IMMUNOLOGICAL MONITORING OF THE PERSONNEL AT RADIATION HAZARDOUS FACILITIES.

The study of possible mechanisms resulting in changes in the immune system after exposure to ionizing radiation is an area that has not been thoroughly evaluated during recent years. This article presents an overview of immunological monitoring studies of personnel from the radiation-hazardous factories that took place over the past 20 years in Russia. The methodology of these studies is based on: (1) the preclinical evaluation of immune status of workers whose occupation involves potential exposure to ionizing radiation; (2) selecting at risk groups according to the nature of immune deficiency manifestation; and (3) studying the changes of immune status of employees with regard to the potential effects of radiation exposure. The principal aim of these studies is accumulation of new data on the impact of radiation exposure on the human immune system and search for the relationship between the clinical manifestations of immune disorders and laboratory parameters of immunity to improve the monitoring system of the health status of the professional workers involved in radiation-hazardous industrial environments and the population living close to these facilities.

Risk of Hematologic Malignancies in the Offspring of Female Workers of the Mayak Nuclear Facility in the Southern Urals, Russian Federation.

Long-term effects of in utero exposure to ionizing radiation remain poorly quantified in humans. In this study, the risk of hematologic malignancies was investigated in offspring of female workers of the Mayak Production Association, a large Russian nuclear facility. Excess relative risks (ERR) for exposure to gamma radiation and plutonium were estimated in a cohort of 8,466 offspring who were born between January 1, 1948 and December 31, 1988 and followed until 2009. An unstable linear ERR of 1.12 (95% CI 0.11-3.44) per 100 mGy gamma exposure in utero was estimated based on 32 incident hematologic malignancies in 277,002 person-years under risk. The ERR was increased in the dose category 20-79 mGy gamma exposure in utero (1.75, 95% CI 0.04; 5.63), while the other dose categories showed decreased or unstable estimates. Leukemia showed an ERR of 1.76 (95% CI 0.01-8.33) per 100 mGy based on 13 cases. There was no consistent association with plutonium exposure. While an increased risk of hematologic malignancies after gamma exposure in utero was suggested, the small numbers prevented more definitive conclusions.

Risk of solid cancer in the offspring of female workers of the Mayak nuclear facility in the Southern Urals, Russian Federation.

Studies of cancer risk following in utero exposure to ionizing radiation are limited in number, particularly for adult-onset cancers, and the evidence is unclear. In the present study, the risk of solid cancer incidence following in utero radiation exposure is examined among 8466 offspring of female nuclear workers at one of the largest nuclear facilities (Mayak Production Association) in the Russian Federation. Poisson regression methods were used to estimate excess relative risks (ERRs) per Gray (Gy). Mother's uterine gamma dose served as a surrogate for fetal gamma dose. During 277,002 person-years of follow-up (1948-2009), there were 177 first primary solid cancers excluding non-melanoma skin cancers. Estimated in utero gamma and plutonium doses exceeded zero for 41 and 23 % of offspring, respectively. Of the 177 solid cancers, 66 occurred among individuals with some in utero exposure to gamma radiation and 53 among those with estimated plutonium exposures. There was no indication of a statistically significantly increased risk of solid cancer incidence from in utero gamma exposure (linear ERR/Gy -1.0; upper 95 % confidence limit 0.5). This result was unchanged after accounting for subsequent occupational exposure. Plutonium doses were estimated but were too low to obtain meaningful risk estimates. Thus, in this cohort in utero radiation exposure was not associated with solid cancer risk. This is consistent with an earlier report of mortality in the cohort, but is based on twice as many cases and less susceptible to biases inherent in mortality analyses. Given the relatively young age of the cohort with respect to cancer, continued follow-up should be done as the number of cancer cases increases.

Lung cancer risks from plutonium: an updated analysis of data from the Mayak worker cohort.

Workers at the Mayak nuclear facility in the Russian Federation offer a unique opportunity to evaluate health risks from exposure to inhaled plutonium. Risks of mortality from lung cancer, the most serious carcinogenic effect of plutonium, were evaluated in 14,621 Mayak workers who were hired in the period from 1948-1982, followed for at least 5 years, and either monitored for plutonium or never worked with plutonium. Over the follow-up period from 1953-2008, there were 486 deaths from lung cancer, 446 of them in men. In analyses that were adjusted for external radiation dose and smoking, the plutonium excess relative risk (ERR) per Gy declined with attained age and was higher for females than for males. The ERR per Gy for males at age 60 was 7.4 (95% CI: 5.0-11) while that for females was 24 (95% CI: 11-56). When analyses were restricted to plutonium doses <0.2 Gy, the ERR per Gy for males at age 60 was similar: 7.0 (95% CI: 2.5-13). Of the 486 lung cancer deaths, 105 (22%) were attributed to plutonium exposure and 29 (6%) to external exposure. Analyses of the 12,708 workers with information on smoking indicated that the relationship of plutonium exposure and smoking was likely sub-multiplicative (P = 0.011) and strongly indicated that it was super-additive (P < 0.001). Although extensive efforts have been made to improve plutonium dose estimates in this cohort, they are nevertheless subject to large uncertainties. Large bioassay measurement errors alone are likely to have resulted in serious underestimation of risks, whereas other sources of uncertainty may have biased results in ways that are difficult to predict.

Cancer mortality following in utero exposure among offspring of female Mayak Worker Cohort members.

Little is known about long-term cancer risks following in utero radiation exposure. We evaluated the association between in utero radiation exposure and risk of solid cancer and leukemia mortality among 8,000 offspring, born from 1948-1988, of female workers at the Mayak Nuclear Facility in Ozyorsk, Russia. Mother's cumulative gamma radiation uterine dose during pregnancy served as a surrogate for fetal dose. We used Poisson regression methods to estimate relative risks (RRs) and 95% confidence intervals (CIs) of solid cancer and leukemia mortality associated with in utero radiation exposure and to quantify excess relative risks (ERRs) as a function of dose. Using currently available dosimetry information, 3,226 (40%) offspring were exposed in utero (mean dose = 54.5 mGy). Based on 75 deaths from solid cancers (28 exposed) and 12 (6 exposed) deaths from leukemia, in utero exposure status was not significantly associated with solid cancer: RR = 0.94, 95% CI 0.58 to 1.49; ERR/Gy = -0.1 (95% CI < -0.1 to 4.1), or leukemia mortality; RR = 1.65, 95% CI 0.52 to 5.27; ERR/Gy = -0.8 (95% CI < -0.8 to 46.9). These initial results provide no evidence that low-dose gamma in utero radiation exposure increases solid cancer or leukemia mortality risk, but the data are not inconsistent with such an increase. As the offspring cohort is relatively young, subsequent analyses based on larger case numbers are expected to provide more precise estimates of adult cancer mortality risk following in utero exposure to ionizing radiation.

How much can we say about site-specific cancer radiation risks?

Studies of Mayak workers and people who lived along the Techa River have demonstrated significant associations between low-dose-rate radiation exposure and increased solid cancer risk. It is of interest to use the long-term follow-up data from these cohorts to describe radiation effects for specific types of cancer; however, statistical variability in the site-specific risk estimates is large. The goal of this work is to describe this variability and provide Bayesian adjusted risk estimates. We assume that the site-specific estimates can be viewed as a sample from some underlying distribution and use Bayesian methods to produce adjusted excess relative risk per gray estimates in the Mayak and Techa River cohorts. The impact of the adjustment is compared to that seen in similar analyses in the atomic bomb survivors. Site-specific risk estimates in the Mayak and Techa River cohorts have large uncertainties. Unadjusted estimates vary from implausibly large decreases to large increases, with a range that greatly exceeds that found in the A-bomb survivors. The Bayesian adjustment markedly reduced the range of the site-specific estimates for the Techa River and Mayak studies. The extreme variability in the site-specific risk estimates is largely a consequence of the small number of excess cases. The adjusted estimates provide a useful perspective on variation in the actual risks. However, additional work on interpretation of the adjusted estimates, extension of the methods used in describing effect modification, and making more use of prior knowledge is needed to make these methods useful.

Lung cancer risk of Mayak workers: modelling of carcinogenesis and bystander effect.

Lung cancer mortality in the period of 1948-2002 has been analysed for 6,293 male workers of the Mayak Production Association, for whose information on smoking, annual external doses and annual lung doses due to plutonium exposures was available. Individual likelihoods were maximized for the two-stage clonal expansion (TSCE) model of carcinogenesis and for an empirical risk model. Possible detrimental and protective bystander effects on mutation and malignant transformation rates were taken into account in the TSCE model. Criteria for non-nested models were used to evaluate the quality of fit. Data were found to be incompatible with the model including a detrimental bystander effect. The model with a protective bystander effect did not improve the quality of fit over models without a bystander effect. The preferred TSCE model was sub-multiplicative in the risks due to smoking and internal radiation, and more than additive. Smoking contributed 57% to the lung cancer deaths, the interaction of smoking and radiation 27%, radiation 10%, and others cause 6%. An assessment of the relative biological effectiveness of plutonium was consistent with the ICRP recommended value of 20. At age 60 years, the excess relative risk (ERR) per lung dose was 0.20 (95% CI: 0.13; 0.40) Sv(-1), while the excess absolute risk (EAR) per lung dose was 3.2 (2.0; 6.2) per 10(4) PY Sv. With increasing age attained the ERR decreased and the EAR increased. In contrast to the atomic bomb survivors, a significant elevated lung cancer risk was also found for age attained younger than 55 years. For cumulative lung doses below 5 Sv, the excess risk depended linearly on dose. The excess relative risk was significantly lower in the TSCE model for ages attained younger than 55 than that in the empirical model. This reflects a model uncertainty in the results, which is not expressed by the standard statistical uncertainty bands.

Lung cancer in Mayak workers.

The cohort of nuclear workers at the Mayak Production Association, located in the Russian Federation, is a unique resource for providing information on the health effects of exposure to plutonium as well as the effects of protracted external dose. Lung cancer mortality risks were evaluated in 21,790 Mayak workers, a much larger group than included in previous evaluations of lung cancer risks in this cohort. These analyses, which included 655 lung cancer deaths occurring in the period 1955-2000, were the first to evaluate both excess relative risk (ERR) and excess absolute risk (EAR) models and to give detailed attention to the modifying effects of gender, attained age and age at hire. Lung cancer risks were found to be significantly related to both internal dose to the lung from plutonium and external dose, and risks were described adequately by linear functions. For internal dose, the ERR per gray for females was about four times higher than that for males, whereas the EAR for females was less than half that for males; the ERR showed a strong decline with attained age, whereas the EAR increased with attained age until about age 65 and then decreased. Parallel analyses of lung cancer mortality risks in Mayak workers and Japanese A-bomb survivors were also conducted. Efforts currently under way to improve both internal and external dose estimates, and to develop data on smoking, should result in more accurate risk estimates in the future.

Lung cancer mortality among nuclear workers of the Mayak facilities in the former Soviet Union. An updated analysis considering smoking as the main confounding factor.

A new analysis of lung cancer mortality in a cohort of male Mayak workers who started their employment in the plutonium and reprocessing plants between 1948 and 1958 has been carried out in terms of a relative risk model. The follow-up has been extended until 1999, moreover a new dosimetry system (DOSES2000) has been established. Particular emphasis has been given to a discrimination of the effects of external gamma-exposure and internal alpha-exposure due to incorporated plutonium. This study has also utilized and incorporated the information from a cohort of Mayak reactor workers, who were exposed only externally to gamma-rays. The influence of smoking as the main confounding factor for lung cancer has been studied. The baseline lung cancer mortality rate was not taken from national statistics but was derived from the cohort itself. The estimated excess relative risk for the plutonium alpha-rays was 0.23/Sv (95%CI: 0.16-0.31). The resulting risk coefficient for external gamma-ray exposure was very low with a statistically insignificant estimate of 0.058/Sv (95%CI: -0.072-0.20). The inferred relative risk for smokers was 16.5 (95%CI: 12.6-20.5).

Cancer mortality risk among workers at the Mayak nuclear complex.

At present, direct data on risk from protracted or fractionated radiation exposure at low dose rates have been limited largely to studies of populations exposed to low cumulative doses with resulting low statistical power. We evaluated the cancer risks associated with protracted exposure to external whole-body gamma radiation at high cumulative doses (the average dose is 0.8 Gy and the highest doses exceed 10 Gy) in Russian nuclear workers. Cancer deaths in a cohort of about 21,500 nuclear workers who began working at the Mayak complex between 1948 and 1972 were ascertained from death certificates and autopsy reports with follow-up through December 1997. Excess relative risk models were used to estimate solid cancer and leukemia risks associated with external gamma-radiation dose with adjustment for effects of plutonium exposures. Both solid cancer and leukemia death rates increased significantly with increasing gamma-ray dose (P < 0.001). Under a linear dose-response model, the excess relative risk for lung, liver and skeletal cancers as a group (668 deaths) adjusted for plutonium exposure is 0.30 per gray (P < 0.001) and 0.08 per gray (P < 0.001) for all other solid cancers (1062 deaths). The solid cancer dose-response functions appear to be nonlinear, with the excess risk estimates at doses of less than 3 Gy being about twice those predicted by the linear model. Plutonium exposure was associated with increased risks both for lung, liver and skeletal cancers (the sites of primary plutonium deposition) and for other solid cancers as a group. A significant dose response, with no indication of plutonium exposure effects, was found for leukemia. Excess risks for leukemia exhibited a significant dependence on the time since the dose was received. For doses received within 3 to 5 years of death the excess relative risk per gray was estimated to be about 7 (P < 0.001), but this risk was only 0.45 (P = 0.02) for doses received 5 to 45 years prior to death. External gamma-ray exposures significantly increased risks of both solid cancers and leukemia in this large cohort of men and women with occupational radiation exposures. Risks at doses of less than 1 Gy may be slightly lower than those seen for doses arising from acute exposures in the atomic bomb survivors. As dose estimates for the Mayak workers are improved, it should be possible to obtain more precise estimates of solid cancer and leukemia risks from protracted external radiation exposure in this cohort.

Bone cancers in Mayak workers.

Bone cancer mortality risks were evaluated in 11,000 workers who started working at the "Mayak" Production Association in 1948-1958 and who were exposed to both internally deposited plutonium and external gamma radiation. Comparisons with Russian and U.S. general population rates indicate excess mortality, especially among females, plutonium plant workers, and workers with external doses exceeding 1 Sv. Comparisons within the Mayak worker cohort, which evaluate the role of plutonium body burden with adjustment for cumulative external dose, indicate excess mortality among workers with burdens estimated to exceed 7.4 kBq (relative risk = 7.9; 95% CI = 1.6-32) and among workers in the plutonium plant who did not have routine plutonium monitoring data based on urine measurements (relative risk = 4.1; 95% CI = 1.2-14). In addition, analyses treating the estimated plutonium body burden as a continuous variable indicate increasing risk with increasing burden (P < 0.001). Because of limitations in current plutonium dosimetry, no attempt was made to quantify bone cancer risks from plutonium in terms of organ dose, and risk from external dose could not be reliably evaluated.

Liver cancers in Mayak workers.

Liver cancer mortality risks were evaluated in 11,000 workers who started working at the "Mayak" Production Association in 1948-1958 and who were exposed to both internally deposited plutonium and external gamma radiation. Comparisons with Russian liver cancer incidence rates indicate excess risk, especially among those with detectable plutonium body burdens and among female workers in the plutonium plant. Comparisons within the Mayak worker cohort which evaluate the role of plutonium body burden with adjustment for cumulative external dose indicate excess risk among workers with burdens estimated to exceed 7.4 kBq (relative risk = 17; 95% CI = 8. 0-36) and among workers in the plutonium plant who did not have routine plutonium monitoring data based on urine measurements (relative risk = 2.8; 95% CI = 1.3-6.2). In addition, analyses treating the estimated plutonium body burden as a continuous variable indicate increasing risk with increasing burden (P < 0.001). Relative risks tended to be higher for females than for males, probably because of the lower baseline risk and the higher levels of plutonium measured in females. Because of limitations in current plutonium dosimetry, no attempt was made to quantify liver cancer risks from plutonium in terms of organ dose, and risk from external dose could not be reliably evaluated.

Lung cancer mortality among male nuclear workers of the Mayak facilities in the former Soviet Union.

An analysis of lung cancer mortality in a cohort of 1,669 Mayak workers who started their employment in the plutonium and reprocessing plants between 1948 and 1958 has been carried out in terms of a relative risk model. Particular emphasis has been given to a discrimination of the effects of external gamma-ray exposure and internal alpha-particle exposure due to incorporated plutonium. This study has also used the information from a cohort of 2,172 Mayak reactor workers who were exposed only to external gamma rays. The baseline lung cancer mortality rate has not been taken from national statistics but has been derived from the cohort itself. For both alpha particles and gamma rays, the results of the analysis are consistent with linear dose dependences. The estimated excess relative risk per unit organ dose equivalent in the lung due to the plutonium alpha particles at age 60 equals, according to the present study, 0.6/Sv, with a radiation weighting factor of 20 for alpha particles. The 95% confidence range is 0.39/Sv to 1.0/Sv. For the gamma-ray component, the present analysis suggests an excess relative risk for lung cancer mortality at age 60 of 0.20/Sv, with, however, a large 95% confidence range of-0.04/Sv to 0.69/Sv.

Characteristics of the cohort of workers at the Mayak nuclear complex.

At Branch No. 1 of the Russian State Research Center "Biophysics Institute", a registry has been created of workers at the "Mayak" Production Association, the first nuclear complex in Russia. This registry includes 18,830 persons hired at Mayak's nuclear reactors and radiochemical and plutonium production plant between 1948 and 1972. Twenty-five percent of these workers are women. As of December 31, 1994, the vital status is known for approximately 90% of the cohort members. A total of 5,118 persons have died. The cause for 97% of total deaths has been ascertained. The cohort members were exposed to both external gamma radiation and internal radiation from incorporated plutonium. The plutonium body burden has been measured in 30% of the cohort members with potential for plutonium exposure. External gamma-ray doses were in the range from tenths of milligrays to about 10 Gy, and plutonium body burdens were up to about 260 kBq. In view of the nature of the Mayak worker cohort, it has the potential to provide reasonably precise, quantitative estimates of the long-term health effects associated with chronic low-dose-rate exposure to external gamma radiation as well as internal radiation from plutonium. However, a number of issues must be addressed before credible risk estimates can be obtained from this cohort. These issues include the development of an appropriate internal comparison group and/or external rates and separating of the effects of internal and external exposures on risk estimates.