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.

Effect of ethanol on the urinary excretion of mandelic and phenylglyoxylic acids after human exposure to styrene.

Administration of ethanol in several doses during human exposure to styrene can inhibit the urinary mandelic and phenylglyoxylic acid excretion in a way similar to that reported when ethanol was administered as a single dose. Sensitivity to this inhibitory effect has been found to differ with individual subjects. Differences in long-term consumption of ethanol resulting in different induction of the oxidizing enzymes are suggested to account for this finding. Intra-individual variation in the influence of acute ethanol ingestion on the excretion rate of the mentioned acids can also occur. The habit of drinking ethanol might be important, even for partial redirection of the styrene metabolism from styrene glycol oxidation to styrene glycol conjugation with beta-glucuronic acid and/or sulfate. The consequences of these observations for the occupational hygiene practice are briefly outlined.

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.

Urinary excretion of mandelic and phenylglyoxylic acids after human exposure to styrene vapour.

The kinetics of the urinary excretion of mandelic and phenylglyoxylic acids were studied in volunteers exposed to the known concentrations of styrene vapour. The level and the time of exposure were suitably changed to simulate situations in the industrial environment. The aim was to find out the reasons for the contradictory reports in the literature and to verify parameters characterizing the course of excretion of both metabolites. It was found that the course of mandelic acid excretion might be influenced by the length of styrene exposure. If exposure was longer than 4 hours the maximum of excretion was at the end of the exposure time; after short-term exposures (4 h or less) it was somewhat delayed. Maximum excretion of phenylglyoxylic acid was delayed both after short-term and 8-hour exposures. Excretion of the metabolites was diphasic (biexponential). The effective half-lives were found to be independent of the level of exposure. The apparent half-lives (determined in the post-exposure time of 0-16 hours) tended to become prolonged at daily repeated exposures. The ratio of mandelic to phenylglyoxylic acid changed considerably with the level of exposure. In biological monitoring it is advisable to determine both metabolites.

Biological monitoring of persons exposed to methanol vapours.

Five volunteers were exposed to constant and suitably graded concentrations of methanol vapours for a period of 8 h. The retention of methanol in the lungs and the course of its excretion in urine were monitored at single and at daily repeated exposures. From the concentration in inspired air, lung retention, minute lung ventilation and duration of exposure, the methanol dose retained in the organism of the experimental subjects was calculated. The dose correlated well with the methanol concentration (mmol/l or mg/l) in whole-shift urine; using other units (mg/l corr., mg/creat., mg/time) the correlation was unsatisfactory. An exposure test was proposed which permits the estimation of the retained methanol dose on the basis of an analysis of whole-shift urine. The test yields good results even if the subjects perform physical work and consequently have enhanced lung ventilation, or in cases where the air besides methanol contains vapours of other organic solvents (ethanol, acetone). The results may be burdened by a certain error if the methanol concentration in air fluctuates extremely, or if exposure is interrupted by breaks. Nonetheless even in such circumstances the test provides valuable information on the level of occupational exposure to methanol.