Heptachlor and its metabolites

Table 3. Relative amounts of C-heptachlor and its metabolites in fish, water and excreta, 10 days after a single injection (38.2 yg/fish).

Exposure. Biomarkers of exposure include various components of commercial chlordane (principally cis- and frans-chlordane, cis- and frans-nonachlor) and its metabolites (principally oxychlordane). These substances are specific for exposure to chlordane. Detection of heptachlor and its metabolite, heptachlor epoxide, could reflect exposure to chlordane, because heptachlor is a component of commercial chlordane, or exposure to heptachlor, which is an insecticide in its own right. Data were not located that permit differentiation of the route, magnitude, or duration of exposure based on biomarkers of exposure. 

Supercritical fluid extraction (SEE) allows the analysis not only of the water samples but more complicated systems as well, e.g., of pesticides in soil samples (41a) and triazines and phenylureas in sediment (41b). Heptachlor and its metabolites, dieldrin, endrin (41c) were extracted from animal tissues by this method using only CO2 or organic solvent containing COj. Twelve OP and OC insecticides were extracted from quite different soil samples, i.e., sand, clay, etc., by SEE either with CO2 or with 3% methanol containing CO2 gas (41d) (Table 1). 

No studies were found correlating levels to which humans were exposed with actual body burdens. However, an attempt was made to correlate blood levels of chlordane, which may contain from 6% to 30% heptachlor, to duration of occupational exposure. Blood samples from 51 male pest control operators who were occupationally exposed to chlordane were tested for the presence of chlordane and its metabolites trans-nonachlor, oxychlordane, and heptachlor epoxide. The blood of 19 male workers with no experience spraying chlordane was also tested as a control. Heptachlor epoxide was detected (from not detectable to 1.6 ppb) in 20% of the blood samples from pest control operators exposed to chlordane (concentration not reported). The total chlordane in the blood was low but demonstrated sizable correlation with the number of spraying days and the amount of chlordane sprayed (Saito et al. 1986). 

Octa- and nonachlordane, oxychlordane and heptachlor Chlordane and its metabolite... 

Obtain organochlorine and carbamate pesticide standards from a commercial source such as Polyscience Corp. or ChemService (Westchester, PA). Obtain standards of phorate and its metabolites from the manufacturer, American Cya-namid Co., Princeton, NJ. Prepare individual and mixture solutions at a level of 1 J,g/)il by dissolving 25 mg of each compound in 25 ml of solvent. For the study of chlorinated pesticides, prepare individual solutions and a mixture of heptachlor, endosulfan (Thiodan), heptachlor epoxide, lindane, dieldrin, and dico-fol (Kelthane) in hexane. For organophosphate pesticides, use phorate and its metabolites phoratoxon, phorate sulfoxide, and phoratoxon sulfoxide in ethyl acetate. For carbamates, use 3-keto carbofuran (a metabolite of carbofuran), carbaryl, and metalkamate (Bux) in ethyl acetate. 

CFs for fish/water are highly variable and depend on test conditions, species of fish, and pesticide. In general, DDT and its metabolites have the greatest CFs, followed by toxaphene, aldrin, dieldrin, chlordane, heptachlor, hepta-chlor epoxide, endrin, and lindane (Table 6.4). Thus, under natural conditions, lindane seldom occurs at high concentrations in fish tissues, whereas significant adulteration of fish with DDT has been reported for numerous lakes, rivers, and estuaries. As with invertebrates, there has been a drop in DDT and dieldrin in tissues in recent years. Suns etaL (1981) reported a 64% decline in SDDT in spottail shiners collected in 1978 and... 

Extremely sensitive analytical methods have been developed for the detection of heptachlor and heptachlor epoxide in various environmental and biological samples (detection limits as low as 10 ng/L). Although most methods were developed for detecting heptachlor and heptachlor epoxide in environmental media, the technology is readily adaptable to biological materials including breast milk, adipose tissue, and serum. These methods can be used to determine whether exposure has occurred. The presence of heptachlor may reflect an exposure to heptachlor or chlordane because it is a metabolite of chlordane. The presence of heptachlor epoxide may reflect an exposure to heptachlor or to chlordane since it is a metabolite of both these pesticides. However, in the absence of stable chlordane residues (e.g., nonachlor and oxychlordane), the heptachlor epoxide would most likely have been derived from heptachlor. 

Uses Heptachlor was first isolated from technical chlordane in 1946. Its extensive use from 1960 to 1970 was primarily for the control of termites, ants, and soil insects. Different formulations such as dusts, wettable powders, emulsifi-able concentrates, and oil solutions were in use for pest management before the imposition of its use. Heptachlor has both nonsystemic stomach action and contact action. Heptachlor epoxide is the principal metabolite (oxidation product) of heptachlor and is formed by different plants and animals. 

Daily oral administrations of 2 or 5 mg kg body weight heptachlor for 78-86 days to pigs, sheep, and rats induced hepatic necrosis. Results of animal tests show that chronic exposure to heptachlor or its epoxide metabolite adversely affects the liver, kidney, and red blood cells. There is evidence that heptachlor and heptachlor epoxide are associated with infertility and improper development of offspring. Animal studies have shown that females were less likely to become pregnant when both males and females were fed heptachlor. The incidence of liver carcinomas increased in rats receiving doses of approximately 1.2 mg kg day of either heptachlor or heptachlor epoxide. 

The effect of proteins on pollutant toxicity includes both quantitative and qualitative aspects. Experiments show that animals fed proteins of low biological value exhibited a lowered microsomal oxidase activity when dietary proteins were supplemented with tryptophan, the enzyme activity was enhanced. Alteration of xenobiotic metabolism by protein deprivation may lead to enhanced or decreased toxicity, depending on whether metabolites are more or less toxic than the parent compound. For example, rats fed a protein-deficient diet show decreased metabolism but increased mortality with respect to pentobarbital, parathion, malathion, DDT, and toxaphene (Table 6.4). On the other hand, rats treated under the same conditions may show a decreased mortality with respect to heptachlor, CC14, and aflatoxin. It is known that, in the liver, heptachlor is metabolized to epoxide, which is more toxic than heptachlor itself, while CC14 is metabolized to CC13, a highly reactive free radical. As for aflatoxin, the decreased mortality is due to reduced binding of its metabolites to DNA. 

Heptachlor and Heptachlor Epoxide. Heptachlor is a cyclodiene insecticide introduced around the same time as DDT and, until recently, was used extensively. It is important to the present discussion because it was the first case where a metabolite of a pesticide was proven to be involved in the toxic response assumed... 

Parathion and Paraoxon. Again, this represents a reaction (the sulfur oxidation of a thiophosphate pesticide) that is familiar to most in the pesticide area. Unlike heptachlor epoxide, paraoxon is not a stable compound and its actual presence in a poisoned animal was very difficult to demonstrate. The oxons of other organo-phosphorothioates are not so elusive. In any event, the paraoxon metabolite is an excellent example of where an understanding of metabolic processes and their potential toxicological significance alerted scientists to the likelihood that such a metabolite existed. Many years of work with similar compounds had established that the insecticidal thiophosphates required oxidation to the P=0 form in order to inhibit the neurotrasmitter acetylcholinesterase, the biochemical basis of their toxic action. Paraoxon was eventually isolated in vivo and now consideration of the oxon is a vital part of the overall risk assessment of this group of pesticides. 

The polychlorinated cyclodienes Aldrin 400) and Heptachlor 402) are converted in vitro by rabbit liver microsomes to their corresponding epoxides (Figure 12). The epoxidase has the characteristics of the mixed-function oxidase system in that it requires both NADPH and oxygen and it is inhibited by SKF 525-A. Dieldrin 401) is detoxified in vivo in the rat through hydrolysis of the epoxy group to a rarzi -dihydrodiol, which subsequently is oxidized to the dicarboxylic acid other metabolites include 9-hydroxydieldrin and a pentachloroketone structure. 

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). 

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