Organophosphates selective toxicity

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. 

Amidases can be found in all kinds of organisms, including insects and plants [24], The distinct activities of these enzymes in different organisms can be exploited for the development of selective insecticides and herbicides that exhibit minimal toxicity for mammals. Thus, the low toxicity in mammals of the malathion derivative dimethoate (4.44) can be attributed to a specific metabolic route that transforms this compound into the nontoxic acid (4.45) [25-27]. However, there are cases in which toxicity is not species-selective. Indeed, in the preparation of these organophosphates, some contaminants that are inhibitors of mammalian carboxylesterase/am-idase may be present [28]. Sometimes the compound itself, and not simply one of its impurities, is toxic. For example, an insecticide such as phos-phamidon (4.46) cannot be detoxified by deamination since it is an amidase inhibitor [24],... 

Studies on the scaleless chicken are underway examining its suitability as a model for assessing toxicity of organophosphates. The first compound selected for field trials was the defoliant DEF (S,S,S-tributylphosphorotrithioate) used during the harvesting of cotton in California and Arizona in the fall (October-November) when air movements are frequently restricted by inversions. DEF has been the subject of sufficient complaints to place it on the pre-RPAR list, although there are no reports of acute or delayed neurotoxicity in humans when it and related chemicals are used according to recommendations. It both inhibits cholinesterases and causes delayed neurotoxicity in hens (3,6). 

Malathion has two carboxyester linkages, which are hydrolyzable by carboxylase enzymes to relatively nontoxic products, as shown in reaction 18.7.1. The enzymes that accomplish this reaction are possessed by mammals, but not by insects, so that mammals can detoxify malathion, whereas insects cannot. The result is that malathion has selective insecticidal activity. For example, although malathion is a very effective insecticide, its LD50 for adult male rats is about 100 times that of parathion, reflecting the much lower mammalian toxicity of malathion than those of some of the more toxic organophosphate insecticides, such as parathion. 

The well-known selectivities of some organophosphates may be explained by the balance of enzymatic events. The reduced toxicity of the insecticide malathion to mammals is largely the result of rapid activation by desulfuration in the insect and the more rapid detoxificaton by carboxylesterases and glutathione transferases in the mammal (3). Design of new pest bioregulators should exploit enhanced activation and decreased detoxification capabilities in the targeted pests. 

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. 

Selective behavior monitors specific toxicity and employs enzyme inhibition tests and reporter genes tests. Examples, are use of cholinesterase for organophosphates and urease for heavy metal ions detection and also transgenic microorganism for specific analyte assessment. 

B32. Berends, F., Mechanisms of aging of organophosphate-inhibited esterases. In Selectivity and Molecular Mechanisms of Toxicity (F. de Matteis and E. A. Lock, eds.), p. 125-152. McMillan Press, London, UK, 1987. 

Although tebufenozide has very high inherent toxicity to caterpillars, it has satisfyingly low toxicity to a wide range of vertebrates, such as mammals, birds, amphibians, and fish (4). As illustrated in Table I, representative mammal and bird species (rat and quail) are, at minimum, four orders of magnitude less susceptible to tebufenozide than is a representative caterpillar species, southern armyworm (Spodoptera eridania). Older broad spectrum neurotoxic insecticides such as the organophosphates or synthetic pyrethroids would typically have much less favorable insect/vertebrate selectivity ratios. 

The organophosphate insecticides, when introduced, about 1945, made a large and welcome addition to what was available. Because a fuller account is given in Section 13.3, it need be said here only that they are nerve poisons which initially act in a quite different way from the pyrethroids and chlorinated hydrocarbons, for they are inhibitors of acetylcholinesterase. The earliest examples, discovered in Germany by Schrader, were as toxic to the spraymen as to the insects. Little by little, adequate selectivity was built into the molecules, and control over their half-life in the field became part of the molecular design also. 

Dimethoate also has an intrinsic selectivity, for it is far more toxic to insects than to mammals. This favourable effect was found, surprisingly, to depend little on differences in S O conversion (as in malathion and diazinon), but to rely mainly on preferential operation of mammalian amidase (Krueger, O Brien and Dauterman, 1960). This discovery introduced an expanded feeling of latitude in designing selective organophosphate insecticides. 

Menazon, also introduced by ICI (1961), is a much more selective systemic insecticide which specifically controls aphids. It is environmentally very acceptable because it does not harm beneficial insects like bees and ladybirds and is very safe because of its low mammalian toxicity. In common with many organophosphates where Y in our general structure is a heterocyclic group, it is made by reacting the appropriate phosphorus acid salt with a chloro-heterocyclic group. 

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