Nitrates in Municipal Drinking Water and Non-Hodgkin Lymphoma: An Ecological Cancer Case-Control Study in Taiwan
Chih-Ching Chang; Shang-Shyue Tsai; Trong-Neng Wu; Chun-Yuh Yangd Abstract
The relationship between nitrate levels in drinking water and increased risk of non-Hodgkin lymphoma (NHL) development has been inconclusive. A matched cancer case-control and a nitrate ecology study was used to investigate the association between mortality attributed to NHL and nitrate exposure from Taiwan's drinking water. All deaths due to NHL in Taiwan residents from 2000 through 2006 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. Each matched control
was selected randomly from the set of possible controls for each case. Data on nitrate-nitrogen (NO3-N) levels of drinking water throughout Taiwan were collected from the Taiwan Water Supply Corporation (TWSC). The municipality of residence for cancer cases
and controls was presumed to be the source of the subject's nitrate exposure via drinking water. The adjusted odds ratios (OR) for NHL death for those with high nitrate levels in their drinking water, as compared to the lowest tertile, were 1.02 (0.87-1.2) and 1.05 (0.89-1.24), respectively. The results of the present study show that there was no statistically
significant association between nitrates in drinking water at levels in this investigation and increased risk of death attributed to NHL.
Keywords:
Introduction
Nitrate in drinking water originates from numerous natural and man-made sources, including wastewaters and agricultural 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, 2004). The U.S.
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., 2005).
However, the effectiveness of this regulatory limit for preventing other health risks such as cancer has not been adequately studied (De Roos et
al., 2003).
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, 1991), after reduction of nitrate to nitrite in saliva (Walker,
1990). 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 (Mirvish et al., 1992; Moller et al., 1989). Nitrate
administered via drinking water was shown to be directly correlated with concentration of total NOC in feces (Rowland et al., 1991). In addition,
populations with high rates of esophageal, gastric, and nasopharyngeal cancer excrete high levels of N-nitrosoproline (Kamiyama et al., 1987; Lu et al., 1986; Yi et al., 1993). These results demonstrate involvement 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., 2003).
N-Nitroso compounds are potent animal carcinogens, inducing tumors at multiple organ sites including hematopoietic system (Bogovski &
Bogovski, 1981; Ward et al., 2005). N-Nitroso compounds were shown to produce tumors in several animal species tested, and it is likely that humans are also affected (Lijinsky, 1986; Ward et al., 2005). However,
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, 1989; Cantor, 1997; Yang et al., 1998; Gulis et al., 2002).
Our hypothesis is derived from animal experiments in which rats (Mirvish et al., 1987) and mice (Mirvish et al., 1990) displayed higher rates of B- and T-cell lymphomas after administration of NOC either in drinking water or by injection. Given the biological plausibility for a role of NOC in
risk of development of non-Hodgkin lymphoma (NHL) 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 NHL. One ecologic study conducted in Slovakia found a positive association between drinking-water nitrates and higher NHL rates (Gulis et al., 2002). Ecologic studies in United Kingdom (Law et al.,
1999) and Italy (Cocco et al., 2003) reported no association with higher NHL frequency. One case-control study in Nebraska found a significant positive association between the average nitrate levels in public water supplies and NHL risk development, and there was evidence of a dose-response relationship with increasing nitrate levels (Ward et al., 1996). Case-control studies in Minnesota (Freedman et al., 2000) and Iowa (Ward et al., 2006) and a single prospective cohort study (Weyer et al.,
2001), however, found no association between nitrate levels in drinking water and higher risk of NHL occurrence.
Studies in Taiwan showed that there was a significant positive association between nitrate levels in drinking water and increased risk of death attributed to gastric (Yang et al., 1998), rectal (Kuo et al., 2007), and
bladder cancer (Chiu et al., 2007), whereas levels of nitrates in drinking water were not correlated with higher risk of death from colon (Yang et al., 2007) and pancreatic cancer (Yang et al., 2009). Since epidemiologic evidence for a link between drinking-water nitrates and NHL is limited, and because there is a need for additional studies using new
independent data from other populations, the present study was
undertaken in Taiwan to explore further whether nitrate levels in drinking water correlate with higher NHL frequency.
MATERIALS AND METHODS
Study Area
Taiwan is divided into 361 administrative districts, which are referred to herein as municipalities. These are the units that are subjected to
statistical analysis. Excluded from the analysis were 30 aboriginal townships and 9 islets, which had different lifestyles and living
environments. This elimination of unsuitable municipalities yielded 322 municipalities.
Data on all deaths of Taiwan residents from 2000 through 2006 was obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health, which is responsible for 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) was recorded on computer tapes. The cancer case group consisted of all eligible NHL
occurring in subjects between 50 and 69 yr of age (International Classification of Disease, ninth revision [ICD-9], codes 200, 202).
The control group consisted of all other deaths excluding those deaths attributed to malignant neoplasms of NHL, stomach (Forman, 1989; Yang
et al., 1998; Cantor, 1997; Sandor et al., 2001; Gulis et al., 2002),
bladder (Thouez et al., 1981; Morales Suarez-Varela, 1993, 1995; Weyer et al., 2001; Gulis et al., 2002; Ward et al., 2003; Yang et al., 2007), colon
and rectum (Geleperin et al., 1976; Jensen, 1982; Morales Suarez-Varela et al., 1995; Weyer et al., 2001; Gulis et al., 2002; De Roos et al., 2003;
Kuo et al., 2007), lung (Hoffmann et al., 1994), esophagus (Yang, 1980;
Wu et al., 1993; Cantor, 1997), head and neck (Andre et al., 1995; Herity et al., 1981), and brain (Barrett et al., 1998). 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 controls
for each case. The most frequent causes of death among the controls were liver cancer (11.6%), diabetes mellitus (10.6%), chronic liver
disease and cirrhosis (5.8%), motor vehicle traffic accidents of unspecified nature (3.8%), and acute myocardial infarction (3.6%).
Nitrate-Nitrogen Levels
Information on the levels of NO3-N in each municipality's treated drinking water supply was obtained from the Taiwan Water Supply Corporation (TWSC) (TWSC/ROC, 1991), to which each waterworks is required to
submit drinking-water quality data including levels of nitrates. Four finished water samples, one for each season, were collected from each
waterworks. The samples were analyzed by the waterworks laboratory office using a standard method (cadmium reduction method). Since the laboratory office examines nitrate levels on a routine basis using
standard methods, it was postulated that the difficulties in analytical variability were 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 determined. Their details are provided in an earlier publication (Yang, 1998; Yang et al., 2000). The final complete data comprised NO3-N data from 252 municipalities. Data collected were the annual mean levels of NO3-N for the year 1990. The municipalities of residence for all cancer cases and controls were
identified from the death certificate and it was assumed that drinking water was the source of the subjects' nitrate exposure. The levels of
nitrates of each municipality were used as an indicator of exposure to nitrate for an individual residing in that municipality.
Statistics
In the analysis, the subjects were divided into tertiles according to the levels of nitrate in their drinking water. Conditional logistic regression was used to estimate the relative risk in relation to the nitrate levels in
drinking water. Odds ratio (OR) and their 95% confidence intervals (95% CI) were calculated using the group with the lowest exposure as the reference group (Breslow & Day, 1980). Values of p < .05 were
considered statistically significant.
RESULTS
In total, 1716 NHL cases with complete records were collected for the period of 2000-2006. Of the 1716 cases, 1005 were males and 711 were females. The mean nitrate concentration in the drinking water of the NHL cases was 0.45 mg/L (SD = 0.47). Controls had a mean nitrate exposure
of 0.41 mg/L (SD = 0.41). Both cancer cases and controls had a mean age of 60.9 yr. Cancer cases lived in municipalities in which 92.2% of the
population was served by a waterworks. For controls this number was 91.2%. Cases had a higher rate (41.7%) of living in metropolitan
municipalities than controls (38.2%) (Table 1).
TABLE 1. Characteristics of the Study Population
Characteristics Cancer
cases Controls
aSD: standard deviation.
bThe urbanization level of each municipality was based on the urban-rural
classification scheme of Tzeng and Wu (1986).
Total subjects 1716 1716
Enrollment municipality 252 252
Gender (%)
Male 1005 (58.6%) 1005 (58.6%)
Female 711 (41.4%) 711 (41.4%)
Mean age in years (SD)a 60.9 ± 5.9 60.9 ± 5.9
Mean NO3-N concentration (SD) 0.45 ± 0.47 0.41 ± 0.41
Drinking water served by waterworks (%) 92.2 ± 16.3 91.2 ± 17.1
Urbanization level of residence (%)b
Metropolitan 715 (41.7%) 656 (38.2%)
City 371 (21.6%) 350 (20.4%)
Town 412 (24.0%) 448 (26.1%)
Rural 218 (12.7%) 262 (15.3%)
Table 2 shows the number of cancer cases and controls with OR for NHL in relation to nitrate levels in drinking water. The OR for death from NHL
were high for the two groups with high levels of nitrate in their drinking water but did not reach statistical significance. Adjustments for possible confounders only slightly altered OR. The adjusted OR (95% CI) were
1.02 (0.87-1.2) for the group with water nitrate levels between 0.19 and 0.45 mg/L and 1.05 (0.89-1.24) for the group with nitrate levels of 0.48 mg/L or more. There were no differences between groups with different levels of nitrates in drinking water.
TABLE 2. Odds Ratios (OR) and 95% Confidence Intervals (CI) for Non-Hodgkin Lymphoma Death by Nitrate Levels in Drinking Water, 2000-2006
Nitrate, mg/L (median)
≤ 0.18 (0.00) 0.19-0.45 (0.38)
0.48-2.86 (0.77)
aOdds ratio adjusted for age and gender.
bAdjusted for age, gender, and urbanization level of residence.
Number of cancer cases 565 (32.9%) 591 (34.5%) 560 (32.6%) Number of controls 587 (34.2%) 588 (34.3%) 541 (31.5%) Crude ORa 1.0 1.05 (0.89-1.23) 1.08 (0.91-1.27) Adjusted ORb 1.0 1.02 (0.87-1.20) 1.05 (0.89-1.24) χ2 for trend = 0.75, p = .39
DISCUSSION
This study used a death-certificate-based cancer case-control study and a nitrate ecology investigation to examine the relationship between mortality attributed to NHL and nitrate exposure levels in drinking water in Taiwan. Data show that there was no statistically significant
association between nitrate levels in drinking water and higher risk of death from NHL. Our findings are consistent with previous reports (Law et al., 1999; Freedman et al., 2000; Weyer et al., 2001; Cocco et al., 2003; Ward et al., 2006) but are in contrast to other previous reports (Ward et al., 1996; Gulis et al., 2002).
Despite their inherent limitations (Morgenstern, 1982), 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, 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 NHL, were reported to be one of the most unequivocally classified causes of death in Taiwan
(Chen & Wang, 1990). Because of a fatal outcome, it is believed that all NHL cases from high or low levels of nitrate exposure in drinking water
had 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 of nitrates in period 20-30 yr prior to 1990. This is important since it is likely that exposure to causal factors would precede cancer mortality by at least 20 yr (the latency
period for carcinogen exposure). The historical levels of nitrates are not available for the study areas. However, it is presumed that the
correlation between the levels of 1990 and levels in past levels of 20-30 yr would be high since the use of nitrogen fertilizers has not changed over time in study areas. In addition, other waterborne contaminants that could potentially confound our results in our model were not
included. However, other contaminants have not been linked strongly to NHL (Cantor, 1997; Freedman et al., 2000). Furthermore, if the
association between other waterborne contaminants and the risk of NHL is not as strong as the one that was observed for nitrate levels in
drinking water, adjustment of other waterborne contaminants might not qualitatively change the conclusion.
Migration from a municipality of high nitrate exposure to one of low nitrate exposure or vice versa may have introduced misclassification bias
and bias in OR estimates (Gladen & Rogan, 1979; Polissar, 1980). Mobility is age dependent, and diseases usually occur with a higher
incidence among older groups and proximal to the location of the environmental “cause” (Polissar, 1980). However, neighboring water sources tend to possess similar chemical composition, and hence even if
an individual moved, the change in exposure to nitrate in drinking water would probably not be significant provided that the old and new
residence were relatively close to one another, which also reduces the uncertainty created by the fact that some residents consume water at
their workplaces or elsewhere. Further, all subjects used for the present study were at least 50 yr 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. Furthermore, urbanizational 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.
Since the measure of effect in this study is mortality rather than incidence, migration during the interval between NHL diagnosis and death also needs to be considered. During this period, NHL diagnosis may influence a decision to migrate and possibly introduce bias. Data are
not available for differences in survival rates of NHL patients between high and low exposure areas. If there was a trend toward migration to more urban or lower nitrate exposure areas because of proximity to medical care, a spurious association between nitrate exposure and NHL death would have existed. Three aspects of this study presumably
minimized this possibility. First, migration due to NHL 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 were between the ages of 50 and 69 yr, and it was presumed that individuals in this age group are more likely to remain in the same residence and that, therefore, most of each one's life span was spent at the address listed on the death certificate.
Intake of nitrate from drinking water and dietary sources may result in increased exposure to NOC through endogenous nitrosation (Mirvish et
al., 1992; Moller et al., 1989). The principal dietary nitrate sources are vegetables. Vegetables also contain vitamin C and other nitrosation inhibitors (Bartsch et al., 1988), and therefore, high intakes may not result in high rates of formation of NOC (Coss et al., 2004). Dietary
intakes of red and processed meat are of particular importance in the formation of fecal NOC (Bingham, 1999; Bingham et al., 2002). There is unfortunately no information available for assessing the dietary nitrate
sources from vegetables and meat for individual study subjects in this investigation. However, there is no reason to believe that there would be
any correlation between the sources of dietary nitrate and the levels of nitrate in drinking water. Furthermore, Chilvers et al. (1984) 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
There are a number of major risk factors for NHL that should be taken into account when investigating the possible of an additional factor (drinking-water nitrate exposure). On the basis of scientific knowledge from epidemiologic studies, individuals at elevated risk of NHL
occurrence include those with primary immunodeficiency diseases, acquired immunodeficiency diseases, and occupational exposure to chemicals (Schottenfeld & Fraumeni, 1996). There is unfortunately no information available on these variables for an individual study subject, and thus it 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 levels of nitrates in drinking water. It is also
unlikely that there would be a direct relationship between other risk factors and levels of nitrates in drinking water.
Exposure to nitrate was determined by linking each study subject's residence to the subject's individual water source. However, it was not
possible to calculate the exact nitrate intake from water for individual subjects, because the amount of water consumed at home or at other places could not be determined. Data on individual exposure are thus still characterized by a lack of precision.
The nitrate concentration in drinking water in Taiwan is below the
guideline value recommended by the World Health Organization (1984) 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. Formam (1989) noted that although environmental 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 exposure to nitrates in drinking water at levels in this study are not associated with risk of death attributed to NHL. Future studies should increase the precision of the estimation of the
individual's intake of nitrate, through both food and water, and control for confounding factors, especially personal risk factors such as primary immunodeficiency diseases, acquired immunodeficiency diseases, and
occupational exposure to chemicals.
Acknowledgments
This study was supported by a grant from the National Science Council, Executive Yuan, Taiwan (NSC-97-2314-B-037-006-MY3).
REFERENCES
1. Andre, K. , Schraub, S. , Mercier, M. and Bontemps, P. (1995) Role of alcohol and tobacco in the aetiology of head and neck cancer: A case-control study in the Doubs region of France. Eur. J. Cancer 31B , pp. 301-309.
2. Barrett, J. H. , Parslow, R. C. , McKinney, P. A. , Law, G. R. and Forman, D. (1998) Nitrate in drinking water and the incidence of gastric, esophageal, and brain cancer in Yorkshire, England. Cancer Causes Control 9 , pp. 153-159.
3. Bartsch, H. , Ohshima, H. and Pignatelli, B. (1988) Inhibitors of endogenous nitrosation. Mechanisms and implications in human cancer prevention. Mutat. Res. 202 , pp. 307-324.
4. Bingham, S. A. (1999) High-meat diets and cancer risk. Proc. Nutr. Soc. 58 , pp. 243-248.
5. Bingham, S. A. , Hughes, R. and Cross, A. J. (2002) Effect of white versus red meat on endogenous -nitrosation in the human colon and further evidence of a dose response. J. Nutr. 132 , pp. 3522S-3525S.
6. Bogovski, P. and Bogovski, S. (1981) Animal species in which -nitroso compounds induce cancer. Int. J. Cancer 27 , pp. 471-474.
7. Breslow, N. E. and Day, N. E. (1980) Statistical methods in cancer research. Vol. I. The analysis of case-control studies International Agency for Research on
Cancer , Lyon
8. Cantor, K. P. (1997) Drinking water and cancer. Cancer Causes Control 8 , pp. 292-308.
9. Chen, C. J. and Wang, C. J. (1990) Ecological correlation between arsenic level in well water and age-adjusted mortality from malignant neoplasms. Cancer Res. 50 , pp. 5470-5474.
10. Chilvers, C. , Inskip, H. , Caygill, C. , Bartholomew, B. , Fraser, P. and Hill, M. (1984) A survey of dietary nitrate in well-water users. Int. J. Epidemiol. 13 , pp. 324-331.
11. Chiu, H. F. , Tsai, S. S. and Yang, C. Y. (2007) Nitrate in drinking water and risk of death from bladder cancer: An ecological case-control study in Taiwan. J.
Toxicol. Environ. Health A 70 , pp. 1000-1004.
12. Cocco, P. , Broccia, G. , Aru, G. , Casula, P. , Muntoni, S. , Cantor, K. P. and Ward, M. H. (2003) Nitrate in community water supplies and incidence of non-Hodgkin's lymphoma in Sardinia, Italy. J. Epidemiol. Commun. Health 57 , pp. 510-511.
13. Coss, A. , Cantor, K. P. , Reif, J. S. , Lynch, C. F. and Ward, M. H. (2004) Pancreatic cancer and drinking water and dietary sources of nitrate and nitrite. Am. J. Epidemiol. 159 , pp. 693-701.
14. De Roos, A. J. , Ward, M. H. , Lynch, C. F. and Cantor, K. P. (2003) Nitrate in public water supplies and the risk of colon and rectum cancers. Epidemiology 14 ,
pp. 640-649.
15. Fields, S. (2004) Global nitrogen: Cycling out of control. Environ. Health Perspect. 112 , pp. A557-A563.
16. Freedman, D. M. , Ward, M. H. and Helzlsouer, K. J. (2000) A case-control study of nitrate in drinking water and non-Hodgkins's lymphoma in Minnesota.
Arch. Environ. Health 55 , pp. 326-329.
17. Forman, D. (1989) Are nitrates a significant risk factor in human cancer?. Cancer Surveys 8 , pp. 443-458.
18. Geleperin, A. , Moses, V. J. and Fox, G. (1976) Nitrate in water supplies and cancer. Illinois Md. J. 46 , pp. 38-42.
19. Gladen, B. and Rogan, W. (1979) Misclassification and the design of environmental studies. Am. J. Epidemiol. 109 , pp. 607-616.
20. Gulis, G. , Czompolyova, M. and Cerhan, J. M. (2002) An ecologic study of nitrate in municipal drinking water and cancer incidence in Trnava District, Slovakia. Environ. Res. 88 , pp. 182-187.
21. Herity, B. , Moriarty, M. , Bourke, G. G. J. and Daly, L. (1981) A case-control study of head and neck cancer in the Republic of Ireland. Br. J. Cancer 43 , pp. 177-182.
22. Hoffmann, D. , Brunnemann, K. D. , Prokopczyk, B. and Djordjevic, M. V. (1994) Tobacco-specific -nitrosamines and areca-derived -nitrosamines: Chemistry,
biochemistry, carcinogenicity, and relevances to humans. J. Toxicol. Environ. Health 41 , pp. 1-52.
23. Jensen, O. M. (1982) Nitrate in drinking water and cancer in northern Jutland, Denmark, with special reference to stomach cancer. Ecotoxicol. Environ. Safety 6 , pp. 258-267.
24. Kamiyama, S. , Ohshima, H. , Shimada, A. , Saito, N. , Bourgade, M.
C. , Ziegler, P. and Bartsch, H. (1987) Urinary excretion of -nitrosoamino acids and nitrate by inhabitants of high- and low-risk areas for stomach cancer in northern Japan. IARC Sci. Publ. 84 , pp. 479-502.
25. Kuo, H. W. , Wu, T. N. and Yang, C. Y. (2007) Nitrates in drinking water and risk of death from rectal cancer in Taiwan. J. Toxicol. Environ. Health A 70 , pp. 1717-1722.
26. Law, G. , Parslow, R. , McKinney, P. and Cartwright, R. (1999) Non-Hodgkin's lymphoma and nitrates in drinking water: A study in Yorkshire, United Kingdom. J.
Epidemiol. Commun. Health 53 , pp. 383-384.
27. Lijinsky, W. (1986) The significance of -nitroso compounds as environmental carcinogens. J. Environ. Sci. Health C4 , pp. 1-45.
28. Lu, S. H. , Ohshima, H. , Fu, H. M. , Tian, Y. , Li, F. M. , Blettner,
M. , Wahrendorf, J. and Bartsch, H. (1986) Urinary excretion of -nitrosoamino acids and nitrate by inhabitants of high- and low-risk areas for esophageal cancer in
northern China: Endogenous formation of nitrosoproline and its inhibition by vitamin C. Cancer Res. 46 , pp. 1485-1491.
29. Mirvish, S. S. , Weisenburger, D. D. , Salmasi, S. and Kaplan, P. A. (1987) Carcinogenicity of 1-(2-hydroxyethyl)-1-nitrosourea and 3-nitroso-2-oxazolidinone administered in drinking water to male MRC-Wistar rats: Induction of bone,
30. Mirvish, S. S. , Weisenburger, D. D. , Joshi, S. S. and Nickols, J. (1990) 2-Hydroxyethylnitrosourea induction of B cell lymphoma in female Swiss mice.
Cancer Lett. 54 , pp. 101-106.
31. Mirvish, S. S. , Grandjean, A. C. , Moller, H. , Fike, S. , Maynard, T. , Jones, L. , Rosinsky, S. and Nie, G. (1992) -Nitrosoproline excretion by rural Nebraskans drinking water of varied nitrate content. Cancer Epidemiol. Biomarkers Prev. 1 , pp. 455-461.
32. Moller, H. , Landt, J. , Pedersen, E. , Jensen, P. , Autrup, H. and Jensen, O. (1989) Endogenous nitrosation in relation to nitrate exposure from drinking water
and diet in a Danish rural population. Cancer Res. 49 , pp. 3117-3121.
33. Morales Suarez-Varela, M. , Llopis, A. and Tejerizo, M. L. (1995) Impact of nitrates in drinking water on cancer mortality in Valencia, Spain. Eur. J. Epidemiol.
11 , pp. 15-21.
34. Morales Suarez-Varela, M. , Llopis-Gonzalez, A. , Tejerizo-Perez, M. L.
and Ferrandiz-Ferragud, J. (1993) Concentration of nitrates in drinking water and its relationship with bladder cancer. J. Environ. Pathol. Toxicol. Oncol. 12 , pp. 229-236.
35. Morgenstern, H. (1982) Uses of ecologic analysis in epidemiological research. Am. J. Public Health 72 , pp. 1336-1344.
36. Polissar, L. (1980) The effect of migration on comparison of disease rates in geographic studies in the United States. Am. J. Epidemiol. 111 , pp. 175-182.
37. Rowland, I. R. , Granli, T. , Bockman, O. C. , Key, P. E. and Massey, R. C. (1991) Endogenous -nitrosation in man assessed by measurement of apparent total -nitroso compounds in feces. Carcinogenesis 12 , pp. 1395-1401.
38. Sandor, J. , Kiss, I. , Farkas, O. and Ember, I. (2001) Association between gastric cancer mortality and nitrate content of drinking water: Ecologic study on
small area inequalities. Eur. J. Epidemiol. 17 , pp. 443-447.
39. Schottenfeld, D. and Fraumeni, J. F. (1996) Cancer epidemiology and prevention 2nd, Oxford University Press , New York
40. Taiwan Water Supply Corporation, Republic of China (1991) The statistical data of water quality Taiwan Water Supply Corporation , Taiwan
41. Thouez, J. P. , Beauchamp, Y. and Simard, A. (1981) Cancer and the
physicochemical quality of drinking water in Quebec. Soc. Sci. Med. 15D , pp. 213-223.
42. Tricker, A. R. and Preussmann, R. (1991) Carcinogenic -nitrosamines in the diet: Occurrence, formation, mechanisms and carcinogenic potential. Mutat. Res. 259 ,
43. Tzeng, G. H. and Wu, T. Y. (1986) Characteristics of urbanization levels in Taiwan districts. Geogr. Res. 12 , pp. 287-323.
44. Walker, R. (1990) Nitrates, nitrites and N-nitroso compounds: A review of the occurrence in food and diet and the toxicological implications. Food Addit. Contam.
7 , pp. 717-768.
45. Ward, M. H. , Mark, S. D. , Cantor, K. P. , Weisenburger, D. D. , Correa-Villasenore, A. and Zahm, S. H. (1996) Drinking water nitrate and the risk of non-Hodgkin lymphoma. Epidemiology 7 , pp. 465-471.
46. Ward, M. H. , Cantor, K. P. , Riley, D. , Merkle, S. and Lynch, C. F. (2003) Nitrate in public water supplies and risk of bladder cancer. Epidemiology 14 , pp. 183-190.
47. Ward, M. H. , deKok, T. M. , Levallois, P. , Brender, J. , Gulis, G. , Nolan, B. T. and VanDerslice, J. (2005) Workgroup report: Drinking-water nitrate and health— Recent findings and research needs. Environ. Health Perspect. 113 , pp. 1607-1614.
48. Ward, M. H. , Cerhan, J. R. , Colt, J. S. and Hartge, P. (2006) Risk of non-Hodgkin lymphoma and nitrate and nitrite from drinking water and diet. Epidemiology 17 , pp. 375-382.
49. Weyer, P. J. , Cerhan, J. R. , Kross, B. C. , Hallberg, G. R. , Kantamneni, J. , Breuer, G. , Jones, M. P. , Zheng, W. and Lynch, C. F. (2001) Municipal
drinking water nitrate level and cancer risk in older women: The Iowa women's health study. Epidemiology 11 , pp. 327-338.
50. World Health Organization (1984) Guidelines for drinking water quality: Vol. 1. Recommendations World Health Organization , Geneva
51. Wu, Y. , Chen, J. , Ohshima, H. , Pignatelli, B. , Boreham, J. , Li, J. , Campbell, T. C. , Peto, R. and Bartsch, H. (1993) Geographic association between
urinaryexcretion of -nitroso compounds and oesophageal mortality in China. Int. J. Cancer 54 , pp. 713-719.
52. Yang, C. S. (1980) Research on oesophageal cancer in China: A review. Cancer Res. 40 , pp. 2633-2644.
53. Yang, C. Y. , Chiu, H. F. , Tsai, S. S. , Cheng, M. F. , Lin, M. C. and Sung, F. C. (2000) Calcium and magnesium in drinking water and risk of death from prostate
cancer. J. Toxicol. Environ. Health A 60 , pp. 17-26.
54. Yang, C. Y. (1998) Calcium and magnesium in drinking water and risk of death from cerebrovascular disease. Stroke 29 , pp. 411-414.
55. Yang, C. Y. , Cheng, M. F. , Tsai, S. S. and Hsieh, Y. L. (1998) Calcium, magnesium, and nitrate in drinking water and gastric cancer mortality. Jpn. J. Cancer Res. 89 , pp. 124-130.
56. Yang, C. Y. , Wu, D. C. and Chang, C. C. (2007) Nitrate in drinking water and risk of death from colon cancer in Taiwan. Environ. Int. 33 , pp. 649-653.
57. Yang, C. Y. , Tsai, S. S. and Chiu, H. F. (2009) Nitrate in drinking water and risk of death from pancreatic cancer in Taiwan. J. Toxicol. Environ. Health A 72 ,
pp. 397-401.
58. Yi, Z. , Ohshima, H. , Bouvier, G. , Roy, P. , Zhong, J. , Li, B. , Brouet, I. , de The, G. and Bartsch, H. (1993) Urinary excretion of -nitrosoamino acids and nitrate
by inhabitants of high- and low-risk areas for nasopharyngeal cancer in southern China. Cancer Epidemiol. Biomarker Prev. 2 , pp. 195-200.
List of Tables
TABLE 1. Characteristics of the Study Population
Characteristics Cancer
cases Controls
aSD: standard deviation.
bThe urbanization level of each municipality was based on the urban-rural
classification scheme of Tzeng and Wu (1986).
Total subjects 1716 1716
Enrollment municipality 252 252
Gender (%)
Male 1005 (58.6%) 1005 (58.6%)
Female 711 (41.4%) 711 (41.4%)
Mean age in years (SD)a 60.9 ± 5.9 60.9 ± 5.9
TABLE 1. Characteristics of the Study Population
Characteristics Cancer
cases Controls
Drinking water served by waterworks (%) 92.2 ± 16.3 91.2 ± 17.1
Urbanization level of residence (%)b
Metropolitan 715 (41.7%) 656 (38.2%)
City 371 (21.6%) 350 (20.4%)
Town 412 (24.0%) 448 (26.1%)
Rural 218 (12.7%) 262 (15.3%)
TABLE 2. Odds Ratios (OR) and 95% Confidence Intervals (CI) for Non-Hodgkin Lymphoma Death by Nitrate Levels in Drinking Water, 2000-2006
Nitrate, mg/L (median)
≤ 0.18 (0.00) 0.19-0.45 (0.38)
0.48-2.86 (0.77)
aOdds ratio adjusted for age and gender.
bAdjusted for age, gender, and urbanization level of residence.
Number of cancer
cases 565 (32.9%) 591 (34.5%) 560 (32.6%)
Number of controls 587 (34.2%) 588 (34.3%) 541 (31.5%)
TABLE 2. Odds Ratios (OR) and 95% Confidence Intervals (CI) for Non-Hodgkin Lymphoma Death by Nitrate Levels in Drinking Water, 2000-2006
Nitrate, mg/L (median) ≤ 0.18 (0.00) 0.19-0.45 (0.38) 0.48-2.86 (0.77) Adjusted ORb 1.0 1.02 (0.87-1.20) 1.05 (0.89-1.24) χ2 for trend = 0.75, p = .39
