Intragastric formation and modulation of N-nitrosodimethylamine in a dynamic in vitro gastrointestinal model under human physiological conditions

Human exposure to carcinogenic N-alkylnitrosamines can occur exogenously via food consumption or endogenously by formation of these compounds through nitrosation of amine precursors. Information on the intragastric formation of NDMA from complex mixtures of precursors and inhibitors in humans is not available. In this study the formation of N-nitrosodimethylamine (NDMA) has been quantitatively analysed in a dynamic in vitro gastrointestinal model, in which gastric conditions can be modulated and closely simulates the physiological situation in humans. Substantial amounts of NDMA were produced when nitrite and dimethylamine or codfish were simultaneously introduced into the model. However, humans are gradually exposed to nitrite by the intake of nitrate-containing food. Nitrate secreted in saliva is converted to nitrite by oral bacteria. To mimic the human exposure to nitrite in a realistic way, nitrite was gradually added into the gastric compartment, simulating the swallowing of nitrite containing oral fluid after the intake of nitrate at the level of 0.1-10 times the ADI. Under these conditions, the cumulative amounts of NDMA formed were 2.3-422 μg NDMA and 1.8-42.7 μg NDMA at a rapid and slow gastric pH decrease, respectively. Beside codfish, various fish species and batches in combination with nitrite, simulating the intake of for times the ADI of nitrate, were investigated. Herring, pollack and plaice were also able to induce NDMA formation. Mackerel, salmon and pike perch did not result in increased NDMA formation. Furthermore, the effect of nitrosation modulators on NDMA formation was investigated. Thiocyanate (2 mM) increased NDMA formation, but the increase was not statistically significant. In contrast, orange jus and tea effectively, but not totally, reduced the amount of NDMA formed in the gastric compartment. These experiments show that (1) the dynamic in vitro gastrointestinal model is an appropriate tool for mechanistic studies on the intragastric formation of nitrosamines, and (2) that the results obtained with this model are helpful in evaluating human cancer risk for the combined intake of codfish-like fish species and nitrate-containing vegetables. © 2003 Elsevier Ltd. All rights reserved

Bioavailability of sodium nitrite from an aqueous solution in healthy adults.

Nitrate intake in humans is high through intake of vegetables such as beets, lettuce, and spinach. Nitrate itself is a compound of low toxicity but its metabolite, nitrite, formed by bacteria in the oral cavity and gastrointestinal tract, has been suspected of potential carcinogenic effects. Nitrite can induce systemic toxicity only after having been absorbed from the gastrointestinal tract. The aim of this study was to determine the absolute bioavailability of nitrite following oral administration in humans. In an open, three-way cross-over study, nine subjects received two single oral doses of sodium nitrite (0.12 and 0.06 mmol NaNO(2)/mmol Hb) and one intravenous sodium nitrite dose (0.12 mmol NaNO(2)/mmol Hb). Plasma samples were analysed to assess the nitrite levels, and pharmacokinetic parameters were calculated. Nitrate and methaemoglobin levels in plasma were also measured as oxidation of nitrite results in the formation of these two compounds. Absolute bioavailability of nitrite was 98% after oral administration of 0.12 mmol NaNO(2)/mmol Hb, and 95% after oral administration of 0.06 mmol NaNO(2)/mmol Hb. Minor adverse effects were observed after the 0.12 mmol NaNO(2)/mmol Hb oral dose. In conclusion, nitrite in solution is highly absorbed from the gastrointestinal tract and the first pass effect in the liver is low

Determination of trichothecenes in duplicate diets of young children by capillary gas chromatography with mass spectrometric detection

Trichothecenes are mycotoxins produced by several fungal genera, mainly Fusarium species, that can contaminate a wide range of cereals used for human and animal consumption. They are associated with various adverse health effects in animals and humans such as feed refusal, vomiting and immunotoxic effects. A method based on capillary gas chromatography with mass spectrometric detection was developed and validated in-house for the determination of nine trichothecenes in duplicate diets of young children. The trichothecenes were extracted from the sample matrix by water/ethanol (90/10). The extracts were cleaned by means of ChemElut(R) and Mycosep(R) columns. The cleaned extracts were evaporated to dryness and derivatized to trimethylsilyl ethers at room temperature. The residues were dissolved in iso-octane and washed with water. The final extracts were analysed for trichothecenes by GC-MS. The response was linear in the range tested (1-10 mg kg(-1)). Recoveries for the trichothecenes were between 70 and 111%, with the exception of nivalenol, which had a low recovery (34%). The limit of quantification for all trichothecenes was below 0.4 mg kg(-1). Seventy-four food samples from young children collected by 74 respondents in a duplicate diet study were analysed for trichothecenes with the developed method. The mean levels of deoxynivalenol, nivalenol, HT-2 toxin and T-2 toxin were 5.8, 0.3, 0.3 and 0.1 mug kg(-1), respectively. Based on the individual results, dietary intake calculations were made. For deoxynivalenol, the tolerable daily intake of 1 mug kg(-1) body weight was exceeded by nine respondents. For the combined intake of T-2 and HT-2 toxin, the temporary tolerable daily intake of 0.06 mg kg(-1) body weight was exceeded by nine respondents

Determination of trichothecenes in duplicate diets of young children by capillary gas chromatography with mass spectrometric detection

Trichothecenes are mycotoxins produced by several fungal genera, mainly Fusarium species, that can contaminate a wide range of cereals used for human and animal consumption. They are associated with various adverse health effects in animals and humans such as feed refusal, vomiting and immunotoxic effects. A method based on capillary gas chromatography with mass spectrometric detection was developed and validated in-house for the determination of nine trichothecenes in duplicate diets of young children. The trichothecenes were extracted from the sample matrix by water/ethanol (90/10). The extracts were cleaned by means of ChemElut(R) and Mycosep(R) columns. The cleaned extracts were evaporated to dryness and derivatized to trimethylsilyl ethers at room temperature. The residues were dissolved in iso-octane and washed with water. The final extracts were analysed for trichothecenes by GC-MS. The response was linear in the range tested (1-10 mg kg(-1)). Recoveries for the trichothecenes were between 70 and 111%, with the exception of nivalenol, which had a low recovery (34%). The limit of quantification for all trichothecenes was below 0.4 mg kg(-1). Seventy-four food samples from young children collected by 74 respondents in a duplicate diet study were analysed for trichothecenes with the developed method. The mean levels of deoxynivalenol, nivalenol, HT-2 toxin and T-2 toxin were 5.8, 0.3, 0.3 and 0.1 mug kg(-1), respectively. Based on the individual results, dietary intake calculations were made. For deoxynivalenol, the tolerable daily intake of 1 mug kg(-1) body weight was exceeded by nine respondents. For the combined intake of T-2 and HT-2 toxin, the temporary tolerable daily intake of 0.06 mg kg(-1) body weight was exceeded by nine respondents

Determination of N-nitrosodimethylamine in artificial gastric juice by gas chromatography-mass spectrometry and by gas chromatography-thermal energy analysis.

: Eur J Cancer Prev 2001 Jun;10(3):265-8 Related Articles, Books, LinkOut Determination of N-nitrosodimethylamine in artificial gastric juice by gas chromatography-mass spectrometry and by gas chromatography-thermal energy analysis. Dallinga JW, Krul CA, Tenfelde A, Moonen EJ, Vermeer IT, van Doorn D, Schothorst RC. Department of Health Risk Analysis and Toxicology, Faculty of Health Sciences, Maastricht University, The Netherlands. [email protected] The thermal energy analyser (TEA) is considered to be the gold standard for the determination of nitrosamines. However, since many laboratories cannot justify the use of such a very specific detection system, alternative detection methods are useful. While standard gas chromatography (GC) detectors lack the selectivity of the TEA detector, mass spectrometry (MS) seems to be the method of choice to combine GC separation with mass selective detection. Moreover, the detection limits of the GC-MS assay in general use are about 4 times lower than those of the GC-TEA assay. A comparison of GC-MS and GC-TEA data on N-nitrosodimethylamine determinations showed a strong correlation between the two assays (R2 = 0.86), demonstrating the exchangeability of these methods