Academic journal article Environmental Health Perspectives

Nitrate from Drinking Water and Diet and Bladder Cancer among Postmenopausal Women in Iowa

Academic journal article Environmental Health Perspectives

Nitrate from Drinking Water and Diet and Bladder Cancer among Postmenopausal Women in Iowa

Article excerpt


Urinary bladder cancer is the sixth most common malignancy in the United States, with an incidence among men that is 4 times greater than that in women [National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER) 2015]. Established risk factors include cigarette smoking (Silverman et al. 2006), certain occupational exposures (Silverman et al. 2006), and ingestion of high levels of arsenic in drinking water [International Agency for Research on Cancer (IARC) 2012; Saint-Jacques et al. 2014]. Increased exposure to disinfection by-products (DBP) in public drinking water supplies has also been associated with increased bladder cancer risk in studies in North America and Europe (Cantor 1997; Cantor et al. 2006; Costet et al. 2011). The relationship between bladder cancer risk and other drinking water contaminants has not been as well studied.

Nitrate is a common drinking water contaminant arising primarily from agricultural sources, such as nitrogen fertilizers and manure and human waste. In the United States, agricultural areas often have elevated levels of nitrate in ground water and in surface waters (Nolan and Stoner 2000; Ward 2009). Nitrate is also found at high levels in certain vegetables. Nitrite sources in the U.S. diet include processed meats, breads, and cereals (IARC 2010). Ingestion of nitrate and nitrite can lead to endogenous formation of N-nitroso compounds (NOC) in the presence of nitrosatable precursors such as amines and amides from meat and fish. NOC also have exogenous sources, including cigarette smoke and meats preserved with nitrite and nitrate salts (IARC 2010).

Ingestion of nitrate and nitrite under conditions that result in the endogenous formation of NOC is classified as a probable human carcinogen by the International Agency for Research on Cancer (IARC 2010) based on animal and mechanistic studies and on limited epidemiologic evidence for stomach and esophagus cancers. Animal data support a role for NOC in causing tumors in numerous organ sites, including the bladder (IARC 2010). In human biomonitoring studies, simultaneous ingestion of nitrate in drinking water at the World Health Organization (WHO) acceptable daily dietary intake level (3.7 mg/kg; WHO 2011) and an amine source resulted in excretion of NOC in the urine (IARC 2010; Vermeer et al. 1998). Intragastric nitrosation is inhibited by antioxidants, including vitamins C and E (IARC 2010; Mirvish 1986), but it is unclear to what extent modification of endogenous NOC formation occurs outside the gastrointestinal tract.

Despite the carcinogenic potential of NOC, nitrate in drinking water has not been extensively evaluated in relation to bladder cancer risk. Case-control studies in Iowa (Ward et al. 2003) and Spain (Espejo-Herrera et al. 2015) found no association between long-term average nitrate levels in public water supplies (PWS) and bladder cancer. Findings from two prospective studies include a significant positive association in the Iowa Women's Health Study (IWHS) (Weyer et al. 2001) and no association in a Dutch cohort (Zeegers et al. 2006). The Spanish study accounted for concomitant exposure to DBP, which are suspected bladder carcinogens, by adjusting for estimated total trihalomethanes (TTHM) in PWS (Espejo-Herrera et al. 2015). To our knowledge, no U.S. study of drinking water nitrate and bladder cancer has accounted for potential confounding by DBP.

In contrast to the inconclusive findings for drinking water nitrate, positive associations between bladder cancer risk and dietary sources of nitrate and nitrite have been identified in three prospective cohorts (Ferrucci et al. 2010; Michaud et al. 2006) and in two case-control studies (Catsburg et al. 2014; Wu et al. 2012). These studies have implicated intake of processed meats or their nitrate/nitrite preservatives as risk factors, but only the studies by Catsburg et al. (2014) and Ferrucci et al. …

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