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Ingested nitrate and nitrite and bladder cancer in Northern New England

Barry, Kathryn Hughes1,*,2; Jones, Rena R.1; Cantor, Kenneth P.1; Freeman, Laura E. Beane1; Wheeler, David C.3; Baris, Dalsu1,*; Johnson, Alison T.4; Hosain, G. M. Monawar5; Schwenn, Molly6,*; Zhang, Han7; Sinha, Rashmi8; Koutros, Stella1; Karagas, Margaret R.9; Silverman, Debra T.1; Ward, Mary H1

doi: 10.1097/EDE.0000000000001112
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BACKGROUND: N-nitroso compounds are hypothesized human bladder carcinogens. We investigated ingestion of N-nitroso compound precursors nitrate and nitrite from drinking water and diet and bladder cancer in the New England Bladder Cancer Study.

METHODS: Using historical nitrate measurements for public water supplies and measured and modeled values for private wells, as well as self-reported water intake, we estimated average nitrate concentrations (mg/L NO3-N ) and average daily nitrate intake (mg/day) from 1970 to diagnosis/reference date (987 cases and 1180 controls). We estimated overall and source-specific dietary nitrate and nitrite intakes using a food frequency questionnaire (1037 cases and 1225 controls). We used unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). We evaluated interactions with factors that may affect N-nitroso compound formation (i.e., red meat, vitamin C, smoking), and water intake.

RESULTS: Average drinking water nitrate concentration above the 95th percentile (>2.07 mg/L) compared with the lowest quartile (≤0.21 mg/L) was associated with bladder cancer (OR=1.5, 95% CI: 0.97-2.3; p-trend=0.01); the association was similar for average daily drinking water nitrate intake. We observed positive associations for dietary nitrate and nitrite intakes from processed meat (highest vs. lowest quintile OR for nitrate=1.4, 95% CI: 1.0-2.0; p-trend=0.04; OR for nitrite=1.5, 95% CI: 1.0-2.1; p-trend=0.04, respectively), but not other dietary sources. We observed positive interactions between drinking water nitrate and red meat (p-interaction 0.05) and processed red meat (0.07).

CONCLUSIONS: Our results suggest the importance of both drinking water and dietary nitrate sources as risk factors for bladder cancer.

1Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD

2Department of Epidemiology and Public Health, University of Maryland School of Medicine, and Program in Oncology, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD

3Department of Biostatistics, Virginia Commonwealth University, Richmond, VA

4Vermont Department of Health, Burlington, VT

5Bureau of Public Health Statistics and Informatics, Department of Health and Human Services, Concord, NH

6Maine Cancer Registry, Augusta, ME

7Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD

8Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD

9Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH

* former affiliation

Conflicts of Interest: None declared

Source of Funding: This work was supported by the Intramural Research Program of the National Cancer Institute. Dr. Barry is supported by 1 K07 CA230182-01 from the National Cancer Institute.

Acknowledgments: We thank Joanne Colt for her contributions to the study design and conduct of the New England Bladder Cancer Study. For his efforts in overseeing the GIS linkages including assignment of drinking water source, we thank John Nuckols (Colorado State University). For their expertise and advice in modeling private well nitrate concentrations, we thank Bernard T. Nolan (USGS) and Joseph Ayotte (USGS). We thank Abigail Flory (Westat, Inc.) and Matthew Airola (Westat, Inc.) for GIS support. We also acknowledge Anne Taylor (Information Management Services, Inc.) for her programming support.

Data availability: Investigators may contact Dr. Debra Silverman, Chief of the Occupational and Environmental Epidemiology Branch at the National Cancer Institute for access to data and code for replication.

Address for correspondence and reprints: Mary H. Ward, Ph.D., Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Room 6E138, Rockville, MD 20850, Email: wardm@mail.nih.gov

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