TOXICOLOGY OF ORGANOCHLORINE INSECTICIDES turnover of inositol phospholipids after the occupation of some cell surface recep-

36 TOXICOLOGY OF ORGANOCHLORINE INSECTICIDES turnover of inositol phospholipids after the occupation of some cell surface recep-

tors by agonists and the involvement of Ca 2 þ (Holian, Marchiarullo, and Stickle, 1984; Stark, Chuang, and Joy, 1987). Lindane does not act as a competitive in- hibitor in enzyme systems which act on myo-inositol but that in a fairly specific manner it inhibits phosphatidylinositol synthase (Parries and Hokin-Neaverson, 1985). Whether these effects of lindane on phosphatidylinositol metabolism are of any importance in vivo is not clear.

An important finding was the demonstration that lindane binds specifically to the GABA–receptor–ionophore complex, probably in the cerebellum (Matsumura and Ghiasuddin, 1983). This results in the effects of GABA and GABAergic transmis- sion being disturbed (Lawrence and Casida, 1984; Matsumura and Ghiasuddin, 1983). The degree of binding for lindane, other BHC isomers, dieldrin, and other chlorinated insecticides correlated with their acute toxicities and abilities to induce convulsions at similar dose levels (Abalis, Eldefrawi, and Eldefrawi, 1985; Casida and Lawrence, 1985; Cole and Casida, 1986; Lawrence and Casida, 1984) espe-

cially the GABA A receptor (Nagata and Narahashi, 1995; Ratra, Kamita, and Casida, 2001; Ratra et al., 2002). In addition, lindane inhibits stereospecifically the GABA-induced 36 CI-influx into rat brain membrane microsacs, whereas has no effect (Abalis, Eldefrawi, and Eldefrawi, 1986; Bloomquist and Soderlund, 1985). Diazepam blocks the anorexic and hypothermic effects of lindane, and this could be taken as evidence for action at this receptor (Woolley et al., 1985). However, the protection by lindane against the convulsant properties of pentylene- tetrazole, which also acts at the GABA–receptor-linked chloride channel, after the insecticide itself has disappeared, shows that the mechanism is highly complex (Fishman and Gianutsos, 1987; Vohland, Portig, and Stein, 1981). Although some work implied that impairment of the GABA–receptor–ionophore complex might not be involved in the neurotoxicity of lindane in vivo, other evidence suggested differently (Bloomquist, Adams, and Soderlund, 1986; Cattabeni, Pastorello, and Eli, 1983; Sunol et al., 1989).

Many of the symptoms of lindane poisoning are similar to those of dysfunction of the hippocampus–limbic system and measurements of glucose uptake by the brain at convulsant doses of lindane show increases in the limbic regions (Camon et al. , 1988b; Woolley et al., 1984). Long-term potentiation by lindane of the evoked potential elicited in the dentate gyrus after stimulation of the prepyriform cortex occurs when levels of the chemical should have greatly diminished (Woolley, 1985; Woolley et al., 1985). Kindling is a sequence of changes resulting from repeated stimulation of a part of the limbic system, such as the amygdala. Progressively severe behavioural signs are observed in the rat, commencing with eye-closing or chewing and climaxing in clonic motor seizure after lindane (Joy, 1982, 1985; Joy and Albertson, 1985, 1988; Joy and Burns, 1988; Stark, Albertson, and Joy, 1986).

kindling acquisition. Exposure of neonates to lindane can greatly enhance their acquisition of kindling in adulthood (Albertson, Joy, and Stark, 1985). Further

37 studies have suggested that the granule cell population of the dentate gyrus be-

LINDANE =HEXACHLOROCYCLOHEXANE (HCH)

comes more excitable and it seems likely that the convulsant action of lindane is explicable by interaction with the GABA receptor (Joy and Albertson, 1985, 1987a, 1987b, 1988). Experiments with cultured neurons from newborn rat dorsal root ganglia supported the hypothesis that lindane in vivo inhibits the GABA–recep- tor-channel complex but also raised the possibility of multiple receptors (Ogata, Vogel, and Narahashi, 1988). Behavioural effects might be linked to the neurotoxi- city phenomena described (Tilson, Shaw, and McLamb, 1987).

Mutation and carcinogenesis In host-mediated tests in mice and in direct tests on indicator organisms, HCH was

not mutagenic (Smith, 1991; Wildemauwe et al., 1983; Wolff et al., 1987). Other in vitro tests have shown little evidence of genotoxic or mutagenic activity of lindane either (IPCS, 1991, 1992; Iverson et al., 1984). Rats are not susceptible to the tumorigenic effects of lindane and HCH (IPCS, 1991, 1992; Smith, 1991). On the other hand, mice seem to develop hepatic tumours in some strains after chronic exposure to lindane and the other isomers as well as technical HCH. The may be more active than the others. In mice with a dominant mutation at the agouti locus that increases susceptibility to strain-specific spontaneous and chemically induced neoplasms, lindane appeared to act as a tumour promoter via a cellular proliferation mechanism, perhaps as with other pesticides, by a non-genotoxic mechanism mediated by inhibition of the gap–junction intercellular communication (Guan and Ruch, 1996). tumours or foci previously initiated by carcinogens such as diethylnitrosamine (Munir, Rao, and Bhide, 1984; Pereira et al., 1982; Schroter et al., 1987; Schulte-Hermann, 1985; Schulte-Hermann and Parzefall, 1981). In contrast, lindane protected rats

against aflatoxin B 1 -induced liver tumours (Angsubhakorn et al., 1989). The rele- vance of these findings to human exposure is questionable. Some studies have implicated a chronic oxidative stress in mechanisms of ter- atological actions of organochlorine pesticides (Hassoun, Bagchi, and Stohs, 1996; Hassoun and Stohs, 1996a, 1996b; Hassoun et al., 1993).