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Journal of Toxicology and Environmental... Sep 1976The effects of piperonyl butoxide (PB) on the metabolism and toxicity of dimethylnitrosamine (DMN) in Swiss mice were determined. PB, at doses of 10 and 20 mg/kg,...
The effects of piperonyl butoxide (PB) on the metabolism and toxicity of dimethylnitrosamine (DMN) in Swiss mice were determined. PB, at doses of 10 and 20 mg/kg, inhibited DMN demethylase 45 min after treatment by 18 and 37%. These inhibitory effects were marked 0.5 hr after PB (640 mg/kg) treatment and reached maximal effects at 2 hr when there was 55% inhibition of enzyme activity. The inhibition by PB continued for 24 hr where enzyme activity was suppressed by 35%. At 48 hr after treatment there was stimulation of enzyme activity. Enzyme kinetic determinations showed no change in Km but Vmax decreased from 129 to 49 mumol CH2O/min-g liver. PB (640 mg/kg) inhibited DMN (500 mg/kg; im) mutagenicity in the host-mediated assay, decreasing the mutant frequency by 42%. Paradoxically, PB (640 mg/kg) had no effect on the alkylation of nucleic acids or proteins in mouse liver, kidney, lung, or spleen. In addition, pretreatment with PB (640 mg/kg) had no effect on the LD50 of DMN.
Topics: Alkylation; Animals; Dimethylnitrosamine; Lethal Dose 50; Liver; Male; Methyltransferases; Mice; Mice, Inbred ICR; Mutagens; Nitrosamines; Piperonyl Butoxide; Time Factors
PubMed: 994247
DOI: 10.1080/15287397609529418 -
Mutation Research 2007Disinfection by-products (DBPs) are formed when disinfectants (chlorine, ozone, chlorine dioxide, or chloramines) react with naturally occurring organic matter,... (Review)
Review
Disinfection by-products (DBPs) are formed when disinfectants (chlorine, ozone, chlorine dioxide, or chloramines) react with naturally occurring organic matter, anthropogenic contaminants, bromide, and iodide during the production of drinking water. Here we review 30 years of research on the occurrence, genotoxicity, and carcinogenicity of 85 DBPs, 11 of which are currently regulated by the U.S., and 74 of which are considered emerging DBPs due to their moderate occurrence levels and/or toxicological properties. These 74 include halonitromethanes, iodo-acids and other unregulated halo-acids, iodo-trihalomethanes (THMs), and other unregulated halomethanes, halofuranones (MX [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone] and brominated MX DBPs), haloamides, haloacetonitriles, tribromopyrrole, aldehydes, and N-nitrosodimethylamine (NDMA) and other nitrosamines. Alternative disinfection practices result in drinking water from which extracted organic material is less mutagenic than extracts of chlorinated water. However, the levels of many emerging DBPs are increased by alternative disinfectants (primarily ozone or chloramines) compared to chlorination, and many emerging DBPs are more genotoxic than some of the regulated DBPs. Our analysis identified three categories of DBPs of particular interest. Category 1 contains eight DBPs with some or all of the toxicologic characteristics of human carcinogens: four regulated (bromodichloromethane, dichloroacetic acid, dibromoacetic acid, and bromate) and four unregulated DBPs (formaldehyde, acetaldehyde, MX, and NDMA). Categories 2 and 3 contain 43 emerging DBPs that are present at moderate levels (sub- to low-mug/L): category 2 contains 29 of these that are genotoxic (including chloral hydrate and chloroacetaldehyde, which are also a rodent carcinogens); category 3 contains the remaining 14 for which little or no toxicological data are available. In general, the brominated DBPs are both more genotoxic and carcinogenic than are chlorinated compounds, and iodinated DBPs were the most genotoxic of all but have not been tested for carcinogenicity. There were toxicological data gaps for even some of the 11 regulated DBPs, as well as for most of the 74 emerging DBPs. A systematic assessment of DBPs for genotoxicity has been performed for approximately 60 DBPs for DNA damage in mammalian cells and 16 for mutagenicity in Salmonella. A recent epidemiologic study found that much of the risk for bladder cancer associated with drinking water was associated with three factors: THM levels, showering/bathing/swimming (i.e., dermal/inhalation exposure), and genotype (having the GSTT1-1 gene). This finding, along with mechanistic studies, highlights the emerging importance of dermal/inhalation exposure to the THMs, or possibly other DBPs, and the role of genotype for risk for drinking-water-associated bladder cancer. More than 50% of the total organic halogen (TOX) formed by chlorination and more than 50% of the assimilable organic carbon (AOC) formed by ozonation has not been identified chemically. The potential interactions among the 600 identified DBPs in the complex mixture of drinking water to which we are exposed by various routes is not reflected in any of the toxicology studies of individual DBPs. The categories of DBPs described here, the identified data gaps, and the emerging role of dermal/inhalation exposure provide guidance for drinking water and public health research.
Topics: Animals; Carcinogens, Environmental; Dimethylnitrosamine; Disinfectants; Disinfection; Humans; Risk Assessment; Water Pollutants, Chemical; Water Purification; Water Supply
PubMed: 17980649
DOI: 10.1016/j.mrrev.2007.09.001 -
Expert Opinion on Drug Safety Feb 2022
Topics: Dimethylnitrosamine; Drug Contamination; Humans; Metformin
PubMed: 34546846
DOI: 10.1080/14740338.2021.1983312 -
Biochemical Pharmacology 1978
Topics: Animals; Dimethylnitrosamine; Hepatectomy; Lethal Dose 50; Male; Microsomes, Liver; Nitrosamines; Oxidoreductases, N-Demethylating; Rats; Time Factors
PubMed: 728228
DOI: 10.1016/0006-2952(78)90052-7 -
Chemosphere Oct 2022N-Nitrosodimethylamine (NDMA) is a commonly identified carcinogenic and genotoxic pollutant in water. In this study, we prepared Ru catalysts supported on carbon...
N-Nitrosodimethylamine (NDMA) is a commonly identified carcinogenic and genotoxic pollutant in water. In this study, we prepared Ru catalysts supported on carbon nanotube (Ru/CNT) and studied the electrocatalytic reduction of N-nitrosamines on Ru/CNT electrode in a three-electrode system. The results show that Ru-based catalyst exhibits a high activity of 793.3 μmol L gCat h for electrochemical reduction of NDMA. Reaction mechanism study discloses that the electrocatalytic reduction of NDMA is accomplished by both direct electron reduction and atomic H* mediated indirect reduction pathways. Further product analysis indicates that NDMA is finally reduced to dimethylamine (DMA) and ammonia. The reduction efficiency of NDMA strongly relies on cathode potential, initial NDMA concentration and solution pH. To verify the universality of Ru/CNT electrode, electrocatalytic reduction of three dialkyl N-nitrosamines with different alkyl groups was performed and Ru catalyst has high catalytic activities for the three N-nitrosamines, while the catalytic efficiency differs with their structures. Simultaneous electrochemical reduction of the three N-nitrosamines indicates that the reduction rates of N-nitrosamines follow the same order in the multiple-component system as that in the single-component system. Catalyst recycling results demonstrate that after 5 consecutive recycling runs Ru/CNT electrode remains almost identical catalytic activity to the fresh catalyst, manifesting the high catalytic stability of Ru/CNT electrode.
Topics: Catalysis; Dimethylnitrosamine; Nitrosamines; Oxidation-Reduction; Water Purification
PubMed: 35728667
DOI: 10.1016/j.chemosphere.2022.135414 -
Mutation Research Mar 1991In the present study the sensitivity of differential lethality as an endpoint for monitoring the presence of organ-specific genotoxic factors within the DNA-repair...
Evaluation of the DNA-repair host-mediated assay. III. Relationship between metabolic activation of dimethylnitrosamine and organ-specific differential lethality induced in E. coli indicator strains.
In the present study the sensitivity of differential lethality as an endpoint for monitoring the presence of organ-specific genotoxic factors within the DNA-repair host-mediated assay (HMA) was determined. The induction of differential lethality in chemically exposed animals was assessed by measuring the recovery ratio Q, i.e., the relative survival of a repair-deficient E. coli K-12 derivative in comparison with its repair-proficient counterpart. Using untreated animals the interindividual fluctuation of the recovery ratio Q was first quantified and then used to determine the level below which it could be considered indicative of chemically induced differential lethality. This Q value was found to be 0.65 or lower. Using this criterion, a significant decrease of the Q value was observed in mice exposed to DMNA at a dose level as low as 15-30 mumole/kg, i.p. Inter-organ transport (liver----extrahepatic organs) of indicator bacteria was studied in reconstruction experiments using the direct-acting methylating agent MNU. These studies showed that inter-organ transport of indicator bacteria did not interfere with MNU-induced differential lethality. Time-related experiments were used to study the effects of inter-organ transport of genotoxic DMNA metabolites. In these studies significant, time-related differences were found in the induction of differential lethality in various organs of mice treated with DMNA. At a dose level of 200 mumole/kg (i.p.) genotoxic factors appeared within 25 min after administration in the liver. In the lungs and kidneys such factors appeared at a substantially slower rate, e.g., 20-120 min after DMNA administration. In persistence experiments differential lethality reached a maximum 30 min after DMNA treatment. No residual effects were detected 60 min after the injection of the carcinogen. These experiments showed that DMNA-derived genotoxic factors diffused from the liver into the bloodstream. The diffusion of these reactive species followed by their transport via the bloodstream to the lungs accounted for maximally 50% of differential lethality observed in bacteria recovered from the latter organ. In contrast, no indications were found for the transport of genotoxic DMNA metabolites from the liver via the bloodstream to the spleen and the kidneys. These results show that organ-specific effects observed in the DNA-repair HMA procedure after DMNA exposure can be primarily attributed to in situ metabolism, rather than diffusion of genotoxic metabolites from the liver to extrahepatic organs.
Topics: Animals; Biotransformation; DNA Repair; Dimethylnitrosamine; Escherichia coli; Kinetics; Liver; Mice; Organ Specificity
PubMed: 2002807
DOI: 10.1016/0027-5107(91)90036-n -
Food and Cosmetics Toxicology Apr 1975
Topics: Administration, Oral; Aging; Animals; Carbon Dioxide; Dimethylnitrosamine; Dose-Response Relationship, Drug; Female; Gastric Mucosa; Injections, Intraperitoneal; Injections, Intravenous; Injections, Subcutaneous; Intestinal Absorption; Intestine, Small; Intubation, Gastrointestinal; Male; Nitrosamines; Rats; Sex Factors
PubMed: 1132850
DOI: 10.1016/s0015-6264(75)80005-8 -
Journal of the National Cancer Institute Mar 1977Alkylation of liver DNA was studied following administration to Sprague-Dawley rats of doses of dimethylnitrosamine (DMN) varying from 0.25 to 20 mg/kg body weight....
Alkylation of liver DNA was studied following administration to Sprague-Dawley rats of doses of dimethylnitrosamine (DMN) varying from 0.25 to 20 mg/kg body weight. Measurements were made of the amounts of O6-methylguanine and 7-methylguanine present in liver DNA at 4 and 24 hours after treatment with the carcinogen. There was a linear relationship between 7-methylguanine levels and dose of the nitrosamine at both of these times. In contrast, the corresponding levels of O6-methylguanine were not directly proportional to dosage but were less than expected, particularly at low doses below 2.5 mg/kg. This discrepancy was significant at 4 hours, but was even more marked at 24 hours. Only doses above 4 mg/kg at the 4-hour time point gave rise to a 0.11 ratio of alkylation of guanine at the O6-position to that at the 7-position. This ratio was that expected for the initial interaction of the alkylating species derived from DMN with DNA. Evidence was obtained to support the hypothesis that these results were due to an enzymatic removal of O6-methylguanine from liver DNA, which occurred much more efficiently at lower initial levels of alkylation. Repeated daily injections of DMN up to 11 days alos gave rise to O6-methylguanine levels that were not proportional to dosage but were relatively greater at higher dose levels. The significance of these findings in the induction of liver cancer by feeding or repeated injection of DMN was explored.
Topics: Alkylating Agents; Animals; DNA; Dimethylnitrosamine; Dose-Response Relationship, Drug; Female; Guanine; Liver; Liver Neoplasms; Methylnitrosourea; Neoplasms, Experimental; Nitrosamines; Rats
PubMed: 839563
DOI: 10.1093/jnci/58.3.681 -
International Journal of Pharmaceutics May 2022Since late 2019, concerns regarding trace levels of the probable human carcinogen N-dimethylnitrosamine (NDMA) in Metformin-containing pharmaceuticals have been an issue...
Since late 2019, concerns regarding trace levels of the probable human carcinogen N-dimethylnitrosamine (NDMA) in Metformin-containing pharmaceuticals have been an issue if they exceeded the maximum allowable intake of 96 ng/day for a medicine with long-term intake. Here, we report results from an extensive analysis of NDMA content along the active pharmaceutical ingredient (API) manufacturing process as well as two different drug product manufacturing processes. Our findings confirm that Metformin API is not a significant source of NDMA found in Metformin pharmaceuticals and that NDMA is created at those steps of the drug product manufacturing that introduce heat and nitrite. We demonstrate that reduction of nitrite from excipients is an effective means to reduce NDMA in the drug product. Limiting residual dimethylamine in the API has proven to be another important factor for NDMA control as dimethylamine leads to formation of NDMA in the drug products. Furthermore, analysis of historical batches of drug products has shown that NDMA may increase during storage, but the levels reached were not shelf-life limiting for the products under study.
Topics: Dimethylamines; Dimethylnitrosamine; Excipients; Humans; Metformin; Nitrites
PubMed: 35421534
DOI: 10.1016/j.ijpharm.2022.121740 -
Zeitschrift Fur Die Gesamte Hygiene Und... Jan 1986
Topics: Carcinogens; Dimethylnitrosamine; Food Contamination; Humans
PubMed: 3962372
DOI: No ID Found