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Does calcium in drinking water modify the association
between nitrate in drinking water and risk of death
from colon cancer?
Hui-Fen Chiu, Shang-Shyue Tsai, Pei-Shih Chen, Trong-Neng Wu
and Chun-Yuh Yang
ABSTRACT
The objective of this study was to explore whether calcium (Ca) levels in drinking water modified the effects of nitrate on colon cancer risk. A matched case–control study was used to investigate the relationship between the risk of death from colon cancer and exposure to nitrate in drinking water in Taiwan. All colon cancer deaths of Taiwan residents from 2003 through 2007 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Controls were deaths from other causes and were pair-matched to the cases by gender, year of birth and year of death. Information on the levels of nitrate-nitrogen (NO3-N) and Ca in drinking water have been collected from Taiwan Water
Supply Corporation (TWSC). The municipality of residence for cases and controls was assumed to be the source of the subject’s NO3-N and Ca exposure via drinking water. We observed evidence of an
interaction between drinking water NO3-N and Ca intake via drinking water. This is thefirst study to
report effect modification by Ca intake from drinking water on the association between NO3-N exposure
and risk of colon cancer mortality.
Hui-Fen Chiu
Department of Pharmacology, Kaohsiung Medical University, Kaohsiung,
Taiwan Shang-Shyue Tsai
Department of Healthcare Administration, I-Shou University, Kaohsiung County,
Taiwan Pei-Shih Chen
Chun-Yuh Yang (corresponding author) Faculty of Public Health,
College of Health Sciences, Kaohsiung Medical University, Kaohsiung,
Taiwan
E-mail: [email protected] Trong-Neng Wu
Graduate Institute of Environmental Health, China Medical University, Taichung, Taiwan
Trong-Neng Wu Chun-Yuh Yang
Division of Environmental Health and Occupational Medicine,
National Health Research Institute, Miaoli, Taiwan
Key words|calcium, colon cancer, drinking water, effect modification, nitrate
INTRODUCTION
Nitrate in drinking water originates from numerous natural and man-made sources, including waste waters and agricul-tural and urban runoff. Nitrogen fertilizer is the largest contributor to anthropogenic nitrogen globally and has been implicated as an even more important source of drinking water nitrate in rural areas (Fields ). The US Environmental Protection Agency (EPA) has established a maximum contaminant level (MCL) in drinking water of 10 mg/L as nitrate-N to protect infants from developing methemoglobinemia (Ward et al. ). However, the effectiveness of this regulatory limit for preventing other health risks such as cancer has not been adequately studied (De Roos et al.).
Nitrate may act as a procarcinogen, interacting with amines and amides in the stomach to form a variety of N-nitroso compounds (NOC) (nitrosation), most of which are potent animal carcinogens (Tricker & Preussmann ), after reduction of nitrate to nitrite in saliva (Walker ). Several studies support a direct relationship between nitrate intake and endogenous formation of NOC. High nitrate levels in drinking water have been associated with increased excreted N-nitrosoproline levels in urine (Moller et al. ; Mirvish et al. ). Nitrate administered via drinking water was shown to be directly correlated with concentration of total NOC in feces (Rowland et al.). In addition, populations with high rates of esophageal, doi: 10.2166/wh.2011.006
gastric and nasopharyngeal cancer excrete high levels of N-nitrosoproline (Lu et al.;Kamiyama et al.;Yi et al. ). These results demonstrate a contribution of drinking water nitrates in nitrosation and suggest that nitrate intake may be used as a surrogate for exposure to target tissues to NOC (De Roos et al.).
NOC are potent animal carcinogens, inducing tumors at multiple organ sites including the colon (Bogovski & Bogovski;Ward et al.). NOC were shown to pro-duce tumors in several animals species tested, and it is likely that humans are also affected (Ward et al.). How-ever, few epidemiologic studies have been conducted to address the association of nitrates in drinking water with cancer risk and most of these studies focused on gastric cancer with mixed results (Forman ; Cantor ;
Yang et al.;Gulis et al.).
Our hypothesis is derived from animal experiments in which rats (Mirvish et al. ) and hamsters (Germann et al.) had higher rates of intestinal tumors after admin-istration of NOC either in drinking water or by injection. Given the biological plausibility for a role of NOC in risk of development of colon cancer and widespread exposure to nitrate in the population, there is a surprising deficit of epidemiologic data concerning the possible association of nitrates in drinking water with colon cancer. One ecologic study conducted in Slovakia found a positive association between drinking water nitrates and colon cancer rates (Gulis et al. ). Other ecologic studies reported no association with colon cancer (Geleperin et al. ;
Jensen;Morales Suarez-Varela et al.). A prospec-tive cohort study of Iowa women found that municipal drinking water nitrate levels were associated with an elev-ated risk of colon cancer that did not consistently increase with exposure (Weyer et al.). De Roos et al. ()conducted a case–control study in Iowa. No associ-ation of colon cancer with measures of nitrate in public water supplies, including average nitrate and the number of years with elevated average nitrate levels, was observed. However, a positive association was observed in a subpopu-lation of high meat or low vitamin C consumers (De Roos et al. ). From a case–control study conducted in
Wisconsin women, McElroy et al. () reported that nitrate exposure from drinking water was not significantly associated with colorectal cancer risk overall. However, a
2.9-fold increased risk of proximal colon cancer was observed (McElroy et al.).
We have previously reported a protective effect of Ca intake via drinking water against colon cancer (Yang et al. a). However, none of the previous studies has explored whether Ca levels in drinking water might modify the associ-ation between NO3-N exposure and health outcomes. If
substantial effect modification by Ca levels in drinking water exists, the true magnitude of the association between NO3-N exposure and colon cancer may be obscured.
Fur-thermore, better knowledge of the modifying factors will help in public policy-making, risk assessment and standard setting.
The objective of this study was to explore whether Ca levels in drinking water modify the effects of NO3-N on
colon cancer risk.
MATERIALS AND METHODS
Study area
Taiwan is divided into 361 administrative districts, which will be referred to herein as municipalities. These are the units that will be subjected to statistical analysis. Excluded from the analysis were 30 aboriginal townships and 9 islets which had different life-styles and living environments (the diets of people in these municipalities are generally rich infiber, antioxidants and nitrosation inhibitors, which may yield beneficial properties and act in a way against colon carcinogenesis). This elimination of unsuitable municipali-ties yielded 322 municipalimunicipali-ties.
Socioeconomic factor
Each municipality in Taiwan was assigned to a degree-of-urbanization category from 1 to 8 based on the urban– rural classification of Tzeng & Wu (), which takes into account variables such as population density, age com-position, economic activity and family income, educational level, environment and health service-related facilities. A municipality with the highest urbanization score, such as the Taipei metropolitan area, was classified in category 1, whereas mountainous areas with the lowest score were 499 H.-F. Chiu et al.|Calcium modifies the effects of nitrate on colon cancer Journal of Water and Health|09.3|2011
assigned to category 8. The urbanization index used in this study serves as a proxy for a large number of explanatory variables such as socioeconomic status and differential exposures to environmental conditions, which are related to the etiology of mortality. For the analyses, the urban– rural classification was further divided into 4 levels: I, metropolitan (categories 1 and 2); II, city (categories 3 and 4); III, town (categories 5 and 6); and IV, rural (cat-egories 7 and 8).
Subject selection
Data on all deaths of Taiwan residents from 2003 through 2007 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 gender, 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 colon cancer deaths occurring in subjects between 50 and 69 years of age (International Classification of Disease, ninth revisions [ICD-9], code 153). In all, 3,707 colon cancer deaths with complete records satisfied this criterion.
The control group consisted of all other deaths excluding those deaths which were associated with gastroin-testinal diseases. The deaths excluded were those caused by malignant neoplasms of stomach (code 151), malignant neo-plasm of small intestine, including duodenum (code 152), malignant neoplasm of colon (code 153), malignant neo-plasm of rectum, rectosigmoid junction and anus (code 154), gastric ulcer (code 531), duodenal ulcer (code 532), peptic ulcer, site unspecified (code 533), gastrojejunal ulcer (code 534), and gastrointestinal hemorrhage (code 578). Subjects who died from bladder (Morales Suarez-Varela et al.;Weyer et al.), lung (Hoffmann et al. ), esophagus (Yang;Wu et al.;Cantor ), liver (Mitacek et al. ), head and neck (Herity et al. ; Andre et al. ) cancers, and non-Hodgkin lym-phoma (NHL) (Ward et al.;Cantor ;Gulis et al. ) were also excluded from the control group because of previously reported associations with nitrate or NOC exposure. Control subjects were pair matched to the cases
by gender, year of birth and year of death. Each matched control was selected randomly from the set of possible con-trols for each case. The most frequent causes of death amongst the controls were diabetes mellitus (12.3%), chronic liver disease and cirrhosis (7.2%), breast cancer (3.6%), acute myocardial infarction (3.6%) and motor vehicle traffic accidents of unspecified nature (3.5%). Nitrate-nitrogen (NO3-N) and Ca levels
Information on the levels of NO3-N and Ca in each
munici-pality’s treated drinking water supply was obtained from the Taiwan Water Supply Corporation (TWSC) (TWSC/ROC ), to which each waterworks is required to submit drinking water quality data including the levels of nitrates and Ca. Fourfinished water samples, one for each season, were collected from each waterworks. The samples were analyzed by the waterworks laboratory office using standard methods (cadmium reduction method and spectrophoto-metric method, respectively). Since the laboratory office examines nitrate and Ca levels on a routine basis using stan-dard methods, it was thought that analytical variability was minimal. Among the 322 municipalities, 70 were excluded as they had more than one supply of drinking water and the exact population served by each could not be deter-mined. Their details are provided in earlier publications (Yang et al. , ; Yang ). The final complete data comprised NO3-N and Ca data from 252
municipali-ties. Ca remains reasonably constant for long periods of time and is quite a stable characteristic of a municipality’s water supply (Bell & Doege). Data collected were the annual mean levels of NO3-N and Ca for the year 1990.
The municipalities of residence for all cases and controls were identified from the death certificate and it was assumed that drinking water was the source of the subjects’ nitrate and Ca exposure. The levels of NO3-N and Ca of each
muni-cipality were used as an indicator of exposure to NO3-N and
Ca for an individual residing in that municipality. Statistics
In the analysis, the subjects were categorized into one of the three NO3-N exposure categories: low (the lowest 50th
percentile among controls; 0.39–0.57 ppm); and high (above the 75th percentile among controls; 0.60–2.86 ppm). Con-ditional logistic regression was used to estimate the association between NO3-N levels present in drinking
water and colon cancer risk. Odds ratio (OR) and their 95% confidence intervals (95% CI) were calculated using the low exposure group as the reference group (Breslow & Day). The association between drinking water NO3-N
levels and risk of colon cancer was stratified by Ca levels in drinking water. The analyses were performed using the SAS software (version 8.2; SAS Institute, Inc., Cary, North Carolina). All statistical tests were two-sided and values of p< 0.05 were considered statistically significant.
RESULTS
A total of 3,707 colon cancer cases with complete records were collected for the period of 2003–2007. Of the 3,707 cases, 2,087 were males and 1,620 females. The majority of both cases (78.0%) and controls (74.1%) were married. Cases had a higher rate (45.0%) of living in metropolitan municipalities than controls (38.2%). Both cases and con-trols lived in municipalities in which more than 90% of the population were served by a waterworks. The mean NO3-N concentration in the drinking water of the colon
cancer cases was 0.45 mg/L (SD¼ 0.46). Controls had a mean NO3-N exposure of 0.43 mg/L (SD¼ 0.47). Cases
(45.8%) were less likely to have lived at a residence served by drinking water with high levels (34.7 mg/L) of Ca than the controls (49.5%) (Table 1).
Of the 252 studied municipalities, 64 (25.4%) had NO3-N levels <0.12 mg/L (the lowest 25th percentile); 73
(29.0%) had NO3-N levels of 0.12–0.38 mg/L (25th–50th
percentile); 52 (20.6%) had NO3-N levels of 0.39–0.60 mg/L
(50th–75th percentile); and 63 (25.0%) had NO3-N levels
>0.60 mg/L (above 75th percentile).Table 2shows the dis-tribution of cases and controls and OR with respect to the levels of NO3-N in drinking water. The crude OR was
signifi-cantly higher than 1.0 for the group with the highest levels of nitrate in their drinking water (OR¼ 1.22, 95% CI ¼ 1.01– 1.36). Adjustments for possible confounders only slightly altered the ORs. The adjusted ORs (95% CI) were 1.02 (0.90–1.15) for the group with water nitrate levels between
0.39 and 0.57 mg/L and 1.16 (1.04–1.30) for the group with nitrate levels of 0.60 mg/L or more. There was a signifi-cant trend towards an elevated risk of death from colon cancer with increasing nitrate levels in drinking water (X2 for trend¼ 13.26, p ¼ 0.001).
Of the 252 studied municipalities, 67 (26.6%) had Ca levels24.4 mg/L (the lowest 25th percentile); 60 (23.8%) had Ca levels of 25.1–34.9 mg/L (25th–50th percentile); 62 (24.6%) had Ca levels of 35.0–49.8 mg/L (50th–75th percen-tile); and 63 (25%) had Ca levels >50.0 mg/L (above 75th percentile). The association between NO3-N levels in
drinking water and colon cancer risk among those with Table 1|Characteristics of the study population
Characteristics Cancer cases (n ¼ 3,707) Controls (n ¼ 3,707) Enrollment municipality 252 252 Gender Male 2,087 (56.3%) 2,087 (56.3%) Female 1,620 (43.7%) 1,620 (43.7%) Age (years) 50–54 736 (19.9%) 736 (19.9%) 55–59 732 (19.7%) 732 (19.7%) 60–64 913 (24.6%) 913 (24.6%) 65–69 1,326 (35.8%) 1,326 (35.8%) Marital status Single 177 (4.7%) 214 (5.8%) Married 2,927 (78.0%) 2,747 (74.1%) Ever married 603 (16.3%) 746 (20.1%) Urbanization level of residence (%)a
Metropolitan 1,669 (45.0%) 1,417 (38.2%) City 808 (21.8%) 802 (21.7%) Town 834 (22.5%) 931 (25.1%) Rural 396 (10.7%) 557 (15.0%) NO3-N level (mg/L) Mean± SDb 0.45± 0.46 0.43± 0.47 <Median (0.38) 1,921 (51.8%) 2,027 (54.7%) Median 1,786 (48.2%) 1,680 (45.3%) Ca level (mg/L) Mean± SDb 33.31± 19.38 34.48± 19.53 <Median (34.6) 2,009 (54.2%) 1,872 (50.5%) Median 1,698 (45.8%) 1,835 (49.5%)
aThe urbanization level of each municipality was based on the urban–rural classification
scheme ofTzeng & Wu (1986).
bStandard deviation.
high (median) and low (<median) Ca intake via drinking water is shown inTable 3. There was a suggestion of inter-action between drinking water nitrate and Ca intake, in that individuals with the highest NO3-N exposure and low
Ca intake from drinking water had a 1.37-fold increased risk of colon cancer (OR¼ 1.37; 95% CI ¼ 1.11–1.69), whereas those with similar nitrate exposure whose drinking water Ca intake was above the median had no statistically significant increased risk (OR ¼ 1.11, 95% CI ¼ 0.96–1.29).
DISCUSSION
This study used a death certificate-based case–control study to examine whether Ca levels in drinking water modified the effects of NO3-N in drinking water on risk of colon cancer
mortality. We found that the risk of colon cancer mortality associated with high NO3-N levels in drinking water was
elevated among those with low Ca intake from drinking water.
Ourfindings suggest that it might be important to con-sider the levels of Ca in drinking water in the evaluation of the relationship between NO3-N exposure and risk of
colon cancer mortality. To our knowledge, this is the first study to report an effect modification by Ca intake from drinking water in the association between NO3-N exposure
and risk of colon cancer mortality. Antioxidants that inhibit endogenous nitrosation include vitamin C and alpha-toco-pherol, which can reduce nitrite to NO (Bartsch et al. ). No experimental study has examined the modulating effect of Ca on colon carcinogenesis specifically induced by nitrate. Nonetheless, our results suggest that Ca may act in a similar way to vitamin C and alpha-tocopherol, which inhib-ited endogenous nitrosation caused by intake of nitrate from drinking water, and therefore individuals who had low levels of Ca intake via drinking water may be at increased risk of exposure to NOC and colon cancer mortality.
Despite their inherent limitations (Morgenstern ), studies of the ecological correlation between mortality and environmental exposures have been used widely to generate or discredit epidemiological hypotheses. Before any con-clusion based on such a mortality analysis is made, the completeness and accuracy of the death registration system need to be evaluated. Since it is mandatory to register death certificates at local household registration offices, the death registration in Taiwan is complete. 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, malignant neoplasms, including colon cancer, were reported to be one of the most unequivocally classified causes of death in Taiwan (Chen & Wang ). Because of a fatal outcome, it is believed that all colon cancer cases from high or low levels of NO3-N and Ca exposure in drinking water had
Table 2|Odds ratios (OR) and 95% confidence intervals (CI) for colon cancer death in relation to nitrate levels in drinking water, 2003–2007
Nitrate, mg/L (median) <0.38 (0.05) 0.39–0.57 (0.44) 0.60 (1.00) No. of cases 1,921 730 1,056 No. of controls 2,052 732 923 Crude ORa 1.0 1.07 (0.94–1.20) 1.22 (1.01–1.36) Adjusted ORb 1.0 1.02 (0.90–1.15) 1.16 (1.04–1.30) X2for trend¼ 13.26, p ¼ 0.001 aOdds ratio adjusted for age and gender.
bAdjusted for age, gender, marital status, urbanization level of residence.
Table 3|Odds ratios for colon cancer by levels of nitrate and Ca in drinking water NO3-N level (median) (mg/L)
0.38 (0.05) 0.39–0.57 (0.44) 0.60 (1.00)
Calcium (mg/L) Cases Controls ORa(95% CI) Cases Controls ORa(95% CI) Cases Controls ORa(95% CI)
34.6 744 844 1.00 192 234 0.89 (0.72–1.11) 791 723 1.11 (0.96–1.29) <34.6 1,177 1,208 1.02 (0.89–1.16) 538 498 1.09 (0.93–1.28) 265 200 1.37b(1.11–1.69) aAdjusted for age, gender, marital status, urbanization level of residence.
b
access to medical care regardless of geographical location in recent years.
Of greater concern is whether the relative levels of nitrate in the period around 1990 correspond to the relative levels occurring in periods 20–30 years earlier. This is important since it is likely that exposure to causal factors would precede cancer mortality (temporality). Nitrate con-tamination in public water supplies in Taiwan was due principally to the use of nitrogen fertilizers in areas of arable farming (Yang et al. b). The historical levels of nitrates are not available for the study areas. However, it is assumed that the correlation between the levels of 1990 and levels in the past 20–30 years would be high since a municipality’s urban development is gradual (the agricul-tural areas decreased gradually). Therefore we feel that the nitrate levels in 1990 were a reasonable indicator of histori-cal levels occurring over the past 20–30 years.
Migration from a municipality of high nitrate and Ca exposure to one of low nitrate and Ca exposure or vice versa may have introduced misclassification bias and bias in OR estimates (Gladen & Rogan;Polissar). The individuals included in the present study were subjects whose residence and place of death were in the same munici-pality. In the event of a death in Taiwan, there is a social custom that the decedent’s family always considers the death to have occurred in the municipality where the person was born. Therefore, the decedent’s residence, place of birth and place of death are likely to be listed as the same municipality, although the place of birth information was not available for this data set. We believe that this ame-liorates the migration problem (Yang ). In addition, mobility is age dependent, and diseases usually occur with a higher incidence amongst older groups and proximate to the location of the environmental ‘cause’ (Polissar ). However, neighboring water sources tend to possess similar chemical composition (Flaten ), and hence even if an individual moved, the change in exposure to nitrate and Ca in drinking water would probably not be significant provided that the new residential municipality is near their old residen-tial municipality (or moving within the same municipality). Also Taiwan’s population is rather stable in terms of mobility compared with populations in most Western industrialized countries (Yu et al. ). It was reported that more than 90% of rural residents lived in the municipality in which
they were born for their entire life (Wu et al.). Further, urbanization levels were included as a control variable in the analysis. Since it is conceivable that municipalities with similar urbanization levels may have similar migration rates, this probably minimized the migration problem in our study. Furthermore, any misclassification of exposure is most likely to be nondifferential, which would reduce the estimated magnitude of association rather than introduce a positive bias in the estimation.
Since the measure of effect in this study is mortality rather than incidence, migration during the interval between colon cancer diagnosis and death must also be considered. During this period, cancer diagnosis may influence a decision to migrate and may have possibly introduced bias. Data are not available for the differences in survival rates of colon cancer patients between high and low nitrate (or Ca) exposure areas. If there is a trend toward migration to more urban areas or lower nitrate (Ca) exposure areas because of proximity to medical care (and thus a better sur-vival rate for colon cancer), for example, a spurious association between nitrate (Ca) exposure and colon cancer death would have been noted. Two aspects of this study presumably minimized this possibility. First, migration due to colon 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. Second, the study subjects in the present study were between the ages of 50 and 69, and it is generally assumed that the elderly are likely to remain in the same residence during the last 20 years of their life (Rademacher et al.). Intake of nitrate from drinking water and dietary sources may result in increased exposure to NOC through endogenous nitrosation (Moller et al. ; Mirvish et al. ). The principal dietary nitrate sources are vegetables. Vegetables also contain vitamin C and other nitrosation inhibitors (Bartsch et al. ), and therefore, high intakes may not result in high rates of formation of NOC (Coss et al. ). Dietary intakes of red and processed meat are of particular importance in the formation of fecal NOC (Bingham;Bingham et al.). There is unfortunately no information available for assessing the dietary nitrate sources from vegetables and meat for individual subjects in this study. However, there is no reason to believe that there would be any correlation between the sources of 503 H.-F. Chiu et al.|Calcium modifies the effects of nitrate on colon cancer Journal of Water and Health|09.3|2011
dietary nitrate and the levels of nitrate in drinking water. Furthermore,Chilvers et al. ()indicated that when the concentration of waterborne nitrate is high, drinking water contributes substantially to total nitrate intake and the potential for nitrite and NOC formation may be increased. It is thus proposed that individuals with higher daily nitrate intake from drinking water and lower intakes of nitrosation inhibitors may be at an elevated risk of colon cancer.
Dietary Ca is the main source of Ca intake. The princi-pal dietary Ca sources are dairy products, dried smallfish, chicken eggs, soybean curd and soybean sauce (Pan et al. ). There is unfortunately no information available for assessing the dietary Ca sources for individual subjects in this study. However, there is no reason to believe that there would be any correlation between the sources of diet-ary Ca and the levels of Ca in drinking water. In Taiwan, the mean daily intake of dietary Ca is only 81.9% of the rec-ommended daily intake (Lee et al. ). One may hypothesize that waterborne Ca can make an important contribution to the total daily intake for subjects with insuf-ficient Ca intake (Yang et al.a). It is thus proposed that individuals with higher daily nitrate intake from drinking water and lower intakes of Ca from drinking water may be at increased risk of colon cancer mortality.
Screening has been shown to be effective in reducing the incidence of, and mortality from, colorectal cancer (Pignone et al.). Unfortunately, there is no information available on the prevalence of screening utilization for individual study municipalities and therefore it could not be adjusted for directly in the analysis. However, there is no reason to believe that there would be any correlations between the habits of undergoing colon cancer screening and nitrate levels in drinking water. We therefore think that the degree to which not controlling for the screening prevalence may have affected our results is not significant.
Some potential limitations of this study need to be noted. The information on nitrate or Ca concentration of drinking water was not obtained individually from the sub-jects, but estimated from their concentrations in the public drinking water supply of their residential municipality. The lifetime residential history and the identification of the pri-mary drinking water source (municipal water supply or private well water) of each subject are also not available even though both cases and controls lived in municipalities
in which more than 90% of the population were served by a waterworks (92.94 and 91.32% for cases and controls, respectively). Our study may thus have been limited by potential exposure misclassification. While these sources of misclassification are important, such misclassification of exposure is most likely to be nondifferential (i.e. unlikely to be associated with colon cancer), which would reduce the magnitude of association rather than introduce a posi-tive bias in the association. Furthermore, our results might have been confounded by the fact that no information on other potential risk factors such as physical activity and meat consumption was available (Slattery ; Chao et al. ). However, there is no reason to believe that there would be any correlation between these risk factors and the levels of nitrates and Ca in drinking water.
The nitrate concentration in drinking water in Taiwan is below the guideline value recommended by the World Health Organization ()of 10 mg/L. This guideline was not based on estimates of cancer risk. In addition, there is no scientific evidence to justify firm conclusions about the safety of any concentration of nitrate in water with regard to cancer risk. Forman ()noted that although environ-mental nitrate exposure probably plays a role in the development of cancer, it does not show a rate-limiting effect. In summary, our data suggest that Ca in drinking water modified the effects of nitrate exposure on risk of colon cancer mortality. Future studies should increase the pre-cision of the estimation of the individual’s intake of nitrates and Ca, through both food and water, and control for confounding factors, especially personal risk factors such as physical activity and meat consumption.
ACKNOWLEDGEMENTS
This study was supported by a grant from the National Science Council, Executive Yuan, Taiwan (NSC-97-2314-B-037-006-MY3).
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