Structure and insecticidal activity of picrotoxinin analogs

Picrotoxinin, a convulsant in mammals, was nontoxic when topically applied on whole house flies. When synergized with piperonyl butoxide, the topical LD₅₀ of picrotoxinin on house flies was 6.50 μg/g or 260 times less toxic on house flies than the synergized insecticide, carbofuran, a carbamate cholinesterase inhibitor.When perfused on the isolated thoracic ganglion of house fly, picrotoxinin was less potent in producing convulsions than carbofuran; however, when assayed on the desheathed thoracic ganglion, picrotoxin was more potent than carbofuran. This suggested a substantial barrier to picrotoxinin preventing diffusion into the house fly central nervous system.Of several picrotoxinin analogs synthesized the 2-iodo,4-isopropyl, 6-methylenebromidecyclohexane-γ-lactone was the most potent convulsant.     

Mode of action of sulfenylated carbamates: Rapid conversion of N,N′-thiodicarbamates to parent carbamate measured by neurophysiological bioassay

Four N,N′-thiodicarbamate derivatives of carbofuran induced uncoupled convulsions with similar latencies following topical application to the cuticle of tethered S_NAIDM house flies, despite considerable differences in their lipophilic properties. There was a small but statistically significant delay in the latency to response to the derivatives compared to carbofuran, but when perfused directly on the exposed thoracic ganglia to assess intrinsic activity, carbofuran acted up to 4.4 times faster than the derivative. It is suggested that the NS bond of the derivatives is cleaved soon after application to the house fly cuticle and carbofuran is released from each derivative in sufficient quantities to accumulate toxic concentrations in the central nervous system at similar rates.     

Behavioural and electrophysiological investigation of 1-(7-ethoxygeranyl)-2-methylbenzimidazole on the house fly Musca domestica

The insecticidal properties of 1-(7-ethoxygeranyl)-2-methylbenzimidazole (EGMB) were investigated on larval and adult house flies. Unsynergised EGMB gave topical LD₅₀ values of 0.53 μg per female fly on NAIDM strain house flies. When flies were pretreated with 5.2 μg piperonyl butoxide, susceptibility was increased (LD₅₀ 0.12 μg per female fly). House fly larvae were less susceptible to EGMB (LD₅₀ 2.2 μg). Poisoning with EGMB resulted in a rapid reduction in locomotor activity of both larval and adult house flies. This reduction in locomotion was progressive and led to complete paralysis. Various parameters of larval nervous system function were investigated in larvae during these early phases of poisoning. As early as 15 min after dosing larvae with LD₉₅ doses of EGMB, sensory nerves were less responsive. Over a somewhat longer time (2–4 h), neurally evoked contractures were adversely affected by EGMB. In some cases, this effect appeared to be due to reduced postsynaptic potential amplitude; in other instances, it appeared to be due to an effect independent of neuromuscular transmission. The close temporal correlation between behavioural and electrophysiological observations suggests that the nervous and muscular systems are important sites of action of EGMB.     

Metabolism of 2,2-dimethyl-2,3-dihydrobenzofuranyl-7 N-dimethoxyphosphinothioyl-N-methylcarbamate in the house fly,rat, and mouse

The metabolism of a selectively toxic derivative of carbofuran, 2,2-dimethyl-2,3-dihydrobenzofuranyl-7 N-dimethoxyphosphinothioyl N-methylcarbamate (PSC), was examined in the house fly, rat, and mouse. In house flies, PSC is metabolized mainly to carbofuran and related oxidation products containing the intact N-methylcarbamyl ester moiety. Degradation to phenolic products was the principal route of metabolism in rodents. The results indicate that the selective toxicity of PSC between insects and mammals is attributable to differing pathways of metabolism.     

Cross-Resistance to Imidacloprid in Strains of German Cockroach (Blattella germanica) and House Fly (Musca domestica)

The toxicity of a promising new insecticide, imidacloprid, was evaluated against several susceptible and resistant strains of German cockroach and house fly. Imidacloprid rapidly immobilized German cockroaches followed by a period of about 72 h during which some cockroaches recovered. After 72 h there was no further recovery. Imidacloprid-treated houseflies were immobilized more slowly than treated cockroaches, with the maximum effect observed after 72 h, and there was no recovery. Based upon 72-h LD₅₀ values imidacloprid was moderately toxic to German cockroaches (LD₅₀ values were 6–8 ng mg^-1) and had only low toxicity to house flies (LD₅₀ 140 ng mg^-1). Piperonyl butoxide (PBO) blocked the observed recovery in German cockroaches. PBO also greatly enhanced the 72-h LD₅₀ of imidacloprid from 43- to 59-fold in cockroaches and 86-fold in house flies. Two strains of German cockroach (Baygon-R and Pyr-R) showed >4-fold cross-resistance to imidacloprid. This cross-resistance could not be suppressed by PBO, suggesting that P450 monooxygenase-mediated detoxication is not responsible for this cross-resistance. Variation in the level of synergism observed with PBO (between strains) suggests the ‘basal’ level of monooxygenase-mediated detoxication of imidacloprid is quite variable between strains of German cockroach. The AVER and LPR strains of house fly showed significant cross-resistance to imidacloprid. PBO reduced the level of cross-resistance in AVER from >4·2-fold to 0·5-fold (i.e. the AVER strain LD₅₀ was half that of the susceptible strain when both were treated with PBO), but PBO did not suppress the cross-resistance in LPR. These data suggest monooxygenases are the mechanism responsible for cross-resistance to imidacloprid in AVER, but not in the LPR strain. © of SCI.     

Sorption of tetrachlorvinphos insecticide (Gardona) to the hemolymph of Periplaneta americana

Tetrachlorvinphos insecticide (Gardona, SI) 8447) sorbs to the hemolymph of the American cockroach via noncovalent bonding. The amount sorbed is dependent upon both the concentration of hemolymph and tetrachlorvinphos used. Acrylamide disc gel electrophoresis and Sephadex column chromatography of the complex revealed that tetrachlorvinphos binds to a variety of proteins in the hemolymph. No one protein serves as a specific carrier.These studies show that 80% of the LD₅₀ dose of tetrachlorvinphos can bind to the hemolymph contained in a single roach. The observed LD₅₀ value could then be considered as an inflated value, since the hemolymph can sorb large quantities of tetrachlorvinphos and thereby reduce the concentration of free compound available for inducing a toxic event. An alternative possibility, however, should not be overlooked. The binding of tetrachlorvinphos to hemolymph can be looked upon as a transport mechanism, whereby the compound is transported throughout the roach, to dissociate from the “carrier” proteins, and to penetrate into or through the cell membrane at the appropriate time. This would have the effect of actually enhancing the toxicity of the compound.     

Steric,electronic, and polar parameters that affect the toxic actions of O-alkyl,O-phenyl phosphonothionate insecticides

The toxic action of a series of O-alkyl, O-substituted-phenyl alkyl- and aryl-phosphonates and phosphonothionates have been evaluated by correlating the linear free energy parameters for steric (E_s), electronic (σ), and polar ($\text{σ}{}^1$) effects with topical LD₅₀ to the house fly and oral LD₅₀ to the white mouse. In molecules free from major steric interactions with the reactive P atom, variations in these linear free energy parameters account for >90% of the variations in the LD₅₀ values, and the degree of correlation with LD₅₀ is at least as precise as that with the biomolecular rate constants for inhibition of the target-site enzyme acetylcholinesterase. The value of correlations of linear free energy parameters with LD₅₀ in understanding quantitative structure-activity relationships is illustrated.     

Toxicity of spinosad to susceptible and resistant strains of house flies,Musca domestica

The toxicity of spinosad, a new insecticide derived from the bacterium Saccharopolyspora spinosa, was evaluated against susceptible and resistant strains of house fly (Musca domestica L.). Spinosad was highly toxic to house flies based on 72-h LD₅₀ values and the symptoms of poisoning were consistent with a neurotoxic mechanism of action. Spinosad was relatively slow acting, with the maximum toxicity noted at 72 h. Piperonyl butoxide and S,S,S,-tribu-tylphosphorotrithioate synergized the toxicity of spinosad by 3·0- and 1·8-fold, respectively, while diethyl maleate had no significant effect. These results suggest that there is a small degree of monooxygenase-mediated spinosad detoxification in house flies, while hydrolases may be only minimally important and glutathione transferases may have no role. There were no substantial levels of cross-resistance detected, except in the LPR strain where a low 4·3-fold cross-resistance was observed. The cyclodiene-resistant OCR strain was 2·7-fold more sensitive to spinosad than the susceptible strain (CS). These results suggest that cross-resistance may not be a limiting factor for the use of spinosad against house flies. © 1998 Society of Chemical Industry     

Structural modifications increase the insecticidal activity of ryanodine

The toxicity of ryanodine ( 1 ) and 9,21-didehydroryanodine ( 2 ) (the principal active ingredients of the botanical insecticide ryania) to adult female house flies (Musca domestica L.) is attributable to binding to the ryanodine receptor (ryr) and thereby disrupting the Ca²⁺-release channel. These ryanoids, assayed in house flies with piperonyl butoxide (PBO) to suppress cytochrome P450-dependent detoxification, give injected KD₅₀ values of 0·07–0·11 μg g^-1, injected LD₅₀ values of 0·39–0·45 μg g^-1 and topical LD₅₀ values of 12– 50 μg g^-1. They inhibit the [³H]ryanodine binding site of house fly and rabbit muscle with IC₅₀ values of 3–10 nM . This study examines the effect of structure on potency, with 15 variants of the cyclohexane substituents, two 4,6-cyclic boron and two methylated derivatives, and four modifications of the isopropyl and ester substituents. The most effective compound examined was 10-deoxy- 2 ( 3 ) which was more potent than 2 by 2–4-fold on injection and 29-fold applied topically following PBO (LD₅₀ 0·41 μg g^-1). Additional high-potency compounds were 10-oxo- 1 and the cyclohexane variants with lactam, 21-nor-9-oxo and 21-nor-10-deoxy substituents. Other modifications usually reduced toxicity. The injected knockdown potency of the ester ryanoids was generally related to their effectiveness in competing with [³H]ryanodine at the ryr of rabbit skeletal muscle. Two non-ester ryanoids, ryanodol and 9,21-didehydroryanodol, were found to be more toxic than predicted from their potency at the ryr and may therefore act in a different manner such as at a K⁺ channel, as suggested by Usherwood and Vais. Clearly ryanoids are challenging prototypes for a potential new generation of insecticides. © 1997 SCI.     

Toxicity and tolerance of sesquiterpene lactones in the migratory grasshopper, Melanoplus sanguinipes (Acrididae)

Sesquiterpene lactones, natural constitutents of the Asteraceae, are toxic to the grasshopper, Melanoplus sanguinipes, when injected into the hemocoel at doses greater than 0.25 μmol/300 mg insect. Dose-dependent sublethal symptoms range from a slight reduction in normal locomotory ability to severe locomotory impairment or paralysis, leading to death. The symptoms appear to be irreversible. Of the four compounds subjected to dose-response testing, parthenin was the most toxic with and LD₅₀ in adult male grasshoppers of 0.55 μmol/insect. Structure-activity relationships for four of the six lactones tested indicate that compounds containing a cyclopentenone ring are equitoxic to males and females, whereas those lacking this functional group are approximately 4 × more toxic to males than females. In contrast to their sensitivity to injected lactones, adult male grasshoppers can tolerate ingestion or topical administration of up to 4 μmol of these compounds without any adverse effects. These results suggest that the integument and alimentary canal in this species provide effective barriers limiting the bioavailability of sesquiterpene lactones to the hemolymph in nature. Possible target sites and mechanisms-of-action for sesquiterpene lactones (once in the bloodstream) are discussed.     

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 4. Physicochemical properties and the rate of progress of the knockdown symptom induced in house flies

A procedure to evaluate the knockdown activity of pyrethroids against house flies in which metabolic factors could be eliminated as far as possible was established. With piperonyl butoxide and NIA 16388 as the inhibitors of oxidative and hydrolytic metabolism, respectively, the “intrinsic” knockdown potencies of 22 substituted benzyl (1R)-trans-chrysanthemates and related compounds were determined 2.5–3 hr after topical application to house flies. From the intrinsic knockdown potency and the rate of progress of the knockdown symptom from the earliest stage of intoxication, a “penetration” rate constant was estimated by first-order kinetics using a two-compartment model. The rate constant was correlated quantitatively with the hydrophobic parameter of the molecule. The lower the hydrophobicity, the higher the rate constant within the range of compounds used in this study.     

An evaluation of the role of oxidative enzymes in Colorado potato beetle resistance to carbamate insecticides

Carbofuran and carbaryl LD₅₀ values were determined with and without piperonyl butoxide pretreatment for a resistant (New Jersey) and two susceptible (Utah and Netherland) populations of Colorado potato beetle larvae. Similar bioassays were conducted with carbofuran for resistant (Rutgers) and susceptible (NAIDM) adult house flies. The degree of resistance development by New Jersey Colorado potato beetles (RR = 848) was greater than that of the laboratory-selected colony of Rutgers house flies (RR = 583). Comparisons of synergist difference calculations including “percentage synergism” (%S), “log percentage synergism” (L%S), and “relative percentage synergism (R%S) for the resistant (R) and the susceptible (S) populations indicated the possibility that monooxygenases and other resistance mechanisms may be involved in Colorado potato beetle resistance to these carbamates. Monooxygenase involvement in resistance of Rutgers house flies was demonstrated in vitro by a 4-fold enhancement of p-nitroanisole O-demethylation over that of NAIDM house flies. O-demethylation of p-nitroanisole could not be demonstrated for potato beetle larvae. Colorado potato beetle resistance was associated with increases in microsomal levels of NADPH-cytochrome c reductase (ca. 2-fold) and NADPH oxidation (1.2-fold). The inability to measure O-demethylation in Colorado potato beetles may have been due to the solubilization of NADPH-cytochrome c reductase during microsomal preparation. Significant differences between resistant and susceptible Colorado potato beetle larvae were not observed in the penetration of [¹⁴C]carbaryl. Excretion of the radiocarbon may have been significantly greater in the resistant New Jersey population, but some of the insecticide may have also rubbed off the cuticle. This increased capacity for excretion, combined with increased levels of monooxygenase enzymes, could account for the high resistance level of this population.     

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.     

Toxicodynamics of malaoxon in house flies

The fate of malaoxon was studied in a susceptible and a resistant strain of house fly following topical application. Sublethal doses were used: 160 pmol for the S-strain (0.17 × LD₅₀) and 1570 pmol for the R-strain (0.1 × LD₅₀). The penetration rates are dose dependent and semilog plots of the external amount vs time show that these rates are not proportional to this external amount. Internal concentrations of malaoxon rapidly increase following administration, reach maximum values between 30 min and 2 hr (depending on dose), and then slowly decrease. The rate of metabolic degradation is highest in the early stage of the intoxication process. A three-compartment pharmacokinetic model is postulated to explain the experimental data quantitatively. The first compartment represents external malaoxon, the other two represent internal parent compound. Statistical analysis shows that the penetration rate is better described with a sum of two exponentials rather than with a single exponential decay. In the model, degradation occurs in the first internal compartment and is assumed to be first order. Malaoxon is distributed between the two internal compartments slowly with first-order kinetics. Parameter estimation with curve-fitting procedures for the internal processes (degradation and exchange) shows that there is not one set of parameter values that can be used for both strains simultaneously. This prompted a study of possible interstrain differences in degradation capacities. It was found that in vitro the R-strain had a fourfold higher oxidative breakdown rate of malaoxon. Taking this difference into account it is possible to explain the two sets of data with one kinetic model, although other alternatives cannot be excluded.     

In vivo measurement of house fly temperature,flight muscle potentials,heartbeat and locomotion during insecticide poisoning

The average heartbeat rate of female adult Musca domestica was near 250 beats/min in vivo at 23°C. However, standard deviation values ranged from ±35 to ±60 depending on the individual house fly. Heartbeat rates in tethered house flies fluctuated between cessation to over 300 beats/min. The heartbeat rate was temperature dependent with a Q₁₀ of 2.3. Either a bite by the Lynx spider, Peucetia vividans (Hentz), or severing the abdomen from the thorax caused the heartbeat to become extremely steady at near 300 beats/min which gradually decreased over several minutes.Application of lethal doses of Monitor or Lindane to the house fly caused thoracic temperature to increase by at most 3°C in conjunction with increased convulsive activity and increased average heartbeat rate. In late stages of poisoning, the heartbeat was relatively uniform indicating a disruption in cardioregulatory nervous activity. Response of the house fly to carbofuran or its N-thiomethyl analog was similar to that of Monitor and Lindane except in late stages of poisoning where the heartbeat continued to exhibit large variations in average rate.     

Effect of synthetic insecticides on the larvae of <Emphasis Type="Italic">Coccinella septempunctata</Emphasis> from Greek populations

Coccinella septempunctata L. is one of the most abundant ladybird species in Greece, preying on several aphid species and other arthropods, of which many are pests of cultivated plants. These pests are usually controlled with chemical insecticides. During this process, however, beneficials are also exposed to pesticides. The development of Integrated Pest Management (IPM) programs against aphids requires the evaluation of the effects of insecticides on beneficial insects. We evaluated the LD₅₀ of imidacloprid, acetamiprid, bifenthrin and deltamethrin on first, second, third and fourth instar larvae of C. septempunctata by topical application. Moreover, we studied their sublethal effects (LD₁₀) on the development, weight and prey consumption of fourth instar larvae. The topical application bioassays showed that deltamethrin and bifenthrin were highly toxic to all larval instars, whereas imidacloprid and acetamiprid were less toxic to fourth instar larvae. The LD₁₀ dose significantly affected, developmental time, adult weight and daily predation. These results show the importance of assessing potential effect of insecticides on C. septempunctata for developing effective IPM programs of aphids in Greece.     

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.     

Selective toxicity of analogs of methyl parathion

Analogs of methyl parathion with various substituents in the aryl ring were examined for quantitative toxicity to the female white mouse and the female house fly. Substitution in the 3-position with the halogens produced Selectivity Ratios for mouse LD₅₀/fly LD₅₀ in the order Cl > Br > IF. The compounds with the highest Selectivity Ratios were 2Cl > 3CF₃ > 3CH₃. The biochemical basis for the selectivity of these compounds was explored by evaluation of the kinetics for the inhibition of purified bovine and house fly acetyl cholinesterase by the PO analogs. Differences in the configuration and reactivity of the active sites of the acetyl cholinesterase of the two species explain in part the selectivity of the toxicants. However, selective metabolism also plays a substantial role.     

Effect of60Co gamma radiation on the rice weevil,Sitophilus oryzae (L.)

The effect of gramma radiation on the rice weevil,Sitophilus oryzae (L.) was studied. Adults were subjected to 12 doses ranging from 0 to 180 Gy of gamma radiation from a⁶⁰Co source. The time to onset of death and the duration of the period of mortality were investigated. Survival of the adults was decreased with increase of the doses. LD₅₀ and LD_99,9 values were calculated.With one figure and one table     

Résumés français: Resumes espanoles

Abstract

Laboratory studies were conducted, using a millet grain bait, to estimate the minimum concentration of 4‐aminopyridine (4‐AP) needed to produce abnormal behaviour and distress calls in house sparrows (Passer domesticus L.). Three concentrations (0.50, 0.75 and 1.0%) were tested and three doses (6, 18 and 30 mg) were administered by forcing birds to eat one, three or five treated grains. There were differences among the three concentrations in time from dosing to first distress call and in abnormal behaviour, but not in the duration and number of distress calls. At each concentration different doses had different effects. Males emitted more and higher pitched distress calls than did females. It is concluded that concentrations of 0.75 and 1.0% could be effective in reducing damage to cereal crops by house sparrows in Pakistan. The calculated LD₅₀ was 5.9 mg/kg (4.5–7.7 mg/kg, 95% confidence limits).