomic Bomb Casualty Commission) in Hiroshima. Other valuable sources of data include various groups of medically exposed patients (such as radiotherapy patients) and occupationally exposed workers (such as the uranium miners, discussed in chapter 12). I08
63
Introduction
Why is it necessary to compare exposed populations with unexposed populations?
Unlike a disease caused by identifiable bacteria, no "signature" has yet been found in cancerous tissue that would link it definitively to prior radiation exposure. Radiogenic cancers are identical in properties, such as appearance under a microscope, growth rate, and potential to metastasize, to cancers occurring in the general population. Finding cancers in an exposed population is not enough to prove they are due to radiation; the same number of cancers might have occurred due to the natural frequency of the disease. The challenge is to separate out the effects of radiation from what would otherwise have occurred. A major step in this direction is to develop follow-up (or cohort) studies, in which an exposed group is followed over time to observe their disease rates, and these rates are then compared with the rates for the general population or an unexposed control group.109
Why is the analysis of epidemiologic data so complicated?
Simply collecting data on disease rates in exposed and control populations is not enough; indeed, casual analysis may lead to serious errors in understanding. Sophisticated data-collection techniques and mathematical models are needed to develop useful risk estimates for several reasons:
1 . Random variation due to sample size.
2. Multiple variables.
3. Limited time span of most studies.
4. Problems of extrapolation.
In addition, individual studies may also be biased in their design or implementation.
What is random variation?
The observed proportion of subjects developing disease in any randomly selected subgroup (sample) of individuals with similar exposures is subject to the vagaries of random variation.
A simple-minded example of this is the classic puzzle of determining, in a drawer of 100 socks, how many are white and how many are black, by pulling out one sock at a time. Obviously, if we pull out all the socks, we know for certain. In most areas of study, though, "pulling out all the socks" is far too expensive and time-consuming. But if we pull only 10, with what degree of confidence can we predict the color of the others? If we pull 20, we will have more confidence. In other words, the larger the sample, the greater our confidence. Using statistical techniques, our degree of confidence can be calculated from the size of the entire population (in this case 100 socks) and the size of the actual sample. The result is popularly called the margin of error.
64
The Atomic Century
The most common examples of this in everyday life are the public opinion polls continually quoted in the news media. As can be seen in the simple example of the drawer of socks, the highest degree of confidence can be achieved simply by pulling all the socks out of the drawer. For public opinion polls, this would be far too expensive; instead, a small sample is selected at random from the population. Nowadays it is common to report not only the actual results, but also the sample size and the margin of error. The margin of error depends not only on the sample size, but also on how high a degree of confidence we desire. The degree of confidence is the probability that our sample has provided a true picture of the entire population. For example, the margin of error will be smaller for 80 percent degree of confidence than for 95 percent. Even where a study covers an entire exposed population, such as the atomic bomb survivors, the issue of random variation remains when we wish to generalize the findings to other populations.
What are multiple variables'!
The effects of radiation will depend upon, or vary, with the dose of radiation received. However, these effects also may vary with other factors- other variables-thai are not dependent upon the radiation dose itself. Examples of such variables are age, gender, latency (time since exposure), and smoking. Data on these other variables must be collected as well as data on the basic elements of radiation dose and disease. The challenge is to then distinguish between disease rates due to radiation and those due to other factors. For example, if the population studied were all heavy smokers, this might explain in part a higher rate of lung cancer. Much of the science of epidemiology is devoted to choosing what factors to collect data on and then developing the multivariate mathematical models needed to separate out the effect of each variable. Radiation effects vary considerably across subgroups and over time or age. Because of this, direct estimates of risk for particular subgroups would be very unstable. Mathematical models must be used. These models allow all the data to be used to develop risk estimates that, while based on sufficiently large estimates to be stable, will be applicable to particular subgroups.
A more subtle problem is mis specification of the model finally chosen to calculate risks. The model may weigh selected factors in a manner that best fits the data from a statistical viewpoint. This model, while fitting the data, may not actually be a "correct" view of nature; another model that does not fit the data quite as well may actually better describe the as-yet-unknown underlying mechanisms.
Why does a limited time span reduce the value of a study?
The most pronounced effects of large exposures to radiation manifest themselves quickly in symptoms loosely termed radiation sickness.
However, another concern is understanding the effects of much lower
65
Introduction
levels of radiation. Unlike the more acute effects of large exposures, these may not appear for some time. Some cancers, for example, do not appear until many years after the initial exposure. These latent effects may continue to appear in a population throughout their entire lifetimes. Calculating the lifetime risk of an exposure requires following the entire sample until all its members have died. Thus far, none of the exposed populations have yet been followed to the ends of their lives, although the radium dial painter study for the group painting before 1930 essentially has been completed, and the follow-up has been closed out."0
Why does extrapolation among human populations pose problems?
As discussed earlier, extrapolating results from one species to another is problematic due to differences in how species respond to radiation.
Even though humans are all members of the same species, there are similar problems when extrapolating results from one group of humans to another group. Within the human species, different groups can have different rates of disease. For example, stomach cancer is much more common and breast cancer much rarer among Japanese than among U.S. residents.
How then should estimates of the radiation-induced excess of cancer among the atomic bomb survivors be applied to the U.S. population? Assumptions are needed to "transport" risk estimates from one human population to another human population that may have very different "normal" risks.
Why does extrapolation from high to low doses pose problems?
Acquiring high-quality human data on low-dose exposure is difficult. Past studies indicate that the effects of low doses are small enough to be lost in the "noise" of random variation. In other words, the random variation due to sample size may be greater than the effects of the radiation. Thus, to estimate the risks of low doses, it is necessary to extrapolate from the effects of high doses down to the lower range of interest. As with extrapolation among species or among human populations, assumptions must be made.
The basic assumption concerns the dose effect. Is the effect of a dose linear? This would mean that half the dose would produce half the effect; one- tenth of the dose would produce one-tenth of the effect, and so forth. Nature is not always so reasonable, however. There are many instances in nature of nonlinear relationships. A nonlinear dose effect, for example, could mean that half the dose would produce 75 percent of the effects. Or, going in the other direction, a nonlinear dose effect could mean that half the dose would produce only 10 percent of the effect. Reliable data are too sparse to settle the issue empirically. Much of the ongoing controversy over low-dose effects concerns which dose effect relationship to assume. Concerning dose response, most radiation advisory committees assume that radiation risks are linear in doses at low levels, although these risks may involve nonlinear terms at higher doses.
Another assumption concerns the effect of dose rate. It is generally
66
The Atomic Century
agreed that the effect of high-dose x rays is reduced if the radiation is received over a period of time instead of all at once. (This reduction in acute effects, due to the cell's ability to repair itself in between exposures, is one of the reasons that modern protocols for radiotherapy use several fractionated doses.) The degree to which this also happens at low doses is less clear. There are few human data on the effect of dose rate on cancer induction. Most estimates of the effect come from animal or cell culture experiments. There is also evidence of quite different dose-rate effects for alpha radiation and neutrons.
How can a specific study be biased?
When applied to an epidemiologic study, the term bias does not refer to the personal beliefs of the investigators, but to aspects of the study design and implementation. There are several possible sources of bias in any study.
What is called a confounding bias may result if factors other than radiation have affected disease rates. Such factors, as mentioned earlier, might be a rate of smoking higher than the general population.
A selection bias may result if the sample was not truly a random selection from the population under study. For example, the results of a study that includes only employed subjects might not be applicable to the general population, since employed people as a group are healthier than the entire population.
An information bias may result from unreliability in a source of basic data. For example, basing the amount of exposure on the memory of the subjects may bias the study, since sick people may recall differently than healthy people. Dose, in particular, can be difficult to determine when studies are conducted on populations exposed prior to the study, since there usually was no accurate measurement at the time of exposure. Sometimes when dose measurements were taken, as in the case of the atomic veterans, the data are not adequate by today's standards."1
Finally, any study is subject to the random variation discussed earlier, which depends on how large the sample is. This is more important for low-dose than for high-dose studies, since the low-dose effects themselves are small enough to be lost amid random variations if the sample is too small.
To summarize, multiple studies may produce somewhat different results because there is an actual difference in the response between populations or because studies contain spurious results due to their own inadequacies. In addition, it must be recognized that the entire body of scientific literature is itself subject to a form of bias known as publication bias, meaning an overreporting of findings of excess risk. This is because studies that demonstrate an excess risk may be more likely to be published than those that do not.
67
Introduction
In view of all these uncertainties, what risk estimates did the Committee choose?
Despite all these uncertainties, it must be pointed out that more is known about the effects of ionizing radiation than any other carcinogen.
The BEIR V Committee of the National Academy of Sciences estimated in 1990 that the lifetime risk from a single exposure to 10 rem of whole-body external radiation was about 8 excess cancers (of any type) per 1,000 people. (This number is actually an average over all possible ages at which an individual might be exposed, weighted by population and age distribution.) For continuous exposure to 0.1 rem per year throughout a lifetime, the corresponding estimate was 5.6 excess cancers (that is, over and above the rate expected in a similar, but nonexposed population) per 1 ,000 people. It is widely agreed that for x rays and gamma rays, this latter figure should be reduced by some factor to allow for a cell's ability to repair DNA, but there is considerable uncertainty as to what figure to use; a figure of about 2 or 3 is often suggested."2
The estimates of lifetime risk from the BEIR V report have a range of uncertainty due to random variation of about 1.4-fold. The additional uncertainties, due to the factors discussed earlier, are likely to be larger than the random variation.
In comparison, for most chemical carcinogens, the uncertainties are often a factor of 10 or more. This agreement among studies of radiation effects is quite remarkable and reflects the enormous amount of scientific research that has been devoted to the subject, as well as the large number of people who have been exposed to doses large enough to show effects.
68
ENDNOTES
1 . In 1974 the AEC's regulatory activities for civilian nuclear power and the use (including medical research) of radioisotopes produced in nuclear reactors were transferred to the Nuclear Regulatory Commission and its research and weapons- development activities to the Energy Research and Development Administration (ERDA) In 1 977 ERDA was incorporated into the new Department of Energy.
2. Captain C. F. Behrens, ed., Atomic Medicine (New York: Thomas Nelson and Sons, 1949), 3.
3. Ibid., 7.
4 Otto Glasser, William Conrad Roentgen and the Early History oj the Roentgen Rays (Springfield, 111., and Baltimore: Charles C. Thomas, 1934), 29; Glasser is quoting O. Lummer of Berlin.
5. Ibid., 271.
6. Ibid., 244-282.
7. Robert Reid, Marie Curie (New York: E. P. Dutton, 1974), 241.
8. Ibid., 86-87.
9. P. Curie and M. S. Curie, "Radium: A New Body, Strongly Radio-Active, Contained in Pitchblende," Scientific American (28 January 1899): 60. The term hyperphosphorescence was suggested by Silvanus Thompson. Reid, Marie Curie, 87. See also Susan Quinn, Marie Curie: A Life (New York: Simon and Schuster, 1995).
10. New York Journal, 21 June 1905, reproduced in David J. DiSantis, M.D., and Denise M. DiSantis, "Radiologic History Exhibit: Wrong Turns on Radiology's Road of Progress," Radiographics (1991): 1 121-1 138, figure 17.
11. Henry S. Kaplan, "Historic Milestones in Radiobiology and Radiation Therapy," Seminars in Oncology 6, no. 4 (December 1979): 480.
12. "Autopsy of a Radiologist," Archives of the Roentgen Ray 18
(April 1914): 393. .
13 Reid, Marie Curie, 274; Barton C. Hacker, The Dragon's Tail: Radiation Safety in the Manhattan Project, 1942-1946 (Berkeley, Calif: University of California
Press, 1987), 22-23.
14. The marketing of one nostrum containing radium, Radiothor, was not officially shut down by the Federal Trade Commission until 1932. "With the institution of regulations, the radioactive patent medicine industry collapsed overnight." Roger M. Macklis, "The Great Radium Scandal," Scientific American 269 (March 1993): 94-99. In the 1920s, the use of capsules containing radium inserted into the nose was introduced as a means of shrinking lymphoid tissue in children to treat middle ear obstructions and infections. During World War II this procedure was used on submariners and Air Force personnel as treatment and, in the case of several hundred submariners, on an experimental basis to test the effectiveness of nasopharyngeal irradiation in shrinking lymphoid tissue and equalizing external and middle ear pressure. In the late 1940s, the observation that no controlled study had ever been conducted to test the treatment's effectiveness in preventing deafness in children led Johns Hopkins researchers to begin the experimental treatment of several hundred children. As the Advisory Committee began its work in 1994, controversy over the long-term effects of this treatment still swirled. Samuel Crane, "Irradiation of Nasopharynx," Annals of Otology, Rhinology, and Laryngology 55 (1946): 779-788; H. L. Holmes and J. D. Harris, "Aerotitis Media in
69
Submariners," Annals of Otology, Rhinology, and Laryngology 55 (1946): 347-371. See chapter 7 and ACHRE Briefing Book, vol. 13, tab E, April 1995, for fuller discussion.
15. Macklis, "The Great Radium Scandal," 94-99.
16. The National Council on Radiation Protection began as the American Committee on X Ray and Radium Protection in 1928, under the aegis of the International Congress of Radiology. A private organization, its members were physicians, physicists, and representatives of the equipment manufacturers. Prior to World War II its main function was to issue recommendations on radiological safety, which were published by the National Bureau of Standards (a federal agency). At times this arrangement created confusion, leading people to believe the publications were official recommendations. After the war, the private group was revived as the National Committee on Radiation Protection. In 1956 it was renamed the National Committee on Radiation Protection and Measurements. In the early 1 960s, it received a congressional charter and was renamed the National Council on Radiation Protection and Measurements. Throughout its history it has coordinated its activities with other groups, such as the International Commission on Radiological Protection' and committees of the National Academy of Sciences (known as the BEAR and BEIR Committees). The most complete record of the NCRP's activities is Lauriston S. Taylor, Organization for Radiation Protection: The Operations of the ICRPandNCRP, 1928-1974 (Washington, D.C.: Office of Technical Information, U.S. Department of Energy.) Lauriston Taylor, a physicist at the National Bureau of Standards, served as the executive director of the organization from its founding in 1 928 to 1974. For further background on the history of radiation protection, see Daniel P. Serwer, The Rise of Radiation Protection: Science, Medicine and Technology in Society, 1896-1935 (Ph.D. diss, in the History of Science, Princeton University, 1976) (Ann Arbor: University Microfilms 77-14242, 1977); Gilbert F. Whittemore, The National Committee on Radiation Protection, 1928-1960: From Professional Guidelines to Government Regulation (Ph.D. diss, in the History of Science, Harvard University, 1986) (Ann Arbor: University Microfilms 87-04465, 1987); J. Samuel Walker, "The Controversy Over Radiation Safety: A Historical Overview," Journal of the American Medical Association 262 (1989): 664-668; D. C. Kocher, "Perspective on the Historical Development of Radiation Standards," Health Physics 61, no. 4 (October 1994).
17. Heinz Haber, The Walt Disney Story of Our Friend the Atom (New York: Simon and Schuster, 1956), 152. The German-born Dr. Haber had come to the United States in 1947 to work for the Air Force School of Aviation Medicine and was a cofounder of the field of space medicine. In the early 1950s he joined the faculty of the University of California at Los Angeles. As Spencer Weart, a historian of the images of the atomic age has recorded, the accompanying Walt Disney movie Our Friend the Atom, which was shown on television and in schools beginning in 1957, was probably the most effective of educational films on the perils and potential of atomic energy. "The great storyteller introduced the subject as something 'like a fairy tale,' indeed the tale of a genie released from a bottle. The cartoon genie began as a menacing giant. . . . But scientists turned the golem into an obedient servant, who wielded the 'magic power' of radioactivity. . . ." Spencer R. Weart, Nuclear Fear: A History of Images (Cambridge, Mass.: Harvard University Press, 1988), 169.
18. Marshall Brucer, Chronology of Nuclear Medicine (St. Louis: Heritage Publications, 1990), 199-200. Radon is a gas at room temperature. Doctors developed an innovative system for capturing radon from used cancer therapy vials and dissolving it in a saline solution, which was then injected.
70
19. Haber, Our Friend the Atom, 152.
20. J. L. Heilbron and Robert W. Seidel, Lawrence and His Laboratory: A History of the Lawrence Berkeley Laboratoiy, vol. 1 (Los Angeles: University of California Press, 1989). The birth and development of nuclear medicine at the University of California's Berkeley and San Francisco branches is the subject of a case study in a supplemental volume to this report.
21. John Stanbury, A Constant Ferment (Ipswich, N.Y.: Ipswich Press, 1991), 57-67.
22. Stafford Warren, interview by Adelaide Tusler (Los Angeles: University of California), 23 June 1966 in An Exceptional Man for Exceptional Challenges, Vol. 2 (Los Angeles: University of California, 1983) (ACHRE No. UCLA-101794-A-1), 421- 422.
23. Manhattan Project researchers focused on polonium in the development of the initiator for the bomb. See Richard Rhodes, The Making of the Atomic Bomb (New York: Simon and Schuster, 1986), 578-580.
24. Manhattan District Program, 31 December 1946 (book 1, "General," volume 7, "Medical Program") (ACHRE No. NARA-052495-A-1), 2.2.
25. Stafford Warren in Radiology in World War II, ed. Arnold Lorentz Ahnfeldt (Washington, D.C.: GPO, 1966), 847.
26. Robert Stone, 10 May 1943 ("Health Radiation and Protection") (ACHRE No. DOE-011195-B-1).
27. Philip J. Close, Second Lieutenant, JAGD, to Major C. A. Taney, Jr., 26 July 1945 ("Determination of Policy on Cases of Exposure to Occupational Disease") (ACHRE No. DOE-120894-E-96), 1.
28. Ibid., 3.
29. Response to ACHRE Request No. 012795-B, Oak Ridge Associated Universities, D. M. Robie to A. ("Tony") P. Polendak, 15 June 1979 ("Storage of records- -Shipment 1161").
30. The story of this early Hanford research is told in Neal D. Hines, Proving Ground: An Account of the Radiobiological Studies in the Pacific 1946-61 (Seattle: University of Washington Press, 1962). As Hines explains, the initial study of the effect of radioactivity on aquatic organisms was undertaken by a University of Washington researcher. The program could not be identified with the Columbia River, and the research was to be conducted in a normal campus setting. The project's name ("Applied Fisheries Laboratory") was selected to disguise its work. The primary researcher initially did not know the true purpose, and the university accepted the work for undisclosed purpose on the assurance that national security required it.
3 1 . Harold Hodge, interview by J. Newell Stannard, transcript of audio recording, 22 October 1980 (ACHRE No. DOE-061794-A-4), 21-22. Stafford Warren, interview by J. Newell Stannard, transcript of audio recording, 7 February 1979 (ACHRE No. DOE-061794-A), 3.
32. Henry DeWolf Smyth, Atomic Energy for Military Purposes: The Official Report on the Development of the Atomic Bomb under the Auspices of the United States Government, 1940-45 (Princeton, N.J.: Princeton University Press, 1945).
33. The organizational history of the Department of Defense is chronicled in The Department of Defense: Documents on Establishment and Organization 1944-1978, eds. Alice C. Cole, Alfred Goldberg, Samuel A. Tucker, Rudolf A. Winnacker (Washington, D.C.: Office of the Secretary of Defense, Historical Office, 1978).
71
34. The program expanded from the base of Manhattan Project research sites such as Oak Ridge, Hanford, Chicago, and the Universities of California, Chicago, and Rochester to take in a growing portion of the university research establishment. The minutes of the January 1947 meeting record an ambitious program to focus on the physical measurement of radiation, the biological effects of radiation, methods for the detection of radiation damage, methods for the prevention of radiation injury, and protective measures. There followed an itemized list of the work to be done at Argonne National Laboratory, Los Alamos, Monsanto, Columbia University, and the Universities of Michigan, Rochester, Tennessee, California, and Virginia.
The University of Rochester was to be the largest university contractor, receiving more than $1 million, followed by the University of California (about one-half million for UCLA, where Stafford Warren was dean of the new medical school, and Berkeley, to which Stone had returned to join Hamilton), Western Reserve (to which Warren's deputy Hymer Friedell was headed), and Columbia (more than $100,000). Argonne received an amount comparable to Rochester; other labs, including Los Alamos National Laboratory and Clinton Laboratories (now Oak Ridge National Laboratory), were scheduled for $200,000 or less. Stafford Warren, Interim Medical Committee, proceedings of 23-24 January 1947 (ACHRE No. UCLA-1 1 1094-A-26). See also ACHRE Briefing Book, vol. 3, tab F, document H.
35. "Report of the Board of Review," 20 June 1947, attached to letter from David Lilienthal, Chairman, AEC, to Dr. Robert F. Loeb, Chairman, AEC Medical Board of Review, 27 June 1947 ("At the conclusion of the deliberations . . .") (ACHRE No. DOE-051094-A-191), 3-4.
36. The Advisory Committee has assembled the minutes of the meetings, and such transcripts as have been retrieved.
37. Shields Warren, interview by Dr. Peter Olch, National Library of Medicine, transcript of audio recording, 10-11 October 1972, 59.
38. Harry H. Davis, "The Atom Goes to Work for Medicine," New York Times Magazine, 26 September 1946 (ACHRE No. DOE-051094-A-408).
39. Marshall Brucer, M.D., Chairman, Medical Division, Oak Ridge Institute for Nuclear Studies, wrote:
Paul Aebersold's isotopes division was the only safely nonsecret part of AEC. Aebersold had unlimited funds, unlimited radioisotopes, and seemingly unlimited energy to promote the unlimited cures that had been held back from the American public for too long. The liberal establishment was in the depths of shame for having ended the war by killing people. Radioisotopes didn't kill people; they cured cancer.
Aebersold spoke at every meeting of one person or more that had one minute or more available on its program. No matter what the meeting's subject, Aebersold's topic was always the same. He sold isotopes.
Marshall Brucer, "Nuclear Medicine Begins with a Boa Constrictor," Journal of Nuclear
Medicine 19, no. 6 (1978): 595.
40. Isotopes Division, prepared for discussion with general manager, "Present and Future Scope of Isotope Distribution," 4 March 1949 (ACHRE No. DOE-01 1895-B- 1).
41. Interview with Shields Warren, 10-11 October 1972, 76.
72
42. Isotopes Division, 4 March 1949, 2.
43. See Kaplan, "Historic Milestones," 480.
44. "Summary of Congressional Hearings on Fellowship Issue," 16 May 1949 (ACHRE No. DOE-061395-D-1).
45. Advisory Committee for Biology and Medicine, proceedings of 10 September 1949 (ACHRE No. DOE-072694-A), 18.
46. Ibid, 19.
47. For a further discussion of the contemplated secret record keeping by the VA, see chapter 10. As noted there, a VA investigation concluded that the "confidential" division was never activated.
48. The VA provided the Advisory Committee with capsule descriptions of experiments, which appeared in periodic VA reports of the time. In fact, the number of descriptions exceeded 3,000 for the portion of the 1944-74 period the reports covered. However, further information on the vast majority of the experiments was typically unavailable, and the VA noted that some of the descriptions may be redundant (or reflect refunding of a single experiment), and some may not have involved humans. Therefore, the "more than 2,000" reflects a very rough estimate adjusted for these considerations.
49. Paul C. Aebersold, address before Rocky Mountain Radiological Society, 9 August 1951 ("The United States Atomic Energy Program: Part I-Overall Progress") (ACHRE No. TEX- 101294- A- 1), 6.
50. By 1955 the program was receiving 8,000 applications a year, including hundreds from abroad. A July 1955 Aebersold summary of accomplishments pronounced that, as a result of the program, there were now 1 00 companies in the radiation instrument business, two dozen suppliers of commercially labeled compounds, pharmaceutical companies, hundreds of isotope specialists, a half-dozen waste disposal firms, and ten safety monitoring companies. Also, 2,693 U.S. institutions had received isotope authorization, including 1,126 industrial firms, 1,019 hospitals and private physicians, 220 colleges and universities, 244 federal and state laboratories, and 47 foundations. "Capsule Summary of Isotopes Distribution Program," July 1955 (ACHRE No. TEX- 101294-A-2).
5 1 . Vannevar Bush, Pieces of the Action (New York: William Morrow and Company, 1970), 65.
52. Ibid.
53. In addition to direct grants to private institutions the AEC pioneered the creation of research consortia. In 1946, for example, the University of Tennessee and a consortium of southeastern universities urged the Manhattan Project to establish the Oak Ridge Institute of Nuclear Studies (ORINS). Following the creation of the AEC, ORINS operated under AEC contract to train researchers and to operate a clinical research facility focused on cancer. In 1966 ORINS became known by the name of its operating contractor, the Oak Ridge Associated Universities, and the research facility is now known as the Oak Ridge Institute for Science and Education (ORISE).
54. Donald C. Swain, "The Rise of a Research Empire: NIH, 1930 to 1950," Science 138, no. 3546 (14 December 1962): 1235. The National Institutes of Health began as the Laboratory of Hygiene in 1887. It was renamed the National Institutes of Health in 1948.
55. Assistant Director, Office of Extramural Research, National Institutes of Health, to Anna Mastroianni, Advisory Committee, 16 July 1995 ("Comments on Draft Chapters of ACHRE Final Report").
73
56. Interview with Shields Warren, 10-1 1 October 1972, 78.
57. Robert S. Stone, M.D., to Lieutenant Colonel H. L. Friedell, U.S. Engineer Corps, Manhattan District, 9 August 1945 ("In reading through the releases . . .") (ACHRE No. DOE-121494-D-2).
58. Robert S. Stone, M.D., to Lieutenant Colonel H. L. Friedell, U.S. Engineer Corps, Manhattan District, 9 August 1945 ("As you and many others are aware, a great many of the people . . .") (ACHRE No. DOE-121494-D-1).
59. Jonathan M. Weisgall, Operation Crossroads: The Atomic Tests at Bikini Atoll (Annapolis, Md.: Naval Institute Press, 1994). For a contemporary account by a doctor who served as a radiation monitor, see David Bradley, No Place to Hide (Boston: Little, Brown and Co., 1948).
60. Weisgall, Operation Crossroads, 266-270.
61. "History of the U.S. Naval Radiological Defense Laboratory, 1946-58" (ACHRE No. DOD-071494-A-1), 1.
62. The Joint Panel was the child of the Committee on Medical Science and Committee on Atomic Energy (hence the term Joint), both of which, in turn, were committees of the Defense Department's Research and Development Board. That board served as the secretary of defense-level coordinator of departmentwide R&D.
63. The Committee has assembled the charter, agenda, reports, and available minutes of the Joint Panel. ACHRE Research Collection Series, Library File, Compilation of the Minutes of the Joint Panel on Medical Aspects of Atomic Warfare, 1948-1953(1994).
64. Howard Andrews, interview by Gilbert Whittemore (ACHRE staff), transcript of audio recording, 3 December 1994 (ACHRE Reseach Project, Interview Series, Targeted Interview Project).
65. In a February 1950 paper, the Public Health Service explained its role in national defense:
During and since WW II, science and technology have introduced new weapons and whole new industries whose effects on human health have not been precisely determined and effective methods against these hazards have not yet been developed.
If, for example, an atomic bomb were to burst over a large city in this country, tens of thousands of burned and injured people could not be given effective treatment because science has not yet found the practical means. . . . The operation of atomic piles and related facilities also presents a variety of problems as to human tolerance of radiation and the disposition of radioactive substances.
"The U.S. Public Health Service and National Defense," February 1950 (ACHRE No.
HHS-071394-A-2), 1.
66. National Institutes of Health, 2 August 1952 ("Assumptions Underlying NIH Defense Planning") (ACHRE No. HHS-071394-A-1).
67. Advisory Committee for Biology and Medicine, transcript (partial) of proceedings of 10 November 1950 (ACHRE No. DOE-012795-C-1). While the document is undated, discussion of the meeting appears in the November 1950 ACBM
74
minutes (12); a letter from Alan Gregg, Chairman, ACBM, to Gordon Dean, Chairman, AEC, 30 November 1950 ("The Advisory Committee for Biology and Medicine held their twenty-fourth . . .") (ACHRE No. DOE-072694-A); and a letter from Marion W. Boyer, AEC General Manager, to Honorable Robert LeBaron, Chairman, Military Liaison Committee, 10 January 1951 ("As you know, one of the important problems . . .") (ACHRE No. DOE-040395-A-1).
68. Behrens, transcript, proceedings of 10 November 1950, 2.
69. Powell, transcript, proceedings of 10 November 1950, 8-10.
70. Cooney, transcript, proceedings of 10 November 1950, 6.
71. Ibid., 7.
72. Ibid., 6.
73. Ibid., 7-8.
74. Warren, transcript, proceedings of 10 November 1950, 13.
75. Ibid., 14.
76. Ibid., 15.
77. Cooney, transcript, proceedings of 10 November 1950, 15.
78. Ibid., 16.
79. "Notes on the Meeting of a Committee to Consider the Feasibility and Conditions for a Preliminary Radiological Safety Shot for Operation 'Windsquall,'" 2 1 - 22 May 1951 (ACHRE No. DOE-030195-A-1), 41.
80. Ibid., 40.
81. Ibid., 19.
82. T. L. Shipman, Health Division Leader, to Alvin Graves, J-Division Leader, 27 December 1951 ("Summary Report Rad Safe and Health Activities at Buster- Jangle") (ACHRE No. DOE-033195-B-1).
83. [AEC] Board of Review to the Atomic Energy Commission, 20 June 1947 ("Report of the Board of Review") (ACHRE No. DOE-071494-A-4), 10.
84. NEPA Medical Advisory Panel, Subcommittee No. IX, "An Evaluation of Psychological Problem of Crew Selection Relative to the Special Hazards of Irradiation Exposure," 22 July 1949 (ACHRE No. DOD-121494-A-2), 20.
85. Ibid., 27.
86. Ibid., 22.
87. Definition of "curie," The Compact Edition of the Oxford English Dictionaiy (Oxford, England: Oxford University Press, 1971), 3937.
88. J. Newell Stannard, Radioactivity and Health: A History (Oak Ridge, Tenn.: Office of Scientific and Technical Information, 1988), 9.
89. Hanson Blatz, ed., Radiation Hygiene Handbook (New York: McGraw-Hill Book Co., 1959), 6-185.
90. Richard G. Hewlett and Oscar E. Anderson, The New World: A Histo>y of the Atomic Energy Commission, Vol. I: 1939-1946 (Berkeley: University of California Press, 1990), reprint of 1962 edition, 107-108.
91. Eric Hall, Radiobiology for the Radiologist, 4th ed. (Philadelphia: J. B. Lippincott, 1994), 3.
92. Ibid., 5.
93. The DNA strand would be about 5 centimeters (cm) long; the average cell diameter is about 20 microns (0.002 cm). Bruce Alberts et al., eds., Molecular Biology of the Cell (New York: Garland, 1983), 385-388.
94. Hall, Radiobiology for the Radiologist, 4th ed., 9-10.
75
95.
Ibid.
96.
Ibid.,
30.
97.
Ibid.,
32-33.
98.
Ibid.,
312.
99.
Ibid.,
324.
100
. Ibid
101. International Commission on Radiological Protection, Recommendations: ICRP Publication No. 60 (New York: Pergamon Press, 1991), cited in Hall, Radiobiology for the Radiologist, 4th ed., 456.
102. Hall, Radiobiology for the Radiobiologist, 4th ed., 355.
103. Committee on the Biological Effects of Ionizing Radiation, National Research Council, Health Effects of Exposure to Low Levels of Ionizing Radiation: BEIR V (Washington, D.C.: National Academy Press, 1990), 2-4.
104. International Commission on Radiological Protection, Recommendations: ICRP Publication No. 60, quoted in Hall, Radiobiology for the Radiologist, 4th ed., 455.
105. ". . . roentgen equivalent man, or mammal (rem). The dose of any ionizing radiation that will produce the same biological effect as that produced by one roentgen of high-voltage x-radiation." Blatz, ed., Radiation Hygiene Handbook, 2-19.
106. Hall, Radiobiology for the Radiobiologist, 4th ed., 458.
107. These include the National Council on Radiation Protection and Measurement (NCRP), the International Commission on Radiation Protection (ICRP), the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), the Committee on the Biological Effects of Ionizing Radiation (BEIR) of the National Research Council, and the Environmental Protection Agency (EPA).
108. In addition, there have been a number of studies of people exposed to low levels of radiation, including military personnel and residents subject to fallout from nuclear weapons testing, workers at and residents near nuclear facilities, patients given diagnostic x rays, and regions with high natural background radiation. Most of these either have not produced convincing positive results or are unsuitable for risk assessment because of the statistical instability of their estimates.
109. Some indirect estimates have been based on "case control" studies, in which diseased cases are compared with unaffected controls to look for differences in their past exposures that could account for their different outcomes.
General reference works include D. G. Kleinbaum, W. Kupper, and H. Morgenstern, Epidemiologic Research: Principles and Quantitative Methods (Belmont, Calif.: Lifetime Learning Publications, 1982), and J. D. Boice, Jr., and J. E. Fraumeni, Jr., Radiation Carcinogenesis: Epidemiology and Biological Significance (New York: Raven Press, 1984).
110. Dr. Shirley Fry to Bill LeFurgy, 31 August 1995 ("HRE Draft Final Report"), 8, contained in Ellyn Weiss, Special Counsel and Director, Office of Human Radiation Experiments, DOE, to Anna Mastroianni, ACHRE, 1 1 September 1995.
111. "[T]he NTPR dose data are not suitable for dose-response analysis." Institute of Medicine, "A Review of the Dosimetry Data Available in the Nuclear Test Personnel Review (NTPR) Program, An Interim Letter Report of the Committee to Study the Mortality of Military Personnel Present at Atmospheric Tests of Nuclear Weapons to the Defense Nuclear Agency" (Washington, D.C.: Institute of Medicine, May 15, 1995), 2.
76
1 12. Committee on the Biological Effects of Ionizing Radiation, National Research Council, Health Effects of Exposure to Low Levels of Ionizing Radiation: BEIR V (Washington, D.C.: National Academy Press, 1990), 22, 162.
77
Part I
ETHICS OF HUMAN SUBJECTS
RESEARCH: A HISTORICAL
PERSPECTIVE
PartI Overview
W hen the Advisory Committee began work in April 1994 we were charged with determining whether "the [radiation] experiments' design and administration adequately met the ethical and scientific standards, including standards of informed consent, that prevailed at the time of the experiments and that exist today" and also to "determine the ethical and scientific standards and criteria by which it shall evaluate human radiation experiments."
Although this charge seems straightforward, it is in fact difficult to determine what the appropriate standards should be for evaluating the conduct and policies of thirty or fifty years ago. First, we needed to determine the extent to which the standards of that time are similar to the standards of today. To the extent that there were differences we needed to determine the relative roles of each in making moral evaluations.
In chapter 1 we report what we have been able to reconstruct about government rules and policies in the 1940s and 1950s regarding human experiments. We focus primarily on the Atomic Energy Commission and the Department of Defense, because their history with respect to human subjects research policy is less well known than that of the Department of Health, Education, and Welfare (now the Department of Health and Human Services). Drawing on records that were previously obscure, or only recently declassified, we reveal the perhaps surprising finding that officials and experts in the highest reaches of the AEC and DOD discussed requirements for human experiments in the first years of the Cold War. We also briefly discuss the research policies of DHEW and the Veterans Administration during these years.
In chapter 2 we turn from a consideration of government standards to an exploration of the norms and practices of physicians and medical scientists who conducted research with human subjects during this period. We include here an
81
Part I
analysis of the significance of the Nuremberg Code, which arose out of the international war crimes trial of German physicians in 1947. Using the results of our Ethics Oral History Project, and other sources, we also examine how scientists of the time viewed their moral responsibilities to human subjects as well as how this translated into the manner in which they conducted their research. Of particular interest are the differences in professional norms and practices between research in which patients are used as subjects and research involving so-called healthy volunteers.
In chapter 3 we return to the question of government standards, focusing now on the 1960s and 1970s. In the first part of this chapter, we review the well- documented developments that influenced and led up to two landmark events in the history of government policy on research involving human subjects: the promulgation by DHEW of comprehensive regulations for oversight of human subjects research and passage by Congress of the National Research Act. In the latter part of the chapter we, review developments and policies governing human research in agencies other than DHEW, a history that has received comparatively little scholarly attention. We also discuss scandals in human research conducted by the DOD and the CIA that came to light in the 1970s and that influenced subsequent agency policies.
With the historical context established in chapters 1 through 3, we turn in chapter 4 to the core of our charge. Here we put forward and defend three kinds of ethical standards for evaluating human radiation experiments conducted from 1944 to 1974. We embed these standards in a moral framework intended to clarify and facilitate the difficult task of making judgments about the past.
82
Government Standards for
Human Experiments:
The 1940s and 1950s
W hen the Advisory Committee began its work, a central task was the reconstruction of the federal government's rules and policies on human experiments from 1944 through 1974. The history of research rules at the Department of Health, Education, and Welfare (DHEW) was well known, at least from 1953 on, when DHEW's National Institutes of Health (NIH) adopted a policy on human subjects research for its newly opened research hospital, the Clinical Center. In the 1960s, the DHEW and some other executive branch agencies undertook regulation of research involving human subjects. These were early steps of a process that culminated, in 1991, in the comprehensive federal policy known as the "Common Rule."' The historical background of this process, including a well-publicized series of incidents and scandals that motivated it, was also widely known and much discussed (see chapter 3).2
By contrast to DHEW, much less was known about the history of research rules for other agencies also involved in research with human subjects during this period, including the Department of Defense (DOD), the Atomic Energy Commission (AEC), and the Veterans Administration (VA). From the perspective of the charge to the Advisory Committee, these agencies were at least as important as DHEW. It was known that in 1953 the secretary of defense issued, in Top Secret, a memorandum on human subjects based on the Nuremberg Code.3 In 1947 an international tribunal had declared the Nuremberg Code the standard by which a group of doctors in Nazi Germany should be judged for their
83
Parti
horrific wartime experiments on concentration camp inmates. However, the actual impact of the Nuremberg Code on the biomedical community in the United States, both inside and outside of government, is a matter of some disagreement (see chapter 2). The general view was that, despite some developments in the 1940s and 1950s, there was little activity within the federal government on issues of human subjects research before the 1960s.
But while scholars have known of the 1953 secretary of defense memorandum, which was declassified in 1975, other relevant Department of Defense documents remained classified or had lain buried in archives. Moreover, relevant records of the Atomic Energy Commission were largely unexplored and in some cases still classified. These records are important because, from its creation in 1947, the AEC distributed radioisotopes that would be used in thousands of human radiation experiments, and it was a funding source for many other experiments (see Introduction). Along with the DOD, also created in 1 947, the AEC was searching for biomedical information needed to understand the effects of radiation as it prepared for the possibility of atomic warfare. Although the AEC was thus the catalyst for a considerable amount of human experimentation after World War II, there has been literally no scholarship on the AEC's position on the use of human beings in radiation-related research.
Now that previously obscure, even classified, records are being made public, it appears that in the first years of the Cold War, officials and experts in the AEC and DOD did discuss the requirements for human experiments. In this chapter we tell what we have learned about those discussions.
We begin by telling the story of the AEC general manager's early declarations on human research, which included a requirement that consent be obtained from patient-subjects. This story requires a careful look at a series of letters and memorandums exchanged in the late 1940s. Together these documents paint a clearly important but nonetheless confusing picture of a new agency's attempts to come to grips with the complexities of human experimentation. We consider not only what these documents say, but what we can piece together about what they meant in the context of the times. Central questions include the precise scope of the activities covered by the requirements and whether and how these 1 947 statements were communicated and put into effect in the AEC's burgeoning contract research and radioisotope distribution programs.
We turn next to the Department of Defense, where we trace the history of rules on the use of healthy "normal volunteer" subjects in military research from the time of Walter Reed through the secretary of defense's 1953 memorandum, and beyond. This memorandum is the earliest known instance in which a federal agency that sponsored human experiments adopted the Nuremberg Code. What is known about how the memorandum was interpreted and implemented by the military establishment takes up much of the rest of this chapter. Here, as in the case of the AEC, key questions concern the scope of the activities covered by requirements and the extent to which they were put into effect.
84
Chapter 1
Finally, we briefly discuss how research involving human subjects was addressed at the National Institutes of Health and the Veterans Administration in the 1950s. The evolution of policies governing human research at DHEW has been well documented and is only summarized here.4 We now know that NIH's 1953 policy was not the earliest federal requirement that consent be obtained from patients as well as healthy subjects. However, in contrast with the 1940s declarations by the AEC, it was a far more visible statement issued by an agency that was emerging as the leading sponsor of human subjects research. In contrast with what is known about NIH, the extent to which there were research rules at the VA in the 1940s and 1950s remains unclear.
A recurring theme in this chapter is the uncertainty about the significance within government agencies of many of the official statements that are discussed. While these statements emanated from high and responsible officials and committees, often they cannot be linked to fuller expressions of commitment by the agencies. Some of these statements were not widely disseminated, and there were no implementing guidelines or regulations and no sanctions for failures to abide by them. Thus, it is sometimes unclear what formal, legal significance these statements had. We are no less interested, however, in what these statements can tell us about how government officials and advisers saw human research at the time and how they understood the obligations surrounding it.
THE ATOMIC ENERGY COMMISSION: A REQUIREMENT FOR "CONSENT" IS DECLARED AT THE CREATION
Even before the AEC came into existence on January 1, 1947, Manhattan Project researchers and officials had begun to lay the groundwork for the expansion of the government's support of biomedical radiation research conducted under federal contract. By the time the AEC began operations, the parallel program to distribute federally produced radioisotopes to research institutions throughout the country was already well under way.
The planning for these undertakings required both reflection on high-level matters of policy and attention to matters of small but critical legal and bureaucratic detail. Both legal rules and administrative processes were uncharted. For example, who would be responsible if things went awry and subjects were injured? When could the government tell private doctors or researchers how to conduct treatment or research? The need for rules seemed obvious, but the particular rules that would be arrived at were not.
In April 1947 and again in November, Carroll Wilson, the general manager of the new agency, wrote letters first to Stafford Warren and then to Robert Stone, both of whom played prominent roles in Manhattan Project medical research, Warren as medical director, and Stone as a key member of the Chicago branch of the project. In these letters, Wilson maintained that "clinical testing" with patients could go forward only where there was a prospect that the patient
85
Part I
could benefit medically and only after that patient had been informed about the testing and there was documentation that the patient had consented. What was the origin of this position, and what was its reach? It appears that these letters were the products of an agency that was not only seeking to devise rules for new programs but also was trying to glean lessons from the experience with the secret research that had been conducted during the Manhattan Project. In the course of setting rules for the future, the AEC and its research community had to confront whether and how to proceed with human experimentation in the face of human experiments, including plutonium injections, conducted under the auspices of the Manhattan Project, experiments that were conducted in secret and that had the potential for both negative public reaction and litigation.
The First Wilson Letter
General Manager Wilson's first 1947 letter on human research, dated April 30, was, at least in part, a straightforward effort to define the rules according to which the AEC would provide contractors with research funding. The need for such rules had been discussed by the AEC's Interim Medical Advisory Committee, chaired by Stafford Warren, in January 1 947 when it met to consider whether "clinical testing" should be part of the AEC contract research program. The report of the meeting records projects involving human subjects at the University of Rochester and the University of California at Berkeley, and perhaps others.5 In a January 30 letter to General Manager Wilson, Stafford Warren reported the committee's conclusion that in the study of health hazards and the use of fissionable and radioactive materials, "final investigations by clinical testing of these materials" would be needed. Warren therefore requested that the AEC legal department determine the "financial and legal responsibility" of the AEC when such "clinical investigations" are carried out under AEC-approved and -financed programs.6 (The term experiment was not used, and the precise meaning of clinical testing is not clear.)
A month later, in early March, Warren met with Major Birchard M. Brundage, chief of the AEC's Medical Division, and two AEC lawyers to consider the terms for the resumption of "clinical testing." In a memorandum for the record, the lawyers summarized the meeting. In the case of "clinical testing" the lawyers
expressed the view that it was most important that it be susceptible of proof that any individual patient, prior to treatment, was in an understanding state of mind and that the nature of the treatment and possible risk involved be explained very clearly and that the patient express his willingness to receive the treatment.7
86
Chapter 1
Initially, the lawyers had proposed that researchers obtain a "written release" from patients. However, "on Dr. Warren's recommendation," the lawyers agreed that it would be sufficient if "at least two doctors certify in writing to the patient's state of mind to the explanation furnished him and to the acceptance of
the treatment.""
In his April 30 letter to Stafford Warren, Wilson announced that the AEC had approved Warren's committee's recommendations for a "program for obtaining medical data of interest to the Commission in the course of treatment of patients, which may involve clinical testing."9 Wilson's letter spelled out ground rules that were agreed upon. The commission understood that "treatment (which may involve clinical testing) will be administered to a patient only when there is expectation that it may have therapeutic effect." In addition, the commission adopted the requirement for documentation of consent agreed upon in Warren's meeting with the lawyers:
[I]t should be susceptible of proof from official records that, prior to treatment, each individual patient, being in an understanding state of mind, was clearly informed of the nature of the treatment and its possible effects, and expressed his willingness to receive the treatment.10
The commission deferred to Warren's request that written releases from the patient not be required. However,
it does request that in every case at least two doctors should certify in writing (made part of an official record) to the patient's understanding state of mind, to the explanation furnished him, and to his willingness to accept the treatment."
Carroll Wilson's April letter was sent to Stafford Warren as head of the Interim Medical Advisory Committee, which was responsible for advising the AEC on its contract research program, and forwarded to Major Brundage at the Oak Ridge office.12 Stafford Warren was at this point dean of the medical school at the University of California at Los Angeles, one of the dozen research institutions involved in the AEC contract research program. With one exception the Advisory Committee on Human Radiation Experiments did not locate documentation that the letter or its contents were communicated to any other research institutions involved with the AEC's contract research program. The exception is the University of California at San Francisco, where there is indirect evidence that someone at that institution had been apprised of Wilson's April letter. Of the eighteen plutonium injections, only the last one, that involving
87
Parti
Elmer Allen, or "CAL-3," took place after the April letter. In Mr. Allen's medical chart, there is a notation signed by two physicians indicating that the "experimental nature" of the procedure was explained and that the patient "agreed."13 Although the note in Mr. Allen's chart suggests an effort on the part of the researchers to comply with Wilson's April letter, the researchers did not comply with the other provision of the Wilson letter, that "treatment (which may involve clinical testing) will be administered to a patient only when there is expectation that it may have therapeutic effect."14 As is discussed in more detail in chapter 5, there was no expectation at the time that Mr. Allen would benefit medically from an injection of plutonium.15
The Second Wilson Letter
The context of the second Wilson letter, as well as its precise terms, further indicates that the April 1947 letter was given little distribution and effect. In the fall of 1947, the AEC laboratory at Oak Ridge requested advice from Carroll Wilson's office on the rules for experiments involving human subjects. Just as the AEC's Washington headquarters had embarked on the funding of a new research program, Oak Ridge was also in the midst of considering the rules governing the expansion of its own medical research program and the distribution of isotopes, which was then headquartered at Oak Ridge. In September 1 947, the manager of Oak Ridge Operations wrote to Wilson, asking, "What responsibilities does the AEC bear for human administration of isotopes (a) by private physicians and medical institutions outside the Project, and (b) by physicians within the project. . . What are the criteria for future human use?"16
Two weeks later. Oak Ridge sent a memorandum to the Advisory Committee for Biology and Medicine (ACBM). The ACBM had succeeded both Stafford Warren's Interim Medical Advisory Committee and the Medical Board of Review, a group appointed by AEC Chairman David Lilienthal to review the AEC's medical program. The memorandum emphasized the need for "medico- legal criteria" for "future human tracer research" because some of that research would be "of no immediate therapeutic value to the patient." The memorandum outlined the pros and cons of "tracer studies":
Pro-
( 1 ) Tracer research is fundamental to toxicity studies.
(2) The adequacy of the health protection which we afford our present employees may in a large measure depend upon information obtained using tracer techniques.
(3) New and improved medical applications can
88
Chapter 1
only be developed through careful experimentation and clinical trial.
(4) Tracer techniques are inherent in the radioisotope distribution program.
Con-
(1) Moral, ethical and medico-legal objections to the administration of radioactive material without the patient's knowledge or consent.
(2) There is perhaps a greater responsibility if a federal agency condones human guinea pig experimentation.
(3) Publication of such researches in some instances will compromise the best interests of the Atomic Energy Commission.
(4) Publication of experiments done by Atomic Energy Commission contractor's personnel may frequently be the source of litigation and be prejudicial to the proper functioning of the Atomic Energy Commission Insurance Branch.17
The questions raised by Oak Ridge were discussed by the ACBM at its October 11, 1947, meeting, which decided to give the "matter more study."18 The minutes of the October 1 1 meeting record that "human experimentation" was then discussed in the context of a request by Dr. Robert Stone to release "classified papers containing certain information on human experimentation with radioisotopes conducted within the AEC research program."19 The request was part of a continuing effort by Stone and other scientists to obtain permission to publish the research, including the plutonium experiments, that they had conducted in secret during the Manhattan Project. Earlier in 1947, the AEC had reversed a decision to declassify a report on the plutonium injections, citing the potential for public embarrassment and legal liability (see chapter 5). The question of what to do with these requests continued to fester.
The minutes explain that the "problem" raised by Stone had been dealt with by Chairman Lilienthal's Medical Board of Review in June. In a cryptic statement, the minutes record the ACBM's agreement that papers on human experiments "should remain classified unless the stipulated conditions laid down by the Board of Review were complied with."20
The "stipulated conditions" referred to are contained in General Manager
89
Part I
Wilson's November 5, 1947, letter to Stone. According to Wilson's letter, at a June meeting the Medical Board of Review concluded that "the matter of human experimentation" would remain classified where certain "conditions" were not satisfied. Wilson then quoted from the "preliminary unpublished and restricted draft of the [Medical Board] report read to the Commissioners" as follows:
The atmosphere of secrecy and suppression makes one aspect of the medical work of the Commission especially vulnerable to criticism. We therefore wish to record our approval of the position taken by the medical staff of the AEC in point of their studies of the substances dangerous to human life. We [the Medical Board of Review] believe that no substances known to be, or suspected of being, poisonous or harmful should be given to human beings unless all of the following conditions are fully met: (a) that a reasonable hope exists that the administration of such a substance will improve the condition of the patient, (b) that the patient give his complete and informed consent in writing, and (c) that the responsible next of kin give in writing a similarly complete and informed consent, revocable at any time during the course of such treatment [emphasis added].21
In other words, the opinion of the Medical Board of Review was presented by Wilson in his November letter as both a prescription for the future conduct of human experiments and a presentation of the criteria that must be met for the declassification of past research. Wilson again referenced these conditions in a letter to ACBM Chairman Alan Gregg, also on November 5. "I am sure," Wilson wrote Gregg, "that this information will assist Dr. Stone in evaluating the present problem and inform him as to the conditions that must be met in future experiments."22 Thus, as discussed in more detail in chapters 5 and 13, the requirement that research proceed only with consent appears to have been coupled with the decision to withhold from the public information about experiments that failed to meet that standard.
Two points should be made about the term informed consent, which appears in the November letter from Wilson to Stone. First, it is not clear what meaning Wilson and the members of the Medical Board of Review attributed to the term. No further explanation was given. Second, it is nevertheless a matter of some historical interest that this term is used at all. Previous scholarship had attributed its first official usage to a landmark legal opinion in a medical malpractice case that was issued a decade later.23-
90
Chapter 1
The April and November 1947 Wilson letters have some common elements, in spite of their differences in detail. They both provided that research with humans proceed (1) only where there is reasonable hope of therapeutic effect; and (2) with documentary proof that the patient-subject was informed of the treatment and its possible effects and had consented to its administration.
But there are many remaining mysteries about the AEC's 1947 statements. In interviews with Advisory Committee staff, Joseph Volpe, who served as an AEC attorney in its early days and became general counsel in 1949, explained that a letter authored by General Manager Wilson could state AEC policy and confidently recollected that informed consent from research subjects would have been required by the first AEC general counsel. This requirement, Volpe maintained, should be reflected in the commission's minutes.24 However, Committee and DOE review of the commission's minutes did not reveal evidence that the "consent" policy was expressly addressed.
Even more troubling is that both Wilson letters precluded research that did not offer patient-subjects a prospect of direct medical benefit. In the context of the concern about the plutonium injections and the other "nontherapeutic" research conducted during the Manhattan Project experiments, this provision readily makes sense. Yet, as Oak Ridge's inquiry to Washington noted, nontherapeutic research in the form of tracer studies had been, and would continue to be, a mainstay of AEC-sponsored isotope research. How could it be that the Wilson letters were intended to ban exactly the kind of research that at the same time the AEC was so actively promoting? It is conceivable that the requirement of the isotope distribution program for risk review prior to the human use of radioisotopes was a means of addressing this notion. However, if the equation between that risk review procedure and the provision in the November Wilson letter seems implicit, the documentary evidence does not provide an express link between the requirement stated in the Wilson letter and the rules of the isotope distribution program.
From Statements to Policy: A Failure of Translation
Despite the fact that they were developed in response to a need for clarity in the way that human research should be conducted, we have found little evidence of efforts to communicate or implement the rules stated by Wilson in coordination with the AEC's biomedical advisory groups and other AEC officials. In some cases the evidence described in the following paragraphs suggests that policies for consent from subjects were established and implemented, while in other cases it suggests that, if there were any such policies, they were unknown or lost. Taken together, however, this evidence further supports the view that the ideas present in General Manager Wilson's 1947 statements were available to those working in the field during this time, albeit perhaps in a primitive form.
Consider, for example, a 1951 exchange between the AEC's Division of
91
Parti
Biology and Medicine (DBM), which directed the AEC's medical research program, and the commission's Los Alamos Laboratory, which was in routine contact with Washington. An information officer at Los Alamos, Leslie Redman, who was charged to review papers that involved human experimentation, asked the DBM for a "definite AEC policy" on "human experimentation." In the course of his work, Redman wrote, he had been advised by "various persons" at Los Alamos that "regulations or policies of the AEC" on human experimentation were available, but he had been unable to locate more than general information about these regulations. According to his letter, his understanding was that
these regulations are comparable to those of the American Medical Association: that an experiment be performed under the supervision of an M.D., with the permission of the patient, and for the purpose of seeking a cure.25
Redman's characterization of the American Medical Association's guidelines, as we shall see in chapter 2, is partly incorrect. The requirement of a therapeutic intent is absent from the AM A guidelines. The possibility of direct therapeutic benefit for the patient was, however, a condition of research according to both of General Manager Wilson's 1947 letters.
Shields Warren, the DBM chief, responded to Redman by citing Wilson's November 5, 1947, letter to Stone and by excerpting the conditions quoted above.26 But Warren did not term these conditions "standards" or "requirements." Rather, Warren's response to Los Alamos "urges" compliance with these "guiding principles."27
Though Los Alamos was provided with the criteria stated by Wilson in November 1947, General Manager Wilson's statements were not routinely communicated in response to requests for guidance from non-AEC researchers. In an April 1948 letter to the DBM, a university researcher explained that the Isotopes Division had approved his request to use phosphorus 32 for "experimental procedures in the human . . . simply for investigational purposes and not for treatment of disease." What, the researcher wanted to know, should be done about "medical-legal aspects" and "permission forms"?28 The request could have been answered by referring to Wilson's 1 947 statements about consent. Instead, the DBM simply referred the researcher to the Isotopes Division at Oak Ridge.29 In its response, the Isotopes Division did not indicate that consent should be solicited, as Wilson had stipulated. The Isotopes Division, stating it could be "of little assistance," declined to provide "legal advice," save to note that "we understand that most hospitals do require patients to sign general releases before entering into treatment."30
From 1947 onward, the AEC had ample opportunity to disseminate a research policy. The AEC routinely provided educational and administrative
92
Chapter 1
materials to applicants for AEC funding and to the far greater number of ZlTcan s foTAEC-produced radioisotopes. The isotopes distribution program, np Sat included a sophisticated structure of regulation, repkte with ; review oSmttees, training courses, and informational brochures (see chapter -t ) At the federal level this included the Subcommittee on Human Applications of the Cotmi ^ilitopc Distribution, whose very purpose was "to review all initial « for radioisotopes to be used experimentally or otherwise in human beings remohasis added]."31 The AEC Subcommittee on Human Applications was supplemented by similar committees at the research institutions where the work
WaS C°fnUpCnnciple, there does not seem to be any reason these local committees could not have been instructed by the Isotopes Division on consent eautemenL- Some evidence suggests that in March 1948 the Subcommittee on Human Applications discussed consent requirements for healthy subjects and "Sheets. In a document dated March 29, 1948, the Subcommittee on Human Applications appeared to resolve that
1 Radioactive materials should be used in experiments involving human subjects when information obtained will have diagnostic value, therapeutic significance, or will contribute to knowledge on radiation protection.
2. Radioactive materials may be used in normal human subjects provided
a. The subject has full knowledge of the act and has given his consent to the procedure.
b. Animal studies have established the assimilation, distribution, selective localization and excretion of the radioisotope or derivative in question.
3. Radioactive materials may be used in patients suffering from diseased conditions of such nature that there is no reasonable probability of the radioactivity employed producing manifest injury provided:
a. Animal studies have established the assimilation, distribution, selective
93
Part I
localization and excretion of the radioisotope or derivative in question.
b. The subject is of sound mind, has full knowledge of the act and has given his consent to the procedure. . . .
4. Investigations are approved ( 1 ) by medical director or his equivalent at the installation responsible for the investigation, (2) by the Director, Division of Biology and Medicine, and (3) full written descriptions of experimental procedures and calculated estimates of radiation to be received by body structure and organs must be submitted.31
We were unable to locate any further references to this document and do not know whether it represented a policy that was adopted. Perhaps it represents the consensus of the Subcommittee on Human Applications, as it had met shortly before that, or perhaps it is simply a draft document prepared by staff.
Whatever the ultimate disposition of this document, it provides some idea of the problems that were under consideration at the time and indicates that views on human use were unsettled. The first numbered item, for example, appears to recommend human radiation experiments when they will offer diagnostic value and therapeutic significance or knowledge about radiation protection. If the document had in fact been adopted, the recognition that isotope experimentation could be undertaken to "contribute to knowledge" (item 1) would appear to revise the Wilson letters' prohibition of nontherapeutic experimentation. The third item also addresses consent and risk of injury to patient-subjects without indicating that there should be any potential benefit. Another peculiarity is found in the second item, which refers to consent from normal human subjects but does not rule out experiments that present risk to the subject.
In any event, at a 1948 meeting the Subcommittee on Human Applications articulated a consent requirement as part of a decision to permit patients suffering from serious diseases to receive "larger doses for investigative purposes."34 This requirement was disseminated to all radioisotope purchasers in 1949.35 The subcommittee allowed investigators to administer "larger doses" to seriously ill patients but only with the patient's consent. While it is possible that the basis for permitting larger doses was an assumption that smaller ones would be of no potential benefit to subjects, item 3 of the just-quoted March 1948 document suggests the assumption was rather that in seriously ill patients other disease processes would be more likely to take their course before radiation injury was manifested.
94
Chapter 1
There is evidence that at least one AEC-funded entity did routinely provide some form of disclosure and consent in the early 1950s. From its opening in 1950 the AEC-sponsored Oak Ridge Institute for Nuclear Studies (ORINS), a research hospital, advised incoming patients that procedures were experimental. Additionally, patients were given written information that advised them that "probable benefit, if any, cannot always be predicted in advance."36 Patients were also asked to sign a form that indicated that they were "fully advised" about the "character and kind of treatment and care," which would be "for the most part experiments with no definite promise of improvement in my physical condition."37 Thus, at least in the case of ORINS, and perhaps at other AEC facilities, a local process was instituted apart from any known communication of the statements by AEC officials.
Nonetheless, there is other evidence that the AEC did not communicate the requirements detailed in General Manager Wilson's 1 947 letters to its own contract research organizations, which, as in the cases of Argonne, Los Alamos, Brookhaven, and Oak Ridge, ;had significant biomedical programs and were engaged in human research. When the Division of Biological and Medical Research at Argonne National Laboratory met in January 1951 to discuss beginning a program of human experimentation in cancer research, one of its members asserted that the ACBM had not established a "general policy concerning human experimentation." The minutes of the meeting at Argonne record that the ACBM "has been approached several times in the past for a general policy and has refused to formulate one."38
In 1956, Los Alamos asked the DBM to "restate its position on the experimental use of human volunteer subjects" for tracer experiments.39 The DBM responded by stating that tracer doses might be administered under certain conditions, which included the provision that subjects be volunteers who were fully informed. The focus of this position seems to have been research with healthy people and not patients, and no reference was made to the provisions of the Wilson letters.40 The DBM's 1956 formulation was given "staff distribution" by Los Alamos and restated in 1962.4'
Also in 1956, the Isotopes Division did state a requirement for healthy subjects. All subjects were to be informed volunteers. As part of its "Recommendations and Requirements" guidebook for the medical uses of radioisotopes, which was distributed to all medical users of radioisotopes, the Isotopes Division stated:
Uses of radioisotopes in normal subjects for experimental purposes shall be limited to:
a. Tracer doses which do not exceed the permissible total body burden for the radioisotope
95
Part I
in question. In all instances the dose should be kept as low as possible.
b. Volunteers to whom the intent of the study and the effects of radiation have been outlined.
c. Volunteers who are unlikely to be exposed to significant additional amounts of radiation.42
These requirements apparently applied to all uses of AEC radioisotopes, whether government or private researchers were involved. The "experimental or nonroutine" use of radioisotopes in any human subjects was limited to institutional programs where local review committees existed to oversee the risk to which subjects were exposed. In stating these requirements, the AEC reiterated that "patients" in whom "there is no reasonable probability of producing manifest injury" may be used in some experiments not normally permitted, but did not reiterate the requirement that consent should be obtained from these patients, as was stated in 1948.
What, then, can be said about the rules and policies of the AEC in the 1940s and 1950s? General Manager Wilson's 1947 letters clearly stipulate a requirement of "informed consent" from patient-subjects, at least where potentially "poisonous or harmful" substances are involved. But with the exception of ORINS there is little indication that this requirement was imposed as binding policy on any AEC facility, contractor, or recipient of radioisotopes. By contrast, later requirements that healthy subjects be informed volunteers and that seriously ill patients be permitted to receive higher doses only with their consent appear to have been more broadly communicated and enforced. The only evidence of general attention to matters of consent from patient-subjects comes from ORINS, whose policies and practices show a striking similarity to those that, as we shall see, were being contemporaneously employed at another facility essentially devoted to experimental work, the NIH's Clinical Center. At the same time, there is evidence of considerable attention in both policy and practice to issues of safety and acceptable risk (see chapter 6). Questions of subject selection, as in the case of seriously ill patients, emerge only in this context of safety; there is no evidence that issues of fairness or concerns about exploitation in the selection of subjects figured in AEC policies or rules of the period.
THE DEPARTMENT OF DEFENSE: CONSENT IS FORMALIZED
The story of research involving human subjects in the U.S. military began at least a century ago. Well before 1944, the beginning of the period of special interest to the Advisory Committee, the military needed healthy subjects to test
96
Chapter 1
means to prevent and treat infectious diseases to which military personnel might be exposed. The notion that consent should be obtained from human subjects was clearly part of this tradition; less clear is how consistently this was applied and what consent actually meant to those in authority.
The most famous example of the early use of subject consent in the military took place at the turn of the century. Walter Reed's successful research on yellow fever, the mosquito-borne disease that bedeviled Panama Canal construction efforts, employed healthy subjects who signed forms indicating their agreement. Whether the practice was required by the Army or self-imposed by Reed is unknown. In 1925 an Army regulation to promote infectious disease research noted that "volunteers" should be used in "experimental" research.43
The Navy also provided early requirements for human subject research. In 1932, the secretary of the Navy granted permission for the conduct of an experiment involving divers on condition that the subjects were "informed volunteers."44 In 1943 the secretary of the Navy also required that all investigators seeking to conduct research with service personnel obtain prior approval from the secretary.45
As we have noted in the Introduction, during World War II, federally funded biomedical research related to the war effort (outside the Manhattan Project) was coordinated by the Committee on Medical Research (CMR) of the Office of Scientific Research and Development, which was part of the Executive Office of the President. The CMR supported a program of human research, during which the question of the rules for the conduct of human research was addressed. In 1942 a University of Rochester researcher, seeking to "work out a human experiment on the chemical prophylaxis of gonorrhea," asked the CMR for "an opinion that such human experimentation is desirable."46 In an October 9, 1942, response, the CMR's chairman offered the following general statement, which was endorsed by the full committee:
[HJuman experimentation is not only desirable, but necessary in the study of many of the problems of war medicine which confront us. When any risks are involved, volunteers only should be utilized as subjects, and these only after the risks have been fully explained and after signed statements have been obtained which shall prove that the volunteer offered his services with full knowledge and that claims for damage will be waived. An accurate record should be kept of the terms in which the risks involved were described.47
In spite of the CMR's statement in response to this researcher's query, it supported other experiments that involved subjects whose capacity to give valid consent to
97
Part I
participation was doubtful, including institutionalized people with cognitive disabilities.4*
During the war, the Navy used consent forms in wartime experiments using prisoners and conscientious objectors, as a proposal for research on an influenza vaccine with prisoners at San Quentin in 1943 shows.49 The form used in this case indicates that the subject is "acting freely and voluntarily without any coercion on the part of any person whomever."50 To be sure, the forms located by the Advisory Committee were called "waiver" or "release" rather than "consent" forms. Thus, the attestation to voluntary participation was punctuated by the release of experimenters from liability. However, at a time when free young men were routinely conscripted into the military, the requirement that subjects, including prisoners and conscientious objectors, must be volunteers seems remarkable.
In sharp contrast with these procedures, the Navy, too, sometimes functioned in a manner inconsistent with a voluntary consent policy for healthy subjects. Surviving subjects have reported that harmful mustard gas experiments on naval personnel at the Naval Research Laboratory in Washington, D.C., during World War II failed to adequately inform subjects and seem to have involved manipulation or coercion of "volunteers."51 The lack of medical follow-up on the subjects of these experiments was sharply criticized in a 1993 report by the Institute of Medicine of the National Academy of Sciences.52
The NEPA Debate on the Ethics of Prisoner Experiments
Many of the researchers and officials who had been involved in Manhattan Project human experiments during the war and then in the 1947 AEC deliberations about human research policy also were engaged in 1949 and 1950 in discussions of the ground rules for research with human subjects in the development of new military technology. This time the forum was the joint AEC- DOD project on Nuclear Energy for the Propulsion of Aircraft (NEPA). The DOD convened an advisory panel of private and public officials to determine how to obtain data needed to answer questions such as whether the air crew would be put at undue risk by the nuclear-powered engine. The participants in the discussion included university researchers Hymer Friedell, Stafford Warren, Robert Stone, and Joseph Hamilton, and AEC officials Shields Warren and Alan Gregg. Shields Warren argued that human experimentation was not appropriate because the research could be done on animals and human data was not likely to produce scientifically valid results (see Introduction).
Robert Stone, the recipient of the November 1947 letter in which AEC General Manager Wilson called for "informed consent," emerged as the primary proponent of human experiments. In a January 1950 discussion paper, he focused on the "ethics of human experimentation."53 After a recitation of a tradition that included Walter Reed's experience and the historical use of prisoners and medical
98
Chapter 1
students as research subjects, Stone cited requirements that had been publicized by the American Medical Association in 1946. These rules provided that subjects must give voluntary consent, that animal experimentation must precede human experimentation, and that human experiments should be "performed under proper medical protection and management."54 (See chapter 2.) Stone argued that it would be possible to conduct NEPA-related experiments with prisoners in compliance with all three of these requirements.
Stone's proposal generated considerable discussion among DOD and AEC experts and officials. In April 1950, the DOD's Joint Panel on the Medical Aspects of Atomic Warfare endorsed the use of prisoners of "true volunteer status" as meeting "the requirements of accepted American standards for the use of human subjects for research purposes."55
However, AEC officials were less than enthusiastic. "Doesn't the prisoner proposal," ACBM Chairman Alan Gregg asked a military official in the course of one discussion, "fall in the category of cruel and unusual punishment?"5 "Not,"
the official replied, "if they would carry out the work as they proposed It
would be on an absolutely voluntary basis, and under every safety precaution that could be built up around it ... it didn't strike me as being cruel and unusual." To which Shields Warren retorted: "It's not very long since we got through trying Germans for doing exactly the same thing."57
In December 1950 the AEC convened a panel to discuss what was known about potential radiation effects on service personnel and whether human research was needed. Joseph Hamilton, Robert Stone's colleague at the University of California, was unable to attend the meeting, and in his regrets he offered his thoughts on the matter. In a letter to Shields Warren, he noted that the proposal to use prisoner volunteers "would have a little of the Buchenwald touch" and reported that he had no "very constructive ideas as to where one would turn for such volunteers should this plan be put into effect."58 He suggested using large primates, even though, from a purely scientific viewpoint, the data collected would not be as useful as data from humans.59
Apparently Stone lost the debate. A decision was made not to conduct experiments with prisoners or other healthy subjects in connection with the NEPA project. However, as will be discussed in more detail in chapter 8, the military contracted with a private hospital to study patients who were being irradiated for cancer treatment, in the hopes of answering the same kinds of questions that would have been addressed if NEPA research with prisoners had gone forward.
Congress Provides for DOD Contractor Indemnification in the Case of Injury
In the aftermath of World War II, the military continued its long-standing program of infectious disease research using human subjects. During the late 1940s and early 1950s the Army Epidemiological Board (AEB) and its 1949
99
Parti
successor, the Armed Forces Epidemiological Board (AFEB), which was established to advise on medical research funded by the DOD and to direct some research undertaken with Army funds, sponsored studies with healthy subjects that focused on hepatitis, dengue fever, and other infectious diseases. Consistent with military tradition, at least some AEB-sponsored researchers were using written permission forms. The forms, frequently referred to as an "Agreement with Volunteer," or a "release," outlined the study and the risks to the subject and protected the DOD from liability.60
In the late 1 940s, some university researchers expressed concern that they were not adequately protected from liability in the case of injury or death of their prisoner-subjects. The ensuing dialogue provides a window on the role of the written releases and the understanding of the rules governing human subject research. In response to a researcher's request to be reimbursed by the Army for a disability policy for the subjects, the Army lawyers replied that the Army could not provide indemnification in the absence of clear congressional authority. Army legal advisers recommended that the researcher "protect himself, the State of New Jersey [the research locale], and the Government by means of the usual waiver."61
In a February 1948 letter, the AEB director, John R. Paul, explained that the "world situation" had placed the rules for human experimentation up for grabs.62
At this stage in the world situation one should proceed cautiously, until standards are set by what ever body is in 'authority.' I am not sure just what the rules are but I understand that . . . some type of vigilance committee has laid down certain principles about volunteers in order to protect this country from the criticisms brought up in Germany during the Nuremberg trials. . . . During the war we more or less made our own policies on this, but I am not sure that this is possible today. . . ,63
The allusion to a "vigilance committee" is unclear. It may be a reference to a committee established by the governor of Illinois to examine the use of prisoners as research subjects in that state and chaired by Andrew Ivy, the principal expert witness for the prosecution at the Nuremberg Medical Trial (see chapter 2). Given the date of the letter, February 18, 1948, it seems likely that Paul had just skimmed through his new copy of the Journal of the American Medical Association— the report of Ivy's committee was published in the February 14, 1948, issue.64
In April 1948, an AEB official made it plain to the researchers that the fact that state authorities or the prison warden gave permission for the experiment
100
Chapter 1
should be of little comfort to them. In case of a lawsuit, responsibility "would devolve entirely upon the individual experimenter."65 Only Congress could provide a solution, but it would be a "dangerous course" to raise the matter publicly. "I have," the AEB official wrote,
given considerable thought to the matter of whether it would be advisable to approach individuals or groups in Congress with the idea of having laws passed relating to payment of compensation for disability or release of the experimenter from liability. I am afraid that this would be a dangerous course, and that it might in fact injure clinical investigations generally. There is a very real possibility that unfavorable publicity would quickly result.66
It appears that the relief sought by researchers was provided by Congress in 1952, however, under the umbrella of a law that provided indemnification for DOD research and development activities as a whole. In October 1952, following the death of a prisoner-subject in an AFEB-sponsored hepatitis study67 and questions raised by the Army Chemical Corps about release forms for "human 'guinea pigs,'"68 the AFEB administrator queried the DOD Legal Office about a recently passed federal law. The law provided authority for the military to indemnify contractors for risks undertaken in "research and development situations." Did the new law "afford relief to the immediate dependents of
prison volunteers when as [a] result of these experiments they should die[?]"6 The answer was yes, but only by providing relief to the researchers first. "From the wording of the law, and from ... the legislative history," the Legal Office replied, "it is a direct indemnification to the contractor and not to the individual
human guinea pig."70
Thus, what appears to have been the first Cold War congressional enactment to deal with human subjects of research addressed the government's obligation to its contractors, not the government's and its researchers' obligations to the subjects. Moreover, the record indicates that a more direct approach was not sought by the DOD because of concerns about public relations. At the same time Congress was acting, however, the DOD itself was secretly debating a new policy for human experiments.
The Secretary of Defense Issues the Nuremberg Code in Top Secret
As the Korean War began in mid- 1950, the military's interest in human experimentation-in connection with chemical and biological as well as atomic and radiation warfare-intensified. The need for a DOD-wide policy on the use of
101
Part I
human subjects in research was noted by Colonel George Underwood, the director of the Office of the Secretary of Defense, in a February 1953 memorandum to the incoming administration of Dwight D. Eisenhower: "There is no DOD policy on the books which permits this type of research [human experiments in the field of atomic, biological, and chemical warfare]."71
From 1950 to 1953 discussions about human research and human research policy were held in several high-level DOD panels, including the Armed Forces Medical Policy Council (AFMPC), the Committee on Medical Sciences (CMS), and the Joint Panel on the Medical Aspects of Atomic Warfare. These groups were headed by civilian researchers, and, in at least the latter two cases, included representatives of the AEC, CIA, NIH, VA, and Public Health Service.
At its September 8, 1952, meeting, the AFMPC heard a presentation from the chief of preventive medicine of the Army Surgeon General's Office on the topic of biological warfare research:
It was pointed out that the research had reached a point beyond which essential data could not be obtained unless human volunteers were utilized for such experimentation. . . . Following detailed discussion, it was unanimously agreed that the use of human volunteers in this type of research be approved.72
At its October 13, 1952, meeting the AFMPC again took up the question of human experimentation. "It was resolved," the chairman wrote to the secretary of defense, "that the ten rules promulgated at the Nuremberg trials be adopted as the guiding principles to be followed. An eleventh rule [barring experiments with prisoners of war] was added by the legal advisor to the Council, Mr. Stephen S. Jackson."73
DOD attorney Jackson evidently was responsible for the inclusion of the Nuremberg Code in the AFMPC's proposed policy. In an October 13, 1952, memo to the chairman of the AFMPC, Jackson
recommended: that the attached principles and conditions for human experimentation, which were laid down by the Tribunal in the Nuremberg Trials, be adopted instead of those previously submitted by me.74
As an addendum to the Nuremberg Code, Jackson proposed a requirement that "consent be expressed in writing before at least one witness." This recommendation followed from the suggestion of Anna Rosenberg, assistant
102
Chapter 1
The Nuremberg Code
1. The voluntary consent of the human subject is absolutely essential.
This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. The latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rest upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.
2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.
3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment.
4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.
6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.
7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.
8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.
9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.
10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill, and careful judgment required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.
103
Parti
secretary of defense for manpower and personnel, who was an expert on labor relations.75
A letter written by the administrator of the Armed Forces Epidemiological Board documents Mr. Jackson's role and motivation:
It was on Mr. Jackson's insistence that the 'Nuremberg Principles' were used in toto in the document, since he stated, these already had international judicial sanction, and to modify them would open us to severe criticism along the line— "see they use only that which suits them."76
Thus, the DOD's counsel cited the 1947 Nuremberg military tribunal ruling as establishing an international legal precedent to which American researchers should be held.
It appears that in succeeding months the AFMPC proposal was received unenthusiastically by other DOD committees that reviewed it. In a November 12, 1952, memorandum, the executive director of the Committee on Medical Sciences pointed out that "human experimentation has been carried on for many years." He contended that
to issue a policy statement on human experimentation at this time would probably do the cause more harm than good; for such a statement would have to be "watered down" to suit the capabilities of the average investigator.77
"Human experimentation," the CMS executive director asserted, "has, in years past, and is at present governed by an unwritten code of ethics," which is "administered informally by fellow workers in the field [and] is considered to be satisfactory. ... To commit to writing a policy on human experimentation would focus unnecessary attention on the legal aspects of the subject."78
Notwithstanding the reservations of the CMS and others,79 the Nuremberg Code proposal had the support of President Truman's secretary of defense, Robert A. Lovett.80 However, the secretary's aide, George V. Underwood, wrote in January 1953, "Since consequences of this policy will fall upon Mr. Wilson [President Eisenhower's nominee for secretary of defense, Charles Wilson], it might be wise to pass to him as a unanimous recommendation from the 'alumni.'"81
In a January 13, 1953, memorandum for the new secretary, the AFMPC "strongly recommended that a policy be established for the use of human volunteers (military and civilian employees) in experimental research at Armed
104
Chapter 1
Forces facilities." The policy would render the research "subject to the principles and conditions laid down as a result of the Nuremberg trials."82
The Wilson Memorandum
26 Feb 1953
Memorandum for the Secretary of the Army
Secretary of the Navy Secretary of the Air Force
Subject: Use of Human Volunteers in Experimental Research
1. Based upon a recommendation of the Armed Forces Medical Policy Council, that human subjects be employed, under recognized safeguards, as the only feasible means for realistic evaluation and/or development of effective preventive measures of defense against atomic, biological or chemical agents, the policy set forth below will govern the use of human volunteers by the Department of Defense in experimental research in the fields of atomic, biological and/or chemical warfare.
2. By reason of the basic medical responsibility in connection with the development of defense of all types against atomic, biological and/or chemical warfare agents. Armed Services personnel and/or civilians on duty at installations engaged in such research shall be permitted to actively participate in all phases of the program, such participation shall be subject to the following conditions:
a. The voluntary consent of the human subject is absolutely essential.
( 1 ) This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element offeree, fraud, deceit, duress, over- reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment.
(2) The concept [sic] of the human subject shall be in writing; his signature shall be affixed to a written instrument setting forth substantially the aforementioned requirements and shall be signed in the presence of at least one witness who shall attest to such signature in writing.
105
Parti
(a) In experiments where personnel from more than one Service are involved the Secretary of the Service which is exercising primary responsibility for conducting the experiment is designated to prepare such an instrument and coordinate it for use by all the Services having human volunteers involved in the experiment. (3) The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.
b. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.
c. The number of volunteers used shall be kept at a minimum consistent with item b., above.
d. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment.
e. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
f. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur.
g. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.
h. Proper preparation should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.
i. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.
j. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.
k. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.
1. The established policy, which prohibits the use of prisoners of war in human experimentation, is continued and they will not be used under any circumstances. 3. The Secretaries of the Army, Navy and Air Force are authorized to conduct experiments in connection with the development of defenses of all types against atomic, biological and/or chemical warfare agents involving the use of human subjects within the limits prescribed above.
106
Chapter 1
4. In each instance in which an experiment is proposed pursuant to this memorandum, the nature and purpose of the proposed experiment and the name of the person who will be in charge of such experiment shall be submitted for approval to the Secretary of the military department in which the proposed experiment is to be conducted. No such experiment shall be undertaken until such Secretary has approved in writing the experiment proposed, the person who will be in charge of conducting it, as well as informing the Secretary of Defense.
5. The addresses will be responsible for insuring compliance with the provisions of this memorandum within their respective Services.
/signed/ C. E. Wilson copies furnished:
Joint Chiefs of Staff
Research and Development Board
Downgraded to UNCLASSIFIED 22 Aug 75 TOP SECRET
On February 26, 1953, Secretary of Defense Wilson signed off on the AFMPC policy. It was issued in a Top Secret memorandum to the secretaries of the Army, Navy, and Air Force. The Wilson memorandum reiterates the principles of the Nuremberg Code, requires written and witnessed informed consent of research subjects, and prohibits the use of prisoners of war. The policy was to "govern the use of human volunteers by the Department of Defense in experimental research in the fields of atomic, biological, and/or chemical warfare for defensive purposes."83
The basis for the classification of the 1953 memorandum is not clear. Since the memorandum dealt with atomic and other unconventional forms of warfare, its classification may have been routine. There is evidence that the DOD had a general desire to keep hidden from public view any indication that it was involved in biological and chemical warfare-related research; the Wilson memorandum, of course, was just such an indication. In September 1952, the Joint Chiefs of Staff advised the services to "[e]nsure, insofar as practicable, that all published articles stemming from BW [biological warfare] and CW [chemical warfare] research and development programs are disassociated from anything which might connect them with U.S. military endeavor."84
In one sense the memorandum is a landmark in its official recognition of the Nuremberg Code, but in another sense it also generates important questions. Having determined to recognize international principles of human rights, why, or how, could the secretary have limited their application to some, but not all, human
107
Parti
experiments? Why was the policy directed exclusively to experiments related to "atomic, biological, and chemical warfare"? Moreover, was the policy intended to govern such research wherever it was conducted; for example, when it was performed by private contractors, as well as by intramural researchers? How was a directive issued in secret implemented?
Communicating the 1953 Wilson Memorandum
That there were problems in the dissemination of Secretary Wilson's Top Secret memorandum is evidenced in a memorandum containing queries by officials of the Armed Forces Special Weapons Project (AFSWP), within a year of the Wilson memorandum's issuance. The AFSWP, now the Defense Nuclear Agency (DNA), was at the hub of DOD nuclear weapons research. In the course of a routine review of research reports, an AFSWP official learned that "volunteers were injured as a consequence of taking part in [a] field experiment" of flashblindness conducted at an atomic bomb test before the Wilson memorandum was issued (see chapter 10). The AFSWP reviewer immediately concluded that a "definite need exists for guidance in the use of human volunteers as experimental subjects."85
On further inquiry, the AFSWP reviewer found that a policy already existed, but had not been disseminated to investigators. A follow-up memorandum, evidently written in early 1954, records:
In November 53 it was learned that there existed a T/S [Top Secret] document signed by the Secretary of Defense which listed various requirements and criteria which had to be met by individuals contemplating the use of human volunteers in Bio- medical or other types of experimentation. ... It was learned that although this document details very definite and specific steps which must be taken before volunteers may be used in experimentation, no serious attempt has been made to disseminate the information to those experimenters who have a definite need-to-know.86
"The lowest level at which it had been circulated," the AFSWP reviewer learned, "was that of the three Secretaries of the Services." Efforts by an assistant secretary to "downgrade" the document had "not been able to obtain concurrence." The reviewer hoped that "this letter shall point up the need for some relaxation of the grip in which this document is now held, at least on a definite need-to-know basis."87 (The application of the Wilson memorandum to further experiments conducted at atomic bomb tests is discussed in chapter 10.)
108
Chapter 1 Implementation in the Army
The Army did take substantial steps to put into effect the Wilson memorandum. In June 1953 the Army chief of staff, John C. Oakes, issued a memorandum implementing the secretary of defense's policy in toto. Referred to in the Army as CS:385, this memorandum was initially classified Top Secret, but was declassified the following year. In addition to the provisions of the Wilson memorandum, the Army document required the prior review and approval of both the surgeon general and the secretary of the Army. The Army's memorandum also contained legal analysis that explained the source of the Army's authority to perform human experiments in the first place and the limits that this authority put on the selection of subjects.81* Even in the midst of the Korean War, the Army did not view it as self-evident that the DOD could engage in human experiments or choose any subjects it wished. The memorandum explained that the authority to experiment on humans came from congressional enactments, including provisions for research and development.1*9
Interestingly, choice of subjects was to be governed by the Army's ability to ensure compensation in the case of death or disability.90 This could be provided, the lawyers declared, only upon express congressional action. In the case of military personnel and contractor employees there was such provision. But there was no such authority in the case of private citizens who offered their services. The Army lawyers recommended, and the CS:385 policy provided, that private citizens not employed by Army contractors could not serve as research subjects.91
On March 12, 1954, the Army Office of the Surgeon General (OSG) issued an unclassified statement entitled "Use of Human Volunteers in Medical Research: Principles, Policies, and Rules."92 This document too restated the Nuremberg principles. In contrast with the Wilson and Oakes memorandums, it was not restricted to research related to atomic, biological, or chemical warfare. Instead, the OSG statement was directed to "medical research" with human volunteers generally.93
Moreover, while CS:385 did not state directly whether it applied to contract researchers, the 1954 OSG statement was transmitted to at least some university researchers with the prefatory note, "To be used as far as applicable as a non-mandatory guide for planning and conducting contract research."94 There is evidence that the OSG's requirements were sometimes more than "non-mandatory guides." For example, in a June 27, 1956, letter to the the Armed Forces Epidemiological Board, a Tulane University public health researcher agreed that his vaccine experiments with prisoner subjects would be conducted only after written consent was obtained from the subjects.95 The Tulane researcher indicated that, with respect to his application for funding, "I have held it up since Dr. Dingle indicated I be familiar with the statement of the Office of the Surgeon General re the use of human volunteers I have read it and believe that our
109
Parti
past and future work have [sic] and will comply with the rules stipulated."96 Moreover, this researcher provided a written statement to supplement his original proposal that explained how the OSG requirements would be met. In another case, a proposal involving measles and normal children, an AFEB official advised the researcher to "take [the OSG policy] into consideration in writing the proposal."97
As discussed earlier, in 1952 the Army obtained congressional authority to indemnify contract researchers in the event that an experiment caused injury or death. There is evidence that the Army sought to link the grant of an indemnification clause (ASPR 7.203.22, "Insurance-Liability to Third Persons") to contractor acceptance of the principles stated by the Army surgeon general. In a March 1957 letter to the University of Pittsburgh, which was proposing to use medical student-volunteers in a (nonradiation) experiment, the Army told Pittsburgh that the provision of the clause was "contingent upon your adhering to the following [March 1954 Office of the Surgeon General] principles, policies, and rules for the use of human volunteers in performing subject medical research contracts."98
While the evidence clearly shows that Army officials sought to apply the Nuremberg Code policy to contractors, it did not meet with complete success, and the full extent of its efforts remains unclear. As we see in chapter 2, in the early 1960s Harvard successfully resisted the inclusion of the Nuremberg Code language in its medical research contracts with the Army. As we see in chapter 8, which discusses DOD funding of research on the effects of total-body irradiation, the indemnification language was included in at least some contracts in which the surgeon general's policy was not mentioned. By 1969, however, the policy may have become standard in Army contracts under the authority of the Medical Research and Development Command.99
There are several possible explanations for the seeming absence of widespread inclusion of the surgeon general's memo as a contractual requirement, at least where indemnification was provided for. First, as discussed below, it is possible that the 1954 policy was meant to apply to research with healthy subjects, and not sick patients. (However, even if that were generally the case, the provision of indemnification might be expected to have triggered reflection on this limitation.) Second, as a related matter, the evidence we are reviewing shows a tension between the government's declaration of a principle and its readiness to actively insist that the principle be honored within the privacy of the doctor- patient relationship.
Finally, Army imposition of the surgeon general's principles may also have depended on the nature of its interest in the research being done. An April 3, 1957, memo distinguished cases where the institution "because of its primary interest, would conduct the research even without support of the OSG," from cases where "the study is conducted at the insistence of OSG." In the former case the strategy would be to seek cost-sharing contracts, in which the institution
110
Chapter 1
would "assume all responsibility for any possible effects resulting from the experimentation." In the latter case, the indemnification clause would be provided, but the March 1954 policy would also be required and included in the contract directly or by reference. ino
It is not clear that the 1954 OSG policy on human volunteers was intended to apply to research with patients. The term volunteer is ambiguous but at the time was commonly used to refer to healthy subjects. Nonetheless, a 1 962 Army memorandum that declared that since World War II "by and large research has been conducted in strict accordance with the Nuremberg Code" mentions patients. I0' The memo reported that a recent survey of contract research found that the volunteers treated in accord with the Nuremberg Code included "3,000 students, 250 patients, and 300 prisoners." It is not known what kind of research these 250 patients were involved in, nor is it known what proportion of the patients who had been subjects of research supported or conducted by the Army since World War II were represented by these 250.
Unfortunately, the 1962 review's confident declaration that Army research complied with the Nuremberg Code was too sanguine. In 1975, following public revelations that the Army and the CIA had conducted LSD experiments on unwitting subjects, the Army inspector general reviewed the application of the June 1953 policy to drug testing. The inspector general's review led to the declassification of the 1953 Wilson memorandum. The inspector general found that the Army had, with one or two exceptions, used only "volunteers" for its drug-testing program. However, the "volunteers were not fully informed, as required, prior to their participation, and the methods of procuring their services in many cases appeared not to have been in accord with the intent of Department of the Army policies governing use of volunteers in research."102
Additional DOD Research Requirements
While the Navy is not known to have taken specific action in response to the 1953 Wilson memorandum, we have already noted that the Navy had long since provided for prior review and voluntary participation in some cases. The 1951 Navy "Manual of the Medical Department" required secretarial approval of human experimentation and the use of volunteers. These requirements applied to "experimental studies of a medical nature" involving "personnel of the Naval Establishment (military and civilian)."103 Participation was to be "on a voluntary basis only."104 The manual also mandated prior review for research with patient- subjects. "Clinical research," including "research projects and therapeutic trials," was to be "authorized by" the Bureau of Medicine and Surgery.105
At least for research with radioisotopes, the requirement for voluntary participation may have applied to patient-subjects as well as healthy subjects. In 1951 the Navy debated adoption of a permission form for the use of radioisotopes for patients at naval hospitals.106 This form, to be signed by either the patient or
111
Parti
the responsible next of kin, authorized the use of "tracer-therapeutic" doses "obtained from the Atomic Energy Commission for research purposes."107
Although it is not clear that the Army rules implementing the 1953 Wilson memorandum applied to patient-subjects, there is some evidence that consent forms that were usually used for surgical procedures were used in patient-related experimental settings involving radioisotopes. In 1955 an official from the Letterman Army Hospital in San Francisco asked the Walter Reed Hospital about the need for written "permission" forms for "test doses" of radioisotopes.108 In response, the Army indicated that a standard form used for operations and anesthesia should also be employed, at the physician's discretion, when "authorization for administration of radioisotope therapy is desired."109
In the Air Force, a 1952 regulation on clinical research mandated safety and administrative procedures for the use of humans in experiments at Air Force medical facilities."0 This regulation required prior group review but did not mention consent provisions or refer to the subjects as volunteers. In 1958 a letter from the Air Force's Air Research and Development Command describes the policy for the use of humans in "hazardous research and development tests." This policy reiterated the requirement for prior review discussed in the 1952 regulation. In this context, however, subjects were to be "volunteers]" who "understood] the degree of risk involved in the experiment.""1
What, then, were the operative rules in the Department of Defense for research involving human subjects in the 1940s and 1950s? By the mid-1950s, for the entire DOD for research related to atomic, biological, and chemical warfare, and for all research involving "human volunteers" in the Army, the formal rules were the ten principles of the Nuremberg Code and the additions included in the secretary of defense's 1953 policy. According to the 1975 testimony of the surgeon general of the Army before the U.S. Senate and the internal review conducted by the Army inspector general, these principles were Army "policy.""2 At the same time, as the inspector general reported in 1975 and as we discuss further in chapter 10, these requirements were not always known or followed. While there were attempts to implement the Army surgeon general's 1954 policy, it is not known how the policy's provisions, including the requirement to obtain voluntary consent, were interpreted. The Navy's 1951 requirements for prior review and voluntariness applied to all research involving Navy personnel.
The extent to which research rules applied to patient-subjects in the clinical setting is less clear. There is some indication that in some cases standard consent forms, akin to the surgical permits in use at the time, were employed with patients at military hospitals who were administered "test doses" of radioisotopes.
112
Chapter 1
THE NATIONAL INSTITUTES OF HEALTH AND THE VETERANS ADMINISTRATION
During the late 1940s and 1950s, the AEC and DOD were by no means the only agencies sponsoring research involving human subjects. The Department of Health, Education, and Welfare (DHEW), through two of its components, the Public Health Service and the NIH, was emerging during this period as the dominant government agency sponsoring human biomedical research. The Veterans Administration (VA) as well conducted a large medical research program that involved the use of radioisotopes in numerous human experiments.
In the early 1950s NIH participated in some of the discussions preceding the issuance of the 1953 secretary of defense memorandum. At the request of a DOD official for information on NIH's approach to the use of human subjects, NIH responded with an April 1952 letter that included a draft statement on the "Ethical Principles Underlying Investigations Involving Human Beings." Among its other provisions, the April 28, 1952, draft states that
[t]he person who is competent to give consent to an investigative procedure must do so. He must have legal capacity to give consent and be able to exercise free choice, without the intervention of any element of force, fraud, deceit, duress, constraint or coercion. He must have sufficient knowledge and comprehension of the nature of the investigation to enable him to make an understanding and enlightened decision. He must therefore be told the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; the inconveniences and hazards reasonably to be expected; and the effects upon his health or person which can reasonably be expected to come from his participation in the investigation. He should understand, furthermore, that by his participation he becomes a co-investigator with the physician."3
Although it is not known what became of this draft statement, around this time NIH had good reason to develop a policy on the use of human subjects. In 1953 NIH opened the Clinical Center, a state-of-the-science research hospital. The center adopted a policy requiring "voluntary agreement based on informed understanding" from all research subjects and written consent from some patient- subjects involved in research that the physician believed to be unusually hazardous."4 Written consent was required from all healthy, "normal" subjects of research beginning in 1954."5 Additionally, NIH began a system of group review of proposed research that became a model for today's institutional review boards
113
Part I
(IRBs)."6 Thus, the NIH policy appears to be the first instance of a single policy that expressly provides for consent from all subjects, be they healthy or sick. Even so, the policy was still limited to research at the Clinical Center and did not apply to the considerable amount of NIH-funded research being undertaken by grantees (extramural research).
The question of whether "patients," as well as healthy, "normal" volunteers, should give written consent arose in the development of the NIH policy. Legal counsel at NIH advised that, "from a legal point of view," there should be a "written statement . . . indicating the patient's awareness of the nature of the particular investigation in which he was to participate and acceptance of any particular inconvenience or risk inherent in his participation.""7 A signed form offered the best proof that a "policy" of "informed consent" was followed for all subjects enrolled in studies at the center.
The NIH attorney wrote that while the Clinical Center's Medical Advisory Board did not disagree with the principle, it did disagree with the need for a written statement:
[0]f the members that expressed their views, and most did so, all rejected such a proposal. The rejection was due, as I understand it, not to any particular detail but rather a more basic objection to written, as opposed to oral, statements. There was apparently, therefore, no objection to providing the patient with enough information to permit him to exercise an informed choice of participation or refusal as long as not reduced to writing for his signature."8
Nonetheless, the principle that all research subjects, including healthy subjects in the "normal volunteer" program and patient-subjects, should make an informed choice seems to be acknowledged in the Medical Advisory Board's position.
The NIH Clinical Center approach adopted by the mid-1950s-written consent from healthy subjects and from only certain patient-subjects— persisted through the early 1960s and was paralleled in policies of the DOD and the AEC. The view that written consent from patients might unnecessarily interfere with doctor-patient relationships prevailed.
Within the NIH, dialogue continued throughout the 1950s, setting the stage for the leading role DHEW was to take in formulating human research regulations in the 1960s (see chapter 3)."9
Although the NIH was by far the dominant agency in research involving human subjects, a significant amount of radioisotope research occurred at the VA. The VA research program employing radioisotopes at VA medical centers began in 1948.120 This program was limited to VA hospitals affiliated with medical
114
Chapter 1
schools. From its inception, this program involved a system of prior group review by local radioisotope committees, normally composed of non-VA-affiliated teaching staff of the affiliated medical school.121 These committees reviewed all research proposals and approved all research conducted at VA radioisotope units.
In its formative years, the advisers to the new VA program included Stafford Warren, Shields Warren, and others who were likely to be familiar with the consent principles articulated by the AEC. Nonetheless, the earliest evidence of a consent policy at the VA comes in the form of a 1958 general counsel's opinion on whether the VA could participate in certain research. The general counsel asserted that
persons who participate [in human subject research] must voluntarily consent to the experiment on themselves. Such consent must rest upon an understanding of the hazards involved. The volunteer may withdraw from the experiment at any time. Moreover, before the experiment, steps to reduce the hazard, as for example, indicated research on animals, must be made.122
This opinion was written in response to two proposed research projects, and it is not known if it was implemented in the projects or applied to others.
CONCLUSION
Records now available show that at the highest reaches of Cold War bureaucracies officials discussed conditions under which human experimentation could take place. These discussions took place earlier and in greater, although by today's standards uncritical and less searching, detail than might have been assumed. Nonetheless, the stated positions that resulted were often developed in isolation from one another, were neither uniform nor comprehensive in their coverage, and were often limited in their effectuation. Several interrelated factors seem to have been prominent in causing these discussions to take place and in determining the scope of the requirements that were declared and the efforts that were undertaken to implement them. We summarize these key factors below.
Administrative and Legal Circumstance
The creation of new programs, or the qualitative expansion of old ones, impelled officials, lawyers, and researchers to reflect on the rules to govern them. While these rules were sometimes cast as "legal" or "financial" requirements, they often included provisions, such as a requirement for written consent, that appear similar to statements in requirements that govern the conduct of research today.
115
Parti
The language used to describe these rules was often that of law or administration, such as "waiver" or "release" forms, or it may have had particular meaning to researchers at the time, such as "clinical testing." As a result, it is often hard to compare these rules to current requirements, which have benefited from intervening decades of linguistic and conceptual refinement.
Professional Cultures
Differing professions brought their own tools and perspectives to discussions of conditions under which human subjects research could proceed. For example, lawyers were likely to insist on obtaining documented evidence of patient consent, while medical professionals emphasized the importance of the trust that underlay the relationship between doctor and patient; they sometimes objected to the use and implications of written consent forms.
If consent procedures were a source of disagreement, the need to minimize risk to subjects was not. In creating and administering the AEC's radioisotope distribution program, physician investigators and other researchers placed a premium on controlling and minimizing risk in the "human use" of radioisotopes. This emphasis on the establishment of administrative and educational procedures to control risk, the details of which are discussed in chapter 6, embodied an essential principle of ethical research.
The requirement for prior review included in the isotope distribution program was, as we have seen, also present elsewhere. Even before 1944, approval of the secretary of the Navy was required for research with human subjects. The secretary of the Army required prior approval of research related to atomic, biological, and chemical warfare in 1953. In the Air Force, secretarial approval of human experiments was codified in 1952. At NIH, prior group review was employed as a policy from 1953 on. The VA, whose program developed under the eye of AEC experts and advisers, relied on local isotope committees.
The Nature of the Subjects
While voluntary consent was acknowledged as a condition of human research by some government agencies well before 1944, it was not as broadly applied as it is today. Requirements of voluntary consent were asserted most clearly and consistently where the subjects were healthy. As a practical matter, healthy subjects are not likely to participate in experiments without specific request, and as a legal matter the invasion of a person's body in the absence of a prior relationship that might justify it has long been unacceptable. Still more important, the arbitrary use of people in experiments is incompatible with respect for human dignity.
116
Chapter 1
The use of patients in medical research appeared in a different historical context from that of healthy subjects, and the agencies appear to have responded accordingly. From the perspective of the medical profession, the age-old tradition of the doctor-patient relationship, as we shall see in the next chapter, provided a justification for research with the potential to benefit patients, but not, of course, for healthy subjects who were not under medical care. There is little evidence that the agencies questioned whether research with patients that did not offer a prospect of benefit warranted a different response. An exception is the position articulated by the AEC's general manager in 1947, which made the possibility of benefit to the patient-subject a condition of permissible research, at least where the research involved "poisonous or harmful" substances. However, there is little indication that this provision was ever implemented.
The period we reviewed in this chapter led to considerable public disquiet about the use of healthy subjects and about the use of ill and institutionalized people in research from which they could not possibly benefit. It was this disquiet, in the wake of several well-publicized incidents, that formed the basis of the mid-1960s reforms of federal policy governing research with human subjects (see chapter 3). The focus on the way that patient-subjects were used in clinical research that offered some prospect of benefit, and particularly on consent issues, came much later. The latter discussion is one that continues today, as is evident from the Advisory Committee's work on current research regulation that is described in part III.
The Degree of Risk
To the extent that there was discussion in the 1940s and the 1950s of consent for patient-subjects, it seemed to arise mainly in circumstances in which those who were ill would be put at unusual risk from the research.
As we have seen, the AEC's radioisotope distribution division concluded that consent was required where patients were being subjected to "larger doses for investigative purposes" that apparently posed unusually hazardous or unknown risks. Similarly, from its establishment at midcentury, the AEC's hospital at Oak Ridge, which focused on new and potentially risky experimental cancer treatment, did have routine requirements for consent. Likewise, from its 1953 birth, the NIH's Clinical Center established a policy that recognized that patient choice was important for all kinds of research with patients, and written consent was required when an experiment involved' an unusual hazard.
Formal Policies and Public Morality
It is important not to get lost in the details of the various documents we have cited in this chapter. What is most significant about the discussions that took place in federal agencies from the mid- 1940s through the 1950s is the fact
117
Part I
that so many of the ideas and values with which we are familiar were apparent then. That does not mean that the same words were used or that when they were used they had the same meaning as they do for us today. But it does mean that there were certainly more or less rough ideas about voluntary consent and minimization of risk. As we have seen in this chapter, these ideas were very much in play in the culture of the time.
118
ENDNOTES
1. The "Common Rule" applies requirements for voluntary consent, prior review, and risk analysis to all federally sponsored research. This rule is discussed in chapter 14.
2. David Rothman, Strangers at the Bedside: A History of How Law and Bioethics Transformed Medical Decision Making (New York: Basic Books, 1991), and Ruth Faden and Tom Beauchamp, A History and Theoiy of Informed Consent (New York: Oxford University Press, 1986).
3. George J. Annas and Michael A. Grodin, eds.. The Nazi Doctors and the Nuremberg Code; Human Rights in Human Experimentation (New York: Oxford University Press, 1992). 343-345.
4. See Faden and Beauchamp, A Histoiy and Theory of Informed Consent, and Mark S. Frankel, "Public Policymaking for Biomedical Research: The Case of Human Experimentation" (Ph.D. diss., George Washington University, 9 May 1976).
5. Stafford L. Warren, Chairman, Interim Medical Advisory Board ("Report of the 23-24 January 1947 Meeting of the Interim Medical Committee of the United States Atomic Energy Commission") (ACHRE No. UCLA-1 1 1094-A-26). The report summarized "specific projects" at twelve institutions. The projects at the University of Rochester included "Study of the Metabolism of Plutonium, polonium, radium, etc. in human subjects" (p. 8). In the case of Berkeley, the projects identified to Dr. Stone were
(1 ) Studies in whole-body radiation of human subjects by external and internal radiation.
(2) Studies on the metabolism of radioactive iodine in animals and man.
(3) Joint studies with Dr. Joseph G. Hamilton to evaluate the therapeutic applications '
of the fission products and the fissionable elements.
(4) Exploration and therapeutic application of other radioactive elements and compounds (p. 1 1).
A 14 March 1947 memorandum from Austin Brues, director of the Biology Division of the Argonne National Laboratory, records that "clinical testing programs" had only been authorized, at least for the time being, at Berkeley and Rochester. However, Brues urged that Argonne also be included. On behalf of this request he cited the University of Chicago's "work using human subjects" with specific reference to a report on plutonium injections. He further noted that human subject work also included the Argonne project list provided at the January meeting. A. M. Brues, Director, Biology Division, to N. Hilberry, Associate Laboratory Director, 14 March 1947 ("Clinical Testing") (ACHRE No. DOE-050195-B).
6. Stafford Warren, Chairman, Interim Medical Advisory Committee, to Carroll Wilson, General Manager, AEC, 30 January 1947 ("The opinion on Clinical Testing . . .") (ACHRE No. DOE-051094-A-439), 1.
19
7. John L. Burling, Deputy General Counsel's Office, AEC, to Edwin Huddleson, Jr., Deputy General Counsel, AEC, 7 March 1947 ("Clinical Testing") (ACHRE No. DOE-051094-A-468), 2-3.
8. Ibid., 3.
9. Carroll L. Wilson, General Manager of the AEC, to Stafford Warren, the University of California at Los Angeles, 30 April 1947 ("This is to inform you that the Commission is going ahead with its plans . . .") (ACHRE No. DOE-051094-A-439), 2.
10. Ibid.
11. Ibid.
12. Robert J. Buettner, Assistant to Chairman, Interim Medical Advisory Committee, AEC, to B. M. Brundage, Chief, Medical Division, AEC, 12 May 1947 ("Transmitted herewith for your information . . .") (ACHRE No. DOE-05 1 094-A-439), 1.
13. Note in medical chart of Cal-3, dated 18 July 1947 ("Elmer Allen chart") (ACHRE No. DOE-05 1 094- A-6 1 5). For more information on this case, see chapter 5.
14. Wilson to Warren, 30 April 1947.
15. University of California at San Francisco, February 1995 ("Report of the UCSF Ad Hoc Fact Finding Committee ") (ACHRE No. UCSF-022495-A-6), 27.
16. J. C. Franklin, Manager, Oak Ridge Operations, to Carroll Wilson, General Manager, AEC, 26 September 1947 ("Medical Policy") (ACHRE No. DOE-1 13094-B- 3), 2. Although the motivation for Oak Ridge's inquiry is not entirely clear, it seems to have come in part from concerns of Albert Holland, M.D., who became the acting medical adviser at Oak Ridge after Major Brundage retired. Holland served on the committee that oversaw the use of radioisotopes in human research, discussed in chapter 6. In November 1947 Holland wrote, in regard to the isotopes distribution program: "How far does the AEC's moral responsibility extend in this program?" Albert Holland, Jr., Medical Adviser, Oak Ridge, to J. C. Franklin, Manager of Oak Ridge Operations, 7 November 1947 ("Medical and Operational Decisions") (ACHRE No. DOE-1 13095-B- 10), 2.
1 7. Unknown author to the Advisory Committee for Biology and Medicine, 8 October 1947 ("It is the desire of the Medical Advisor's Office . . .") (ACHRE No. DOE- 05 1094-A-502).
18. Atomic Energy Commission, Advisory Committee for Biology and Medicine, minutes of 1 1 October 1947 (ACHRE No. DOE-072694-A-1), 10.
19. Ibid.
20. Ibid.
21 . Carroll Wilson, General Manager, AEC, to Robert Stone, University of California, 5 November 1947 ("Your letter of September 18 regarding the declassification of biological and medical papers was read at the October 1 1 meeting of the Advisory Committee for Biology and Medicine.") (ACHRE No. DOE-052295-A-1).
22. Carroll Wilson, General Manager, AEC, to Alan Gregg, Chairman of the AEC Advisory Committee for Biology and Medicine, 5 November 1947 ("I want to thank you for your letter of October 14 concerning the questions raised by Dr. Stone in his letter to me of September 18 regarding declassification of biological and medical papers containing information on the experimental use of radioisotopes in human beings conducted under AEC sponsorship.") (ACHRE No. DOE-052295-A-I).
23. Salgo v. Leland Stanford Jr. University Board of Trustees, 317 P. 2d 170 (1957).
120
24. Joseph Volpe, interview by Gregg Herken, Dan Guttman, and Debra Holland (ACHRE), transcript of audio recording, 6 October 1994 (ACHRE Research Project Series, Interview Program Files, Targeted Interview Project), 24-42.
In a May 1995 interview, Volpe agreed that a letter written by the general manager constituted a "policy." The transcript of the interview records:
Interviewer: . . . today there are regular procedures for getting
something recognized as a policy, including publication and so forth. In 1947, when the general manager writes a letter, is that a policy?
Mr. Volpe: Yes, Yes.
Mr. Volpe noted that while the question of the precise authority of the general manager was not without controversy. Chairman Lilienthal "believed in delegation of authority and so always took measures to strengthen the general manager's hand on these things." Joseph Volpe, interview by Barbara Berney, Steve Klaidman, Dan Guttman, Lanny Keller, Jonathan Moreno, Patrick Fitzgerald, and Gilbert Whittemore (ACHRE), transcript of audio recording, 18 May 1995 (ACHRE Research Project Series, Interview Program Files, Targeted Interview Project), 37-38.
25. Leslie M. Redman, Los Alamos Laboratory, to Dr. Alberto F. Thompson, Chief, Technical Information Service, DBM, 22 January 1951 ("I find myself concerned in the course of duty with the review of papers relating to human experimentation.") (ACHRE No. DOE-051094-A-609).
26. Warren did not cite the context for Wilson's discussion of these conditions, that is, the need for criteria for declassification.
27. Shields Warren, Director, DBM, to Leslie Redman, "D" Division, Los Alamos National Laboratory, 5 March 1951 (". . . to reply to your letter of January 22, 1951, concerning policies on human experimentation.") (ACHRE No. DOE-051094-A- 603).
28. Everett Idris Evans, M.D., Medical College of Virginia, to John Z. Bowers, M.D., Assistant to the Director, DBM, AEC, 8 April 1948 ("We have recently obtained approval from the Isotopes Division for human use of P32. . .") (ACHRE No. DOE- 051094-A-64).
29. John Z. Bowers, Assistant to Director, DBM, AEC, to Everett Idris Evans, M.D., Medical College of Virginia, 27 April 1948 ("Thank you for recent letter requesting information regarding isotopes.") (ACHRE No. DOE-050194-A-480).
30. Nathan H. Woodruff, Chief Technical Division, Isotopes Division, to Everett I. Evans, M.D., Medical College of Virginia, 14 May 1948 ("Your letter of April 8 to Dr. Bowers has been referred to me for answer.") (ACHRE No. NARA-082294-A-10).
3 1 . U.S. Atomic Energy Commission, Advisory Committee for Biology and Medicine, agenda of 14 February 1948 (ACHRE No. DOE-072694-A), 2.
32. In addition to the document discussed above, there is some indication that the AEC Isotopes Division was charged with ensuring that consent was obtained. In the early 1970s, when the AEC conducted an investigation into the plutonium experiments. Shields Warren told the investigators that his recollection was that ethical issues were addressed at the time by the issuance of prospective policies. Warren stated:
I think the way it [concern about the plutonium
121
injections] was handled was that Alan Gregg and 1 agreed the best way to do [it] was to see that the rules were properly drawn up by the . . . Human Applications Isotope Committee, which had then come into being, so that use without full safeguards could not occur, and that we saw no point in bringing this up after the fact as long as we were sure that nothing of this sort could happen in the future.
Shields Warren, interview by L. A. Miazga, Sidney Marks, Walter Weyzen (AEC), transcript of audio recording, 9 April 1974, 10-11 (ACHRE No. DOE-121294-D-14).
33. Unknown author, unpublished draft, 29 March 1948 ("The Experimental Use of Radioactive Materials in Human Subjects at AEC Establishments") (ACHRE No. DOE-050194-A-267).
34. Subcommittee on Human Applications, minutes of 22-23 March 1948, as discussed in the minutes of the 13 March 1949 meeting. S. Allan Lough, Chief, Radioisotopes Branch, to H. L. Friedell, G. Failla, J. G. Hamilton, and A. H. Holland, 19 July 1949 ("Revised Tentative Minutes of March 13, 1949 Meeting of the Subcommittee on Human Applications of Committee of U.S. Atomic Energy Commission, AEC Building, Washington, DC") (ACHRE No. DOE-101 194-A-13), 5.
35. The subcommittee was not definitive about when larger doses were permitted, however. The policy was to apply in "instances in which the disease from which a patient is suffering permits the administration of larger doses for investigative purposes." U.S. Atomic Energy Commission, Isotopes Division, September 1949 ("Supplement No. 1 to Catalogue and Price List No. 3, July 1949") (ACHRE No. DOD- 122794-A-l), 3-4.
36. While these statements were perhaps more than was told to patient-subjects in other institutions, they did not necessarily provide details about the research. In the application for admission, the applicant agreed to "such operations and biopsies as are deemed necessary and advisable by the hospital." Oak Ridge Institute of Nuclear Studies, 1950 ("Application for Admission to the Medical Division Hospital") (ACHRE No. DOE-121494-C-1), 1.
Upon admission, the applicant was required to sign a "Waiver and Release" that did not describe the treatment, but included a lengthy release from the patient, the patient's "heirs, executors, administrators, and assigns," for any "causes of action, claims, demands, damages, loss, costs, and expenses, whether direct or consequential," associated with or resulting from the care of the hospital. This form notes that the hospital has described the "character and kind of treatment." Oak Ridge Institute of Nuclear Studies, 1950 ("Waiver and Release") (ACHRE No. DOE-121494-C-3), 1.
37. Oak Ridge Institute for Nuclear Studies, 1950 ("Waiver and Release") (ACHRE No. DOE-121494-C-3).
38. Program Committee of the Division of Biological and Medical Research of the Argonne National Laboratory, minutes of 22 January 1951 (ACHRE No. DOE- 051095-B), 3.
39. Thomas Shipman, M.D., Health Division Leader, Los Alamos Laboratory, AEC, to Dr. Charles Dunham, Director, DBM, AEC, 18 June 1956 ("Two questions have recently arisen— one of them specific, the other general— wherein we need an opinion from you.") (ACHRE No. DOE-091994-B-1).
122
40. Charles Dunham, Director, DBM, AEC, to Thomas Shipman, Health Division Leader, Los Alamos Laboratory, 5 July 1956 ("This is in response to your letter of June 18.") (ACHRE No. DOE-091994-B-2). In addition to consent, Dunham indicated that the research should proceed so long as (a) the doses were small, "true tracer doses"; (b) the proposal was approved by a senior medical officer; and (c) the work was supervised by a licensed physician.
41. T. L. Shipman, Health Division Leader, Los Alamos Laboratory, to Staff Distribution, 12 July 1956 ("Administration of Tracer Doses to Humans") (ACHRE No. DOE-091994-B-3), 1. Also, T. L. Shipman, Health Division Leader, Los Alamos Laboratory, to "Distribution," 3 September 1963 ("Administration of Tracer Doses to Humans For Experimental Purposes") (ACHRE No. DOE-091994-B-4), 1.
42. Isotopes Extension, Division of Civilian Application, U.S. AEC, "The Medical Uses of Radioisotopes, Recommendations and Requirements of the Atomic Energy Commission" (Oak Ridge, Tenn.: AEC, Februaiy 1956), 15.
43. U.S. Department of the Army, AR 40-210, The Prevention of Communicable Diseases of Man— General (21 April 1925).
44. Charles W. Shilling, Medical Corps, USN. Retired, undated paper ("History of the Research Division, Bureau of Medicine and Surgery, USN") (ACHRE No. DOD- 080295-A), 74.
45. The Secretary of the Navy to All Ships and Stations, 7 April 1943 ("Unauthorized Medical Experimentation on Service Personnel") (ACHRE No. DOD- 091494-A-2).
46. J. E. Moore, M.D., to Dr. A. N. Richards, excerpt of letter dated 6 October 1942 ("I have recently received an inquiry from Dr. Charles M. Carpenter of the University of Rochester School of Medicine who believes that he may be able to work out a human experiment on the chemical prophylaxis of gonorrhea.") (ACHRE No. NARA-060794-A-1).
47. A. N. Richards to J. E. Moore, 31 October 1942 (" Revision of Dr. Richards' letter of October 9, 1942") (ACHRE No. NARA-060794-A-1 ). Stafford Warren, the Manhattan Project medical director, also came from the University of Rochester. It is not clear how, if at all, the CMR's views on human experiments were accounted for in Manhattan Project research.
48. Rothman, Strangers at the Bedside, 30-50.
49. The Chief of the Bureau of Medicine and Surgery to the Officer-in-Charge, Naval Laboratory Research Unit No. 1, University of California, Berkeley, California, 6 March 1943 ("Proposed Clinical Evaluation of Influenza Antiserum, and Messages concerning Influenza Virus Specimens") (ACHRE No. DOD-062194-C-1).
50. Ibid., 2.
51. Institute of Medicine, National Academy of Sciences, Veterans at Risk: The Health Effects of Mustard Gas and Lewisite (Washington, D.C.: National Academy Press, 1993), 66-69.
52. Ibid., 214.
53. Robert S. Stone, unpublished paper, "Irradiation of Human Subjects as a Medical Experiment," 31 January 1950 (ACHRE No. NARA-070794-A).
54. American Medical Association, Judicial Council, "Supplementary Report of the Judicial Council," Journal of the American Medical Association 132 (1946): 1090.
55. The Under Secretary of the Navy to the Secretary of Defense, 24 April 1950 ("Recommendation that the Armed Service conduct experiments on human subjects to
123
determine effects of radiation exposure") (ACHRE No. NARA-070794-A).
56. Atomic Energy Commission, Advisory Committee for Biology and Medicine, transcript (partial) of meeting, 10 November 1950 (ACHRE No. DOE-0 12795- C-l), 28.
57. Ibid., 28-29.
58. J. G. Hamilton, University of California, to Shields Warren, DBM, AEC, 28 November 1950 ("Unfortunately, it will not be possible for me to be at the meeting on December 8 . . .") (ACHRE No. DOE-072694-B-45), 1.
59. Ibid.
60. Adam J. Rapalski, Administrator, the Armed Forces Epidemiological Board, DOD, to Chief, Legal Office, 5 January 1952 ("Draft of 'Agreement with Volunteer'") (ACHRE No. DOD-040895-A).
61. Lieutenant Colonel Robert J. O'Connor, Chief, Legal Officer, JAGD, to Colonel Frank L. Baier, Army Medical Research and Development, 23 October 1947 ("Protection of Research Project Volunteers") (ACHRE No. NARA-012395-A-4).
62. John R. Paul, Director, AEB, DOD, to Dr. Joseph Stokes, Jr., Children's Hospital, Philadelphia, Pennsylvania, 18 February 1948 ("This is in reply to your hand written request for a comment [from] me re your letter to Dr. Macleod dated 1 1 February on the subject of funds for the reimbursement of volunteer prisoners . . .") (ACHRE No. NARA-012395-A-1).
63. Ibid.
64. Committee Appointed by Governor Dwight H. Green of Illinois, "Ethics Governing the Service of Prisoners As Subjects In Medical Experiments," Journal of the American Medical Association 136, no. 7 (1948): 457-458.
65. C. J. Watson, M.D., Commission on Liver Disease, Army Epidemiological Board, to Colin MacLeod, President of the Board, AEB, 5 April 1948 ("I have given considerations in the past few weeks to the matter of using volunteers in penal institutions for experimentation . . .") (ACHRE No. NARA-012395-A-2).
66. Ibid.
67. "Prisoner Dies After Injection in Disease Study," Washington Post, 6 May 1952,3.
68. L. M. Harff, Contract Insurance Branch, to File, 25 April 1952 ("Research and Development Contracts-Medical Investigations) (ACHRE No. DOD-012295-A).
69. Adam J. Rapalski, Administrator, AEB, to Chief Legal Office, 14 October 1952 ("Applicability of Section 5, Public Law 557-82d Congress") (ACHRE No. NARA- 012395-A).
70. Adam J. Rapalski, Administrator, AEB, to Members of the AEB, undated memorandum ("Applicability of Section 5, Public Law 557-82nd Congress") (ACHRE No. NARA-012395-A). In congressional hearings, the activities used to illustrate the purpose of the indemnification provision included test piloting, damage that might be caused by cloud modification research, and cataracts caused by the operation of a cyclotron. In addition, however, biomedical human experimentation was specifically addressed in the following exchange between Representative Edward Hebert and Colonel W. S. Triplet, from the Army Research and Development Division:
Mr. Hebert. Colonel, would you expand on the proposal to make the Government liable for losses and damages? . . .
124
Colonel Triplet. There have been some experiments or types of research in the past which would have come under section 5 [the indemnification provision]. There are more coming up in the future. One of the early cases, long before the time of the bill, I would cite as an example is Dr. Reed in Cuba in 1900 utilized the services of 21 volunteers to study yellow fever, an extremely dangerous experiment. Two of these volunteers died. Eighteen of the others became seriously ill. As a result a special medal was awarded these people by Congress. That is an example of the type of experiment that at the present time is going on in the medical service. Subcommittee Hearings on H. R. 1 1 80 to Facilitate the Performance of Research and Development Work by and on Behalf of the Departments of the Army, the Navy, and the Air Force, and for Other Purposes; House of Representatives, Committee on Armed Services, Subcommittee no. 3, 6 June 1952, 621 (ACHRE No. NARA-10495-D).
71. Colonel George V. Underwood, Director, Executive Office, Office of the Secretary of Defense, to Mr. Kyes, Deputy Secretary of Defense, 5 February 1953 ("Use of Human Volunteers in Experimental Research") (ACHRE No. DOD-062194-A).
72. Melvin Casberg, Chairman, AFMPC, to the Secretary of Defense, 24 December 1952 ("Human