Influence of alpha and gamma radiations and non-radiation risk factors on the incidence of malignant liver tumors among Mayak PA workers.

This Mayak worker-based study focuses on evaluating possible associations between malignant liver cancers and chronic alpha irradiation, chronic gamma irradiation, and non-radiation risk factors (alcohol consumption, smoking, viral hepatitis, chemical exposure, and chronic digestive diseases). This is the first multivariate study related to liver cancer among Mayak workers. The study was performed using the nested, case-control approach and includes 44 cases of malignant liver tumors diagnosed from 1972 to 1999, and 111 matched controls. Adjusted odds ratio (OR(ad)) was evaluated relative to a group of workers with alpha radiation doses to liver (D(alpha)) < 2.0 Gy. Dose estimates of D(alpha) > 2.0 Gy (corresponding (239)Pu body burden estimates >20.4 kBq) were significantly associated (p < 0.003) with the occurrence of hemangiosarcomas (HAS) but only marginal significance (0.05 < p < 0.1) was found for hepatocellular cancers (HCC). The ORad for HAS was 41.7 [95% confidence interval (CI): 4.6, 333] for a group with D(alpha) in the range >2.0-5.0 Gy and was 62.5 (7.4, 500) for a group with D(alpha) > 5.0-16.9 Gy. The attributable risk (AR) was calculated as 82%. For HCC, O(Rad) was estimated as 8.4 (0.8, 85.3; p < 0.07) for a group with D(alpha) in the range >2.0-9.3 Gy. For the indicated group, the AR was 14%. An association with high external gamma-ray doses (D(gamma)) to the total body was revealed for both HCC and for combined liver cancers when dose was treated as a continuous variable. However, we find no evidence that chronic low doses of gamma rays are associated with liver cancer occurrence. Cholangiocarcinoma (CHC) was not associated with either alpha- or gamma-ray exposure. As expected, an association between alcohol abuse and HCC was inferred [O(Rad) = 3.3 (1.2, 9); AR = 41%] but not for CHC or HAS.

Modifying effects of health status, physiological, and dosimetric factors on extrapulmonary organ distribution and excretion of inhaled plutonium in workers at the Mayak Production Association.

This paper summarizes the systemic organ distribution of plutonium in workers exposed by chronic inhalation at the Mayak Production Association (MPA). Using results of radiochemical measurements in soft tissue and bone samples collected at autopsy of 853 autopsy cases, this paper provides data on the effects of various chronic diseases and malignant tumors as well as exposure time, age, sex, and body burden on systemic retention of plutonium in 22 extrapulmonary organs and on the urinary excretion rate of the nuclide. Some aspects of this work have been reported already. The results of present autopsy studies showed that liver pathology accompanied by strong fatty dystrophy of hepatocytes results in a significant relative decrease in the fraction of systemic plutonium in the liver and contravariant increase in the skeletal fraction. The average fractions of systemic plutonium in the liver and the skeleton of those MPA workers were 15% and 75%, respectively, in comparison with 47% and 45% in healthy individuals. Some of the plutonium also redistributed from the liver via blood to other systemic soft tissues. Plutonium not redistributed was excreted with urine. The results of multivariate regression analysis indicated some time-related and sex-related changes not connected with pathology for the liver and the skeleton retention fractions and excretion rate of plutonium. The current ICRP biokinetic models do not account for the influence of different pathological processes in the body on plutonium distribution in systemic organs and urinary excretion. This could have significant consequences for dosimetry calculations and risk estimations.

Chromosomal aberrations in lymphocytes of peripheral blood among Mayak facility workers who inhaled insoluble forms of 239PU.

A cytogenetic study was performed on 79 plutonium (Pu) workers chronically exposed to alpha radiation from inhaled, low-transportable (insoluble) compounds of airborne 239Pu and to external gamma rays. Body burden estimates for 239Pu ranged from 0 to 15.5 kBq. Chromosomal aberrations (CAs) (stable and unstable) among peripheral blood lymphocytes and cumulative alpha radiation doses were evaluated approximately 25 y after first contact with 239Pu. For the cytogenetic analyses, a standard two-day peripheral blood lymphocyte culture technique was applied. While alpha radiation doses continually increase up to the time of cytogenetic measurements, significant gamma ray exposures essentially ceased long before the time of measurement, so that alpha and gamma doses were not correlated. For the exposed workers, the mean 239Pu body burden (estimate), evaluated at the time of the cytogenetic measurement, was 1.23 +/- 0.26 kBq and the corresponding mean absorbed external gamma ray dose (estimate) to the total body was 0.076 +/- 0.009 Gy. Single and multivariate regression analyses were performed on the CA data. Stable, unstable and total aberrations increased as the 239Pu body burden increased over the range 0-4.5 kBq. However, above this range little additional increase was observed. CAs were weakly correlated with time since the first intake of 239Pu. No relationship between chromatid aberrations and 239Pu incorporation was found. Unstable (but not stable) aberrations were correlated with gamma radiation dose. No significant relationship of CA and smoking was found.

The effect of state of health on organ distribution and excretion of systemic plutonium in the Mayak workers.

The extrapulmonary distribution of plutonium in 20 organs (excluding the respiratory tract) was studied in workers who chronically inhaled plutonium at the radiochemical plants of the Mayak Production Association (Ozyorsk, Russia). The data were obtained by radiochemical analysis of soft tissue and bones samples collected at autopsy of 591 workers. The systemic plutonium distribution was determined in healthy individuals as well as in those with health impairment, specifically for those with liver diseases. Twenty-five years after the beginning of inhalation, systemic fractions in the liver and skeleton of individuals who were healthy at the time of death approximate the ratio 45%:45% proposed in the International Commission on Radiological Protection (ICRP) Publication 30. Pathological processes in the liver, accompanied by fatty dystrophy of hepatocytes, increased plutonium clearance from the liver. There was a considerable shift of the plutonium from the liver to the skeleton in individuals who died from liver disease. The average fractions of systemic plutonium in the liver and skeleton of those individuals were 14% and 78% respectively, which did not correspond to ICRP models, indicating a significant effect of disease conditions. Plutonium that was not redistributed was excreted. The urinary excretion rate of plutonium also correlated with state of health. The observed excretion as a fraction of systemic content was 1.64 x 10(-5) d(-1) for individuals in good health and 2.34 x 10(-5) d(-1) for individuals with various chronic diseases. The current models do not account for the influence of different pathological processes in the body on plutonium distribution and retention in systemic organs. This could have significant consequences for dosimetry calculations and risk estimations.

Interaction of radiation and smoking in lung cancer induction among workers at the Mayak nuclear enterprise.

For radiation-related cancer risk evaluation, it is important to assess not only influences of individual risk factors but also their interactive effects (e.g., additive, multiplicative, etc.). Multivariate analysis methods adapted for interactive effects allow such assessments. We have used a multivariate analysis approach to investigate the pair-wise interactions of the previously identified three main etiological factors for lung cancer induction in Russian workers of the Mayak Production Association (PA) nuclear enterprise. These three factors are as follows: (1) body burden of inhaled plutonium-239 (239Pu), an influence on absorbed alpha-radiation dose; (2) cumulative, absorbed external gamma-radiation dose to the lung; and (3) level of cigarette smoking as indicated by a smoking index (SI). The SI represents the cigarettes smoked per day times years smoking. The Mayak PA workers were exposed by inhalation to both soluble and insoluble forms of 239Pu. Based on a cohort of 4,390 persons (77% male), we conducted a nested, case-control study of lung cancer induction using 486 matched cases and controls. Each case was matched to two controls. Matching was based on five factors: sex, year of birth, year work began, profession, and workplace. Three levels of smoking were considered: low (SI = 1 to 499), used as a reference level; middle (SI = 500 to 900); and high (SI = 901 to 2,000). For lung cancer induction, a supra-multiplicative effect was demonstrated for high external gamma-ray doses (> 2.0 Gy) plus high 239Pu intakes (body burden >2.3 kBq). This observation is consistent with the hypothesis of curvilinear dose-response relationships for lung cancer induction by high- and low-LET radiations. The interaction between radiation (external gamma rays or 239Pu body burden) and cigarette smoke was found to depend on the smoking level. For the middle level of smoking in combination with gamma radiation (> 2.0 Gy) or 239Pu body burden (> 2.3 kBq), results were consistent with additive effects. However, for the high level of smoking in combination with gamma radiation (> 2.0 Gy) or 239Pu body burden (> 2.3 kBq), results were consistent with the occurrence of multiplicative effects. These results indicate that low-dose risk estimates for radiation-induced lung cancer derived without adjusting for the influence of cigarette smoking could be greatly overestimated. Further, such systematic error may considerably distort the shape of the risk vs. dose curve and could possibly obscure the presence of a dose threshold for radiation-induced lung cancer.

Extrapulmonary organ distribution of plutonium in healthy workers exposed by chronic inhalation at the Mayak production association.

The systemic distribution of plutonium was determined for "healthy" workers who chronically inhaled plutonium at the radiochemical plants of the Mayak Production Association. The data were obtained by radiochemical analysis of soft tissues and bones samples collected upon autopsy of 120 workers who died from acute coronary diseases and accidents. The soft tissue samples were wet-ashed using nitric acid and hydrogen peroxide. Bone samples were ashed in a muffle furnace at 500 degrees C. Plutonium was extracted on anionite and coprecipitated with bismuth phosphate. The precipitation was blended with ZnS powder, and the alpha-activity was measured by ZnS solid scintillation counting in a low-background alpha radiometer. Twenty-five years after the beginning of inhalation exposures, the average percentage of plutonium in the skeleton and liver was 50% and 42% of systemic burden, respectively. A multivariate regression was used to quantify the effects of exposure time, "transportability" of the various compounds, plutonium body content, and age on systemic plutonium distribution. The early retention of plutonium in the liver is assumed to be greater than that in the skeleton. The initial distribution of plutonium between the liver and the skeleton, immediately after entering the circulatory system, was 50:38%, respectively. With time, the fraction of plutonium found in the liver decreased, while the fraction in the skeleton increased at a rate of 0.5% y(-1) of systemic deposition. Exposure time had a greater effect on the relative retention of plutonium in the main organs when compared to age. The statistical estimates that characterized the relative plutonium distribution were less stable for the liver than for the skeleton, likely due to the slower turnover of skeletal tissues and the retention of plutonium in bone.

Multifactorial analysis of lung cancer dose-response relationships for workers at the Mayak nuclear enterprise.

Dose-response relationships for alpha-radiation-induced lung cancers (adenocarcinoma, squamous carcinoma and small cell carcinoma) were developed by multifactorial analysis using data for Mayak nuclear enterprise workers chronically exposed by inhalation to 239Pu. The three most important lung cancer risk factors (smoking, plutonium incorporation, and external gamma irradiation), out of six factors previously identified, were used. Relative risks (odds ratios) were determined for 500 nuclear enterprise workers (162 cancer cases, 338 control) for different dose levels using a case-control study design and logistic regression. A threshold at about 3.7 kBq or 0.80 Gy was discovered for incorporated plutonium, which is satisfactorily described by linear-quadratic and quadratic models. Excess relative risk was 0.020 kBq(-2) and 0.97 Gy(-2). This quadratic function was mainly due to adenocarcinoma. A trend for decreasing risk was noted for the lowest levels of plutonium incorporation, near permissible level. No clear-cut dose-response relationship for lung cancer induction by chronic external gamma irradiation was obtained. Lung cancer induction by cigarette smoking had a linear dependence: smoking of one pack of papiroses (a type of Russian cigarette) per day for 5 y increases the lung cancer risk twofold. The effect was most clearly manifested for squamous-cell carcinoma.

The influence of radiation and nonradiation factors on the lung cancer incidence among the workers of the nuclear enterprise Mayak.

For the estimation of radiation lung cancer risk for a human being it is important to take into account different etiological factors because of the polyetiology of this disease. This work was the aim of a retrospective investigation ("case-control") of 500 workers of a nuclear enterprise that had been gamma-irradiated in a wide dose range and had had exposure to airborne 239Pu. One hundred sixty-two persons contracted lung cancer (morbidity), and 338 persons that had not fallen ill served as pair control. Eleven potential risk factors were evaluated using a logistic regression model, five insignificant factors were excluded, and the remaining factors were arranged (by odds ratio) in decreasing order: smoking > plutonium pneumosclerosis > plutonium incorporation in body > chronic obstructive pulmonary diseases (COPD) > decrease of body mass > external gamma-irradiation. The percentage of histologically confirmed adenocarcinoma among the nuclear enterprise workers was 74%, which is significantly higher than 33% among the population that did not work at the enterprise, particularly in the case of high (more than 11 kBq) plutonium incorporation by the nuclear workers. The localization of tumors in this cohort is more frequently in the lower and middle lung lobes and at the periphery. Each of the histological types of lung cancer has manifested a different degree of correlation with particular factors. The adenocarcinoma has the most frequent correlation with the radiation factors; the odds ratio for plutonium incorporation and plutonium pneumosclerosis is 2.9 (95% CI = 1.0-8.4); for external gamma-irradiation the odds ratio is 1.9 (0.99-3.5); the odds ratio for smoking is 4.3 (1.9-9.9). The squamous-cell carcinoma has the highest correlation with non-occupational factors: with smoking the OR is 6.8 (1.2-38.7), with the chronic obstructive pulmonary diseases the odds ratio is 3.9 (1.8-8.4), and with body mass decrease the odds ratio is 2.1 (0.94-4.6); odds ratio for plutonium incorporation is 4.2 (1.4-12.8). The small-cell carcinoma has correlation with body mass decrease [odds ratio = 2.9 (1.2-7.6)] and high level of smoking [smoking index > 500; odds ratio = 3.5 (1.4-8.9)]. The portion of the occupational cancers among the workers of the nuclear enterprise, evaluated on the base of attributive risk, is 26%, with 57% for adenocarcinoma, 9% for squamous-cell carcinoma, and 8% for small-cell carcinoma. The investigation is continued to assess the dose-effect and factors interactions.

Factors effecting the morbidity in populations living in the vicinity of atomic industry plants.

In order to examine the effects of radiation, chemicals, and social factors on the incidence of different diseases in the population living in the vicinity of atomic industry facilities, the site of the Production Association 'Mayak' has been selected for detailed analyses. Diseases under study were morbidity among newborns including congenital anomalies, diseases of respiratory organs, and cancer. Using a regression model, no statistically significant correlation was found between incidence and radiation exposure.