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PubMed1983

N,N-Dimethylformamide-induced effects on hepatic and renal xenobiotic enzymes with emphasis on aldehyde metabolism in the rat.

Male Wistar rats were dosed with N,N-dimethylformamide (DMF) in drinking water at four concentration levels (0,0.1,0.5 or 1.0 g/l) for 2 or 7 weeks. Upon evaluation of the effects in the liver increased values were found for the following parameters: liver/body weight-ratio, GSH content, ethoxycoumarin O-deethylase and UDPglucuronosyltransferase activities. The GSH content, deethylase activity and, transiently, the glucuronidation activity were slightly increased also in the kidneys. Oxidative N-demethylation of DMF by hepatic microsomes in vitro was not enhanced by oral treatment. No DMF-dependent formaldehyde liberation in vitro could be detected under conditions where formaldehyde liberation from N,N-dimethylnitrosamine could be demonstrated. However, the endogenous rate of formaldehyde generation by liver microsomes isolated from DMF-treated rats was enhanced with the highest oral dose of DMF. The daily intake of DMF lowered the activities of both formaldehyde and propionaldehyde dehydrogenases in the liver soluble fraction. No inhibition of these dehydrogenases was shown in vitro by DMF (less than or equal to 10 mM) or by its main urinary metabolite N-methylformamide (less than or equal to 10 mM). The observed impairment of aldehyde oxidation in liver and kidneys of the rat after the DMF intake could explain the mechanism behind the alcohol intolerance observed in man after DMF-exposure.

Alcohol Dehydrogenase↗

PubMed1995

Dimethylformamide as an enhancer of cavitation-induced cell lysis in vitro.

Polar solvents, including dimethylformamide (DMF), have been investigated as anticancer drugs, but their potential usefulness is constrained by hepatotoxic side effects. The ability to enhance drug cytotoxicity with ultrasound would be valuable in creating locally intense chemotherapy while minimizing effects peripheral to the treatment site. The effects of continuous wave ultrasound (US) (985 kHz; 0.5-2.5 W/cm2) were evaluated on cultured HL-60 human promyelocytic leukemia cells alone and with a noncytotoxic DMF dose (0.11 M). The cells were insonified in a configuration that created no cell lysis without the introduction of albumin-stabilized microbubbles into the exposure chamber. When microbubbles were introduced, US with bubbles induced cell lysis, and the presence of DMF significantly increased the lysis induced by ultrasound with bubbles. The necessary presence of microbubbles for the DMF-US synergism to occur suggests that a likely mechanism is acoustic cavitation, initiated by the presence of microbubbles as nuclei. Detection of subharmonics confirmed the presence of cavitation, and cell lysis was well correlated with the subharmonic amplitude. The results show that albumin-stabilized microbubbles, similar to those currently used as US contrast agents, may provide a significant source of nuclei and improve prospects for cancer therapy using acoustic cavitation. The evidence presented supports the hypothesis that cell damage is due to a sonochemical rather than to a sonomechanical process.

Cell Membrane↗

PubMed1976

Inhibition of bacterial growth by the nitrofurantoin solvent dimethylformamide.

For quantitative susceptibility tests, stock solutions of nitrofurantoin are often prepared in dimethylformamide. Since 1.0 or 2.0 ml of the solvent will inhibit microbial growth, currently recommended procedures for antimicrobic dilution tests should be modified by adding only 0.1 or 0.2 ml of stock drug solutions to the agar or broth medium.

Bacteria↗

PubMed1973

Proteins released from cell envelopes of Pseudomonas aeruginosa on exposure to ethylenediaminetetraacetate: comparison with dimethylformamide-extractable proteins.

Isolated cell envelopes of Pseudomonas aeruginosa were treated with N,N'-dimethylformamide (DMF) or with ethylenediaminetetraacetate (EDTA). DMF solubilized 73% of the dry weight of the cell envelope, 76% of the protein, 78% of the carbohydrate, and 76% of the phosphorus. Electron microscopy showed that DMF caused extensive alterations in the appearance of the cell envelope with blebs and bleblike vesicles predominating. After incubation with EDTA, the cell envelopes appeared to have lost material, but still retained the cell-like morphology. Analysis of DMF-solubilized proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed 16 protein bands. There were three major proteins that predominated, however, with molecular masses of 43,000 (protein A), 16,500 (protein B), and 72,000 daltons (protein C). Evidence is presented that protein A and protein B are glycoproteins. Gel electrophoresis of EDTA-solubilized material revealed that a number of proteins were released from the cell envelope. However, electrophoresis of an isolated protein-lipopolysaccharide complex released by EDTA showed that protein A and protein B were the major protein components of this complex. These data suggest that protein A and protein B are components of the outer cell wall membrane of P. aeruginosa. There is suggestive evidence that these proteins may play a role in maintaining the structural integrity of the cell envelope. Whether these proteins also have enzymatic activity could not be discerned from the present study, although it is possible that they may be associated with the terminal stages of lipopolysaccharide synthesis.

Bacterial Proteins↗

PubMed2005

Total body burden arising from a week's repeated dermal exposure to N,N-dimethylformamide.

BACKGROUND: Hazardous chemicals and their metabolites may accumulate in the body following repeated airborne exposures and skin contact. AIMS: To estimate the contribution of skin absorption to total body burden of N,N-dimethylformamide (DMF) across a working week in two groups with similar levels of respiratory exposure but dissimilar skin contact. METHODS: Twenty five workers in a synthetic leather (SL) factory, 20 in a copper laminate circuit board (CLCB) factory, and 20 age and sex matched non-DMF exposed subjects, were recruited. Environmental monitoring of DMF exposure via respiratory and dermal routes, as well as biological monitoring of pre-shift urinary N-methylformamide (U-NMF), were performed for five consecutive working days. RESULTS: Environmental and biological monitoring showed no detectable exposure in controls. The average airborne DMF concentration (geometric mean (GM) 3.98 ppm, geometric standard deviation (GSD) 1.91 ppm), was insignificantly lower for SL workers than for CLCB workers (GM 4.49, GSD 1.84 ppm). Dermal DMF exposure and U-NMF values, however, were significantly higher for SL workers. A significant pattern of linear accumulation was found across a five day work cycle for SL workers but not for CLCB workers. CONCLUSIONS: Dermal exposure to DMF over five consecutive days of occupational exposure can result in the accumulation of a significant DMF body burden. The long term exposure response under both repeated and intermittent conditions of substantial skin exposure is worthy of note.

Adult↗

PubMed2005

The use of biomarkers of exposure of N,N-dimethylformamide in health risk assessment and occupational hygiene in the polyacrylic fibre industry.

BACKGROUND: N,N-dimethylformamide (DMF) was recently prioritised for field studies by the National Toxicology Program based on the potency of its reproductive toxic effects. AIMS: To measure accurately exposure to DMF in occupational settings. METHODS: In 35 healthy workers employed in the polyacrylic fibre industry, N-methylformamide (NMF) and N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC) in urine, and N-methylcarbamoylated haemoglobin (NMHb) in blood were measured. Workplace documentation and questionnaire information were used to categorise workers in groups exposed to low, medium, and high concentrations of DMF. RESULTS: All three biomarkers can be used to identify occupational exposure to DMF. However, only the analysis of NMHb could accurately distinguish between workers exposed to different concentrations of DMF. The median concentrations were determined to be 55.1, 122.8, and 152.6 nmol/g globin in workers exposed to low, medium, and high concentrations of DMF, respectively. It was possible by the use of NMHb to identify all working tasks with increased exposure to DMF. While fibre crimpers were found to be least exposed to DMF, persons washing, dyeing, or towing the fibres were found to be highly exposed to DMF. In addition, NMHb measurements were capable of uncovering working tasks, which previously were not associated with increased exposure to DMF; for example, the person preparing the fibre forming solution. CONCLUSIONS: Measurement of NMHb in blood is recommended rather than measurement of NMF and AMCC in urine to accurately assess exposure to DMF in health risk assessment. However, NMF and AMCC are useful biomarkers for occupational hygiene intervention. Further investigations regarding toxicity of DMF should focus on highly exposed persons in the polyacrylic fibre industry. Additional measurements in occupational settings other than the polyacrylic fibre industry are also recommended, since the population at risk and the production volume of DMF are high.

Acetylcysteine↗

PubMed1979

Dimethylformamide and alcohol intolerance.

Facial flushing and other symptoms were reported by 19 of a group of 102 men who worked with dimethylformamide (DMF). Twenty-six of the 34 episodes occurred after the workers had consumed alcoholic drinks. The metabolite N-methylformamide (MF) was detected in the urine on 45 occasions, the highest recorded concentration being 77 microliter/litre. The highest recorded concentration of DMF in air was 200 ppm. The DMF-ethanol reaction is possibly attributable to the inhibition of acetaldehyde metabolism, probably by MF.

Air Pollutants, Occupational↗

PubMed1990

Triple combination of retinoic acid, low concentration of cytarabine and dimethylformamide induces differentiation of human acute myeloid leukaemic blasts.

Differentiation induction therapy provides an alternative for treatment of patients with acute myeloid leukaemia (AML) who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy. The effect of a triple combination of retinoic acid (RA) + low concentration of cytarabine (Ara-C) + dimethylformamide (DMF) on the differentiation of blasts from 24 AML patients was studied. Nonadherent mononuclear cells were cultured at a concentration of 5 x 10(5) cells/ml in 24-well tissue culture plates containing RPMI 1640 culture medium with 20% fetal calf serum, 10% autologous serum and 10% 5637-conditioned medium and incubated with 10(-6) M RA, 10(-6) M Ara-C and/or 100 mM DMF alone and in combination with each other for 6 days in primary culture at 37 degrees C in a humidified incubator under 5% CO2. The triple combination of 10(-6) M RA + 10(-6) M Ara-C + 100 mM DMF induced 90% of blasts from 22 out of 24 AML patients to differentiate. These highly effective results justify a clinical trial of this triple combination for AML patients who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Hepatotoxicity of N, N-dimethylformamide (DMF) in acute poisoning with the veterinary euthanasia drug T-61.

1. We report on a patient who was resuscitated after a suicide attempt with the veterinary euthanasia product T-61 and treated with N-acetylcysteine (NAC) to prevent hepatotoxicity from N,N-dimethylformamide (DMF), the solvent of T-61. 2. Serum concentrations of DMF were high as compared with values published on occupational exposure. 3. The patient showed only a transient increase in liver enzymes with eventually a full recovery. 4. The hepatoprotective effect of NAC was studied in a rat model using the rise in serum sorbitol dehydrogenase (SDH) as a marker for DMF-induced hepatotoxicity. 5. Four series of randomized, controlled and double-blind experiments were carried out and consistently showed a lower increase in SDH in NAC-treated animals in each series. The difference was statistically significant only when the data of the 4 series were pooled. This is probably due to the large interindividual variations in the effect of DMF. 6. We hypothesize that in the rat NAC may have a protective effect. Whether NAC is also protective in patients, in which it is administered after exposure to DMF, cannot be concluded from the present experiments.

Acetylcysteine↗

PubMed2004

Carcinogenicity and chronic toxicity after inhalation exposure of rats and mice to N,N-dimethylformamide.

Carcinogenicity and chronic toxicity of N,N-Dimethylformamide (DMF) were examined by inhalation exposure of groups of 50 rats and 50 mice of both sexes to DMF vapor at a concentration of 0, 200, 400 or 800 ppm (v/v) for 6 h/d, 5 d/wk, for 104 wk. In rats, incidences of hepatocellular adenomas and carcinomas significantly increased in the 400 and 800 ppm-exposed groups and in the 800 ppm-exposed group, respectively. The hepatocellular adenoma did not increase significantly in the 400 ppm-exposed female rats, but its incidence exceeded a range of historical control data in the Japan Bioassay Research Center (JBRC). In mice, incidences of hepatocellular adenomas and carcinomas significantly increased in all the DMF-exposed groups. Incidence of hepatoblastomas significantly increased in the 200 and 400 ppm-exposed male mice, and 4 cases of hepatoblastomas in the 400 ppm-exposed female mice and the 800 ppm-exposed male mice exceeded the range of historical control data of the JBRC. Incidences of altered cell foci increased in the liver of exposed rats and mice in an exposure concentration-related manner, and those foci were causally related to the hepatocellular tumors. Liver weights increased in both rats and mice exposed to DMF at 200 ppm and above. Increased levels of gamma-GTP, ALT, AST and total bilirubin in exposed rats of both sexes and AST and ALT in exposed mice of both sexes were noted. It was concluded that 2-yr inhalation exposure to DMF increased incidences of hepatocellular adenomas and carcinomas in rats and incidences of hepatocellular adenomas, carcinomas and hepatoblastomas in mice, and that hepatocarcinogenicity of DMF was more potent in mice than in rats.

Administration, Inhalation↗

PubMed1982

[The toxicity of N,N-dimethylformamide (DMF)].

Industrial use of N, N-dimethylformamide (DMF) is increasing in recent years. The toxic properties of this substance are reviewed from the standpoint of industrial hygiene. Hepatotoxicity has been emphasized by many authors. Care should be taken against the skin absorption of DMF. N-methylformamide (MF) was identified as the major urinary metabolite of DMF. Measurements of MF in urine have been found effective as a means of biological monitoring of DMF exposure.

Abnormalities, Drug-Induced↗

PubMed2001

Causal relationship between a case of severe hepatic dysfunction and low exposure concentrations of N,N-dimethylformamide in the synthetics industry.

A 19-year-old man suffered hepatic dysfunction after 5 months of exposure to N,N-dimethylformamide (DMF) at his job in the synthetic resins industry. Laboratory data revealed elevated levels of AST (578 IU/l), ALT (1193 IU/l), and gamma-GTP (107 IU/l), no viral infection with HAV, HBV, or HCV, and no history or evidence of hepatic injury, although he did have a slight abdominal abnormality and swelling which was detected by palpation. His urinary N-methylformamide level, as a biological exposure index of DMF, was 42.8 mg/l, indicating 10-30 ppm of DMF exposure. After 2 months he was reinstated in two workplaces, the former where he worked in the morning and the other in the afternoon where environmental DMF concentrations were less than those in the former workplace. On the 18th day after his reinstatement, his liver function became exasperated again. After the second period of medication and one month of rest from work, he had fully recovered and was reinstated, but to a workshop without DMF exposure.

Adult↗

PubMed1984

Subchronic inhalation toxicity of dimethylformamide in rats and mice.

Fisher F344 rats and B6C3F1 mice were exposed to concentrations of 0, 150, 300, 600 and 1200 ppm of dimethylformamide (DMF) for 6 hours a day, 5 days a week for 12 weeks. Detailed clinical observations were obtained weekly and body weights biweekly on all animals. Clinical chemistry and hematology evaluations were made on all rats and approximately half the mice at terminal sacrifice. Gross necropsy examinations were made on all animals. Histopathologic evaluations were conducted on selected tissues of animals of both species at all dose levels. Few overt signs of toxicity were seen in either rats or mice. There was a dose related depression in body weight gain in rats that was significant at the 1200 ppm level from the second week of study onwards. A total of 11 mice died or were sacrificed moribund during the study, 8 from the high dose and 2 from the 600 ppm dose level. Both clinical chemistry (in rats only) and gross necropsy observations, and histopathology of tissues indicate the possibility that liver may be the target in specific organ toxicity. The no-effect DMF dose was below the 150 ppm level for both rats and mice and the maximum tolerated dose was below the 600 ppm level.

Air Pollutants↗

PubMed1986

Acute and subchronic toxicity of dimethylformamide and dimethylacetamide following various routes of administration.

Dimethylformamide (DMF, CAS No. 68-12-2) and dimethylacetamide (DMAC, CAS No. 127-19-5) are widely used for their superior solvent properties. A series of single and multiple dose experiments in rodents were conducted to determine the target organs, and to establish doses which, under various routes of administration, produced those changes. DMF produced moderate irritation in the rabbit eye, with the corneal response clearing in 2 to 4 weeks. DMAC produced only mild, quickly reversible conjunctival irritation. Oral doses of DMF to the rat of 2,250 mg/kg or greater produced lethality which was associated with liver damage. Lethality occurred following oral doses of 4,500 mg/kg DMAC with LD50's for male and female rats of 5,809 and 4,930 mg/kg, respectively. The 1 hour LC50 by inhalation for DMAC in the rat was 2,475 ppm or greater. Sensory irritation was produced in the mouse at concentrations of 1,658 ppm or greater for DMF. Repeated oral doses of 450 mg DMF/kg to rats produced reduced body weight gain and liver injury with both changes being reversible. DMAC tested similarly produced body weight effects, liver injury, and testicular changes in the rat with all changes again being readily reversible. Dermal doses of 2,000 mg/kg of either DMF or DMAC were poorly tolerated by rabbits. DMAC was slightly more toxic with all treated rabbits dying of acute hepatic necrosis. Repeated inhalation of 2,000-2,500 ppm produced mortality in rats exposed to DMF but not DMAC. Liver injury was seen with DMF, testicular changes with DMAC. DMF and DMAC both produced slight anemia and leukocytosis in rats during 90 days of feeding. Liver weights were elevated in rats fed DMF, but not DMAC, at a level of 1,000 ppm. The "no-observed effect level" in rats fed DMF for 90 days was 200 ppm. The overall toxicologic profiles of both DMAC and DMF are similar with the target organ being the liver.

Acetamides↗

PubMed1992

Developmental toxicity of dimethylformamide in the rat following inhalation exposure.

Dimethylformamide (DMF) is a widely used industrial solvent. DMF has been reported to be a developmental toxin when given to rodents by injection or following dermal administration. In this study, groups of pregnant rats were exposed by inhalation to either 0 (control), 30, or 300 ppm DMF from gestation day 6 through 15. In the 300 ppm rats, both maternal weight gain during gestation and fetal weights were lower than those of the controls. Fetal resorptions were not increased in this group. No significant differences among either maternal or fetal rats were seen in the 30 ppm group compared to controls. Both fetal and maternal toxicity were noted at 300 ppm and the no observed effect level under these experimental conditions was 30 ppm for both the dams and the conceptuses. DMF did not produce malformations in the rat fetus even at a level that was toxic to the dam.

Abnormalities, Drug-Induced↗

PubMed1993

Dimethylformamide pharmacokinetics following inhalation exposures to rats and mice.

Whole-body inhalation exposures to N,N-dimethylformamide (DMF) were conducted with rats and mice. The exposure concentrations were 10, 250, and 500 ppm DMF. The exposure routines consisted of single 1-, 3-, or 6-hour exposures and ten 6-hour exposures (ten exposure days in 2 weeks). Area under the plasma concentration curve (AUC) values were determined following exposure for DMF and "N-methylformamide" ["NMF" represented N-methylformamide plus N-(hydroxymethyl)-N-methylformamide (DMF-OH)]. The DMF AUC values increased 8- and 29-fold for rats and mice, respectively, following single six-hour exposures to 250 and 500 ppm DMF. These data are indicative of saturation of DMF metabolism. Peak "NMF" plasma concentrations for rats and mice, following single 6-hour exposures, did not increase as DMF exposure concentrations increased from 250 to 500 ppm. In addition, the "NMF" plasma levels in rats following a single 6-hour 500 ppm DMF exposure did not decay by 24 hours post exposure. These "NMF" plasma data also indicate saturation of DMF metabolism. Multiple exposures to 500 ppm DMF resulted in a 3- and 4-fold reduction in DMF AUC values for rats and mice, respectively, compared to AUC values following a single six-hour 500 ppm DMF exposure. This indicates enhanced metabolism of DMF resulting from multiple 500 ppm DMF exposures and together with saturation of DMF metabolism suggest using exposure levels below 500 ppm in a chronic bioassay. Selected plasma samples were simultaneously assayed for NMF and DMF-OH. The "NMF" values consisted of between 30 to 60 percent DMF-OH depending upon the exposure group (conversely NMF represented 30 to 60 percent of the "NMF" levels). Urinary analysis of all samples revealed DMF-OH represented over 90 percent of the summed DMF, DMF-OH and NMF quantities.

Administration, Inhalation↗

PubMed1993

Dimethylformamide pharmacokinetics following inhalation exposure in monkeys.

Male and female cynomolgus monkeys received whole-body inhalation exposures to dimethylformamide (DMF) at concentrations of 30, 100, and 500 ppm for 6 hours a day, 5 days a week over a 13-week period. Serial blood samples were drawn at the conclusion of the first day of exposure and following 15, 29, 57, and 85 days of testing. Area under the plasma concentration curve (AUC) values were determined for DMF and "NMF" [N-methylformamide (NMF) plus N-(hydroxymethyl)-N-methylformamide (DMF-OH)]. Urine samples were also collected and assayed for DMF, NMF and DMF-OH. The systemic exposure to DMF increased disproportionately as the airborne DMF concentrations increased. DMF AUC values increased 19- to 37-fold in male and 35- to 54-fold in female monkeys as the inhalation concentrations increased 5-fold (100 to 500 ppm). These data are consistent with saturation of DMF metabolism as inhaled DMF concentrations increased from 100 to 500 ppm. AUC values, peak plasma concentrations, and plasma half-lives were essentially unaltered over the duration of the study within each exposure concentration tested. Estimated plasma half-lives ranged from 1 to 2 hours and 4 to 15 hours for DMF and "NMF" respectively. DMF was rapidly converted to "NMF" following 30 ppm exposures, with "NMF" plasma concentrations higher than DMF plasma concentrations at the 0.5 hour time-point. In plasma samples simultaneously assayed for DMF-OH and NMF, the concentration of DMF-OH exceeded, was equal to, or was less than NMF concentrations depending upon the plasma sample. DMF-OH was always the main urinary metabolite (56 to 95 percent) regardless of exposure level or time on study.

Administration, Inhalation↗

PubMed2002

The metabolism and liver toxicity of N,N-dimethylformamide in the isolated perfused rat liver.

N,N-dimethylformamide (DMF) is metabolized by the microsomal cytochrome p-450 into mainly N-hydroxymethyl- N-methylformamide (HMMF), which further breaks down to N-methyformamide (NMF). However, the detailed mechanism of its toxicity remains unclear. We investigated the metabolism and the toxicity of DMF using the isolated perfused liver model. DMF was added to the recirculating perfusate of the isolated perfused rat liver at concentrations of 0, 10 and 25 mM. Samples were collected from the inferior vena cava at 0, 30, 45, 60, 75, and 90 minutes following addition of the DMF. The metabolites of DMF were analyzed using Gas-chromatography (GC). The changes in the rate of oxygen consumption by the DMF were monitored during perfusion. The enzyme activities (aspartic aminotransferase:AST, alanine aminotransferase:ALT, and lactic dehydrogenase:LDH)) in the perfusate were monitored to see if DMF caused hepatotoxicity. As the perfusion progressed, the DMF concentration in the perfusate decreased, but the level of NMF increased to a maximum of 1.16 mM. The rate of oxygen consumption increased at DMF concentrations of 10 mM and 25 mM. However, when a known inhibitor of cytochrome p-450, SKF 525A (300 micro M), was used to pretreat the perfusate prior to the addition of the DMF, the rate of oxygen consumption was significantly inhibited, indicating the cytochrome p-450 system was responsible for the conversion of DMF to NMF. On addition of the DMF, the activities of the enzymes AST, ALT and LDH were significantly increased a time and dose dependent manner. However, following pretreatment with SKF 525A, their releases were inhibited.

Animals↗