Correlations of in vitro and in vivo hepatotoxicity for five haloalkanes.
Five haloalkanes--CBrCl3, CCl4, CHCl3, and 1,1,1-and 1,1,2-trichloroethane (TCE)--were ranked for their relative hepatotoxicity in an in vitro system of isolated hepatocyte suspensions and in vivo by po administration of the test chemical to fasted rats of the same strain and sex as used for the hepatocytes. Cytotoxic parameters used for ranking in the in vitro system were GOT and LDH release, and the results were expressed in terms of EC50 values (the dissolved haloalkane concentration required to release 50% of the cell content of each enzyme after 2 hr of exposure) for rank determination. Cytotoxic parameters measured in vivo were SGOT and SGPT, and the ranking was based on ED50 values (the haloalkane dose that produced an above normal serum transaminase level in 50% of the test animals). With these parameters, the potency rankings in each system were the same except that of 1,1,1-TCE, which was more cytotoxic in the in vitro system than would have been expected from the animal experiments. Purification of the 1,1,1-TCE to remove stabilizers, use of phenobarbital-induced hepatocytes or hepatocytes from starved rats, and administration of the haloalkanes ip instead of po failed to improve the correlation. The discrepancy could be resolved, however, by factoring air: medium partition coefficient data into the EC50 values to take into account differences in the volatility and aqueous and lipid solubility of the chemicals, and hence their retention in vivo. These observations encourage the belief that isolated hepatocyte systems have value for ranking structurally related chemicals as to their cytotoxic potential, even though their mechanisms of action may differ.
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001975:Bromotrichloromethane / Q000633:toxicity*; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002725:Chloroform / Q000031:analogs & derivatives* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014240:Trichloroethanes / Q000633:toxicity*
D006843:Hydrocarbons, Chlorinated; D014240:Trichloroethanes; D002725:Chloroform; D002251:Carbon Tetrachloride; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001975:Bromotrichloromethane