Synthetic pyrethroids: Toxicity and synergism on dietary exposure of Tribolium castaneum (Herbst) larvae

The potency of six dietary pyrethroids, as toxicants and inhibitors of weight gain in first- and fourth-instar Tribolium castaneum (Herbst) larvae, decreased in the order of cis-cypermethrin and deltamethrin > trans-cypermethrin and cis-permethrin > fenvalerate and trans-permethrin. Dosages that reduced larval weight also delayed pupation and emergence, probably due to their antifeeding activity. Three oxidase inhibitors (piperonyl butoxide, O, O-diethyl O-phenyl phosphorothioate, and O-isobutyl O-prop-2-ynyl phenylphosphonate), at a dietary concentration of 100 mg kg^?1, had little or no effect on the toxicity of trans-permethrin, but strongly synergised the toxicity of cis-cypermethrin by about 3-, 3- and 10-fold, respectively. Piperonyl butoxide also synergised the toxicity of cis-permethrin, trans-cypermethrin and deltamethrin, but not that of fenvalerate. On the other hand, an esterase inhibitor, profenofos, did not enhance the potency of any of the α-cyano-3-phenoxybenzyl pyrethroids. Oxidases appear to be more important than esterases in pyrethroid detoxification by T. castaneum larvae.     

Selective inhibition of separate esterases in rat and mouse liver microsomes hydrolyzing malathion,trans-permethrin,and cis-permethrin

Separate esterase activities of rat and mouse liver microsomes hydrolyzing malathion, trans-permethrin, and cis-permethrin were differentiated on the basis of their sensitivities to inhibition by paraoxon and α-naphthyl N-propylcarbamate (NPC). In rat liver microsomes, the malathionhydrolyzing activity was more sensitive to both inhibitors and showed a different time course of NPC inhibition than the activities hydrolyzing the permethrin isomers. Paraoxon completely inhibited trans-permethrin hydrolysis, but only partially inhibited that of cis-permethrin. The paraoxonsensitive trans- and cis-permethrin-hydrolyzing activities were not differentially inhibited, but separate inhibition curves were obtained for the inhibition of trans- and cis-permethrin hydrolysis by NPC. The mouse liver esterase activity hydrolyzing trans-permethrin showed a similar paraoxon sensitivity to that of rat liver, but that the paraoxon-sensitive portion of the cis-permethrinhydrolyzing activity was 5.5-fold less sensitive to paraoxon than the corresponding rat liver activity and was clearly differentiated from the mouse liver trans-permethrin-hydrolyzing activity. The mouse liver malathion-hydrolyzing activity was 100-fold less sensitive to paraoxon and 14-fold less sensitive to NPC than the corresponding rat liver activity. Rat and mouse liver esterase activities hydrolyzed trans- and cis-permethrin at similar rates under standard assay conditions, but mouse liver esterases were 10-fold less active in hydrolyzing malathion. The higher specific activity of rat liver malathion-hydrolyzing esterases resulted from the greater apparent affinity and maximum velocity for malathion hydrolysis. These results demonstrate that the hydrolysis of malathion, trans-permethrin, and cis-permethrin by rat and mouse liver microsomal preparations involves several esterases with differing substrate specificities and inhibitor sensitivities.     

Decreased nerve sensitivity and decreased cuticular penetration as mechanisms of resistance to pyrethroids in a (1R)-trans-permethrin-selected strain of the house fly

A fenthion-resistant strain of the house fly (Musca domestica L.) was selected with bioresmethrin resulting in ca. 90-fold resistance to the selecting agent. This strain was subsequently selected with (1R)-trans-permethrin producing ca. 140-fold resistance to this latter insecticide. The permethrin-resistant (147-R) strain was highly cross-resistant to several other pyrethroids and demonstrated resistance to knockdown by these insecticides as well as by DDT. The sensitivity of the central nervous system to four pyrethroids was investigated. The 147-R strain was 2.6-fold less sensitive to (1R)-trans-ethanoresmethrin than the susceptible (NAIDM-S) strain, and >43-fold and >67-fold less sensitive to (1R,S)-cis, trans-tetramethrin and (1R)-trans-permethrin, respectively. It also displayed decreased penetration of (1R,S)-trans-[¹⁴C]permethrin when compared to the NAIDM-S strain. Lower nerve sensitivity and decreased cuticular penetration are potential mechanisms of resistance to pyrethroids in house flies in the United States.     

In vitro metabolism and interaction of profenofos by human, mouse and rat liver preparations

Biotransformations of profenofos were studied in vitro. Two metabolites, desthiopropylprofenofos and hydroxyprofenofos, were detected by LC-MS after incubation of profenofos with human liver homogenates and different mammalian liver microsomes. The rank order of desthiopropylprofenofos formation in liver microsomes based on intrinsic clearance (V_max/K_m) was mouse > human > rat, while for profenofos hydroxylation it was mouse > rat > human. In view of the ratio between desthiopropylation and hydroxylation intrinsic clearance rates, human liver microsomes were most active in profenofos bioactivation. The interspecies differences and interindividual variation were within range of the default uncertainty/safety factors for chemical risk assessment. CYP3A4, CYP2B6 and CYP2C19 were identified as profenofos-oxidizing enzymes in human liver on the basis of recombinant expressed enzymes and correlation with CYP model activities. The rank order of CYPs in profenofos activation was CYP3A4 > CYP2B6 > CYP2C19, whereas it was the contrary for profenofos hydroxylation. Profenofos inhibited relatively potently several human liver microsomal activities: the lowest IC₅₀ values were about 3 μM for CYP1A1/2 and CYP2B-associated activities. Profenofos is extensively metabolized by liver microsomal CYP enzymes and its interaction potential with several CYP activities is considerable.     

Substrate-specificity and toxicological significance of pyrethroid-hydrolyzing esterases of mouse liver microsomes

An esterase or esterases in acetone powder preparations of mouse liver microsomes hydrolyze the cyclopropanecarboxylate ester linkage of pyrethroid insecticide chemicals derived from primary alcohols. The rate of cleavage of (+)-trans-chrysanthemates with various alcohol moieties decreases in the following order: 5-propargyl-2-furylmethyl; 5-benzyl-3-furylmethyl (bioresmethrin); 3-phenoxybenzyl; tetrahydrophthalimidomethyl esters. The hydrolysis rate of benzylfurylmethyl esters with various acid moieties decreases in the order: (+)- or (?)-trans-chrysanthemate; (+)-trans-ethanochrysanthemate; tetramethylcyclopropanecarboxylate; (+)- or (?)-cis-chrysanthemate or (+)-cis-ethanochrysanthemate. The trans-isomers of chrysanthemates and ethanochrysanthemates are hydrolyzed from 2.6- to more than 50-fold more rapidly than the corresponding cis-isomers. This enzyme system does not hydrolyze secondary alcohol esters, i.e., allethronyl (+)-trans- and (+)-cis-chrysanthemates.On intraperitoneal administration to mice, the (+)-trans-chrysanthemate and -ethanochrysanthemate of benzylfurylmethanol are of very low toxicity relative to the corresponding (+)-cis-isomers and the tetramethylcyclopropanecarboxylate. S,S,S-tributyl phosphorotrithioate (DEF) pretreatment increases the toxicity of these five compounds by 2.6- to more than 188-fold, with the exception of bioresmethrin whose toxicity is not altered. When the toxicity is increased, it is probably the result of esterase inhibition since DEF strongly inhibits the esterase activity of fresh liver microsomes while the mixed-function oxidase system remains active. The oxidase system metabolizes the chrysanthemates more rapidly than the ethanochrysanthemates of benzylfuryl-methanol. Depending upon the pyrethroid involved, the esterase or the mixed-function oxidase system, or both may be responsible for limiting the toxicity of these pyrethroids to mice.     

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.     

Photolysis of organophosphorus insecticides on soil surfaces

Photolysis on soil surfaces of the organophosphorus insecticides diazinon, methidathion and profenofos was studied under artificial sunlight conditions. All three compounds were readily degraded under the conditions used. The rate of degradation decreased in the order diazinon, profenofos, methidathion and was always greater in moist than in dry soil. The same order of stability was also observed from photolysis studies in aqueous solution. The major photolysis products identified were 2-isopropyl-6-methylpyrimidin-4-ol from diazinon, 5-methoxy-3H-1,3,4-thiadiazol-2-one from methidathion and 4-bromo-2-chlorophenol and 4-bromo-2-chlorophenyl ethyl hydrogen phosphate from profenofos. The same compounds were formed in hydrolysis studies and also upon photodecomposition in aqueous solutions of diazinon and methidathion. Profenofos, however, showed a different photolytic reaction in aqueous systems, forming O-(2-chlorophenyl) O-ethyl S-propyl phosphorothioate. Soil photolysis studies together with hydrolysis experiments could be a useful quick method for obtaining early information on the chemical breakdown products which are to be expected in the soil environment.     

The effect of pretreatment with S,S,S-tributyl phosphorotrithioate on deltamethrin resistance and carboxylesterase activity in Aphis gossypii (Glover) (Homoptera: Aphididae)

The synergism of S,S,S-tributyl phosphorotrithioate (DEF) and its effect on carboxylesterase activity were investigated in deltamethrin-selected resistant (DRR) and susceptible (DSS) strains of cotton aphids, Aphis gossypii (Glover). Compared to the DSS strain, the DRR strain showed 23,900-fold resistance to deltamethrin, and 7560- and 99-fold cross-resistance to bifenthrin and ethofenprox, respectively. The synergist, DEF, increased the toxicity of both deltamethrin and bifenthrin, but not of ethofenprox when DEF was pretreated of 15 h. DEF exhibited significant inhibition on the carboxylesterase activity in the DRR strain, but no significant effect on that of the DSS strain in vitro. After the cotton aphids exposing to DEF, the carboxylesterase activity decreased gradually until 15 h and then gradually recovered until 24 h in the DRR strain, which fluctuated according to the effect of DEF on the deltamethrin toxicity detected using DEF pretreatment in the DRR strain. Therefore, our studies suggested that the effect of DEF on carboxylesterase was associated with deltamethrin resistance in the DRR strain.     

Absence of enhanced detoxication of permethrin in pyrethroid-resistant house flies

The mechanisms of resistance to pyrethroids were studied in a permethrin-selected (147-R) strain of the house fly, Musca domestica L. Approximately 12-fold synergism was obtained with a mixture of (1R)-trans-permethrin:piperonyl butoxide (1:5) so that the resistance decreased from 97-fold to 22-fold. Tests with the esterase inhibitor S,S,S-tributyl phosphorotrithioate produced very little synergism in either the resistant (R) strain (1.6-fold) or the susceptible (S) strain (1.9-fold). An investigation of the microsomal components revealed that compared to the S strain, the R strain demonstrated twice as much cytochrome P-450 and cytochrome b₅ and double the rate of NADPH-cytochrome c reductase activity. In addition, the rate of p-nitroanisole O-demethylation was found to be six times greater in the R strain. An in vivo accumulation study showed that the R strain displayed a decreased rate of penetration of trans-[¹⁴C]permethrin. When treated at equitoxic doses the R strain was found to tolerate 50-fold more internal permethrin than the S strain. An in vitro metabolism study indicated that there was no difference between strains in the overall rate of metabolism of trans-[¹⁴C]permethrin. The evidence obtained supports the conclusion that several resistance factors are involved but that decreased sensitivity of the nervous system to the action of pyrethroids is the principal mechanism of resistance in the 147-R strain.     

Developmental changes in trans-permethrin and α-naphthyl acetate ester hydrolysis during the last larval instar of Pseudoplusia includens

The hydrolysis of trans-permethrin and α-naphthyl acatate by midgut, fat body, and cuticle homogenates from Pseudoplusia includens (Walker) was monitored during the development of the last instar. The midgut homogenates appeared to have two pH optima (7.6 and 8.6) for the hydrolysis of trans-permethrin, the fat body homogenates had one optimum (7.4–7.8), and the cuticle homogenates had a major optimum at 6.6. Hydrolysis of both substrates peaked during the late feeding stages for midgut and cuticle homogenates, although relative changes were not the same. Hydrolysis of trans-permethrin peaked during the late feeding stage in fat body homogenates, while hydrolysis of α-naphthyl acetate continually increased through the prepupal stage. Thus, the hydrolysis of α-naphthyl acetate is not necessarily associated with the hydrolysis of trans-permethrin. The LD₅₀ values for trans-permethrin on the different stages appeared to reflect the influence of hydrolysis.     

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.     

Carboxylesterases from Boophilus microplus hydrolyze trans-permethrin

An esterase which hydrolyzes the ester bond of trans-permethrin has been partially purified from homogenates of larvae of the cattle tick. The final (gel filtration) step showed two distinct peaks of p-nitrophenylbutyrate-hydrolyzing activity. The trans-permethrin-hydrolyzing activity of the lower-molecular-weight enzyme cochromatographed with the p-nitrophenylbutyrate-hydrolyzing activity of that enzyme. Little trans-permethrin hydrolysis was observed in the high-molecular-weight peak. The yield of the low-molecular-weight enzyme increased on extraction of the homogenates with Triton X-100. Inhibition studies using the low-molecular-weight enzyme and trans-permethrin as substrate indicated that hydrolysis was due largely to a carboxylesterase (EC 3.1.1.1).     

In vitro metabolism of EPN and EPNO in susceptible and resistant strains of house flies

EPN is twice as toxic as EPNO to house flies from both the Diazinon-resistant strain and the susceptible strain. EPN and EPNO are also eight times more toxic to the susceptible than the resistant strain. This is due to the ability of the resistant strain to metabolize these compounds to a greater extent. Metabolism by the glutathione S-transferases present in the 100,000g supernatant is more extensive than that by the NADPH-dependent microsomal mixed-function oxidases. The glutathione S-transferases are the major route of metabolism for EPN and appear to be the principal mechanism conferring resistance. EPN was metabolized by the microsomal fraction via oxidative desulfuration to the oxygen analog, EPNO, and by oxidative dearylation to p-nitrophenol. EPNO was metabolized by the same system to p-nitrophenol and desethyl EPNO as well as to an unknown metabolite. The soluble fraction metabolized EPN to p-nitrophenol, S-(p-nitrophenyl)glutathione, O-ethyl phenylphosphonothioic acid, and S-(O-ethyl phenylphosphonothionyl)glutathione. The identification of the latter conjugate demonstrates a new type of metabolite of organophosphorus compounds. EPNO was metabolized by the soluble fraction to p-nitrophenol and S-(p-nitrophenyl)glutathione.     

Delayed acute toxicity of O,S,S-trimethyl phosphorodithioate and O,O,S-trimethyl phosphorothioate to the rat

The toxicity and LD₅₀ of O,S,S-trimethyl phosphorodithioate were reexamined in the rat. Animals treated orally (single dose) with this compound exhibited early cholinergic signs followed at approximately 5 hr by delayed toxic signs, with an LD₅₀ of 43 mg/kg. Contamination of O,S,S-trimethyl phosphorodithioate by as much as 5% (w/w) O,O,O-trimethyl phosphorothioate provided only limited antagonism to the dithioate's toxicity. In contrast, the addition of 5% O,O,S-trimethyl phosphorodithioate to O,O,S-trimethyl phosphorothioate gave protection against the toxic effects of the latter compound up to 80 mg/kg of toxicant. Pretreatment of rats with as little as 5% O,O,O-trimethyl phosphorothioate, 24 hr prior to treatment with 200 mg/kg O,O,S-trimethyl phosphorothioate, gave complete protection against the toxic effects of this compound. Conversely, administration of 10% (w/w) O,O,O-trimethyl phosphorothioate 4 or 24 hr after treatment with 60 or 80 mg/kg of O,O,S-trimethyl phosphorothioate provided only partial protection at 4 hr and no protection from the effects of the toxicant at 24 hr. The ability of O,O,O-trimethyl phosphorothioate to antagonize the toxicity of this compound depended markedly on the route of administration (oral, intravenous, or intraperitoneal). At 4 hr past treatment with toxicant, only oral administration of the antagonist provided full protection. Intraperitoneal and intravenous administration of antagonist 4 hr after treatment with toxicant were partially effective and completely ineffective, respectively, in halting the toxic effects of this compound.     

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.     

Metabolism of permethrin isomers in American cockroach adults,house fly adults,and cabbage looper larvae

Forty-two insect metabolites of [1RS,trans]-and [1RS,cis]-permethrin are tentatively identified in studies with Periplaneta americana adults, Musca domestica adults, and Trichoplusia ni larvae involving administration of ¹⁴C preparations labeled in either the alcohol or acid moieties. The less-insecticidal trans isomer is generally metabolized more rapidly than the more-insecticidal cis isomer, particularly in cabbage looper larvae, and metabolites retaining the ester linkage appear in larger amount with cis-permethrin. Although the dichlorovinyl group effectively blocks oxidation in the acid side chain, the permethrin isomers are metabolized by hydrolysis and hydroxylation at the geminal-dimethyl group (either trans- or cis-methyl substituent) and the phenoxybenzyl group (predominantly at the 4′-position in all species but also at the 6-position in house flies). The alcoholic and phenolic metabolites are excreted as glucosides, and the carboxylic acids are excreted as glucosides and amino conjugates (glycine, glutamic acid, glutamine, and serine) with considerable species variation in the preferred conjugating moiety.     

Mechanisms of resistance to diflubenzuron in the house fly, Musca domestica (L.)

The mechanisms of resistance to the chitin synthesis inhibitor diflubenzuron were investigated in a diflubenzuron-selected strain of the house fly (Musca domestica L.) with > 1000 × resistance, and in an OMS-12-selected strain [O-ethyl O-(2,4-dichlorophenyl)phosphoramidothioate] with 380 × resistance to diflubenzuron. In agreement with the accepted mode of action of diflubenzuron, chitin synthesis was reduced less in larvae of the resistant (R) than of a susceptible (S) strain. Cuticular penetration of diflubenzuron into larvae of the R strains was about half that of the S. Both piperonyl butoxide and sesamex synergized diflubenzuron markedly in the R strains, indicating that mixed-function oxidase enzymes play a major role in resistance. Limited synergism by DEF (S,S,S-tributyl phosphorotrithioate) and diethylmaleate indicated that esterases and glutathione-dependent transferases play a relatively small role in resistance. Larvae of the S and R strains exhibited a similar pattern of in vivo cleavage of ³H- and ¹⁴C-labeled diflubenzuron at N₁C₂ and N₁C₁ bonds. However, there were marked differences in the amounts of major metabolites produced: R larvae metabolized diflubenzuron at considerably higher rates, resulting in 18-fold lower accumulation of unmetabolized diflubenzuron by comparison with S larvae. Polar metabolites were excreted at a 2-fold higher rate by R larvae. The high levels of resistance to diflubenzuron in R-Diflubenzuron and R-OMS-12 larvae are due to the combined effect of reduced cuticular penetration, increased metabolism, and rapid excretion of the chemical.     

三种植物次生物质对B型烟粉虱羧酸酯酶活性及其对药剂敏感度的影响

采用人工饲料添加法,研究了不同浓度的槲皮素、2-十三烷酮和葫芦素B 3种植物次生物质对B型烟粉虱Bemisia tabaci羧酸酯酶(CarE)活性的影响,同时比较研究了用3种植物次生物质处理后敌敌畏、脱叶磷、灭多威、乐果和氧乐果5种药剂对CarE 的抑制中浓度(I50)的变化。结果表明: 0.01~1.0 mg/mL的槲皮素对B型烟粉虱成虫CarE活性均具有明显的诱导增加作用,最高为对照的4.32倍; 0.1和0.5 mg/mL的2-十三烷酮处理使CarE活性比对照分别下降了22%和58%; 0.75~30.0 mg/L的葫芦素B对烟粉虱CarE活性均表现为抑制作用;用1.0 mg/mL的槲皮素处理24 h后,敌敌畏和脱叶磷对烟粉虱CarE的I50值分别增加为对照的20.05和3.16倍; 3.75 mg/L 的葫芦素B处理后,敌敌畏和灭多威对CarE 的I50值分别增加为对照的25.94、2.45倍; 1.0 mg/mL的2-十三烷酮处理后敌敌畏、脱叶磷和乐果对CarE 的I50值分别降低了89%、83%和90%。     

Effects of the synergist S,S,S-tributyl phosphorotrithioate on indoxacarb toxicity and metabolism in the European corn borer, Ostrinia nubilalis (Hübner)

The toxicity of the oxadiazine insecticide indoxacarb to the European corn borer, Ostrinia nubilalis (Hübner) (Lepidoptera: Crambidae), was evaluated in the presence and absence of S,S,S-tributyl phosphorotrithioate (DEF), an inhibitor of hydrolytic metabolism. Bioassays involving topical application of different concentrations of indoxacarb to third instars of a susceptible O. nubilalis laboratory strain were performed, and in vitro metabolism experiments involving [¹⁴C] indoxacarb were examined to determine the role of hydrolytic metabolism in indoxacarb activation. Indoxacarb toxicity decreased in the presence of DEF indicating antagonism of toxicity. Results of in vivo and in vitro inhibition experiments indicated a reduction of indoxacarb activation and formation of the hydrolytic metabolite. These results are consistent with the proposed mechanism of hydrolytic activation for this compound.     

Cross-resistance spectrum in pyrethroid-resistant Culex quinquefasciatus

Strains of Culex quinquefasciatus Say, selected with biopermethrin [(1R)-trans-permethrin] or with (1R)-cis-permethrin, were examined in the larval stage for crossresistance to 30 pyrethroids, DDT, dieldrin, temephos, propoxur, and two organotin compounds. The (1R)-trans-Permethrin-R strain [resistance factor (RF) = 4100-fold] and the (1R)-cis-Permethrin-R strain (RF= 450-fold) of C. quinquefasciutus were cross-resistant to all pyrethroids tested [RF= 12-fold for an allethrin isomer to about 6000-fold for (RS,RS)-fenvalerate] as well as to DDT (RF= about 2000-fold). However, they were not significantly Cross-resistant to dieldrin, temephos, propoxur, and the two organotin compounds. Changes in the alcohol moiety, structural isomerism, and susceptibility of the cyclopropane C-3 side chain to oxidative attack are important factors in determining the level of cross-resistance to various pyrethroids. Limited synergism of the pyrethroids by S,S,S-tributyl phosphorotrithioate and piperonyl butoxide (PB), and of DDT by chlorfenethol and PB, suggested that some non-metabolic mechanism, such as kdr, may be an important component of resistance to pyrethroids as well as to DDT in this mosquito.