Liver disease associated with occupational exposure to the solvent dimethylformamide.

Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
Annals of internal medicine (Impact Factor: 13.98). 06/1988; 108(5):680-6.
Source: PubMed

ABSTRACT to characterize an outbreak of liver disease among workers in a fabric coating factory; and to determine the outbreak's cause and natural history and strategies for clinical recognition, treatment, and prevention.
clinical-epidemiological investigation.
academic medical center, Occupational Medicine Clinic, and worksite.
fifty-eight of sixty-six workers participated in the study. All had standard liver function tests at least once. Forty-six workers completed a questionnaire; 27 had more extensive clinical evaluation for recognized liver abnormalities.
a plant-wide outbreak of liver disease was recognized after a new employee presented with signs and symptoms of hepatitis. Evaluation of the worksite showed that dimethylformamide, a widely used industrial solvent and known hepatotoxin, was being used to coat fabric in poorly ventilated areas without appropriate skin protection. No other major hepatotoxic exposure was identified. Overall, 36 of 58 (62%) workers tested had elevations of either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels. Enzyme abnormalities occurred almost exclusively in production workers (35 of 46 were abnormal), whereas only 1 of 12 nonproduction workers showed any elevations in enzyme levels (P less than 0.0001). Serologic tests excluded known infectious causes of hepatitis in all but 2 workers and changes characteristic of toxic liver injury were confirmed by histologic examinations of biopsy specimens from 4 workers. The ratio of AST to ALT levels was one or less in all but 1 worker. After modification of work practices and removal of workers most severely affected from exposure, improvement in liver enzyme abnormalities and symptoms in most patients were seen, although some patients showed persistent elevations of enzyme levels.
an outbreak of toxic liver disease has been associated with exposure to dimethylformamide in the workplace. The diagnosis of toxic liver disease was established by the clinical histories, negative viral serologies, an enzyme pattern of ALT levels being greater than AST levels, epidemiologic data on coworkers, and liver biopsy specimens. The high prevalence of unsuspected liver enzyme abnormalities in these workers suggests that occupational liver disease may occur more frequently than is generally recognized.

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    ABSTRACT: A diffusive sampling method with water as absorbent was examined in comparison with 3 conventional methods of diffusive sampling with carbon cloth as absorbent, pumping through National Institute of Occupational Safety and Health (NIOSH) charcoal tubes, and pumping through NIOSH silica gel tubes to measure time-weighted average concentration of dimethylformamide (DMF). DMF vapors of constant concentrations at 3–110 ppm were generated by bubbling air at constant velocities through liquid DMF followed by dilution with fresh air. Both types of diffusive samplers could either absorb or adsorb DMF in proportion to time (0.25–8 h) and concentration (3–58 ppm), except that the DMF adsorbed was below the measurable amount when carbon cloth samplers were exposed at 3 ppm for less than 1 h. When both diffusive samplers were loaded with DMF and kept in fresh air, the DMF in water samplers stayed unchanged for at least for 12 h. The DMF in carbon cloth samplers showed a decay with a half-time of 14.3 h. When the carbon cloth was taken out immediately after termination of DMF exposure, wrapped in aluminum foil, and kept refrigerated, however, there was no measurable decrease in DMF for at least 3 weeks. When the air was drawn at 0.2 l/min, a breakthrough of the silica gel tube took place at about 4 000 ppm min (as the lower 95% confidence limit), whereas charcoal tubes could tolerate even heavier exposures, suggesting that both tubes are fit to measure the 8-h time-weighted average of DMF at 10 ppm.
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    ABSTRACT: N,N-dimethylformamide (DMF), an organic solvent widely used in industry, is bioactivated by cytochrome P450 (P450) to reactive metabolites which are believed to be responsible for the hepatotoxicity observed in animals and humans. A decrease of the activating enzyme has been reported in rats treated with DMF, although the specific P450 isoform(s) involved and the nature of the reactive species responsible for this and the other toxic effects are still being investigated. In the present work, the effect of DMF and of the structurally related N,N-dimethylacetamide (DMAc) on the activating enzyme and the nature of the reactive species involved in the mechanism of P450 inactivation by the two chemicals were investigated in vitro. Incubation of liver microsomes from pyridine-induced rats with either substrate resulted in a dose-dependent (0-20 mM) loss of P450 (up to 28 and 24% for DMF and DMAc, respectively), microsomal haem (up to 24 and 20% for DMF and DMAc, respectively), but not protoporphyrin IX content. Moreover, bubbling of CO through the incubation mixture gave almost complete protection against substrate-dependent P450 inactivation, and the spin trapping agent N-tert-butyl-alpha-phenylnitrone, but neither glutathione nor vitamin C, provided a significant protection against DMF- or DMAc-dependent haem loss. Finally, electron spin resonance analysis of microsomal incubations in presence of DMF or DMAc showed spectral evidence for a carbon centered radical intermediate. The results indicate, overall, that both compounds are metabolized in vitro by P450, probably CYP2E1, to free radical metabolites which attack the haem prosthetic group, leading to suicidal enzyme inactivation.
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    ABSTRACT: A factory survey was conducted in a plant whereN,N-dimethylformamide (DMF) was in use during the production of polyurethan plastics and related materials. In all, 318 DMF-exposed workers (195 men and 123 women) and 143 non-exposed controls (67 men and 76 women) were examined for time-weighted average exposure (to DMF and other solvents by diffusive sampling), hematology, serum biochemistry, subjective symptoms, and clinical signs. Most of the exposed workers were exposed only to DMF, whereas others were exposed to a combination of DMF and toluene. DMF exposure in the former group was up to 7.0 ppm (geometric mean on a workshop basis), whereas it was up to 2.1 ppm in combination with 4.2 ppm toluene. Both hematology and serum biochemistry, results (including aspartate and alanine aminotransferases, -glutamyl transpeptidase and amylase) were essentially comparable among the 3 groups. There was, however, a dose-dependent increase in subjective symptoms, especially during work, and in digestive system-related symptoms such as nausea and abdominal pain in the past 3-month period. The prevalence rate of alcohol intolerance complaints among male (assumedly) social drinkers was also elevated in relation to DMF dose.
    International Archives of Occupational and Environmental Health 12/1991; 63(7):461-468. · 2.10 Impact Factor

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