There has been a growing concern over the contamination of pharmaceutical products with nitrosamines (NAs) such as N-nitrosodimethylamine (NDMA). To quantify NA levels in drugs using reversed-phase ...liquid chromatography (LC), the sample solution should achieve a high drug concentration to detect trace NAs, and an appropriate amount of hydrophilic NAs should be retained. However, these are difficult to achieve, and no suitable method has yet been developed. The present study was the first to develop a sample preparation method to achieve this by combining drugs with formic acid (FA), followed by the removal of active pharmaceutical ingredients (APIs) from samples via crystallization. This method was successfully applied for the sensitive quantification of eight NAs in poorly water-soluble acidic atorvastatin (ATS) and basic itraconazole (ITC) via LC–ultraviolet (LC-UV) detection. The removal rate of ITC via recrystallization exceeded 99.96 %, whereas most NAs remained as solutes. Assuming that the enhancement in ITC solubility directly translates to heightened analytical sensitivity, a > 100-fold increase in sensitivity was attained compared to conventional methodologies. This sample preparation method would be applicable to other poorly water-soluble drugs, contributing to the control of NA content in various formulations to realize the safe delivery of pharmaceuticals to patients.
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•Formic acid dissolves poorly water-soluble drugs at high concentrations.•A sample preparation method suiy for sensitive determination of trace impurities in drugs was developed.•Its sensitivity was expected to be > 100 times higher than that of the conventional method.
•Oxidized myofibrillar protein was treated with different levels of ferulic acid (FA).•FA reduced carbonyl, dityrosine, sulfhydryl and free amine contents dose-dependently.•FA promoted ...oxidation-induced loss of surface hydrophobicity and α-helix content.•FA reduced sodium nitrite and formation of 3-nitrotyrosine and N-nitrosodimethylamine.•Protein oxidation variables positively correlated with nitrozation indexes.
This study investigated the effects of ferulic acid (FA) on the oxidative stability and nitrozation of porcine myofibrillar proteins (MPs) under oxidative stress. The addition of FA significantly (P < 0.05) inhibited the formation of carbonyl and dityrosine, and reduced the sulfhydryl and free amine content compared with the oxidized MPs. Moreover, FA intensified oxidation-initiated loss of surface hydrophobicity and α-helix conformation, and enhanced protein cross-linking. A progressive quenching of MP endogenous fluorescence intensity was observed with the increase of FA concentration, and the emission wavelength showed a slight red shift. Beside, the addition of FA significantly eliminated sodium nitrite and almost completely inhibited the formation of 3-nitrotyrosine (3-NT) and N-nitrosodimethylamine (NDMA) at 200 μmol/g. Principal component analysis indicated that there were positive correlations between protein oxidation variables (carbonyl, dityrosine and surface hydrophobicity) and nitrozation indexes (3-NT and NDMA), as well as between 3-NT and NDMA. These results suggest that FA could suppress the nitration via controlling MP's oxidation.
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Direct potable reuse is becoming a feasible option to cope with water shortages. It requires more stringent water quality assurance than indirect potable reuse. Thus, the development of a ...high-rejection reverse osmosis (RO) membrane for the removal of one of the most challenging chemicals in potable reuse – N-nitrosodimethylamine (NDMA) – ensures further system confidence in reclaimed water quality. This study aimed to achieve over 90% removal of NDMA by modifying three commercial and one prototype RO membrane using heat treatment. Application of heat treatment to a prototype membrane resulted in a record high removal of 92% (1.1-log) of NDMA. Heat treatment reduced conductivity rejection and permeability, while secondary amines, selected as N-nitrosamine precursors, were still well rejected (>98%) regardless of RO membrane type. This study also demonstrated the highly stable separation performance of the heat-treated prototype membrane under conditions of varying feed temperature and permeate flux. Fouling propensity of the prototype membrane was lower than a commercial RO membrane. This study identified a need to develop highly selective RO membranes with high permeability to ensure the feasibility of using these membranes at full scale.
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•Heat-treated prototype RO membrane achieved a 92% removal of NDMA.•Rejection by the RO membrane remained stable under variable temperature and flux.•Rejection of DMA, an NDMA precursor, by the high rejection RO membrane was 99%.•However, permeability was considerably reduced by heat treatment.
N-nitrosamines are formed during different industrial processes and are of significant concern due to their carcinogenic and mutagenic properties. This study reports concentrations of N-nitrosamines ...in eight different industrial wastewater treatment plants in Switzerland and the variability of their abundance. Only four N-nitrosamines species, N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodibutylamine (NDPA) and N-nitrosomorpholine (NMOR) were above the limit of quantification in this campaign. Remarkably high concentrations (i.e. up to 975 μg NDMA/L, 90.7 μg NDEA/L, 1.6 μg NDPA/L and 710 μg NMOR/L) of these N-nitrosamines were detected at seven of eight sites. These concentrations are two to five orders of magnitude higher than those typically detected in municipal wastewater effluents. These results suggest that industrial effluents may be a major source of N-nitrosamines. Although very high concentrations of N-nitrosamine have been detected in industrial discharges, various processes in surface water can partially mitigate their concentrations (e.g. photolysis, biodegradation and volatilization) and hence the risk to human health and aquatic ecosystems. Nevertheless, there is little information on long-term effects on aquatic organisms and therefore the discharge of N-nitrosamines to the environment should be avoided until the impact on ecosystems is assessed. During winter a less efficient mitigation of N-nitrosamines can be expected (lower biological activity, less sunlight) and therefore, emphasis should be put on this season in future risk assessment studies.
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•4 N-nitrosamines out 8 were detected in the effluents of eight industrial sites.•High NDMA concentrations are released by industries (0.2–975 μg/L).•Industrial compared to municipal discharges are more important for N-nitrosamines.
: N‐nitrosamines, biogenic amines, and residual nitrites are harmful substances and are often present in cured meats. The effects of different cooking methods (boiling, pan‐frying, deep‐frying, and ...microwave) were investigated on their contents in dry‐cured sausage. The various N‐nitrosamines were isolated by a steam distillation method and analyzed by gas chromatography mass spectrometry (GC‐MS). The biogenic amines were determined after extraction with perchloric acid as dansyl derivatives by high‐performance liquid chromatography (HPLC) method. The results showed that initial dry‐cured raw sausage contained 5.31 μg/kg of total N‐nitrosamines. Cooking by deep‐frying or pan‐frying resulted in products having the highest (P < 0.05) contents, compared with boiling or microwave treatments, which were not different from the raw. Although frying increased the content of N‐nitrosodimethylamine (NDMA), N‐nitrosodiethylamine (NDEA), and N‐nitrosopyrrolidine (NPYR), it decreased the contents of histamine and cadaverine. Boiling and microwave treatments decreased the total biogenic amines significantly (P < 0.05). Residual nitrite was significantly reduced by cooking treatments. The results suggest that boiling and microwave treatments were more suitable methods for cured meat.
Practical Application: N‐nitrosamines and biogenic amines are considered potentially harmful substances to humans and often present in dry‐cured sausage. Different cooking methods may effect the content of these harmful substances. However, little information exists on the different cooking methods on dry‐cured meats.
This study investigated N-nitrosomorpholine (NMOR) genotoxicity following UVA irradiation without metabolic activation. Following UVA irradiation, the photo treated NMOR (irradiated NMOR) was ...directly mutagenic, without UVA or metabolic activation, in the Ames test. The activity was relatively stable, and approximately 79% of the activity remained after 10 days of storage at 37 °C, 4 °C, or -20 °C. Micronuclei (MN) formation was observed in HaCaT cells after treatment with irradiated NMOR without metabolic activation. The action spectrum of MN formation in response to NMOR irradiation followed the NMOR absorption curve. In vivo, MN formation was observed in the peripheral blood reticulocytes of mice injected with irradiated NMOR under the inhibition of cytochrome P450-mediated metabolism of NMOR. Volatile NMOR may attach to environmental materials and be irradiated with environmental UVA light. Photoactivated NMOR-attached air pollutants could float in the air and fall onto the human body, leading to genotoxicity induced by the irradiated NMOR.
Healthcare marketing authorization holders are undertaking widespread risk assessment activities following the discovery of dialkyl N-nitrosamines in certain drug substances and products. A ...contribution to this exercise is the kinetic modeling of the reaction of secondary amines with nitrite ion in aqueous solution and identification of conditions where this would present a risk of N-nitrosamine formation. Herein, we describe automated experimental nitrosation studies on di-n-butylamine that highlight the conservative nature of the modeling approach and support the conclusion that N-nitrosamine formation only becomes a significant risk in solution at pH < 6 and at higher concentrations of nitrite. We report kinetic modeling with an updated treatment of temperature dependence and further experimentation on di-n-butylamine demonstrating our approach to be valid. Our experimentation extends to the consideration of N-nitrosamine formation from tertiary amines, which are considered less prone to nitrosation, as the mechanism includes a dealkylative step. We show a 2 orders of magnitude reduction in the rate of formation of N-nitrosodibutylamine from tributylamine compared with di-n-butylamine for the considered pH, nitrite, and amine concentrations.
The influence of membrane characteristics on the rejection of eight N-nitrosamines was investigated using one nanofiltration (NF), one seawater reverse osmosis (SWRO) and six low pressure reverse ...osmosis (LPRO) membranes. The rejection of the two lowest molecular weight N-nitrosamines, namely N-nitrosodimethylamine (NDMA) and N-nitrosomethylethylamine (NMEA), varied in the range from 8–82% to 23–94%, respectively. In general, the rejection of NDMA and NMEA increased with decreasing membrane permeability. The impact of membrane characteristics became less important for higher molecular weight N-nitrosamines. Among the four LPRO membranes (i.e. ESPA2, LFC3, TFC-HR and 70LW) that are commonly used for water reclamation applications, similar rejections were obtained for NDMA (37–52%) and NMEA (69–82%). In addition, rejection values of NDMA and NMEA among two LPRO membranes (i.e. ESPA2 and 70LW) were almost identical when compared under variable permeate flux and feed temperature conditions. However, it is noteworthy that the ESPAB membrane could achieve very high rejection of NDMA (as high as 71%) despite having a similar permeability to the LPRO membranes. Results reported here suggest that membrane characteristics associated with permeability such as the pore size and thickness of the active skin layer can be a key factor determining N-nitrosamine rejection.
► The rejection of NDMA and NMEA by NF/RO membranes varied significantly. ► LPRO membranes show similar rejections of N-nitrosamines. ► LPRO membranes show similar rejection trends against variable operating conditions. ► The rejection of NDMA and NMEA was well correlated with the membrane permeability. ► The ESPAB membrane shows high NDMA rejection amongst LPRO membranes.
N-nitrosamines are a class of carcinogenic chemicals. Despite considerable efforts to reduce their occurrence in drinking water, drugs and animal-derived foods, there have been few reports on the ...dietary assessment of N-nitrosamines in dried aquatic products, and their potential dietary exposure risk has remained unclear. Therefore, six N-nitrosamines were investigated in dried aquatic products in this study. The target analytes were quantified by LC-MS/MS coupled with the steam distillation. Among six N-nitrosamines, N-nitrosodimethylamine (NDMA) was detected in 77.8% (154/198) of the samples with an average level of 5.84 μg/kg and 28.8% of the tested samples exceeded the limit set in Chinese National Standard for Food Safety 2762–2017. Furthermore, N-nitrosodiethylamine (NDEA) was only detected in four samples and no other classes of N-nitrosamines were detected. Expanding upon this discovery, we further evaluated the carcinogenic risk of NDMA exposure in dried aquatic products via the margin of exposure (MOE) approach. The average intake of NDMA from dried aquatic products ranged from 1.90 to 2.04 ng/kg. bw/day for the male adults and from 3.17 to 4.84 ng/kg. bw/day for the male adolescents. Based on the average exposure of NDMA, the MOE value indicated no potential carcinogenic risks for the adults. However, the MOE value for the adolescents was significantly lower than 10,000, indicating the potential carcinogenic risks. For the 95th percentile highly exposed population, their MOE values were also below 10,000, indicating an associated carcinogenic risk for all age groups. Therefore, there is an urgent need to decrease or even eliminate the contamination of NDMA in dried aquatic products.
•Investigate the occurrence of N-nitrosamines in aquatic products on a large scale.•Assess the dietary exposure of N-nitrosodimethylamine.•Report the risk of N-Nitrosodimethylamine based on bench mark dose limit and margin of exposure.
This study aims to provide longitudinal and spatial insights to the rejection of N-nitrosamines by reverse osmosis (RO) membranes during sampling campaigns at three full-scale water recycling plants. ...Samples were collected at all individual filtration stages as well as at a cool and a warm weather period to elucidate the impact of recovery and feed temperature on the rejection of N-nitrosamines. N-nitrosodimethylamine (NDMA) was detected in all RO feed samples varying between 7 and 32 ng/L. Concentrations of most other N-nitrosamines in the feed solutions were determined to be lower than their detection limits (3–5 ng/L) but higher concentrations were detected in the feed after each filtration stage. As a notable exception, in one plant, N-nitrosomorpholine (NMOR) was observed at high concentrations in RO feed (177–475 ng/L) and permeate (34–76 ng/L). Overall rejection of NDMA among the three RO systems varied widely from 4 to 47%. Data presented here suggest that the feed temperature can influence rejection of NDMA. A considerable variation in NDMA rejection across the three RO stages (14–78%) was also observed. Overall NMOR rejections were consistently high ranging from 81 to 84%. On the other hand, overall rejection of N-nitrosodiethylamine (NDEA) varied from negligible to 53%, which was considerably lower than values reported in previous laboratory-scale studies. A comparison between results reported here and the literature indicates that there can be some discrepancy in N-nitrosamine rejection data between laboratory- and full-scale studies probably due to differences in water recoveries and operating conditions (e.g. temperature, membrane fouling, and hydraulic conditions).
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•NDMA was detected in the feed of three RO plants with a range of 7–32 ng/L.•A significantly high NMOR (177–475 ng/L) was observed in the feed of an RO plant.•Of the 8 N-nitrosamines, only NDMA, NDEA, NMOR & NDBA were detected in RO permeate.•NDMA rejections varied significantly with a range of 4–47% among three RO plants.•Rejections of NDMA and NDEA can vary significantly among RO stages.
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