BioMed CentralBMC Cancer ssOpen AcceResearch article Kidney cancer mortality in Spain: geographic patterns and possible hypotheses Gonzalo López-Abente*1,2, Nuria Aragonés1,2, Beatriz Pérez-Gómez1,2, Rebeca Ramis1,2, Enrique Vidal1,2, Javier García-Pérez1,2, Pablo Fernández- Navarro1,2 and Marina Pollán1,2 Address: 1Cancer and Environmental Epidemiology Area, National Centre for Epidemiology, Carlos III Institute of Health, Sinesio Delgado 6, 28029 Madrid, Spain and 2CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain Email: Gonzalo López-Abente* - glabente@isciii.es; Nuria Aragonés - naragones@isciii.es; Beatriz Pérez-Gómez - bperez@isciii.es; Rebeca Ramis - rramis@isciii.es; Enrique Vidal - evidal@isciii.es; Javier García-Pérez - jgarcia@isciii.es; Pablo Fernández- Navarro - pfernandezn@isciii.es; Marina Pollán - mpollan@isciii.es * Corresponding author Abstract Background: Since the second half of the 1990s, kidney cancer mortality has tended to stabilize and decline in many European countries, due to the decrease in the prevalence of smokers. Nevertheless, incidence of kidney cancer is rising across the sexes in some of these countries, a trend which may possibly reflect the fact that improvements in diagnostic techniques are being outweighed by the increased prevalence of some of this tumor's risk factors. This study sought to: examine the geographic pattern of kidney cancer mortality in Spain; suggest possible hypotheses that would help explain these patterns; and enhance existing knowledge about the large proportion of kidney tumors whose cause remains unknown. Methods: Smoothed municipal relative risks (RRs) for kidney cancer mortality were calculated in men and women, using the conditional autoregressive model proposed by Besag, York and Molliè. Maps were plotted depicting smoothed relative risk estimates, and the distribution of the posterior probability of RR>1 by sex. Results: Municipal maps displayed a marked geographic pattern, with excess mortality in both sexes, mainly in towns along the Bay of Biscay, including areas of Asturias, the Basque Country and, to a lesser extent, Cantabria. Among women, the geographic pattern was strikingly singular, not in evidence for any other tumors, and marked by excess risk in towns situated in the Salamanca area and Extremaduran Autonomous Region. This difference would lead one to postulate the existence of different exposures of environmental origin in the various regions. Conclusion: The reasons for this pattern of distribution are not clear, and it would thus be of interest if the effect of industrial emissions on this disease could be studied. The excess mortality observed among women in towns situated in areas with a high degree of natural radiation could reflect the influence of exposures which derive from the geologic composition of the terrain and then become manifest through the agency of drinking water. Published: 9 October 2008 BMC Cancer 2008, 8:293 doi:10.1186/1471-2407-8-293 Received: 2 June 2008 Accepted: 9 October 2008 This article is available from: http://www.biomedcentral.com/1471-2407/8/293 © 2008 López-Abente et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 11 (page number not for citation purposes) BMC Cancer 2008, 8:293 http://www.biomedcentral.com/1471-2407/8/293Background During the 1980s and 90s, kidney cancer mortality increased throughout Europe. There was a trend towards stabilization in subsequent years, though this was princi- pally in western European countries, with the rates contin- uing to be very high in the eastern European countries [1]. The incidence of these tumors follows a trend which, though very similar to that of mortality in a good number of countries, is not in others, where it continues to rise across the sexes (e.g., Norway, Ireland, UK England, UK Scotland) [1,2]. In the closing decades of the 20th century, mortality due to this tumor registered an annual increase in Spain of 2.9% among men and 1.4% among women [3], and it is estimated that there were approximately 4000 new cases in 2002 [4]. The most frequent histologic type of kidney cancer in Spain is renal cell carcinoma (RCC) (accounting for around 80% of cases), followed by transitional cell carcinomas of the renal pelvis, ureter and urethra [2]. The male:female incidence ratio is 2:1, though adjusted rates vary from 4.8–11.3 cases per 100,000 pop- ulation in men, to 2.3–4.1 in women, depending upon the geographic area in question [2]. It has been argued that the growing incorporation in recent decades of new diagnostic techniques, such as echography, computed tomography, and magnetic resonance imaging, may have had an influence on the observed rise in incidence [5], though the most recent reviews conclude that the described increase is associated with the rise in prevalence of this tumor's risk factors [6]. Established risk factors for kidney cancer include cigarette smoking, obesity, diabetes, and hypertension [7]. How- ever, these factors are thought to explain only half the incidence [5,8]. In the scientific literature other risk factors have been proposed, such as ingestion of some drugs (phenacetin, diuretics) [9], intake of certain dietary com- ponents (doneness of red meat) [10], or consumption of tea and coffee, with controversial results [7]. With respect to alcohol consumption, most studies (with differing designs) report no association with kidney cancer, though some do cite evidence of a possible protective effect found exclusively among women [11], exclusively among men [12], or in both sexes [13]. Another possible, less studied risk factor for kidney cancer is exposure to substances contained in drinking water, such as products resulting from disinfection of the water [14,15], nitrites, precursors of N-nitroso compounds [16,17] and some radionuclides. Regarding this last expo- sure, water from bedrock frequently contains higher con- centrations of natural radionuclides than does water from other sources. Bladder and kidneys receive a radiation dose when radioactive isotopes are excreted into urine [18]. Studies conducted in Spain [19,20] and those under- taken in other countries [21] coincide in concluding that there is a wide variability of content in natural radionu- clides depending upon the nature of the terrain and the geographic location, something that might in turn have a bearing on the spatial patterns of this disease. Spatial analysis of health events (spatial epidemiology) is a discipline that, albeit still in the development phase, is already enjoying a space of its own in the field of health research [22,23]. Its ability to suggest and detect the pos- sible sources of heterogeneity (generally of environmental origin) which determine the spatial patterns of incidence and mortality due to different diseases, imbues this tool with great interest in the sphere of epidemiology and pub- lic health. Its potential is, moreover, being reinforced by the ever increasing availability of geographically-indexed population mortality and incidence data, together with advances in computation techniques and Geographic Information Systems. These circumstances are favoring the analysis of the geographical distribution of health data with growing levels of disaggregation [24], a field that encompasses the so-called small-area studies. The aim of this study was to show the spatial distribution patterns of kidney cancer in men and women, and discuss, in the light of known risk factors, possible hypotheses that would help explain these patterns and enhance existing knowledge about the large proportion of kidney tumors whose cause remains unknown. Methods As case source, we used individual death entries for the period 1989–1998 corresponding to kidney cancer (Inter- national Classification of Diseases, 9th Revision/ICD-9 code 189), broken down by town or city, nationwide. These data were furnished by the National Statistics Insti- tute (Instituto Nacional de Estadística – INE) for the produc- tion of a municipal cancer mortality atlas, of which these results form part [25]. Municipal populations, broken down by age group (18 groups) and sex, were obtained from the 1991 census and 1996 municipal roll. These years correspond to the mid- points of the two quinquennia that comprise the study period (1989–1993 and 1994–1998). The person-years for each five-year period were obtained by multiplying these populations by 5. Standardized mortality ratios (SMR) were calculated as the ratio of observed to expected deaths. To calculate expected cases, the overall Spanish mortality rates for the above two 5-year periods were multiplied by each town's person-years, broken down by age group, sex and quin- quennium.Page 2 of 11 (page number not for citation purposes) BMC Cancer 2008, 8:293 http://www.biomedcentral.com/1471-2407/8/293For map-plotting purposes, smoothed municipal relative risks (RRs) were calculated using the conditional autore- gressive model proposed by Besag, York and Molliè (BYM). This model was introduced by Clayton and Kaldor [26], developed by Besag, York and Molliè [27], and sub- sequently applied in the field of ecological studies [28]. These models are based on fitting Poisson spatial models with observed cases as the dependent variable, expected cases as offset, and two types of random effects terms which take the following into account: a) municipal con- tiguity (spatial term); and b) municipal heterogeneity. The models were fitted using Markov chain Monte Carlo simulation methods with non-informative priors [29]. Posterior distributions of relative risk were obtained using WinBugs [30]. The criterion of contiguity used was adja- cency of municipal boundaries. Convergence of the simu- lations was verified using the BOA (Bayesian Output Analysis) R program library [31]. Given the great number of parameters of the models, the convergence analysis was performed on a randomly selected sample of 10 towns and cities, taking 4 strata defined by municipal size. Con- vergence of the estimators was achieved before 100,000 iterations. For the maps shown, a "burn-in" (iterations discarded to ensure convergence) of 300,000 iterations was performed and the posterior distribution was derived with 5,000. A Geographic Information System was used to plot municipal maps that depicted smoothed RR estimates and the distribution of the posterior probability (pp) that RR>1 (Bayesian version of p value). With regard to this indicator, we followed Richardson's criterion [32], which recommends that probabilities above 0.8 should be deemed significant. Separate analyses were performed for men and women. Results From 1989 to 1998, a total of 14116 kidney cancer deaths were registered in Spain, 9431 among men and 4685 among women. In 5220 towns and cities no death due to this cause was registered. Using these data and conven- tional computers, it was possible to compile and ascertain the posterior distribution of relative risk on the basis of a single spatial model that included all of Spain's 8077 towns and cities and the 46398 adjacencies existing between them. To give an overall picture, Figure 1 depicts kidney cancer mortality by province for both sexes. There were only six provinces with SMRs greater than 1.15, namely, Alava, Guipuzcoa, Biscay, Navarre, Asturias and Badajoz. The lowest SMRs were registered in Galicia, Aragon, the Valen- cian Region, Murcian Region and Mediterranean prov- inces of Andalusia. Table 1 shows the results for observed and expected deaths by province, in order to be able to assess the magnitude of the relative risk and differences by sex. Figures 2 and 3 depict the distribution of: a) the smoothed RRs for kidney cancer in men and women; and, b) the posterior probability (pp) that RR>1. This second map "filters" the previous one, flagging the areas in which excess mortality is more likely. As the patterns for each sex displayed notable similarities and differences [25], the respective results are shown sep- arately. The maps show that the highest mortality in both sexes was concentrated in towns along the Bay of Biscay coastline of the Asturian, Cantabrian and Basque Country Autonomous Regions. The different mortality pattern reg- istered by women was noteworthy, with excess risk in the west of the country, covering wide swathes of Salamanca and Extremadura. In men, the only excess mortality observed in this area exclusively affected two towns, i.e., Badajoz and Mérida. Discussion Municipal maps of kidney cancer distribution display a marked geographic pattern, with excess mortality in both sexes chiefly in towns along the Bay of Biscay, including areas of Asturias, the Basque Country and, to a lesser extent, Cantabria. Among women, special mention must be made of the existence of a strikingly singular pattern, not in evidence for any other tumors and marked by excess risk in towns situated in the Salamanca area and Extremaduran Autonomous Region. This difference would lead one to postulate the existence of different exposures of environmental origin in the various regions. Possible misclassification errors involved in the study of RCC mortality render a high degree of caution necessary when it comes to assessing the patterns observed in the results. Despite the fact that undercertification of renal cancers has been reported by studies on the accuracy of death certification in Spain [33], there are not too many arguments that would support possible inconsistencies and differences of criteria in the coding of death certifi- cates, i.e., if the certification/coding of deaths were not correct, the errors would not necessarily follow any pat- tern, and there would be no agreement between incidence and mortality data. Another explanations for possible dif- ferences in kidney cancer mortality across the country, as differences in survival rates due to the distribution of tumor stage at diagnosis are difficult to maintain because the universal accessibility to the health care system. Bear- ing in mind the characteristics of the Spanish National Health Care System, we would have no reason to suspect that there might be differential access to health care and diagnosis between regions.Page 3 of 11 (page number not for citation purposes) BMC Cancer 2008, 8:293 http://www.biomedcentral.com/1471-2407/8/293Table 1: Kidney cancer mortality by province: Spain, 1989–1998. TOTAL MEN WOMEN Province obs exp SMR obs exp SMR p-val obs exp SMR p-val ALMERIA 108 147.4 0.733 81 100.2 0.809 0.972 27 47.3 0.571 0.999 CADIZ 301 284.7 1.057 201 191.1 1.052 0.224 100 93.6 1.069 0.234 CORDOBA 266 265.6 1.002 183 176.7 1.036 0.301 83 88.9 0.933 0.713 GRANADA 236 262.2 0.900 144 177.3 0.812 0.994 92 84.9 1.084 0.203 HUELVA 131 147.9 0.886 87 98.2 0.886 0.861 44 49.7 0.885 0.768 JAEN 194 230.9 0.840 134 157.4 0.851 0.969 60 73.5 0.816 0.939 MALAGA 331 363.5 0.911 210 245 0.857 0.988 121 118.4 1.022 0.384 SEVILLE 506 483.9 1.046 330 319.5 1.033 0.268 176 164.4 1.071 0.172 HUESCA 80 107.1 0.747 49 75.1 0.652 0.999 31 32 0.970 0.520 TERUEL 66 79 0.835 39 54.8 0.712 0.984 27 24.2 1.114 0.248 ZARAGOZA 338 351.7 0.961 235 236.1 0.995 0.512 103 115.5 0.892 0.869 ASTURIAS 640 463.8 1.38 447 304.8 1.466 < 0.001 193 158.9 1.214 0.004 BALEARIC ISLES 240 263.1 0.912 169 177.1 0.954 0.713 71 86 0.825 0.945 LAS PALMAS 184 199.3 0.923 133 136.9 0.971 0.610 51 62.4 0.818 0.919 SANTA CRUZ 135 215.7 0.626 93 146.5 0.635 1 42 69.3 0.606 1 CANTABRIA 234 206.7 1.132 163 136.5 1.194 0.012 71 70.2 1.011 0.431 ALBACETE 85 132.3 0.642 54 91.2 0.592 1 31 41.1 0.755 0.937 CIUDAD REAL 174 189.9 0.916 104 127.6 0.815 0.982 70 62.3 1.124 0.149 CUENCA 72 103.1 0.698 43 71.4 0.602 1 29 31.7 0.916 0.640 GUADALAJARA 66 72.8 0.907 46 50.9 0.904 0.725 20 21.9 0.912 0.608 TOLEDO 223 209.7 1.063 150 143.6 1.044 0.281 73 66.1 1.104 0.180 AVILA 76 89.1 0.853 54 61.7 0.876 0.819 22 27.4 0.802 0.826 BURGOS 163 154.4 1.056 114 105.1 1.084 0.180 49 49.3 0.995 0.477 LEON 230 237.6 0.968 137 160.8 0.852 0.969 93 76.8 1.210 0.032 PALENCIA 76 82.2 0.924 55 54.8 1.003 0.454 21 27.4 0.767 0.872 SALAMANCA 165 166.4 0.992 100 112.3 0.891 0.867 65 54.1 1.200 0.065 SEGOVIA 56 71.9 0.779 39 49.1 0.795 0.918 17 22.8 0.747 0.868 SORIA 52 53.3 0.976 37 36.5 1.015 0.422 15 16.8 0.891 0.613 VALLADOLID 197 176 1.119 128 118.3 1.082 0.174 69 57.7 1.197 0.063 ZAMORA 93 114.5 0.812 60 77.8 0.771 0.978 33 36.7 0.898 0.697 BARCELONA 1710 1669 1.025 1125 1098.6 1.024 0.208 585 570.4 1.026 0.262 GERONA 211 204 1.034 140 138.9 1.008 0.440 71 65.1 1.091 0.212 LERIDA 125 163.5 0.765 83 113.8 0.729 0.998 42 49.7 0.845 0.847 TARRAGONA 212 219.5 0.966 145 150.1 0.966 0.641 67 69.4 0.965 0.583 ALICANTE 401 459.8 0.872 283 313.3 0.903 0.956 118 146.4 0.806 0.991 CASTELLON 164 181.8 0.902 110 124.1 0.886 0.890 54 57.8 0.935 0.659 VALENCIA 676 749.8 0.902 462 500.8 0.923 0.958 214 249.1 0.859 0.987 BADAJOZ 286 242.2 1.181 179 161.6 1.108 0.081 107 80.6 1.327 0.002 CACERES 181 169.6 1.067 110 114 0.965 0.622 71 55.6 1.277 0.020 CORUNNA 377 426.9 0.883 243 278.1 0.874 0.983 134 148.8 0.900 0.881 LUGO 132 207.4 0.637 80 141.3 0.566 1 52 66 0.787 0.956 ORENSE 130 191.1 0.68 75 127.6 0.588 1 55 63.5 0.866 0.842 PONTEVEDRA 274 311.6 0.879 179 199.9 0.895 0.927 95 111.7 0.851 0.940 MADRID 1788 1588.3 1.126 1234 1035.2 1.192 < 0.001 554 553.1 1.002 0.474 MURCIA 266 338.6 0.786 185 229 0.808 0.998 81 109.6 0.739 0.997Page 4 of 11 (page number not for citation purposes) BMC Cancer 2008, 8:293 http://www.biomedcentral.com/1471-2407/8/293On examining the incidence data reported in officially certified Spanish population cancer registers and pub- lished in "Cancer Incidence in Five Continents, Volume IX" [2], the coincidence with mortality patterns can be appreciated. The highest incidence rates for both sexes were those registered in the Basque Country and Asturian Autonomous Communities (1998–2001), there being no data for the Provinces of Salamanca, Cáceres and Badajoz, as population-registry-based information is still lacking in these areas. Smoking habit is the most widely established risk factor for both histologic types of kidney cancer [34]. Yet, the patterns shown in the maps presented here diverge con- siderably from the patterns described for lung and bladder cancer among men and women, respectively [35]. Neither is there any concordance between the geographic pattern NAVARRE 249 209.8 1.187 170 138.8 1.225 0.005 79 71 1.112 0.157 ALAVA 123 91.4 1.345 82 62.3 1.316 0.007 41 29.1 1.408 0.014 GUIPUZCOA 360 238.5 1.509 227 157.3 1.443 < 0.001 133 81.2 1.637 < 0.001 VIZCAYA 563 406.6 1.385 386 269.7 1.431 < 0.001 177 136.9 1.293 < 0.001 LA RIOJA 121 111.2 1.088 87 75.6 1.151 0.088 34 35.6 0.955 0.563 CEUTA 32 17.3 1.847 19 11.6 1.642 0.015 13 5.7 2.262 0.002 MELILLA 17 13.8 1.23 8 9.1 0.875 0.564 9 4.7 1.926 0.021 Observed and expected cases, SMRs and p-values shown for both sexes, men and women. Provinces grouped by autonomous region. SMR: Standardised mortality ratio Table 1: Kidney cancer mortality by province: Spain, 1989–1998. (Continued) Provincial distribution of kidney cancer mortality: Spain, 1989–1998Figure 1 Provincial distribution of kidney cancer mortality: Spain, 1989–1998.                                                                            !                        "         #            $          Page 5 of 11 (page number not for citation purposes) BMC Cancer 2008, 8:293 http://www.biomedcentral.com/1471-2407/8/293 Page 6 of 11 (page number not for citation purposes) Municipal distribution of kidney cancer mortality in men: Spain, 1989–1998Figure 2 Municipal distribution of kidney cancer mortality in men: Spain, 1989–1998. Distribution pattern of the smoothed relative risk under the BYM model and posterior probability of RR being greater than 1. Renal cancer. Men 1989-1998 Posterior Probability RR>1 0.9 - 1 (118) 0.8 - (192) 0.2 - (4902) 0.1 - (1830) 0 - (1150) Renal cancer. Men 1989-1998 Smoothed RR >= 1.50 (28) 1.30 - (135) 1.10 - (624) 1.05 - (438) 0.95 - (1807) 0.91 - (1013) 0.77 - (3202) 0.67 - (672) < 0.67 (273) BMC Cancer 2008, 8:293 http://www.biomedcentral.com/1471-2407/8/293 Page 7 of 11 (page number not for citation purposes) Municipal distribution of kidney cancer mortality in women: Spain, 1989–1998Figure 3 Municipal distribution of kidney cancer mortality in women: Spain, 1989–1998. Distribution pattern of the smoothed relative risk under the BYM model and posterior probability of RR being greater than 1. Renal cancer. Women 1989-1998 Posterior Probability RR>1 0.9 - 1 (131) 0.8 - (506) 0.2 - (6425) 0.1 - (675) 0 - (455) Renal cancer. Women 1989-1998 Smoothed RR. >= 1.50 (10) 1.30 - (81) 1.10 - (1702) 1.05 - (960) 0.95 - (1950) 0.91 - (1421) 0.77 - (1853) 0.67 - (35) < 0.67 (180) BMC Cancer 2008, 8:293 http://www.biomedcentral.com/1471-2407/8/293observed and the prevalence of obesity. Specifically, inso- far as prevalence of obesity among women aged 35–64 years is concerned, only one of the provinces with excess risk, Badajoz, figures among the 10 provinces with highest prevalences of obesity [36]. Areas with excess kidney cancer mortality along the coast of the Bay of Biscay also register higher mortality due to other smoking-related tumors, among men in particular. As has been remarked above, however, the pattern of kid- ney cancer mortality is not concordant with that observed for other causes of death strongly related with tobacco [25]. Similarly, excess mortality due to ischemic heart or cerebrovascular diseases is not observed along the coast of the Bay of Biscay, so that other risk factors described (cig- arette smoking, obesity, diabetes, and hypertension)[7] would not appear to explain this pattern. Attention should be drawn to the fact that excess kidney cancer on the Bay of Biscay is located in a heavily industrialized area (mining and heavy metal industry). As shown in the Euro- pean Pollutant Emission Register (EPER), this area receives the highest industrial cadmium, arsenic, nickel and benzene emissions in Spain [37], substances which are classified in IARC group 1 in terms of their carcino- genic activity (human carcinogens) [38] and for which an association with renal cancer has been documented [39- 43]. Nonetheless, no references could be found in the lit- erature which analyze the possible influence of industrial pollution on RCC. The pattern displayed by female mortality in western parts of central mainland Spain (Salamanca, Cáceres, and Bada- joz) is somewhat fuzzy, with smoothed RRs not exceeding 1.3, and posterior probabilities of RR>1 exceeding 0.80 over wide areas and reaching 0.90 in very few towns, something that could be interpreted as a consequence of the smoothing procedure. However, this possible artifact should affect other areas, and yet it would not appear to do so. Taking the late introduction of the smoking habit among Spanish women into account [36], the peculiarities of the pattern displayed in women can be assumed to be attrib- utable to other factors (dietary or environmental). Reviewing the known risk factors and possible explana- tions for the higher risk of this disease among women in the province of Salamanca and Extremadura, there are very few environmental components: 1) to which women might be more exposed; and 2) for which the kidney might be the target organ. Given the geologic composition of the terrain in these provinces [44,45], consumption of drinking water is one of the possibilities that could fit such a scenario. As men consume more alcohol than women, their liquid intake can be surmised to involve a lower consumption of publicly supplied water, water that may contain components which, in the context of chronic exposure, could well cause some form of renal toxicity. It has been shown that chronic ingestion of certain radionu- clides (uranium) in drinking water may affect renal func- tion [46]. Due to the lower prevalence of smokers among women, the effect of environmental factors might be more visible among them, since the presence of a risk fac- tor such as tobacco, with a far higher RR, would partially mask the influence of environmental factors whose effect magnitude was substantially lower. Salamanca, Cáceres and Badajoz are all provinces rich in uranium ore, and in one of them concentrations of radio- nuclides (U, Th, Ra) in groundwater (bedrock) have been found which were 5–30 times higher than in surface water, whereas one third of the samples contained Ra con- centrations that exceeded the recommended limits [45]. In this respect, it must be said that the percentage of the population relying on a groundwater supply is 23% in Castile-León and 33% in Extremadura [47]. On the other hand, there is evidence of the existence of other granitic areas in Galicia, where natural radiation is high [44] and yet no excess risk of kidney cancer has been observed. The radiologic situation of this area's drinking water is not known because no systematic studies have been undertaken [48]. In this Autonomous Region the percentage of the population supplied with groundwater is 12%, a figure very much lower than that for Spain as a whole [47]. Due to their chalky soils and highly mineral- ized waters, the areas in Spain that register the maximum consumption of bottled water are the Balearic Isles, Cata- lonia, the Valencian Region, Castile-La Mancha, Murcia, and Aragon [49], and these same areas are shown in the maps as having lower-than-expected kidney cancer mor- tality. A growing number of cohort studies have reported that alcohol consumption has a protective effect as against risk of RCC: in men [50]; in women [12,51]; or in both [52]. The mechanism of action whereby alcohol serves to reduce RCC risk has not been elucidated. Some authors are of the opinion that it may be the ethanol itself that produces the protective effect, since the effect is not con- fined to any one type of alcoholic beverage. In the studies consulted, no estimate is made of the effect of the reduc- tion in daily water intake attributable to consumption of alcoholic beverages. Mean daily intake of water in Spain is 1,574.4 ml (+- 327) among adults (aged over 17 years) [53]. Regardless of the fact that moderate consumption of alcohol has a slightly protective effect vis-à-vis RCC [54], persons who received an important part of their liquid intake in the form of alcoholic beverages (e.g., wine or beer) would be far less exposed to agents conveyed inPage 8 of 11 (page number not for citation purposes) BMC Cancer 2008, 8:293 http://www.biomedcentral.com/1471-2407/8/293publicly piped drinking water, whether from surface or underground sources. The nationwide survey on diet and eating habits points to estimated alcohol consumption as being very much higher in men. The prevalence of male alcohol consumers in these provinces is extremely high (72% and 74% male vs. 38% and 47% female alcohol consumers in Extrema- dura and Castile-Leon, respectively) [36]. Exposure to products resulting from the disinfection of water is also being targeted for study in connection with urinary bladder tumors [55,56], though ecologic mortal- ity [14] and experimental animal research studies suggest a possible relationship with renal tumors [57,58]. Other compounds related with the water supply are nitrates. Nitrate has steadily accumulated in our water supply and is the most common chemical contaminant in the world's groundwater aquifers [17]. In agricultural regions, nitrate inputs are largely due to nitrogen fertilizer use [59]. Nitrates are a precursor in the formation of N- nitroso compounds (NOC), most of which are animal carcinogens [60]. Specific NOC cause renal cancers in ani- mal studies [61]. Other sources of NOC exposure include preformed NOC found in preserved meats and fish, tobacco, and certain occupational exposures [62]. Nitrate contamination of groundwater in Spain seriously affects (> 50 mg/l) the entire Mediterranean seaboard, which displays no excess risks of kidney cancer in either sex. Among the most affected inland areas are the Man- chegan plain, the Ebro delta and some sections of the Guadalquivir valley. Locally, the presence of nitrates affects different areas of the Duero (central Duero, Esla- Valderaduey, and Arenales), Tagus (La Alcarria, Tiétar and Ocaña), Sur (Campo de Níjar, Dalías, and Fuente Piedra), and Segura river basins (Campo de Cartagena, Guad- alentín, and Vegas del Segura). At a lower degree of inten- sity (25 through 50 mg/l), this contamination affects many water supply points across Asturias and the Basque Country [63]. Conclusion Municipal kidney cancer distribution maps display a marked geographic pattern. The maps show that highest mortality in both sexes is concentrated in towns along the Bay of Biscay, covering areas of Asturias, the Basque Autonomous Region and, to a lesser extent, Cantabria. The reasons for this pattern of distribution are not at all clear, and it would thus be of interest to study the effect of industrial emissions and immissions on this disease. Interventions targeted at decreasing prevalence of smok- ing, obesity and, perhaps, hypertension might tend to sta- bilize or reduce the incidence and mortality, and only go some way towards mitigating the geographic differences displayed. The different pattern registered by female mor- tality in towns in the Salamanca area and the Extrema- duran Autonomous Region is noteworthy but, subject in all cases to the necessary caution, this could in part be explained by exposures linked to the geologic composi- tion of the terrain and, in turn, to the local drinking water. Competing interests The authors declare that they have no competing interests. Authors' contributions GLA, MP, NA, and BPG were all involved in designing the study. GLA and RR performed the statistical analysis. GLA wrote the first draft of the manuscript to which all authors subsequently contributed. All authors made contributions to the statistical analyses and interpretation of results, and revised the manuscript for important intellectual content. All authors read and approved the final manuscript. Acknowledgements This study was financed by Grant No. EPY-1176/02 from the Carlos III Insti- tute of Health (ISCIII) and the Consortium for Biomedical Research in Epi- demiology & Public Health (CIBERESP). The authors would like to thanks Diana Gómez-Barroso for her help with the mapping and Pilar Martín Loz- ano for her assistance with the bibliographic material. References 1. 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