Effect of pyrethroid insecticides on EEG activity in conscious,immobilized rats

Preseizure and seizure EEG patterns elicited by the pyrethroid insecticides, deltamethrin and cis-permethrin, were compared in immobilized Sprague-Dawley rats. Deltamethrin (1–3 mg/kg, iv) produced a preseizure EEG pattern of high-amplitude, slow, 2- to 5-Hz synchronized cortical waves or spike-wave complexes. cis-Permethrin (20–40 mg/kg, iv) elicited an immediate EEG change characterized by 6- to 12-Hz high-amplitude waves with intermingled high-voltage spikes. DDT (50–70 mg/kg, iv) produced a sustained EEG activation similar to that seen after cis-permethrin, but of higher frequency. All three insecticides produced generalized EEG seizure activity, but this was more prominently associated with poisoning due to deltamethrin. cis-Permethrin and DDT gave rise to EEG seizures only at lethal doses. Electrodes stereotaxically positioned in ventral hippocampus, caudate, putamen, thalamus, septum, red nucleus, and cerebellum detected no preferential activation of any of these subcortical sites in either preconvulsive or convulsive phases of poisoning. These results indicate that both deltamethrin and cis-permethrin can have marked effects on mammalian EEG activity. This does not support the hypothesis of differing sites of action, i.e., peripheral vs. central, for the two types of compound. The more pronounced seizure-inducing action of deltamethrin may instead reflect a greater efficacy of cyanopyrethroids at target sites within the central nervous system.     

Interaction of pyrethroids with mammalian spinal neurons

The effects of intravenous administration of non-cyano (cis-permethrin) and cyano-substituted (deltamethrin) pyrethroids were studied on spontaneous and evoked ventral root activity in rat spinal cord and on spontaneous firing of ventral horn interneurons in the cat. Both pyrethroids had dramatic facilitatory effects on spontaneous firing rates of ventral roots and spinal interneurons and increased the amplitude of mono- and polysynaptically mediated ventral root responses to dorsal root stimulation. Spontaneous and evoked afferent sensory activity was slightly enhanced by cis-permethrin, but not by deltamethrin. In the cat diazepam (0.5 mg/kg, iv) was equally effective in antagonizing the facilitation of interneuronal firing resulting from either deltamethrin or cis-permethrin. These effects of pyrethroids on spinal neurons may underly the production of tremor and choreoathetosis-salivation toxicity symptoms in mammals.     

Sulfur in pesticide action and metabolism: Edited by J. D. Rosen,P. S. Magee,and J. E. Casida,American Chemical Society,Washington, D.C., 1981. 172 pp., $33.00

The distribution of ¹⁴C-acid-, ¹⁴C-alcohol-, and ¹⁴C-cyano-labeled deltamethrin and selected metabolites were followed in the liver, blood, cerebrum, cerebellum, and spinal cord after iv administration of a toxic, but nonlethal dose (1.75 mg/kg) to rats. Approximately 50% of the dose was cleared from the blood within 0.7–0.8 min, after which the rate of clearance decreased. 3-Phenoxybenzoic acid (PBacid) was isolated from the blood in vivo, and was also the major metabolite when ¹⁴C-alcohol-labeled deltamethrin was incubated with blood in vitro. Deltamethrin levels in the liver peaked at 7–10 nmol/g at 5 min and then decreased to 1 nmol/g by 30 min. In contrast, peak central nervous system levels of deltamethrin were achieved within 1 min (0.5 nmol/g), decreasing to 0.2 nmol/g at 15 min, and remaining stable until 60 min. peak levels of deltamethrin did not correspond to the severity of toxicity, although the levels of non-pentane-soluble radiolabel did appear to correlate with motor signs of toxicity. Experiments with brain homogenates, using in vivo concentrations of deltamethrin, failed to reproduce the pentane-unextractable radioactivity in vitro nor was any metabolism demonstrated.     

Evidence for different mechanisms of action of the three pyrethroids,deltamethrin, cypermethrin,and fenvalerate,on the excitation threshold of myelinated nerve

The effects of three α-cyano pyrethroids (deltamethrin, fenvalerate, and cypermethrin) on the electrophysiological function of single myelinated nerve fibers from Rana esculenta were investigated. The time course of pyrethroid-induced changes on the threshold interval, V_s − V_m (V_s: threshold voltage; V_m: membrane potential), as well as stationary membrane parameters determining this interval was measured on the same nerve preparation (membrane potential V_m, stationary transition voltage V_Tr, stationary sodium conductance). The results suggest that the mechanisms of changing the threshold interval are different for the three pyrethroids. Deltamethrin and cypermethrin increase this interval until inexcitability, deltamethrin by increasing the stationary sodium conductance and cypermethrin by blocking the sodium conductance. Fenvalerate, however, insignificantly affects the threshold interval because both V_m and V_s are shifted parallel by about the same amount in the same direction (depolarization). These qualitatively different effects of chemically related substances differentiate the pyrethroids from other classes of substances which are effective on the nerve function and suggests that the molecular mechanisms underlying the pyrethroid effects might have a unique quality.     

Lethal and sublethal effects of three insecticides on the aphid parasitoid, <Emphasis Type="Italic">Lysiphlebus fabarum</Emphasis> Marshall (Hymenoptera: Aphidiidae)

Lysiphlebus fabarum Marshall is the main parasitoid of the black bean aphid, Aphis fabae Scopoli. Lethal and sublethal effects of insecticides, thiacloprid+deltamethrin, pirimicarb and pymetrozine were evaluated on the parasitoid under laboratory conditions. One-day-old mummies were exposed to the recommended field concentration of either insecticides via dipping method. Adult emergences were reduced by 82.67, 19.98 and 10.67 % for thiacloprid+deltamethrin, pirimicarb and pymetrozine treatments, respectively. Thiacloprid+deltamethrin had the most adverse effect on the fecundity of the emerged females, while pirimicarb and pymetrozine did not have such effects. According to International organization for biological control (IOBC) insecticide toxicity classification, thiacloprid+deltamethrin resulted to be moderately harmful (E = 97.39%), whereas pirimicarb (E = 15.78%) and pymetrozine (E = 5.15%) were harmless. Thiacloprid+deltamethrin negatively affected five of the estimated demographic parameters (GRR, R ₀ , r _m , λ and T ). Pirimicarb negatively affected GRR, R ₀ and T, while it had no adverse effects on r _m and λ. None of the studied demographic parameters were affected by pymetrozine. Our results suggest that pirimicarb and pymetrozine can be considered as safe for L. fabarum, but that thiacloprid+deltamethrin can have serious detrimental of this parasitoid in the field.     

Cross-resistance, genetics and stability of resistance to deltamethrin in a population of Chrysoperla carnea from Multan, Pakistan

Broad-spectrum insecticides are still widely being used. Chrysoperla carnea has been shown to develop resistance to the insecticides in the field. Knowledge of the evolution and genetics of resistance to insecticides in natural enemies could enable to explain how effectively natural enemies can be implemented in different IPM systems. To examine this, a population of C. carnea from Multan Pakistan was collected and was subjected to deltamethrin selection in the laboratory. Bioassays at generation G₁ gave resistance ratios of 47, 86, 137, 76 and 110 for deltamethrin, alphamethrin lambdacyhalothrin, chlorpyrifos and profenofos respectively compared with susceptible Lab-PK. Bioassays at G₄ with a deltamethrin-selected population (Delta-SEL) showed that selection gave resistance ratios of 896 and 30 for deltamethrin compared with the Lab-PK and UNSEL, respectively. Cross-resistance to other insecticides tested was observed in the selected population. A notable feature of the Delta-SEL strain was that resistance to deltamethrin, alphamethrin, lambdacyhalothrin, chlorpyrifos and profenofos did not decline over the course of four generations. Synergism tests with microsomal oxidase (MO) and esterase-specific inhibitors indicated that the deltamethrin resistance was associated with MO and, possibly, esterase activity. Reciprocal crosses between the Delta-SEL and Lab-PK strains indicated that resistance was autosomal and incompletely dominant. A direct test of monogenic inheritance suggested that resistance to deltamethrin was controlled by more than one locus. The broad spectrum of resistance, cross resistance, incompletely dominant mode of inheritance and stability of resistance to insecticides suggest that Delta-SEL population of C. carnea could be compatible with most spray programs.     

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.     

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.     

Two classes of pyrethroid action in the cockroach

Pyrethroids are divided into two classes (Types I and II) based on their effects on the cercal sensory nerves recorded in vivo and in vitro and on the symptomology they produce in dosed cockroaches, Periplaneta americana. Type I compounds include pyrethrins, S-bioallethrin, [1R,cis]resmethrin, kadethrin, the 1R,trans and 1R,cis isomers of tetramethrin, phenothrin, and permethrin, and an oxime O-phenoxybenzyl ether. Electrophysiological recordings from dosed individuals reveal trains of cercal sensory spikes and sometimes also spike trains from the cercal motor nerves and in the CNS. Low concentrations of these pyrethroids act in vitro to induce repetitive firing in a cercal sensory nerve following a single electrical stimulus. This in vitro measurement, standardized for evaluating structure-activity relationships, shows that only 1R, insecticidal isomers are highly effective neurotoxins. The most potent compounds on the isolated nerve are [1R,trans]- and [1R,cis]tetramethrin, each active at 3 × 10^?13M. The poisoning symptoms of Type I compounds are restlessness, incoordination, hyperactivity, prostration, and paralysis. Type II compounds include [1R,cis,αS]- and [1R,trans,αS]cypermethrin, deltamethrin, and [S,S]fenvalerate. These α-cyanophenoxybenzyl pyrethroids do not induce repetitive firing in the cercal sensory nerves either in vivo or in vitro; moreover, they cause different symptoms, including a pronounced convulsive phase. Two other pyrethroids with an α-cyano substituent, i.e., fenpropathrin and an oxime O-α-cyanophenoxybenzyl ether, are classified as Type I based on their action on a cercal sensory nerve but the symptoms with these compounds resemble Type II. The two classes of pyrethroid action evident with the cockroach are discussed relative to their neurophysiological effects and symptomology in other organisms.     

Mutation of threonine 422 to glutamic acid mimics the phosphorylation state and alters the action of deltamethrin on Cav2.2

Effects of deltamethrin on voltage-sensitive calcium channels (VSCC) from rat brain (Ca_v2.2) expressed in Xenopus oocytes were assessed electrophysiologically. Deltamethrin reduced peak current of wild-type Ca_v2.2 in a stereospecific and concentration-dependent manner with an EC₅₀ of 1 × 10⁻⁹ M. Phosphorylation of threonine 422 enhances voltage-sensitive calcium current, increases the probability that Ca_v2.2 will open under depolarizing conditions and antagonizes the inhibition of the channel by the betagamma subunit of heterotrimeric G-protein (Gβγ). Site-directed mutagenesis of threonine 422 to glutamic acid (T422E) results in a channel that acts as if it were permanently phosphorylated. Deltamethrin (10⁻⁷ M) significantly enhanced peak current via the T422E channel (1.5-fold) compared to the nontreated control and the increase was significantly greater than for either the wild-type (T422) or T422A (permanently unphosphorylated mutant) channels. The effect of deltamethrin on T422E Ca_v2.2 was stereospecific and concentration-dependent with an EC₅₀ of 9.8 × 10⁻¹¹ M. Thus, Ca_v2.2 is modified by deltamethrin but the resulting perturbation is dependent upon the phosphorylation state of threonine 422.     

The toxic effects of pyrethroid deltamethrin on the common carp (Cyprinus carpio L.) embryos and larvae

Deltamethrin, a synthetic pyrethroid pesticide contaminating aquatic ecosystems as a pollutant, was investigated in the present study for toxic effects on embryos and larvae of common carp, Cyprinus carpio as a model. The control and five test experiments were repeated five times. The water temperature in the experimental units was kept at 24 ± 1 °C. The number of dead embryos significantly increased in response to deltamethrin concentrations 0.005, 0.05, 0.5, 5, 25, and 50 μg L⁻¹ (p<0.05 for each cases). Dose-response decreases in hatching success were recorded as 75.2, 64.6, 47.4, 26.0, 14.4, and 9.0%, respectively. The lowest concentration of deltamethrin (0.005 μg L⁻¹) produced a significantly decrease in number of dead larvae compared to control group (p<0.05). With increasing deltamethrin concentrations, the larvae exposed duration 1-48 h significantly increased the number of dead larvae (p<0.05 for each cases). The 48 h LC₅₀ values (with 95% confidence limits) of deltamethrin for common carp embryos and larvae were estimated as 0.213 (0.103-0.404) and 0.074 (0.011-0.260) μg L⁻¹, respectively. The results provide evidence that deltamethrin pollution may have an adverse effect on the reproduction and development of carp, which should be considered when this chemical is used in agricultural areas near aquatic ecosystems.     

Comparative effects of lindane and deltamethrin on mortality, growth, and cellulase activity in earthworms (Eisenia fetida)

Laboratory tests were conducted to compare the effects of various concentrations of lindane and deltamethrin on mature earthworms (Eisenia fetida) cultured in artificial soil during typical acute (14d) and subchronic (42d) exposure periods. The effects of the two pesticides on earthworm mortality, growth inhibition, and cellulase activity were determined for different exposure durations. The toxicity order for earthworm mortality from the 14-day exposure was lindane > deltamethrin, with median lethal concentrations (LC₅₀) of 162.1 and 432.9 mg kg⁻¹, respectively. Earthworms exposed to deltamethrin showed dose-dependent toxic effects on growth and cellulase activity only from the acute exposures, whereas lindane’s effects on these activities were seen correlated with both the acute and subchronic doses. Also, changes in biomass and cellulase activity during the subchronic exposure period appear to be a more sensitive parameter than the LC₅₀ value in assessing pesticidal injury.     

Genetic Analysis of Deltamethrin Resistance in Laboratory-Selected Strains of Drosophila melanogaster MEIG

The genetic basis of deltamethrin resistance or sensitivity in two strains of Drosophila melanogaster was studied by means of chromosomal analysis. Eight homozygote combinations of resistant (SR) and sensitive (HS₁) strains were constructed by chromosome substitution and were tested using topical bioassay and electrophysiological tests. The analysis of the data showed that resistance to lethal effects was multigenic, with the major factor(s) located on the first (X) and second chromosomes. One significant positive interaction between the two chromosomes was also found. For the resistance to knockdown (measured by time-based topical test), the second chromosome was found to be much more important than the first and third chromosomes. However, analysis of the onset of the deltamethrin-induced electrical activity for each constructed strain suggested that reduced nerve sensitivity (probably associated to the deltamethrin resistance) was linked to both chromosomes X and 2. Similarly, bursts of large excitatory junctional currents (which were observed in sensitive and wild strains following topical application of deltamethrin) were not observed in resistant strains when these two chromosomes originated from the SR strain. A good correlation was found between the latency and LD₅₀ suggesting that the same factors might be involved in the electrophysiological effects and the lethal effects. In our strains, resistance most probably corresponds to reduced nerve sensitivity. Our data are consistent with the location of the sodium channel gene in Drosophila on the chromosome X but clearly demonstrate that this major gene cannot by itself explain target site resistance to deltamethrin.     

PKC-dependent phosphorylations modify the action of deltamethrin on rat brain N-type (CaV2.2) voltage-sensitive calcium channel

Voltage clamp electrophysiological studies using wild type Ca_V2.2 and its β₃ subunit coexpressed in Xenopus oocytes revealed that deltamethrin increased the rate of activation, prolonged inactivation and reduced peak current. Site-directed mutagenesis of threonine 422 to glutamic acid (T422E, one of five protein kinase C (PKC)-dependent phosphorylation sites) resulted in a channel that acted as if it were permanently phosphorylated. This resulted in an increased probability of opening during depolarization and a reduced inhibition by the βγ subunit of heterotrimeric G-protein. Deltamethrin treatment of T422E Ca_V2.2 enhanced peak current ∼50% over ethanol-treated controls with an EC₅₀ of 9.8 × 10⁻¹¹ M.Phosphorylation of wild type Ca_V2.2 is evoked by the phorbol ester, phorbol 12-myristrate, 13 acetate (PMA), by activating endogenous protein kinase C (PKC) in oocytes. PKC-dependent phosphorylation activated by PMA of wild type Ca_V2.2 has been previously shown to slow channel deactivation and increased Ca²⁺ influx and subsequent neurotransmitter release. Following PMA-activated phosphorylation, deltamethrin significantly increased peak current and slowed deactivation of the phosphorylated channel, which would be consistent with slower channel closure, greater Ca²⁺ influx and enhanced neurotransmitter release seen in vivo. Deltamethrin treatment in the absence of PMA-activated phosphorylation resulted in no effect on the deactivation kinetics of unphosphorylated Ca_V2.2 or the T422E mutant. Thus, Ca_V2.2 is modified by deltamethrin but the resulting perturbations are dependent upon its PKC-dependent phosphorylation state.     

Deltamethrin resistance in the cotton mealybug, <Emphasis Type="Italic">Phenacoccus solenopsis</Emphasis> Tinsley: Cross-resistance to other insecticides,fitness cost analysis and realized heritability

The cotton mealybug, Phenacoccus solenopsis Tinsley (Homoptera: Pseudococcidae) is a devastating pest that cause rigorous damage to the number of crops through feeding, managed by using various insecticides. To assess the risk of resistance and design a strategy for resistance management, a field collected population of P. solenopsis was selected with deltamethrin in the laboratory for six generations to investigate the cost to its fitness and to examine cross resistance to different insecticides. Bioassay results at G₈ showed that the deltamethrin selected population (Delta-SEL) developed a resistance ratio of 100-fold compared to that of the unselected population (UNSEL). The deltamethrin resistance population exhibited strong cross-resistance to acetamiprid and lambda-cyhalothrin, but no cross-resistance to profenofos when compared to that of the UNSEL. The relative fitness of the Delta-SEL population was 0.37, with considerably lower survival rates from crawler to second instar, fecundity, hatchability, number of next generation nymphs, net reproductive rate and biotic potential compared with that of the UNSEL. The cost of fitness associated with deltamethrin resistance was evident in the Delta-SEL population. The present study provided useful information for management strategies to overcome development of resistance.     

Using synergists to detect multiple insecticide resistance in field populations of rice stem borer

The rice stem borer, Chilo suppressalis (Walker), an important insect pest of rice in China, has developed resistances to several classes of insecticides in field. In order to investigate multiple resistance mechanisms, synergistic tests were conducted with the Ruian (RA) population and Lianyungang (LYG) population, two representative populations to different insecticides. Results showed that diethyl maleate (DEM), S,S,S-tributyl phosphorotrithioate (DEF) and piperonyl butoxide (PBO), had no significant synergistic or inhibitory effect on the high level of resistance to monosultap (313.4-fold) and moderate level to chlorpyrifos (36.9-fold) in Ruian field population from the year 2011 (RA11). DEF significantly synergized the activity of triazophos in RA11 population (536.8-fold), with synergism ratio of 1.92. DEF and PBO significantly suppressed 43.3% and 40.4% of resistance to fipronil in RA11 population (48.4-fold), respectively, with the synergistic ratios of 1.76 and 1.69. When pretreated with PBO, the activity of deltamethrin against RA11 population were significantly synergized, with synergism ratio of 9.57, and with reducing resistance levels from 152.5- to 15.9-fold. The results of this study indicated that resistance to several classes of insecticide among the field populations of C. suppressalis might be provided by the combination of the multiple resistance mechanisms. Metabolic resistance mechanism might be the major reason for the evolution for resistance to deltamethrin and fipronil, while resistance to monosultap, triazophos and chlorpyrifos is not associated with metabolic resistance.     

In vitro and in vivo effects of some pesticides on carbonic anhydrase enzyme from rainbow trout (Oncorhynchus mykiss) gills

Here we investigated the in vitro and in vivo effects of the pesticides, deltamethrin, diazinon, propoxur and cypermethrin, on the activity of rainbow trout (rt) gill carbonic anhydrase (CA). The enzyme was purified from rainbow trout gills using Sepharose 4B-aniline-sulfanilamide affinity chromatography method. The overall purification was approx. 214-fold. SDS-polyacrylamide gel electrophoresis showed a single band corresponding to a molecular weight of approx. 29 kDa. The four pesticides dose-dependently inhibited in vitro CA activity. IC₅₀ values for deltamethrin, diazinon, propoxur and cypermethrin were 0.137, 0.267, 0.420 and 0.460 μM, respectively. In vitro results showed that pesticides inhibit rtCA activity with rank order of deltamethrin > diazinon > propoxur > cypermethrin. Besides, in vivo studies of deltamethrin were performed on CA activity of rainbow trout gill. rtCA was significantly inhibited at three concentrations (0.25, 1.0 and 2.5 μg/L) at 24 and 48 h.     

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.     

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.     

Pyrethroid toxicology in the frog

Adult Rana pipiens pipiens (Shreber) are highly sensitive to insecticidal α-cyano-3-phenoxybenzyl esters administered subcutaneously, i.e., LD₅₀ 0.13–0.35 mg/kg for deltamethrin and the most potent isomer of each of cis-cypermethrin, fenpropathrin, and fenvalerate and 0.65 mg/kg for (1R,αS)-trans-cypermethrin. Pyrethroids lacking the α-cyano substituent [pyrethrins, S-bioallethrin, kadethrin, and the Cis- and trans-isomers of (1R)-tetramethrin, (1RS)-resmethrin, (1R)-phenothrin, and (1R)-permethrin] vary greatly in their toxicity (LD₅₀ 0.14 to > 60 mg/kg) and the trans isomers are much less toxic than the corresponding cis isomers. The trans/cis specificity is due in large part to relative detoxification rates based on synergism studies with the resmethrin and permèthrin isomers and liver pyrethroid esterase assays with the permethrin and cypermethrin isomers. Poisoning by the noncyano compounds involves hyperactivity and tremors whereas by the cyanophenoxybenzyl esters involves tonic seizures and choreoathetosis, i.e., types I and II syndromes, respectively. Picrotoxinin, t-butylbicyclophosphate, and five other small cage compounds give a third type of syndrome with clonic seizures. Diazepam and its 2′-fluoro-4-methyl-4,5-dihydro analog (RO 5-3636) are more effective than 23 other compounds tested in protecting against deltamethrin toxicity. Diazepam is most effective in alleviating the Type II syndrome, intermediate with the type I syndrome, and is not active with picrotoxinin.