Heptachlor metabolism

Biotransformation of certain chlorinated hydrocarbon insecticides results in their conversion to metabolites which are less polar than the parent chemical. Heptachlor and aldrin are converted to the more lipophilic compounds heptachlor epoxide and dieldrin, respectively, whereas DDT is converted to DDE. The primary residue of DDT, which persists to the present day in animals and humans after exposure over a decade ago, is DDE. Following biotransformation, these compounds distribute to tissues which are higher in neutral lipid content than are the major organs of metabolism and excretion, the liver and kidney. These lipid-rich tissues are relatively, deficient in the so-called mixed-function oxidase (MFO) enzyme systems necessary for biotransformation of the halogenated hydrocarbons to more polar and thus more easily excreted compounds. As a result, these lipophilic chemicals remain unchanged in adipose tissue with only limited amounts returning to the circulation for possible metabolism and excretion. Paradoxically, aldrin and heptachlor metabolism results in an increased rather than reduced body load. This is opposite of the pattern seen for most other pesticide classes. 

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. 

Microorganisms such as Nocardiopsis sp., an actinomycete, can metabolize cis- and trans-chlo-rdane to at least eight solvent-soluble substances, including dichlorochlordene, oxychlordane, hep-tachlor, heptachlor endo-epoxide, chlordene chlorohydrin, and 3-hydroxy-trans-chlordane (Beeman and Matsumura 1981). Based on studies of chlordane metabolism in animals, four metabolic pathways are proposed (Feroz and Khan 1979a WHO 1984 Nomeir and Hajjar 1987 USEPA 1988) ... 

Although technical chlordane is a mixture of compounds, two metabolites — heptachlor epoxide and oxychlordane — can kill birds when administered through the diet (Blus et al. 1983). These two metabolites originate from biological and physical breakdown of chlordanes in the environment, or from metabolism after ingestion. Heptachlor can result from breakdown of cis- and trans-chlordane, eventually oxidizing to heptachlor epoxide oxychlordane can result from the breakdown of heptachlor, m-chlordane, tra .s-chlordane, or fram-nonachlor (Blus et al. 1983). Heptachlor epoxide has been identified in soil, crops, and aquatic biota, but its presence is usually associated with the use of heptachlor, not technical chlordane — which also contains some heptachlor (NRCC 1975). Various components in technical chlordane may inhibit the formation of heptachlor epoxide or accelerate the decomposition of the epoxide, but the actual mechanisms are unclear (NRCC 1975). 

Levels of Significant Exposure to Heptachlor and Heptachlor Epoxide - Oral 2-2 Metabolic Scheme for Heptachlor in Rats ... 

Granulation and discoloration of kidneys and a decrease in kidney-to-brain-weight ratio was reported in minks fed 6.19 mg/kg/day of heptachlor daily for 28 days (Aulerich et al. 1990). Rats receiving 0.5 mg/kg/day of heptachlor in the diet in an intermediate-duration study showed a statistically significant increase in blood urea (Enan et al. 1982). Increased blood urea may indicate renal inefficiency in metabolism and clearance of protein by-products. This study is limited in that histologic examination was not included in the study design and insufficient dose levels were utilized to establish a dose response. 

Of 50 adult rats used in a reproductive/developmental study, 22% of those that received 6 mg/kg/day heptachlor in the diet developed lens cataracts 4.5-9.5 months following exposure. In addition, 6-8% of the pi offspring and 6% of the p2 offspring of these rats also developed cataracts 19-21 days after birth (Mestitzova 1967). The author of this study eliminated the possibility of a vitamin B deficiency or a recessive genetic trait as the cause of the cataracts. She could not rule out the possibility of altered vitamin B metabolism caused by heptachlor. 

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. 

The major fecal metabolites in male rats administered a single oral dose of "C-heptachlor are heptachlor epoxide, 1-exo-hydroxychlordene, 1-exo-hydroxy-2,3-exo-epoxychlordene, and 1,2-dihydroxydihydrochlordene, as well as two unidentified products (Figure 2-2) (Tashiro and Matsumura 1978). By day 3, 50% of the dose was excreted in the feces. About 72% of the radioactivity was eliminated in the feces in the form of metabolites and 26.2% as parent compound by day 10. The same metabolites were identified in the comparative in vitro study using rat and human microsomal preparations (Tashiro and Matsumura 1978). Heptachlor epoxide is metabolized one step further to a dehydrogenated derivative of 1-exo-hydroxy-2,3-exo-epoxychlordene. Less than 0.1 % of radiolabel was seen of this compound in an in vitro study using human liver microsomes (Tashiro and Matsumura 1978). 

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). 

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. 

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. 

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. 

L.B. Willett and C.P. Hodgson of Ohio State University, in collaboration with the U.S. Department of Agriculture, are currently investigating reproductive, metabolic, and nutritional disorders following heptachlor exposure from contaminated food in cattle (FEDRIP 1990). These investigators will also determine the cellular alterations that can influence reproductive or other homeostatic mechanisms. 

A relatively small proportion of heptachlor epoxide was formed. Heptachlor epoxide was never found to be greater than 10% of the total C in the water sample. The authors concluded that the major pathway of heptachlor in aquatic systems is rapid abiotic hydrolysis of heptachlor to 1-hydroxychlordene followed by metabolism to 1-hydroxychlordene epoxide (Lu et al. 1975). 

Heptachlor is metabolized by the freshwater microcrustacean, Daphnia magna, to heptachlor epoxide or 1-hydroxychlordene, 1-Hydroxychlordene is then converted to 1-ketochlordene,... 

Analytical methods exist for measuring heptachlor, heptachlor epoxide, and/or their metabolites in various tissues (including adipose tissue), blood, human milk, urine, and feces. The common method used is gas chromatography (GC) coupled with electron capture detection (ECD) followed by identification using GC/mass spectrometry (MS). Since evidence indicates that heptachlor is metabolized to heptachlor epoxide in mammals, exposure to heptachlor is usually measured by determining levels of heptachlor epoxide in biological media. A summary of the detection methods used for various biological media is presented in Table 6-1. 

Kacew S, Singhal RL. 1973. The influence of p,p-DDT, a-chlordane, heptachlor, and endrin on hepatic and renal carbohydrate metabolism and cyclic AMP-adenyl cyclase system. Life Sci 13 1363-1371. 

Weatherholtz WM, Campbell TC, Webb RE. 1969. Effect of dietary protein levels on the toxicity and metabolism of heptachlor. J Nutr 98 90-94. 

Source When heptachlor is ingested by dairy animals, it is metabolized to heptachlor epoxide, and stored in the fatty tissues. Heptachlor epoxide is present in the excreted milk and can be present in other dairy products (Meyer et al, 1960). 

Schimmel, S.C., Patrick, J.M., Jr., and Forester, J. Heptachlor uptake, depuration, retention, and metabolism by spot Leiostomusxanthurus), J. Toxicol. Environ. Health, 2(1) 169-178, 1976a. 

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