Carcinogenicity of nitrate, nitrite, and cyanobacterial peptide toxins.

In June, 2006, 19 scientists from eight countries met at the International Agency for Research on Cancer (IARC) in Lyon, France, to assess the carcinogenicity of ingested nitrate and nitrite, and the cyanobacterial peptide toxins microcystin-LR and nodularins. These agents are linked environmentally through the runoff of agricultural fertilisers that increase nitrogen concentrations in surface water and groundwater, and that could contribute to cyanobacterial growth in surface water. The assessments will be published as volume 94 of the IARC Monographs. Nitrate and nitrite are naturallyoccurring ions. In the past century, the global nitrogen cycle has been increasingly aff ected by nitrogen fi xation for agricultural activities, which now exceeds the amount that occurs naturally. Both groundwater and surface water can be contaminated by excess nitrate as a result of agricultural activities. Human exposure to nitrate and nitrite is mainly from the ingestion of food. Important sources include vegetables, cereal products, and cured meat. Drinking-water is generally not the main source of nitrate, unless concentrations exceed the WHO guideline of 50 mg/L, which is especially found in contaminated groundwater. Ingested nitrate (NO3) is excreted in the saliva and reduced to nitrite (NO 2) mainly by oral bacteria. Under acidic conditions in the stomach, nitrite then reacts readily with nitrosatable compounds, especially sec ondary amines and alkyl amides, to generate N-nitroso compounds. Several N-nitroso compounds are potential human carcinogens. The nitrosation reactions can be inhibited by the presence of vitamin C or other antioxidants. Some epidemiological studies assessed the risk of cancer in people who had high intake of nitrite or nitrate and low intake of vitamin C, a dietary pattern that could result in increased endogenous formation of N-nitroso compounds. The Working Group weighted these studies more heavily than studies without this information. From the epidemiological studies of nitrate in food, no increased risk of cancer was seen. For nitrate in drinkingwater, epidemiological studies were few, exposure levels were low, and endogenous nitrosation was not often considered. For ingested nitrite, the risk for stomach cancer was investigated in seven well-designed case-control studies. Six of these showed consistent, positive associations, four of which were signifi cant. Two studies looked at eff ect modifi cation, and the risk was most pronounced in people who had high nitrite and low vitamin C intake. Neither of the two cohort studies reported a clear positive association. No study accounted for potential confounding or eff ect modifi cation by Helicobacter pylori, an important risk factor for stomach cancer. For oesophageal cancer, two well-designed case-control studies investigated an association with nitrite intake. Both reported a positive association for nitrite intake overall; for people with high nitrite and low vitamin C intake, these associations were signifi cant. For brain tumours, two of fi ve casecontrol studies in children showed positive associations with nitrite intake. In one study, children born to mothers with the highest intake of nitrite from cured meat during pregnancy had a three-fold increased risk for brain tumours. The other study reported an increased risk for astroglial brain tumours in the children of mothers whose drinking-water had high nitrite concentrations. For adult brain cancer, no clear pattern emerged from seven case-control studies. The Working Group concluded that there is “limited evidence of carcinogenicity” for nitrite in food based on the association with stomach cancer. For nitrate in food and nitrate or nitrite in drinking-water, the studies provide “inadequate evidence of carcinogenicity”. No increased incidence of tumours was recorded in mice and rats if nitrate alone was added to the drinking-water or to the diet, providing inadequate evidence of carcinogenicity. Mice given nitrite in drinking-water showed a signifi cant trend in the incidence of forestomach papillomas and carcinomas combined. Rats exposed to nitrite in utero and throughout life had an increased incidence of lymphoreticular tumours, and mice with similar exposure had raised incidences of lymphoma and lung tumours. These results provide limited evidence of carcinogenicity for nitrite alone. Many studies of mice and rats tested nitrite in combination with specifi c secondary or tertiary amines or amides, added to the diet or drinkingwater, or by gastric intubation. Most combinations resulted in increased incidences of benign and malignant tumours at many organ sites. The Working Group concluded that these results provided “suffi cient evidence of carcinogenicity” for nitrite in combination with amines or amides. The combination of positive and negative results from epidemiological Upcoming meetings