Neurotoxicological Effects and the Mode of Action of Pyrethroid Insecticides

Abstract

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.VI. SummaryAlthough pyrethroid insecticides have been introduced on a large scale fairly recently, extensive data have been published on their mode of action, and valuable information is available on potential side effects in man.The basic mechanism of action of the pyrethroids on the vertebrate nervous system has been investigated in detail. All available evidence clearly indicates that the primary neurotoxic target site of this chemically diverse class of insecticides is confined to the voltage-dependent sodium channels in excitable membranes. The stereoselective interaction of pyrethroids with a fraction of the sodium channels results in a prolongation of the inward sodium current during excitation, as pyrethroid-modified sodium channels stay open much longer than normal. The prolonged sodium current induced by the pyrethroids results in pronounced repetitive activity, notably in sense organs, but — depending on pyrethroid structure — also in sensory nerve fibers, motor nerve terminals, and skeletal muscle fibers. Besides repetitive firing, membrane depolarization resulting in enhanced neurotransmitter release and eventually block of excitation may also occur.Studies on sense organs in the vertebrate skin have shown that the cyano pyrethroids evoke more intense repetitive activity than the noncyano pyrethroids. This is accounted for by large, quantitative differences in the prolongation of the sodium current by cyano and noncyano pyrethroids. For a range of pyrethroids the symptoms observed in experimental animal poisoning correlate well with the extent to which the sodium current is prolonged.Postsynaptic neurotransmitter responses are unaffected by concentrations of pyrethroids that cause marked sodium channel modification. At high concentrations insecticidal as well as noninsecticidal pyrethroid isomers cause a nonspecific suppressive effect on the postsynaptic neurotransmitter response.Cardiovascular effects of pyrethroids can be attributed to modification of presynaptic as well as postsynaptic sodium channels.Paresthesia and other peripheral sensory phenomena, e.g., respiratory irritation, are repeatedly experienced in man after occupational exposure to cyano pyrethroids in particular. These symptoms, which are most likely caused by repetitive firing of sensory nerve endings, should be considered a warning of overexposure, indicating that adequate preventive measures should be taken. The quality as well as the intensity of the peripheral sensory phenomena depends not only on pyrethroid structure, but also varies with the formulation and with environmental factors.The question whether repeated occurrence of peripheral repetitive firing may eventually lead to injury of sensory nerve endings or central sensory adaptation remains unanswered. The guinea pig flank provides an adequate model to quantify the cutaneous sensations of pyrethroids. This model may be particularly useful to compare the degree of skin sensory irritation caused by different formulations of pyrethroids and could also be of value to investigate possible chronic effects.Lethal and near-lethal doses of pyrethroids cause sparse axonal damage in a fraction of the exposed animals, which is reversed after cessation of exposure. Threshold concentrations from acute and chronic studies are available. After prolonged chronic exposure to lower doses of pyrethroids axonal damage has not been observed. It has been suggested that the histopathological changes are unrelated to the basic neuroexcitatory action of pyrethroids. The hen sciatic nerve is not suitable for studying pyrethroid-induced nerve damage, as — in contrast to organophosphates — birds are highly insensitive to pyrethroids.The limited information available on neurobehavioral effects of pyrethroids is difficult to evaluate, as the significance of such data for toxicological risk assessment is still under debate.