Potentiation of halomethane hepatotoxicity by chlordecone: A hypothesis for the mechanism

Abstract

A major toxicological issue today is the possibility of unusual toxicity due to interaction of toxic chemicals upon environmental or occupational exposures to two or more chemicals, at ordinarily harmless levels individually. While some laboratory models exist for such interactions for the simplest case of only two chemicals, progress in this area has suffered for want of a model where the two interactants are individually nontoxic. One such model is available, where prior exposure to nontoxic levels of the pesticide Kepone R (chlordecone) results in a 67 — fold amplication of CC1 4 lethality in rats. Extensive hepatotoxicity observed in this interaction is characterized by histopathological alterations, perturbation of related biochemical parameters and is followed by complete hepatic failure. This propensity for chlordecone to potentiate hepatotoxicity of halomethanes such as CC1 4, CHC1 3, and BrCC1 3 has been a subject of intense study to unravel the underlying mechanism. Mechanisms such as induction of microsomal cytochrome P - 450 by chlordecone and greater lipid peroxidation are inadequate to explain the remarkably powerful potentiation of halomethane toxicity. Compelling experimental evidence supports the hypothesis that hepatocellular division during early time points after the administration of CC1 4 is an important determinant of the progression (or repair of it) of the liver injury and consequent destruction (or restoration) of the hepatolobular architecture and function. This paper advances a hypothesis for the mechanism of hepatotoxic and lethal effect of CC1 4 as being primarily related to the accelerated progression of liver injury due to suppressed hepatocellular regeneration and hepatolobular restoration. This is in contrast to the widely accepted putative mechannism, one which invokes only bioactivation followed by runaway lipid peroxidation as the events determining the course of the progressive phase of liver injury. The concept being advanced in this paper accepts bioactivation (and perhaps lipid peroxidation) as the primary initiating events of cell injury, but maintains that they are not the determinants of the progressive phase of liver injury. The biological issue of whether the cells are incapacitated from regenerating is the determinant of the progression of liver injury, and therefore, the ultimate outcome of hepatotoxicity and lethality.