Abstract  Combined p.o. administration of sodium nitrite and dimethylamine or methylbenzylamine to male mice produced acute synergistic toxicity, as evidenced by relative weight loss, mortality, and liver necrosis. Similar results were obtained when p.o. dosage of dimethylamine was followed by single administration of sodium nitrite at intervals up to 3 hr; toxicity was, however, markedly reduced when sodium nitrite was administered prior to dimethylamine. The incidence of mortality and liver necrosis was dependent on the time interval separating successive administrations of sodium nitrite and dimethylamine.

Abstract  It is a well-known fact that dimethylnitrosamine (DMNA) causes the formation of liver cancer. And it is also recognized that DMNA is generated from dimethylamine in food and nitrite, a food additive, and that it is produced secondarily in the stomach. But there is a report that shows that albino rats practically given dimethylamine and sodium nitrite have developed no cancer. Therefore, in order to see whether the report is right or not, the present authors kept albino rats for 78 days giving them various degrees of concentration of sodium nitrite and dimethylamine solutions diluted with drinking water. As the result, no formation of tumours was found in the livers of those rats. But the decrease in the vitamin A content of their livers was observed, which suggested the disturbance of the liver function. Then in expectation of the probability that a longer period of administration of sodium nitrite and dimethylamine and a higher concentration of sodium nitrite might develop liver cancer, the authors kept rats for 410 days giving them higher concentrations of sodium nitrite (15 g/l and 30 g/l) as well as an ordinary concentration of it (5 g/l ), together with dimethylamine. The rats given sodium nitrite at higher concentrations died of methaemoglobinemia in a week or two, but the ones given at an ordinary concentration survived. One rat died on the 318th day, in whose liver a tumour was observed to have grown. Some tumours were also found in the spleen and the mesentery, which are considered to be metastatic tumours. One of the animals killed on the 410th day was found to have developed a tumour in the liver alone, which suggests that these tumours were liver-idiopathic. These tumours are conjectured through a pathohistological examination to be fibrous sarcomata of vascular origin. Judging from these results, the warning that these substances in food, i.e. dimethylamine and sodium nitrite, when they are ingested for a long time regardless of their quantities, will possibly cause the development of tumours in the liver cannot be disregarded.

Abstract  An accidental food poisoning outbreak occurred resulting in the death of 14 of the 22 affected persons. Chemical analysis of food materials revealed the presence of sodium nitrite and potassium arsenate. Analysis of urine, gastric contents, liver and kidney, collected at the time of autopsy, confirmed the presence of these chemical substances in high concentrations. Epidemiological data indicated that the food poisoning occurred due to the accidental use of sodium nitrite and potassium arsenate instead of table salt in the preparation of tamarind (Tamarindus indica) soup.

Abstract  Increased lipid peroxidation and reduced antioxidant activity have been reported with pregnancy complications. Given that exogenous oxidants stimulate formation of lipid peroxides, the authors investigated the relationship between exposure to nitrogen-oxidizing species and pregnancy complications and took into account markers of antioxidant and oxidant status. The study sample included pregnant women who were from an area polluted by oxidized nitrogen compounds. Methemoglobin, a biomarker of individual exposure, was determined, as were measures of oxidant/antioxidant status, including glutathione balance and lipid peroxide levels. Only 10 women experienced normal pregnancies. The most common complications were anemia (67%), threatened abortion/premature labor (33%), and signs of preeclampsia (23%). Methemoglobin was elevated significantly in all three conditions, compared with normal pregnancies. Reduced:total glutathione decreased, whereas lipid peroxide levels increased. These results suggest that maternal exposure to environmental oxidants can increase the risk of pregnancy complications through stimulation of the formation of cell-damaging lipid peroxides and from a decrease in maternal antioxidant reserves.

Abstract  Water ingestion estimates are important for the assessment of risk to human populations of exposure to water-borne pollutants. This paper reports mean and percentile estimates of the distributions of daily average per capita water ingestion for a number of age range groups. The age ranges, based on guidance from the US EPA's Risk Assessment Forum, are narrow for younger ages when development is rapid and wider for older ages when the rate of development decreases. Estimates are based on data from the United States Department of Agriculture's (USDA's) 1994-1996 and 1998 Continuing Survey of Food Intake by Individuals (CSFII). Water ingestion estimates include water ingested directly as a beverage and water added to foods and beverages during preparation at home or in local establishments. Water occurring naturally in foods or added by manufacturers to commercial products (beverage or food) is not included. Estimates are reported in milliliters (ml/person/day) and milliliters per kilogram of body weight (ml/kg/day). As a by-product of constructing estimates in terms of body weight of respondents, distributions of self-reported body weights based on the CSFII were estimated and are also reported here.

Abstract  In recent years, several studies have addressed a possible relationship between nitrate exposure and childhood type 1 insulin-dependent diabetes mellitus. The present ecologic study describes a possible relation between the incidence of type 1 diabetes and nitrate levels in drinking water in The Netherlands, and evaluates whether the World Health Organization and the European Commission standard for nitrate in drinking water (50 mg/L) is adequate to prevent risk of this disease. During 1993-1995 in The Netherlands, 1,104 cases of type 1 diabetes were diagnosed in children 0-14 years of age. We were able to use 1,064 of these cases in a total of 2,829,020 children in this analysis. We classified mean nitrate levels in drinking water in 3,932 postal code areas in The Netherlands in 1991-1995 into two exposure categories. One category was based on equal numbers of children exposed to different nitrate levels (0.25-2.08, 2.10-6.42, and 6.44-41.19 mg/L nitrate); the other was based on cut-off values of 10 and 25 mg/L nitrate. We determined standardized incidence ratios (SIRs) for type 1 diabetes in subgroups of the 2,829,020 children with respect to both nitrate exposure categories, sex, and age and as compared in univariate analysis using the chi-square test for trend. We compared the incidence rate ratios (IRRs) by multivariate analysis in a Poisson regression model. We found an effect of increasing age of the children on incidence of type 1 diabetes, but we did not find an effect of sex or of nitrate concentration in drinking water using the two exposure categories. For nitrate levels > 25 mg/L, an increased SIR and an increased IRR of 1.46 were observed; however, this increase was not statistically significant, probably because of the small number of cases (15 of 1,064). We concluded that there is no convincing evidence that nitrate in drinking water at current exposure levels is a risk factor for childhood type 1 diabetes mellitus in The Netherlands, although a threshold value > 25 mg/L for the occurrence of this disease can not be excluded.

Abstract  OBJECTIVE: To study different nutrients and food additives as risk factors for insulin dependent diabetes mellitus in childhood.

DESIGN: Prospective case-control study. Parents of the children being studied were asked to fill in a questionnaire regarding the children's frequency of consumption of various foods. Parents of children with diabetes were asked about the period before onset of the disease.

SETTING: Population based study throughout Sweden.

SUBJECTS: 339 Children aged 0-14 who had recently developed insulin dependent diabetes mellitus and 528 control children matched for age, sex, and county of residence who were traced through the official Swedish population register.

MAIN OUTCOME MEASURES: Foods were classified according to their content of protein, fat, carbohydrates, monosaccharides or disaccharides, nitrosamines, nitrates or nitrites, vitamin C, and fibres. The frequency of intake was categorised as high, medium, and low and the relative risk for developing insulin dependent diabetes was estimated for the three frequencies of intake and calculated as odds ratios.

RESULTS: Significant linear trends for dose response in odds ratios by frequency of intake were shown for solid foods containing high amounts of protein (odds ratio for low frequency of intake 1.0; medium 2.3; and high 5.5), and nitrosamines (1.0; 1.7; 2.6) and significant but non-linear trends were found for carbohydrates (1.0; 1.3; 4.4) and nitrates or nitrites (1.0; 0.8; 2.4). The significant trends were not affected when the results were standardised for possible confounders. No significant increases in odds ratios were found for protein, monosaccharides and disaccharides, vitamin C, and fibres.

CONCLUSION: Nutrients and food additives such as protein, carbohydrate, and nitrosamine compounds may influence the risk of developing insulin dependent diabetes in childhood and significant trends in odds ratios indicate a causal relation.

Abstract  In order to detect possible formation of carcinogenic N-nitroso compounds from nitrite and nitrosatable compounds in meat, studies were carried out with 70 male and 140 female F0 rats, divided into six groups, and 60, 100, 70, 60, 60 and 66 of their male and female offspring. One control group received casein and other groups chopped pork as the sole protein source (45%, mass/mass) on a fresh basis, either salted (sodium chloride) or not. For test groups, nitrite was also added to the meat before autoclaving and storing the diet and represented mass fractions of 200, 1 000 and 4 000 mg/kg, as sodium nitrite. The results do not demonstrate any effect on reproduction and no significant carcinogenic effect was revealed. However, an observed tendency toward an increased number of tumour-bearing rats in the highest dose group, plus the possible formation of carcinogenic N-nitroso compounds in nitrite-treated meat products, led to a recommendation to reduce the use of nitrite. Results from a concomitant study demonstrate that it is possible to produce many cured-meat products with the addition of only 50 mg/kg nitrite.

Abstract  OBJECTIVE: Increasing evidence suggests that nitric oxide participates in the pathophysiology of intestinal barrier function/dysfunction and inflammation. Increases in inducible nitric oxide synthase (iNOS) mRNA and protein expression have been observed in colonic mucosal biopsies of adults with inflammatory bowel disease (IBD). It is unclear whether iNOS induction is specific for IBD or a reflection of nonspecific mucosal inflammation. Furthermore, the characteristics of iNOS mRNA expression in pediatric patients with gastrointestinal disorders remains ill-defined. Our objective was to examine the relationship between iNOS mRNA expression and gastrointestinal mucosal inflammation in a pediatric population.

METHODS: Esophageal and colonic mucosal biopsies were obtained during endoscopy. Total RNA was isolated from these biopsies and reverse transcription-polymerase chain reaction (RT-PCR) performed (35 PCR cycles) using two 20-bp primers that amplified a predicted 372-bp conserved iNOS mRNA fragment.

RESULTS: Biopsies were obtained from 29 children (22 boys; mean age 10.6 yr [range 1.7-16.5 yr]). Endoscopic and histological findings included normal esophageal mucosa (n = 3), esophagitis (n = 10), normal rectal mucosa (n = 2), ulcerative colitis (n = 10), and Crohn disease (n = 4). Evidence of iNOS mRNA was detected by PCR amplification in six of 10 patients with ulcerative colitis and in two of four patients with Crohn disease. However, iNOS mRNA was not amplified in any esophageal biopsy or in rectal mucosa biopsies with normal histology.

CONCLUSIONS: These data indicate that upregulation of iNOS mRNA expression in colonic mucosa is a feature of IBD in children. iNOS mRNA expression is not upregulated in esophageal mucosa or in the absence of colonic inflammation. Further studies designed to determine the site- and cell-specificity of iNOS mRNA upregulation in mucosal biopsies from children with IBD may further illuminate the pathophysiology of these disorders.

Abstract  Incidence rates for adenocarcinoma of the esophagus and gastric cardia have been rising rapidly. We examined nutrient intake as a risk factor for esophageal and gastric cancers in a population-based case-control study in Connecticut, New Jersey, and western Washington state. Interviews were completed for cases with histologically confirmed esophageal adenocarcinoma (n = 282), adenocarcinoma of the gastric cardia (n = 255), esophageal squamous cell carcinoma (n = 206), and noncardia gastric adenocarcinoma (n = 352), along with population controls (n = 687). Associations between nutrient intake and risk of cancer were estimated by adjusted odds ratios (ORs), comparing the 75th versus the 25th percentile of intake. The following nutrients were significantly inversely associated with risk of all four tumor types: fiber, beta-carotene, folate, and vitamins C and B6. In contrast, dietary cholesterol, animal protein, and vitamin B12 were significantly positively associated with risk of all four tumor types. Dietary fat [OR, 2.18; 95% confidence interval (CI), 1.27-3.76] was significantly associated with risk of esophageal adenocarcinoma only. Dietary nitrite (OR, 1.65; 95% CI, 1.26-2.16) was associated with noncardia gastric cancer only. Vitamin C supplement use was associated with a significantly lower risk for noncardia gastric cancer (OR, 0.60; 95% CI, 0.41-0.88). Higher intake of nutrients found primarily in plant-based foods was associated with a reduced risk of adenocarcinomas of the esophagus and gastric cardia, whereas higher intake of nutrients found primarily in foods of animal origin was associated with an increased risk.

Abstract  Nitrate in drinking water has been implicated as a possible risk factor for non-Hodgkin's lymphoma. The authors examined the association between non-Hodgkin's lymphoma and waterborne nitrate through a population-based case-control study of white men in Minnesota. The authors, by linking residential histories with community water records, estimated average long-term exposure to nitrate in drinking water from 1947 to 1975 for 73 cases diagnosed between 1980 and 1982 and for 147 controls who used community water supplies. No association was found between nitrate levels in community water supplies and non-Hodgkin's lymphoma within the range of study exposures (median of highest exposure category = 2.4 mg nitrate/l [range = 0.1-7.2 mg/l]). The findings provide some safety assurance for those who use water systems that have nitrate levels that are less than 2.4 mg/l.

Abstract  Methemoglobinemia is an unusual and potentially fatal condition in which hemoglobin is oxidized to methemoglobin and loses its ability to bind and transport oxygen. The most common cause of methemoglobinemia is the ingestion or inhalation of oxidizing agents such as nitrates or nitrites (e.g., sodium nitrite, which is used commonly as a preservative in curing meats and fish). This report summarizes the investigation of an incident of methemoglobinemia in five members of a household in New York who became ill after eating a meal seasoned with a white crystalline substance from a plastic bag labeled "Refined Iodized Table Salt" (Figure). The findings underscore the need for proper storage of hazardous materials to avoid unintentional ingestion and the importance of collaboration by multiple agencies to address a potential public health emergency.

Abstract  Nitrate and nitrite are precursors of N-nitroso compounds, which induce tumors of the pancreas in animals. The authors evaluated the relation of dietary nitrate and nitrite to pancreatic cancer risk in the NIH-AARP Diet and Health Study. Nitrate and nitrite intakes were assessed at baseline using a 124-item food frequency questionnaire. During approximately 10 years of follow-up between 1995 and 2006, 1,728 incident pancreatic cancer cases were identified. There was no association between total nitrate or nitrite intake and pancreatic cancer in men or women. However, men in the highest quintile of summed nitrate/nitrite intake from processed meat had a nonsignificantly elevated risk of pancreatic cancer (hazard ratio = 1.18, 95% confidence interval: 0.95, 1.47; P-trend = 0.11). The authors observed a stronger increase in risk among men for nitrate/nitrite intake from processed meat at ages 12-13 years (highest quintile vs. lowest: hazard ratio = 1.32, 95% confidence interval: 0.99, 1.76; P-trend = 0.11), though the relation did not achieve statistical significance. The authors found no associations between adult or adolescent nitrate or nitrite intake from processed meats and pancreatic cancer among women. These results provide modest evidence that processed meat sources of dietary nitrate and nitrite may be associated with pancreatic cancer among men and provide no support for the hypothesis in women.

Abstract  Eighteen communities of Weld County, Colorado, USA were selected to study the possible relationship between high nitrate levels in potable water supplies and the incidence of hypertension. The control group consisted of nine communities that had no nitrates in their potable water supplies and the study group of nine communities that had nitrate levels ranging from 19 to 125 ppm. A survey of Weld County General Hospital records yielded 487 cases of both primary and secondary hypertension in patients from the exposed and control communities for the period 1 January 1969 to 1 January 1975. The mean annual incidence rate for the control group was 7·9/1000 population compared with a rate of 5·9/1000 population for the exposed group. There was an earlier onset of hypertension amongst those residents of the exposed communities; i.e. the exposed group exhibited a peak among the 50 to 59 age group and the control group peaked later in the 70 to 70 age group.

Abstract  The lethal effects of sodium nitrite can be antagonized by the administration of various combinations of methylene blue, oxygen, and hyperbaric oxygen. The potency ratios were compared in groups of mice pretreated with methylene blue (2 or 20 mg/kg) and/or oxygen (1 ATA or 2 ATA). Hyperbaric oxygen (2 ATA) was found to be more effective than oxygen (1 ATA) or air with or without methylene blue at 2 mg/kg. When the dose of methylene blue was increased to 20 mg/kg, oxygen (1 ATA) was more effective than air, but hyperbaric oxygen was no more efficacious than oxygen (1 ATA).

Abstract  Carcinogenic risk of small doses of precursors of nitroso compounds, i.e. sodium nitrite (total dose in 0.2-2.0 g/mouse in drinking water) and morpholine (total dose is 0.23 g/mouse in bread) was studied in 520 CBA and 290 C57Bl mice during 96 weeks. It is shown that under these conditions the carcinogenic effect was more pronounced in CBA mice: there was a significant increase in general incidence of tumours, particularly liver tumours and hemoblastoses in CBA females and malignant liver tumours in CBA males.

Abstract  A subchronic oral toxicity study with potassium nitrite (KNO2) was carried out in rats. Groups of ten male and ten female 6-wk-old rats received KNO2 in the drinking-water (tap-water) at levels of 0, 100, 300, 1000 and 3000 mg/litre for a period of 13 wk. The potassium concentration in the nitrite solutions was equalized by adding potassium chloride (KCl) up to the potassium level of the 3000-mg KNO2/litre solution. An additional group of ten males and ten females received drinking-water supplemented with KCl only, at an amount resulting in a potassium concentration equivalent to that of the 3000-mg KNO2/litre solution. Body weight, food intake and food efficiency were decreased at 3000-mg/litre level in males, while liquid intake was decreased in males given 1000 and 3000 mg/litre and in females given 3000 mg/litre. There was significant increase in the methaemoglobin concentration in animals given 3000 mg/litre, while slight decreases in red blood cell variables occurred at the 1000- and 3000-mg/litre dose. No impaired renal function was observed in any of the test groups, although the relative weight of the kidneys and the plasma urea nitrogen level was increased at 3000 mg/litre. There was a slight decrease in plasma alkaline phosphatase activity at 3000 mg/litre. A small amount of nitrite was present in the saliva of the rats receiving 3000 mg/litre but there was no evidence of increased mutagenic activity in the urine of these rats. Interestingly, hypertrophy of the adrenal zone glomerulosa was observed in all test groups, the incidence and degree being dose related. It was concluded that in the study reported here the no-effect level is lower than 100 mg KNO2/litre in the drinking-water, which is equivalent to a level lower than 10 mg KNO2/kg body weight/day.

Abstract  Long-term feeding studies were conducted in Sprague-Dawley rats and Syrian golden hamsters using various dietary concentrations of nitrite and morpholine (up to 1000 ppm of each) or N-nitrosomorpholine (5 or 50 ppm). Most combinations of the two chemicals induced a high incidence of hepatocellular carcinoma in rats and a lower incidence in hamsters. The highest level of nitrite and morpholine (1000 ppm of each) had a stronger potential for carcinogenesis in both rats and hamsters than did a dietary level of 50 ppm of preformed N-nitrosomorpholine. Nitrite and morpholine also induced angiosarcomas in both species, most frequently in the liver, with the lung as the next most common site. The nitrite concentration in the diet seemed to have a greater effect on the incidence of hepatocellular carcinoma and angiosarcoma in the rat than did the concentration of morpholine. Dietary concentrations of 5 ppm each of nitrite and morpholine induced hepatocellular carcinoma and angiosarcoma in some rats. High concentrations of sodium nitrite alone were associated with a relatively high incidence of lymphoreticular tumours.

Abstract  A mixture of 0·1% disulfiram together with 0·2% sodium nitrite in powdered rat diet was fed to 20 male and 20 female Fischer 344 rats for 78 wk, after which the animals were observed until death. Ten of the males and 12 of the females died with tumours of the oesophagus, tongue, squamous stomach and nasal cavity. None of these tumours was observed in rats fed either disulfiram or sodium nitrite alone at similar doses. The tumours were attributed to the reaction of disulfiram and nitrite in the stomach, with the formation of nitrosodiethylamine, which has given rise to these tumours in Fischer rats from the same colony.

Abstract  The EPA limit for nitrate (10 mg/l No3-N) in drinking water was established to prevent infantile methaemoglobinemia, an acute condition confined almost exclusively to infants less than three months. This condition is clinically detectable at methaemoglobin levels of approximately 10%. Several studies in the Soviet Union have suggested that elevated methaemoglobin levels from ingested nitrate may not be confined to the young infant and have reported an association between increased methaemoglobin levels of up to 7% in schoolchildren and drinking water with a nitrate concentration of 23-204 mg/l NO3-N. an epidemiologic study of 102 children aged 1-8 conducted in Washington County, Illinois, did not show that ingestion of water with a nitrate concentration of 22-111 mg/l NO3-N was related to increasing methaemoglobin levels nor that the children had high or above normal methaemoglobin levels. The potential for transmission of infections waterborne disease in this area was demonstrated, however, as a large percentage of the wells used for drinking water contained high numbers of total and faecal coliforms.

Abstract  Nitrate and nitrite were measured in the saliva of two populations who differed in their risk of developing gastric cancer. Surprisingly, the levels of both ions were significantly higher in the low-risk group.

Abstract  Chronic administration of sodium nitrite (1 g/1) in drinking water of pregnant mice and their offspring caused a significant increase in the isolation-induced aggression of the male young. The cessation of administration of sodium nitrite reduced the aggressive behavior of the experimental group to the control level.

Abstract  Three groups of 24 male, and three groups of 24 female F344 rats were fed sodium nitrite for 2 years. Two male and two female groups received 2000 parts per million sodium nitrite mixed with powdered food. The remaining pair of groups received 2000 parts per million in drinking water at the rate of 100 ml per week. A similar pair of groups of untreated animals were maintained as controls. There was little difference in survival between the treated groups and the controls. The incidence of liver neoplasms, which were carcinomas and neoplastic nodules, in the two groups of females treated with sodium nitrite in feed was significantly higher than in the controls, but there was no significant difference in the males. The incidence of monocytic leukemia for each of the nitrite-treated groups was always lower than that for the matching untreated control groups, with the difference attaining or approaching significance in five of the six cases.