Health risk assessment of N-nitrosodimethylamine in drinking water in Nanjing, Jiangsu Province / 环境与职业医学

Background N-nitrosodimethylamine (NDMA), a new disinfection by-product in drinking water, has attracted extensive attention due to its high detection rate and concentration. Objective To investigate the concentration of NDMA in drinking water in Nanjing situated in the lower Yangtze River Basin of China, and to evaluate associated human health risk. Methods In dry period (January–March) and wet period (July–September) of 2021, raw water, finished water, and tap water from 16 centralized water treatment plants in Nanjing were collected to detect the concentration of NDMA in water samples by solid phase extraction and gas chromatography-triple quadrupole mass spectrometry with programmable temperature vaporizer-based large volume injection. The concentrations of NDMA in water samples of different water types, water periods, and disinfection methods were analyzed, and the daily exposure levels and carcinogenic risk values of NDMA in drinking water of different exposure routes and different exposed populations were calculated. Monte Carlo simulation was implemented with Crystal Ball 11 software to establish a health risk assessment model and conduct sensitivity analysis. Results A total of 61 drinking water samples were collected in Nanjing, and NDMA was positive in all the water samples, with concentrations ranging from 1.36 to 25.65 ng·L−1 and an overall average concentration of (8.00±4.06) ng·L−1. There were no statistically significant differences in the average concentrations of NDMA among raw water, finished water, and tap water samples (F=2.875, P=0.064), between wet season and dry season (t=−0.855, P=0.397), or among different disinfection methods by liquid chlorine, sodium hypochlorite, and chlorine dioxide (F=0.977, P=0.385). The results of health risk assessment showed that the average carcinogenic risk of NDMA and its P95 were 5.95×10−6 and 1.12×10−5 respectively for oral intake of drinking water, and the values for dermal contact were both lower than 1.00×10−6. The mean carcinogenic risks of exposure to drinking water NDMA in children, adolescents, and adults were 1.84×10−6, 8.27×10−7, and 3.28×10−6, respectively. The results of sensitivity analysis showed that the contributions of daily drinking water volume and NDMA concentration in drinking water to the calculated health risk were high, and the contribution of body weight was negative. Conclusion There is a potential carcinogenic risk of NDMA in the drinking water of Nanjing section of the lower Yangtze River Basin，but it is within the acceptable range.

Distribution and health risk assessment of N-nitrosodimethylamine in urban drinking water in China / 环境与职业医学

Background Nitrosamines, especially N-nitrosodimethylamine (NDMA), are highly carcinogenic and frequently detected in drinking water systems in China, indicating potential human health risk through drinking water. Objective This study aims to analyze the distribution of NDMA in urban drinking water around China and to evaluate relevant human health risk, thus providing recommendations for drinking water safety standards. Methods The database of China National Knowledge Infrastructure was searched using nitrosamines and drinking water as key words in Chinese, and PubMed was searched usingN-nitrosodimethylamine or nitrosodimethylamine or NDMA, drinking water, and China as key words in English for relevant literature published from January 1, 2000 to March 1, 2021. Eligible data were extracted to statistically analyze the spatiotemporal exposure levels of NDMA in raw and finished water serving Chinese cities. According to the health risk assessment model for carcinogens recommended by the United States Environmental Protection Agency (US EPA), the cancer risk via drinking water of NDMA in finished water was evaluated for different age groups and different regions. Results A total of 102 studies were retrieved, 21 of which met the inclusion criteria and were finally included. The NDMA concentrations in 347 raw water samples and 276 finished water samples were extracted and studied, with positive rates of 82.4% and 67.0%, levels of not detected (ND)-141 and ND-67.1 ng·L−1, and the 95th quantiles of 51.4 and 32.1 ng·L−1, respectively. The level of NDMA in raw water was higher than that in finished water in cities of East and North China (P<0.05). East China had the highest average concentrations of NDMA in raw and finished water (21.4 and 9.0 ng·L−1 respectively). In East China, the average concentrations of NDMA in raw and finished water from 2018 to 2019 (5.9 and 6.1 ng·L−1 respectively) were significantly lower than those from 2015 to 2017 (28.7 and 16.5 ng·L−1 respectively) (P<0.05). The average concentration of NDMA in rivers, lakes, ponds, and streams as drinking water sources (20.8 ng·L−1) was significantly higher than that in groundwater sources (8.0 ng·L−1) and in reservoir sources (6.5 ng·L−1) (P<0.05). The average concentration of NDMA in finished water with pre-chlorination (9.4 ng·L−1) was higher than that without (6.0 ng·L−1) (P<0.05). The cancer risk of NDMA through drinking water for children over 1 year old in China decreased with older age, and the risk of infants aged 1~<2 years (2.52×10−4) was 23 times higher than that of adults (1.09×10−5) (P<0.05). Conclusion Raw water pollution is the main source of NDMA in urban drinking water in China, and current water treatment technology can partially remove NDMA. The NDMA level in finished water of East China shows a downward trend in recent two years. The carcinogenic risk of NDMA via drinking water for children is higher than that for adults, and their health risk management needs to be strengthened. The study findings recommend 35 ng·L−1 as the limit of NDMA water quality safety standard in China.

Metformin and nitrosamine impurities

Metformin is considered as gold standard anti-diabetic drug and is the preferred initial pharmacologic agent for most of the patients with type 2 diabetes mellitus. Metformin is cheap, widely available and safe, backed by pharmaco-epidemiological evidence of more than 60 years regular use in clinical practice. Due to its durable efficacy, once initiated, metformin will be continued as long as it is tolerated and not contraindicated.  It has got additional benefits on cholesterol, liver, cardio vascular system and cancer. Recent evidence and recall of metformin extended release formulation due to detection of excess amount of cancer-causing nitrosamine impurities has created concern among health care providers and patients. Adherence to regulatory guidelines and use of approved technologies in manufacturing and quality control may help in solving the issue.

Development of Urinary Bladder Pre-Neoplasia by Schistosoma haematobium Eggs and Chemical Carcinogen in Mice

Schistosoma haematobium is a biocarcinogen of human urinary bladder (UB). The present study investigated developing UB cancer mouse model by injecting S. haematobium eggs into the bladder wall and introduction of chemical carcinogens. Histopathological findings showed mild hyperplasia to epithelial vacuolar change, and high grade dysplasia. Squamous metaplasia was observed in the S. haematobium eggs+NDMA group at week 12 but not in other groups. Immunohistochemistry revealed significantly high expression of Ki-67 in urothelial epithelial cells of the S. haematobium eggs+BBN group at week 20. The qRT-PCR showed high expression of p53 gene in S. haematobium eggs group at week 4 and S. haematobium eggs+BBN group at week 20. E-cadherin and vimentin showed contrasting expression in S. haematobium eggs+BBN group. Such inverse expression of E-cadherin and vimentin may indicate epithelial mesenchymal transition in the UB tissue. In conclusion, S. haematobium eggs and nitrosamines may transform UB cells into squamous metaplasia and dysplasia in correlation with increased expression of Ki-67. Marked decrease in E-cadherin and increase in p53 and vimentin expressions may support the transformation. The present study introduces a promising modified animal model for UB cancer study using S. haematobium eggs.

Relationship between N-nitrosodimethylamine and risk of digestive tract cancers: a Meta analysis based on cohort studies / 中华流行病学杂志

Objective To analyze the relationship between N-nitrosodimethylamine (NDMA) and the risk of digestive tract cancers.Methods The papers about the relationship between NDMA and the risk of digestive tract cancers published from 1980 to 2012 were retrieved following databases:Chinese BioMedical Literature Database (CBM),the Chinese Journal Full-text Database (CNKI),Wanfang Database,PubMed and EBSCO.The fix and random effect model was used and statistical analyses were conducted by using RevMan 5.1 software.Results Thirteen papers were found,in which 7 about digestive tract cancers were used in this Meta analysis.The NDMA had significant positive effect on the incidence of digestive tract cancers (RR=1.12,95％ CI:1.03-1.21).The relationship between NDMA and esophageal cancer was not significant (RR =1.18,95 ％CI:0.98-1.41) but NDMA could increase the risk of gastric cancer (RR=1.08,95％ CI:1.00-1.18).For the subtypes of esophageal and gastric cancer,NDMA had positive relationship with esophageal squamous cell carcinoma (RR=l.72,95％ CI:1.01-2.96),but had no significant relationship with esophageal adenocarcinoma,cardiac carcinoma and gastric adenocarcinoma.Conclusion The population-based cohort studies have showed that the NDMA could significantly increase the risk of digestive tract cancers,but the effects differed with subtypes of esophageal and gastric cancer.However,it is necessary to collect more evidence due to the limited studies and obvious differences in the study design,sampling and exposure measurement of these cohort studies.

Relationship between N-nitrosodimethylamine and risk of digestive tract cancers: a Meta analysis based on cohort studies / 中华流行病学杂志

Objective To analyze the relationship between N-nitrosodimethylamine (NDMA) and the risk of digestive tract cancers.Methods The papers about the relationship between NDMA and the risk of digestive tract cancers published from 1980 to 2012 were retrieved following databases:Chinese BioMedical Literature Database (CBM),the Chinese Journal Full-text Database (CNKI),Wanfang Database,PubMed and EBSCO.The fix and random effect model was used and statistical analyses were conducted by using RevMan 5.1 software.Results Thirteen papers were found,in which 7 about digestive tract cancers were used in this Meta analysis.The NDMA had significant positive effect on the incidence of digestive tract cancers (RR=1.12,95％ CI:1.03-1.21).The relationship between NDMA and esophageal cancer was not significant (RR =1.18,95 ％CI:0.98-1.41) but NDMA could increase the risk of gastric cancer (RR=1.08,95％ CI:1.00-1.18).For the subtypes of esophageal and gastric cancer,NDMA had positive relationship with esophageal squamous cell carcinoma (RR=l.72,95％ CI:1.01-2.96),but had no significant relationship with esophageal adenocarcinoma,cardiac carcinoma and gastric adenocarcinoma.Conclusion The population-based cohort studies have showed that the NDMA could significantly increase the risk of digestive tract cancers,but the effects differed with subtypes of esophageal and gastric cancer.However,it is necessary to collect more evidence due to the limited studies and obvious differences in the study design,sampling and exposure measurement of these cohort studies.

Role of ERK1/2 Kinase in the expression of iNOS by NDMA in human neutrophils.

Potential role of ERK1/2 kinase in conjunction with p38 in the regulation of inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, and superoxide anion generation by human neutrophils (PMNs) exposed to N-nitrosodimethylamine (NDMA) was determined. Increased synthesis of NO due to the involvement of iNOS in neutrophils exposed to NDMA was observed. In addition, intensified activation of ERK1/2 and p38 kinases was determined in these cells. Inhibition of kinase regulated by extracellular signals (ERK1/2) pathway, in contrast to p38 pathway, led to an increased production of NO and expression of iNOS in PMNs. Moreover, as a result of inhibition of ERK1/2 pathway, a decreased activation of p38 kinase was observed in neutrophils, while inhibition of p38 kinase did not affect activation of ERK1/2 pathway in these cells. An increased ability to release superoxide anion by the studied PMNs was observed, which decreased after ERK1/2 pathway inhibition. In conclusion, in human neutrophils, ERK1/2 kinase is not directly involved in the regulation of iNOS and NO production induced by NDMA; however, the kinase participates in superoxide anion production in these cells.

A STUDY OF INHIBITING EFFECT OF ORDINARY VEGETABLES ON THE FORMATION OF N-NITROSO COMPOUNDS / 营养学报

The inhibiting effect of 11 kinds of ordinary vegetables including eggplant, cucumber, Chinese cabbage, fresh kidney bean, tomato, paprika, spinach, carrot, onion and celery on the formation of N-nitroso compounds was studied. Most vegetables inhibited the formation of N-nitrosodimethylamine when am-inopyrine and nitrite added to the vegetable juice and citric acid buffer were incubated in a model system simulated stomach condition (pH 3.00, T 37℃) for 1 hr. The inhibiting rate related to the contents of ascorbic acid in the vegetables ranged from 32.70% to 97.61%. Onion, fresh kidney bean, spinach and eggplant inhibited the formation of N-nitrosodimethylamine effectively with the inhibiting rate of 77.91%, 73.40%, 57.48% and 30.75% respectively (the inhibiting effect of ascorbic acid contained in the vegetables had been excluded). The relationship between the dose and the inhibiting effect of onion, fresn kidney bean, spinach and eggplant was good with the correlation coeffecient 0.756, 0.917, 0.607 and 0.801 (p