TOXICOLOGY OF ORGANOCHLORINE INSECTICIDES iodinase activity in vivo but the significance of these findings on the thyroid hormone

58 TOXICOLOGY OF ORGANOCHLORINE INSECTICIDES iodinase activity in vivo but the significance of these findings on the thyroid hormone

metabolism and action is unknown (Zhou et al., 1995). In rats, methoxychlor induced hepatic CYP2B1 and CYP3A enzymes levels, but in regimes with multiple treatment and less efficiently than DDT (Li, Dehal, and Kupfer, 1995).

Effects on organs and tissues Mixed mutagenicity results have been reported for methoxychlor (Oberly et al.,

1993) and increased occurrence of neoplasms of all sorts have been shown in rats and carcinoma of the testes in some mice only after feeding high doses of the technical product for 2 years (Reuber, 1979a, 1979b). Large doses of methoxychlor also produce dosage-dependent chronic nephritis and hypertrophy of the kidneys, mammary glands, and uteri of swine and cystic tubular nephropathy in rats (Tegeris et al. , 1966; Tullner, 1962). The liver seems relatively insensitive to methoxychlor but testicular changes have been frequently observed as well as atresia of ovarian follicles, albeit at high doses (Bal, 1984; Smith, 2001; Tullner, 1962).

Effects on reproduction Large doses of methoxychlor have oestrogenic effects and mating and litter size of

rats and mice are reduced, male and female offspring reproductive performance is decreased, and female pups may have early vaginal opening (Cummings, 1997). The potency appears to be 1 =10 000th of diethylstilboestrol.

The oestrogenicity of methoxyclor probably is due to metabolites not the parent compound. In vitro pure methoxychlor itself is not oestrogenic whereas metabolites are, for instance bis(hydroxyphenyl)trichloroethane (Bulger, Muccitelli, and Kupfer, 1978a, 1978b). The oestrogenic activity in vivo of impure methoxy- chlor in inducing paramers of uterine proliferation, uterus growth, uterine orinithine decarboxylase and epidermal growth factor receptor, creatine kinase and peroxidase may be partly caused by the demethylated analogues as metabolites and impurities that are also metabolites (Bulger, Feil, and Kupfer, 1985; Bulger, Muccitelli, and Kupfer, 1978a; Cummings, 1997; Cummings and Metcalf, 1994; Kupfer and Bulger, 1987; Metcalf, Laws, and Cummings, 1996). By both in vitro and in vivo criteria, 1,1-dichloro bis(4-hydroxyphenyl)ethane is the most potent agent. Methoxychlor affects the decidual cell response of the rat uterus and embryo transport rate might also be effected (Cummings, 1997; Cummings and Gray, 1987; Cummings and Perreault, 1990).

Some evidence suggests that reproductive effects of methoxychlor metabolites in male rats (Bal, 1984; Tullner, 1962) may be mediated, in part, by elevation of prolactin concentration and release, which in turn influences hypothalamic levels of gonadotropin-releasing hormone (Goldman et al., 1986). It has been reported that methoxychlor fed to lactating dams affected the reproductive tract of suckling females (Appel and Eroschenko, 1992). In studies of the effect of methoxychlor on

59 reproductive tract development following neonatal exposure of mice, precocious

MIREX AND CHLORDECONE

vaginal opening, cornification and increased tract size, and ovarian atrophy were observed in females and reduced serum testosterone, testicular DNA content, semi- nal vesicles, and prostate in males (Cooke and Eroschenko, 1990; Eroschenko, 1991; Eroschenko, Abuel-Atta, and Grober, 1995; Eroschenko and Osman, 1986). Rats dosed with methoxychlor before and following birth had immune and reproductive changes at doses of 0, 5, 50, or 150 mg kg day in a large study. Primary adult effects were reproductive and 5 mg kg day was not a NOAEL (Chapin et al., 1997). Methoxychlor prevented ovariectomy-induced bone loss in the rat (Dodge et al., 1996).

The oestrogenic effects of methoxychlor are not restricted to those on uterine or other reproductive physiology and function. Both running wheel activity (oestrogen controlled) and sex behaviour in rats and hamsters were induced by 400 mg kg day (Gray et al., 1988). Exposure of pregnant mice to methoxychlor seems to cause changes in behaviour of male offspring (vom Saal et al., 1995). Although it is usually assumed that the methoxychlor metabolites act in an identical manner to oestradiol, this may not always be true (Eroshenko, 1991; Cummings, 1997).

Toxicity to humans The rapid metabolism and excretion of methoxychlor suggests that at most expo-

sure levels humans are at little risk, including absorption from cow’s milk. Volun- teers given methoxychlor at rates of up to 2 mg kg day

for 8 weeks were without detectable effect on health, clinical chemistry, or the morphology of blood, bone marrow, liver, small intestine, or testis; the highest dosage administered being similar to that considered safe for occupational intake at the time (Stein, Serrone, and Coulston, 1965). Apparently there has been no confirmed case of poisoning, occupational or otherwise, firmly attributed to methoxychlor and residues have rarely been found in human tissues (Smith, 2001).