Contribution of liquid water content (LWC) to the levels of the carcinogenic particulate nitro(so) compounds and the chemistry affecting LWC were investigated based on the observation of seven nitrosamines and two nitramines in rural (Seosan) and urban (Seoul) area in South Korea during October 2019 and a model simulation. The concentrations of both the total nitrosamines and nitramines were higher in Seosan (12.48 ± 16.12 ng/m³ and 0.65 ± 0.71 ng/m³, respectively) than Seoul (7.41 ± 13.59 ng/m³ and 0.24 ± 0.15 ng/m³, respectively). The estimated LWC using a thermodynamic model in Seosan (12.92 ± 9.77 μg/m³) was higher than that in Seoul (6.20 ± 5.35 μg/m³) mainly due to higher relative humidity (75 ± 9% (Seosan); 62 ± 10% (Seoul)) and higher concentrations of free ammonia (0.13 ± 0.09 μmol/m³ (Seosan); 0.08 ± 0.01 μmol/m³ (Seoul)) and total nitric acid (0.09 ± 0.07 μmol/m³ (Seosan); 0.04 ± 0.02 μmol/m³ (Seoul)) in Seosan while neither fog nor rain occurred during the sampling period. The relatively high concentrations of the particulate nitrosamines (>30 ng/m³) only observed probably due to the higher LWC (>10 μg/m³) in Seosan. It implies that aqueous phase reactions involving NO₂ and/or uptake from the gas phase enhanced by LWC could be promoted in Seosan. Strong correlation between the concentrations of nitrosodi-methylamine (NDMA), an example of nitrosamines, simulated by a kinetic box model including the aqueous phase reactions and the measured concentration of NDMA in Seosan (R = 0.77; 0.37 (Seoul)) indicates that the aqueous phase reactions dominantly enhanced the NDMA concentrations in Seosan. On the other hand, it is estimated that the formation of nitrosamines by aqueous phase reaction was not significant due to the relatively lower LWC in Seoul compared to that in Seosan. Furthermore, it is presumed that nitramines are mostly emitted from the primary emission sources. This study implies that the concentration of the particulate nitrosamines can be promoted by aqueous phase reaction enhanced by LWC.

N-nitrosamines (NAs) are an emerging group of disinfection by-products that occur as a mixture in drinking water. Although the potency of the individual NA components in drinking water is negligible, their combined effect is rarely reported. We tested whether multicomponent NAs mixtures at environmentally relevant levels would produce significant effects when each component was combined at extremely low concentrations i.e. a million times lower than its No Observed Effect Concentration (NOEC). Mixture L (the maximum values detected in drinking water) or mixture M (one order of magnitude higher than detected) were fed to male and female Sprague-Dawley (SD) rats since PND 28 for seven days. We found that the body weight gains and the triglyceride (TG) levels increased significantly in mixture M treated male rats. Correspondingly, an obesogenic microbiota profile was obtained in the mixture M treated young male rat: Firmicutes/Bacteroidetes and the obesity-related taxa including Alistipes, Ruminococcus were enriched. Collectively, this is the first in vivo demonstration of NAs mixtures at environmentally relevant levels. Despite the complicated relationship between gut microbiota and obesity, our study has demonstrated that changes in gut microbiota may contribute to the development of obesity after the exposure. Our results highlight that changes in gut microbiota could be a risk factor for obesity, which emphasizes the need to include gut microbiota in the traditional mammalian risk assessment.

Nitrosamines, as ubiquitous environmental carcinogens with adverse impact on human health, were crucial inducers of esophageal cancer (EC). Esophageal inflammation (EI) was an important biological process and considered to be associated with the progression of EC. However, the underlying regulatory mechanism of EI process caused by nitrosamines exposure remained largely unclear. In this study, a metabolomics approach based on mass spectrometry was utilized to explore the effect of nitrosamines exposure to ICR mice. Also, the changes of pivotal metabolic enzyme levels, urinary nitrosamines and histopathological analysis were evaluated. The results showed that nitrosamines exposure was intimately interrelated with EI process in mice. Metabolomics profiling analysis indicated that nitrosamines caused significant alterations of metabolic pathway predominantly enriched in fatty acid metabolism. Targeted metabolomics analysis revealed that nitrosamines promoted decomposition of fatty acids and facilitated fatty acid β-oxidation (FAO) of mice. The significant increase of carnitine palmitoyltransferase 1 (CPT1) and downregulation of acetyl-CoA acyltransferase 2 (ACAA2) would promote FAO in EI process induced by nitrosamines. Additionally, the exposure levels of more than half of nitrosamines in urine were correlated with inflammatory fatty acid biomarkers. Overall, this study found that EI triggered by nitrosamines may be associated with the promotion of FAO, and provided novel insights for evaluating the underlying mechanism of environmental pollutant-caused toxicity based on metabolomics.

Nitrate, nitrite, and nitrosamines intake from the diet creates human health risks. In this study, nitrate/nitrite intake from diet and its association with nitric oxide (NO) level in humans have been surveyed. Besides nitrate/nitrite, nitrosamines risks were also determined from the diet. This study was conducted as a pilot study; 33 heathy adults participated in and completed the Food Frequency Questionnaire (FFQ) for 3 days. Then, concentrations of nitrate, nitrite, and nitrosamines were studied by the literature review. Also, the association between the intake of nitrate and nitrite with salivary and urinary NO was evaluated by Bayesian bi-variate analysis. Then, the health risk was assessed for nitrate/nitrite from food groups and drinking water, and nitrosamines from food groups based on hazard index (HI) and cancer risk with the Monte Carlo simulation. The nitrate/nitrite intakes had no association with NO level in the saliva and urine samples. The mean of HI value for the mean of 3 days was 3.57 and 0.32 from food groups and drinking water, respectively. The cancer risk amount of nitrosamines from food groups was (1.74 to 2.22) × 10⁻³ based on 95% confidence interval (CI 95%) values. This study showed the Iranian diet had a high risk, but drinking water consumption was safe based on nitrate/nitrite and nitrosamines for humans. There is a need to determine the concentration of nitrosamines in drinking water in Iran and to recommend for decrease risk of nitrate, nitrite, and nitrosamines exposure by food groups.

A method that utilizes solid-phase microextraction (SPME) coupled with gas chromatography (GC) and chemical ionization tandem mass spectrometry (MS/MS) was developed for analyzing a group of emerging pollutants, N-nitrosamines, in water. The developed analytical method requires a water sample of less than 5 ml and only 1.5 h for complete analysis. The method detection limits for N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine, and N-nitrosodi-n-propylamine were in the range of 3.2 to 3.5 ng/l; for N-nitrosomorpholine, it was 15.2 ng/l. The method was successfully employed to measure the N-nitrosamine concentration at trace levels of nanogram per liter in four water treatment plants (WTPs) and one water distribution system. In the WTPs, only NDMA was detected in the treatment processes. Within the treatment train, NDMA was observed after chlorination. The level of NDMA significantly declined after slow sand filtration due presumably to microbial degradation. The NDMA concentration collected from consumer tap water was about 40% higher on average than that in the finished water. The excellent performance of the SPME/GC/MS/MS method in various water matrices as well as the shorter analysis time and smaller sample volume compared to currently used extraction techniques makes it an alternative means for the analysis of N-nitrosamine in drinking water, wastewater, and laboratory research with small reactors.

A myriad of tobacco-associated chemicals may have possibilities to developmental/reproductive axis and endocrine-disruption impacts. Mostly they breach the biotransformation of cholesterol in mitochondria by interfering with steroidogenic pathway genes, prompting to adverse effects in steroid biosynthesis; however, studies are scanty. The quantitative structure–activity relationship (QSAR) modeling and comparative docking strategies were used to understand structural features of dataset compounds that influence developmental/reproductive toxicity and estrogen and androgen receptor–binding abilities, and to predict binding levels of toxicants with steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (CYP11A1) active sites. Developed QSAR models presented good robustness and predictive ability that were determined from the applicability domain and, clustering and classification of chemicals by performing self-organizing maps. Accordingly, the exorbitant amount of polycyclic aromatic hydrocarbons (PAHs) and a limited number of other chemicals including N-nitrosamines and nicotine was represented as potential developmental/reproductive toxicants as well as estrogen and androgen receptor binders. From the docking analysis, hydrogen bonding, nonpolar, atomic π-stacking, and π-cation interactions were found between PAHs (bay and fjord structural pockets) and functional hotspot residues of StAR and CYP11A1, which strengthened the subtle structural changes at domains. These govern barrier effects to cholesterol binding and/or locking cholesterol to complicate its ejection from the Ω1 loop of StAR, and further mitigates steroid biosynthesis through cholesterol by CYP11A1; therefore, they are presumably considered as block-cluster mechanisms. These outcomes are significant to be hopeful to estimate developmental/reproductive toxicity and endocrine-disruption activities of other environmental pollutants, and could be useful for further assessment to discover binding mechanisms of PAHs with other steroidogenesis pathway genes.

Studies have shown that environmental carcinogens exerted an important function in the high incidence of esophageal cancer (EC). Nitrosamines have been identified as important environmental carcinogens for EC. This study aimed to investigate the metabolic disturbances and new key toxicological markers in the malignant transformation process of normal esophageal epithelial cells (Het-1A) induced by MNNG (N-methyl-N′-nitro-N-nitrosoguanidine). Untargeted metabolomic and lipidomic profiling analysis by using ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS) were applied to explore the metabolic network alterations of Het-1A cells. The metabolomic results showed that significant alterations were observed in metabolic signatures between different generations (P5, P15, P25, P35) and the control cell group (P0). A total of 48 differential endogenous metabolites were screened and identified, mainly containing fatty acids, amino acids, and nucleotides. The differential metabolites were predominantly linked to the pathway of biosynthesis of unsaturated fatty acids metabolism. The cell lipidomic profiling revealed that the most differential lipids contained fatty acids (FAs), phosphatidylcholines (PC), phosphatidylethanolamines (PE), and phosphatidylserines (PS). The enrichment of the lipidomic pathway also confirmed that the lipid metabolism of biosynthesis of unsaturated fatty acids was the significant variation during the cell malignant transformation. Furthermore, we detected the expression of the upstream regulatory enzymes related to the unsaturated fatty acids to explore the regulation mechanism. The expression of stearoyl-CoA desaturase (SCD), ELOVL fatty acid elongase 1 (ELOVL1) promoted, and fatty acid desaturase 1 (FADS1) inhibited the key fatty acids of unsaturated fatty acids metabolism compared to the control cell group. Overall, our results revealed that lipid fatty acid metabolism was involved in the malignant transformation of Het-1A cells induced by MNNG and deepened the awareness of the carcinogenic mechanism of environmental exposure pollutants.

Approximately 99.1% of South Koreans have access to drinkable tap water from river basins. Due to such a high access rate, the South Korean government has been running, since 2013, a long-term program for monitoring the quality of tap water for drinking. Under this program, the maximum allowed concentrations of N-nitroso-di-n-methylamine (NDMA) and N-nitrosomethylethylamine (NMEA) are defined and applied. In this study, the data from this monitoring program were used to investigate the changes in six N-nitrosamine substances in the finished water of 33 drinking water treatment plants (DWTPs) in South Korea from 2013 to 2020, based on time and location. The effect of the applied water treatment steps on the appearance of N-nitrosamines was analyzed. The excess cancer risk (ECR) due to the oral intake of these substances was assessed. The results before the maximum allowed concentrations of NDMA and NMEA were defined showed that the oral intake ECR of these substances exceeded the carcinogenesis risk of one per one million people per year. After the maximum allowed concentrations of the substances were applied, the concentrations of the substances in the finished water of the DWTPs significantly dropped. The drinking water treated through sand filtration, and then with granular activated carbon, showed the highest efficiency in preventing the appearance of NDMA. Considering the potency of N-nitrosamines in tap water for drinking, the levels of these substances in the finished water of DWTPs in South Korea should be continuously monitored.

Chloramination of drinking water and wastewater can generate carcinogenic nitrosamines, among which, nitrosodipropylamine (NDPA) with large molecular weight and weak polarity has been commonly found. However, knowledge on the formation of NDPA remains highly limited. Laboratory tests were conducted to quantify NDPA formation during chloramination of nitrogenous precursors, including dipropylamine and methyldipropylamine, and pesticides such as trifluralin, oryzalin, and vernolat. Results showed that all precursors exhibited > 10.0% NDPA yields after 24 h. Oryzalin and trifluralin accomplished the highest (13.63%) and lowest (11.31%) yield, respectively. Maximal yields of all precursors were observed at pH 9.0 and temperature 288 K. Maximums of NDPA yield from oryzalin (18.27%) and vernolat (19.54%) were formed at Cl:N of 0.7:1.0, but maximal yields of dipropylamine (18.44%), methyldipropylamine (22.98%), and trifluralin (33.06%) were achieved at Cl:N of 1.2:1.0. Maximal NDPA yields of dipropylamine (37.14%), methyldipropylamine (32.84%), and vernolat (49.02%) were observed at [NH₂Cl]₀:[precursor]₀ = 500, but highest yields of trifluralin (30.24%) and oryzalin (25.53%) were accomplished at [NH₂Cl]₀:[precursor]₀ = 50. Bromide and organic contents in tap and raw water reduced NDPA due to competition for NH₂Cl. Chloramination of water impacted by amines and pesticides should be careful of NDPA formation.

Since nitrosamine disinfection by products is highly carcinogenic, they have attracted considerable attention due to their increased presence in ambient waterways and potable water supplies. For the present study, the potential formation of nitrosamines from corresponding precursor secondary amines during ozonation was investigated. The results revealed that five nitrosamines were observed during the ozonation of their corresponding secondary amines. The molar yields initially increased and then decreased with longer contact times and higher ozone doses. These phenomena indicated that ozone not only promoted nitrosamine formation but also degraded the formed nitrosamines. High pH had a positive influence on nitrosamine formation at room temperature. Further, coexisting substances including nitrate, nitrite, humic acid, and tert-butanol inhibited the generation of nitrosamines due to hydroxyl radical (·OH) competition and scavengers, whereas in the presence of hydroxylamine, nitrosamine formation increased considerably without ozone due to its capacity for independent formation between secondary amines and hydroxylamine. Further, the generation of nitrosamines from secondary amines was primarily attributed to O₃ and ·OH oxidation, which was produced through the decomposition of ozone. The transformation pathways were mainly comprised of the indirect routes between the O₃/·OH intermediates. The findings of this study were helpful toward expanding the knowledge of nitrosamine formation during the corresponding precursor secondary amine ozonation process.