Work package 4.1. Feasibility of pooled analysis and cancer in the Techa River in utero cohort
The overall objective is to facilitate the possibility to derive long-term cancer risk estimates for subjects exposed in uteroto protracted low-to-medium dose rate ionising radiation. This will be accomplished through:
Task 4.1.1 In utero cohort definition (URCRM, DCS; months: 1-2). Definitions of the Techa River in utero exposed cohort will be elaborated and eligibility criteria will be defined.
Task 4.1.2 Analysis of cohort specificity and sensitivity URCRM, DCS; months: 2-3). To analyse cohort specificity and sensitivity using quality control criteria developed in the framework of the SOUL project. The level of concordance between persons eligible for inclusion in the study cohort and those actually included will be evaluated by checks of a random sample.
Task 4.1.3 Extension of follow-up through 2009 (URCRM; months: 1-18). Cancer incidence/mortality follow-up will be extended through 2009 to encompass 60 years (from January 1, 1950 through December 31, 2009). Using routine methods of follow-up the URCRM staff will update information on vital status and cancer cases in the Techa River in uterocohort. Vital status will be followed using information from queries to address bureaus, tax books, interviews and medical examinations, cause of death register and death certificates available at the URCRM, and new death certificates which will be abstracted. The source of information on cancer will include notifications on cancer diagnosed for the first time (i.e. forms filled out in RF for each new cancer case), information from cancer registries at regional oncology dispensaries, patient’s medical histories stored at the URCRM archives and death certificates. The information on vital status and cancer diagnosis among in utero cohort members will be entered into the computer database.
Task 4.1.4. Coding of cancer cases (URCRM; months: 12-18). All cancer cases identified among in utero cohort subjects will be entered into the cancer register and coded in accordance with ICD9 rules.
Task 4.1.5 Analysis of completeness and quality of information (URCRM, DCS; months: 12-18). Quality control procedures developed in the framework of SOUL project will be applied for checking of completeness and quality of follow-up and cancer data. The procedures will include assessment of the proportion of study subjects lost to follow-up and the proportion of deaths with unknown cause; double blinded coding of a 5% random sample of cancer cases with an estimation of the misclassification level; the assessment of proportions of morphologically verified cancers and cancer confirmed by death certificate only.
Task 4.1.6 Assessment of feasibility and study power of pooling Mayak & Techa in utero cohorts (URCRM, SUBI, DCS; months: 15-24). Statistical power calculations for a combined cohort of subjects irradiated in utero due to mother’s occupational exposure (Mayak PA) or residence in radioactively contaminated area (Techa River) will be performed.
Task 4.1.7 Cancer risk analysis (URCRM, DCS; months: 18-30). Cancer risk analysis in the Techa in utero cohort will be carried out with adjustment for potential confounders. The data will be stratified by sex, ethnicity, attained age, follow-up period, radiation exposure doses. Different dose-response models will be fitted to the data to describe dose-effect relationship. Feasibility of cancer-site specific analyses will be tested. Models to explore factors modifying the radiation-associated risk will be tested.
Work package 4.2. Pooled analysis of Mayak and Techa River in utero cohorts
The overall objective is to assess long-term cancer risks following protracted low-to-medium dose rate in utero exposure. To increase the study power and to characterize more precisely the shape and magnitude of dose-response relationship a combined analysis of the female Mayak workers and Techa River in utero exposed cohorts will be performed. The study implementation will include:
Task 4.2.1 Assessment of compatibility and quality of data in Mayak and Techa in utero cohorts (DCS, SUBI, URCRM; months: 31-33). An assessment of compatibility and quality of vital status follow-up and cancer data in Mayak and Techa River in utero cohorts will be performed.
Task 4.2.2 Study protocol development (DCS, SUBI, URCRM; months: 31-36). Study protocol and analytical approach to the data analysis using two cohorts of individuals irradiated in utero due to maternal occupational and environmental exposures will be elaborated.
Task 4.2.3 Cancer risk analysis in the pooled in utero cohort (DCS, SUBI, URCRM; months: 36-48). The analyses will be based on excess relative risk models. The data will be stratified by gender, ethnicity, attained age, follow-up period, and radiation exposure doses. Dose-response models will be fitted to the data to describe dose- effect relationships. Cancer-site specific risk analyses will be performed. Models to explore factors modifying the radiation-associated risk will be tested.
Task 4.2.4 Coordination with related research in the Southern Urals (HPA, SUBI, URCRM, HGUM, UCLan)
To coordinate activities and avoid duplication with related research being carried out by others, particularly in the Russian Federation and the USA, an International Contact Group (ICG) will be set up to make decisions on key aspects of Southern Urals research; for example, regarding the use of dosimetry systems and criteria for defining study cohorts. The ICG will contain individuals in the Russian Federation, European Union and the USA who are leading major areas of radiation risk research in the Southern Urals. In order to assist decision-making, representation will be restricted to two persons from each of the RF, EU and USA who will meet every 2-3 months, often via telephone conference. The EU and RF members will:
Members of the SOLO consortium will also liaise with other Southern Urals researchers through their involvement in meetings of International groups on Epidemiology and Dosimetry, which will usually held around the same time as PMG meetings.
Work package 4.3. Internal dosimetry for those exposed in utero
This work will provide biokinetic and dosimetric models for in utero exposure to radionuclides of concern for Techa and Mayak exposures, principally isotopes of strontium and plutonium but also iodine. Because radionuclides are retained in body tissues of the newborn infant, it is also necessary to develop postnatal models and also consider transfer of radionuclides in breast-milk. The models will be used to calculate doses to offspring following radionuclide exposures of their mothers as part of the overall assessment of doses to Techa and Ozyorsk cohorts.
Task 4.3.1 Biokinetic model for Sr transfer to breast milk (URCRM, HPA). Work begun under SOUL will be completed, using Techa-specific data to adapt the ICRP model for the transfer of strontium to the suckling infant in breast-milk. Adjustments will also be made to the maternal model used to deliver strontium to the infant, necessitated by 90Sr intake re-evaluation performed in the framework of US-Russia Project and data on changes in Ca diet consumption by the pregnant women. A publication will be prepared and submitted to a peer reviewed journal.
Task 4.3.2 Assessment of radioactive exposure for Ozyorsk in utero cohort (SUBI). Ozyorsk residents identified as having beenexposed in utero will be interviewed. Measurements will be made of 241Am by WBC (gamma-spectrometry) and 239Pu in urine samples (alpha-spectrometry). A report will be produced that will then be used to judge whether the data will be useful for biokinetic modelling and input to epidemiological studies.
Task 4.3.3 Dosimetry models for in utero exposure (UF). Work under SOUL will be completed to provide fetal models for a full series of developmental stages, using specimens available at UF to prepare detailed models of the fetal skeleton and other organs. A report will be produced for SOLO internal information.
Task 4.3.4 Dosimetry models of the pregnant woman and fetus (UF, URCRM). In order to model doses to the fetus from radionuclides present in maternal organs and also doses from external exposures, it is necessary to include fetal models within maternal models. Within the timescale (and funding) of this project, it may be that only selected times will be considered. The models will be adapted to be Urals specific (skeletal weight, etc.). A publication will be prepared and submitted to a peer reviewed journal.
Task 4.3.5 Biokinetic model for in utero exposure to plutonium (SUBI, HPA, URCRM). The ICRP model for the calculation of dose to the fetus from plutonium isotopes employs a simple concentration ratio method. Available published data could be used to develop an improved model with greater physiological realism. This task will be undertaken if it is considered worthwhile on the basis that:
A report will be produced for SOLO internal information.
Task 4.3.6 Biokinetic model for in utero exposure to iodine (HPA, SUBI, URCRM). The ICRP model for the calculation of dose to the fetus from iodine isotopes could be made more physiologically realistic using available published data. In particular, consideration of transfer to the fetus in late gestation could be improved. This task will be undertaken if it is considered worthwhile on the basis that:
A publication will be prepared and submitted to a peer reviewed journal.
Task 4.3.7 Assessment of organ and tissue doses in utero and postnatally (URCRM, SUBI). The models developed will be used to calculate dose coefficients (all beneficiaries) and, with exposure data, to calculate doses to TROC members and members of the Ozyorsk sub-cohort. Evaluation of associated uncertainties, resulting from uncertainties in TRDS-based intake of radionuclides, biokinetic and dosimetric models will be performed. A final report for SOLO information will be prepared and consideration given to an open-literature publication.
Work package 4.4. Cause-of-death register for Techa River population
In the framework of the SOUL project, a cause-of-death registry was created for the catchment area encompassing 5 raions (Kaslinsky, Krasnoarmeysky and Kunashaksky raions in Chelyabinsk Oblast; Dalmatovsky and Kataisky raions in Kurgan Oblast). The cause-of-death registry includes all deaths registered in that area over the time period from 1950 through 2005, totalling about 148,000 cases. The registry provides informational support for epidemiological studies of radiation exposure effects among the population of interest. The system developed for coding of causes of death ensures high quality of information to be used in analyses of causes of both cancer and non-cancer mortality for the exposed residents.
It is planned in the framework of the present project to expand this cause-of-death registry (CDR) for the catchment area for the period from 2006 through 2009. It is expected that information on about 14,000 new deaths registered in the catchment area will be entered in the CDR which will provide adequate informational support to work-packages 4.1 and 4.2. In addition, the availability of these data will allow us to estimate the background death rates (mortality among unexposed residents) in the catchment area, and to perform a comparative analysis of mortality.
Task 4.4.1 Information collection (URCRM; months: 1-15). Death certificates will be copied for the deceased in the catchment area (ca 14,000).
Task 4.4.2 Data entry (URCRM; months: 1-39). Information derived from paper records will be entered into the CDR database; to ensure adequate quality of data entry, specific dictionaries will be maintained. Textual information on causes of death will be spell-checked.
Task 4.4.3 Coding (URCRM; months: 4-42). The semi-automatic coding system will be used to code the causes of death. New records will be examined by two independent coders.
Task 4.4.4 Improvement of the coding system (URCRM; months: 7-36). Dictionaries for the semi-automatic coding system will be maintained. Improvements will be made in the system for semi-automatic coding.
Task 4.4.5 Linkage of CDR with the fixed cohorts (URCRM; months: 7-45). Study cohort members will be identified among individuals listed in the CDR. Data on causes of death will be transferred to the researchers involved in WP4.1 and WP4.2.
Task 4.4.6 Demographic characteristics of the population (URCRM, DCS; months: 37-42). Information will be obtained on the gender and age distribution for the population living in the catchment area for the follow-up period 2006-2009.
Task 4.4.7 Mortality analysis (URCRM, DCS; months: 40-48). Exposed and unexposed individuals in the cause-of-death registry will be identified and comparative analyses of mortality for both groups will be undertaken.