N-nitrosodimethylamine Research Articles

Evaluation of groundwater travel time through a multilayered aquifer using multiple tracers and a novel transport approximation

AbstractAquifer long-term replenishment (ALTR) is a managed aquifer recharge (MAR) strategy by which reclaimed water is continuously delivered by injection wells to depleted, confined aquifer systems to increase groundwater storage and increase the potentiometric surface over space and time. One implication of large-scale continuous recharge is a large radial impact and the need to quantify transport in radially extensive strata. The use of an artificial tracer can be cost-prohibitive as the radial front moves further from the injection well. This investigation employs a novel approximation for radial transport to track the radial front of recharge, injectate constituents and simulation of tracer breakthrough concentrations under transient recharge rates, variable depth-dependent flow distributions over time, and variable influent concentrations. Six constituents—sulfate, chloride, total organic carbon (TOC), fluoride, 1,4-dioxane and N-nitrosodimethylamine (NDMA)—were chosen to evaluate conservative transport and semiqualitatively assess attenuation of nonconservative constituents relative to conservative tracers. Results indicate that sulfate acted as the most effective conservative tracer for characterization of transport and travel times at the study site. The analytical model was modified to account for variable operations at the MAR demonstration facility and was effective in simulating breakthrough curves over the period of performance, particularly sulfate concentrations at a monitoring well located 104 m from the injection well. The behavior of the remaining constituents is discussed, and the qualities of an effective intrinsic tracer for future ALTR projects are identified.

Highly Sensitive and Robust LC-MS/MS Method for Determination up to 15 Small Molecule Nitrosamine Impurities in Pharmaceutical Drug Substances.

Nitrosamine impurities have been classified as probable human carcinogens for decades. These impurities were reported in water, food, tobacco, pesticides, and plastics but received attention in mid-2018 when N-nitrosodimethylamine (NDMA) was reported in valsartan drug products. Subsequently, it was revealed that several small molecule and complex nitrosamine impurities can form in any active pharmaceutical ingredient (API) or drug product in which secondary or tertiary amines are present (as API or as impurities) along with a nitrosating agent. Consequently, regulators have provided several guidelines for the risk assessment of nitrosamine formation during manufacturing, storage, or from contaminated supply chains. This has led to a demand for validated analytical methods that quantify N-nitrosamine impurities in pharmaceutical products. In this study, a highly sensitive and robust analytical method was developed and validated for quantitatively determining up to 15 small nitrosamines at low levels (0.01 ppm) in sartan drug substances. The study also suggests that this method can be extended not only to corresponding sartan drug products but could also be used as a generic screening method to test a variety of drug substances, and drug products with the minimum required optimization of method conditions.

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.

Premised research on dietary exposure to benzo[a]pyrene, acrylamide, and Nnitrosodimethylamine from common fried and grilled dishes in North Vietnam

Fried and grilled cooking methods and the widespread consumption of certain dishes may expose the population to elevated levels of potentially carcinogenic compounds, such as benzo[a]pyrene (BaP), acrylamide, and N-nitrosodimethylamine (NDMA). This study aims to quickly estimate dietary exposure to these contaminants and assess the associated carcinogenic risk for several common Vietnamese fried and grilled dishes. The concentrations of the target compounds were obtained from the study showed that BaP, NDMA, and acrylamide are the groups of substances of greatest concern. The analytical results of 235 samples of meat and meat products (grilled/fried/smoked), seafood and seafood products (grilled/fried/smoked), processed oils, and potatoes showed that 12 samples detected acrylamide in the range of 5.0 – 162.0 µg/kg found in grilled/fried dishes and 5.0 – 4605 µg/kg for fried potatoes. Additionally, 204 samples detected NDMA in all groups in the range of 0.20 – 15.0 µg/kg, and 27 samples detected BaP in the range of 5.2 – 88 µg/kg in grilled/roasted food. Combined with information on food consumption patterns to estimate dietary exposure, four age groups were divided into under 6 years old, 6 – 18 years old, 18 – 50 years old, and over 50 years old, which showed that the consumption of processed foods by age groups was very different. In particular, the age group from 6 to 50 years old was the group that consumed the most of these foods (14.1 – 140 g/day). Specifically, up to 94.4% of people interviewed ate fried meat, 88.8% ate fried seafood and 85% ate fried potatoes. Risk characterization using the margin of exposure (MOE) and Cancer Slope Factor approaches indicate that certain dishes, such as grilled/smoked meat and fish, and deep-fried foods, may pose a significant cancer risk to Vietnamese consumers.

Inhibition effect of non-contact biocontrol bacteria and plant essential oil mixture on the generation of N-nitrosamines in deli meat during storage

To reduce the risk of N-nitrosamines in deli meat products, this study formulated a novel non-contact N-nitrosamines inhibiting preservative IV (NIP-IV) consisting of biocontrol bacteria and plant essential oils (EOs) (Stenotrophomonas rhizophila SR-1 + Paenibacillus provencensis PP-2 + Bacillus subtilis CF-3+ cinnamon EO + grapefruit EO). Luncheon pork, spiced beef, and red sausage were taken as representatives of typical deli meat products and used to validate the effectiveness of NIP-IV in inhibiting N-nitroso dimethylamine (NDMA) production. The results showed that NIP-IV restrain protein degradation and lipid oxidation in deli meat products and effectively control microbial activity. Biogenic amines, such as phenethylamine, spermidine, cadaverine, and tyramine, were reduced. The conversion of nitrite to NDMA in deli meats was effectively inhibited by NIP-IV. Volatile organic compounds were the key to excellent NIP-IV non-contact preservation. Butyric acid, 3-methylbutanoic acid, benzaldehyde, d-limonene, and (E)-cinnamaldehyde were significantly negatively correlated with NDMA in deli meat products.

NDMA enhances claudin-1 and -6 expression viaCYP2E1/ROS in AGS cells

Carcinogenic N-nitroso compounds, especially N-nitroso dimethylamine, increase the risk of gastric cancer development. Cytochrome P450-2E1 metabolizes this compound, thus generating an oxidant microenvironment. We aimed to evaluate in gastric adenocarcinoma cells if its effect on CYP2E1 and ROS affects signaling pathways associated with gastric cancer oncogenesis. The impact of N- nitroso dimethylamine upon CYP2E1 and ROS activation/secretion was evaluated by the DCFDA assay protocol, TER measurements, Stat3, pSTAT3, ERK1/2, and pERK1/2 expression, claudins-1 and -6 expression, and finally mRNA values of IL-1β IL-6, IL-8 and TNFα. Our results showed that exposure to N- N-nitroso dimethylamine disrupts the regulation of Stat3 and Erk1/2, alters the expression of claudin-1 and claudin-6 tight junction proteins, and increases the secretion of pro-inflammatory cytokines. These alterations induce a continuous local inflammatory process, an event identified as a gastric cancer promoter. In summary, N-nitroso dimethylamine can disrupt cell mechanisms associated with gastric cancer oncogenesis.

Colorimetric Detection of Aqueous N-Nitrosodimethylamine via Photonitrosation of a Naphtholsulfonate Indicator.

N-Nitrosamines are contaminants found throughout the environment, including in drinking water, and many nitrosamines are likely potent carcinogens. Correspondingly, there is a need for rapid and cost-effective in-field detection methods that can provide timely information about their contamination levels in water. This study details a colorimetric assay for detecting aqueous N-nitrosodimethylamine (NDMA) by photochemical nitrosation of a commercial naphtholsulfonate, to offer an attractive alternative to traditional laboratory-based analysis. The resulting naphthoquinone-oxime coordinates to aqueous iron(II) ions to form a green complex, allowing for direct visual detection. Characterization via Mössbauer and electron paramagnetic resonance (EPR) spectroscopy, alongside single-crystal structure determination, provides comprehensive structure information on the iron indicator complex. Optimization of detection conditions, including UV irradiation and response times, led to an improved colorimetric detection method with a limit of detection of 0.66 ppm for NDMA. The practical applicability and selectivity of this colorimetric detection scheme make it a promising candidate for the development of field-deployable sensors for NDMA in environmental water samples.

Combined Toxic Effects and Mechanisms of Chloroacetic Acid and N-Nitrosodimethylamine on Submerged Macrophytes

Disinfection by-products (DBPs) such as chloroacetic acids (CAAs) and N-Nitrosodimethylamine (NDMA) are prevalent pollutants in surface waters, particularly with the increasing use of chlorine-based disinfectants. The entry of these DBPs into water bodies may increase accordingly, posing ecological risks to aquatic life. To assess the toxic effects of CAAs and NDMA on submerged macrophytes, Vallisneria natans was exposed to different concentrations of CAAs (1.0, 10.0, and 100.0 μg L−1) and NDMA (0.1, 1.0, and 10.0 μg L−1). A RI value of <1 indicates that simultaneous exposure to CAAs and NDMA can produce an antagonistic effect. Both CAAs and NDMA adversely affect the photosynthetic system of plants. In the NDMA treatment group, chlorophyll a content decreases with increasing concentration, accounting for 96.03%, 60.80%, and 58.67% of the CT group, respectively. Additionally, it effectively triggers the plant’s antioxidant response, with significant increases in SOD, POD, and GSH levels. Among these, the combined treatment group AN2 (10 + 1 μg L−1) showed the most significant change in SOD activity, reaching 3.57 times that of the CT group. Ultrastructural changes also revealed stress responses in leaf cells and damage to organelles. Furthermore, metabolomics provided insights into the metabolic responses induced by CAAs or NDMA in V. natans leaves, where the composition and metabolism of lipids, fatty acids, cofactors and vitamins, amino acids, nucleotides, and some antioxidants were regulated, affecting plant growth. This study provides preliminary information for the ecological risk assessment of submerged plants by complex contamination with the disinfection by-products CAA and NDMA.

Efficient electrochemical degradation of ranitidine by a novel Bi-coated titanium oxide electrode: Performance and mechanism

Ranitidine (RAN) is a commonly prescribed medication that poses ecological risks due to its potential to transform into the carcinogenic byproduct N-nitrosodimethylamine (NDMA) in the environment. Herein, we synthesized a novel bismuth-coated titanium oxide (Bi-Ti4O7) electrode using a straightforward coating method and evaluated its effectiveness in the electrochemical oxidation of RAN. The Bi-Ti4O7 electrode achieved a degradation efficiency of 90.41 % for an initial RAN concentration of 10 mg/L within 120 min, greatly outperforming the pristine Ti4O7 electrode. The incorporation of Bi enhances the oxygen vacancies and charge transfer characteristics, facilitating direct electron transfer between RAN and the Bi-Ti4O7 electrode. The potential degradation pathways of RAN by the Bi-Ti4O7 electrode included C–S bond cleavage, C–N bond cleavage, and electrophilic oxidation. No NDMA was generated during the oxidation process, and the toxicity of RAN oxidation intermediates was greatly reduced. The Bi-Ti4O7 electrode demonstrated excellent stability, maintaining over 90 % degradation efficiency across 30 cycles, and showed wide applicability across different pH levels and wastewater types with negligible Bi ion release (0.148 µg/L). These results underscore the potential of Bi-Ti4O7 as an effective and sustainable solution for RAN-polluted wastewater treatment.

Natural vs. anthropogenic sources of N-Nitrosodimethylamine precursors in surface water

N-nitrosodimethylamine (NDMA) is a carcinogenic disinfection byproduct formed from reactions between dichloramine and organic nitrogen-containing precursors. It is unclear if NDMA precursors in surface water intakes originate in anthropogenic (i.e., wastewater) or natural sources. The Truckee River has a single point source release of treated wastewater effluent, making it an ideal system to study the relative importance of precursor sources. Three Lagrangian sampling events were conducted. NDMA formation potential (FP, a measurement of precursors) above the wastewater outfall indicated that the natural background of NDMA precursors was 2-28 ng/L. NDMA FP increased to 18-31 ng/L immediately downstream of the wastewater outfall, but decreased rapidly in a first order manner, and were not statistically different from the upstream samples in only ∼6 km. This suggests that the dominant source of NDMA precursors may be wastewater derived only near wastewater outfalls and deviates from the previous belief that wastewater-derived precursors are responsible for NDMA formation in drinking water sources located further downstream. Additionally, given the rapid loss of the wastewater precursors in this study, precursors which are slow to biodegrade/photolyze/adsorb to sediment are likely to be poor surrogates for the overall wastewater NDMA precursor pool. To understand temporal changes in the wastewater impact on environmental NDMA precursor loading, two 24-hour sampling events were conducted near (<3 km) the wastewater outfall and demonstrated that temporal changes in the NDMA precursors directly downstream of the wastewater outfall are directly linked to the wastewater flow contribution.

Optimizing ozone treatment for pathogen removal and disinfection by-product control for potable reuse at pilot-scale

Reclaimed water poses environmental and human health risks due to residual organic micropollutants and pathogens. Ozonation of reclaimed water to control pathogens and trace organics is an important step in advanced water treatment systems for potable reuse of reclaimed water. Ensuring efficient pathogen reduction while controlling disinfection byproducts remains a significant challenge to implementing ozonation in reclaimed water reuse applications. This study aimed to investigate ozonation conditions using a plug flow reactor (PFR) to achieve effective pathogen removal/inactivation while minimizing bromate and N-Nitrosodimethylamine (NDMA) formation. The pilot scale study was conducted using three doses of ozone (0.7, 1.0 and 1.4 ozone/total organic carbon (O3/TOC) ratio) to determine the disinfection performance using actual reclaimed water. The disinfection efficiency was assessed by measuring total coliforms, Escherichia coli (E. coli), Pepper Mild Mottle Virus (PMMoV), Tomato Brown Rugose Fruit Virus (ToBRFV) and Norovirus (HNoV). The ozone CT values ranged from 1.60 to 13.62 mg min L−1, resulting in significant reductions in pathogens and indicators. Specifically, ozone treatment led to concentration reductions of 2.46–2.89, 2.03–2.18, 0.46–1.63, 2.23–2.64 and > 4 log for total coliforms, E. coli, PMMoV, ToBRFV, and HNoV, respectively. After ozonation, concentrations of bromate and NDMA increased, reaching levels between 2.8 and 12.0 μg L−1, and 28–40.0 ng L−1, respectively, for average feed water bromide levels of 86.7 ± 1.8 μg L−1 and TOC levels of 7.2 ± 0.1 mg L−1. The increases in DBP formation were pronounced with higher ozone dosages, possibly requiring removal/control in subsequent treatment steps in some potable reuse applications.

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.

N-nitrosodimethylamine removal by a novel silver/sulfur-coated nanoscale zero-valent iron/activated carbon composite: Adsorption kinetics, mechanisms, and degradation pathways

The removal of disinfection by-products from water is of critical importance to achieve the water purification. N-nitrosodimethylamine (NDMA), an emerging nitrogenous disinfection by-product produced by the chlorine-ammonia disinfection, remains significantly hazardous even at low concentrations. Herein, an activated carbon (AC)-supported nanoscale zero-valent iron (nZVI) coated with sulfur (S) and silver (Ag) composite (Ag@S-nZVI/AC) was synthesized, characterized via several techniques and evaluated for NDMA removal performance. The results demonstrated that crystalline Ag and mackinawite (FeS) coated amorphous nZVI spheres were successfully anchored on AC. The removal of NDMA at ultra-lower concentrations by the Ag@S-nZVI/AC composite was better fitted by pseudo-second-order (PSO) kinetic and Freundlich isotherm models. NDMA was chemically adsorbed in multiple layers on heterogeneous surface of the Ag@S-nZVI/AC composite via spontaneous endothermic process. The adsorption constant (KF) of NDMA removal by Ag@S-nZVI/AC at T=298 K was 9.89 times greater than that of NDMA removal by pristine AC. The van der Waals forces, hydrogen bonds and surface-mediated electron transfer were the main mechanisms responsible for the highly effective remediation of ultra-lower concentrations of NDMA from drinking water. The decomposition of NDMA was significantly enhanced by Ag@S-nZVI/AC, resulting in the generation of more dimethylamine (DMA), ammonium and the nitrogen-containing compounds. The decomposition process involved the oxidation of FeS, S and Fe0 surface as well as the hydrogenation of Ag. The post-leaching concentrations of Fe, Ag and S in treated drinking water were lower than the standard permissible limits.

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.

N-Nitrosodimethylamine formation from anthropogenic nitrogenous compounds during preozonation and post-chloramination with characteristic low treatment dose.

One effective option to minimize N-nitrosodimethylamine (NDMA) in finished drinking water is to identify and control its precursors. However, previous works to identify significant precursors use formation potential (FP) tests using high doses to assure the maximum NDMA formation rather than the NDMA formation in finished waters. In this study, we applied characteristic low treatment doses of ozone (O3)-to-dissolved organic carbon (DOC) of target compounds of 0.8mg/mg and NH2Cl of 2.5 ± 0.2mg Cl2/L to evaluate the NDMAFP yields of organic compounds bearing N,N-dimethylamine (DMA) and N,N-dimethylhydrazine (DMH) during preozonation and post-chloramination. The results in pH-buffered Milli-Q water showed a significant decrease from ≤ 52% to non-detectable levels in the O3-NDMAFP yields of O3-reactive precursors (i.e., DMH-like compounds) after preozonation and post-chloramination. Similarly, a significant decrease from 0.5 to 12% to nonquantifiable levels was observed for the NH2Cl-NDMAFP yields of NH2Cl-reactive precursors; however, the NH2Cl-NDMAFP yields of N,N-dimethylbenzylamine (DMBzA)-like compounds only decreased from ~ 110 to ≤ 43%, suggesting that these compounds could contribute to NH2Cl-NDMAFPs even after preozonation. The effect of the matrix in sewage-effluent and lake water samples varied and was specific for precursors; for example, the O3-NDMAFP yield of 1,1,1',1'-tetramethyl-4,4'-(methylene-di-p-phenylene) disemicarbazide (TMDS), an important O3-reactive NDMA precursor, did not significantly decrease when tested in sewage-effluent samples. Based on the previous occurrence concentration of TMDS in sewage samples, we estimated an NDMAFP of ~ 315 ng/L. This estimate exceeds the guidance concentrations of NDMA (3-100ng/L), highlighting the importance of TMDS and its related compounds for NDMA formation.

Effects of Inoculating Autochthonous Starter Cultures on Changes of N-Nitrosamines and Their Precursors in Chinese Traditional Fermented Fish during In Vitro Human Digestion.

The objective of this research was to investigate the impact of inoculating autochthonous starter cultures on the alterations in microorganisms, biogenic amines, nitrite, and N-nitrosamines in Chinese traditional fermented fish products (CTFPs) during in vitro human digestion. The results revealed that gastric digestion significantly (p < 0.05) inhibited the proliferation of lactic acid bacteria, yeast, Staphylococcus, and Enterobacteriaceae, whereas various microorganisms proliferated extensively during small intestine digestion. Meanwhile, small intestine digestion could significantly increase (p < 0.05) levels of putrescine, cadaverine, and tyramine. The reduced content observed in inoculated fermentation groups suggests that starter cultures may have the ability to deplete biogenic amines in this digestion stage. Gastric digestion significantly (p < 0.05) inhibited nitrite accumulation in all CTFPs samples. Conversely, the nitrite content increased significantly (p < 0.05) in all groups during subsequent small intestine digestion. However, the rise in the inoculated fermentation groups was smaller than that observed in the spontaneous fermentation group, indicating a potentially positive role of inoculated fermentation in inhibiting nitrite accumulation during this phase. Additionally, gastric digestion significantly (p < 0.05) elevated the levels of N-nitrosodimethylamine (NDMA) and N-nitrosopiperidine in CTFPs. Inoculation with L. plantarum 120, S. cerevisiae 2018, and mixed starter cultures (L. plantarum 120, S. cerevisiae 2018, and S. xylosus 135 [1:1:1]) effectively increased the degree of depletion of NDMA during this digestion process.

Bacterial dealkylation of benzalkonium chlorides in wastewater produces benzyldimethylamine, a potent N-nitrosodimethylamine precursor

N-nitrosodimethylamine (NDMA) is a carcinogenic disinfection byproduct that forms during chloramine disinfection of municipal wastewater effluents which are increasingly used to augment drinking water supplies due to growing water scarcity. Knowledge of wastewater NDMA precursors is limited and the known pool of NDMA precursors has not closed the mass balance between precursor loading, precursor NDMA yield, and formed NDMA. Benzalkonium chlorides (BACs) are the most prevalent quaternary ammonium surfactants and have antimicrobial properties. The extensive utilization of BACs in household, commercial and industrial products has resulted in their detection in wastewater at elevated concentrations. We report the formation of a potent NDMA precursor, benzyldimethylamine (BDMA) from the biodegradation of BACs during activated sludge treatment. BDMA formation and NDMA formation potential (FP) were functions of BAC and mixed liquor suspended solids concentration at circumneutral pH, and the microbial community source. Sustained exposure to microorganisms reduced NDMA FP through successive dealkylation of BDMA to less potent precursors. BAC alkyl chain length (C8 – C16) had little impact on NDMA FP and BDMA formation because chain cleavage occurred at the C–N bond. Wastewater effluents collected from three facilities contained BDMA from 15 to 106 ng/L, accounting for an estimated 4 to 38 % of the NDMA precursor pool.

New Perspectives on the Interactions between Adsorption and Degradation of Organic Micropollutants in Granular Activated Carbon Filters.

The removal of organic micropollutants in granular activated carbon (GAC) filters can be attributed to adsorption and biological degradation. These two processes can interact with each other or proceed independently. To illustrate the differences in their interaction, three 14C-labeled organic micropollutants with varying potentials for adsorption and biodegradation were selected to study their adsorption and biodegradation in columns with adsorbing (GAC) and non-adsorbing (sand) filter media. Using 14CO2 formation as a marker for biodegradation, we demonstrated that the biodegradation of poorly adsorbing N-nitrosodimethylamine (NDMA) was more sensitive to changes in the empty bed contact time (EBCT) compared with that of moderately adsorbing diclofenac. Further, diclofenac that had adsorbed under anoxic conditions could be degraded when molecular oxygen became available, and substantial biodegradation (≥60%) of diclofenac could be achieved with a 15 min EBCT in the GAC filter. These findings suggest that the retention of micropollutants in GAC filters, by prolonging the micropollutant residence time through adsorption, can enable longer time periods for degradations than what the hydraulic retention time would allow for. For the biologically recalcitrant compound carbamazepine, differences in breakthrough between the 14C-labeled and nonradiolabeled compounds revealed a substantial retention via successive adsorption-desorption, which could pose a potential challenge in the interpretation of GAC filter performance.

Metformin drugs under simulated gastric conditions can generate high nitrite-dependent levels of N-nitrosodimethylamine

N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), group 2A carcinogens, were detected in finished drug products, including metformin, ranitidine, sartans and other drugs which caused multiple recalls in the USA and Europe. Important studies also reported the formation of NDMA when ranitidine and nitrite were added to simulated gastric fluid. Our objective was to screen finished drug products from Europe and USA for nitrosamine impurities and investigate the formation of NDMA in metformin finished drug products when added to simulated gastric fluid. One dosage unit of 30 different commercially available drugs, including metformin, sartans, and ranitidine were tested for NDMA, NDEA, and dimethylformamide (DMF) impurities, using a liquid chromatography-mass spectrometry (LC–MS) method. Then, 6 metformin finished drug products were tested in stomach conditions for 2 h at 37 °C in a 100 mL solution with a pH of 2.5 and different nitrite concentrations (40, 10, 1, 0.1 mM) and tested for NDMA, and DMF using LC–MS. We measured NDMA, NDEA, and DMF in 30 finished drug products. NDMA and DMF were quantified for metformin drug products in simulated gastric fluid with different nitrite concentrations. None of the 30 drugs showed concerning levels of NDMA, NDEA, or DMF when tested as single tablets. However, when metformin tablets are added to simulated gastric fluid solutions with high nitrite concentrations (40 mM and 10 mM), NDMA can reach amounts of thousands of nanograms per tablet. At the closest concentration to physiologic conditions we used, 1 mM, NDMA is still present in the hundreds of nanograms in some metformin products. In this in vitro study, nitrite concentration had a very important effect on NDMA quantification in metformin tablets added to simulated gastric fluid. 1 mM nitrite caused an increase above the acceptable daily intake set by the U.S. Food and Drug Administration (FDA) for some of the metformin drugs. 10 mM, 40 mM nitrite solutions generated NDMA amounts exceeding by more than a hundred times the acceptable daily intake set by the FDA of 96 nanograms. These findings suggest that metformin can react with nitrite in gastric-like conditions and generate NDMA. Thus, patients taking metformin could be exposed to NDMA when high nitrite levels are present in their stomach, and we recommend including a statement within the Patient Package Inserts/Instructions for use.

The role of magnetite for enhancing reduction of N-nitrosodimethylamine by zero-valent iron

Mixed-valent iron mineral has significant effects in redox reaction and engineering applications. Magnetite (Fe3O4) combined with zero-valent iron (ZVI) were chosen to reduce N-nitrosodimethylamine (NDMA). Enhancement had been shown in ZVI-Fe3O4 system than the sum of removals of ZVI and Fe3O4 systems. Lower solution pH value facilitated the removal of NDMA, the concentration of dissolved oxygen (DO) had little effect. The main reduction products of NDMA by ZVI-Fe3O4 were 1,1-dimethylhydrazine (UDMH) and dimethylamine (DMA). The total nitrogen mass was unbalanced. By capturing the active species in the ZVI-Fe3O4 system, active hydrogen atoms had been determined. Catalytic hydrogenation was proposed to be the mechanism. Electrochemical tests showed that ZVI-Fe3O4 had a lower open circuit potential and a higher corrosion current than ZVI, the presence of Fe3O4 promoted the corrosion of ZVI. Scanning electron microscope (SEM) and X-ray diffraction (XRD) analyses of solid powders showed that the corrosion was more serious and no other substances were formed on the surface of powders in ZVI-Fe3O4 system after reaction. X-ray photoelectron spectroscopy (XPS) showed that the value of ratio of peak area of Fe(III) to Fe(II) of ZVI-Fe3O4 surfaces was lowest. The Fe(III) on the powders’ surface could be reduced by ZVI and the surface passivation of ZVI would be prevented, which would be benefit for the generation of active hydrogen atoms.