Dr. Barrett N. Fountos
Office of Health Studies
U.S. Department of Energy
Germantown, MD
Phone: 301-903-6740
Fax: 301-903-1413
E-mail: barrett.fountos@hq.doe.gov
Number of Human Subjects projects reported: 4
| EH-98-EH98028 | "Molecular Epidemiology of Lung Cancer in Workers from the MAYAK Nuclear Enterprise" |
| EH-00-01 | "Russian Human Radiobiology Tissue Repository for the Exposed Mayak Workers" |
| EH-00-POC | "A validated high-LET radiation specific biomarker in the Mayak worker cohort" |
| EH-01-DE-AI01-01-01EH01010 | "Development of a Unified Research Database for the Mayak Worker and Ozyorsk Population Studies " |
"Molecular Epidemiology of Lung Cancer in Workers from the MAYAK Nuclear Enterprise"
Principal Investigator: Dr. Steven A. Belinsky, Lovelace Respiratory Research Institute
Project started in: 1998
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lovelace Respiratory Research Institute (FWA00004217)
Most recent approval: 08/19/03
IRB approval number: 98-039
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
The molecular mechanisms that result in the elevated risk for lung cancer associated with exposure to radiation have not been well characterized. Workers from the MAYAK nuclear enterprise are an ideal cohort in which to study the molecular epidemiology of cancer associated with radiation exposure and to identify the genes targeted for inactivation that in turn affect individual risk for radiation-induced lung cancer. Epidemiology studies of the MAYAK cohort indicate a significantly higher frequency for adenocarcinoma and squamous cell carcinoma in workers than in a control population and a strong correlation between these tumor types and plutonium exposure. Two hypotheses will be evaluated through the proposed studies. First, radiation exposure targets specific genes for inactivation by promoter methylation. This hypothesis is supported by our recent studies with the MAYAK population that demonstrated the targeting of the p16 gene for inactivation by promoter methylation in adenocarcinomas from workers. Second, genes inactivated in tumors can serve as biomarkers for lung cancer risk in a cancer-free population of workers exposed to plutonium. Support for this hypothesis is based on exciting preliminary results of our nested, case-control study of persons from the Colorado cohort. In that study, a panel of methylation markers for predicting lung cancer risk is being evaluated in sputum samples from incident lung cancer cases and controls.
Three specific aims are proposed to evaluate these hypotheses. Specific Aim 1 will determine the frequency for methylation of the PAX5 ƒÑ, PAX5 ƒÒ, H-cadherin, GATA5, and BMP3B genes in adenocarcinomas from plutonium-exposed workers and unexposed subjects. Specific Aim 2 will extend these studies to determine the frequency for methylation of the p16, MGMT, DAP-K, and genes listed under aim 1 in squamous cell carcinomas from plutonium-exposed workers and unexposed subjects. Finally, specific Aim 3 will establish a prospective cohort of cancer-free persons exposed to plutonium and an unexposed population. We will determine at entrance into the cohort the cross-sectional frequency for methylation in exfoliated cells in sputum of the four genes most commonly methylated in tumors associated with plutonium exposure. Together, these studies will increase our fundamental knowledge of the mechanisms leading to radiation-induced lung cancer associated with exposure to airborne plutonium.
"Russian Human Radiobiology Tissue Repository for the Exposed Mayak Workers"
Principal Investigator:
Dr. Ruth Neta,
Office of Health (EH-5)
Phone: 301-903-1757
email: ruth.neta@eh.doe.gov
Project started in: 2000
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Lawrence Livermore National Laboratory (FWA00004274)
Most recent approval: 09/01/00
Explanation of IRB approval:
The proposal for conduct of the Repository and the Informed Consent Forms for blood and biopsy specimens collection were reviewed and approved by the IRB Chair at the Lawrence Livermore Laboratories (Dr. Andrew Wyrobek). No research activities are conducted by the repository.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 500
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
The Russian Human Radiobiology Tissue Repository has been established at the Southern Ural Biophysics Institute, in Ozyorsk, Southern Urals in the Russian Federation, supported jointly by the Russian Ministry of Health and the Office of Health Studies, U.S. DOE. It is anticipated that this repository will serve as a resource to the radiobiology scientific community in current and future studies on the effects of chronic radiation exposure on human health. The inventory of archived tissues includes specimens from 700 deceased workers, employed from 1948 to 1972, at the first nuclear weapons facility, “Mayak”. In addition, donations of blood and buccal cells, as well as of tissues removed at the time of surgery and/or biopsy from the members of the Mayak cohort undergoing medical treatment or diagnostic procedures, are also being included. To date 700 archived autopsies, which consist of formalin-preserved organs, paraffin blocks, and histology slides were inventoried. For all these cases occupational, dosimetry, and detailed medical information is available. For 342 individuals malignant tumors at different sites are available, mainly solid cancers of lung, stomach, liver, intestine, as well as cases of leukemia. Almost all the registrants at the Repository started their work at Mayak PA during the early years, at the time of highest radiation exposure. For the 680 inventoried cases, the external gamma exposures are known for 649 workers (95.5 percent), of whom 545 were exposed to protracted doses exceeding 0.5 Gy, with known maximum annual doses ranging from 0.01 – 0.5 Gy for about 44 percent, and 49 percent of the 680 individuals have annual doses exceeding 0.5 Gy. Pu body burden is known for 66 percent. Of these, 245 individuals had exposures greater than 1.48 kBq, and 52 individuals, greater than 23.7 kBq. Malignant tumors were the cause of death in almost half of the cases. A computerized database of the Repository has been set up.
In addition to the collection of archived tissues, efforts are under way to obtain and store donations of new specimens (frozen lymphocytes, EBV-immortalized B-cells, frozen erythrocytes, tumors of different sites, and extracted DNA). Donations were obtained to date from 880 individuals. Of these 880, the external doses of exposure ranged from 1 to 5 Gy for 80 percent, and were higher than 5 Gy for 5.6 percent. Pu body burden ranged from 1.48 - 11.84 kBq for 40 percent and were greater than 11.84 kBq for 1.9 percent. More than 5,000 members of the 19,000 cohort of workers employed from 1948 to 1972 are still residing in the city of Ozyorsk, with more than 2,000 of these individuals exposed to doses exceeding 0.5 Gy.
"A validated high-LET radiation specific biomarker in the Mayak worker cohort"
Principal Investigator: Dr. David J. Brenner, Columbia University
Project started in: 2000
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Columbia University (FWA00002636)
Most recent approval: 06/07/03
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 31
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
a. OBJECTIVES
The overall goal of this work is to test the hypothesis that a specific chromosomal biomarker exists and is detectable for past exposure to high-linear energy transfer (LET) radiation such as a plutonium alpha particles, even in the presence of other mutagens or clastogens, such as tobacco, organic chemicals, or gamma rays. Such a biomarker would significantly increase the power of epidemiological studies of individuals exposed to densely-ionizing radiations such as alpha particles (e.g., radon, Pu workers) or neutrons (e.g., DOE/Nuclear Regulatory Commission (NRC) workers, airline personnel).
The proposed biomarker is the ratio of induced intra-arm to inter-chromosomal aberrations - the H value (ratio of different types of chromosome aberrations). Both theoretical and experimental studies have suggested that this ratio will be different by a factor of about three between low and high LET. Because both types of aberrations (intra-arm and inter-chromosomal aberrations) are 1) frequent and 2) measurable at long times after exposure, the H ratio appears to be a practical biomarker of high-LET exposure.
The hypotheses under test are:
i)that this H value will be significantly and detectably different for alpha particles compared to that produced by chemical carcinogens / clastogens, such as tobacco or hydrocarbons, and also different from that produced by x-rays or gamma-rays.
ii)that an intermediate-dose in-vivo plutonium exposure can be reliably identified and reconstructed with adequate statistical power, even if the subject had also received significant exposure to chemical carcinogens/clastogens or gamma rays. This would be done using fluorescent in-situ hybridization (FISH) technology to measure the H value. Appropriate probes for intra-arm aberrations have been developed, and probes for inter-chromosomal aberrations are readily available.
b. METHODOLOGY
To make FISH-based H-value measurements on peripheral blood lymphocytes from individuals in the Mayak worker cohort who were exposed to a wide range of plutonium exposures and gamma ray exposures. The blood work and chromosome preparations (slides) are being done under a different grant to Mayak scientists. At Columbia, we analyze the metaphase preparations. The large number of individuals involved, together with the broad spectrum of exposures, means that this cohort offers a unique opportunity to test the hypotheses about the H value.
In the current (Phase I) component, we are establishing co-operative relationships, accessing the Mayak worker registries, and establishing protocols including QA/QC. In addition, to assess feasibility, we are assessing H values on 25 individuals, whose blood was obtained and processed by Mayak scientists, under the auspices of their grant.
c. IONIZING RADIATION
None.
INVOLVEMENT OF HUMAN SUBJECTS
PROCEDURES INVOLVING HUMAN SUBJECTS
d1.The required volume of peripheral blood is collected aseptically in a sodium heparinized vacutainer tube or syringe.
RISKS
d2. The hazard for this procedure is minimal; a faint soreness or bruise in the area of the needle puncture may occur.
PRIVACY/CONSENT
d3:No personal identifiers are linked to the blood samples, only details of the past exposure to radiation, as well as age, gender, and smoking history.
"Development of a Unified Research Database for the Mayak Worker and Ozyorsk Population Studies"
Principal Investigator: Dr. Dale L. Preston, Radiation Effects Research Foundation
Project started in: 2001
Funding for Human Subjects Research:
This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 1
Identifier or number: 1
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: Radiation Effects Research Foundation (FWA00001317)
Most recent approval: 02/15/02
Explanation of IRB approval:
IRB approval was received in a previous year of the project. The project's total length is three years.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 50000
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
Objectives: Creation of a unified database containing information needed to conduct epidemiological, dosimetric, and clinical studies on the Mayak worker cohort and related populations.
Methodology: The database is a distributed relational database with the primary information stored on servers at the location responsible for collection of specific types of data.
The populations in this study have had internal and external exposures to ionizing radiation due to their occupation or their place of residence. However, this project involves no contact with the members of the study cohorts.
The database is being designed to protect the privacy and confidentiality of information on people included in the study cohorts. In particular, access to the database will be restricted to those involved and access to tables containing confidential information will be further restricted.
Risk: There are no risks to human subjects as a result of this project.