Nitrate Intake Does Not Influence Bladder Cancer Risk: The Netherlands Cohort Study

Article excerpt

OBJECTIVES: N-nitroso compounds, endogenously formed from nitrate-derived nitrite, are suspected to be important bladder carcinogens. However, the association between nitrate exposure from food or drinking water and bladder cancer has not been substantially investigated in epidemiologic studies.

METHODS: We evaluated the associations between nitrate exposure and bladder cancer in the Netherlands Cohort Study, conducted among 120,852 men and women, 55-69 years of age at entry. Information on nitrate from diet was collected via a food frequency questionnaire in 1986 and a database on nitrate content of foods. Individual nitrate exposures from beverages prepared with tap water were calculated by linking the postal code of individual residence at baseline to water company data. After 9.3 years of follow-up and after excluding subjects with incomplete or inconsistent dietary data, 889 cases and 4,441 subcohort members were available for multivariate analyses. We calculated incidence rate ratios (RR) and corresponding 95% confidence intervals (CIs) using Cox regression analyses. We also evaluated possible effect modification of dietary intake of vitamins C and E (low/high) and cigarette smoking (never/ever).

RESULTS: The multivariate RRs for nitrate exposure from food, drinking water, and estimated total nitrate exposure were 1.06 (95% CI, 0.81-1.31), 1.06 (95% CI, 0.82-1.37), and 1.09 (95% CI, 0.84-1.42), respectively, comparing the highest to the lowest quintiles of intake. Dietary intake of vitamins C and E (low/high) and cigarette smoking (never/ever) had no significant impact on these results.

CONCLUSION: Although the association between nitrate exposure and bladder cancer risk is biologically plausible, our results in this study do not support an association between nitrate exposure and bladder cancer risk.

KEY WORDS: bladder cancer, cohort study, epidemiology, etiology, nitrate. Environ Health Perspect 114:1527-1531 (2006). doi:10.1289/ehp.9098 available via [Online 13 July 2006]


Nitrate is a natural compound of green vegetables, such as lettuce and spinach, and root vegetables, such as beets. Nitrate is also present in drinking water (Gangolli et al. 1994; McKnight et al. 1999; van Loon et al. 1997, 1998). In the late 1990s, the concentration of nitrate in the Netherlands increased in vegetables and drinking water due to cultivation and the use of artificial fertilizers (van Loon et al. 1998), and these nitrate concentrations have remained stable to date (Versteegh et al. 2004). This continued high concentration causes growing concern because of the potential health risks of the metabolites of nitrate and because of their potential relationship with cancer.

There is still a relative deficit of epidemiologic data addressing the association between nitrate exposure and cancer risk. Most of the epidemiologic studies that are available have focused on gastric cancer risk (Boeing et al. 1991; Buiatti et al. 1990; Cantor 1997; Forman 1989; Hansson et al. 1994; Risch et al. 1985; van Loon et al. 1997), but showing little support for the supposed relationship between nitrate and gastric cancer risk. However, an association between nitrate exposure and bladder cancer risk is biologically plausible.

After ingestion, approximately 20% of nitrate is endogenously transformed to nitrite by the bacterial flora of the oral cavity (Weyer et al. 2001). Nitrite can react in the stomach with foodborne secondary amines or amides to form N-nitroso compounds (NOCs), depending on the availability of nitrate in the stomach (Mirvish et al. 1987; van Loon et al. 1998; Walker 1990; Weyer et al. 2001). Because approximately 70% of the orally ingested nitrate is excreted in the urine, nitrosation may also occur in the bladder (Gulis et al. 2002; Preston-Martin and Correa 1989; Weyer et al. 2001). Several lifestyle-related factors can influence nitrosation. …