title: Epidemic of liver disease caused by hydrochlorofluorocarbons used as ozone-sparing substitutes of chlorofluorocarbons.
abstract: BACKGROUND
  Hydrochlorofluorocarbons (HCFCs) are used increasingly in industry as substitutes for ozone-depleting chlorofluorocarbons (CFCs). Limited studies in animals indicate potential hepatotoxicity of some of these compounds. We investigated an epidemic of liver disease in nine industrial workers who had had repeated accidental exposure to a mixture of 1,1-dichloro-2,2,2-trifluoroethane (HCFC 123) and 1-chloro-1,2,2,2-tetrafluoroethane (HCFC 124). All nine exposed workers were affected to various degrees. Both compounds are metabolised in the same way as 1-bromo-1-chloro-2,2,2-trifluoroethane (halothane) to form reactive trifluoroacetyl halide intermediates, which have been implicated in the hepatotoxicity of halothane. We aimed to test whether HCFCs 123 and 124 can result in serious liver disease.
  
  
  METHODS
  For one severely affected worker liver biopsy and immunohistochemical stainings for the presence of trifluoroacetyl protein adducts were done. The serum of six affected workers and five controls was tested for autoantibodies that react with human liver cytochrome-P450 2E1 (P450 2E1) and P58 protein disulphide isomerase isoform (P58).
  
  
  RESULTS
  The liver biopsy sample showed hepatocellular necrosis which was prominent in perivenular zone three and extended focally from portal tracts to portal tracts and centrilobular areas (bridging necrosis). Trifluoroacetyl-adducted proteins were detected in surviving hepatocytes. Autoantibodies against P450 2E1 or P58, previously associated with halothane hepatitis, were detected in the serum of five affected workers.
  
  
  CONCLUSIONS
  Repeated exposure of human beings to HCFCs 123 and 124 can result in serious liver injury in a large proportion of the exposed population. Although the exact mechanism of hepatotoxicity of these agents is not known, the results suggest that trifluoroacetyl-altered liver proteins are involved. In view of the potentially widespread use of these compounds, there is an urgent need to develop safer alternatives.
authors.affiliation: Catholic University of Louvain, Faculty of Medicine, Brussels, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Hoet
authors.forename: M L
authors.initials: ML
authors.lastname: Graf
authors.forename: M
authors.initials: M
authors.lastname: Bourdi
authors.forename: L R
authors.initials: LR
authors.lastname: Pohl
authors.forename: P H
authors.initials: PH
authors.lastname: Duray
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: R M
authors.initials: RM
authors.lastname: Peter
authors.forename: S D
authors.initials: SD
authors.lastname: Nelson
authors.forename: N
authors.initials: N
authors.lastname: Verlinden
authors.forename: D
authors.initials: D
authors.lastname: Lison
mesh_terms: D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017402:Chlorofluorocarbons / Q000009:adverse effects*; D064227:Chlorofluorocarbons, Ethane; D005617:Chlorofluorocarbons, Methane / Q000009:adverse effects*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004196:Disease Outbreaks; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure / Q000009:adverse effects*; D014269:Trifluoroacetic Acid / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017402:Chlorofluorocarbons; D064227:Chlorofluorocarbons, Ethane; D005617:Chlorofluorocarbons, Methane; C072959:1,1,1,2-tetrafluoro-2-chloroethane; C067411:2,2-dichloro-1,1,1-trifluoroethane; D014269:Trifluoroacetic Acid; D019392:Cytochrome P-450 CYP2E1