Selective toxicity insecticides

Dr. John E. Casida from the University of California Berkeley is inveshgating the fundamental basis for the selective toxicity of insecticides, including endosulfan, acting at the gamma-aminobutyric acid (GABA) receptor of mammals and insects. The research is sponsored by the National Institute of Environmental Health Sciences. 

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. 

Table 1 shows the ratios of LD50 values of various insecticidal components for mammals and insects, i.e., indexes for selective toxicity. 

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. 

A few organophosphorus insecticides are also phosphoramidates, hydrolysis of the P-N bond being considered a route of detoxification. This is exemplified by the metabolism of acephate (9.82, Fig. 9.15), whose mechanisms of activation and detoxification have recently been re-examined in mice to better understand the relative innocuity of the compound in mammals and its selective toxicity in insects [156],... 

The basis for the selective toxicity of malathlon provided the rationale for the design of the N-dlmethoxyphosphlnothloyl derivatives of methylcarbamates esters as selectively toxic Insecticides (general structure below). 

A number of methylcarbamate derivatives containing the N-S-S linkage also have been disclosed recently in the patent literature as selectively toxic insecticides (31,32). Typical examples of these compounds are given as follows ... 

It was the selective toxicity of the insecticide DDT that was destined to have a most profound effect on attitudes to chemical safety. DDT was a chemical that had first been synthesised decades before the Swiss chemist Muller discovered its potent insecticidal action in the late r930s. What was so remarkable about DDT was its selectivity. Even in extremely small doses, it was lethal to many species of insect yet it was remarkably non-toxic to humans even at quite high doses (Figure 6.3). The manufacture of DDT is... 

The control of insects has, traditionally, been associated with interference with nerve function. This makes many insecticides relatively toxic to non-target organisms, and particularly beneficial insects and mammals, including man. Selectivity will not be reviewed in any detail as this is associated with a number of factors such as penetration to the target site... 

Hydrolytic reactions. There are numerous different esterases responsible for the hydrolysis of esters and amides, and they occur in most species. However, the activity may vary considerably between species. For example, the insecticide malathion owes its selective toxicity to this difference. In mammals, the major route of metabolism is hydrolysis to the dicarboxylic acid, whereas in insects it is oxidation to malaoxon (Fig. 5.12). Malaoxon is a very potent cholinesterase inhibitor, and its insecticidal action is probably due to this property. The hydrolysis product has a low mammalian toxicity (see chap. 7). 

The onset of symptoms depends on the particular organophosphorus compound, but is usually relatively rapid, occurring within a few minutes to a few hours, and the symptoms may last for several days. This depends on the metabolism and distribution of the particular compound and factors such as lipophilicity. Some of the organophosphorus insecticides such as malathion, for example (chap. 5, Fig. 12), are metabolized in mammals mainly by hydrolysis to polar metabolites, which are readily excreted, whereas in the insect, oxidative metabolism occurs, which produces the cholinesterase inhibitor. Metabolic differences between the target and nontarget species are exploited to maximize the selective toxicity. Consequently, malathion has a low toxicity to mammals such as the rat in which the LD50 is about 10 g kg-1. 

It therefore appears that neurons in the substantia nigra might ultimately be destroyed because genetic factors lead to neuronal protein accumulation and free radical-induced oxidative stress that causes the degeneration and death of these neurons. As indicated earlier, however, the influence of environmental factors should be considered.49,64 It has been theorized, for example, that environmental toxins (e.g., herbicides, insecticides, fungicides) accelerate the neuronal destruction in people with Parkinson disease.14 Much of this evidence is based on the finding that a compound known as l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) appears to be selectively toxic to these neurons and can invoke parkinsonism in primates.84... 

Agricultural chemicals include many compounds, such as insecticides, herbicides, fungicides, and rodenticides, in which toxicity to the target organism is a desired quality whereas toxicity to nontarget species is to be avoided. Development of such selectively toxic chemicals is one of the applied roles of... 

Selective toxicity refers to differences in toxicity between two species simultaneously exposed. See Figure 9.26, where rats show a higher response than mice to a certain dose. This is the basis for the effectiveness of pesticides and drugs. For example, an insecticide is lethal to insects but relatively nontoxic to animals in the same vein, antibiotics are selectively toxic to microorganisms while virtually non-toxic to humans. 

Pest control with insecticides is based on the probability that species differ greatly in susceptibility to toxicants and that it is possible to show selective toxicity among species, i.e., controlling one without harming others in the same environment. Evidence has shown that this probability is high, even though its basis is not always understood (Terriere, 1982). In this chapter we will compare the xenobiotic metabolizing enzyme activity of various species to learn how much this may contribute to toxicity differences. 

There are several other interesting phenomena associated with metabolism, namely, synergism, antagonism, selective toxicity, enzyme induction, and resistance. It will be seen that all of these involve some modification of metabolic activity resulting in changing the toxicity of insecticides. 

With the preceding discussion as background, it would be easy to understand how the selective toxicity of insecticide occurs, showing that some species are more susceptible to the toxicants than others. In fact, we would not be able to develop selective insecticides if it were not for the species differences that have evolved. Metabolism is not the only mechanism for selectivity, however. Ecological selectivity, which involves particular behavioral characteristics of the target pest, is also important, e.g., the use of insecticide bait against some species, or systemic insecticides against others. 

A good example of selective toxicity is illustrated in Figure 9.11. Malathion is a weakly active insecticide, whereas malaoxon is a strongly active insecticide. One of the main reasons why malathion is highly toxic to insects but not to mammals is that the latter have high carboxylesterase activities, which rapidly attack the two carboxylesters, but the... 

Another example of insecticide selectivity is shown in Figure 9.12. Acephate is a proinsecticide that has to be converted to methamidophos, an active insecticide, by a carboxy-lamidase. It has been shown that this hydrolase is much more active in insects than in mammals. This explains why acephate is very toxic to insects but not to mammals. 

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