Magnesium and calcium in drinking water and risk of death from ovarian cancer

ARTICLE

Auteur(s) : Hui-Fen Chiu¹, Chih-Ching Chang², Chun-Yuh Yang¹

¹ Department of Pharmacology, Kaohsiung Medical University, Kaohsiung, Taiwan ; 
² Institute of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan

Introduction

In Taiwan, ovarian cancer is the eleventh leading cause of cancer mortality [1]. The age-adjusted mortality rate for ovarian cancer was 2.64 per 100,000 in 1999. There is substantial geographic variation in ovarian cancer mortality within the country [2]. Such a geographic distribution may suggest an environmental risk factor.

Little is known about the etiology of ovarian cancer [3]. The only established risk factors for ovarian cancer are parity and use of oral contraceptives [4]. Dietary factors, including high fat and dairy products diets, have been suggested as important etiologic factors in the development of ovarian cancer [5-10]. In addition three previous epidemiologic studies examined the potential association of calcium with ovarian cancer [10-12]. One study reported a significant protective effect of calcium intake on ovarian cancer risk [12]; a second study reported no association between calcium intake and ovarian cancer risk [11]; and a third study found no association between calcium intake and ovarian cancer risk, however the rate ratio suggested a positive trend rather than an inverse trend [10].

Magnesium, which together with calcium is the main determinant of water hardness, may protect against deaths from cancer [13, 14]. Two biologically plausible mechanisms are considered by which magnesium could prevent carcinogenesis. Intracellular magnesium may enhance the fidelity of DNA replication or magnesium may prevent changes which trigger the carcinogenic process [15]. To our knowledge, the association between magnesium intake and ovarian cancer risk has not been investigated in previous epidemiologic studies.

Dietary calcium is the main source of calcium intake. In Taiwan, the mean daily intake of dietary calcium is 507 mg. This figure is only 81.9% of the recommended daily intake [16]. The major portion of magnesium intake is via food, and to a lesser extent via drinking water [17]. There is no available data for assessing the percentage that drinking water contributes to the total magnesium intake in Taiwan. Nonetheless, in the modern-day world, intake of dietary magnesium is often lower than the recommended dietary amounts of 350 mg/day [18]. For individuals at the borderline of calcium and magnesium deficiency, waterborne calcium and magnesium may make an important contribution to their total daily intake.

We have found that there is a significant protective association between drinking-water calcium levels and colorectal [19, 20], gastric [21], and breast cancer [22] but not prostate [23], and esophageal cancer [24] whereas water levels of magnesium are associated with a protective effect against gastric [21], breast [22], prostate [23] and esophageal cancer [24] but not colorectal cancer [19, 20]. The objective of this study was to examine further the relationship between the levels of calcium and magnesium in drinking water and deaths from ovarian cancer. This is one in a series of similar studies evaluating the relationship between calcium and magnesium in drinking water and risk of cancer at various sites.

Materials and methods

Study Area

Taiwan is divided into 361 administrative districts, which will be referred to herein as municipalities. Of these, 30 aboriginal townships and 9 islets were excluded from our analyses since their residents had substantially different life-styles and living environments. This elimination of unsuitable municipalities left 322 municipalities for the analysis.

Subject Selection

Data on all deaths of Taiwan residents from 1986 through 2000 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health, which is in charge of the death registration system in Taiwan. For each death, detailed demographic information, including sex, year of birth, year of death, cause of death, place of death (municipality), and residential district (municipality) were recorded on computer tapes. The case group consisted of all eligible ovarian cancer deaths occurring in people between 50 and 69 years of age (International Classification of Disease, ninth revisions [ICD-9], code 183).

A roster of potential controls was formed comprising all other deaths, excluding those deaths caused by malignant neoplasms of esophagus (ICD-9 code 150) [24], stomach (ICD-9 code 151) [21], colon (ICD-9 code 153) [19], rectum, rectosigmoid junction and anus (ICD-9 code 154) [20], pancreas (ICD-9 code 157) [25], breast (ICD-9 code 174) [22], prostate (ICD-9 code 185) [23] and cardiovascular disease (ICD-9 codes 410-414) [26], cerebrovascular diseases (ICD-9 codes 430-438) [27], hypertension (ICD-9 codes 401-405) [28] and diabetes mellitus (ICD-9 code 250) [29] because of previously reported negative correlations with hardness (calcium or magnesium) levels in drinking water. Control subjects were pair-matched to the cases by sex, year of birth, and year of death. Each matched control was selected randomly from the set of possible controls for each case. The most frequent causes of death among the controls were lung cancer (10.0%), chronic liver disease and cirrhosis (8.7%), liver cancer (8.3%), other forms of heart disease (ICD codes 420-429) (6.2%), cervix uteri cancer (6.2%), and diseases of the respiratory system (ICD-9 codes 460-519) (5.7%). To be eligible, all study subjects needed to have residence and place-of-death in the same municipality.

Calcium and Magnesium Levels in Drinking Water

Information on the levels of calcium and magnesium in each municipality's treated drinking water supply was obtained from the Taiwan Water Supply Corporation [30], to whom each waterworks is required to submit drinking water quality data, including the levels of calcium and magnesium. Four finished water samples, one for each season, were collected from each waterworks. The samples were analyzed by the laboratory offices of each waterworks using spectrophotometric methods. Since all laboratory offices examine calcium and magnesium levels on a routine basis using standard methods (spectrophotometric methods), it was thought that the problem of analytical variability was minimal. Among the 322 municipalities, 70 were excluded as they were supplied by more than one waterworks and the exact population served by each waterworks could not be determined. Their details have already been described in earlier publications [9-29]. The final complete data consisted of drinking water quality data from 252 municipalities. Hardness (calcium and magnesium) remains reasonably constant for long periods of time and is a quite stable characteristic of a municipality's water supply [31]. Data collected included the annual mean levels of calcium and magnesium for the year 1990. The municipality of residence for all cases and controls was identified from the death certificate and was assumed to be the source of the subject's calcium and magnesium exposure via drinking water. The levels of calcium and magnesium of that municipality were used as an indicator of exposure to those substances for an individual residing in that municipality.

Statistics

In the analysis, the subjects were divided into tertiles according to the levels of calcium and magnesium in their drinking water. Conditional logistic regression was used to estimate the relative risk of death from ovarian cancer in relation to the calcium and magnesium levels in the drinking water. Odds ratio (ORs) and their 95% confidence intervals (95% CIs) were calculated using the group with the lowest exposure as the reference group [32].

The analyses were performed using SAS software. All statistical tests were two-sided. Values of p < 0.05 were considered statistically significant.

Results

A total of 933 ovarian cancer deaths with complete records were collected for the period from 1986-2000.

The mean calcium levels in the drinking water of the cases was 33.5 mg/liter (SD = 19.1). Controls (n = 933) had a mean calcium exposure of 36.3 mg/liter (SD = 19.5). The mean magnesium concentrations in the drinking water were 10.7 mg/liter (SD = 7.1) and 12.2 mg/liter (SD = 8.0) for the cases and controls respectively. Both cases and controls had a mean age of 59.6. Cases lived in municipalities in which 91.6% of the population was served by a waterworks. For controls this number was 90.3%. Cases had a higher rate (46.1%) of living in metropolitan municipalities than the controls (37.6%) table I.

Table II shows the numbers of cases and controls and ORs in relation to calcium levels in their drinking water. The crude ORs were significantly lower for the group with the highest calcium level (0.78, 95% CI 0.62-0.97), but when adjusted for magnesium levels, calcium intake from drinking water was positively, although not significantly, associated with increased risk of death from ovarian cancer.

Table II. Odds ratios (ORs) and 95% confidence interval (CIs) for ovarian cancer death by calcium levels in drinking water, 1986-2000

The ORs for death from ovarian cancer were significantly lower for the two groups with high levels of magnesium in their drinking water. Adjustments for possible confounders only slightly altered the ORs. There was a significant trend toward a decreased risk of death from ovarian cancer with increasing magnesium levels in drinking water (X² = 19.01, P < 0.001) table III.

Table III. Odds ratios (ORs) and 95% confidence interval (CIs) for ovarian cancer death by magnesium levels in drinking water, 1986-2000

Discussion

This study used a death certificate based case-control approach to examine the relationship between ovarian cancer mortality and calcium and magnesium levels in the drinking water in Taiwan. There was a significant protective dose-response relationship between magnesium but not calcium levels and risk of ovarian cancer.

Despite their inherent limitations [33], studies of the ecological correlation between mortality and environmental exposures have been used widely to generate or discredit epidemiological hypotheses. Before any conclusion based on such a mortality analysis is made, however, the completeness and accuracy of the death registration system should be evaluated. The death registration in Taiwan is very complete since it is mandatory to register death certificates at local household registration offices and since the household registration information is verified annually through a door-to-door survey. Although causes of death may be misdiagnosed and/or misclassified, the problem has been minimized through the improvement in the verification and classification of causes of death in Taiwan since 1972. Furthermore, Taiwan is a small island with a convenient communication network, and the accessibility of medical service facilities is comparable among study municipalities. Differences in mortality between the municipalities in this study do not appear to result from systematic differences in recording and codification.

Some information on the levels of water hardness was available for the study areas in 1980. The correlation between 1980 and 1990 hardness levels for the study areas was reasonably high (r = 0.85). Hardness data were supplied by the Water Quality Research Center of the Taiwan Water Supply Corporation, which conducts routine water analyses to assess the suitability of water for drinking from the different water sources and at various points in the distribution system. In addition, the waterworks in each municipality received a questionnaire requesting information on whether any changes had occurred in the water supply or the treatment of the water during the past twenty years. No municipalities were excluded because of changes in water quality (eg. the use of water softeners) during the past few decades. It was felt that the hardness (calcium and magnesium) levels in drinking water have remained reasonably stable. We, therefore, assumed that calcium and magnesium levels in 1990 were a reasonable indicator of historical calcium and magnesium exposure levels from drinking water.

Migration from a municipality of high calcium and magnesium exposure to one of low calcium and magnesium exposure or vice versa could have introduced misclassification bias and bias in our ORs estimates [34, 35]. Mobility is age dependent, and diseases usually occur with a higher incidence among older groups and near the location of the environmental “cause” [35]. However, neighboring water sources tend to have similar chemical composition, which also reduces the uncertainty created by the fact that some residents consume water at their workplaces or elsewhere. Also, all subjects used for the present study were at least 50 years old, it is generally assumed that the elderly are more likely to remain in the same residence for a significant portion of their life span. Thus, the migration problem is probably minor.

Since the measure of effect in this study is mortality rather than incidence, migration during the interval between cancer diagnosis and death must also be considered. During this period, cancer diagnosis may influence a decision to migrate and possibly introduce bias. Although data is not available for the difference of survival rate of ovarian cancer patients between metropolitan areas and country areas, if, for example, there was a better survival rate for ovarian cancer in metropolitan areas than in country areas, a tendency for ovarian cancer patients to migrate to urban areas might exist, leading to a spurious association. This seems unlikely, since the 5-year survival rate for ovarian cancer has been reported to be as low as 42% in the United States and is one of the poorest among all cancer sites [3]. Also three aspects of this study presumably minimized this possibility. First, migration due to cancer diagnosis would be unlikely, since for this cohort of decedents the subject's occupational status would weigh against a move requiring a job change late in life. Next, urbanization level was included as a control variable in the analysis. Finally, the study subjects in the present study were between the ages of 50 and 69, and it was assumed that individuals in this age group are more likely to remain in the same residence and, therefore, that most of their life time was spent at the address as listed on the death certificate.

We observed a significant protective dose-response effect of drinking water magnesium levels on the risk of death from ovarian cancer, with ORs of 0.71 and 0.57 for the two groups with the highest levels of magnesium in their drinking water. Our study appears to be the first investigation to report a possible protective effect of magnesium intake via drinking water against ovarian cancer.

In the general population, the major portion of magnesium intake is via food, and to a lesser extent via drinking water [17]. There is no available data in the present study for assessing the percentage that drinking water contributes to the total magnesium intake. However, the average current intake of dietary magnesium is often lower than the recommended dietary amounts of 350 mg/day [18]. For individuals at the borderline of magnesium deficiency, waterborne magnesium can make an important contribution to their total intake. In addition, the loss of magnesium from food is lower when the food is cooked in magnesium-rich water [36]. Another reason why magnesium in water can play a critical role is its higher bioavailability. Magnesium in water appears as hydrated ions, which are more easily absorbed than magnesium in food [18, 37]. The contribution of water magnesium among persons who drink water with high magnesium levels could thus be crucial in the prevention of magnesium deficiency. Our results support the hypothesis that magnesium exerts a protective effect against cancer [15].

In this study, after adjustment for magnesium, calcium intake from drinking water was even positively, although not significantly, associated with the risk of death from ovarian cancer, with ORs of 1.31 (0.98-1.74) and 1.15 (0.86-1.53) respectively for the two higher calcium levels. This finding is consistent with a study in which calcium from dietary intake was measured [10]. The reason for not finding any effect of calcium intake on risk of ovarian cancer may be because calcium and magnesium in the drinking water are highly correlated (correlation coefficient is 0.66). This may create collinearity in the regression model making it difficult to detect an independent effect of calcium.

Parity, oral contraceptives use, and dairy and fat consumption represent possibly important confounders in the present study [3]. There is unfortunately no information available on these variables for individual study subjects and they could not be adjusted for directly in the analysis. However, there is no reason to believe that there would be any correlation between these confounders and the levels of calcium and magnesium of the water [38].

Conclusion

The results of the present study show that drinking magnesium-rich water on a regular basis may exert a protective effect on the risk of death from ovarian cancer. Future studies of magnesium intake and ovarian cancer should include estimates of magnesium intake from drinking water as well as from diet and supplements.

Acknowledgement

This study was partly supported by a grant from the National Science Council, Executive Yuan, Taiwan (NSC-87-2314-B-037-074).

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