Chapter 1 CANCER INCIDENCE AMONG NUCLEAR WORKERS IN RUSSIA BASED ON DATA FROM THE INSTITUTE OF PHYSICS AND POWER ENGINEERING: A PRELIMINARY ANALYSIS

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1 Chapter 1 CANCER INCIDENCE AMONG NUCLEAR WORKERS IN RUSSIA BASED ON DATA FROM THE INSTITUTE OF PHYSICS AND POWER ENGINEERING: A PRELIMINARY ANALYSIS Ivanov V.K. 1, Tsyb A.F. 1, Rastopchin Eu.M. 1, Gorski A.I. 1, Maksioutov M.A. 1, Vayzer V.I. 2, Suspitsin Yu.V. 3, Fedorov Yu.V. 3 1 Medical Radiological Research Center of Russian Academy of Medical Sciences, Obninsk; 2 Institute of Physics and Power Engineering, Obninsk; 3 Medical Units of Obninsk One group that has the potential to be exposed to radiation is workers in the nuclear industry. Results of a systematic medical follow-up and dosimetric monitoring of these workers can form the basis for a study of the relationship between cancer incidence and radiation dose. As part of such efforts in Russia, a major institution of the nuclear industry was selected with an established medical care unit, archiving capabilities and dosimetry department: the Institute of Physics and Power Engineering (IPPE) in Obninsk. In the study a comparative analysis of cancer incidence rates for the IPPE workers and for the general population of Russia in was carried out. The subjects were the IPPE workers hired before This restriction was imposed to reduce the uncertainty associated with the possible latent period in the development of solid cancers. Thus the possibility of including persons who already had the disease at the time when they were hired was minimized. The analysis is based on information about 158 cancer cases, including 24 cancers in persons under individual dosimetric monitoring. A statistically significant excess in cancer incidence was found among the IPPE workers compared with a comparison population (the general population of Russia) for some types of cancers. The SIR values for all cancers (ICD-9: ) is 0.93 (0.76, % CI) for males and 1.42 (1.06, % CI) for females. A statistically significant excess for all cancers was also observed for residents of Obninsk compared to the control comparison population. The corresponding SIR value was 1.20 (1.12, %CI) for males and 1.58 (1.49, % CI). An important reason for the observed excess in cancer incidence compared to the control population may be the higher level of health care in the socalled nuclear cities of Russia which may have resulted in increased diagnosis and registration of cancers. However a statistically significant dependence of the cancer incidence on the dose of ionizing radiation was not established. The excess relative risk per 1 Gy for all types of cancer was 0.91 (-2.75, % CI) for males and 0.40 (-6.94, % CI) for females. These estimates should be considered to be preliminary, as the number of cases considered in the analysis of the dose response is small (17 males and 7 females). Introduction The study of the health status of nuclear workers has at least two aspects: 1. Assessment of the health status by comparing the incidence rates for different diseases among the nuclear workers and the general population. 2. Direct estimation of the relationship between incidence rates and chronic and relatively low radiation doses. The first task requires a knowledge of the sex and age factors related to the incidence of diseases in the study group and the general population, as well as demographic data about the nuclear workers. In the second case, the dose and the chronology of radiation exposure are needed for each worker in addition to the medical information (incidence rates). 5

2 For cancers, the dose dependences of incidence rates and mortality have been derived in terms of radiation risks for atomic bomb survivors and for patients exposed to radiation for therapeutic purposes [1-5]. These estimates of radiation risks, however, were made for relatively high doses and dose rates. Exclusion of high doses (more than Sv) from the study of cancer incidence in the Japanese cohort leads to a significant change in the dose dependence of cancer incidence [6]. In this sense, the cohort of the Chernobyl emergency workers (average dose 0.1 Sv) is somewhat intermediate in the estimation of radiation risks [7]. It should be noted that radiation risks from exposure to low doses and low dose rates are estimated using different extrapolation methods [2], which involve significant uncertainties. Direct estimates of the effects of chronic low radiation doses on the development of cancer can be obtained by studies of cancer incidence among workers in the nuclear industry. A study of the dose dependence of cancer incidence should be based on systematic specialized medical follow-up and dosimetric monitoring of the subjects. Such research is being carried out in the USA [8], Canada [9], UK [10] and other countries. To take advantage of the accumulated experience from these studies, international projects involving many countries have also been initiated [11]. In Russia large-scale radiation epidemiological projects on the effects of radiation on the health of nuclear workers have not been undertaken, with the exception of studies of the workers at the «Mayak» plant [12] 1. In the present paper the issues related to cancer incidence among the personnel of the Institute of Physics and Power Engineering (IPPE), Obninsk, Russia, are discussed. The cancer incidence rates in the IPPE workers and the general population of Russia are compared and the dependence of the incidence of different cancers on radiation dose is estimated. Materials and methods General information about IPPE After the nuclear weapons tests og the 1940s and 1950s the former USSR started developing both military technologies and building nuclear facilities and nuclear power plants. In 1946 Laboratory «B» of the USSR Ministry of Internal Affairs was set up not far from Moscow. Although the activities of the laboratory were classified, they were directed at solving the scientific and technical problems associated with the development of nuclear power and technology. The first nuclear power plant was built at the same location in 1954 and the IPPE was set up later on this base. Today the laboratory of the State Research Center of Russian Federation IPPE in Obninsk, which is 100 km from Moscow, is one of the largest centers of nuclear science and technology in the country. The Institute conducts studies in nuclear physics, the physics of nuclear reactors and protection, reactor building, radiation material science, radiation chemistry, etc. Like most workers of the nuclear industry, the IPPE personnel are subject to annual medical examinations, the results of which are written down in medical records. Dosimetric monitoring of a fraction of the IPPE workers is conducted on a permanent basis by the radiation safety department. 1 Nuclear power industry enterprise belonging to the military sector of Russia, founded in Chelyabinsk oblast of Russia in 1948, which is currently known as the chemical plant Mayak. 6

3 The personnel department of the IPPE maintains a database of information about all employees. The numbers of IPPE personnel from 1986 to 1997 are shown in Figure 1. As can be seen from the figure, the number of employees at IPPE was almost constant (at about 10,000 persons) up to the early 1990s, but since 1991 the number decreased sharply and is now 5,000 persons. Number of IPPE workers Year Fig. 1. Numbers of workers in IPEE from The squares are all IPPE workers and circles are those workers under individual dosimetric monitoring. Collection of medical information The method for registration of the IPPE workers with cancer is described below. All residents of Obninsk are subject to annual primary screening in two clinics. This is basically a prophylactic examination and usually takes place when patients visit the doctors for other reasons. The IPPE workers engaged in hazardous activities are subject to more frequent and more thorough examinations (by more doctors with different specialties) compared to other residents. If cancer is suspected, a patient is referred to the cancer specialist to confirm the diagnosis, and, if necessary, the diagnosis is verified at the Medical Radiological Research Center (MRRC) in Obninsk, the leading Russian organization in fundamental and clinical radiobiology, experimental radiology, radiopharmaceutics, radiation epidemiology, radiation diagnostics and cancer therapy. If the diagnosis is confirmed, a specially designed form is completed. This form contains information on the condition of the patient at diagnosis, histological (X-ray, clinical, etc.) ascertainment of diagnosis, treatment, follow-up, etc. When a cancer patient dies, the cause of death is recorded and the form is placed in the archive of deceased cancer patients of Obninsk located in the cancer department of the city hospital. Apart from the specially designed forms, information about cancer patients can be obtained from the regular medical records stored in the registration office of the city hospital (medical unit N 8). To ensure that the database of cancer patients who were or are working in IPPE is as accurate and as complete as possible, a special method was developed to check the registration of cancer patients. First, a list of 7

4 cancer patients registered in the cancer department of the city hospital is compiled under the guidance of the chief oncologist of Obninsk. Those who were registered and died and whose records were placed in the archive are also included in the list. These lists are then given to the IPPE personnel department where the IPPE workers (present or former) are identified and their personal data are verified, in particular the date of birth, occupation, date of employment. When the verified lists are received, a member of the city hospital staff fills in a questionnaire for each patient whose employment at the IPPE has been confirmed. As the questionnaires accumulate, they are given to MRRC to be reviewed carefully to ensure quality and completeness and then are entered into the database. The information is first subjected to computer checks (syntactical and logical) and only then is it entered the database. The questionnaires that fail the checks are returned for additional verification. To date, information on 505 cancer cases among the IPPE workers is available. These cases were diagnosed between 1966 and Collection of dosimetric information The dosimetry unit of the IPPE has been operating since the Institute was founded. In the past, personal dosimetric information was kept on paper in specialized archives along with information on radiation doses received before employment at the IPPE. Individual dosimetric monitoring (IDM) is performed centrally by the radiation safety department and consists of measurement of external radiation doses (from γ-, X-,β-particle and neutron radiation sources) and estimation of internal radiation dose. The IDM of external irradiation covered between 10 to 35% of the IPPE workers in different years. The annual collective radiation dose at the IPPE is about 4 person-sv, and the average individual dose is about 2-3 msv. The maximum individual doses do not exceed 30 msv a year. Doses of X- and γ-radiation are determined using thermoluminescent dosimeters with tissue-equivalent filters in the energy range 50 KeV - 3 MeV with a sensitivity of 0.01 msv. Exposure to β-particles is monitored with dosimeters composed of film detectors covered by different layers of materials that simulate the layers of the skin. Doses of neutron radiation are determined using the neutron activation method. Internal radiation doses are determined using a whole-body counter. Exposure to uranium and transuranium radionuclides is evaluated from biophysical measurements. Under the current regulations, dosimetry data must be preserved on paper for 70 years. The criterion for putting personnel under individual dosimetric monitoring is that external irradiation has occurred at levels of more than 2 msv per year, or the possibility that a dose has been received above the established dose limit (emergencies, accidents). For internal irradiation, the possibility of radionuclide intake during contact with radionuclides (hot laboratory, preventive repair of reactors, etc.) is the guideline for using IDM. The instruments used for IDM are subject to annual calibration checks by State Standards organizations. Since 1991 individual doses have been entered into a computer, hence linking medical and dosimetric information does not present much difficulty. Such linking, however, also requires working with paper documents, which is rather time-consuming. It can be seen from Figure 1 that the number of workers under IDM since 1991 has not change as greatly as the total number of the IPPE personnel. The collective doses for the IPPE personnel in were within person-sv, and the mean annual doses were within msv. 8

5 As was mentioned above, for the IPPE workers employed in 1991 and later, the IDM annual data, including the retrospective data, are preserved on both paper and computer. Using annual individual dosimetric data, individual cumulative doses can be estimated. The dose was estimated as the cumulative dose received by the time of the completion of follow-up minus the latent period. Therefore the doses received during the latent period were not included in the cumulative dose. The latent period was set as 10 years for solid cancers, 5 years for thyroid cancers and 2 years for leukemias. It should be noted that the contribution of internal exposure to the total dose received by the IPPE workers under study does not exceed 1%, which is much lower the error in measuring the external dose. Thus the contribution of internal irradiation to the total dose was not taken into account. Population under study In this analysis, the IPPE employees of are studied. Two groups of workers can be identified: 1. All employees of the IPPE in the period from 1991 to The IPPE employees of covered by IDM. For this study the groups include only IPPE workers employed before This restriction was imposed to reduce the uncertainty associated with the possible latent period in developing solid cancer. We thus minimized the possibility of including those who already had the disease at the time they were employed in the study cohort. Table 1 Characteristics of the cohort of the IPPE employees during who were hired before 1981 All workers Workers under IDM Males Females Males Females Number of persons Number of cancer cases Number of person-years Mean follow-up period (years) Mean attained age at end of follow-up (years) This study was limited to those employed during the period because the available computer database contains individual dosimetric information (including retrospective data) for the IPPE workers employed in this period. Earlier information on doses is available only on paper. The characteristics of the study cohorts are presented in Table 1, which contains information on the distribution of the IPPE workers by sex, person-years, mean follow-up period, mean attained age and number of cancer cases diagnosed. Of the workers under IDM, seven persons with cumulative doses more than 500 msv were excluded from the study. Methods of analysis The person-time at risk for development of a disease of a given type was estimated as the difference in the dates T 1 and T 0, where T 1 is date of the completion of the last follow-up, date of leaving IPPE, date of cancer diagnosis, date of death, or 1 January 1998, whichever come first. The incidence rate is defined as the ratio of total cases to total time at risk measured in person-years. 9

6 To determine the differences between the cancer incidence rates of the IPPE workers and the general population of Russia, the standardized incidence ratio (SIR) was estimated [13]. For this purpose, we used the ageand sex-specific cancer incidence rates for the population of Russia published in [14]. That publication contains all Russian cancer incidence rates for both sexes with 5-year age intervals for cancers of the most frequent sites, based on information supplied by regional cancer dispensaries and specialized cancer clinics. These data are the official statistics on cancer incidence in Russia. To study the dose dependence of the incidence rate, the data for the individual IPPE workers were grouped. The data in the present analysis were split in 10 strata by attained age (15-20, 20-25, 30-35, 35-40, 40-45, 45-50, 50-55, 55-60, 60+ years), 3 groups by dose (0-25, 25-50, 50+ msv) and 2 groups by sex. Let i be the index of the sex-age group and j be the index of the dose group. Y ji is number of cases, P ij are person-years, M ij is the incidence rate in stratum ij. M ij for a given class of diseases can be determined as follows: M ij = Y ij / P ij. (1) It seems reasonable to assume [13, 15] that the values of Y ij are independent random values with a Poisson distribution and the mathematical formulation E(Y ij ) = P ij M ij. To determine the dose dependence of M ij, M ij should be presented as a parametric function with its parameters determined from the maximization of the likelihood function: L = Σ {Y ij ln(p ij M ij ) - P ij M ij }, (2) where M ij = f(d ij ), where D ij is the mean dose in stratum ij. In this work we used a simple function: f(d ij ) = M i0 (1 + βd ij ). (3) Equation (3) is used to determine the significance of the dose dependence of the relative risk. As a statistical test we used the test of the ratio of likelihood maxima at zero hypothesis β=0. The background dose group (j=0) was the group 0-25 msv. Estimation of the parameters of equation (3), statistical tests and the determination of confidence levels were carried out using the software program AMFIT [15]. Results In the period from 1991 to 1997, a total of 158 cancer cases were detected among the IPPE workers in the study cohorts; 24 of these workers were under IDM. Table 2 shows the distribution of cancer incidence for the study groups. Figures 2 and 3 show the distribution of the IPPE workers by attained age for all those employed 10 years or more (i.e. hired prior to 1981) working in IPPE from 1991 to 1997 and covered by IDM during this period. Table 3 compares the cancer incidence rates of the IPPE workers and the general population of Russia. The SIRs for IPPE workers in are presented by individual year in Figure 4. For persons under IDM, the number of cancer cases was too small to calculate SIRs by year. The SIRs for the total study period for these persons were 0.42 (0.24, 0.67) for males and 1.41 (0.56, 2.90) for females. To estimate a possible dependence of the cancer incidence rate on cumulative dose, the distribution of which is shown in Figure 5, with mean values given in Table 4, the excess relative risk was derived [3]. The excess relative risk per 1 Gy for all cancers was 0.91 (-2.75, % CI) for males and 0.40 (-6.94, % CI) for females. These estimates, however, should be treated as preliminary, because the number of cases considered in the analysis of the dose-response relationship was small (17 males and 7 females). 10

7 Table 2 Cancer incidence among the workers at IPEE Cancer site ICD-9 All With IDM [16] Males Females Males Females Oral cavity Esophagus Stomach Colon Rectum Gallbladder Pancreas Larynx Trachea, bronchus, lung Bones and articular cartilages Connective and other soft tissues Melanoma of skin Other malignant neoplasms of skin Breast Cervix uteri Corpus uteri Ovaries Other malignant neoplasms of female genital organs Prostate Bladder Kidney Renal pelvis Unspecified localization of uropoietic organs Eye Nervous system Thyroid Unspecified localization Lymphosarcoma and reticulosarcoma Hodgkin s disease Multiple myeloma Chronic lymphoid leukemia Myeloid leukemia All cancers

8 25 Male Female 20 Percentag (75+ (65- (70- (60- (55- (50- (45- (40- (35- (30- (25- (20- Attained Fig. 2. Distribution, by attained age, of the cohort of the IPPE employees of Male Female Percentag (75+ (65- (70- (60- (55- (50- (45- (40- (35- (30- (25- (20- Attained Fig. 3. Distribution, by attained age, of the cohort of those IPPE employees of under individual dosimentic monitoring. Table 3 Number of cases and SIR for some classes of cancers diagnosed among the IPPE workers Cancer site ICD-9 Number of cases SIR [16] Males Females Males Females All cancers (0.76, 1.12) a 1.42 (1.06, 1.87) Digestive organs (0.56, 1.18) 1.01 (0.44, 1.98) Stomach (0.53, 1.50) 0.68 (0.08, 2.36) 12

9 Respiratory and thoracic organs (0.31, 0.78) 0.69 (0.01, 3.38) Trachea, bronchus, lung (0.31, 0.82) 0.74 (0.9, 3.66) Bones, connective tissue, skin and breast (1.62, 3.76) 1.73 (1.08, 2.62) Skin (1.57, 3.86) 1.65 (0.60, 3.56) Melanoma skin (1.06, 9.96) 1.65 (0.02, 8.1) Breast (0.96, 2.84) Genitourinary organs (1.11, 2.73) 3.81 (2.03, 6.5) Corpus uteri (1.34, 6.11) Prostate (0.3, 3.0) - Bladder (0.5, 3.0) 3.95 (0.05, 19.5) Kidney, renal pelvis, unspecified localization of uropoietic organs a The 95% confidence levels are given in parentheses , 189.1, (1.48, 5.30) 0 4,0 Males Females 3,5 3,0 2,5 SIR 2,0 1,5 1,0 0,5 0, Calendar year Fig. 4. SIRs for all cancers for the IPPE workers in Percentag Cumulative dose Fig. 5. Distribution of the cohort of the IPPE workers in by cumulative external radiation dose. Table 4 Mean cumulative external radiation doses in the cohort of the IPPE workers in

10 All Males Females Mean dose for cancer patients (msv) Mean dose for healthy people (msv) Mean dose for all persons (msv) The values of the excess relative risk per unit dose were positive, even though they were not statistically significant, and therefore the question of the dose dependence of the cancer incidence remains open and requires further study. Discussion The effect of low-doses and low-dose-rate irradiation on human health has not been studied thoroughly in Russia until recently, although many people are exposed to such levels. A study of the health consequences of low radiation doses should rely on either the experience of other studies or the direct long-term follow-up of the exposed population, including medical and dosimetric monitoring. The last requirement is satisfied by workers in the nuclear industry, since these workers are under individual dosimetric monitoring and are subject to regular medical examination as part of their occupational safety programs. The application of results from other studies of radiation effects on human health is problematic because of the paucity of studies on low doses and dose rates. At the same time, if the conclusions from the studies of the relationship between high doses and incidence of diseases, especially cancers, are used, the models have to be extrapolated [2] to the region of low doses, which results in considerable uncertainties. In the present work, the study population was the staff of the Institute of Physics and Power Engineering located in Obninsk, Russia. The cancer incidence among the IPPE personnel employed during and recruited before 1981 was studied. The selection of 1991 as the starting year for our study was made because the computerized database contains dosimetry information starting from Prior to 1991, dosimetric information was recorded on paper and is stored in archives. The restriction of the study to workers employed before 1981 was done to reduce the possibility of including persons with a pre-existing cancer. With the study exclusions in mind, 158 cancer cases were studied; of those 24 cases were persons under individual dosimetric monitoring. Due to the indicated constraints and the limited number of cases, the results of the analysis should be considered preliminary. The cancer incidence rates for the IPPE workers compared to the general population of Russia are statistically significantly higher for all cancers for females (SIR=1.42 (1.06, 1.87)); for cancers of the bone, connective tissues and skin for males (SIR=2.53 (1.62, 3.76)); for cancers of the bone, connective tissues, skin and breast for females (SIR=1.73 (1.08, 2.62)); and for cancers of the genitourinary organs both males (SIR=1.79 (1.11, 2.73)) and females (SIR=3.81 (2.03, 6.5)). No statistically significant difference of the SIR from unity was found for the other cancer classes due to the limited number of cases. The finding of a statistically significant excess in the incidence rate for some cancer sites among the IPPE personnel compared to the general Russian population was unexpected and is not consistent with the well-known phenomenon referred to as the healthy worker effect when applied to nuclear workers. This can possibly be explained both by technological factors and by the fact that the nuclear industry in Obninsk was and is the main industry. As a result, the level of health care for the residents, many of whom work at nuclear facilities, is better than in Russia on 14

11 average. Evidence for this can be found by comparing the estimates of cancer SIR for the IPPE workers with that for residents of Obninsk (Table 5). The population of Obninsk in the period considered was about 107 thousand people. The mean age in 1991 was 31.5 years for men and 35.1 years for women. As is seen from Table 5, the SIR values for the nuclear workers and the residents of Obninsk are comparable within statistical errors. The similarity in the cancer incidence rates for IPPE workers and the Obninsk population suggests that the people in Obninsk received good medical care and that the differences between the nuclear workers and the Russian rates are not radiation-associated effects, but rather are due to better registration of diseases among Obninsk residents. On the other hand, it should be remembered that many residents of Obninsk worked for a long time at other facilities of the nuclear industry of Russia. Table 5 Results of SIR analysis of cancer incidence rates in IPPE ( ) and in Obninsk population ( ) (control) ICD-9 Obninsk IPPE [16] Males Females Males Females (1.12, 1.28) a 1.58 (1.49, 1.69) 0.93 (0.76, 1.12) 1.42 (1.06, 1.87) (1.86, 2.60) 1.78 (1.60, 1.97) 2.53 (1.62, 3.76) 1.73 (1.08, 2.62) (1.14, 1.69) 3.41 (2.93, 3.93) 1.79 (1.11, 2.73) 3.81 (2.03, 6.5) a The 95% confidence levels are indicated in parentheses. The study of the dose dependence of the cancer incidence rates revealed a lack of robustness in the estimates of relative risk; the linear trend of the relative risk dependence is positive, but the estimates of excess relative risk are not statistically significant, which is most probably associated with the small number of cancer cases and the small size of the cohort under study (person-years). Extending the size of the cohort of the IPPE workers under IDM by including those who left the Institute before 1991 would probably allow more definitive conclusions to be drawn about the value of radiation risks. Conclusions Based on the analysis of the data for the IPPE workers, including their medical and dosimetric information, the cancer incidence rates in the IPPE workers and the general population of Russia were compared and preliminary conclusions are drawn about the dose dependence of incidence rates for malignant neoplasms. As a whole, a statistically significant excess of cancer incidence among the IPPE personnel compared to the general population of Russia was found for all cancers (females); for bone, connective tissue, skin (males and females) and breast (females); and for genitourinary organs (males and females). The highest excess was found for skin cancer (males). The result for skin is most likely due to ascertainment or treatment bias rather than to radiation. Cancer incidence at these sites was also significantly elevated in the general population of Obninsk compared to the rates for the general population of Russia, suggesting that the increased incidence observed for the IPPE workers may be due to better diagnosis and registration of cancer in the city of Obninsk. Estimates of the excess relative risk per unit dose in the study of the dose dependence of the cancer incidence rate were positive but not statistically significant. The excess relative risk per 1 Gy for all cancers was 0.91 (-2.75,

12 95% CI) for males and 0.40 (-6.94, % CI) for females. The absence of statistical significance may be due to the limited number of cases studied. These estimates should be considered to be preliminary, as the number of cases included in the analysis of dose response is too small (17 males and 7 females) to perform an adequate analysis of the dose response. The similarity in the cancer incidence rates for IPPE workers and the Obninsk population suggests that people in Obninsk received good medical care and that the differences between the nuclear workers and the rates for the general population of Russia are not associated with radiation, but rather due to better registration of diseases among the residents of Obninsk. Our study is one of the few attempts to understand the effects of radiation on the health of nuclear workers in Russia. The results should be treated as preliminary and they require further refinement. An increase in the size of the study cohort and an extension of the follow-up period would allow a reduction of the uncertainties involved in the analysis. Acknowledgments The authors are grateful to the administration of the IPPE, the staff of the radiation safety department, personnel department and other departments of IPPE, the staff of Obninsk health care establishments, the specialists of the Medical Radiological Research Center of Russian Academy of Medical Sciences for the medical and dosimetric data and assistance. Special thanks are due to the IAEA for the financial support through Project 9305/R0. 16

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