Environment and Breast Cancer: Science Review

Evidence From Humans
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Ingested Nitrate and Breast Cancer in the Spanish Multicase-Control Study on Cancer (MCC-Spain)
Espejo-Herrera, N., Gracia-Lavedan, E., Pollan, M., Aragones, N., Boldo, E., Perez-Gomez, B., Altzibar, J. M., Amiano, P., Zabala, A. J., Ardanaz, E., Guevara, M., Molina, A. J., Barrio, J. P., Gomez-Acebo, I., Tardon, A., Peiro, R., Chirlaque, M. D., Palau, M., Munoz, M., Font-Ribera, L., Castano-Vinyals, G., Kogevinas, M., Villanueva, C. M. Environ Health Perspect. 2016. 124:7, 1042-9.
Topic area
Environmental pollutant - Drinking water
Study design
Hospital-based case control
Funding agency
Instituto de Salud Carlos III
Study Participants
Menopausal Status
The menopausal status of women included in this study is listed here.
Analyses stratified by menopausal status
Number of Controls
Controls: 1,520
Participant selection: Inclusion and exclusion criteria
Criteria used to select participants in the study.
Participants were from the Spanish Multicase-Control Study on Cancer (MCC-Spain), and cases aged 20-85 identified in oncology reference hospitals in 8 Spanish provinces, diagnosed 2008-2013, without history of breast cancer and lived in catchment area for at least 6 months before diagnosis. Female controls were identified from administrative records of primary care health centers within hospitals' catchment areas, frequency-matched to cases by province and 5-eyar age interval.
Exposure Investigated
Exposures investigated
Lifetime annual average exposure to nitrate in drinking water from age 18 to 2 years before study interview. Annual average nitrate levels in drinking water from 1940 on based on current nitrate measurements (2004-2010) from Sistema de Informacion Naciona
How exposure was measured
Environmental measurements GIS/geographic location Questionnaire, in person
Exposure assessment comment
Authors note exposure misclassification could be a concern because of data imputation for long-term nitrate exposure, especially for years < 1980.
Breast cancer outcome investigated
Primary incident breast cancer
Confounders considered
Other breast cancer risk factors, such as family history, age at first birth, and hormone replacement therapy use, that were taken into account in the study.
Study area, age, education, BMI, family history of breast cancer, age at first childbirth, age at menopause, use of oral contraceptives, energy intake.
Genetic characterization included
If the study analyzed relationships between environmental factors and inherited genetic variations, this field will be marked Yes. No, if not.
Strength of associations reported
Nitrate intake (mg/day)
Overall (vs <2.2 mg/day):
≥ 2.2 - 3.8 OR 0.98 (95% CI 0.79-1.23)
> 3.8-8.1 OR 1.01 (95% CI 0.80-1.28)
> 8.1 OR 1.08 (95% CI 0.82-1.43)

Premenopausal (vs <2.2 mg/day):
≥ 1.8-3.1 OR 1.31 (95% CI 0.83-2.06)
> 3.1-6.3 OR 1.03 (95% CI 0.64-1.66)
> 6.3 OR 1.14 (95% CI 0.67-1.94)

ER+ (vs <2.2 mg/day)
≥ 2.6-6.0 OR 1.02 (95% CI 0.83-1.26)
> 6.0 OR 1.16 (95% CI 0.89-1.52)
Results Comments
Considering exposure during early adulthood (18-30 years of age) did not appreciably change results among premenopausal or postmenopausal women. OR = 1.29 (95% CI 0.92, 1.81) for highest vs lowest nitrate intake among postmenopausal women.
BACKGROUND: Ingested nitrate leads to endogenous formation of N-nitroso compounds that are breast carcinogens in animals, but human evidence is limited. OBJECTIVE: We evaluated ingested nitrate as a risk factor for breast cancer (BC) in a multicase-control study. METHODS: Hospital-based incident BC cases and population-based controls were recruited in eight Spanish regions in 2008-2013; participants provided residential and water consumption from 18 years of age and information on known BC risk factors. Long-term nitrate levels (1940-2010) were estimated and linked with residential histories and water consumption to calculate waterborne ingested nitrate (milligrams/day). Dietary ingested nitrate (milligrams/day) was calculated using food frequency questionnaires and published dietary nitrate contents. Interactions with endogenous nitrosation factors and other variables were evaluated. A total of 1,245 cases and 1,520 controls were included in the statistical analysis. RESULTS: Among the study regions, average +/- SD waterborne ingested nitrate ranged from 2.9 +/- 1.9 to 13.5 +/- 7.5 mg/day, and dietary ingested nitrate ranged from 88.5 +/- 48.7 to 154 +/- 87.8 mg/day. Waterborne ingested nitrate was not associated with BC overall, but among postmenopausal women, those with both high nitrate (> 6 vs. < 2.6 mg/day) and high red meat intake (>/= 20 vs. < 20 g/day) were more likely to be cases than women with low nitrate and low red meat intake (adjusted odds ratio = 1.64; 95% confidence interval: 1.08, 2.49; overall interaction p-value = 0.17). No association was found with dietary nitrate. CONCLUSIONS: Waterborne ingested nitrate was associated with BC only among postmenopausal women with high red meat consumption. Dietary nitrate was not associated with BC regardless of the animal or vegetable source or of menopausal status. CITATION: Espejo-Herrera N, Gracia-Lavedan E, Pollan M, Aragones N, Boldo E, Perez-Gomez B, Altzibar JM, Amiano P, Zabala AJ, Ardanaz E, Guevara M, Molina AJ, Barrio JP, Gomez-Acebo I, Tardon A, Peiro R, Chirlaque MD, Palau M, Munoz M, Font-Ribera L, Castano-Vinyals G, Kogevinas M, Villanueva CM. 2016. Ingested nitrate and breast cancer in the Spanish Multicase-Control Study on Cancer (MCC-Spain). Environ Health Perspect 124:1042-1049; http://dx.doi.org/10.1289/ehp.1510334.
Author address
ISGlobal Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
Controls participation rate
53% response rate