This study highlights the persistence of a marked geographic pattern in risk of gastric cancer mortality in Spain, which affects both sexes and which has not been observed for any other tumor. Special mention should be made of the high risk that extends across a broad swathe of the Northern Iberian Plateau (Meseta), covering the Autonomous Region of Castile & Leon and spreading northeast towards the Basque Country, Navarre and La Rioja, and west to Portugal and northern Extremadura. In addition, two further areas with excess risk were identified, namely, the Atlantic Coast of Galicia and the interior of Catalonia. This pattern's similarity in men and women and its maintenance over time suggest that distribution of stomach cancer here in Spain could be related to long-standing environmental exposures shared by both sexes, as gastric cancer is known to be the result of decades of interaction between chronic inflammation and exposure to carcinogens.
When it comes to interpreting the results, some factors must be taken into account. Firstly, mortality is not the best indicator for studying cancer distribution. However, mortality continues to be the only comprehensive source of cancer information in Spain. Though the geographic distribution of specific-cause mortality might be affected by differences in the quality of death certification between one part of the country and another, there are not too many arguments that could support possible inconsistencies and differences of criteria in the coding of death certificates. Gastric cancer is a well-certified cause of death in Spain, with detection and confirmation rates both exceeding 80% . Another explanation for possible differences in cancer mortality among regions refers to variation in survival rates due to differences in the health care system across the country. Bearing in mind the characteristics of the Spanish National Health Care System, with universal accessibility, we would have no reason to suspect that there might be differential access to health care and diagnosis between regions.
The methodology used for the study of spatial disease patterns has traditionally relied on standardized mortality ratios (SMRs) . For small geographic units, the use of SMRs introduces an extra source of variability, in the form of random variability, since sparsely populated areas with few or zero cases can generate extreme SMR values . The Bayesian approach attempts to solve this problem, by using smoothing techniques that help identify the underlying geographic pattern. This approach is not entirely free of limitations, however, and there are authors who feel that Bayesian disease-mapping models are essentially conservative .
As previously mentioned, in Spain the gastric cancer mortality risk pattern is characterized by its singularity, the enormous similarity it displays across the sexes, and its persistence over time, inasmuch as its pattern has been known since the 1980s . This pattern might partially be explained by geographic differences in the prevalence of Helicobacter pylori infection. This bacterium was classified as a carcinogen (Group 1) by the International Agency for Research on Cancer in 1994, due to its relationship with gastric cancer , and is currently viewed as the principal risk factor for noncardia gastric cancer . Nonetheless the biologic pathways leading from H. pylori infection to gastric cancer are not yet well known. Despite the fact that over half the world population is infected, only a small percentage of infected subjects develop the cancer, and as H. pylori infection is equally prevalent in men and women, men have approximately twice the risk of gastric cancer. Prevalence of H. pylori infection displays important geographic differences worldwide, ranging from 40% or less in developed countries to 70% or more in developing countries . According to published studies, Spain is situated in an intermediate position vis-à-vis industrialized and developing countries. Local studies have reported H. pylori infection prevalences from as low as 43%  to as high as 69% , but there are still wide areas of our country for which this information is lacking, not making possible to link data of gastric cancer mortality and prevalence of the infection.
Until the discovery of Helicobacter pylori, diet was the most important factor associated with gastric cancer. This is a very complex variable, that includes nutrient intake as well as exposure to contaminants. It is generally accepted that consumption of fruit and vegetables affords protection against the development of this tumor [28–30], whereas salt, and foods with higher levels of N-nitroso compounds are deemed to be risk factors [31–33]. In Spain, the foods that most contribute to exposure to nitrites and nitrosamines are meat products, cereals, vegetables and fruit in the case of the former, and processed meat, beer, cheese and broiled fish in the case of the latter . Even so, there is no conclusive evidence as to the relationship between nitrogenated compounds and gastric cancer in humans. Moreover, the effect of such compounds could vary in accordance with intake of other substances, chemical or biologic contaminants and certain dietary components such as vitamins, H. pylori infection, and different patterns of genetic susceptibility .
The rising south-north and coast-inland gradient observed in the risk pattern, which is particularly marked in Castile & Leon and continues into Portugal [23, 36] has been classically attributed to dietary habits, i.e., areas with regular consumption of cured, smoked and salted food, and low intake of fruit and fresh vegetables [37–40]. However, dietary patterns have changed, and Castile & Leon has become one of the Spanish regions with higher intake of vegetables and fruits.
An alternative explanation for the described pattern would be the existence of some environmental exposure linked to the geologic characteristics of this region. Areas with highest gastric cancer mortality in the Autonomous Region of Castile & Leon basically coincide with the Tertiary Duero River Basin, an area in which elevated levels of certain contaminants have been detected, both in soils and in underground waters, principal among which is arsenic [41–44]. Most of the towns affected by this problem, essentially farming communities, rely on underground water for crop irrigation [41, 45]. Although the possible existence of contaminants associated with pesticide use is not ruled out, studies undertaken to date mainly link these high levels of arsenic to its presence in the rocky substrate and its subsequent seepage into underground water through natural geochemical mechanisms , which in turn suggests that exposure to this toxin among residents in such areas could go back many years.
The presence of arsenic in underground water in concentrations above WHO drinking-water guideline limits is a problem of enormous importance in many areas of the world. Curiously, many of the affected countries register the highest rates of gastric cancer worldwide, as is the case with China and Japan.
A possible role of arsenic in gastric carcinogenesis, whether directly or as a co-factor that facilitates the action of another mutagenic agent, seems to be a plausible hypothesis. It is a highly toxic compound that affects the gene repair pathways [46, 47] and may, moreover, cause gastric irritation . There is sufficient evidence to show that arsenic in drinking-water causes cancers of the urinary bladder, lung, and skin in humans, and might be related with liver or kidney neoplasms . At present, however, there are few epidemiologic studies that have reported an association between exposure to arsenic and development of gastric cancer [50, 51]. Notwithstanding, it is interesting to note that gastric cancer incidence and mortality decline in developed countries in the second half of the 20th century, commonly attributed to improvements in food preservation and preparation, also coincides with a decrease in the consumption of water drawn from deep underground sources and the parallel rise in the number of persons supplied with potable water piped from surface sources.
There are other metals too that could also be present in the designated area, due fundamentally to industrial pollution, a major cause of water pollution. According to the data reported to the EPER in 2001, which lists industrial contaminant releases to air and water, Castile & Leon ranks second in Spain in terms of tons of chrome released directly into water, mainly into the tributaries of the Ebro and Duero Rivers . In relation to chrome emissions, Burgos province -in Castile & Leon- ranks second at national level, only behind Tarragona, a coastal province which releases part of its waste into the Mediterranean Sea. Hexavalent chrome, a recognized carcinogen, raises the risk of gastric cancer in experimental studies . Its genotoxic and mutagenic effect in vitro is boosted in the presence of certain dietary components . Further data are still needed, however, to clarify the relationship between digestive tumors and exposure to this agent, which, in the general population, is essentially delivered by diet and drinking water.
Other toxins present in the Duero basin are nitrates . Although these occur naturally in some groundwater, in most cases higher levels are thought to result from human activities. In Spain, though drinking water accounts for a small percentage of the total intake of these agents, gastric cancer mortality has been correlated with increasing exposure to nitrates in drinking water, not only in an area with high gastric cancer mortality rates  but also in a low risk region [57, 58]. While similar results have been reported in Hungary , there are studies that do not support this hypothesis . It should be noted that nitrate pollution also indicates low water quality and so might be accompanied by other pollutants. Moreover nitrate contamination is a problem common to many Spanish aquifers, and is therefore not specific to high gastric cancer risk areas.
The excess risk displayed by both sexes in the interior of Catalonia has been previously described, and attributed to the more rural, inland population's dietary habits -associated with stomach cancer- and to the absence of readily accessible health centers . Nonetheless, the implication of other environmental exposures should not be ruled out. Local aquifers are heavily overexploited, and Catalonia is home to the river basin registering the greatest use of water for human consumption in Spain .
With respect to the excess gastric cancer risk observed on the Atlantic Coast of Galicia, it is worth noting that the towns with the highest risks countrywide in both sexes are all situated on the Morrazo Peninsula (Pontevedra province), a small geographic area with over 90,000 inhabitants. The sex ratio in this area is close to unity, something which suggests the possible implication of environmental risk factors. The economy of these towns is based on fishing, preparation of dried and salted fish, and shellfishing, mussel breeding in particular. Contaminants present in the estuaries, such as certain microorganisms, chemical pollutants (heavy metals, persistent organochlorinated pollutants, and polycyclic aromatic hydrocarbons) and marine toxins can indeed rise to high levels in shellfish and crustaceans. Such toxicants would reach the gastric mucosa by ingestion of local fish and seafood. One of these biotoxins is okadaic acid, which is present in mussels and involved in diarrhetic shellfish poisoning. This toxin has been shown to behave as a tumor promoter in mice and been proposed as a cause of digestive cancers in humans .
Finally, it should be stressed that the map depicting the male:female ratio of estimated risks at a municipal level suggests that tobacco may play an important role in men in those areas where this ratio is higher, given the similarity between its spatial distribution and the male risk pattern of dying from tobacco-related tumors, such as lung and bladder cancer . In Spain, the prevalence of female smokers until 1960-70 was very low ; in fact, time trend in lung-cancer mortality rates in women did not reflect changes in smoking patterns until the 90s, when a increase in mortality among younger generations was detected, showing the early phase of the smoking-related lung-cancer epidemic among Spanish females . Although the role of tobacco in this tumor's development has been subject of debate for many years, recent studies are furnishing evidence supporting the fact that smoking is an important risk factor for cardia gastric cancer [67, 68]. Our results are in accord with the consistent relationship found by other authors between tobacco and male stomach cancer, and the lower evidence of this association for females .
To sum up, this paper suggests possible environmental hypotheses that might help to explain the persistence of the peculiar spatial gastric cancer mortality pattern over time, similar across the sexes. Some environmental contaminants, such as chrome, arsenic, nitrites or marine toxins delivered via diet and drinking water, could act as genotoxic agents or as irritants of the gastric mucosa. The possible modifying role of those environmental toxicants on the effect of the principal known risk factors, including H. pylori infection, diet, or smoking, could be an interesting topic that would be worth bearing in mind in future studies.