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Epidemiologic Notes and Reports Outbreak of Occupational Hepatitis -- Connecticut

On September 28, 1986, a previously healthy, 40-year-old male factory worker who had experienced several days of abdominal pain and nausea was seen at the emergency room at Yale-New Haven Hospital, New Haven, Connecticut. Liver function tests revealed an elevated aspartate aminotransferase (AST) level of 949 U/L (normal = 35 U/L). Alkaline phosphatase and bilirubin assays were all normal. Hepatitis A IgM antibody and hepatitis B surface antigen and antibody were negative, as was an abdominal ultrasound.

Further history revealed that the patient had become ill after working for 2 weeks at a plant where fabrics are coated with a polyurethane polymer. He had no history of significant alcohol use or blood transfusions. When the patient was removed from the workplace, his symptoms resolved. Subsequent liver function tests have revealed partial resolution of his hepatitis. However, 2 months later, his alanine aminotransferase (ALT) level was still elevated at 207 U/L (normal = 32 U/L), and his AST level was 49 U/L. Within 1 month, three other co-workers were seen with similar symptoms and liver enzyme abnormalities.

Inspection of the patients' workplace showed that large quantities of dimethylformamide (DMF), a solvent which is widely used in manufacturing acrylic fibers and polyurethanes, were being used in poorly ventilated areas. DMF and smaller quantities of other solvents including toluene; methyl ethyl ketone; and 1,1,1 trichloroethane were mixed with polyurethane polymer, coated onto the fabric, and then evaporated from the polyurethane-coated fabric as it dried. The company has 66 employees, most of whom work directly in the production of polyurethane-coated materials. The employees are generally young (mean age = 35 years) and healthy.

Forty-five of the employees agreed to have liver screening tests, including AST, ALT, bilirubin, g-glutamyl transpeptidase (GGT), alkaline phosphatase, and lactate dehydrogenase. Thirty of the 45 employees screened had elevated levels of AST, ALT, or GGT. Eleven had elevations that were more than twice the normal level for one or more of these liver enzymes. In all but one employee, the ALT level was greater than the AST level. In addition, workers directly involved with producing the polyurethane-coated material had higher liver enzyme elevations than did nonproduction workers.

Based on these findings, the professional staff at the Yale Occupational Medicine Program urged immediate termination of the production process until protective engineering controls had been adequately installed. These instructions have been followed. This cohort of workers will be followed to help ascertain whether DMF causes chronic liver damage. Reported by C Redlich, MD, J Sparer, MSCE, D Cowan, W Beckett, MD, H Miller, M Cherniack, MD, M Cullen, MD, Occupational Medicine Program, Yale University Medical Center; Office of the Director, National Institute for Occupational Safety and Health, CDC.

Editorial Note

Editorial Note: Although the hepatotoxic effects of industrial chemicals such as carbon tetrachloride (CCl((4))), chlordecone (kepone), and monovinyl chloride are widely known, occupationally induced liver disease is regarded by some as a historic problem (1). However, there is continuing evidence that chemically induced hepatic disease is an important occupational health problem for selected U.S. workers. This outbreak of subacute hepatic disease, occurring during routine workplace exposure to DMF, without evidence of a chemical spill or accidental release, further emphasizes the importance of this problem.

Because of its excellent solvent properties and lack of volatility, DMF is widely used in manufacturing polymerized films, fibers, and coatings, particularly in acrylic and spandex fabrics. It is readily absorbed through the skin and lungs, metabolized by the liver, and excreted in urine. In several earlier toxicologic assays, chronic exposure to DMF produced liver abnormalities in cats, rats, rabbits, mice, and dogs (2,3). When these occurred, air concentrations were above the current federally permissible exposure limit (PEL) of 10 parts per million. There have been several reported cases of human liver injury accompanied by abdominal pain and elevated hepatic transaminases, but these have been attributed to accidental overexposures (4,5). An antabuse-like reaction of flushing and dizziness, caused by coincident ethanol ingestion, has also been described among DMF workers, but without measurable liver injury (6).

Since two-thirds of the tested employees had elevated liver enzymes even though there was no documentation of recent or chronic liver infection for any of them, this outbreak raises concerns about whether DMF poses a significant and overlooked human health hazard or whether other agents or factors could be responsible. When introduced independently, the other solvents used (methyl ethyl ketone; toluene; and 1,1,1 trichloroethane) have been only minimally associated with human or animal liver toxicity. A potentiating effect is indeed possible, however. Liver damage, induced by the well-known hepatotoxin carbon tetrachloride, can be aggravated by simultaneous exposure to a variety of organic chemicals of lesser or immeasurable hepatotoxicity (7,8).

There are precedents that reinforce the possibility that serious human hepatotoxins may not have yet been recognized. For some of the most severe occupational hepatotoxins, such as trinitrotoluene, dimethylnitrosamine, polychlorinated biphenyls, and tetrachloroethane, the epidemiologic identification of human liver disease preceded an adequate exploration of animal hepatotoxicity. On the other hand, human liver disease from the organochloride insecticide, kepone, reached national attention through reports in the lay press in the mid-1970s, although parallel animal toxicities had been demonstrated a decade earlier.

Adverse human effects from DMF and other dimethylamides merit a much closer look. Perhaps this review should also include the classes of halogenated hydrocarbons and nitroaromatics from which the most damaging identified hepatotoxins have emerged.


  1. Zimmerman HJ. Hepatotoxicity. New York: Appleton-Century Croft, 1978:303-18.

  2. Massmann W. Toxicological investigations on dimethylformamide. Br J Ind Med 1956;13:51-4.

  3. Clayton JW, Barnes JR, Hood DB, Schepers GW. The inhalation toxicity of dimethylformamide (DMF). Am Hyg Assoc J 1963;24:144-54.

  4. Potter HP. Dimethylformamide-induced abdominal pain and liver injury. Arch Environ Health 1973;27:340-1.

  5. Reinl W, Urban HJ. Erkrankungen durch dimethylformamid. Int Arch Gewerbepath 1965;21:333-46.

  6. Lyle WH, Spence TW, McKinneley WM, Duckers K. Dimethylformamide and alcohol intolerance. Br J Ind Med 1979;36:63-6.

  7. Klasen CD, Plaa GL. Comparison of the biochemical alterations elicited in livers from rats treated with carbon tetrachloride, chloroform and 1,1,1 trichloroethane. Biochem Pharmacol 1969;18:2019-27.

  8. Cornich HH, Adefuni J. Potentiation of carbon tetrachloride toxicity by aliphatic alcohols. Arch Environ Health 1967;14:447-9.

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