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Beetroot juice (BRJ) has become increasingly popular amongst athletes aiming to improve sport performances. BRJ contains high concentrations of nitrate, which can be converted into nitric oxide (NO) after consumption. NO has various functions in the human body, including a vasodilatory effect, which reduces blood pressure and increases oxygen- and nutrient delivery to various organs. These effects indicate that BRJ may have relevant applications in prevention and treatment of cardiovascular disease. Furthermore, the consumption of BRJ also has an impact on oxygen delivery to skeletal muscles, muscle efficiency, tolerance and endurance and may thus have a positive impact on sports performances. Aside from the beneficial aspects of BRJ consumption, there may also be potential health risks. Drinking BRJ may easily increase nitrate intake above the acceptable daily intake, which is known to stimulate the endogenous formation of N-nitroso compounds (NOC's), a class of compounds that is known to be carcinogenic and that may also induce several other adverse effects. Compared to studies on the beneficial effects, the amount of data and literature on the negative effects of BRJ is rather limited, and should be increased in order to perform a balanced risk assessment.

Beetroot juice (BRJ) has become increasingly popular amongst athletes aiming to improve sport performances. BRJ contains high concentrations of nitrate, which can be converted into nitric oxide (NO) after consumption. NO has various functions in the human body, including a vasodilatory effect, which reduces blood pressure and increases oxygen- and nutrient delivery to various organs. These effects indicate that BRJ may have relevant applications in prevention and treatment of cardiovascular disease. Furthermore, the consumption of BRJ also has an impact on oxygen delivery to skeletal muscles, muscle efficiency, tolerance and endurance and may thus have a positive impact on sports performances. Aside from the beneficial aspects of BRJ consumption, there may also be potential health risks. Drinking BRJ may easily increase nitrate intake above the acceptable daily intake, which is known to stimulate the endogenous formation of N-nitroso compounds (NOC's), a class of compounds that is known to be carcinogenic and that may also induce several other adverse effects. Compared to studies on the beneficial effects, the amount of data and literature on the negative effects of BRJ is rather limited, and should be increased in order to perform a balanced risk assessment.

Background Nitrate is converted to nitrite in the human body and subsequently can react with amines and amides in the gastrointestinal tract to form N-nitroso compounds (NOCs), which are known to be carcinogenic in animals. Humans can be exposed to nitrate via consumption of drinking water and diet, especially green leafy vegetables and cured meat. The contribution of nitrate from drinking water in combination with meat intake has not been investigated thoroughly. Therefore, in the present pilot study, we examined the effect of nitrate from drinking water, and its interaction with the consumption of white and processed red meat, on the endogenous formation of NOCs, taking into account the intake of vitamin C, a nitrosation inhibitor. Methods Twenty healthy subjects were randomly assigned to two groups consuming either 3.75 g/kg body weight (maximum 300 g per day) processed red meat or unprocessed white meat per day for two weeks. Drinking water nitrate levels were kept low during the first week (N-nitroso compounds (ATNC), compliance markers, and genotoxic potential in human colonic Caco-2 cells. Results Urinary nitrate excretion was significantly increased during the high drinking water nitrate period for both meat types. Furthermore, levels of compliance markers for meat intake were significantly increased in urine from subjects consuming processed red meat (i.e. 1-Methylhistidine levels), or unprocessed white meat (i.e. 3-Methylhistidine). ATNC levels significantly increased during the high drinking water nitrate period, which was more pronounced in the processed red meat group. Genotoxicity in Caco-2 cells exposed to faecal water resulted in increased genotoxicity after the interventions, but results were only significant in the low drinking water nitrate period in subjects consuming processed red meat. Furthermore, a positive correlation was found between the ratio of nitrate/vitamin C intake (including drinking water) and the level of ATNC in faecal water of subjects in the processed red meat group, but this was not statistically significant. Conclusions Drinking water nitrate significantly contributed to the endogenous formation of NOC, independent of the meat type consumed. This implies that drinking water nitrate levels should be taken into account when evaluating the effect of meat consumption on endogenous formation of NOC. Trial registration Dutch Trialregister: 29707. Registered 19th of October 2018. Retrospectively registered.

Nitrate levels in our water resources have increased in many areas of the world largely due to applications of inorganic fertilizer and animal manure in agricultural areas. The regulatory limit for nitrate in public drinking water supplies was set to protect against infant methemoglobinemia, but other health effects were not considered. Risk of specific cancers and birth defects may be increased when nitrate is ingested under conditions that increase formation of N-nitroso compounds. We previously reviewed epidemiologic studies before 2005 of nitrate intake from drinking water and cancer, adverse reproductive outcomes and other health effects. Since that review, more than 30 epidemiologic studies have evaluated drinking water nitrate and these outcomes. The most common endpoints studied were colorectal cancer, bladder, and breast cancer (three studies each), and thyroid disease (four studies). Considering all studies, the strongest evidence for a relationship between drinking water nitrate ingestion and adverse health outcomes (besides methemoglobinemia) is for colorectal cancer, thyroid disease, and neural tube defects. Many studies observed increased risk with ingestion of water nitrate levels that were below regulatory limits. Future studies of these and other health outcomes should include improved exposure assessment and accurate characterization of individual factors that affect endogenous nitrosation.

Endogenous formation of N-nitroso compounds (NOCs), which are known animal carcinogens, could contribute to human carcinogenesis but definitive evidence is still lacking. To investigate the relevance of NOCs in human colorectal cancer (CRC) development, we analyzed whole genome gene expression modifications in human colon biopsies in relation to fecal NOC exposure. We had a particular interest in patients suffering from intestinal inflammation as this may stimulate endogenous NOC formation, and consequently predispose to CRC risk. Inflammatory bowel disease (IBD) patients diagnosed with ulcerative colitis and irritable bowel syndrome patients without inflammation, serving as controls, were therefore recruited. Fecal NOC were demonstrated in the majority of subjects. By associating gene expression levels of all subjects to fecal NOC levels, we identified a NOC exposure-associated transcriptomic response that suggests that physiological NOC concentrations may potentially induce genotoxic responses and chromatin modifications in human colon tissue, both of which are linked to carcinogenicity. In a network analysis, chromatin modifications were linked to 11 significantly modulated histone genes, pointing towards a possible epigenetic mechanism that may be relevant in comprehending NOC-induced carcinogenesis. In addition, pro-inflammatory transcriptomic modifications were identified in visually non-inflamed regions of the IBD colon. However, fecal NOC levels were slightly but not significantly increased in IBD patients, suggesting that inflammation did not strongly stimulate NOC formation. We conclude that NOC exposure is associated with gene expression modifications in the human colon that may suggest a potential role of these compounds in CRC development.

La spécialisation des techniques agricoles que nous connaissons ces dernières décennies, particulièrement dans les régions rurales, est à l’origine de l’abus de fertilisants. Ces derniers sont actuellement reconnus comme étant les causes principales de la contamination de l’eau souterraine par les nitrates. Suite à leur ingestion via l’eau potable, les nitrates sont transformés en nitrites par la flore buccale. Une fois dans l’estomac les nitrites réagissent avec certaines amines provenant de l’alimentation pour générer des nitrosamines cancérogènes. L’objectif de notre étude était d’estimer quantitativement l’excès de risque de cancer (ER) pour les populations de sept régions rurales du Québec qui consomme l’eau potable provenant de réseaux municipaux alimentés en eau souterraine. Le territoire à l’étude était caractérisé par une agriculture intensive d’élevage. Les médianes (et 95e centiles) régionales des concentrations de nitrates mesurées dans les réseaux de ces régions étaient de : 0,18 (2,74); 0,48 (10,35); 0,15 (1,28); 0,32 (11); 0,05 (0,76); 0,10 (4,69); 0,09 (2,13) mg N-NO3-/l. Nous avons envisagé un scénario de transformation complète des nitrites et de certaines amines (diméthylamine, diéthylamine, n-butylamine, méthyléthylamine) en nitrosamines spécifiques : N-diméthylnitrosamine (NDMA), N-diéthylnitrosamine (NDEA), N-n-dibutylnitrosamine (NDBA) et N-méthyléthylnitrosamine (NMEA). Pour estimer la concentration de nitrites formés dans l’estomac, nous avons considéré une consommation définie d’eau potable, le volume de l’estomac et un taux de transformation des nitrates en nitrites. Supposant les quantités de nitrites et de chaque amine constantes pendant 1h, nous avons considéré la constante de nitrosation spécifique à chaque amine pour évaluer la dose d’exposition journalière à chaque nitrosamine équivalente formée. Par la suite, la combinaison de cette dose à un estimateur de potentiel cancérogène qhumain spécifique à chaque nitrosamine, nous a permis d’évaluer l’ER associé à chacune d’elles. Globalement l’analyse a démontré que les ER les plus élevés, estimés pour le NDBA, étaient de l’ordre de 10-6, ne contribuant pas de façon significative à une augmentation du risque de cancer pour ces populations., Specialization of agricultural practices in rural regions over the past few decades has led to overuse of fertilizers which are main causes of groundwater contamination by nitrates. After their ingestion through drinking water, nitrates are transformed into nitrites by the oral flora. Once in the stomach, nitrites react with some amines from food supply to form nitrosamines with some being probably carcinogenic to humans. The aim of this study was to quantitatively estimate the possible excess cancer risk (ER) for populations of seven rural regions in Quebec that consume water from public drinking water systems using groundwater. The studied regions practice extensive breeding agriculture. The regional medians (and 95th percentile) of nitrate levels in water from those seven regions were: 0.18 (2.74); 0.48 (10.35); 0.15 (1.28); 0.32 (11); 0.05 (0.76); 0.10 (4.69) and 0.09 (2.13) mg N-NO3-/l, respectively. Indeed, we first considered a scenario of complete transformation of nitrites and some amines (dimethylamine, diethylamine, n-butylamine and methylethylamine) into specific nitrosamines: N-dimethylnitrosamine (NDMA), N-diethylnitrosamine (NDEA), N-nitrosodi-n-butylamine (NDBA) and N-nitrosomethylethylamine (NMEA). Gastric nitrite concentrations were estimated on the basis of defined drinking water intake, stomach volume, and the transformation rate of nitrates into nitrites. Considering that levels of nitrites and each amine were kept constant for 1 hour, and taking in account the nitrosatability rate constant specific to each amine, we then estimated the daily doses of the corresponding endogenously formed nitrosamines. Furthermore combination of dose with the human cancer potency factor qhuman specific to each nitrosamine, allowed the estimation of excess cancer risk. The highest ER estimated for NDBA was in the order of 10-6, thus not contributing to a significant increase in the risk of cancer for that population.

Carcinogenic activity of endogenously synthesized N-nitrosobis(2-hydroxypropyl)amine (BHP) from bis(2-hydroxypropyl)amine (BHPA) and tris(2-hydroxypropyl)amine (THPA) in the presence of sodium nitrite (SN) was investigated in male Wistar rats. The following results were obtained. 1) The synthesis of BHP from BHPA and THPA in the presence of SN was demonstrated in vitro and in vivo in the preliminary experiment and also confirmed by the urinary excretion of BHP in rats treated with 1% BHPA and 2% THPA in diet together with 0.3% SN in drinking water. 2) Tumors in nasal cavity and lung were induced in rats treated with 1% BHPA in diet together with 0.3% SN in drinking water for 94 weeks, the incidences of which reached 74% and 58%, respectively. However, no tumors were found in the target organs of BHP in rats treated with 2% THPA in diet and 0.3% SN in drinking water for 102 weeks. 3) The initiation activity for liver by endogenously synthesized BHP was observed in rats treated with 1% BHPA in diet together with 0.15% and 0.3% SN in drinking water by the quantitative analysis of glutathione S-transferase placental form (GST-P)-positive foci but was not observed in rats treated with 2% THPA in diet together with 0.15% and 0.3% SN in drinking water. These results indicate that endogenously synthesized BHP has a carcinogenic activity similar to that of exogenously administered BHP, and that BHPA is more important as the precursor for endogenous BHP synthesis. Since the precursors of nitrosamines are widely distributed in the environment, endogenously synthesized nitrosamines may play an important role in the development of human cancer.