Carbofuran triggers flight motor output in pyrethroid-blocked reflex pathways of the house fly

The initiation of flight from loss of tarsal contact (flight reflex responses) and the tergotrochanteral muscle (TTM) responses evoked by brain stimulation were analyzed during carbofuran, permethrin, deltamethrin, and DDT poisoning in the house fly. Blockage of the flight reflex by LD₅₀ doses of permethrin or deltamethrin was rapid, but the effects of DDT on the flight reflex took hours to develop. In addition, carbofuran treatment induced spontaneous flight in blocked preparations by an action in the central nervous system. This result suggests that pyrethroid blockage of the flight reflex was due to an action on sensory nerves, since the central flight program and its associated efferent systems were functionally intact. The relevance of this finding in terms of pyrethroid knockdown is discussed. The TTM response was unaffected by permethrin or deltamethrin both early and late in the poisoning process, possibly because the evoked TTM response does not involve peripheral sensory nerves, which seem to be important sites of pyrethroid action early in poisoning. Carbofuran induced repetitive firing and blockage of the TTM response within 1 hr, but normal responses were observed late in poisoning, which is consistent with the reversibility of carbamate inhibition of acetylcholinesterase. DDT caused no change in the evoked TTM response until bursts were recorded about 15 hr after treatment; this was another example of a slowly developing DDT effect. The protracted development of various DDT actions was concordant with a hypothesis of reduced efficacy at a proposed target site, viz., the sodium channels of nerve membranes.     

Action of cismethrin and deltamethrin on functional attributes of isolated presynaptic nerve terminals from rat brain

Isolated presynaptic nerve terminals (synaptosomes) prepared from rat brain were used to evaluate the actions of a tremor (T)-syndrome (cismethrin) and a choreoathetosis-salivation (CS)-syndrome (deltamethrin) pyrethroid on the functional attributes of synaptosomes by measuring calcium influx and endogenous neurotransmitter (l-glutamate) release with fluorescent assays. Both cismethrin and deltamethrin stimulated calcium influx, however, only deltamethrin enhanced Ca²⁺-dependent neurotransmitter release and its action was stereospecific, concentration-dependent, stimulated by depolarization, unaltered by tetrodotoxin, and blocked by ω-conotoxin GVIA. Our results delineate a separate action of deltamethrin on presynaptic nerve terminals from that elicited by cismethrin and implicate Ca_v2.2 calcium channels as target sites for deltamethrin that is consistent with the observed in vivo release of neurotransmitter at the onset of convulsive symptom caused by CS-syndrome pyrethroids. This information will allow a more complete understanding of the molecular and cellular nature of pyrethroid-induced neurotoxicity and expands our knowledge of the structure–activity relationships of pyrethroids in regards to their action on voltage-sensitive calcium channels.     

Binary mixtures of pyrethroids produce differential effects on Ca influx and glutamate release at isolated presynaptic nerve terminals from rat brain

Isolated rat brain synaptosomes were used to evaluate the action of pyrethroid mixtures on Ca²⁺ influx and subsequent glutamate release under depolarizing conditions. In equipotent binary mixtures at their respective and/or estimated EC₅₀s with deltamethrin always as one of the two components, cismethrin, λ-cyhalothrin, cypermethrin, esfenvalerate and permethrin were additive and S-bioallethrin, fenpropathrin and tefluthrin were less-than-additive on Ca²⁺ influx. In binary mixtures with deltamethrin always as one of the two components, esfenvalerate, permethrin and tefluthrin were additive and λ-cyhalothrin was less-than-additive on glutamate release. Binary mixture of S-bioallethrin and cismethrin was additive for both Ca²⁺ influx and glutamate release. Only a subset of pyrethroids (S-bioallethrin, cismethrin, cypermethrin, and fenpropathrin) in binary mixtures with deltamethrin caused a more-than-additive effect on glutamate release. These binary mixtures were, however, only additive (cismethrin and cypermethrin) or less-than-additive (S-bioallethrin and fenpropathrin) on Ca²⁺ influx. Therefore, increased glutamate release evoked by this subset of pyrethroids in binary mixture with deltamethrin is not entirely occurring by Ca²⁺-dependent mechanisms via their action at voltage-sensitive calcium channels. These results suggest that pyrethroids do not share a common mode of toxicity at presynaptic nerve terminals from rat brain and appear to affect multiple target sites, including voltage-sensitive calcium, chloride and sodium channels.     

CNS insensitivity to pyrethroids in the resistant kdr strain of house flies

Solutions of tetramethrin, RU 11679, or cismethrin caused uncoupled convulsions in 30–40 min in exposed thoracic ganglia from S_NAIDM house flies at concentrations down to 10^?10M: whereas these same compounds at 10^?6M concentrations failed to produce poisoning symptoms when perfused onto the exposed ganglia of the kdr strain of house fly. The pyrethroid analogs examined had a negative temperature coefficient of action on the exposed thoracic ganglia from S_NAIDM flies. DDT and GH-74 possessed positive temperature coefficients of action on the exposed thoracic ganglion of susceptible house flies. It is concluded that the central nervous system of the kdr strain of house fly is resistant to pyrethroid action; furthermore, the resistance appears to be widespread throughout the house fly nervous system, involving sensory, motor, and central neural elements.     

Structure-related effects of pyrethroid insecticides on the lateral-line sense organ and on peripheral nerves of the clawed frog, Xenopus laevis

The effects of seven different pyrethroid insecticides on the lateral-line sense organ and on peripheral nerves of the clawed frog, Xenopus laevis, were investigated by means of electrophysiological methods. The results show that two classes of pyrethroid can be clearly distinguished. (i) Pyrethroids without an α-cyano group (permethrin, cismethrin, and bioresmethrin). These noncyano pyrethroids induce short trains of nerve impulses in the lateral-line sense organ. In peripheral nerve branches they induce a depolarizing afterpotential and repetitive firing. These effects are very similar to those previously reported for allethrin. (ii) Pyrethroids with an α-cyano-3-phenoxybenzyl alcohol (cypermethrin, fenpropathrin, deltamethrin, and fenvalerate). In the lateral-line sense organ these α-cyano pyrethroids induce very long trains of nerve impulses which may last for seconds and may contain hundreds or even thousands of impulses. The α-cyano compounds do not cause repetitive activity in peripheral nerves. Instead they induce a quickly reversible, stimulus frequency-dependent suppression of the action potential. Since the chemical structure of cypermethrin differs from that of permethrin only in the α-cyano group and because all four α-cyano compounds act in a very similar way, it is concluded that the α-cyano substituent is responsible for the large differences in neurotoxic effects. In the lateral-line sense organ the duration of nerve impulse trains induced by the noncyano as well as the α-cyano pyrethroids increases dramatically when the temperature is lowered. Further, in sensory fibers the effects of both classes of pyrethroid on the nerve action potential are more pronounced compared to their effects on motor fibers. It is argued that the different neurotoxic effects reported here originate from a common mechanism of action of pyrethroids, which is a prolongation of the transient increase of sodium permeability of the nerve membrane associated with excitation.It is concluded that the sodium channel in the nerve membrane is the major target site of noncyano and α-cyano pyrethroids.     

Permethrin and deltamethrin residues on lettuce

Permethrin and deltamethrin, two synthetic pyrethroid insecticides, are registered in several countries for use on lettuce. Both chemicals were applied on autumn and spring grown lettuce in the glasshouse. When applied at the normal prescribed dose rates of 25 and 12.5 g a.i. ha^?1, < 1 mg kg^?1 of either compound was found in the lettuce at harvest, even when applied only a few days before harvest. The total amount of active ingredient applied was too low to reach the 1 mg kg^?1 level when evenly applied on marketable lettuce heads weighing about 200 g each. Applying a higher dose than 25 g permethrin a.i. ha^?1 or 12.5 g deltamethrin a.i. ha^?1, or applying two applications in the 2 weeks prior to harvest, may well result in residue levels higher than the maximum residue limit of 1 mg kg^?1 for permethrin and certainly higher than the maximum residue limit of 0.2 mg kg^?1 for deltamethrin, which is more persistent.     

Deltamethrin: A neurophysiological study of the sites of action

Recent experiments on the mode of action of pyrethroids have indicated that those pyrethroids containing an α-cyano phenoxybenzyl group may act on GABA-mediated chloride channels. The crayfish stretch receptor neuron provides a useful preparation for examining the effects of pyrethroids on these channels and on sodium channels. The lowest concentration of deltamethrin to have an effect on sodium channels was 10⁻¹² M, but the response of the preparation to GABA appeared to be unaffected by concentrations of deltamethrin up to 10⁻⁷ M. Although 10⁻⁶ M deltamethrin had a slight effect on the GABA response of the dactyl abductor muscle, it appears that the majority of the effects of cyano pyrethroids in invertebrates could be accounted for solely by their action on sodium channels.     

Some effects of cismethrin on the rabbit nervous system

The effects of cismethrin, 5-benzyl-3-furylmethyl (1 R)-cis-chrysanthemate, in the spinal rabbit have been investigated at the level of the sensory receptors, in an afferent nerve, and in the spinal cord. Cismethrin causes a lowering of the threshold of some sensory receptors and the appearance of spontaneous activity, which may be in bursts, in some afferent fibres that were previously silent. When recordings were made from the afferent nerve, in addition to phenomena arising from the effects on sensory receptors, there was repetitive firing in the nerve when action potentials were evoked by electrical stimulation. The effects on the spinal cord were such as to increase the excitability of reflex arcs. There was also a change in the normal pattern of facilitation and inhibition as measured by the amplitude of the second of two suitably spaced monosynaptic responses and it is suggested that this is an indirect effect of cismethrin intoxication. The cumulative effect of the changes brought about in nervous activity in the system described here could account at least in part for the convulsions observed in intoxicated animals.     

The relationship between the pharmacokinetics of intravenous cismethrin and bioresmethrin and their mammalian toxicity

The distribution and excretion of [¹⁴C]alcohol-labeled cismethrin and bioresmethrin was determined after intravenous administration to rats. Initially the label distribution of both isomers was similar, but differences occurred at later times mainly due to the retention of 5-benzyl-3-furylcarboxylic acid, a metabolite of bioresmethrin, in high concentration in the blood. Retention of this metabolite accounted for the slower excretion of bioresmethrin label compared to cismethrin. After administration of either isomer, parent pyrethroid was rapidly cleared from the blood and liver, and both isomers rapidly entered the central nervous system reaching peak concentrations within 2–5 min. Brain cismethrin concentrations exceeding 3.5 nmol/g were associated only with animals showing tremors. These levels of cismethrin are maintained for up to 30 min but bioresmethrin was depleted more rapidly possibly due to brain metabolism. It is concluded that the low toxicity of bioresmethrin is possibly due to the inability of this isomer to interact with the site of action in the central nervous system and not, as previously suggested, primarily because of more rapid metabolism in the liver.     

Anthelmintic Actions of the Cyclic Depsipeptide PF1022A and its Electrophysiological Effects on Muscle Cells of Ascaris suum

The cyclic depsipeptide PF1022A, given orally to mice, showed very good anthelmintic activity against Heligmosomoides polygyrus and Heterakis spumosa at 50 mg kg⁻¹. In vitro, PF1022A was very active against Trichinella spiralis and had good activity against Nippostrongylus brasiliensis at 1 μg ml⁻¹. An 18-membered enniatin analogue, JES 1798, showed good activity only against N. brasiliensis at 10 μg ml⁻¹. The optical antipode of PF1022A had poor activity even at 100 μg ml⁻¹. The effects of PF1022A on the membrane potential and input conductance of somatic muscle of Ascaris suum were examined using a two-microelectrode current-clamp technique. PF1022A did not antagonize the effects of the selective nicotinic agonist levamisole. PF1022A and an analogue, JES 1798, but not the PF1022A antipode, produced a small time-dependent increase in input conductance associated with no potential change. The increase in input conductance did not occur in the Cl⁻-free bathing solution, suggesting that the increase in input conductance was mediated by Cl⁻ ions. The addition of high concentrations of Ca²⁺ to the preparation after the addition of PF1022A did not lead to production of Ca²⁺-activated Cl⁻ channels, suggesting that its mode of action was not that of a Ca²⁺ ionophore. The mechanism by which the cyclic depsipeptide might increase the Cl⁻ conductance is discussed.     

A new aqueous suspension concentrate formulation of cis‐permethrin and its insecticidal activity

Isomers of pyrethroids usually have different insecticidal activities. Permethrin, a non‐cyano pyrethroid, is not an exception and cis‐permethrin is much more active than the trans‐isomer against Triatoma infestans, vector of Chagas' Disease in Argentina. The large‐scale separation of cis‐ and trans‐permethrin was performed by successive recrystallizations from ethanol‐water mixtures. An aqueous suspension concentrate (flowable) formulation of pure crystalline cis‐permethrin was prepared and assayed for its insecticidal activity on wood and ceramic surfaces against nymph V of T infestans. This formulation was at least three times more effective than deltamethrin, with LC₅₀ values on ceramic of 0.11 µg cm⁻² and 0.33 µg cm⁻² respectively. On wood surfaces, the LC₅₀ value was 0.57 µg cm⁻² compared with 3.20 µg cm⁻² for deltamethrin. Against other insect species such as Periplaneta americana, Aedes aegypti and Culex quinquefasciatus, the suspension concentrate formulation of cis‐permethrin was, however, less effective than similar formulations of deltamethrin or β‐cypermethrin. © 2000 Society of Chemical Industry     

Action of pyrethroids on a nerve-muscle preparation of the clawed frog,Xenopus laevis

The effects of a range of pyrethroids on end-plate potentials and muscle action potentials were studied in the pectoralis nerve-muscle preparation of the clawed frog, Xenopus laevis. The noncyano pyrethroids allethrin, cismethrin, bioresmethrin, and IR-cisphenothrin caused moderate presynaptic repetitive activity only, resulting in the occurrence of multiple end-plate potentials (epps). Trains of repetitive muscle action potentials without presynaptic repetitive activity were observed after the α-ethynyl pyrethroid S-5655 and after the α-cyano pyrethroids cypermethrin, deltamethrin, FCR 1272, and FCR 2769. An intermediate group of pyrethroids consisting of the non-cyano compounds 1R-permethrin, des-cyano-deltamethrin, NAK 1901 and NAK 1963, and the α-cyano pyrethroids cyphenothrin and fenvalerate caused both types of effect. The insecticidally inactive S-enantiomers of permethrin had no effect on the nerve-muscle preparation. Trains of repetitive action potentials in pyrethroid-treated muscle fibers were followed by a depolarizing afterpotential which in general decayed more rapidly for the non-cyano pyrethroids than for the α-cyano pyrethroids. The rate of decay of the depolarizing afterpotential decreased gradually as the temperature was lowered, whereas the pre- and postsynaptic repetitive activity remained largely unaffected over a large temperature range. It is concluded that in muscle membrane like in nerve membrane the pyrethroid-induced repetitive activity is due to a prolongation of the sodium current and that a clear distinction between non-cyano pyrethroids on the one hand and α-cyano compounds on the other cannot be made on the basis of the present results.     

Protective action of fenvalerate,deltamethrin, and four stereoisomers of permethrin against black flies (Simulium spp.) attacking cattle

Fenvalerate, deltamethrin, (1R)-cis-permethrin, (1R)-trans-permethrin and (1S)-trans-permethrin, applied topically to the entire body surface of steers at a rate of 1 mg a.i. kg⁻¹, provided 70% or better protection from black flies on cattle for 16, 9, 8, 6 and 6 days, respectively. The (1S)-cis stereoisomer of permethrin was ineffective as a protectant against black flies at a rate of 1 mg a.i. kg⁻¹ when applied as a total body spray. One poly(vinyl chloride) ear tag containing 10% permethrin, in each ear of steers, provided protection from black fly attack for up to 13 days under field conditions. Poly(vinyl chloride) ear tags containing 8% fenvalerate, installed in each ear of steers, did not provide satisfactory protection from black flies under field conditions.     

Synthetic Pyrethroid Insecticides: Some Studies with Locusts

Abstract

Laboratory studies were carried out to determine the course of poisoning and toxicity of some synthetic pyrethroid insecticides (bioresmethrin, cismethrin, cypermethrin, deltamethrin, fenpropathrin, fenvalerate and permethrin) against the desert locust. From doses in excess of the LD₉₉ all the insecticides were quick acting; from doses of about the LD₉₉ or less the insects are rapidly knocked down or show symptoms of poisoning, but may recover. The symptoms which follow treatment by the various insecticides are described. Although these insecticides are all highly toxic to locusts there are many other insecticides which are similarly toxic, can be sprayed at high concentrations and are much cheaper.     

Pesticide residues in foodstuffs in England and Wales. Part II: Inorganic bromide ion in cucumber,tomato and self-blanching celery grown in soil fumigated with bromomethane,and the ‘natural’ bromide ion content in a range of fresh fruit and vegetables

Surveys of inorganic bromide ion residues in tomatoes, cucumbers and selfblanching celery, commercially produced in England following soil sterilisation with bromomethane, have been carried out since 1979. The mean bromide ion level in 29 late-season cucumber samples was approximately 28 mg kg⁻¹ and ranged up to 109 mg kg⁻¹. Analysis of 242 tomato samples gave estimated mean bromide ion levels per plant ranging from 6 to 187 mg kg⁻¹ in fruit picked throughout the season from seven holdings, on six of which bromomethane had been used fairly recently prior to planting. A statistically significant fall in bromide levels over the growing season was shown on four of the sites. In 38 samples of self-blanching celery, the mean bromide ion level was 104 mg kg⁻¹ even though the mean interval between fumigation and planting was in excess of 1 year. Retail surveillance indicated that a large number of crops are likely to have bromide ion levels below 10mg kg⁻¹.     

The bioaccumulation and biotransformation of cis,trans-cypermethrin in the rat

The disposition of the pyrethroid insecticide cypermethrin, (RS)-a-cyano-3-phenoxybenzyl (1RS)-cis, trans-3-(2,2-dichlorovinly)-2, 2-dimethylcyclopropane-carboxylate, has been studied in male and female rats following a single toxic oral dose (200mg kg⁻¹) of two radiolabelled forms ([¹⁴C-benzyl] and [¹⁴C-cyclopropyl]) of the insecticide. The bioaccumulation and elimination of ¹⁴C-benzyl-labelled cypermethrin, following repeated administration at a sub-toxic dose (2mg kg⁻¹), has also been studied in male and female rats. Although, at the toxic dose, radioactivity from the two radiolabelled forms was rapidly eliminated in urine and faeces, the increased excretion in the faeces, over that for low doses, was evidence that absorption was incomplete. The major pathways of metabolism involved cleavage of the ester bond, with subsequent hydroxylation and glucuronidation of the cyclopropyl acid moieties, together with hydroxylation and sulphation of the 3-phenoxybenzyl moiety. The absence of sex- or dose-dependent changes was reflected by the constant proportions of these metabolites found in the urine. Constant levels of radioactivity in tissues were achieved rapidly, generally within the first week of repeated administration. Elimination was rapid on the cessation of dosing, although less rapid from the fat and skin. The material in the fat was mainly the cis-isomers of cypermethrin, which were eliminated with a mean half-life of 18.2 days, compared with 3.4 days for the trans-isomers.     

Pyrethroid residues in sediment and water samples from mesocosm and farm pond studies of simulated accidental aquatic exposure

This paper describes the residue analysis of water and hydrosoil samples taken from two separate large-scale aquatic ecotoxicology trials designed to assess the environmental fate and effects of the pyrethroids lambda-cyhalothrin and cypermethrin. Comparison of the results demonstrates the high degree of reproducibility of the chemical residue found the day after treatment using experimental mesocosms (lambda-cyhalothrin) as opposed to an in-use farm pond (cypermethrin). Both studies showed that pyrethroid residues were rapidly lost from the water column: residues of lambda-cyhalothrin were less than 2 ng litre^?1 following the final application of a cumulative seasonal exposure equivalent to twelve ?drift’? and six ?run-off’? events, each delivering a dose equivalent to that expected from a typical event under field conditions. Hydrosoil appeared to act as a sink for pyrethroid residues and, under the stringent test conditions of the mesocosm study, lambda-cyhalothrin residues reached 3.2 μg kg^?1 following the seasonal exposure described above. The cypermethrin farm-pond study illustrated the localised pattern of exposure expected under natural field conditions, with site topography and cultivation practices which represent an average ?worst case’?. Residues in hydrosoil reached a maximum level of approximately 25 μg kg^?1 in one sampling zone at one interval, and thereafter declined to a level of < 9 μg kg^?1 within four months.     

Residues of cypermethrin,fenvalerate and deltamethrin on cauliflower

Following the application of Cypermethrin, fenvalerate and deltamethrin to a cauliflower crop at rates of 50, 50 and 12 g a.i. ha^-1, the maximum initial deposits of these insecticides on heads and leaves were 1.10 and 0.75, 1.14 and 0.60, and 0.32 and 0.12 mg kg^-1, respectively. These residue values for fenvalerate were less than the maximum residue limit (MRL) of 2 mg kg^-1 for this crop. While the maximum initial deposits of Cypermethrin and deltamethrin on cauliflower leaves were less than their respective MRL values of 1 and 0.2 mg kg^-1 for brassica leafy vegetables, it took one day for their residues on cauliflower heads to decline below this level.     

Pyrethroid insecticides: Potent,stereospecific enhancers of mouse brain sodium channel activation

Deltamethrin and NRDC 157, pyrethroid insecticides that produce different poisoning syndromes in mammals, enhanced veratridine-dependent, sodium channel-mediated ²²Na⁺ uptake in mouse brain synaptosomes. Concentrations producing half-maximal enhancement were 2.5 × 10^?8M (deltamethrin) and 2.2 × 10^?7M (NRDC 157). This effect was stereospecific: The nontoxic 1S enantiomers had no significant effect on veratridine-dependent activation. At high deltamethrin concentrations, enhancement was maximal at 5 × 10^?5?1 × 10^?4M veratridine. Pyrethroid enhancement was completely blocked by 5 × 10^?6M tetrodotoxin, and neither pyrethroid affected ²²Na⁺ uptake in the absence of veratridine at concentrations up to 1 × 10^?5M. The relative potencies of deltamethrin and NRDC 157 in the synaptosomal sodium channel assay agree well with their relative acute toxicities to mice when administered by intracerebral injection. These findings demonstrate that pyrethroids exemplifying both characteristic poisoning syndromes are potent, stereospecific modifiers of sodium channel function in mammalian brain.     

Effects of topical and bath applications of the insecticide deltamethrin on electrical activity in a leg mechanoreceptor of the cockroach,Periplaneta americana

Two different methods were used to analyze the effects of topical and bath applications of low concentrations of deltamethrin. The first method enabled the analysis of the receptor potential as well as that of the spike activity generated by mechanical or electrical stimulation of the mechano-receptor. The second method enabled recording of the conducted spike activity originating from a mechanical stimulation of the receptor and propagated along the sensory nerve. Topical application of small amounts of deltamethrin (10⁻⁹ to 10⁻⁷ g) had little effect on the receptor potential induced by mechanical stimulation of the sensory hair but blocked the action potentials within a few minutes. Electrical stimulation of the receptor cell revealed that conduction in the dendrite was affected first by the insecticide. The effects of topical application on conducted activity were compared with those of bath applications (2 × 10⁻⁸ to 2 × 10⁻⁷ M) and no significant difference was found, suggesting a rapid penetration of the insecticide through the cuticle. These effects were not reversible and this absence of reversibility was not correlated with the integrity of the barrier which protects the receptor cell from rapid changes in the ionic composition of the hemolymph. Deltamethrin was never found to induce bursts of activity in the mechanoreceptor cell under investigation either at rest or following mechanical or electrical stimulation. There are, however, some indications that other receptor cells may respond differently to this insecticide.