TOXICOLOGY OF ORGANOCHLORINE INSECTICIDES Expression and turnover of connexins and some phosphorylated forms have been

52 TOXICOLOGY OF ORGANOCHLORINE INSECTICIDES Expression and turnover of connexins and some phosphorylated forms have been

implicated to be involved in these processes (Ruch et al., 1994; Tateno et al., 1994). In in vivo studies high levels of DDT have been shown to induce liver tumours in rats and mice although these reports have not always been repeatable (Cabral et al., 1982; Fitzhugh and Nelson, 1947; NCI, 1978; Rossi et al., 1977; Turusov, Rakitsky, and Tomatis, 2002). Certainly DDT promotes carcinogenesis initiated by aflatoxin and other chemicals (Peraino et al., 1975; Schulte-Hermann, 1985; Scribner and Mottet, 1981; Williams and Numoto, 1984). The significance of these findings for humans is open to question.

Influence on reproduction Recent concern that chlorinated chemicals may act as endocrine disruptors has

resurrected interest in early work on the oestrogenicity of DDT (see Smith, 1991). Some of the earlier studies on DDT oestrogenicity probably stemmed from

the fact that the o, p 0 -analogue was present at significant quantities in the technical product. o, p 0 -DDT acts on the uterus probably as a long-lasting oestrogen receptor agonist, although it seems that its actions may not be identical to oestradiol (Galand et al. , 1987; Robison, Schmidt, and Stancel, 1985a; Robison, Sirbasku, and Stancel,

1985b). Relative to a potent chemical such as diethylstilboestrol, o, p 0 -DDT is about

1 =10 000 less active so that at environmental exposure levels and the fact that it is metabolized faster than p, p 0 -DDT make it seem unlikely to be a major hazard in this respect. Recent evidence supports the view that the DDT metabolite p, p 0 -DDE can disrupt male reproductive development by acting as an antiandrogen by binding to androgen receptors in a non-productive way (Kelce et al., 1995, 1997). DDE, like vinclozolin and flutamide, changed the expression of androgen receptor regulated genes in castrated male rats. Exposure of Long–Evans rats, but to less degree Sprague–Dawley, to DDE in utero by lactation can show changes in ano-genital distance but not testes, epididymus, seminal vesicles or ventral prostate weights and at maternal doses at or above 10 mg =kg. In Holtzman rats, effects on prostate

development by in utero or lactational exposure to p, p 0 -DDE has been shown (Loeffler and Peterson, 1999; O’Connor et al., 1999; You et al., 1998). Investiga- tions on the influence of DDT on reproduction, including multigeneration studies, have shown no clear effects in dogs, rats, and mice except at high overtly toxic doses (Smith, 2001).

General metabolic responses p ,p 0 -DDT, p, p 0 -DDE, o, p 0 -DDT, and various metabolites of these will cause a vari-

ety of metabolic changes to occur, principally in the liver. Foremost of these is the induction of microsomal enzymes. Studies are mainly old and this is reflected in the types of analyses performed (Smith, 2001). Multiple bi-daily doses of DDT to female rats induced hepatic CYP2B and 3A proteins but not CYP1A1 or 1E1

53 and caused elevated hydroxylation at positions 16 and 6

DDT

Dehal, and Kupfer, 1995). DDT, DDE, and DDD all induced CYP2B and 3A in male rat liver, roughly to the same degree despite marked differences in retention (Nims et al., 1998). Changes in lipid metabolism that have been observed are either linked to microsomal proliferation or of unknown significance, for instance in the lung (Narayan, Dani, and Misra, 1990). Some immunotoxic effects of DDT have been ascribed to inhibition of the functional activity of macrophages (Nunez, Estrada, and Calderon-Aranda, 2002).

Toxicity to humans Acute intentional and accidental exposures Early studies of the exposure of human volunteers to DDT focused on oral and

dermal administration of large acute doses to volunteers particularly with respect to the storage of DDE and relative to animal studies. On the whole few effects were observed with perhaps paraesthesia of the tongue and mouth, confusion and slight tremors at high oral doses. Very high accidental or attempted suicidal exposure led to convulsions being observed in a few cases although the exact doses are unknown. Recovery was often within 1 or 2 days. In fact, the acute toxicity of DDT to humans seems remarkably low (Smith, 1991, 2001).

Chronic exposure and response The safety record for humans in the use of DDT is phenomenally good considering

the huge quantities distributed (Coulston, 1985; Smith, 1991, 2001). It was used for mass delousing in such a way that the bodies and inner clothing of thousands of people of all ages and states of health were liberally dusted. By necessity, the applicators worked in a cloud of the material. Other applicators have sprayed the interior of hundreds of millions of homes in tropical and subtropical countries under conditions of extensive dermal and respiratory exposure. Some people made or formulated DDT for many years. Dermatitis was commonly observed among workers who used DDT solutions but the rashes were probably due to the solvent. Paraesthesia of the extremities, headache, dizziness, and tremor of the tongue and hands have been linked with DDT production, but studies of other workers making or formulating DDT have shown little evidence of adverse effects to the individual or fertility (see Smith, 2001, for original references).

The most heavily exposed workers whose health have been investigated are those associated with malaria control. In Brazil, examinations failed to show consistent symptoms of DDT neurotoxicity although in Indian sprayers, serum DDT levels were 8.5 times higher than controls and visuomotor functions were slightly depressed (Misra, Nag, and Murti, 1984). The levels of DDT and its metabolites in the sera from applicators in malaria control in Natal were