Mechanisms of pyrethroid neurotoxicity: Implications for cumulative risk assessment

Mechanism of action of insecticidal secondary metabolites of plant origin

Pyrethroid insecticides interact with a variety of neurochemical processes, but not all of these actions are likely to be involved in the disruption of nerve function. Several lines of evidence suggest that the voltage-sensitive sodium channel is the single principal molecular target site for all pyrethroids and DDT analogs in both insects and mammals. The alterations of sodium channel functions identified in both biophysical and biochemical studies are directly related to the effects of these compounds on intact nerves. The pyrethroid recognition site of the sodium channel exhibits the stringent stereospecificity predicted by in vivo estimates of intrinsic neurotoxicity in both insects and mammals. Type I and Type II compounds produce qualitatively different effects on sodium channel tail currents, divergent actions on intact nerves, and different effects on the excitability of vertebrate skeletal muscle. Moreover, compounds that are defined as intermediate in the Type I/Type II classification scheme are also intermediate in their effects on sodium channel kinetics. The range of different actions on sensory and motor nerve pathways arising from these qualitatively different effects at the level of the sodium channel appear to be sufficient to explain the distinct poisoning syndromes that have been identified in both insects and mammals. Thus, it does not appear necessary to invoke different primary target sites for Type I and Type II compounds to explain their actions in whole animals. Although the voltage-sensitive sodium channel is likely to be the principal site of pyrethroid action, it is probably not the only site involved in intoxication. Insect neurosecretory neurons are sensitive to very low concentrations of pyrethroids, and disruption of the neuroendocrine system has been implicated as a factor contributing to the irreversible effects of pyrethroid intoxication in insects. Since action potentials in these nerves are carried by calcium ions through TTX-insensitive voltage-gated cation channels, these findings provide evidence that pyrethroids can alter neuronal excitability through an action on voltage-sensitive channels other than the sodium channel. Actions on voltage-sensitive calcium channels may also be involved in the effects of pyrethroids on neurotransmitter release in mammals. The proconvulsant actions of pyrethroids mediated through the peripheral-type benzodiazepine receptor may also contribute to pyrethroid intoxication. Both Type I and Type II compounds are potent proconvulsants in vivo at doses well below those required to produce pyrethroid-dependent intoxication.(ABSTRACT TRUNCATED AT 400 WORDS)

Neurotoxic actions of pyrethroid insecticides

Recalling the pertinent provisions of the relevant international environmental conventions, especially the Rotterdam Convention on the Prior Informed Consent Procedure for Certain Hazardous Chemicals and Pesticides in International Trade, and the Basel Convention on the Control of Transboundary Movements of Hazardous Wastes and their Disposal including the regional agreements developed within the framework of its Article 11,

Stockholm Convention on persistent organic pollutants

Neuroexcitatory symptoms of acute poisoning of vertebrates by pyrethroids are related to the ability of these insecticides to modify electrical activity in various parts of the nervous system. Repetitive nerve activity, particularly in the sensory nervous system, membrane depolarization, and enhanced neurotransmitter release, eventually followed by block of excitation, result from a prolongation of the sodium current during membrane excitation. This effect is caused by a stereoselective and structure-related interaction with voltage-dependent sodium channels, the primary target site of the pyrethroids. Near-lethal doses of pyrethroids cause sparse axonal damage that is reversed in surviving animals. After prolonged exposure to lower doses of pyrethroids axonal damage is not observed. Occupational exposure to pyrethroids frequently leads to paresthesia and respiratory irritation, which are probably due to repetitive firing of sensory nerve endings. Massive exposure may lead to severe human poisoning symptoms, which are generally treated well by symptomatic and supportive measures.

/pdf/neurotoxicological-effects-and-the-mode-of-action-of-mfikldv6ht.pdf

Moustafa A. Abbassy

Papers

Bioactivity of two major constituents isolated from the essential oil of Artemisia judaica L.

Pyrethroid action on the nicotinic acetylcholine receptor/channel

Alcohol modulation of drug binding to the channel sites of the nicotinic acetylcholine receptor.

Adverse Haematological and Biochemical Effects of Certain Formulated Insecticides in Male Rats

Insecticidal, antifeedant and antifungal activities of two glucosides isolated from the seeds of Simmondsia chinensis