Investigations on the liver toxicity of a blend of HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and HCFC-124 (2-chloro-1,1,1,2-tetrafluoroethane) in guinea-pigs.
2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) has been developed as a substitute for ozone-depleting chlorofluorocarbons (CFCs). It is a structural analogue of halothane and similarities in the metabolic pathways and liver toxicity of both compounds have been described. The present study was initiated after an accidental outbreak of hepatitis in an industrial setting to examine whether concomitant exposure to 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124), which is not hepatotoxic, could enhance the liver toxicity of HCFC-123. Male Hartley guinea-pigs were exposed for 4 h to 5,000 ppm HCFC-123 alone or blended with 5,000 ppm HCFC-124, either once (single exposure) or on 5 consecutive days (repeated exposure). The animals were killed either 24 or 48 h after the last exposure. A transient cytolytic action of HCFC-123 was evident by increased mean serum levels of alanine aminotransferase at 24 h and isocitrate dehydrogenase at 24 and 48 h, both after a single or repeated exposure. The liver toxicity of HCFC-123 was confirmed by pathological examination of liver tissue, which showed mild (foci of necrotic hepatocytes) to moderate (multifocal random degeneration and necrosis) damage. Steatosis was also observed and was more pronounced after repeated exposure than after single. One animal out of 6 that were repeatedly exposed to the blend and sacrificed at 24 h showed liver lesions similar to halothane hepatitis. Although a few other animals responded markedly in the blend-treated group, on average, no significant difference in the biochemical or pathological lesions was found between the groups treated with HCFC-123 alone or with the blend. Urinary excretion of trifluoroacetic acid and chlorodifluoroacetic acid increased dose-dependently upon exposure to HCFC-123 and indicated accumulation after repeated exposure. No difference in metabolite excretion was found between animals treated with HCFC-123 alone or blended with HCFC-124. Treatment with HCFC-123 depleted hepatic glutathione levels by about 40 and 25% after single and repeated exposure, respectively; the amplitude of this reduction was not modified by co-exposure to HCFC-124. In conclusion, this study confirmed the hepatotoxicity of HCFC-123, based on biochemical, histopathological and metabolite studies, and found only very limited indication of a potentiation by HCFC-124 of this hepatotoxic effect.
Hoet
P
P
Université Catholique de Louvain, Faculty of Medicine, Industrial Toxicology and Occupational Medicine Unit, Brussels, Belgium. hoet@toxi.ucl.ac.be
Buchet
J P
JP
Sempoux
C
C
Nomiyama
T
T
Rahier
J
J
Lison
D
D
D000280:Administration, Inhalation; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D021461:Animals, Outbred Strains; D001219:Aspartate Aminotransferases / Q000097:blood; D017402:Chlorofluorocarbons / Q000008:administration & dosage / Q000633:toxicity* / Q000652:urine; D064227:Chlorofluorocarbons, Ethane; D005617:Chlorofluorocarbons, Methane / Q000008:administration & dosage / Q000633:toxicity* / Q000652:urine; D002784:Cholesterol / Q000032:analysis; D004338:Drug Combinations; D005230:Fatty Acids, Nonesterified / Q000032:analysis; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology; D005978:Glutathione / Q000032:analysis; D005990:Glycerol / Q000032:analysis; D006168:Guinea Pigs; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D019570:Inhalation Exposure; D007521:Isocitrate Dehydrogenase / Q000097:blood; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009336:Necrosis
D017402:Chlorofluorocarbons; D064227:Chlorofluorocarbons, Ethane; D005617:Chlorofluorocarbons, Methane; D004338:Drug Combinations; D005230:Fatty Acids, Nonesterified; C072959:1,1,1,2-tetrafluoro-2-chloroethane; C067411:2,2-dichloro-1,1,1-trifluoroethane; D002784:Cholesterol; D007521:Isocitrate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D005990:Glycerol