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NATIONAL RESEARCH COUNCIL

COMMISSION ON LIFE SCIENCES

2101 Constitution Avenue Washington, D.C. 20418

BOARD ON RADIATION EFFECTS RESEARCH

NAS Room 342

TEL: (202) 334-2232 FAX: (202) 334-1639

January 21, 1998

Dr. Jerome Puskin

US Environmental Protection Agency

Radiation Studies Branch

401 M Street, SW Washington, DC 20460

Dear Dr. Puskin:

The Environmental Protection Agency Office of Radiation and Indoor Air asked the National Research Council to evaluate whether sufficient new data exist to warrant a reassessment of health risks reported in Health Effects of Exposure to Low Levels of Ionizing Radiations (BEIR V) in 1990. To respond to this request, the National Research Council assembled the Committee on Health Risks of Exposure to Low Levels of Ionizing Radiations. The work of the committee was conducted in what was called the BEIR VII phase 1 study. To assist the committee during its deliberations, various scientists were consulted for advice, and a workshop on the impact of biology on risk assessment was held in collaboration with the Department of Energy Office of Health and Environmental Research. The intent of the workshop was to address the implications of new understanding of the biologic basis of radiation injury and carcinogenesis for risk assessment. Through this letter, we are providing you in advance a summary report of the committee 's recommendations. This is being done in order to enable you to begin to move forward as soon as possible in making a decision on the appropriateness of undertaking additional study of the subject.

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NATIONAL RESEARCH COUNCIL COMMISSION ON LIFE SCIENCES 2101 Constitution Avenue Washington, D.C. 20418 BOARD ON RADIATION EFFECTS RESEARCH NAS Room 342 TEL: (202) 334-2232 FAX: (202) 334-1639 January 21, 1998 Dr. Jerome Puskin US Environmental Protection Agency Radiation Studies Branch 401 M Street, SW Washington, DC 20460 Dear Dr. Puskin: The Environmental Protection Agency Office of Radiation and Indoor Air asked the National Research Council to evaluate whether sufficient new data exist to warrant a reassessment of health risks reported in Health Effects of Exposure to Low Levels of Ionizing Radiations (BEIR V) in 1990. To respond to this request, the National Research Council assembled the Committee on Health Risks of Exposure to Low Levels of Ionizing Radiations. The work of the committee was conducted in what was called the BEIR VII phase 1 study. To assist the committee during its deliberations, various scientists were consulted for advice, and a workshop on the impact of biology on risk assessment was held in collaboration with the Department of Energy Office of Health and Environmental Research. The intent of the workshop was to address the implications of new understanding of the biologic basis of radiation injury and carcinogenesis for risk assessment. Through this letter, we are providing you in advance a summary report of the committee 's recommendations. This is being done in order to enable you to begin to move forward as soon as possible in making a decision on the appropriateness of undertaking additional study of the subject. The National Research Council is the principal operating agency of the National Academy of Sciences and the National Academy of Engineering to serve government and other organizations

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The following is a synopsis of the conclusions of the BEIR VII phase 1 study: In the committee's judgment, information that has become available since publication of the 1990 Health Effects of Exposure to Low Levels of Ionizing Radiations (BEIR V) makes this an opportune time to proceed with BEIR VII phase 2 –a comprehensive reanalysis of health risks associated with low levels of ionizing radiations. Such a study should begin as soon as possible and is expected to take about 36 months to complete. The committee based that judgment on the following considerations: Substantial new epidemiologic evidence has accumulated since the 1990 BEIR V report was published. The present committee's phase 1 report will cite 39 new epidemiologic studies that fall into this category (see Table 1). Additional studies that have a direct bearing on the subject should become available in the next 3 years, the estimated period required to complete the phase 2 study. Some of the new epidemiologic data are on subjects on which information had been sparse, such as cancer mortality in those exposed to whole-body irradiation in childhood. Studies of carcinogenesis completed since publication of the last BEIR report have focused on mechanisms and the cellular and molecular events that are involved in the neoplastic process. The understanding of molecular events involved in carcinogenesis has increased significantly. Mechanisms that might be involved in radiation carcinogenesis have been identified. Further knowledge of these mechanisms that should become available in the next 3 years might affect estimation of the radiation-response curve at low doses. Over the next few years, investigators will be applying two closely linked approaches using animal models of carcinogenesis. These will likely contribute to a

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better understanding of mechanisms of radiation-induced cancer. In the first of these two approaches, genetically engineered mice having alterations in specific genes will be used to determine the influence of these genes on the susceptibility of the mice to radiation-induced cancer. In the second approach, studies will be conducted of the inherent differences in susceptibility to radiation-induced cancer among different mouse strains, the objective being to identify the genes involved in controlling susceptibility. Researchers responsible for this new generation of animal studies are taking advantage of the current rapid developments in molecular genetics. Progress on both approaches should be substantial over the next few years. Significant results of relevance to risk estimation are expected to be available for the proposed BEIR VII phase 2 study. Evidence regarding specific biologic events that can affect the shape of the dose-response curve at low doses is also accumulating. Information on such phenomena as DNA repair, signal transduction, chromosomal instability, and adaptation, although preliminary, might eventually affect risk analyses of low-dose and low-dose-rate exposures. The committee recommends that the group responsible for the proposed phase 2 study Include a comprehensive review of all relevant epidemiologic data related to low-LET (low linear energy transfer), i.e. sparsely ionizing, radiation. Define and establish principles on which quantitative analyses can be based, including requirements for epidemiologic data and cohort characteristics. In this respect, the group should consider biologic factors (such as the dose and dose-rate effectiveness factor, relative biologic effectiveness, genomic instability, and adaptive responses) and appropriate models (favoring simple as opposed to complex models) to develop etiologic models, estimate population detriment, and attribute causation in specific cases.

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Assess the current status and relevance to risk models of biologic data and models of carcinogenesis. This should include a critical assessment of all data that might affect the shape of the response curve at low doses, in particular, evidence of thresholds or the lack thereof in dose-response relationships and the influence of adaptive responses and radiation hormesis. Consider potential target cells and problems that might exist in determining dose to the target cell. Consider any recent evidence regarding genetic effects not related to cancer. Any such data, even if obtained from high radiation exposures or at high dose rates, should be considered. With respect to modeling, the committee recommends that the group responsible for the proposed phase 2 study Develop appropriate risk models for major cancer types and other outcomes, including benign disease and genetic effects. Specifically, the responsible group should develop models appropriate for probability-of-causation tables and should consider the fitting of purely empirical models to original data from studies or combined studies, the fitting of purely empirical models with meta-analytic techniques, and the fitting of semiempirical biology-based models to epidemiologic data. Provide examples of specific risk calculations based on the models and explain the appropriate use of the risk models. Describe and define the limitations and uncertainties of the risk models and their results. The group conducting the proposed phase 2 study should be directed to develop

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best-risk estimates as opposed to developing conservative models for purposes of radiation protection. Discuss the role and effect of modifying factors, including host (such as individual susceptibility and variability, age, and sex), environment, and lifestyle. Identify critical gaps in knowledge that should be filled by future research. To accomplish the above charge, the membership of the group responsible for the proposed BEIR VII phase 2 study will require expertise in epidemiology, biostatistics, radiation physics and dosimetry, molecular biology, risk assessment, cancer modeling, animal and cellular radiation biology, somatic cell genetics, cell-cycle regulation and apoptosis, and ionizing radiation-induced DNA damage and its repair. The committee recommends that the experts chosen have adequate resources and access to data for the computing, statistical analyses, and modeling required to complete the study. We trust that this synopsis of the recommendations of the committee will meet your current needs. The complete report of the committee will be published and provided to your office when it has received the committee's final approval and has been subjected to the National Research Council peer-review process. Sincerely, Richard B. Setlow, Ph.D. Chairman, Committee on Health Effects of Exposure to Low Levels of Ionizing Radiations (BEIR VII Phase 1)

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Table 1 is a summary of the more important epidemiologic data that have been published since the 1990 publication of the BEIR V report. Included are studies that are expected to provide new and useful data during the 3-year term of the proposed BEIR VII, Phase II, study. Although not exhaustive, the list should serve as a guide to some of the pertinent new and upcoming epidemiologic data on the subject.

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Table 1. Summary of Epidemiologic Studies of Low-LET Ionizing Radiation and Cancer, 1990 STUDY REFERENCE TYPE OF STUDY SERIES SEX NO. IN STUDY YEARS OF FOLLOW-UP CANCER SITES REPORTED Ankylosing spondylitis patients Weiss et al. Cancer mortality following x-ray treatment for ankylosing spondylitis. Int J Cancer 1994;59:327-338. Cohort Mortality Male and Female 15,577 1935-1992 All cancer and multiple cancer sites   Weiss et al. Leukemia mortality after x-ray treatment for ankylosing spondylitis. Rad Res 1995;142:1-11. Cohort Mortality Male and Female 14,767 1935-1992 Leukemia Atomic-bomb survivors Preston et al. Cancer incidence in atomic-bomb survivors. Part III: leukemia, lymphoma, and multiple myeloma 1950-1987. Rad Res 1994;137:568-597 (2 suppl). Cohort Incidence Male and Female 93,696 1950-1987 Leukemia, lymphoma, multiple myeloma   Thompson et al. Cancer incidence in atomic-bomb survivors. Part II: solid tumors, 1958-1987. Rad Res 1994;137:517-567. Cohort Incidence Male and Female 79,972 1958-1987 Multiple cancer sites (solid tumors)   Ron et al. Incidence of benign gastrointestinal tumors among atomic-bomb survivors. Amer J Epi 1995;142:68-75. Cohort Incidence Male and Female 80,311 1958-1989 Benign tumors of stomach, colon, and rectum   Pierce et al. Studies of the mortality of atomic bomb survivors. Report 12, Part 1. Cancer:1950-1990. Rad Res 1996;146:1-27. Cohort Mortality Male and Female 86,572 1950-1990 Non leukemias, leukemia, and multiple cancer sites Atomic-bomb survivors (case-control study) Land et al. A case control interview study of breast cancer among Japanese A-bomb survivors. I. Main effects. Cancer Causes and Control 1994;5:157-169. Case-control   Female Cases: 196 Controls: 566 1955-1981 Breast cancer   Land et al. A case-control interview study of breast cancer among Japanese A-bomb survivors. II. Interactions with radiation dose. Cancer Causes and Control 1994;5:167-176.   Atomic-bomb survivors (in utero cohorts) Delongchamp et al. Cancer mortality among atomic-bomb survivors exposed in utero or as young children, October 1950-May 1992. Rad Res 1997;147:385-395. Cohort Mortality Male and Female 17,601 1950-1992 Non leukemias, leukemia, and multiple cancer sites

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Canadian fluoroscopy Howe. Lung Cancer Mortality between 1950 and 1987 Following Exposure to fractionated moderate dose rate ionizing radiation in the Canadian Fluoroscopy Study and a comparison with lung cancer mortality in the Atomic Bomb Survivors Study. Radiat Res 1995; 142:295-304. Cohort Mortality Male and Female 64,172 1950-1987 Lung cancer   Howe and McLaughlin. Breast cancer mortality between 1950 and 1987 after exposure to fractionated moderate dose rate ionizing radiation in the Canadian fluoroscopy study and a comparison with breast cancer mortality in the Atomic bomb survivors study. Rad Res 1996;145:694-707. Cohort Mortality Female 31,917 1950-1987 Breast cancer Cervical cancer patients Kleinerman et al. Second primary cancer after treatment for cervical cancer. Cancer 1995;76:442-452. Cohort Incidence Female 86,193 1935-1990 Multiple cancer sites Contralateral breast (Denmark) Storm et al. Adjuvant radiotherapy and risk of contralateral breast cancer. J Nat Cancer Inst 1992;84:1245-1250. Case-control in a cohort   Female Cohort: 56,540 Cases: 691 Controls: 691 1943-1986 Breast cancer Contralateral breast (U.S.A.) Boice et al. Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med 1992;326:781-785. Case control within a cohort   Female Cohort: 4,109 Cases: 655 Controls: 1,189 1935-1987 Breast cancer Fallout from Nevada Test Site Kerber et al. A cohort study of thyroid disease in relation to fallout from nuclear weapons testing. JAMA 1993;270:2076-2082. Cohort Incidence Male and Female 2,473 1965-1986 Thyroid cancer and other thyroid disease   Simon et al. The Utah leukemia case-control study: dosimetry methodology and results. Hlth Phys 1995;6814:460-471. Case-Control   Male and Female Cases: 1,177 Controls: 5,330 1952-1981 Leukemia Massachusetts fluoroscopy Davis et al. Cancer mortality in a radiation-exposed cohort of Massachusetts tuberculosis patients. Cancer Res 1989;49:6130-6136. Cohort Mortality Male and Female 13,385 1929-1986 Multiple cancer sites   Boice et al. Frequent chest x-ray fluoroscopy and breast cancer incidence among tuberculosis patients in Massachusetts. Rad Res 1991;125:214-222. Cohort Incidence Female 4,940 1925-1986 Breast cancer

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Multiple diagnostic x-rays of scoliosis patients Hoffman et al. Breast cancer in women with scoliosis exposed to multiple diagnostic x-rays. J Natl Cancer Inst 1989;81:1307-1312. Cohort Incidence Female 1,030 1935-1986 Breast cancer Nuclear industry workers (combined analysis) Cardis et al. Effects of low doses and low dose rates of external ionizing radiation: cancer mortality among nuclear industry workers in three countries. Rad Res 1995;142:117-132. Cohort Mortality Male and Female 95,673 1943-1988 Multiple cancer sites   Cardis et al. Direct estimates of cancer mortality due to low doses of radiation: an international study. Lancet 1994;344:1039-1043. Cohort Mortality Male and Female 95,673 1943-1988 Solid tumors and leukemia Nuclear workers at Mayak Production Association Koshurnikova et al. NCRP Proceedings, 1996, 113:T2, 113-122. Cohort Mortality Male and Female 18,879 1948-1993 Lung cancer and leukemia Pelvic radiotherapy for benign gynecologic disease Inskip et al. Leukemia, lymphoma and multiple myeloma after pelvic radiotherapy for benign disease. Rad Res 1993;135:108-124. Cohort Mortality Female 12,955 1929-1985 Multiple hematopoietic cancers Pooled analysis of external radiation and thyroid cancer Ron et al. Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Rad Res 1996;141:259-277. Cohort Case-control Incidence Male and Female 120,000 1926-1990 Thyroid cancer Radiation treatment for benign head and neck conditions (benign thyroid tumors) Wong et al. Benign thyroid tumors: general risk factors and their effects on radiation risk estimation. Amer J Epi 1996;144:728-733. Cohort Incidence Male and Female 544 1939-1991 Benign thyroid nodules Radiation treatment for benign head and neck conditions (thyroid cancer and thyroid nodules) Schneider et al. Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: evidence for the prolonged effects of radiation on the thyroid. J Clin Endocrinol Metab 1993;77:362-269. Cohort Incidence Male and Female 4,296 1939-1990 Thyroid cancer and nodules Radiation treatment for breast cancer Curtis et al. Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N Engl J Med 1992;326:1745-1751. Case-control within cohort   Female Cohort: 82,700 Cases: 90 Controls: 264 1973-1985 Leukemia Radiation treatment for peptic ulcer Griem et al. Cancer following radiotherapy for peptic ulcer. J Natl Cancer Inst 1994;86:842-849. Cohort Mortality Male and Female 3,609 1937-1985 Multiple cancer sites

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                Radiotherapy treatment for Hodgkin's Disease (breast cancer) Hancock et al. Breast cancer after treatment of Hodgkin's Disease. J Natl Cancer Inst 1993;85:25-31. Cohort Incidence and Mortality Female 885 1961-1990 Breast cancer Radiotherapy treatment for Hodgkin's Disease (gastro intestinal cancer) Birdwell et al. Gastrointestinal cancer after treatment of Hodgkin 's Disease. Int J Rad Oncol Biol Phys 1997;37:67-73. Cohort Incidence and Mortality Male and Female 2,441 1961-1993 Multiple cancer sites (gastrointestinal only) Radiotherapy treatment for metropathia hemorrhagic anemia Darby et al. Mortality in a cohort of women given x-ray therapy for metropathia hemorrhagica. Int J Cancer 1994;56:793-801. Cohort Mortality Female 2,067 1940-1991 Multiple cancer sites Radiotherapy treatment for pituitary adenoma Brada et al. Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma. Br Med J 1992;304:1343-1346. Cohort Incidence Male and Female 334 1962-1986 Multiple cancer sites (solid tumors only) Radiotherapy treatment for skin, hemangioma in childhood Furst et al. Tumors after radiotherapy for skin hemangioma in childhood. Act Oncologica 1990; 29:557-562. Case-control within a cohort   Male and Female Cohort: 14,647 Cases: 94 Controls: 359 1920-1986 Multiple cancer sites (solid tumors) Radiotherapy treatment for thymus enlargement Shore et al. Overview of radiation induced skin cancer in humans. Int J Radiat Biol 1990;57:809-827. Cohort Incidence Male and Female 7,450 1953-1989 Skin cancer Radiotherapy treatment for uterine bleeding Inskip et al. Cancer mortality following radium treatment for uterine bleeding. Rad Res 1990;123:331-344. Cohort Mortality Female 4,153 1925-1984 Multiple cancer sites Tinea capitis (Israel) Ron et al. Thyroid neoplasia following low-dose radiation in childhood. Rad Res 1989;120:516-531. Cohort Incidence Male and Female 10,834 1950-1986 Thyroid cancer and other thyroid disease   Ron et al. Radiation induced skin carcinomas of the head and neck. Rad Res 1991;125:318-329. Cohort Incidence Male and Female 27,060 1950-1980 Melanoma, other skin cancer and benign skin tumors Women treated for infertility Ron et al. Mortality following radiation treatment for infertility of hormonal origin or amenorrhea. Int J Cancer 1994; 23:1165-1173 Cohort Mortality Female 816 1925-1991 Multiple cancer sites

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STUDY REFERENCE DESCRIPTION In utero exposure Doll and Wakeford. Risk of childhood cancer from fetal irradiation, Brit J Radiol 1997; 70:130-139 A review of case-control and cohort studies of childhood cancers.