Pyrethroid insecticides, neurotoxicity

Taylor, K.S., G.D. Waller, and L.A. Crowder. 1987. Impairment of a classical conditioned response of the honey bee (Apis mellifera L.) by sublethal doses of synthetic pyrethroid insecticides. Apidologie 18 243-252. Theophilidis, G., M. Benaki, and E. Papadopoulu-Mourkidou. 1997. Neurotoxic action of six pyrethroid insecticides on the isolated sciatic nerve of a frog (Rana ridibunda). Comp. Biochem. Physiol. 118C 97-103. Tippe, A. 1987. Evidence for different mechanisms of action of the three pyrethroids, deltamethrin, cypermethrin, and fenvalerate, on the excitation threshold of myelinated nerve. Pestic. Biochem. Physiol. 28 67-74. 

Clark JM (1995) Effects and mechanisms of action of pyrethrins and pyrethroid insecticides. In Chang LW, Dyer RS (eds) Handbook of neurotoxicity. Marcel Dekker, New York, NY, pp 511-546... 

Soderlund DM (2011). Molecular mechanisms of pyrethroid insecticide neurotoxicity recent advances. Arch Toxicol, in press... 

Shafer TJ, Meyer DA, Crofton KM (2005) Developmental neurotoxicity of pyrethroid insecticides critical review and future research needs. Environ Health Perspect 113 123-136... 

Ion transport is central to nerve impulse transmission both along the axon and at the synapse and many neurotoxicants elicit effects by interfering with the normal transport of these ions (Figure 11.6). The action potential of an axon is maintained by the high concentration of sodium on the outside of the cell as compared to the low concentration inside. Active transporters of sodium (Na+K+ ATPases) that actively transport sodium out of the cell establish this action potential. One action of the insecticide DDT resulting in its acute toxicity is the inhibition of these Na+K+ ATPases resulting in the inability of the nerve to establish an action potential. Pyrethroid insecticides also elicit neurotoxicity through this mechanism. DDT also inhibits Ca2+Mg2+ ATPases, which are important to neuronal repolarization and the cessation of impulse transmission across synapses. 

Controversy exists over the possible role of PB. Large doses of PB can cause bromide psychosis (Rothenberg et al. 1990). The literature is conflicted as to whether a genetic variation of butyrylcholinest-erase can cause a severe reaction to PB (Loewenstein-Lichtenstein et al. 1995 Lotti andMoretto 1995 Senecal and Osterloh 1990). PB also may act synergistically with A/,A/-diethyl-m-toluamide, or DEET, an insect repellent, and permethrin, a pyrethroid insecticide. DEET, PB, and permethrin in various combinations are more neurotoxic to hens than are these agents when administered alone (Abou-Donia et al. 1996). 

In the last century, the development of organophosphorus, carbamate, and organochloride insecticides was followed by synthetic pyrethroids. As a result, pyrethroids are now used frequently in the domestic milieu. Pyrethroid insecticides are synthetically derived from the molecular structure or sharing the same mechanism of action of natural pyrethrins that have broader spectmm of activity, more stability, and residual activity (persists longer than that of natural pyrethrins) and include the following allethrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flumethrin, fluvalinate, tau-fluvalinate, and permethrin (see structure in Fig. 137.2). They are lipophilic compounds and generally of low acute oral toxicity to mammals but are very toxic to aquatic organisms. When synthetic pyrethroids are administered to mammals parenterally, the synthetic pyrethroids are neurotoxic. 

Pyrethroid insecticides are generally classified into one of two large groups on the basis of the central neurotoxic syndrome that they produce [5, 6]. Type I pyrethroids are esters of chrysanthemic acid and an alcohol, having a furan ring and terminal side chain moieties, and absence of a cyano moiety. Allethrin was the first pyrethroid identified in 1949. Allethrin and other pyrethroids such as phenothrin and permethrin with the basic cyclopropane carboxylic ester structure are type I pyrethroids. The insecticidal activity of these synthetic pyrethroids was enhanced further by the addition of a cyano group to give ot-cyano type II pyrethroids such as deltamethrin, fenvalerate, cyfluthrin, cyhalothrin, and lambda-cyhalothrin (Fig. 137.2). 

At the present time, no predictive QSAR models were found that describe the neurotoxicity of the pyrethroids insecticides. 

The sections on the metabolism and neurotoxicity of the pyrethroids in this review provide a starting point that feeds into the physiological and biochemical parameters that are needed to develop PBPK/PD models for assessing risks to the pyrethroids. The development of such pyrethroid model parameters requires knowledge of their discovery, chemistry, chirality, their isomers, and their chromatographic separation. To this end. Sect. 2 above (viz.. Nature of Pyrethroid Insecticides) was developed with a listing of 15 of the most important pyrethroids... 

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... 

Insect resistance and environmental pollution due to the repeated application of persistent synthetic chemical insecticides have led to an Increased interest in the discovery of new chemicals with which to control Insect pests. Synthetic insecticides, including chlorinated hydrocarbons, organophosphorus esters, carbamates, and synthetic pyrethroids, will continue to contribute greatly to the increases in the world food production realized over the past few decades. The dollar benefit of these chemicals has been estimated at about 4 per 1 cost (JJ. Nevertheless, the repeated and continuous annual use in the United States of almost 400 million pounds of these chemicals, predominantly in the mass agricultural insecticide market (2), has become problematic. Many key species of insect pests have become resistant to these chemicals, while a number of secondary species now thrive due to the decimation of their natural enemies by these nonspecific neurotoxic insecticides. Additionally, these compounds sometimes persist in the environment as toxic residues, well beyond the time of their Intended use. New chemicals are therefore needed which are not only effective pest... 

Pyrethroids. Pyrethroids, such as natural pyrethrins and synthetic analogs, allethrin, permethrin, and others, are well known for their neurotoxicity (48-59). However, as a major class of insecticide, they have a remarkable safety margin for mammals, principally because of the rapid metabolic degradation of pyrethroids in mammalian species (48-50). The acute toxicity of pyrethroids involves two distinct syndromes in rats and mice (49-51). The first one, T syndrome or tremor (Type I), is characterized by a rapid onset of tremor, initially in the limbs and gradually extending over the whole body. Death is associated with clonic seizures. The second... 

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. 

Neurotoxic antifeedants from Compositae should provide important leads into strategies that ameliorate the control of the Diabrotica complex. Phytochemicals with combined effects that result in loss of insecticide resistance, reduced feeding, decreased life span, and neurotoxicity in rootworms may be a practical avenue to low chemical input strategies for com production. Also, phytochemical antagonism of cyclodiene resistance may have important consequences to future control of com rootworm by insecticides such as avermectins and pyrethroids (e.g. tefluthrin) which, certainly in the former case (121) and at least secondarily in the latter case (122), act on the GABA gated-chloride ionophore complex. 

Pyrethroids are neurotoxic synthetic compounds used as insecticides. Cypermethrin and fenvalerate have been reported as causing positive allergic patch tests, but only fenvalerate was relevant in an agricultural worker. 

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