sodium-nitrite and Esophageal-Neoplasms

The objective of this study is to investigate the risk of esophageal carcinoma in a cohort with long-term occupational exposure to sodium nitrite. The method used was a retrospective cohort study. A small wood screw manufacturer was founded in 1977 and closed down in 2000. In their production process, the sodium nitrite solution was used to serve as anticorrosive and coolant fluid. One hundred sixty workers in turning and milling shops had direct exposure to sodium nitrite through skin, mouth, and airway because of lack of occupational protective knowledge (study group), whereas 255 workers from other workshops without direct contact with sodium nitrite served as control group. The incidence, diagnosis, and treatment of esophageal carcinoma as well as other malignant tumors in these two groups were followed until the end of 2007. The sodium nitrite exposure time in the study group ranged from 16 to 23 years, with an average of 22.1 years. During 30 years of follow-up, there were 11 esophageal carcinomas and 10 other malignant tumors (4 hepatic cell carcinomas, 3 lung cancers, 2 breast cancers, and 1 leukemia) documented in the study group, while no cancer developed in the control group. The risk for esophageal carcinoma was significantly increased in the study group compared with the control group (relative risk = 1.26, 95% confidence interval = 1.08-1.46, chi-square = 116.83, P < 0.001). Long-term exposure to sodium nitrite markedly increases the risk of esophageal carcinoma in human body.

Topics: Adolescent; Adult; Aged; Breast Neoplasms; Carcinoma; Chi-Square Distribution; China; Construction Materials; Esophageal Neoplasms; Female; Follow-Up Studies; Humans; Incidence; Kaplan-Meier Estimate; Leukemia; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Occupational Exposure; Retrospective Studies; Risk; Sodium Nitrite; Young Adult

Combined treatment with sodium nitrite (NaNO2) and ascorbic acid (AsA) has already been shown to promote rat forestomach carcinogenesis, possibly due to nitric oxide generation under acidic conditions. We hypothesized that a similar effect might occur in the esophagus when the luminal pH is decreased by acid reflux. To clarify this possibility, reflux esophagitis model rats (F344 male) were coadministered 0.2% NaNO2 in the drinking water and 1% AsA in the diet. After 32 weeks of the combined treatment, a significant increase in the incidence of epithelial hyperplasias of the lower-middle and lowest parts of the esophagus were observed compared with the basal-diet group, along with exacerbation of dysplasia and extension of the lesions. Additionally, one squamous cell papilloma was found only in the combined-treatment group. Subsequently, we confirmed the enhancing effects of NaNO2 and AsA cotreatment in the rat N-bis(2-hydroxypropyl)nitrosamine-initiated esophageal tumorigenesis model. The incidence of hyperplasia was enhanced in all segments, along with the incidence and multiplicity of squamous cell papillomas in the lowest segment of the esophagus. Thus, the data demonstrate that combined treatment with NaNO2 and AsA exerts promoting effects on rat esophageal carcinogenesis under acid reflux conditions, as in the forestomach. These findings suggest that the risk of excessive intake of a combination of nitrite and antioxidants for esophageal carcinogenesis is appreciable, particularly in patients with reflux esophagitis.

Topics: Animals; Antioxidants; Ascorbic Acid; Carcinoma, Squamous Cell; Cocarcinogenesis; Disease Models, Animal; Esophageal Neoplasms; Esophagitis, Peptic; Food Preservatives; Male; Rats; Rats, Inbred F344; Sodium Nitrite

The luminal microenvironment including acid and nitric oxide (NO) has been implicated in Barrett's esophagus carcinogenesis. We investigated the ability of acid and NO to induce DNA damage in esophageal cells.. Transformed and primary Barrett's esophagus and adenocarcinoma cells were exposed to either acid, (pH 3.5), +/- antioxidant or NO from a donor or generated by acidification of nitrite in the presence of ascorbate +/- NO scavenger. Phosphorylation of histone H2AX and the neutral comet assay were used to detect DNA double-strand breaks (DSBs). Intracellular levels of reactive oxygen species and NO were detected with fluorescent dyes. Mitochondrial viability was measured with a rhodamine dye. Long-term survival was assessed by clonogenic assay.. Exposure to acid (pH 3.5) for > or =15 minutes induced DSBs in all cell lines (P < .05). There was a concomitant increase in intracellular reactive oxygen species in the absence of mitochondrial damage, and pretreatment with antioxidants inhibited DNA damage. Exposure to physiologic concentrations of NO produced from the NO donor or acidification of salivary nitrite induced DSBs in a dose- (>25 micromol/L) and cell-dependent manner (adenocarcinoma >Barrett's esophagus, P < .05). This occurred preferentially in S-phase cells consistent with stalled replication forks and was blocked with a NO scavenger. NO also induced DSBs in primary Barrett's esophagus cells treated ex vivo. Cells were able to survive when exposed to acid and NO.. Both acid and NO have the potential to generate DSBs in the esophagus and via distinct mechanisms.

Topics: Adenocarcinoma; Antioxidants; Ascorbic Acid; Barrett Esophagus; Cell Line, Tumor; Cell Survival; Cell Transformation, Neoplastic; Comet Assay; DNA Breaks, Single-Stranded; Dose-Response Relationship, Drug; Esophageal Neoplasms; Gastric Acid; Histones; Humans; Hydrazines; Hydrogen-Ion Concentration; Mitochondria; Nitric Oxide; Nitric Oxide Donors; Phosphorylation; Reactive Oxygen Species; S Phase; Sodium Nitrite; Time Factors

To study farm compost polluted water that may induce pharyngo-esophageal, gastric and liver carcinoma in chickens.. 280 chickens were randomized into 4 groups: experiment group 100 chickens fed with compost water + NaNO(2) by stomach tube. The other 180 were evenly randomized into 3 control groups (60 each), fed with compost water, NaNO(2) and tap water in the same way. The farm compost was prepared with corn stalks, rice straws, excreta of men and livestock. The compost water, after being nitrosified and acidified, was fed through stomach tube 5 - 7.5 ml/session, twice a week. Besides, a solution consisting of the respective formula of each group added with 3 - 4 L water with pH adjusted to 3 - 4 by 1N HCL was given ad lib to all chickens in each group for 26.5 months.. In the experiment group, there were pharyngo-esophageal carcinoma 16 (16.3%), gastric adenocarcinoma 5 (10.4%) and liver carcinoma 3 (6.3%), in contrast to none in the 3 control groups, showing significant differences (P < 0.01, P < 0.01, P < 0.05).. Successful simulation of the layout of esophageal carcinoma high morbidity area and the mimic of chicken gastric fluid strongly support our compost etiological hypothesis that the nitrosified and acidified compost water are carcinogenic, very well causing esophageal, gastric and liver carcinoma.

Topics: Adenocarcinoma; Animals; Carcinoma, Squamous Cell; Chickens; Esophageal Neoplasms; Feces; Female; Liver Neoplasms; Male; Pharyngeal Neoplasms; Random Allocation; Sewage; Sodium Nitrite; Stomach Neoplasms; Water Pollution, Chemical

For carcinogenic risk assessment of combinations of N-nitroso precursors in man, the effects of feeding methylurea (MU) or morpholine (Mor) plus sodium nitrite (NaNO2) were investigated using a multi-organ carcinogenesis model. In experiment 1, to initiate multiple organs, groups of 10 or 20 male F344 rats were treated with 6 carcinogens targeting different organs. Starting a week after completion of this initiation phase, animals were given 0.1% MU or 0.5% Mor in their food and/or 0.15% NaNO2 in their drinking water for 23 weeks. The induction of tumors and/or preneoplastic lesions in the forestomach and esophagus was significantly increased in the group receiving MU plus NaNO2. The numbers and areas of liver glutathione S-transferase placental form (GST-P)-positive foci were significantly elevated with MU or Mor plus NaNO2. Experiment 2 was conducted to assess formation of N-nitroso compounds in the stomach, and to detect DNA adduct generation in target organs by immunohistochemical staining. Groups of 5 or 14 animals were starved overnight, then given 0.4% MU or 2.0% Mor in the diet, or basal diet alone for 1 h. Then NaNO2 or distilled water was given intragastrically. The mean gastric N-methyl-N-nitrosourea yield in the MU plus NaNO2 group was 7700 micrograms at 2 h after combined administration. The mean N-nitrosomorpholine yield in the group given Mor plus NaNO2 was 6720 micrograms. Immunohistochemically, N7-methyldeoxyguanosine-positive nuclei were evident in the forestomach epithelium at 8 h after the combination treatment with MU plus NaNO2.

Topics: Administration, Oral; Animal Feed; Animals; Biomarkers, Tumor; Carcinogenicity Tests; Carcinogens; Drug Interactions; Esophageal Neoplasms; Glutathione Transferase; Humans; Liver; Liver Neoplasms; Male; Methylurea Compounds; Morpholines; Neoplasms, Experimental; Nitroso Compounds; Precancerous Conditions; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach Neoplasms; Water Supply

Cancers and precancerous lesions of the esophagus were efficiently induced in rats by the simulation of a clinico-epidemiological setting; that is, the administration of precursors of nitrosamine. Six week old non-inbred male Wistar rats were given 2g/kg bodyweight of sarcosine ethyl ester hydrochloride (SEEH) and concurrently 0.3g/kg bodyweight of sodium nitrite (NaNO2), precursors of N-nitrososarcosine ethyl ester (NSEE), in 2% sucrose as drinking water. Group 1 received the precursors twice a week for 6 weeks followed by 8 weeks observation, and group 2, once every 3 days for 7 weeks followed by 26 weeks observation. At the end of treatment, no tumor had developed in the esophagus of rats in group 1, but the [3H]-thymidine labeling indices in both basal and superficial layer cells were higher than in the control group. On subsequent observation, papillomas appeared in group 1 (33.3%), and carcinomas in group 2 (33.3%), within 4 weeks. The tumors induced in group 1 were mostly papillomas and rarely carcinomas. When the observation was prolonged in group 2, 100% of the animals had cancer in week 20. The pathological changes of the lesions paralleled the sequential development of human squamous cell carcinoma of the esophagus. Our system has the advantages in that papillomas and cancers can be induced in rats in a short time and the agents used are less toxic than preformed nitrosamines administered previously by gastric intubation. It would serve as a useful experimental tool to study premalignant lesions and cancers of the esophagus.

Topics: Animals; Carcinogens; Carcinoma; Disease Models, Animal; Esophageal Neoplasms; Male; Nitrosamines; Precancerous Conditions; Rats; Rats, Wistar; Sodium Nitrite

Five groups of rats (22 per group) were intubated with precursors of N-Nitrosomethylbenzylamine (NMBzA), i.e. methylbenzylamine (1 mmol/kg) and sodium nitrite (0.5 mmol/kg), and five varieties of Chinese tea. One positive control group was intubated with precursors of NM2A without tea and one negative control group with tap water and sodium nitrite. After 12 week's treatment, significantly less lesions and papillomas in esophageal mucosa, examined by naked eye or by microscope, were found in the tea-treated groups than in the non-tea-treated positive control group. The results confirmed the anti-tumour ability of Chinese tea by blocking the in vivo formation of NMBzA in rats.

Topics: Animals; Benzylamines; Carcinogens; Dimethylnitrosamine; Esophageal Neoplasms; Male; Papilloma; Plant Extracts; Rats; Rats, Inbred Strains; Sodium Nitrite; Tea

The concurrent administration of N-nitroso-N-methylbenzylamine (NMBA) (10 mg/l drinking water) and sodium nitrite (5 g or 1 g/kg basic diet) induces enhanced progression of esophageal tumors. Pathologic changes of the respiratory system, which do not occur with administration of NMBA alone, are also observed. These findings call for re-evaluation of the toxicological significance of nitrite.

Topics: Animals; Cocarcinogenesis; Dimethylnitrosamine; Drug Synergism; Esophageal Neoplasms; Female; Neoplasms, Experimental; Nitrites; Rats; Respiratory System; Sodium Nitrite

Topics: Amines; Animals; Benzylamines; Carcinogens; Dimethylnitrosamine; Esophageal Neoplasms; Male; Neoplasms, Experimental; Nitrites; Rats; Rats, Inbred Strains; Sodium Nitrite; Stomach Neoplasms; Zinc

Previous studies in Linxian, an area of China with a high incidence of esophageal carcinoma, showed that fungal infections are common in the esophageal epithelium of patients with either premalignant changes or early esophageal carcinoma. Fungi of the genus Candida were the most frequent invaders. In these areas nitrate and nitrite are often present in high concentrations in drinking water and staple grains. The present studies have established the ability of Candida albicans to augment the nitrosative formation of the esophagus-specific carcinogen, benzylmethylnitrosamine (NBMA; N-nitroso-N-methylbenzylamine). Stationary C. albicans cultures, with pH held at 6.8, were incubated with the precursors of NBMA, benzylmethylamine (BMA; N-methylbenzylamine) and NaNO(2). There was a significant increase in the amount of NBMA formed in these cultures, compared to precursors-only controls. The amount of NBMA synthesized depended on fungal cell number. Exponentially growing cultures were also able to cause NBMA formation. The identity of the NBMA was confirmed by high-performance liquid chromatographic coelution with authentic NBMA in three solvent systems and by mass spectroscopy. Boiled cells and conditioned medium in which cells had been incubated were not effective in enhancing nitrosation. Cultured Candida released acidic metabolites that reduced the pH of the medium when only a low concentration of buffer was present. Spontaneous nitrosation of BMA was enhanced under these acidic conditions. Thus, C. albicans infecting the esophageal epithelium could cause local formation of NBMA by both cell-mediated catalysis and extracellular decrease in pH.

Topics: Benzylamines; Biotransformation; Candida albicans; Chromatography, High Pressure Liquid; Dimethylnitrosamine; Esophageal Neoplasms; Humans; Kinetics; Mass Spectrometry; Sodium Nitrite

Topics: Animals; Carcinogens; Diet; Diethylnitrosamine; Disulfiram; Drug Interactions; Esophageal Neoplasms; Female; Gastric Mucosa; Male; Neoplasms, Experimental; Nitrites; Rats; Rats, Inbred F344; Sodium Nitrite