The Cyclodiene Insecticides

Flodstrom S, Warngard L, Hemming H, et al. 1988. Tumor promotion related effects by the cyclodiene insecticide endosulfan studied in vitro and in vivo. Pharmacol Toxicol 62 230-235. 

The organochlorine insecticides (henceforward OCs) can be divided into three main gronps, each of which will be discnssed separately in the sections that follow. These are (1) DDT and related componnds, (2) the cyclodiene insecticides, and (3) isomers of hexachlorocyclohexane (HCH Brooks 1974 Fignre 5.1). 

The cyclodiene insecticides aldrin, dieldrin, endrin, heptachlor, endosulfan, and others were introduced in the early 1950s. They were used to control a variety of pests, parasites, and, in developing countries, certain vectors of disease such as the tsetse fly. However, some of them (e.g., dieldrin) combined high toxicity to vertebrates with marked persistence and were soon found to have serious side effects in the field, notably in Western European countries where they were extensively used. During the 1960s, severe restrictions were placed on cyclodienes so that few uses remained by the 1980s. 

Photolysis of 2-bromo-4,4-dimethyl-2-cyclohexenone only affords reduction, even in a nucleophilic medium343,344. Apparently, this substrate is structurally not suitable to form a vinyl cation. Formation of vinyl radical-derived products is also the main process for all vinylic halides, if their irradiation is performed in an apolar medium. Such photochemical reductive dehalogenation and especially dechlorination reactions have been extensively studied in the past, not in the least because of their importance as abiotic transformation of persistent polychlorinated environmental pollutants. Examples are the cyclodiene insecticides aldrin and dieldrin, which contain a vicinal dichloroethene chromophore. In recent... 

Epoxidation Epoxidation is an important microsomal reaction. For example, the cyclodiene insecticide aldrin can be oxidized to its epoxide dieldrin (as shown in Chapter 4, Figure 4.4), and heptachlor is oxidized to heptachlor epoxide. There is no great increase in toxicity in this case, but the epoxides are more environmentally persistent than their precursors. Moreover, some of the epoxides produced in the microsomal oxidation are highly reactive and can form adducts with cellular macromolecules such as proteins, RNA, and DNA, often resulting in chemical carcinogenesis. 

Researchers were also able to establish the link between declines of other predatory species such as the European sparrowhawk and the use of organo-chlorine pesticides other than DDT. For instance, the cyclodiene insecticides aldrin, dieldrin, and he-ptachlor used as seed treatments caused massive mortality of both seed-eating species and their predators. All of the insecticides had the following points in common they were highly soluble in fats and refractory to metabolism. The impacts on the predatory species typically take place in periods of food stress when fat soluble residues are released from fat stores and returned into general circulation. In a food-stressed individual, the brain remains as the most lipid rich tissue and this is where contaminants move to. Toxicity results when threshold values in brain tissue are exceeded. At sublethal levels, documented effects of cyclodiene insecticides in birds have included changes in their reproductive, social, and avoidance behaviors. 

Table IV lists the insecticidal activity of cyclic sulfites In this case, the exo cyclic sulfites of 5,6-bis(hydroxymethyl)-7-isopropylidenebicyclo[2.2 l]hept-2-ene [20] was active whereas the corresponding endo Isomer [18] was inactive Monoepoxldation [21 and 22] and diepoxidation [23] of the exo cyclic sulfite resulted in a slight increase in activity Compound 15 was the most active among this series of compounds The LD q value of this compound was estimated to be about 1 pg/fly when topically applied to houseflies without any synergists (data not shown) The C-7 isopropylidene group proved to be unnecessary for high activity by comparison with compound 18. The activity decreased after epoxidation [16] or hydrogenation [17] of the endocyclic double bond The cyclodiene insecticide endosulfan was about 10 times as active as [15] ...

A rapid, competition immunoassay has been developed that detects chlorinated cyclodiene insecticides in meat, fish and milk products. The assay, a competition enzyme-linked inununosorbent assay, employs a monoclonal antibody that recognized all of the cyclodiene insecticides it was tested against. A simple method to extract heptachlor and related cyclodiene insecticides that is compatable with the immunoassay is described. The sensitivity of the immunoassay is sufficent to detect cyclodienes at the tolerance level in beef. We anticipate initial application of this assay as a screening aid. 

Development of immunoassays for residue analysis of small molecules has been well documented in the literature (8-9. 141 and by the articles in this volume. Recently, Dreher and Podratzki (101 reported the development of an immunoassay for endosulfan and its metabolites using a rabbit polyclonal antiserum. This assay however, did not readily detect other related cyclodiene insecticides. We report here the development of a monoclonal antibody that detectes all nine of the cyclodiene insecticides tested plus toxaphene, and the incorporation of this antibody to an immunoassay for detecting these compounds in meat, fish, and dairy products at, or below, the tolerance levels. 

Immunoassay Development in Meat. The results presented above clearly indicate that the LLNL-Hept-2 antibody recognized all of the cyclodiene insecticides tested with roughly equal affinity. The next problem that needed to be solved was analyzing for pesticide residues in adipose tissue, the site of accumulation in animals. The heptachlor had to be extracted from the fat sample in a manner that is chemically compatible with an immunoassay. In... 

The classic reaction to the cyclodiene insecticides (e.g, driordatre, toxaph, heptachlor) b intermittent cranial to caudal epileptiform seizures with little or tro hyperesthesia. There b rarely, if ever, any votrriting as would be seen with metaldehyde or tire orgarrophosphates badcosb, and the seizures are not tetarric trr hyperesthetic as with strychnine todcosb. 

The case of DDT is an excellent example of the obsolescence of an important pesticidal chemical (Table 29.3). Many compositions of the chlorinated hydrocarbon group were found that were more highly active—either broadly or narrowly effective—than DDT. Indeed this compound stimulated the research and development for toxaphene, the cyclodiene insecticides DDD, dicofol, and so on, and even some of the fungicides and herbicides. 

There is considerable, but variable, cross resistance from DDT to other chlorinated hydrocarbons such as benzene hexachloride and the cyclodiene insecticides. However, when one substitutes a para-methoxy group for para-chlorine in the DDT molecule, a far less persistent—and somewhat less active—but... 

Balasubramaniam E, Paul V, Jayakumar AR, et al. 1996. The effect of chronic cyclodiene insecticide treatment on some pharmacological actions of diazepam in rats. Environ Toxicol and Pharm(2) 141-146. 

Tumer KO, Syvanen M, Meizel S. 1997. The human acrosome reaction is highly sensitive to inhibition by cyclodiene insecticides. J Androl 18(6) 571-575. 

In one example (Lawrence and Casida 1984, Abalis et al. 1985) rat brain microsacs were used to test the action of cyclodiene insecticides such as dieldrin and endrin on the GABA receptors contained therein. The influx of radiolabeled CL into the microsacs via the pore channel of the receptor was inhibited by these chemicals. A similar assay was developed using microsacs from cockroach nerve. Assays with this preparation showed again the inhibitory effect of a cyclodiene (this time heptachlor epoxide) on CL influx. Also, that microsacs from cyclodiene resistant cockroaches were insensitive to the inhibitory effect of picrotoxinin, which binds to the same site on the GABA receptor (Kadous et al. 1983). 

Walker, C.H. and Newton, 1. (1998). Effects of cyclodiene insecticides on the sparrowhawk in Britain—a reappraisal of the evidence. Ecotoxicology 7, 185-189. 

Technical chlordane is a mixture of chlorinated hydrocarbons that has been used as an insecticide since its introduction in 1947. Chlordane was the first cyclodiene insecticide to be used in agriculture and was the second most important organochlorine insecticide in the United States in 1976/1977, behind toxaphene, with an estimated annual production of 9 million kg (Nomeir and Hajjar 1987). Chlordane is a leading insecticide in controlling termites, with about 1.2 million homes in the United States alone treated annually for this purpose (Nomeir and Hajjar 1987). 

Matsumura F. 1985. Involvement of picrotoxinin receptor in the action of cyclodiene insecticides. Neurotoxicology 6(2) 139-164. 

Stanker LH, Watkins B, Vanderlaan M, et al. 1989. Analysis of heptachlor and related cyclodiene insecticides in food products. In Vanderlaan M, ed. ACS (American Chemical Society) Symposium Series, 451. Immunoassays for trace chemical analysis Monitoring toxic chemicals in humans, food and the environment Meeting, Honolulu, Hawaii, December 17-22. Washington, DC American Chemical Society, 108-123. 

Transfer of the aquatic animals, after absorption of the cyclodiene, to insecticide-free water showed variations in elimination pattern related with the chemical as well as its concentration in the body. It follows a somewhat biphasic response, there is initial rapid elimination of high concentration followed by a slow elimination at lower body concentrations (Fig. 3)(21,22, 23). Xenopus, even at low body levels of cis-chlordane, eliminate it at slightly faster rate than fish. Photo-cis-chlordane seems to be eliminated at a faster rate than cis-chlordane by both goldfish and bluegill (Table 2). The elimination of photo-cis-chlordane by goldfish and bluegill and of photodieldrin by blue-gill shows a biphasic response (Fig. 3). 

Cyclodiene insecticides produce intense nerve excitation in both vertebrate and invertebrate species (Matsumura 1985 Matsumura and Tanaka 1984). It has been suggested that the biochemical mechanisms by which these chemicals induce hyperexcitation in the central nervous system are due to the release of neurotransmitters caused by the interactions of the insecticide with the picrotoxinin receptor. 

Georgacakis, E. and Khan, M.A.Q. Toxicity of the photoisomers of cyclodiene insecticides to freshwater animals. Nature... 

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