BIOLOGICAL EFFECTIVENESS OF NEUTRONS Research Needs February 1994 Submitted to The Science Panel of the Committee on Interagency Radiation Research and Policy Coordination Prepared by G.W. Casarett, L.A. Braby, J.J. Broerse, MM. Elkind, D.T, Goodhead, and N.L. Oleinick ER CNSTFHBUTiON OF THIS DOCUMENT IS UNUMfTED DISCLAIMER This report was prepared as an account of work sponsored by an agency of the United States Government. Neither the United States Government nor any agency thereof, nor any of their employees, make any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights. Reference herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recommendation, or favoring by the United States Government or any agency thereof. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof. DISCLAIMER Portions of this document may be illegible in electronic image products. Images are produced from the best available original document. COMMITTEE ON INTERAGENCY RADIATION RESEARCH AND POLICY COORDINATION 1019 Nineteenth Street, NW, Suite 700 Washington, D.C 20036 May 31, 1994 Dr. Alvin L. Young Chairman, CIRRPC Office of Agricultural Biotechnology U.S. Department of Agriculture 14th and Independence Avenue, S.W. Washington, DC 20250-2200 Dear Dr. Young: As Chairman of the Science Panel of the Committee on Interagency Radiation Research and Policy Coordination (CIRRPC), I am pleased to provide you with the final report on the Biological Effectiveness of Neutrons: Research Needs. This report was written by an independent, multidisciplinary, knowledgeable task group of eminent scientists. It was prepared for the CIRRPC Science Panel in response to a request from the Department of Energy to provide a conceptual plan for a research program that would provide a basis for determining more precisely the biological effectiveness of neutron radiation with emphasis on endpoints relevant to the protection of human health. This request is consistent with the provision in CIRRPC's Charter that "...[the CIRRPC] Science Panel assist the Committee in preparing an appropriate research agenda on selected radiation issues..." The CIRRPC Science Panel and knowledgeable scientists from both the United States and European radiation research communities reviewed an earlier draft of the report. The task group carefully considered all of the specific comments received and incorporated such comments as were considered appropriate. Overall, the report received high marks for quality. The Science Panel was provided a prepublication copy of the final report to note any changes made as a result of the review. The Science Pane! considers this report an important contribution to science and recommends that it be made available to Federal agencies and other individuals and organizations interested in planning radiation research agendas. Sincerely, Randall S. Caswell, Ph.D. Chairman, CIRRPC Science Panel Enclosure: as stated in COMMITTEE ON INTERAGENCY RADIATION RESEARCH AND POLICY COORDINATION 1019 Nineteenth Street, NW, Suite 700 Washington, D.C. 20036 May 27, 1994 Dr. Randall S. Caswell Chairman, CIRRPC Science Panel U.S. Department of Commerce National Institute for Science and Technology Building 245, Room C-229 Gaithersburg, MD 20899 Dear Dr. Caswell: The Subpanel on High-LET Radiation is pleased to transmit the final report on the Biological Effectiveness of Neutrons: Research Needs, which was prepared by an international task group for the Science Panel of the Committee on Interagency Radiation Research and Policy Coordination. All of the task group members have concurred with forwarding the report to the Science Panel for publication so it can be used by the Federal agencies in planning their agenda in this particular area of radiation research. It has indeed been my pleasure to work with such a distinguished group of scientists in developing this important contribution to science. Sincerely, Bruce W. Wachholz, Ph.D. CIRRPC Science Subpanel on High-LET Radiation Enclosure: as stated v TASK GROUP ON RESEARCH NEEDS RELATED TO THE BIOLOGICAL EFFECTIVENESS OF NEUTRONS GEORGE W. CASARETT*, Ph.D., Chairman, University of Rochester Medical School, Rochester, New York LESLIE A. BRABY, Ph.D., Battelle Pacific Northwest Laboratory, Richland, Washington JOHANNES J. BROERSE, Ph.D., Institute of Applied Radiobiology and Immunology, TNO, Rijswijk, The Netherlands MORTIMER M. ELKIND, Ph.D., Department of Radiological Health Sciences, Colorado State University, Ft. Collins, Colorado DUDLEY T. GOODHEAD, Ph.D., Medical Research Council, Radiobiology Unit Harwell, Didcot, United Kingdom NANCY L. OLEINICK, Ph.D., Department of Radiology, Case Western Reserve University, Cleveland, Ohio ORAU Technical Liaison DIANE S. FLACK, M.S., Technical Advisor •Deceased vn DEDICATED TO DR. GEORGE W. CASARETT The task group dedicates this report to Dr. George W. Casarett, who served as Chairman of the group and a co-author until his death. This report is the last of over 200 publications and numerous other contributions Dr. Casarett made to the fields of radiation pathology, radiobiology, radiation carcinogenesis, risk analysis, and radiation protection. His expertise in radiobiology, especially in radiation pathology, was recognized by his membership in and appointment to numerous prestigious scientific committees and organizations, including the National Council on Radiation Protection and Measurements, the National Research Council/National Academy of Sciences' Committee on the Biological Effects of Ionizing Radiations, and the International Commission on Radiological Protection. His pursuit of scientific knowledge, dedication to teaching, professional relationships with his colleagues, and devotion to his family serve as examples for his colleagues and friends in both the radiobiology research and radiation protection communities, including those of us who were fortunate enough to have worked with him on the development of this report. IX ACKNOWLEDGMENTS The task group expresses its appreciation to the Committee on Interagency Radiation Research and Policy Coordination for supporting the development of this report on research needs related to the biological effectiveness of neutrons. Comments provided by representatives of the Federal agencies and non-Federal scientists on a draft of the report were invaluable in producing the final report. The Oak Ridge Associated Universities' Washington Office staff also deserves special acknowledgment for their assistance in accomplishing this task. Particular appreciation is extended to Delores Bigby and Brenda Campbell for preparing the many drafts of this report and to Mary Grace L. Belcher for her assistance in editing the final report. XI BIOLOGICAL EFFECTIVENESS OF NEUTRONS Research Needs CONTENTS Page SUMMARY xxiii CHARGE AND OBJECTIVES APPROACH TOPICS COVERED IN THE REPORT RESEARCH NEEDS RESEARCH RECOMMENDATIONS AND PRIORITIES I INTRODUCTION 1 BACKGROUND 1 CHARGE 1 RADIOBIOLOGY IN RADIATION PROTECTION 2 RELATIVE BIOLOGICAL EFFECTIVENESS (RBE) 2 BIOLOGICAL EFFECTIVENESS OF NEUTRONS 4 DOSE-RATE DEPENDENCIES 5 RESEARCH NEEDS 7 II RADIOBIOLOGICAL PRINCIPLES 9 SINGLE-HIT TARGET THEORY 9 MULTI-TRACK EFFECTS 10 Low DOSES AND LOW DOSE RATES 12 Low-Dose Region (I) 14 Intermediate-Dose Region (II) 15 High-Dose Region (III) 16 RADIATION QUALITY AND RELATIVE BIOLOGICAL EFFECTIVENESS (RBE) 16 DEVIATIONS FROM CONVENTIONAL EXPECTATIONS 17 RESEARCH NEEDS 18 xiii Page IH ORGANIZING DATA FOR PREDICTION OF RISKS 21 INTRODUCTION 21 BACKGROUND AND CURRENT STATUS 22 Effects in Single Cells 22 Response in Tissues and Animals 25 RESEARCH NEEDS 27 Phenomenological Models 27 Mechanistic Modeling 28 IV PHYSICS AND DOSIMETRY 31 INTRODUCTION 31 INTERACTION OF RADIATION WITH MATTER 32 DOSIMETRY 37 RESEARCH NEEDS 39 Basic Research 40 Applied Research 41 V CHEMICAL AND MOLECULAR MECHANISMS UNDERLYING CELLULAR RESPONSES 45 INTRODUCTION 45 CURRENT STATUS AND GENERAL CONSIDERATIONS 45 Energy Deposition and Its Immediate Consequences 45 Radiation Track Structure and the Spatial Distribution of Chemical Species 46 Radiation Chemistry in Elementary Systems 46 Primary Cellular Targets 48 Damage to DNA 48 Efficiency of Radiation and Dose/Damage Relationships 48 Limitations of Simplified Experimental Systems 49 Distribution of Damage in Sensitive Cellular Targets 50 RESEARCH NEEDS „ 52 Emphasis on Fundamental Research 52 High-LET Radiations as the Principal Focus 52 Radiation Chemistry 53 Development of Methodology 54 Identification of Clustered Lesions 56 Effects of Conformation of Cellular Targets 56 Relationship of Molecular Studies to Radiobiological Parameters 57 Enzymatic Processing of Initial Damage 57 Alterations in Gene Regulation by Radiation 58 xiv Page VI CELLULAR AND GENETIC STUDIES 61 INTRODUCTION 61 HIGH- VERSUS LOW-DOSE RADIOBIOLOGY 62 RELATIONSHIP BETWEEN ENDPOINTS 62 GENETIC MECHANISMS 63 Neoplastic Transformation 63 Oncogenes and Radiation-Induced Changes in Cells and Tumors ...... 65 Somatic Mutations 66 ENHANCED NEOPLASTIC TRANSFORMATION BY PROTRACTED EXPOSURES OF FISSION-SPECTRUM NEUTRONS 67 RESEARCH NEEDS 68 Technical Developments 68 Oncogenes 69 Mutations 71