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Leukemia, Lymphomas, and Myeloma Mortality in the Vicinity of Nuclear Power Plants and Nuclear Fuel Facilities in Spain¹

Cancer Epidemiology Unit of the National Center for Epidemiology, Carlos III Institute of Health, 28029 Madrid, Spain [G. L-A., N. A., M. P., M. R.], and Epidemiology Unit, Madrid Regional Health Authority, 28004 Madrid, Spain [A. G.]

	Abstract

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Mortality due to hematological tumors in towns near Spain’s seven nuclear power plants and five nuclear fuel facilities during the period 1975–1993 was ascertained. The study was based on 610 leukemia-, 198 lymphoma-, and 122 myeloma-induced deaths in 489 towns situated within a 30-km radius of such installations. As control areas, we used 477 towns lying within a 50- to 100-km radius of each installation, matched by population size and a series of sociodemographic characteristics (income level, proportion of active population engaged in farming, proportion of unemployed, percentage of illiteracy, and province). Relative risk (RR) for each area and the trends in risk with increasing proximity to an installation were analyzed using log-linear models. None of the nuclear power plants registered an excess risk of leukemia-induced mortality in any of the surrounding areas. Excess risk of leukemia mortality was, however, observed in the vicinity of the uranium-processing facilities in Andújar [RR, 1.30; 95% confidence interval, 1.03–1.64] and Ciudad Rodrigo (RR, 1.68; 95% confidence interval, 0.92–3.08). Excess risk of multiple-myeloma mortality was found in the area surrounding the Zorita nuclear power plant. Statistical testing revealed that, with the single exception of multiple myeloma, none of the tumors studied showed evidence of a rise in risk with proximity to an installation. No study area yielded evidence of a raised risk of leukemia mortality among persons under the age of 25 years. More specific studies are called for in areas near installations that have been fully operational for longer periods. In this connection, stress should be laid on the importance of using dosimetric information in all future studies.

	Introduction

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Because of the contradictory nature of their results, studies into cancer incidence and mortality in areas near nuclear installations have not served to dispel existing doubts as to the possible adverse population effects of radioactive discharges emanating from the routine running of such installations. The report that appeared in late 1983 concerning a cluster of leukemias in young residents living in the vicinity of a nuclear fuel reprocessing plant in Sellafield (England) resulted in a considerable amount of investigation. In the main, this research has tended to focus on leukemias in persons under the age of 25. There has been confirmation of excess risk of childhood leukemias in areas near the Sellafield plant (1 , 2) , the Dounreay and Hunterston facilities in Scotland (3, 4, 5, 6) , and the Aldermaston Atomic Weapons Establishment (7 , 8) in England. Reports have also been received of excess risk of leukemia- and lymphoma-related mortality in the proximity of some NPPs³ (9, 10, 11) . Etiological studies have in turn been conducted in an effort to ascertain the role played by radiation from such installations in disease (12, 13, 14, 15) . A considerable number of studies carried out in different countries have reported an absence of risk in areas around NFFs and NPPs (16, 17, 18, 19, 20, 21, 22, 23, 24) . Radioactive discharges in the vicinity of these kinds of installations involve very low doses, far below the level of natural background radiation. It has, therefore, been argued that these doses are unable to account for the excess risk of the incidence of certain malignancies, thus giving rise to a number of alternative hypotheses (10 , 13 , 25) .

Whatever the case, the role played by exposure to low levels of ionizing radiation in the etiology of cancer continues to stimulate debate and study. The epidemiological designs most favored for the purpose of investigating this possible relationship are: (a) follow-up of worker cohorts with dosimetric controls (26, 27, 28, 29, 30) ; (b) case-control studies, basically of childhood leukemias (8 , 12 , 13 , 31 , 32) ; and (c) cancer incidence and mortality studies in populations residing near and around nuclear installations (9 , 17 , 33, 34, 35) .

Spain currently has 7 NPPs, with a total of 10 reactors (9 fully operational and 1 in the process of being dismantled) and nine nuclear fuel facilities (three fully operational, one shut down and five in the process of being dismantled). Although the country’s first NPP came into operation in 1968, no study has ever been conducted to assess the specific risk faced by populations residing near these kinds of installations. Mortality drawn from death certificates was the only nation-wide source of information in Spain, on which a first analysis of this nature could be based. We, therefore, proceeded to carry out a cancer mortality study covering towns situated in the proximity of NPPs and NFF. This paper reports on the results of that study with respect to leukemia, lymphomas, and multiple-myeloma mortality. The analysis presented here sought: (a) to quantify the RR of death in the vicinity of such installations; (b) to ascertain said risk before and after the date on which these installations first came into operation; (c) to study changes in risk in accordance with the subjects’ relative proximity to the respective installations; and (d) given the descriptive and exploratory nature of this study, to provide additional pointers for new research.

	Materials and Methods

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We studied cancer mortality in towns situated near 7 NPPs with 10 reactors that had been operational in the period 1975–1993 and 5 NFFs that had been operational in the same period. With the exception of El Cabril, which is a NWSF built on the site of an abandoned uranium mine, the NFFs are uranium-concentrate processing facilities located in mining areas where the ore is extracted. Of the remaining installations, three were excluded because they were experimental research reactors and a fourth because it came into service in 1993. Fig. 1 shows the site of these installations. This was a retrospective cohort study whose population base was made up of the inhabitants of towns neighboring the nuclear installations under review. For the purposes of description and analysis, the area falling within a 30-km radius of any such installation was called the "exposed zone"; and towns (selected as outlined below) lying within a 50–100-km radius of said installation were called the "reference zone." Although the choice of a 30-km radius was arbitrary, it roughly coincides with the area used in other studies.

View larger version (27K): [in this window] [in a new window]   Fig. 1. Sites of NPPs and NFFs in Spain.

Follow-up covered the period January 1, 1975, to December 31, 1993. For all of the NPPs as a whole, 316 towns within a 30-km radius and 303 within a 50 to 100-km radius were included in the study, matched by income level, number of inhabitants, proportion of the active population engaged in farming, proportion of unemployed, percentage of illiteracy, and province. These towns were selected at random from among all of those that met the matching conditions. For all of the nuclear fuel facilities as a whole, 173 (there were originally 177, but four towns merged with another two) and 174 towns in the exposed and reference zones, respectively, were included in the study, matched as above. The small disparities in the number of towns were attributable to changes in municipal boundary lines between 1981 and 1991 or to the impossibility of matching. The study covered a total of 644,044 persons in the exposed zone for all types of installations. Sociodemographic data were taken from the 1991 census (36) and information on income levels was taken from the Spanish Market Yearbook (Anuario del Mercado Español; Ref. 37 ). The distance chosen excluded all of the towns lying between 30 and 50 kms of any nuclear facility.

This paper presents the results on mortality due to leukemias (ICD-8 204–207, ICD-9 204–208), Hodgkin’s disease (ICD 201), non-Hodgkin’s lymphomas (ICD 200, 202) and multiple myeloma (ICD 203). The latency periods used were 1 year for leukemias (38) and 10 years for all other tumors. A latency period of 10 years rules out the possibility of studying cancer mortality other than that due to leukemias for the areas surrounding the Ascó, Cofrentes, Trillo and Juzbado facilities, because all these plants were inaugurated relatively recently. Data specific to this study were supplied on computer files by the National Statistics Institute (Instituto Nacional de Estadística). Individual records were broken down by cause, sex, age group, year of death and town of residence. Town-of-residence data for deceased persons are treated as confidential in Spain in the case of towns having fewer than 10,000 inhabitants, thus calling for a special agreement with the National Statistics Institute for the purposes of this study.

To obtain a population breakdown by sex, age, and year for towns included in the study, recourse was had to the 1981 population census, 1986 municipal roll, and 1991 census, as furnished by the National Statistics Institute. 1981-census data were restricted to towns of over 5000 inhabitants, so that the 1981 age-based distribution of populations in towns of under 5000 inhabitants had to be estimated on the basis of the 1986 and 1991 distributions, by categorizing age into 5-year age groups (18 groups) and using a procedure appropriate for small localities (39) . Relying on a log-linear polynomial regression model (39) , interpolation was used to estimate annual municipal population figures for the period 1981–1991. Pre-1981 and post-1991 populations were extrapolated by adopting a linear procedure, allocating more weight to the nearest census year. With the annual population estimates for each town, person-years for each age band (0–4, 5–14, 15–24, 25–34, 35–44, 45–54, 55–64, 65–74, and 75+), sex, and period (1975–1978, 1979–1983, 1984–1988, and 1989–1993) were then calculated, taking into account those variables that had changed over time, such as operational start-up of reactors and installations.

For analysis purposes, log-linear models were fitted on the assumption that the number of deaths per stratum followed a Poisson distribution. In these models, observed cases were the dependent variable and, as an external standard (40) , concurrent Spanish cause-specific mortality rates were used, with expected cases being computed by age, sex, and time period for each town in the exposed and reference (control) zones. Expected cases were included as offset in the models. A term that we called "exposure" (a radius of 30 km or less from the facility), was included as the independent variable. The regression coefficient of this exposure term provided us with the logarithm of the ratio between the respective SMRs for the exposed and reference zones, something that we, in a departure from the traditional use of the term, called "relative risk" (RR). This estimator was adjusted for age, sex, time period, and matching variables. In the case of leukemia-related mortality, results specific to the under-25 age group are shown.

Similar models were fitted to study the effect of distance on mortality. This variable was constructed by categorizing distances in the 0–30-km belt into 5 levels (consisting of circular sectors having equal surface areas) and using towns situated at a distance of 50–100 km as the reference level. Expressed in kilometers, the cutoff points for the intervals were as follows: 0-, 13.4-, 19.6-, 23.2-, 26.8–30, and 50–100. This was included in all of the models both as a categorical and as a continuous variable (in kilometers), which rendered it possible: (a) in the former case, to estimate the effect for the respective distances; and (b) in the latter case, to ascertain the existence of radial effects (rise in RR with increasing proximity to an installation) and, by applying the likelihood ratio test, the statistical significance of such distance-induced effects. Matching variables were included in this analysis as continuous covariates centered around their mean to ensure control of possible gradients in these variables with proximity to the installation. In view of the heterogeneity of the installations, we ran specific analyses on individual installations and a joint analysis on all the installations.

We studied changes in risk by comparing the position before and after the date on which NPPs and fuel facilities first came into operation (start-up), taking latency periods into account. These periods were included in the assessment of risk before start-up. The statistical significance of this change was obtained by means of the likelihood ratio test, which evaluates the interaction term, exposure x plant operation, in regression models.

RR CIs were calculated using the SEs of the parameters yielded by the model. Model results were checked and corrected for over-dispersion problems (41) using the robust methods recommended by Breslow (42) for the purpose because these methods are insensitive to the form adopted by variance.

	Results

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Table 1 sets out the socioeconomic characteristics of populations residing near nuclear installations. According to the 1991 census, the study populations in 30-km belts totaled 302,861 and 341,203 for NPPs and NFFs, respectively. Furthermore, Table 1 shows these contributions to the study in terms of person-years.

In the exposed zone around the Vandellós power plant (Table 2) , the RR for leukemias was 1.19 (95% CI, 0.82–1.73). Within a 15-km radius, the RR for leukemias was 1.59. Yet on categorization and application of the statistical test, none of these diseases appeared to evince (distance-related) radial effects (Table 4) .

Because of the fact that Ascó, Cofrentes, and Trillo came into operation relatively recently, only the results for leukemias are shown (Tables 2 and 4) . In no case did the pattern of risk prove remarkable.

The results for leukemias among the under-25 age group are shown in Table 2 . The number of cases was very low overall, Garoña being the only installation where the RR exceeded 1, though even here, the excess risk was not statistically significant.

The last column in Table 4 shows the P for trend of the effect according to distance. The only malignancy to register a clear and statistically significant distance-induced gradient (radial effect) was multiple myeloma in Zorita.

With respect to leukemias, the pre-and post-start-up mortality levels proved very similar for the three areas in which the study was feasible. In the case of multiple myeloma, the post-start-up risk proved higher for the Zorita and Garoña catchment areas, yet the increase was not statistically significant.

NFFs.
Table 3 shows the RRs for the nuclear fuel facilities. The Andújar area registered excess leukemia mortality (RR 1.30; 95% CI 1.03–1.64). In the 15-km sector surrounding the Ciudad Rodrigo facility, the RR was 1.68 (95% CI, 0.92–3.08). In all, 14 of the 30 deaths took place in the Ciudad Rodrigo metropolitan area.

Table 4 reports the results of the analysis of risk in accordance with the distance to the uranium-concentrate processing plants and the El Cabril NWSF. None of the causes studied registered a pattern that indicated a rise in risk with proximity and at the same time proved statistically significant with the test used. The El Cabril storage facility is located in a relatively deserted area, only 9 towns lying within a 30-km radius; the nearest is over 16 kms away. For distances under 20 kms, the of leukemias was in excess of 2.

We were able to study the start-up effect (Table 5) in the case of the La Haba, Ciudad Rodrigo, and Juzbado facilities. Available data failed to show evidence of a statistically significant rise in mortality.

	Discussion

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Overall, the results point to a rise in risk of death from multiple myeloma in the area surrounding the Zorita NPP. Similarly, the possible existence of excess risk of leukemias in the proximity of the Andújar and Ciudad Rodrigo facilities argues in favor of more specific studies in areas adjacent to nuclear fuel facilities.

The validity of death-certificate diagnoses for investigating cancer is generally accepted (17 , 19 , 35 , 43) . Mortality data, although showing a high degree of accuracy in cancers of the lymphatic tissue and hematopoietic system (43 , 44) , are nevertheless not the most ideal means for studying diseases such as childhood leukemia because of therapeutic improvements that have succeeded in lowering mortality without altering incidence. Yet, with the single exception of Tarragona, none of the provinces studied are equipped with population-based cancer registries that would otherwise enable cancer incidence to be studied in these areas.

In the calculation of person-years, interpolation and extrapolation techniques had to be used. These techniques were applied in the same way to all of the provinces and towns included in the various studies. Hence, any possible deviations that are inherent in the estimates will be equally present in all of the areas compared.

Specific methodological problems are posed by investigation into relatively rare diseases in areas adjacent to sources of contamination. Stress has been laid on the importance of ascertaining disease-frequency and -distribution in other areas similar in size to those being studied (45) , a suggestion that was followed in our design. Indeed, a great part of the SMRs obtained from comparison with overall Spanish mortality were under 1 for the exposed and reference zones (Tables 2 and 3) . Diagnostic verification of all of the cases is essential, because findings yielded by small areas are more sensitive to errors of classification, diagnosis, and reporting than those obtained for larger areas (45) . Here however, case-diagnosis verification was ruled out by the very nature of our study, yet possible errors of classification would necessarily affect exposed and nonexposed towns in each region alike. In general, the areas compared in this study were rural. Reference towns were matched to exposed towns by sociodemographic variables and would, thus, indirectly maintain their comparability insofar as diagnostic accuracy and accessibility to the healthcare system are concerned. Sociodemographic information for the entire study period was not available. However, bearing in mind the characteristics of the Spanish National Health System, we would have no reason to suspect that there might be differential access to health care and diagnosis between exposed and reference areas.

In theoretical terms, comparison of SMRs are open to criticism on the basis that, internally, the SMRs use different standard populations. In this study, thanks to the matching procedure followed in the design, differences in structure between the populations compared were not very marked. The method of comparison of SMRs adopted in the presentation of these results was chosen because: (a) it was the same as that used in the references (9 , 17) ; (b) it included the comparison with Spanish mortality, and (c) it allowed all of the age strata to be collapsed, thereby reducing sensitivity to instability in age-specific rates (40) . Moreover, analysis based on comparison of mortality rates (rate ratios) via models that use person-years as offset and include age, was found to yield equivalent results.

The study of the distance variable seeks to associate mortality with the nuclear installation as the putative source of contamination. Distance to the installation tends to be used as a surrogate variable for exposure in cases in which dosimetric information or the radiological history of an installation’s environs is not forthcoming (46 , 47) , with reconstruction of such data constituting a field of investigation in itself (48) . Indeed, in this respect, the study is "ecological," in that individual levels of exposure are unknown and the inhabitants of any given town are thus implicitly assumed to have received similar exposures. There will inevitably be persons who have resided for part of their lives in exposed towns and then moved to nonexposed areas and vice versa.

The Zorita power plant’s area in the Province of Guadalajara showed evidence of an excess risk of multiple myeloma cases. Although not statistically significant, this excess risk remained in evidence even when the whole country was taken as reference. Yet, analysis adjusted for geographical location is nevertheless, to be preferred. Excess risk of myeloma connected with ionizing radiation has been documented in follow-up studies of Japanese atomic-bomb survivors (49) and nuclear industry workers (50, 51, 52, 53) . A raised risk has also been found in populations residing near English-based nuclear installations that were commissioned before 1955 (9) . Guadalajara is a province with a myeloma mortality risk verging on the average for Spain (54) , yet its municipal pattern of distribution is marked by a cluster in the southwest of the province where the NPP is situated. There are no grounds for thinking that different biological and/or genetic determinants may have a nonhomogeneous distribution in the natural agrarian region to which the Zorita area belongs. Apart from ionizing radiation, known risk factors for myeloma include certain specific occupational exposures, such as pesticides, benzene, paints and solvents, and engine exhausts (55) . Increased risk of myeloma has been reported for farm workers and workers in the petroleum refining, rubber and plastics manufacturing, and wood products industries. There are no petroleum refineries or plastics-related industries in this area. The exposed and reference towns were matched according to the proportion of farm workers. Moreover, based on the information available, no differences in crop cultivation were identified as between the areas compared. The data (in conjunction with the presence of a radial pattern peaking at a distance of 14 km from the plant), though not technically attributable to the nuclear installation by virtue of the nature of this study, nevertheless, lend heightened interest to using case-by-case diagnostic verification to ascertain the true incidence of this disease in the province.

With respect to leukemia-related mortality, mention should be made of: (a) excess risks observed in the environs of the Andújar facility; and (b) figures on the borderline of statistical significance in the Vandellós, Zorita, and Ciudad Rodrigo catchment areas. In this analysis, no distinction was drawn between types of leukemia because of the importance of the number of deaths certified as leukemia of unspecified cell type. Nevertheless, exploratory exclusion of specified chronic lymphatic leukemia produced very similar results.

No excess risk of leukemia-related mortality was detected in the population aged 0–24 years residing within a 30-km radius of any NPP. The only area to register a high RR was that of Garoña, but here, the excess risk failed to attain statistical significance. Joint analysis registered: an RR of 0.70 for areas surrounding the different NPPs and 1.02 for areas surrounding the different NFFs. In view of the length of the follow-up period, the statistical power of the studies on the respective installations is low with respect to the under-25 age group. With a total of 40 expected cases for all of the NPP catchment areas, the probability (power) of detecting a 50% rise in risk (RR = 1.5) is 86% (with a type I error of 5%).

Exposure to environmental radon is the greatest single source of human exposure to ionizing radiation (56) . The influence of natural radiation on mortality could not be incorporated into this analysis. All of the towns selected (exposed and reference zones) in the Zorita and Vandellós areas lie in localities that have extremely low levels of natural radiation. Rates of exposure are below 10 µRoentgen/h, equivalent to an average effective dose of 1.09 µSievert/year (109 mrem/year; Ref. 57 ). We, therefore, think that adjusting the effect estimates for levels of natural radiation in these two areas would have no influence whatsoever on the results. However, such an adjustment may well be of greater interest in the case of uranium-concentrate and NFF catchment areas located in parts of the country with high levels of natural radiation (Ciudad Rodrigo, Juzbado, and Andújar).

The results reported here have to be interpreted with a great deal of caution, because of the nature of the study and the limitations described above. Being an ecological and exploratory study, any possible deduction linking the presence of nuclear installations to cancer mortality in their environs, must be viewed as largely speculative. More specific studies are called for in the Vandellós, Zorita, and Garoña areas, sites of the first NPPs to be built in Spain. In this connection, stress should be laid on the importance of using dosimetric information in all future studies.

	Acknowledgments

 
We are grateful to Miguel Mata, Nuria Garreta, and the National Statistics Institute for their help in obtaining the mortality and population data. We thank Michael Benedict for his help with the English.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by Grant 96/300 from Spain’s Fondo de Investigación Sanitaria (Health Research Fund).

² To whom requests for reprints should be addressed, at Servicio de Epidemiología del Cáncer, Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Sinesio Delgado, 6, 28029 Madrid, Spain. E-mail: glabente{at}isciii.es

³ The abbreviations used are: NPP, nuclear power plant; NFF, nuclear fuel facility; NWSF, nuclear waste storage facility; SMR, standardized mortality ratio; ICD, International Classification of Diseases; RR, relative risk; CI, confidence interval.

Received 2/ 1/99; revised 6/29/99; accepted 7/12/99.

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