Formation Of Carcinogenic N-nitroso Compounds Research Articles

Source-specific nitrate intake and all-cause mortality in the Danish Diet, Cancer, and Health Study.

Nitrate and nitrite are naturally occurring in both plant- and animal-sourced foods, are used as additives in the processing of meat, and are found in water. There is growing evidence that they exhibit a spectrum of health effects, depending on the dietary source. The aim of the study was to examine source-dependent associations between dietary intakes of nitrate/nitrite and both all-cause and cause-specific mortality. In 52,247 participants of the Danish Diet, Cancer and Health Study, associations between source-dependent nitrate and nitrite intakes--calculated using comprehensive food composition and national drinking water quality monitoring databases--and all-cause, cardiovascular disease (CVD)-related, and cancer-related mortality over 27 years were examined using restricted cubic splines within Cox proportional hazards models adjusting for demographic, lifestyle, and dietary confounders. Analyses were stratified by factors hypothesised to influence the formation of carcinogenic N-nitroso compounds (namely, smoking and dietary intakes of vitamin C, vitamin E, folate, and polyphenols). Plant-sourced nitrate intake was inversely associated with all-cause mortality [HRQ5vsQ1: 0.83 (0.80, 0.87)] while higher risks of all-cause mortality were seen for higher intakes of naturally occurring animal-sourced nitrate [1.09 (1.04, 1.14)], additive permitted meat-sourced nitrate [1.19 (1.14, 1.25)], and tap water-sourced nitrate [1.19 (1.14, 1.25)]. Similar source-dependent associations were seen for nitrite and for CVD-related and cancer-related mortality except that naturally occurring animal-sourced nitrate and tap water-sourced nitrate were not associated with cancer-related mortality and additive permitted meat-sourced nitrate was not associated with CVD-related mortality. No clear patterns emerged in stratified analyses. Nitrate/nitrite from plant sources are inversely associated while those from naturally occurring animal-sources, additive-permitted meat sources, and tap water-sources are positively associated with mortality.

Ingested nitrate and nitrite and end-stage renal disease in licensed pesticide applicators and spouses in the Agricultural Health Study.

Nitrate and nitrite ingestion has been linked to kidney cancer, possibly via the endogenous formation of carcinogenic N-nitroso compounds. These exposures might also contribute to end-stage renal disease (ESRD). We investigated associations of drinking water nitrate and dietary nitrate and nitrite intakes (total and by food type) with incident ESRD in the Agricultural Health Study. We also explored modifying effects of vitamin C and heme iron intake, which may affect endogenous nitrosation. We performed complete case analyses among private pesticide applicators and their spouses. We obtained water nitrate estimates for participants whose primary drinking water source at enrollment (1993-1997) was public water supplies (PWS) or private wells (N = 59,632). Average nitrate concentrations were computed from historical data for PWS users and predicted from random forest models for private well users. Analysis of dietary nitrate and nitrite was restricted to the 30,177 participants who completed the NCI Dietary History Questionnaire during follow-up (1999-2003). Incident ESRD through 2018 was ascertained through linkage with the U.S. Renal Data System. We estimated adjusted hazard ratios (HRs) and 95%CI for associations of tertiles (T) of exposure with ESRD overall and explored effects in strata of vitamin C and heme iron intake. We identified 469 incident ESRD cases (206 for dietary analysis). Water nitrate and total dietary nitrate/nitrite were not associated with ESRD, but increased ESRD was associated with nitrate and nitrite from processed meats. We found apparent associations between nitrite and ESRD only among participants with vitamin C <median (T3 vs. T1 HR: 2.26, 95%CI: 1.05, 4.86) and with heme iron ≥median (T3 vs. T1 HR: 1.73, 95%CI: 0.89, 3.39). ESRD incidence was associated with dietary nitrate/nitrite from processed meat among all study participants and with total dietary nitrite among participants with lower vitamin C or higher heme iron intake. There are few well-established environmental risk factors for end-stage renal disease (ESRD), a worldwide public health challenge. Ingestion of nitrate and nitrite, which may lead to endogenous formation of carcinogenic N-nitroso compounds, has been linked to some cancers and chronic diseases. We investigated these exposures in relation to ESRD in an agricultural cohort. ESRD incidence was associated with dietary nitrate/nitrite from processed meat and with total dietary nitrite among subgroups with lower vitamin C or higher heme iron intake. This study provides preliminary evidence that points to dietary nitrite and possibly dietary nitrate intake as a potential contributor to ESRD.

Study on sulfur vulcanized natural rubber formulated with nitrosamine safe diisopropyl xanthogen polysulfide/tertiary butyl benzothiazole sulphenamide binary accelerator system

An outstanding interest on elimination of nitrosamine generation in traditional sulfur vulcanization systems has led to introduce nitrosamine safe accelerator/s to produce safe natural rubber (NR) vulcanizates. It is an effective way to prevent formation of carcinogenic N-nitroso compounds during manufacture of rubber products. In the present study, behavior of nitrosamine safe binary accelerator system consisting of diisopropyl xanthogen polysulfide (DIXP) with commonly used non-regulated accelerator N-tert-butyl-2-benzothiazole sulfenamide (TBBS) was investigated in efficient sulfur vulcanization of NR. Cure characteristics, physico-mechanical properties and crosslink density of vulcanizates prepared with different combinations of the accelerator system were evaluated and compared with those of individual accelerators. The study reveals that moduli and strength properties of the vulcanizate prepared with DIXP accelerator are inferior to those of the vulcanizate prepared with TBBS accelerator. Nevertheless, optimum cure time of the DIXP compounds is lower in comparison to TBBS compounds. Moreover, progressive replacement of DIXP with TBBS in the accelerator system showed a synergistic effect in regard to cure characteristics and physico-mechanical properties.

Inulin-fortification of a processed meat product attenuates formation of nitroso compounds in the gut of healthy rats

Intake of red and processed meat has been suspected to increase colorectal cancer risk potentially via endogenous formation of carcinogenic N-nitroso compounds or increased lipid and protein oxidation. Here we investigated the effect of inulin fortification of a pork sausage on these parameters. For four weeks, healthy Sprague-Dawley rats (n = 30) were fed one of three diets: inulin-fortified pork sausage, control pork sausage or a standard chow diet. Fecal content of apparent total N-nitroso compounds (ATNC), nitrosothiols and nitrosyl iron compounds (FeNO) were analyzed in addition to liver metabolism and oxidation products formed in liver, plasma and diets. Intriguingly, inulin fortification reduced fecal ATNC (p = 0.03) and FeNO (p = 0.04) concentrations. The study revealed that inulin fortification of processed meat could be a strategy to reduce nitroso compounds formed endogenously after consumption.

Haem iron intake and risk of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

BackgroundEpidemiological studies suggest that haem iron, which is found predominantly in red meat and increases endogenous formation of carcinogenic N-nitroso compounds, may be positively associated with lung cancer. The objective was to examine the relationship between haem iron intake and lung cancer risk, using detailed smoking history data and serum cotinine to control for potential confounding.MethodsIn the European Prospective Investigation into Cancer and Nutrition (EPIC), 416 746 individuals from ten countries completed demographic and dietary questionnaires at recruitment. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for incident lung cancer (n=3 731) risk relative to haem iron, non-haem iron, and total dietary iron intake. A corresponding analysis was conducted among a nested subset of 800 lung cancer cases and 1,489 matched controls for whom serum cotinine was available.ResultsHaem iron was associated with lung cancer risk, including after adjustment for details of smoking history (time since quitting, number of cigarettes per day): as a continuous variable (HR per 0.3 mg/1000 kcal 1.03, 95% CI 1.00 – 1.07), and in the highest versus lowest quintile (HR 1.16, 95%CI 1.02 – 1.32; trend across quintiles: P = 0.035). In contrast, non-haem iron intake was related inversely with lung cancer risk; however, this association attenuated after adjustment for smoking history. Additional adjustment for serum cotinine did not considerably alter the associations detected in the nested case-control subset.ConclusionsGreater haem iron intake may be modestly associated with lung cancer risk.

Abstract 4242: Mass spectroscopic analysis of MGMT tryptic peptides allows detection of O6-alkylguanine adducts in oligodeoxyribonucleotides, temozolomide modified calf thymus DNA and human colorectal cancer DNA

Abstract Background: Red and processed meat consumption increases human colorectal cancer (CRC) risk, potentially by heme-catalysed formation of carcinogenic N-nitrosocompounds (NNOC) that form mutagenic O6-alkylguanine (O6-alkG) DNA adducts. NNOC formation cannot be accurately estimated from meat consumption alone due to in situ processing required for their formation. We are thus developing a novel approach to assess NNOC exposure by quantifying O6-alkylguanine DNA adducts that result from their exposure, using the known action of the DNA repair protein, O6-alkylguanine O6-alkyltransferase (MGMT), to irreversibly transfer the O6-alkyl to an active site cysteine residue in MGMT. Methods: Oligodeoxyribonucleotides (ODNs) containing O6-methylguanine (O6-MeG), O6-carboxymethylguanine (O6-CMG), O6-carboxyethylguanine (O6-CEG) were synthesised by alcohol modification of an ODN containing the convertible base 2-amino-6-methylsulfonylpurine. O6-MeG containing calf thymus (CT) DNA was prepared by incubation with temozolomide (TMZ). Both maltose binding protein-MGMT (MBP-MGMT) and his-tagged MGMT (his-MGMT) fusion proteins were expressed, purified, and MGMT functional activity determined by tritium transfer using CT DNA methylated with [3H]-N-Nitrosomethylurea. Double stranded O6-alkG-containing ODNs, unmodified ODN and methylated CT DNA were incubated with MBP-MGMT and the resulting alkylated MGMT digested with trypsin and analysed by mass spectrometry using MALDI-TOF. Human CRC DNA samples were incubated with his-MGMT which was then recovered using Ni-coated magnetic beads. MGMT was digested in situ with trypsin and the tryptic peptides analysed by MALDI-TOF. Results: S-methylcysteine (m/z 1329.7), S-carboxymethylcysteine (m/z 1373.7) and S-carboxyethylcysteine, modified MGMT active site peptides were detected in tryptic digests of MBP-MGMT incubated with O6-MeG-, O6-CMG- and O6-CEG-containing ODNs respectively. Only the unmodified active site peptide (m/z 1315.7) was found after incubating MGMT with unmodified ODN. Subsequent MS analysis of tryptic digests of MGMT incubated with TMZ modified CT DNA also revealed the active site peptide containing S-methylcysteine. Using this approach, pilot studies revealed the presence of O6-MeG, O6-CMG and O6-CEG in CRC DNA. Conclusions: These results demonstrate proof of principle and confirm that this approach could be used to characterise O6-alkylguanine adducts in human CRC DNA. Citation Format: Rasha A. Abdelhady, Perdita E. Barran, David M. Williams, Andrew C. Povey. Mass spectroscopic analysis of MGMT tryptic peptides allows detection of O6-alkylguanine adducts in oligodeoxyribonucleotides, temozolomide modified calf thymus DNA and human colorectal cancer DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4242. doi:10.1158/1538-7445.AM2017-4242

Mechanisms Linking Colorectal Cancer to the Consumption of (Processed) Red Meat: A Review

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world. The vast majority of CRC cases have been linked to environmental causes rather than to heritable genetic changes. Over the last decades, epidemiological evidence linking the consumption of red and, more convincingly, of processed red meat to CRC has accumulated. In parallel, hypotheses on carcinogenic mechanisms underlying an association between CRC and the intake of red and processed red meat have been proposed and investigated in biological studies. The hypotheses that have received most attention until now include (1) the presence of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, two groups of compounds recognized as carcinogenic, (2) the enhancing effect of (nitrosyl)heme on the formation of carcinogenic N-nitroso compounds and lipid peroxidation. However, none of these hypotheses completely explains the link between red and processed red meat intake and the CRC risk. Consequently, scientists have proposed additional mechanisms or refined their hypotheses. This review first briefly summarizes the development of CRC followed by an in-depth overview and critical discussion of the different potential carcinogenic mechanisms underlying the increased CRC risk associated with the consumption of red and processed red meat.

Effects Of Polyphenols On The Endogenous Formation Of Nitroso Compounds In Simulated Gastric Conditions

There is considerable epidemiological evidence supporting a positive association between red and processed meat intake and risk of colorectal cancer. There are several potential mechanism for this positive association, in particular the formation of carcinogenic N-nitroso compounds. Previously, we could show a close relationship between red meat and ATNC (apparent total nitroso compounds) formation. Polyphenols can reduce the formation of N-nitroso compounds in vitro. In this study, we have investigated the protective effect of different polyphenols in a simulated gastric system. The in vitro effect of quercetin, rutin, (-)-epicatechin, rosmarinic acid, ascorbic acid and several plant extracts containing these compounds were tested in an acidic gastric juice environment (bovine serum albumin, haemin and haemoglobin were dissolved in 7mM HCl, pH2.2, 1 mM NaNO2 were added to start the reaction). Different classes nitroso compounds were determined using chemical denitrosation with chemiluminescence detection. This enabled us not only to measure ATNC but also nitrosothiols and iron-nitrosyl (nitrosyl haem) complexes separately to have more information of the mechanism. The highest concentration of ATNC were observed after 20 mins of reaction time, while nitrite concentrations gradually decreased to almost 0 µmol/L. The formation of nitroso compounds were investigated in a simplified stomach environment to simulate high nitrate and high red meat intake with and without the addition of polyphenols. Our results did not show a consistent effect of phenolic compounds on the formation of total nitroso compounds, nitrosothiols or iron-nitrosyl complexes.

Nitrate in vegetables and their impact on human health. A review

Vegetables are the major source of dietary nitrate, with wide variations in nitrate content. The presence of nitrate in vegetables is often associated with harmful effects on human health, i.e. with toxic effects of methaemoglobinaemia and the possibility of causing an endogenous formation of carcinogenic N-nitroso compounds. However, it is also associated with beneficial health effects, since nitrate represent an important alternative pathway to bioactive NO and its important physiological roles in vascular and immune function. In this review the concentrations of nitrate in different vegetables from different countries are given. Furthermore, the reasons for the different contents of nitrate in vegetables, the daily intakes and comparisons to the acceptable daily intake (ADI) values, legislation, metabolism and toxicology of nitrate are described as well as harmful and beneficial effects of nitrate on human health.

Diet Composition Is Associated with Endogenous Formation of N-Nitroso Compounds in Obese Men1–3

Endogenous formation of carcinogenic N-nitroso compounds (NOC) occurs in the human gut. Red meat is considered the most important dietary component linked to NOC formation, although nitrate and vitamin C (VitC) also contribute. We previously showed that high-protein weight-loss diets increased fecal NOC and this was enhanced by simultaneous carbohydrate restriction. Although previous studies have focused on the effect of either 1 or 2 dietary components on endogenous NOC formation, no study to date has investigated the combined contribution of various dietary components. The current study therefore assessed the joint impact of several known dietary contributors to the endogenous formation of NOC in obese men. It also aimed to identify further novel contributors and investigate their role in explaining shifts in endogenous formation of NOC. Three dietary trials were conducted in obese men consuming body weight maintenance or weight-loss diets, with NOC measured in fecal samples. Consumption of meat-based weight-loss diets increased (P < 0.001) fecal NOC. Red meat intake was positively correlated with the fecal log NOC concentration (r = 0.60; P < 0.001). Dietary carbohydrate and sugar were negatively correlated with the fecal log NOC concentration (r = -0.66 for both; P < 0.001). Multiple regression analysis identified several dietary components that drive endogenous NOC formation, namely, red meat, nitrate, VitC, total energy, and nonstarch polysaccharides. We present a regression model that predicts endogenous NOC formation in obese men based on their dietary intakes. This model could improve the estimation of endogenous NOC formation, currently used in epidemiological studies into diet and cancer.

Heme Iron from Meat and Risk of Colorectal Cancer: A Meta-analysis and a Review of the Mechanisms Involved

Red meat and processed meat intake is associated with a risk of colorectal cancer, a major cause of death in affluent countries. Epidemiological and experimental evidence supports the hypothesis that heme iron present in meat promotes colorectal cancer. This meta-analysis of prospective cohort studies of colon cancer reporting heme intake included 566,607 individuals and 4,734 cases of colon cancer. The relative risk of colon cancer was 1.18 (95% CI: 1.06-1.32) for subjects in the highest category of heme iron intake compared with those in the lowest category. Epidemiological data thus show a suggestive association between dietary heme and risk of colon cancer. The analysis of experimental studies in rats with chemically-induced colon cancer showed that dietary hemoglobin and red meat consistently promote aberrant crypt foci, a putative precancer lesion. The mechanism is not known, but heme iron has a catalytic effect on (i) the endogenous formation of carcinogenic N-nitroso compounds and (ii) the formation of cytotoxic and genotoxic aldehydes by lipoperoxidation. A review of evidence supporting these hypotheses suggests that both pathways are involved in heme iron toxicity.

When Does Nitrate Become a Risk for Humans?

Is nitrate harmful to humans? Are the current limits for nitrate concentration in drinking water justified by science? There is substantial disagreement among scientists over the interpretation of evidence on the issue. There are two main health issues: the linkage between nitrate and (i) infant methaemoglobinaemia, also known as blue baby syndrome, and (ii) cancers of the digestive tract. The evidence for nitrate as a cause of these serious diseases remains controversial. On one hand there is evidence that shows there is no clear association between nitrate in drinking water and the two main health issues with which it has been linked, and there is even evidence emerging of a possible benefit of nitrate in cardiovascular health. There is also evidence of nitrate intake giving protection against infections such as gastroenteritis. Some scientists suggest that there is sufficient evidence for increasing the permitted concentration of nitrate in drinking water without increasing risks to human health. However, subgroups within a population may be more susceptible than others to the adverse health effects of nitrate. Moreover, individuals with increased rates of endogenous formation of carcinogenic N-nitroso compounds are likely to be susceptible to the development of cancers in the digestive system. Given the lack of consensus, there is an urgent need for a comprehensive, independent study to determine whether the current nitrate limit for drinking water is scientifically justified or whether it could safely be raised.

N-nitrosamine inhibition by strawberry, garlic, kale, and the effects of nitrite-scavenging and N-nitrosamine formation by functional compounds in strawberry and garlic

High nitrate and amine-rich food intake may result in an increased risk of endogenous formation of carcinogenic N-nitroso compounds (NOCs). We studied the effects of whole strawberries, garlic and kale on the formation of N-nitrosodimethylamine (NDMA) in a traditional Korean diet (amine and nitrate-rich) in simulated saliva and gastric conditions. The addition of whole strawberries, kale and garlic juices in the diet reduced NDMA formation by amine and nitrate. Strawberries and garlic juice were more effective than kale. To identify active compound, isolated fractions were prepared from strawberries or garlic juice samples by preparative liquid chromatography. Inhibition of NDMA formation and nitrite-scavenging ability of each fraction (strawberries: S1–S4; garlic juice: A1–A5) was tested. Fraction A4 inhibited NDMA formation by 50.5 ± 5.4% and increased the effect of nitrite-scavenging by 72.3 ± 8.7%. Fractions A3 and A4 were identified as 1,2-benzendicarboxy acid (A3) and S-oxodially disulfide (A4) compounds by mass spectrophotometry and 13C nuclear magnetic resonance.

Neutrophil-mediated formation of carcinogenic N-nitroso compounds in an in vitro model for intestinal inflammation

In order to study neutrophil-mediated formation of carcinogenic N-nitroso compounds as a mechanism of inflammation-related colon carcinogenesis, we designed an in vitro model for intestinal inflammation, consisting of a coincubation system with human colon cells (Caco-2 cells) and activated human neutrophils (PMN), as important immunoreactive cells. We investigated whether nitrosamines and nitrosamides could be formed upon addition of dimethylamine, morpholine and methylurea to the coincubations as nitrosatable precursors, which are known to produce carcinogenic N-nitroso compounds. Incubations of pure nitric oxide with dimethylamine and morpholine showed that NO-mediated formation of nitrosodimethylamine and nitrosomorpholine is possible under the incubation conditions. During the coincubations of activated PMN and Caco-2 cells, 0.34 nmol nitrite/10 6 PMN was produced. Dose-dependent formation of NMOR was observed in this PMN/Caco-2 system; addition of 5 mM morpholine resulted in a significantly increased NMOR formation of 4.2 nM. However, no detectable NDMA and methylnitrosourea were formed in this coincubation system. These results suggest that activated human neutrophils are able to synthesize carcinogenic N-nitrosamines, e.g. NMOR, which implies a risk of colon carcinogenesis during chronic inflammation. However, the observed relatively low level of nitrosation suggests that also other risk factors are contributing to the association between chronic inflammation and colon cancer risk.

The effect of intra-gastric acidity and flora on the concentration of N-nitroso compounds in the stomach

Correa's hypothesis proposes that gastric carcinogenesis is due to atrophic gastritis and hypochlorhydria which permit gastric bacterial colonization, the reduction of dietary nitrates to nitrites and the formation of potentially carcinogenic N-nitroso compounds (NOCs). To test the hypothesis that omeprazole-induced hypochlorhydria is associated with increased intra-gastric concentrations of nitrate-reducing bacteria (NRB), nitrites and NOCs. Single-blind study in healthy volunteers. Fourteen healthy subjects (seven female, mean age 24 years), free of Helicobacter pylori infection, received a one-week course of placebo followed by a two-week course of omeprazole, 20 mg daily. Fasted gastric samples, aspirated using a sterile double-lumen nasogastric tube at the end of the 1 st week (placebo) and the 2nd and 3rd weeks (omeprazole), were cultured aerobically and anaerobically; gastric pH and intra-gastric concentrations of nitrates, nitrites and NOCs were also determined. After weeks 1, 2 and 3, the intra-gastric concentrations of nitrate-reducing bacteria exceeded 10(5) colony-forming units (c.f.u.)/ml in 3, 7 and 9 subjects, respectively (P > 0.05). A gastric pH greater than 4.0 was associated with increased NRB (P < 0.05); however, neither increased gastric pH nor increased NRB, alone or in combination, was associated with increased intra-gastric concentrations of nitrites or NOCs (P > 0.05). A two-week increase in gastric pH in healthy, H. pylori-negative subjects was associated with increased intra-gastric concentrations of nitrate-reducing bacteria but not of nitrites or N-nitroso compounds. These data suggest that reduced gastric acid secretion is not a necessary precursor to the formation of carcinogenic N-nitroso compounds and that other mechanisms should be invoked to explain gastric carcinogenesis.

Nitrate contamination of drinking water: relationship with HPRT variant frequency in lymphocyte DNA and urinary excretion of N-nitrosamines.

We studied peripheral lymphocyte HPRT variant frequency and endogenous nitrosation in human populations exposed to various nitrate levels in their drinking water. Four test populations of women volunteers were compared. Low and medium tap water nitrate exposure groups (14 and 21 subjects) were using public water supplies with nitrate levels of 0.02 and 17.5 mg/l, respectively. Medium and high well water nitrate exposure groups (6 and 9 subjects) were using private water wells with mean nitrate levels of 25 and 135 mg/l, respectively. Higher nitrate intake by drinking water consumption resulted in a dose-dependent increase in 24-hr urinary nitrate excretion and in increased salivary nitrate and nitrite levels. The mean log variant frequency of peripheral lymphocytes was significantly higher in the medium well water exposure group than in the low and medium tap water exposure groups. An inverse correlation between peripheral lymphocyte labeling index and nitrate concentration of drinking water was observed. Analysis of N-nitrosamine in the urine of 22 subjects by gas chromatography-mass spectrometry revealed the presence of N-nitrosopyrrolidine in 18 subjects. Analysis of the mutagenicity of well water samples showed that a small number of the well water samples were mutagenic in the Ames Salmonella typhimurium test after concentration over XAD-2 resin. In conclusion, consumption of drinking water, especially well water, with high nitrate levels can imply a genotoxic risk for humans as indicated by increased HPRT variant frequencies and by endogenous formation of carcinogenic N-nitroso compounds from nitrate-derived nitrite.

Characterization of bacterial cytochrome cd(1)-nitrite reductase as one enzyme responsible for catalysis of nitrosation of secondary amines.

Bacterial formation of carcinogenic N-nitroso compounds may play a role in the etiology of human cancer. Biochemical and immunological studies in denitrifying bacteria (Pseudomonas aeruginosa) strongly support the identification of cytochrome cd(1)-nitrite reductase as the enzyme responsible for the catalysis of nitrosation through the production of nitric oxide or NO(+)-like species. Interestingly, electron paramagnetic resonance studies have shown that large quantities of nitric oxide or NO(+)-species were also produced by non-denitrifying enterobacteria (Escherichia coli, Proteus morganii).

Nitrate contamination of drinking water: evaluation of genotoxic risk in human populations.

Nitrate contamination of drinking water implies a genotoxic risk to man due to the endogenous formation of carcinogenic N-nitroso compounds from nitrate-derived nitrite. Thus far, epidemiological studies have presented conflicting results on the relation of drinking water nitrate levels with gastric cancer incidence. This uncertainty becomes of relevance in view of the steadily increasing nitrate levels in regular drinking water supplies. In an attempt to apply genetic biomarker analysis to improve the basis for risk assessment with respect to drinking water nitrate contamination, this study evaluates peripheral lymphocyte chromosomal damage in human populations exposed to low, medium, and high drinking water nitrate levels, the latter being present in private water wells. It is shown that nitrate contamination of drinking water causes dose-dependent increases in nitrate body load as monitored by 24-hr urinary nitrate excretion in female volunteers, but this appears not to be associated with peripheral lymphocyte sister chromatid exchange frequencies.

Nitrite from inflammatory cells—A cancer risk factor in ulcerative colitis?

Elevated levels of luminal nitrite and a lowered luminal pH were found in 77 percent of patients with acute ulcerative colitis. No luminal nitrite was found in healthy control subjects. Nitrites are a secretory product of activated macrophages and neutrophils of the lamina propria, whereas the lowered luminal pH is due to diminished bicarbonate formation by impaired colonocytes. A hypothesis is put forward that nitrites, lowered pH, and bacterial amines are conducive to formation of carcinogenic n-nitroso compounds, which reflect a cancer risk in patients with ulcerative colitis dependent on the type and extent of inflammatory cell activation as well as metabolic impairment of colonic epithelial cells.

Occurrence of non‐gastric cancer in the digestive tract after remote partial gastrectomy: Analysis of an Amsterdam cohort

If peptic ulcer surgery favors the formation of carcinogenic N-nitroso compounds in the gastric remnant, an increased risk of cancer at sites in the gastrointestinal tract distant from the stomach might be predicted. To estimate the risk of carcinomas in the digestive tract, other than the stomach, occurring after partial gastrectomy, we analyzed an Amsterdam cohort of 2,633 post-gastrectomy patients operated on for benign disease between 1931 and 1960. Mortality in the study population was compared with the general Dutch population through person-year analysis. An excess mortality of biliary tract cancer (O/E:2.64; CL:1.32-4.72; p less than 0.01) and pancreatic cancer (O/E:1.65; CL:1.06-2.44; p less than 0.05) was found in males more than 5 years after surgery; females showed only an increased risk of pancreatic cancer in the first 5 years postoperatively (O/E:15.33; CL:1.85-55.43; p less than 0.01), probably due to misdiagnosis. All other non-gastric sites of the digestive tract carried no increased risk for cancer. In males, mortality due to colorectal cancer more than 5 years post-operatively was significantly decreased (O/E:0.58; CL 0.34-0.92; p less than 0.01). The excess mortality of biliary-tract and pancreatic cancer in males, which increases with the duration of post-operative interval, is consistent with a dose-response phenomenon. This study therefore supports the hypothesis that carcinogens are not only locally activated in the gastric remnant, but are hepatically excreted and initiate cancer in the biliary tree and pancreatic duct. Further exploration of this mechanism of carcinogenesis is warranted, since it may also explain the pathogenesis of pancreatic and biliary cancers in patients without gastrectomy.