Abstract
Ingested nitrate leads to the endogenous synthesis of N-nitroso compounds (NOCs), animal carcinogens with limited human evidence. We aimed to evaluate the risk of colorectal cancer (CRC) associated with nitrate exposure in drinking water and diet. A case-control study in Spain and Italy during 2008-2013 was conducted. Hospital-based incident cases and population-based (Spain) or hospital-based (Italy) controls were interviewed on residential history, water consumption since age 18, and dietary information. Long-term waterborne ingested nitrate was derived from routine monitoring records, linked to subjects' residential histories and water consumption habits. Dietary nitrate intake was estimated from food frequency questionnaires and published food composition databases. Odd ratios (OR) were calculated using mixed models with area as random effect, adjusted for CRC risk factors and other covariables. Generalized additive models (GAMs) were used to analyze exposure-response relationships. Interaction with endogenous nitrosation factors and other covariables was also evaluated. In total 1,869 cases and 3,530 controls were analyzed. Average waterborne ingested nitrate ranged from 3.4 to 19.7 mg/day, among areas. OR (95% CIs) of CRC was 1.49 (1.24, 1.78) for >10 versus ≤5 mg/day, overall. Associations were larger among men versus women, and among subjects with high red meat intake. GAMs showed increasing exposure-response relationship among men. Animal-derived dietary nitrate was associated with rectal, but not with colon cancer risk. In conclusion, a positive association between CRC risk and waterborne ingested nitrate is suggested, mainly among subgroups with other risk factors. Heterogeneous effects of nitrate from different sources (water, animal and vegetables) warrant further research.
Highlights
Nitrate is a widespread contaminant in drinking water due to the overuse of fertilizers in agriculture 1 and urban sewage 2
We aimed to evaluate the risk of colorectal cancer (CRC) associated with nitrate exposure in drinking water and diet
nitroso compounds (NOCs) are carcinogenic in several animal species 7, but human evidence is limited, nitrate is classified as probable human carcinogen under conditions resulting in endogenous nitrosation 8
Summary
Nitrate is a widespread contaminant in drinking water due to the overuse of fertilizers in agriculture 1 and urban sewage 2. Nitrate is a main dietary component of vegetables, and an approved food additive for preserved meat, together with nitrite 4. Nitrate ingestion through diet and drinking water are the main routes of human exposure. Ingested nitrate is reduced to nitrite, which subsequently reacts with amines and amides to produce N-nitroso compounds (NOCs) in the gastrointestinal system. The intake of vitamins C and E may inhibit endogenous nitrosation, whereas meat intake and chronic gastrointestinal acidic or inflammatory conditions, may increase it 5. NOCs are carcinogenic in several animal species 7, but human evidence is limited, nitrate is classified as probable human carcinogen (group 2A) under conditions resulting in endogenous nitrosation 8
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