TOXICOLOGY OF ORGANOCHLORINE INSECTICIDES cyclodiene insecticides in the liver may lead to a variety of dechlorinated and hydro-

42 TOXICOLOGY OF ORGANOCHLORINE INSECTICIDES cyclodiene insecticides in the liver may lead to a variety of dechlorinated and hydro-

xylated products with a number of isomeric forms that can combine with cellular macromolecules and also be converted to glucuronides and sulphates for excretion. Some metabolites are stored more readily in the body organs than others. In mice cis and trans-chlordanes are less readily stored than the metabolite oxychlordane (Hirasawa and Takizawa, 1989). The metabolism of dieldrin has been studied in particular detail with rats, mice, monkeys, and other species. Some of the metabolites reported for the chlorinated cyclodiene-type insecticides are listed in Table 2.3.

Table 2.2 Microsomal metabolism of isodrin to endrin and further meta- bolites showing increased toxicity and greater affinity for the rat brain GABA receptor complex

Acute toxicity

Binding affinity

IC 50 (mM) Isodrin

LD 50 (mg =kg)

1.4 Endrin

0.22 syn -12-Hydroxyendrin

0.043 anti-12-Hydroxyendrin

0.036 Data from Casida and Lawrence (1985).

Table 2.3 Some identified metabolites of cyclodiene chlorinated insecticides Insecticide

Metabolite

Chlordane

trans -Chlordane Oxychlordane 1,2-Dichlordene 1-Hydroxy-2-chlordene 1-Hydroxy-2-chloro-2,3-epoxy chlordene

Heptachlor

1-Chloro-3-hydroxychlordene 1-Hydroxy-chlordene 1-Hydroxy-2,3-epoxychlordene

6,7-trans-Dihydroaldrindiol Ketodieldrin pentachloroketone Hexachlorohexahydroindene-carboxylic acid

Endrin

anti- 12-Hydroxyendrin syn- 12-Hydroxyendrin 12-Ketoendrin

Endosulfan

Sulphate derivative

Many of the hydroxylated products are conjugated as sulphates or glucuronides. Glutathione conjugation has not been studied in any detail (Smith, 1991).

43 Mutagenesis and cancer

CYCLODIENE AND RELATED INSECTICIDES

Various studies show slight activity in mutational or chromosomal aberration assays and even formation of DNA adducts, but this seems to have little bearing on the development of tumours. With endosulfan, DNA adducts have been observed in cultured hepatic cells and parallels CYP3A induction (Dubois et al., 1996), al- though it has been concluded that the pesticide has no carcinogenic potential (Hack, Ebert, and Leist, 1995). Some of the insecticides, including chlordane and dieldrin, cause liver tumours in mice after prolonged administration in the diet. This pre- sumably occurs by non-genotoxic mechanisms and the evidence suggests that rats are less susceptible (Smith, 1991). Changes in liver histology with hypertrophy and induction of microsomal cytochrome P-450 activities are observed at quite low doses, e.g. 10 ppm in the diet of dieldrin, but it is equivocable whether there are any associated increases in the rate of liver tumour induction. For some of these insecticides, e.g. endrin, it is possible that neurotoxicity occurs with lower doses than that required to accumulate the body burdens necessary for liver tumour development. There is a marked formation of Mallory bodies in the liver tumours of mice fed dieldrin (Meierhenry et al., 1983) possibly by hepatocyte prema- ture ageing and polyploidization perhaps involving an oxidative stress mechanism (Klaunig et al., 1995; van Ravenswaay, Toussaint, and Schmitt, 1988). Other stud- ies have implicated inhibition of intercellular communication, as suggested for a variety of pesticides causing tumours (Zhong-Xiang, 1986).

Neurotoxicity The neurotoxic action of dieldrin on the central nervous system typifies the

neurotoxicities of the chlorinated cyclodiene-type insecticides. A major site of action appears to be at the synapse. Dieldrin binds to the picrotoxin binding site of the GABA–receptor–ionophore complex (Abalis, Eldefrawi, and Eldefrawi, 1985; Casida and Lawrence, 1985; Cole and Casida, 1986; Eldefrawi et al., 1985; Lawrence and Casida, 1984; Matsumura and Ghiasuddin, 1983). This seems to be a similar mechanism for endrin and endosulfan. The degree of binding seems to correlate with acute toxicity (Nagata and Narahashi, 1994) and with convulsions, although other studies have been interpreted as not completely consistent with this explanation (Joy and Albertson, 1985). The exact brain location is probably similar to that demonstrated in the studies with lindane (Woolley et al., 1985) as the synaptic processes of the thalamocortical relay. Parallel increases in blood flow and evoked response amplitude have been seen in rat cerebral cortex seizures initiated by dieldrin (Ray, Lister, and Roy, 1986). Transient hypothermia after a large dose of dieldrin has been reported and a reduction in food intake described (Woolley et al., 1985) but it is not known whether this occurs by the GABAergic pathway. Although changes in various amino acids and amines of the brain have been shown following toxicity by these insectides it is difficult to explain these