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Comparative Biochemistry and... Mar 2024N-nitrosodimethylamine (NDMA), one of the new nitrogen-containing disinfection by-products, is potentially cytotoxic, genotoxic, and carcinogenic. Its potential...
N-nitrosodimethylamine (NDMA), one of the new nitrogen-containing disinfection by-products, is potentially cytotoxic, genotoxic, and carcinogenic. Its potential toxicological effects have attracted a wide range of attention, but the mechanism is still not sufficiently understood. To better understand the toxicological mechanisms of NDMA, zebrafish embryos were exposed to NDMA from 3 h post-fertilization (hpf) to 120hpf. Mortality and malformation were significantly increased, and hatching rate, heart rate, and swimming behavior were decreased in the exposure groups. The result indicated that NDMA exposure causes cardiac and spinal developmental toxicity. mRNA levels of genes involved in the apoptotic pathway, including p53, bax, and bcl-2 were significantly affected by NDMA exposure. Moreover, the genes associated with spinal and cardiac development (myh6, myh7, nkx2.5, eph, bmp2b, bmp4, bmp9, run2a, and run2b) were significantly downregulated after treatment with NDMA. Wnt and TGF-β signaling pathways, crucial for the development of diverse tissues and organs in the embryo and the establishment of the larval spine, were also significantly disturbed by NDMA treatment. In summary, the disinfection by-product, NDMA, exhibits spinal and cardiac developmental toxicity in zebrafish embryos, providing helpful information for comprehensive analyses and a better understanding the mechanism of its toxicity.
Topics: Animals; Zebrafish; Dimethylnitrosamine; Larva; Embryo, Nonmammalian; Heart
PubMed: 38158031
DOI: 10.1016/j.cbpc.2023.109823 -
Journal of Applied Toxicology : JAT Aug 2023N-Nitrosamines are potent carcinogens and considered non-threshold carcinogens in various regulatory domains. However, recent data indicate the existence of a threshold...
N-Nitrosamines are potent carcinogens and considered non-threshold carcinogens in various regulatory domains. However, recent data indicate the existence of a threshold for genotoxicity, which can be adequately demonstrated. This aspect has a critical impact on selecting the methodology that is applied to derive occupational exposure limits (OELs). OELs are used to protect workers potentially exposed to various chemicals by supporting the selection of appropriate control measures and ultimately reducing the risk of occupational cancer. Occupational exposures to nitrosamines occur during manufacturing processes, mainly in the rubber and chemical industry. The present study derives OELs for inhaled N-nitrosamines, employing the benchmark dose (BMD) approach if data are adequate and read-across for nitrosamines without adequate data. Additionally, benchmark dose lower confidence limit (BMDL) is preferred and more suitable point-of-departure (PoD) to calculate human health guidance values, including OEL. The lowest OEL (0.2 μg/m ) was derived for nitrosodiethylamine (NDEA), and nitrosopiperidine (NPIP) (OEL = 0.2 μg/m ), followed by nitrosopyrrolidine (NPYR) (0.4 μg/m ), nitrosodimethylamine (NDMA), nitrosodimethylamine (NMEA), and nitrosodipropylamine (NDPA) (0.5 μg/m ), nitrosomorpholine (NMOR) (OEL = 1 μg/m ), and nitrosodibutylamine (NDBA) (OEL = 2.5 μg/m ). Limits based on "non-threshold" TD50 slope calculation were within a 10-fold range. These proposed OELs do not consider skin absorption of nitrosamines, which is also a possible route of entry into the body, nor oral or other environmental sources. Furthermore, we recommend setting a limit for total nitrosamines based on the occupational exposure scenario and potency of components.
Topics: Humans; Carcinogens; Dimethylnitrosamine; Benchmarking; Nitrosamines; Diethylnitrosamine; Occupational Exposure
PubMed: 36840679
DOI: 10.1002/jat.4455 -
Georgian Medical News Sep 2023The purposeful oblivion of the objective truth, the disregard of scientific reality, the denial of the contributions and successes of surrounding researchers, the...
NITROSOGENESIS, ANTIDEPRESSANTS AND THE SERTRALIN INDUCED NEVUS ASSOCIATED CUTANEOUS MELANOMA: THE NDMA/ NNK (NDSRIS) CONTAMINATION AS MOST POTENT MELANOMA INDUCTORS: ALEA IACTA EST.
The purposeful oblivion of the objective truth, the disregard of scientific reality, the denial of the contributions and successes of surrounding researchers, the substitution of priorities in clinical routine and the unwillingness to reason in the right direction often lead to disastrous consequences in the field of public health. Controlled projects almost never lead to a significant contribution or breakthrough in medicine that will be remembered by future generations. Another illustrative example in this regard is the link shared above to the saga of the worldwide cancer pandemic and its possible real cause: the contamination of drugs with nitrosamines/NDSRIs. The carcinogenic action of nitrosamines in rats under experimental conditions was demonstrated as early as the early 1960s (1954) by Barnes and Magee. The series of subsequent experiments in their numerous research studies was strongly indicative of a pathogenetic role of nitrosamines / dimethylnitrosamine / in the development of liver cancer and kidney cancer. Starting from the fact that contact with nitrosamines is of primary importance for the development of tumours in animals, there is practically no circumstance that would lead us to believe that the intake of the same mutagens in man would have a different carcinogenic effect from that already known to us (as was found under experimental conditions as early as 1954, but in animals). On the contrary, to this day the incidence of cancer is increasing every year and, according to global statistics, it is projected to increase by nearly 50% or 18 million new cases by 2040. The intake of (un)identified nitrosamines found in drugs as contaminants is increasing analogously to the shared breakneck cancer incidence. In addition to the number of identified carcinogens or NDSRIs, the number of affected drug classes is also progressively growing and in mid-2023 this number amounts to over 250 drugs according to the official data of the FDA bulletin of 08.04.2023. In practice, the population/patients have been in a continuous, still ongoing, multicentric prospective study since 1954. The parameters of the ˝experiment˝ are probably pre-set, crystallizing gradually over time and imposed forcefully in the form of hypnotic suggestions and directives by regulators. Encouragingly , the results of the prospective study are also available, are not one-sided and have been published in dozens of international journals as well as in part in the well-known Cancer Journal of the clinicians / Impact factor 254,7. The bad news is that in most of these observations and results, there is no correlation of what is shared between, say, 1) mandatory alternative-free intake of mutagen-contaminated drugs and 2) the breakneck development of heterogeneous cancers/including melanomas, and the scientific vision of the studies is currently rather one-sided. Cancer incidence is skyrocketing (according to Globocan/Cancer Journal for the Clinicians), and not a single worldwide study has commented on its potential link to actual contamination of the most commonly used drugs worldwide with nitrosamines/NDSRIs. For the past 5 years, the team of the Bulgarian Society of Dermatological Surgery has been committed to formalizing the final results of these prospective nationwide observational studies and providing full transparency on the relationship between the intake of actual/potential nitrosamine-contaminated drugs and the development of skin cancer. Over 95% of newly reported skin cancers during this period (2016-2023) were associated with prior intake of drugs listed in the 2023 FDA as potentially nitrosamine/NDSRIs contaminated or carcinogens. Melanoma is one of the most significant patterns of tumor arising after contact of the human body with nitrosamines. Whether the drugs affected by the contamination are from the group of sartans, beta blockers, hydrochlorothiazide, calcium antagonists, ACE inhibitors or antidepressants- the ultimate side effect remains the same and is known to the scientific community as or by the frightening and loud name : melanoma. We report the occurrence of another case of nevus associated cutaneous melanoma and multiple dysplastic nevi after taking the antidepressant Sertraline. A drug declared according to the official FDA bulletin of 08.04.2023 as potentially contaminated with class 2 nitrosamines/ NDSRIs: having similar to completely identical carcinogenic potency as that of NDMA and NNK. Or reciprocal to that in valsartan, irbesartan, olmesartan, repeatedly described already as possible melanoma inducers. According to the literature search, this is also the first case in the world of Sertraline-induced nevus associated cutaneous melanoma, and we share the view/ thesis that the real inducer of the tumor is in fact the impurities in the medication in the form of contaminants or nitrosamines: the so-called NDSRIs. The nitrosogenesis of skin cancer is a more than significant concept that has been cleverly concealed by the scientific community until recently. The reason for this concealment could be sought in the paramount importance or central role that the nitrosogenesis occupies at the base of the "pyramid" guaranteeing billions of dollars of monthly revenue to the regulators of globalism.
Topics: Humans; Rats; Animals; Melanoma; Skin Neoplasms; Prospective Studies; Sertraline; Nitrosamines; Carcinogens; Nevus; Nevus, Pigmented; Antidepressive Agents; Melanoma, Cutaneous Malignant
PubMed: 37991956
DOI: No ID Found -
Journal of Chromatographic Science Apr 2024N-nitrosamine pollutants are probable carcinogens. Regulatory agencies declared their presence in the drugs unsafe for human consumption and demanded their recall. Using...
An Analytical Method for Determining N-Nitrosodimethylamine and N-Nitrosodiethylamine Contamination in Irbesartan, Olmesartan and Metformin by UPLC-APCI-MS/MS in Tablet Dosage Form.
N-nitrosamine pollutants are probable carcinogens. Regulatory agencies declared their presence in the drugs unsafe for human consumption and demanded their recall. Using ultra-performance liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry (UPLC-APCI-MS/MS) in tablet dosage form based on International Conference on Harmonization (ICH) tripartite guideline criteria, we aim to develop and test a new approach for identifying and validating nitrosamine-contaminants, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in irbesartan, olmesartan and metformin. The column was Phenomenex Luna-C18, 100 × 3.0 mm and 3.0 μm. A mobile gradient phase of formic acid in either water or methanol separated the impurities. NDMA and NDEA had retention times of 0.85 and 2.55 min, respectively. The detector's linearity was established at concentrations ranging from 0.6 to 100 ng/mL. R2 for NDMA and NDEA were 0.9996 and 0.9998, respectively, with a linear response function established at 0.6-100 ng/mL. Limit of detection and limit of quantification for NDMA and NDEA were 0.35, 0.29 and 0.55, 0.37 ng/mL, respectively. On average, recovery rates for NDMA and NDEA ranged from 96.0 to 98.4 and 96.2 to 98.0%, respectively. The relative standard deviation for NDMA and NDEA was 3.46 and 2.69, respectively. According to the ICH guidelines, the developed method was quick, sensitive and valid. The pharmaceutical formulations of irbesartan, olmesartan and metformin may be regularly examined using the approach provided here.
Topics: Irbesartan; Tandem Mass Spectrometry; Chromatography, High Pressure Liquid; Metformin; Reproducibility of Results; Linear Models; Dimethylnitrosamine; Drug Contamination; Limit of Detection; Tablets; Tetrazoles; Diethylnitrosamine; Imidazoles
PubMed: 37622601
DOI: 10.1093/chromsci/bmad068 -
Chemical & Pharmaceutical Bulletin 2024The recent discovery of N-nitrosodimethylamine (NDMA), a mutagenic N-nitrosamine, in pharmaceuticals has adversely impacted the global supply of relevant pharmaceutical...
The recent discovery of N-nitrosodimethylamine (NDMA), a mutagenic N-nitrosamine, in pharmaceuticals has adversely impacted the global supply of relevant pharmaceutical products. Contamination by N-nitrosamines diverts resources and time from research and development or pharmaceutical production, representing a bottleneck in drug development. Therefore, predicting the risk of N-nitrosamine contamination is an important step in preventing pharmaceutical contamination by DNA-reactive impurities for the production of high-quality pharmaceuticals. In this study, we first predicted the degradation pathways and impurities of model pharmaceuticals, namely gliclazide and indapamide, in silico using an expert-knowledge software. Second, we verified the prediction results with a demonstration test, which confirmed that N-nitrosamines formed from the degradation of gliclazide and indapamide in the presence of hydrogen peroxide, especially under alkaline conditions. Furthermore, the pathways by which degradation products formed were determined using ranitidine, a compound previously demonstrated to generate NDMA. The prediction indicated that a ranitidine-related compound served as a potential source of nitroso groups for NDMA formation. In silico software is expected to be useful for developing methods to assess the risk of N-nitrosamine formation from pharmaceuticals.
Topics: Nitrosamines; Ranitidine; Gliclazide; Indapamide; Dimethylnitrosamine; Pharmaceutical Preparations
PubMed: 38296559
DOI: 10.1248/cpb.c23-00550 -
Environmental Science & Technology Sep 2023The Crow River, a tributary of the Mississippi River in Minnesota, U.S.A., that is impacted by agricultural activities and municipal wastewater discharges, was sampled...
Spatiotemporal Variability in -Nitrosodimethylamine Precursor Levels in a Watershed Impacted by Agricultural Activities and Municipal Wastewater Discharges and Effects of Lime Softening.
The Crow River, a tributary of the Mississippi River in Minnesota, U.S.A., that is impacted by agricultural activities and municipal wastewater discharges, was sampled approximately monthly at 12 locations over 18 months to investigate temporal and spatial variations in -nitrosodimethylamine (NDMA) precursor levels. NDMA precursors were quantified primarily by measuring NDMA formed under the low chloramine dose uniform formation conditions protocol (NDMA) and occasionally using the high dose formation potential protocol (NDMA). Raw water NDMA concentrations (2.2 to 128 ng/L) exhibited substantial temporal variation but relatively little spatial variation. An increase in NDMA was observed for 126 of 169 water samples after lime-softening treatment. A kinetic model indicates that under chloramine-limited UFC test conditions, the increase in NDMA can be attributed to a decrease in competition between precursors and natural organic matter (NOM) for chloramines and reduced interactions of precursors with NOM. NDMA concentrations correlated positively with dissolved nitrogen concentration (ρ = 0.44, < 0.01) when excluding the spring snowmelt period and negatively correlated with dissolved organic carbon concentration (ρ = -0.47, < 0.01). Overall, NDMA precursor levels were highly dynamic and strongly affected by lime-softening treatment.
Topics: Dimethylnitrosamine; Wastewater; Water Softening; Water
PubMed: 37671798
DOI: 10.1021/acs.est.3c01767 -
Journal of Food and Drug Analysis Mar 2024Liver fibrosis occurs due to injury or inflammation, which results in the excessive production of collagen and the formation of fibrotic scar tissue that impairs liver...
Liver fibrosis occurs due to injury or inflammation, which results in the excessive production of collagen and the formation of fibrotic scar tissue that impairs liver function. Despite the limited treatment options available, freshwater clams may hold promise in the treatment of liver fibrosis. In this study, we demonstrated the effects of ethanol extract of freshwater clam (FCE), ethyl acetate extract of FCE (EA-FCE), and trans-2-nonadecyl-4-(hydroxymethyl)-1,3-dioxolane (TNHD) on liver fibrosis induced by dimethylnitrosamine (DMN). Administration of FCE and TNHD alleviated liver injury, including tissue damage, necrosis, inflammation scores, fibrosis scores, serum enzymes, and triglyceride levels. Furthermore, we analyzed the expression of fibrosis-related proteins, such as α-smooth muscle actin (α-SMA) and transforming growth factor (TGF-β), as well as the hydroxyproline content, which decreased after treatment with FCE and TNHD. Animal experiments revealed that FCE and TNHD can reduce liver fibrosis by inhibiting cytokines that activate stellate cells and decreasing extracellular matrix (ECM) secretion. Cell experiments have shown that TNHD inhibits the MAPK/Smad signaling pathway and TGF-β1 activation, resulting in a reduction in the expression of fibrosis-related proteins. Therefore, freshwater clam extracts, particularly TNHD, may have potential therapeutic and preventive effects for the amelioration of liver fibrosis.
Topics: Animals; Dimethylnitrosamine; Liver Cirrhosis; Bivalvia; Inflammation; Dioxolanes
PubMed: 38526593
DOI: 10.38212/2224-6614.3491 -
Chemosphere Oct 2023The use of reverse osmosis (RO) for water reclamation has become an essential part of the water supply owing to the ever-increasing water demand and the utmost...
The use of reverse osmosis (RO) for water reclamation has become an essential part of the water supply owing to the ever-increasing water demand and the utmost performance of the RO membranes. Despite the global RO implementation, its inferior rejection against low molecular weight contaminants of emerging concerns (CECs) (i.e., N-nitrosodimethylamine (NDMA)) and propensity to fouling remain bottle-neck thus affecting process robustness for water reuse. This study aims to enhance both the rejection and antifouling properties of the RO membrane. Herein for the first time, we report RO membrane modification using polydopamine nanospheres (PDA) followed by aminated-graphene oxide (AGO) deposition as an effective approach to overcome these challenges. The modification of the RO membrane using PDA-AGO resulted in 89.3 ± 2.7% rejection compared to the pristine RO membrane which demonstrated 69.2 ± 2.1% NDMA rejection. This significant improvement can be ascribed to the plugging and shielding of defective areas (formed during interfacial polymerization) of the polyamide layer through active PDA and AGO layers and to the added sieving mechanism that arose through narrow channels of the AGO owing to its reduction. Moreover, the in-situ and non-destructive fouling monitoring using optical coherence tomography (OCT) revealed that the PDA-AGO coating enhanced both the anti-scaling and anti-biofouling characteristics. The improved hydrophilicity and bactericidal effect together with roughness and surface charge suppression synergistically enhanced anti-fouling properties. This study provides a new direction for safe and cost-effective water reuse practices. The membrane with high selectivity against CECs such as NDMA has the potential to eliminate permeate staging using second pass RO and other advanced oxidation processes which are utilized as a tertiary treatment to make reclaimed water suitable for potable/non-potable application.
Topics: Dimethylnitrosamine; Biofouling; Nanospheres; Osmosis; Water Purification; Membranes, Artificial; Water
PubMed: 37478994
DOI: 10.1016/j.chemosphere.2023.139557 -
AAPS PharmSciTech Jan 2024Between February 2020 and January 2022, the Food and Drug Administration (FDA) recalled 281 metformin extended-release products due to the presence of...
Between February 2020 and January 2022, the Food and Drug Administration (FDA) recalled 281 metformin extended-release products due to the presence of N-nitrosodimethylamine (NDMA) above the acceptable daily intake (ADI, 96 ng/day). Our previous studies indicated presence of NDMA levels above ADI in both metformin immediate and extended-release products. When metformin products have NDMA impurities, it is indispensable to check for the same impurities in metformin combination products. Therefore, the objective of the present study was to evaluate in-use stability of commercial metformin combination products for NDMA. For this purpose, metformin products in combination with glyburide (GB1-GB12), glipizide (GP1-GP8), pioglitazone (P1-P3), alogliptin (A1, A2), and linagliptin (L1, L2) were repacked in pharmacy vials, stored at 30°C/75% RH for 3 months, and monitored for NDMA impurity. The NDMA level varied from 0 to 156.8 ± 32.8 ng/tablet initially and increased to 25.4 ± 5.1 to 455.0 ± 28.4 ng/tablet after 3 months of exposure to in-use condition. Initially, 18 products have NDMA level below ADI limit before exposure which decreased to 7 products (GB5, GP3, GP5, A1, A2, L1, and L2) meeting specification. In conclusion, in-use stability study provides quality and safety risk assessment of drug products where nitroso impurities are detected in the probable condition of use.
Topics: United States; Humans; Nitrosamines; United States Food and Drug Administration; Dimethylnitrosamine; Metformin; Tablets
PubMed: 38267707
DOI: 10.1208/s12249-023-02724-3 -
Chemosphere Feb 2024The contribution of ozonation to the formation of particulate nitrosodi-methylamine (NDMA) in the aqueous aerosol phase was investigated using measurement data from 2018...
The contribution of ozonation to the formation of particulate nitrosodi-methylamine (NDMA) in the aqueous aerosol phase was investigated using measurement data from 2018 in Seoul, Republic of Korea and a box model. The correlation between the NDMA concentration and aerosol liquid water content and box model results showed that aqueous aerosol phase reactions, including nitrosation and ozonation, might contribute to the formation of NDMA. The concentration of NDMA and the ratio of O/dimethylamine exhibited a negative correlation, suggesting that the contribution of ozonation to NDMA formation may not be significant. Furthermore, when the daily concentration of NDMA exceeded 10 ng/m, the pH was 3.96 ± 0.48, indicating that the impact of ozonation on NDMA concentration might not be significant. To quantitatively investigate the contribution of ozonation, the ozonation mechanism that forms NDMA was included in the box model developed in our previous study. The model results showed that the ozonation contributed to the ambient concentration of NDMA (7.9 ± 3.8% (winter); 1.9 ± 3.0% (spring); 10.0 ± 0.77% (summer); 3.6 ± 7.3% (autumn)). It is estimated that the relatively higher O/NO ratio in summer (1.63 ± 0.69; 0.64 ± 0.52 (winter); 1.14 ± 0.92 (spring); 0.52 ± 0.54 (autumn)) could enhance ozonation and that relatively lower pH in summer (2.2 ± 0.4; 5.3 ± 1.2 (winter); 3.9 ± 1.2 (spring); 3.9 ± 0.7 (autumn)) could hinder nitrosation compared to that in other seasons.
Topics: Dimethylnitrosamine; Ozone; Hydrogen-Ion Concentration; Water Pollutants, Chemical; Methylamines; Water; Atmosphere; Aerosols; Water Purification
PubMed: 38008293
DOI: 10.1016/j.chemosphere.2023.140794