N-nitrosopiperidine Research Articles

Real-time monitoring of aqueous total N-nitrosamines by UV photolysis and chemiluminescence.

N-nitrosamines such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosopiperidine (NPIP), and N-nitrosopyrrolidine (NPYR) have been established as potent carcinogens that can induce diverse types of cancer. Several studies have extensively investigated the accurate quantification of total N-nitrosamines (TONO) and the intricate nature of the matrix in which they are detected. The potential for the formation of N-nitrosamines in post-combustion CO2 capture (PCCC) and water treatment has raised concerns. This study outlines a unique method for the quantification of TONO in aqueous matrices using UV photolysis and the subsequent detection of NO by chemiluminescence. This method offers benefits such as operation in the continuous mode and handling of high sample flow rates to achieve a low limit of detection (LOD) and a low limit of quantification (LOQ). The observed LODs for the individual N-nitrosamines of NDMA, N-nitrosomorpholine (NMOR), N-nitrosodibutylamine (NDBA), and NPIP range between 0.06 and 0.2µM at a sample flow rate of 0.25mL/min, while the LOD range is reduced to between 0.02 and 0.06µM at 0.75mL/min. Linear responses for the NO produced from specific N-nitrosamines are observed between 0.5 and 10µM. The developed method is resistant to interfering chemicals (i.e., nitrite, amines, and carbonyls) and exhibits high specificity.

Using Celery Powder in a Semi-Dry Fermented Sausage 'Heat-Treated Sucuk': Nitrosamine Formation, Lipid Oxidation, and Volatile Compounds.

This study investigated the effect of using celery powder (CP) as source of pre-converted nitrite (treatments: A: 150 mg/kg NaNO2, B: 100 mg/kg NaNO2 + CP as 50 mg/kg NaNO2 equivalent, C: 50 mg/kg NaNO2 + CP as 100 mg/kg NaNO2 equivalent, D: CP as 150 mg/kg NaNO2 equivalent) on the physicochemical and microbiological properties in heat-treated sucuk (HTS), a kind of semi-dry fermented sausage. The influence of cooking time (CT) on the nitrosamine formation in HTS with and without CP was also determined. The results indicated that the use of CP increased the pH value and decreased the aw value. Micrococcus/Staphylococcus and residual nitrite were not affected by the use of CP. TBARS value varied from 0.78 to 0.90 mg MDA/kg. CP did not affect the abundance of hexanal in HTS, however, it increased the abundance of camphene. The results of PCA showed that treatments A, B, and C had similar volatile compound profiles. CP did not affect both N-nitrosodimethylamine and N-nitrosodiethylamine, but their levels increased as the CT increased. Increased CT also resulted in increased N-nitrosopiperidine (NPIP) in all treatments, but the cooking for 1 min did not cause a significant increase in treatments A, B, and C. CP leads to a significant increase in NPIP content, especially after 3 and 5 min of cooking in HTS.

A comprehensive review on various carcinogenic aspects of N-nitrosopiperidine (NPIP)

A comprehensive review on various carcinogenic aspects of N-nitrosopiperidine (NPIP)

N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP

The finding of N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) in marketed drugs has led to implementation of risk assessment processes intended to limit exposures to the entire class of N-nitrosamines. A critical component of the risk assessment process is establishing exposure limits that are protective of human health. One approach to establishing exposure limits for novel N-nitrosamines is to conduct an in vivo transgenic rodent (TGR) mutation study. Existing regulatory guidance on N-nitrosamines provides decision making criteria based on interpreting in vivo TGR mutation studies as an overall positive or negative. However, point of departure metrics, such as benchmark dose (BMD), can be used to define potency and provide an opportunity to establish relevant exposure limits. This can be achieved through relative potency comparison of novel N-nitrosamines with model N-nitrosamines possessing robust in vivo mutagenicity and carcinogenicity data. The current work adds to the dataset of model N-nitrosamines by providing in vivo TGR mutation data for N-nitrosopiperidine (NPIP). In vivo TGR mutation data was also generated for a novel N-nitrosamine impurity identified in sitagliptin-containing products, 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine (NTTP). Using the relative potency comparison approach, we have demonstrated the safety of NTTP exposures at or above levels of 1500 ng/day.

Quantum chemical calculations of nitrosamine activation and deactivation pathways for carcinogenicity risk assessment.

N-nitrosamines and nitrosamine drug substance related impurities (NDSRIs) became a critical topic for the development and safety of small molecule medicines following the withdrawal of various pharmaceutical products from the market. To assess the mutagenic and carcinogenic potential of different N-nitrosamines lacking robust carcinogenicity data, several approaches are in use including the published carcinogenic potency categorization approach (CPCA), the Enhanced Ames Test (EAT), in vivo mutagenicity studies as well as read-across to analogue molecules with robust carcinogenicity data. We employ quantum chemical calculations as a pivotal tool providing insights into the likelihood of reactive ion formation and subsequent DNA alkylation for a selection of molecules including e.g., carcinogenic N-nitrosopiperazine (NPZ), N-nitrosopiperidine (NPIP), together with N-nitrosodimethylamine (NDMA) as well as non-carcinogenic N-nitrosomethyl-tert-butylamine (NTBA) and bis (butan-2-yl) (nitros)amine (BBNA). In addition, a series of nitroso-methylaminopyridines is compared side-by-side. We draw comparisons between calculated reaction profiles for structures representing motifs common to NDSRIs and those of confirmed carcinogenic and non-carcinogenic molecules with in vivo data from cancer bioassays. Furthermore, our approach enables insights into reactivity and relative stability of intermediate species that can be formed upon activation of several nitrosamines. Most notably, we reveal consistent differences between the free energy profiles of carcinogenic and non-carcinogenic molecules. For the former, the intermediate diazonium ions mostly react, kinetically controlled, to the more stable DNA adducts and less to the water adducts via transition-states of similar heights. Non-carcinogenic molecules yield stable carbocations as intermediates that, thermodynamically controlled, more likely form the statistically preferred water adducts. In conclusion, our data confirm that quantum chemical calculations can contribute to a weight of evidence approach for the risk assessment of nitrosamines.

Simultaneous determination of low molecular weight nitrosamines in pharmaceutical products by fast gas chromatography mass spectrometry

Control of N-nitrosamines has been in the focus of health authorities in recent years because many of these compounds are probable human carcinogens. In July 2018 the U.S. Food and Drug Administration (FDA) announced a recall for valsartan-containing medicines due to contamination with the carcinogenic low molecular weight nitrosamine, N-nitrosodimethylamine (NDMA). It has become clear that the problem can not only exist in the case of sartans, but in any active pharmaceutical ingredient (API)/drug product in which secondary or tertiary amines are present (as API or as impurities) and a nitrosating agent is available. The decision was made by regulators, according to which manufacturers of pharmaceutical products are obliged to perform a risk assessment for the potential presence of nitrosamines in active pharmaceutical ingredients and drug products. This resulted in a high demand for validated analytical methods that are able to quantify N-nitrosamines at low ppb levels in pharmaceutical products.In this work we have developed and validated a generic fast GC-MS method suitable for the quantitative determination of a wide range of low molecular weight nitrosamines, which include N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), N-nitroso-diphenylamine (NDPh), N-nitrosodipropylamine (NDPA), N-nitrosomethylethylamine (NMEA), N-nitrosomorpholine (NMOR), N-nitrosopiperidine (NPIP), N-nitroso-ethylisopropylamine (EIPNA), N-nitroso-diisopropylamine (DIPNA), N-nitroso-N-methylaniline (NMPA), 1-Methyl-4-nitrosopiperazine (MeNP) and N-nitroso-pyrrolidine (NPYR). The advantage of the method is that it is possible to screen low molecular weight nitrosamines in low concentrations with a short analysis time in a wide range of APIs and drug products.

Effect of Black Garlic on Microbiological Properties, Lipid Oxidation, Residual Nitrite, Nitrosamine Formation and Sensory Characteristics in a Semi-Dry Fermented Sausage.

This study was conducted with the aim of determining the effects of different black garlic (BG) levels (1%, 2% and 3%) on quality characteristics of a semi-dry fermented sausage (heat-treated sucuk). In addition, the effect of cooking time (0, 1 or 3 min at 180 °C on a hot plate) on nitrosamine formation was investigated. Fresh garlic (FG, 1%) was evaluated as the control group. BG (2% and 3%) caused a reduction in the count of lactic acid bacteria while leading to an increase in pH. FG1% gave the highest number of Micrococcus/Staphylococcus, as well as aw value. The thiobarbituric acid reactive substance (TBARS) value increased with increasing BG levels. FG (1%) showed the highest residual nitrite amount (p < 0.05). The scores for color, taste and general acceptability were reduced by the use of BG (p < 0.05). No significant difference was observed between the garlic treatments in terms of N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) when no additional cooking was applied. Cooking time was determined to have no significant effect on NDMA in 3% BG. The use of BG caused an increase in N-Nitrosopiperidine (NPIP) (p < 0.05). As for PCA, a closer correlation between NPIP and the groups containing BG was observed, while there was a strong correlation between NDMA and the FG group cooked for 3 min. The use of BG caused an increase in NPIP, but affected NDMA and NDEA depending on the cooking time.

Occurrence and mass loads of N-nitrosamines discharged from different anthropogenic activities in Desheng River, South China

N-nitrosamines are widespread in various bodies of water, which is of great concern due to their carcinogenic risks and harmful mutagenic effects. Livestock rearing, domestic, agricultural, and industrial wastewaters are the main sources of N-nitrosamines in environmental water. However, information on the amount of N-nitrosamines these different wastewaters contribute to environmental water is scarce. Here, we investigated eight N-nitrosamines and assessed their mass loadings in the Desheng River to quantify the contributions discharged from different anthropogenic activities. N-nitrosodimethylamine (NDMA) (< 1.6-18ng/L), N-nitrosomethylethylamine (NMEA) (< 2.2ng/L), N-nitrosodiethylamine (NDEA) (< 1.7-2.4ng/L), N-nitrosopyrrolidine (NPYR) (< 1.8-18ng/L), N-nitrosomorpholine (NMOR) (< 2.0-3.5ng/L), N-nitrosopiperidine (NPIP) (< 2.2-2.5ng/L), and N-nitrosodi-n-butylamine (NDBA) (< 3.3-16ng/L) were detected. NDMA and NDBA were the dominant compounds contributing 89% and 92% to the total N-nitrosamine concentrations. The mean cumulative concentrations of N-nitrosamines in the livestock rearing area (26 ± 11ng/L) and industrial area (24 ± 4.8ng/L) were higher than those in the residential area (16 ± 6.3ng/L) and farmland area (15 ± 5.1ng/L). The mean concentration of N-nitrosamines in the tributaries (22ng/L) was slightly higher than that in the mainstem (17ng/L), probably due to the dilution effect of the mainstem. However, the mass loading assessment based on the river's flow and water concentrations suggested the negligible mass emission of N-nitrosamines into the mainstem from tributaries, which could be due to the small water flow of tributaries. The average mass loads of N-nitrosamines discharged into the mainstem were ranked as the livestock rearing area (742.7g/d), industrial area (558.6g/d), farmland area (93.9g/d), and residential areas (83.2g/d). In the livestock rearing, residential, and industrial area, NDMA (60.9%, 53.6%, and 46.7%) and NDBA (34.6%, 33.3%, and 44.9%) contributed the most mass loads; NDMA (23.4%), NDEA (15.8%), NPYR (10.1%), NPIP (12.8%), and NDBA (37.8%) contributed almost all the mass loads in the farmland area. Photodegradation amounts of NDMA (0.65 ~ 5.25µg/(m3·day)), NDBA (0.37 ~ 0.91µg/(m3·day)), and NDEA (0 ~ 0.66µg/(m3·day)) were also calculated according to the mass loading. Quantifying the contribution of different anthropogenic activities to the river will provide important information for regional river water quality protection. Risk quotient (RQ) values showed the negligible ecological risks for fish, daphnid, and green algae.

Simultaneous determination of heterocyclic aromatic amines and N-nitrosamines in fried bacon cubes and slices using LC-(ESI/APCI)-MS/MS

Bacon manufacturing involves several processing steps including nitrite curing, followed by cooking processes, typically frying. During these processes, harmful processing contaminants such as N-nitrosamines (NAs) and heterocyclic aromatic amines (HAAs) can be formed. Consequently, we developed and validated a multi-class method for quantification of the most frequently reported HAAs and NAs in fried bacon. Satisfactory repeatability and reproducibility with limits of quantification between 0.1 and 0.5 ng g−1 for most of the compounds were achieved. Quantification in pan-fried bacon cubes and slices revealed generally low levels of individual HAAs (≤1.5 ng g−1), except in ready-to-eat bacon (0.9–2.9 ng g−1). Differences in amounts of individual HAAs were observed in cubes and slices, most likely due to meat thickness. Among volatile NAs (VNAs), only N-nitrosopiperidine (NPIP), N-nitrosopyrolidine (NPYR), and N-nitrosodibutylamine (NDBA) were found at generally low concentrations (≤5 ng g−1). In contrast, non-volatile NAs (NVNAs) were present in all tested samples at considerably higher amounts, for example, N-nitroso-thiazolidine-4-carboxylic acid (NTCA) at 12–77 ng g−1. N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodipropylamine (NDPA) were not detected in any samples. Statistical evaluation and principal component analysis revealed some differences among tested samples. Dietary exposure estimation of the Danish population to HAAs and NAs showed the highest exposure in the teenage group (10–17 years).

N-Nitrosamines and their precursors in wastewater effluents from selected industries in Spain

N-nitrosamines (NAs), and N-nitrosodimethylamine (NDMA) in particular, are hazardous disinfection byproducts (DBPs) relevant when wastewater impacts drinking water sources and, in water reuse practices. Our study investigates the concentrations of NDMA and five additional NAs and their precursors in industrial wastewater effluents. Aiming to identify potential differences between industrial typologies, wastewaters from 38 industries belonging to 11 types of the UN International Standard Industrial Classification of All Economic Activities system (ISIC) were analysed. Results show that the presence of most NAs and their precursors cannot be linked to a specific industry type as these were in general very different within the classes. Nevertheless, N-nitrosomethylethylamine (NMEA) and N-nitrosopiperidine (NPIP) as well as precursors for N-nitrosodiethylamine (NDEA), NPIP and N-nitrosodibuthylamine (NDBA) could be rank with different concentrations between ISIC classes (p-value < 0.05). Specific industrial wastewater with notable high concentrations of NAs and their precursors were identified too. The effluents with the highest concentration of NDMA belong to the ISIC C2011 class (Manufacture of basic chemical), while the effluents with the highest concentration of NDMA precursors were from the ISIC C1511 class (Tanning and dressing of leather; dressing and dyeing of fur). Other relevant NAs found were NDEA in ISIC class B0810 (Quarrying of stone, sand, and clay) and ISIC class C2029 (Manufacture of other chemical products).

Maternal exposure to nitrosamines in drinking water during pregnancy and birth outcomes in a Chinese cohort

Maternal exposure to regulated disinfection by-products (DBPs) during pregnancy has been linked with adverse birth outcomes. However, no human studies have focused on drinking water nitrosamines, a group of emerging unregulated nitrogenous DBPs that exhibits genotoxicity and developmental toxicity in experimental studies. This cohort study included 2457 mother-infant pairs from a single drinking water supply system in central China, and maternal trimester-specific and entire pregnancy exposure of drinking water nitrosamines were evaluated. Multivariable linear and Poisson regression models were used to estimate the associations between maternal exposure to nitrosamines in drinking water and birth outcomes [birth weight (BW), low birth weight (LBW), small for gestational age (SGA) and preterm delivery (PTD)]. Elevated maternal N-nitrosodimethylamine (NDMA) exposure in the second trimester and N-nitrosopiperidine (NPIP) exposure during the entire pregnancy were associated with decreased BW (e.g., β = −88.6 g; 95% CI: −151.0, −26.1 for the highest vs. lowest tertile of NDMA; p for trend = 0.01) and increased risks of PTD [e.g., risk ratio (RR) = 2.16; 95% CI: 1.23, 3.79 for the highest vs. lowest tertile of NDMA; p for trend = 0.002]. Elevated maternal exposure of N-nitrosodiethylamine (NDEA) in the second trimester was associated with increased risk of SGA (RR = 1.80; 95% CI: 1.09, 2.98 for the highest vs. lowest tertile; p for trend = 0.01). Our study detected associations of maternal exposure to drinking water nitrosamines during pregnancy with decreased BW and increased risks of SGA and PTD. These findings are novel but require replication in other study populations.

Characteristics and health risk assessment of volatile N-nitrosamines in the plasma of adults in Guangdong Province, China

N-nitrosamines are strong carcinogens that are widely present in the environment. This study developed a method, and analyzed the concentrations of volatile N-nitrosamines (VNAs) in the plasma of adults in Guangdong Province, China. Finally, the health risks to adults in Guangdong Province, China, with dietary exposure to VNAs were assessed. Gas chromatography/mass spectrometry (GC/MS) in electron impact (EI) ionization source mode was used to quantitatively analyze VNAs, and to perform accurate mass determination. The lower limit of detection (LOD) of nine nitrosamines are ranged from 0.01 to 2.14 ng/mL. The recovery rate ranged from 83 % to 116 %, and the relative standard deviation (RSD) was < 10 %. The method developed is simple, rapid, and provides good reproducibility and high sensitivity. N-nitrosodimethylamine (NDMA), N-nitrosomethylethylamine (NMEA), N-nitrosodinbutylamine (NDBA), N-nitrosopiperidine (NPIP), N-nitrosopyrrolidine (NPYR), N-nitrosomorpholine (NMOR) and N-nitrosodiphenylamine (NDPhA) were detected in 92 adult plasma samples. NDMA and NMEA were detected in 56.5 % and 44.6 % of the samples, followed by NPIP (34.8 %). NDMA had the highest median concentration (43.7 ng/mL) in the total samples. There were gender-related differences found in the concentrations of NDBA and NDPhA. The exposure risk assessment results showed that the two highest daily dietary intakes of VNAs were N-nitrosodi-n-propylamine (NDPA) and NDMA, and aquatic products and pickled vegetables contributed the most total nitrosamine intake. The lifetime cancer risk of adults ranged from 2.88 × 10−10 to 7.46 × 10−5, and the risk associated with NDMA, NDPA, N-nitrosodiethylamine (NDEA), NMEA and NPIP are important and should attract more attention. This study aimed to explore the exposure levels of VNAs in the plasma of adults in Guangdong Province, China, and to assess the health risks of dietary intake of VNAs, which provides a basis of the effect of VNAs exposure on human health.

Studies on a novel method for the determination of nitrosamines in food by HPLC-UV-FLD coupling with terbium-doped carbon dots

In this paper, a novel, selective and sensitive high performance liquid chromatography-UV photolysis-fluorescence detection (HPLC-UV-FLD) method for nitrosamines (NAs) is proposed based on terbium-doped carbon dots (Tb-CDs). Experimental studies have shown that nitrosamines can be degraded by UV photolysis with wavelength at 254 nm to produce NO2−, while NO2− can rapidly and specifically quench the fluorescence of Tb-CDs. Based on this principle, N-nitrosodimethylamine (NDMA), Nnitrosomorpholine (NMor), N-nitrosopyrrolidine (NPYR), N-nitrosodiethylamine (NDEA) and N-nitrosopiperidine (NPIP) are separated within 8 min by HPLC. These five kinds of NAs showed a good linear relationship in the range of 10–2000 μg/L, and the limit of detection was as low as 2.25 μg/L. The proposed method is successfully applied to the detection of sweet potato, lotus root, potato, water chestnut, tomato and cucumber. The sample recoveries range from 77.35 % to 119.3 %.

Development of a fully automated analytical platform based on static headspace-gas chromatography-tandem mass spectrometry for the analysis of five N-nitrosamines in dried aquatic products of animal origin.

The development of rapid and sensitive monitoring methods for trace N-nitrosamines (NAs) in foodstuffs is essential for mitigating the potential health risks to consumers. In the present study, an analytical platform based on one step fully automated static headspace sampling and gas chromatography-tandem mass spectrometry (GC-MS/MS) was developed and validated for the analysis of N-nitrosamines in dried aquatic products of animal origin. The samples and sodium chloride solution mixture were incubated in a heated headspace vial for analyte evaporation, coupled to automatic sampling and online GC-MS/MS analysis. The proposed method requires minimal sample preparation and organic solvent consumption. Five N-nitrosamines including N-nitroso dimethylamine, N-nitroso methyl ethylamine, N-nitroso pyrolidine, N-nitroso piperidine and N-nitroso diphenylamine were selected as model compounds to optimize the significant factors by a using Box-Behnken design. The optimum conditions achieved limits of detections in the range 0.08-0.29 μg kg-1 , with correlation coefficient over 0.998. Relative recoveries in dried aquatic product sample were in the range 76.9-92.4%, with relative SDs of 1.9-7.2%. These results confirm the reliability of the developed method for further application in trace level monitoring of the target analytes in foodstuffs. © 2022 Society of Chemical Industry.

Absolute Quantitation of N-Nitrosamines by Coulometric Mass Spectrometry without Using Standards.

Carcinogenic N-nitrosamines were recently found in the sartan family of drugs and caused many drug recalls. Both of their detection and quantification are therefore important. Methods reported for N-nitrosamine quantitation rely on the use of standards and are just applicable to simple N-nitrosamines. There is an urgent need to quantify N-nitrosamines derived from drugs with a complicated structure that lack standards. To tackle the issue, this study describes a novel absolute quantitation strategy for N-nitrosamines using coulometric mass spectrometry (CMS) without standards. In our approach, N-nitrosamine is first converted into electrochemically active hydrazine via zinc reduction under acidic condition and the resulting hydrazine can then be easily quantified using CMS. To validate our method, six simple N-nitrosamines, N-nitrosodiethylamine (NDEA), N-nitroso-4-phenylpiperidine (NPhPIP), N-nitrosodiphenylamine (NDPhA), N-nitrosodibutylamine (NDBA), N-nitrosodipropylamine (NDPA), and N-nitrosopiperidine (NPIP), were chosen as test samples, and they all were quantified with excellent measurement accuracy (quantitation error ≤1.1%). Taking this one step further, as a demonstration of the method utility, a drug-like N-nitrosamine, (R)-N-(2-(6-chloro-5-methyl-1'-nitroso-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)propan-2-yl)acetamide (VII), was also synthesized and successfully quantified using our method at 15 ppb level in a complex formulation matrix, following solvent extraction, N-nitrosamine isolation, and reductive conversion. Because of the feature of requiring no standards, CMS provides a simple and powerful approach for N-nitrosamine absolute quantitation and has great potential for analysis of other drug impurities or metabolites.

Study on the levels of N-nitrosamine compounds and untargeted metabolomics in patients with colorectal cancer.

Plasma samples were collected from 34 patients with advanced CRC and 92 healthy persons (control group), and the levels of 9 VNAs were measured using GC-MS. Untargeted metabolomics analysis was performed using LC-MS/MS. Partial least squares discriminant analysis (PLS-DA) and hierarchical cluster analysis were used to determine differential metabolites between the 2 groups. Receiver operating characteristic (ROC) curve analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed on the differential metabolites. It turnedoutthatthe detection rates of N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR) in patients with CRC were higher than in the control group (P < 0.05). N-nitrosomethylethylamine (NMEA) and N-nitrosodiphenylamine (NDPhA) were not detected in CRC patients. NDMA, N-nitrosodibutylamine (NDBA), N-nitrosopiperidine (NPIP), and NPYR were detected in male and female patients with CRC. There was no difference in VNAs exposure between the sexes of CRC patients. In the positive and negative ion mode, a total of 132 differential metabolites and 6 differential metabolic pathways were detected. Adenosine 5'-monophosphate, hypoxanthine, 11,12-epoxy-(5Z,8Z,11Z)-icosatrienoic acid, 16(R)-HETE, acetylcarnitine, and lysophosphatidic acid (LPA 20:5, LPA 20:4) were candidate biomarkers with higher predictive value. Hypoxanthine and xanthine metabolic pathways were associated with changes in VNAs in CRC patients. In summary, the effects of changes of VNAs in the plasma of CRC patients (especially NDMA and NPYR) on the progression of CRC should attract attention. Abnormalities of adenine and guanine and downstream hypoxanthine-xanthine metabolic pathways were closely related to changes of VNAs and metabolomics in CRC patients.

The occurrence of volatile and non-volatile N‐nitrosamines in cured meat products from the Danish market

Several epidemiological studies emphasize the consumption of processed meat products as a risk factor of colorectal cancer, linking N-nitrosamines (NAs) formed during nitrite curing to this cancer risk. The occurrence of volatile N-nitrosamines (VNAs) has over the years been intensively studied while the knowledge on the occurrence and toxicity of non-volatile N-nitrosamines (NVNAs) is still limited. Therefore, this study focuses on quantification of both VNAs and NVNAs in a large selection of processed meat products. For this purpose, a robust, specific and sensitive method allowing analysis of seven VNAs and two NVNAs was optimized and validated using kassler, sausage, and salami. The limit of quantification achieved was 0.1–0.5 ng·g−1 for most of the VNA, and 2.3–4.2 ng·g−1 for the NVNA. In one hundred commercial samples N-nitroso-thiazolidine-4-carboxylic acid (NTCA) was the most frequently detected (97 samples) among all target NAs and it was found at concentrations ranging from 3.1 ng·g−1 to 1660 ng·g−1. The samples contained relatively low mean levels of the individual VNAs (≤1 ng·g−1). The levels of N-nitrosodimethylamine (NDMA), N-nitrosopyrrolidine (NPYR), and N-nitrosopiperidine (NPIP) ranged from non-detectable to 3.8, 10.8 and 2.9 ng·g−1, respectively. A correlation between the detected residual levels of nitrite and/or nitrate and concentrations of individual NAs could not be demonstrated. Based on principle component analysis (PCA) some correlations between salami, sausage and bacon and NAs could be shown.

Determination of dietary exposure and extraction efficiency of nitrosamine from cooked meat

Meat products are claimed to be a source of carcinogenic nitrosamines (NAs) exposure in food. In this study, dietary exposure of six nitrosamines: N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR), N-nitrosopiperidine (NPIP), N-nitrosodipropylamine (NDPA), N-nitrosodibutylamine (NDBA) were estimated by Gas chromatography method. Four types of processed beef products were collected from different restaurants of Dhaka city, Bangladesh and analyzed by Gas chromatography-Mass spectrometry (GC-MS) after extracting under different methods. Nitrosamines were extracted by three different methods: i) Ultrasonic, ii) Autoclave for 10 min, iii) Autoclave for 20 min, and mean recoveries were 73%, 85% and 62% respectively. The LOD (limit of detection) and the LOQ (limit of quantification) for the six nitrosamines were in the range of 0.05–0.3 μg/kg and 0.85–1.5 μg/kg, respectively. The total nitrosamine content in beef products were Shik kabab (20.87 μg/kg) > Burger patty (20.44 μg/kg) > Steak (15.84 μg/kg) >Chap (14.95 μg/kg). The daily dietary exposure for commonly consumed beef products ranged from 0.029 to 0.056 μg/kg body weight which was less than the limit set by World Health Organization (WHO). Simultaneous determination of six nitrosamines by Gas chromatography can be used for monitoring the content of nitrosamines in meat products to ensure food safety.

Dietary N-Nitroso Compounds and Risk of Hepatocellular Carcinoma: A USA-Based Study.

N-nitroso compounds (NOCs) are among the most potent dietary carcinogens. N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), and N-nitrosopiperidine (NPIP) are abundant in foods and carcinogenic to the liver. We investigated the relationship between dietary NOCs and HCC risk. In this large, hospital-based, case-control study of 827 pathologically or radiologically confirmed HCC cases and 1,013 controls, NOC intake was calculated by linking food frequency questionnaire-derived dietary data with a comprehensive NOC concentration database. Multivariable-adjusted ORs and 95% CIs of HCC by quartiles of NOC consumption were estimated using logistic regression models, with the lowest quartile as the referent. We further investigated joint effects of consuming the highest quartile of NOCs that were associated with increased HCC risk and hepatitis, diabetes, or alcohol drinking on HCC risk. After adjustment for confounding factors, higher intake of NDEA from plant sources (ORQ4 vs. Q1 =1.58; 95% CI=1.03-2.41), NDMA from plant sources (ORQ4 vs. Q1 =1.54; 95% CI=1.01-2.34), and NPIP (ORQ4 vs. Q1 =2.52; 95% CI=1.62-3.94) was associated with increased HCC risk. No association was observed for nitrate or total NOC intake and HCC risk. Higher consumption of HCC-inducing NOCs and positive hepatitis virus status jointly increased the risk of developing HCC. In conclusion, though some of our findings may indicate the presence of reverse causation owing to lower meat intake among cases with chronic liver diseases before HCC diagnosis, the potent dietary HCC carcinogens, NDEA, NDMA, and NPIP, and their enhanced carcinogenic effects among chronic carriers of hepatitis virus warrant further prospective investigation.

The occurrence of volatile N-nitrosamines in heat-treated sucuk in relation to pH, aw and residual nitrite.

In this study, the occurrence of volatile nitrosamines were investigated in heat-treated sucuk, a kind of semi-dry fermented sausage. The pH, aw and residual nitrite of the samples were also determined. In addition, a principal component analysis (PCA) was also performed in order to elucidate the relationship between nitrosamine and these variables. Significant differences between brands were found in terms of NDMA (N- Nitrosodimethylamine), NPYR (N-Nitrosopyrolidine) and NPIP (N-Nitrosopiperidine) (p<0.05). NDMA and NPYR varied from 1.71 to 3.57µg/kg and 1.65 to 7.29µg/kg, respectively. Higher levels were found for NPIP (5.19 to 16.40µg/kg). NDEA (N-Nitrosodiethylamine) and NDBA (N- Nitrosodibutylamine) were not found in any of the heat-treated sucuk samples. The residual nitrite content was under 10mg/kg in all samples. The aw and pH values varied between 0.913 and 0.940 and between 4.28 and 5.47, respectively. In PC1 explaining 72% of the variance, NDMA and NPYR were placed on the negative side, NPIP on the positive side. Residual nitrite and aw were more effective for NPIP, while pH was an important parameter for NDMA and NPYR.