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PubMed2000

Biological monitoring of workers exposed to N,N-dimethylformamide in the synthetic fibre industry.

OBJECTIVES: Monitoring of workplace air and biological monitoring of 23 workers exposed to N,N-dimethylformamide (DMF) in the polyacrylic fibre industry was carried out on 4 consecutive days. The main focus of the investigation was to study the relationship between external and internal exposure, the suitability of the metabolites of DMF for biological monitoring and their toxicokinetic behaviour in humans. METHODS: Air samples were collected using personal air samplers. The limit of detection (LOD) for DMF using an analytical method recommended by the Deutsche Forschungsgemeinschaft (DFG) was 0.1 ppm. The urinary metabolites, N-hydroxymethyl-N-methylformamide (HMMF), N-methylformamide (NMF), and N-acetyl-S-(N-methylcarbamoyl)-cysteine (AMCC), were determined in one analytical run by gas chromatography with thermionic sensitive detection (GC/TSD). The total sum of HMMF and NMF was determined in the form of NMF. The LOD was 1.0 mg/l for NMF and 0.5 mg/l for AMCC. RESULTS AND CONCLUSIONS: The external exposure to DMF vapour varied greatly depending on the workplace (median 1.74 ppm, range < 0.1-159.77 ppm). Urinary NMF concentrations were highest in post-shift samples. They also covered a wide range (< 1.0-108.7 mg/l). This variation was probably the result of different concentrations of DMF in the air at different workplaces, dermal absorption and differences in the protective measures implemented by each individual (gloves, gas masks etc.). The urinary NMF concentrations had decreased almost to zero by the beginning of the next shift. The median half-time for NMF was determined to be 5.1 h. The concentrations of AMCC in urine were determined to be in the range from < 0.5 to 204.9 mg/l. Unlike the concentrations of NMF, the AMCC concentrations did not decrease during the intervals between the shifts. For the exposure situation investigated in our study, a steady state was found between the external exposure to DMF and the levels of AMCC excreted in urine about 2 days after the beginning of exposure. AMCC is therefore excreted more slowly than NMF. The half-time for AMCC is more than 16 h. Linear regression analysis for external exposure and urinary excretion of metabolites was carried out for a sub-group of 12 workers. External exposure to 10 ppm DMF in air (the current German MAK value) corresponds to an average NMF concentration of about 27.9 mg/l in post-shift urine from the same day and an average AMCC concentration of 69.2 mg/l in pre-shift urine from the following day. NMF in urine samples therefore represents an index of daily exposure to DMF, while AMCC represents an index of the average exposure over the preceding working days. AMCC is considered to be better suited for biomonitoring purposes because (1) it has a longer half-time than NMF and (2) its formation in humans is more closely related to DMF toxicity.

Acetylcysteine↗
PubMed1998

N,N-dimethylformamide--influence of working conditions and skin penetration on the internal exposure of workers in synthetic textile production.

OBJECTIVES: This study examined the external and internal exposure to the solvent N,N-dimethylformamide (DMF) of 126 workers from a factory producing synthetic fibers. METHODS: Air measurements were carried out using personal air samplers with diffusion tubes (Drager, ORSA 5). For the purpose of biological monitoring the levels of N-methylformamide (NMF) in urine were measured in preshift and postshift samples. Determinations were carried out using gas chromatography. Anamnestic data were collected with standardized questionnaires, including personal data, working history and current working conditions, and former and current illness with regard to the effects of DMF. Skin diseases were documented by a dermatologist. RESULTS: DMF concentrations measured in the air ranged between <0.1 and 37.9 ppm (median 1.2 ppm). Concentrations of NMF varied from 0.05 to 22.0 mg/l (preshift values) and from 0.9 to 100.0 mg/l (postshift values). The creatinine-related values (0.02-44.6 mg/g preshift; 0.4-62.3 postshift) were subject to less variation and therefore represented the level of exposure better than the values related to volume. Additional investigation of a subcollective (n=31) over a period of 4 days showed that NMF did not accumulate in the organism. The positive but relatively weak association observed between the DMF concentrations measured in the workplace air and the values recorded for internal exposure in this study can be explained by influencing factors such as dermal absorption or protective clothing. Interindividual differences in internal exposure were found for the specific work areas. The German BAT value (15 mg NMF/l urine) was exceeded in 36 persons (29%) despite the use of breathing protection and protective gloves, without increased values being measured in the air. Increased absorption without higher-level exposure could particularly also be observed in employees with eczema. CONCLUSIONS: From the point of view of the prevention of disease, biological monitoring is the best instrument for exposure assessment of workers exposed to DMF.

Adult↗
PubMed1999

Liver function in workers exposed to N,N-dimethylformamide during the production of synthetic textiles.

OBJECTIVE: In a factory producing synthetic fibers the hepatotoxic effects of the solvent N,N-dimethylformamide (DMF) were investigated in 126 male employees, especially with regard to the combination effects of DMF exposure and ethyl alcohol consumption. A collective of similar structure from the same factory served as a control collective. METHODS: Reference is made to the results of air measurements and biological monitoring presented in a previous publication. The DMF concentrations in the air ranged from < 0.1 (detection limit) to 37.9 ppm (median 1.2 ppm). Concentrations of the DMF metabolite N-methylformamide (NMF) in urine were 0.05-22.0 mg/l (preshift) and 0.9-100.0 mg/l (postshift), corresponding to 0.02-44.6 mg/g creatinine (preshift) and 0.4-62.3 mg/g creatinine (postshift). A standardized anamnesis was drawn up for relevant previous illnesses and other factors influencing liver function. The laboratory tests included parameters especially relevant to the liver (e.g., AST, ALT, gamma-GT, hepatitis B and C antibodies, and carbohydrate-deficient transferrin). RESULTS: The results indicate a statistically significant toxic influence of DMF on liver function. Alcohol has a synergistic effect. The effects of DMF and those of alcohol are dose-dependent. Under the existing workplace conditions the hepatotoxic effects of alcohol are more severe than those of DMF. In the exposed group there was a statistically significantly greater number of persons who stated that they had drunk less since the beginning of exposure (13% versus 0). This corresponded with the data on symptoms occurring after alcohol consumption (71% versus 4%). In the work areas with lower-level exposure to DMF there was greater alcohol consumption. It corresponded to that of the control collective not exposed to DMF. CONCLUSION: In this study we tried to differentiate and quantify the interaction between DMF exposure and alcohol consumption and the influence of both substances on liver function. The experience gained from former occupational health surveillance in DMF-exposed persons and from the present study show that there are individual differences in tolerance of interactions between DMF and ethyl alcohol. Further studies are necessary for the evaluation of these individual degrees of susceptibilitiy.

Adult↗
PubMed2001

Insertion polymorphism of CYP2E1 and urinary N-methylformamide after N,N- dimethylformamide exposure in Japanese workers.

OBJECTIVES: This study examined whether consideration of the *1C/*1D CYP2E1 insertion polymorphism is important for interpreting the biological monitoring of exposure to N,N-dimethylformamide (DMF) in Japanese workers. METHODS: The insertion genotype, airborne DMF exposure on the last day of a work week, and NMF in urine sampled just after the last workshift of the week were determined in 44 male and female Japanese workers. RESULTS AND CONCLUSIONS: The allelic frequency of this CYP2E1 polymorphism was 0.261 in this Japanese population of workers. The CYP2E1 insertion polymorphism did not contribute to NMF levels even after consideration of BMI or alcohol intake. The results indicate that CYP2E1 insertion polymorphism does not appear to be an important determinant for the interpretation of biological exposure to DMF by the measurement of urinary NMF.

Adult↗
PubMed1992

The periodate oxidation of sucrose in aqueous N,N-dimethylformamide.

Sucrose has been oxidized with sodium periodate in 0-50% aqueous N,N-dimethylformamide (DMF). In 50% aqueous DMF the reaction is selective for the glucose ring, yielding a dialdehyde. The increased selectivity is not due to conformational factors but is ascribed to the dissociation of water from cyclic periodate ester species which makes the reaction via the acyclic ester on fructose unfavourable.

Carbohydrate Sequence↗
PubMed1984

In vivo and in vitro oxidative biotransformation of dimethylformamide in rat.

In rats and in humans, dimethylformamide (DMF) is mainly metabolized into N-hydroxymethyl-N-methylformamide (DMF-OH). The in vitro oxidation of DMF by rat liver microsomes is decreased in the presence of catalase and superoxide dismutase. The radical scavengers, dimethylsulfoxide (DMSO), tertiary butyl alcohol (t-butanol), aminopyrine, hydroquinone and trichloroacetonitrile reduce the oxidation of DMF to DMF-OH in vitro and in vivo. Conversely, DMF inhibits the demethylation of DMSO, t-butanol and aminopyrine. The addition of iron-EDTA to the incubation system induces the production of N-methylformamide (NMF) from DMF. These results support the hypothesis that the metabolic pathway leading from DMF to DMF-OH and NMF involves hydroxyl radicals. Superoxide radical and hydrogen peroxide take part in the metabolic process. DMF is preferentially metabolized into DMF-OH. NMF appears mainly when the production of hydroxyl radicals is stimulated, the methyl group being recovered as formic acid.

Animals↗
PubMed1988

Comparison of the effects of transforming growth factor beta, N,N-dimethylformamide, and retinoic acid on transformed and nontransformed fibroblasts.

In order to compare the effects of transforming growth factor (TGF beta) with those of the differentiation promoters N,N-dimethylformamide (DMF) and retinoic acid (RA), the antiproliferative and fibronectin-inducing activities of the three agents were examined. AKR-2B mouse embryo fibroblasts and their chemically transformed counterpart AKR-MCA cells were used as the model system. Growth in monolayer culture of both cell lines was inhibited by TGF beta (EC50 approximately 1 ng/ml), DMF (EC50 approximately 0.5%), and RA (EC50 approximately 1 microM) in a concentration-dependent manner. Time-dependent elevation in fibronectin expression was also observed with all three agents. The EC50 for growth inhibition of both cell lines by TGF beta agreed well with that obtained for stimulation of fibronectin synthesis. A 3-h exposure to TGF beta is sufficient to obtain the maximal fibronectin level observed at 48 h in AKR-2 B cells but not in AKR-MCA cells. Our results indicate that in this system the effects of TGF beta are similar to those of the chemical differentiation inducers DMF and RA. Furthermore, our data also suggest that the TGF beta signal may be processed differently by nontransformed and transformed fibroblasts.

Animals↗
PubMed1989

Differences between rodents and humans in the metabolic toxification of N,N-dimethylformamide.

The widely used industrial solvent N,N-dimethylformamide (DMF) causes liver damage in occupationally exposed persons and is suspected of involvement in the generation of certain occupational malignancies. Here the extent of the biotransformation of DMF to three urinary metabolites has been compared in humans and rodents. The metabolites, which were quantified by gas chromatography (GC) are N-(hydroxymethyl)-N-methylformamide (HMMF), which yielded N-methylformamide on GC analysis, a species which decomposed to formamide on GC analysis, and N-acetyl-S-(N-methylcarbamoyl) cysteine (AMCC), measured after derivatization with ethanol to give ethyl N-methylcarbamate. Ten volunteers who absorbed between 28 and 60 mumol/kg DMF during an 8-hr exposure to DMF in the air at 60 mg/m3 excreted in the urine within 72 hr between 16.1 and 48.7% of the dose as HMMF, between 8.3 and 23.9% as formamide, and between 9.7 and 22.8% as AMCC. AMCC, together with HMMF, was also detected in the urine of workers after occupational exposure to DMF. The portion of the dose (0.1, 0.7, or 7.0 mmol/kg given ip) which was metabolized in mice, rats, or hamsters to HMMF varied between 8.4 and 47.3% of the dose; between 7.9 and 37.5% were excreted as formamide and only between 1.1 and 5.2%, as AMCC. The results suggest that there is a quantitative difference between the metabolic pathway of DMF to AMCC in humans and rodents. It is argued that the hepatotoxic potential of DMF may be linked to the extent of its metabolic conversion to AMCC.

Adult↗
PubMed1981

Carcinogenicity and mutagenicity of solvents. I. Glycidyl ethers, dioxane, nitroalkanes, dimethylformamide and allyl derivatives.

The carcinogenicity and/or mutagenicity as well as structural features and relationships of the glycidylethers (principally phenyl-, butyl-, allyl-, and isopropyl-), dioxane, nitroalkanes (nitro methane, ethane and propane), dimethylformamide and allyl derivatives (chloride, alcohol and amine) were examined. Additionally, considerations of the production, use patterns, estimated populations at risk, TLV's and metabolism of the above agents were discussed.

Allyl Compounds↗
PubMed1991

New findings in the metabolism of N,N-dimethylformamide--consequences for evaluation of occupational risk.

Using a novel gas chromatographic method, specific mercapturic acids produced in the biotransformation of several formamide analogues have been quantified. Thus, N-acetyl-S-(N-methylcarbamoyl)cysteine, derived from an important industrial solvent N,N-dimethylformamide, was found to be a minor metabolite in rodents but an important one in humans. Because manifestations of hepatotoxicity of formamide analogues were always linked with the production of mercapturic acids, the risk from exposure to DMF in humans appears to be higher than that estimated from toxicological experiments on laboratory animals.

Air Pollutants, Occupational↗
PubMed1987

The organic solvents acetone, ethanol and dimethylformamide potentiate the mutagenic activity of N-methyl-N'-nitro-N-nitrosoguanidine, but have no effect on the mutagenic potential of N-methyl-N-nitrosourea.

The frequency of recessive chlorophyll and embryonic lethals included by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Arabidopsis thaliana was markedly increased when exposure of the seeds to MNNG (3 h) was carried out in the presence of 4-12% acetone, 4-16% ethanol or 8-32% dimethylformamide. The enhancement of MNNG mutagenicity was proportional to the concentrations of these organic solvents. In contrast, neither of them, applied at the same conditions and doses, influenced the mutagenic activity of N-methyl-N-nitrosourea. The solvents without mutagens did not influence the spontaneous rate of mutations and revealed no or very weak toxic effect as measured by the seed germination.

Acetone↗
PubMed1988

Modulation of the urokinase receptor in human colon cell lines by N,N-dimethylformamide.

The present study documents the effect of the planar, polar differentiation promoter N,N-dimethylformamide (DMF) on urokinase binding to colon carcinoma cells. Exposure of the colon carcinoma cell lines to the agent resulted in enhanced specific binding of radioactive urokinase to all cells tested. Insulin binding to the cells was, however, unaffected by DMF. A DMF exposure period of 45 h was required to observe maximum urokinase binding to two representative cell lines FET and RKO. Optimal stimulation of both cell lines occurred with 0.8% DMF. Scatchard analysis revealed the dissociation constants to be unchanged by the agent with the increased binding of radioactive plasminogen activator reflecting an up-regulation of binding sites. In this regard, the cell line RKO upon exposure to DMF, displayed approx. 700,000 receptors/cell, the highest value published, to date, for any cell line.

Cell Line↗
PubMed1992

13-week inhalation toxicity study of dimethylformamide (DMF) in cynomolgus monkeys.

This study was conducted to assess the subchronic inhalation toxicity of dimethylformamide (DMF) in the cynomolgus monkey. Particular attention was paid to the liver since DMF has been shown to produce liver damage in rodents, dogs, and humans. Groups of three cynomolgus monkeys/sex/group received whole-body exposures for 6 hr/day, 5 days/week for 13 weeks to 0, 30, 100, or 500 ppm DMF. Evaluations for toxicity included body and organ weights, clinical observations, hematology, serum chemistry, urinalysis, and gross and microscopic examinations. Clinical laboratory evaluations were conducted twice prior to the start of the study at exposure weeks 2, 4, 8, and 12 and at necropsy. Semen, collected from male monkeys three times prior to the start of the study and weekly during the course of the study, was analyzed for sample volume, sperm count, motility, and morphology. In addition, daily vaginal swabs were obtained from all females prior to exposure to determine mean menses cycle length. Although there was a slight trend toward increased cycle length, this trend could not be definitely attributed to compound exposure. Based on extensive monitoring of the monkeys' clinical condition, semen quantity and quality, and clinical and pathological evaluations, no exposure-related adverse health effects were detected following exposure to concentrations of DMF ranging from 30 to 500 ppm for 13 weeks.

Administration, Inhalation↗
PubMed1991

Studies on the prenatal toxicity of N,N-dimethylformamide in mice, rats and rabbits.

Prenatal toxicity studies with N,N-dimethylformamide (DMF) in rabbits, rats and mice were carried out using the oral (gavage), dermal, inhalation and ip injection routes of administration. Administration of DMF by gavage led to an increase in malformations in rats and mice in the absence of overt maternal toxicity. The lowest-observable-effect level was 182 mg/kg body weight/day in mice and 166 mg/kg body weight/day in rats. After dermal administration a dose-dependent incidence of teratogenicity was observed in rats at 94-944 mg/kg/body weight/day in the absence of overt maternal toxicity. In rabbits dermal administration led to a steeper increase in the dose-response relationship and at 400 mg/kg body weight/day to a clear teratogenic effect in the presence of slight maternal toxicity. The 200 mg/kg body weight/day dose appeared to be the no-adverse-effect level. Inhalation in rats caused foetotoxicity and embryolethality at 287 ppm. A clear teratogenic effect was shown in rabbits at 450 ppm and a marginal effect at 150 ppm. The no-effect level for does and foetuses was 50 ppm. Ip injection in mice caused clear teratogenicity at 944 mg/kg body weight/day and slight embryotoxicity at 378 mg/kg body weight/day. The rabbit appears to be more sensitive than the rat to DMF-related prenatal toxicity and should, therefore, be used as the basis for the evaluation of teratogenic risk in humans.

Abnormalities, Drug-Induced↗
PubMed1981

Some observations on dimethylformamide hepatotoxicity.

Dimethylformamide (DMF) and its biotransformation products monomethylformamide (MMF) and formamide (F) were administered intraperitoneally to rats. Serum levels of sorbitol dehydrogenase (SDH) were studied at 3 h intervals from 9 h to 30 h after administration. Liver histology at 12, 21 and 30 h proved elevated SDH levels to be an indication of liver necrosis. DMF 479 mg/kg produced elevated enzyme levels at 27 h and 30 h while half the dose, 240 mg/kg, produced elevated levels from 15 h onwards. MMF 387 mg/kg produced elevated SDH levels at all times studied. F did not give elevated levels at any time. DMF (479 mg/kg) and MMF (387 mg/kg) administered simultaneously produced elevated SDH levels from 24 h onwards. These findings suggest that DMF hepatotoxicity is mediated by a degradation product of MMF and that DMF delays the hepatotoxic effect induced by MMF.

Animals↗
PubMedDate not supplied

Lack of mutagenic activity of dimethylformamide.

Different test systems have been utilized to evaluate the mutagenic and carcinogenic properties of dimethylformamide (DMF), an aliphatic amide used as a solvent in chemical industry. The Ames test was performed on different strains of Salmonella typhimurium, whereas the ability of DMF to induce structural aberrations in eukaryotic chromosomes was tested by in vitro observations on human lymphocytes and in vivo experiments on mouse bone marrow. Furthermore, male mice were treated with DMF for the induction of sperm abnormalities. The negative results obtained in all test systems as well as the absence of positive reports in man or in experimental animals with respect to induction of cancers suggest strongly that DMF is devoid of mutagenic or carcinogenic properties.

Animals↗
PubMed1984

Study on in vivo and in vitro metabolism of dimethylformamide in male and female rats.

The study of dimethylformamide (DMF) metabolism by rat tissues in vitro indicates that formaldehyde is not a metabolic product as previously reported [1]. Furthermore, no other monocarbon derivative (CO, CH3OH, HCOOH, CH4) was detected when DMF was incubated with a fortified liver preparation. One metabolic product is methylhydroxymethylformamide (DMF-OH) measured as N-methylformamide (NMF) due to the breakdown of the hydroxymethyl group during gas chromatography. It was usually believed that the main metabolite excreted in urine following administration of DMF to male and female rats was NMF. The results of this study indicate that DMF-OH constitutes the main metabolite in vivo. A quantitatively less important urinary metabolite, hydroxymethylformamide (NMF-OH), is determined as formamide (F) by gas chromatography. In male and female rats, partial hepatectomy reduces markedly the in vivo biotransformation of DMF. Following administration of DMF or NMF, the total amount of metabolites (DMF-OH and/or NMF-OH) excreted in urine is identical in both sexes, but female rats excrete more unchanged parent compound than male rats. The rate of NMF-OH excretion in urine following high doses of DMF supports the hypothesis that DMF may inhibit its own biotransformation.

Aminopyrine↗
PubMed1987

Dimethylformamide (DMF) hepatotoxicity.

Scattered case reports of accidental exposure and a few epidemiological studies have indicated that the liver is the main target organ following acute and chronic exposure to dimethylformamide (DMF). This has been confirmed in several animal species. In humans, ethanol intolerance is one of the earliest manifestations of (excessive) exposure to DMF, followed at higher exposure levels by various complaints (nausea, vomiting, abdominal pain) and the release of liver cytolytic enzymes in the plasma. The metabolic pathway of DMF has been recently clarified, but the primary cellular lesion responsible for its hepatotoxicity is still unknown.

Animals↗