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Ingested Nitrate and Nitrite and Bladder Cancer in Northern New England

Barry, Kathryn Hughesa,b; Jones, Rena R.a; Cantor, Kenneth P.a; Beane Freeman, Laura E.a; Wheeler, David C.c; Baris, Dalsua; Johnson, Alison T.d; Hosain, G. Monaware; Schwenn, Mollyf; Zhang, Hang; Sinha, Rashmih; Koutros, Stellaa; Karagas, Margaret R.i; Silverman, Debra T.a; Ward, Mary H.a

doi: 10.1097/EDE.0000000000001112
Cancer
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SDC

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/d) from 1970 to diagnosis/reference date (987 cases and 1,180 controls). We estimated overall and source-specific dietary nitrate and nitrite intakes using a food frequency questionnaire (1,037 cases and 1,225 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 with 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 versus 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.

From the aOccupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD

bDepartment 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

cDepartment of Biostatistics, Virginia Commonwealth University, Richmond, VA

dVermont Department of Health, Burlington, VT

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

fMaine Cancer Registry, Augusta, ME

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

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

iDepartment of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH.

Submitted February 1, 2019; accepted September 25, 2019.

This work was supported by the Intramural Research Program of the National Cancer Institute. K.H.B. is supported by 1 K07 CA230182-01 from the National Cancer Institute.

The authors report no conflicts of interest.

Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com).

Barry and Jones are co-first authors and Karagas, Silverman, and Ward are co-last authors.

Baris currently at Section on Development and Affective Neuroscience, Emotion and Development Branch, National Institute of Mental Health.

Barry and Baris were formerly at Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; and Schwenn was formerly at Maine Cancer Registry, Augusta, ME.

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.

Correspondence: Mary H. Ward, Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Room 6E138, Rockville, MD 20850. E-mail: wardm@mail.nih.gov.

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