Joint Coordinating Committee for Radiation Effects Research (JCCRER)

Project 2.2: Mayak Worker Epidemiology

Principal Investigators:

R.F.: Mikhail Sokolnikov Koshurnikova, Southern Urals Biophysics Institute
U.S.: Ethel Gilbert, National Cancer Institute

Brief Description: This epidemiologic study is designed to obtain quantitative estimates of carcinogenic risks from both protracted external exposure and from internal exposure to plutonium based on analyses of data from the Mayak worker cohort. The cohort consists of 26,000 workers first employed at any time between 1948 and 1982. Vital status is known through 2000. Risks of cancers of the lung, liver, and bone are being expressed as functions of doses to these organs and of potential modifying factors such as sex, time since exposure, and age at exposure. In addition, researchers will investigate whether risks of cancers of sites other than lung, liver, and bone are related to external dose and to plutonium exposure. Uncertainties in risk estimates that are developed will be quantified. In order to meet these objectives, further improvements in the data are being implemented. These include the continual updating of follow-up and the collection of further data on smoking from medical records. The results of this study are likely to enhance our understanding of protracted radiation exposure risks to humans and provide definitive data for the improvement and validation of radiation protection standards.

Results to date: This is the first study to demonstrate a statistically significant association between occupational exposure to plutonium and bone, lung, and liver cancer. These analyses were performed using the Mayak worker Doses 2000 database. Now that the Project 2.4 dosimetrists have completed the "Doses 2005" database, Project 2.2 researchers will analyze the data using the most recent dose estimates and compute new cancer risk estimates linked to radiation dose.

Projected end date: September 2009.

Principal Investigators:

R.F.: Evgeny Vasilenko (External Dosimetry Team Leader), Mayak and Victor Khokhryakov (Internal Dosimetry Team Leader), Southern Urals Biophysics Institute
U.S.: Scott Miller, University of Utah, Robert Scherpelz (External Dosimetry Team Leader), Pacific Northwest National Laboratory, and Melinda Krahenbuhl (Internal Dosimetry Team Leader), University of Utah

Brief Description: This dose reconstruction project is to establish a computerized database of individual internal and external radiation doses and uncertainty about those doses for each member of the 26,000 Mayak worker cohort under study in Project 2.2, Mayak Worker Epidemiology. The work product will be an electronic database containing updated individual dose estimates by year called "Doses 2008." As a result, improved doses for risk assessment analysis of causes of health effects from radiation exposure will be available. These data are also being used for other projects in Direction 2. This project is perhaps one of the most important of the 9 current projects within the Russian Health Studies Program. Without good dosimetry data, epidemiologists and biostatisticians will not be able to assess radiation-induced cancer risks from exposure to gamma, neutron, and alpha radiation. The Mayak worker cohort under study has the largest number of individuals and the highest chronic radiation exposures of any known population on earth. Approximately one-fourth of the exposed workers were women. Detailed health and exposure records are available at Mayak, thereby facilitating radiation health effects research.

Results to date: In addition to providing the dosimetric data for Project 2.2, Mayak Worker Epidemiology, this project has enhanced the understanding of plutonium metabolism in the human body and improved the biokinetic models for assessing dose from plutonium uptakes. These outcomes will be of direct benefit to DOE in improving the determination of dose to DOE workers from plutonium exposure. Improved doses have been calculated for a fraction of the group of workers. Dose calculations and uncertainty analysis of the doses continues. The Mayak worker dosimetry database "Doses 2005" was completed in 2005. Project 2.2 researchers will analyze the data using the most recent dose estimates and will produce revise radiation cancer risk estimates by September 2007.

Projected end date: September 2008.

Project 2.4 Team members in Ozersk, Russia: Dong-Ok Choe (external dosimetry), Melinda Krahenbuhl (U.S. internal dosimetry team leader), Scott Miller (U.S. Principal Investigator), John Fix (former U.S. external dosimetry team leader), Robert Scherpelz (new U.S. external dosimetry team leader), and Alexander Danilov (interpreter) (2003).

Principal Investigators:

R.F.: Sergey Romanov, Southern Urals Biophysics Institute
U.S.: Raymond Guilmette, Los Alamos National Laboratory

Brief Description: In phase III, researchers developed and implemented an effective, improved modeling approach for estimating organ doses to individual Mayak workers and linked best central estimates of dose with quantitative measures of uncertainty in the doses. In addition, investigators used Monte Carlo computational methods to calculate alpha particle radiation dose and dose rate patterns in the parenchymal regions of the lung so as to evaluate the extent and magnitude of non-uniformity of radiation dose delivered to this region of the lung. The main objective of phase IV of Project 2.5 is to obtain new knowledge and implement additional tools that will facilitate the development of a new harmonized plutonium dosimetry system, which will eventually replace the Mayak Worker Doses 2005 dosimetry system in Project 2.4, Mayak Worker Dosimetry. This includes: 1) experimentally addressing several issues that are crucial for lung dosimetry modeling, i.e., assessing the dose contribution from submicron alpha-emitting aerosols in the air of Mayak workplaces; further validating the fixed plutonium compartment and its incorporation into the physiologically realistic plutonium biokinetic model for lung; and evaluating the rapid absorption of plutonium from the lungs into the blood; 2) combining plutonium dose estimates with the uncertainties for individual Mayak workers by using available urine bioassay and/or postmortem tissue data together with the Bayesian approach implemented as the LANL/SUBI IMPDOS III computer code for individual dose assessment; and 3) applying the probability distributions for intake and biokinetic model parameters to assess the dose for workers monitored for plutonium to Mayak worker cohort members for whom little or no plutonium monitoring data are available.

Results to date: This project is provided valuable insights into the radiobiology and dosimetry of plutonium sequestered for decades in the lungs of Mayak workers. It was the first study to demonstrate in humans that inhaled plutonium is sequestered in the lung parenchyma. This information is being used to modify the human respiratory tract dosimetry models for improved lung dosimetry. In Phase II, microscopic analyses of the distribution of plutonium in the lungs of 24 Mayak workers showed that there was significantly more plutonium retained in the parenchymal regions of the lung than was predicted using either ICRP 66 or ICRP 30 respiratory tract dosimetry models. This long-term retention occurred for both allegedly more soluble and less soluble forms of the inhaled plutonium aerosol. Although in some cases, the fraction of plutonium remaining in lung was a small fraction of the plutonium body burden at death, this portion still contributed a significant amount of the total radiation dose to lung because of its very long retention time, i.e., decades after exposure. The consequence of underestimating the lung dose is that it leads to overestimating the risk coefficient per unit dose for radiation-induced lung diseases in epidemiological studies. Thus, using models that do not accurately represent the central values of dose for a population of measured data will introduce bias into the dose and risk assessment.

Projected end date: September 2010.

Principal Investigators:

R.F.: Vitaliy Telnov, Southern Urals Biophysics Institute
U.S.: Steve Belinsky, Lovelace Respiratory Research Institute

Brief Description: This molecular epidemiology study is to test for existence of early molecular markers of lung cancer due from radiation exposure following the inhalation of airborne plutonium. The first working hypothesis is that the frequency of methylation of the CpG islets of MGMT, p16, DAP-kinase, RASSF1A, and other genes in adenocarcinomas and squamous cell carcinomas is higher in plutonium-exposed workers than in unexposed subjects. The second working hypothesis is that the abnormal methylation of critical regulatory genes of carcinogenesis serves as a biomarker for the pre-clinical diagnosis of lung cancer in living plutonium-exposed workers.

Results to date: The original project demonstrated that plutonium plant workers with adenocarcinoma of the lung, when compared to controls and after adjustment for age and gender, had a statistically significant increased risk of methylation of the p16 tumor suppressor gene. This means that the gene designed to prevent lung cancer was inactivated by the exposure to inhaled plutonium. The current phase of the research is to examine methylation profiles in both adenocarcinomas and squamous cell carcinomas of the lung and to begin population-based studies in former Mayak workers. Given the renewed threat of nuclear terrorism following the tragedy of September 11, 2001, follow-up studies will determine whether specific methylation changes could be evaluated as intermediate biomarkers in risk assessment of persons exposed to radiation.

Projected end date: September 2008.

Principal Investigators:

R.F.: Tamara Azizova, Southern Urals Biophysics Institute
U.S.: David Brenner, Columbia University

Brief Description: This molecular epidemiology study is to develop a new biological dosimetry test using blood samples to determine internal and external radiation exposures. More specifically, by analyzing heritable changes in chromosomes in blood samples from Mayak workers exposed to different combinations of external and internal radiation for many years, the investigators will develop a calibrated test that will provide an estimate of both the internal and external ionizing radiation doses. Such a biomarker would significantly increase the power of epidemiologic studies of individuals exposed to densely-ionizing radiations, such as alpha particles, e.g., radon, plutonium workers, or neutrons, e.g., DOE/NRC workers, airline personnel. Ultimately, the blood test will be submitted to the U.S. Food and Drug Administration for approval.

Results to date: This study was the first to demonstrate a statistically significant dose-response between plutonium exposure and intra-arm chromosomal aberrations from worker blood samples. In fact, the test was sensitive enough to distinguish internal from external exposures. The current research is focused on calibrating the doses with the effects so as to develop a blood test for use in the nuclear, airline, and aerospace industries.

Projected end date: September 2008.

Principal Investigators:

R.F.: Klara Muksinova, Southern Urals Biophysics Institute
U.S.: Christopher Loffredo, Georgetown University

Brief Description: The aim of this project is to establish and maintain a state-of-the-art tissue repository designed to serve as a resource for studies of the effects of protracted internal and external radiation exposure on human health. Presently, the repository is located at the Southern Urals Biophysics Institute in Ozersk. It includes samples of archival autopsy tissues from 800 registrants, samples of surgical tissues from more than 250 individuals, and samples of blood and its components from about 1,600 Mayak workers. The storage conditions of the biosamples in the repository were designed to provide optimal long-term preservation of tissue samples. In conjunction with medical, occupational, and dosimetry information, data collected in the repository are used in molecular epidemiology studies. Such studies can be used to establish an association between disease and radiation exposure in individuals.

Results to date: Samples of tumor and other tissues for 155 registrants were delivered to the U.S. researchers working on several projects in the Russian Health Studies Program, i.e., Project 2.5, Plutonium Microdosimetry in the Lung, Project 2.6, Molecular Markers of Lung Cancer, and Project 2.7, Radiation Biomarkers. Methods of transportation of tissue samples from Russia to other countries by international air mail have been tested and implemented. A website in both Russian and English describes the contents of the repository and the procedures for researcher access to the contents. Further collection and storage of tissue samples in optimal conditions and intensification of efforts to inform scientists worldwide on the established repository and its biosamples are underway.

Projected end date: September 2012.

Completed Direction 1 Population Studies Under the JCCRER

Project 1.2a: Data Preservation and Scanning

Principal Investigators:

R.F.: Nikolai Startsev, Urals Research Center for Radiation Medicine
U.S.: Donna Cragle, Oak Ridge Institute for Science and Education

Description: This was a data preservation/records management project focused on establishing a document imaging system at URCRM for preserving valuable medical records of residents of the Southern Urals region exposed to radiation due to the operations at Mayak and environmental releases from there. These documents contain information from 1951 to the present with details on medical examinations, individual dose measurements, addresses, causes of death, and other data necessary for epidemiologic studies and dose reconstruction.

Results: Computer scanning equipment was installed. Scanning, verification, indexing, and creation of a computer database of the scanned documents were completed.

Date completed: September 2005.

Project 2.1: Metabolism and Dosimetry of Plutonium Industrial Compounds

Principal Investigators:

R.F.: Valentin Khokhryakov, Southern Urals Biophysics Institute
U.S.: Ronald E. Filipy, Washington State University Tri-Cities

Brief Description: This project was the first collaborative dosimetric project between scientists of the two countries. The project began as a one-year feasibility study to compare the two autopsy programs and progressed to a five-year project with the objective of combining and jointly analyzing the actinide metabolism data collected by the two registries: the Dosimetric Registry of the Mayak Production Association (DRMPA) and the United States Transuranium and Uranium Registries (USTUR). The first priority task of the feasibility study involved a series of sample exchanges to verify that no systematic differences were present in the analytical results obtained by both Registries. The results of the laboratory intercomparisons led to the conclusion that the data accumulated by both registries are reliable, correct, and can be used in joint investigations of actinide metabolism in humans. The primary objective of Phase 2 of Project 2.1 was to combine the data accumulated by both registries, create a joint database, and perform a mutual analysis of the unique information regarding the metabolism and dosimetry of plutonium and americium in the human body.

Results to date: High priority tasks involving the metabolism study and biokinetic modeling were begun during the project. The first important dosimetric finding was made regarding the systemic distribution of plutonium and 241-Am in humans: liver diseases were shown to affect the distribution of plutonium in the body, suggesting a translocation of the actinides from the liver to the skeleton. A comparative analysis of the SUBI lung model used at Mayak for dose assessment with the ICRP 66 model showed an advantage of the SUBI dosimetric lung model after long periods (10 and more years) of inhalation. The SUBI laboratory has since obtained modern instrumentation and reagents and updated radiochemical methods. The whole body counter from the Rocky Flats Plant became operational for measurements of actinides body burden in the Mayak workers.

Date completed: March 2000

Principal Investigators:

R.F.: Nadezda Okladnikova, Southern Urals Biophysics Institute
U.S.: Niel Wald, University of Pittsburgh

Brief Description: The main aim of this project was to validate the current dose-response models for acute exposure and develop new dose-response models for chronic exposure to external gamma rays and/or incorporated Pu-239.

Results to date: The study resulted in the development and establishment of the clinical-dosimetry database for 591 Mayak workers. This database included demographic, medical, and dosimetry information for 60 cases of acute radiation syndrome (ARS), 207 cases of chronic radiation sickness (CRS), 121 cases of plutonium pneumosclerosis, and 209 workers, who were not diagnosed with an occupational disease (control group). The procedure of performing quality control of the database was developed and carried out to compare the completeness and correspondence of the primary data with the information contained in the database. A code book containing the guidance for coding the primary data was prepared. A library, including "clear" standard data sets, was created. A data access agreement was developed. The database includes data for more than 17,500 person-years of follow-up and consists of more than 3.5 million individual data points. Vital status is known for 90.4% of the workers. Individually measured external gamma doses are available for 93.7% of the workers, and doses of internal exposure are available for 32.5% of the workers who were exposed to Pu-239 aerosols.

For more details, please refer to the following publications in English:

1. Claycamp HG, Sussman NB, Okladnikova ND, Azizova TV, Pesternikova VS, Sumina MV, Teplyakov II. Classification of Chronic radiation sickness cases using neural networks and classification trees. Health Phys. 2001 Nov; 81(5): 522-529
2. Claycamp HG, Sussman NB, Okladnikova ND, Azizova TV, Pesternikova VS, Sumina MV, Teplyakov II. Classification of Chronic radiation sickness cases using neural networks and classification trees. Health Phys. 2001 Nov; 81(5): 522-529
3. Scott BR, Lyzlov AF, Osovets SV. Evaluating the risk of death via the hematopoietic syndrome mode for prolonged exposure of nuclear workers to radiation delivered at very low rates. Health Phys. 1998 May; 74(5): 545-53
4. Okladnikova ND, Pesternikova VS, Sumina MV, Doshchenko VN. Occupational diseases from radiation exposure at the first nuclear plant in the USSR. Sci Total Environ. 1994 Mar 1; 142(1-2): 9-17
5. Okladnikova ND, Claycamp HG, Azizova TV, Belyaeva ZD, Pesternikova VS, Scott BR, Sumina MV, Teplyakov II, Boecker BB, Vasilenko EK, Khokhryakov VF, Fevralyov AN, Schekhter-Levin S, Wald N. Deterministic effects of occupational radiation exposures in some workers of the first atomic plant. Medical Radiology and Radiation Safety, 2001; 46(6): 84-93

Principal Investigators:

R.F.: Sergey Romanov, Southern Urals Biophysics Institute and Evgeny Vasilenko, Mayak
U.S.: Eric Grant, Radiation Effects Research Foundation

Brief Description: The fundamental goal of this project was to improve the quality and accessibility of the data needed for studies of radiation health effects and dosimetry in Mayak workers and the Ozersk population carried out by SUBI researchers and their collaborators. This project was developed to combine databases located in four different laboratories of two Russian organizations so as to facilitate researcher access to data. Much of this work has been accomplished through the creation of a unified relational database that serves as the source of primary data required for the radiation effects research studies along with the development of easy-to-use tools for accessing these data in formats needed by researchers. Efforts included:

• The continued development of the data access tools with particular emphasis on implementing requested features based on user feedback;
• Incorporation of additional data that has been identified for inclusion into the unified database;
• Development of quality assurance and quality control procedures for data contained in the unified database; and
• Technical support and administration of the existing database.