Nitrosamines are a class of carcinogens which have been detected widely in food,water,some pharmaceuticals as well as tobacco.The objectives of this paper include reviewing the basic information on tobacco consumption...Nitrosamines are a class of carcinogens which have been detected widely in food,water,some pharmaceuticals as well as tobacco.The objectives of this paper include reviewing the basic information on tobacco consumption and nitrosamine contents,and assessing the health risks of tobacco nitrosamines exposure to Chinese smokers.We searched the publications in English from“Web of Science”and those in Chinese from the“China National Knowledge Infrastructure”in 2022 and collected 151 literatures with valid information.The content of main nitrosamines in tobacco,including 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone(NNK),N-nitrosonornicotine(NNN),N-nitrosoanatabine(NAT),N-nitrosoanabasine(NAB),total tobacco-specific nitrosamines(TSNA),and N-nitrosodimethylamine(NDMA)were summarized.The information of daily tobacco consumption of smokers in 30 provinces of China was also collected.Then,the intakes of NNN,NNK,NAT,NAB,TSNAs,and NDMA via tobacco smoke were estimated as 1534ng/day,591 ng/day,685 ng/day,81 ng/day,2543 ng/day,and 484 ng/day by adult smokers in30 provinces,respectively.The cancer risk(CR)values for NNN and NNK inhalation intake were further calculated as 1.44×10^(-5)and 1.95×10^(-4).The CR value for NDMA intake via tobacco smoke(inhalation:1.66×10^(-4))indicates that NDMA is similarly dangerous in tobacco smoke when compared with the TSNAs.In China,the CR values caused by average nitrosamines intake via various exposures and their order can be estimated as the following:smoke(3.75×10^(-4))>food(1.74×10^(-4))>drinking water(1.38×10^(-5)).Smokers in China averagely suffer 200%of extra cancer risk caused by nitrosamines in tobacco when compared with non-smokers.展开更多
The presence of N-nitroso compounds,particularly N-nitrosamines,in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects.This systematic review investigates...The presence of N-nitroso compounds,particularly N-nitrosamines,in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects.This systematic review investigates their toxicity in active pharmaceutical ingredients(APIs),drug products,and pharmaceutical excipients,along with novel analytical strategies for detection,root cause analysis,reformulation strategies,and regulatory guidelines for nitrosamines.This review emphasizes the molecular toxicity of N-nitroso compounds,focusing on genotoxic,mutagenic,carcinogenic,and other physiological effects.Additionally,it addresses the ongoing nitrosamine crisis,the development of nitrosamine-free products,and the importance of sensitive detection methods and precise risk evaluation.This comprehensive overview will aid molecular biologists,analytical scientists,formulation scientists in research and development sector,and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.展开更多
Objective Nan'ao County in Guandong Province is a high-risk area of esophageal cancer in Southern China. Of the suspected etiological factors in the environment, N-nitrosamines and their precursors have received t...Objective Nan'ao County in Guandong Province is a high-risk area of esophageal cancer in Southern China. Of the suspected etiological factors in the environment, N-nitrosamines and their precursors have received the greatest attention. Methods Sixty samples of the diet ingested by the inhabitants were collected and detected for volatile N-nitrosamines and their precursors. Five N-nitrosamines detected by Gas Chromatography-Thermal Energy Analyzer were N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosopyrrolidine, N-nitrosopiperidine and N-nitrosomethyl-benzylamine. Results The average content of 5 volatile N-nitrosamines in the diet was 312.0 μg/kg (median). The daily intake of the nitrosamines was 286.5 μg/head/day. Only the ability to exogenously synthesize N-nitrosopiperidine was powerful among 5 volatile N-nitrosamines. By a computerized stepwise regression analysis and curve fitting, we studied the correlation among the nitrosamines, the precursors and the major food items in the samples. Conclusion It demonstrated that a relatively high content of volatile N-nitrosamines was present in the diet collected in the area.展开更多
An improved method was developed for the determination of the four major tobacco-specific nitrosamines（TSNAs） in mainstream cigarette smoke. The new method offers decreased sample preparation and analysis time as co...An improved method was developed for the determination of the four major tobacco-specific nitrosamines（TSNAs） in mainstream cigarette smoke. The new method offers decreased sample preparation and analysis time as compared to traditional methods. This method uses isotope dilution liquid chromatography coupled with a tandem mass spectrometer with electrospray ionization and is significantly more sensitive than traditional methods. It also shows no evidence of artifactual formation of TSNAs. Sample concentrations were determined for four TSNAs in mainstream smoke using two isotopically labeled TSNAs analogues as internal standards. Mainstream smoke was collected on an industry standard 44-ram Cambridge filter pad, extracted with 0.1 mol/L ammonium acetate, purified by solid-phase extraction, and analyzed without further sample cleanup. The analytical column is a 3.9 mm×150 mm Waters Symmertry Shield RP18 column and volume fraction of the mobile phase is 50% methanol, 50% water containing 0.1% acetic acid. The results show that the linear range is 0.5-100.0 mg/L except for N-nitrosoanabasine （NAB） from 0.25 to 50.0 mg/L. The limits of detection are 0.1 mg/L for N-nitrosonornicotine （NNN）, 0.08 mg/L for 4-（methylnitrosamino）-1- （3-py-ridyl）-1-butanone （NNK）, 0.05 mg/L for N-nitrosoanatabine （NAT） and 0.06 mg/L for NAB. The recoveries of the four TSNAs are from 90.2% to 105.7%.展开更多
Volatile nitrosamines (VNAs) are a group of compounds classified as probable (group 2A) and possible (group 2B) carcinogens in humans. Along with certain foods and contaminated drinking water, VNAs are detected at hig...Volatile nitrosamines (VNAs) are a group of compounds classified as probable (group 2A) and possible (group 2B) carcinogens in humans. Along with certain foods and contaminated drinking water, VNAs are detected at high levels in tobacco products and in both mainstream and side-stream smoke. Our laboratory monitors six urinary VNAs—N-nitrosodimethylamine (NDMA), N-nitrosomethylethylamine (NMEA), N-nitrosodiethylamine (NDEA), N-nitrosopiperidine (NPIP), N-nitrosopyrrolidine (NPYR), and N-nitrosomorpholine (NMOR)—using isotope dilution GC-MS/ MS (QQQ) for large population studies such as the National Health and Nutrition Examination Survey (NHANES). In this paper, we report for the first time a new automated sample preparation method to more efficiently quantitate these VNAs. Automation is done using Hamilton STAR<sup>TM</sup> and Caliper Staccato<sup>TM</sup> workstations. This new automated method reduces sample preparation time from 4 hours to 2.5 hours while maintaining precision (inter-run CV < 10%) and accuracy (85% - 111%). More importantly this method increases sample throughput while maintaining a low limit of detection (<10 pg/mL) for all analytes. A streamlined sample data flow was created in parallel to the automated method, in which samples can be tracked from receiving to final LIMs output with minimal human intervention, further minimizing human error in the sample preparation process. This new automated method and the sample data flow are currently applied in bio-monitoring of VNAs in the US non-institutionalized population NHANES 2013-2014 cycle.展开更多
The effects of riboflavin deficiency and simultaneously nitrosodimethylamine (NDMA) given by gastric intubation on the hepatic glutathione (GSH) content were examined in rats. On different days of the experiment, hepa...The effects of riboflavin deficiency and simultaneously nitrosodimethylamine (NDMA) given by gastric intubation on the hepatic glutathione (GSH) content were examined in rats. On different days of the experiment, hepatic GSH content of the riboflavin deficient rats decreased to 55-61% of the control rats. When NDMA was given 6 mg kg by gastric intubation to riboflavin deficient rats, hepatic GSH content decreased markedly to 39-43% of the control rats. After supplying riboflavin, hepatie GSH content of the deficient rats recovered to the level of the control rats. These results suggest that alterations of rat hepatic GSH content during riboflavin deficiency may imply as one of the promoting effects of riboflavin deficiency on the carcinogenesis of nitrosamines.展开更多
Nitrosamines are classified by IARC as Group 2B carcinogens. Usually they might be present in organic foods as products of reaction between secondary amines and nitrosation system. The aim of the study was to test the...Nitrosamines are classified by IARC as Group 2B carcinogens. Usually they might be present in organic foods as products of reaction between secondary amines and nitrosation system. The aim of the study was to test the concentration of nitrosamines in Bulgarian products. High performance liquid chromatography with UV detector was used for identification and quantitation. A standard solution of N-nitrosodiethanolamine was used as a reference substance and in the validation procedure of samples. The limit of detection of the method was determined to 14× 10^-9 g/mL. The results of the testing showed that analyzed organic foods produced in Bulgaria did not contain nitrosamines above the limit of detection of the method.展开更多
The effects of administering similar doses of some simple alkylating agents to rats by different regimens have been compared.Two of the compounds were methylating agents,nitrosodimeth- ylamine and azoxymethane;two wer...The effects of administering similar doses of some simple alkylating agents to rats by different regimens have been compared.Two of the compounds were methylating agents,nitrosodimeth- ylamine and azoxymethane;two were ethylating agents,nitrosodiethylamine and azoxyethane and nitrosomethylethylamine was both a methylating and an ethylating agent.The treatments gave rise to tumors in almost all treated rats.The results indicate the importance ofpharmacoki- netics in determining which organs are the targets of the alkylating carcinogens.1989 Academic Press.Inc.展开更多
The carcinogenic tobacco-specific nitrosamines N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) form hemoglobin adducts in laboratory animals and humans. These adducts release 4-hydr...The carcinogenic tobacco-specific nitrosamines N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) form hemoglobin adducts in laboratory animals and humans. These adducts release 4-hydroxy-l-(3-pyridyl)-l-butanone (HPB) upon mild base hydrolysis. HPB released from human hemoglobin can be quantified by gas chromatography-mass spectrometry. It is the only available biochemical marker for determination of exposure to, and metabolic activation of, carcinogens present only in tobacco. Levels of HPB were highest in snuff-dippers, followed by smokers and nonsmokers. Large interindividual variations in adduct levels were observed. The relationship between HPB levels in globin and DNA of rats treated with NNK has been investigated in order to aid in interpretation of the data from humans. These studies have provided the initial database for understanding the metabolic activation of tobacco-specific nitrosamines in humans.展开更多
The potential toxic effects of nitrate-nitrite-nitrosamine on pancreatic β cell have remained a controversial issue over the past two decades. In this study, we reviewed epidemiological studies investigated the assoc...The potential toxic effects of nitrate-nitrite-nitrosamine on pancreatic β cell have remained a controversial issue over the past two decades. In this study, we reviewed epidemiological studies investigated the associations between nitrate-nitrite-nitrosamines exposure, from both diet and drinking water to ascertain whether these compounds may contribute to development of type 1 diabetes. To identify relevant studies, a systematic search strategy of Pub Med, Scopus, and Science Direct was conducted using queries including the key words "nitrate", "nitrite", "nitrosamine" with "type 1 diabetes" or "insulin dependent diabetes mellitus". All searches were limited to studies published in English. Ecologic surveys, case-control and cohort studies have indicated conflicting results in relation to nitrate-nitrite exposure from drinking water and the risk of type 1 diabetes. A null, sometimes even negative association has been mainly reported in regions with a mean nitrate levels < 25 mg/L in drinking water, while increased risk of type 1 diabetes was observed in those with a maximum nitrate levels > 40-80 mg/L. Limited data are available regarding the potential diabetogenic effect of nitrite from drinking water, although there is evidence indicating dietary nitrite could be a risk factor for development of type 1 diabetes, an effect however that seems to be significant in a higher range of acceptable limit for nitrate/nitrite. Current data regarding dietary exposure of nitrosamine and development of type 1 diabetes is also inconsistent. Considering to an increasing trend of type 1 diabetes mellitus(T1DM) along with an elevated nitrate-nitrite exposure, additional research is critical to clarify potential harmful effects of nitrate-nitritenitrosamine exposure on β-cell autoimmunity and the risk of T1DM.展开更多
The presence of mutagenic and carcinogenic nitrosamines in water is of great concern. In this study, seven nitrosamines including N-nitrosodimethylamine （NDMA）, N-nitrosodiethylamine （NDEA）, N-nitrosomethylethylam...The presence of mutagenic and carcinogenic nitrosamines in water is of great concern. In this study, seven nitrosamines including N-nitrosodimethylamine （NDMA）, N-nitrosodiethylamine （NDEA）, N-nitrosomethylethylamine （NMEA）, N-nitrosopyrrolidine （NPyr）, N-nitrosopiperidine （NPip）, N-nitrosodi-n-propylamine （NDPA）, and N-nitrosodi-n-butyl-amine （NDBA） were investigated in river water and ground water samples collected from 5 representative cities （Jilin, Songyuan, Harbin, Jiamusi and Tongjiang） along the Songhua River. The total concentrations of nitrosamines in ground water were n.d. （not detected） to 60.8 ng/L, NDMA was the most frequently detected nitrosamines in ground water, followed by NDEA and NPip. Relatively high detected frequency and concentrations of NDMA were also observed in river water samples, and the total nitrosamines＇ concentration at midstream is always higher than that at upstream and downstream. After 24 hr chlorination, concentration of NDMA, NDBA was obviously increased but NDEA was reduced. Furthermore, UV2s4 showed a better relationship with NDMA-FP rather than dissolved organic carbon （DOC）. NI-h-N. and TDN.展开更多
Municipal wastewater discharge is considered as one of the main sources of N-nitrosamine precursors which can impact the qualities of downstream source waters and reclaimed wastewaters for potable reuse. N –Nitrosami...Municipal wastewater discharge is considered as one of the main sources of N-nitrosamine precursors which can impact the qualities of downstream source waters and reclaimed wastewaters for potable reuse. N –Nitrosamine precursors can be removed to various degrees during biological wastewater treatment(e.g., the activated sludge(AS) process). So far, little is known about the impact of the AS process on N-nitrosamine formation under practical disinfection condition(e.g., uniform formation condition(UFC)). In this study, N-nitrosamine UFC from selected model compounds, sewage components(i.e., blackwaters and greywaters) and sewage samples were comprehensively investigated during batch AS treatment tests. N –Nitrosodimethylamine(NDMA) formation from the tested precursor compounds(i.e., trimethylamine(TMA) and sumatriptan(SMTR)) under UFC chloramination decreased mostly after 6 or 24 hr treatment with different types of AS(i.e., domestic rural AS, domestic urban AS, and textile AS), and the reductions in NDMA UFC were comparable to their NDMA formation potential(FP) reductions. In urine and feces blackwaters, NDMA UFC increased after 6 or 24 hr treatment with the domestic(i.e., rural and urban) AS, while NDMA FP decreased substantially. The increases in NDMA UFC after AS treatment was presumably attributed to the removal of bulk organic matters(e.g., dissolved organic carbon(DOC)) which favored NDMA formation under UFC. On the other hand, in laundry greywaters having relatively abundant DOC, N-nitrosamine UFC was less affected by DOC removal before or after AS treatment, but decreased to similar degrees with N-nitrosamine FP. In sewage samples collected from wastewater treatment plants, N-nitrosamines UFC tended to increase or remain constant during AS treatment, despite the decreases in their FPs. These results suggest that biological wastewater treatment(e.g., the AS process) may not effectively reduce N-nitrosamine formation(e.g., measured under UFC) partially because the concurrent removal of bulk organic matters(e.g., DOC) favored N-nitrosamine formation in s econdary effluents.展开更多
The Reference Listed drug(RLD)plays a critical role in the development and research of generic medicinal products,serving as the comparator product used in the marketing authorization application of new generic medici...The Reference Listed drug(RLD)plays a critical role in the development and research of generic medicinal products,serving as the comparator product used in the marketing authorization application of new generic medicinal product and re-evaluation of generic medicinal product.In China,RLDs are sourced from various origins,but their quality and market availability can be constrained by multiple factors,including emergent issues such as nitrosamine impurities.Five classes of medicinal products have been reported to be at risk for containing nitrosamine impurities:sartan-based medicines,metformin-containing products,ranitidine medicines,rifampicin medicines,and Champix.This paper explores the control strategies implemented by drug regulatory agencies in the United States and the European Union to manage nitrosamine impurities and assesses their impact on the market availability and quality of RLDs in China.The aim is to offer valuable insights for generic drug manufacturers and regulatory bodies both domestically and internationally.展开更多
[Objectives]This study was conducted to investigate the application of Sargassum fusiforme(Harv.)Setch.in cigarettes.[Methods]Tobacco-specific nitrosamines in the smoke of cigarettes added with ethanol extract of S.fu...[Objectives]This study was conducted to investigate the application of Sargassum fusiforme(Harv.)Setch.in cigarettes.[Methods]Tobacco-specific nitrosamines in the smoke of cigarettes added with ethanol extract of S.fusiforme were determined,and the compounds related to the aroma of S.fusiforme were identified by flavor-smelling experiment.[Results]With the addition of the ethanol extract of S.fusiforme,the decrease in the total amount of four tobacco-specific nitrosamines in mainstream cigarette smoke reached 16.42%.The results of the flavor-smelling experiment showed that the aroma of S.fusiforme might be related to(R)-5,6,7,7A-tetrahydro-4,4,7A-trimethyl-2(4H)-benzofuranone,glycerol,ethyl palmitate,methyl palmitate,ethyl linoleate,methyl(Z,Z,Z)-9,12,15-octadecatrienoate,ethyl(Z,Z,Z)-9,12,15-octadecatrienoate,phytol,and tetradecanoic acid.[Conclusions]The ethanol extract of S.fusiforme has the potential function of reducing the content of tobacco-specific nitrosamines in smoke and improving the taste of cigarettes.展开更多
Background:Complementary medicine is an interesting field for extracting bio-active compounds from various plant and animal sources.The hepatoprotective effect of the methanolic extract of a species of sea cucumber ca...Background:Complementary medicine is an interesting field for extracting bio-active compounds from various plant and animal sources.The hepatoprotective effect of the methanolic extract of a species of sea cucumber called Holothuria leu-cospilota in an animal model of liver cancer caused by dimethyl nitrosamine(DMN)was studied.Methods:Wistar female rats were randomly divided into five groups(n=12):control(intact),positive control(received 1%DMN[10 mg/kg/week,intraperitoneally]for 12 weeks),and three treatment groups(received 50,100,and 200 mg/kg/day H.leu-cospilota extract orally for 12 weeks along with intraperitoneal administration of 1%DMN[10 mg/kg/week]).In all groups,ultrasound was performed on the liver every week to check its density.Blood sampling and liver isolation were performed on three occasions,at 4,8,and 12 weeks,to check liver enzymes and the histopathological condition of the liver tissue(every week,four animals from each group were randomly selected).Results:Liver density changes were evident from the eighth week onward in the positive control group.Histopathological results indicated pathologic changes in the positive control group after 4 weeks.The increase in liver enzymes in the posi-tive control group was significantly different from that in the treatment and control groups.Conclusions:We demonstrated the hepatoprotective effect of H.leucospilota on DMN-induced liver damage in rats using biochemical and histological parameters and ultrasonography.More additional research(in silico or in vitro)is needed to find the exact mechanism and the main biological compound in H.leucospilota.展开更多
INTRODUCTIONChina is a country with a high incidence of liver cancer insome areas.Liver cancer has a wide distribution andthreatens human health seriously.A rough estimationshows that out of a population of 1.2×1...INTRODUCTIONChina is a country with a high incidence of liver cancer insome areas.Liver cancer has a wide distribution andthreatens human health seriously.A rough estimationshows that out of a population of 1.2×10~8 in liver展开更多
This manuscript is reviewing the presence of substances of safety concern that may be generated in different types of meat products.Such substances include N-nitrosamines that can be generated under certain conditions...This manuscript is reviewing the presence of substances of safety concern that may be generated in different types of meat products.Such substances include N-nitrosamines that can be generated under certain conditions when using nitrite as preservative,the polycyclic aromatic hydrocarbons generated as a consequence of particular smoking processes,heterocyclic aromatic amines generated under particular cooking conditions,compounds released from the oxidation of lipids and proteins,Maillard reaction products like acrylamide and carboxymethyl lysine,and amines that can be generated and accumulated in fermented meats.These hazardous compounds,their mechanisms of generation,risks for health and ways of preventing its presence in meat products are briefly described in this review.展开更多
AIM:To investigate hepatitis virus, genetic and environmental factors, and their interactions in predisposing patients to liver diseases in Northeast India. METHODS:A total of 104 jaundice patients and 124 community c...AIM:To investigate hepatitis virus, genetic and environmental factors, and their interactions in predisposing patients to liver diseases in Northeast India. METHODS:A total of 104 jaundice patients and 124 community controls were included. Serological analysis was performed by routine enzyme-linked immunosorbent assay, and nucleic acid testing for hepatitis viruses was done by polymerase chain reaction (PCR), followed by PCR direct sequencing for viral genotyping. Cytochrome P450 2E1 (CYP2E1) polymorphism was studied by PCR-restriction fragment length polymorphism. Nitrite and volatile nitrosamines in indigenous foods consumed routinely by the Northeast Indian ethnic population were estimated by Griess’s reagent and GC-MS, respectively.RESULTS: Hepatitis A virus (HAV) infection was predominantly prevalent (36.5%) in our cohort, followed by hepatitis B virus (HBV), hepatitis E virus (HEV) andhepatitis C virus. HBV genotype D and HEV genotype 1 were the most dominant. CYP2E1 c1/c2 genotype frequency was comparatively higher in alcoholic (P<0.0001,OR =30.5) and cryptogenic (P=0.014, OR=8.714) patients, and was associated with significantly higher hepatitis risk (P=0.0.007,OR=6.489). Mutant C allele of Cyp2E1 DraⅠ frequency was comparatively higher in HAV (P=0.006), alcoholic (P =0.003) and cryptogenic (P=0.014) cases, and was associated with overall hepatitis risk (P=0.026, OR=5.083). Indigenous foods, Gundruk, Kharoli, betel leaf and nuts were found to have the highest nitrite content. CONCLUSION: Apart from viral factors, CYP2E1 polymorphism might be associated with increased risk of liver diseases in Northeast India. Indigenous foods that contain nitrite and nitrosamine might be an associated risk factor.展开更多
Reactive nitrogen oxygen species（RNOS） implicate damage in biological systems,especially leading to inflammation,neurodegenerative and cardiovascular diseases,and cancer by altering the functions of biomolecules thr...Reactive nitrogen oxygen species（RNOS） implicate damage in biological systems,especially leading to inflammation,neurodegenerative and cardiovascular diseases,and cancer by altering the functions of biomolecules through the N-nitrosation and N-nitration reactions.The mechanisms of N-nitrosation and N-nitration reactions of ammonia and dimethylamine by RNOS,i.e.,N2O3,N2O4,N2O5 and ONOOH,were investigated at the CBS-QB3 level of theory.The computational results indicate that the N-nitrosation reaction prefers a concerted mechanism,in which a H-abstraction and ON-addition occur simultaneously,whereas a stepwise mechanism（also called a free radical mechanism） is more favorable for most nitrating agents in the N-nitration reaction,where NO2 first abstracts a hydrogen atom from the nitrogen of amines and then the induced intermediate reacts with NO2 once more to form the nitration products.However,the concerted pathway is still a feasible process for some nitrating agents such as N2O5.In addition,the relationship between the structures of different RNOS and their nitrosating or nitrating abilities was also investigated.展开更多
基金supported by the National Natural Science Foundation of China(No.22076091)the Key Technology Research and Development Program of Shandong(No.2020CXGC011406)+1 种基金the Natural Science Foundation of Beijing(No.8212029)the joint project of the State Key Joint Laboratory of Environmental Simulation and Pollution Control(No.21L01ESPC)。
文摘Nitrosamines are a class of carcinogens which have been detected widely in food,water,some pharmaceuticals as well as tobacco.The objectives of this paper include reviewing the basic information on tobacco consumption and nitrosamine contents,and assessing the health risks of tobacco nitrosamines exposure to Chinese smokers.We searched the publications in English from“Web of Science”and those in Chinese from the“China National Knowledge Infrastructure”in 2022 and collected 151 literatures with valid information.The content of main nitrosamines in tobacco,including 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone(NNK),N-nitrosonornicotine(NNN),N-nitrosoanatabine(NAT),N-nitrosoanabasine(NAB),total tobacco-specific nitrosamines(TSNA),and N-nitrosodimethylamine(NDMA)were summarized.The information of daily tobacco consumption of smokers in 30 provinces of China was also collected.Then,the intakes of NNN,NNK,NAT,NAB,TSNAs,and NDMA via tobacco smoke were estimated as 1534ng/day,591 ng/day,685 ng/day,81 ng/day,2543 ng/day,and 484 ng/day by adult smokers in30 provinces,respectively.The cancer risk(CR)values for NNN and NNK inhalation intake were further calculated as 1.44×10^(-5)and 1.95×10^(-4).The CR value for NDMA intake via tobacco smoke(inhalation:1.66×10^(-4))indicates that NDMA is similarly dangerous in tobacco smoke when compared with the TSNAs.In China,the CR values caused by average nitrosamines intake via various exposures and their order can be estimated as the following:smoke(3.75×10^(-4))>food(1.74×10^(-4))>drinking water(1.38×10^(-5)).Smokers in China averagely suffer 200%of extra cancer risk caused by nitrosamines in tobacco when compared with non-smokers.
文摘The presence of N-nitroso compounds,particularly N-nitrosamines,in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects.This systematic review investigates their toxicity in active pharmaceutical ingredients(APIs),drug products,and pharmaceutical excipients,along with novel analytical strategies for detection,root cause analysis,reformulation strategies,and regulatory guidelines for nitrosamines.This review emphasizes the molecular toxicity of N-nitroso compounds,focusing on genotoxic,mutagenic,carcinogenic,and other physiological effects.Additionally,it addresses the ongoing nitrosamine crisis,the development of nitrosamine-free products,and the importance of sensitive detection methods and precise risk evaluation.This comprehensive overview will aid molecular biologists,analytical scientists,formulation scientists in research and development sector,and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.
基金The study was supported by grant of the research project of science and technology of the Provincial Higher Education Office, the Provincial Health Office and Li Ka-shing's endowment.
文摘Objective Nan'ao County in Guandong Province is a high-risk area of esophageal cancer in Southern China. Of the suspected etiological factors in the environment, N-nitrosamines and their precursors have received the greatest attention. Methods Sixty samples of the diet ingested by the inhabitants were collected and detected for volatile N-nitrosamines and their precursors. Five N-nitrosamines detected by Gas Chromatography-Thermal Energy Analyzer were N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosopyrrolidine, N-nitrosopiperidine and N-nitrosomethyl-benzylamine. Results The average content of 5 volatile N-nitrosamines in the diet was 312.0 μg/kg (median). The daily intake of the nitrosamines was 286.5 μg/head/day. Only the ability to exogenously synthesize N-nitrosopiperidine was powerful among 5 volatile N-nitrosamines. By a computerized stepwise regression analysis and curve fitting, we studied the correlation among the nitrosamines, the precursors and the major food items in the samples. Conclusion It demonstrated that a relatively high content of volatile N-nitrosamines was present in the diet collected in the area.
基金Project(2005JC02) supported by China Tobacco Hunan Industrial Corporation Limited
文摘An improved method was developed for the determination of the four major tobacco-specific nitrosamines（TSNAs） in mainstream cigarette smoke. The new method offers decreased sample preparation and analysis time as compared to traditional methods. This method uses isotope dilution liquid chromatography coupled with a tandem mass spectrometer with electrospray ionization and is significantly more sensitive than traditional methods. It also shows no evidence of artifactual formation of TSNAs. Sample concentrations were determined for four TSNAs in mainstream smoke using two isotopically labeled TSNAs analogues as internal standards. Mainstream smoke was collected on an industry standard 44-ram Cambridge filter pad, extracted with 0.1 mol/L ammonium acetate, purified by solid-phase extraction, and analyzed without further sample cleanup. The analytical column is a 3.9 mm×150 mm Waters Symmertry Shield RP18 column and volume fraction of the mobile phase is 50% methanol, 50% water containing 0.1% acetic acid. The results show that the linear range is 0.5-100.0 mg/L except for N-nitrosoanabasine （NAB） from 0.25 to 50.0 mg/L. The limits of detection are 0.1 mg/L for N-nitrosonornicotine （NNN）, 0.08 mg/L for 4-（methylnitrosamino）-1- （3-py-ridyl）-1-butanone （NNK）, 0.05 mg/L for N-nitrosoanatabine （NAT） and 0.06 mg/L for NAB. The recoveries of the four TSNAs are from 90.2% to 105.7%.
文摘Volatile nitrosamines (VNAs) are a group of compounds classified as probable (group 2A) and possible (group 2B) carcinogens in humans. Along with certain foods and contaminated drinking water, VNAs are detected at high levels in tobacco products and in both mainstream and side-stream smoke. Our laboratory monitors six urinary VNAs—N-nitrosodimethylamine (NDMA), N-nitrosomethylethylamine (NMEA), N-nitrosodiethylamine (NDEA), N-nitrosopiperidine (NPIP), N-nitrosopyrrolidine (NPYR), and N-nitrosomorpholine (NMOR)—using isotope dilution GC-MS/ MS (QQQ) for large population studies such as the National Health and Nutrition Examination Survey (NHANES). In this paper, we report for the first time a new automated sample preparation method to more efficiently quantitate these VNAs. Automation is done using Hamilton STAR<sup>TM</sup> and Caliper Staccato<sup>TM</sup> workstations. This new automated method reduces sample preparation time from 4 hours to 2.5 hours while maintaining precision (inter-run CV < 10%) and accuracy (85% - 111%). More importantly this method increases sample throughput while maintaining a low limit of detection (<10 pg/mL) for all analytes. A streamlined sample data flow was created in parallel to the automated method, in which samples can be tracked from receiving to final LIMs output with minimal human intervention, further minimizing human error in the sample preparation process. This new automated method and the sample data flow are currently applied in bio-monitoring of VNAs in the US non-institutionalized population NHANES 2013-2014 cycle.
文摘The effects of riboflavin deficiency and simultaneously nitrosodimethylamine (NDMA) given by gastric intubation on the hepatic glutathione (GSH) content were examined in rats. On different days of the experiment, hepatic GSH content of the riboflavin deficient rats decreased to 55-61% of the control rats. When NDMA was given 6 mg kg by gastric intubation to riboflavin deficient rats, hepatic GSH content decreased markedly to 39-43% of the control rats. After supplying riboflavin, hepatie GSH content of the deficient rats recovered to the level of the control rats. These results suggest that alterations of rat hepatic GSH content during riboflavin deficiency may imply as one of the promoting effects of riboflavin deficiency on the carcinogenesis of nitrosamines.
文摘Nitrosamines are classified by IARC as Group 2B carcinogens. Usually they might be present in organic foods as products of reaction between secondary amines and nitrosation system. The aim of the study was to test the concentration of nitrosamines in Bulgarian products. High performance liquid chromatography with UV detector was used for identification and quantitation. A standard solution of N-nitrosodiethanolamine was used as a reference substance and in the validation procedure of samples. The limit of detection of the method was determined to 14× 10^-9 g/mL. The results of the testing showed that analyzed organic foods produced in Bulgaria did not contain nitrosamines above the limit of detection of the method.
文摘The effects of administering similar doses of some simple alkylating agents to rats by different regimens have been compared.Two of the compounds were methylating agents,nitrosodimeth- ylamine and azoxymethane;two were ethylating agents,nitrosodiethylamine and azoxyethane and nitrosomethylethylamine was both a methylating and an ethylating agent.The treatments gave rise to tumors in almost all treated rats.The results indicate the importance ofpharmacoki- netics in determining which organs are the targets of the alkylating carcinogens.1989 Academic Press.Inc.
文摘The carcinogenic tobacco-specific nitrosamines N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) form hemoglobin adducts in laboratory animals and humans. These adducts release 4-hydroxy-l-(3-pyridyl)-l-butanone (HPB) upon mild base hydrolysis. HPB released from human hemoglobin can be quantified by gas chromatography-mass spectrometry. It is the only available biochemical marker for determination of exposure to, and metabolic activation of, carcinogens present only in tobacco. Levels of HPB were highest in snuff-dippers, followed by smokers and nonsmokers. Large interindividual variations in adduct levels were observed. The relationship between HPB levels in globin and DNA of rats treated with NNK has been investigated in order to aid in interpretation of the data from humans. These studies have provided the initial database for understanding the metabolic activation of tobacco-specific nitrosamines in humans.
基金supported by the Research Institute for Endocrine Sciences of Shahid Beheshti University of Medical Sciences
文摘The potential toxic effects of nitrate-nitrite-nitrosamine on pancreatic β cell have remained a controversial issue over the past two decades. In this study, we reviewed epidemiological studies investigated the associations between nitrate-nitrite-nitrosamines exposure, from both diet and drinking water to ascertain whether these compounds may contribute to development of type 1 diabetes. To identify relevant studies, a systematic search strategy of Pub Med, Scopus, and Science Direct was conducted using queries including the key words "nitrate", "nitrite", "nitrosamine" with "type 1 diabetes" or "insulin dependent diabetes mellitus". All searches were limited to studies published in English. Ecologic surveys, case-control and cohort studies have indicated conflicting results in relation to nitrate-nitrite exposure from drinking water and the risk of type 1 diabetes. A null, sometimes even negative association has been mainly reported in regions with a mean nitrate levels < 25 mg/L in drinking water, while increased risk of type 1 diabetes was observed in those with a maximum nitrate levels > 40-80 mg/L. Limited data are available regarding the potential diabetogenic effect of nitrite from drinking water, although there is evidence indicating dietary nitrite could be a risk factor for development of type 1 diabetes, an effect however that seems to be significant in a higher range of acceptable limit for nitrate/nitrite. Current data regarding dietary exposure of nitrosamine and development of type 1 diabetes is also inconsistent. Considering to an increasing trend of type 1 diabetes mellitus(T1DM) along with an elevated nitrate-nitrite exposure, additional research is critical to clarify potential harmful effects of nitrate-nitritenitrosamine exposure on β-cell autoimmunity and the risk of T1DM.
基金supported by the Natural Science Foundation of China (Nos. 51238001, 51508077)the Fundamental Research Funds for the Central Universities (No. 2412015KJ025)
文摘The presence of mutagenic and carcinogenic nitrosamines in water is of great concern. In this study, seven nitrosamines including N-nitrosodimethylamine （NDMA）, N-nitrosodiethylamine （NDEA）, N-nitrosomethylethylamine （NMEA）, N-nitrosopyrrolidine （NPyr）, N-nitrosopiperidine （NPip）, N-nitrosodi-n-propylamine （NDPA）, and N-nitrosodi-n-butyl-amine （NDBA） were investigated in river water and ground water samples collected from 5 representative cities （Jilin, Songyuan, Harbin, Jiamusi and Tongjiang） along the Songhua River. The total concentrations of nitrosamines in ground water were n.d. （not detected） to 60.8 ng/L, NDMA was the most frequently detected nitrosamines in ground water, followed by NDEA and NPip. Relatively high detected frequency and concentrations of NDMA were also observed in river water samples, and the total nitrosamines＇ concentration at midstream is always higher than that at upstream and downstream. After 24 hr chlorination, concentration of NDMA, NDBA was obviously increased but NDEA was reduced. Furthermore, UV2s4 showed a better relationship with NDMA-FP rather than dissolved organic carbon （DOC）. NI-h-N. and TDN.
基金Water Research Foundation (Project #4591) for their financial supports of this work。
文摘Municipal wastewater discharge is considered as one of the main sources of N-nitrosamine precursors which can impact the qualities of downstream source waters and reclaimed wastewaters for potable reuse. N –Nitrosamine precursors can be removed to various degrees during biological wastewater treatment(e.g., the activated sludge(AS) process). So far, little is known about the impact of the AS process on N-nitrosamine formation under practical disinfection condition(e.g., uniform formation condition(UFC)). In this study, N-nitrosamine UFC from selected model compounds, sewage components(i.e., blackwaters and greywaters) and sewage samples were comprehensively investigated during batch AS treatment tests. N –Nitrosodimethylamine(NDMA) formation from the tested precursor compounds(i.e., trimethylamine(TMA) and sumatriptan(SMTR)) under UFC chloramination decreased mostly after 6 or 24 hr treatment with different types of AS(i.e., domestic rural AS, domestic urban AS, and textile AS), and the reductions in NDMA UFC were comparable to their NDMA formation potential(FP) reductions. In urine and feces blackwaters, NDMA UFC increased after 6 or 24 hr treatment with the domestic(i.e., rural and urban) AS, while NDMA FP decreased substantially. The increases in NDMA UFC after AS treatment was presumably attributed to the removal of bulk organic matters(e.g., dissolved organic carbon(DOC)) which favored NDMA formation under UFC. On the other hand, in laundry greywaters having relatively abundant DOC, N-nitrosamine UFC was less affected by DOC removal before or after AS treatment, but decreased to similar degrees with N-nitrosamine FP. In sewage samples collected from wastewater treatment plants, N-nitrosamines UFC tended to increase or remain constant during AS treatment, despite the decreases in their FPs. These results suggest that biological wastewater treatment(e.g., the AS process) may not effectively reduce N-nitrosamine formation(e.g., measured under UFC) partially because the concurrent removal of bulk organic matters(e.g., DOC) favored N-nitrosamine formation in s econdary effluents.
基金Subject construction funding project of Institute for Chemical Drug Control(Grant No.2024HYZX42)in National Institutes for Food and Drug Control,Beijing,China。
文摘The Reference Listed drug(RLD)plays a critical role in the development and research of generic medicinal products,serving as the comparator product used in the marketing authorization application of new generic medicinal product and re-evaluation of generic medicinal product.In China,RLDs are sourced from various origins,but their quality and market availability can be constrained by multiple factors,including emergent issues such as nitrosamine impurities.Five classes of medicinal products have been reported to be at risk for containing nitrosamine impurities:sartan-based medicines,metformin-containing products,ranitidine medicines,rifampicin medicines,and Champix.This paper explores the control strategies implemented by drug regulatory agencies in the United States and the European Union to manage nitrosamine impurities and assesses their impact on the market availability and quality of RLDs in China.The aim is to offer valuable insights for generic drug manufacturers and regulatory bodies both domestically and internationally.
文摘[Objectives]This study was conducted to investigate the application of Sargassum fusiforme(Harv.)Setch.in cigarettes.[Methods]Tobacco-specific nitrosamines in the smoke of cigarettes added with ethanol extract of S.fusiforme were determined,and the compounds related to the aroma of S.fusiforme were identified by flavor-smelling experiment.[Results]With the addition of the ethanol extract of S.fusiforme,the decrease in the total amount of four tobacco-specific nitrosamines in mainstream cigarette smoke reached 16.42%.The results of the flavor-smelling experiment showed that the aroma of S.fusiforme might be related to(R)-5,6,7,7A-tetrahydro-4,4,7A-trimethyl-2(4H)-benzofuranone,glycerol,ethyl palmitate,methyl palmitate,ethyl linoleate,methyl(Z,Z,Z)-9,12,15-octadecatrienoate,ethyl(Z,Z,Z)-9,12,15-octadecatrienoate,phytol,and tetradecanoic acid.[Conclusions]The ethanol extract of S.fusiforme has the potential function of reducing the content of tobacco-specific nitrosamines in smoke and improving the taste of cigarettes.
文摘Background:Complementary medicine is an interesting field for extracting bio-active compounds from various plant and animal sources.The hepatoprotective effect of the methanolic extract of a species of sea cucumber called Holothuria leu-cospilota in an animal model of liver cancer caused by dimethyl nitrosamine(DMN)was studied.Methods:Wistar female rats were randomly divided into five groups(n=12):control(intact),positive control(received 1%DMN[10 mg/kg/week,intraperitoneally]for 12 weeks),and three treatment groups(received 50,100,and 200 mg/kg/day H.leu-cospilota extract orally for 12 weeks along with intraperitoneal administration of 1%DMN[10 mg/kg/week]).In all groups,ultrasound was performed on the liver every week to check its density.Blood sampling and liver isolation were performed on three occasions,at 4,8,and 12 weeks,to check liver enzymes and the histopathological condition of the liver tissue(every week,four animals from each group were randomly selected).Results:Liver density changes were evident from the eighth week onward in the positive control group.Histopathological results indicated pathologic changes in the positive control group after 4 weeks.The increase in liver enzymes in the posi-tive control group was significantly different from that in the treatment and control groups.Conclusions:We demonstrated the hepatoprotective effect of H.leucospilota on DMN-induced liver damage in rats using biochemical and histological parameters and ultrasonography.More additional research(in silico or in vitro)is needed to find the exact mechanism and the main biological compound in H.leucospilota.
基金National Natural Science Foundation of China,№48970193
文摘INTRODUCTIONChina is a country with a high incidence of liver cancer insome areas.Liver cancer has a wide distribution andthreatens human health seriously.A rough estimationshows that out of a population of 1.2×10~8 in liver
基金Grants AGL2017-89831-R,AGL2015-64673-R and FEDER funds from the Spanish Ministry of Economy,Industry and Competitiveness are acknowledged.Ramon y Cajal postdoctoral contract to LM is also acknowledged。
文摘This manuscript is reviewing the presence of substances of safety concern that may be generated in different types of meat products.Such substances include N-nitrosamines that can be generated under certain conditions when using nitrite as preservative,the polycyclic aromatic hydrocarbons generated as a consequence of particular smoking processes,heterocyclic aromatic amines generated under particular cooking conditions,compounds released from the oxidation of lipids and proteins,Maillard reaction products like acrylamide and carboxymethyl lysine,and amines that can be generated and accumulated in fermented meats.These hazardous compounds,their mechanisms of generation,risks for health and ways of preventing its presence in meat products are briefly described in this review.
基金Supported by Gauhati University,Guwahati,Assam,India
文摘AIM:To investigate hepatitis virus, genetic and environmental factors, and their interactions in predisposing patients to liver diseases in Northeast India. METHODS:A total of 104 jaundice patients and 124 community controls were included. Serological analysis was performed by routine enzyme-linked immunosorbent assay, and nucleic acid testing for hepatitis viruses was done by polymerase chain reaction (PCR), followed by PCR direct sequencing for viral genotyping. Cytochrome P450 2E1 (CYP2E1) polymorphism was studied by PCR-restriction fragment length polymorphism. Nitrite and volatile nitrosamines in indigenous foods consumed routinely by the Northeast Indian ethnic population were estimated by Griess’s reagent and GC-MS, respectively.RESULTS: Hepatitis A virus (HAV) infection was predominantly prevalent (36.5%) in our cohort, followed by hepatitis B virus (HBV), hepatitis E virus (HEV) andhepatitis C virus. HBV genotype D and HEV genotype 1 were the most dominant. CYP2E1 c1/c2 genotype frequency was comparatively higher in alcoholic (P<0.0001,OR =30.5) and cryptogenic (P=0.014, OR=8.714) patients, and was associated with significantly higher hepatitis risk (P=0.0.007,OR=6.489). Mutant C allele of Cyp2E1 DraⅠ frequency was comparatively higher in HAV (P=0.006), alcoholic (P =0.003) and cryptogenic (P=0.014) cases, and was associated with overall hepatitis risk (P=0.026, OR=5.083). Indigenous foods, Gundruk, Kharoli, betel leaf and nuts were found to have the highest nitrite content. CONCLUSION: Apart from viral factors, CYP2E1 polymorphism might be associated with increased risk of liver diseases in Northeast India. Indigenous foods that contain nitrite and nitrosamine might be an associated risk factor.
基金supported by the National Natural Science Foundation of China (No 20672011)Beijing Natural Science Foundation (No 2092008)Beijing Nova Program (No 2008B09)
文摘Reactive nitrogen oxygen species（RNOS） implicate damage in biological systems,especially leading to inflammation,neurodegenerative and cardiovascular diseases,and cancer by altering the functions of biomolecules through the N-nitrosation and N-nitration reactions.The mechanisms of N-nitrosation and N-nitration reactions of ammonia and dimethylamine by RNOS,i.e.,N2O3,N2O4,N2O5 and ONOOH,were investigated at the CBS-QB3 level of theory.The computational results indicate that the N-nitrosation reaction prefers a concerted mechanism,in which a H-abstraction and ON-addition occur simultaneously,whereas a stepwise mechanism（also called a free radical mechanism） is more favorable for most nitrating agents in the N-nitration reaction,where NO2 first abstracts a hydrogen atom from the nitrogen of amines and then the induced intermediate reacts with NO2 once more to form the nitration products.However,the concerted pathway is still a feasible process for some nitrating agents such as N2O5.In addition,the relationship between the structures of different RNOS and their nitrosating or nitrating abilities was also investigated.
