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

Onderzoek naar de effectiviteit van bodembewerking op het gehalte van dioxines en dioxine-achtige PCB's in het Rijnmondgebied

In het verleden is (met name in het voorjaar) in koemelk in het Rijnmondgebied een relatief hoge concentratie dioxines en dioxine-achtige PCB's aangetroffen. Vermindering van de inname van dioxines en dioxine-achtige PCB's via de bodem kan bereikt worden door de bovenste bodemlaag van 0-10 cm d.m.v. grondomwerking te vermengen met de eronder liggende laag die veel minder verontreinigd is. Om de effectiviteit van zo’n bewerking vast te stellen zijn op een perceel waar recent (najaar 2007) een dergelijke omwerking is uitgevoerd grondmonsters genomen en op dioxines en dioxine-achtige PCB's onderzocht. Ter controle zijn grondmonsters genomen op een naastliggend perceel waarvan met zekerheid bekend is dat de grond de afgelopen decennia niet is omgewerkt

Risk assessment of N-nitrosodimethylamine formed endogenously after fish-with-vegetable meals

The consumption of fish and nitrate-rich vegetables may lead to the formation of the genotoxic carcinogen N-nitrosodimethylamine (NDMA) in the stomach. To assess human cancer risk associated with this formation, a dynamic in vitro gastrointestinal model was used to simulate NDMA formation in the stomach after a fish + vegetable meal. The experimental results were combined with statistical modeling of Dutch food consumption data resulting in predicted exposures to endogenously formed NDMA in the population. The 95th percentile of the long-term exposure distribution was around 4 ng/kg-bw in young children and 0.4 ng/kg-bw in adults. By comparing this exposure with the Benchmark Dose Lower bound (BMDL) 10 for liver cancer in a chronic carcinogenicity study, a chronic margin of exposure (MOE) was calculated of 7000 and 73,000 for young children and adults. Furthermore, the long-term exposure distribution was combined with a dose-response analysis of the liver cancer incidence data to obtain a cancer risk distribution for the human population. The 95th percentile of that distribution was 6 x 10(-6) extra risk for 5-year-old children and 8 x 10(-7) for adults. The liver cancer data allowed for the analysis of the relationship between tumor incidence and time to tumor. For an extra risk of 10(-6), the decrease in time to tumor was conservatively estimated at 3.8 min in the rat, equivalent to 0.1 days in humans. We also combined acute exposure estimates with the BMDL10 from an acute carcinogenicity study for NDMA, resulting in an acute MOE of 110,000. We conclude that the combined consumption of fish and nitrate-rich vegetables appears to lead to marginal increases of additional cancer risk

A mycotoxin-dedicated total diet study in the Netherlands in 2013 : Part I - Design

A mycotoxin-dedicated total diet study (mTDS) allowing assessment of occurrence and dietary exposure to these substances was developed and carried out in the Netherlands in 2013. First, literature was searched to establish the occurrence profile of mycotoxins. Next, foods as consumed according to the Dutch National Food Consumption Surveys (DNFCS) for young children and persons aged 7-69 years, categorised in several food categories, were ranked according to their summed consumption. Subsequently, foods with the highest consumptions were included to cover >85% of the consumption of a particular food category. In some cases, foods other than those contributing to the upper 85% consumption within a food category were included based on their expected high mycotoxin contamination. In some other cases, foods not contributing to mycotoxin exposure were excluded. This resulted in 130 foods to be included in this mTDS. Since a sample size of 12 was established per food, 1,560 food items were purchased for the population aged 7-69 years. Fifty seven additional food items were purchased to take into account the different consumption profile of young children. The 1,617 food items were prepared as consumed based on information available in the food consumption surveys. The prepared food items were combined according to the different consumption forms of the 130 selected foods (e.g. fresh, canned or frozen). This resulted in 213 subsamples, which were proportionally to their consumption further pooled into 88 composite samples. These composite samples covered 87 and 88% of the amount foods consumed by young children and the population aged 7-69 years, respectively. This design allows analysis of mycotoxin occurrence and the subsequent exposure assessment using aggregated food categories reflected by the 88 composite samples, as well as a more refined approach by analysing 213 subsamples

A novel source for dioxins present in recycled fat from gelatin production

Within a survey on dioxins in animal fat used as feed ingredient, a sample originating from pigs offal was shown to contain 50 ng Toxic Equivalents (TEQ) PCDD/PCDFs kg(-1) fat. Further investigation revealed fat samples with levels as high as 440 ng TEQ kg(-1) fat and contaminated feed with a highest level of 8.4 ng TEQ kg(-1) feed. The congener pattern was dominated by 1,2,3,7,8-PeCDD and 2,3,7,8-TCDD, and was not recognized from any previous incident or known dioxin source. Remarkably, 2,3,7,8-substituted congeners were much more abundant than their non-2,3,7,8-substituted counterparts. The sampled fat was derived from a gelatin production W, plant. Broken filters, used to clean the hydrochloric acid (HCl) used in the process, caused the dioxin contamination. The fat was primarily used for pig feed. A new physiologically-based pharmacokinetic (PBPK) model for lipophilic contaminants in growing slaughter pigs predicted levels at slaughter varying between 40 pg TEQ g(-1) fat (worst-case) and 2.5-7 pg TEQ g(-1) fat under more realistic scenarios. Almost 300 farms were temporarily blocked. Many fat samples of pigs were analyzed using a combined approach of DR CALUXO and GC/HRMS. Levels in contaminated pig fat were around the EU-limit of 1 pg TEQ g(-1) fat, with some samples up to 2-3 pg TEQ g(-1) fat. Of 80 negative samples analyzed by DR CALIJX (R) and GC/HRMS no false-negatives were obtained, whereas 36 and 62 of the 80 samples classified suspected with the bioassay had GC/HRMS levels above respectively the tolerance and action limits. It is concluded that novel and unexpected dioxin sources remain a threat to the food chain and require the proper evaluation and monitoring of production processes, including chemicals used therein. (c) 2007 Elsevier Ltd. All rights reserved