Pyrethroids selective toxicity

Pyrethroids show very marked selective toxicity (Table 12.2). They are highly toxic to terrestrial and aquatic arthropods and to fish, but only moderately toxic to rodents, and less toxic still to birds. The selectivity ratio between bees and rodents is 10,000- to 100,000-fold with topical application of the insecticides. They therefore appear to be environmentally safe so far as terrestrial vertebrates are concerned. There are, inevitably, concerns about their possible side effects in aquatic systems, especially on invertebrates. 

As these compounds seem to lose the selective toxicity characterized by natural pyrethrins, we should learn from natural pyrethrins to develop safer pyrethroids. 

Pyrethroids are a collective term for compounds that are obtained by modifying the structure of natural insecticidal ingredients, pyrethrins, contained in pyrethrum while maintaining safety, to improve efficacy and provide different characteristics from pyrethrins that show high selective toxicity comparable to pyrethrins. 

Pyrethrins and synthetic pyrethroids are among the safest of the topically applied ectoparasiticides, because of their selective toxicity for insects (mam-malian-to-insect toxic dose ratio is greater than 1000, compared with 33 for organophosphates and 16 for carbamate insecticides). In contrast to the very wide margin of safety for mammalian species, pyrethroids are toxic to fish. The synergistic action of pyrethrins and piperonyl butoxide (in combination preparations) is due to the inhibition by piperonyl butoxide of the microsomal enzyme system of some arthropods. Preparations of synthetic pyrethroids (permethrin, cypermethrin) often contain a mixture of drug isomers in varying proportions. 

Fore recently a comparable enhanced inhibition in resistant strains has been observed with aryloxadiazolone anticholinesterases (38). A second promising example is the discovery that some natural and synthetic isobutylamides are selectively toxic against houseflies that carry the super-kdr resistance trait (39). This gene causes an alteration in the sensitivity of the site of action for DDT and pyrethroids and is a major threat to the continued efficacy of synthetic pyrethroids in many of their applications. 

The major inhibitory neurotransmitter in invertebrates is Y-aminobutyric acid (GABA). Inhibitory neurones are found both in the CNS and at the neuromuscular junction in invertebrates (1), whereas they are not found at the neuromuscular junction in mammals. The widespread distribution of GABA-ergic neurones in insects is probably partly responsible for the selective toxicity towards insects of certain commercial insecticides, e.g., cyclodienes (2-41. avermectin (5), and perhaps some pyrethroids ( ). 

Abernathy CO, Casida JE (1973) Pyrethroid insecticides esterase cleavage in relation to selective toxicity. Science 179 1235-1236... 

Wester RC, Bucks DAW, Maibach HI (1994) Human in vivo percutaneous absorption of pyrethrin and piperonyl butoxide. Food Chem Toxicol 32 51-53 Wheelock CE, Wheelock AM, Zhang R, Stok JE, Morisseau C, Le Valley SE (2003) Evaluation of alpha-cyanoesters as fluorescent substrates for examining intraindividual variation in general and pyrethroid-selective esterases in human liver microsomes. Anal Bioehran 315 208—222 Wheelock CR, Miller JL, Miller MJ, Phillips BM, Huntley SA, Gee SJ, Tjeerdem RS, Hammock BD (2006) Use of carboxylesterase activity to remove pyrethroid-associated toxicity to Ceiiodaphnia dubia and Hyalella azteca toxicity in identification evaluations. Environ Toxicol Chem 25 973-984... 

Mechanism of action can be an important factor determining selectivity. In the extreme case, one group of organisms has a site of action that is not present in another group. Thus, most of the insecticides that are neurotoxic have very little phytotoxicity indeed, some of them (e.g., the OPs dimethoate, disyston, and demeton-5 -methyl) are good systemic insecticides. Most herbicides that act upon photosynthesis (e.g., triaz-ines and substituted ureas) have very low toxicity to animals (Table 2.7). The resistance of certain strains of insects to insecticides is due to their possessing a mutant form of the site of action, which is insensitive to the pesticide. Examples include certain strains of housefly with knockdown resistance (mutant form of Na+ channel that is insensitive to DDT and pyrethroids) and strains of several species of insects that are resistant to OPs because they have mutant forms of acetylcholinesterase. These... 

The organophosphorons insecticides dimethoate and diazinon are mnch more toxic to insects (e.g., housefly) than they are to the rat or other mammals. A major factor responsible for this is rapid detoxication of the active oxon forms of these insecticides by A-esterases of mammals. Insects in general appear to have no A-esterase activity or, at best, low A-esterase activity (some earlier stndies confnsed A-esterase activity with B-esterase activity) (Walker 1994b). Diazinon also shows marked selectivity between birds and mammals, which has been explained on the gronnds of rapid detoxication by A-esterase in mammals, an activity that is absent from the blood of most species of birds (see Section 23.23). The related OP insecticides pirimiphos methyl and pirimiphos ethyl show similar selectivity between birds and mammals. Pyrethroid insecticides are highly selective between insects and mammals, and this has been attributed to faster metabolic detoxication by mammals and greater sensitivity of target (Na+ channel) in insects. 

Ortego, L.S. and Benson, W.H. (1992) Effects of dissolved humic material on the toxicity of selected pyrethroid insecticides, Environmental Toxicology and Chemistry 11 (2), 261-265. 

In laboratory microcosms, ira 5-permethrin was selectively degraded compared to the other diastereomer, cw-permethrin, by six bacterial strains [19]. These strains also preferentially biotransformed 15-cw-bifenthrin over their antipodal l/ -cw-enantiomers, which were more toxic to daphnids [19]. Enantioselectivity was more pronounced for cw-permethrin than for cw-bifenthrin, and was strain-dependent. The (—)-enantiomer of both pyrethroids was preferentially depleted in sediments adjacent to a plant nursery, suggesting that in situ microbial biotransformation was enantioselective [20]. Although all enantiomers of permethrin were hydrolyzed quickly in C-labeled experiments in soils and sediments, the degradates of both cis- and irara-permethrin s -enantiomers were mineralized more quickly than those of the 5-enantiomer, while degradation products of cA-permethrin were more persistent than those of the trans-isomex [185]. Enantioslective degradation of fenvalerate in soil slurries has also been reported [83]. These smdies underscore how enantiomer-specific biotransformation can affect pyrethroid environmental residues, the toxicity of which is also enantiomer-dependent [18-20]. 

The molecular basis for the evolution of distinct kdr mutations in different insects and arachnids remains unclear. Assuming that the pyrethroid binding site(s) (and/or the pyrethroid response domain) is composed of multiple amino acid residues, there are two ways by which different mutations can be selected in different insects and arachnids. First, the random mutation hypothesis mutation in any pyrethroid binding site/response domain affects pyrethroid toxicity without impacting normal sodium channel functional properties. Thus, selection of different mutations in different insects and arachnids is purely random. Second, the nonrandom mutation hypothesis mutation in any pyrethroid binding site/response domain affects pyrethroid toxicity, but some mutations also drastically alter normal sodium channel functional properties in one species, but not in another, presumably because of different sodium channel backbone sequences. That is, there may be severe fimess costs for some mutations, if placed out of their native protein context. 

Pyrethroids occupy a central position among insecticides because of their high selectivity and low toxicity [34]. Chrysanthemic esters (33), the carboxylic acid components of this important class of compounds, can be synthesized by asymmetric cyclopropanation of olefins (cf Section 3.1.7) by diazoacetates in the presence of a chiral Schiff base-Cu complex (Scheme 9 and Structures 34 and 35) [35-37]. 

Lloyd (1973) carried out laboratory toxicity tests using a selection of candidate pyrethroids on T. ctistaneum and susceptible anti resistant S. grants riusm. The results were bioresmethrin > resmethrin > bioallethrin > allethrin > tetra-methrin, When synergized with PBO the same pattern emerged. The results are shown in Table 16.4. 

There are literally thousands of chemicals and/or formulations in the major categories (i.e., insecticides, herbicides, fungicides, roden-ticides, fumigants, nematocides) of pesticides. Therefore, no attempt was made to provide a review of representatives of all the major classes of pesticides. In the section which follows, selected pesticides from three chemical classes, the organophosphates, the halogenated hydrocarbons, and the pyrethroids, will be discussed in regard to the differences and similarities between acute and chronic toxicity. The criteria for selection of the examples are mainly related to the availability of current information in the literature. 

The aforementioned parasites and predators are all somewhat tolerant of the pyrethroids, an attribute that gives some hope for at least a modicum of natural-enemy conservation when these compounds are used in mid-season. It seems reasonable that careful evaluations of comparative toxicity data for Heliothis and some key major natural enemies could lead to identification of nonpyrethroid insecticides that if needed could be used with at least some degree of selectivity against the first two generations of the pest. However, such data are scarce, and more work is needed to provide an adequate data base that would allow more flexibility in choosing an appropriate chemical. Given the history of resistance in the tobacco budworm to various classes of insecticides, it would be advisable to alternate classes of insecticides early in the season to avoid selecting populations of the pest for multiple resistance. 

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