Mechanism of the lethal interaction of chlordecone and CCl4 at non-toxic doses.

There is significant interest in the possibility of unusual toxicity due to interaction of toxic chemicals upon environmental or occupational exposures even though such exposures may involve levels ordinarily considered harmless individually. While many laboratory and experimental models exist for such interactions, progress in this area of toxicology has suffered for want of a model where the interactants are individually non-toxic. We developed such a model where prior exposure to non-toxic levels of the pesticide Kepone (chlordecone) results in a 67-fold amplification of CCl4 lethality in experimental animals. The mechanism(s) by which chlordecone amplifies the hepatotoxicity of halomethanes such as CCl4, CHCl3, and BrCCl3 has been a subject of intense study. The biological effects of this interaction include extensive hepatotoxicity characterized by histopathological alterations, hepatic dysfunction, and perturbation of related biochemical parameters. Close structural analogs of chlordecone such as mirex and photomirex do not share the propensity of chlordecone to potentiate halomethane toxicity. Mechanisms such as induction of microsomal cytochrome P-450 by chlordecone and greater lipid peroxidation are inadequate to explain the remarkably powerful potentiation of toxicity and lethality. Time-course studies in which liver tissue was examined 1-36 h after CCl4 administration were conducted. While animals receiving a normally nontoxic dose of CCl4 alone show limited hepatocellular necrosis by 6 h, proceeding to greater injury after 12 h, recovery phase ensues as revealed by greatly increased number of mitotic figures. Such regeneration and hepatic tissue repair processes are totally suppressed in animals exposed to chlordecone prior to CCl4. Thus, the arrested hepatocellular repair and renovation play a key role in the potentiation of CCl4 liver injury by chlordecone. These findings have allowed us to propose a novel hypothesis for the mechanism of chlordecone amplification of halomethane toxicity and lethality. While limited injury is initiated by the low dose of CCl4 by bioactivation followed by lipid peroxidation, this normally recoverable injury permissively progresses due to arrested hepatocellular regeneration and tissue repair processes. Recent studies designed to test this hypothesis have provided additional supporting evidence. Hepatocellular regeneration stimulated by partial hepatectomy was unaffected by 10 ppm dietary chlordecone, while these animals were protected from the hepatotoxic and lethal actions of CCl4 if administered at the time of maximal hepatocellular regeneration. The protection was abolished when CCl4 was administered upon cessation of hepatocellular regeneration.