Heptachlor epoxide, toxicity

As mentioned earlier (Figure 5.5), aldrin and heptachlor are rapidly metabolized to their respective epoxides (i.e., dieldrin and heptachlor epoxide) by most vertebrate species. These two stable toxic compounds are the most important residues of the three insecticides found in terrestrial or aquatic food chains. In soils and sediments, aldrin and heptachlor are epoxidized relatively slowly and, in contrast to the situation in biota, may reach significant levels (note, however, the difference between aldrin and dieldrin half-lives in soil shown in Table 5.8). The important point is that, after entering the food chain, they are quickly converted to their epoxides, which become the dominant residues. 

Chlordane-induced mortality of the long-billed curlew (Numenius americanus) has been documented at least four times since 1978, despite restriction of technical chlordane use since 1980 to subterranean applications for termite control (Blus et al. 1985). Death of these curlews was probably due to over-winter accumulations of oxychlordane of 1.5 to 5.0 mg/kg brain FW and of heptachlor epoxide at 3.4 to 8.3 mg/kg — joint lethal ranges for oxychlordane and heptachlor epoxide in experimental birds — compared to 6 mg/kg brain for oxychlordane alone and 9 mg/kg for heptachlor epoxide alone (Blus et al. 1985). Additional research is needed on toxic interactions of chlordane components with each other and with other chemicals in the same environment. 

No studies were located regarding death in humans after oral exposure to heptachlor or heptachlor epoxide. However, since heptachlor is a major component of the insecticide chlordane, chlordane poisoning can be considered when evaluating heptachlor toxicity data. In the case study of a woman who ingested 6 g of chlordane with suicidal intent and died 9.5 days following ingestion, no information was presented on the composition of the chlordane. Therefore, the amount of heptachlor exposure is unknown, and the effect of other components of chlordane cannot be ruled out (Derbes et al. 1955). 

Two calves receiving 2.5 or 5 mg/kg/day of heptachlor formulation (25% heptachlor) for 15 or 6 days, respectively, died after the last doses were administered (Buck et al. 1959). In contrast, among six calves given single doses of heptachlor epoxide formulation (25% heptachlor epoxide), two received 25 mg/kg, and three received 15, 10, or 5 mg/kg/day. All died within 3 hours to 3 days. These results indicate that heptachlor epoxide is more toxic to young calves than technical-grade heptachlor. 

In order to assess the potential extent of human exposures and health effects, members of dairy farm families who consumed raw dairy products known to be contaminated with heptachlor epoxide were studied (Stehr-Green et al. 1986). These individuals and an unexposed urban reference population were compared with regard to serum pesticide levels and liver toxicity. The farm family members had significantly higher mean serum levels of heptachlor epoxide (0.81 0.94 ppb), oxychlordane (0.70 0.75 ppb), and transnonachlor (0.79 0.60 ppb) than the unexposed population. This study is limited because exposure level, duration, and frequency of exposure are not known. There was no increase in prevalence of abnormal liver function tests in the dairy farm families... 

No studies were located regarding metabolism of heptachlor or heptachlor epoxide in humans. However, animal studies have shown that heptachlor undergoes epoxidation to produce heptachlor epoxide, which is more toxic than its parent compound. Heptachlor epoxide is further metabolized and excreted. In an in vitro liver study, human and rat liver microsomes metabolized heptachlor to the same products but in different proportions (Tashiro and Matsumura 1978). It was also shown in this study that rat microsomal preparations were four times more efficient in the metabolic conversion of heptachlor to heptachlor epoxide than were human microsomal preparations. 

Heptachlor is formed through the metabolism of chlordane. Heptachlor epoxide is formed through the epoxidation of heptachlor and has been shown to be a cosubstrate of the same enzyme responsible for the epoxidation of aldrin to dieldrin (Gillett and Chan 1968). Heptachlor epoxide is considered more toxic than its parent compound and, like heptachlor, is primarily stored in adipose tissue (Barquet et al. 1981 Burns 1974 Greer etal. 1980 Harradine and McDougall 1986). 

Death. Occupational mortality studies of pesticide workers exposed to heptachlor have not revealed an excess number of deaths in these cohorts compared to the general U.S. population. This may possibly be explained as a healthy worker effect. The ERA has described human case reports in which convulsions and death were reported following suicidal ingestion of technical-grade chlordane, which typically contains 6-30% heptachlor, but these effects cannot be attributed to heptachlor or heptachlor epoxide. There are no controlled, quantitative human data for any route of exposure. Acute lethality data were located for animals exposed via the oral and dermal routes. Both heptachlor and heptachlor epoxide may be considered very toxic via the oral route on the basis of acute animal data in rats and mice. Intermediate oral exposure to these compounds also caused up to 40% and 100% mortality in rats and mice, respectively. There appear to be differences in sensitivity in males and females in some species with the males being most sensitive. Heptachlor epoxide is more toxic than heptachlor. Heptachlor may be considered very toxic to extremely toxic via the dermal route on the basis of acute lethality data in rats and mice. The severity of acute effects may possibly depend upon the extent of formation of heptachlor epoxide and the species tested. 

There are data from animal studies in mice, rats, and pigs that indicate that both carbohydrate metabolism and lipid metabolism may be affected by exposure to heptachlor or heptachlor epoxide (Enan et al. 1982 Halacka et al. 1974 Kacew and Singhal 1973 Pelikan 1971). Alterations in gluconeogenic enzymes and an increase in cellular steatosis in the liver have been reported. Granulomas and fibrotic liver have also been observed. In addition, hepatocellular carcinoma was identified as causally related to heptachlor in the diet in a mouse study conducted by the National Cancer Institute (NCI 1977). The existing evidence suggests that heptachlor and heptachlor epoxide are hepatic toxicants. 

There are no data available that suggest that heptachlor or heptachlor epoxide are developmental toxicants at the levels measured in human populations. 

Other work has indicated that chlordane and heptachlor are energy transfer inhibitors as evidenced by marked decreases in oxidative phosphorylation of rat hepatic mitochondria following in vitro incubation of the mitochondria with the pesticides (Ogata et al. 1989). Interestingly, even though heptachlor epoxide is more toxic than either chlordane or heptachlor in tests of general toxicity, it was less effective in inhibiting mitochondrial respiration. 

Nutritional factors may influence the toxicity of pesticides. Research in this area has primarily focused on the role of dietary proteins, particularly sulfur-containing amino acids, trace minerals, and vitamins A, C, D, and E. Studies in rats show that inadequate dietary protein enhances the toxicity of most pesticides but decreases, or fails to affect, the toxicity of a few. The results of these studies have shown that at one-seventh or less normal dietary protein, the hepatic toxicity of heptachlor is diminished as evidenced by fewer enzyme changes (Boyd 1969 Shakman 1974). The lower-protein diets may decrease metabolism of heptachlor to heptachlor epoxide. 

Male weanling rats were fed a 5%, 20%, or 40% casein diet for 10 days and then given heptachlor intraperitoneally. The animals receiving the 5% casein diet showed a three-fold tolerance to heptachlor toxicity, but the toxicity of heptachlor epoxide was not affected (Weatherholtz et al. 1969). This was probably due to inability of weanling rats to metabolically convert heptachlor to the more toxic heptachlor epoxide. This fact is further supported by the observation that changes in protein percentage in diet did not affect the toxicity of heptachlor epoxide itself. 

No studies were located indicating that any populations are unusually susceptible to heptachlor or heptachlor epoxide. There is a possibility that very young children may exhibit particular susceptibility to hepatic effects because of the immaturity of the hepatic microsomal system. Heptachlor is bioactivated to produce heptachlor epoxide which is more toxic than heptachlor. Preadolescent children have a greater rate of glutathione turnover, and they are expected to be more susceptible to heptachlor epoxide-induced toxicity. Their susceptibility would probably depend upon their ability to detoxify heptachlor epoxide. Individuals who show reduced liver function for other... 

There is some evidence in laboratory animals that high-protein diets cause more rapid conversion of heptachlor to heptachlor epoxide and therefore increase the toxicity resulting from exposure to heptachlor. The lack of corroborating data in humans on this phenomenon, however, makes it difficult to postulate that high- or very high-protein diets would significantly increase susceptibility to heptachlor toxicity. 

This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to heptachlor and heptachlor epoxide. However, because some of the treatment discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposures to heptachlor or heptachlor epoxide. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. 

Since the metabolized form of heptachlor, heptachlor epoxide, is the most toxic, it may be possible to reduce the toxic effects of heptachlor by inhibiting the enzyme catalyzing this conversion. This is the same enzyme that catalyzes the epoxidation of aldrin to dieldrin (Gillett and Chan 1968). Further research into the specificity of this enzyme, drugs that could inhibit the enzyme, and any side effects of these drugs could help to determine the feasibility of such a treatment strategy. 

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