The Techa River Cohort: study design and follow-up methods

Residents living on the banks of the Techa River in the Southern Urals region of Russia were exposed to radioactive contamination from the Mayak plutonium production and separation facility that discharged liquid radioactive waste into this river. This paper describes the methods used to establish and follow the Extended Techa River Cohort (ETRC), which includes almost 30,000 people living along the Techa River who were exposed to a complex mixture of radionuclides, largely 90Sr and 137Cs. The system of regular follow-up allows ascertainment of vital status, cause of death and cancer incidence. With over 50 years of follow-up and over 50% deceased, the ETRC now provides a valuable opportunity to study a wide range of health effects, both early and late, associated with protracted internal and external radiation exposures. The wide range of doses allows analysis of the nature of the dose-response relationship based on internal comparisons. Other features of the cohort are the high proportion (40%) exposed under age 20, and the inclusion of both sexes. The limitations of the study include loss to follow-up due to difficulties in tracing some cohort members and migration and incomplete ascertainment of cause of death.     

Minisatellite germline mutation rate in the Techa River population

Germline mutation at eight minisatellite loci has been studied among the irradiated families from the Techa River population and non-exposed families from the rural area of the Chelyabinsk and Kurgan Oblasts. The groups were matched by ethnicity, parental age, occupation and smoking habit. A statistically significant 1.7-fold increase in mutation rate was found in the germline of irradiated fathers, whereas maternal germline mutation rate in the exposed families was not elevated. Most of the minisatellite loci showed an elevated paternal mutation rate in the exposed group, indicating a generalised increase in minisatellite germline mutation rate in the Techa River population. These data suggest that the elevated minisatellite mutation rate can be attributed to radioactive exposure. The spectra of paternal mutation seen in the unexposed and exposed families were indistinguishable.     

Characterization of immunity status in exposed residents of the Techa riverside villages 50 years after the onset of radiation exposure

The goal of the study was to assess the state of immunity in exposed residents of the Techa riverside villages 50 years, or more, after the onset of radiation exposure. 127 chronically exposed persons and 55 unexposed persons were studied. The mean dose to red bone marrow (RBM) was 0.69 Sv in exposed subjects, the mean dose to soft tissue was 0.07 Sv, the mean dose rate amounted to 0.10 Sv/yr to RBM and 0.02 Sv/yr to soft tissues in 1950. The state of the basic links of the immunity system (cellular, humoral, mononuclear phagocyte system, cytokine spectrum, etc.) was assessed using conventional methods. Exposed persons manifested a significant reduction in the absolute counts of CD3+, CD4+, CD 11b+, CD16+ lymphocytes in the peripheral blood, as well as an increase in the relative counts of CD8+. The group comprised of the Techa riverside residents demonstrated an increased immunoregulatory index (exposed individuals: 1.47; controls: 1.71, p = 0.001). An increased production of Immunoglobulin A and increased proportions of CD25+ lymphocytes were revealed in exposed individuals. Changes in the phagocytic activity of neutrophils and monocytes were insignificant, and were primarily associated with changes in the proportions of pagocytes in the peripheral blood stream. The state of the immunity in chronically exposed individuals at late time after the begin of exposure is characterized by a number of specific features reflected primarily on the cellular immunity. No relationship between immunity changes and accumulated exposure dose and dose rate were noted over the period of maximum radiation exposures (1950).     

Tobacco use,body mass and cancer mortality in Mumbai Cohort Study

Background: Tobacco use and body mass are major risk factors for many cancers. Despite this, very little is known about their combined effect on cancer mortality. These relationships are virtually unexplored in populations having patterns of both tobacco use and body habitus atypical of those typically enrolled in epidemiologic studies. Methods: A prospective cohort study of 148,173 men and women aged ≥35 years was conducted in Mumbai, India. Subjects were recruited during 1991–1997, measured for a variety of risk factors, including tobacco use and anthropometry, and then followed for approximately 5–6 years. Results: During 774,129 person-years of follow up, a total of 796 cancer deaths were observed. Tobacco use, especially smoking in men, was associated with particularly high risk of death in extreme categories of body mass. At highest risk were underweight smoking males [hazard ratio (HR) = 9.45, 5.87, and 5.75 for those smokers who were extremely thin (<16.0 kg/m²), very thin (16.0 to <17.0 kg/m²), or thin (17.0 to <18.5), respectively]. Significant effects of underweight among never and smokeless tobacco users disappeared with exclusion of individuals with ≤2 years of follow up. Extremely thin (<16.0 kg/m²) women smokeless tobacco users had an elevation in risk, HR = 2.95, that actually appeared to increase (to 3.21) with exclusion of individuals who were diagnosed within 2 years of follow up. Conclusion: Tobacco use and undernutrition are known to be serious problems in developing countries. The current study underlines the strikingly elevated risk of cancer when they occur together.     

The effects of chronic radiation exposure on the frequency of mutations at minisatellite DNA loci in residents of the Techa Riverside Villages

The frequency of mutations at eight minisatellite DNA loci (B6.7, CEB1, CEB15, CEB25, CEB 36, MS1, MS31 and MS32) in peripheral blood cells were assessed for exposed residents of the Techa riverside villages as a function of individual exposure doses. The frequency of minisatellite mutations was found to be significantly higher in male gametes than in female ones; no clear-cut dose-effect relationship was traced. There was no evidence of dependence of mutation frequency on exposure dose rates in the year of conception, the offspring's intrauterine red bone marrow dose and soft tissues doses.     

Solid cancer mortality associated with chronic external radiation exposure at the French atomic energy commission and nuclear fuel company

Studies of nuclear workers make it possible to directly quantify the risks associated with ionizing radiation exposure at low doses and low dose rates. Studies of the CEA (Commissariat à l'Energie Atomique) and AREVA Nuclear Cycle (AREVA NC) cohort, currently the most informative such group in France, describe the long-term risk to nuclear workers associated with external exposure. Our aim is to assess the risk of mortality from solid cancers among CEA and AREVA NC nuclear workers and its association with external radiation exposure. Standardized mortality ratios (SMRs) were calculated and internal Poisson regressions were conducted, controlling for the main confounding factors [sex, attained age, calendar period, company and socioeconomic status (SES)]. During the period 1968-2004, there were 2,035 solid cancers among the 36,769 CEA-AREVA NC workers. Cumulative external radiation exposure was assessed for the period 1950-2004, and the mean cumulative dose was 12.1 mSv. Mortality rates for all causes and all solid cancers were both significantly lower in this cohort than in the general population. A significant excess of deaths from pleural cancer, not associated with cumulative external dose, was observed, probably due to past asbestos exposure. We observed a significant excess of melanoma, also unassociated with dose. Although cumulative external dose was not associated with mortality from all solid cancers, the central estimated excess relative risk (ERR) per Sv of 0.46 for solid cancer mortality was higher than the 0.26 calculated for male Hiroshima and Nagasaki A-bomb survivors 50 years or older and exposed at the age of 30 years or older. The modification of our results after stratification for SES demonstrates the importance of this characteristic in occupational studies, because it makes it possible to take class-based lifestyle differences into account, at least partly. These results show the great potential of a further joint international study of nuclear workers, which should improve knowledge about the risks associated with chronic low doses and provide useful risk estimates for radiation protection.     

Cancer incidence and mortality after low-dosage radiation exposure: Epidemiological aspects

Current recommendations for limiting exposure to ionizing radiation are based on the linear no-threshold (LNT) model for radiation carcinogenesis under which every dose, no matter how low, bears some cancer risk. In this review, epidemiological evidence is discussed that the LNT hypothesis is incorrect at low doses. A large set of data was accumulated that show that cancer risk after ordinarily encountered radiation exposure (natural background radiation, medical X-rays, etc.) is much lower than estimates based on the LNT model. The discovery of low-level radiation hormesis (stimulating effect) implies a non-linear dose-response curve in the low-dosage region. Further studies in this field will provide new insights into the mechanisms of radiation carcinogenesis.     

Cancer incidence and mortality after low-dose radiation exposure: epidemiological aspects

Current recommendations for limiting exposure to ionizing radiation are based on the linear-no-threshold (LNT) model for radiation carcinogenesis under which every dose, no matter how low, carries with it some cancer risk. In this review, epidemiological evidences are discussed that the LNT hypothesis is incorrect at low doses. A large set of data was accumulated that showed that cancer risk after ordinarily encountered radiation exposure (natural background radiation, medical X-rays, etc.) is much lower than projections based on the LNT model. The discovery of the low-level radiation hormesis (stimulating effect) implies a non-linear dose-response curve in the low-dose region. The further studies in this field will provide new insights about the mechanisms of radiation carcinogenesis.     

Obesity and liver cancer mortality in Asia: The Asia Pacific Cohort Studies Collaboration

While obesity is associated with liver cancer in studies from western societies, the paucity of data from Asia limits insights into its aetiological role in this population. We examined the relationship between body mass index (BMI) and liver cancer mortality using data from the Asia Pacific Cohort Studies Collaboration. In 309,203 Asian study members, 4 years of follow-up gave rise to 11,135 deaths from all causes, 420 of which were ascribed to liver cancer. BMI, whether categorised according to current guidelines for Asian groups or World Health Organisation recommendations, was not associated with liver cancer in any of our analyses.     

Protracted low-dose radiation priming and response of liver to acute gamma and proton radiation

Abstract

This study evaluated liver from C57BL/6 mice irradiated with low-dose/low-dose-rate (LDR) γ-rays (0.01 Gy, 0.03 cGy/h), with and without subsequent exposure to acute 2 Gy gamma or proton radiation. Analyses were performed on day 56 post-exposure. Expression patterns of apoptosis-related genes were strikingly different among irradiated groups compared with 0 Gy (p < 0.05). Two genes were affected in the Gamma group, whereas 10 were modified in the LDR + Gamma group. In Proton and LDR + Proton groups, there were six and 12 affected genes, respectively. Expression of genes in the Gamma (Traf3) and Proton (Bak1, Birc2, Birc3, Mcl1) groups was no longer different from 0 Gy control group when mice were pre-exposed to LDR γ-rays. When each combined regimen was compared with the corresponding group that received acute radiation alone, two genes in the LDR + Gamma group and 17 genes in the LDR + Proton group were modified; greatest effect was on Birc2 and Nol3 (> 5-fold up-regulated by LDR + Protons). Oxygen radical production in livers from the LDR + Proton group was higher in LDR, Gamma, and LDR + Gamma groups (p < 0.05 vs. 0 Gy), but there were no differences in phagocytosis of E. coli. Sections stained with hematoxylin and eosin (H&E) suggested more inflammation, with and without necrosis, in some irradiated groups. The data demonstrate that response to acute radiation is dependent on radiation quality and regimen and that some LDR γ-ray-induced modifications in liver response were still evident nearly 2 months after exposure.     

Childhood energy intake and adult mortality from cancer: the Boyd Orr Cohort Study.

OBJECTIVE: To examine the relation between energy intake in childhood and adult mortality from cancer. STUDY DESIGN: Cohort study. SETTING: 16 rural and urban centres in England and Scotland. SUBJECTS: 3834 people who took part in Lord Boyd Orr''s Carnegie survey of family diet and health in prewar Britain between 1937 and 1939 who were followed up with the NHS, central register. Standardised methods were used to measure household dietary intake during a one week period. MAIN OUTCOME MEASURES: Cancer mortality. RESULTS: Significant associations between childhood energy intake and cancer mortality were seen when the confounding effects of social variables were taken into account in proportional hazards models (relative hazard for all cancer mortality 1.15 (95% confidence interval 1.06 to 1.24), P = 0.001, for every MJ increase in adult equivalent daily intake in fully adjusted models). This effect was essentially limited to cancers not related to smoking (relative hazard 1.20; 1.07 to 1.34; P = 0.001), with similar effects seen in men and women. CONCLUSION: This positive association between childhood energy intake and later cancer is consistent with animal evidence linking energy restriction with reduced incidence of cancer and the association between height and human cancer, implying that higher levels of energy intake in childhood increase the risk of later development of cancer. This evidence for long term effects of early diet confirm the importance of optimal nutrition in childhood and suggest that the unfavourable trends seen in the incidence of some cancers may have their origins in early life.     

Altitude, radiation, and mortality from cancer and heart disease

The variation in background radiation levels is an important source of information for estimating human risks associated with low-level exposure to ionizing radiation. Several studies conducted in the United States, correlating mortality rates for cancer with estimated background radiation levels, found an unexpected inverse relationship. Such results have been interpreted as suggesting that low levels of ionizing radiation may actually confer some benefit. An environmental factor strongly correlated with background radiation is altitude. Since there are important physiological adaptations associated with breathing thinner air, such changes may themselves influence risk. We therefore fit models that simultaneously incorporated altitude and background radiation as predictors of mortality. The negative correlations with background radiation seen for mortality from arteriosclerotic heart disease and cancers of the lung, the intestine, and the breast disappeared or became positive once altitude was included in the models. By contrast, the significant negative correlations with altitude persisted with adjustment for radiation. Interpretation of these results is problematic, but recent evidence implicating reactive forms of oxygen in carcinogenesis and atherosclerosis may be relevant. We conclude that the cancer correlational studies carried out in the United States using vital statistics data do not in themselves demonstrate a lack of carcinogenic effect of low radiation levels, and that reduced oxygen pressure of inspired air may be protective against certain causes of death.     

Ecotoxicological study of bottom sediments from reservoir 11 of the Techa River cascade

The ecotoxicological properties of sediments from reservoir R-11 of the Techa River cascade are studied in comparison to the Shershni reservoir. Radiochemical analysis of sediment and water samples from R-11 show that the radioactivity of the sediments ranges from 240 to 360 kBq/dm³ dry weight for ⁹⁰Sr and from 10 to 161 kBq/dm³ dry weight for ¹³⁷Cs. The absorbed doses for Oligochaeta from R-11 are calculated on the basis of radiochemical data. The hydrobiological studies include (1) study of the population density and diversity of Oligochaeta species in the reservoirs and (2) laboratory bioassay of sediments with Tubifex tubifex as a biomonitor species. The results indicate that the Oligochaeta population density in R-11 is less than in the Shershni reservoir. No significant effects of the absorbed dose rate on population density, survival rate, or fertility are found in a laboratory Tubificidae bioassay of R-11 sediments. However, a decrease in fertility is noted in experiments at a higher absorbed dose.     

Fetal radiation exposure induces testicular cancer in genetically susceptible mice

The prevalence of testicular germ cell tumors (TGCT), a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. Since the majority of testicular cancers are derived from germ cells at the stage of transformation of primordial germ cell (PGC) into gonocytes, the increase has been attributed to maternal/fetal exposures to environmental factors. We examined the effects of an estrogen (diethylstilbestrol, DES), an antiandrogen (flutamide), or radiation on the incidence of testicular germ cell tumors in genetically predisposed 129.MOLF-L1 (L1) congenic mice by exposing them to these agents on days 10.5 and 11.5 of pregnancy. Neither flutamide nor DES produced noticeable increases in testis cancer incidence at 4 weeks of age. In contrast, two doses of 0.8-Gy radiation increased the incidence of TGCT from 45% to 100% in the offspring. The percentage of mice with bilateral tumors, weights of testes with TGCT, and the percentage of tumors that were clearly teratomas were higher in the irradiated mice than in controls, indicating that irradiation induced more aggressive tumors and/or more foci of initiation sites in each testis. This radiation dose did not disrupt spermatogenesis, which was qualitatively normal in tumor-free testes although they were reduced in size. This is the first proof of induction of testicular cancer by an environmental agent and suggests that the male fetus of women exposed to radiation at about 5-6 weeks of pregnancy might have an increased risk of developing testicular cancer. Furthermore, it provides a novel tool for studying the molecular and cellular events of testicular cancer pathogenesis.     

Preliminary FISH-based assessment of external dose for residents exposed on the Techa River

This paper presents the results of a feasibility cytogenetic study using the fluorescence in situ hybridization (FISH) translocation assay for residents of villages located on the Techa River (Southern Urals, Russia) contaminated with liquid radioactive wastes from the Mayak plutonium facility in 1949-1956. The study was conducted with two groups of donors that differed in their main pathways of exposure. The first group comprised 18 residents of the middle Techa region who were exposed predominantly from ingestion of radionuclides (mostly (89,90)Sr) via the river water and local foodstuffs. The second group included 20 residents of Metlino, the closest village to the site of releases, who were exposed to external γ radiation from the contaminated river bank and exposed internally from dietary intake of radionuclides. A significant linear dependence between the radiation-induced translocation frequency and individual red bone marrow dose from incorporated (89,90)Sr, calculated with the Techa River Dosimetry System (TRDS), was found in the first group of donors. This allowed us to take the contribution of (89,90)Sr to the total radiation-induced translocation frequency into account for the second group of donors and to analyze translocations resulting from external γ-ray exposure. Individual doses from external exposure derived from the corrected translocation frequency for the second group of donors (Metlino residents), using a linear dose-response coefficient of 0.015 translocation/cell/Gy recommended by Edwards et al. in 2005, were shown to vary up to 2.1 Gy, with an average value of 0.48 Gy, which was in agreement with TRDS-based external dose estimates for Metlino residents.