HEPATOTOXICITY AND LETHALITY OF HALOMETHANES IN MONGOLIAN GERBILS PRETREATED WITH CHLORDECONE, PHENOBARBITAL OR MIREX

The hepatotoxic and lethal effects of CBrCl3, CCl4 and CHCl3 were investigated in gerbils with or without prior exposure to dietary chlordecone (CD), phenobarbital (PB) and mirex (MX) at 10, 225 and 10 ppm, respectively, for 15 days. Gerbils were quite sensitive to these halomethanes (48 h LD50: 20, 80 and 400-mu-l/kg, respectively). CD, known to potentiate hepatotoxic and lethal effects of halomethanes in rats, failed to potentiate the toxic effects of any of these three halomethanes in gerbils. PB and MX were also ineffective. Since stimulation of early hepatocellular regeneration has been shown to be responsible for the recovery from the toxicity of a low dose of CCl4, liver cell regeneration and tissue repair were studied in gerbils after CCl4 administration. The objectives of these studies were to investigate the possible reasons for the high sensitivity of gerbils to halomethane toxicity and to investigate the mechanism for their refractoriness to CD-potentiated halomethane toxicity. A low and a high dose of CCl4 (15 and 80-mu-l/kg, i.p. respectively) were used to study the time-course of liver injury in gerbils pretreated with or without CD. The low dose of CCl4 stimulated cellular regeneration as indicated by the increase of H-3-thymidine (H-3-T) incorporation in hepatic nuclear DNA. The cellular regeneration and tissue repair activities resulted in complete recovery from the limited liver injury in both CD-pretreated and control gerbils. In contrast to rats, however, the process of cell division in gerbils occurred much later, 2 days after CCl4 administration. Evidence from histomorphometric studies was consistent with serum enzyme and H-3-T incorporation data. Significant increase in hepatocyte mitosis did not occur until 42 h after CCl4 administration. Hepatic injury assessed as hepatocellular necrosis and lipid accumulation was evident as early as 24 h after CCl4 injection and was maximal at 42 and 72 h after CCl4 in CD-pretreated and control gerbils, respectively. Administration of a high dose of CCl4 alone significantly impeded tissue repair. More than 65% of the hepatocytes were necrotic in both CD-pretreated and control gerbils 24 h after the administration of a LD50 dose of CCl4. H-3-T incorporation did not increase up to 48 h after CCl4 in either group. These findings suggest that the absence of early stimulation of hepatocellular division and tissue repair might be responsible for the very high toxicity of a low dose of CCl4 in gerbils. Since there is no early tissue proliferative response in gerbils after CCl4 administration, CD+CCl4 interactive ablation of liver proliferative response cannot occur, making gerbils refractory to CD-potentiation of CCl4 toxicity.