Direction 2: Worker Health Effects Research
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.
Project 2.4: Mayak Worker Dosimetry
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).
Project 2.5: Improved Plutonium Dose Assessment Methods in Mayak Workers
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.
Project 2.6: Molecular Markers of Lung Cancer in Mayak
Workers
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.
Project 2.7: Radiation Biomarkers
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.
Project
2.8: Mayak Worker Tissue Repository
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.
Completed Direction 2 Worker Studies Under the JCCRER
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
Project 2.3: The Deterministic Effects of Occupational
Exposure (Funded by the Nuclear Regulatory Commission)
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:
- 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
- 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
- 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
- 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
- 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
Date completed: May 2002.
Project 2.9: Database Integration
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.
Results to date: Prior to the development of the unified
database, each of the four Russian laboratories involved in
studies of the Mayak worker and offspring cohorts independently
collected and organized their data in a manner unsuited for
joint studies. This project has led to significant progress
toward creating a unified, shared database in which each participating
group contributes and takes responsibility for the maintenance
and documentation for those data for which they have particular
expertise.
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