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Kilo et al. 2016

Purpose

There are still concerns regarding occupational exposure to hepatotoxic DMF. This study was designed to evaluate possible liver damaging effects of DMF under current workplace conditions in synthetic fibres industries. Methods Among other laboratory parameters, liver function parameters (alkaline phosphatase (ALP), aspartate aminotransferase, alanine aminotransferase and gammaglutamyltransferase), the mean corpuscular erythrocyte volume (MCV) and carbohydrate-deficient transferrin (CDT) of the workforce of two companies present at the days of study were investigated. Internal exposure to DMF was assessed via three different biomarkers [sum of N-methylformamide and N-hydroxymethyl-N-methylformamide, N-acetyl-S-(N-carbamoyl)cysteine (AMCC) and 3-methyl-5-isopropylhydantoin (MIH)]. Alcohol consumption was assessed by means of direct ethanol metabolites (ethylglucuronide and ethylsulfate).

Results

None of the tested liver enzyme activities showed a positive association with any of the three exposure markers, nor did CDT and MCV. CDT was negatively associated with AMCC and the ALP activity negatively with all three exposure markers. Changes in liver function are seen mainly in conjunction with ethanol consumption but also with increasing body weight and age. MCV was associated with smoking. Almost half of the workers stated to experience alcohol flush reaction.

Conclusion

The present study indicates that long-term exposure to DMF, which was specified by median urinary AMCC levels of 4.84 mg/g creatinine and DMF haemoglobin adduct levels of 60.5 nmol/MIH/g globin, respectively, does not result in any adverse liver effects. In contrast, these DMF exposure levels still elicit certain alcohol intolerance reactions.

For the summary of other available literature please refer to "Additional information"

Additional information

Alcohol intolerance related to DMF exposure

In 1979, Lyle and coworkers found facial flushing and other symptoms in 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 symptoms included abdominal pain, flushing of skin on face, and arms, reddening of eyes, stomach ache, nausea etc. The flushing symptoms occurred at airborne DMF concentrations of 20 ppm. The highest recorded concentration of DMF in air was 200 ppm. The metabolite N-methylformamide (MF) was detected in the urine on 45 occasions, the highest recorded concentration being 77 µL/L. The authors attributed the DMF-ethanol reaction to the inhibition of acetaldehyde metabolism, probably by MF. Usually, the effects of alcohol intolerance persisted for several hours after working shift. However, there is single case noted, by a patient whose flushing symptoms persisted for many months after exposure ended (Cox and Mustchin, 1969). Lauwerys et al. studied workers exposed to DMF in an acrylic factory for the presence of biological signs of liver dysfunction and the NMF-concentration (pre- and post-shift), respectively (Lauwerys et al., 1980). The average DMF concentrations measured were in the range between 1.3 and 46.6 mg/m³ (median 13 mg/m³). NMF in urine samples collected at the end of the work shift did not exceed 40-50 mg/g creatinine. This level indicates an exposure which was reported as “safe” with regard to the acute and long term action of liver function. Serum liver enzymes (transaminases, OCT, 7-GT, AP) and bilirubin measurement were not different from those made in the control group. Nevertheless, some workers reported experiences of alcohol intolerance at the end of the day when they had been exposed to peak concentrations of DMF vapour. Similar findings were observed by Yonemoto et al. (Yonemoto et al., 1980). The cases of alcohol intolerance were reported in workers exposed for 3 years to 1-5 ppm DMF, although no increase in GOT, GPT, 7-GT was demonstrated. The amount of daily NMF excretion ranged from 0.4 to 19.56 mg. However, NMF excretion was delayed in workers with alcohol consumption. Cai et al. (Cai et al., 1992) reported that in workers exposed to max. 7 ppm DMF, the levels of liver function indicators were similar to controls, but subjective symptoms increased in a dose-dependent manner and the prevalence rate of alcohol intolerance complaints was elevated especially in workers with alcohol consumption. Authors suggested that a level at which no alcohol intolerance would occur is below that causing liver damage (Lauwerys et al., 1980, Yonemoto et al., 1980). In more recent studies (Wrbitzky and Angerer, 1998, Wrbitzky, 1999), a synergistic effect of alcohol consumption and increased liver indices was confirmed. Wrbitzky and Angerer found that exposure even to 22.2 ± 31 mg/m³ (7.3 ± 10.2 mL/m³) DMF in the air (corresponding to 16 ± 16 mg NMF/g creatinine) did not produce increased liver enzyme values in workers. It applies only to workers without alcohol consumption. In opposite to this, in workers with alcohol consumption, the liver indices were increased already at 1.4 mL/m³ (4.2 mg/m³), the value below German MAK value of 15mg/m³. Flush symptoms reported by these workers occurred in 71.5 % of persons compared to only 3.8 % in control persons. The effects of DMF and those of alcohol on liver values were dose-dependent. Furthermore, Wrbitzky using variance analysis showed that though alcohol consumption together with DMF exposure yields to a pronounced Influence at liver indices, DMF alone possesses a minor influence (Wrbitzky, 1999). An additional examination of urine samples of 17 workers at the end of working day revealed that no alcohol intolerance symptoms were reported at average NMF concentrations in urine of 19 ± 24.9 mg NMF/L urine (range 1.07 - 99.96 mg NMF/L) (Angerer and Drexler, 2005; reported in MAK, 40. Lieferung, 2006). This range of metabolite NMF in urine corresponds to about 0.4 - 62.3 mg/g creatinine, reported by Wrbitzky and Angerer, the values at which pronounced complaints after alcohol consumption were reported. Such discrepancies could be related to a complex of factors such as level of exposure resulted both from inhalation and dermal exposure, individual susceptibility and amount of alcohol intake.

 

Further observations

In the cohort study conducted by Chen et al (1988a) of 3859 actively employed workers with potential exposure to DMF and to DMF and acrylonitrile (ACN) in a fibre production facility.

When compared with company and national rates, there was no increase in the incidence of testicular cancer in 2530 actively employed workers exposed to DMF only.

Further, there was a significant increase in prostate cancer (10 observed vs. 5.1 expected from company rates and 5.2 expected from national rates; p < 0.10 for both comparisons) in the 3859 workers exposed either to DMF or to both DMF and ACN. However, when only DMF-exposed workers (2530) were considered, the standardized incidence rate (SIR) (4 observed vs. 2.4 expected from company rates) was not significant.

Chen et al. (1988a) also reported a significant increase in the incidence of cancer of the buccal cavity/pharynx (9 observed vs. 1.6 expected from company rates; p < 0.10) in the 2530 DMF-exposed workers. When combined with data from 1329 workers exposed to both DMF and ACN, the increase (11 observed) was significant when compared with the company rate (3.2 expected, p < 0.01), but not when compared with national rates (6.6 expected). There was no relation to the level or duration of exposure. All cases were heavy, long-term smokers.

Excess mortality from ischemic heart disease in DMF-exposed workers in a U.S. ACN fibre plant was observed in a historical cohort study (Chen et al., 1988b). Between 1950 and 1982, there were 62 deaths due to ischemic heart disease (40.3 expected from company rates; p < 0.01). The increase was not significant in comparison with the state (South Carolina) rates. A similar observation was made for a second group of 1329 employees at the plant who were potentially exposed to both DMF and CAN (65 deaths observed, 48.3 expected from company rates; p < 0.05) (Chen et al., 1988a). However, the rate was not significantly higher than either state or national rates. Lifestyle factors were suggested to be more likely causes than exposure to DMF.

A case-control study conducted by Walrath et al. (1989) in 4 factories producing and processing dimethylformamide with an average of 8724 male employees per year described for the years 1956 to 1985 a total of 39 oral cavity and throat carcinomas, 6 liver tumours, 43 prostate carcinomas, 11 testis tumours and 38 malignant melanomas. Summary analyses over all plants combined show no statistically significant association between ever having been exposed to DMF and subsequent development of cancers of the buccal cavity and pharynx, liver, malignant melanoma, prostate, and testis.

Fiorito et al. (1997) observed a significant increase in serum hepatic enzyme levels in 12 of 75 workers employed in a synthetic leather factory, exposed to 7 ppm (21 mg/m³) of DMF. Serum analysis revealed that the mean values of liver function indices (ALT, AST, GGTP, AP) were significantly higher in the exposed group compared to controls, as was the percentage of workers with abnormal liver function: 17 of 75 (22.7 %) had abnormal transaminase values, compared to 4 % in controls.

The evaluation of ‘‘paired enzymes’’ showed that 12 of 75 subjects had abnormal ‘‘paired enzymes,’’ while 11 others had higher BA levels. To avoid confounding factors, liver function tests were analyzed in subjects positive and negative for hepatitis markers and no difference was found. ANCOVA revealed that ALT, AST, GGTP, and PA are significantly higher (P < 0.001) in exposed workers also when data are adjusted for BMI and serum cholesterol level.

Major et al. (1998) reported an increase in serum enzymes (significance not reported) in 26 workers exposed to 0.2 -8 ppm (0.6 - 24 mg/m³) DMF with concomitant exposure to ACN (acrylonitrile). Urine ACN and monomethyl-formamide (MMF) excretions of the exposed subjects were almost doubled after work shifts. An increase in lymphocyte count (in months 0 and 7), and severe alterations in the liver function were observed in the exposed subjects. Repeated increases of total leukocyte counts (WBC) and urine hyppuric acid levels as well as repeated increases of GPT and GGT indicate serious alterations in hematology, and in liver functions of the exposed subjects.