TOXICOLOGY OF ORGANOCHLORINE INSECTICIDES toxicity (Table 2.1) not greatly different from that of DDT but it is more readily

34 TOXICOLOGY OF ORGANOCHLORINE INSECTICIDES toxicity (Table 2.1) not greatly different from that of DDT but it is more readily

absorbed by the skin and therefore is more toxic by the dermal route than DDT. In rats, the acute toxicity of the isomers of BHC decreases in the order (Woodard and Hagan, 1947) but the toxicity of repeated doses decreases in the order of the different isomers is directly related to their storage and inversely related to their rate of metabolism (Davidow and Frawley, 1951; Macholz et al., 1986).

Absorption and distribution Although the

over 30 times more Frawley, 1951). This explains why the repeatedly even though the isomer is more toxic when given as a single dose. The difference in storage is explained by differences in metabolism. clohexane also seems to accumulate more than lindane, especially in the brain (Eichler, Heupt, and Paul, 1983; Stein et al., 1980). The storage of isomers of HCH can be less at higher than at lower dietary levels and the more rapid equilibrium and relatively less storage at higher dosages are consistent with a dosage-related induction of microsomal enzymes (Macholz and Kujawa, 1985; Smith, 1991).

Metabolism and excretion Not surprisingly multiple lindane administrations will induce expression of a num-

ber of drug metabolism enzymes involved in its oxidation and excretion, such as cytochrome P-450 isoforms and glutathione transferases (Kraus, Gross, and Kloft, 1981; Kumar and Dwivedi, 1988; Wolff and Suber, 1986) that may be genetically variable and be responsible in mice for strain differences in toxicity (Liu and Morgan, 1986; Robinson et al., 1975).

Isomers of HCH are metabolized by slightly different routes and the biotrans- formation of lindane in mammals alone is complex. Many of the products or intermediates, when given separately, are converted to other metabolites not usually detected during the metabolism of HCH isomers. Full details of the metabolism of lindane and related chemicals can be found elsewhere (Macholz and Kujawa, 1985; Smith, 1991). Metabolism involves not only phase I pathways, such as oxidation by cytochrome P-450, but also phase II pathways, such as conjugation of alcohol and phenol products to form glucuronides. Hydroxylations, epoxidations, cis and trans- dehydrochlorinations, isomerizations, and desaturations lead to a large number of chlorinated cyclohexanols, cyclohexenols, and phenols (Chadwick and Freal, 1972a, 1972b; Chadwick et al., 1978b; Chadwick et al., 1981; Chadwick et al., 1987; Fitzloff and Pan, 1984; Fitzloff, Portig, and Stein, 1982; Stein, Protig, and Koransky, 1977; Tanaka, Kurihara, and Nakajima, 1977, 1979a, 1979b). Under anaerobic conditions lindane is dechlorinated to chlorobenzene and benzene

35 (Baker, Nelson, and Van Dyke, 1985). There is little evidence that lindane is

LINDANE =HEXACHLOROCYCLOHEXANE (HCH)

converted to other HCH isomers or to hexachlorobenzene in rats (Chadwick and Copeland, 1985; Copeland and Chadwick, 1979). Most of the di- and trichloro- phenyl mercapturates observed in the urine of lindane-treated rats arise by con- jugation of hexachlorocyclohexenes and pentachlorocyclohexenes with glutathione, followed by dechlorination (Kurihara, Tanaka, and Nakajima, 1979; Portig et al., 1979). Many of the alcohol and phenol metabolites are excreted as glucuronides or sulphates. The types and amounts of alcohols and phenols can be varied in rodents by a number of factors including age of the animals, fibre content of diet, obesity, strain, and inducers of drug metabolism enzymes (Chadwick et al., 1978b; Chadwick et al., 1981, 1986; Chadwick et al., 1987; Copeland et al., 1986; Liu and Morgan, 1986).

The metabolism of other isomers of HCH besides lindane has not been studied in as much detail as that of the -isomer but probably occurs by routes very similar to those described above for lindane (Smith, 1991).

Neurotoxicity and behaviour The different isomers of HCH have opposite pharmacological actions. Lindane is a

stimulant of the nervous system, causing violent epileptiform convulsions that are rapid in onset and generally followed by death or recovery within 24 h (Coper, Herken and Klempau, 1951; Joy, 1982; McNamara and Krop, 1948; van Asperen, 1954; Woolley, 1985; Woolley et al., 1985). Lindane may also cause hypothermia and anorexia in rats (Aldegunde villar et al., 1981; Camon et al., 1988a; Woolley, 1985). The The Following subcutaneous injection of mice with effects is delayed compared with that of the characterized by tremors of the extremities and inability of the animals to make coordinated movements. In studies of the relationships between the observable effects of lindane and the level and time course of concentrations in blood and brain, a good correlation was observed between dosages and frequency of onset of tonic seizure, intensity, and lethality (Tussell, Engel, and Casida, 1977).

The main site of action of lindane, unlike that of DDT, appears to be at the synapse with both excitatory and inhibitory effects (Joy and Albertson, 1985). The possible effect of inhibition of Na þ ,K þ -ATPases on Ca 2 þ extrusion still requires more study (Woolley et al., 1985). These effects occur at concentrations of lindane greater than required for antagonism of the GABA–receptor complex and among different HCH isomers are not specific for the -isomer (Bondy and Halsall, 1988; Joy and Burns, 1988). The actions do not appear to be a consequence of direct inhibition (Kamijima and Casida, 2000; Magour, Maser, and Steffen, 1984). Some biochemical changes after exposures to lindane or HCH do not seem to have direct connections with toxicity (Smith, 1991). For instance, there has been interest in the