Radiation-related risks of leukemia among Chornobyl cleanup workers from Ukraine

*Lydia B. Zablotska, UCSF 

Keywords: leukemia; radiation-induced leukemia; chronic lymphocytic leukemia; radiation; Chernobyl Nuclear Accident, Chornobyl, Ukraine, 1986; radiation dose response relationship; matched case-control study

Lydia B. Zablotska,1 Dimitry Bazyka,2 Jay H. Lubin,3 Nataliya Gudzenko,2 Mark P. Little,3 Maureen Hatch,3 Stuart C. Finch,4 Irina Dyagil,2 Robert F. Reiss,5 Vadim Chumak,2 Andre Bouville,3 Vladimir Drozdovitch,3 Victor P. Kryuchkov,6 Ivan Golovanov,6 Elena Bakhanova,2 Nataliya Babkina,2 Tatiana Lubarets,2 Volodymyr Bebeshko,2 Anatoly Romanenko,2 Kiyohiko Mabuchi3 1 Department of Epidemiology and Biostatistics, University of California San Francisco School of Medicine, San Francisco, California, USA 2 Research Center for Radiation Medicine, Kyiv, Ukraine 3 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA 4 Robert Wood Johnson Medical School, Camden, New Jersey, USA 5 Departments of Pathology and Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA 6 Burnasyan Federal Medical Biophysical Centre, Moscow, Russia

Address correspondence to Dr. Lydia B. Zablotska, Department of Epidemiology and Biostatistics, University of California San Francisco School of Medicine, 3333 California St., Suite #280, San Francisco, CA 94118, USA. Phone: 1-415-476-4673. Fax: 1-415-563-4602. E-mail: lydia.zablotska@ucsf.edu

The effects of ionizing radiation on leukemia have been clearly demonstrated by studies of individuals exposed to high doses of radiation, generally at high dose-rates, such as the study of the survivors of the atomic bombings of Hiroshima and Nagasaki (A-bomb study) (1) and radiation treatment studies (2, 3). Nussbaum and Köhnlein suggested that A-bomb survivors data have become “the authoritative standard to which all findings from epidemiological studies on other exposed populations, such as nuclear workers, have been compared” ((4), p.658). While higher-dose studies provide more precise risk estimates than lower-dose studies, linear extrapolations of risk estimates necessitate several assumptions about populations who may have very different types of exposure (e.g., high doses and high-dose rates) as well as differ on non-radiation characteristics. Questions remain about the effects of lower doses delivered over prolonged time, such as exposures of environmental and occupational concern. Because individual studies are small and lack statistical power, it was thought that combined studies would provide better evidence of the effects of low doses of ionizing radiation on leukemia. In the largest to date pooled analysis, nuclear workers were monitored for external radiation on a monthly or yearly level providing a rough estimate of the “dose-rate” effect. Overall, estimates were compatible with the estimates from the high-dose studies and confirmed that extrapolations from the high-dose studies did not underestimate radiation-related risks from low-dose exposure. However, despite including a half a million workers from 15 countries, the confidence interval of the leukemia risk estimate remained wide and the point estimate was not significant (excess relative risk per gray (ERR/Gy) = 1.93, 90% confidence interval (CI): <0, 7.14, p=0.089) (5). The accident at the Chornobyl nuclear power plant in northern Ukraine in April 1986 resulted in a release of large amounts of radiation. Although studies in the general population lack statistical power due to generally low doses, workers cleaning up the site and its surroundings after the accident (~230,000 from Ukraine) received sufficiently high doses at low dose-rates to yield reasonable statistical power to detect any effect on leukemia risk (6). Initial studies based on Chornobyl State Registries provided some evidence of increased risk of leukemia from exposure to cleanup work, but the magnitude of risk remained questionable due to large uncertainties in dose estimation and case verification procedures in the Registries (7-9, 6). To address these concerns, several case-control studies were initiated in the late 1990s nested within national Chornobyl State Registry cohorts in Ukraine, Belarus, Russia and Baltic countries (10-12). These studies used a unified WHO-developed study protocol (13) and a specially-developed questionnaire-based radiation dose reconstruction method (14) and, thus, offer the best chance for producing more accurate risk estimates. Both studies showed increased risks of all leukemia, and separately of CLL and non-CLL (10, 11). To improve statistical precision of risk estimates and to clarify the issue of possible differences in risk for various subtypes of leukemia, we extended our original study of leukemia in cleanup workers from Ukraine (11) to ascertain all leukemia cases occurring over a combined period of 20 years after the accident (1986-2006). A complete description of study methods has been published previously (13). In brief, we conducted a case-control study nested in a cohort of 110,645 male Ukrainian workers who were aged 20 to 60 years during cleanup activities in 1986-1990 following the Chornobyl nuclear power plant accident, who were registered in the Chornobyl State Registry of Ukraine before 1992, and who resided in Kyiv City or in any one of five study oblasts (areas similar to a state or province): Cherkasy, Chernihiv, Dnipropetrovsk, Kharkiv and Kyiv at the time of interview (13). Cases were confirmed by the international panel of hematopathologists based on the description of the clinical courses and histological confirmation of the diagnosis from the medical records (available for all cases) and bone marrow aspirates/ biopsy slides and/or peripheral blood smears (available for 70% of cases). Acute leukemia types were classified using the WHO system of classification (15). CLL diagnoses were based on the criteria established by the NCI Working group (16). A time-and-motion dose reconstruction method, known as Realistic Analytical Dose Reconstruction with Uncertainty Estimation (RADRUE) (17, 18) combined data on work history from dosimetric questionnaires with field radioactivity measurements. Interviews were conducted in person by trained interviewers and included the work history questions with regards to locations of work and residence while in the 30-km exclusion zone around the Chornobyl nuclear power plant, types of work, transportation routes, and corresponding dates. For deceased subjects, proxy interviews were conducted with next-of-kin for demographic and medical information and with co-workers for work histories in the 30-km exclusion zone. Proxy interviews were conducted for 69 (50%) deceased cases and 43 (5%) deceased controls. The present analysis is based on 137 confirmed cases with radiation dose estimates, including 79 CLL and 58 non-CLL cases, and 863 controls selected from the cohort of cleanup workers and individually matched to cases on year of birth and place of residence. Seventy-eight percent of study participants had bone marrow doses below 100 mGy and 87% below 200 mGy. Cases and controls did not differ by urban vs. rural residential status at the time of interview, age at first radiation exposure in the 30-km Chornobyl zone, or education; however, more cases than controls were proxy-interviewed (p<0.001). For all leukemias, we found a significant, linear dose-response relationship with continuous radiation dose, with an estimated ERR/Gy=1.26 (95% CI: 0.03-3.58, p=0.041) and 2.38 (95%CI: 0.49-5.87, p=0.004) for all leukemia interviewed 2-15 years after initiation of chemotherapy treatment. Linear dose-responses were also significant for both non-CLL (ERR/Gy = 2.21, 95% CI: 0.05-7.61, p=0.039) and CLL (ERR/Gy = 2.58, 95% CI: 0.02-8.43, p=0.047), with no evidence of heterogeneity (p=0.888). Although not significant, risk estimates tended to decrease with increasing time from first radiation exposure in the Chornobyl zone and to increase with increasing age at first exposure (p=0.162, p=0.249, respectively). Our results confirm and significantly strengthen the evidence from our previous study (11) that showed significant effects of protracted radiation exposure at low doses on the risk of leukemia incidence. The estimated risk of non-CLL was lower but compatible with the risk in the A-bomb study (19), providing some evidence of the sparing of late effects of radiation administered at a low dose-rate in comparison with the effects of almost instantaneous exposures. Further, our results indicate that risk estimates are similar for CLL and non-CLL. Increased risks of CLL were reported in the studies of Chornobyl cleanup workers from Belarus, the Russian Federation and Baltic countries (10) and from uranium miners with exposures to alpha particles and gamma radiation in Czechoslovakia, Germany, and Canada (20-22). On the other hand, the lack of a radiation effect on CLL has been reported from the analysis of incidence data in UK radiation workers (23) and also the Tech River residents (24). The inconsistent results from studies of various exposed groups are puzzling, and indicate the need for more intensive investigations in other irradiated populations. CLL is the most common type of leukemia in this cleanup worker population and, as they age, will rapidly increase in rates, raising concern for medical consequences. The radiogenic risk for CLL also has important public health implications in other populations as it is the most prevalent type of leukemia in Western populations, with approximately 20,000 cases estimated to be diagnosed in the U.S. in 2011 (25). Further investigations are needed to develop a better understanding of the association between radiation and CLL. References

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