TOXICOLOGY OF ORGANOCHLORINE INSECTICIDES metabolism by reduction of the ketone group to give chlordecone alcohol (chlor-

62 TOXICOLOGY OF ORGANOCHLORINE INSECTICIDES metabolism by reduction of the ketone group to give chlordecone alcohol (chlor-

decol) and subsequent glucuronidation (Blanke et al., 1978; Fariss et al., 1980). Interestingly, this is only a minor metabolite in rats, mice, and guinea pigs but much more significant in humans and the Mongolian gerbil (Houston et al., 1981). The species differences seemed to be explained by the presence of a specific aldo-ketose reductase in humans, gerbils (Molowa, Shayne, and Guzelian 1986a; Molowa et al., 1986b) and possibly pigs (Soine, Blanke, and Schwartz, 1983). Despite the formation of chlordecone alcohol in humans, the overall rate of clear- ance of chlordecone appears to be greater in rats and mice.

Experimental in vivo toxicity Deaths of rats and mice from chlordecone are preceded by abnormal gait and severe

tremors. The acute dermal LD 50 values for rats are approximately 10 times that of the oral doses, reflecting the solubility of the pesticide in the intestinal tract (Egle, Guzelian, and Borzelleca, 1979; Gaines, 1969; Larson et al., 1979b; Smith, 1991). Chronic administration leads to a decreased weight gain, liver enlargement as well as changes in the adrenals (hyperplasia of the zona fasiculata and zona reticularis), kidney, and testes (Baggett, Thureson-Klein, and Klein, 1980; Klingensmith and Mehendale, 1982). Over a prolonged period hepatocellular carcinomas and adeno- mas occur to an increased degree in mice and rats that survive chronic administra- tion of chlordecone at low doses in their diets (approximately 20 ppm) for up to 2 years (Larson et al., 1979b; NCI, 1976; Reuber, 1978). There is little evidence to support the view that chlordecone is a mutagen in its hepatocarcinogenic action (Smith, 1991) and is more likely acting as an epigenetic carcinogen (Sirica et al., 1989). The most characteristic feature of chlordecone toxicity is the effects on reproduction described below.

Mechanistic studies

A great many studies have been concerned with the inhibition of mitochondrial and membrane bound Na þ ,K þ -ATPases, and certain Mg þ -ATPases caused by chlor- decone perhaps associated with energy production (see Smith, 1991). Other studies on both liver and brain implicate aspects of calcium metabolism linked to ATPases (Herr, Gallus, and Tilson, 1987; Hoskins and Ho, 1982) in a mechanism that does not occur with mirex. It was proposed that chlordecone increases free intra-

synaptosomal Ca 2 þ by a non-specific leakage through the plasma membrane and by passage through voltage-sensitive Ca 2 þ due to membrane depolarization (Komulainen and Bondy, 1987). This is compatible with increased synaptosomal calcium levels causing depolarization of the membrane-enhancing release of neuro- transmitters. Chlordecone may, through activation of serotonin neurons, cause de- creased GABAergic activity in the striatum and thereby an increase in cholinergic tone, inducing tremors (Gandolfi et al., 1984). The relationship between brain

63 ATPases, calcium homeostasis and neurotransmitter turnover is still not understood.

MIREX AND CHLORDECONE

It is known that chlordecone does not bind to the picrotoxin binding site of the GABA–receptor complex as do lindane, cyclodienes, and toxaphenes (Lawrence and Casida, 1984).

A variety of studies have demonstrated that chlordecone potentiates CCl 4 hepatic toxicity and that partial hepatectomy protects against this. Potentiation occurs at doses of chlordecone that do not increase lipid peroxidation or cytochrome P-450 activity (Mehendale, 1989; Smith, 1991). The findings do not seem to be explained

by greater CCl 4 metabolism. Chlordecone enhances the suppression of calcium sequestration by microsomes (Hegarty, Glende, and Recknagel, 1986) and it is thought that chlordecone suppresses hepatocellular regeneration after necrosis

caused by CCl 4 (Carpenter et al., 1996; Chaudhury and Mehendale, 1991; Kodavanti, Rao, and Mehendale, 1993; Kodavanti et al., 1992; Rochelle and Curtis, 1994; Soni and Mehendale, 1993; Soni and Mehendale, 1998) although neonatal rats are resistant to this effect (Cai and Mehendale, 1993; Dalu and Mehendale, 1996; Dalu, Rao, and Mehendale 1998; Dalu et al., 1995; Gilroy, Carpenter, and Curtis, 1994). Chlordecone also seems to inhibit the transfer of metabolites from hepatocyte to the bile canaliculus possibly by interference of particular ABC trans- porters (Gilroy, Carpenter, and Curtis, 1994; Guzelian, 1982).

Reproductive effects Early studies in rats, mice, and birds showed clearly that chlordecone affects