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Radiobiology of nuclear terrorism: report on an interagency workshop (Bethesda, MD, December 17–18, 2001)
Int. J. Radiation Oncology Biol. Phys., Vol. 54, No. 2, pp. 327–328, 2002 Copyright © 2002 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/02/$–see front matter
PII S0360-3016(02)02956-5
REPORT
RADIOBIOLOGY OF NUCLEAR TERRORISM: REPORT ON AN INTERAGENCY WORKSHOP (BETHESDA, MD, DECEMBER 17–18, 2001) JOHN E. MOULDER, PH.D. Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI
INTERAGENCY MODERATE-DOSE RADIATION WORKSHOP
summary of the workshop discussions and recommendations was published in Radiation Research in July 2002 (8). The purpose of this commentary is to bring the issue to the attention of the radiation oncology community. Participants in the Workshop came from academia, as well as from government agencies, and covered fields ranging from molecular biology to animal physiology to clinical trials. The summary that follows is based on personal notes taken by the author (a presenter at the Workshop and a member of the “writing committee”), on the summary published in Radiation Research (8) and on the draft posted on the NCI web site (7). The Workshop discussions were wideranging and included the basic radiobiology relevant to injuries caused by doses of 1–10 Sv; biodosimetry problems and issues; and what resources were available now, and what could be made available within 1–5 years, for prophylaxis and treatment of radiation injuries caused by doses of 1–10 Sv. (The Workshop made an important distinction between prophylactic approaches, which begin therapy before radiation exposure, and treatment strategies, which begin therapy after exposure.) Finally, the group made some specific recommendations concerning research, technology, prophylaxis and treatment strategies, and personnel expertise issues.
The diagnosis, prophylaxis, and treatment of normal tissue injuries after exposure to ionizing radiation are of great importance to patients with cancer, to populations potentially subject to accidental or intentional radiation exposure, to workers in the nuclear power industry, and to members of the military. In these populations, partial or whole body exposure in the range of 1–10 Sievert (Sv) is possible (1–3). In the United States, exposure to doses of 10⫹ Sv has been the subject of research by the National Cancer Institute (NCI); and exposure to radiation doses ⬍1 Sv, such as that from nuclear fallout or space exploration, has been researched by the Department of Energy and the National Aeronautics and Space Administration. Except for research by the Department of Defense and the Armed Forces Radiobiology Research Institute that is aimed at protecting members of the armed forces and research aimed at the consequences of the total body irradiation used in conditioning regimens for bone marrow transplantation (4), the intervening dose range of roughly 1–10 Sv has received relatively little attention. The events of September 11, 2001 focused attention on the possibility of nuclear terrorism (5), and 1–10 Sv is arguably the dose range of biologic interest, because doses in this range pose a risk of acute effects, but are also potentially survivable (1–3). Because of this interest, a coalition of U.S. government agencies (NCI, Department of Defense/Armed Forces Radiobiology Research Institute, and Department of Energy) and the Radiation Research Society convened an interdisciplinary workshop in December 2001 “to focus on molecular, cellular and tissue changes that occur [at 1–10 Sv] and potential mechanisms of radioprotection” (6). The Workshop was also intended to “determine the research opportunities and resources required [and] develop a research-action plan for further discussion and implementation” (7). A “draft” report on this workshop was posted on the NCI web site in mid-February (7), but it appears that a “final” report may never be published. A
RECOMMENDATIONS OF THE WORKSHOP The following have been paraphrased from Moulder (8). Determine genetic and epigenetic mechanisms that govern individual susceptibility to radiation, including both normal tissue injuries and carcinogenesis. Develop and characterize genetic, protein, chromosomal, and tissue biomarkers for exposure in the range of 1–10 Sv. Develop systems for analysis of gene and protein expression in irradiated normal tissues. Identify physiologic and molecular targets for prophylaxis and treatment of radiation injuries.
Reprint requests to: John E. Moulder, Ph.D., Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. Tel: (414) 456-4670; Fax:
(414) 456-6553; E-mail: [email protected] Received May 1, 2002. Accepted for publication May 13, 2002. 327
328
I. J. Radiation Oncology
● Biology ● Physics
Define the functional effects of ionizing irradiation on stem and parenchymal cells of tissues and organs that develop acute or chronic radiation injuries. Investigate the role of oxidative stress in the cellular and tissue response to ionizing irradiation and the role of antioxidants for prophylaxis and treatment of radiation injuries. Develop strategies for the prophylaxis and treatment of radiation injuries, based on both optimizing current approaches and discovering new molecular, cellular, and tissue targets. Support long-term animal studies to determine the consequences of radiation-induced parenchymal cell dysfunction, including studies of strategies for prophylaxis and treatment of radiation injuries. Conduct epidemiologic studies of late normal tissue toxicity in people exposed to ionizing radiation in cancer treatment and in accidental or intentional exposures. Develop high throughput assays based on molecular targets to identify novel protectors of normal tissue injury. Develop detection technology for rapid analysis of molecular biomarkers of ionizing radiation exposure for large numbers of samples. Facilitate cooperation and collaboration among industry, government agencies, and academic communities for the development, testing, and production of new agents for the prophylaxis and treatment of radiation injuries. Increase the pool of researchers with expertise in normal tissue and animal radiation biology, and increase the pool of experts in health physics, radiation protection, and dosimetry. Recruit individuals with expertise in cellular biology, molecular biology, physiology, and wound healing into the normal-tissue radiobiology field.
Volume 54, Number 2, 2002
Include training in the diagnosis, prophylaxis, and treatment of the late normal-tissue effects of ionizing radiation in the education of oncologists. Support and expand national capabilities for medical radiologic response. CONCLUSION The issues discussed by the Workshop (8) provide an overview of what we currently know about the consequences of human exposure at 1–10 Sv and what we could do now to treat or prevent those consequences. The Workshop discussions also outline what could potentially be developed in the near future (1–5 years) to improve our ability to diagnose, triage, prevent, and treat such radiation injuries. The Workshop also made a number of recommendations that describe basic, preclinical, and clinical research programs that would benefit not only radiation accident and terrorism preparedness, but also clinical radiation oncology. The Workshop participants also discussed how these recommendations could be implemented. Suggestions ranged from asking the relevant federal agencies to review their research portfolios on normal tissue radiation injury, to targeted research on radiation toxicology and biodosimetry, to having a follow-up workshop on drug development that would include participants from the pharmaceutical industry and the Food and Drug Administration. Regrettably, the implementation suggestions were not included in the draft (7) posted on the NCI web site. The elimination of all discussion of implementation, plus the fact that the Workshop report currently exists only as an unpublicized draft whose “conclusions are those of the Workshop participants and not those of the individual agencies,” does not create optimism that the Workshop recommendations will actually be implemented.
REFERENCES 1. Jarrett DG. Medical management of radiological casualties. Bethesda: Armed Forces Radiobiology Research Institute; 1999. 2. National Council on Radiation Protection and Measurements. Management of terrorist events involving radioactive material (NCRP Report No. 138). Bethesda: National Council on Radiation Protection and Measurements; 2001. 3. Ricks RC, Berger ME, O’Hara FM. The medical basis for radiation-accident preparedness: The clinical care of victims. New York: Parthenon Publishing Group; 2002. 4. Moulder JE. Multiorgan problems associated with total and partial body irradiation. In: Ricks RC, Berger ME, O’Hara FM, editors. The medical basis for radiation-accident preparedness: The clinical care of victims. New York: Parthenon Publishing Group; 2002. p. 175–190.
5. Rose CM. Radiation scientists and homeland security. Radiat Res 2002;157:607– 609. 6. Letter of invitation (October 29, 2001) to the Moderate-Dose Radiation Workshop participants from N. Coleman, J. Mitchell, W.F. Blakely, and B. Wacholz. 7. Workshop Draft Report: Molecular and Cellular Biology of Moderate Dose (1–10 Sv) Radiation and Potential Mechanisms of Radiation Protection, Radiation Research Program, Division of Cancer Treatment, NCI. Contact individual: Helen B. Stone, Tel: 301-496-6360; E-mail: stoneh@mail. nih.gov. 8. Moulder JE. Report on an interagency workshop on the radiobiology of nuclear terrorism. Radiat Res 2002;158:118 –124.
PII S0360-3016(02)02956-5
REPORT
RADIOBIOLOGY OF NUCLEAR TERRORISM: REPORT ON AN INTERAGENCY WORKSHOP (BETHESDA, MD, DECEMBER 17–18, 2001) JOHN E. MOULDER, PH.D. Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI
INTERAGENCY MODERATE-DOSE RADIATION WORKSHOP
summary of the workshop discussions and recommendations was published in Radiation Research in July 2002 (8). The purpose of this commentary is to bring the issue to the attention of the radiation oncology community. Participants in the Workshop came from academia, as well as from government agencies, and covered fields ranging from molecular biology to animal physiology to clinical trials. The summary that follows is based on personal notes taken by the author (a presenter at the Workshop and a member of the “writing committee”), on the summary published in Radiation Research (8) and on the draft posted on the NCI web site (7). The Workshop discussions were wideranging and included the basic radiobiology relevant to injuries caused by doses of 1–10 Sv; biodosimetry problems and issues; and what resources were available now, and what could be made available within 1–5 years, for prophylaxis and treatment of radiation injuries caused by doses of 1–10 Sv. (The Workshop made an important distinction between prophylactic approaches, which begin therapy before radiation exposure, and treatment strategies, which begin therapy after exposure.) Finally, the group made some specific recommendations concerning research, technology, prophylaxis and treatment strategies, and personnel expertise issues.
The diagnosis, prophylaxis, and treatment of normal tissue injuries after exposure to ionizing radiation are of great importance to patients with cancer, to populations potentially subject to accidental or intentional radiation exposure, to workers in the nuclear power industry, and to members of the military. In these populations, partial or whole body exposure in the range of 1–10 Sievert (Sv) is possible (1–3). In the United States, exposure to doses of 10⫹ Sv has been the subject of research by the National Cancer Institute (NCI); and exposure to radiation doses ⬍1 Sv, such as that from nuclear fallout or space exploration, has been researched by the Department of Energy and the National Aeronautics and Space Administration. Except for research by the Department of Defense and the Armed Forces Radiobiology Research Institute that is aimed at protecting members of the armed forces and research aimed at the consequences of the total body irradiation used in conditioning regimens for bone marrow transplantation (4), the intervening dose range of roughly 1–10 Sv has received relatively little attention. The events of September 11, 2001 focused attention on the possibility of nuclear terrorism (5), and 1–10 Sv is arguably the dose range of biologic interest, because doses in this range pose a risk of acute effects, but are also potentially survivable (1–3). Because of this interest, a coalition of U.S. government agencies (NCI, Department of Defense/Armed Forces Radiobiology Research Institute, and Department of Energy) and the Radiation Research Society convened an interdisciplinary workshop in December 2001 “to focus on molecular, cellular and tissue changes that occur [at 1–10 Sv] and potential mechanisms of radioprotection” (6). The Workshop was also intended to “determine the research opportunities and resources required [and] develop a research-action plan for further discussion and implementation” (7). A “draft” report on this workshop was posted on the NCI web site in mid-February (7), but it appears that a “final” report may never be published. A
RECOMMENDATIONS OF THE WORKSHOP The following have been paraphrased from Moulder (8). Determine genetic and epigenetic mechanisms that govern individual susceptibility to radiation, including both normal tissue injuries and carcinogenesis. Develop and characterize genetic, protein, chromosomal, and tissue biomarkers for exposure in the range of 1–10 Sv. Develop systems for analysis of gene and protein expression in irradiated normal tissues. Identify physiologic and molecular targets for prophylaxis and treatment of radiation injuries.
Reprint requests to: John E. Moulder, Ph.D., Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. Tel: (414) 456-4670; Fax:
(414) 456-6553; E-mail: [email protected] Received May 1, 2002. Accepted for publication May 13, 2002. 327
328
I. J. Radiation Oncology
● Biology ● Physics
Define the functional effects of ionizing irradiation on stem and parenchymal cells of tissues and organs that develop acute or chronic radiation injuries. Investigate the role of oxidative stress in the cellular and tissue response to ionizing irradiation and the role of antioxidants for prophylaxis and treatment of radiation injuries. Develop strategies for the prophylaxis and treatment of radiation injuries, based on both optimizing current approaches and discovering new molecular, cellular, and tissue targets. Support long-term animal studies to determine the consequences of radiation-induced parenchymal cell dysfunction, including studies of strategies for prophylaxis and treatment of radiation injuries. Conduct epidemiologic studies of late normal tissue toxicity in people exposed to ionizing radiation in cancer treatment and in accidental or intentional exposures. Develop high throughput assays based on molecular targets to identify novel protectors of normal tissue injury. Develop detection technology for rapid analysis of molecular biomarkers of ionizing radiation exposure for large numbers of samples. Facilitate cooperation and collaboration among industry, government agencies, and academic communities for the development, testing, and production of new agents for the prophylaxis and treatment of radiation injuries. Increase the pool of researchers with expertise in normal tissue and animal radiation biology, and increase the pool of experts in health physics, radiation protection, and dosimetry. Recruit individuals with expertise in cellular biology, molecular biology, physiology, and wound healing into the normal-tissue radiobiology field.
Volume 54, Number 2, 2002
Include training in the diagnosis, prophylaxis, and treatment of the late normal-tissue effects of ionizing radiation in the education of oncologists. Support and expand national capabilities for medical radiologic response. CONCLUSION The issues discussed by the Workshop (8) provide an overview of what we currently know about the consequences of human exposure at 1–10 Sv and what we could do now to treat or prevent those consequences. The Workshop discussions also outline what could potentially be developed in the near future (1–5 years) to improve our ability to diagnose, triage, prevent, and treat such radiation injuries. The Workshop also made a number of recommendations that describe basic, preclinical, and clinical research programs that would benefit not only radiation accident and terrorism preparedness, but also clinical radiation oncology. The Workshop participants also discussed how these recommendations could be implemented. Suggestions ranged from asking the relevant federal agencies to review their research portfolios on normal tissue radiation injury, to targeted research on radiation toxicology and biodosimetry, to having a follow-up workshop on drug development that would include participants from the pharmaceutical industry and the Food and Drug Administration. Regrettably, the implementation suggestions were not included in the draft (7) posted on the NCI web site. The elimination of all discussion of implementation, plus the fact that the Workshop report currently exists only as an unpublicized draft whose “conclusions are those of the Workshop participants and not those of the individual agencies,” does not create optimism that the Workshop recommendations will actually be implemented.
REFERENCES 1. Jarrett DG. Medical management of radiological casualties. Bethesda: Armed Forces Radiobiology Research Institute; 1999. 2. National Council on Radiation Protection and Measurements. Management of terrorist events involving radioactive material (NCRP Report No. 138). Bethesda: National Council on Radiation Protection and Measurements; 2001. 3. Ricks RC, Berger ME, O’Hara FM. The medical basis for radiation-accident preparedness: The clinical care of victims. New York: Parthenon Publishing Group; 2002. 4. Moulder JE. Multiorgan problems associated with total and partial body irradiation. In: Ricks RC, Berger ME, O’Hara FM, editors. The medical basis for radiation-accident preparedness: The clinical care of victims. New York: Parthenon Publishing Group; 2002. p. 175–190.
5. Rose CM. Radiation scientists and homeland security. Radiat Res 2002;157:607– 609. 6. Letter of invitation (October 29, 2001) to the Moderate-Dose Radiation Workshop participants from N. Coleman, J. Mitchell, W.F. Blakely, and B. Wacholz. 7. Workshop Draft Report: Molecular and Cellular Biology of Moderate Dose (1–10 Sv) Radiation and Potential Mechanisms of Radiation Protection, Radiation Research Program, Division of Cancer Treatment, NCI. Contact individual: Helen B. Stone, Tel: 301-496-6360; E-mail: stoneh@mail. nih.gov. 8. Moulder JE. Report on an interagency workshop on the radiobiology of nuclear terrorism. Radiat Res 2002;158:118 –124.