Derivation of whole blood biomonitoring equivalents for titanium for the interpretation of biomonitoring data.

Biomonitoring equivalents (BEs) have been increasingly applied for biomonitoring purposes by regulatory bodies worldwide. The present report describes the development of a BE for titanium based on a 4-step process: (i) identification of a critical study/point of departure (PoD) supporting an established oral exposure guidance value (OEGV);, (ii) review the available oral PK data and application of a pharmacokinetic model for titanium; (iii) selection of the most appropriate biomarker of exposure in a specific tissue and calculation of steady-state tissue levels corresponding to the PoD in the critical study; and (iv) derivation of BE value adjusting for the uncertainties considered in the original OEGV assessment. Using the above 4-step approach, a blood BE value of 32.5 µg titanium/L was derived. Key components of the analysis included a pharmacokinetic model developed by investigators at the Netherlands National Institute of Public Health (RIVM) and a two-year rodent bioassay of titanium conducted by the US National Cancer Institute. The most sensitive pharmacokinetic parameter involved in the current BE derivation is the oral absorption factor of 0.02%. The provisional BE proposed in this article may be updated as new information on the pharmacokinetics of titanium becomes available.

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.

Lung cancer risk due to exposure to incorporated plutonium.

An epidemiological study has been carried out among 1,479 male workers who started working at the "Mayak" Production Association in 1948-1958 and were exposed to external gamma radiation and plutonium aerosols. Lung cancer mortality for the follow-up period 1948-1993 has been analyzed. No statistically significant association of lung cancer mortality and external gamma-ray dose has been revealed in the range of accumulated doses of 0.2-5.5 Gy. Association of lung cancer mortality and the dose of alpha-particle radiation to the lung is statistically significant. In the dose range below 30 Sv, this association can be described in terms of a linear nonthreshold function. Lifetime lung cancer risk in the dose range below 30 Sv is 1.21 x 10(-2)Sv(-1).

Mortality among workers with chronic radiation sickness.

This study is based on a registry containing medical and dosimetric data of the employees who began working at different plants of the Mayak nuclear complex between 1948 and 1958 who developed chronic radiation sickness. Mayak is the first nuclear weapons plutonium production enterprise built in Russia and includes nuclear reactors, a radiochemical plant for plutonium separation, and a plutonium production plant. Workers whose employment began between 1948 and 1958 exhibited a 6-28% incidence of chronic radiation sickness at the different facilities. There were no cases of chronic radiation sickness among those who began working after 1958. Data on doses of external whole-body gamma-irradiation and mortality in workers with chronic radiation sickness are presented.

Mortality among personnel who worked at the Mayak complex in the first years of its operation.

Epidemiological studies revealed increased cancer mortality among persons who began working at the Mayak complex during the period 1948-1958. Estimation of cancer risk was carried out for the sites of cancer that showed increased mortality and dependence on dose of external gamma- or internal alpha-irradiation.